194423-06-8Relevant articles and documents
Tyrosine kinase inhibitors. 19. 6-alkynamides of 4-anilinoquinazolines and 4-anilinopyrido[3,4-d]pyrimidines as irreversible inhibitors of the erbB family of tyrosine kinase receptors
Klutchko, Sylvester R.,Zhou, Hairong,Winters, R. Thomas,Tran, Tuan P.,Bridges, Alexander J.,Althaus, Irene W.,Amato, Danielle M.,Elliott, William L.,Ellis, Paul A.,Meade, Mary Ann,Roberts, Billy J.,Fry, David W.,Gonzales, Andrea J.,Harvey, Patricia J.,Nelson, James M.,Sherwood, Veronica,Han, Hyo-Kyung,Pace, Gerry,Smaill, Jeff B.,Denny, William A.,Showalter, H. D. Hollis
, p. 1475 - 1485 (2007/10/03)
Structure-activity relationships for inhibition of erbB1, erbB2, and erbB4 were determined for a series of alkynamide analogues of quinazoline- and pyrido[3,4-ui]pyrimidine-based compounds. The compounds were prepared by coupling the appropriate 6-aminoquinazolines or 6-aminopyrido[3,4-d]pyrimidines with alkynoic acids, using EDCI·HCl in pyridine. The compounds showed pan-erbB enzyme inhibition but were on average about 10-fold more potent against erbB1 than against erbB2 and erbB4. For cellular inhibition, the nature of the alkylating side chains was an important determinant, with 5-dialkylamino-2- pentynamide type Michael acceptors providing the highest potency. This is suggested to be due to an improved ability of the amine to participate in an autocatalysis of the Michael reaction with enzyme cysteine residues. Pyrido[3,4-d]pyrimidine analogue 39 was selected for in vivo evaluation and achieved tumor regressions at 10 mg/kg in the A431 human epidermoid carcinoma and at 40 mg/kg for the SF767 human glioblastoma and the SKOV3 human ovarian carcinoma. Complete stasis was observed at 40 mg/kg in the BXPC3 human pancreatic carcinoma as well as in the H125 human non-small-cell lung carcinoma.
USE OF QUINAZOLINE COMPOUNDS FOR THE TREATMENT OF POLYCYSTIC KIDNEY DISEASE
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, (2008/06/13)
This invention provides a method of treating or inhibiting polycystic kidney disease in a mammal in need thereof which comprises administering to said mammal a compound having formula (1) wherein X is phenyl which is optionally substituted; R and R1 are each, independently, hydrogen, halogen, alkyl, alkoxy, hydroxy, or trifluoromethyl; R2 is hydrogen, alkyl, alkoxy, hydroxy, trifluoromethyl; Y is a radical selected from the group consisting of (a), (b), (c), (d), (e), (f) and (g); R3 is independently hydrogen, alkyl, carboxy, carboalkoxy, phenyl, or carboalkyl; n = 2-4; or a pharmaceutically acceptable salt thereof, with the proviso that each R3 of Y may be the same or different.
6-Substituted-4-(3-bromophenylamino)quinazolines as putative irreversible inhibitors of the epidermal growth factor receptor (EGFR) and human epidermal growth factor receptor (HER-2) tyrosine kinases with enhanced antitumor activity
Tsou,Mamuya,Johnson,Reich,Gruber,Ye,Nilakantan,Shen,Discafani,DeBlanc,Davis,Koehn,Greenberger,Wang,Wissner
, p. 2719 - 2734 (2007/10/03)
A series of new 6-substituted-4-(3-bromophenylamino)quinazoline derivatives that may function as irreversible inhibitors of epidermal growth factor receptor (EGFR) and human epidermal growth factor receptor (HER-2) tyrosine kinases have been prepared. These inhibitors have, at the C-6 position, butynamide, crotonamide, and methacrylamide Michael acceptors bearing water-solublilizing substituents. These compounds were prepared by acylation of 6-amino-4-(3-bromophenylamino)quinazoline with unsaturated acid chlorides or mixed anhydrides. We show that attaching a basic functional group onto the Michael acceptor results in greater reactivity, due to intramolecular catalysis of the Michael addition and/or an inductive effect of the protonated basic group. This, along with improved water solubility, results in compounds with enhanced biological properties. We present molecular modeling and experimental evidence that these inhibitors interact covalently with the target enzymes. One compound, 16a, was shown to have excellent oral activity in a human epidermoid carcinoma (A431) xenograft model in nude mice.