DE2655094A1 - ISOXAZOLE DERIVATIVES, THE PROCESS FOR THEIR MANUFACTURING AND THE PRODUCTS CONTAINING THE SAME - Google Patents

Description

Isoxazole derivatives, processes for their preparation and compositions containing these compounds
Addition to patent application P 25 24 959.5 (HOE 75 / F 149)

The subject of the main application P 25 24 959.5 (HOE 75 / F 149jsind 5-methyl-isoxazole-4-carboxylic acid anilides of the formula I

(D

wherein R ¹ , R ² and R ^{3 can be} identical or different and alkyl with 1, 2 or 3 carbon atoms, alkoxy with 1, 2 or 3 carbon atoms, alkylthio with 1, 2 or 3 carbon atoms, which groups each completely or partially by identical or different halogen atoms, such as fluorine, chlorine, bromine or iodine, can be substituted, halogen, such as fluorine, chlorine, bromine or iodine, nitro, cyano, carbalk-

80 9 824/0044 / ²

oxy with 1, 2 or 3 carbon atoms in the alkyl group, mean in which

"1 2

R and R continue to represent hydrogen, but in which case

3 3

R cannot be methyl, but in which case R can also be phenyl, which is optionally single or double Fluorine, chlorine, bromine, iodine, alkyl with 1, 2 or 3 carbon atoms or Alkoxy can be substituted by 1,2 or 3 carbon atoms, or Phenoxy, which is optionally in each case once or twice by fluorine ,. Chlorine, bromine, iodine, alkyl with 1, 2 or 3 carbon atoms or Alkoxy may be substituted with 1, 2 or 3 carbon atoms, means

1 7 3

or in which R is hydrogen and R and R together are one Methylenedioxy group or together with the phenyl ring carrying them mean a naphthalene ring.

In a further development of the subject matter of the main application, new pharmacologically active 5-methyl-isoxazole-4-carboxylic acid anilides were now used of the formula I found in which one ,, two or

1 3
three of the radicals R to R now also represent carboxyl and / or hydroxyl groups in addition to the meaning given above for the other groups.

Preference is given to compounds of the formula I in which either R

how
Hydrogen, halogen, fluorine, chlorine , bromine or iodine or trifluorine

2 1 2

methyl and R carboxyl, or R hydroxyl and R halogen such as Are fluorine, chlorine, bromine or iodine, trifluoromethyl or carboxyl, and each R is hydrogen.

The process for making the compounds of the invention of the formula I is characterized in that a 5-methylisoxazole-4-carboxylic acid derivative is used of formula II

CU)

in which X is a balogen atom, preferably chlorine or bromine, a YO- or ZO-CO-O- group; where Y for optionally through

809824/00 4 4

Fluorine, chlorine, bromine, iodine, methyl, ethyl, methoxy, ethoxy, trifluoromethyl, nitro or cyano "single, double or triple substituted phenyl or for the acyl radical according to formula II and Z for (C ₁ -C ₄ I-AIlCyI, Phenyl or benzyl, with an aniline of the formula III

(III)

12 3

wherein R, R and R have the meanings given above.

The reaction is conveniently carried out in a partition or solvent carried out, which behaves indifferently towards the reaction partners. For example, nitriles such as Acetonitrile, ethers, such as diethyl ether, tetrahydrofuran or Dioxane and alcohols such as methanol, ethanol, propanol or isopropanol in question.

The preferred method for preparing the compounds of the formula I according to the invention is the reaction of the carboxylic acid chloride of the formula II with an aniline of the formula III. It proves to be advantageous to carry out the reaction in the presence of acid-binding agents, such as potassium or sodium carbonate, alkali or alkaline earth metal hydroxides or alcoholates, organic bases, for example triethylamine _f pyridine, picoline or quinoline or the respective aniline used in excess at temperatures between 0 and preferably perform 160 ⁰ C between 20 and 8O ⁰ C. The reaction times can range from a few minutes to two hours.

The 5-methyl-isoxazole-4-carboxylic acid derivatives required as starting materials of formula II are according to DRP 634 286 by reacting Athoxymethylidenacetoessigester with hydroxylamine to 5-methylisoxasol-4-carboxylic acid ester i. acid saponification of the so

809824/0044 ^{/ 4}

obtained ester, preferably a mixture of glacial acetic acid and
concentrated hydrochloric acid in a ratio of 1: 1 to 5-methylisoxazole-4-carboxylic acid and convert this carboxylic acid into the carboxylic acid halides, esters or mixed anhydrides by customary methods.

Possible carboxylic acid derivatives of the formula II are:
5-methylisoxazole-4-carboxylic acid phenyl ester, in particular the 2,4-dichlorophenyl ester or the 2,4,6-trichlorophenyl ester, furthermore 5-methylisoxazole-4-carboxylic acid anhydrides, especially those in which X is the methoxycarbonyloxy radical, the ethoxycarbonyloxy radical, the phenoxycarbonyloxy radical or the phenoxycarbonyloxy radical mean .

80 98 2 k / 004 U-.

Manufacturing examples

1. 5-Methylisoxazole-4-carboxylic acid (2-carboxy-4-chloro) anilide der Formula I.

a) 0.1 mol of 2-amino-5-chlorobenzoic acid of the formula III (17.2 g) dissolved in 200 ml of tetrahydrofuran are at room temperature dropwise with a solution of 0.05 mol of 5-methylisoxazole-4-carboxylic acid chloride of the formula II (7.3 g) in 20 ml of tetrahydrofuran are added with stirring. After another 20 minutes While stirring, the precipitate is filtered off and boiled with 200 ml of 2 η hydrochloric acid. The remaining precipitate is filtered off with suction, washed neutral with water and dried. 13.1 g (S3% of theory) are obtained in this way crystalline colorless powder; Melting point after recrystallization from ethanol: 240 to 243 ° C (decomp.).

b) 0.1 mol of 2-amino-5-chlorobenzoic acid of the formula III (17.2 g) and 0.1 mole (4-fluoro) phenyl 5-methylisoxazole-4-carboxylate of formula II (22.1 g) dissolved in 100 ml of tetrahydrofuran are refluxed for 80 minutes. After that, the Sucked off precipitate and boiled with 200 ml of 2 η hydrochloric acid. The remaining precipitate is filtered off with suction Washed with water until neutral and dried. 19.4 g (69% of theory) of crystalline powder with a melting point are obtained in this way (after recrystallization from ethanol) 240 to 243 ° C (decomp.).

c) 0.1 mol of 2-amino-5-chlorobenzoic acid of the formula III (17.2 g) and 0.1 mol (methoxycarbonyl) -5-methylisoxazole-4-carboxylate of formula II (18.5 g) is dissolved in 150 ml of tetrahydrofuran Heated under reflux for 70 minutes. The precipitate which has separated out is then filtered off with suction and treated with 200 ml of 2η hydrochloric acid boiled out. The remaining precipitate is filtered off with suction, washed neutral with water and dried. Man thus receives 20.2 g (72% of theory) of a crystalline powder with a melting point (after recrystallization from ethanol) 240 to 243 ° C (dec.).

809824/0044 ^{/ 6}

Following the procedures given above, those in Table listed compounds.

Table 1: 5-methylisoxazole-4-carboxylic acid anilides of the formula I.

No. R ¹ R ² R ³ melting point ⁰ C

1 H H 4-OH 160-163

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 (dec.)

7 H 2-OH 3-COOH 198 - 201 (decomp.)

8 H 3-COOH 4-OH 247-251 (dec.)

9 H 2-COOH 4-OH 228-231 (decomp.)

H 2-COOH 4-Cl 240-243 (dec.)

H 2-OH 4-Cl 186-188

H 2-COOH 5-Br> 300 (decomp.)

H 2-OH 5-Cl 84-86

1. S-methylisoxazole ^ -carboxylic acid (4-hydroxy) anilide

2. 5-methylisoxazole-4-carboxylic acid (4-carboxy) anilide

3. 5-methylisoxazole-4-carboxylic acid (4-carboxy-3-hydroxy) anilide

4. 5-methylisoxazole-4-carboxylic acid (3-carboxy) anilide

5. 5-methylisoxazole-4-carboxylic acid (2-carboxy) anilide

6. S-methylisoxazole-4-carboxylic acid (5-carboxy-2-hydroxy) anilide

7. S-methylisoxazole ^ carboxylic acid (3-carboxy-2-hydroxy) anilide

8. S-methylisoxazole ^ carboxylic acid (3-carboxy-4-hydroxy) anilide

9. S-methylisoxazole ^ -carboxylic acid (2-carboxy-4-hydroxy) anilide

10. S-methylisoxazole ^ carboxylic acid (2-carboxy-4-chloro) anilide

11. 5-Methylisoxazole-4-carboxylic acid (4-chloro-2-hydroxy) anilide

12. 5-Methylisoxazole-4-carboxylic acid (5-bromo-2-carboxy) anilide

13. 5-Methylisoxazole-4-carboxylic acid (5-chloro-2-hydroxy) anilide

809824/0044

Claims (6)

PATENT CLAIMS: anilide of the formula I. 5-methyl-isoxazole-4-carboxylic acid (D 12 3 wherein R, R and R can be the same or different and Alkyl with 1,2 or 3 carbon atoms, alkoxy with 1, 2 or 3 carbon atoms, alkylthio with 1, 2 or 3 carbon atoms, soft groups in each case completely or partially by identical or different halogen atoms, such as fluorine , chlorine, Bromine or iodine can be substituted, halogen, such as fluorine, chlorine, bromine or iodine, nitro, cyano, carbalkoxy with 1, 2 or 3 carbon atoms in the alkyl group, 12th
mean, in which R and R still mean hydrogen, in which case, however, R ^J cannot be methyl, in which case, however, R additionally phenyl, which is optionally in each case once _{or twice by fluorine 7} chlorine, bromine, iodine, alkyl with 1,2 or 3 carbon atoms or alkoxy can be substituted with Τ, 2 or 3 carbon atoms, or phenoxy, which can optionally be substituted once or twice by fluorine, chlorine, bromine, iodine, alkyl with 1, 2 or 3 carbon atoms or alkoxy with 1, 2 or 3 carbon atoms can be substituted, or in which R 2 3 Is hydrogen and R and R together are a methylenedioxy group or together with the phenyl ring bearing them mean a naphthalene ring, characterized in that one, 13th
two or three of the radicals R to R represent a carboxyl-hydroxyl group in addition to the meaning given above for the other groups. and or 2. Compounds according to formula I in claim 1, characterized in that that R is hydrogen, halogen or trifluoromethyl and 2 1 2 R carboxyl or R hydroxyl and R halogen, trifluoromethyl 809824/0044 3 ″ or carboxyl, while R in each case denotes hydrogen. 3. Process for the preparation of the compounds of formula I in Claim 1, characterized in that a 5-methylisoxazole-4-carboxylic acid derivative is used of formula II in which X is either a halogen atom, preferably chlorine or bromine, a YO or ZO-CO-0 group, where Y is optionally represented by fluorine, chlorine, bromine, iodine, methyl, ethyl, methoxy, ethoxy, trifluoromethyl, nitro or Cyan mono-, disubstituted or disubstituted phenyl or the acyl radical corresponding to the formula II and Z represent (C _{1 -C 4} ) -alkyl, phenyl or benzyl, with an aniline of the formula III (III) 12 3 wherein R, R and R have the meanings given above. 4. The method according to claim 3, characterized in that one starts from 5-methylisoxazole-4-carboxylic acid chloride of the formula II and carrying out the reaction in the presence of an acid-binding agent. 5. Medicament, characterized in that it contains a compound of the formula I according to Claims 1 or 1 , in a mixture with a pharmaceutically customary carrier and / or constituent. 809824/0044 ^{/ 9} 6. Use of a compound of the formula I according to claim 1 or 2 for combating inflammation, fever and pain? 8 0 3 8 2 u ■ : · J; U