Amide-glycyrrhizic acid with phenylboronic acid, exhibiting anti-inflammatory and antiulcer activity

 

(57) Abstract:

Usage: as an anti-inflammatory and antiulcer funds. The inventive product - amide b-glycyrrhizic acid with phenylboronic acid: 1-o-[ 3, 20-11,30 dioxo-30 - N -(meta-aminophenylalanine acid)-Olean-12-EN-3-yl] -2-o-[ b - D-6-oxo-6-deoxy-6 - N-(meta-aminophenylalanine acid)-glyukopiranozil] - b - D-6-oxo-6-deoxy-6 - N -(meta - aminophenylalanine acid) - glucopyranosid. Yield 69%, so different. > 250°C, []2D0= +40 deg. (C = 0,025 sportdiscus). BF C60H80N3O19B3-glycyrrhizic acid with pinivora new acid 1-0-[(3 , 20 )-11,30-dioxo-30-N-(meta-aminophenylalanine acid)-Olean-12-EN-3-yl]-2-0-[ -D-6-oxo-6-DESA - XI-6-N-(meta - aminophenylalanine acid)-glyukopiranozil] --D-6-oxo - 6-deoxy-6-N-(meta-aminophenylalanine acid)-glucopyranosid formula I

where R exhibiting anti-inflammatory and antiulcer activity.

The specified connection, its properties and the method of obtaining not described in literature.

The main drawback is widely used in medicine antiphlogistic steroid and non-steroid type (ortofen, voltaren, indomethacin, prednisolone, phenylbutazone, Brufani funds deprived of this undesirable property is relevant.

-Glycyrrhizin acid (ha) and its derivatives are known as anti-inflammatory and antiulcer substance with low toxicity.

Consequently, as a structural analogue in the study of biological activity of the proposed compound I chose-Ledger.

The aim of the invention is the search for new chemical compounds in the series of derivatives-glycyrrhizic acid, which has high anti-inflammatory activity, combined with antiulcer action.

This goal is achieved amidon-glycyrrhizin (GC) acid of formula I exhibiting anti-inflammatory and antiulcer activity.

Pharmacological properties of the compounds I.

Acute toxicity of compound I was determined to outbred mice weighing 15-20 g when introduced into the stomach.

The toxicity parameters were calculated by Litchfield and Wilcoxon signed. This compound belongs to the class IV hazardous substance (LD50> 7000 mg/kg).

Anti-inflammatory effect of amide (I) was studied on 2 models of inflammation caused by carrageenan and formalin. The quality is aemy in medicine highly active antiphlogistic voltaren (LD50voltaren 380 mg/kg orally) and glikopeptid Ledger with methyl ester of L-phenylalanine (Glikopeptid II).

The target compound was introduced into the stomach in doses of 100, 50 and 25 mg/kg over 1 h to play inflammation and after 1 and 2 h after. In models of inflammation caused by carrageenan, the connection I in the dose delays the development of inflammation compared to the control (see table.1).

Anti-inflammatory activity of amide exceeds the effect of protivopostavlenie glycyrrhizic acid in doses of 100 and 25 mg/kg inflammation induced by formalin, the proposed connection has anti-inflammatory action similar to voltaren and very glycoside dose of 50 mg/kg and at a dose of 100 mg/kg was superior to active Comparators.

In contrast to the known non-steroidal anti-inflammatory drugs connection I prevent destruction of the gastric mucosa. The antiulcer activity of amide (I) was studied on the model of experimental gastric ulcers in rats induced by indomethacin and Cincotta, in comparison with antiulcer effect known antiulcer tools carbenoxolone disodium salt acid succinate-glycyrrhetic acid. Compound I was administered the ID (I) reduces the degree of the damage of the gastric mucosa compared with control 1.6 times. Model Zinovievich ulcers amide (I) reduced the degree of the damage of the gastric mucosa in comparison with control 2 times more efficient. The antiulcer activity of the compounds was similar to the effect of glycyrrhizic acid and carbenoxolone when introduced into equal doses in this experimental model of gastric ulcers. Unlike carbenoxolone (LD50101 mg/kg intraperitoneally) amide (I) is less toxic. Thus, compound I is a hazardous substance with pronounced anti-inflammatory activity, combined with antiulcer effect, which distinguishes it from known anti-inflammatory drugs (aspirin, voltaren, indomethacin and others).

Amide I received with the activated (N-hydroxysuccinimide ether), glycyrrhizic acid without prior protection of the hydroxyl groups of the carbohydrate chain glycoside. When processing companies with excess N-hydroxysuccinimide (HOSu) in the presence of N,N'-dicyclohexylcarbodiimide (DCGK) in dry tetrahydrofuran received Tris-oxysuccinimide ether-SC at 0aboutWith that without selection were subjected to interaction with phenylboronic acid (II) in the presence of an excess of triethylamine (tea) at room temperature. In the and, alcohol and ether. Yield 55%

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

Anti-inflammatory effect of amide (I) was studied in outbred mice for 2 models of inflammation, caused by a 1% solution carragenine and 3% formalin solution. Phlogogenic was introduced in the aponeurosis of the foot of one of the hind legs at a dose of 0.05 ml of the Studied compound I gave the animals through the probe intragastrically at doses of 25, 50 and 100 mg/kg for 1 h prior to the introduction of logogen and after 1 and 2 h after playback edema. The results of the experiments are given in table.1.

As Comparators used well-known anti-inflammatory voltaren, -glitsirrizi - new acid and glikopeptid II.

P R I m m e R 2. The study of the antiulcer action of the amide (I).

Antiulcer activity of compound I studied on the model of experimental destruction of the gastric mucosa of rats, caused by the intragastric administration of indomethacin and Cincotta. On the antiulcer activity of the drug was judged to reduce the destruction of the gastric mucosa of rats. On the eve of the play-destruction rats fasted for two days. The target compound was administered to the animals for 1 hour before vosproizvedennym anesthesia, removed stomachs and visually take into account all of the mucous membranes.

As reference drugs used-glycyrrhizinic acid and known antiulcer drug carbenoxolone (the disodium salt of the acid succinate glycyrrhetic acid) in equal doses (100 mg/kg).

The results of the experiments are given in table.2.

The antiulcer activity of the preparation is analogous to the effect of carbenoxolone and glycyrrhizic acid when introduced into equal doses.

P R I m e R 3. Getting amide (I).

To a solution of 1.64 g (2 mmol), glycyrrhizic acid (92-95%) in 60 ml of dry tetrahydrofuran at 0aboutadded 1.2 g (10.4 mmol) of N-hydroxysuccinimide (HOSu) and 1.3 g (6 mmol) N,N'-dicyclohexylcarbodiimide and stirred at this temperature for 2.5-3 h, then at room 6-7 h and leave the mixture overnight at 4-8aboutC. Filtered the precipitation of dicyclohexylamine, the filtrate is cooled in the tank with ice, added 0.96 g phenylboronic acid (7.6 mmol) and kept at room temperature with periodic mixing 24 hours Poured the mixture into 300 ml of ice water, acidified with citric acid to pH 3, the precipitate was filtered light brown, washed it several who isofemale from a mixture of chloroform, alcohol and ether. Yield analytically pure amide (I) of 1.30 g (55%). So different. > >250aboutS. [D2040about(0,025; alcohol, dioxane). Rf0,51 (ratio of chloroform, methanol and water 45:10:1).

IR , cm-1: 3600-3200 (OH,NH); 1705, 1660 (C=O), 1540 (CONH).

UVmaxMeOH(lg ): 211 nm (4,46); 242 nm (4,23).

C60H80N3O19B33H2O. Mol.m. (1233,73).

Calculated C 58,41; H 7,03; N 3,40.

Found, C 57,86; H 6,97; N 2,95.

Dissolved in a mixture of ethanol and methanol 2:1, chloroform and alcohol (5:1, tetrahydrofuran, dioxane, DMF, insoluble in water, ether, hexane.

Thus, the amide (I) is a hazardous substance with pronounced anti-inflammatory activity, combined with antiulcer effect, which distinguishes the compound from the known anti-inflammatory drugs. Compound less toxic than the Comparators.

Amide b-glycyrrhizic acid with phenylboronic acid formula

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where

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exhibiting anti-inflammatory and antiulcer activity.

 

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