ISOXAZOLE DERIVATIVES AND PROCESS FOR THEIR MANUFACTURE

DERIVES DE L'ISOXAZOLE ET PROCEDE DE PRODUCTION

English Abstract

Abstract of the Disclosure:
5-Methylisoxazcle-4-carboxylic acid anilides of the
general formula


Image

wherein R1, R2 and R3 have the meanings as defined in the
following, process for preparing them, pharmaceutical prepa-
rations containing them and their use in the treatment of
inflammations, fevers and pain.

Claims

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

1. A process for the preparation of a 5-methylisoxazole-
4-carboxylic acid anilide of the general formula I

Image (I)

wherein any two or more of R1, 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 the same or different halogen atoms;
a halogen atom;
a nitro group;
a cyano group; or
an alkoxycarbonyl radical having 1, 2 or 3 carbon atoms in
the alkyl moiety;
and wherein R1 and R2 may furthermore represent hydrogen
atoms, in which case R3 cannot represent a methyl group, but
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;
or wherein R1 represents a hydrogen atom and R2 and R3 together
represent a methylenedioxy group or, together with the phenyl
ring carrying them, a naphthalene ring, wherein one, two or
all of the radicals R1 to R3 represents a carboxy group, a
hydroxy group, or carboxy and hydroxy groups, and the remaining
group or groups, if any, have the meanings given above,
in which a 5-methylisoxazole-4-carboxylic acid derivative of the
general formula II

Image (II)


wherein X represents
a) a halogen atom;
b) a YO- group in which Y represents
(i) a phenyl radical which is unsubstituted or substituted
once, twice or three times by a fluorine, chlorine,
bromine, or iodine atom, or by a methyl, ethyl, methoxy,
ethoxy, trifluoromethyl, nitro or cyano group, or
(ii) the acyl radical corresponding to the formula II; or
c) a ZO-CO-O- group in which Z represents a (C1-C4)-alkyl
radical or a phenyl or benzyl radical;
is reacted with an aniline of the general formula III







Image (III)


wherein R1, R2 and R3 have the meanings given above.


2. A compound of the formula I as defined in claim 1,
whenever obtained according to a process as claimed in claim 1
or by an obvious chemical equivalent thereof.


3. A process as claimed in claim 1 for the preparation
of a compound of the formula I wherein R1 represents a hydrogen
or halogen atom or a trifluoromethyl group and R3 represents
a carboxy group, or R1 represents a hydroxy group and R3 a halogen
atom or a trifluoromethyl or carboxy group, while in each instance
R2 represents a hydrogen atom.


4. A compound of the formula I as set forth in claim 1
wherein R1, R2 and R3 are as defined in claim 3, whenever
obtained according to a process as claimed in claim 3 or by an
obvious chemical equivalent thereof.


5. A process as claimed in claim 1 in which the compound
of the formula II is 5-methyl-4-carboxylic acid chloride and the
reaction is carried out in the presence of an acid binding agent.


6. A compound of the formula I as defined in claim 1,
whenever obtained according to a process as claimed in claim 5
or by an obvious chemical equivalent thereof.




11

Description

10~4S6~


The subject matter of our co-pending Canadian patent
application Serial Number 254,134 is 5-methylisoxazole-4-carboxy-
lic acid anilides of the general formula



S ~ CON11~



in which any two or more of Rl, R2 and R3 may be the same or
different and each represents
an alkyl radical having l, 2 or 3 carbon atoms, an alkoxy radical
having l, 2 or 3 carbon atoms, or an alkylthio radical having l,
2 or 3 carbon atoms, each of which radicals may be unsubstituted
or completely or partially substituted by the same or different
halogen atoms, such as fluorine, chlorine, bromine or iodine atoms;
a halogen atom, such as a fluorine, chlorine, bromine or iodine
atom;
a nitro group;
a cyano group; or
an alkoxycarbonyl radical having l, 2 or 3 carbon atoms in the
alky moiety;
and in which R and R may furthermore represent hydrogen atoms,
in which case R3 cannot represent a methyl group, but addition-
ally 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 l,
2 or 3 carbon atoms, or by an alkoxy radical having l, 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


~k

10'34S6~

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 in which Rl represents a hydrogen atom and R2 and R3 together
represent a methylenedioxy group or, together with the phenyl
ring carrying them, a naphthalene ring.
In a further development on the subject of the afore-
said specification, new pharmacologically active 5-methylisoxa-
zole-4-carboxylic acid anilides of the general formula I have
been found in which one, two or all of the radicals Rl to R3 now
represent a carboxy and/or hydroxy group or groups and the re-
maining group or groups, if any, have the meanings given above.
Preferred compounds are those of the general formula I,
in which either Rl represents a hydrogen atom or a halogen atom,
such as a fluQrine, chlorine, bromine or iodine atom, or a tri-
fluoromethyl group, and R3 represents a carboxy group, or
represents a hydroxy group and R3 a halogen atom such as a
flo~urine, chlorine, bromine or iodine atom, a trifluoromethyl or
carboxy group, and R2 in each case represents a hydrogen atom.
The process for the manufacture ofthe compounds accord-
ing to ~he invention of the general formula I comprises reacting
a 5-methylisoxazole-4-carboxylic acid derivative of the general
formula
,~0

2 5 N~(~ C \X I I
`O CH 3

in which X represents
a) a halogen atom, preferably a chlorine or bromine atom;
b) a YO- group in which Y represents
-- 3

109'~5fi4

(i~ a phenyl radical which is unsubstituted or substituted
once, twice or three times by a fluorine, chlorine,
bromine or iodine atom, or by a methyl, ethyl, methoxy,
ethoxy, trifluoromethyl, nitro or cyano group, or
(ii) the acyl radical corresponding to the formula II; or
c) a ZO-CO-O- group in which Z represents a (Cl-C4)-alkyl radical
or a phenyl or benzyl radical;
with an aniline of the general formula



2 ~ R2 III



in which Rl, R2 and R3 have the meanings given above.
The reaction is advantageously carried out in a dispers-
ing agent or solvent that is inert towards the reactants, for
example in a nitrile, such as acetonitrile; and ether, such as
diethyl ether, tetrahydrofuran or dioxan; or an alcohol, such as
methanol, ethanol, propanol or isopropanol.
A preferred process for the preparation ofthe compounds
according to theinvention of the general formula I is the reaction
of the carboxylic acid chloride ofthe formula II with an aniline
of the general formula III. It has proved advantageous in this
case for the reaction to be carried out in the presence ofan acid
binding agent, such as 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 160C, preferably from 20 to

80C. The reaction time may be from a few minutes to two hours.
A 5-methylisoxazole-4-carboxylic acid derivative of the
-- 4 --


lO9 ~S64

general formula II requlred as starting material may be obtained
in accordance with German Patent 634 286 by reacting ethoxymethyli-
deneacetoacetic ester with hydroxylamine to form the 5-methyliso-
xazole-4-carboxylic acid ester, by acid hydrolysis of the ester
so obtained, preferably with a mixture of glacial acetic acid and
concentrated hydrochloric acid in the ratio l : 1 to form 5-
methylisoxazole-4-carboxylic acid, and converting this carboxylic
acid according to customary methods into a carboxylic acid
halide, ester or mixed anhydride.
The following are examples of carboxylic acid deriva-
tives of the general formula II:
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 ethoxy-
carbonyloxy radical, the phenoxycarbonyloxy radical or the
benzyloxycarbonyloxy radical.
The following Examples illustrate the invention:
Manufacturing Examples
l. 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 II (7.3 g) in 20 ml of tetrahydro-
furan is added dropwise at room temperature, while stirring, to
0.1 mole of 2-amino-5-chlorobenzoic acid of the formula III
(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

.

lO~ S64

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 243C (with decomposition).
b) 0.1 mole of 2-amino~5-chlorobenzoic acid of the formula
III (17.2 g) and 0.1 mole of 4-fluorophenyl 5-methylisoxazole-4-
carboxylate of the formula II (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 suction-filtered 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 recrystalliza-
tion from ethanol) of 240 to 243C (with decomposition) are
lS obtained.
c) 0.1 mole of 2-amino-5-chlorobenzoic acid of the formula
III (17.2 g) and 0.1 mole of methoxycarbonyl-5-methylisoxazole-
4-carboxylate ofthe formula II (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 theoreti-
cal yield) of a crystalline powder having a melting point (after
recrystallization from ethanol) of 240 to 243~C are obtained.
The compounds listed in Table 1 were prepared in accor-
dance with the process described above.

10~'15fi4

Table 1: 5-methylisoxazole-4-carboxylic acid anilides of the
general formula I
No. R R2 R3 Melting point 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 H 3-COOH 242 - 245
H H 2-COOH 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)
H 2-COOH 4-C1 240 - 243 (with decomposition)
11 H 2-OH 4-C1 186 - 188
15 12 H 2-COOH 5-Br > 300 (with decomposition)
13 H 2-OH 5-C1 84 - 86
14 H 3-COO~ 4-C1 244 - 250 (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
-- 7 --

~O~S64

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




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