BMN Tyrphostins as Potent Inhibitors of EGFR
J ournal of Medicinal Chemistry, 1996, Vol. 39, No. 25 4909
Syn th etic Meth od s. The synthesis of the intermediate bis-
acetonitriles III is described together with and preceding the
synthesis of compounds 1-24, under the title III and the
number of the corresponding dimeric tyrphostin.
(b) 3,4-Dihydroxybenzaldehyde (1.1 g, 8 mM), 0.95 g, 4 mM,
of compound III-6 from part a, and 3 drops of piperidine in 20
mL of ethanol were refluxed for 3 h. Cooling and filtering gave
1 g, 53% yield, of a yellow solid: mp 248 °C; NMR (acetone-
d
6
) δ 8.05 (2H, s, vinyl), 7.66 (2H, d, J ) 2.1 Hz, H
dd, J ) 8.3, 2.1 Hz, H ), 6.94 (2H, d, J ) 8.3 Hz, H
m), 1.63 (4H, m), 1.44 (2H, m).
2
), 7.36 (2H,
), 3.40 (4H,
Com p ou n d 1. (a ) III-1. 1,3-Propanediamine (2.2 g, 30
mM) and 6.4 g, 64 mM, of methyl cyanoacetate were stirred
for 2 h at room temperature. After the exothermic reaction
subsided a solid was formed. Trituration with ethanol, filter-
ing, and recrystallization from ethanol gave 4.6 g, 74% yield,
6
5
Com p ou n d 7. (a ) III-7. 1,6-Diaminohexane (2.9 g, 25
mM) and 6.6 g, 66 mM, of methyl cyanoacetate were stirred
for 1 h at room temperature. The semisolid was triturated
with ethanol, filtered, and recrystalized from ethanol to give
of a white solid: mp 148 °C; NMR (acetone-d
6
) δ 3.58 (4H, s),
3
2
.28 (4H, q, J ) 6.7 Hz), 1.70 (2H, quin, J ) 6.7 Hz); MS m/ e
+
4 g, 64% yield, of a white solid: mp 140 °C; NMR (acetone-d
δ 3.55 (4H, s), 3.22 (4H, m), 1.30 (4H, m), 1.10 (4H, m).
6
)
08 (M , 22), 140 (M - NHCOCH
CN, 17), 124 (16), 112 (27), 111(C
CN, 100), 98 (57), 97 (32), 72 (M - 2COCH CN, 20).
b) 3,4-Dihydroxy-5-bromobenzaldehyde (0.3 g, 1.4 mM),
.15 g, 0.7 mM, of compound III-1 from part a, and 15 mg of
2
CN, 10), 125 (M -
NHCOCH
2
2
H
3
NH COCH
2
2
-
(
b) 3,4-Dihydroxybenzaldehyde (1.1 g, 8 mM), 1 g, 4 mM,
2
of compound III-7 from part a, and 20 mg of â-alanine in 15
mL of ethanol were refluxed for 3 h. Cooling and filtering gave
(
0
2
d
.1 g, 96% yield, of a yellow solid: mp 260 °C; NMR (DMSO-
) δ 7.90 (2H, s, vinyl), 7.53 (2H, d, J ) 2.0 Hz, H ), 7.26 (2H,
), 6.85 (2H, d, J ) 8.1 Hz, H ), 3.18 (4H, m),
â-alanine in 25 mL of ethanol were refluxed for 3 h. Cooling
and filtering gave 0.24 g, 57% yield, of a green-yellow solid:
6
2
dd, J ) 8.1 Hz, H
1
6
5
mp 283 °C; NMR (DMSO-d ) δ 8.26 (br t, NH), 7.92 (2H, s,
6
.50-1.25 (8H, m); MS m/ e 250 (7), 210 (10), 165 (11), 153
vinyl), 7.59 (2H, d, J ) 2.1 Hz), 7.54 (2H, d, J ) 2.1 Hz), 4.0-
(51), 123 (12), 114 (31), 111 (106), 110 (22), 98 (99).
3
.1 (6H, m).
Com p ou n d 8. (a ) III-8. 1,10-Diaminodecane (3.5 g, 20
Com p ou n d 2. 3,4-Dihydroxybenzaldehyde (0.7 g, 5.1 mM),
.5 g, 2.4 mM, of III-1 (see compound 1 (a)), and 4 drops of
mM) and 5 g, 50 mM, of methyl cyanoacetate were stirred for
h at room temperature. The solid was triturated with
ethanol and filtered to give 4.9 g, 79% yield, of a white solid:
mp 131 °C; NMR (acetone-d ) δ 3.54 (4H, s), 3.21 (4H, t, J )
.8 Hz), 1.50 (4H, m), 1.30 (12H, m).
b) 3,4-Dihydroxybenzaldehyde (0.55 g, 4 mM), 0.61 g, 2
0
1
piperidine in 25 mL of ethanol were refluxed to 4 h. Water
and 5 drops of HCl were added, and the reaction mixtures was
extracted with ethyl acetate. Evaporation, tritation with
6
6
ethanol-CH
green-yellow solid: mp 277 °C; NMR (DMSO-d
s, vinyl), 7.54 (2H, d, J ) 2.1 Hz, H ), 7.28 (2H, dd, J ) 8.2,
.1 Hz, H ), 6.87 (2H, d, J ) 8.2 Hz, H ), 3.22 (4H, t, J ) 5.8
Hz), 1.72 (2H, quin, J ) 5.8 Hz); MS m/ e 328 (30), 387 (11),
61 (17), 203 (17), 201 (21), 188 (59), 164 (55), 161 (100), 159
27), 137 (21), 123 (29), 114 (34), 111 (51), 110 (44), 105 (36),
2
Cl
2
, and filtering gave 0.34 g, 32% yield, of a light
(
6
) δ 7.94 (2H,
mM, of compound III-8 from part a, and 3 drops of piperidine
in 15 mL of ethanol were refluxed for 3 h. Cooling, filtering,
2
2
6
5
and washing with CH
solid: mp 218 °C; NMR (DMSO-d
2
Cl
2
gave 0.92 g, 77% yield, of a yellow
) δ 7.90 (2H, s, vinyl), 7.53
), 7.29 (2H, dd, J ) 8.3, 2.2 Hz, H ), 6.85
2H, d, J ) 8.3 Hz, H ), 3.17 (4H, m), 1.50-1.30 (16H, m).
Com p ou n d 9. (a ) III-9. m-Xylylenediamine (4.1 g, 30
6
2
(
(
(
2H, d, J ) 2.2 Hz, H
2
6
5
9
8 (46).
Com p ou n d 3. (a ) III-3. 1,2-Diaminoethane (1.8 g, 30 mM)
mM) and 7.4 g, 75 mM, of methyl cyanoacetate were stirred
for 1 h at room temperature. Trituration with ethanol,
filtering, and recrystallization from ethanol gave 5.8 g, 72%
and 6.6 g, 66 mM, of methyl cyanoacetate were stirred for 1 h
at room temperature. Trituration with ethanol, filtering, and
recrystallization from ethanol gave 5 g, 86% yield, of a white
yield, of a white solid: mp 170 °C; NMR (acetone-d ) δ 7.27
6
solid, mp 183 °C; NMR (acetone-d
.36 (4H, br s).
b) 3,4-Dihydroxybenzaldehyde (0.83 g, 6 mM), 0.58 g, 3
6
) δ 3.55 (4H, s, CH
2
CN),
(4H, m), 3.65 (4H, s), 4.43 (4H, m).
3
(b) 3,4-Dihydroxybenzaldehyde (0.55 g, 4 mM), 0.54 g, 2
mM, of compound III-9 from part a, and 3 drops of piperidine
in 20 mL of ethanol were refluxed for 3 h. Concentration and
(
mM, of compound III-3 from part a, and 3 drops of piperidine
in 20 mL of ethanol were refluxed for 4 h. Cooling and filtering
gave 1.12 g, 86%, of a yellow solid: mp 295 °C; NMR (DMSO-
trituration with CH
orange solid: mp 246 °C; NMR (DMSO-d
7.54 (2H, d, J ) 2.1 Hz, H ), 7.30 (6H, m), 6.85 (2H, d, J ) 8.2
Hz, H ), 4.40 (4H, m).
2
Cl
2
gave 0.44 g, 43% yield, of a yellow-
6
) δ 7.97 (2H, s, vinyl),
d
6
) δ 7.94 (2H, s, vinyl), 7.54 (2H, d, J ) 2.1 Hz, H
2
), 7.27 (2H,
), 3.36 (4H,
2
dd, J ) 8.2, 2.1 Hz, H ), 6.87 (2H, d, J ) 8.2 Hz, H
br s); MS m/ e 270 (7), 314 (20), 203 (29), 189 (30), 161 (66),
6
5
5
Com p ou n d 10. (a ) III-10. Cyclohexane-1,3-bis(methy-
lamine) (3 g, 21 mM) and 6 g, 60 mM, of methyl cyanoacetate
were stirred overnight at room temperature. Trituration with
ethanol and filtering gave 2.17 g, 37% yield, of a white solid:
1
23 (70), 110 (100), 105 (25), 98 (21).
Com p ou n d 4. (a ) III-4. 1,4-Diaminobutane (2.2 g, 25 mM)
and 5.5 g, 55 mM, of methyl cyanoacetate were stirred for
.5 h at room temperature. Trituration and recrystallization
from ethanol gave 3.85 g, 69% yield, of a white solid: mp 145
C; NMR (acetone-d ) δ 3.55 (4H, s), 3.24 (4H, m), 1.56 (4H,
mp 160 °C; NMR (acetone-d
d, J ) 7.0 Hz), 1.8-0.6 (10H, m); (DMSO-d
6
) δ 3.79 (4H, s, CH
) 8.25 (br s, NH),
CN), 2.92 (4H, br s), 1.70-0.6 (10H, m).
b) Compound III-10 (0.44 g, 1.6 mM) from part a, 0.45 g,
.2 mM, of 3,4-dihydroxybenzaldehyde, and 20 mg of â-alanine
2
CN), 3.09 (4H,
0
6
3
3
.61 (4H, s, CH
2
(
°
6
m).
(
b) 3,4-Dihydroxybenzaldehyde (0.83 g, 6 mM), 0.67 g, 3
in 20 mL of ethanol were refluxed for 7 h. Cooling and filter-
ing gave 0.75 g, 91% yield, of a yellow solid: mp 225 °C;
mM, of compound III-4 from part a, and 3 drops of piperidine
in 20 mL of ethanol were refluxed for 3 h. Cooling and filtering
gave 1.2 g, 86% yield, of a yellow solid: mp 283 °C; NMR
NMR (DMSO-d
(
(
6
) δ 8.22 (br s, NH), 7.90 (2H, s, vinyl), 7.53
2H, d, J ) 2.0 Hz, H ), 7.27 (2H, dd, J ) 8.2, 2.0 Hz, H ), 6.85
2H, d, J ) 8.2 Hz, H ), 3.05 (4H, m, CH NH), 1.7-0.6 (10H,
2
6
(
7
3
DMSO-d
6
) δ 7.92 (2H, s, vinyl), 7.53 (2H, d, J ) 2.0 Hz, H
2
),
),
6
2
.27 (2H, dd, J ) 8.3, 2.0 Hz, H ), 6.85 (2H, d, J ) 8.3 Hz, H
.22 (4H, br s), 1.60 (4H, br s); MS m/ e 463 (M , 100), 274
6
5
m).
+
Com p ou n d 11. 5-Nitrovanilline (0.78 g, 4 mM), 0.45 g, 2
mM, of compound III-4 (see compound 4 (a)), and 3 drops of
piperidine in 10 mL of ethanol were refluxed for 2 h. Cooling
and filtering gave 0.68 g, 58% yield, of an orange solid: mp
(60).
Com p ou n d 5. 3,4,5-Trihydroxybenzaldehyde (0.51 g, 3
mM,), 0.33 g, 1.5 mM, of compound III-4 (a), and 3 drops of
piperidine in 10 mL of ethanol were refluxed for 2 h. Cooling
and filtering gave 0.7 g, 94% yield, of a deep yellow solid: mp
1
7
68 °C; NMR (DMSO-d
6
) δ 8.25 (2H, s, vinyl), 8.12 (2H, s, H
6
),
.85 (2H, s, H ), 3.91, 3.70 (2 s, 6H, OCH
2
3
), 3.08 (4H, m), 1.40
>
310 °C; NMR (DMSO-d
.20 (4H, m), 1.50 (4H, m).
Com p ou n d 6. (a ) III-6. 1,5-Diaminopentane (2.3 g, 25
6
) δ 7.80 (2H, s, vinyl), 7.01 (4H, s),
(
4H, m); MS m/ e 554 (M - CN, 100), 470 (22), 421 (36), 399
3
(48), 333 (43).
Com p ou n d 12. (a ) III-12. 1,2-Diaminocyclohexane (2.3
mM) and 6.6 g, 64 mM, of methyl cyanoacetate were stirred
for 1 h at room temperature. Trituration from ethanol gave
g, 20 mM) and 4.5 g, 45 mM, of methyl cyanoacetate were
stirred for 2 h at room temperature. Ethanol was added and
the solid filtered and washed with ethanol to give 1.8 g, 36%
4
.1 g, 69% yield, of a white solid: mp 125 °C; NMR (acetone-
) δ 3.55 (4H, s), 3.21 (4H, q, J ) 7.0 Hz), 1.53 (4H, m), 1.37
d
6
yield, of a white waxy solid: mp 83 °C; NMR (acetone-d
3.52 (4H, s), 3.30 (2H, m), 2.0-1.7 (8H, m).
6
) δ
(2H, m).