Note : Les descriptions sont présentées dans la langue officielle dans laquelle elles ont été soumises.
1~78390
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NEW NITROIMIDAZOLES
This invention relates to nitroimidazolylvinylthiadiazoles,
their production, and formulations containing same for use as
chemotherapeutics in the treatment of microbial infections in
humans and animalsO .
It is known that nitroheterocycles such as nitrofurans,
nitrothiazoles and nitroimidazoles are effective as agents for
treating baoteria, fungi and Proto~oa. The minimum inhibition
concentrations of prior art preparations, for example metroni-
dazol or tinidazol, are of the order of between Ool and 2 /ug/mlO .
However, their action and tolerance levels are not always satis-
factory. There is therefore a need to synthesize new compounds
with increased effectivenessO
We have now found that compounds of formula I
02N~ -CH = C~,~ -113
where R1 i8 alkyl of 1 to 4 carbon atoms which may be substi-
tuted by hydroxy or alkoxy of 1 to 4 carbon atoms in the alkyl,
R2 is hydrogen or methyl, and R3 is hydrogen, alkyl of 1 to 24
carbon atoms, unsubstituted or substituted phenyl, or hetro-
aryl have valuable pharmacological propertiesO
, , , . . ; j~. .,... ~
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Examples of R are methyl, ethyl, isopropyl, n~t~,
~-hydroxyethyl, ~-methoxyethyl or ~-ethoxyethylO
Examples of suitable alkyl radicals of 1 to 24 carbon ^
atoms for R3 are methyl, ethyl, n-propyl, i-propyl, n-butyl,
sec. butyl, isobutyl, amyl, n-hexyl, n-heptyl, n-octyl, 2-ethyl-
hexyl, nonyl, decyl, undecyl, dodecyl, tridecyl, pentadecyl,
octadecyl, cosyl, docosyl and tetradocosylO -
When R~ is phenyl, the latter may be substituted once or
several times, preferably once or twice, by radicals inert
under the conditions of preparationO Special mention should be
made of the ~ollowing as inert substit~lents D halogen, such as
fluoro, chloro, bromo, iodo, nitro and alkyl of 1 to 4 carbon
atoms which in their turn may be substituted by one or more
halogen atoms, such as trifluoromethyl, alkoxy of 1 to 4 carbon
atoms, acylated and dialkylated amino groups each w;th 1 to 4
carbon atoms in the alkyl or acylO Examples of substituted
phenyl are 2-fluorophenyl, 4-fluorophenyl, 3-chlorophenyl,
2-bromophenyl, 3-bromophenyl, 4-iodophenyl, 2,4-dichlorophenyl,
3,5-dichlorophenyl, 2-methylphenyl, 3-ethylphenyl, 4-i-propyl-
phenyl, 2,4-dimethylphenyl, 3,5-dimethylphenyl, 4-nitrophenyl,
3,5-dimethoxyphenyl, 4-dimethylaminophenyl, 4-trifluoromethyl-
phenyl and 4-acetylaminophenyl.
Examples of suitable heteroaryl radicals for R3 are
pyridyl, furyl, thienyl, oxadiazolyl and thiadiazolylO
Of the radicals mentioned above the following are pre-
ferred: for R methyl, ethyl, R hydroxyethyl, ~-methoxyethyl
and ~-ethoxymethyl, for R2 hydrogen and methyl, and for R3
alkyl of 1 to 13 carbon atoms, of which alkyl of 1 to 6 carbon
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Or Z~ 31,601/32,183
atoms and phenyl are particularly preferred; of the heteroaro-
matic radicals pyridine, which may be attached in the 2-, 3- or
4-position, is particularly preferredO Preferred substituted
phenyl radicals are 2-chlorophenyl, 3-chlorophenyl, 4-chloro-
phenyl, 2-methylphenyl, 3-methylphenyl, 4-methylphenyl, 4-di-
methylaminophenyl and 4-nitrophenyl.
Of these compounds those in which R1 is methyl, R2 is
hydrogen or methyl and R3 is hydrogen, methyl, ethyl, phenyl or
pyridyl are particularly preferred~
The compounds of the ;nvention may be prepared by reacting
in known manner 2-substituted 1,3,4-thiadiazoles of the general
formula II
3 ~ ~ R,2 II
R CH2
where R2 and R3 have the above meanings with a 5-nitroimidazole-
2-carboxaldehyde of the general formula III
N
02N R1 CH0
..
where R1 has the above meanings at elevated temperatures and in
the presence or absence of an acid condensation catalyst and
in the presence or absence of a solvent. The aldehydes of
formula III may also be used as acetals or acy~a~ls; special
mention should be made here of acetals obtained from reactions
with methanol and ethanol and the acylal obtained from reaction
with acetic acid.
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The reaction can be represented by the following equation
N - N ~ N- N
2 ,~ CH0 R ~ 02N ~ -CH=CH ~S~ -R3
Some of the 1,3,4-thiadiazoles of formula II used as
starting materials are known compounds or can be easily obtained
for example by the process described by Ro Stollé, BerO dtschr
chemr Ges. 32~ 797 (1899)3 in which N,N'-diacylhydrazines are
reacted at elevated temperature with P2S5 in an aromatic hydro-
carbon, eOgO, xyleneO
The compounds of the invent;on may be advantageously pre-
pared by reacting a compound of formula II with a compound of
formula III or its acetal or acylal at temperatures of between
50 and 220C preferably in the presence of an acid condensation
catalyst, e.gO a Lewis acid, a mineral acid or an acid ion
exchanger, and, if desired, in the presence of a solvent~
When a solvent is used the preferred temperature range is
between 90 and 150C, and when no solvent is used the preferred
range is between 150 and 200Co
Suitable catalysts are the acid condensation catalysts con-
ventionally used in aldehyde condensation which are employed in
amounts of 00005 to 1 mole, preferably 0O05 to 002 mole, of
catalyst per mole of starting material IIo Examples of acid con-
densation catalysts are polyphosphoric acid, borofluoride and
zinc chlorideO The preferred catalyst ;s zinc chloride.
The starting materials are generally used in a stoichio-
metric ratio, although one of the compounds may be used in an
excessO The reaction is generally carried out at atmospheric
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pressure; superatmospheric or subatmospheric pressure may how-
ever be an advantage in specific cases. The reaction may be
ef~ected in the presence or absence of a solventO Solvents that
have proved particularly suitable are lower carboxylic acids
such as acetic acid and propionic acid, their anhydrides and
mixtures of a lower carboxylic acid and the particular anhydrideO
In the mixtures of carboxylic acid and carboxylic anhydride
the ratio is advantageously between 9:1 and 1~9~
Generally the reaction is over within a few hours. Working
up presents no problems; it can be effected for example by the :
addition of a precipitating agent, especially water or acetone,
to the reaction mixture, precipitation o~ the reaction product,
suction ~iltration, washing with water and alcohol, and recry-
stallization ~rom a suitable solvent~
The ~ollowing compounds are specified in addition to those
described in the Examples:
2-thienyl-5- C~ methyl-5-nitroimidazol-2-yl~-vinyl]-1,3,4-
thiadiazole
2-n-propyl-5- C-ethyl-2-(l-methyl-5-nitroimidazol-2-yl)-viny~ -
1,3,4-thiadiazole
2-ethyl~5-~1-methyl-2-(1-ethyl-5-nitroimidazol-2-~ lny~ -
1,3,4-thiadiazole
2-methyl-5-~2-(1-ethyl-5-nitroimidazol-2-yl)-vinyl]-1,3,4-
thiadiazole
2-thienyl-5- ~-methyl-2-(1-methyl-5-nitroimidazol-2-yl)-vinyl~-
1,3,4-thiadiazole
2-furyl-5- L2-(1-methyl-5-nitroimidazol-2-yl)-~11,3,4-thiadia-
zole
,. . .: . . : ::~: . :: ,.
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2-methyl-5-L2-~1-hydroxyethyl-5-nitroimidazol-2-yl)-viny ~-
1,3,4-thiadiazole
2-ethyl-5-~1-methyl-2-(1-hydroxyethyl-5-nitroimidazol-2-yl)-
viny~ -1,3,4-thiadiazole.
The compounds of the invention exhibit a good action on
microorganisms. They are outstandingly ef~ective for the treat-
ment o~ infections by Flagellata, especially Trichomonas and
Trypanosoma, and by Entamoaba histolytica in humans and animalsO
They may also have a very good bacterial action in thresh-
1~ hold concentrations of ~10 5, for example the compounds of
Working Examples 6 and 70
Table 1
Minimum inhibition concentrations (MIC) on Trichomonas
~aginalis
Compound MICRelat;ve effectiveness
~ug/ml~Metronidazol = loO
Example 1 0.02 500
Example 2 0.01 10.0
Example 5 0~01 10.0
Example 10 ~ Or Ol~ 10 o O
Example 6 ~ 0.01 >lOoO
Example 7 ~ 0.01> lOo O
Metronidazol 0.1 loO
Trinidazol Ool 100
The tests were carried out in vitro using the quantitative
tube-dilution test described by P0 Klein, Bakteriologische
Grundlagen der chemotherapeutischen Laboratoriumspraxis,
Springer-Verlag Berlin-Goettingen-Heidelberg, 1957.
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.......
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It is surprising that with the introduction of a thiadia-
zole radical attached via an ethylene bridge it has been possible
to exceed the e~fectiveness of prior art commercial products,
e.gO, metronidazol and tinidazol, against Trichomonada infec-
tion~ up to more than ten times~
Special mention is made of the compounds of Examples 1,5,
7 and 10 for their action on Trichomonada7
The action against infections caused by Trypanosomas and `
Entamoeba histolytica can be illustrated on the mouse (NMRI
strains) using methods described in Handbuch ~r experimentelle
Pharmakologie, Erganzungswerk 16, Erzeugung von Krankheitszu-
~tanden durch das Experiment, Part 9, pages 150 to 292, Springer-
Verlag, Berlin-Goettingen-Heidelberg, 1964~
1. Trypanosoma brucei - ;nfections o~ the mouse
Various dosages were ;nvestigatedO The curing o~ the in-
fection was determined microscopically and in a culture~ There
was also po~t-observation for 25 days after treatment was dis-
continued in order to establi~h whether there was any recidivation.
Example 1 lx50 mg/kg perorally, acute 100% action, 70%
recidivation
Example 2 llx50 mg/kg perorally, no action
Example 5 llx50 mg/kg perorally~ no action
Example 10 llx50 mg/kg perorally, acute 100% action, no
recidivation
Example 6 llx50 mg/kg perorally, no action
Example 7 llx50 mg/kg, acute 100% action, 30~ recidivation
Suramin, 7x50 mg/kg intraperitoneally, acute 80% action,
no recidivation
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Metronidazol llx50 mg/kg perorally, no action
Tinidazol 22x50 mg/kg perorally, no action
20 Trypanosoma gambiense - infection of mouse
Same method as in the case of Trypanosoma brucei
Example 1 llx50 mg/kg perorally, acute 100% action, 80%
recidivation
Example 2 llx50 mg/kg perorally, no action
Example 5 llx50 mg/kg perorally, no action
Example 10 llx50 mg/kg perorally9 acute 100% action, 60%
recidivation
Example 6 llx50 mg/kg perorally, no action
Example 7 llx50 mg/kg perorally, no action
Suramin 7x50 kg/kg intraperitoneally, acute 50% action,
no recidivation
3. Trypanosoma congolense - infection of mouse
Same method as in the case of ~rypanosoma brucei
Example 1 llx50 mg/kg perorally9 acute 100% action, 20% no
recidivation
Example 2 llx50 mg/kg perorally, no action
Example 5 llx50 mg/kg perorally, no action
Example 10 llx50 mg/kg perorally, acute 100% action, no
recidication
Example 6 llx50 mg/kg perorally, no action
Example 7 llx50 mg/kg perorally, no action
Suramin 7x50 mg/kg intraperitoneally, acute 70% action.
no recidivation
". ~: ,
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4. Entamoeba histolytica (tube-dilution test)
The PN and Q strains were tested.
The minimum inhibition concentrations were as follows:
Example 1 ~ 0.01 /ug/ml
Example 2 0.1 "
Example 5 ~ 0.01 "
Example 10 < 0.01 "
Example 6 ~ 0.01 "
Example 7 ~ OoOl tt
Mentronidazol 0.1 "
The experiments were carried out in vitro using the
quantitative tube-dilution test described by PO Klein,
Bakteriologische Grundlagen der chemotherapeutischen Laboratoriums-
praxis, Springer-Verlag, Berlin-Goettingen-Heidelberg, 19570
The results show that special mention should be made of
the compounds of Examples 1 and 10 by virtue of their action
and in comparison with Suramin,which is the constituent of the
prior art preparations Germanin and Naganol. The action on
Entamoeba histolytica in vitro can also be described as very
good to good. As can be seen from the Table the action of
metronidazol is surpassed more than 10 times~
5~ Trichomonas vaginal - infection of mice
~arious dosages were investigatedO The curing of the in-
fection was determined microscopically and in a culture.
Example 1 100% cure with 5x25 mg/kg perorally
Example 2 10% cure with 5x50 mg/kg perorally
Example 5 100% cure with 5x25 mg/kg perorally
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Example 10 100% cure with 5x25 mg/kg perorally
Example 6 50% cure with 5x50 mg/k~ perorally
Example 7 100% cure with 5x50 mg/kg perorally
Metronidazol 100% cure with 5x25 mg/kg perorally
Tinidazol 100% cure with 5x25 mg/kg perorally
The LD 50 toxicity figures for the compounds of Examples 1,
7 and 10 on mice, NMRI strain, administered orally and with a
week's observation period are over 1500 mg/kg~
The compounds of the invention can therefore be administered
to humans and animals for therapeutic purposes ~or the treat-
ment of trichomoniasis, trypanosomiasis and amoebic dysentery.
They are also suitable for treating leishmaniasis~
~ention should be made of the following preferred active
compounds:
2-phenyl-5- C2-(l-methyl-5-nitroimidazol-2-yl)-vinyl~-1,3,4-
thiadiazole
2-(4-pyridyl)-5- C2~ methyl-5-nitroimidazol-2-yl)-vinyl]-
1,3,4-thiadiazole
2-~2-(1-methyl-5-nitroimidazol-2-yl)-viny ~ -1,3,4-thiadiazole
2-ethyl-5- ~ -(1-methyl-5-nitroimidazol-2-yl)-viny~ -1,3,4-thia-
diazole.
Particularly preferred compounds are:
2-methyl-5-~2-(1 methyl-5-nitroimidazol-2-yl)-viny~ -1,3,4-
thiadiazole
and
2-ethyl-5- C-methyl-2-(l-methyl-5-nitroimidazol-2-yl)-viny~ -
1,3,4-thiadiazole.
The present invention accordingly also relates to chemo-
therapeutic agents or formulations for treating microbial in-
-- 10 --
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fections in humans and animals which contain a compound of for-
mula I as active ingredient in addition to the conventional
carriers and diluents, and also to the use of the new compounds
for therapeutic purposes.
The chemotherapeutic agents or formulations are manufactured
in a conventional manner using conventional carriers or diluents -
~and the conventionally used pharmaceutical auxiliaries in
accordance with the desired mode of administration in a suit-
able dosage unitO
The preferred formulations are suitable for oral admini-
strationO They may be in the form for example of tablets,
coated tablets, dragées, capsules, pills, powders or suspensionsO
On account of the relatively sparing solubility of the compounds
of the invention oral administration is preferredO
Naturally parenteral formulations, such as injection
solutions, are also suitable~ Suppositories are a further
example of formulations that can be used. For the treatment of
trichomoniasis pharmaceutical formulations for the vagina, such
as vaginal tablets, globuli and powders, are also suitable.
The dose to be administered depends on the nature and
the severity of the disorderO Amounts of up to 5 g per day may
be administered
Single doses to be administered several times a day if
desired are advantageously 50 to 1000 mg per doseO In the case
of Trypanosoma infections the single doses are advantageously
between 500 and 1000 mg, in the case of Entamoeba infections
between 100 and 500 mg, and in the case of Trichomonada infec-
tions between 100 and 300 mg.
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As a rule the single doses are administered from two to
five daily and generally treatment of Trypanosoma infections
lasts from 14 to 20 days, that of Entamoeba infections from 5 to
8 days, and that of Trichomonada infections al50 from 5 to 8
days.
For use in practise the compounds according to the invention
can be processed with the carriers conventionally used in
galenical pharmacy D
Tablets can be made for example by mix;ng the active ingre-
dient with known auxiliaries, for example inert diluents such
as dextrose, sugar, sorbitol, mannitolg PVP, calcium carbonate,
calcium phosphate and lactose, disintegrants such as lndian
corn, starchor alginic acid, binders such as starch or gelatines,
lubricants such as magnesium stearate or talcg and/or agents
for achieving a depot effect, such as carboxy~polymethylene,
carboxymethylcellulose, cellulose acetate phthalate or poly-
vinyl acetate. The tablets may also consist of a plurality of
coatings.
Accordingly~ dragees may be prepared by coating cores made
in the same way as the tablets with agents conventionally used
in dragee coatings, for example collidone or shellac, gum
arabic, talc, titanium dioxide or sugar. The shell of the
dragée may also consist of a plurality of coatings, and the
auxiliaries mentioned above in connection with the tablets may
be usedO
Suspensions of the active ingredients according to the
invention may also conta;n flavoring agents such as saccharine,
cyclamate and sugar, and for example aromatics such as vanillin
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or orange extractO They may also contain auxiliaries that pro-
mote suspension such as sodium carboxymethylcellulose, and pro-
tective colloids such as p-hydroxybenzoatesO Capsules containing
active ingredients may be manufactured for example by mixing the
active ingredient with an inert carrier such as lactose or sorbi-
tol and encapsulating the mixture in gelatine capsulesO Suitable
suppositories may be manufactured for example by mixing the
active ingredient with the appropriate carriers such as neutral
fats or polyethylene ~slycol or derivatives thereofO
EXAMPLE 1
Preparation of 2-methyl-5- [-(1-methyl-5-nitroimidazol-2-yl)-
vinyl~ -1,3,4-thiadiazole
11.4 g of 2,5-dimethyl-1,3,4-thiadiazole, 1505 g of 1-methyl-
5-nitroimidazole-2-carboxyaldehyde with 002 g of zinc chloride
are heated in a stirred apparatus for 10 hou~s at reflux tempera-
ture in a mixture of 50 ml of glacial acetic acid and 20 ml of
acetic anhydrideO After cooling, the precipitated solid is
washed with glacial acetic acid and recrystallized from dimethyl-
formamideO 1506 g of colored crystals, ~p = 248C, is obtained,
corresponding to 62% of the theoryO
EXAMPLE 2
2-phenyl-5-~-(1-methyl-5-nitroimidazol-2-yl)-vinyl~l-1,3,4-
thiadiazole
1706 g of 2-methyl-5-phenyl-1,3,ll-thiadiazole, 1505 g of
1-methyl-5-nitroimidazole-2-carboxaldehyde and 005 g of ZnC12
are heated in 100 ml of acetic acid and 50 ml of acetic anhydride
for 7 hours at reflux temperatureO After water has been added to
the reaction mixture, the precipitated solid is recrystallized
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from glacial acetic acidO 1705 g of a product melting at 257C
is obtained, corresponding to 56% of the theory.
EXAMPLE 3
2-(2-chlorophenyl)-5- ~-(1-methyl-5-nitroimidazol-2-yl)-viny ~ -
1,3,4-thiadiazole
21 g of 2-methyl-5-(2-chlorophenyl)-1,3,4-thiadiazole and
15.5 g of 1-methyl-5-nitroimidazole-2-carboxaldehyde are heated
with 005 g of ZnCl2 in a mixture of 100 ml of acetic acid and
50 ml of acetic anhydride for 6 hours at reflux temperatureO
After cooling, ether is added to the reaction mixture, and the
precipitated solid is washed with water and recrystallized from
dimethylformamideO 1805 g of product is obtained, corresponding
to 53% of the theoryO The compound melts at 239Co
EXAMPLE 4
2-~4-chlorophenyl)-5- ~-(1-methyl-5-nitroimidazol-2-yl)-vinyl~-
1,3,4-thiadiazole
21 g of 2-methyl-5-(4-chlorophenyl)-1,3,4-thiadiazole and
2208 g of 1-methyl-5-nitroimidazol-2-carboxaldehyde are heated
with 0~5 g of ZnC12 in a mixture of 100 ml of acetic acid and
50 ml acetic anhydride for 5 hours at reflux temperatureO After
cooling, ether is added to the reaction mixture, and the pre-
cipitated solid is washed with water and recrystallized from
dimethylformamideO 2705 g of product of obtained, corresponding
to 77% of the theoryO The compound melts at 268Co
EXAMPLE 5
2-(4-pyridyl)-5- ~2-(1-methyl-5-nitroimidazol-2-yl)-viny~ -1,3,4-
thiadiazole
808 g of 2-methyl-5-(4-pyridyl)-1,3,4-thiadiazole and 7.7 g
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of 1-methyl-5-nitroimidazole-2-carboxaldehyde are heated with
0.2 g of ZnC12 in a mixture of 50 ml of glacial acetic acid and
25 ml of acetic anhydride for 6 hours at reflux temperature.
After cooling, the precipitated solid is suction filtered,
washed with concentrated ammonia and recrystallized from dimethyl-
formamide. The melting point of the product obtained is 240 -
241C
EXAMPLE 6
_
2- 2-(1-methyl-5-nitroimidazol-2-yl)-viny ~ -1,3,4-thiadiazole
0.3 g of zinc chloride is added to 15.5 g of 1-methyl-5-
nitroimidazol-2-carboxaldehyde which has been dissolved in 100 ml
of acetic acid and 50 ml of acetic anhydride and the whole is
dripped into 10 g of 2-methyl-1,3,4-thiadiazole, which has been
dissolved in a mixture of 100 ml of acetic acid and 50 ml of
acetic anhydride, over a period of 5 hours at reflux tempera-
tureO After 24 hours the reaction mixture is freed of the solvent
by evaporation and ether is addedO After the reaction product
has been washed with water it is recrystallized from xylene.
9.3 g of product, corresponding to 39% of the theory, is ob-
tained. The compound melts at 214C.
EXAMPLE 7
2-ethyl-5- C2~ methyl-5-nitroimidazol-2-yl)-vinyl} 1,3,4-
thiadiazole
A solution of 15O5 g of 1-methyl-5-nitroimidazole-2-
carboxaldehyde in 50 ml of acetic acid and 25 ml of acetic an-
hydride is added at reflux temperature over a period of 10 hours
to 12.8 g of 5-ethyl-2-methyl-1,3,4-thiadiazole and 0.5 g of
ZnCl2 which have been dissolved in 100 ml of acetic acid and
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. . . ;: .
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50 ml of acetic anhydrideO The mixture is kept at reflux tem-
perature for a further 20 hours and the solvent is then eva-
poratedO The residue is washed with acetone and passed through
a ready-to-use silica gel column (Type A of MessrsO ~lerck) and
eluted with C~Cl3/CH30H = 98 : 2~ 5.6 g of the abovementioned
reaction product with a melting point of 165C is obtained; this
corresponds to 21% of the theory
EXAMPLE 8
2-methyl-5- C-methyl-2-(1-methyl-5-nitroimidazol-2-yl)-vinyl~-
1,3,4-thiadiazole
The acetone solution from Example 7 is concentrated, the
residue passed through a ready-to-use silica gel column (Type A
of Messrs Merck) and eluted with CHCl3/CH30H = 98 ~ 20 Yield
5.4 g, melting point 249Co There is also obtained 304 g of the
stereoisomeric compound with a melting point of 155Co
The total yield from Examples 7 and 8 is 54% of the theoryO
EXAMPLE 9
2-n-tridecyl-5-~2-(1-methyl-5-nitroimidazol-2-yl)-viny~ -1,3,4-
thiadiazole
8045 g of 2-tridecyl-5-methyl-1,3,4-thiadiazole, 4,65 g of
1-methyl-5-nitroimidazole-2-carboxaldehyde and 005 g of zinc
chloride are heated in 40 ml of acetic acid and 15 ml of acetic
anhydride for 24 hours at reflux temperatureO After the solvent
has been removed, the residue is recrystallized from alcoholO
701 g of product is obtained, corresponding to 61% of the theory.
The melting point is 91C.
EXAMPLE 10
2-ethyl-5~ methyl-2-(1-methyl-5-nitroimidazol-2-yl)-vinyl~-
1,3,4-thiadiazole
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4.65 g of 1-methyl-5-nitroimidazole-2-carboxaldehyde,
which has been dissolved in 80 ml of acetic acid and 35 ml of
acetic anhydride, is dripped into 1701 g of 2,5-diethyl-1,3,4-
thiadiazole, which has been dissolved in a mixture of 60 ml of
acetic acid, 25 ml of acetic anhydride and 0~5 g of zinc
chloride, over a period of 5 hours at reflux temperature. After
being heated for a further 24 hours at reflux temperature the
reaction mixture is concentrated by removing the solvent and
water is added. The precipitated reaction product is then sub-
jected to sublimation and recrystallized from propanolO 2 9 g
of product, corresponding to 35% of the theory, is obtainedO
The compound melts at 125Co
Examples of formulations prepared in conventional manner
1. Tablet
lo An active ingredient of formula I 120 mg
Lactose 200 mg
Methylcellulose 15 mg
Cornstarch 50 mg
Talc 11 mg
Magnesium stearate 4 mg
400 mg
20 An active ingredient of formula I 120 mg
Lactose 178 mg
Avicel 80 mg
Polywachs 6000 20 mg
Magnesium stearate 2 mg
400 mg
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2. Vaginal tablet
1. An active ingredient of formula I 80 mg
Lactic acid 30 mg
Glucose 670 mg
Lactose 200 mg
Hydroxypropylmethylcellulose20 mg
1 g
2. An active ingredient of formula I 80 mg
Boric acid 30 mg
Lactose 890 m~
1 g
30 Example of a tablet
1. Compound of Example 1 or Example 10
as active ingredient 200 mg
2~ Polyvinylpyrrolidone (mean MoWo 25~000) 20 mg
3. Polyethylene glycol tmean M~Wo 4~000) 14 mg
4~ Hydroxypropylmethyl cellulose40 mg
5~ Talc 4 mg
60 Magnesium stearate 2 mg
2 80 mg
The active ingredient is moistened with polyvinylpyrrolidone
in a 10% aqueous solution, passed through a sieve with 1.0 mm
apertures and dried at 50Co This granulated material is mixed
with polyethylene glycol (mean M.W. 4,000) hydroxypropylmethyl-
cellulose, talc and magnesium stearate and pressed into tablets
à 280 mg.
4. Example of a dragée
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1. Compound o~ Example 1 or Example 10
as active in~redient 150 mg
2. Lactose 60 mg
3. Cornstarch 30 mg
4. Polyvinylpyrrolidone 4 mg
50 Magnesium stearate 1 mg
245 mg
The mixture of active ingredient with lactose and corn-
starch is granulated through a 1. 5 mm sieve dried at 50C and
then passed through a lo 0 mm sieveO The granulated material thus
obtained is mixed with magnesium stearate and pressed into
dragée cores. The latter are then covered in conventional manner
with a coating consisting essentially of sugar and talcO
5. Example of a suppository
1 suppository contains
Active ingredient 250 mg
Suppository composition (eOg.,
Witepsol H 19) 1500 mg
1750 mg
The suppository composition is melted. At 38C the finely
pulverized ingredient is dispersed homogeneously in the melt. It
is then poured into precooled suppository molds at 35co
-- 19 --
. . -
