ꢀ
M. Jaronczyk et al. / European Journal of Medicinal Chemistry 49 (2012) 200e210
208
d
(ppm) ¼ 8.52 (d,1H, J ¼ 2.6 Hz), 8.28 (dd,1H, J1 ¼2.5 Hz, J2 ¼ 9.22 Hz),
6.2.6. 4,4-Dimethyl-1-{4-[4-(6-nitro-quinolin-2-yl)-piperazin-1-
yl]-butyl}-piperidine-2,6-dione (8)
7.95 (d, 1H, J ¼ 9.27 Hz), 7.64 (d, 1H, J ¼ 9.24 Hz), 7.05 (d, 1H,
J ¼ 9.29 Hz), 3.87e3.76 (m, 6H), 2.68e2.54(m, 6H), 2.45e2.38(m, 4H),
1.93 (t, 4H, J ¼ 6.38), 1.61e1.53 (m, 2H). Rf: 0.45 (10% MeOH/DCM).
4ꢄHCl: C22H27N5O4ꢄHCl; m.p. ¼ 180 ꢂC-182 ꢂC.
From 6-nitroquipazine (1) and 1-(4-bromobutyl)-4,4-
dimethylpiperidine-2,6-dione (26): 60% dark brown oil. 1H NMR
(CDCl3)
d
(ppm) ¼ 8.52 (d, 1H, J ¼ 2.6 Hz), 8.28 (dd, 1H, J1 ¼ 2.6 Hz,
1H NMR (CDCl3)
d(ppm) ¼ 8.78 (d,1H,J ¼ 2.57 Hz), 8.38 (d,1H,
J2 ¼ 9.25 Hz), 7.95 (d, 1H, J ¼ 9.33 Hz), 7.65 (d, 1H, J ¼ 9.24 Hz), 7.05
(d, 1H, J ¼ 9.28 Hz), 3.88e3.76 (m, 6H), 2.57 (t, 6H, J ¼ 4.9 Hz), 2.50
(s, 4H), 2.42 (t, 2H, J ¼ 6.8 Hz), 1.56 (t, 4H, J ¼ 3.55 Hz), 1.08 (s, 6H);
J ¼ 9.3 Hz), 8.25 (dd, 1H, J1 ¼ 2.63 Hz, J2 ¼ 2.63 Hz), 7.67 (d, 1H,
J ¼ 9.25 Hz), 7.5 (d, 1H, J ¼ 9.3 Hz), 4.78 (d, 2H, J ¼ 5.24), 3.65e3.55
(m, 6H), 3.12e3.04 (m, 4H), 2.6 (t, 4H, J ¼ 6.44), 1.89e1.64 (m, 4H),
1.58e1.43 (m, 2H);
13C NMR (CDCl3)
d
(ppm) ¼ 171.8, 158.2, 151.3, 141.6, 138.4, 126.8,
124.0, 123.4, 120.8, 110.7, 57.9, 52.8, 46.2, 44.4, 38.9, 29.7, 28.9, 27.4,
25.7; Rf: 0.38 (10% MeOH/DCM).
Anal. calcd for C22H27N5O4ꢄHClꢄ0.5H2O: C, 56.11; H, 6.21; N,
14.87%. Found: C, 55.94; H, 6.17; N, 14.77%.
8ꢄHCl: C24H31N5O4ꢄHCl, m.p. ¼ 173 ꢂC-174 ꢂC.
1H NMR (CDCl3)
d
(ppm) ¼ 8.79 (d, 1H, J ¼ 2.65 Hz), 8.4 (d, 1H,
6.2.3. 8-{4-[2-methyl-4-(6-nitro-quinolin-2-yl)-piperazin-1-yl]-
butyl}-8-azaspiro[4.5]-decane-7,9-dione (5)
J ¼ 9.36 Hz), 8.29 (dd, 1H, J1 ¼ 2.6 Hz, J2 ¼ 2.71 Hz), 7.78 (d, 1H,
J ¼ 9.27 Hz), 7.51 (d, 1H, J ¼ 9.4 Hz), 4.76 (d, 2H, J ¼ 13.77), 3.7e3.5
(m, 7H), 3.1e3.05 (m, 4H), 2.54 (s, 4H), 1.85e1.7 (m, 2H), 1.49e1.45
(m, 2H), 0.98 (s, 6H).
From 30-methyl-6-nitroquipazine (20) and 8-(4-bromobutyl)-8-
azaspiro[4.5]decane-7,9-dione (27). Brown semi-solid 60%. 1H
NMR(CDCl3)
d
(ppm) ¼ 8.52 (d, 1H, J ¼ 2.56), 8.29 (dd, 1H, J1 ¼ 2.54,
Anal. calcd for C24H31N5O4ꢄHClꢄ0.5H2O: C, 57.77; H, 6.67; N,
J2 ¼ 9.22), 7.95 (d, 1H, J ¼ 9.33), 7.65 (d, 1H, J ¼ 9.24), 7.05 (d, 1H,
J ¼ 9.35), 4.25 (d, 2H, J ¼ 12.94), 3.79 (t, 2H, J ¼ 6.62), 3.49e3.40 (m,
1H), 3.15e3.07 (m, 1H), 3.03e2.93 (m, 1H), 2.79e2.70 (m, 1H), 2.59
(s, 4H), 2.53e2.50 (m, 1H), 2.42e2.32 (m, 2H), 1.75e1.65 (m, 6H),
1.54e1.50 (m. 10H), 1.15 (d, 3H, J ¼ 6.18); 13C NMR (CDCl3)
14.03%. Found: C, 57.67; H, 6.74; N, 13.95%.
6.2.7. 2-{4-[4-(6-Nitro-quinolin-2-yl)-piperazin-1-yl]-butyl}-
isoindole-1,3-dione (9)
From 6-nitroquipazine (1) and 2-(4-bromobutyl)-1H-isoindole-
d
(ppm) ¼ 172.0, 158.1, 151.4, 141.7, 138.3, 126.8, 124.0, 123.3, 120.7,
1,3(2H)-dione (28). Dark brown crystals 61%. 1H NMR (CDCl3)
110.6, 54.5, 52.8, 51.0, 50.2, 44.7, 39.3, 39.1, 37.3, 25.8, 24.0, 23.1,
15.6; Rf ¼ 0.46 (10% MeOH/DCM).
d
(ppm) ¼ 8.52 (d, 1H, J ¼ 2.55 Hz), 8.28 (dd, 1H, J1 ¼ 2.67 Hz,
J2 ¼ 9.26 Hz), 7.95 (d, 1H, J ¼ 9.32 Hz), 7.87e7.82 (m, 2H), 7.76e7.69
(m, 2H), 7.64 (d, 1H, J ¼ 9.28), 7.05 (d, 1H, J ¼ 9.35), 3.85 (t, 4H,
J ¼ 5.02), 3.73 (t, 2H, J ¼ 6.89), 2.57 (t, 2H, J ¼ 4.99), 2.45 (t, 2H,
J ¼ 7.25), 1.80e1.59 (m, 4H); Rf: 0.41 (10% MeOH/DCM).
9ꢄHCl: C25H25N5O4ꢄHCl; m.p. ¼ 219 ꢂC-220 ꢂC.
5ꢄHCl: C27H35N5O4ꢄHCl; m.p. 192e195 ꢂC. Anal. calcd for
C27H35N5O4ꢄHClꢄ0.5H2O: C, 60.16; H, 6.92; N, 12.99%. Found: C,
60.15; H, 7.08; N, 12.99%.
6.2.4. 8-{4-[4-(6-Nitro-quinolin-2-yl)-piperazin-1-yl]-butyl}-8-
azaspiro[4.5]decane-7,9-dione (6)
1H NMR (CDCl3)
d
(ppm) ¼ 8.77 (d, 1H, J ¼ 2.66 Hz), 8.38 (d, 1H,
J ¼ 9.35 Hz), 8.27 (dd, 1H, J1 ¼ 2.59 Hz, J2 ¼ 2.72 Hz), 7.66 (d, 1H,
J ¼ 9.23 Hz), 7.49 (d, 1H, J ¼ 9.3 Hz), 4.71 (d, 2H, J ¼ 13.8 Hz),
3.64e3.57 (m, 6H), 3.27e3.12 (m, 4H), 1.77e1.65 (m, 4H).
Anal. calcd for C25H25N5O4ꢄHClꢄ0.5H2O: C, 59.46; H, 5.39; N,
13.87%. Found: C, 60.26; H, 5.49; N, 13.85%.
From 6-nitroquipazine (1) and 8-(4-bromobutyl)-8-azaspiro
[4.5]decane-7,9-dione (27). Dark brown oil 67%.1H NMR (CDCl3)
d
(ppm) ¼ 8.53 (d, 1H, J ¼ 2.5 Hz), 8.28 (dd, 1H, J1 ¼ 2.53 Hz,
J2 ¼ 9.21 Hz), 7.95 (d,1H, J ¼ 9.31 Hz), 7.65 (d,1H, J ¼ 9.2 Hz), 7.05 (d,
1H, J ¼ 9.4 Hz), 3.88e3.76 (m, 6H), 2.59e2.54 (m, 8H), 2.42 (t, 2H,
J ¼ 6.8), 1.75e1.68 (m, 4H), 1.63e1.47 (m, 6H); 13C NMR (CDCl3)
6.3. Preparation of compounds 10 and 11
d
(ppm) ¼ 172.1, 158.3, 151.4, 141.6, 138.5, 126.9, 124.1, 123.4, 120.9,
110.7, 58.0, 52.9, 44.7, 44.5, 39.6, 39.2, 37.4, 29.9, 25.8, 24.1; Rf: 0.54
(10% MeOH/DCM).
6.3.1. 1-{4-[4-(5-chloroquinolin-2-yl)piperazin-1-yl]butyl}-4,4-di-
methylopiperydine-2,6-dione (10)
6ꢄHCl: C26H33N5O4ꢄHCl, m.p. ¼ 193e194 ꢂC.
To the solution of 5-chloroquipazine (29) (1.223 g, 4.9 mmol) in
40 mL of anhydrous toluene 2.74 g, (2 equiv.) of bromoimide (26),
2.76 g (4 equiv.) of anhydrous potassium carbonate and 0.19 g of 18-
crown-6 were added. The reactions mixture was heated under
reflux for 4 days. The resulted suspension was filtered off and the
residue was evaporated. Combined solid residues were purified
with the aid of column chromatography on silica gel (0e3% MeOH/
DCM) to give brown oil of 10 (0.940, 43%). 1H NMR (CDCl3)
1H NMR (CDCl3)
d
(ppm) ¼ 8.81 (d, 1H, J ¼ 2.46 Hz), 8.42 (d, 1H,
J ¼ 9.32 Hz), 8.31 (dd, 1H, J1 ¼ 2.7 Hz, J2 ¼ 2.78 Hz), 7.77 (d, 1H,
J ¼ 9.22 Hz), 7.54 (d, 1H, J ¼ 9.33 Hz), 4.78 (d, 2H, J ¼ 13.8),
3.69e3.55 (m, 6H), 3.09 (s, 4H), 2.62 (s, 4H), 1.8e1.65 (m, 2H),
1.62e1.59 (m, 4H), 1.48e1.41 (m, 6H);
Anal. calcd for C26H33N5O4ꢄHClꢄ0.5H2O: C, 59.48; H, 6.72; N,
13.34%. Found: C, 59.49; H, 6.93; N, 13.25%.
d
(ppm) ¼ 8.22 (d, 1H, J ¼ 9.36 Hz), 7.56 (d, 1H, J ¼ 7.62 Hz), 7.63 (d,
6.2.5. 4,4-Dimethyl-1-{4-[2-methyl-4-(6-nitro-quinolin-2-yl)-
piperazin-1-yl]-butyl}-piperidine-2,6-dione (7)
1H, J ¼ 8.95 Hz), 7.38 (t, 1H, J ¼ 8.41 Hz), 7.38 (dd, 1H, J1 ¼ 7.60 Hz,
J2 ¼ 8.40 Hz), 6.98 (d, 1H, J ¼ 9.40 Hz), 3.77 (t, 2H, J ¼ 6.76 Hz), 3.73
(t, 4H, J ¼ 4.88 Hz), 2.52 (t, 4H, J ¼ 5.00 Hz), 2.46 (s, 4H), 1.55e1.52
From 30-methyl-6-nitroquipazine (20) and 1-(4-bromobutyl)-4,4-
dimethylpiperidine-2,6-dione (26). Brown semi oil 52%. 1H
(m, 4H), 1.04 (s, 6H). 13C NMR (CDCl3)
d
(ppm) ¼ 171.7, 157.3, 148.7,
NMR(CDCl3)
d
(ppm) ¼ 8.51 (d, 1H, J ¼ 2.59), 8.28 (dd, 1H, J1 ¼ 2.65,
133.9, 130.9, 129.1, 125.6, 122.1, 120.7, 110.0, 77.0, 58.1, 52.9, 46.3,
44.8, 39.2, 29.0, 27.5, 25.9, 24.2; Rf ¼ 0.25 (5% MeOH/DCM).
10ꢄHCl: C22H33N5O2ꢄHCl.
J2 ¼ 9.26), 7.94 (d, 1H, J ¼ 9.30), 7.64 (d, 1H, J ¼ 9.27), 7.05 (d, 1H,
J¼ 9.34), 4.26 (d, 2H, J ¼ 12.94), 3.80 (t, 2H, J¼ 6.70), 3.49e3.37(m,1H),
3.14e3.08 (m, 1H), 3.03e2.92 (m, 1H), 2.80e2.74 (m, 1H), 2.56e2.50
(m, 1H), 2.50 (s, 4H), 2.44e2.32 (m, 2H), 1.54e1.25 (m, 4H), 1.14 (d,
Anal. calcd. for C22H33N5O2ꢄHClꢄ3H2O: C, 55.92; H, 7.04; N,
10.87%. Found: C, 55.92; H, 6.85; N, 10.96%.
3H, J¼ 6.22),1.08 (s, 6H); 13CNMR (CDCl3)
(ppm) ¼ 171.8, 158.2, 151.5,
d
141.6, 138.5, 126.9, 124.1, 123.5, 120.8, 110.7, 54.6, 52.9, 51.1, 50.3, 46.3,
44.7, 39.2, 29.0, 27.6, 25.9, 23.3, 15.6; Rf ¼ 0.45 (10% MeOH/DCM).
7ꢄHCl: C25 H33 N5O4ꢄHCl; m.p. 177e181 ꢂC.
6.3.2. 8-{4-[4-(6-aminoquinolin-2-yl)piperazin-1-yl]butyl}-8-
azaspiro-[4.5]decane-7,9-dione (30)
1-{4-[4-(6-Nitrochinolin-2-ylo)-piperazyn-1-ylo]butylo}-8-
azaspiro[4.5]decano-7,9-dion (6) (0.325 g, 0.7 mmol) was dissolved
in concentrated hydrochloric acid (8 mL) and 0.52 g (4 equiv.) of tin
Anal. Calcd for C25H33N5O4ꢄHClꢄ0.5H2O: C, 58.53; H, 6.88; N,
13.65%. Found: C, 58.36; H, 7.03; N, 13.66%.