AZD2461 Chemical Properties

Density 

1.33±0.1 g/cm3(Predicted)

storage temp. 

2-8°C

solubility 

insoluble in H2O; ≥16.35 mg/mL in DMSO; ≥45.2 mg/mL in EtOH with ultrasonic

form 

powder

pka

12.07±0.40(Predicted)

color 

white to beige

AZD2461 Usage And Synthesis

Uses

4-[4-Fluoro-3-[(4-methoxypiperidin-1-yl)carbonyl]benzyl]phthalazin-1(2H)-one is a phthalazinone derivative and potential PARP inhibitor.

Biochem/physiol Actions

AZD2461, an olaparib analog, is an orally available, potent and selective PARP1 and PARP2 inhibitor that is a poor substrate for drug transporters. AZD2461 exhibits a high efficacy in olaparib-resistant tumors that overexpress P-glycoprotein.

Synthesis

Example 1; 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (231 g, 1.206 mol) was added to a solution of dichloromethane (4.7 g, 0.251 mol) containing 4-methoxypiperidine hydrochloride (183 g, 1.206 mol), 5-[(3,4-dihydro-4-oxo-1-phthalazinyl)methyl]-2-fluorobenzoic acid (300 g, 1.005 mol), and 4-dimethylamino pyridine (30.7 g, 0.251 mol) in a solution of dichloromethane (4 L) was reacted at 23 °C. The resulting suspension was stirred at room temperature overnight. The reaction mixture was washed sequentially with 2 M hydrochloric acid (5 L) and 50% saturated sodium carbonate solution (3 L), followed by drying with anhydrous magnesium sulfate, filtration and concentration in vacuo to give the crude product. The crude product was slurried in ethyl acetate (750 mL) for 5 days, filtered and dried at 45 °C for 5 h to afford 4-[4-fluoro-3-[(4-methoxypiperidin-1-yl)carbonyl]benzyl]phthalazin-1(2H)-one (Compound 1) (290 g, 72.9% yield).1H NMR (400.132 MHz, DMSO) δ 1.26-1.35 ( 1H, m), 1.40-1.49 (1H, m), 1.69-1.73 (1H, m), 1.84-1.89 (1H, m), 2.99-3.07 (1H, m), 3.25 (3H, s), 3.27-3.34 (2H, m), 3.39-3.44 (1H, m), 3.86-3.95 (1H, m), 4.33 (2H, s). 4.33 (2H, s), 7.19-7.24 (1H, m), 7.33-7.35 (1H, m), 7.39-7.43 (1H, m), 7.81-7.91 (2H, m), 7.97 (1H, d), 8.27 (1H, d), 12.57 (1H, s); m/z (ES+) (M + H)+ = 396.31 ; HPLC tR = 1.90 min. Figure 1 illustrates the powder XRD pattern of the product showing it in crystalline form. Figure 2 illustrates the DSC analysis of the product.

in vivo

IC 50

PARP2: 2 nM (IC₅₀); PARP1: 5 nM (IC₅₀); PARP3: 200 nM (IC₅₀)

storage

Store at -20°C

References

[1] Patent: US2011/15393, 2011, A1. Location in patent: Page/Page column 7

AZD2461(1174043-16-3)Related Product Information

• FLURBIPROFEN AXETIL
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• Veliparib
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• Olaparib