1404
S. Cockerill et al. / Bioorg. Med. Chem. Lett. 11 (2001) 1401–1405
from 6-chloronicotinic acid (Scheme 1). Curtius rearrange-
ment and ortholithiation of the Boc-amine 4 allowed a
facile preparation of the anthranilic acid equivalent 5.
Reaction with formamidine acetate furnished the chloro-
pyridopyrimidinone 6. Chlorination and aniline intro-
duction in acetonitrile to give 8 could be followed by
reaction with dimethylamine to give 9 (GW974 where
NHAr is 12). Alternatively, in order to allow efficient
parallel synthesis of the analogues described herein,
chloropyridopyrimidinone 6 could be reacted with
dimethylamine to furnish the dimethylaminopyridopyr-
imidinone 7. Subsequent chlorination could then be
followed by parallel introduction of a variety of anilines.
Synthesis of aniline top halves was straightforward as
exemplified in Scheme 2 for the N-benzyl indazolyl-
amine 12. Alkylation of the nitro bicycle (5-nitroindazole
shown) was followed by hydrogenation. In the cases of
anilines required for B, C, D and F in Figure 3, these
were prepared as mixtures and separated by flash chro-
matography. Indazole aniline B could also be isolated
free of the 2 regioisomer by an acetone–water recry-
stallisation in 30% yield from the 5-nitroindazole. 2-
Benzyl benzimidazole aniline for E in Figure 3 was pre-
pared by known methods.11
Summary
Described herein is the identification and evaluation of
GW974, a potent inhibitor of the tyrosine kinase activ-
ity of EGFr/c-erbB-2. This in vitro potency transcribed
to in vivo potency in xenografts overexpressing both
receptor kinases. At higher doses in the BT474 xeno-
graft, tumour shrinkage was observed and found to be
irreversible, that is no regrowth of tumours was
observed upon cessation of dosing. GW974 represents
valuable progress in the identification of combined
EGFr/c-erbB-2 inhibitors as an approach to cancer
chemotherapy with low toxicity.
References and Notes
1. (a) ONKOS reports. Based on seven country prevalence/
incidence data (France, Germany, Spain, Italy, Japan, UK,
USA). (b) Slamon, D. J.; Clark, G. M.; Wong, S. G. Science
1987, 235, 177. Macias, A.; Azavedo, E.; Hagerstrom, T.
Anticancer Res. 1987, 7, 459.
Scheme 1. (1) (PhO)2PON3, Et3N, tert-BuOH, Á, 83%; (2) (i) n-BuLi,
TMEDA, toluene,À60 to À15; (ii) CO2, 65%; (iii) aq NaOH, 85%;
(3) formamidine acetate, AcOH, 79%; (4) aq Me2NH, EtOH, MeCN,
90%; (5) (i) POCl3, Et3N, 90%; (ii) ArNH2, MeCN, Á, 60–90%;
(6) aq. Me2NH, EtOH, MeCN, 90%; (7) (i) POCl3, Et3N, 90%;
(ii) ArNH2, MeCN, Á, 60–90%.
2. (a) For a recent review of progress in this area, see:
Noonberg, S. B.; Benz, C. C. Drugs 2000, 59, 753. (b)
Bonomi, P.; Perez-Soler, R.; Chachoua, A.; Huberman, M.;
Karp, D.; Rigas, J.; Hammond, L.; Rowinsky, E.; Preston,
G.; Ferrante, K. J.; Allen, L. F.; Proceedings of the 11th
NCI-EORTC-AACR Symposium, Amsterdam, 2000. Goss,
G.; Lorimer, L.; Miller, W.; Hirte, H.; Stewart, D.; Batiste,
G.; Mathews, S.; Averbuch, S.; Seymour, L.; Proceedings of the
11th NCI-EORTC-AACR Symposium, Amsterdam, 2000.
3. Barker, A. J. Davies, J. H. Eur. Patent, 520,722, 1994.
4. Woodburn, J. R.; Barker, A. J.; Gibson, K. H. Abstract
4251, Proceedings of the 88th Annual Meeting of the Amer-
ican Association for Cancer Research, San Diego CA, Apr
12–16, 1997.
5. Shewchuk, L.; Hassell, A.; Wisely, B.; Rocque, W.;
Holmes, W.; Veal, J.; Kuyper, L. F. J. Med. Chem. 2000, 43,
133.
6. Bridges, J.; Zhou, H.; Cody, D. R.; Rewcastle, G. W.;
McMichael, A.; Showalter, H. D. H.; Fry, D. W.; Kraker,
A. J.; Denny, W. A. J. Med. Chem. 1996, 39, 267.
7. Rewcastle, G. W.; Palmer, B. D.; Thompson, A. M.;
Bridges, A. J.; Cody, D. R.; Zhou, H.; Fry, D. W.; McMichael,
A.; Kraker, A. J.; Denny, W. A. J. Med. Chem. 1996, 39, 1823.
8. 7-Substituted quinazolines and pyridopyrimidines have
Scheme 2. (1) K2CO3, benzyl bromide followed by aq acetone recry-
stallisation, 30%; (2) H2, Pd/C, 95%.