Coumarin tyramine glycoside compound and application thereof in preparation of PTP1B (protein tyrosine phosphatase 1B) inhibitor and antidiabetic drug

Abstract

The invention discloses a coumarin tyramine glycoside compound and application thereof in preparation of PTP1B (protein tyrosine phosphatase 1B) inhibitors and antidiabetic drugs. The structural formula of the compound is # imgabs0 #, in the formula, R represents fat (aromatic) acyl or monosaccharide substituent, and R'represents hydrogen atom or acetyl; 4-methoxycoumarin 4 '-acetyl-O-L-rhamnose is used as an initial raw material, fat (aromatic) acyl or monosaccharide substituent groups are introduced into hydroxyl at the second position and hydroxyl at the third position of L-rhamnose at the same time, and then protecting groups of glycosyl are removed, so that the L-rhamnose is prepared. Pharmacological activity tests show that the compounds have good inhibitory activity on protein tyrosine phosphatase 1B, which indicates that the coumarin tyramine glycoside compounds can be researched and utilized as novel PTP1B inhibitors and antidiabetic drugs.

Description

Technical Field

[0001] The invention belongs to the technical field of chemical drugs, and specifically relates to a coumarin tyrosine glycoside compound and application thereof in the preparation of a PTP1B inhibitor and an anti-diabetic drug. Background Art

[0002] Diabetes has become one of the fastest growing diseases and 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, among which type II diabetes (T2DM) is a metabolic disease characterized by hyperglycemia caused by insufficient insulin secretion or insulin resistance without therapeutic intervention. Many studies have shown that protein tyrosine phosphatase 1B (PTP1B) is an effective drug target for anti-type II diabetes, and insulin resistance can be effectively improved by inhibiting the overexpression of PTP1B. However, so far, there are no PTP1B inhibitors on the market, and most of the drugs currently in clinical trials come from natural products and their analogs. The natural product Teuvisside A is a coumarin tyrosine glycoside compound isolated from a perennial herbaceous plant, Sanguisorba officinalis, which has significant anti-hyperglycemic activity in liver cancer HepG2 cells and mouse embryonic fibroblast 3T3-L1 adipocytes (Kong Lingyi et al. Journal of natural product. 2014, 77: 200-205). Based on the natural product Teuvisside A of coumarin tyrosine glycoside, molecular structure optimization and obtaining simplified coumarin tyrosine glycoside compounds are effective ways to achieve innovative drug research.

[0003] There is no report on the existing technology of simplifying and modifying the molecular structure of the coumarin tyrosine glycoside compound Teuvisside A to screen for PTP1B inhibitors, especially there is no report on the introduction of fatty (aromatic) acyl groups, monosaccharide substitutes and other groups into the C-2 and C-3 sites of the L-rhamnose glycosyl of coumarin tyrosine glycoside to carry out research on PTP1B enzyme inhibitory activity. Summary of the invention

[0004] The purpose of the present invention is to provide a class of coumarin tyrosine glycoside compounds and a new use of the compound.

[0005] For the above purpose, the structural formula of the coumarin tyrosine glycoside compound used in the present invention is as follows:

[0006]

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

[0008] Furthermore, when R′ represents an acetyl group, it is preferred that the R is selected from any one of stearoyl, palmityl, n-octanoyl, n-heptanoyl, benzoyl, 3-phenylpropionyl, 4-methoxycinnamoyl, 3,4-dimethoxycinnamoyl, 3,4,5-trimethoxycinnamoyl, and 2,4-dimethylbenzoyl.

[0009] Furthermore, when R′ represents a hydrogen atom, it is preferred that the R is selected from any one of L-rhamnosyl and D-mannosyl.

[0010] The synthesis route and specific synthesis method of the coumarin tyrosine glycoside compound of the present invention are as follows:

[0011]

[0012] 1. Synthesis of coumarin tyrosine glycoside compounds 2 to 11

[0013] When R is selected from any one of stearoyl, palmityl, n-octanoyl, n-heptanoyl, benzoyl, 3-phenylpropionyl, 4-methoxycinnamoyl, 3,4-dimethoxycinnamoyl, 3,4,5-trimethoxycinnamoyl, and 2,4-dimethylbenzoyl, and R′ is selected from acetyl, dry dichloromethane is used as solvent to react compound 1 with N,N′-dicyclohexylcarbodiimide, 4-dimethylaminopyridine, ROH( That is, stearic acid, palmitic acid, octanoic acid, 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, and react at room temperature with stirring for 5 hours; after the reaction is completed, filter, concentrate under reduced pressure, and separate by petroleum ether / ethyl acetate silica gel column chromatography to obtain coumarin tyrosine glycoside compounds 2-11.

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

[0015] When R is selected from any one of L-rhamnosyl and D-mannosyl, and R′ is selected from hydrogen atom, dry dichloromethane is used as solvent, Molecular sieves were used as dehydrating agents, and compound 1 was mixed with fully acetyl-protected rhamnose trichloroacetimidate and fully acetyl-protected mannose trichloroacetimidate in a molar ratio of 1:1-6.5, and trimethylsilyl trifluoromethylsulfonate (TMSOTf) was added at 0°C under nitrogen protection, with a molar ratio of compound 1 to TMSOTf of 1:0.1-0.2, and stirred at room temperature for 1 hour; after the reaction was completed, the mixture was filtered, the solvent was evaporated under reduced pressure, and the concentrate was chromatographed on a silica gel column to obtain compounds 12 and 13, respectively. Using anhydrous methanol as solvent, compounds 12 and 13 were mixed with sodium methoxide in a molar ratio of 1:0.5-6, and stirred at room temperature for 1-3 hours; after the reaction was completed, the mixture was concentrated under reduced pressure and chromatographed on a silica gel column to obtain coumarin tyrosine glycoside compounds 14 and 15, respectively.

[0016] The present invention also provides the use of coumarin tyrosine glycoside compounds in the preparation of PTP1B inhibitors and antidiabetic drugs, which are prepared according to conventional pharmaceutical preparations and pharmaceutically acceptable carriers according to conventional preparation processes of various preparations and can be tablets, granules, and capsules.

[0017] The beneficial effects of the present invention are as follows:

[0018] The present invention uses 4-methoxycoumarin tyramine 4′-acetyl-OL-rhamnose as a matrix, introduces a fatty (aromatic) acyl group or a monosaccharide substituent at the 2nd and 3rd hydroxyl groups of L-rhamnose, and then removes the protective group of the glycosyl to prepare a coumarin tyramine glycoside compound. According to pharmacological activity detection, such compounds show good inhibitory activity on protein tyrosine phosphatase 1B, and can be used to prepare PTP1B inhibitors and drugs for treating diabetes. DETAILED DESCRIPTION

[0019] The present invention is further described in detail below in conjunction with the embodiments, but the protection scope of the present invention is not limited to these embodiments.

[0020] Example 1

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

[0022] 1. Synthesis of coumarin tyrosine glycoside compounds 2 to 11

[0023] Compound 1 (100 mg, 0.2 mmol), N,N′-dicyclohexylcarbodiimide (250 mg, 1.2 mmol), 4-dimethylaminopyridine (148 mg, 1.2 mmol), and stearic acid (1.2 mmol) were dissolved in dry dichloromethane (20 mL), and stirred at room temperature for 5 h. After the reaction, the mixture was filtered, concentrated under reduced pressure, and chromatographed on a silica gel column (eluent: petroleum ether / ethyl acetate = 5:1) to obtain coumarin tyrosine glycoside compound 2.

[0024] The above stearic acid is replaced with equimolar amounts of palmitic acid, octanoic acid, heptanoic acid, benzoic acid, 3-phenylpropionic acid, 4-methoxycinnamic acid, 3,4-dimethoxycinnamic acid, 3,4,5-trimethoxycinnamic acid and 2,4-dimethylbenzoic acid to obtain coumarin tyrosine glycoside compounds 3 to 11.

[0025] The structural characterization data of compound 2 are: 1 H NMR(400MHz, CDCl3)δ7.57(d,J=15.5Hz,1H),7.47–7.40(m,2H),7.26(s,1H) ,7.14(d,J=7.9Hz,1H),7.06–6.98(m,2H),6.87(d,J=8.3Hz,2H),6.20(d,J= 15.5Hz,1H),5.60(t,J=6.0Hz,1H,H-1'),5.52(dd,J=10.7,3.5Hz,1H),5.45 –5.39(m,2H),5.15(t,J=10.0Hz,1H),4.04–3.94(m,1H),3.82(s,3H,OMe),3. 61(q,J=6.6Hz,2H),3.54–3.44(m,1H),2.83(t,J=6.8Hz,1H),2.43(td,J=7. 7,4.0Hz,2H),2.25(t,J=7.5Hz,2H),2.04(d,J=1.7Hz,3H),1.97–1.88(m,1H) ,1.68(dq,J=14.7,7.6,6.0Hz,4H),1.58(q,J=10.5,7.3Hz,3H),1.25(s,50H ,CH2),1.20(d,J=6.0Hz,2H),1.08(d,J=12.8Hz,1H),0.91–0.80(m,6H,CH3); 13 C NMR (101MHz, CDCl3) δ172.99,172.88,169.96,166.28,160.94,154.78,140.81,133.21 ,129.98,129.43,127.55,118.18,116.69,114.28,95.96,71.06,69.55,68.80,67.20,5 5.41,49.20,40.93,34.95,34.23,34.03,32.00,29.79,29.74,29.60,29.58,29.45,29.38,29.17,25.68,25.07,25.01,24.89,22.77,20.88,17.56,14.21; HRMS (ESI) m / z theoretical value C 62 H99 NO 10 [M+H] + :1018.7342, measured value 1018.7294.

[0026] The structural characterization data of compound 3 are: 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: 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, measured value 738.4190.

[0028] The structural characterization data of compound 5 are: 1 H NMR (400MHz, CDCl3) δ7.57(d,J=15.5Hz,1H),7.42(d,J=8.2Hz,2H),7.14(d,J=8. 1Hz,2H),7.04–6.90(m,2H),6.86(d,J=8.3Hz,2H),6.21(d,J=15.5Hz,1H),5.72( t,J=6.0Hz,1H),5.52(dd,J=10.5,3.5Hz,1H),5.45–5.36(m,2H),5.15(t,J=10.0 Hz,1H),4.63(s,1H),4.00(dq,J=12.8,6.7Hz,1H),3.81(s,3H),3.61(q,J=6.6Hz, 2H),3.44(q,J=10.9,9.3Hz,1H),2.82(t,J=6.9Hz,2H),2.43(td,J=7.6,3.9Hz,2 H),2.32(t,J=7.5Hz,1H),2.25(t,J=7.5Hz,2H),2.04(s,3H),1.92(dd,J=12.9,4 .0Hz,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=3.3Hz,1H),1.08(dd,J=12.1,3.4Hz,1H),0.88(q,J=6.6Hz,9H); 13 C NMR (101MHz, CDCl3) δ172.98,172.86,169.96,166.38,160.92,154.75,140.82 ,133.20,129.95,129.41,127.54,118.17,116.66,114.26,95.95,71.05,69.5 5,68.80,67.18,55.39,49.29,40.95,34.91,34.20,33.87,31.48,29.75,28.78,25.62,24.99,24.95,24.80,22.53,20.85,17.53,14.08; HRMS (ESI) m / z theoretical value C 40 H 55 NO 10 [M+H] + :710.3899, measured value 710.3879.

[0029] The structural characterization data of compound 6 are: 1 H NMR(400MHz, CDCl3)δ8.09(d,J=7.7Hz,2H),7.93(d,J=7.7Hz,2H),7.66–7.54(m,2H),7.56–7.40(m,6H),7.36(t ,J=7.6Hz,2H),7.21–7.14(m,2H),7.09(dd,J=8.6,1.7Hz,2H),6.91–6.82(m,2H),6.21(dd,J=15.6,1.6Hz,1H,H- 1'),5.86(dd,J=10.0,3.8Hz,1H),5.78(dt,J=3.5,1.9Hz,1H),5.66(s,1H),5.50(td,J=10.0,1.6Hz,1H),3.82(d ,J=1.7Hz,3H,OMe),3.63(q,J=6.6Hz,2H),2.85(t,J=6.9Hz,2H),2.00(d,J=1.6Hz,3H),1.33–1.23(m,3H,H-6'); 13 CNMR (101MHz,CDCl3)δ170.13,166.28,165.65,165.63,160.93,154.86,140.76,133.68,133.43,133.33,130.03,130.01,129.83,129.42,129.29,129.25,128.70,128.55,127.59,118.27,116.77,114.29,95.95,71.19,70.65,69.94,67.27,55.41,40.93,34.97,20.87,17.66; HRMS (ESI) m / z theoretical value C 40 H 39 NO 10 [M+H] + :694.2647, measured value 694.2632.

[0030] The structural characterization data of compound 7 are: 1H NMR (400MHz, CDCl3) δ7.58(d,J=15.5Hz,1H),7.44(d,J=8.2Hz,2H),7.31–7.12(m,13H),7.01(d,J=8.1Hz,2H),6. 88(d,J=8.2Hz,2H),6.19(d,J=15.5Hz,1H,H-1'),5.53(d,J=3.6Hz,1H),5.41(d,J=3.4Hz,1H),5.35(s,1H),5.14 (t,J=9.9Hz,1H),3.99(dq,J=12.3,6.4Hz,1H),3.82(s,3H,OMe),3.62(q,J=6.6Hz,2H),2.99(t,J=7.7Hz,2H),2. 92–2.81(m,4H),2.77(d,J=7.8Hz,2H),2.50(t,J=7.7Hz,2H),1.93(d,J=1.5Hz,3H),1.19(d,J=6.1Hz,3H,H-6'); 13 C NMR (101MHz, CDCl3) δ172.06,172.01,169.99,166.25,160.97,154.74,140.82,1 40.30,140.02,133.27,129.99,129.43,128.62,128.60,128.37,128.32,127.58 ,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 theoretical value C 44 H 47 NO 10 [M+H] + :750.3273, measured value 750.3253.

[0031] The structural characterization data of compound 8 are: 1H NMR(400MHz, CDCl3)δ7.71(d,J=16.0Hz,1H),7.66–7.41(m,7H),7.45–7.39(m,2H),7.16(d,J=8.1Hz,2H),7.10–7.0 4(m,2H),6.93(d,J=8.2Hz,2H),6.86(t,J=7.3Hz,4H),6.48(dd,J=16.0,1.8Hz,1H),6.24(dd,J=15.8,13.3Hz,2H),5 .68(d,J=6.6Hz,1H,H-1'),5.61(d,J=3.4Hz,1H),5.55(s,1H),5.35(t,J=10.0Hz,1H),4.11(dt,J=10.3,5.7Hz,1H) ,3.84(d,J=16.8Hz,9H,OMe),3.63(q,J=6.6Hz,2H),2.84(t,J=6.9Hz,2H),2.05(s,3H),1.26(d,J=6.2Hz,3H,H-6'); 13 C NMR (101MHz, CDCl3) δ170.24,166.38,166.29,166.25,161.77,161.63,160.91,156.86,154 .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 theoretical value C 46 H 47 NO 12 [M+H] + :806.3171, measured value 806.3145.

[0032] The structural characterization data of compound 9 are: 1H NMR (400MHz, CDCl3) δ7.74–7.65(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=8.7,2.3Hz,3H),6.82(dd,J=8.3,1.9Hz,1H),6.49(dd,J=15.9,1.9Hz,1H),6.23(ddd,J=18.4,15.8,1.9Hz,2H ),5.72(dt,J=10.3,2.7Hz,1H,H-1'),5.63(d,J=3.5Hz,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=6.7Hz,2H),2.85(t,J=6.9Hz,2H),2.06(d,J=1.8Hz,3H),1.26(t,J=2.3Hz,3H,H-6'); 13 C NMR (101MHz, CDCl3) δ170.40,166.30,166.28,166.15,160.93,154.85,151.57,151.40,149. 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 theoretical value C 48 H 51 NO 14 [M+H] + :866.3382, measured value 866.3362.

[0033] The structural characterization data of compound 10 are: 1H NMR (400MHz, CDCl3) δ7.65(dd,J=15.8,1.5Hz,1H),7.59(s,1H),7.55(d,J=2.0Hz,1H),7.43(d,J=8.2Hz,2H),7.26(s,1H),7.17(d,J=8.1Hz,2H ),7.10–7.03(m,2H),6.90–6.83(m,2H),6.80(d,J=1.6Hz,2H),6.70(d,J=1.6Hz,2H),6.53(dd,J=15.9,1.6Hz,1H),6.29(dd,J=15.8,1.6Hz,1H ),6.21(dd,J=15.6,1.6Hz,1H),5.72(dd,J=10.8,3.5Hz,1H),5.64(d,J=3.3Hz,2H),5.55(s,1H),5.41–5.31(m,1H),4.11(dq,J=12.2,6.4Hz,1 H),3.91(s,6H),3.90(s,3H),3.86(s,3H),3.81(s,9H),3.62(q,J=6.6H z,2H),2.84(t,J=6.9Hz,2H),2.06(d,J=1.6Hz,3H),1.30–1.23(m,6H); 13 C NMR (101MHz, CDCl3) δ170.46,166.27,166.02,165.84,160.91,154.76,153.54,153.43,146 .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 theoretical value C 48 H 51 NO 16 [M+H] + :926.3594, measured value 926.3572.

[0034] The structural characterization data of compound 11 are: 1H NMR (400MHz, CDCl3) δ7.93(d,J=8.0Hz,1H),7.73(dd,J=8.0,1.7Hz,1H),7.58(d,J=15.5Hz,1H),7.47–7.40(m,2H),7. 26(d,J=1.7Hz,1H),7.20–7.13(m,3H),7.13–6.93(m,8H),6.91–6.82(m,2H),6.21(dd,J=15.6,1.7Hz,1H,H-1'),5.85 (dd,J=10.4,3.8Hz,1H),5.76(q,J=2.4Hz,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=6.6Hz,2H),2.85(t,J=6.9Hz,2H),2.56–2.50(m,6H),2.34(d,J=22.2Hz,6H),2.01(s,3H),1.26(d,3H,H-6'); 13 C NMR (101MHz, CDCl3) δ170.10,166.48,166.30,166.28,160.92,154.95,143.36,143.16,14 1.06,140.86,140.74,133.22,132.69,132.63,131.44,131.17,130.87,129.99,129.42,12 7.60,126.80,126.70,125.70,125.53,118.29,116.79,114.28,96.05,71.44,70.35,69.27,67.31,55.41,40.93,34.96,22.09,21.95,21.52,21.45,20.91,17.70; HRMS (ESI) m / z theoretical value C 44 H 47 NO 10 [M+H] + :750.3273, measured value 750.3257.

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

[0036] At 0°C and nitrogen protection, compound 1 (300 mg, 0.62 mmol) and peracetylated rhamnose trichloroacetimidate (3.70 mmol) were dissolved in anhydrous dichloromethane (50 mL), and the activated Molecular sieves, stirred for 30 min, after the molecular sieves fully absorbed the water in the reaction bottle, TMSOTf (0.12 mL, 0.08 mmol) was added, stirred at room temperature for 1 h, the reaction was quenched with triethylamine, filtered, the solvent was evaporated under reduced pressure, and 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 a cation exchange resin, filtered, concentrated under reduced pressure, and purified by silica gel column chromatography (eluent: MeOH / CH2Cl2 = 1:10) to obtain coumarin tyrosine glycoside compound 14.

[0037] The above-mentioned fully acetylated rhamnose trichloroacetimidate was replaced with an equal mole of fully acetylated mannose trichloroacetimidate to first obtain compound 13. Compound 12 was then replaced with an equal mole of compound 13 to obtain coumarin tyrosine glycoside compound 15.

[0038] The structural characterization data of compound 12 are: 1 H NMR (400MHz, CDCl3) δ7.57(d,J=15.5Hz,1H),7.43(d,J=8.4Hz,2H),7.14(q,J=8.8Hz ,2H),7.01(q,J=7.7,6.9Hz,2H),6.87(d,J=8.2Hz,2H),6.20(d,J=15.5Hz,1H),5.75– 5.62(m,1H),5.47(d,J=10.0Hz,1H),5.41–5.27(m,2H),5.09(tt,J=8.8,3.9Hz,2H), 5.01(dt,J=9.2,4.2Hz,3H),4.99–4.92(m,1H),4.68(q,J=3.4Hz,1H),4.52(q,J=4.6, 3.1Hz,1H),4.19(ddd,J=29.3,9.9,3.2Hz,1H),4.08(d,J=19.5Hz,1H),3.87(td,J=1 0.5,5.5Hz,1H),3.82(s,3H),3.65(dd,J=13.4,6.5Hz,1H),3.63–3.44(m,3H),2.83(t ,J=6.6Hz,2H),2.24–2.11(m,2H),2.09(s,2H),2.10–1.92(m,14H),1.83(d,J=14.1H z,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 (101MHz, CDCl3) δ170.50,170.46,169.98,169.87,166.32,160.94,155.61,140.74,133.15,1 29.96,129.39,127.60,124.92,124.59,118.26,117.00,116.84,114.29,99.36,98.26,97.32,76 .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 theoretical value C 50 H 63 NO 22 [M+H] + :1030.3914, measured value 1030.3732.

[0039] The structural characterization data of compound 13 are: 11H NMR (400 MHz, CDCl3) 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 13C NMR (101 MHz, CDCl3) 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 calculated for C 54 H 67 NO 26 [M + H]+ :1146.4024, measured value 1146.3822.

[0040] The structural characterization data of compound 14 are: 1 H NMR (400MHz, Methanol-d4) δ7.56–7.47(m,3H),7.21(d,J=8.1Hz,2H),7.05(t,J=7.8Hz,2H),6.97(d,J= 8.3Hz,2H),6.47(d,J=15.7Hz,1H),5.41(d,J=9.0Hz,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=21.3,10.2,6.4Hz,2H),3.53(t,J=7.6Hz,2 H),3.48(d,J=9.4Hz,1H),3.37(d,J=18.4Hz,1H),3.35(s,3H),2.85(t,J=7.3Hz,2H),1.38–1.22(m,9H); 13 C NMR(101MHz,CD3OD)δ168.86,162.38,156.27,141.25,134.08,130.65,13 0.21,128.66,125.29,119.06,117.57,117.43,115.13,99.76,98.69,98. 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 / zC 36 H 49 NO 15 [M+K] + :Theoretical value: 774.2095, measured value: 774.2734.

[0041] The structural characterization data of compound 15 are: 1H NMR (400MHz, Methanol-d4) δ7.24–7.15(m,3H),6.90(d,J=7.9Hz,2H),6.72(d,J=8.2Hz,2H),6.66(d,J=8.3Hz,2H),6 .15(d,J=15.7Hz,1H),5.24(d,J=11.1Hz,1H,H-1'),5.17(t,J=4.1Hz,1H),4.25(d,J=9.1Hz,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=8.7Hz,1H),3.21(t,J=7.4Hz,2 H),3.11(dt,J=18.8,9.1Hz,1H),3.03(s,4H),2.95(q,J=10.9,7.7Hz,1H),2.53(t,J=7.3Hz,2H),0.93(s,3H,H-6'); 13 C NMR(101MHz,MeOD)δ168.85,162.39,156.08,141.25,130.68,130.22,128.66 ,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, measured value 790.2042.

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

[0043]

[0044]

[0045]

[0046] Example 2

[0047] Application of the coumarin tyrosine glycoside compound of the present invention in the preparation of PTP1B inhibitors and antidiabetic drugs

[0048] The above compounds 2 to 11, 14 and 15 were respectively used as test compounds to test their inhibitory activities against protein tyrosine phosphatase 1B (PTP1B). The specific test conditions are as follows:

[0049] 200 μL reaction system contains PTP1B (recombinant expression), buffer (25mM HEPES, 50mM sodium chloride, 2.5mM EDTA, 0.1% BSA, pH 7.2) and test compound, and blank control (without PTP1B and test compound) and negative control (without test compound) are set up at the same time, react at 37°C for 10min, add protein tyrosine phosphatase substrate PNPP, react at 37°C for another 30min, add 2M Na2CO3 aqueous solution to terminate the reaction, and measure OD value at 405nm. Inhibition rate is calculated according to OD value, inhibition rate = [1-(OD sample-OD blank) / (OD negative-OD blank)] × 100%. The test results are shown in Table 2.

[0050] Table 2 In vitro PTP1B inhibitory activity of compounds 2-11, 14 and 15

[0051] Compound Inhibition rate % (50μM) Compound Inhibition rate % (50μM) 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] From the activity results in Table 2, it can be seen that the coumarin tyrosine glycoside compounds of the present invention exhibit excellent in vitro inhibitory activity against protein tyrosine phosphatase 1B, which is higher than the inhibitory activity of the positive control drug sodium orthovanadate, indicating that such coumarin tyrosine glycoside compounds can be used to prepare PTP1B inhibitors and drugs for treating diabetes.

Claims

1. A coumarin tyrosine glycoside compound, characterized in that The structural formula of the compound is shown below: Among them, R is selected from any one of stearoyl, palmityl, n-octanoyl, n-heptanoyl, benzoyl, 3-phenylpropionyl, 4-methoxycinnamoyl, 3,4-dimethoxycinnamoyl, 3,4,5-trimethoxycinnamoyl, 2,4-dimethylbenzoyl, L-rhamnosyl, and D-mannosyl, and R′ is selected from a hydrogen atom or an acetyl group.

2. The coumarin tyrosine glycoside compound according to claim 1, characterized in that: The R is selected from any one of stearoyl, palmityl, n-octanoyl, n-heptanoyl, benzoyl, 3-phenylpropionyl, 4-methoxycinnamoyl, 3,4-dimethoxycinnamoyl, 3,4,5-trimethoxycinnamoyl, and 2,4-dimethylbenzoyl, and R′ represents acetyl.

3. The coumarin tyrosine glycoside compound according to claim 1, characterized in that: The R is selected from any one of L-rhamnosyl and D-mannosyl, and R' represents a hydrogen atom.

4. Use of the coumarin tyrosine glycoside compound according to claim 1 in the preparation of a PTP1B inhibitor.

5. Use of the coumarin tyrosine glycoside compound according to claim 1 in the preparation of antidiabetic drugs.

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