There is disclosed a substituted nitroimidazole compound, 1-methyl-2-methylsulfonyl-4-nitroimidazole which is an antiprotozoal and bactericidal compound with the unique and surprising property of being totally non-mutagenic and thus of a much higher degree of safety than is found with other nitroimidazoles. Compositions and methods for the antiprotozoal and bactericidal uses of such compounds are also disclosed.

BACKGROUND OF THE INVENTION 
The compound 1-methyl-2-methylsulfonyl-4-nitroimidazole is a known compound 
having been disclosed in the Indian Journal of Chemistry, Section B, 21B 
(11), pp. 1006-21. The compound was published only with respect to 
spectral studies thereof and no mention was made of its biological 
activities or relative mutagenicity. 
SUMMARY OF THE INVENTION 
This invention is concerned with 1-methyl-2-methylsulfonyl-4-nitroimidazole 
as an antiprotozoal and bactericidal agent with unique safety due to an 
undetectable level of mutagenic activity in standard mutagenicity tests. 
Thus it is an object of this invention to describe such a compound and its 
preparation. A further object is to describe the biological activity and 
the mutagenicity tests for such compounds. A still further object is to 
describe compositions containing such compound as the active component 
thereof. Further objects will become apparent from a reading of the 
following description.

DESCRIPTION OF THE INVENTION 
The compound 1-methyl-2-methylsulfonyl-4-nitroimidazole has the following 
structure: 
##STR1## 
The compound may conveniently be prepared from the corresponding 
5-nitroimidazole in a rearrangement reaction using, for example, potassium 
iodide in a solvent such as N,N-dimethylformamide. The reaction is heated 
at a temperature up to the reflux temperature of the reaction mixture, or 
temperatures in excess of its reflux temperature in a pressure vessel. The 
heating is conveniently carried out for from 1 to 4 hours and upon 
cooling, the product is isolated using standard techniques. 
Nitroimidazoles are known generally to be mutagenic compounds and are 
usable only in those instances where the disease being treated is of such 
a level of seriousness that the negative effects of the mutagenicity of 
the compound are balanced against the conditions resulting from the 
disease. Thus, the discovery of a non-mutagenic drug which could be used 
to treat protozoal diseases has been long sought. 
One very well accepted measure of the mutagenicity of chemicals, which has 
generally also been closely correlated with the carcinogenicity of such 
compounds, is the Ames Mutagenicity Test. This test involves the addition 
to a fermentation medium in which is growing a particular organism 
identified as Ames Salmonella TA100, and measuring the number of mutant 
organisms formed. Greater numbers of mutants over the background number of 
spontaneous mutants is an indication of greater mutagenicity of the 
compound. Generally a series of varying concentrations of the test 
compound is employed to determine threshold levels if possible. 
In one such Ames mutagenicity test 
1-methyl-2-methylsulfonyl-4-nitroimidazole was compared to two 
commercially available nitroimidazoles, ronidazole 
(1-methyl-2-[(carbamoyloxy)methyl]-5-nitroimidazole) and metronidazole 
(1-(2-hydroxyethyl-2-methyl-5-nitroimidazole). At 3 .mu.g per plate 
ronidazole had 358 mutants per plate while metronidazole and the instant 
compound were indistinguishable from background. At 30 .mu.g per plate, 
ronidazole had 2682 mutants per plate and metronidazole had 142 mutants 
per plate while the instant compound was still indistinguishable from 
background. At 100 and 300 .mu.g per plate metronidazole had 443 and 1374 
mutants per plate respectively, while the instant compound was still at 
barely a threshold level of 30 and 65 mutants per plate respectively. The 
instant compound continued to show no more than a threshold level at 400, 
500 and 600 .mu.g per plate by recording 0, 54 and 0 mutants per plate 
respectively. Such levels of mutagenicity are not statistically 
significantly different from background and as such, the instant compound 
would be considered non-mutagenic. 
Thus, considering the rapidly increasing mutagenic activity of ronidazole 
and metronidazole and the continuing statistically insignificant levels of 
mutagenic activity with the instant compound, it is apparent that the 
instant compound represents a considerable breakthrough in treating 
protozoal and bacterial diseases with a new level of safety, unachieved 
and unachievable with prior therapies. 
The instant compound has antiprotozoal and antibacterial activity, and is 
particularly active against the causative organisms of the protozoal 
parasitic diseases trichomoniasis and enterohepatitis. It is also 
effective against amoebiasis and trypanosomiasis, as well as against the 
PPLO (Pleuropneumonia-like organisms) and schistosomes. 
Trichomoniasis is a protozoan disease caused by parasites of the genus 
Trichomonas. The compound of the invention is effective against the 
particularly troublesome form of trichomoniasis known as T. vaginalis 
vaginitis, caused by infestation of the vagina with T. vaginalis. In 
treating this disease, the compound may be administered either orally or 
topically. For oral administration unit dosage, forms such as tablets or 
capsules are normally employed which may contain from about 50 to about 
500 mg of active ingredient. These are prepared by techniques known in the 
art, and contain the usual diluents, granulating agents, extenders and/or 
lubricating agents known to be satisfactory for the compounding of tablets 
and capsules. 
It is preferred to administer the compound of the invention orally at a 
dose level of from about 25-1000 mg/day, in either single or divided doses 
with divided doses being used more frequently than a single dose. An 
example of a suitable compressed tablet is the following: 
______________________________________ 
Component: Mg per tablet 
______________________________________ 
1-methyl-2-methylsulfonyl-4-nitro- 
250 
imidazole 
Dicalcium phosphate 100 
Lactose 75 
Starch 50 
Guar gum 12 
Magnesium stearate 2-3 
______________________________________ 
If desired, tablets may be sugar coated or enteric coated by standard 
techniques. Alternatively, the antitrichomonal agent may be formulated in 
capsule form using fillers such as lactose, starch or kaolin. A typical 
capsule would contain 250 mg of, for instance, 
1-methyl-2-methylsulfonyl-4-nitroimidazole, 2-3 mg of magnesium stearate 
and about 75 mg of lactose in a No. 0 size capsule. Tablets and capsules 
containing smaller quantities of active ingredient may be made by reducing 
proportionately the amounts of excipients and diluents illustrated above. 
Alternatively, the compound may be administered orally in liquid 
pharmaceutical vehicles such as solutions, emulsions, syrups or 
suspensions containing the diluents, flavoring agents and preservatives 
customarily employed in the pharmaceutical art. 
For topical application, creams or suppositories containing the active 
ingredient may be used. To illustrate, a cream is prepared by mixing 
sufficient quantities of hydrophilic ointment and water, containing from 
about 5-10% by weight of the compound, in sufficient quantities to produce 
a cream having the desired consistency. 
Enterohepatitis is a disease occurring primarily in turkeys and is caused 
by the protozoan parasite Histomonas meleagridis. It is also known as 
turkey blackhead disease. The compound of this invention is useful in the 
prevention and treatment of this disease and for this purpose is 
administered to turkeys mixed with an element of turkey sustenance, i.e. 
in the feed or drinking water. Although the optimum dose level will depend 
on the severity of the infection, good control of enterohepatitis is 
obtained by orally administering to the turkeys a feed containing from 
about 0.003% to about 0.1% by weight of the instant compound. When the 
material is administered via the drinking water, somewhat higher levels 
may be employed, especially for therapeutic use. For instance, the 
drinking water may contain up to about 0.2% by weight of the active 
ingredient with good results. 
As previously stated, the compound described herein may also be employed 
against trypanosomiasis, amoebiasis and the pleuro-pneumonia like 
organisms which have come to be known as PPLO. 
The compound is effective against PPLO when the compound is administered to 
fowl or swine in feed containing from about 0.003% to about 0.1% by weight 
of the compound. The preferred dosage level, however, is between from 
about 0.003% to 0.08% by weight. 
When used as antibacterial agents, the instant compound may be formulated 
in oral and topical dosage forms, at the dosage levels discussed above 
with respect to trichomoniasis. 
The following example is provided in order that the invention might be more 
fully understood. It should not be construed as being limitative. 
Potassium iodide (4.8 g) and 1-methyl-2-methylsulfonyl-5-nitroimidazole 
(5.0 g) were combined in N,N-dimethylformamide (30 ml) and the reaction 
mixture heated to 160.degree. C. for 2 hours. Upon cooling, the reaction 
mixture was added to 150 ml of a water and ice mixture. The product 
precipitated and was filtered and dried affording 4.4 g of 
1-methyl-2-methylsulfonyl-4-nitroimidazole.