3886
M. Laronze-Cochard et al. / European Journal of Medicinal Chemistry 44 (2009) 3880–3888
(1.50 mmol) and Et3N (240 mg, 330
m
L, 2.38 mmol) dissolved in
254, 355, 386 nm. IR (KBr)
n
3436 (NH), 3066, 1652 (CO), 1533, 1476,
9.19 (s, 1H, H-9), 8.70 (t, J ¼ 5.7 Hz,
CH2Cl2 (2 mL); Stirring: 72 h. Dilution with EtOAc (100 mL); Extrac-
tion and purification by column chromatography (eluent: CH2Cl2/
MeOH, 90/10 / 80/20) gave 8a as a yellow powder (119 mg, 43%);
1251 cmꢂ1. 1H NMR (DMSO-d6)
d
2H, 2 ꢁ NHCO), 8.15 (d, J ¼ 8.1 Hz, 2H, H-1, H-3), 7.77 (d, J ¼ 6.2 Hz,
2H, H-3, H-6), 7.64 (t, J ¼ 7.1 Hz, 2H, H-2, H-7), 5.14 (d, J ¼ 5.7 Hz, 4H,
2 ꢁ H-10, 2 ꢁ H-100), 3.66 (t, J ¼ 7.7 Hz, 4H, 2 ꢁ H-50, 2 ꢁ H-50), 3.11 (s,
18H, 6 ꢁ CH3), 2.86 (t, J ¼ 7.7 Hz, 4H, 2 ꢁ H-40, 2 ꢁ H-400). 13C NMR
mp 152–155 ꢀC. UV
l
245, 356, 386 nm. IR (KBr)
2828, 2775, 1678 (CO), 1661, 1528, 1414, 1264, 1145 cmꢂ1
(CDCl3)
n
3356 (NH), 2942,
.
1H NMR
d
8.82 (s, 1H, H-9), 8.60 (t, J ¼ 6.3 Hz, 2H, 2 ꢁ NHCO), 7.97 (dd,
(DMSO-d6)
d
168.7 (2 ꢁ NHCO), 145.8 (C-4a, C-10a), 137.1 (C-9), 136.5
J ¼ 8.5, 1.1 Hz, 2H, H-1, H-8), 7.81 (dd, J ¼ 6.7, 1.1 Hz, 2H, H-3, H-6),
7.52 (dd, J ¼ 8.5, 6.7 Hz, 2H, H-2, H-7), 5.23 (d, J ¼ 6.3 Hz, 4H, 2 ꢁ H-10,
2 ꢁ H-100), 3.03 (s, 4H, 2 ꢁ H-40, 2 ꢁ H-400), 2.22 (s, 12H, 4 ꢁ CH3). 1H
(C-4, C-5), 127.9 (C-3, C-6), 127.7 (C-1, C-8), 126.2 (C-9a, C-8a), 125.9
(C-2, C-7), 62.0 (C-50, C-500), 52.5 (6 ꢁ CH3), 39.2 (C-10, C-100), 29.3 (C-
40, C-400). MS (ESIþ) m/z ¼ 592.2 [M–I]þ. Anal. calcd. for
C27H39I2N5O2: 45.07 C%, 5.46 H%, 9.74 N%; found: 45.38 C%, 5.69 H%,
9.48 N%.
NMR (DMSO-d6)
d
9.19 (s, 1H, H-9), 8.63 (t, J ¼ 6.0 Hz, 2H, 2 ꢁ NHCO),
8.13 (d, J ¼ 8.4 Hz, 2H, H-1, H-8), 7.73 (d, J ¼ 6.0 Hz, 2H, H-3, H-6), 7.64
(t, J ¼ 8.2 Hz, 2H, H-2, H-7), 5.12 (d, J ¼ 6.0 Hz, 4H, 2 ꢁ H-10, 2 ꢁ H-100),
3.06 (s, 4H, 2 ꢁ H-40, 2 ꢁ H-400), 2.26 (s, 12H, 4 ꢁ CH3). 13C NMR
4.1.6.5. 2,20-[4,5-Acridindiylbis(methyleneimino)]bis[N-methyl-N-(3-
oxopropyl)pyrrolidinium] diiodide (14b). Tertiary amine 10b:
(CDCl3)
d
170.2 (2 ꢁ NHCO), 146.8 (C-4a, C-10a), 136.9 (C-9), 136.0 (C-
4, C-5),129.5 (C-3, C-6),127.9 (C-1, C-7),126.6 (C-9a, C-8a),125.8 (C-2,
C-7), 63.1 (C-40, C-400), 45.8 (4 ꢁ CH3), 40.5 (C-10, C-100). MS (ESIþ) m/
z ¼ 408.2 [M þ H]þ. EI-MS m/z (%) ¼ 407 (100, [M]þ), 349 (52). HRMS
calcd. for C23H29N5O2: 407.2321; found: 407.2308.
50.0 mg (0.10 mmol); CH2Cl2: 10 mL; MeI: 710 mg (310
5.0 mmol); Stirring: 2 h. Yield: 55 mg (72%). Brown amorphous
solid. UV 220, 253, 356, 386 nm. IR (KBr) 3436 (NH), 3268, 3066,
2951, 1652 (CO), 1537, 1458, 1423, 1238 cmꢂ1 1H NMR (DMSO-d6)
mL,
l
n
.
4.1.5.2.2. N,N0-[4,5-Acridindiylbis(methylene)]bis(3-dimethylami-
nopropanamide) (8b). Prepared in 65% yield from 6 and 3-(N,N-
dimethylamino)propanoic acid hydrochloride according to the
General procedure. For details see, Supplementary information.
d
9.19 (s, 1H, H-9), 8.71 (t, J ¼ 5.4 Hz, 2H, 2 ꢁ NHCO), 8.14 (d,
J ¼ 8.4 Hz, 2H, H-1, H-8), 7.78 (d, J ¼ 6.6 Hz, 2H, H-3, H-6), 7.65 (t,
J ¼ 7.6 Hz, 2H, H-2, H-7), 5.14 (d, J ¼ 5.4 Hz, 4H, 2 ꢁ H-10, 2 ꢁ H-100),
3.69 (t, J ¼ 7.6 Hz, 4H, 2 ꢁ H-50, 2 ꢁ H-500), 3.50 (d, J ¼ 5.0 Hz, 8H,
4 ꢁ H-70, 4 ꢁ H-700), 3.03 (s, 6H, 2 ꢁ CH3), 2.88 (t, J ¼ 7.6 Hz, 4H,
2 ꢁ H-40, 2 ꢁ H-400), 2.11 (sl, 8H, 4 ꢁ H-80, 4 ꢁ H-800). 13C NMR
4.1.6. General procedure for the quaternization of 8a,b, 10a,b
and 11a with MeI
(DMSO-d6)
d
168.8 (2 ꢁ NHCO), 145.8 (C-4a, C-10a), 137.0 (C-9),
To a solution of tertiary amines (8, 10, 11) in distilled CH2Cl2 was
added at 0 ꢀC, iodomethane dissolved in CH2Cl2. The suspension
was stirred at room temperature under N2 atmosphere, filtered,
washed with diethylether and dried to give the corresponding
quaternary ammonium salts.
136.5 (C-4, C-5), 128.0 (C-3, C-6), 127.7 (C-1, C-8), 126.2 (C-9a, C-8a),
125.9 (C-2, C-7), 63.8 (2 ꢁ C-70, 2 ꢁ C-700), 59.7 (C-50, C-500), 47.8
(2 ꢁ CH3), 39.1 (C-10, C-100), 30.0 (C-40, C-400), 21.3 (2 ꢁ C-80, 2 ꢁ C-
800). MS (ESIþ) m/z ¼ 644.3 [M–I]þ. Anal. calcd. for C31H43I2N5O2:
48.26 C%, 5.61 H%, 9.08 N%; found: 48.58 C%, 5.99 H%, 9.41 N%.
4.1.6.1. 2,20-[4,5-Acridindiylbis(methyleneimino)]bis(N,N,N-trimethyl-
2-oxoethylammonium) diiodide (13a). Prepared in 91% yield from 8a
and iodomethane according to the General procedure. For details see,
Supplementary information.
4.1.7. Synthesis of compounds 16–19
Procedure A: To a suspension of primary amine, K2CO3, and
tetrabutylammonium hydrogen sulfate (TBAHS) in distilled CH2Cl2
was added 4,5-bis(bromomethyl)acridine 2 and the mixture was
stirred at 50 ꢀC for 3–24 h under N2 atmosphere. The precipitate
was filtered, the filtrate was extracted with CH2Cl2 (ꢁ2) and
washed with 1 N aqueous NaOH solution.
Procedure B: To a solution of 4 in distilled DMSO was added the
primary amine and the reaction mixture was stirred at room
temperature. The mixture was extracted with EtOAc (ꢁ2) and
washed with brine.
4.1.6.2. 2,20-[4,5-Acridindiylbis(methyleneimino)]bis[N-methyl-N-(2-
oxoethyl)pyrrolidinium] diiodide (14a). Prepared in 61% yield from
10a and iodomethane according to the General procedure. For
details see, Supplementary information.
4.1.6.3. 2,20-[4,5-Acridindiylbis(methyleneimino)]bis[N-methyl-N-(2-
oxoethyl)piperidinium] diiodide (15a). Tertiary amine 11a: 58.0 mg
Purification (Procedures A and B): the combined organic layers
were dried over MgSO4, filtered and concentrated under reduced
pressure. The residue was crystallized or purified by column
chromatography.
(0.12 mmol); CH2Cl2: 10 mL; MeI: 851 mg (375
Stirring: 15 h. Yield: 65 mg (70%). Yellow powder; mp 231–233 ꢀC.
UV 252, 338, 347, 356, 367, 386 nm. IR (KBr) 3427 (NH), 3216,
3048, 2934, 1674 (CO), 1529, 1445, 1252, 758 cmꢂ1. 1H NMR (DMSO-
d6)
mL, 6.0 mmol);
l
n
d
9.22 (s, 1H, H-9), 9.06 (br s, 2H, 2 ꢁ NHCO), 8.18 (d, J ¼ 8.2 Hz,
4.1.7.1. 4,5-Bis(benzylaminomethyl)acridine (16). Procedure B: 4,5-
bis(chloromethyl)acridine 4: 50 mg (0.18 mmol); DMSO: 15 mL;
benzylamine: 235 mg (240 mL, 0.40 mmol); Stirring: 6 h. Extrac-
2H, H-1, H-8), 7.82 (d, J ¼ 6.4 Hz, 2H, H-3, H-6), 7.67 (t, J ¼ 7.5 Hz, 2H,
H-2, H-7), 5.19 (d, J ¼ 5.4 Hz, 4H, 2 ꢁ H-10, 2 ꢁ H-100), 4.31 (s, 4H,
2 ꢁ H-40, 2 ꢁ H-400), 3.66–3.50 (m, 8H, 4 ꢁ H-60, 4 ꢁ H-600), 3.31 (s,
6H, 2 ꢁ CH3), 1.86 (br s, 8H, 4 ꢁ H-70, 4 ꢁ H-700), 1.58 (br s, 4H,
tion: EtOAc (2 ꢁ 25 mL) and brine (10 mL). Purification by column
chromatography (CH2Cl2/MeOH, 90/10) afforded 16 as a beige
2 ꢁ H-80, 2 ꢁ H-800). 13C NMR (DMSO-d6)
d
163.6 (2 ꢁ NHCO), 145.7
powder (33 mg; 44%); mp 350 ꢀC. UV
l
252, 358 nm. IR (KBr)
n 3445
(C-4a, C-10a), 137.2 (C-9), 135.6 (C-4, C-5), 128.5 (C-3, C-6), 128.1
(C-1, C-8), 126.2 (C-9a, C-8a), 125.9 (C-2, C-7), 61.5 (2 ꢁ C-60
2 ꢁ C-600), 60.8 (C-40, C-400), 49.4 (2 ꢁ CH3), in DMSO peaks (C-10,
C-100), 20.8 (C-80, C-800), 19.6 (2 ꢁ C-70, 2 ꢁ C-700). MS (ESIþ)
m/z ¼ 644.4 [M–I]þ. Anal. calcd. for C31H43I2N5O2: 48.26 C%, 5.61
H%, 9.08 N%; found: 48.39 C%, 5.91 H%, 9.37 N%.
(NH), 2916, 2704, 1635, 1427, 754 cmꢂ1. 1H NMR (CDCl3)
d
8.77 (s,
1H, H-9), 7.94 (d, J ¼ 8.5 Hz, 2H, H-1, H-8), 7.68 (d, J ¼ 6.7 Hz, 2H, H-
3, H-6), 7.49 (t, J ¼ 7.6 Hz, 2H, H-2, H-7), 7.37–7.23 (m, 10H, 2 ꢁ H-50,
2 ꢁ H-500, 2 ꢁ H-60, 2 ꢁ H-600, H-70, H-700), 4.51 (s, 4H, 2 ꢁ H-10, 2 ꢁ H-
100), 3.79 (s, 4H, 2 ꢁ H-30, 2 ꢁ H-300). 1H NMR (DMSO-d6)
d 9.90 (br s,
2H, H-20, H-200), 9.30 (s, 1H, H-9), 8.31 (d, J ¼ 8.3 Hz, 2H, H-1, H-8),
8.08 (d, J ¼ 6.5 Hz, 2H, H-3, H-6), 7.74–7.69 (m, 6H, H-2, H-7, 2 ꢁ H-
50, 2 ꢁ H-500), 7.42 (m, 6H, 2 ꢁ H-60, 2 ꢁ H-600, H-70, H-700), 4.93 (s, 4H,
2 ꢁ H-10, 2 ꢁ H-100), 4.41 (s, 4H, 2 ꢁ H-30, 2 ꢁ H-300). 13C NMR (CDCl3)
4.1.6.4. 2,20-[4,5-Acridindiylbis(methyleneimino)]bis(N,N,N-trimethyl-
3-oxopropylammonium) diiodide (13b). Tertiary amine 8b: 100 mg
(0.23 mmol); CH2Cl2: 8 mL; MeI: 1.63 g (715
m
L,11.5 mmol); Stirring:
d
146.6 (C-4a, C-10a), 138.8 (C-40, C-400), 136.8 (C-9), 136.1 (C-4, C-5),
24 h. Yield: 139 mg (84%). Yellow powder; mp 158–159 ꢀC. UV
l
220,
130.3 (C-3, C-6), 128.6 (2 ꢁ C-60, 2 ꢁ C-600),128.4 (2 ꢁ C-50, 2 ꢁ C-500),