(S)-2-(4-(Piperidin-3-yl)phenyl)-2H-indazole-7-carboxamide Tosylate Monohydrate

 

 as tosylate H2o

1613220-15-7 cas

free 1038915-60-4

• 2-[4-(3S)-3-Piperidinylphenyl]-2H-indazole-7-carboxamide
• Niraparib
•  Jones, Philip; Journal of Medicinal Chemistry 2009, V52(22), P7170-7185

• MK-​4827

(S)-2-(4-(Piperidin-3-yl)phenyl)-2H-indazole-7-carboxamide Tosylate Monohydrate 1

................... The solid was collected and dried in vacuo at 40 °C to afford 1 as the tosylate monohydrate salt (797 g, 86%, >99 wt %, >99%ee) as a tan-coloured solid.

Mp = 144 °C. ¹H NMR (600 MHz, CD₃OD) δ 8.95 (1H, s), 8.15 (1H, dd, J = 7.1, 1.2 Hz), 8.02 (2H, m), 8.00 (1H, dd, J = 8.3, 1.2 Hz), 7.72 (2H, m), 7.49 (2H, m), 7.25 (1H, dd, J = 8.3, 7.1 Hz), 7.22 (2H, d, J = 8.0 Hz), 3.49–3.43 (2H, m), 3.16–3.04 (3H, m), 2.34 (3H, s), 2.09–2.05 (2H, m), 1.96–1.82 (2H, m).

¹³C NMR (150.9 MHz, CD₃OD) δ 169.7, 148.1, 143.7, 143.0, 141.9, 140.5, 131.8, 130.0, 129.8, 127.3, 127.1, 125.4, 124.2, 123.3, 122.4, 50.2, 45.2, 41.1, 30.9, 24.0, 21.4.

 

 

 

Discovery of 2-{4-[(3S)-Piperidin-3-yl]phenyl}-2H-indazole-7-carboxamide (MK-4827): A Novel Oral Poly(ADP-ribose)polymerase (PARP) Inhibitor Efficacious in BRCA-1 and -2 Mutant Tumors

Philip Jones*, Sergio Altamura, Julia Boueres, Federica Ferrigno, Massimiliano Fonsi, Claudia Giomini, Stefania Lamartina, Edith Monteagudo, Jesus M. Ontoria, Maria Vittoria Orsale, Maria Cecilia Palumbi, Silvia Pesci, Giuseppe Roscilli, Rita Scarpelli, Carsten Schultz-Fademrecht, Carlo Toniatti and Michael Rowley

IRBM/Merck Research Labs Rome, Via Pontina km 30,600, 00040 Pomezia, Italy

J. Med. Chem., 2009, 52 (22), pp 7170–7185

DOI: 10.1021/jm901188v, http://pubs.acs.org/doi/abs/10.1021/jm901188v?source=chemport

 

*To whom correspondence should be addressed. Current address: Department of Medicinal Chemistry, Merck Research Labs Boston, Avenue Louis Pasteur 33, Boston, MA 02115-5727. Phone: +1-617-992-2292. Fax: +1-617-992-2405. E-mail: philip_jones@merck.com.

Abstract

We disclose the development of a novel series of 2-phenyl-2H-indazole-7-carboxamides as poly(ADP-ribose)polymerase (PARP) 1 and 2 inhibitors. This series was optimized to improve enzyme and cellular activity, and the resulting PARP inhibitors display antiproliferation activities against BRCA-1 and BRCA-2 deficient cancer cells, with high selectivity over BRCA proficient cells. Extrahepatic oxidation by CYP450 1A1 and 1A2 was identified as a metabolic concern, and strategies to improve pharmacokinetic properties are reported. These efforts culminated in the identification of 2-{4-[(3S)-piperidin-3-yl]phenyl}-2H-indazole-7-carboxamide 56 (MK-4827), which displays good pharmacokinetic properties and is currently in phase I clinical trials. This compound displays excellent PARP 1 and 2 inhibition with IC₅₀ = 3.8 and 2.1 nM, respectively, and in a whole cell assay, it inhibited PARP activity with EC₅₀ = 4 nM and inhibited proliferation of cancer cells with mutant BRCA-1 and BRCA-2 with CC₅₀ in the 10−100 nM range. Compound 56 was well tolerated in vivo and demonstrated efficacy as a single agent in a xenograft model of BRCA-1 deficient cancer.

//////////1613220-15-7, 1038915-60-4, 2-[4-(3S)-3-Piperidinylphenyl]-2H-indazole-7-carboxamide, Niraparib, mk 4827