WO1995001790A1 - Use of taxoids for treating parasitic diseases - Google Patents

Abstract

The use of docetaxel and analogues thereof for treating parasitic diseases such as malaria, trypanosomiasis, toxoplasmosis and Pneumocystis carinii pneumoniae is disclosed.

Description

 APPLICATION OF TAXOIDS TO THE TREATMENT OF DISEASES OF PARASITIC ORIGIN

The present invention relates to the application of taxoids such as docetaxel (Taxotère®) and its analogs to the treatment of diseases of parasitic origin such as malaria, trypanosomiasis, toxoplasmosis and infections of Pneumocystis carinii pneumoniae.

Docetaxel is an antimitotic agent that interacts with tubulin, a protein that makes up the mitotic spindle. In vitro, docetaxel increases the rate of assembly of tubulin into microtubules and inhibits the disassembly of microtubules into tubulin. Due in particular to these properties, docetaxel and its analogs constitute powerful anticancer agents which are more particularly active on solid tumors.

It has now been found that docetaxel and its analogs are also useful in the treatment of parasitic diseases where microtubules play a decisive role in the morphogenesis of the various evolutionary stages. More particularly, docetaxel and its analogues make it possible to effectively treat malaria.

Malaria is a parasitic disease to which 2 billion people are exposed. Currently, a large number of strains of Plasmodium falciparum. parasite which is responsible for severe forms of malaria are resistant to conventional chemotherapy (chloroquine and derivatives, quinine or mefloquine). It is therefore necessary, in the absence of effective vaccines against malaria, to have products which can act on the different phases of development of the parasite.

Due to their mechanism of action, docetaxel and its derivatives can be used for the treatment of other parasitic diseases such as trypanosomiasis or opportunistic infections caused by microorganisms or parasites in AIDS carriers, such as Pneumocystis carinii pneumoniae and Toxoplasma gondii.

It has now been found, and this is the subject of the present invention, that docetaxel and its analogs constitute particularly effective antiparasitic agents at doses much lower than those necessary to obtain an effect. antitumor.

The activity of docetaxel and its analogues can be demonstrated by in vitro tests on erythrocyte cultures of different strains of Plasmodium falciparum sensitive to chloroquine (strain F32 / Tanzania) or resistant to chloroquine (strains FcBl / Columbia or FcR3 / Gambia). It is possible to determine the effect of the product by in vitro tests of 42 or 72 hours by determining the concentrations inhibiting by 50% the growth of the parasite (IC50).

It has been shown that under these conditions docetaxel reacts selectively to nanomolar concentrations on the parasite.

While the Plasmodium falciparum FcBl / Colombia strain manifests vis-à-vis chloroquine an IC50 close to 178 ± 10 ng.ml'l, corresponding to resistance to chloroquine, the IC50 during the 72-hour tests is close to 5 ± 1 nM vis-à-vis docetaxel and 71 ± 8 nM vis-à-vis taxol. Similar results are obtained from the strain sensitive to chloroquine F32 / Tanzania (IC50 = 12.9 ± 0.3 ng.ml "!) Or from the strain resistant to chloroquine FcR3 / Gambia (IC50 = 228 ± 16 ng.ml " ¹ ).

The dose-response curves of the 42-hour inhibition tests have an original biphasic appearance with the existence of an intermediate plateau (for concentrations between 10 "^ and 10" ° ^* M) indicating the presence of high targets and of lower affinity for docetaxel. This phenomenon can be demonstrated by using synchronized cultures and by adding docetaxel to the different parasitic stages. At substantially micromolar concentrations, docetaxel acts on red blood cells parasitized by young stages (ring and trophozoite forms corresponding to the first thirty hours of the erythrocyte cycle). At nanomolar concentrations, docetaxel acts on the dividing forms of the parasite

(schizonts). The erythrocyte membrane and / or cytoskeleton are also targets of docetaxel at micromolar concentrations since preincubations of healthy erythrocytes with docetaxel inhibit the invasion of erythrocytes by infesting forms (merozoites)

The concentrations at which docetaxel manifests its antiparasitic activity are approximately 1000 times lower than those determined for docetaxel in preclinical or clinical antitumor trials.

Docetaxel, tested on in vitro cultures of epimastigote forms of Trypanosoma cruzi. agent of Chagas disease or American trypanosomiasis, has an IC50 close to 100 nM whereas, for taxol, the IC50 is close to 400 nM.

Docetaxel also manifests its activity on Babesia divergens which is the agent of bovine babesiosis which can develop in humans, especially in splenectomized individuals, with an overwhelming evolution. The CI50 is close to 50-60 nM for docetaxel on Babesia divergens in in vitro culture on human red blood cells.

The present invention relates to pharmaceutical compositions containing docetaxel and / or its analogs useful in the treatment of parasitic diseases which involve a mechanism of action on the polymerization and depolymerization of microtubules.

These compositions are generally adapted to the chosen route of administration which, preferably, is the parenteral route. Parenteral administration includes intravenous, intraperitoneal, intramuscular or subcutaneous administration. More particularly preferred is intraperitoneal or intravenous administration.

The pharmaceutical compositions can be prepared according to the usual methods using one or more suitable pharmaceutical acceptable adjuvants, carriers or excipients. Suitable carriers include diluents, sterile aqueous media and various non-toxic solvents. Preferably, the compositions are in the form of aqueous solutions or suspensions, injectable solutions which may contain emulsifying agents, dyes, preservatives or stabilizers.

The choice of adjuvants or excipients can be determined by the solubility and chemical properties of the product, the particular mode of administration and good pharmaceutical practices.

For parenteral administration, aqueous or non-aqueous sterile solutions or suspensions are used. For the preparation of nonaqueous solutions or suspensions can be used natural vegetable oils such as olive oil, sesame oil or paraffin oil or injectable organic esters such as ethyl oleate .

Aqueous sterile solutions can consist of a solution of docetaxel or its analogues in water. The aqueous solutions are suitable for intravenous administration as long as the pH is suitably adjusted and the isotonicity is achieved, for example, by a sufficient amount of sodium chloride or glucose. Sterilization can be carried out by heating or by any other means which does not alter the composition.

It is understood that all the products entering into the compositions must be pure and non-toxic for the quantities used. The compositions can contain at least 0.01% of therapeutically active product. The amount of active ingredient in a composition is such that a suitable dosage can be prescribed. Preferably, the compositions are prepared in such a way that a unit dose contains from 0.01 to 10 mg approximately of active product for parenteral administration.

In humans, the doses are generally between 0.001 and 20 mg / kg. By intraperitoneal route, the doses are generally between 0.01 and 10 mg kg, preferably between 0.05 and 5 mg kg and, even more specifically between 0.05 and 0.5 mg / kg. It is understood that, in order to choose the most appropriate dosage, the route of administration, the patient's weight, his general state of health, his age and all the factors which may influence the effectiveness of the treatment must be taken into account.

Docetaxel and its analogues which are suitable for carrying out the invention correspond to the general formula:

dans laquelle :

in which :

Ar represents an aryl radical,

Rj represents a benzoyl radical or an R2-O-CO- radical in which R2 represents:

- a straight or branched alkyl radical containing 1 to 8 carbon atoms, alkenyl containing 2 to 8 carbon atoms, alkynyl containing 3 to 8 carbon atoms, cycloalkyl containing 3 to 6 carbon atoms, cycloalkenyl containing 4 to 6 carbon atoms or bicycloalkyl containing 7 to 11 carbon atoms, these radicals being optionally substituted by one or more substituents chosen from halogen atoms and hydroxy radicals, alkyloxy containing 1 to 4 carbon atoms, dialkoylamino of which each alkyl part contains 1 to 4 carbon atoms, piperidino, morpholino, piperazinyl-1 (optionally substituted at -4 by an alkyl radical containing 1 to 4 carbon atoms or by a phenylalkyl radical in which the alkyl part contains 1 to 4 carbon atoms), cycloalkyl containing 3 to 6 carbon atoms, cycloalkenyl containing 4 to 6 carbon atoms, phenyl, cyano, carboxy or alkyloxycarbonyl, the alkyl part of which contains 1 to 4 carbon atoms,

- or a phenyl radical optionally substituted by one or more atoms or radicals chosen from halogen atoms and alkyl radicals containing 1 to 4 carbon atoms, alkyloxy containing 1 to 4 carbon atoms,

- or a saturated or unsaturated nitrogen heterocyclyl radical containing 4 to 6 members and optionally substituted by one or more alkyl radicals containing 1 to 4 carbon atoms, and

R3 represents - a straight or branched alkyl radical containing 1 to 8 carbon atoms, alkenyl containing 2 to 8 carbon atoms, alkynyl containing 2 to 8 carbon atoms, cycloalkyl containing 3 to 6 carbon atoms, cycloalkenyl containing 4 to 6 atoms of carbon or bicycloalkyl containing 7 to 11 carbon atoms, these radicals being optionally substituted by one or more substituents chosen from halogen atoms and hydroxy radicals, alkyloxy containing 1 to 4 carbon atoms, dialkoylamino of which each alkyl part contains 1 with 4 carbon atoms, piperidino, morpholino, piperazinyl-1 (optionally substituted at -4 by an alkyl radical containing 1 to 4 carbon atoms or by a phenylalkyl radical in which the alkyl part contains 1 to 4 carbon atoms), cycloalkyl containing 3 to 6 carbon atoms, cycloalkenyl containing 4 to 6 carbon atoms, optionally substituted phenyl, cyano, carboxy or alkyloxycarbonyl do the alkyl part contains 1 to 4 carbon atoms,

- or an aryl radical optionally substituted by one or more "S atoms or radicals chosen from halogen atoms and alkyl radicals containing 1 to 4 carbon atoms, alkyloxy containing 1 to 4 carbon atoms,

- or a saturated or unsaturated nitrogen heterocyclyl radical containing 4 to 6 members and optionally substituted by one or more alkyl radicals containing 1 to 4 carbon atoms, it being understood that the cycloalkyl, cycloalkenyl or bicycloalkyl radicals may be optionally substituted by one or more alkyl radicals containing 1 to 4 carbon atoms.

Preferably the aryl radicals represented by Ar and R3 are phenyl or α- or β-naphthyl radicals optionally substituted by one or more atoms or radicals chosen from halogen atoms (fluorine, chlorine, bromine, iodine) and alkyl radicals , alkenyls, alkynyls, aryls, arylalkyls, alkoxy, alkylthio, aryloxy, arylthio, hydroxy, hydroxyalkyl, mercapto, formyl, acyl, acylamino, aroylamino, alkoxycarbonylamino, amino, alcoylamino, dialcoylamino, carboxy, alkoxycarbonyl, carbamoyl, dialkoylcarbamoyl, cyano, nitro and trifluoromethyl radicals, including allyl and trifluoromethyl radicals, including alkyl and trifluoromethyls other radicals contain 1 to 4 carbon atoms, that the alkenyl and alkynyl radicals contain 2 to 8 carbon atoms and that the aryl radicals are phenyl or α- or β-naphthyl radicals, and that the radical R3 cannot represent an unsubstituted phenyl radical.

Preferably, the heterocyclic radicals represented by Ar are aromatic heterocyclic radicals having 5 members and containing one or more atoms, identical or different, chosen from nitrogen, oxygen or sulfur atoms, optionally substituted by one or more substituents, identical or different, chosen from halogen atoms (fluorine, chlorine, bromine, iodine) and alkyl radicals containing 1 to 4 carbon atoms, aryls containing 6 to 10 carbon atoms, alkoxy containing 1 to 4 carbon atoms, aryloxy containing 6 to 10 carbon atoms, amino, alkylamino containing 1 to 4 carbon atoms, dialkoylamino in which each alkyl part contains 1 to 4 carbon atoms, acylamino in which the acyl part contains 1 to 4 carbon atoms, alkoxycarbo¬ nylamino containing 1 to 4 carbon atoms, acyl containing 1 to 4 carbon atoms, arylcarbonyl the aryl part of which contains 6 to 10 carbon atoms, cyano, carboxy, carbamoyl , alkylcarbamoyl in which the alkyl part contains 1 to 4 carbon atoms, dialcoylcarbamoyl in which each alkyl part contains 1 to 4 carbon atoms or alkoxycarbonyl in which the alkoxy part contains 1 to 4 carbon atoms.

Docetaxel and its analogs of general formula (I) can be prepared according to the methods which are described in European patents EP 0 253 738 and EP 0 336 841 and in international application PCT WO 92/09589.

The following example illustrates the invention.

EXAMPLE

Ampoules of 5 cm3 each containing 2.5 mg of docetaxel in solution in injectable solution are prepared according to the usual technique.

Claims

1 - Application of docetaxel and its analogues of general formula

in which: Ar represents an aryl radical, Ri represents a benzoyl radical or an R2-O-CO- radical in which R2 represents: - a straight or branched alkyl radical containing 1 to 8 carbon atoms, alkenyl containing 2 to 8 carbon atoms, alkynyl containing 3 to 8 carbon atoms, cycloalkyl containing 3 to 6 carbon atoms, cycloalkenyl containing 4 to 6 carbon atoms or bicycloalkyl containing 7 to 11 carbon atoms, these radicals being optionally substituted by one or more substituents chosen from halogen atoms and hydroxy radicals, alkyloxy containing 1 to 4 carbon atoms, dialkoylamino of which each alkyl part contains 1 to 4 carbon atoms, piperidino, morpholino, piperazinyl-1 (optionally substituted at -4 by an alkyl radical containing 1 to 4 carbon atoms or by a phenylalkyl radical in which the alkyl part contains 1 to 4 carbon atoms), cycloalkyl containing 3 to 6 carbon atoms, cycloalkenyl containing 4 to 6 carbon atoms, phenyl, cyano, carboxy or alkyloxycarbonyl of which the alkyl part contains 1 to 4 atom s of carbon, - or a phenyl radical optionally substituted by one or more atoms or radicals chosen from halogen atoms and alkyl radicals containing 1 to 4 carbon atoms, alkyloxy containing 1 to 4 carbon atoms, - or a saturated or unsaturated nitrogen heterocyclyl radical containing 4 to 6 members and optionally substituted by one or more alkyl radicals containing 1 to 4 carbon atoms, and R3 represents a straight or branched alkyl radical containing 1 to 8 carbon atoms, alkenyl containing 2 to 8 carbon atoms, alkynyl containing 2 to 8 carbon atoms, cycloalkyl containing 3 to 6 carbon atoms, cycloalkenyl containing 4 to 6 carbon atoms or bicycloalkyl containing 7 to 11 carbon atoms, these radicals being optionally substituted by one or more substituents chosen from halogen atoms and hydroxy, alkyloxy radicals containing 1 to 4 carbon atoms, dialcoylamino each alkyl part of which contains 1 to 4 carbon atoms, piperidino, morpholino, piperazinyl-1 (optionally substituted at -4 by an alkyl radical containing 1 to 4 carbon atoms or by a phenylalkyl radical the alkyl part of which contains 1 to 4 carbon atoms), cycloalkyl containing 3 to 6 carbon atoms, cycloalkenyl containing 4 to 6 carbon atoms, optionally substituted phenyl, cyano, carboxy or alkyloxycarbonyl of which the alkyl part contains 1 to 4 carbon atoms carbon, - or an aryl radical optionally substituted by one or more atoms or radicals chosen from halogen atoms and alkyl radicals containing 1 to 4 carbon atoms, alkyloxy containing 1 to 4 carbon atoms, - or a saturated nitrogen heterocyclyl radical or unsaturated containing 4 to 6 members and optionally substituted by one or more alkyl radicals containing 1 to 4 carbon atoms, it being understood that the cycloalkyl, cycloalkenyl or bicycloalkyl radicals can be optionally substituted by one or more alkyl radicals containing 1 to 4 atoms carbon, to the preparation of a drug effective in therapy in the treatment of diseases of parasitic origin. 2 - Application according to claim 1 characterized in that the medicament is intended for the treatment of malaria. 3 - Application according to claim 1 characterized in that the medicament is intended for the treatment of trypanosomiasis. 4 - Application according to claim 1 characterized in that the medicament is intended for the treatment of toxoplasmosis 5 - Application according to claim 1 characterized in that the medicament is intended for the treatment of infections with Pneumocystis carinii pneumoniae.