Saponin glycyrrhetic acid, which has anti-ulcer activity

 

The invention relates to new chemical compounds, in particular saponin glycyrrhetic acid - 6',6"-di--D-galactopyranosyl 3-O-[2'-O-(-D - glucuronidase)--D-glucuronidase) methyl ester of glycyrrhetic acid of formula IIB, showing antiulcer activity. Compound IIB is low-toxic substance with pronounced anti-ulcer activity, exceeding the effect of the known anti-ulcer drug carbenoxolone 2 times when administered orally 2 times less dose. table 1.

The invention relates to new chemical compounds, specifically similar to the new triterpene glycoside - glycyrrhizic acid (GA) (I) - saponin glycyrrhetic acid: 6',6"- Di--D-galactopyranosyl 3-O-[2'-O-(-D-glucuronidase)--D-glucuronidase) methyl ester of glycyrrhetic acid of the formula (IIB),showing antiulcer (five) activity. The specified connection and its properties are not described in literature.

Glycyrrhizin acid (D the th and diverse biological activity (anti-inflammatory, antiulcer, antiallergic, antiviral, antitumor, and other) (Tolstikov, A., Baltina L. A., Schulz, E. E., A. Pokrovsky, glycyrrhizin acid. // Bioorgan. chemistry, 1997, T. 23, 9, S. 691-709).

The task, which directed the claimed technical solution is to find new modified analogues of CC, high five activities.

In the claimed technical solution synthesized a new molecule - saponin glycyrrhetic acid of the formula (IIB), showing antiulcer activity.

Acute toxicity of saponin (IIB) was determined on outbred mice weighing 15-20 g when introduced into the stomach by the method of Cerberus (Elizarova O. N. The determination of threshold doses of industrial poisons when administered orally. M.: Medicine, 1971. S. 47-48). This compound at a dose up to 1000 mg/kg toxic effects not caused and can be classified as class III hazardous substance.

The antiulcer activity of saponin (IIB) was studied on the model of acetylsalicylic gastric ulcers in rats. The target compound was administered to the animals once in the stomach at doses of 25 and 100 mg/kg for 1 h before playback destruction of the stomach. The antiulcer activity of saponin (IIB) was compared with the activity of known protiva simultaneously a structural analogue of the compounds. Clinical use of carbenoxolone is limited due to the presence of side effects (pseudoaldosteronism) (Finney R. S. H., Tamoky A. L. The pharmacologic properties of glycyrrhetinic acid hydrogen succinate (dissodium salt). // J. Pharmacy and Pharmacology, 1960, v. l2, p. 49-58; Tolstikov, A., Baltina L. A., N. Serdyuk.G. Glycyrrhetic acid. // Chem. Pharm. Zhur. , 1998, 8, S. 5-14). In addition, carbenoxolone is more toxic drug: LD50=101 mg/kg (Finney R. S. H., Tarnoky A. L. The pharmacologic properties of glycyrrhetinic acid hydrogen succinate (dissodium salt). // J. Pharmacy and pharmacology, 1960, v. l2, p. 49-58).

The results of the experiments presented in the table.

As can be seen from the table, saponin (IIB) has a pronounced anti-ulcer effect in the studied doses, and antiulcer effect of compound (IIB) is superior to the effect of carbenoxolone (50 mg/kg) ~2 times at the dose of 25 mg/kg, i.e. 2 times less dose.

Synthesis of saponin (IIB) was performed by condensation of 2,3,4,6-Tetra-O-acetyl--D-galactopyranoside 30 methyl ether Penta-O-acetyl-GK (I) in the presence of freshly prepared Ag2CO3(reagent Fetisova) in anhydrous conditions in dichloroethane. Acetate saponin (IIA) is selected in homogeneous by TLC condition column chromatography on silica gel with a yield of 66%. Dezazetilirovanie with whom the M.) (IIB), contains 2 balance-D-galactopyranose associated with diglucuronides part of the civil code of ester bonds and which is modified with a similar group with a long carbohydrate chain. The structure of saponin (IIB) was confirmed by spectral methods.

The essence of the technical solution is illustrated by the following examples.

Example 1. Getting saponin (IIB) 1. 30 Methyl ether of peracetate 6',6"-di-O--D-galactopyranosyl 3-O-[2'-O-(-D-glucuronidase)--D-glucuronoside) glycyrrhetic acid (IIA). A mixture of 1.04 g (1 mmol) of Penta-O-acetate 30-methyl ester GK (I), 1 g of molecular sieves 4 a0, 1.4 g of freshly prepared reagent Fetisova* and 2 mmol of peracetate l--bromo-D-galactopyranose in 50 ml of dry dichloroethane was heated 6 hours without access of moisture in the darkness. The precipitate of the silver salt was filtered, washed with 20 ml of dichloromethane, the filtrate was evaporated in vacuum at ~50oC. the Dry residue was chromatographically on a column of silica gel, elwira mixture of benzene-acetone, 25: 1 (v/v) with control by TLC in the system chloroform-alcohol, 25: 1 (v/v). Fractions with the desired product (IIa) (Rf0,22) were combined, evaporated and peracre is +62o(0,04; Meon). The IR spectrumcm-1: 1760 (SLA); 1670 (C11=About). UV spectrumEtOHmax(lg): 246 nm (4,1). Found, %: C 54,78; N 6,44. With81H110About393H2O. Calculated,%: C 55,22; N 6,29. An NMR spectrum1N (Dl3,, M. D.): 0,74; 0,80; 1,00; 1,12; 1,15; 1,22; 1,34 (all s, 21 H, 7 CH3); 2,0-2,2 (all of which, 39 N., 13 Ac); 3,68 (s, 3H, och3); 3,9-4,1 (m, H-5', H-5" GC; 2 N-5 Galp; 4 N-6 Galp); to 4.46 (d, J=6,7 Hz; 1 H, H-1' Ledger); 4,96 (d, 1 H, J=6,8 Hz; H-1 GK); 5,0-5,3 (m, 2 H-3 Galp; 2 N-4 Galp; H-3', H-3" CC"); 5,42 (d, 1H, J=3.1 Hz; H-1/Galp); of 5.50 (d, 1 H, J=3.2 Hz; H-1Galp); the ceiling of 5.60 (s, 1H, =C12-N). An NMR spectrum13With (CDCl3,, M. D.): 103,50 (C1' Ledger); 102,74 (Cl GC); 170,87 (C6' Ledger); 170,76 (C6" CC"); 94,16 (C1-D-Galp); 91,92 (Cl-D-Galp); 61,80 and 61,63 (2 C6 Galp). Other signals carbohydrate portion: 77,26; 73,15; 72,99; 72,86; 72,04; 71,89; 71,68; 71,42; 70,41; 69,50; 68,37; 68,23; 67,66; 67,29; 67,09; 66,25. Aglyamova part: 39,19 (Cl); 90,06 (C3); 55,22 (C4); 61,15 (C9); 200,05 (C11); 128,58 (C12); 170,44 (C13); 45,38 (C14); 48,42 (C18); 43,18(C20); 176,97 (C30); 51,80 (A31); CH3WITH: 170,27; 170,16; 170,08; 169,72; 169,23; 169,14; 169,00; 167,07 (CO); 20,96; 20,83; 20,66 (CH3).

2. 30 Methyl ether 6',6"- di-is coronopifolia) glycyrrhetic acid (IIB). 0.5 g of peracetate (IIA) was stirred in 20 ml of 0.5% solution of KOH in Meon-CH2CL2at 20-2201 h, treated with cation exchange resin KU-2-8 (H+-form) to pH ~5 and evaporated in vacuum at ~30oC. the Remainder of perioadele of dry methanol ether. Yield 0.39 g (78%). Hygroscopic amorphous substance yellowish color. []20D+4520(0,04; tO). The IR spectrumcm-1: 3600-3200 (OH); 1725 (co3); 1660 (C11= O). UV spectrumEtOHmax(lg): 244 nm (4,1). Found,%: C 53,85; N 6,80. With55-N84O263H2O. Calculated, %: 54,35; N 6,94.

An NMR spectrum1H(DMF-d7,, M. D.): 0,75; 0,78; 0,97; 1,08; 1,14; 1,26; 1,40 (all, N, 7 CH3); 2.40 a (s, 1H, H-9); the 3.65 (s, 1H, och3); 4,36 (D., 1H, H-1' Ledger); 4,48 (D. 1H, H-1 GK); 4,70 (ush. s, 1H, H-1-D-Galp); 5,10 (ush. C., 1H, H-1-D-Galp); of 5.50 (s, 1H, -WITH12-N). An NMR spectrum13(DMF-d7,, M. D. ): 104,54 (C1' Ledger); 103,24 (1 GK); 172,50 (C6' Ledger); 173, 0mm (C6" CC"); 98,62 (Cl-D-Galp); 93,79 (Cl-D-Galp). Other signals: 77,78; 77,15; 76,10; 75,80; 74,76; 74,00; 73,49; 72,95; 72,29; 72,00; 71,80; 71,40; 70,75; 70,14; 69,51; S); 167,65 (C13); 45,73 (C14); 48, 97mm (C18); 43,70 (C20); 177,24(C30); 51,95 (A31).

Example 2. The study of the antiulcer action of saponin (IIB).

Antiulcer activity of saponin (IIB) was studied on white outbred rats weighing 180-210 g on experimental models of gastric ulcers caused by acetylsalicylic acid. The day before modeling ulcers animals were deprived of food and water, contained in the premises of the vivarium at a temperature not higher than +16oC. the Investigated compound was injected through a tube into the stomach at doses of 25 and 100 mg/kg Over 1 h was administered intragastrically acetylsalicylic acid at a dose of 150 mg/kg twice with an interval of 6 hours in 1 day, animals were scored under ether anesthesia, pull the stomach and visually take into account all of the mucous membranes. On the antiulcer activity of the preparations was judged to reduce the destruction of the gastric mucosa of rats. As referenceparam used known antiulcer agent carbenoxolone. The results of the experiments are shown in the table.

It is established that the antiulcer activity of the compound (IIB) in a dose of 25 mg/kg exceeds the action carbenoxolone dose of 50 mg/kg 2 times. This compound is less toxic than carbenoxolone.

Sources INF. 23, 9, S. 691-709.

2. Elizarova O. N. The determination of threshold doses of industrial poisons when administered orally. M.: Medicine, 1971. S. 47-48.

3. Finney R. S. H., Tarnoky A. L. The pharmacologic properties of glycyrrhetinic acid hydrogen succinate (dissodium salt). // J. Pharmacy and pharmacology, 1960, v. l2, p. 49-58.

4. Tolstikov, A., Baltina L. A., N. Serdyuk.G. Glycyrrhetic acid. // Chem.-Pharm. Zhur., 1998, 8, S. 5-14.5

Claims

Saponin glycyrrhetic acid of formula (II b)R=Me, R2=H
showing antiulcer activity.

 

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