Note: Descriptions are shown in the official language in which they were submitted.
~03973Z
The present invcntion relates to imidazoles and processes for the
production thereof. The invention provides new imidazoles of the formula I
' '
,,L--N~N-X-R5 (1) ;
wherein one of the groups Rl and R2 is a hydrogen or lower alkyl and the other
a nitro group, R3 is a lower alkyl, hydroxyloweralkyl, loweralkoxyloweralkyl,
lower alkylsulphonylloweralkyl or aminoloweralkyl, X is a carbonyl, thio-
carbonyl, sulphinyl or sulphonyl group and R5 when X is a carbonyl group is
amino, loweralkylamino or diloweralkylamino group, and when X is a thiocarbonyl, -
sulphinyl or sulphonyl, R5 is a lower alkyl, aryl, amino, alkylamino or di-
loweralkylamino group, their salts and N-oxides.
The term "lower" as used hereinbefore or hereinbelow in connection
with the definition of organic compounds, groups and radicals, signifies that
such compounds, groups and radicals contain up to and including 7 carbon atoms
preferably up to 4 carbon atoms.
Examples of lower alkyl groups are preferably methyl, ethyl, n-
propyl, isopropyl, n-butyl, isobutyl, sec. butyl, tert. butyl, n-pentyl,
isopentyl, neopentyl, n-hexyl, iso-hexyl or n-heptyl groups.
~ydroxyloweralkyl groups have at most 7 carbon atoms, particularly
up to 4 carbon atoms, wherein the lower alkyl portion has the above mentioned
meaning, like e.g. hydroxymethyl, 3-hydroxy-n-propyl and particularly 2-
hydroxyethyl.
Loweralkoxyloweralkyl residues are e.g. those in which the lower
part has up to 7 carbon atoms, particularly up to 4 carbon atoms e.g. methoxy-
methyl, ethoxymethyl, n-propoxymethyl, n-butoxymethyl, 2-~n-butoxy)-ethyl,
3-(n-propoxy)-propyl or in particular 2-methoxyethyl.
Loweralkylsulphonylloweralkyl residues are e.g. lower alkyl groups
as mentioned above which carry a lower alkyl sulphonyl group such as methyl-
D
;
, .. - . . . . . .~ . . .
: - `
1039732
sulphonylmethyl, ethylsulphonylmethyl, 2-methylsulphonylethyl, n-propyl- ~
sulphonylmethyl, 2-n-propylsulphonylethyl, 3-n-propylsulphonyl-n-propyl or ~ -
ethylsulphonylethyl and in particular 2-ethylsulphonylethyl.
Aminoloweralkyl is e.g. an above mentioned lower alkyl which
carries an amino group, in particular a tertiary amino group. A tertiary
amino group is e.g. diloweralkylamino, such as dimethylamino, N-methyl-N-
ethylamino, diethylamino, di-n-propylamino or di-n-butylamino or loweralkylene-
amino in which the lower alkylene part may be interrupted by a hetero atom
such as oxaloweralkyleneamino, thialoweralkyleneamino or azaloweralkylene-
amino, e.g. pyrrolidino, piperidino, morpholino, thiomorpholino, 2,6-dimethyl-
thiomorpholino, piperazino, N'-methylpiperazino, or N'-(~-hydroxyethyl)-
piperazino. Aminoloweralkyl is e.g. dimethylaminomethyl, diethylaminomethyl,
2-dimethylaminoethyl, pyrrolidinomethyl, 2-pyrrolidinoethyl, 3-pyrrolidino-n-
propyl, piperidinomethyl, morpholino-methyl, 2-morpholino-ethyl, 2-thio-
morpholino-ethyl, piperazino-methyl, 2-piperazino-ethyl, N'-methyl-piperazino-
methyl, 3-(N-methylpiperazino)-n-propyl and N'-(~-hydroxyethyl)-piperazino-
methyl.
The aryl group R5 is an optionally substituted aryl residue e.g.
a phenyl or naphthyl group optionally substituted by one or more than one
substituent as well as an optionally substituted 5,6,7,8-tetrahydro-1-or 2-
naphthyl residue. Preferred are optionally mono- or di-substituted phenyl or
naphthyl radicals, particularly mono-substituted phenyl or naphthyl radicals
~nd especially mono-substituted phenyl radicals.
The aryl residue R5 may be substituted e.g. by the above-defined
loweralkyl groups, loweralkoxy groups, halogen atoms such as chlorine, bromine
or fluorine or by a trifluoromethyl gro~up.
The new compounds show valuable pharmacological properties. They
~ ~ show, in particular, activity against bacteria, especially against gram
; negative bacteria, protozoa e.g. trichomonads and amoeba and helminths, e.g.
~30 schistosomes and above all amoeba, as shown in experimental animals, e.g. on
the liver of hamsters infected with Entamoeba histolytica, at a dose between
10 and 100 mg/kg p.o.. Thus, the new imidazoles are useful against amoeba,
- 2 - r
~039'73Z - ~:
schistosomes, trichomonads and bacteria. Further, the new compounds are use-
ful as starting materials or intermediates for the preparation of other -
compounds, in particular, therapeutically active compounds.
The invention refers particularly to compounds of formula Ia
~ ~ ~Ia)
02N N N ~ N-X-R5
R3 ;~
wherein Rl represents hydrogen or a loweralkyl group, R3 a loweralkyl,
hydroxyloweralkyl, loweralkoxyloweralkyl, loweralkylsulphonylloweralkyl or
aminoloweralkyl group, X and R5 have the earlier defined meanings, their salts
and N-oxides.
Furthermore the invention refers particularly to compounds of
formula Ib,
02N " ________N
N y N~X~R5 ~Ib)
;~ wherein R2 represents hydrogen or a lower alkyl group, R3 a lower alkyl,
; hydroxyloweralkyl, loweralkoxyloweralkyl, loweralkylsulphonylloweralkyl or
aminoloweralkyl group, X and R5 have the earlier defined meanings, their
~` ; salts and N-axides. ;
Particularly the invention refers to compounds of formula Ia,
wherein Rl and R3 have the meanings as defined under formula Ia, X is a car-
bonyl group and R5 represents amino, loweralkylamino or diloweralkylamino
~` 2~ group and to compounds of formula Ib, wherein R2, R3 have the meanings as
define~d under formula~Ib, X is a carbonyl group and R5 is a amino, loweralkyl-
~- amino or diloweralkylamino group, their salts and N-oxides.
Also of particular interest are compounds of formula Ia and Ib,
wherein~Rl or R2, R5, have the me~nings defined above~ X is a thiocarbonyl
~ 3 ~
10397~Z
and R5 a loweralkyl, aryl, amino, loweralkylamino or diloweralkylamino group,
their salts and N-oxides.
Of particular interest are compounds of formulae Ia and Ib,
wherein Rl or R2, R3 have the meanings defined above and X is a sulphinyl or
sulphonyl group and R5 is a lower alkyl, aryl, amino, loweralkylamino or
diloweralkylamino group, their salts and N-oxides.
~ e invention concerns primarily of compounds of formulaeIa and
Ib, wherein Rl or R2 have the meanings given under formula Ia or Ib, R3
represents lower alkyl as for example methyl, ethyl or hydroxyloweralkyl as for
example ~-hydroxymethyl or ~-hydroxypropyl, X is a carbonyl group, and R5
amino, loweralkylamino or diloweralkylamino, their salts and N-oxides.
Of similar interest are compounds of formulae Ia and Ib, wherein
X is a thiocarbonyl, sulphinyl or sulphonyl group, Rl or R2 have the meaning
given under formulae Ia or Ib, R3 is a lower alkyl group as for example a
methyl or ethyl group or lowerhydroxy alkyl, as for example, ~-hydroxyethyl
or ~-hydroxypropyl and R5 an amino, loweralkylamino or diloweralkylamino group,
their salts and N-oxides.
Among the nitroimidazole compounds which are to be mentioned
especially are l-(methylsulphonyl)-2-oxo-3-[1-methyl-5-nitro-imidazolyl (2)]-
tetrahydroimidazole, 1-N,N-diethylcarbamoyl-2-oxo-3-[1-methyl-5-nitro-
imidazolyl(2)]-tetrahydroimidazol and 1-N,N-dimethylcarbamoyl-2-oxo-3-[1-
methyl-5-nitro-imidazolyl-(2)]-tetrahydroimidazol, 1-N-ethylthiocarbamoyl-2-
oxo-3-[1-methyl-5-nitro-imidazolyl-2]-tetrahydroimidazole, l-N-methylthio-
carbamoyl-2-oxo-3-[1-methyl-5-nitroimidazolyl-2]-tetrahydroimidazole whose
use result in eradication of abscess on the liver of healthy hamsters infected
with Entamoeba histolytica.
These compounds are thus useful as antiamoebic preparations for
which purposes doses of 10 to 100 mg/kg p.o. are indicated. '~
The new imidazoles are prepared by methods which are in themselves
3Q known. For example, compound of the formula I may be prepared by the reaction
of a compound of the formula II ;~
- 4 - ;
D
103973Z :
Rl N
/~,/\ t
R3
wherein Rl, R2 and R3 have the meanings defined earlier and Z is a hydroxy
group, esterified with an inorganic or organic acid, a free or etherified
; mercapto group, an ammonium group, a sulphinyl group or a sulphonyl group
with a compound of the formula III
: r ~
HN \ / N-X-R5 (III)
.~, ~
' .
;. O
` wherein R5 and X have the meanings defined under formula I.
A reactive esterified hydroxy group Z is, in particular, a hy-
droxy group that is esterified with an inorganic or organic acid, above all
hydrohalic acid, such as hydrochloric, hydrobromic or hydroiodic acid,
sulphuric acid or an organic sulphonic acid, such as an aromatic sulphonic
acid, e.g. benzenesulphonic, p-bromobenzene sulphonic or p-toluenesulphonic
acid, or an aliphatic sulphonic acid, such as an alkanesulphonic acid e.g.
methanesulphonic acid or ethanesulphonic acid.
¦ An etherified mercapto group is e.gu an optionally substituted
~I phenylmercapto or benzyl mercapto group or in particular a lower alkyl mer-
i capto group, such as ethyl or methylmercapto group.
; hn ammonium group is, in particular, a quaternary ammonium group,
above all a tri-loweralkyl ammonium group e.g. trimethyl or triethylammonium
~20 group or the cation of an aromatic nitrogen base e.g. pyridinium or quino-
linium group.
A sulphonyl group is, in particular, that of an organic sulphonic
acid, especially an aromatic sulphonic acid residue. The group Z stands pre-
ferably for benzenesulphonyl, p-bromobenzenesulphonyl, p-toluenesulphonyl or
above all methyl sulphonyl.
The reaction is carried out in the presence of a basic condensing
.
D - 5 _
-
103973Z
agent or the compound of formula II is reacted in the form of its N-metal
derivatives, such as N-alkali metal derivatives e.g. by the treatment of the
compound of formula III with an amide, hydride, an hydroxide or alcoholate
of an alkali metal such as lithium, sodium or potassium without isolation of
the intermediate, if necessary. Selected basic condensing agents are e.g.
alkali earth hydroxide, such as sodium hydroxide, potassium hydroxide and
calcium hydroxide or organic tertiary bases, such as trialkylamine, e.g. tri-
methylamine and triethylamine or pyridine. The reaction is carried out, if
necessary, at a higher temperature and/or in the presence of an inert solvent,
such as those with polar functional groups e.g. dimethylformamide, dimethyl-
acetamide, dimethyl-sulphoxide, acetonitrile or a cyclic-aliphatic-ether such
as dioxan or tetrahydrofuran.
According to a second process compounds of formula I are prepared
by nitration of a compound of the formula IV
R 1 N
~ 11 (IV)
R 2 N ~ N ~ N-X-R5
R3
wherein one of the residues Rll and R'2 is a hydrogen atom and the other a
hydrogen or a loweralkyl group.
The nitration of a compound of the formula IV is carried out by ; ;!
the usual nitration methods e.g. with nitric acid or a nitrating mixture or
a mixture of nitric acid and a carboxylic acid, such as acetic acid, with a
mixed anhydride of nitric acid and a carboxylic acid such as acetic acid, by
thermal and/or acid treatment of a nitrate salt of the compound IV, with -
; dinitrogen tetroxide, e.g. dinitrogen tetroxide/BF3, if necessary, in a suit-
able solvent e.g. nitrohydrocarbon, such as nitroalkane e.g. nitromethane
or with nitrogen tetroxide eDg. in acetonitrile, or with a N-nitroderivative.
N-nitro compounds are e.g. nitroamides, such as nitrourethanes,
nitroguanidine, nitrobiuret and nitro urea e.g. ethylene dinitrourea.
The acid treatment of a nitrate salt of a compound of the formula
D ~ .. ~ . .
:
.
1039732 ~ i
IV may be carried out at a higher temperature between 40-100, e.g. between
60-80.
Compounds of formula I may be prepared according to a third
process which comprises reacting a compound of formula V
Rl
N
R2~ ~ N ~ N ~ NH (V)
R3
wherein Rl, R2, R3, have the meanings given before with a compound Z-X-R5 (VI)
wherein X and R5 have the previously defined meanings and Z is a reactive
esterified hydroxy group, a reactive etherified mercapto group, an ammonium
group, a sulphinyl group, a sulphonyl group or Z and X together form a cyano
10 group. -
l`he reactive esterified hydroxyl group and other reactive groups
defined for the group Y are the same as those described earlier for the group
,~ Z under the first process. The reaction is carried out under conditions used
for such condensations and described earlier.
According to a four~h process nitroimidazoles of formula I are
prepared by reacting a compound of formula VII
.:
R ~ N ~ ~ (Vll)
R3
~, wherein R1J R2, have earlier defined meanings, with a compound of the formula
R5-X-MH2 (VIII), wherein R5 and X have the meanings defined earlier.
The reaction of a compound of the formula VII with a compound of
the formula R5-X-NH2 (VIII) is preferably carried out with the application of
heat, if necessary, in a high boiling inert solvent. It may also be carried
out with the aid of suitable dehydrating agents such as phosphorus pentoxide.
Compounds of the general formula I may be converted into one
7 -
~''' ,
, , ~ . .... -
;,: ~ . : , : - , - ~ ,
1039732 ~:
another by known methods. For example, compounds wherein R3 is a hydroxy-
loweralkyl may be converted to loweralkoxy-loweralkyl by alkylation with
suitable alkylating agents.
For example, hydroxyloweralkyl substituted derivatives may be
reacted with a reactive ester such as an ester of a lower alkanol, preferably
in the presence of a basic condensation agent, as for example in the presence
of an alkali metal hydroxide or with a diazoloweralkane, such as diazomethane,
preferably in the presence of borontrifluoride. However, it is also possible
to convert a hydroxy-lower alkyl radical, R3 into an amino-lower alkyl radical
in the usual manner. Thus it is possible first to convert a resulting
hydroxy-lower alkyl compound into a compound possessing a reactive esterified
.
~ hydroxy-lower alkyl radical, a reactive ester being, in particular, an ester
. . ,of strong inorganic or organic acids, such as, in particular, hydrogen
~ halide acids, for example hydrochloric acid, hydrobromic acid or hydroiodic
.'! acid, toluenesulphonic acids, such as, in particular, arylsulphonic acids, for
~ example benzenesulphonic acid or toluenesulphonic acids, alkylsulphonic acids
!j or sulphuric acid. For example, a hydroxy-lower alkyl compound can be con-
verted into a halogeno-lower alkyl compound by treatment with halogenating
agents, such as thionyl chloride, phosphorus oxychloride or phosphorous penta-
~ 20 bromide. In the resulting reactive ester the reactive esterified hydroxyl
¦ group can then be replaced in the usual manner by an amino group, for example
by treatment with corresponding amines.
In compounds of the formula I when R3 is an aminolower alkyl group
containing at least one replaceable hydrogen atom attached to the nitrogen,
this can be substituted. For example, in compounds of the formula I in which
R3 is a primary or secondary amino group, such groups may be substituted by
i reaction with a reactive ester of an alcohol corresponding to the substituent
of the amino group of the aminoloweralkyl radical. ~
, Furthermore it is possible to N-oxidise an imidazole of the ~ -
formula I which carries a N-heterocyclic radical.
The oxidation is carried out in the usual manner, for example
with N-oxidising agents, such as hydrogen peroxide, ozone, inorganic per-acids,
- 8 - ~.
D
:~.
1(~3973Z
for example persulphuric acids, such as Caro's acid, or especially organic
peroxy compounds, above all organic per-acids, such as peracetic acid, per-
trifluoroacetic acid, perbenzoic acid or monoperphthalic acid, which can also
be substituted, for example by halogen atoms, such as chlorine atoms, for
instance chloromonoperphthalic acid or m-chloroperbenzoic acid or tertiary
hydroperoxide compounds, such as tert.-butyl peroxide or cumene peroxide,
optionally in the presence of catalysts such as vanadium, titanium or molyb- `
denum compounds.
Resulting compounds of the formula I, with a N-oxidised N-hetero-
cyclic radical, can be converted by reduction into the corresponding compounds
of the formula I, with a N-heterocyclic radical.
The reduction is carried out in the usual manner, advantageously
; by the action of phosphorous halides.
Resulting compounds of the formula I, in which X is a sulphinyl
group can be oxidised to the S-dioxides (sulphones).
The oxidation to the sulphones can be carried out in a manner
which is in itself known, for example by reaction with a S-oxidising agent,
such as hydrogen peroxide~ per-acids, especially peracetic acid, perbenzoic
, acids or monoperphthalic acids, which can also be substituted, for example by
, 20 halogen atoms, l-chlorobenzotriazole, chromic acid, potassium permanganate,
hypohalites or nitric acid, nitrous gases and the like, or electrolytically.
In these reactions, whilst on warming and/or using at least 2 mol equivalents
~! of the oxidising agent the sulphones are obtained.
Resulting S-dioxides can be reduced to the corresponding S-oxides
of the formula I, for example with a reducing agent, such as a di-light metal
hydride, for example with sodium boronhydride, or a light metal hydride such
as diborane or a boronhydride-etherate for example BH3-tetrahydrofurane, or
above all dichloroborane or, for example, with acetyl chloride, sulphites or
hydriodic acid, or especially with triphenylphosphine.
In the above reductions care must be taken, where relevant, that
further groups which can be reduced are not attacked. Thus care must in
particular be taken, during the reduction9 that any halogen atoms bound to
_ g _
.
. . ~ .
-:- - . ~
, - . : , : .
~039'~;~2
aromatic rings which may be present are not replaced by hydrogen.
Very particularly, it is necessary to ensure that the nitro group
(Rl or R2) is not reduced. Catalysts which are not affected by sulphur are
preferentially to be used, and if necessary the hydrogen absorption should be
followed volumetrically and the hydrogenation stopped after the calculated ~ -
amount has been absorbed.
Compounds of the formula I which contain a nitro group as the
radical R2 can be rearranged to give the corresponding 4-nitroimidazolesJ that
is to say compounds of the formula I which contain a nitro group as the
radical Rl. Such a rearrangement is effected, for example, by the action of,
for instance, an excess of alkali metal iodide, especially potassium iodide,
in the presence of an inert solvent, preferably a solvent with polar functional
groups, such as dimethylformamide, dimethylacetamide, dimethylsulphoxide,
acetonitrile or hexamethylphosphoric acid triamide.
; The rearrangement of R2=nitro compounds into Rl=nitro compounds
of the formula I can also be effected by the action of an iodide which corres- ~
ponds to the radical R3, namely R3I, such as for example, the action of methyl -
iodide on compounds of the formula I which contain a methyl group as the R
s radical. In this rearrangement, the unsubstituted nitrogen atom of the
; 20 imidazole ring is quaternised. Thereafter, the quaternary salt is pyrolised.
This rearrangement also takes place, for example, in the prosence of an inert
solvent, preferably the solvents described above.
The subsequent conversion can be carried out individually or in
combination and in optional sequence. Care must be taken in individual
operations that other functional groups are not attacked.
The reactions of this invention are carried out in the usual
manner, at room temperature or with cooling or heating, under atmospheric or
superatmospheric pressure, if necessary, in the presence of diluents, cata-
.
lysts and condensing agents, and/ r in the atmosphere of an inert gas, e.g.
nitrogen.
Compounds of the formula III according to the first process are
prepared by the action of a compound of the formula IX
-- 10 --
D
1~39732
:` :
(IX),
HN ~ NH
'` .
:.
i.e. imidazolidin-2-one, with a compound of the formula R5-X-Z, wherein
R5, X and Z have the earlier defined meanings.
The compounds of the formula IV according to the second process
- are prepared by the reaction of a suitable imidazole derivative carrying a
,
replaceable group of the type Z of formula II with a compound of the formula
III according to the methods described under the first process for such con-
:",;
'',i'! densation.
~ Compounds of the formula VII according to the fourth process are
-~
~, 10 prepared by the reaction of an imidazole derivative carrying a replaceable
~: group in the 2-position with a compound of the formula X
HN o ( )
'i`~ 0
`~ namely, oxazolid-2-one.
The new nitro-imidazoles described herein as intermediates and P
starting materials also show valuable pharmacological properties. Thus,
... .
`~ they show, in particular, at a dosage of 10 to 100 mg/kg p.o. action against
;~ bacteria especially gram negative bacteria, protozoa and wor~s, for example,
trichomonads, schistosomes, coccidia and, particularly, amoeba as can be
shown in animal experiments, for example, from the liver of healthy hamsters
. ~ .
~: 20 artificially infected with Entamoeba histolytica. Imidazoles of this inven-
tion can, therefore, in particular, be used as agents against amoeba,
schistosomes, trichomonads and bacteria.
~-,`~ .
: 1 ~
:i. :
D 11
~03973z
Depending on the process conditions and the starting
substances, the final substances, are obtained in the free form or
in the form of their acid addition salts which is also included ~ ¦
in the invention. Thus, for example, basic, neutral or mixed salts
and where relevant also hemihydrates, monohydrates, sesquihydrates ~ ;
or polyhydrates thereof can be obtained. The acid addition salts
of the new compounds can be converted into the free compound in a
manner which is in itself known, for example with basic agents, such
as alkalis or ion exchangers. On the other hand, the resulting free
bases can form salts with organic or inorganic acids. The acids
- used for the manufacture of acid addition salts are in particular
those suitable for forming therapeutically usable salts. As examples
t of such acids there may be mentioned: hydrogen halide acids, sulphuric
acids, phosphoric acids, nitric acid, perchloric acid, aliphatic,
alicyclic, aromatic or heterocyclic carboxylic acids or sulphonic
acids, such as formic acid, acetic acid, propionic acid, succinic
acid, glycolic acid, lactic acid, malic acid, tartaric acid, citric
.,~ . . .
y~ acid, ascorbic acid, maleic acid, hydroxymaleic acid or pyruvic acid;
phenylacetic acid, benzoic acid, or p-aminobenzoic acid, anthranilic
acid, p~hydroxybenzoic acid, salicylic acid or p-aminosalicylic acid,
embonic acid, methanesulphonic acid, ethanesulphonic acid, hydroxy-
ethanesulphonic acid and ethylenesulphonic acid; halogenobenzene-
`l sulphonic acid, toluenesulphonic acid, naphthalenesulphonic acid
of sulphanilic acid; methionine, tryptophane, lysine or arginine.
, .
: '~ .
, ,:,
, - 12 -
~; .'. ''' '
., ,. ,~ ~
103973Z
These or other sal~s of the new compollnds, such as, :Eor
example, the picra~es~ can also serve for ~he purification of the ~
resulting free bases, by converting the Lrce bases iTltO salts, ~ ~-
isolatillg these and again liberating the bases from the salts.
Because o~ the close relationships between the new compounds in
the free form and in the form of their salts, the free compounds
are where appropiate also to be understood to include the correspon-
ding salts, in the preceding and following text.
'~
The invention also relates to those embodiments of the
process in which a process is stopped at any stage Gr in which
a compound obtainable as an intermediate product at any stage is
used as the starting compound and the missing steps are carried
out, or a starting substance is formed under the reaction condi-
tions or used, where relevant, in the form of a salt and/or race~
i mate or optical antipode.
,1 ~, ..
, Depending on the number of the asymmetrical C atoms and ;~
, on the choice of the starting substances and procedures, the new
.,j
compounds can be in the form of racemate mixtures, racemates or
', optical antipodes.
, . . .
;~j Racemate mixtures can be separated into the pure racemateson the basis of the physico-chemical differences of the constituents,
~n a Icnown manner, for example by chromatography and/or fractional
crystallisation.
~ .
J Pure racemates can be resolved into the diastereomers
according to known methods, for example by recrystallisation from
an optically active solvent, with the aid of microorganisms or by
reaction with an optically active acid which forms salts with the
J~
j~ ' "".~
103973Z ~
racemic compollnd and separation of the salts obtained in this
manner, for example on the basis of their different solubilities,
and from the diastereomers the antipodes can be liberated by the
action of sui~able agel~ts Par~icularly customary optically active
acids are, for example, the D- and I.-forms of tartaric acid, di-o-
-toluyl-tartaric acid, malic acid, mandelic acid, camphor-10-sul-
phonic or quinine acid. Resulting salts may be converted into other
salts or into the free and optically active bases, and an optically
active base may be converted into an acid addition salt by the
methods referred to above.
,: :
According to their antimicrobial activity the compounds of
formula I, theiE 5-N-oxides and their salts may be
used to protect a high molecular weight hydrophobic or other
organic material susceptible to bacterial or other microbial
7l deterioration by contacting the organic material with, impregnating
in or otherwise treating with, the compounds in amo~mts up to about
5 % by weight. The compounds also find application as growth-promoting
;i . .
~ additives to animal feedstuffs, to which they may be added in propor-
,.~
~ tion of from 5 to 500 parts per million.
3 :: :
Accordingly, the invention also provides a therapeutic
1 composition comprising an antimicrobially effective proportion of `
i a compound of formula I, or their 5-N-oxides or pharmaceutically
! acceptable salts thereof and a pharmacologically acceptable solid
carrier or liquid diluent.
:~ '' : : `
The pharmaceutical compositions according to the invention
contain at least one compound of the general formula I, or their
5-N-oxides or a pharmaceutically acceptable salt
` thereof as active substance together with a conventional pharma-
;'J D ,~
'' 1 ., ' ' ~
- ~039732
ceutical carrier. The type of carrier actually used depends to a
great e~tent on th~ iniended appllcatlon; for external use, for
example in disinfecting healthy skin, disinfecting wounds and in
treating dermatoses and affection~ o-f ~he mucous membranes caused
by bacterial or fungi, ointments, powders and tinctures are used ~-
in particular. The ointment bases may be anhydrous, for instance -~
they can consist of mixtures of wool fat and soft paraffin, or
they can consist of aqueous emulsions in which the active substance
is suspended. Suitable carriers for powders are, for instance, rice
starch and other starches; the bulk weight of the carriers may be
made lighter, i-E desired, for example by adding highly despersed
silicic acid, or may be made heavier by adding talcum. The tinc-
tures may contain at least one active ingredient of the formula 1,
or 5-N-oxides thereof or a salt thereof in aqueous
ethanol, in particular 45 % to 75 % ethanol, to which 10 % to ~0 %
of glycerol may be added, if desired. Solutions prepared from poly-
, .
ethylene glycol and other convential solubility promoters, and also,
optionally from emulsifying agents, may be used with particular
advantage in disinfecting healthy skin. The content of active
ingredient in pharmaceutical compositions or external application
... .
~ is preferably in the range o from 0,1 % to 5 %.
~ ~ ,
Gargles or concentrates for their preparation, and tablets
for slow dissoluti.on in the mouth, are suitable for the disinfec-
tion of the mouth and throat. The former are preferably prepared ;
~ from alcoholic solutions containing 1 % to 5 % of active substance
:-~ ~ J~ : .
~ V ' ~ '
:''Z . ~,' .'
Z
''~Z ' ' `- ''
.. ,~ . .
Z - -:
., , . . :
103973Z ~ :~
t~ .~hich glycerol or flavourings may be added. Lozenges, that is
solid dosage units 5 preferably have a relatively high con~ent of
s~lgar or similar substances and a relatively low content of active
substance, for instance 0,2 to 20 % by weight, as well as the usual ~;~
convential additives such as binding agents and flavourings.
. ' ,
Solid dosage units, in particular tablets, dragee~s (sugar
coated tablets) and capsules, are convenient for use in intestinal
disinfectlon. These ~mits preferably contain from 10 % to 90 % of
the compound o;f the general formula I, their 5-N oxides
.
or a salt thereof to enable the administration of daily doses ~ -
of from 0,1 to 2,5 grams to adults, or of suitably reduced doses
to children to be made. Tablets and dragee cores are produced by
combining the compounds of the general formula I, their 5-N oxides
or a pharmaceutically acceptable salt thereof with
solid, pulverulent carriers such as lactose, saccharose, sorbitol, :
....
maize starch, potato starch or amylopectin, cellulose derivatives
J. or gelatines, preferably with the addition of lubricants such as
.1 magnesium or calcium stearate or polyethylene glycols of suitable
molecular weight. Dragee cores may then be coated, for example with
concentrated sugar solutions which can also contain gum arabic,
~ talcum and/or titanium dioxide, or they may be coated with a lacquer
;~ dissolved in volatile organic solvents or mixtures oE solvents.
,1 . . . ...
'~ Dyestuffs can be added to these coatings, for instance to differen- ~
!l . . ' ~,
tiate between varying dosages. Soft gelatine capsules and other
~ closed capsules consist, for example, of a mixture oE gelatines ~ :
;~ and glycerol and may contain, for example, mixtures of the compound `
of formula I, their 5-N oxides or a pharmaceutically
acceptable salt thereof with polyethylene glycol. Hard gelatine
.~ . .... ..
¦ D c
, .. .. . .
.. .,, ... ~
.. i~.. ~ . . . ... .. , .. , . ,.. .... ; . ., .. . . . . ~. . .
103973Z
cc~ Lles con~ain, for e~campl~, granulates of an active substance
with solid pulver~llenl-carriers, for instance lactose, saccharose,
sorbitol, mannitoi, starches (such as potato starch, maize starch
or amylopectln), cellulose derivatives of gelatines, and magnesium
stearate or stearic acic3.
In all forms of administration compounds of the general
i formula I, their 5-N oxides or a salt thereof can
be present as sole active ingredients or they can also be combined
with other known pharmacologically active, and especially anti- -
bacterial and/or antimycotically or other antimicrobially active
substances, for example to broaden the range of application. They
can be combined for example, with 5,7-dichloro-2-methyl-8-quinolinol
or other derivatives of 8-quinolinol or other derivatives of 8-quino-
linol, with sulfamerazine or sulfafurazole or other derivatives of
sulfanilamide, with chloramphenicol or tetracycline or other anti-
biotics, with 3,4',S-tribromosalicylanilide or other halogenated
salicylanilides,with halogenated carbanilides, with halogenated
benzoxazoles or benzoxazolones, with polychloro-hydroxy-diphenyl-
~ methanes, with halogen-dihydroxy-diphenyl sulphides, with 4,4'-di- ;~
..
chloro-2-hydroxy-diphenylether or 2,4,~'-trichloro-2-hyclroxydiphenyl-
ether or other polyhalogenhydroxydiphenylethers, or with bactericidal
quaternary compounds or with certain dithiocarbamic acid derivatives
such as tetramethylthiuram disulphide or with other nitrofurans.
Also, carriers which themselves have favourable pharmacological
properties may be used, for instance sulphur as a powder base or
zinc stearate as a component of ointment bases.
., ~ . .
'q
`~ The invention also provides a method of protecting an organic
material susceptible to bacterial or other microbial attack which
comprises treating the material with a compound of formula I, their -
~ D ,7 ;
9732
5-~ o~ides or an acid addition salt thereof. The organic material
may be a natural cr synthetic polymeric material, a proteinaceous
or carbohydrate substance, or a natural or synthetic fibre or
textile material formed therefrom.
.~ ' ." .. ,.. ,.~'
The invention also provides an animal feedstuff composition
comprising a compound of formula I, their 5-N oxides or a salt there-
of in an amount sufficient to promote the growth of the animal fed
with the composition.
.. . .
~ Preparation of Tablets
.. ' .
100 g of 1-(methylsulphonyl)-2-oxo-3-[1-methyl-5-nitro~imida-
zolyl-(2)]-tetrahydroimidazole are mixed with 60.0 g of maize starch
and 35.0 g of lactose, ~he mixture is moistened with a solution of
5.0 g of gelatin and 3.0 g of glycerol in 70.0 g of water and
granulated through a sieve. The granulate is mixed with a mixture
of 15.0 g of talcum, 10.0 g of maize starch and 2.0 g of magnesium
Z stearate. The resulting mixture is pressed into 1,000 tablets,
, each containing 100 mg of active substance. If desired, the tablets
;,''ZZ can be grooved for better adaption of the dosage. ,
J,
I _eparation of Dragées
~Z Compositionfor 1,000 draÆées
J
I l-tmethylsulphonyl)-2-
oxo-3-[1-methyl-5-nitro- :
imidazolyl-(2)]-tetrahydro-
~ imidazole 100.0 g
`~ Maize starch 27.0 g
Gelatine 8.0 g
~ _~_ - :
.~ ,, .
~: .
-~lZ L~
.. Z -:
~ : . .-
l.. . ` . ! ' ' . ....... . .: .. ... . ...
103973Z
Il Glycerol 2.0 g
Dis~illed wa~er q-.s. ad 100 ml
~laize starch 10.0 g
; III Talcum 7.0 g
Magnesium stearate 1.0_~
155.0 g
IV White dragée coating
Shellac 2.0 g
Sugar 50.0 g
Talcum 38.0 g
Gum arabic 7.4 g
Colloidal silicon dioxide 2.2 g
- Titanium dioxide 0.4 g
~ .
:`5~1 Composition I is granulated in the heat with composition II
through a sieve of 1.2 mm mesh diameter. The dried granulate is
mixed with composition III and the resulting mixture is pressed
1. .
into 1,00 dragée cores. These are then coated with composition IV ~
and dried. The dragées obtained weigh 255.0 mg and contain 100 mg ~-
of active substance.
`i PreParatlon of Syrup
"?
ComPosition for 1 liter
(methylsulphonyl)-2-oxo-
-3-[1-methyl-5-nitro-imida-
~, zolyl--(2)]-tetrahydroimida-
;` zole 100.0 g
;' Colloidal solicone dioxide 13.0 g
,?l p-Hydroxybenzoic acid methyl
ester 1.4 g
~ p-Hydroxybenzoic acid propyl `
'~'t, ester ` _ 0.6 ~ ;
t ~ 115.0 g
.' ' . ...
~.... .
.~ ., /,9 "'-
~1 `
103~73Z -
Composition for 1 liter
115.0 g
Citric acid 1.0 g
Sodium cyclamate 5.0 g
~; Distilled water 610.0 g
Glycerol 100.0 g
; Sodium carboxymethyl
cellulose 4.0 g
Sugar 320.0 g
1155 0 g
- The active substance and the colloidal silicon dioxide are
passed through a sieve of 1.2 mm mesh diameter (I).
' ,:
; . . . . -
The p-hydroxybenzoic acid esters, the citric acid and the
sodium cyclamate are dissolved in the given amount of boiling
distilled water, the glycerol is then added to this solution (II).
The sodium carboxymethyl cellulose and the sugar are thoroughly
$' mixed (III). ~ -
,s.~
Composition III is then added at 75C to Solution II under
~; stirring until complete dissolution of III. The viscous, slightly
turbid liquid is cooled to room temperature, filtered, if necessary,
and mixed with composition I. Water ls added to the resultlng
mixture up to the prescribed weight of 1,155.0 g and the syrup
obtained is homogenized.
.~ , .~ ', '.
,~ Some examples will now begin, all parts and percentages
being by weight unless otherwise stated. The temperatures are
given in centigrade.
~ .
.~ '' , .' ,' ,
`l . . :.
,1 1) . ,~o
.. ~ , .
.~ .... ,, , ,, .~. , .. , ~.. . .. .. .. . . . .
`" 103973Z
Example 1
.
To a solution of 7.95g 1-(methylthlocarbamoyl)-2-
oxo-2,3,4,5-tetrahydroimidazole in lO0 ml dimethyl formamide
is added 2.4 g of a 50% slurry of sodium hydride in mineral
oil The mixLure is heated and stirred at 50 for 30 min.
10.25g of 1-methyl-2-methanesulphonyl-5-nitroimidazole are
now added and the mixture stirred at 100 for 4 hrs.The
solution is concentrated in vacuo to a small voLume and treated
with water. The crystalline precipitate is filtered off,
washed with water and ether. It is then recrystallized
from alcohol to give l-(methylthiocarbamoyl)-2-oxo-3-
[l-methyl-5-nitroimidazolyl-(2)]-tetrahydroimidazole of
. : `
the formula
- '
02N ~ ~ -C-NHCH3
melting at 185-187.
~ I . .
,~ ,
The starting material l-(methylthiocarbamoyl)-2-
oxo-2,3,4,5-tetrahydroimidazole required Eor the above reaction
is made as follows: a mixture of 86g ethyleIleurea and 73g
methylisothiocyanate is heated at 100 with stirring for
4 hrs.The crystalline mass obtained on cooling is rubbed
with ether and water, filtered and washed with alcohol-ether
mixture. It is recrystallized from me~hanol; m.p. 168-1~
., . :.
- ~03973Z
Example 2
To a solution of 4.7g 1-(benzyl~ ocarbamoyl)-2-
oxo-2,3,4,5-tetrahydroimidazole in 50 ml dimethyl Eormamide
is added 0.95g of a 50% slurry of sodi~n hydride in mineral
oil. The mixture is heated and stirred at 50 for 30 min.
4.1g of 1-methyl-2-methanesulpllonyl-5-nitroimidazole are
now added and the mixture stirred at 100 for 4 hrs.The
.:
solution is concentrated in vacuo to a small volume, ~reated
with water and the mixture extracted with chloroform, The
chloroform solution is washed with water, dried over sodium
i~ sulphate and evaporated in vacuo. Trituration of the residue
with ether and crystallization of the resultant solid from
,. . .
chloroform-alcohol affords l-(benzylthiocarbamoyl)-2-oxo-3-
[l-methyl-5-nitroimidazolyl-(2)-]-tetrahydroimidazole melting
at 178-180.
The starting thiocarbamoylimidazole required for
the above reaction is made as follows: 86g ethyleneurea and
149g benzylisothiocyanate are treated togel:her with stirring
for 6 hrs.at 150. Upon cooling, a solid mass is obtained,
which is triturated with ether and then with hot alcohol and
filtered. Recrystallization from chloroform-methanol gives
l-(benzylthiocarbamoyl)-2-oxo-tetrahydroimidazole.
Example 3
To a solution of Sg of l-(methylcarbamoyl)-2-oxo-
2,3,4,5-tetrahydroimidazole in 50 ml dimethyl formamide is
added 1.7 g of 50% slurry of sodium hydride in mineral oil.
' The mixture is stirred at 50 for 1 hr. A solution of 7,2g
. ~ :
`~ D - ~
::
i .
i - ~ - . . . ~ .
103973Z ~ ~
of l~metllyl-2--methanesulphonyl-5 nitrolmidazole in 30 ml
dimethyl formamide is now added and the mixtur2 stirred at
100 for 3 hrs.The solvent is then removed in vacuo and
water is added to the residue. The resultant red solution
is then extracted with chloroform to give an oil, which upon
rubbing with methanol affords a solid, recrystallized thrice
from methanol to give l-(methylcarbamoyl)-2-oxo-3-[1-methyl-
5-nitroimidazolyl-(2)]-tetrahydromidazole melting at 176-177.
The starting methylcarbamoylimidazole for the above
experiment is made by heating a mixture of 8.6 g ethylene-
urea and 5 7 g methylisocyanate in a sealed tube at 130
or 3 hrs.and crystallizing the solid so obtained first
from water and then from chloroform-methanol; m.p. 198-200.
:', .
Example 4
To a solution of 16.4g 1-(methylsulphonyl)-2-oxo-2,
3,4,5-tetrahydroimidazole in 120 ml dimethyl Eormamide is
added 4 8 g of a 50% slurry of sodium hydride in mlneral oil,
The mixture is stirred at 50 Eor 30 min. A solution oE 20,5g
l-methyl-2-methanesulphonyl-5-nitroimidazole in 70 ml dimethyl-
formamide is now added and the mixture heated at 100 for 1 hr.
The solvent is then removed in vacuo and the residue dissolved
in water. Upon cooling, a crystalline precipitate is obtained,
which is filtered off and recrystallized from acetone-methanol
to afford l-(methylsulphonyl)-2-oxo-3-[1-methyl-5-nitro-
D ~3 ~ -
, ", :.. : -
:: , . . .
~0 39'~3 Z ;
imidazolyl-(2)]-~etrahydroimidazole melting at 202-204.
Tlle starting 1 (methyls-ulphonyl)~2 oxo-2,3,4,5-
tetrahydroimidazole for the above reaction is made as follows:
A mixture of 86 g ethyleneurea and 115 g methanesulphonyl
chloride is heated for 6 hrS.at 120 with stirring,
while a stream of nitrogen is bubbled in to remove hydrogen
chloride. After cooling, water is added and the mixture
heated on a steam bath till a crystalline powder is formed,
; .
This is filtered off, washed with alcohol-ether and recrystallized `~
~ from methanol; m.p. 192-195~.
.,, . :,.
Example 5 -
To 8 g 1-(benzylthiocarbamoyl)-2-oxo-3-[1-methyl-5-
nitroimidazolyl-(2)]-2,3,4,5-tetrahydroimidazole in 80 ml
dimethylsulphoxide is added 5 ml of concentrated sulphuric
acid and the solution is heated on a steam bath for 2 days,
It is then diluted with water and the resultant precipitate
filtered off. This is dissolved in ethyl acetate and ether
added to give a solid. Crystailization from ethylacetate-
ether affords l-(benzylcarbamoyl)-2-oxo-3-[1-methyl-5-
nitroimidazolyl-(2)]-2,3,4,5-tetrahydroimidazole melting at
113-115. ;~
. . '.
. ~ .
. :. ... . - :~
. i . . ,
.. ~
.. . . . . . ... . ..
~03973Z :
~ - Ex~mple 6
~ ,, ~ .
To a suspensioll of l~Sg 50% sodi~l hydride in 10 ml ~;
dry dimethyl formamide is added with s~irring during 15 min~
a solution of 5.. g of 1-N-ethylthiocarbamoyl-2-oxo-tetrahydro-
imidazole in 20 ml dry dimethyl formamide. The reaction mixture
is stirred under nitrogen at 50 for 30 minO and a solution
of 4.5 g of 1-methyl-2-methylsulphonyl-5-nitroimidazole
in 10 ml dry dimethyl formamide is added during 5 min., and
' then heated at 100 for 4 hrs.The solvent is evaporated of; under vacuo; residue triturated with 50 ml water and extracted with
~ ethylene dichloride. The ethylene dichloride extract is
J dried over anhydrous sodium sulphate and evaporated off to
dryness. The residue is chromatographed over silica gel.
The fraction that is eluted with 2% methanol in chloroform
~ affords l-N-ethylthiocarbamoyl-2-oxo~3-[1-methyl-5-nitro~
j imidazolyl-(2)]-tetrahydroimidazole which melts at 213 after
recrystallization from a mixture of methylenech]oride and hexane.
~, The starting material requlred for the above xeaction
is prepared as follows: A mixture of 3,6 of ethyleneurea
and 8,7 g of ethyl isothiocyanate is heated at 100 for 4 hrs.
On cooling, the crystalline product was recrystalliæed from a ;~
mixture of ethanol and ether to afford l-N-ethyl;thio-
carbamoyl-2-oxo-tetrahydroimidazole which melts at 135-136,
~: '"'' ' " "
,1 ' : :.. ` ., ' ' '
~039732
Æxample 7
To a suspension o~ 2.2 g 50% sodium hydride in 10 ml
dry dimethyl formamide is added under stirring during 15 minO,
a solution of 8 7 g of l-(N~N-dimethylsulphamoyl)-2~oxo-
tetrahydroimidazole in 20 ml dry dimethyl formamide. The
reaction mixture is stirred under nitrogen at 50 for 1 hr
and a solution of 9.25 g of 1-methyl-2-methylsulphonyl-5-nitro-
imidazole in 20 ml of dry dimethyl formamide is added all
at once. The reaction mixture is heated under stirring and
nitrogen at 95 for 3 hrs.The solvent is removed by distillation
in vacuo and res;due triturated with 45 ml water. The
resulting suspension is extracted with ethylene dichloride,
dried and evaporated to dryness. The res-idue is washed
with hexane and triturated with acetone to give a crystalline
solide. This is recrystallized from a mixture of methylene
chloride and ether to afford l-N,N(dimethyl-sulphamoyl)-2-
oxo-3-[1-methyl-5-nitroimidazolyl-(2)]-tetrahydroimidazole
which melts at 217.
The starting material required for the above reaction
is prepared as follows: ~ mixture of 17.2g of ethylene urea i
and 28.7 g of N,N-dimethyl sulphamoyl chlorid~ is heated at
110 for 3 hours. The reaction mixture is cooled and tri-
turated with 100 ml methanol. Some solid material separated
..
which is discarded. The filtrate is evaporated off to dryness
and the re~idue is dissolved in 5% methanol in chloroform
and chromatographed on a column of 150 g of silica gelO The -
_ ' ' :,'.' .
D ~6
.. .
, ~, ,
~ 03973Z
fraction which eluted with 2% methanol in chloroform is
recrystallised from a mixture of methylenechloride and hexane
to give l-(N,N-dimethylsulphamoyl)-2-oxo-tetrahydroimidazole
which melts at 129~
.. . .
Example 8
A mixture of 34,4 g ethylene urea and 54,2 g N,N- ;
diethylcarbamyl chloride is heated under nitrogen at 110
for 3 hrs.The reaction mixture is cooled and diluted with
200 ml acetone. It is filtered and the filtrate evaporated off
~j to dryness. The oily product i9 chromatographed on a column
;~ of 450 g of silica gel. The fraction which eluted from 3%
j methanol in chloroform yields l-(N,N-diethylcarbamoyl)-
2-oxo-tetrahydroimidazole as a colourless oil.
To a suspension of 5,8 g 50% sodium hydrid in 20 ml -
dry dimethyl formamide is added under stirring during 15 min,
a solution o 22 g of above mentioned l-(N,N-diethylcarbamoyl)-
2-oxo-tetrahydroimidazole in 40 ml oE dry dimethyl form~mide.
`jg The reaction mixture is stirred under nitrogen at 50 for 1 hr
and a solution of 24.6 g of l-methyl-2-methylsulphonyl-
5-nitroimidazole in 40 ml of dry dimethyl formamide is added
all at once.
The reaction mixture is worked up in the manner
~ described under example 6 and the dark oily residue (36 g) ~ ~
:.1 ., . ' ~'
~ 0 39~ 3 Z
is c~ron~l~o3r2plled over a column of 3G0 g of sillca gel.
The flaction that eluted with 2.5% meth~nol in ch]oroorm yields
a crystalline substance ~hich is recrystallized from a -
mixture of methylene chlorid and hexane to give l-N,N-diethyl ~ -
carbamoyl-2-oxo-3-~1-me~hyl-5-nltro-imidazolyl-(2)]-
tetrahydroimidazole which melts at 133.
Example 9
.~ ' - ..
To a suspension of 24.5 g of 50% sodium hydride in
Z 100 ml dry dimethyl formamide is added under stirring
:-j .
during 15 min,-a solution of 78.5 g of l-(N,N-dimethyl
carbamoyl)-2-oxo-tetrahydroimidazole in 150 ml of dry dimethyl
l formamide. The reaction mixture is stirred under nitrogen
'.t~Z at 50 for l hr. and a solution of 102.5 g of l-methyl-2-
methyl-sulphonyl-5-nitro~imidazole in 100 ml dry dimethyl
formamide is added during 10 min. The reaction mixture
Z is heated under stirring and nitrogen at 100 for 3 hours,
`J Is is worked up as described under example 6 and tlle residue
Z is recrystallised from a mixture of methylene chloride
and hexane to afford l-N, N-dimethyl~carbamoyl-2~oxo-3-
[l-methyl-5-nitro-imida7.olyl-(2)]-tetrahydroimidazole which
¦ melts at l90-191~
j The starting material required is prepared as follows:
~ . ,
~Z A mixture of 86 g of ethylene urea and 118 g of N,N-dimethyl
,'~ ' .
`; D ~ ~:
.,,, . : :
;. .. . . .
"`~
103973Z ~ -
carbamoyl-cl~loride in 200 ml ethylene dichloride is heated ~ -
under reflux for 3 hr~,under ni~rogen. The solution is
evaporated oEf to dryness and the residue dissolved in
chloroform and chromatographed on a column of 1.5 kg of silica
gel, The fractions that eluted with 5% methanol in chloro-
form are comhined and recrystallized from a m ixture of methylene ;-~
chloride and hexane to afford l-N,N-dimethyl-carbamoyl-2-
oxo-tetrahydroimidazole which mel~s at 134-136.
i . ::
.. . . ..
~, , ,
Example 10 ' ~
;~ . ~ ,. .
,.. .
, To a suspension of4.5gof 50% sodium hydride in 10 ml
;j dry dimethyl formamide is added under stirring during 15 min " a
solution of 16g of 1-ethyl-sulphonyl-2-oxo-tetrahydroimidazole
in 30 ml dry dimethyl formamide. The reaction is stirred
under nitrogen at 50 for 45 min. and a solution of 18,5 g
of l-methyl-2-methylsulphonyl-5-nitro-imidazole in 30 ml
dry dimethyl formamide is added all- at once and the reaction
mixture heated at 100 or 3 hrs.
' ' :".
It is worked up in the manner described under
example 6 and the residue is recrystallized from a mixture
. .. ..
o~ methylene chloride and hexane to afford l-N-ethyl-sulphonyl-
2-oxo-3-[1-methyl-S-nitro-imidaæolyl-(2)]-tetrahydroimidazole
~ which melts at 176-177,
:~
. . .
~ The starting material required is prepared as follows:
~ . :. . -
~ : , ' '. .' :'
~ D
,. .
, . ......
1~ . - . ... ...
103973Z
A i~Ture of 29.2 g of ethyleneurea and 43,7 g of etllane
sulphonyl chloride is h~atecl at 110 for 3 Ixr~ under nitrogen.
The reaction mixture is trituxated with 30 ml methanol and
filtered. The filtrate is evaporated off and ~he residue
is dissol~ed in chlorofoxm and chromatographed on a column
of 75~ g of silica gel. The fraction which eluted with 5%
methanol in chloroform, is recrystallized from a mixture of
methylene chloride and hexane to afford l-ethylsulphonyl-2-
oxo-tetrahydxoimidazole which melts at 114-116.
. , .
Example 11 ~
,; -
To a suspetlsion of 1.2 g of 50% sodium hydride in
10 ml dry dimethyl formamide is added under stirring during
15 minutes, a sol~ition of 5.8 g of 1-(4-fluorophenylsulphonyl)-
2-oxo-tetrahydroimidazole in 28 ml dry dimethyl formamide.
The reaction mixture is stirred under nitrogen at room
temperature for 1 hr and then at 50 for an other hour. A
solution of 5 g of 1-methyl-2-methylsulphonyl-3-nitroimidazole
in 10 ml dry dimethyl formamide ls added all at once. The
. :,
reaction mixture is heated under stirring and nitrogen at 100
for 3 hrs. and worked up in the manner descrlbed under
example 6. The residue is chromatographed on a column of
150 g silica gel, The fractions which eluted with 2.5% methanol
~j in chloroform gives a crystalline substance which is recrystallised
from a mixture of methylene chloride and hexane to afford
,; : . '
~ l-N-(4-fluorophenylsulphonyl)-2-oxo-3-[1-methyl-5-nitro-
l~ imidazolyl-(2)]-tetrahydroimidazole which melts at 198-200.
I ~.i ~ ~ 30
.. - ` - . . .
1~ .
~03973Z
. The s~arting.material required is yrepared as follows:
A mixture of 17.2 g o ethyleneurea and 19.5 g of p-f]uorobenzene
sulphonyl chloride lS heate~ at 110 Eor 3 1/2 hrS.The residue
is recrystallized from a mixture of methanol and water to .;
afford l-(4-fluorophenylsulphonyl)-2-oxo-tetrahydroimidazole
which melts at 183-185.
:', ,:
Example 12
- A solution of 0,4 g of 2-oxo~3-[1-methyl-4-nitro-
imidazolyl-(2)]-tetrahydroimidazole in 8 ml dry dimethyl : .
formamide is added dropwise to a suspension of 0.1 g of 50% ~j'!"'-'~ ;!:
sodium hydride in 2 ml dry dimethyl formamide. The reaction
mixture is stirred at room temperature for 15 minutes and
a solution of 0.2 g of methyl isocyanate in 2 ml dry dimethyl .:
formamide is added and the reaction mixture heated for 3 hrs. ~ ~ -
at 100 and worked up in the manner described under example 6.
The residue is chromatographed on a column of ~0 g silica gel,
The fraction which eluted with 5% methano]. in chloroform aEfords
l-N-methyl-carbamoyl-2-oxo-3-[l-methyl-5-nltro-ilnidazolyl-
(2)]-tetrahydroimidazole which melts at 176-177. . : . .
!
! Example 13
To a stirred suspension of 1.3 g of 50% sodium hydride
:l dispersion in mineral oil.in 20 ml dry dimethyl formamide is added .`.
1 . . . ...
l 3/
1:D -~ ~
;.~ .. . .~ . :.
. .
,; .
lQ3973Z
dropwise a solution of l-piperidinocarbonyl-2-oxo-tetrahydroimidazole in 15 ml
dimethylformanide at ambient temperature. The temperature of the reaction is
raised to 50 and stirred for 30 min. A solution of 5.12 g of 1-methyl-2-
methylsulfonyl-5-nitro-imidazole in 20 ml dimethyl formamide is added dropwise
in the course of 20 min, the temperature raised to 95 and maintained for 1 hr.
The solvent is removed under reduced pressure~ the residue washed with ether
and treated with water containing crushed ice. The residue after removal of
aqueous layer is treated with isopropanol ether (5:1). The colourless granular
precipitate is recrystallised from ethyl acetate-hexane to afford l-piperidino-
carbonyl-2-oxo-3-[1-methyl-5-nitro-imidazolyl-(2)]-tetrahydroimidazole melting
at 152.
.,
Example 14
To a stirred suspension of 1.92 g of 50% sodium hydride dispersion
in mineral oil in 25 ml dry dimethyl formamide is added dropwise a solution
of 7.96 g of 1-morpholinocarbonyl-2-oxo-tetrahydroimidazole in 15 ml dry di-
,~ .
methylformamide at ambient temperature. The above suspension is stirred at50 for 30 min. A solution of 8.2 g of 1-methyl-2-methylsulfonyl-5-nitro-
imidazole in 15 ml dimethyl formamide is added in the course of 5 min. The
temperature of the reaction is raised to 95 and stirring continued for 2 hrs.
The solvent is removed under reduced pressure, the residue is
.1 : .
D ~ :
, .
, ~3.~; .
103973Z
washed with ether and treated with crushed ice, The solid
obtained is filtered to give 1-morpholinocarbonyl-2-oxo-3-
[l-methyl-5-nitro-imidazolyl-(2)]-tetrahydroimidazole
melting at 180 after crystalliza~ion from ether,
l-Morpholinocarbonyl-2-oxo-tetrahydroimidazole used ~ ;-
as starting material is prepared as follows: To a s~irred
solution of 22.27 g of 1-chloro-carbonyl-2-oxo-tetrahydro
imidazole in 80 ml anhydrous benzene is added dropwise a ~ ~;
solution of 26,1 g of morpholine in 20 ml benzene. The
mixture is refluxed for 4 hrs,The product is filtered off, ;~
treated with a saturated solution of NaHC03 and filtered,
Recrystallization from isopropanol affords l-morpholinocarbonyl- ;
2-oxo-tetrahydroimidazole melting at 158,
Example 15
A solution of 2.9 g 1-(methylsulphonyl)--2-oxo-3-
[l-methyl-5-nitroimidazolyl (2)]-tetrahydroimidazo].e and
1,9 g methyloxonium fluoborate in 200 ml dry chloro~orm is set
aside at room temperature for 72 hrs,A thick oil separates out,
which crystallizes on treatment with alcohol. The solid is
filtered off, boiled with acetone and filtered, The residue is
crystalliæed rom aqueous alcohol to give 1-methyl-2-[3-(methyl-
sulphonyl)-2-oxo-1,2,3,4-tetrahydroimidazolyl (1)]-3-ethyl-5 ~ ;~
nitroimidazolium fluoborate of the formula
' " '
~ D ~ -
1039~13Z
o~ r~_SO~cll3
C1~3 4
melting at 265-267.
Example 16
A solution of 3.0 g 1-(methylsulphonyl)-2-oxo-3-
[l-methyl-5-nitroimidazolyl (2)]-tetrahydroimidazole in 30 ml
dimethylformamide containing 3.0 g potassiumiodide is heated
under reflux for 16 hours.The solvent is removed in vacuo and
the residue treated with water and filtered. The~ filtrate is
ma.de acidic with 2N hydrochloric acid, cooled and filtered to
remove unreacted starting material. The filtrate is cooled fur-
ther and the crystals that separate are filtered off and recry-
stallized twice from acetone-methanol to give l-(methylsulphonyl-
3 2-oxo-3-[1-methyl-4-nitroimidazolyl(2)]-tetrahydroimidazole
3 melting at 180-181.
.. . .
~; Example 17
.~ , , .
~ A solution of 3.0g 1-(methylthiocarl)amoyl)~~2~OxO~3~
;~ .
~l-methyl-5-nitroimidazolyl (2)]-tetrahydroimidazole in 25 ml
dimethylformamide containing 3.0 g potassium iodide is heated
under reflux for 16 hr. The solvent is removed in vacuo and water
added to the residue. The mixture is filtered and the precipitate
washed sucessively with hot ethanol and methanol and crystallized -
D ~y ~:
~3
; . .
'` :~ ' . ' ' ~ ,
~ - ' ''' '
~03973Z : :
- twice from acetone-methanolto give l-(methylthiocarbamoyl)-2-
oxo-3-[1-methyl-4-nitroimidazolyl (2)]-tetrahydroimidazole
melting at 239-241~.
; ~
` Example 18
A solution of 0.49 g 1-(methylsulphonyl)-2-oxo-tetra- -
hydroimidazole in 5 ml dimethylformamide is stirred with -
0.15 g of a 50~/0 suspension of sodium hydride in mineral oil
at 50 for 1 hr. It is then treated with 0,57 g of 1-methyl-2-
~, (methylsulfinyl)-5-nitroimidazole and the solution heated and
stirred at 100 for 3 hours. The solvent is evaporated off in vacuo
and the water added to the residue. The crystalline precipitate is
filtered off and recrystallized from acetone-methanol to give
l-(methylsulphonyl)-2-oxo-3-[1-methyl-5-nitroimidazolyl(2)]-
tetrahydroimidazole melting at 202-204 and is identical with the
, .. .
preparation described in Example 4.
The starting l-methyl-2-(methylsulfinyl)-5-nitroimidazole
for the above reaction is made as ~ollows:
A solution of 3.4 g 1-methyl-2-(methylmercapto)-5-
7 nitroimidazole and 5 ml 30% aqueous hydrogen peroxide in
i 20 ml methoxyethanol is heated at 100 with freshly prepared
j~ titanium dioxide for 6 hrs.It is then diluted with water
and filtered. The filtrate is extracted with chloroform
1~ and the chloroform layer evaporated to give 2.5 g of an oil
,,. ~ which solidifies slowly upon standing. The solid is crystalllzed ~
~: . :' ,'-'
,t
-D 3~
.: . .
1039'73Z
once from ethanol and then from chlorofor~ether to give
l-methyl-2-(methylsulfinyl)-5-nitroimidazole.
' . ' . .
Example 19
To a suspension of 6,1 g 50% sodium hydride in 20 ml
dry dimethyl formamide is added under stirring during 15 min.
a solution of 30 g 1-(N,N-diethylsulphamoyl)-2-oxo-tetrahydro-
imidazole in 50 ml dry dimethyl formamide, The reaction
mixture is stirred under nitrogen at 50 for 1 hour and a
solution of 25.6 g of 1-methyl-2-methylsulphonyl-5-nitro-imidazole
in 40 ml of dry dimethyl formamide is added all at once, The
reaction is heated under stirring and nitrogen at 95 for 3 hours,
The solvent is removed by distillation in vacuo and the residue
triturated with 100 ml water, The resulting suspension is extracted
with ethylene dichloride, dried and evaporated to dryness, The
residue is chromatographed on a column of silica gel and the
fraction that elutes with 1% methanol in chloroform afords a
crystalline mass, This is recrystallized from a mixture of methy-
"
~;' lene chloride and ether to afford l-N,N-diethyl sulphamoyl-2-
oxo-3-[1-methyl-5-nitroimidazolyl-(2)]tetrahydroimidazole which
melts at 14~-147,
The starting material required for the above reaction
is prepared as follows:
- ,
- . .
'~ , ' .' .
, ~. 3C . :-
.. . . .
,~ ..
.~' , ~'''~'
.. . . . . . ~ . . . . . .
~39732
A mixture of 51. 6 g of ethylene urea and 90 g of N,N-
diethyl-sulphamoyl-chloride is heated at 110 for 3 hours. The
reaction mixture is cooled and triturated with 300 ml of methanol,
filtered and the filtrate evaporated off to dryness and the residue -
~
dissolved in 5% methanol in chlorofonn and chromatographed on a ;~
column of silica gel. That fraction which elutes with 5% methanol ~ -
.. .::
in chloroform is recrystallized fro~ a mixture of methylenechlorid
and hexane to give l-(N,N-diethylsulphamoyl ~ -2-oxo-tetrahydroimida-
zole which melts at 80-82.
.,~. ~ .. ~.
Example 20
To a stirred suspension of 1,6 g of 50~b sodium hydride
dispersion in mineral oil in 30 ml dry dimethyl formamide is
added during 15 min. a solution of 5.9 g of l-pyrrolidino-
carbonyl-2-oxo-tetrahydroimidazole in 15 ml dry dimethyl forma-
mide. The reaction is stirred under nitrogen at 50 for 1 hour
.: .. . ..
and a solution of 6.6 g of 1-methyl-2-methyl-sulphonyl-5-nitro-
imidazole in 20 ml dry dimethyl formamide is added ~11 at once,
The mixture is heated under stirring and nitrogen at 95 for 1
hour, The solvent is removed by distillation in vacuo and the ~ ,'
residue is trituxated with water and extracted with ethylene
,
dichloride, dried and evaporated to dryness. The residue is chro-
matographed over silica gel and that fraction which elutes with 3% ,
methanol in chloroform affords a crystalline mass. This is re-
. . ~ ,.
~ crystallised from a mixture of methylene chloride and hexane to ~
., . ~
~;affoFd l-pyrrolidino-carbonyl-2-oxo-3~[1-methyl-5-nitro-imidazolyl
. .
:~D ~7
~ 03973Z
(2)]-tetrahydroimidazole which melts at 155-156.
The starti~g material required for the above reaction
is prepared as follows:
A mixture of 40 g ethylene urea and 72 g of l-pyrrolidino-
car~onyl chloride (b.p. 100-104/4.5 mm Hg.) is heated at 110 ~ -
for 3 hours. The reaction mixture is cooled, 200 ml of
chloroform added, the insoluble material filtered off and
the filtrate evaporated to dryness. It is chromatographed on
a column of silica gel. That fraction which elutes with 4%
of methanol in chloroform is recrystallised from ethylacetate
to give l-pyrrolidino-carbonyl-2-oxo-tetrahydroimidazole which
melts at 153-154.
' ~ .
- Example 21
To a suspension of 3.5 g of 50% sodium hydride in
20 ml dimethyl formamide is added under stirring during 15 minu-
tes, a solution of 15.6 g of 1-pyrrolidino-sulphonyl-2-oxo-
tetrahydroimidazole in 40 ml dry dimethyl formamide, The
reaction mixture is stirred under nitrogen at 50 or 1 hour, ~ ~
and a solution of 14,4 g of 1-methyl-2-methyl-sulphonyl-5- ;
nitroimidazole in 30 ml dry dimethyl formamide is added all
at once, The reaction mixture is heated under stirring and ni- -~
trogen at 95 for 3 hours, The solvent is removed by distillation
in vacuo and the residue is triturated with 50 ml of water when a
crystalline precipitate is formed, This is filtered and recrystallised
from a mixture of methylene chloride and ether to afford l-pyrro-
lidino-sulphonyl-2-oxo-3-[1-methyl-5 nitro~imidazolyl-(2)]-
~;D
., ~ . . ~ . -.
~()3973Z -~ :
tetrahydroimidazole which melts at 226 -;
,:
The starting material required for the above reaction
is prepared as follows: ~ -
A mixture of 30 g of ethyleneurea and 64,5 g of pyrroli-
......... -
dino~l-sulphonylchloride (b.p. 120/11 mm Hg.) is heated at 110
for 3 hours. The reaction mixture is cooled, dissoved in 300 ml
chloroform, filtered, the filtrate evaporated off and the residue
is redissolved in 2.5% methanol in chloroform and chromatographed
on a column of silicagel. That fraction which elutes with ~
2,5% methanol in chloroform affords 1-pyrrolidino-sulphonyl-2-oxo- ;
tetrahydroimidazole which is recrystallized from ethylacetate,
m.p, 150,
:
Example 22
.: .
. ., :;.
To a stirred suspension of 1.92 g of 50% sodium hydride
dispersion in mineral oil in 20 ml dry dimethyl formamide is
added dropwise a solution of 9,3 g of 1-piperidino-sulfonyl-2-
oxo-tetrahydroimidazole in 15 ml dimethyl formamide at amblent
temperature. The temperature of the reaction is raised to 50
and stirred for 30 min. A solution of 8,2 g of 1-methyl-2-methyl- ;~
sulfonyl-5-nitroimidazole in 25 ml of dimethyl formamide is added
... ... .
in one lot and the temperature of the reaction is maintained for 2 hrs.
at 100. The solvent is removed under reduced pressure and the ;
residue treated with water containing crushed ice, The redsidue ~ ~
', "' ~.
~D~
-~46 -
'.
.
. .
1039'73Z
after removal of the aqueous layer is treated with isopropanol-
ether (5:1). The pale yellow precipitate so obtained is recry-
stallised from ethyl acetate to afford l-piperidino-sulfonyl-2-oxo-
3-[l methyl-5-nitroimidazolyl-(2)]-tetrahydroimidazole melting
at 192,
The starting material is prepared as follows:
To 17.4 of ethyleneurea is added with shaking 36 g
of piperidinosulfonyl chloride (b.p 130/llmm) and the mixture
kept under nitrogen at 100 for 3 hrs.The mixture is cooled
and the gummy material treated with methanol-isopropanol (1:1)
to give a granular product of l-piperidinosulfonyl-2-oxo-tetrahy-
droimidazole which melts at 201 on recrystallization from -~
methanol.
,,,~',
0 ~; :
