Journal of Medicinal Chemistry
Article
(2 × CH-Ph), 128.3 (2 × CH-Ph), 127.7 (C-indole), 127.2 (CH-Ph),
112.2 (CH6-indole), 109.5 (CH7-indole), 103.5 (CH4-indole), 102.0
(CH3-indole), 78.6 (-C), 73.6 (CH), 66.7 (CH2-O), 63.6 (CH2-
Ph), 53.9 (2 × CH2), 52.0 (CH2-indole), 44.9 (CH2-CCH), 41.8
(N-CH3), 36.2 (CH2), 32.8 (CH2), 32.4 (CH2), 30.1 (N-CH3); MS
(EI) m/z (%) 91 (48) [PhCH2]+, 202 (100), 361 (3) [M −
NCH3CH2CCH)]+, 429 (4) [M]+. Anal. Calcd for C28H35N3O: C,
78.28; H, 8.21; N, 9.78. Found: C, 77.99; H, 8.45; N, 9.79. 4·2HCl:
white powder; mp 221−3 °C; IR (KBr) ν 3424, 3195, 2928, 2561,
(0.5 g, 1.88 mmol, 1.2 equiv) in 8 mL of DMF, NaH (0.1 g, 2.5 mol,
1.6 equiv, 60% mineral oil) was added. The reaction mixture was
stirred at room temperature overnight and then heated at 70 °C for 8
h. Then the mixture was concentrated, diluted with water, and
extracted with CH2Cl2. The organic phase was washed with brine,
dried (MgSO4), and evaporated. The crude product was purified by
flash chromatography (CH2Cl2/MeOH, 50:1 to 30:1, v/v) to give
compound 6 (0.547 g, 76%) as a white solid: Rf = 0.28 (CH2Cl2/
MeOH, 20:1); mp 93−94 °C; IR (KBr) ν 3260, 2937, 2918, 1619,
1
2506, 1619, 1486, 1471, 1210 cm−1; H NMR (300 MHz, D2O) δ
1489, 1472, 1203, 1193, 1160, 1008 cm−1 1H NMR (500 MHz,
;
7.33−7.25 (m, 6H, CH7-indole + 5H-Ph), 7.06 (d, J = 2.4 Hz, 1H,
CH4-indole), 6.84 (dd, J = 9.0, 2.4 Hz, 1H, CH6-indole), 6.58 (s, 1H,
CH3-indole), 4.45 (s, 2H, CH2), 4.08 (s, 2H, CH2), 3.96 (t, J = 6.2
Hz, 2H, O-CH2-), 3.84 (d, J = 2.4 Hz, 2H, CH2-CCH), 3.59 (s, 3H,
indole-CH3), 3.32 (d, J = 12.6 Hz, 2H, CH2), 2.96 (t, J = 2.4 Hz, 1H,
CCH), 2.85−2.75 (m 5H, CH2 + N-CH3), 1.84 (d, J = 13.6 Hz, 2H,
CH2), 1.75−1.63 [m, 1H, CH], 1.61−1.53 (m, 2H, CH2-CH2O-),
1 . 3 2 − 1 . 1 8 ( m , 2 H , C H 2 ) . A n a l . C a l c d f o r
C28H35N3O·2HCl·1/3(H2O): C, 66.13; H, 7.47; Cl, 13.94; N, 8.26.
Found: C, 66.04; H, 7.89; Cl, 13.84; N, 8.59.
CDCl3) δ 7.32−7.23 (m, 5H), 7.17 (d, J = 8.8 Hz, 1H, CH7-indole),
7.03 (d, J = 2.3 Hz, 1H, CH4-indole), 6.85 (dd, J = 8.8 and 2.4 Hz, 1H,
CH6-indole), 6.32 (s, 1H, CH3-indole), 3.98 (t, J = 6.6 Hz, 2H,
-CH2O-), 3.67 (s, 2H, CH2-N), 3.73 (s, 3H, N-CH3), 3.49 (s, 2H,
CH2-Ph), 3.31 (d, J = 2.4 Hz, CH2-CCH, 2H), 2.88 (d, J = 10.5 Hz,
2H, CH2pip), 2.34 (s, 3H, N-CH3), 2.28 (t, J = 2.4 Hz, 1H, CCH),
2.00−1.85 (m, 2H, CH2pip), 1.83−1.73 (m, 2H, CH2-CH2O), 1.66
(br d, J = 9.4 Hz, CH2pip), 1.51−1.45 (m, 2H, CH2-(CH2)2O), 1.34−
1.22 (M, 4H, CH2pip + CH2-(CH2)3O); 13C NMR (125 MHz,
CDCl3) δ 153.5 (C5-indole) 138.5 (C-Ph), 137.0 (C2-indole), 133.3
(C7a-indole), 129.2 (2 × CH2Ph), 128.1 (2 × CHPh), 127.5 (C3a-
indole), 126.8 (CH-Ph), 112.0 (CH6-indole), 109.5 (CH7-indole),
103.4 (CH4-indole), 102.0 (CH3-indole), 78.4 (-C), 73.4 (CH),
68.8 (CH2-O), 63.5 (CH2-Ph), 53.9 (2 × CH2-piperidine), 51.8 (N-
CH2-indole), 44.7 (CH2-CCH), 41.7 (N-CH3), 36.3 (CH2-
(CH2)3O), 35.6 (CH-piperidine), 32.3 (2 × CH2-piperidine), 29.8
(N-CH3), 29.7 (CH2-CH2O), 23.3 [CH2-(CH2)2O]; MS (EI) m/z
(%) 91 (55) [PhCH2]+, 172 (71), 228 (45), 366 (41) [M − Bn]+, 388
[M − NCH3CH2CCH)]+, 418 (8) [M − CH2CCH)]+, 457 (26)
[M]+. Anal. Calcd for C30H39N3O: C, 78.73; H, 8.59; N, 9.18. Found:
C, 78.65; H, 8.71; N, 9.07. 6·2HCl: white powder; mp 197−9 °C; IR
(KBr) ν 3421, 3195, 2928, 2851, 2561, 2509, 1619, 1485, 1472, 1458,
N-{[5-(3-(1-Benzylpiperidin-4-yl)propoxy)-1-methyl-1H-
indol-2-yl]methyl}-N-methylprop-2-yn-1-amine (5). To a solu-
tion of 1-methyl-2-{[ethyl(prop-2-yn-1-yl)amino]ethyl}-1H-indol-5-ol
452 (0.22 g, 0.963 mmol) and 1-nenzyl-4-(3-chloropropyl)piperidine
12 (0.36 g, 1.44 mmol, 1.5 equiv) in DMF (5 mL), NaH (69.4 mg,
1.73 mmol, 1.8 equiv, 60% /mineral) was added. The reaction mixture
was stirred at room temperature overnight and then heated at 100 °C
for 1 h. After complete reaction (TLC analysis), the mixture was
concentrated, diluted with water, and extracted with CH2Cl2. The
organic phase was washed with brine, dried (MgSO4), and evaporated
at reduced pressure. The crude product was purified by flash
chromatography (CH2Cl2/AcOEt, 10:1 to 5:1, v/v) to give compound
5 (0.268 g, 63%) as a white solid: Rf = 0.28 (CH2Cl2/MeOH, 20:1);
mp 90−91 °C; IR (KBr) ν 3265, 2935, 2908, 2799, 2760, 1619, 1489,
1471, 1395, 1269, 1204, 1190, 1160, 1029 cm−1; 1H NMR (400 MHz,
CDCl3) δ 7.35−7.25 (m, 5H, Ph), 7.19 (d, J = 8.8 Hz, 1H, CH7-
indole), 7.05 (d, J = 2.14 Hz, 1H, CH4-indole), 6.85 (dd, J = 8.8 and
2.3 Hz, 1H, CH6-indole), 6.35 (s, 1H, CH3-indole), 3.98 (t, J = 6.6
Hz, 2H, O-CH2-), 3.75 (s, 3H, indole-CH3), 3.69 (s, 2H, indole-CH2),
3.52 (s, 2H, CH2-Ph), 2.33 (d, J = 2.2 Hz, 2H, CH2-CCH), 2.91 (d,
J = 10.8 Hz, CH2), 2.36 (s, 3H, N-CH3), 2.31 (t, J = 2.0 Hz, CCH),
1.97 (t, J = 12 Hz, 2H, CH2), 1.83 [m, 2H, CH2-(CH2O)], 1.72 (d, J =
9.1 Hz, 2H, CH2), 1.46−1.41 [m, 2H, CH2-(CH2)2O], 1.29−1.31 (m,
3H, CH+CH2); 13C NMR (100 MHz, CDCl3) δ 153.2 (C5-indole),
138.3 (C-Ph), 136.9 (C2-indole), 133.3 (C-indole), 129.2 (2 × CH-
Ph), 128.0 (2 × CH-Ph), 127.4 (C-indole), 126.8 (CH-Ph), 112.0
(CH6-indole), 109.5 (CH7-indole), 103.3 (CH4-indole), 102.0
(CH3-indole), 78.3 (-C), 73.4 (CH), 69.0 (CH2-O), 63.4
(CH2-Ph), 53.8 (2 × CH2), 51.7 (indole-CH2), 44.6 (CH2-C),
41.5 (N-CH3), 35.5 (CH-piperidine), 32.8 [CH2-(CH2)2O], 32.2
(2CH2), 29.8 (indole-N-CH3), 26.7 [CH2-CH2O]; MS (EI) m/z (%)
91 (77) [PhCH2]+, 352 (22) [M − CH2Ph]+, 374 (100) [M −
NCH3CH2CCH)]+, 404 (7) [M − CH2CCH)]+, 428 (5) [M -
CH3]+, 443 (40)[M]+. Anal. Calcd for C29H37N3O: C, 78.51; H, 8.41;
N, 9.47. Found: C, 78.36; H, 8.31; N, 9.23. 5·2HCl: white powder; mp
203−5 °C; IR (KBr) ν 3193, 2937, 2512, 1619, 1486, 1469, 1209
cm−1; 1H NMR (300 MHz, D2O) δ 7.32−7.22 (m, 6H, CH7-indole +
5H-Ph), 7.05 (d, J = 2.2 Hz, 1H, CH4-indole), 6.83 (dd, J = 9.0, 2.3
Hz, 1H, CH6-indole), 6.58 (s, 1H, CH3-indole), 4.45 (s, 2H, CH2),
4.07 (s, 2H, CH2), 3.90 (t, J = 6.1 Hz, 2H, O-CH2-), 3.83 (d, J = 2.2
Hz, 2H, CH2-CCH), 3.59 (s, 3H, indole-CH3), 3.30 (d, J = 12.0 Hz,
2H, CH2), 2.97−2.94 (m, 1H, CCH), 2.81−2.72 (m 5H, CH2 + N-
CH3), 1.84−1.75 (m, 2H, CH2), 1.65−1.55 (m, 2H, CH2), 1.49−1.36
(m, 1H, CH), 1.41−1.46 [m, 2H, CH2-(CH2)2O], 1.29−1.09 (m, 4H).
Anal. Calcd for C29H37N3O·2HCl: C, 67.43; H, 7.61; Cl, 13.73; N,
8.13. Found: C, 67.38; H, 7.81; Cl, 13.13; N, 8.02.
1
1408, 1209 cm−1; H NMR (300 MHz, D2O) δ 7.33−7.24 (m, 6H,
CH7-ind + 5H-Ph), 7.05 (d, J = 2.2 Hz, 1H, CH4-ind), 6.84 (dd, J =
9.0, 2.4 Hz, 1H, CH6-ind), 6.59 (s, 1H, CH3-ind), 4.48 (s, 2H, CH2),
4.05 (s, 2H, CH2), 3.90 (t, J = 6.5 Hz, 2H, O-CH2-), 3.86 (d, J = 2.2
Hz, 2H, CH2-CCH), 3.58 (s, 3H, indole-CH3), 3.28 (d, J = 12.3 Hz,
2H, CH2), 2.98 (t, J = 2.3 Hz, 1H, CCH), 2.77−2.70 (m 5H, CH2 +
N-CH3), 1.76 (d, J = 13.9 Hz, 2H, CH2), 1.61−1.51 (m, 2H, CH2),
1.41−1.23 (m, 3H, CH + CH2), 1.29−1.05 (m, 4H). Anal. Calcd for
C30H39N3O·2HCl: C, 67.91; H, 7.79; Cl, 13.36; N, 7.92. Found: C,
67.54; H, 7.45; Cl, 13.25; N, 8.10;
N-{[5-(2-Bromoethoxy)-1-methyl-1H-indol-2-yl)methyl}-N-
methylprop-2-yn-1-amine (25). A mixture of 1-methyl-2-{[ethyl-
(prop-2-yn-1-yl)amino]ethyl}-1H-indol-5-ol 1452 (0.215 g, 0.942
mmol), 1,2-dibromoethane (1.77 g, 9.42 mmol), and potassium
carbonate (0.65 g, 4.71 mmol) in 2-butanone (8 mL) was reacted at 85
°C for 6 h. The mixture was evaporated in vacuo, and the residue was
partitioned between dichloromethane (10 mL) and water (10 mL).
The organic layer was dried (Na2SO4) and evaporated. The residue
was purified by column chromatography, eluting with 4% methanol in
dichloromethane, affording compound 25 (117.3 mg, 37%): Rf = 0.76
(CH2Cl2/AcOEt, 10:1); mp 75−77 °C; IR 3274, 29712937, 2877,
2800, 1619, 1579, 1488, 1473, 1400, 1267, 1205, 1198, 1159, 1118,
1
1025, 889, 842, 794, 776, 690 cm−1; H NMR (300 MHz, CDCl3) δ
7.2 (d, J = 8.8 Hz, 1H, CH7-indole), 7.07 (d, J = 2.4 Hz, 1H, CH4-
indole), 6.9 (dd, J = 8.8, 2.5 Hz, 1H, CH6-indole), 6.36 (s, 1H, CH3-
indole), 4.33 (t, J = 6.4 Hz, 2H, -CH2-O-), 3.75 (s, 3H, N-CH3), 3.69
(s, 2H, N-CH2), 3.66 (t, J = 6.4 Hz, 2H, -CH2-Br), 3.32 (d, J = 2.4 Hz,
2H, N-CH2-C), 2.36 (s, 3H, N-CH3), 2.31 (t, J = 2.4 Hz, 1H,
CH); 13C NMR (75 MHz, CDCl3) δ 152.2 (C5-indole), 137.3 (C2-
indole), 133.8 (C7a-indole), 127.4 (C3a-indole), 112.2 (CH6-indole),
109.7 (CH7-indole), 104.4 (CH4-indole), 102.1 (CH3-indole), 78.3
(-C), 73.5 (CH), 69.1 (CH2-O), 51.7 (CH2-N), 44.7 (-CH2-
C), 41.5 (N-CH3), 29.9 (N-CH3), 29.6 (CH2-Br); MS (EI) m/
z(%): 131 (48), 160 (66) [M − ((Br(CH2)2)-NCH3CH2CCH)]+,
267 (100) [M − NCH3CH2CCH)]+, 334 (25)[M]+. Anal. Calcd for
C16H19BrN2O: C, 57.32; H, 5.71; Br, 23.83; N, 8.36. Found: C, 57.50;
H, 5.70; Br, 23.24; N, 8.54.
N-{[5-(4-(1-Benzylpiperidin-4-yl)butoxy)-1-methyl-1H-indol-
2-yl]methyl}-N-methylprop-2-yn-1-amine (6). To a solution of
1-methyl-2-{[ethyl(prop-2-yn-1-yl)amino]ethyl}-1H-indol-5-ol 452
(0.35 g, 1.56 mmol) and 1-benzyl-4-(4-chlorobutyl)piperidine 13
8263
dx.doi.org/10.1021/jm200853t | J. Med. Chem. 2011, 54, 8251−8270