GB2075009A

GB2075009A - Isoxazoles

Info

Publication number: GB2075009A
Application number: GB8108545A
Authority: GB
Original assignee: Egyt Gyogyszervegyeszeti Gyar
Current assignee: Egyt Gyogyszervegyeszeti Gyar
Priority date: 1980-03-19
Filing date: 1981-03-18
Publication date: 1981-11-11
Also published as: HU180567B; FI70011B; IT1211010B; SU1152518A3; SE454695B; YU42560B; ES8302674A1; SU1158044A3; DK151959C; DK23087A; DK153549B; CH646157A5; JPS56158774A; DK151959B; ES501095A0; SE8101703L; ES511894A0; GB2075009B; DE3110817A1; DK23187A

Abstract

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

Description

SPECIFICATION New Isoxazole Derivatives, Compositions Containing Them and a Process for their Preparation This invention relates to new isoxazole derivatives, pharmaceutical compositions containing the same, and a process for the preparation thereof.

It is known that 3-hydroxy-5-methylisoxazole can be used as plant-protecting agent [Merck Index, 9. (1961), page 123.]. Partially saturated isoxazole derivatives used as tumor-inhibiting agents are described in Tetrahedron Letters 2549 (1973) and in J. Antib. 28A, 91(1975).

According to a feature of the invention there are provided new isoxazole derivatives of the general formula (I)

wherein R represents a C,, alkyl or a phenyl group, R2 stands for a halogen atom or a (C14 alkoxy)-carbonyl group, R1 represents a group of the formula -CH(NH2) COOH, or a guanyl-thio, a bis-(C1 < aIkoxycarbonyl-(C1)alkanoyl-a mido)-methyl, an amino-oxy, a carbamoyl-amino-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 C,, alkyl, C38 cycloalkyl, w-halogen-(C1 alkyl), di-(C,, alkyl)-amino-(C,~4 alkyl), 2,6- dihalogenbenzyl group or a p-amino-phenyl-sulfonyl group which latter may be N-substituted by a C,, alkanoyl group, and R4 stands for a hydrogen atom or a C,, 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 R, stands for a guanyl-thio group, R2 may represent only chlorine.

The term "lower alkyl group" refers to straight-chained or branched saturated aliphatic hydrocarbyl groups containing 1-4 carbon atoms, such as methyl, ethyl, n-propyl, isopropyl, and nbutyl. The alkoxy group of the lower alkoxy-carbonyl groups can be straight-chained or branched and contains 1-4 carbon atoms (e.g. methoxy, ethoxy, n-propoxy, isopropoxy, etd.). The term "halogen atom" refers to all the four halogen atoms, i.e. fluorine, chlorine, bromine or iodine. The term "C,, cycloalkyl group" may be cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl group. The term "aryl group" refers to mono- or bicyclic, preferably substituted aromatic hydrocarbyl groups. The term "C,, alkanoyl group" refers to the acyl radical of lower alkane carboxylic acids (e.g. acetyl, propionyl, and butyryl).The heterocyclic ring formed by R3, R4 and the adjacent nitrogen atom may be preferably a piperidino or a morpholino ring.

Preferred representatives of the new compounds having the general formula (I) are those wherein R stands for methyl. Also preferred are the compounds of the general formula (I) wherein R2 represents chlorine.

Of the new compounds of the general formula (I) the following are particularly preferred: 3-methyl-4-chloroisoxazol-5-yl-methyleneoxy-guanidine, 3-methyl-4-chloro-5-/bromoethylamino-methyl/isoxazole and acid addition salts, particularly hydrochloddes, thereof.

The acid addition salts of the compounds of the general formula (I) can be formed with pharmaceutically acceptable inorganic or organic acids (e.g. hydrogen chloride, hydrogen bromide, sulfuric, phosphoric, tartaric, fumaric, maleic, and citric acids).

According to a further feature of the present invention there is provided a process for the preparation of compounds of the general formula (I) in which: a.) to prepare a compound of the general formula (la)

wherein R and R2 have the same meanings as above, and R3 and R4 represent a C,, alkyl group, a compound of the general formula (II)

wherein R and R2 have the same meanings as above, is reacted with a dialkyl-(C,~4 alkanoyl-amido)malonate of the general formula (Ill)

wherein R3 and R4 have the same meanings as above, or b.) to prepare a compound of the general formula (lb)

wherein R and R2 have the same meanings as above, a compound of the general formula (la) is hydrolyzed with simultaneous decarboxylation, or c) to prepare a compound of the general formula (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)

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 (le)

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)

wherein R and R2 have the same meanings as above, R6 and R6 each represent a lower alkyl or aryl group or R5 stands for aryl and Re represents hydrogen, is hydrolyzed in acid medium, or e3) a compound of the general formula (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 (Vl)

wherein R and R2 have the same meanings as above, and Rg stands for hydrogen or phenyl, or a compound of the general formula (ill)

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 (VII I)

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)

wherein R and R2 have the same meanings as above, and Ac represents a C,, 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 sulfonyloxy group, or f) to prepare a compound of the general formula (If)

wherein R and R2 have the same meanings as above, f1) a compound of the general formula (le) is reacted with cyanamide, or f2) a compound of the general formula (Xl)

is heated with a compound of the general formula (le), or f3) a compound of the general formula (le) is reacted with a compound of the general formula (XII)

wherein R13 stands for lower alkyl, or with a salt thereof, or f4) a compound of the general formula (XIII)

wherein R and R2 have the same meanings as above, is warmed with an ammonium halide, or f5) a compound of the general formula (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)

g) to prepare a compound of the general formula (Ig)

wherein R and R2 have the same meanings as above, a compound of the general formula (le) is reacted with alkali cyanate, or h) to prepare a compound of the general formula (Ih)

wherein R and R2 have the same meanings as above, R3, represents a C14 alkyl or a C38 cycloalkyl group, and R4 stands for a hydrogen atom or a C1 -4 alkyl group, or R3, and R4 may form, together with the adjacent nitrogen atom a 6 membered heterocyclic 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)

wherein R3 and R4 have the same meanings as above, or j) to prepare a compound of the general formula (Ij)

wherein R and R2 have the same meanings as above, j1) a compound of the general formula (II) is reacted with ethylene imine, or i2) a compound of the general formula (XVII)

wherein R and R2 have the same meanings as above, is brominated, or j3) a compound of the general formula (XVIII)

wherein R and R2 have the same meanings as above, is reduced, or k) to prepare a compound of the general formula (Ik)

wherein R and R2 have the same meanings as above, and R'3, stands for hydrogen and R'4 may represent hydrogen, di-(C,, aíkyl)-amino-(C1~4 alkyl), 2,6-dihalogen-benzyl or p-amino-phenylsulfonyl optionally N-substituted by a C14 alkanoyl group, or R'3 andR'4, represent together a 2,6-dihalogen-benzylidene group, or R'3 and R'4 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 (II) thus-obtained,

wherein R and R1 have the same meanings as above, is preferably reacted with hydrazine, the compound of the general formula (Im) thus-obtained

wherein R and R2 have the same meanings as above, is preferably condensed with a 2,6-dihalogenbenzaldehyde, the compound of the general formula (In) thus-obtained

wherein R and R2 have the same meanings as above, and Hal is halogen, is preferably reduced with a reducing agent; or if desired, a compound of the general formula (Im) is reacted with a p-(C,, alkanoyl)-amino-benzenesulfonic chloride, the compound of the general formula (Ip) thus-obtained

wherein Rand R2 have the same meanings as above, and Ac represents a C,, alkanoyl group, is preferably hydrolized; or, if desired, a compound of the general formula (Im) is reacted with a di-(C,, alkyl)-amino-(C1 alkyl) halogenide, and, if desired, a compound of the general formula (I) thusobtained is converted into its acid addition salt.

The method a) of the process according to the invention is preferably carried out in the presence 'of an alkali hydride, preferably sodium hydride in dimethylformamide. As reaction medium diethyl ether, tetrahydrofuran, dimethylsulfoxide or benzene can also be used. The reaction can be carried out between 200C and the boiling point of the reaction mixture. The starting material of the general formula (II) and the dialkyl-alkanoyl-amido-malonate is preferably used in an equimolar amount.

According to the method b) of the process according to the invention the hydrolysis of the compound of the general formula (la) is carried out with a mineral acid, preferably with hydrochloric acid or sulfuric acid. Nitric acid can not be used because of the risk of nitration. The reaction can be performed under heating, preferably at about 100 C.

According to the method c) of the process according to the invention a compound of the general formula (II) is reacted with thiocarbamide in an alkanol, preferably in ethanol, in a temperature interval ranging from room temperature to the boiling point of the reaction mixture, preferably under heating.

The reaction according to the method d) is preferably performed in the presence of an acid binding agent. Organic bases, preferably triethylamine can be mentioned as suitable acid binding agents. The reaction can be carried out in a suitable organic solvent (e.g. a ketone such as acetone or hexamethyl-phosphoric acid triamide, or dimethylformamide,). One proceeds preferably under heating, e.g. at about 100 C.

According to the method e1) of the process according to the invention a compound of the general formula (Id) is reacted with hydrazine. The reaction is carried out in an organic solvent. Chlorinated hydrocarbons e.g. dichloromethane, dichloroethane or chloroform are preferably used for this purpose.

The temperature of the reaction can be varied from about 200C to the boiling point of the reaction mixture. The end-product can be preferably converted into its hydrochloride with hydrochloric acid.

According to the method e2) of the process according to the invention a compound of the general formula (IV) is hydrolized in acid medium. The reaction can be preferably carried out with hydrochloric acid, under heating, optionally at about 100 C.

According to the method e3) of the process a compound of the general formula (V) is treated with hydrazine or alkyl hydrazine, preferably n-butyl-hydrazine, and with hydrochloric acid. The reaction can be performed in a chlorinated hydrocarbon or alkanol as reaction medium. One proceeds preferably under heating, at the boiling point of the reaction mixture.

According to the method e4) a compound of the general formula (Vl) or (VII) is subjected to acid hydrolysis. The reaction is optionally carried out with hydrochloric acid under heating, preferably at about 1000C.

The reaction according to the method e5), that is the hydrolysis of the compound of the general formula (VIII), wherein R12 stands for t-butyl, with trifluoroacetic acid is performed at about OOC-- 200 C, preferably at about 1 OOC. The starting compound of the general formula (VIII), wherein R12 represents benzyl, is preferably hydrolized with a mixture of acetic acid and hydrogen bromide under cooling, at about OOC. The reaction mixture is treated first with alkali then with hydrochloric acid. The hydrolysis of the starting materials of the general formula (VIII), wherein R12 is ethyl, is preferably carried out with hydrochloric acid at about room temperature.

According to the method e6) of the process according to the invention a compound of the general formula (IX) is, preferably after desacylation, reacted with a compound of the general formula (X), wherein X stands for halogen, preferably chlorine, or a suifonyl-oxy group preferably methanesulfonyl oxy or toluenesulfonyl-oxy group. On using compounds of the general formula (X), wherein X stands for chlorine, the reaction is preferably carried out in tetrahydrofuran in the presence of sodium methoxide at a temperature of about OOC. When using a compound of the general formula (X), wherein X represents sulfonyl-oxy group, the reaction is preferably performed in the presence of sodium methylate at room temperature.

The reaction according to the method f1) of the process according to the invention is preferably carried out in water, in a mixture of water and an alkanol, in tetrahydrofuran or in dioxane. The temperature may range from 200C to 100 C.

According to the method f2) of the process according to the invention a compound of the general formula (Xl) is heated with a compound of the general formula (le). The reaction is preferably carried out in methanol as reaction medium, at the boiling point of the reaction mixture.

According to the method f3) a compound of the general formula (le) is reacted with a compound of the general formula (XII). The compounds of the general formula (XII), wherein R13 stands for methyl, are preferably used as starting materials. The reaction is preferably performed in water as medium at room temperature.

According to the method f4) of the process according to the invention a compound of the general formula (XIII) is reacted with an ammonium halogenide, preferably with ammonium chloride. The reaction is preferably carried out under heating, preferably in the melt, at 120-1 400C.

According to the method f5) of the process according to the invention a compound of the general formula (XIV) is reacted with a hydroxy guanidine of the general formula (XV) The reaction is preferably carried out in the presence of an alkali alcoholate, preferably sodium methoxide, in the corresponding alkanol, preferably methanol as medium, under heating.

According to the method g) a compound of the general formula (le) is reacted with an alkali cyanate. Potassium cyanate is preferably used for this purpose. As reaction medium water or aqueous alkanol is preferably used. The reaction is carried out at a temperature interval ranging from 200C to the boiling point of the reaction mixture.

The reaction according to the method h) is preferably carried out in the presence of an acid binding agent. An organic bases, e.g. triethylamine, are preferably used for this purpose. The reaction is preferably carried out in an organic solvent (e.g. in an alkanol such as ethanol, etc.), under heating, at the boiling point of the reaction mixture.

According to the method j1) of the process according to the invention a compound of the general formula (I'l) is reacted with ethylene imine. The reaction is preferably carried out in an organic solvent, e.g. acetone. It is preferable to add the ethylene imine to the starting material of the general formula (II) at a temperature of -5-1 00C, and then to heat the reaction mixture to boiling. The end-product is preferably converted into its hydrochloride by precipitating with hydrogen chloride.

According to the method j2) of the process according to the invention a compound of the general formula (XVII) is brominated. Hydrogen bromide, phosphorus tribromide, thionyl bromide or sulfuryl bromide are preferably used for this purpose. The reaction is carried out in a suitable solvent e.g.

dimethyl sulfoxide at a temperature of about 0--200C.

The reduction of a compound of the general formula (XVIII) according to the method j3) can be carried out with boron hydride, preferably with an adduct of boron hydride and tetrahydrofuran. It is preferable to perform the reaction in a suitable solvent, particularly in tetrahydrofuran. The temperature of the reaction is about 0--200C.

According to the method k) of the process according to the invention a compound of the general formula (II) is reacted with an alkali phthalimide, preferably with potassium phthalimide. The reaction is preferably carried out in a solvent, e.g. dimethylformamide or acetone, under heating at about the boiling point of the solvent.

The compound of the general formula (II) thus-obtained can be converted into the corresponding compound of the general formula (Im) by reducing with hydrazine. The reaction is preferably carried out in a suitable organic solvent, e.g. in chlorinated hydrocarbons, e.g. dichloromethane, dichloroethane, or chloroform.

A compound of the general formula (Im) can be converted into the corresponding compound of the general formula (In) by reacting with a 2,6-dihalogen-benzaldehyde. The reaction is preferably carried out in the presence of an organic base e.g. triethylamine, in an organic solvent, e.g. alkanol, such as ethanol. The reaction is performed under heating, preferably at the boiling point of the reaction mixture.

The compound of the general formula (In) thus-obtained can be reduced into the corresponding 2,6-dihalogen-benzyl derivative.

Complex metal hydrides, e.g. sodium boronhydride are preferably used as reducing agents. The reaction is optionally performed in a suitable organic solvent, e.g. anhydrous alcohol such as methanol. It is preferable to add the complex metal hydride under cooling, and then to heat the reaction mixture to boiling.

The compound of the general formula (Im) can be converted into the corresponding compound of the general formula (Ip) with a p-alkanoyl-amido-benzenesulfonic chloride. The reaction is preferably carried out in the presence of an acid binding agent, e.g. organic bases, such as triethylamine. As reaction medium, suitable organic solvents, preferably chlorinated hydrocarbons, such as dichloromethane, dichloroethane, and chloroform can be used. It is preferable to perform the reaction at room temperature.

The compound of the general formula (Ip) thus obtained is hydrolized into the corresponding paminophenyl-sulfonyl derivative. The hydrolysis is preferably carried out under heating in acid medium, preferably with a mineral acid, e.g. hydrochloric acid. Nitric acid can not be used because of the risk of nitration.

A compound of the general formula (Im) is reacted with a diaikyl-amino-alkyl halide, preferably with a chloride. This reaction results in a compound of the general formula (Ik), wherein R'3 stands for hydrogen and R'4 represents a dialkyl-amino-alkyl group. The reaction is preferably carried out in the presence of an acid binding agent, e.g. organic bases, such as triethylamine, in a suitable organic solvent e.g. alkanols, such as ethanol, under heating.

The compounds of the general formula (I) can be converted in a known way into acid addition salts, that is by reacting with about one molar equivalent of an acid in a suitable solvent. The compounds thus-obtained can be isolated by methods known per se.

The compounds of the general formula (II) are, due to the reactivity of the bromine atom in allyl position, very reactive and can be used for the preparation of different isoxazole derivatives.

The 3-substituted 4-halogen-5-bromomethyl derivatives of the general formula (II) can be prepared as follows: Acetyl acetone is reacted with sulfuryl chloride, the 3-chloroacetyl acetone thus-obtained is converted into 3,5-di-methyl-4-chloroisoxazole by reacting with hydroxylamine. The corresponding bromo and iodo derivative is prepared by brominating or iodinating of 3,5-dimethyl-isoxazole in the presence of nitric acid. When reacting 3,5-dimethyl-4-halogen isoxazole with N-bromo-succinimide, awl'most exclusively the corresponding 3-methyl-4-halogen-5-bromomethyl isoxazole is obtained.

The compounds of the general formula (III) are known, and can be produced by known methods.

The starting compounds of the general formula (IV) can be prepared by reacting a compound of the general formula (II) with a compound of the general formula (XIX)

wherein R5 and R6 have the same meanings as above. The reaction can be carried out in the presence of an alkali alcoholate, preferably sodium methoxide in the corresponding alkanol, preferably methanol, under heating.

The starting materials of the general formula (V) can be prepared by reacting a compound of the general formula (II) with a compound of the general formula (XX)

wherein R7 and R8 have the same meanings as above and Y stands for hydrogen or alkali metal.

The reaction can be carried out in the presence of a suitable organic solvent, such as tetrahydrofuran or dimethylformamide between 206C--1000C, preferably in the presence of triphenyl phosphine.

The starting compounds of the general formula (VI) can be produced by reacting a compound of the general formula (II) with a compound of the general formula (XXI)

wherein R9 has the same meaning as above.

The reaction is preferably carried out in an aqueous alkanol in the presence of about one molar equivalent of an alkali hydroxide under heating.

The starting compounds of the general formula (VII) can be produced by reacting compound of the general formula (II) with a compound of the general formula (XXII)

wherein R10 and R11 have the same meanings as above.

The reaction is preferably carried out in the presence of an alkali metal, e.g. 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)

wherein R12 has the same meanings as above.

The reaction is preferably carried out in the presence of an acid binding agent. For this purpose organic bases, e.g. triethylamine are preferably used. As reaction medium, suitable organic solvents (e.g. dimethylformamide) can be used. One proceeds under heating, preferably at about 40--800C, particularly at about 600C.

The starting compounds of the general formula (IX) can be prepared by reacting a compound of the general formula (II) with an alkali alcoholate, e.g. potassium methoxide, in a suitable solvent, e.g.

dimethylformamide, under heating (at about 600C).

The compounds of the general formula (XII) are known or can be prepared by known methods.

The starting materials of the general formula (XIII) can be prepared as follows: A compound of the general formula (le) is converted into a compound of the general formula (XXIV)

wherein R and R2 have the same meanings as above, by reacting with an alkali cyanate (e.g. potassium cyanate) in acid medium, e.g. in hydrochloric acid, under heating e.g. at about 90-950C. The compounds of the general formula (XXIV) can be produced also by reacting a compound of the general 'formula (le) first with benzoyl-isothiocyanate and then with alkali. The first step of the reaction is preferably carried out in a suitable organic solvent, e.g. acetone at room temperature.The second step is performed with an alkali metal hydroxide, e.g. potassium hydroxide, under heating, e.g. at about 100 C. The compound of the general formula (XXIV) thus-obtained can be converted into the corresponding compound of the general formula (Xlil) into mercury oxide in a suitable solvent, e.g. a mixture of chloroform and water at room temperature.

The starting material of the general formula (XVII) can be prepared by reacting a compound of the general formula (II) with P-amino-ethanol. The reaction can be performed in a suitable solvent and in the presence of an acid binding agent, e.g. in acetone or water in the presence of alkali carbonate, in dimethylformamide or hexamethyl-phosphorous triamide in the presence of triethylamine. The temperature can be varied between 200C 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 (II) into a compound of the general formula (XXV)

wherein R and R2 have the same meanings as above.

The reaction can be carried out either with hexamethylene tetramine in a suitable solvent, e.g.

ethanol under heating and then hydrolyzing with an acid or with alkali metal phthalimide in a suitable solvent, e.g. dimethylformamide under heating e.g. at about 100 C, or with hydrazine in a suitable solvent e.g. in dichloromethane at about 200C. The compound of the general formula (XXV) thus obtained can be converted into the corresponding compound of the general formula (XVIII) with bromoacetyl bromide. The reaction can be carried out in a suitable solvent, e.g. a mixture of acetone and water in the presence of an acid binding agent e.g. inorganic bases, such as sodium bicarbonate at room temperature.

The new compounds according to the invention possess strong and relatively prolonged hypotensive effect and certain members of the compounds exerts also antiphlogistic and antipyretic effects.

On cats and rabbits the strongest decrease in blood pressure was achieved with 3-methyl-4chloroisoxazol-5-yl-methyleneoxy-guanidine and 3-methyl-4-chloro-5-(bromomethyl-aminomethyl)isoxazole hydrochloride. On cats the fourtieth part of the LD, dose of 3-methyl-4 chloroisoxazol-5-yi-methyleneoxy-guanidine determined i.v. on mice results in a 40% decrease of blood pressure and the twentieth part of the LDso dose of the 3-methyl-4-chloro-5-(bromomethylaminomethyl) isoxazole hydrochloride determined i.v. on mice results in a 44% decrease.

When administered the tenth part of the LDso dose of the same compounds determined i.v. on mice enterally to anaesthetised rabbits, a strong and permanent decrease in blood pressure was observed. 30 minutes after the administration the blood pressure was lower by 25 and 1 8% respectively, 90 minutes after the administration by 33 and 48% respectively than before. None of the compounds influences essentially the heart-frequence. The tenth part of the LDEo dose (i.v.) of L-ex- methyl-dopa, when administered enterally, decreases the blood pressure of the rabbits by 14% 30 minutes after the administration and by 37% 90 minutes after the administration.This means that the strength of the effect of 3-methyl-4-chloroisoxazol-5-yl-methyleneoxy-guanidine and 3-methyl-4 chloro-5-bromomethylamino-methyl isoxazole hydrochloride is of similar order of magnitude than that of L-a-methyl-dopa. The advantage of the new compounds according to the invention is that they are effective when administered either orally or intravenously while L-a-methyl-dopa is active only when administered i.v.

A tenth of the LDso dose (determined i.v. on mice) of the following compounds of the general formula (I), administered i.v. to anaesthetised cats, gives a strong hypotensive effect of short duration: 3-methyl-4-chloro-5-aminomethyl isoxazole 3-methyl-4-bromo-5-aminooxy-methyl isoxazole N-(3-methyl-4-chloroisoxazol-5-yl-methyleneoxy)carbamide 3-methyl-4-chloro-5-(N,N-diethylaminomethyl)isoxazole hydrochloride 3-m ethyl-4-bromo-5-(N,N-diethyla mino-methyl)isoxazole hydrochloride 3-methyl-4-chloro-5-(N-cyclohexylamino-methyl)isoxazole hydrochloride and 3-methyl-4-chloro-5-(N-morpholino-methyl)isoxazole hydrochloride.

The diuretic effect of N-(3-methyl-4-chloroisoxazol-5-yI-methyleneoxy)carbamide surpasses significantly that of Theophylline. 3-methyl-4-chloroisoxazol-5-yI-methylamine hydrochloride possesses also a prolonged hypotensive effect, but induces a bradycardic effect. The strong antifebrile effect of 3-methyl-4-bromo-5-(N-morpholino-methyl)isoxazole hydrochloride is remarkable. A tenth of the also dose of this compound causes a similar decrease in the fever produced with pyrogo as 20 mg/kg dose of amidazophen.

The antiinflammatory effect of the new compounds according to the invention was also determined. A tenth of the LD, dose (i.v., on mice) was administered to rats and the inhibition of the oedema induced by local administration of 0.05 ml/3 mg of dextrane was determined. The results obtained are summarized in the following Table: Compound Inhibition of No. of Example oedema (%) 7. (chloro derivative) 38 1 5. (chloro derivative) 36 16. 34 9. 32 13. 29 According to a further feature of the invention there is provided a pharmaceutical composition containing as active agent a compound of the general formula (I) or a pharmaceutically acceptable acid addition salt thereof and suitable inert, non-toxic solid or liquid pharmaceutical carrier.

The carriers may be such generally used in pharmacy e.g. calcium carbonate, magnesium stearate, water, poly-alkylene glycol and starch. The above pharmaceutical compositions can be formulated by known methods in solid e.g. tablets, capsules, dragées, and suppositories, or in liquid form e.g. solutions, suspensions, and emulsions.

The daily dosage of the compounds of the general formula (I) depends on several factors, e.g. the activity of the given compound, and the condition of the patient and is always determined by the physician's prescriptions.

The invention is illustrated by the following Examples of non-limiting character. Examples 1 and 2 describe the preparation of the compounds of the general formula (II) used as starting materials.

Example 1 Preparation of 3-methyl-4-halogen-5-bromomethyl isoxazoles 0.1 mole of the corresponding 3,5-dimethyl-4-halogen isoxazole is dissolved in 150 ml of anhydrous carbon tetrachloride, then 0.5 g of benzoylperoxide are added and the solution is heated to boiling. Thereafter 0.12 moles of N-bromosuccinimide are added in small portions in 1.5 hours, then the mixture is boiled for 4-5 hours. After cooling the solution the separated succinimide is filtered off and the filtrate is evaporated. The residual syrup is 3-methyl-4-halogen-5-bromomethyl isoxazole (about 90-1 00%). which can be used without any further purification.

Example 2 Preparation of 3-phenyl-4-ethoxycarbonyl-5-bromomethyl isoxazole On starting from 3-phenyl-5-methylisoxazole-4-carboxylic ethyl ester, one proceeds as described in Example 1.

Example 3 Preparation of 3-methyl-4-halogen-5-(2',2'-diethoxycarbonyl-2'-acetamidoethyl)isoxazoles 0.1 mole of sodium hydride is suspended in 25 ml of anhydrous N,N-dimethylformamide, then a soiution of 0.1 mole of diethyl-acetamido-malonate in 45 ml of anhydrous N,N-di-methylformamide are added in small portions, under stirring. The mixture is stirred at room temperature for 12 hours, then a solution of 0.1 mole of 3-methyl-4-halogen-5-bromo-methyl-isoxazole in 15 ml of anhydrous N.N-dimethylformamide is dropwise added, and the mixture is stirred further for 12-14 hours.

Thereafter it is poured onto broken ice. The resulting oily substance slowly solidifies. Then it is filtered and the filter cake is washed with a 1:1 mixture of ether and petroleum ether. The crude 3-methyl-4halogen-(2',2'-diethoxycarbonyl-2'-acetamidoethyl)isoxazole is recrystallized.

Chloro derivative: Yield: 50% M.p.: 111-1120C Recrystallization: from the mixture of ethanol and water Analysis calculated: 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 Bromo derivative: Yield: 48% M.p.: 118-1190C Recrystallization: from ethanol Analysis calculated: C%=42.99, H%=4.89, N%=7. 16 found: C%=42.95, H%=4.99, N%=7.14 lodo derivative: Yield: 15% M.p.: 97-990C Recrystallization: from the mixture of ethanol and water Analysis calculated: 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-halogenisoxazol-5-yl-alanine hydrochloride 0.1 mole of 3-methyl-4-halogen-(2',2',-diethoxycarbonyl-2'-acetamidoethyl)isoxazole is hydrolized with 220 ml of concentrated hydrochloric acid at 1 000C for 8-12 hours. The solution is clarified with active carbon, then it is concentrated to a fifth of its previous volume. The separated crystalline precipitate is filtered off, dried in vacuum exsiccator over calcium chloride and potassium hydroxide and recrystallized.

Chloro derivative: Yield: 75% M.p.: 187-1890C (decomp.) Recrvstallization: from 6N HCl Analysis calculated: C%=34.87, H%=4.18, N%=11.62, Cl%=14.7, Cí-%=14.7 found: C%=34.79, H%=4.16, N%=11.52, C1%=14.57, Cl-%=14.9 Bromo derivative: Yield 63% M.p.: 206-2070C (decomp.) Recrystallization: from 6N HCI Analysis calculated: C%=29.44, H%=3.53, N%=9.81, Cl-=1 2.41, Br%=27.99 found: C%=29.53, H%=3.60, N%=9.82, CI-=12.40, Br%=27.98 lodo derivative: Yield: 10% M.p.: 202-2040C (decomp.) Analysis calculated: C%=25.28, H%=3.03 found:C%=23.32, H%=3.13 Example 5 Preparation of (S-3-Methyl-4-halogenisoxazol-5-yl)-methyl-isothiocarbamide Hydrobromide or S-(3-Phenyl-4-ethoxycarbonyl-isoxazol-5-yl)-methyl-isothiocarbamide Hydrobromide 0.1 mole of 3-methyl-4-halogen-5-bromomethyl isoxazole or 0.1 mole of 3-phenyl-4ethoxycarbonyl-5-bromomethyl isoxazole and 0.11 moles of thiocarbamide are boiled in 30 ml of an hydros ethanol for 2-3 hours. The solution is cooled, clarified with active carbon, then diluted with 60-1 00 ml of anhydrous ether. The separated white crystals are filtered off, washed with anhydrous ether and recrystallized from anhydrous ethanol.

3-Methyl-4-bromo Derivative Yield: 49% M.p.: 173-1740C Analysis calculated: 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-4iodo Derivative Yield: 40% M.p.: 168-1710C Analysis calculated: C%=19.06, H%=2.40, N%=11.11, S%=8.48 found: C%=18.86, H%=23.3, N%=11.30, S%=8.50 3-Phenyl-4-ethoxycarbonyl Derivative Yield: 50% M.p.: 200-2020C (decomp.) Analysis calculated: 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 Example 6 Preparation of 3-Methyl-4chloro(bromo)-5-(phthal imido-oxymethyl)isoxazole 0.1 mole of 3-methyl-4-chloro(bromo)-5-bromomethyl isoxazole is dissolved in 120 ml of anhydrous N,N-dimethylformamide, then 0.11 moles of N-hydroxy-phthalimide and 0.11 moles of triethylamine are added and the mixture is kept on a water bath heated to 100 C. Then it is cooled, diluted with water and the separated crystals are filtered off, washed with cold water and recrystallized.

Chloro derivative: Yield: 89% M.p.: 152-153 C Recrystallization: from ethanol Analysis calculated: C%=53.54, H%=3.10, N%=9.57, Cl%=12.11 found: C%=53.08, H%=2.99, N%=9.58, Ci%=12.15 Bromo derivative: Yield: 90% M.p.: 154-1560C Recrystallization: from ethanol/water Analysis calculated: C%=46.31, H%=2.59, N%=8.31, Br%=23.7 found: C%=47.0 , H%=2.59, N%=8.25, Br%=23.67 Example 7 Preparation of 3-Methyl-4-chloro(bromo)5-aminooxymethyl isoxazole Hydrochloride 0.14 moles of 3-methyl-4-chloro(bromo)-5-(phthalimido-oxymethyí)isoxazole are dissolved in 500 ml of anhydrous dichloromethane or dichloroethane, then 60 g of 98% hydrazine hydrate are added and the solution is stirred at room temperature for 1 6-20 hours. The separated phthaloylhydrazide is dissolved, washed with dichloroethane and the filtrate, combined with the wash liquor, is evaporated. The residue is dissolved in 200 ml of anhydrous ether, the solution is dried over magnesium sulfate, concentrated to a third of its previous volume and saturated with anhydrous hydrogen chloride. The separated product is filtered off, washed with anhydrous ether and recrystallized.

Chloro derivative: Yield: 87% M.p.: 198-2000C Recrystallization: from anhydrous ethanol Analysis calculated: 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, C1%=17.77, Cl-%=17.78 Bromo derivative: Yield: 83% M.p.: 180-1820C Recrystallization: from anhydrous ethanol Analysis calculated:C%=24.66, H%=3.11, N%=11.5, Cl-%=14.56, Br%=32.80 found: C%=25.1 1, H%=3.08, N%=11.37, Cl-%=14.50, Br%=32.72 Example 8 Preparation of N-(3-Methyl-4-chloro(bromo)isoxazol-5-yl-methyleneoxy)-carbamide 0.05 moles of 3-methyl-4-chloro bromo-5-aminooxymethyl-isoxazole hydrochloride are dissolved in 35 ml of water under heating, then a solution of 0.055 moles of potassium cyanate in 45 ml of hot water is added. The mixture is boiled for half an hour, clarified with active carbon and, when it is still hot, filtered. The filtrate is cooled, the separated crystals are filtered off and washed with ice-cold water.

Chloro derivative: Yield: 85% M.p.: 157-1580C Recrystallization: from water Analysis calculated: C%=35.04, H%=3.92, N%=20.43, Cl%=17.24 found: C%=34.83, H%=3.87, N%=20.59, Cl%=17.18 Bromo derivative: Yield: 60% M.p.: 1630C Recrystallization: from water Analysis calculated: C%=28.82, H%=3.22, N%=16.8, Br%=31.95 found: C%=29.11, H%=3.16, N%=16.78, Br%=31.82 Example 9 Preparation of 3-Methyl-4-chloroisoxazol-5-yl-methyleneoxy-guanidine 0.04 moles of 3-methyl-4-chloro-5-aminooxy-methyl isoxazole are dissolved in 40 ml of water, 1.8 g of cyanamide are added, and the mixture is allowed to stand at room temperature for 12-14 hours.Then it is heated, kept at 1 000C for 40 minutes and evaporated in vacuo. The crystalline mass thus-obtained is recrystallized from the mixture of ethanol and diethylether.

Yield: 75% M.p.: 176-1780C Analysis calculated: C%=29.89, H%=4.18, N%=23.24, Cí%=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-(phthalimido-methyl)-isoxazole 0.1 mole of 3-methyl-4-chloro-5-bromomethyl isoxazole is dissolved in 50 ml of N,Ndimethylformamide or anhydrous acetone, then 0.15 mole of potassium phthalimide are added and the mixture is kept at 100 C for 5 hours. Then it is cooled, poured onto 0.5 kg of broken ice, the crystalline precipitate is filtered and washed with ice-cold ethanol. After drying the crude product is recrystallized from ethanol.

Yield: 60% M.p.: 124-126 C Analysis calculated: C%=56.43, 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-chloroisoxazol-5-yl-methylamine Hydrochloride 0.1 mole of 3-methyl-4-chloro-5-phthalimido-methyl-isoxazole is dissolved in 250 ml of anhydrous dichloromethane, then 52 g of 98% hydrazine hydrate are added and the mixture is stirred at room temperature for 24 hours. 3-Methyl-4-chloroisoxazol-5-yl-methylamine is separated from the reaction mixture and its hydrochloride is formed. The pure product can be obtained by recrystallization from anhydrous ethanol.

Yield: 82% M.p.: 178-1 800C (decomp.) Analysis calculated: C%=32.80, H%=4.40, N%=15.30, Cl%=19.23, Cl-%=19.23 found: C%=32.68, H%=4.36, N%=15.47, Cl%=19.25, Cl-%=19.40 Example 12 Preparation of 3-Methyl-4-chloro (bro mo)-5-(N,N-diethyla mino-methyl)isoxazole Hydrochloride 0.1 mole of 3-methyl-4-chloro(bromo)-5-bromomethyl-isoxazole is dissolved in 80 ml of anhydrous ethanol, 0.22 moles of diethylamine are added and the solution is boiled for two hours.

Thereafter the mixture is evaporated to a third of its previous volume, diluted with 120 ml of water and extracted thrice with a total amount of 45 ml of ether, washed, dried over magnesium sulfate, then saturated with anhydrous hydrochloric acid. The separated product is filtered off, washed with anhydrous ether and recrystallized.

Chloro derivative: Yield: 82% M.p.: 19O-1920C Analysis calculated: 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 Bromo derivative: Yield: 85% M.p.: 198-2000C Recrystallization: from anhydrous ethanol Analysis calculated: C%=38.00, H%=5.67, N%=9.85, 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-cyclohexylamino-methyl)isoxazole Hydrochloride 0.1 mole of 3-methyl-4-chloro-5-bromomethyl isoxazole is dissolved in 75 ml of anhydrous ethanol, then 0.11 moles of cyclohexylamine and 0.11 moles of triethylamine are added.The solution is boiled for two hours. The title-compound is obtained from the reaction mixture by proceeding in the way described in Example 12.

Yield: 55% M.p.: 225-2270C Recrystallization: from anhydrous ethanol Analysis calculated: C%=50.0, H%=6.49, N%=1 Q.60, Cl%=13.42, Cl-%=13.42 found: C%=49.52, H%=6.38, N%=10.59, CI%=13.50, Cl-%=13.69 Example 14 Preparation of 3-Methyl-4-chloro-5-(N-piperidino-methyl)-isoxazole Hydrochloride 0.04 moles of 3-methyl-4-chloro-5-bromomethyl isoxazole are dissolved in 25 ml of anhydrous ethanol and 0.44 moles of piperidine and 0.44 moles of triethylamine are added. The solution is boiled for 2 hours. The title-compound is obtained from the reaction mixture by proceeding in the way described in Example 1 2.

Yield: 60% M.p.: 213-2140C (decomp.) Recrystallization: from anhydrous ethanol Analysis calculated: C%=47.82, H%=6.42, N%=11.15, C1%=14.11, Cl-%=14.11 found: C%=48.05, H%=6.43, N%=11.15, CI%=14.00, Cl-%=13.97 Example 15 Preparation of 3-Methyl-4-chloro(bromo)-5-(N-morpholino-methyl)isoxazole Hydrochloride 0.1 mole of 3-methyl-4-chloro(bromo)-5-bromomethyl isoxazole is dissolved in 80 ml of anhydrous ethanol, then 0.11 moles of morpholine and 0.11 moles of triethylamine are added and the reaction mixture is boiled for two hours. The title-compound is obtained by proceeding as described in Example 12.

Chloro derivative: Yield: 62%.

M.p.: 215-2160C Recrystallization: from anhydrous ethanol Analysis calculated: C%=42.56, H%=5.55, N%=11.03, Cl%=13.96, Cl-%=13.96 found: C%=42.96, H%=5.94, N%=11.02, Cl%=13.89, Cl-%=13.90 Bromo derivative: Yield: 65% M.p.: 216-2180C Recrystallization: from anhydrous ethanol Analysis calculated: 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 3Methyl-4-chloro-5-(bromoethylamino-methyl)isoxazole Hydrochloride 0.35 moles of 3-methyl-4-chloro-5-bromomethyl isoxazole are dissolved in 390 ml of anhydrous acetone, the solution is cooled to -5 - -1 00C, and a solution of 19.6 ml of ethyleneimine in 80 ml of anhydrous acetone is added, under stirring. Thereafter the reaction mixture is stirred for 2 hours, cooled and poured into 1 litre of icy water. The separated sticky mass is extracted first with 200 ml, then twice with a total amount of 100 ml of ether.The ether phase is separated from the precipitate (8.2 g, m.p.: 138-141 C), washed twice with 400 ml of water, dried over magnesium sulfate, concentrated to a third of its previous volume, and saturated with anhydrous hydrochloric acid. The separated product is filtered off and recrystallized from anhydrous ethanol.

Yield: 25% M.p.: 164-1660C Analysis calculated: C%=33.03, H%=4.35, N%=9.66, Cl%=12.22, Cl-%=1 2.22, found: Br%=27.55 A.31, N%=10.05, C1%=12.28, Cl-%=12.34, %=37.87, Br%=27.44 Example 17 Preparation of 3-Methyl-4chloro-5-(2',6'-dichlorobenzalamino-methyl)isoxazole 0.065 moles of 3-methyl-4-chloroisoxazol-5-il-methyl-amine hydrochloride are dissolved in 50 ml of anhydrous ethanol, then 0.07 moles of triethylamine and 0.07 moles of 2,6dichlorobenzaldehyde are added. The reaction mixture is boiled for an hour, clarified with active carbon and, when it is still hot, filtered. The solution is cooled, the separated crystals are filtered off and recrystallized from ethanol.

Yield: 60% M.p.: 86.5-87.50C 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'-dichlorobenzyl-a mino-methyl)isoxazole Hydrochloride 0.01 mole of 3-methyl-4-chloro-5-2t,6t-dichlorobenzalamino-methyl isoxazole is dissolved in 50 ml of anhydrous methanol and 0.5 g of sodium boron hydride are added in small portions, under cooling. The solution is boiled for 20 minutes, cooled and evaporated. The residue is dissolved in ether, the ether solution is washed with water and dried over magnesium sulfate. The salt of the end-product is separated with anhydrous hydrochloric acid and recrystallized from anhydrous ethanol.

Yield: 70% M.p.: 192194 C (decomp.) 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-%=10.47 Example 19 Preparation of 3-Methyl-4-chl oro-5-[N-(p-acetamido-benzene-sulfonamido)-methyl] isoxazole 90 ml of dichloromethane, 1 6.2 ml of triethylamine and 16.2 g of p-acetamido-benzenesulfonic chloride are added to 0.06 moles of 3-methyl-4-chloroisoxazol-5-yl-methylamine hydrochloride, and the mixture is stirred at room temperature for 16 hours. Then 90 ml of distilled water are added. The end-product separates under vigorous stirring. It is filtered off, washed with cold water and recrystallized from ethanol.

Yield: 73% M.p.: 183-1840C Analysis calculated: 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-amino-benzene-sulfonamido)-methyl]isoxazole 0.02 moles of 3-methyl-4-chloro-5-[N-(p-acetamido-benzene-sulfonamido)-methyl]isoxazole are hydrolized with 60 ml of 1 N hydrochloric acid at 100 C for 5 hours. The hot solution is clarified with active carbon and filtered. The filtrate is cooled, the separated crystals are filtered off and recrystallized from 1 N hydrochloric acid.

Yield: 94% M.p.: 183-1840C Analysis calculated: 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, Cl%=11.67, S%=10.61 Example 21 Preparation of 3-Methyl-4-chloro-5-(dimethylamino-ethylamino-methyl)isoxazole-bis- hydrochloride A solution of 3-methyl-4-chloroisoxazol-5-yl-methyl-amine hydrochloride, 0.1 mole of dimethylamino-ethylchloride hydrochloride and 43 ml of triethylamine in 200 ml of an hydros ethanol is boiled for 6 hours then ailowed to stand at room temperature for 12 hours. The separated triethylamine hydrochloride is filtered off, the filtrate is evaporated, the residue is dissolved in 35 ml of anhydrous ethanol and evaporated again. The residual pale yellow syrup is dissolved in ahydrous ether and the solution is saturated with hydrochloric acid. The separated 3-methyl-4-chloro-5-(dimethylamino-ethylamino-methyl)isoxazole-bis-hydrochloride is filtered off and dried over potassium hydroxide.

Yield: 44% M.p.: 150--1600C (decomp.) Analysis calculated: C%=37.19, H%=6.24, N%=14.46 found: C%=37.76, H%=6.1 8, N%=14.57

Claims

1. An isoxazole derivative of the general formula (I) or an acid addition salt thereof,

wherein R represents a C1 -4 alkyl or a phenyl group, R2 denotes a halogen atom or a (C,, alkoxy)-carbonyl group, R1 represents a group of the formula -CH(NH2)-COOH. or a guanyl-thio, a bis-(C,~4 alkoxycarbonyl-acetamido)-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 alkyl, C34 cycloalkyl, c.)-halogen-(C,~4 alkyl), di-(C,, alkyl)-amino-(C1 < alkyl), 2,6- dihalogenbenzyl group or a p-amino-phenyl-sulfonyl group which latter may be N-substituted by a C,, alkanoyl group, and R4 stands for a hydrogen atom or a C,, alkyl group, or R3 and R4 together represent a 2,6-dihalogen-benzyiidene 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.

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

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

4. 3-Methyl-4-ch loroisoxazo 1-5-yl-methyleneoxy-gua nidine, 3-methyl-4-chloro-5 (bromoethylamino-methyl)isoxazole,3-methyl-4-chloro-5-amino-oxy-methyl isoxazole and acid addition salts thereof.

5. 3-Methyl-4-chloro-5-am inomethyl isoxazole,3-methyl-4-bromo-5-aminooxy-methyl isoxazole, N-(3-methyl-4-chloroisoxazol-5-yl-methyleneoxy)carbamide,3-methyl-4-chloro-5-(N,N- diethylamino-methyl)isoxazole,3-methyl-4-bromo-5-(N,N-diethylamino-methyl)isoxazole,3-methyl-4- chloro-5-(N-cyclohexylamino-methyl)isoxazole, and 3-methyl-4-chloro-5-(N-morpholinomethyl)isoxazole and acid addition salts thereof.

6. The hydr,ochloride of a compound as claimed in claim 4 or claim 5.

7. A pharmaceutical composition comprising a compound of the general formula (I), wherein R, R1 and R2 are as defined in claim 1, or a pharmaceutically acceptable acid addition salt thereof, together with an appropriate inert, non-toxic, solid or liquid pharmaceutical carrier.

8. A pharmaceutical composition as claimed in claim 7 which contains 3-methyl-4 chloroisoxazol-5-yl-methyleneoxy-guanidine,3-methyl-4-chloro-5-(bromo-ethylamino- methyl)isoxazole, 3-methyl-4-chloro-5-aminooxy-methyl isoxazole or an acid addition salt thereof.

9. A process for the preparation of an isoxazole derivative of the general formula (I) or an acid addition salt thereof,

wherein R represents a C,, alkyl or phenyl group, R2 denotes a halogen atom or a (C14 alkoxy)-carbonyl group, R1 represents a group of the formula -CH(NH2)-COOH, or a guanyl-thio, a bis (C~4alkoxycarbonyl-C1~4 alkanoylamido)-methyl, an amino-oxy, a carbamoylamino-oxy, a guanidinooxy, a phthalimido-oxy group or a group of the general formula -NR3R4, wherein R3 stands for a hydrogen atom or a C,, alkyl, C3 cycloalkyl, w-halogen-(C14 alkyl), di-(C,, alkyl)-amino-(C1~4 alkyl), 2,6-dihalogenbenzyl group or a p-amino-phenyl-sulfonyl group which latter may be N-substituted by a C,, alkanoyl group, and R4 stands for a hydrogen atom or a C,, 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, wherein a.) to prepare a compound of the general formula (la)

wherein R and R2 have the same meanings as above, is reacted with a dialkyl-(C,, alkanoylamido)malonate of the general formula (III)

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

wherein R and R2 have the same meanings as above, a compound of the general formula (I) is hydrolyzed with simultaneous decarboxylation, or c.) to prepare a compound of the general formula (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)

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 (le)

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)

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 Re represents hydrogen, is hydrolized in acid medium, or e3.) a compound of the general formula (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)

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)

wherein R and R2 have the same meanings as above, and R10 and R1, stand for lower alkyl or phenyl, is subjected to acid hydrolysis, or yes.) a compound of the general formula (VIII)

wherein R and R2 have the same meanings as above, and R,2 represents t-butyl, benzyl or ethyl, is subjected to acid hydrolysis, or eye.) a compound of the general formula (IX)

wherein R and R2 have the same meanings as above, and Ac represents a C,, 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)

wherein R and R2 have the same meanings as above, f1.) a compound of the general formula (le) is reacted with cyanamide, or f2.) a compound of the general formula (XI)

is heated with a compound of the general formula (le), or (f3) a compound of the general formula (le) is reacted with a compound of the general formula (XII)

wherein R3 stands for lower alkyl, or with a salt thereof, or f4.) a compound of the general formula (XIII)

wherein R and R2 have the same meanings as above, is warmed with an ammonium halide, or f5.) a compound of the general formula (XIV)

or g.) to prepare a compound of the general formula (Ig)

wherein R and R2 have the same meanings as above, a compound of the general formula (le) is reacted with alkali cyanate, or h.) to prepare a compound of the general formula (Ih)

wherein R and R2 have the same meanings as above, R3, represents a C14 alkyl or a C3e cycloalkyl group, and R4 stands for a hydrogen atom or a C,, alkyl group, or R3 and R4 may form, together with the adjacent nitrogen atom a 6 membered heterocyclic 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)

wherein R3 and R4 have the same meanings as above, or j.) to prepare a compound of the general formula (Ij)

wherein R and R2 have the same meanings as above, j.) a compound of the general formula (II) is reacted with ethylene imine, or i2-) a compound of the general formula (XVII)

wherein R and R2 have the same meanings as above, is brominated, or j3,) a compound of the general formula (XVIII)

wherein R and R2 have the same meanings as above, is reduced, or k.) to prepare a compound of the general formula (Ik)

wherein R and R2 have the same meanings as above, and R'31 stands for hydrogen and R'4 may represent hydrogen, di-(C,, alkyl)-amino-(C,~4 alkyl), 2,6-dihalogen-benzyl or p-amino-phenyl-sulfonyl optionally N-substituted by a C1 -4 alkan oyl group, or R'3 and R'4 represent together a 2,6-dihalogen- benzylidene group, or R'3 and R'4 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 (II) thus-obtained,

wherein R and R' have the same meanings as above, is reacted with hydrazine, the compound of the general formula (Im) thus-obtained

wherein R and R2 have the same meanings as above, is reduced with a reducing agent; or, if desired, a compound of the general formula (In) is reacted with a p-(C1 < alkanoyl)-amino-benzenesulfonic chloride, the compound of the general formula (Ip) thus-obtained,

wherein R and R2 have the same meanings as above, and Ac represents a C,, alkanoyl group, is hydrolyzed; or, if desired, a compound of the general formula (In) is reacted with a di-(C1~4 alkyl) amino-(C,,)-alkylhalide, and, if desired, a compound of the general formula (I) thus-obtained is converted into its acid addition salt.

1 0. A process according to the method a.) of claim 9, which comprises carrying out the reaction in the presence of sodium hydride in dimethylformamide, tetrahydrofuran, dimethylsulfoxide or benzene.

11. A process according to the method b.) of claim 9, which comprises carrying out the hydrolysis with hydrochloric acid or sulfuric acid.

12. A process according to the method c.) of claim 9, which comprises carrying out the reaction in an alkanol under heating.

1 3. A process according to the method d.) of claim 9, which comprises carrying out the reaction in the presence of triethylamine or an acid binding agent.

14. A process according to the method e1.) of claim 9, which comprises carrying out the reaction in a chlorinated hydrocarbon as medium, in a temperature interval ranging from 200C to the boiling point of the reaction mixture.

1 5. A process according to the method e5) of claim 9, which comprises hydrolyzing 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.

1 6. A process according to the method eye.) of claim 9, which comprises using a starting material of the general formula (X) in which X stands for chlorine, methanesulfonyloxy or p-toluenesulfonyl-oxy.

17. A process according to the method f1.) of claim 9, which comprises carrying out the reaction in water, in the mixture of water and alkanol, in tetrahydrofuran or in dioxane, at the temperature of 200 C-i 000C.

1 8. A process according to the method f2.) of claim 9, which comprises carrying out the reaction in methanol.

19. A process according to the method f3.) of claim 9, which comprises using as starting material a compound of the general formula (XII), wherein R3 stands for methyl, or a hydrogen sulfate thereof, and carrying out the reaction in water at room temperature.

20. A process according to the method f4.) of claim 9, which comprises carrying out the reaction with ammonium chloride in the melt.

21. A process according to the method f5.) of claim 9, which comprises carrying out the reaction in the presence of an alkali alcoholate, in the corresponding alkanol as medium, under heating.

22. A process according to the method g.) of claim 9, which comprises carrying out the reaction by using potassium cyanate in water or in an aqueous alkanol as medium, at a temperature interval ranging from 2O0C to the boiling point of the reaction mixture.

23. A process according to the method h.) of claim 9, which comprises carrying out the reaction in the presence of an acid binding agent, preferably in triethylamine.

24. A process according to the method j.) of claim 9, which comprises carrying out the reaction in acetone.

25. A process according to the method i2 ) of claim 9, which comprises using hydrogen bromide, phosphorus tri-bromide, sulfuryl bromide or thionyl bromide as brominating agent.

26. A process according to the method j3.) of claim 9, which comprises carrying out the reaction with boron hydride, or an adduct of boron hydride and tetrahydrofuran.

27. A process according to the method k.) of claim 9, which comprises reacting the compound of the general formula (Im) with 2,6-dihalogen-benzaldehyde in the presence of triethylamine as an acid binding agent.

28. A process according to the method k.) of claim 9, which comprises reducing the compound of the general formula (Im) with a complex metal hydride.

29. A process according to the method k.) of claim 9, which comprises reacting the compound of the general formula (Im) with p-alkanoyl-amido-benzenesulfony chloride in the presence of triethylamine as an acid binding agent.

30. A process according to the method k) of claim 9, which comprises hydrolyzing the compound of the general formula (Ip) with hydrochloric acid.

31. A process according to the method k.) of claim 9, which comprises reacting the compound of the general formula (In) with a dialkyl-amino-alkyl halide in the presence of triethylamine as an acid binding agent.

32. A process as claimed in claim 9 substantially as hereinbefore described.

33. A process as claimed in claim 9 substantially as hereinbefore described with reference to any of the Examples.

34. A process for the preparation of a pharmaceutical composition as claimed in claim 7 or claim 8, wherein a compound of the general formula (I) or an acid addition salt thereof is converted into a pharmaceutical composition in a conventional manner, utilizing an appropriate inert, non-toxic, solid or liquid pharmaceutical carrier.