GB1595467A

GB1595467A - 5-methyliso-oxazole-4-carboxylic acid anilides having pharmaceutical activity

Info

Publication number: GB1595467A
Application number: GB5034677A
Authority: GB
Original assignee: Hoechst AG
Current assignee: Hoechst AG
Priority date: 1976-12-04
Filing date: 1977-12-02
Publication date: 1981-08-12
Also published as: DE2655094A1; JPS5371069A; IT1113801B; BE861502R; NL7713148A; ATA866277A; CA1094564A; IE46102B1; DK538577A; FR2372813B2; ES464553A2; LU78626A1; IE46102L; FR2372813A2; AT362788B; CH614945A5

Abstract

Novel 5-methyl-isoxazole-4-carboxylic acid anilides of the formula I <IMAGE> wherein one, two or three of the radicals R1, R2 and R3 denote a carboxyl group and/or a hydroxyl group and the remaining radicals R1, R2 and R3, which may be identical or different, denote alkyl having 1, 2 or 3 carbon atoms, alkoxy having 1, 2 and 3 carbon atoms or alkylthio having 1, 2 or 3 carbon atoms, which groups may each be completely or partially substituted by identical or different halogen atoms, or denote hydrogen, halogen, nitro, cyano or carbalkoxy having 1, 2 or 3 carbon atoms in the alkyl group, are prepared by reacting a 5-methyl-isoxazole-4-carboxylic acid derivative with an appropriately substituted aniline. The compounds of the formula I are pharmacologically active. They exhibit a powerful antiphlogistic, antipyretic and analgesic action. Their toxicity is low and their gastric toleration is good.

Description

(54) 5-METHYLISOXAZOLE-4-CARBOXYLIC ACID ANILIDES HAVING PHARMACEUTICAL ACTIVITY (71) We, HOECHST AKTIENGESELLSCHAFT, a body corporate organised according to the laws of the Federal Republic of Germany, of 6230 Frankfurt/Main 80, Postfach 80 03 20, Federal Republic of Germany, do hereby declare the invention for which we pray that a patent may be granted to us, and the method by which it is to be performed, to be particularly described in and by the following statement:- This invention relates to isoxazole derivatives and is an improvement in, or modification of, the invention of our U.K. Patent No. 1,547,452.

U.K. Patent No. 1,547,452 describes and claims 5 - methyl - isoxazole - 4 carboxylic acid anilides of the general formula

in which R1 and R2, which may be identical or different, each represents a hydrogen atom; an alkyl group of 1, 2 or 3 carbon atoms, an alkoxy group of 1, 2 or 3 carbon atoms, an alkylthio group of 1, 2 or 3 carbon atoms, the alkyl groups of which may be substituted partly or totally by identical or different halogen atoms, for example, fluorine, chlorine, bromine or iodine atoms, or represents a halogen atom, for example, a fluorine, chlorine, bromine or iodine atom, or represents a nitro or cyano group or an alkoxycarbonyl group having 1, 2 or 3 carbon atoms in the alkyl moiety, R3 represents an alkyl group of 1, 2 or 3 carbon atoms, an alkoxy group of 1, 2 or 3 carbon atoms, an alkylthio group of 1, 2 or 3 carbon atoms, the alkyl groups of which may be substituted partly or totally by identical or different halogen atoms, for example, fluorine, chlorine, bromine or iodine atoms, or represents a halogen atom, for example, a fluorine, chlorine, bromine or iodine atom, or represents a nitro or cyano group or an alkoxycarbonyl group having 1, 2 or 3 carbon atoms in the alkyl moiety; or represents a phenyl group which may carry one or two substituents selected from fluorine, chlorine, bromine and iodine atoms, alkyl groups of 1, 2 or 3 carbon atoms and alkoxy groups of 1, 2 or 3 carbon atoms, or a phenoxy group which may carry one or two substituents selected from fluorine chlorine, bromine and iodine atoms, alkyl groups of 1, 2 or 3 carbon atoms and alkoxy groups of 1, 2 or 3 carbon atoms; or in which R1 stands for a hydrogen atom, and R2 and R3 together represent a methylenedioxy group or, together with the phenyl ring, to which they are linked, represent a naphthalene ring; with the proviso that R3 does not represent a methyl group when R1 and R2 both represent hydrogen atoms.

We have now found that pharmacological properties are also shown by compounds of the above general formula in which at least one of the radicals R' to R3 represents a carboxy or hydroxy group and the remaining group or groups, if any, have the meanings given above.

Accordingly, the present invention provides a compound of the general formula

in which any two or more of R', R2 and R3 may be the same or different and each represents an alkyl radical having 1, 2 or 3 carbon atoms, an alkoxy radical having 1, 2 or 3 carbon atoms, or an alkylthio radical having 1,2 or 3 carbon atoms, each of which radicals may be unsubstituted or completely or partially substituted by one or more of the same or different halogen atoms; a halogen atom; a nitro group; a cyano group; an alkoxycarbonyl radical having 1,2 or 3 carbon atoms in the alkyl moiety; a hydroxy group; a carboxy group; or a hydrogen atom; and in which R2 and R3 together may represent a methylenedioxy group or, together with the phenyl ring carrying them, a naphthalene ring; and in which if one of R' to R3 represents a hydrogen atom, one other may represent a phenyl radical which may be unsubstituted or substituted in each case once or twice by fluorine, chlorine, bromine or iodine or by alkyl having 1, 2 or 3 carbon atoms or alkoxy having I, 2 or 3 carbon atoms, or may represent a phenoxy radical which may be unsubstituted or substituted in each case once or twice by fluorine, chlorine, bromine or iodine or by alkyl having 1, 2 or 3 carbon atoms or alkoxy having 1, 2 or 3 carbon atoms; and wherein at least one of R' to R3 represents a carboxy or hydroxy group.

One or both of R1 and R2 may represent a hydrogen atom and if one represents a hydrogen atom, R3 additionally may represent a phenyl radical which may be unsubstituted or substituted in each case once or twice by a fluorine, chlorine, bromine or iodine atom, by an alkyl radical having 1, 2 or 3 carbon atoms, or by an alkoxy radical having 1, 2 or 3 carbon atoms, or may represent a phenoxy radical which may be unsubstituted or substituted in each case once or twice by a fluorine, chlorine, bromine or iodine atom, by an alkyl radical having 1, 2 or 3 carbon atoms or by an alkoxy radical having 1, 2 or 3 carbon atoms.

The present invention also provides a salt, especially a physiologically tolerable salt, of such a compound.

Preferred compounds of the invention are those of the general formula I in which either R' represents a hydrogen atom or a halogen atom, e.g. a fluorine, chlorine, bromine or iodine atom, or a trifluoromethyl group, and R2 represents a carboxy group; or R1 represents a hydroxy group and R2 a halogen atom, e.g. a fluorine, chlorine, bromine or iodine atom, a trifluoromethyl or carboxy group; and R3 in each case represents a hydrogen atom.

The present invention also provides a process for the preparation of a compound of the invention of the general formula I or a salt thereof, which comprises reacting a 5 - methylisoxazole - 4 - carboxylic acid derivative of the general formula

in which X represents a) a halogen atom, preferably a chlorine or bromine atom; b) a YO- group in which Y represents (i) a phenyl radical which is unsubstituted or substituted by one, two or three substituents selected from fluorine, chlorine, bromine and iodine atoms, and methyl, ethyl, methoxy, ethoxy, trifluoromethyl, nitro and cyano groups, or (ii) the acyl radical corresponding to the formula II, that is,

c) a ZO-CO-O- grou in which Z represents a (C1-C4)-alkyl radical or a phenyl or benzyl radical; with an aniline of the general formula

in which R1, R2 and R3 have the meanings given above or with a salt thereof.

Preferably, a substituted phenyl radical Y contains one substituent or two or three identical substituents.

The reaction is advantageously carried out in a dispersing agent or solvent that is inert towards the reactants, for example in a nitrile, e.g. acetonitrile; an ether, e.g. diethyl ether, tetrahydrofuran or dioxan; or an alcohol, e.g. methanol, ethanol, propanol or isopropanol.

Preferably the compound of the general formula II is the carboxylic acid chloride. It has proved advantageous in this case for the reaction to be carried out in the presence of an acid-binding agent, e.g. potassium or sodium carbonate, an alkali metal hydroxide or alcoholate, an alkaline earth metal hydroxide or alcoholate, an organic base, for example triethylamine, pyridine, picoline or quinoline, or the aniline reactant used in excess, at temperatures of from 0 to 160"C, preferably from 20 to 800 C. The reaction time may be from a few minutes to two hours.

If desired, a compound of the general formula I obtained may be converted into a salt thereof.

A 5 - methylisoxazole - 4 - carboxylic acid derivative of the general formula II required as starting material may be obtained in accordance with the method described in German Patent 634,286. In this method ethoxymethylideneacetoacetic ester is reacted with hydroxylamine to form the 5 - methyl - isoxazole - 4 carboxylic acid ester, the ester is hydrolysed under acid conditions, preferably with a mixture of glacial acetic acid and concentrated hydrochloric acid in the ratio 1:1, and the 5 - methylisoxazole - 4 - carboxylic acid formed is converted according to a customary method into a carboxylic acid halide, ester or mixed anhydride.

The following are examples of carboxylic acid derivatives of the general formula ll: 5 - methylisoxazole - 4 - carboxylic acid phenyl esters, especially the 2,4 dichlorophenyl ester or the 2,4,6 - trichlorophenyl ester; and 5 - methylisoxazole - 4 - carboxylic acid anhydrides, especially those in which X represents the methoxycarbonyloxy radical, the ethoxycarbonyloxy radical, the phenoxycarbonyloxy radical or the benzyloxycarbonyloxy radical.

Compounds of the invention of the general formula I and their physiologically tolerable salts may be used for combating inflammations, fevers and pain.

Accordingly, the present invention provides a pharmaceutical preparation, which comprises a compound of the general formula I of the invention or a physiologically tolerable salt thereof, in admixture or conjunction with a pharmaceutically suitable carrier. Preferably the preparation is in dosage unit form.

The following Examples illustrate the invention: 1. 5-methylisoxazole-4-carboxylic acid 2-carboxy-4-chloroanilide of the general formula I a) A solution of 0.05 mole of 5 - methylisoxazole - 4 - carboxylic acid chloride of the formula If (7.3 g) in 20 ml of tetrahydrofuran is added dropwise at room temperature, while stirring, to 0.1 mole of 2 - amino - 5 - chlorobenzoic acid of the formula 1it (17.2 g) dissolved in 200 ml of tetrahydrofuran. After stirring for a further 20 minutes the precipitate that has formed is suction-filtered off and extracted by boiling with 200 ml of 2N hydrochloric acid. The remaining precipitate is suction-filtered off, washed with water until neutral, and dried. In this manner 13.1 g (93% of the theoretical yield) of a colorless crystalline powder are obtained; melting point after recrystallization from ethanol: 240 to 2430C (with decomposition).

b) 0.1 mole of 2 - amino - 5 - chlorobenzoic acid of the formula 111(17.2 g) and 0.1 mole of 4 - fluorophenyl 5 - methylisoxazole - 4 - carboxylate of the formula it (22.1 g) dissolved in 100 ml of tetrahydrofuran are refluxed for 80 minutes. Subsequently the precipitate is suction-filtered off and extracted by boiling with 200 ml of 2N hydrochloric acid. The remaining precipitate is suctionfiltered off, washed with water until neutral and dried. In this manner 19.4 g (69 /" of the theoretical yield) of crystalline powder having a melting point (after recrystalization from ethanol) of 240 to 2430C (with decomposition) are obtained.

c) 0.1 mole of 2 - amino - 5 - chlorobenzoic acid of the formula it1 (17.2 g) and 0.1 mole of methoxycarbonyl 5 - methylisoxazole - 4 - carboxylate of the formula it (18.5 g) dissolved in 150 ml of tetrahydrofuran are refluxed for 70 minutes. Subsequently the precipitate that has formed is suction-filtered off and extracted by boiling with 200 ml of 2N hydrochloric acid. The remaining precipitate is suction-filtered off, washed with water until neutral and dried. In this manner 20.2 g (72% of the theoretical yield) of a crystalline powder having a melting point (after recrystallization from ethanol) of 240 to 2430C (with decomposition) are obtained.

The compounds listed in Table 1 were prepared in accordance with the process described above.

Table 1: 5 - methylisoxazole - 4 - carboxylic acid anilides of the general formula I No. R1 R2 R3 Melting point OC H H H 4-OH 16-163 2 H H 4-COOH 128-130 3 H 3-OH 4-COOH 228-231 4 H 3-COOH H 242-245 5 H 2-COOH H 208-211 6 H 2-OH 5-COOH 231-234 (with decomposition) 7 H 2-OH 3-COOH 198-201 (with decomposition) 8 H 3-COOH 4-OH 247-251 (with decomposition) 9 H 2-COOH 4-OH 228-231 (with decomposition) 10 H 2-COOH 4-Cl 24--243 (with decomposition) 11 H 2-OH 4-Cl 186-188 12 H 2-COOH 5-Br > 300 (with decomposition) 13 H 2-OK 5-C1 84-86 14 H 3-COOH 4-C1 244250 (with decomposition) 1. 5 - Methylisoxazole - 4 - carboxylic acid 4 - hydroxyanilide 2. 5 - Methylisoxazole - 4 - carboxylic acid 4 - carboxyanilide 3. 5 - Methylisoxazole - 4 - carboxylic acid 4 - carboxy - 3 - hydroxyanilide 4. 5 - Methylisoxazole - 4 - carboxylic acid 3 - carboxyanilide 5. 5 - Methylisoxazole - 4 - carboxylic acid 2 - carboxyanilide 6. 5 - Methylisoxazole - 4 - carboxylic acid 5 - carboxy - 2 - hydroxyanilide 7. 5 - Methylisoxazole - 4 - carboxylic acid 3 - carboxy - 2 - hydroxyanilide 8. 5 - Methylisoxazole - 4 - carboxylic acid 3 - carboxy - 4 - hydroxyanilide 9. 5 - Methylisoxazole - 4 - carboxylic acid 2 - carboxy - 4 - hydroxyanilide 10. 5 - Methylisoxazole - 4 - carboxylic acid 2 - carboxy - 4 - chloroanilide 11. 5 - Methylisoxazole - 4 - carboxylic acid 4 - chloro - 2 - hydroxyanilide 12. 5 - Methylisoxazole - 4 - carboxylic acid 5 - bromo - 2 - carboxyanilide 13. 5 - Methylisoxazole - 4 - carboxylic acid 5 - chloro - 2 - hydroxyanilide 14. 5 - Methylisoxazole - 4 - carboxylic acid 3 - carboxy - 4 - chloroanilide

Claims

WHAT WE CLAIM IS:- 1. A compound of the general formula

in which any two or more of R', R2 and R3 may be the same or different and each represents an alkyl radical having I, 2 or 3 carbon atoms, an alkoxy radical having I, 2 or 3 carbon atoms, or an alkylthio radical having 1, 2 or 3 carbon atoms, each of which radicals may be unsubstituted or completely or partially substituted by one or more of the same or different halogen atoms; a halogen atom; a nitro group; a cyano group; an alkoxycarbonyl radical having 1, 2 or 3 carbon atoms in the alkyl moiety; a hydroxy group; a carboxy group; or a hydrogen atom; and in which R2 and R3 together may represent a methylenedioxy group or, together with the phenyl ring carrying them, a naphthalene ring and in which if one of R' to R3 represents a hydrogen atom, one other may represent a phenyl radical which may be unsubstituted or substituted in each case once or twice by fluorine, chlorine, bromine or iodine or by (C1-C3) alkyl or (C1-C3) alkoxy, or may represent a phenoxy radical which may be unsubstituted or substituted in each case once or twice by fluorine, chlorine, bromine or iodine or by (C1-C3) alkyl or (C1- C3) alkoxy; and wherein at least one of R1 to R3 represents a carboxy or hydroxy group, or a salt of such a compound.
2. A compound as claimed in claim 1, wherein R1 represents a hydrogen or halogen atom or a trifluoromethyl group and R2 represents a carboxy group; or R1 represents a hydroxy group and R2 a halogen atom or a trifluoromethyl or carboxy group; whilst R3 in each case represents a hydrogen atom.
3. A compound as claimed in claim 1 which is shown in Example 1 or Table 1 herein.
4. A salt of a compound claimed in any one of claims I to 3.
5. A physiologically tolerable salt of a compound claimed in any one of claims 1 to 3.
6. A process for the preparation of a compound claimed in claim 1 or a salt thereof, which comprises reacting a compound of the general formula

in which X represents a) a halogen atom, b) a YO- group in which Y represents (i) a phenyl radical which is unsubstituted or substituted by one, two or three of the same or different substituents selected from fluorine, chlorine, bromine and iodine atoms and methyl, ethyl, methoxy, ethoxy, trifluoromethyl, nitro and cyano groups, or (ii) the acyl radical corresponding to the formula II; or c) a ZO-CO-O- grou in which Z represents a (C1-C4)-alkyl radical or a phenyl or benzyl radical; with an aniline of the general formula

in which R1, R2 and R3 have the meanings given in claim 1, or with a salt thereof.
7. A process as claimed in claim 6, wherein the compound of the general formula 11 is 5 - methylisoxazole - 4 - carboxylic acid chloride, and the reaction is carried out in the presence of an acid-binding agent.
8. A process as claimed in claim 7, wherein the reaction is carried out at a temperature in the range of from 20 to 800 C.
9. A process as claimed in claim 6, wherein the compound of the general formula 11 is the 2,4 - dichlorophenyl ester, the 2,4,6 - trichlorophenyl ester, or the anhydride in which X represents the methoxycarbonyloxy, ethoxycarbonyloxy, phenoxycarbonyloxy or benzyloxycarbonyloxy radical.
10. A process as claimed in claim 6, carried out substantially as described in the Example herein.
11. A compound as claimed in claim 1, whenever prepared by a process as claimed in any one of claims 6 to 10.
12. A salt of a compound claimed in claim 1, whenever prepared by a process as claimed in any one of claims 6 to 10.
13. A physiologically tolerable salt of a compound claimed in claim I, whenever prepared by a process as claimed in any one of claims 6 to 10.
14. A pharmaceutical preparation which comprises a compound as claimed in any one of claims 1 to 3, 5, 11 and 13, in admixture or conjunction with a pharmaceutically suitable carrier.
15. A pharmaceutical preparation as claimed in claim 14, which is in dosage unit form.