Cabozantinib (marketed under the tradename Cometriq, formerly known as XL184) is asmall molecule inhibitor of the tyrosine kinases c-Met and VEGFR2, and has been shown to reduce tumor growth, metastasis, and angiogenesis.

It was developed by Exelixis Inc.

Cabozantinib was granted orphan drug status by the U.S. Food and Drug Administration(FDA) in January 2011.

Cabozantinib was approved by the U.S. FDA in November 2012 for the treatment of medullary thyroid cancer.It is currently undergoing clinical trials for the treatment of prostate, ovarian, brain, melanoma, breast, non-small cell lung, pancreatic, hepatocellular and kidney cancers.

In October 2011, cabozantinib met its primary endpoint in a phase 3 clinical trial (EXAM) conducted by Exelixis investigating its effect on progression-free survival in medullary thyroid cancer.A new drug application was submitted in the first half of 2012, and on November 29, 2012 cabozantinib was granted marketing approval by the U.S. FDA under the name Cometriq for treating patients with medullary thyroid cancer.

Grapefruit and grapefruit juice should be avoided as they may increase the concentration of the drug in the blood.

It is not yet known if Cometriq is safe and effective in children.

In 2009 a phase II study for relapsed glioblastoma multiforme reported encouraging interim results.

Positive data from clinical trials in 2011 indicate cabozantinib is beneficial in metastatic advanced prostate cancer (castration-resistant prostate cancer). 97% of patients either had stabilization or improvement in bone malignancies. The median time to disease progression was 29 weeks.

One US trial reported in May 2011: The best results were seen in patients with liver, prostate, and ovarian cancer: 22 of 29 patients with liver cancer, 71 of 100 patients with prostate cancer, and 32 of 51 with ovarian cancer experienced either partial tumor shrinkage or stable disease. Fifty-nine out of 68 patients who had bone metastases had their metastases shrink or disappear during the trial.

A pivotal trial for thyroid cancer should report interim results mid-2011.

It is undergoing clinical trials for the treatment of prostate, ovarian, brain, melanoma, breast, non-small cell lung, hepatocellular and kidney cancers.

The U.S. Food and Drug Administration approved Exelixis Inc’s cabozantinib on November 29, 2012 as a treatment for medullary thyroid cancer (MTC) that has spread to other parts of the body.

Chemical Structure of Cabozantinib L-Malate Salt (Cometriq) 

Name:Cabozantinib L-Malate;Cabozantinib S-Malate; XL 184; BMS907351
Chemical Name: N-(4-((6,7-Dimethoxyquinolin-4-yl)oxy)phenyl)-N-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide (2S)-2-Hydroxybutanedioic Acid
CAS Number: 1140909-48-3
Brand Name: Cometriq
Developer: Exelixis Inc(South San Francisco, California)
Approval Date: November 29th, 2012(US FDA)
Treatment for: Thyroid Cancer

Chemical Synthesis of Cabozantinib L-Malate Salt (Cometriq) 

Reference for the Preparation of Cabozantinib L-Malate

1)St Clair Brown, Adrian; Lamb, Peter; Gallagher, William P.; Preparation of malate salts of N-[4-[[6,7-bis(methyloxy)quinolin-4-yl]oxy]phenyl]-N’-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide and crystalline forms thereof for the treatment of cancer; PCT Int. Appl. (2010), WO 2010083414

2)Bannen, Lynne Canne; Chan, Diva Sze-ming; Chen, Jeff; Dalrymple, Lisa Esther; Forsyth, Timothy Patrick; Huynh, Tai Phat; Jammalamadaka, Vasu; Khoury, Richard George; Leahy, James William; Mac, Morrison B.;Preparation of quinolines and quinazolines as inhibitors of c-Met and other tyrosine kinases and therapeutic uses against proliferative diseases; PCT Int. Appl. (2005), WO 2005030140 A2

Synthesis Cabozantinib into two fragments, one clip from the dicarboxylic acid 1 starts, one-pot method carboxylic acid 1 and after conversion to the acid chloride-fluoroaniline ( 2 ) reaction of 3 , 3 with oxalyl chloride into the acid chloride 4 . Another fragment from the 5 and 6 obtained by condensation of 7 , 7 obtained in the reduction of the nitro 8 , 8 and 4 in alkaline conditions condensation Cabozantinib.