S. Chennamaneni et al. / European Journal of Medicinal Chemistry 56 (2012) 17e29
27
(6H, s), 1.54 (2H, m); 13C NMR (CDCl3)
d
169.32, 163.66
129.73, 128.86, 124.09, 123.99, 111.41 (d, J ¼ 22.2 Hz), 106.32 (d,
J ¼ 23.6 Hz), 44.12, 38.58, 38.31, 34.02, 26.10, 22.62, 10.79; ESI-MS
calculated for C25H29FNO2S [M þ H]þ: 426.19, found: 426.28.
(d, J ¼ 246 Hz), 147.08, 145.81, 141.99, 139.69, 138.67, 133.13,
130.34, 129.81, 128.33, 124.12, 123.86 (d, J ¼ 9 Hz), 111.21 (d,
J ¼ 23 Hz), 106.30 (d, J ¼ 24 Hz), 59.50, 45.14, 44.12, 40.77, 34.02,
25.06, 10.70; ESI-MS calculated for C25H30FN2O2S [M þ H]þ:
441.20, found: 441.30.
4.1.4. General procedure for preparation of Sulindac derivatives
(36e41)
The coupling reaction between 2-(5-fluoro-2-methyl-1H-inden-
3-yl)acetic acid and 2-dimethylaminoethylamine was carried out
according to the procedure of method 2. The resulting product was
used directly for the next step. To a solution of N-(2-(dimethylamino)
ethyl)-2-(5-fluoro-2-methyl-1H-inden-3-yl)acetamide (110 mg,
0.4 mmol) and the appropriate aldehyde (0.44 mmol) in 2 ml
methanol was added 0.5 ml of 1 N aqueous sodium hydroxide. The
mixturewasstirredatrefluxfor2 h. Thesolutionwascooledandthen
diluted with water. The precipitated solid was filtered and washed
with water. Finally, the crude product was subjected to recrystalli-
zation or column chromatography to afford the final product.
4.1.3.7. N-(n-Butyl)-(Z)-5-fluoro-2-methyl-1-{[4-(methylsulfinyl)phe
nyl]methylene}-1H-indene-3-acetamide (31). n-Butylamine was
used; yellow solid, yield 84%; 1H NMR (CDCl3)
d 7.74 (2H, d,
J ¼ 8.4 Hz), 7.69 (2H, d, J ¼ 8.4 Hz), 7.20 (2H, m), 6.86 (1H, dd, J ¼ 2.4,
8.8 Hz), 6.60 (1H, dt, J ¼ 2, 8.8 Hz), 5.60 (1H, br), 3.52 (2H, s), 3.22
(2H, q, J ¼ 6.8 Hz), 2.82 (3H, s), 2.21 (3H, s), 1.41 (2H, m), 1.25 (2H,
m), 0.87 (3H, t, J ¼ 7.2 Hz); 13C NMR (CDCl3)
d 169.22, 163.58 (d,
J ¼ 246 Hz), 146.64 (d, J ¼ 9 Hz), 145.71, 141.69, 139.67, 138.84,
132.91, 130.45, 129.72, 128.81, 124.07, 123.95, 111.33 (d, J ¼ 22 Hz),
106.29 (d, J ¼ 24 Hz), 44.07, 39.68, 33.95, 31.77, 20.18, 13.91, 10.79;
ESI-MS calculated for C24H27FNO2S [M þ H]þ: 412.17, found: 412.26.
4.1.4.1. N-[2-(Dimethylamino)ethyl]-(Z)-5-fluoro-2-methyl-1-{[4-
(methylthio)phenyl]methylene}-1H-indene-3-acetamide (36). 4-Met
hylthiobenzyldehyde was used; yellow solid, yield 37%; 1H NMR
4.1.3.8. N-(n-Hexyl)-(Z)-5-fluoro-2-methyl-1-{[4-(methylsulfinyl)phe-
nyl]methylene}-1H-indene-3-acetamide (32). n-Hexylamine was
used; yellow solid, yield 76%; 1H NMR (CDCl3)
d
7.74 (2H, d,
(CDCl3)
d
7.45 (2H, m), 7.39 (1H, dd, J ¼ 5.2, 8.4 Hz), 7.29 (2H, m), 7.16
J ¼ 8.4 Hz), 7.68 (2H, d, J ¼ 8.4 Hz), 7.20 (2H, m), 6.86 (1H, dd, J ¼ 2.4,
8.8 Hz), 6.60 (1H, m), 5.58 (1H, br), 3.52 (2H, s), 3.21 (2H, q,
J ¼ 6.8 Hz), 2.82 (3H, s), 2.21 (3H, s), 1.42 (2H, m), 1.21 (6H, m), 0.84
(1H, s), 6.87 (1H, dd, J ¼ 2.4, 8.8 Hz), 6.60 (1H, m), 6.23 (1H, br), 3.51
(2H, s), 3.28 (2H, m), 2.55 (3H, s), 2.32 (2H, t, J ¼ 6.4 Hz), 2.21 (3H, s),
2.11 (6H, s); 13C NMR (CDCl3)
d
169.56, 163.33 (d, J ¼ 244.9 Hz),
(3H, t, J ¼ 6.8 Hz); 13C NMR (CDCl3)
d
169.11, 163.61 (d, J ¼ 246 Hz),
146.52 (d, J ¼ 9.1 Hz), 140.23, 139.51, 138.91, 133.02, 131.94, 130.25,
130.12, 126.09, 123.93 (d, J ¼ 8.4 Hz), 110.96 (d, J ¼ 22.1 Hz), 105.98
(d, J ¼ 23.6 Hz), 57.88, 45.26, 37.26, 34.00, 15.58, 10.81; ESI-MS
calculated for C24H28FN2OS [M þ H]þ: 411.19, found: 411.29.
146.61 (d, J ¼ 9 Hz), 145.80, 141.69, 139.64, 138.84, 132.92, 130.44,
129.71, 128.87, 124.08, 123.98, 111.41 (d, J ¼ 23 Hz), 106.31 (d,
J ¼ 24 Hz), 44.10, 39.93, 34.01, 31.58, 29.65, 26.65, 22.72, 14.18, 10.79;
ESI-MS calculated for C26H31FNO2S [M þ H]þ: 440.21, found: 440.30.
4.1.4.2. N-[2-(Dimethylamino)ethyl]-(Z)-5-fluoro-2-methyl-1-[(4-
4.1.3.9. N-(n-Octyl)-(Z)-5-fluoro-2-methyl-1-{[4-(methylsulfinyl)phe-
nyl]methylene}-1H-indene-3-acetamide (33). n-Octylamine was
methoxyphenyl)methylene]-1H-indene-3-acetamide
oxybenzaldehyde was used; yellow solid, yield 37%; 1H NMR
(CDCl3)
(37). 4-Meth
used; yellow solid, yield 76%; 1H NMR (CDCl3)
d
7.74 (2H, d,
d
7.48 (2H, m), 7.43 (1H, dd, J ¼ 5.2, 8.4 Hz), 7.19 (1H, s), 6.97
J ¼ 8.4 Hz), 7.69 (2H, d, J ¼ 8.4 Hz), 7.20 (2H, m), 6.86 (1H, dd, J ¼ 2.4,
8.8 Hz), 6.60 (1H, m), 5.59 (1H, br), 3.52 (2H, s), 3.21 (2H, q,
J ¼ 7.2 Hz), 2.82 (3H, s), 2.21 (3H, s), 1.42 (2H, m), 1.21 (10H, m), 0.86
(2H, m), 6.87 (1H, dd, J ¼ 2.4, 8.8 Hz), 6.61 (1H, m), 6.23 (1H, br),
3.89 (3H, s), 3.52 (2H, s), 3.28 (2H, m), 2.31 (2H, t, J ¼ 6 Hz), 2.21 (3H,
s), 2.11 (6H, s); 13C NMR (CDCl3)
d
169.65, 163.23 (d, J ¼ 244.1 Hz),
(3H, t, J ¼ 7.2 Hz); 13C NMR (CDCl3)
d
169.16, 163.61 (d, J ¼ 246 Hz),
159.96, 146.37, 139.46, 139.05, 131.46, 131.19, 130.85, 130.21, 128.83,
123.78 (d, J ¼ 8.4 Hz), 114.16, 110.87 (d, J ¼ 22.9 Hz), 105.85 (d,
J ¼ 23.6 Hz), 57.88, 55.58, 45.26, 37.26, 34.01, 10.82; ESI-MS calcu-
lated for C24H28FN2O2 [M þ H]þ: 395.21, found: 395.30.
146.64 (d, J ¼ 8.4 Hz), 145.78, 141.72, 139.67, 138.84, 132.92, 130.45,
129.73, 129.76, 128.85, 124.08, 123.98, 111.39 (d, J ¼ 22.9 Hz), 106.34
(d, J ¼ 23.6 Hz), 44.09, 39.94, 34.00, 31.93, 29.70, 29.39, 27.02, 22.83,
14.30, 10.79; ESI-MS calculated for C28H35FNO2S [M þ H]þ: 468.24,
found: 468.34.
4.1.4.3. N-[2-(Dimethylamino)ethyl]-(Z)-5-fluoro-2-methyl-1-[(3,4,5-
trimethoxyphenyl)methylene]-1H-indene-3-acetamide (38). 3,4,5-
Trimethoxybenzaldehyde was used; yellow solid, yield 50%; 1H
4.1.3.10. N-(1-Methylhexyl)-(Z)-5-fluoro-2-methyl-1-{[4-(methylsul-
finyl)phenyl]methylene}-1H-indene-3-acetamide (34). 2-Aminohe-
NMR (CDCl3)
d
7.46 (1H, dd, J ¼ 5.6, 8.4 Hz), 7.17 (1H, s), 6.89 (1H, dd,
ptane was used; yellow solid, yield 61%; 1H NMR (CDCl3)
d
7.74
J ¼ 2.4, 8.8 Hz), 6.76 (2H, s), 6.62 (1H, m), 6.280 (1H, br), 3.93 (3H, s),
(2H, d, J ¼ 8 Hz), 7.69 (2H, d, J ¼ 8 Hz), 7.20 (2H, m), 6.86 (1H, dd,
J ¼ 2.4, 8.8 Hz), 6.60 (1H, m), 5.30 (1H, d, J ¼ 8.4 Hz), 3.91 (1H, m),
3.51 (2H, s), 2.82 (3H, s), 2.21 (3H, s), 1.34e1.17 (8H, m), 1.06 (3H, d,
3.85 (6H, s), 3.52 (2H, s), 3.29 (2H, m), 2.34 (2H, t, J ¼ 6 Hz), 2.21 (3H,
s), 2.13 (6H, s); 13C NMR (CDCl3)
d
169.62, 163.36 (d, J ¼ 245 Hz),
153.40, 146.61, 140.30, 138.83, 138.28, 132.01, 131.95, 130.64, 130.02,
124.23 (d, J ¼ 9.2 Hz), 110.87 (d, J ¼ 22.1 Hz), 106.67, 106.06 (d,
J ¼ 23.7 Hz), 61.29, 57.97, 56.40, 45.27, 37.27, 33.94, 10.79; ESI-MS
calculated for C26H32FN2O4 [M þ H]þ: 455.23, found: 455.33.
J ¼ 6.4 Hz), 0.83 (3H, t, J ¼ 6.8 Hz); 13C NMR (CDCl3)
d 168.46, 163.61
(d, J ¼ 246 Hz), 146.69, 145.79, 141.73, 139.68, 138.77, 133.01, 130.47,
129.72, 128.80, 124.08, 123.98, 111.38 (d, J ¼ 22.9 Hz), 106.30 (d,
J ¼ 23.7 Hz), 45.71, 44.11, 36.83, 34.20, 31.75, 25.77, 22.71, 21.14,
14.18, 10.78; ESI-MS calculated for C27H33FNO2S [M þ H]þ: 454.22,
found: 454.32.
4.1.4.4. N-[2-(Dimethylamino)ethyl]-(Z)-5-fluoro-2-methyl-1-[(4-
chlorophenyl)methylene]-1H-indene-3-acetamide
(39). 4-Chloro
benzaldehyde was used; yellow solid, yield 31%; 1H NMR (CDCl3)
4.1.3.11. N-(3-Methylbutyl)-(Z)-5-fluoro-2-methyl-1-{[4-(methyl-
sulfinyl)phenyl]methylene}-1H-indene-3-acetamide (35). 3-Methy
lbutylamine was used; yellow solid, yield 66%; 1H NMR (CDCl3)
d
7.42 (4H, m), 7.23 (1H, dd, J ¼ 5.2, 8.4 Hz), 7.14 (1H, s), 6.87 (1H, dd,
J ¼ 2.4, 8.8 Hz), 6.59 (1H, m), 6.24 (1H, br), 3.51 (2H, s), 3.28 (2H, m),
2.32 (2H, t, J ¼ 6 Hz), 2.20 (3H, s), 2.12 (6H, s); 13C NMR (CDCl3)
d
7.74 (2H, d, J ¼ 8.4 Hz), 7.69 (2H, d, J ¼ 8.4 Hz), 7.20 (2H, m), 6.85
d
169.41, 163.46 (d, J ¼ 245.7 Hz), 146.71, 141.09, 138.68, 135.11,
(1H, dd, J ¼ 2.4, 8.8 Hz), 6.61 (1H, m), 5.53 (1H, br), 3.52 (2H, s), 3.24
134.38, 132.57, 130.86, 129.95, 129.03, 123.92 (d, J ¼ 9.1 Hz), 111.08
(d, J ¼ 22.9 Hz), 106.19 (d, J ¼ 23.6 Hz), 57.85, 45.26, 37.25, 34.00,
10.77; ESI-MS calculated for C23H25ClFN2O [M þ H]þ: 399.16, found:
399.26.
(2H, m), 2.82 (3H, s), 2.21 (3H, s), 1.50 (1H, m), 1.30 (2H, m), 0.86
(6H, d, J ¼ 6.8 Hz); 13C NMR (CDCl3)
d 169.07, 163.62 (d,
J ¼ 246.4 Hz), 146.57, 145.85, 141.71, 139.65, 138.85, 132.89, 130.45,