Pazopanib

pazopanib

5-[[4-[(2,3-Dimethyl-2H-indazol-6-yl)methylamino]-2-pyrimidinyl]amino]-2-methylbenzolsulfonamide

Pazopanib is a small molecule inhibitor of multiple protein tyrosine kinases with potential antineoplastic activity. It is developed by GlaxoSmithKline and was FDA approved on October 19, 2009.

GW 786034

M.Wt: 437.53
C21H23N7O2S

Pazopanib CAS No.: 444731-52-6

CAS No.: 635702-64-6 (PAZOPANIB HYDROCHLORIDE)

VOTRIENT (pazopanib) is a tyrosine kinase inhibitor (TKI). Pazopanib is presented as the hydrochloride salt, with the chemical name 5-[[4-[(2,3-dimethyl-2H-indazol-6- yl)methylamino]-2-pyrimidinyl]amino]-2-methylbenzenesulfonamide monohydrochloride. It has the molecular formula C₂₁H₂₃N₇O₂S•HCl and a molecular weight of 473.99. Pazopanib hydrochloride has the following chemical structure:

Pazopanib hydrochloride is a white to slightly yellow solid. It is very slightly soluble at pH 1 and practically insoluble above pH 4 in aqueous media.

Tablets of VOTRIENT are for oral administration. Each 200 mg tablet of VOTRIENT contains 216.7 mg of pazopanib hydrochloride, equivalent to 200 mg of pazopanib free base. The inactive ingredients of VOTRIENT are:Tablet Core: Magnesium stearate, microcrystalline cellulose, povidone, sodium starch glycolate. Coating: Gray film-coat: Hypromellose, iron oxide black, macrogol/polyethylene glycol 400 (PEG 400), polysorbate 80, titanium dioxide.

Pazopanib (trade name Votrient) is a potent and selective multi-targeted receptortyrosine kinase inhibitor of VEGFR-1, VEGFR-2, VEGFR-3, PDGFR-a/β, and c-kit that blocks tumor growth and inhibits angiogenesis. It has been approved for renal cell carcinoma and soft tissue sarcoma by the U.S. Food and Drug Administration.Pazopanib may also be active in ovarian cancer Pazopanib also appears effective in the treatment of non-small cell lung carcinoma.

1. FDA Approves GlaxoSmithKline’s Votrient(TM) For Advanced Renal Cell Cancer”. Medical News Today. 20 October 2009. Retrieved 8 June 2010.
2.  Sleijfer, S.; Ray-Coquard, I.; Papai, Z.; Le Cesne, A.; Scurr, M.; Schöffski, P.; Collin, F.; Pandite, L.; Marreaud, S.; De Brauwer, A.; Van Glabbeke, M.; Verweij, J.; Blay, J. -Y. (2009).“Pazopanib, a Multikinase Angiogenesis Inhibitor, in Patients with Relapsed or Refractory Advanced Soft Tissue Sarcoma: A Phase II Study from the European Organisation for Research and Treatment of Cancer-Soft Tissue and Bone Sarcoma Group (EORTC Study 62043)”. Journal of Clinical Oncology 27 (19): 3126–3132.doi:10.1200/JCO.2008.21.3223. PMID 19451427. edit
3.  “FDA Approves Glaxo Cancer Drug Votrient”. Reuters. 26 April 2012. Retrieved 27 April 2012.
4.  “Pazopanib shows encouraging activity in several tumour types, including soft tissue sarcoma and ovarian cancer”. FierceBiotech. 2008-09-15. Retrieved 2010-08-10.

JUNE 4 2013 old article cut paste

GlaxoSmithKline’s (GSK) Votrient (pazopanib) has met the primary objective of a statistically significant improvement in the time to disease progression or death that is the progression-free survival (PFS) against placebo in Phase III ovarian cancer..

http://clinicaltrials.pharmaceutical-business-review.com/news/gsks-votrient-meets-primary-objective-in-phase-iii-ovarian-cancer-trial-030613

Pazopanib is a highly bio-available, multi- tyrosine kinase inhibitor of vascular endothelial growth factor receptor (VEGFR)-l, -2, -3, platelet-derived factor receptor (PDGFR) -α, -β, cytokine receptor (cKit), interleukin-2 receptor inducible T-cell kinase (Itk), leukocyte-specific protein tyrosine kinase (Lck), and transmembrane glycoprotein receptor tyrosine kinase (c-Fms). Pazopanib was recently approved by the Food and Drug Administration (FDA) for the treatment of patients with advanced renal cell carcinoma; thus adding to the other FDA-approved VEGF pathway inhibitors, sunitinib, bevacizumab (in combination with interferon) and sorafinib for this same indication.

Processes by which pazopanib and its intermediates can be synthesized have been described in US Patent No. 7,105,530 as well as in the published PCT application WO03/106416.

U.S. patent no. 7,105,530 disclosed pyrimidineamines and their derivatives thereof. These compounds are antineoplastic agents, and are useful in the treatment of various cancers and renal cell carcinoma. Among them pazopanib hydrochloride, chemically 5-[4-[N-(2,3-Dimethyl-2H-indazol-6-yl)-N-methylamino]pyrimidin-2- ylamino]-2-methylbenzenesulfonamide hydrochloride. Pazopanib hydrochloride is represented by the following structure:
Pazopanib hydrochloride is a potent and selective multi-targeted receptor tyrosine kinase inhibitor of VEGFR (Vascular endothelial growth factor receptors)- 1, VEGFR-2, VEGFR-3, PDGFR (Platelet-derived growth factor receptors )-a/p, and c-kit that blocks tumor growth and inhibits angiogenesis. It has been approved for renal cell carcinoma by the U.S. Food and Drug Administration. Pazopanib hydrochloride may also be active in ovarian cancer and soft tissue sarcoma. Pazopanib hydrochloride also appears effective in the treatment of non-small cell lung carcinoma. Pazopanib hydrochloride is marketed under the brand name Votrient® by Glaxosmithkline in the form of tablet.

Processes for the preparation of pazopanib hydrochloride and related compounds were disclosed in U.S. patent no. 7,105,530 and U.S. patent no. 7,262,203.

According to U.S. patent no. 7,105,530, pazopanib hydrochloride can be prepared by reacting the N-(2-chloropyrimidin-4-yl)-N,2,3-trimethyl-2H-indazol-6-amine with 5- amino-2-methylbenzenesulfonamide in the presence of hydrochloric acid in isopropanol and ether.

U.S. patent application publication no. 2006/0252943 disclosed a process for the preparation of pazopanib hydrochloride. According to this patent, pazopanib hydrochloride can be prepared by reacting the N-(2-chloropyrimidin-4-yl)-N,2,3- trimethyl-2H-indazol-6-amine with 5-amino-2-methylbenzenesulfonamide in the presence of hydrochloric acid in ethanol or methanol or tetrahydrofuran or acetonitrile and dioxane.

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Drugs of the Future, 2006, 31 (7): 585-589
WO0306416

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Marcus Baumann, Ian R. Baxendale, Steven V. Ley and Nikzad Nikbin

Innovative Technology Centre, Department of Chemistry, University of Cambridge, Lensfield Road, CB2 1EW Cambridge, UK

 Corresponding author email

Editor-in-Chief: J. Clayden

Beilstein J. Org. Chem. 2011, 7, 442–495.

Pazopanib (246, Votrient) is a new potent multi-target tyrosine kinase inhibitor for various human cancer cell lines. Pazopanib is considered a promising replacement treatment to imatinib and sunitinib and was approved for renal cell carcinoma by the FDA in late 2009. The indazole system is built up via diazotisation and spontaneous cyclisation of 2-ethyl-5-nitroaniline (247) using tert-butyl nitrite. The resulting indazole structure 249 can be methylated entirely regioselectively with either Meerwein’s salt, trimethyl orthoformate or dimethyl sulfate. A tin-mediated reduction of the nitro group unmasks the aniline which undergoes nucleophilic aromatic substitution to introduce the pyrimidine system with the formation of 253. Methylation of the secondary amine function with methyl iodide prior to a second S_NAr reaction with a sulfonamide-derived aniline affords pazopanib .