Cyclobutylmethyl and phenyl substituted curcumin derivatives, processes for their preparation and use

Abstract

The application relates to the technical field of biological medicine, in particular to a cyclobutyl methyl and phenyl substituted curcumin derivative as well as a synthesis method and application thereof. The cyclobutyl methyl and phenyl substituted curcumin derivative is prepared by introducing a multi-membered ring into a beta-diketone structure of curcumin and changing the benzene ring structures at two ends. In vitro tumor inhibition research shows that the killing effect of the newly synthesized curcumin derivative on tumor cells is stronger than that of curcumin derivatives ASC-J9 and ASC-JM17.

Description

TECHNICAL FIELD

[0001] The present application relates to the technical field of biological medicine, and particularly relates to a cyclobutylmethyl and phenyl substituted curcumin derivative, a preparation method and application thereof. BACKGROUND

[0002] Dimethoxycurcumin (ASC-J9) is a curcumin derivative with multiple biological activities, which can enhance the degradation of androgen receptor and can play a therapeutic role on androgen receptor related tumors, but its anti-tumor activity is still difficult to meet the clinical needs. It is reported that a new ASC-J9 derivative ASC-JM17 is prepared by introducing a cyclobutylmethyl between the beta diketone structures of ASC-J9. Compared with ASC-J9, ASC-JM17 has stronger targeted degradation ability of androgen receptor, and also shows stronger antioxidant capacity.

[0003] At present, the researches related to ASC-JM17 mainly focus on the treatment of spinal cerebellar ataxia, Huntington's disease and prostate cancer. SUMMARY

[0004] The purpose of the present application is to synthesize new curcumin derivatives with anti-hepatoma effect by changing the substituents on the beta diketone structure or benzene ring of curcumin. The curcumin derivative designed and synthesized in the present application has a chemical general formula as follows:

[0005]

[0006] In the formula, R1 is a cyclobutylmethyl or a phenyl.

[0007] R2 is a fluorine, an acetylamino or a methyl sulfonamide in ortho, meta or para position.

[0008] The chemical name and chemical structural formula of the newly synthesized curcumin derivative are as follows:

[0009] A1: N,N'-(((1E,6E)-4-(cyclobutylmethyl)-3,5-dioxabutyl-1,6-diene-1,7-diyl)bis(4,1-phenyl))diacetylamino

[0010]

[0011] A2: N,N'-(((1E,6E)-4-(cyclobutylmethyl)-3,5-dioxabutyl-1,6-diene-1,7-diyl)bis(3,1-phenyl))dimethyl sulfonamide

[0012]

[0013] A3: N,N'-(((1E,6E)-4-(cyclobutylmethyl)-3,5-dioxo-1,6-dien-1,7-diyl)bis(4,1- phenyl))dimethanesulfonamide

[0014]

[0015] A4: (1E,6E)-4-(cyclobutylmethyl)-1,7-bis(2-fluorophenyl)hepta-1,6-diene-3,5-dione

[0016]

[0017] A5: (1E,6E)-4-(cyclobutylmethyl)-1,7-bis(3-fluorophenyl)hepta-1,6-diene-3,5-dione

[0018]

[0019] A6: (1E,6E)-4-(cyclobutylmethyl)-1,7-bis(4-fluorophenyl)hepta-1,6-diene-3,5-dione

[0020]

[0021] A7: (1E,6E)-4-(cyclobutylmethyl)-1,7-bis(2,4-difluorophenyl)hepta-1,6-diene-3,5-dione

[0022]

[0023] A8: (1E,6E)-4-(cyclobutylmethyl)-1,7-bis(3,4-difluorophenyl)hepta-1,6-diene-3,5-dione

[0024]

[0025] B1: N,N'-(((1E,6E)-4-phenyl-3,5-dioxo-1,6-dien-1,7-diyl)bis(4,1-phenyl))diacetamide

[0026]

[0027] B2: N,N'-(((1E,6E)-4-phenyl-3,5-dioxo-1,6-dien-1,7-diyl)bis(3,1-phenyl))dimethanesulfonamide

[0028]

[0029] B3: N,N'-(((1E,6E)-4-phenyl-3,5-dioxoazulene-1,6-diyl)bis(4,1- phenyl))dimethanesulfonamide

[0030]

[0031] B4: (1E,6E)-4-phenyl-1,7-bis(2-fluorophenyl)hepta-1,6-diene-3,5-dione

[0032]

[0033] B5: (1E,6E)-4-phenyl-1,7-bis(4-fluorophenyl)hepta-1,6-diene-3,5-dione

[0034]

[0035] B6: (1E,6E)-4-phenyl-1,7-bis(2,4-difluorophenyl)hepta-1,6-diene-3,5-dione

[0036]

[0037] The preparation method and synthetic route of the novel curcumin derivative are as follows:

[0038]

[0039] (1) Preparation of acetylacetone derivative: acetylacetone, bromide and base are added to a solvent, and the reaction is stirred at 25-60°C for 8-12 hours in the dark. After the reaction is completed, the solvent is removed by rotary evaporation, and the acetylacetone derivative is separated and purified by vacuum distillation.

[0040] The solvent is DMF or isopropanol; the base is potassium carbonate or cesium carbonate; and the bromide is bromomethylcyclobutyl or bromobenzene.

[0041] The molar ratio of acetylacetone, bromide and base is 1:1-1.2:2-3.

[0042] (2) Preparation of curcumin derivative: the acetylacetone derivative prepared in step (1), boric acid, tributyl borate, n-butylamine and benzaldehyde with different substituents are added to DMF, and the reaction is stirred at 25-80°C for 2-5 hours in the dark. After the reaction is completed, 20% aqueous acetic acid is added and stirred for 8 hours. The filter residue is collected, and the product is recrystallized from methanol to obtain the curcumin derivative.

[0043] Among them, benzaldehyde with different substituents are: p-acetamidobenzaldehyde, 3-methanesulfonamidobenzaldehyde, p-methanesulfonamidobenzaldehyde, 2-fluorobenzaldehyde, 3-fluorobenzaldehyde, 4-fluorobenzaldehyde, 2,4-difluorobenzaldehyde, 3,4-difluorobenzaldehyde.

[0044] The molar ratio of acetylacetone derivative, benzaldehyde with different substituents, boric acid, tributyl borate and n-butylamine is 1:2-2.5:0.5-1:2-2.5:1-1.5.

[0045] The beneficial effects of the present application are:

[0046] (1) The present application uses acetylacetone, bromide and benzaldehyde with different substituents as raw materials to synthesize curcumin derivatives at a lower cost.

[0047] (2) The biological activity of acetylacetone can be enhanced by introducing a polybasic ring at position 3, and the modification of the substituent group on the benzene ring can also have a similar effect. By applying both to the modification of curcumin, new curcumin derivatives with high anti-tumor activity are obtained.

[0048] (3) The new curcumin derivatives provided by the present application have stronger killing effect on tumor cells than curcumin derivatives ASC-JM17 and ASC-J9. DETAILED DESCRIPTION

[0049] The specific embodiments of the present application are further described in detail below. The following examples are used to illustrate the present application, but are not used to limit the scope of the present application.

[0050] Example 1

[0051] (1) Preparation of 3-(cyclobutylmethyl)pentane-2,4-dione

[0052] Acetylacetone 2g (20.0mmol) and potassium carbonate 5.52g (40.0mmol) were dissolved in 15mL DMF, and bromomethylcyclobutyl 3.55g (24.0mmol) was added. The reaction was stirred at 60°C for 5 hours. After the reaction solution A was cooled, 150ml distilled water was added to dissolve it, and ethyl acetate (EA) was used for extraction. The organic phase was collected and dried with anhydrous sodium sulfate, and the solid was removed by filtration. After the solution was rotary evaporated to remove the solvent, it was purified by reduced pressure distillation to obtain a yellow liquid.

[0053] (2) Preparation of N,N'-(((1E,6E)-4-(cyclobutylmethyl)-3,5-dioxabicyclo[4.1.0]-1,6-diene-1,7-diyl)bis(4,1-phenyl))diacetamido

[0054] To 3-(cyclobutylmethyl)pentane-2,4-dione 500 mg (2.97 mmol) in 3 mL of DMF, p-acetamidobenzaldehyde 969.9 mg (5.95 mmol), boronic acid 91.9 mg (1.49 mmol), tributyl borate 1.37 g (5.95 mmol) and n-butylamine 108.8 mg (1.49 mmol) were added, the reaction was stirred at 80 °C for 3 h, 20% aqueous acetic acid 30 mL was added, stirred for 3 h, suction filtered, and the filter residue was collected. Recrystallization was performed using methanol, and the orange-yellow solid powder was obtained by drying, 933.5 mg, yield 68.5%. 1 H NMR (400 MHz, DMSO-d6) δ 10.19 (s, 2H), 7.73 (d, J = 8.5 Hz, 2H), 7.69 - 7.56 (m, 9H), 7.26 (d, J = 15.5 Hz, 1H), 6.92 (d, J = 16.1 Hz, 1H), 2.06 (d, J = 4.8 Hz, 7H), 1.93 (dd, J = 13.6, 6.1 Hz, 4H), 1.73 (d, J = 5.9 Hz, 3H), 1.62 (t, J = 9.2 Hz, 1H). 13 C NMR (101 MHz, DMSO-d6) δ 195.28, 183.02, 168.69, 168.62, 143.06, 141.71, 141.18, 140.64, 139.93, 129.68, 129.65, 129.39, 129.22, 128.65, 123.65, 119.34, 118.91, 118.85, 110.31, 37.90, 35.15, 33.73, 29.92, 27.79, 26.98, 24.11, 17.91, 17.80. HRMS: m / z of [M+Na] + caculated for C 28 H 30 N2O4 481.2155, found 481.2155.

[0055] Example 2

[0056] (1) Preparation method of 3-(cyclobutylmethyl)pentane-2,4-dione is the same as step (1) in Example 1.

[0057] (2) Preparation of N,N'-(((1E,6E)-4-(cyclobutylmethyl)-3,5-dioxabicyclo[1.1.0]hexa-1,7- dien-1,7-diyl)bis(3,1-phenyl))dimethanesulfonamide

[0058] To 3-(cyclobutylmethyl)pentane-2,4-dione 500 mg (2.97 mmol) in 3 mL of DMF, 3-methanesulfonamidobenzaldehyde 1.19 g (5.95 mmol), boronic acid 91.9 mg (1.49 mmol), tributyl borate 1.37 g (5.95 mmol) and n-butylamine 108.8 mg (1.49 mmol) were added, and the reaction was stirred at 80 °C for 3 h. 20% aqueous acetic acid 30 mL was added, and the mixture was stirred for 3 h. The mixture was filtered, and the residue was collected. The residue was recrystallized using methanol, and dried to obtain an orange-yellow solid powder 1138.4 mg in 72.3% yield. 1 H NMR (400 MHz, DMSO-d6) δ 10.13 (s, 2H), 7.77 (d, J = 8.6 Hz, 2H), 7.70 (d, J = 8.6 Hz, 2H), 7.62 (d, J = 15.7 Hz, 2H), 7.23 (dd, J = 11.8, 8.2 Hz, 5H), 6.93 (d, J = 16.1 Hz, 1H), 3.06 (d, J = 5.1 Hz, 6H), 2.79 (d, J = 7.4 Hz, 1H), 2.33 (s, 1H), 1.93 (dd, J = 13.2, 6.2 Hz, 4H), 1.73 (s, 3H), 1.62 (s, 1H). 13 C NMR (101 MHz, DMSO-d6) δ 195.57, 182.95, 142.98, 140.65, 139.02, 135.98, 135.16, 129.97, 125.95, 123.88, 123.64, 122.02, 121.66, 121.27, 119.56, 119.38, 110.92, 59.61, 37.81, 35.06, 33.71, 27.81, 27.02, 17.96, 17.78. HRMS: m / z of [M+Na] + C 26 H 30 N2O6S2 553.1444, found 553.1444.

[0059] Example 3

[0060] (1) Preparation of 3-(cyclobutylmethyl)pentane-2,4-dione according to the method of Example 1, step (1).

[0061] (2) Preparation of N,N'-(((1E,6E)-4-(cyclobutylmethyl)-3,5-dioxabicyclo[1.1.0]hexa-1,7- dien-1,7-diyl)bis(4,1-phenyl))dimethanesulfonamide

[0062] To 3-(cyclobutylmethyl)pentane-2,4-dione 500 mg (2.97 mmol) in 3 mL of DMF was added p-toluenesulfonamide benzaldehyde 1.19 g (5.95 mmol), boronic acid 91.9 mg (1.49 mmol), tributyl borate 1.37 g (5.95 mmol) and n-butylamine 108.8 mg (1.49 mmol), stirred at 80 °C for 3 h, added 20% aqueous acetic acid 30 mL, stirred for 3 h, suction filtered, collected the filter residue. Recrystallized using methanol, oven dried to get orange yellow solid powder 877.0 mg, yield 55.7%. 1 H NMR (400 MHz, DMSO-d6) δ 9.90 (s, 2H), 7.70 - 7.56 (m, 3H), 7.52 - 7.36 (m, 5H), 7.34 - 7.22 (m, 3H), 6.91 (dd, J = 32.4, 16.1 Hz, 1H), 3.03 (d, J = 13.2 Hz, 6H), 2.79 (d, J = 7.0 Hz, 1H), 2.42 - 2.30 (m, 1H), 2.26 - 2.16 (m, 1H), 1.94 (dd, J = 15.5, 8.5 Hz, 3H), 1.82 - 1.59 (m, 4H). 13 C NMR (101 MHz, DMSO-d6) δ 195.30, 183.02, 140.41, 140.29, 130.15, 129.86, 129.71, 119.82, 118.86, 118.64, 110.46, 37.90, 29.91, 27.80, 26.97, 17.91. HRMS: m / z of [M+Na] + C 26 H 30 N2O6S2 553.1444, found 553.1444.

[0063] Example 4

[0064] (1) Preparation of 3-(cyclobutylmethyl)pentane-2,4-dione was the same as step (1) in Example 1.

[0065] (2) Preparation of (1E,6E)-4-(cyclobutylmethyl)-1,7-bis(2-fluorophenyl)hepta-1,6- diene-3,5-dione

[0066] To a solution of 3-(cyclobutylmethyl)pentane-2,4-dione 500 mg (2.97 mmol) in 3 mL of DMF, 2-fluorobenzaldehyde 738.2 mg (5.95 mmol), boronic acid 91.9 mg (1.49 mmol), tributyl borate 1.37 g (5.95 mmol) and n-butylamine 108.8 mg (1.49 mmol) were added. The reaction was stirred at 80 °C for 3 h, 20% aqueous acetic acid 30 mL was added, stirred for 3 h, suction filtered, and the filter residue was collected. Recrystallization was performed using methanol, and the orange yellow solid powder 464.0 mg was obtained by oven drying, with a yield of 41.1%. 1 H NMR (400 MHz, DMSO-d6) δ 8.05 - 7.98 (m, 1H), 7.89 (t, J = 7.7 Hz, 1H), 7.74 (dd, J = 24.9, 15.9 Hz, 2H), 7.55 - 7.42 (m, 3H), 7.31 (dq, J = 11.9, 8.1, 7.7 Hz, 4H), 7.12 (d, J = 16.2 Hz, 1H), 4.54 (t, J = 6.9 Hz, 1H), 2.81 (d, J = 7.2 Hz, 1H), 2.44 - 2.17 (m, 1H), 2.02 - 1.57 (m, 7H). 13 C NMR (101 MHz, Chloroform-d) δ 182.24, 161.76, 159.24, 133.28, 133.26, 130.24, 130.16, 128.72, 128.69, 123.47, 123.43, 122.79, 122.71, 122.60, 122.49, 115.35, 115.13, 110.06, 37.10, 30.60, 26.82, 17.40. 19 F NMR (282 MHz, DMSO-d6) δ -115.33, -116.13. HRMS: m / z of [M+Na] + C 24 H 22 F2O2 403.1491, found 403.1491.

[0067] Example 5

[0068] (1) Preparation of 3-(cyclobutylmethyl)pentane-2,4-dione was performed according to the procedure of Example 1, step (1).

[0069] (2) Preparation of (1E,6E)-4-(cyclobutylmethyl)-1,7-bis(3-fluorophenyl)hepta-1,6- diene-3,5-dione

[0070] To a solution of 3-(cyclobutylmethyl)pentane-2,4-dione 500 mg (2.97 mmol) in 3 mL of DMF, 3-fluorobenzaldehyde 738.2 mg (5.95 mmol), boronic acid 91.9 mg (1.49 mmol), tributyl borate 1.37 g (5.95 mmol) and n-butylamine 108.8 mg (1.49 mmol) were added. The reaction was stirred at 80 °C for 3 h, 20% aqueous acetic acid 30 mL was added, stirred for 3 h, suction filtered, and the filter residue was collected. Recrystallization was performed using methanol, and the orange-yellow solid powder was obtained by oven drying, 591.6 mg, yield 52.4%. 1 H NMR (400 MHz, DMSO-d6) δ 7.82 - 7.75 (m, 1H), 7.66 (dt, J = 15.1, 7.1 Hz, 4H), 7.58 (d, J = 7.8 Hz, 1H), 7.52 - 7.43 (m, 3H), 7.28 (qd, J = 8.2, 2.4 Hz, 2H), 7.15 (d, J = 16.1 Hz, 1H), 4.47 (t, J = 6.9 Hz, 1H), 2.87 (d, J = 7.3 Hz, 1H), 2.39 - 2.16 (m, 1H), 2.03 - 1.84 (m, 3H), 1.69 (dq, J = 35.2, 8.7 Hz, 4H). 13 C NMR (101 MHz, Chloroform-d) δ 183.01, 164.30, 161.85, 140.10, 140.07, 137.76, 137.68, 130.54, 130.45, 124.30, 124.28, 122.12, 116.96, 116.75, 114.26, 114.05, 110.97, 38.11, 31.61, 27.87, 18.47. 19 F NMR (282 MHz, DMSO-d6) δ -112.72, -112.86. HRMS: m / z of [M+Na] + C 24 H 22 F2O2403.1491, found 403.1491.

[0071] Example 6

[0072] (1) Preparation of 3-(cyclobutylmethyl)pentane-2,4-dione was performed according to the procedure of Example 1, step (1).

[0073] (2) Preparation of (1E,6E)-4-(cyclobutylmethyl)-1,7-bis(4-fluorophenyl)hepta-1,6- diene-3,5-dione

[0074] To a solution of 3-(cyclobutylmethyl)pentane-2,4-dione 500 mg (2.97 mmol) in 3 mL of DMF, 4-fluorobenzaldehyde 738.2 mg (5.95 mmol), boronic acid 91.9 mg (1.49 mmol), tributyl borate 1.37 g (5.95 mmol) and n-butylamine 108.8 mg (1.49 mmol) were added, the reaction was stirred at 80 °C for 3 hours, 20% aqueous acetic acid 30 mL was added, stirred for 3 h, suction filtration, the filter residue was collected. Recrystallized with methanol, oven dried to obtain an orange yellow solid powder 742.9 mg, yield 65.8%. 1 H NMR (400 MHz, DMSO-d6) δ 7.89 (dd, J = 8.5, 5.7 Hz, 2H), 7.85 - 7.80 (m, 2H), 7.67 (dd, J = 15.9, 10.0 Hz, 2H), 7.34 - 7.25 (m, 5H), 6.99 (dd, J = 34.8, 16.0 Hz, 1H), 4.48 (t, J = 7.0 Hz, 1H), 2.83 (d, J = 7.3 Hz, 1H), 2.39 - 2.16 (m, 1H), 1.93 (dt, J = 24.0, 8.0 Hz, 3H), 1.81 - 1.56 (m, 4H). 13 C NMR (101 MHz, Chloroform-d) δ 183.15, 164.98, 162.49, 140.08, 139.41, 131.76, 131.72, 130.01, 129.92, 123.68, 120.65, 120.62, 116.21, 115.99, 110.47, 110.45, 38.11, 31.63, 27.90, 18.48. 19 F NMR (282 MHz, DMSO-d6) δ -109.28, -110.17. HRMS: m / z of [M+Na] + C 24 H 22 F2O2 403.1491, found 403.1491.

[0075] Example 7

[0076] (1) Preparation method of 3-(cyclobutylmethyl)pentane-2,4-dione is the same as step (1) in Example 1.

[0077] (2) Preparation of (1E,6E)-4-(cyclobutylmethyl)-1,7-bis(2,4-difluorophenyl)hepta-1,6-diene-3,5-dione

[0078] To a solution of 3-(cyclobutylmethyl)pentane-2,4-dione 500 mg (2.97 mmol) in 3 mL of DMF, 2,4-difluorobenzaldehyde 845.5 mg (5.95 mmol), boronic acid 91.9 mg (1.49 mmol), tributyl borate 1.37 g (5.95 mmol) and n-butylamine 108.8 mg (1.49 mmol) were added. The reaction was stirred at 80 °C for 3 h, 20% aqueous acetic acid 30 mL was added, stirred for 3 h, suction filtered, and the filter residue was collected. Recrystallization was performed using methanol, and oven dried to give an orange yellow solid powder 446.2 mg, yield 36.1%. 1 H NMR (400 MHz, DMSO-d6) δ 8.12 (td, J = 8.8, 6.6 Hz, 1H), 7.98 (q, J = 8.3 Hz, 1H), 7.76 - 7.61 (m, 2H), 7.47 - 7.36 (m, 4H), 7.27 - 7.17 (m, 2H), 7.06 (dd, J = 29.2, 16.1 Hz, 1H), 4.50 (t, J = 7.0 Hz, 1H), 2.80 (d, J = 7.2 Hz, 1H), 2.41 - 2.10 (m, 1H), 1.93 (dt, J = 15.0, 5.2 Hz, 2H), 1.80 - 1.59 (m, 4H). 13 C NMR (101 MHz, Chloroform-d) δ 183.13, 164.88 (d, J = 12.3 Hz), 163.05 (d, J = 12.0 Hz), 162.36 (d, J = 12.4 Hz), 160.50 (d, J = 11.9 Hz), 133.34, 132.45, 130.85 (d, J = 4.8 Hz), 130.75 (d, J = 4.8 Hz), 123.27, 123.20, 120.12 (d, J = 3.9 Hz), 120.00 (d, J = 4.0 Hz), 112.18 (d, J = 3.7 Hz), 111.96 (d, J = 3.8 Hz), 110.99 (d, J = 1.8 Hz), 105.00, 104.75, 104.49, 102.19, 38.11, 31.59, 27.85, 18.43. 19 F NMR (282 MHz, DMSO-d6) δ -105.31, -106.19, -110.58, -111.52. HRMS: m / z of [M+Na] + C 24 H 20 F4O2 439.1291, found 439.1291.

[0079] Example 8

[0080] (1) The preparation method of 3-(cyclobutylmethyl)pentane-2,4-dione is the same as step (1) in Example 1.

[0081] (2) Preparation of (1E,6E)-4-(cyclobutylmethyl)-1,7-bis(3,4-difluorophenyl)hepta-1,6-diene-3,5-dione

[0082] Dissolve 3-(cyclobutylmethyl)pentane-2,4-dione 500 mg (2.97 mmol) in 3 mL DMF, add 3,4-difluorobenzaldehyde 845.5 mg (5.95 mmol), boronic acid 91.9 mg (1.49 mmol), tributyl borate 1.37 g (5.95 mmol) and n-butylamine 108.8 mg (1.49 mmol), stir the reaction at 80°C for 3 hours, add 20% aqueous acetic acid 30 mL, stir for 3 hours, suction filter, collect the filter residue. Recrystallize using methanol, and dry in an oven to obtain 530.2 mg of orange yellow solid powder, yield 42.9%. 1 H NMR (400 MHz, DMSO-d6) δ 8.08 (ddd, J = 12.3, 7.9, 2.0 Hz, 1H), 7.96 (ddd, J = 10.1, 7.8, 2.0 Hz, 1H), 7.71 - 7.57 (m, 4H), 7.52 (dt, J = 10.7, 8.5 Hz, 2H), 7.43 (d, J = 15.5 Hz, 1H), 7.11 (d, J = 16.1 Hz, 1H), 4.41 (t, J = 6.9 Hz, 1H), 2.86 (d, J = 7.3 Hz, 1H), 2.37 - 2.15 (m, 1H), 2.02 - 1.83 (m, 3H), 1.81 - 1.58 (m, 4H). 13 C NMR (101 MHz, Chloroform-d) δ 182.85, 152.57 (d, J = 12.9 Hz), 151.90 (d, J = 13.2 Hz), 150.05 (d, J = 12.5 Hz), 149.42 (d, J = 13.1 Hz), 139.18 (d, J = 2.3 Hz), 132.73, 132.69, 132.67, 132.63, 125.00, 124.97, 124.94, 124.90, 121.76 (d, J = 2.5 Hz), 117.97, 117.79, 116.23, 116.05, 110.83, 38.09, 31.57, 27.86, 18.47. 19 F NMR (282 MHz, DMSO-d6) δ -134.89, -135.79, -137.85, -138.07. HRMS: m / z of [M+Na] +caculated for C 24 H 20 F4O2 439.1291,found 439.1291.

[0083] Example 9

[0084] (1) Preparation of 3-phenylpentane-2,4-dione

[0085] Acetylacetone 2 g (20.0 mmol) and potassium carbonate 5.52 g (40.0 mmol) were dissolved in 15 mL of DMF, and phenyl bromide 3.74 g (24.0 mmol) was added, and the reaction was stirred at 60°C for 5 hours. After the reaction solution A was cooled, 150 mL of distilled water was added to dissolve it, and ethyl acetate (EA) was extracted, and the organic phase was collected and dried with anhydrous sodium sulfate, and the solid was removed by filtration, and the solution was rotary evaporated to remove the solvent, and then purified by reduced pressure distillation to obtain a yellow liquid.

[0086] (2) N,N'-(((1E,6E)-4-phenyl-3,5-dioxabicyclo-1,6-diene-1,7-diyl)bis(4,1- phenyl))diacetamido

[0087] 3-phenylpentane-2,4-dione 200 mg (1.14 mmol) was dissolved in 3 mL of DMF, and p-acetamidobenzaldehyde 370.7 mg (2.27 mmol), boric acid 35.1 mg (0.57 mmol), tributyl borate 522.8 mg (2.27 mmol), and n-butylamine 41.5 mg (0.57 mmol) were added, and the reaction was stirred at 80°C for 3 hours, 20% acetic acid aqueous solution 30 mL was added, and stirred for 3 hours, and filtered, and the filter residue was collected. Recrystallization was performed using methanol, and the obtained orange yellow solid powder 417.7 mg was dried to obtain an orange yellow solid powder 417.7 mg, and the yield was 78.6%. 1 H NMR (400 MHz, DMSO-d6) δ 10.15 (s, 2H), 7.65-7.49 (m, 10H), 7.34 (dt, J=7.5, 1.5 Hz, 6H), 6.35 (d, J=15.7 Hz, 2H), 2.04 (s, 6H). 13 C NMR (101 MHz, DMSO-d6) δ 182.31, 169.10, 141.87, 141.20, 135.04, 132.45, 129.55, 129.50, 129.23, 128.46, 120.07, 119.47, 116.27, 49.06, 24.54. HRMS: m / z of [M+Na] + caculated for C 29 H 26 N2O4 489.1788,found489.1788.

[0088] Example 10

[0089] (1) Preparation of 3-phenylpentane-2,4-dione was the same as step (1) in Example 9.

[0090] (2) Preparation of N,N'-(((1E,6E)-4-phenyl-3,5-dioxoazulene-1,6-diyl)bis(3,1- phenyl))dimethanesulfonamide

[0091] 3-phenylpentane-2,4-dione 200 mg (1.14 mmol) was dissolved in 3 mL DMF, 3- methanesulfonamidobenzaldehyde 452.6 mg (2.27 mmol), boric acid 35.1 mg (0.57 mmol), tributyl borate 484.3 mg (2.27 mmol) and n-butylamine 41.5 mg (0.57 mmol) were added, the reaction was stirred at 80 °C for 3 hours, 20% aqueous acetic acid 30 mL was added, stirred for 3 h, suction filtration, the filter residue was collected. Recrystallized with methanol, oven dried to obtain orange yellow solid powder 298.7 mg, yield 48.7%. 1 H NMR (400 MHz, DMSO-d6) δ 9.86 (s, 2H), 7.65 (d, J = 15.7 Hz, 2H), 7.54 (dd, J = 5.2, 1.9 Hz, 3H), 7.43 (d, J = 2.8 Hz, 1H), 7.41 - 7.29 (m, 4H), 7.25 - 7.11 (m, 6H), 6.44 (d, J = 15.7 Hz, 2H), 2.98 (s, 6H). 13 CNMR (101 MHz, DMSO-d6) δ 182.26, 141.24, 139.56, 135.98, 134.53, 132.38, 130.57, 129.30, 128.68, 124.25, 122.44, 121.67, 118.63, 116.91. HRMS: m / z of [M+Na] + caculated for C 27 H 26 N2O6S2 561.1126, found 561.1126.

[0092] Example 11

[0093] (1) Preparation of 3-phenylpentane-2,4-dione was the same as step (1) in Example 9.

[0094] (2) Preparation of N,N'-(((1E,6E)-4-phenyl-3,5-dioxoazulene-1,6-diyl)bis(3,1- phenyl))dimethanesulfonamide

[0095] Dissolve 3-phenylpentane-2,4-dione 200 mg (1.14 mmol) in 3 mL DMF, add p-toluenesulfonamide benzaldehyde 452.6 mg (2.27 mmol), boric acid 35.1 mg (0.57 mmol), tributyl borate 484.3 mg (2.27 mmol) and n-butylamine 41.5 mg (0.57 mmol), stir the reaction at 80 °C for 3 hours, add 20% aqueous acetic acid 30 mL, stir for 3 h, suction filter, collect the filter residue. Recrystallize using methanol, oven dry to obtain orange yellow solid powder 426.9 mg, yield 69.8%. 1 H NMR (400 MHz, DMSO-d6) δ 10.09 (s, 2H), 7.63 (d, J = 15.7 Hz, 2H), 7.52 (d, J = 6.7 Hz, 3H), 7.36 (dd, J = 18.1, 7.6 Hz, 6H), 7.17 (d, J = 8.2 Hz, 4H), 6.36 (d, J = 15.7 Hz, 2H), 3.16 (d, J = 4.7 Hz, 1H), 3.03 (s, 6H). 13 C NMR (101 MHz, DMSO-d6) δ 182.29, 141.01, 140.98, 134.93, 132.43, 129.97, 129.94, 129.24, 128.48, 120.58, 119.29, 116.39. HRMS: m / z of [M+Na] + C 27 H 26 N2O6S2 561.1126, found 561.1126.

[0096] Example 12

[0097] (1) Preparation of 3-phenylpentane-2,4-dione as in Example 9, step (1).

[0098] (2) Preparation of (1E,6E)-4-phenyl-1,7-bis(2-fluorophenyl)hepta-1,6-diene-3,5-dione

[0099] To a solution of 3-phenylpentane-2,4-dione 200 mg (1.14 mmol) in 3 mL of DMF, 2-fluorobenzaldehyde 281.9 mg (2.27 mmol), boronic acid 35.1 mg (0.57 mmol), tributyl borate 484.3 mg (2.27 mmol) and n-butylamine 41.5 mg (0.57 mmol) were added, the reaction was stirred at 80 °C for 3 h, 20% aqueous acetic acid 30 mL was added, stirred for 3 h, suction filtered, and the filter residue was collected. Recrystallization was performed using methanol, and the orange-yellow solid powder 235.1 mg was obtained by drying, with a yield of 53.3%. 1 H NMR (400 MHz, Chloroform-d) δ 7.84 (d, J = 15.9 Hz, 1H), 7.49 - 7.42 (m, 2H), 7.37 (q, J = 3.2 Hz, 1H), 7.33 - 7.20 (m, 6H), 7.16 - 6.88 (m, 5H), 6.61 (d, J = 15.9 Hz, 1H), 6.31 (d, J = 15.9 Hz, 1H), 4.12 - 3.77 (m, 1H). 13 CNMR (101 MHz, DMSO-d6) δ 200.38, 182.29, 162.41, 159.90, 134.80, 134.18, 132.84, 132.75, 132.33, 131.92, 130.45, 130.42, 130.09, 129.25, 129.21, 128.63, 128.43, 125.60, 124.90, 122.75, 122.64, 117.26, 116.80, 116.59, 116.52. 19 FNMR (282 MHz, DMSO-d6) δ -114.81 (dt, J = 11.7, 6.8 Hz), -115.32 (dq, J = 11.9, 6.5, 6.1 Hz). HRMS: m / z of [M+Na] + caculated for C 25 H 18 F2O2 411.1171, found 411.1171.

[0100] Example 13

[0101] (1) Preparation of 3-phenylpentane-2,4-dione as in Example 9, step (1).

[0102] (2) Preparation of (1E,6E)-4-phenyl-1,7-bis(4-fluorophenyl)hepta-1,6-diene-3,5-dione

[0103] To a solution of 3-phenylpentane-2,4-dione 200 mg (1.14 mmol) in 3 mL of DMF, p-fluorobenzaldehyde 281.9 mg (2.27 mmol), boronic acid 35.1 mg (0.57 mmol), tributyl borate 484.3 mg (2.27 mmol) and n-butylamine 41.5 mg (0.57 mmol) were added, the reaction was stirred at 80 °C for 3 h, 20% aqueous acetic acid 30 mL was added, stirred for 3 h, suction filtered, the filter residue was collected. Recrystallized using methanol, oven dried to obtain orange yellow solid powder 238.6 mg, yield 54.1%. 1 H NMR (400 MHz, Chloroform-d) δ 7.66 (d, J = 15.7 Hz, 2H), 7.52 - 7.42 (m, 3H), 7.35 - 7.28 (m, 6H), 7.04 - 6.94 (m, 4H), 6.41 (d, J = 15.7 Hz, 2H), 2.45 (dd, J = 7.4, 1.8 Hz, 1H). 13 C NMR (101 MHz, DMSO-d6) δ 182.31, 164.90, 162.42, 140.37, 134.70, 132.41, 132.03, 131.61, 131.58, 130.88, 130.79, 129.29, 128.60, 121.74, 116.72, 116.62, 116.51. 19 F NMR (282 MHz, DMSO-d6) δ -109.66 (tt, J = 8.7, 5.5 Hz), -110.14. HRMS: m / z of [M+Na] + C 25 H 18 F2O2 411.1171, found 411.1171.

[0104] Example 14

[0105] (1) Preparation of 3-phenylpentane-2,4-dione as in Example 9, step (1).

[0106] (2) Preparation of (1E,6E)-4-phenyl-1,7-bis(2,4- fluorophenyl)hepta-1,6-diene-3,5-dione

[0107] To a solution of 3-phenylpentane-2,4-dione 200 mg (1.14 mmol) in 3 mL of DMF, 2,4-difluorobenzaldehyde 322.6 mg (2.27 mmol), boronic acid 35.1 mg (0.57 mmol), tributyl borate 484.3 mg (2.27 mmol) and n-butylamine 41.5 mg (0.57 mmol) were added, the reaction was stirred at 80 °C for 3 h, 20% aqueous acetic acid 30 mL was added, stirred for 3 h, suction filtered, and the filter residue was collected. Recrystallization was performed using methanol, and the orange-yellow solid powder 361.2 mg was obtained by drying, with a yield of 89.4%. 1 H NMR (400 MHz, Chloroform-d) δ 7.77 (d, J = 15.9 Hz, 1H), 7.62 (d, J = 16.0 Hz, 2H), 7.51 - 7.43 (m, 2H), 7.40 - 7.35 (m, 1H), 7.32 - 7.15 (m, 4H), 7.04 (d, J = 44.1 Hz, 1H), 6.84 - 6.71 (m, 3H), 6.53 (d, J = 15.9 Hz, 1H), 6.28 - 6.16 (m, 1H), 3.90 (t, J = 7.3 Hz, 1H). 13 C NMR (101 MHz, DMSO-d6) δ 182.23, 173.22, 160.28, 160.15, 134.39, 133.38, 132.31, 132.26, 132.14, 131.91, 129.25, 128.63, 128.45, 124.48, 119.63, 119.55, 117.16, 113.19, 112.97, 105.58, 105.32, 105.06. 19 F NMR (282 MHz, DMSO-d6) δ -105.91 (p, J = 9.1 Hz), -106.42 - -106.56 (m), -110.07 (q, J = 9.9 Hz), -110.51 - -110.70 (m). HRMS: m / z of [M+Na] + C 25 H 16 F4O2 447.0992, found 447.0992.

[0108] Test Example 1

[0109] The method and results of the study of the cell proliferation activity of curcumin derivatives A1-A8, B1-B6 are as follows:

[0110] 1. Preparation of experimental drugs: The curcumin derivatives prepared in Examples 1-14 of the present application were dissolved in dimethyl sulfoxide to prepare a solution with a concentration of 4 mmol / L. Different concentrations of curcumin derivatives were diluted to 1.25, 2.5, 5, 10, 20 and 40 μmol / L using DMEM medium. ASC-JM17 and ASC-J9 were also diluted to 6 concentrations in the same way.

[0111] 2. Cell lines: Human hepatoma cells (HepG2) and mouse embryonic fibroblasts (3T3).

[0112] 3. Cell viability experiment:

[0113] The killing effect of different concentrations of curcumin derivatives on cells was detected by the MTT method. When the cells grew to the logarithmic phase, they were resuspended and diluted to a concentration of 50,000 cells / mL using trypsin digestion, 100 μL of which was inoculated into a 96-well plate. After incubation for 24 h, different concentrations of ASC-JM17, ASC-J9 and curcumin derivatives were added, with 4 parallel groups for each concentration, and a corresponding blank control group was set, and incubated in a 37°C constant temperature incubator for 24 h. Without removing the culture medium, 20 uL of MTT (5 mg / mL) was added per well, and incubated for 4 h. The culture medium was removed, 200 uL of DMSO was added to each well, and the shaking bed was shaken at low speed for 30 min. The absorbance was detected at 490 nm by a microplate reader.

[0114] The results showed that the IC 50 values of ASC-JM17 and ASC-J9 for HepG2 cells were 29.86 and 33.577 μM, respectively, while the IC 50 values of curcumin derivatives A1-A3 for HepG2 cells were 6.49, 12.27 and 14.13 μM, respectively, which had stronger HepG2 cell inhibition. The cancer cell inhibition activities of ASC-JM17, ASC-J9 and curcumin derivatives are shown in Table 1.

[0115] Table 1. Cancer cell inhibition activities of ASC-JM17, ASC-J9 and curcumin derivatives

[0116]

[0117] According to the killing effect of curcumin derivatives on cancer cells, MTT experiments were performed on 3T3 cells using curcumin derivatives A1-A3. The results showed that the IC 50 value of curcumin derivative A2 for 3T3 cells was 25.54, which was significantly higher than the IC 50 value for HepG2 cells; the IC 50 values of ASC-JM17 and ASC-J9 for 3T3 cells were also higher than the IC50 However, the fold of increase was not as significant as A2, indicating that curcumin derivative A2 was able to exert more effective selective anti-tumor effect than ASC-JM17 and ASC-J9. The 3T3 cell inhibition activity of curcumin derivatives is shown in Table 2.

[0118] Table 2. 3T3 cell inhibition activity of curcumin derivatives

[0119]

[0120] Finally, the method of the present application is only a preferred embodiment, and is not intended to limit the protection scope of the present application. Any modification, equivalent replacement, improvement, etc. made within the spirit and principle of the present application shall be included in the protection scope of the present application.

Claims

1. A cyclobutylmethyl and phenyl-substituted curcumin derivative, characterized in that, The chemical formula of the curcumin derivative is as follows: ， Among them, R1 is cyclobutylmethyl, phenyl, R2 is meta, para-fluorine, acetylamino, methyl sulfonamide group.

2. The curcumin derivative according to claim 1, characterized in that, The chemical name and chemical formula of the curcumin derivative are as follows: A1: N, N'-((((1E, 6E)-4-(cyclobutylmethyl)-3,5-dioxo-1,6-diene-1,7-diyl) bis(4,1-phenyl)) diacetylamino A2: N, N'-((((1E, 6E)-4-(cyclobutylmethyl)-3,5-dioxo-1,6-diene-1,7-diyl) bis(3,1-phenyl)) dimethyl sulfonamide A3: N, N'-((((1E, 6E)-4-(cyclobutylmethyl)-3,5-dioxo-1,6-diene-1,7-diyl) bis(4,1-phenyl)) dimethyl sulfonamide A5: (1E, 6E)-4-(cyclobutylmethyl)-1,7-bis(3-fluorophenyl) hept-1,6-diene-3,5-dione A6: (1E, 6E)-4-(cyclobutylmethyl)-1,7-bis(4-fluorophenyl) hept-1,6-diene-3,5-dione A8: (1E, 6E)-4-(cyclobutylmethyl)-1,7-bis(3,4-difluorophenyl) hept-1,6-diene-3,5-dione B1: N, N'-((((1E, 6E)-4-phenyl-3,5-dioxo-1,6-diene-1,7-diyl) bis(4,1-phenyl)) diacetylamino B2: N, N'-((((1E, 6E)-4-phenyl-3,5-dioxo-1,6-diene-1,7-diyl) bis(3,1-phenyl)) dimethyl sulfonamide B3: N, N'-((((1E, 6E)-4-phenyl-3,5-dioxo-1,6-diene-1,7-diyl) bis(4,1-phenyl)) dimethyl sulfonamide 。 3. The method for preparing curcumin derivatives according to claim 1, characterized in that, The preparation method of the curcumin derivative comprises the following steps: (1) Preparation of acetylacetone derivative: acetylacetone, bromide and base are added to a solvent, and the reaction is carried out under heating and stirring in the dark; after the reaction is completed, the solvent is removed by rotary evaporation, and the acetylacetone derivative is separated and purified by vacuum distillation; (2) Preparation of curcumin derivative: the acetylacetone derivative prepared in step (1), boric acid, tributyl borate, n-butylamine and benzaldehyde with different substituents are added to a solvent, and the reaction is carried out under heating and stirring in the dark; after the reaction is completed, 20% acetic acid aqueous solution is added for stirring, the filter residue is collected, and the curcumin derivative is obtained by recrystallization.

4. The method for preparing curcumin derivatives according to claim 3, characterized in that, In step (1), the bromide is bromomethylcyclobutane and bromobenzene.

5. The method for preparing curcumin derivatives according to claim 3, characterized in that, In step (1), the molar ratio of acetylacetone, bromide and base is 1:1-1.2:2-3; the solvent is N,N-dimethylformamide and isopropanol.

6. The method for preparing curcumin derivatives according to claim 3, characterized in that, In step (1), the temperature of heating and stirring reaction is 25-60°C; the time of heating and stirring reaction is 8-12 hours.

7. The method for preparing curcumin derivatives according to claim 3, characterized in that, In step (2), the benzaldehyde with different substituents is p-acetylamino benzaldehyde, 3-methyl sulfonamide benzaldehyde, p-methyl sulfonamide benzaldehyde, 3-fluorobenzaldehyde, 4-fluorobenzaldehyde and 3,4-difluorobenzaldehyde.

8. The method for preparing curcumin derivatives according to claim 3, characterized in that, In step (2), the molar ratio of acetylacetone derivative, benzaldehyde with different substituents, boric acid, tributyl borate and n-butylamine is 1:2-2.5:0.5-1:2-2.5:1-1.5; the solvent is N,N-dimethylformamide.

9. The method for preparing curcumin derivatives according to claim 3, characterized in that, In step (2), the temperature of heating and stirring reaction is 25-80 DEG C, and the time of heating and stirring reaction is 2-5 hours.

10. Use of curcumin derivative according to claim 1, characterized in that, The curcumin derivative is used for preparing an antitumor medicament.

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