阅读说明：本技术 一种阿比特龙前体化合物及其制备方法和应用 (Abiraterone precursor compound and preparation method and application thereof ) 是由 雷昊言 于 2021-08-26 设计创作，主要内容包括：本发明公开了一种新型阿比特龙药物的前体化合物及其制备方法和应用,所述化合物的结构如式I所示。本发明还提供了式I化合物制备方法、式I化合物的盐酸盐及其制备方法、以及它们在制备CYP17酶抑制剂药物中的应用。本发明化合物提供了改进的口服生物利用度和药物动力学特性,其可以作为人体CYP17酶抑制剂,可用于治疗泌尿生殖系或与雄激素相关的疾病,如癌症或其他雄激素相关疾病,包括前列腺癌、乳癌和前列腺肥大等。(The invention discloses a precursor compound of a novel abiraterone medicine, a preparation method and application thereof, wherein the structure of the compound is shown as a formula I. The invention also provides a preparation method of the compound shown in the formula I, a hydrochloride of the compound shown in the formula I, a preparation method of the hydrochloride and an application of the hydrochloride and the hydrochloride in preparation of CYP17 enzyme inhibitor medicaments. The compounds of the present invention provide improved oral bioavailability and pharmacokinetic profiles which are inhibitors of the human CYP17 enzyme and are useful in the treatment of urogenital or androgen-related conditions such as cancer or other androgen-related conditions including prostate cancer, breast cancer and prostatic hypertrophy.)

1. A compound of formula I or a pharmaceutically acceptable salt thereof:

2. a process for the preparation of a compound of formula I according to claim 1, comprising the steps of:

step one, reacting abiraterone with N, N' -carbonyldiimidazole in a solvent to generate an intermediate Cpd-1;

step two, reacting the intermediate Cpd-1 with 2- [2- (dimethylamino) ethoxy ] ethanol in the presence of a solvent and a base to obtain the compound shown in the formula I.

3. The method of claim 2, wherein:

in the first step, the reaction temperature is 20-30 ℃, and the reaction time is 1min-24 h; the solvent is one or a mixture of more of dichloromethane, acetone, ethyl acetate, DMF, DMSO and pyridine;

in the second step, the reaction temperature is 20-100 ℃, and the reaction time is 1min-24 h; the solvent is one or a mixture of more of toluene, DMSO, dioxane and tetrahydrofuran; the alkali is selected from sodium carbonate, sodium bicarbonate, potassium carbonate, sodium hydroxide, potassium hydroxide, triethylamine or pyridine.

4. The pharmaceutically acceptable salt of the compound of formula I of claim 1, having the formula:

wherein HA is an inorganic acid or an organic acid;

preferably, the pharmaceutically acceptable salts of the compounds of formula I are selected from the following compounds:

5. a process for preparing a pharmaceutically acceptable salt of a compound of formula I according to claim 4, comprising the steps of:

dissolving the compound of the formula I in a solvent, adding an equivalent amount of acid HA, and reacting to obtain a pharmaceutically acceptable salt of the compound of the formula I; wherein the acid HA is as defined in claim 4.

6. The process for the preparation of the salt of the compound of formula I according to claim 5, wherein the reaction temperature is 20-30 ℃ and the reaction time is 1min-24 h; the solvent is one or a mixture of more of dichloromethane, acetone and ethyl acetate.

7. A pharmaceutical composition comprising a compound of claim 1 or a pharmaceutically acceptable salt thereof.

8. Use of a compound according to claim 1 or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 7, for the manufacture of a medicament for the inhibition of the CYP17 enzyme.

9. Use of the compound of claim 1 or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition of claim 7 for the preparation of a medicament for the prevention or treatment of an androgen-related disease.

10. Use according to claim 9, wherein the androgen-related diseases include genitourinary diseases, such as genitourinary cancer or prostatic hypertrophy; the genitourinary cancer includes prostate cancer, breast cancer, ovarian cancer, etc.

Technical Field

The invention belongs to the field of precursor compounds, and particularly relates to an abiraterone precursor compound and a preparation method and application thereof.

Background

Prostate cancer is the most common malignant lethal tumor worldwide and the incidence increases with age. The current trend of aging in the population leads to a rapid increase in prostate cancer patients, which has a relatively rapid rate of increase in the last 10 years in our country and is the sixth place in the onset of male disease. Mortality is second in the first incidence of male morbidity in the united states. According to the american cancer society data, about 21.8 million men are diagnosed with prostate cancer each year in the united states, and 3.2 million die as a result.

Prostate cancer has been a relatively rare disease in china, but the incidence of this disease has also been on the rise in recent years. Epidemiological data show that the incidence of prostate cancer in china increases from 1.71 people/10 million men in 1993 to 7.9 people/10 million men in 2005. According to the data counted by the national cancer center in 2014, the incidence rate of the prostate cancer in China is about 9.80/10 ten thousand male population, and the prostate cancer rate is rising at a rate of 10% per year. That is, after 10 years, the incidence of prostate cancer in china will increase 1-fold or even more severely. With the aging phenomenon of the Chinese society becoming more and more serious, the onset of the Chinese prostate cancer may enter a peak stage in the next 10 years. Chinese population is large, and aging speed is high. Prostate cancer, a male condition, will also become more common.

Some diseases in the body have been shown to be caused by hyperandrogenism in the body, such as benign hyperplasia of the prostate, prostate cancer, etc. Androgens play an important role in the development, growth and spread of prostate cancer. In particular, the two most important classes of androgens are testosterone and dihydrotestosterone. Of these, 90% of testosterone is synthesized by the testes, and the remaining 10% is synthesized by the adrenal glands. Testosterone is further converted to more active dihydrotestosterone by a reductase (steroid 5 α -reductas). Minute amounts of testosterone and dihydrotestosterone in the body stimulate the growth of prostate cancer.

CYP17(17 alpha-hydroxylase/C17, 20-lyase) is a cytochrome P450 enzyme located in the testis and adrenal gland as well as other tissues such as prostate tumor tissue. It is a key enzyme in the androgen biosynthetic pathway, catalyzing two sequential reactions of testosterone biosynthesis: pregnenolone and progesterone are first converted to their 17 α -hydroxy derivatives by 17 α -hydroxylase activity, followed by both C17, 20-lyase activity to form Dehydroepiandrosterone (DHEA) and androstenedione, respectively. DHEA and androstenedione are both androgens and are precursors of testosterone. Testosterone is further converted to more active dihydrotestosterone by a reductase (steroid 5 α -reductas).

If the tumor is confined to the prostate, the patient may be resected by surgery or radiation therapy. In men with prostate tumors, approximately 15% of human cancers will spread. For these patients, there is currently no cure. The aim of the treatment is to prevent the testes from producing testosterone and other androgens, which are indissoluble in the growth of prostate cancer cells. Drug treatment of prostate cancer has become a very important treatment when patients fail, for example, with radical prostatectomy or radiation therapy.

The CYP17 enzyme inhibitor can not only inhibit the biosynthesis of androgen in testis, but also inhibit the biosynthesis of androgen in adrenal gland and other tissues such as prostate tumor tissue, and has better therapeutic action compared with the current clinical castration therapy which only can inhibit the biosynthesis of androgen in testis. The CYP17 enzyme inhibitor with high selectivity and strong effect can reduce the androgen level in vivo by inhibiting the initial link in androgen biosynthesis, and is clinically used for treating prostatic cancer.

Based on the above-mentioned epidemiological and molecular biological recognition, the work for preventing and treating prostate cancer is very slow, and the research and development of CYP17 enzyme inhibitor is an important direction for the drug therapy of prostate cancer. As a novel CYP17 enzyme inhibitor, abiraterone acetate was developed by Centocor Ortho for the treatment of prostate cancer. Abiraterone acetate was approved by the U.S. FDA on day 28/4/2011 and was used in combination with prednisone to treat castration-resistant prostate cancer, which is marketed under the trade name Zytiga. Year 2011, 28/7/t, Zytiga was approved by the health canada department. In prostate cancer patients, hormone testosterone can stimulate the growth of tumors, castration treatment including drug or surgical treatment can reduce the production of testosterone or block the action of testosterone, but the treatment cannot inhibit the production of androgen in other parts of the body, and prostate cancer can still continue to grow. Abiraterone targets to inhibit the activity of CYP17 enzyme which regulates androgen production, reduces androgen production, and thereby slows down tumor growth. Median survival was prolonged by 3.9 months (14.8 and 10.9 months, respectively, with p <0.0001) in patients receiving abiraterone acetate in combination with prednisone compared to placebo, i.e. the risk of mortality was reduced by 35%.

Therefore, the method is worthy of further research for searching new abiraterone ester prodrug and providing new clinical choices.

Disclosure of Invention

The purpose of the invention is as follows: aiming at the technical problems, the invention provides an abiraterone precursor compound and a preparation method and application thereof. The abiraterone precursor compound is a novel compound, can be comparable to abiraterone acetate, is even superior to the abiraterone acetate in certain aspects, and has great market value.

The technical scheme is as follows: in order to achieve the purpose of the invention, the technical scheme adopted by the invention is as follows:

the invention provides a compound shown as a formula I, or a pharmaceutically acceptable salt thereof:

the invention further provides pharmaceutically acceptable salts of compounds of formula I, having the structural formula:

wherein HA is an inorganic acid or an organic acid.

Preferably, the pharmaceutically acceptable salts of the compounds of formula I are selected from the following compounds:

the invention also provides a method for preparing the compound shown in the chemical formula I, which comprises the following steps:

step one, reacting abiraterone with N, N' -carbonyldiimidazole in a solvent to generate an intermediate Cpd-1.

And step two, after the intermediate Cpd-1 and 2- [2- (dimethylamino) ethoxy ] ethanol react in a solvent in the presence of alkali, the intermediate Cpd-1 is subjected to post-treatment and purification to obtain the compound shown in the formula I.

The invention also provides a preparation method of the pharmaceutically acceptable salt of the compound shown in the formula I, which comprises the following steps:

alternatively, the compound of formula I is dissolved in a solvent and an equivalent amount of acid is added to give a salt of the compound of formula I.

The product is subsequently refined.

A process for the preparation of a compound of formula I and pharmaceutically acceptable salts thereof, as shown in the following reaction scheme:

in the preparation process, the first reaction is carried out at room temperature, preferably room temperature (25 ℃), and the reaction time is not particularly limited, and is usually 1 minute to 24 hours, preferably 1 to 20 hours. The solvents used are typically dichloromethane, acetone, ethyl acetate, DMF, DMS0, pyridine, etc. After the reaction is finished, concentrating to remove the reaction solvent, adding a proper solvent for crystallization, and performing suction filtration to obtain an intermediate. The solvent used is usually tetrahydrofuran, acetonitrile, petroleum ether, methyl tert-ether and the like.

The second reaction is carried out at room temperature to 100 deg.C, preferably at 60 deg.C, and the reaction time is not particularly limited, and is usually 1 minute to 24 hours, preferably 1 to 20 hours. The solvent used is usually toluene, DMSO, dioxane, tetrahydrofuran, etc. The base used is usually sodium carbonate, sodium bicarbonate, potassium carbonate, sodium hydroxide, potassium hydroxide, triethylamine, pyridine, etc.

The third reaction step is carried out at room temperature, preferably room temperature (25 ℃), and the reaction time is not particularly limited, and is usually 1 minute to 24 hours, preferably 1 to 20 hours. The solvent used is typically dichloromethane, acetone, ethyl acetate, and the like.

The fourth step of refining is carried out at the temperature of-20 ℃ to 100 ℃. The solvent used is usually petroleum ether, ethyl acetate, methanol, ethanol, methyl t-butyl ether, n-hexane, tetrahydrofuran, etc.

The present invention provides a pharmaceutical composition comprising a compound of formula I or a pharmaceutically acceptable salt thereof.

Preferably, the pharmaceutical composition further comprises one or more pharmaceutically acceptable carriers, diluents or excipients.

The invention also provides an application of the compound shown in the formula I or the pharmaceutically acceptable salt thereof or the pharmaceutical composition in preparing CYP17 enzyme inhibitor medicaments.

The invention also provides application of the compound shown in the formula I or pharmaceutically acceptable salts thereof or the pharmaceutical composition in preparing medicaments for preventing or treating androgen related diseases.

Further, the androgen-related diseases include genitourinary system diseases (such as genitourinary system cancer or prostatic hyperplasia, etc.) or other androgen-related diseases (such as androgenic alopecia, androgen-related non-genitourinary system cancer, etc.); the genitourinary cancer includes prostate cancer, breast cancer, ovarian cancer, other genitourinary cancers, and the like.

The mechanism of action of the compounds of the invention: animal experiments prove that the compound has excellent prodrug characteristics, can be quickly absorbed in vivo and then degraded into an active ingredient abiraterone, and other degradation products are analyzed into corresponding alcohol and carbon dioxide from a chemical angle, so that the compound is safe and effective to a human body.

Has the advantages that: compared with the prior art, the invention has the following advantages:

1. clinical research shows that the abiraterone acetate as a prodrug of abiraterone can be absorbed by human body after being taken orally, and the abiraterone acetate is deacetylated in vivo to obtain the active ingredient abiraterone. The compound of the formula I provided by the invention also has the characteristics of a prodrug, can be quickly absorbed in vivo and then degraded into an active ingredient abiraterone, and the other degradation products are corresponding alcohol and carbon dioxide, so that the compound is safe and effective.

2. The IC of the present invention was obtained from the in vitro cell proliferation toxicity test of example 10₅₀Is superior to the existing abiraterone acetate.

3. Pharmaceutically acceptable salts of the compounds of formula I have excellent water solubility.

4. Comparative pharmacokinetic studies in Beagle dogs, example 12, showed that the compound of formula I and abiraterone, and abiraterone C, were detected simultaneously in vivo following administration of LHY-AB614_maxMuch higher than the compound of formula I. After the abiraterone acetate is administrated, only abiraterone is detected in vivo, which shows that the abiraterone acetate is rapidly metabolized into abiraterone after entering the body. Oral administration of LHY-AB614, in comparison to abiraterone acetate, C of abiraterone_maxSignificant increase in T_maxThe compound of the invention can maintain high blood concentration in vivo for a long time by oral administration, which has great advantages clinically. In addition, compared with abiraterone acetate, the oral AUC of LHY-AB614 is obviously increased, which shows that the compound of the invention can obviously improve the oral bioavailability.

Detailed Description

The technical solutions of the present invention are further described in detail by the following specific examples, but it should be noted that the following examples are only used for describing the content of the present invention and should not be construed as limiting the scope of the present invention.

EXAMPLE 1 Synthesis of LHY-AB614 Compound

A dry 500mL round bottom flask was charged with abiraterone (10g,28.6mmol,1.0eq) using 150mL of CH₂Cl₂Dissolve, add CDI (14g,85.8mmol,3.0eq) and react at room temperature. After 8h, the reaction was checked by TLC (PE: EA: 1), and the starting material disappeared completely. The reaction was concentrated, 100mL of dry THF was added, stirred at room temperature for 30min, filtered with suction, and the filter cake was washed with dry THF (50mL × 3). The solid was collected and dried to give compound Cpd-1(10g,22.6mmol) in 79% yield.

A dry 250mL round bottom flask was charged with compound Cpd-1(10g,22.6mmol,1.0eq) and KOH (250mg,4.5mmol,0.2eq), 100mL toluene, and finally 2- [2- (dimethylamino) ethoxy ] ethoxy]Ethanol (4.1mL,29.4mmol,1.3eq), 60 deg.CThe reaction was carried out overnight, and the reaction was checked by TLC, and the starting material disappeared completely. Spin-drying the solvent, washing the resulting solid compound with water, CH₂Cl₂Extraction, combined organic phases, drying, concentration and purification by column chromatography gave the product of formula I (5.7g,11.2mmol) in 49% yield. 1H NMR (400MHz, CDCl)₃)δ8.59(s,1H),8.43(d,J＝3.9Hz,1H),7.61(d,J＝7.8Hz,1H),7.19(dd,J＝7.6,4.9Hz,1H),5.96(s,1H),5.41(d,J＝3.5Hz,1H),4.52–4.40(m,1H),4.31–4.19(m,2H),3.72–3.61(m,2H),3.57(t,J＝5.7Hz,2H),2.50(t,J＝5.6Hz,2H),2.44–2.33(m,2H),2.25(s,7H),2.08–1.98(m,3H),1.94–1.84(m,2H),1.81–1.35(m,8H),1.16–1.08(m,1H),1.04(s,3H),1.02(s,3H).13C NMR(101MHz,CDCl₃)δ154.57,151.69,148.00,147.96,139.77,133.70,132.97,129.27,123.08,122.65,77.83,69.33,68.83,66.73,58.77,57.51,50.25,47.36,45.91,38.09,36.82,36.78,35.23,31.85,31.56,30.43,27.70,20.88,19.28,16.65.EI-MS:m/z calcd for C₃₁H₄₄N₂O₄[M+H]⁺508.7Found:509.3

Dissolving the formula I (10g) in 100mL ethyl acetate at room temperature, introducing and drying to obtain HCl gas, adding 100mL petroleum ether after the reaction is completed, and separating out a product LHY-AB 614. Discarding the supernatant, and drying to obtain crude LHY-AB 614.

At room temperature, crude LHY-AB614 (1g) is dissolved in 1.2mL of methanol, 25mL of tetrahydrofuran is slowly added dropwise, the mixture is stirred vigorously at room temperature, a white solid is separated out, and a filter cake is dried after suction filtration to obtain purer LHY-AB614(800mg, purity 99.6%).

EXAMPLE 2 Synthesis of LHY-AB615 Compound

Dissolving the formula I (1g) in 10mL ethyl acetate at room temperature, adding equivalent phosphoric acid, after the reaction is completed, adding 20mL petroleum ether, and precipitating a product LHY-AB 615. And (4) carrying out suction filtration and drying to obtain a crude LHY-AB615 product.

Crude LHY-AB615 (1g) was dissolved in 1.2mL of methanol at room temperature, 25mL of tetrahydrofuran was slowly added dropwise, stirred vigorously at room temperature to precipitate a white solid, which was filtered off and the filter cake dried to afford relatively pure LHY-AB615(820mg, 99.5% purity).

EXAMPLE 3 Synthesis of LHY-AB616 Compound

Dissolving the formula I (1g) in 10mL ethyl acetate at room temperature, adding equivalent methanesulfonic acid, adding 20mL petroleum ether after the reaction is completed, and precipitating a product LHY-AB 616. And (4) carrying out suction filtration and drying to obtain a crude LHY-AB616 product.

At room temperature, crude LHY-AB616 (1g) is dissolved in 1.2mL of methanol, 25mL of tetrahydrofuran is slowly added dropwise, the mixture is stirred vigorously at room temperature, a white solid is separated out, and a filter cake is dried after suction filtration to obtain purer LHY-AB616(790mg, 99.7% purity).

EXAMPLE 4 Synthesis of LHY-AB617 Compound

Dissolving the formula I (1g) in 10mL of acetone at room temperature, adding pyruvic acid with equivalent weight, adding 20mL of petroleum ether after the reaction is completed, and separating out the product LHY-AB 617. And (4) carrying out suction filtration and drying to obtain a crude LHY-AB617 product.

At room temperature, crude LHY-AB617 (1g) is dissolved in 1.2mL of methanol, 25mL of tetrahydrofuran is slowly added dropwise, the mixture is stirred vigorously at room temperature to precipitate a white solid, and a filter cake is dried after suction filtration to obtain pure LHY-AB617(800mg, purity 99.7%).

EXAMPLE 5 Synthesis of LHY-AB618 Compound

Dissolving the formula I (1g) in 10mL ethyl acetate at room temperature, adding equivalent benzoic acid, after the reaction is completed, adding 20mL petroleum ether, and precipitating a product LHY-AB 618. And (4) carrying out suction filtration and drying to obtain a crude LHY-AB618 product.

Crude LHY-AB618 (1g) was dissolved in 1.2mL of methanol at room temperature, 25mL of tetrahydrofuran was slowly added dropwise, vigorous stirring at room temperature to precipitate a white solid, which was filtered off and the filter cake dried to afford relatively pure LHY-AB618(820mg, 99.6% purity).

EXAMPLE 6 Synthesis of LHY-AB619, a Compound

Dissolving the formula I (1g) in 10mL ethyl acetate at room temperature, adding equivalent p-toluenesulfonic acid, adding 20mL petroleum ether after complete reaction, and precipitating a product LHY-AB 619. And (4) carrying out suction filtration and drying to obtain a crude LHY-AB619 product.

At room temperature, crude LHY-AB619 (1g) is dissolved in 1.2mL of methanol, 25mL of tetrahydrofuran is slowly added dropwise, the mixture is stirred vigorously at room temperature, a white solid is separated out, and a filter cake is dried after suction filtration to obtain purer LHY-AB619(800mg, purity 99.8%).

EXAMPLE 7 Synthesis of LHY-AB620 Compound

Dissolving the formula I (1g) in 10mL ethyl acetate at room temperature, adding equivalent maleic acid, after the reaction is completed, adding 20mL petroleum ether, and precipitating a product LHY-AB 620. And (4) carrying out suction filtration and drying to obtain a crude LHY-AB620 product.

Crude LHY-AB620 (1g) was dissolved in 1.2mL of methanol at room temperature, 25mL of tetrahydrofuran was slowly added dropwise, stirred vigorously at room temperature to precipitate a white solid, which was filtered off and the filter cake dried to afford relatively pure LHY-AB620(840mg, 99.7% purity).

EXAMPLE 8 Synthesis of LHY-AB621 Compound

Dissolving the formula I (1g) in 10mL of ethyl acetate at room temperature, adding equivalent succinic acid, adding 20mL of petroleum ether after the reaction is completed, and precipitating a product LHY-AB 621. And (4) carrying out suction filtration and drying to obtain an LHY-AB621 crude product.

At room temperature, crude LHY-AB621 (1g) is dissolved in 1.2mL of methanol, 25mL of tetrahydrofuran is slowly added dropwise, the mixture is stirred vigorously at room temperature, a white solid is separated out, and a filter cake is dried after suction filtration to obtain pure LHY-AB621(830mg, purity 99.8%).

EXAMPLE 9 Synthesis of LHY-AB622 Compound

Dissolving the formula I (1g) in 10mL ethyl acetate at room temperature, adding equivalent malic acid, after the reaction is completed, adding 20mL petroleum ether, and precipitating the product LHY-AB 622. And (4) carrying out suction filtration and drying to obtain a crude LHY-AB622 product.

Crude LHY-AB622 (1g) was dissolved in 1.2mL of methanol at room temperature, 25mL of tetrahydrofuran was slowly added dropwise, vigorous stirring was carried out at room temperature to precipitate a white solid, which was filtered off and the filter cake was dried to give relatively pure LHY-AB622(810mg, 99.7% purity).

Example 10 abiraterone carboxylate prodrug cellular Activity assay

By usingChemiluminescence cell viability detection method (CTG method) for evaluating half Inhibitory Concentration (IC) of abiraterone acetate and LHY-AB614 in proliferation of LNCAP clone FGC and VCAP₅₀)。

Exponential phase cells were collected and viable cell counts were performed. Adjusting with corresponding mediumEach cell suspension was brought to the appropriate concentration. Adding 90 μ l cell suspension to 96-well cell culture plate, spreading appropriate amount of cells in plate hole, and culturing at 37 deg.C with 5% CO₂Incubate for 24 hours.

DMSO was dissolved in the test sample as a stock solution at an initial concentration of 50. mu.M, and the solution was diluted 3-fold in the medium to 10 Xthe working solution at 9 concentration points. Cisplatin as reference compound was dissolved in DMSO at an initial concentration of 100. mu.M and diluted 3-fold in medium to 10 Xworking solution at 9 concentration points. Then, 10. mu.L per well was added to the cells. Then at 37 ℃ with 5% CO₂Incubate for 72 hours.

The 96-well plate was equilibrated at room temperature for about 30 minutes, and then 50. mu.l of CTG solution was added per well. Cells were lysed by mixing for 2 minutes using a microplate shaker. The fluorescence signal was stabilized by standing at room temperature for 20 minutes. The fluorescence signal values were determined using an Envision2104 plate reader. Sigmoidal dose-response curves were plotted using a non-linear regression model using GraphPad Prism software and IC calculated₅₀The value is obtained. The results are shown in Table 1. IC of LHY-AB614 on LNCAP cells and VCAP cells₅₀The values are 3.2uM and 5.7uM respectively, which are significantly better than abiraterone acetate.

TABLE 1 inhibition of LNCAP and VCAP cells by test and control compounds

Example 11LHY-AB614-622 solubility test

200mg of LHY-AB614-622 was weighed and 1mL of physiological saline was added. LHY-AB614-622 was found to dissolve well. LHY-AB614-622 was shown to have better solubility in physiological saline and >200 mg/mL.

2mg of abiraterone acetate was weighed, dissolved in 1mL of physiological saline, and stirred overnight. After suction filtration, the filtrate was subjected to HPLC analysis. Abiraterone acetate was dissolved in methanol to make a 0.1mg/mL solution as a control. As a result, the abiraterone acetate is extremely difficult to dissolve in water, and the solubility in normal saline is less than 0.1 mg/mL.

Example 12 comparative study of the pharmacokinetic Properties of LHY-AB614 beagle dogs

In order to prove that the LHY-AB614 of the invention is superior to the bioavailability of the existing abiraterone acetate in vivo, the abiraterone acetate is taken as a reference medicament to evaluate the bioavailability and the bioequivalence. 4 healthy Beagle dogs with the weight range of 6-8 kg are fasted for 12h before the experiment, and are fed with a low-fat standard meal uniformly after administration. No other medications were taken during the first two weeks and the duration of the trial. 4 Beagle dogs were randomly divided into two groups A, B (2 dogs each). LHY-AB614 was orally administered at a dose of 46.8mg/kg (32.2 mg/kg for abiraterone), and abiraterone acetate was orally administered at a dose of 42.3mg/kg (37.8 mg/kg for abiraterone). Taking blank blood before taking medicine, taking 1mL of blood after taking medicine for 0.25h, 0.5h, 1.0h, 2.0h, 4.0h, 6.0h, 8.0h and 24.0h respectively in an EDTA-K2 anticoagulation tube, after fully mixing with the blood, immediately placing in wet ice and centrifugally separating plasma as soon as possible, and filling the plasma obtained after centrifugation in a marked EP tube. Taking 50 mu L of plasma sample, adding 300 mu L of carbamazepine acetonitrile solution containing 10ng/mL for protein precipitation, and after vortex for 5min, placing the sample in a centrifuge for 10min by using 5500 g. 100 μ L of the supernatant was removed, and 300 μ L of 50% -methanol water was added to dilute the supernatant, followed by 5 μ L injection after vortexing. And (3) determining the in-vivo drug concentration of LHY-AB614, abiraterone acetate and abiraterone by an HPLC-MS/MS method.

TABLE 2 pharmacokinetic parameters of LHY-AB614 and Abiraterone in plasma after oral administration of LHY-AB614 to Beagle dogs

TABLE 3 pharmacokinetic parameters of Abiraterone in plasma after oral Abiraterone acetate administration to Beagle dogs

As a result, LHY-AB614 and abiraterone can be simultaneously detected in vivo after LHY-AB614 administration, and C of abiraterone_maxMuch higher than LHYAB 614. After the abiraterone acetate is administrated, only abiraterone is detected in vivo, which shows that the abiraterone acetate is rapidly metabolized into abiraterone after entering the body. Compared with abiraterone acetate, the oral administration of LHY-AB614 has the advantages that the Cmax of the abiraterone is obviously increased, the Tmax is unchanged, and the compound can maintain high blood concentration in vivo for a long time by oral administration, so that the clinical advantage is realized. In addition, compared with abiraterone acetate, the oral AUC of LHY-AB614 is obviously increased, which shows that the compound can obviously improve the oral bioavailability.