Amide-glycyrrhizic acid with 6-amino-2-thio-uracil, exhibiting anti-aids activity

 

(57) Abstract:

Usage: as an anti-AIDS funds. The inventive product: 3 - 0 - [ 2 - 0- ( b-D-glucopyranosyloxy) - b - D - glucopyranosyloxy] - ( 3 - b , 20 b) - 11,30 - dioxo - 30 - (N - 6 - amino - 2 - thio - uracil) - 30 - norolean - 12 - ene, the yield of 65.2% so pl. 198 - 200°C BF C46H65N3O16S . Reagent 1: -glycyrrhizin acid. Reagent 2: 6-amino-2-thiouracil. Reaction conditions: in an environment of dry pyridine, in the presence of N,N-dicyclohexylcarbodiimide. LD507 g/kg 1 tab.

The invention relates to new biologically active compound, particularly to amide-glycyrrhizic acid with 6-amino-2-thio-uracil: 3-0-[2-0-( -D-glucopyranosyloxy)- -D-glucopyranosyloxy] -(3 , 20 )-11,30-dioxo-30-(N-6-amino-2-thio-uracil)-30-norolean-12-EN Fort - mules 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]. Some of these compounds are already undergoing clinical trials in patients. One of these drugs, avlo, what GK connection that is present in the aqueous extract of licorice root (Glycyrrhiza glabra) effectively inhibits the reproduction of HIV in cell culture [2, 3]. 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 T4 lymphocytes and decrease the amount of viral antigen [4].

The mechanism of the antiviral action of GC remains unidentified. It is assumed that one factor may be the blocking of GC protein kinase [5], the phosphorylation of which molecules of T4 receptor is required for binding of the virus with T4 receptor [6]. It was also established that the Ledger directly inhibits the binding of HIV to the cell [5].

However, SC is ineffective as an inhibitor of HIV replication 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.

The objective is achieved by amidon-GK formula (I) exhibiting anti-AIDS activity.

Pharmacological properties of the compounds

Antiviral activity of compound (I) was studied on the model of primary HIV-1-infected lymphoid cells MT-4. Plant concentrations of 500-1000 µg/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). Were used for comparison one of the most effective for the treatment of AIDS drugs - azidothymidine (AZT) [7], the mechanism of action associated with the blocking of viral reverse transcriptase and termination of viral DNA synthesis, and glycyrrhizinic acid (GK), effectively inhibitory reproduction of HIV-1 in cells.

The main disadvantage of AZT is its high toxicity [8].

It is established that the investigated compound (I) inhibits the reproduction of HIV-1 in culture cells MT-4 at concentrations of 0.5 to 1.0 mg/ml the level of antiviral activity of the amide (I) is not inferior to AZT and companies at a concentration of 1.0 mg/ml

Unlike AZT amide (I) has a less significant toxic effect on the cell culture, and the reduction of ConCentra case, the derived-SC 8 times higher (at a concentration of 500 μg/ml), than in the case of AZT and 2.7 times higher than in the case of GC in the same breeding.

The compound (I) is less toxic than AZT. LD50amide (I) 7 g/kg

The connection class III hazardous substance.

Synthesis of amide (I) is carried out by treating the mixture, glycyrrhizic acid and 6-amino-2-thio-uracil in DMF - pyridine (5 : 1, v/v) N,N'-dicyclohexylcarbodiimide at 50-60aboutC for 6 hours. The product was led from a mixture of DMF - H2O. The Yield Of 65.2%.

Thus, the proposed new low-risk derivative-glycyrrhizic acid - amide 6-amino-2-S-uracil (I) effectively inhibits the reproduction of HIV-1 in vitro (in culture cells (MT-4), is less toxic than azidothymidine.

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

Antiviral activity of compound I has been studied in models of primary HIV-1-infected lymphoid cells MT-4. Solution of the drug in DMSO (20 - 50 mg/ml) were introduced into a suspension of HIV-1-infected cells to final concentrations of 500-1000 µg/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 with fermentado analysis) in the culture fluid on the 4th day of cultivation compared with the control (without addition of drug). As the comparison drug 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 acid (GK), effectively inhibitory reproduction of HIV-1 in cells.

The table shows the results of the experiments. It is established that the investigated compound (I) inhibits the reproduction of HIV-1 in cell culture at concentrations of 0.5 to 1.0 mg/kg By the level of antiviral activity of the compound is not inferior to AZT and companies at a concentration of 1.0 mg/ml

Unlike AZT amide (I) has a less significant toxic effect on the cell culture, and the reduction of drug concentration leads to the disappearance of toxic effects on the cell culture. The number of living cells in the case of amide (I) 8 times (in a dilution of 500 µg/ml) than in the case of AZT and 2.7 times higher than in the case of GC in the same breeding.

Thus, the first set of ability derived-GK - amide, 6-amino-2-S-uracil (I) effective to inhibit the reproduction of HIV in cell culture.

P R I m m e R 2. Getting am what-amino-2-S-uracil and 5 ml dry pyridine, then 0.7 g (3.4 mmol) of N,N'-dicyclohexylcarbodiimide and stirred the mixture at 50-60aboutC for 6 hours. Leave the mixture overnight at room temperature, the precipitate is filtered off, dicyclohexylamine, the filtrate is poured into 200 ml of cold water, acidified with citric acid to pH 3 and the precipitate is filtered off amide (I), washed with water several times, dried in air, then at 110-120aboutC. Obtain 0.95 g (100%) of the target product, which crystallized from DMF - water. The output of 0.62 g (65.2 percent) amide (I), homogeneous by TLC (white powder). So pl. 198-200aboutC [ ]D20= +20 - +25oC (=0,02; dioxane). Rf= 0,52 is 0.55 (chloroform-methanol-water = 45 : 10 : 1).

IR , cm-1(vaseline oil): 3600-3200 (OH); 3328 (NH); 1720, 1700 (COOH); 1660, 1650 (C = 0); 1630, 1580 (pyrimidine); 1540 (NH, amide II).

UVmaxdioxane(lg ): 247 nm (3,99).

Found, %: 57,47; N 6,87; N To 3.58; S 3,88.

WITH46H65N3O16S. Mol. m 948,06.

Calculated, %: C 58,27; H 6,91; N 4,43; S 3,38.

Amide - glycyrrhizic acid with 6-amino-2-thio-uracil General formula

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where

R1=

exhibiting anti-AIDS activity.

 

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exhibiting anti-AIDS activity

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