Pterostilbene 10-methylamine urea derivatives and preparation method and application thereof

Abstract

The invention discloses a pterostilbene 10-methylamine urea derivative and a preparation method and application thereof, and belongs to the technical field of pharmaceutical chemical synthesis. The invention comprises the following steps: dissolving carbonyl imidazole (CDI) in dichloromethane to obtain solution A, dissolving phenylamine / fatty amine in dichloromethane to obtain solution B, dropping solution B into solution A, stirring at room temperature for 3 hours, adding water for washing after the stirring reaction, drying the organic phase, and concentrating to obtain intermediates b1 to b3. Then, the intermediates b1 to b3 and the chloride salts c1 to c5 of the pterostilbene 10-methylamine derivative are dissolved in dichloromethane, triethylamine is added for catalytic reaction, and the reaction is heated to reflux at 40°C for 6 hours. After the reaction is completed, the pterostilbene 10-methylamine urea derivative is obtained by chromatographic separation, which has good anti-inflammatory effect and is non-toxic, and is expected to become a new anti-inflammatory drug, and the preparation method of the invention is simple and easy to implement.

Description

Technical Field

[0001] The invention belongs to the technical field of pharmaceutical chemical synthesis, and in particular relates to pterostilbene 10-methylamine urea derivatives and preparation methods and applications thereof. Background Art

[0002] Inflammation is a common immune defense reaction. When the body is stimulated externally or internally, the body's inflammatory response will be immediately initiated. Normal inflammation is beneficial to improving the body's immunity. However, excessive inflammatory response can lead to chronic or systemic inflammation, causing a variety of inflammation-related diseases, such as arthritis, gastroenteritis, and prostatitis. Although various steroid and non-steroidal drugs have been approved for the treatment of inflammation-related diseases, their side effects, drug resistance, and the complex microenvironment of the inflammatory site make these diseases prone to recurrence and difficult to heal. Therefore, the discovery and study of bioactive compounds and their anti-inflammatory mechanisms remain crucial.

[0003] Pterostilbene, chemical name 3,5-dimethoxy-4'-hydroxy trans-stilbene, structural formula is It was first isolated and identified from Pterocarpus santalinus in 1972. It is an active ingredient of the pouch-shaped female bract of Pterocarpus santalinus. It was subsequently found in Guangxi blood clovers, blue strawberries, grapes and propolis. Studies have shown that Pterocarpus santalinus has antioxidant, anti-aging, cell proliferation inhibition, anti-leukemia, anti-cancer, blood lipid and blood sugar lowering and antifungal activities. These effects of Pterocarpus santalinus show its important research value and good application prospects in the fields of medicine, health food and cosmetics. However, the natural content of Pterocarpus santalinus and its derivatives is low, which is not conducive to its further research and application. Due to the low content of Pterocarpus santalinus in natural plants, high extraction cost and limited production capacity, it is very important to choose a suitable method to chemically synthesize Pterocarpus santalinus. The problems faced by the existing chemical synthesis of Pterocarpus santalinus mainly include the following two aspects: First, how to ensure the single trans configuration of the product; Second, how to improve the overall yield. If the reaction steps are cumbersome, the overall yield of the reaction will inevitably be reduced, and its actual production application value will be reduced. Summary of the invention

[0004] In order to solve the above technical problems, the present invention provides pterostilbene 10-methylamine urea derivatives and preparation methods and applications thereof.

[0005] To achieve the above object, the present invention provides the following technical solutions:

[0006] One of the technical solutions of the present invention:

[0007] A pterostilbene 10-methylamine urea derivative, the general structural formula of which is as follows:

[0008]

[0009] Among them, the substituent R 1 , R 2 are independently selected from benzyl, p-fluorobenzyl, p-methoxybenzyl, phenethyl, p-fluorophenethyl, 3,4-dimethoxyphenethyl, CH 3 (CH 2 ) 3 - and CH 3 O(CH 2 ) 3 -One of them.

[0010] Preferably, the pterostilbene 10-methylamine urea derivative has the following structural formula:

[0011]

[0012] The second technical solution of the present invention:

[0013] The present invention also provides a method for preparing the pterostilbene 10-methylamine urea derivative, comprising the following steps:

[0014] Dissolve carbonyl imidazole (CDI) in dichloromethane to obtain solution A, dissolve phenylamine or fatty amine in dichloromethane to obtain solution B, add solution B dropwise into solution A, stir at room temperature for 3 hours, add water for washing after the stirring reaction, dry the organic phase, and concentrate to obtain intermediates b1 to b3;

[0015] Any one of the intermediates b1 to b3 and any one of the pterostilbene 10-methylamino derivative chloride salts c1 to c5 are dissolved in dichloromethane, triethylamine is added to catalyze the reaction, and the reaction is heated under reflux at 40° C. for 6 hours. After the reaction is completed, the pterostilbene 10-methylamine urea derivative is separated by silica gel column chromatography to obtain the pterostilbene 10-methylamino urea derivative.

[0016] Preferably, the general structural formula of the chloride salts of pterostilbene 10-methylamino derivatives C1 to C5 is:

[0017] Where R 1 for

[0018] Preferably, the preparation method of the chloride salts C1 to C5 of the pterostilbene 10-methylamino derivatives is:

[0019] Step 1: Add 10 mmol of pterostilbene, 12.5 mmol of bromide (n-butyl bromide, 4-(2-bromoethyl)-1,2-dimethoxybenzene or 1-bromo-3-methoxypropane) and 20 mmol of sodium hydroxide to 50 ml of acetone solution, heat under reflux at 56°C with stirring for 6 hours. After the reaction is completed, add water and ethyl acetate for extraction, evaporate the solution to obtain product I.

[0020] Step 2: Under ice bath conditions, 5 mmol of product I was dissolved in 20 mL of DMF solvent, and 7.5 ml of phosphorus oxychloride was added. After the reaction stabilized, it was stirred at room temperature for 3 h. After the reaction was completed, water and ethyl acetate were added for extraction. The solution was evaporated and separated by silica gel chromatography to obtain product II.

[0021] Step 3: Dissolve 1 mmol of product II, 0.95 mmol (benzylamine, p-fluorobenzylamine, p-methoxybenzylamine, n-butylamine or 3-methoxypropylamine) and 1.5 mmol of sodium triacetoxyborohydride in 10 mL of dichloromethane solution, heat under reflux and stir for 6 h. After the reaction is completed, add water for extraction, evaporate to dryness, add 4 mL of ethyl acetate and 200 μL of concentrated hydrochloric acid, stir and slurry at room temperature for 1 h, filter, evaporate the solid to obtain the product (c1-c5).

[0022] Preferably, the phenyl-containing amine is one of benzylamine, p-fluorobenzylamine, p-methoxybenzylamine, phenethylamine and 3,4-dimethoxyphenethylamine;

[0023] The fatty amine is CH 3 (CH 2 ) 3 NH 3 and CH 3 O(CH 2 ) 3 NH 3 One of;

[0024] Preferably, the molar ratio of the carbonyl imidazole (CDI) to the phenylamine or fatty amine is 1.05:1.

[0025] Preferably, the molar volume ratio of the intermediate b1 to intermediate b3, pterostilbene 10-methylamino derivative chloride salts c1 to c5 and triethylamine is 2 mmol:2 mmol:3 mL.

[0026] The third technical solution of the present invention:

[0027] The present invention also provides the use of the pterostilbene 10-methylamine urea derivatives in the preparation of anti-inflammatory drugs.

[0028] The fourth technical solution of the present invention:

[0029] The present invention also provides the use of the pterostilbene 10-methylamine urea derivatives in the preparation of antipyretic and analgesic drugs.

[0030] The fifth technical solution of the present invention:

[0031] The present invention also provides an anti-inflammatory drug, the active ingredient of which is the pterostilbene 10-methylamine urea derivative.

[0032] Compared with the prior art, the present invention has the following advantages and technical effects:

[0033] (1) The present invention provides novel pterostilbene 10-methylamine urea derivatives. The derivatives exhibit significant anti-inflammatory effects at low micromolar concentrations and have no significant toxicity to human normal liver cells L02 and mouse mononuclear macrophage leukemia cells RAW264.7. Among them, Q1 to Q8 have an IC of 1.17 and 1.20, respectively, on LPS-induced nitric oxide release. 50 The values ​​were 26.66±1.07, 33.89±2.78, 30.99±1.3, 23.24±2.35, 29.22±1.52, 27.02±2.63, 19.89±1.78 and 9.96±3.15 μM / L, and the overall anti-inflammatory effect was equivalent to or better than the positive drug indomethacin; this type of product is expected to be developed into a new anti-inflammatory drug.

[0034] (2) The yield of the final product of the present invention is high, and the yields of Q1 to Q8 are 72%, 45%, 60%, 58%, 82%, 77%, 55% and 70%, respectively.

[0035] (3) The product of the present invention has a unique trans configuration and no cis isomer. This conclusion is confirmed by the ortho coupling constants (16 Hz) of the two olefinic hydrogens (H-7 and H-8) on the olefinic bonds of all products: 7.26 (d, J = 16.0 Hz, 1H, H-8), 6.83 (d, J = 16.0 Hz, 1H, H-7).

[0036] (4) The reaction reagents of the present invention are conventional chemical reagents, and the preparation method is simple and easy. There are not many preparation steps: the preparation steps of intermediate b are 2 steps, the preparation steps of intermediate c are 3 steps, and the step of preparing the final product from intermediate b and intermediate c is 1 step. The reaction temperature is from room temperature to a maximum of 56°C, and the reaction conditions are mild, safe, and easy to operate. BRIEF DESCRIPTION OF THE DRAWINGS

[0037] The drawings constituting a part of the present application are used to provide a further understanding of the present application. The illustrative embodiments and descriptions of the present application are used to explain the present application and do not constitute an improper limitation on the present application. In the drawings:

[0038] Figure 1 The toxicity of intermediates (c1-c5) and pterostilbene 10-methylamine urea derivatives (Q1-Q8) to L02 cells;

[0039] Figure 2 The toxicity of pterostilbene 10-methylamine urea derivatives (Q1~Q8) on RAW264.7 cells. DETAILED DESCRIPTION

[0040] Various exemplary embodiments of the present invention will now be described in detail. This detailed description should not be considered as limiting the present invention, but should be understood as a more detailed description of certain aspects, features, and embodiments of the present invention.

[0041] It should be understood that the terms described in the present invention are only for describing special embodiments and are not intended to limit the present invention. In addition, for the numerical range in the present invention, it should be understood that each intermediate value between the upper and lower limits of the scope is also specifically disclosed. Each smaller range between the intermediate value in any stated value or stated range and any other stated value or intermediate value in the described range is also included in the present invention. The upper and lower limits of these smaller ranges can be independently included or excluded in the scope.

[0042] Unless otherwise indicated, all technical and scientific terms used herein have the same meanings as those generally understood by those skilled in the art. Although the present invention describes only preferred methods and materials, any methods and materials similar or equivalent to those described herein may also be used in the implementation or testing of the present invention. All documents mentioned in this specification are incorporated by reference to disclose and describe the methods and / or materials associated with the documents. In the event of a conflict with any incorporated document, the content of this specification shall prevail.

[0043] It will be apparent to those skilled in the art that various modifications and variations may be made to the specific embodiments of the present invention description without departing from the scope or spirit of the present invention. Other embodiments derived from the present invention description will be apparent to those skilled in the art. The present invention description and examples are exemplary only.

[0044] The words “include,” “including,” “have,” “contain,” etc. used in this document are open-ended terms, meaning including but not limited to.

[0045] All raw materials used in the examples of the present invention are commercially available.

[0046] The technical solution of the present invention is further illustrated by the following embodiments.

[0047] The synthetic route of the pterostilbene 10-methylamine urea derivatives (Q1 to Q8) of the present invention is as follows:

[0048]

[0049] The symbol "*" represents the substituent R 1 or R 2 Other chemical structures.

[0050] Preparation method of c1-c5:

[0051] Step 1: Add 10 mmol of pterostilbene, 12.5 mmol of bromide (n-butyl bromide, 4-(2-bromoethyl)-1,2-dimethoxybenzene or 1-bromo-3-methoxypropane) and 20 mmol of sodium hydroxide to 50 ml of acetone solution, heat under reflux at 56°C with stirring for 6 hours. After the reaction is completed, add water and ethyl acetate for extraction, evaporate the solution to obtain product I.

[0052] Step 2: Under ice bath conditions, 5 mmol of product I was dissolved in 20 mL of DMF solvent, and 7.5 ml of phosphorus oxychloride was added. After the reaction stabilized, it was stirred at room temperature for 3 h. After the reaction was completed, water and ethyl acetate were added for extraction. The solution was evaporated and separated by silica gel chromatography to obtain product II.

[0053] Step 3: Dissolve 1 mmol of product II, 0.95 mmol (benzylamine, p-fluorobenzylamine, p-methoxybenzylamine, n-butylamine or 3-methoxypropylamine) and 1.5 mmol of sodium triacetoxyborohydride in 10 mL of dichloromethane solution, heat under reflux and stir for 6 h. After the reaction is completed, add water for extraction, evaporate to dryness, add 4 mL of ethyl acetate and 200 μL of concentrated hydrochloric acid, stir and slurry at room temperature for 1 h, filter, evaporate the solid to obtain the product (c1-c5).

[0054] The specific synthesis method of pterostilbene 10-methylamine urea derivatives (Q1-Q8) is shown in Examples 1-8.

[0055] Example 1

[0056] The preparation method of the pterostilbene 10-methylamine urea derivative numbered Q1 is as follows:

[0057] 5.25 mmol of carbonyl imidazole (CDI) was dissolved in 5 mL of dichloromethane to obtain solution A, and 5 mmol of n-butylamine was dissolved in 5 mL of dichloromethane to obtain solution B. Solution B was added dropwise to solution A and stirred at room temperature for 3 h. After the reaction was completed, water was added for washing, and the organic phase was dried and concentrated to obtain intermediate b1.

[0058] 2 mmol of intermediate b1 and 2 mmol of pterostilbene 10-methylamino derivative chloride salt c4 were dissolved in 10 mL of dichloromethane, and 3 mL of triethylamine was added to catalyze the reaction. The mixture was heated to reflux at 40°C for 6 h. After the reaction was completed, the pterostilbene 10-methylamino urea derivative Q1 (Chinese name: (E)-1,3-dibutyl-1-(2-(4-isobutoxyphenylvinyl)-4,6-dimethoxybenzyl)urea) was obtained by separation on a silica gel column. The solid was white, with a melting point of 75-76°C and a structural formula of:

[0059] Molecular formula: C 30 H 44 N 2 O4 , molecular weight: 496.33; yield: 72%. NMR data: 1 H NMR (500 MHz, CDCl 3 )δ7.42(d,J=8.7Hz,2H,H-10,H-14),7.31(d,J=16.0Hz,1H,H-8),6.85-6.79(m,3H,H-11,H-13,H-7),6.70(d,J=2.4Hz,1H,H-3),6. 32(d,J=2.4Hz,1H,H-4),4.57-4.54(m,3H,-NH-,H-15),3.80(s,3H,H-25),3.75(s,3H,H-26),3.66(d,J=6.6Hz,2H,H-27),3.14(td ,J=7.2,5.4Hz,2H,H-21),2.90(dd,J=8.8,6.8Hz,2H,H-16),2.01(q,J=7.4Hz,1H,H-28),1.38-1.31(m,4H,H-22,H-17),1.21-1.18 (m,2H,H-23),1.13-1.08(m,2H,H-18),0.95(d,J=6.7Hz,6H,H-29,H-30),0.79(t,J=7.3Hz,3H,H-24),0.75(t,J=7.4Hz,3H,H-19). 13 C NMR (126 MHz, CDCl 3 )δ159.86(C-4),159.29(C-2),159.11(C-12),157.90(C-20),140.31(C-6),130.70(C-8),129.92(C-9),12 8.16(C-11,C-13),124.08(C-7),116.63(C-1),114.68(C-11,C-13),101.70(C-3),97.37(C-5),74.47(C-27 ),55.62(C-25),55.38(C-26),45.10(C-15),40.71(C-16),39.50(C-21),32.55(C-28),29.82(C-17),28.28(C-22),20.26(C-18),20.17(C-23),19.29(C-29,C-30),13.89(C-19),13.85(C-24). Mass spectral data: HRMS(ESIˉ)m / z Calcd.for

[0060] ˉˉ

[0061] C 30H 43 N 2 O 4 [MH]495.3223 found 495.3228.

[0062] Example 2

[0063] The preparation method of the pterostilbene 10-methylamine urea derivative numbered Q2 is as follows:

[0064] 5.25 mmol CDI was dissolved in 5 mL dichloromethane to obtain solution A, and 5 mmol n-butylamine was dissolved in 5 mL dichloromethane to obtain solution B. Solution B was added dropwise to solution A and stirred at room temperature for 3 h. After the reaction was completed, water was added for washing, and the organic phase was dried and concentrated to obtain intermediate b1.

[0065] 2 mmol of intermediate b1 and 2 mmol of pterostilbene 10-methylamino derivative chloride salt c5 were dissolved in 10 mL of dichloromethane, and 3 mL of triethylamine was added to catalyze the reaction. The mixture was heated to reflux at 40°C for 6 h. After the reaction was completed, the pterostilbene 10-methylamino urea derivative Q2 (Chinese name: (E)-3-butyl-1-(2-(4-isobutoxyphenylvinyl)-4,6-dimethoxybenzyl)-1-(3-methoxypropyl)urea) was obtained by separation through a silica gel column. The solid was white, with a melting point of 72-73°C and a structural formula of: Molecular formula: C 30 H 44 N 2 O 5 , molecular weight: 512.33, yield: 45%. NMR data: 1 H NMR (500 MHz, CDCl 3)δ7.46(d,J=8.8Hz,2H,H-10,H-14),7.40(d,J=16.1Hz,1H,H-8),6.84-6.79(m,3H,H-11,H-13,H-7),6.72(d,J=2.4Hz,1H,H-3), 6.31(d,J=2.4Hz,1H,H-5),5.26(t,J=5.2Hz,1H,-NH-),4.70(s,2H,H-15),3.79(s,3H,H-25),3.74(s,3H,H-26),3.66(d,J=6.5Hz ,2H,H-27),3.14(d,J=7.0Hz,7H,H-16,H-18,H-19),3.00(t,J=6.6Hz,2H,H-21),2.00(dq,J=13.4,6.7Hz,1H,H-27),1.42(q,J=6 .1Hz,2H,H-17),1.35-1.30(m,2H,H-22),1.23-1.19(m,2H,H-23),0.95(d,J=6.7Hz,6H,H-29,H-30),0.79(t,J=7.3Hz,3H,H-24). 13 C NMR (126 MHz, CDCl 3 )δ158.70(C-4),158.43(C-2),157.95(C-12),157.39(C-20),139.23(C-6),129.13(C-8),129.04(C-9),127. 25(C-10,C-14),123.32(C-7),116.02(C-1),113.59(C-11,C-13),100.31(C-3),96.22(C-5),73.40(C-27),68 .23(C-19),57.32(C-18),54.68(C-25),54.30(C-26),40.69(C-21),39.77(C-15),37.98(C-16),31.42(C-28),27.26(C-17),27.23(C-22),19.15(C-23),18.25(C-29,C-30),12.85(C-24). Mass spectral data: HRMS(ESIˉ)m / zCalcd.for C 30 H 43 N 2 O 5 ˉ[MH]ˉ511.3172found 511.3177.

[0066] Example 3

[0067] The preparation method of the pterostilbene 10-methylamine urea derivative numbered Q3 is as follows:

[0068] 5.25 mmol CDI was dissolved in 5 mL dichloromethane to obtain solution A, and 5 mmol 3-methoxypropylamine was dissolved in 5 mL dichloromethane to obtain solution B. Solution B was added dropwise to solution A and stirred at room temperature for 3 h. After the reaction was completed, water was added for washing, and the organic phase was dried and concentrated to obtain intermediate b2.

[0069] 2 mmol of intermediate b2 and 2 mmol of pterostilbene 10-methylamino derivative chloride salt c1 were dissolved in 10 mL of dichloromethane, and 3 mL of triethylamine was added to catalyze the reaction. The mixture was heated to reflux at 40°C for 6 h. After the reaction was completed, the pterostilbene 10-methylamino urea derivative Q3 (Chinese name: (E)-1-benzyl-1-(2-(4-isobutoxyphenylvinyl)-4,6-dimethoxybenzyl)-3-(3-methoxypropyl) urea) was obtained by separation on a silica gel column. The pterostilbene 10-methylamino urea derivative Q3 was a yellow oily liquid with the structural formula: Molecular formula: C 33 H 42 N 2 O 5 , molecular weight: 546.31, yield: 60%. NMR data: 1 H NMR (500 MHz, CDCl 3 )δ7.31(d,J=8.6Hz,2H,H-10,H-14),7.26(d,J=16.0Hz,1H,H-8),7.18-7.11(m,3H,H-19,H-20,H-21),7.04(dd,J=6.9,1.8Hz,2H,H-18,H-22) ,6.83(d,J=16.0Hz,1H,H-7),6.78(d,J=8.6Hz,2H,H-11,H-13),6.69(d,J=2.4Hz,1H,H-3),6.27(d,J=2.4Hz,1H,H-5),5.04(t,J=5.4Hz,1H,-N H-),4.66(s,2H,H-16),4.21(s,2H,H-15),3.78(s,3H,H-28),3.66(d, J=6.5Hz,2H,H-30),3.63(s,3H,H-29),3.23(q,J=6.2Hz,2H,H-26),3.1 7(t,J=6.0Hz,2H,H-26),3.05(s,3H,H-27),2.01(dp,J=13.3,6.7Hz,1H ,H-31),1.58(p,J=6.2Hz,2H,H-25),0.96(d,J=6.7Hz,6H,H-32,H-33). 13C NMR (126 MHz, CDCl 3 )δ159.99(C-4),159.45(C-2),159.10(C-12),158.54(C-23),140.40(C-6),138.55(C-17),130.85(C-8),129.88(C -9),128.57(C-18,C-22),128.23(C-10,C-14),126.80(C-20),126.67(C-19,C-21),124.12(C-7),116.11(C-1),11 4.63(C-11,C-13),101.67(C-3),97.40(C-5),74.47(C-30),71.25(C-26),58.54(C-27),55.55(C-28),55.39(C-29),48.35(C-15),40.23(C-16),39.06(C-24),29.70(C-25),28.31(C-26),19.32(C-32,C-33). Mass spectral data: HRMS(ESIˉ)m / z Calcd.forC 33 H 41 N 2 O 5 ˉ[MH]ˉ545.3015found 545.3021.

[0070] Example 4

[0071] The preparation method of the pterostilbene 10-methylamine urea derivative numbered Q4 is as follows:

[0072] 5.25 mmol CDI was dissolved in 5 mL dichloromethane to obtain solution A, and 5 mmol 3-methoxypropylamine was dissolved in 5 mL dichloromethane to obtain solution B. Solution B was added dropwise to solution A and stirred at room temperature for 3 h. After the reaction was completed, water was added for washing, and the organic phase was dried and concentrated to obtain intermediate b2.

[0073] 2 mmol of intermediate b2 and 2 mmol of pterostilbene 10-methylamino derivative chloride salt c2 were dissolved in 10 mL of dichloromethane, and 3 mL of triethylamine was added to catalyze the reaction. The mixture was heated to reflux at 40°C for 6 h. After the reaction was completed, the pterostilbene 10-methylamino urea derivative Q4 (Chinese name: (E)-1-(4-fluorobenzyl)-1-(2-(4-isobutoxyphenylvinyl)-4,6-dimethoxybenzyl)-3-(3-methoxypropyl)urea) was obtained by separation on a silica gel column. The product is a white solid with a melting point of 61-62°C and a structural formula: Molecular formula: C 33 H 41 FN 2 O5 , molecular weight: 564.30, yield: 58%. NMR data: 1 HNMR (500MHz, CDCl 3 )δ7.36(d,J=8.5Hz,2H,H-10,H-14),7.26(d,J=16.0Hz,1H,H-8),7.06(dd,J=8.4,5.4Hz,2H,H-18,H-22),6.92-6.88(m,3H,H-7,H- 19,H-21),6.86(d,J=8.6Hz,2H,H-11,H-13),6.75(d,J=2.4Hz,1H,H-3),6.35(d,J=2.3Hz,1H,H-5),5.25(t,J=5.3Hz,1H,-NH-),4. 67(s,2H,H-16),4.26(s,2H,H-15),3.85(s,3H,H-28),3.74(d,J=6.6Hz,2H,H-30),3.72(s,3H,H-29),3.32(dt,J=17.8,6.0Hz,4H, H-24,H-26),3.16(s,3H,H-27),2.09(dp,J=13.3,6.7Hz,1H,H-31),1.69(p,J=6.2Hz,2H,H-25),1.04(d,J=6.7Hz,6H,H-32,H-33). 13 C NMR (126 MHz, CDCl 3 )δ161.77(d,J=244.4Hz,C-20),160.08(C-4),159.35(C-2),159.20(C-12),158.52(C-23),140.35(C-6),1134.32(d,J=3.1Hz ,C-17),131.07(C-8),129.73(C-9),128.35(d,J=8.1Hz,C-18,C-22),128.16(C-10,C-14),123.89(C-7),115.81(C-1),115.23 (d, J = 21.2 Hz, C-19, C-21), 114.66 (C-11, C-13), 101.72 (C-3), 97.44 (C-5), 74.48 (C-30), 71.47 (C-26), 58.59 (C-27), 55.54 (C-28), 55.40 (C-29), 47.67 (C-15), 40.26 (C-16), 39.27 (C-24), 29.68 (C-25), 28.30 (C-26), 19.31 (C-32, C-33). Mass spectral data: HRMS (ESI -)m / z Calcd.for C 33 H 40 FN 2 O 5 - [MH] - 563.2921 found 563.2927.

[0074] Example 5

[0075] The preparation method of the pterostilbene 10-methylamine urea derivative numbered Q5 is as follows:

[0076] 5.25 mmol CDI was dissolved in 5 mL dichloromethane to obtain solution A, and 5 mmol 3-methoxypropylamine was dissolved in 5 mL dichloromethane to obtain solution B. Solution B was added dropwise to solution A and stirred at room temperature for 3 h. After the reaction was completed, water was added for washing, and the organic phase was dried and concentrated to obtain intermediate b2.

[0077] 2 mmol of intermediate b2 and 2 mmol of pterostilbene 10-methylamino derivative chloride salt c3 were dissolved in 10 mL of dichloromethane, and 3 mL of triethylamine was added to catalyze the reaction. The mixture was heated to reflux at 40°C for 6 h. After the reaction was completed, the pterostilbene 10-methylamino urea derivative Q1 (Chinese name: (E)-1-(2-(4-isobutoxyphenylvinyl)-4,6-dimethoxybenzyl)-1-(4-methoxybenzyl)-3-(3-methoxypropyl)urea) was obtained by separation on a silica gel column. The solid was white, with a melting point of 79-80°C and a structural formula of: Molecular formula: C 34 H 44 N 2 O 6 , molecular weight: 576.32, yield: 82%. NMR data: 1 H NMR (500 MHz, CDCl 3) δ 7.32 (d, J = 8.2 Hz, 2H, H-10, H-14), 7.25 (d, J = 16.0 Hz, 1H, H-8), 6.95 (d, J = 8.2 Hz, 2H, H-11, H-13), 6.83 (d, J = 16.0 Hz, 1H, H-7), 6.78 (d, J = 8.9 Hz, 2H, H-18, H-22), 6.72 - 6.67 (m, 3H, H-19, H-21, H-3), 6.28 (d, J = 2.2 Hz, 1H, H-5), 5.02 (t, J = 5.4 Hz, 1H, -NH-), 4.64 (s, 2H, H-16), 4.14 (s, 2H, H-15), 3.78 (s, 3H, H-29), 3.68 (s, 3H, H-30), 3.67 - 3.65 (m, 5H, H-28, H-31), 3.22 (q, J = 6.1 Hz, 2H, H-24), 3.17 (t, J = 6.0 Hz, 2H, H-26), 3.08 (s, 3H, H-27), 2.01 (dt, J = 13.3, 6.6 Hz, 1H, H-32), 1.58 (p, J = 6.3 Hz, 2H, H-25), 0.96 (d, J = 6.7 Hz, 6H, H-33, H-34). 13 C NMR (126 MHz, CDCl 3 ) δ 159.97 (C-4), 159.44 (C-2), 159.10 (C-20), 158.57 (C-12), 158.52 (C-23), 140.39 (C-6), 130.79 (C-8), 130.52 (C-17), 129.90 (C-9), 128.22 (C-19, C-21), 127.97 (C-10, C-14), 124.20 (C-7), 116.21 (C-1), 114.62 (C-18, C-22), 113.93 (C-11, C-13), 101.68 (C-3), 97.41 (C-5), 74.47 (C-31), 71.21 (C-26), 58.56 (C-27), 55.59 (C-28), 55.38 (C-29), 55.24 (C-30), 47.81 (C-15), 40.17 (C-16), 38.97 (C-34), 29.75 (C-25), 28.29 (C-26), 19.31 (C-33, C-34). HRMS data: HRMS (ESIˉ) m / z Calcd. for C 34 H 43 N 2 O 6 ˉ[M - H]ˉ 575.3121 found 575.3127.

[0078] Example 6

[0079] The preparation method of the pterostilbene 10-methylamine urea derivative numbered Q6 is as follows:

[0080] 5.25 mmol CDI was dissolved in 5 mL dichloromethane to obtain solution A, and 5 mmol 3-methoxypropylamine was dissolved in 5 mL dichloromethane to obtain solution B. Solution B was added dropwise to solution A and stirred at room temperature for 3 h. After the reaction was completed, water was added for washing, and the organic phase was dried and concentrated to obtain intermediate b2.

[0081] 2 mmol of intermediate b2 and 2 mmol of pterostilbene 10-methylamino derivative chloride c4 were dissolved in 10 mL of dichloromethane, and 3 mL of triethylamine was added to catalyze the reaction. The mixture was heated to reflux at 40°C for 6 h. After the reaction was completed, the pterostilbene 10-methylamino urea derivative Q1 (Chinese name: (E)-1-butyl-1-(2-(4-isobutoxyphenylvinyl)-4,6-dimethoxybenzyl)-3-(3-methoxypropyl)urea) was obtained by separation on a silica gel column. The pterostilbene 10-methylamino urea derivative Q1 is a yellow oily liquid with the structural formula:

[0082] Molecular formula: C 30 H 44 N 2 O 5 , molecular weight: 512.33, yield: 77%. NMR data: 1 H NMR (500 MHz, CDCl 3)δ7.50 (d, J = 8.4 Hz, 2H, H-10, H-14), 7.42 (d, J = 16.0 Hz, 1H, H-8), 6.92 - 6.86 (m, 3H, H-11, H-13, H-7), 6.78 (d, J = 2.3 Hz, 1H, H-3), 6.39 (d, J = 2.3 Hz, 1H, H-5), 5.13 (t, J = 5.2 Hz, 1H, -NH-), 4.68 (s, 2H, H-15), 3.86 (s, 3H, H-25), 3.81 (s, 3H, H-26), 3.73 (d, J = 6.6 Hz, 2H, H-27), 3.37 (t, J = 5.8 Hz, 2H, H-16), 3.33 (q, J = 5.8 Hz, 2H, H-23), 3.24 (s, 3H, H-24), 2.94 - 2.88 (m, 2H, H-21), 2.09 (dq, J = 13.3, 6.7 Hz, 1H, H-28), 1.71 (p, J = 6.1 Hz, 2H, H-22), 1.41 (dd, J = 10.1, 5.5 Hz, 2H, H-17), 1.16 (q, J = 7.4 Hz, 2H, H-18), 1.02 (d, J = 6.6 Hz, 6H, H-29, H-30), 0.81 (t, J = 7.4 Hz, 3H, H-19). 13 C NMR (126 MHz, CDCl 3 )δ159.81 (C-4), 159.43 (C-2), 159.04 (C-12), 157.80 (C-20), 140.29 (C-6), 130.38 (C-8), 130.07 (C-9), 128.22 (C-10, C-14), 124.24 (C-7), 116.75 (C-1), 114.66 (C-11, C-13), 101.49 (C-3), 97.27 (C-5), 74.46 (C-

[0083] 27), 72.04 (C-23), 58.66 (C-24), 55.62 (C-25), 55.37 (C-26), 44.78 (C-15), 39.53 (C-16), 39.05 (C-21), 29.69 (C-28), 29.58 (C-22), 28.29 (C-17), 20.28 (C-18), 19.30 (C-29, C-30), 13.83 (C-19). HRMS data: HRMS (ESIˉ) m / z Calcd. for C 30 H 43 N 2 O 5 ˉ[M - H]ˉ511.3172 found 511.3177.

[0084] Example 7

[0085] The preparation method of the pterostilbene 10-methylamine urea derivative numbered Q7 is as follows:

[0086] 5.25 mmol CDI was dissolved in 5 mL dichloromethane to obtain solution A, and 5 mmol 3-methoxypropylamine was dissolved in 5 mL dichloromethane to obtain solution B. Solution B was added dropwise to solution A and stirred at room temperature for 3 h. After the reaction was completed, water was added for washing, and the organic phase was dried and concentrated to obtain intermediate b2.

[0087] 2 mmol of intermediate b2 and 2 mmol of pterostilbene 10-methylamino derivative chloride salt c5 were dissolved in 10 mL of dichloromethane, and 3 mL of triethylamine was added to catalyze the reaction. The mixture was heated to reflux at 40°C for 6 h. After the reaction was completed, the pterostilbene 10-methylamino urea derivative Q7 (Chinese name: (E)-1-(2-(4-isobutoxyphenylvinyl)-4,6-dimethoxybenzyl)-1,3-bis(3-methoxypropyl)urea) was obtained by separation on a silica gel column. The pterostilbene 10-methylamino urea derivative Q7 is a yellow oily liquid with the structural formula:

[0088] Molecular formula: C 30 H 44 N 2 O 6 , molecular weight: 528.32, yield: 55%. NMR data: 1 H NMR (500 MHz, CDCl 3)δ 7.45 (d, J = 8.4 Hz, 2H, H-10, H-14), 7.40 (d, J = 16.0 Hz, 1H, H-8), 6.84 - 6.79 (m, 3H, H-11, H-13, H-7), 6.72 (d, J = 2.4 Hz, 1H, H-3), 6.31 (d, J = 2.3 Hz, 1H, H-5), 5.44 (t, J = 5.3 Hz, 1H, -NH-), 4.70 (s, 2H, H-15), 3.79 (s, 3H, H-25), 3.74 (s, 3H, H-26), 3.66 (d, J = 6.6 Hz, 2H, H-27), 3.28 (t, J = 6.1 Hz, 2H, H-16), 3.25 - 3.21 (m, 2H, H-21), 3.18 (s, 3H, H-24), 3.15 (s, 5H, H-19, H-23), 2.98 (t, J = 6.8 Hz, 2H, H-18), 2.01 (dt, J = 13.3, 6.7 Hz, 1H, H-28), 1.62 (q, J = 6.4 Hz, 2H, H-22), 1.44 (q, J = 6.3 Hz, 2H, H-17), 0.96 (d, J = 6.7 Hz, 6H, H-

[0089] 29, H-30). 13 C NMR (126 MHz, CDCl 3 )δ 159.77 (C-4), 159.51 (C-2), 159.00 (C-12), 158.28 (C-

[0090] 20), 140.27 (C-6), 130.16 (C-8), 130.11 (C-9), 128.29 (C-10, C-14), 124.38 (C-7), 116.97 (C-1), 114.64 (C-11, C-13), 101.35 (C-3), 97.26 (C-5), 74.45 (C-27), 71.15 (C-23), 69.47 (C-18), 58.59 (C-24), 58.38 (C-19), 55.72 (C-25), 55.35 (C-26), 41.70 (C-15), 38.92 (C-16), 38.71 (C-21), 30.03 (C-28), 28.30 (C-22), 28.18 (C-17), 19.31 (C-29, C-30). High Resolution Mass Spectrometry Data: HRMS (ESIˉ) m / z Calcd. for

[0091] ˉˉ

[0092] C 30 H 43 N 2O 6 [MH]527.3121 found 527.3127.

[0093] Example 8

[0094] The preparation method of the pterostilbene 10-methylamine urea derivative numbered Q8 is as follows:

[0095] 5.25 mmol CDI was dissolved in 5 mL dichloromethane to obtain solution A, and 5 mmol 3,4-dimethoxyphenylethylamine was dissolved in 5 mL dichloromethane to obtain solution B. Solution B was added dropwise to solution A and stirred at room temperature for 3 h. After the reaction was completed, water was added for washing, and the organic phase was dried and concentrated to obtain intermediate b3.

[0096] 2 mmol of intermediate b3 and 2 mmol of pterostilbene 10-methylamino derivative chloride salt c5 were dissolved in 10 mL of dichloromethane, and 3 mL of triethylamine was added to catalyze the reaction. The mixture was heated to reflux at 40°C for 6 h. After the reaction was completed, the pterostilbene 10-methylamino urea derivative Q8 (Chinese name: (E)-3-(3,4-dimethoxyphenylethyl)-1-(2-(4-isobutoxyphenylvinyl)-4,6-dimethoxybenzyl)-1-(3-methoxypropyl)urea) was obtained by separation on a silica gel column. The solid was white, with a melting point of 87-88°C and a structural formula of: Molecular formula: C 36 H 48 N 2 O 7 , molecular weight: 620.35, yield: 70%. NMR data: 1 H NMR (500 MHz, CDCl 3)δ 7.49 (d, J = 8.7 Hz, 2H, H-10, H-14), 7.44 (d, J = 16.0 Hz, 1H, H-8), 6.83 (d, J = 16.0 Hz, 1H, H-7), 6.79 (d, J = 8.7 Hz, 2H, H-11, H-13), 6.72 (d, J = 2.4 Hz, 1H, H-3), 6.67 (d, J = 8.6 Hz, 1H, H-25), 6.61 - 6.59 (m, 2H, H-24, H-3), 6.30 (d, J = 2.3 Hz, 1H, H-5), 5.31 (t, J = 5.6 Hz, 1H, -NH-), 4.70 (s, 2H, H-15), 3.79 (s, 3H, H-31), 3.75 (s, 3H, H-32), 3.72 (s, 3H, H-29), 3.70 (s, 3H, H-30), 3.59 (d, J = 6.5 Hz, 2H, H-33), 3.37 (q, J = 6.7 Hz, 2H, H-21), 3.10 (t, J = 5.7 Hz, 2H, H-18), 3.05 (s, 3H, H-19), 2.95 (t, J = 6.7 Hz, 2H, H-22), 2.61 (t, J = 7.2 Hz, 2H, H-16), 1.97 (dt, J = 13.3, 6.7 Hz, 1H, H-34), 1.39 (p, J = 6.3 Hz, 2H, H-17), 0.92 (d, J = 6.7 Hz, 6H, H-35, H-36). 13 C NMR (126 MHz, CDCl 3 )δ 159.81 (C-4), 159.50 (C-2), 159.05 (C-12), 158.23 (C-20), 148.76 (C-26), 147.29 (C-27), 140.20 (C-6), 132.51 (C-8), 130.20 (C-23), 130.05 (C-9), 128.30 (C-10, C-14), 124.30 (C-7), 120.57 (C-25), 116.88 (C-1), 114.67 (C-11, C-13), 112.06 (C-24), 111.16 (C-28), 101.35 (C-3), 97.26 (C-5), 74.41 (C-33), 69.27 (C-18), 58.26 (C-19), 55.89 (C-31), 55.75 (C-29), 55.68 (C-30), 55.36 (C-32), 42.71 (C-15), 41.67 (C-16), 38.95 (C-21), 36.25 (C-22), 28.26 (C-34), 28.15 (C-17), 19.27 (C-35, C-36). High Resolution Mass Spectrometry data: HRMS

[0097] ˉ-ˉ

[0098] (ESI) m / z Calcd.for C 36 H 47 N 2 O 7 [MH]619.3383 found 619.3389.

[0099] The catalog numbers, structural formulas, names and molecular formulas of pterostilbene 10-methylamine urea derivatives (Q1 to Q8) are shown in Table 1.

[0100] Table 1 Chemical molecular structures of pterostilbene 10-methylamine urea derivatives

[0101]

[0102]

[0103]

[0104] In vitro anti-inflammatory activity test of pterostilbene 10-methylamine urea derivatives Q1-Q8 prepared in Examples 1-8:

[0105] 1. Cell culture

[0106] Cells: Mouse mononuclear macrophage leukemia cells (RAW264.7) were obtained from the Natural Drug Screening Center of the Kunming Institute of Botany, Chinese Academy of Sciences and the Shanghai Cell Bank. The cells were maintained in DMEM medium containing 10% fetal bovine serum, 100 μg / mL penicillin, and 100 μg / mL streptomycin and incubated at 310K with 5% CO 2 Culture in a humidified incubator and subculture every 1 day.

[0107] 2. Anti-inflammatory activity test method

[0108] Pterostilbene 10-methylamine urea derivatives (Q1-Q8) and indomethacin were dissolved in DMSO at a concentration of 40 μM / L as stock solutions. The stock solutions were diluted with culture medium to obtain working solutions of different concentrations. Each cell line was inoculated in a 96-well plate with 1×10 cells per well. 6 cells and cultured at 37°C (5% CO 2) after 48 h, the cells were treated with fresh medium containing 5 μg / mL lipopolysaccharide (LPS) and incubated for 3 h. The cells were then treated with fresh medium containing the required concentrations of pterostilbene 10-methylamine urea derivatives (Q1~Q8) and indomethacin (positive drug) and incubated for another 24 h under the same conditions. After 24 h of drug treatment, 50 μL / well of supernatant was aspirated into a new 96-well plate. According to the instructions of the NO kit, 50 μL of component I was first added to each well, and then 50 μL of component II was added to each well. The optical density was measured by absorbance at 540 nm on a microplate spectrophotometer. The IC was obtained by analyzing the relationship between the inhibition percentage and log [concentration, μM] using GraphPad Prism 5. 50 All measurements were repeated 3 times, and the IC 50 Values ​​are mean ± SD.

[0109] 3. Experimental results:

[0110] The inhibitory activities of pterostilbene 10-methylamine urea derivatives (Q1-Q8) and indomethacin on LPS-induced NO release are shown in Table 2.

[0111] The toxic effects of pterostilbene 10-methylamine urea derivatives (Q1-Q8) on human normal stem cells L02 and mouse mononuclear macrophage leukemia cells RAW 264.7 are shown in Figure 1 , Figure 2 The vertical axis represents cell activity. It can be seen that at a concentration of 20 μM / L, the positive control cisplatin and intermediates (c1-c5) have very obvious toxic effects, while pterostilbene 10-methylamine urea derivatives (Q1-Q8) have no obvious toxic effects.

[0112] Table 2 Inhibitory activity of pterostilbene 10-methylamine urea derivatives on LPS-induced NO release (IC 50 ,μM)

[0113] Compound <![CDATA[IC 50 (μM / L)]]> Q1 26.66±1.07 Q2 33.89±2.78 Q3 30.99±1.39 Q4 23.24±2.35 Q5 29.22±1.52 Q6 27.02±2.63 Q7 19.89±1.78 Q8 9.96±3.15 Indomethacin 24.07±1.74

[0114] Note: Indomethacin is an anti-inflammatory positive control.

[0115] The above are only preferred specific implementations of the present application, but the protection scope of the present application is not limited thereto. Any changes or substitutions that can be easily thought of by a person skilled in the art within the technical scope disclosed in the present application should be included in the protection scope of the present application. Therefore, the protection scope of the present application should be based on the protection scope of the claims.

Claims

1. A pterostilbene 10-methylamine urea derivative, characterized in that: The general structure is as follows: Wherein, the substituents R1 and R2 are independently selected from one of benzyl, p-fluorobenzyl, p-methoxybenzyl, phenethyl, p-fluorophenethyl, 3,4-dimethoxyphenethyl, CH3(CH2)3- and CH3O(CH2)3-.

2. The pterostilbene 10-methylamine urea derivative according to claim 1, characterized in that: The structural formula is as follows:

3. A method for preparing the pterostilbene 10-methylamine urea derivatives according to any one of claims 1 to 2, characterized in that: The following steps are involved: Dissolve carbonyl imidazole in dichloromethane to obtain solution A, dissolve phenylamine or fatty amine in dichloromethane to obtain solution B, add solution B dropwise into solution A, stir at room temperature for 3 hours, add water for washing after the stirring reaction, dry the organic phase, and concentrate to obtain intermediates b1 to b3; Dissolve any one of the intermediates b1 to b3 and any one of the chloride salts c1 to c5 of the pterostilbene 10-methylamino derivatives in dichloromethane, add triethylamine to catalyze the reaction, heat under reflux at 40° C. for 6 h, and after the reaction is completed, separate by silica gel column chromatography to obtain the pterostilbene 10-methylamino urea derivative; The structural formulas of the intermediates b1 to b3 are as follows: Where R2 is The phenyl-containing amine is one of benzylamine, p-fluorobenzylamine, p-methoxybenzylamine, phenylethylamine and 3,4-dimethoxyphenylethylamine; the fatty amine is one of CH3(CH2)3NH3 and CH3O(CH2)3NH3; The general structural formula of the pterostilbene 10-methylamino derivative chloride salts C1 to C5 is: Where R1 is 4. The method for preparing the pterostilbene 10-methylamine urea derivatives according to claim 3, characterized in that: The molar ratio of the carbonyl imidazole to the phenylamine or fatty amine is 1.05:

1.

5. The method for preparing the pterostilbene 10-methylamine urea derivatives according to claim 3, characterized in that: The molar volume ratio of the intermediate b1 to intermediate b3, pterostilbene 10-methylamino derivative chloride salts c1 to c5 and triethylamine is 2 mmol: 2 mmol: 3 mL.

6. Use of the pterostilbene 10-methylamine urea derivatives according to any one of claims 1 to 2 in the preparation of anti-inflammatory drugs.

7. Use of the pterostilbene 10-methylamine urea derivatives according to any one of claims 1 to 2 in the preparation of antipyretic and analgesic drugs.

8. An anti-inflammatory drug, characterized in that: The active ingredient is the pterostilbene 10-methylamine urea derivative according to any one of claims 1 to 2.

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