| Identification | Back Directory | [Name]
AZD2461 | [CAS]
1174043-16-3 | [Synonyms]
CS-739
AZD2461
AZD 2461, >=98%
AZD2461 USP/EP/BP
4-[4-Fluoro-3-[(4-methoxypiperidin-1-yl)carbonyl]benzyl]phthalazin-1(2H)-one
4-[[4-fluoro-3-(4-methoxypiperidine-1-carbonyl)phenyl]methyl]-2H-phthalazin-1-one
4-[[4-Fluoro-3-[(4-methoxy-1-piperidinyl)carbonyl]phenyl]methyl]-1(2H)-phthalazinone
1(2H)-Phthalazinone, 4-[[4-fluoro-3-[(4-methoxy-1-piperidinyl)carbonyl]phenyl]methyl]- | [Molecular Formula]
C22H22FN3O3 | [MDL Number]
MFCD24386811 | [MOL File]
1174043-16-3.mol | [Molecular Weight]
395.43 |
| Chemical Properties | Back Directory | [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 |
| Hazard Information | Back Directory | [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]
AZD-2461 (10 mg/kg, p.o.) enhances the antitumor activity of temozolomide in a mouse colorectal xenograft and exhibits low effect on mouse bone marrow cells. However, the increased bone marrow tolerability of AZD-2461 is not seen in rat models[1]. AZD-2461 (0.5% v/w HPMC, p.o.) increases the survival of mice bearing KB1P tumors after short-term treatment, and long-term treatment is well tolerated, but can not lead to tumor eradication[3]. | [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 |
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