Tyrosine Kinase Inhibitors
J ournal of Medicinal Chemistry, 1996, Vol. 39, No. 4 925
ylamino)ethyl]-1H-imidazo[4,5-g]quinazoline (11) (0.18 g, 70%).
Dihydrochloride salt: mp (EtOH) 220-230 °C dec; H NMR
(br s, 1 H, NH), 9.02 (s, 1 H), 8.62 (s, 1 H), 8.56 (s, 1 H), 8.37
(br s, 1 H, H-2′), 8.04 (s, 1 H), 8.01 (br d, 1 H, H-6′), 7.37 (t, J
) 8.1 Hz, 1 H, H-5′), 7.29 (br d, J ) 8.7 Hz, 1 H, H-4′), 4.47 (t,
J ) 6.1 Hz, 2 H, CH2), 2.71 (t, J ) 6.1 Hz, 2 H, CH2), 2.20 (s,
6 H, CH3); 13C NMR δ 158.1 (s), 152.3 (d), 149.6 (d), 145.3 (s),
143.0 (s), 141.4 (s), 138.5 (s), 130.3 (d), 125.6 (d), 123.8 (d),
121.2 (s), 120.3 (d), 112.4 (d, C-9), 110.9 (s), 106.5 (d), 57.7 (t),
45.1 (q), 42.3 (q). Anal. (C19H19BrN6) C, H, N. Trihydrochlo-
ride salt, mp 294 °C dec. Anal. (C19H19BrN6‚3HCl) C, H, N.
8-[(3-Br om oph en yl)am in o]-9-ch lor o-3-[2-(dim eth ylam i-
n o)eth yl]-3H-im id a zo[4,5-g]qu in a zolin e (14): Sch em e 3.
When the reduction of 42b was performed with either Fe dust
and dilute HCl in 65% aqueous EtOH, or by hydrogenation
over Pt on charcoal in acidic (HCl) methanol, a less soluble
byproduct was isolated and identified as 6-amino-4-[(3-bro-
mophenyl)amino]-5-chloro-7-{[2-(dimethylamino)ethyl]amino}-
quinazoline (43c): mp (EtOAc) 165-166 °C; 1H NMR [(CD3)2-
SO] δ 9.27 (br s, 1 H, NH), 8.32 (s, 1 H, H-2), 8.14 (br s, 1 H,
H-2′), 7.71 (br d, J ) 8.1 Hz, 1 H, H-6′), 7.29 (t, J ) 8.0 Hz, 1
H, H-5′), 7.21 (br d, J ) 7.9 Hz, 1 H, H-4′), 6.64 (s, 1 H, H-8),
5.97 (t, J ) 4.5 Hz, 1 H, NH), 5.71 (br s, 2 H, NH2), 3.31 (q, J
) 6.1 Hz, 2 H, CH2), 2.56 (t, J ) 6.4 Hz, 2 H, CH2), 2.22 (s, 6
H, CH3); 13C NMR δ 153.5 (s), 150.4 (d), 147.0 (s), 142.0 (s),
141.3 (s), 133.8 (s), 130.2 (d), 124.8 (s), 123.0 (d), 121.3 (d),
119.8 (d), 105.3 (s), 104.4 (s), 101.6 (d), 56.9 (t), 45.2 (q), 41.1
1
[free base in (CD3)2SO] δ 9.80 (br s, 1 H, NH), 8.81 (s, 1 H),
8.63 (s, 1 H), 8.60 (s, 1 H), 8.25 (br s, 1 H, H-2′), 8.06 (s, 1 H),
7.97 (br d, J ) 7.3 Hz, 1 H, H-6′), 7.40 (t, J ) 8.0 Hz, 1 H,
H-5′), 7.32 (br d, J ) 8.3 Hz, 1 H, H-4′), 4.47 (t, J ) 6.1 Hz, 2
H, CH2), 2.79 (t, J ) 6.1 Hz, 2 H, CH2), 2.22 (s, 6 H, CH3).
Anal. (C19H19BrN6‚2HCl‚H2O) C, H, N.
8-[(3-Br om oph en yl)am in o]-3-m eth yl-3H-im idazo[4,5-g]-
qu in a zolin e (12): Sch em e 3. Meth od A. Reaction of
3-methyl-3H-imidazo[4,5-g]quinazolin-8(7H)-one15 (39) with
P2S5 in pyridine as above gave 3-methyl-3H-imidazo[4,5-g]-
quinazoline-8(7H)-thione (40) (88%): mp (AcOH) > 380 °C; 1H
NMR [(CD3)2SO] δ 8.91 (s, 1 H), 8.53 (s, 1 H), 8.12 (s, 1 H),
7.91 (s, 1 H), 3.93 (s, 3 H, NCH3). Anal. (C10H8N4S) C, H, N,
S. Treatment of 40 with MeI/KOH as above gave 3-methyl-
8-(methylthio)-3H-imidazo[4,5-g]quinazoline (41) (82%): mp
(EtOH) 286-287.5 °C; 1H NMR [(CD3)2SO] δ 8.96 (s, 1 H), 8.64
(s, 1 H), 8.39 (s, 1 H), 8.16 (s, 1 H), 3.98 (s, 3 H, NCH3), 2.74
(s, 3 H, SCH3). Anal. (C11H10N4S) C, H, N, S. Reaction of 41
with 3-bromoaniline hydrochloride in 2-propanol as above gave
8-[(3-bromophenyl)amino]-3-methyl-3H-imidazo[4,5-g]quinazo-
1
line (12) (52%): mp (MeOH) 312-313.5 °C; H NMR [(CD3)2-
SO] δ 9.86 (s, 1 H, NH), 9.02 (s, 1 H), 8.54 (s, 1 H), 8.37 (br s,
1 H, H-2′), 8.01 (m, 2 H, H-4 and H-6′), 7.36 (t, J ) 8.0 Hz, 1
H, H-5′), 7.28 (br d, 1 H, H-4′), 3.96 (s, 3 H, NCH3); 13C NMR
δ 158.1 (s), 152.4 (d), 149.8 (d), 145.4 (s), 143.0 (s), 141.4 (s),
139.2 (s), 130.3 (d), 125.6 (d), 123.9 (d), 121.2 (s), 120.4 (d),
112.4 (d), 110.9 (s), 106.4 (d), 31.0 (q). Anal. (C16H12BrN5) C,
H, N.
(t); HREIMS found M•+ 434.06100/436.0598/438.0577, C18H20
BrClN6 requires 434.0621/436.0592/438.05714. Anal. (C18H20
BrClN6) C, H, N, Cl.
-
-
Reaction of 43c with formic acid as above gave 8-[(3-
bromophenyl)amino]-9-chloro-3-[2-(dimethylamino)ethyl]-3H-
imidazo[4,5-g]quinazoline (14): mp (EtOH) 182-183 °C; 1H
NMR [(CD3)2SO] δ 9.80 (br s, 1 H, NH), 8.63 (s, 1 H), 8.56 (s,
1 H), 8.22 (br s, 1 H, H-2′), 8.07 (s, 1 H), 7.82 (br d, J ) 7.8
Hz, 1 H, H-6′), 7.37 (t, J ) 7.9 Hz, 1 H, H-5′), 7.33 (br d, J )
8.0 Hz, 1 H, H-4′), 4.47 (t, J ) 5.9 Hz, 2 H, CH2), 2.70 (t, J )
5.9 Hz, 2 H, CH2), 2.19 (s, 3 H, CH3); 13C NMR δ 156.9 (s),
151.9 (d), 150.0 (d), 147.1 (s), 141.1 (s), 140.3 (s), 137.8 (s),
130.4 (d), 126.2 (d), 124.1 (d), 121.3 (s), 120.8 (d), 117.3 (s, C-9),
Meth od B. A mixture of 28 (1.09 g, 3 mmol) and 40%
aqueous methylamine (10 mL, 0.115 mol) in 2-propanol (100
mL) was heated at 100 °C in a sealed pressure vessel for 4 h
to give 4-[(3-bromophenyl)amino]-7-(methylamino)-6-nitro-
quinazoline (42a ) (1.05 g, 94%), identical with an authentic
sample.5 Reduction of 42a as previously described5 gave
6-amino-4-[(3-bromophenyl)amino]-7-(methylamino)-6-nitro-
quinazoline (43a ), which was treated with refluxing HCO2H
as above, to give 8-[(3-bromophenyl)amino]-3-methyl-3H-im-
idazo[4,5-g]quinazoline (12) identical in all respects to the
compound prepared above.
108.4 (s), 106.5 (d), 57.7 (t), 45.0 (q), 42.5 (t). Anal. (C19H18
BrClN6) C, H, N.
-
9-[(3-Br om op h en yl)a m in o]-1H-im id a zo[4,5-f]qu in a zo-
lin e (15): Sch em e 4. A solution of 1H-imidazo[4,5-f]quinazo-
line-9(8H)-thione16 (44) (1.01 g, 5 mmol) and KOH (0.36 g, 6.5
mmol) in 50% MeOH/water (50 mL) was treated with MeI (0.34
mL), and the mixture was stirred overnight at room temper-
ature. Solvent was removed under reduced pressure to give
a precipitate of 9-(methylthio)-1H-imidazo[4,5-f]quinazoline
(45) (0.61 g, 57%): mp (EtOAc) 235-237 °C; 1H NMR [(CD3)2-
SO] δ 13.23 (m, 1 H, NH), 9.05 (s, 1 H), 8.60 (s, 1 H), 8.24 (d,
J ) 8.7 Hz, 1 H), 7.81 (d, J ) 8.9 Hz, 1 H), 2.71 (s, 3 H, SCH3).
Anal. (C10H8N4S) C, H, N.
A solution of 45 (0.43 g, 2 mmol), 3-bromoaniline (0.5 g, 3
mmol), and 3-bromoaniline hydrochloride (0.63 g, 3 mmol) in
2-propanol was heated under reflux for 16 h, and the resulting
precipitate was treated with aqueous NH3 to give 9-[(3-
bromophenyl)amino]-1H-imidazo[4,5-f]quinazoline (15) (0.52
g, 77%): mp (EtOH) 335-337 °C; 1H NMR [(CD3)2SO] δ 11.53
(s, 1 H, NH), 8.79 (s, 1 H), 8.68 (s, 1 H), 8.53 (dd, J ) 1.8, 1.9
Hz, 1 H, H-2′), 8.15 (d, J ) 8.8 Hz, 1 H), 7.81 (br d, J ) 8.6
Hz, 1 H, H-6′), 7.71 (d, J ) 8.9 Hz, 1 H), 7.41 (t, J ) 8.0 Hz,
H-5′), 7.32 (br d, J ) 7.8 Hz, 1 H, H-4′). Anal. (C15H10BrN5)
C, H, N.
6-[(3-Br om op h en yl)a m in o]-1H-im id a zo[4,5-h ]qu in a zo-
lin e (16): Sch em e 5. 6-Bromo-7-chloroquinazolin-4(3H)-one17
(46) (7.17 g, 27.6 mmol) was added to a mixture of concentrated
H2SO4 (10 mL) and fuming HNO3 (10 mL), and the solution
was heated at 100 °C for 3 h, before being cooled and poured
onto ice-water. The precipitate was collected and recrystal-
lized from AcOH to give 6-bromo-7-chloro-8-nitroquinazolin-
4(3H)-one (47) (4.87 g, 58%): mp (AcOH) 295.5-296.5 °C; 1H
NMR [(CD3)2SO] δ 12.90 (br s, 1 H, NH), 8.54 (s, 1 H, H-5),
8.31 (s, 1 H, H-2); 13C NMR δ 157.9 (s), 149.9 (d), 145.7 (s),
140.5 (s), 131.8 (d), 129.5 (s), 123.7 (s), 119.4 (s). Anal. (C8H3-
BrClN3O3) C, H, N.
8-[(3-Br om oph en yl)am in o]-3-[2-(dim eth ylam in o)eth yl]-
3H-im id a zo[4,5-g]qu in a zolin e (13): Sch em e 3. A mixture
of 28 (0.91 g, 25 mmol) and N,N-dimethylethylenediamine
(0.88 g, 0.1 mol) in i-PrOH (50 mL) was heated under reflux
for 15 min when a deep-red precipitate was obtained. After
cooling, the solid was collected, washed with water, and dried
to give 4-[(3-bromophenyl)amino]-7-{[2-(dimethylamino)ethyl]-
amino}-6-nitroquinazoline (42b) (1.06 g, 98%): mp (i-PrOH)
1
226.5-228 °C; H NMR [(CD3)2SO] δ 10.21 (br s, 1 H, NH),
9.49 (s, 1 H, H-5), 8.49 (s, 1 H, H-2), 8.17 (br s, 1 H, H-2′),
8.04 (t, J ) 4.3 Hz, 1 H, NH), 7.88 (br d, J ) 7.3 Hz, 1 H,
H-6′), 7.36 (t, J ) 7.9 Hz, 1 H, H-5′), 7.31 (br d, J ) 7.9 Hz, 1
H, H-4′), 3.39 (q, J ) 5.7 Hz, 2 H, CH2), 2.59 (t, J ) 6.0 Hz, 2
H, CH2), 2.25 (s, 6 Hz, CH3). Anal. (C18H19BrN6O2), C, H, N.
A suspension of 42b (1.51 g, 35 mmol) in MeOH (250 mL)
was combined with Na2S‚9H2O (24.0 g, 0.1 mol) in H2O (100
mL), and the resulting dark red solution was heated under
reflux for 2 h to give a clear orange solution. Concentration
of the solution and cooling gave 6-amino-4-[(3-bromophenyl)-
amino]-7-{[(2-(dimethylamino)ethyl]amino}quinazoline (43b)
(0.89 g, 64%): mp (CH2Cl2) 172.5-173.5 °C; 1H NMR [(CD3)2-
SO] δ 9.17 (br s, 1 H, NH), 8.31 (s, 1 H, H-2), 8.22 (t, J ) 1.9
Hz, 1 H, H-2′), 7.85 (br d, J ) 8.2 Hz, 1 H, H-6′), 7.30 (s, 1 H,
H-5), 7.27 (t, J ) 8.1 Hz, 1 H, H-5′), 7.16 (br d, J ) 7.9 Hz, 1
H, H-4′), 6.62 (s, 1 H, H-8), 5.60 (t, J ) 5.0 Hz, 1 H, NH), 5.18
(br s, 2 H, NH2), 3.28 (q, J ) 6.4 Hz, 2 H, CH2), 2.57 (t, J )
6.6 Hz, 2 H, CH2, 2.23 (s, 6 H, CH3). Anal. (C18H19BrN6) C,
H, N.
A solution of 43b (0.401 g, 1 mmol) in formic acid (40 mL)
was heated under reflux for 1 h, and the formic acid was then
removed under reduced pressure. The residue was dissolved
in water and filtered, and the solution was basified with
concentrated ammonia to give 8-[(3-bromophenyl)amino]-3-[2-
(dimethylamino)ethyl]-3H-imidazo[4,5-g]quinazoline (13) (0.25
g, 61%): mp (EtOH) 274-275.5 °C; 1H NMR [(CD3)2SO] δ 9.87
A suspension of 47 (4.0 g, 13 mmol) in n-BuOH (100 mL)
was saturated with anhydrous ammonia gas, the the mixture