A perillyl alcohol phenolic derivative, and a preparation method and application thereof

Abstract

The application discloses a perillyl alcohol phenolic derivative, a preparation method and application thereof. The application provides a perillyl alcohol phenolic derivative with a structure as shown in formula I, a pharmaceutical composition containing the compound with the structure as shown in formula I, and isotopic derivatives, chiral isomers, conformers, different salts, prodrugs, preparations and the like of the compounds. The perillyl alcohol phenolic compound provided by the application can be used in a single drug form in treatment of cancers, and can also be used in combination with other drugs. For example, the perillyl alcohol phenolic compound is combined with a chemotherapy drug or a targeted anti-tumor drug, and has certain therapeutic effect on treatment of lung cancer, breast cancer, brain glioma, liver cancer, gastric cancer, prostate cancer and the like.

Description

Technical Field

[0001] This invention relates to the field of medicinal chemistry, specifically to a perillyl alcohol phenolic derivative, its preparation method, and its application. Background Technology

[0002] Perillyl alcohol (POH) is a monoterpene that is widely found in a variety of plants. It has broad-spectrum, high-efficiency, and low-toxicity anticancer effects, and has made great progress in the treatment of diseases such as glioblastoma, lung cancer, skin cancer, and breast cancer.

[0003] Recent studies have focused on the chemical modification of perillaldehyde and the testing of its bioactivity. Perillaldehyde undergoes esterification with butyric acid, and the resulting ester compounds increased the induction of cell death in human glioma cells T98G by fourfold. M, Maciejczyk A, Trytek M, et al. Biocatalytic synthesis of terpene esters and their biological activity in human glioma cells[J]. Current Pharmaceutical Biotechnology, 2021, 23(6):760-765.). Amine compounds were synthesized by introducing a substituted piperazine group at the allyl position outside the ring of perillol. These compounds exhibited stronger inhibitory effects on the proliferation of A549 and HCT116 cells than perillol alone (Zhang Meihui, Xu Liying, Hui Zi, et al. Synthesis of perillol analogs and their in vitro antitumor cell proliferation activity[J]. Journal of Shenyang Pharmaceutical University, 2014, 31(10):768-771+777.). Perillyl alcohol glycosides were synthesized and their antiproliferative activity against A549 and PC-3 cells was tested in vitro. Several of them showed stronger in vitro cytotoxicity than perillyl alcohol (Nitin S, Jianjun Z, Qing Y, et al. The identification of perillyl alcohol glycosides with improved antiproliferative activity[J]. Journal of Medicinal Chemistry, 2014, 57(17):7478–7484.). Summary of the Invention

[0004] The first object of the present application is to provide a perillyl alcohol phenolic derivative to overcome the deficiencies of the prior art, taking perillyl alcohol as a lead compound, introducing phenol containing different substituents at the exocyclic allyl position to enhance its anticancer activity, a series of perillyl alcohol phenolic derivatives are synthesized, and it is proved by pharmacological tests that they can inhibit the proliferation of various tumor cells, and their main effect is anti-tumor.

[0005] A perillyl alcohol phenolic derivative, or an optical isomer, a pharmaceutically acceptable salt, a prodrug, a deuterium derivative, a hydrate, a solvate thereof, the structural formula of the perillyl alcohol phenolic derivative is as shown in formula (I):

[0006]

[0007] Among them:

[0008] R 1 , R 2 , R 3 , R 4 Each is independently selected from H, F, Cl, Br, I, OH, NH2, CN, COOH, C 6～14 aryl, 5- to 15-membered heteroaryl, -O-C 6～14 aryl, -OCF3, -NCOC 1～6 alkyl, -O-5- to 15-membered heteroaryl, C 1～10 alkyl, C 1～10 alkoxy, C 1～10 alkylthio, C 2～6 alkenyl, C 2～6 alkynyl, -COOC 1～6 alkyl, -CONHC 1～6 alkyl, C 3～8 cycloalkyl or 3- to 9-membered heterocycloalkyl.

[0009] As preferred, the structural formula of the perillyl alcohol phenolic derivative is any one of the following formulae 1-15:

[0010]

[0011] The second object of the present application is to provide a preparation method of the above-mentioned perillyl alcohol phenolic derivative, the method comprising the following steps:

[0012] Step (1), dissolving perillyl alcohol in pyridine (py) and reacting with acetic anhydride (Ac2O) to obtain intermediate B;

[0013] Step (2), dissolving intermediate B in dichloromethane (CH2Cl2), adding acetic acid (AcOH), and then slowly adding an aqueous sodium hypochlorite solution to obtain intermediate C;

[0014] Step (3), reacting intermediate C with monomer E, sodium hydride (NaH) in N, N-dimethylformamide (DMF) to obtain intermediate D;

[0015] Step (4), dissolving intermediate D in DMF, and reacting in a microwave synthesis instrument to obtain the compound shown in formula (I);

[0016] The synthetic route is as follows:

[0017]

[0018] Wherein:

[0019] R 1 , R 2 , R 3 , R 4 Each independently selected from H, F, Cl, Br, I, OH, NH2, CN, COOH, C 6～14 aryl, 5- to 15-membered heteroaryl, -O-C 6～14 aryl, -OCF3, -NCOC 1～6 alkyl, -O-5- to 15-membered heteroaryl, C 1～10 alkyl, C 1～10 alkoxy, C 1～10 alkylthio, C 2～6 alkenyl, C 2～6 alkynyl, -COOC 1～6 alkyl, -CONHC 1～6 alkyl, C 3～8 cycloalkyl or 3- to 9-membered heterocycloalkyl.

[0020] The solvent used in the preparation process of the perillyl alcohol phenolic derivative and the solvent used in the preparation process of the perillyl alcohol phenolic derivative are common reaction solvents and do not have special requirements.

[0021] A third object of the present application is to provide the use of the above-mentioned perillyl alcohol phenolic derivative, or an optical isomer, a pharmaceutically acceptable salt, a prodrug, a deuterated derivative, a hydrate, or a solvate thereof in the preparation of a medicament for treating tumors.

[0022] Preferably, the tumor includes lung cancer, breast cancer, brain glioma, liver cancer, gastric cancer, prostate cancer, cervical cancer, fibrosarcoma, colon cancer, melanoma, lymphoma, chronic myelogenous leukemia or myeloblast leukemia.

[0023] A fourth object of the present application is to provide a pharmaceutical composition containing a safe and effective amount of the above-mentioned perillyl alcohol phenolic derivative.

[0024] Preferably, the pharmaceutical composition further comprises a pharmaceutically acceptable excipient.

[0025] The present application has at least the following beneficial effects:

[0026] The present application introduces a phenol into the molecule of linalool, and synthesizes linalool phenol derivatives by etherification of the corresponding phenol after chlorination of the exocyclic allyl group of linalool as raw material, and Claisen rearrangement. These derivatives have stronger physiological activity and improved anticancer ability, and the preparation method is simple and feasible, easy to operate. The application of these derivatives and their pharmaceutical salts or compositions in the preparation of anticancer drugs has good application prospect, such as being used for treating lung cancer, breast cancer, brain glioma, liver cancer, gastric cancer, prostate cancer, cervical cancer, fibrosarcoma, colon cancer, melanoma, lymphoma, chronic myelogenous leukemia or myeloblast leukemia, etc. DETAILED DESCRIPTION

[0027] The present application will be further described below in combination with specific examples, but the protection scope of the present application is not limited to this. Those skilled in the art should understand that according to the teaching of the prior art, the modification or replacement of the corresponding technical features still belongs to the scope of the present application.

[0028] Compounds B and C can be prepared by the preparation method disclosed in the patent document with the patent number ZL201410119760.4, which will not be specifically described in the examples of the present patent.

[0029] Example 1: general method for synthesizing compound D

[0030]

[0031] NaH (120 mg, 3 mmol, content 60%) was placed in a dry 50 mL reaction bottle under ice bath, and DMF (3 mL), phenol (E, 1.1 mmol), and compound C (228.72 mg, 1 mmol) were sequentially added. The reaction was stirred at room temperature for 2-5 h, and after the reaction was completed by TLC detection, a proper amount of water was added to quench the reaction. The reaction liquid was extracted with ethyl acetate (15 mL x 3), and the obtained organic phase was sequentially washed with water (20 mL x 3) and saturated brine (15 mL x 2), and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure, and then separated and purified by silica gel column chromatography (developing agent: petroleum ether: ethyl acetate = 12: (1-6): 1) to obtain compounds D1-D15.

[0032] Example 2-16: general method for synthesizing compound I

[0033]

[0034] Compound D (0.5-0.8 mmol) was added to a 2-5 mL microwave reaction tube, DMF (2.5 mL) was added, and the reaction was carried out at 250 °C for 40 min in a microwave synthesis instrument. After the reaction was completed, water (10 mL) was added, and ethyl acetate (15 mL x 3) was extracted. The obtained organic phase was washed with water (20 mL x 3), saturated brine (15 mL x 2) in turn, and dried over anhydrous sodium sulfate. Filtration. The filtrate was concentrated under reduced pressure, and then separated and purified by silica gel column chromatography (developing agent: petroleum ether: ethyl acetate = 7: (1-4): 1) to obtain compound I: 1-15.

[0035] According to this synthesis method, the following compounds were obtained:

[0036]

[0037] Compound 1: yellow solid. Yield 40.0%. Melting point 37.4-37.7 °C. LC-MS: [M-H] - m / z 243.2. 1 HNMR (500 MHz, CDCl3) δ 7.12 (td, J = 7.8, 1.5 Hz, 1H), 7.11-7.06 (m, 1H), 6.90-6.85 (m, 1H), 6.81 (d, J = 8.0 Hz, 1H), 5.70-5.65 (m, 1H), 4.95 (s, 1H), 4.90-4.76 (m, 1H), 4.00 (d, J = 13.4 Hz, 2H), 3.44 (s, 2H), 2.26-2.20 (m, 1H), 2.18-2.13 (m, 1H), 2.11-2.07 (m, 1H), 2.02-1.96 (m, 1H), 1.91 (ddt, J = 9.8, 4.7, 2.2 Hz, 1H), 1.58-1.50 (m, 1H), 1.26 (s, 1H). 13 C NMR (126 MHz, CDCl3) δ 154.74, 152.83, 137.18, 131.13, 127.96, 125.30, 122.54, 120.77, 116.04, 110.16, 67.24, 39.05, 37.07, 31.01, 27.83, 26.16.

[0038]

[0039] Compound 2: light yellow oil. Yield 50.3%. LC-MS: [M-H] - m / z 257.2. 1HNMR (500 MHz, CDC13) δ 6.92 (dd, J = 8.1, 1.8 Hz, 1 H), 6.90 - 6.85 (m, 1 H), 6.71 (d, J = 8.1 Hz, 1 H), 5.75 - 5.55 (m, 1 H), 5.23 (s, 1 H), 4.95 (s, 1 H), 4.84 (d, J = 1.3 Hz, 1 H), 3.99 (s, 2 H), 3.40 (s, 2 H), 2.26 (s, 3 H), 2.24 - 2.18 (m, 1 H), 2.18 - 2.12 (m, 1 H), 2.09 (s, 1 H), 2.04 - 1.97 (m, 1 H), 1.92 (dt, J = 12.4, 2.5 Hz, 1 H), 1.75 (s, 1 H), 1.55 - 1.51 (m, 1 H), 1.26 (s, 1 H). 13 C NMR (126 MHz, CDC13) δ 152.97, 152.50, 137.29, 131.72, 130.00, 128.46, 124.88, 122.49, 115.97, 110.13, 67.29, 39.05, 37.33, 31.05, 27.86, 26.18, 20.62.

[0040]

[0041] Compound 3: pale yellow liquid. Yield 21.5%. LC-MS: [M-H] - m / z 271.2. 1 HNMR (500 MHz, CDC13) δ 6.96 (dd, J = 8.1, 1.9 Hz, 1 H), 6.91 (d, J = 1.7 Hz, 1 H), 6.74 (d, J = 8.1 Hz, 1 H), 5.70 - 5.67 (m, 1 H), 5.21 (s, 1 H), 4.95 (s, 1 H), 4.84 (s, 1 H), 3.99 (s, 2 H), 3.42 (s, 2 H), 2.56 (q, J = 7.6 Hz, 2 H), 2.26 - 2.21 (m, 1 H), 2.17 (d, J = 10.6 Hz, 1 H), 2.10 (s, 2 H), 2.04 - 1.99 (m, 1 H), 1.94 - 1.90 (m, 1 H), 1.74 (s, 1 H), 1.55 - 1.50 (m, 1 H), 1.20 (t, J = 7.6 Hz, 3 H). 13C NMR (126 MHz, CDC13) δ 152.94, 152.64, 137.30, 136.61, 130.56, 127.22, 124.90, 122.48, 115.99, 110.14, 67.29, 39.10, 37.39, 31.04, 28.11, 27.89, 26.19, 16.01.

[0042]

[0043] Compound 4: yellow liquid. Yield 29.7%. LC-MS: [M-H] - m / z 271.2. 1 HNMR (500 MHz, CDC13) δ 6.84 (s, 1H), 6.74 (s, 1H), 5.71 - 5.66 (m, 1H), 4.98 (d, J = 11.7 Hz, 2H), 4.90 - 4.87 (m, 1H), 3.99 (s, 2H), 3.40 (s, 2H), 2.23 (s, 4H), 2.20 (s, 3H), 2.19 - 2.15 (m, 1H), 2.11 - 2.09 (m, 1H), 2.00 (dq, J = 6.1, 2.0 Hz, 1H), 1.92 (ddt, J = 9.7, 4.7, 2.1 Hz, 1H), 1.58 - 1.51 (m, 1H), 1.32 (s, 1H). 13 C NMR (126 MHz, CDC13) δ 152.94, 152.64, 137.30, 136.61, 130.56, 127.22, 124.90, 122.48, 115.99, 110.14, 67.29, 39.10, 37.39, 31.04, 28.11, 27.89, 26.19, 16.01.

[0044]

[0045] Compound 5: white solid. Yield 17.9%. Melting point 34.1 - 34.5 °C. LC-MS: [M-H] - m / z 271.2. 1HNMR (500 MHz, CD3OD) δ 6.46 (d, J = 4.9 Hz, 2H), 5.69 (s, 1H), 4.69 (s, 1H), 4.33 (d, J = 1.6 Hz, 1H), 3.92 (s, 2H), 3.35 (s, 2H), 2.25 (dd, J = 14.8, 5.7 Hz, 2H), 2.19 (s, 3H), 2.13 (s, 5H), 2.10 - 2.06 (m, 1H), 2.06 - 1.99 (m, 1H), 1.98 - 1.93 (m, 1H), 1.58 (dq, J = 11.0, 5.8 Hz, 1H). 13 CNMR (126 MHz, CD3OD) δ 121.94, 121.83, 112.87, 106.11, 65.94, 48.12, 47.95, 47.78, 47.61, 47.44, 47.27, 47.10, 40.34, 30.87, 30.68, 27.94, 25.90, 19.77.

[0046]

[0047] Compound 6: yellow liquid. Yield 46.7%. LC-MS: [M-H] - m / z 285.2. 1 HNMR (500 MHz, CDCl3) δ 6.98 - 6.86 (m, 2H), 6.73 (d, J = 8.1 Hz, 1H), 5.69 (s, 1H), 4.95 (s, 1H), 4.84 (s, 1H), 4.00 (d, J = 11.3 Hz, 2H), 3.42 (s, 2H), 2.53 - 2.42 (m, 2H), 2.26 - 2.17 (m, 2H), 2.10 (t, J = 17.9 Hz, 2H), 2.04 - 1.99 (m, 1H), 1.95 - 1.89 (m, 1H), 1.63 - 1.52 (m, 3H), 0.91 (t, J = 7.3 Hz, 3H). 13 C NMR (126 MHz, CDCl3) δ 152.66, 137.31, 131.17, 127.86, 124.76, 122.46, 115.92, 110.15, 67.30, 39.09, 37.41, 37.30, 31.04, 27.89, 26.19, 24.92, 13.90.

[0048]

[0049] Compound 7: white solid. Yield 71.3%. Melting point 33.1-33.4 °C. LC-MS: [M-H] -m / z 285.2. 1 HNMR (500 MHz, CDC13) δ 6.99 (dd, J = 8.2, 1.9 Hz, 1H), 6.94 (d, J = 1.7 Hz, 1H), 6.74 (d, J = 8.2 Hz, 1H), 5.69 (d, J = 3.7 Hz, 1H), 5.28 (s, 1H), 4.95 (s, 1H), 4.83 (s, 1H), 4.01 (d, J = 13.6 Hz, 2H), 3.42 (s, 2H), 2.83 (p, J = 6.9 Hz, 1H), 2.24 (d, J = 16.5 Hz, 1H), 2.19 - 2.13 (m, 1H), 2.12 - 2.08 (m, 1H), 2.08 - 2.04 (m, 1H), 2.00 (d, J = 17.8 Hz, 1H), 1.95 - 1.89 (m, 1H), 1.56 (dd, J = 11.7, 6.0 Hz, 1H), 1.21 (d, J = 6.9 Hz, 6H). 13 C NMR (126 MHz, CDC13) δ 152.89, 152.64, 141.28, 137.28, 129.17, 125.67, 124.84, 122.49, 115.91, 110.13, 67.29, 39.16, 37.41, 33.37, 31.03, 27.91, 26.20, 24.39.

[0050]

[0051] Compound 8: white solid. Yield 46.7%. Melting point 33.1-34.3 °C. LC-MS: [M-H] - m / z 299.2. 1 HNMR (500 MHz, CDC13) δ 6.99 (dd, J = 8.2, 1.9 Hz, 1H), 6.94 (d, J = 1.7 Hz, 1H), 6.74 (d, J = 8.2 Hz, 1H), 5.69 (d, J = 3.7 Hz, 1H), 5.28 (s, 1H), 4.95 (s, 1H), 4.83 (s, 1H), 4.01 (d, J = 13.6 Hz, 2H), 3.42 (s, 2H), 2.83 (p, J = 6.9 Hz, 1H), 2.24 (d, J = 16.5 Hz, 1H), 2.19 - 2.13 (m, 1H), 2.12 - 2.08 (m, 1H), 2.08 - 2.04 (m, 1H), 2.00 (d, J = 17.8 Hz, 1H), 1.95 - 1.89 (m, 1H), 1.56 (dd, J = 11.7, 6.0 Hz, 1H), 1.21 (d, J = 6.9 Hz, 6H). 13C NMR (126 MHz, CDC13) δ 152.86, 152.36, 143.63, 137.34, 128.15, 124.76, 124.36, 122.44, 115.59, 110.22, 67.31, 39.17, 37.71, 34.16, 31.71, 31.02, 27.93, 26.21.

[0052]

[0053] Compound 9: yellow liquid, yield 73.2%. LC-MS: [M-H] - m / z 313.2. 1 HNMR (500 MHz, CDC13) δ 7.12 - 6.99 (m, 2H), 6.74 (d, J = 8.3 Hz, 1H), 5.69 (s, 1H), 4.94 (s, 1H), 4.82 (s, 1H), 4.05 - 3.95 (m, 2H), 3.43 (s, 2H), 2.29 - 2.22 (m, 1H), 2.22 - 2.14 (m, 2H), 2.12 - 2.08 (m, 1H), 2.01 (d, J = 4.6 Hz, 1H), 1.95 - 1.89 (m, 1H), 1.61 - 1.51 (m, 3H), 1.25 (d, J = 8.0 Hz, 6H), 0.66 (t, J = 7.4 Hz, 3H). 13 C NMR (126 MHz, CDC13) δ 152.86, 152.36, 143.63, 137.34, 128.15, 124.76, 124.36, 122.44, 115.59, 110.22, 67.31, 39.17, 37.71, 34.16, 31.71, 31.02, 27.93, 26.21.

[0054]

[0055] Compound 10: white solid. Yield 23.4%. Melting point 33.6 - 34.3 °C. LC-MS: [M-H] - m / z 325.0. 1HNMR (500 MHz, CDC13) δ 6.97 (dd, J = 8.2, 2.2 Hz, 1H), 6.92 (d, J = 2.1 Hz, 1H), 6.74 (d, J = 8.2 Hz, 1H), 5.71 - 5.66 (m, 1H), 5.09 (d, J = 8.0 Hz, 1H), 4.95 (s, 1H), 4.86 - 4.81 (m, 1H), 3.99 (s, 2H), 3.42 (s, 2H), 2.41 (tt, J = 8.2, 3.3 Hz, 1H), 2.26 - 2.20 (m, 1H), 2.19 - 2.13 (m, 1H), 2.10 (dd, J = 7.1, 3.6 Hz, 1H), 2.04 - 1.99 (m, 1H), 1.92 (ddt, J = 9.8, 4.7, 2.3 Hz, 1H), 1.87 - 1.79 (m, 4H), 1.75 - 1.70 (m, 1H), 1.65 (s, 1H), 1.59 - 1.51 (m, 1H), 1.37 (t, J = 10.6 Hz, 5H). 13 CNMR (126 MHz, CDC13) δ 154.75, 154.24, 140.14, 138.35, 129.91, 127.07, 126.15, 123.31, 115.82, 109.47, 67.30, 45.20, 40.65, 36.29, 36.08, 36.07, 32.26, 29.32, 28.11, 27.33, 27.25.

[0056]

[0057] Compound 11: white solid. Yield 48.9%. Melting point 34.8-35.1 °C. LC-MS: [M-H] - m / z 355.2. 1 HNMR (500 MHz, CDC13) δ 6.97 (dd, J = 8.2, 2.2 Hz, 1H), 6.92 (d, J = 2.1 Hz, 1H), 6.74 (d, J = 8.2 Hz, 1H), 5.71 - 5.66 (m, 1H), 5.09 (d, J = 8.0 Hz, 1H), 4.95 (s, 1H), 4.86 - 4.81 (m, 1H), 3.99 (s, 2H), 3.42 (s, 2H), 2.41 (tt, J = 8.2, 3.3 Hz, 1H), 2.26 - 2.20 (m, 1H), 2.19 - 2.13 (m, 1H), 2.10 (dd, J = 7.1, 3.6 Hz, 1H), 2.04 - 1.99 (m, 1H), 1.92 (ddt, J = 9.8, 4.7, 2.3 Hz, 1H), 1.87 - 1.79 (m, 4H), 1.75 - 1.70 (m, 1H), 1.65 (s, 1H), 1.59 - 1.51 (m, 1H), 1.37 (t, J = 10.6 Hz, 5H). 13C NMR (126 MHz, CD3OD) δ 154.92, 153.89, 141.43, 138.34, 129.49, 125.77, 123.26, 115.35, 109.43, 67.26, 58.09, 40.31, 38.70, 36.42, 33.11, 32.49, 32.46, 32.32, 29.26, 27.24.

[0058]

[0059] Compound 12: yellow liquid. Yield 39.3%. LC-MS: [M-H] - m / z 273.2. 1 HNMR (500 MHz, CDC13) δ 6.75 (d, J = 8.5 Hz, 1H), 6.70 - 6.66 (m, 2H), 5.69 - 5.66 (m, 1H), 4.96 (s, 1H), 4.85 (d, J = 1.3 Hz, 1H), 4.00 (d, J = 13.3 Hz, 2H), 3.75 (s, 3H), 3.41 (s, 2H), 2.25 - 2.20 (m, 1H), 2.18 - 2.14 (m, 1H), 2.13 - 2.05 (m, 2H), 2.02 - 1.95 (m, 1H), 1.91 (ddt, J = 9.8, 4.7, 2.3 Hz, 1H), 1.57 - 1.51 (m, 1H). 13 C NMR (126 MHz, CDC13) δ 153.73, 152.62, 148.65, 137.31, 126.42, 122.44, 116.79, 116.71, 112.74, 110.34, 67.28, 55.84, 39.10, 37.45, 31.06, 27.88, 26.19.

[0060]

[0061] Compound 13: white solid. Yield 63.8%. Melting point 33.7 - 34.0 °C. LC-MS: [M-H] - m / z 261.2. 1HNMR (500 MHz, CDC13) δ 6.85 - 6.82 (m, 1H), 6.81 (d, J = 2.1 Hz, 1H), 6.77 - 6.73 (m, 1H), 5.70 - 5.67 (m, 1H), 5.08 (s, 1H), 4.98 (s, 1H), 4.85 (d, J = 1.2 Hz, 1H), 4.01 (d, J = 13.7 Hz, 2H), 3.41 (s, 2H), 2.25 - 2.19 (m, 1H), 2.16 (dd, J = 16.5, 5.1 Hz, 1H), 2.13 - 2.05 (m, 2H), 2.02 - 1.96 (m, 1H), 1.90 (ddt, J = 9.9, 4.8, 2.4 Hz, 1H), 1.57 - 1.52 (m, 1H). 13 C NMR (126 MHz, CDC13) δ 158.16, 156.26, 152.12, 150.68, 137.40, 122.29, 117.42, 117.23, 117.02, 116.95, 114.34, 114.16, 110.83, 67.29, 39.09, 37.32, 31.04, 27.86, 26.17.

[0062]

[0063] Compound 14: yellow solid. Yield 48.2%. Melting point 35.3-36.1 °C. LC-MS: [M-H] - m / z 277.2. 1 HNMR (500 MHz, CDC13) δ 7.10 - 7.06 (m, 2H), 6.77 - 6.72 (m, 1H), 5.68 (dd, J = 2.4, 1.3 Hz, 1H), 5.41 (s, 1H), 4.98 (s, 1H), 4.85 (d, J = 1.2 Hz, 1H), 4.01 (d, J = 13.6 Hz, 2H), 3.40 (s, 2H), 2.22 (dd, J = 16.9, 4.0 Hz, 1H), 2.15 - 2.09 (m, 2H), 2.00 (ddd, J = 14.7, 4.1, 2.0 Hz, 1H), 1.90 (ddt, J = 9.8, 4.8, 2.4 Hz, 1H), 1.67 (s, 1H), 1.56 - 1.50 (m, 1H), 1.25 (s, 1H). 13 C NMR (126 MHz, CDC13) δ 153.43, 152.13, 137.34, 130.73, 127.81, 127.08, 122.37, 117.38, 110.85, 67.28, 39.08, 37.02, 31.02, 27.85, 26.16.

[0064]

[0065] Compound 15: yellow solid. Yield 45.9%. Melting point 33.9-34.7 °C. LC-MS: [M-H] - m / z 361.2. 1 HNMR (500 MHz, DMSO-d6) δ 9.06 (s, 1H), 7.22 (t, J = 7.6 Hz, 2H), 7.16 (d, J = 7.3 Hz, 2H), 7.11 (t, J = 7.1 Hz, 1H), 6.88 (dd, J = 8.3, 2.3 Hz, 1H), 6.83 (d, J = 2.2 Hz, 1H), 6.69 (d, J = 8.3 Hz, 1H), 5.53 (s, 1H), 4.73 (s, 1H), 4.58 (s, 1H), 3.75 (s, 2H), 3.38 (s, 1H), 3.26 (s, 2H), 1.99 (dd, J = 31.9, 14.5 Hz, 3H), 1.85 (dd, J = 18.7, 8.2 Hz, 2H), 1.74 - 1.69 (m, 1H), 1.56 (s, 6H), 1.34 (dq, J = 11.4, 5.9 Hz, 1H). 13 C NMR (101 MHz, DMSO-d6) δ 152.93, 152.89, 150.95, 140.22, 137.82, 128.69, 127.84, 126.33, 125.31, 124.97, 124.76, 119.94, 114.33, 108.95, 64.86, 41.68, 38.86, 34.98, 30.68, 30.66, 30.55, 27.65, 25.84.

[0066] Example 17: Compound Inhibition of Proliferation of Various Tumor Cells

[0067] The target compounds were determined for the proliferation inhibition effect on human lung cancer cells A549, human glioma cells U87, human prostate cancer cells PC-3 and human hepatoma cells Huh1 by CCK-8 method.

[0068] 1) Take the tested cells in logarithmic growth phase, trypsinize, count, and inoculate in 96 empty culture plates at a concentration of 5 x 10 4 / mL, 100 μL per well (5 x 10 3 cells per well), and culture in a 37 °C, 5% CO2 incubator for 24 h;

[0069] 2) Dilute the test drug with 10% FBS / DMEM or RPMI 1640 complete medium to different concentrations. Replace the culture medium containing different concentrations of the test sample in the experimental group, and replace the culture medium containing the same volume of solvent (DMSO) in the control group. Set up 3 parallel holes for each group, and continue to culture at 37°C, 5% CO2 incubator for 48h;

[0070] Among them, A549 cells, PC-3 cells use RPMI 1640 complete medium, U87 cells, Huh1 cells use DMEM complete medium.

[0071] 3) Add CCK-8 solution 10μL per well, continue to culture at 37°C for 1h, and measure the absorbance value (OD value) of each well at 490nm on the microplate reader;

[0072] 4) Calculate the survival rate and inhibition rate (IR%) using the following formula

[0073] IR% = [(Ac-As) / (Ac-Ab)]x100%

[0074] Use GraphPad Prism 7.0 software to draw S-type dose-survival curve and calculate IC 50 value using nonlinear regression model.

[0075] As: absorbance of experimental wells (culture medium containing cells, CCK-8, test drug)

[0076] Ac: absorbance of control wells (culture medium containing cells, CCK-8, solvent (DMSO))

[0077] Ab: absorbance of blank wells (culture medium without cells and test drug, CCK-8)

[0078] The results are shown in Tables 1-3. Compared with perillyl alcohol, the anti-tumor cell proliferation effect of all compounds was enhanced to varying degrees.

[0079] Table 1 Results of perillyl alcohol and formula I compound on tumor cell proliferation inhibition at 100μM concentration

[0080]

[0081]

[0082] “ND”: Not detected.

[0083] Select some compounds with better activity to determine IC 50 value by the above experimental method, and the results are shown in Table 2. Compared with perillyl alcohol, the selected compounds have lower IC50 Values, wherein compound 11 showed better anti-tumor cell proliferation effect with lower IC 50 Values (28-36 μM), Table 2 Half maximal inhibitory concentration of target compounds on tumor cells

[0084]

[0085] "ND": Not detected.

Claims

1. A perillyl alcohol phenolic derivative, characterized in that, The structural formula is any one of the following formula 1-15:

2. The method of claim 1, wherein the preparation of the perillyl alcohol phenolic derivative is characterized by, The preparation method comprises the following steps: Step (1), dissolving perillyl alcohol in pyridine py and reacting with acetic anhydride Ac2O to obtain intermediate B; Step (2), dissolving intermediate B in dichloromethane CH2Cl2, adding acetic acid AcOH, and then adding dropwise sodium hypochlorite NaClO aqueous solution to obtain intermediate C; Step (3), reacting intermediate C with substituted phenol and sodium hydride NaH in N,N-dimethylformamide DMF to obtain intermediate D; Step (4), dissolving intermediate D in DMF and reacting in a microwave synthesis instrument to obtain The compound according to claim 1.

3. Use of the perillyl alcohol phenolic derivative according to claim 1 in the preparation of a medicament for treating tumors.

4. Use according to claim 3, characterized in that, The tumors include lung cancer, breast cancer, brain glioma, liver cancer, gastric cancer, prostate cancer, cervical cancer, fibrosarcoma, colon cancer, melanoma, lymphoma, chronic myelogenous leukemia or myeloblast leukemia.

5. A pharmaceutical composition, characterized by, A safe and effective amount of the perillyl alcohol phenolic derivative according to claim 1.

6. The pharmaceutical composition of claim 5, wherein, Also comprising a pharmaceutically acceptable excipient.

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