CA1163631A - Isoxazole derivatives and a process for the preparation thereof - Google Patents

Abstract

ABSTRACT OF THE DISCLOSURE

The invention relates to new isoxazole derivatives of the general formula (I) and acid addition salts thereof, (I) wherein R represents a C1-4 alkyl or a phenyl group, R2 denotes a halogen atom or a (C1-4 alkox )-carbonyl group, R1 represents a group of the formula -CH(NH2)-COOH, or a guanyl-thio, a bis(C1-4 alkoxycarbonyl-C1-4 alkanoylamido)-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.
The new compounds of the general formula (I) can be prepared from the starting material of the general formula (II)

Description

1163~31 ~EW IS~AZO~E DERIVATIVES AND A P~OCESS FOR TEE

PREPAR~TION THEREOF

This invention relate~ to n~w i~o~a~ole derivati~es and pharmaceutical compositions containi~g the ~ame, further-more to a prQCess for the preparstion thereof.
It i~ known that 3-hydroxy-5-methyli~o~azole ¢a~ be used as plant-protectinB aeent ~ erck Inde~, 9. tl961) J
page 1237. Partially saturated ieoxazole derivati~e~ u~ed as tumor-inhibitin~ agent~ are de~cribed in Tetrahedron Letters 2549 (1973) and in J. Antib. ~L- 91 tl975).
A¢cordin~ to a feature o~ the invent~on there are pro~idad new i~oxazole deri~ati~e~ o~ the goneral ~ormula (I) ~ C~ *l (I) `~ wherein R repre~ents a Cl_4 alkyl or a phenyl group, ~2 ~ta~d~ for a haloge~ atom or a (Cl_4 alko~y)-carbonyl group, q~
~ Rl r~present~ a group of the iormula -C~(NH2)-COO~, or a ;: guanyl-thio, a bi~-(Cl_4 alkoxy~s*~ny~ ~_4alkanoyl~mido)~
an amino-o~y, a carbamoyl-amino-o~y, a guanidino-o~y, a : : phthalimido-o~y group or a group of the ~eneral formula -~R3R~, ~h~rçis R3 ~ta~d~ for a hydro~en atom or a Cl_4 alkyl, a3_6 cycloalkyl, w-halogen-(Cl 4 alkyl), : di-(Cl_4 alkyl)-amino-(Cl_4 alkyl), 2,6-dihalogenbenzyl group or a p-amino-phenyl-aul~onyl group ~hich latter 3

- 2 - ~163631 may be N-~ubstituted by a Cl_4 alkanoyl ~roup, and R4 sta~d~ ~or a hydro~e~ atom or a Cl 4 alkyl group, or R3 a~d R4 to~ether repre~ent a 2,6~dihalogen-benzylidene group9 or R3 and R4 forn~ together with the adjacent nitrogen atom a 6 membered heterocyclic ring which may optionally contain an o~y~en as a further hetero atom, with the provi~o that ii R represento methyl a~d Rl stands for a ~uanyl-thio group, R2 may repre~ent only chlorine.
~ he term "lower alkyl ~roup" reier~ to straight-chained or branched ~aturated aliphatic hydrocarbyl groups contalning 1-4 carbon atom~, ~uch a~ methyl, ethyl, n-propyl, i80-propyl, n-butyl, etc. The alko~y ~roup of the lower alko~y-carbonyl groups can be ~traieht-chained or branched and contains 1-4 carbon atom~ (e.g. methoxy, etho~y, n-propoxyt isopropoxy, etc.). l'he term "halogen atom" refers to all the ~our halogen atom~, i.e. ~luorine, chlorine, bromine or iodine. The term "C3_6 ¢ycloalkyl group" may be cyclopropyl, cyclobutyl, oyclopentyl and cyclohexyl group. ~he term "aryl group" reier~ to mono- or bicyclic, pre~erably sub~tituted aromat~ c hydrocarbyl groupa. The term "Cl i ~lkanoyl group"
refer~ to the acyl radical of lo~er alkane carbs2ylic a¢ide (e.g. acetyl, propionyl, butiryl, etc.). The heterocyclic ri~8 ~ormed by R3, R4 and the adjacent nitrogen atom may be pref~rably a plperidino or a morpholino ring.
Pre~erred repre3~ntatives of the new ¢ompounds having the gener~l formula (I) are thoae wherein R ~tands for methyl.
o preierred ~re the compounds o~ the general formula (I) wherein R2 repreflents chlorine.
: 0~ the ~ew oompou~d~ of the general iormula (I) the following are parti¢ularly preferred:

~,r ~?

~.

3 1163~

3~methyl-4-chloroiso2a~ol-5-yl-methyleneoxy-guanidine, 3-methyl-4-chloro-5-(bromoethylamino-methyl)isoxazole and acid additio~ ~alt~, particularly hydrochlorides, thereo$.
~ he acid addition ~alts of the compounds o~ the general formula (I) ¢an be ~ormed with pharmaceutically tolerable anor~anic or or~anic acid~ (e.~. hydrogen chlor1de, hydrogen bromide, sulfuric, pho~phoric, tartaric, ~umaric, maleic, citric acid, etc.).
~ ccording to a further ~ature of the pre3ent inve~tion thsre i~ provided a procee~ ~or the preparation o~ compound3 of the general formula (I) a~ ~ollo~:
a) To prepare a compound o~ the general formula (Ia) R~R2 COOR3 (Ia) CH2-C-N~GO-R4 ~herein COOR3 R and R2 have the ~ame meanings aa above, and R3 and R4 repre~ent a Cl_4 alkyl group, a compound Or the general formula (II) R R2 (II) ~1 `
O CH2-Br wherein R and R2 ha~e the ~ame meaninge ae above, i~ rea~ted with ~a dialk~l-(Cl_4 alkanoyl-amido)-maloDate of the ~eneral ~ormula (III~

1 1636~1 coo~3 HC-NH-CO-R4 (III~

~herein R3 and R4 ha~e the same meaninB~ as above, or b) to prepare a compound o~ the ~eneral formula tIb) (Ib) ~ O CH2-CH-COOH
wh~rein N~2 R and R2 have the ~ame ~eaning~ as abo~e, a compound of the general ~ormula (Ia) i8 hydrolized, or c) to prepare a compound oi the general formula (Ic) CH2-S-C ~ (Ic) ~herei~
R and R2 ha~e the aame meaning~ a~ above, a compound of the general ~ormula (II) i~ reacted with thio¢arbamide, or d) to prepare a compou~d of the general formula (Id) R ~ N2-O-~ ~ (Id) wherein O
R ~nd R~ the ~ame mea~lngs a~ abo~e, a compound of the general ~ormula (II) i9 reacted with ~ ^' _ 5 _ 116363 ~-hydro~y-phthalimide, or e3 to prepsre a compound o~ the general ~ormula (~) (Ie) ~herein R and R2 have the ~ame meanirlg~ a~ above, el) a compound of the general formula (Id) i9 reacted with hydrazine, or e2) a compound of the general formula (IV) R ~ R2 ~ ~ / 5 (IV~
O CH2-0-N=C ~

wherein R and R2 have the ~am~ meaning~ as abo~e, R5 and R6 each repreeent a lower alkyl or aryl group or R5 etande for aryl and R6 repreeent~ hydrogen, ~9 hydrolized in acid mediu~, or e3~ a compound of th~ general formula (V) ~o 1C~2-O-]J~

: ~herein :; ~ R and R2 ha~ the same meaning3 as abo~e, and R7 and ~ repre~ent a hydrogen atom or a phenyl group, : i3 r-ac:ted ~ith hydrazine or with a ls~er alkyl hydrazine a~d hydrochloric acid, or .

.

e4) a compound of the general formula tVI) ~ ~VI) O C~2-O-N}1-9_Rg ~herein 0 R and R2 have the ~ame meaniDgs as above, and Rg ~ta~d~ ~or hydrogen or phenyl, or a ¢ompound o~
the gensral formula tVII) R~ R2 (VII) ~o aH2-0~ Rll wherein ORl~
R and R2 ha~e the ~a~e meanings as above, and ~0 and Rll ~tand ior lower alkyl or pheDyl, is sub~oted to acid hydroly~is, or e5~ a oompound of the ~eneral formula tVIII) (VIII) -O-NH-II_OR12 O
where~
R a~d R2 have the ~ame meanings a~ above, and R12 1~ ~ repre~e~ts t-butyl, benzyl or ethyl, :: :
sub~scted to ac~d hydrolysis, or e6) a compound o~ the ge~eral formula tI~) R ~2 (I~) OCH2-OAc , ~ :
.~ , ``.:

wherein R and R2 have the same meanillgs as above, and Ac represents a Cl 4 alkanoyl group, is optionally desacylated and reacted with an amine of the general formula [X]

H2N-X [X]
wherein X represents a halogen atom or a sulfonyl-oxy group, or f./ to prepare a compound of the general formula [If]

`r~' N \ 0 ~ ~ CH2-0-NH-C-NH2 ~If]

NH
whereln R and R2 have the same meaning as above, fl./ a compound of the general formula rIe] is reacted with cyanamide, or f2-/ a compound of the general formula [XI]
Cl~

~ N ~ 3 [XI]
H2N-C=NH
is heated with a compound of the general formula ~Ie]`, or ;~ f3./ a compound of the general formula IIe] is reacted ~;
-:-with a compound of the general formula (~II) R13-S-C (3II~

~herein R13 ~tands for lower alkyl, or with a salt thereof, or f4) a compound o~ the general ~ormu~a (~III) (~III) ~ O CH2-0-NH-CN
whersin R and R2 ha~e the ~ame mea~ings a~ above, i~ ~armed ~ith an ammonium haloge~ide, or ) a ¢ompound of the general ~ormula (gIV) (~IV) CH2 Hal wherein : R and ~2 ba~e the ~ame meani~8e a~ abo~e, and Hal :
represents halogen, ie reacted with a compound of the ge~eral ~ormula (~V) ' H2N-C (~
~-OH
or 1 163~31 g) to prepare a compound of the ~eneral formula tIg) (Ig) N ~ o CH2-0-NH-C-NH2 ~herein R and R2 have the ~ame m9ani~89 a~ above, a compound of the ~e~eral formula (Ie) i~ reacted with alkali cyanate, or h) to prepare a compound o~ the general formula (Ih) ~2 R' tIh) ~ O CH2-N R' where$n 4 R a~d R2 ha~e the ~ame mea~ings a~ above, R3 represente a Cl 4 alkyl or a C3_6 cy¢loalkyl group, and Ri stands ior a hydrogen atom or a Cl_4 alkyl group, or R'3 and Ri may form, together with the adjacent nitrogen atom a 6 member~d heterocyclic ring, which may optionally contain an oxy~en ae a iurther hetero atom, : a oompound of the general formula (II) i~ reacted ~ith an ami~e of the general ~srmula (XVI) R' (~VI) :~ ~herein R3 and R; ha~e the ~ame meaninge a~ al~ove, or i) to prepare a compou~d o~ the gen~ral formula (Ii) ~:

~ ~.
,:

11~3~31 R R2 (Ii) CH2-1~H- (G~2 )2-Br wherein R a~d R2 have the same mea~ings as aboYe, il) a compound of the general formula fII) i9 reacted with ethylene imine~ or i2) a compound o~ the general formula (XVII) (~VII) wherein R and R2 have the ~ame neanings as abo~e, i~ brominated, or i3) a ¢o~pound of the general ~ormula (XVIII) R ~ 2 (~VIII) O CH2-NH-c-cH2-Br where~ O
R and R2 haYe the ~ame meanings as abo~e, i9 reduced, or j) to prepare a aompound oi the general ~ormula tI~) ~: R R
2 (I~) 1163~31 wherein R and R2 ha~e the ~ame meanings as above, and R3 ' stands ~or hydrogen and Ri' may represent hydro~en, di-(Cl_4 slkyl)-amino-tCl 4 alkyl), 2,6-dihalogen-benzyl or p-amino-phenyl-~ul~onyl optionally N-~ub3tituted by a Cl 4 alkano~l group, or ~ ' and R4' represent together a 2,6-dihalo~en-benzylidene ~roup, or R3' and R4 ' may form, to~ether with the ad~aoent nitrogen atom a phthalimido group, a compound of the general formula (II~ i~ reacted with an alkali phthalimide~ the compound of the general formula (Ik~
thu~-obtained, ~ CR2 ~ ~ (Ik) wherein R and Rl have the same meaning~ 88 above, i~ pre~erably reacted with hydrazine, the compound o~ the ~eneral ~ormula (Il) thu~-obtained R_ R2 (Il) wherei~
R and R2 have the oame meaning~ a~ above, ia preferably condensed ~ith a 2~6~dihalogen-benzaldehyde, the compound o~ the general ~ormula (Im) thu~-obtained ~ . , - 12 - 116363~

R R (Im~
~ ~ 2 ~ o 1 CH2-N_GH-- ~

~herein Hal R and R2 ha~e the eame meanings a~ above, and Hal ie halogen, i~ preferably redu¢ed with a reduaing agent; or if desired, a compound o~ ths ~eneral formula (Il) i~ reacted with a p-(Cl_4 alkanoyl)-amino-benzenesul~onic chloride, the compound of the ~eneral formula (In) thu~-obtained R R2 tIn) ~ ¢ a~2-~-S
wher~in R and R2 ha~e the esme mea~ing~ a~ above, and ~c repre~entc a Cl_4 alkanoyl eroup, i~ preferably hydrolized; or, if desired, a compound o~ the general formula (Il~ is reacted with a di-tCl_4 alk~l)-amino-(l 4 alkyl~ hal~genide, and, i~ de~ired, a co~pound of the ge~eral formula (I~ thu~-obtained i~ con~erted into ~ts acid addition ~alt.
The ~ethod a ) Or the process s¢cording to the in~ention i~ pr~erably sarried out in the pre~en¢e of an alkali hydride (preferably ~odium hydride~ in dimethyl~ormamide. A~ reaction medium diethyl ether, tetrahydrofurane, dimethylsulioxide or benzen0 ca~ al~o be u3ed. The reaction can be carried out between 20 C and the boiline point of the reaction mixture. The ~tarting material of the general formula (II) a~d the dialkyl-, ' 1 1~363 1 alkanoyl-am~do-malonate i8 preferably used in an equimolar amount.
According to the method b) of the process accordin~
to the invention the hydrolysi~ of the compound o~ the general formula (Ia) i9 carried out with a mineral acid, preferably with hydrochloric acid or ~ulfuric acid. Nitric scid cannot be used because of the ri~ of nitrat~on. The reaction can be performed under heating, preferably at about 100 C.
Accordln6 to the method c) of the proces~ acoordin~ to the invention a compound of the ~eneral formula (II) i9 reacted with thiocarbamide in an alkanol, preferably in ethanol, in a temperature interval ran8ing from room temperature to the boili~g point o~ the reactio~ mi~ture, preferably under heating.
The reaction according to the method d) i~ preierably performed in the preeence o~ an scid binding a8ent~ Organic ba~es, preferably triethylamine can be mentioned a~ 3uitable aoid binding agent~. The reaction can be carried out in a ~uitable organic ~olvent (e.~. ketone such a~ acetone or he~amethyl-pho~phori¢ acid triamide, dimethylforma~ide, eto.) One proceedo preferably under heatin~ (e.g. at about 100 C).
Accordine to tha method el) of the prooess acoording to the i~ention a compound o~ the general formula (Id) i~
reacted with hydrazine. The reaction i~ carrled out in a~
organi¢ ~olvent. Chlori~ated hydrocarbona (e.~. dichloro-methane, dichloroethane or chloro~orm) are preferably u~ed for thi~ purpose. ~he temperature of the rea¢tion can be varied ~rom about 20 9C to the boiling poi~t of the reaction mixturec The end-product can be preierably converted into it3 hydrochloride with hydrochloric acid.

~ ~' .

. ~

1 1~3~3 According to the method e2) of the pro¢ess accordin~
to the invention a compound of the 3eneral formula tIV) i9 hydrolized in acid medium. The reaction can preferably be carried out with hydrochloric acid, under heating, optionally at about 100 C.
Accordi~g to the method e3) of the proce~s a compound of the general formula (V) i~ treated with hydrazlne or alkyl hydrazine (preferably n-butyl-hydrazine) and with hydrochloric acid. The reaction can be per~ormed in a chlorin-ated hydrocarbon or alkanol as rsaction medium. One proceed~
preferably under heating, at the boiling point of the reaction mixture.
According to the method e4) a compound o~ the general formula tVI) or (VII) is ~ubjected to acid hydrolysis. $he reaction i8 optionally carried out with hydrochloric acid under heating, preferably at about 100 C.
The reaction according to the method e5), that i8 the hydroly~i~ o~ the compound of the general formula (VIII), wherein R12 ~tand3 for t-butyl, with trifluoroacetic acid i~ per~ormed at about 0 C - 20 C, preferably at about 10 C.
The starting compound of the general formula (VIII), ~herein R12 repre~ent3 b~yl, i~ preferably hydrolized with a mixture of acetic acid a~d hydrogen bromide under cooling, at about 0 C. ~he reaction mi~ture i~ treated fir~t with alkali then with hydrochloric acid. The hydroly~ia of the ~tarting material~ o~ the general formula (VIII)~ ~herein ethyl, i~ preferably carried out ~ith hydrochloric a~id at about room temperature.
~ ccording to the method e6~ oi the process according to the invention a compound of the general formula (IX) i~, , .

1 1~3631 preferably after de~acylation, reacted with a compound of the general iormula (X~, wherein X stand~ ior halQgen, preferably chlorine, or a sulionyl-oxy group ~preferably methanesulfonyl-o~y or toluenesulio~yl-oxy group~. 0~ using compounds of the general formula (~, wherein X stand~ for chlorine, the reaction is preferably carried out in tetrahydrofurane in the presence of ~odium methylate at a temperature of about 0 C. When using a compound of the general formula (~ herein X represents sulfonyl-oxy group, the reaction i9 preierably performed in the pre~ence of sodium methylate at room temperature.
The reaction according to the method fl) of the proce~
according to the invention i8 preierably carried out in water, in a mixture oi water and an alkanol, in tetrahydrofurane or in dioxane. The temperature may ra~8e ~rom 20 C to 100 C.
According to the method ~2) ~ the proce3s according to the invention a compound of the general iormula (XI) is heated w~th a compound of the general ~ormula (Ie). The reaction is preferably carried out in methanol a~ reaction medium, at the boillng point oi the reaction mi~ture.
~ ccording to the method f3) a compound of the general iormula (Ie~ ia reacted with a compound of the general ~ormula ~XII~. ~he compound~ oi thc general formula (XII), wherein R13 stande for methyl, are pre~erably u~ed as starting materials.
The reaction i~ preferably per~ormed in ~ater as madium at room temporature.
According to the method ~4) oi the pro¢eo~ according to the in~ention a compound of the general formula (~III) i~
reacted with an ammonium halogenide, preferably with ammonium ohlorid~. The reaction i~ preferably carried out under heating, pre~erably in the melt, at 120 - 140 C.

~ ~63631 According to the method f5) of the process according to the invention a compound of the general ~ormula (XIV) i9 reacted with a hydroxy guanidine of the general formuls (~V).
~he reaction i9 preferably carried out in the presence of an alkali alcoholate (preferably ~odium methylate) in the corresponding alkanol tprefersbly methanol) as medium, under heating.
According to the method g) a compound of the ~eneral formula (Ie) i9 reacted with an alkali cyanate. Potassium cyanate i~ preferably used for thi~ purpose. A~ reaction medium water or aqueouo alkanol is preferably u~ed. The reactio~
i~ carried out at a temperature interval ranging ~rom 20 C
to the boiling point o~ the reaction mixture.
~ he reaction accordin~ to the method h~ is preferably ca~ried out in the pre~ence of an acid binding agent. Anorganic ba~e~ te. 8. triethylamine~ are pre~erably u~ed for this purpose. The reaction i~ preferably carried out in an organic eolvent (e. g. in an alkanol such as ethanol, etc.), under heatin8, at the boiling point of the reaction mixture.
According to the method il) o~ the proces~ according to the i~ventio~ a compound of the general formula (II) i8 reacted with ethylene imine. The reaction is pre~erably carried out in an organic sol~ent (e.g. acetone). It is prefer-able to add the ethylene imine to the ~tartinB material oi the ge~eral formula (II) at a temperature of -5 - -10 C, and then to heat the reaction mi~ture to boiling. The en~product i9 preferably converted into ~ts hydrochloride by preclpitating with hydrogen chloride.
- Accordin~ to the method i2) of the proceas accordin8 to the invention a compound of the general formula (~VII) ig ..~

` ~163631 -- 17 --brominated. Hydrogen bromide, pho~phorus tribromide, thionyl bromide or ~ulfuryl bromide are prefers~ly u~ed for this purpose. The reaction i~ carried out in a suitable solvent (e. g. dimethyl ~ulfoxyde~ at a temperature o~ about 0 - 20 C.
The reduction of a compound of the general formula t~VIII) a¢cording to the method i3) can be carried out with boron hydride, preferably with an adduct of boron hydride and tetrahydrofurane. It i~ preferable to perform the reaction in a ~uitable solvent, particularly in tetrahydrofurane. The temperature of the reaction i~ about 0 - 20 C.
Accordi~g to the method ~) o~ the process according to the invention a compound of the general iormula (II) i8 reacted with an alkali phthalimide, preferably with potas~ium phthalimide. The reaction i8 preferably carried out in a solvent (e. gO dimethylformamide or acetone) under heatin at about the boiling point o~ the eolventO
The compound of the general formula (Ik) thus-obtained can be converted into the corre~ponding compound of the general formul~ by reducin8 with hydrazine. ~he reaction i9 preferably carried out in a ~uitable organic ~olvent, e. g. in ¢hlorinated hydrocarbons (e. 8. di¢hloromethane, dichloroethane, chloro~orm).
A compound of the general ~ormula (Il~ can be converted inbo the correspondi~g oo~pound of the general formula (I~) by rea¢ting ~ith a 2,6-dihalogen-ben~aldehyde. The reaction preferably carried out in the prs~ence of an organic baee (e~g. triethylamine), in an organic ~olvent (e. g. alkanol?
ch as ethanol, etc.~. The reaction is performed under heati~g, pr~ferably at the boiling poi~t of the reaction mi~ture.
~; The compound o~ the general formula (Im) thus-obtained ' ~: lX

- 18 - 11 63~3 1 can be reduced into the correspondin~ 2,6-dihalogen-benzyl derivative.
Comple~ metal hydrides (e.~. ~odium boron hydride) are preferably u~ed a~ reducing sgents. ~he reaction i~ optionally performed in a ~uitabls or~anic solvent (e. g. anhydrous alcohole 3uch ag methanol). It i~ preferable to add the complex metal hydride under cooling, and then to hest th~ reaction mi~ture to boilin~.
~ he compound of the ~eneral formula (Il) can be converted into the corresponding compound of the ~eneral formula (In) with a p-alkanoyl-amido-benzenesulfonic chloride. The reaction i~ preferably carried out in the presence of an acid binding a8ent. (e.g. organi¢ bsses, such as triethylamine). As reaction medium, ~uitable organic 301vent~, preferably chlorinated hydrocarbon~ t~uch as dichloromethane, dichloroethsne, chloro-~orm7 etc.) can be u~ed. It i~ preferable to perform the reaction at room temperatur~.
The compound o~ the ~eneral formula (In) thus-obtained i9 hydrolizsd into the corresponding p-aminophenyl-sulfonyl derivat~ve. The hydroly~ia i~ proferably carried out under heating in acid medium, preferably with a mineral acid, e.g.
hydrochloric aoid. Nitrio acid ¢annot be u3ed because of the rlek of nitration.
compound of the general formula (Il) i3 reactod ~ith a dialkyl-amino-alkyl halo~e~ide, proferably with a chloride.
~hi~ reaction re~ults in a compound of the general formula tI~), wherein R3' ~tands for hydrogen and R;' repre3ents a dislkyl-amino-alkyl group. The reaction i3 preferably carried out in the pre~ence o~ an acid bindin8 a8ent (e. B. organic base~, ~uch a~ triethylamine), in a ~uitable organic ~olvent te.g.

... ..

1~6363 1 alkanols, such a~ ethanol), under heating.
The compounds of the ~eneral formula (I) can be converted i~ a known way into acid sddition yalt~ that is b~ reacting with about one molar equi~alent of an acid in a suitable ~olvent.
The compounds thus-obtained can be isolated by method~ known ~E_9e.
__ The compounds of the ~eneral formula fII) are, due to the reactivity of the bromine atom in allyl po~ition, ~ery rea¢ti~e a~d can be u~ed for the preparation of different iso~azole derivati~ee.
The 3-~ubstituted 4-halogen-5-bromomethyl deri~atives of the general iormula (II) can be prepared a~ follows:
A¢etyl acetone i9 reacted ~ith sulfuryl chloride, the 3-¢hloroa¢etyl acetone thua-obtained i~ con~erted into 3,5-di-methyl-4-chloroi~o~azole by rea¢tin~ with hydro~ylamine. $he ¢orreHponding bromo and iodo derivative is prepared by bromi~ati~ or iodinating of 3,5-dimethyl-iso~azole in the pre~en¢e oi nitric acid. ~hen reacting 3,5-dimethy1-4-halo3en iso~azole ~ith N-bromo-auccinimide, almost e~clueivel~ the corre~pondlng 3-methyl-4-halogen-5-bromomethyl i~o~azole i~
obtained.
~ he ¢ompound~ oi the ge~eral formula (III) are know~, and ¢an be produc-d by k~own ~ethods.
~ he startiDg ¢ompound~ of tho general iormula (IV) can be prepared by Feacting a compound of the goneral formula (II) with a compound o~ th~ general formula (XI~

~0-NsC (XIX)~
\ R6 wherein R5 a~d R6 ha~e the same meaning~ a~ abo~e.

- - ' 1 1~36~1 The reaction can be carried out in the pre~ence of an alkali alcoholate (preferably ~odium methylate) in the corre~ponding alkanol (preferably methanol), under heating.
The ~tarting material~ of the general formula (V) can be prepared by reacting a compound of the general ~ormula (II~
with a compound o~ the general formula ~XX) ~ R7 Y-ON. ¦ (~X) ~ R8 wherein O
R7 a~d ~ have the ~ame meaning~ as abo~e and Y stand~ for hydrogen or alkali metal.
~ he reaction can be carried out in the pre~ence of a ~uitable or~anic solvent, ~uch a~ tetrahydrofurane or dimethyl-formamide between 20 a - loo c, preferably in the pre~ence of triphenyl phosphine.
The ~tarting compound~ of the general formula (VI) can be produced by reacting a compound of the general formula (II) wlth a ¢ompound o~ the general formula (XXI) ~O-NH-C-R
O t~ ) wherein R9 ha~ the ~ams meani~g as above.
~ he reaction i~ preferably carried out in a~ squeou~
alkohol in the preae~ce of about o~e molar equivalent of a~ alkali hydrox~e under heatin~. ~
The starting ¢ompounds of the general formula (VII) csn be produced by reacti~g a compound of the general formula (II) ~, ~

1 163~1 with a compound of the ~eneral formula (~XIII) ~ XII) ~10 wherein Rlo a~d Rll have the same meanings as above.
The reaction i9 pre~erably carried out in the presence of an alkali (e.g. ~odium or pota~sium hydro~ide~.
The starting materials of the general formula (VIII) can be prepared by reacting a compound of the general ~ormula (II) with a compound o~ the general ~ormula (XglII) O (XgIII) wherein R12 ha3 the ~a~ meani~g~ ao above.
The reaction i~ preferably carried out in the pre~ence of an acid binding a8ent. For thi~ purpose or~anic base~, e.g.
triethylamine are preferably u~ed. A~ reaction medium, suitable organic ~olvente (e.g. dim~thylformamide) can be u~ed. Ono proceeda under heating, preferably at about 40-80 C, particularly at about 60 C.
~ he starting compounds o~ the general formula (I~) can be prepared by reacting a compound of the general formula (II) ~ith an alkali al~oholate, e. g. potassium methylate, in a ~uitable ~ol~ent, e.g. dimethylformamide, under heating (at about 60 C~.
; The compounds of the ge~eral formula ~XII) are kno~ or can be prspared by known method~.
~ he ~tarti~g materials of the general formula (~III) can . ~ , ,;~

-llS3~31 be prepared a~ follow~:
A compound of the general formula (Ie) is converted into a compound of the general formula tX~IV) R ~R

S (~IV) 5'` o CH2-0-1~H-C ~

wherein R and R2 have the same meanin~s as above, by reacting with an alkali cyanate te.g. potas~ium cyanate) in acid medium te.~. in hydrochloric acid) under heating tat about 90-95 C). The compounds o~ the general formula (XXIV) can be prepared alao by reacti~g a compound of the general formula (Ie~ ~irst with benzoyl-i~othiocyanate and then ~ith alkali. Ths first step of the reaction i9 pre~er-ably carried out in a suitable organic ~ol~e~t (e.g. acetone) at room temperature. The ~econd step is performed with an alkali hydroxlde (e.g. potas~ium hydroxide) under heating (at about 100 C). The compound o~ the general foxmula (~XIV) thus-obtained can be con~erted into the correaponding compound of the genexal ~ormula (~III) with mer¢ur~ oxide in a suitable ~ol~ent te.g. a mi~ture of chloro~orm and water) at room temperature.
~ he atarting ~aterial of the general ~ormula tXVII) can be prepared by reactin~ a compound o~ the ge~eral formula (II) with p-amino-ethanol. The reaotion can be performed in a ~uitable ~olvent and in the preaence of an a¢id binding agent (e.g. in acetone or water i~ the presence of alkali carbonate, in dimethyl~ormamide or hesamethyl-phoaphorou~ triamide in the pre~ence of triethylamine~. The temperature can be varied - 23 - 1163~31 between 20 C and the boiling point of the ~olvent.
The ~tarting materials o~ the general formula t~VIII~
can be prepared by converting a compound of the ~eneral formula (II) into a compound of the ~eneral formula tXXV) . . ~
. (X~V) N~ O ~ CH2 NH2 wherein R and R2 have the same ~aninB~ as abo~e.
The reaction can be carried out either ~ith hegamethylens tetramine in a 3uitable solvent (e.g. ethanol) under heating and then hydrolizing with an acid or with alkali phthalimide in a ~uitable solvent (e.e. dimethylformamide) under heatinB
(e.~. at about 100 C), or with hydrazine in a ~uitable solvent (e.g. in dichloromethane) at about 20 C. The compound of the general ~ormula (~V~ thu~-obtai~ed can be converted into the corre~pondin~ compound of the general formula (XVIII) with bromoacetyl bromide. The reaction can be carried out in a ~uitable 301~ent (e.g. a mi~ture of acetone and water) in the pre~ence o~ an acid binding agent (e.g. anor~ani¢ bases, such as sodium bicarbonate) at room temperature.
The ne~ compound~ accordi~g to the invention pos~e~ strong and relatively prolonged hypotensi~e ef~ect and certain memb~r~
o~ the cnmpound~ e~erts al3c antiphlogistic and antipyretic e~ect~.
On cats and rabbit~ the ~tronge3t decreaae in blood pressure was achie~ed with 3-methyl-4-chloroisoxazol-5-yl-methyleneo~y-guanidine and 3-methyl-4-chloro-5-(bromomethyl-amino-methyl)iso~azole hydrochloride. On cat~ the fourtieth -7,j .

part o~ the LD50 do~e of 3-methyl-4-chloroi~oxazol-5-yl-mlethyleneoxy-~uanidi~e determined i.v. on mice re~ul~s in a 40 ~ decrease of blood pre~ure and the twentieth part o~ the LD50 d09e ~ the 3-methyl-4-chloro-5-(bromomethyl-aminomethyl) isoxazole hydrochloride determined i.v. on mice results in a 44 % decrea~e.
When admini~tered the tenth part o~ the LD50 do~e of the ~ame cQmpounds determined i.v. on mice enterally to anaesthetised rabbits~ a strong and permanent decrea~e in blood pressure ~as observed. 30 minute~ after the admini~tration ~hc blood pressure wa~ lower by 25 and 1~ % re~pectively, 90 minute3 after the sdministration by 33 and 48 % respectively than before. No~e of the compound3 influences e~entially the heart-frequence.
The tenth part of the ID50 do~e (i.v.) of ~-d,methyl-dopa, when administered enterally, deareasea the blood pressure o~
the rabbits by 14 ~ 30 minutes aiter the administration and by 37 % 90 minutes after the administration. ~his means that the ~trength of the effect of 3-methyl-4-chloroieo~azol-5-yl-methyleneo~y-guanidine and 3-methyl-4-chloro-5-(bromomethylamino-methyl~ieoxazole hydrochloride is of ~imilar order o~ magnitude tha~ that of ~-~Jmethyl-dopa. The advantage o~ the new compounds ac¢ording to the invention is that they are effe¢tive when administered either orally or intravenou~ly, while ~ methyl-~op8 i3 active only whe~ admini~tered i.v.
A tenth of the ID50 do~e tdetermined i.v. on mice) o~
the ~ollo~ing compounds o~ the general formula (I), admini~tered i.v. to anae~thetised cats, gi~es a ~trong h~potensi~e effect of ~hort duration. ~
3-methyl-4-chloro-5-aminomethyl isoxazole 3-methyl-4-bromo-5-aminooxy-methyl isoxazole :' .

1183~31 - ~5 -N-(3-methyl-4-chloroiso~azol-5-yl-methyleneoxy~carbsmide 3~-methyl-4-chloro-5-(N,N-diethylamino-methyl)isoxazole hydro-chloride 3-methyl-4-bromo-5-(N,N-diethylamino-methyl)isoxazole hydro-chloride 3-methyl-4-chloro-5-(N-cyclohexylamino-methyl)isoxaæole hydro-chloride and 3 methyl-4-chloro-5-(N-morpholino-methyl)isoxazole hydrochloride.
The diuretic ef~ect of N-t3-methyl-4-chloroi~o~azol-5-yl-methyleneoxy)carbamide surpas~es significantly that of Theo-phylline. 3-methyl-4-chloroisoxazol-5-yl-methylamine hydrochloride pos~e~ses alao a prolonged hypotensi~e e~iect, but induces a bradycardic effect. The ~trong antiYebrile effect of 3-methyl-

4-bromo-5-(~-morpholino-methyl)i30~azole hydrochloride i8 remarkable. A tenth of the ID50 dose of thie compound cau~es a ~imilar decrease in the fever produced with pyro~o a~
20 mg/kg do~e of amidazophen.
The antiinflammatory effect of the new compounds according to the in~ention ~a~ also determined. A tenth of the LD50 dose (i.v., on mice~ ~aY administered to rats and the inhibition of the oedema induced by local administration of 0.05 ml h mg of de~trane wa~ determined. ~he re~ult~ obtained are summarized in the follo~ing ~able:
Compound I~hibition of o. of Bxsmple oedema r~ _ 7 (chloro derivative) 38 15 (chloro derivati~e) 36 ;~ 9 32 .

1 163~31 Accordin~ to a ~urther ~eature of the invention there i9 provided a pharmaceutical compo~ition containing as active agent a compound o~ the general formula (I) or a pharmaceutically acceptable acid addition salt thereo~ and ~uitable inert, non-toxic ~olid or liquid pharmaceutical carrier.
The carrier~ may be such generally used in pharmacy (e.g. calcium carbonate, magne~ium 3tearate, water, poly-alkylene glycole, starch, etc.). The above pharmaceutical composit~on~ can be ~ormulated b~ known method~ in solid (e~g. tablets, capsules, dragées, suppo~itorie~, etc.) or in liquid (e.g. ~olutions, su~pen~ions, emul~ions, etc) ~orm.
The daily do~age of the compounds o~ the general formula (I~ depend~ on ~everal ~actor~ (e.g. the activity o~ the given compound, the condition of the patient, etc.) and i9 always determined by the phy~ician'~ pre~cription~.
The in~e~tion is illu~trated by the ~ollowing E2amples oi non-limiting character. E~amples 1 and 2 describe the preparation of the ¢ompounds of the general formula (II) u~ed as starting material~.

1163~31 ~xam~
P~eparation of ~methyl-4-halo~en-5 _romom~ xazole~
O.1 mole of the corresponding 3,5-dimethyl-4-halogen isoxazole i~ di~olved in 150 ml o~ anhydrous carbon tetra-chloride, then 0.5 g of benzoylperoxide sre added and the solution i~ heated to boiling. Thereafter 0.12 moles of N-bromosuccinimide are added in small portion~ in 1.5 hourY, then the mixture i9 boiled for 4-5 hours. After cooling the solution the separated ~uccinimide i9 filtered off a~d the filtrate i9 e~aporated. The residual syrup i~ 3-methyl-4-halogen-5-bromomethyl i~ogazole (about 90-103 ~), which can be used without any further purification.

Example 2 Pr~e~ , ~f ~hen~1-4-ethoxyc_rbony1-5-bromomethyl i~oxazole On 3tarting from 3-pheny1-5-methyli~oxazole-4-carboxylic ethyl e~ter, one proceeds as de~cribed in Example 1.
Preparation e~ar~tion o~ 3-met~ haloRen-5-(2'.2'-diethoxycarbon~
2'-acetamido~ l)iaoxazole~
__ _ 0.1 mole of ~odium hydr~de io su~pended in 25 ml of a~hydrou~ N,N-di~ethylformamide, then a solution o~ 0.1 mole o~ diethyl-acetamido-malonate in 45 ml of anhydrou~ N,N-di-methylformamide are added in s~all portions, under stirri~g.
~he mixt~re i8 ~tirred at room temperature for 12 hours, then a aolution o~ 0.1 mole o~ 3-methyl-4-halogen-5-bromo-methyl-ieo~azole in 15 ml of anhydrou~ N,N-dimethylformamide i~ dropwl3e added, a~d the mi~ture i~ stirred further for 12-14 hour3. ~herea~ter it i9 poured onto broken ice. ~he resulti~8 oily ~ubstance 910wly ~olidi~ie~. ~hen ~ i9 filtered and the filter cake i9 washed with a 1:1 mi~ture oi~ ether a~d petroleum ether. ~he crude 3-methy1-4-halo~en-(2',2'-dietho~ycarbony1-2'-acetamidoethyl)i~o~azole i9 recry~tallized.
Chloro deri~at~ve--Yield: 50 ~
M.p.: 111 - 112 C
Recrystallization: ~rom the mi~ture of ethanol and water nalysi~: calculated C%=48.49, H~=5.52, ~s8~08 9 C1%-10.22 found C~-48.13, H~=5.47, N%=8.05, C1%-10.35 romo deriYatiYe: _ ___ Yield: 48 ~0 M.p.: 118 - 119 C
Recrystallization: from ethsnol Analysi~: calculated: C~_42.99, H%=4.89, N%=7.16 ~ound: C%=42.95, H~o=4.99~ N%=7.14 Iodo derivati~e-.
Yield: 15 %
M.p.: 97 - 99 ~C.
Recry~tall~zation: from the mixture of ethanol and water ~naly~ oalculated: C~=28.37, Hg-4.37, N~6.38 found: C%=38.38, H~=4.42, N%=6.38 E~am~
Preparation oi _ -~-methyl-4-halo~eniso2azol-5-yl-alanine drochloride 0.1 mole o~ 3-methyl-4-halogen-(2',2',-diethoxycarbonyl-2'-~cetamidoethyl)isoxazole i8 hydrolized wlth 220 ml o~
concentrated hydrochloric aoid at 100 C ~or 8-12 hours.

, 1 1636~1 he solution i~ clari~ied with active carbon, then it i9 concent~ated to a fith of it~ previou~ ~Jolume. ~he separated cry~talline precipitate i9 filtered o~f, dried in ~acuum e:~siccator over calcium chloride and pota3sium hydroxide and recrystallized.
Chloro derivative:
Yield: 75 ~
M.p.: 187-189 C (decomp.) Recry~tallization: from 6N HCl Analysi~: calculated: C,g~34.87~ ~Y4~18~ ~=11062, Cl~=14.7, Cl~ .7 found~-34.79, H~=4.16, N~=11.52,Cl~=14.57, Cl %~14.9 ~romo derivati~e:
. ~ .
Yleld: 63 ~
M.p.: 206-207 C (decomp.) Recry~tallization: ~rom 6N HCl ~alg3i~: ¢alculated: C%=29.44, H9~=3.53, 1~%59 .81, Cl =1~.41, ~ r%=27.99 found: C~=29.53, H%53.60, 1~=9.82, Cl _12.40, Br%=27.98 Iodo derivative:
Yield: 10 %
ll~.p.: 202-204 C (decomp.) Analy~is: calculated: C9~=25.28, H%=3.03 found: C~=23.32, H~=3.13 Example~
~aration of S~ methyl-4-halo~eeniaoxazol-5-Yl)-meth~l-i~othiocarbamide h~;drobromide or S- (3-~henyl-4-etho~carbo~Yl-1 1~3~31 ~soxazoa~ methyl-i~othiocarbamide hydrobromide O.1 mole of 3-methyl-4-halo~e~-5-bromomethyl isoxazole or 0.1 mole of 3-phenyl-4~ethoxycarbony1-5-bromomethyl isoxazole and 0.11 moles of thiocarbamide are boiled i~
30 ml of anhydrou~ ethanol for 2-3 hour~. The solution i~
cooled, clarified with actiYe carbon, then diluted with 60-100 ml of anhydrous ether. ~he ~eparated white cry~tal~
are filtered of~, washed with a~hydrou~ ether and recry~tallized from anhydrou~ etha~ol.
~-met~ bromo derivative:
Yield: 49 %
M.p.: 173 ~ 174 C
A~aly~ calculated: C~s21~77~ H%=2~74~ ~%=12~ 68~ S~=9~68 found: C~z21.52, H~-2.71, ~12.60, S%-9.85 do derivative:
Yield: 40 ~
~p.: 168-171 C
Analy~i~: calculated: C%=19~06t H%-2~40~ ~%=11~ %~8~48 found: a~-ls.s6, H~=23~3~ 30~ $%~8~50 ~pheny~ oxY¢arbon~l derivative:
Yield: 50 %
M.p.: 2Q0-202 C (decomp.) Analysi~: calculated: C%=43.52, H%-4~17~ N%=10~87~ S%=8.29 found: C%543.21, H~=4~12~ N%_10~87~ S%=8~37 Example 6 ~ _ation of ~-meth~ _o(bromo)-5 ~ hthalimido-~m~i30xa~01e 0.1 mole o~ ~-methyl-4-chloro (bromo )-5-bromomethyl i~o~azole i~ dis~ol~ed in 120 ml o~ anh~ydrou~ N,~-dimethy~l Iormamide, the~ 0.11 mole~ of N-hydro~-phthalimide and 'X

o. 11 mole9 o~ triethylamine are added ~nd the mixture i~
kept on a ~ater bath heated to 100 C. Then it i9 cooled, diluted with water and the ~eparated crystal~ are filtered off, wa~hed with cold water and recrystallized.
Chloro deri~ative:
Yield: 89 ~
M.p.: 152-153 C
Recry~tallization: from ethanol Analysig: calculated: C%553.54, ~=3.10, N%~9.57, Cl~=12.11 found: ~%=53.08, H%=2.99, N~=9.58, C1%_12.15 Bromo derivative:
___ _ Yield: 90 %
M.p.: 154-156 a Recrystallization: from ethanol~water Analy~io: calculated: C~=46.31, H~=2.59, N~.31, Br~=23.7 ~ound: C~.47.0, H~=2,59, N~=8.25, ~r%=23.67 ~a~.:z _r~ tion of ~_~_thyl-4-chloro(bromo)-5-aminooxYmethyl iao~azole_~droohlorlde 0.14 moles o~ 3-methy1-4-chloro(bromo)-5-(phthalimido-oxymethyl)i~oxazole are di~solved in 500 ml o~ anhydrouo dichloromethane or dichloroethane, the~ 60 ~ of 98 % hydra~`ine hydrate are added and the solution is stirred at room temperature ~or 16-20 hour~. The ~eparated phthaloyl-hydrazide is di~solved, ~a~hed with dichloroethane and the filtrate, combined ~ith the wa~h liquor, i9 evaporated. The re~idue i9 dissolved in 200 ml of anhydrou~ ether, the solution i~ dried over magnesium ~uliate 9 co~oentrated to a third of its previou~ volume and ~aturated with anhydrou~ hydrogen chloride. ~he ~eparated _ .' ~

~1636 product i9 filtered of~, washed with snhydrou~ ether and recrystallized.
ChlorQ deri~ative:
Yield: 87 ~
.p.: 198-200 C
Recr~tallization: from anhydrous ethanol Analysi~: calculated: C%=30.17, H~=4.05, N~=14.08, Cl~=17.81, Cl-~-17.81 found: C~30.02, H%33.99, N%=14.06, C1%_17.77, Cl %~17.78 ~romo deri~ative:
Yield: 83 ~
M.p.: 18~ - 182 C
Recryatallizatio~: from anhydroua ethanol Analy~ calculated: C~924.66, H~3.11, N~=11.5, Cl %~14.56, Br~=32.80 found: C~=25.11, B%-3.08, N%=11.37, Cl ~314.50, ~ r%_32.72 ~ le 8 _reparation of N ~ thYl-4-chlorotbromo~-iaoxazol-5-~1 -methgleneox~)-carbamide 0.05 molee of 3-methyl-4-chloro(bromo)-5-aminoo~ymethyl-i~oxaz~le hydrochloride are di~ol~ed in 35 ml of ~ater under heating, then a ~olution of 0.055 moles of potasaium cya~ate i~ 45 ml of hot water i~ added. The mixture is beiled for hal~ an hour, clarified with acti~e carbon and, when it i~ ~till hot, ~iltered. The ~iltrate i9 cooled, the separated cry~tala are filtered off and ~a~hed with ice-cold ~ater.

.

_ 33 _ 1163~3 Chloro deriva _ve:
Yield: 85 ~
M.p.: 157-158 C
Recry~tallization: from water Analysis: calculated: C~=35004~ H~o=3.92~ ~=20.43, Cl~=17.24 found: C%-34.83, H%=3.8~, N%=20.59~ Cl~=17.18 Bromo derivative:
______ Yield: 60 ~
M.p.: 163 C
Recrystalli ation: from ~water Analy~is: oalculated: C%=28.82~ H~-3.22, ~%=16.8, Br~=31~95 ~ound: C~=29.11, H~=3.16, N%~16.78, ~r%=31. 82 Preparation of 3-meth~ oi~oxazol=2=gL~ h,~
~__nidine 0.04 mole~ of 3-methy1-4-¢hloro-5-aminooxg-methyl i~o2azole are dis~olved in 40 ml o~ water, 108 ~ of cyan-amide are added, and the mi~ture is allo~ed to ~tand at room temperature ~or 12-14 hour3. Then it i~ heated, kept at 100 C for 40 minutea and evaporated in ~acuo. The cry~talline ma3~ thus-obtained i~ recrystallised from the mixture o~ ethanol and diethylether.
Yield: 75 %
M~p.~ 176 - 178 C
~alysi~: ealculated: C~a29.89, H%=4.18, ~%-23.24, Cl~-14.70, Cl ~-14.70 ~ound: C~-29.91, E%-4.68, N~_23.40, C1%-14.62, Cl ~-14~59 .~ ,,.

~ 16363 1 Example 10 Pr~ at _ of 3-methyl-4-chloro-5-fphthalimido-methxl) i9 o~azole 0.1 mole of 3-methyl-4-chloro-5-bromomethyl i~oxazole il3 dis~olved in 50 ml of ~,N-dimethylformamide or anhydrou~
acetone, then 0.15 mole oi potas~ium phthalimide are added and the mi~ture i~ kept at 100 a ~or 5 hour~. Then it i9 cooled, poured onto 0.5 kg of broken ice 7 the crystalline precipitate is filtered and wa~hed with ice-cold ethanol.
Aiter drying the crude product i3 recry~tallized from ethanol.
Yield: 60 ~
M.p.: 124 - 126 C
Analysi~: calculated: C~=56.43, H~=3.28, ~%=1012, C1%=12.81 found: C~556.29, H~o=3.28, N~=1212, Cl~s12.86 xample 11 PreParatlo~ o~ ethYl-4-¢hloroiso$azol-5-Yl-methYlamine hvdrochlor _ 0.1 mole of 3-methyl-4-chloro-5-(phthalimido,-methyl)-isoxazole i~ dissol~ed in 250 ml o~ anhydrouo dichloromethane, the~ 52 g oi 98 % hydrazine hydrate are added and the mi~ture i~ Ytirred at room temperature ior 24 hours, 3-~ethyl-4-chloroi~o$azol-5-yl-methylamine i9 ~eparated ~rom the reaction mixture and its hydrochloride i9 ~ormed. ~he pure product can be obtai~ed by recry~tallization ~rom anhydrous ethanol.
Yield: 82 %
M.p.: 178 - 180 C (decomp.) A~alysi3: calculated: C%=32.80, H~=4.40, ~%=15.30, C1%=19.23, Cl-~=19.23 .~

_ 35 _ 1163631 found: C~=32.68, H~=4,36, N~=15.47, Cl~=19.25, Cl-~=19.40 Exam~l~ 12 ~rep ration of ~ met~a=~_hloro(bromo)-~tN,N-diet lamino-m~ )isogazole h~drochloride _____ __ 0.1 mole of 3-methyl-4-chloro(bromo)-5~bromomethyl-i~oxazole i~ dissolved in 80 ml of anhydrou~ ethsnol, 0.22 mole3 of diethylamine are added and the ~olution i9 boiled for two hour~. Thereafter the mi~ture i~ evzporated to a third o~ it~ previou~ volu~e, diluted with 120 ml of water and extracted thrice with a total amount of 45 ml of ether, washed, dri~d ovsr ma~nesium sul~ate, then ~aturated ~ith anhydrous hydrochloric acid. The ~eparated product i9 filtered off, wa~hed with anhydrou3 ether and recry~tallized.
_loro derivative:
Yi~ld: 82 ~
M.p.: 190-192 C
Analysis: calculated: C~=45.19, H~6~74~ N~ 71~ C1%=14~82 Cl-~=14~82 found: C%=45.62, H%~6~68~ ~%=11~70~ C1%s14~68 Cl-%=14 ~81 ~romo derivative:
Yield: 85 %
M.p.: 198-200 ~
Xecry~tallizatiou: from anhydrou~ ethanol Analyai~: caloulated: C%=38~00~ H~a5~67~ N%-9.85, Cl %s12.46, ~ r~228.09 found: C%=37.68, H~-5.62, N%-9.60, Cl ~812.43, Br~-28.00 E3~le 1~
__ Preparation of ~_m~t~ chloro ~ cyclohe~21amino-methyl)isQxazole ~rochloride ____ __ _ 0.1 mole OI 3-methy1-4-chloro-5-bromomethyl isoxazole i~ di~solved in 75 ml of anhydrous ethanol, then 0.11 mQles of cyclohexylamine and Ooll mole~ of triethylamine are added. The solution ia boiled for two hour~. ~he title-compound i~ obtai~ed from the reaction mixture by proceedi~g in the way de~ribed in Example 12.
Yield: 55 %
M.p.: 225-227 C
Recry~tallization: from anhydrou~ ethanol Analy~i~: calculated: C~o-50.0~ H~-6~49, ~%Y10.60~ Cl%213~42, Cl-~.13.42 found: C%,49.52, ~%=6.38, N%s10.59, C1~13.50, Cl-%=13.69 xam~
Pre~aration of ~-met~yl=4-chlor~ ~ N-pi~eridino-methyl)-ia_xazole h~drochloride 0.04 molea of 3-methyl-4-chloro-5-bromomethyl i~o~azole are di~olved in 25 ml of anhydrou~ ethanol and 0.44 moles of piperidine and 0.44 mole~ oi triethylamine are added.
The ~olution ia boiled for 2 hour~. The title-compound i8 obtained fro~ the reaction mixture by proceeding in the w~y described i~ Example 12.
Yield: 60 ~
M.p.: 213-214 C (decomp~) Recry~tallization: from anh~drou~ etha~ol Analy~i~: calculated: C%-47.82s H~36.42, N%-11.15, Cl~=l4.
C1-%-14.11.
~,... .

1 1~3631 - ~7 -~ound: C~=48 . 05, H~s6 . 43, ~5sll .15, Cl~=14 . 00, C1-~Y13 . 97 ~ample 15 _reparation of 3-me thYl-4-chloro Lbromo)-5-rN-morpholino-m~t~Yl)i o~azole hydrochloride 0.1 mole o~ 3-methyl-4-chloro (bromo )-5-bromomethyl i30~azole i~ di~olved in 80 ml of anhydrous ~thanol, then 0.11 moles o~ morpholine and 0.11 mole~ o~ triethylamin~
are added and thé reaction mixture i9 boiled for two hours.
The title-compound i~ obtained by proceeding a~ describsd in E~ample 12.
Chloro derivative:
Yield: 62 %
M.p.: 215 - 216 C
Recrystallization: from anhydrou~ ethanol Analy~i~: calculated: C%-42.56, H%-5.55, N~=11.03, Cl~_13.96, Cl-%=13~96 found: C%-42.96, E%~5.94, N%~11.02, C1%al3~89 Cl-~=13.90 ~romo d~rivative:
Yield: 65 %
M.p.: 216 - 218 a Recry~tallization: from anhgdrous ethanol A~alysi~: calculated: C%-36. 22, H~-4.73, N~-9,45, Cl %=11.88, Br~=26.77 found: c~36.63, H~=4.70, N%59.52, Cl %-11.89, Br%-26.79 fi 1 163~ 3 1 E~ample 1 Preparation of ~ chl~r~ ~ moet~lam i~30xazole hYdrochloride _ _ _____~ _ 0.35 moles of 3-methyl-4-chloro-5-bromomethyl i~oxazole are dissolved in 390 ml of anhydrou~ acetone, the solution i3 cooled to -5 - -10 C, and a ~olution o~ 19.6 ml of ethyleneimine in 80 ml of anhydrou~ acetone is added, under stirring. Therea~ter the reaction mixture i9 stirred for 2 hours, cooled and poured into 1 litre of icy water. The separated ~ticky maas i9 e~tracted first with 200 ml, then twice with a total amount of 100 ml of ether. The ether phaae i8 separated from the precipitated (8.2 g, m.p.: 138--141 C), ~ashed twice with 400 ml of water, drled o~er magnesium ~ulfate, concentrated to a third of it~ previou~
volume, and 3aturated with anhydrou~ hydrochloric acid. The separated pr~duct i~ filtered off and recrystallized from anhydrous ethanol.
~ield: 25 ~
M.p.: 164 - 166 Pc Analy~ia: calculsted: C%s33.03, H~54.35, N~.9.66, Cl~=12.22, Cl-%312.22, Br%-27.55 found: C%-37.87, H~-4.31, N%~10.05, C1%-12.28, Cl-~-12.34, Br~-27.44 E~a~
ratio~ o~ meth~1-4-chaoro-5-(2'.6'-dichlorobenzal-amino-methyl) i~o~azole -- . .
0~065 moles of 3-methyl-4-chloroisoxazol-5-il-methyl-amine hydrochloride are di~olved in 50 ml of anhydrous ethanol~ then 0.07 moles of triethylamine and 0.07 moles of ~ . , , .1 2,6 dichlorobenzaldehyde are added. The reaction mixture i9 boiled for an hour, clarified with sctive carbon and, when it is still hot, filtered. The solution i~ cooled, the separated crystal~ are filtered off and recrystallized from ethanol.
Yield: 60 ~
M.p.: 86.5 - 87.5 C
Analysis: calculated: C~=47.47, ~_2.99, N~=9.23, Cl~=35.04 found: C~-48~01, H~=3.00, N%=9.22, Cl~-35.11 Example 18 Preparation_o~ 3 methyl-4-chloro-5- ~',6'-dichlorobenzyl-amino-meth~ o~azole ~ro hloride 0.01 mole of 3-methyl-4-chloro-5-(2',6~-dichlorobenzal-amino-methyl) i~o~azole i9 dissolved in 50 ml of anhydrous methanol and 0.5 g of eodium boron hydride are added in smsll portion~, under coolin~. The solution i9 boiled for 20 minutes, cooled and evaporated. The residue is dissolved in ether, the ether eolutio~ i9 washed with ~ater and dried over magnesium sulfate. The salt of the end-product is separated with anhydrou~ hydrochloric acid and recrystallized from anhydrou~ ethanol.
Yield: 70 %
M.p~: 192 - 194 C (decomp.) Analy~is: calculated: C%-42.13, H%=3.54, ~%-8.19, C1%=31.10, Cl-%=10.36 fou~d: C~=41~90, H~-3.31, ~%=8.00, Cl~=30.93, Cl-%=10.47 E3~:amP1e 12 ~ ara~ meth~1-4-¢hloro-5-(N-/p~ gzene-1 16~6~1 sulfonamid_~_methyl)isoxazole _ _____ ___ _ ____ 90 ml of dichloromethane, 16.2 ml of triethylamine and 16.2 g ofp~acetamido-benzene~ulfonic chloride are add~d to 0.06 mole~ of 3-methyl-4-chloroisoxa201-5-yl-methylamine hydrochloride, and the mixture i~ stirred at room temperature for 16 hour~. Th~n 90 ml of di~tilled water are added. The e~d-product separates under vigorou~ ~tirring. It i9 filtered off, wa~hed with cold water and recrystallized from ethanol.
Yield: 73 %
M.p.: 183 - 184 C
~naly~i~: calculated: C~=45.41, ~%,4.10, N%=12.22, S~-9.32 found: C%=45.01, H~_4.06, ~=11.97, $%-9.33 E~amPle 20 ___ re~_ratiQn of ~_m~ a=~=~hloro-5-(N-/P-amino-benzene-ethYl)i~o~azole 0.02 mole~ of 3-methyl-4-chloro-5-(N-/p-acetamido-benzene-~ulfonamido/-methyl)i~o~azole are hydrolized ~ith 60 ml of lN hydrochloric acid at 100 C for 5 hours. The hot solution i9 clarified with active carbon and ~iltered.
The filtrate i9 cooled, the eeparated crystal~ are filtered off and recrystallized from 1~ hgdrochloric acid.
Yield: 94 M.p.: 183 - 184 C
Analysis: calculated: C%543.78, H%24.01, N%~13.92, C1%s11.75, S~=10.62 found: C%s44.14, H~=3.98, N~=13.50, C1%~11.67, S%=10.61 E_ample 21 __ Preparation of 3-methyl-4-chloro-~!dimethylam _ -ethylami~_-methyl)i~o~a_ole-bi~-hydrochloride A solution o~ 3-methy1-4-chloroi~o~azol-5-yl-methyl-amine hydrochloride, 0.1 mole of dimethylamino-ethylchloride hydrochloride and 43 ml of trieth~lamine in 200 ml of anhydrous ethanol i8 boiled for 6 hour~ then allo~ed to stand at room temperature ~or 12 hours. ~he separated triethylamine hydrochloride is ~iltered o~f, the filtrate i~ evaporated, the re~idue i~ dissolved in 35 ml of anhydrous ethanol and evaporated aBain. The residual pale yello~ syrup is dissolved in anhydrous ether and the solution is ~aturated with hydro-chlori¢ acid. ~he ~eparated 3-methyl-4-chloro-5-(dimethyl-amino-ethylamino-methyl)isoxazole-bi3-hydrochloride i~
filtered o~f and dried over potassium hydro~ide.
Yield: 44 ~
M.p.: 150 - 160 C (decomp.) Analy~ calculated: C%=37.19, H~=6.24, ~-14.46 found: C%=37.76, H~=6.18, D~=14.57 .

Claims (40)

THE EMBODIMENTS OF THE INVENTION IN WHICH AN EXCLUSIVE
PROPERTY OR PRIVILEGE IS CLAIMED ARE DEFINED AS FOLLOWS:

1. A process for the preparation of an isoxazole derivative of the general formula [I] or an acid addition salt thereof, [I]

wherein R represents a C1-4 alkyl or 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/C1-4 alkanoylamidoX-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 piperidino or a morpholino group with the proviso that if R
represents methyl and R1 stands for a guanyl-thio group, R2 may represent only chlorine, characterized by a./ to prepare a compound of the general formula /Ia/

[Ia]

wherein R and R2 have the same meanings as above, and R3 and R4 represent a C1-4 alkyl group, a compound of the general formula [II]

[II]

wherein R and R2 have the same meanings as above, is reacted with a dialkyl-/C1-4 alkanoyl-amido/-malonate of the general formula [III]

[III]

wherein R3 and R4 have the same meanings as above, or b./ to prepare a compound of the general formula [Ib]

[Ib]

wherein R and R2 have the same meanings as above, a compound of the general formula /Ia/ is hydrolized, or c./ to prepare a compound of the general formula /Ic/

[Ic]

wherein R and R2 have the same meanings as above, a compound of the general formula [II] is reacted with thiocarbamide, or d./ to prepare a compound of the general formula [Id]

[Id]

wherein R and R2 have the same meanings as above, a compound of the general formula [II] is reacted with n-hydroxy-phthalimide, or e./ to prepare a compound of the general formula [Ie]

[Ie]

wherein R and R2 have the same meanings as above, e1./ a compound of the general formula [Id] is reacted with hydrazine, or e2./ a compound of the general formula [IV]

[IV]

wherein R and R2 have the same meanings as above, R5 and R6 each represent a lower alkyl or aryl group or R5 stands for aryl and R6 represents hydrogen, is hydrolized in acid medium, or e3./ a compound of the general formula [V]

[V]

wherein R and R2 have the same meanings as above, and R7 and R8 represent a hydrogen atom or a phenyl group, is reacted with hydrazine or with a lower alkyl hydrazine and hydrochloric acid, or e4./ a compound of the general formula [VI]

[VI]

wherein R and R2 have the same meanings as above, and R9 stands for hydrogen or phenyl, or a compound of the general formula [VII]

[VII]

wherein R and R2 have the same meanings as above, and R10 and R11 stand for lower alkyl or phenyl, is subjected to acid hydrolysis, or e5./ a compound of the general formula [VIII]

[VIII]

wherein R and R2 have the same meanings as above, and R12 represents t-butyl, benzyl or ethyl, is subjected to acid hydrolysis, or e6./ a compound of the general formula [IX]

[IX]

wherein R and R2 have the same meanings as above, and Ac represents a C1-4 alkanoyl group, is optionally desacylated and reacted with an amine of the general formula [X]

H2N - X [X]

wherein X represents a halogen atom or a sulfonyl-oxy group, or f./ to prepare a compound of the general formula [If]

[If]

wherein R and R2 have the same meanings as above, f1./ a compound of the general formula [Ie] is reacted with cyanamide, or f2./ a compound of the general formula [XI]

[XI]

is heated with a compound of the general formula [Ie], or f3./ a compound of the general formula [Ie] is reacted with a compound of the general formula [XII]

[XII]
wherein R13 stands for lower alkyl, or with a salt thereof, or f4./ a compound of the general formula [XIII]

[XIII]

wherein R and R2 have the same meanings as above, is warmed with an ammonium halogenide, or f5./ a compound of the general formula [XIV]
[XIV]

wherein R and R2 have the same meanings as above, and Hal represents halogen, is reacted with a compound of the general formula [XV]
[XV]
or g./ to prepare a compound of the general formula [Ig]

[Ig]
wherein R and R2 have the same meanings as above, a compound of the general formula [Ie] is reacted with alkali cyanate, or h./ to prepare a compound of the general formula [Ih]

[Ih]

wherein R and R2 have the same meanings as above, R'3 represents a Cl-4 alkyl or a C3-6 cycloalkyl group, and R'4 stands for a hydrogen atom or a Cl-4 alkyl group, or R'3 and R'4 may form together with the adjacent nitrogen atom a 6 membered hetero-cyclic ring, which may optionally contain an oxygen as a further hetero atom, a compound of the general formula [II] is reacted with an amine of the general formula [XVI]

[XVI]

wherein R'3 and R'4 have the same meanings as above, or i./ to prepare a compound of the general formula [Ii]

[Ii]
wherein R and R2 have the same meanings as above, i1/ a compound of the general formula [II] is reacted with ethylene imine, or i2./ a compound of the general formula [XVII]

[XVII]
wherein R and R2 have the same meanings as above, is brominated, or i3./ a compound of the general formula [XVIII]

[XVIII]

wherein R and R2 have the same meanings as above, is reduced, or j./ to prepare a compound of the general formula [Ij]

[Ij]

wherein R and R2 have the same meanings as above, and R"3 stands for hydrogen and R"4 may represent hydrogen, di-/Cl-4 alkyl/-amino-/Cl-4 alkyl/, 2,6-dihalogen-benzyl or p-amino-phenyl-sulfonyl optionally N-substituted by a Cl-4 alkanoyl group, or R"3 and R"4 represent together a 2,6-dihalogen-benzylidene group, or R3 and R4 may form, together with the adjacent nitrogen atom a phthalimido group, a compound of the general formula [II] is reacted with an alkali phthalimide, the compound of the general formula [Ik] thus-obtained, [Ik]

wherein R and R1 have the same meanings as above, is preferably reacted with hydrazine, the compound of the general formula [Il] thus-obtained [Il]

wherein R and R2 have the same meanings as above, is preferably condensed with a 2,6-dihalogen-benzaldehyde, the compound of the general formula [Im] thus-obtained [Im]

wherein R and R2 have the same meanings as above, is preferably reduced with a reducing agent; or, if desired, a compound of the general formula [Il] is reacted with a p-/Cl-4 alkanoyl/-amino-benzenesulfonic chloride, the compound of the general formula [In] thus-obtained, [In]

wherein R and R2 have the same meanings as above, and Ac represents a Cl-4 alkanoyl group, is preferably hydrolized; or, if desired, a compound of the general formula [Il] is reacted with a di-/Cl-4 alkyl/-amino-/Cl-4/-alkyl halogenide, and, if desired, a compound of the general formula [I] thus-obtained is converted into its acid addition salt.

2. A process as claimed in claim 1, wherein R represents methyl.

3. A process as claimed in claim 1 or 2, wherein R2 represents chlorine.

4. A process as claimed in claim 1 wherein R is methyl, R2 is chlorine, and R1 is guanidino-oxy.

5. A process of preparing 3-methyl-4-chloroisoxazol-5-yl-methyleneoxy-guanidine which comprises reacting an aqueous solution of 3-methyl-4-chloro-5-amino-oxy-methyl isoxazole with cyanamide.

6. A process as claimed in claim 1 wherein R is methyl, R2 is chlorine, and R1 is bromoethylamino.

7. A process of preparing 3-methyl-4-chloro-5-/bromoethylamino-methyl/isoxazole hydrochloride which comprises reacting 3-methyl-4-chloro-5-bromoethyl isoxazole dissolved in anhydrous acetone with ethyleneimine which is in solution with anhydrous acetone.

8. A process as claimed in claim 1 wherein R is methyl, R2 is chlorine, and R1 is amino-oxy.

9. A process of preparing 3-methyl-4-chloro/bromo/-5-amino-oxymethyl isoxazole hydrochloride which comprises reacting 3-methyl-4-chloro-5-phthalimido-oxymethyl) isoxazole dissolved in dichloromethane or dichloroethane with hydrazine hydroate.

10. A process according to the method a./ of claim 1, characterized by carrying out the reaction in the presence of sodium hydride in a suitable solvent.

11. A process according to claim 10 wherein said suitable solve is selected from the group consisting of dimethylformamide, tetrahydrofurane, dimethylsuifoxide or benzene.

12. A process according to the method b./ of claim 1, characterized by carrying out the hydrolysis with hydrochloric acid or sulfuric acid.

13. A process according to the method c./ of claim 1, characterized by carrying out the reaction in an alkanol under heating.

14. A process according to the method d./ of claim 1, characterized by carrying out the reaction in the presence of an acid binding agent.

15. A process according to the method el./ of claim 1, characterized by carrying out the reaction in a chlorinated hydrocarbon as medium, in a temperature interval ranging from 20°C to the boiling point of the reaction mixture.

16. A process according to the method e5./ of claim 1, characterized by hydrolizing the compound of the general formula [VIII], wherein R12 stands for t-butyl, benzyl or ethyl, with trifluoroacetic acid or with a mixture of acetic acid and hydrogen bromide or hydrochloric acid.

17. A process according to the method e6./ of claim 1, characterized by using a starting material of the general formula [X] in which X stands for chlorine, methanesulfonyl-oxy or p-toluenesulfonyl-oxy.

18. A process according to the method fl./ of claim 1, characterized by carrying out the reaction in water, in the mixture of water and alkanol, in tetrahydrofurane or in dioxane, at the temperature of 20°C - 100°C.

19. A process according to the method f2./ of claim 1, characterized by carrying out the reaction in methanol.

20. A process according to the method f3./ of claim 1, characterized by using as starting material a compound of the general formula [XII], wherein R13 stands for methyl, or a hydrogen sulfate thereof, and carrying out the reaction in water at room temperature.

21. A process according to the method f4./ of claim 1, characterized by carrying out the reaction with ammonium chloride in the melt.

22. A process according to the method f5./ of claim 1, characterized by carrying out the reaction in the presence of an alkali alcoholate, in the corresponding alkanol as medium, under heating.

23. A process according to the method g./ of claim 1, characterized by carrying out the reaction by using potassium cyanate in water or in an aqueous alkanol as medium, at a temperature interval ranging from 20°C to the boiling point of the reaction mixture.

24. A process according to the method h./ of claim 1, characterized by carrying out the reaction in the presence of an acid binding agent.

25. A process according to claim 14 or 24 wherein said acid binding agent is triethylamine.

26. A process according to the method il/. of claim 1, characterized by carrying out the reaction in acetone.

27. A process according to the method i2./ of claim 1, characterized by using hydrogen bromide, phosphorus tribromide, sulfuryl bromide or thionyl bromide as brominating agent.

28. A process according to the method i3./ of claim 1, characterized by carrying out the reaction with boron hydride.

29. A process according to claim 28 wherein said boron hydride is in the form of an adduct of boron hydride and tetrahydrofurane.

30. A process according to the method j./ of claim 1, characterized by reacting the compound of the general formula [Il] with 2,6-dihalogen-benzaldehyde in the presence of an acid binding agent.

31. A process according to the method j./ of claim 1, characterized by reducing the compound of the general formula [Im] with a complex metal hydride.

32. A process according to claim 31 wherein the complex metal hydride is sodium boron hydride.

33. A process according to the method j./ of claim 1, characterized by reacting the compound of the general formula [Il] with p-alkanoyl-amido-benzenesulfonic chloride in the presence of an acid binding agent.

34. A process according to the method j./ of claim 1, characterized by hydrolizing the compound of the general formula [In] with hydrochloric acid.

35. A process according to the method j./ of claim 1, characterized by reacting the compound of the general formula [Il] with a dialkyl-amino-alkyl halogenide in the presence of an acid binding agent.

36. A process according to claims 30, 33 or 35 wherein said acid binding agent is triethylamine.

37. An isoxazole derivative of the general formula [I] or an acid addition salt thereof, [I]
wherein R represents a Cl-4 alkyl or a phenyl group, R2 denotes a halogen atom or a /Cl-4 alkoxy/-carbonyl group, R1 represents a group of the formula -CH/NH2/-COOH, or a guanyl-thio, a bis-/Cl-4 alkoxycarbonyl-Cl-4 alkanoylamido/-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 cyclo-alkyl, .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 piperidino or a morpholino group with the proviso that if R
represents methyl and R1 stands for a guanyl-thio group, R2 may represent only chlorine, whenever prepared by the process of claim 1, or by an obvious chemical equivalent thereof.

38. 3-Methyl-4-chloroisoxazol-5-yl-methyleneoxy-guaniddine and its acid addition salts,whenever prepared by the process of claim 4 or 5, or by an obvious chemical equivalent thereof.

39. 3-Methyl-4-chloro-5-(bromoethylamino-methyl)isoxazzole, and its acid addition salts, whenever prepared by the process of claim 6 or 7, or by an obvious chemical equivalent thereof.

40. 3-Methyl-4-chloro-5-amino-oxy-methyl isoxazole and its acid addition salts, whenever prepared by the process of claim 8 or 9, or by an obvious chemical equivalent thereof.