Glycyrrhetinic acid derivative, pharmaceutical composition and application thereof

Abstract

The invention provides a glycyrrhetinic acid derivative, a pharmaceutical composition and application of the glycyrrhetinic acid derivative and relates to the technical field of pharmaceutical chemistry, a main framework of the prepared glycyrrhetinic acid derivative is glycyrrhetinic acid with carbamido, and the glycyrrhetinic acid derivative with the carbamido is obtained by modifying the 3-site, 11-site, 18-site and 30-site of the glycyrrhetinic acid and modifying the 3-site, 11-site, 18-site and 30-site of the glycyrrhetinic acid. Therefore, the compound has nanomole-level inhibitory activity on soluble epoxide hydrolase. On the basis of 18alpha / 18beta-glycyrrhetinic acid, different ureido substituents are introduced to the 30th site, the activity difference between the different substituents is small, but when the different ureido substituents are connected to the 20th site of the 18alpha / 18beta-glycyrrhetinic acid, the inhibition effect of the 18alpha / 18beta-glycyrrhetinic acid on soluble epoxide hydrolase is greatly reduced. The glycyrrhetinic acid derivative prepared by the invention has an efficient inhibition effect on soluble epoxide hydrolase, so that the inhibition effect on inflammation can be realized by inhibiting the soluble epoxide hydrolase, and the glycyrrhetinic acid derivative has a good application prospect.

Description

Technical Field

[0001] The present invention relates to the technical field of pharmaceutical chemistry, and in particular to a glycyrrhetinic acid derivative, a pharmaceutical composition and application thereof. Background Art

[0002] Inflammation is an evolutionarily conserved, tightly regulated protective mechanism that includes immune, vascular, and cellular biochemical reactions. Normal inflammatory responses are time-limited and generally beneficial to the host. However, long-term, chronic inflammation can continue to damage human organs and tissues, and may even cause cancer, threatening human life and health.

[0003] Licorice is a traditional Chinese herbal medicine that contains a variety of biologically active natural compounds such as glycyrrhizic acid (GL) and glycyrrhetinic acid (GA), of which 3β and 18β stereo configurations are the main products (Formula 1-2), and have anti-inflammatory, antiviral, liver-protective and anti-tumor effects. Glycyrrhetinic acid is a triterpene aglycone component of the natural product glycyrrhizic acid and is abundant in the root of licorice. Glycyrrhizic acid exerts its anti-inflammatory effect by inhibiting the production of reactive oxygen species (ROS) by neutrophils, and can also promote the production of interleukin (IL)-10 by dendritic cells in the liver of hepatitis mice. In addition, glycyrrhizic acid reduces the expression levels of iNOS, TNF-α, IL-1β and IL-6, prevents oxidative stress and relieves inflammation by regulating the p38 mitogen-activated protein kinase (p38-mapk) and c-Jun N-terminal kinase (p-JNK) signaling pathways in cerebrovascular cells, and by inhibiting the p38-mapk, p-JNK and NF-κB signaling pathways in lung cells. Glycyrrhetinic acid is the main bioactive hydrolysis product of glycyrrhizic acid and can be used to treat a variety of inflammatory diseases including hepatitis. Studies have shown that Glycyrrhetinic acid can significantly inhibit the production of nitric oxide (NO), prostaglandin E2 (PGE2) and ROS induced by LPS (Lipopolysaccharides), and reduce the protein and mRNA (messenger RNA) levels of iNOS (inducible nitric oxide synthase) and COX-2 (Cyclooxygenase 2) in LPS-induced macrophages. Glycyrrhetinic acid may also exert anti-inflammatory effects by inhibiting the production of excessive NO, PGE2 and ROS and inhibiting the activity of NF-kappa B and PI3K. Although studies have shown that glycyrrhetinic acid has multiple mechanisms in anti-inflammatory effects, it has defects such as unclear targets, low activity and poor water solubility, making it difficult to further rationally design and improve drugability.

[0004]

[0005] Soluble epoxide hydrolase (sEH) is an important hydrolase in mammals. In recent years, studies have found that sEH plays an important role in the production of human inflammation and is considered to be a key enzyme in regulating inflammation. Soluble epoxide hydrolase catalyzes the hydrolysis of arachidonic acid lipid intermediate epoxyeicosatrienoic acids (EETs) through the cytochrome P450 (cytochrome P450 enzyme system, CYP450) cyclooxygenase pathway, converting EETs into dihydroxyeicosatrienoic acids (dihydroxyeicosatrienoic acids). Endogenous EETs are derived from arachidonic acid (AA) oxidized by cytochrome P450. They are important signaling molecules in organisms and have the functions of regulating ion transport and gene expression, vasodilation, and anti-inflammatory. In animals, there are many pathways to degrade EETs, among which sEH metabolizing EETs into DHETs is the main metabolic pathway, which reduces the concentration of EETs and the physiological activity. A large number of studies have shown that inhibiting sEH and thus stabilizing EETs can significantly reduce inflammation and pain. Therefore, sEH inhibitors are an effective method for treating various inflammatory-related diseases.

[0006] So far, AR9281, GSK2256294 and EC5026 have entered clinical trials, but no sEH inhibitor drugs are currently on the market. A large number of compounds in natural products have also shown inhibitory effects on sEH, such as natural ureas, triterpenes, flavonoids and phenylpropionic acid. Unfortunately, many compounds reported as sEH inhibitors have IC50 values ​​at the micromolar level, which is not worth further preclinical research.

[0007] Therefore, for the anti-inflammatory target soluble epoxide hydrolase, there is an urgent need for a new skeleton soluble epoxide hydrolase inhibitory compound with IC50 values ​​at the nanomolar level. Summary of the invention

[0008] The present invention provides a glycyrrhetinic acid derivative, a pharmaceutical composition and application thereof, so as to solve the problem of how to provide an inhibitor of soluble epoxide hydrolase with a new skeleton to reduce its IC50 value for soluble epoxide hydrolase.

[0009] In a first aspect, an embodiment of the present invention provides a glycyrrhetinic acid derivative, wherein the glycyrrhetinic acid derivative has the following general structural formula I:

[0010]

[0011] In the formula I, Y is selected from any one of CH-OH and carbonyl;

[0012] X is selected from any one of carbonyl and methylene groups;

[0013] R 1 Selected from C 1-4 Alkyl, tetrahydropyranyl, N-(C 1-4 alkylformyl)piperidinyl, N-(halogenated C 1-4 alkylformyl) piperidinyl, pyridinyl, substituted phenyl (R-Ph); wherein R is selected from any one of methoxy, trifluoromethoxy, aminosulfonyl, and methylsulfonyl;

[0014] The hydrogen at position 18 is selected from the α-position or β-position stereo configuration.

[0015] Preferably, Y is selected as a CH-OH group.

[0016] Preferably, X is selected as a carbonyl group.

[0017] Preferably, the R 1 Any one selected from the group consisting of isopropyl, isobutyl, tetrahydropyranyl, N-acetylpiperidinyl, N-propionylpiperidinyl, pyridinyl, methoxyphenyl, difluoromethoxyphenyl, trifluoromethoxyphenyl, aminosulfonylphenyl and methylsulfonylphenyl.

[0018] Preferably, Y is selected from a CH-OH group, X is selected from any one of a carbonyl group and a methylene group, and R 1 Any one selected from isopropyl, isobutyl, tetrahydropyranyl, N-acetylpiperidinyl, N-propionylpiperidinyl, 4-pyridyl, 4-methoxyphenyl, 4-difluoromethoxyphenyl, 4-trifluoromethoxyphenyl, 4-aminosulfonylphenyl and 4-methylsulfonylphenyl.

[0019] Preferably, the X is selected as a carbonyl group, and the R 1 Any one selected from the group consisting of isopropyl, tetrahydropyranyl, N-propionylpiperidinyl, 4-pyridyl, 4-methoxyphenyl, 4-difluoromethoxyphenyl, 4-trifluoromethoxyphenyl, 4-aminosulfonylphenyl and 4-methylsulfonylphenyl.

[0020] Preferably, the specific structural formula of the glycyrrhetinic acid derivative is:

[0021]

[0022]

[0023] In a second aspect, an embodiment of the present invention provides a glycyrrhetinic acid derivative pharmaceutical composition, which comprises at least one of the glycyrrhetinic acid derivatives, isotope-labeled substances, solvates, polymorphs, pharmaceutically acceptable salts or prodrug compounds thereof as described in any one of the first aspect above.

[0024] In a third aspect, an embodiment of the present invention provides a use of the glycyrrhetinic acid derivative as described in the first aspect above, or the glycyrrhetinic acid derivative pharmaceutical composition as described in the second aspect above, in the preparation of an anti-inflammatory drug.

[0025] Preferably, the anti-inflammatory drug is used to inhibit inflammation caused by soluble epoxide hydrolase.

[0026] The present invention includes the following advantages:

[0027] (1) The main skeleton of the glycyrrhetinic acid derivative provided by the present invention is glycyrrhetinic acid with a urea group, and the glycyrrhetinic acid is modified at the 3rd, 11th, 18th and 30th positions to have nanomolar inhibitory activity against the sEH enzyme;

[0028] (2) The glycyrrhetinic acid derivatives provided by the present invention are based on 18α-glycyrrhetinic acid or 18β-glycyrrhetinic acid, and different ureido substituents are introduced at the 30th position. The activity difference between different substituents is small, among which (tetrahydropyran-4-yl)methyl)ureido and (pyridin-4-yl)methyl)ureido have the best effect;

[0029] (3) The embodiment of the present invention introduces the glycyrrhetinic acid skeleton described in the general formula I to obtain a novel soluble epoxide hydrolase inhibitory compound, which has a good inhibition rate on soluble epoxide hydrolase, with the lowest IC50 being about 3 nM;

[0030] (4) The glycyrrhizic acid derivatives in the embodiments of the present invention have a highly effective inhibitory effect on soluble epoxide hydrolases, thereby achieving an inhibitory effect on inflammation by inhibiting soluble epoxide hydrolases, and have good application prospects. DETAILED DESCRIPTION

[0031] The following examples are provided for a better understanding of the present invention, but are not intended to limit the best mode of implementation, nor to limit the content and protection scope of the present invention. Any product identical or similar to the present invention obtained by anyone under the inspiration of the present invention or by combining the features of the present invention with other prior arts shall fall within the protection scope of the present invention.

[0032] The specific experimental steps or conditions are not specified in the examples, and the conventional experimental steps or conditions described in the prior art in the art can be used. The reagents and other instruments used without indicating the manufacturer are all conventional reagent products that can be obtained commercially. The various chemicals used in the present invention are all commercially available, and the nuclear magnetic resonance and mass spectrometer used to determine the structures of the following compounds are provided by the Analysis and Testing Center of Beijing Institute of Technology.

[0033] The first aspect of the present invention provides a glycyrrhetinic acid derivative, wherein the glycyrrhetinic acid derivative has the following general structural formula I:

[0034]

[0035] In the formula I, Y is selected from any one of CH-OH and carbonyl;

[0036] X is selected from any one of carbonyl and methylene groups;

[0037] R 1 Selected from C 1-4 Alkyl, tetrahydropyranyl, N-(C 1-4 alkylformyl)piperidinyl, N-(halogenated C 1-4 alkylformyl) piperidinyl, pyridinyl, substituted phenyl (R-Ph); wherein R is selected from any one of methoxy, trifluoromethoxy, aminosulfonyl, and methylsulfonyl;

[0038] The hydrogen at position 18 is selected from the α-position or β-position stereo configuration;

[0039] Preferably, Y is selected as a CH-OH group with a β-position stereo configuration, and the hydrogen at position 18 is selected as a β-position stereo configuration;

[0040] Preferably, Y is selected as a CH-OH group with a β-position stereo configuration, and the hydrogen at position 18 is selected as an α-position stereo configuration.

[0041] C 1-4 Alkyl refers to a straight or branched saturated monovalent hydrocarbon group having 1 to 4 carbon atoms. 1-4 Alkyl represents straight-chain and branched alkyl groups having 1, 2, 3 or 4 carbon atoms, such as methyl, ethyl, propyl, butyl, isopropyl, isobutyl, sec-butyl or tert-butyl.

[0042] C 1-4 Alkylformyl represents RC(=O)-, where R is C 1-4 The alkylformyl group is, for example, acetyl, propionyl, butyryl, valeryl, isobutyryl.

[0043] In the present invention, the halogen refers to fluorine, chlorine, bromine and / or iodine. Accordingly, the halogenated refers to fluorinated, chloro, brominated and / or iodinated. Within the scope of the present invention, when an atom, residue, group or part is halogenated, the atom at the halogenated position may be monosubstituted, disubstituted or polysubstituted up to full substitution by halogen atoms, for example, halogenated C 1-4 Alkylformyl, halogenated methoxy, halogenated methylsulfonyl, such as trifluoroacetyl, trifluoromethoxy, difluoromethoxy, trifluoromethylsulfonyl.

[0044] The second aspect of the present invention provides a glycyrrhetinic acid derivative pharmaceutical composition, which comprises at least one of the glycyrrhetinic acid derivatives, isotope-labeled substances, solvates, polymorphs, pharmaceutically acceptable salts or prodrug compounds thereof described in any one of the first aspects above.

[0045] The third aspect of the present invention provides a use of the glycyrrhetinic acid derivative as described in any one of the first aspect above, or the glycyrrhetinic acid derivative pharmaceutical composition as described in the second aspect above, in the preparation of an anti-inflammatory drug;

[0046] Wherein, the anti-inflammatory drug is used to inhibit inflammation caused by soluble epoxide hydrolase.

[0047] An embodiment of the present invention also provides a method for preventing and / or treating inflammation-related diseases, comprising administering to a patient a preventive or therapeutically effective amount of at least one of the compound of Formula I, its racemate, stereoisomer, tautomer, isotope-labeled substance, solvate, polymorph, pharmaceutically acceptable salt, prodrug compound thereof, or the pharmaceutical composition.

[0048] In some alternative embodiments, the patient is a mammal, preferably a human.

[0049] In the embodiments of the present invention, the pharmaceutical composition also includes any and all solvents, dispersion media, coatings, antibacterial and antifungal agents, isotonic agents and absorption delaying agents for pharmaceutically active substances, which are reagents and materials known in the art. In addition to any conventional media or agents that are incompatible with the compound, any conventional media or agents can be considered for use in the pharmaceutical composition, and supplementary compounds can also be added to the composition.

[0050] In the embodiments of the present invention, various pharmaceutically acceptable acids can form pharmaceutically acceptable salts on the basic nitrogen of the compound. The acid can be an inorganic acid or an organic acid; the inorganic acid is hydrochloric acid, sulfuric acid, hydrobromic acid, hydroiodic acid or phosphoric acid; the organic acid is acetic acid, malonic acid, methanesulfonic acid, succinic acid, p-toluenesulfonic acid, citric acid, maleic acid, fumaric acid, malic acid or citric acid.

[0051] The prodrug compounds in this specification are administered with a certain structure that is not disclosed, but are metabolized or converted into the compounds disclosed in this article in the human body and exert pharmacological effects as active ingredients. The conventional method for preparing prodrugs can be found in "Design of Prodrugs" (H.Bundgaad, Elsevier, 1985).

[0052] The patient refers to any animal including mammals, preferably mice, rats, other rodents, rabbits, dogs, cats, pigs, cows, sheep, horses or primates in the present embodiment, and most preferably humans.

[0053] The therapeutically effective amount refers to the amount of active compound or drug that causes the biological or medical response that the researcher, veterinarian, physician or other clinician is seeking in a tissue, system, animal, individual or human, and includes one or more of the following: (1) Preventing disease: for example, preventing a disease, disorder or condition in an individual who is susceptible to the disease, disorder or condition but has not yet experienced or developed the pathology or symptoms of the disease. (2) Inhibiting disease: for example, inhibiting a disease, disorder or condition in an individual who is experiencing or developing the pathology or symptoms of the disease, disorder or condition (i.e., preventing further development of the pathology and / or symptoms). (3) Alleviating disease: for example, alleviating a disease, disorder or condition in an individual who is experiencing or developing the pathology or symptoms of the disease, disorder or condition (i.e., reversing the pathology and / or symptoms).

[0054] In order to enable those skilled in the art to further understand the technical solution of the present invention, a glycyrrhetinic acid derivative, a pharmaceutical composition and application thereof provided by the present invention are further illustrated by way of specific embodiments below.

[0055] The following is a brief description of the synthesis method of the compounds of the present invention. In the following synthesis examples, the synthesis of the intermediates mainly involves Clemmensen reduction, acid-amine condensation, amide reduction, urea group construction, oxidation reaction, etc.

[0056] Specifically, the synthesis methods of representative specific compounds of the present invention are shown below.

[0057] Synthesis Example 1-Synthesis of Compound C1:

[0058]

[0059] The synthetic route of compound 2 is as follows:

[0060]

[0061] 18β-Glycyrrhetinic acid (0.55 g, 1.17 mmol) was dissolved in 10 mL of 1,4-dioxane, zinc powder (1.5 g, 22.9 mmol, 20 eq) was added, and HCl (2.5 mL of 12 M concentrated hydrochloric acid + 5 mL of dioxane) was added dropwise under an ice-water bath. The reaction was completed within 5 h, filtered through diatomaceous earth, washed with dichloromethane and saturated brine for three times, the organic phase was collected and rotary evaporated, and recrystallized from ethyl acetate to obtain a white solid (compound 2) (0.24 g, 0.53 mmol, yield 55%).

[0062] HRMS(ESI)[MH] - m / z calculation for C 30 H 47 O3:455.3531; found:455.3542.

[0063] 1 H NMR(400MHz, Methanol-d4)δ5.27(t,J=3.7Hz,1H),3.15(dd,J=11.4,4.9Hz,1H),2.10–1.76(m,7H),1.62(m,7H),1.51–1.42(m,1H),1.41 –1.27(m,5H),1.15(d,J=16.1Hz,6H),1.07–0.95(m,10H),0.89(ddt,J=13.4,4.5,2.3Hz,1H),0.79(d,J=4.0Hz,6H),0.75(d,J=1.9Hz,1H)

[0064] The synthetic route of compound 3 is as follows:

[0065]

[0066] Compound 2 (0.5 g, 1.09 mmol) was dissolved in dry dichloromethane, and N,N,N′,N′-tetramethyl-O-(7-azabenzotriazole-1-yl) urea hexafluorophosphate HATU (0.456 g, 1.199 mmol, 1.1 eq) and diisopropylethylamine DIEA (0.95 mL, 2.398 mmol, 2.2 eq) were added. After reacting for 20 min, 25% ammonia water (0.2 mL, 2.725 mmol, 2.5 eq) was added. The reaction was basically completed in 4 h, and the product was washed three times with saturated ammonium chloride solution. A white solid (compound 3) (0.359 g, 0.79 mmol, yield 72%) was obtained by silica gel column chromatography (mobile phase: dichloromethane / ethanol, 10 / 0.1 v / v). HRMS (ESI) [M+H] + m / zcalcd for C 30 H 50NO2:456.3836; found:456.3835.

[0067] 1H NMR (CDCl3, 400MHz) δ: 5.64 (s, 1H), 5.45 (s, 1H), 5.27 (t, J = 3.7Hz, 1H), 3.22 (dd, J = 10.9, 4.7Hz, 1H), 2.80 (s, 1H), 2.04–1.28 (m, 19H), 1.15 (d, J = 3. 5Hz, 6H), 1.00 (s, 3H), 0.98 (s, 1H), 0.95 (d, J=10.0Hz, 6H), 0.89 (ddd, J=1 4.4,5.0,2.8Hz,1H),0.80(d,J=5.0Hz,6H),0.74(dd,J=11.6,1.9Hz,1H).

[0068] The synthetic route of compound 4 is as follows:

[0069]

[0070] Compound 3 (0.225 g, 0.495 mmol) was dissolved in 10 mL of DME, and aluminum chloride (0.52 g, 3.96 mmol, 8 eq) was added. Sodium borohydride (0.187 g, 4.95 mmol, 10 eq) was added in batches within 30 min under an ice-water bath. After reacting for 24 h, the mixture was quenched with water, and the pH was adjusted to 9 with 1N sodium hydroxide. The mixture was extracted with dichloromethane and purified by column chromatography (mobile phase: dichloromethane / ethanol, 10 / 0.2 v / v, then dichloromethane / ethanol / ammonia water, 10 / 0.2 / 0.1 v / v / v) to give a white solid (compound 4) (55 mg, 0.124 mmol, 25%).

[0071] HRMS(ESI)[M+H] + m / z calculation for C 30 H 50 NO2:442.4043; found:442.4036.

[0072] 1H NMR(Methanol-d4,400MHz)δ:5.30(t,J=3.6Hz,1H),3.15(dd,J=11.3,4.9Hz,1 H),3.05(d,J=13.1Hz,1H),2.86(d,J=13.1Hz,1H),2.08(td,J=13.6,4.4Hz,1H ),2.01–1.77(m,5H),1.70–1.47(m,8H),1.51–1.19(m,6H),1.18(s,3H),1.08– 0.96(m,13H),0.96–0.85(m,1H),0.89(s,3H),0.79(s,3H),0.83–0.72(m,1H).

[0073] The synthetic route of compound C1 is as follows:

[0074]

[0075] Dissolve CDI (81 mg, 0.504 mmol, 2.4 eq) and aminomethyltetrahydropyran (0.07 mL, 0.57 mmol, 2.7 eq) in anhydrous dichloromethane and react for 2-3 h. Then, dissolve compound 4 (100 mg, 0.21 mmol) in anhydrous dichloromethane and drop into the reaction solution. After 24 h, wash the organic phase three times with saturated ammonium chloride. Collect the organic phase and evaporate it in vacuum. After silica gel column chromatography (mobile phase: dichloromethane / ethanol, 10 / 0.1 v / v), a white solid 5 (compound C1) (32 mg, 0.055 mmol, yield 26%) is obtained. Melting point: 149-152°C.

[0076] HRMS(ESI)[M+H] + m / z calculation for C 37 H 63 N2O3:583.4833; found:583.4826.

[0077] 1H NMR(CDCl3,400MHz)δ:5.18(t,J=3.6Hz,1H),4.81(t,J=6.2Hz,1H),4.55(t,J=6.1Hz,1H ),3.97(ddd,J=11.7,4.6,1.8Hz,2H),3.36(td,J=11.8,2.0Hz,2H),3.21(dt,J=10.4,5. 0Hz,2H),3.16–3.01(m,3H),1.99–1.68(m,6H),1.66–1.57(m,6H),1.56–1.49(m,5H),1. 40–1.16(m,9H),1.13(s,3H),1.02–0.89(m,10H),0.86–0.79(m,9H),0.77–0.69(m,1H).

[0078] 13 C NMR(CDCl3,100MHz)δ:158.6,144.7,122.2,79.0,67.7,55.2,47.7,46.4,44.8,43.0,41.7,39.8,38.8,3 7.0,36.5,35.9,34.8,32.7,32.4,31.1,30.7,28.4,28.1,27.3,27.1,26.1,23.6,18.4,16.8,15.6,15.5

[0079] Synthesis Example 2-Synthesis of Compound C2:

[0080]

[0081] The synthetic route of compound C2 is as follows:

[0082]

[0083] Dissolve CDI (81 mg, 0.504 mmol, 2.4 eq) and isobutylamine (0.04 mL, 0.42 mmol, 2 eq) in anhydrous dichloromethane and react for 2 h. Dissolve compound 4 (90 mg, 0.21 mmol) in dichloromethane and dropwise add the reaction solution. The reaction is complete in 4-6 h. Wash the organic phase three times with saturated ammonium chloride. Collect the organic phase and evaporate it in vacuum. Column chromatography (mobile phase: dichloromethane / ethanol, 10 / 0.1 v / v) gives white solid 6 (compound C2) (27 mg, 0.0504 mmol, yield 24%). Melting point: 148-150°C.

[0084] HRMS(ESI)[M+H] + m / z calculation for C 35 H61 N2O2:541.4728; found:541.4727.

[0085] 1H NMR (CDCl3, 400MHz) δ: 5.19 (t, J=3.6Hz, 1H), 4.63 (t, J=5.8Hz, 1H), 4.45 (t, J= 6.0Hz,1H),3.27–3.09(m,3H),2.99(q,J=5.9,4.8Hz,2H),2.06–1.88(m,4H),1. 87–1.68(m,2H),1.67–1.37(m,12H),1.37–1.17(m,3H),1.14(s,3H),1.00(s,3 H),0.93(dd,J=15.2,7.7Hz,14H),0.84(s,6H),0.79(s,3H),0.77–0.69(m,1H).

[0086] 13C NMR(CDCl3,100MHz)δ:158.7,144.6,122.3,79.0,55.2,48.1,47.7,46.4,44.7,43.1,41.7,39.8,38.8,3 7.0,36.5,34.7,32.7,32.4,31.0,29.7,29.0,28.4,28.2,27.3,27.2,26.1,23.5,20.1,18.4,16.8,15.6

[0087] Synthesis Example 3-Synthesis of Compound C3:

[0088]

[0089] The synthetic route of compound 7 is as follows:

[0090]

[0091] 18β-Glycyrrhetinic acid (2 g, 4.25 mM, 1 eq) was dissolved in 100 ml of dichloromethane. HATU (1.78 g, 4.675 mM, 1.1 eq) and DIEA (1.55 mL, 9.35 mM, 2.2 eq) were added to the reaction solution in sequence. The solution was observed to change from turbid to clear. Ammonia water (0.82 mL, 10.63 mM, 2.5 eq) was then added and the reaction was continued for 6-8 h. After the reaction was complete, saturated ammonium chloride was added to wash the organic phase three times. The organic phase was collected and rotary evaporated. The white solid 7 (compound 7) (1.9 g, 4.08 mmol, yield 96%) was obtained by recrystallization with anhydrous methanol.

[0092] The synthetic route of compound 8 is as follows:

[0093]

[0094] Nickel chloride ethylene glycol dimethyl ether complex (80 mg, 0.364 mmol, 0.2 eq) and compound 7 (0.3 g, 0.639 mmol, 1.0 eq) were dissolved in 50 mL of dry toluene, the container was evacuated for 5 minutes and backfilled with argon three times, and refluxed in a preheated 115°C oil bath. After 10 minutes, phenylsilane (0.5 mL, 4.05 mmol, 6.3 eq) was added, and the reaction changed from orange to black. The reaction was carried out in a 115°C oil bath for 24 hours, maintaining an argon atmosphere. After the reaction was complete, ethyl acetate was added for dilution, and the pH was adjusted to 9 with 1 N NaOH. The reaction solvent was spin-dried, and then the liquid was extracted with ethyl acetate and water. The organic layer was filtered with diatomaceous earth and subjected to column chromatography (mobile phase: dichloromethane / ethanol / ammonia water, 10 / 0.2 / 0.1 v / v) to obtain a white solid 8 (compound 8) (216 mg, 0.47 mmol, yield 74%).

[0095] HRMS(ESI)[M+H] + m / z calculation for C 30 H 50 NO2:456.3836; found:456.3843.

[0096] 1H NMR (MeOD, 400MHz) δ: 5.69 (s, 1H), 3.22 (dd, J = 11.0, 5.3Hz, 1H), 2.81–2.72 ( m,3H),2.32(s,1H),2.09–1.90(m,J=4.3Hz,2H),1.82(td,J=13.8,4.6Hz,1H ),1.69–1.62(m,4H),1.50–1.28(m,7H),1.36(s,3H),1.28–1.14(m,2H),1.1 2(m,4H),1.05–0.90(m,9H),0.84(d,J=29.5Hz,7H),0.69(d,J=11.5Hz,1H).

[0097] The synthetic route of compound C3 is as follows:

[0098]

[0099] Dissolve CDI (120 mg, 0.74 mmol, 2.2 eq) and 4-aminomethyltetrahydropyran (0.06 mL, 0.5 mmol, 1.51 eq) in dry dichloromethane and react for 2-3 h. Dissolve compound 8 (150 mg, 0.329 mmol) in dichloromethane and drop into the reaction solution. After the reaction is complete, wash the organic phase with saturated ammonium chloride, collect the organic phase and evaporate it in vacuum, and then chromatograph it on a silica gel column (mobile phase: dichloromethane / ethanol, 10:0.1 v / v) to obtain white solid 9 (compound C3) (110 mg, 0.184 mmol, yield 56%). Melting point: 141-142°C.

[0100] HRMS(ESI)[M+H] + m / z calculation for C 37 H 61 N2O4:597.4626; found:597.4625.

[0101] 1H NMR (CDCl3, 400MHz) δ: 5.52 (s, 1H), 4.69 (t, J = 6.0Hz, 1H), 4.43 (t, J = 6.3Hz, 1H), 3.89 (dd, J = 11.3, 4.4Hz ,2H),3.29(tt,J=11.8,2.6Hz,2H),3.19–2.98(m,5H),2.72(dt,J=13.6,3.6Hz,1H),2.24(s,1H),2.17(d d,J=14.1,4.5Hz,1H),1.99(td,J=13.6,4.4Hz,1H),1.81–1.63(m,2H),1.63–1.50(m,10H),1.37–1.29(m ,3H),1.29–1.27(s,3H),1.22–1.07(m,6H),1.05(s,6H),0.96–0.71(m,12H),0.62(d,J=11.4Hz,1H).13C NMR(CDCl3,100MHz)δ:200.4,170.4,158.5,128.3,78.8,67.7,61.9,55.0,46.7,46.2,45.4,44.3,43.4,41.1,39.2,3 9.2,37.2,35.9,34.9,32.7,32.2,31.1,30.6,29.7,28.6,28.3,28.1,27.3,26.6,26.4,23.6,18.7,17.5,16.4,15.6.

[0102] Synthesis Example 4-Synthesis of Compound C4:

[0103]

[0104] The synthetic route of compound C4 is as follows:

[0105]

[0106] N,N′-Carbonyldiimidazole CDI (81 mg, 0.504 mmol, 1.5 eq) and isobutylamine (0.04 mL, 0.42 mmol, 1.27 eq) were dissolved in anhydrous dichloromethane DCM and reacted for 2-3 h. Compound 8 (150 mg, 0.329 mmol) was dissolved in dichloromethane and added dropwise to the reaction solution. After the reaction was complete, the organic phase was washed with saturated ammonium chloride, and the organic phase was collected and vacuum evaporated. The white solid 10 (compound C4) (98 mg, 0.181 mmol, yield 55%) was obtained by silica gel column chromatography (mobile phase: dichloromethane / ethanol, 10 / 0.1 v / v). Melting point: 145-147°C.

[0107] HRMS(ESI)[M+H] + m / z calculation for C 35 H 61 N2O2:555.4520; found:555.4518.

[0108] 1 H NMR (CDCl3, 400MHz) δ: 5.52 (s, 1H), 4.81 (d, J = 7.7Hz, 1H), 4.62 (s, 1H), 3.19–3.12 (m, 2H), 3.12 (d, J = 6.9Hz, 1H), 2.92 (t, J = 5.8Hz, 2H), 2. 72(dt,J=13.7,3.7Hz,1H),2.25(s,1H),2.15(dd,J=14.0,4.4Hz,1H),1.99(td,J=13.6,4.4Hz,1H),1.75(dt,J=14.0,7.0Hz,1H),1.66–1.5 3(m,3H),1.53(d,J=10.1Hz,3H),1.50–1.39(m,1H),1.36(d,J=11.2Hz,1H),1.29(s,3H),1.26(d,J=3.5Hz,1H),1.25–1.06(m,4H),1.05(s ,6H),0.93(d,J=4.5Hz,4H),0.91–0.83(m,1H),0.81(dd,J=15.2,6.7Hz,12H),0.74(d,J=15.9Hz,1H),0.73(s,3H),0.62(d,J=11.0Hz,1H).

[0109] 13C NMR (CDCl3, 100MHz) δ: 200.5, 170.5, 170.5, 158.8, 128.2, 78.8, 61.9, 55.0, 48.0, 46.7, 45.4, 44.2, 43.4, 41. 2,39.2,38.9,37.2,35.9,34.9,32.7,31.0,28.6,28.1,27.3,26.6,23.5,20.2,20.0,18.7,17.5,16.4,15.6.

[0110] Synthesis Example 5-Synthesis of Compound C5:

[0111]

[0112] The synthetic route of compound C5 is as follows:

[0113]

[0114] Compound 8 (220 mg, 0.48 mM, 1 eq) was dissolved in 10 mL of anhydrous dichloromethane, DIEA (0.16 mL, 0.96 mM, 2 eq) was added, and the reaction system was placed in an ice-water bath at 0°C. Triphosgene (43 mg, 0.144 mM, 0.3 eq) was dissolved in 3 mL of anhydrous dichloromethane and added dropwise to the reaction system via a constant pressure dropping funnel. After the addition was complete, p-trifluoromethoxybenzylamine (0.07 mL, 0.48 mM, 1 eq) was immediately added, and the reaction was continued for 30-60 min. The organic phase was washed three times with saturated brine, and the organic phase was collected and rotary evaporated. The white solid 11 (compound C5) (150 mg, 0.223 mM, yield 46%) was obtained by silica gel column (mobile phase: dichloromethane / ethanol, 10 / 0.1 v / v). Melting point: 162-164°C

[0115] HRMS(ESI)[M+H] + m / z calculation for C 39 H 56 F3N2O4:673.4187; found:673.4186.

[0116] 1H NMR (400MHz, Methanol-d4) δ7.40(d,J=8.6Hz,2H),7.21(d,J=7.7Hz,2H),5.65(s,1H),4.44–4.30(m,2H),3.48(dd,J= 13.6,5.8Hz,1H),3.19(dd,J=11.8,4.6Hz,1H),2.93(dd,J=13.7,4.8Hz,1H),2.77(dt,J=13.4,3.6Hz,1H),2.45(s,1H ),2.40(dd,J=13.6,4.3Hz,1H),2.17(td,J=13.6,4.4Hz,1H),1.89(td,J=13.6,4.5Hz,1H),1.80–1.44(m,9H),1.42(s ,3H),1.35–1.18(m,5H),1.16(s,6H),1.10–0.96(m,6H),0.92(s,3H),0.87(s,3H),0.82(s,3H),0.78(d,J=9.8Hz,1H).

[0117] 13 C NMR (100MHz, CDCl3) δ200.4,170.4,158.4,148.3,138.4,128.8,128.2,121.2,78.8,61.9,55.0,46.7,45.4,44.4,43.8,43 .3,41.0,39.2,39.2,37.1,35.8,34.8,32.7,32.2,31.1,28.6,28.2,28.1,27.3,26.6,26.4,23.5,18.7,17.5,16.4,15.6.

[0118] Synthesis Example 6-Synthesis of Compound C6:

[0119]

[0120] The synthetic route of compound C6 is as follows:

[0121]

[0122] Compound 8 (280 mg, 0.62 mM, 1 eq) was dissolved in 10 mL of anhydrous dichloromethane, DIEA (0.2 mL, 1.23 mM, 2 eq) was added, and the reaction system was placed in an ice-water bath at 0°C. Triphosgene (54 mg, 0.186 mM, 0.3 eq) was dissolved in 3 mL of anhydrous dichloromethane and added dropwise to the reaction system via a constant pressure dropping funnel. After the addition was complete, 4-aminomethylpropionylpiperidine (104 mg, 0.62 mM, 1 eq) was immediately added, and the reaction was continued for 30-60 min. The organic phase was washed three times with saturated brine, and the organic phase was collected and rotary evaporated. The white solid 12 (compound C6) (150 mg, 0.23 mM, yield 38%) was obtained by silica gel column (mobile phase: dichloromethane / ethanol, 10 / 0.15 v / v). Melting point: 174-176°C

[0123] HRMS(ESI)[M+H] + m / z calculation for C 40 H 66 N3O4:652.5048; found:652.5058.

[0124] 1 H NMR (400MHz, Chloroform-d) δ5.52(s,1H),4.99(s,1H),4.77(d,J=6.0Hz,1H),4.52(d,J=13.2Hz,1H),3.79(d,J=13. 4Hz,1H),3.27(m,1H),3.15(dd,J=11.0,5.1Hz,2H),2.94(m,3H),2.72(dt,J=13.9,4.1Hz,1H),2.45(m,J=12.7,2.9Hz ,1H),2.33–2.19(m,4H),1.99(td,J=13.7,4.4Hz,1H),1.80–1.44(m,10H),1.42–1.31(m,3H),1.29(s,3H),1.25–1.10 (m,5H),1.09–1.01(m,10H),0.93(s,3H),0.87(m,2H),0.81(s,3H),0.77(s,3H),0.73(s,3H),0.62(d,J=12.1Hz,1H).

[0125] 13C NMR (100MHz, CDCl3) δ200.3,172.4,170.5,158.7,128.2,78.8,61.9,55.0,46.5,45.6,45.4,44.3,43.3,41.8,41.0,40.8,39.2, 37.1,37.0,35.9,35.0,32.7,32.2,31.3,30.4,29.7,28.7,28.3,28.1,27.3,26.6,26.6,26.5,23.6,18.7,17.5,16.4,15.6,9.7.

[0126] Synthesis Example 7-Synthesis of Compound C7:

[0127]

[0128] The synthetic route of compound C7 is as follows:

[0129]

[0130] Compound 7 (250 mg, 0.55 mM, 1 eq) was dissolved in 10 mL of anhydrous dichloromethane, DIEA (0.18 mL, 1.10 mM, 2 eq) was added, and the reaction system was placed in an ice-water bath at 0°C. Triphosgene (50 mg, 0.165 mM, 0.3 eq) was dissolved in 3 mL of anhydrous dichloromethane and added dropwise to the reaction system via a constant pressure dropping funnel. After the addition was complete, 4-pyridinemethylamine (0.06 mL, 0.55 mM, 1 eq) was immediately added, and the reaction was continued for 1-2 h. The organic phase was washed three times with saturated brine, and the organic phase was collected and rotary evaporated. The white solid 13 (compound C7) (180 mg, 0.31 mM, yield 55%) was obtained by silica gel column (mobile phase: dichloromethane / ethanol, 10 / 0.2 v / v). Melting point: 174.1-175.4°C

[0131] HRMS(ESI)[M+H] + m / z calculation for C 37 H 56 N3O3:590.4316; found:590.4315.

[0132] 1H NMR(400MHz,Chloroform-d)δ8.53(d,J=5.0Hz,2H),7.27(s,2H),5.55(s,1H),5.44(t,J=6.0Hz,1H),4.91–4.75(m,1H),4.40(d,J=6.0Hz,2 H),3.33(dd,J=13.6,6.5Hz,1H),3.21(dd,J=11.1,5.1Hz,1H),3.07(dd,J=13.6,5.9Hz,1H),2.76(dt,J=13.5,3.6Hz,1H),2.31(s,1H),2.24 (dd,J=14.1,4.6Hz,2H),2.04(td,J=13.6,4.3Hz,1H),1.81(td,J=13.5,4.4Hz,1H),1.59(m,5H),1.44–1.37(m,2H),1.35(s,3H),1.28(d,J= 16.1Hz,3H),1.22–1.13(m,2H),1.11(d,J=2.2Hz,6H),1.00(s,3H),0.95(s,2H),0.85(d,J=6.9Hz,6H),0.80(s,3H),0.68(d,J=11.3Hz,1H).

[0133] 13 C NMR (175MHz, CDCl3) δ200.4,170.6,158.4,149.1,128.2,122.5,78.7,61.9,55.0,46.6,45.4,44.4,43.3,40.8, 39.2,39.2,37.1,35.8,34.9,32.7,32.2,31.2,28.6,28.3,28.1,27.3,26.5,26.4,23.6,18.7,17.5,16.4,15.6.

[0134] Synthesis Example 8-Synthesis of Compound C8:

[0135]

[0136] The synthetic route of intermediate 1 is as follows:

[0137]

[0138] Methylsulfonylbenzylamine (0.5 g, 2.7 mM, 1 eq) was dissolved in tetrahydrofuran and dichloromethane (v / v=1:1), placed in an ice-water bath, and triethylamine (0.32 mL, 1 eq) was added. p-Nitrophenyl chloroformate (0.54 g, 1 eq) was dissolved in tetrahydrofuran and dichloromethane (v / v=1:1) and added dropwise into the reaction system. The addition time was controlled at about 30 min. The reaction was complete after 1 h. The mixture was filtered with diatomaceous earth, the original solvent was rotary evaporated, and the mixture was extracted with dichloromethane and saturated brine three times. The organic phase was collected and rotary evaporated to obtain intermediate 1 (0.61 g, yield 65%).

[0139] The synthetic route of compound C8 is as follows:

[0140]

[0141] Compound 8 (140 mg, 0.31 mM) was dissolved in 2 ml of dichloromethane, then 10 ml of acetonitrile was added, intermediate 1 (130 mg, 1.2 eq) and pyridine (0.13 mL, 5 eq) were added, refluxed at 80 ° C, reacted for 1 h, the original solvent was dried, and passed through a silica gel column (mobile phase: dichloromethane / ethanol, 10 / 0.2 v / v) to obtain a white solid powder 14 (compound C8) (120 mg, yield 58%). Melting point: 189-191 ° C

[0142] HRMS(ESI)[M+H] + m / z calculation for C 39 H 59 N2O5S:667.4139; found:667.4144.

[0143] 1H NMR (400MHz, Chloroform-d) δ7.77(d,J=8.0Hz,2H),7.39(d,J=8.1Hz,2H),5.60(s,1H),5.44(t,J=6.1Hz,1H),4.87(t,J=6.2Hz,1H),4.42(d,J=5.9 Hz,2H),3.33(dd,J=13.7,6.4Hz,1H),3.22(dd,J=10.7,5.5Hz,1H),3.08( d,J=6.0Hz,1H),3.05(s,3H),2.77(dt,J=13.3,3.6Hz,1H),2.33(s,1H),2. 30–2.21(m,1H),2.05(td,J=13.5,4.4Hz,1H),1.81(td,J=13.8,4.4Hz,1H ),1.59(dd,J=11.8,4.8Hz,4H),1.55–1.46(m,2H),1.45–1.38(m,2H),1.36 (s,3H),1.33–1.25(m,3H),1.18(td,J=14.2,13.8,3.7Hz,2H),1.11(s,6H ),1.00(s,5H),0.86(d,J=8.7Hz,6H),0.80(s,3H),0.69(d,J=11.4Hz,1H).

[0144] 13 C NMR (100MHz, CDCl3) δ200.5,170.7,158.4,146.8,138.8,128.2,127.9,127.6,78.8,61.9,55.0,46.6,45.4,44.5,44.3,43.6 ,43.4,40.8,39.2,39.2,37.2,35.9,34.9,32.7,32.2,31.3,28.7,28.3,28.1,27.3,26.6,26.4,23.6,18.7,17.5,16.4,15.6.

[0145] Synthesis Example 9-Synthesis of Compound C9:

[0146]

[0147] The synthetic route of intermediate 2 is as follows:

[0148]

[0149] Aminosulfonylbenzylamine (0.6 g, 2.7 mM, 1 eq) was dissolved in tetrahydrofuran and dichloromethane (v / v=1:1), placed in an ice-water bath, triethylamine (0.32 mL, 1 eq) was added, p-nitrophenyl chloroformate (0.54 g, 1 eq) was dissolved in tetrahydrofuran and dichloromethane (v / v=1:1) and added dropwise into the reaction system. The addition time was controlled at about 30 min. The reaction was complete after 1 h, filtered with diatomaceous earth, the original solvent was rotary evaporated, extracted with dichloromethane and saturated brine three times, the organic phase was collected, and rotary evaporated to obtain intermediate 2 (0.45 g, yield 35%).

[0150] The synthetic route of compound C9 is as follows:

[0151]

[0152] Compound 8 (210 mg, 0.46 mM) was dissolved in 2 ml of dichloromethane, then 10 ml of acetonitrile was added, intermediate 2 (194 mg, 1.2 eq) and pyridine (0.13 mL, 5 eq) were added, refluxed at 80 ° C, reacted for 1 h, the original solvent was dried, and passed through a silica gel column (mobile phase: dichloromethane / ethanol, 10 / 0.3 v / v) to obtain a white solid powder 15 (compound C9) (130 mg, yield 41%). Melting point: 196-198 ° C

[0153] HRMS(ESI)[M+H] + m / z calculation for C 38 H 58 N3O5S:668.4092; found:668.4102.

[0154] 1 H NMR(400MHz,Chloroform-d)δ7.61(d,J=7.9Hz,2H),7.20(d,J=7.9Hz,2H),6.00(s,2H),5.76(s,1H),5.63 (s,1H),5.23(s,1H),4.31(m,2H),3.38(s,1H),3.17(d,J=9.7Hz,1H),3.03–2.89(m,1H),2.62(d,J=12.2Hz ,1H),2.31(s,1H),2.26–2.17(m,1H),2.03(m,1H),1.69–1.45(m,7H),1.38(m,6H),1.27(m,3H),1.16(d,J =10.5Hz,1H),1.06(d,J=15.7Hz,6H),0.98(s,4H),0.91–0.80(m,7H),0.76(s,3H),0.66(d,J=11.4Hz,1H).

[0155] 13 C NMR (175MHz, CDCl3) δ201.5,172.0,158.8,145.3,140.6,128.0,127.4,126.4,78.6,61.9,54.9,53.4,46.8,45.6,44.0,43 .5,40.2,39.2,39.1,37.1,35.8,35.0,32.7,32.2,31.8,28.7,28.3,28.1,27.2,26.6,26.4,23.5,18.7,17.4,16.4,15.7.

[0156] Synthesis Example 10-Synthesis of Compound C10:

[0157]

[0158] The synthetic route of compound C10 is as follows:

[0159]

[0160] DMP (85 mg, 0.2 mM, 1.2 eq) was dissolved in 10 mL of anhydrous dichloromethane, and compound C3 (0.1 g, 0.17 mM) was dissolved in 5 mL of anhydrous dichloromethane and dripped into the reaction system dropwise. Argon was always filled in the entire system. After the reaction was complete, the organic phase was washed three times with saturated sodium bicarbonate solution, and the organic phase was collected and evaporated. After silica gel column chromatography (mobile phase: dichloromethane / ethanol, 10 / 0.15 v / v), a white solid 16 (compound C10) (66 mg, 0.111 mM, yield 65%) was obtained. Melting point: 90.5-92.5 ° C

[0161] HRMS(ESI)[M+H] + m / z calculation for C 37 H 59 N2O4:595.4469; found:595.4470.

[0162] 1H NMR (400MHz, Methanol-d4) δ5.67(s,1H),3.98–3.87(m,2H),3.52–3.33(m,3H),3.11(dd,J=13.6,6.5Hz,1H),2.97(dd, J=13.6,6.7Hz,1H),2.90–2.80(m,2H),2.64–2.53(m,2H),2.47–2.35(m,2H),2.17(td,J=13.6,4.4Hz,1H),1.90(td,J= 13.7,4.6Hz,1H),1.82–1.67(m,2H),1.65–1.57(m,5H),1.55–1.45(m,3H),1.43(s,3H),1.40–1.35(m,1H),1.34–1.26( m,4H),1.25(s,4H),1.21(d,J=4.1Hz,1H),1.19(s,3H),1.08(d,J=12.7Hz,6H),1.01(m,1H),0.92(s,3H),0.86(s,3H).

[0163] 13 C NMR (175MHz, CDCl3) δ217.4,199.6,170.8,158.3,128.2,67.7,61.1,55.5,47.8,46.6,46.3,45.2,44.4,43.4,41.1,39. 8,36.7,35.9,35.8,34.9,34.3,32.2,32.1,31.0,30.6,29.7,28.7,28.3,26.5,26.5,26.4,23.5,21.4,18.8,18.6,15.7.

[0164] Synthesis Example 11-Synthesis of Compound C11:

[0165]

[0166] The synthetic route of compound 18 is as follows:

[0167]

[0168] 18α-Glycyrrhetinic acid 17 (2.0 g, 4.25 mM, 1 eq) was dissolved in 100 ml of dichloromethane. HATU (1.78 g, 4.675 mM, 1.1 eq) and DIEA (1.55 mL, 9.35 mM, 2.2 eq) were added to the reaction solution in sequence. The solution was observed to change from turbid to clear. Ammonia water (0.82 mL, 10.63 mM, 2.5 eq) was then added and the reaction was continued for 6-8 h. After the reaction was complete, saturated ammonium chloride was added to wash the organic phase three times. The organic phase was collected and rotary evaporated. The white solid 18 (compound 18) (1.9 g, 4.26 mmol, yield 96%) was obtained by recrystallization with anhydrous methanol.

[0169] The synthetic route of compound 19 is as follows:

[0170]

[0171] Nickel chloride glycol dimethyl ether complex (80 mg, 0.364 mmol, 0.2 eq) and compound 18 (0.3 g, 0.639 mmol, 1.0 eq) were dissolved in 50 mL of dry toluene, the container was evacuated for 5 minutes and backfilled with argon three times, and refluxed in a preheated 115°C oil bath. After 10 minutes, phenylsilane (0.5 mL, 4.05 mmol, 6.3 eq) was added, and the reaction changed from orange to black. The reaction was carried out in a 115°C oil bath for 24 hours, and the argon atmosphere was maintained. After the reaction was complete, ethyl acetate was added for dilution, and the pH was adjusted to 9 with 1 N NaOH. The reaction solvent was spin-dried, and then the liquid was extracted with ethyl acetate and water. The organic layer was filtered with diatomaceous earth, and the white solid 19 (compound 19) (158 mg, 0.35 mmol, yield 54%) was obtained by column chromatography (mobile phase: dichloromethane / ethanol / ammonia water, 10 / 0.2 / 0.1 v / v)

[0172] HRMS(ESI)[M+H] + m / z calculation for C 30 H 50 NO2:456.3836; found:456.3835.

[0173] 1H NMR(400MHz,Chloroform-d)δ5.57(d,J=1.9Hz,1H),3.24(dd,J=11.3,5.0Hz,1H),2.71 (dt,J=13.4,3.6Hz,1H),2.50(s,2H),2.31–2.22(m,2H),2.00(td,J=13.7,5.0Hz,1H), 1.73–1.40(m,10H),1.37(s,3H),1.35–1.24(m,3H),1.22(s,3H),1.19(d,J=11.7Hz,2H ),1.16(s,3H),1.02(s,3H),1.00–0.93(m,1H),0.92(s,3H),0.83(s,3H),0.69(s,4H). 13 CNMR(175MHz, CDCl3)δ200.0,166.8,124.0,78.8,60.7,56.3,55.0,45.0,43.9,40.8,39.1,39.1,37.8 ,36.9,36.5,36.0,35.5,33.8,32.9,29.4,28.1,27.3,26.8,21.0,20.8,18.5,17.6,16.6,16.1,15.7.

[0174] The synthetic route of compound C11 is as follows:

[0175]

[0176] Dissolve CDI (120 mg, 0.74 mmol, 2.2 eq) and 4-aminomethyltetrahydropyran (0.06 mL, 0.5 mmol, 1.51 eq) in dry dichloromethane and react for 2-3 h. Dissolve compound 19 (150 mg, 0.329 mmol) in dichloromethane and drop into the reaction solution. After the reaction is complete, wash the organic phase with saturated ammonium chloride, collect the organic phase and evaporate it in vacuum, and then chromatograph it on a silica gel column (mobile phase: dichloromethane / ethanol, 10:0.1 v / v) to obtain a white solid 20 (compound C11) (127 mg, 0.214 mmol, yield 65%). Melting point: 152.5-154°C

[0177] HRMS(ESI)[M+H] + m / z calculation for C 37 H 61 N2O4:597.4626; found:597.4622.

[0178] 1H NMR(400MHz,Chloroform-d)δ5.45(d,J=1.8Hz,1H),5.05–4.82(m,2H),3.88(dd,J=11.7,4.3Hz,2H),3.28(tt,J=11.6,1.8H z,2H),3.15(dd,J=11.2,5.0Hz,1H),3.01(q,J=6.0Hz,3H),2.87(dd,J=13.4,6.0Hz,1H),2.60(dt,J=13.4,3.5Hz,1H),2.19( s,1H),2.17–2.09(m,1H),1.89(td,J=13.7,4.9Hz,1H),1.68–1.33(m,14H),1.26(s,3H),1.24–1.16(m,4H),1.10(d,J=5.9Hz ,5H),1.05(s,3H),0.93(s,3H),0.88(dd,J=13.2,4.0Hz,1H),0.82(s,3H),0.74(s,3H),0.62(d,J=11.5Hz,1H),0.58(s,3H). 13 C NMR (100MHz, CDCl3) δ200.5,167.3,159.0,123.7,78.8,67.7,60.8,55.0,53.3,46.2,45.0,44.0,40.8,39.2,39.1,3 7.7,36.9,36.3,35.9,35.9,35.6,33.8,33.0,30.7,29.7,28.1,27.3,26.8,21.3,20.8,18.5,17.6,16.6,16.1,15.7.

[0179] Synthesis Example 12-Synthesis of Compound C12:

[0180]

[0181] The synthetic route of compound C12 is as follows:

[0182]

[0183] Dissolve CDI (81 mg, 0.504 mmol, 1.5 eq) and isobutylamine (0.04 mL, 0.42 mmol, 1.27 eq) in anhydrous dichloromethane and react for 2-3 h. Dissolve compound 19 (150 mg, 0.329 mmol) in dichloromethane and drop into the reaction solution. After the reaction is complete, wash the organic phase with saturated ammonium chloride, collect the organic phase and evaporate it in vacuum, and then perform silica gel column chromatography (mobile phase: dichloromethane / ethanol, 10 / 0.1 v / v) to obtain white solid 21 (compound C12) (112 mg, 0.188 mmol, yield 57%). Melting point: 166.1-167.9°C

[0184] HRMS(ESI)[M+H] + m / z calculation for C 35 H 59 N2O3:555.4520; found:555.4524.

[0185] 1 H NMR(400MHz,Chloroform-d)δ5.46(d,J=1.8Hz,1H),4.68(s,1H),4.64(s,1H),3. 15(dd,J=11.2,5.0Hz,1H),3.01(dd,J=13.5,5.8Hz,1H),2.93(t,J=5.9Hz,3H),2. 61(dt,J=13.4,3.6Hz,1H),2.19(s,1H),2.17–2.10(m,1H),1.90(td,J=13.7,4.9H z,1H),1.72–1.33(m,11H),1.26(s,3H),1.25–1.17(m,4H),1.12(s,4H),1.05(s,3 H),0.93(s,3H),0.84(d,J=6.5Hz,10H),0.74(s,3H),0.62(dd,J=11.7,1.8Hz,1H) ,0.58(s,3H).13CNMR(175MHz,CDCl3)δ200.3,167.0,158.8,123.8,78.8,60.7,55 .0,53.3,48.1,44.9,43.9,40.7,39.2,39.1,37.7,36.9,36.3,35.9,35.6,33.8,33.0,29.6,29.0,28.1,27.3,26.7,21.2,20.8,20.2,18.5,17.6,16.6,16.0,15.7.

[0186] Synthesis Example 13-Synthesis of Compound C13:

[0187]

[0188] The synthetic route of compound C13 is as follows:

[0189]

[0190] Compound 19 (220 mg, 0.48 mM, 1 eq) was dissolved in 10 mL of anhydrous dichloromethane, DIEA (0.16 mL, 0.96 mM, 2 eq) was added, and the reaction system was placed in an ice-water bath at 0°C. Triphosgene (43 mg, 0.144 mM, 0.3 eq) was dissolved in 3 mL of anhydrous dichloromethane and added dropwise to the reaction system via a constant pressure dropping funnel. After the addition was complete, p-trifluoromethoxybenzylamine (0.07 mL, 0.48 mM, 1 eq) was immediately added, and the reaction was continued for 30-60 min. The organic phase was washed three times with saturated brine, and the organic phase was collected and rotary evaporated. The white solid 22 (compound C13) (129 mg, 0.192 mM, yield 40%) was obtained by silica gel column (mobile phase: dichloromethane / ethanol, 10 / 0.1 v / v). Melting point: 156.5-157.7°C

[0191] HRMS(ESI)[M+H] + m / z calculation for C 39 H 56 F3N2O4:673.4187; found:673.4183.

[0192] 1H NMR(400MHz,Chloroform-d)δ7.30(d,J=8.6Hz,2H),7.13(d,J=8.6Hz,2H),5.47(d,J=1.8Hz,1H),5.20(t,J=5.9Hz,1H),4.86(t,J=6.4Hz,1H), 4.36(dd,J=5.9,2.5Hz,2H),3.21(dd,J=11.2,5.0Hz,1H),3.09(dd,J=13.4,6.8Hz,1H),2.93(dd,J=13.4,6.0Hz,1H),2.66(dt,J=13.4,3.5Hz, 1H),2.24(s,1H),2.21–2.13(m,1H),1.95(td,J=13.7,5.0Hz,1H),1.72 –1.35(m,8H),1.31(s,3H),1.30–1.22(m,2H),1.18(s,3H),1.16–1.12( m,2H),1.11(s,3H),1.09–1.01(m,2H),0.99(s,3H),0.91(dd,J=14.9,5 .6Hz,2H),0.85(s,3H),0.80(s,3H),0.68(d,J=9.8Hz,1H),0.62(s,3H).

[0193] 13 C NMR (175MHz, CDCl3) δ200.4,167.0,158.5,148.3,138.4,128.8,123.7,121.1,78.8,60.8,55.0,53.3,44.9,43.9,43.7,40 .7,39.2,39.1,37.7,36.9,36.3,35.9,35.6,33.8,32.9,29.6,28.1,27.3,26.7,21.1,20.8,18.5,17.6,16.6,16.0,15.7.

[0194] Synthesis Example 14-Synthesis of Compound C14:

[0195]

[0196] The synthetic route of compound C14 is as follows:

[0197]

[0198] Compound 19 (280 mg, 0.62 mM, 1 eq) was dissolved in 10 mL of anhydrous dichloromethane, DIEA (0.2 mL, 1.23 mM, 2 eq) was added, and the reaction system was placed in an ice-water bath at 0°C. Triphosgene (54 mg, 0.186 mM, 0.3 eq) was dissolved in 3 mL of anhydrous dichloromethane and added dropwise to the reaction system via a constant pressure dropping funnel. After the addition was complete, 4-aminomethylpropionylpiperidine (104 mg, 0.62 mM, 1 eq) was immediately added, and the reaction was continued for 30-60 min. The organic phase was washed three times with saturated brine, and the organic phase was collected and rotary evaporated. The white solid 23 (compound C14) (161 mg, 0.248 mM, yield 40%) was obtained by silica gel column (mobile phase: dichloromethane / ethanol, 10 / 0.15 v / v). Melting point: 169.5-170.5°C

[0199] HRMS(ESI)[M+H] + m / z calculation for C 40 H 66 N3O4:652.5048; found:652.5055.

[0200] 1 H NMR(400MHz,Chloroform-d)δ5.50(d,J=1.8Hz,1H),5.07–4.88(m,2H),4.60(d,J=13.2Hz,1H),3.85(d,J=13.5Hz,1H),3.19(tt,J=13.0,5 .6Hz,2H),3.02(m,4H),2.66(dt,J=13.3,3.6Hz,1H),2.57–2.46(m,1H),2.33(qd,J=7.5,2.4Hz,2H),2.25(s,1H),2.23–2.16(m,1H),1.96 (td,J=13.9,5.0Hz,1H),1.72(td,J=14.0,13.6,7.3Hz,4H),1.63–1.54(m,4H),1.53–1.37(m,5H),1.33(s,3H),1.29(m,2H),1.16(d,J=16 .0Hz,7H),1.12(d,J=2.5Hz,6H),1.00(s,3H),0.95(dd,J=13.1,4.3Hz,2H),0.89(s,3H),0.80(s,3H),0.68(d,J=10.7Hz,1H),0.64(s,3H). 13C NMR (100MHz, CDCl3) δ200.3,172.3,167.1,158.8,123.7,78.8,60.8,55.0,53.3,45.6,45.5,45.0,43.9,41.7,40.7,39.2,39.1, 37.7,37.1,36.9,36.3,35.9,35.7,33.8,33.0,30.4,29.6,28.1,27.3,26.8,26.6,21.3,20.8,18.5,17.6,16.6,16.1,15.7,9.7.

[0201] Synthesis Example 15-Synthesis of Compound C15:

[0202]

[0203] The synthetic route of compound C15 is as follows:

[0204]

[0205] Compound 19 (250 mg, 0.55 mM, 1 eq) was dissolved in 10 mL of anhydrous dichloromethane, DIEA (0.18 mL, 1.10 mM, 2 eq) was added, and the reaction system was placed in an ice-water bath at 0°C. Triphosgene (50 mg, 0.165 mM, 0.3 eq) was dissolved in 3 mL of anhydrous dichloromethane and added dropwise to the reaction system via a constant pressure dropping funnel. After the addition was complete, 4-pyridinemethylamine (0.06 mL, 0.55 mM, 1 eq) was immediately added, and the reaction was continued for 1-2 h. The organic phase was washed three times with saturated brine, and the organic phase was collected and evaporated by rotary evaporation, and passed through a silica gel column (mobile phase: dichloromethane / ethanol, 10 / 0.2 v / v) to obtain a white solid 24 (compound C15) (168 mg, 0.286 mM, yield 52%). Melting point: 178-180°C

[0206] HRMS(ESI)[M+H] + m / z calculation for C 37 H 56 N3O3:590.4316; found:590.4326.

[0207] 1H NMR (400MHz, Methanol-d4) δ8.63–8.33(m,2H),7.37(d,J=4.9Hz,2H),5.53(s,1H),4.40(s,2H),3.19(dd,J=11.7,4.6H z,1H),3.04(d,J=2.8Hz,2H),2.66(dt,J=13.4,3.7Hz,1H),2.39(s,1H),2.34(dd,J=11.0,4.3Hz,1H),2.05(td,J=13.8 ,4.8Hz,1H),1.75(m,2H),1.69–1.61(m,2H),1.55(m,3H),1.51(s,1H),1.46(d,J=13.1Hz,2H),1.40(s,3H),1.37–1.29 (m,3H),1.23(d,J=7.9Hz,5H),1.17(s,4H),1.01(s,5H),0.95(s,3H),0.82(s,3H),0.78(d,J=11.6Hz,1H),0.72(s,3H). 13 C NMR (100MHz, CDCl3) δ200.5,167.2,158.6,149.9,149.1,123.6,122.2,78.8,60.8,55.0,53.3,45.0,43.9,43.3,40.7, 39.2,39.1,37.6,36.9,36.3,35.9,35.6,33.8,32.9,29.6,28.1,27.3,26.8,21.2,20.8,18.5,17.6,16.6,16.1,15.7.

[0208] Synthesis Example 16-Synthesis of Compound C16:

[0209]

[0210] The synthetic route of compound C16 is as follows:

[0211]

[0212] Compound 19 (140 mg, 0.31 mM) was first dissolved in 2 ml of dichloromethane, then 10 ml of acetonitrile was added, intermediate 1 (130 mg, 1.2 eq) and pyridine (0.13 mL, 5 eq) were added, refluxed at 80°C, reacted for 1 h, the original solvent was dried, and passed through a silica gel column (mobile phase: dichloromethane / ethanol, 10 / 0.2 v / v) to obtain a white solid powder 25 (compound C16) (103 mg, 0.155 mM, yield 50%). Melting point: 185-187°C

[0213] HRMS(ESI)[M+H] + m / z calculation for C 39 H 59 N2O5S:667.4139; found:667.4150.

[0214] 1 H NMR(400MHz,Chloroform-d)δ7.77(d,J=8.0Hz,2H),7.39(d,J=8.1Hz,2H),5.79(s,1H),5.50(s,1H),5.39(d,J=6.3Hz,1H),4.42(s,2H), 3.21(dd,J=11.2,5.1Hz,1H),3.08(dd,J=13.5,6.0Hz,1H),3.04(s,3H),2.93(dd,J=13.5,5.4Hz,1H),2.63(dt,J=13.3,3.4Hz,1H),2.25 (s,1H),2.19(d,J=10.6Hz,1H),1.96(td,J=13.7,5.0Hz,1H),1.73–1.54(m,6H),1.53–1.38(m,5H),1.33(s,3H),1.30–1.23(m,2H),1.15 (d,J=10.9Hz,5H),1.11(s,3H),0.99(s,3H),0.93(dd,J=13.2,3.7Hz,1H),0.87(s,3H),0.79(s,3H),0.68(d,J=11.6Hz,1H),0.64(s,3H).

[0215] 13 C NMR (175MHz, CDCl3) δ200.5,167.4,158.8,146.8,138.8,127.9,127.6,123.6,78.7,60.8,55.0,53.2,45.0,44.5,43.9,43.6 ,40.7,39.2,39.1,37.6,36.9,36.3,35.9,35.7,33.8,32.8,29.7,28.1,27.2,26.8,21.2,20.8,18.5,17.5,16.6,16.1,15.7.

[0216] Synthesis Example 17-Synthesis of Compound C17:

[0217]

[0218] The synthetic route of compound C17 is as follows:

[0219]

[0220] Compound 19 (210 mg, 0.46 mM) was first dissolved in 2 ml of dichloromethane, then 10 ml of acetonitrile was added, intermediate 2 (194 mg, 1.2 eq) and pyridine (0.13 mL, 5 eq) were added, refluxed at 80°C, reacted for 1 h, the original solvent was dried, and passed through a silica gel column (mobile phase: dichloromethane / ethanol, 10 / 0.3 v / v) to obtain a white solid powder 26 (compound C17) 153 mg, 0.23 mM, yield 50%). Melting point: 201-203°C

[0221] HRMS(ESI)[M+H] + m / z calculation for C 38 H 58 N3O5S:668.4092; found:668.4100.

[0222] 1 H NMR (400MHz, Methanol-d4) δ7.83(d,J=8.3Hz,2H),7.44(d,J=8.1Hz,2H),5.51(d,J=1.9Hz,1H),4.40(s,2H),3.17(dd,J=11.7, 4.5Hz,1H),3.08–2.95(m,2H),2.62(dt,J=13.5,3.7Hz,1H),2.38(s,1H),2.31(dt,J=11.3,2.7Hz,1H),2.02(td,J=13.8,4.8Hz ,1H),1.77–1.66(m,2H),1.66–1.57(m,2H),1.57–1.40(m,6H),1.38(s,3H),1.31(d,J=11.8Hz,2H),1.23(d,J=11.6Hz,1H),1.2 0(s,3H),1.15(s,4H),1.03(dd,J=13.2,3.7Hz,1H),0.99(s,3H),0.91(s,3H),0.80(s,3H),0.75(d,J=11.6Hz,1H),0.71(s,3H).

[0223] 13C NMR(175MHz,MeOD)δ201.1,168.5,159.8,145.1,142.1,127.0,126.0,123.1,78.0,60.6,54.9,44.9,43.8,42.8,40.7, 38.9,38.8,37.3,36.7,36.0,35.6,35.6,33.5,32.4,29.2,27.3,26.5,26.4,20.3,19.8,17.8,17.3,15.8,15.1,15.0.

[0224] Synthesis Example 18-Synthesis of Compound C18:

[0225]

[0226] The synthetic route of compound C18 is as follows:

[0227]

[0228] DMP (85 mg, 0.2 mM, 1.2 eq) was dissolved in 10 mL of anhydrous dichloromethane, and compound 11 (0.1 g, 0.17 mM) was dissolved in 5 mL of anhydrous dichloromethane and dripped into the reaction system dropwise. Argon gas always filled the entire system. After the reaction was complete, the organic phase was washed three times with saturated sodium bicarbonate solution, and the organic phase was collected and evaporated. After silica gel column chromatography (mobile phase: dichloromethane / ethanol, 10 / 0.15 v / v), a white solid 27 (compound C18) (67 mg, 0.112 mM, yield 66%) was obtained. Melting point: 87.7-89.0°C

[0229] HRMS(ESI)[M+H] + m / z calculation for C 37 H 59 N2O4:595.4469; found:595.4457.

[0230] 1H NMR(400MHz,Chloroform-d)δ5.49(d,J=1.8Hz,1H),5.03(dt,J=21.4,6.2Hz,2H),3.92–3.84(m,2H),3.28 (m,2H),3.02(dq,J=6.7,3.9Hz,3H),2.88(dd,J=13.5,6.0Hz,1H),2.77(m,1H),2.56(m,1H),2.34–2.23(m, 2H),2.19–2.10(m,1H),1.92(m,1H),1.78–1.58(m,3H),1.57–1.43(m,4H),1.41–1.29(m,4H),1.27(s,3H), 1.24(s,4H),1.23–1.16(m,4H),1.10(d,J=8.2Hz,5H),1.03(s,4H),1.00(s,3H),0.82(s,3H),0.59(s,3H). 13 C NMR (100MHz, CDCl3) δ217.2,199.7,167.7,159.0,123.6,67.7,60.0,55.4,53.3,47.7,46.1,45.1,43.8,40.8,39. 7,37.6,36.5,36.3,36.0,35.6,34.2,33.1,33.0,30.7,29.7,26.8,26.4,21.5,21.2,20.8,18.9,18.4,16.1,15.9.

[0231] The technical effects and advantages of the present invention are verified by applying the glycyrrhetinic acid derivatives of the present invention to inhibit soluble epoxide hydrolases.

[0232] Specifically, the verification method of the glycyrrhetinic acid derivative in the embodiment of the present invention is to incubate the glycyrrhetinic acid derivative prepared by the present invention with a sample containing a soluble epoxide hydrolase and the endogenous hydrolysis substrate 14,15-EET of the hydrolase, and detect the content of the hydrolysis product 14,15-DHET, and use its relative production amount to reflect the inhibitory effect of the compound on the soluble epoxide hydrolase. The specific steps are as follows:

[0233] 1:10 (mg / μL) pre-cooled PBS (phosphate buffer saline) (pH=7.4) was added to the collected brain tissue samples of adult (weight 25-30g) male C57BL / 6J mice, and the samples were disrupted with a homogenizer (Bertin Precellys 24-Dual, Bertin Technologies) for 30 seconds (4°C, 4500rpm), and then centrifuged at 9000g for 15 minutes at 4°C in a small low-temperature centrifuge, and the supernatant was diluted 20 times. In an EP (eppendorf) tube, 160 μL PBS, 20 μL tissue fluid diluted 20 times, and 2 μL of a compound with a concentration gradient of 10000, 5000, 1000, 500, 100, 50, 10, 1, 0.1, and 0.01 μg / mL (final concentration 100, 50, 10, 5, 1, 0.5, 0.1, 0.01, 0.001, and 0.0001 μg / mL) were added and incubated at room temperature for 15 minutes. The negative control was PBS without tissue diluent but with solvent added (180 μL PBS plus 2 μL DMSO), and the positive control was the same concentration sample diluent plus an equal volume of solvent (160 μL PBS plus 20 μL tissue fluid diluted 20 times plus 2 μL DMSO). After the room temperature incubation, all samples were placed on ice, and the enzyme reaction substrate (10 μL 14,15-EET (10 μg / mL)) was quickly added and mixed, and then incubated in a shaker at 37°C. After the incubation, the samples were placed on ice and 10 μL 800 nM t-TUCB (No. 6757, Tocris Bioscience, UK, Bristol) was quickly added to terminate the reaction, and the final volume of the reaction system was 200 μL. In order to detect the enzyme activity, the concentration of the reaction product 14,15-DHET was detected using high performance liquid chromatography-mass spectrometry. The pretreatment is as follows: 1. Add an equal volume (200 μL) of a mixture of methanol and acetonitrile (50 / 50, v / v) to the sample, the mixture contains 0.4% acetic acid and internal standards 11,12-EET-d11 and 11,12-DHET-d11 (20 ng / mL); 2. Mix with a homogenizer at 4500 rpm for 10 minutes and place at -20°C for 2 hours to precipitate the protein; 3. After the sample is centrifuged for 10 minutes (14000 rpm), the supernatant is collected for UPLC-MS / MS analysis. The relative enzyme activity of sEH is calculated by comparing the amount of 14,15-DHET produced at a certain concentration of the test compound with that without an inhibitor, and the inhibition rate is 100% minus the relative enzyme activity.

[0234] The inhibition rate % (5 μg / mL) is the inhibition rate of the tested compound on sEH at 5 μg / mL.

[0235] Among them, the positive control compounds are TPPU and EC5026.

[0236] The verification results of the glycyrrhetinic acid derivatives prepared by the present invention are shown in Table 1:

[0237] Table 1: Inhibitory activity of glycyrrhetinic acid derivatives prepared in the present invention on soluble epoxide hydrolases

[0238]

[0239]

[0240]

[0241] The results of the positive control compounds are shown in Table 2:

[0242] Table 2 Inhibitory activity of positive control compounds on soluble epoxides under the same conditions

[0243]

[0244] The results of negative control compounds are shown in Table 3:

[0245] Table 3 Inhibitory activity of negative control compounds on soluble epoxides under the same conditions

[0246]

[0247] As can be seen from Tables 1 and 2, 18β-glycyrrhetinic acid has no inhibitory effect on soluble epoxide hydrolase (sEH) at a dose of 5 μg / mL. The inhibition rates of positive control compounds TPPU and EC5026 on sEH were 99.5% and 99.74%, respectively, and the IC50s were 44nM and 19nM, respectively. The glycyrrhetinic acid derivatives prepared by the present invention have equivalent or better sEH inhibitory activity (the IC50 of compounds C3, C11, C5, C6, C7, C14 and C15 is less than 10nM), indicating that the compounds synthesized based on the glycyrrhetinic acid skeleton of the present invention can enhance the interaction with sEH. From the data of the negative control compounds in Table 3, it can be seen that the inhibition rates of compounds C19, C20, C21 and C22 on sEH are about 8%, 1%, 38% and 43% respectively. The inhibition rate of the negative control compounds on sEH is relatively low. This is because the urea group is directly connected to the carbon at position 20 of the E ring, indicating that the urea group structure at position 20 of glycyrrhetinic acid cannot improve its inhibitory activity on sEH. However, when the urea group structure is connected to position 30 of glycyrrhetinic acid, that is, a methylene group is retained between the carbon at position 20 and the urea group, it has good sEH inhibitory activity and a very low IC50. Therefore, the present invention obtains a new type of sEH inhibitory compound by introducing the glycyrrhetinic acid skeleton described in general formula I, which has a good inhibition rate on sEH, and the lowest IC50 is about 3nM.

[0248] In summary, the main skeleton of the glycyrrhetinic acid derivative prepared by the present invention is glycyrrhetinic acid with a urea group, and by modifying the 3rd, 11th, 18th and 30th positions of glycyrrhetinic acid, it has a nanomolar level of inhibitory activity against sEH. On the basis of 18α / 18β-GA, different urea substituents were introduced at the 30th position, and the activity was better than the inhibitory activity of the positive control compound TPPU against sEH. However, when different urea substituents were connected to the 20th position of 18α / 18β-GA, its inhibitory effect on sEH was greatly reduced. The configuration of the hydrogen at the 18th position of glycyrrhetinic acid and whether the carbonyl at the 11th position is reduced have no decisive effect on sEH inhibition. After the 3rd position is changed to a carbonyl group, the activity is slightly reduced compared to when the hydroxyl group is retained. The glycyrrhetinic acid derivative prepared by the present invention has a highly efficient inhibitory effect on sEH, so that the inhibitory effect on inflammation can be achieved by inhibiting sEH, and has good application prospects.

[0249] The above is a detailed introduction to a glycyrrhetinic acid derivative, a pharmaceutical composition and its application provided by the present invention. Specific examples are used herein to illustrate the principle and implementation mode of the present invention. The description of the above embodiments is only used to help understand the method of the present invention and its core idea. At the same time, for a person skilled in the art, according to the idea of ​​the present invention, there will be changes in the specific implementation mode and the scope of application. In summary, the content of this specification should not be understood as a limitation on the present invention.

Claims

1. A glycyrrhetinic acid derivative, characterized in that: The glycyrrhetinic acid derivative has the following general structural formula I: In the formula I, Y is selected from any one of CH-OH and carbonyl; X is selected from any one of carbonyl and methylene groups; R 1 Selected from C 1-4 Alkyl, tetrahydropyranyl, N-(C 1-4 alkylformyl)piperidinyl, N-(halogenated C 1-4 alkylformyl) piperidinyl, pyridinyl, substituted phenyl (R-Ph); wherein R is selected from any one of methoxy, halogenated methoxy, aminosulfonyl, methylsulfonyl, and halogenated methylsulfonyl; The hydrogen at position 18 is selected from the α-position or β-position stereo configuration.

2. The glycyrrhetinic acid derivative according to claim 1, characterized in that The Y is selected to be a CH-OH group.

3. The glycyrrhetinic acid derivative according to claim 1, characterized in that The X is selected to be a carbonyl group.

4. The glycyrrhetinic acid derivative according to claim 1, characterized in that The R 1 Any one selected from the group consisting of isopropyl, isobutyl, tetrahydropyranyl, N-acetylpiperidinyl, N-propionylpiperidinyl, pyridinyl, methoxyphenyl, difluoromethoxyphenyl, trifluoromethoxyphenyl, aminosulfonylphenyl and methylsulfonylphenyl.

5. The glycyrrhetinic acid derivative according to claim 1, characterized in that The Y is selected from a CH-OH group, the X is selected from any one of a carbonyl group and a methylene group, and the R 1 Any one selected from isopropyl, isobutyl, tetrahydropyranyl, N-acetylpiperidinyl, N-propionylpiperidinyl, 4-pyridyl, 4-methoxyphenyl, 4-difluoromethoxyphenyl, 4-trifluoromethoxyphenyl, 4-aminosulfonylphenyl and 4-methylsulfonylphenyl.

6. The glycyrrhetinic acid derivative according to claim 5, characterized in that The X is selected as a carbonyl group, the R 1 Any one selected from the group consisting of isopropyl, tetrahydropyranyl, N-propionylpiperidinyl, 4-pyridyl, 4-methoxyphenyl, 4-difluoromethoxyphenyl, 4-trifluoromethoxyphenyl, 4-aminosulfonylphenyl and 4-methylsulfonylphenyl.

7. The glycyrrhetinic acid derivative according to claim 1, characterized in that The specific structural formula of the glycyrrhetinic acid derivative is:

8. A pharmaceutical composition of a glycyrrhetinic acid derivative, characterized in that: The glycyrrhetinic acid derivative pharmaceutical composition comprises at least one of the glycyrrhetinic acid derivative, its isotope label, solvate, polymorph, pharmaceutically acceptable salt or prodrug compound as described in any one of claims 1 to 7.

9. Use of the glycyrrhetinic acid derivative according to any one of claims 1 to 7, or the glycyrrhetinic acid derivative pharmaceutical composition according to claim 8, in the preparation of anti-inflammatory drugs.

10. The use according to claim 9, characterized in that: The anti-inflammatory drug is used for inhibiting inflammation caused by soluble epoxide hydrolase.

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