Amide-glycyrrhizic acid methyl ester, l - histidine, exhibiting anti-aids activity

 

(57) Abstract:

Usage: as an anti-AIDS funds. The inventive product 3-0[2-0-( b-D-glucopyranosyloxy)- b-D-glyukopiranozil-uranyl]-(3 b , 20 b )-11,30-dioxo-30-(N-L-histidine methyl ester)-30-norolean-12-ene, output 43,9% BF C49H67N3O17. so pl. 250 - 251C []2D0= +40(C = 0,01, dioxanonane).

The invention relates to new biologically active compound, particularly, to amide-glycyrrhizic acid with methyl ester of L-histidine: 3-0-[2-0-( -D-glucopyranosyloxy)- -D-glucopyranosyloxy]-(3 , 20 )-11,30-dioxo-30-(N-L-histidine methyl ester)-30-norolean- -12-ene of the formula I

exhibiting anti-AIDS activity.

The specified connection and its properties are not described in literature.

At the present time all over the world are intensively conducted research to find cures AIDS. Known for more than 50 drugs that suppress the reproduction of human immunodeficiency virus (HIV) in vitro [1]. One of these drugs is glycyrrhizin acid (ha) [2-6]. It is also shown that the introduction of the Ledger in high doses (800-1600 mg/day) to patients with AIDS makes them increase in the content of PM lymphocytes and a reduction in the number of virus the Ledger ineffective as an inhibitor of HIV replication is not chronically infected cells.

The aim of the present invention is the search for new compounds in the series of derivatives-glycyrrhizic acid, which has anti-AIDS activity.

This goal is achieved amidon-glycyrrhizic acid of the formula (I) exhibiting anti-AIDS activity.

Pharmacological properties of the described compounds

Antiviral activity of the described compound (I) was studied on the model of primary HIV-1-infected lymphoid cells MT-4. The amide solution in dimethyl sulfoxide (DMSO) (25 mg/ml 50 mg/ml) were introduced into a suspension of HIV-1-infected cells to final concentrations of 500-1000 g/ml DMSO to a final concentration of 0.5-2.0%. In preliminary experiments it was found that DMSO at the indicated concentrations does not block the reproduction of HIV-1. About the inhibition of reproduction of HIV-1 in cells judged to reduce the activity of the reverse transcriptase and reduced accumulation of viral antigen (enzyme-linked immunosorbent assay) in the culture fluid 4 days of culture compared with the control (without addition of drug).

As Comparators used purified-glycyrrhizinic acid (92-95%), effective inhibitory reproduction of HIV-1 in the cells is vtorogo associated with blocking viral treatment transcriptase and termination of viral DNA synthesis [7]. The main disadvantage of this drug is its high toxicity [8].

Found that amide (I) effectively inhibits the reproduction of HIV-1 in cell culture at concentrations of 0.5 to 1.0 mg/ml (99.4-99.6 percent) (table. 1). The level identified antiviral activity of compound (I) is similar to AZT-Ledger.

The compound (I) is less toxic than AZT.

LD50amide (I) > 7000 mg/kg of Compound I class III hazardous substance.

Synthesis of amide (I) is conducted by the method of activated (II-hydroxysuccinimide) esters without prior protection of the Oh-groups of the carbohydrate chains of the molecules of the glycoside. The output of the amide (I) 43,9% . Analytically pure product is obtained by recrystallization from dimethylformamide - water.

Thus, a new low-risk derivative-glycyrrhizic acid amide (I), inhibits the reproduction of HIV-1 in vitro (in culture cells (MT-4), is less toxic than azidothymidine with anti-AIDS activity similar to the activity of AZT and GK.

P R I m e R 1. The study of anti-AIDS activity.

Antiviral activity of amide I has been studied in models of primary HIV-1-infected lymphoid cells MT-4 (in vitro). Solutions of drugs in DMSO/ml, DMSO to a final concentration of 0.5-2.0% . In preliminary experiments it was found that DMSO at concentrations of 0.5-2.0% does not block the reproduction of HIV-1. About the inhibition of reproduction of HIV-1 in cells judged to reduce the activity of the reverse transcriptase and reduced accumulation of viral antigen (enzyme-linked immunosorbent assay) in the culture fluid 4 days of culture compared with the control (without addition of drug). As Comparators used one of the most effective for the treatment of AIDS drugs - azidothymidine (AZT) and-glycyrrhizinic acid ( -CC), is also effective inhibitory reproduction of HIV-1 in cells. The results of the experiments are shown in the table.

As can be seen from the table, studied the compound (I) inhibits the reproduction of HIV-1 in cell culture at concentrations of 0.5 to 1.0 mg/ml of virus (anti-HIV) activity compound (I) is similar to AZT and the General Ledger. Thus, the first set of the ability of the amide-glycyrrhizic acid with methyl ester of L-histidine (I) effective to inhibit the reproduction of HIV-1 in cell culture.

P R I m m e R 2. Getting amide (I).

To a solution of 1.64 g (2 mmol), glycyrrhizic acid (92-95% is closeclicked and stirred in ice bath for 2-3 h, at room temperature for 6 hours, left overnight in the refrigerator, the precipitate is filtered off, dicyclohexylamine, the filtrate is placed in an ice bath, was added 1.5 g (5.9 mmol) of methyl ester of L-histidine (base), 2 ml of distilled triethylamine and stood with periodic stirring 24 hours Pour the mixture into cold water (300 ml), the precipitate is filtered off, washed with water and dried. Obtain 0.96 g (49.2 percent ) amide (I), which periostat from DMF - H2O. the Yield analytically pure product 0,86 g (43.9 per cent); amorphous substance yellowish, T decomp. 250-251aboutC [ ]D20= +40about(=0,01; dioxane-methanol);

IR , cm-1: 3600-3150 (HE, NH); 1740 (Sooma); 1700 (COOH); 1660 (C=O); 1600 (imidazole); 1530 (NH).

UVmaxdioxane-methanol(lg ): 220 nm (4,71); 265 nm (4,70).

Found, %: C 59,23; N 6,98; N 4,46.

C49H67N3O17.

Calculated, %: C 60,42; N. Of 7.35; N Or 4.31.

Amide - glycyrrhizic acid with methyl ester of L-histidine General formula

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where

R =

exhibiting anti-AIDS activity.

 

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