CN102579462B - Application of Glycyrrhetinic Acid Derivatives in the Preparation of Anti-inflammatory Drugs - Google Patents

Abstract

The invention discloses the application of glycyrrhetinic acid derivatives in the preparation process of anti-inflammatory drugs, in particular to the glycyrrhetinic acid derivatives as well as pharmaceutically acceptable salt thereof, drug compositions containing the derivatives and anti-inflammatory action of the drug compositions, wherein, the glycyrrhetinic acid derivatives can release gaseous signal molecule hydrogen sulfide. The invention discloses and provides the glycyrrhetinic acid derivatives that can release gaseous signal molecule H2S, wherein, glycyrrhetinic acid and gaseous signal molecule hydrogen sulfide release groups are coupled through ester bonds or amido bonds so as to obtain the glycyrrhetinic acid derivatives. Pharmacology experimental results show that the glycyrrhetinic acid derivatives achieve remarkable anti-inflammatory action and have no significant gastrointestinal tract injury, and show that the glycyrrhetinic acid derivatives can be used for preparing the drugs for treating various inflammations and related diseases thereof.

Description

Application of Glycyrrhetinic Acid Derivatives in the Preparation of Anti-inflammatory Drugs

technical field

The invention relates to the field of medicines, in particular to a class of glycyrrhetinic acid derivatives capable of releasing gas signal molecule hydrogen sulfide and pharmaceutically acceptable salts thereof, and pharmaceutical compositions containing these derivatives, which have anti-inflammatory effects, especially in Application of the medicine for preparing anti-inflammatory diseases.

Background technique

Licorice root, a leguminous plant, is an important traditional Chinese medicine. The main active ingredient of licorice is glycyrrhizic acid and its salt (Glycyrrhizin), which is hydrolyzed by gastric acid in the human body to glycyrrhetinic acid (GA for short). Modern studies have shown that GA has various pharmacological activities such as anti-inflammation, anti-oxidation, anti-ulcer, anti-virus, anti-arrhythmia, hypolipidemic, anti-tumor and anti-allergic effects. GA has obvious curative effect on inflammatory bowel disease, rheumatoid arthritis, gingivitis, periodontitis and oral ulcer. However, clinical application is often accompanied by pseudoaldosteronism, manifested as hypokalemia after long-term use.

Long-term or large-scale use of classic NSAIDs can cause side effects on the gastrointestinal tract, causing secondary damage to patients and secondary economic burdens on individuals and society. Although the new generation of non-steroidal anti-inflammatory drugs such as coxibs have greatly reduced gastrointestinal side effects, they can cause cardiovascular events such as increased blood pressure, stroke, myocardial infarction, etc., which are still difficult to meet clinical requirements.

The latest research has found that endogenous hydrogen sulfide (H ₂ S) is widely involved in the regulation of physiological functions of the nervous, cardiovascular, digestive and other systems, and is considered to be the third gas signal molecule after NO and CO. More and more studies have proved that H ₂ S plays an important pathophysiological role in cardiovascular, nervous, inflammatory and other multi-system or disease processes. Hydrogen sulfide can relax vascular smooth muscle; inhibit the formation of pulmonary hypertension during hypoxia, regulate the reconstruction of pulmonary vascular structure; significantly reduce the blood pressure of hypertensive rats, and inhibit the proliferation of smooth muscle cells; significantly reduce myocardial ischemia-reperfusion injury. H ₂ S can reduce lipopolysaccharide-induced edema and increased vascular permeability and other inflammatory reactions in rats; it has anti-inflammatory and anti-oxidative effects in the early stage of inflammation, and can also prevent gastric mucosal damage caused by non-steroidal anti-inflammatory drugs. The damage is reduced by 60% to 70%.

Some anti-inflammatory drugs such as 5-aminosalicylic acid, diflunisal, naproxen, ketonophenol, etc. and ADT-OH (a compound with a strong ability to release H ₂ S, 5-p-hydroxyphenyl-3H -1,2-dithiolene-3-thione (abbreviated as ADT-OH) coupling compound, its anti-inflammatory activity is stronger than the parent compound, and significantly reduce its gastrointestinal side effects (see: open No. WO 2006125293, WO 2006111791, WO2006037623, US 20080004245 patent application publication specification).

However, there is no report in the prior art on the anti-inflammatory activity of H ₂ S donor glycyrrhetinic acid derivatives and pharmaceutically acceptable salts thereof.

Contents of the invention

The purpose of the present invention is to provide a new application of glycyrrhetinic acid derivatives, that is, the application of glycyrrhetinic acid derivatives in the preparation of anti-inflammatory drugs.

In order to achieve the above-mentioned purpose of the invention, the technical solution adopted in the present invention is: the application of glycyrrhetinic acid derivatives in the preparation of anti-inflammatory drugs, the structural formula of the glycyrrhetinic acid derivatives is selected from:

Structural formula one

Structural formula two

Structural formula three

or structural formula four

或

X选自：NH或O；Y为(CH₂)_n、CH(CH₃)(CH₂)₂、(CH₂)₂O(CH₂)₂、CH₂CH＝CHCH₂或CH₂C≡CCH₂，其中，n＝2～6；Z选自：O或NH。In the formula, R ₁ is selected from: H, CH ₃ CO, C ₂ H ₅ CO, C ₃ H ₇ CO or COCH ₂ COOH; R ₂ is selected from:

or

X is selected from: NH or O; Y is (CH ₂ ) _n , CH(CH ₃ )(CH ₂ ) ₂ , (CH ₂ ) ₂ O(CH ₂ ) ₂ , CH ₂ CH=CHCH ₂ or CH ₂ C≡ CCH ₂ , wherein, n=2-6; Z is selected from: O or NH.

In a preferred technical solution, the glycyrrhetinic acid derivative is selected from compounds represented by structural formula 1 or structural formula 3.

In a further preferred technical scheme, the glycyrrhetinic acid derivative is:

In the formula, R ₁ is selected from: H or CH ₃ CO; X is O; Y is (CH ₂ ) _n , n=2-4; Z represents O.

或

为反应物，甘草次酸或甘草次酸的酯化衍生物中的羧基和

中的氨基发生缩合反应或者

的溴发生取代反应，制备得到结构式一所述甘草次酸衍生物；In the above technical scheme, the glycyrrhetinic acid derivative is composed of a glycyrrhetinic acid group and a hydrogen sulfide donor through an ester bond or an amide bond; the application number of the glycyrrhetinic acid derivative and its preparation method is It is recorded in the Chinese invention patent application of 201110139249.7 that in the above technical scheme, the preparation method of the glycyrrhetinic acid derivative described in the structural formula 1 comprises the following steps: using glycyrrhetinic acid or one of the esterified derivatives of glycyrrhetinic acid and

or

As a reactant, the carboxyl group and

The amino group in the condensation reaction or

The bromine generation substitution reaction, prepares the glycyrrhetinic acid derivative described in structural formula one;

式中，R₁选自：CH₃CO、C₂H₅CO、C₃H₇CO或COCH₂COOH；所述甘草次酸的酯化衍生物是由甘草次酸通过酯化反应制备得到；Wherein, the structural formula of the esterification derivative of glycyrrhetinic acid is:

In the formula, R ₁ is selected from: CH ₃ CO, C ₂ H ₅ CO, C ₃ H ₇ CO or COCH ₂ COOH; the esterified derivative of glycyrrhetinic acid is prepared from glycyrrhetinic acid through esterification;

与溴代烷基胺BrYNH₂发生取代反应制备得到；所述是由

和二溴烷烃发生取代反应制备得到。said By

Prepared by substitution reaction with bromoalkylamine BrYNH ₂ ; By

It can be prepared by substitution reaction with dibromoalkane.

In the above technical scheme, the preparation method of the glycyrrhetinic acid derivative described in structural formula 2 is similar to the method for preparing the glycyrrhetinic acid derivative described in structural formula 1. The difference is that the glycyrrhetinic acid is first reduced to obtain compound 1, and then its Esterification derivative compound 2, one of compound 1 or compound 2 and

或

为反应物，制备得到结构式二所述甘草次酸衍生物；

or

As a reactant, a glycyrrhetinic acid derivative described in structural formula 2 is prepared;

所述化合物2的结构式为The structural formula of the compound 1 is

The structural formula of the compound 2 is

哌嗪

吗啡啉吡咯二甲胺(CH₃)₂NH或二乙胺Et₂NH中的一种反应制备得到化合物4；以化合物4和

或

为反应物，化合物4中的羧基和的氨基缩合或

中的溴取代，制备得到结构式三所述甘草次酸衍生物；In the above technical scheme, the preparation method of the glycyrrhetinic acid derivative described in structural formula three is: glycyrrhetinic acid and haloacetyl chloride generate compound 3, compound 3 and piperidine

Piperazine

Morpholine pyrrole Compound 4 is prepared by one reaction in dimethylamine (CH ₃ ) ₂ NH or diethylamine Et ₂ NH; compound 4 and

or

As the reactant, the carboxyl group in compound 4 and Amino condensation or

The bromine in is substituted, and the glycyrrhetinic acid derivative described in structural formula three is prepared;

A为Br、Cl；所述化合物4的结构式为

The structural formula of the compound 3 is

A is Br, Cl; The structural formula of the compound 4 is

In the above technical scheme, the preparation method of the glycyrrhetinic acid derivative described in the structural formula 4 is similar to the preparation method of the glycyrrhetinic acid derivative described in the structural formula 3, the difference is that the glycyrrhetinic acid is first reduced to obtain the compound 1, and then according to the preparation The preparation method of the glycyrrhetinic acid derivative described in Structural Formula 3 is to prepare the glycyrrhetinic acid derivative described in Structural Formula 4 by using compound 1 instead of glycyrrhetinic acid as the starting reactant.

The present invention also claims the application of the medically acceptable salts of the above-mentioned glycyrrhetinic acid derivatives in the preparation of anti-inflammatory drugs.

The glycyrrhetinic acid derivatives or the medically acceptable salts thereof in the present invention can be formulated and administered alone or in combination with more than one acceptable carrier. For example, solvents, thinners, etc. It can be administered in oral dosage forms, such as tablets, capsules, dispersible powders, granules and the like. Various dosage forms of the pharmaceutical composition of the present invention can be prepared according to well-known methods in the field of pharmacy. These pharmaceutical formulations may contain, for example, 0.05% to 90% by weight active ingredient, more usually between about 15% and 60% active ingredient in combination with a carrier. The dose of the compound of the present invention can be 0.005-5000 mg/kg/day, and the dose can also be used beyond this dose range according to the severity of the disease or different dosage forms.

The results of pharmacological experiments show that the above-mentioned glycyrrhetinic acid derivatives have a strong inhibitory effect on the mouse model of xylene-induced ear swelling and inflammation, and the activity of the preferred glycyrrhetinic acid derivatives is significantly stronger than that of glycyrrhetinic acid; and no obvious gastric Intestinal injury can be used to treat and prevent various inflammation or inflammation-related diseases. The inflammation or inflammation-related diseases are selected from rheumatoid arthritis, osteoarthritis, rheumatoid arthritis, gouty arthritis, lupus erythematosus syndrome, bronchitis, bursitis, tenosynovitis, psoriasis, eczema, burns, dermatitis , inflammatory bowel disease, Crohn's disease, gastritis, irritable bowel syndrome, ulcerative colitis, colorectal cancer, arteritis nodosa, thyroiditis, rheumatic fever, gingivitis, periodontitis, mouth ulcers, Nephritis, swelling after injury, myocardial ischemia, various infectious pneumonia, physicochemical pneumonia and allergic pneumonia, chronic obstructive pulmonary disease, spastic analgia and rectal fissure, hepatic cholecystitis, cholangitis, cirrhosis cholangitis, primary biliary cirrhosis, and cholecystitis.

Due to the use of the above-mentioned technical solutions, the present invention has the following advantages compared with the prior art:

1. In the structure of glycyrrhetinic acid, the present invention introduces a group that can release gas signal molecule _H2S , synthesizes a series of new compounds, and obtains compounds with higher anti-inflammatory activity than glycyrrhetinic acid, and no Significant gastrointestinal injury.

2. The compounds of the present invention can reduce the occurrence of cardiovascular events due to the release of an appropriate amount of hydrogen sulfide. Therefore, the compound of the present invention can avoid gastrointestinal tract damage and/or cardiovascular adverse events or other toxic and side effects caused by clinically applied non-steroidal anti-inflammatory drugs.

Description of drawings

Fig. 1 is the result of the gastrointestinal tract injury experiment in Example 9.

Detailed ways

The present invention will be further described below in conjunction with accompanying drawing and embodiment:

Embodiment one:

Preparation of 5-[4-(2-bromoethoxy)phenyl]-3H-1,2-dithiole-3-thione (5a)

ADT-OH (0.325g, 1.4mmol), 1,2-dibromoethane (0.50mL, 5.8mmol), anhydrous _K2C03 ( _0.396g , 2.8mmol), dissolved in 10mL dry DMF, 120 ℃ reaction 2h. After cooling, it was diluted with 20 mL of ethyl acetate, washed with water (3×20 mL), and dried over anhydrous Na ₂ SO ₄ . Filter, evaporate to dryness under reduced pressure, and recrystallize from acetone-water to obtain 0.388 g of dark brown product, yield 81.5%, mp: 126.0-127.0°C. ¹ HNMR (400MHz, CDCl ₃ ), δ (ppm): 7.59 (d, 2H, J=8.9Hz, ArH), 7.36 (s, 1H, =CH), 6.96 (d, 2H, J=8.9Hz, ArH ), 4.33 (t, 2H, J=6.1Hz, CH ₂ ), 3.65 (t, 2H, J=6.1Hz, CH ₂ ); ¹³ CNMR (400MHz, CDCl ₃ ), δ(ppm): 212.554, 170.180, 158.775, 132.260, 126.120, 122.226, 113.014, 65.455, 26.026.

The above identification data prove that the obtained compound is 5-[4-(2-bromoethoxy)phenyl]-3H-1,2-dithiole-3-thione (5a), and its structural formula is:

Preparation of Compound I ₁

GA (0.47g, 1.0mmol, purchased from Sichuan Superhuman Phytochemical Co., Ltd., content > 98%), 5a (0.33g, 1.0mmol), anhydrous K ₂ CO ₃ (0.138g, 1.0mmol) and catalytic amount KI , added to 15mL of anhydrous DMF, and reacted at room temperature for 16h. Diluted with 50 mL of water, extracted with ethyl acetate (3×30 ml), combined the organic layers and dried over anhydrous Na ₂ SO ₄ . Filtration, evaporation to dryness, and column chromatography [petroleum ether (60-90): ethyl acetate = 3:1 (v/v)] gave 0.62 g of a red solid, yield 86.2%, mp: 220.5-221.5°C. ¹ HNMR (400MHz, CDCl ₃ ), δ (ppm): 7.62 (d, 2H, J=8.8Hz, ArH), 7.39 (s, 1H, =CH), 7.01 (d, 2H, J=8.8Hz, ArH ), 5.60 (s, 1H, C ₁₂ -H), 4.50 (m, 2H, OCH ₂ ), 4.27 (t, 2H, OCH ₂ ), 3.23 (m, 1H, C ₃ -H), 2.78 (brs, 1H, OH), 2.32(s, 1H, C ₉ -H), 1.35(s, 3H, CH ₃ ), 1.16(s, 3H, CH ₃ ), 1.12(s, 3H, CH ₃ ), 1.09(s , 3H, CH ₃ ), 1.00 (s, 3H, CH ₃ ), 0.81 (s, 3H, CH ₃ ), 0.74 (s, 3H, CH ₃ ); ¹³ CNMR (400MHz, CDCl ₃ ), δ (ppm) ：215.533，200.554，176.753，173.349，169.535，169.518，162.089，135.186，129.113，128.886，124.996，115.961，79.140，66.660，62.727，62.232，55.308，48.714，45.785，44.558，43.551，41.437，39.538，39.514，38.079 , 37.471, 33.101, 32.188, 31.551, 28.983, 28.687, 28.497, 27.708, 26.832, 26.794, 23.842, 19.030, 17.863, 16.796, 16.002; IR (KBr, cm ^-1 ): 3442.0 (OH) ), 1653.1(C=O), 1635.0, 1602.8, 1575.8, 1489.6(C=C), 1172.0(C=S); HR-MS: Calcd.For C ₄₁ H ₅₄ O ₅ S ₃ [M+H] ⁺ : 723.3206, Found: 723.3191.

The above identification data prove that the obtained compound is compound I ₁ , and its structural formula is:

Embodiment two:

Preparation of 5-[4-(3-bromopropoxy)phenyl]-3H-1,2-dithiole-3-thione (5b)

Using 1,3-dibromopropane as raw material, it was prepared according to the method of 5a, with a yield of 83.2%, and mp: 79.0-80.0°C. ¹ HNMR (400MHz, CDCl ₃ ), δ (ppm): 7.62 (d, 2H, J=8.8Hz, ArH), 7.40 (s, 1H, =CH), 7.00 (d, 2H, J=8.7Hz, ArH ), 4.19 (t, 2H, J=5.8Hz, CH ₂ ), 3.62 (t, 2H, J=6.3Hz, CH ₂ ), 2.36 (p, 2H, J=6.0Hz, CH ₂ ); ¹³ CNMR ( 400MHz, CDCl ₃ ), δ (ppm): 212.460, 170.437, 159.454, 132.073, 126.065, 121.751, 112.886, 63.118, 29.453, 27.178.

The above identification data prove that the obtained compound is 5-[4-(3-bromopropoxy)phenyl]-3H-1,2-dithio-3-thione (5b), and its structural formula is:

Preparation of Compound I ₂

Using GA and 5b as raw materials, it was prepared according to the synthesis method of _I1 . It was a red solid with a yield of 86.6%, and mp: 79.1-80.7°C. ¹ HNMR (400MHz, CDCl ₃ ), δ (ppm): 7.54 (d, 2H, J=8.8Hz, ArH), 7.31 (s, 1H, =CH), 6.91 (d, 2H, J=8.8Hz, ArH ), 5.54 (s, 1H, C ₁₂ -H), 4.24 (t, 2H, OCH ₂ ), 4.06 (t, 2H, OCH ₂ ), 3.16 (dd, 1H, C ₃ -H), 2.72 (brs, 1H, OH), 2.26(s, 1H, C ₉ -H), 2.10(p, 2H, CH ₂ ), 1.29(s, 3H, CH ₃ ), 1.08(s, 3H, CH ₃ ), 1.07(s , 3H, CH ₃ ), 1.03 (s, 3H, CH ₃ ), 0.93 (s, 3H, CH ₃ ), 0.74 (s, 3H, CH ₃ ), 0.69 (s, 3H, CH ₃ ); ¹³ CNMR ( 400MHz，CDCl ₃ )，δ(ppm)：215.213，200.442，176.583，173.337，169.515，162.304，134.798，128.899，128.658，124.447，115.692，78.889，72.011，65.004，62.039，61.222，55.101，48.673，45.620，44.286 ，43.420，41.251，39.342，37.923，37.288，32.918，32.038，31.292，28.757，28.717，28.642，28.320，27.919，27.467，26.632，26.566，23.641，21.307，19.397，18.850，16.618，15.853；IR(KBr，cm ^-1 ): 3567.4 (OH), 1732.1 (C=O), 1652.4 (C=O), 1599.4, 1522.6, 1492.6 (C=C), 1179.7 (C=S); HR-MS: Calcd.For C ⁴² H ⁵⁶ O ⁵ S ³ [M+H] ⁺ : 737.3383, Found: 737.3387.

The above identification data prove that the obtained compound is compound I ₂ , and its structural formula is:

Embodiment three:

Preparation of 5-[4-(4-bromobutoxy)phenyl]-3H-1,2-dithiole-3-thione (5c)

Using 1,4-dibromobutane as raw material, it was prepared according to the method of 5a, with a yield of 79.4%, and mp: 70.0-71.0°C. ¹ HNMR (400MHz, CDCl ₃ ), δ (ppm): 7.60 (d, 2H, J=8.7Hz, ArH), 7.38 (s, 1H, =CH), 6.96 (d, 2H, J=8.7Hz, ArH ), 4.07(t, 2H, J=5.9Hz, CH ₂ ), 3.50(t, 2H, J=6.4Hz, CH ₂ ), 2.08(m, 2H, CH ₂ ), 1.99(m, 2H, CH ₂ ); ¹³ CNMR (400MHz, CDCl ₃ ), δ (ppm): 212.439, 170.554, 159.670, 132.006, 126.057, 121.553, 112.834, 64.759, 30.795, 26.729, 25.133.

The above identification data prove that the obtained compound is 5-[4-(4-bromobutoxy)phenyl]-3H-1,2-dithiole-3-thione (5c), and its structural formula is:

Preparation of Compound I ₃

Using GA and 5c as raw materials, it was prepared according to the synthesis method of _I1 . It was a red solid with a yield of 89.2%, and mp: 138.2-139.2°C. ¹ HNMR (400MHz, CDCl ₃ ), δ (ppm): 7.60 (d, 2H, J=8.8Hz,), 7.39 (s, 1H, =CH), 6.98 (d, 2H, J=8.8Hz, ArH) , 5.64 (s, 1H, C ₁₂ -H), 4.20 (t, 2H, CH ₂ ), 4.08 (t, 2H, CH ₂ ), 3.23 (m, 1H, C ₃ -H), 2.78 (brs, 1H , OH), 2.34(s, 1H, C ₉ -H), 1.37(s, 3H, CH ₃ ), 1.16(s, 3H, CH ₃ ), 1.13(s, 3H, CH ₃ ), 1.12(s, 3H, CH ₃ ), 1.01 (s, 3H, CH ₃ ), 0.81 (s, 6H, CH ₃ ); ¹³ CNMR (400MHz, CDCl ₃ ), δ (ppm): 215.234, 200.481, 176.668, 173.396, 169.582, 162.512，134.737，128.810，128.690，124.261，115.706，78.893，67.907，64.179，62.053，55.122，48.687，45.619，44.250，43.434，41.266，39.349，37.950，37.299，32.951，32.068，31.309，28.794，28.668，28.328， 27.492, 26.671, 26.602, 26.027, 25.743, 23.630, 18.884, 17.691, 16.604, 15.844; IR (KBr, cm ^-1 ): 3446.9 (OH), 1722.7 (C=O), 1653.4 (C=O), 1647.7, 1602.3, 1489.6 (C=C), 1177.1 (C=S); HR-MS: Calcd. For C ₄₃ H ₅₈ O ₅ S ₃ [M+H] ⁺ 751.3519, Found: 751.3477.

The above identification data prove that the obtained compound is compound I ₃ , and its structural formula is:

Embodiment four:

Preparation of 3-O-acetylglycyrrhetinic acid (6a):

GA (1.88g, 4.0mmol) was dissolved in 10mL of pyridine, and acetic anhydride (3.78mL, 40.0mmol) was added dropwise with stirring at room temperature. After reacting for 12 hours, it was poured into ice water, filtered, and recrystallized from acetone-water to obtain 1.90 g of a white solid, with a yield of 92.7%, and mp: 312.0-313.0°C. ¹ HNMR (400MHz, CDCl ₃ ), δ(ppm): 5.72(s, 1H, C ₁₂ -H), 4.52(dd, 1H, J=11.13, 4.51Hz, C ₃ -H), 2.37(s, 1H , C ₉ -H), 2.06(s, 3H, CH ₃ ), 1.37(s, 3H, CH ₃ ), 1.23(s, 3H, CH ₃ ), 1.17(s, 3H, CH ₃ ), 1.13(s , 3H, CH ₃ ), 0.88 (s, 6H, CH ₃ ), 0.84 (s, 3H, CH ₃ ).

Above-mentioned identification data proves that gained compound is 3-O-acetyl glycyrrhetinic acid (6a), and its structural formula is:

Preparation of Compound I ₄

Using 6a and 5a as raw materials, it was prepared by referring to the synthesis method of _I1 . It was a red solid with a yield of 86.0%. The melting point is 96.0-97.0°C. ¹ HNMR (400MHz, CDCl ₃ ), δ (ppm): 7.63 (d, 2H, J=8.8Hz, ArH), 7.40 (s, 1H, =CH), 7.01 (d, 2H, J=8.8Hz, ArH ), 5.60 (s, 1H, C ₁₂ -H), 4.50 (m, 2H, OCH ₂ ), 4.27 (t, 2H, OCH ₂ ), 3.23 (m, 1H, C ₃ -H), 2.78 (brs, 1H, OH), 2.32(s, 1H, C ₉ -H), 2.05(s, 3H, CH ₃ ), 1.35(s, 3H, CH ₃ ), 1.16(s, 3H, CH ₃ ), 1.12(s , 3H, CH ₃ ), 1.09 (s, 3H, CH ₃ ), 1.00 (m, 4H, CH ₃ & CH ₂ ), 0.80 (s, 3H, CH ₃ ), 0.72 (s, 3H, CH ₃ ); IR (KBr, cm ^-1 ): 1732.1 (C=O), 1692.4 (C=O), 1602.6, 1575.6, 1491.4, 1464.5 (C=C), 1178.9 (C=S); HR-MS: Calcd.For C ₄₃ H ₅₇ O ₆ S ₃ [M+H] ⁺ : 765.3312, Found: 765.3314.

The above identification data prove that the obtained compound is compound I ₄ , and its structural formula is:

Embodiment five:

Preparation of Compound I ₅

Using 6a and 5b as raw materials, it was prepared according to the synthesis method of _I1 . It was a red solid with a yield of 89.5%, and mp: 253.2-254.2°C. ¹ HNMR (400MHz, CDCl ₃ ), δ (ppm): 7.62 (d, 2H, J=8.8Hz, ArH), 7.40 (s, 1H, CH=CH), 6.98 (d, 2H, J=8.8Hz, ArH), 5.61(s, 1H, C ₁₂ -H), 4.52(m, 1H, C ₃ -H), 4.31(t, 2H, J=6.2Hz, OCH ₂ ), 4.12(t, 2H, J= 6.1Hz, OCH ₂ ), 2.35(s, 1H, C ₉ -H), 2.18(m, 2H, CH ₂ ), 2.06(s, 3H, CH ₃ ), 1.35(s, 3H, CH ₃ ), 1.16 (s, 3H, CH ₃ ), 1.15 (s, 3H, CH ₃ ), 1.10 (s, 3H, CH ₃ ), 0.88 (s, 6H, CH ₃ ), 0.75 (s, 3H, CH ₃ ); ¹³ CNMR(400MHz，CDCl ₃ )，δ(ppm)：215.341，200.253，176.574，173.274，171.275，169.441，162.292，134.889，128.901，128.681，124.528，115.698，80.797，64.973，61.972，61.199，55.220，48.704，45.631 ，44.299，43.431，41.246，39.024，38.261，37.930，37.161，32.884，32.048，31.314，28.750，28.650，28.258，26.595，23.787，23.582，21.567，18.865，17.580，16.908，16.659；IR(KBr，cm ^-1 ): 1732.1 (C=O), 1651.9 (C=O), 1596.7 1577.3, 1520.7, 1489.9 (C=C), 1180.4 (C=S); HR-MS: Calcd.ForC ₄₄ H ₅₉ O ₆ S ₃ [ M+H] ⁺ 779.3468, Found: 779.3468.

The above identification data prove that the obtained compound is compound I ₅ , and its structural formula is:

Embodiment six:

Preparation of Compound I ₆

Using 6a and 5c as raw materials, it was prepared according to the synthesis method of _I1 . It was a red solid with a yield of 89.6%, and mp: 253.8-254.8°C. ¹ HNMR (400MHz, CDCl ₃ ), δ (ppm): 7.61 (d, 2H, J=8.7Hz, ArH), 7.40 (s, 1H, CH=CH), 6.98 (d, 2H, J=8.7Hz, ArH), 5.64 (s, 1H, C ₁₂ -H), 4.23-4.16 (m, 2H, OCH ₂ ), 4.08 (t, 2H, OCH ₂ ), 2.36 (s, 1H, C ₉ -H), 2.06 (s, 3H, CH ₃ ), 1.36 (s, 3H, CH ₃ ), 1.16 (s, 6H, CH _{3 ), 1.12 (s, 3H, CH 3 )} , 0.88 (s, 6H, CH ₃ ), 0.80 (s, 3H, CH ₃ ); IR (KBr, cm ^-1 ): 1729.1 (C=O), 1705.8 (C=O), 1654.0 (C=O), 1601.0, 1576.6, 1491.2 (CH=CH), 1178.8 (C=S); HR-MS: Calcd. For C ₄₅ H ₆₁ O ₆ S ₃ [M+H] ⁺ 793.3625, Found: 793.3635.

The above identification data prove that the obtained compound is compound I ₆ , and its structural formula is:

Embodiment seven:

Preparation of 11-deoxyglycyrrhetinic acid (1)

In 20mL of dioxane, add 20g of zinc powder (activated with HgCl ₂ ), GA (2.0g, 4.26mmol), react at room temperature, add 1.20mL of concentrated hydrochloric acid dropwise at the same time, filter after 2h, concentrate, column chromatography [petroleum Ether (60-90):ethyl acetate=7:1 (v/v)] to obtain 1.48 g of white solid, yield 74.0%, mp: 330.1-331.0°C. IR (KBr, cm ^-1 ): 3437.7 (-COOH), 1707.4 (-COOH); HR-MS: Calcd. For C ₃₀ H ₄₇ O ₃ [MH] ^- 455.3531, Found: 455.3524.

Above-mentioned identification data proves that gained compound is 11-deoxyglycyrrhetinic acid (1), and its structural formula is:

Preparation of compound I ₇

Using compounds 1 and 5b as raw materials, it was prepared by referring to the synthesis method of compound _I1 in Example 1. It was a red solid with a yield of 92.2%, and mp: 141.0-142.0°C. ¹ HNMR (400MHz, CDCl ₃ ), δ (ppm): 7.62 (d, 2H, J=8.6Hz, ArH), 7.40 (s, 1H, =CH), 6.98 (d, 2H, J=8.6Hz, ArH ), 5.13(m, 1H, C ₁₂ -H), 4.30(t, 2H, J=6.5Hz, CH ₂ ), 4.14(t, 2H, J=6.1Hz, CH ₂ ), 3.22(m, 1H, C ₃ -H), 2.18 (p, 2H, J=6.1Hz, CH ₂ ), 1.14 (s, 3H, CH ₃ ), 1.12 (s, 3H, CH ₃ ), 0.99 (s, 3H, CH ₃ ) , 0.92(s, 3H, CH ₃ ), 0.91(s, 3H, CH ₃ ), 0.78(s, 3H, CH ₃ ), 0.74(s, 3H, CH ₃ ); ¹³ CNMR (400MHz, CDCl ₃ ), δ(ppm)：177.314，173.157，162.385，144.711，134.857，131.169，129.067，128.816，122.712，115.689，79.213，65.822，65.072，60.765，55.362，48.610，47.787，44.539，43.068，41.728，39.963，38.984，38.535 , 37.120, 32.801, 32.179, 31.472, 28.861, 28.781, 28.444, 28.307, 27.431, 27.102, 26.328 ^, 26.197, 23.685, 18.549, 16.956, 15.825, 15.715; , 1669.6, 1653.4, 1635.9, 1601.7 (CH=CH), 1178.9 (C=S); HR-MS: Calcd. For C ₄₂ H ₅₉ O ₄ S ₃ [M+H] ⁺ 723.3570, Found: 723.3570.

The above identification data prove that the obtained compound is compound I ₇ , and its structural formula is:

Embodiment eight:

Xylene-induced mouse ear swelling test, the experimental method refers to the literature ([1] Xu Shuyun, Bian Rulian, Chen Xiu edited. Pharmacological Experimental Methodology [M]. Third Edition, Beijing: People's Medical Publishing House, 2002, 911; [2] ] The Pharmaceutical Bureau of the Ministry of Health of the People's Republic of China. A Compilation of Guiding Principles for Preclinical Research of New Drugs (Western Medicine) [B] (Pharmacy Pharmacology Toxicology), 1993, 121-124).

The test compound was prepared into a 2.00 mmol·L ^-1 suspension with 0.5% CMC-Na solution. The dosage of the positive control drug aspirin was set at 200 mg·kg ^-1 . 10 mice in each group were fasted for 12 h before administration and had free access to water. Orally administered to mice, the dosage volume is 0.2mL·10g ^-1 . One hour after administration, 20 μL of xylene was evenly applied to both sides of the mouse's right auricle with a microsampler to induce inflammation, and the left auricle was used as a control. After 1 hour of inflammation, the mice were sacrificed by dislocation of the cervical spine, and the two ears were removed along the baseline of the auricle, and a piece of each ear was removed from the same position with a punch (mm in diameter) and weighed with an electronic balance. The weight of the inflammatory ear piece minus the weight of the control side ear piece is the degree of swelling.

Inhibition rate = (negative control - test compound) / negative control × 100%

The anti-inflammatory activity of 7 glycyrrhetinic acid derivatives was evaluated by xylene-induced mouse ear swelling model, and the results are shown in Table 1.

As can be seen from Table 1, all class I compounds all show stronger ear swelling inhibitory effect, and the inhibitory rate of some compounds exceeds 60%, and the inhibitory rate of most new compounds is all higher than original parent compound, Some reached nearly twenty percent.

Table 1 Anti-inflammatory effects of class I compounds on xylene-induced ear swelling in mice

compound Dose (mg.kg ^-1 ) Inhibition rate(%) CMC-Na _ _ Aspirin 200 41.5 GA 18.8 37.8 I ₁ 28.9 26.5 I ₂ 29.4 33.9 I ₃ 30.0 55.6 I ₄ 30.6 60.7 I ₅ 31.1 47.0 I ₆ 31.7 56.1 I ₇ 28.9 39.4

Example 9: Gastrointestinal injury experiment

Healthy male SD rats were purchased from Shanghai Slater Experimental Animal Center, weighing (average 100 g), randomly divided into groups, and fasted for 24 hours before the experiment, without water. Rats were fed with standard feed, bedding and rat food were replaced in time every day, and rat cages were kept clean. During the experiment, a vehicle control group, a diclofenac group, and a test drug group were respectively set up. Each animal in the vehicle control group was intragastrically administered; in the diclofenac control group, each animal was intragastrically administered diclofenac sodium solution at a dose of 20 mg/kg; Animals in the group were sacrificed 6 hours after administration, and the effects of the drug on the gastrointestinal tract of rats were observed and compared according to the following methods, and the correlation index was calculated. The gastric scissors were flattened along the greater curvature of the stomach, and the gastric ulcer index (UI) was calculated according to the Guth standard: 1 point for the length of the ulcer surface less than 1 mm, 2 points for 1-2 mm, 3 points for 2-3 mm, and 3 points for 3-4 mm. 4 points, if it is larger than 4mm, it will be divided into several segments, and each segment will be calculated according to the above method. If the ulcer width > 1 mm, the score will be × 2, and the point-like bleeding points will be calculated as 0.5 points each. The cumulative and added score of each rat is the total gastric ulcer index of the rat. The t test was used to analyze whether there were significant differences in gastric ulcer index among the groups. The experimental results are shown in Figure 1.

The results in Fig. 1 show that compared with the diclofenac group, the gastric ulcer index of each test substance group is very small, and there is a very significant difference (P<0.01). At the same time, after dissection, it was found that the stomachs of the rats in the diclofenac group had different degrees of color changes, mainly yellow-white or pale; while the rats in the groups of the test substances did not observe the above-mentioned changes in the stomachs of the rats, nor did other abnormal changes. Obvious notice.

Claims (2)

1. The application of glycyrrhetinic acid derivatives or their medically acceptable salts in the preparation of anti-inflammatory drugs, the structural formula of the glycyrrhetinic acid derivatives is selected from: Structural formula one

, Structural formula two

; In the formula, R ₁ is H or CH ₃ CO; X is O; Y is (CH ₂ ) _n , wherein, n=2~6; Z is O. 2. The application of the glycyrrhetinic acid derivatives or their medically acceptable salts in the preparation of anti-inflammatory drugs according to claim 1, characterized in that the glycyrrhetinic acid derivatives are selected from the compounds represented by structural formula one.

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