Journal of Medicinal Chemistry
ARTICLE
174.87, 166.813, 65.69, 52.51, 49.36, 30.24. ES-MS: m/z 222.0038 [M ꢀ
H]ꢀ, C6H8NO6S requires 222.0072.
(3H, t, J 6.8), 1.21ꢀ1.26 (10H, m), 1.39ꢀ1.42 (2H, m), 3.08 (2H, dd, J
12.8, 6.8), 3.35 (1H, s), 6.86 (1H, d, J 8.4), 6.93 (1H, dd, J 8.4, 2.4), 8.15
(1H, d, J 2.8), 8.21 (1H, t, J 5.6), 9.97 (1H, bs), 10.27 (1H, s). 13C NMR
(DMSO): δ 167.64, 166.07, 145.99, 128.18. 123.56, 122.56, 119.96, 116.25,
43.93, 39.15, 31.68, 29.35, 29.15, 29.12, 26.83, 22.55, 14.41. ES-MS: m/z
341.1625 [M þ H]þ, C17H26N2O3Cl requires 341.1632.
(S)-2-(N-Octylsulfamoyl)-N-(2-oxotetrahydrofuran-3-yl)-
acetamide (19a). White crystals (64%) yield from 18a using GP4 and
purification by preparative TLC (EtOAc). Mp: 132ꢀ134 °C. FT-IR (KBr):
3325, 3252, 1773, 1671, 1542, 1320, 1147 cmꢀ1. 1H NMR (CDCl3): δ 0.89
(3H, t, J 7.2), 1.28ꢀ1.37 (10H, m5), 1.54ꢀ1.61 (2H, m), 2.39ꢀ2.49 (1H,
m), 2.65ꢀ2.74 (1H, m), 3.16 (2H, dd, J 13.2, 7.2), 4.01 (2H, s), 4.30ꢀ4.36
(1H, m), 4.56ꢀ4.61 (1H, m), 4.62ꢀ4.66 (1H, m), 5.26 (1H, t, J 6.0), 7.01
(1H, d, J 7.6). ES-MS: m/z 335.1628 [M þ H]þ, C14H27N2O5S, requires
335.1641.
N1-(2-Carbamoylphenyl)-N3-octylmalonamide (25e). White
solid (52%) from 2-aminobenzamide and 3a using GP13 (CH2Cl2). Mp:
120ꢀ121 °C. FT-IR (KBr): 3402, 3306, 3201, 1685, 1634, 1592, 1449,
1521, 752 cmꢀ1. 1H NMR (CDCl3): δ0.89 (3H, t, J 7.2), 1.26ꢀ1.31 (10H,
m), 1.52ꢀ1.59 (2H, m), 3.34 (2H, dd, J 12.8, 6.8), 3.46 (1H, s), 6.04 (1H,
d), 6.26 (3H, s), 7.14ꢀ7.18 (1H, dt, J 8.0, 1.2), 7.50 (1H, bs), 7.52ꢀ7.60
(2H, m), 8.57 (1H, d, J 8.0), 11.59 (1H, s). 13C NMR (CDCl3): δ 167.61,
165.52, 165.01, 138.38. 133.25, 127.37, 124.67, 123.53, 121.81, 44.36, 39.75,
31.80, 29.35, 29.25, 29.19, 26.95, 22.65, 14.11. ES-MS: m/z 334.2123 [M þ
H]þ, C18H28N3O3 requires 334.2131, 317.1853 [M ꢀ NH2]þ.
(S)-N-Octyl-2-(N-(2-oxotetrahydrofuran-3-yl)sulfamoyl)ace-
tamide (19b). n-Octylamine (2 mmol), DMAP (3 mmol), and DCI
(2.2 mmol) were added sequentially to a stirred solution of 18b
(2 mmol) in dry CH2Cl2 (15 mL). Stirring was continued for 16 h.
After evaporation, the residue was dissolved in EtOAc (25 mL) and the
solution was washed with saturated aqueous NaHCO3 solution (3 ꢁ
10 mL), 1 M aqueous HCl (3 ꢁ 10 mL), and brine (15 mL). The organic
layer was dried over MgSO4, filtered, and evaporated. The residue was
dissolved in cold Me2CO (2ꢀ4 mL) and left to stand. When remaining
DCU had crystallized, this was filtered off. The filtrate was evaporated and the
residue purified by preparative TLC (EtOAc) to afford the title compound as
white crystals (22%). Mp: 94ꢀ96 °C. FT-IR (KBr): 3386, 3323, 1761, 1683,
1560, 1327, 1168 cmꢀ1. 1H NMR (CDCl3): δ 0.89 (3H, t, J 6.8), 1.27ꢀ1.33
(10H, m), 1.52ꢀ1.57 (2H, m), 2.33ꢀ2.46 (1H, m), 2.71ꢀ2.79 (1H, m),
3.28 (2H, m), 4.07 (1H, s, J 14.2), 4.26 (1H, s, J 14.2), 4.27ꢀ4.34 (1H, m),
4.45ꢀ4.52 (1H, m), 4.46ꢀ4.51 (1H, m), 6.21 (1H, d, J 7.6), 6.69 (1H, t).
ES-MS: m/z 335.1638 [M þ H]þ, C14H27N2O5S requires 335.1641.
General Procedure 12 (GP12). The appropriate amine (1 mmol)
and Et3N (155 μL, 1.1 mmol) were added to a stirred solution of 2217,34
(300 mg, 1 mmol) in dry MeCN (30 mL). The mixture was stirred for 16
h and then refluxed for 3 h. The solution was cooled, evaporated, and the
residue was dissolved in EtOAc. The solution was washed with 1 M
aqueous KHSO4 (2 ꢁ 20 mL), dried over MgSO4, and evaporated.
3-Oxo-N-(thiazol-2-yl)dodecanamide (23c). White solid
(30%) from thiazol-2-amine using GP12 and purification by preparative
TLC (EtOAcꢀhexane, 1:1). Mp: 137ꢀ139 °C. FT-IR (KBr): 3427, 1719,
1679, 1587 cmꢀ1. 1H NMR (CDCl3): δ 0.9 (3H, t, J 7.0), 1.22ꢀ1.29 (12H,
m), 1.62 (2H, bm), 2.57 (2H, quart, J 7.2, 4.2), 3.34 (2H, s), 7.12 (1H, d, J
3.6), 7.56 (1H, d, J 3.6), 8.21 (1H, s). 13C NMR (CDCl3): δ 207.14, 164.4,
162.92, 138.6, 107.95, 47.93, 42.6, 32.17, 29.72, 29.38(2), 29.18, 23.2, 22.79,
14.12. ES-MS: m/z 297.1624 [M þ H]þ, C15H25N2O2S requires 297.1637.
General Procedure 13 (GP13). Et3N (210 μL, 1.5 mmol),
N1-(2-(Dimethylcarbamoyl)phenyl)-N3-octylmalonamide
(25f). Pink solid (66%) from 2-(dimethylamino)benzamide and 3a
using GP13 (CH2Cl2). Mp: 59ꢀ60 °C. FT-IR (KBr): 3304, 3160, 1685,
1660, 1605, 1484, 1530, 722 cmꢀ1. 1H NMR (CDCl3): δ 0.90 (3H, t, J
6.8), 1.24ꢀ1.34 (10H, m), 1.49ꢀ1.55 (2H, m), 3.03 (3H, s), 3.15 (3H,
s), 3.28 (2H, dd, J 13.2, 7.2), 3.36 (1H, s), 7.14ꢀ7.18 (1H, dt, J 8.0, 1.2),
7.21 (1H, bs), 7.27ꢀ7.29 (1H, dd, J 8.0, 1.2), 7.38ꢀ7.43 (1H, dt, J 8.2,
1.2), 9.71 (1H, s). 13C NMR (CDCl3): δ 168.76, 166.55, 164.51, 139.98.
130.35, 127.71, 124.31(2), 121.43, 42.43, 39.59, 37.71(2), 31.98, 30.09,
29.45(2), 26.82, 22.86, 14.11. ES-MS: m/z 362.2459 [M þ H]þ,
C20H32N3O3 requires 362.2444; 317.1866 [M ꢀ NMe2]þ.
N1-(3-Carbamoylphenyl)-N3-octylmalonamide (25g). Pink
solid (33%) from 3a and 3-aminobenzamide using GP13 (H2Oꢀ
dioxane). Mp: 185ꢀ187 °C. FT-IR (KBr): 3374, 3307, 3171, 1659, 1637,
1586, 1452, 1541, 791 cmꢀ1. 1H NMR (DMSO-d6): δ 0.87 (3H, t, J 6.8),
1.24ꢀ1.27 (10H, m), 1.35ꢀ1.41 (2H, m), 3.06 (2H, dd, J 12.8, 6.8), 3.23
(1H, s), 7.34 (1H, s), 7.37 (1H, t, J 8.0), 7.53ꢀ7.55 (1H, dt, J 8.0, 1.2),
7.74ꢀ7.76 (1H, dd, J8.0, 1.2), 7.94 (1H, bs), 8.02 (1H, t, J2.0), 8.05 (1H, d, J
8.0), 10.21 (1H, s). 13C NMR (CDCl3): δ 168.16, 166.62, 164.15, 138.63.
134.45, 129.17, 125.17, 123.63, 117.28, 42.46, 39.71, 31.90, 30.15, 29.42(2),
26.81, 22.83, 14.10. ES-MS: m/z 334.2146 [M þ H]þ, C18H28N3O3
requires 334.2131.
N1-Octyl-N3-(pyridin-2-yl)malonamide (25i). Purple crystals
(17%) from pyridine-2-amine and 3a using GP13 (CH2Cl2, washing of
EtOAc solution with aqueous HCl was omitted). Mp: 134ꢀ136 °C. FT-IR
1
(KBr): 3306, 3117, 1645, 1679, 1578, 1438, 1555, 778 cmꢀ1. H NMR
(CDCl3): δ 0.88 (3H, t, J 6.8 Hz), 1.27ꢀ1.30 (10H, m), 1.52ꢀ1.58 (2H,
EDC HCl (0.23 g, 1.2 mmol), and the appropriate amine (1.2 mmol) were
m), 2.86 (1H, s), 3.28 (2H, dd, J 9.6, 6.8), 3.57 (1H, s), 7.16 (1H, s), 7.23
3
(1H, t, J 6.4), 7.93 (1H, t, J 8.0), 8.19 (1H, t, J 8.8), 8.44 (1H, d, J 4.8). 13
C
added to a stirred solution of the appropriate carboxylic acid (1 mmol, 0.215
g) in CH2Cl2 or H2Oꢀdioxane (15 mL). Stirring was continued for 16 h.
After evaporation, the residue was dissolved in EtOAcꢀCH2Cl2 (20 mL).
The solution was washed with saturated aqueous NaHCO3 solution (3 ꢁ
10 mL), 1 M aqueous HCl (3 ꢁ 10 mL), and brine (15 mL). The organic
layer was dried over MgSO4, filtered, and evaporated.
NMR (CDCl3): δ 167.1, 164.10, 150.16, 146.15, 139.1, 120.21, 116.21,
42.58, 39.76, 31.89, 30.1, 29.37, 29.32, 26.81, 22.76, 14.1. ES-MS: m/z:
292.2016 [M þ H]þ, C16H26N3O3 requires 292.2025.
N1-Cycloheptyl-N3-octylmalonamide (25j). Off-white crystals
(39%) from cycloheptylamine and 3a using GP13 (CH2Cl2). Mp:
53ꢀ55 °C. FT-IR (KBr): 3299, 1662, 1552 cmꢀ1. 1H NMR (CDCl3): δ
0.90 (3H, t, J 5.2), 1.21ꢀ1.39 (10H, m), 1.43ꢀ1.61 (8H, m), 1.63ꢀ1.67
(4H, m), 1.89ꢀ1.95 (2H, m), 3.13 (2H, s), 3.24ꢀ3.29 (2H, m), 3.95 (1H,
m), 6.72 (1H, bs), 6.88 (1H, d). 13C NMR (CDCl3): δ 167.18, 166.10,
50.69, 43.37, 39.68, 34.82(2), 31.79, 29.36, 29.23, 29.19, 27.97(2), 26.91,
24.00(2), 22.64, 14.09. ES-MS: m/z 311.2687 [M þ H]þ, C18H35N2O2
requires 311.2699.
N1-(2-Hydroxyphenyl)-N3-octylmalonamide (25c). Lustrous
white crystals (82%) from 3a and 2-aminophenol using GP13 (H2Oꢀ
dioxane). Mp: 84ꢀ86 °C. FT-IR (KBr): 3327, 3261, 3095, 1676, 1643, 1614,
1601, 1455, 1546, 744 cmꢀ1. 1H NMR (CDCl3 with a drop of DMSO): δ
0.82 (3H, t, J 6.4), 1.18ꢀ1.31 (10H, m), 1.47 (2H, bs), 3.20 (2H, t, J 6.4),
3.39 (1H, s), 6.78 (1H, t, J 7.6), 6.90 (1H, d, J 8.0), 6.98 (1H, t, J 7.6), 7.47
(1H, d, J 8.0), 7.65 (1H, s), 8.0 (1H, bs), 9.97 (1H, s). 13C NMR (DMSO):
δ 166.64, 165.07, 150.1, 128.1. 126.46, 123.16, 121.98, 116.12, 42.31, 40.1,
32.18, 29.99, 29.51, 29.27, 27.21, 23.22, 14.13. ES-MS: m/z 307.2034 [M þ
H]þ, C17H27N2O3 requires 307.2022.
Ex Vivo Concanavalin A Stimulated Murine Peripheral Blood
Leukocyte Proliferation Assay. This was carried out as previously
described.17 Test compounds were dissolved at 10 mM in DMSO and then
diluted with tissue culture medium and DMSO to a final constant DMSO
concentration of 1% (v/v) for the entire test concentration range.
Cytotoxicity Assay. Jurkat E6.1 cells were exposed to serially
diluted test compounds in physiological saline (control) at 37 °C in 5%
N1-(5-Chloro-2-hydroxyphenyl)-N3-octylmalonamide (25d).
White solid (36%) from 3a and 2-amino-4-chlorophenol using GP13
(H2Oꢀdioxane). Mp 80ꢀ82 °C. FT-IR (KBr): 3373, 3253, 3100, 1677,
1644, 1608, 1598, 1422, 1544, 809 cmꢀ1. 1H NMR (DMSO-d6): δ 0.85
3357
dx.doi.org/10.1021/jm2001019 |J. Med. Chem. 2011, 54, 3348–3359