Coumarin tyramine glycoside compounds and their use in the preparation of ptp1b inhibitors and anti-diabetic drugs

Abstract

The application discloses a coumarin tyramine glycoside compound and application thereof in preparation of PTP1B inhibitors and anti-diabetic drugs, and a structural formula of the compound is shown in the following formula: wherein R represents a fatty (aromatic) acyl or a monosaccharide substituent, and R' represents a hydrogen atom or an acetyl group; the compound is prepared by taking 4-methoxycoumarin tyramine 4'-acetyl-O-L-rhamnose as a starting material, introducing a fatty (aromatic) acyl or a monosaccharide substituent into a 2-position hydroxyl and a 3-position hydroxyl of L-rhamnose at the same time, and then removing a protecting group of a sugar group. Pharmacological activity tests show that the compound has good inhibitory activity on protein tyrosine phosphatase 1B, and it is indicated that the coumarin tyramine glycoside compound can be researched and utilized as a new type of PTP1B inhibitor and anti-diabetic drug.

Description

TECHNICAL FIELD

[0001] The present application belongs to the technical field of chemical drugs, and particularly relates to a coumarin tyramine glycoside compound and application thereof in preparation of PTP1B inhibitors and anti-diabetic drugs. BACKGROUND

[0002] Diabetes has become one of the fastest growing diseases today and has become the third largest chronic non-communicable disease in the world. According to the definition of the World Health Organization, diabetes mellitus (DM) is a serious chronic disease, and type II diabetes (T2DM) is a metabolic disease caused by insufficient insulin secretion or insulin resistance, characterized by high blood sugar without treatment intervention. A number of studies have shown that protein tyrosine phosphatase 1B (PTP1B) is an effective drug target for anti-type II diabetes, and the overexpression of PTP1B can effectively improve insulin resistance. However, so far there is no PTP1B inhibitor on the market, and most of the drugs in the clinical trial stage are derived from natural products and their analogues. The natural product Teuvisside A is a coumarin tyramine glycoside compound isolated from a perennial herbaceous plant Teucrium viscidum, which has significant anti-hyperglycemic activity in hepatoma HepG2 cells and mouse embryonic fibroblast 3T3-L1 adipocytes (Kong L et al. Journal of natural product. 2014, 77: 200-205). Based on the coumarin tyramine glycoside natural product Teuvisside A, the molecular structure is optimized to obtain a simplified coumarin tyramine glycoside compound, which is an effective way to realize the research of innovative drugs.

[0003] There is no report on the molecular structure simplification and modification of the coumarin tyramine glycoside compound Teuvisside A to screen PTP1B inhibitors, especially the introduction of fatty (aromatic) acyl, monosaccharide and other groups at the L-rhamnose glycosyl C-2 and C-3 sites of the coumarin tyramine glycoside to carry out the research on the PTP1B enzyme inhibition activity. SUMMARY

[0004] The purpose of the present application is to provide a class of coumarin tyramine glycoside compounds, and to provide a new use for the compounds.

[0005] In order to achieve the above purpose, the coumarin tyramine glycoside compound used in the present application has the following structural formula:

[0006]

[0007] wherein R is selected from any one of stearoyl, palmitoyl, n-octanoyl, n-heptanoyl, benzoyl, 3-phenylpropionyl, 4-methoxycinnamoyl, 3,4-dimethoxycinnamoyl, 3,4,5-trimethoxycinnamoyl, 2,4-dimethylbenzoyl, L-rhamnosyl, D-mannosyl, and R' is selected from hydrogen atom or acetyl group.

[0008] Further, when R' represents acetyl group, it is preferred that R is selected from any one of stearoyl, palmitoyl, n-octanoyl, n-heptanoyl, benzoyl, 3-phenylpropionyl, 4-methoxycinnamoyl, 3,4-dimethoxycinnamoyl, 3,4,5-trimethoxycinnamoyl, 2,4-dimethylbenzoyl.

[0009] Further, when R' represents hydrogen atom, it is preferred that R is selected from any one of L-rhamnosyl, D-mannosyl.

[0010] The synthetic route and specific synthesis method of the coumarin tyramine glycoside compound of the present application are as follows:

[0011]

[0012] 1. Synthesis of coumarin tyramine glycoside compounds 2-11

[0013] When R is selected from any one of stearoyl, palmitoyl, n-octanoyl, n-heptanoyl, benzoyl, 3-phenylpropionyl, 4-methoxycinnamoyl, 3,4-dimethoxycinnamoyl, 3,4,5-trimethoxycinnamoyl, 2,4-dimethylbenzoyl, and R' is selected from acetyl group, compound 1 is stirred with N,N'-dicyclohexylcarbodiimide, 4-dimethylaminopyridine, ROH (i.e. stearic acid, palmitic acid, n-octanoic acid, n-heptanoic acid, benzoic acid, 3-phenylpropionic acid, 4-methoxycinnamic acid, 3,4-dimethoxycinnamic acid, 3,4,5-trimethoxycinnamic acid, 2,4-dimethylbenzoic acid) in a molar ratio of 1:3-6:6:2-8 in dry dichloromethane at room temperature for 5 h. After the reaction is completed, filtration is performed, and the filtrate is concentrated under reduced pressure and separated by silica gel column chromatography with petroleum ether / ethyl acetate to obtain coumarin tyramine glycoside compounds 2-11.

[0014] 2. Synthesis of coumarin tyramine glycoside compounds 14 and 15

[0015] When R is selected from any one of L-rhamnosyl, D-mannosyl, and R' is selected from hydrogen atom, compound 1 is stirred with N,N'-dicyclohexylcarbodiimide, 4-dimethylaminopyridine, ROH (i.e. stearic acid, palmitic acid, n-octanoic acid, n-heptanoic acid, benzoic acid, 3-phenylpropionic acid, 4-methoxycinnamic acid, 3,4-dimethoxycinnamic acid, 3,4,5-trimethoxycinnamic acid, 2,4-dimethylbenzoic acid) in a molar ratio of 1:3-6:6:2-8 in dry dichloromethane at room temperature for 5 h. After the reaction is completed, filtration is performed, and the filtrate is concentrated under reduced pressure and separated by silica gel column chromatography with petroleum ether / ethyl acetate to obtain coumarin tyramine glycoside compounds 14 and 15. The molecular sieve is a water removing agent, compound 1 is mixed with per-acetyl-protected rhamnose trichloroacetimidate and per-acetyl-protected mannose trichloroacetimidate respectively at a molar ratio of 1:1-6.5, trifluoromethylsulfonic acid trimethylsilane (TMSOTf) is added at 0°C under nitrogen protection, the molar ratio of compound 1 and TMSOTf is 1:0.1-0.2, and the reaction is stirred at room temperature for 1h; after the reaction is completed, filtration is performed, the solvent is removed by evaporation under reduced pressure, and the concentrate is subjected to silica gel column chromatography to obtain compound 12 and 13 respectively. Compound 12 and 13 are mixed with sodium methoxide respectively at a molar ratio of 1:0.5-6 in anhydrous methanol, the reaction is stirred at room temperature for 1-3h; after the reaction is completed, the concentrate is obtained by evaporation under reduced pressure, and silica gel column chromatography is performed to obtain coumarin tyramine glycoside compounds 14 and 15 respectively.

[0016] The application further provides a use of the coumarin tyramine glycoside compound in preparation of a PTP1B inhibitor and an anti-diabetic drug, which is prepared into tablets, granules or capsules according to a conventional preparation process of various preparations with a pharmaceutically acceptable carrier.

[0017] The application has the following beneficial effects:

[0018] The application takes 4-methoxy coumarin tyramine 4'-acetyl-O-L-rhamnose as a mother body, introduces a fatty (aromatic) acyl or a monosaccharide substituent into the 2-hydroxyl and 3-hydroxyl of L-rhamnose, and then removes the protecting group of the sugar group to prepare the coumarin tyramine glycoside compound. The compound shows good inhibitory activity on protein tyrosine phosphatase 1B through pharmacological activity detection, and can be used for preparing a PTP1B inhibitor and a drug for treating diabetes. DETAILED DESCRIPTION

[0019] The application is further described in detail below in combination with examples, but the protection scope of the application is not limited to the examples.

[0020] Example 1

[0021] Synthesis of coumarin tyramine glycoside compounds 2-15

[0022] 1. Synthesis of coumarin tyramine glycoside compounds 2-11

[0023] Compound 1 (100mg, 0.2mmol), N,N'-dicyclohexyl carbodiimide (250mg, 1.2mmol), 4-dimethylamino pyridine (148mg, 1.2mmol) and stearic acid (1.2mmol) are dissolved in dry dichloromethane (20mL), and the reaction is stirred at room temperature for 5h; after the reaction is completed, filtration is performed, the concentrate is obtained by evaporation under reduced pressure, and silica gel column chromatography is performed (eluent: petroleum ether / ethyl acetate=5:1) to obtain coumarin tyramine glycoside compound 2.

[0024] The stearic acid was replaced by equal molar palmitic acid, n-octanoic acid, n-heptanoic acid, benzoic acid, 3-phenylpropionic acid, 4-methoxycinnamic acid, 3,4-dimethoxycinnamic acid, 3,4,5-trimethoxycinnamic acid, 2,4-dimethylbenzoic acid in turn to obtain coumarin tyramine glycoside compounds 3-11.

[0025] The structural characterization data of compound 2 are as follows: 1 H NMR (400 MHz, CDC13) δ 7.57 (d, J = 15.5 Hz, 1H), 7.47-7.40 (m, 2H), 7.26 (s, 1H), 7.14 (d, J = 7.9 Hz, 1H), 7.06-6.98 (m, 2H), 6.87 (d, J = 8.3 Hz, 2H), 6.20 (d, J = 15.5 Hz, 1H), 5.60 (t, J = 6.0 Hz, 1H, H-1’), 5.52 (dd, J = 10.7, 3.5 Hz, 1H), 5.45-5.39 (m, 2H), 5.15 (t, J = 10.0 Hz, 1H), 4.04-3.94 (m, 1H), 3.82 (s, 3H, OMe), 3.61 (q, J = 6.6 Hz, 2H), 3.54-3.44 (m, 1H), 2.83 (t, J = 6.8 Hz, 1H), 2.43 (td, J = 7.7, 4.0 Hz, 2H), 2.25 (t, J = 7.5 Hz, 2H), 2.04 (d, J = 1.7 Hz, 3H), 1.97-1.88 (m, 1H), 1.68 (dq, J = 14.7, 7.6, 6.0 Hz, 4H), 1.58 (q, J = 10.5, 7.3 Hz, 3H), 1.25 (s, 50H, CH2), 1.20 (d, J = 6.0 Hz, 2H), 1.08 (d, J = 12.8 Hz, 1H), 0.91-0.80 (m, 6H, CH3); 13 C NMR (101 MHz, CDC13) δ 172.99, 172.88, 169.96, 166.28, 160.94, 154.78, 140.81, 133.21, 129.98, 129.43, 127.55, 118.18, 116.69, 114.28, 95.96, 71.06, 69.55, 68.80, 67.20, 55.41, 49.20, 40.93, 34.95, 34.23, 34.03, 32.00, 29.79, 29.74, 29.60, 29.58, 29.45, 29.38, 29.17, 25.68, 25.07, 25.01, 24.89, 22.77, 20.88, 17.56, 14.21; HRMS (ESI) m / z calcd for C 62 H99 NO 10 [M+H] + :1018.7342, measured value 1018.7294.

[0026] The structural characterization data of compound 3 are as follows: 1 H NMR(400MHz, CDCl3)δ7.58(d,J=15.5Hz,1H),7.47–7.40(m,2H),7.27(s,1H),7.15( d,J=8.0Hz,2H),7.06–6.99(m,2H),6.92–6.84(m,2H),6.20(dd,J=15.5,1.8Hz,1H) ,5.65–5.58(m,1H),5.52(dd,J=10.4,3.6Hz,1H),5.42(dd,J=5.6,2.5Hz,2H),5.21 –5.11(m,1H),4.14(d,J=8.1Hz,1H),4.01(dd,J=9.4,6.4Hz,1H),3.83(s,3H,OMe), 3.62(q,J=6.6Hz,2H),3.53–3.45(m,1H),2.83(t,J=6.8Hz,2H),2.44(dd,J=8.8,6. 1Hz,2H),2.25(t,J=7.6Hz,2H),2.04(d,J=1.8Hz,3H),1.93(dd,J=12.9,4.1Hz,3H) ,1.67(d,J=6.0Hz,2H),1.57(t,J=7.8Hz,4H),1.38–1.27(m,10H,CH2),1.26(s,46H ,CH2),1.20(d,J=6.0Hz,2H),1.08(dd,J=18.6,6.8Hz,2H),0.92–0.84(m,6H,CH3); 13 C NMR (101MHz, CDCl3) δ173.00,172.88,169.96,166.27,160.92,156.82,154.77,140.80,1 33.20,129.97,129.42,127.54,118.18,116.67,114.27,95.95,71.05,69.54,68.79,67. 19,55.41,49.18,40.93,34.95,34.23,34.03,32.00,29.79,29.74,29.59,29.57,29.45,29.38,29.17,25.68,25.07,25.02,24.89,22.77,20.89,17.55,14.21; HRMS(ESI) m / z theoretical value C58 H 91 NO 10 [M+H] + :962.6716, measured value 962.6692.

[0027] The structural characterization data of compound 4 are as follows: 1 H NMR(400MHz, CDCl3) δ7.57(d,J=15.5Hz,1H),7.46–7.39(m,2H),7.14(d,J=8.1 Hz,2H),7.01(d,J=7.9Hz,2H),6.90–6.83(m,2H),6.20(dd,J=15.7,1.7Hz,1H), 5.66(t,J=6.1Hz,1H),5.51(dt,J=10.2,2.3Hz,1H),5.45–5.38(m,2H),5.15(t ,J=10.0Hz,1H),4.51(s,1H),4.05–3.94(m,1H),3.82(s,3H,OMe),3.61(q,J=6. 7Hz,2H),3.45(q,J=10.8,8.7Hz,1H),2.83(t,J=6.9Hz,2H),2.43(t,J=7.6Hz, 2H),2.31(q,J=7.5Hz,1H),2.25(t,J=7.6Hz,2H),2.04(d,J=1.8Hz,3H),1.92(d d,J=12.8,4.0Hz,2H),1.66(p,J=12.0Hz,4H),1.57(t,J=7.1Hz,3H),1.40–1.2 4(m,25H),1.20(d,J=6.2Hz,3H),1.08(d,J=10.5Hz,1H),0.87(d,J=6.3Hz,6H); 13 C NMR (101MHz, CDCl3) δ172.99,172.88,169.97,166.34,160.91,154.75,140.83,13 3.19,129.96,129.42,127.53,118.14,116.66,114.26,95.93,71.04,69.54,68.7 8,67.18,55.40,49.28,40.94,34.92,34.21,33.90,31.73,31.71,29.09,29.07,28.99,25.63,25.04,24.97,24.86,22.67,20.87,17.54,14.14; HRMS(ESI) m / z theoretical value C 42 H 59 NO 10[M+H] + :738.4212, found 738.4190.

[0028] Structural characterization data for compound 5 are: 1 H NMR (400 MHz, CDC13) δ 7.57 (d, J = 15.5 Hz, 1H), 7.42 (d, J = 8.2 Hz, 2H), 7.14 (d, J = 8.1 Hz, 2H), 7.04 - 6.90 (m, 2H), 6.86 (d, J = 8.3 Hz, 2H), 6.21 (d, J = 15.5 Hz, 1H), 5.72 (t, J = 6.0 Hz, 1H), 5.52 (dd, J = 10.5, 3.5 Hz, 1H), 5.45 - 5.36 (m, 2H), 5.15 (t, J = 10.0 Hz, 1H), 4.63 (s, 1H), 4.00 (dq, J = 12.8, 6.7 Hz, 1H), 3.81 (s, 3H), 3.61 (q, J = 6.6 Hz, 2H), 3.44 (q, J = 10.9, 9.3 Hz, 1H), 2.82 (t, J = 6.9 Hz, 2H), 2.43 (td, J = 7.6, 3.9 Hz, 2H), 2.32 (t, J = 7.5 Hz, 1H), 2.25 (t, J = 7.5 Hz, 2H), 2.04 (s, 3H), 1.92 (dd, J = 12.9, 4.0 Hz, 2H), 1.73 - 1.51 (m, 7H), 1.44 - 1.30 (m, 2H), 1.33 - 1.23 (m, 23H), 1.23 - 1.13 (m, 4H), 1.12 (d, J = 3.3 Hz, 1H), 1.08 (dd, J = 12.1, 3.4 Hz, 1H), 0.88 (q, J = 6.6 Hz, 9H); 13 C NMR (101 MHz, CDC13) δ 172.98, 172.86, 169.96, 166.38, 160.92, 154.75, 140.82, 133.20, 129.95, 129.41, 127.54, 118.17, 116.66, 114.26, 95.95, 71.05, 69.55, 68.80, 67.18, 55.39, 49.29, 40.95, 34.91, 34.20, 33.87, 31.48, 29.75, 28.78, 25.62, 24.99, 24.95, 24.80, 22.53, 20.85, 17.53, 14.08; HRMS (ESI) m / z calcd for C 40 H 55 NO 10 [M+H] + :710.3899, found 710.3879.

[0029] Structural characterization data for compound 6 are: 1 H NMR (400 MHz, CDC13) δ 8.09 (d, J = 7.7 Hz, 2H), 7.93 (d, J = 7.7 Hz, 2H), 7.66 - 7.54 (m, 2H), 7.56 - 7.40 (m, 6H), 7.36 (t, J = 7.6 Hz, 2H), 7.21 - 7.14 (m, 2H), 7.09 (dd, J = 8.6, 1.7 Hz, 2H), 6.91 - 6.82 (m, 2H), 6.21 (dd, J = 15.6, 1.6 Hz, 1H, H-1'), 5.86 (dd, J = 10.0, 3.8 Hz, 1H), 5.78 (dt, J = 3.5, 1.9 Hz, 1H), 5.66 (s, 1H), 5.50 (td, J = 10.0, 1.6 Hz, 1H), 3.82 (d, J = 1.7 Hz, 3H, OMe), 3.63 (q, J = 6.6 Hz, 2H), 2.85 (t, J = 6.9 Hz, 2H), 2.00 (d, J = 1.6 Hz, 3H), 1.33 - 1.23 (m, 3H, H-6'); 13 CNMR (101 MHz, CDC13) δ 170.13, 166.28, 165.65, 165.63, 160.93, 154.86, 140.76, 133.68, 133.43, 133.33, 130.03, 130.01, 129.83, 129.42, 129.29, 129.25, 128.70, 128.55, 127.59, 118.27, 116.77, 114.29, 95.95, 71.19, 70.65, 69.94, 67.27, 55.41, 40.93, 34.97, 20.87, 17.66; HRMS (ESI) m / z calcd for C 40 H 39 NO 10 [M+H] + : 694.2647, found 694.2632.

[0030] Structural characterization data for compound 7 are: 1H NMR (400 MHz, CDC13) δ 7.58 (d, J = 15.5 Hz, 1H), 7.44 (d, J = 8.2 Hz, 2H), 7.31 - 7.12 (m, 13H), 7.01 (d, J = 8.1 Hz, 2H), 6.88 (d, J = 8.2 Hz, 2H), 6.19 (d, J = 15.5 Hz, 1H, H-1'), 5.53 (d, J = 3.6 Hz, 1H), 5.41 (d, J = 3.4 Hz, 1H), 5.35 (s, 1H), 5.14 (t, J = 9.9 Hz, 1H), 3.99 (dq, J = 12.3, 6.4 Hz, 1H), 3.82 (s, 3H, OMe), 3.62 (q, J = 6.6 Hz, 2H), 2.99 (t, J = 7.7 Hz, 2H), 2.92 - 2.81 (m, 4H), 2.77 (d, J = 7.8 Hz, 2H), 2.50 (t, J = 7.7 Hz, 2H), 1.93 (d, J = 1.5 Hz, 3H), 1.19 (d, J = 6.1 Hz, 3H, H-6'); 13 C NMR (101 MHz, CDC13) δ 172.06, 172.01, 169.99, 166.25, 160.97, 154.74, 140.82, 140.30, 140.02, 133.27, 129.99, 129.43, 128.62, 128.60, 128.37, 128.32, 127.58, 126.47, 126.40, 118.22, 116.68, 114.31, 95.86, 70.97, 69.82, 69.06, 67.20, 55.43, 40.93, 35.47, 35.37, 34.97, 30.81, 30.56, 20.76, 17.54; HRMS (ESI) m / z calcd for C 44 H 47 NO 10 [M+H] + : 750.3273, found 750.3253.

[0031] Structural characterization data for compound 8 are: 1H NMR (400 MHz, CDC13) δ 7.71 (d, J = 16.0 Hz, 1H), 7.66 - 7.41 (m, 7H), 7.45 - 7.39 (m, 2H), 7.16 (d, J = 8.1 Hz, 2H), 7.10 - 7.04 (m, 2H), 6.93 (d, J = 8.2 Hz, 2H), 6.86 (t, J = 7.3 Hz, 4H), 6.48 (dd, J = 16.0, 1.8 Hz, 1H), 6.24 (dd, J = 15.8, 13.3 Hz, 2H), 5.68 (d, J = 6.6 Hz, 1H, H-1'), 5.61 (d, J = 3.4 Hz, 1H), 5.55 (s, 1H), 5.35 (t, J = 10.0 Hz, 1H), 4.11 (dt, J = 10.3, 5.7 Hz, 1H), 3.84 (d, J = 16.8 Hz, 9H, OMe), 3.63 (q, J = 6.6 Hz, 2H), 2.84 (t, J = 6.9 Hz, 2H), 2.05 (s, 3H), 1.26 (d, J = 6.2 Hz, 3H, H-6'); 13 C NMR (101 MHz, CDC13) δ 170.24, 166.38, 166.29, 166.25, 161.77, 161.63, 160.91, 156.86, 154.87, 146.16, 145.80, 140.72, 133.20, 132.98, 130.17, 130.08, 129.98, 129.63, 129.41, 128.42, 127.60, 126.95, 118.29, 116.75, 114.54, 114.51, 114.45, 114.33, 114.28, 96.07, 71.34, 69.99, 68.99, 67.27, 55.48, 55.43, 55.40, 40.93, 34.02, 20.93, 17.60; HRMS (ESI) m / z calcd for C 46 H 47 NO 12 [M+H] + : 806.3171, found 806.3145.

[0032] The structural characterization data of compound 9 are as follows: 1H NMR (400 MHz, CDC13) δ 7.74 - 7.65 (m, 1H), 7.65 - 7.53 (m, 2H), 7.47 - 7.40 (m, 2H), 7.20 - 7.02 (m, 7H), 7.00 (s, 1H), 6.88 (dt, J = 8.7, 2.3 Hz, 3H), 6.82 (dd, J = 8.3, 1.9 Hz, 1H), 6.49 (dd, J = 15.9, 1.9 Hz, 1H), 6.23 (ddd, J = 18.4, 15.8, 1.9 Hz, 2H), 5.72 (dt, J = 10.3, 2.7 Hz, 1H, H-1'), 5.63 (d, J = 3.5 Hz, 2H), 5.56 (s, 1H), 5.41 - 5.32 (m, 1H), 4.17 - 4.05 (m, 1H), 4.01 - 3.79 (s, 15H, OMe), 3.63 (q, J = 6.7 Hz, 2H), 2.85 (t, J = 6.9 Hz, 2H), 2.06 (d, J = 1.8 Hz, 3H), 1.26 (t, J = 2.3 Hz, 3H, H-6'); 13 C NMR (101 MHz, CDC13) δ 170.40, 166.30, 166.28, 166.15, 160.93, 154.85, 151.57, 151.40, 149.38, 149.24, 146.42, 146.09, 140.77, 133.24, 130.00, 129.42, 127.59, 127.16, 123.50, 123.13, 118.25, 116.75, 114.69, 114.66, 114.28, 111.02, 110.99, 109.72, 109.39, 96.06, 71.37, 69.98, 69.01, 67.24, 56.06, 56.03, 55.94, 55.40, 40.93, 34.96, 20.96, 17.61; HRMS (ESI) m / z calcd for C 48 H 51 NO 14 [M+H] + : 866.3382, found 866.3362.

[0033] The structural characterization data of compound 10 are: 1H NMR (400 MHz, CDC13) δ 7.65 (dd, J = 15.8, 1.5 Hz, 1H), 7.59 (s, 1H), 7.55 (d, J = 2.0 Hz, 1H), 7.43 (d, J = 8.2 Hz, 2H), 7.26 (s, 1H), 7.17 (d, J = 8.1 Hz, 2H), 7.10 - 7.03 (m, 2H), 6.90 - 6.83 (m, 2H), 6.80 (d, J = 1.6 Hz, 2H), 6.70 (d, J = 1.6 Hz, 2H), 6.53 (dd, J = 15.9, 1.6 Hz, 1H), 6.29 (dd, J = 15.8, 1.6 Hz, 1H), 6.21 (dd, J = 15.6, 1.6 Hz, 1H), 5.72 (dd, J = 10.8, 3.5 Hz, 1H), 5.64 (d, J = 3.3 Hz, 2H), 5.55 (s, 1H), 5.41 - 5.31 (m, 1H), 4.11 (dq, J = 12.2, 6.4 Hz, 1H), 3.91 (s, 6H), 3.90 (s, 3H), 3.86 (s, 3H), 3.81 (s, 9H), 3.62 (q, J = 6.6 Hz, 2H), 2.84 (t, J = 6.9 Hz, 2H), 2.06 (d, J = 1.6 Hz, 3H), 1.30 - 1.23 (m, 6H); 13 C NMR (101 MHz, CDC13) δ 170.46, 166.27, 166.02, 165.84, 160.91, 154.76, 153.54, 153.43, 146.48, 146.14, 140.77, 140.46, 140.34, 133.29, 130.01, 129.58, 129.54, 129.41, 127.54, 118.19, 116.69, 116.22, 116.16, 114.26, 105.43, 95.97, 77.42, 77.10, 76.78, 71.28, 69.97, 69.11, 67.18, 61.07, 61.03, 56.27, 56.16, 55.40, 40.93, 34.95, 20.97, 17.59; HRMS (ESI) m / z calcd for C 48 H 51 NO 16 [M+H] + 926.3594, found 926.3572.

[0034] The structural characterization data of compound 11 are as follows: 1H NMR (400 MHz, CDC13) δ 7.93 (d, J = 8.0 Hz, 1H), 7.73 (dd, J = 8.0, 1.7 Hz, 1H), 7.58 (d, J = 15.5 Hz, 1H), 7.47 - 7.40 (m, 2H), 7.26 (d, J = 1.7 Hz, 1H), 7.20 - 7.13 (m, 3H), 7.13 - 6.93 (m, 8H), 6.91 - 6.82 (m, 2H), 6.21 (dd, J = 15.6, 1.7 Hz, 1H, H-1'), 5.85 (dd, J = 10.4, 3.8 Hz, 1H), 5.76 (q, J = 2.4 Hz, 1H), 5.63 (s, 2H), 5.51 - 5.39 (m, 1H), 4.20 - 4.07 (m, 2H), 3.82 (s, 3H, OMe), 3.63 (q, J = 6.6 Hz, 2H), 2.85 (t, J = 6.9 Hz, 2H), 2.56 - 2.50 (m, 6H), 2.34 (d, J = 22.2 Hz, 6H), 2.01 (s, 3H), 1.26 (d, 3H, H-6'); 13 C NMR (101 MHz, CDC13) δ 170.10, 166.48, 166.30, 166.28, 160.92, 154.95, 143.36, 143.16, 141.06, 140.86, 140.74, 133.22, 132.69, 132.63, 131.44, 131.17, 130.87, 129.99, 129.42, 127.60, 126.80, 126.70, 125.70, 125.53, 118.29, 116.79, 114.28, 96.05, 71.44, 70.35, 69.27, 67.31, 55.41, 40.93, 34.96, 22.09, 21.95, 21.52, 21.45, 20.91, 17.70; HRMS (ESI) m / z calcd for C 44 H 47 NO 10 [M+H] + : 750.3273, found 750.3257.

[0035] 2. Synthesis of coumarin tyramine glycoside compounds 14 and 15

[0036] Compound 1 (300 mg, 0.62 mmol) and per-acetylated rhamnose trichloroacetimidate (3.70 mmol) were dissolved in dry dichloromethane (50 mL) at 0 °C under nitrogen protection, and activated DIBAL-H (1.0 M in toluene, 3.70 mL, 3.70 mmol) was added dropwise. The reaction mixture was stirred at 0 °C for 1 h, and then quenched with MeOH (1 mL). The mixture was concentrated and purified by column chromatography (petroleum ether / ethyl acetate = 2 / 1) to give compound 14 (100 mg, 0.18 mmol, 29% yield) and compound 15 (100 mg, 0.18 mmol, 29% yield). Molecular sieves were added and stirred for 30 min, after the molecular sieves absorbed the water in the reaction flask, TMSOTf (0.12 mL, 0.08 mmol) was added, stirred at room temperature for 1 h, then the reaction was quenched with triethylamine, filtered, the solvent was removed under reduced pressure, the concentrate was purified by silica gel column chromatography (eluent: petroleum ether / ethyl acetate = 2:1) to obtain compound 12. Compound 12 (0.08 mmol) was dissolved in anhydrous methanol (50 mL), sodium methoxide (8 mg, 0.15 mmol) was added, stirred at room temperature for 1 h, adjusted to neutral with cation exchange resin, filtered, concentrated under reduced pressure, and then purified by silica gel column chromatography (eluent: MeOH / CH2Cl2=1:10) to obtain the coumarin tyramine glycoside compound 14.

[0037] The above fully acetylated rhamnose trichloroacetimidate was replaced with an equimolar amount of fully acetylated mannose trichloroacetimidate to obtain compound 13. Then compound 12 was replaced with an equimolar amount of compound 13 to obtain the coumarin tyramine glycoside compound 15.

[0038] The structural characterization data of compound 12 are as follows: 1 H NMR (400 MHz, CDCl3) δ 7.57 (d, J = 15.5 Hz, 1H), 7.43 (d, J = 8.4 Hz, 2H), 7.14 (q, J = 8.8 Hz, 2H), 7.01 (q, J = 7.7, 6.9 Hz, 2H), 6.87 (d, J = 8.2 Hz, 2H), 6.20 (d, J = 15.5 Hz, 1H), 5.75-5.62 (m, 1H), 5.47 (d, J = 10.0 Hz, 1H), 5.41-5.27 (m, 2H), 5.09 (tt, J = 8.8, 3.9 Hz, 2H), 5.01 (dt, J = 9.2, 4.2 Hz, 3H), 4.99-4.92 (m, 1H), 4.68 (q, J = 3.4 Hz, 1H), 4.52 (q, J = 4.6, 3.1 Hz, 1H), 4.19 (ddd, J = 29.3, 9.9, 3.2 Hz, 1H), 4.08 (d, J = 19.5 Hz, 1H), 3.87 (td, J = 10.5, 5.5 Hz, 1H), 3.82 (s, 3H), 3.65 (dd, J = 13.4, 6.5 Hz, 1H), 3.63-3.44 (m, 3H), 2.83 (t, J = 6.6 Hz, 2H), 2.24-2.11 (m, 2H), 2.09 (s, 2H), 2.10-1.92 (m, 14H), 1.83 (d, J = 14.1 Hz, 2H), 1.78 (s, 3H), 1.72 (s, 3H), 1.37-1.13 (m, 17H), 1.10-1.03 (m, 1H), 0.85 (d, 3H); 13C NMR (101 MHz, CDC13) δ 170.50, 170.46, 169.98, 169.87, 166.32, 160.94, 155.61, 140.74, 133.15, 129.96, 129.39, 127.60, 124.92, 124.59, 118.26, 117.00, 116.84, 114.29, 99.36, 98.26, 97.32, 76.29, 72.02, 71.34, 70.75, 70.49, 70.37, 70.04, 69.41, 69.19, 68.72, 67.61, 67.01, 55.41, 40.93, 34.94, 29.75, 25.71, 24.55, 21.01, 20.85, 20.80, 20.73, 17.68, 17.52, 17.44; HRMS (ESI) m / z calcd for C 50 H 63 NO 22 [M+H] + : 1030.3914, found 1030.3732.

[0039] The structural characterization data of compound 13 are as follows: 1H NMR (400 MHz, CDC13) δ 7.56 (d, J = 15.5 Hz, 1H), 7.42 (d, J = 8.2 Hz, 2H), 7.14 (d, J = 8.1 Hz, 2H), 7.03 - 6.93 (m, 2H), 6.87 (d, J = 8.3 Hz, 2H), 6.19 (d, J = 15.5 Hz, 1H), 5.64 (d, J = 6.1 Hz, 1H), 5.52 (d, J = 2.7 Hz, 2H), 5.33 (s, 1H), 5.31 - 5.20 (m, 2H), 5.15 (ddd, J = 21.7, 9.6, 2.8 Hz, 2H), 4.90 (dt, J = 20.6, 9.9 Hz, 1H), 4.70 (dd, J = 6.5, 3.7 Hz, 1H), 4.64 (q, J = 2.8 Hz, 1H), 4.23 (q, J = 7.2, 5.2 Hz, 2H), 4.17 - 4.08 (m, 2H), 4.08 - 3.95 (m, 2H), 3.82 (s, 3H), 3.72 - 3.55 (m, 4H), 2.82 (t, J = 7.0 Hz, 2H), 2.10 (d, J = 1.9 Hz, 1H), 2.03 (dd, J = 10.6, 6.5 Hz, 5H), 1.94 (d, J = 1.9 Hz, 2H), 1.85 (s, 1H), 1.80 (s, 2H), 1.75 (d, J = 4.8 Hz, 6H), 1.30 (s, 1H), 1.27 (s, 1H), 1.25 (s, 2H), 1.14 (d, J = 6.2 Hz, 3H); 13 C NMR (101 MHz, CDC13) δ 170.74, 170.66, 170.39, 170.24, 169.82, 169.55, 166.29, 160.97, 154.78, 140.84, 133.02, 129.92, 129.40, 127.52, 125.51, 124.88, 124.80, 118.14, 116.70, 116.44, 114.31, 97.36, 97.33, 97.06, 76.42, 73.00, 72.21, 71.80, 71.60, 71.32, 71.10, 70.89, 70.17, 69.67, 68.34, 67.29, 65.54, 65.44, 62.43, 62.07, 55.41, 41.00, 34.96, 29.74, 26.19, 25.45, 24.65, 21.10, 21.00, 20.79, 20.75, 20.50, 17.61, 17.44, 14.17; HRMS (ESI) m / z calcd for C 54 H 67 NO 26 [M+H]+ :1146.4024, found 1146.3822.

[0040] Structural characterization data for compound 14 are: 1 H NMR (400 MHz, Methanol-d4) δ 7.56 - 7.47 (m, 3H), 7.21 (d, J = 8.1 Hz, 2H), 7.05 (t, J = 7.8 Hz, 2H), 6.97 (d, J = 8.3 Hz, 2H), 6.47 (d, J = 15.7 Hz, 1H), 5.41 (d, J = 9.0 Hz, 1H, H-1'), 5.02 (s, 1H), 4.66 - 4.56 (m, 1H), 4.25 - 4.08 (m, 1H), 4.07 - 3.99 (m, 1H), 3.86 (s, 3H, OMe), 3.71 (ddd, J = 21.3, 10.2, 6.4 Hz, 2H), 3.53 (t, J = 7.6 Hz, 2H), 3.48 (d, J = 9.4 Hz, 1H), 3.37 (d, J = 18.4 Hz, 1H), 3.35 (s, 3H), 2.85 (t, J = 7.3 Hz, 2H), 1.38 - 1.22 (m, 9H); 13 C NMR (101 MHz, CD3OD) δ 168.86, 162.38, 156.27, 141.25, 134.08, 130.65, 130.21, 128.66, 125.29, 119.06, 117.57, 117.43, 115.13, 99.76, 98.69, 98.65, 74.93, 73.66, 73.29, 73.21, 72.91, 72.78, 72.03, 71.90, 70.65, 70.35, 70.01, 69.04, 55.62, 42.14, 35.60, 18.06, 17.95, 17.83; HRMS (ESI) m / z C 36 H 49 NO 15 [M+K] + : Calcd 774.2095, found 774.2734.

[0041] Structural characterization data for compound 15 are: 1H NMR (400 MHz, Methanol-d4) δ 7.24 - 7.15 (m, 3H), 6.90 (d, J = 7.9 Hz, 2H), 6.72 (d, J = 8.2 Hz, 2H), 6.66 (d, J = 8.3 Hz, 2H), 6.15 (d, J = 15.7 Hz, 1H), 5.24 (d, J = 11.1 Hz, 1H, H-1'), 5.17 (t, J = 4.1 Hz, 1H), 4.25 (d, J = 9.1 Hz, 1H), 3.88 - 3.74 (m, 1H), 3.73 - 3.61 (m, 1H), 3.63 - 3.55 (m, 1H), 3.54 (s, 3H, OMe), 3.46 - 3.31 (m, 2H), 3.27 (d, J = 8.7 Hz, 1H), 3.21 (t, J = 7.4 Hz, 2H), 3.11 (dt, J = 18.8, 9.1 Hz, 1H), 3.03 (s, 4H), 2.95 (q, J = 10.9, 7.7 Hz, 1H), 2.53 (t, J = 7.3 Hz, 2H), 0.93 (s, 3H, H-6'); 13 C NMR (101 MHz, MeOD) δ 168.85, 162.39, 156.08, 141.25, 130.68, 130.22, 128.66, 125.39, 119.05, 117.51, 115.14, 100.99, 98.84, 98.70, 82.18, 81.02, 77.75, 76.83, 73.84, 73.78, 72.88, 72.03, 70.78, 70.33, 68.29, 62.52, 55.62, 49.44, 49.23, 49.01, 48.80, 48.59, 48.37, 48.16, 42.14, 35.60, 17.86; HRMS (ESI) m / z C 36 H 49 NO 17 [M+Na] + : Theoretical value 790.2893, found 790.2042.

[0042] Substituents and yields of compounds 2-11, 14 and 15 of Table 1

[0043]

[0044]

[0045]

[0046] Example 2

[0047] Use of the coumarin tyramine glycoside compound in the preparation of PTP1B inhibitors and anti-diabetic drugs

[0048] The compounds 2-11, 14 and 15 were respectively used as the test compounds to test their inhibitory activity on protein tyrosine phosphatase 1B (PTP1B), and the specific test conditions were as follows:

[0049] The 200 μL reaction system contained PTP1B (recombinant expression), buffer (25 mM HEPES, 50 mM sodium chloride, 2.5 mM EDTA, 0.1% BSA, pH 7.2) and the test compound, and blank control (without PTP1B and the test compound) and negative control (without the test compound) were set up at the same time, and the reaction was carried out at 37°C for 10 min, then the protein tyrosine phosphatase substrate PNPP was added, and the reaction was carried out at 37°C for another 30 min, then the reaction was terminated by adding 2 M Na2CO3 aqueous solution, and the OD value was determined at 405 nm. The inhibition rate was calculated according to the OD value, and the inhibition rate = [1-(OD sample-OD blank) / (OD negative-OD blank)]x100%. The test results are shown in Table 2.

[0050] Table 2 Inhibitory activity of the compounds 2-11, 14 and 15 on PTP1B in vitro

[0051] Compound % Inhibition (50 μM) Compound % Inhibition (50 μM) 2 95.91±0.05 8 95.98±0.03 3 99.30±0.00 9 96.22±0.03 4 88.21±0.04 10 87.75±0.00 5 94.62±0.03 11 86.68±0.10 6 96.64±0.02 14 95.45±0.06 7 98.86±0.02 15 95.20±0.08 Teuvisside A 93.63±0.10 Sodium orthovanadate 85.79±0.01

[0052] As can be seen from the activity results in Table 2, the coumarin tyramine glycoside compounds of the present application exhibit excellent inhibitory activity on protein tyrosine phosphatase 1B in vitro, and the inhibitory activity is higher than that of the positive control drug sodium orthovanadate, which indicates that the coumarin tyramine glycoside compounds can be used for preparing PTP1B inhibitors and drugs for treating diabetes.

Claims

1. A coumarin tyramine glycoside compound, characterized by The structural formula of the compound is as follows: Wherein, R is selected from any one of stearoyl, palmitoyl, n-octanoyl, n-heptanoyl, benzoyl, 3-phenylpropionyl, 4-methoxycinnamoyl, 3, 4-dimethoxycinnamoyl, 3, 4, 5-trimethoxycinnamoyl, 2, 4-dimethylbenzoyl, R' represents acetyl.

2. Use of the coumarin tyramine glycoside compound of claim 1 in the preparation of a PTP1B inhibitor.

3. Use of the coumarin tyramine glycoside compound of claim 1 in the preparation of an anti-diabetic drug.

Images