Y. Yoneda et al. / Bioorg. Med. Chem. 10 (2002) 1347–1359
1355
HCl (5.0 mL) was added. The mixture was stirred at
room temperature for 7 h, and concentrated in vacuo.
The resulting solid was collected and washed with Et2O
to give 10 as an amorphous powder (300 mg, 40%): IR
(KBr, cmꢀ1) 3402, 2941, 2717, 2544, 1620, 1510, 1450,
1016, 796, 536; 1H NMR (CD3OD, 400 MHz) d 1.29 (m,
2H), 1.53 (m, 1H), 1.79–1.95 (m, 12H), 2.74 (m, 1H),
2.89–3.17 (m, 9H), 3.52 (m, 2H), 4.05 (m, 1H), 4.23 (m,
2H), 4.63 (m, 1H), 7.32–7.54 (m, 4H), 7.79 (d, J=8.3
Hz, 1H), 7.88 (d, J=7.8 Hz, 1H), 7.98 (d, J=8.8Hz,
1H); MS (FAB) m/z 422 (M+H)+. Anal. calcd for
2H), 4.63 (d, J=13.7 Hz, 1H), 7.34 (d, J=7.3 Hz, 1H),
7.44 (t, J=7.6 Hz, 1H), 7.53 (m, 2H), 7.80 (d, J=8.3
Hz, 1H), 7.89 (d, J=7.3 Hz, 1H), 8.00 (d, J=8.3 Hz,
1H); MS (FAB) m/z 411 (M+H)+.
N-(1-Methylpiperidin-4-yl)-N0-[1-(1-naphthylacetyl)piper-
idin-4-ylmethyl]-1,4-diaminobutane (12c). Amorphous
powder; IR (KBr, cmꢀ1) 3432, 2940, 2864, 2752, 2552,
1
1636, 1510, 1452, 786; H NMR (CD3OD, 400 MHz) d
1.09–1.22 (m, 2H), 1.62–2.11 (m, 12H), 2.73 (m, 1H),
2.85 (s, 3H), 2.90 (d, J=6.8 Hz, 2H), 2.99–3.17 (m, 9H),
3.50 (m, 2H), 4.05 (m, 1H), 4.22 (m, 2H), 4.63 (m, 1H),
7.31–7.54 (m, 4H), 7.79 (d, J=8.3Hz, 1H), 7.87 (m, 1H),
7.98 (d, J=7.8 Hz, 1H); MS (FAB) m/z 465 (M+H)+.
.
.
C27H39N3O 2HCl 1.4H2O: C, 62.39; H, 8.49; N, 8.08.
Found: C, 62.49; H, 8.91; N, 8.07.
.
.
4-[N-(tert-Butoxycarbonyl)-N-(4-oxobutyl)amino]methyl-
1-(1-naphthyl)acetylpiperidine (11). To a stirred solution
of oxalyl chloride (0.22 mL, 2.4 mmol) in CH2Cl2 (20
mL) was added DMSO (0.41mL, 4.8 mmol) at ꢀ78 ꢂC.
After 5 min, a solution of 9 (1.0 g, 2.2 mmol) in CH2Cl2
was added. The mixture was stirred at the same tem-
perature for 30 min, and then triethyamine (1.7 mL,
12.2 mmol) was added. The stirred mixture was allowed
to rise to room temperature for 30 min, then diluted
with H2O, and extracted with CH2Cl2. The extracts
were washed with H2O and brine, dried over anhydrous
Na2SO4, and concentrated in vacuo. The residue was
purified by silica gel column chromatography (hexane/
EtOAc, 1:2, v/v) to afford 11 as a yellowish oil (0.7 g,
71%): IR (KBr, cmꢀ1) 2932, 1724, 1690, 1642, 1470,
Anal. calcd for C29H44N4O 3HCl 0.8H2O: C, 59.19; H,
8.32; N, 9.52. Found: C, 59.27; H, 8.05; N, 9.43.
N-[2-(1-Methylpyrrolidin-2-yl)ethyl]-N0 -[1-(1-naphthyl-
acetyl)piperidin-4-ylmethyl]-1,4-diaminobutane
(12d).
Amorphous powder; IR (KBr, cmꢀ1) 3416, 2948, 2792,
2724, 1624, 1450, 792, 588; 1H NMR (CD3OD,
400 MHz) d 1.13–1.21 (m, 2H), 1.75–2.42 (m, 12H),
2.74–3.70 (m, 17H), 4.05 (m, 1H), 4.23 (m, 2H), 4.62 (m,
1H), 7.32–7.54 (m, 4H), 7.79 (d, J=8.3 Hz, 1H), 7.88 (d,
J=7.3 Hz, 1H), 7.98 (d, J=8.3 Hz, 1H); MS (FAB) m/z
+
.
465 (M+H) . Anal. calcd for C29H44N4O 3HCl
.
1.3H2O: C, 58.30; H, 8.37; N, 9.38; Cl, 17.80. Found: C,
58.55; H, 8.28; N, 9.02; Cl, 17.70.
1450, 1420, 1368, 1276, 1256, 1230, 1164, 1136, 786; H
N-[3-(1-Imidazolyl)propyl]-N0-[1-(1-naphthylacetyl)piperi-
din-4-ylmethyl]-1,4-diaminobutane (12e). Amorphous
powder; IR (KBr, cmꢀ1) 3428, 2952, 2800, 2764, 1622,
1
NMR (CDCl3, 400 MHz) d 0.80–1.60 (m, 4H), 1.43 (s,
9H), 1.69 (d, J=13.2 Hz, 1H), 1.82 (m, 3H), 2.44 (t,
J=6.8 Hz, 2H), 2.62 (m, 1H), 2.98 (m, 2H), 3.17 (m,
2H), 3.84 (m, 1H), 4.16 (s, 2H), 4.69 (m, 1H), 7.32 (d,
J=6.8 Hz, 1H), 7.42 (t, J=7.8 Hz, 1H), 7.52 (m, 2H),
7.77 (d, J=8.3 Hz, 1H), 7.87 (d, J=7.8 Hz, 1H), 8.00
(m, 1H), 9.77 (s, 1H); MS (EI) m/z 452 (M)+.
1
1452, 794, 590; H NMR (CD3OD, 400 MHz) d 1.09–
1.21 (m, 2H), 1.74–2.02 (m, 6H), 2.32–2.36 (m, 2H), 2.71
(m, 1H), 2.89 (d, J=6.8 Hz, 2H), 2.99–3.16 (m, 8H),
4.05 (m, 1H), 4.21 (m, 2H), 4.42 (t, J=6.8 Hz, 2H), 4.62
(m, 1H), 7.31–7.53 (m, 4H), 7.58 (s, 1H), 7.73 (s, 1H),
7.78 (d, J=8.3 Hz, 1H), 7.87 (d, J=7.8 Hz, 1H), 7.97
The following compounds were prepared in a similar
manner described for the preparation of 8a starting
from 11.
(d, J=8.3 Hz, 1H), 9.05 (s, 1H); MS (FAB) m/z 462
+
.
.
(M+H) . Anal. calcd for C28H39N5O 3HCl H2O: C,
57.09; H, 7.53; N, 11.89; Cl, 18.06. Found: C, 57.10; H,
7.65; N, 11.88; Cl, 18.32.
N-[1-(1-Naphthylacetyl)piperidin-4-ylmethyl]-N0-(4-piper-
idinylmethyl)-1,4-diaminobutane (12a). Amorphous
powder; IR (KBr, cmꢀ1) 2948, 2740, 1632, 1598, 1452,
786; 1H NMR (CD3OD, 400 MHz) d 1.09–1.21 (m, 2H),
1.50–1.56 (m, 2H), 1.74–2.14 (m, 10H), 2.70–3.16 (m,
12H), 3.42 (m, 2H), 4.04 (m, 1H), 4.22 (d, J=16.1Hz,
1H), 4.25 (d, J=16.1 Hz, 1H), 4.62 (m, 1H), 7.32
(d, J=7.3 Hz, 1H), 7.42 (m, 1H), 7.52 (m, 2H), 7.78
(d, J=8.3 Hz, 1H), 7,87 (m, 1H), 7.98 (d, J=7.8 Hz,
1H); MS (FAB) m/z 451(M+H) +. Anal. calcd
N-[1-(1-Naphthylacetyl)piperidin-4-ylmethyl]- N0 -[1-(4-
pyridyl)piperidin-4-ylmethyl]-1,4-diaminobutane
(12f).
Mp 225–230 ꢂC; IR (KBr, cmꢀ1) 3444, 2940, 2792,
1
1640, 1546, 1448, 1256, 1218, 796; H NMR (CD3OD,
400 MHz) d 1.16–1.43 (m, 4H), 1.85–2.06 (m, 10H), 2.80
(m, 1H), 2.91–3.20 (m, 12H), 4.20 (m, 1H), 4.24 (m,
2H), 4.30 (m, 2H), 4.65 (m, 1H), 7.17 (d, J=7.8 Hz,
2H), 7.33–7.54 (m, 4H), 7.80 (d, J=7.8 Hz, 1H), 7.88 (d,
J=7.8 Hz, 1H), 8.00 (d, J=7.8 Hz, 1H), 8.10 (d, J=7.3
Hz, 2H); MS (FAB) m/z 528 (M+H)+. Anal. calcd for
.
.
for C28H42N4O 3HCl 0.5H2O; C, 59.10; H, 8.15; N,
9.85; Cl, 18.69. Found: C, 59.02; H, 7.97; N, 9.98; Cl,
18.61.
.
.
C33H45N5O 3HCl 2.7H2O: C, 57.80; H, 7.85; N, 10.21.
Found: C, 57.78; H, 7.58; N, 9.95.
N-(3-Aminopropyl)-N0 -[1-(1-naphthylacetyl)piperidin-4-
ylmethyl]-1,4-diaminobutane (12b). Amorphous powder;
IR (KBr, cmꢀ1) 3440, 2940, 2808, 2780, 1640, 1442, 788;
1H NMR (CD3OD, 400 MHz) d 1.08–1.25 (m, 2H), 1.83
(m, 6H), 2.04 (m, 1H), 2.11 (q, J=7.6 Hz, 2H), 2.73–
3.29 (m, 9H), 2.75 (t, J=11.7 Hz, 1H), 2.92 (d, J=7.3
Hz, 2H), 4.07 (d, J=14.2 Hz, 1H), 4.24 (q, J=16.1 Hz,
N,N-Dimethylamino-N0-[1-(1-naphthylacetyl)piperidin-4-
ylmethyl]-1,4-diaminobutane (12g). Amorphous powder;
IR (KBr, cmꢀ1) 3410, 2943, 2748, 2472, 1639, 1442,
1
1211, 982, 787, 536; H NMR (CD3OD, 400 MHz) d
1.16–1.19 (m, 2H), 1.79–2.03 (m, 7H), 2.91 (s, 6H),
2.74–3.48 (m, 8H), 4.04 (m, 1H), 4.23 (m, 2H), 4.61 (m,
1H), 7.32–7.53 (m, 4H), 7.79–7.99 (m, 3H); MS (FAB)