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J. Konter et al. / Bioorg. Med. Chem. 16 (2008) 8294–8300
5.3. Experimental data for compounds shown in Scheme 1
5H), 3.52 (s, 3H), 3.73–3.77 (dd, J = 8.2, 4.9 Hz, 2H), 3.83–3.95
(dd, J = 6.7, 6.6 Hz, 1H), 4.30–4.39 (quin, J = 5.7 Hz, 1H), 4.39–4.53
(dd, J = 40.7, 14.8 Hz, 2H), 5.24 (s, 2H), 6.73 (d, J = 9.1 Hz, 2H),
6.89 (d, J = 9.1 Hz, 2H), 6.97 (d, J = 13.6 Hz, 2H), 7.29 (d, J = 8.1 Hz,
1H), 7.48 (d, J = 14.7 Hz, 2H), 7.56 (d, J = 8.4 Hz, 1H); 13C NMR:
400 MHz (CDCl3): d 49.3, 51.3, 51.7, 57.0, 67.7, 67.8, 74.7, 97.9,
108.0, 115.3, 118.7, 121.1, 127.2, 128.4, 129.5, 131.3, 133.0,
134.6, 135.9, 138.8, 145.8, 152.4; FAB-MS m/z (%): 255 (40), 257
(33), 307 (100), 432 (20), 446 (28), 459 (33), 487 (43), 518 (50),
593 (24, [M+H]+); Anal. Calcd for C26H30Cl2N6 O6: C, 52.62; H,
5.10; N, 14.16. Found: C, 52.95; H, 5.21; N, 13.82.
5.3.1. 1-(4-{[2-(2,4-Dichlorophenyl)-2-(1H-imidazol-1-
ylmethyl)-1,3-dioxolan-4-yl]methoxy}phenyl)piperazine (2a)
White powder (99% yield); mp 173 °C; 1H NMR: 400 MHz
(CDCl3): d 3.03 (s, 8H), 3.32–3.36 (dd, J = 9.6, 6.7 Hz, 1H), 3.72–
3.77 (dd, J = 8.2, 4.9 Hz, 2H), 3.86–3.90 (dd, J = 6.7, 6.6 Hz, 1H),
4.31–4.37 (quin, J = 5.7 Hz, 1H), 4.39–4.53 (dd, J = 40.7, 14.8 Hz,
2H), 6.76 (d, J = 9.1 Hz, 2H), 6.88 (d, J = 9.1 Hz, 2H), 6.97 (d,
J = 13.6 Hz, 2H), 7.25 (d, J = 8.1 Hz, 1H), 7.48 (d, J = 14.7 Hz, 2H),
7.57 (d, J = 8.4 Hz, 1H); 13C NMR: 400 MHz (CDCl3): d 46.3, 51.3,
51.8, 67.6, 67.8, 74.9, 108.0, 115.3, 118.1, 121.1, 127.2, 128.6,
129.5, 131.3, 133.0, 134.7, 135.9, 138.8, 146.8, 152.3; EI-MS m/z
(%): 83 (15), 173 (20), 183 (39), 432 (28), 445 (61), 460 (100),
471 (32), 489 (16, [M+H]+) Anal. Calcd for C24H26Cl2N4O3: C,
58.90; H, 5.35; N, 11.45. Found: C, 58.90; H, 5.36; N, 11.38.
5.3.7. O2-Methoxymethyl-1-(phenylpiperazin-1-yl)diazen-1-
ium-1,2-diolate (5b)
Yellow solid (61% yield); mp 187 °C; 1H NMR: 250 MHz (CDCl3):
d 3.36 (mc, 4H), 3.51 (s, 3H), 3.64 (mc, 4H), 5.24 (s, 2H), 6.89–6.97
(m, 3H), 7.25–7.29 (m, 2H); 13C NMR: 250 MHz (CDCl3): d 48.3,
51.0, 57.0, 97.9, 117.2, 121.2, 129.3, 150.3; Anal. Calcd for
5.3.2. Sodium 1-(4-{[2-(2,4-dichlorophenyl)-2-(1H-imidazol-1-
ylmethyl)-1,3-dioxolan-4-yl]methoxy}phenyl)-4-(diazen-1-
ium-1,2-diolat)piperazine (3a)
C12H18N4O3: C, 54.12; H, 6.81; N, 21.04. Found: C, 54.25; H, 6.78;
N, 20.86.
Crude white solid (82% yield); mp 165–170 °C dec; 1H NMR:
400 MHz (DMSO-d6): d 3.05 (m, 4H), 3.28–3.41 (m, 5H), 3.72–
3.77 (dd, J = 8.2, 4.9 Hz, 2H), 3.86–3.90 (dd, J = 6.7, 6.6 Hz, 1H),
4.31–4.37 (quin, J = 5.7 Hz, 1H), 4.39–4.53 (dd, J = 40.7, 14.8 Hz,
2H), 6.76 (d, J = 9.1 Hz, 2H), 6.88 (d, J = 9.1 Hz, 2H), 6.97 (d,
J = 13.6 Hz, 2H), 7.25 (d, J = 8.1 Hz, 1H), 7.48 (d, J = 14.7 Hz, 2H),
7.57 (d, J = 8.4 Hz, 1H); Anal. Calcd for C24H25Cl2N6NaO5: C,
50.45; H, 4.41; N, 14.71. Found: C, 50.54; H, 4.06; N, 14.37.
5.3.8. O2-(1-(4-{[2-(2,4-Dichlorophenyl)-2-(1H-imidazol-1-
ylmethyl)-1,3-dioxolan-4-yl]methoxy}phenyl)piperazine-4-
carboxymethyl)-1-(pyrrolidin-1-yl)diazen-1-ium-1,2-diolate
(6a)
Column purification on silica gel with ethyl acetate:acetoni-
trile (1:1) then methanol washout to give orange solid (38%
yield); mp 237 °C; 1H NMR: 400 MHz (CDCl3): d 1.93 (m, 4H),
3.02–3.13 (m, 8H), 3.32–3.36 (m, 1H), 3.55 (mc, 4H), 3.72–3.77
(m, 2H), 3.86–3.90 (dd, J = 6.7, 6.6 Hz, 1H), 4.31–4.37 (quin,
J = 5.7 Hz, 1H), 4.39–4.53 (dd, J = 40.7, 14.8 Hz, 2H), 4.80 (s,
2H), 6.76 (d, J = 9.1 Hz, 2H), 6.90 (m, 2H), 6.97 (m, 2H), 7.25
(d, J = 8.1 Hz, 1H), 7.49 (d, J = 14.7 Hz, 2H), 7.57 (d, J = 8.3 Hz,
1H); 13C NMR: 400 MHz (CDCl3): d 22.9, 36.8, 51.3, 51.7, 53.5,
67.6, 67.7, 71.4, 74.8, 108.0, 115.3, 118.8, 121.2, 127.2, 128.4,
129.5, 131.3, 133.0, 134.6, 135.9, 138.8, 145.6, 152.9, 166.7;
FAB-MS m/z (%): 202 (48), 217 (55), 235 (50), 255 (100), 432
(38), 446 (51), 459 (70), 471 (63), 489 (64), 517 (39), 547 (82),
600 (69), 660 (42, M++H), 682 (19, [M+Na]+), 698 (17, M++K);
Anal. Calcd for C30H35Cl2N7 O6: C, 54.55; H, 5.34; N, 14.84.
Found: C, 54.17; H, 5.43; N, 14.78.
5.3.3. Sodium 1-(phenylpiperazin-1-yl)diazen-1-ium-1,2-
diolate (3b)
White powder (86% yield); mp 148 °C dec; 1H NMR: 250 MHz
(NaOD): d 3.10–3.31 (m, 8H), 6.82–6.94 (m, 3H), 7.15–7.21 (m,
2H); Anal. Calcd for C10H13N4NaO2: C, 49.18; H, 5.37; N, 22.94.
Found: C, 49.22; H, 5.37; N, 22.88.
5.3.4. 1-(4-{[2-(2,4-Dichlorophenyl)-2-(1H-imidazol-1-
ylmethyl)-1,3-dioxolan-4-yl]methoxy}phenyl)-4-(O2-ethyl-
diazen-1-ium-1,2-diolat)piperazine (4a)
From 1.4 mmol 3a a brown solid after column purification with
ethanol:acetone (1:1) as eluent (62% yield); mp 181 °C; 1H NMR:
250 MHz (CDCl3): d 1.39 (t, J = 7.0, 3H) 3.07 (m, 4H), 3.26–3.41
(m, 5H), 3.72–3.77 (dd, J = 8.2, 4.9 Hz, 2H), 3.86–3.90 (dd, J = 6.7,
6.6 Hz, 1H), 4.25–4.53 (m, 5H), 6.74 (d, J = 9.1 Hz, 2H), 6.88 (d,
J = 9.1 Hz, 2H), 6.97 (d, J = 13.6 Hz, 2H), 7.25 (d, J = 8.1 Hz, 1H),
7.48 (d, J = 14.7 Hz, 2H), 7.59 (d, J = 8.4 Hz, 1H); 13C NMR:
250 MHz (CDCl3): d 14.4, 46.3, 51.3, 51.8, 67.6, 67.8, 69.8, 74.9,
108.0, 115.3, 118.6, 121.1, 127.2, 128.6, 129.3, 131.7, 133.0,
134.7, 135.9, 138.8, 145.8, 152.9; Anal. Calcd for C26H30Cl2N6O5:
C, 54.08; H, 5.24; N, 14.55. Found: C, 53.98; H, 5.23; N, 14.22.
5.3.9. O2-[(1-Phenylpiperazine-4-carboxymethyl)-1-
(pyrrolidin-1-yl)]diazen-1-ium-1,2-diolate (6b)
Column purification with ethanol/acetone (1:1) as eluent gave
orange oil (58% yield); 1H NMR: 250 MHz (CDCl3): d 1.80 (m, 4H),
2.58 (m, 4H), 3.16 (mc, 4H), 3.37 (s, 2H), 3.76 (mc, 4H), 6.87–6.95
(m, 3H), 7.25–7.31 (m, 2H); 13C NMR: 250 MHz (CDCl3): d 23.8,
41.7, 43.4, 49.4, 49.9, 53.9, 58.5, 116.5, 120.4, 129.3, 151.0, 168.6;
Anal. Calcd for C16H23N5O3: C, 57.64; H, 6.95; N, 21.01. Found: C,
57.53; H, 6.99; N, 21.17.
5.3.5. O2-Ethyl-1-(phenylpiperazin-1-yl)diazen-1-ium-1,2-
diolate (4b)
5.3.10. 1-(4-{[2-(2,4-Dichlorophenyl)-2-(1H-imidazol-1-
ylmethyl)-1,3-dioxolan-4-yl]methoxy}phenyl)piperazine-4-
carboxymethylnitrate (7a)
Brown plates (72% yield); mp 198 °C; 1H NMR: 250 MHz
(CDCl3): d 1.40 (t, J = 7.0 Hz, 3H), 3.37 (t, J = 5.0 Hz, 4H), 3.58 (t,
J = 5.1 Hz, 4H), 3.31 (q, J = 7.1 Hz, 2H), 6.88–6.96 (m, 3H), 7.26–
7.33 (m, 2H); 13C NMR: 250 MHz (CDCl3): d 14.5, 48.8, 51.3, 69.8,
117.2, 120.6, 129.3, 150.3; Anal. Calcd for C12H18N4O2: C, 57.58;
H, 7.25; N, 22.38. Found: C, 57.69; H, 7.28; N, 22.22.
Crude light orange solid after column purification with
methanol on silica gel (86% yield); mp > 250 °C; 1H NMR:
250 MHz (CDCl3): d 3.03 (m, 4H), 3.27 (m, 5H), 3.47 (s, 2H),
3.72–3.78 (m, 2H), 3.83–3.90 (dd, J = 6.6, 6.6 Hz, 1H), 4.30–
4.57 (m, 3H), 6.76 (d, J = 9.0 Hz, 2H), 6.88–6.98 (m, 4H), 7.25
(mc, 1H), 7.48 (d, J = 14.4 Hz, 2H), 7.49 (d, J = 8.4 Hz, 1H); 13C
NMR: 250 MHz (CDCl3): d 39.6, 50.1, 50.7, 51.2, 51.7, 67.5,
67.6, 74.7, 108.0, 115.3, 119.2, 121.2, 127.2, 128.5, 129.5,
131.4, 133.0, 134.6, 135.9, 138.8, 145.1, 153.3; Anal. Calcd for
5.3.6. 1-(4-{[2-(2,4-Dichlorophenyl)-2-(1H-imidazol-1-
ylmethyl)-1,3-dioxolan-4-yl]methoxy}phenyl)-4-(O2-
methoxymethyl-diazen-1-ium-1,2-diolat)piperazine (5a)
From 1.0 mmol 3a a beige solid after column purification with
dichloromethane:methanol (9:1) as eluent (47% yield); mp
186 °C; 1H NMR: 400 MHz (CDCl3): d 3.05 (m, 4H), 3.28–3.41 (m,
C26H27Cl2N5 O7: C, 52.71; H, 4.59; N, 11.82. Found: C, 53.01;
H, 4.53; N, 11.68.