Abiraterone derivative as well as preparation method and application thereof

Abstract

The invention provides an abiraterone derivative as well as a preparation method and application thereof. The abiraterone derivative has a chemical structural formula as shown in a formula (I). The abiraterone derivative disclosed by the invention can be converted into an active substance abiraterone in vivo, has the characteristics of good absorption, good plasma stability, ideal permeable membrane transport capability, good druggability and high safety, and can be used for treating diseases related to excessive androgen. # imgabs0 #

Description

Technical Field

[0001] The present invention relates to the field of pharmaceutical chemistry, and in particular to an abiraterone derivative and a preparation method and use thereof. Technical Background

[0002] Prostate cancer is a common type of cancer in 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 the production of androgens by inhibiting 17α-hydroxylase / C17-20 lyase (CYP17) in testicular, adrenal, and prostate tumor tissues, thereby treating prostate cancer.

[0003] Abiraterone has extremely poor solubility (<0.5 μg / mL), which makes it difficult to dissolve after taking the drug, resulting in poor bioavailability and extremely unsatisfactory absorption in the intestine. Abiraterone acetate, a prodrug of abiraterone approved by the FDA for marketing in 2011, has limited improvement in the solubility of abiraterone (<0.5 μg / mL). When the artificial membrane in vitro permeation test (PAMPA) simulates the permeability of the intestine, abiraterone acetate does not show properties superior to abiraterone. Studies have pointed out that abiraterone acetate may not enter the blood in the form of a prodrug, but forms a local abiraterone supersaturation phenomenon under the decomposition of intestinal esterases (A. Sharma, et al., Molecules, 2022, 27, 2969.), allowing the abiraterone molecule to break through the limitation of apparent solubility and have a certain bioavailability (T. Solymosi. et al., J. Chem. Eng. Data, 2018, 63, 4453-4458). In addition to the above possible absorption methods, abiraterone may have other absorption mechanisms, but abiraterone and abiraterone acetate do have bioavailability defects. 55% of abiraterone acetate is excreted from the feces in the prototype form, and 22% is excreted from the feces in the form of abiraterone, while the amount of drug that actually enters the blood is less than 10%. In addition, another significant defect of the marketed preparations of abiraterone acetate is the food effect caused by its high fat solubility, which requires patients to strictly control the medication time when taking the drug. This medication method that requires strict time control is extremely unfriendly to the main prostate cancer patient population, which is mainly elderly patients. In addition, due to the poor pharmacokinetic properties of abiraterone, the blood drug concentration of abiraterone in different patients is prone to large differences, and absorption will be affected by intestinal flora and intestinal food (S.Geboers, et al., J.Pharm.Sci, 2016, 105, 2974-2981). Although abiraterone acetate has been optimized by optimizing formulations at home and abroad, it is still difficult to fundamentally change its bioavailability and food effect problems. From an industrial perspective, the development of abiraterone acetate-related formulations is extremely limited due to its poor physical and chemical properties. In summary, the clinical application of abiraterone has many deficiencies and needs to be improved. Developing a drug related to abiraterone that can solve the above-mentioned defects has great clinical practical significance and commercial value. Summary of the invention

[0004] After extensive and in-depth research, the present invention has designed and synthesized a series of abiraterone phosphate prodrugs with the general structural formula (I) shown in the present invention. After pharmacokinetic testing, the abiraterone phosphate prodrug of the present invention is effectively converted into the active substance abiraterone in vivo after administration. Compared with the reference drug, the abiraterone phosphate prodrug of the present invention can significantly increase the in vivo exposure of abiraterone, improve the absorption pharmacokinetic properties of abiraterone, and reduce the food effect. Under the same dosage, after the abiraterone phosphate prodrug of the present invention is administered, the peak time and peak concentration of abiraterone in the blood are similar to those of the reference drug, which has the potential to better solve the defects of the control drug while ensuring the safety and effectiveness of clinical use. The existing results suggest that the abiraterone phosphate prodrug in the present 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 preparations including but not limited to tablets, injections, oral liquid preparations and other dosage forms.

[0005] The first aspect of the present invention provides a novel abiraterone derivative having a chemical structural formula (I) and stereoisomers and pharmaceutically acceptable salts thereof:

[0006]

[0007] In the formula,

[0008] X 1 and X 2 Independently selected from NH, O, S, or a five-membered or six-membered heterocyclic ring containing N, O, or S;

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

[0010] Any of the following;

[0011] B is selected from

[0012] R 1 Selected from hydrogen, substituted or unsubstituted C1-10 alkyl, substituted or unsubstituted C5-12 aryl, substituted or unsubstituted benzyl;

[0013] R 2 , R 3 are each independently selected from hydrogen, substituted or unsubstituted C 1-10 Alkyl, substituted or unsubstituted C 5-10Aryl, substituted or unsubstituted benzyl, mercapto, hydroxy, amino, hydroxyalkyl, carboxyalkyl, aminoalkyl, mercaptoalkyl, 3-6 membered cycloalkyl, 5-6 membered heterocycloalkyl, 5-10 membered aryl, 5-10 membered heteroaryl;

[0014] R 4 , R 5 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;

[0015] R a , R b are each 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, hydroxyl, hydroxyalkyl, amino, aminoalkyl, mercaptoalkyl;

[0016] X 3 is selected from O, S or NH.

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

[0018]

[0019] Preferably, X 1 , X 2 are independently selected from O, S or NH.

[0020] Preferably, the structure of the abiraterone derivative of the present invention is any one selected from formula (III) to (X):

[0021]

[0022] Preferably, when Ra and Rb are each independently selected from a thiol group, the thiol groups of Ra and Rb selectively form a disulfide bond. More preferably, the abiraterone derivative of the present invention is selected from any one of the compounds listed in Table 1 below:

[0023] Table 1 Compound structural formula and its number

[0024]

[0025]

[0026]

[0027] The second aspect of the present invention provides a method for preparing the abiraterone derivatives and stereoisomers and pharmaceutically acceptable salts thereof of the present invention, comprising the following steps:

[0028]

[0029] in,

[0030] (a) Compound 1 reacts with N,N-diethylphosphoramidite di-tert-butyl ester or N,N-diisopropylphosphoramidite di-tert-butyl ester to obtain Compound 2;

[0031] (b) Compound 2 is hydrolyzed by reacting with dilute hydrochloric acid to obtain compound 3;

[0032] (c) Compound 3 is subjected to a condensation reaction to obtain an abiraterone derivative having a structure represented by formula (I) and its stereoisomers and pharmaceutically acceptable salts.

[0033] Preferably, step (a) comprises: suspending compound 1 in dichloromethane in an inert gas environment, adding 1H-tetrazole and N,N-diethylphosphoramidite di-tert-butyl ester to react at room temperature for 30 minutes, then cooling to -78°C to react for 30 minutes, and forming compound 2 by an oxidant.

[0034] Preferably, step (b) comprises: dissolving compound 2 in a mixed solvent consisting of dichloromethane and methanol, adding an excess of dilute hydrochloric acid with an organic solvent as solvent at 0°C, and reacting for 30 minutes to obtain compound 3.

[0035] Preferably, step (c) comprises: dissolving compound 3 and a compound containing a hydroxyl group, an amino group or a thiol group in pyridine, adding an organic non-nucleophilic base, heating to 65° C., adding a pyridine solution of triphenylphosphine and 2,2'-dithiodipyridine, and generating the abiraterone derivative after 16 hours.

[0036] Preferably, 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.

[0037] It should be understood that, for the compound represented by compound (I) of the present invention, those skilled in the art can prepare it by combining other organic synthesis methods, and are not limited to the above method.

[0038] The third aspect of the present invention is to provide a pharmaceutical composition comprising the abiraterone derivatives and stereoisomers and pharmaceutically acceptable salts thereof of the present invention, and pharmaceutically acceptable carriers or excipients.

[0039] The last aspect of the present invention provides the use of the abiraterone derivatives and stereoisomers and pharmaceutically acceptable salts thereof, or the above-mentioned pharmaceutical compositions in the preparation of drugs for treating diseases related to excessive androgen secretion, such as drugs for treating prostate cancer, castration-resistant prostate cancer or other prostate cancer-related diseases.

[0040] It should be understood that within the scope of the present invention, the above-mentioned various technical features of the present invention and the various technical features described in detail below can be combined with each other to form a new or preferred technical solution. Each feature disclosed in the specification can be replaced by any alternative feature that provides the same, equal or similar purpose. Due to space limitations, they are not described one by one here. BRIEF DESCRIPTION OF THE DRAWINGS

[0041] Figure 1 to Figure 3 It is the serum concentration ratio of the abiraterone concentration in serum after administration of the compounds listed in Table 1 to the abiraterone concentration in serum after administration of abiraterone acetate (Q0), wherein the average abiraterone concentration in serum after administration of abiraterone acetate is 100%.

[0042] Figure 4 Comparison of plasma pharmacokinetic parameters AUC0-t of each compound after single oral administration to beagle dogs (10 mg / kg, n=6, Mean±SD) DETAILED DESCRIPTION

[0043] the term

[0044] In the present invention, unless otherwise specified, the terms used have the general meanings well known to those skilled in the art.

[0045] In the present invention, the halogen is F, Cl, Br or I.

[0046] In the present 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, preferably methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, etc.

[0047] In the present invention, the term "3-6 membered cycloalkyl" means that the number of carbon atoms forming a closed ring system is 3, 4, 5 or 6. 5-6 membered and 5-10 membered are similarly defined, both referring to the number of atoms forming a closed ring system.

[0048] In the present invention, the term "hetero" atom refers to atoms other than carbon, such as N, S, O, P.

[0049] In the present invention, the terms "aryl" and "heteroaryl" refer to compounds with aromaticity in the field of chemistry, common five-membered rings such as furan, pyrrole, thiophene, imidazole, pyrazole, oxazole, isoxazole and thiazole, six-membered rings such as benzene, pyridine, pyrazine, pyrimidine, pyridazine, triazine, and polycyclic rings such as the above five-membered and six-membered ring structures, and six-membered and six-membered ring structures, such as benzimidazole, indole, purine, naphthalene, quinoline, etc.

[0050] In the present invention, the term "unsubstituted" means that the part outside the skeleton is hydrogen; the term "substituted" means that there are atoms other than hydrogen in the part outside the skeleton connected to the skeleton in the form of a single bond. Common substituents include but are not limited to: methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, tert-butyl, hydroxyl, thiol, amino, nitro, halogen, guanidine, urea, cyano, ester, amide, carboxyl, alkoxy, alkylamino, etc.

[0051] In the present invention, the term "benzyl" refers to a structure in which a benzene ring is connected to a methylene group. The term "thiol" is -SH; the term "hydroxyl" is -OH; the term "amino" is -NH 2 ; Hydroxyalkyl is -O-alkyl; Aminoalkyl is -NH-alkyl; Mercaptoalkyl is -S-alkyl; Alkoxycarbonyl (ester group) is R is an alkyl group; an alkylcarbonyl group is R is an alkyl group; the disulfide bond is -SS-.

[0052] Pharmaceutical composition

[0053] The present invention also provides a pharmaceutical composition, which comprises active ingredients within a safe and effective range and a pharmaceutically acceptable carrier.

[0054] The "active ingredient" described in the present invention refers to a compound that conforms to the general formula (I) described in the present invention.

[0055] The "active ingredients" and pharmaceutical compositions described in the present invention are used to prepare drugs for treating prostate cancer, castration-resistant prostate cancer or other prostate cancer-related diseases.

[0056] "Safe and effective range" refers to the dosage range in which the active ingredient can exert its efficacy without causing harm to the body. Or the dosage range between the minimum effective dose and the minimum toxic dose.

[0057] "Pharmaceutically acceptable carriers" include additives other than active ingredients specified in pharmaceutical regulations and in compliance with laws and regulations, including fillers, solvents, solubilizers, co-solvents, excipients, lubricants, pH adjusters, emulsifiers, preservatives, colorants, sustained-release and controlled-release materials, etc.

[0058] The dosage forms of the active ingredients or pharmaceutical compositions of the present invention include, but are not limited to, tablets, injections, powder injections, suppositories, implants, and the like.

[0059] The compounds of the present invention can be administered alone or in combination with other drugs for combined therapy.

[0060] Unless otherwise defined, the terms used herein have the same meanings as those familiar to those skilled in the art. The preferred implementation methods and materials described herein are for exemplary purposes only.

[0061] It should be understood that within the scope of the present invention, the various technical features described in the present invention and the technical features described in the specific examples below can be combined with each other to form a new or preferred technical solution. Each feature disclosed herein can be replaced by any alternative feature that provides the same, equal or similar purpose. Non-creative modifications to the present invention by technical means known in the art are all within the scope of protection of this patent.

[0062] The following examples are intended to enable those skilled in the art to more clearly understand and implement the present invention. It must be noted that the examples are only for illustrative purposes and are not intended to limit the present invention.

[0063] The following reactions were all detected by thin layer chromatography, and the color was developed using ultraviolet light (in the case of ultraviolet absorption) or a thin layer color developer such as potassium permanganate.

[0064] The structures of the products in the exemplary reactions were determined by nuclear magnetic resonance (NMR) and mass spectrometry (MS) when they could be isolated.

[0065] Unless otherwise specified, the raw materials and reagents used in the reaction were purchased from the market or synthesized according to known methods. Unless otherwise specified, the raw materials and reagents were used directly without treatment.

[0066] The compound was purified by silica gel column chromatography, and the commonly used elution system was: dichloromethane: methanol; petroleum ether: ethyl acetate.

[0067] The inert gas environment described in the examples generally refers to a nitrogen environment.

[0068] The room temperature in the examples is generally 20°C-30°C.

[0069] In the examples, the overnight reaction time is generally 12h-15h.

[0070] [Example 1] Preliminary screening of compound activity

[0071] 1.1 Purpose

[0072] According to the existing public data reports, we synthesized the compounds with public information, and preliminarily synthesized some of the compounds designed independently. Through rapid biological activity tests, we preliminarily screened the compound design ideas to clarify the potential activity of the patented compounds and verify the activity of the compounds with public information. This provides reference research data for the subsequent clarification of the compound design direction.

[0073] 1.2 Test materials

[0074] Reference drugs abiraterone acetate, abiraterone, and diclofenac sodium were purchased from Aladdin (abiraterone, abiraterone acetate: specification 25 mg, purity ≥ 99%; diclofenac sodium: specification 5 g, purity ≥ 99%);

[0075] The compounds listed in Table 1 were obtained by independent synthesis, and the synthesis routes and steps are as follows:

[0076]

[0077] a) reacting abiraterone 1 with di-tert-butyl N,N-diethylphosphoramidite to obtain intermediate 2;

[0078] b) intermediate 2 is hydrolyzed by reacting with dilute hydrochloric acid to obtain abiraterone phosphate 3;

[0079] c) Abiraterone phosphate 3 is subjected to condensation reaction to obtain the target compound I.

[0080] In step a, abiraterone 1 is suspended in dichloromethane in an inert gas environment, and 1H-tetrazole and N,N-diethylphosphoramidite di-tert-butyl ester are added to react 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 acid intermediate. The reaction solution is cooled to -78°C and reacted for 30 minutes to form intermediate 2 through the oxidation of the oxidant. The N,N-diethylamino group in N,N-diethylphosphoramidite di-tert-butyl ester can be other types of N,N-disubstituted amino groups. The oxidant is preferably meta-chloroperbenzoic acid, or it can be other types of organic peroxides;

[0081] In step b, the intermediate 2 is dissolved in a mixed solvent consisting of dichloromethane and methanol, and an excess of dilute hydrochloric acid with an organic solvent as a solvent is added at 0°C, and the reaction is carried out for 30 minutes to obtain the intermediate 3. The mixed solvent consisting of dichloromethane and methanol has an optimal ratio of 5:1, and the solvent of the dilute hydrochloric acid can be 1,4-dioxane or a saturated alkane, or methanol, isopropanol;

[0082] In step c, the intermediate 3 and various hydroxyl compounds, amino compounds, and thiol compounds are dissolved in pyridine, an organic non-nucleophilic base is added, and the mixture is heated to 65° C., and a pyridine solution of triphenylphosphine and 2,2'-dithiodipyridine is added. After 16 hours, the target compound (I) is generated. Various hydroxyl compounds, amino compounds, and thiol compounds are corresponding compounds that conform to the chemical structures of the substituents in the general formula (I). The organic non-nucleophilic bases are typically triethylamine, N,N-diisopropylethylamine, and 1,8-diazabicyclo[5.4.0]undec-7-ene;

[0083] Drug solution: According to the drug preparation method of FDA pharmacology review (APPLICATION NUMBER: 202379Orig1s000, PHARMACOLOGY REVIEW(S), Reference ID: 2935605, page 72), 15% ethanol, 4% Tween-80 and saline were used for preparation. First, each compound was dissolved in an appropriate amount of ethanol, and then Tween-80 was added and mixed thoroughly, and then diluted with saline to the required dosage concentration (the dosage of each compound was 20 mg / kg, and the dosage volume was 0.1 mL / 10 g body weight, which was equivalent to a drug solution concentration of 2 mg / mL).

[0084] KM mice: male, weighing 25-35 g, were purchased from Guangdong Medical Animal Center.

[0085] 1.3 Experimental methods

[0086] The compounds listed in Table 1 were subjected to preliminary activity screening tests.

[0087] The LC-MS / MS method was used to determine the plasma drug concentration of abiraterone in the plasma of mice at specific time points after administration of each compound, and the pharmacokinetic enhancement potential of each compound was preliminarily evaluated.

[0088] Animal administration method: All mice were fasted for 12 hours, and then gavaged with each compound at a dose of 10 mg / kg. Referring to the above-mentioned FDA public information, the experiment was simplified to quickly obtain the data on the exposure degree of the required compound. In order to avoid losing biological samples at a high exposure time period, this study used 0.5hr, 1hr, and 2hr to obtain mouse blood samples (n=4), and the samples at the three time points were processed according to the following method and mixed in equal volumes.

[0089] Plasma collection: About 0.1 mL of blood was collected from the medial canthal vein of the mouse eye at each time point in the above table. The collected whole blood was placed in a centrifuge tube containing EDTA, gently swirled and mixed, and centrifuged (1500-1600 g, 10 min) to separate the plasma. The obtained plasma samples were stored in a -60 degrees Celsius refrigerator for later use.

[0090] LC-MS / MS was used to analyze biological samples. The analysis method steps and test conditions are shown in Table 2.

[0091] Table 2 LC-MS / MS analysis method and test conditions for the compounds listed in Table 1

[0092]

[0093]

[0094] Data processing: Taking the concentration of abiraterone in serum after administration of abiraterone acetate as 100%, the concentration of abiraterone in serum after administration of other compounds was compared with the concentration of abiraterone in serum after administration of abiraterone acetate to investigate the improvement of the pharmacokinetic properties of abiraterone acetate by each compound.

[0095] 1.4 Experimental Results

[0096] The experimental results are as follows Figure 1 to Figure 3 The results show that after administration of different compounds, the exposure in mice is different. Among them, the exposure of Q1 compounds in vivo is not significantly increased, while the exposure of Q2-Q9 compounds in vivo is significantly increased.

[0097] Among them, Q1-1 in the Q1 compound is a publicly reported compound (H. Ying, RSC Adv., 2022, 12, 13111-13115). After the structure of Q1 was expanded and tested, the experimental results showed that the Q1 compound did not significantly increase the exposure of abiraterone in vivo. Therefore, the structural idea of ​​Q1 compounds was abandoned, and computer drug design software was used again for drug design, and a small number of representative compounds were synthesized for biological screening. The results showed that Q2-Q9 has the potential to increase the exposure in vivo.

[0098] In order to further verify the intended development purpose of the above compounds, each representative compound was subsequently synthesized in a small trial and verified in vivo using large animals to further determine the compatibility of the compound with the design purpose.

[0099] [Example 2] Synthesis of intermediates

[0100] 2.1 Synthesis of compound 2

[0101] 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-dodecahydro-3H-cyclopenta[2, 1-i]phenanthrene-7-ylbis(2-methylpropan-2-yl)phosphate ion, and its chemical structure is shown below:

[0102]

[0103] The intermediate compound 2 was synthesized using compound 1, i.e. abiraterone, as a raw material.

[0104]

[0105] Abiraterone (Compound 1, 630.8 mg, 1.8 mmol) was dissolved in 25 ml of anhydrous dichloromethane, and tetrazole (252.87 mg, 3.61 mmol) and di-tert-butyl N, N-diethylphosphoramidite (1 ml, 3.61 mmol) were added under nitrogen. After half an hour of reaction at room temperature, 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 20 ml of dichloromethane. The mixture was washed with sodium thiosulfate solution, sodium bicarbonate solution, and saturated brine in turn, and dehydrated with sodium sulfate or magnesium sulfate. The collected organic phase was filtered and concentrated with a rotary evaporator. The crude oil was gradient eluted with a petroleum ether: ethyl acetate system. The product was a colorless oily substance. Yield: 778.4 mg (79.62%).

[0106] H 1 NMR (CDCl 3 ): 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=15.8, 6.5, 3.3Hz, 1H), 2.06 (m, 4H), 1.98 (m, 4H), 1.86 (dt, J=21.6, 7.3Hz, 1H), 1.7 6(m, 2H), 1.62(m, 5H), 1.50(s, 18H), 1.14(m, 1H), 1.08(s, 3H), 1.04(s, 3H).

[0107] C 13 NMR (CDCl 3 ): 151.39, 147.21, 147.13, 140.32, 134.23, 133.24, 129.65, 123.22, 122.10, 77.26, 77.20, 57.46, 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

[0108] P 31 NMR (CDCl 3 ): -10.38

[0109] Mass spectrum (ESI): theoretical value: 542.33 (M+H) + , measured value: 542.3332 (M+H) +

[0110] 2.2 Synthesis of compound 3

[0111] Compound 3 is P,P-dihydroxyphosphinic acid-(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-dodecahydro-3H-cyclopenta[2,1-i]phenanthrene-7-yl ester, and its chemical structure is shown below:

[0112]

[0113] Compound 2 (541.71 mg, 1.0 mmol) was dissolved in a mixed solvent consisting of 15 ml of anhydrous dichloromethane and 3 ml of anhydrous methanol, cooled to 0°C, and 2 ml of a 4N solution of hydrogen chloride in dioxane was added under nitrogen protection. After half an hour of reaction, the mixture was concentrated under reduced pressure to remove all volatile components, and the remaining white solid was the product. Yield: 420.5 mg (97.91%).

[0114] 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).

[0115] 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.

[0116] P 31 NMR (MeOD): -0.56

[0117] Mass spectrum (ESI): theoretical value: 430.22 (M+H) + , measured value: 430.2202 (M+H) +

[0118] [Example 3] Preparation of representative compounds of abiraterone derivative compounds Q1 to Q9

[0119] 3.1 Preparation of Compound Q1-6

[0120] 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-dodecahydro-3H-cyclopenta[2, 1-i]phenanthren-7-ylphenyl[(2-methoxy-2-oxyylideneethyl)amino]phosphonate ion, and its chemical structure is shown below:

[0121]

[0122] Compound 3 (395 mg, 0.919 mmol) was dissolved in 10 ml of anhydrous pyridine. 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 in sequence under nitrogen protection and heated to 65°C. After 10 minutes, 5 ml of pyridine solution of triphenylphosphine (723.93 mg, 2.76 mmol) and 2,2'-dithiodipyridine (608.05 mg, 2.76 mmol) were added and reacted for 16 hours. After the reaction, the mixture was concentrated under reduced pressure to remove most of the volatiles, and toluene was added in small amounts several times to azeotropically remove pyridine. The crude product was separated with 0-10% methanol: dichloromethane. Yield: 250.8 mg (47.29%).

[0123] H 1 NMR (CDCl 3): 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).

[0124] C 13 NMR (CDCl 3 ): 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.

[0125] P 31 NMR (CDCl 3 ): 1.74, 1.69 (mixture of R and S configurations)

[0126] Mass spectrum (ESI): theoretical value: 577.28, found value: 577.2898 (M+H) + .

[0127] 3.2 Preparation of Compound Q2-1

[0128] Compound Q2-1 is phenyl 2-methoxy-2-oxyylideneethyl (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-dodecahydro-3H-cyclopenta[1, 2-i]phenanthrene-7-yl phosphate ion, and its chemical structure is shown below:

[0129]

[0130] Compound 3 (395 mg, 0.919 mmol) was dissolved in 10 ml of anhydrous pyridine. 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 in sequence under nitrogen protection and heated to 65°C. After 10 minutes, 5 ml of pyridine solution of triphenylphosphine (723.67 mg, 2.76 mmol) and 2,2'-dithiodipyridine (607.84 mg, 2.76 mmol) were added and reacted for 16 hours. After the reaction, the mixture was concentrated under reduced pressure to remove most of the volatiles, and toluene was added in small amounts several times to azeotropically remove pyridine. The crude product was separated with 0-10% methanol: dichloromethane. Yield: 230.8 mg (43.44%).

[0131] H 1 NMR (CDCl 3 ): 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), 4.4 3(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).

[0132] C 13 NMR (CDCl 3 ): 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, 120.11(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.

[0133] P 31 NMR (CDCl 3 ): -7.34, -7.42 (mixture of R and S configurations)

[0134] Mass spectrum (ESI): theoretical value: 578.27, found value: 578.2701 (M+H) + .

[0135] 3.3 Preparation of Compound Q3

[0136] 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-dodecahydro-3H-cyclopenta[2, 1-i]phenanthrene-7-ylphenylhydroxyphosphonate ion, and its chemical structure is shown below:

[0137]

[0138] Compound 3 (395 mg, 0.919 mmol) was dissolved in 10 ml of anhydrous pyridine. Phenol (86.55 mg, 0.919 mmol) and N, N-diisopropylethylamine (DIPEA, 0.62 ml, 3.68 mmol) were added in sequence under nitrogen protection and heated to 65 ° C. After 10 minutes, 5 ml of pyridine solution of triphenylphosphine (723.67 mg, 2.76 mmol) and 2,2'-dithiodipyridine (607.84 mg, 2.76 mmol) were added and reacted for 16 hours. After the reaction, it was diluted with 20 ml of dichloromethane, the alkali and pyridine were washed with 0.1 N HCl, and then alkalized with 0.5 NaOH. The alkalized aqueous phase was acidified with 0.1 N HCl again to extract the product back into the organic phase. Na 2 SO 4 After drying, the mixture was concentrated under reduced pressure. The crude product was separated using 0-10% methanol: dichloromethane. Yield: 382.0 mg (82.15%). 1 NMR (CDCl 3 ): 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).

[0139] C 13 NMR (CDCl 3): 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.

[0140] P 31 NMR (CDCl 3 ): -5.47

[0141] Mass spectrum (ESI): theoretical value: 506.24, found value: 506.2475 (M+H) +

[0142] 3.4 Preparation of Compound Q4-1

[0143] Compound Q4-1 is phenyl 2-[(2-hydroxyethyl)disulfide]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-dodecahydro-3H-cyclopenta[1, 2-i]phenanthrene-7-yl phosphate ion, and its chemical structure is shown below:

[0144]

[0145] Compound 3 (391 mg, 0.911 mmol) was dissolved in 10 ml of anhydrous pyridine. 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 in sequence under nitrogen protection and heated to 65°C. After 10 minutes, 5 ml of pyridine solution of triphenylphosphine (718.02 mg, 2.73 mmol) and 2,2'-dithiodipyridine (602.09 mg, 2.73 mmol) were added and reacted for 16 hours. After the reaction, the mixture was concentrated under reduced pressure to remove most of the volatiles, and toluene was added in small amounts several times to azeotropically remove pyridine. The crude product was separated with 0-10% methanol: dichloromethane. Yield: 271.5 mg (46.36%).

[0146] H 1 NMR (CDCl 3): 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, 1H), 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).

[0147] C 13 NMR (CDCl 3 ): 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.

[0148] P 31 NMR (CDCl 3 ): -7.34, -7.46 (mixture of R and S configurations)

[0149] Mass spectrum (ESI): theoretical value: 642.25, found value: 642.2545 (M+H) +

[0150] 3.5 Preparation of Compound Q5-3

[0151] 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-dodecahydro-3H-cyclopenta[2, 1-i]phenanthrene-7-yl 2-(acetylthio)ethylphenyl phosphate ion, and its chemical structure is shown below:

[0152]

[0153] 3.5.1 Preparation of substrate - compound 4

[0154] Compound 4 is ethanethioic acid-S-(2-hydroxyethyl) ester, and its chemical structure is shown below:

[0155]

[0156] Under nitrogen protection, add 2-iodoethanol (0.78 ml, 10.0 mmol) to a toluene solution of 15 ml thioacetic acid (0.82 ml, 11.5 mmol), and slowly drop 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU, 1.72 ml, 11.5 mmol) at 0°C. The solution naturally returns to room temperature and is stirred for 3 hours. After the reaction is complete by thin layer detection, water is added to terminate the reaction. Take the organic phase and wash it with saturated brine. After the brine wash, the organic phase is washed with Na 2 SO 4 Dry, filter and concentrate. The crude product was eluted with ethyl acetate: petroleum ether gradient system (0:10→1:1). Yield: 431.0 mg (31.2%).

[0157] H 1 NMR (CDCl 3 ): 3.77 (t, J=6.1Hz, 2H), 3.09 (t, J=6.1Hz, 2H), 2.38 (s, 3H).C 13 NMR (CDCl 3 ): 196.40, 61.73, 32.05, 30.65.

[0158] Mass spectrum (ESI): 121.0 (M+H) +

[0159] 3.5.2 Preparation of Compound Q5-3

[0160] Compound 3 (588.41 mg, 1.37 mmol) was dissolved in 10 ml of anhydrous pyridine. 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 in sequence under nitrogen protection and heated to 65°C. After 10 minutes, 5 ml of pyridine solution of triphenylphosphine (1.08 g, 4.11 mmol) and 2,2'-dithiodipyridine (905.47 mg, 4.11 mmol) were added and reacted for 16 hours. After the reaction, the mixture was concentrated under reduced pressure to remove most of the volatiles, and toluene was added in small amounts several times to azeotropically remove pyridine. The crude product was separated with 0-10% methanol: dichloromethane. Yield: 518.0 mg (38.41%).

[0161] 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, 5 H), 1.88(m, 1H), 1.76(m, 2H), 1.69(m, 2H), 1.50(m, 1H), 1.10(s, 3H), 1.06(s, 3H).

[0162] C 13 NMR (CDCl 3 ): 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, 31.46, 30.57, 30.34, 29.80, 29.52, 29.43, 29.21, 20.80, 19.22, 16.58.

[0163] P 31 NMR (CDCl 3 ): -7.65

[0164] Mass spectrum (ESI): theoretical value: 608.26 (M+H) + , measured value: 608.2642 (M+H) +

[0165] 3.6 Preparation of Compound Q6-3

[0166] Compound Q6-3 is P,P-bis[(2-methoxy-2-oxyylideneethyl)amino]phosphinic acid-(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-dodecahydro-3H-cyclopenta[2,1-i]phenanthrene-7-yl ester, and its chemical structure is shown below:

[0167]

[0168] Compound 3 (395 mg, 0.919 mmol) was dissolved in 10 ml of anhydrous pyridine. Glycine methyl ester hydrochloride (346.4 mg, 2.76 mmol) and N, N-diisopropylethylamine (DIPEA, 0.94 ml, 5.52 mmol) were added in sequence under nitrogen protection and heated to 65°C. After 10 minutes, 5 ml of pyridine solution of triphenylphosphine (723.67 mg, 2.76 mmol) and 2,2'-dithiodipyridine (607.84 mg, 2.76 mmol) were added and reacted for 16 hours. After the reaction, the mixture was concentrated under reduced pressure to remove most of the volatiles, and toluene was added in small amounts and multiple times to remove pyridine by azeotropy. Na 2 SO 4 Dry, filter, and concentrate under reduced pressure. The obtained crude product is separated with 0-10% methanol: dichloromethane. Yield: 296.42 mg (56.38%).

[0169] H 1 NMR (CDCl 3 ): 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), 3.21 (m, 2 H), 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).

[0170] C 13 NMR (CDCl 3 ): 171.96, 151.62, 147.82, 147.76, 139.90, 133.81, 133.02, 129.31, 123.06, 122.52, 76.28, 57.44, 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.

[0171] P 31 NMR (CDCl 3 ):12.17

[0172] Mass spectrum (ESI): theoretical value: 572.28 (M+H) + , measured value: 572.2884 (M+H) + .

[0173] 3.7 Preparation of Compound Q7-2

[0174] Compound Q7-2 is 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-dodecahydro-3H-cyclopenta[1,2-i]phenanthrene-7-ylphosphate ion, and its chemical structure is shown below:

[0175]

[0176] Under nitrogen protection, compound 3 (259.63 mg, 0.604 mmol), chloromethyl pivalate (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 and heated to 65°C. After reacting for 3 hours, the mixture was naturally cooled to room temperature, 20 ml of ethyl acetate was added to dilute the reaction solution, and the mixture was washed with saturated brine and Na 2 SO 4 Dry, filter and concentrate under reduced pressure. Separate the crude product with ethyl acetate: petroleum ether system (ethyl acetate 20% to 100% gradient). Yield: 109.1 mg (27.44%).

[0177] H 1 NMR (CDCl 3 ): 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).

[0178] C 13 NMR (CDCl 3): 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.

[0179] P 31 NMR (CDCl 3 ):-4.90.

[0180] Mass spectrum (ESI): theoretical value: 658.35, found value: 658.3586 (M+H) + .

[0181] 3.8 Preparation of Compound Q8-3

[0182] Compound Q8-3 is bis(8,8-dimethyl-3,6-dioxy-5-aza-2,7-dioxanonan-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-dodecahydro-3H-cyclopenta[1,2-i]phenanthrene-7-yl phosphate ion, and its chemical structure is shown below:

[0183]

[0184] 3.8.1 Preparation of substrate - compound 5

[0185] Compound 5 is ({[(2-methylpropan-2-yl)oxy]carbonyl}amino)acetic acid chloromethyl ester, and its chemical structure is shown below:

[0186]

[0187] Dissolve 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) in a mixed layer solution of water and dichloromethane (1:1, 20 ml). Stir vigorously at 0°C for 10 minutes. Add 5 ml of dichloromethane solution of chloromethyl chlorosulfonate (0.65 ml, 6.40 mmol). React at room temperature for 2 hours. After 2 hours, take the organic phase, wash with saturated brine, and add Na 2 SO 4Dry, filter, and concentrate under reduced pressure. The crude product is separated using ethyl acetate: petroleum ether system (1:5). Yield: 676.0 mg (57.03%).

[0188] H 1 NMR (CDCl 3 ): 5.75 (s, 2H), 5.04 (brs, 1H), 4.00 (d, J = 5.6Hz, 2H), 1.46 (s, 9H). C 13 NMR (CDCl 3 ): 168.81, 155.57, 80.38, 68.93, 42.34, 28.23

[0189] Mass spectrum (ESI): 224.6 (M+H) +

[0190] 3.8.2 Preparation of Compound Q8-3

[0191] Under nitrogen protection, 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 and heated to 65°C. After reacting for 3 hours, the mixture was naturally cooled to room temperature, 20 ml of ethyl acetate was added to dilute the reaction solution, and the mixture was washed with saturated brine and Na 2 SO 4 Dry, filter and concentrate under reduced pressure. Separate the crude product with ethyl acetate: petroleum ether system (ethyl acetate 20% to 100% gradient). Yield: 130.37 mg (26.83%).

[0192] H 1 NMR (CDCl 3 ): 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, 4 H), 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).

[0193] C 13 NMR (CDCl 3 ): 170.25, 152.52, 147.72, 147.45, 137.90, 132.81, 133.02, 129.31, 123.06, 122.52, 83.54, 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.

[0194] P 31 NMR (CDCl 3 ): -5.62

[0195] Mass spectrum (ESI): theoretical value: 804.38 (M+H) + ,826.37(M+Na) + , measured value: 804.3919 (M+H) + ,826.3743(M+Na) +

[0196] 3.9 Preparation of Compound Q9-4

[0197] 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-dodecahydro-3H-cyclopenta[1, 2-a]phenanthrene-7-yl]oxy}-8-(methoxycarbonyl)-6-oxyylidene-6λ5-1, 2, 5, 7, 6-dithiadiazaphosphorus heterocyclic nonane-4-carboxylic acid methyl ester, and its chemical structure is shown below:

[0198]

[0199] Compound 3 (391 mg, 0.910 mmol) was dissolved in 10 ml of anhydrous pyridine. Under nitrogen protection, cystine dimethyl ester dihydrochloride (310.67 mg, 0.910 mmol) and N, N-diisopropylethylamine (DIPEA, 0.62 ml, 3.64 mmol) were added in sequence and heated to 65°C. After 10 minutes, 5 ml of pyridine solution of triphenylphosphine (716.35 mg, 2.73 mmol) and 2,2'-dithiodipyridine (601.68 mg, 2.73 mmol) were added and reacted for 16 hours. After the reaction, the mixture was concentrated under reduced pressure to remove most of the volatiles, and toluene was added in small amounts and multiple times to remove pyridine by azeotropy. Na 2 SO 4After drying, the mixture was concentrated under reduced pressure. The crude product was separated using 0-10% methanol: dichloromethane. Yield: 375.84 mg (62.38%).

[0200] H 1 NMR (CDCl 3 ): 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), 1.88(m , 2H), 1.77(m, 1H), 1.65(m, 4H), 1.10(s, 1H), 1.06(s, 3H), 0.89(m, 1H).

[0201] C 13 NMR (CDCl 3 ): 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.

[0202] P 31 NMR (CDCl 3 ):10.63

[0203] Mass spectrum (ESI): theoretical value: 662.25, found value: 662.2549 (M+H) +

[0204] [Example 4] Biological Activity Test

[0205] 4.1 Experimental Purpose

[0206] The LC-MS / MS method was used to investigate and determine the plasma drug concentrations of the drug prototype and active metabolite abiraterone in beagle dogs after administration of the reference drug preparation (abiraterone acetate) and each compound. The absorption kinetics of each compound after fasting and feeding were evaluated with reference to relevant pharmacokinetic parameters.

[0207] 4.2 Experimental materials and drug preparation methods

[0208] Reference drug abiraterone acetate: purchased from JD Pharmacy.

[0209] Compounds Q1-Q9 were synthesized according to the method of Example 2.

[0210] Dissolve the above test substances in 5% CMC-Na solution, disperse them thoroughly by ultrasonication, dilute and prepare a test solution with a concentration of 10 mg / mL, and administer by gavage at a dosage volume of 1 mL / kg. Samples that cannot be completely dissolved should be fully shaken before administration.

[0211] Beagle dogs were purchased from Guangdong Medical Animal Center.

[0212] 4.3 Experimental methods

[0213] The animal grouping and administration information are shown in Table 3. The reference drug abiraterone acetate and the compounds Q1-Q9 listed in Table 3 were administered at a dose of 10 mg / kg, and the beagle dogs were divided into 2 groups according to the administration method, with 3 animals in each group for each compound. Group 1: fasting on the first day, fasting state, oral administration; on the 10th day, normal feeding, oral administration. Group 2: normal feeding on the first day, oral administration; on the 10th day, fasting, fasting state, oral administration.

[0214] Table 3 Animal grouping and dosing information

[0215]

[0216] Plasma collection: about 0.5 mL of blood was collected from the dog's forelimb vein at each time point in the above table. The collected whole blood was placed in an EDTA anticoagulant tube, inverted several times to mix thoroughly, and stored in an ice-water mixture. Within 1 hour, centrifuged (1500-1600 g, 10 min) to separate the plasma. The obtained plasma samples were stored in a -60 degrees Celsius refrigerator for later use.

[0217] LC-MS / MS was used to analyze biological samples. The analysis method steps and test conditions are shown in Table 4.

[0218] Table 4 LC-MS / MS analysis method steps and test conditions for the compounds listed in Table 3

[0219]

[0220]

[0221] 4.4 Experimental Results

[0222] The results are as follows Figure 4As shown in Table 5, each compound and the reference drug are almost completely converted into the active substance Abiraterone in the body, and will not affect the subsequent metabolism of Abiraterone (similar T1 / 2). Fasting and normal feeding states show that the food effect of the reference drug is obvious, and whether fasting significantly affects the absorption of the drug. The compounds of the present invention better solve the food effect problem of the reference drug, and at the same dosage, the peak time and peak concentration of each compound of the present invention are similar to the reference drug, which better guarantees the consistency of future clinical use potential and safety and effectiveness.

[0223] Table 5 Plasma pharmacokinetic parameters of each compound after single oral administration to beagle dogs (10 mg / kg, n=6, Mean±SD)

[0224]

Claims

1. An abiraterone derivative and its stereoisomers and pharmaceutically acceptable salts, characterized in that: It has the structure shown in formula (I): In the formula, X1 and X2 are independently selected from NH, O, S, or a five-membered or six-membered heterocyclic ring containing N, O, or S; A is selected from hydrogen, substituted or unsubstituted C 1-6 alkyl, substituted or unsubstituted 5-10 membered aryl, substituted or unsubstituted 3-6 membered cycloalkyl, substituted or unsubstituted 5-10 membered heteroaryl, or Any of the following: 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, hydroxy, amino, hydroxyalkyl, carboxyalkyl, aminoalkyl, mercaptoalkyl, 3-6 membered cycloalkyl, 5-6 membered heterocycloalkyl, 5-10 membered aryl, 5-10 membered heteroaryl; R4, 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 are each 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, hydroxyl, 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 a 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 any one selected from formula (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 a thiol group, R a With R b The sulfhydryl groups selectively form disulfide bonds.

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 and its stereoisomers and pharmaceutically acceptable salts according to claim 1, characterized in that: The following steps are involved: in, (a) Compound 1 reacts with N,N-diethylphosphoramidite di-tert-butyl ester or N,N-diisopropylphosphoramidite di-tert-butyl ester to obtain Compound 2; (b) Compound 2 is hydrolyzed by reacting with dilute hydrochloric acid to obtain compound 3; (c) Compound 3 is subjected to a condensation reaction to obtain an abiraterone derivative having a structure represented by formula (I) and its stereoisomers and pharmaceutically acceptable salts.

8. The preparation method according to claim 7, characterized in that: The step (a) comprises: suspending the compound 1 in dichloromethane in an inert gas environment, adding 1H-tetrazole and N,N-diethylphosphoramidite di-tert-butyl ester to react at room temperature for 30 minutes, then cooling to -78°C to react for 30 minutes, and forming compound 2 through an oxidant; the step (b) comprises: dissolving the compound 2 in a mixed solvent consisting of dichloromethane and methanol, adding an excess of dilute hydrochloric acid with an organic solvent as a solvent at 0°C, and reacting for 30 minutes to obtain compound 3; the step (c) comprises: dissolving the compound 3 and a compound containing a hydroxyl group, an amino group or a thiol group in pyridine, adding an organic non-nucleophilic base, heating to 65°C, adding a pyridine solution of triphenylphosphine and 2,2'-dithiodipyridine, 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 saturated alkane.

10. A pharmaceutical composition, characterized in that Contains the abiraterone derivative and its stereoisomers and pharmaceutically acceptable salts as described in any one of claims 1 to 6, and a pharmaceutically acceptable carrier or excipient.

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

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