956104-40-8

Basic information

• Product Name: ARN-509
• Synonyms: ARN-509;4-(7-(6-cyano-5-(trifluoroMethyl)pyridin-3-yl)-8-oxo-6-thioxo-5,7-diazaspirooctan-5-yl)-2-fluoro-N-MethylbenzaMide;AR509;AR509 100G;4-[7-[6-Cyano-5-(trifluoromethyl)pyridin-3-yl]-8-oxo-6-thioxo-5,7-diazaspiro[3.4]octan-5-yl]-2-fluoro-N-methylbenzamide;Benzamide, 4-[7-[6-cyano-5-(trifluoromethyl)-3-pyridinyl]-8-oxo-6-thioxo-5,7-diazaspiro[3.4]oct-5-yl]-2-fluoro-N-methyl-;4-[7-[6-Cyano-5-(trifluoromethyl)pyridin-3-yl]-8-oxo-6-thioxo-5,7-diazaspiro[3.4]octan-5-yl]-2-fluoro-N-methylbenzamide ARN-509;ARV-509
• CAS NO: 956104-40-8
• Molecular Formula: C₂₁H₁₅F₄N₅O₂S
• Molecular Weight: 477.4347128
• EINECS: -0
• Product Categories: Inhibitors;LG
• Mol File: 956104-40-8.mol
• Article Data: 23

Chemical Properties

• Appearance: /
• Density: 1.59±0.1 g/cm3(Predicted)
• Solubility: ≥23.85 mg/mL in DMSO; insoluble in H2O; ≥7.33 mg/mL in EtOH
• PKA: 13.83±0.46(Predicted)
• CAS DataBase Reference: ARN-509(CAS DataBase Reference)
• NIST Chemistry Reference: ARN-509(956104-40-8)
• EPA Substance Registry System: ARN-509(956104-40-8)

Safety Data

• Hazardous Substances Data: 956104-40-8(Hazardous Substances Data)

Usage

Description

ARN-509 is a selective and competitive androgen receptor inhibitor with IC50 of 16 nM in a cell-free assay, useful for prostate cancer treatment. Phase 3.

In vitro

ARN-509 (< 10 μM) inhibits androgen-mediated induction or repression of mRNA expression levels for 13 endogenous genes including PSA and TMPRSS2 in the LNCaP/AR prostate cancer cell line. ARN-509 (< 10 μM) inhibits the proliferative effect of R1881 (30 pM) in the LNCaP/AR prostate cancer cell line. ARN-509 (10 μM) impairs AR nuclear localization and thus reduces the concentration of AR available to bind androgen response elements (ARE) in LNCaP cells expressing AR-EYFP. ARN-509 (10 μM) is able to effectively compete with R1881 (1 nM) and prevent AR from binding to promoter regions. ARN-509 inhibits R1881-induced VP16-AR–mediated transcription with IC50 of 0.2 μM in Hep-G2 cells expressing a VP16-AR fusion protein and an ARE-driven luciferase reporter.

In vivo

ARN-509 (10 mg/kg/d, oral) inhibits tumor growth with decreased proliferative index and increased apoptotic rate in castrate male immunodeficient mice harboring LNCaP/AR-luc xenograft tumors. ARN-509 dose dependently inhibits tumor growth with highest efficacy at dose of 30 mg/kg/day in castrate male immunodeficient mice harboring LNCaP/AR-luc xenograft tumors. ARN-509 dosed at 10 mg/kg/d for 28 days results in a 3-fold reduction in prostates weight associated with lacking glandular secretory activity and 1.7-fold reduction in epididymis weight in adult male dogs. ARN-509 (10 mg/kg/d, oral) inhibits cell proliferation of prostate tissues in adult male dogs. ARN-509 is safe and well tolerated in 24 patients with metastatic CRPC who has progressed on prior treatments and peak plasma concentrations occurred 2 to 3 hours after administration. ARN-509 results in durable PSA declines at doses ranging from 30 to 300 mg in patients with metastatic CRPC. ARN-509 shows powerful anti-cancer activity and induces durable remissions long after therapy completion in castrate resistant prostate cancer mouse models.

Uses

Apalutamide is a second-generation antiandrogen used in the treatment of prostate cancer. It is a potent antagonist of androgen receptor with IC50 value of 16 nM. Binds androgen receptors, thereby inhibiting nuclear translocation, DNA binding and transcriptional activation. ARN-509 has therapeutic applications in non-metastatic, castration-resistant prostate cancer.

Pharmaceutical Applications

Apalutamide, also known as ARN-509, is used to treat certain types of castration-resistant prostate cancer or prostate cancer that has not spread to other parts of the body, but has not been helped by other medical treatments. Apalutamide is in a class of medications called androgen receptor inhibitors. It works by blocking the effects of androgen to stop the growth and spread of cancer cells. On September 17, 2019, the Food and Drug Administration approved apalutamide (ERLEADA, Janssen Biotech, Inc) for patients with metastatic castration-sensitive prostate cancer (mCSPC). Apalutamide was initially approved in 2018 for patients with non-metastatic castration-resistant prostate cancer.

Mechanism of action

Apalutamide, also known as ARN-509 and JNJ-56021927 , is an androgen receptor antagonist with potential antineoplastic activity. ARN-509 binds to AR in target tissues thereby preventing androgen-induced receptor activation and facilitating the formation of inactive complexes that cannot be translocated to the nucleus. This prevents binding to and transcription of AR-responsive genes. This ultimately inhibits the expression of genes that regulate prostate cancer cell proliferation and may lead to an inhibition of cell growth in AR-expressing tumor cells.

Upstream product

• 915087-26-2 4-(1-cyano-cyclobutanylamino)-2-fluoro-N-methyl-benzamide 
• 951753-87-0 5-isothiocyanato-3-(trifluoromethyl)pyridine-2-carbonitrile 
• 3796-23-4 3-(trifluoromethyl)pyridine 
• 22253-72-1 3-(trifluoromethyl)pyridine-N-oxide 
• 22264-50-2 1-aminocyclobutane-1-carboxylic acid 
• 74-89-5 methylamine 
• 99368-66-8 2-hydroxyl-5-nitro-3-(trifluoromethyl)pyridine 
• 915087-25-1 2-fluoro-N-methyl-4-amino-benzamide 
• 573762-57-9 2-cyano-3-(trifluoromethyl)-5-nitropyridine 
• 573762-62-6 5-amino-3-(trifluoromethyl)pyridine-2-carbonitrile 
• 1332391-11-3 4-[6-[6-cyano-5-(trifluoromethyl)-3-pyridyl]-5-oxo-7-thioxo-6,8-diazaspiro[3.4]octan-8-yl]-2-fluorobenzamide 
• 215597-35-6 methyl 1-aminocyclobutanecarboxylate 
• 292621-45-5 4-bromo-2-fluorobenzamide 
• 179232-29-2 methyl 4-bromo-2-fluorobenzoate 

Relevant articles and documents

PROCESS FOR THE PREPARATION OF APALUTAMIDE

Aspect of the present application relates to process for the preparation of crystalline form of Apalutamide and process for the preparation of Apalutamide in the presence of neutralizing agent selected from triethylsilylchloride, trimethylsilyl chloride, zinc chloride, aluminium chloride, iron chloride, sodium chloride, acetic acid, ammonium chloride or mixture thereof followed by treating with acid to obtain Apalutamide.

Method for preparing

The invention relates to a method for preparing an intermediate and an epalutamide, wherein the compound is represented by the formula (5). The preparation method of the compound represented by the formula (5) comprises the following steps: preparing compound represented by formula (3) by using the compound as an intermediate. Compound of formula (4) and Thithio reagent is reacted to form the compound represented by formula (5). The thio reagent is a phenyl thioformate. A combination of one or more N-thiocarbonyldiimidazole, 1,1 -thiocarbonyl DI-2 (1H) - pyridine. The inventors have found that 4 - (1 - carboxamide - cyclobutylamino) -2 - fluoro - N - methyl - benzamide, 5 - amino -2 - cyano -3 - trifluoromethyl pyridine and sodium thiochloroformate can be obtained in a higher yield than the prior art by one-step reaction under appropriate conditions. Based on this finding, the present invention was obtained and presented by further study.

Method for synthesizing apalutamide and intermediate thereof and intermediate

The invention discloses a preparation method of Boc-apalutamide, wherein the method comprises the steps: under the catalytic action of a catalyst, reacting 6-thio-5,7-diazaspiro[3.4]octyl-8-one with N-(4-bromo-2-fluorobenzoyl)tert-butyl carbamate, and reacting with 2-cyano-3-trifluoromethyl-5-bromopyridine to obtain Boc-apalutamide. According to the invention, 6-thio-5,7-diazaspiro[3.4]octyl-8-oneis used as a substrate, and Boc-apalutamide: N-(4-(7-(6-cyan-5-trifluoromethylpyridin-3-yl)-8-oxo-6-thio-5,7-diazaspiro[3.4]-5-octyl)-2-fluorobenzoyl)-N-methyl tert-butyl carbamate can be directly obtained by a one-pot method. And the final product apalutamide can be obtained through a simple Boc removal reaction. The process is simple in steps and suitable for industrial mass production.