4184 Journal of Medicinal Chemistry, 2010, Vol. 53, No. 10
Hen et al.
was dispersed in petroleum ether (50 mL), and 10% HCl
solution was added until pH 1 was reached. The organic phase
was separated from the aqueous phase and washed three times
with brine. The aqueous solutions were combined and extracted
with petroleum ether (3Â50 mL). The petroleum ether extracts
were combined, dried over MgSO4, filtered, and evaporated
under reduced pressure. The oily products were further distilled
under reduced pressure to yield the pure corresponding acids.
The structures of the free carboxylic acids were identified by the
1H NMR and GC/MS. The purified acids were converted with
thionyl chloride to acyl chlorides according to a previously
published method.49 For the synthesis of an appropriate amide,
the acyl chloride (9 mmol) of an individual acid dissolved in
20 mL of dry acetone was added dropwise to a stirred solution of
suitable aromatic aminosulfonamide (9.2 mmol) and pyridine
(9.1 mmol) in 50 mL of dry acetone. After addition, the reaction
mixture was stirred for 12 h at room temperature and then the
solvent was evaporated under reduce pressure. The residue was
dissolved in 100 mL ethyl acetate and the organic phase washed
three times with 20 mL of distilled water (3 Â 20 mL). Then 10%
HCl solution was added until pH 1 was reached, and the organic
phase was separated from the aqueous phase and washed three
times with brine. The aqueous solutions were combined and
extracted with ethyl acetate (3 Â 50 mL). The ethyl acetate extracts
were combined, dried over MgSO4, filtered, and evaporated
under reduced pressure.
The obtained products were purified by crystallization using
ethanol/petroleum ether mixture (1:3) to give (60-93% yield)
white crystals.
2,2-Dimethyl-N-(4-sulfamoylphenyl)propionamide (9). White
crystals; 88% yield; mp 228-229 °C. 1H NMR (300 MHz,
CD3SOCD3, δ): 1.25 (s, 9H), 7.25 (s, 2H, SO2NH2), 7.73 (d,
J=9, 2H, H-Ar), 7.85 (d, J=9, 2H, H-Ar), 9.58 (s, 1H, NH).
Anal. (C11H16N2O3S) C, H, N.
2-Methyl-N-(4-sulfamoylphenyl)butyramide (10). White crys-
tals; 82% yield; mp 205-207 °C. 1H NMR (300 MHz,
CD3SOCD3, δ): 0.83-0.97 (t, J = 9, 3H), 1.10-1.15 (d, J =
6.3, 3H), 1.31-1.46 (m, 1H), 1.52-1.65 (m, 1H), 2.44 (m, 1H),
7.20 (s, 2H, SO2NH2), 7.61-7.83 (m, 4H, H-Ar), 10.21 (s, 1H,
NH). Anal. (C11H16N2O3S) C, H, N.
2-Ethyl-N-(4-sulfamoylphenyl)butyramide (11). White crys-
tals; 63% yield; mp 207-209 °C. 1H NMR (300 MHz,
CD3SOCD3, δ): 0.88-1.10 (t, J = 6, 6H), 1.43-1.73 (br m,
4H), 2.26 (m, 1H), 7.21 (s, 2H, SO2NH2), 7.62-7.80 (m, 4H,
H-Ar), 10.22 (s, 1H, NH). Anal. (C12H18N2O3S) C, H, N.
2-Ethyl-3,3-dimethyl-N-(4-sulfamoylphenyl)butyramide (12).
White crystals; 81% yield; mp 252-254 °C. 1H NMR (300
MHz, CD3SOCD3, δ): 0.83 (t, J = 7.5, 3H), 0.98 (s, 9H),
1.41-1.71 (br m, 2H), 2.09-2.18 (dd, J = 8.7, 2.7, 1H), 7.22
(s, 2H, SO2NH2), 7.61-7.84 (m, 4H, H-Ar), 10.21 (s, 1H, NH).
Anal. (C14H22N2O3S) C, H, N.
7.62-7.82 (m, 4H, H-Ar), 10.22 (s, 1H, NH). Anal.
(C12H18N2O3S) C, H, N.
2-Ethyl-N-(4-sulfamoylphenyl)pentanamide (17). White “cotton-
like” powder; 83% yield; mp 203-205 °C. 1H NMR (300 MHz,
CD3SOCD3, δ): 0.84 (t, J = 6.6, 6H), 1.19-1.62 (br m, 6H),
2.20-2.43 (m, 1H), 7.24 (s, 2H, SO2NH2), 7.60-7.83 (m, 4H,
H-Ar), 10.20 (s, 1H, NH). Anal. (C13H20N2O3S) C, H, N.
2-Isopropyl-N-(4-sulfamoylphenyl)pentanamide (18). White
crystals; 89% yield; mp 217-219 °C. 1H NMR (300 MHz,
CD3SOCD3, δ): 0.78-0.90 (m, 9H), 1.12-1.36 (m, 2H),
1.36-1.63 (br m, 2H), 1.65-1.85 (m, 1H), 2.05-2.22 (m, 1H),
7.23 (s, 2H, SO2NH2), 7.61-7.84 (m, 4H, H-Ar), 10.20 (s, 1H,
NH). Anal. (C14H22N2O3S) C, H, N.
2-Ethyl-3-methyl-N-(4-sulfamoylphenyl)pentanamide (19).
White crystals; 71% yield; mp 203-205 °C. 1H NMR (300
MHz, CD3SOCD3, δ): 0.78-0.90 (m, 9H), 1.05-1.22 (m, 1H),
1.40-1.68 (m, 4H), 2.08-2.22 (m, 1H), 7.22 (s, 2H, SO2NH2),
7.63-7.82 (m, 4H, H-Ar), 10.21 (s, 1H, NH). Anal.
(C14H22N2O3S) C, H, N.
2-Isopropyl-3-methyl-N-(4-sulfamoylphenyl)pentanamide (20).
White crystals; 69% yield; mp 230-233 °C. 1H NMR (300
MHz, CD3SOCD3, δ): 0.81-1.00 (m, 12H), 1.03-1.26 (m,
1H), 1.38-1.58 (m, 1H), 1.72-1.80 (m, 1H), 1.90-2.08 (m,
1H), 2.08-2.24 (m, 1H), 7.23 (s, 2H, SO2NH2), 7.60-7.83 (m,
4H, H-Ar), 10.20 (s, 1H, NH). Anal. (C15H24N2O3S) C, H, N.
2-Propyl-3-methyl-N-(4-sulfamoylphenyl)pentanamide (21).
White crystals; 72% yield; mp 223-226 °C. 1H NMR (300
MHz, CD3SOCD3, δ): 0.81-0.98 (m, 9H), 1.05-1.30 (br m,
2H), 1.30-1.63 (br m, 5H), 2.24-2.30 (m, 1H), 7.23 (s, 2H,
SO2NH2), 7.60-7.84 (m, 4H, H-Ar), 10.20 (s, 1H, NH). Anal.
(C15H24N2O3S) C, H, N.
2-tert-Butyl-N-(4-sulfamoylphenyl)pentanamide (22). White
crystals; 60% yield; mp 260-264 °C. 1H NMR (300 MHz,
CD3SOCD3, δ): 0.82-0.89 (t, J = 6.6, 3H), 0.89-1.08 (s, 9H),
1.08-1.22 (m, 1H), 1.32-1.44 (m, 2H), 1.56-1.78 (m, 1H), 2.26
(dd, J = 9, 3, 1H), 7.22 (s, 2H, SO2NH2), 7.63-7.81 (m, 4H,
H-Ar), 10.21 (s, 1H, NH). Anal. (C15H24N2O3S) C, H, N.
2-Ethyl-4-methyl-N-(4-sulfamoylphenyl)pentanamide (23). White
powder; 87% yield; mp 199-200 °C. 1H NMR (300 MHz,
CD3SOCD3, δ): 0.77-0.93 (m, 9H), 1.10-1.38 (m, 1H),
1.38-1.65 (br m, 4H), 2.36-2.45 (m, 1H), 7.21 (s, 2H, SO2NH2),
7.60-7.84 (m, 4H, H-Ar), 10.22 (s, 1H, NH). Anal.
(C14H22N2O3S) C, H, N.
3-Methyl-N-(4-sulfamoylphenyl)pentanamide (24). White
crystals; 76% yield; mp 204-206 °C. 1H NMR (300 MHz,
CD3SOCD3, δ): 0.83-0.92 (m, 6H), 1.14-1.23 (m, 1H),
1.23-1.40 (m, 1H), 1.83-1.98 (m, 1H), 2.09-2.23 (dd, J =
15, 7.5, 1H), 2.23-2.36 (dd, J = 15, 6, 1H), 7.21 (s, 2H,
SO2NH2), 7.61-7.84 (m, 4H, H-Ar), 10.22 (s, 1H, NH). Anal.
(C12H18N2O3S) C, H, N.
2-Ethyl-N-(4-sulfamoylphenyl)hexanamide (25). White pow-
der; 90% yield; mp 188-190 °C. 1H NMR (300 MHz,
CD3SOCD3, δ): 0.78-0.86 (m, 6H), 1.12-1.37 (m. 4H),
1.37-1.65 (br m, 4H), 2.23-2.46 (m, 1H), 7.20 (s, 2H, SO2NH2),
7.64-7.81 (m, 4H, H-Ar), 10.20 (s, 1H, NH). Anal.
(C14H22N2O3S) C, H, N.
2-Isopropyl-3-methyl-N-(4-sulfamoylphenyl)butyramide (13).
1
White crystals; 81% yield; mp 244 °C. H NMR (300 MHz,
CD3SOCD3, δ): 0.85-0.95 (t, J = 6, 12H), 1.81-2.13 (m, 3H),
7.23 (s, 2H, SO2NH2), 7.60-7.82 (m, 4H, H-Ar), 10.22 (s, 1H,
NH). Anal. (C14H22N2O3S) C, H, N.
2,2-Dimethyl-N-(4-sulfamoylbenzyl)propionamide (26). White
crystals; 70% yield; mp 157-158 °C. 1H NMR (300 MHz,
CD3SOCD3, δ): 1.15 (s, 9H), 4.32 (d, J = 6, 2H), 7.30 (s, 2H,
SO2NH2), 7.42 (d, J = 7.8, 2H, H-Ar), 7.80 (d, J = 8.1, 2H,
H-Ar), 8.17 (t, J=6.6, 1H, NH). Anal. (C12H18N2O3S) C, H, N.
3,3-Dimethyl-N-(4-sulfamoylbenzyl)butyramide (27). White
crystals; 80% yield; mp 205-207 °C. 1H NMR (300 MHz,
CD3SOCD3, δ): 0.98 (s, 9H), 2.09 (s, 2H), 4.30 (d, J = 6, 2H),
7.38 (s, 2H, SO2NH2), 7.45 (d, J = 9, 2H, H-Ar), 7.80 (d, J = 9,
2H, H-Ar), 8.32 (t, J=6.7, 1H, NH). Anal. (C13H20N2O3S) C,
H, N.
2-Isopropyl-3,3-dimethyl-N-(4-sulfamoylphenyl)butyramide
(14). White crystals; 76% yield; mp 248-250 °C. 1H NMR (300
MHz, CD3SOCD3, δ): 0.91-1.00 (m, 15H), 1.00-1.14 (s, 1H),
2.05 (m, 1H), 7.25 (s, 2H, SO2NH2), 7.62-7.82 (m, 4H, H-Ar),
10.22 (s, 1H, NH). Anal. (C15H24N2O3S) C, H, N.
3,3-Dimethyl-N-(4-sulfamoylphenyl)butyramide (15). White
crystals; 82% yield; mp 211-213 °C. 1H NMR (300 MHz,
CD3SOCD3, δ): 1.10 (s, 9H), 2.21 (s, 2H), 7.23 (s, 2H, SO2NH2),
7.61-7.84 (m, 4H, H-Ar), 10.21 (s, 1H, NH). Anal. (C12H18-
N2O3S) C, H, N.
2-Methyl-N-(4-sulfamoylphenyl)pentanamide (16). White pow-
der; 93% yield; mp 216-218 °C. 1H NMR (300 MHz,
CD3SOCD3, δ): 0.85 (t, J = 6.6, 3H), 1.15 (d, J = 6.9, 3H),
1.18-1.38 (m, 4H), 1.52-1.64 (m, 1H), 7.24 (s, 2H, SO2NH2),
2-Ethyl-N-(4-sulfamoylbenzyl)butyramide (28). White crys-
tals; 62% yield; mp 148-150 °C. 1H NMR (300 MHz,
CD3SOCD3, δ): 0.88-1.03 (t, J = 6, 6H), 1.42-1.70 (br m,