Androgen receptor antagonist, pharmaceutical composition, and use thereof

Abstract

The present invention relates to an androgen receptor antagonist, a pharmaceutical composition comprising same, and a pharmaceutical use thereof. The compound has a structure represented by the following formula (I). The compound has excellent androgen receptor affinity and can be used for the prevention and treatment of related diseases. The present invention further relates to a pharmaceutical composition and a use thereof.

Description

androgen receptor antagonists, pharmaceutical compositions and their applications Technical Field

[0001] This invention relates to the pharmaceutical field, specifically to a pharmaceutical compound, and more specifically to an androgen receptor antagonist and a pharmaceutical composition comprising the same. Background Technology

[0002] The androgen receptor (AR), a key member of the nuclear receptor superfamily, triggers a series of physiological responses and regulates gene expression and cellular function upon binding to androgens (such as testosterone and dihydrotestosterone). The development of androgen receptor antagonists (AR antagonists) is of great significance for the treatment of various diseases. These drugs competitively bind to AR, blocking androgen signaling pathways and thus inhibiting the physiological effects of androgens, playing a crucial role in the treatment of diseases such as prostate cancer and benign prostatic hyperplasia. With a deeper understanding of the mechanism of AR action, the application scope of AR antagonists is constantly expanding, showing potential in the treatment of androgen-related alopecia, acne, and hirsutism. Notably, research indicates that AR antagonists may have a protective effect in certain neurodegenerative diseases, opening up new areas for their application.

[0003] Prostate cancer is one of the most common malignant tumors in men worldwide and a leading cause of cancer-related deaths in men. With an aging population and advancements in diagnostic technology, the incidence of prostate cancer is on the rise. Currently, androgen deprivation therapy (ADT) is the standard treatment for advanced prostate cancer. However, most patients progress to castration-resistant prostate cancer (CRPC) within 18-24 months of ADT, posing a significant challenge to clinical treatment. AR antagonists play a crucial role in prostate cancer treatment. First-generation AR antagonists, such as bicalutamide, have significantly improved patient prognosis, while newer generation drugs, such as enzalutamide, have further improved treatment outcomes. However, the use of AR antagonists still faces some limitations; some patients develop acquired resistance, leading to treatment failure. Furthermore, these drugs may cause side effects such as fatigue and cognitive decline, impacting patients' quality of life. Given the limitations of existing treatment options and the urgent clinical need, there remains a pressing need to develop safer and more effective AR antagonists to provide patients with better treatment options.

[0004] CN108976171A (an earlier patent application published by the applicant) discloses a compound with a thioimidazolyl group that can simultaneously target the androgen receptor (AR) and histone deacetylase 6 (HDAC6), with the compound Zeta55 showing the best efficacy. However, there is still room for further optimization of Zeta55 in inhibiting AR activity. Furthermore, pharmacokinetic studies have shown that Zeta55 has an oral half-life (T1 / 2) of 2.95 hours and an oral bioavailability of only 17.6% (Maojun Zhou et al., Discovery of a novel AR / HDAC6 dual inhibitor for prostate cancer treatment, Journal of Aging Research, Volume 13, Issue 5, pp 6982-6998), indicating significant potential for improvement in its pharmacokinetic properties. Summary of the Invention

[0005] According to the present invention, a compound is proposed that regulates the function of nuclear hormone receptors, particularly androgen receptors. This compound can lead to the disappearance of prostate cancer cells and tumors.

[0006] The compounds of the present invention have the following structure:

[0007] The chemical name of the compound is 4-(3-(4-cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2-thioimidazolidine-1-yl)-2-fluoro-benzamide.

[0008] The present invention also relates to a pharmaceutical compound comprising a therapeutically effective dose of the above-described compound or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier, diluent or adjuvant.

[0009] In one embodiment, the pharmaceutical composition is a solution comprising dimethyl sulfoxide, carboxymethyl cellulose, polysorbate, and water.

[0010] The implementation of the method includes methods for preventing or treating hyperplastic conditions such as hormone-sensitive or hormone-refractory prostate cancer, and may include administering a compound according to the invention or a pharmaceutically acceptable salt thereof to a person in need, thereby preventing or treating the hyperplastic condition. The compound may be administered by close injection, by injection into a tissue, by intraperitoneal administration, or by oral administration.

[0011] In the embodiments, the compounds of the present invention have a strong affinity for the androgen receptor (AR), can inhibit the expression of downstream proteins in the AR pathway, and have a significant inhibitory effect on the proliferation of tumor cells with high androgen receptor expression. They can be used to prevent or treat diseases related to androgen receptor abnormalities, including but not limited to prostate cancer (including castration-resistant and metastatic subtypes), androgenetic alopecia, polycystic ovary syndrome, benign prostatic hyperplasia, breast cancer (AR-positive subtype), and as an adjunct to gender reassignment therapy; at the same time, they can be extended to potential indications such as metabolic syndrome and non-alcoholic fatty liver disease, and are especially suitable for cases with AR mutations or treatment resistance.

[0012] Compared to Zeta55, the compound according to the present invention has the following advantages:

[0013] (1) Zeta110 has a 3.04-fold increased affinity for AR.

[0014] (2) Zeta110 increased the inhibitory activity against prostate cancer cell growth by 5.34-5.43 times.

[0015] (3) In the pharmacokinetics experiment in rats, the T1 / 2 of oral Zeta110 was prolonged by 3.08 times and the oral bioavailability was increased by 3.97 times.

[0016] This finding was unexpected. Compared to Zeta55, Zeta110 retained its AR-inhibiting activity but lost its HDAC6-inhibiting activity (IC50 > 10 μM). However, we unexpectedly found that Zeta110 was significantly superior to Zeta55 in terms of AR affinity, prostate cancer cell growth inhibition activity, and pharmacokinetic properties, demonstrating its potential therapeutic advantages. Attached Figure Description

[0017] Figure 1 is a graph showing the Zeta110 combined with AR.

[0018] Figure 2 is a graph showing the transcriptional activity of Zeta110 in inhibiting AR.

[0019] Figure 3 is a graph showing that Zeta110 effectively inhibits the growth of prostate cancer xenograft tumors.

[0020] Figure 4: Photograph showing the effectiveness of Zeta110 in treating androgenetic alopecia in a mouse model. Detailed Implementation

[0021] This invention is based on an accidental discovery made by the inventors while studying the drug metabolism of Zeta55 class compounds. They found that these drugs produce a metabolite in vivo: benzamide, after the N-hydroxyl group is removed. This substance exhibits potential, and even more pronounced, AR antagonistic properties, and therefore has the potential to treat androgen receptor-related diseases. The applicant has thus filed this invention.

[0022] The compound according to the present invention has the following structure:

[0023] Compounds of Formula I can exist as pharmaceutically acceptable salts, which are also within the scope of this invention.

[0024] The compounds of the present invention can be used in the form of pharmaceutical compositions comprising a therapeutically effective amount of the compound of the present invention as defined herein and a pharmaceutically acceptable carrier or diluent.

[0025] The form of the pharmaceutical compositions according to the invention can be adapted to be administered to patients requiring treatment, such as mammals like humans, via various routes of administration, including oral, intranasal, intraperitoneal, or non-gastrointestinal administration, via intravenous, intramuscular, local, or subcutaneous routes, or via tissue injection. Such compositions and formulations should contain at least 0.01% of one or more compounds of the invention. The percentages of the compositions and formulations can, of course, vary and can be, for example, from about 0.05% to about 2% by weight of a given unit dosage form. The amount of the compound in such therapeutically useful compositions results in an effective dose level.

[0026] The compounds of this invention can be administered systemically, such as orally, in combination with pharmaceutically acceptable carriers such as inert diluents or assimilated edible carriers, or by inhalation or inhalation. They can be encapsulated in hard or soft-shell capsules, compressed into tablets, or directly mixed with food consumed by the patient. For oral therapeutic administration, the compounds of this invention can be combined with one or more excipients and used in the form of ingestible tablets, lozenges, tablets, capsules, elixirs, suspensions, syrups, wafers, etc. The compounds can be combined with fine, inert powdered carriers and inhaled or inhaled by the patient. Such compositions and formulations should contain at least 0.1% of one or more compounds of this invention.

[0027] Tablets, lozenges, pills, capsules, etc., may also contain: binders such as tragacanth gum, gum arabic, corn starch, or gelatin; excipients such as dicalcium phosphate; disintegrants such as corn starch, potato starch, alginic acid, etc.; lubricants such as magnesium stearate; and sweeteners such as sucrose, fructose, lactose, or aspartame, or flavorings such as peppermint, wintergreen oil, or cherry flavoring. When the unit dosage form is a capsule, in addition to the above types of materials, it may also contain a liquid carrier such as vegetable oil or polyethylene glycol. Various other materials may be present as coatings or otherwise alter the physical form of the solid unit dosage form. For example, tablets, pills, or capsules may be coated with gelatin, wax, shellac, sugar, etc. Syrups or elixirs may contain active compounds, sucrose or fructose as sweeteners, methylparaben and propylparaben as preservatives, dyes, and flavorings such as cherry or orange flavoring. Of course, any materials used to prepare any unit dosage form should be pharmaceutically acceptable and substantially non-toxic in dosage. Furthermore, the compounds of this invention can be introduced into sustained-release formulations and devices. For example, the compounds can be introduced into time-release capsules, time-release tablets, and time-release pills.

[0028] Useful solid carriers include finely dispersed solids such as talc, clay, microcrystalline cellulose, silica, bauxite, etc. Other solid carriers include non-toxic polymer nanoparticles or microparticles. Useful liquid carriers include water, alcohols or glycols, or water / alcohol / glycol blends, wherein the compounds of the present invention can optionally be dissolved or dispersed at effective levels by means of non-toxic surfactants. Adjuvants such as fragrances and additional antimicrobial agents can be added to optimize performance for a given application. The resulting liquid compositions can be applied by absorbent pads, used to impregnate bandages and other dressings, or sprayed onto the affected area using a pump-type or aerosol sprayer.

[0029] The amount of the compound of the present invention required for treatment varies not only with the specific salt selected, but also with the route of administration, the nature of the condition being treated, and the patient's age and condition, and is ultimately determined by the attending physician or clinician.

[0030] The effective dosage and route of administration of the reagents of this invention are conventional. The precise amount (effective dosage) of the reagent varies from patient to patient, depending on factors such as patient type, age, weight and general or clinical condition, the severity or mechanism of any condition being treated, the specific reagent or carrier used, the method and pace of administration, etc. The effective therapeutic dosage can be empirically determined through conventional procedures known to those skilled in the art.

[0031] Generally, a suitable dose can be from about 0.01 to about 500 mg / kg / day, such as from about 0.1 to about 500 mg / kg body weight / day, or from about 0.1 to about 100 mg / kg body weight / day. For example, a suitable dose could be about 1 mg / kg, 10 mg / kg, or 50 mg / kg body weight / day.

[0032] The compounds of the present invention are conveniently administered in unit dosage forms; for example, each unit dosage form contains about 0.0005 to about 500 mg, about 0.01 to about 50 mg, about 0.05 to about 10 mg, or about 5 mg of active ingredient.

[0033] The compounds of the present invention can be administered to achieve, for example, peak plasma concentrations of about 0.5 to about 75 μM, about 1 to 50 μM, about 2 to about 30 μM, or about 5 to about 25 μM. Exemplary desired plasma concentrations include at least or no more than 0.25, 0.5, 1, 5, 10, 25, 50, 75, 100, or 200 μM. This can be achieved, for example, by intravenous injection of a 0.05-5% solution of the compounds of the present invention (optionally in saline), or by oral administration in a large pill containing about 1-1000 mg of the compound. Desired blood levels can be maintained by continuous infusion to provide about 0.0005 to about 25 mg / kg body weight / hour, for example, at least or no more than 0.0005, 0.005, 0.05, 0.5, 5, or 25 mg / kg / hour. Alternatively, this level can be achieved by intermittent infusions containing about 0.002 to about 100 mg / kg body weight, for example, at least or no more than 0.002, 0.02, 0.2, 2, 20, 50 or 100 mg of compound / kg body weight.

[0034] The compounds of the present invention can be conveniently administered as a single dose or as fractions administered at appropriate intervals, for example as 2, 3, 4 or more sub-dose per day. The sub-dose itself can be further divided, for example, into a number of discrete, loosely separated administrations; such as by multiple inhalations from an inhaler.

[0035] Compound preparation examples

[0036] (1) Synthesis of methyl 2-fluoro-4-aminobenzoate (2)

[0037] 2-Fluoro-4-aminobenzoic acid (25.00 g, 161.25 mmol) and 100 mL of methanol were added to a 250 mL three-necked flask. Concentrated sulfuric acid (10.3 mL, 193.50 mmol) was then added dropwise. The mixture was heated to reflux and reacted for 12 h. After cooling to room temperature, sodium carbonate solution was added to adjust the pH to 8, resulting in the precipitation of a brown solid. 500 mL of water was then added, and the mixture was filtered to obtain 24.34 g of compound 2, a brown solid, with a yield of 89.3%. The mp values ​​were 105.9–107.2 °C. 1 H NMR (500MHz, CDCl3): δ7.76 (t, J=10.0Hz, 1H), 6.43-6.41 (m, 1H), 6.36-6.33 (m, 1H), 3.87 (s, 3H).

[0038] (2) Synthesis of methyl 4-((1-cyanocyclobutyl)amino)-2-fluorobenzoate (3)

[0039] In a 250 mL two-necked flask, methyl 2-fluoro-4-aminobenzoate 2 (7.84 g, 46.41 mmol), cyclobutanone (5.21 g, 74.25 mmol), trimethylcyanosilane (6.91 g, 69.61 mmol), and 80 mL of acetic acid were added. The mixture was heated to 80 °C and reacted for 12 h. The reaction was monitored by TLC (petroleum ether:ethyl acetate = 20:3). After the reaction was complete, 400 mL of water was added to the reaction solution, and a reddish-brown solid precipitated out. After filtration and drying, 10.89 g of compound 3, a reddish-brown solid, was obtained, with a yield of 94.7%. mp 126.7–127.3 °C. 1 H NMR (500MHz, CDCl3): δ7.78 (t, J = 5.0Hz, 1H), 6.40-6.38 (m, 1H), 6.31-6.28 (m, 1H), 5.11(s,1H),3.84(s,3H),2.80-2.78(m,2H),2.36-2.40(m,2H),2.23-2.00(m,2H).

[0040] (3) Synthesis of methyl 4-7-(4-cyano-3-(trifluoromethyl)phenyl)-8-oxo-6-thio-5,7-diazaspiro[3.4]octane-5-yl)-2-fluorobenzoate (4)

[0041] Compound 3 (15.20 g, 61.29 mmol), 3-trifluoromethyl-4-cyanoaniline (13.63 g, 73.31 mmol), and 120 mL of ultra-dry N,N-dimethylacetamide were added to a 250 mL two-necked flask. After stirring and dissolving, sulfur phosgene (7.9 mL, 91.93 mmol) was added dropwise over approximately 20 min. The mixture was then heated to 70 °C and reacted for 24 h. The reaction was monitored by TLC (PE:EA:MeOH = 20:10:1). After cooling to room temperature, 60 mL of methanol, 15 mL of concentrated hydrochloric acid, and 60 mL of water were added. The mixture was refluxed and stirred for 3 h. After cooling to room temperature, 800 mL of water was added to quench the reaction. The mixture was then extracted with ethyl acetate (150 mL × 3), washed twice with saturated brine, dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure. The mixture was then slurried with 90 mL of ethanol, filtered, and dried to obtain 8.86 g of solid, with a yield of 30.3%. 1 H NMR (500MHz, CDCl3): δ8.19(t,J=5.0Hz,1H),8.01-7.98(m,2H),7.87-7.85(m,1H),7.26-7.20( m,2H),4.01(s,3H),2.76-2.71(m,2H),2.60-2.53(m,2H),2.31-2.25(m,1H),1.77-1.71(m,1H).

[0042] (4) Synthesis of 4-(7-(4-cyano-3-(trifluoromethyl)phenyl)-8-oxo-6-thio-5,7-diazaspiro[3.4]oct-5-yl)-2-fluorobenzoic acid (5)

[0043] Compound 4 (9.56 g, 20.03 mmol) and 80 mL of methanol were added to a 250 mL single-necked flask. 80 mL of 1 mol / L sodium hydroxide solution was added to the mixture, and the mixture was stirred at 20 °C for 4 h. After the reaction was complete, 2 mol / L dilute hydrochloric acid was added to adjust the pH to 4, and then 500 mL of water was added. A white solid precipitated out. After filtration and drying, 9.08 g of compound 5 was obtained as a grayish-white solid, with a yield of 97.8%. 1 H NMR (500MHz, CD3OD): δ8.30(t,J=5.0Hz,1H),7.99-7.97(m,2H),7.86-7.84(m,1H),7.25- 7.19(m,2H),2.73-2.68(m,2H),2.58-2.51(m,2H),2.32-2.26(m,1H),1.76-1.70(m,1H).

[0044] (5) Synthesis of 4-(7-(4-cyano-3-(trifluoromethyl)phenyl)-8-oxo-6-thio-5,7-diazaspiro[3.4]oct-5-yl)-2-fluorobenzamide (Zeta110)

[0045] Compound 5 (10.00 g, 21.58 mmol) and 40 mL of dichloromethane were added to a 100 mL double-necked flask. Under nitrogen protection, thionyl chloride (5.13 g, 43.16 mmol) was slowly added, and the mixture was heated to reflux for 12 h. The reaction was monitored by TLC. After the reaction was complete, the solvent was directly removed under reduced pressure to obtain intermediate 6. Intermediate 6 was then dissolved in 20 mL of THF, and triethylamine (4.5 mL, 32.37 mmol) was slowly added dropwise under ice-water bath conditions. Then, 81 mL of 0.4 mol / L NH3 solution of dioxane was added, and the reaction was carried out at room temperature for 6 h. The reaction was monitored by TLC. After the reaction was complete, the reaction was quenched with ice water, and then extracted with ethyl acetate (80 mL × 3). The organic phases were combined, washed twice with 40 mL of 1 mol / L sodium hydroxide, once with 100 mL of water, and once with saturated brine. The mixture was then dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure to give 9.52 g of a pale yellow solid, with a yield of 95.4%. MW, 462.42; 1 H NMR (500MHz, DMSO-d6): δ8.39(d,J=8.3Hz,1H),8.24(d,J=1.6Hz,1H),8.06(dd,J=8.2,1.7Hz,1H),7.95(s,1H),7.85(t,J=8.1Hz,1H),7.79( s,1H),7.46(dd,J=10.6,1.8Hz,1H),7.38(dd,J=8.1,1.8Hz,1H),2.66-2.62(m,2H),2.49-2.43(m,2H),2.01-1.92(m,1H),1.61-1.53(m,1H).

[0046] Bioactivity assay of compound Zeta110

[0047] Experiments combining with AR

[0048] Using PolarScreen TMThe androgen receptor competitive assay kit (green) compares the ability of Zeta110, Zeta55, and enzalutamide (ENZa) to competitively bind to the GST-labeled recombinant AR ligand-binding domain (LBD). The green fluorescent ketone tracer included in the kit decreases in activity and increases in fluorescence polarization upon binding to AR-LBD (GST). Conversely, when compounds competitively bind to AR-LBD (GST), the binding of Fluormone Tracer to AR-LBD (GST) decreases, and the fluorescence polarization value decreases.

[0049] Prepare the reaction system using AR-LBD (GST) and Fluormone Tracer. Add 10 μL of the reagent dissolved in DMSO to the detection plate, cover the plate to prevent light exposure, and incubate at room temperature for at least 4 hours. Measure the fluorescence polarization value (mP) of each well using a fluorescence polarization plate reader. Perform data analysis and plotting using Graphpad Prism software to obtain the half-maximal inhibitory concentration (IC50) and nonlinear regression curve of the test compound.

[0050] The results show (see Figure 1) that Zeta110 competitively combines with AR-LBD ICs 50 The value is 3.04 μM. Compared to Zeta55 (IC) 50 =8.73μM) and ENZa(IC 50 Compared to 4.15μM, Zeta110 has a stronger binding ability to AR.

[0051] Assay for inhibiting AR transcriptional activity

[0052] The effect of Zeta110 on AR transcriptional activity was further explored using a dual-luciferase reporter gene assay. The MMTV-Luc plasmid containing the AR target promoter was constructed. Both the AR plasmid and the MMTV-Luc plasmid were co-transfected into cells. AR activated the target promoter, leading to luciferase expression, and the expression level of luciferase was directly proportional to AR activation. Adding dihydrotestosterone (DHT) to the cells activated AR, increased luciferase expression, and enhanced fluorescence signal; adding an AR antagonist weakened the fluorescence signal.

[0053] Selected healthy VCaP cells, passaged 3-4 times after resuscitation, were seeded in 96-well plates. When the confluence reached 90%, plasmid transfection was performed. VCaP cells were transfected with MMTV-Luc and AR plasmids. 24 hours after transfection, cells were treated with DMSO, 10 nM DHT, or 10 nM DHT + a specified concentration of compound for 24 hours. The original culture medium was completely aspirated, and 100 μL / well cell lysis buffer was added for lysis for 20 minutes. The cells were then centrifuged, and the supernatant was mixed with 100 μL of luciferase assay reagent. Chemiluminescence was detected immediately using a multi-mode microplate reader. Data were analyzed and plotted using Graphpad Prism software.

[0054] To quantitatively compare the differences in AR transcriptional activity inhibition by Zeta110, Zeta55, and ENZa, VCaP cells were treated with a series of concentration gradients of Zeta110, Zeta55, and ENZa. The results showed that the IC50 of Zeta110 inhibited AR transcriptional activity. 50 The value was 0.40 μM, indicating a stronger inhibitory effect than ENZa(IC). 50 =0.69μM) and Zeta55 (IC 50 =0.94μM)(Figure 2).

[0055] Assay to inhibit the proliferation of AR-positive prostate cancer cells

[0056] The effect of Zeta110 on the proliferation of AR-positive prostate cancer cells was determined using the CCK-8 assay. Suspensions of AR-positive prostate cancer VCaP and LNCaP cells, as well as AR-negative prostate cancer PC3 and DU145 cell suspensions, were prepared. Cells were seeded in 96-well plates (100 μL per well). After cell attachment, a series of concentration gradients of Zeta110, Zeta55, and Zeta109 (another major metabolite of Zeta55) were added. After 7 days of treatment, CCK-8 reagent was added, and the cells were incubated at 37°C. The absorbance at 450 nm was measured using a microplate reader. Data processing and analysis were performed using Graphpad Prism software, and the IC50 value was calculated.

[0057] Second-generation AR antagonists approved by the FDA include ENZa (Enzalutamide), ARN509 (Apalutamide), and ODM201 (Darolutamide), which have shown promising antitumor effects in the treatment of PCa. The CCK-8 assay was used to compare the effects of Zeta110, Zeta55, and the aforementioned three second-generation AR antagonists in inhibiting PCa cell proliferation. The results are shown in Table 1.

[0058] Table 1. Results of Zeta110's inhibition of prostate cancer cell proliferation

[0059] As shown in Table 1, Zeta110, Zeta55, ENZa, ARN509, and ODM201 inhibited the proliferation of VCaP cells by IC50. 50 The values ​​were 0.41 μM, 2.19 μM, 9.54 μM, 13.12 μM, and 14.73 μM, respectively, and the IC50 values ​​inhibited LNCaP cell proliferation. 50 The values ​​were 1.30 μM, 7.06 μM, 13.07 μM, 10.71 μM, and 17.77 μM, respectively. The results indicate that Zeta110 exhibits a significant advantage in inhibiting prostate cancer cell proliferation, with its inhibitory activity being significantly enhanced compared to Zeta55 and three second-generation AR antagonists.

[0060] Pharmacokinetics of Zeta110

[0061] Twelve SD rats purchased from Hunan Slack Jingda Experimental Animal Co., Ltd. were used. Six rats were randomly selected for gavage administration (50 mg / kg), and the other six were administered via sublingual vein injection (5 mg / kg). Rats were fasted for 12 hours prior to administration but allowed free access to water. The dosage was calculated based on the rats' body weight. Blood collection time points were set at 0, 5 min, 15 min, 0.5 h, 1 h, 2 h, 4 h, 6 h, 8 h, 10 h, 24 h, and 36 h, with 0.2 mL of blood collected from the tail vein. After centrifugation at 4000 rpm for 15 min, the supernatant was collected and stored at -80℃ or directly determined using HPLC-MS / MS. Individual data are expressed as mean ± standard deviation (X±s), and peak concentration (C0) is expressed as mean ± standard deviation (X±s). max Peak time (T) max The measured average value was used, and the area under the plasma drug concentration-time curve (AUC) was calculated using PhoenixWinnonlin 8.0 software. 0-t ), Area under the plasma drug concentration-time curve (AUC) 0-∞ ), half-life (t) 1 / 2 Key pharmacokinetic parameters, such as oral bioavailability (F(AUC)). 0-t The calculation formula is: F(AUC) 0-t ) = AUC (0-t)灌胃 *Dose 静注 / AUC (0-t)静注 *Dose 灌胃 ×100%

[0062] Following oral and intravenous administration, the plasma drug concentration-time curves of Zeta110 were measured and are shown in Table 2. Based on the obtained pharmacokinetic parameters, the oral bioavailability of Zeta110 was calculated to be 69.84%, and the T0.05 value was 69.84%.1 / 2 It's 9 hours.

[0063] Table 2. Pharmacokinetic Results of Zeta110

[0064] Inhibitory activity assay on CRPC xenograft tumor growth

[0065] A CRPC xenograft tumor model was established using 5-week-old male CB17 / SCID mice purchased from Beijing Vital River Laboratory Animal Technology Co., Ltd. 1×10 7 VCaP cells were suspended in a 100 μL mixture of DMEM and Matrigel (BD) at a 1:1 volume ratio and injected into the right axilla of mice. Mouse condition and tumor growth were monitored. The tumor was classified as 150 mm². 3 Castration was performed on the mice. After the tumors resumed growth, the mice were randomly divided into three groups of six mice each, based on tumor volume and mouse weight. The mice were administered solvent, Zeta 11050 mg / kg, and Zeta 5550 mg / kg by gavage once a day for 40 consecutive days.

[0066] The experimental results (as shown in Figure 3) showed that, compared with the solvent group and the Zeta55 50 mg / kg group, the tumor volume growth rate of mice in the Zeta110 50 mg / kg group was significantly slowed down, indicating that Zeta110 has a significant inhibitory effect on the growth of prostate cancer xenograft tumors, and the tumor-suppressing effect is more significant than that of Zeta55.

[0067] Efficacy of Zeta110 in treating androgenetic alopecia in a mouse model

[0068] This experiment used 12 healthy adult male C57BL / 6 mice, aged 6-8 weeks and weighing 18-22 grams. The mice were randomly divided into two groups (control group and Zeta110 group), with 6 mice in each group. The mice were acclimatized for one week before the formal experiment began.

[0069] During the experiment, mice were subcutaneously injected with dihydrotestosterone (DHT) solution on their backs daily for 7 consecutive days to induce an androgenetic alopecia model. At the end of the 7th day, the backs of the mice were uniformly shaved to mark the experimental areas.

[0070] After shaving, the control group had solvent applied to the shaved area (blank control), while the Zeta110 group had a reagent containing Zeta110 applied to the shaved area. Both groups were treated once a day for 7 consecutive days.

[0071] The experimental results (see Figure 4) showed that, compared with the control group, the Zeta110 group significantly reduced the area of ​​hair loss and significantly accelerated the growth rate of new hair. This indicates that Zeta110 has a good therapeutic effect in improving androgenetic alopecia in mice. These experiments demonstrate that Zeta110, a metabolite of Zeta55, has excellent effects in inhibiting AR transcriptional activity, inhibiting the growth of prostate cancer xenograft tumors, and treating androgenetic alopecia.

Claims

1. An androgen receptor antagonist, characterized in that a structure having the formula: Or its medicinal salt.

2. A pharmaceutical composition comprising a therapeutically effective amount of the androgen receptor antagonist of claim 1 or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

3. A pharmaceutical composition comprising a therapeutically effective amount of the androgen receptor antagonist of claim 1 or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable diluent.

4. A pharmaceutical composition comprising a therapeutically effective amount of the androgen receptor antagonist of claim 1 or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable adjuvant.

5. The pharmaceutical composition according to any one of claims 2-4, wherein it is a solution, gel, foam, powder, suspension, powder, capsule, tablet or pill.

6. The use of the androgen receptor antagonist of claim 1 or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for treating androgen receptor-related diseases.

7. According to claim 6, the disease is prostate cancer, androgenetic alopecia, polycystic ovary syndrome, acne, benign prostatic hyperplasia, AR-positive subtype breast cancer, gender reassignment-related diseases, non-alcoholic fatty liver disease, and cases with AR mutations or treatment resistance.

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