Acridine Derivatives
J ournal of Medicinal Chemistry, 2003, Vol. 46, No. 21 4473
brown hygroscopic solid. 1H NMR (CDCl3): δ 1.95 (8 H, m,
N(CH2CH2)2), 2.39 (6 H, s, CH3), 2.61-2.67 (6 H, m, COCH2-
CH2N and HNCH2CH2N), 2.72 (8 H, s, N(CH2CH2)2), 2.88-
2.94 (4 H, m, COCH2CH2N), 3.91-3.96 (2 H, m, HNCH2CH2N),
7.32-7.33 (1 H, m, H-3/7), 7.78-7.79 (1H, m, H-3/7), 7.93-
8.00 (2 H, m, H-8, 1), 8.06-8.10 (1 H, m, J ) 9.4 Hz, H-4),
8.96-8.97 (1 H, m, H-5), 11.54-11.62 (2 H, s, NHCO). MS,
m/z: 546.3580 (C31H44N7O2 M + H requires 546.3556).
2,6-Bis(3-pyr r olidin -1-ylpr opion am ido)-9-(3-am in oph e-
n yla m in o)a cr id in e (29). 2,6-Bisamido-9-chloroacridine 5
(500 mg, 1.0 mmol) was treated with 1,3-phenylenediamine
(0.32 g) according to the general procedure to give the desired
product 29 (110 mg, 19%) as an orange solid. 1H NMR
(CDCl3): δ 1.89-1.93 (8 H, m, N(CH2CH2)2), 2.57-2.64 (4 H,
m, COCH2CH2N), 2.73-2.79 (8 H, m, N(CH2CH2)2), 2.90-2.94
(4 H, m, COCH2CH2N), 6.13 (1 H, s, H-2′), 6.25-6.29 (2 H, m,
H-4′, 6′), 6.96-7.02 (1 H, t, J ) 7.9 Hz, H-5′), 7.52-7.62 (1 H,
m, H-3, 5 or 4, 8), 7.65-7.66 (1 H, m, H-3, 5 or 4, 8), 7.87-791
(1 H, m, H-3, 5 or 4, 8), 7.96-8.00 (1 H, m, H-3, 5 or 4, 8),
8.11-8.12 (1 H, m, H-1/5), 839-8.40 (1 H, m, H-1/5), 11.37 (1
H, s, NHCO), 11.52 (1 H, s, NHCO). MS, m/z: 566.3232
(C33H40N7O2 M + H requires 566.3243).
2,6-Bis(3-pyr r olidin -1-ylpr opion am ido)-9-(2-am in oph e-
n yla m in o)a cr id in e (30). 2,6-Bisamido-9-chloroacridine 5
(500 mg, 1.0 mmol) was treated with 1,2-phenylenediamine
(0.32 g) according to the general procedure to give the desired
product 30 (400 mg, 70%) as an orange solid. 1H NMR
(CDCl3): δ 1.86-1.88 (8 H, m, N(CH2CH2)2), 2.53-2.57 (4 H,
m, COCH2CH2N), 2.60-2.69 (8 H, m, N(CH2CH2)2), 2.82-2.87
(4 H, t, J ) 5.8 Hz, COCH2CH2N), 6.55 (2 H, m, H-3′/4′/5′/6′),
6.83-6.95 (2 H, m, H-3′/4′/5′/6′), 7.11 (1 H, m), 7.59-7.71 (3
H, m), 7.95 (1 H, m), 8.25 (1 H, s), 11.13 (1 H, s, NHCO), 11.48
(1 H, s, NHCO). MS, m/z: 566.3260 (C33H40N7O2 M + H
requires 566.3243).
2,6-Bis(3-p yr r olid in -1-ylp r op ion a m id o)-9-p h en yla m i-
n oa cr id in e (31). 2,6-Bisamido-9-chloroacridine 5 (500 mg, 1.0
mmol) was treated with aniline (0.3 mL) according to the
general procedure to give the desired product 31 (240 mg, 44%)
as an orange solid. 1H NMR (CDCl3): δ 1.86-1.92 (8 H, m,
N(CH2CH2)2), 2.55-2.62 (4 H, m, COCH2CH2N), 2.68-2.72 (8
H, m, N(CH2CH2)2), 2.985-2.92 (4 H, m, COCH2CH2N), 6.82-
6.85 (2 H, d, J ) 8.6 Hz, H-2, 6), 6.90-6.96 (1 H, t, H-3), 7.18-
7.24 (2 H, dd, H-3, 5), 7.55-7.66 (2 H, m, J ) 9.3 and 2.2 Hz,
H-3, 6), 7.84-7.88 (1 H, d, J ) 9.3 Hz, H-4/7), 7.95-7.99 (1 H,
d, J ) 9.3 Hz, H-4/7), 8.08 (1 H, m, H-1/5), 8.37 (1 H, m, H-1/
5), 11.46 (1 H, s, NHCO), 11.59 (1 H, s, NHCO). MS, m/z:
551.3114 (C33H39N6O2 M + H requires 551.3134).
2,6-Bis(3-p yr r olid in -1-ylp r op ion a m id o)-9-(3-(d im eth y-
la m in o)p r op yla m in o)a cr id in e (32). 2,6-Bisamido-9-chloro-
acridine 5 (500 mg, 1.0 mmol) was treated with N,N-
dimethylpropylamine (0.4 mL) according to the general
procedure to give the desired product 32 (210 mg, 38%) as a
yellow solid. 1H NMR (CDCl3): δ 1.92-1.95 (10 H, m,
N(CH2CH2)2 and HNCH2CH2CH2N), 2.39 (6 H, s, N(CH3)2),
2.58-2.66 (6 H, m, COCH2CH2N and HNCH2CH2CH2N), 2.71
(8 H, s, N(CH2CH2)2), 2.87-2.93 (4 H, m, COCH2CH2N), 4.12-
4.17 (2 H, m, HNCH2CH2CH2N), 7.70 (1 H, m), 7.88-8.07 (4
H, m), 8.96 (1 H, m), 11.48 (1 H, s, NHCO), 11.65 (1 H, s,
NHCO). MS, m/z: 560.3732 (C32H46N7O2 M + H requires
560.3713). Found, HCl salt: C 50.38, H 7.52, N 12.91%. Calcd
(anhydrous C32H45N7O2‚4HCl‚3.0 mol of H2O): C 50.60, H 7.30,
N 12.91%.
2,6-Bis(3-p yr r olid in -1-ylp r op ion a m id o)-9-cycloh exy-
la m in oa cr id in e (33). 2,6-Bisamido-9-chloroacridine 5 (500
mg, 1.0 mmol) was treated with cyclohexylamine (0.35 mL)
according to the general procedure to give the desired product
33 (230 mg, 41%) as a yellow solid. 1H NMR (CDCl3): δ 1.06-
1.66 (6 H, m, HNCH(CH2CH2)2CH2), 1.77 (4 H, m, HNCH(CH2-
CH2)2CH2), 1.95 (8 H, m, N(CH2CH2)2), 2.59-2.66 (4 H, m,
COCH2CH2N), 2.73-2.75 (8 H, m, N(CH2CH2)2), 2.89-2.96 (4
H, m, COCH2CH2N), 3.89 (1 H, m, HNCH(CH2CH2)2CH2),
7.30-7.34 (1 H, m), 7.84-8.05 (4 H, m), 8.83-8.84 (1 H, m),
11.58 (1 H, s, NHCO), 11.60 (1 H, s, NHCO). MS, m/z:
557.3592 (C31H44N7O2 M + H requires 557.3604).
2,7-Bis(3-p yr r olid in -1-ylp r op ion a m id o)-9-(4-m et h ox-
yp h en yla m in o)a cr id in e (34). 2,7-Bisamido-9-chloroacridine
6 (150 mg, 0.3 mmol) was treated with p-anisidine (0.5 mL)
according to the general procedure to give the desired product
34 (100 mg, 52%) as a bright-orange solid. Mp >320 °C. 1H
NMR (DMSO): δ 1.66 (8 H, m, N(CH2CH2)2), 2.50 (12 H, m,
COCH2CH2N, N(CH2CH2)2), 2.71 (4 H, t, J ) 6.8 Hz,
COCH2CH2N), 3.65 (3 H, s, OCH3), 6.62 (2 H, d, J ) 8.6 Hz,
H-3′,5′), 6.74 (2 H, d, J ) 8.6 Hz, H-2′,6′), 7.92 (2 H, m, J )
9.3 Hz, H-3,6), 8.01 (2 H, d, J ) 9.3 Hz, H-4,5), 8.33 (2 H, m,
H-1,8), 10.36 (2 H, s, NHCO). MS (EI), m/z: 581.3260
(C34H41N6O3 M + H requires 581.3240).
2,7-Bis(3-pyr r olidin -1-ylpr opion am ido)-9-(2-am in oph e-
n yla m in o)a cr id in e (35). 2,7-Bisamido-9-chloroacridine 6
(150 mg, 0.3 mmol) was treated with 1,2-phenylenediamine
(70 mg) according to the general procedure to give the desired
1
product 35 (90 mg, 53%) as a dark-red solid. Mp >320 °C. H
NMR (CDCl3): δ 1.79 (8 H, m, N(CH2CH2)2), 2.46 (4 H, t, J )
5.8 Hz, COCH2CH2N), 2.58 (8 H, m, N(CH2CH2)2), 2.77 (4 H,
t, J ) 5.8 Hz, COCH2CH2N), 6.39 (1 H, m, H-1′), 6.48 (1 H, m,
H-4′), 6.82 (2 H, m, H-1′,2′), 7.55 (2 H, dd, J ) 9.3 Hz, J ) 2.3
Hz, H-3,6), 7.98 (2 H, d, J ) 9.3 Hz, H-4,5), 8.18 (2 H, d, J )
2.3 Hz, H-1,8), 11.26 (2 H, s, NHCO). MS, m/z: 566.3219
(C33H40N7O2 M + H requires 566.3243).
2,7-Bis(3-pyr r olidin -1-ylpr opion am ido)-9-(3-am in oph e-
n yla m in o)a cr id in e (36). 2,7-Bisamido-9-chloroacridine 6
(150 mg, 0.3 mmol) was treated with 1,3-phenylenediamine
(70 mg) according to the general procedure to give 36 (100 mg,
59%) as brown solid. Mp >320 °C. 1H NMR (CDCl3): δ 1.75 (8
H, m, N(CH2CH2)2), 2.45 (4 H, t, J ) 5.8 Hz, COCH2CH2N),
2.56 (8 H, m, N(CH2CH2)2), 2.76 (4 H, t, J ) 5.8 Hz,
COCH2CH2N), 5.96 (1 H, s, H-2′), 6.04 (1 H, d, J ) 7.4 Hz,
H-4′), 6.12 (1 H, d, J ) 8.6 Hz, H-6′), 6.85 (2 H, dd, J ) 8.6
Hz, J ) 5.75 Hz, H-5′), 7.69 (2 H, dd, J ) 9.3 Hz, J ) 2.25 Hz,
H-3,6), 8.00 (2 H, d, J ) 9.3 Hz, H-4,5), 8.12 (2 H, d, J ) 2.3
Hz, H-1,8), 11.52 (2 H, s, NHCO). MS, m/z: 566.3249
(C33H40N7O2 M + H requires 566.3243).
2,7-Bis(3-p yr r olid in -1-ylp r op ion a m id o)-9-(3-d im eth y-
la m in op h en yla m in o)a cr id in e (37). 2,7-Bisamido-9-chloro-
acridine 6 (150 mg, 0.3 mmol) was treated with N,N-dimethyl-
1,3-phenylenediamine (85 mg) according to the general
procedure to give the desired product 37 (70 mg, 39%) as a
dark-brown solid. Mp >320 °C. 1H NMR (CDCl3): δ 1.75 (8 H,
m, N(CH2CH2)2), 2.53 (4 H, t, J ) 6.0 Hz, COCH2CH2N), 2.64
(8 H, m, N(CH2CH2)2), 2.75 (6 H, s, N(CH2)2), 2.85 (4 H, t, J )
6.0 Hz, COCH2CH2N), 6.04 (1 H, m, J ) 7.8 Hz, H-4′), 6.23 (2
H, m, H-2′,6′), 6.92 (1 H, dd, J ) 7.3 Hz, J ) 7.3 Hz, H-5′),
7.81 (2 H, dd, J ) 9.3 Hz, J ) 2.3 Hz, H-3,6), 8.02 (2 H, d, J
) 9.3 Hz, H-4,5), 8.10 (2 H, d, J ) 2.3 Hz, H-1,8), 11.28 (2 H,
s, NHCO). MS, m/z: 594.3572 (C35H44N7O2 M + H requires
594.3556).
2,7-Bis(3-pyr r olidin -1-ylpr opion am ido)-9-(4-am in oph e-
n yla m in o)a cr id in e (38). 2,7-Bisamido-9-chloroacridine 6
(150 mg, 0.3 mmol) was treated with 1,4-phenylenediamine
(70 mg) according to the general procedure to give the desired
1
product 38 (55 mg, 32%) as a dark-red solid. Mp >320 °C. H
NMR (CDCl3): δ 1.79 (8 H, m, N(CH2CH2)2), 2.45 (4 H, t, J )
6.0 Hz, COCH2CH2N), 2.57 (8 H, m, N(CH2CH2)2), 2.76 (4 H,
t, J ) 6.0 Hz, COCH2CH2N), 6.48 (2H, d, J ) 8.8 Hz, H-3′,5′),
6.66 (2H, d, J ) 8.8 Hz, H-2′,6′), 7.60 (2 H, dd, J ) 9.0 Hz, J
) 2.3 Hz, H-3,6), 7.98 (2 H, d, J ) 9.0 Hz, H-4,5), 8.19 (2 H, d,
J ) 2.3 Hz, H-1,8), 11.43 (2 H, s, NHCO). MS, m/z: 566.3225
(C33H40N7O2 M + H requires 566.3243).
2,7-Bis(3-p yr r olid in -1-ylp r op ion a m id o)-9-(4-(d im eth y-
la m in o)p h en yla m in o)a cr id in e (39). 2,7-Bisamido-9-chlo-
roacridine 6 (150 mg, 0.3 mmol) was treated with N,N-
dimethyl-1,4-phenylenediamine (90 mg) according to the general
procedure to give the desired product 39 (50 mg, 28%) as a
dark-brown solid. Mp >320 °C. 1H NMR (CDCl3): δ 1.77 (8 H,
m, N(CH2CH2)2), 2.47 (4 H, t, J ) 5.7 Hz, COCH2CH2N), 2.54
(8 H, m, N(CH2CH2)2), 2.78 (4 H, t, J ) 5.75 Hz, COCH2CH2N),
2.82 (6 H, s, N(CH2)2), 6.57 (2 H, d, J ) 9.0 Hz, H-3′,5′), 6.77
(2 H, d, J ) 9.0 Hz, H-2′,6′), 7.70 (2 H, dd, J ) 9.2 Hz, J ) 2.2
Hz, H-3,6), 8.01 (2 H, d, J ) 9.2 Hz, H-4,5), 8.12 (2 H, d, J )