NOVEL URSODEOXYCHOLIC ACID DERIVATIVE

Abstract: An ursodeoxycholic acid derivative of formula (I) has therapeutic activity in biliary calculosis, biliary dyscinesia, reflux gastritis and in some hepatopathies.

Description: NOVEL URSODEOXYCHOLIC ACID DERIVATIVE The present invention relates to a novel ursodeoxycholic acid derivative, namely ursodeoxycholic acid L-e^i-glycerophosphorylethanolamide of formula I: as well as to the pharmaceutically acceptable salts thereof, such as those in which the acid hydroxy residue of phosphorus is salified with alkali or alkali-earth metals. Therapy with ursodeoxycholic acid in the field of biliary calculosis has been known for a long time (Nakagawa, et al., Lancet, 2_ , 367, 1977). The metabolic pathway of said acid also has widely been studied; particularly ursodeoxycholic acid proved to be more effective than the 7- position epi er thereof, i.e. chenodeoxycholic acid, possibly due to the lower liability of the hydroxy group at the 7-position to undergo inactivation (Ferrari et al. , Febε. Lett., 75, 176, 1977). Moreover, cholesterol solubility iε known to derive from a proper cholesterol/biliary acids/phospholipides ratio. Now, compound I has been found to have surprising pharmacological activities, together with an extremely poor or no toxicity. Said activities, which have been evidenced by pharmacokinetic tests on Wistar rats, are remarkably ' higher than those of ursodeoxycholic acid, used as the control drug. A further advantage of the compound of the invention is provided by the watersolubility of said molecule, which makes it easier to be administered and therefore suited to various pharmaceutical formulations. Therefore, another object of the present invention is provided by pharmaceutical compositions for the treatment of biliary calculosis, biliary dyscinesias, of some hepatopathies and of reflux gastritis, containing as the active ingredient the ursodeoxycholic acid L-° -gl cerophosphorylethanolamide. A further object of the present invention is provided by the use of amide I for the treatment of biliary calculosis, biliary dyscinesias, reflux gastritis and some hepatopathies. The word "use" in the present invention means all the procedures related to the preparation of the compound of the invention, including the purification as well as the formulation into pharmaceutical compositions suited for the administration and/or the confections suited for the administration itself. Finally, the invention relates to a process for the preparation of amide I, which process consists in the condensation of ursodeoxycholic acid and L-c**/ -glycero- phosphorylethanola ine by means of the condensing agent EEDQ (i.e., N-ethoxycarbonyl-2-ethoxy-l,2-dihydroquinoli- ne), which is a known reactant for the preparation of polypeptides under mild not racemizing conditions (Bellau, et al. , JACS, 90_, 1652, 1968). The following non limiting examples illustrate the invention in more detail. EXAMPLE 1 Triethylamine (21,33 ml; 153,06 mmoles) are added to a solution obtained dissolving L- o.-glycerophosphoryl- ethanolamine (21,39 g; 99,49 mmoles) in water (2,0 M; 49,3 mmoles) at room temperature. Thereafter, a solution obtained dissolving ursodeoxycholic acid (30 g; 76,53 mmoles) and EEDQ (28,39 g; 114,79 mmoles) in dimethylformamide (0,57 M; 134 ml) is added thereto at room temperature. The mixture is left to react for about 72 hours at r.t., under strong stirring, then DMF and water are evaporated under 0,1 mm Hg, till obtaining an oil which is taken up into about 800 ml of water and 100 ml of methanol, adjusting pH of the resulting solution to about 3 with diluted hydrochloric acid 1:1. After that, impurities are extracted more times with chloroform, finally the solution is concentrated to obtain such a volume as to be directly loaded on an Amberlite IR-120 (Na + ) column (about 300 ml of wet resin; column diameter 4 cm; flow rate = 10' /min.). The column is eluted with water (about 1,5 1) and the eluate is extracted directly with n-butanol (4 x 200 ml). The butanol extracts are then dried over Na„SO„ and 2 4 evaporated to dryness under vacuum. After drying under 0,1 mm Hg, about 32 g of a white crystalline slightly hygroscopic product are obtained. Yield: 68%. EXAMPLE 2 The procedure of Example 1 is repeated till evaporation under 0,1 mm Hg of the DMF/water mixture. Then the resulting oil is taken up into water and purified by continuous extraction with ethyl acetate. After that, the aqueous εolution iε concentrated to such a volume aε to be directly loaded on an A berlite IR-120 (Na ) column. From this moment, the procedure of Example 1 is followed, to obtain a product having the following characteristicε: 1 H-NMR (80 MHz) (CD OD) : pp . 0,75-2,40 ; 3,40-4,10. Elemental analysis: C = 56,85% (theory = 56,96%) H = 8,40% (theory = 8,35%) N = 2,24% (theory = 2,29% tD = + 36,8 Cl in ethanol m.p. = 120°C. The above disclosed data clearly show that the compounds of the invention can effectively be used for the therapy of biliary calculosiε, biliary dyεcineεias, reflux gastritiε and some hepatopathieε. To this purpose, compound I or a pharmaceutically acceptable salt thereof is administered to the patient either in the pure form or as a pharmaceutical composition, preferably by the oral or parenteral routes. The pharmaceutical compositions used are the conventional ones, prepared according to the techniques described, for example, in "Remington's Pharmaceutical Sciences Handbook" Hack Pub. Co., N.Y. USA. The dosage will depend on various factors, such as the severity of the pathology to be treated, the patient conditions (weight, sex, age): generally, it will be 200 to 700 mg/die for compound I or the equivalent of a salt thereof, possibly divided in more administrationε.

Claims: CLAIMS 1. The compound of formula I and the pharmaceutically acceptable saltε thereof. 2. A proceεs for the preparation of compound I, in which process ursodeoxycholic acid is reacted with L-o -glycerophosphorylethanolamine in the presence of a condensing agent. 3. A procesε as claimed in claim 2 , in which N-ethoxycarbonyl-2-ethoxy-l,2-dihydroquinoline is used as the condensing agent. 4. Pharmaceutical compositionε containing aε the active ingredient the compound of claim 1 in admixture with an appropriate carrier or excipient. 5. The use of the compound of claim 1 for the preparation of a medicament useful for the therapy of biliary calculosiε, biliary dyscinesias, reflux gastritis and hepatopathies.

Inventors: PALAZZI CAMILLO MARIA FRANCESC, SCOLASTICO CARLO, PALAZZI, CAMILLO, MARIA, FRANCESCO, GIULIO, SCOLASTICO, CARLO
Applicants: ISTITUTO CHEMIOTERAPICO
Application year: 1989
Main classification: C07J51
IPC codes: A61K31, A61P1, C07J51