DE3012825A1 - Antiprotozoal agents e.g. against Trichomonas vaginalis - contg. racemic-threo-1-para-chloro-phenoxy-1-imidazol-1-yl-3,3-di:methyl- -2-butanol - Google Patents

Abstract

New antiprotozoal agents contain racemic-threo-1-(4-chloro- phenoxy) 1-(1-imidazolyl)-3,3-dimethyl-2-butanol (I) and/or its physiologically tolerable acid addition salts. (I) (an antimycotic agent disclosed in DE2850057) has been found to have strong antiprotozoal activity against organisms such as Trichomonas vaginalis, T.foetus, Lamblia intestinalis, Entamoeba histolytica, Histomonas maleagrimitis etc. A combination of antimycotic and antiprotozoal activity is esp. used. (I) is active orally, locally and parenterally. (I) may be administered in the form of pharmaceutical formulations such as tablets, dragees, capsules, pills, granulates, suppositories, solutions, suspensions, emulsions, pastes, ointments, gels, creams, lotions, powders and sprays.

Description

Protozoan remedy, process for its preparation, as well

its use The present invention relates to its use of (+) - threo-1- (4-chlorophenoxy) -l- (l-imidazolyl) -3,3-dimethyl-2-butanol as a protozoal agent.

It has already become known that 1- (2-hydroxyethyl) -2-methyl-5-nitroimidazole (Metronidazole) to combat protozoal diseases such as trichomonasis and amoebiasis, is used (cf. e.g. Chemotherapy of infection, p.349 ff, (1977), Oxford, University Press, New York). However, its effect does not include such against fungal infections, such as those often occurring in trichomoniasis, for example appear. Effective antimycotics such as bisphenyl- (2-chlorophenyl) -imidazol-l-yl-methane (Clotrimazole) (compare DE-PS 1 617 481) are in turn opposed to Trichomonas infections at most only effective to a limited extent when used locally.

It has been found that the (+) - threo-1v (4-chlorophenoxy) -l- (l-imidazolyl) -3,3-dimethyl-2-butanol of the formula and its physiologically compatible acid addition salts have a strong protozoal effect.

Surprisingly, this shows (+) - threo-1- (4-chlorophenoxy) -1- (1-imidazoly- dimethyl-2-butanol in addition to a very good antifungal activity, an excellent protozoal effect, especially when used orally.

The substance to be used according to the invention is therefore a comparison to the state of the art, a valuable addition to pharmacy.

The active ingredient to be used according to the invention and its acid addition salts have not yet been described. The substance, its manufacture and its use as an antimycotics, however, are the subject of a separate, older application which has not yet been published (see German patent application P 28 50 057 [TEA 19 2743 of November 18, 1978); and can be prepared by the process described there by adding the 1- (4-chlorophenoxy) -l- (1-imidazolyl) -dimethyl-2-butanone of the formula with secondary alcoholates, such as, in particular, aluminum isopropoxide, in the presence of an organic solvent, such as, in particular, isopropanol, preferably at the boiling point of the solvent.

The ketone of the formula (II) to be used as the starting material is known (Compare DE-OS 21 05 490).

It is obtained by the process described there by adding 1- (4-chlorophenoxy) -l-bromo (chloro) -3,3-dimethyl-2-butanone with imidazole, optionally in the presence of an acid binder, at temperatures converts between 60 and 1200C.

For the preparation of acid addition salts of the compound of the formula (I) all physiologically compatible acids are possible. These preferably include the hydrohalic acids, such as hydrochloric acid and hydrobromic acid, in particular hydrochloric acid, furthermore phosphoric acid, nitric acid, sulfuric acid, mono- and bifunctional carboxylic acids and hydroxycarboxylic acids, such as acetic acid, Maleic acid, succinic acid, fumaric acid, tartaric acid, citric acid, salicylic acid, Sorbic acid, lactic acid and sulfonic acids such as p-toluenesulfonic acid and 1,5-naphthalenedisulfonic acid.

The salts of the compounds of the formula (1) can be used in a simple manner by customary salt formation methods, e.g.

by dissolving the compounds of formula (I) in a suitable inert Solvent and adding the acid such as hydrochloric acid and in a known manner, for example by filtering off and optionally by washing be cleaned with an inert organic solvent.

The compound according to the invention is characterized by a high level of effectiveness against parasitic protozoa. It is suitable for combating Protozoal diseases in humans and animals such as those caused by, for example Trichomonas vaginalis, Trichomonas fetus, Lamblia intestinalis, Entamoeba histolytica, Histomonas meleagrimitis u.a .. The agent according to the invention can be used orally and parenterally or applied locally. For the treatment of humans there are dosages from 50 to 2000 mg / day is possible, depending on the duration of treatment. For the Oral administration primarily comes into consideration in tablets, capsules and syrup. When treating larger herds of animals (e.g. turkeys), the treatment can be carried out via the Feed or drinking water.

Suitable injection solutions are used for parenteral administration and for local administration jellies, creams or suppositories (e.g. vaginal tablets) used.

The present invention includes pharmaceutical preparations, in addition to non-toxic, inert pharmaceutically suitable carriers or contain more than one active ingredient according to the invention or one or more There are active ingredients according to the invention and processes for the production of these preparations.

The present invention also includes pharmaceutical preparations in dosage units. This means that the preparations in the form of individual parts, e.g. tablets, Dragees, capsules, pills, suppositories and ampoules are present, the active ingredient content of which is a fraction or a multiple of a single dose correspond. The dosage units can be, for example, 1, 2, 3 or 4 single doses or Contain 1/2, 1/3 or 1/4 of a single dose.

A single dose preferably contains the amount of active ingredient required for an application is administered and usually a whole, half an or a third or a quarter of a daily dose.

Among non-toxic, inert pharmaceutically acceptable carriers are solid, semi-solid or liquid diluents, fillers and formulation auxiliaries of any kind to understand.

Preferred pharmaceutical preparations are tablets, coated tablets, Capsules, pills, granules, suppositories, solutions, suspensions and emulsions, Called pastes, ointments, gels, creams, lotions, powders and sprays.

Tablets, coated tablets, capsules, pills and granules can be the or the active ingredients contain substances in addition to the usual carriers, such as (a) fillers and extenders, e.g. starches, milk sugar, cane sugar, glucose, mannitol and silicic acid, (b) binding agents, e.g. carboxymethyl cellulose, alginates, gelatine, polyvinylpyrrolidone, (c) humectants, e.g. glycerin, (d) disintegrants, e.g.

Agar-agar, calcium carbonate and sodium bicarbonate, (e) dissolution retarder, e.g. paraffin and (f) absorption accelerator, e.g. quaternary ammonium bindings, (g) wetting agents, e.g., cetyl alcohol, glycerol monostearate, (h) adsorbents, e.g. Kaolin and bentonite and (i) lubricants, e.g. talc, calcium and magnesium stearate and solid polyethylene glycols or mixtures of the substances listed under (a) to (i).

The tablets, coated tablets, capsules, pills and granules can be used with the customary coatings and casings, optionally containing opacifying agents be and also be composed so that they only or the active ingredient or preferably in a certain part of the intestinal tract, possibly delayed used as embedding materials, e.g. polymer substances and waxes can be.

The active ingredient (s) can optionally be combined with one or more the above-mentioned carriers are also available in microencapsulated form.

In addition to the active ingredient (s), suppositories can contain the usual water-soluble ones or water-insoluble carriers, e.g. polyethylene glycols, fats, e.g.

Cocoa fat and higher esters (e.g. C14 alcohol with C16 fatty acid) or Mixtures of these substances.

Ointments, pastes, creams and gels can be used in addition to the active ingredient or ingredients contain the usual carriers, e.g. animal and vegetable fats, waxes, Paraffin, starch, tragacanth, cellulose derivatives, polyethylene glycols, silicones, bentonites, Silica, talc and zinc oxide or mixtures of these substances.

Powders and sprays can be the usual ones in addition to the active ingredient or ingredients Contain carrier substances, e.g. lactose, talc, silica, aluminum hydroxide, Calcium silicate and polyamide powder or mixtures of these substances. Sprays can also be used the usual propellants e.g. contain chlorofluorocarbons.

Solutions and emulsions can, in addition to the active ingredient or ingredients, the customary carriers such as solvents, solubilizers and emulsifiers, e.g. Water, ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, Benzyl benzoate, propylene glycol, 1,3-butylene glycol, dimethylformamide, oils, in particular Cottonseed oil, peanut oil, corn oil, oliban oil, castor oil and sesame oil, glycerine, Glycerin formal, tetrahydrofurfuryl alcohol, polyethylene glycols and fatty acid esters of sorbitan or mixtures of these substances.

The solutions and emulsions can also be used for parenteral administration are in sterile and blood isotonic form.

In addition to the active ingredient (s), suspensions can contain the usual carriers such as liquid diluents, e.g. water, ethyl alcohol, propylene glycol, suspending agents, e.g. ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline Cellulose, aluminum metahydroxide, bentonite, agar-agar and tragacanth or mixtures of these substances.

The formulation forms mentioned can also contain colorants and preservatives as well as additives that improve smell and taste, e.g. peppermint oil and eucalyptus oil and sweeteners such as saccharine.

The therapeutically active compounds are intended to be in those listed above pharmaceutical preparations preferably in a concentration of about 0.1 to 99.5, preferably from about 0.5 to 95 percent by weight of the total mixture be.

The pharmaceutical preparations listed above can except the active ingredients according to the invention also contain further pharmaceutical active ingredients.

The manufacture of the pharmaceutical preparations listed above takes place in the usual way by known methods, e.g. by mixing the Active ingredients with the carrier (s).

Example A Protozoal activity on the experimental model with Trichomonas vaginalis infected mice Description of the experiment: CF, -Winkelmann- weighing about 20g Mice (spf) become intraperitoneal with 2 to 14 million parasites grown in vitro infected. Suspended in water with the help of Cremophor EL (0.2 ml per 0.1 g of active ingredient) Test substance is administered orally using a stomach tube on 5 consecutive days. The first treatment takes place 4 hours before the infection, the further treatments follow every 24 hours.

In the case of a single treatment, this takes place 2 hours after the infection.

On the 7th day after infection, the mice are sacrificed and dissected. the macroscopically detectable abscesses are counted and assessed as well as living ones Parasites examined microscopically.

The number of positive animals per test group is used for evaluation (4 - 5 animals per dose and experiment) as well as the macroscopic and microscopic Findings based on that of Jones, W.R. (Brit.Pharmacol. 2, 217-220, 1947) and by Thompson, R.E. et al (Amer. J. Trop.

Med. 30, 203-215, 1950) developed procedures with the control group compared. In the summary assessment used below, the following apply: Effect = animals cured or only a few parasites detectable.

Trace effect - number and size of abscesses and parasite density clearly lower than in the untreated controls.

ineffective = number and size of abscesses and parasite ends = ht corresponds that of the untreated control animals.

Evaluation: As can be seen from Table A below, it works the active ingredient (2) according to the invention as well as that-not antifungal at the same time effective metronidazole and thus like that which is now generally recognized as a trichomonacid Standard preparation. The active ingredient (2) according to the invention is incomparably effective better against Trichomonas vaginalis than the highly effective antifungal clotrimazole; this is capable of experimental Trichomonas vaginalis infections when administered orally the mouse can only be hinted at in the toxic dose range.

- Table A Protozoa effectiveness on the experimental model of mice infected with TrichOmonas vainalis Dose frequency of findings animal in numbers mg / kg effect trace un- Active ingredient effect effective OH CH2 5x1O0 83 17% 30 CH2 5x5O 75% 25% 30 CH NO 5x25 75% 13% 12% 40 X r 5xlO 45% 11% 44% 45 (MetronidazoL) (known) I. c 5x500 - cjg 50S 16 sxsoo ~ (500 dead toxicity t N 5x250 - 25% 75% 24 (Clotrimazole) (known) Ex. (2) 5xloo 100% ~ - 30 5x50 86% ~ 14% 35 5x25 43% 43% 14% 35 5x10 14% 29% 57% 35 5x5 - - 100% 10 1x500 100% - - 30 1x250 17% 83% - 30 1x125 - 67% 33% 30 1x50 - - 100% 5 Production examples Example 1 10 kg (34.16 mol) of 1- (4-chlorophenoxy) -l- (l-imidazolyl) -3,3-dimethyl-2-butanone, 3.44 kg (16.74 mol) of aluminum isopropoxide and 28 l of isopropanol are dissolved in heated in a 40 l glass kettle for 16 hours at a bath temperature of 98-1020C.

During this, 12 l of solvent are distilled off. That when cooling down the The product precipitating in the reaction solution is mixed with 20 l of isopropanol, to 70.degree heated, drained hot into a 100 1 enamel kettle and while stirring with a Solution of 6.91 kg (57.6 mol) of sodium hydrogen sulfate in 32 l of water. Man lets stir for 8 hours and then sucks off through a clay suction cup. The moist residue is slurried in 13 l of ethanol and treated with a solution of 10.3 l of 10% sodium hydroxide solution and 25.7 1 of water are added. The mixture is stirred for 4 hours, filtered off with suction, and the residue is added with 20 l of water, sucks off again and dries. 7.5 kg (66.7% of theory) are obtained (+) - threo-1- (4-chlorophenoxy) -1- (1-imidazolyl) -3, 3-dimethyl-2-butanol of melting point 158-1590C.

Example 2 The 7.5 kg of (+) - threo-1- (4-chlorophenoxy) -l- (l-imidazolyl) -3, 3-dimethyl-2-butanol obtained according to Example 1 are stirred in 37.5 liters of 2N hydrochloric acid . After 50 liters of n-butanol have been added, the mixture is stirred for 2.5 hours, the organic phase is separated off, washed twice with 12.5 liters of 2N hydrochloric acid and concentrated. The residue is slurried cold with 10 l of methylene chloride and filtered off with suction. The residue is washed with 6 l of methylene chloride and dried at 50 ° C. in a fan. 8 kg (95% of theory) (+) - threo-1- (4-chlorophenoxy) -l- (l-imidazolyl) -3,3-dimethyl-2-butanol hydrochloride with a melting point of 236-370 ° C. are obtained.

Claims (10)

Claims 1. Antiprotozoal agents, characterized by a Content of () -threo-1- (-) - threo-1- (4-chlorophenoxy) -1- (1-imidazolyl) -3, 3-dimethyl-2-butanol and / or its physiologically acceptable acid addition salts. 2. A process for the preparation of an antiprotozoal agent, characterized in that that (- +) -threo-1- (4-chlorophenoxy) -1- (1-imidazolyl) -3,3-dimethyl-2-butanol and / or its physiologically beneficial acid addition salts with inert, non-toxic, pharmaceutically suitable carriers mixed. 3. A method for the preparation of an oral antiprotozoal agent, thereby characterized in that (-) - threo-1- (4-chlorophenoxy) -1- <1-imidazolyl) -3,3-dimethyl-2-butanol and / or its physiologically acceptable acid addition salts with inert, non-toxic, pharmaceutically acceptable carriers mixed. 4. A method for the preparation of a local antiprotozoal agent, thereby characterized in that (- +) -threo-1- (4-chlorophenoxy) -1 - (1 -imidazolyl) -3,3-dimethyl-2-butanol and / or its physiologically acceptable acid addition salts with inert, non-toxic, pharmaceutically suitable carriers mixed. 5. Process for the preparation of a parenteral antiprotozoal agent, characterized in that (- +) - threo-1- (4-chlorophenoxy) -1- (1-imidazolyl) -3,3-dimethyl-2-butanol and / or its physiologically acceptable acid addition salts with inert, non-toxic, pharmaceutically suitable carriers mixed. 6. A method for the treatment of protozoal infections, characterized in that that one (- +) -threo-1 - (4-chlorophenoxy) -1 - (1 -imidazolyl) -3, 3-dimethyl-2-butanol and / or its physiologically acceptable acid addition salts humans or animals applied who are sick with protozoal infections. 7. A method for the treatment of protozoal infections, characterized in that that one (- +) - threo-1- (4-chlorophenoxy) -1- (1-imidazolyl) -3, 3-dimethyl-2-butanol and / or its physiologically acceptable acid addition salts humans or animals who are suffering from Trichomonas vaginalis infections. 8. A method for the treatment of protozoal infections, characterized in that that (-) - threo-1- (4-chlorophenoxy) -1- (1-imidazolyl) -3,3-dimethyl-2-butanol and / or its physiologically acceptable acid addition salts humans or animals applied who have Trichomonas fctus infections. 9. A method for the treatment of protozoal infections, characterized in that that one (-) -threo-1 - (4-chlorophenoxy) -1- (1-imidazolyl) -3, 3-dimethyl-2-butanol and / or its physiologically acceptable acid addition salts humans or animals who are suffering from lamblia intestinalis infections. 10. A method for the treatment of protozoal infections, characterized in that that one (- +) -threo-1 - (4-chlorophenoxy) -1- (1-imidazolyl) -3,3-dimethyl-2-butanol and / or its physiologically acceptable acid addition salts humans or animals applied who are sick with Entamoeba hiotolytica infections.