Tripterine derivative and application thereof

[0054] Example 1

[0055] X is Y is n=2; Ar is different R 1 When substituted phenyl, the preparation of compounds I-1~I-12

[0056] Step A:

[0057]

[0058] Weigh 5mmol substituted trans-cinnamic acid derivative 1, and slowly add 10ml SOCl 2 , Stirring at room temperature for 1h, if the reactant does not dissolve, heat to 40℃ and stir for 0.5h, evaporate the solvent to obtain substituted cinnamic acid chloride; then add a small amount of anhydrous dichloromethane to dissolve, transfer the resulting solution to a constant pressure dropping funnel In the medium, weigh 10mmol piperazine and dissolve it in 20ml glacial acetic acid, slowly add the solution in the constant pressure dropping funnel to the piperazine dropwise, and stir at room temperature for 2 hours. The reaction solution was adjusted to pH 7-9 with 40% NaOH, extracted with dichloromethane three times, the organic phases were combined, and the organic phases were washed three times with saturated NaCl, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain a yellow oil. After silica gel column chromatography (dichloromethane:methanol=20:1), a pale yellow oily solid was obtained with a yield of 60-83%.

[0059] Step B:

[0060]

[0061] Weigh 0.1g (0.221mmol) of Tripterygium wilfordii, add 5ml DMF to dissolve it, add 0.101g (0.265mmol) HATU, 155ul (0.884mmol) DIPEA, stir at room temperature for 30min, then add 0.243mmol of compound 3, and stir at 100°C for reaction 5h, cool to room temperature, pour the reaction solution into water, stir while pouring, and precipitate a large amount of reddish brown solid, filter with suction, and dry. Preparative thin-layer chromatography is used to obtain target compounds I-1 to I-12 with a yield of 45% to 74%.

[0062] Some compound analysis data:

[0063] Compound I-1: (E)-1-(4-(3-hydroxy-9β,13α-dimethyl-2-oxo-24,25,26-trinor oleanorane-1 (10 ),3,5,7-tetraene-29-acyl)piperazin-1-yl)-3-phenyl-2-propene-1-one

[0064] δ H (400MHz,cdcl 3 ) 7.70 (1H, d, J 15.4), 7.56 - 7.46 (2H, m), 7.42 - 7.30 (3H, m), 7.00 (1H, d, J 6.3), 6.94 (1H, s), 6.84 (1H, d, J 15.4), 6.51 (1H, s), 6.34 (1H, d, J 7.2), 3.89-3.54 (8H, m), 2.33 (2H, d, J 15.3), 2.20 (3H, s), 2.16 (1H,d,J 13.7), 2.10-2.04(1H,m), 1.45(3H,s), 1.31(3H,s), 1.30(3H,s), 1.15(3H,s), 0.59(3H, s).

[0065] δ C (101MHz,cdcl 3 )178.28,176.32,169.73,165.68,164.43,146.09,143.60,135.01,133.98,129.78,128.78,127.82,127.42,119.55,118.34,117.14,116.47,44.76,44.69,42.88,40.25,39.60,38.35.99,36.27 ,34.10,33.39,31.91,31.03,30.76,30.62,29.99,29.67,28.92,22.47,18.79,10.22.

[0066] Compound I-6: (E)-1-(4-(3-hydroxy-9β,13α-dimethyl-2-oxo-24,25,26-trinoroleanane-1(10 ),3,5,7-tetraene-29-acyl)piperazin-1-yl)-3-(3,4,5-(trimethoxy)phenyl)-2-propen-1-one

[0067] δ H (400MHz,cdcl 3 ) 7.61(1H,d,J 15.3), 7.01(1H,d,J7.0), 6.94(1H,s), 6.71(3H,d,J 14.3), 6.51(1H,s), 6.35(1H, d, J7.1), 3.88 (6H, s), 3.87 (3H, s), 3.84-2.59 (8H, m), 2.33 (2H, d, J 15.1), 2.20 (3H, s), 1.45 (3H ,s), 1.31(3H,s), 1.29(3H,s), 1.15(3H,s), 0.58(3H,s).

[0068] δC(101MHz,cdcl3)178.27,176.30,169.71,165.61,164.43,153.37,145.99,143.69,139.82,134.01,130.55,127.39,119.51,118.34,117.16,115.69,105.09,60.93,56.19,44.77,44.71,42.77,44.71,42.77 40.25, 39.57, 38.26, 36.26, 35.91, 34.13, 33.39, 31.88, 31.01, 30.79, 30.60, 29.99, 29.66, 29.28, 28.86, 27.18, 22.37, 18.77, 10.22.

[0069] Compound I-9: (E)-1-(4-(3-hydroxy-9β,13α-dimethyl-2-oxo-24,25,26-trinoroleanane-1(10 ),3,5,7-tetraene-29-acyl)piperazin-1-yl)-3-(4-methylphenyl)-2-propen-1-one

[0070] δ H (400MHz,cdcl 3 ) 7.67 (1H, d, J 15.4), 7.47 (2H, d, J8.7), 7.00 (1H, d, J6.8), 6.94 (1H, s), 6.88 (2H, d, J8.7) , 6.71 (1H, d, J 15.3), 6.51 (1H, s), 6.34 (1H, d, J7.2), 3.74 (3H, s), 4.20-3.50 (8H, m), 2.33 (2H, d ,J 15.0), 2.20(3H,s), 1.45(3H,s), 1.31(3H,s), 1.30(3H,s), 1.15(3H,s), 0.59(3H,s).

[0071] δ C (101MHz,cdcl 3 )178.27,176.31,169.67,165.97,164.38,160.99,146.00,143.32,133.92,129.42,127.76,127.42,119.54,118.33,117.10,114.22,113.90,55.32,44.76,44.69,42.88,40.23,39.60,38.22,36.28. ,36.01,34.08,33.38,31.90,31.02,30.75,30.62,29.99,28.93,22.48,18.77,10.20

[0072] Compound I-12: (E)-1-(4-(3-hydroxy-9β,13α-dimethyl-2-oxo-24,25,26-trinoroleanane-1(10 ),3,5,7-tetraene-29-acyl)piperazin-1-yl)-2-methyl-3-phenyl-2-propen-1-one

[0073] δ H (400MHz,cdcl 3 )7.41--7.27(5H,m), 7.02(1H,d,J7.0), 6.96(1H,s), 6.57(1H,s), 6.54(1H,s), 6.36(1H,d,J7. 2), 4.02 - 2.86 (8H, m), 2.21 (3H, s), 2.12 (3H, s), 1.46 (3H, s), 1.31 (3H, s), 1.31 (3H, s), 1.16 (2H) ,s),0.60(3H,s).

[0074] δ C (101MHz,cdcl 3 )178.29,176.28,172.60,169.74,164.44,146.00,135.55,134.05,132.17,130.50,129.04,128.35,127.64,127.40,119.49,118.36,117.15,44.74,44.63,42.90,40.24,39.61,38.21,36.25, ,34.06,33.40,31.91,31.02,30.73,30.67,29.96,28.93,22.54,18.78,16.29,10.23.

[0075] Example 2

[0076] X is Y is n=2; Ar is different R 1 When substituted phenyl, the preparation of compounds I-13~I-24

[0077] Step A:

[0078]

[0079] Weigh 5mmol substituted trans-cinnamic acid derivative 1, and slowly add 10ml SOCl 2 , Stir at room temperature for 1h, if the reactant does not dissolve, heat to 40℃ and stir for 0.5h, evaporate the solvent to obtain the substituted cinnamic acid chloride, then add 10ml of anhydrous dichloromethane to dissolve it, add 3ml of methanol dropwise, stir at room temperature for 10min, Concentrate under reduced pressure to obtain compound 4; add 20ml of ethylenediamine to the obtained compound 4, react under reflux for 2h, let cool to room temperature, pour the reaction solution into water, extract 3 times with ethyl acetate, combine the organic phases, and saturate the organic phases Washed with NaCl 3 times, dried with anhydrous sodium sulfate, and concentrated under reduced pressure to obtain a yellow oil with a yield of 52-73%.

[0080] Step B:

[0081]

[0082] Weigh 0.1g (0.221mmol) triptolide (Cel), add 5ml DMF to dissolve it, add 0.101g (0.265mmol) HATU, 155ul (0.884mmol) DIPEA, stir at room temperature for 30min, then add 0.243mmol of compound 3, room temperature The reaction was stirred for 5 hours, the reaction solution was poured into water, and stirred while pouring, a large amount of reddish brown solid was precipitated, filtered with suction, and dried. Preparative thin-layer chromatography is used to obtain target compounds I-13 to I-24 with a yield of 38% to 90%.

[0083] Some compound analysis data:

[0084] Compound I-13: (E)-1-(4-(3-hydroxy-9β,13α-dimethyl-2-oxo-24,25,26-trinoroleanane-1(10 ),3,5,7-tetraene-29-acyl)ethylenediamine-1-yl)-3-phenyl-2-propen-1-one

[0085] δ H (400MHz, dmso) 8.73(1H,s), 8.39(1H,s), 7.78(5H,s), 7.69(1H,s), 7.49(1H,d,J 15.8), 7.00(1H,d,J5 .4), 6.70(1H,d,J 15.9), 6.34(1H,s), 6.22(1H,d,J7.4), 3.27-3.03(4H,m), 3.03-2.93(1H,m), 2.39(1H,d,J 16.1),2.06(3H,s),1.32(3H,s),1.17(3H,s),1.05(3H,s),1.03(3H,s),0.49(3H,s) ).

[0086] δ C (101MHz, dmso)177.94,177.43,168.21,165.72,163.01,146.40,138.92,134.89,133.11,129.52,128.94,127.57,126.80,121.94,120.05,117.82,117.21,44.51,43.97,42.03,39.54,38.88,37.97 ,37.72,36.14,34.84,33.47,33.04,31.45,30.55,30.25,29.38,28.88,28.18,21.50,17.81,10.11.

[0087] Compound I-20: (E)-1-(4-(3-hydroxy-9β,13α-dimethyl-2-oxo-24,25,26-trinoroleanane-1(10 ),3,5,7-tetraene-29-acyl)ethylenediamine-1-yl)-3-(4-chlorophenyl)-2-propen-1-one

[0088] δ H (400MHz, dmso) 8.67 (1H, s), 8.18 (1H, s), 7.58 (3H, d, J8.1), 7.48 (2H, d, J8.3), 7.40 (1H, d, J 15.8) , 7.01 (1H, d, J6.6), 6.55 (1H, d, J 15.6), 6.35 (1H, s), 6.22 (1H, d, J6.7), 3.33-2.90 (8H, m), 2.38 (1H,d,J 15.2),2.08(3H,s),1.33(3H,s),1.17(3H,s),1.05(3H,s),1.03(3H,s),0.50(3H,s) .

[0089] δ C (101MHz,dmso)177.97,177.45,168.25,165.47,163.02,146.43,137.57,133.96,133.88,133.16,129.29,129.00,126.82,122.77,120.07,117.85,117.25,44.53,43.98,42.06,38.88,38.04,37.75 ,36.16,34.88,33.48,33.04,31.47,30.56,30.26,29.41,28.90,28.20,21.52,17.83,10.13.

[0090] Compound I-23: (E)-1-(4-(3-hydroxy-9β,13α-dimethyl-2-oxo-24,25,26-trinoroleanane-1(10 ),3,5,7-tetraene-29-acyl)ethylenediamine-1-yl)-3-phenylpropyl-1-one

[0091] δ H (400MHz, dmso) 8.69 (1H, s), 7.83 (1H, s), 7.62 (1H, s), 7.25-7.11 (5H, m), 7.06 (1H, d, J6.8), 6.40 (1H, s), 6.34 (1H, d, J7.1), 3.02-2.75 (4H, m), 2.77 (2H, t, J7.7), 2.39 (1H, d, J 14.5), 2.31 (2H, t, J7.7), 2.18(1H,d,J8.3), 2.09(3H,s), 1.38(3H,s), 1.21(3H,s), 1.07(3H,s), 1.03(3H,s) ,0.52(3H,s).

[0092] δ C (101MHz, dmso)177.96,177.36,171.76,168.27,163.02,146.41,141.27,133.17,128.23,128.17,126.81,125.85,120.08,117.92,117.23,44.55,43.99,42.07,39.53,38.89,38.01,37.77,37.77,37.77, ,36.19,34.86,33.37,33.07,31.48,31.07,30.59,30.28,29.39,28.90,28.24,21.51,17.83,10.10.

[0093] Example 3

[0094] The inhibitory effect of tripterygium wilfordii derivative of the present invention on tumor cell growth

[0095] The MTT method was used to detect the growth inhibitory effects of ovarian cancer cells SKOV-3 and OVCAR3. 2×10 3 The cells were seeded in a 96-well plate and allowed to adhere to the wall and grow for 48 hours before adding test drugs of various concentrations. After incubation, add 50μLMTT solution (2mg/mL) to each well, continue to incubate for 4h, shake the plate to remove the culture solution, add DMSO, and measure the absorbance at 570nm. The cell growth inhibition rate caused by the test drug was obtained by the ratio of absorbance (%) between the drug-added group and the blank control group, and the IG was calculated 50 , The results are shown in Table 1.

[0096] Table 1. Growth inhibitory activity of compounds on tumor cells

[0097]

[0098]