1140909-48-3

Usage

Uses

Used in Oncology:
Cabozantinib Malate is used as a potent multitargeted inhibitor for various receptor tyrosine kinases, including VEGFR2, Met, FLT3, Tie2, Kit, and Ret. It is particularly effective in inhibiting VEGFR2 with an IC50 of 0.035 nM and also demonstrates significant inhibition of c-Met, Ret, Kit, Flt-1/3/4, Tie2, and AXL with respective IC50 values of 1.3 nM, 4 nM, 4.6 nM, 12 nM/11.3 nM/6 nM, 14.3 nM, and 7 nM. This makes it a valuable agent in the treatment of various types of cancer, including progressive, metastatic, medullary thyroid cancer.
Used in Anticancer Drug Development:
Cabozantinib Malate is used as a research compound in the development of new anticancer drugs. Its multitargeted inhibition profile allows for the exploration of its potential synergistic effects when combined with other chemotherapeutic agents, potentially enhancing chemo-sensitivity and efficacy in resistant cases.
Used in Drug Delivery Systems:
Cabozantinib Malate can be utilized in the development of novel drug delivery systems to improve its bioavailability, delivery, and therapeutic outcomes. This may involve the use of various organic and metallic nanoparticles as carriers for targeted delivery to cancer cells, enhancing the overall effectiveness of the treatment.

Pharmacological effects

Cabozantinib S-MALATE，formerly known as XL184, trade name Cabometyx, is developed by Exelixis biopharmaceutical company in the United States. The drug is mainly targeted at MET and VEGFR2 tyrosine kinases that associated with the growth and proliferation of prostate cancer, inhibiting tumor metastasis and angiogenesis. Cabozantinib S-MALATE , the malate of Cabozantinib, is an effective VEGFR2 inhibitor, and IC50 is 0.035 nM. It also inhibits c-Met, Ret, Kit, Flt-1/3/4, Tie2 and AXL, and IC50 is 1.3 nM, 4 nM, 4.6 nM, 12 nM/11.3 nM/6 nM, 14.3 nM and 7 nM respectively. Cabozantinib(Cometriq) was granted orphan drug status by the U.S. Food and Drug Administration (FDA) in January 2011. Cabozantinib(Cometriq) is approved by the U.S. FDA for medullary thyroid cancer. and advanced renal cell carcinoma in people who have received prior anti-angiogenic therapy. It is currently undergoing clinical trials for the treatment of prostate, bladder, ovarian, brain, melanoma, breast, non-small cell lung, pancreatic, and hepatocellular cancers. Cabozantinib (S)-malate salt is a white to off-white solid that is practically insoluble in aqueous media.

Precautions

Cometriq has a boxed warning that increases the incidence of gastrointestinal perforation and fistula Formation and severe bleeding. If you have severe stomach pain, or if you feel that you are suffocating and vomiting while eating or drinking, call your doctor. Warnings and precautions include thrombosis events, Wound complications, hypertension, jaw osteonecrosis, palm-toe erythema paresthesia Syndrome (PPES), proteinuria and reversible posterior leukoencephalopathy syndrome (RPLS).

Biological Activity

cabozantinib malate is a potent inhibitor of met andvegf receptor2 with ic50 values of 1.3nm and 0.035nm [1].cabozantinib is a pan-tyrosine kinase inhibitor and is developed as an oral treatment of various cancers including mtc, gbm, nsclc, pancreatic carcinoma, breast and colon cancer. the targets of cabozantinib are met, vegfr-2, ret, flt3, kit, axl as well as tek. in cellular assays, cabozantinib inhibits the phosphorylation of met, vegfr2, kit, flt3 and axl with ic50 values of 7.8, 1.9, 5.0, 7.5 and 42μm, respectively [1, 2].as a pan-tyrosine kinase inhibitor, cabozantinib can affect many biological processes. cabozantinib inhibits the tubule formation of hmvec cells with ic50 value of 6.7nm. in b16f10 cells, cabozantinib inhibits hgf-inducedmigration and invasion with ic50 values of 31nm and 9nm, respectively. moreover, cabozantinib shows anti-proliferation efficacy in a variety of tumors such as snu-5, hs746t, mda-mb-231 and u87mg. it is also reported that the combination of cabozantinib and gefitinib can cause potent inhibition of the gefitinib-resistant hcc827gr6 cell line [1, 2].

Clinical Use

Cabozantinib (S)-malate (Cometriq?), which was discovered and developed by Exelixis, gained approval by the U.S. FDA in November 2012. The drug’s indication is for the treatment of medullary thyroid cancer (MTC), and is the second drug for this disease after AstraZeneca’s vandetanib (Caprelsa?). The drug was successfully launched on January 24, 2013. Cabozantinib inhibits multiple receptor tyrosine kinases including RET, MET, VEGFR-1, -2 and -3, KIT, TRKB, FLT-3, AXL, and TIE-2. It is currently also undergoing clinical trials for the treatment of prostate, ovarian, brain, melanoma, breast, non-small cell lung, pancreatic, hepatocellular and kidney cancers.

Synthesis

Of the three syntheses of cabozantinib reported, the kilo-gram scale process route is described in the scheme.The preparation began with 6,7-dimethoxy-quinoline-4-ol (46) which upon treatment with POCl3 provided chloride 47 in 70% yield. Exposure of 47 to 4-aminophenol under basic conditions using t- BuONa furnished diaryl ether 48 in 72% yield. This aniline was then coupled with amidoacid chloride 51 (which arose from the activation of commercial diacid 49 to the corresponding monochloride and coupling with p-fluoroaniline and subsequent exposure to oxalyl chloride to furnish the transient acid chloride) to construct cabozantinib as the free base 52 in 95% yield. Salt formation of cabozantinib 52 was carried out with (S)-malic acid, which ultimately delivered the final product of cabozantinib (S)- malate (VIII) in 75% yield.

references

[1] yakes f m, chen j, tan j, et al. cabozantinib (xl184), a novel met and vegfr2 inhibitor, simultaneously suppresses metastasis, angiogenesis, and tumor growth. molecular cancer therapeutics, 2011, 10(12): 2298-2308.[2] zhang y, guessous f, kofman a, et al. xl-184, a met, vegfr-2 and ret kinase inhibitor for the treatment of thyroid cancer, glioblastoma multiforme and nsclc. idrugs, 2010, 13(2): 112.

InChI:InChI=1S/C28H24FN3O5.C4H6O5/c1-35-24-15-21-22(16-25(24)36-2)30-14-11-23(21)37-20-9-7-19(8-10-20)32-27(34)28(12-13-28)26(33)31-18-5-3-17(29)4-6-18;5-2(4(8)9)1-3(6)7/h3-11,14-16H,12-13H2,1-2H3,(H,31,33)(H,32,34);2,5H,1H2,(H,6,7)(H,8,9)/t;2-/m.0/s1

Upstream product

• 190728-24-6 6,7?dimethoxy?4?(4?nitrophenoxy)quinoline 
• 97-67-6 (S)-Malic acid 
• 190728-25-7 4-((6,7-dimethoxyquinolin-4-yl)oxy)aniline 
• 123-30-8 4-amino-phenol 
• 113020-21-6 1,1-cyclopropanedicarboxylic acid monomethyl ester 
• 40258-99-9 1-(chlorocarbonyl)cyclopropane-1-carboxylic acid 
• 598-10-7 cyclopropane-1,1-dicarboxylic acid 
• 35654-56-9 6,7-dimethoxy-4-chloroquinoline 
• 13425-93-9 6,7-dimethoxyquinoline-4-ol 
• 849217-68-1 cabozantinib 

Downstream Products

• 849217-68-1 cabozantinib 

Relevant academic research and scientific papers

Preparation method of cabozantinib or salt thereof

The invention relates to a preparation method of cabozantinib or a salt thereof, which comprises the following steps: taking a compound shown as a formula I and 1-((4-fluorophenyl)carbamoyl)cyclopropanecarboxylic acid as raw materials, conducting reacting

POLYMORPHS OF N-(4-(6,7-DIMETHOXYQUINOLIN-4-YLOXY) PHENYL)-N'-(4-FLUOROPHENYL)CYCLOPROPANE-1, 1-DICARBOXAMIDE, (S)- MALATE, METHODS OF PRODUCTION AND PHARMACEUTICAL USES THEREOF

A novel crystalline forms of (N-(4-(6,7-dimethoxyquinolin-4-yloxy) phenyl)-N'-(4-fluorophenyl) cyclopropane-1, 1-dicarboxamide, (S)-malate, pharmaceutical compositions containing said crystalline forms and the use of said crystalline forms in the treatment of progressive, unresectable locally advanced or metastatic medullary thyroid carcinoma and advanced renal cell carcinoma (RCC) in people who have received prior anti-angiogenic therapy, are disclosed. The present invention is further directed to a process for the preparation of the novel crystalline forms.

Method of Treating Cancer and Bone Cancer Pain

This invention is directed to the treatment of cancer, particularly lung cancer, breast cancer, melanoma, renal cell carcinoma, thyroid cancer that has metastasized to the bone. The invention is also directed to a method for treating bone cancer pain in a

Method of Treating Cancer

This invention is directed to the treatment of cancer, particularly castration-resistant prostate cancer and osteoblastic bone metastases, with a dual inhibitor of MET and VEGF.

Preparation method of cabozantinib (S)-malate and intermediate thereof

The invention relates to a preparation method of cabozantinib (S)-malate and an intermediate thereof. The method includes: taking 4-chloro-6, 7-dimethoxyquinoline (I) as the starting raw material, andconducting substitution, condensation and salt formatio

A pharmaceutical salt for the nepali kind and its preparation method

The invention relates to novel crystal forms of L-malate and hydrobromide of an anti-cancer drug N-(4-{[6,7-bis(methoxy)quinoline-4-yl] oxo} phenyl)-N'-(4-fluorophenyl) cyclopropane-1,1-dicarboamide and a preparation method of the novel crystal forms. Pea

LIQUID DOSAGE FORMS TO TREAT CANCER

This invention relates to a liquid pharmaceutical composition comprising cabozantinib to treat locally advanced or metastatic solid tumors, particularly advanced urothelial cancer or renal cell carcinoma in patients in need thereof.

PROCESS FOR THE PREPARATION OF N-(4-(6,7-DIMETHOXYQUINOLIN-4-YLOXY) PHENYL)-N'-(4-FLUOROPHENYL)CYCLOPROPANE-1, 1-DICARBOXAMIDE, (2S)-HYDROXYBUTANEDIOATE AND ITS POLYMORPHS THEREOF

The present invention also relates to process for the preparation of N-(4-(6,7-dimethoxy quinolin-4-yloxy)phenyl)-N' -( 4-fluorophenyl)cyclopropane-1, 1-dicarboxamide (S)-malate compound of formula-1a and its polymorphs thereof, represented by the followi

Cabozantinib malate compound and medicine composition therewith

The invention provides a cabozantinib malate compound in a new crystal form and a preparation method thereof. The cabozantinib malate compound in the new crystal form has excellent stability and is free of significant changes on maximum single impurity content and maximum total impurity content at a high temperature (40 DEG C) under high humidity with light irradiation.

DRUG COMBINATIONS TO TREAT MULTIPLE MYELOMA

This invention relates to the combination of a C-Met inhibitor and a proteasome inhibitor to treat cancer, particularly multiple myeloma.