K. Matsuno et al. / Bioorg. Med. Chem. Lett. 13 (2003) 3001–3004
3003
moderate activity, whereas the benzylthiourea analogue
3b was devoid of any activity (ꢀ100-fold), despite the
difference of activity for the corresponding 6,7-dime-
thoxy analogues (1a and 1b) was approximately 10-fold.
This discrepancy of activity indicates distinct SAR and
it is unsuitable for assessing possibility to find a optimal
replacement for the 6,7-dimethoxyquinazoline moiety,
therefore we investigated the effect on combination of
substituents on the quinazoline ring and N-substituted
(thio)urea moiety for several potent analogues.
(6c), and morpholine (6d) to 6,7-dimethoxyquinazoline
also completely eliminated activity. Therefore, 6,7-
dialkoxysubstitution on the quinazoline ring was
optimal for the potent activity.
The 4-anilino-6,7-dimethoxyquinazolines are well-
known as potent EGF receptor (EGFR) tyrosine kinase
inhibitors by several groups.20À22 The observed SARs
with PDGFR and EGFR are almost similar. Both
receptors preferred 6,7-dimethoxy and 6,7-diethoxy
substitution and disfavoured 2-substitution and 8-sub-
stitution on quinazoline ring. These results indicate
some clues for future understanding of the difference in
interaction between PDGFR and EGFR with their
inhibitors.
With regard to the quinazoline analogues with one sub-
stituent (compounds 4 series), 7-Me (4j) and 7-Cl (4k)
enhanced activity comparing the unsubstituted quina-
zoline analogues (3a and 3b); however the activity was
weaker than corresponding initial dimethoxy analogues
1a and 1b, respectively. Other substitution (4a–4i, 4l–4o)
led to the retention or reduction in activity. Among
methyl analogues, 7-Me (4j) with potent activity and 6-
Me (4c) with moderate activity were observed, 5-Me
analogue (4a) was a weak inhibitor. Among MeO-sub-
stituted analogues (4b, 4h, 4o), the order of potency is 6-
position=7-position»5-position. NO2 analogues also
showed similar SAR to methyl analogues, with 7-sub-
stitution (4l) being more potent than 6-substitution (4g);
however, nitro group itself has a large detrimental effect
for activity. Regarding the class of substituents, bulki-
ness had a negative effect for halogen analogues (4d–4f);
however for alkoxy analogues (4h–4i) it had a relatively
negligible effect on activity. Furthermore, 7-COOMe
analogue (4m) showed modest activity, whereas 7-
COOH analogue (4n) was inactive, suggesting that the
polar substitution was not suitable, presumably due to
low cellular penetration because of the whole cell assay.
In summary, we investigated the SARs for position and
variety of the substituents on quinazoline ring. 6,7-Dial-
koxy substitution was optimal and further modifications
of these substituents could be possible.
Acknowledgements
The technical assistance of Ms. Kumi Aoki, Miyuki
Akimoto and Chika Okitsu is acknowledged. The
authors gratefully appreciate Mrs. Yumiko Aono for
her excellent technical assistance in chemical synthesis.
References and Notes
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Further addition of substituent on 6,7-dimethoxy-
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