Design of EGFR Tyrosine Kinase Inhibitors
J ournal of Medicinal Chemistry, 1999, Vol. 42, No. 6 1025
116.4 (s,), 108.3 (s), 96.7 (d), 89.9 (d), 55.4 (q); EIMS m/z 301
at 80 °C and extracted with dichloromethane. The organic
phase was washed with 1 M NaOH, dried, and evaporated to
yield 8.4 g of a yellow oil, which consisted of a mixture of
product 16 and residual 3-chlorobenzyl cyanide, which could
not be separated. The crude product was used for the next step
without further purification: 1H NMR (CDCl3) δ 7.79 (dd, 1H),
7.38-7.10 (m, 5H), 6.69-6.62 (m, 2H), 6.3 (brs, 1H); GCMS
m/z 245 (M+).
(M+). Anal. (C16H12ClNO3) C, H, N, O.
3-(3-Ch lor oph en yl)-5,7-dih ydr oxy-4(1H)-qu in olon e (12).
An amount of 0.02 mL (1.03 mmol) of boron tribromide was
added to a suspension of 81.5 mg (0.27 mmol) of the quinolone
11 in 10 mL of toluene and refluxed for 18 h. The dark-brown
suspension was cooled to 0 °C and methanol added. The
solution was evaporated and the residue triturated with
diethyl ether, which was removed by decantation leaving a
crude brown residue. Purification by flash chromatography
(toluene/ethyl acetate, 6:4) gave 11.7 mg (15.5% yield) of 12
as a yellow solid: mp 145-147 °C; 1H NMR (DMSO-d6) δ 14.70
(s, 1H), 12.26 (d, 1H), 10.32 (s, 1H), 8.16 (d, 1H), 7.79 (t, 1H),
7.66-7.60 (m, 1H), 7.46-7.25 (m, 2H), 6.35 (d, 1H), 6.06 (d,
1H); 13C NMR (DMSO-d6) 178.7, 163.0, 162.4, 141.6, 139.3,
137.0, 132.6, 129.7, 128.0, 126.8, 126.3, 115.9, 107.4, 97.8, 91.7;
EIMS m/z 287 (M+), corresponding to C15H10ClNO3.
3-(3-Ch lor op h en yl)-4(1H)-qu in olon e (17). To the mixture
of the ketone 16 and 3-chlorobenzyl cyanide (2.77 g, 4.76 mmol)
was carefully added boron trifluoride etherate (4.16 mL, 33.1
mmol). Methanesulfonyl chloride (1.28 mL, 16.6 mmol) was
added, and the reaction mixture was heated to 80 °C for 3 h
and then poured onto 1 M NaOH. The precipitate so formed
was collected by filtration, washed with water and toluene,
dispersed in hot hexane, filtered, and dried in vacuo to yield
717.4 mg of crude product. This was adsorbed on silica gel,
which then was washed with toluene/ethyl acetate (3:2) for
removal of the starting materials. Desorption of 17 was
achieved by refluxing the silica gel with ethyl acetate. The
adsorbent was removed by filtration and the filtrate dried and
evaporated. The residue obtained was washed with acetone
to give 310 mg (21% yield) of quinolone 17 as a white powder:
mp 300-301 °C; 1H NMR (DMSO-d6) δ 12.1 (brs, 1H), 8.28 (s,
1H), 8.23 (d, 1H), 7.92 (t, 1H), 7.74-7.59 (m, 3H), 7.47-7.30
(m, 3H); 13C NMR (DMSO-d6) 174.5 (e), 139.2 (e), 138.7 (o),
138.3 (e), 132.5 (e), 131.8 (o), 129.6 (o), 127.9 (o), 126.6 (o),
126.1 (o), 125.9 (e), 125.6 (o), 123.5 (o), 118.3 (o), 117.9 (e);
EIMS m/z 255 (M+). Anal. (C15H10ClNO) C, H, N, O.
3-(3-Ch lor op h en yl)-5-h yd r oxy-7-m et h oxy-N-m et h yl-
4(1H)-qu in olon e (13). An amount of 0.123 g (0.41 mmol) of
3-(3-chlorophenyl)-5-hydroxy-7-methoxy-4(1H)-quinolone (11)
was dissolved in 4 mL of DMF. Then 0.03 mL (0.48 mmol) of
methyl iodide and 0.1 g (1 mmol) of potassium carbonate were
added. The reaction mixture was stirred at room temperature
for 30 min, poured into water, and extracted with ethyl acetate.
The organic phase was dried and the solvent removed in vacuo
to yield 0.12 g (93% yield) of a yellow solid. Crystallization
from toluene gave 13 as fine yellow needles: mp 177.4-183.0
1
°C; H NMR (DMSO-d6) δ 15.27 (s, 1H), 8.40 (s, 1H), 7.80 (t,
1H), 7.70-7.66 (m, 1H), 7.46-7.37 (m, 2H), 6.45 (d, 1H), 6.33
(d, 1H), 3.88 (s, 3H), 3.85 (s, 3H); 13C NMR (DMSO-d6) 178.1
(e), 163.9 (e), 163.9 (e), 145.1 (o), 141.9 (e), 136.5 (e), 132.7 (e),
129.7 (o), 127.9 (o), 126.8 (o), 126.5 (o), 116.1 (e), 108.3 (e),
96.9 (o), 89.7 (o), 55.6 (o), 41.0 (o); EIMS m/z 315 (M+). Anal.
(C17H14ClNO3) C, H, N, O.
Ack n ow led gm en t. We gratefully acknowledge the
contributions of Andreas Wicki and Roland K. Sigel for
the synthesis of compounds 5a , 9, 16, and 17 and the
excellent technical assistance of B. Adam, U. Duerler,
I. Oberkirch, R. Reuter, and R. Roth.
3-(3-Ch lor op h en yl)-5-h yd r oxy-7-m eth oxy-N-(2-p h en yl-
eth yl)-4(1H)-qu in olon e (14). Quinolone 11 (60 mg, 0.198
mmol) was dissolved in 5 mL of DMF. Then, 0.1 mL (0.74
mmol) of 2-phenylethyl bromide and 0.1 g (1 mmol) of potas-
sium carbonate were added. The reaction mixture was stirred
at room temperature for 17 h, then poured into water and
extracted with ethyl acetate. The organic phase was dried and
the solvent removed in vacuo to yield 74 mg of a yellow oil.
Purification by flash chromatography (toluene/ethyl acetate,
9:1) and crystallzation from toluene gave 43 mg (63% yield) of
14 (mp 142.6-144.5 °C) in the form of yellow needles: 1H NMR
(CDCl3) δ 15.11 (s, 1H), 7.34-7.02 (m, 10H), 6.38 (d, 1H), 6.31
(d, 1H), 4.27 (t, 2H), 3.88 (s, 3H), 3.14 (t, 2H); 13C NMR (CDCl3)
179.2 (e), 165.7 (e), 164.6 (e), 142.8 (o), 140.9 (e), 136.9 (e),
135.9 (e), 134.0 (e), 129.3 (o), 129.2 (o, 2 C), 129.0 (o, 2 C),
128.4 (o), 127.6 (o), 127.1, 126.8 (o), 125.3 (o), 118.1 (e), 109.2
(e), 96.4 (o), 89.7 (o), 55.6 (o), 55.5 (e), 34.3 (e); EIMS m/z 405
(M+). Anal. (C24H20ClNO3) C, H, N, O.
Met h yl [3-(3-Ch lor op h en yl)-5-h yd r oxy-7-m et h oxy-4-
oxo-4H-qu in olin -1-yl]a ceta te (15). Prepared in analogy to
13 and 14. From 0.1 g (0.332 mmol) of the quinolone 11 and
0.032 mL (0.332 mmol) of bromoacetic acid methyl ester, 69
mg (52% yield) of 15 was obtained as yellow needles: mp
151.4-156.5 °C (crystallization from toluene); 1H NMR (CDCl3)
δ 14.82 (s, 1H), 7.57-7.40 (m, 3H), 7.22-7.32 (m, 2H), 6.33
(d, 1H), 5.97 (d, 1H), 4.72 (s, 2H), 3.82 (s, 3H), 3.80 (s, 3H);
13C NMR (CDCl3) 179.6 (e), 167.3 (e), 165.2 (e), 164.7 (e), 142.8
(o), 141.6 (e), 135.6 (e), 134.1 (e), 129.5 (o), 128.5 (o), 127.5 (o),
126.8 (o), 119.4 (e), 108.8 (e), 96.7 (o), 89.4 (o), 55.6 (o), 54.4
(e), 53.2 (o); EIMS m/z 373 (M+). Anal. (C19H16ClNO5) C, H,
N, O.
Refer en ces
(1) Aaronson, S. A. Growth Factors and Cancer. Science 1991, 254,
1146-1152.
(2) Fry, D. W.; Kraker, A. J .; Conners, R. C.; Elliott, W. L.; Nelson,
J . M.; Showalter, H. D.; Leopold, W. R. Strategies for the
discovery of novel tyrosine kinase inhibitors with anticancer
activity. Anti-Cancer Drug Des. 1994, 9, 331-351.
(3) Levitzki, A.; Gazit, A. Tyrosine Kinase Inhibition: An Approach
to Drug Development. Science 1995, 267, 1782-88.
(4) Ullrich, A.; Schlessinger, J . Signal Transduction by Receptors
with Tyrosine Kinase Activity. Cell 1990, 61, 203-212.
(5) Elder, J . T.; Fisher, G. J .; Lindquist, P. B.; Bennett, G. L.;
Pittelkow, M. R.; Coffey, R. J .; Ellingsworth, L.; Derynck, R.;
Voorhees, J . J . Overexpression of transforming growth factor R
in psoriatic epidermis. Science 1989, 243, 811-814.
(6) Fry, D. W. Protein tyrosine kinases as therapeutic targets in
cancer chemotherapy and recent advances in the development
of new inhibitors. Exp. Opin. Invest. Drugs 1994, 3, 577-595.
(7) Traxler, P.; Lydon, N. Recent Advances in Protein Tyrosine
Kinase Inhibitors. Drugs Future 1995, 20, 1261-1274.
(8) Spada, A. P.; Myers, M. R. Small molecule inhibitors of tyrosine
kinase activity. Exp. Opin. Ther. Patents 1995, 5, 805-817.
(9) Bridges, A. J . The current status of tyrosine kinase inhibitors:
do the diarylamine inhibitors of the EGF receptor represent a
new beginning? Exp. Opin. Ther. Patents 1995, 5, 1245-1257.
(10) Traxler, P. Protein tyrosine kinase inhibitors in cancer treat-
ment. Exp. Opin. Ther. Patents 1997, 7, 571-588.
(11) Ward, W. H. J .; Cook, P. N.; Slater, A. M.; Davies, D. H.;
Holdgate, G. A.; Green, L. R. Epidermal growth factor receptor
tyrosine kinase. Investigation of catalytic mechanism, structure-
based searching and discovery of a potent inhibitor. Biochem.
Pharmacol. 1994, 48, 659-666.
(12) Fry, D. W.; Kraker, A. J .; McMichael, A.; Ambroso, L. A.; Nelson,
J . M.; Leopold, W. R.; Connors, R. W.; Bridges, A. J . A Specific
Inhibitor of the Epidermal Growth Factor Receptor Tyrosine
Kinase. Science 1994, 265, 1093-1095.
(13) Rewcastle, G. W.; Denny, W. A.; Bridges, A. J .; Zhou, H.; Cody,
D. R.; McMichael, A.; Fry, D. W. Tyrosine Kinase Inhibitors. 5.
Synthesis and Structure-Activity Relationships for 4-(Phenyl-
methyl-amino]-and 4-(Phenylamino)quinazolines as Potent Ad-
enosine 5′-Triphosphate Binding Site Inhibitors of the Tyrosine
Kinase Domain of the Epidermal Growth Factor Receptor. J .
Med. Chem. 1995, 38, 3482-3487.
1-(2-Am in op h en y1)-2-(3-ch lor op h en yl)eth a n on e (16).
Freshly distilled aniline (2.2 mL, 23 mmol) dissolved in 25 mL
of 1,2-dichloroethane was added dropwise to a solution of 25.3
mL (25.3 mmol) of BCl3 in dichloromethane cooled to 0 °C; 5.9
mL (46 mmol) of 3-chlorobenzyl cyanide and 3.37 g (25.3 mmol)
of AlCl3 were added to the white suspension, and the reaction
mixture was stirred at 80 °C for 20 h and cooled to 0 °C; 2 N
HCl was added to the brown mixture, upon which a yellow
precipitate formed. The mixture was then refluxed for 30 min