JOURNAL OF ENZYME INHIBITION AND MEDICINAL CHEMISTRY
925
exchangeable), 9.27 (s, 1H, OH, D2O exchangeable), 8.38, 8.33 (2s, J ¼ 4.4, Hz, 1H, C4H-pyrrole), 6.19, 6.17 (2d, J ¼ 4.0, 4.0 Hz, 1H,
1H, N ¼ CH), 7.65–7.62 (m, 1H, ArH), 7.33–7.30 (m, 2H, ArH), C3H-pyrrole), 4.31, 3.80 (2s, 2H, CH2C¼O) 3.93, 3.92 (2s, 3H, N-
7.17–7.15 & 6.98–6.95 (2 m, 1H, ArH), 6.86–6.81 (m, 1H, ArH), CH3), 2.38 (s, 3H, ArCH3); 13C NMR (100 MHz, DMSO-d6) d: 184.8,
6.75–6.67 (m, 1H, ArH), 6.75–6.67 (m, 1H, ArH), 6.59, 6.57 (2d, 184.7, 170.7, 164.9, 141.9, 141.8, 137.9, 137.9, 137.5, 137.4, 136.2,
J ¼ 4.0, 4.0 Hz, 1H, C4H-pyrrole), 6.15, 6.11 (2d, J ¼ 4.0, 4.0 Hz, 1H, 133.7, 133.4, 130.8, 130.7, 129.4, 129.4, 129.1, 129.1, 128.2, 128.0,
C3H-pyrrole), 4.15, 3.79 (2s, 2H, CH2C¼O), 3.90, 3.87 (2s, 3H, N- 123.8, 122.2, 122.2, 121.3, 121.2, 120.0, 112.4, 112.0, 110.2, 109.8,
CH3), 2.39 (s, 3H, ArCH3); 13C NMR (100 MHz, DMSO-d6) d: 184.8, 107.4, 106.5, 33.5, 33.5, 33.1, 30.9, 21.4; Anal. Calcd. for
184.7, 170.2, 164.9, 148.3, 146.4, 146.1, 146.0, 145.7, 142.3,
141.9,141.8, 137.7, 137.5, 137.4, 137.1, 130.8, 130.6, 129.4, 129.3,
129.1, 129.1, 122.2, 122.1, 121.0, 120.2, 119.6, 119.1, 117.8, 117.3,
117.0, 110.0, 109.8, 33.5, 33.4, 32.7, 31.2 21.5; Anal. Calcd. for
C22H21N3O4 (391.42): C, 67.51; H, 5.41; N, 10.74, found C, 67.80; H,
5.62; N, 11.02.
C24H22N4O2 (398.46): C, 72.34; H, 5.57; N, 14.06, found C, 72.60; H,
5.71; N, 14.27.
N0-((1H-Indol-3-yl)methylene)-2–(1-methyl-5–(4-methylbenzoyl)-1H-
pyrrol-2-yl) acetohydrazide (5f). Creamy white solid: 85% yield; mp
168–170 ꢁC; IR (KBr, cmꢀ1) 3417, 3294 (2 NH str), 3078 (CH aro-
matic), 2958, 2924 (CH aliphatic), 1666 (C¼O str), 1593 (C¼N str),
1273, 740; 1H NMR (400 MHz, DMSO-d6) d: 11.56 (s, 1H, NH, D2O
exchangeable), 11.32, 11.24 (2s, 1H, OH/NH, D2O exchangeable),
8.39, 8.23 (2s, 1H, N ¼ CH), 8.20, 8.13 (2d, J ¼ 8.0, 8.0 Hz, 1H, ArH),
7.81–7.80 (m, 1H, ArH), 7.65–7.62 (m, 2H, ArH), 7.45–7.42 (m, 1H,
ArH), 7.32–7.30 (m, 2H, ArH), 7.22–7.18 (m, 1H, ArH), 7.15–7.10 (m,
1H, ArH), 6.59 (t, J ¼ 4.0, Hz, 1H, C4H-pyrrole), 6.15 (d, J ¼ 4.0 Hz,
1H, C3H-pyrrole), 4.22, 3.73 (2s, 2H, CH2C¼O) 3.94, 3.91 (2s, 3H, N-
CH3), 2.39 (s, 3H, ArCH3); 13C NMR (100 MHz, DMSO-d6) d: 184.8,
184.7, 169.8, 164.2, 144.4, 141.9, 141.8, 141.3, 138.2, 137.9, 137.5,
137.5, 137.4, 130.8, 130.5, 129.4, 129.3, 129.1, 124.5, 123.0, 122.2,
122.0, 121.0, 120.8, 112.3, 111.9, 111.8, 110.0, 109.6, 33.5, 33.4,
33.1, 31.3, 21.5; Anal. Calcd. for C24H22N4O2 (398.46): C, 72.34; H,
5.57; N, 14.06, found C, 72.59; H, 5.81; N, 14.32.
N0-(2,4-Dihydroxybenzylidene)-2–(1-methyl-5–(4-methylbenzoyl)-
1H-pyrrol-2-yl) acetohydrazide (5c). Light brown solid: 85% yield;
mp 226–228 ꢁC; IR (KBr, cmꢀ1) 3300–3100 (br, 2OH, NH str), 3032
(CH aromatic), 2985, 2954 (CH aliphatic), 1670 (C¼O str), 1631,
1608 (C¼N str), 1265, 748; 1H NMR (400 MHz, DMSO-d6) d: 11.69,
11.40 (2s, 1H, OH, D2O exchangeable), 11.31, 11.20 (2s, 1H, OH/
NH, D2O exchangeable), 9.95, 9.81 (2s, 1H, OH, D2O exchangeable),
8.29, 8.20 (2s, 1H, N ¼ CH), 7.63 (d, J ¼ 8.0 Hz, 2H, ArH), 7.49, 7.43
(2d, J ¼ 8.4, 8.4 Hz, 1H, ArH), 7.31 (d, J ¼ 8.0 Hz, 2H, ArH), 6.59–6.57
(m, 1H, C4H-pyrrole), 6.36–6.30 (m, 2H, ArH), 6.13, 6.10 (2d, J ¼ 4.0,
4.0 Hz 1H, C3H-pyrrole), 4.11, 3.74 (2s, 2H, CH2C¼O) 3.90, 3.86 (2s,
3H, N-CH3), 2.39 (s, 3H, ArCH3); 13C NMR (100 MHz, DMSO-d6) d:
184.8, 184.7, 169.8, 164.5, 161.1, 160.8, 159.7, 158.5, 148.5, 142.7,
141.9, 141.8, 137.8, 137.5, 137.4, 137.3, 131.6, 130.7, 130.6, 129.4,
129.3, 129.2, 129.1, 122.2, 122.1, 112.0, 110.8, 110.7, 109.9, 109.7,
108.1, 103.0, 33.5, 33.4, 32.8, 31.2, 21.5; Anal. Calcd. for
C22H21N3O4 (391.42): C, 67.51; H, 5.41; N, 10.74, found C, 67.62; H,
5.65; N, 10.98.
General procedure for the preparation of tolmetin hydra-
zones (6a–c)
A mixture of tolmetin hydrazide 4 (0.01 mol) and isatin or 5-substi-
tuted isatin (0.01 mol) were dissolved in absolute ethanol contain-
ing 0.5 ml of glacial acetic acid. The reaction mixture was refluxed
for 6 h. After cooling the separated solid was filtered, washed with
ethanol and crystallised from ethanol.
N0-(Benzo[d][1,3]dioxol-5-ylmethylene)-2–(1-methyl-5–(4-methyl-
benzoyl)-1H-pyrrol-2-yl)acetohydrazide (5d). Creamy white solid:
88% yield; mp 242–244 ꢁC; IR (KBr, cmꢀ1) 3417 (NH str), 3093 (CH
aromatic), 2974, 2912 (CH aliphatic), 1670 (C¼O str), 1624, 1604
(C¼N str), 1265, 744; 1H NMR (400 MHz, DMSO-d6) d: 11.57, 11.45
(2s, 1H, OH/NH, D2O exchangeable), 8.14, 7.95 (2s, 1H, N ¼ CH),
7.63 (d, J ¼ 8.0 Hz, 2H, ArH), 7.35, 7.25 (2d, J ¼ 1.6, 1.6 Hz, 1H, ArH),
7.31 (d, J ¼ 8.0 Hz, 2H, ArH), 7.16, 7.13 (2dd, J ¼ 1.6, 8.0 & 1.6,
8.0 Hz, 1H, ArH), 6.98, 6.97 (2d, J ¼ 8.0, 8.0 Hz, 1H, ArH), 6.59–6.57
(m,1H, C4H-pyrrole), 6.11 (d, J ¼ 4.0 Hz, 1H, C3H-pyrrole), 6.08 (s,
2H, OCH2O), 4.17, 3.73 (2s, 2H, CH2C¼O) 3.90, 3.87 (2s, 3H, N-CH3),
2.39 (s, 3H, ArCH3); 13C NMR (100 MHz, DMSO-d6) d: 184.8, 184.7,
170.5, 164.9, 161.1, 149.3, 148.4, 147.1, 143.6, 141.8,137.9, 137.5,
137.4, 130.7, 130.6, 129.4, 129.3, 129.1, 129.3, 129.0, 128.8, 125.5,
123.7, 123.5, 122.2, 122.1, 110.0, 109.7, 109.0, 108.8, 106.4, 105.6,
105.5, 102.1, 102.0, 101.9, 33.4, 33.4, 33.0, 31.1, 21.5; Anal. Calcd.
for C23H21N3O4 (403.43): C, 68.47; H, 5.25; N, 10.42. found C, 68.71;
H, 5.44; N, 10.69
2–(1-Methyl-5–(4-methylbenzoyl)-1H-pyrrol-2-yl)-N0-(2-oxoindolin-
3-ylidene) acetohydrazide (6a). Yellow solid: 90% yield; mp
193–195 ꢁC; IR (KBr, cmꢀ1) 3200–3155 (br, 2 NH str), 3081 (CH aro-
matic), 2954, 2920 (CH aliphatic), 1693 (br, C¼O str), 1624 (C¼N
str), 1265, 744; 1H NMR (400 MHz, DMSO-d6) d: 13.00, 12.65 (2s,
1H, OH/NH, D2O exchangeable), 11.27 (s, 1H, NH, D2O exchange-
able), 7.65–7.58 (m, 3H, ArH), 7.39 (t, J ¼ 7.6 Hz, 1H, ArH), 7.31 (d,
J ¼ 8.0 Hz, 2H, ArH), 7.11 (t, J ¼ 7.6 Hz, 1H, ArH), 6.97–6.92 (m, 1H,
ArH), 6.60 (d, J ¼ 4.0, Hz, 1H, C4H-pyrrole), 6.19 (d, J ¼ 4.0 Hz, 1H,
C3H-pyrrole), 4.35, 4.07 (2s, 2H, CH2C¼O) 3.88 (s, 3H, N-CH3), 2.39
(s, 3H, ArCH3); 13C NMR (100 MHz, DMSO-d6) d: 184.9, 171.7, 162.9,
142.9, 142.0, 137.4, 132.1, 129.4, 129.2, 123.1, 122.2, 120.1, 111.6,
110.3, 33.4, 30.1, 21.5; Anal. Calcd. for C23H20N4O3 (400.43): C,
68.99; H, 5.03; N, 13.99, found C, 69.21; H, 5.18; N, 14.24
N0-(5-Bromo-2-oxoindolin-3-ylidene)-2–(1-methyl-5–(4-methylben-
zoyl)-1H-pyrrol-2-yl)acetohydrazide (6b). Yellow solid: 83% yield;
N0-((1H-Indol-2-yl)methylene)-2–(1-methyl-5–(4-methylbenzoyl)-1H-
pyrrol-2-yl) acetohydrazide (5e). Reddish brown solid, 84% yield;
mp 198–200 ꢁC; IR (KBr, cmꢀ1) 3313, 3205 (2 NH str), 3055 (CH aro- mp 195–197 ꢁC; IR (KBr, cmꢀ1) 3200–3130 (br, 2 NH str), 3050 (CH
matic), 2951, 2920 (CH aliphatic), 1666 (C¼O str), 1604 (C¼N str), aromatic), 2993, 2927 (CH aliphatic), 1697 (br, C¼O str), 1600
1265, 738; 1H NMR (400 MHz, DMSO-d6) d: 11.68, 11.59 (2s, 1H, (C¼N str), 1265, 748; 1H NMR (400 MHz, DMSO-d6) d: 12.93, 12.56
NH, D2O exchangeable), 11.56, 11.44 (2s, 1H, OH/NH, D2O (2s, 1H, OH/NH, D2O exchangeable), 11.38 (s, 1H, NH, D2O
exchangeable), 8.29, 8.09 (2s, 1H, N ¼ CH), 7.65 (d, J ¼ 8.0 Hz, 2H, exchangeable), 7.79–7.71 (m, 1H, ArH), 7.64 (d, J ¼ 8.0 Hz, 2H, ArH),
ArH), 7.57, 7.56 (2d, J ¼ 8.0, 8.0 Hz, 1H, ArH), 7.45 (d, J ¼ 8.0 Hz, 1H, 7.55 (dd, J ¼ 2.0, 8.4 Hz, 1H, ArH), 7.32 (d, J ¼ 8.0 Hz, 2H, ArH), 6.92
ArH), 7.30 (d, J ¼ 8.0 Hz, 2H, ArH), 7.21–7.14 (m, 1H, ArH), 7.05–6.99 (d, J ¼ 8.4 Hz, 1H, ArH), 6.60 (d, J ¼ 4.0, Hz, 1H, C4H-pyrrole), 6.19
(m, 1H, ArH), 6.84, 6.81 (2d, J ¼ 2.4, 2.4 Hz, 1H, ArH), 6.60 (d, (d, J ¼ 4.0 Hz, 1H, C3H-pyrrole), 4.37, 4.13 (2s, 2H, CH2C¼O), 3.87