WO2006069499A1 - Triterpenes type protein tyrosine phosphatase 1b inhibitors and the preparation method and the use - Google Patents

Abstract

The present invention relates to a class of triterpenes type PTP1B inhibitors having structures as below. Pharmacological studies indicate that this class of compounds or the physiological acceptable salts thereof have inhibitory activity against PTP1B and they can be used as insulin sensitizers and manufacture of a medicament for the treatment of disease caused by insulin resistance. The present invention relates to the preparation method of this class of compounds.

Description

 Triterpenoid protein tyrosine phosphatase 1B inhibitor and preparation method and use thereof

 The present invention relates to a class of triterpenoids which exhibit high inhibitory activity against protein tyrosine phosphatase IB (PTP1B). These compounds act as PTP1 B inhibitors and insulin sensitizers for the treatment of diabetes, obesity and its complications caused by insulin resistance. The invention also relates to a process for the preparation of such compounds. technical background:

 Diabetes mellitus is a group of clinical syndromes caused by the interaction of genetic and environmental factors, due to absolute or relative deficiency of insulin secretion and decreased sensitivity of target tissue cells to insulin, causing sugar, protein, fat, water, and electrolytes. A series of metabolic disorders. Clinically, hyperglycemia is the main common mark. Long-term disease can cause multiple system damage. Acute metabolic disorders such as ketoacidosis can occur when the condition is severe and stress. Serious complications such as coronary heart disease, iron deficiency or hemorrhagic cerebrovascular disease, blindness, and gangrene in the diabetic population were significantly higher than those in the non-diabetic population. Therefore, diabetes and its complications have become a worldwide public health problem that seriously threatens human health.

 Currently, diabetes is generally divided into two categories, type I diabetes (insulin-dependent diabetes mellitus, IDDM) and type II diabetes (non-insulin-dependent diabetes mellitus, NIDDM). More than 90% of diabetes is type 2 diabetes. WHO estimates that the number of people with diabetes will rise from 135 million in 1995 to 300 million in 2025 due to an aging population, obesity, unhealthy diet and a lack of lifestyle.

 Type I diabetes patients have genetic susceptibility due to HLA-D gene on the short arm of chromosome 6 and abnormal response to environmental factors, especially viral infection or chemical toxic substances, directly or indirectly through autoimmune reactions, causing islets Beta cells are destroyed, resulting in insufficient insulin. The clinical features are acute onset, more common symptoms such as polyphagia, polyuria, polydipsia, and weight loss. There is a tendency to develop ketoacidosis, and insulin therapy must be relied upon to maintain life.

 Type II diabetes also has strong hereditary and environmental factors, and it is significantly heterogeneous. The pathogenesis is diverse and complex, and there are large differences among patients. In general, it can be summarized as the relative deficiency of insulin secretion and insulin resistance. A series of studies on people with type 2 diabetes, especially obese diabetics, have confirmed that insulin resistance is a key factor in the development and progression of type 2 diabetes. Based on the study of insulin signaling pathways in adipocytes and muscle cells, the development of insulin sensitizers to improve insulin resistance is the focus of new drug research for type II diabetes and one of its main directions.

Type II diabetes is characterized by resistance to insulin action by insulin-sensitive tissues such as skeletal muscle, liver, and adipose tissue. Although the specific mechanism is still unclear, the attenuation or even blockade of insulin signaling in its conduction pathway must be a direct factor. Insulin binds to its receptor extracellular alpha subunit to activate the intrinsic tyrosine kinase activity of the receptor intracellular beta subunit, resulting in autophosphorylation of key tyrosine residues in the regulatory domain, thereby fully activating insulin receptor tyrosine The kinase activity of the insulin receptor, the insulin receptor tyrosine kinase, then transmits the signal by phosphorylating its substrate. With intracellular insulin With the deepening of the understanding of reversible tyrosine phosphorylation in the pathway, the role of protein tyrosine phosphatase (PTPases) in balancing the levels of related protein tyrosine phosphorylation in this pathway has received increasing attention. PTPases may act on multiple pathways in the pathway, such as dephosphorylation of autophosphorylation-activated insulin receptor (IR) to reduce receptor kinase activity; or such as insulin receptor substrate 1 (IRS-1), The protein tyrosine residues in the substrate of the insulin receptor substrate 2 (IRS-2), She and other insulin receptors are dephosphorylated, thereby negatively regulating the insulin-receptor receptor pathway. An imbalance in enzyme activity between tyrosine kinases in specific PTPases and insulin pathways may be responsible for insulin resistance in type 2 diabetes. Therefore, it is becoming more and more important to treat type 2 diabetes by finding inhibitors of PTPases that selectively act on this pathway to inhibit its activity, and to enhance and prolong insulin signaling.

PTPases include a large family of transmembrane (receptor) and intracellular (non-receptor) enzymes involved in the regulation of a range of important life processes. Although a variety of PTPases are expressed in insulin-sensitive tissues, such as transmembrane CD45 and LAR-PTPase; intracellular SHPTP-1, SHPTP-2, PTP1B, PTP1C, etc., only a few PTPases may be in the insulin pathway. The receptor or receptor pathway affects normal insulin action. Current research focuses on LAR-PTPa _Se , SHPTP-2 and PTP1B.

PTP1B is the first PTPase to be purified and characterized biologically, with a total length of approximately 50 KD. Early studies have demonstrated that dephosphorylation of insulin receptors is effective in vitro; microinjection of PTP1B derived from human placenta into Xenopus oocytes will reduce insulin-induced oocyte maturation and S6 peptide phosphorylation. It was subsequently found that PTP1B was highly expressed in all insulin-sensitive tissues; after administration of PTP1B antibody by osmotic shock, DNA synthesis and PI3 kinase activity levels were significantly increased in mouse KRC-7 hepatocytes stimulated by insulin, IR autophosphorylation level, IR The level of kinase activity and the level of IRS-1 tyrosine phosphorylation were also significantly elevated. Recent studies have shown that PTP1B interacts directly with activated IR; it also shows the highest selective activity of IRS-1 in vitro; high expression of PTP1B in rat fibroblasts can significantly reduce ligand-induced IR phosphorylation Levels of adenovirus-mediated gene transfection, high expression of PTP1B in insulin-targeted skeletal and hepatic model cell lines L6 muscle cells and Fao cells, significantly inhibiting insulin-induced IR and IRS-1 tyrosine Acid phosphorylation, and thus significantly inhibits the formation of IRS-1 and PI3 kinase P85 subunit complexes and phosphorylation of Akt, MAPK, and insulin-induced glycogen synthesis is also inhibited [Egawa K. et al. J. Biol Chem. 276(13), 10207-10211.]. In the same way, PTP1B was highly expressed in model cell 3T3-L1 cells of another insulin-targeted tissue adipose tissue, which also significantly inhibited insulin-induced tyrosine phosphorylation of IR, IRS-1 and PI3 kinase, P42 and P44 MAPK phosphoric acid. The level of chemistry is also significantly reduced, while Akt phosphorylation levels and activity are not affected [Venable CL et al. J. Biol. Chem. 275 (24), 18318-18326]. The high expression of PTP1B had no effect on the basic, medium and maximum insulin-induced glucose transport and had no effect on the transported EC ₅₍₎ insulin concentration. These studies demonstrate that PTP1B is capable of negatively regulating the insulin signaling pathway and acting primarily on the insulin receptor. More important experimental evidence comes from PTP1B knockout mice. Elchebly et al. reported that PTP1B knockout mice produced by homologous recombination have normal growth, fertility, and significant sensitivity to insulin, and this enhancement is associated with insulin receptors and insulin in the liver and skeletal muscle. Enhancement of phosphorylation levels in bulk substrate 1 [Elchebly M., et al. Science, 283, 1544-1548.] Surprisingly, PTP1B knockout mice It is also resistant to food-induced weight gain and insulin resistance. Klaman et al. used the same method to generate PTP1B knockout mice, and the same results were obtained, and it was found that the PTP1B knockout mice were resistant to food-induced weight gain due to the decrease in fat cell volume. , and the number of fat cells does not change. PTP1B knockout mice have elevated levels of basic metabolism and overall energy expenditure [Klaman LD, et al. Molecular and Cellular Biology, 20(15), 5479-5489]. These experiments have more strongly demonstrated the important role of PTP1B in insulin sensitivity, energy expenditure, and fat storage, making it clear that it is a potential drug target for the treatment of type 2 diabetes and obesity.

Some progress has been made in the study of PTP1B selective inhibitors, but most of them are limited to peptides or peptoid compounds, such as the inhibitor EEDE (F ₂ PMP) M based on the substrate sequence of PTP1B dephosphorylation (Ki = 7.2). nM), Glu-F ₂ PMP-F ₂ PMP (IC ₅₀ = 40 nM), although these peptide inhibitors have strong inhibitory activity and high selectivity, they are peptide phosphate compounds It is difficult to become a drug candidate compound. Recently, a series of non-peptide non-phosphorus compound PTP1B inhibitors have been reported, which have certain selectivity and, more importantly, some of them have a significant effect on reducing glucose and insulin levels in plasma of ob/ob mice. This is the first direct evidence of pharmacology that demonstrates that PTP1B inhibitors have anti-diabetic activity. [Malamas, MS, et al. J. Med. Chem., 2000, 43, 1293-1310] These undoubtedly provide us with an opportunity to find new small molecule non-peptide organic compounds as efficient, highly selective PTP1B inhibitors. Summary of the invention

 The object of the present invention is to provide a class of triterpenoids which are useful as protein tyrosine phosphatase PTP1B inhibitors and insulin sensitizers for the treatment of various diabetes, obesity and complications thereof. Another object of the present invention is to provide a method for synthesizing such compounds by using oleanolic acid or ursolic acid or cola acid or 2oc-hydroxy sinoic acid or betulinic acid as a starting material.

 The triterpenoid PTP1B inhibitor of the present invention is a compound having the structure of the following formula I or a physiologically acceptable salt thereof:

among them! ^ is an alkyl group or hydrogen;

₂ is - Cs alkyl or hydrogen;

R ₃ is hydrogen, hydroxy, amino, halogen or fluorenyl;

R4 is a hydroxyl group, an amino group, a halogen or a fluorenyl group; Is ^-^. Anthracenyl, -C20 unsaturated hydrocarbon group, YCH(R ₅ ), CONH(CH ₂ ) _n CH(R ₆ )COOH or CONH(CH ₂ ) _n CONH(CH ₂ ) _m CH(R ₇ )COOH, wherein n is 1 -20, m is 1-20; Y is a fluorenyl group of d-Cso or an unsaturated hydrocarbon group of d-o; and R ₅ , R ₆ , and R ₇ are each independently selected from an alkyl group of d-C ₅ , An aromatic group, a substituted aromatic group.

 The aryl group in the aryl group or the substituted aryl group in the present invention means a phenyl group, a pyridyl group, a fluorenyl group, a furyl group, a thienyl group or a pyrrolyl group.

 A preferred compound of the invention is a triterpenoid PTP1B inhibitor of formula I or a physiologically acceptable salt thereof, wherein is hydrogen;

Is an alkyl or hydrogen of d-C ₅ ;

 Is hydrogen, hydroxy, amino, halogen or sulfhydryl;

 Is hydrogen, hydroxy, amino, halogen or sulfhydryl;

Is an alkyl group of ^^^, an unsaturated hydrocarbon group of -CM, YCH(R ₅ ), CONH(CH ₂ ) _n CH(R ₆ )COOH or CONH(CH ₂ ) _n CONH(CH ₂ ) _m CH(R ₇ COOH, wherein η is 1-20, m is 1-20; Y is a fluorenyl group of dC ₂ Q or an unsaturated hydrocarbon group; R ₅ , R ₇ are each independently selected from C, _C ₅ fluorenyl group , an aromatic group, a substituted aromatic group.

 Another preferred compound of the invention is a triterpenoid PTP1B inhibitor of structural formula I or is physiologically acceptable

±卜, —

among them! ^ is one. An alkyl group of ₅ ;

For one. ₅ sulfhydryl or hydrogen;

R ₃ is hydrogen, hydroxy, amino, halogen or fluorenyl;

 Is hydrogen, hydroxy, amino, halogen or sulfhydryl;

X is a fluorenyl group of d-Czo, an unsaturated hydrocarbon group of d-Czo, YCH(R ₅ ), CONH(CH ₂ ) „CH(R ₆ )COOH or CONH(CH ₂ ) _n CONH(CH ₂ ) _m CH( R ₇ )COOH, wherein n is 1 -20, m is 1-20; Y is a fluorenyl group of d-o or an unsaturated hydrocarbon group of -, ^, and R ₅ , and R ₇ are each independently selected from d- C ₅ thiol, aryl, substituted aryl.

 The invention is implemented by the following steps:

After screening studies, it was found that the chloroform fraction of the ethanol extract of the commonly used hypoglycemic Chinese medicine Corydalis Cous officinalis showed better inhibition of PTP1B activity (IC ₅ .<20 yg/mL), which was separated by activity and found from the chloroform site. A reactive monomeric compound ursol ic acid (IC ₅ : 13. 45 μ Μ), oleanol ic acid ( IC ₅ : 21. 90 μ M), 2a-hydroxy Ursol ic acid 2. 5 μ Μ) and 2ot-hydroxy hydroxy acid (2a-hydroxyo 1 ean o 1 ic aci d 5. 0 μ M) ₀

The invention uses oleanolic acid, ursolic acid, colanic acid or 2α-hydroxy sinoic acid as raw materials to synthesize 28-long-chain fatty acid derivatives by Wittig or Wittig-Horner reaction, and obtains 3 positions by substituting 3-hydroxyl groups. Other substituted 28-long chain fatty acid derivatives; or by condensing with various amino acids, synthesizing a 28-peptide chain derivative, and then obtaining 3 other substituted 28-peptide chain derivatives by substituting the 3-position hydroxyl group. W 200

Synthesis route of 28-long-chain fatty acid triterpene derivative Compound A can be obtained by NaH/Mel or CH ₂ N _{2 /} TBDMSC1 or 2, 2 dimethoxypropane to obtain 3-methyl ether-28-methyl ester or 3-tert. Butyl dimethyl chlorosilyl ether ether - 28 - methyl ester or 2, 3 acetone fork derivative, and then reduced by LiAlH ₄ to obtain alcohol B. B is oxidized by oxalyl chloride to give aldehyde C. Aldehyde C is reacted by Wittig reaction or Wittig-Homer to give compound D, wherein n is 0-20. Compound D is then hydrogenated to give the 28-long chain fatty acid derivative E. Compound E is further deprotected by 3-tert-butyldimethylsilyl group or methoxy deprotected or deprotected with acetone fork to give 28-long chain fatty acid derivative G. Compound G is reductively deaminated by IBX oxidation or reacted with hydrogen sulfide and trialuminum or HX to give product I. Compound E is obtained by reacting an α-position with a halogen or by condensing with an α-substituted amino acid to obtain a compound F. Compound F is further deprotected by 3-tert-butyldimethylsilyl sulfonyl group or methoxy deprotected or acetone fork deprotected to give 28-long chain fatty acid derivative hydrazine. The compound Η is deamidated by deuteration by hydrazine oxidation or reacted with hydrogen sulfide and trialuminum or by hydrazine treatment to obtain product J. The product obtained was confirmed by NMR.

R ₃ =H; R ₄ =SH, NH _2l X

3=SH, NH ₂ , X; R ₄ =SH, NH ₂ , X

Synthesis route of 28-peptide chain triterpene derivatives Compound A is reacted with a mixed solution of acetic anhydride and pyridine (1:1, V/V) to obtain an acetylated product K of Compound A. Compound Κ is treated with a certain amount of oxalyl chloride to give compound L. Compound L is reacted with the methyl ester of the amino acid and the methyl ester of the dipeptide in an anhydrous aprotic solvent (eg, methylene chloride, trichloromethane, 1, 4-dioxane), which requires the addition of some organic base. As a catalyst, (e.g., triethylamine, pyridine, diisopropylethylamine, N, N-dimethylpiperidine, etc.). The reaction temperature is generally carried out at room temperature, and the reaction time is usually from 1 to 3 h, and TLC is usually used to detect the degree of completion of the reaction. Then, the acetyl group is protected with NaOH. After the completion of the reaction, the product is directly subjected to solvent removal under reduced pressure, and the concentrate is subjected to column chromatography to obtain the final products M and N. The reaction yield is generally from 75% to 90%. Compound M or N is oxidized by IBX to reductively deamination or is reacted with hydrogen sulfide and trialuminum or HX to give product O or P. The product obtained was confirmed by NMR. DRAWINGS

Figure 1 shows the effect of compound L-5 on the K _m value of PTP1B against the substrate pNPP.

Figure 2 shows the effect of compound L-5 on the _at value of PTP1B on the substrate pNPP.

Figure 3 shows the effect of compound L-5 on the level of tyrosine phosphorylation of Πβ in CHO/IR cells. Beneficial effect

 The present invention demonstrates that a series of compounds synthesized are a novel class of protein tyrosine phosphatase IB inhibitors which are derivatives derived from natural products as compared to the currently known PTP1B inhibitors; The parent ursolic acid and oleanolic acid are clinically used drugs with low toxicity and very safe; the raw materials for synthesizing these compounds are ursolic acid and oleanolic acid are very cheap. detailed description

 The invention is further illustrated by the following specific examples, without limiting the invention.

Ή-NMR was measured with a Varian Mercury AMX300 model; MS was measured with a VG ZAB-HS or VG-7070 meter, except for the EI source (70 ev); all solvents were re-distilled before use. The anhydrous solvent was obtained by drying according to the standard method; except for the description, all the reactions were carried out under the protection of Ar gas and traced by TLC, and the post-treatment was washed with saturated brine and anhydrous MgS0 ₄ ; The column chromatography using silica gel (200-300 mesh) was used; the silica gel used, including 200-300 mesh and GF _254, was produced by Qingdao Ocean Chemical Plant or Yantai Yuanbo Silicone Company. The PTP1B, TCPTP, CDC25A, CDC25B, LAR high-throughput screening models and CHO/IR cell model construction methods refer to the Guide to Molecular Cloning: PNpp. 2Na (p-nitrophenyl phosphate disodium salt) purchased from Shanghai Bio-Bio Ltd.; Insulin (insulin injection) was purchased from Shanghai First Biochemical Pharmaceutical Co., Ltd.; F12 medium and serum were purchased from GibcoTM. Example 1 Preparation of Compound A-1

 Sodium hydride (40 mg, 50%, 0.870 mmol) was dissolved in dry DMF (5 mL) and stirred for 10 min. Then, oleanolic acid (60 mg, 0.132 mmol) was added in an ice bath, and after 20 min, a solution of iodothymidine in DMF (2 mL) was added and stirred at room temperature overnight. The unreacted sodium hydride was quenched with EtOAc (EtOAc)EtOAc. /V) Purified white solid A-1 (58 mg, 0.121 mmol).

NMR NMR (CDC1 ₃ , 300 MHz) (δ): 5.28 (m, 1H, -CH in 12), 3.61 (s, 3H, -CH ₃ in -COOCH ₃ ): 3.35 (s, 3H, -CH ₃ in CH ₃ 0-), 2.82 (m, 1H, -CH in 18), 2.67 (m, 1H, -CH in 3); ¹³ C NMR (CDC1 ₃ , 75.0 MHz) (δ) 38.51 (Cl), 22.17 ( C-2), 88.88 (C-3), 38.86 (C-4), 55.95 (C-5), 18.39 (C-6), 32.84 (C-7), 39.47 (C-8), 47.80 (C -9), 37.23 (C-10), 23.63 (C-ll), 122.620 (C-12), 143.981 (C-13), 41.804 (C-14), 27.860 (C-15), 23.24 (C- 16), 46.89 (C-17), 41.46 (Cl 8), 46.05 (C-19), 30.09 (C-20), 34.03 (C-21), 32.56 (C-22), 28.30 (C-23) , 16.52 (C-24), 15.47 (C-25), 17.07 (C-26), 26.13 (C-27), 178.50 (C-28), 33.32 (C-29), 23.84 (C-30), 57.75 (-CH ₃ in CH ₃ 0-), 51.75 (-CH ₃ in -COOCH3). Example 2 Preparation of Compound Bl

 A-1 (500 mg, 1.093 mmol) was dissolved in dry tetrahydrofuran (25 mL;), then lithium aluminum hydride (100 mg, 2.632 mmol) was added and stirred at room temperature overnight under argon. Unreacted lithium aluminum hydride was quenched with a small amount of ethyl acetate, then iced water and chloroform (50 mL). The mixture was transferred to a sep. funnel, chloroform layer was dried, dried over anhydrous sodium sulfate, and evaporated to give a white solid B-1 (460 mg, 1.016 mmol), yield 93%.

'HNMR (CDC1 ₃ , 300 MHz) (δ): 5.19 (m, 1Η, -CH in 12), 3.53 (d, 15 Hz, 1H, -CH in 28), 3.35 (s, 3H, -CH ₃ in CH3O-), 3.17 (d, J = 15 Hz, 1H, -CH in 28), 2.67 (m, 1H, -CH in 18); ¹³ C NMR (CDC1 ₃ , 75.0 MHz) (S): 38.73 (Cl ), 22.21 (C-2), 88.88 (C-3), 38.93 (C-4), 55.96 (C-5), 18.47 (C-6), 32.19 (C-7), 40.03 (C-8) , 47.81 (C-9), 37.14 (C-10), 22.95 (C-11), 122.59 (C-12), 144.47 (C-13), 41.90 (C-14), 25.76 (C-15), 22.23 (C-16), 34.33 (C-17), 42.57 (C-18), 46.71 (C-19), 30.50 (C-20), 32.80 (C-21), 31.27 (C-22), 28.33 (C-23), 16.57 (C-24), 15.72 ( C-25), 16.95 (C-26), 25.75 (C-27), 69.82 (C-28), 33.45 (C-29), 23.82 (C-30), 50.21 (-CH ₂ in- CH ₂ - OH). Example 3 Preparation of Compound C-1

 Dissolve oxalyl chloride (0.4 mL, 4.4 mmol) in dichloromethane (10 mL), cool to -60 °C, and slowly dilute DMSO (0.68 mL, 8.8 mmol) in dichloromethane (10 mL) Add and stir at -60 °C for 5 min. A solution of B-l (1.824 g, 4 mmol) in dichloromethane (20 mL) was slowly added dropwise and stirred at -60 °C for 15 min, then triethylamine (2.8 mL, 20 mmol). The temperature was slowly raised to room temperature and stirred for 48 h. The reaction mixture was cooled with ice-cooled EtOAc (EtOAc m.) The rate is 90%.

NMR NMR (CDC1 ₃ , 300 MHz) (δ): 9.39 (s, 1Η, -CH in 28), 5.33 (m, 1H, -CH in 12), 3.36 (s, 3H, -CH ₃ in CH3O-) , 2.60 (m, 1H, -CH in 18); ^l3 C NMR (CDC1 ₃ , 75.0 MHz) (S): 38.61 (C-1), 22.21 (C-2), 88.86 (C-3), 38.90 ( C-4), 55.97 (C-5), 18.40 (C-6), 31.82 (C-7), 39.82 (C-8), 47.77 (C-9), 37.02 (C-10), 23.66 (C -11), 123.53 (C-12), 143.21 (C-13), 41.92 (C-14), 26.95 (C-15), 22.33 (C-16), 49.32 (C-17), 40.63 (C- 18), 45.82 (C-19), 30.87 (C-20), 33.38 (C-21), 32.97 (C-22), 28.35 (C-23), 16.56 (C-24), 】5.55 (C- 25), 17.25 (C-26), 25.77 (C-27), 207.76 (C-28), 33.31 (C-29), 22.66 (C-30), 57.77 (- CH ₃ in CH ₃ 0-), . Example 4 Preparation of Compound D-1

Add sodium hydride (240 mg, 50%, 1 mmol) to DME (10 mL) under argon, stir for 10 min, cooled to 20 ° C, (diethoxy-phosphoryl)-ethyl acetate (224 mg, 1 mmol) was added and stirred at room temperature for 1 h. Add C-1 (20 mg, 0.043 mmol) in DME (2 mL) at 25 ° C, stir at room temperature for 1 h, then heat back Stream 3h. After cooling, a large amount of ice water was added to the reaction solution, which was extracted with chloroform (50 mL), dried over anhydrous sodium sulfate and evaporated. , V/V) Purified pale yellow powder D-1 (17 mg, C. 032 mmol), yield 75.4%.

NMR NMR (CDC1 ₃ , 300 MHz) (S): 6.90 (d, J = 16.2 Hz, 1H, -CH in - CH=CH-), 5.75 (d, J== 16.2 Hz, 1H, -CH in 28 ), 5.29 (m, 1H, -CH in 12), 3.35 (s, 3H, -CH ₃ in CH ₃ 0-), 2.67 (m, 1H, -CH in 3), 2.37 (m, 1H, -CH) In 18); ^l3 C NMR (CDC1 ₃ , 75.0 MHz) (S) 38.51 (Cl), 22.17 (C-2), 88.88 (C-3), 38.86 (C-4), 55.48 (C-5), 18.72 (C-6), 32.78 (C-7), 39.92 (C-8), 47.93 (C-9), 37.75 (C-10), 23.80 (C-ll), 123.09 (C-12), 144.20 (C-13), 41.91 (C-14), 27.18 (C-15), 26.41 (C-16), 39.55 (C-17), 44.00 (C-18), 46.65 (C- 19), 30.98 ( C-20), 34.52 (C-21), 34.23 (C-22), 29.15 (C-23), 16.92 (C-24), 15.92 (C-25), 17.04 (C-26), 26.15 (C -27), 119.51 (C-28), 32.78 (C-29), 23.80 (C-30), 57.78 (-CH ₃ in CH ₃ 0-), 159.28 (-CH in _CH=CH-), 167.54 ( C in -CO-), 60.30 (-CH ₂ - in - COCH ₂ -), 14.55 (-CH ₃ in -CH ₂ CH ₃ ). Example 5 Preparation of Compound E-1

 D-1 (50 mg, 0.095 mmol) was dissolved in ethyl acetate (25 mL). Pd-C (10 mg). Filtration over celite, EtOAc (EtOAc:EtOAc)

NMR NMR (CDC1 ₃ , 300 MHz) (δ): 5.18 (m, 1H, -CH in 12), 4.11 (q,J= 7.2 Hz, 2H, -CH ₂ - in -COCH2), 3.34 (s, 3H , -CH ₃ in -CH ₂ CH ₃ ), 2.65 (m, 1H, -CH in 3); ^{, 3} C NMR (CDC1 ₃ , 75.0 MHz) 38.74 (Cl), 22.26 (C-2), 88.94 (C -3), 38.94 (C-4), 55.96 (C-5), 18.47 (C-6), 32.73 (C-7), 40.07 (C-8), 47.86 (C-9), 37.16 (C- 10), 23.83 (C-ll), 122.73 (C-12), 144.62 (C-13), 41.79 (C-14), 25.84 (C-15), 22.16 (C-16), 34.56 (C-17 ), 47.28 (Cl 8), 46.87 (Cl 9), 29.59 (C-20), 34.62 (C-21), 32.77 (C-22), 28.33 (C-23), 16.58 (C-24), 15.75 (C-25), 16.87 (C-26), 26.32 (C-27), 32.16 (C-28), 33.48 (C-29), 23.83 (C-30), 57.78 (-CH ₃ in C3⁄40-) , 34.96 (-CH ₂ in -CH ₂ CO -), 177.94 (C in -CO-), 60.30 (-CH ₂ - in -COCH2-), 14.53 (-CH ₃ in _CH ₂ CH ₃ ). Example 6 Preparation of Compound G1

 E-l (40 mg, 0.080 mmol) was dissolved in acetonitrile (10 mL), sodium iodide (50 mg) was added, and then trimethylchlorosilane (0.5 mL) was added and refluxed for 6 h. A little ice water was added to the mixture, which was diluted with chloroform (50 mL). Purification by silica gel column chromatography (EtOAc:EtOAc:EtOAc:

NMR NMR (CDC1 ₃ , 300 MHz) (δ): 5.20 (m, 1Η, -CH in 12), 3.21 (m, 1H, -CH in 3); ¹³ C NMR (CDC1 ₃ , 75.0 MHz) (δ) : 39.30 (Cl), 28.47 (C-2), 78.44 (C-3), 39.76 (C-4), 56.18 (C-5), 18.47 (C-6), 32.77 (C-7), 40.07 ( C-8), 47.86 (C-9), 37.75 (C-10), 23.83 (C-ll), 122.73 (Cl 2), 144.62 (C-13), 41.79 (C-14), 25.84 (C- 15), 22.16 (C-16), 34.56 (C-17), 47.29 (Cl 8), 46.87 (Cl 9), 29.59 (C-20), 34.62 (C-21), 32.77 (C-22), 29.15 (C-23), 16.92 (C-24), 15.75 (C-25), 16.87 (C-26), 26.32 (C-27), 32.16 (C-28), 33.48 (C-29), 23.83 (C-30), 34.96 (-CH ₂ in -CH ₂ CO-), 181.27 (Cin-CO-). Example 7 Preparation of Compound G-2

 D-l (40 mg, 0.080 mmol) was dissolved in acetonitrile (10 mL), sodium iodide (50 mg) was added, and then trimethylsilyl chlorosilane (0.5 mL) was added and refluxed for 6 h. A little ice water was added to the reaction mixture, which was diluted with chloroform (50 mL). Purification by silica gel column chromatography (EtOAc:EtOAc:EtOAc:EtOAc

 'Η NMR (CDCI3, 300 MHz) (δ): 6.98 (d, J = 16.2 Hz, 1H, -CH in -CH=CH-), 5.78 (d, J =

16.2 Hz, 1H, -CH in 28), 5.20 (m, 1H, -CH in 12), 3.21 (m, 1H, -CH in 3); ^l3 C NMR (CDC1 ₃ ,

75.0 MHz) (S): 39.30 (C-l), 28.47 (C-2), 78.44 (C-3), 39.76 (C-4), 56.18 (C-5), 18.47

(C-6), 32.77 (C-7), 40.07 (C-8), 47.86 (C-9), 37.75 (C-10), 23.83 (C-ll), 122.73 (C-12),

144.62 (C-13), 41.79 (C-14), 25.84 (C-15), 22.16 (C-16), 34.56 (C-17), 47.29 (C-18),

46.87 (C-19), 29.59 (C-20), 34.62 (C-21), 32.77 (C-22), 29.15 (C-23), 16.92 (C-24),

15.75 (C-25), 16.87 (C-26), 26.32 (C-27), 118.96 (C-28), 33.48 (C-29), 23.83 (C-30), 159.28 (-CH in -CH=CH-), 172.67 (C in -CO-). Example 8 Preparation of Compound A 2

 Methyl oleate (470 mg, 1 mmol) was dissolved in 10 mL of anhydrous DMF, then imidazole (98 mg, 1.2 mmol), TBDMSCl (180 mg, 1.2 mmol). Diluted with 100 mL of distilled water, suction filtered, washed with EtOAc EtOAc (EtOAc)

Ή-NMR (CDC1 ₃ , 300 MHz) (δ): 0.03 (s, 6Η, -(CH ₃ ) ₂ Si-), 2.82 (m, - CH in 18), 3.17 (m, 1H, H in 3) , 3.62 (s, 3H, -CH ₃ in COOCH ₃ ), 5.27 (m, 1H, H in 12); ^l3 C NMR (CDC1 ₃ , 75.0 MHz) (δ): 39.52 (Cl), 27.84 (C-2 ), 79.70 (C-3), 39.54 (C-4), 55.54 (C-5), 18.75 (C-6), 32.97 (C-7), 39.47 (C-8), 47.89 (C-9) , 37.15 (C-10), 23.66 (C-ll), 122.67 (C-12), 143.99 (C-13), 41.85 (C-14), 27.92 (C-15), 23.30 (C-16), 46.95 (C-17), 41.52 (C-18), 46.10 (C-19), 30.91 (C-20), 34.03 (C-21), 32.62 (C-22), 28.76 (C-23)', 16.32 (C-24), 15.54 (C-25), 17.05 (C-26), 26.14 (C-27), 178.50 (C-28), 33.34 (C- 29), 23.84 (C-30), - 3.52 (-CH ₃ in - (CH ₃ ) ₂ Si- ), -4.66 (-CH _{3 in -} (CH ₃ ) ₂ Si- ), 26.15 (-CH ₃ in (CH ₃ ) ₃ C-). Example 9 Preparation of Compound B-2

 Compound A-2 (584 mg, 1 mmol) was dissolved in dry THF (20 mL). Add water (0.09 mL) to quench, add (5 mol/L) NaOH (0.06 mL), water (0.29 mL), stir for 1 h, filter with a sand funnel, and use (20 mL) After washing, the filtrate was evaporated in vacuo to give a white solid.

NMR NMR (CDC1 ₃ , 300 MHz) (<5): 5.19 (m, 1H, -CH in 12), 3.56 (d, 1H, J = 15.2 Hz, -CH in 28), 3.17 (m, 1H, H In 28), 3.17 (m, 1H, H in 3) 0.03 (s, 6H, -(CH ₃ ) ₂ Si-); ¹ C NMR (CDC1 ₃ , 75.0 MHz) (S): 38.81 (Cl), 28.75 (C-2), 79.66 (C-3), 40.01 (C-4), 55.46 (C-5), 18.77 (C-6), 32.86 (C-7), 40.01 (C-8), 47.82 ( C-9), 37.14 (C-10), 23.77 (C-ll), 122.64 (C-12), 144.43 (C-13), 41.90 (C-14), 27.86 (C-15), 26.22 (C-16), 37.02 (C-17), 42.55 (C-18), 46.68 (C-19), 31.16 ( C-20), 34.33 (C-21), 31.26 (C-22), 28.75 (C-23), 16.33 (C-24), 15.76 (C-25), 16.94 (C-26), 25.92 (C -27), 69.86 (C-28), 33.45 (C-29), 23.82 (C-30), -3.52 (-CH ₃ in -(CH ₃ ) ₂ Si-), -4.66 (-CH ₃ in- (CH ₃ ) ₂ Si-), 26.15 (-CH ₃ in (CH ₃ ) ₃ C-). Example 10 Preparation of Compound C-2

 Dissolve oxalyl chloride (0.4 mL, 4.4 mmol) in dichloromethane (10 mL), cool to -60 V, and slowly add DMSO (0.68 mL, 8.8 mmol) in dichloromethane (10 mL). Stir at -60 °C for 5 min. A solution of B-2 (2.112 g, 4 mmol) in dichloromethane (20 mL) was slowly added dropwise and stirred at -60 °C for 15 min, then triethylamine (2.8 mL, 20 mmol). The temperature was slowly raised to room temperature and stirred for 48 h. The solution of methylene chloride was washed three times with (10 mL) water, dried over sodium sulfate, and evaporated to dryness to give a pale yellow solid C-2 (2.11 g, 3.8 mmol) yield 95%.

'HNMR (CDC1 ₃ , 300 MHz) (δ): 9.39 (s, 1H, -CH in 28), 5.33 (m, 1H, -CH in 12), 2.60 (m, 1H, -CH in 18), 0.03 ( s, 6H, -(CH ₃ ) ₂ Si-); ¹³ C NMR (CDC1 ₃ , 75.0 MHz) (δ): 38.79 (Cl), 27.90 (C-2), 82.32 (C-3), 39.61 ( C-4), 55.59 (C-5), 18.79 (C-6), 33.12 (C-7), 39.89 (C-8), 47.89 (C-9), 37.18 (C-10), 23.74 (C -11), 123.63 (C-12), 143.26 (C-13), 41.98 (C-14), 27.02 (C-15), 22.43 (C-16), 49.36 (C-17), 40.74 (C- 18), 45.90 (C-19), 30.93 (C-20), 33.47 (C-21), 28.06 (C-22), 28.84 (C-23), 16.39 (C-24), 15.66 (C-25 ), 17.30 (C-26), 25.85 (C-27), 207.78 (C-28), 33.37 (C-29), 23.74 (C-30). Example 11 Preparation of Compound D-2

Take triphenylphosphonium 4-bromobutyrate (1.28 g, 3 mmol) in (10 mL) dry tetrahydrofuran, add sodium tert-butoxide (168 mg, 1.5 mmol), stir for 15 min, add C-2 ( 555 mg, 1 mmol), reaction for 3 h. After adding (10 mL) of water, the mixture was extracted with EtOAc (EtOAc)EtOAc. V/V) purified to pale yellow powder D-2 (543.3 mg, 0.87 mmol), yield 87%.

Ή-NMR (CDC1 ₃ , 300 MHz) (J): 2.43 (m , 2H , -CH ₂ - in -CH=CH-CH ₂ -) , 2.46 (t , J = 5.7 Hz , 2H , -CH ₂ - In -CH ₂ -COOH), 3.22 (m , 1H , H in 3) , 5.12 (m , 1H , -CH= in -CH=CH-) , 5.21 (t, J=3.2 Hz, ΙΗ , Ηϊη 12) , 5.30 (d , J = 12.6 Hz, 1H, =CH- in =CH-COOH). Example 12 Preparation of Compound G-3

 Compound D-2 (628 mg, 1 mmol) was dissolved in (10 mL) tetrahydrofuran, (10 mL) trifluoroacetic acid: water (9:1) mixture was stirred and stirred overnight (10 mL) chloroform After three times, the chloroform layer was dried over anhydrous sodium sulfate and evaporated to dryness. EtOAcjjjjjjj Mmmol), yield 32%.

Ή-NMR (CDC1 ₃ , 300 MHz) (S): 2.43 (m , 2H , -CH ₂ - in -CH=CH-CH ₂ -) , 2.46 (t, J = 5.7 Hz, 2H , -CH ₂ - In -CH ₂ -COOH) 3.22 (m, 1H, H in 3) , 5.12 (m , 1H , -CH= in -CH=CH-) , 5.21 (t , J =3.2 Hz, 1H , H in 12) , 5.30 (d , J = 12.6 Hz, 1H , =CH- in =CH-COOH); ^l3 C NMR (Pyridine, 75.0 MHz) (S): 37.68 (Cl), 25.75 (C-2), 78.42 (C -3), 39.72 (C-4), 56.10 (C-5), 19.13 (C-6), 35.07 (C-7), 40.35 (C-8), 48.88 (C-9), 37.68 (C- 10), 24.22 (C-ll), 128.58 (Cl 2), 145.60 (C-13), 42.55 (C-14), 28.45 (C-15), 28.01 (C-16), 39.99 (C-17) , 48.46 (C-18), 46.68 (Cl 9), 31.13 (C-20), 35.46 (C-21), 34.07 (C-22), 29.14 (C-23), 16.91 (C-24), 15.95 (C-25), 17.79 (C-26), 26.51 (C-27), 123.21 (C-28), 33.83 (C-29), 24.29 (C-30), 141.60 (=CH- in -CH= CH-), 31.13 (-CH ₂ - in - C3⁄4-COOH), 25.48 (-CH ₂ - in =CH-CH ₂ -), 175.84 (C in _COOH). Example 13 Preparation of Compound G-4

 Compound G-3 (509 mg, 1 mmol) was dissolved in 5 mL of ethyl acetate, 5% EtOAc (5 mg) was added, and the mixture was stirred overnight under hydrogen atmosphere. G-4 (500 mg, 0.98 mmol) Yield 98%.

Ή-NMR (CDC1 ₃ , 300 MHz) (S): 2.46 (t, 2H, J = 5.8 Hz, -CH ₂ - in -CH ₂ -COOH), 3.22 (m, 1H, H in 3), 5.21 ( t, 1H, J = 3.4 Hz, H in 12); ¹³ C NMR (CDC1 ₃ , 75.0 MHz) (S): 38.83 (Cl), /u/u/ i/JOOOsoosild 66-690900Ζ7 5s) 802()6. ) 8ς8ι(3) 6683. 9Γ6Ζ.3)(8.)δ9) ί7--- - -.·.

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 Take 28-butyric acid ursolic acid derivative (512 mg, 1 mmol) in 10 mL of dry dichloromethane, add EDC (230 mg, 1.2 mmol), HOBT (162 mg, 1.2 mmol) under nitrogen atmosphere Stir for 20 min, dissolve the hydrochloride salt of phenylalanine methyl ester (258.6 mmg, 1.2 mmol) in 5 mL of dry dichloromethane, add 1 mL of re-distilled triethylamine, and add this solution to E-2. The mixed solution was stirred overnight under a nitrogen atmosphere, and the organic phase was washed three times with 5 mL of brine, dried, and evaporated to dryness, and the obtained oil was subjected to silica gel column chromatography ( petroleum ether: ethyl acetate = 5: 1, V / V) separation and purification. To the product was added THF (12 mL), MeOH (EtOAc) The pH was adjusted to about 3 with 1 M of dilute hydrochloric acid, and extracted with chloroform (20 mL). The chloroform layer was washed three times with (20 mL) saturated NaCl solution, dried over anhydrous sodium sulfate, and evaporated to dryness. -2 (524.1 mg, 0.71 mmol), yield 71%.

Ή-NMR (CDC1 ₃ , 300 MHz) (S): 2.46 (t, 2H, J = 5.8 Hz, -CH ₂ - in -CH ₂ -COOH), 3.22 (m, 1H, H in 3), 7.11 ( m, 2H, H in -ph), 7.24 (m, 3H, H in -ph); ¹³ C NMR (CDC1 ₃ , 75.0 MHz) (<5): 38.83 (Cl), 22.21 (C-2), 79.32 (C-3), 38.99 (C-4), 55.42 (C-5), 18.58 (C-6), 32.79 (C-7), 40.08 (C-8), 47.88 (C-9)' 37.16 ( C-10), 23.86 (C-ll), 122.14 (C-12), 145.13 (C-13), 41.83 (C-14), 25.88 (C-15), 23.39 (C-16), 33.41 (C -17), 47.48 (C-18), 46.89 (C-19), 39.92 (C-20), 33.54 (C-21), 39.75 (C-22), 26.30 (C-23), 15.82 (C- 24), 15.82 (C-25), 16.99 (C-26), 25.88 (C-27), 31.18 (C-28), 17.46 (C-29), 21.52 (C-30), 26.33 (-CH ₂ - in -CH ₂ -CH ₂ -), 27.42 (-CH ₂ - in - CH ₂ -CH ₂ -), 34.27 (-CH ₂ - in -CH ₂ -COOH), 174.88 (C in - COOH), 53.55 (-NH-CH(-CH ₂ -ph)-COOH), 173.86 (C in -CONH-), 38.31 (-CH ₂ -ph), 136.37 (C in -ph), 131.32 (mC in -ph), 129.65 (oC in -ph), 127.78 (pC in -ph). Example 16 Preparation of Compound H-3

Take 28-butyric acid colaic acid derivative (528 mg, 1 mmol) dissolved in 10 mL of dry dichloromethane, add EDC (230 mg, 1.2 mmol), HOBT (162 mg, 1.2 mmol) under nitrogen atmosphere Stir for 20 min, dissolve the hydrochloride salt of phenylalanine methyl ester (258.6 mmg, 1.2 mmol) in 5 mL of dry dichloromethane, then add 1 mL of re-distilled triethylamine. Add this solution to E-2. In a mixed solution, stir under a nitrogen atmosphere overnight, and the reaction was finished with 5 mL of a saturated food. /u/u/ O i/JOOOsoosild 66-690900ZAV7

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40.08 (C-8), 47.88 (C-9), 37.16 (C-10), 23.86 (C-ll), 122.27 (C-12), 145.18 (C-13), 41.83 (C-14), 25.88 (C-15), 23.39 (C-16), 33.41 (C-17), 47.48 (C-l3⁄4), 46.89 (C-19), 39.92 (C-20), 33.54 (C-21), 39.75 ( C-22), 26.30 (C-23), 15.82 (C-24), 15.82 (C-25), 16.99 (C-26), 25.88 (C-27), 31.18 (C-28), 34.79 (C -29), 23.84 (C-30), 39.82 (-CH- in-CH-COOH), 178.52 (C in -COOH), 38.50 (-CH ₂ -ph), 136.29 (C in -ph), 131.32 ( mC in -ph), 129.60 (oC in -ph), 127.82 (pC in -ph). Example 18 Preparation of Compound D-3

 Compound D-2 (628 mg, 1 mmol) was dissolved in dry THF (20 mL). Add water (0.09 mL) to quench, add (5mol/L) NaOH (0.06 mL), water (0.29 mL), stir for 1 h, filter with a sand core funnel, and wash with (20 mL) dichloromethane. The filtrate was rotary evaporated under reduced pressure to give a white solid. Oxalyl chloride (0.1 mL, 1.1 mmol) was dissolved in dichloromethane (5 mL), cooled to -60 °C, EtOAc (0.17 mL, 2.2 mmol) in dichloromethane (5 mL) Stir at -60 ° C for 5 min. A solution of the above white solid product in dichloromethane (5 mL) was slowly added dropwise, and stirred at -60 ° C for 15 min, then triethylamine (0.7 mL, 5 mmol) was added. The temperature was slowly raised to room temperature and stirred for 48 h. The methylene chloride solution was washed three times with (10 mL) water, dried over sodium sulfate and evaporated Take 4 bromobutyric acid triphenylphosphonium salt (1.28 g, 3 mmol) dissolved in (10 mL) dry tetrahydrofuran, add sodium tert-butoxide (168 mg, 1.5 mmol) and stir for 15 min. The product was obtained as a yellow solid (555 mg, 1 mmol). After adding (10 mL) of water, the mixture was extracted with EtOAc (EtOAc) (EtOAc) , V/V) Purified pale yellow powder D-3 (393 mg, 0.58 mmol), yield 58%.

Ή-NMR (CDC1 ₃ , 300 MHz) (δ): 0.03 (s, 3Η, -(CH ₃ ) ₂ Si -), 3.18 (m, 1H, H in 3), 5.13 (m, 3H), 5.42 ( m, 2H). Example 19 Preparation of Compound G-5

Compound D-3 (678 mg, 1 mmol) was dissolved in (10 mL) tetrahydrofuran, (10 mL) trifluoroacetic acid: water (9:1) mixture was stirred and stirred overnight (10 mL) chloroform After three times, the chloroform layer was dried over anhydrous sodium sulfate and evaporated to dryness. EtOAcjjjjjjjjjj Mmmol), yield 38%.

Ή-NMR (CDC1 ₃ , 300 MHz) (δ): 2.37 (t, 2H, J = 5.6 Hz, -CH ₂ - in - CH ₂ -COOH), 3.22 (m, 1H, H in 3), 5.21 ( m, 1H, H in 12), 5.21 (m, 2H, H in -CH=CH-), 5.43 (m, 2H, H in -CH=CH-COO-); ¹³ C NMR (CDC1 ₃ , 75.0 MHz (S): 38.67 (Cl), 28.35 (C-2), 79.33 (C-3), 38.97 (C-4), 55.43 (C-5), 18.55 (C-6), 33.64 (C-7 ), 39.90 (C-8), 48.36 (C-9), 37.24 (C-10), 22.91 (C-11), 127.97 (C-12), 145.40 (C-13), 42.08 (C-14) , 29.22 (C-15), 24.05 (C-16), 39.45 (C-17), 47.94 (C-18), 46.33 (C-19), 30.87 (C-20), 34.75 (C-21), 32.90 (C-22), 29.92 (C-23), 15.84 (C-24), 15.53 (C-25), 17.34 (C-26), 26.21 (C-27), 122.48 (C-28), 33.68 (C-29), 23.74 (C-30), 34.37 (-CH ₂ - in -CH ₂ -COOH ), 27.67 (-CH ₂ - in =CH-CH ₂ -), 27.60 (-CH ₂ - in - CH ₂ -CH=), 27.39 (-CH ₂ - in =CH-C3⁄4-), 177.86 (C in-COOH). Example 20 Preparation of Compound G-6

 Compound G-5 (564 mg, 1 mmol) was dissolved in 5 mL of ethyl acetate, 5% EtOAc (5 mg) was added, and the mixture was stirred overnight under hydrogen atmosphere. Powder G-6 (541 mg, 0.96 mmol) Yield 96

%.

Ή-NMR (CDC1 ₃ , 300 MHz): 2.35 (t, 2H, J = 5.8 Hz, -CH ₂ -CQO-), 3.22 (m, 1H, H in 3), 5.16(t, lH, J=3.2 Hz, Hin l2). Example 21 Preparation of Compound D-4

Compound D-3 (678 mg, 1 mmol) was dissolved in dry tetrahydrofuran (20 mL), then lithium aluminum hydride was added (76 mg, 2 mmol), stirred at room temperature overnight under argon. Add water (0.09 mL) to quench, add (5 mol/L) NaOH (0.06 mL), water (0.29 mL), stir for 1 h, filter with a sand funnel, and use (20 mL) Washing (supplemental amount), the filtrate was rotary evaporated under reduced pressure to give a white solid. Oxalyl chloride (0.1 mL, 1.1 mmol) was dissolved in dichloromethane (5 mL), cooled to -60 °C, and DMSO (0.17 mL, 2.2 mmol) in dichloromethane (5 mL) Stir at -60 °C for 5 min. A solution of the above white solid product in dichloromethane (5 mL) was slowly added dropwise, and stirred at -60 °C for 15 min, then triethylamine (0.7 mL, 5 mmol). The temperature was slowly raised to room temperature, stirred for 48 ho. The methylene chloride solution was washed three times with water (10 mL), dried over sodium sulfate and evaporated. Take triphenylphosphonium 4-bromobutyrate (1.28 g, 3 mmol) dissolved in (10 mL) dry tetrahydrofuran, add sodium tert-butoxide (168 mg, 1.5 mmol) and stir for 15 min. The product was yellow solid and was reacted for 3 h. After adding (10 mL) of water, the mixture was extracted with EtOAc (EtOAc) (EtOAc) V/V) Purified to pale yellow powder D-4 (440 mg, 0.60 mmol), yield 60%.

1H-NMR (CDC1 ₃ , 300 MHz) (δ): 0.03 (s, 6Η, -(CH ₃ ) ₂ Si-), 3.19 (m, 1H, H in 3), 5.2 l(m, 4H), 5.41 (m, 3H). Example 22 Preparation of Compound G-7

 Compound D-4 (732 mg, 1 mmol) was dissolved in (10 mL) tetrahydrofuran, (10 mL) trifluoroacetic acid: water (9:1) mixture was stirred and stirred overnight (10 mL) chloroform After three times, the chloroform layer was dried over anhydrous sodium sulfate and evaporated to dryness. The purified oil was purified by silica gel column chromatography (ethyl ether: ethyl acetate = 2:1, V/V) to obtain white powder G-7 (229 mg) , 0.38 mmol), yield 38%.

Ή-NMR (CDC1 ₃ , 300 MHz) (δ): 3.22 (m, 1Η, Η in 3), 5.21 (m, 4Η), 5.42 (m, 3H); ¹³ C NMR (CDC1 ₃ , 75.0 MHz) ( δ): 38.63 (Cl), 29.36 (C-2), 79.32 (C-3), 38.95 (C-4), 55.38 (C-5), 18.53 (C-6), 33.60 (C-7), 39.86 (C-8), 48.33 (C-9), 37.21 (C-10), 22.88 (Cl l), 127.88 (C-12), 145.40 (C-13), 42.05 (C-14), 29.91 ( C-15), 23.72 (C-16), 39.41 (C-17), 47.91 (C-18), 46.30 (C-19), 30.87 (C-20), 34.73 (C-21), 32.86 (C -22), 28.32 (C-23), 15.51 (C-24), 14.35 (C-25), 17.34 (C-26), 26.20 (C-27), 122.40 (C-28), 33.64 (C- 29), 24.01 (C-30), 34.40 (-CH ₂ - in - CH2-COOH), 27.36, 27.44, 27.50, 27.58, 27.76, 28.32 (6C, -CH ₂ - in =CH-CH ₂ - or - CH ₂ -CH=), 178.70 (C in—COOH). WH X ZD) Ζζ-ζ\ ίΖ-D) LZ'SZ ZZ-D) 9S ZZ \Z-3) O £ '(03"3) Ζ.8Ό£'(6ΐ-θ) '(81-3) WL L\-D) d '(91-0) ZZ LVZi SO '(Π_ ) ZZ'i Xl )

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Z.T000/S00ZN3/X3d 66t690/900Z OAV (C-25), 17.30 (C-26), 26.19 (C-27), 122.70 (C-28), 33.60 (C-29), 24.55 (C-30), 34.38 (-CH ₂ - in- CH2 -COOH), 142.00, (=CH- in-CH-CH-), 29.95 (-CH ₂ - in =CH-CH ₂ -), 29.95 (-CH ₂ - in -CH ₂ -CH=), 179.32 ( C in — COOH). Example 25 Preparation of Compound D-6

 Compound D-5 (484 mg, 1 mmol) was dissolved in 5 mL of ethyl acetate, 5% EtOAc (5 mg) was added, and the mixture was stirred overnight under hydrogen atmosphere. White powder D-6 (489 mg, 0.93 mmol), Yield 93

%.

Ή-NMR (CDC1 ₃ , 300 MHz) (δ): 2.33 (t, J = 5.8 Hz, 2H, -CH ₂ -COO-) 2.67 (m, 1H, H in 3) _: 3.36 (s, 3H, - OCH ₃ ), 5.16 (m, 1H, H in 12). Example 26 Preparation of Compound D-7

Compound D-5 (484 mg, 1 mmol) was dissolved in dry THF (20 mL). Add water (0.09 mL) to quench, add 5 N NaOH (0.06 mL), water (0.29 mL), stir for 1 h, filter with a sand core funnel, wash with (20 mL) dichloromethane, and filtrate. The mixture was rotary evaporated to give a white solid. Oxalyl chloride (0.1 mL, U mmol) was dissolved in dichloromethane (5 mL), cooled to -60 °C j DMSO (0.17 mL, 2.2 mmol) in dichloromethane (5 mL) Stir at -60 'C for 5 min. The solution of the above white solid product in dichloromethane (5 mL) was slowly added dropwise, and stirred at -60 °C for 15 min, then triethylamine (0.7 mL, 5 mmol) was added. The temperature was slowly raised to room temperature and stirred for 48 h. The solution was washed three times with (10 mL) water, dried over sodium sulfate and evaporated. Take triphenylphosphonium 4-bromobutyrate (1.28 g, 3 mmol) dissolved in (10 mL) dry tetrahydrofuran, add sodium tert-butoxide (168 mg, 1.5 mmol) and stir for 15 min. The product was yellow solid and was reacted for 3 h. After adding (10 mL) of water, the mixture was extracted with EtOAc (EtOAc)EtOAc. V/V) purified to pale yellow powder D-7 (375 mg, 0.65 mmol), yield 65%. Ή-NMR (CDC1 ₃ , 300 MHz) (S): 2.66 (m, 1H, H in 3), 3.37 (s, 3H, -OCH ₃ ), 5.13 (m, 3H), 5.42 (m, 2H); ¹³ C-NMR (CDC1 ₃ , 75.0 MHz) (δ): 38.66 (Cl), 22.12 (C-2), 88.95 (C-3), 38.52 (C-4), 57.67 (C-5), 18.37 ( C-6), 32.69 (C-7), 40.00 (C-8), 47.78 (C-9), 37.07 (C-10), 23.73 (C-ll), 122.18 (C-12), 145.07 (C -13), 41.70 (C-14), 25.85 (C-15), 23.26 (C-16), 33.34 (C-17), 47.39 (Cl 8), 46.79 (C-19), 28.25 (C-20 ), 33.49 (C-21), 39.67 (C-22), 26.20 (C-23), 15.63 (C-24), 14.34 (C-25), 16.88 (C-26), 25.78 (C-27) , 31.09 (C-28), 34.66 (C-29), 23.79 (C-30), 34.24 (-CH ₂ - in -CH ₂ -COOH), 179.84 (C in -COOH). Example 27 Preparation of Compound D-8

 The compound D-7 (578 mg, 1 mmol) was dissolved in 5 mL of ethyl acetate, 5% EtOAc (5 mg) was added, and the mixture was stirred overnight under a hydrogen atmosphere. White powder D-8 (523 mg, 0.90 mmol) Yield 90

%.

Ή-NMR (CDC1 ₃ , 300 MHz) (δ): 2.33 (t, 2Η, J= 5.7 Hz, -C3⁄4-COO-) 2.67 (m, 1H, H in 3) _: 3.36 (s, 3H, -OCH ₃ ), 5.16 (m, 1H, H in 12). Example 28 Preparation of Compound D-9

Compound D-7 (578 mg, 1 mmol) was dissolved in dry THF (20 mL). Add water (0.09 mL) to quench, add 5 M NaOH (0.06 mL), water (0.29 mL), stir for 1 h, filter with a sand core funnel, wash with (20 mL) dichloromethane, and filtrate. The mixture was rotary evaporated to give a white solid. Oxalyl chloride (0.1 mL, 1.1 mmol) was dissolved in dichloromethane (5 mL), cooled to -60 °C, and DMSO (0.17 mL, 2.2 mmol) in dichloromethane (5 mL) Stir and stir at -60 V for 5 min. The solution of the above white solid product in dichloromethane (~5 mL) was slowly dropped, and stirred at -60 °C for 15 min, then triethylamine (0.7 mL, 5 mmol) was added. The temperature was slowly raised to room temperature and stirred for 48 h. Dichloromethane

127.19 (.-C in -ph), 123.39 (pC in -ph), 171.09 (-CO- in CH ₃ -CO-), 21.42 (CH ₃ in CH ₃ -CO -). Example 30 Preparation of Compound M-2

 Take Ml (78.9 mg, 0.12 mmol), add THF (12 mL), methanol (8 mL), 4 M NaOH aqueous solution (5 mL), stir overnight, and adjust pH to about 3 with 1 M diluted hydrochloric acid. </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> <RTIgt;

Ή-NMR (pyridine, 300 MHz) (δ): 3.46 (d, J = 6.3 Ηζ, ΙΗ, -CH- in 18), 3.64 (m, 2H, CH ₂ in CH ₂ -ph), 3.65 (m, 1 H, -CH- in 3), 5.271 (m, 1H, -H in -CONH-), 7.34 (m, 2H, -H in -ph), 7.42 (m, 3H, -H in -ph); ¹³ C-NM (CDC1 ₃ , 75.0 MHz) (δ): 39.18 (Cl), 27.95 (C-2), 78.22 (C-3), 38.14 (C-4), 55.93 (C-5), 18.88 ( C-6), 33.42 (C-7), 39.54 (C-8), 48.27 (C-9), 37.46 (C-10), 24.10 (C-1 1), 123.68 (C-12), 144.36 ( C-13), 42.1 8 (C-14), 28.24 (C-15), 24.00 (C-16), 46.94 (C- 17), 42.33 (C- 18), 46.70 (C- 19), 30.16 ( C-20), 34.61 (C-21), 33.19 (C-22), 28.95 (C-23), 16.70 (C-24), 15.72 (C-25), 17.06 (C-26), 26.16 (C -27), 174.89 (C-28), 54.90 (C- l '), 177.58 (C-2'), 39.94 (CH ₂ in -CH ₂ -ph), 136.04 (C in -ph), 130.33 (mC In -ph), 128.87 ( -C in -ph), 127.20 (pC in -ph). Example 31 Preparation of Compound M-3

The acid chloride of acetylated oleanolic acid (103.3 mg, 0.2 mmol) was taken and dissolved in (10 mL) anhydrous dichloromethane. The hydrochloride salt of (95.4 mg, 0.4 mmol) of i^-amino acid methyl ester was dissolved in (10 mL) anhydrous dichloromethane, and (0.5 mL) triethylamine was added to give the eleven amino acid methyl ester hydrochloride. Completely dissolved in anhydrous dichloromethane, then added to the reserve solution, stirred for 3 h, concentrated, separated by silica gel column (petroleum ether: ethyl acetate = 10: 1 V/V), concentrated Dry to give a white solid (115.7 mg, 0.17 mmol). To the product was added THF (12 mL), EtOAc (EtOAc) Adjust the pH to about 3 with 1M dilute hydrochloric acid. 9Z

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Z.T000/S00ZN3/X3d 66t690/900Z OAV = 15: 1 V/V). Concentration and drying gave a white solid (136.7 mg, 1.72 mmol). To the product was added THF (12 mL), EtOAc (EtOAc) Adjust the pH to about 3 with 1 M dilute hydrochloric acid, extract with chloroform (20 mL), then rinse the chloroform layer three times with (20 mL) saturated NaCl solution, dry over anhydrous sodium sulfate, and then dilute the solvent to give a pale yellow solid N -2 (118.8 mg, 1.44 mmol), yield 87%.

Ή-NMR (CDC1 ₃ , 300 MHz) {δ): 2.13 (t, J = 7.5 Hz, 2Η, -CH ₂ - in 10'), 3.02 (m, IH, H in V), 3.14 (m, 2H , CH ₂ in -CH ₂ -ph), 3.19 (m, IH, H in 3), 3.29 (m, IH, m, 1H, H in Γ), 4.91 (m, 1H, CH in -CONHCH-), 5.29 (s, IH, -CH in 12), 6.03 (m, IH, -NH- in -CONHCH2), 6.19 (d, J= 7.8, IH, H in 12'), 7.10 (m, 2H, -H In -ph), 7.30 (m, 2H, -H in -ph) _; ^l3 C-NMR (CDC1 ₃ , 75.0 MHz) (δ): 37.61 (C-1), 27.16 (C-2), 79.27 (C -3), 38.94 (C-4), 55.34 (C-5), 18.48 (C-6), 32.96 (C-7), 39.89 (C-8), 47.93 (C-9), 37.22 (C- 10), 23.62 (C-11), 125.89 (C-12), 140.19 (C-13), 42.75 (C-14), 28.02 (C-15), 27.30 (C-16), 47.71 (C-17 ), 54.24 (C-18), 39.29 (C-19), 40.00 (C-20), 31.08 (C-21), 36.66 (C-22), 28.35 (C-23), 15.90 (C-24) , 15.73 (C-25), 17.13 (C-26), 23.45 (C-27), 173.62 (C-28), 17.46 (C-29), 21.43 (C-30), 39.89 (C-1') , 25.02 (C-2'), 29.89-29.24 (C- (3'-8')), 25.78 (C-9), 37.12 (C-10'), 173.62 (C-ΙΓ), 53.24 (C- 12'), 178.84 (C-13'), 136.40 (C in -ph), 129.70 (mC in -ph), 128.60 (oC in -ph), 127.12 (pC in -ph). Example 35 Preparation of Compound N-3

 Acetyl chloride of acetylated oleanolic acid (103.3 mg, 0.2 mmol) was dissolved in (10 mL) anhydrous dichloromethane. Dissolve (159.8 mg) eleven amino acid-(L) tyrosine methyl ester hydrochloride in (10 mL) anhydrous dichloromethane, add (0.5 mL) triethylamine to make eleven amino acids - (L) The hydrochloride salt of the amino acid methyl ester was completely dissolved in anhydrous dichloromethane, and the latter was added to the reserve solution, stirred for 3 h, concentrated, and separated by silica gel chromatography (petroleum ether: ethyl acetate = 15 : 1 V/V) concentrated, dried to give a white solid (140.2 mg, 1.66 mmol). To the product was added THF (12 mL), MeOH (EtOAc) The pH was adjusted to about 3 with 1 M dilute hydrochloric acid, extracted with chloroform (20 mL), and then washed with EtOAc (EtOAc) (EtOAc) -3 (118.8 mg, 1.51 mmol), yield 91%.

Ή-NMR (CDC1 ₃ , 300 MHz) (S): 2.11 (t, J = 7.5 Hz, 2H, -CH- in 10'), 2.42 (d, J = 11.2 Hz, IH, -CH.in 18) , 3.11 (m, IH, H in Γ), 3.17 (m, 2H, CH ₂ in -CH ₂ -ph), 3.23 (m, IH, -CH- in 3), 3.25 (m, IH, H in Γ ), 4.79 (m, IH, H in 12'), 5.32(s, IH, -CH in 12), 6.10 (m, IH, -NH- in -CONHCH ₂ ), 6.21(d,J=7.8, IH , -NH- in - CONHCH), 7.21 (m, 2H, -H in -ph), 7.25 (m, 2H, -H in -ph); ^{, 3} C-NMR (CDC1 ₃ , 75.0 MHz) (S) : 38.85 (C-1), 27.02 (C-2), 79.13 (C-3), 37.52 (C-4) _; 55.19 (C-5), 18.39 (C-6), 32.45 (C-7), 39.84 (C-8), 47.43 (C-9), 36.59 (C-10), 23.81 (C-ll), 122.92 (C-12), 145.22 (C-13), 42.60 (C-14), 27.40 (C- 15), 23.73 (C- 16), 46.82 (C-17), 42.23 (C- 18), 46.45 ( C- 19), 30.75 (C-20), 34.30 (C-21), 27.22 (C-22), 28.25 (C-23), 15.49 (C-24), 14.40 (C-25), 17.05 (C -26), 25.88 (C-27), 173.78 (C-28), 33.10 (C-29), 23.71 (C-30), 39.80 (Cl,), 23.75 (C-2'), 29.79-29.23 ( C- (3,-9')), 173.63 (C-Ι Γ), 53.20 (C- 12'), 178.90 (C-13'), 136.14 (C in -ph), 129.22 (mC in -ph) , 128.32 (oC in -ph), 174.12 (pC in -ph). Example 36 PTP1 B inhibitory activity test

 I. Test principle: The molecular structure of the human protein tyrosine phosphatase IB (hPTPlB) catalytic domain is expressed in the E. coli system. The purified hPTPlB recombinant protein can hydrolyze the phospholipid bond of the substrate pNPP. The product has a strong light absorption at 410 nm, so it is possible to directly observe the change in light absorption at 410 nm to observe changes in enzyme activity and inhibition of enzyme activity by the compound. The standard assay system is as follows: 50 mM Mops, pH 7.0, 1 mM EDTA, 2 mM DTT, 2 mM PNPP, 2% DMSO, 40 nM hPTP1 B.

 pNPP 410 nm II. Observation index: The optical absorption at 410 nm is measured dynamically for 3 min, and the slope of the first-order reaction of the kinetic curve is used as the activity index of the enzyme.

3. Sample test: 1. Dissolve 1 mg sample in 200 μΐ DMSO. 20 was added to the A2-H11 sample well of a 96-well polypropylene plate, and then 80 DMS0 was added as a mother plate. 2. 2 μΐ of the sample was added to the corresponding sample well of a 96-well polystyrene plate using the Biomek 2000 automatic sample loading system as a daughter plate for screening. 3. Add 2 L DMSO to the sample well Al-D E12-H12 as a 100% enzyme activity control. 4. Add 2 μΐ of different concentrations of positive control (four concentrations diluted by 10 g/mL) to sample wells A12-D12 and E1-H1. 5. Add 88 μΐ Assay mi x to the sample wells A1-H12. 6. Add 10 μΐ hPTP lB to the sample wells A1-H12. 7. Measure the light absorption at 410 nm on a SpectraMAX 340 for 3 minutes. 8. Export the data as a text file and open it in Excel. The V _{ma of the} sample wells A1-D1 and E12-H12 is averaged as 100% enzyme activity. The inhibition rate of the compound to PTP1B was obtained by the following formula:

% inhibition rate = ( 1 - each screening hole value I blank control V _mx average) X 100%

Test compound: oleanolic acid, ursolic acid, G-1, G-2, G-3, G-4, H-1, H-2, H-3, H-4, G-5, G- 6. G-7, G-8, D-7, M-2, M-3, M-4, N-1, N-2, N-3. IV. Test results: The screening result is the percentage inhibition rate of enzyme activity when the concentration of the compound is 2 (^g/mL, when the inhibitory activity is higher than 50%, IC ₅ o is obtained by routine screening, positive control 4 [4-(4-oxalyl-phenoxymethyl)-benzyloxy]-phenyl-oxo-acetic acid ,

The IC ₅₀ was 5.4 μΜ (Christopher T. Seto, et al. J. Med. Chem., 2002 _; 45, 3946-3952) o Each test compound inhibited the IC _{5 of} hPTP-ΙΒ. The values are shown in Table 1. Example 37 Selectivity Test of PTP1B Inhibition by Compounds of the Invention

In this test, the selective inhibitory effect of the compound of the present invention on PTP1B was observed by comparing the inhibitory activities of the compounds of the present invention against phospholipases (PTPs) (TCPTP, CDC25A, CDC25B and LAR) of the same family of PTP1B. The test conditions and methods for inhibiting the activity of test compounds and compounds against TCPTP, CDC25A, CDC25B and LAR were the same as those in Example 36, and each test compound inhibited IC ₅ of TCPTP, CDC25A, CDC25B, and LAR. The values are shown in Table 1.

 The results of the tests shown in Table 1 indicate that the compounds of the present invention have a high inhibitory effect on PTP1B, while the same family of phospholipases (PTPs) (TCPTP, CDC25A, CDC25B and LAR) are weak, and it can be seen that the compound of the present invention is PTP1B. Has a better selective inhibition effect. Table 1 Test compound inhibition PTP1B, TCPTP, CDC25A, CDC25B, LAR activity data

IC ₅₀ (uM)

 Compound chemical structure

 PTP1 B TCPTP CDC25A CDC25B LAR

21. 90 5. 94 +

Oleanolic acid . Ύ*ΟΟΟΗ weak effect weak effect weak

 ± 1. 81 0. 08

5. 76 +

 Ursolic acid ■ Ι · | Γ*ΟΟΟΗ weak effect weak effect weak

0. 79

Z.T000/S00ZN3/X3d 66t690/900Z OAV

Example 38 Effect of Compound N-2 on the Binding Capacity and Catalytic Rate of PTP1B to Substrate pNPP

First, the test method: 1, in the 96-well polystyrene plate sample hole A1_H1; A3-H3; A5-H5; A7-H7; A9-H9; A11-H11 respectively added 625 nM double dilution with DMS0 Six concentrations of L-5 DMS0 solution 2 μΐ. 2. In sample wells A1-A12; B1-B12; C1-C12; D1-D12; E1-E12; F1-F12; G1-G12; HI-H12 DMSO solution of 10 concentrations of substrate pNPP diluted twice with DMS0 starting at 40 mM was added with 10 μΙ _α 3 and sample wells A1-H12 were added to 88 μΐ Assay mix, respectively. 6. Add 10 μΐ ΡΤΡ1Β to the sample well Al-H12. 7. Measure the light absorption at 410 nm on a SpectraMAX 340 for 3 minutes.

II. Test Results: Compound N-2 inhibited PTP1B with an IC50 of 250 nM, which has high inhibitory activity. Moreover, as the concentration of the inhibitor increased, the binding capacity of PTP1B to the substrate pNPP, that is, Km became larger, and the catalytic rate (kcat) of the substrate did not change significantly (see Fig. 1 and Fig. 2). Thus, the compound is a competitive inhibitor of a class of PTP1B. Example 39 Effect of Compound N-2 on IR Phosphorylation Level in CHO/IR Cells I. Test principle: The phosphorylation level of insulin receptor IR in insulin-sensitive cells is tightly regulated by protein tyrosine kinases and protein tyrosine phosphatases. PTP1B is in this The process plays a role as a negative regulator. By detecting changes in IR phosphorylation levels in CHO/IR cells (National New Drug Screening Center), it is possible to determine whether PTP1B inhibitors enter cells and function intracellularly.

 2. Test methods: 1. Cell seeding: Cells with good growth state were connected to 6-well plates at a density of 3-4 X 105 cells/well, 2 mL of medium per well F12 + 10% NCS. 2. Hunger: After 24 hours, serum-free F12 medium, 2 mL, overnight for 12 h. 3. Administration: Remove the old medium, add fresh F12, l mL, and incubate for 20 minutes. Compound 1 was diluted with 1 mL of F12 serum-free medium and added to each well for 2.5 hours. Positive and negative controls were made with 1 mM Na3V04 and 0.1% DMSO, respectively. 4. Insulin stimulation: Insulin with a final concentration of ΙΟηΜ was added to each well for 10 minutes. Or no insulin stimulation. 5. Take the sample: Discard the medium and add 100 μL of X 1 loading buffer per well to lyse the cells.

 III. Test results: The study of compound N-2 showed that the phosphorylation level of IR increased significantly with the increase of inhibitor concentration. It can be seen that N-2 plays an inhibitory role in the dephosphorylation of IR in cells, indicating that such compounds may enhance the signal of insulin stimulation and can alleviate insulin resistance to some extent.

Claims

Rights request

1. A triterpenoid PTP1B inhibitor having the structure of the following formula I or a physiologically acceptable salt thereof:

among them! ^ is a sulfhydryl group or hydrogen;

R ₂ is an alkyl group or hydrogen of d _C ₅ ;

R ₃ is hydrogen, hydroxy, amino, halogen or fluorenyl;

 Is a hydroxyl group, an amino group, a halogen or a fluorenyl group;

for. , ^^ alkyl, dC ₂ o unsaturated hydrocarbon group, YCH(R ₅ ), CONH(CH ₂ ) _n CH(R ₆ )COOH or CONH(CH ₂ ) _n CONH(CH ₂ ) _m CH(R ₇ COOH, wherein η is 1-20, m is 1-20; Y is C!-C^ alkyl or ^^^ unsaturated hydrocarbon group; R ₅ , R ₆ , R ₇ are each independently selected from - Cs Sulfhydryl, aryl, substituted aryl;

 The aryl group in the aryl group or substituted aryl group means a phenyl group, a pyridyl group, a fluorenyl group, a furyl group, a thienyl group or a pyrrolyl group.

The triterpenoid PTP1B inhibitor according to claim 1, or a physiologically acceptable salt thereof, which is characterized in that! ^ is hydrogen;

Is an alkyl or hydrogen of d-C ₅ ;

R ₃ is a hydroxyl group, an amino group, a halogen or a fluorenyl group;

 R4 is a hydroxyl group, an amino group, a halogen or a fluorenyl group;

Is a thiol group of ^^, an unsaturated hydrocarbon group of dC ₂₀ , YCH(R ₅ ), CONH(CH ₂ ) _n CH(R ₆ )COOH or CONH(CH ₂ ) _n CONH(CH ₂ ) _m CH(R ₇ ) COOH wherein η is 1-20 and m is 1-20; Y is an alkyl group of dC^. And an unsaturated hydrocarbon group; R ₅ , R ₆ , and R ₇ are each independently selected from an alkyl group, an aromatic group, and a substituted aromatic group.

The triterpenoid PTP1 B inhibitor according to claim 1, or a physiologically acceptable salt thereof, which is one of them. ₅垸 时;

 Is a sulfhydryl group or a hydrogen of -C5;

Is a hydroxyl group, an amino group, a halogen or a fluorenyl group R4 is a hydroxyl group, an amino group, a halogen or a fluorenyl group;

Is ^-^. Alkyl, dC o unsaturated hydrocarbon group, YCH(R ₅ ), CONH(CH ₂ ) _n CH(R ₆ )COOH or CONH(CH ₂ ) _n CONH(CH ₂ ) _m CH(R ₇ )COOH, wherein n is 1 -20 and m is 1 -20; Y is

An alkyl group or an unsaturated hydrocarbon group; R ₅ , R ₆ , and R ₇ are each independently selected from the group consisting of a fluorenyl group, an aryl group, and a substituted aryl group of d-C ₅ .

The method for preparing a triterpenoid PTP1B inhibitor according to claim 1, which is characterized in that oleanolic acid, ursolic acid, colanic acid or 2α-hydroxy sinoic acid is used as a raw material, and is passed through Wi Uig or Wittig- The Horner reaction synthesizes a 28-long-chain fatty acid derivative, and then obtains 3 other substituted 28-long-chain fatty acid derivatives by substituting the 3-position hydroxyl group; synthesizing the 28-peptide chain derivative by condensation with various amino acids, and then substituting 3 The hydroxyl group at the position obtains 3 other substituted 28-peptide chain derivatives.

The use of the triterpenoid PTP1 B inhibitor according to claim 1 or a physiologically acceptable salt thereof as an insulin sensitizer.

The triterpenoid PTP1 B inhibitor according to Claim 1 or a physiologically acceptable salt thereof, which has activity of inhibiting PTP1B activity as a medicament for treating diabetes, obesity and complications thereof caused by insulin resistance.