Glikopeptid-glycyrrhizic acid with debutalbum ester of l-glutamic acid, exhibiting anti-inflammatory and antiulcer activity

 

(57) Abstract:

Usage: as an anti-inflammatory and antiulcer funds. The inventive product - 3-0[2-0-(N - b-D-glucopyranosyloxy-L-glutamic acid disutility ether)-N - b-D-glucopyranosyloxy-L-glutamic acid disutility ether-(3 b , 20 b) -11,30-dioxo-30-(N-L-glutamic acid disutility ether)-30-norolean-12-ene. Yield 80%, []2D0= 30(C = 0,02, methanol). BF C81H131N3O5. LD50= 650 mg/kg (intraperitoneally).

The invention relates to new chemical compound, specifically to glycopeptide-glycyrrhizic acid with debutalbum ester of L-glutamic acid: 3-0-[2-0[(N- -D-glucopyranosyloxy-L-glutamic acid disutility ether)-N-D-glucopyranosyloxy-L-glutamic acid BEUtility ether-(3 , 20 )-11,30-dioxo-30-(N-D-glutamic acid disutility ether)-30-norolean-12-EN General formula I,

< / BR>
where R L-Glu(OBu)2exhibiting 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 asteroidea the gastrointestinal tract. Therefore, the search for new anti-inflammatory drugs deprived of this undesirable property is relevant.

-Glycyrrhizin acid (ha) and its derivatives are known as anti-inflammatory and antiulcer agents (1-5), with low toxicity.

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 glycopeptide-glycyrrhizic acid of the formula (I) exhibiting anti-inflammatory and antiulcer activity.

Pharmacological properties of the compounds I were studied in the laboratory investigations of new drugs THEIR psybnc, Ural branch of the USSR Academy of Sciences. Acute toxicity of compound I was determined to outbred mice weighing 15-20 g intraperitoneal route of administration and the introduction into the stomach. The toxicity parameters were calculated by Litchfield and Wilcoxon signed LD50= =650(500-845) mg/kg (intraperitoneally) and 7000 mg/kg (intragastrically).

This connection refers to 8 class of low-hazard substances.

Anti-inflammatory effect of glycopeptide I studied the Ali purified-glycyrrhizinate acid (LD505000 mg/kg) is widely used in medicine highly active antiphlogistic - ortofen (LD50ortofena = 380 mg/kg orally) and glikopeptid glycyrrhizic acid with methyl ester of L-phenylalanine (glikopeptid II) LD50= =135 mg/kg intraperitoneally.

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 similar to ortofen. Anti-inflammatory activity of glycopeptide exceeds the effect of protivopostavlenie glycyrrhizic acid at all tested doses (table. 1). Inflammation induced by formalin, the proposed connection has anti-inflammatory action similar to ortofen and the glycoside (table. 2).

In contrast to the known non-steroidal anti-inflammatory drugs connection I prevent destruction of the gastric mucosa. Antiulcer effect of glycopeptide (I) was studied on the model of experimental gastric ulcers in rats caused by aspirin, compared with antiulcer effect known antiulcer tools - carbenoxolone - disodium salt to the enta dose of 100 mg/kg

On the model of aspirin-induced ulcers glikopeptid (I) significantly reduces the degree of the damage of the gastric mucosa (p 0,001) compared with control 2.5 times. The antiulcer activity of compounds similar carbenoxolone and glycyrrhizic acid when introduced into equal doses. Unlike carbenoxolone (LD50= 101 mg/kg intraperitoneally) [6], glikopeptid (I) 6.5 times less toxic. Thus, the proposed connection I is a hazardous substance with pronounced anti-inflammatory activity, combined with antiulcer effect, which distinguishes it from known anti-inflammatory (aspirin, ortofen, indomethacin and up.).

Synthesis of glycopeptide (I) was performed by the method of activated (N-hydroxysuccinimide) esters without prior protection of the hydroxyl groups of the carbohydrate chains of the molecules of the glycoside.

When processing glycyrrhizic acid N-hydroxysuccinimide (HOSu) in the presence of N, N'-dicyclohexylcarbodiimide (DCGK) in dry dioxane was obtained Tris-oxysuccinimide ether glycyrrhizic acid, which without isolation was subjected to interaction with hydrochloride dibutylamino ester of L-glutamic acid in the presence of wt is cromatografia on silica gel by elution with a mixture of solvents chloroform-methanol = 50 : 1 and 25 : 1 (v/v).

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

Anti-inflammatory effect of glycopeptide I was studied in outbred mice in two 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 drug-ortofen and glycyrrhizinic acid. As can be seen from the data table. 1, the connection I in the studied doses has a pronounced anti-inflammatory effect similar to the effect ortofena and superior activity of glycyrrhizic acid on the model carragenine swelling.

P R I m m e R 2. Removing the antiulcer action of glycopeptide (I).

Antiulcer activity of compound I studied on the model of experimental destruction of the gastric mucosa of rats caused by intragastric introduction of aspirin (150 mg x 2). On the antiulcer activity of the drug the components rats fasted for two days. The target compound was administered to the animals for 1 h prior to playback of gastric ulcers in a dose of 100 mg/kg one day after playing destructions animals were scored under chloroform anesthesia, took stomachs and visually take into account all of the mucous membranes. As reference drugs used glycyrrhizinic acid and famous and 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 connection I reduces the degree of the damage of the gastric mucosa of rats 2.5 times compared with the control. 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 glycopeptide (I).

To a solution of 1.6 g (2 mmol), glycyrrhizic acid (92-95%) in 50 ml of dry dioxane at 0aboutWith added 42 g (10.4 mmol) of N-hydroxysuccinimide 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, to the filtrate, cooled in a bath with LDO Yergali at room temperature with periodic mixing 24 hours The solvent was removed in vacuo, the residue was dissolved in methylene chloride (200 ml), washed sequentially with 5% HCl solution, water, 5% solution of NaHCO3, water and dried over MgSO4. By evaporation of the solvent in vacuo got 2,48 g (80%) of glycopeptide (I), which is cleaned on a column of silica gel L (100/240 , Czechoslovakia), elwira mixture of chloroform - methanol 100 :1, 50 : 1, 25 : 1, 10 : 1 (v/v). A mixture of 50 : 1 and 25 : 1 was washed 1,59 g (64%) of analytically pure product (I) in the form of an amorphous substance of a yellowish color. Rf= 0.5 (chloroform-methanol-water = 45 : 10 : 1) (Silufol). [ ]D20= +30o(=0,02; methanol).

IR, cm-1: 1740 (Saavi); 1690 (CONH, amide I); 1650 (C11= 0); 1530 (CO H, Amin II).

UVmaxMeOH(lg ): 249 nm (4.09 to).

Found, %: C 60,19; H 8,24; N 2,73.

C81H131N3O25.

Calculated, %: C 60,30; H 8,53; N 2,72.

Soluble in acetone, methanol, tetrahydrofuran, dioxane, alcohol, dimethylformamide.

Thus, glikopeptid (I) is meloxicam substance with pronounced anti-inflammatory activity, combined with antiulcer effect, which distinguishes the compound from the known anti-inflammatory drugs, used the deposits.

Glikopeptid - glycyrrhizic acid with debutalbum ester of L-glutamic acid formula

< / BR>
where R - L - glu (OBu)2,

exhibiting anti-inflammatory and antiulcer activity.

 

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