1233953-83-7

Upstream product

• 848133-74-4 3-(4-acetamido-3-ethoxyaniline)-2-cyanopropenoic acid ethyl ester 
• 848133-76-6 7-ethoxy-6-acetylamino-4-chloro-quinoline-3-carbonitrile 
• 524955-09-7 3-chloro-4-(2-pyridylmethoxy)aniline 
• 848655-78-7 4-acetamido-3-ethoxyaniline 
• 121-88-0 5-Nitro-2-aminophenol 
• 6959-47-3 2-chloromethylpyridine hydrochloride 
• 116496-76-5 4-acetamido-3-ethoxynitrobenzene 
• 25351-89-7 N-(2-hydroxy-4-nitrophenyl)acetamide 
• 3964-52-1 2-chloro 4-aminophenol 
• 915941-95-6 N-(4-[3-chloro-4-(pyridin-2-ylmethoxy)phenylamino]-3-cyano-7-ethoxyquinoline-6-yl)acetamide 
• 848139-78-6 6-amino-4-[[3-chloro-4-(pyridin-2-ylmethoxy)phenyl]amino]-7-ethoxyquinoline-3-carbonitrile 
• 1201080-09-2 N-(3-cyano-7-ethoxy-4-oxo-1,4-dihydroquinolin-6-yl)acetamide 
• 110-89-4 piperidine 
• 1233953-82-6 3-chloro-N-(4-(3-chloro-4-(pyridin-2-ylmethoxy)anilino)-3-cyano-7-ethoxyquinolin-6-yl)propanamide 

Relevant academic research and scientific papers

Irreversible inhibition of epidermal growth factor receptor activity by 3-aminopropanamides

Irreversible epidermal growth factor receptor (EGFR) inhibitors contain a reactive warhead which covalently interacts with a conserved cysteine residue in the kinase domain. The acrylamide fragment, a commonly employed warhead, effectively alkylates Cys797 of EGFR, but its reactivity can cause rapid metabolic deactivation or nonspecific reactions with off-targets. We describe here a new series of irreversible inhibitors containing a 3-aminopropanamide linked in position 6 to 4-anilinoquinazoline or 4-anilinoquinoline-3- carbonitrile driving portions. Some of these compounds proved to be as efficient as their acrylamide analogues in inhibiting EGFR-TK (TK = tyrosine kinase) autophosphorylation in A549 lung cancer cells. Moreover, several 3-aminopropanamides suppressed proliferation of gefitinib-resistant H1975 cells, harboring the T790M mutation in EGFR, at significantly lower concentrations than did gefitinib. A prototypical compound, N-(4-(3-bromoanilino)quinazolin-6- yl)-3-(dimethylamino)propanamide (5), did not show covalent binding to cell-free EGFR-TK in a fluorescence assay, while it underwent selective activation in the intracellular environment, releasing an acrylamide derivative which can react with thiol groups.

IRREVERSIBLE EGFR INHIBITOR COMPOUNDS WITH ANTIPROLIFERATIVE ACTIVITY

The invention concerns a derivative of Formule (VII) wherein R27, R28 are, independently of each other, hydrogen, (C1-C6)alkyl, (CH2)n- COOR33, (CH2)n-CONR33R34, (CH2)n-NR33R34 or (CH2)n-morpholine; or NR27R28 is — N N-R27 selected from morpholine, piperidine and Formula (VIII), where R33, R34 are, independently, hydrogen or (C1-C6)alkyl; R29 is hydrogen or (C1-C6)alkyl; R30 is hydrogen or -OR35, where R35 is (C1-C6)alkyl, (CH2)n-NR33R34 or (CH2)n-piperidine or (CH2)n-morpholine, where R33, R34 are, independently, hydrogen or (C1-C6)alkyl; Y is a nitrogen atom or a carbon atom substituted by a cyano group; R31 and R32 are, independently of each other, hydrogen, bromine, chlorine, fluorine, ethinyl or methyl; X is hydrogen, bromine, chlorine, fluorine or -O(CH2)n-Q; Q is an aryl or heteroaryl group, optionally substituted by one or more substituents selected, independently of each other, from hydrogen, chlorine, fluorine, the CF3 radical or - NO2; n is a whole number selected from 0, 1, 2, 3, 4, 5, or 6. The derivatives of the invention are used as irreversible EGFR inhibitors with antiproliferative activity.