3-o-2-deoxy--l-rhamnopyranoside methyl ester of glycyrrhetic acid, manifesting hepatoprotective activity

 

(57) Abstract:

The invention relates to organic chemistry, to new chemical compound, namely 3-O-[2-deoxy--L-rhamnopyranose]-11-oxo-20-methoxycarbonyl-30-norolean-12-EN-3-Olu formula

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showing hepatoprotective activity. The proposed connection is a low-toxic substance with pronounced hepatoprotective activity. Hepatoprotective effect of compound (I) exceeds the effect of glycyrrhizic acid and known hepato of celebra. table 2.

The proposed connection relates to new biologically active chemical compound, particularly to 3-O-[2-deoxy - a - L-rhamnopyranose]-11-oxo-20-methoxycarbonyl-30-norolean-12-EN-3-Olu (1) formula:

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showing hepatoprotective activity (Number of State registration 10616295).

Recently conducted an intensive search for new substances with hepatoprotective properties, increasing the stability of liver pathological effects, reinforcing its neutralizing function by increasing the activity of its enzyme systems, as well as contributing to the restoration of its functions in different lesions.

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Ledger protects hepatocytes of rat poisoning CCl4and galactosamine [1], and for prophylactic introduction protects rat hepatocytes from necrosis [2]. GK reduces transaminase serum in mice poisoned CCl4i.e. is hepatoprotector [3, 4]. GC in combination with amino acids used in Japan for the treatment of chronic viral hepatitis and cirrhosis of the liver (drug SNMC) [4].

Currently, as a special hepatoprotective funds put into practice some domestic products of the flavonoid patterns, one of which is silimar (Siliborum) [5], also used in the treatment of hepatitis and cirrhosis of the liver. Therefore, as a pharmacological analogue we used zelibor in equal doses with the proposed glycoside (1) and GK.

In the claimed technical solution synthesized a new low-toxic compound among the glycosides of glycyrrhetic acid, namely 3-O-[2-deoxy - a-L-rhamnopyranoside] -11-oxo-20-methoxycarbonyl (1) was determined on outbred mice weighing 15-20 g when introduced into the stomach. The toxicity parameters were calculated by Lichfield and Wilcoxon signed. LD50compounds (1) amounted to 5500 mg/kg On the basis of the Decision of the state Committee of standards of the USSR on 10 March 1976 579 N this connection belongs to class IV hazardous substance.

Effect of compound (1) on the functional state of the liver was assessed by zhelchesekretornoyj and the excretory functions of the liver of intact rats and in animals with experimental hepatitis induced CCl4in comparison with glycyrrhizic acid and siliborum. All drugs were administered at a dose of 50 mg/kg the results of the experiments are given in table. 1 and 2.

It is established that the compound (1) dose of 50 mg/kg increases the secretion of bile by hepatocytes of rats compared with control (p < 0.05) like kalibaru and Ledger (PL.1), however, the compound (1) in all periods of observation increases the secretion of bile better known hepato of celebra in intact rats, especially on the 2nd and 9th hours of experience (p< 0.05). Effect of compound (1) was also more pronounced than that of GL (2). The compound (1) increases zheleobrazovatel function of hepatocytes more effective than Comparators (table. 1).

In table. 2 shows the effect of compound (1) on the functional state of the liver Ave is Naya liver as compared with intact animals. As can be seen from the table, the compound (1) were more active than Comparators - zelibor and GK (2) when the CCl4- hepatitis. Zelibor increases the functional activity of hepatocytes only 1 hour experience. GK - 1-th clock surveillance, and the compound (1) increases the secretion of bile in all stages of the experiment (p< 0.05-0.01). In addition, the compound (1) increases the bile production (total weight of bile) in animals with experimental hepatitis more glycyrrhizic acid and celebra (PL. 2).

Thus, 3-O-2-deoxy - a-L-rhamnopyranoside methyl ester of glycyrrhetic acid (1) has a pronounced hepatoprotective effect at a dose of 50 mg/kg, exceeding the effect of known hepato of celebra and glycyrrhizic acid.

Synthesis of compound (1) was performed by the method of electrophilic glycosylation [6] methyl ester of glycyrrhetic acid (3) di-O-acetyl-L-ramalam (4) in methylene chloride in the presence of di-(SIM-kallidin)-iodone perchlorate (IDCP) and molecular sieves 4 (scheme I).

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Intermediate 2-deoxy-2-iodine-glycoside (5) was isolated by column chromatography on silica gel and was desiderable by hydrogenolysis in the presence of 10% Pd/C and triethylamine.

Obrazuyuscikh was 74%.

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

Example 1. Obtain 3-O-[2-deoxy - a-L-rhamnopyranose]-11 - oxo-20-methoxycarbonyl-30-norolean-12-EN-3-ol (1).

2 mmol (0.43 g), di-O-acetyl-L-rannala (4) and 2 mmol (0.97 g), methyl ester of glycyrrhetic acid (3) was dissolved in 50 ml of absolute CH2Cl2in the presence of calcined molecular sieves 4 is stirred for 30 minutes, then add 1.1 g (samkalden)2ICO4(IDCP). The mixture is stirred for 3-4 hours (control by TLC), filtered, washed with 10% solution of Na2S2O3(2 15 ml), dried with Na2SO4, evaporated. Allocate using column chromatography on silica gel (CH2Cl2- MeOH, 200 : 1, 150:1, 100:1, 50:1). The mixture of solvent 150:1 ---> 100:1 wash 1.38 g of the glycoside (5) (84%), which was dissolved in 60 ml of ethyl acetate, add a few drops of Et3N, in the presence of 1.4 g of 10% Pd/C hydronaut within 10 days. The catalyst is filtered off, the solvent evaporated, the residue is dissolved in 130 ml of methanol, poured 20 ml of 5% solution of KOH in methanol, after 1.5 hours neutralize ionoobmennoi resin KU-2-8 (H+-form), the solvent evaporated, the glycoside (6) is recovered from methylene chloride - l2) : MeOH = 10:1). Found, %: C - 72.3; H, 9.4. Calculated, %: C - 72.3; H - 9.5. []2D0= +58o(0.06, CHCl3). UV spectrum (MeOH),max/247.0 nm (lg 4.32). IR spectrum (cm-1, liquid paraffin) : 1650 (C11=0), 1730 - 1720 (COOMe), 3600-3200 (OH). An NMR spectrum13With (CDCl3, , M. D.): 20.8 (C2), 88.6 (C3), 200.4 (C11), 128.6 (C12), 169.3 (C13), 174.0 (C30), 51.9 (C31), 100.2 (Cl'), 39.3 (C2'), 69.5 (C3'), 78.5 (C4'), 67.7 (C5'), 17.5 (C6').

Example 2. The study of hepatoprotective activity.

Effect of compound (1) on the functional state of the liver was assessed by zhelchesekretornoyj and the excretory functions of the liver by the method of N. P. Skakunova and A. N. Oleinik (1967) [7] in intact rats and in animals with experimental hepatitis (CCl4). Bile secretion was expressed in mg/min per 100 g weight of the animal, and biliary excretory function by the total number of selected bile for each hour and in the amount of 4 hours of observation per 100 g mass. rats. Experiments were performed on 54 rats weighing 180-200 g as Comparators used glycyrrhizinic acid is the main glycoside licorice and known hepatoprotector - zelibor in equal doses (50 mg/kg).

In the first series of experiments studied the effect of these drugs on the functional state of the liver in the intact animals. Re the AET bile secretion by hepatocytes of rats in all periods compared with control (p > 0.05). During all periods of observation connection (1) enhances secretion of bile more effective than Comparators - celebra (p < 0.05) and glycyrrhizic acid. The compound (1) also stimulates zheleobrazovatel function of the hepatocytes of the liver more pronounced than Ledger and silimar.

In the next series of experiments we studied the effect of drugs on the functional activity of rat liver in hepatitis caused by CCl4by the method of [8].

The results of the experiments are presented in table. 2. When hepatitis sharply oppressed jelcheobrazovanie and the excretory function of the liver as compared with intact animals (p < 0.05-0.01).

As can be seen from table 2 that the compound (1) increases the secretion of bile in all stages of the experiment (p < 0.05 - 0.01). The product comparison - zelibor increases the functional activity of hepatocytes only in 1st hour surveillance, and GK - in the first 3 hours of experience. The compound (1) also increases bile production more efficient Ledger and celebra (PL. 2).

Conclusions:

3-O-[2-deoxy - a-L-rhamnopyranose]-11-oxo-20-methoxycarbonyl-30-norolean-12-EN-3-ol is an effective, low-toxic hepatoprotector, superior in activity Comparators Ledger and silimar.

3-O-2-Deoxy--L-Ratnapura

 

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