3-o-2-deoxy--d-galacto - or-l-rhamnopyranoside methyl ester of glycyrrhetic acid, manifesting antiulcer activity and stimulating reparative regeneration of the skin

 

(57) Abstract:

The invention relates to organic chemistry, new chemical compounds, namely 3-O-2-deoxy-a-D-galacto - and-L-rhamnopyranoside methyl ester of glycyrrhetic acid of General formula

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showing antiulcer activity and stimulating reparative regeneration of the skin. The proposed compounds are toxic substances with high antiulcer activity, exceeding the effect of carbenoxolone and glycyrrhizic acid, in combination with a strong stimulating effect on reparative regeneration of the skin. 6 table.

The invention relates to new biologically active chemical compounds, specifically to 3-O-2-deoxy-glycosides methyl ester of glycyrrhetic acid of General formula

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3-O-[2-deoxy- -D-galactopyranosyl] -11-oxo-20 - methoxycarbonyl-30-norolean-12-EN-3-ol (1) and 3-O-[2-deoxy - a-L-rhamnopyranose] -11-oxo-20-methoxycarbonyl-30-norolean-12-EN-3-ol (2), showing antiulcer activity and stimulating reparative regeneration of the skin.

Compounds (1), (2) and their properties are not described in literature.

Number of the State registration of the compounds (1) and (2) sootvetst for compounds (1) and (2) is glycyrrhizin acid (ha) (3) [1]. Due to the fact that you know a more efficient connection in a five-part activity, the mapping of the compounds (1, 2) conducted with carbenoxolone (4) - disodium succinate salt of glycyrrhetic acid produced a number of foreign firms. The main disadvantage of carbenoxolone is its toxicity. So LD50(4) is 101 mg/kg (intraperitoneally) [2].

Mapping by stimulation of reparative regeneration of the skin (RSC) for (1, 2) conducted with methyluracil - known stimulator RSC [3]. During the study the authors of this application it was found that the Ledger along with the known property of the five activity has the property to stimulate the RSC, so it is also used as a reference drug.

Therefore, the search for new, less toxic compounds in the range derivative of glycyrrhetic acid with a higher five-activity in comparison with GC and carbenoxolone combined with other types of physiological activity, is relevant.

In the claimed technical solution synthesized new low-toxic compounds - derivative of glycyrrhetic acid, namely 3-O-[2-deoxy- -D-galactopyranosyl] -11-oxo-20-methoxycarbonyl - 30-norolean-12-EN-3-ol (1) and 3-O-[2-det youdim effect on RSC.

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Acute toxicity of the compounds was determined on outbred mice weighing 15-20 g when introduced into the stomach. The toxicity parameters were calculated by Litchfield and Wilcoxon signed. LD50connection (2) amounted to 5500 mg/kg

Connection (1) when administered to mice prior to 2000 mg/kg toxic effects not caused. On the basis of the Decision of the state Committee of standards of the USSR on March 10, 1976 N 579 these substances belong to the class IV hazardous substance.

Antiulcer effect of the proposed compounds were studied on rats in 2 experimental models of gastric ulcers induced by indomethacin and aspirin, compared with carbenoxolone and General Ledger. The tested substance was administered to the animals through a tube into the stomach in a dose of 100 mg/kg the results of the experiments are presented in table. 1 and 2.

It is established that the investigated compounds protect the gastric mucosa from ulceration. The antiulcer activity of compound (1) is more pronounced than in carbenoxolone and GK on the model of indomethacin ulcers, and connection (2) protects the gastric mucosa of rats from expressing more effective pharmacological and structural analogues on the model of indomethacin and aspirin-induced ulcers (table. 2).

In us, as the comparison drug used methyluracil and General Ledger. Studies were performed on three models of skin wounds - layered patchwork wounds (table. 3, 4), on the model of the chemical (table. 5) and thermal (PL. 6) burns in the form of a 5-percentage of ointments on the vaseline.

In groups of animals treated with compounds (1) and (2), the healing of skin wounds were more active than in the comparison groups with methyluracil and Ledger (PL. 3, 4).

On the model of a chemical burn, which caused the rats of concentrated hydrochloric acid, the compound (1) stimulate skin regeneration is more efficient than the methyluracil and GK on the 7th day of treatment.

On the 15th day after playing burn in all groups of animals skin regeneration was greater than in animals treated with methyluracil and Ledger (PL. 5).

On the model of thermal burns of the skin of rats at the 15-day treatment the healing of skin wounds was more effective than in animals which were treated with GK and methyluracil (PL. 6).

Thus, compounds (1) and (2) have a higher antiulcer activity than Ledger and carbenoxolone. High five activity proposed compounds combined with a stimulating effect on reparative regeneration of the skin, which is ASS="ptx2">

The synthesis of compounds (1) and (2) conducted under conditions known method [4] by electrophilic glycosylation of methyl ester of glycyrrhetic acid (7) using acetates D-galactal (5) and L-rannala (6) in methylene chloride in the presence of molecular sieves 4 and (SIM kallidin)2iodone perchlorate (8) (scheme 1). Protected 2-deoxy-2-iodine-derivatives (9, 10) after purification column chromatography was deyodirovania by hydrogenolysis in the presence of 10% Pd/C and triethylamine and was unblocked 5% solution of KOH in methanol. The total yield of 2-deoxy-glycosides (1) and (2) amounted to 67.9 and 74%, respectively.

The essence of the technical solution is illustrated by the following examples.

Example 1. Obtain 3-O-[2-deoxy- -D-galactopyranosyl] -11-oxo-20 - methoxycarbonyl-30 - norolean-12-EN-3-ol (1).

2 mmol (0.55 g) tri-O-acetyl-D-galactal (5), 2 mmol (0.97 g) methyl ester of glycyrrhetic acid (7) was dissolved in 50 ml of absolute CH2Cl2in the presence of calcined molecular sieves 4 , stirred for 30 minutes, then add 1.1 g (SIM kallidin)2IClO4(8). The mixture is stirred for 4-5 hours (control by TLC), methylene chloride:methanol = 10:1), filtered, washed with 10% solution of Na2silicagel (ethyl acetate: pentane - 1:7, 1:5, 1:3, 1:2, 1:1). The solvent system of 1:3 ---> 1:2 wash 1.39 g of glycoside (9) (79%), which was dissolved in 50 ml of ethyl acetate, add a few drops of Et3N, in the presence of 1.4 g of 10% Pd/C hydronaut within 7 days. The catalyst is filtered off, the solvent evaporated, the residue is dissolved in 130 ml of methanol, poured 20 ml of 5% solution of KOH in methanol, after 2 hours, neutralized with ion-exchange resin KU-2-8

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(H+-form), the solvent evaporated, the compound (1) was isolated from methylene chloride - pentane. Output 0,86 g (86%), white powder. So pl. = 226 - 228oC.

C37H58O8(630,9), Rf= 0,37 (CH2Cl2: MeOH = 10:1).

Found, %: C 70,4; H 9,3.

Calculated, %: C 70,4; H 9,3.

[]2D0=+88o(from 0.05, CHCl3).

UV spectrum (MeOH),max/nm: 246,4 (lg 3,89).

IR spectrum (cm-1, liquid paraffin): 1650 (C11=O), 1730-1720 (COOMe), 3600-3200 (OH).

An NMR spectrum13C (CDCl3, , ppm): 21,7 (C2), 81,8 (C3), to 200.3 (C11), of 128.6 (C12), 169,4 (C13), 177,0 (C30), 51,8 (C31), 93,6 (C1'), 33,3 (C2'), 69,9 (C3'), 65,8 (C4'), 69,9 (C5'), and 63.9 (C6').

Example 2. Obtain 3-O-[2-deoxy - a-l-rhamnopyranose] -11-oxo-20-methoxycarbonyl-30-norolean-12-EN-3-ol (2).

2 mmol (0.4 g), di-O-acetyl-L-rannala (6), 2 mmol (0.97 g)tempered molecular sieves 4 is stirred for 30 minutes, then add 1.1 g (SIM kallidin)2IClO4(8). The mixture is stirred for 3-4 hours (control by TLC), filtered, washed with 10% solution of Na2S2O3(G ml), dried with Na2SO4, evaporated. Allocate using column chromatography on silica gel (CH2Cl2- MeOH, 200:1, 150:1, 100:1, 50:1). The mixture of solvent 150:1 ---> 100:1 wash of 1.38 g of the glycoside (10) (84%), which was dissolved in 60 ml of ethyl acetate, add a few drops of Et3N, in the presence of 1.4 g of 10% Pd/C hydronaut within 8 days. The catalyst is filtered off, the solvent evaporated, the residue is dissolved in 130 ml of methanol, poured 20 ml of 5% solution of KOH in methanol, 1.5 hours neutralized ion exchange resin KU-2-8 (H+-form), the solvent evaporated, the glycoside (2) is recovered from methylene chloride - pentane. The output of 1.11 g (89%) of white powder. So pl. = 186-188oC.

C37H58O7(614,9), Rf= 0,48 (CH2Cl2: MeOH = 10:1).

Found, %: C 72,3; H 9,4.

Calculated, %: C 72,3; H 9,5.

[]2D0= + 58o(from 0.06%, CHCl3).

UV spectrum (MeOH), max/nm: 247,0 (lg 4,32).

IR spectrum (cm-1, liquid paraffin): 1650 (C11= O), 1730-1720 (COOMe), 3600-3200 (OH).

Spec Is C5'), 17,5 (C6').

Example 3. The study of antiulcer activity.

Five active compounds (1) and (2) was studied in rats in two models of experimental destruction of the gastric mucosa of rats induced by indomethacin and aspirin. Ulcerative destruction of the stomach in adult rats weighing 200-250 g were caused by the administration of indomethacin and aspirin treatment (20 mg/kg). The studied compounds were 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 ether anesthesia, were removed stomachs and visually take into account all of the mucous membranes. As reference drugs used glycyrrhizinic acid (3) and carbenoxolone (4) in equal doses of 100 mg/kg the results of the experiments are given in table. 1 and 2. As can be seen from the tables, the compounds (1) and (2) remove the degree of ulceration of the gastric mucosa (p < 0,001) compared to control.

Example 4. To study the effect of compounds (1) and (2) on reparative regeneration of the skin.

The influence of compounds (1) and (2) for RSC studied on rats on three models of skin injuries. As Comparators used glycyrrhizinic acid (3) and plastic surgery. Layered flap is determined the average size of the Russian Academy of Sciences, they divided the animals into groups and started treatment 5%-tion ointment drugs on vaseline (daily treatment). The results of the experiments are given in table. 3 and 4. On the 7th day of treatment in all groups of animals, which were treated with compounds (1) and (2), the average area of RAS decreased significantly, and using ointments compounds (1) and (2) regeneration of the skin were more active than in the treatment of plastic surgery. On the 15-day treatment groups, which were treated with compounds (1) and (2), the healing of skin wounds was more pronounced than in the groups treated GC and plastic surgery.

In the next series of experiments used a model of a chemical burn, which is caused on the side surface rats 1-2 drops of concentrated hydrochloric acid. The next day was determined by the initial area after burn and started treatment 5% ointment connection (1) on the vaseline. The results of the experiments are given in table. 5. On the 7th day of treatment in the group of animals treated with compound (1), wound healing was more pronounced than in the groups treated GC and methyluracil. On the 15th day after playing burn in the group of animals treated with compound (1), skin regeneration was greater than in the comparison group.

In another series of experiments on the sides of the. On the 7th day of the treatment effect of the compound (2) was similar to the Comparators (CC and methyluracil). On the 15th day of treatment in the group of animals treated with compound (2), wound healing took place more effectively than in the comparison groups (table. 6).

Conclusions:

thus, the antiulcer activity of compounds (1) and (2) exceeds the effect of glycyrrhizic acid and carbenoxolone on the model of indomethacin and aspirin-induced ulcers;

connection (1) and (2) in the form of 5% of the energy ointments are effective stimulators of reparative regeneration of skin wounds and is superior to active Comparators - Ledger and plastic surgery.

3-O-2-Deoxy-a-D-galacto - or-L-rhamnopyranoside methyl ester of glycyrrhetic acid of General formula

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where R = R1= R2,

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showing antiulcer activity and stimulating reparative regeneration of the skin.

 

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