Abiraterone derivative, preparation method therefor, and use thereof

Abstract

The present invention provides an abiraterone derivative, a preparation method therefor, and a use thereof. The abiraterone derivative has a chemical structural formula as shown in formula (I). The abiraterone derivative of the present invention can be converted in vivo into an active substance abiraterone, has the characteristics of good absorption, good plasma stability, desirable transmembrane transport capability, good potential to be manufactured as a drug, and high safety, and can be used for treating diseases related to androgen excess.

Description

An abiraterone derivative, its preparation method and uses

[0001] This application claims priority to Chinese Patent Application No. CN202510061548.5, filed on January 14, 2025. Technical Field

[0002] This invention relates to the field of medicinal chemistry, specifically to an abiraterone derivative, its preparation method, and its uses. Technical Background

[0003] Prostate cancer is a common type of cancer among men and the fifth leading cause of death in men (A. Barsouk, et al., Med. Sci. 2020, 8(3), 28). Abiraterone is an androgen biosynthesis inhibitor that reduces androgen production by inhibiting 17α-hydroxylase / C17-20 lyase (CYP17) in testicular, adrenal, and prostate tumor tissues, thereby being used to treat prostate cancer.

[0004] Abiraterone's extremely poor solubility (<0.5 μg / mL) leads to difficulty in dissolution after administration, resulting in poor bioavailability and extremely poor intestinal absorption. The abiraterone acetate prodrug, approved by the FDA in 2011, offers limited improvement in abiraterone solubility (<0.5 μg / mL). In artificial membrane permeation assays (PAMPA) simulating intestinal permeability, abiraterone acetate did not exhibit superior properties compared to abiraterone. Some studies suggest that abiraterone acetate may not enter the bloodstream as a prodrug, but rather undergoes localized abiraterone supersaturation due to intestinal esterase degradation (A. Sharma, et al., Molecules, 2022, 27, 2969), allowing the abiraterone molecule to overcome apparent solubility limitations and achieve some bioavailability (T. Solymosi, et al., J. Chem. Eng. Data, 2018, 63, 4453-4458). Besides the aforementioned possible absorption mechanisms, abiraterone may have other absorption mechanisms, but abiraterone and abiraterone acetate do indeed have bioavailability defects. 55% of abiraterone acetate is excreted unchanged in feces, and 22% is excreted in feces as abiraterone, with less than 10% actually entering the bloodstream. Furthermore, another significant drawback of marketed abiraterone acetate formulations is the food effect due to their high lipid solubility, requiring patients to strictly control the timing of medication. This strict timing requirement is extremely unfriendly to the predominantly elderly prostate cancer patient population. Moreover, due to abiraterone's poor pharmacokinetic properties, blood concentrations can vary significantly among different patients, and absorption is affected by gut microbiota and intestinal food (S. Geboers, et al., J. Pharm. Sci., 2016, 105, 2974-2981). Although extensive optimization of abiraterone acetate has been conducted both domestically and internationally through formulation optimization, it remains difficult to fundamentally change its bioavailability and food effects. From an industrialization perspective, the development of related formulations of abiraterone acetate is severely limited due to its poor physicochemical properties. In summary, the clinical application of abiraterone has many shortcomings that urgently need improvement. Developing a drug for abiraterone that can overcome these deficiencies has significant clinical practical value and commercial potential. Summary of the Invention

[0005] This invention, through extensive and in-depth research, has designed and synthesized a series of abiraterone phosphate prodrugs with the general structural formula shown in (I). Pharmacokinetic testing has shown that the abiraterone phosphate prodrugs of this invention are effectively converted into the active substance abiraterone in vivo after administration. Compared with the reference drug, the abiraterone phosphate prodrugs of this invention significantly increase the in vivo exposure of abiraterone, improve the pharmacokinetic properties of abiraterone absorption, and reduce the food effect. At the same dosage, after administration of the abiraterone phosphate prodrugs of this invention, the time to peak concentration and peak concentration of abiraterone in the blood are similar to those of the reference drug, demonstrating the potential to address the shortcomings of the control drug while ensuring clinical safety and efficacy. Current results suggest that the abiraterone phosphate prodrugs of this invention can be used to treat prostate cancer, castration-resistant prostate cancer, or other prostate cancer-related diseases, and can be applied to the development of other formulations, including but not limited to tablets, injections, and oral liquid preparations.

[0006] In a first aspect, the present invention provides a novel abiraterone derivative having the general chemical formula (I), its stereoisomers, and a pharmaceutically acceptable salt thereof:

[0007] In the formula,

[0008] X1 and X2 are independently selected from NH, O, S, or five- or six-membered heterocycles containing N, O, or S;

[0009] A is selected from hydrogen, substituted or unsubstituted C. 1-6 Alkyl, substituted or unsubstituted 5-10 aryl, substituted or unsubstituted 3-6 cycloalkyl, substituted or unsubstituted 5-10 heteroaryl, or

[0010] Any one of them;

[0011] B is selected from

[0012] R1 is selected from hydrogen, substituted or unsubstituted C1-10 alkyl, substituted or unsubstituted C5-12 aryl, substituted or unsubstituted benzyl;

[0013] R2 and R3 are each independently selected from hydrogen, substituted or unsubstituted C. 1-10 Alkyl, substituted or unsubstituted C 5-10 Aryl, substituted or unsubstituted benzyl, mercapto, hydroxyl, amino, hydroxyalkyl, carboxylalkyl, aminoalkyl, mercaptoalkyl, 3-6 membered cycloalkyl, 5-6 membered heterocycloalkyl, 5-10 membered aryl, 5-10 membered heteroaryl;

[0014] R4 and R5 are each independently selected from hydrogen, substituted or unsubstituted C. 1-10 Alkyl, substituted or unsubstituted C5-10 Aryl, benzyl, mercapto, hydroxy, amino, hydroxyalkyl, aminoalkyl, mercaptoalkyl, alkoxycarbonyl, alkylcarbonyl, 3-6 membered cycloalkyl, 5-6 membered heterocycloalkyl, 5-10 membered aryl, 5-10 membered heteroaryl;

[0015] R a R b Each is independently selected from hydrogen, substituted or unsubstituted C. 1-10 Alkyl, substituted or unsubstituted 3-6 membered cycloalkyl, substituted or unsubstituted C 5-10 Aryl, benzyl, mercapto, hydroxy, hydroxyalkyl, amino, aminoalkyl, mercaptoalkyl;

[0016] X3 is selected from O, S, or NH.

[0017] Preferably, A is a benzene ring, X2 is O or S, and B is... It has the structure shown in formula (II-1) or formula (II-2):

[0018] Preferably, X1 and X2 are independently selected from O, S or NH.

[0019] Preferably, the structure of the abiraterone derivative of the present invention is selected from any one of formulas (III) to (X):

[0020] Preferably, when Ra and Rb are each independently selected from thiol groups, the thiol groups of Ra and Rb selectively form disulfide bonds.

[0021] More preferably, the abiraterone derivative of the present invention is selected from any one of the compounds listed in Table 1 below:

[0022] Table 1. Structural formulas and their numbers of compounds.

[0023] A second aspect of the present invention provides a method for preparing the abiraterone derivative of the present invention, its stereoisomers, and pharmaceutically acceptable salts, comprising the following steps:

[0024] in,

[0025] (a) Compound 1 was reacted with N,N-diethylphosphamide di-tert-butyl ester or N,N-diisopropylphosphamide di-tert-butyl ester to give compound 2;

[0026] (b) Compound 2 reacts with dilute hydrochloric acid to hydrolyze and yields compound 3;

[0027] (c) Compound 3 was condensed to give an abiraterone derivative having the structure shown in formula (I), its stereoisomers, and pharmaceutically acceptable salts.

[0028] Preferably, step (a) includes: suspending compound 1 in dichloromethane in an inert gas environment, adding 1H-tetrazole and N,N-diethylphosphamide di-tert-butyl ester, reacting at room temperature for 30 minutes, then cooling to -78°C and reacting for 30 minutes, thereby forming compound 2 through an oxidizing agent.

[0029] Preferably, step (b) includes: dissolving compound 2 in a mixed solvent of dichloromethane and methanol, adding an excess of dilute hydrochloric acid in an organic solvent at 0°C, and reacting for 30 minutes to obtain compound 3.

[0030] Preferably, step (c) includes: dissolving compound 3 and a compound containing hydroxyl, amino, or thiol groups in pyridine, adding an organic nonnucleophilic base, heating to 65°C, adding a pyridine solution of triphenylphosphine and 2,2'-dithiopyridine, and generating the abiraterone derivative after 16 hours.

[0031] Preferably, the volume ratio of dichloromethane to methanol in the above mixed solvent is 5:1, and the above organic solvent is 1,4-dioxane or a saturated alkane.

[0032] It should be understood that the compounds shown in compound (Ⅰ) of this invention can be prepared by those skilled in the art through other organic synthesis methods, and are not limited to the methods described above.

[0033] A third aspect of the present invention is to provide a pharmaceutical composition comprising the abiraterone derivative of the present invention and its stereoisomers and a pharmaceutically acceptable salt, and a pharmaceutically acceptable carrier or excipient.

[0034] The final aspect of the invention provides the use of the abiraterone derivatives of the invention and their stereoisomers and pharmaceutically acceptable salts, or the pharmaceutical compositions thereof, in the preparation of medicaments for treating diseases related to excessive androgen secretion, such as medicaments for treating prostate cancer, castration-resistant prostate cancer, or other prostate cancer-related diseases.

[0035] It should be understood that, within the scope of this invention, the various technical features described above and in detail below can be combined to form new or preferred technical solutions. The various features disclosed in the specification can be replaced by any alternative features that provide the same, equivalent, or similar purpose. Due to space limitations, they will not be elaborated upon here. Attached Figure Description

[0036] Figures 1 to 3 show the serum concentration ratios of abiraterone in serum after administration of the compounds listed in Table 1 to the serum concentration of abiraterone in serum after administration of abiraterone acetate (Q0), where the average concentration of abiraterone in serum after administration of abiraterone acetate is 100%.

[0037] Figure 4 shows the comparison of plasma pharmacokinetic parameters AUC0-t for each compound after a single oral gavage administration in beagle dogs (10 mg / kg, n = 6, Mean ± SD). Detailed Implementation

[0038] the term

[0039] In this invention, unless otherwise specified, the terms used have the general meanings known to those skilled in the art.

[0040] In this invention, the halogen is F, Cl, Br or I.

[0041] In this invention, the term "C1-10 alkyl" refers to a straight-chain or branched saturated alkyl group having 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 carbon atoms. Methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, etc., are preferred.

[0042] In this invention, the term "3-6 membered cycloalkyl" refers to a closed ring system consisting of 3, 4, 5, or 6 carbon atoms. "5-6 membered" and "5-10 membered" are similarly defined, both referring to the number of atoms forming a closed ring system.

[0043] In this invention, the term "heterogeneous" atom refers to atoms other than carbon, such as N, S, O, and P.

[0044] In this invention, the terms "aryl" and "heteroaryl" refer to aromatic compounds in the chemical field. Common five-membered rings include furan, pyrrole, thiophene, imidazole, pyrazole, oxazole, isoxazole, and thiazole; six-membered rings include benzene, pyridine, pyrazine, pyrimidine, pyridazine, and triazine; and polycyclic rings commonly include structures with fused five-membered and six-membered rings, or six-membered and six-membered rings, such as benzimidazole, indole, purine, naphthalene, and quinoline.

[0045] In this invention, the term "unsubstituted" means that the portion outside the skeleton is hydrogen; the term "substituted" means that the portion outside the skeleton has atoms other than hydrogen connected to the skeleton in the form of single bonds. Common substituents include, but are not limited to: methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, tert-butyl, hydroxy, mercapto, amino, nitro, halogen, guanidinyl, urea, cyano, ester, amide, carboxyl, alkoxy, alkylamino, etc.

[0046] In this invention, the term "benzyl" refers to a structure in which a benzyl ring is attached to a methylene group. The term "thiol" is -SH; the term "hydroxyl" is -OH; the term "amino" is -NH2; hydroxyalkyl is -O-alkyl; aminoalkyl is -NH-alkyl; mercaptoalkyl is -S-alkyl; alkoxycarbonyl (ester) is... R represents an alkyl group; alkyl carbonyl group represents... R is an alkyl group; the disulfide bond is -SS-.

[0047] Pharmaceutical Composition

[0048] The present invention also provides a pharmaceutical composition comprising an active ingredient within a safe and effective range, and a pharmaceutically acceptable carrier.

[0049] The "active ingredient" as described in this invention refers to a compound that conforms to the general formula (I) described in this invention.

[0050] The "active ingredient" and pharmaceutical composition described in this invention are used to prepare drugs for treating prostate cancer, castration-resistant prostate cancer, or other prostate cancer-related diseases.

[0051] "Safe and effective range" refers to the dosage range within which the active ingredient can exert its medicinal effect without causing harm to the body. Or, it is the dosage range between the minimum effective dose and the minimum toxic dose.

[0052] "Pharmaceutical acceptable carriers" include additives other than active ingredients that comply with pharmaceutical regulations, including fillers, solvents, solubilizers, cosolvents, excipients, lubricants, pH adjusters, emulsifiers, preservatives, colorants, sustained-release and controlled-release materials, etc.

[0053] The dosage forms of the active ingredients or pharmaceutical compositions of the present invention include, but are not limited to, tablets, injections, powder for injection, suppositories, implants, etc.

[0054] The compounds of this invention can be administered alone or in combination with other drugs for treatment.

[0055] Unless otherwise defined, all terms used herein have the same meanings as those familiar to those skilled in the art. The preferred practices and materials described herein are for illustrative purposes only.

[0056] It should be understood that, within the scope of this invention, the various technical features described herein and in the specific examples below can be combined with each other to form new or preferred technical solutions. Each feature disclosed herein can be replaced by any alternative feature providing the same, equivalent, or similar purpose. Any non-inventory modifications to this invention made using techniques well-known in the art are within the scope of this patent protection.

[0057] The following embodiments are intended to enable those skilled in the art to more clearly understand and implement the present invention. It must be noted that these embodiments are merely illustrative and are not intended to limit the scope of the invention.

[0058] The following reactions were all detected using thin-layer chromatography, with color development using ultraviolet light (in cases with ultraviolet absorption) or thin-layer colorimetric reagents such as potassium permanganate.

[0059] The products in the example reactions, where they could be separated, were structurally determined by nuclear magnetic resonance (NMR) and mass spectrometry (MS).

[0060] Unless otherwise stated, all raw materials and reagents used in the reaction were commercially available or synthesized using known methods. Unless otherwise stated, the raw materials and reagents were used directly without any further processing.

[0061] The compounds were purified using silica gel column chromatography. Commonly used elution systems were: dichloromethane:methanol; petroleum ether:ethyl acetate.

[0062] The inert gas environment mentioned in the example usually refers to a nitrogen environment.

[0063] In this example, the room temperature is typically 20℃-30℃.

[0064] In practice, the overnight reaction time is typically 12-15 hours.

[0065] [Example 1] Preliminary screening of compound activity

[0066] 1.1 Experimental Objective

[0067] Based on publicly available information, compounds with existing information were synthesized, along with some preliminarily synthesized self-designed compounds. Rapid biological activity testing was used to initially screen the compound design ideas, clarifying the potential activities of the patented compounds and verifying the activities of compounds with existing information. This provides reference research data for subsequently clarifying the direction of compound design.

[0068] 1.2 Test Materials

[0069] The reference drugs, abiraterone acetate, abiraterone, and diclofenac sodium, were all purchased from Aladdin (abiraterone, abiraterone acetate: 25mg, purity ≥99%; diclofenac sodium: 5g, purity ≥99%).

[0070] The compounds listed in Table 1 were obtained through in-house synthesis. The synthetic routes and steps are as follows:

[0071] a) Abiraterone 1 was reacted with N,N-diethylphosphamide ditert-butyl ester to give intermediate 2;

[0072] b) Intermediate 2 reacts with dilute hydrochloric acid to hydrolyze and give abiraterone phosphate 3;

[0073] c) Abiraterone phosphate 3 was condensed to obtain target compound I.

[0074] In step a, abiraterone 1 is suspended in dichloromethane under an inert gas atmosphere, and 1H-tetrazole and N,N-diethylphosphite di-tert-butyl ester are added and reacted at room temperature for 30 minutes. Tetrazole replaces the N,N-diethylamino group and reacts with the hydroxyl group of abiraterone to form a trivalent phosphorous intermediate. This reaction solution is then cooled to -78°C and reacted for 30 minutes, forming intermediate 2 through oxidation by an oxidizing agent. The N,N-diethylamino group in N,N-diethylphosphite di-tert-butyl ester can be other types of N,N-disubstituted amino groups. The preferred oxidizing agent is m-chloroperoxybenzoic acid, but other types of organic peroxides can also be used.

[0075] In step b, intermediate 2 is dissolved in a mixed solvent of dichloromethane and methanol, and excess dilute hydrochloric acid in an organic solvent is added at 0°C. After reacting for 30 minutes, intermediate 3 is obtained. The optimal ratio of the mixed solvent of dichloromethane and methanol is 5:1. The solvent for the dilute hydrochloric acid can be 1,4-dioxane or a saturated alkane, or methanol or isopropanol.

[0076] In step c, intermediate 3 is dissolved in pyridine with various hydroxyl, amino, and mercapto compounds. An organic non-nucleophilic base is added, and the mixture is heated to 65°C. A pyridine solution of triphenylphosphine and 2,2'-dithiopyridine is then added. After 16 hours, the target compound (Ⅰ) is generated. The various hydroxyl, amino, and mercapto compounds are the corresponding compounds that conform to the chemical structures of the substituents in general formula (Ⅰ). Typical organic non-nucleophilic bases include triethylamine, N,N-diisopropylethylamine, and 1,8-diazabicyclo[5.4.0]undec-7-ene.

[0077] Drug solution: Prepared according to the FDA Pharmacology Review (APPLICATION NUMBER: 202379Orig1s000, PHARMACOLOGY REVIEW(S), Reference ID: 2935605, page 72) using 15% ethanol, 4% Tween-80, and physiological saline. First, dissolve each compound in an appropriate amount of ethanol, then add Tween-80 and mix thoroughly. Dilute with physiological saline to the required dosing concentration (the dosage of each compound is 20 mg / kg, and the dosing volume is 0.1 mL / 10 g body weight, equivalent to a drug solution concentration of 2 mg / mL).

[0078] KM mice: male, weighing 25-35g, purchased from Guangdong Provincial Medical Animal Center.

[0079] 1.3 Experimental Methods

[0080] Preliminary activity screening tests were conducted on the compounds listed in Table 1.

[0081] The plasma concentrations of abiraterone in mice were determined at specific time points after administration of each compound using LC-MS / MS, and the pharmacokinetic enhancement potential of each compound was preliminarily evaluated.

[0082] Animal administration method: After fasting for 12 hours, all mice were administered each compound solution by gavage at a dose of 10 mg / kg. Referring to the aforementioned FDA information and simplifying the experiment to rapidly obtain data on the required compound exposure levels, and to minimize the loss of biological samples during periods of high exposure, this study obtained mouse blood samples at 0.5 hr, 1 hr, and 2 hr (n=4), and the samples from the three time points were processed and mixed in equal volumes as described below.

[0083] Plasma collection: At each time point in the table above, about 0.1 mL of blood was collected from the inner canthal vein of the mouse eye. The collected whole blood was placed in a centrifuge tube containing EDTA, gently swirled to mix, and centrifuged (1500-1600g, 10 min) to separate the plasma. The obtained plasma sample was stored in a -60°C freezer for later use.

[0084] Biological samples were analyzed using LC-MS / MS. The analytical methods and test conditions are shown in Table 2.

[0085] Table 2 shows the LC-MS / MS analytical methods and test conditions for the compounds listed in Table 1.

[0086] Data processing: The serum concentration of abiraterone after administration of abiraterone acetate was taken as 100%. The serum concentration of abiraterone after administration of other compounds was compared with that after administration of abiraterone acetate to examine the improvement of the pharmacokinetic properties of abiraterone acetate by each compound.

[0087] 1.4 Experimental Results

[0088] The experimental results are shown in Figures 1-3. The results indicate that the exposure levels in mice varied after administration of different compounds. Specifically, the exposure levels of compounds in class Q1 did not increase significantly, while the exposure levels of compounds in classes Q2-Q9 increased significantly.

[0089] Among the Q1 class compounds, Q1-1 is a publicly reported compound (H. Ying, RSC Adv., 2022, 12, 13111-13115). After expanding the structure of Q1, tests were conducted, and the results showed that Q1 class compounds did not significantly increase the in vivo exposure of abiraterone. Therefore, the structural approach of Q1 class compounds was abandoned, and a new drug design was performed using computer-aided drug design software. A small number of representative compounds were synthesized for biological screening. The results showed that Q2-Q9 classes have the potential to increase in vivo exposure.

[0090] To further verify the intended development purpose of the above compounds, small-scale synthesis of each representative compound was subsequently carried out, and in vivo verification was conducted in large animals to further determine the matching between the compounds and the design purpose.

[0091] [Example 2] Synthesis of intermediates

[0092] 2.1 Synthesis of Compound 2

[0093] Compound 2 is (3aS,3bR,7S,9aR,9bS,11aS)-9a,11a-dimethyl-1-(pyridin-3-yl)-3a,3b,4,6,7,8,9,9a,9b,10,11,11a-dodecano-3H-cyclopenta[2,1-i]phenanthrene-7-ylbis(2-methylpropyl-2-yl)phosphate ion, and its chemical structure is shown below:

[0094] Intermediate compound 2 was synthesized using compound 1, namely abiraterone, as a raw material.

[0095] Abiraterone (compound 1, 630.8 mg, 1.8 mmol) was dissolved in 25 mL of anhydrous dichloromethane. Tetraazole (252.87 mg, 3.61 mmol) and N,N-diethylphosphamide di-tert-butyl ester (1 mL, 3.61 mmol) were added under nitrogen atmosphere. After reacting at room temperature for half an hour, the mixture was cooled to -72°C, and a dichloromethane solution of 3-chloroperoxybenzoic acid (934.33 mg, 5.41 mmol dissolved in 20 mL of anhydrous dichloromethane) was slowly added. After one hour, the reaction solution was diluted with another 20 mL of dichloromethane. The mixture was washed successively with sodium thiosulfate solution, sodium bicarbonate solution, and saturated brine, and dehydrated with sodium sulfate or magnesium sulfate. The collected organic phase was filtered and concentrated using a rotary evaporator. The oily crude product was eluted using a petroleum ether:ethyl acetate gradient system. The product was a colorless oily substance. Yield: 778.4 mg (79.62%).

[0096] H 1NMR (CDCl3): 8.63 (s, 1H), 8.48 (d, J=3.7Hz, 1H), 7.70 (dt, J=7.8, 1.7Hz, 1H), 7 .27 (m, 1H), 6.03 (m, 1H), 5.42 (m, 1H), 4.15 (m, 1H), 2.48 (m, 2H), 2.28 (ddd, J=1 5.8, 6.5, 3.3Hz, 1H), 2.06 (m, 4H), 1.98 (m, 4H), 1.86 (dt, J=21.6, 7.3Hz, 1H), 1 .76(m, 2H), 1.62(m, 5H), 1.50(s, 18H), 1.14(m, 1H), 1.08(s, 3H), 1.04(s, 3H).

[0097] C 13 NMR (CDCl3): 151.39, 147.21, 147.13, 140.32, 134.23, 133.24, 129.65, 123.22, 122.10, 77.26, 77.20, 5 7.46, 51.89, 50.20, 47.31, 40.05, 36.90, 35.16, 31.80, 31.47, 30.37, 29.91, 29.87, 20.78, 19.22, 16.54

[0098] P 31 NMR (CDCl3): -10.38

[0099] Mass spectrometry (ESI): Theoretical value: 542.33 (M+H) + Measured value: 542.3332 (M+H) +

[0100] 2.2 Synthesis of Compound 3

[0101] Compound 3 is P,P-dihydroxyphosphono-(3aS,3bR,7S,9aR,9bS,11aS)-9a,11a-dimethyl-1-(pyridin-3-yl)-3a,3b,4,6,7,8,9,9a,9b,10,11,11a-dodecano-3H-cyclopenta[2,1-i]phenanthrene-7-yl ester, and its chemical structural formula is shown below:

[0102] Compound 2 (541.71 mg, 1.0 mmol) was dissolved in a mixed solvent of 15 mL anhydrous dichloromethane and 3 mL anhydrous methanol. The solution was cooled to 0 °C, and 2 mL of a 4N hydrogen chloride solution of dioxane was added under nitrogen protection. After reacting for half an hour, the solution was concentrated under reduced pressure to remove all volatile components. The remaining white solid was the product. Yield: 420.5 mg (97.91%).

[0103] H 1 NMR (MeOD): 8.78 (s, 1H), 8.63 (d, J=5.3Hz, 1H), 8.46 (d, J=8.2Hz, 1H), 7.88 (dd, J =8.1, 5.6Hz, 1H), 6.40(m, 1H), 5.47(m, 1H), 4.06(m, 1H), 2.43(m, 3H), 2.15(m, 3H) , 2.03 (d, J=12.3Hz, 1H), 1.93 (m, 1H), 1.83 (dd, J=10.8, 4.8Hz, 1H), 1.70 (m, 5H), 1.54(td, J=11.7, 6.2Hz, 1H), 1.30(m, 2H), 1.15(s, 3H), 1.14(s, 3H), 0.91(m, 1H).

[0104] C13NMR(MeOD): 149.02, 141.08, 140.60, 140.23, 136.09, 133.78, 126.06, 121.77, 76.71, 76.6 7, 57.50, 50.29, 39.77, 36.74, 36.36, 34.57, 31.57, 31.06, 30.22, 29.33, 20.50, 18.23, 15.30.

[0105] P 31 NMR (MeOD): -0.56

[0106] Mass spectrometry (ESI): Theoretical value: 430.22 (M+H) + Measured value: 430.2202 (M+H) +

[0107] [Example 3] Preparation of representative compounds Q1-Q9 of abiraterone derivatives

[0108] 3.1 Preparation of compound Q1-6

[0109] Compound Q1-6 is (3aS,3bR,7S,9aR,9bS,11aS)-9a,11a-dimethyl-1-(pyridin-3-yl)-3a,3b,4,6,7,8,9,9a,9b,10,11,11a-dodecano-3H-cyclopenta[2,1-i]phenanthrene-7-ylphenyl[(2-methoxy-2-oxoylideneethyl)amino]phosphonate ion, and its chemical structure is shown below:

[0110] Compound 3 (395 mg, 0.919 mmol) was dissolved in 10 mL of anhydrous pyridine. Under nitrogen protection, glycine methyl ester hydrochloride (115.47 mg, 0.919 mmol), phenol (86.58 mg, 0.919 mmol), and N,N-diisopropylethylamine (DIPEA, 0.62 mL, 3.68 mmol) were added sequentially, and the mixture was heated to 65 °C. After 10 minutes, a pyridine solution of triphenylphosphine (723.93 mg, 2.76 mmol) and 2,2'-dithiodipyridine (608.05 mg, 2.76 mmol) was added, and the reaction was allowed to proceed for 16 hours. After the reaction, the mixture was concentrated under reduced pressure to remove most of the volatiles, and pyridine was removed by azeotropic addition of toluene in small amounts several times. The crude product was separated using 0–10% methanol:dichloromethane. Yield: 250.8 mg (47.29%).

[0111] H 1 NMR (CDCl3): 8.63 (s, 1H), 8.48 (d, J=4.7Hz, 1H), 7.67 (d, J=7.9Hz, 1H), 7.35 (m, 2H), 7.25 (m, 3H), 7.18 (m, 1H), 6.01 (m, 1H), 5.43 (m, 1H), 4.35 (m, 1H), 3. 82 (m, 1H), 3.76 (s, 3H), 3.44 (m, 1H), 2.47 (m, 2H), 2.28 (m, 1H), 2.08 (m, 4H), 1.89 (m, 1H), 1.72 (m, 5H) 1.60 (m, 2H) 1.50 (m, 1H), 1.09 (s, 3H), 1.06 (s, 3H).

[0112] C 13 NMR(CDCl3): 167.13, 156.40, 151.64, 147.83(d), 133.77, 132.99, 129.65, 129.27(d), 124.79, 123.06, 122.74, 120.22(d) , 78.09, 57.45, 52.43, 50.19, 47.34, 43.02, 40.07, 39.91, 36.82, 36.62, 35.19, 31.80, 31.50, 30.39, 20.83, 19.24, 16.58.

[0113] P 31 NMR (CDCl3): 1.74, 1.69 (mixture of R and S configurations)

[0114] Mass spectrometry (ESI): Theoretical value: 577.28, Measured value: 577.2898 (M+H) + .

[0115] 3.2 Preparation of compound Q2-1

[0116] Compound Q2-1 is a phenyl 2-methoxy-2-oxoylidene ethyl (3aS,3bR,7S,9aR,9bS,11aS)-9a,11a-dimethyl-1-(pyridin-3-yl)-3a,3b,4,6,7,8,9,9a,9b,10,11,11a-dodecano-3H-cyclopenta[1,2-i]phenanthrene-7-yl phosphate ion, and its chemical structure is shown below:

[0117] Compound 3 (395 mg, 0.919 mmol) was dissolved in 10 mL of anhydrous pyridine. Under nitrogen protection, methyl glycolate (82.84 mg, 0.919 mmol), phenol (86.55 mg, 0.919 mmol), and N,N-diisopropylethylamine (DIPEA, 0.62 mL, 3.68 mmol) were added sequentially, and the mixture was heated to 65 °C. After 10 minutes, a pyridine solution of triphenylphosphine (723.67 mg, 2.76 mmol) and 2,2'-dithiodipyridine (607.84 mg, 2.76 mmol) was added, and the reaction was allowed to proceed for 16 hours. After the reaction, the mixture was concentrated under reduced pressure to remove most of the volatiles, and pyridine was removed by azeotropic addition of toluene in small amounts several times. The crude product was separated using 0–10% methanol:dichloromethane. Yield: 230.8 mg (43.44%).

[0118] H 1 NMR (CDCl3): 8.64 (s, 1H), 8.49 (d, J=4.7Hz, 1H), 7.73 (d, J=7.9Hz, 1H), 7.31 (m , 2H), 7.25 (m, 3H), 7.02 (t, J=7.4Hz, 1H), 6.00 (s, 1H), 5.34 (m, 1H), 4.67 (m, 1H) , 4.43 (m, 1H), 3.78 (s, 3H), 2.52 (m, 2H), 2.29 (m, 1H), 2.08 (m, 4H), 1.87 (m, 3H) , 1.77(m, 1H), 1.67(m, 2H), 1.61(m, 2H), 1.50(m, 1H), 1.09(s, 3H), 1.06(s, 3H).

[0119] C 13NMR (CDCl3): 167.94, 151.29, 150.58, 146.87, 140.72, 139.55, 134.56, 133.40, 129.84, 125.19, 123.38, 122.89, 121.70, 120.1 1(d), 79.92, 67.97, 63.72, 57.45, 52.37, 50.17, 47.35, 39.72, 36.78, 36.66, 36.59, 35.16, 31.66, 30.37, 20.82, 19.20, 16.56.

[0120] P 31 NMR (CDCl3): -7.34, -7.42 (mixture of R and S configurations)

[0121] Mass spectrometry (ESI): Theoretical value: 578.27, Measured value: 578.2701 (M+H) + .

[0122] 3.3 Preparation of compound Q3

[0123] Compound Q3 is (3aS,3bR,7S,9aR,9bS,11aS)-9a,11a-dimethyl-1-(pyridin-3-yl)-3a,3b,4,6,7,8,9,9a,9b,10,11,11a-dodecano-3H-cyclopenta[2,1-i]phenanthrene-7-ylphenylphosphonate ion, and its chemical structure is shown below:

[0124] Compound 3 (395 mg, 0.919 mmol) was dissolved in 10 mL of anhydrous pyridine. Under nitrogen protection, phenol (86.55 mg, 0.919 mmol) and N,N-diisopropylethylamine (DIPEA, 0.62 mL, 3.68 mmol) were added sequentially, and the mixture was heated to 65 °C. After 10 minutes, a pyridine solution of triphenylphosphine (723.67 mg, 2.76 mmol) and 2,2'-dithiodipyridine (607.84 mg, 2.76 mmol) was added, and the reaction was allowed to proceed for 16 hours. The mixture was then diluted with 20 mL of dichloromethane, washed with 0.1 N HCl to remove the alkali and pyridine, and alkalized with 0.5 NaOH. The alkalized aqueous phase was then acidified again with 0.1 N HCl, and the product was extracted back into the organic phase. After drying with Na₂SO₄, the product was concentrated under reduced pressure. The crude product was separated using a 0–10% methanol:dichloromethane solution. Yield: 382.0 mg (82.15%). H 1NMR (CDCl3): 8.62 (s, 1H), 8.46 (d, J=4.6Hz, 1H), 7.67 (d, J=4.6Hz, 1H), 7.36 (m , 2H), 7.29(m, 3H), 7.21(m, 1H), 6.00(s, 1H), 5.34(m, 1H), 4.16(m, 1H), 3.70(d , J=11.1Hz, 1H), 2.45 (m, 1H), 2.36 (t, J=12.2Hz, 1H), 2.26 (m, 1H), 2.03 (m, 5H) , 1.73(m, 1H), 1.65(m, 2H), 1.59(m, 2H), 1.51(m, 1H), 1.27(s, 3H), 1.04(s, 3H).

[0125] C 13 NMR (CDCl3): 159.86, 147.74, 147.60, 141.08, 133.87, 129.08, 128.97, 123.06, 122.42, 121.38, 120.14, 120.11, 75.90, 57.54, 50.30, 47.37, 45.05, 40.32, 37.09, 36.69, 35.26, 31.81, 31.52, 30.45, 29.82, 29.79, 29.69, 20.82, 19.27, 16.56.

[0126] P 31 NMR (CDCl3): -5.47

[0127] Mass spectrometry (ESI): Theoretical value: 506.24, Measured value: 506.2475 (M+H) +

[0128] 3.4 Preparation of compound Q4-1

[0129] Compound Q4-1 is a phenyl-2-[(2-hydroxyethyl)dithio]ethyl(3aS,3bR,7S,9aR,9bS,11aS)-9a,11a-dimethyl-1-(pyridin-3-yl)-3a,3b,4,6,7,8,9,9a,9b,10,11,11a-dodecano-3H-cyclopenta[1,2-i]phenanthrene-7-yl phosphate ion, and its chemical structure is shown below:

[0130] Compound 3 (391 mg, 0.911 mmol) was dissolved in 10 mL of anhydrous pyridine. Under nitrogen protection, 2-hydroxyethyl disulfide (0.11 mL, 0.911 mmol), phenol (85.88 mg, 0.911 mmol), and N,N-diisopropylethylamine (DIPEA, 0.62 mL, 3.65 mmol) were added sequentially, and the mixture was heated to 65 °C. After 10 minutes, a pyridine solution of triphenylphosphine (718.02 mg, 2.73 mmol) and 2,2'-dithiodipyridine (602.09 mg, 2.73 mmol) was added, and the reaction was allowed to proceed for 16 hours. After the reaction, the mixture was concentrated under reduced pressure to remove most of the volatiles, and pyridine was removed by azeotropic addition of toluene in small amounts several times. The crude product was separated using 0–10% methanol:dichloromethane. Yield: 271.5 mg (46.36%).

[0131] H 1 NMR (CDCl3): 8.64 (s, 1H), 8.48 (d, J=4.7Hz, 1H), 7.68 (d, J=7.9Hz, 1H), 7.37 (m, 2H), 7.25(m, 3H), 7.21(m, 1H), 6.02(s, 1H), 5.41(m, 1H), 4.39(m, 2H), 3.94(t, J=5.7Hz, 1 H), 3.88(m, 1H), 3.00(m, 1H), 2.49(m, 2H), 2.27(m, 1H), 2.08(m, 4H), 1.90(m, 1H), 1. 67(m, 8H), 1.52(m, 2H), 1.15(m, 1H), 1.10(s, 3H), 1.07(s, 3H), 0.91(t, J=6.9Hz, 1H).

[0132] C 13 NMR (CDCl3): 149.93, 147.67, 145.67, 141.78, 139.16, 137.36, 133.89, 129.74, 129.34, 127.19, 125.15, 123.09, 122.95, 120.12 , 78.41, 65.87, 60.41, 54.04, 50.23, 47.36, 41.91, 41.31, 37.91, 36.81, 36.61, 36.44, 35.22, 30.40, 29.70, 20.84, 19.20, 16.56.

[0133] P 31 NMR (CDCl3): -7.34, -7.46 (mixture of R and S configurations)

[0134] Mass spectrometry (ESI): Theoretical value: 642.25, Measured value: 642.2545 (M+H) +

[0135] 3.5 Preparation of compound Q5-3

[0136] Compound Q5-3 is (3aS, 3bR, 9aR, 9bS, 11aS)-9a,11a-dimethyl-1-(pyridin-3-yl)-3a,3b, 4, 6, 7, 8, 9, 9a, 9b, 10, 11, 11a-dodecano-3H-cyclopenta[2,1-i]phenanthrene-7-yl 2-(acetylthio)ethylphenyl phosphate ion, and its chemical structure is shown below:

[0137] 3.5.1 Preparation of substrate-compound 4

[0138] Compound 4 is ethanethioic acid-S-(2-hydroxyethyl) ester, and its chemical structural formula is shown below:

[0139] Under nitrogen protection, 2-iodoethanol (0.78 ml, 10.0 mmol) was added to a toluene solution of thioacetic acid (0.82 ml, 11.5 mmol) in 15 ml, and 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU, 1.72 ml, 11.5 mmol) was slowly added dropwise at 0 °C. The solution was allowed to return to room temperature naturally and stirred for 3 hours. The reaction was terminated by adding water after thin-layer chromatography to confirm its completeness. The organic phase was washed with saturated brine. After washing with brine, the organic phase was dried over Na2SO4, filtered, and concentrated. The crude product was eluted with a gradient of ethyl acetate:petroleum ether (0:10 → 1:1). Yield: 431.0 mg (31.2%).

[0140] H 1 NMR (CDCl3): 3.77 (t, J=6.1Hz, 2H), 3.09 (t, J=6.1Hz, 2H), 2.38 (s, 3H).

[0141] C 13 NMR (CDCl3): 196.40, 61.73, 32.05, 30.65.

[0142] Mass spectrometry (ESI): 121.0 (M+H) +

[0143] 3.5.2 Preparation of compound Q5-3

[0144] Compound 3 (588.41 mg, 1.37 mmol) was dissolved in 10 mL of anhydrous pyridine. Under nitrogen protection, compound 4 (164.63 mg, 1.37 mmol), phenol (128.93 mg, 1.37 mmol), and N,N-diisopropylethylamine (DIPEA, 0.93 mL, 5.48 mmol) were added sequentially, and the mixture was heated to 65 °C. After 10 minutes, a pyridine solution of triphenylphosphine (1.08 g, 4.11 mmol) and 2,2'-dithiodipyridine (905.47 mg, 4.11 mmol) was added, and the reaction was allowed to proceed for 16 hours. After the reaction, the mixture was concentrated under reduced pressure to remove most of the volatiles, and pyridine was removed by azeotropic addition of small amounts of toluene. The crude product was separated using 0–10% methanol:dichloromethane. Yield: 518.0 mg (38.41%).

[0145] H 1 NMR (CDCl3): 8.64 (s, 1H), 8.49 (d, J=4.6Hz, 1H), 7.81 (d, J=4.6Hz, 1H), 7.36 (m, 2H) , 7.23 (m, 3H), 7.21 (m, 1H), 6.08 (s, 1H), 5.40 (m, 1H), 4.27 (t, J=6.5Hz, 2H), 3.83 (d, J=11.1Hz, 1H), 3.15(t, J=6.5Hz, 2H), 2.48(m, 2H), 2.37(s, 3H), 2.29(m, 1H), 2.06(m , 5H), 1.88(m, 1H), 1.76(m, 2H), 1.69(m, 2H), 1.50(m, 1H), 1.10(s, 3H), 1.06(s, 3H).

[0146] C 13 NMR (CDCl3): 194.81, 150.93, 146.05, 140.69, 139.56, 133.72, 129.73, 129.23, 125.09, 123.67, 123.17, 122.85, 121.69, 120.06, 79.46, 66 .28, 61.71, 57.49, 50.21, 47.34, 39.85, 37.04, 36.65, 35.10, 31.86, 3 1.46, 30.57, 30.34, 29.80, 29.52, 29.43, 29.21, 20.80, 19.22, 16.58.

[0147] P 31 NMR (CDCl3): -7.65

[0148] Mass spectrometry (ESI): Theoretical value: 608.26 (M+H) +Measured value: 608.2642 (M+H) +

[0149] 3.6 Preparation of compound Q6-3

[0150] Compound Q6-3 is P,P-bis[(2-methoxy-2-oxoylideneethyl)amino]phosphono-(3aS,3bR,7S,9aR,9bS,11aS)-9a,11a-dimethyl-1-(pyridin-3-yl)-3a,3b,4,6,7,8,9,9a,9b,10,11,11a-dodecano-3H-cyclopenta[2,1-i]phenanthrene-7-yl ester, and its chemical structural formula is shown below:

[0151] Compound 3 (395 mg, 0.919 mmol) was dissolved in 10 mL of anhydrous pyridine. Under nitrogen protection, glycine methyl ester hydrochloride (346.4 mg, 2.76 mmol) and N,N-diisopropylethylamine (DIPEA, 0.94 mL, 5.52 mmol) were added sequentially, and the mixture was heated to 65 °C. After 10 minutes, a pyridine solution of triphenylphosphine (723.67 mg, 2.76 mmol) and 2,2'-dithiodipyridine (607.84 mg, 2.76 mmol) was added, and the reaction was allowed to proceed for 16 hours. After the reaction, the mixture was concentrated under reduced pressure to remove most of the volatiles, and pyridine was removed by azeotropic addition of toluene in small amounts several times. The product was dried over Na₂SO₄, filtered, and concentrated under reduced pressure. The crude product was separated using 0–10% methanol:dichloromethane. Yield: 296.42 mg (56.38%).

[0152] H 1 NMR (CDCl3): 8.64 (s, 1H), 8.48 (d, J=4.8Hz, 1H), 7.67 (d, J=7.8Hz, 1H), 7.25 (dd, J=7.8, 4 .8Hz, 1H), 6.02 (s, 1H), 5.44 (d, J=5.0Hz, 1H), 5.32 (s, 1H), 4.24 (m, 1H), 3.77 (s, 6H), 3.2 1(m,2H),2.43(m,2H),2.28(m,1H),2.07(m,4H),1.98(m,2H),1.87(m,3H),1.77(m,2H),1 .69(m, 3H), 1.60(m, 2H), 1.50(m, 1H), 1.16(m, 1H), 1.14(m, 1H), 1.08(s, 3H), 1.06(s, 3H).

[0153] C 13NMR (CDCl3): 171.96, 151.62, 147.82, 147.76, 139.90, 133.81, 133.02, 129.31, 123.06, 122.52, 76.28, 57.4 4, 52.31, 50.20, 47.34, 42.69, 40.26, 36.86, 36.62, 35.19, 31.80, 31.50, 30.39, 29.85, 20.83, 19.25, 16.58.

[0154] P 31 NMR (CDCl3): 12.17

[0155] Mass spectrometry (ESI): Theoretical value: 572.28 (M+H) + Measured value: 572.2884 (M+H) + .

[0156] 3.7 Preparation of compound Q7-2

[0157] Compound Q7-2 is a bis{[(2,2-dimethylpropionyl)oxy]methyl}(3aS,3bR,7S,9aR,9bS,11aS)-9a,11a-dimethyl-1-(pyridin-3-yl)-3a,3b,4,6,7,8,9,9a,9b,10,11,11a-dodecano-3H-cyclopenta[1,2-i]phenanthrene-7-yl phosphate ion, and its chemical structure is shown below:

[0158] Compound 3 (259.63 mg, 0.604 mmol), methyl tert-pentanoate (273.12 mg, 1.81 mmol), triethylamine (0.5 mL, 3.63 mmol), and tetrabutylammonium bromide (194.88 mg, 0.604 mmol) were dissolved in 5 mL of N-methylpyrrolidone under nitrogen protection and heated to 65 °C. After reacting for 3 hours, the mixture was allowed to cool to room temperature naturally. The reaction solution was diluted with 20 mL of ethyl acetate, washed with saturated brine, dried over Na₂SO₄, and filtered. The crude product was concentrated under reduced pressure and separated using an ethyl acetate:petroleum ether system (ethyl acetate gradient 20%–100%). Yield: 109.1 mg (27.44%).

[0159] H 1NMR (CDCl3): 8.64 (s, 1H), 8.49 (d, J=4.7Hz, 1H), 7.68 (d, J=7.9Hz, 1H), 7.26 (dd , J=7.9, 4.7Hz, 1H), 6.02(m, 1H), 5.68(m, 4H), 5.46(m, 1H), 4.29(m, 1H), 2.50(m , 2H), 2.29(m, 1H), 2.08(m, 4H), 1.90(m, 2H), 1.78(m, 2H), 1.70(m, 3H), 1.62(m, 2H), 1.51 (m, 1H), 1.27 (d, J=1.8Hz, 18H), 1.14 (m, 1H), 1.09 (s, 3H), 1.07 (s, 3H).

[0160] C 13 NMR (CDCl3): 176.70, 147.70, 139.45, 133.90, 133.06, 129.35, 123.10, 123.01, 82.79, 79.52, 57.46, 50 .24, 47.36, 39.73, 38.76, 36.76, 36.57, 35.21, 31.79, 31.50, 30.39, 29.40, 26.87, 20.84, 19.18, 16.56.

[0161] P 31 NMR (CDCl3): -4.90.

[0162] Mass spectrometry (ESI): Theoretical value: 658.35, Measured value: 658.3586 (M+H) + .

[0163] 3.8 Preparation of compound Q8-3

[0164] Compound Q8-3 is bis(8,8-dimethyl-3,6-dioxoylide-5-aza-2,7-dioxanon-1-yl)(3aS,3bR,7S,9aR,9bS,11aS)-9a,11a-dimethyl-1-(pyridin-3-yl)-3a,3b,4,6,7,8,9,9a,9b,10,11,11a-dodecano-3H-cyclopenta[1,2-i]phenanthrene-7-yl phosphate ion, and its chemical structure is shown below:

[0165] 3.8.1 Preparation of substrate-compound 5

[0166] Compound 5 is ({[(2-methylprop-2-yl)oxy]carbonyl}amino)chloromethyl acetate, and its chemical structural formula is shown below:

[0167] N-BOC glycine (928.48 mg, 5.30 mmol), tetrabutylammonium hydrogen sulfate (179.96 mg, 0.53 mmol), and sodium bicarbonate (1.76 g, 21.00 mmol) were dissolved in a mixture of water and dichloromethane (1:1, 20 mL) in a layered solution. The mixture was stirred vigorously at 0 °C for 10 minutes. 5 mL of a dichloromethane solution of chloromethyl chlorosulfonate (0.65 mL, 6.40 mmol) was added. The reaction was allowed to proceed at room temperature for 2 hours. After 2 hours, the organic phase was collected, washed with saturated brine, dried over Na₂SO₄, and filtered. The crude product was concentrated under reduced pressure and separated using an ethyl acetate:petroleum ether system (1:5). Yield: 676.0 mg (57.03%).

[0168] H 1 NMR (CDCl3): 5.75 (s, 2H), 5.04 (brs, 1H), 4.00 (d, J=5.6Hz, 2H), 1.46 (s, 9H).

[0169] C 13 NMR (CDCl3): 168.81, 155.57, 80.38, 68.93, 42.34, 28.23

[0170] Mass spectrometry (ESI): 224.6 (M+H) +

[0171] 3.8.2 Preparation of compound Q8-3

[0172] Compound 3 (259.63 mg, 0.604 mmol), compound 5 (676.0 mg, 3.02 mmol), triethylamine (0.34 mL, 2.42 mmol), and tetrabutylammonium bromide (194.88 mg, 0.604 mmol) were dissolved in 5 mL of N-methylpyrrolidone under nitrogen protection and heated to 65 °C. After reacting for 3 hours, the mixture was allowed to cool to room temperature naturally. The reaction solution was diluted with 20 mL of ethyl acetate, washed with saturated brine, dried over Na₂SO₄, and filtered. The crude product was concentrated under reduced pressure and separated using an ethyl acetate:petroleum ether system (ethyl acetate gradient 20%–100%). Yield: 130.37 mg (26.83%).

[0173] H 1NMR (CDCl3): 8.64 (s, 1H), 8.49 (d, J=4.8Hz, 1H), 7.73 (d, J=7.8Hz, 1H), 7.30 (dd, J=7.8, 4 .8Hz, 1H), 6.02 (s, 1H), 5.68 (m, 4H), 5.44 (d, J=5.0Hz, 1H), 5.27 (s, 1H), 4.24 (m, 1H), 3.99 (m, 4H), 3.27 (m, 2H), 2.49 (m, 2H), 2.28 (m, 1H), 1.88 (m, 2H), 1.87 (m, 2H), 1.77 (m, 2H), 1. 68(m, 2H), 1.61(m, 2H), 1.50(m, 21H), 1.16(m, 1H), 1.15(m, 1H), 1.09(s, 3H), 1.06(s, 3H).

[0174] C 13 NMR (CDCl3): 170.25, 152.52, 147.72, 147.45, 137.90, 132.81, 133.02, 129.31, 123.06, 122.52, 83.5 4, 78.71, 57.56, 50.16, 47.44, 42.16, 40.17, 36.98, 36.62, 35.96, 31.63, 29.33, 21.23, 19.10, 16.67.

[0175] P 31 NMR (CDCl3): -5.62

[0176] Mass spectrometry (ESI): Theoretical value: 804.38 (M+H) + 826.37 (M+Na) + Measured value: 804.3919 (M+H) + 826.3743(M+Na) +

[0177] 3.9 Preparation of compound Q9-4

[0178] Compound Q9-4 is (4R,8R)-6-{[(3aS,3bR,7S,9aR,9bS,11aS)-9a,11a-dimethyl-1-(pyridin-3-yl)-3a,3b,4,6,7,8,9,9a,9b,10,11,11a-dodecano-3H-cyclopenta[1,2-a]phenanthrene-7-yl]oxy}-8-(methoxycarbonyl)-6-oxoylide-6λ5-1,2,5,7,6-dithiadiazaphosphazenecyclononane-4-carboxylate, and its chemical structural formula is shown below:

[0179] Compound 3 (391 mg, 0.910 mmol) was dissolved in 10 mL of anhydrous pyridine. Under nitrogen protection, dimethyl cysteine ​​dihydrochloride (310.67 mg, 0.910 mmol) and N,N-diisopropylethylamine (DIPEA, 0.62 mL, 3.64 mmol) were added sequentially, and the mixture was heated to 65 °C. After 10 minutes, a pyridine solution of triphenylphosphine (716.35 mg, 2.73 mmol) and 2,2'-dithiodipyridine (601.68 mg, 2.73 mmol) was added, and the reaction was allowed to proceed for 16 hours. After the reaction, the mixture was concentrated under reduced pressure to remove most of the volatiles, and pyridine was removed by azeotropic addition of toluene in small amounts several times. The product was dried over Na₂SO₄ and concentrated under reduced pressure. The crude product was separated using 0–10% methanol:dichloromethane. Yield: 375.84 mg (62.38%).

[0180] H 1 NMR (CDCl3): 8.64 (s, 1H), 8.48 (d, J=4.7Hz, 1H), 7.66 (d, J=7.9Hz, 1H), 7. 24(dd, J=7.9, 4.7Hz, 1H), 5.44(m, 1H), 4.57(m, 1H), 4.29(m, 1H), 3.79(m, 6H), 3.22(m, 2H), 2.73(m, 1H), 2.49(m, 1H), 2.32(m, 2H), 2.09(m, 4H), 1.8 8(m, 2H), 1.77(m, 1H), 1.65(m, 4H), 1.10(s, 1H), 1.06(s, 3H), 0.89(m, 1H).

[0181] C 13 NMR (CDCl3): 171.74, 160.09, 157.70, 147.91, 133.74, 129.23, 123.02, 122.51, 67.97, 57.45, 52 .95, 52.71, 47.36, 36.82, 36.62, 35.22, 31.79, 31.51, 30.44, 29.69, 25.61, 20.84, 19.24, 16.56.

[0182] P 31 NMR (CDCl3): 10.63

[0183] Mass spectrometry (ESI): Theoretical value: 662.25, Measured value: 662.2549 (M+H) +

[0184] [Example 4] Bioactivity Test

[0185] 4.1 Experimental Objective

[0186] The plasma concentrations of the parent drug and the active metabolite abiraterone in beagle dogs were investigated and determined by LC-MS / MS after administration of the reference drug formulation (abiraterone acetate) and each compound. The differences in absorption kinetics between fasting and feeding were evaluated with reference to relevant pharmacokinetic parameters.

[0187] 4.2 Experimental Materials and Drug Preparation Methods

[0188] Reference drug abiraterone acetate: purchased from JD Pharmacy.

[0189] Compounds Q1-Q9: synthesized according to the method in Example 2.

[0190] Dissolve the test substances separately in 5% CMC-Na solution, disperse thoroughly by ultrasonication, and dilute to a concentration of 10 mg / mL. Administer by gavage at a volume of 1 mL / kg. For samples that cannot be completely dissolved, shake well before administration.

[0191] Beagle: Purchased from Guangdong Provincial Medical Animal Center.

[0192] 4.3 Experimental Methods

[0193] Animal grouping and administration information are shown in Table 3. Beagles were divided into two groups of three dogs each, administered the reference drug abiraterone acetate and compounds Q1-Q9 listed in Table 3 at a dose of 10 mg / kg. Group 1: Day 1: Fasted and administered via gavage; Day 10: Normal feeding and administered via gavage. Group 2: Day 1: Normal feeding and administered via gavage; Day 10: Fasted and administered via gavage.

[0194] Table 3 Animal grouping and drug administration information

[0195] Plasma collection: Collect approximately 0.5 mL of blood from the canine forelimb vein at each time point listed in the table above. Place the collected whole blood in an EDTA anticoagulant tube, invert it several times to mix thoroughly, and store it in an ice-water mixture. Centrifuge (1500-1600g, 10 min) within 1 hour to separate the plasma. Store the obtained plasma sample in a -60°C freezer for later use.

[0196] Biological samples were analyzed using LC-MS / MS. The analytical methods and test conditions are shown in Table 4.

[0197] Table 4 lists the LC-MS / MS analytical procedures and test conditions for the compounds listed in Table 3.

[0198] 4.4 Experimental Results

[0199] The results are shown in Figure 4 and Table 5. All compounds, including the reference drug, were almost entirely converted to the active substance abiraterone in vivo, without affecting the subsequent metabolism of abiraterone (similar to T1 / 2). Fasting and normal feeding conditions showed that the reference drug exhibited a significant food effect, with fasting significantly impacting drug absorption. The compounds of this invention effectively addressed the food effect issue of the reference drug, and at the same dosage, the time to peak concentration and peak concentration of each compound of this invention were similar to those of the reference drug, thus ensuring good consistency in future clinical application potential and safety and efficacy.

[0200] Table 5. Plasma pharmacokinetic parameters of each compound after a single oral gavage administration in beagle dogs (10 mg / kg, n = 6, Mean ± SD)

Claims

1. An abiraterone derivative, its stereoisomers, and pharmaceutically acceptable salts, characterized in that, It has the structure shown in equation (I): In the formula, X1 and X2 are independently selected from NH, O, S, or five- or six-membered heterocycles containing N, O, or S; A is selected from hydrogen, substituted or unsubstituted C. 1-6 Alkyl, substituted or unsubstituted 5-10 aryl, substituted or unsubstituted 3-6 cycloalkyl, substituted or unsubstituted 5-10 heteroaryl, or Any one of them; B is selected from R1 is selected from hydrogen, substituted or unsubstituted C1-10 alkyl, substituted or unsubstituted C5-12 aryl, substituted or unsubstituted benzyl; R2 and R3 are each independently selected from hydrogen, substituted or unsubstituted C. 1-10 Alkyl, substituted or unsubstituted C 5-10 Aryl, substituted or unsubstituted benzyl, mercapto, hydroxyl, amino, hydroxyalkyl, carboxylalkyl, aminoalkyl, mercaptoalkyl, 3-6 membered cycloalkyl, 5-6 membered heterocycloalkyl, 5-10 membered aryl, 5-10 membered heteroaryl; R4 and R5 are each independently selected from hydrogen, substituted or unsubstituted C. 1-10 Alkyl, substituted or unsubstituted C 5-10 Aryl, benzyl, mercapto, hydroxy, amino, hydroxyalkyl, aminoalkyl, mercaptoalkyl, alkoxycarbonyl, alkylcarbonyl, 3-6 membered cycloalkyl, 5-6 membered heterocycloalkyl, 5-10 membered aryl, 5-10 membered heteroaryl; R a R b Each is independently selected from hydrogen, substituted or unsubstituted C. 1-10 Alkyl, substituted or unsubstituted 3-6 membered cycloalkyl, substituted or unsubstituted C 5-10 Aryl, benzyl, mercapto, hydroxy, hydroxyalkyl, amino, aminoalkyl, mercaptoalkyl; X3 is selected from O, S, or NH.

2. The abiraterone derivative and its stereoisomers and pharmaceutically acceptable salts according to claim 1, characterized in that, A is a benzene ring, X2 is O or S, and B is... It has the structure shown in formula (II-1) or formula (II-2):

3. The abiraterone derivative and its stereoisomers and pharmaceutically acceptable salts according to claim 1, characterized in that, X1 and X2 are independently selected from O, S, or NH.

4. The abiraterone derivative and its stereoisomers and pharmaceutically acceptable salts according to claim 3, characterized in that, The structure of the abiraterone derivative is selected from any one of formulas (III) to (X):

5. The abiraterone derivative and its stereoisomers and pharmaceutically acceptable salts according to claim 1, characterized in that, When R a R b When each is independently selected from the thiol group, R a With R b The thiol group selectively forms a disulfide bond.

6. The abiraterone derivative and its stereoisomers and pharmaceutically acceptable salts according to claim 1, characterized in that, The abiraterone derivative is selected from any one of the following compounds:

7. A method for preparing the abiraterone derivative according to claim 1, its stereoisomers, and pharmaceutically acceptable salts, characterized in that, Includes the following steps: in, (a) Compound 1 was reacted with N,N-diethylphosphamide di-tert-butyl ester or N,N-diisopropylphosphamide di-tert-butyl ester to give compound 2; (b) Compound 2 reacts with dilute hydrochloric acid to hydrolyze and yields compound 3; (c) Compound 3 was condensed to give an abiraterone derivative having the structure shown in formula (I), its stereoisomers, and pharmaceutically acceptable salts.

8. The preparation method according to claim 7, characterized in that, Step (a) includes: suspending compound 1 in dichloromethane in an inert gas environment, adding 1H-tetrazole and N,N-diethylphosphamide di-tert-butyl ester, reacting at room temperature for 30 minutes, then cooling to -78°C and reacting for 30 minutes to form compound 2 by an oxidant; Step (b) includes: dissolving compound 2 in a mixed solvent of dichloromethane and methanol, adding excess dilute hydrochloric acid in an organic solvent at 0°C, reacting for 30 minutes to obtain compound 3; Step (c) includes: dissolving compound 3 and a compound containing hydroxyl, amino, or thiol groups in pyridine, adding an organic nonnucleophilic base, heating to 65°C, adding a pyridine solution of triphenylphosphine and 2,2'-dithiopyridine, and generating the abiraterone derivative and its stereoisomers and pharmaceutically acceptable salts after 16 hours.

9. The preparation method according to claim 8, characterized in that, The volume ratio of dichloromethane to methanol in the mixed solvent is 5:1, and the organic solvent is 1,4-dioxane or a saturated alkane.

10. A pharmaceutical composition, characterized in that, It contains an abiraterone derivative and its stereoisomers as described in any one of claims 1-6, a pharmaceutically acceptable salt, and a pharmaceutically acceptable carrier or excipient.

11. Use of the abiraterone derivative and its stereoisomers and pharmaceutically acceptable salts as described in any one of claims 1-6, or the pharmaceutical composition of claim 10, in the preparation of a medicament for treating diseases related to excessive androgen secretion.

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