Abiraterone derivative, pharmaceutical composition, and preparation method therefor and use thereof

Abstract

Disclosed in the present invention are an abiraterone derivative, a pharmaceutical composition, and a preparation method therefor and the use thereof. Provided in the present invention is an abiraterone derivative as represented by formula (1) or formula (2), or a pharmaceutically acceptable salt thereof. In contrast to existing abiraterone derivative structures in which each molecule contains one abiraterone molecule, the compound of the present invention contains two abiraterone molecules per molecule. The compound of the present invention has long-acting sustained-release characteristics, can be injected subcutaneously or intramuscularly, maintains the blood drug level for 12 weeks (3 months) or longer, and is used for treating prostate cancer.

Description

An abiraterone derivative, a pharmaceutical composition, its preparation method and application

[0001] This application claims priority to Chinese Patent Application No. 2024118956988, filed on December 20, 2024; Chinese Patent Application No. 2025111867263, filed on August 22, 2025; and Chinese Patent Application No. 2025118933961, filed on December 15, 2025. The full text of the aforementioned Chinese patent applications is incorporated herein by reference. Technical Field

[0002] This invention belongs to the field of pharmaceutical compounds, specifically relating to abiraterone derivatives, pharmaceutical compositions, their preparation methods, and applications. Background Technology

[0003] Abiraterone is a selective inhibitor of cytochrome P450 17A1 (CYP17A1). CYP17A1 possesses 17α-hydroxylase and 17,20-lyase activities, and is essential for the synthesis of androgenic steroids (such as androstenedione, testosterone, and dihydrotestosterone). Therefore, abiraterone can inhibit androgen synthesis in testicular, adrenal, and prostate cancer cells by inhibiting CYP17A1 activity, thereby reducing the levels of testosterone and other androgenic steroids and inhibiting the progression of prostate cancer.

[0004] Abiraterone has poor water solubility and permeability, classifying it as a Class IV molecule in Biopharmaceutics Classification (BCS). It is poorly absorbed, but it can be administered orally as a prodrug of abiraterone acetate (chemical name: 17-(3-pyridyl)-androst-5,16-diene-3β-acetate, also known as abiraterone acetate). The trade name for abiraterone acetate is... (Chinese product name is) Abiraterone acetate, available in 250mg tablets, has a recommended therapeutic dose of 1000mg once daily orally. It was approved by the FDA in 2011 for use in combination with prednisone or prednisolone to treat metastatic castration-resistant prostate cancer (mCRPC). In 2018, its indications were expanded to include newly diagnosed high-risk metastatic endocrine-sensitive prostate cancer (mHSPC), including patients who have not received endocrine therapy or have received endocrine therapy for no more than 3 months. Abiraterone acetate has become a first-line treatment for metastatic prostate cancer, consistently recommended by international and domestic guidelines.

[0005] However, abiraterone acetate is also a BCS class IV compound. The oral bioavailability of the tablets is also very low (less than 5%), requiring a higher dose (1000mg, 4 tablets each time) to exert its effect. Furthermore, the oral administration of this drug is significantly affected by food, resulting in large individual variability. The instructions state that this medication must be taken at least 2 hours after a meal, and no food should be consumed for at least 1 hour after taking it. Compared to taking it on an empty stomach, taking a single dose with a meal results in lower C-values ​​for abiraterone. max and AUC 0-∞ (Exposure) increased by 17 times and 10 times, respectively. Since prostate cancer patients are mostly elderly, with an average age of diagnosis of approximately 67 years, they are prone to forgetfulness and have poor medication adherence. Not being able to take the medication on an empty stomach increases drug exposure and raises the incidence of adverse reactions. Reducing the impact of food and improving patient adherence are unmet clinical needs in the clinical practice of abiraterone acetate tablets. A domestic company has developed abiraterone acetate tablets (II) that, through improved formulation and manufacturing processes, incorporates nanocrystal technology and the oral absorption enhancer SNAC, achieving a dosage of 300 mg once daily. The efficacy of 1000mg was comparable, reducing the influence of food (but Cmax and AUC were still approximately twice that of the fasted state when the drug was taken with food). However, the blood concentration of the tablet still fluctuated significantly within 24 hours after oral administration (300mg Cmax in healthy subjects on an empty stomach). max The steady-state C concentration was 171±84.3 ng / ml, and the concentration of mCRPC patients was 300 mg once daily. max The median time to peak concentration (Cmin) was 164.69 ± 104.18 ng / ml, with a median time to peak concentration of 1.5 h, indicating a rapid clearance of abiraterone. Studies in mCRPC patients have shown that for patients who have received chemotherapy, an oral abiraterone acetate plasma concentration (Cmin) > 8.4 ng / ml predicts longer progression-free survival (PFS) and overall survival (OS). For mCRPC patients who have not received chemotherapy, lower levels of abiraterone (e.g., 2 ng / ml) may be necessary to achieve efficacy and reduce the toxicity and safety risks associated with excessively high concentrations. Considering that elderly prostate cancer patients are prone to forgetfulness, difficulty swallowing, and choking when taking medication, there is still a need and room for improvement in daily medication adherence and compliance for long-term prostate cancer treatment.

[0006] Long-acting drugs can significantly reduce the frequency of medication, improve patient compliance, and the stable and sustainable drug release and blood concentration also reduce the occurrence of adverse reactions. However, there are currently no long-acting abiraterone drugs or formulations available for patients. Developing an injectable long-acting abiraterone prodrug would not only eliminate the influence of food compared to existing oral abiraterone acetate, but also significantly reduce the frequency of medication and improve patient compliance.

[0007] US patent Propella (WO2020180942, CN114026106) discloses a fatty acid ester precursor compound or a pharmaceutically acceptable salt thereof, with abiraterone decanoate as the preferred prodrug molecule. The prepared compositions are used for intramuscular, intradermal, or subcutaneous injection. However, fatty acid ester prodrugs generally do not improve the water solubility of the drug. Abiraterone decanoate, when prepared as an oil solution and administered intramuscularly, is mainly transported via the lymphatic system. Examples show significant accumulation in tissues such as lymph nodes and lungs, and the prodrug maintains a high concentration in plasma, resulting in a slow conversion to the parent drug abiraterone, potentially posing unknown safety risks. Summary of the Invention

[0008] To address the aforementioned technical problems, this invention provides an abiraterone derivative, a pharmaceutical composition, its preparation method, and its applications. Unlike existing abiraterone derivatives, which contain one abiraterone molecule per molecule, the compound of this invention contains two abiraterone molecules per molecule. The compound of this invention exhibits long-acting sustained-release characteristics and can be administered subcutaneously or intramuscularly, maintaining blood drug concentrations for 12 weeks (3 months) or longer, for the treatment of prostate cancer.

[0009] The present invention provides an abiraterone derivative as shown in formula (1) or formula (2), or a pharmaceutically acceptable salt thereof;

[0010] in,

[0011] The Linker1 is Or C 6-20 Alkylene;

[0012] The Linker2 is Or C 6-20 Alkylene;

[0013] m1 and m2 can be 1, 2, 3, 4, 5 or 6 independently;

[0014] n can be any value between 2 and 20 independently.

[0015] In a certain scheme, m1 and m2 are independently 1 or 2.

[0016] In a certain scheme, m1 and m2 are the same.

[0017] In one particular scheme, m1 and m2 are both 2.

[0018] In a given scheme, n is independently 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20; for example, n is independently 2, 5, 6, 7, 9, 11, 12 or 13.

[0019] In a certain scheme, n is 7-14, for example 7, 9, 11, 12 or 13.

[0020] In one scheme, the C 6-20 Alkylene is independently C 8-10 Alkylene.

[0021] In one scheme, Linker1 is

[0022] In one scheme, Linker2 is

[0023] In one embodiment, the abiraterone derivative shown in equation (1) is as shown in equation (1-1) or equation (1-2):

[0024] Where n is independent as described in the previous scheme.

[0025] In one embodiment, the abiraterone derivative as shown in formula (1) or formula (2) is selected from any of the following compounds:

[0026] The present invention also provides a composition comprising a therapeutically effective amount of one or more abiraterone derivatives as shown in formula (1) or formula (2), or a pharmaceutically acceptable salt thereof (referring to the abiraterone derivatives as shown in formula (1) or formula (2)).

[0027] The present invention also provides a pharmaceutical composition comprising a therapeutically effective amount of an abiraterone derivative as shown in formula (1) or formula (2), or a pharmaceutically acceptable salt thereof; and a pharmaceutically acceptable excipient.

[0028] In one embodiment, the pharmaceutical composition is an oil solvent, an in situ forming depot (ISFD, such as an in situ gel, in situ precipitant, or in situ implant), a nanocrystalline formulation, or a microcrystalline formulation.

[0029] In one embodiment, when the pharmaceutical composition is an oil solvent, the pharmaceutically acceptable excipient comprises a solvent selected from one or more of corn oil, sesame oil, castor oil, olive oil, and N-methylpyrrolidone and N,N-dimethylacetamide, for example, N-methylpyrrolidone.

[0030] In one embodiment, when the pharmaceutical composition is an oil solvent, the pharmaceutically acceptable excipient comprises a cosolvent selected from one or both of benzyl alcohol and benzyl benzoate.

[0031] In one embodiment, when the pharmaceutical composition is an in-situ formed formulation, the pharmaceutically acceptable excipient comprises a solvent selected from one, two, or three of N-methylpyrrolidone, N,N-dimethylacetamide, benzyl alcohol, and benzyl benzoate.

[0032] In one embodiment, when the pharmaceutical composition is an in-situ formed formulation, the pharmaceutically acceptable excipient further includes a polymer carrier selected from one or more of PLGA, PLA, PDLLA, PEG-PLGA, PEG-PLA, PEG-PDLLA, PLGA-PEG-PLGA, PLA-PEG-PLA, and PDLLA-PEG-PDLLA.

[0033] In one embodiment, when the pharmaceutical composition is a nanocrystalline or microcrystalline formulation, the pharmaceutically acceptable excipients include one or more of surfactants, suspending agents, buffers, and pH adjusters.

[0034] The surfactant may be selected from one or more of polysorbate 20 (Tween 20), polysorbate 80 (Tween 80), and poloxamer (such as poloxamer 188).

[0035] The suspending agent may be selected from one or more of polyethylene glycol 4000 (PEG4000), sodium carboxymethyl cellulose, and sodium hyaluronate.

[0036] The buffer may be selected from one or more of citrate, acetate and phosphate.

[0037] The pH adjuster may be selected from one or more of citric acid, acetic acid, phosphoric acid, hydrochloric acid, and sodium hydroxide.

[0038] In one embodiment, the composition is used for subcutaneous or intramuscular injection.

[0039] In one embodiment, the composition comprises any of the following:

[0040] In one embodiment, the composition comprises any of the following:

[0041] In one embodiment, the composition comprises any of the following:

[0042] In one embodiment, the composition is compound 4a. The micron-sized suspension uses ethanol as the solvent for compound 4a and 1% CMC-Na aqueous buffer as the dispersant. For example, the 1% CMC-Na aqueous buffer may contain 1% Tween 20, 1% CMC-Na, 0.75% citrate monohydrate, 0.6% sodium dihydrogen phosphate monohydrate, and 0.54% sodium hydroxide.

[0043] The present invention also provides a method for preparing abiraterone derivatives as shown in formula (1) or formula (2), or pharmaceutically acceptable salts thereof, which is method one or method two:

[0044] Method 1 includes the following steps: In an organic solvent, in the presence of a base and a condensing agent, abiraterone reacts with compound a-1 or a-2 to obtain the abiraterone derivative shown in formula (1):

[0045] Method 2 includes the following steps: In an organic solvent, in the presence of a base, abiraterone, triphosgene, and compound b-1 or b-2 are reacted to obtain the abiraterone derivative shown in formula (2):

[0046] Where m1, m2, and n have the definitions described in this paper.

[0047] In one embodiment, in method one, the organic solvent is a conventional solvent in the art, such as a halogenated hydrocarbon solvent, or chloroform for example.

[0048] In one embodiment, in method one, the base is a conventional base reagent in the art, such as an organic base, or more specifically, 4-dimethylaminopyridine.

[0049] In one embodiment, in method one, the condensing agent is a conventional condensing agent in the art, such as 1-ethyl-(3-dimethylaminopropyl)carbodiimide, or the hydrochloride salt of 1-ethyl-(3-dimethylaminopropyl)carbodiimide.

[0050] In one embodiment, in method two, the organic solvent is a conventional solvent in the art, such as a halogenated hydrocarbon solvent, or more specifically, dichloromethane.

[0051] In one embodiment, in method two, the base is a conventional base reagent in the art, such as an organic base, or triethylamine, for example.

[0052] The present invention also provides the use of an abiraterone derivative as described in any of the preceding embodiments, or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition thereof, in the preparation of a medicament for treating prostate cancer.

[0053] In one protocol, the prostate cancer is metastatic prostate cancer, such as castration-resistant prostate cancer (mCRPC) or high-risk metastatic endocrine therapy-sensitive prostate cancer (mHSPC).

[0054] The present invention provides a method for treating prostate cancer, comprising administering to a patient in need of this treatment a therapeutically effective amount of an abiraterone derivative as described in any of the preceding regimens, or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition thereof.

[0055] In one protocol, the prostate cancer is metastatic prostate cancer, such as castration-resistant prostate cancer (mCRPC) or high-risk metastatic endocrine therapy-sensitive prostate cancer (mHSPC).

[0056] Terminology Explanation

[0057] Unless otherwise specified, "derivative" as used herein refers to abiraterone derivatives. When represented by a specific structural formula, it may refer to a single compound with a fixed structure or a mixture of substances represented by an average degree of polymerization.

[0058] Unless otherwise stated, the structures described herein are intended to include all isomers (e.g., enantiomers, diastereomers, and geometric isomers (or conformational isomers) of that structure; for example, R and S configurations of each asymmetric center, (Z) and (E) double bond isomers, and (Z) and (E) conformational isomers. Therefore, single stereochemical isomers of the compounds of the present invention, as well as mixtures of enantiomers, diastereomers, and geometric isomers (or conformational isomers), are within the scope of this invention.

[0059] Furthermore, unless otherwise stated, the structures described herein are also intended to include compounds that differ only in the presence of one or more isotopically enriched atoms. For example, compounds having the structures of this invention (except for replacing hydrogen with deuterium or tritium, or using enriched atoms) 13 C or 14 All carbon substitutions for carbon (C) are within the scope of this invention. Such compounds can be used, for example, as analytical tools or probes in bioassays, or as therapeutic agents.

[0060] It should also be understood that certain compounds of the present invention may be in a free form for therapeutic purposes, or, where appropriate, as a pharmaceutically acceptable derivative or prodrug. According to the present invention, pharmaceutically acceptable derivatives or prodrugs include, but are not limited to, pharmaceutically acceptable salts, esters, salts of such esters, or any other adducts or derivatives that, upon administration to a patient in need, can directly or indirectly provide the compounds otherwise described herein or their metabolites or residues.

[0061] The compounds of this invention can exist in the form of solvates. A "solvate" is a substance formed by the combination of a compound with a stoichiometric or non-stoichiometric solvent. Solvent molecules in a solvate can exist in an ordered or disordered arrangement. The solvents include, but are not limited to, water, methanol, and ethanol.

[0062] The compounds of this invention can exist in polymorphic form. "Crystal form" refers to the strict periodic arrangement of ions or molecules in three-dimensional space in a defined manner, with a regular repetition at certain intervals; due to the different periodic arrangements, multiple crystal forms can exist, which is the phenomenon of polymorphism.

[0063] The compounds of this invention can exist as tautomers. A "tautomer" is a functional group isomer resulting from the rapid movement of an atom between two positions in a molecule. For example, acetone and 1-propen-2-ol can interconvert through the rapid movement of hydrogen atoms to oxygen and carbon.

[0064] Those skilled in the art should know that Mw, for a specific compound, represents the molecular weight, and for polydisperse polymers, it represents the weight-average molecular weight; Mn represents the number-average molecular weight. In the embodiments herein, unless otherwise specified, Mw (e.g., Example 3) indicates that the substance used is a monodisperse short-chain polyethylene glycol with a fixed degree of polymerization, i.e., representing the actual molecular weight; Mn (e.g., Examples 4 and 5) indicates a polydisperse polyethylene glycol substance.

[0065] Those skilled in the art should understand that, unless otherwise specified, "n" in the molecular structure represents the number of repeating units, i.e., the degree of polymerization. When the derivative is a monodisperse polymer, the value of n is a specific numerical value. When the derivative is a polydisperse polymer, the degree of polymerization is not a fixed value but a range, usually expressed as an average value. In this case, n refers to the average value of the degree of polymerization. Unless otherwise specified, the derivatives in this invention include both monodisperse and polydisperse polymers.

[0066] The term "alkylene" refers to a divalent saturated aliphatic hydrocarbon group; for example, an alkylene with 6 to 20 carbon atoms, preferably an alkylene with 8 to 10 carbon atoms.

[0067] The structural formula of the group described in this application uses the following... This refers to the fact that the corresponding group is connected to other fragments or groups in the compound through this site.

[0068] Furthermore, it should be noted that, unless otherwise explicitly stated, the descriptive phrase "...independently" used in this invention should be interpreted broadly, meaning that the described entities are independent of each other and can independently be the same or different specific functional groups. More specifically, the descriptive phrase "...independently" can mean either that the specific options expressed by the same symbol in different functional groups do not affect each other, or that the specific options expressed by the same symbol in the same functional group do not affect each other.

[0069] "Pharmaceutical composition" means a mixture containing one or more of the compounds described herein or their physiologically / pharmacologically acceptable salts or prodrugs, along with other chemical components, such as physiologically / pharmacologically acceptable carriers and excipients. The purpose of a pharmaceutical composition is to facilitate administration to a living organism, thereby promoting the absorption of the active ingredient and the exertion of its biological activity.

[0070] "Pharmaceutically acceptable salts" refer to salts obtained by reacting a compound with a pharmaceutically acceptable acid or base. When a compound contains a relatively acidic functional group, a base addition salt can be obtained by contacting the compound with a sufficient amount of a pharmaceutically acceptable base in a suitable inert solvent. When a compound contains a relatively basic functional group, an acid addition salt can be obtained by contacting the compound with a sufficient amount of a pharmaceutically acceptable acid in a suitable inert solvent. See Handbook of Pharmaceutical Salts: Properties, Selection, and Use (P. Heinrich Stahl, Camille G. Wermuth, 2011, 2nd Revised Edition) for details.

[0071] The term "therapeutic effective amount" refers to the amount of compound administered to a patient that is sufficient to effectively treat the disease. Therapeutic effective amount will vary depending on the compound, the type of disease, the severity of the disease, the patient's age, etc., but may be adjusted as appropriate by those skilled in the art.

[0072] The term "pharmaceutical excipients" refers to the excipients and additives used in the production of pharmaceuticals and the dispensing of prescriptions. It includes all substances contained in pharmaceutical preparations, excluding the active ingredient. See the Pharmacopoeia of the People's Republic of China (2020 edition) or the Handbook of Pharmaceutical Excipients (Raymond C. Rowe, 2009) for details.

[0073] The term “treatment” refers to any of the following: (1) alleviating one or more biological manifestations of a disease; (2) interfering with one or more points in the biological cascade that triggers the disease; or (3) slowing the development of one or more biological manifestations of a disease.

[0074] The term "patient" refers to any animal, preferably a mammal, that is about to receive or has already received administration of the compound or composition according to embodiments of the invention, with humans being the most preferred. The term "mammal" includes any mammal. Examples of mammals include, but are not limited to, cattle, horses, sheep, pigs, cats, dogs, mice, rats, rabbits, guinea pigs, monkeys, and humans, with humans being the most preferred.

[0075] The abiraterone derivatives described in this invention have a sustained-release period of up to 3 months or longer.

[0076] Without violating common sense in the field, the above-mentioned preferred conditions can be combined arbitrarily to obtain various preferred embodiments of the present invention.

[0077] The reagents and raw materials used in this invention are all commercially available.

[0078] The positive and progressive effects of this invention are as follows: each molecule of the compound contains two abiraterone molecules. The compound exhibits a long-acting sustained-release characteristic, allowing for subcutaneous or intramuscular injection to maintain blood drug concentrations for 12 weeks (3 months) or longer, thus enabling its use in the treatment of prostate cancer and improving patient compliance. Attached Figure Description

[0079] Figure 1 shows the plasma concentration of protobiraterone in male SD rats after intramuscular injection of different abiraterone derivative molecules / formulations.

[0080] Figure 2 shows the plasma concentration of the original abiraterone after subcutaneous injection of different abiraterone derivative molecules / formulations in male SD rats.

[0081] Figure 3 shows the plasma concentration of abiraterone derivative molecules after intramuscular injection in male SD rats with different abiraterone derivative molecules / formulations.

[0082] Figure 4 shows the plasma concentration of abiraterone derivative molecules after subcutaneous injection in male SD rats with different abiraterone derivative molecules / formulations.

[0083] Figure 5 shows the plasma concentration of abiraterone in male SD rats after intramuscular injection of compound 8a.

[0084] Figure 6 shows the plasma concentration of compound 8a in male SD rats after intramuscular injection of compound 8a.

[0085] Figure 7 shows the plasma testosterone concentration in male SD rats after intramuscular injection of compound 8a.

[0086] Figure 8 shows the plasma concentration of dihydrotestosterone in male SD rats after intramuscular injection of compound 8a.

[0087] Figure 9 shows the plasma concentration of protobiraterone in male SD rats after intramuscular injection of different abiraterone derivative molecules / formulations.

[0088] Figure 10 is a magnified view of the data from the first 24 hours of Figure 9.

[0089] Figure 11 shows the plasma concentration of abiraterone derivatives after intramuscular injection of different abiraterone derivative molecules / formulations in male SD rats.

[0090] Figure 12 is a magnified view of the data from the first 24 hours of Figure 11.

[0091] Figure 13 shows the concentration of abiraterone in the testes of male SD rats after intramuscular injection of different drugs. Detailed Implementation

[0092] The technical solution of the present invention will be further described in detail below with reference to specific embodiments. It should be understood that the following embodiments are merely illustrative and explanatory of the present invention, and should not be construed as limiting the scope of protection of the present invention. All technologies implemented based on the above content of the present invention are covered within the scope of protection intended by the present invention.

[0093] Unless otherwise stated, the raw materials and reagents used in the following examples are commercially available products or can be prepared by known methods.

[0094] The abiraterone derivative compounds described in this invention were characterized and identified by liquid chromatography-mass spectrometry (LC-MS). Specifically, for abiraterone prodrug derivatives (e.g., compounds 4a and 5a) obtained using polydisperse polyethylene glycol or polyethylene glycol dicarboxylic acid linkers, the [M / 2+H] characterization was performed. + Calculate the value of n for the strongest signal.

[0095] The English-Chinese terminology for mass spectrometry used in this invention is shown in the table below:

[0096] Unless otherwise specified, all reactions in this invention are carried out under continuous magnetic stirring, in a dry nitrogen or argon atmosphere, using a dry solvent, and the reaction temperature is expressed in degrees Celsius (°C).

[0097] Positive reference: Synthesis of abiraterone prodrug decanoate

[0098] Abiraterone (5.00 g, 14.31 mmol, 1.0 equiv), 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride (4.11 g, 21.46 mmol, 2.0 equiv), 4-diaminopyridine (0.35 g, 2.86 mmol, 0.2 equiv), and n-decanoic acid (2.71 g, 15.74 mmol, 1.1 equiv) were dissolved in dichloromethane (75 mL) and reacted at an internal temperature of 40 °C for 16 hours. After the reaction was completed, the reaction solution was concentrated under reduced pressure, chloroform (50 mL) was added, and the mixture was washed once with water (100 mL), once with saturated ammonium chloride solution (100 mL), and once with saturated brine (100 mL). The solution was concentrated to obtain a yellow oily substance. Acetonitrile (200 mL) was added to the oily substance while stirring, and the mixture was stirred rapidly for 16 hours. The mixture was then filtered to obtain a compound (5.2 g, 72%), which was a white solid. LC-MS: (ESI, m / z) = 504.41 [M+H] +

[0099] Example 1

[0100] Abiraterone (6.0 g, 17.17 mmol, 1 equiv), 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride (4.94 g, 25.75 mmol, 1.5 equiv), 4-dimethylaminopyridine (0.42 g, 3.43 mmol, 0.2 equiv), and sebacic acid (2.08 g, 10.30 mmol, 0.6 equiv) were dissolved in chloroform (60 mL). The reaction mixture was kept at 60 °C for 18 hours. After the reaction was complete, the reaction solution was concentrated under reduced pressure, and ethyl acetate (100 mL) was added until completely dissolved. The sample was washed once with water (100 mL), once with saturated ammonium chloride solution (100 mL), and once with saturated saline solution (100 mL). After concentration, the sample was separated by column chromatography (the mobile phase was ethyl acetate / petroleum ether = 0-85% V / V, which means that the ethyl acetate content increased linearly from 0% to 85% to elute abiraterone, and then the product was eluted with ethyl acetate at 85% V / V until purification was complete; the column chromatography conditions in the following examples refer to the meaning in this example). Compound 1a (5.2 g, 34%) was obtained, and LC-MS (ESI, m / z) = 865.54 [M+H]. + .

[0101] Example 2

[0102] Abiraterone (5.0 g, 14.31 mmol, 1 equiv), triethylamine (2.9 g, 28.61 mmol, 2 equiv), and decanediol (1.25 g, 7.15 mmol, 0.5 equiv) were dissolved in dichloromethane (50 mL). A dichloromethane solution of triphosgene (16.98 g, 57.22 mmol) was added dropwise at 0 °C. After the addition was complete, the reaction was maintained at 40 °C for 16 hours. After completion, the solution was concentrated under reduced pressure to remove dichloromethane. Then, ethyl acetate (100 mL) was added, followed by filtration. The organic phase was washed once with water (100 mL), once with saturated ammonium chloride solution (100 mL), and once with saturated brine (100 mL). After concentration, column chromatography was performed (mobile phase: ethyl acetate / petroleum ether = 0-85% V / V) to give compound 2a (2 g, 14%). LC-MS: (ESI, m / z) = 925.59 [M / 2+H] +

[0103] Example 3

[0104] Abiraterone (5.80 g, 16.59 mmol, 2 equiv), 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride (3.18 g, 16.59 mmol, 2 equiv), 4-dimethylaminopyridine (2.6 g, 16.59 mmol, 2 equiv), and polyethylene glycol dicarboxylic acid (5 g, 8.30 mmol, 1 equiv, M... W 250.25) was dissolved in chloroform (50 mL), and the reaction was carried out at an internal temperature of 60 °C for 18 hours. After the reaction was completed, the reaction solution was concentrated under reduced pressure, and ethyl acetate (100 mL) was added. After complete dissolution, the solution was washed once with water (100 mL), once with saturated ammonium chloride aqueous solution (100 mL), and once with saturated brine (100 mL). After concentration, the solution was separated by column chromatography (mobile phase: ethyl acetate / petroleum ether = 0-85% V / V) to give compound 3a (4.5 g, 38%). LC-MS: (ESI, m / z) = 885.74 [M+H] +

[0105] Example 4

[0106] Abiraterone (10.81 g, 30.93 mmol, 2.0 equiv) and polyethylene glycol dicarboxylic acid (10 g, 15.64 mmol, Average) were added. Mn = 600), triethylamine (4.0 g, 30.93 mmol), 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride (5.93 g, 30.93 mmol, 2.0 equiv), and 4-dimethylaminopyridine (3.78 g, 30.93 mmol, 2.0 equiv) were dissolved in chloroform (100 mL). The reaction mixture was reacted at 60 °C for 18 hours. After the reaction was complete, the reaction solution was concentrated under reduced pressure, and ethyl acetate (100 mL) was added. After complete dissolution, the solution was washed once with water (100 mL), once with saturated ammonium chloride solution (100 mL), and once with saturated brine (100 mL). After concentration, the solution was separated by column chromatography (mobile phase: ethyl acetate / petroleum ether = 0-85% V / V) to give compound 4a (9.1 g, 44%). LC-MS: (ESI, m / z) = 663.64 [M / 2+H] +

[0107] Example 5

[0108] Abiraterone (10 g, 28.61 mmol, 2 equiv), PEG600 (8.58 g, 14.31 mmol, Average Mn 600), and triethylamine (5.79 g, 57.22 mmol, 7.98 mL) were dissolved in chloroform (50 mL). A chloroform solution of triphosgene (16.98 g, 57.22 mmol) was added dropwise at 0 °C. After the addition was complete, the mixture was allowed to return to room temperature and reacted for 18 hours. After the reaction was complete, the reaction solution was concentrated under reduced pressure, and ethyl acetate (100 mL) was added. After complete dissolution, the mixture was washed once with water (100 mL), once with saturated ammonium chloride aqueous solution (100 mL), and once with saturated brine (100 mL). After concentration, the mixture was separated by column chromatography (mobile phase: ethyl acetate / petroleum ether = 0-55% V / V) to give compound 5a (5.1 g, 21%). LC-MS: (ESI, m / z)=693.71[M / 2+H] +

[0109] Example 6

[0110] Abiraterone (7.43 g, 21.25 mmol, 2 equiv), 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride (4.07 g, 21.25 mmol, 2 equiv), 4-dimethylaminopyridine (2.6 g, 21.25 mmol, 2 equiv), and polyethylene glycol dicarboxylic acid Bis-PEG8-acid (5 g, 10.63 mmol, 1 equiv, Mw) were added. 470.51) was dissolved in chloroform (50 mL), and the reaction was carried out at an internal temperature of 60 °C for 18 hours. After the reaction was completed, the reaction solution was concentrated under reduced pressure, and ethyl acetate (100 mL) was added. After complete dissolution, the solution was washed once with water (100 mL), once with saturated ammonium chloride aqueous solution (100 mL), and once with saturated brine (100 mL). After concentration, the solution was separated by column chromatography (mobile phase: ethyl acetate / petroleum ether = 0-85% V / V) to give compound 6a (4.5 g, 38%). LC-MS: (ESI, m / z) = 567.62 [M / 2+H] +

[0111] Example 7

[0112] Abiraterone (8.20 g, 23.45 mmol, 2 equiv), 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride (4.50 g, 23.45 mmol, 2 equiv), 4-dimethylaminopyridine (2.86 g, 23.45 mmol, 2 equiv), and polyethylene glycol dicarboxylic acid Bis-PEG7-acid (5 g, 11.72 mmol, 1 equiv, Mw) were added. 426.46) was dissolved in chloroform (50 mL), and the reaction was carried out at an internal temperature of 60 °C for 18 hours. After the reaction was completed, the reaction solution was concentrated under reduced pressure, and ethyl acetate (100 mL) was added. After complete dissolution, the solution was washed once with water (100 mL), once with saturated ammonium chloride aqueous solution (100 mL), and once with saturated brine (100 mL). After concentration, the solution was separated by column chromatography (mobile phase: ethyl acetate / petroleum ether = 0-85% V / V) to give compound 7a (4.1 g, 32%). LC-MS: (ESI, m / z) = 545.61 [M / 2+H] +

[0113] Example 8

[0114] Abiraterone (10.81 g, 30.93 mmol, 2 equiv), 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride (5.93 g, 30.93 mmol, 2 equiv), 4-dimethylaminopyridine (3.78 g, 30.93 mmol, 2 equiv), and polyethylene glycol dicarboxylic acid Bis-PEG12-acid (10 g, 15.46 mmol, 1 equiv, Mw) were added. Compound 646.72) was dissolved in chloroform (100 mL) and reacted at an internal temperature of 60 °C for 18 hours. After the reaction was complete, the reaction solution was concentrated under reduced pressure, and ethyl acetate (150 mL) was added. After complete dissolution, the solution was washed once with water (150 mL), once with saturated ammonium chloride aqueous solution (150 mL), and once with saturated brine (150 mL). After concentration, the solution was separated by column chromatography (mobile phase: petroleum ether / ethyl acetate = 0-85% V / V). The system was then changed to dichloromethane / methanol (10% methanol) to give compound 8a (10.2 g, 49%). LC-MS: (ESI, m / z) = 655.66 [M / 2+H] +

[0115] Example 9

[0116] Abiraterone (18.28 g, 52.3 mmol, 2 equiv), 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride (10.03 g, 52.3 mmol, 2 equiv), 4-dimethylaminopyridine (6.39 g, 52.3 mmol, 2 equiv), and polyethylene glycol dicarboxylic acid Bis-PEG6-acid (10 g, 26.15 mmol, 1 equiv, Mw) were added. 382.4) was dissolved in chloroform (100 mL), and the reaction was carried out at an internal temperature of 60 °C for 18 hours. After the reaction was completed, the reaction solution was concentrated under reduced pressure, and ethyl acetate (150 mL) was added. After complete dissolution, the solution was washed once with water (150 mL), once with saturated ammonium chloride aqueous solution (150 mL), and once with saturated brine (150 mL). After concentration, the solution was separated by column chromatography (mobile phase: ethyl acetate / petroleum ether = 0-85% V / V). The system was then changed to dichloromethane / methanol (10% methanol) to give compound 9a (9.35 g, 33%). LC-MS: (ESI, m / z) = 523.58 [M / 2+H] +

[0117] Example 10

[0118] Abiraterone (18.77 g, 53.7 mmol, 2 equiv), 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride (10.3 g, 53.7 mmol, 2 equiv), 4-dimethylaminopyridine (6.56 g, 53.7 mmol, 2 equiv), and polyethylene glycol dicarboxylic acid Bis-PEG10-acid (15 g, 26.85 mmol, 1 equiv, Mw) were added. 558.61) was dissolved in chloroform (150 mL), and the reaction was carried out at an internal temperature of 60 °C for 18 hours. After the reaction was completed, the reaction solution was concentrated under reduced pressure, and ethyl acetate (150 mL) was added. After complete dissolution, the solution was washed once with water (150 mL), once with saturated ammonium chloride aqueous solution (150 mL), and once with saturated brine (150 mL). After concentration, the solution was separated by column chromatography (mobile phase: ethyl acetate / petroleum ether = 0-85% V / V). The system was then changed to dichloromethane / methanol (10% methanol) to give compound 10a (15.0 g, 44%). LC-MS: (ESI, m / z) = 611.58 [M / 2+H] +

[0119] Example 11

[0120] Abiraterone (19.03 g, 54.43 mmol, 2 equiv), 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride (10.44 g, 54.43 mmol, 2 equiv), 4-dimethylaminopyridine (6.65 g, 54.43 mmol, 2 equiv), and polyethylene glycol dicarboxylic acid Bis-PEG14-acid (20 g, 27.22 mmol, 1 equiv, Mw 734.82) were dissolved in chloroform (200 mL). The reaction mixture was kept at 60 °C for 18 hours. After the reaction was completed, the reaction solution was concentrated under reduced pressure, and ethyl acetate (200 mL) was added. After complete dissolution, the solution was washed once with water (200 mL), once with saturated ammonium chloride solution (200 mL), and once with saturated brine (200 mL). After concentration, the solution was separated by column chromatography (mobile phase: ethyl acetate / petroleum ether = 0.85%). The mixture was then changed to a dichloromethane / methanol (10% methanol) system to obtain compound 11a (15.2 g, 40%). LC-MS (ESI, m / z) = 699.8 [M / 2+H]. +

[0121] Example 12. Solubility test of abiraterone derivatives

[0122] Long-acting sustained-release derivatives or formulations are typically administered via subcutaneous or intramuscular injection. Common formulation forms include oil solutions (usually intramuscular), microspheres (subcutaneous or intramuscular), nanocrystals / microcrystals (subcutaneous or intramuscular), and in-situ forming depots (ISFD, including gels / in-situ precipitation, usually subcutaneous injection). Microsphere manufacturing processes are complex, while nanocrystals / microcrystals and ISFD formulations have relatively simpler processes. Therefore, this example mainly investigates the solubility of abiraterone derivative molecules in aqueous stabilizer / dispersant systems that may be involved in the preparation of nanocrystals / microcrystals, in organic solvents that may be involved in ISFD, and in oil solvents, as shown in Table 1.

[0123] Table 1. Code correspondence of abiraterone derivative molecules

[0124] Example 12A. Solubility test of abiraterone derivatives in aqueous system

[0125] The solubility of various abiraterone derivatives in aqueous systems was tested as follows. The results are shown in Table 2-3.

[0126] For each solvent studied, weigh a sufficient amount of the derivative into a separate glass vial and add 1 ml of solvent. Sonicate and vortex the resulting suspension. If the derivative is completely dissolved, add more derivative until an excess is observed. If a large excess of undissolved derivative is present, add more diluent. Record the total mass and volume used. Seal each vial tightly and wrap it with foil to protect it from light if necessary.

[0127] Transfer the liquid from each vial to a centrifuge tube. Centrifuge the tubes at 13,000 rpm until a clear interface appears. Collect the supernatant and filter the sample using a 0.22 or 0.45 μm syringe filter. Analyze the filtered liquid using HPLC. Dilute the sample if necessary to bring the concentration within the range of standards.

[0128] Table 2. Aqueous solubility of abiraterone derivatives (compounds 1a-5a)

[0129] Table 3. Aqueous solubility of abiraterone derivatives (compounds 6a-11a)

[0130] a. The 7.5% PEG400 buffer is a mixed solution composed of 1% Tween 20, 7.5% PEG400, 0.75% citrate monohydrate, 0.6% sodium dihydrogen phosphate monohydrate, and 0.54% sodium hydroxide.

[0131] b. The 7.5% PEG4000 buffer solution is a mixed solution composed of 1% Tween 20, 7.5% PEG4000, 0.75% citrate monohydrate, 0.6% sodium dihydrogen phosphate monohydrate, and 0.54% sodium hydroxide.

[0132] c. 1% CMC-Na buffer is a mixed solution composed of 1% Tween 20, 1% CMC-Na, 0.75% citrate monohydrate, 0.6% sodium dihydrogen phosphate monohydrate, and 0.54% sodium hydroxide.

[0133] Example 12B. Solubility test of abiraterone derivatives in organic / oil solvent systems

[0134] The solubility of various abiraterone derivatives in organic / oil solvent systems was tested as follows. The results are shown in Table 4-5.

[0135] For each solvent studied, weigh an appropriate amount of the derivative into a separate glass vial and add a certain amount of solvent. Sonicate and vortex the resulting suspension. If the derivative is completely dissolved, add more derivative until an excess is observed. If a large excess of undissolved derivative is present, diluent can be added. Record the total mass and volume used. Each vial should be tightly capped and wrapped with foil to protect from light if necessary.

[0136] Transfer the liquid from each vial to a centrifuge tube. Centrifuge the tubes at 13,000 rpm until a clear interface appears. Collect the supernatant and filter the sample using a 0.22 or 0.45 μm syringe filter. Analyze the filtered liquid using HPLC. Dilute the sample if necessary to bring the concentration within the range of standards.

[0137] Table 4. Solubility of abiraterone derivatives (compounds 1a-5a) in organic solvent / oil solvent systems

[0138] Table 5. Solubility of abiraterone derivatives (compounds 6a-11a) in organic solvent / oil solvent systems

[0139] Example 13. Preparation of animal experimental samples of abiraterone derivatives

[0140] Prepare abiraterone derivative formulations according to Table 6.

[0141] Table 6. Information on preparations of abiraterone derivatives *Note: AD is a compound of Yangshen, and its solvent system was formulated with reference to Yangshen patent CN114026106A; abiraterone acetate (AA), derivative molecules ADD, AP1, AP2, AP3 and AP4 have low solubility in corn oil / sesame oil, and obvious stratification occurs when dissolved in the AD system. Therefore, corn oil is not used. Other clinically acceptable solvent / formulation systems that can achieve the target dosage concentration are used according to the target route of administration; for subcutaneous injection of each derivative molecule, since AP1 molecule (compound 2a) precipitates after being dissolved to the target concentration in NMP and left at room temperature for 1 hour (possibly due to supersaturation precipitation), a certain proportion of benzyl alcohol (BA, F6) is added to solubilize it.

[0142] Example 13A. Preparation of abiraterone acetate microcrystalline suspension (F1)

[0143] The following is a method for preparing an injectable (intramuscular reservoir) microcrystalline suspension of abiraterone acetate (F1):

[0144] Prepare an aqueous buffer solution containing 1% Tween 20, 7.5% PEG4000, 0.75% citrate monohydrate, 0.6% sodium dihydrogen phosphate monohydrate, and 0.54% sodium hydroxide. Dilute this buffer solution three times with purified water and filter it through a 0.45 μm PES membrane. Weigh 600.52 mg of abiraterone acetate (AA) and place it in a 10 mL glass vial. Add 7.5 mL of anhydrous ethanol and mix thoroughly until completely dissolved. In a separate 40 mL glass vial, add 30 mL of 1.875% PEG4000 aqueous buffer solution. Start stirring and slowly add the abiraterone acetate ethanol solution dropwise to the vial using a 10 mL syringe. Continue stirring for 5 min after the addition is complete to obtain F1. Aliquot 3.5 mL into 10 mL vials, partially stopper them, and freeze-dry using a Christ lyophilizer (Epsilon 2-4LSC Plus). The obtained lyophilized powder was reconstituted with 0.3 ml of purified water per bottle. The final concentration of the abiraterone acetate microcrystalline suspension (F1) after reconstitution was 138.5 mg / ml, which is equivalent to a final concentration of abiraterone of 123.3 mg / ml.

[0145] Example 13B. Preparation of abiraterone decanoate oil solution (F2)

[0146] The following is a method for preparing an injectable (intramuscular reservoir) oil solution of abiraterone decanoate (F2):

[0147] Weigh 481.9 mg of abiraterone decanoate (AD) and place it in a 4 mL glass vial. Add 0.6 mL of 33.3% benzyl alcohol / 66.7% benzyl benzoate solution and seal the vial. Dissolve the abiraterone decanoate by sonication and vortexing. Add 1.4 mL of corn oil to the clear solution and tighten the cap again. Continue to sonicate and vortex repeatedly to obtain a homogeneous clear oil solution. The final concentration of the abiraterone decanoate oil solution (F2) is 180.9 mg / mL, which translates to a final abiraterone concentration of 125.1 mg / mL.

[0148] Example 13: Preparation of ADD solution (F3)

[0149] The following is a sample preparation method for an injectable (intramuscular reservoir) solution of ADD (F3):

[0150] Weigh 402.5 mg of ADD and place it in a 4 mL glass vial. Add 1.94 mL of 33.3% benzyl alcohol / 66.7% benzyl benzoate solution and seal the vial. Then dissolve abiraterone sebacate by sonication and vortexing. The final concentration of the ADD solution (F3) is 129.8 mg / mL, which translates to a final concentration of 104.6 mg / mL of abiraterone.

[0151] Example 13: Preparation of 3D.AP3 microcrystalline suspension (F4)

[0152] The following is a method for preparing an injectable (intramuscular reservoir) microcrystalline suspension of AP3 abiraterone derivatives (F4):

[0153] Prepare an aqueous buffer solution containing 1% Tween 20, 1% CMC-Na, 0.75% citrate monohydrate, 0.6% sodium dihydrogen phosphate monohydrate, and 0.54% sodium hydroxide. Weigh 533.7 mg of AP3 and place it in a 5 mL glass vial. Add 1.974 mL of anhydrous ethanol and mix thoroughly until completely dissolved. In a separate 20 mL glass vial, add 7.895 mL of 1% CMC-Na aqueous buffer solution. Start stirring and slowly add the AP3 ethanol solution dropwise using a 5 mL syringe, stirring continuously for 5 min after the addition is complete. Transfer the solution to a 10 mL centrifuge tube and centrifuge at 5000 rpm for 5 min. Discard the supernatant and add 2.1 mL of 1% CMC-Na aqueous buffer solution. Vortex repeatedly to resuspend the precipitate at the bottom of the centrifuge tube and disperse it evenly to obtain F4. The final concentration of AP3 micron-sized crystal suspension was 162.2 mg / ml, which is equivalent to a final concentration of abiraterone of 85.3 mg / ml.

[0154] Example 13: Preparation of AP1 solution (F5)

[0155] The following is a sample preparation of an injectable (intramuscular reservoir) solution of 33.3% benzyl alcohol and 66.7% benzyl benzoate (F5):

[0156] Weigh 372.7 mg of AP1 and place it in a 4 mL glass vial. Add 1.69 mL of 33.3% benzyl alcohol / 66.7% benzyl benzoate solution and seal the vial. Then dissolve AP1 by sonication and vortexing. The final concentration of the AP1 solution (F5) is 179.9 mg / mL, which is equivalent to a final abiraterone concentration of 135.5 mg / mL.

[0157] Example 13 Preparation of F.AP1 solution (F6)

[0158] The following is a sample preparation of an injectable (subcutaneous reservoir) solution of 17.5% benzyl alcohol and 82.5% N-methylpyrrolidone (F6):

[0159] Weigh 378.2 mg of AP1 and place it in a 4 mL glass vial. Add 1 mL of 17.5% benzyl alcohol / 82.5% N-methylpyrrolidone solution and seal the vial. Then dissolve AP1 by sonication and vortexing. The final concentration of the AP1 solution (F6) is 261.8 mg / mL, which is equivalent to a final abiraterone concentration of 197.2 mg / mL.

[0160] Example 13: Preparation of G.AP2 solution (F7)

[0161] The following is a sample preparation method for an injectable (subcutaneous reservoir) N-methylpyrrolidone solution (F7) for AP2:

[0162] Weigh 362.1 mg of AP2 and place it in a 4 mL glass vial. Add 0.625 mL of N-methylpyrrolidone and seal the vial. Then dissolve AP2 by sonication and vortexing. The final concentration of the AP2 solution (F7) is 397.1 mg / mL, which is equivalent to a final abiraterone concentration of 312.7 mg / mL.

[0163] Example 13 Preparation of H.AP3 solution (F8)

[0164] The following is a sample preparation method for an injectable (subcutaneous reservoir) N-methylpyrrolidone solution (F8) for AP3:

[0165] Weigh 683.0 mg of AP3 and place it in a 4 mL glass vial. Add 0.625 mL of N-methylpyrrolidone and seal the vial. Then dissolve AP3 by sonication and vortexing. The final concentration of the AP3 solution (F8) is 446.4 mg / mL, which is equivalent to a final abiraterone concentration of 234.8 mg / mL.

[0166] Example 13I. Preparation of AP4 solution (F9)

[0167] The following is a sample preparation method for an injectable (subcutaneous reservoir) N-methylpyrrolidone solution (F9) for AP4:

[0168] Weigh 712.3 mg of AP4 and place it in a 4 mL glass vial. Add 0.625 mL of N-methylpyrrolidone and seal the vial. Then dissolve the AP4 by sonication and vortexing. The final concentration of the AP4 solution (F9) is 426.8 mg / mL, which is equivalent to a final concentration of 214.8 mg / mL of abiraterone.

[0169] Example 14. Preparation of animal experimental samples of abiraterone derivatives

[0170] Prepare abiraterone derivative formulations according to Table 7.

[0171] Table 7. Information on preparations of abiraterone derivatives

[0172] Example 14A. Preparation of Compound 6a Solution (F10)

[0173] The injectable solution (F10) of compound 6a was prepared as follows:

[0174] Weigh 852.94 mg of compound 6a and place it in a 4 mL glass vial. Add 0.316 mL of benzyl alcohol and 1.264 mL of benzyl benzoate, and then make up the volume with corn oil (0.73 mL). After complete dissolution, filter and determine the drug concentration. The final concentration of the compound 6a solution was 262.23 mg / mL, which translates to a final abiraterone concentration of 161.71 mg / mL.

[0175] Example 14B. Preparation of compound 7a solution (F11)

[0176] The injectable solution (F11) of compound 7a was prepared as follows:

[0177] Weigh 819.67 mg of compound 7a and place it in a 4 mL glass vial. Add 0.316 mL of benzyl alcohol and 1.264 mL of benzyl benzoate, then make up the volume with corn oil (0.76 mL). After complete dissolution, filter and determine the drug concentration. The final concentration of the compound 7a solution was 233.00 mg / mL, which translates to a final abiraterone concentration of 149.49 mg / mL.

[0178] Example 14C. Preparation of Compound 8a solution (F12)

[0179] The injectable solution (F12) of compound 8a was prepared as follows:

[0180] Weigh 987.80 mg of compound 8a and place it in a 4 mL glass vial. Add 0.316 mL of benzyl alcohol and 1.264 mL of benzyl benzoate, and then make up the volume with corn oil (0.60 mL). After complete dissolution, filter and determine the drug concentration. The final concentration of the compound 8a solution was 317.85 mg / mL, which translates to a final abiraterone concentration of 169.64 mg / mL.

[0181] Example 14D. Preparation of Compound 9a solution (F13)

[0182] The injectable solution of compound 9a (F13) was prepared as follows:

[0183] Weigh 785.29 mg of compound 9a and place it in a 4 mL glass vial. Add 0.316 mL of benzyl alcohol and 1.264 mL of benzyl benzoate, then make up the volume with corn oil (0.80 mL). After complete dissolution, filter and determine the drug concentration. The final concentration of the compound 9a solution was 258.49 mg / mL, which translates to a final abiraterone concentration of 172.84 mg / mL.

[0184] Example 14E. Preparation of a solution of compound 10a (F14)

[0185] The injectable solution of compound 10a (F14) was prepared as follows:

[0186] Weigh 919.82 mg of compound 10a and place it in a 4 mL glass vial. Add 0.316 mL of benzyl alcohol and 1.264 mL of benzyl benzoate, and then make up the volume with corn oil (0.66 mL). After complete dissolution, filter and determine the drug concentration. The final concentration of the compound 10a solution was 294.53 mg / mL, which translates to a final abiraterone concentration of 168.53 mg / mL.

[0187] Example 14F. Preparation of Compound 11a solution (F15)

[0188] The injectable solution of compound 11a (F15) was prepared as follows:

[0189] Weigh 1062.46 mg of compound 11a and place it in a 4 mL glass vial. Add 0.316 mL of benzyl alcohol and 1.264 mL of benzyl benzoate, and then make up the volume with corn oil (0.53 mL). After complete dissolution, filter and determine the drug concentration. The final concentration of the compound 11a solution was 350.30 mg / mL, which translates to a final abiraterone concentration of 175.17 mg / mL.

[0190] Example 14. Preparation of Compound 6a solution (F16)

[0191] The following is a sample of compound 6a that can be injected subcutaneously (F16):

[0192] Weigh 855.29 mg of compound 6a and place it in a 4 mL glass vial. Add 0.905 mL of N-methylpyrrolidone and filter through a 0.45 μm PTFE filter after complete dissolution. The final concentration of the compound 6a solution is 500.89 mg / mL, which is equivalent to a final abiraterone concentration of 308.88 mg / mL.

[0193] Example 14H. Preparation of Compound 7a solution (F17)

[0194] The following is a sample of compound 7a that can be injected subcutaneously (F17):

[0195] Weigh 821.41 mg of compound 7a and place it in a 4 mL glass vial. Add 0.935 mL of N-methylpyrrolidone and filter through a 0.45 μm PTFE filter after complete dissolution. The final concentration of the compound 7a solution is 445.46 mg / mL, which is equivalent to abiraterone concentration of 285.81 mg / mL.

[0196] Example 14I. Preparation of Compound 8a Solution (F18)

[0197] The following is a sample of compound 8a that can be injected subcutaneously (F18):

[0198] Weigh 986.43 mg of compound 8a and place it in a 4 mL glass vial. Add 0.775 mL of N-methylpyrrolidone and filter through a 0.45 μm PTFE filter after complete dissolution. The final concentration of the compound 8a solution is 576.32 mg / mL, which is equivalent to a final abiraterone concentration of 307.58 mg / mL.

[0199] Example 14J. Preparation of Compound 9a Solution (F19)

[0200] The following is a sample of compound 9a that can be injected subcutaneously (F19):

[0201] Weigh 792.21 mg of compound 9a and place it in a 4 mL glass vial. Add 0.975 mL of N-methylpyrrolidone and filter through a 0.45 μm PTFE filter after complete dissolution. The final concentration of the compound 9a solution is 478.02 mg / mL, which is equivalent to abiraterone concentration of 319.62 mg / mL.

[0202] Example 14K. Preparation of Compound 10a solution (F20)

[0203] The following is a sample of compound 10a that can be injected subcutaneously (F20):

[0204] Weigh 917.71 mg of compound 10a and place it in a 4 mL glass vial. Add 0.835 mL of N-methylpyrrolidone and filter through a 0.45 μm PTFE filter after complete dissolution. The final concentration of the compound 10a solution is 507.92 mg / mL, which is equivalent to abiraterone concentration of 290.63 mg / mL.

[0205] Example 14. Preparation of Compound 11a solution (F21)

[0206] The following is a sample of compound 11a that can be injected subcutaneously (F21):

[0207] Weigh 1067.72 mg of compound 11a and place it in a 4 mL glass vial. Add 0.705 mL of N-methylpyrrolidone and filter through a 0.45 μm PTFE filter after complete dissolution. The final concentration of the compound 11a solution is 608.98 mg / mL, which is equivalent to a final abiraterone concentration of 304.53 mg / mL.

[0208] Test Example 1: Pharmacokinetic Study of Abiraterone Derivative Formulation in Male SD Rats

[0209] I. Experimental Methods

[0210] Forty-five male 8-9 week old SD rats of SPF grade and similar body weight were selected as experimental animals and randomly divided into 9 groups (n=5 per group). The above-mentioned formulation was administered intramuscularly or subcutaneously to the hind leg of each animal at a dose of abiraterone 90 mg / kg. Blood samples were collected from the jugular vein before administration and at 15 min, 30 min, 1 h, 2 h, 4 h, 8 h, 24 h, 48 h, 72 h, 7 days, 10 days, 14 days, 17 days, 21 days, 28 days, 35 days, 42 days, 49 days, 56 days, (63 days) 9 weeks, (70 days) 10 weeks, (84 days) 12 weeks, and (98 days) 14 weeks. The concentrations of abiraterone derivatives and abiraterone in rat plasma were determined using a validated LC-MS / MS method.

[0211] 1.1 Experimental apparatus, see Table 8 below:

[0212] Table 8

[0213] 1.2 Chromatographic columns, see Table 9 below:

[0214] Table 9

[0215] 1.3 Detection Method

[0216] 1.3.1 Mass Spectrometry Parameters

[0217] The mass spectrometry parameters of abiraterone, abiraterone acetate, abiraterone decanoate, and compounds 1a, 2a, and 3a are shown in Table 10 below:

[0218] Table 10

[0219] The mass spectrometry parameters of compounds 4a and 5a are shown in Table 11 below:

[0220] Table 11

[0221] 1.3.2 Chromatographic methods, see Table 12 below:

[0222] Table 12

[0223] Animal grouping and drug dosage information is shown in Table 13 below.

[0224] Table 13 *Note 1: The group is consistent with the formulation group in Table 6. *Note 2: The dosage and concentration of each derivative molecule are calculated based on the amount contained in abiraterone.

[0225] II. Experimental Results

[0226] The pharmacokinetic parameters of abiraterone in rat plasma after administration are shown in Table 14 (intramuscular injection) and Table 15 (subcutaneous injection), and the pharmacokinetic parameters of abiraterone derivatives are shown in Table 16 (intramuscular injection) and Table 17 (subcutaneous injection).

[0227] Figure 1 shows the plasma concentrations of the parent abiraterone after intramuscular injection of each derivative molecule sample: F4 (compound 4a) showed the highest plasma abiraterone exposure, the best absorption, and sustained release of abiraterone for 98 days, with an AUC of lastThe concentration of F1 (abiraterone acetate) was 1.4 times that of F2 (abiraterone caprylate); the blood concentration of F1 (abiraterone acetate) was significantly lower than that of F2 and F4 starting at day 14; compound 2a (F5) had the worst absorption, with blood concentrations consistently below 0.5 ng / ml for the first 28 days, and undetectable after day 28; compared with F4 (compound 4a) and F3 (compound 1a), the in vivo absorption and conversion of abiraterone bimolecular derivatives prepared with short-chain polyethylene glycol dicarboxylic acid as a linker was significantly higher than that prepared with sebacic acid as a linker; compared with the plasma concentration of proto-abiraterone after intramuscular injection of F3 (compound 1a, ester bond) and F5 (compound 2a, carbonate bond), the exposure of F3 was higher than that of F5, suggesting that when alkylene chains are used as linkers, the rate of hydrolysis and conversion of ester bonds to proto-abiraterone in vivo is faster than that of carbonate bonds.

[0228] Figure 2 shows the plasma abiraterone concentrations of each derivative molecule after subcutaneous injection: F8 (compound 4a) showed the highest plasma exposure to the original abiraterone, followed by F9 (compound 5a), while F6 (compound 2a) showed the lowest plasma exposure to abiraterone.

[0229] Figure 3 shows the plasma concentrations of derivative molecules after intramuscular injection in rats. F2 (abiraterone decanoate) was continuously detectable from day 0 to 98, while F4 (compound 4a) was undetectable from day 10 onwards. Based on the pharmacokinetic parameters of the derivative molecules in Table 16, the plasma exposure of the Yangshen compound abiraterone decanoate derivative was the highest, while the plasma exposure of the F4 (compound 4a) derivative was about 10 times lower than that of abiraterone decanoate, and the plasma exposure of F1 (abiraterone acetate) was more than 100 times lower than that of abiraterone decanoate. Combining the plasma concentrations of the original abiraterone and the pharmacokinetic parameters after administration of each molecule, it can be inferred that the conversion rate of the F2 (abiraterone decanoate) derivative was slower, while the conversion rate of the F4 (compound 4a) derivative was significantly faster than that of abiraterone decanoate.

[0230] Figure 4 shows the concentration of derivative molecules in the plasma of rats after subcutaneous injection. F8 (compound 4a) was undetectable from day 10 onwards, and F9 (compound 5a) derivative molecules were undetectable at all time points. However, the concentration of the original abiraterone in the plasma of both groups was high, indicating that compounds 4a and 5a were well absorbed after subcutaneous injection and could be rapidly converted into abiraterone. The conversion rate of compound 5a was relatively faster, that is, when short-chain polyethylene glycol is used as a linker, the hydrolysis rate of carbonate bonds is slightly faster than that of ester bonds.

[0231] Table 14. Pharmacokinetic parameters of abiraterone in plasma after intramuscular injection in rats

[0232] Table 15. Pharmacokinetic parameters of abiraterone in plasma after subcutaneous injection in rats

[0233] Table 16. Pharmacokinetic parameters of derivative molecules in plasma after intramuscular injection in rats

[0234] Table 17. Pharmacokinetic parameters of derivative molecules in plasma after subcutaneous injection in rats

[0235] In summary, the abiraterone bimolecular derivatives prepared using short-chain polyethylene glycol dicarboxylic acid subunits or short-chain polyethylene glycol subunits as linkers in this invention exhibit significantly improved solubility in NMP compared to abiraterone acetate or abiraterone decanoate. This makes them more suitable for preparing in-situ reservoir formulations for subcutaneous injection, and allows for higher blood exposure of the parent drug after subcutaneous injection. Similarly, the derivatives described in this invention can also be formulated into other dosage forms for intramuscular injection. Compared to abiraterone prodrugs prepared using existing technologies (such as abiraterone acetate and abiraterone decanoate), the abiraterone derivatives described in this invention show a significantly faster rate of conversion to parent abiraterone after intramuscular or subcutaneous injection, resulting in lower plasma derivative concentrations and reducing the unknown safety risks that may arise from excessive derivative molecule exposure.

[0236] Test Example 2: Pharmacokinetic Study of Abiraterone Derivative Formulation in Male SD Rats

[0237] I. Experimental Methods

[0238] Sixty SPF-grade male SD rats aged 8-9 weeks with similar body weights were selected as experimental animals and randomly divided into 12 groups (n=5 per group). The above-mentioned formulation was administered intramuscularly or subcutaneously to the hind leg of each animal at a dose of abiraterone 90 mg / kg. Blood samples were collected from the jugular vein before administration and at 15 min, 30 min, 1 h, 2 h, 4 h, 8 h, 24 h, 48 h, 72 h, 7 days (168 h), 10 days, 14 days, 17 days, 21 days, 28 days, 35 days, 42 days, 49 days, 56 days, 63 days, 70 days (10 weeks), and 84 days (12 weeks). The concentrations of abiraterone derivatives and abiraterone in rat plasma were determined using a validated LC-MS / MS method.

[0239] The sample testing methods are as follows:

[0240] 1.1 Experimental apparatus, same as in Table 8

[0241] 1.2 Chromatographic column, same as table 9

[0242] 1.3 Detection Method

[0243] 1.3.1 Mass Spectrometry Parameters

[0244] Including abiraterone, compound 6a, compound 7a, compound 8a, compound 9a, compound 10a, and compound 11a, with parameters as in Table 10.

[0245] 1.3.2 Chromatographic method, same as in Table 12, except that mobile phase B is replaced with a mixed solution of acetonitrile and methanol (acetonitrile and methanol volume ratio 2:8) containing 0.1% FA by volume.

[0246] Animal grouping and dosage information are shown in Table 18 below:

[0247] Table 18 *Note: The dosage and concentration of each derivative molecule are calculated based on the amount of abiraterone contained, and the formulation is consistent with the formulation group in Table 7.

[0248] II. Experimental Results

[0249] The pharmacokinetic parameters of abiraterone in plasma after intramuscular injection in rats are shown in Table 19, and the pharmacokinetic parameters of abiraterone derivatives are shown in Table 20.

[0250] Following intramuscular injection, the plasma abiraterone concentrations of each derivative molecule were as shown in Figures 9 (0-2016h) and 10 (0-24h). In all groups, the plasma abiraterone exposure decreased sequentially from G6 (compound 11a), G3 (compound 8a), G5 (compound 10a), G1 (compound 6a), G2 (compound 7a), to G4 (compound 9a). G6 (compound 11a) and G3 (compound 8a) showed higher plasma abiraterone exposure, faster and better absorption, and sustained abiraterone release for 84 days, with final plasma concentrations of 1.15±0.03 ng / mL and 1.15±0.02 ng / mL, respectively, indicating continued efficacy. Similarly, G5 (compound 10a) showed faster absorption and higher plasma concentrations.

[0251] The plasma concentrations of derivative molecules after intramuscular injection in rats are shown in Figures 11 (0-2016h) and 12 (0-24h). Low concentrations of derivative molecules were detected in rats from all groups, significantly lower than the concentration of the parent compound abiraterone, indicating that all compounds can be rapidly converted to parent abiraterone in vivo with a high conversion rate. Among the groups, G6 (compound 11a) had the highest derivative molecule concentration, and its derivative conversion rate (89.32% by AUC) was lower than that of G3 (compound 8a, 96.31% by AUC).

[0252] The pharmacokinetic parameters of abiraterone in plasma after subcutaneous injection in rats are shown in Table 21, and the pharmacokinetic parameters of abiraterone derivative molecules are shown in Table 22. After subcutaneous injection, the plasma exposure, drug concentration, and absorption of each abiraterone derivative molecule were significantly lower than those in the corresponding intramuscular injection group. Considering the dosage and injection volume, intramuscular injection was the preferred route of administration.

[0253] The animals showed no abnormal behavior throughout the experiment, indicating good safety and tolerability.

[0254] Table 19. Pharmacokinetic parameters of abiraterone in plasma after intramuscular injection in rats

[0255] Table 20. Pharmacokinetic parameters of derivative molecules in plasma after intramuscular injection in rats

[0256] Table 21. Pharmacokinetic parameters of abiraterone in plasma after subcutaneous injection in rats

[0257] Table 22. Pharmacokinetic parameters of derivative molecules in plasma after subcutaneous administration in rats

[0258] Test Example 3: Pharmacokinetic Study of Compound 8a in Male SD Rats

[0259] I. Experimental Methods

[0260] Preparation of an injectable solution of compound 8a: 987.80 mg of compound 8a was weighed and placed in a 4 mL glass vial. 0.316 mL of benzyl alcohol, 1.264 mL of benzyl benzoate, and 0.60 mL of corn oil were added. Compound 8a was then dissolved by sonication and vortexing. The final concentration of the compound 8a solution was 317.85 mg / mL, which translates to a final abiraterone concentration of 169.64 mg / mL.

[0261] Five male 7-8 week old SD rats (SPF grade, weighing 320-350g) were selected as experimental animals. The injectable solution of compound 8a was administered intramuscularly to the hind leg of each animal at a dose of abiraterone 90 mg / kg. Blood samples were collected from the jugular vein at 15 min, 30 min, 1 h, 2 h, 4 h, 8 h, 24 h, 48 h, 72 h, 7 days, 10 days, 14 days, 17 days, 21 days, 28 days, 35 days, 42 days, 49 days, 56 days, 63 days, 70 days, and 84 days after administration. The concentrations of abiraterone, compound 8a, testosterone, and dihydrotestosterone in rat plasma were determined using a validated method.

[0262] II. Experimental Results

[0263] The pharmacokinetic parameters of the original abiraterone in rat plasma after intramuscular injection of compound 8a are shown in Table 23, and the pharmacokinetic parameters of compound 8a are shown in Table 24.

[0264] Table 23. Pharmacokinetic parameters of precursor abiraterone in plasma of rats 8 years after intramuscular injection of compound

[0265] Table 24. Pharmacokinetic parameters of compound 8a in plasma after intramuscular injection of compound 8a in rats

[0266] Figure 5 shows the pharmacokinetic concentrations of proto-abiraterone in rat plasma after intramuscular injection of compound 8a. Compound 8a was continuously released in rats for at least 84 days after intramuscular injection, and the proto-abiraterone plasma concentration was maintained at 1.3–15 ng / mL.

[0267] Figure 6 shows the plasma concentration of compound 8a in rats after intramuscular injection. Following intramuscular injection, low concentrations of compound 8a were detected in rats, with plasma concentrations maintained at 0.064–1.246 ng / mL over 84 days, significantly lower than the concentration of the parent compound abiraterone. Rat pharmacokinetic (PK) studies indicated that compound 8a can be rapidly converted to parent abiraterone in vivo with a high conversion rate.

[0268] After intramuscular injection of compound 8a, the plasma testosterone concentration in rats is shown in Figure 7, and the dihydrotestosterone concentration is shown in Figure 8. After intramuscular injection, compound 8a can significantly inhibit the levels of testosterone and dihydrotestosterone for up to 84 days, and the dihydrotestosterone concentration is below the lower limit of quantitation from 7 to 84 days, achieving a rapid and potent inhibitory effect on dihydrotestosterone.

[0269] Test Example 4: Tissue Distribution Study of Abiraterone Derivative Formulation in Male SD Rats

[0270] I. Experimental Methods

[0271] Preparation of an injectable solution of compound 8a: Weigh 4.6759 g of compound 8a and place it in a 20 mL glass vial. Add 1.5 mL of benzyl alcohol and 6.0 mL of benzyl benzoate, and then make up the volume with corn oil, i.e., add 2.825 mL of corn oil. Then dissolve compound 8a by sonication and vortexing. After complete dissolution, filter through a 0.22 μm PES filter. The final concentration of the compound 8a solution was 319.7 mg / mL, which translates to a final abiraterone concentration of 170.63 mg / mL.

[0272] Preparation of blank solvent: Prepare according to the excipient solvent composition ratio of the injectable solution of compound 8a. Measure 3.0 ml of benzyl alcohol and 12.0 ml of benzyl benzoate, add 5.65 ml of corn oil, mix well to obtain blank solvent, which serves as blank control group for tissue distribution study.

[0273] Preparation of AD (abiraterone decanoate) injectable solution: The sample was prepared according to the formulation and preparation method disclosed in patent CN119136813A. 3.5998 g of AD was weighed and placed in a 20 mL glass vial. 2.0036 g of benzyl alcohol and 4.0002 g of benzyl benzoate were added, and the volume was adjusted to 20 mL with corn oil. AD was then dissolved by sonication and vortexing. After complete dissolution, the solution was filtered through a 0.22 μm PES filter. The final concentration of the AD solution was 189.8 mg / mL, which translates to a final abiraterone concentration of 131.68 mg / mL.

[0274] Preparation of Zytiga powder: Take an appropriate amount of Zytiga tablets (manufactured by Jassen, 250 mg / tablet) and place them in a 5 mL polycarbonate grinding flask. Add two 5.5 mm steel balls. Set the grinding machine program to 18 M / S, one cycle, and grind into powder after 2 minutes. Take an appropriate amount of Zytiga powder and prepare a suspension with a concentration of 10.08 mg / mL using purified water.

[0275] Sixty-four male SD rats aged 7-8 weeks (SPF grade, weighing 240-260g) were selected as experimental animals and randomly divided into two groups: a drug-containing group (n=20 per group) and a blank control group (n=4 per group). Injectable solutions of compound 8a and AD were administered intramuscularly to the hind legs of each animal at a dose of 90 mg / kg abiraterone (the blank control group received the same injection volume as compound 8a). Zytiga powder suspension was administered every 24 hours. Animals were fasted for 12 hours before administration, but were allowed normal water intake. Feeding was given 4 hours after administration (±20 min). In the drug-containing group, four animals were euthanized at 2, 6, 24, 72, and 168 hours after the first administration. In the blank control group, animals were euthanized at 168 hours. After perfusion, testes were rapidly collected, rinsed with pre-cooled saline, and excess liquid was blotted with filter paper. The weight was recorded, and the samples were placed in cryovials, frozen in liquid nitrogen, and then transferred to -80°C for storage. Tissue incubated overnight at -80℃ was cryogenically ground into powder using an appropriate amount of magnetic beads. Methanol was added at a 1:3 (w / v) ratio, followed by low-temperature wet homogenization (containing 2% inhibitor) until no particles remained. The homogenate was then centrifuged at 4℃, 10,000×g, for 10 min, and the supernatant was collected, maintaining a low temperature throughout the process. The concentration of the parent abiraterone in the testicular supernatant homogenate was determined using a validated method.

[0276] II. Experimental Results

[0277] The concentrations of abiraterone in the testes of rats after administration are shown in Table 25 and Figure 13. After 7 days of daily oral administration of Zytiga, the concentrations of abiraterone in the testes were high at 2 and 6 hours, but decreased significantly in the later stages, which was detrimental to maintaining efficacy. Compared with 7 days of daily oral administration of Zytiga and a single intramuscular injection of AD, a single intramuscular injection of compound 8a showed significant distribution in the testes, with abiraterone concentrations continuously increasing from 2 to 168 hours, maintaining a stable concentration for a long period. Furthermore, the abiraterone concentrations in the testes at all time points were higher than those of AD after a single intramuscular injection. The rat tissue distribution experiment indicates that intramuscular injection of compound 8a has the potential to translate into improved clinical efficacy and safety.

[0278] Table 25. Abiraterone concentration in rat testes after administration

[0279] The embodiments of the technical solution of the present invention have been described above by way of example. It should be understood that the protection scope of the present invention is not limited to the above embodiments. Any modifications, equivalent substitutions, improvements, etc., made by those skilled in the art within the spirit and principles of the present invention should be included within the protection scope of the claims of this application.

Claims

1. An abiraterone derivative as shown in formula (1) or formula (2), or a pharmaceutically acceptable salt thereof; in, The Linker1 is Or C 6-20 Alkylene; The Linker2 is Or C 6-20 Alkylene; m1 and m2 can be 1, 2, 3, 4, 5 or 6 independently; n can be any value between 2 and 20 independently.

2. The abiraterone derivative as shown in formula (1) or formula (2) as claimed in claim 1, characterized in that, It meets one or more of the following conditions: (1) m1 and m2 are independently 1 or 2, preferably 2; (2) m1 and m2 are the same; (3) n is independently 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20, preferably n is 7-14; (4) The C 6-20 Alkylene is independently C 8-10 Alkylene.

3. The abiraterone derivative as shown in formula (1) or formula (2) as claimed in claim 1 or 2, or a pharmaceutically acceptable salt thereof, characterized in that, n can be 2, 5, 6, 7, 9, 11, 12 or 13 independently.

4. The abiraterone derivative as shown in formula (1) or formula (2) as described in any one of claims 1-3, characterized in that, The abiraterone derivatives shown in formula (1) are as shown in formula (1-1) or formula (1-2): Wherein, n is independently as described in any one of claims 1-3.

5. The abiraterone derivative as shown in formula (1) or formula (2) as claimed in any one of claims 1-4, characterized in that, The abiraterone derivatives shown in formula (1) or formula (2) are selected from any of the following compounds:

6. A pharmaceutical composition comprising a therapeutically effective amount of an abiraterone derivative as described in any one of claims 1-5, as shown in formula (1) or (2), or a pharmaceutically acceptable salt thereof; and a pharmaceutically acceptable excipient.

7. The pharmaceutical composition according to claim 6, characterized in that, The pharmaceutical composition is an oil-based solvent, an in-situ formed formulation, a nanocrystalline formulation, or a microcrystalline formulation; preferably, it satisfies one or more of the following conditions: (1) When the pharmaceutical composition is an oil solvent, the pharmaceutically acceptable excipient comprises a solvent selected from one or more of corn oil, sesame oil, castor oil, olive oil and N-methylpyrrolidone, N,N-dimethylacetamide, for example, the solvent is N-methylpyrrolidone; (2) When the pharmaceutical composition is an oil solvent, the pharmaceutically acceptable excipient includes a cosolvent selected from one or both of benzyl alcohol and benzyl benzoate; (3) When the pharmaceutical composition is an in-situ formed formulation, the pharmaceutically acceptable excipient comprises a solvent selected from one, two or three of N-methylpyrrolidone, N,N-dimethylacetamide, benzyl alcohol and benzyl benzoate; (4) When the pharmaceutical composition is an in situ formed formulation, the pharmaceutically acceptable excipients further include a polymer carrier, wherein the polymer carrier is selected from one or more of PLGA, PLA, PDLLA, PEG-PLGA, PEG-PLA, PEG-PDLLA, PLGA-PEG-PLGA, PLA-PEG-PLA and PDLLA-PEG-PDLLA; (5) When the pharmaceutical composition is a nanocrystalline or microcrystalline formulation, the pharmaceutically acceptable excipients include one or more of surfactants, suspending agents, buffers and pH adjusters; (6) The composition is used for subcutaneous or intramuscular injection.

8. The pharmaceutical composition according to claim 6, characterized in that, It meets one or more of the following conditions: (1) The surfactant is selected from one or more of polysorbate 20 (Tween 20), polysorbate 80 (Tween 80) and poloxamer (such as poloxamer 188); (2) The suspending agent is selected from one or more of polyethylene glycol 4000 (PEG4000), sodium carboxymethyl cellulose and sodium hyaluronate; (3) The buffer is selected from one or more of citrate, acetate and phosphate; (4) The pH adjuster is selected from one or more of citric acid, acetic acid, phosphoric acid, hydrochloric acid and sodium hydroxide; Preferably, it satisfies one or more of the following conditions: (1) The composition comprises any of the following schemes: (2) The composition is compound 4a The micron-sized suspension uses ethanol as the solvent for compound 4a and 1% CMC-Na aqueous buffer as the dispersant. For example, the 1% CMC-Na aqueous buffer may contain 1% Tween 20, 1% CMC-Na, 0.75% citrate monohydrate, 0.6% sodium dihydrogen phosphate monohydrate, and 0.54% sodium hydroxide.

9. A method for preparing an abiraterone derivative as shown in formula (1) or formula (2) as described in any one of claims 1-5, wherein the method is method one or method two: Method 1 includes the following steps: In an organic solvent, in the presence of a base and a condensing agent, abiraterone reacts with compound a-1 or a-2 to obtain the abiraterone derivative shown in formula (1): Method 2 includes the following steps: In an organic solvent, in the presence of a base, abiraterone, triphosgene, and compound b-1 or b-2 react to give the abiraterone derivative shown in formula (2): Wherein, m1, m2, and n are independently defined as in any one of claims 1-5.

10. The method for preparing the abiraterone derivative as shown in formula (1) or formula (2), or a pharmaceutically acceptable salt thereof, is characterized in that, It meets one or more of the following conditions: (1) In Method 1, the organic solvent is a halogenated hydrocarbon solvent, such as chloroform; (2) In Method 1, the base is an organic base, for example, 4-dimethylaminopyridine; (3) In Method 1, the condensing agent is 1-ethyl-(3-dimethylaminopropyl)carbodiimide, or is the hydrochloride salt of 1-ethyl-(3-dimethylaminopropyl)carbodiimide; (4) In Method 2, the organic solvent is a halocarbon solvent, for example, dichloromethane; (5) In Method 2, the base is an organic base, for example, triethylamine.

11. Use in the preparation of an abiraterone derivative as shown in formula (1) or formula (2) as claimed in any one of claims 1-5, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition as claimed in any one of claims 6-8, in the preparation of a medicament for treating prostate cancer, preferably, said prostate cancer is metastatic prostate cancer, such as castration-resistant prostate cancer or high-risk metastatic endocrine therapy-sensitive prostate cancer.

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