Note : Les descriptions sont présentées dans la langue officielle dans laquelle elles ont été soumises.
:
HOE 75/F 183 K
9~
,
The present invention relates to 1-methyl-2-(phenyl-oxy~
methyl)-5-nitro-imidazoles and to a process for their manufacture. :~
1-(2-hydroxyethyl)-2-methyl-5-nitro-imidazole ~Metronidazol)
is being used for the treatment of protozoal diseases, such as
trichomoniasis and'amoebiasis. .
Object of this invention are 1-methyl-2-~phenyl oxymethyl)- . .
5-nitro-imidazo].es of the formula I .
.
. . . .......... .
CH2 - { ~ A-R (I)
2 ~ H3 ~ R2 - . . .
-- . . . . ....... .. . . .. . . .
in which A stands for a sulfur atom or a sulfoxide (-SO-) group, ':
h vd ro en.,
. ' R1 stands for methyl or ethyl, and.R2 fo~ met Iyl or halogen. .-.:
Further object of this invention is a process for the ~
.
manufacture of 1-methyl-2-(phenyl-oxymethyl)-5-ni.tro-imidazoles
of the formula I, which comprises ~ '
:, ' - . .
-~ .. a) reacting a ni~ro-'imidazole of the formula II ........... . '-~
., . :
N
CH2 - X ' (II) .:.
2 ~ ~
CH~ .
in which X stands for a halogen atom, such as fluorine,
chlorine, bromine or iodine atom, or for an acyloxy group, . '
such as an acetoxy, propionyloxy, butyryloxy, benzoyloxy, :
,:;: .
- toloyloxy, nitrobenzoyloxy group, or for an arylsulfonyloxy : :
group, such as a benzene-sulfonyloxy, toluenesulfonyloxy, or :~
nitrobenzene-su].'fonyloxy group, with a phenol or an alkali ' -~
metal or ammonium salt thereof, which corresponds to the
- 2 ~
`~
. . .
HOE 75/F 183 K
9~0 ~'' ~~ ~~ '. :~ .
~ '
formula IIl
Y-0 ~ A-R~
~2 ~ '
.. . ..... . . . . . . . . . ~ ~
~ in which Y stands for a hydrogen atom, an alkali metal ion, ;~
- : espec.ially a sodium or potassium ion, or ammonium, and A, ~ ;
and R2 are defined as above, or~ : ~
.. ., ,, , .- . .
.- b) alkylatlng a niero-imidazole of the formu1a IV - ~
.
~ ~ - C}lz - C ~ S~Y ~ (LV) ~ ~:
'' ' `,~-''`' ,
in which Y and R2 are defined as above, and optionally o-xi- ~.
dizing the so-obtained sulfide compound of formula I to yield . : ;~
a sulfoxide.
As starting compounds of formula II, there may be used,for
:; . :. ..
;~ example, 1-methyl-2-chloro-methyl-5-nitro-imidazole, 1-methyl-
2-bromo-methyl-5-nitro-lmidazole, 1-methyl-2-iodo-methyl-5-nitro-. ~.
imidazole, 1-methyl-2-acetyloxy-methyl-5-nitro-imidazole, 1- . '~
methyl.-2-benzoyloxy-methyl-5-nitro-imidazole,.1-methyl-2-(4~
nitrobenzoyloxy)-methyl-5-nitro-imidazole or 1-methyl-2-(toluene~ `
sulfonyloxy)-methyl-5-nitro-imldazole.: - .:~
,::.
These starting compounds of formula I~I may be prepared ac- .:~
cording to German Offenlegungsschrift No. 1,595,929 by reacting ~ ::
1-methyl-2-hydroxymethyl-5-nitro-imidazole (cf. German Offen~
legungsschrift No. 1j470,102) with a thionyl halide, or by re- .
acting it with an acetyl, benzoyl, 4-nitrobenzoyl.or 4-toluene-
~ 3 ~
~'.'`~';~,
r-~
,,
-~ HOE 75/F 183 K
~69911~
sulfonyl halide or anhydride.
As starting compounds of formula III, there may be used,
for example, 4-methyl-mercapto-phenol, 4-ethyl-mercapto-phen~ ,
4-methyl-sulfinyl-phenol, 4-ethyl-sulfinyl-phenol, 3-methyl-, 3-
fluoro-, 3-chloro-, 3-bromo-, 3-iodo-4-methyl-, -~-ethyl-mercapto-
phenol, 3-methyl-, 3-fluoro-, 3-chloro-, 3-bromo-/ 3-iodo-4
methyl- or -4-ethyl-sulfinyl phenol.
Instead of the free phenols, the alkali metal or ammoni-
um salts thereof may also be used.
The starting compounds of ~ormula III may be prepared by
reacting 4~mercapto-phenol corresponding substituted in 3-position
with one molar equivalent ofadialkyl sulfate in the presence of
one molar equivalent of an alkaline substance, a dialkyl sulfate
used being dimethyl or diethyl sulfate.
The alkyl-sulfinyI-phenols are prepared by reacting an
alkyl-mercapto-phenol with a molar e~uivalent of an oxidizing
agent, for example hydrogen peroxide or a peroxo acid, for example
peracetic acid, perbenzalc acid, or m-chloroperbenzoic acid, as
well as nitric acid or chromic acid.
As starting material of formula IV, t~ere are mentioned ,
l-methyl-2-(4-mercaptophenyl-oxymethyl(-5-nitro-imidazole, 1-
methyl-2-(3-methyl-4-mercaptophenyl-oxymethyl)-5-nitro-imidazole,
l-methyl-2-(3-fluoro-4-mercaptophenyl oxymethyl)-5-nitro-imi-
dazole, l-methyl-2-(3-chloro-4-mercaptophenyl-oxymethyl)-5-nitro-
imidazole, l-methyi-2-(3-bromo-4-mercaptophenyl-oxymethyl)-5-nitro-
imidazole,1-methyl-2-(3-iodo-4-mercaptophenyl-oxymethyl)-5-nitro-
imidazole, or an alkali metal salt thereof. Since the mercapto
compounds easily oxidize in the air to yield disulfides, their
-i isolation is avoided and, instead, the mercapto compound in
-- 4
. ,.., . : , .: . .. ., ,.:: :,:". : ,: : , , . ,::
. : .. ::, ... : : :: ,, . , ::, .. , .,, .. , :. :., . " . .:.. :.,.:.:. , , ' . " ,.. . .:: :.:
HOE 75/F 183 K
69~
- question is alkylated in stat;u nascendi to yield the end product
of formula I.
This compound is obtained by hydrolysis of the correspond-
ing 'I-methyl-2-(4-thiocyanatophenyl-oxymethyl)-5-nitro-imidazole' -
with.concentrated sulfuric acid at room tempera-ture under a
nitrogen atmosphere in the presence of an alkylating agent, ~or
example dimethyl sulfate. 1-Methyl-2-(4-thiocyanatophenyl-oxy-
methyl)-5-nitro-lmidaæole (m.p. 140C~ and the R2-substi'tuted
- produts thereof are obtained by reacting a compound of formula
II with 4-thiocyanato-phenol. - '
Methods a) and b) of the process of the inventlon are-
advantageously carried out using equimolar amounts of the start-
ing compounds used, advantageously in a solvent or dispersing
agent in the case of a).
Method b) of this process may also be carried out in the
--,.
absence of such a solvent or dispersing agent. In this case,
the alkylating agent used as a reaction component in excess
~erves as the reaction medium. -'
' For ~he reactions accordiny to method a), polar solvents
2G are preferably used, for example alcohols, such as methanol,
ethanol, propanol,'isopropanol, butanol, 2-methoxy-ethànol, 2~
ethoxy-ethanol; ketones, such as acetone, diethyl-ketone, methyl-'' ~; ;
- . .~-.
- ethyl-ketone, methyl-isobutyl-ketone; amides, such as dimethyl-
.
~ formàmide, dimethylacetamide, N-methyl-pyrrolidone, tetramethyl-
urea, hexamethyl phosphoric acid triamide, dimethyl-sulfoxide; -'
heterocyclic bases, such as pyridine, picoline or quinoline.
When the free phenols of formula III are used, it is ad-
vantageous to use an acid scavenger, for example a base , such ';;~
~9 as triethylamine or pyridine, and alkali metal or alkaline earth -
- 5 - ;
L~
HOE 75/F 183 K
69~
metal carbonat:es and bicarbonates, hydroxides and alkoxides, or
example methoxide, ethoxide or butoxide.
- The reaction temperature suitable for method a) ranges from
.
0 to 80C, but advantageously it is room temperature~ The re-
,
action time ranges from a few minutes to several hours.
The alkylation reaction temperature for method b) ranges
from 20 to 80C, preferably from 20 to 60C. The reaction time
ranges from four to eighteen hours.
As alkalyting agents, there are used,- for example, methyl
1Q or ethyl halides, especially the iodides; dimethyl or diethyl
si1lfate; and arylsulfonic acld esters, especially 4-toluene~
~ . . ..
sulonic acid methyl or ethyl ester. ---
- The sulfides of formula I (A = -S-), obtained according to
the said methods a) and b), may be converted by oxidation into
the corresponding sulfoxides (A= -So-~, The oxidation reaction
is suitably carried out using one molar equivalent of an oxidiz-
ing agent, for example hydrogen peroxide or a peroxo acid l such
as peracetic acid, perbenzoic acid, m-chloroperbenzoic acid, as ~ -
well as nitric acid or chromic acid. The oxidation temperature
generally ranges from 0 to 30C.
- :,
The products of t~e invention are isolated accordin~ to ;~
the-usual methods by distillation of the solvent used or dilution -~
of the reaction solution with water, optionally foll~wed by a
purification by recrystallization from a suitable solvent or
mixture of solvents.
The new 1-methyl-2-(phenyl-oxymethyl)-5-nitro-imidazoles
of formula I according to the invention are suitable for the
treatment of protozoal diseases in humans and animals as caused,
29 for example by infections with Trichomonas vaginalis and Enta-
:
.. .'
;:
`
HOE 75/F 183 K
69910
moeba hist*lytica. Moreover, they are effectlve against bacteria
and fungi~
The new compounds of the invention may be administered by `
- the oral or local route. The oral administration is generally
- 5 made-in the form of tablets or capsules containing, per daily
dosage unit, from about 10 to 750 mg of the active ingredient,
in admixture with a conventional diluent and/or ~xipient. De- ~`
pending on the case, the individual dosage unit ranges from 2
to 100 mg of active substance per kg of body weight of the
1Q patient. For local administration, gels, creams, ointments or
suppositories may be used.
The following Examples illustrate the invention.
E X A M P L E 1: (Method a)
': ` ' : -
~ Methyl-2-(4-methylthiophenyl-oxymethyl)-5-nitro-imidazole
~ 13.8 Grams (0.1 mol) of a potassium carbonate powder
are added to a solution of 14.0 g (0.1 mol) of 4-methylmer-
capto-phenol in 30 ml of dimethylformamide; then a solution
of 17.6 g (0.1 mol~ of 1-methyl-2-chloromethyl 5-nitro-imi-
dazole in 40 ml of dimethylformamide is added dropwise while
2a stirring at 25~C. The weakly exothermic reaction is kept -;
at a maximum temperature of 35C by cooling with ice water.
Stirring o the mixture is continued for 1 hour at 25C, ;;
the reaction mlxture is poured onto ice/water, the-precipi-
- tate is suction-filtered, washed with water and recrystalliz-
` 25 ed from methanol with an addition of charcoal.
In thls manner, 19.5 g (70 ~ of the theoretical yield)
of 1-methyl-2-(4-methylthiophenyl-oxymethyl)-5-nitro-imida-
zole are obtained as light-yellow crystals, melting point:
29 116C.
-- F-~
, :
~6~9~
HOE 75/F 183 K
According to the process described above, the following
compounds are prepared:
1.2: From l-methyl-2-chloromethyl-5-nitro-imidazole (MCNI) and
4-ethyl-mercapto-phenol, the 1-methyl-2-(4-ethylthio-
phenyl-oxymethyl)-5-nitro-imidazole, m.p. 90C.
1.3: 1-Methyl-2-(3-methyl-4-methylthiophenyl-oxymethyl)-5-nitro-
,
imidazole
To a solution of 15.4 g (0.1 mol of 3-methyl-4-methyl-
mercaptophenal in 30 ml of dimethylformamide, 13.8 g (0.1 mol) of ;'
potassium carbonate powder are added, and then a solution of~l7.6 g
(0.1 mol) of 1-methyl-2-chloromethyl-5-nitro-imidazole in 40 ml of
dimethylformamide is added dropwise while stirring at 25C. The
temperature of the faintly exothermaL reaction is adjusted to at
most 35C by cooling with ice water. ~he mixture is then stirred
lS for another hour at 25C, poured onto ice/water, the precipitate
is suction-filtered, washed with water and recrystallized from
methanol with an additlon of charcoal to yield 21.7 g (74 ~ of
~the theoretical yield) of l-methyl-2-(3-methyl-4-methylthlophenyl-
~oxymethyl)-5-nitro-imidazole in the form of yellow crystals, m.p.
:::
~108C.
According to this method, the following compounds are
prepared:
1.4: From l-methyl-2-chloromethyl-S-nitro-imidazole (MCNI) and
3-methyl-4-ethylmercaptophenol, the 1-methyl-2-(3-methyl-
4-ethylthiophenyl-oxymethyl)-5-nitro-imidazole, m.p. 80C;
1.5: from MCNI and 3-chloro-4-methylmercaptophenol, the l-methyl-
2-(3-chloro-4-methylthiophenyl-oxymethyl)-5-nitro-
`-'28 imidazole, m.p. 114C, and
~ 8 -
99~ _ E 75/F 183 K
~''
1.6: from MCNI and 3-chloro-4-ethylmercaptophenol, the 1-methyl-
2-(3 chloro-4-ethylthiophenyl-oxymethyl)-5-nitro imidazole
m.p. 86C. -
E X A M P L E 2: ~oxidation)
2 1: 1-Methy ~ - ;
.
:, :
imidazole
::
27.9 Grams (0.1 mol) of 1-methyl-2-(4-methylthiophenyl-
oxymethyl)-5-nitro-imidazole are dissolved in 200 ml of
chloroform, and the solution is added dropwise while stir-~
~0 ring at 25C to a solution of ~7.25 g (0.1 mol) of m~chloro~
- ,~
perbenzoic acid in 70 ml of chloroform~ The reaction mix-
ture is stirred for 1 hour at 25C, the solution is shaken -~
with dilu-te sodium carbonate solution, the chloroform phase
,~. ,.~,
is separated, dried over sodium sulfate and~evaporated.
The residue is recrystallized from ethanol with the addi-
tion of charcoal.
Thus, 21.5 g (73 % of the theoretical yield) of 1-
methy1-2-(4-methyl-sulfinylphenyl-oxymethyl~-5-nitro-imi-
.:,:
dazole are obtained as yellowish crystals, m.p. 130C.
According to the method described above, the followirlg
compound is prepa~ed:
2.2: Erom 1-methyl-2-(4-ethylthiophenyl-oxymethyll-5-nitro-imi-
.
dazole, the 1-methyl-2-(4-ethylsulfinylphenyl-oxymethyl)~
5-nitro~imidazole, m.p. 103C. ;
2.3: 1-M~ -2-(3-methyl-4-methylsulfinylphenyl-oxyme hyl)-5-
nitro-imidazole
29.3 g (0.1 mol) of i-methyl-2-(3-methyl-4-methylthio-
phenyloxymethyl)-5-nitro-imidazole are dissolved in 200 ml
29 of chloroform, and the solution is added dropwise while
6 9
~ -r
HOE 75/F 183 K
-- 106~91~
stirring at 25C to a solution of 17.25 g (0.1 mol) of
3 - chloroperbenzoic acid in 70 ml of chloroform. The
reaction mixture is stirred for 1 hour at 25C, shaken
with dilute sodium carbonate solution, the chloroform
phase is separated, dried o~r sodium sulfate and con-
centrated by evaporation. The residue i5 recrystallized
from ethanol with an addition of charcoal, to yield 21.0
g (68 % of the theoretical yield) of 1-methyl-2-(3-
methyl-4-methylsulfinylphenyl-oxymethyl)-5-nitro-imida-
zole in the form of yellow crystals, m.p. 121C.
According to this method, the following compounds are
prepared:
2.4: From l-methyl-2-~3-methyl-4-ethylthiophenyl-oxymethyl)-5-
nitro-imidazole, the l-methyl-2-(3-methyl-4-ethylsul-
finylphenyl-oxymethyl)-5-nitro-imidazole;
2.5: from 1-methyl-2-(3-chloro-4-methylthiophenyl-oxymethyl)-5-
nitro-imidazole, the l-methyl-2-(3-chloro-4-methylsul-
finylphenyl-oxymethyl)-S-nitro-imidazole, and
~2.6: from 1-methyl-2-(3-chloro-4-ethylthiophenyl-oxymethyl)-5-
~ ~ nitro-imidazole, the 1-methyl-2-(3-chloro-4-ethylsul-
finylphenyl-oxymethyl)-5-nitro-imidazole.
~E X;A M P L E 3: (Method b)
3.1: 1-Methyl-2-~4-methylthiophenyl-oxymethyl)-5-nitro~imidazole
5.8 g tQ.02mols) of 1-methyl-2-(4-thiocyanatophenyl-
oxymethyl)=5-nitro-imidazole are introduced portionwise
while stirring, under a nitrogen atmosphere~ at room
temperature, into a mixture o~ 26.5 ml of concentrated
sulfuric acid and 5.0 g ~0.04 mol) of dimethylsulfate
and allowed to stand overnight at room temperature.
3D The solution is then heated to 60C for 30 minutes,
cooled and poured
- 10 -
, , : ,: . . , .. : . ,: ',:. . :'::. ::: ~,: ' .. :-.: :
~ HOE 75/F 183 K
~L~369~
.
onto ice/water. The precipitate is suction-filtered and -~
washed with water. In addition to bis-4,4'-(1-methyl-5-
nitro-imidazolyl-2-methoxy)-diphenyl disulfide (m.p. 160C),
column chromatographical purification on silica gel yields
the 1-methyl-2-(4-methylthlophenyl-oxymethyl)-5-nitro-
imidazole, m.p. 116C.
:
~ .
'. ~ :
:: .
. . *
~. .
:~ :
. - .
. : :
~:
:
'
.
-- 1 1 ---
' ' ' " ' ' ; ' ` ' ; '; ! ~ , , ., .; "
.` ` . ' . . : . , ' , :,`.: . ,. , ~`,. ' '' ' :' ':',' ,':,
