T.K. Mazu et al. / European Journal of Medicinal Chemistry 46 (2011) 2378e2385
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for 12 h and then allowed to cool to rt. The solvent was removed
5.5.8. 5-(5-Cyclohexylpentyl)-8-(methylthio)-5H-pyrido [3,2-b]
under vacuum, the residue was diluted with H2O (50 mL) and
extracted with EtOAc (3 ꢂ 30 mL). The pooled organic layer was
washed with brine (30 mL), dried over anhydrous Na2SO4, solvent
was removed under vacuum and the crude product purified on
column chromatography using hexanes as eluent. The pure product
9, was an oily liquid (2.17 g, 90% yield). 1H NMR (300 MHz, CDCl3):
indole (10h)
Yellow oily liquid (87 mg, 51% yield), 1H NMR (300 MHz, CDCl3):
d8.87 (d, 2H, J ¼ 7.8 Hz), 8.41 (dd, 2H, J ¼ 5.4, 1.6 Hz), 7.98 (d, 1H,
J ¼ 7.3 Hz), 7.46 (t, 2H, J ¼ 4.1 Hz), 3.85 (d, 2H, J ¼ 1.2 Hz), 2.7 (s, 3H),
1.96e1.73 (m, 12H), 1.15e0.84 (m, 7H).
d
0.8 (t, 2H, J ¼ 10.2 Hz), 1.00e1.38 (m, 9H), 1.52e168 (m, 6H),
5.5.9. 5-(5-Cyclohexylpentyl)-8-methoxy-5H-pyrido [3,2-b]indole
(10i)
1.70e1.80 (m, 2H), 3.10 (t, 2H, J ¼ 6.9 Hz).
Yellow oily liquid (94 mg, 53% yield), 1H NMR (300 MHz, CDCl3):
d
8.99 (d, 2H, J ¼ 4.6 Hz), 8.81(t, 2H, J ¼ 7.8 Hz), 7.97e7.54 (m, 3H),
5.5. General procedure for the synthesis of derivatives of 5-(5-
Cyclohexylpentyl)-5H-pyrido [3,2-b]indole, 10
4.1 (t, 2H, J ¼ 6.1 Hz), 2,31(s, 3H), 1.84e1.76 (m, 10H), 1.31e1.12
(m, 7H), 0.86 (t, 2H, J ¼ 1.4 Hz).
To a solution of 8 (100 mg) in dried 1, 2-dimethoxyethane (5 ml),
NaH (20 mg, 0.83 mmol) and then 9 (636 mg, 2.27 mmol) were
added. The reaction was stirred at rt for 12 h, solvent was removed
under reduced pressure and the residue partitioned between H2O
(10 ml) and EtOAc (2 ꢂ 30 ml). The pooled organic phase was
washed with brine, dried over anhydrous Na2SO4 and the solvent
was removed under reduced pressure. The crude product was
purified by column chromatography (hexane: EtOAc 4:1).
5.5.10. 5-(5-Cyclohexylpentyl)-5H-pyrido [3,2-b]indole-8-
carbonitrile (10j)
Yellow oily liquid (68 mg, 38% yield), 1H NMR (300 MHz, CDCl3):
d
8.76 (d, 2H, J ¼ 6.8 Hz), 8.67 (t, 2H, J ¼ 2.1 Hz), 7.81e7.43 (m, 3H),
3.61 (t, 2H, J ¼ 4.5 Hz), 2.15e1.84 (m, 10H), 1.57e1.16 (m, 6H), 0.87
(t, 3H, J ¼ 7.2 Hz).
5.6. General procedure for the synthesis of derivatives of 5-(5-
cyclohexylpentyl)-1-methyl-5H-pyrido [3,2-b]indol-1-ium iodide, 11
5.5.1. 5-(5-Cyclohexylpentyl)-5H-pyrido [3,2-b]indole (10a)
Yellow oily liquid (76.2 mg, 40% yield), 1H NMR (300 MHz,
To a solution of 10 (100 mg) in toluene (3 ml), methyl iodide
(0.3 g, 2.1 mmol) was added in a pressure tube and sealed. The
reaction mixture was stirred at 110 ꢀC for 24 h, and then allowed to
cool to rt, diluted with Et2O (15 mL), to form a precipitate which
was filtered and washed with Et2O (3 ꢂ 20 ml). The crude product
was recrystallized from MeOH.
CDCl3):
d
8.55 (dd, 1H, J ¼ 1.2, 1.2 Hz), 8.40 (dd, 1H, 6.0, 1.8 Hz),
7.69e7.44 (m, 3H), 7.37e7.29 (m, 2H), 4.30 (t, 2H, J ¼ 4.8 Hz),
2.04e1.63 (m, 8H), 1.34e1.13 (m, 9H), 0.88(t, 2H, J ¼ 8 Hz).
5.5.2. 6-Chloro-5-(5-cyclohexylpentyl)-5H-pyrido [3,2-b]indole (10b)
Yellow oily liquid (96.3 mg, 55% yield), 1H NMR (300 MHz,
CDCl3):
d
9.01 (d, 2H, J ¼ 6.6 Hz), 8.85 (t, 2H, J ¼ 6.2 Hz), 8.02 (d, 1H,
5.6.1. 5-(5-cyclohexylpentyl)-1-methyl-5H-pyrido [3,2-b]indol-1-
ium iodide (11a)
J ¼ 8.1 Hz) 7.85 (d, 2H, J ¼ 2.5 Hz), 4.1(t, 2H, J ¼ 5.1 Hz), 2.1e1.78
(m, 10H), 1.68e1.44 (m, 7H), 0.98 (t, 2H, J ¼ 1.8 Hz).
Yellow solid (28.5 mg, 32.9%), mp: 228e230 ꢀC; (DMSO-d6):
d8.96 (d, 1H, J ¼ 8.7 Hz), 8.90 (d, 1H, J ¼ 6.0 Hz), 8.56 (d, 1H,
5.5.3. 7-Chloro-5-(5-cyclohexylpentyl)-5H-pyrido[3,2-b]indole(10c)
J ¼ 8.4 Hz), 8.20e8.00 (m, 2H), 7.90 (t, 1H, J ¼ 7.5 Hz), 7.54 (t, 1H,
J ¼ 7.2 Hz), 4.80 (s, 3H), 4.66 (t, 2H, J ¼ 6.9 Hz),1.78(t, 2H, J ¼ 6.6 Hz),
1.64e1.52 (m, 5H), 1.30e1.20 (m, 4H), 1.14e1.00 (m, 6H), 0.80e0.74
(t, 2H, J ¼ 10.2 Hz). Anal. Calcd for C23H31IN2: C, 59.74; H, 6.76;
N, 6.06. Found: C, 59.48; H, 6.71; N, 5.95.
Yellow oily liquid (80.6 mg, 46% yield), 1H NMR (300 MHz,
CDCl3):
d
8.96 (d, 2H, J ¼ 4.8 Hz), 8.6 (t, 2H, J ¼ 5.8 Hz), 8.21 (d, 1H,
J ¼ 2.1 Hz), 7.81 (d, 2H, J ¼ 3.4 Hz), 4.3 (t, 2H, J ¼ 4.8 Hz), 2.03e1.78
(m, 6H), 1.54e1.16 (m, 8H), 1.02e0.89(m, 5H).
5.5.4. 8-Chloro-5-(5-cyclohexylpentyl)-5H-pyrido[3,2-b]indole(10d)
5.6.2. 6-Chloro-5-(5-cyclohexylpentyl)-1-methyl-5H-pyrido [3,2-b]
indol-1-ium iodide (11b)
Yellow oily liquid (91.1 mg, 52% yield), 1H NMR (300 MHz,
CDCl3):
d
8.99 (d, 1H, J ¼ 3.5 Hz), 8.97 (d, 2H, J ¼ 4.3 Hz), 8.62 (d, 2H,
Yellow solid (35% yield), mp: 246e248 ꢀC; 1H NMR (300 MHz,
J ¼ 2.1 Hz), 7.84 (t, 2H, J ¼ 4.5 Hz), 4.36 (t, 2H, J ¼ 1.6 Hz), 1.85e1.65
CDCl3):
d
9.01 (d, 2H, J ¼ 6 Hz), 8.63 (d, 1H, J ¼ 1.8 Hz), 8.14e8.08 (m,
(m, 10H), 1.29e1.16 (9m, 7H), 0.86 (t, 2H, J ¼ 2.8 Hz).
2H), 7.95e7.91 (m,1H), 4.82 (s, 3H),1.76e1.58 (m, 6H),1.21e1.00 (m,
12 H), 0.78 (t, 3H). Anal. Calcd for C23H30ClIN2: C, 55.69; H, 6.09;
N, 5.64. Found: C, 55.69; H, 6.09; N, 5.61.
5.5.5. 5-(5-Cyclohexylpentyl)-8-(trifluoromethyl)-5H-pyrido [3,2-b]
indole (10e)
Yellow oily liquid (65.5 mg, 42% yield), 1H NMR (300 MHz,
5.6.3. 7-Chloro-5-(5-cyclohexylpentyl)-1-methyl-5H-pyrido [3,2-b]
indol-1-ium iodide (11c)
CDCl3):
d
8.71 (s, 1H), 8.61 (d, 1H, J ¼ 3.5 Hz), 7.81e7.79 (m, 3H), 7.6
(d, 2H, J ¼ 4.3 Hz), 4.36e4.17 (m, 2H), 1.92 (t, 2H, J ¼ 7.8 Hz),
1.88e1.16 (m, 12H), 1.58e0.89 (m, 7H).
Yellow solid (55% yield), mp: 234e235 ꢀC; 1H NMR (300 MHz,
CDCl3):
d
9.62 (d, 1H, J ¼ 5.7 Hz), 8.77 (d, 1H, J ¼ 9 Hz), 8.34 (d, 2H,
J ¼ 1.5 Hz), 8.18e8.13 (m, 2H), 5.04 (s, 3H), 4.58 (t, 2H, J ¼ 7.2 Hz),
1.90 (d, 2H, J ¼ 7.5 Hz), 1.65e1.56 (m, 12H), 1.33e1.12 (m, 5H). Anal.
Calcd for C23H30ClIN2: C, 55.60; H, 6.09; N, 5.64. Found: C, 55.35;
H, 6.09; N, 5.66.
5.5.6. 5-(5-Cyclohexylpentyl)-8-fluoro-5H-pyrido [3,2-b]indole (10f)
Yellow oily liquid (71 mg, 39% yield), 1H NMR (300 MHz, CDCl3):
d
8.81 (d, 2H, J ¼ 3.6 Hz), 8.78 (d, 1H, J ¼ 4.2 Hz), 8.2 (d, 2H,
J ¼ 1.8 Hz), 7.86 (t, 2H, J ¼ 5.6 Hz), 3.8 (t, 2H, J ¼ 2.7 Hz), 1.98e1.76
(m, 10H), 1.52e1.18 (m, 6H), 0.98 (t, 3H, J ¼ 4.8 Hz).
5.6.4. 8-Chloro-5-(5-cyclohexylpentyl)-1-methyl-5H-pyrido [3,2-b]
indol-1-ium iodide (11d)
5.5.7. 5-(5-Cyclohexylpentyl)-8-methyl-5H-pyrido[3,2-b]indole(10g)
Yellow solid (57% yield), mp: 244e245 ꢀC; 1H NMR (300 MHz,
Yellow oily liquid (103 mg, 56% yield), 1H NMR (300 MHz,
CDCl3): d8.54e8.52 (m, 2H), 8.34 (s, 1H), 7.65e7.62 (m, 2H), 7.47 (d,
CDCl3):
d
8.63 (d,1H, J ¼ 4.7 Hz), 8.45 (d, 2H, J ¼ 1.5 Hz), 8.01 (dd, 2H,
2H, J ¼ 1.2 Hz), 4.23 (s, 3H), 1.64e1.31 (m, 14H), 1.28e1.13 (m, 6H).
Anal. Calcd for C24H32ClIN2: C, 55.60; H, 6.09; N, 5.64. Found:
C, 55.39; H, 6.02; N, 5.65.
J ¼ 6.3, 2.1 Hz), 7.74 (d, 2H, J ¼ 2.6 Hz), 4.01e3.80 (m, 2H),1.98 (t, 3H,
J ¼ 6.8 Hz), 1.78e1.43 (m, 10H), 1.21 0.89 (m, 9H).