TWI448471B - Synthesis of Glycyrrhizic Acid Ester Derivatives and Deoxy Glycyrrhizic Acid Ester Compounds - Google Patents

Description

Method for synthesizing glycyrrhetinic acid derivatives and deoxyglycyrrhetinate compound

The present invention relates to a method for directly synthesizing glycyrrhetinic acid using glycyrrhizic acid, and further relates to a 11-deoxy-18α-glycyrrhetinic acid ester compound and a preparation method thereof, and a pharmaceutical composition comprising 11-deoxy-18α-glycyrrhetinate And its application in the treatment of liver damage and inflammation.

Glycyrrhiza uralensis is the root and stem of leguminous licorice, and its main pharmacological active substance is glycyrrhizic acid and its glycosidic acid Glycyrrhetinic acid. Modern research shows that glycyrrhetinic acid has many effects such as anti-inflammatory, anti-ulcer, anti-virus (hepatitis virus, AIDS, etc.), blood fat reduction, and prevention and treatment of tumors.

Glycyrrhetinic acid is structurally similar to hydrocortisone, and many clinical trials have demonstrated that glycyrrhetinic acid has anti-inflammatory effectiveness. Zakirov's study found that 3-amino-11-deoxyglycyrrhetinic acid showed significant anti-inflammatory activity against aseptic arthritis in various animals. Toyoshima et al. prepared 11-deoxyglycyrrhetinic acid maleate and its salts as an anti-inflammatory agent, and also as an anti-ulcer agent and an immunomodulator, see U.S. Patent No. 4,448,788. It has been reported in the literature that a salt of glycyrrhetinic acid such as sodium glycyrrhetinate has an anti-inflammatory effect.

In 1946, Revers first reported the anti-ulcer effect of licorice. Scientific researchers have synthesized glycyrrhetinic acid succinate half-sodium disodium salt and found it to cure stomach ulcers (see UK Patent Publication No. GB843133). In 1972, the French Demande study found that 3-acetamido-18β-glycyrrhetic acid and its aluminum salt were effective in the treatment of duodenal ulcer and gastric ulcer. In addition, the therapeutic effects of 11-deoxyglycyrrhetinic acid amide and 3-oxo-ethylglycine glycosic acid decylamine on ulcer disease are also very noticeable. In 1985, Takizawa et al. in Japan found that glycyrrhetinic acid inhibited the proliferation of murine skin tumors (Jpn J Cancer Res. 1986 77(1) P33-8).

However, glycyrrhetinic acid and its derivatives have aldosterol (DCA) activity, which is often accompanied by side effects in clinical use. For example, glycyrrhetinic acid preparation can cause sodium retention, high blood pressure and low potassium alkaline poisoning. John S. Baran et al. found that 11-deoxyglycyrrhetinic acid has substantially no aldosterol activity and thus has no such side effects (John S. Baran et al. Journal of Medicinal Chemistry, 1974, Vol. 17, (2) P184 -191). In order to overcome or alleviate these side effects and improve the solubility and absorption of glycyrrhetinic acid, and make it easy to make a suitable type of preparation, domestic and foreign scholars have modified and modified glycyrrhetinic acid to synthesize a series of licorice Acid derivative (Soo-Jong Um et al. Bioorganic & Medicinal Chemistry 2003, 11, P5345-5352).

In the synthesis of glycyrrhetinic acid derivatives, glycyrrhetinic acid is mainly prepared by glycyrrhizic acid, and then the structure of glycyrrhetinic acid is chemically modified and modified. A literature on the use of glycyrrhizic acid as a precursor and hydrothermal synthesis of methyl glycyrrhetinate has been reported in the literature (Liu Wencong, Luo Yunqing, et al. Hydrothermal synthesis of methyl glycyrrhetinate), Journal of Northeast Normal University: Natural Science Edition , 2007, 39(4): 154-156), but the method needs to be carried out under high temperature and high pressure, the reaction time is long, the equipment requirements are high, and it is not suitable for industrialization. produce. The inventors have found that a simple method for directly producing glycyrrhetinic acid derivatives of glycyrrhizic acid or a salt derivative thereof requires only one step of reaction, and it is not necessary to obtain glycyrrhetinic acid first, and then the modification is carried out. The method uses a low temperature. No need for high pressure, high yield, low cost, suitable for industrial production.

The present inventors further obtained the 11th carbon deoxygenated glycyrrhetinic acid ester, specifically 11-deoxy-18α-glycyrrhetinate, on the basis of simple synthesis of the glycyrrhetinic acid ester derivative. These 11-deoxy-18α-glycyrrhetinic acid have anti-inflammatory and anti-ulcer activities, and also have activity for treating liver damage; and have reduced side effects, good fat solubility, and high absorption and utilization of the human body.

The present invention relates to a compound of the formula II, that is, 11-deoxy-18α-glycyrrhetinate, a preparation method thereof, and a composition formed by mixing the same with a pharmaceutical carrier, and the above substances in the fields of treating inflammation, ulcers and liver damage Applications. The present invention also relates to a method for synthesizing a glycyrrhetinate derivative.

The compounds of formula II to which the invention relates are as follows:

Wherein, R ₁ is H, linear or branched C ₁ -C ₁₈ alkyl methyl acyl, linear or branched C ₁ -C ₁₈ alkenyl, acyl or aryl carboxylic acyl methyl; R ₂ is A linear or branched C ₁ -C ₁₈ alkoxy or aryloxy group having an 18th carbon position in an alpha configuration or a beta configuration.

R ₁ is preferably H, linear or branched C ₁ -C ₆ acyl group A, or a linear or branched C ₁ -C ₆ alkenyl carboxylic acyl, more preferably H; R ₂ representing Preferably, it is a linear or branched C ₁ -C ₆ alkoxy group, more preferably an ethoxy group; and the 18th carbon position is preferably an α configuration.

The compound of formula II of the present invention is preferably 11-deoxy-18?-glycyrrhetic acid ethyl ester.

The present invention also provides a method of synthesizing a compound of formula II by subjecting the 11th carbon position of the compound of formula I below to deoxygenation to give the corresponding compound of formula II wherein R1 is hydrogen. If desired, the third carbon position hydroxyl group can be further esterified to give the corresponding compound of formula II, as shown in formula I below.

In formula I, R ₂ is a linear or branched C ₁ -C ₁₈ alkoxy or aryloxy group, and the 18th carbon position is in the alpha or beta configuration.

The means of deoxygenation is carried out using reduction methods well known to those skilled in the art including, but not limited to, Clemmensen reduction, catalytic hydrogenation, and the like. The Clemmensen reduction method uses zinc amalgam and hydrochloric acid to reduce the carbonyl group at the 11th carbon position to a methylene group, and the solvent used may be tetrahydrofuran, 1,4-dioxane or the like; catalytic hydrogenation may be used. A commonly used catalyst such as platinum, palladium or an oxide thereof may be, for example, methanol, ethanol, 1.4-dioxane, tetrahydrofuran or the like. The hydroxyesterification can be carried out by using a carboxylic acid or a carboxylic acid anhydride, and the reaction is carried out in an inert organic solvent such as 1,4-dioxane or tetrahydrofuran, and the temperature of the reaction is selected depending on the carboxylic acid or carboxylic anhydride used.

The compounds of formula I are either commercially available or can be prepared by the synthetic methods provided herein.

The method for synthesizing a compound of the following formula I provided by the present invention,

Wherein R _{2 is} as defined above, the step comprising: using one or more of an alkyl alcohol or an aromatic alcohol (R ₂ H) and a glycyrrhizic acid, a glycyrrhizic acid or a glycyrrhizic acid derivative in the presence of a dehydrating agent such as hydrazine or concentrated sulfuric acid The reaction is carried out to prepare a glycyrrhetinic acid ester of the formula I. Among them, glycyrrhizinate can be enumerated as potassium, sodium, ammonium, calcium or magnesium salt of glycyrrhizic acid.

Glycyrrhizic acid, glycyrrhizic acid or glycyrrhizic acid derivatives can be purchased directly, or can be obtained as a salt or a derivative by extracting glycyrrhizic acid from licorice. Among them, 18α-glycyrrhizic acid can be obtained by catalytic isomerization of natural glycyrrhizinate by the method of ZL02111693.8.

The ruthenium chloride may be grass chlorobenzene, acetamidine chloride or sulfonium chloride, and the sulfonium chloride may be sulfonium chloride, benzene sulfonium chloride or p-toluene sulfonium chloride. Each of the 1 molar glycyrrhizic acid, glycyrrhizic acid, or glycyrrhizic acid derivative requires 1 to 20 moles of bismuth chloride, 0.5 to 10 moles of concentrated sulfuric acid, and 3 to 5 moles of bismuth chloride. Mohr, the amount of concentrated sulfuric acid is preferably 0.5 to 5 moles.

In the method of synthesizing the glycyrrhetinic acid of the formula I, the reaction is carried out in a solvent Or, taking the alcohol participating in the reaction as a solvent, the reaction solvent is a solvent capable of dissolving glycyrrhizic acid, glycyrrhizic acid salt and/or glycyrrhizic acid derivative, such as N,N-dimethylformamide, N-methylpyrrolidone, Tetrahydrofuran and the like. When the alkyl alcohol is a lower alcohol, it is preferred to use the alcohol participating in the reaction as a solvent.

In a specific embodiment, the method for preparing the glycyrrhetinic acid ester of the formula I comprises: adding glycyrrhizic acid, glycyrrhizic acid or glycyrrhizic acid derivative to anhydrous ethanol, adding concentrated sulfuric acid or hydrazine chloride, heating under reflux, cooling, and crystallizing out Solid, filtered, refined with ethanol / water, dried to give the target compound; or add glycyrrhizic acid or glycyrrhizic acid salt to anhydrous methanol, add ethyl hydrazine chloride, heat to reflux, cool, crystallize solid, filter, refine with ethanol / water , drying, to obtain the target compound.

The term "linear or branched C ₁ -C ₁₈ alkyl" refers to a straight or branched saturated aliphatic hydrocarbon group consisting of a carbon atom and a hydrogen atom, which is bonded to the remainder of the molecule by a single bond. The alkyl group has 1 to 18 carbon atoms, preferably 1 to 6 carbon atoms. The alkyl group may be unsubstituted or substituted by one or more substituents selected from the group consisting of a halogen and a hydroxyl group. Examples of unsubstituted alkyl groups include, but are not limited to, methyl, ethyl, propyl, 2-propyl, n-butyl, isobutyl, tert-butyl, n-pentyl, 2-methylbutyl, neopentyl. , n-hexyl, 2-methylhexyl and so on.

The term "linear or branched C ₁ -C ₁₈ alkenyl" refers to a straight or branched, unsaturated aliphatic hydrocarbon group consisting of a carbon atom and a hydrogen atom, which contains at least one unsaturated bond by means of A single bond is attached to the rest of the molecule. The alkenyl group has 1 to 18 carbon atoms, preferably 1 to 6 carbon atoms. The alkenyl group may be unsubstituted or substituted by one or more substituents selected from halogen, hydroxy or carboxy. Examples of unsubstituted alkenyl groups include, but are not limited to, ethenyl, propenyl, propen-2-yl, n-butenyl, isobutenyl, n-pentenyl, 2-methylbutenyl, n-hexenyl, 2- Methylhexenyl and the like.

The term "aryl" refers to an all-carbon monocyclic or fused polycyclic aromatic ring group having a fully conjugated π-electron system having from 6 to 14 carbon atoms, preferably from 6 to 12 carbon atoms. Most preferably it has 6 carbon atoms. The aryl group may be unsubstituted or substituted with one or more selected from the group consisting of an alkyl group, an aryl group, an aralkyl group, an amine group, a halogen, and a hydroxyl group. Examples of unsubstituted aryl groups include, but are not limited to, phenyl, naphthyl, and anthracenyl.

The invention also provides the use of a compound of formula II and a composition comprising a compound of formula II for the treatment of one or more of inflammation, ulceration and liver damage.

The compounds of formula II of the present invention may be administered alone, and are, of course, generally in the form of a pharmaceutical formulation comprising at least one of the compounds of formula II as an active ingredient, and one or more pharmaceutically acceptable carriers. These carriers vary depending on the mode of administration. Formulations comprising a compound of the invention may be administered topically or systemically, including orally, rectally, nasally, sublingually, dermally, vaginally, and the like.

Oral compositions can be solid, gel or liquid. Examples of solid preparations include, but are not limited to, tablets, capsules, granules, and bulk powders. These preparations may optionally contain a binder, a diluent, a disintegrant, a lubricant, a glidant, a sweetener, and/or a flavoring agent, and the like.

The invention also provides a veterinary composition comprising at least one of the above active ingredients and at least one veterinary carrier, which may be for cattle, horses, Materials for administration to sheep, cats, dogs, horses, rabbits or other animals are solid, liquid or gaseous materials acceptable to the active ingredient in the veterinary art. These veterinary compositions can be administered by oral and parenteral routes. .

The present inventors synthesized glycyrrhetinate by a simple method, and in particular, synthesized 11-deoxy-18α-glycyrrhetinate. 11-Deoxy-18α-glycyrrhetinic acid has anti-inflammatory and anti-ulcer activity; it can be used for treating liver damage, inhibiting hepatocyte necrosis and protecting liver damage, and has the prospect of treating liver disease; especially for acute liver injury and drugs Hepatic injury has a therapeutic effect, and has low side effects, good fat solubility, easy absorption, and high absorption and utilization. Compared with glycyrrhizin and diammonium glycyrrhizinate, the bioavailability is high, and the enzyme-reducing effect is obvious.

The compound of the formula II of the present invention has an anti-inflammatory action and a therapeutic effect on drug-induced liver damage. In addition, the compound of the formula II of the present invention, especially the preferred compound, is effective for liver damage caused by D-Galn, can effectively inhibit the elevation of serum transaminase, and is superior to glycyrrhizin and diammonium glycyrrhizinate, especially for oral administration. . Moreover, it is also effective for liver damage caused by TAA, can effectively inhibit the elevation of serum transaminases, and is superior to diammonium glycyrrhizinate, which can inhibit hepatocyte necrosis and is superior to diammonium glycyrrhizinate.

The simple synthesis method of the present invention directly uses glycyrrhizic acid or a derivative thereof as a starting material, and obtains glycyrrhetinic acid ester by a simple and high-yield method, thereby obtaining a glycyrrhetinic acid ester which is deoxygenated at the 11th carbon position. It is conducive to the full utilization of natural resources licorice and reduces waste of resources.

The invention is illustrated by the following examples, which are not intended to limit the scope of the invention.

The reagents used in the specific examples below are all analytically pure reagents.

Instrument: Infrared spectroscopy was carried out by PE's Spectrum one Fourier transform infrared spectrometer using KBr pellets; ¹ H NMR, ¹³ C-NMR spectra using BRUKER AV-500 NMR spectrometer, solvent: CDCl ₃ , TSM as internal standard .

Example 1: Synthesis of 18β-glycyrrhetinate methyl ester

Method 1: 10 g of 18β-glycyrrhizic acid was added to 100 ml of anhydrous methanol, 5 ml of ethyl hydrazine chloride was added, and the mixture was heated under reflux for 2 hours. 100 ml of water was added thereto, and the solid was crystallized, filtered, purified by ethanol/water, and dried to give the title compound. The recovery rate was 82%.

Method 2: 20 g of 18β-glycyrrhizic acid monoammonium salt was added to 100 ml of anhydrous methanol, 10 ml of ethyl hydrazine chloride was added, and the mixture was heated under reflux for 2 hours, the color became brown, 200 ml of water was added, and the solid was crystallized, filtered, and refined with ethanol/water. , dried, the obtained compound, the recovery was 79%.

IR: νas(-OH)3387cm ^-1 , νas(-COOCH ₃ )1725cm ^-1 , νas(=O)1657, 1621cm ^-1 , νas (A area) 1387, 1361cm ^-1 , νas (B area) 1322 1278, 1246cm ^-1 .

Example 2: Synthesis of 18α-glycyrrhetinic acid ethyl ester

Method 1: 10 g of 18α-glycyrrhizic acid was added to 100 ml of absolute ethanol, 5 ml of ethyl hydrazine chloride was added, and the mixture was heated under reflux for 2 hours, and 100 ml of water was added thereto. After cooling, the solid was crystallized, filtered, purified with 80% ethanol and dried to give the title compound.

Method 2: Add 10 g of 18α-glycyrrhizic acid to 100 ml of absolute ethanol, add 1 ml of concentrated sulfuric acid, heat to reflux for 8 hours, add 100 ml of water, cool, crystallize solid, filter, refine with ethanol/water, and dry to obtain the target compound, and recover. The rate is 82%.

¹ H-NMR (ppm): 0.72 (s, 3H), 0.81 (s, 3H), 1.00 (s, 3H), 1.14 (s, 3H), 1.20 (s, 3H), 1.22 (s, 3H), 1.26 (t, 3H), 1.35 (s, 3H), 4.14 (q, 2H), 5.57 (s, 1H).

¹³ C-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 11-deoxy-18α-glycyrrhetinic acid ethyl ester

11 g of 18α-glycyrrhetinic acid ethyl ester and 6 g of zinc powder were added to 150 ml of 1,4-dioxane, a little water was added thereto, hydrogen chloride gas was introduced, and the reaction was stirred for 5 hours. Filtration, evaporation of the solvent from the mother liquid, stirring with 50 ml of water and 100 ml of ethyl acetate, layering, and the organic layer was washed with water, evaporated, and evaporated with EtOAc.

IR: νas (-OH) 3374 cm ^-1 , νas (-COOCH 3 ) 1727 cm ^-1 , νas (A region) 1382 cm ^-1 , νas (B region) 1300, 1278 cm ^-1 .

¹ H-NMR: (ppm) 0.66 (s, 3H), 0.79 (s, 3H), 0.96 (s, 3H), 0.99 (s, 3H), 1.00 (s, 3H), 1.15 (s, 3H), 1.22 (s, 3H), 1.25 (t, 3H), 4.12 (q, 2H), 5.18 (t, 1H).

¹³ C-NMR (ppm): 14.19, 15.24, 15.69, 15.83, 17.44, 18.30, 20.93, 23.17, 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 effect of 11-deoxy-18α-glycyrrhetinic acid ethyl ester on D-Galn acute liver injury model mice

(1) 11-Deoxy-18α-glycyrrhetinic acid ethyl ester and compound glycyrrhizin injection were compared in the D-Galn acute liver injury model of ICR male mice.

Test method: 60 ICR male mice were randomly divided into 6 groups, 10 in each group: control group, compound glycyrrhizin injection group (60 mg/kg), compound glycyrrhizin gavage group (240 mg/kg), 11- Deoxy-18α-glycyrrhetinic acid ethyl ester high dose group (240mg/kg), medium dose group (120mg/kg), low dose group (60mg/kg). Each group was intraperitoneally injected (IP) or intragastrically (IG) in a volume of 10 ml/kg for 6 days, and the control group was given an equal amount of 0.5% CMC-Na by intragastric administration. The results are as follows:

(2) 60 ICR male mice were randomly divided into 6 groups, 10 in each group: control group, diammonium glycyrrhizinate raw material group (240mg/kg), diammonium glycyrrhizinate injection group (60mg/kg), 11- Deoxy-18α-glycyrrhetinic acid ethyl ester high dose group (240mg/kg), medium dose (120mg/kg), low dose group (60mg/kg), continuous administration for 7 days, control group IG given an equal amount of 0.5% CMC-Na. The results are as follows:

Example 5: Therapeutic effect of 11-deoxy-18α-glycyrrhetinate on mice with acute liver injury model of TAA

50 ICR male mice were randomly divided into 5 groups, 10 in each group: control group, diammonium glycyrrhizinate group (240 mg/kg), 11-deoxy-18α-glycyrrhetinic acid ethyl ester high dose group (240 mg/kg) In the middle dose group (120 mg/kg) and the low dose group (60 mg/kg), the control group IG was given an equal amount of 0.5% CMC-Na. The results are as follows:

Example 6: Anti-inflammatory effect of 11-deoxy-18α-glycyrrhetinic acid ethyl ester

Injection of carrageenan in rats' ankles caused swelling and observed the anti-inflammatory effects of the drug. among them:

(1) Experimental materials

Animals: male SD rats, 150-180 g; inflammatory agent: carrageenan; test substance: 11-deoxy-18α glycyrrhetinic acid ethyl ester was formulated with 1% CMC-Na to the desired concentration; positive Drug: indomethacin, formulated with 1% CMC-Na to the desired concentration;

(2) Experimental method

50 rats were randomly divided into 5 groups and 10 mice in each group. The control group, the positive group (administering indomethacin 10 mg/kg), and the test drug each dose group (30, 60, 120 mg/kg). Each group of animals was administered continuously for 3 days. Before the last administration, the volume of the left hind paw of the rats before administration was measured by micropipette measurement. Then, the drug or CMC-Na was administered by intragastric administration, and after 1 hour, the freshly prepared carrageenan was aspirated with a 0.25 ml syringe, and the needle was injected into the left hind paw of the rat with a 4 gauge needle, 0.05 ml/paw, and then at 1, 3, respectively. At 4, 5, and 7 hours, the left hind paw volume of the rats was measured twice in the same manner, and the average value was taken. The difference in the volume of the foot before and after the inflammation was the degree of swelling.

(3) Statistical processing

Measurement data ±s indicates that the experimental data of each group were compared using the t-test of two sample means. p < 0.05 or p < 0.01 was considered statistically significant.

(4) Experimental results

Rats had a significant swelling 1 h after subcutaneous injection of carrageenan. It can be seen from Table 5 that each dose of the test drug can significantly inhibit rat paw swelling caused by carrageenan at 4 hours.

(5 Conclusion

The results of the present experiment show that the compound of the present invention can effectively inhibit rat paw swelling caused by carrageenan, reduce inflammatory exudation, and has a significant anti-inflammatory effect.

Example 7: Protective effect of 11-deoxy-18α-glycyrrhetinic acid ethyl ester on liver injury induced by BCG+LPS

(1) Experimental drugs, laboratory animals and experimental instruments

1.1 Drugs:

11-Deoxy-18α glycyrrhetinic acid ethyl ester: provided by the Chinese Medicine Laboratory of the R&D Center of Jiangsu Zhengda Tianqing Pharmaceutical Co., Ltd. Biphenyl diester dropping pills: produced by Beijing Union Pharmaceutical Factory. The daily dose was 45 mg as a positive control. The drugs were formulated to the appropriate concentration with physiological saline according to the experimental requirements.

BCG (BCG): Shanghai Institute of Biological Products. Lipopolysaccharide (LPS): American Sigma product. AST, ALT kit: Nanjing Institute of Bioengineering.

1.2 animals

Kunming mice were purchased from the Experimental Animal Center of China Pharmaceutical University. The volume of the mouse drug solution was 0.25 ml/10 g.

1.3 instruments

UV spectrophotometer UV-265.

(2) Experimental method

A total of 60 Kunming mice, 18 to 22 g, were randomly divided into six groups according to body weight: normal control group, control group, bifendate control group, and each dose of 11-deoxy-18α glycyrrhetinic acid. Ethyl ester group (240, 120, 60 mg/kg). After 3 days of adaptive feeding in each group, 5×10 ⁷ live bacteria were injected into the tail vein of each group except for the normal control group. On the second day, the animals in each group were given normal saline (normal control group and control group) or test drugs for 7 consecutive days. One hour after the last gavage, 10 μg of LPS was injected into the tail vein once per mouse except the normal group. The normal control group was injected with the same amount of normal saline twice in the same manner. When the time to be sampled was reached, the animals were fasted, and 12 hours after free drinking, blood was taken from the eyelids, and serum was separated by centrifugation at 2500 rpm for 15 minutes to measure serum alanine aminotransferase (ALT) and aspartate aminotransferase (AST). Results Inter-group t-test, see Table 6:

(3) Experimental results

It can be seen from the experimental results that the compound of the formula II of the present invention, particularly 11-deoxy-18α glycyrrhetinic acid ethyl ester, has a good liver-protecting enzyme-lowering effect and can effectively treat liver cell damage caused by immune factors.

Example 8: Protective effect of the compound of formula II of the present invention on liver injury induced by acetaminophen in mice

(1) Test materials

11-Deoxy-18α glycyrrhetinic acid ethyl ester: provided by the Chinese Medicine Laboratory of the R&D Center of Jiangsu Zhengda Tianqing Pharmaceutical Co., Ltd. Biphenyl diester dropping pills: produced by Beijing Union Pharmaceutical Factory. The daily dose was 45 mg as a positive control. Acetaminophen: produced by Jinzhou Biochemical Pharmaceutical Factory. The drugs were formulated to the appropriate concentration with physiological saline according to the experimental requirements. AST, ALT kit: Nanjing Institute of Bioengineering.

(2) Experimental method:

Sixty mice were randomly divided into 6 groups: normal control group; biphenyl diester group (positive drug group); control group; each dose of 11-deoxy-18α glycyrrhetinic acid ethyl ester group (240, 120, 60 mg) /kg); After 3 days of adaptive feeding of each group of animals, each group of animals was administered with continuous intragastric administration for 10 days (1 time/day), and normal control group and control group were given normal saline, 0.2 ml/each. After the last administration for 6 hours, except for the normal control group, the other groups were intraperitoneally injected with 400 mg ‧ kg ^-1 acetaminophen. After 12 hours, blood was taken from the ocular vein to measure the activity of ALT and AST. Results Inter-group t-test, see Table 7:

(3) Experimental results

The liver damage caused by acetaminophen is mainly caused by the large amount of acetaminophen being metabolized in the body by the P450 enzyme system to produce excessive N-acetic acid-p-benzoquinone imine (NAPQI), which leads to the depletion of intrahepatic glutathione (GSH). NAPQI forms a covalent bond with hepatocyte macromolecules (such as proteins), causing hepatocyte necrosis. The experimental results show that the compound of the formula II of the present invention, especially 11-deoxy-18 α glycyrrhetinic acid ethyl ester can reduce AST, ALT, effectively protect liver cell damage caused by acetaminophen, and can be used for treating liver damage caused by drugs.

The above is intended to be illustrative only and not limiting. Any equivalent modifications or alterations to the spirit and scope of the invention are intended to be included in the scope of the appended claims.

Claims (11)

a compound having the following formula II, Wherein, R ₁ is H, linear or branched C ₁ -C ₁₈ alkyl methyl acyl, linear or branched C ₁ -C ₁₈ alkenyl, acyl or aryl carboxylic acyl methyl; R ₂ is Ethoxy; the 18th carbon position is the alpha configuration. The compound of claim 1, wherein the compound is 11-deoxy-18α-glycyrrhetinic acid ethyl ester. A method of preparing a compound of formula I, Wherein R ₂ is a linear or branched C ₁ -C ₁₈ alkoxy or aryloxy group; the 18th carbon position is in the α or β configuration; the method comprises: R ₂ in the presence of a dehydrating agent H is reacted with one or more of glycyrrhizic acid, glycyrrhizic acid or glycyrrhizic acid derivatives, wherein the dehydrating agent is hydrazine or concentrated sulfuric acid, and hydrazine is methyl sulfonium chloride, benzene sulfonium chloride or p-toluene sulfonium chloride . The method of claim 3, wherein the ratio of glycyrrhizic acid, glycyrrhizic acid or glycyrrhizic acid derivative to cerium chloride is 1 mole: 1 to 20 moles; glycyrrhizic acid, glycyrrhizic acid or licorice The ratio of the amount of the acid derivative to the concentrated sulfuric acid is 1 mole: 0.5 to 10 moles. A process for the preparation of a compound according to claim 1 comprising the deoxygenation of the 11th carbon position of the compound of formula I wherein the 18th carbon position is in the alpha configuration, in an organic solvent, And further esterifying at a hydroxyl group at the third carbon position; wherein R ₂ is an ethoxy group. The method of claim 5, wherein the deoxygenation is carried out by a Clemson reduction method or a catalytic hydrogenation method. A pharmaceutical composition comprising the compound as described in claim 1 or 2 as an active ingredient, and further comprising one or more pharmaceutically acceptable carriers. A use according to the compound of claim 1 or 2 or the composition of claim 7 for the preparation of a medicament for treating inflammation and/or treating liver damage. The compound of claim 1, which is for use in the treatment of inflammation and/or liver damage. The composition of claim 7, which is for the treatment of inflammation and/or liver damage. Such as the compound or patent application described in claim 9 The composition of claim 10, wherein the liver damage is a drug-induced liver injury.