Tetrahydrobenzindole Derivatives
J ournal of Medicinal Chemistry, 2002, Vol. 45, No. 11 2205
6-Meth oxy-2a -[4-(4-p h en yl-1,2,3,6-tetr a h yd r op yr id yl)-
bu tyl]-2a,3,4,5-tetr ah ydr oben zo[cd]in dol-2(1H)-on e (25e).
This compound was prepared from 15 and 4-phenyl-1,2,3,6-
tetrahydropyridine hydrocloride (50% yield). Mp 134 °C; 1H
NMR (CDCl3) δ 1.06-1.19 (1H, m), 1.27-1.55 (4H, m), 1.75-
1.90 (3H, m), 2.03-2.17 (2H, m), 2.29-2.41 (2H, m), 2.52-
2.64 (5H, m), 2.72-2.82 (1H, m), 3.03-3.13 (2H, m), 3.79 (3H,
s), 6.01 (1H, m), 6.56-6.65 (2H, m), 7.19-7.37 (5H, m), 8.07
(1H, br s); TSPMS m/z 417 (M + H+). Anal. (C27H32N2O2‚H2O)
C, H, N.
m), 1.45-1.60 (2H, m), 1.77-1.96 (3H, m), 2.00-2.10 (1H, m),
2.11-2.24 (1H, m), 2.43-2.54 (2H, m), 2.59-2.69 (1H, m),
2.72-2.90 (5H, m), 3.60 (2H, s), 3.80 (3H, s), 6.69 (2H, m), 6.79
(1H, d, J ) 7.8 Hz), 6.88 (1H, d, J ) 2.2 Hz), 7.12 (2H, m),
7.85 (1H, br s), 7.85 (1H, br s); TSPMS m/z 430 (M + H+).
Anal. (C27H31N3O2‚H2O) C, H, N.
2a -[4-(9-Meth yl-1,2,3,4-tetr a h yd r op yr id o[3,4-b]in d ol-2-
yl)bu tyl]-2a,3,4,5-tetr ah ydr oben z[cd]in dol-2(1H)-on e (26c).
This compound was prepared from 9 and 20c trifluoroacetate
(57% yield). Mp 180-181 °C; 1H NMR (CDCl3) δ 1.03-1.16
(1H, m), 1.27-1.40 (2H, m), 1.44-1.60 (2H, m), 1.74-1.93 (3H,
m), 2.02-2.18 (2H, m), 2.45-2.67 (3H, m), 2.70-2.90 (5H, m),
3.53 (3H, s), 3.60 (2H, s), 6.65 (1H, d, J ) 7.5 Hz), 6.77 (1H, d,
J ) 7.8 Hz), 7.02-7.15 (3H, m), 7.22 (1H, d, J ) 7.3 Hz), 7.43
(1H, d, J ) 7.5 Hz), 8.76 (1H, br s); TSPMS m/z 414 (M + H+).
Anal. (C27H31N3O‚1/2H2O) C, H, N.
2a -[4-(9-Meth oxym eth yl-1,2,3,4-tetr a h yd r op yr id o[3,4-
b]in dol-2yl)bu tyl]-2a,3,4,5-tetr ah ydr oben z[cd]in dol-2(1H)-
on e (26d ). This compound was prepared from 9 and 20d
trifluoroacetate (39% yield). Mp 100-101 °C; 1H NMR (CDCl3)
δ 1.06-1.16 (1H, m), 1.28-1.40 (2H, m), 1.45-1.60 (2H, m),
1.74-1.93 (3H, m), 2.01-2.18 (2H, m), 2.47-2.64 (3H, m),
2.71-2.88 (5H, m), 3.19 (3H, s), 3.67 (2H, br s), 5.30 (2H, s),
6.66 (1H, d, J ) 7.8 Hz), 6.77 (1H, d, J ) 7.8 Hz), 7.05-7.11
(2H, m), 7.16 (1H, dd), 7.37 (1H, d, J ) 8.1 Hz), 7.43 (1H, d,
J ) 7.5 Hz), 8.56 (1H, br s); TSPMS m/z 444 (M + H+). Anal.
(C28H33N3O2‚3/2H2O) C, H, N.
2a -[4-(9-Acetyl-1,2,3,4-tetr a h yd r op yr id o[3,4-b]in d ol-2-
yl)bu tyl]-2a,3,4,5-tetr ah ydr oben z[cd]in dol-2(1H)-on e (26e).
This compound was prepared from 9 and 20e trifluoroacetate
(56% yield). Mp 141-142 °C; 1H NMR (CDCl3) δ 1.02-1.15
(1H, m), 1.28-1.42 (2H, m), 1.42-1.60 (2H, m), 1.75-1.94 (3H,
m), 2.03-2.28 (2H, m), 2.44-2.55 (2H, m), 2.58-2.88 (9H, m),
3.88 (2H, s), 6.67 (1H, d, J ) 7.5 Hz), 6.77 (1H, d, J ) 7.8 Hz),
7.08 (1H, dd), 7.20-7.29 (2H, m), 7.37 (1H, d, J ) 6.8 Hz),
7.78 (1H, d, J ) 6.8 Hz), 8.55 (1H, s); TSPMS m/z 442 (M +
H+). Anal. (C28H31N3O2‚2/5H2O) C, H, N.
2a-[4-(9-Allyl-1,2,3,4-tetr ah ydr opyr ido[3,4-b]in dol-2-yl)-
bu tyl]-2a ,3,4,5-tetr a h yd r oben z[cd ]in d ol-2(1H)-on e (26f).
This compound was prepared from 9 and 20f trifluoroacetate
(46% yield). Mp 140 °C; 1H NMR (CDCl3) δ 1.06-1.18 (1H,
m), 1.30-1.42 (2H, m), 1.46-1.59 (2H, m), 1.76-1.94 (3H, m),
2.06-2.19 (2H, m), 2.46-2.57 (2H, m), 2.60-2.69 (1H, m),
2.74-2.90 (5H, m), 3.88 (2H, s), 4.54-4.60 (2H, m), 4.88 (1H,
dd, J ) 17.1, 1.3 Hz), 5.09 (1H, dd, J ) 10.3 Hz), 5.89 (1H, m),
6.67 (1H, d, J ) 7.8 Hz), 6.77 (1H, d, J ) 7.7 Hz), 7.04-7.16
(3H, m), 7.22 (1H, d, J ) 8.0 Hz), 7.36 (1H, br s), 7.46 (1H, d,
J ) 7.5 Hz); EIMS m/z 439 (M+). Anal. (C29H33N3O‚1/2H2O) C,
H, N.
2a -[4-(9-Dim eth ylca r ba m oyl-1,2,3,4-tetr a h yd r op yr id o-
[3,4-b]in d ol-2-yl)bu tyl]-2a ,3,4,5-tetr a h yd r oben z[cd ]in d ol-
2(1H)-on e (26g). This compound was prepared from 9 and
20g trifluoroacetate (90% yield). Mp 141 °C; 1H NMR (CDCl3)
δ 1.00-1.13 (1H, m), 1.25-1.38 (2H, m), 1.44-1.58 (2H, m),
1.74-1.92 (3H, m), 2.02-2.18 (2H, m), 2.44-2.65 (3H, m),
2.70-2.86 (5H, m), 3.01 (6H, s), 3.70 (2H, br s), 6.65 (1H, d,
J ) 7.6 Hz), 6.75 (1H, d, J ) 7.8 Hz), 7.06 (1H, dd), 7.10-7.21
(3H, m), 7.41 (1H, d, J ) 7.6 Hz), 8.98 (1H, br s); TSPMS m/z
471 (M + H+). Anal. (C29H34N4O2‚9/5H2O) C, H, N.
6-Car bam oyl-2a-[4-(4-ph en yl-1,2,3,6-tetr ah ydr opyr idyl)-
bu tyl]-2a ,3,4,5-tetr a h yd r oben zo[cd ]in d ol-2(1H)-on e (25f).
A solution of 12 (270 mg, 0.74 mmol), 1,2,3,6-tetrahydro-4-
phenylpyridine hydrochloride (290 mg, 1.5 mmol), and diiso-
propylethylamine (0.51 mL, 2.9 mmol) in DMF was stirred at
room temperature for 17 h. The reaction mixture was poured
into AcOEt, and the whole was washed with H2O. The organic
layer was dried (Na2SO4) and evaporated. The residue was
purified by silica gel column chromatography (eluent: CHCl3/
MeOH ) 30/1) to afford colorless crystals. Aqueous LiOH (4
N, 6 mL, 24 mmol) was added to the crystals in THF (6 mL),
and the mixture was refluxed for 30 h. Aqueous HCl (5 N)
was added, and the mixture was extracted with CHCl3. The
organic layer was dried (Na2SO4) and evaporated to afford the
carboxylic acid derivative as colorless crystals. A solution of
the crystals, DCC (270 mg, 1.3 mmol), and HOBT (170 mg,
1.3 mmol) in DMF (12 mL) was stirred at room temperature
for 3 h and then was cooled to 0 °C. Aqueous NH3 (28%, 6 mL)
was added, and the mixture was stirred at room temperature
for 2 h and then was evaporated. The residue was purified on
an HP-20 (Mitsubishi Chemical) (eluent: H2O/MeOH ) 10/1
and then MeOH) to afford 25f as colorless crystals (150 mg,
48% yield). Mp 119 °C; 1H NMR (CD3OD) δ 0.96-1.08 (1H,
m), 1.08-1.54 (4H, m), 1.54-1.64 (1H, m), 1.65-2.00 (3H, m),
2.00-2.12 (1H, m), 2.12-2.28 (1H, m), 2.30-2.45 (2H, m),
2.51-2.61 (2H, m), 2.63-2.74 (2H, m), 2.95-3.11 (4H, m),
3.40-3.50 (1H, m), 6.07 (1H, m), 6.76 (1H, d, J ) 8.0 Hz),
7.19-7.50 (6H, m), 7.86 (1H, br s); TSPMS m/z 430 (M + H+).
Anal. (C27H31N3O2‚13/5H2O) C, H, N.
6-Br om o-2a -[4-(4-p h en yl-1,2,3,6-tetr a h yd r op yr id yl)bu -
t yl]-2a ,3,4,5-t et r a h yd r oben zo[cd ]in d ol-2(1H)-on e (25g).
This compound was prepared from 13 and 4-phenyl-1,2,3,6-
tetrahydropyridine hydrocloride (73% yield). Mp 140-141 °C;
1H NMR (CDCl3) δ 1.03-1.17 (1H, m), 1.24-1.55 (4H, m),
1.72-1.93 (3H, m), 2.03-2.20 (2H, m), 2.28-2.42 (2H, m),
2.48-2.79 (6H, m), 3.03-3.14 (2H, m), 6.01 (1H, s), 6.59 (1H,
d, J ) 8.3 Hz), 7.19-7.31 (6H, m), 9.16 (1H, br s); TSPMS m/z
465, 467 (M + H+). Anal. (C26H29N2OBr‚1/2H2O) C, H, N.
6-Hyd r oxy-2a -[4-(4-p h en yl-1,2,3,6-tetr a h yd r op yr id yl)-
bu tyl]-2a,3,4,5-tetr ah ydr oben zo[cd]in dol-2(1H)-on e (25h ).
This compound was prepared from 14 and 4-phenyl-1,2,3,6-
tetrahydropyridine hydrocloride (89% yield). 1H NMR (CDCl3)
δ 1.01-1.14 (1H, m), 1.22-1.37 (2H, m), 1.39-1.54 (2H, m),
1.73-1.93 (3H, m), 2.00-2.22 (3H, m), 2.31-2.42 (2H, m),
2.50-2.82 (6H, m), 3.08-3.14 (2H, m), 6.04 (1H, m), 6.53 (1H,
d, J ) 8.0 Hz), 6.59 (1H, d), 7.19-7.38 (5H, m), 7.98 (1H, br
s); TSPMS m/z 403 (M + H+). Hydrochloride. Mp 120-122 °C
(AcOEt/MeOH). Anal. (C26H30N2O3‚HCl‚3/5H2O) C, H, N.
2a -[4-(2,3,4,9-Tet r a h yd r o-1H -p yr id o[3,4-b]in d ol-2-yl)-
bu tyl]-2a,3,4,5-tetr ah ydr oben zo[cd]in dol-2(1H)-on e (26a).
This compound was prepared from 9 and 1,2,3,4-tetrahydro-
9H-pyrido[3,4-b]indole (38% yield). Mp 151-152 °C; 1H NMR
(CD3OD) δ 1.06-1.10 (1H, m), 1.22-1.36 (2H, m), 1.46-1.60
(2H, m), 1.76-1.95 (3H, m), 2.01-2.08 (1H, m), 2.11-2.24 (2H,
m), 2.44-2.57 (2H, m), 2.60-2.70 (1H, m), 2.75-2.90 (5H, m),
3.60 (2H, s), 6.69 (1H, d, J ) 7.5 Hz), 6.79 (1H, d, J ) 7.8 Hz),
6.96 (1H, dd, J ) 7.4, 7.0 Hz), 7.04 (1H, dd, J ) 6.8 Hz), 7.12
(1H, dd), 7.25 (1H, d), 7.36 (1H, d), 7.85 (1H, br s); TSPMS
m/z 400 (M + H+). Anal. (C26H29N2O‚9/5H2O) C, H, N.
2a -[4-(6-Meth oxy-2,3,4,9-tetr a h yd r o-1H-p yr id o[3,4-b]-
in d ol-2-yl)bu tyl]-2a ,3,4,5-tetr a h yd r oben z[cd ]in d ol-2(1H)-
on e (26b). This compound was prepared from 9 and 6-methoxy-
1,2,3,4-tetrahydro-9H-pyrido[3,4-b]indole (88% yield). Mp 132-
133 °C; 1H NMR (CD3OD) δ 1.00-1.10 (1H, m), 1.22-1.35 (2H,
2a -[4-(9-Ca r b a m oylm et h yl-1,2,3,4-t et r a h yd r op yr id o-
[3,4-b]in d ol-2-yl)bu tyl]-2a ,3,4,5-tetr a h yd r oben z[cd ]in d ol-
2(1H)-on e (26h ). This compound was prepared from 9 and
20h trifluoroacetate (91% yield). Mp 139-140 °C; 1H NMR
(CDCl3) δ 1.01-1.14 (1H, m), 1.20-1.36 (2H, m), 1.40-1.55
(2H, m), 1.75-1.90 (3H, m), 1.99-2.18 (2H, m), 2.42-2.53 (2H,
m), 2.55-2.67 (1H, m), 2.70-2.87 (5H, m), 3.52 (2H, s), 4.58
(2H, s), 5.58 (1H, br s), 6.52 (1H, br s), 6.65 (1H, d, J ) 7.5
Hz), 6.76 (1H, d, J ) 7.8 Hz), 7.05-7.20 (4H, m), 7.44 (1H, d,
J
) 7.8 Hz), 9.04 (1H, s); TSP m/z 457 (M + H+). Anal.
(C28H32N4O2‚H2O) C, H, N.
2a -[4-(9-Dim eth ylca r ba m oylm eth yl-1,2,3,4-tetr a h yd r o-
p yr id o[3,4-b]in d ol-2-yl)b u t yl]-2a ,3,4,5-t et r a h yd r ob en z-
[cd ]in d ol-2(1H)-on e (26i). This compound was prepared from
9 and 20i trifluoroacetate (72% yield). Mp 220 °C (dec); 1H