JOURNAL OF ENZYME INHIBITION AND MEDICINAL CHEMISTRY
3
2-Hydroxy-4-(4-methoxyphenyl)-6-phenylcyclohexa-1,3-diene
carbohydrazide (3a)
General procedure for the preparation of 5a–f
A mixture of the corresponding hydrazide 4a,b (10 mmol) and the
appropriate isothiocyanate derivative (10 mmol) in ethanol (20 ml)
was heated under reflux for 3 h. The formed solid was filtered off,
washed with ethanol and crystallized from ethanol.
Compound 3b was prepared from compound 2b and 98% hydra-
1
zine hydrate by stirring at RT 67% yield, mp 124–127 ꢀC. H NMR d
2.69 (dd, 1H, J ¼ 4.7, J ¼ 17.6, H5cyclohex.ax.), 2.79 (ddd, 1H,
J ¼ 2.1 Hz, J ¼ 11.2 Hz, J ¼ 17.6 Hz, H50cyclohex.eq.), 3.72 (m, 1H,
H6cyclohex), 3.87 (s, 3H, OCH3), 6.30 (brs, 3H, NHNH2, D2O
exchange), 6.87 (d, 1H, J ¼ 1.8 Hz, H3cyclohex), 6.98–7.50 (m, 9H,
Ar–Hs), 10.80 (brs, 1H, OH, D2O exchange). 13C NMR d 29.8
(C6cyclohex.), 34.8 (C5cyclohex.), 55.5 (OCH3), 114.2, 114.3, 123.7, 127.6,
128.6, 131.2, 133.0, 137.1, 138.6, 142.5 (Ar–Cs), 160.4 (C¼O). MS
(EI): m/z (%): 336.21 (14.91). Anal. calcd. For C20H20N2O3 (336.38):
C, 71.41; H, 5.99; N, 8.33. Found: C, 71.78; H, 6.07; N, 8.51.
3-Hydroxy-6-(4-methoxyphenyl)-4-phenyl-N-methyl-4,5-dihydroin-
dazole-1-carbothioamide (5a)
Compound 5a was prepared from compound 4a and methyl iso-
thiocyanate. 88% yield, mp 220–224 ꢀC. 1H NMR d 2.80, 2.84 (dd,
1H, J ¼ 3.2 Hz, J ¼ 16.8 Hz, H5indazol.eq), 3.00 (s, 3H, CH3), 3.11 (ddd,
1H, J ¼ 1.8, J ¼ 8.3 Hz, J ¼ 16.7 Hz, H50indazol.ax.), 3.79 (s, 3H, OCH3),
4.10, 4.14 (dd, 1H, J ¼ 3.0 Hz, J ¼ 8.1 Hz, H4indazol) 6.61 (d, 1H,
J ¼ 1.8 Hz, H7indazol), 7.10–8.30 (m, 9H, Ar–Hs), 10.36 (s, 1H, NH,
D2O exchange), 11.05 (s, 1H, OH, D2O exchange). 13C NMR d 31.1
(NHCH3), 34.7 (C4indazol), 36.3 (C5indazol), 55.6 (OCH3), 114.3, 114.6,
122.1, 126.9, 127.6, 128.6, 131.9, 132.1 (Ar–Cs), 137.1 (C7aindazol),
144.9 (C6indazol), 147.1, 147.7 (C4 of the 2 phenyl rings), 160.5
(C3indazol), 178.6 (C¼S). MS (EI): m/z (%): 391.24 (1.80). Anal. calcd.
for C22H21N3O2S (391.49): C, 67.50; H, 5.41; N, 10.73. Found: C,
67.84; H, 5.44; N, 10.49.
2-Hydroxy-4,6-bis(4-methoxyphenyl) cyclohexa-1,3-diene
carbohydrazide (3b)
Compound 3b was prepared from compound 2b and 98% hydra-
zine hydrate. 73% yield, mp 144–146 ꢀC. 1H NMR d 2.75 (dd, 1H,
J ¼ 4.7 Hz, J ¼ 17.8 Hz, H5cyclohex.ax.), 2.97 (ddd, 1H, J ¼ 2.2 Hz,
J ¼ 11.2 Hz, J ¼ 17.7 Hz, H50cyclohex.eq.), 3.72 (m, 1H, H6cyclohex), 3.87
(s, 6H, 2OCH3), 6.26 (brs, 3H, NHNH2, D2O exchange), 6.81 (d, 1H,
J ¼ 1.9 Hz, H3cyclohex), 6.91–7.45 (m, 9H, Ar–Hs and OH). 13C NMR d
30.0 (C6cyclohex.), 35.1 (C5cyclohex.), 55.5, 55.6 (2OCH3), 114.2, 114.3,
123.7, 128.5, 133.1, 137.1, 137.9, 146.4 (Ar–Cs), 159.0 (C¼O). MS
(EI): m/z (%): 336.48 (1.10). Anal. calcd For C21H22N2O4 (336.41): C,
68.84; H, 6.05; N, 7.65. Found: C, 68.97; H, 6.13; N, 7.69.
3-Hydroxy-4,6-bis(4-methoxyphenyl)-N-methyl-4,5-dihydroindazole-
1-carbothioamide (5b)
Compound 5b was prepared from compound 4b and methyl iso-
thiocyanate. 90% yield, mp 170–173 ꢀC. 1H NMR d 2.80, 2.85 (dd,
1H, J ¼ 3.2 Hz, J ¼ 16.8 Hz, H5indazol.eq), 2.99 (ddd, 1H, J ¼ 1.8,
J ¼ 8.3 Hz, J ¼ 16.7 Hz, H50indazol.ax.), 3.08 (s, 3H, CH3), 3.79 (s, 3H,
OCH3), 4.10, 4.14 (dd, 1H, J ¼ 3.0 Hz, J ¼ 8.1 Hz, H4indazol) 6.61 (d,
1H, J ¼ 1.8 Hz, H7indazol), 7.10–8.30 (m, 9H, Ar–Hs), 10.30 (s, 1H, NH,
D2O exchange), 11.01 (s, 1H, OH, D2O exchange). 13C NMR d 31.2
(NHCH3), 34.9 (C4indazol), 36.0 (C5indazol), 55.4, 55.7 (2OCH3), 114.2,
114.4, 122.0, 126.9, 128.4, 131.9, 132.1 (Ar–Cs), 137.1 (C7aindazol),
144.9 (C6indazol), 158.3, 159.9 (C4 of the two phenyl rings), 160.4
(C3indazol), 178.5 (C¼S). MS (EI): m/z (%): 421.48 (3.61). Anal. calcd.
for C23H23N3O3S (421.51): C, 65.54; H, 5.50; N, 9.97. Found: C,
65.81; H, 5.57; N, 10.04.
General procedure for the preparation of 4a,b
A mixture of 2a or 2b (10 mmol) and hydrazine hydrate (0.32 ml,
10 mmol) in ethanol (20 ml) was heated under reflux for 8 h. The
reaction mixture was evaporated under reduced pressure. After
cooling, the reaction mixture was poured onto crushed ice and
the solid thus obtained was filtered off, washed with water and
crystallized from ethanol to give 4a and 4b, respectively.
4-Phenyl-6-(4-methoxyphenyl)-4,5-dihydro-1H-indazol-3-ol (4a)
Compound 4a was prepared from compound 2a and 98% hydra-
zine hydrate under reflux. 76% yield, mp 107–110 ꢀC. 1H NMR d
2.86, 2.90 (dd, 1H, J ¼ 3.1 Hz, J ¼ 16.7 Hz, H5indazol.eq.), 3.12 (ddd,
1H, J ¼ 1.7 Hz, J ¼ 8.4 Hz, J ¼ 16.68 Hz, H50indazol.ax.), 3.79 (s, 3H,
OCH3), 4.15 (dd, 1H, J ¼ 3.0 Hz, J ¼ 8.2 Hz, H4indazol), 6.27 (s, 1H, NH,
3-Hydroxy-6-(4-methoxyphenyl)-4-phenyl-N-ethyl-4,5-dihydroinda-
zole-1-carbothioamide (5c)
D2O exchange), 6.66 (d, 1H, J ¼ 3.0 Hz, H7indazol), 7.00–7.70 (m, 9H, Compound 5c was prepared from compound 4a and ethyl isothio-
Ar–Hs), 10.80 (brs, 1H, OH, D2O exchange). 13C NMR d 29.8
cyanate. 83% yield, mp 202–205 ꢀC. 1H NMR d 1.01 (t, 3H, J ¼ 7.2,
(C4indazol), 34.8 (C5indazol), 55.5 (OCH3), 114.4, 114.6, 126.4, 127.7,
CH3 ethyl), 2.72, 2.74 (dd, 1H, J ¼ 3.2 Hz, J ¼ 16.8 Hz, H5indazol.eq),
2.83 (ddd, 1H, J ¼ 1.8 Hz, J ¼ 8.3 Hz, J ¼ 16.7 Hz, H50indazol.ax.), 3.50
128.5, 128.8, 129.6, 133.0 (Ar–Cs), 137.1 (C7indazol), 145.9, 146.3 (C4
of the 2 phenyl rings), 159.1 (C3indazol). MS (EI): m/z (%): 318.09
(q, 2H, J ¼ 7.2, CH2 ethyl), 3.78 (s, 3H, OCH3), 4.11,4.14 (dd, 1H,
(12.02). Anal. calcd. For C20H18N2O2 (318.37): C, 75.45; H, 5.70; N,
8.80. Found: C, 75.49; H, 5.76; N, 8.94.
J ¼ 3.0 Hz, J ¼ 8.1 Hz, H4indazol), 6.60 (d, 1H, J ¼ 1.8 Hz, H7indazol),
6.95–8.37 (m, 9H, Ar–Hs), 10.27 (s, 1H, NH, D2O exchange), 10.99
(s, 1H, OH, D2O exchange). 13C NMR d 15.0 (CH3 ethyl), 34.6
(C4indazol), 35.8 (CH2 ethyl), 38.1 (C5indazol), 55.6 (OCH3), 114.2, 122.1,
127.0, 127.4, 128.1, 128.6, 128.9, 131.9, 132.1 (Ar–Cs), 137.2
(C7aindazol), 144.9 (C6indazol), 159.9 (C4 of the two phenyl rings),
160.5 (C3indazol), 177.6 (C¼S). MS (EI): m/z (%): 405.17 (1.90). Anal.
calcd. for C23H23N3O2S (405.51): C, 68.12; H, 5.72; N, 10.36. Found:
C, 68.35; H, 5.81; N, 10.49.
4,6-Bis(4-methoxyphenyl)-4,5-dihydro-1H-indazol-3-ol (4b)
Compound 4b was prepared from compound 2b and 98% hydrazine
hydrate under reflux. 78% yield, mp 86–89 ꢀC. 1H NMR d 2.84, 2.88
(dd, 1H, J¼ 3.1 Hz, J¼ 16.8 Hz, H5indazol.eq.), 3.14 (ddd, 1H, J ¼ 1.7 Hz,
J¼ 8.4 Hz, J¼ 16.69 Hz, H50indazol.ax.), 3.80 (s, 6H, 2OCH3), 4.16,4.18 (dd,
1H, J¼ 3.0 Hz, J¼ 8.3 Hz, H4indazol), 6.20 (s, 1H, NH, D2O exchange),
6.89 (s, 1H, H3cyclohex), 7.00–7.70 (m, 8H, Ar–Hs), 10.79 (brs, 1H, OH,
D2O exchange). 13C NMR d 33.4 (C4indazol), 35.0 (C5indazol), 55.3, 55.6
3-Hydroxy-4,6-bis(4-methoxyphenyl)-N-ethyl-4,5-dihydroindazole-1-
(2OCH3), 114.2, 114.4, 128.2, 128.5, 129.6, 132.7 (Ar–Cs), 137.5 carbothioamide (5d)
(C7indazol), 157.9. 158.1 (C4 of the two phenyl rings), 160.4 (C3indazol).
MS (EI): m/z (%): 348.36 (2.81). Anal. calcd. for C21H20N2O3 (348.40): C,
72.40; H, 5.79; N, 8.04. Found: C, 72.53; H, 5.84; N, 8.17.
Compound 5d was prepared from compound 4b and ethyl iso-
thiocyanate. 86% yield, mp 210–213 ꢀC. 1H NMR d 1.11 (t, 3H,
J ¼ 7.2, CH3 ethyl), 2.71, 2.73 (dd, 1H, J ¼ 3.2 Hz, J ¼ 16.8 Hz,