Amide-glycyrrhizic acid with 6-aminouracil exhibiting anti-aids activity

 

(57) Abstract:

Usage: as an anti-AIDS funds. The inventive product - amide b-glycyrrhizic acid with 6-aminouracil; 3-0-[2-0-( b-D-glucopyranosyloxy)- b-D-glucopyranosyloxy] -(3 b , 20 b) -11,30-dioxo-30-(N-6-aminouracil)-30-norolean-12-ene. BF C46H65N3O17. Output 98.9 per cent , so pl. 261 - 264C. Reagent 1: -glycyrrhizin acid. Reagent 2: 6-aminouracil. Reaction conditions: in an environment of dry DMF, in the presence of N,N-dicyclohexylcarbodiimide at 50 - 60C. table 1.

The invention relates to new biologically active compound, particularly, to amide-glycyrrhizic acid with 6-aminouracil: 3-0-[2-0-( -D-glucopyranosyloxy)- -D-glucopyranosyloxy] -(3 , 20 )-11,30-dioxo-30-(11-6-aminouracil)-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]. In 1987-88 biennium by the work group of Japanese researchers have shown that glycyrrhizin acid ">

The main disadvantage of GA is its lowefficiency as inhibitor of reproduction of HIV in chronically infected cells.

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

This goal is achieved amidon-GK formula (I) exhibiting anti-AIDS activity.

Pharmacological properties of the described compounds.

Antiviral activity of compound I has been studied in models of primary HIV-1-infected lymphoid cells MT-4. The solution in dimethyl sulfoxide (DMSO) (20 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 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 on the 4th day of cultivation compared with the control (without addition of drug).

For comparison used the points the user by blocking viral reverse transcriptase and termination of viral DNA synthesis [4], and glycyrrhizinic acid ( -GK) (92-95% purity), effectively inhibitory reproduction of HIV-1 in cells in vitro.

The main disadvantage of AZT is its high toxicity [5].

It is established that the investigated compound (I) inhibits the reproduction of HIV-1 in culture cells MT-4 at concentrations of 0.5 mg/ml to 1.0 mg/ml (level 98.2 99.3 percent). The level identified antiviral activity derived-glycyrrhizic acid (I) is not inferior to AZT and comparable with glycyrrhizic acid.

Unlike AZT amide (I) does not affect the cell culture toxicity. Moreover, the number of living cells is significantly higher than in control infected cells without addition of drugs (table. 1) and 10 times higher than in the case of cells treated with AZT and GK.

The compound (I) is less toxic than AZT on LD50. So LD50amide (I) > 7000 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 class III hazardous substance.

Synthesis of amide (I) is carried out by processing, glycyrrhizic acid and 6-aminouracil in a mixture of DMF - pyridine N,N'-dicyclohexylcarbodiimide. The product was led of the mixture is rezinovoi acid amide and 6-aminouracil (I) effectively inhibits the reproduction of HIV-1 in vitro (in culture cells (MT-4), is less toxic than azidothymidine.

The invention is demonstrated by the following examples:

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

Antiviral activity presents the compound (I) was studied on the model of primary HIV-1-infected lymphoid cells MT-4. Solution of the drug in DMSO (20 mg/kg 50 mg/ml) were introduced into a suspension of HIV-1-infected cells 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 on the 4th day of cultivation compared with the control (without addition of drug). As Comparators used one of the most effective for the treatment of AIDS drugs - azidothymidine (AZT), the mechanism of action associated with the blocking of viral reverse transcriptase and termination of viral DNA synthesis, and glycyrrhizinic Caledonia experiments. It is established that the investigated compound effectively inhibits the reproduction of HIV-1 in cell culture at concentrations of 0.5 mg/ml to 1.0 mg/ml level identified antiviral activity of compound (I) is not inferior to AZT and comparable to the General Ledger. Unlike AZT derivative of GK (I) does not affect the cell culture toxic effects: the number of living cells is significantly higher than in control infected cells without the addition of the drug and much higher than in the case of AZT-Ledger.

Thus, the installed capacity derived-glycyrrhizic acid - amide and 6-aminouracil (I) effective to inhibit the reproduction of HIV-1 in cell culture.

P R I m m e R 2. Getting 3-0-[2-0 (D glucopyranosyloxy)- -D-glucopyranosyloxy] -(3 , 20 )-11,30-dioxo - 30- -(N-6-aminouracil)-30-norolean-12-ene (I).

To a solution of 0.82 g (1 mmol) of glycyrrhizic acid and 20 ml of dry N, N'-dimethylformamide (DMF) was added 0.45 g (4 mmol) of 6-aminouracil, 5 ml dry pyridine and 0.7 g (3.4 mmol) of N,N'-dicyclohexylcarbodiimide (DCGK) and stirred at 50-60about8 h, leave the mixture overnight at room temperature, the precipitate is filtered off, dicyclohexylamine, the filtrate is poured into 200 ml of cold water, acidified limo is safe Cabinet. The output of 0.92 g (98.9 per cent). After crystallization from DMF-dioxane-water and drying in vacuum at 50-60aboutWith (3 h) obtain 0.65 g (69,9%) of the target product (GHG) emissions in the form of a white powder, homogeneous by TLC. So pl. 261-264aboutC (with decomp); []D20= +30o+35o(from 0.01; methanol-dioxane); Rf= 0,51 is 0.55 (chloroform:methanol-water = 45 : 10 : 1).

IR( , cm-1) (vaseline oil): 3600-3200 (OH); 3328 (NH); 1720, 1700 (COOH); 1656, 1652 (C= 0); 1624, 1576, 1504 (the pyridine ring), 1532 (CONH, Amide P).

UVmaxMeOH-dioxane(lg ): 248 nm (4,19).

Found, %: C 58,49; H 6,86; N Of 5.05.

C46H65N3O17. Mol. m 932.

Calculated, %: C 59,28; N 7,03; N 4,51.

Amide - glycyrrhizic acid with 6-aminouracil General formula

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exhibiting anti-AIDS activity.

 

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