Abiraterone derivatives and processes for their preparation

Abstract

The application discloses an abiraterone derivative and a preparation method thereof. The abiraterone derivative has a structure as shown in a general formula (I). The abiraterone derivative has high bioavailability and good tumor inhibition effect, and has a high drug prospect.

Description

[0001] This application claims priority to Chinese Patent Application No. 202011448745.6, filed on December 12, 2020. The entire contents of the aforementioned Chinese Patent Application are hereby incorporated by reference. TECHNICAL FIELD

[0002] The present application relates to an abiraterone derivative, a preparation method thereof and an application thereof. Specifically, the present application relates to an abiraterone derivative represented by general formula (I), a stereoisomer or a pharmaceutically acceptable salt thereof, a preparation method thereof, a pharmaceutical composition containing the same and a use thereof in the preparation of a medicament. BACKGROUND

[0003] Abiraterone is a CYP17 enzyme inhibitor. Its prodrug, abiraterone acetate, was approved by FDA in 2011 for the treatment of prostate cancer patients, and the recommended oral dose is 1000 mg once a day combined with prednisone 5 mg twice a day. Although abiraterone acetate has great clinical value, it has poor solubility (less than 0.01 mg / mL), low bioavailability (less than 10% in humans), large food effect (high-fat food can increase drug exposure by 5 to 10 times), significant inter-individual pharmacokinetic differences, and abiraterone acetate is a substrate of CYP3A4 liver enzyme, its metabolism may be inhibited or induced by other drugs taken at the same time, which has potential drug-drug interaction risks. The above characteristics affect the clinical application of abiraterone acetate. SUMMARY

[0004] The technical problem to be solved by the present application is to overcome the defects of poor solubility, low bioavailability, large food effect or significant inter-individual pharmacokinetic differences of abiraterone in the prior art. To this end, the present application provides an abiraterone derivative and a preparation method thereof. The abiraterone derivative of the present application has the following advantages: high water solubility, improved drug absorption and metabolism distribution in the body, high oral bioavailability of the drug, reduced food effect, less drug dosage, low drug administration frequency, high patient compliance, high safety and long time effect when prolonging the action time.

[0005] The present application solves the above technical problems by the following technical solutions.

[0006] The present application provides a compound represented by general formula (I), a stereoisomer thereof, a pharmaceutically acceptable salt thereof or a solvate thereof:

[0007]

[0008] wherein R1 is

[0009] R2 is -C(=O)O-C 1-6alkyl (i.e. -C(=O)O-C 1-6 alkyl (i.e. -C(=O)O-C

[0010] R a is a hydrogen atom or C 1-6 alkyl;

[0011] R b and R b’ are each independently a hydrogen atom, C 1-6 alkyl, a natural or pharmaceutically acceptable amino acid side chain;

[0012] R c is C 1-6 alkyl, benzyl or C 6-14 aryl substituted C 2-6 alkyl (the number of C 6-14 aryl substitutions can be one or more, when more than one, the C 6-14 aryls can be the same or different).

[0013] In a preferred embodiment of the present application, in R2, the C 1-6 alkyl is methyl, ethyl, n-propyl, i-propyl, n-butyl, sec-butyl, i-butyl or t-butyl, for example, ethyl. 1-6

[0014] In a preferred embodiment of the present application, in R a , the C 1-6 alkyl is methyl, ethyl, n-propyl, i-propyl, n-butyl, sec-butyl, i-butyl or t-butyl, for example, methyl.

[0015] In a preferred embodiment of the present application, in R b and R b’ , the C 1-6 alkyl is methyl, ethyl, n-propyl, i-propyl, n-butyl, sec-butyl, i-butyl or t-butyl.

[0016] In a preferred embodiment of the present application, in R c , the C 1-6 alkyl is methyl, ethyl, n-propyl, i-propyl, n-butyl, sec-butyl, i-butyl or t-butyl, for example, i-propyl.

[0017] In a preferred embodiment of the present application, in R c , the C 6-14 aryl substituted C 2-6 alkyl is ethyl, n-propyl, i-propyl, n-butyl, sec-butyl, i-butyl or t-butyl. 2-6

[0018] ​​In a preferred embodiment of the present application, R c In a preferred embodiment of the present application, the C 6-14 In a preferred embodiment of the present application, the C 2-6 In a preferred embodiment of the present application, the C 6-14 The aryl group is phenyl, naphthyl, anthryl or phenanthryl, for example phenyl.

[0019] In a preferred embodiment of the present application, the compound of formula (I) is a compound of formula I-1 and / or I-2:

[0020]

[0021] In a preferred embodiment of the present application, the compound of formula (I), the stereoisomer thereof, the pharmaceutically acceptable salt thereof or the solvate thereof, wherein one or more atoms are atoms present in a non-natural abundance, or wherein all atoms are atoms present in a natural abundance.

[0022] In a preferred embodiment of the present application, the compound of formula (I), the stereoisomer thereof, the pharmaceutically acceptable salt thereof or the solvate thereof, wherein one or more atoms are atoms present in a non-natural abundance, or wherein all atoms are atoms present in a natural abundance.

[0023] In a preferred embodiment of the present application, R a is a hydrogen atom.

[0024] In a preferred embodiment of the present application, R b and R b’ are each independently a hydrogen atom or a C 1-6 alkyl group.

[0025] Preferably, R b and R b’ , wherein one substituent (i.e. R b or R b’ ) is a hydrogen atom and the other substituent (i.e. R b or R b’ ) is a C 1-6 alkyl group.

[0026] In a preferred embodiment of the present application, R c is a C 1-6 alkyl group.

[0027] In a preferred embodiment of the present application, is the carbon marked with * refers to a chiral carbon of S configuration, a chiral carbon of R configuration or an achiral carbon; preferably, the carbon marked with * refers to a chiral carbon of S configuration.

[0028] In a preferred embodiment of the present application, , wherein R a is a hydrogen atom; R b and Rb’ one of the substituents is a hydrogen atom and the other is a C 1-6 alkyl (e.g., methyl); R c is a C 1-6 alkyl.

[0029] In a preferred embodiment of the present application, the compound of formula (I) is a compound of formula I-1: is for example

[0030] In a preferred embodiment of the present application, the compound of formula (I) is a compound of formula I-1:

[0031]

[0032] R a is a hydrogen atom;

[0033] R b and R b’ one of the substituents is a hydrogen atom and the other is a C 1-6 alkyl;

[0034] R c is a C 1-6 alkyl.

[0035] In a preferred embodiment of the present application, the compound of formula (I) is a compound of formula I-1:

[0036]

[0037] R1is

[0038] R2is -C(=O)O-C 1-6 alkyl;

[0039] R a is a hydrogen atom or C 1-6 alkyl;

[0040] R b and R b’ are each independently a hydrogen atom, C 1-6 alkyl or a natural or pharmaceutically acceptable amino acid side chain;

[0041] R c is a C 1-6 alkyl or benzyl.

[0042] In a preferred embodiment of the present application, the compound of formula (I) is a compound of formula I-1:

[0043] Ra is a hydrogen atom;

[0044] R b is a hydrogen atom or a methyl group; b’ each independently is a hydrogen atom or a methyl group;

[0045] R c is a methyl group, an ethyl group, a propyl group, an isopropyl group or a benzyl group;

[0046] R2is -C(=O)O-C 1-3 alkyl.

[0047] In a preferred embodiment of the present application, the compound as shown in general formula (I) is a compound as shown in general formula (Ia):

[0048] (P atom is in S configuration) or

[0049] (P atom is in R configuration).

[0050] The present application also provides a preparation method of the compound as shown in general formula (I), the stereoisomer thereof, the pharmaceutically acceptable salt thereof or the solvate thereof, which comprises the following steps:

[0051] reacting a compound as shown in general formula II, a compound as shown in general formula III and abiraterone in a solvent in the presence of a base to obtain the compound as shown in general formula (I);

[0052]

[0053] wherein, X1and X2are each independently halogen (for example, Cl); the carbon marked with * refers to an S configuration chiral carbon, an R configuration chiral carbon or an achiral carbon; R2, R a , R b , R b’ and R c are as defined above.

[0054] The conditions and operations of the reaction can be conventional conditions and operations in the art for such reactions, and the present application particularly prefers the following conditions and operations:

[0055] The base is preferably an organic base, preferably triethylamine.

[0056] The molar ratio of the base to the abiraterone is preferably 8:1-1:1, more preferably 4.0:1.

[0057] The compound as shown in general formula II is preferably ethyl dichlorophosphoryl formate.

[0058] The molar ratio of the compound of formula II to the abiraterone is preferably 3:1-1:1, more preferably 1:1.

[0059] The compound of formula III is preferably L-alanine isopropyl ester hydrochloride.

[0060] The molar ratio of the compound of formula III to the abiraterone is preferably 3:1-1:1, more preferably 1:1.

[0061] The solvent is preferably a halogenated hydrocarbon solvent, preferably dichloromethane.

[0062] The temperature of the reaction is preferably -40°C to 50°C, more preferably room temperature.

[0063] The progress of the reaction can be monitored in a manner known in the art, typically with the reaction being deemed complete when the abiraterone no longer reacts or disappears. The time of the reaction is preferably 1 hour to 16 hours, more preferably 3 hours.

[0064] The present application also provides a pharmaceutical composition comprising a therapeutically effective amount of the compound of formula (I), stereoisomer thereof, pharmaceutically acceptable salt thereof or solvate thereof, and a pharmaceutically acceptable carrier or excipient.

[0065] The present application also provides use of a substance X in the preparation of a medicament for preventing or treating a tumor; the substance X is the compound of formula (I), stereoisomer thereof, pharmaceutically acceptable salt thereof, solvate thereof or the above-mentioned pharmaceutical composition.

[0066] In the use, the tumor is preferably prostate cancer.

[0067] The present application also provides a method for preventing or treating a tumor, which comprises administering to a subject a therapeutically effective amount of a substance X; the substance X is the compound of formula (I), stereoisomer thereof, pharmaceutically acceptable salt thereof, solvate thereof or the above-mentioned pharmaceutical composition.

[0068] In the treatment method, the tumor is preferably prostate cancer.

[0069] The elements carbon, hydrogen, oxygen, nitrogen or halogen involved in the groups and compounds of the present application include their isotopic cases, and the elements carbon, hydrogen, oxygen or nitrogen involved in the groups and compounds of the present application are optionally further replaced by one or more of their corresponding isotopes, wherein the isotopes of carbon include 12 C, 13 C and 14C, isotopes of hydrogen include protium (H), deuterium (D, also called heavy hydrogen), tritium (T, also called super-heavy hydrogen), isotopes of oxygen include 16 O, 17 O and 18 O, isotopes of nitrogen include 14 N and 15 N, isotopes of fluorine 19 F, isotopes of chlorine include 35 Cl and 37 Cl, isotopes of bromine include 79 Br and 81 Br.

[0070] “Natural or pharmaceutically acceptable amino acid”: the basic skeleton of a protein molecule is an amino acid sequence, there are 20 basic amino acids that constitute the protein, these 20 basic amino acids are the basis for biological post-modification of proteins, in addition, on the basis of these basic amino acids, hydroxyproline, hydroxylysine and other derived amino acids are biosynthesized, these biosynthesized amino acids are collectively referred to as “natural amino acids”; amino acids synthesized by artificial methods are “unnatural amino acids”. “Pharmaceutically acceptable amino acid” refers to a natural or unnatural amino acid that is pharmaceutically acceptable.

[0071] “Side chain of an amino acid” refers to a moiety covalently attached to a D or L-amino acid structure and can be represented as -CH(COOH)(NH2)-R. For example, in the case of alanine -CH(COOH)(NH2)(CH3), the side chain of the amino acid (R) is -CH3.

[0072] In the present invention, “=O” is the usual custom in the art, which refers to an oxygen atom connected by a double bond, such as the double-bonded oxygen atom in the carbonyl group connected to the carbon atom.

[0073] In the present invention, “alkyl” as a group or part of a group refers to a straight-chain or branched-chain aliphatic group including 1 to 20 carbon atoms. Preferably, 1 to 10 alkyl groups, more preferably 1 to 6 alkyl groups. Examples of alkyl groups include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, t-butyl, sec-butyl, n-pentyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, 2,2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 1-ethyl-2-methylpropyl, 1,1,2-trimethylpropyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 2,2-dimethylbutyl, 1,3-dimethylbutyl, 2-ethylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 2,3-dimethylbutyl, and the like.

[0074] "Alkoxy" refers to a group of the formula (alkyl-O-). Alkyl is defined herein. C1-C6 alkoxy groups are preferred. Examples include, but are not limited to, methoxy, ethoxy, n-propyloxy, isopropyloxy, n-butyloxy, isobutyloxy, t-butyloxy, and the like.

[0075] "Halogen" refers to fluorine, chlorine, bromine, and iodine.

[0076] "Amino" refers to -NH2.

[0077] "Alkoxy" refers to a group of the formula (alkyl-O-). Alkyl is defined herein. C1-C6 alkoxy groups are preferred. Examples include, but are not limited to, methoxy, ethoxy, n-propyloxy, isopropyloxy, n-butyloxy, isobutyloxy, t-butyloxy, and the like.

[0078] "DMSO" refers to dimethyl sulfoxide.

[0079] "Et" refers to ethyl.

[0080] "Benzyl" refers to -CH2-phenyl.

[0081] "TMS" refers to trimethylsilyl.

[0082] "Optionally" or "optional" means that the subsequently described event or circumstance can or can not occur, and thus the description includes instances where the event or circumstance occurs and instances where it does not. For example, "alkyl optionally substituted with F" means that the alkyl group can or can not be substituted with F, and the description includes instances where the alkyl group is substituted with F and instances where the alkyl group is not substituted with F.

[0083] "Pharmaceutical composition" means a mixture of one or more of the compounds described herein, or physiologically acceptable salts thereof, with other ingredients

[0084] "Carrier" refers to a carrier or diluent with which the compound is administered and which does not itself induce the production of antibodies to the administered compound, and which does not have biological or physiological activity at the site of

[0085] "Excipient" refers to an inert substance added to a pharmaceutical composition to further the administration of a compound. Examples of excipients include, but are not limited to, calcium carbonate, calcium phosphate, various sugars and types of starch, cellulose derivatives, gelatin, vegetable oils, polyethylene glycols, diluents, granulating agents, binders, lubricants, disintegrating agents, and the like.

[0086] "Prodrug" refers to a drug that can be converted to a more active drug by Biological activity physiological conditions or by solvolysis. Prodrugs of the present application are prepared by modifying functional groups in estradiol in such a way that their modifications can be readily removed in vivo to give estradiol.

[0087] "Stereoisomer" refers to isomers that have the same molecular formula but different structures resulting from the spatial arrangement of atoms.

[0088] "Effective amount" means an amount of a compound that elicits the pharmacologic or biologic response of a tissue, system, or subject that is being sought, including the amount of a compound that, when administered to a subject, is sufficient to prevent, to some extent, the onset or progression of one or more symptoms of a condition or disorder being treated.

[0089] "Pharmaceutically acceptable salt" means a pharmaceutically acceptable, non-toxic acid or base salt, including salts of inorganic acids and bases, salts of organic acids and bases.

[0090] "Solvate" means a compound formed by the crystallization of a compound with a solvent (including but not limited to: water, methanol, ethanol, etc.). Solvates are classified as stoichiometric solvates and non-stoichiometric solvates.

[0091] In the present application, the numbers or letters in the lower right corner of R in "R1, R2, R a , R b , R b’ , R c …" refer to the number of R, not the number of R. DETAILED DESCRIPTION

[0092] The examples below provide preparations of representative compounds of Formula (I) and related structural identification data. It must be understood that the following examples are intended to illustrate the application and are not intended to limit the application.

[0093] The structure of the compounds is determined by nuclear magnetic resonance (NMR) and / or mass spectrometry (MS).

[0094] 1 H NMR spectra were recorded on a Bruker instrument (400 MHz) and chemical shifts are reported in ppm. Tetramethylsilane internal standard (0.00 ppm) was used and the solvent was dimethyl sulfoxide-d6 (DMSO-d6), chloroform-d (CDCI3), methanol-d (CD3OD) and tetramethylsilane (TMS) was the internal standard. 1 H NMR notation: s = singlet, d = doublet, t = triplet, q = quartet, m = multiplet, br = broad, dd = doublet of doublets, dt = doublet of triplets. If coupling constants are given, they are in Hz.

[0095] Mass spectra were recorded on a LC / MS instrument and ionization can be ESI or APCI.

[0096] Thin layer chromatography silica gel plate, Yantai Huanghai HSGF254 or Qingdao GF254 silica gel plate was used. The specification of silica gel plate used in thin layer chromatography (TLC) was 0.15mm-0.2mm, and the specification of silica gel plate used in thin layer chromatography separation and purification of product was 0.4mm-0.5mm.

[0097] Column chromatography generally used Yantai Huanghai silica gel 200-300 mesh silica gel as carrier.

[0098] HPLC determination used Agilent 1260DAD high pressure liquid chromatograph (Zorba x SB-C18 100 x 4.6mm).

[0099] In the following examples, unless otherwise specified, all temperatures are in degrees Celsius.

[0100] Unless otherwise specified, various starting materials and reagents were obtained from commercial sources or synthesized according to known methods, and the commercially available starting materials and reagents were used directly without further purification, unless otherwise specified. The commercially available sources include, but are not limited to, Aldrich Chemical Company, ABCR GmbH & Co. KG, Acros Organics, Shanyuan Chemical Technology (Shanghai) Co., Ltd., Sinopharm Chemical Co., Ltd., Bailingwei Technology Co., Ltd., and the like.

[0101] The compounds were purified by silica gel column chromatography and thin layer chromatography, and the eluent system was selected from: A: petroleum ether and ethyl acetate system; B: dichloromethane and methanol system; C: dichloromethane: ethyl acetate; D: petroleum ether: dichloromethane system; wherein the volume ratio of the solvents is different according to the polarity of the compound, and a small amount of acidic or basic reagent can also be added for adjustment, such as acetic acid or triethylamine, etc.

[0102] Unless otherwise specified in the examples, the reaction was carried out under a nitrogen atmosphere. Unless otherwise specified in the examples, the solution refers to an aqueous solution.

[0103] Unless otherwise specified in the examples, the reaction temperature was room temperature. Room temperature is the most suitable reaction temperature, which is 20℃-30℃.

[0104] Example 1 2-(((S)-(2,6-diisopropylphenoxy)(ethoxycarbonyl)phosphoryl)amino)propionic acid isopropyl ester abiraterone

[0105]

[0106] First step

[0107] Ethyl (bis(trimethylsilyl)oxy)formate

[0108] Triethyl methyl phosphate (100 g, 0.476 mol) was dissolved in 1 L of acetonitrile, and trimethylbromosilane (220 g, 1.43 mol) was added. The mixture was stirred at 65 °C for 3 hours. After cooling to room temperature, the solution was concentrated to give the title compound 1a (140 g, yellow liquid), which was used directly in the next step.

[0109] Step 2

[0110] Ethyl dichlorophosphorylcarbamate

[0111] Dissolve 1a (140 g, 0.47 mol) in 1.5 L of dichloromethane, add N,N-dimethylformamide (1 ml), cool to 0 °C in an ice-salt bath, add oxaloyl chloride (180 g, 1.41 mol) dropwise, then heat to room temperature and react overnight. Concentrate and distill under reduced pressure using an oil pump to give title product 1b (72 g, pale yellow liquid), yield: 78.89%.

[0112] Step 3

[0113] 2-(((S)-(2,6-diisopropylphenoxy)(ethoxycarbonyl)phosphoryl)amino)propionate isopropyl abiraterone

[0114]

[0115] Ethyl dichlorophosphorylcarbamate 1b (177 g, 0.93 mol) was dissolved in 4.5 L of dichloromethane and cooled to -60 °C under argon protection. Abiraterone (325 g, 0.93 mol) and L-alanine isopropyl hydrochloride (156 g, 0.93 mol) were added. After the addition was complete, triethylamine (375 g, 3.71 mol) was added dropwise. After the addition was complete, the reaction was maintained at this temperature for 30 min, and then naturally warmed to room temperature for 3 h. The reaction solution was washed successively with 10% sodium carbonate aqueous solution and saturated brine. The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was purified by silica gel column chromatography (ethyl acetate / petroleum ether (V / V) = 1:10-1:2) to give title product 1 (120 g white solid), yield: 22.3%.

[0116] MS m / z(ESI): 522.5 [M+1]

[0117] 1 H NMR (400MHz, CDCl3): δ8.61(s,1H),8.46(d,1H),7.67(d,1H),7.28(m,1H),6.00(s,1H),5.43(m,1H),5.04 (m,1H),4.40(m,1H),4.30(m,2H),4.15(m,1H),3.70(m,5H),2.50(m,2H),2.35(m,1H),2.15-1.02(m,28H)

[0118] Example 2 (S)-2-(((S)-(2,6-diisopropylphenoxy)(ethoxycarbonyl)phosphoryl)amino)propionic acid isopropyl ester Abiraterone 1-I

[0119] (R)-2-(((S)-(2,6-diisopropylphenoxy)(ethoxycarbonyl)phosphoryl)amino)propionic acid isopropyl ester Abiraterone 1-II

[0120]

[0121] Compound 1 was prepared chiral:

[0122] Preparation conditions:

[0123] Column: CHIRALPAK IG-3 (25 cm*3 cm*5 um)

[0124] Mobile phase: A (Hexane: DCM = 2: 1) (0.1% DEA) B IPA

[0125] Gradient: Mobile phase A / Mobile phase B = 1 / 1

[0126] Flow rate: 50 mL / min

[0127] Test conditions:

[0128] CHIRALPAK IG-3, 0.46*5 cm; 3 pm, mobile phase B is n-hexane: dichloromethane = 2: 1; mobile phase C is ethanol. Mobile phase B: mobile phase C = 1: 1.

[0129] Compound 1-I 70 g, white solid; retention time 1.828 min (chiral HPLC: 98.5%)

[0130] 1 H NMR (400 MHz, CDC13): δ 8.61 (s, 1H), 8.46 (d, 1H), 7.67 (d, 1H), 7.28 (m, 1H), 6.00 (s, 1H), 5.43 (m, 1H), 5.04 (m, 1H), 4.40 (m, 1H), 4.30 (m, 2H), 4.15 (m, 1H), 3.70 (m, 5H), 2.50 (m, 2H), 2.35 (m, 1H), 2.15-1.02 (m, 28H)

[0131] P NMR (400 MHz, CDC13): δ -0.29. By phosphorus spectrum, it is confirmed that the chemical shift δ -0.29 is S configuration.

[0132] Compound 1-II 40 g yellow liquid; retention time 2.766 min (chiral HPLC: 99.1%)

[0133] 1 H NMR (400 MHz, CDC13): δ 8.61 (s, 1H), 8.46 (d, 1H), 7.67 (d, 1H), 7.28 (m, 1H), 6.00 (s, 1H), 5.43 (m, 1H), 5.04 (m, 1H), 4.40 (m, 1H), 4.30 (m, 2H), 4.15 (m, 1H), 3.70 (m, 5H), 2.50 (m, 2H), 2.35 (m, 1H), 2.15-1.02 (m, 28H)

[0134] P NMR (400 MHz, CDC13): δ -0.03. By phosphorus spectrum, it is confirmed that the chemical shift δ -0.03 is R configuration.

[0135] Biological evaluation

[0136] Test Example 1, in vivo pharmacokinetic study of SD rats

[0137] Test animals: 6 healthy adult Sprague-Dawley (SD) rats, male, 180-250 g, purchased from Chengdu Dashuo Experimental Animal Co., Ltd.

[0138] Drug preparation:

[0139] A certain amount of abiraterone was accurately weighed, DMA, ethanol and PEG200 were added to dissolve, and then physiological saline was added and vortexed to mix uniformly. The final solvent ratio for administration was DMA: ethanol: PEG200: physiological saline (10: 10: 40: 40, v / v / v), and the compound was freshly prepared before use.

[0140] A certain amount of compound 1 was accurately weighed, ethanol and Tween 80 were added to dissolve, and then physiological saline was added and vortexed to mix uniformly. The final solvent ratio for administration was ethanol: Tween 80: physiological saline (15: 5: 80, v / v / v), and the compound was freshly prepared before use.

[0141] Dosing and detection: SD rats were randomly divided into 2 groups, 3 rats in each group; the rats were fasted for not less than 8 hours before dosing, and free water was provided, and the rats were allowed to eat 4 hours after dosing. The animals in the 2 groups were respectively given intravenous injection (IV) of abiraterone (dose of 5 mg / kg) and oral gavage (PO) of compound 1 (dose of 25 mg / kg), and about 0.1 ml of venous blood was collected at different time points before and after dosing, and was heparin-anticoagulated, centrifuged to separate the plasma, and was stored at -80℃. The LC-MS / MS method was used to respectively determine the concentrations of abiraterone (original drug) and compound 1 (prodrug) in the plasma. After the SD rats were given oral gavage of compound 1 of the application, the original form (prodrug form) of compound 1 was not detected in the plasma at each time point, and only abiraterone was detected. The main pharmacokinetic parameters were calculated based on the detected plasma drug concentration of abiraterone after the administration of compound 1, and the results are shown in Table 1.

[0142] Table 1. Pharmacokinetic test results of SD rats

[0143]

[0144] Conclusion: After the oral gavage administration of compound 1 to rats, the absorption is rapid, and the main form in vivo is abiraterone, and according to the exposure level of abiraterone in the plasma, the absolute bioavailability of oral administration is 70.5%.

[0145] Test Example 2. Androgen inhibition test in rats

[0146] Healthy male rats, 32, weighing 180-220 g, were randomly divided into 4 groups, 8 in each group, and raised in SPF environment, temperature 20-22℃, relative humidity 40-70%, 12h / 12h light and dark, free drinking and free water, and adaptive observation for 5 days before starting the test. The compound or abiraterone acetate was dissolved in ethanol: soil temperature 80: normal saline (15:5:80, v / v / v), and the animals in each group were respectively given oral gavage with blank solvent (Vehicle), abiraterone acetate 100mg / kg (0.255mM / kg), compound 1-I 50mg / kg (0.084mM / kg), compound 1-I 100mg / kg (0.167mM / kg), once a day, for 14 consecutive days. After 7 days and 14 days of administration, the rats were collected, the serum was separated, and the concentration of testosterone in the serum was determined; at the same time, after 14 days of administration, the animals were sacrificed, and the testis, prostate ventral lobe and seminal vesicle were immediately separated and weighed. After 7 days of administration, the average serum testosterone levels of the solvent control group, abiraterone acetate 100mg / kg group, compound 1-I 50mg / kg group and compound 1-I 100mg / kg group were 10.176, 7.794, 8.66 and 5.68ng / ml respectively; after 14 days of administration, they were 12.28, 0.759, 0.88 and 0.783ng / ml respectively (Table 2). After 14 days of administration, the weights of male hormone-sensitive organs are shown in Table 3.

[0147] Table 2 Effect of continuous administration of compounds on serum testosterone in rats

[0148] Group Day 7 Day 14 Vehicle 10.176±5.23 12.281±7.41***

[0149] Abiraterone acetate 7.794±2.55 0.759±0.21*** Compound 1-I, 50 mg / kg 8.668±3.01 0.901±0.43*** Compound 1-I, 100 mg / kg 5.680±2.36* 0.783±0.20***

[0150] Note: *P<0.05, VS Vehicle; ***P<0.001, VS Vehicle

[0151] Table 3 Effect of continuous oral administration of compounds for 14 days on the weight of androgen-sensitive organs

[0152] Group Prostate ventral lobe Testis Seminal vesicle Vehicle 0.35±0.07 2.58±0.24 0.63±0.16 Abiraterone acetate, 100 mg / kg 0.19 ± 0.07 ＊ ]] 2.22±0.21 0.15 ± 0.03 ＊＊ ]] Compound 1-I, 50 mg / kg 0.32±0.29 2.46±0.51 0.29 ± 0.09 ＊＊ ]] Compound 1-I, 100 mg / kg 0.21 ± 0.04 ＊ ]] 2.52±0.30 0.12 ± 0.07 ＊＊ ]]

[0153] Note: *P<0.01, VS Vehicle; **P<0.001, VS Vehicle

[0154] From Tables 2 and 3, it can be seen that when the administration dose of compound 1-I is 65.5% (0.167 / 0.255) of the number of molecules (mM / kg) of abiraterone acetate, the inhibition of serum testosterone occurs earlier, and the effect on androgen-sensitive organ weight is comparable, indicating that the compound has better pharmacodynamic activity.

[0155] Test Example 3 Prostate cancer cell VCaP mouse transplanted tumor efficacy test

[0156] Human prostate cancer cells were cultured in DMEM medium containing 10% FBS at 37°C, 5% CO2, and when the confluence reached about 80-90%, the cells were digested with trypsin-EDTA, washed twice with PBS, then centrifuged and resuspended in pre-cooled PBS, counted by a cell counter, resuspended in PBS and adjusted to a cell concentration of 2x10 7 / ml. Male Balb / c nu mice were acclimated in a laboratory environment for 5 days, and VCaP cells were inoculated subcutaneously in the right flank, with an inoculation cell amount of 2x10 6 / each, an inoculation volume of 0.2 ml (containing 50% Matrigel), and when the tumor grew to about 100 mm 3 , castration surgery was performed, and after 3 weeks of postoperative adaptation, the animals were screened for group entry and efficacy experiments. A total of 5 groups were orally gavaged with blank solvent, abiraterone acetate 0.5 mM / kg, or compound 1-I at low (0.1 mM / kg), medium (0.25 mM / kg), and high (0.5 mM / kg) doses, once a day, for 40 consecutive days. Abiraterone acetate and compound 1-I were dissolved in ethanol: Doulton 80: physiological saline (15:5:80, v / v / v).

[0157] Tumor volume was measured twice a week during the experiment. The calculation was according to the formula: tumor volume (mm 3 ) = 1 / 2 x (long diameter x short diameter 2 ) (mm).

[0158] Tumor growth curves were plotted, and tumor inhibition rates were calculated. The calculation formula was: T / C (%) = (T-T0) / (C-C0) x 100, where T and C were the tumor volumes at the end of the experiment; T0 and C0 were the tumor volumes at the beginning of drug administration after grouping.

[0159] Tumor inhibition rate (TGI) (%) = 100-T / C (%).

[0160] After the end of the experiment, the animals were sacrificed, and the tumor tissue was peeled off and weighed. The inhibition of tumor growth by abiraterone acetate and compound 1-I is shown in Tables 4 and 5.

[0161] Table 4 Inhibition rate of VCaP transplanted tumor by gavage administration of compound

[0162] Group T / C (%) TGI (%) Vehicle - - Abiraterone acetate 0.5 mmol / kg 60.99 39.01 Compound 1-I, 0.1 mmol / kg 63.25 36.75 Compound 1-I, 0.25 mmol / kg 60.33 39.67 Compound 1-I, 0.5 mmol / kg 60.42 39.58

[0163] Table 5 Effect of compound on VCaP nude mouse transplanted tumor weight after continuous administration

[0164] Group Tumor weight (g) Relative tumor weight (%) Inhibition rate (%) Vehicle 0.423±0.232 - - Abiraterone acetate, 0.5 mmol / kg 0.284±0.207 67.14 31.86 Compound 1-I, 0.1 mmol / kg 0.253±0.100 59.85 40.15 Compound 1-I, 0.25 mmol / kg 0.243±0.116 57.31 42.69 Compound 1-I, 0.5 mmol / kg 0.235±0.159 55.42 45.58

[0165] As shown in Tables 4 and 5, all doses of compound 1-I showed inhibitory activity against VCaP mouse xenografts. The efficacy of the compound at a dose of 0.25 mM / kg was comparable to that of abiraterone acetate at a dose of 0.5 mM / kg, indicating that compound 1-I can achieve the efficacy of abiraterone acetate at a lower dose.

[0166] Test Example 4: Pharmacokinetic Study in Beagle Dogs

[0167] Experimental animals: 3 healthy adult male beagles, 6-8kg, purchased from Chengdu Dashuo Experimental Animal Co., Ltd.

[0168] Drug preparation:

[0169] Accurately weigh a certain amount of abiraterone, add DMA, ethanol and PEG200 to dissolve, then add physiological saline and vortex mix thoroughly. The final drug delivery solvent ratio is DMA:ethanol:PEG200:physiological saline (10:10:40:40, v / v / v). The compound should be freshly prepared immediately before use.

[0170] Accurately weigh a certain amount of compound 1-I, add ethanol and Tween 80 to dissolve it, then add physiological saline and vortex mix thoroughly. The final drug delivery solvent ratio is ethanol:Tween 80:physiological saline (15:5:80, v / v / v). The compound should be freshly prepared immediately before use.

[0171] Administration and Testing: Three healthy adult male beagle dogs were fasted for at least 12 hours before administration, with free access to water. They were allowed to eat 4 hours after administration. Compound 1-I (10 mg / kg) was administered orally (PO). Approximately 0.5 ml of venous blood was collected before and after administration, anticoagulated with heparin, and the plasma was separated by centrifugation and stored at -80°C for analysis. After the first round of administration, the dogs were washed for one week, and then abiraterone (2 mg / kg) was administered intravenously via the forelimb. Approximately 0.5 ml of venous blood was collected before and after administration, anticoagulated with heparin, and the plasma was separated by centrifugation and stored at -80°C for analysis. The concentrations of abiraterone (current drug) and compound 1-I (prodrug) in the plasma were determined using LC-MS / MS.

[0172] The main pharmacokinetic parameters of compound 1-I after administration are shown in Table 6; the main pharmacokinetic parameters were calculated based on the detected plasma drug concentration of abiraterone, and the results are shown in Table 7.

[0173] Table 6. Pharmacokinetic results of compound 1-I in beagle dogs

[0174]

[0175] Table 7. Pharmacokinetic Results of Abiraterone in Beagle Dogs

[0176]

[0177] Compound 1-I was administered to beagle dogs by gavage, and the original form (prodrug form) of compound 1-I was detected in plasma at each time point, and abiraterone was also detected.

[0178] Conclusion: After compound 1-I was administered to beagle dogs by gavage, it was rapidly absorbed, and existed in vivo in the form of prodrug and original drug abiraterone. According to the exposure level of abiraterone in plasma, the absolute bioavailability of oral administration was calculated to be 39.4%.

[0179] All documents referred to in this disclosure are incorporated herein by reference as if each individual document were incorporated by reference. In addition, it is to be understood that the application can be carried out by specifically different embodiments and that each disclosed embodiment can be implemented with or without the corresponding benefits disclosed herein.

Claims

1. A compound of Formula (I) or a pharmaceutically acceptable salt thereof: ###0001### Formula (I) wherein: the compound of Formula (I) satisfies one or more of the following conditions: (1) the compound of Formula (I) is a compound of Formula I-1 and / or I-2: ###0002### Formula I-1 and / or I-2 (2) the compound of Formula (I) or a pharmaceutically acceptable salt thereof, wherein one or more atoms are present in a non-natural abundance, or wherein all atoms are present in a natural abundance. (I)； wherein R1is ; R2is -C(=O)O-C 1-6 alkyl; R a is a hydrogen atom; R b and R b’ each independently is a hydrogen atom or a C 1-6 alkyl group; R c is C 1-6 alkyl.

2. The compound as claimed in claim 1, represented by the general formula (I) or pharmaceutically acceptable salt thereof, wherein (3) the compound of Formula (I) is a compound of Formula I-1: ###0003### Formula I-1 (4) the compound of Formula (I) is a compound of Formula I-2: ###0004### Formula I-2 (5) the compound of Formula (I) is a compound of Formula I-1 and / or I-2: ###0005### Formula I-1 and / or I-2 (6) the compound of Formula (I) or a pharmaceutically acceptable salt thereof, wherein one or more atoms are present in a non-natural abundance, or wherein all atoms are present in a natural abundance. (1) In R2, the -C(=O)OC 1-6 C in alkyl 1-6 The alkyl group is methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, or tert-butyl; (2) R b and R b’ , wherein the C 1-6 alkyl is methyl, ethyl, n-propyl, i-propyl, n-butyl, s-butyl, i-butyl or t-butyl; (3) R c In particular, the C 1-6 alkyl is methyl, ethyl, n-propyl, i-propyl, n-butyl, s-butyl, i-butyl or t-butyl; (4) For The carbon marked with an asterisk refers to an S configuration chiral carbon, an R configuration chiral carbon, or an achiral carbon. the compound of Formula (I) satisfies one or more of the following conditions: ； which is any one of the following schemes:

3. The compound as claimed in claim 1, represented by the general formula (I) or pharmaceutically acceptable salt thereof, wherein Scheme 1: ###0006### Scheme 1 wherein: the compound of Formula (I) is a compound of Formula I-1: ###0007### Formula I-1 the compound of Formula (I) is a compound of Formula I-2: ###0008### Formula I-2 (1) In R2, the -C(=O)O-C 1-6 C in alkyl is 1 1-6 alkyl is ethyl; (2) R a In particular, the C 1-6 alkyl is methyl; (3) R c In particular, the C 1-6 alkyl is isopropyl; (4) For The carbon marked with an asterisk refers to a chiral carbon of S configuration.

4. The compound as claimed in claim 1, represented by the general formula (I) or pharmaceutically acceptable salt thereof, wherein R b and R b’ wherein one substituent is a hydrogen atom and the other substituent is a C 1-6 alkyl group.

5. The compound of formula (I) as claimed in claim 1, characterized in that, To .

6. The compound as claimed in claim 5, represented by the general formula (I) or pharmaceutically acceptable salt thereof, wherein To .

7. The compound of formula (I) as claimed in claim 1, characterized in that, the compound of Formula (I) or a pharmaceutically acceptable salt thereof, wherein: (1) the compound of Formula (I) is a compound of Formula I-1: ###0009### Formula I-1 (2) the compound of Formula (I) is a compound of Formula I-2: ###0010### Formula I-2 the compound of Formula (I) is a compound of Formula I-1: ###0011### Formula I-1 the compound of Formula (I) is a compound of Formula I-2: ###0012### Formula I-2 which comprises the following steps: ； R a is a hydrogen atom; R b and R b’ wherein one substituent is a hydrogen atom and the other substituent is a C 1-6 alkyl group; R c is C 1-6 alkyl; in the presence of a base, reacting a compound of Formula II, a compound of Formula III, and abiraterone in a solvent to form the compound of Formula (I); which satisfies one or more of the following conditions: R a is a hydrogen atom; R b and R b’ each independently is a hydrogen atom or a methyl group; R c is methyl, ethyl, propyl, isopropyl or benzyl; R2is -C(=O)O-C 1-3 alkyl.

8. The compound of formula (I) as claimed in claim 1, characterized in that, (1) the base is an organic base; , or .

9. A process for the preparation of a compound of formula (I) or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 8, wherein, (2) the molar ratio of the base to the abiraterone is 8: 1 to 1: 1; (3) the compound of Formula II is ethyl dichlorophosphoryl formate; ； wherein X1and X2are each independently halogen; the carbon marked with * means an S-configuration chiral carbon, an R-configuration chiral carbon, or an achiral carbon; R2, R a , R b , R b’ , and R c are each independently as defined in any one of claims 1 to 8.

10. The method of preparing a compound of Formula (I) or a pharmaceutically acceptable salt thereof according to claim 9, wherein (4) the molar ratio of the compound of Formula II to the abiraterone is 3: 1 to 1: 1; (5) the compound of Formula III is L-alanine isopropyl ester hydrochloride; (6) the molar ratio of the compound of Formula III to the abiraterone is 3: 1 to 1: 1; (7) the solvent is a halogenated hydrocarbon solvent; (8) the temperature of the reaction is -40 °C to 50 °C. which satisfies one or more of the following conditions: (1) the base is triethylamine; (2) the molar ratio of the base to the abiraterone is 4.0: 1; (3) the molar ratio of the compound of Formula II to the abiraterone is 1: 1; 11. The method of preparing a compound of Formula (I) or a pharmaceutically acceptable salt thereof according to claim 10, wherein (4) the molar ratio of the compound of Formula III to the abiraterone is 1: 1; (5) the solvent is dichloromethane; (6) the temperature of the reaction is room temperature.

12. A pharmaceutical composition comprising a therapeutically effective amount of a compound of Formula (I) or a pharmaceutically acceptable salt thereof according to any one of claims 1-8, and a pharmaceutically acceptable carrier or excipient.

13. Use of a substance X in the manufacture of a medicament for preventing or treating a tumor; the substance X is a compound of Formula (I) or a pharmaceutically acceptable salt thereof according to any one of claims 1-8 or a pharmaceutical composition according to claim 12.

14. The use according to claim 13, wherein: the tumor is prostate cancer. ​ ​ ​ ​ ​

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