Netupitant derivative as well as preparation method and application thereof

Abstract

The invention provides a netupitant derivative as well as a preparation method and application thereof. The netupitant derivative has a structure as shown in a formula (I). Researches show that the netupitant derivative has a remarkable inhibition effect on non-small cell lung cancer and prostate cancer cells, and can remarkably inhibit proliferation, activity and clone formation of the non-small cell lung cancer and the prostate cancer cells, inhibit expression of RORC genes, inhibit AR and ROR gamma protein expression levels and promote cell apoptosis; the traditional Chinese medicine composition has very good effects of resisting non-small cell lung cancer and prostatic cancer. The compound can be synthesized through simple chemical synthesis steps, the cost is low, large-scale industrial production is easy to realize, and the compound has important application value in the aspect of development of non-small cell lung cancer and prostate cancer anticancer drugs.

Description

Technical Field

[0001] The present invention belongs to the field of pharmaceutical technology. More specifically, it relates to a netupitant derivative, its preparation method and application. Background Art

[0002] Non-small cell lung cancer and prostate cancer are two of the most common malignant tumors in the world. The former ranks first in both incidence and mortality rates globally, while the latter ranks fourth in terms of incidence.

[0003] The clinical treatment methods for non-small cell lung cancer mainly include surgery, radiotherapy, chemotherapy, targeted therapy, and immunotherapy. Among them, small molecule targeted drugs against specific targets are the most widely used, including gefitinib for EGFR mutations, sotorasib for KRAS-G12C mutations, crizotinib for ALK mutations, etc. However, the vast majority of patients develop drug resistance to targeted drugs as the treatment progresses, especially in patients with advanced stage or those who have received multiple lines of treatment. Therefore, there is an urgent need to explore new and effective targeted drugs for non-small cell lung cancer patients to reduce clinical drug resistance and improve the effectiveness of clinical treatment.

[0004] Endocrine therapy is the main treatment method for prostate cancer. Most early-stage prostate cancer patients are androgen-dependent prostate cancer. Therefore, endocrine therapy by blocking androgen receptors has significant effects. However, after treatment for a median time of 14 - 30 months, almost all patients gradually turn into castration-resistant prostate cancer, and androgen blockade therapy is no longer effective. Therefore, solving the problem of drug resistance in congenital or acquired androgen-targeted therapy is a severe challenge in the clinical treatment of prostate cancer.

[0005] Netupitant is a new drug that can effectively prevent nausea and vomiting caused during the acute and delayed phases (within 25 - 120 hours after the start of chemotherapy) of cancer chemotherapy. Research shows that it has obvious curative effects on breast cancer, and relevant research has entered phase II clinical trials. Summary of the Invention

[0006] The technical problem to be solved by the present invention is to overcome the deficiencies and shortages of the relatively scarce treatment drugs for existing prostate cancer and non-small cell lung cancer patients, and to attempt to develop a new drug with significant inhibitory effects on prostate cancer and non-small cell lung cancer based on netupitant.

[0007] The object of the present invention is to provide a netupitant derivative.

[0008] Another object of the present invention is to provide a preparation method of the netupitant derivative.

[0009] Another object of the present invention is to provide the use of the netupitant derivative in the preparation of a medicament for treating prostate cancer and non-small cell lung cancer, and an anticancer drug containing the netupitant derivative.

[0010] The above object of the present invention is achieved by the following technical solutions:

[0011] The present invention provides a netupitant derivative having the structure shown in formula (I):

[0012]

[0013] The netupitant derivative is obtained by modifying netupitant, and has a significant inhibitory effect on non-small cell lung cancer and prostate cancer cells. It can significantly inhibit the proliferation, activity and colony formation of non-small cell lung cancer and prostate cancer cells, inhibit the expression of the RORC gene, inhibit the expression levels of AR and RORγ proteins, and promote apoptosis of cells; it has a very good effect against non-small cell lung cancer and prostate cancer.

[0014] Therefore, the present invention also claims protection for:

[0015] The use of the netupitant derivative or a pharmaceutically acceptable salt thereof in the preparation of a medicament for treating non-small cell lung cancer.

[0016] The use of the netupitant derivative or a pharmaceutically acceptable salt thereof in the preparation of a medicament for treating prostate cancer.

[0017] The use of the netupitant derivative or a pharmaceutically acceptable salt thereof in the preparation of a medicament for inhibiting the proliferation, activity and colony formation of non-small cell lung cancer cells A549 or H157.

[0018] The use of the netupitant derivative or a pharmaceutically acceptable salt thereof in the preparation of a medicament for inhibiting the proliferation, activity and colony formation of prostate cancer cells C4-2B or 22RV1.

[0019] And an anticancer drug containing the netupitant derivative or a pharmaceutically acceptable salt thereof.

[0020] The term "pharmaceutically acceptable" refers to a carrier, diluent or excipient, and / or the salt formed is generally chemically or physically compatible with other components constituting a pharmaceutical dosage form and is physiologically compatible with the receptor.

[0021] The term "acceptable salt" refers to the acid addition and / or base salts formed by the above-mentioned compounds or their stereoisomers with inorganic and / or organic acids and bases, including zwitterionic salts (inner salts), and also including quaternary ammonium salts, such as alkylammonium salts. These salts can be directly obtained during the final separation and purification of the compound. They can also be obtained by appropriately (e.g., equimolarly) mixing the above-mentioned compound or its stereoisomer with a certain amount of acid or base. These salts may form precipitates in solution and be collected by filtration, or recovered after evaporation of the solvent, or prepared by lyophilization after reaction in an aqueous medium.

[0022] More preferably, the pharmaceutically acceptable salts are pharmaceutically acceptable inorganic salts or organic salts.

[0023] Specifically, pharmaceutically acceptable salts include but are not limited to: sulfates, citrates, acetates, oxalates, chlorides, bromides, iodides, nitrates, bisulfates, phosphates, acid phosphates, isonicotinates, lactates, salicylates, acid citrates, tartrates, oleates, tannates, pantothenates, bitartrates, ascorbates, succinates, maleates, gentisates, fumarates, gluconates, glucuronates, galacturonates, formates, benzoates, glutamates, methanesulfonates (mesylates), ethanesulfonates, benzenesulfonates, p-toluenesulfonates, and pamoates; or ammonium salts (e.g., primary amine salts, secondary amine salts, tertiary amine salts, quaternary ammonium salts), metal salts (e.g., sodium salts, potassium salts, calcium salts, magnesium salts, manganese salts, iron salts, zinc salts, copper salts, lithium salts, aluminum salts).

[0024] Furthermore, the dosage form of the anticancer drug can be an injection, capsule, tablet, pill or granule.

[0025] In addition, the present invention also provides a method for preparing the netupitant derivative, which specifically includes the following steps:

[0026] S1. Weigh Cu(MeCN)4PF6, ligand L, rac-BINOL, LiOtBu, and LiOAc into a reaction vessel, and then add 1,4-dioxane.

[0027] S2. Then add n-octyne, styrene, and netupitant to the reaction vessel.

[0028] S3. Seal the reaction vessel, and stir and irradiate at 390 - 395 nm under a 5 - 20 W light at 20 ± 0.5 °C for 9 - 11 h.

[0029] S4. When the reaction in step S3 is completed, quench with water, extract with ethyl acetate, collect the organic phase, dry and concentrate to obtain the crude product.

[0030] S5. Purify the crude product obtained in S4 by silica gel column chromatography. The brown liquid obtained after the eluate is separated is then rotary evaporated at a low speed to obtain a light brown solid.

[0031] Among them, in steps S1 and S2, the mass ratio of Cu(MeCN)4PF6: ligand L: rac-BINOL: LiOtBu: LiOAc: n-octyne: styrene: netupitant is (5 - 10):(22 - 28):(10 - 15):(45 - 50):(36 - 45):(18 - 25):(120 - 130):(660 - 720).

[0032] The conditions for silica gel column chromatography in step S5 are as follows: the mobile phase is chloroform: methanol = (8 - 12):1 (V / V), the silica gel is 300 - 500 mesh silica gel, and the column chromatography temperature is 15 - 25 °C.

[0033] More preferably, in steps S1 and S2, the mass ratio of Cu(MeCN)4PF6: ligand L: rac-BINOL: LiOtBu: LiOAc: n-octyne: styrene: netupitant is (7 - 8):(24 - 26):(11 - 12):(47 - 49):(39 - 40):(21 - 23):(123 - 126):(690 - 700).

[0034] More preferably, in steps S1 and S2, the mass ratio of Cu(MeCN)4PF6: ligand L: rac-BINOL: LiOtBu: LiOAc: n-octyne: styrene: netupitant is (7.4 - 7.5):(25 - 25.1):(11.2 - 11.6):(47.8 - 48.2):(39.5 - 40):(22 - 22.1):(124 - 125):(693 - 695).

[0035] Specifically and most preferably, in steps S1 and S2, the mass ratio of Cu(MeCN)4PF6: ligand L: rac-BINOL: LiOtBu: LiOAc: n-octyne: styrene: netupitant is 7.44:25.07:11.4:48.0:39.6:22.02:124.88:693.90.

[0036] In steps S1 and S2, the dosage of 1,4-dioxane, calculated by the amount ratio with netupitant, is 1,4-dioxane: netupitant = 3 - 5 mL: 694 mg.

[0037] More preferably, in steps S1 and S2, the dosage of 1,4-dioxane, calculated by the amount ratio with netupitant, is 1,4-dioxane: netupitant = 4.0 mL: 694 mg.

[0038] In step S3, the temperature needs to be strictly controlled at 20 ± 0.5 °C (20 °C, with a fluctuation not exceeding 0.5 °C). If the temperature changes, the impurities will increase.

[0039] Preferably, in step S3, stir and irradiate at 20 °C for 10 h.

[0040] Preferably, the power of the light in step S3 is 8 - 15 W. More preferably, it is 10 W.

[0041] Optionally, the light in step S3 can be LED light or xenon light.

[0042] Preferably, the conditions for silica gel column chromatography in step S5 are as follows: the mobile phase is chloroform:methanol = 10:1 (V / V), the silica gel is 400 - mesh silica gel, and the column chromatography temperature is 20 °C.

[0043] The present invention has the following beneficial effects:

[0044] Based on netupitant, the present invention has synthesized a new netupitant derivative through modification. It has a significant inhibitory effect on non - small cell lung cancer and prostate cancer cells, can significantly inhibit the proliferation, activity and colony formation of non - small cell lung cancer and prostate cancer cells, inhibit the expression of the RORC gene, inhibit the expression levels of AR and RORγ proteins, and promote cell apoptosis; it has a very good anti - non - small cell lung cancer and prostate cancer effect.

[0045] Moreover, this netupitant derivative can be synthesized from netupitant through simple chemical synthesis steps, which is simple, low - cost, and easy to achieve large - scale industrial production, and has important application value in the development of anti - non - small cell lung cancer and prostate cancer drugs. Description of the Drawings

[0046] Figure 1 It is the nuclear magnetic resonance hydrogen spectrum of the netupitant derivative (HJL - S - 202) obtained in the present invention.

[0047] Figure 2 It is the nuclear magnetic resonance carbon spectrum of the netupitant derivative (HJL - S - 202) obtained in the present invention.

[0048] Figure 3 It is the nuclear magnetic resonance fluorine spectrum of the netupitant derivative (HJL - S - 202) obtained in the present invention.

[0049] Figure 4 It is the HPLC spectrum of the netupitant derivative (HJL - S - 202) obtained in the present invention.

[0050] Figure 5Statistical chart of the inhibitory proliferation data of the netupitant derivative (HJL-S-202) obtained in the present invention against various non-small cell lung cancer and prostate cancer cell lines (A549, H157, C4-2B, 22RV1).

[0051] Figure 6 Statistical chart of the inhibitory activity data of the netupitant compound (HJL-S-202) obtained in the present invention against various non-small cell lung cancer and prostate cancer cell lines (A549, H157, C4-2B, 22RV1).

[0052] Figure 7 Microscopic images and statistical charts of the colony formation inhibition of non-small cell lung cancer and prostate cancer cells by netupitant compounds (HJL-S-202) at different concentrations.

[0053] Figure 8 Statistical chart of the fluorescence intensity of the reporter gene targeting RORγ by netupitant compounds (HJL-S-202) at different concentrations.

[0054] Figure 9 Western blot images of apoptosis-related protein (c-Caspase7) and the effects on two drug targets (AR, RORγ) of non-small cell lung cancer and prostate cancer cell lines (A549, H157, C4-2B, 22RV1) by netupitant compounds (HJL-S-202) at different concentrations. Detailed implementation methods

[0055] The present invention will be further described below in conjunction with the accompanying drawings of the specification and specific embodiments, but the embodiments do not impose any form of limitation on the present invention. Unless otherwise specified, the reagents, methods, and equipment used in the present invention are conventional reagents, methods, and equipment in the technical field.

[0056] Unless otherwise specified, the reagents and materials used in the following examples are all commercially available.

[0057] The reagents used in the above examples are as follows:

[0058] The CAS number of netupitant is 290297-26-6, and the structural formula is as follows:

[0059]

[0060] The structure of ligand L is as follows:

[0061]

[0062] Tetraethylcyanocuprate hexafluorophosphate (Cu(MeCN)4PF6), CAS number is 64443-05-6.

[0063] 1,1'-Biphenyl-2,2'-diol (rac-BINOL), CAS No. 602-09-5.

[0064] Lithium tert-butoxide (LiOtBu), CAS No. 1907-33-1.

[0065] Lithium acetate (LiOAc), CAS No. 546-89-4.

[0066] 1,4-Dioxane, CAS No. 54841-74-6.

[0067] 1-Octyne, CAS No. 629-05-0.

[0068] Styrene, CAS No. 100-42-5.

[0069] Example 1 Chemical Synthesis and Characterization of Netupitant Derivative (HJL-S-202)

[0070] 1. The chemical synthesis of the netupitant derivative specifically includes the following steps:

[0071] S1. Weigh the compounds Cu(MeCN)4PF6 (7.44 mg, 0.02 mmol, 10 mol%), ligand L (25.07 mg, 0.03 mmol, 15 mol%), rac-BINOL (11.4 mg, 0.04 mmol, 20 mol%), LiOtBu (48.0 mg, 0.6 mmol, 3.0 equivalents), and LiOAc (39.6 mg, 0.6 mmol, 3.0 equivalents) in the following proportions into a dry glass tube, and add 1,4-dioxane (4.0 mL);

[0072] S2. Add 1-octyne (22.02 mg, 0.2 mmol, 1.0 equivalent), styrene (124.88 mg, 1.2 mmol, 6.0 equivalents), and netupitant (693.90 mg, 1.2 mmol, 6.0 equivalents);

[0073] S3. Seal the reaction tube with a rubber stopper and stir and irradiate at 20 °C for 10 h under a 390 - 395 nm LED (10 W);

[0074] S4. When the reaction in step S3 is completed, quench with water, extract with ethyl acetate (EA), collect the organic phase, dry and concentrate to obtain the crude product;

[0075] S5. Purify the crude product obtained in S4 by silica gel column chromatography. The eluate obtained is a brown liquid after layering, and then rotary evaporate at low speed to obtain the pure product, a light brown solid (120.5 mg, 78% yield, 95% ee).

[0076] Among them, the conditions for silica gel column chromatography are as follows: the mobile phase is chloroform: methanol = 10:1 (V / V), the silica gel is 400-mesh silica gel, and the column chromatography temperature is 20 °C.

[0077] 2. Characterization of netupitant derivatives

[0078] The obtained light brown solid powder was detected by nuclear magnetic resonance and high performance liquid chromatography, and the obtained spectra are as Figures 1 to 4 shown. After analysis and detection, the physicochemical property data of the structure of this compound are as follows:

[0079] HRMS(ESI): Calcd for C 46 H 53 N4F5O + H + , [M + H]+: 773.4212, found: 773.4214.

[0080] HPLC conditions: Chiralcel column INC (n-hexane / ethanol = 80 / 20, 0.1% diethylamine, flow rate 0.8 ml / min, λ = 230 nm), tR (major) = 10.5 min, tR(minor) = 11.7 min.

[0081] NMR nuclear magnetic data:

[0082] 1 1H NMR(400 MHz, CDCl3) δ 8.05(s, 1H), 7.68 - 7.51(m, 3H), 7.36 - 7.16(m, 9H), 6.54(s, 1H), 3.87 - 3.75(m, 1H), 3.68 - 3.53(m, 4H), 2.75 - 2.45(m, 7H), 2.41 - 2.04(m, 10H), 1.51 - 1.24(m, 14H), 0.89(t, J = 6.9 Hz, 3H).

[0083] 1313C NMR (101 MHz, CDCl3) δ 175.6, 158.1, 148.0, 147.3, 141.4, 139.0 (t, J = 26.7 Hz), 136.8, 134.4, 131.7 (q, J = 32.6 Hz), 130.6 - 129.5 (m), 128.7, 129.1 - 128.1 (m), 127.3, 127.1, 125.5, 125.1, 123.6 (q, J = 273.7 Hz), 123.0, 121.2 (t, J = 246.4 Hz), 120.7, 108.2, 84.5, 79.9, 54.8, 47.5 (t, J = 26.6 Hz), 47.3, 46.2, 45.3, 32.4 (t, J = 4.4 Hz), 31.7, 31.3, 28.8, 28.5, 23.5, 22.5, 20.0, 18.7, 14.0.

[0084] 19 19F NMR (376 MHz, CDCl3) δ -62.50 (s, 3F), -91.59 - -95.36 (m, 2F).

[0085] From the analysis of the mass spectrometry and nuclear magnetic resonance results, the molecular formula of compound (Ι) can be determined to be C 46 H 53 N4F5O.

[0086] From the planar structure, a chiral center C-3 of compound (I) was found. Due to the presence of a flexible long chain in this compound, the accurate configuration could not be obtained by ECD calculation. However, the chirality of this compound with a monoglycerol fragment and only one chiral center can be determined by optical rotation. If the optical rotation value is negative, the chiral center is in the S configuration; if it is positive, it is in the R configuration.

[0087] Therefore, the optical rotation of the light brown solid powder was measured, and the optical rotation data of this compound was obtained as [α] D 20 = 13.0 (c = 0.1, CHCl3). It can be determined that the configuration of compound (I) is R.

[0088] In summary, the obtained light brown solid powder is a netupitant derivative, and the specific structural formula is shown as formula (I) below:

[0089]

[0090] This netupitant derivative was named HJL-S-202, and the following examples further studied the activity of this compound.

[0091] Example 2 Anticancer Activity Test of Netupitant Derivative (HJL-S-202)

[0092] 1. Cell culture

[0093] In the present invention, the prostate cancer cell lines (22RV1 and C42B) and non-small cell lung cancer cell lines (A549 and H157) used are cultured in RPIM-1640 medium (hereinafter referred to as the medium) containing 10% fetal bovine serum, 1% penicillin and streptomycin, incubated at a constant temperature of 37°C in a cell culture incubator containing 5% CO2.

[0094] 2. Cell proliferation counting

[0095] (1) Take prostate cancer cells (22RV1 and C42B) and non-small cell lung cancer cells (A549 and H157) in the logarithmic growth phase, digest the cells with trypsin, and inoculate them evenly in a six-well plate at a density of 2 mL per well according to 1.3×10 5 / well for 22RV1, 3×10 4 / well for C42B, and 4×10 4 / well for A549 and H157, and incubate in a constant temperature incubator for 24 h.

[0096] (2) After 24 h of cell culture, add the corresponding amount of DMSO to the control group, and add HJL-S-202 to the drug treatment group according to the concentration gradient.

[0097] (3) After 96 h of drug treatment, observe the cell state under a microscope, wash the cells twice with PBS, and then digest the cells with trypsin for counting.

[0098] The results are shown in Figure 5 , and it can be seen from the figure that the compound HJL-S-202 can inhibit the proliferation of prostate cancer and non-small cell lung cancer cells in a dose-dependent manner.

[0099] 3. Determination of cell viability by CCK8 method

[0100] (1) Take prostate cancer cells and non-small cell lung cancer cells in the logarithmic growth phase. After digestion and counting with trypsin, dilute 1000 cells evenly in 100 μL of medium and inoculate them in a 96-well plate.

[0101] (2) After the cells adhere after 24 h of culture, add 50 μL of fresh medium containing the drug solvent to each well of the control group, and add the same volume of medium containing HJL-S-202 to the drug treatment group according to the concentration gradient.

[0102] (3) After incubating the cells with the drug continuously for 4 days, add 10 μL of CCK8 reagent to each well of the 96-well plate, and continue to incubate in an incubator containing 5% CO2 at 37°C for 1-2 hours. Measure the absorbance at 450 nm according to the instructions of the CCK8 kit.

[0103] (4) The final result is displayed as a percentage, and the in vitro IC50 value is calculated using GraphPad Prism 8 software. The inhibition rate calculation formula is [OD (drug-treated group) - OD (control group)] / [OD (control group) - OD (blank group)] × 100%.

[0104] The results are shown in Figure 6 , and it can be seen from the figure that compound HJL-S-202 can dose-dependently inhibit the cell viability of prostate cancer and non-small cell lung cancer cells.

[0105] 4. Colony formation assay

[0106] (1) Cells in the logarithmic growth phase are taken, digested with trypsin and counted, and then evenly inoculated into a six-well plate at 800 - 1000 cells per well and cultured in a constant temperature incubator.

[0107] (2) After the cells adhere to the wall, the control group is added with a medium containing the drug solvent, and the drug-treated group is added with HJL-S-202 at concentration gradients, with 3 replicate wells set in each group. After drug treatment, the fresh medium is changed every 3 days, and the corresponding concentration of HJL-S-202 is added.

[0108] (3) After culturing for 9 - 15 days, wait until the control group forms visible white cell clone clusters with the naked eye.

[0109] (4) Discard the medium in the six-well plate, wash the cells once with fresh normal temperature phosphate buffer (PBS), add 4% paraformaldehyde, and fix at room temperature for 15 min; discard the fixing solution, wash once with PBS, add 1 ml of crystal violet staining solution to each well under light-proof conditions, and stain for 30 min; after staining, suck out the crystal violet staining solution, slowly wash away the excess staining solution with running water, dry at room temperature and then scan the plate to calculate the number of cell clone clusters formed in each well.

[0110] The results are shown in Figure 7 , and it can be seen from the figure that compound HJL-S-202 can dose-dependently inhibit the colony formation of prostate cancer and non-small cell lung cancer cells.

[0111] 5. Dual-luciferase reporter gene

[0112] (1) Well-conditioned 293T cells are evenly diluted at a density of 1.2×104 in 100 μL of medium, inoculated into a 96-well plate, and cultured overnight;

[0113] (2) After 24 h, when the cell density increases to 70 - 80%, prepare the transfection solution and add it to the 96-well plate. The components are as follows:

[0114] A. 0.25 μL Lipofectamine 2000 + 5 μL Opti-MEM medium;

[0115] B. 25 ng pCMV-RORγ-LBD + 25 ng PFR-luci + 10 ng PGC-1α + 40 ng TK-RL + 5 μL Opti-MEM medium.

[0116] (3) The control group was added with 50 μL of medium containing the drug solvent, and the dosing group was added with HJL-S-202 according to the concentration gradient, with 3 replicate wells set in each group.

[0117] (4) After 24 h of drug treatment, the results were measured using the Beyotime dual-luciferase reporter gene kit.

[0118] The results are shown in Figure 8 , and it can be seen from the figure that the compound HJL-S-202 can dose-dependently inhibit the gene expression level of RORγ.

[0119] 6. Western blotting

[0120] (1) Take 22RV1 cells in the logarithmic growth phase, digest and count them, and evenly inoculate 1.3×10⁵ cells per well into a six-well plate.

[0121] (2) After culturing for 24 h until the cells adhered, treat the cells with HJL-S-202 according to the concentration gradient for 48 h.

[0122] (3) After the cells were treated with different concentrations of HJL-S-202 for 48 h, the cells were collected. The collected cells were treated with the cell lysate RIPA containing protease inhibitors and phosphatase inhibitors for about 30 minutes, and then the lysate was centrifuged at 15000 rpm and 4 °C for 15 min. Take the supernatant and quantify it using the BCA working solution. The remaining protein was added with 5×loading buffer according to the volume and boiled for denaturation.

[0123] (4) According to the BCA quantification results, take an appropriate amount of the denatured protein supernatant and add it to a 6% - 15% polyacrylamide gel. Separate the protein samples by sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE) for about 120 min, and then transfer them to a nitrocellulose membrane (PVDF membrane). Block the membrane with a TBS-T solution containing 5% non-fat milk powder at room temperature for 1 h, then wash the PVDF membrane 3 times with the TBS-T solution, and incubate it with the corresponding primary antibody overnight at 4 °C. The next day, incubate it with the secondary antibody corresponding to the primary antibody species at room temperature for 1 h. Finally, visualize and analyze the protein bands on the membrane using a developer.

[0124] The results are shown in Figure 9, As can be seen from the figure, compound HJL-S-202 can dose-dependently inhibit the protein expression levels of AR and RORγ in non-small cell lung cancer cell line A549 and promote the apoptosis of A549 cells.

[0125] The above embodiments are preferred embodiments of the present invention, but the embodiments of the present invention are not limited to the above embodiments. Any other changes, modifications, substitutions, combinations, and simplifications made without departing from the spirit and principle of the present invention shall be equivalent replacement methods and are all included in the protection scope of the present invention.

Claims

1. A netupitant derivative, characterized in that: It has the structure shown in formula (I):

2. Use of the netupitant derivative or a pharmaceutically acceptable salt thereof according to claim 1 in the preparation of an anti-non-small cell lung cancer drug.

3. Use of the netupitant derivative or a pharmaceutically acceptable salt thereof according to claim 1 in the preparation of an anti-prostate cancer drug.

4. Use of the netupitant derivative or a pharmaceutically acceptable salt thereof according to claim 1 in the preparation of a drug for inhibiting proliferation, activity and clone formation of non-small cell lung cancer cells A549 or H157.

5. Use of the netupitant derivative or a pharmaceutically acceptable salt thereof according to claim 1 in the preparation of a drug for inhibiting the proliferation, activity and clone formation of prostate cancer cells C4-2B or 22RV1.

6. An anticancer drug, characterized in that: Containing the netupitant derivative or a pharmaceutically acceptable salt thereof as claimed in claim 1.

7. The method for preparing the netupitant derivative according to claim 1, characterized in that: The following steps are involved: S1. Weigh Cu(MeCN)4PF6, ligand L, rac-BINOL, LiOtBu, and LiOAc into a reaction vessel, and then add 1,4-dioxane; S2, adding n-octyne, styrene and netupitant to the reaction vessel; S3, seal the reaction vessel, irradiate with stirring at 390-395nm, 5-20W light, 20±0.5℃ for 9-11h; S4. When the reaction in step S3 is completed, quench with water, extract with ethyl acetate, collect the organic phase, dry and concentrate to obtain a crude product; S5, purifying the crude product obtained in S4 by silica gel column chromatography, and the obtained eluate is separated into layers to obtain a brown liquid, which is then rotary evaporated to obtain a light brown solid; Wherein, in steps S1 and S2, the mass ratio of Cu(MeCN)4PF6: ligand L: rac-BINOL: LiOtBu: LiOAc: n-octyne: styrene: netupitant is (5-10): (22-28): (10-15): (45-50): (36-45): (18-25): (120-130): (660-720); The conditions for silica gel column chromatography in step S5 are as follows: the mobile phase is chloroform:methanol=(8-12):1 (V / V), the silica gel is 300-500 mesh silica gel, and the column chromatography temperature is 15-25°C.

8. The preparation method according to claim 7, characterized in that: In step S3, the mixture was irradiated with stirring at 20°C for 10 h.

9. The preparation method according to claim 7, characterized in that: The power of the light in step S3 is 8-15W.

10. The preparation method according to claim 7, characterized in that: The conditions of silica gel column chromatography in step S5 are as follows: the mobile phase is methyl chloride:methanol=10:1 (V / V), the silica gel is 400 mesh silica gel, and the column chromatography temperature is 20°C.

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