P. W. Manley et al. / Bioorg. Med. Chem. Lett. 14 (2004) 5793–5797
5797
alternative pharmacophore elements and, that it is pos-
sible to identify compounds based upon this scaffold,
which differentiate between the Abl and PDGFR kin-
ases. Although in this series of ureas, potent inhibitors
of recombinant c-Abl were identified, the cellular activ-
ity against Bcr-Abl kinase was lower by a factor of P10-
fold. The reason for this discrepancy is unclear.
Although a number of the ureas were potent inhibitors
of PDGFR and c-Kit kinases, their pharmacokinetic
profiles were unattractive and they were not developed
further.
(br s, 1H), 7.94 (dd, J = 8.1Hz, J = 5.4Hz, 1H), 8.29 (m,
H), 8.60 (d, J = 5.1Hz, 1H), 8.92 (d, J = 5.4Hz, 1H), 8.95
2
(
(
d, J = 8.1Hz, 1H), 9.16 (br s, 1H), 9.40 (m, 1H) and 10.47
br s, 1H).
1
2. As a typical example, urea 18 was prepared as follows: 3-
Amino-N,N-dimethylaniline dihydrochloride (0.287g,
1.375mmol) and triethylamine (0.87mL, 6.25mmol) was
added to a stirred mixture of 5 (0.6g, 1.25mmol) in DMF
(
5mL). After stirring for 4hat 40 °C, the solvent was
evaporated off under reduced pressure and the residue was
treated withaqueous 1N NaOH and extracted with
2 2 2 4
CH Cl . The combined extracts were dried (Na SO )
and the solvent was evaporated off to give a residue, which
was chromatographed (silica gel; CH Cl –MeOH) to
2
2
afford 18 as a yellow crystalline solid (323mg, 59% yield):
mp 229–231°C; NMR (DMSO-d ) d 2.18 (s, 3H), 2.84 (s,
H), 6.32 (dd, J = 8.3, J = 2.4Hz, 1H), 6.67 (dd,
J = 7.9Hz, J = 1.2Hz, 1H), 6.91 (t, J = 2.1Hz, 1H), 7.02
t, J = 8.1Hz, 1H), 7.09 (s, 2H), 7.40 (d, J = 5.2Hz, 1H),
.49 (dd, J = 8.0Hz, J = 4.7Hz, 1H), 7.76 (br s, 1H), 8.45–
Acknowledgements
6
6
We thank P. Fille, G. Goutte, Hj. Haas and D. Kempf
for technical assistance and James D. Griffin (Dana-
Faber Cancer Centre, Boston, MA) for supplying the
murine 32D cells, Brian Druker, (Oregon Health
Sciences University, Portland, Oregon) for the A31 cells
and Jonathan Fletcher (Brigham & WomenÕs Hospital,
Boston, MA) for the GIST cells.
(
7
8.52 (m, 4H), 8.65 (dd, J = 4.8Hz, J = 1.6Hz, 1H), 8.89
(br s, 1H) and 9.24 (dd, J = 2.3Hz, J = 0.7Hz, 1H). Anal.
25 7
(C25H N O) C, H, N.
3. Geissler, J. F.; Roesel, J. L.; Meyer, T.; Trinks, U. P.;
Traxler, P.; Lydon, N. B. Cancer Res. 1992, 52, 4492–
4498.
4. Bhat, A.; Kolibaba, K.; Oda, T.; Ohno-Jones, S.; Heaney,
1
1
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6
23. The compounds were also evaluated against the third
target of STI571, c-Kit, in GIST882 cells (derived from a
human gastrointestinal stromal tumor and which express a
c-Kit isoform carrying a mutation within Exon 13 leading
to constitutive activation of the receptor kinase). In terms
7
. Manning, G.; Whyte, D. B.; Martinez, R.; Hunter, T.;
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of activity (mean IC50, n P 3) only compounds 6
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(560nM), 16 (80nM), 17 (411nM), 18 (93nM), 19
(180nM) and 23 (108nM), showed significant activity at
concentrations below 2lM (STI571: IC50 96 ± 12nM;
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1. The pivotal urethane 5 was prepared as follows: The
amine 4 (1.0g, 3.61mmol) was added to a stirred solution
of 4-nitrophenylchloroformate (0.87g, 4.32mmol) in
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31663.
1
CH
2
Cl
2
(26mL) at 0°C over 30min. After stirring for 2h
at room temperature, the precipitate was filtered off,
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washed with CH Cl and dried to yield the HCl salt 5
2
2
(
1.5g, 86% yield) as an orange powder: NMR (DMSO-d
6
)
27. Ertl, P.; Rohde, B.; Selzer, P. J. Med. Chem. 2000, 43,
3714–3717.
d 2.21 (s, 3H), 7.19–7.24 (m, 2H), 7.53–7.57 (m, 3H), 7.90