CH646157A5 - Isoxazole derivatives and pharmaceutical preparations containing them - Google Patents

Abstract

The isoxazole derivatives of the general formula I and their acid addition salts can be used in therapy as a result of their hypotensive, anti-inflammatory and febrifugal properties. The symbols in formula I have the meaning indicated in Claim 1. <IMAGE>

Description

       

  
 

** WARNING ** beginning of DESC field could overlap end of CLMS **. 

 



   PATENT CLAIMS 1.  Compounds of the general formula I
EMI1. 1
 and acid addition salts thereof, wherein R is Clw alkyl or phenyl; R2 represents halogen or (Cl 1-alkoxy) carbonyl and Rl represents a group of the formula
EMI1. 2nd
   Guanylthio, bis - [(C 1 4-alkoxy) carbonyl] - [(Cl-4-alkanoyl) amino] methyl, aminooxy, carbamoylaminooxy, guanidinooxy, phthalimidooxy or a group of the general formula -NR3R4,

   wherein R3 is hydrogen, Cl-4-alkyl, G-6-cycloalkyl, (o-halogen- (Cx alkyl), di- (CI-4-alkyl) -amino- (Cl-4-alkyl), 2,6- Represents dihalobenzyl or a p-aminophenylsulfonyl group optionally substituted on the nitrogen atom by a Cl-4-alkanoyl group, and R4 is hydrogen or CI-4-alkyl or R3 and R4 together form a 2,6-dihalobenzylidene group, or R3 and R4 together with the adjacent nitrogen atom form a phthalimido group, or Ra and R4 together with the adjacent nitrogen atom form a six-membered heterocyclic ring which may also contain an oxygen atom;

   with the proviso that if R is methyl and Rl is guanylthio, R2 is different from chlorine. 



   2nd  Compounds according to claim 1, in which R represents methyl. 



   3rd  Compounds according to claim 1 or 2, characterized in that R2 represents chlorine. 



   4th    3-methyl-4-chloro-isoxazol-5-yl-methyleneoxy-guanidine; 3-methyl-4-chloro-5- (2-bromoethylaminomethyl) isoxazole; 3-methyl-4-chloro-5-aminooxymethyl isoxazole; and acid addition salts, especially hydrochlorides thereof, as compounds according to claim 1. 



   5.  Pharmaceutical preparations, characterized in that they contain as active ingredient a compound of general formula I or a pharmaceutically suitable acid addition salt thereof and inert, solid or liquid pharmaceutical carriers and auxiliaries. 



   6.  Pharmaceutical preparations according to claim 5, characterized in that they are 3-methyl-4-chloroisoxazol-5-yl-methylenoxy-guanidine or 3-methyl-4-chloro5- (2-bromoethylaminomethyl) isoxazole or acid addition salts, in particular hydrochlorides thereof, as active ingredient , contain. 



   The present invention relates to new isoxazole derivatives and pharmaceutical preparations containing these compounds. 



   It is known that 3-hydroxy-5-methyl-isoxazole can be used as a crop protection agent [Merck Index, 9.  Edition (1961), page 123].  Partially saturated isoxazole derivatives which can be used as antitumor agents have been described in Tetrahedron Letters 2549 (1973) and in J.    Antib.  28A, (1975). 



   The invention relates on the one hand to new isoxazole derivatives of the general formula (I)
EMI1. 3rd
 and acid addition salts thereof, wherein R is Cl-4 alkyl or phenyl; R2 represents halogen or (Cl-4-alkoxy) carbonyl and Rl represents a group of the formula
EMI1. 4th
 Guanylthio, bis - [(CI-4-alkoxy) carbonyl] - [(Cl-4-alkanoyl) amino] methyl, aminooxy, carbamoylaminooxy, guanidinooxy, phthalimidooxy or a group of the general formula -NR3R4, where R3 is hydrogen , C1-4-alkyl, C3-6-cycloalkyl, e3-halogen- (CI-4-alkyl), di- (C14-alkyl) -amino- (Ci-4-alkyl), 2,6-dihalobenzyl or one,

   p-amino-phenylsulfonyl group optionally substituted by a Cl-alkanoyl group on the nitrogen atom and R4 is hydrogen or CI-4-alkyl or R3 and R4 together form a 2,6-dihalobenzylidene group, or R3 and R4 together with the adjacent one Nitrogen atom form a phthalimido group; or R3 and R4 together with the adjacent nitrogen atom form a six-membered heterocyclic ring which may also contain an oxygen atom; with the proviso that if R is methyl and Rl is guanylthio, R2 is different from chlorine. 



   The term lower alkyl group used in the description means straight-chain or branched saturated aliphatic hydrocarbon groups with 1-4 carbon atoms (e.g. B.  Methyl, methyl, n-propyl, isopropyl, n-butyl, etc. ).  The alkoxy portion of the lower alkoxycarbonyl groups can be straight or branched and contain 1-4 carbon atoms (e.g. B.  Methoxy, ethoxy, n-propoxy, isopropoxy, etc. ).  The term halogen atom includes the chlorine, bromine, fluorine and iodine atoms.  The term C3-6 cycloalkyl group can e.g. B.  represent cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl.  The term aryl group refers to mono- or bicyclic, optionally substituted, aromatic hydrocarbon groups. 

  The term Cl-4-alkanoyl group refers to the acid residue of lower alkane carboxylic acids (e.g. B.  Acetyl, propionyl, butiryl, etc. ).  The heterocyclic ring formed by R3 and R4 and the adjacent nitrogen atom can, for. B.  be a piperidino or morpholino ring. 



   An advantageous connecting group of the general formula (I) are those derivatives in which R represents methyl. 



  Another advantageous connecting group of the general formula (I) are those derivatives in which Rz denotes chlorine. 



   Particularly advantageous representatives of the compounds of the general formula are the following derivatives: 3-methyl-4chloro-isoxazol-5-yl-methyleneoxy-guanidine and 3-methyl-4-chloro-5- (bromoethylaminomethyl) isoxazole and acid addition salts, especially hydrochlorides thereof . 



   The acid addition salts of the compounds of general formula (I) can be salts formed with pharmaceutically suitable, inorganic or organic acids, (e.g. B.  Hydrochloride, hydrobromide, sulfate, phosphate or   



  Tartarates, fumarates, maleinates, citrates, lactates etc. ). 



   The compounds of the general formula (I), in which R 1, R 2 and R have the above meaning, can be prepared by a) preparing compounds of the general formula (Ia)
EMI2. 1
 where R is as defined above and R3 and R4 are Cl-4-alkyl, a compound of the general formula (II)
EMI2. 2nd
 in which Rund R have the above meaning, with a dialkyl (CI-4-alkanoylamido) malonate of the general formula (III)
EMI2. 3rd
 wherein R3 and R4 are as indicated above; or b) for the preparation of compounds of the general formula (Ib)
EMI2. 4th
 wherein R and R have the above meaning, hydrolyzed a compound of general formula (Ia);

   or c) for the preparation of compounds of the general formula (Ic)
EMI2. 5
 wherein Rund R have the above meaning, a compound of general formula (II) with thiourea; or d) for the preparation of compounds of the general formula (Id)
EMI2. 6
 where R 2 has the meaning given above, reacting a compound of the general formula (11) with N-hydroxy-phthalimide; or e) for the preparation of compounds of the general formula (Ie)
EMI2. 7
 in which R3 have the meaning given above, ei) reacting a compound of the general formula (Id) with hydrazine;

   or e2) a compound of the general formula (IV)
EMI2. 8th
 wherein R 2 has the above meaning, Rs and R6 both represent lower alkyl or both aryl or Rs represent aryl and R6 represent hydrogen, hydrolyzed in an acid medium; or ea) a compound of the general formula (V)
EMI2. 9
 wherein R has the meaning given above and R7 and Rs are hydrogen or phenyl, treated with hydrazine or a lower alkyl hydrazine and hydrochloric acid;

   or e4) a compound of the general formula (VI) or (VII)
EMI2. 10th
 wherein R 2 has the above X 3 meaning, Rs is hydrogen or phenyl and Rlo and Rl 1 are lower alkyl or phenyl, subject to acidic hydrolysis; or it) a compound of the general formula (VIII)
EMI3. 1
 wherein Rund R have the meaning given above and Rl2 stands for t-butyl, benzyl or ethyl, is subjected to acidic hydrolysis;

   or it) a compound of the general formula (IX)
EMI3. 2nd
 wherein R 2 has the meaning given above and Ac is a CI-4 alkanoyl group, optionally deacylated and reacted with an amine of the general formula X. 



  H2N-X (X), wherein X is halogen or a sulfonyloxy group; or f) for the preparation of compounds of the general formula (If)
EMI3. 3rd
 in which R 2 has the meaning given above, fi) reacting a compound of the general formula (Ie) with cyanamide; or f2) a compound of the general formula (Ie) with a compound of the general formula (XI)
EMI3. 4th
 wherein R and R have the above meaning heated; or f3) a compound of the general formula (Ie) with a compound of the general formula (XII)
EMI3. 5
 or a salt thereof, wherein R13 is lower alkyl; or f4) a compound of the general formula (XIII)
EMI3. 6
 wherein R and R are as defined above, heated with an ammonium halide;

   or fs) a compound of the general formula (XIV)
EMI3. 7
 wherein R 2 has the meaning given above and Hlg is halogen, with a compound of the formula (XV); or
EMI3. 8th
 g) for the preparation of compounds of the general formula (Ig)
EMI3. 9
 wherein R and R2 are as defined above, reacting a compound of the general formula (Ie) with an alkali metal cyanate;

   or h) for the preparation of compounds of the general formula (Ih)
EMI3. 10th
 where round R2 have the above meaning; R3t is Cl-4 alkyl or C3 6-cycloalkyl, R4 'represents hydrogen or CI-4-alkyl or R3' and R4 'together with the adjacent nitrogen atom form a six-membered, optionally also containing an oxygen atom, heterocyclic ring) a compound of general formula (II) with an amine of the general formula (XVI)
EMI3. 11
 where RS3 and Rt4 have the above meaning;

   or i) for the preparation of compounds of the general formula (Ii)
EMI3. 12
 in which R 2 has the above meaning, il) reacting a compound of the general formula (II) with ethylene imine; or i2) a compound of the general formula (XVIII)
EMI4. 1
 in which round R2 have the above meaning, brominated; or i3) a compound of the general formula (XVIII)
EMI4. 2nd
 where Rund R have the above meaning reduced;

   or j) for the preparation of compounds of the general formula (Ij)
EMI4. 3rd
 where R has the meaning given above and R "3 for hydrogen and R" 4 for hydrogen, di- (Cx 4-alkyl) -amino- (Cl-alkyl), a p- substituted on the nitrogen atom optionally by Cl-4-alkanol Aminophenylsulphonyl group or 2,6-dihalobenzyl or R "3 and R" together form a 2,6-dihalobenzylidene group, or R "and R" 4 together with the adjacent nitrogen atom form a phthalimido group) a compound of the general formula (II) reacted with an alkali metal phthalimide;

   if desired, a compound of the general formula (Ik) obtained
EMI4. 4th
 where R 2 has the above meaning, reacted with hydrazine; if desired, a compound of the general formula (I1) obtained
EMI4. 5
 wherein R and R have the above meaning, condensed with a 2,6-dihalobenzaldehyde; if desired, a compound of the general formula (Im) obtained
EMI4. 6
 wherein Rund R have the above meaning, reduced with a reducing agent;

   if desired, reacting a compound of the general formula (I1) with a p- (C1-4-alkanoyl) aminobenzosulfonic acid chloride, if desired a compound of the general formula (In) obtained
EMI4. 7
 wherein R 2 has the above meaning and Ac is a Cl-4 alkanoyl group, hydrolyzed; if desired, reacting a compound of the general formula (I1) with a di- (C14-alkyl) -amino- (C i -alkyl halide) and, if desired, converting a compound of the general formula (I) thus obtained into an acid addition salt. 



   Method a) of the above process can advantageously be carried out in the presence of an alkali metal hydride / advantageously sodium hydride) in dimethylformamide.  Diethyl ether, tetrahydrofuran, dimethyl sulfoxide or benzene can also be used as the reaction medium.  The reaction can be carried out between 20 ° C. and the boiling point of the reaction mixture.  The starting material of the general formula (11) and the dialkylalkanoylamidomalonate can advantageously be used in approximately equimolar amounts. 



   According to method b), the hydrolysis of the compounds of general formula (Ia) can be carried out with a mineral acid, advantageously hydrochloric acid or sulfuric acid, in particular hydrochloric acid.  Nitric acid cannot be used due to the possible nitration.  The reaction can be carried out with heating, advantageously at about 100.degree. 



   According to method c) of the above process, a compound of the general formula (II) is reacted with thiourea in an alkanol (in particular ethanol) at a temperature between room temperature and the boiling point of the reaction mixture, advantageously with heating. 



   Method d) of the above process is advantageously carried out in the presence of an acid binder.  Organic bases, in particular triethylamine, can advantageously be used for this purpose.  The reaction can be carried out in a suitable organic solvent (e.g. B.  Ketones, such as acetone or hexamethylphosphoric acid diamide, dimethylformamide) can be carried out.  One works preferably under heating, e.g. B.  at around 100 C.    



   According to method el) of the above process, a compound of the general formula (Id), in which R and R2 have the above meaning, is reacted with hydrazine.  The reaction is carried out in an organic solvent. 



  For this purpose chlorinated hydrocarbons (e.g. B. 



  Dichloromethane, dichloroethane or chloroform) can be used.  The reaction temperature can be between about 20 "C and the boiling point of the reaction mixture.  The end product can advantageously be separated off with hydrochloric acid in the form of the hydrochloride. 

 

   According to method e2) of the above process, a compound of the general formula (IV) (in which R is the above meaning, Rs and R6 are both lower alkyl or both are aryl or Rs is aryl and R6 is hydrogen) in acid Medium hydrolyzed.  The reaction can advantageously be carried out using hydrochloric acid with heating, preferably at about 100.degree. 



   According to method e3), a compound of the general formula (V) (in which R has the meaning given above and R7 and Rs are hydrogen or phenyl) is treated with hydrazine or an alkylhydrazine (advantageously n-butyl hydrazine) and with hydrochloric acid.  The process can be carried out in a chlorinated hydrocarbon or alkanol as the medium.  You can advantageously work with heating - especially at the boiling point of the reaction mixture. 



   According to method e4) of the above process, a compound of the general formula (VI) or (VIII) (in which R is the same as above, Re is hydrogen or phenyl and Rlo and Rl 1 are lower alkyl or phenyl) is subjected to acidic hydrolysis subject.  The reaction can advantageously be carried out using hydrochloric acid with heating, in particular at about 100 ° C. 



   According to one embodiment of the method es) of the above process, a compound of the general formula (VIII) (in which R is the above meaning and Rl2 is t-butyl, benzyl or ethyl), in which Rl2 is tert.  Butyl is hydrolyzed with trifluoroacetic acid at about 0-20 "C, especially at about 10" C.  The starting materials of the general formula (VIII), in which Ri2 is benzyl, can advantageously be hydrolyzed with a mixture of acetic acid and hydrogen bromide with cooling at about 0 ° C.  The reaction mixture is treated first with an alkali and then with hydrochloric acid. 

  The hydrolysis of the starting materials of the general formula (VIII), in which R 12 is ethyl, can advantageously be carried out with hydrochloric acid at about room temperature. 



   According to the method es) of the above process, a compound of the general formula (IX) is reacted with a compound of the general formula (X), if appropriate after deacylation.  X represents halogen (advantageously chlorine) or a sulfonyloxy group (advantageously methanesulfonyloxy or toluenesulfonyloxy.  If compounds of the general formula (X) in which X is chlorine are used, the reaction can advantageously be carried out in tetrahydrofuran in the presence of sodium methylate at about 0.degree.  Using compounds in which X is a sulfonyloxy group, one can work in methanol in the presence of sodium methylate at about room temperature. 



   Method fi) of the above process can advantageously be carried out in water, a mixture of water and an alkanol, tetrahydrofuran or dioxane.  It is advantageous to work in the water.  The reaction temperature is between 20 C and 100 C.    



   According to method f2) of the above process, a compound of the general formula (Ie) is heated with a compound of the general formula (XI).  The reaction is advantageously carried out in methanol as a medium at the boiling point of the reaction mixture. 



   According to method f3) of the above process, a compound of the general formula (Ie) is reacted with a compound of the general formula (XII).  Compounds of the general formula (XII) in which R 13 is methyl can advantageously be used as the starting material.  The reaction is advantageously carried out in an aqueous medium at room temperature. 



   According to method f4) of the above process, a compound of the general formula (XIII) is reacted with an ammonium halide - advantageously ammonium chloride. 



  The reaction is advantageously carried out with heating - advantageously in the melt at 120-140 "C. 



   According to method fs) of the above process, a compound of the general formula (XIV) is reacted with the hydroxyguanidine of the general formula (XV).  The reaction can advantageously be carried out in the presence of an alkali metal alcoholate (advantageously sodium methylate) in the corresponding alkanol (advantageously methanol) with heating. 



   According to method g) of the above process, a compound of general formula (Ie) is reacted with an alkali metal cyanate.  Potassium cyanate can advantageously be used for this purpose.  Water or an aqueous alkanol can advantageously be used as the reaction medium.  The reaction temperature is between 20 "C and the boiling point of the reaction mixture. 



   Method h) of the above process can advantageously be carried out in the presence of an acid binder.  For this purpose, inorganic bases (e.g. B. 



  Triethylamine) can be used.  The reaction can be carried out in an organic solvent (e.g. B.  Alkanols such as ethanol, etc.) are carried out.  It is advantageous to work with heating, especially at the boiling point of the reaction mixture. 



   According to process variant il) of the above process, a compound of the general formula (11) is reacted with ethyleneimine.  The reaction can advantageously be carried out in an organic solvent (e.g. B.  Acetone).  The procedure advantageously is such that the ethyleneimine is fed to the starting material of the general formula (II) at a temperature between -5 "C and -10" C and then the reaction mixture is heated to boiling.  The end product can advantageously be isolated by precipitation of the hydrochloride with hydrochloric acid. 



   According to method i2) of the above process, a compound of the general formula (XVII) is brominated.  Hydrogen bromide, phosphorus tribromide, thionyl bromide or sulfuryl bromide can advantageously be used as the brominating agent.  The reaction is carried out in a suitable solvent (e.g. B.  Dimethyl sulfoxide) performed.  The reaction temperature is about 0-20 "C.    



   According to method i3) of the above process, a compound of the general formula (XVIIII) is reduced.  The reduction can advantageously be carried out using hydrogen boron - preferably using a tetrahydrofuran adduct.  You can work in a suitable solvent, especially tetrahydrofuran.  The reaction temperature is between about 0 C and 20 "C.    



   According to method j), a compound of general formula (II) is reacted with an alkali metal phthalimide - in particular phthalimide potassium.  The reaction is carried out in a suitable solvent (e.g. B.  Dimethylformamide or acetone) with heating - in particular at about 100 "C or at the boiling point of the solvent - carried out. 



   The compound of the general formula (Ik) thus obtained can be converted into the corresponding compound of the general formula (I1) by reduction with hydrazine. 



  The reaction can be carried out in a suitable organic solvent, e.g. B.  in chlorinated hydrocarbons, such as dichloromethane, dichloroethane or chloroform. 



   A compound of the general formula (I1) can be converted into the corresponding compound of the general formula (Im) by condensation with a 2,6-dihalobenzaldehyde.  The reaction can advantageously be carried out in the presence of an organic base, such as triethylamine.  You can advantageously in a suitable organic solvent (such as alkanols z. B.  Ethanol, etc.) work.  The reaction is carried out with heating, advantageously at the boiling point of the reaction mixture. 

 

   A compound of the general formula (Im) obtained can be reduced to the corresponding 2,6-dihalobenzyl derivative.  Complex metal hydrides (e.g. B.  Sodium borohydride) can be used.  The reduction can be carried out in a suitable organic solvent (e.g. B.  Section.  Alkanols such as methanol) can be carried out.  The procedure can be advantageous by carrying out the addition of the complex metal hydride with cooling and then heating the reaction mixture to boiling. 



   A compound of the general formula (I1) obtained can be reacted with a p-alkanoylamidobenzosulfonic acid chloride to give the corresponding compound of the general formula (In).  The reaction is advantageously carried out in the presence of an acid binder (e.g. B.  organic bases such as triethylamine).  Suitable organic solvents, advantageously chlorinated hydrocarbons (such as dichloromethane, dichloroethane, chloroform, etc.), can be used as the reaction medium. It is advantageous to work at room temperature. 



   A compound of the general formula (In) obtained can be converted into the corresponding p-aminophenylsulfonyl derivative by hydrolysis. 



   The hydrolysis can be carried out in an acidic medium, in particular with a mineral acid, advantageously hydrochloric acid.  Because of the nitration, nitric acid cannot be used.  The reaction is carried out with heating. 



   A compound of the general formula (I1) can also be reacted with a dialkylamino alkyl halide - expediently with a chloride.  This reaction gives compounds of the general formula (Ij), in which R "3 is hydrogen and R" 4 is a dialkylaminoalkyl group.  The reaction is advantageously carried out in the presence of an acid binder, such as organic bases, especially triethylamine.  The reaction is carried out in a suitable organic solvent (e.g. B.  Alkanols such as ethanol) are carried out with heating. 



   Salt formation is carried out in a known manner by reacting a compound of the general formula (I) with an approximately molar equivalent amount of the corresponding acid in a suitable solvent. 



   The compounds of general formula (I) thus obtained can be isolated and purified by methods known per se. 



   As a result of the reactivity of the bromine atom in the allyl position, the compounds of the general formula (II) used as starting material are very reactive and are suitable for the preparation of various isoxazole derivatives.  The 3-substituted-4-halogeno-5-bromomethyl derivatives of the general formula (11) can be prepared as follows: acetylacetone is reacted with sulfuryl chloride, the 3-chloro-acetyl-acetone obtained is converted into the 3 by reaction with hydroxylamine 5-Dimethyl-4-chloro-izoxazole transferred.  The corresponding bromine and iodine derivatives are obtained by bromination carried out in the presence of nitric acid or  Iodination of 3,5-dimethyl-isoxazole prepared. 

  By reacting the 3,5-dimethyl-4-halogeno-isoxazoles with N-bromo-succinimide, almost exclusively the corresponding 3-methyl-4-halogeno-5-bromomethyl-isoxazoles are obtained. 



   The compounds of the general formula (III) are known or  can be produced by methods known per se. 



   The starting materials of the general formula (IV) can be obtained by reacting a compound of the general formula (11) with a compound of the general formula (XIX)
EMI6. 1
 (wherein R5 and Rb have the meaning given above).  The reaction can be carried out in the presence of an alkali alcoholate (advantageously sodium methylate) in the corresponding alkanol (advantageously methanol) with heating. 



   The starting materials of the general formula (V) can be obtained by reacting a compound of the general formula (II) with a compound of the general formula (XX)
EMI6. 2nd
 (wherein R7 and Rs have the above meaning and Y represents hydrogen or alkali metal).  The reaction can be carried out in the presence of a suitable organic solvent (such as tetrahydrofuran or dimethylformamide) between 20 ° C. and 100 ° C., advantageously in the presence of triphenylphosphine. 



   The starting materials of the general formula (VI) can be prepared by reacting a compound of the general formula (II) with a compound of the general formula (XXI)
EMI6. 3rd
 (where Rs has the above meaning).  The reaction can advantageously be carried out in an aqueous alkanol in the presence of an approximately equivalent amount of alkali hydroxide with heating. 



   The starting materials of the general formula (VII) can be prepared by reacting a compound of the general formula (II) with a compound of the general formula (XXII)
EMI6. 4th
 (in which Rio and R1 have the above meaning).  The reaction can advantageously in the presence of an alkali (z. B. 



  Sodium or potassium hydroxide). 



   The starting materials of the general formula (VIII) can be prepared by reacting a compound of the general formula (II) with a compound of the general formula (XXIII)
EMI6. 5
 (where Ru2 has the above meaning).  The reaction is advantageously carried out in the presence of an acid binder.  For this purpose, organic bases (e.g. B.  Triethylamine) can be used.  Suitable organic solvents (e.g. B.  Dimethylformamide) can be used.  It is advantageous to work with heating at about 40-80 C, preferably at about 60 "C.    



   The starting sites of the general formula (IX) can be reacted with a compound of the general formula (11) with a metal alkanoate (e.g. B.  Potassium acetate) in a suitable r. osl; ngsmittel (z. B.  Dimethylformamide) with heating (advantageously at about 60 "C). 



   The compounds of the general formula (XII) are known or can be prepared in a manner known per se. 



   The starting materials of the general formula (XIII) can be prepared as follows:
A compound of general formula (le) is mixed with an alkali metal thiocyanate (e.g. B.  Potassium thiocyanate) in an acidic medium (e.g. B.  in hydrochloric acid) with heating (e.g. B.  at 90-95 "C) converted to a compound of general formula (XXIV)
EMI7. 1
 (where R and R2 have the above meaning).  These compounds of the general formula (XXIV) can also be prepared by reacting a compound of the general formula (Ie) with benzoyl isothiocyanate and subsequent alkaline treatment.  The first stage of this process can advantageously be carried out in a suitable organic solvent (e.g. B. 

  Acetone) at room temperature and the second step with an alkali hydroxide (e.g. B.  aqueous potassium hydroxide) with heating (at about 100 "C).  The compound of general formula (XXIV) thus prepared is treated with mercury oxide in a suitable solvent (e.g. B.  a mixture of chloroform and water) at room temperature into the corresponding compound of general formula (XIII). 



   The starting materials of the general formula (XVII) can be prepared by reacting a compound of the general formula (II) with p-aminoethanol.  The reaction can be carried out in a suitable solvent and in the presence of an acid binder (e.g. B.  in acetone or water in the presence of alkali carbonate or  in dimethylformamide or hexamethylphosphoric acid triamide in the presence of triethylamine).  The reaction temperature is between about 20 "C and the boiling point of the solvent. 



   The starting materials of the general formula (XVIII) can be prepared by converting a compound of the general formula (11) into a compound of the general formula (XXV)
EMI7. 2nd
 (where R and R are as above).  The reaction can be carried out either with hexamethylenetetramine in a suitable solvent (e.g. B.  Ethanol) with heating and subsequent acidic hydrolysis or with alkali metal phthalimide in a suitable solvent (e.g. B.  Dimethylformamide) with heating (e.g. B.  at about 100 C); or with hydrazine in a suitable solvent (e.g. B.  Dichloromethane) at about 20 "C. 

  The compound of the general formula (XXV) thus obtained (in which R and R have the above meaning) is converted into the corresponding compound of the general formula (XVIII) by reaction with bromoacetyl bromide.  This reaction can be carried out in a suitable solvent (e.g. B.  a mixture of acetone and water) in the presence of an acid binding agent (e.g. B.  inorganic bases such as sodium carbonate) can be carried out at room temperature. 



   The novel compounds of general formula (I) according to the invention have a strong and relatively long-lasting, hypotensive effect, with some representatives of this group of compounds also having an anti-inflammatory and antipyretic effect. 



   The greatest reduction in blood pressure in mice and rabbits was caused by the 3-methyl-4-chloro-isoxazol-5-yl-methyleneoxy-guanidine and the 3-methyl-4-chloro-5- (bromoethylaminomethyl) isoxazole hydrochloride.  In cats, a fortieth of the LDsn dose (i. v.  on mice) of 3-methyl-4-chloro-isoxazol-5-yl-methylenoxy-guanidine i. v.  blood pressure by 40%; one twentieth of the LDsn dose (i. v.  in mice) of 3-methyl-4-chloro-5- (bromethylamino-methyl) -isoxazole hydrochloride lowers the blood pressure of cats i. v.  by 44%. 

  In anesthetized cats, one tenth of the LDsii dose (i. v.  in mice), administered enterally, a strong and permanent decrease in blood pressure.  30 minutes after the administration, the blood pressure is around 25% or  18% and 90 minutes after administration by 33% or  48% lower than before entering the test substance. 



  None of the above connections significantly affect heart rate.  One tenth of the LDso dose (i. v. ) of L-a-methyl-dopa, when administered enterally, lowers rabbit blood pressure by 34% 30 minutes after administration and by 37% 90 minutes after administration. 



  This means that the potency of 3-methyl-4-chloro-isoxazol-5-yl-methylenoxy-guanidine and 3-methyl-4-chloro-5- (bromoethylaminomethyl) isoxazole hydrochloride is of the same order of magnitude as that of La -Methyl dopa.  The advantage of the novel compounds according to the invention is that they are effective both by oral and intravenous administration, whereas the L-a-methyl-dopa i. v.  is ineffective. 



   One twentieth of the LDso dose (i. v.  on mice) of the following compounds of general formula (I) i. v.  in anesthetized cats, a strong but short-term drop in blood pressure causes: 3-methyl-4-chloro-5-aminooxymethyl-isoxazole; 3-methyl-4-bromo-5-aminooxymethyl isoxazole; N- (3-methyl-4-chloro-isoxazol-5-yl-methyleneoxy) urea; 3-methyl-4-chloro-5- (N, N-diethylaminomethyl) isoxazole hydrochloride; 3-methyl-4-bromo-5- (N, N -diethylaminomethyl) isoxazole hydrochloride; 3-methyl-4-chloro-5- (N-cyclohexylaminomethyl) isoxazole hydrochloride; 3-methyl-4-chloro-5- (N-morpholinomethyl) isoxazole hydrochloride. 

 

   The diuretic effect of the N- (3-methyl-4-chloro-isoxazol-5-yl-methyleneoxy) urea significantly exceeds that of theophylline.  The 3-methyl-4-chloro-isoxazol-5-yl-methylamine hydrochloride has a permanent hypotensive effect, but causes bradycardia.  The strong antipyretic effect of 3-methyl-4-bromo-5- (Nmorpholinomethyl) isoxazole hydrochloride is remarkable.  A tenth of the LDsn dose of this compound lowers the pyorogoral fever in rabbits to the same extent as a 20 mg / kg dose of amidazophen. 



   The anti-inflammatory activity of the compounds according to the invention is demonstrated by the following experiment.  One tenth of the LD5 (dose (i. v.  in mice), rats were administered and the inhibition of the odor induced by local input of 0.05 ml / 3 mg dextran was determined. 

  The results obtained are summarized in the table below: Test compound inhibition of edema,% 3-methyl-4-chloro-5-aminooxymethyl-38 isoxazole 3-methyl-4-chloro-5- (N-morpholino-36 methyl) -isoxazole hydrochloride 3-methyl-4-chloro-5- (bromoethylamino-34 methyl) -isoxazole hydrochloride 3-methyl-4-chloro-isoxazol-5-yl- 32 methyleneoxy-guanidine 3-methyl-4-chloro 5- (N-cyclohexylamino-29 methyl) isoxazole hydrochloride
The invention furthermore relates to pharmaceutical preparations which contain as active ingredient a compound of the general formula (I) or a pharmaceutically suitable acid addition salt thereof and suitable, inert, solid or liquid pharmaceutical carriers. 

  The active ingredient can according to known methods of the pharmaceutical industry and using conventional pharmaceutical carriers and excipients (z. B.  Talc, calcium carbonate, magnesium stearate, chalk, water, polyalkylene glycols, starch, etc.) can be formulated.  The pharmaceutical preparations can be used as solid (e.g. B.  Tablets, capsules, suppositories, coated tablets, etc.) or liquid (e.g. B.  Solutions, suspensions or emulsions). 



   The daily dose of the active ingredients of the general formula (I) depends on the circumstances of the given matter (e.g. B.     the condition of the patient, etc.) and is prescribed by the doctor. 



   Further details of our invention can be found in the examples below, without restricting the scope of protection to these examples. 



   The preparation of the compounds of the general formula (11) used as starting material is described in Preparation Examples 1 and 2. 



   Production Example 1
Preparation of 3-methyl-4-halogen-5-bromomethyl-isoxazole derivatives
0.1 mol of the corresponding 3,5-dimethyl-4-halogeno-isoxazole is dissolved in 150 ml of anhydrous carbon tetrachloride.  After adding 0.5 g of benzoyl peroxide, the solution is heated to boiling.  0.12 mol of N-bromo-succinimide is added to the mixture in small portions over an hour and a half, after which the reaction mixture is heated to boiling for a further 4-5 hours. 



  After cooling, the excreted succinimide is filtered off.  The remaining syrup-like 3-methyl-4-halogen5-bromomethyl-isoxazole can be used for further reactions without further purification.  Yield: 90-100%.    



   Production Example 2
Preparation of 3-phenyl-4-ethoxycarbonyl-5-bromomethyl-isoxazole
The compound mentioned in the title is prepared from the 3-phenyl4-ethoxycarbonyl-5-methyl-isoxazole in an analogous manner to Example I. 



   Example 3
Preparation of 3-methyl-4-halogeno-5- (2 '2' -di / ethoxy-carbonyl / -2 '-acetamido-ethyl) -isoxazole derivatives
0.1 mol of sodium hydride is suspended in 25 ml of anhydrous N, N-dimethylformamide, after which a solution of 0.1 mol of diethylacetamidomalonate and 45 ml of anhydrous dimethylformamide is added in small portions with stirring.  The mixture is stirred at room temperature for 12 hours, then a solution of 0.1 mol of 3-methyl-4-halogeno-5-bromomethyl-isoxazole and 15 ml of anhydrous dimethylformamide is added dropwise and stirring is continued for 12-24 hours.  The reaction mixture is poured onto about 1 kg of crushed ice, the slowly settling oily precipitate is filtered off and the filter cake is washed with a mixture of ether and petroleum ether (1: 1). 

  The crude 3-methyl-4-halogen-5- (2 ', 2 -di- / ethoxycarbonyl / -2' -acetamido-ethyl) -isoxazole obtained is recrystallized. 



   4-chloro derivative, yield 50%, F. : 111-112 "C.    



   Recrystallization from a mixture of ethanol and water Analysis: Ber. : C 48.49%; H 5.52%; N 8.08%; Cl 10.22% found : C 48.13%; H 5.47%; N 8.05%; Cl 10.35%
4-bromo derivative, yield: 48%.  F. : 118-119.5 "C Analysis: calc. : C 42.99%; H 4.89%; N 7.16% found. : C 42.95%; H 4.99%; N 7.14%
4-iodine derivative, yield: 15%, F. : 97-99 "C recrystallization from a mixture of ethanol and water Analysis: Ber. : C 28.37%; H 4.37%; N 6.38% found. : C 38.38%; H 4.42%; N 6.38%
Example 4
Preparation of DL-3-methyl-4-halo-isoxazol-5-ylalanine hydrochloride
0.1 Moi 3-methyl-4-halogeno-5- (2 ', 2' -di / ethoxycarbonyl / -2'-acetamidoethyl) isoxazole is mixed with 220 ml concentrated hydrochloric acid at 1 00 "C for 8-12 hours hydrolyzed. 

  The solution is clarified with activated carbon, filtered and concentrated to a fifth of the original volume.  The precipitated crystalline precipitate is filtered, dried in a vacuum desiccator over a mixture of calcium chloride and potassium hydroxide and finally recrystallized. 



   4-chloro derivative, yield: 75%, F. : 187-189 "C (decomposition) recrystallization from 6 N hydrochloric acid Analysis: calc. : C34.87%; H4, 18%; N 11.62%; Cd 14.7%: Cl- 14.7% found. : C 34.79%; H 4.16%; N 11.52%; C114.57 (10: Cl- 14.9 "-".    



   4-bromo derivative, yield: 63%, F. : 206-207 "C (decomposition) recrystallization 6 N hydrochloric acid analysis:
Ber. : C 29 * 44, ó; H 3.53Ul'o; N 9.81%;
Cl- 12.41 "i1; Br 27.99%; Found. : C '9.53%; H 3.609o: N 9.82%; Cl-12.40%; Br 27.98%. 



   4-iodine derivative, yield: 10%, F. : 202-204 "C (decomposition) analysis:
Ber. : C 25.28%; H 3.03% found : C 23.32 so; H 3.13%. 



   Example 5
Production of S- (3-methyl-4-halogen-isoxazol-5-yl) - methyl-isothiourea hydrobromide or  S- (3-phenyl-4-ethoxycarbonyl-isoxazol-5-yl) methyl-isothiourea hydrobromide 0.1 mol of 3-methyl-4-halogen-5-bromomethyl-isoxazole or 0.1 mol of 3-phenyl-4- Ethoxycarbonyl-5-bromomethyl-isoxazole and 0.11 mol of thiourea are heated in 30 ml of anhydrous ethanol for 2-3 hours.  The cooled dark solution is clarified with activated carbon and diluted with about 60-100 ml of anhydrous ether.  The separated white crystals are filtered, washed with anhydrous ether and recrystallized. 



   3-methyl-4-bromo derivative, yield: 49%, F. : 173-174 "C
Recrystallization from anhydrous ethanol Analysis: Ber. : C 21.77%; H 2.74%; N 12.68%; S 9.68% found : C 21.52%; H 2.71%; N 12.60%; S 9.85%. 



   3-methyl-4-iodine derivative, yield: 40%, F. : 168-171 C.
Recrystallization from anhydrous ethanol Analysis: Ber. : C 19.06%; H 2.40%; N 11.11%; S 8.48% found : C 18.86%; H 2.33%; N 11.30%; S 8.50%. 



   3-phenyl-4-ethoxycarbonyl derivative, yield: 50%, F. : 200-202 "C (decomposition) recrystallization from anhydrous ethanol Analysis: Ber. : C 43.52%; H 4.17%; N 10.87%; S 8.29% found : C 43.21%; H 4.12%; N 10.87%; S 8.37%. 



   Example6
Preparation of 3-methyl-4-halogen-5- (phthalimido-oxymethyl) isoxazole derivatives
0.1 mol of 3-methyl-4-halogen-5-bromomethyl-isoxazole is dissolved in 120 ml of anhydrous dimethylformamide.  After adding 0.11 mol of N-hydroxy-phthalimide and 0.11 mol of triethylamine, the mixture is heated in a water bath (temperature 100 ° C.) for 2 hours for 2 hours.  The reaction mixture is cooled, diluted with cold water, the crystalline precipitate which has separated out is filtered off, washed with cold water and recrystallized. 



   4-chloro derivative, yield: 89%, F. : 152-153 "C.     Recrystallization from ethanol Analysis: Ber. : C 53.54%; H 3.10%; N 9.57%; Cl 12.11% found : C 53.08%; H 2.99%; N 9.58%; Cl 12.15, ó.    



   4-bromo derivative, yield: 90%, F. : 154-156 "C.    



   Recrystallization from a mixture of ethanol and water Analysis: Ber. : C 46.31%; H 2.59%; N 8.31%; Br 23.7%; Gef. : C 47.00%; H 2.59%; N 8.25%; Br 23.67%. 



   Example 7
Preparation of 3-methyl-4-halogen-5-aminooxymethylisoxazole hydrochloride
0.14 mol of 3-methyl-4-halogeno-5- (phthalimido-oxymethyl) isoxazole is dissolved in 500 ml of anhydrous dichloromethane or dichloroethane.  After adding 60 g of 98% hydrazine hydrate, the mixture is stirred for 16-20 hours at room temperature.  The phtahloyl hydrazide which has separated out is filtered off, washed with dichloroethane, the filtrate is combined with the washing liquids and evaporated to dryness.  The residue is taken up in 200 ml of anhydrous ether, the ethereal solution is dried over magnesium sulfate, concentrated to about a third and saturated with dry hydrogen chloride gas.  The precipitated product is filtered, washed with anhydrous ether and recrystallized. 



   4-chloro derivative, yield: 87%, F. : 189-200 "C.    



   Recrystallization from anhydrous ethanol Analysis: Ber. : 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%. 



   4-bromo derivative, yield: 83%, F. : 180-182 "C.    



   Recrystallization from anhydrous ethanol Analysis: Ber. : C 24.66%; H 3.11%; N 11.5%;
Cl- 14.56%; Br 32.80% found : C 25.11%; H 3.08%; N 11.37%;
Cl- 14.50%; Br 32.72%. 

 

   Example 8
Production of N- (3-methyl-4-halo-isoxazol-5-yl-methyleneoxy) urea
0.05 mol of 3-methyl-4-halogeno-5-aminooxymethyl-isoxazole hydrochloride is dissolved in 35 ml of water, after which a solution of 0.055 mol of potassium cyanate and 45 ml of warm water is added.  The reaction mixture is boiled for half an hour, clarified with activated carbon and filtered off hot.  After the solution has cooled, the target product crystallizes, which is filtered and washed with water. 



   4-chloro derivative, yield: 85%, F. : 157-158 C recrystallization from water Analysis: Ber. : C 35.04%: H 3.92%; N 20.43% Cl 17.940, 'o Found. : C 34.83%; H 3.87%; N 20.59%: Cl 17.18%.      



   4-bromo derivative, yield: 60%, F. : 163 C. 



   Recrystallization from water Analysis: Ber. : C 28.82%; H 3.22%; N 16.8%; Br 31.95% found : C 29.110 / 0; H 3.16%; N 16.78%; Br 31.82%. 



   Example 9
Preparation of 3-methyl-4-chloro-isoxazol-5-ylmethylenoxyguanidin
1.8 g of gyanamide are added to a solution of 0.04 mol of 3-methyl-4-chloro-5-aminooxymethyl-isoxazole and 40 ml of water.  The solution is left to stand at room temperature for 12-14 hours, then heated at 100 C for 40 minutes and concentrated to dryness under reduced pressure.  The crystalline mass obtained is recrystallized.  The pure compound mentioned in the title is obtained in a yield of 75%, melting point: 176-178 ° C. (after recrystallization from a mixture of ethanol and diethyl ether). 



  Analysis: Ber. : C 29.89%; H 4.18%; N 23.24%; Cl 14.70%;
Cl- 14.70% found : C 29.91%; H 4.68%; N 23.40%; Cl 14.62%;
Cl- 14.59%. 



      Example 10
Preparation of 3-methyl-4-chloro-5- (phthalimidomethyl) isoxazole
0.1 mol of 3-methyl-4-chloro-5-bromomethyl-isoxazole are dissolved in 50 ml of dimethylformamide or anhydrous acetone.  After adding 0.15 mol of phthalimide potassium, the reaction mixture is kept at a temperature of 1000 ° C. for 5 hours.  After cooling, the mixture is poured onto about 0.5 kg of crushed ice, the crystalline precipitate is filtered and washed with ice-cold ethanol.  The crude product is dried and recrystallized.  The compound mentioned in the title is obtained in a yield of 60%. 

  F. : 124-1 26'C.     (after recrystallization from ethanol) Analysis: Ber. : C 56.43 - / 0; H 3.28%; N 10.12%; Cl 12.81% found : C 56.29 <, "; H 3.28%; N 12.12%; Cl 12.86%.



   Example 11
Preparation of 3-methyl-4-chloro-isoxazol-5-yl-methyl amine hydrochloride
0.1 mol of 3-methyl-4-chloro-5- (phthalimidomethyl) isoxazole is dissolved in 250 ml of anhydrous dichloromethane, whereupon 52 g of 98% hydrazine hydrate are added. The reaction mixture is stirred for 24 hours at room temperature and out The compound mentioned in the title is obtained in a yield of 82%. F .: 178-80 ° C. (decomposition after recrystallization from anhydrous ethanol).



  Analysis: 13er .: (32.80 "(,: H 4.40U-0; N 15.30; Cl 19.23%; Cl- 19.23" r Found: (32.68 "; H 4.36 ' ! f,: N 15.470, ó Cl 19.25 'o; Cl- 19.40 "".



   Example 12
Production of 3-methyl-4-halogen-5- (N, N-diethylamino-methyl) -isoxazole hydrochloride
0.1 mol of 3-methyl-4-halogen-5-bromomethyl-isoxazole is dissolved in 80 ml of anhydrous ethanol. After adding 0.22 mol of diethylamine, the reaction mixture is heated to boiling for 2 hours; concentrated to about a third, diluted with 120 ml water and extracted three times with 20 ml ether. The ethereal solution is washed three times with 15 ml of water, dried over magnesium sulfate and saturated with hydrogen chloride gas in the cold. The precipitated product is filtered, washed with anhydrous ether and recrystallized.



   4-chloro derivative, yield: 82%, m .: 190-192 "C.



  Analysis: Calc .: C 45.19%; H 6.74%; N 11.71%; Cl 14.82%;
Cl- 14.82%.



   Found: C 45.62%; H 6.68%; N 11.70%; Cl 14.68%;
Cl- 14.81%.



   4-bromo derivative, yield: 85%, m .: 198-200 "C.



   Recrystallization from anhydrous ethanol Analysis: Calc .: C 38.00%; H 5.67%; N 9.81%;
Cl- 12.46%: Br 28.09%.



  Found: C 37.68%; H 5.62%; N 9.60%;
Cl- 12.43%; Br 28.00%.



   Example 13
Preparation of 3-methyl-4-chloro-5- (N-cyclohexylaminomethyl) isoxazole hydrochloride
0.1 mol of 3-methyl-4-chloro-5-bromomethyl-isoxazole is dissolved in 75 ml of anhydrous ethanol. After adding 0.11 mol of cyclohexylamine and 0.11 mol of triethylamine, the solution is heated to boiling for 2 hours and worked up in the manner described in Example 12. After recrystallization from anhydrous ethanol, the compound mentioned in the title is obtained in a yield of 55%.



      F .: 225-227 C.



  Analysis: Calc .: C 50.00%: H 6.49%; N 10.60%; Cl 13.42%; Cl-13.42%.



  Found: C 49.52%; H 6.38%; N 10.59%; Cl 13.50%;
Cl- 13.69%.



   Example 14
Preparation of 3-methyl-4-chloro-5- (N-piperidino methyl) isoxazole hydrochloride
0.04 mol of 3-methyl-4-chloro-5-bromomethyl-isoxazole is dissolved in 25 ml of anhydrous ethanol, after which 0.44 mol of piperidine and 0.44 mol of triethylamine are added.



  The reaction solution is heated to boiling for 2 hours and worked up in the manner described in Example 12. The compound mentioned in the title is obtained in a yield of 60%. F .: 213-214 "C (after recrystallization from anhydrous ethanol).



  Analysis: Calculated: C 47.82%; H 6.42%; N 11.15%; Cl 14.11%;
Cl- 14.11%.



  Found: C 48.05%; Fi 6.43%; N 11.15%; Cl 14.00%: Cl- 13.97
Example 15
Production of 3-methyl-4-halogen-5- (N-morpholino-methyl) -isoxazole hydrochloride
0.1 mol of 3-methyl-4-hn-5-bromomethyl-isoxazole is dissolved in 80 ml of anhydrous ethanol. After adding 0.11 mol of morpholine and 0.11 mol of triethylamine, the reaction mixture is heated to boiling for 2 hours and worked up in the manner given in Example 12. 4-chloro derivative, yield: 62%, F .: 215-216 "C (after recrystallization from anhydrous ethanol) Analysis: Calc .: C 42.56%; H 5.55%; N 11.03%; Cl 13 , 96%
Cl- 13.96%.



  Found: C 42.96%; H 5.49%; N 11.02%; Cl 13.89%;
Cl- 13.90%.



   4-bromine derivative, yield: 65%, F .: 216-218 "C (after recrystallization from anhydrous ethanol) Analysis: Calc .: C 36.22%; H 4.73%; N 9.45%;
Cl- 11.88%; Br 26.77%.



  Found: C 36.63%; H 4.70%; N 9.52%;
Cl- 11.89%; Br 26.79%.



   Example 16
Preparation of 3-methyl-4-chloro-5- (bromoethylaminomethyl) isoxazole hydrochloride
0.35 mol of 3-methyl-4-chloro-5-bromomethyl-isoxazole is dissolved in 390 ml of anhydrous acetone and the solution is dissolved in cooling at a temperature between -5 C and -10 "C, a solution of 19.6 ml of ethylene imine and 80 ml of anhydrous acetone are added with stirring. The reaction mixture is heated to boiling for 2 hours, cooled and poured into 1 liter of ice-cold water. The excreted viscous substance is extracted once with 200 ml and three times with 100 ml of ether. The ethereal phase is extracted separated from the precipitate (8.2 g, m.p .: 138-141 "C.), washed twice with 400 ml of water each time, dried over magnesium sulfate and concentrated to about a third of the original volume.



   The title compound is precipitated by introducing anhydrous hydrogen chloride. The crude product is recrystallized. The compound mentioned in the title is obtained in a yield of 25%. F .: 164-166 "C (after recrystallization from anhydrous ethanol).



  Analysis: Calc .: C 33.03%; H 4.35%; N 9.66%; Cl 12.22%;
Cl- 12.22%; Br 27.55%.



  Found: C 37.87%; H 4.31%; N 10.05%; Cl 12.28%;
Cl- 12.34%; Br 27.44%.



   Example 1 7
Preparation of 3-methyl-4-chloro-5- (2 ', 6' -dichlorobenzalamino-methyl) -isoxazole
0.065 mol of 3-methyl-4-chloro-isoxazol-5-yl-methylamine hydrochloride is taken up in 50 ml of anhydrous ethanol, after which 0.07 mol of triethylamine and 0.07 mol of 2,6-dichlorobenzaldehyde are added. The reaction mixture is stirred for one hour, clarified with activated carbon and filtered off hot. After cooling, the crystals which have separated out are filtered and recrystallized. The compound mentioned in the title has a yield of 60%. F .: 86.5-87.5'C. (after recrystallization from ethanol).



  Analysis: Calculated: C 47.47%; H 2.99%; N 9.23%; Cl 35.04% Found: C 48.01; H 3.00%; N 9.22%; Cl 35.11.



   Example 18
Preparation of 3-methyl-4-chloro-5- (2 ', 6' -dichlorobenzylamino-methyl) -isoxazole hydrochloride
0.01 mol of 3-methyl-4-chloro-5- (2 ', 6' -dichlorobenzalaminomethyl) isoxazole are dissolved in 50 ml of anhydrous methanol. 0.5 g of sodium borohydride are added to the solution with cooling in small portions. During the addition, the benzalamino compound used as the starting material goes into solution. The reaction mixture is heated to boiling for 20 minutes, then cooled and evaporated to dryness. The residue is taken up in ether, the ethereal solution is washed with water and dried over magnesium sulfate. The end product is precipitated by introducing anhydrous hydrogen chloride and recrystallized.

  The compound mentioned in the title is obtained in a yield of 70%.



     F .: 192-194 C (after recrystallization from anhydrous ethanol).



  Analysis: Calculated: C 42.13%; H 3.54%; N 8.19%; Cl 31.10%;
Cl- 10.36% Found: C 41.90%; H 3.31%; N 8.00%; Cl 30.93%;
Cl- 10.48%.



   Example 19
Preparation of 3-methyl-4-chloro-5- (N- / p-acetamidobenzenesulfonamido / -methyl) -isoxazole
90 ml of dichloromethane and 16.2 ml of triethylamine are added to 0.06 mol of 3-methyl-4-chloro-isoxazol-5-ylmethylamine hydrochloride. After 16.2 g of p-acetamido-benzenesulfonyl chloride have been added, the reaction mixture is stirred at room temperature for 16 hours. 90 ml of distilled water are added. The mixture is stirred vigorously. The end product that is separated out is filtered, washed with cold water and recrystallized. The compound mentioned in the title is obtained in a yield of 73%. F .: 183-184 "C (after recrystallization from ethanol).

 

  Analysis: Calc .: C 45.41%; H 4.10%; N 12.22%; S 9.32% Found: C 45.01%; H 4.06%; N 11.97%; S 9.33%.



   Example 20
Preparation of 3-methyl-4-chloro-5- (N- / p-aminobenzenesulfonamido / -methyl / -isoxazole
0.02 mol of 3-methyl-4-chloro-5- (N- / p-acetamidobenzenesulfonamido / -methyl) isoxazole is hydrolyzed with 60 ml of 1 N hydrochloric acid at 100 ° C. for 5 hours. The hot solution is clarified with activated carbon and filtered off. After cooling, the crystalline end product separates, which is filtered off and recrystallized. The compound mentioned in the title is obtained in a yield of 94%. F .: 183-1 840C (after recrystallization from 1 N hydrochloric acid).



  Analysis: Calc .: C 43.78%; H 4.01%; N 13.92%; Cl 11.75%;
S 10.62% Found: C 44.14%; H 3.98%; N 13.50%; C 11.67%;
S 10.61%.



   Example 21
Preparation of 3-methyl-4-chloro-5- (dimethylaminoethylamino methyl) isoxazole hydrochloride
A solution of 0.1 mol of 3-methyl-4-chloro-isoxazol-5-yl-methylamine hydrochloride, 0.1 mol of dimethylaminoethyl chloride hydrochloride and 43 ml of triethylamine in 200 ml of anhydrous ethanol is heated to boiling for 6 hours. The reaction mixture is left to stand at room temperature for 12 hours, the precipitated triethylamine hydrochloride is filtered off, the filtrate is evaporated to dryness, the residue is taken up in 35 ml of anhydrous ethanol and the mixture obtained is again evaporated to dryness. The remaining light yellow syrup is dissolved in anhydrous ether. The compound mentioned in the title is precipitated by introducing anhydrous chlorohydrogen, filtered and dried over potassium hydroxide.

  Yield: 44%, m .: 150-160 "C (decomposition).



  Analysis: Calc .: C 37.19%; H 6.24 / ó; N 14.46% Found: C 37.76%; H 6.18%; N 14.57%.


    

Claims (6)

 PATENT CLAIMS 1. Compounds of general formula I EMI1.1  and acid addition salts thereof, wherein R is Clw alkyl or phenyl; R2 represents halogen or (Cl 1-alkoxy) carbonyl and Rl represents a group of the formula EMI1.2    Guanylthio, bis - [(C 1 4-alkoxy) carbonyl] - [(Cl-4-alkanoyl) amino] methyl, aminooxy, carbamoylaminooxy, guanidinooxy, phthalimidooxy or a group of the general formula -NR3R4,  wherein R3 is hydrogen, Cl-4-alkyl, G-6-cycloalkyl, (o-halogen- (Cx alkyl), di- (CI-4-alkyl) -amino- (Cl-4-alkyl), 2,6- Represents dihalobenzyl or a p-aminophenylsulfonyl group optionally substituted on the nitrogen atom by a Cl-4-alkanoyl group, and R4 is hydrogen or CI-4-alkyl or R3 and R4 together form a 2,6-dihalobenzylidene group, or R3 and R4 together with the adjacent nitrogen atom form a phthalimido group, or Ra and R4 together with the adjacent nitrogen atom form a six-membered heterocyclic ring which may also contain an oxygen atom;  with the proviso that if R is methyl and Rl is guanylthio, R2 is different from chlorine.  2. Compounds according to claim 1, in which R represents methyl.  3. Compounds according to claim 1 or 2, characterized in that R2 represents chlorine.  4. 3-methyl-4-chloro-isoxazol-5-yl-methyleneoxy-guanidine; 3-methyl-4-chloro-5- (2-bromoethylaminomethyl) isoxazole; 3-methyl-4-chloro-5-aminooxymethyl isoxazole; and acid addition salts, especially hydrochlorides thereof, as compounds according to claim 1.  5. Pharmaceutical preparations, characterized in that they contain as active ingredient a compound of general formula I or a pharmaceutically suitable acid addition salt thereof and inert, solid or liquid pharmaceutical carriers and auxiliaries.  6. Pharmaceutical preparations according to claim 5, characterized in that they are 3-methyl-4-chloroisoxazol-5-yl-methylenoxy-guanidine or 3-methyl-4-chloro5- (2-bromoethylaminomethyl) -isoxazole or acid addition salts, in particular as the active ingredient Hydrochloride thereof.  The present invention relates to new isoxazole derivatives and pharmaceutical preparations containing these compounds.  It is known that 3-hydroxy-5-methyl-isoxazole can be used as a crop protection agent [Merck Index, 9th edition (1961), page 123]. Partially saturated isoxazole derivatives which can be used as antitumor agents have been described in Tetrahedron Letters 2549 (1973) and in J. Antib. 28A, (1975).  The invention relates on the one hand to new isoxazole derivatives of the general formula (I) EMI1.3  and acid addition salts thereof, wherein R is Cl-4 alkyl or phenyl; R2 represents halogen or (Cl-4-alkoxy) carbonyl and Rl represents a group of the formula EMI1.4  Guanylthio, bis - [(CI-4-alkoxy) carbonyl] - [(Cl-4-alkanoyl) amino] methyl, aminooxy, carbamoylaminooxy, guanidinooxy, phthalimidooxy or a group of the general formula -NR3R4, where R3 is hydrogen , C1-4-alkyl, C3-6-cycloalkyl, e3-halogen- (CI-4-alkyl), di- (C14-alkyl) -amino- (Ci-4-alkyl), 2,6-dihalobenzyl or one,  p-amino-phenylsulfonyl group optionally substituted by a Cl-alkanoyl group on the nitrogen atom and R4 is hydrogen or CI-4-alkyl or R3 and R4 together form a 2,6-dihalobenzylidene group, or R3 and R4 together with the adjacent one Nitrogen atom form a phthalimido group; or R3 and R4 together with the adjacent nitrogen atom form a six-membered heterocyclic ring which may also contain an oxygen atom; with the proviso that if R is methyl and Rl is guanylthio, R2 is different from chlorine.  The term lower alkyl group used in the description means straight-chain or branched saturated aliphatic hydrocarbon groups with 1-4 carbon atoms (e.g. methyl, methyl, n-propyl, isopropyl, n-butyl, etc.). The alkoxy portion of the lower alkoxycarbonyl groups can be straight or branched and contain 1-4 carbon atoms (e.g. methoxy, ethoxy, n-propoxy, isopropoxy, etc.). The term halogen atom includes the chlorine, bromine, fluorine and iodine atoms. The term C3-6 cycloalkyl group can e.g. represent cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl. The term aryl group refers to mono- or bicyclic, optionally substituted, aromatic hydrocarbon groups. The term Cl-4-alkanoyl group refers to the acid residue of lower alkane carboxylic acids (e.g. acetyl, propionyl, butiryl, etc.). The heterocyclic ring formed by R3 and R4 and the adjacent nitrogen atom can e.g. be a piperidino or morpholino ring.    An advantageous connecting group of the general formula (I) are those derivatives in which R represents methyl. Another advantageous connecting group of the general formula (I) are those derivatives in which Rz denotes chlorine.  Particularly advantageous representatives of the compounds of the general formula are the following derivatives: 3-methyl-4chloro-isoxazol-5-yl-methyleneoxy-guanidine and 3-methyl-4-chloro-5- (bromoethylaminomethyl) isoxazole and acid addition salts, especially hydrochlorides thereof .  The acid addition salts of the compounds of the general formula (I) can be salts formed with pharmaceutically suitable, inorganic or organic acids (e.g. hydrochlorides, hydrobromides, sulfates, phosphates or ** WARNING ** End of CLMS field could overlap beginning of DESC **.