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R. Filosa et al. / European Journal of Medicinal Chemistry 42 (2007) 293e306
123.7; 124.1; 125.1; 125.7; 129.1; 141.3; 147.1; 149.8; 151.4;
158.1. MS (ESI) m/z: 627.3; 382.0.
138.7; 138.7; 147.7; 147.8; 147.9; 148.7; 154.5; 154.6;
156.3. MS (ESI) m/z: 479.2.
6.5.2. 3,8-Bis((2-(4-methoxyphenyl)pyridin-4-yl)methyl)-
3,8-diazabicyclo[3.2.1]octane (2b)
6.5.6. 3,8-Bis((2-p-tolylpyridin-4-yl)methyl)-3,8-diaza bicyclo
[3.2.1]octane (2f)
Elution with hexane/EtOAc (7:3) afforded 2f (48%) as
The residue was chromatographed on silica gel using
CH2Cl2/MeOH (95:5) as an eluent to provide 2b (82%) as
a yellow solid. Compound 2b was converted into its hydro-
1
a pale oil. Mp: 264 ꢀC; H NMR (CDCl3): 1.93e2.04 (m,
4H); 2.44 (s, 6H); 2.49 (d, 2H, J ¼ 10.8 Hz); 2.66 (dd, 2H,
J ¼ 10.8e2.85 Hz); 3.18 (br, 2H); 3.58 (s, 2H); 3.61 (s, 2H);
7.22 (d, 1H, J ¼ 5.26 Hz); 7.27e7.35 (m, 5H); 7.73 (s, 1H);
7.80 (s, 1H); 7.93 (d, 4H, J ¼ 7.23); 8.63 (d, 2H,
J ¼ 5.26 Hz). 13C NMR (CDCl3): 21.1; 24.1; 55.7; 56.9;
58.7; 63.1; 124.1; 124.9; 125.1; 125.7; 128.9; 132.1; 140.9;
148.3; 154.2. MS (ESI) m/z: 475.2.
1
chloric salt. Mp: 198.5 ꢀC; H NMR (CDCl3): 2.4 (s, 4H);
2.86 (d, 2H, J ¼ 12.72 Hz); 2.97 (d, 2H, J ¼ 12.72 Hz); 3.87
(s, 3H); 3.88 (s, 3H); 3.93 (s, 2H); 4.04 (s, 2H); 4.55 (s,
2H); 7.16 (d, 2H, J ¼ 6.58 Hz); 7.19 (d, 2H, J ¼ 7.02 Hz);
7.80 (d, 2H, J ¼ 8.99 Hz); 7.88 (d, 2H, J ¼ 8.77 Hz); 7.90
(d, 1H, 6.14 Hz); 8.00 (d, 1H, J ¼ 6.14 Hz); 8.16 (s, 1H);
8.36 (s, 1H); 8.54 (d, 1H, J ¼ 6.14 Hz); 8.72 (d, 1H,
J ¼ 6.14 Hz). 13C NMR (CDCl3): 26.3; 55.3; 56.2; 59.2;
59.9; 60.9; 114.1; 119.6; 121.5; 128.1; 123.1; 132.1; 149.4;
149.5; 157.1; 160.4. MS (ESI) m/z: 507.5; 1035.0.
6.5.7. 3,8-Bis((2-m-tolylpyridin-4-yl)methyl)-3,8-diaza bicyclo
[3.2.1]octane (2g)
Elution with petroleum ether/EtOAc (9:1e8:2) afforded 2g
1
(75%) as a white solid. Mp (2g$HCl): 266.3 ꢀC; H NMR
6.5.3. 3,8-Bis((2-(3-methoxyphenyl)pyridin-4-yl)methyl)-
3,8-diazabicyclo[3.2.1]octane (2c)
(CDCl3): 2.03 (br, 4H); 2.45 (s, 6H); 2.5 (d, 2H,
J ¼ 10.8 Hz); 2.6 (d, 2H, J ¼ 10.8 Hz); 3.22 (s, 2H); 3.61 (s,
2H); 3.66 (s, 2H); 7.26e7.28 (m, 4H); 7.41 (t, 2H,
J ¼ 7.87 Hz); 7.55 (s, 2H); 7.79 (d, 2H, J ¼ 7.87); 7.86 (s,
2H); 8.69 (d, 2H, J ¼ 5.04 Hz). 13C NMR (CDCl3): 21.1;
24.1; 55.7; 56.9; 58.7; 63.1; 124.1; 124.7; 125.3; 125.7;
128.7; 132.4; 140.8; 148.2; 154.1. MS (ESI) m/z : 475.4.
The residue was chromatographed on silica gel using light
petroleum/EtOAc (2:8) as an eluent to provide 2c (62%) as
a yellow solid. Compound 2c was converted into its hydro-
chloric salt. Mp: 198.7 ꢀC; 1H NMR (D2O): 2.4 (br, 4H);
2.95 (d, 2H, J ¼ 12.72 Hz); 2.97 (d, 2H, J ¼ 12.72 Hz); 3.89
(s, 3H); 3.90 (s, 3H); 3.99 (s, 2H); 4.07 (s, 2H); 4.6 (s, 2H);
7.25e7.33 (m, 2H); 7.37e7.5 (m, 4H); 7.55e7.64 (m, 2H);
8.02 (dd, 1H, J ¼ 1.53e6.36 Hz); 8.11 (dd, 1H, J ¼ 1.53e
6.36 Hz); 8.25 (s, 1H); 8.42 (s, 1H); 8.65 (d, 1H,
J ¼ 6.14 Hz); 8.33 (d, 1H). 13C NMR (D2O): 23.4; 54.1;
55.0; 56.1; 59.3; 64.1; 114.1; 114.7; 117.3; 118.1; 121.7;
122.1; 125.0; 126.1; 126.8; 127.9; 132.1; 133.2; 142.3;
144.1; 149.1; 153.4; 160.1. MS (ESI) m/z: 507.2.
6.5.8. 3,8-Bis((2-(4-acetamidophenyl)pyridin-4-yl)methyl)-
3,8-diazabicyclo[3.2.1]octane (2h)
Elution with CHCl3/MeOH (95:5e9:1) afforded 2j (77%)
1
as a white solid. Mp (2h$HCl): 254.3 ꢀC; H NMR (CDCl3):
1.95e2.10 (m, 4H); 2.24 (s, 6H); 2.5 (d, 2H, J ¼ 10.8 Hz);
2.66 (dd, 2H, J ¼ 10.8e2.63 Hz); 3.18 (s, 2H); 3.60 (s, 2H);
3.64 (s, 2H); 4.0 (br, 2NH2); 4.48 (s, 4H); 7.25 (d, 2H,
J ¼ 5.26 Hz); 7.36 (s, 2H); 7.66 (d, 4H, J ¼ 8.77 Hz); 7.73
(s, 2H); 8.01 (d, 4H, J ¼ 8.77 Hz); 8.67 (d, 2H, J ¼ 5.26 Hz).
13C NMR (CDCl3): 22.7; 23.5; 55.7; 56.9; 58.7; 63.1; 118.7;
120.3; 124.1; 124.7; 130.1; 134.3; 134.4; 141.9; 148.4;
150.1; 155.6. MS (ESI) m/z: 561.3.
6.5.4. 3,8-Bis((2-(4-hydroxyphenyl)pyridin-4-yl)methyl)-
3,8-diazabicyclo[3.2.1]octane (2d)
Elution with hexane/EtOAc (1:1e2:8) afforded 2d (65%) as
a pale oil. Mp: 263.2 ꢀC; 1H NMR (DMSO): 1.99 (m, 4H); 2.38
(d, 2H, J ¼ 9.21 Hz); 2.60 (d, 2H, J ¼ 9.21 Hz); 3.12 (s, 2H);
3.58 (s, 2H); 3.60 (s, 2H); 6.87 (d, 4H, J ¼ 8.11 Hz); 7.21 (d,
1H, J ¼ 5.04 Hz); 7.27 (d, 1H, J ¼ 5.04 Hz); 7.74 (s, 1H); 7.8
(s, 1H); 7.91 (d, 4H, J ¼ 8.11 Hz); 8.51 (t, 2H, J ¼ 4.6 Hz);
9.72 (d, 2H, J ¼ 3.51 Hz). 13C NMR (DMSO): 24.6; 53.8;
57.2; 57.8; 58.5; 108.9; 114.0; 117.1; 119.9; 126.3; 128.2;
147.4; 147.6, 148.4; 154.5; 157. MS (ESI) m/z: 478.5.
6.5.9. 3,8-Bis((2-(3-acetamidophenyl)pyridin-4-yl)methyl)-
3,8-diazabicyclo[3.2.1]octane (2i)
Elution with CHCl3/MeOH (95:5e9:1) afforded 2i (63%)
1
as a pale oil. Mp: 176 ꢀC; H NMR (CDCl3): 1.95e2.04 (m,
4H); 2.2 (s, 6H); 2.48 (d, 2H, J ¼ 10.8); 2.63 (d, 2H,
J ¼ 10.8); 3.15 (s, 2H); 3.58 (s, 2H); 3.62 (s, 2H); 7.01 (d,
2H, J ¼ 5.26 Hz); 7.57 (s, 2H); 7.73 (d, 4H, J ¼ 8.77 Hz);
7.97 (d, 4H, J ¼ 8.77 Hz); 8.60 (d, 2H, J ¼ 5.26 Hz). 13C
NMR (CDCl3): 22.7; 23.5; 55.7; 56.9; 58.7; 63.1; 118.7;
120.3; 124.1; 124.7; 130.1; 134.3; 134.4; 141.9; 148.4;
150.1; 155.6. MS (ESI) m/z: 561.3.
6.5.5. 3,8-Bis((2-(3-hydroxyphenyl)pyridin-4-yl)methyl)-
3,8-diazabicyclo[3.2.1]octane (2e)
Elution with petroleum ether/EtOAc (1:1e8:2) afforded 2e
1
(63%) as a white solid. Mp: 93.3 ꢀC; H NMR (CDCl3): 1.99
(br, 4H); 2.38 (d, 2H, J ¼ 9.21 Hz); 2.6 (d, 2H, J ¼ 9.21 Hz);
3.12 (s, 2H); 3.58 (s, 2H); 3.60 (s, 2H); 6.83 (d, 2H,
J ¼ 7.89 Hz); 7.31 (m, 4H); 7.46 (d, 2H, J ¼ 7.89 Hz) 7.51
(s, 1H); 7.80 (s, 1H); 7.86 (s, 2H); 8.57 (t, 2H, J ¼ 4.37 Hz);
9.56 (d, 2H, J ¼ 4.6 Hz). 13C NMR (CDCl3): 24.6; 53.7;
57.2; 57.9; 58.4; 11.9; 114.5; 115.7; 118.1; 120.8; 128.3;
6.5.10. 3,8-Bis((2-(4-chlorophenyl)pyridin-4-yl)methyl)-3,8-
diazabicyclo[3.2.1]octane (2j)
Elution with light petroleum/EtOAc (9:1e7:3) afforded 2j
(82%) as a white solid. Mp (2j$HCl): 245.3 ꢀC; rt: 17.84 min;
1H NMR (CDCl3): 2.07 (m, 4H); 2.50 (d, 2H, J ¼ 10.8 Hz);