4
992
J. Faist et al. / Bioorg. Med. Chem. 21 (2013) 4988–4996
1
163, 1031, 1011, 745, 698; UV (CH
NMR (CDCl ) d = 0.71 (t, J = 7.1 Hz, 6H, 2 -H), 1.42 (d, J = 13.3 Hz,
H, 3-H), 1.82–1.91 (m, 2H, 5-H, 8-H), 2.07–2.12 (m, 1H, 5-H),
2
Cl
2
, (log
e
)): 230 (3.513); 1
H
5.2.1.4. (2SR,6RS,7RS)-(±)-3-Diethylamino-N-(4-(4-methylpi-
perazin-1-yl)-6,7-diphenylbicyclo[2.2.2]octan-2-yl)propiona-
mide (11a). The reaction of bicyclo-octanamine 3a (0.307 g,
0.818 mmol), triethylamine (0.124 g, 1.23 mmol) and 3-chloropro-
00
3
1
2
00
.14 (q, J = 7.1 Hz, 4H, 1 -H), 2.26-2.33 (m, 1H, 3-H), 2.31 (s, 3H,
NCH
3
), 2.35 (ddd, J = 12.8, 9.8, 3.0 Hz, 1H, 8-H), 2.47 (d,
pionyl chloride (0.156 g, 1.23 mmol) in CH
-chloropropionamide 5a (0.332 g, 0.712 mmol, 87%). 5a, diethyl-
amine (2.5 mL), CH Cl (1 mL) and a catalytic amount of KI yielded
2 2
Cl (15 mL) gave
0
J = 16.8 Hz, 1H, 2 -H), 2.47-2.58 (m, 4H, N(CH
J = 16.8 Hz, 1H, 2 -H), 2.71 (d, J = 3.2 Hz, 1H, 1-H), 2.71–2.82 (m,
2
)
2
), 2.66 (d,
x
0
2
2
4
H, N(CH )
2 2
), 3.12 (t, J = 9.2 Hz, 1H, 6-H), 3.20 (t, J = 9.8 Hz, 1H, 7-
after 120 h 11a (0.235 g, 0.358 mmol, 66%). IR = 3057, 3026, 2934,
H), 4.35–4.44 (m, 1H, 2-H), 7.09 (d, J = 8.2 Hz, 1H, NH), 7.10–7.39
2872, 2794, 1645, 1600, 1541, 1497, 1448, 1164, 1012, 746, 698;
1
3
00
1
(
m, 10H, aromatic H); C NMR (CDCl
3
) d = 11.48 (C-2 ), 30.25 (C-
UV (CH
2
Cl
2
, (log
e
)): 230 (3.510), 266 (2.857); H NMR (CDCl
3
)
0
0
5
4
), 33.20 (C-8), 33.75 (C-7), 37.15 (C-3), 39.22 (C-1), 40.73 (C-6),
d = 0.92 (t, J = 7.2 Hz, 6H, 2 -H), 1.43 (br d, J = 13.5 Hz, 1H, 3-H),
1.64–1.74 (m, 1H, 2 -H), 1.80–1.99 (m, 4H, 2 -H, 3 -H, 5-H, 8-H),
00
0
0
0
5.30 (N(CH
2
)
2
), 45.80 (NCH
3
), 47.93 (C-1 ), 48.43 (C-2), 55.66
0
00
0
(
N(CH
2
)
2
), 56.37 (C-4), 56.52 (C-2 ), 125.61, 126.15, 126.20,
2.08–2.18 (m, 2H, 3-H, 5-H), 2.26–2.42 (m, 6H, 1 -H, 3 -H, 8-H),
2.33 (s, 3H, NCH ), 2.46–2.60 (m, 4H, N(CH ), 2.70–2.84 (m, 4H,
N(CH , 2.99 (d, J = 3.5 Hz, 1H, 1-H), 3.11 (t, J = 9.5 Hz, 1H, 6-H),
3.20 (t, J = 9.9 Hz, 1H, 7-H), 4.31–4.38 (m, 1H, 2-H), 7.10–7.39 (m,
1
C
27.21, 128.19, 128.37 (aromatic C), 143.19, 144.03 (aromatic
), 171.53 (CO); HRMS (EI+) calcd for C31 O: 488.3515;
3
2 2
)
q
H
44
N
4
2 2
)
found: 488.3546.
1
3
1
0H, aromatic H), 7.42–7.45 (br, 1H, NH);
C NMR (CDCl
3
)
0
0
0
5
.2.1.2. (2SR,6RS,7RS)-(±)-N-(4-(4-Methylpiperazin-1-yl)-6,7-
diphenylbicyclo[2.2.2]octan-2-yl)-2-pyrrolidinoacetamide
9a). The reaction of bicyclo-octanamine 3a (0.292 g, 0.779 mmol),
triethylamine (0.118 g, 1.17 mmol) and chloroacetyl chloride
0.132 g, 1.17 mmol) in CH Cl (15 mL) gave -chloroacetamide
a (0.324 g, 0.716 mmol, 92%). 4a, pyrrolidine (2.5 mL) and a cata-
d = 10.62 (C-2 ), 32.16 (C-2 ), 32.53 (C-5), 33.72 (C-7), 33.98 (C-
8), 34.77 (C-3), 37.28 (C-1), 40.00 (C-6), 45.09 (C-1 ), 45.38
00
0
(
(N(CH
(N(CH
2
)
)
2
), 45.85 (NCH
3
), 48.42 (C-3 ), 48.60 (C-2), 55.78
2
2
), 56.49 (C-4), 125.54, 126.06, 126.20, 127.32, 128.17,
), 171.61 (CO);
O: 502.3672; found: 502.3698.
(
2
2
x
128.41 (aromatic C), 143.33, 144.99 (aromatic C
HRMS (EI+) calcd for C32
q
4
46 4
H N
lytic amount of KI yielded after 48 h 9a (0.253 g, 0.520 mmol, 73%).
IR = 3057, 3024, 2932, 2874, 2795, 1646, 1600, 1542, 1497, 1447,
5.2.1.5. (2SR,6RS,7RS)-(±)-N-(4-(4-Methylpiperazin-1-yl)-6,7-
diphenylbicyclo[2.2.2]octan-2-yl)-3-pyrrolidinopropionamide
(12a). The reaction of bicyclo-octanamine 3a (0.229 g, 0.609 mmol),
triethylamine (0.092 g, 0.913 mmol) and 3-chloropropionyl
1
2 2
164, 1032, 1013, 747, 698; UV (CH Cl , (loge)): 230 (3.255), 266
1
(
3.077); H NMR (CDCl
3
00
) d = 1.41 (br d, J = 13.3 Hz, 1H, 3-H),
00
1
2
8
.53–1.60 (m, 4H, 3 -H, 4 -H), 1.82–1.92 (m, 2H, 5-H, 8-H), 2.04–
00
00
00
00
.13 (m, 3H, 2 -H, 5-H, 5 -H), 2.26–2.40 (m, 4H, 2 -H, 3-H, 5 -H,
chloride (0.116 g, 0.913 mmol) in CH
propionamide 5a (0.247 g, 0.530 mmol, 87%). 5a, pyrrolidine
(2.5 mL), CH Cl (1 mL) and a catalytic amount of KI yielded after
2 2
Cl (10 mL) gave x-chloro-
-H), 2.31 (s, 3H, NCH
3
), 2.47–2.57 (m, 4H, N(CH
2
)
2
), 2.51 (d,
0
0
J = 16.3 Hz, 1H, 2 -H), 2.64 (d, J = 16.3 Hz, 1H, 2 -H), 2.72 (d,
2
2
J = 3.4 Hz, 1H, 1-H), 2.72–2.84 (m, 4H, N(CH
)
2 2
), 3.13 (t, J = 9.2 Hz,
72 h 12a (0.261 g, 0.521 mmol, 98%). IR = 3426, 3190, 3054,
1
7
H, 6-H), 3.19 (t, J = 9.5 Hz, 1H, 7-H), 6.83 (d, J = 8.2 Hz, 1H, NH),
2929, 2872, 2793, 1666, 1601, 1555, 1496, 1447, 1377, 1341,
1292, 1162, 1012, 767, 748, 699; UV (CH Cl , (loge)): 230
2 2
13
00
.10–7.40 (m, 10H, aromatic H); C NMR (CDCl
3
) d = 23.79 (C-3 ,
0
0
1
C-4 ), 29.81 (C-5), 33.13 (C-8), 33.77 (C-7), 37.44 (C-3), 39.59 (C-
(3.940), 265 (3.720); H NMR (CDCl
3
00
) d = 1.38 (br d, J = 13.7 Hz,
0
0
0
1
), 40.68 (C-6), 45.43 (N(CH
2
)
2
), 45.90 (NCH
3
), 48.33 (C-2), 54.08
1H, 3-H), 1.64–1.71 (m, 4H, 3 -H, 4 -H), 1.67–1.79 (m, 2H, 2 -H,
8-H), 1.81–1.93 (m, 2H, 3 -H, 5-H), 1.98 (ddd, J = 16.2, 8.0, 4.4 Hz,
1H, 2 -H), 2.06–2.18 (m, 4H, 2 -H, 3-H, 5-H, 5 -H), 2.23–2.32 (m,
3H, 2 -H, 3 -H, 5 -H), 2.32 (s, 3H, NCH
3.0 Hz, 1H, 8-H), 2.45–2.60 (m, 4H, N(CH
N(CH , 3.02 (d, J = 4.1 Hz, 1H, 1-H), 3.11 (t, J = 9.3 Hz, 1H, 6-H),
3.20 (t, J = 9.8 Hz, 1H, 7-H), 4.35–4.43 (m, 1H, 2-H), 7.10–7.37 (m,
3
10H, aromatic H), 8.18 (d, J = 6.7 Hz, 1H, NH); C NMR (CDCl )
d = 23.42 (C-3 , C-4 ), 33.17 (C-5), 33.63 (C-2 ), 33.64 (C-7), 34.42
(C-8), 34.86 (C-3), 36.32 (C-1), 39.82 (C-6), 45.27 (N(CH ), 45.86
0
0
00
0
0
(
C-2 , C-5 ), 55.75 (N(CH
2
)
2
), 56.45 (C-4), 59.16 (C-2 ), 125.65,
0
00
00
126.20, 126.29, 127.29, 128.36, 128.50 (aromatic C), 143.31,
144.14 (aromatic ), 170.46 (CO); HRMS (EI+) calcd for
C O: 486.3359; found: 486.3358.
0
0
0
00
C
q
3
), 2.41 (ddd, J = 12.2, 9.8,
31
H
42
N
4
2 2
) ), 2.66–2.83 (m, 4H,
2 2
)
5
.2.1.3. (2SR,6RS,7RS)-(±)-N-(4-(4-Methylpiperazin-1-yl)-6,7-
1
3
diphenylbicyclo[2.2.2]octan-2-yl)-2-piperidinoacetamide
10a). The reaction of bicyclo-octanamine 3a (0.290 g, 0.772 mmol),
triethylamine (0.117 g, 1.16 mmol) and chloroacetyl chloride
0.130 g, 1.16 mmol) in CH Cl (15 mL) gave -chloroacetamide
a (0.321 g, 0.710 mmol, 92%). 4a, piperidine (2.5 mL) and a cata-
lytic amount of KI yielded after 48 h 10a (0.223 g, 0.445 mmol,
0
0
00
0
(
2 2
)
0
00
00
(
4
2
2
x
(NCH
(N(CH
128.35 (aromatic C), 143.28, 145.21 (aromatic C
HRMS (EI+) calcd for C32 O: 500.3515; found: 500.3504.
3
), 47.91 (C-2), 50.69 (C-3 ), 52.88 (C-2 , C-5 ), 55.78
), 56.40 (C-4), 125.48, 125.86, 126.12, 127.26, 128.10,
), 171.52 (CO);
2 2
)
q
6
1
2%). IR = 3057, 3025, 2934, 2869, 2793, 1676, 1600, 1497, 1451,
162, 1129, 1039, 1011, 794, 746, 698; UV (CH Cl , (log )): 230
) d = 1.27–1.40 (m, 7H, 3-H,
-H, 4 -H, 5 -H), 1.82 (br t, J = 12.8 Hz, 1H, 8-H), 1.85–1.92 (m,
44 4
H N
2
2
e
1
(
3.487), 268 (3.061); H NMR (CDCl
3
5.2.1.6. (2SR,6RS,7RS)-(±)-N-(4-(4-Methylpiperazin-1-yl)-6,7-
diphenylbicyclo[2.2.2]octan-2-yl)-3-piperidinopropionamide
(13a). The reaction of bicyclo-octanamine 3a (0.220 g, 0.587 mmol),
triethylamine (0.089 g, 0.880 mmol) and 3-chloropropionyl chlo-
0
0
00
00
3
3
2
0
0
00
H, 2 -H, 5-H, 6 -H), 2.10 (ddd, J = 13.5, 9.2, 1.9 Hz, 1H, 5-H),
00
00
0
.13–2.20 (m, 2H, 2 -H, 6 -H), 2.18 (d, J = 16.2 Hz, 1H, 2 -H), 2.28
(
td, J = 13.5, 3.0 Hz, 1H, 3-H), 2.31 (s, 3H, NCH
3
), 2.38 (ddd,
ride (0.112 g, 0.880 mmol) in CH
onamide 5a (0.238 g, 0.511 mmol, 87%). 5a, piperidine (2.5 mL),
CH Cl (1 mL) and a catalytic amount of KI yielded after 72 h 13a
2 2
Cl (10 mL) gave x-chloropropi-
0
J = 12.8, 9.8, 3.0 Hz, 1H, 8-H), 2.47 (d, J = 16.2 Hz, 1H, 2 -H), 2.48–
2
.59 (m, 4H, N(CH
2
2
) ), 2.69–2.81 (m, 4H, N(CH
2
)
2
), 2.81 (d,
2
2
J = 3.5 Hz, 1H, 1-H), 3.12 (t, J = 9.2 Hz, 1H, 6-H), 3.19 (t, J = 9.8 Hz,
(0.197 g, 0.263 mmol, 75%). IR = 3423, 3222, 3053, 2928, 2816,
1
7
4
H, 7-H), 4.37–4.45 (m, 1H, 2-H), 6.83 (d, J = 8.2 Hz, 1H, NH),
2792, 1665, 1601, 1542, 1496, 1446, 1377, 1350, 1162, 1011,
13
1
.08-7.39 (m, 10H, aromatic H); C NMR (CDCl
3
) d = 23.51 (C-
), 25.78 (C-3 , C-5 ), 30.56 (C-5), 33.59 (C-8), 33.67 (C-7), 36.60
), 45.83 (NCH ),
), 56.40 (C-4),
766, 748, 699; UV (CH
NMR (CDCl
1.70 (m, 2H, 2 -H, 3 -H), 1.81 (ddd, J = 12.6, 9.8, 1.8 Hz, 1H, 8-H),
2
Cl
2
, (log
e
)): 230 (3.878), 262 (3.523);
H
0
0
00
00
00
00
00
3
) d = 1.37–1.54 (m, 7H, 3-H, 3 -H, 4 -H, 5 -H), 1.58–
0
0
(
C-3), 38.86 (C-1), 40.34 (C-6), 45.32 (N(CH
2
)
2
3
00
00
0
4
6
8.05 (C-2), 54.24 (C-2 , C-6 ), 55.68 (N(CH
2
)
2
1.88 (ddd, J = 13.0, 9.6, 2.2 Hz, 1H, 5-H), 1.92–2.09 (m, 4H, 2 -H,
0
00
0
00
00
00
1.78 (C2 ), 125.50, 125.99, 126.20, 127.24, 128.26, 128.39 (aro-
2 -H, 3 -H, 6 -H), 2.10–2.24 (m, 4H, 2 -H, 3-H, 5-H, 6 -H), 2.33 (s,
3H, NCH ), 2.41 (ddd, J = 12.6, 9.8, 3.0 Hz, 1H, 8-H), 2.46–2.59 (m,
4H, N(CH ), 2.71–2.85 (m, 4H, N(CH , 3.09 (d, J = 3.3 Hz, 1H,
matic C), 143.22, 144.35 (aromatic C
calcd for C32 O: 500.3515; found: 500.3531.
q
), 169.93 (CO); HRMS (EI+)
3
H
44
N
4
2
)
2
2 2
)