NO742091L - - Google Patents

Description

Nitroimidazole thiocaramates.

The invention relates to new N-lower alkyl-0-(2-lower alkyl-5-nitro-1-imidazolyl)ethyl 7thiocarbamates, with formula:

where R and R<1> denote lower alkyl, as well as their therapeutically active non-toxic acid addition salts.

In the present context, "lower alkyl" can denote straight-chain or branched groups with from 1-5 C atoms, such as e.g. methyl, ethyl, propyl, isopropyl, butyl, pentyl and the like.

The compounds of formula (i) are prepared in a simple manner by reacting a suitable nitroimidazole-ethanol of formula (II) with a suitable lower alkyl isothiocyanate (III) in the presence of a base such as e.g. a trialkylamine, pyridine, sodium acetate or the like,

in an aprotic organic solvent. Typical such solvents are aromatic hydrocarbons, such as e.g. benzene, toluene, xylene etc. dialkyl ketones such as e.g. diethyl ketone, methyl isobutyl ketone etc., ethers such as tetrahydrofuran, dioxane and the like, as well as aetonitrile. The reaction is preferably carried out under reflux.

The bases of formula (I) can be converted to the corresponding therapeutically active, non-toxic acid addition salts by reaction

with suitable inorganic acids such as e.g. hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, phosphoric acid, nitric acid and similar acids, or with suitable organic acids such as e.g. acetic acid, propionic acid. glycolic acid, lactic acid, oxalic acid, malonic acid, sulfamic acid, p-toluenesulfonic acid, etc. For their part, salts of formula (I) can be converted into the corresponding free bases by ordinary treatment with suitable alkalis.

Nitroimidazole derivatives of formula (I) and their acid addition salts have antiparasitic activity, particularly activity against protozoa, such as e.g. against organisms that cause parasitic diseases, such as trichomoniasis, enterohepatitis and amoebiasis. Typical of such causative organisms are Trichomonas vaginalis, Trichomonas columbae, Histomonas meleagridis and Entamoeba histolytica. It will naturally be understood that the compounds in question have different degrees of effectiveness against the different organisms.

The present compounds are particularly useful, as will be apparent from the following experiments, in the treatment of the protozoan disease trichomoniasis. which is caused by parasites of the genus Trichomonas. They are effective against the particularly unpleasant form of trichomoniasis called T. vaginalis vaginitis which is caused by infection of the vagina with T. vaginalis.

A. Trichomonas vaginalis in mice;

Adult mice are artificially infected by subcutaneous injection

of 1 x 10^ (- 100,000) live Trichomonas vaginalis at the beginning of the experiment (day 0). Treatment with the respective trial compound is started at the same time, with a standard oral dose of 160, 80, 40, 20, 10 or 5 mg/kg body weight. The particular dose for each group of mice is repeated for four consecutive days. All the animals are killed on experimental day 7 and the presence or absence of Trichomonas at the injection site is used as a criterion for the effectiveness of the compound. All control animals that have received saline instead of the active compound show. to be heavily infected with Trichomonas seven days after infection. It has been found that with oral doses of approx. 5 - 160 mg/kg the animals become negative (i.e. no Trichomonas

can be found in the injection area) after treatment with five repeated daily doses of the compound in question.

B. Trichomonas vaginalis in rats;

The ovaries are removed from young female rats (average body weight 100 g) and treated 10 days later with 10 mg of ovocyclino.

10 days after this ovocycline treatment, the rats are in pseudoestrus and at this time they are infected intravaginally with 3' - 4 x 10^ live Trichomonas vaginalis per rat. A week later, a sample of vaginal discharge is taken as a "control sample", which indicates the presence or absence of Trichomonas. Positive animals are treated orally with the relevant compound in standard doses of 40, 20, 10, 5 and 2.5 mg/kg body weight given for 5 consecutive days. The treatment is then stopped and a week later vaginal discharge is taken again and examined for the presence or absence of Trichomonas. According to this experiment, the animals become negative for Trichomonas at dosage levels of 2.5 - 40 mg/kg.

In the treatment of T. vaginalis vaginitis, the trial compounds in question can be given orally or topically as pharmaceutical preparations, preferably as dosage units, containing an effective amount of antiprotozoal compound, in admixture with pharmaceutical carriers. For oral administration, dosage units such as tablets, capsules or powders are usually used which contain from approx. 25 to approx. 500 mg of active substance, preferably fraz. 25 - 250 mg. These are produced in known ways and contain the usual diluents, granulating agents, drying agents, fillers, lubricants etc. which is known to be satisfactory for the composition of tablets, capsules and powders. If desired, the tablets can be coated with a sugar coating or coated for intestinal absorption in the usual way. Alternatively, the compounds in question can be given orally in liquid pharmaceutical carrier media such as solutions, emulsions, syrups, elixirs, suspensions and the like. as contains diluents, flavourings, preservatives, dyes etc., of the type usually used in pharmacy. For such preparations, a dosage unit can consist of a teaspoon, tablespoon etc. You can also use parenteral drugs in connection with suitable carriers such as e.g. sterile water, particularly in connection with water-soluble salts of formula (I), although other liquid injectable carriers may be used as well as other ingredients, e.g. to make the compounds soluble or preserve them. It is. advantageous to give the compounds orally in dosage amounts of from approx. 25 - 1,000 mg/day,

in single or divided doses.

Typical examples of a fixed dosage unit for oral use are the following:

A. Capsules (10,000 capsules. 250 mg active substance):

B. Tablets (5,000 pressed tablets, 50 mg active substance):

For topical use, vaginal creams or suppositories containing the active ingredients can be used. E.g. such a cream is prepared by mixing sufficient amounts of hydrophilic oil and water containing from approx. 5 - 10% by weight active ingredient, to a cream with a desired consistency.

In addition to the antiparasitic effect of the relevant compounds against Trichomonas, they have also been shown to be effective against Histomonas. Enterohepatitis is a disease that mainly occurs in turkeys and is caused by the protozoan parasite Histomonas meleagridis. It is also known as turkey blackhead disease. Nitroimidazole derivatives of formula (I) and their salts are useful for the prevention and treatment of this disease and are given for this purpose to turkeys, in admixture with a feed element for turkeys, e.g. in the food or drinking water. Although the optimum dosage level will depend on the particular compound and the progress of the infection, good control of enterohepatitis is achieved by giving the turkeys a feed containing from 0.003 to 0.1% by weight of active substance. When the substance is given via the drinking water, somewhat higher levels can be used, especially for therapeutic use. E.g. the drinking water can contain up to approx. 0.2% by weight active substance with good results.

The following experimental technique demonstrates the antiprotozoal effect of the relevant compounds against Histomonas meleagridis, where. the decrease in turkey body weight is taken as an indicator of such an effect. Young turkeys (3-4 weeks old, 120 - 150 g body weight) are infected rectally (in the cloaca) with 2 ml of suspension containing Histomonas meleagridis (day 0). The suspension is prepared by mincing the liver and both coeca from an artificially infected turkey in 50 ml of saline. All the animals are placed individually in cages and given food and water ad libitum during the experiment. The food consists of ordinary, ready-to-buy turkey meat that does not contain additives, cocci-diostat or drugs. The test compound in question is mixed with the food in different concentrations (0.01, 0.02, 0.05-, 0.1 ....%) and given to the animals from day 2 to day 9. Increase in body weight, food intake and mortality is noted daily. Mean increase in body weight (i.e. the ratio of the body weight on day 7 in relation to the body weight on day 0) is taken as a measure, as the body °- weight increase for non-infected control animals on day 7 compared to day 0 is 160%, while the body weight loss for infected control animals in the same period is only 120%. Significant effects of the compounds are assumed to exist if the increase in body weight for the treated animals on day 7 is at least 150% compared to the body weight on day 0. It has been found that the compounds in question in fSr concentrations of approx. 0.01 - 0.1% leads to such an increase of 150% or more in body weight.

In light of the antiparasitic effect of the compounds in question, a method for inhibiting protozoan growth is hereby provided, which consists in administering internally or applying topically to a warm-blooded animal infected with protozoan organisms a pharmaceutical composition, preferably as a dosage unit, containing an effective antiprotozoan amount of a compound among the group of nitroimidazole derivatives of formula (i) as well as their therapeutically active acid addition salts in mixture with pharmaceutical carriers.

The following examples shall illustrate the invention without limiting it. Quantities are on a weight basis where nothing else is indicated.

Example I

A mixture of 5.1 parts of 2-methyl-5-nitro-1-imidazole-ethanepl, 2.2 parts of methyl isothiocyanate, 3 parts of triethylamine and 80 parts of acetonitrile is stirred under reflux for 3 days. When diisopropyl ether is added, the product precipitates. It is filtered off and recrystallized from acetonitrile (activated charcoal) and gives N-methyl-O-2-(2-methyl-5-nitro-1-imidazolyl)ethylthiocarbamate, melting point 182 - 188°C. Ordinary treatment with nitric acid gives the corresponding nitrate salt.

Example II

The process from example I is repeated except that an equivalent amount of both ethyl and n-propyl isothiocyanate is used instead of the methyl isothiocyanate used, giving respectively the

• corresponding N-ethyl and N-n-propyl derivatives. The N-ethyl derivative: melting point 129.5°C, the NTn-propyl derivative: melting point 102.2°C. Example III

A mixture of 6 parts of 2-isopropyl-5-nitro-1-imidazole-ethanol, 2.3 parts of methyl isothiocyanate, 6 parts of triethylamine and 80 parts of acetonitrile is stirred under reflux for 24 hours. refresher

the agent is evaporated in a vacuum and the residue is rubbed out in diisopropyl ether, whereby the product solidifies. It is filtered off and crystallized from a mixture of 2-propanol and water and gives 2.8 parts of 0-(2-isopropyl-5-nitro-1-imidazolyl)ethyl 7-N-methylthiocarbamate, melting point 134.5 - 135 .5°C. Usual treatment with ethereal HC1 gives the corresponding hydrochloride salt.

Example IV

By repeating the process from example III, except that an equivalent amount of ethyl and n-butyl isothiocyanate is used instead of the methyl isothiocyanate, the corresponding N-ethyl and N-n-butyl derivatives are obtained.

Example V

A mixture of 8.5 parts |3-(2-methyl-5-nitro-1-imidazolyl)-ethanol, 5 parts isopropyl isothiocyanate, 8 parts triethylamine and 80 parts acetonitrile is stirred and refluxed over a weekend. The reaction product is evaporated and the residue is triturated in 80 parts of 2-propanol. The product is filtered off and purified by column chromatography on silica gel with chloroform as eluent. The pure fractions are collected and the eluent is evaporated. The residue is crystallized from 2-propanol, yielding 3.6 parts of N-isopropyl-2-methyl-5-nitro-1-imidazoleethanol-thiocarbamate, melting point 153.2°C.

Claims (5)

1. Process for the production of O-(nitroimidazolyl)-ethyl thiocarbamates with formula: and their therapeutically active acid addition salts, where R and R"1" each denote lower alkyl, characterized by reacting a compound of formula with a compound of formula in the presence of a base, in an aprotic organic solvent, and, if desired, converting the compounds into therapeutically active acid addition salts. 2. Process for the production of N-methyl-0-(2-methyl-5-nitro-1-imidazolyl)-ethylthiocarbamate, characterized by reacting 2-methyl-5-nitro-1-imidazole ethanol with methyl isothiocyanate. 3. Process for the production of 0-(2-isopropyl-5-1-imidazolyl)-ethyl7-N-methylthiocarbamate, characterized in that 2-isopropyl-5-nitro-1-imidazole-ethanol is reacted with methyl isothiocyanate. 4. Process for the production of N-isopropyl-2-methyl-5-nitro-l-imidazoleethanol thiocarbamate, characterized in that p-(2-methyl-5-nitro-l-imidazolyl)ethanol is reacted with isopropyl isothiocyanate. 5. Preparation for the treatment of parasitic diseases, characterized in that the active ingredient has formula I as stated in claim 1.