Osimertinib mesylate Chemical Properties

Melting point:

>232°C (dec.)

storage temp. 

-20°C Freezer, Under inert atmosphere

solubility 

DMSO (Slightly), Methanol (Slightly)

form 

Solid

color 

Off-White to Yellow

InChI

InChI=1S/C28H33N7O2.CH4O3S/c1-7-27(36)30-22-16-23(26(37-6)17-25(22)34(4)15-14-33(2)3)32-28-29-13-12-21(31-28)20-18-35(5)24-11-9-8-10-19(20)24;1-5(2,3)4/h7-13,16-18H,1,14-15H2,2-6H3,(H,30,36)(H,29,31,32);1H3,(H,2,3,4)

InChIKey

FUKSNUHSJBTCFJ-UHFFFAOYSA-N

SMILES

S(O)(=O)(=O)C.CN1C2=CC=CC=C2C(C2C=CN=C(NC3C=C(NC(=O)C=C)C(N(C)CCN(C)C)=CC=3OC)N=2)=C1

Safety Information

HS Code 

29339900

Osimertinib mesylate Usage And Synthesis

Description

Osimertinib is active against exon 19 deletions, exon 21 mutations, and also the exon 20 T790M mutations. It is preferentially selective for mutated EGFR, and therefore toxicity at therapeutic doses is lower than for first- and second-generation agents. Notably, osimertinib is able to cross the blood-brain barrier, making it active against disease in the CNS.

Uses

Osimertinib mesylate (AZD9291) is the mesylate form of osimertinib, which is an oral, third-generation epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI) drug.

Application

Osimertinib mesylate is approved to treat: Non-small cell lung cancer that has certain EGFR gene mutations. It is used in adults: As adjuvant therapy after surgery to remove the cancer; As the first therapy for cancer that has spread to other parts of the body, or in patients whose cancer has spread to other parts of the body and got worse during or after treatment with another EGFR tyrosine kinase inhibitor.

Definition

ChEBI: A methanesulfonate (mesylate) salt prepared from equimolar amounts of osimertinib and methanesulfonic acid. Used for treatment of EGFR T790M mutation positive non-small cell lung cancer.

Indications

The collection of ibrutinib (Imbruvica(R), Pharmacyclics Inc.), afatinib, and osimertinib represents the small, yet expanding, group of covalent SMKIs. Ibrutinib is a non-receptor Bruton’s tyrosine kinase inhibitor approved for the treatment of relapsed chronic lymphocytic leukemia. Afatinib, approved for NSCLC in 2013 and squamous NSCLC in 2016, is a second-generation irreversible EGFR inhibitor that targets wild-type EGFR, the mutant T790M EGFR, and HER2. Osimertinib (AZD9291), which was approved by FDA in November 2015, is a third-generation irreversible EGFR inhibitor that selectively targets the mutant T790M EGFR. Rociletinib, which shares a high degree of structural similarity with that of osimertinib, is a promising covalent EGFR inhibitor developed by Clovis Oncology aimed for the treatment of patients with EGFR T790M-mutated NSCLC, until the company terminated its development in May 2016 following a negative vote fromthe FDA’sOncologic Drugs Advisory Committee.

brand name

Tagrisso^TM

General Description

Class: receptor tyrosine kinase
Treatment: NSCLC
Oral bioavailability = 70%
Elimination half-life = 48 h
Protein binding = 94.7%

Side effects

Osimertinib toxicity is dose-dependent and is associated with fewer gastrointestinal and dermatologic adverse events than with other approved EGFR TKIs.

Synthesis

Friedel-Crafts arylation of commercial N-methylindole (203) with commercial dichloropyrimidine 202 gave the 3- pyrazinyl indole 204 in good yield. Subsequent SNAr with nitroaniline 205 (available from a one-step nitration from the commercially available des-nitroaniline) provided aminopyrazine 206. Next, SN Ar reaction of 206 with N,N,N??- trimethylated ethylenediamine delivered 207 in near quantitative yield, and this was followed by nitro reduction with iron under acidic conditions to give rise to the triaminated arene 208 in 85% yield. Because acrylates are notoriously difficult to install directly due to their highly reactive nature and propensity to polymerize, a clever two-step acylation/ elimination sequence was employed using 3-chloropropanoyl chloride, and this was immediately followed by mesylate salt formation, which furnished the osimertinib mesylate (XXVI) in excellent yield. This seven-step process which derives from readily available feedstock delivered the final product in nearly 57% overall yield from starting materials 202 and 203.

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