2640 J ournal of Medicinal Chemistry, 1997, Vol. 40, No. 16
Gamage et al.
9-[[4-[[2-(Dieth ylam in o)eth yl]am in o]-3-m eth oxyph en yl]-
EtOAc) 194-196 °C; 1H NMR ((CD3)2SO) δ 0.88 (t, J ) 4.7
Hz, 6 H, 2 CH3), 1.31 (m, 12 H, 2 (CH2)3), 1.31 (m, 4 H, 2 CH2),
3.32 (t, J ) 7.5 Hz, 4 H, 2 CH2), 6.75 (d, J ) 9.0 Hz, 2 H,
H-4′,5), 7.20 (d, J ) 8.9 Hz, 2 H, H-3′,5′), 7.37 (t, J ) 7.5 Hz,
2 H, H-2,7), 7.95 (m, 4 H, H-3,6,2′,6′), 8.25 (br s, 2 H, H-1,8).
Anal. (C31H39N3‚HCl‚1.5H2O) C, H, N, Cl.
a m in o]a cr id in e (19): from reduced 56 and 9-chloroacridine
1
(87%); mp (MeOH/EtOAc) 248 °C dec; H NMR (D2O) δ 1.46
(t, J ) 7.2 Hz, 6 H, 2 CH3), 3.48 (q, J ) 7.2 Hz, 4 H, 2 CH2-
CH3), 3.57 (t, J ) 5.9 Hz, 2 H, CH2), 3.77 (s, 5 H, OCH3, CH2N),
6.68 (s, 1 H, H-3′), 6.78 (d, J ) 8.2 Hz, 1 H, H-5′or H-6′), 6.89
(d, J ) 8.3 Hz, 1 H, H-5′ or H-6′), 7.28 (t, J ) 7.7 Hz, 2 H,
H-3,6), 7.61 (d, J ) 8.3 Hz, 2 H, H-4,5), 7.72 (d, J ) 8.6 Hz, 2
H, H-1,8), 7.87 (t, J ) 7.6 Hz, 2 H, H-2,7). Anal. (C26H30N4O‚
2HCl‚2.5H2O) C, H, N.
9 -[[4 -[(N -P e n t y l a m i n o )m e t h y l ]p h e n y l ]a m i n o ]-
a cr id in e (35): from reduced 71 and 9-chloroacridine (45%);
1
mp (MeOH/EtOAc) 244-247 °C; H NMR (CD3OD) δ 0.97 (t,
J ) 7.0 Hz, 3 H, CH3), 1.40-1.44 (m, 4 H, 2 CH2), 1.75-1.84
(m, 2 H, CH2), 3.12 (t, J ) 8.1 Hz, 2 H, CH2), 4.31 (s, 2 H,
CH2), 7.44-7.48 (m, 2 H, Ar), 7.52 (d, J ) 8.5 Hz, 2 H, H-3′,5′),
7.70 (d, J ) 8.5 Hz, 2 H, H-2′,6′), 7.98-8.04 (m, 2 H, ArH),
8.23 (d, J ) 8.7 Hz, ArH). Anal. (C25H27N3‚2HCl‚H2O) C, H,
N, Cl.
9-[[3-Meth oxy-4-(N-eth yl-N-m eth yla m in o)p h en yl]a m i-
n o]a cr id in e (21): from reduced 53 and 9-chloroacridine (75%);
mp (MeOH/EtOAc) 218-222 °C; 1H NMR ((CD3)2SO) δ 1.16
(t, J ) 7.1 Hz, 3 H, CH3), 2.50 (s, 3 H, CH3), 3.13 (br s, 2 H,
CH2), 3.79 (s, 3 H, OCH3), 7.13 (d, J ) 7.1 Hz, 1 H, H-6′), 7.36
(br s, 1 H, H-3′), 7.45 (t, J ) 7.6 Hz, 2 H, H-3,6), 7.85 (br s, 1
H, H-5), 8.04 (t, J ) 7.6 Hz, 2 H, H-2,7), 8.19 (d, J ) 8.2 Hz,
2 H, H-4,5), 8.32 (d, J ) 8.7 Hz, 2 H, H-1,8), 11.77 (br s, 1 H,
NH), 12.13 (br s, 1 H, NH), 15.23 (br s, 1 H, NH). Anal.
(C23H23N3O‚2HCl‚H2O) C, H, N, Cl.
9-[[4-(N-P yr r olidin om eth yl)ph en yl]am in o]acr idin e (36):
from reduced 72 and 9-chloroacridine (81%); mp (MeOH/
EtOAc) 269-270 °C; 1H NMR (D2O) δ 2.11 (m, 2 H, CH2), 2.28
(m, 2 H, CH2), 3.31 (m, 2 H, CH2), 3.64 (m, 2 H, CH2), 4.51 (s,
2H, CH2), 7.34 (d, J ) 8.2 Hz, 2 H, H-3′,5′), 7.45 (t, J ) 7.8
Hz, 2 H, H-3,6), 7.64 (d, J ) 8.2 Hz, 2 H, H-2′,6′), 7.70 (d, J )
8.7 Hz, 2 H, H-4,5), 7.82 (d, J ) 8.8 Hz, 2 H, H-1,8), 7.99 (t, J
) 7.7 Hz, 2 H, H-2,7). Anal. (C24H23N3‚2HCl‚0.5H2O) C, H,
N, Cl.
9-[(4-Hexylp h en yl)a m in o]a cr id in e (38): from reduced 65
and 9-chloroacridine (75%); mp (MeOH/EtOAc) 229-234 °C;
1H NMR (CD3OD) δ 0.91 (t, J ) 6.9 Hz, 3 H, CH3), 1.28-1.40
(m, 8 H, 4 CH2), 1.70 (quintet, J ) 7.4 Hz, 2 H, CH2), 2.73 (t,
J ) 7.6 Hz, 2 H, CH2), 7.33-7.43 (m, 6 H, ArH), 7.90-7.99
(m, 4 H, ArH), 8.17 (d, J ) 8.95 Hz, 2 H, ArH). Anal.
(C26H28N2‚HCl) C, H, N, Cl.
9-[[4-(N -H e xyl-N -m e t h yla m in o)p h e n yl]a m in o]a cr i-
d in e (22): from reduced 49 and 9-chloroacridine (80%); mp
1
(MeOH/EtOAc) 214-216 °C; H NMR (CD3OD) δ 0.87 (t, J )
6.8 Hz, CH3), 1.29 (m, 6 H, 3 CH2), 1.53 (m, 2 H, CH2), 3.49
(m, 2 H, CH2), 7.02 (br s, 2 H, H-4,5), 7.33 (d, J ) 8.4 Hz, 2 H,
H-3′,5′), 7.41 (t, J ) 7.6 Hz, 2 H, H-2,7), 7.97 (t, J ) 7.5 Hz, 2
H, H-3,6), 8.04 (d, J ) 8.4 Hz, 2 H, H-2′,6′), 8.26 (d, J ) 8.4
Hz, 2 H, H-1,8), 11.49 (s, 1 H, NH), 14.42 (s, 1 H, NH). Anal.
(C26H29N3‚2HCl‚0.5H2O) C, H, N, Cl.
9-[[4-(N-Hexyl-N-m eth yla m in o)-3-m eth oxyp h en yl]a m i-
n o]a cr id in e (23): from reduced 51 and 9-chloroacridine (81%);
1
mp (MeOH/EtOAc) 197-200 °C; H NMR (CD3OD) δ 0.91 (t,
9-[[4-[(N ,N -D ie t h y la m in o )p r o p y l]p h e n y l]a m in o ]-
a cr id in e (39): from reduced 58 and 9-chloroacridine (35%);
J ) 6.8 Hz, 3 H, CH3), 1.33 (m, 6 H, 3 CH2), 1.57 (m, 2 H,
CH2), 3.02 (s, 3 H, CH3), 3.30 (m, 4 H, 2 CH2), 3.84 (s, 3 H,
OCH3), 7.04 (dd, J ) 8.5, 2.3 Hz, 1 H, H-5′), 7.15 (d, J ) 2.3
Hz, 1 H, H-3′), 7.46 (t, J ) 7.7 Hz, 2 H, ArH), 7.94-8.02 (m,
4 H, ArH), 8.23 (d, J ) 8.8 Hz, 2 H, H-1,8). Anal. (C27H31N3O‚
2HCl) C, H, N.
1
mp (MeOH/EtOAc) >200 °C; H NMR ((CD3)2SO) δ 1.22 (t, J
) 7.2 Hz, 6 H, 2 CH3), 2.04 (m, 2 H, CH2), 2.75 (t, J ) 7.5 Hz,
2 H, CH2), 3.02 (m, 2 H, CH2), 3.10 (m, 4 H, 2 CH2), 7.34-7.39
(m, 6 H, ArH), 7.95 (t, J ) 8.0 Hz, 2 H, ArH), 8.09 (d, J ) 8.5
Hz, 2 H, ArH), 8.24 (d, J ) 8.8 Hz, 2 H, ArH), 8.74 (s, 1 H,
NH). Anal. (C26H29N3‚2HCl‚0.5H2O) C, H, N, Cl.
9-[[4-(N-Hexyl-N-m eth ylam in o)ph en yl]am in o]-6-ch lor o-
2-m eth oxya cr id in e (24): from reduced 49 and 6,9-dichloro-
2-methoxyacridine (72%); mp (MeOH/EtOAc) 223.5-225.5 °C;
1H NMR (CD3OD) δ 0.92 (t, J ) 6.3 Hz, 3 H, CH3), 1.35 (m, 6
H, 3 CH2), 1.60 (m, 2 H, CH2), 3.10 (s, 3 H, CH3), 3.48 (t, J )
7.6 Hz, 2 H, CH2), 3.71 (s, 3 H, OCH3), 7.10 (br s, 2 H, H-2′,6′),
7.35 (d, J ) 8.8 Hz, 2 H, H-3′,5′), 7.39 (d, J ) 9.4 Hz, 1 H,
H-3), 7.57 (br s, 1 H, H-4), 7.66 (dd, J ) 9.4, 2.6 Hz, 1 H, H-7),
7.81 (d, J ) 9.3 Hz, 1 H, H-5), 7.89 (d, J ) 1.9 Hz, 1 H, H-1),
1.19 (d, J ) 9.4 Hz, 1 H, H-8). Anal. (C27H29N3ClO‚2HCl) C,
H, N.
9-[[4-(Hexyloxy)p h en yl]a m in o]a cr id in e (41): from re-
duced N-(hexyloxy)-4-nitrobenzene and 9-chloroacridine (86%);
1
mp (MeOH/EtOAc) 248-251 °C; H NMR (CD3OD) δ 0.95 (t,
J ) 7.1 Hz, 3 H, CH3), 1.35-1.45 (m, 4 H, 2 CH2), 1.49-1.56
(m, 2 H, CH2), 1.83 (quintet, J ) 7.0 Hz, 2 H, CH2), 4.06 (t, J
) 6.4 Hz, 2 H, OCH2), 7.08 (d, J ) 8.9 Hz, 2 H, H-2′,6′), 7.36
(d, J ) 8.9 Hz, H-3′,5′), 7.42 (dt, J ) 7.8, 1.15 Hz, 2 H, H-2,7),
7.89 (d, J ) 8.5 Hz, 2 H, H-4,5), 7.96 (dt, J ) 7.7, 1.1 Hz, 2 H,
H-3,6), 8.17 (d, J ) 8.8 Hz, 2 H, H-1,8). Anal. (C25H26N2O‚
HCl) C, H, N, Cl.
9-[[4-(N,N-Dip r op yla m in o)p h en yl]a m in o]a cr id in e (28):
from reduced N,N-dipropyl-4-nitroaniline and 9-chloroacridine
(94%); mp (MeOH/EtOAc) 232-237 °C; 1H NMR ((CD3)2SO) δ
0.91 (t, J ) 7.3 Hz, 6 H, 2 CH3), 1.58 (sextet, J ) 7.35 Hz, 4
H, 2 CH2), 3.39 (m, 4 H, 2 CH2), 6.75 (d, J ) 9.0 Hz, 2 H,
H-3′,5′) 7.22 (d, J ) 8.9 Hz, 2 H, H-2′6′), 7.39 (t, J ) 7.4 Hz,
2 H, H-2,7), 7.95 (m, 4 H, H-3,4,5,6), 8.28 (d, J ) 8.65 Hz, 2
H, H-1,8). Anal. (C25H27N3‚HCl‚0.5H2O) C, H, N, Cl.
9-[[4-(N,N-Dibu tyla m in o)p h en yl]a m in o]a cr id in e (29):
from reduced N,N-dibutyl-4-nitroaniline and 9-chloroacridine
(97%); mp (MeOH/EtOAc) 220-224 °C; 1H NMR ((CD3)2SO) δ
0.93 (t, J ) 7.2 Hz, 6 H, 2 CH3), 1.33 (sextet, J ) 7.2 Hz, 4 H,
2 CH2), 1.54 (quintet, J ) 7.6 Hz, 4 H, 2 CH2), 3.33 (t, J ) 7.2
Hz, 4 H, 2 CH2), 6.75 (d, J ) 8.9 Hz, 2 H, H-3′,5′), 7.23 (d, J
) 8.8 Hz, 2 H, H-4,5), 7.38 (t, J ) 7.3 Hz, H-2,7), 7.90 (m, 4 H,
H-3,6,2′,6′), 8.26 (d, J ) 8.7 Hz, 2 H, H-1,8), 11.41 (br s, 1 H,
NH). Anal. (C27H31N3‚HCl‚1.5H2O) C, H, N.
9-[[4-(N,N-Dip en tyla m in o)p h en yl]a m in o]a cr id in e (30):
from reduced 68 and 9-chloroacridine (96%); mp (MeOH/
EtOAc) 222-224 °C; 1H NMR ((CD3)2SO) δ 0.89 (t, J ) 6.6
Hz, 6 H, 2 CH3), 1.29-1.33 (m, 8 H, 4 CH2), 1.50-1.62 (m, 4
H, 2 CH2), 3.36 (m, 4 H, 2 CH2), 6.76 (d, J ) 9.0 Hz, 2 H,
H-2′,6′), 7.22 (d, J ) 8.8 Hz, 2 H, H-3′,5′), 7.38 (t, J ) 7.3 Hz,
2 H, ArH), 7.89-8.01 (m, 4 H, ArH), 8.26 (d, J ) 8.6 Hz, 2 H,
H-1,8). Anal. (C29H35N3‚HCl) C, H, N, Cl.
9-[3-(2-Am in op yr id yl)]a cr id in e (7). Meth od of Sch em e
1. N-Acetoxy-2-amino-5-nitropyridine (1.96 g, 10.8 mmol) was
hydrogenated over Pd/C in MeOH (40 mL), and the solution
was filtered directly into a solution of 9-chloroacridine (2.01
g, 10 mmol) in MeOH (30 mL). After 15 h at room tempera-
ture, the crude product was precipitated by the addition of
EtOAc, then dissolved in 2 N ethanolic HCl, and heated under
reflux for 1 h. The cooled mixture was diluted with EtOAc,
and the product was recrystallized from MeOH/EtOAc to give
7 as the dihydrochloride salt (0.7 g, 22%): mp 260-268 °C;
1H NMR (D2O) δ 7.12 (d, J ) 9.5 Hz, 1 H, H-5′), 7.57 (t, J )
7.8 Hz, 2 H, H-3,6), 7.65 (d, J ) 9.7 Hz, 1 H, H-6′), 7.72 (d, J
) 8.4 Hz, 2 H, H-4,5), 7.93 (s, 1 H, H-2′), 7.98 (d, J ) 8.8 Hz,
2 H, H-1,8), 8.03 (t, J ) 7.7 Hz, 2 H, H-2,7). Anal. (C18H14N4‚
2HCl‚H2O) C, H, N, Cl.
3,6-Bis(dim eth ylam in o)-9-[[4-(N-h exyl-N-m eth ylam in o)-
p h en yl]a m in o]a cr id in e (25). Meth od of Sch em e 2. 3,6-
Bis(dimethylamino)-9-(methylthio)acridine10 (45) (0.5 g, 1.6
mmol) and phenol (1.9 g) were heated at 100 °C for 15 min.
N-Hexyl-N-methyl-4-nitroaniline (49) (307 mg, 1.6 mmol) was
hydrogenated (MeOH/Pt/C) and filtered into the above mix-
ture, which was then stirred at 100 °C for 2 h while the MeOH
was allowed to evaporate. The mixture was then cooled to
room temperature, Me2CO (75 mL) and concentrated HCl (8
mL) were added, the mixture was stirred for 2 h, and the
product was then precipitated by addition of EtOAc. The
resulting gummy material was recrystallized twice from
9-[[4-(N,N-Dih exyla m in o)p h en yl]a m in o]a cr id in e (31):
from reduced 69 and 9-chloroacridine (76%); mp (MeOH/