Journal of Medicinal Chemistry
ARTICLE
and 7f. Colorless viscous liquid, 68% yield. Analytical data for 8f: IR
(KBr, cmꢀ1): 3441, 2925, 1710, 1615, 1552, 1450, 1248, 1170. 1H NMR
(CDCl3, 300 MHz): δ 8.04 (d, 2H, J = 7.5 Hz, ArꢀH), 7.96 (d, 1H, J =
7.8 Hz, ArꢀH), 7.73 (m, 1H, ArꢀH), 7.59 (m, 2H, ArꢀH), 7.42 (m,
1H, ArꢀH), 7.32 (m, 1H, ArꢀH), 7.14 (m, 1H, ArꢀH), 5.34 (m, 1H,
SCH2CH), 5.09 (m, 2H, 2 ꢁ CH2CHdCCH3), 4.44 (t, 2H, J = 6.3 Hz,
COOCH2), 4.37 (t, 2H, J = 6.6 Hz, OCH2), 3.58 (d, 2H, J = 7.8 Hz,
SCH2), 1.89ꢀ2.02 (m, 8H, 2 ꢁ CHCH2CH2CH), 1.50ꢀ1.70 (m, 18H,
4 ꢁ CHdCCH3, CH2CH2CH2CH2CH2). MS (ESI) m/z = 669 [M þ
4-(2-(N-Methyl-2-((2E,6E)-3,7,11-trimethyldodeca-2,6,10-
trienylthio)benzamido)ethoxy)-3-(phenylsulfonyl)-1,2,5-
oxadiazole-2-oxide (8k). The title compound was obtained starting
from 1 and 7k. Colorless viscous liquid, 60% yield. Analytical data for 8k:
IR (KBr, cmꢀ1): 3281, 2925, 1627, 1552, 1448, 1372, 1157. 1H NMR
(CDCl3, 300 MHz): δ 8.07 (d, 2H, J = 7.5 Hz, ArꢀH), 7.94 (m, 1H,
ArꢀH), 7.76 (m, 1H, ArꢀH), 7.59 (m, 3H, ArꢀH), 7.31 (m, 2H,
ArꢀH), 5.30 (m, 1H, SCH2CH), 5.07 (m, 2H, 2 ꢁ CH2CHdCCH3),
4.77 (m, 2H, OCH2), 4.06 (d, 2H, J = 7.8 Hz, SCH2), 3.53 (m, 2H,
NCH2), 3.02 (m, 3H, NCH3), 1.89ꢀ2.02 (m, 8H, 2 ꢁ CHCH2CH2CH),
1.50ꢀ1.68 (m, 12H, 4 ꢁ CHdCCH3). MS (ESI) m/z = 640 [M þ 1]þ.
1]þ. Anal. calcd for C35H44N2O7S2 5.5H2O: C, 54.74; H, 7.22; N, 3.65.
3
Found: C, 54.66; H, 6.92; N, 3.60.
Anal. calcd for C33H41N3O6S2 1.5H2O: C, 59.44; H, 6.55; N, 6.30.
3-(Phenylsulfonyl)-4-(2-(2-(2-((2E,6E)-3,7,11-trimethyldo-
deca-2,6,10-trienylthio)benzoyloxy)ethoxy) ethoxy)-1,2,5-
oxadiazole-2-oxide (8g). The title compound was obtained starting
from 1 and 7g. Colorless viscous liquid, 67% yield. Analytical data for 8g:
IR (KBr, cmꢀ1): 3451, 2924, 1712, 1617, 1449, 1249, 1170. 1H NMR
(CDCl3, 300 MHz): δ 7.96 (d, 1H, J = 7.8 Hz, ArꢀH), 7.91 (d, 2H, J =
7.2 Hz, ArꢀH), 7.62 (t, 1H, J = 7.5 Hz, ArꢀH), 7.49 (m, 2H, ArꢀH),
7.30 (m, 2H, ArꢀH), 7.16 (m, 1H, ArꢀH), 5.33 (m, 3H, SCH2CH,2 ꢁ
CH2CHdCCH3), 4.37 (m, 4H, 2 ꢁ CH2O), 3.73 (m, 4H, CH2OCH2),
3.58 (d, 2H, J = 7.2 Hz, SCH2), 1.89ꢀ2.02 (m, 8H, 2 ꢁ
CHCH2CH2CH), 1.50ꢀ1.68 (m, 12H, 4 ꢁ CHdCCH3). MS (ESI)
m/z = 671 [M þ 1]þ. Anal. calcd for C34H42N2O8S2: C, 60.87; H, 6.31;
N, 4.18. Found: C, 60.59; H, 6.52; N, 3.97.
3
Found: C, 59.61; H, 6.19; N, 6.23.
3-(Phenylsulfonyl)-4-(2-(4-(2-((2E,6E)-3,7,11-trimethyldo-
deca-2,6,10-trienylthio)benzoyl)piperazin-1-yl)ethoxy)-1,2,
5-oxadiazole-2-oxide (8l). The title compound was obtained start-
ing from 1 and 7l. Colorless viscous liquid, 63% yield. Analytical data for
1
8l: IR (KBr, cmꢀ1): 3427, 2925, 1616, 1448, 1169, 1010. H NMR
(CDCl3, 300 MHz): δ 8.05 (d, 2H, J = 7.8 Hz, ArꢀH), 7.75 (m, 1H,
ArꢀH), 7.61 (m, 2H, ArꢀH), 7.38 (m, 1H, ArꢀH), 7.28 (m, 3H,
ArꢀH), 5.28 (m, 1H, SCH2CH), 5.08 (m, 2H, 2 ꢁ CH2CHdCCH3),
4.58 (t, 2H, J = 5.1 Hz, CH2O), 3.84 (d, 2H, J = 4.5 Hz, NCH2), 3.56 (m,
2H, SCH2), 2.91 (m, 4H, CON(CH2)2), 2.63 (m, 4H, N(CH2)2),
1.89ꢀ2.04 (m, 8H, 2 ꢁ CHCH2CH2CH), 1.50ꢀ1.67 (m, 12H, 4 ꢁ
CHdCCH3). MS (ESI) m/z = 695 [M þ 1]þ. Anal. calcd for
C36H46N4O6S2: C, 62.22; H, 6.67; N, 8.06. Found: C, 61.95; H, 6.83;
N, 7.96.
(S)-3-(Phenylsulfonyl)-4-((1-(2-((2E,6E)-3,7,11-trimethyl-
dodeca-2,6,10-trienylthio)benzoyl)pyrrolidin-2-yl)methoxy)-
1,2,5-oxadiazole-2-oxide (8m). The title compound was obtained
starting from 1 and 7m. Colorless viscous liquid, 65% yield. Analytical
data for 8m: [R]D24: ꢀ36.4. IR (KBr, cmꢀ1): 3474, 2965, 1630, 1552,
1448, 1169. 1H NMR (CDCl3, 300 MHz): δ 8.05 (m, 2H, ArꢀH), 7.93
(m, 1H, ArꢀH), 7.76 (m, 1H, ArꢀH), 7.61 (m, 2H, ArꢀH), 7.43 (t, 1H,
J = 7.2 Hz, ArꢀH), 7.39 (m, 1H, ArꢀH), 7.29 (m, 1H, ArꢀH), 5.19 (m,
1H, SCH2CH), 5.07 (m, 2H, 2 ꢁ CH2CHdCCH3), 4.90 (m, 1H,
NCH), 4.65 (m, 2H, OCH2), 3.51 (d, 2H, J = 7.8 Hz, SCH2), 3.30 (m,
2H, NCH2), 1.89ꢀ2.02 (m, 8H, 2 ꢁ CHCH2CH2CH), 1.50ꢀ1.68 (m,
16H, 4 ꢁ CHdCCH3, CHCH2CH2). MS (ESI) m/z = 666 [M þ 1]þ.
Anal. calcd for C35H43N3O6S2: C, 63.13; H, 6.51; N, 6.31. Found: C,
62.95; H, 6.44; N, 6.29.
3-(Phenylsulfonyl)-4-(1-(2-((2E,6E)-3,7,11-trimethyldode-
ca-2,6,10-trienylthio)benzoyl)piperidin-4-yloxy)-1,2,5-oxa-
diazole-2-oxide (8n). The title compound was obtained starting
from 1 and 7n. Colorless viscous liquid, 70% yield. Analytical data for 8n:
IR (KBr, cmꢀ1): 3432, 2929, 1623, 1440, 1285, 1169, 1085. 1H NMR
(CDCl3, 300 MHz): δ 8.05 (m, 2H, ArꢀH), 7.77 (t, 1H, J = 7.2 Hz,
ArꢀH), 7.63 (m, 2H, ArꢀH), 7.40 (m, 1H, ArꢀH), 7.26 (m, 3H,
ArꢀH), 5.27 (m, 1H, SCH2CH), 5.18 (m, 2H, 2 ꢁ CH2CHdCCH3),
5.08 (m, 1H, OCH), 3.88 (m, 2H, SCH2), 3.47 (m, 4H, N(CH2)2),
1.89ꢀ2.02 (m, 12H, 2 ꢁ CHCH2CH2CH, C(CH2)2), 1.50ꢀ1.68 (m,
12H, 4 ꢁ CHdCCH3). MS (ESI) m/z = 666 [M þ 1]þ. Anal. calcd for
C35H43N3O6S2: C, 63.13; H, 6.51; N, 6.31. Found: 62.88; H, 6.74;
N, 6.07.
4-(2-(N-(2-Hydroxyethyl)-2-((2E,6E)-3,7,11-trimethyldo-
deca-2,6,10-trienylthio)benzamido)ethoxy)-3-(phenylsulfonyl)-
1,2,5-oxadiazole-2-oxide (8o). A solution of 1 (0.36 g, 1.00 mmol)
and oxalyl chloride (0.5 mL) in dry dichloromethane (5 mL) was stirred
at room temperature for 4 h. The solvent was removed under reduced
pressure. The crude residue was dissolved in 5 mL of dichloromethane
and slowly added to the mixture of 8o (0.33 g, 1.00 mmol) and
triethylamine (0.3 mL) in 10 mL of dichloromethane under an ice bath,
and stirring was continued for 12 h. After filtration, the filtrate was
evaporated to dryness in vacuo, and the crude product was purified by
3-(Phenylsulfonyl)-4-(6-(2-((2E,6E)-3,7,11-trimethyldode-
ca-2,6,10-trienylthio)benzoyloxy)hexyloxy)-1,2,5-oxadiazole-
2-oxide (8h). The title compound was obtained starting from 1 and 7g.
Colorless viscous liquid, 65% yield. Analytical data for 8g: IR
1
(KBr, cmꢀ1): 3420, 2930, 1710, 1615, 1450, 1248, 1170. H NMR
(CDCl3, 300 MHz): δ 8.04 (m, 2H, ArꢀH), 7.95 (m, 1H, ArꢀH), 7.75
(t, 1H, J = 7.5 Hz, ArꢀH), 7.61 (m, 2H, ArꢀH), 7.43 (m, 1H, ArꢀH),
7.30 (m, 1H, ArꢀH), 7.15 (m, 1H, ArꢀH), 5.34 (m, 1H, SCH2CH),
5.08 (m, 2H, 2 ꢁ CH2CHdCCH3), 4.42 (t, 2H, J = 6.3 Hz, COOCH2),
4.34 (t, 2H, J = 6.6 Hz, OCH2), 3.57 (d, 2H, J = 7.5 Hz, SCH2),
1.89ꢀ2.02 (m, 8H, 2 ꢁ CHCH2CH2CH), 1.50ꢀ1.68 (m, 16H, 4 ꢁ
CHdCCH3, COOCH2CH2, CH2CH2O), 1.25 (m, 4H, OCH2CH2-
CH2CH2). MS (ESI) m/z = 683 [M þ 1]þ. Anal. calcd for C36H46-
N2O7S2: C, 63.32; H, 6.79; N, 4.10. Found: C, 63.06; H, 6.98; N, 3.80.
3-(Phenylsulfonyl)-4-(2-(2-((2E,6E)-3,7,11-trimethyldode-
ca-2,6,10-trienylthio)benzamido)ethyloxy)-1,2,5-oxadiazole-
2-oxide (8i). The title compound was obtained starting from 1 and 7i.
Colorless viscous liquid, 67% yield. Analytical data for 8i: IR
1
(KBr, cmꢀ1): 3333, 2928, 1621, 1554, 1453, 1260, 1167, 1021. H
NMR (CDCl3, 300 MHz): δ 8.02 (d, 2H, J = 7.8 Hz, ArꢀH), 7.70 (m,
2H, ArꢀH), 7.55 (t, 2H, J = 7.8 Hz, ArꢀH), 7.36 (m, 2H, ArꢀH), 7.18
(m, 1H, ArꢀH), 5.25 (m, 1H, SCH2CH), 5.08 (m, 2H, 2 ꢁ
CH2CHdCCH3), 4.64 (t, 2H, J = 4.8 Hz, CH2O), 3.96 (m, 2H,
NCH2), 3.53 (d, 2H, J = 7.2 Hz, SCH2), 1.89ꢀ2.02 (m, 8H, 2 ꢁ
CHCH2CH2CH), 1.50ꢀ1.68 (m, 12H, 4 ꢁ CHdCCH3). MS (ESI)
m/z = 626 [M þ 1]þ. Anal. calcd for C32H39N3O6S2 0.2H2O: C, 61.06;
3
H, 6.31; N, 6.68. Found: C, 61.22; H, 6.78; N, 6.23.
3-(Phenylsulfonyl)-4-(3-(2-((2E,6E)-3,7,11-trimethyldode-
ca-2,6,10-trienylthio)benzamido)propoxy)-1,2,5-oxadiazole-
2-oxide (8j). The title compound was obtained starting from 1 and 7j.
Colorless viscous liquid, 67% yield. Analytical data for 8j: IR
(KBr, cmꢀ1): 3444, 1630, 1552, 1449, 1168, 1068. 1H NMR (CDCl3,
300 MHz): δ 8.00 (d, 2H, J = 7.5 Hz, ArꢀH), 7.74 (t, 1H, J = 7.5 Hz,
ArꢀH), 7.61 (m, 3H, ArꢀH), 7.40 (m, 2H, ArꢀH), 7.30 (m, 1H,
ArꢀH), 5.26 (m, 1H, SCH2CH), 5.07 (m, 2H, 2 ꢁ CH2CHdCCH3),
4.59 (t, 2H, J = 6.0 Hz, OCH2), 3.71 (d, 2H, J = 7.8 Hz, SCH2), 3.55 (d,
2H, J = 7.5 Hz, NCH2), 2.26 (m, 2H, NCH2CH2), 1.89ꢀ2.02 (m, 8H,
2 ꢁ CHCH2CH2CH), 1.50ꢀ1.68 (m, 12H, 4 ꢁ CHdCCH3). MS (ESI)
m/z = 640 [M þ 1]þ. Anal. calcd for C33H41N3O6S2: C, 61.95; H, 6.46;
N, 6.57. Found: C, 61.70; H, 6.70; N, 6.30.
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dx.doi.org/10.1021/jm1014814 |J. Med. Chem. 2011, 54, 3251–3259