HU195209B - Process for producing mefloquine-quinate salts with antimalarian effect and pharmaceutical preparations comprising the same - Google Patents

Abstract

Mefloquine quinate, i.e. alpha-2-piperidinyl-2,8- bis(trifluoromethyl) -4-quinolinemethanol quinate, of formula (I), is new.

Description

The present invention relates to a novel compound of formula (I), α- (2-piperidinyl) -2,8-bis (trifluoromethyl) -4-quinoline-methanol (mefloquine) kinase salt. Mefloquine has anti-malarial effects in humans; It is active against both chloroquine-sensitive and chloroquine-resistant strains of Plasmodium falciparum. The kinase salts of the present invention have a significantly higher solubility in aqueous media and a better pharmacokinetic profile against malaria-causing parasites than the hydrochloride salt described in the literature. The present invention also provides pharmaceutical compositions comprising the compounds of the present invention as active ingredients.

Compounds of formula (I) wherein n is 1 or 2 have a better pharmacokinetic profile against known malaria parasites. The compound of formula (I) wherein n is 1, i.e. meftokin kinate, unexpectedly has good water solubility in view of the water solubility of mefloquine hydrochloride; the solubility of mefloquine kinate is 100 g / 100 ml water and that of mefloquine hydrochloride is 1 g / 100 ml water.

The compounds of formula (I) are prepared according to the invention by reacting tinic acid (1,3,4,5-tetrahydroxycyclohexanecarboxylic acid) with the mefloquine free base of formula (II) in an inert solvent. The amount of cinnamic acid used may range from 0.75 to 2.25 moles per mole of mefloquine. Preferably 1.0 to 2.0 moles of cinnamic acid are used per mole of mefloquine. The mefloquine of formula (II) is mixed with a 50% aqueous solution of the appropriate amount of tinic acid, and the inert solvent is added to the mixture to dissolve the reagent at two room temperatures and 100 ° C. The resulting solution was filtered and the solvent removed from the filtrate in vacuo at a temperature below 100 ° C. Upon evaporation to dryness, the compound of formula (I) is obtained in solid form. This desired product is collected and dried.

Inert solvents include, for example, alcohols such as methanol, ethanol, isopropyl alcohol, and the like. and amides such as dimethylformamide and dimethylacetamide.

The mefloquine of formula (II) is a known compound which can be obtained by conventional methods of preparation.

The in vitro activity of the compounds of the present invention against malaria was determined by a standard pharmacological test on P. falciparum.

The activity of α- (2-piperidine) -2,8-bis (trifluoromethyl) -4-quinoline methanol kinate (mefloquine quinate) and dicadinate against malaria was reported by Lebras et al., American Journal of Tropical Medicine and Hygiene. , 32 (3), 447-451 (1983)]. Two human isolates of P. falciparum were compared with mefloquine kinase and mefloquine hydrochloride. The results are expressed as the _IC50 value given in the following table. (The inhibition concentration is calculated from a graph showing the percent maturation of the sisons and the logarithm of the concentration of drug to be tested.

Tribe

IC ₅₀ µm / l)

Mefloquine Kinate Mefloquine Hydrochloride

FCM1 7

West African strain 175 (116.1) * 120 (109.4) * chloroquine-sensitive

FCM24

Guyana strain 140 (92.9) * 120 (109.4) * chloroquine-resistant * Mefloquine is given in brackets.

The effect of mefloquine kinate in the above standard in vitro assay was similar to that of mefloquine hydrochloride. However, since the water solubility of mefloquine kinate is unexpectedly higher than the values obtained for the meflo2 free base, it has a better pharmacokinetic profile than mefloquine kinate.

The IC _{50 for} mefloquin dinicate is 100 nM against FCM17 '(West African, chloroquine-sen65).

-2195209

In accordance with the present invention, anti-malarial pharmaceutical compositions are prepared from known compounds of formula (I) and non-toxic pharmaceutically acceptable carriers in conventional unit dosage forms. The components are used in a non-toxic amount sufficient to elicit the desired chemotherapeutic effect in the animal or human being treated, but without undesirable toxic effects. The formulations contain the active ingredient in an effective, non-toxic amount ranging from 125 mg to 1000 mg per unit dose, but the amount of active ingredient is also affected by the specific biological effect desired, the activity of the compound employed and the condition of the patient.

A variety of pharmaceutical formulations can be used, including those for oral administration in tablet form with a solid carrier, or in the form of a powder or granules in hard gelatine capsules, suppositories, pills or lozenges. The amount of solid carrier can be varied over a wide range, but is preferably from 125 mg to 500 mg. A liquid carrier can be used to form a syrup, emulsion, soft gelatin capsule, sterile injectable liquid, for example, by ampoule, or as an aqueous solution or a non-aqueous liquid suspension. Because of the high solubility of mefloquine kinate, aqueous solutions are readily prepared and used to prepare sterile injectable liquid formulations.

The pharmaceutical compositions are prepared by methods known to those skilled in the art, such as mixing, granulating, slitting, or mixing and dissolving the components, as required, in the desired end product.

When necessary to achieve a curative or preventive anti-malarial effect, the human or animal to be treated is administered a compound of formula (I) with an activity, usually in admixture with a vehicle, that is not yet toxic but sufficient to produce the desired effect. The route of administration may be any route by which the active ingredient is delivered to the site of action within the body, including oral and parenteral administration.

Preferably one or a few daily, for example

1-3, the same dose is administered orally; the required daily dose is 125-1000 mg. The drug may be administered parenterally daily eg. dose, the required daily dose is the same as that for oral formulations.

The following illustrates the preparation of compounds of formula (I) and pharmaceutical compositions containing them as active ingredients. The examples are not limiting.

EXAMPLE 1 Preparation of α- (2-piperidinyl) -2,8-bis (trifluoromethyl) -4-quinolinemethanol kinate (Compound A)

To a 50% aqueous solution of 1.9 g of quinic acid was added 1.0 g of α- (2-piperidinyl) -2,8-bis (trifluoromethyl) -4-quinoline methanol at room temperature with stirring. Ethanol (10 mL) was added and the mixture was heated to 40 ° C to make a solution. The solution was filtered and the ethanol and water evaporated to dryness under reduced pressure. The desired product solidified as a white crystalline solid. The crystals have a melting point of 180 ° C and are soluble in water.

Analysis results:

Found: C, 50.49; H, 4.90; N, 4.90; F, 19.81;

Found: C, 50.61; H, 4.71; N, 4.72.

2C F% = 19.86.

Similarly, the dinic acid salt is prepared

2.0 Moles of cinnamic acid. M.p. 180 ° C (dec.).

Example 2

An example of a formulation according to the invention is as follows: One component of Compound A is dissolved in 20 parts of water. The formulation is administered orally to treat 30 laries at a dose of 4 mg active ingredient / kg body weight.

Claims (5)

35 i. A process for the preparation of new compounds of the general formula wherein n is 1 or 2, characterized in that the compound of formula (II) is reacted with tinic acid in an inert solvent. ⁴ θ 2. The method of claim 1 for the preparation of (I) a compound of formula wherein n is 1, characterized in that quinic acid and compound (II), 1.0 mol, 1.0 M was used. 45 A process for the preparation of a compound of formula (I) according to claim 1 wherein n is 2, characterized in that 2.0 molar of tinic acid and 1.0 mol of compound of formula II are used. 50 4. A process according to any one of claims 1 to 6, wherein the resulting α- (2-piperidinyl) -2,8-bis (trifluoromethyl) -4-quinolinemethanol kinate or the α- (2-piperidinyl) -2,8- bis (trifluoromethyl) -4-quinolinemethanol 55 dinolate is isolated as a solid salt. 5. A process for the preparation of a pharmaceutical composition comprising mixing a compound of general formula (I) according to claim 1, wherein n is 1 or 2, with a pharmaceutically acceptable carrier, to form a pharmaceutical composition.