3-0-succinyl-11-oxo-ursolic acid and its diamontina salt, manifesting immunostimulirutuyu activity

 

(57) Abstract:

The invention relates to new biologically active compounds, specifically to C-O-succinoyl-11-oxo-ursolic acid, its giammarino salt of the formula

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where X = H, NH4showing immunostimulirutuyu activity. table 1.

The invention relates to new chemical compounds of the class of triterpenoids, particularly to 3-O-succinoyl-11-oxo-ursolic acid of the formula (I)

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where X is H, NH4,

Having immunostimulatory activity.

Analogues according to the structure of compound I are 3-O-succinoyl-glycyrrhetic acid II, and glycyrrhizin acid and glycyrrhizin acid III.

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Compound II as disodium salts are highly effective anti-ulcer agent and is used in the clinic for stomach ulcers (drug carbenoxolone [1] ). Immunostimulatory properties carbenoxolone unknown. Glycyrrhizin acid III is immunoregulation. However, its disadvantage lies in the fact that, although in small doses immunostimulating action, in high doses, it manifests itself as an immunosuppressant [2,3]. This property may adversely overdoses monostilius action in a wide range of doses.

The problem is solved by getting a new substance-3-O-succinoyl-11-oxo-ursolic acid, of the formula I.

The method of obtaining immunostimulant I is in the handling of ursolic acid (IV) of succinic anhydride in the presence of anhydrous pyridine and oxidation of the resulting 3-O-succinoyl-of ursolic acid (V, yield 90%) with chromic anhydride in acetic acid (yield 62%).

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Compound I can be used both directly and in the form of water-soluble salts, such as giammarino.

The advantage of the new connection I is that the starting compound for its synthesis is ursolic acid IV, which can be easily obtained by extraction of available plant materials - products that accumulate in the processing of sea buckthorn, cranberry or cranberry.

The connection I belongs to the 3rd class of mild-hazard substances. LD50substances with intraperitoneal injection of 500 mg/kg

Immunostimulatory properties of patented compounds were studied in outbred mice weighing 18-20 g at immunization weak antigen. The compounds were administered at doses of 5 mg/kg or 100 mg/kg intraperitoneally or subcutaneously. The control group animals vontrol). The results are given in the table.

From the data table. it is seen that compound (I) has pronounced immunostimulating properties, because the antibody titers in the serum derived from immunization albumin with this drug is similar to titers of antibodies in the sera after immunization with complete adjuvant's adjuvant and 30 times higher than the introduction of albumin without the drug. It should be noted that glycyrrhizin acid (III) and acid succinate of ursolic acid (V) by activity are much smaller than full adiuvante's adjuvant.

This invention is illustrated in the examples.

Example 1. Synthesis of 3-O-succinoyl of ursolic acid (V). In a round bottom flask with a capacity of 100 ml was loaded 10 g (0.0219 mol) of dried acid in 30 ml of toluene, was added 6 g (0.06 mol) of succinic anhydride and 15 ml of dry pyridine.

The reaction mass was heated for 3 h, the solvent was distilled in vacuum. The residue was dissolved by boiling in 50 ml of water, after cooling, the precipitated residue was filtered and washed with water (3x10 ml). After drying obtained 11.1 g (90%) acid succinate of ursolic acid (V). So pl. 218-220oC (from methanol). IR spectrum , cm-1):3440 (OH), 1720, 1670 (C=O). Range PMR (CD3OD, , M. D.): 0.90, 0.92, 0.(1H,H3), 5.26 m (1H,H12).

Example 2. Obtain 3-O-succinoyl 11-ketorolaco acid (I). In a round bottom flask with a capacity of 100 ml equipped with a stirrer and a thermometer was loaded 3.0 g (0,054 mol) acid succinate of ursolic acid (V), 40 ml of glacial acetic acid and heated with stirring to dissolve. To the solution was added dropwise 2.0 g (0.02 mole) of chromic anhydride in 15 ml of acetic acid. The mixture was stirred at a temperature of 97+2oC for 2 h, then the reaction mass was poured into 300 ml of water, the precipitate was filtered, washed with 1% solution of soda and water. The product was dried in air and was chromatographically on a column of silica gel. Received 1.9 g (62%) of substance (I), so pl. 231-233oC (from methanol). IR spectrum , cm-1):3440 (OH), 1720, 1670 (C=O). Range PMR (CD3OD, , M. D.): 0.93, 0.94, 1.03, 1.16, 1.19, 1.23, 1.40 (21H, Me), 1.31-1.65 m (12H), 2.15 m (1H, H11), 2.50 m (1H, H9), 2.61 m (4H, OCOCH2CH2), 2.80 m(1H,H18), 3.56 tons (1H, H19), 4.55 m (1H,H3), 5.59 (1H, H12). C34H52O6.

Example 3. Getting giammarino salt (I). A solution of 1.9 g of the acid (I) in 50 ml of methyl tert.butyl ether saturated with ammonia for 1 min at 0oC. the Resulting precipitate was filtered, washed with ether and dried n (21H, Me), 1.31-1.65 m (17H), 2.10 m (2H,CH2), 2.54 m (1H, H9and 4H, OCOCH2CH2), 2.80 m (1H, H18), 4.50 m (1H, H3), 5.57 (1H, H12). UV spectrummaxnm (): 253 (4200). C34H56N2O7.

Example 4. Immunostimulatory properties of the compound (I) was studied on 144 animals. Outbred mice were injected subcutaneously with 500 μg bovine albumin in 0.5 ml sterile saline. The investigated compound was administered the next day in doses of 5 mg/kg or 100 mg/kg intraperitoneally or subcutaneously. Control animals were injected with bovine albumin without drug (negative control) or with complete adjuvant's adjuvant (positive control). Re-introduction of albumin at a dose of 100 mg/mouse was performed at 28 days. Serum was obtained at 14 and 36 days and was investigated by the method of enzyme immunoassay individually from each animal. The experiments were repeated twice for each dose and method of administration took 6 mice.

Thus, the new compound (I) has the following advantages:

- it is available, as obtained from available raw materials (of ursolic acid);

a way of producing it simple in technological design and does not require expensive reagents and equipment:

- connected the I immunosuppressive properties, inherent to its closest analogue - glycyrrhizic acid.

3-O-succinoyl-11-oxo-ursolic acid and its diamontina salt of the formula

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where X Is N, NH4,

showing immunostimulirutuyu activity.

 

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