1374640-70-6

Basic information

• Product Name: CO-1686
• Synonyms: CO-1686;AVL-301;CNX-419;CO-1686 (AVL-301);CO-1686/CO1686;N-[3-[[2-[[4-(4-Acetyl-1-piperazinyl)-2-methoxyphenyl]amino]-5-(trifluoromethyl)-4-pyrimidinyl]amino]phenyl]-2-propenamide;Clovis CO-1686;CO-1686(free base)
• CAS NO: 1374640-70-6
• Molecular Formula: C₂₇H₂₈F₃N₇O₃
• Molecular Weight: 555.5515296
• EINECS: -0
• Product Categories: Inhibitors
• Mol File: 1374640-70-6.mol
• Article Data: 7

Chemical Properties

• Appearance: /
• Density: 1.372±0.06 g/cm3(Predicted)
• Storage Temp.: Amber Vial, -20°C Freezer, Under inert atmosphere
• Solubility: DMSO (Slightly), Methanol (Slightly)
• PKA: 13.23±0.70(Predicted)
• CAS DataBase Reference: CO-1686(CAS DataBase Reference)
• NIST Chemistry Reference: CO-1686(1374640-70-6)
• EPA Substance Registry System: CO-1686(1374640-70-6)

Safety Data

• Statements: 23-25-36
• Safety Statements: 24
• Hazardous Substances Data: 1374640-70-6(Hazardous Substances Data)

Usage

Anti-cancer drugs

On May 20, 2014, Clovis Oncology announced that the US FDA had granted its test drug CO-1686 for breakthrough treatment drug qualification, as a second line, single administrated drug for the treatment of EFGR mutation non-small cell lung cancer (NSCLC) of the T790M mutation patients. The awarding for this breakthrough therapeutic drug eligibility was based on the efficacy and safety results of Co-1686 in an ongoing Phase 1/2 study. Data of related study have shown that CO-1686 is a third-generation EGFR inhibitor, being used for the treatment of non-small cell lung cancer, overcoming the drug resistance generated from the EGFR T790M mutations, and has excellent efficacy and tolerability on NSCLC with T790M + EGFR mutations. Its major market competitor, the third-generation EGFR inhibitor, AZD9291 (AstraZeneca) has also gained FDA's groundbreaking drug eligibility. CO-1686 is a novel, oral-administrated, targeted covalent (irreversible) inhibitor of the epidermal growth factor receptor (EGFR) mutations, being able to suppress key activation mutations and T790 drug-resistant mutations, leaving the wild-type EGFR signal unused. This drug was developed for the treatment of NSCLC patients carrying initially activated EGFR mutations and major resistant mutant T790M. The above information is compiled and edited by Xiao Nan of lookchem.

Biological activity

Rociletinib (CO-1686, AVL-301) is an irreversible, mutation-selective EGFR inhibitor that targets EGFRL858R/T790M and EGFRWT with a Ki of 21.5 nM and 303.3 nM, respectively. Phase 2. Target: EGFR (L858R/T790M) EGFR (wt) IC50: 21.5 nM (Ki) 303.3 nM (Ki)

In vitro study

CO-1686 inhibited the p-EGFR in EGFR-expressing cells with an IC50 ranging from 62 to 187 nM while inhibiting EGFR phosphorylation. In three WT EGFR-expressing cells, the IC50 is larger than 2,000 nM. CO-1686 can selectively inhibit the growth of mutant EGFR expressing NSCLC cells with a GI50 ranging from 7 to 32 nM while inducing apoptosis. The CO-1686-resistant NSCLC cell line exhibited a signal for epithelial-mesenchymal transition and increased susceptibility to AKT inhibitors.

In vivo studies

In all EGFR mutant models, as well as in transgenic mice expressing human EGFRL858R-and EGFRL858R/T790M, CO-1686 caused significant tumor growth inhibition in a dose-dependent manner.

Synthesis method

5-fluoro-2-nitroanisole was condensed with piperazine, acetylated and reduced to give 1-(3-methoxy-4-aminophenyl)-4-acetylpiperazine (4) In addition, use 2, 4-dichloro-5-trifluoro methyl pyrimidine to undergo condensation with 3-nitroaniline, reduction and amidation to obtain N-[3-(2-Chloro-5-trifluoromethyl-pyrimidin-4-amino) phenyl] acrylamide (7). 4 and 7 were condensed to give the EGFR inhibitor, the anticancer drug CO-1686 with a total yield of about 71% (based on 2, 4-dichloro-5-trifluoromethyl pyrimidine). Reference: Synthesis of CO-1686 [J]. Chinese Pharmaceutical Industry, 2014, 45 (8): 710-713. OF: (1) Lai Yisheng, male, professor, doctoral supervisor, engaged in anti-inflammatory and anti-tumor drugs studied. (2) Zhang Shan, female, graduate students, professional direction: medicinal chemistry.

Description

CO-1686 is an irreversible kinase inhibitor that specifically targets mutant forms of the epidermal growth factor receptor (EGFR) including T790M (Ki = 21.5 nM) with significantly reduced activity at the wild-type form of the receptor (Ki = 303.3 nM). CO-1686 has been shown to inhibit the proliferation of non-small cell lung cancer (NSCLC) cells expressing mutant EGFR with GI50 values ranging from 7-32 nM in vitro, inducing apoptosis. It also demonstrates anti-tumor activity in NSCLC EGFR mutant xenograft and transgenic models dosed orally at 100 mg/kg/day.

Uses

CO 1686 is seen as an irreversible epidermal growth factor receptor (EFGR1) kinase inhibitor.

references

[1] walter a o, tjin r, haringsma h, et al. co-1686, an orally available, mutant-selective inhibitor of the epidermal growth factor receptor (egfr), causes tumor shrinkage in non-small cell lung cancer (nsclc) with t790m resistance mutations. mol cancer ther, 2011, 10(11 suppl).[2] walter a o, sjin r t t, haringsma h j. discovery of a mutant-selective covalent inhibitor of egfr that overcomes t790m-mediated resistance in nsclc.

Upstream product

• 54-20-6 5-trifluoromethyluracil 
• 7530-31-6 N-(4-Amino-phenyl)-acrylamide 
• 625-36-5 2-chloropropionyl chloride 
• 1021426-42-5 1-(4-{4-amino-3-methoxyphenyl}piperazine-1-yl)ethan-1-one 
• 13889-98-0 N-acetylpiperidine 
• 448-19-1 4-fluoro-2-methoxy-1-nitrobenzene 
• 814-68-6 acryloyl chloride 
• 16230-24-3 Ν-(3-aminophenyl)prop-2-enamide 
• 1116229-11-8 1-(4-{3-methoxy-4-nitrophenyl}piperazine-1-yl)ethan-1-one 
• 1374507-25-1 N-[3-[[2-chloro-5-(trifluoromethyl)pyrimidin-4-yl]amino]phenyl]prop-2-enamide 
• 1374507-24-0 N′-(2-chloro-5-(trifluoromethyl)pyrimidin-4-yl)phenyl-1,3-diamine 
• 1374507-23-9 tert-butyl (3-((2-chloro-5-(trifluoromethyl)pyrimidin-4-yl)amino)phenyl)aminocarboxylate 
• 3932-97-6 2,4-dichloro-5-trifluoromethylpyrimidine 
• 68621-88-5 (3-aminophenyl)carbamic acid tert-butyl ester 

Downstream Products

• 1446700-26-0 C₂₇H₂₈F₃N₇O₃*BrH 
• 1446700-26-0 C₂₇H₂₈F₃N₇O₃*2BrH 

Relevant articles and documents

Preparation method of epidermal growth factor receptor mutation inhibitor

The preparation method of the epidermal growth factor receptor mutation inhibitor comprises the following steps: (a) carrying out substitution reaction on a compound 1 and a compound 2 under the action of alkali and an organic solvent to obtain a compound 3; (b) carrying out substitution reaction on the compound 3 and a compound 4 under the action of alkali and an organic solvent to obtain a compound 5; (c) carrying out substitution reaction on the compound 5 and a compound 6 under the action of alkali and an organic solvent to obtain a compound 7; and (d) carrying out hydrolysis reaction on the compound 7 under the action of acid and an organic solvent to obtain the compound Rociletinib. According to the preparation method of the epidermal growth factor receptor mutation inhibitor, raw materials needed in each step are low in price and easy to purchase, the synthesis route is short, no isomer is generated, an intermediate is easy to separate and purify, column chromatography is not needed, and the obtained product is high in purity, high in atom utilization rate, high in yield, convenient to purify and safe and simple in reaction; the industrial production can be carried out.

Anti-cancer drug Rociletinib and preparation of intermediate thereof

The invention discloses an anti-cancer drug Rociletinib and preparation of an intermediate thereof. The preparation comprises the steps of dissolving a compound III into an organic solvent, reacting with a compound IIC under the catalytic action of concentrated hydrochloric acid, trifluoroacetic acid or p-toluenesulfonic acid to obtain a compound IV; performing a de-BOC protecting group reaction on the compound IV in a polar organic solvent under the action of an acid catalyst, so as to obtain an intermediate compound V; dissolving the compound V into the organic solvent, reacting with chloropropionylchloride fully, then obtaining a compound I under the action of organic alkali or inorganic alkali; the invention provides a new process of preparation of the intermediate Rociletinib, the obtained product is good in purity, high in quality, low in cost and is suitable for industrialized production. The formula is shown in the description.

SALTS OF AN EPIDERMAL GROWTH FACTOR RECEPTOR KINASE INHIBITOR

The present invention provides a salt form and compositions thereof, which are useful as an inhibitor of EGFR kinases and which exhibits desirable characteristics for the same. Examples include hydrobromide and bis-besylate salts of N-(3-(2-(4-(4-acerylpiperazin-1-yl)-2-methoxyphenylamino)-5-(trifluoromethyl)pyrimidin-4-ylamino)phenyl)acrylamide). The salts and their polymorphs are evaluated for their properties such as stability, solubility, and pharmacokinetics.