TRADUCTION NON-DISPONIBLE

ISOXAZOLE DERIVATIVES, PROCESS FOR THEIR MANUFACTURE AND AGENTS CONTAINING THESE COMPOUNDS

Abrégé anglais

Abstract of the disclosure:
5-Methylisoxazole-4-carboxylic acid amides of the general
formula
<IMG>
wherein R has the meanings as defined in the following, and
their salts, process for preparing these compounds, pharma-
ceutical preparations containing them and their use for the
treatment of pain, fevers and inflammations.

Revendications

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 the 5-methylisoxazole-
4-carboxylic acid amide of the general formula I
<IMG> (I)
wherein R represents thienyl, pyridyl, thiazolyl, thiazolinyl,
benzothiazolyl, benzoxazolyl, benzimidazoylyl or pyrazolyl,
which ring system is unsubstituted or substituted by an
alkyl radical or alkoxy radical each having one, two or
three carbon atoms, by a halogen atom, a nitro group, or
the oxo group, and the addition salts thereof with a
physiologically tolerable acid,
in which a 5-methyl-isoxazole-4-carboxylic acid derivative
of the general formula II
(II)
<IMG>
17

wherein X represents
a) a halogen atom;
b) a YO-group, wherein 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 or
trifluoromethyl, nitro or cyano group, or
(ii) the acyl radical corresponding to the general formula
(II); or
c) a ZO-CO-O-group wherein Z represents-a (C1-C4)-alkyl
radical, a benzyl radical or a phenyl radical;
is reacted with an unsaturated heterocyclic amine of the general
formula III
H2N-R (III)
wherein R is as defined above,
and, to prepare a salt of the compounds of the formula I, a
compound of the formula I is reacted with a physiologically
tolerable acid.
2. A process as claimed in claim 1 in which the preparation
is carried out in the presence of an inert solvent.
3. A process as claimed in claim 1 in which a carboxylic
acid chloride of the formula II is reacted with an amine of the
formula III in the presence of an acid-binding agent at a
temperature of from 0 to 160°C.
18

4. A 5-methylisoxazole-4-carboxylic acid amide of
the general formula I as defined in claim 1 and the addition
salts thereof with the physiologically tolerable acid, whenever
obtained according to a process as claimed in claim 1, claim 2
or claim 3 or by an obvious chemical equivalent thereof.
5. A process for the preparation of N-(chloro-pyridyl)-
5-methylisoxazole-4-carboxamide in which 5-methylisoxazole-4-
carboxylic acid chloride is reacted with 2-amino-5-chloropyridine
and the resulting product is subsequently isolated.
6. N-(5-Chloro-2-pyridyl)-5-methylisoxazole-4-carboxamide
whenever obtained according to a process as claimed in claim 6
or by an obvious chemical equivalent thereof.
19

Description

34~
The subject matter of our co-pending Canadian
application Serial Number 254,134, filed June 4, 1976, is
5-methylisoxazole-4-carboxylic acid anilides of the genexal
formula
CONH
~O CH3 R
in which any two or more of Rl, 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, Z or 3 carbon atoms, each of which radicals .
may be unsubstituted or substituted completely or partially
by ~he same or different halogen a-toms, such as fluorine,
chorine, 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 1, 2 or 3 carbon atoms in
the alkyl moiety;
and wherein Rl and R2 may furthermore represent hydrogen atoms,
in which case R3 cannot represent a methyl group, but
~ 2 -
1~, .' .
., ~

u~
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 in which Rl represents a hydrogen atom and R2 and R3
together represent a methylenedioxy group or together with
the phenyl r:ing carrying them represent a napthalene ring.
In a further development of the subject of the afore-
said specification, new pharmaeologically active 5-methyl-
isoxazole-4-carboxylic acid amides of the general formula
O
~ ~ H-R (I)
CH3
have now been found in which R represents a mononuclear,
binuclear or trinuclear, unsaturated heterocylic radical
having in the ring system 3 to 13 carbon atoms and one, two,
three or four hetero atoms selected from oxygen, sulfur
and nitrogen, one of whieh at most is other than nitrogen,
which ring system is unsubstituted or substituted, preferably

3~
once, twlce or three tlmes, by an alkyl ~adical or alkoxy
radlcal each having one, two or three carbon atoms, by a
halogen atom, such as a fluorine, chlorine, bromine or
iodine atom, a nitro group, a hydroxy radical, a carboxy
radical, a carbamoyl radical or the oxo group. This further
development also relates to the addition salts of these
compounds with a physiologically tolerable acid.
Suitable radicals R are~ for example, thienyl, pyridyl,
pyrimidinyl, pyrazinyl, pyridazinyl, imidazolyl, thiazolyl,
thiazolinyl, oxazolyl, thiadiazolyl, benzothiazolyl,
benzoxazolyl, benzimidazolyl, quinolyl, pyrazolyl, acridinyl
and tetrazolyl radicals, éach of which may be unsubstituted
or substituted by the above-mentioned groupsO
Preferred compounds are those of the general formula
I in which R represents a pyridyl radical which is unsubstituted
or substituted once, twice or three times by a halogen atom,
such as fluorine, chlorine, bromine or iodine atom, a
pyrimidinyl radical which is unsubstituted or substituted
once, twice or three times by a (CL-C3)-alkyl radical and/or
by the oxo group~ or a thiazolyl radical which is unsubstituted
or suhstituted by a nitro group.
The process for the manufacture of the compounds of
the general formula (I) comprises reacting a 5-methylisoxazole-
4-carboxylic acid derivative of the general formula
, ,,~
:.~
'' '

23~.
~ X (II)
N~o C~I3
in which X represents
a) halogen atom, preferably a chlorine or brimine 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 or
trifluoromethyl, nitro or cyano group, or
(ii) the acyl radical corresponding to the
formula (II3; or
c3 a ZO-CO-O-group in which Z represents a (Cl-C4)-
alkyl radical, a benzyl radical or a phenyl
radical;
with an unsaturated heterocylic amine of the general formula
H2N-R (III)
in which R has the same meaning as that given with respect
to the general formula (I).
The reaction is advantageously carried out in a
dispersing agent or a solvent that is inert towards the
reactants. Suitable polar solvents that may be used are,
,:

3~
for example, nitrlles, such as acetonitrile, ethers, such as
diethyl ether, tetrahydrofuran or dioxan; and alcohols, such
as methanol, ethanol, propanol or isopropanol. Non-polar
solvents, such as benzene, toluene and cyclohexane, may also
be used.
A pre~erred manufa.cturing process is the reaction
of the carboxylic ac.id chloride of the formula (II) with
an amine of the general formula (III). It isadvantageous in
this case for the reaction to be carried out in the presence
of an acid-binding agent, such as potassium or sodium
carbonate, an alkali methal hydroxide, alkaline earth metal
hydroxide, alkali metal alcoholate or alkaline earth metal
alcoholate, an organic base, for example triethylamine,
pyridine, picoline or quinoline or the amine 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 general formula (II) required clS starting material may be
obtained in accordance with Gerrnan Patent 634 286 by reacting
ethoxymethylideneacetoacetic ester with hydroxlamine to form
the 5-methylisoxazole-4-carboxylic acid ester, by acid
hydrolysis of the esker so obtained, preferably with a mixture
of glacial acetic acid and concentrated hydrochloric acid in
the ratio lol, 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.
- 6
.. ~ . _ ., _ . _ . _ . . , . .. , ., . ... _ .. .. _ .. , .. , . , _ _ . . . _ .. . . . .
' ~
'
'

The following are examples of carboxylic acid
derivatives of the general formula (II):
5 methylisoxa201e-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
q
- or the benzyloxycarbonyloxy radical.
The compounds according to the invention of the
general formula (I~ are generally substances that are readily
crystallizable. They can be converted into acid addition
salts by physiologically tolerable acids. In particular,
strong acids, such as hydrohalic acids, especially hydrochloric
acid, sulfuric acid, phosphoric acid, p-toluene-sulfonic acid,
methanesulfonic acid and cyclohexylamidosulonic acid come
into consideration here.
The 5-methylisoxazole-4 carboxylic acid amides of the
general formula (I) have valuable pharmacological properties.
In particular they exhibit antiphlogistic, antipyretic and
analgesic properties. Their toxicity is low, and their
compatibility with the stomach is good.
The following Examples illustrate the invention
Manufacturing Examples
1. N-(5-bromo-2-pyridyl) 5-m thylisoxazole-4-
carboxamide of the general formula (I).
. _ .
a) A solution of 0.05 mole o~ 5-methylisoxazole-4-
-- 7 --
r-
_ . ~ _ . ~ . _ _ _ . _ _ _ , _ ., _ .. . _ . .. _ . _ _ ~ _ . _ . , ~, , ~ _, _ _ _ _ _ _ _ _ _ _,,, _ _ _ _, _ _ _ . , _ . ~ _
_ _ _ . _ _ _ , , ~ ,, ~

carboxylic acid chloride of the formula (II) (7.3 g) in
20 ml of tetrahydrofuran is added dropwise at room temperature,
while stirring, to 0.1 mole of 2-amino-5-bromopyridine of the
formula (III) (17.3 g) dissol~ed in 200 ml of tetrahydrofuran.
After stirring for a further 10 minutes/ the precipitate
I formed is filtered off and the filtrate is evaporated to
¦ dryness under reduced pressure. 13.6 g (96% of the theoretical
yield) of a colorless crystalline product are obtained; melting
point from ethanol: 168-169C.
b) 0.1 mole of 2-amino-5-bromopyridine of the formula
(III) (17.3 g) and 0.1 mole of 2,4-dichlorophenyl 5-
methylisoxazole-4-carboxylate of the formula (II) (27.2 g)
dissolved in 150 ml of tetrahydrofuran are refluxed for 75
minutes. The solution is then brought to dryness under
reduced pressure and the oily residue is digested with
cyclohexane.
After decanting, the residue is dissolved in 300 ml
of chloroform and shaken with 200 ml of 2N hydrochloric acid.
The chloroform phase is wa~hed with water until
neutral, dired, and brought to dryness under reduced pressure.
21~4 g (76~ of the theoretical yield) of a crystalline
product are obtainedl melting point after recrystallization
from ethanol: 168 to 169C.
c) 0.1 mole of 2~amino-5-bromopyridine of the formula
(II) (17.3 g) and 0.1 mole of benzyloxycarbonyl 5-methyli-
soxaxole-4-carboxylate of the formula II (26.1 g), dissolved
in 200 ml of tetrahydrofuran, are refluxed for 90 minutes.
-- 8 --
, . ,. , ~ .r
'' ' . " ' ' '
. .

3~L~
The mixture is brouyht to dryness under reduced pressure and
the residue is d.igested with cyclohexane. After decanting,
the re~idue is dissolved in 300 ml of chloroform and shaken
with 200 ml of 2N hydrochloric acid. The chloroform phase
is washed with water until neutral, dried and brought to
dryness under reduced pressure. In this manner 20.6 g (73
oE the theoretical. yield) of a crystalline product are ob-
tained; melting point after recrystallization for ethanol:
168 to 169C.
In accordance with the process described above:
N-(3-pyridy~ 5-methylisoxazole-4-carboxamide hydro-
chloride of the formula (I) is obtained by reaction 5-
emthylisoxazole-4-carboxylic acid chloride of the formula
(II) with 3-aminopyridine of the formula (III),
. No(4-methyl-2-thiazolyl) 5-methylisoxazole-4-carbo~de
hydrochloride of the formula (I) is obtained by reacting 5-
methylisoxazole-4-carboxylic acid chloride of the formula
(II) with 2-amino-4-methylthiazole of the formula ~III),
N-(4-pyridyl) 5-methylisoxazole-4-carboxamide hydro-
chloride of the formula (I) is obtained by reacting 2,4-
dichlorophenyl 5-methylisoxazole 4-carboxylate of the formula
(II) with .2-amino-4-pyridine of the formula ~III),
N-(4-antipyrinyl) 5-methylisoxazole-4-carboxamide
hydrochloride of the formula (I) is obtained by reacting 5- . -
methylisoxazole-4-carboxylic acid chloride of the formula (II)
with 4-aminoantipyrine of the formula (III),
N-(4-chloro~2-benzothiazolyl) 5-methylisoxazole-4-
carboxamide of the formula I is obtained by reacting 2,4-
~ ''

110~341
dichlorophenyl 5-methylisoxazole-4-carboxylate of the formula
(II) with 2-amino-4-chlorobenzothiazole of the ormula (III),
N-(2-pyridyl) 5-methylisoxazole-4~carboxamide hydro-
chloride of the formula (I) i5 obtained by reactiny 2,4-di-
chlorophenyl 5-methylisoxazole-4-carbosylate of the formula
II with 2-amino-pyridine of the formula (III),
N-(5-bromo-2-pyridly) 5-methylisoxazole-4-carboxamide
of the formula (I) i5 obtained by reacting 5-methylisoxazole-
4-carboxylic acid chloride of the formula (II) with 2-amino-5-
bromopyridine of the formula (III),
N-(1,3-dimethyl-2~4-dioxo-1,2,3,4-tetrahydro-6-
pryimidinyl) 5-methylisoxazole-4-carboxamide of the formula
(I) is obtained by reacting 5-methylisoxazole-4-carboxylic
acid chloride of the form~la (II) with 6-amino-1,3-dimethyl-
2,4-dioxo-1,2,3,4-tetrahydropyrimidine of the formula (III), :
N-(5-nitro-2-thiazolyl) 5-methyli~soxazole-4-carboxamide
hydrochloride of the formula (I) is obtained by reacting :~
5-methylisoxazole-4-carboxylic acid chloride of the formula.
(II~ with 2-amino-5-nitrothiazole of the formula (III),
N-(2 thiazolin-2-yl) 5-methylisoxazole-4-carboxamide
hydrochloride o~ the formula (I) is obtained by reacting
2,4-dichlorophenyl 5-methylisxoaæole-4-carboxylate o the
formula (II) with 2-amino-2-thiazoline of the formula (III),
N-[5-(p-nitrophenyl)sulfonyl-2-thiazolyl] S-methyl-
isoxazole-4-carboxamide of the formula (I) is obtained by -
reacting benzyloxycarbonyl 5-methylisoxazole-4-carboxylate o -
the formula (II) with 2-amino-5-(p-nitrophenyl)sulfonyl-thiazole
-- 10 --

of the formula (III),
N-(2-Benzothiazolyl) 5-methylisoxazole-4-carboxamide
hydrochlor.ide of the forrnula (I) is obtained by reactiny
benzyloxycarbonyl 5-methylisoxazole-4-carboxylate of the
formula (II) with 2-aminobenzothiazole of the formula (III),
N-(2-benzimidazolyl) 5-methylisoxazole-4-carboxamide
hydrochloride of the formula (I) is obt,ained by reacting
2,4-dichlorophenyl 5-methylisoxazole-4-carboxylate of the
formula (II) with 2-amino-benzimidazole of the formula (III),
N (5-chloro-2-benzoxazolyl) 5-methylisoxazole-4-
carboxamide of the formula (I) is obtained by reacting
benzyloxycarbonyl S-methyl~isoxazole-4-carboxylate of the
ormula (II) with 2-amino-5-chlorobenzoxazole of the formula
(III), ~
N-(5-nitro-2-pyridyl) 5-methylisoxazole-4-carboxamide
of the formula (I) is obtained by reacting 2,4-dichlorophenyl
5-methylisoxazole-4-carboxylate of the formula (II) with
2-amino-5-nitorpyridine of the formula (III)~
N-(3,5-dibromo-2-pyridyl) 5-methylisoxazole-4-carboxamide
of the formula (I) is obtained ,by reacting benzyloxycarbonyl 5-
methylisoxazole-4-carboxylate of the formula (II) with 2-amino-
3,5-dibromopyridine of the formula (III),
N-(S-chloro-2-pyridyl) 5-methylisoxazole~4~carboxamide
of the formula (I) is obtained by reacting 5-methylisoxazole-4-
carboxylic acid chloride of the formula (II) with 2-amino-5-
chloropyridine of the formula (III),
~ 11 --
.. .

3l
N-(2'chloro-3-pyridyl) 5-methylisoxazole-4-carboxamide
of the Eormula (I) is obtained by reactin~ 5~methylisoxazole-4-
carboxylic acid chloride of the formula (II) with 3-amino-2-
chloropyridine of the formula (III),
N-(4-methyl-3-thienyl) 5-methylisoxazole-4-carboxamide
of the formula (I) is obtained by reacting 5-methylisoxazole-4-
carboxylic acid chloride of the formula (II) with 3-amino-4-
methylthiophene of the formula (III),
N-(6~methoxy-2-benzothiazolyl) 5-methylisoxazole-4-
carboxamide of the formula (I) is obtained by reacting 2,4-
dichlorophenyl 5-methylisoxazole-4-carboxylate of the formula
(II) with 2-amino-6-methoxybenzothiazole of the formula (III),
N-(5-chloro-2-thiazolyl) 5-methylisoxazole-4-carboxamide
of the formula (I) is obtained by reacting 2,4-dichlorophenyl
5-methylisoxazole-4-carboxylate of the formula (II) with 2
amino-5-chlorothiazole of the formula (III),
N-(2-methoxy-5-pyridyl) 5-methylisoxazole:4~carboxamide
o~ the formula (I) i8 obtained by reacting 5-methylisoxazole-4-
carboxylic acid chloride of the formula (II) with 5-amino-2
methoxypyridine of the formula (III),
N-(6-ethoxy-2-benzothiazolyl) 5-methylisoxazole-4- ~ ::
carboxamide of the formula (I) is obtained by reacting
benzyloxycarbonyl 5-methylisoxazole-4-carboxylate of the
formula (II) with 6-ethoxy-2-aminobenzothiazole of the
formula (III),
N-(5-hrcm~-2-thLazolyl) 5-methylisoxazole-4-carboxamide
of the formula (I) is obtained by reacting 5'methylisoxazole-4-
carboxylic acid chloride of the formula (II) with 2-amino-5-
bromothiazole of the formula (III).
- 1~ - .
': :

z3~
Ta~le 1: 5-Methylisoxazole-4-carboxylic acid amides of the
formula I
No. R Melting point ~C
1 ~ ~ 250-252 (with decomposi-
. HCl tion)
S
. HCl 221-223
N CH3
3 ~ .~HCl 210-215 (with decomposi-
H3C :.
_ ~ CII3,.
4 O ~ ~ .HCl 172-174
~ ~ ~ 218-220
Cl
6 ~ 239 242
.HC1
Br 168-l69
- 13 ~ ' ;
'
, .... .

HOE 76~F 294
Table l corlt.inued
NoO R Melting point C
_._
8 ~ ~CII3 192-194
CH3
S~/~
~ ~ ~ O HCl 151-154
~ HCl 260-265 (wi~h decompositiv~
11 ~ ~ o ~ 185-187 (with decompo~ition)
O :.
12 - ~ ~ . HCl 234-237 ~with decompc~ition)
13 ~ Cl 230-235 (w.ith dq omposikion~
14 - ~ ~ 170~175 ~with decompo~i.tion~
~ 1~ Cl
1~ -
.

3~
Table 1 continued
No . R Melting poin t C
--~ NO2 202-203
Br
16 N ~ 165-167
17 ~ Cl 165-168
18 ~3 112-114 (with decom-
>~N ~ position)
Cl
C~ '
19 ~: S 113-I15 - `
20--~5 \~O-CH3 . 215-2i9 (with decom-
~lJ ~ HCl position)
21 ~ ~ Cl - ~ 210-220 (with decom-
'~N ~ position)
H
-- 15 -- .
,'ii '~ .
. .
~' , , ' .

3~
H0~ 76/F' 294
Table 1 continued
~oc R M~lting point C
22 ~--C~CH3 154~156 (with decomposition~
S~,~ O -C 2H5
23 ~ HCl 216 221 ~th decompo~ tion)
S~ Br
24 ~ ~ o HCl 203~211 (with~ decolr,positi~n)
N ~\ ~ ~ :
d '
. .
: , ''