Journal of Medicinal Chemistry
ARTICLE
determination was performed using an Agilent diode array detector.
Mass determination was performed using an Agilent 6130 mass spectro-
meter with electrospray ionization in the positive mode. 1H NMR
spectra were recorded on Varian 400 MHz spectrometers. Chemical
shifts are reported in ppm with undeuterated solvent (DMSO-h6 at 2.50
ppm) as internal standard for DMSO-d6 solutions. All of the analogues
for assay have purity greater than 95% based on both analytical methods.
High resolution mass spectrometry was recorded on an Agilent 6210
time-of-flight LC/MS system. Confirmation of molecular formula was
accomplished using electrospray ionization in the positive mode with the
Agilent Masshunter software (version B.02).
(Z)-N-(Naphthalen-1-yl)-2-(2-oxoindolin-3-ylidene)hydra-
zinecarbothioamide (2). Compound 2 was prepared by reacting
isatin with 4-(10-napthyl)-3-thiosemicarbazide (Trans World, Rockville,
MD), yield 24%. 1H NMR (400 MHz, DMSO-d6) δ ppm 12.88 (1 H, s),
11.26 (1 H, s), 11.12 (1 H, s), 7.99ꢀ8.05 (1 H, m), 7.96 (1 H, d, J =
8.0 Hz), 7.84ꢀ7.91 (1 H, m), 7.76 (1 H, d, J = 7.4 Hz), 7.52ꢀ7.63 (4 H,
m), 7.34ꢀ7.42 (1 H, m), 7.11(1 H, t, J = 7.4Hz), 6.96 (1 H, d, J = 7.8 Hz).
LC-MS: RT (min) = 6.162. HRMS calculated for C19H15N4OS (M + H)
347.0973, found 347.0964.
(Z)-N-(2,3-Dihydro-1H-inden-5-yl)-2-(2-oxoindolin-3-yli-
dene)hydrazinecarbothioamide (3). Compound 3 was prepared
by reacting tert-butylcarbazate with 5-indanyl isothiocyanate (Oakwood
Products, West Columbia, SC), and the t-Boc group was immediately
removed by acid hydrolysis. The resulting 4-(5-indanyl)-3-thiosemicarba-
zide was reactedwith isatin, yield 44%. 1H NMR (400 MHz, DMSO-d6) δ
ppm12.75(1 H, s), 11.23 (1H, s), 10.72(1 H, s), 7.78 (1 H, d, J =7.4 Hz),
7.44 (1 H, s), 7.37 (1 H, td, J = 7.6, 1.0 Hz), 7.29ꢀ7.34 (1 H, m),
7.22ꢀ7.28 (1 H, m), 7.11 (1 H, t, J = 7.4 Hz), 6.94 (1 H, d, J = 7.8 Hz),
2.83ꢀ2.94 (4 H, m), 2.00ꢀ2.11 (2 H, m). LC-MS: RT (min) = 6.562.
HRMS calculated for C18H17N4OS (M + H) 337.1129, found 337.1124.
(Z)-2-(2-Oxoindolin-3-ylidene)-N-phenylhydrazinecarbothio-
amide (4). Compound 4 was prepared by reacting isatin with 4-phenyl-
3-thiosemicarbazide, yield 89%. 1H NMR (400 MHz, DMSO-d6) δ
ppm 12.79 (1 H, s), 11.25 (1 H, s), 10.81 (1 H, s), 7.78 (1 H, d, J =
7.4 Hz), 7.61(2 H, d, J = 7.6Hz), 7.43 (2 H, t, J = 7.8Hz), 7.38 (1H, td, J =
7.7, 1.2 Hz), 7.28 (1 H, t, J = 7.3 Hz), 7.11 (1 H, t, J = 7.3 Hz), 6.95 (1 H, d,
J = 7.8). LC-MS: RT (min) = 5.910. HRMS calculated for C15H13N4OS
(M + H) 297.0805, found 297.0808.
(Z)-2-(2-Oxoindolin-3-ylidene)-N-(pyridin-3-yl)hydrazine-
carbothioamide (5). Compound 5 was prepared by reacting tert-
butylcarbazate with 3-pyridyl isothiocyanate, yield 79%. The t-Boc group
was removed by acid hydrolysis, and the resulting 4-(30-pyridyl)-
3-thiosemicarbazide was reacted with isatin, yield 49%. 1H NMR (400
MHz, DMSO-d6) δ ppm 12.93 (1 H, s), 11.29 (1 H, s), 10.99 (1 H, s),
8.83 (1 H, s), 8.52 (1 H, d, J = 4.7 Hz), 8.18 (1 H, d, J = 7.6 Hz), 7.75 (1
H, d, J = 7.6 Hz), 7.58 (1 H, dd, J = 7.6, 5.1 Hz), 7.39 (1 H, td, J = 7.7,
1.2 Hz), 7.13 (1 H, t, J = 7.3 Hz), 6.96 (1 H, d, J = 7.8 Hz). LC-MS: RT
(min) = 3.735. HRMS calculated for C14H12N5OS (M + H) 298.0769,
found 298.0762.
br s), 2.10 (3 H, br s), 1.67 (6 H, br s). LC-MS: RT (min) = 7.367. HRMS
calculated for C19H23N4OS (M + H) 355.1599, found 355.1595.
(Z)-N-Cyclohexyl-2-(2-oxoindolin-3-ylidene)hydrazine-
carbothioamide (8). Compound 8 was prepared by reacting tert-
butylcarbazate with cyclohexyl isothiocyanate, yield 71%. The t-Boc group
was removed by acid hydrolysis, and the resulting 4-cyclohexyl-3-thiose-
1
micarbazide was reacted with isatin, yield 94%. H NMR (400 MHz,
DMSO-d6) δ ppm 12.56 (1 H, s), 11.19 (1 H, s), 8.82 (1 H, d, J = 8.4 Hz),
7.73 (1 H, d, J = 7.4 Hz), 7.35 (1 H, td, J = 7.7, 1.1 Hz), 7.10 (1 H, t, J = 7.3
Hz), 6.93 (1 H, d, J = 7.8 Hz), 4.11ꢀ4.29 (1 H, m), 1.85ꢀ1.98 (2 H, m),
1.69ꢀ1.84 (2 H, m), 1.56ꢀ1.69 (1 H, m), 1.41ꢀ1.56 (2 H, m),
1.22ꢀ1.39 (2 H, m), 1.05ꢀ1.21 (1 H, m). LC-MS: RT (min) = 6.472.
HRMS calculated for C15H19N4OS (M + H) 303.1274, found 303.1278.
(Z)-N-Butyl-2-(2-oxoindolin-3-ylidene)hydrazinecarbothio-
amide (10). Compound 10 was prepared by reacting isatin with 4-butyl-
3-thiosemicarbazide (Trans World, Rockville, MD), yield 78%. 1H NMR
(400 MHz, DMSO-d6) δ ppm 12.55 (1 H, s), 11.19 (1 H, s), 9.25 (1 H, t,
J = 5.8 Hz), 7.67 (1 H, d, J = 7.4 Hz), 7.35 (1 H, td, J = 7.7, 1.2 Hz), 7.10
(1 H, t, J = 7.2 Hz), 6.93 (1 H, d, J = 7.8 Hz), 3.61 (2 H, q, J = 6.7 Hz), 1.61
(2 H, quin, J = 7.4 Hz), 1.34 (2 H, sxt, J = 7.4 Hz), 0.92 (3 H, t, J = 7.4 Hz).
LC-MS: RT (min) = 6.084. HRMS calculated for C13H17N4OS (M + H)
277.1118, found 277.1117.
(Z)-N-Isopropyl-2-(2-oxoindolin-3-ylidene)hydrazinecarbo-
thioamide (11). Compound 11 was prepared by reacting isatin with
4-isopropyl-3-thiosemicarbazide, yield 40%. 1H NMR (400 MHz,
DMSO-d6) δ ppm 12.56 (1 H, s), 11.20 (1 H, s), 8.86 (1 H, d, J = 8.2
Hz), 7.73 (1 H, d, J = 7.4 Hz), 7.36 (1 H, td, J = 7.7, 1.1 Hz), 7.10 (1 H, t,
J = 7.3 Hz), 6.93 (1 H, d, J = 7.8 Hz), 4.53 (1 H, dt, J = 8.2, 6.7 Hz), 1.27 (6
H, d, J = 6.7 Hz). LC-MS: RT (min) = 5.722. HRMS calculated for
C12H15N4OS (M + H) 263.0961, found 263.0966.
(Z)-N-Methyl-2-(2-oxoindolin-3-ylidene)hydrazinecarbo-
thioamide (12). Compound 12 was prepared by reacting isatin with
4-methyl-3-thiosemicarbazide (Trans World, Rockville, MD), yield 97%.
1H NMR (400 MHz, DMSO-d6) δ ppm 12.59 (1 H, s), 11.20 (1 H, br s),
9.20ꢀ9.29 (1 H, m), 7.63 (1 H, d, J = 7.2 Hz), 7.35 (1 H, td, J = 7.7, 1.2
Hz), 7.10 (1 H, t, J = 7.5 Hz), 6.93 (1 H, d, J = 7.8 Hz), 3.08 (3 H, d, J = 4.5
Hz). LC-MS: RT (min) = 4.880. HRMS calculated for C10H11N4OS (M
+ H) 235.0648, found 235.0651.
(Z)-N-(2-Methoxyphenyl)-2-(2-oxoindolin-3-ylidene)hydra-
zinecarbothioamide (14). Compound 14 was prepared by reacting
isatin with 4-(20methoxyphenyl)-3-thiosemicarbazide (Trans World,
1
Rockville, MD), yield 99%. H NMR (400 MHz, DMSO-d6) δ ppm
12.79 (1 H, s), 11.25 (1 H, s), 10.43 (1 H, s), 7.85 (1 H, d, J = 7.0 Hz), 7.69
(1 H, d, J = 7.4 Hz), 7.38 (1 H, td, J = 7.7, 1.1 Hz), 7.25ꢀ7.32 (1 H, m),
7.07ꢀ7.18 (2 H, m), 6.98ꢀ7.04 (1 H, m), 6.95 (1 H, d, J = 7.8 Hz), 3.87
(3 H, s). LC-MS: RT (min) = 6.199. HRMS calculated for C16H15N4O2S
(M + H) 327.0910, found 327.0916.
(Z)-2-(2-Oxoindolin-3-ylidene)-N-(3,4,5-trimethoxyphenyl)-
hydrazinecarbothioamide (15). Compound 15 was prepared by
reacting isatin with 4-(30,40,50-trimethoxyphenyl)-3-thiosemicarbazide
(Trans World, Rockville, MD), yield 79%. 1H NMR (400 MHz,
DMSO-d6) δ ppm 12.79 (1 H, s), 11.26 (1 H, s), 10.70 (1 H, s), 7.79
(1 H, d, J = 7.4 Hz), 7.34ꢀ7.41 (1 H, m), 7.12 (1 H, t, J = 7.6 Hz), 7.08 (2
H, s), 6.95 (1 H, d, J = 7.6 Hz), 3.78 (6 H, s), 3.68 (3 H, s). LC-MS: RT
(min) = 5.705. HRMS calculated for C18H19N4O4S (M + H) 387.1133,
found 387.1134.
(Z)-N-(2-Chlorophenyl)-2-(2-oxoindolin-3-ylidene)hydra-
zinecarbothioamide (16). Compound 16 was prepared by reacting
isatin with 4-(20-chlorophenyl)-3-thiosemicarbazide (Trans World, Rock-
ville, MD), yield 93%. 1H NMR (400 MHz, DMSO-d6) δ ppm 12.85 (1
H, s), 11.26 (1 H, s), 10.79 (1 H, s), 7.71 (1 H, d, J = 7.4 Hz), 7.55ꢀ7.63
(2 H, m), 7.34ꢀ7.47 (3 H, m), 7.11 (1 H, t, J = 7.6 Hz), 6.95 (1 H, d,
J = 7.8 Hz). LC-MS: RT (min) = 6.235. HRMS calculated for C15H12-
ClN4OS (M + H) 331.0415, found 331.0416.
(Z)-N-Benzyl-2-(2-oxoindolin-3-ylidene)hydrazinecarbo-
thioamide (6). Compound 6 was prepared by reacting isatin with
4-benzyl-3-thiosemicarbazide, yield 91%. 1H NMR (400 MHz, DMSO-
d6) δ ppm 12.66 (1 H, s), 11.21 (1 H, s), 9.81 (1 H, t, J = 6.2 Hz), 7.65
(1 H, d, J = 7.4 Hz), 7.31ꢀ7.42 (5 H, m), 7.23ꢀ7.30 (1 H, m), 7.09 (1 H,
t, J = 7.3 Hz), 6.93 (1 H, d, J = 7.8 Hz), 4.88 (2 H, d, J = 6.3 Hz). LC-MS:
RT (min) = 6.024. HRMS calculated for C16H15N4OS (M + H)
311.0973, found 311.0968.
(Z)-2-(2-Oxoindolin-3-ylidene)-N-(adamantyl)hydrazine-
carbothioamide (7). Compound 7 was prepared by reacting isatin
with 4-(10-adamantyl)-3-thiosemicarbazide (Trans World, Rockville,
MD), yield 67%. 1H NMR (400 MHz, DMSO-d6) δ ppm 12.49 (1 H,
s), 11.21 (1 H, s), 7.99 (1 H, s), 7.67 (1 H, d, J = 7.4 Hz), 7.36 (1 H, td, J =
7.7, 1.0 Hz), 7.08 (1 H, t, J = 7.6 Hz), 6.93 (1 H, d, J = 7.8 Hz), 2.30 (6 H,
5885
dx.doi.org/10.1021/jm2006047 |J. Med. Chem. 2011, 54, 5878–5889