HYDROSOLUBLE UBIDECARENONES DERIVATIVES AND THEIR PREPARATION

Abstract: Ubidecarenones are effectively dissolved in aqueous media by means of N-acyl-2-amino-ethanesulphonates, wherein the acyl residues have more than 5 carbon atoms. Pharmaceutical compositions containing ubidecarenones so solubilized are particularly effective as moycardioenergetics.

Description: Λ- Hydrosoluble ubidecarenones derivates and their preparation. The present invention relates to pharmaceutica preparations containing soluble ubidecarenones prepared b disperding in acqueous media mixtures having differen ratios of ubidecarenones and acyl derivatives of 2-amino- ethansulphonic acid. The ubidecarenones form an important class of lipo- soluble vitaminic principles, particularly 2,3-dimethoxy- 5-methyl-8-decaprenyl-l,4-benzoquinone, known as ubideca- renone-10, localized at the mitochondrial level, plays a key-role in mammals in the electron-transfer system and more generally in the energy production. Because of said important metabolic roles, the ubiquinone-10 is widely used in a large number of cardiac pathologies, protecting the myocardium from ischemic phe- nomena and preserving the functions thereof. Because of its complete insolubility in aqueous media the drug is generally administered by the oral route in form of franules, tablets and soft capsules, generally at a dosage of 10 mg. The experiments carried out show a critical role of the administration form in the drug's absorption, which is usually slight. The availability of biocompatible hydrosoluble formulation is therefore particularly desired. The development of biocompatible, hydrosoluble formulations is of particular interest for a better bio- availability of ubidecarenone-10 both in the pharmaceuti¬ cal and cosmetic use. The present invention concerns the development of a sys.tem able to carry in aqueous media the ubidecarenones, thanks to the interaction with amphipatic ions of general formula RNH-CH -CH -SO , wherein R is an acyl radical having more than 5 carbon atoms, preferably a natural fatty acid of the normal, iso, an eiso series or cycloal- kyl, saturated or unsaturated having from 8 to 26 carbon atoms. This class of amphipatic molecules is surprisingly able to carry the ubidecarenones in water, in form of micellar and/or liposomial aggregates, even using an equi- molar ratio of the two compounds. A molar excess of the amphipatic solubilizing spe- cies is preferably used, from 2 to 4 times higher than the vitamin, said conditions granting a better and faster solubilization. The preparation of hydrosoluble ubidecarenones may be carried out in different ways, for instance by sonica- ting an acqueous solution of the amphipatic species, to which the ubidecarenone is added or preferably by dispers¬ ing in water, under vigorous stirring, a mixture of ubide¬ carenone and N-acyl-2-amino-ethanesulphonate, prepared by evaporation of a solution of the two compounds in an orga- nic solvent, in which both are soluble. The micellar and/or liposomial systems so prepared are stable over long periods of time, even at extremely low or high environmental temperatures, that may be more¬ over lyophilized, yielding generally materials of waxy consistency, easily soluble in water by simple stirring. Important characteristics of the invention, under the pharmaceutical profile, are: a) the stability in time of the micellar and/or liposomial aggregates, formed by combining in aqueous solution ubidecarenones and N-acyl-2-amino-ethanesulphonates; b) the low toxicity of the solubilizing agent, which is biodegradable and metabolizable, because derived from the formation of an amide bond, which may be cleaved by amidases present in the body, said bond linking a fatty acid to 2-amino-ethanesulphonic acid, both naturally present metabolites in man; c) an improved bioavailability of ubidecarenone both by the oral and injection route; d) an improved stability of ubidecarenones towards undesi- red degradative processes; e) a more effective therapeutic action in comparison to the formulations presently marketed. The invention provides therefore pharmaceutical compositions containing as the active principle compounds of ubidecarenone and N-acyl-2-amino-ethanesulphonates optionally in admixture with conventional excipients. The composition of the invention may be used in the pharmacological use in many fields and particularly as myocardioenergetics, indicated in the alterations of the myocardium characterized by reduced inotropism: senile myocardiosclerosis, congestive heart failure, chronic pulmonary heart, in combination with digitalis and other cardiotonics; as adjuvant in the treatment of acute and chronic ischemic cardiopathies and of the arterial hyper- tension, prevention of cardiac damages due to the use of some cardiotoxic antitumoral agents (adriamycin and dauno- mycin) . The daily theraperutic dose, the administration route and frequency depend on various factors (diagnosis, patient's conditions, etc.), but they will be anyhow easi¬ ly determined, case by case, absolutely in non-critical way as a consequence, inter alia, of the very low toxicity of the system components. The compositions of the inven¬ tion may moreover comprise other active principles having complementary activity. The procedures generally described in the present invention, because of their simplicity or limited cost, are easily suited to the development of preparative pro¬ cesses on the industrial scale. The following examples illustrate the preparation of different kinds of soluble ubidecarenones. They necessarily concern only some of the numerous possibilities which can be envisaged and, without any limitative character, they only define the scope of the invention. EXAMPLE 1 62.5 g of 2-amino-ethansulphonate, suspended in 500 ml of anhydrous dimethylformamide, were reacted at 70°C for 10 hours with 410 g of oleic anhydride, in the presen¬ ce of 0.5 g of dimethylami opyridine as a catalyst. After evaporation of the solvent under vacuo, the oily residue was repeatedly triturated in ethyl ether. 190 g of N-oleyl-2-amino-ethansulphonate as a waxy, white solid, were obtained. 2 2 T Thhee HH--NNMMRR ssppectrum in CDC1 shows the signal of the acyl moiety, in the correct integration ratio, at o 5.3; 2.4; 1.9; I.r.: 1.3 and 0.9 and those of 2-amino- ethanesulphonate at S 3.7 and 4.6. 86.2 g of ubidecarenone-10 were added to 81 g of N-oleyl-2-aminoethansulphonate, dissolved in 2.8 liters of water. The obtained biphasic system, after sonication, yields an homogeneous phase of micellar and/or liposomial kind, stable in time and to the environmental parameters. For instance, freezing of the solution or its heating do not change the chemico-physical state of the dispersed supermolecular aggregates. EXAMPLE 2 87.5 g of 2-amino-ethanesulphonate, suspended in 500 ml of anhydrous pyridine, were reacted at 50°C for 10 hours with 311 g of linolenic acid chloride. After evaporation of the solvent under vacuo, the oily residue was first triturated in ethyl ether and then, dissolved in water, was dialyzed against water. After lyophilization 255 g of N-linoleyl-2-amino-ethanesulphona- te as a white, waxy solid, were obtained. The H -NMR spectrum recorded in CDC1 shows, in the correct integra¬ tion ratios the signals of the acyl moiety at S 5.3; 2.8; 2.4; 1.9;1.6;1.3;0.9 and those of 2-amino-ethanesulphonate at S 3.7 and 4.6. 172 g of ubidecarenone-10 and 321 g of N-linoleyl- 2-amino-ethanesulphonate were dissolved in 2 1 of 1 CHC1 . After evaporation of the solvent under vacuum, 3.4 liters of water were added under vigorous stirring. An homogeneous system, yellow-orange in colour, of micellar and/or liposomial kind, stable in time and to the environ- mental parameters was obtained. EXAMPLE 3 43.1 g of ubidecarenone-10 and 64.2 g of arachido- nyl-2-amino-ethanesulphonate were dissolved in 1 1 of CHC1 . After removal of the solvent, 2 1 of water were added under vigorous stirring, till the formation of a stable micellar and/or liposomial system. After freezing and lyophilization of the solution a waxy compound orange in colour, readily soluble in the presence of water, was obtained.

Claims: CLAIMS 1. Hydrosoluble ubidecarenones derivatives obtained by addition to the ubidecarenones of N-acyl-2-amino-ethane- sulphonate wherein the acyl residue has more than 5 carbon atoms and is preferably a natural fatty acid, saturated or unsaturated of the normal, iso, anteiso or cycloalkyl series, having from 8 to 26 carbon atoms. 2. A process for the preparation of the derivatives of claim 1, characterized in that ubidecarenones are subjected to sonication in acqueous solutions of N-acyl-2-amino- ethanesulphonates, generally used in a stoichiometric ratio with respect to the ubidecarenone higher than 1:1 (moles of ubidecarenones/moles of N-acyl-2-amino-ethane- sulphonate), preferably 1:2-4. 3. A process for the preparation of the derivatives of claim 1, characterized in that a mixture of ubidecarenone and N-acyl-2-amino-ethanesulphonate (molar ratio from 1:1 to 1:4), obtained by evaporation of a solution of the two compounds in an organic solvent in which both are soluble, is subjected to mechanical dispersion. 4. Pharmaceutical compositions containing as the acti¬ ve principle an hydrosoluble ubidecarenone derivative according to claim 1, in admixture with the usual exci- pients and vehicles.

Inventors: DE ROSA MARIO, ZAPPIA VINCENZO, DE ROSA, MARIO, ZAPPIA, VINCENZO
Applicants: ROSA MARIO DE, ZAPPIA VINCENZO, DE ROSA, MARIO, ZAPPIA, VINCENZO
Application year: 1987
Main classification: A61K9
IPC codes: A61K8, A61K9, A61K31, A61K47, A61Q19