Estradiol antidepressant derivatives, their preparation methods and pharmaceutical uses

Abstract

This invention belongs to the field of biomedicine and discloses estradiol derivatives or pharmaceutically acceptable salts thereof with the structure shown in Formula I: R is selected from R1, which is selected from F, Cl, Br, and I; L is selected from straight-chain or branched alkyl groups with 2 to 10 carbon atoms. This invention also discloses the use of the estradiol derivatives or pharmaceutically acceptable salts thereof in the preparation of drugs for treating depression and anxiety. Furthermore, this invention discloses the use of the estradiol derivatives or pharmaceutically acceptable salts thereof in the preparation of drugs targeting ERβ / SERT for treating depression and anxiety. The estradiol derivatives of this invention can simultaneously and effectively inhibit SERT and activate ERβ, thereby synergistically enhancing serotonergic neurotransmission and regulating neuroplasticity, and enhancing antidepressant efficacy through multi-target synergistic effects.

Description

Technical Field

[0001] This invention belongs to the field of biomedicine, specifically relating to novel estradiol-based antidepressant derivatives, their preparation methods, and pharmaceutical applications. Technical Background

[0002] Depression is a common mental disorder, primarily characterized by low mood, loss of interest, and anhedonia. Some severely affected patients may also experience anxiety, self-blame, guilt, or suicidal attempts. Research indicates that approximately 300 million people will experience major depressive disorder at some point in their lives. Suicide is the most serious consequence of depression, affecting about 15% of all depression sufferers.

[0003] 5-hydroxytryptamine (5-HT or serotonin) is a monoamine neurotransmitter closely related to depression. Numerous studies have shown a strong correlation between depression and low 5-HT levels in the brain. Selective serotonin reuptake inhibitors (SSRIs), such as sertraline, paroxetine, fluoxetine, fluvoxamine, and citalopram, are widely used antidepressants in clinical practice. These drugs exert their antidepressant effect by inhibiting the reuptake of 5-HT in the brain, thereby increasing the concentration of monoamine neurotransmitters in the synaptic cleft. However, these drugs commonly have side effects such as nausea, drowsiness, sweating, dizziness, sexual dysfunction, hypertension, anxiety, dry mouth, lightheadedness, and constipation, leading to poor patient compliance. Slow onset of action is another significant drawback; it takes 3–4 weeks to achieve therapeutic effects, exhibiting a marked clinical delay. Due to these side effects, some patients discontinue treatment before the drugs take effect. Therefore, the development of novel antidepressants based on new mechanisms that are safe, effective, and have few side effects has important clinical value. Summary of the Invention

[0004] The purpose of this invention is to overcome the technical problems of existing antidepressants having single targets and multiple side effects. This invention uses the natural product estradiol (E2) as a lead compound and introduces fluoxetine, a selective serotonin reuptake inhibitor (SSRI) activity, and a 3-(tetrahydropiperidinyl)indole derivative into the 3-position of E2, providing a class of estradiol derivatives, their preparation methods, and applications. The estradiol derivatives are dual-target regulators that act on both ERβ and the serotonin transporter (SERT), effectively inhibiting SERT and activating the estrogen receptor (ERβ), thereby exerting a safe and efficient antidepressant effect and achieving more significant antidepressant efficacy.

[0005] The objective of this invention is achieved through the following technical solution:

[0006] A class of novel estradiol antidepressant derivatives or pharmaceutically acceptable salts thereof with structures as shown in Formula I:

[0007]

[0008] Where R is selected from R1 is selected from F, Cl, Br, I; L is selected from straight-chain or branched alkyl groups with 2 to 10 carbon atoms.

[0009] Preferably, R1 is selected from F and Cl, and L is selected from formula -(CH2). n - The straight-chain alkyl group is shown, n = 3 to 8 integers.

[0010] In some preferred embodiments of the present invention, R is selected from... R1 is selected from F, Cl, Br, and I; L is selected from straight-chain or branched alkyl groups with 2 to 10 carbon atoms; but does not include: R is selected from R1 is selected from F, n = 8.

[0011] In some more preferred embodiments of the present invention, R is selected from... R1 is selected from F and Cl; L is selected from formula -(CH2). n -, n = 3 to 8; but excluding: R is selected from R1 is selected from F, n = 8.

[0012] Specifically, estradiol derivatives or pharmaceutically acceptable salts thereof with the following structures:

[0013]

[0014] As a preferred embodiment of the present invention, the estradiol derivative or its pharmaceutically acceptable salt with the following structure is provided:

[0015]

[0016] Pharmaceutically acceptable salts of the estradiol derivatives include: sodium salts, potassium salts, hydrochlorides, hydrobromides, nitrates, perchlorates, phosphates, sulfates, formates, acetates, aconates, ascorbic acid salts, benzenesulfonates, benzoates, cinnamates, citrates, heptanoates, fumarates, glutamates, glycolates, lactates, maleates, malonates, mandelates, methanesulfonates, naphthalene-2-sulfonates, phthalates, salicylates, sorbates, stearates, succinates, tartrates, or p-toluenesulfonates.

[0017] Another object of the present invention is to provide a method for preparing the estradiol derivative described above, the synthetic route of which is as follows:

[0018]

[0019] R and L are as described above;

[0020] Includes the following steps:

[0021] Step (1): Using acetone as the reaction solvent and cesium carbonate as the acid-binding agent, estradiol reacts with the bromoalkane represented by formula BrLBr to generate compound II;

[0022] Step (2): Using acetonitrile as the reaction solvent and potassium carbonate as the acid-binding agent, under nitrogen protection, with or without a catalyst, compound RH and compound II react to generate estradiol derivatives.

[0023] In step (1), the molar ratio of estradiol to bromoalkane is 1:2.75 to 1:3.25, preferably 1:3; the molar ratio of cesium carbonate to estradiol is 2.75:1 to 3.25:1, preferably 1:3; the reaction temperature is the temperature corresponding to the reflux of the reaction system; and the reaction time is 6 to 7 hours.

[0024] After the reaction was completed, the reaction solution was concentrated under reduced pressure to 1 / 6 to 1 / 7 of its original volume. It was then extracted 2 to 4 times with an appropriate amount of water and ethyl acetate. The organic phases were combined and washed successively with saturated sodium chloride solution, dried over anhydrous sodium sulfate, concentrated to dryness, and purified by normal-phase silica gel column chromatography to obtain compound II.

[0025] The eluent for the normal-phase silica gel column chromatography is PE:EA = 12:1 to 10:1 V / V. Those skilled in the art can adjust the eluent ratio appropriately based on the polarity of the target compound.

[0026] In step (2), the molar ratio of compound RH to compound II is 1:1 to 1.15:1; the molar ratio of potassium carbonate to compound RH is 1.5:1 to 2:1; the reaction temperature is the temperature corresponding to the reflux of the reaction system; and the reaction time is 12 hours.

[0027] when When compound RH and compound II react in the presence of a catalyst, the reflux reaction temperature is 70°C; the catalyst is potassium iodide; the molar ratio of the catalyst to compound RH is 1:2; when At that time, compound RH and compound II reacted to form estradiol derivatives in the absence of a catalyst, and the reflux reaction temperature was 100℃.

[0028] when After the reaction was completed, an appropriate amount of pure water was added, the mixture was stirred at room temperature, filtered, and the filter cake was collected. Using methanol as a poor solvent, the mixture was slurried at room temperature (25℃) at a ratio of 1.2:15 g / mL of filter cake to methanol, filtered, the filter cake was collected, dried under vacuum, and purified by normal-phase silica gel column chromatography to obtain the estradiol derivative.

[0029] The pulping time is 30 minutes.

[0030] The eluent for the normal-phase silica gel column chromatography is DCM:MeOH = 95:5 V / V. Those skilled in the art can adjust the eluent ratio appropriately based on the polarity of the target compound.

[0031] when After the reaction was completed, the reaction solution was concentrated under reduced pressure to 1 / 6.25 to 1 / 17 of the original volume. Appropriate amounts of water and ethyl acetate were added for extraction 2 to 4 times. The organic phases were combined and washed successively with saturated sodium chloride solution, dried with anhydrous sodium sulfate, concentrated to dryness, and purified by normal-phase silica gel column chromatography to obtain estradiol derivatives.

[0032] The eluent for the normal-phase silica gel column chromatography is PE:EA = 3:1 V / V. Those skilled in the art can adjust the eluent ratio appropriately based on the polarity of the target compound.

[0033] The present invention also provides the use of the estradiol derivatives thereon or pharmaceutically acceptable salts thereof in the preparation of medicaments for treating depression and anxiety.

[0034] The present invention also provides the use of the estradiol derivatives thereon or pharmaceutically acceptable salts thereof in the preparation of medicaments targeting ERβ / SERT for the treatment of depression and anxiety.

[0035] The present invention also provides a pharmaceutical composition comprising the novel estradiol derivative and a pharmaceutically acceptable carrier.

[0036] Preferably, the dosage form of the pharmaceutical composition is any one of the following: tablets, capsules, powders, granules, syrups, liquids, transdermal patches, suspensions, lyophilized powder for injection, or injections.

[0037] Compared with the prior art, the present invention has the following beneficial effects:

[0038] Currently, antidepressants developed based on the monoamine hypothesis and commonly used in clinical practice generally suffer from drawbacks such as single target and numerous side effects. The estradiol derivative of this invention can simultaneously and effectively inhibit SERT and activate ERβ, thereby synergistically enhancing serotonergic neurotransmission and regulating neuroplasticity. Through multi-target synergistic effects, it enhances the antidepressant efficacy, has the characteristics of high efficiency and safety, and can also avoid many of the side effects of current antidepressants, showing promise for development into a novel antidepressant. Attached Figure Description

[0039] Figure 1 Compound I1 - Compound I 18 Results of in vitro cytotoxicity studies and cytoprotective activity against corticosterone-induced damage to rat adrenal pheochromocytoma (PC12) cells; where A represents the activity test results of different concentrations of corticosterone-induced PC12 cell damage; B represents compound I1-compound I 18 Results of cytoprotective activity assay for PC12 cell damage induced by 200 μM corticosterone.

[0040] Figure 2 The figure shows the effects of the compound on depressive behavior in mice modeled by chronic unpredictable mild stress (CUMS). A represents the total distance traveled in the open field test (OFT); B represents the average speed in the OFT; C represents the number of rearings in the OFT; D represents the immobility time in the forced swimming test (FST); E represents the immobility time in the tail suspension test (TST); and F represents the reversal of the decrease in sugar preference rate in the sugar water preference test (SPT).

[0041] Figure 3 The figure shows the effect of the compound on depressive behavior in mice modeled with chronic social frustration stress (CSDS); where A represents the social interaction ratio in the Social Interaction Test (SIT); B represents the distance in the Off-The-Flight Test (OFT); C represents the average velocity in the OFT; and D represents the immobility time in the Free-Station Test (FST). Figure 3 E represents the static time statistics in TST; F represents the reversal result of the decrease in sugar water preference rate in SPT.

[0042] Figure 4 Compound I 11The results of expression detection of phosphorylated cyclic adenosine monophosphate response element-binding protein (p-CREB), brain-derived neurotrophic factor (BDNF), SERT, and ERβ in the whole brain of mice are shown in the figure. Among them, A is the Western Blot of p-CREB and BDNF proteins, B is the relative expression change of p-CREB protein, C is the relative expression change of BDNF protein, D is the Western Blot of SERT and ERβ proteins, E is the relative expression change of ERβ protein, and F is the relative expression change of SERT protein. Detailed Implementation

[0043] Various exemplary embodiments of the present invention are now described in detail. This detailed description will enable those skilled in the art to fully understand the present invention, but it should not be considered as a limitation of the present invention, but rather as a more detailed description of certain aspects, features, and embodiments of the present invention. It should be understood that the terminology used in this invention is merely for describing particular embodiments and is not intended to limit the present invention.

[0044] Abbreviations: Ethyl acetate: EA; Petroleum ether: PE; Dichloromethane: DCM; Methanol: MeOH; Fluoxetine: Flu.

[0045] Example 1

[0046] Synthesis of (8R,9S,13S,14S,17S)-3-(3-(4-(6-fluoro-1H-indol-3-yl)-3,6-dihydropyridin-1(2H)-yl)propoxy)-13-methyl-7,8,9,11,12,13,14,15,16,17-decahydro-6H-cyclopentan[a]phenanthrene-17-ol (compound I1)

[0047]

[0048] Under ice bath conditions, piperidine-4-one hydrochloride (compound 1, 3.7 g, 27.29 mmol) and 6-fluoro-1H-indole (compound 2a, 1.1 g, 8.14 mmol) were added to a 100 mL flask and dissolved in 40 mL of a 2 mol / L methanol solution of potassium hydroxide. The mixture was refluxed at 80 °C for 7 h under nitrogen protection. The reaction progress was monitored by thin-layer chromatography (TLC) and examined under UV and fluorescence light. After the reaction was complete, a suitable amount of pure water was added to the reaction solution, resulting in the precipitation of a yellow precipitate. The precipitate was filtered, and the filter cake was dried under vacuum to obtain 6-fluoro-3-(1,2,3,6-tetrahydropyridin-4-yl)-1H-indole (compound 3a, yellow solid).

[0049] Add (8R,9S,13S,14S,17S)-13-methyl-7,8,9,11,12,13,14,15,16,17-decahydro-6H-cyclopentadien[a]phenanthrene-3,17-diol (i.e., estradiol, compound 4, 1.8 g, 6.60 mmol) to a 100 mL flask, dissolve in 30 mL of acetone, add cesium carbonate (6.48 g, 19.88 mmol) and 1,3-dibromopropane (2 mL), heat to reflux at 50 °C for 7 h, monitor the reaction progress by TLC, and examine in an iodine tank. After the reaction was complete, the reaction solution was concentrated to 5 mL under reduced pressure, and extracted three times with appropriate amounts of water and ethyl acetate. The organic phases were combined, washed three times with water-saturated sodium chloride solution, and dried over anhydrous sodium sulfate to remove water. The organic phase was concentrated to dryness by rotary evaporation and then subjected to normal-phase silica gel column chromatography (eluent: PE:EA = 12:1V / V) to obtain a white solid, namely (8R,9S,13S,14S,17S)-3-(3-bromopropoxy)-13-methyl-7,8,9,11,12,13,14,15,16,17-decahydro-6H-cyclopentan[a]phenanthrene-17-ol (compound 5a).

[0050] Compound 3a (300 mg, 1.38 mmol) was dissolved in 50 mL of acetonitrile. Anhydrous potassium carbonate (360 mg, 2.60 mmol) and compound 5a (500 mg, 1.22 mmol) were added sequentially, followed by potassium iodide (115 mg, 0.69 mmol) as a catalyst. The reaction was carried out under nitrogen protection at 70 °C overnight under reflux. The reaction progress was monitored by TLC and examined under UV and fluorescence light. After the reaction was completed, an appropriate amount of pure water was added, and the mixture was stirred at room temperature for 30 min. The mixture was then filtered, and the filter cake was collected. Using methanol as a poor solvent, the mixture was purified by stirring at room temperature (25 °C) for 30 min at a filter cake to methanol ratio of 1.2:15 g / mL. The mixture was then filtered, the filter cake was collected, dried under vacuum, and purified by normal-phase silica gel column chromatography (eluent: DCM:MeOH = 95:5 V / V) to obtain compound I1 (white solid, yield 83.1%).

[0051] 1 H NMR (500MHz, DMSO-d6)δ H11.18(s,1H),7.79(dd,J=8.9,5.4Hz,1H),7.38(d,J=2.5Hz,1H),7.19-7.11(m,2H),6.88(td,J=9.3,2.4 Hz,1H),6.68(dd,J=8.5,2.8Hz,1H),6.61(d,J=2.7Hz,1H),6.12(d,J=3.5Hz,1H),4.52(d,J=4.7Hz,1H), 3.98(t,J=6.4Hz,2H,3.52(s,1H),3.13(q,J=2.9Hz,2H),2.76(q,J=4.3Hz,2H),2.65(t,J=5.8Hz,2H),2. 55(d,J=7.0Hz,2H),2.49(s,1H),2.31-2.20(m,1H),2.16-2.04(m,1H),1.99-1.04(m,14H),0.66(s,3H). 13 C NMR(125MHz,DMSO-d6)δc 160.06,156.92,137.91,137.46,137.36,132.65,129.83,126.62,123 .78,122.06,121.61,118.42,114.61,112.52,108.08,98.20,80.55,66 .15,54.96,53.34,50.62,50.04,44.03,43.31,39.11,37.09,30.41,29.74,28.99,27.37,27.04,26.55,23.28,11.76.HRMS(ESI)calculated for C 34 H 41 FN2O2[M+H] + :529.3225,found 529.3205.

[0052] Example 2

[0053] Synthesis of (8R,9S,13S,14S,17S)-3-(4-bromobutyl)-13-methyl-7,8,9,11,12,13,14,15,16,17-decahydro-6H-cyclopentadien[a]phenanthrene-17-ol (compound I2)

[0054]

[0055] Referring to Example 1, (8R,9S,13S,14S,17S)-3-(4-bromobutoxy)-13-methyl-7,8,9,11,12,13,14,15,16,17-decahydro-6H-cyclopentan[a]phenanthrene-17-ol (compound 5b) was synthesized by replacing 1,3-dibromopropane with an equal amount of 1,4-dibromobutane in Example 1. Compound 5a in Example 1 was replaced with an equal amount of compound 5b under otherwise unchanged conditions to obtain compound I2 (white solid, yield 76%).

[0056] 1 H NMR (500MHz, DMSO-d6)δ H 11.16(s,1H),7.79(dd,J=8.9,5.5Hz,1H),7.37(d,J=2.5Hz,1H),7.14(dd,J=9.9,2.4Hz,2H),6.88(td,J=9.3 ,2.5Hz,1H),6.69(dd,J=8.6,2.7Hz,1H),6.61(d,J=2.7Hz,1H),6.12(d,J=3.5Hz,1H),4.49(d,J=4.8Hz,1H),3 .95(t,J=6.4Hz,2H),3.52(td,J=8.4,3.9Hz,1H),3.10(q,J=2.9Hz,2H),2.81-2.72(m,2H),2.62(t,J=5.7Hz,2 H), 2.49 (s, 1H), 2.44 (t, J = 7.1Hz, 2H), 2.29-2.19 (m, 1H), 2.14-2.03 (m, 1H), 1.93-1.04 (m, 16H), 0.66 (s, 3H). 13 C NMR (125MHz, DMSO-d6)δc 160.05,156.90,137.88,137.46,137.36,132.58,129.81,126.59,123.7 2,122.07,121.62,118.58,114.65,112.52,108.06,98.18,80.55,67.61 ,57.88,53.31,50.57,50.04,44.02,43.31,39.10,37.09,30.42,29.74,29.08,27.36,27.15,26.52,23.53,23.27,11.75.HRMS(ESI)calculated for C 35 H 43 FN2O2[M+H] + :543.3381,found 543.3360.

[0057] Example 3

[0058] (8R,9S,13S,14S,17S)-3-((5-(4-(6-fluoro-1H-indol-3-yl)-3,6-dihydropyridin-1(2H)-yl)pentyl)oxy)-13-methyl-7,8,9,11,12,13,14,15,16,17-decahydro-6H-cyclopentan[a]phenanthrene-17-ol (compound I3)

[0059]

[0060] Referring to Example 1, 1,3-dibromopropane in Example 1 was replaced with an equal amount of 1,5-dibromopentane to generate (8R,9S,13S,14S,17S)-3-((5-bromopentyl)oxy)-13-methyl-7,8,9,11,12,13,14,15,16,17-decahydro-6H-cyclopentan[a]phenanthrene-17-ol (compound 5c); Compound 5a in Example 1 was replaced with an equal amount of compound 5c, with other conditions remaining unchanged, to obtain compound I3 (white solid, yield 75%).

[0061] 1 H NMR (500MHz, DMSO-d6)δ H 11.16(s,1H),7.78(dd,J=8.9,5.4Hz,1H),7.37(d,J=2.5Hz,1H),7.20-7.10(m,2H),6.94-6.82(m,1H),6 .67(dd,J=8.6,2.8Hz,1H),6.60(d,J=2.7Hz,1H),6.11(t,J=3.5Hz,1H),4.49(d,J=4.8Hz,1H),3.91(t,J= 6.5Hz,2H),3.52(td,J=8.5,4.2Hz,1H),3.09(q,J=2.8Hz,2H),2.80-2.71(m,2H),2.61(t,J=5.7Hz,2H),2 .48(s,1H),2.40(t,J=7.1Hz,2H),2.30-2.20(m,1H),2.15-2.03(m,1H),1.96-1.03(m,18H),0.66(s,3H). 13CNMR (125MHz, DMSO-d6)δc 160.04,156.93,137.87,137.45,137.35,132.58,129.80,126.59,123.71 ,122.06,121.52,118.53,114.63,112.46,107.87,98.18,80.55,67.72,58 .36,53.32,50.68,50.04,44.03,43.31,39.11,37.09,30.42,29.75,29.21,29.05,27.38,26.80,26.54,24.09,23.28,11.76.HRMS(ESI)calculated forC 36 H 45 FN2O2[M+H] + :557.3538, found 557.3520.

[0062] Example 4

[0063] Synthesis of (8R,9S,13S,14S,17S)-3-((6-(4-(6-fluoro-1H-indol-3-yl)-3,6-dihydropyridin-1(2H)-yl)hexyl)oxy)-13-methyl-7,8,9,11,12,13,14,15,16,17-decahydro-6H-cyclopentan[a]phenanthrene-17-ol (compound I4)

[0064]

[0065] Referring to Example 1, (8R,9S,13S,14S,17S)-3-((6-bromohexyl)oxy)-13-methyl-7,8,9,11,12,13,14,15,16,17-decahydro-6H-cyclopentan[a]phenanthrene-17-ol (compound 5d) was synthesized by replacing 1,3-dibromopropane with an equal amount of 1,6-dibromohexane in Example 1. Compound 5a in Example 1 was replaced with an equal amount of compound 5d under the same conditions to obtain compound I4 (white solid, yield 76%).

[0066] 1 H NMR (500MHz, DMSO-d6)δ H11.16(s,1H),7.78(dd,J=8.9,5.5Hz,1H),7.36(d,J=2.5Hz,1H),7.19-7.09(m,2H),6.93-6.82(m,1H),6 .66(dd,J=8.6,2.7Hz,1H),6.59(d,J=2.7Hz,1H),6.10(t,J=3.6Hz,1H),4.49(d,J=4.8Hz,1H),3.90(t,J= 6.5Hz,2H),3.52(td,J=8.4,3.9Hz,1H),3.08(q,J=2.7Hz,2H),2.81-2.69(m,2H),2.60(t,J=5.6Hz,2H),2 .48(s,4H),2.38(t,J=7.3Hz,2H),2.29-2.20(m,1H),2.15-2.03(m,1H),1.95-1.03(m,20H),0.66(s,3H). 13 C NMR(125MHz,DMSO-d6)δc 160.05,156.93,137.86,137.46,137.37,132.58,129.80,126.57,123.70,1 22.07,121.52,118.52,114.62,112.46,108.05,98.18,80.55,67.69,58.37 ,53.32,50.67,50.04,44.02,43.31,39.10,37.09,30.42,29.74,29.24,29.04,27.37,27.23,27.02,26.53,26.01,23.28,11.75.HRMS(ESI)calculated forC 37 H 47 FN2O2[M+H] + :571.3694,found 571.3672.

[0067] Example 5

[0068] Synthesis of (8R,9S,13S,14S,17S)-3-((7-(4-(6-fluoro-1H-indol-3-yl)-3,6-dihydropyridin-1(2H)-yl)heptyl)oxy)-13-methyl-7,8,9,11,12,13,14,15,16,17-decahydro-6H-cyclopentan[a]phenanthrene-17-ol (compound I5)

[0069]

[0070] Referring to Example 1, 1,3-dibromopropane in Example 1 was replaced with an equal amount of 1,7-dibromoheptane to generate (8R,9S,13S,14S,17S)-3-((7-bromoheptyl)oxy)-13-methyl-7,8,9,11,12,13,14,15,16,17-decahydro-6H-cyclopentan[a]phenanthrene-17-ol (compound 5e); Compound 5a in Example 1 was replaced with an equal amount of compound 5e, with other conditions remaining unchanged, to obtain compound I5 (white solid, yield 81%).

[0071] 1 H NMR (500MHz, DMSO-d6)δ H 11.17(s,1H),7.78(dd,J=8.8,5.4Hz,1H),7.37(d,J=2.2Hz,1H),7.19-7.10(m,2H),6.88(td,J=9.3,2.4Hz ,1H),6.66(dd,J=8.5,2.7Hz,1H),6.59(d,J=2.7Hz,1H),6.11(d,J=3.6Hz,1H),4.49(d,J=4.8Hz,1H),3.89 (t,J=6.5Hz,2H),3.52(td,J=8.4,4.6Hz,1H),3.17-3.05(m,2H),2.79-2.71(m,2H),2.63(d,J=5.8Hz,2H), 2.48(s,1H),2.41(t,J=7.4Hz,2H),2.32-2.20(m,1H),2.15-2.03(m,1H),1.93-1.04(m,22H),0.66(s,3H). 13 C NMR(125MHz,DMSO-d6)δc 160.06,156.93,137.83,137.48,137.38,132.57,129.82,126.55,123.75,12 2.05,121.49,116.53,114.60,112.39,108.07,98.20,80.55,67.66,58.29,53 .15,50.57,50.04,44.01,43.30,39.10,37.09,30.43,29.75,29.24,29.20,2 8.84,27.42,27.37,26.84,26.55,26.03,23.28,11.74.HRMS(ESI)calculated for C 38 H 49 FN2O2[M+H] + :585.3851,found585.3835.

[0072] Example 6

[0073] Synthesis of (8R,9S,13S,14S,17S)-3-((8-(4-(6-fluoro-1H-indol-3-yl)-3,6-dihydropyridin-1(2H)-yl)octyl)oxy)-13-methyl-7,8,9,11,12,13,14,15,16,17-decahydro-6H-cyclopentan[a]phenanthrene-17-ol (compound I6)

[0074]

[0075] Referring to Example 1, 1,3-dibromopropane in Example 1 was replaced with an equal amount of 1,8-dibromooctane to generate (8R,9S,13S,14S,17S)-3-((8-bromooctyl)oxy)-13-methyl-7,8,9,11,12,13,14,15,16,17-decahydro-6H-cyclopentano[a]phenanthrene-17-ol (compound 5f); Compound 5a in Example 1 was replaced with an equal amount of compound 5f, with other conditions remaining unchanged, to obtain compound I6 (white solid, yield 80%).

[0076] 1 H NMR (500MHz, DMSO-d6)δ H 11.16(s,1H),7.78(dd,J=8.9,5.4Hz,1H),7.36(d,J=2.5Hz,1H),7.17-7.10(m,2H),6.87(td,J=9.3,2.5Hz ,1H),6.65(dd,J=8.5,2.7Hz,1H),6.58(d,J=2.7Hz,1H),6.14–6.05(m,1H),4.49(d,J=4.8Hz,1H),3.89(t, J=6.5Hz,2H),3.52(td,J=8.4,4.2Hz,1H),3.07(q,J=2.8Hz,2H),2.80-2.69(m,2H),2.60(t,J=5.6Hz,2H), 2.48(s,1H),2.37(t,J=7.3Hz,2H),2.29-2.20(m,1H),2.14-2.03(m,1H),1.97-1.01(m,24H),0.66(s,3H). 13 C NMR (125MHz, DMSO-d6)δ C160.05, 156.92, 137.84, 137.45, 137.35, 132.55, 129.78, 126.55, 123.68, 122.05, 121.57, 116.64, 114.58, 112.42, 108.04, 97.97, 80.54, 67.65, 58.47, 53.32 ,50.67,50.02,44.00,43.29,39.09,37.08,30.40,29.72,29.42,29.21,29.20, 29.05,27.42,27.38,27.04,26.52,25.97,23.25,11.73.HRMS(ESI)calculated for C 39 H 51 FN2O2[M+H] + :599.3969,found 599.3992.

[0077] Example 7

[0078] Synthesis of (8R,9S,13S,14S,17S)-3-(3-(4-(6-chloro-1H-indol-3-yl)-3,6-dihydropyridin-1(2H)-yl)propoxy)-13-methyl-7,8,9,11,12,13,14,15,16,17-decahydro-6H-cyclopentan[a]phenanthrene-17-ol (compound I7)

[0079]

[0080] Referring to Example 1, 6-chloro-3-(1,2,3,6-tetrahydropyridin-4-yl)-1H-indole (compound 3b) was synthesized by replacing compound 2a in Example 1 with an equal amount of 6-chloro-1H-indole (compound 2b), and compound 3a in Example 1 was replaced with an equal amount of compound 3b, with other conditions remaining unchanged, to obtain compound I7 (white solid, yield 72%).

[0081] 1 H NMR (500MHz, DMSO-d6)δ H11.27(s,1H),7.81(d,J=8.6Hz,1H),7.43(dd,J=7.8,2.3Hz,2H),7.15(d,J=8.6Hz,1H),7.04(dd,J=8.6,2.0H z,1H),6.68(dd,J=8.6,2.7Hz,1H),6.61(d,J=2.7Hz,1H),6.12(d,J=3.5Hz,1H),4.52(d,J=4.8Hz,1H),3.98( t,J=6.3Hz,2H),3.52(td,J=8.4,4.4Hz,1H),3.16(d,J=7.4Hz,2H),2.81-2.72(m,2H),2.72-2.62(m,2H),2.5 6(s,2H),2.53(s,1H),2.26(dd,J=13.7,3.6Hz,1H),2.10(t,J=10.8Hz,1H),1.99-0.99(m,14H),0.66(s,3H). 13 C NMR (125MHz, DMSO-d6)δ C 156.91,137.91,137.87,132.67,129.72,126.62,126.41,124.31,123 .94,121.88,119.95,118.59,116.58,114.61,112.53,111.79,80.55,6 6.11,54.89,53.24,50.55,50.05,44.03,43.32,39.11,37.09,30.42,29.75,28.96,27.38,26.96,26.55,23.28,11.76.HRMS(ESI)calculated for C 34 H 41 ClN2O2[M+H] + :545.2890,545.2920.

[0082] Example 8

[0083] Synthesis of (8R,9S,13S,14S,17S)-3-(4-(4-(6-chloro-1H-indol-3-yl)-3,6-dihydropyridin-1(2H)-yl)butoxy)-13-methyl-7,8,9,11,12,13,14,15,16,17-decahydro-6H-cyclopentan[a]phenanthrene-17-ol (compound I8)

[0084]

[0085] Referring to Example 1, compound 3b was synthesized by replacing compound 2a in Example 1 with an equal amount of compound 2b; compound 5b was synthesized by replacing 1,3-dibromopropane in Example 1 with an equal amount of 1,4-dibromobutane; compound 3a in Example 1 was replaced with an equal amount of compound 3b, and compound 5a in Example 1 was replaced with an equal amount of compound 5b, with other conditions remaining unchanged, to obtain compound I8 (white solid, yield 74%).

[0086] 1 H NMR (500MHz, DMSO-d6)δ H 11.25(s,1H),7.80(d,J=8.6Hz,1H),7.42(t,J=2.6Hz,2H),7.13(d,J=8.6Hz,1H),7.03(dd,J=8.6,2.0Hz,1H) ,6.68(dd,J=8.6,2.7Hz,1H),6.60(d,J=2.7Hz,1H),6.18-6.04(m,1H),4.52(d,J=4.7Hz,1H),3.94(t,J=6.4Hz ,2H),3.52(td,J=8.3,3.7Hz,1H),3.09(q,J=2.9Hz,2H),2.79-2.70(m,2H),2.62(t,J=5.6Hz,2H),2.49(s,1H) ,2.43(t,J=7.1Hz,2H),2.23(dd,J=13.5,3.8Hz,1H),2.08(t,J=11.4Hz,1H),1.92-1.03(m,16H),0.65(s,3H). 13 C NMR (125MHz, DMSO-d6)δ C 156.89,137.87,137.87,132.58,129.69,126.59,126.39,124.23,123.9 6,121.89,119.92,118.79,116.66,114.65,112.51,111.77,80.55,67.5 9,57.82,53.23,50.52,50.04,44.02,43.31,39.10,37.09,30.43,29.74,29.04,27.36,27.14,26.53,23.48,23.28,11.75.HRMS(ESI)calculated for C 35 H 43 ClN2O2[M+H] + :559.3047,found559.3075.

[0087] Example 9

[0088] Synthesis of (8R,9S,13S,14S,17S)-3-((5-(4-(6-chloro-1H-indol-3-yl)-3,6-dihydropyridin-1(2H)-yl)pentyl)oxy)-13-methyl-7,8,9,11,12,13,14,15,16,17-decahydro-6H-cyclopentan[a]phenanthrene-17-ol (compound I9)

[0089]

[0090] Referring to Example 1, compound 3b was synthesized by replacing compound 2a in Example 1 with an equal amount of compound 2b; compound 5c was synthesized by replacing 1,3-dibromopropane in Example 1 with an equal amount of 1,5-dibromopentane; and compound 3a in Example 1 was replaced with an equal amount of compound 3b, and compound 5a in Example 1 was replaced with an equal amount of compound 5c, with other conditions remaining unchanged, to obtain compound I9 (white solid, yield 71%).

[0091] 1 H NMR (500MHz, DMSO-d6)δ H 11.25(s,1H),7.79(d,J=8.6Hz,1H),7.41(dd,J=4.0,2.3Hz,2H),7.13(d,J=8.6Hz,1H),7.03(dd,J=8. 6,2.0Hz,1H),6.66(dd,J=8.6,2.7Hz,1H),6.59(d,J=2.7Hz,1H),6.10(t,J=3.6Hz,1H),4.50(d,J=4.7H z,1H),3.90(t,J=6.5Hz,2H),3.51(td,J=8.4,3.7Hz,1H),3.10(s,2H),2.79-2.70(m,2H),2.62(d,J=5. 8Hz,2H),2.45-2.38(m,2H),2.28-2.20(m,1H),2.08(t,J=8.9Hz,1H),1.96-1.00(m,18H),0.65(s,3H). 13 C NMR (125MHz, DMSO-d6)δ C156.93,137.87,137.87,132.59,129.69,126.58,126.40,124.28,123.94 ,121.86,119.94,118.51,116.58,114.63,112.45,111.79,80.55,67.70,5 8.19,53.13,50.55,50.04,44.02,43.31,39.11,37.09,30.42,29.75,29.18,28.87,27.37,26.63,26.54,24.04,23.28,11.76.HRMS(ESI)calculated forC 36 H 45 ClN2O2[M+H] + :573.3203,found 573.3230.

[0092] Example 10

[0093] (8R,9S,13S,14S,17S)-3-((6-(4-(6-chloro-1H-indol-3-yl)-3,6-dihydropyridin-1(2H)-yl)hexyl)oxy)-13-methyl-7,8,9,11,12,13,14,15,16,17-decahydro-6H-cyclopentan[a]phenanthrene-17-ol (compound I) 10 Synthesis of

[0094]

[0095] Referring to Example 1, compound 3b was synthesized by replacing compound 2a in Example 1 with an equal amount of compound 2b; compound 5d was synthesized by replacing 1,3-dibromopropane in Example 1 with an equal amount of 1,6-dibromohexane; and compound 3a in Example 1 was replaced with an equal amount of compound 3b, and compound 5a in Example 1 was replaced with an equal amount of compound 5d, with other conditions remaining unchanged, to obtain compound I. 10 (White solid, yield 76%).

[0096] 1 H NMR (500MHz, DMSO-d6)δ H11.26(s,1H),7.80(d,J=8.6Hz,1H),7.42(t,J=2.6Hz,2H),7.13(d,J=8.6Hz,1H),7.03(dd,J=8.6,2.0Hz,1H ),6.65(dd,J=8.6,2.7Hz,1H),6.58(d,J=2.7Hz,1H),6.10(t,J=3.6Hz,1H),4.52(d,J=4.8Hz,1H),3.89(t,J= 6.4Hz,2H),3.52(td,J=8.5,4.1Hz,1H),3.10(s,2H),2.79-2.70(m,2H),2.63(t,J=5.6Hz,2H),2.48(s,1H), 2.40(t,J=7.2Hz,2H),2.24(dd,J=13.6,3.6Hz,1H),2.08(t,J=10.6Hz,1H),1.90-1.05(m,20H),0.66(s,3H). 13 C NMR(125MHz,DMSO-d6)δc 156.92,137.88,137.86,132.58,129.69,126.58,126.41,124.27,123.95,1 21.86,119.94,118.52,116.59,114.62,112.46,111.79,80.55,67.68,58.2 1,53.15,50.55,50.04,44.01,43.31,39.10,37.09,30.43,29.74,29.23,28 .87,27.37,27.17,26.85,26.54,25.99,23.28,11.75.HRMS(ESI)calculated for C 37 H 47 ClN2O2[M+H] + :587.3360,found 587.3387.

[0097] Example 11

[0098] (8R,9S,13S,14S,17S)-3-((7-(4-(6-chloro-1H-indol-3-yl)-3,6-dihydropyridin-1(2H)-yl)heptyl)oxy)-13-methyl-7,8,9,11,12,13,14,15,16,17-decahydro-6H-cyclopentan[a]phenanthrene-17-ol (compound I) 11 Synthesis of

[0099]

[0100] Referring to Example 1, compound 3b was synthesized by replacing compound 2a in Example 1 with an equal amount of compound 2b; compound 5e was synthesized by replacing 1,3-dibromopropane in Example 1 with an equal amount of 1,7-dibromoheptane; and compound 3a in Example 1 was replaced with an equal amount of compound 3b, and compound 5a in Example 1 was replaced with an equal amount of compound 5e, with other conditions remaining unchanged, to obtain compound I. 11 (White solid, yield 85%).

[0101] 1 H NMR (500MHz, DMSO-d6)δ H 11.25(s,1H),7.79(d,J=8.6Hz,1H),7.41(d,J=2.1Hz,2H),7.13(d,J=8.7Hz,1H),7.03(dd,J=8.6,2.0Hz,1H), 6.65(dd,J=8.5,2.7Hz,1H),6.58(d,J=2.7Hz,1H),6.10(t,J=3.7Hz,1H),4.52(d,J=4.7Hz,1H),3.89(t,J=6.5H z,2H),3.51(td,J=8.5,4.3Hz,1H),3.07(q,J=2.8Hz,2H),2.80-2.69(m,2H),2.59(t,J=5.6Hz,2H),2.48(s,1H ),2.37(t,J=7.3Hz,2H),2.24(dd,J=13.5,3.5Hz,1H),2.08(t,J=11.6Hz,1H),1.94-1.03(m,22H),0.66(s,3H). 13 C NMR(125MHz,DMSO-d6)δc 156.92,137.86,137.85,132.57,129.66,126.57,126.37,124.17,123.96,12 1.87,119.90,118.89,116.70,114.61,112.42,111.76,80.54,67.66,58.44,5 3.32,50.65,50.03,44.01,43.30,39.10,37.09,30.42,29.74,29.20,29.20,2 9.10,27.45,27.37,27.01,26.54,26.01,23.27,11.75.HRMS(ESI)calculated for C 38 H 49 ClN2O2[M+H] +:601.3555,found 601.3543.

[0102] Example 12

[0103] (8R,9S,13S,14S,17S)-3-((8-(4-(6-chloro-1H-indol-3-yl)-3,6-dihydropyridin-1(2H)-yl)octyl)oxy)-13-methyl-7,8,9,11,12,13,14,15,16,17-decahydro-6H-cyclopentan[a]phenanthrene-17-ol (compound I) 12 Synthesis of

[0104]

[0105] Referring to Example 1, compound 3b was synthesized by replacing compound 2a in Example 1 with an equal amount of compound 2b; compound 5f was synthesized by replacing 1,3-dibromopropane in Example 1 with an equal amount of 1,8-dibromooctane; and compound 3a in Example 1 was replaced with an equal amount of compound 3b, and compound 5a in Example 1 was replaced with an equal amount of compound 5f, with other conditions remaining unchanged, to obtain compound I. 12 (White solid, yield 80%).

[0106] 1 H NMR (500MHz, DMSO-d6)δ H 11.25(s,1H),7.79(d,J=8.6Hz,1H),7.46-7.37(m,2H),7.13(d,J=8.6Hz,1H),7.03(dd,J=8.6,2.0Hz,1H),6. 64(dd,J=8.6,2.7Hz,1H),6.58(d,J=2.7Hz,1H),6.09(t,J=3.7Hz,1H),4.51(d,J=4.8Hz,1H),3.88(t,J=6.5Hz ,2H),3.51(td,J=8.4,4.1Hz,1H),3.06(q,J=2.8Hz,2H),2.79-2.70(m,2H),2.59(t,J=5.6Hz,2H),2.48(s,1H) ,2.36(t,J=7.3Hz,2H),2.24(dd,J=13.4,3.6Hz,1H),2.08(t,J=11.8Hz,1H),1.97-0.99(m,24H),0.65(s,3H). 13C NMR(125MHz,DMSO-d6)δc 156.93,137.87,137.84,132.56,129.67,126.56,126.38,124.16,123.97,121. 86,119.90,118.90,116.71,114.59,112.41,111.77,80.55,67.67,58.48,53.3 3,50.66,50.03,44.01,43.30,39.10,37.09,30.43,29.74,29.44,29.22,29.22 ,29.11,27.42,27.37,27.06,26.54,25.99,23.27,11.75.HRMS(ESI)calculated for C 39 H 51 ClN2O2[M+H] + :615.3711,found615.3731.

[0107] Example 13

[0108] (8R,9S,13S,14S,17S)-13-methyl-3-(3-(methyl(3-phenyl-3-(4-(trifluoromethyl)phenoxy)propyl)amino)propoxy)-7,8,9,11,12,13,14,15,16,17-decahydro-6H-cyclopentadien[a]phenanthrene-17-ol (compound I) 13 Synthesis of

[0109]

[0110] Compound 5a was dissolved in 50 mL of acetonitrile, and N-methyl-3-phenyl-3-(4-(trifluoromethyl)phenoxy)prop-1-amine hydrochloride (compound 6, 1.1 eq) and anhydrous potassium carbonate (2 eq) were added sequentially. The mixture was refluxed at 100 °C overnight under nitrogen protection. The reaction progress was monitored by TLC and examined under UV light. After the reaction was completed, the reaction solution was concentrated to 5 mL under reduced pressure, and extracted three times with appropriate amounts of water and ethyl acetate. The organic phases were combined, washed three times with water-saturated sodium chloride solution, and dried over anhydrous sodium sulfate. The organic phase was concentrated to dryness by rotary evaporation. The crude product was purified by normal-phase silica gel column chromatography (eluting agent: PE:EA = 3:1 V / V) to obtain compound I. 13 (White solid, yield 70%).

[0111] 1 H NMR (500MHz, DMSO-d6)δ H7.53(d,J=8.4Hz,2H),7.45-7.22(m,5H),7.13(d,J=8.6Hz,1H),7.04(d,J=8.6Hz,2H),6.69-6.49(m,2H),5.50(dd,J=8.3,4.7Hz,1H),4.5 0(d,J=4.6Hz,1H),3.92-3.75(m,2H),3.53(dt,J=8.8,4.3Hz,1H),2.79-2.70(m,2H),2.50-1.93(m,10H),1.87-1.15(m,14H),0.66(s,3H). 13 C NMR(125MHz,DMSO-d6)δc 161.06,156.81,141.50,137.79,132.50,129.03,128.12,127.26,127.22,126 .54,126.47,126.25,123.56,121.60,121.28,116.46,116.46,114.52,112.28, 80.50,77.75,65.56,53.75,53.49,49.96,43.96,43.26,42.48,39.03,37.03, 36.18,30.34,29.67,27.32,27.03,26.47,23.23,11.69.HRMS(ESI)calculated for C 38 H 46 F3NO3[M+H] + :622.3463,found622.3479.

[0112] Example 14

[0113] (8R,9S,13S,14S,17S)-13-methyl-3-(4-(methyl(3-phenyl-3-(4-(trifluoromethyl)phenoxy)propyl)amino)butoxy)-7,8,9,11,12,13,14,15,16,17-decahydro-6H-cyclopentadien[a]phenanthrene-17-ol (compound I) 14 Synthesis of

[0114]

[0115] Referring to Example 13, compound 5a in Example 13 was replaced with an equal amount of compound 5b, while other conditions remained unchanged, to obtain compound I. 14 (White solid, yield 73%).

[0116] 1H NMR (500MHz, DMSO-d6)δ H 7.51(d,J=8.5Hz,2H),7.44-7.19(m,5H),7.12(d,J=8.6Hz,1H),7.01(d,J=8.4Hz,2H),6.64-6.49(m,2H),5.47(dd,J=8.2,4.9Hz,1H),4.5 0(d,J=4.7Hz,1H),3.97-3.79(m,2H),3.52(td,J=8.5,3.3Hz,1H),2.80-2.66(m,2H),2.49-1.99(m,10H),1.94-1.06(m,16H),0.66(s,3H). 13 C NMR(125MHz,DMSO-d6)δc 161.09,156.83,141.51,137.80,132.53,129.06,128.13,127.27,127.24,126.53,126.46,125.98,123.83,121.63,121.38 116.48,116.48,114.51,112.36,80.51,77.88,67.44,57.16,53.41,49.99,43.98,43.27,42.27,3 9.06,37.04,36.15,30.36,29.69,27.34,27.01,26.50,23.69,23.24,11.70.HRMS(ESI)calculated for C 39 H 48 F3NO3[M+H] + :636.3659,found 636.3636.

[0117] Example 15

[0118] (8R,9S,13S,14S,17S)-13-methyl-3-((5-(methyl(3-phenyl-3-(4-(trifluoromethyl)phenoxy)propyl)amino)pentyl)oxy)-7,8,9,11,12,13,14,15,16,17-decahydro-6H-cyclopentan[a]phenanthrene-17-ol (compound I) 15 Synthesis of

[0119]

[0120] Referring to Example 13, compound 5a in Example 13 was replaced with an equal amount of compound 5c, while other conditions remained unchanged, to obtain compound I. 15 (White solid, yield 71%).

[0121] 1 H NMR (500MHz, DMSO-d6)δ H 7.55(d,J=8.5Hz,2H),7.48-7.20(m,5H),7.14(d,J=8.6Hz,1H),7.05(d ,J=8.6Hz,2H),6.70-6.52(m,2H),5.50(dd,J=8.3,4.7Hz,1H),4.50(d,J =4.7Hz,1H),3.84(t,J=6.5Hz,2H),3.52(td,J=8.6,3.8Hz,1H),2.75(q, J=4.5,3.8Hz,2H),2.50-1.97(m,10H),1.88-1.09(m,18H),0.66(s,3H). 13 C NMR (125MHz, DMSO-d6) δc161.10,156.88,141.48,137.81,132.54,129.06,128.15,127. 26,127.23,126.55,126.48,125.98,123.83,121.64,121.38,116.48,116.48,114.51,11 2.37,80.51,77.84,67.59,57.44,53.37,49.99,43.98,43.27,42.32,39.06,37.04,36.0 7,30.36,29.69,29.08,27.33,26.86,26.49,23.89,23.24,11.70.HRMS(ESI)calculated for C 40 H 50 F3NO3[M+H] + :650.3816,found650.3816.

[0122] Example 16

[0123] (8R,9S,13S,14S,17S)-13-methyl-3-((6-(methyl(3-phenyl-3-(4-(trifluoromethyl)phenoxy)propyl)amino)hexyl)oxy)-7,8,9,11,12,13,14,15,16,17-decahydro-6H-cyclopentan[a]phenanthrene-17-ol (compound I) 16 Synthesis of

[0124]

[0125] Referring to Example 13, compound 5a in Example 13 was replaced with an equal amount of compound 5d, while other conditions remained unchanged, to obtain compound I. 16 (White solid, yield 77%).

[0126] 1 H NMR (500MHz, DMSO-d6)δ H 7.53(d,J=8.6Hz,2H),7.44-7.22(m,5H),7.13(d,J=8.7Hz,1H),7.04(d,J =8.5Hz,2H),6.67-6.53(m,2H),5.48(dd,J=8.3,4.8Hz,1H),4.50(d,J=4. 8Hz,1H),3.83(t,J=6.5Hz,2H),3.52(td,J=8.6,3.9Hz,1H),2.74(dq,J=1 0.4,6.4,5.5Hz,2H),2.50-1.97(m,10H),1.95-1.04(m,20H),0.66(s,3H). 13 C NMR(125MHz,DMSO-d6)δc161.12,156.88,141.51,137.81,132.53,129.05,128.13,127.27 ,127.24,126.54,126.45,123.84,125.99,121.65,121.39,116.48,116.47,114.52,112.3 7,80.51,77.83,67.57,57.56,53.31,50.00,43.98,43.27,42.34,39.07,37.05,36.10,30 .37,29.70,29.13,27.34,27.13,27.01,26.50,25.89,23.24,11.71.HRMS(ESI)calculated forC 41 H 52 F3NO3[M+H] + 664.3961, found 664.3945.

[0127] Example 17

[0128] (8R,9S,13S,14S,17S)-13-methyl-3-((7-(methyl(3-phenyl-3-(4-(trifluoromethyl)phenoxy)propyl)amino)heptyl)oxy)-7,8,9,11,12,13,14,15,16,17-decahydro-6H-cyclopentadien[a]phenanthrene-17-ol (compound I) 17 Synthesis of

[0129]

[0130] Referring to Example 13, compound 5a in Example 13 was replaced with an equal amount of compound 5e, while other conditions remained unchanged, to obtain compound I. 17 (White solid, yield 74%).

[0131] 1 H NMR (500MHz, DMSO-d6)δ H 7.53(d,J=8.6Hz,2H),7.44-7.21(m,5H),7.13(d,J=8.6Hz,1H),7.04(d,J=8.6Hz,2H),6.68-6.52(m,2H),5.48(dd,J=8.4,4.7Hz,1H),4.51( d,J=4.6Hz,1H),3.85(t,J=6.5Hz,2H),3.52(td,J=8.6,2.9Hz,1H),2.80-2.72(m,2H),2.50-2.00(m,10H),1.93-1.09(m,22H),0.66(s,3H). 13 C NMR(125MHz,DMSO-d6)δc 161.08,156.88,141.45,137.81,132.52,129.07,128.16,127.27,127.24,126.55,12 6.43,125.99,123.83,121.69,121.40,116.47,116.47,114.53,112.37,80.51,77.74, 67.60,57.50,53.18,49.99,43.98,43.27,42.19,39.06,37.05,37.04,30.37,29.71, 29.31,29.15,29.14,27.34,27.15,26.50,25.92,23.24,11.71.HRMS(ESI)calculated for C 42 H 54 F3NO4[M+H] + 678.4129, found 678.4129.

[0132] Example 18

[0133] (8R,9S,13S,14S,17S)-13-methyl-3-((8-(methyl(3-phenyl-3-(4-(trifluoromethyl)phenoxy)propyl)amino)octyl)oxy)-7,8,9,11,12,13,14,15,16,17-decahydro-6H-cyclopentan[a]phenanthrene-17-ol (compound I) 18 Synthesis of

[0134]

[0135] Referring to Example 13, compound 5a in Example 13 was replaced with an equal amount of compound 5f, while other conditions remained unchanged, to obtain compound I. 18 (White solid, yield 71%).

[0136] 1 H NMR (500MHz, DMSO-d6)δ H 7.53(d,J=8.6Hz,2H),7.44-7.22(m,5H),7.13(d,J=8.6Hz,1H),7.04(d,J=8.6 Hz,2H),6.68-6.52(m,2H),5.49(dd,J=8.4,4.7Hz,1H),4.50(d,J=4.8Hz,1H), 3.86(t,J=6.5Hz,2H),3.52(dt,J=9.3,4.7Hz,1H),2.74(dq,J=10.2,6.2,5.3H z,2H),2.61-2.53(m,1H),2.45-2.03(m,9H),2.01-1.03(m,24H),0.66(s,3H). 13 CNMR(125MHz,DMSO-d6)δc 161.11,156.88,141.52,137.81,132.53,129.06,128.14,127.27,127.24,126.55,126. 44,125.99,123.84,121.64,121.38,116.46,116.46,114.52,112.37,80.51,77.80,67. 58,57.61,53.26,49.99,43.98,43.27,42.34,39.06,37.04,36.10,30.36,29.70,29.13 ,29.10,29.09,27.34,27.22,27.09,26.50,25.91,23.24,11.71.HRMS(ESI)calculated for C 43 H 56 F3NO4[M+H] +692.4285, found 692.4264.

[0137] Example 19

[0138] Example 1 of effect verification

[0139] Compound I1 - Compound I 18 In vitro cytotoxicity and cytoprotective activity against corticosterone-induced PC12 cell damage.

[0140] (I) In order to investigate and evaluate compound I1-compound I 18 To investigate the potential toxicity of compound I1 to nerve cells, the inventors used the CCK8 assay. 18 Cytotoxicity in PC12. The specific experimental procedure is as follows:

[0141] Remove PC12 cells stored at -80℃ and immediately transfer them to a 37℃ water bath for resuscitation. Centrifuge at 1000 rpm for 5 min, remove the supernatant, resuspend the cells in DMEM complete medium, seed the cells in culture flasks, and incubate them in an incubator until they enter the logarithmic growth phase for subsequent experiments. Discard the old medium and wash the culture flasks with phosphate-buffered saline (PBS) to remove poorly functioning cells and metabolites. Add 1 mL of trypsin to digest the cells for 30 s, then add an equal volume of complete medium and gently pipette to stop digestion. Observe the bottom of the flask change from turbid to clear, then centrifuge at 1000 rpm for 5 min. Resuspend the cells in fresh complete medium and dilute the PC12 cells to 5 × 10⁶ cells / mL. 4 / mL, evenly pipette the cells, and seed 100μL into a 96-well plate each time, and incubate for 24h.

[0142] Dosing group: Compound I1-Compound I 18 First, dissolve the compound in a small amount of dimethyl sulfoxide (DMSO), then dilute it to the experimental concentration with complete culture medium to obtain drug-containing complete culture medium. Discard the old culture medium and add fresh drug-containing complete culture medium. Set up 3 replicates per group. The blank group only added an equal amount of complete culture medium and DMSO. Both the drug-treated group and the blank group were cultured for 24 h. Add 10 μL of CCK8 reagent to each well and react in an incubator for 1 h. Subsequently, measure the absorbance (OD value) at 450 nm using a microplate reader, calculate the cell inhibition rate, and calculate the half-maximal inhibitory concentration (IC50) of the compound on PC12 cells. 50 ).

[0143] The formula for calculating cell inhibition rate is: Cell inhibition rate % = [(OD value of blank group – OD value of drug-treated group) / OD value of blank group] × 100%.

[0144] The results are shown in Table 1. All compounds showed positive effects on the IC50 of PC12 cells. 50All values ​​were above 5 μM, indicating that the compounds of this invention have low cytotoxicity and a certain degree of safety.

[0145] Table 1. Compounds I1-I 18 Half-maximal inhibitory concentration for PC12 neurons

[0146]

[0147] (II) Corticosterone can reduce cell viability and induce PC12 cell damage, thereby promoting the development of depression. The corticosterone-induced PC12 cell damage model is a classic in vitro antidepressant drug screening cell model. In vitro cytotoxicity experiments showed that the compounds of this invention had no significant killing effect on PC12 cells. Therefore, the inventors further used the corticosterone-induced PC12 cell damage model to evaluate the neuroprotective effect of the compounds of this invention. The specific experimental procedure is as follows:

[0148] Weigh out corticosterone, add DMSO, and sonicate and vortex until completely dissolved to obtain a 100 mM corticosterone stock solution. Aliquot 30 μL into low-adsorption centrifuge tubes and store at -20°C protected from light. Using the corticosterone stock solution, finely prepare complete culture media with corticosterone concentrations of 50 μM, 100 μM, 200 μM, 400 μM, and 800 μM. Before use, sterilize the working solution using a 0.22 μm filter membrane.

[0149] Weigh out 10 -8 mol compound I 1- compound I 18 Add the compound to a 1.5 mL centrifuge tube, add an appropriate amount of DMSO, and vortex thoroughly to completely dissolve the compound, obtaining a 10 μM stock solution. Take 10 μL of the stock solution and add it to 990 μL of PBS to obtain a 100 nM transition solution. Take 10 μL of the transition solution and add it to 9.99 mL of complete culture medium containing 200 μM corticosterone to obtain the drug-containing culture medium (compound I1-compound I). 18 The final concentration is 0.1 nM.

[0150] PC12 cells were incubated with complete culture medium for 24 h. The old medium was then discarded, and complete culture medium at concentrations of 50 μM, 100 μM, 200 μM, 400 μM, and 800 μM corticosterone were added, respectively. Cell viability was determined using the CCK8 assay. The results are shown below. Figure 1 As shown in Figure A, the cell viability decreased to approximately 50% after treatment with 200 μM corticosterone for 24 h, therefore this concentration was chosen as the modeling condition.

[0151] PC12 cells were seeded in 96-well plates (cell density 5 × 10⁶ cells / well). 4After culturing for 24 hours and observing normal cell growth, the old culture medium was discarded, and the cells were divided into groups for drug administration as follows: blank group (no cells and drugs, only complete culture medium), control group (cells inoculated, but no drug administration), model group (cells inoculated, replaced with complete culture medium with a final concentration of corticosterone of 200 μM), and drug administration group (cells inoculated, replaced with complete culture medium containing both corticosterone and the compound). Each group was incubated for 24 hours, and 10 μL of CCK-8 was added to each well. The cells were cultured for another 1 hour, and the optical density (OD value) of each well was measured at a wavelength of 450 nm to calculate the cell viability.

[0152] Cell survival rate calculation formula: Cell survival rate % = [(OD value of drug-treated group – OD value of blank group) / (OD value of control group – OD value of blank group)] × 100%.

[0153] The results are as follows Figure 1 As shown in B, compound I1-compound I 18 All of these compounds can increase the viability of damaged PC12 cells and protect them from corticosterone-induced neurotoxicity. Among them, compounds I7 and I... 11 I 13 I 16 I 17 The effects are better, especially with compounds I7 and I. 11 The effect is significant, and it can be used as a candidate compound.

[0154] Example 2 of effect verification

[0155] Evaluation of compound I7 and compound I 11 Antidepressant effect in a mouse model of chronic unpredictable mild stress (CUMS).

[0156] Experimental mice: SPF-grade ICR male C57 mice (weight 22±2g, purchased from Nanjing Anjiekang Biotechnology Co., Ltd.).

[0157] One hundred mice were randomly divided into 10 groups: control group, model group, positive control group (Flu), nucleus group (E2), ligand group (PF3A), combined drug administration group (PF3A-E2), low-dose compound I7 group (I7Low), high-dose compound I7 group (I7 High), and compound I... 11 Low-dose group (I) 11 Low) and compound I 11 High-dose group (I) 11 High).

[0158] Except for the control group, mice in all other groups underwent CUMS modeling for 4 weeks. The modeling methods are shown in Table 2.

[0159] Table 2. CUMS Modeling Scheme

[0160]

[0161]

[0162] Tail clamping: Clamp the base of the mouse's tail with a clamp for 15 minutes; Moist bedding: Wet the bedding in the cage with water for 24 hours; Restraint: Place the animal in an artificial ventilated centrifuge tube and restrict its movement for 6 hours; Fasting: Deprive the animal of food for 24 hours; Water restriction: Deprive the animal of water for 24 hours; Standing on ice: Place the animal in a bucket of ice water and make it stand for 15 minutes; Horizontal shaking: Shake the cage horizontally for 15 minutes; No bedding: Deprive the animal of bedding for 24 hours; Foreign object: Place a block in the cage for 24 hours; Reversed day and night: Turn off the lights at 7 am and turn them on at 7 pm until 7 am the next day.

[0163] On the second day of the third week of CUMS modeling, the medication was administered via gavage, 30 minutes before the start of the modeling procedure daily, for two weeks. The interval between consecutive administrations was maintained at 23-25 ​​hours. The dosages were as follows: positive control group (fluoxetine 10 mg / kg), nucleus group (E2 10 mg / kg), ligand group (compound 3b 10 mg / kg), combined administration group (compound 3b and E2 mass ratio 1:1, total dose 10 mg / kg, compound 3b dose 5 mg / kg, E2 dose 5 mg / kg), low-dose compound I7 group (compound I7 dose 5 mg / kg), high-dose compound I7 group (compound I7 dose 10 mg / kg), and compound I... 11 Low-dose group (compound I) 11 The dosage of compound I is 5 mg / kg. 11 In the high-dose group (administered dose 10 mg / kg), the above-mentioned compound or drug was dissolved in physiological saline, and a small amount of DMSO was added to promote dissolution. After thorough mixing, the drug was administered by gavage. Mice in the control group and model group were given an equal volume (10 mL / kg) of DMSO and physiological saline alone. No modeling was performed after the last administration.

[0164] Two hours after the last administration, mice underwent the open field test (OFT), tail suspension test (TST), forced swimming test (FST), and sucrose preference test (SPT). Results are shown below. Figure 2 The study found that, compared with the control group, the model group mice exhibited decreased voluntary movement ability during OFT, specifically a significant reduction in total distance traveled and a significant decrease in average speed. Figure 2 B) A significant increase in the number of times the mice stood upright indicates a decrease in their activity level and a high level of stress. Figure 2 A- Figure 2 C); In FST and TST, the immobility time of the model group mice was significantly increased, indicating an increased sense of despair in the mice. Figure 2 D- Figure 2 E); The above results indicate that the CUMS depression model was successfully established. Compared with the model group, compounds I7 and I... 11 All compounds can reduce FST / TST immobility time and improve stress levels, thereby effectively reversing depressive behavior in model mice. Compound I, in particular, can significantly reduce FST / TST immobility time and improve stress levels. 11 The effect was more significant, superior to compound I7, the positive control drug fluoxetine, the relevant structural control, and the combined administration group. In OFT, specifically, the number of upright movements was significantly reduced, while the total distance traveled and the average speed showed no significant difference, meaning it did not affect the mice's basic activity ability. Figure 2 A- Figure 2 C); In FST and TST, this was specifically manifested as a significant reduction in immobility time, which significantly improved the behavioral despair state in model mice. Figure 2 D- Figure 2 E). The selectivity of sucrose intake in the CUMS model group mice was significantly reduced, but compounds I7 and I were still present. 11 Gavage administration significantly increased the sugar water preference rate in depressed model mice. Figure 2 F). Considering the antidepressant effects of the compound in the CUMS mouse model, compound I was selected. 11 The optimal candidate compounds will be further studied.

[0165] Example 3 of effect verification

[0166] Compound I 11 Antidepressant effect in a mouse model of chronic social frustration stress (CSDS)

[0167] Experimental mice: SPF-grade male ICR C57 mice (weight 22±2g, purchased from Nanjing Anjiekang Biotechnology Co., Ltd.); SPF-grade male ICR CD-1 retired breeding mice (7-8 months old, purchased from Nanjing Annokang Biotechnology Co., Ltd.).

[0168] Screening of aggressive CD-1 male mice: Before modeling, retired male CD-1 breeding mice were housed individually for 7 days to establish territorial awareness. Male C57 mice were then placed in cages with aggressive CD-1 mice. The latency period of the first attack, the number of attacks (biting / chasing, etc.), and the duration of the attack (≥3 seconds of continuous behavior) were recorded. Sixty aggressive CD-1 male mice were selected based on an attack latency period of <30 seconds (high aggression) and an attack frequency of >10 times / 10 minutes.

[0169] Sixty male C57 mice were randomly divided into six groups: control group, model group, positive control group (Flu), combined drug administration group (PF3A-E2), and compound I. 11 Low-dose group (I) 11 Low), compound I 11 High-dose group (I) 11 High). CSDS modeling was performed on all mice except the control group for 17 days. The specific experimental procedure is as follows:

[0170] Implementing social frustration stress: Aggressive CD-1 male mice and C57 mice were placed in separate cages as instructed, allowing the C57 mice to experience social frustration. On the first day, the perforated barrier was removed for direct contact for 10 minutes; on the second day, for 9 minutes; on the third day, for 8 minutes; and thereafter, for 5 minutes each day. Afterward, the aggressor (CD-1 male mouse) and the intruder (C57 mouse) were separated by a perforated barrier, maintaining visual / olfactory contact, and they lived together on opposite sides. During direct contact, the C57 mouse was required to be defeated by the CD-1 male mouse 17 times or more over 17 days. Exposing the C57 mice to different aggressors and repeatedly subjecting them to physiological and psychological stress for a certain period of time ultimately led to social frustration and depressive behaviors such as compliance, surrender, social phobia, and self-isolation.

[0171] On day 4 of CSDS modeling, gavage administration was initiated, with daily gavage administered 30 minutes before the start of the modeling procedure. Administration continued for two weeks, with intervals between administrations maintained at 23-25 ​​hours. Dosage was as follows: positive control group (fluoxetine dose 10 mg / kg), combination therapy group (compound 3b and E2 mass ratio 1:1, total dose 10 mg / kg, compound 3b dose 5 mg / kg, E2 dose 5 mg / kg), and compound I... 11 Low-dose group (administered dose 5 mg / kg), compound I 11 In the high-dose group (administered dose 10 mg / kg), the above-mentioned compound or drug was dissolved in physiological saline, and a small amount of DMSO was added to promote dissolution. After thorough mixing, the drug was administered by gavage. The control group and the model group mice were given an equal volume (10 mL / kg) of DMSO and physiological saline alone.

[0172] Two hours after the last administration, mice underwent Social Interaction Tests (SIT), OFT, TST, FST, and SPT. Results are shown below. Figure 3 The study found that, compared to the control group, the social coefficient of the model group C57 mice was reduced in SIT, indicating that the mice developed social phobia, self-isolation, and social frustration and depression behaviors. Figure 3A); In OFT, the total distance traveled by C57 mice in the model group was significantly reduced, and the average speed was significantly decreased, indicating a decrease in the activity level of the mice. Figure 3 B- Figure 3 C); In FST and TST, the immobility time of C57 mice in the model group was significantly increased, indicating an increased sense of despair in the mice ( Figure 3 D- Figure 3 E); The above results indicate that a CSDS depression model was successfully established. Compared with the model group, compound I 11 It also showed significant antidepressant effects in the CSDS mouse model, and was superior to the positive control fluoxetine group and the combination therapy group. In SIT, specifically, it was demonstrated by the administration of compound I. 11 The social coefficient of the mice was significantly increased, indicating a significant improvement in the social phobia state of the mice. Figure 3 A); In the OFT test, there was no significant difference in the total distance and average speed between the drug-treated group and the model group, meaning it did not interfere with the mice's basic activity ability. Figure 3 B- Figure 3 C) In FST and TST, compound I was given 11 The immobility time of the mice was significantly reduced, which significantly improved the behavioral despair state of the model mice. Figure 3 D- Figure 3 E). The CSDS model group mice showed a significant decrease in selectivity for sucrose intake within 24 hours, but compound I... 11 Gavage administration significantly increased the sugar water preference rate in depressed model mice. Figure 3 F). Overall, compound I 11 It can alleviate depressive-like behavior in CSDS model mice, and its effect is better than that of the positive control drug fluoxetine.

[0173] Example 4 of effect verification

[0174] To clarify compound I 11 To investigate the potential mechanism of action of its antidepressant activity, the inventors first used Western blotting to analyze changes in the expression levels of p-CREB and BDNF in the whole brain tissue of mice. The specific experimental procedure is as follows:

[0175] In efficacy verification example 3, C57 mice were administered the following day after all behavioral tests were completed: positive control group (fluoxetine dose 10 mg / kg), compound I... 11 Low-dose group (administered dose 5 mg / kg), compound I 11In the high-dose group (administered dose 10 mg / kg), the above-mentioned compound or drug was dissolved in an equal volume of physiological saline, and a small amount of DMSO was added to promote dissolution. After thorough mixing, the drug was administered by gavage. The control group and the model group mice were given an equal volume (10 mL / kg) of DMSO and physiological saline alone.

[0176] Two hours after administration, the mice were transferred to the dissection room for tissue sampling. Brain tissue sampling: The mice were euthanized by cervical dislocation, decapitated, and the intact brain tissue was quickly removed. Residual blood was washed away with PBS, and the brain tissue was flash-frozen in dry ice and then stored in a -80°C freezer.

[0177] Brain tissue protein extraction: The entire process was performed on ice at a rapid pace to minimize protein degradation in the brain tissue. 200 mg of whole brain tissue was collected, minced, and placed in 2 mL of lysis buffer. The mixture was incubated on ice for 30 min to lyse. The lysed tissue was then homogenized four times at -10°C and 60 Hz using a cryogenic homogenizer to prepare a brain tissue homogenate. The homogenate was centrifuged at 12,000 rpm for 5 min at 4°C, and the supernatant was carefully collected. Protein quantification was performed using the BCA method, calculating the protein content of each sample based on the measured optical density. Using the sample with the lowest protein concentration as a standard, all samples were adjusted to the same concentration to obtain 200 μL of standardized protein samples. Finally, 50 μL of loading buffer was added to each sample group and mixed thoroughly. The proteins were denatured in a 95°C metal bath for 10 min to obtain protein samples suitable for subsequent experiments.

[0178] Gel preparation: Following the instructions, add 10% ammonium persulfate and TEMED to the 10% separating gel and stacking gel kits, respectively. Vortex to mix, then quickly add the separating gel, and evenly add the stacking gel on top. Insert the sample comb. Place the assembled glass plate in a 37°C oven and allow it to stand until the gel is completely solidified.

[0179] Electrophoresis: Insert the glass plate into the electrophoresis tank, inject the electrophoresis buffer, and slowly pull out the sample comb. After thoroughly vortexing the sample, add it to the lane. Add 5 μL of protein sample and 2 μL of protein marker to each well. Initially, run at a constant voltage of 80V for 30 minutes. After observing the sample, switch the voltage to 120V and continue electrophoresis for 60 minutes.

[0180] Transfer: The polyvinylidene fluoride (PVDF) membrane was pre-activated with methanol and placed on a gel containing the target protein. The transfer current was set to a constant 300 mA for 100 min.

[0181] Immunoblotting: After transfer, the PVDF membrane was washed three times with TBST, 5 min each time, followed by blocking in blocking buffer containing 5% skim milk powder at room temperature for 2 h. After blocking, it was rinsed three times with TBST, 10 min each time. The primary antibody reagent for protein assay was diluted with antibody dilution buffer according to the manufacturer's instructions, and the membrane was treated overnight at 4°C with different primary antibodies. The antibody dilutions were as follows: Serotonin transporter Rabbit pAb (1:750), Estrogen Receptor beta Rabbit pAb (1:2500). The next day, the primary antibody was replaced with TBST, and the membrane was rinsed three times, 10 min each time. The secondary antibody reagent was diluted with TBST and 5% skim milk powder, and the PVDF membrane was placed on a shaker and incubated at low speed at room temperature for 2 h. After incubation, the membrane was rinsed three times with TBST, 5 min each time. The membrane was placed in a Tianneng developer, developing buffer was added, and the band signals were detected. The bands were analyzed using ImageJ.

[0182] The results are as follows Figure 4 A- Figure 4 As shown in Figure F, compared with the control group, the expression levels of p-CREB, BDNF, and ERβ in the brain tissue of the model group mice were significantly decreased, while the expression level of SERT was increased. Compound I 11 It can reverse protein expression levels in CSDS model mice. Compared with the positive control drug fluoxetine, administration of a high dose of compound I... 11 Compound I significantly increased the expression levels of p-CREB, BDNF, and ERβ in mouse brain tissue, while decreasing the expression level of SERT. This indicates that compound I... 11 ERβ can be activated by upregulating p-CREB and promoting BDNF expression, thereby activating the positive feedback loop of BDNF / TrkB and exerting a neuroprotective effect.

[0183] In summary, the compounds of this invention increase serotonin levels in mice by upregulating ERβ expression and downregulating SERT expression, suggesting that they may promote neuroplasticity and counteract depressive-like behavior by activating the p-CREB-BDNF signaling pathway. Compound I, in particular... 11 It is a candidate compound with the potential to be further developed into an antidepressant, showing even more effective efficacy.

[0184] The above description is only a preferred embodiment of the present invention. The scope of protection of the present invention is not limited thereto. Any equivalent substitutions or modifications made by those skilled in the art within the scope of the technology disclosed in the present invention, based on the technical solution and inventive concept of the present invention, should be covered within the scope of protection of the present invention.

Claims

1. An estradiol derivative with the structure shown in Formula I, or a pharmaceutically acceptable salt thereof: in, R is selected from R1 is selected from F, Cl, Br, I; L is selected from straight-chain or branched alkyl groups with 2 to 10 carbon atoms.

2. The estradiol derivative or a pharmaceutically acceptable salt thereof according to claim 1, characterized in that: R1 is selected from F and Cl, and L is selected from -(CH2). n -, n = 3 to 8 integers.

3. Estradiol derivatives with the following structures or pharmaceutically acceptable salts thereof:

4. Estradiol derivatives with the following structures or pharmaceutically acceptable salts thereof:

5. The estradiol derivative or a pharmaceutically acceptable salt thereof according to any one of claims 1-4, characterized in that: Pharmaceutically acceptable salts of the estradiol derivatives include sodium salts, potassium salts, hydrochlorides, hydrobromides, nitrates, perchlorates, phosphates, sulfates, formates, acetates, aconates, ascorbic acid salts, benzenesulfonates, benzoates, cinnamates, citrates, heptanoates, fumarates, glutamates, glycolates, lactates, maleates, malonates, mandelates, methanesulfonates, naphthalene-2-sulfonates, phthalates, salicylates, sorbates, stearates, succinates, tartrates, or p-toluenesulfonates.

6. A method for preparing the estradiol derivative according to claim 1, characterized in that: The synthesis route is as follows: Wherein, R and L are as described in claim 1; Includes the following steps: Step (1): Using acetone as the reaction solvent and cesium carbonate as the acid-binding agent, estradiol reacts with the bromoalkane represented by formula BrLBr to generate compound II; Step (2): Using acetonitrile as the reaction solvent and potassium carbonate as the acid-binding agent, under nitrogen protection, with or without a catalyst, compound RH and compound II react to generate estradiol derivatives.

7. The method for preparing the estradiol derivative according to claim 6, characterized in that: In step (1), the molar ratio of estradiol to bromoalkane is 1:2.75 to 1:3.25; the molar ratio of cesium carbonate to estradiol is 2.75:1 to 3.25:1; and the reaction temperature is the temperature corresponding to the reflux of the reaction system. In step (2), the molar ratio of compound RH to compound II is 1:1 to 1.15:1; the molar ratio of potassium carbonate to compound RH is 1.5:1 to 2:1; and the reaction temperature is the temperature corresponding to the reflux of the reaction system. When R = When compound RH and compound II react in the presence of a catalyst, they generate an estradiol derivative; the catalyst is potassium iodide; the molar ratio of the catalyst to compound RH is 1:

2. When R = When compound RH and compound II react in the absence of a catalyst, they produce an estradiol derivative.

8. The use of the estradiol derivative or a pharmaceutically acceptable salt thereof as described in any one of claims 1-4 in the preparation of a medicament for treating depression and anxiety.

9. The use of the estradiol derivative or a pharmaceutically acceptable salt thereof as described in any one of claims 1-4 in the preparation of a medicament for the treatment of depression and anxiety by targeting ERβ / SERT.

10. A pharmaceutical composition, characterized in that: The pharmaceutical composition comprises the estradiol derivative as described in any one of claims 1-4 and a pharmaceutically acceptable carrier.

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