Method for synthesis of ester and glycyrrhetinic acid derivative and deoxyglycyrrhetinic acid ester compound

FIELD: chemistry.

SUBSTANCE: invention relates to a compound of formula II, methods of producing a compound of formula I

and formula II

,

a pharmaceutical composition and versions of use for treating inflammation and/or liver damage. In the compound of formula II, R1 is H; R2 is a linear or branched C1-C18alkoxy; C-18 is in an α-configuration.

EFFECT: high efficiency of the method.

18 cl, 7 tbl, 8 ex

 

The technical field

The present invention relates to a method for the synthesis of esters of glycyrrhetic acid directly from glycyrrhizic acid, and also refers to the connection of ester 11-deoxy-18α-glycyrrhetinic acid and method thereof, pharmaceutical compositions containing the ester of 11-deoxy-18α-glycyrrhetinic acid, and the use of the compounds in the treatment of liver injury, inflammation and the like.

The level of technology

Licorice treats Glycyrrhiza radix et rhizoma. Main pharmacologically active substances are glycyrrhizin acid and its aglycone, glycyrrhetinic acid. Recent studies have shown that glycyrrhetic acid has anti-inflammatory, antiulcer, anti-virus (hepatitis, HIV etc), hypolipidemic, preventive, anti-tumor and other similar actions.

Glycyrrhetic acid has a structure similar to that of hydrocortisone. Numerous clinical studies have confirmed the anti-inflammatory effect of glycyrrhetic acid. Zakirov found that 3-amino-11-deoxypyridinoline acid showed significant anti-inflammatory activity against non-infectious arthritis in different animals. Toyoshima with co-authors (Toyoshima et al.) got hydro is aleat 11-desoxycortisol acid and its salts, which were used as anti-inflammatory agents, antiulcer agents, immunomodulators, see also U.S. patent 4448788. Some materials also reported that salt glycyrrhetic acid, such as glycyrrhetinic sodium, anti-inflammatory action.

In 1946 Reverse (Revers) first reported the antiulcer activity Glycyrrhizae Radixe rhizoma. Scientists have synthesized the disodium salt of hydrosylate glycyrrhetic acid and found that this compound had the ability to treat peptic ulcer (patent GB 843133). In 1972, the Demand (Demande) from France found that 3-acetyl-18β-glycyrrhetic acid and aluminum salts have a significant therapeutic effect in the treatment of duodenal ulcer and gastric ulcer. In addition, as was found, amide 11-desoxycortisol acid amide 3-oxo-acetyl glycyrrhetic acid and other similar compounds also have significant therapeutic effect against ulcers and therefore attracted a lot of attention. In 1985 Takizawa et al. (Takizawa et al.). from Japan found that glycyrrhetic acid has inhibitory activity against proliferation of skin tumors in mice (Jpn J Cancer Res. 1986, 77 (1) P33-8).

Glycyrrhetic acid and its derivatives provoke the development of almost the Roma (DCA), therefore, their use in clinical practice is often accompanied by side effects, such as carbenoxolone sodium, the product of glycyrrhetic acid, can cause fluid retention and sodium, increased blood pressure and hypokalemia. John C. Faithful et al. (John S. Baran et al.) found that 11-deoxypyridinoline acid virtually no provokes aldosterone and, thus, does not cause the above side effects (John S. Baran et al. Journal of Medicinal Chemistry, 1974, Vol.17, (2) P184-191). In order to eliminate or reduce these side effects and to increase the solubility and absorption of glycyrrhetic acid and to facilitate its receipt in proper dosage, domestic and foreign experts explored the possibility of modification and changes in the structure of glycyrrhetic acid and synthesized a series of derivatives of glycyrrhetinic acid (Soo-Jong Um et al. Bioorganic & Medicinal Chemistry 2003, 11, P5345-5352). When the synthesis of derivatives of glycyrrhetinic acid, glycyrrhetic acid was obtained mainly from glycyrrhizic acid, and then chemically modified and rebuilt the structure of glycyrrhetic acid. Reported that methyl-glycyrrhetinic synthesized by the hydrothermal method with the use of glycyrrhizic acid as the starting material (Liu Wencong, Luo Yunqing, Studies on the synthesis of methyl gycyrrhetinate by hydrothermal method, Journal of Northeast Normal University: Natural Science Edition, 2007, 39 (4): 154-156). However, this method should be implemented at high temperature and high pressure for a long period of reaction time, the application of this method places high demands on the equipment, and therefore it is not suitable for industrial production. The authors of the present invention have developed a simple method of obtaining derivatives of ester glycyrrhetic acid directly from glycyrrhizic acid or its salts derivatives only in one stage, without the need to first obtain glycyrrhetic acid, and then to modify. This process is carried out at a low temperature, it does not require high pressure, provides a high yield and low cost and, thus, suitable for industrial production.

On the basis of this simple method for the synthesis of the authors of the present invention also received esters of glycyrrhetic acid, desoximetasone position C-11, that is, 11-deoxy-18α-glycyrrhetinate. Obtained 11-deoxy-18α-glycyrrhetinate have anti-inflammatory and antiulcer actions, as well as the ability to treat lesion (dysfunction) of the liver, with less side effects, a good solubility in lipids and a high rate of absorption in the forehead is cescom the body.

Brief description of the invention

The present invention relates to the compound of formula II, namely, complex ether 11-deoxy-18α-glycyrrhetinic acid, the method of its production and the composition formed by mixing the compounds with pharmaceutical carriers, as well as the use of compounds in the treatment of inflammation, ulcers and liver damage. The present invention also relates to a method of synthesis of derivatives of ether glycyrrhetic acid.

The present invention relates to the following connection formula II:

where R1represents H, linear or branched C1-C18alkylaryl, linear or branched C1-C18alkenylacyl, or kiltormer; R2represents a linear or branched C1-C18alkoxy or aryloxy; C-18 is in the α-configuration or the β-configuration.

R1preferably represents H, linear or branched C1-C6alkylaryl or linear or branched C1-C6alkenylacyl, more preferably H;

R2preferably represents a linear or branched C1-C6alkoxy, more preferably, ethoxy;

C-18 is preferably in the α-configuration.

Preferably the compound of formula II infusion is his invention represents an ethyl 11-deoxy-18α-glycyrrhetinate.

In the present invention is also a method of synthesis of compounds of formula II: compound of formula I detoksiziruet position C-11 to obtain the corresponding compounds of formula II in which R1represents hydrogen. If necessary, the hydroxyl in position C-3 atrificial to obtain the corresponding compounds of formula II.

In the formula I R2represents a linear or branched C1-C18alkoxy or aryloxy, C-18 is in the α-configuration or the β-configuration.

Desoxidation can be done using any method of recovery, well known to experts in the art, including, but not limited to, the method of recovering Clemmensen, a method of catalytic hydrogenation and other similar methods. Method of recovering Clemmensen involves using zinc amalgam and hydrochloric acid in order to restore the carbonyl at position C-11 to methylene, and the solvent can be used tetrahydrofuran, 1,4-dioxane. Method of catalytic hydrogenation involves the possible use of any conventional catalyst, such as platinum, palladium or palladium oxide, and the solvent can be used, for example, methanol, ethanol, 1,4-dioxane, tetrahydro the furan and other similar substances. The etherification of the hydroxyl can be performed by reaction with a carboxylic acid or carboxylic acid anhydride, and the reaction can be carried out in an inert organic solvent such as 1,4-dioxane, tetrahydrofuran, and the reaction temperature can be selected depending on the carboxylic acid or carboxylic acid anhydride.

The compound of formula I is commercially available or can be obtained in accordance with the synthesis method proposed in the present invention.

In the present invention, a method of synthesis of the following compounds of formula I,

where R2defined above, the method includes:

in the presence of dehydrating agents, such as acylchlorides or concentrated sulphuric acid, the interaction of one or more compounds from a number of glycyrrhizin acid, salt of glycyrrhizic acid or a derivative of glycyrrhizic acid with aliphatic alcohols or aromatic alcohols (R2H) obtaining a complex ester of glycyrrhetinic acid of formula I. the Salts of glycyrrhizic acid can represent, for example, potassium, sodium, ammonium, calcium or magnesium salts of glycyrrhizic acid.

Glycyrrhizin acid, salts of glycyrrhizic acid or derivative glycyrrhizin is howling acid can be obtained or extracted from Glycyrrhizae obtaining glycyrrhizic acid, which is then converted into salts of glycyrrhizic acid or a derivative of glycyrrhizic acid. 18α-glycyrrhizin acid can be obtained by catalyzed by alkali isomerization reactions of natural glycyrrhizic acid by the method described in the patent of China N ZL 02111693.8.

Acylchlorides can be oxalicacid, acetylchloride or sulphonylchloride or similar substance, and sulphonylchloride can be methylsulfonylamino, benzosulphochloride or p-toluensulfonate or other similar substances. In this case on 1 mol glycyrrhizic acid, salts of glycyrrhizic acid or a derivative of glycyrrhizic acid requires 1-20 mol acylchlorides, 0.5 to 10 mol of concentrated sulfuric acid. Preferably the number of acylchlorides 3-5 mol, and the amount of concentrated sulfuric acid is 0.5 to 5 mol.

In the method of synthesis of glycyrrhetic acid ester of the formula I, the reaction is carried out in a solvent or taken for the solvent participates in the reaction of the alcohol. The solvent in the reaction is a solvent capable of dissolving the glycyrrhizinic acid, salts of glycyrrhizic acid and/or derivatives glycyrrhizic acid, such as N,N-dimethylformamide, N-organic, tetrahydrofuran, and other similar substances. the hen is involved in the reaction of aliphatic alcohol is a lower alcohol, preferably use is involved in the reaction of alcohol as a solvent.

In a specific embodiment of the invention is a method of obtaining glycyrrhetic acid ester of formula I includes: adding glycyrrhizic acid, salts of glycyrrhizic acid or a derivative of glycyrrhizic acid to anhydrous ethanol, then adding concentrated sulfuric acid or acylchlorides, boiling under reflux, followed by cooling and crystallization, followed by filtration, treatment with ethanol/water and drying to obtain the target compounds; or adding glycyrrhizic acid, salts of glycyrrhizic acid in anhydrous methanol, then add acetylchloride, boiling under reflux, followed by cooling and crystallization, followed by filtration, treatment with ethanol/water and drying obtaining the target compound.

The term "linear or branched C1-C18alkyl" refers to linear or branched saturated aliphatic hydrocarbon groups containing carbon atoms and hydrogen atoms, which are connected to other portions of the molecule by a single bond. The specified alkyl contains 1 to 18 carbon atoms, preferably 1-6 carbon atoms. The alkyl group can be unsubstituted or substituted od is them or more substituents, selected from halogen and hydroxyl. Examples of unsubstituted alkyl include, but are unrestricted by them, methyl, ethyl, propyl, 2-propyl, n-butyl, isobutyl, tert-butyl, n-pentyl, 2-methylbutyl, neopentyl, n-hexyl, 2-etylhexyl and other similar groups.

The term "linear or branched C1-C18alkenyl" refers to linear or branched unsaturated aliphatic hydrocarbon groups containing carbon atoms and hydrogen atoms and containing at least one unsaturated bond, which are connected to other portions of the molecule by a single bond. Specified alkenyl contains 1-18 carbon atoms, preferably 1-6 carbon atoms. Alchemilla group can be unsubstituted or substituted by one or more substituents selected from halogen, hydroxyl or carboxyl. Examples of the unsubstituted alkenyl include, but are unrestricted by them, vinyl, propenyl, propen-2-yl, 1-butenyl, Isobutanol, 1-pentenyl, 2-methylbutanol, 1-hexenyl, 2-methylhexane and other similar groups.

The term "aryl" refers to groups with aromatic ring containing one carbon ring or multiple condensed aromatic rings with a fully conjugated π-electron system, containing 6-14 carbon atoms, preferably 6-12 carbon atoms, more preferably 6 atoms of carbon is and. Aryl can be unsubstituted or substituted by one or more substituents selected from alkyl, aryl, arylalkyl, amine, halogen and hydroxyl. Examples of unsubstituted aryl include, but are unrestricted by them, phenyl, naftalina and anthracene group.

The present invention also proposed a compound of the formula II and one or more methods of using the compositions containing the compound of formula II for the treatment of inflammation, ulcers and liver failure.

The compound of formula II of the present invention can be entered by itself. In General, the compounds can be obtained in the form of pharmaceutical preparations that contain at least one of the compounds of formula II as an active ingredient, and may contain one or more pharmaceutically acceptable carriers. These drives vary in accordance with the methods of administration. Drugs, containing compounds presented in this invention, can be entered locally or systematically, including oral, rectal, intranasal, sublingual, dermal, vaginal, and other similar methods.

The oral composition may be solid, heliobates or liquid. Examples of solid preparations include but are not limited to tablets, capsules, granules and powders. These drugs may optionally contain a binder, Rabba Italy, baking powder, grease, preventing clumping, sweetener and/or flavoring.

The present invention also proposed a veterinary composition comprising at least one of the above active components and at least one of the veterinary carriers. Veterinary carriers can be a substance that can be entered cattle, horses, sheep, cats, dogs, horses, rabbits or other animals, and can be a solid, liquid or gaseous substance, acceptable in the veterinary field and compatible with the active components. Veterinary composition can be entered orally parenterale or other similar methods.

The authors present invention synthesize an ester of glycyrrhetinic acid in a simple way and, in particular, to synthesize an ester of 11-deoxy-18α-glycyrrhetinic acid. Ester 11-deoxy-18α-glycyrrhetinic acid has anti-inflammatory, antiulcer action and can be used for the treatment of liver failure, inhibition of necrosis of liver cells and protect the liver from damage, and, thus, promising in the treatment of liver diseases, in particular for the treatment of acute liver disease and drug-induced liver injury, with small side e what effects, good rastvorimosti in lipids, rapid absorption, high utilization rate. Compared with glycyrrhizin and diammonium glycyrrhizinate this connection has greater bioavailability and a significant reduction of transaminases.

Example 6 shows that the compound of formula II of the present invention has anti-inflammatory action.

In examples 7 and 8 shows that the compound of formula II of the present invention has a therapeutic effect against drug liver damage.

In tables 1 and 2 shows that the compound of formula II of the present invention, particularly preferred compounds have an effect on the D-galactosamine (D-Caln)-induced liver damage and can significantly inhibit the secretion of serum transaminases, and their action is better than action of glycyrrhizic acid and diammonium glycyrrhizinate. In particular oral introduction has the best Dammam.

In tables 3 and 4 shows that the compound of formula II of the present invention, particularly preferred compounds have an effect on TAA-induced liver damage and can significantly inhibit the secretion of serum transaminases, and their action is better than the effect of diammonium glycyrrhizinate. These compounds can also inhibit necrosis CL is current liver, and their action is better than the effect of diammonium glycyrrhizinate.

In the present invention proposed a synthesis of ester glycyrrhetic acid in a simple way directly using glycyrrhizic acid or its derivatives as a source of substances with a high product yield, and then the production of esters of 11-deoxy-glycyrrhetic acid. When fully used Glycyrrhiza and reduced waste.

The following examples are presented to illustrate the present invention and do not limit the scope of the present invention.

Examples

The reagents used in the following specific examples, have the grade of "pure for analysis".

Equipment: infrared spectroscopy was used FTIR spectrometer Spectrum one company D and tablet of KBr. For registration of spectra1H NMR,13C-NMR was used NMR spectrometer BRUKER AV-500 with CDCl3as solvent and TSM as an internal standard.

Example 1. Synthesis of methyl 18β-glycyrrhetinic

Method 1: 10 g 18β-glycyrrhizic acid was added in 100 ml of anhydrous methanol, and then there was added 5 ml of acetylchloride. The reaction mixture is boiled under reflux for 2 hours, then was added 100 ml of water. The mixture was cooled and subjected to crystallization to obtain the firmness of the water phase, then was filtered. The product was purified using ethanol/water and dried to obtain the title compound with a yield of 82%.

Method 2: 20 g 18β-glycyrrhizinate of monoamine was added in 100 ml of anhydrous ethanol, and then there was added 10 ml of acetylchloride. The reaction mixture is boiled under reflux for 2 hours, then, after the mixture has acquired a brown color, was added 200 ml of water. The mixture was cooled and subjected to crystallization to obtain a solid phase, after which it was filtered. The product was purified using ethanol/water and dried to obtain the title compound with a yield of 79%.

IR: νac(HE) 3387 cm-1, νac(-COOCH3) 1725 cm-1, νac(=O), 1657, 1621 cm-1, νac(zone a) 1387, 1361 cm-1, νac(area) 1322, 1278, 1246 cm-1.

Example 2. Synthesis of ethyl 18α-glycyrrhizinate

Method 1: 10 g 18α-glycyrrhizic acid was added in 100 ml of anhydrous ethanol, and then there was added 5 ml of acetylchloride. The reaction mixture is boiled under reflux for 2 hours, then was added 100 ml of water. The mixture was cooled and subjected to crystallization to obtain a solid phase, after which it was filtered. The product was purified using 80%ethanol and dried to obtain the title compound with a yield of 85%.

Method 2: 10 g 18α-glycyrrhizic acid was added to 100 ml of b is wodnego ethanol, then there was added 1 ml of concentrated sulfuric acid. The reaction mixture is boiled under reflux for 8 hours, then was added 100 ml of water. The mixture was cooled and subjected to crystallization to obtain a solid phase, after which it was filtered. The product was purified using ethanol/water and dried to obtain the title compound with a yield of 82%.

1H-NMR (ppm): 0,72 (s, 3H), 0,81 (s, 3H), and 1.00 (s, 3H), 1.14 in (s, 3H), of 1.20 (s, 3H), 1,22 (s, 3H), of 1.26 (t, 3H), of 1.35 (s, 3H), 4,14 (q, 2H), to 5.57 (s, 1H).

13C-NMR (ppm): 14,13; 15,62; 15,94; 16,47; 17,54; 18,49; 20,65; 20,75; 26,65; 27,22; 28,07; 28,40; 31,70; 33,75; 35,45; 35,97; 36,84; 37,60; 39,02; 39,09; 40,37; 42,39; 43,80; 44,89; 54,99; 60,42; 60,66; 78,70; 124,08; 165,64; 178,20; 199,74.

Example 3. Synthesis of ethyl 11-deoxy-18α-glycyrrhetinate

11 g of ethyl 11-deoxy-18α-glycyrrhetinate and 6 g of zinc powder was added in 150 ml of 1,4-dioxane, after which there was added a small amount of water and barbotirovany with gaseous hydrogen chloride. The reaction mixture was stirred for 5 hours, then filtered. The mother liquor is evaporated and to the residue was added 50 ml of water and 100 ml of ethyl acetate. Stirred the mixture and the separated phase. The organic phase is washed with water, evaporated to dryness and purified technical product using ethanol/water to obtain 8.6 g of white crystals.

IR: νac(HE) 3374 cm-1, νac(-COOCH3) 1727 cm-1, νac(zone a) 1382 cm-1, νac(area) 1300, 178 cm -1.

1H-NMR: (ppm) of 0.66 (s, 3H), of 0.79 (s, 3H), of 0.96 (s, 3H), 0,99 (s, 3H), and 1.00 (s, 3H)and 1.15 (s, 3H), 1,22 (s, 3H), 1,25 (t, 3H), of 4.12 (q, 2H), by 5.18 (t, 1H).

13C-NMR (ppm): 14,19; 15,24; 15,69; 15,83; 17,44; 18,30; 20,93; 23,17; 26,28; 27,27; 28,14; 28,73; 32,38; 34,15; 34,96; 36,07; 36,86; 38,11; 38,76; 38,86; 39,46; 39,55; 42,70; 43,67; 47,24; 55,31; 60,20; 79,02; 117,55; 142,09; 179,03.

Example 4. Therapeutic effects of ethyl 11-deoxy-18α-glycyrrhetinate on D-galactosamine-induced acute liver injury model in mice

1. Comparison of therapeutic effects from the introduction of ethyl 11-deoxy-18α-glycyrrhetinate and compound glycyrrhizin on models in male ICR mice.

Methods: 60 male ICR mice were randomly divided into 6 groups of 10 mice in each group: control group, a group of mice that did the injection compound glycyrrhizin (60 mg/kg), the group of mice that were administered the compound glycyrrhizin by infusion into the stomach (240 mg/kg), the group of mice that were administered a high dose of ethyl 11-deoxy-18α-glycyrrhetinate (240 mg/kg), the group of mice that were administered an average dose of ethyl 11-deoxy-18α-glycyrrhetinate (120 mg/kg), a group of mice, which was administered a low dose of ethyl 11-deoxy-18α-glycyrrhetinate (60 mg/kg). Substances mice were administered a dose of 10 ml/kg intraperitoneally or by infusion into the stomach every day for 6 days. The control group mice were treated with equivalent amount of 0.5% Na-CMC through infusion into the stomach. The results present the Lena in the following table.

Table 1
Therapeutic effects of ethyl 11-deoxy-18α-glycyrrhetinate on D-Galn-induced acute liver injury model in mice
GroupDose, mg/kgRoute of administrationNALTAST
IU/mlEngibarov tion, %IU/mlEngibarov tion, %
The control group-infusion into the stomach102084±16191952±1644
Injection connec-tion glycyrrhizin60Intraperitoneal administration10629±422*70523±344*73
240 infusion into the stomach10896±734*57767±638*61
240infusion into the stomach10311±256**85317±214**84
ethyl 11-deoxy-18α - glycyrrhetinate120infusion into the stomach10474±345**77414±340**79
60infusion into the stomach10833±564*60777±533*60
Compared with control group * p<0,05, **p<0,01.

60 male ICR mice were randomly divided into 6 groups of 10 mice in each group: control group, a group of mice that were injected source connection diammonium glycyrrhizinate (240 mg/kg), the group of mice that did the injection of glitzy is resinate diammonium (60 mg/kg), the group of mice that were administered a high dose of ethyl 11-deoxy-18α-glycyrrhetinate (240 mg/kg), the group of mice that were administered an average dose of ethyl 11-deoxy-18α-glycyrrhetinate (120 mg/kg), the group of mice that were administered a low dose of ethyl 11-deoxy-18α-glycyrrhetinate (60 mg/kg). Substances mice were administered continuously for 7 days. The control group mice were treated with equivalent amount of 0.5% Na-CMC. The results are presented in the following table.

Table 2
Therapeutic effects of ethyl 11-deoxy-18α-glycyrrhetinate on D-Galn-induced acute liver injury model in mice
GroupDose, mg/kgRoute of administrationNIU/mlInhibition, %IU/mlEngibarov tion, %
Control-e-infusion into the stomach101949±13071140±799
Glyceri-C is NAT diammonium 60intraperitoneal administration10383±393**80308±389**73
240infusion into the stomach10993±479*49566±291*50
Ethyl 11-deoxy-18α-pitirre-tint240infusion into the stomach10372±440**81266±192**77
120infusion into the stomach10452±432**77292±215**74
60infusion into the stomach10767±739*61353±256**69
Compared with control group * p<0,05 ** p&l; 0,01.

Example 5. Therapeutic effects of ethyl 11-deoxy-18α-glycyrrhetinate on TAA-induced acute liver injury model in mice

50 male ICR mice were randomly divided into 5 groups with 10 mice in each group: control group, a group of mice that were administered the diammonium glycyrrhizinate (240 mg/kg), the group of mice that were administered a high dose of ethyl 11-deoxy-18α-glycyrrhetinate (240 mg/kg), the group of mice that were administered an average dose of ethyl 11-deoxy-18α-glycyrrhetinate (120 mg/kg), the group of mice that were administered a low dose of ethyl 11-deoxy-18α-glycyrrhetinate (60 mg/kg). The control group mice were treated with equivalent amount of 0.5% Na-CMC. The results are presented in the following table.

Table 3
The action of ethyl 11-deoxy-18α-glycyrrhetinate on the serum transaminases in TAA-induced acute liver injury model in mice
ALTACT
GroupDose, mg/kgMethod introduction
of
NIU/mlIngabire-tion, %IU/mlInhibition, %
The control group-Pliva
tion in the stomach
102279±8721717±744
The diammonium glycyrrhizinate240Pliva
tion in the stomach
101568±721311039±623*40
Pliva
tion in the stomach
10992±558**56738±258**57
Ethyl 11-deoxy-18α-glycyrrhetinate120Pliva
tion in the stomach
101117±707**51823±530** 52
Pliva
tion in the stomach
101177±701**48940±582*45
Compared with model group, *p<0,05 **p<0,01

Table 4
The action of ethyl 11-deoxy-18α-glycyrrhetinate to necrosis clearpace in TAA-induced acute liver damage in mice
GroupDose, mg/kgThe way the introduction ofColi-chest-inThe degree of liver cell necrosisThe average degree
01234
The control group-Infusion in Gelu-Doc1001 6302.2
The diammonium glycyrrhizinate240Infusion into the stomach1007300**1.3**
Infusion into the stomach10163001.2**
240
Ethyl 11-deoxy-18α-glycyrrhetinate120infusion into the stomach10154001.3**
60Infusion into the stomach 10145001.4*
Compared with model group, * p<0,05 **p<0,01.

Example 6. Anti-inflammatory action of ethyl 11-deoxy-18α-glycyrrhetinate

By injection of carrageenan caused a swelling of the paws of rats and observed the swelling in order to evaluate the anti-inflammatory effect. When you do this:

(1) Materials

Animals: male rats of SD, 150-180,

Means causing inflammation: carrageenan.

Test drug: ethyl 11-deoxy-1α-glycyrrhetinic was dissolved in 1% Na-CMC to obtain the required concentration.

Medicine for confirmation testing: indomethacin was dissolved in 1% Na-CMC to obtain the required concentration.

(2) Methods

50 rats were randomly divided into 5 groups with 10 rats in each group: control group, group confirmatory testing (administration of indomethacin 10 mg/kg), groups with different doses of the test drugs (30, 60, 120 mg/kg). Drugs animals in each group were injected continuously for 3 days. Prior to the recent introduction of a measured volume of the left hind paw of rats by using a micropipette. Then animals were treated with the test drug or Na-CMC through infusion in the RCU. After 1 hour were injected with freshly prepared carrageenan subcutaneously into the left hind paws of rats in accordance with a dosage of 0.05 ml/paw with a syringe 0.25 ml and needle NO.4. The volume of the left hind paws of rats was measured by the above method at time 1, 3, 4, 5, and 7 hours after dosing, each time the measurement was made twice and calculated averages. The difference between these values before and after the provocation

(3) Statistical analysis

The data presented in the form ofx±s. For comparison the experimental data in each group used a t-test Student for the average for the two samples. P<0.05 or P<0,01 considered as statistically significant.

(4) Results

Within 1 hour after subcutaneous injection of carrageenan paw of the rat was considerably swollen. Table 5 shows that the groups with different doses of the test drug after 4 hours began to decrease swelling of the paws of rats induced by carrageenan.

0,17±0,07**
Table 5
The effect of compounds on carrageenan-induced edema in the paws of rats (Number of rats in group 10)
GroupDose, mg/kgThe degree of swelling of the paws after provocation inflammation (ml)
1 h3 hours4 h5 h7 h
The control group---0,24±0,100,32±0,090,49±0,120,53±0,110,38±0,11
The test medication300,20±0,100,27±0,100,33±0,11*0,39±0,11*0,27±0,12
600,17±0,080,29±0,150,37±0,11*0,37±0,07**0,29±0,09
1200,20±0,050,32±0,110,34±0,09**0,42±0,12*0,28±0,09
Indometacin100,13±0,05**0,24±0,09**0,22±0,06**0,16±0,05**
Compared with control group * p<0,05, ** p<0,01.

(5) Conclusions

The results indicate that a connection is proposed in the present invention can greatly reduce carrageenan-induced paw edema in rats, reduce inflammatory exudate and to possess significant anti-inflammatory action.

Example 7. Protective effect of ethyl 11-deoxy-18a-glycyrrhetinate against BCG+LPS-induced liver injury.

(1) the Test medicine, laboratory animal and equipment

1.1 Drug

Ethyl 11-deoxy-18α-glycyrrhetinate: provided by the laboratory of traditional Chinese medicine, centre of research and development pharmaceutical company Jiangsu Chia tai Tianjin, LLC (Jiangsu Chia Tai Tianqing Pharmaceutical Co., Ltd). Tablets containing befindet: made Beijing United Pharmaceutical Factory (Beijing Union Pharmaceutical factory). The daily dosage for humans is 45 mg, used as medicine for confirmation testing. All drugs were prepared in appropriate concentrations using saline solution in accordance with the requirements of the experiment.

Bacillus is almetta-guérin (BCG): a product of the Institute of biological products in Shanghai. Lipopolysaccharide (LPS): the product of the company Sigma, USA. ACT, ALT set: the product of the Institute of bioengineering Jiang Zheng (Nanjing Jiancheng on) in Nanjing.

1.2 Animals

Cominsky mouse, ordered in laboratory animal center of the University of Chinese Medicine. The amount of drugs for infusion into the stomach of the mouse was 0.25 ml/10 g

1.3 Equipment

Ultrafioletoviy spectrophotometer UV-2650

(3) Method

60 males cominskey mice weighing 18-22 g were randomly divided into 6 groups according to weight: the group of normal control group, model control group control using bifendate, groups with different doses of ethyl 11-deoxy-18α-glycyrrhetinate (240, 120, 60 mg/kg). After adaptive feeding mice for 3 days, each mouse, except for animals in the group of normal control, was injected 5×107live bacteria BCG via the tail vein. On the second day of the animals in each group were injected with saline (group normal control group, model control) or the test drug by injection into the stomach within 7 days. Within 1 hour after the last injection in the stomach of each mouse, with the exception of animals in the group of normal control, was administered 10 μg LPS via the tail vein. Animals in the group of normal control were treated with equivalent volume of saline. After creating the dressed animals left at night on an empty stomach and allowed unlimited access to drinking water within 12 hours, blood sampling was produced by orbital bleeding. The blood was centrifuged with a speed of 2500 rpm for 15 min to separate serum and serum alanine aminotransferase (ALT), were measured aspartataminotransferaza (ACT). Was determined by t-criterion of student groups, see table 6.

Table 6
The action of ethyl 11-deoxy-18α-glycyrrhetinate on liver function in mice with BCG+LPS-induced liver damage(X±s,n=10)
Groupmg/kgAST(IU/l)ALT(IU/l)
Normal controlEquivalent volume of salineof 114.3±20.6to 91.6±3,8
Model controlEquivalent volume of salinereach 232.5±39,6#152,2±19,4#
Befind the t 5,85shall be 152.3±41,6*110,5±11,9*
Ethyl 11-deoxy-18α-glycyrrhetinate240169,3±38,4*89,4±13,2*
120190,1±43,3*to 108.7±20,0*
60227,2±59,7to 105.3±18,61*
Note: compared with the group of normal control, #P<0,05; compared with group model control *P<0,05.

(4) Results

The results indicate that the compound of formula II of the present invention, in particular ethyl 11-deoxy-18α-glycyrrhetinate, has a high activity in relation to the protection of the liver and the reductase activity and can effectively influence the immune factors induced liver damage.

Example 8. Protective effect of the compounds of formula II of the present invention against acetaminophen-induced liver damage in mice

(1) Materials:

Ethyl 11-deoxy-18α-glycyrrhetinate: provided by the laboratory of traditional Chinese medicine, centre of research and development pharmaceutical company Jiangsu Chia tai Tianjin, About What About (Jiangsu Chia Tai Tianqing Pharmaceutical Co., Ltd.). Tablets containing befindet: made Beijing United Pharmaceutical Factory (Beijing Union Pharmaceutical factory). The daily dosage for humans is 45 mg, used as medicine for confirmation testing. All drugs were prepared in appropriate concentrations using saline solution in accordance with the requirements of the experiment. ACT, ALT set: the product of the Institute of bioengineering Jiang Zhang in Nanjing (Nanjing Jiancheng on bioengineering research institute).

(2) Method

60 mice were randomly divided into 6 groups: group normal control, group control using bifendate (a group of drugs with a positive effect), group, model control group with different doses of ethyl 11-deoxy-18α-glycyrrhetinate (240, 120, 60 mg/kg). After adaptive feeding mice for 3 days, each mouse was injected drugs by infusion into the stomach for 10 days (once a day). Animals in the group of normal control and model group were injected with saline in the amount of 0.2 ml/mouse. 6 hours after the last injection the animals in each group, except for animals in the group of normal control, did intraperitoneal injection of acetaminophen in quantities of 400 mg/kg After 12 hours produced blood sampling by orbital bleeding. Measured actionactionlistener (ALT), aspartate aminotransferase (ACT). Was determined by t-test Student groups, see table 7.

Table 7
The effect of the compounds of formula II on the functioning of the liver mouse with minophen-induced liver damage(X±s,n=10)
Groupmg/kgAST (IU/l)ALT (IU/l)
Normal controlEquivalent volume of saline112,5±21,898,1±13,2
Model controlEquivalent volume of saline275,1±33,4#180,2±21,5#
Befindet5,85162,3±31,7*134,6±12,9*
Ethyl 11-deoxy-18α-glycyrrhetinate240 122,3±28,0*119,4±15,2*
120158,1±46,9*133,3±28,7*
60203,5±55,4*172,0±39,8
Note: compared with the group of normal control, #P<0,05; compared with group model control *P<0,05.

(2) the Results

The main reason for acetaminophen-induced liver injury is the fact that the body under the action of P450 enzyme system metabolizes a large number of acetaminophen and produces too much N-acetyl-p-benzoquinoneimine (NAPQI), which leads to reduced levels of hepatic glutathione (GSH), and NAPQI and large molecules (such as proteins) of the liver cells will be covalently contact, thereby causing the necrosis of liver cells. Experimental results indicate that the compound of formula II of the present invention, in particular ethyl 11-deoxy-18α-glycyrrhetinate, can reduce the level of ACT, ALT and effectively protect against acetaminophen-induced liver injury, and it can be used for the treatment of drug liver damage.

1. The compound of formula II

where R1represents H;
R2pre is is a linear or branched C 1-C18alkoxy;
C-18 is in α-configuration; and the compound of formula II is methyl 11-deoxy-18α-glycyrrhetinate.

2. The compound according to claim 1, wherein R2represents a linear or branched C1-C6alkoxy.

3. The compound according to claim 1 represents an ethyl 11-deoxy-18α-glycyrrhetinate.

4. The method of obtaining the compounds of formula I,

where R2represents a linear or branched C1-C18alkoxy;
C-18 is in α-configuration;
the method includes the interaction of R2H in the presence of dehydrating substances with one or more compounds selected from the group comprising glycyrrhizinic acid, salt of glycyrrhizic acid or a derivative of glycyrrhizic acid.

5. The method according to claim 4, characterized in that the specified R2represents a linear or branched C1-C6alkoxy, and specified dehydrating substance is acylchlorides or concentrated sulfuric acid.

6. The method according to claim 5, characterized in that the specified acylchlorides is methylsulfonylamino, benzosulphochloride or p-toluensulfonate.

7. The method according to any of claims 4 to 6, characterized in that the quantitative ratio of glycyrrhizic acid salt is glitzirrizinova acid or a derivative of glycyrrhizic acid to the number of acylchlorides is 1:1-20 by moles

8. The method according to any of claims 4 to 6, characterized in that the quantitative ratio of glycyrrhizic acid, salts of glycyrrhizic acid or a derivative of glycyrrhizic acid to the amount of concentrated sulfuric acid is 1:0.5 to 10 moles.

9. A method of obtaining a compound according to claim 1, comprising: desoxidation the compounds of formula I according to the position C-11, in an organic solvent, while the C-18 is in α-configuration, and

thus R2represents a linear or branched C1-C18in alkoxy.

10. The method according to claim 9, wherein R2represents a linear or branched C1-C6alkoxy.

11. The method according to claim 5, characterized in that desoxidation spend way to restore Clemmenson.

12. Pharmaceutical composition for treating inflammation and/or liver, in which the compound according to any one of claims 1 to 3 is used as the active ingredient, and optionally containing one or more pharmaceutically acceptable carrier.

13. The use of compounds according to any one of claims 1 to 3 to obtain the drug for the treatment of inflammation and/or liver damage.

14. The use of compounds according to any one of claims 1 to 3 for the treatment of inflammation and/or liver damage.

15. The application 14, characterized in that borage is their liver is a drug-induced liver damage.

16. The use of a composition according to item 12 to obtain drugs for the treatment of inflammation and/or liver damage.

17. The use of a composition according to item 12 for the treatment of inflammation and/or liver damage.

18. The application 17, characterized in that the liver is a drug-induced liver damage.



 

Same patents:

FIELD: chemistry.

SUBSTANCE: invention relates to a method of obtaining derivatives of betulin 3,28-disulfate, possessing a property of a complement inhibitor. Sulphation of betulin is carried out in N,N-dimethylformamide with a mixture of sulphamic acid and urea at a temperature of 60-70°C for 2-3 hours, product separation is carried out by cooling of the reaction mass, dilution it with water, extraction with butanol, washing with water, processing of the butanol extract with the following concentration of the butanol layer and separation of the target product. Claimed are 3 versions of processing the butanol extract.

EFFECT: improving properties of derivatives.

4 cl, 4 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to chemical-pharmaceutical industry and concerns a method for preparing a method for preparing betulin 3-acetate-28-sulphate of formula I - that is a biologically active substance being of the utmost interest for medicine. Betulin 3-acetate-28-sulphate is sulphated in N,N-dimethylformamide by a complex of SO3-dimethylformamide at temperature 30-50°C for 1-2 hours to recover an end product.

EFFECT: synthesis of new water-soluble sulphated betulin derivatives, extended range of the sulphatising agent, simplified process ensured by using liquid SO3.

1 cl, 1 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: presented agent - glycoside (1) is a practically non-toxic substance for cells, 12 times less toxic for MT-4 cells than a comparator drug GC (purity 97%) and ensures high-effective inhibition of RNA-dependent DNA-polymerase activity of HIV-1 reverse transcriptase (RT). Also, the present invention provides a method for preparing 3-O-β-D-glucopyranosyl-β-D-glucopyranoside olean-9(11), 12(13)-diene-30-acid (1) which consists in GC recovery by 4.5-5.5-fold sodium boron hydride excess in a mixture of isopropanol-water (1:1), boiling for 1-2 h; it is followed by processing of a reaction mixture with 5% hydrogen chloride (pH 1-2) at 20-22°C and extraction in butanol to produce mixed glycosides (1) and (4) in the relation of 2:1 to be processed by highly acidic cation exchange resins (CU2-8, Dowex 50, amberlite resin IR-120) in the H+- form in 70-75% ethanol and column chromatographic separation on silicagel to prepare the target product.

EFFECT: what is declared is the agent representing 3-O-β-D-glucopyranosyl-β-D-glucopyranoside olean-9(11), 12(13)-diene-30-acid of formula (1) - an analogue of glycyrrhizic acid showing anti-HIV-1 virus activity, inhibiting collection of virus-specific protein p24, and exceeds glycyrrhizic acid by selectivity index (SI) in 4,8 times.

2 cl, 3 ex, 1 tbl

FIELD: chemistry.

SUBSTANCE: method of producing moronic acid involves treating 3β,28-diacetoxyolean-18(19)-ene with an alcoholic solution of an alkali while boiling, followed by separation of the formed 3β,28-dihydroxyolean-18(19)-ene, which is treated with a Jones reagent with molar ratio of 3β,28-dihydroxyolean-18(19)-ene to Jones reagent equal to 1:10 in acetone, mixing the reaction mixture for 4-5 hours at temperature of 0 - +5°C and separating the end product, where 3β,28-diacetoxyolean-18(19)-ene is obtained by reacting allobetulin with acetic acid anhydride in the presence of a catalytic amount of perchloric acid with molar ratio allobetulin: acetic anhydride: perchloric acid equal to 1:100:0.1, while boiling for 15-20 hours and then separating the product.

EFFECT: high efficiency of use.

2 cl, 1 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention relates to chemical-pharmaceutical industry and deals with method of obtaining betulin 3,28-disulfate, biologically active substance which is complement inhibitor and is of great interest for medicine. Betulin sulfation is performed in N,N-dimethylformamide with SO3-dimethylformamide complex at temperature 30-50°C for 3-4 hours, after which reaction mixture is cooled to 10-15°C, diluted with 2-fold volume of 75% water-ethanol solution, containing 4% of sodium hydroxide, inorganic part is separated, and betulin disulfate is isolated in form of sodium salt after evaporation of mother liquor, then recrystallised from ethanol.

EFFECT: improvement of ecological compatibility due to replacement of toxic elements.

1 cl, 1 ex

FIELD: chemistry.

SUBSTANCE: method involves preliminary grinding of birch bark to 0.1 mm particles, followed by hydrolysis while boiling in 15-25% aqueous solution of an alkali with hydromodulus of 8-10 for 2-3 hours. The alkaline hydrolysate is then filtered and washed on a filter with water until neutral water is obtained with subsequent recrystallisation from ethanol or isopropanol. The method enables to achieve 95-97% extraction of betulin from birch bark.

EFFECT: simplification of the method by cutting the number of steps of the process, faster extraction of the end product, avoiding use of highly flammable alcohols.

1 cl, 2 tbl, 1 ex

FIELD: chemistry.

SUBSTANCE: invention relates to bioorganic chemistry and medicine and specifically to novel biologically active lupane-series triterpenoid derivatives (betulin, betulinic acid, betulonic acid), more specifically 6-hydroxy-N'-[3-oxolup-20(29)-en-28-oyl]-2,5,7,8-tetramethyl-3,4-dihydro- 2H-chromene-2-carbohydrazide (1) and 6-hydroxy-N'-[3β-hydroxylup-20(29)-en-28-oyl]-2,5,7,8-tetramethyl-3,4-dihydro-2H-chromene-2-carbohydrazide (2) which exhibits anti-inflammatory activity. Compounds 1 and 2 are hybrid molecules composed of fragments of betulonic acid (3) or betulinic acid (4) and 6-hydroxy-2,5,7,8-tetramethyl-3,4-dihydro-2H-chromene-2-carboxylic acid (Trolox acid) (5) bound by a hydrazide bridge. The compounds are obtained by reacting Trolox acid with a hydrazine monohydrate in pure tetrahydrofuran in the presence of CDI and condensation of a hydrazide derivative (9) with acid chlorides of betulonic acid and betulinic acid (7) and (8), obtained immediately before the reaction through the action of oxalyl chloride on acids (7) and (8). The condensation reaction is carried out in pure CH2Cl2 while boiling for 12 hours using N-ethyl-N'-(3-dimethylaminopropyl)carbodiimide (EDC) (preferably in two-fold molar excess) as a condensation agent with molar ratio of hydrazide 9 to acid chloride 7 or 8 equal to 8-1.1:1.0. Reaction products 1 or 2 are separated by column chromatography on silica gel. Output of hybrid compounds is equal to 65%. In vitro tests of hybrid molecules 1 and 2 and betulinic acid (4) on their effect on production of nitrogen oxide and activity of macrophagal arginase in macrophages, activated by lipopolysaccharides showed that betulinic acid suppressed both production of nitrogen oxide (characteristic M1) and activity of arginase (characteristic M2). Hybrid molecules 1 and 2, unlike betulinic acid, had selective action on macrophages (enabled to obtain macrophages with phenotype M2 while maintaining production of such anti-inflammatory cytokines as IL-10 and TGF-B). Compounds 1 and 2 also exhibited immunoregulating activity since they suppressed Th1-type immune response.

EFFECT: use of such compounds is efficient in different autoimmunie diseases.

3 cl, 6 ex, 2 tbl

FIELD: chemistry.

SUBSTANCE: extract of plant material containing betulin is dissolved in a hydrocarbon solvent or mixtures thereof with boiling point in the range of 120…250°C, heated to boiling and boiled while stirring until complete dissolution of betulin. The insoluble fraction of polyolefins and phytosterols is separated by hot filtration of the obtained solution and dried in a vacuum at temperature 80°C. The filtrate is then cooled to temperature 0…5°C, wherein the precipitated betulin is filtered and also dried in a vacuum at temperature 80°C. Also, the mixture of hydrocarbons of the solvent can contain up to 20% aromatic hydrocarbons.

EFFECT: method achieves more complete extraction and separation of products of processing plant maerial.

2 cl, 2 ex, 1 tbl

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention relates to pharmaceutical industry, in particular to method of obtaining betulinic acid. Method of obtaining betulinic acid, including betulin dispersing in donor coordinating solution, oxidation of betulin by chrome (IV) compound in presence of aluminium sulfate under specified conditions, purification of obtained betulonic acid and its reduction by sodium borohydride in isopropyl alcohol to betulinic acid.

EFFECT: method makes it possible to increase target product output.

5 cl, 1 tbl, 4 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to a chemical compound, namely N-[3-oxo-lupano-28-yl]-morpholine of formula (1): possessing antitumour and antimetastatic activity and representing a corrector of hepatotoxic damages caused by a tumour process and cytostatic polychemotherapy, and may be applicable in medicine as a pharmaceutic agent for reducing manifestation of morphological liver damages accompanying oncological diseases, including as a part of the integrated antitumour therapy.

EFFECT: preparation of the chemical compound possessing antitumour and antimetastatic activity.

1 cl, 10 ex, 6 tbl, 3 dwg

FIELD: chemistry.

SUBSTANCE: invention relates to a method of obtaining derivatives of betulin 3,28-disulfate, possessing a property of a complement inhibitor. Sulphation of betulin is carried out in N,N-dimethylformamide with a mixture of sulphamic acid and urea at a temperature of 60-70°C for 2-3 hours, product separation is carried out by cooling of the reaction mass, dilution it with water, extraction with butanol, washing with water, processing of the butanol extract with the following concentration of the butanol layer and separation of the target product. Claimed are 3 versions of processing the butanol extract.

EFFECT: improving properties of derivatives.

4 cl, 4 ex

FIELD: chemistry.

SUBSTANCE: described is a method of producing betulin from birch bark which involves extracting crushed birch bark with an organic solvent, concentrating the extract, precipitating betulin by adding hot water, filtering and drying. The extraction process is carried out in a microwave field.

EFFECT: betulin obtained using said method can be used to produce pharmaceutical preparations.

4 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to A-pentacyclic triterpenoids of general formula: , wherein R=H, R1= , or ; R=NH2, R1= or .

EFFECT: compounds exhibit antiviral activity, including against type I herpes simplex virus (HSV-1, strain 1 C), HSV-1 and HIV-1, and may be also used as intermediates for new biologically active compounds.

3 cl, 2 tbl, 7 ex

FIELD: chemistry.

SUBSTANCE: invention relates to a method of producing 16α, 17α-cyclohexanopregn-5-en-3β-ol-20-one acetate of formula I , by hydrogenating 16α, 17α-cyclohex-3',4'-enopregn-5-en-3β-ol-20-one acetate in the medium of a polar organic solvent in the presence of a palladium catalyst on a support made from highly porous high-strength material based on the gamma-form of aluminium oxide, on which palladium is deposited in amount of 0.2-5%; the process is carried out at hydrogen pressure of 2-10 atm.

EFFECT: simple and considerably shorter duration of the process.

2 cl, 8 ex

FIELD: chemistry.

SUBSTANCE: described is an effective low-toxicity agent, which is methyl ether of 2-cyano-3,12-dioxo-18βH-olean-1(2),11(9)-dien-30-ic acid of formula (I): having anti-oxidant, anti-inflammatory, neuroprotective, hypolipidemic, hypocholesterolemic, hypoglycemic, hepatoprotective and immunosuppressive activity.

EFFECT: agent has low toxicity and is synthesised based on readily available plant material.

1 cl, 13 ex, 16 tbl

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to chemical-pharmaceutical industry and concerns a method for preparing allobetulin 3-sulphate sodium salt that is a biologically active substance being of the utmost interest for medicine. Allobetulin is sulphated in N,N-dimethylformamide by the SO3-dimethylformamide complex at temperature 30-50°C for 4-5 hours and thereafter processed in 75% water-ethanol solution containing 4% sodium hydroxide to pH 7-8 to recover an end product.

EFFECT: synthesis of new water-soluble sulphated betulin derivatives, extended range of the sulphatising agent, simplified process ensured by using liquid SO3.

1 cl, 1 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to chemical-pharmaceutical industry and concerns a method for preparing allobetulin 3-sulphate sodium salt that is a biologically active substance being of the utmost interest for medicine. Allobetulin is sulphated in N,N-dioxane by the SO3-dioxane complex at temperature 30-50°C for 4-6 hours and thereafter processed in 75% water-ethanol solution containing 4% sodium hydroxide to pH 7-8 to recover an end product.

EFFECT: synthesis of new water-soluble sulphated betulin derivatives, extended range of the sulphatising agent, simplified process ensured by using liquid SO3.

1 cl, 1 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to chemical-pharmaceutical industry and concerns a method for preparing betulin 3-acetate-28-sulphate sodium salt that is a biologically active substance being of the utmost interest for medicine. Betulin 3-acetate is sulphated in 1,4-dioxane by the SO3-dioxane complex at temperature 20-30°C for 2-3 hours; the reaction mixture is thereafter processed in 75% water-ethanol solution containing 4% sodium hydroxide to pH 7-8 to recover an end product.

EFFECT: synthesis of new water-soluble sulphated betulin derivatives, extended range of the sulphatising agent, simplified process ensured by using liquid SO3.

1 cl, 1 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to chemical-pharmaceutical industry and concerns a method for preparing betulinic acid 3-sulphate disodium salt that is a biologically active substance being a complement inhibitor and being of the utmost interest for medicine. Betulinic acid is sulphated in 1,4-dioxane by the SO3-dioxane complex at temperature 30-50°C for 4-5 hours; the reaction mixture is thereafter processed in 75% water-ethanol solution containing 4% sodium hydroxide to pH 7-8 to recover an end product.

EFFECT: extended range of the sulphatising agent, simplified process ensured by using liquid SO4.

1 cl, 1 ex

FIELD: chemistry.

SUBSTANCE: method of producing 16α,17α-cyclohexano-5,6-epoxypregn-3β-ol-20-one acetate involves treatment of 16α,17α-cyclohexanopregn-5-en-3β-ol-20-one acetate with p-carbomethoxyperbenzoic acid in a medium of polar methylene chloride and the process is carried out at temperature of 25-30°C and molar ratio of 16α,17α-cyclohexanopregn-5-en-3β-ol-20-one acetate: p-carbomethoxyperbenzoic acid of 1:1.1-1.5. The end product contained in the solution is easily separated after filtering the p-carbomethoxybenzoic acid precipitate.

EFFECT: safety and simplification of the disclosed method and increase in directivity of the process towards obtaining an -isomer of the end product; invention can be used to produce an intermediate product during synthesis of pregnane steroid hormones which are valuable hormonal agents used in medicine.

2 cl, 4 ex

FIELD: chemistry.

SUBSTANCE: analgesic peptide has the following amino acid sequence: H2N-Ile1-Ser2-Ile3-Asp4-Pro5-Pro6-Cys7-Arg8-Phe9-Cys10-Tyrll-Hisl2-Arg13-Aspl4-Glyl5-Serl6-Glyl7-Asnl8-Cys19-Val20-Tyr21-Asp22-Ala23-Tyr24-Gly25-Cys26-Gly27-Ala28-Val29-COOH. Said peptide can be used as a medicinal agent for treating pathologies associated with tissue acidosis and treating neurologic diseases associated with ASIC3 receptor function, as well as for determining the topology and molecular mechanisms of the function of the ASIC3 channel, and in test systems for detecting and testing novel anti-pain preparations, agonists and antagonists of the ASIC3 receptor.

EFFECT: analgesic action owing to inhibition of the functional activity of proton-activated ion channels.

9 dwg, 11 ex

Up!