Triazole Derivatives Inhibiting Eosinophilia
J ournal of Medicinal Chemistry, 1996, Vol. 39, No. 15 3025
mL, 56 mmol) was added to the solution. Stirring further at
0 °C for 10 min and at room temperature for 30 min, the
mixture was poured into 1 N HCl and extracted with CHCl3.
The organic layer was washed with brine, dried over MgSO4,
and concentrated under reduced pressure to give a yellow oil
3.39 (d t, 2H, J ) 5.2, 6.5 Hz, CH2), 3.57 (q, 2H, J ) 7.4 Hz,
CH2), 4.34 (t, 1H, J ) 5.2 Hz, OH), 7.63 (s, 1H, CH), 8.19 (brs,
2H, NH2), 10.02 (brs, 1H, NH).
Met h od B. 5-Am in o-1-[(d im et h yla m in o)(t h ioca r b o-
n yl)]-1H-1,2,4-tr ia zole (3). To a solution of 3-amino-1H-
1,2,4-triazole (4.00 g, 47.6 mmol) in pyridine (30 mL) was
added dimethylthiocarbamoyl chloride (6.46 g, 52.3 mmol).
After stirring for 24 h at room temperature, the reaction
mixture was concentrated under reduced pressure. The
residue was extracted with AcOEt, and the extract was washed
with brine and dried over MgSO4. After removal of the solvent,
purification with column chromatography on silica gel (CHCl3/
MeOH, 10/1) gave a mixture of 3 and 3-amino-1-[(dimethyl-
amino)(thiocarbonyl)]-1H-1,2,4-triazole (2:1, 1.63 g, 20%). Re-
crystallization from AcOEt gave 3 as white crystals: mp
139.5-140.5 °C; IR (KBr, cm-1) 3360, 1645, 1516; 1H-NMR
(DMSO-d6) δ 3.17 (s, 3H, CH3), 3.42 (s, 3H, CH3), 6.80 (brs,
2H, NH2), 7.53 (s, 1H, CH).
1
(8.54 g, quantitative): IR (KBr, cm-1) 2910, 2840, 2070; H-
NMR (CDCl3) δ 0.90 (t, 3H, J ) 7.1 Hz, CH3), 1.28-1.36 (m,
4H, CH2), 1.42 (quint, 2H, J ) 7.0 Hz, CH2), 1.70 (quint, 2H,
J ) 7.0 Hz, CH2), 3.51 (t, 2H, J ) 7.0 Hz, CH2).
5-Am in o-1-[(n -h exyla m in o)(t h ioca r b on yl)]-1H -1,2,4-
tr ia zole (1d ). The procedure used for the preparation of 1a
(method A) was repeated with 2 as a starting material. After
purification with column chromatography on silica gel (hexane/
AcOEt, 5/1), a mixture of 1d and 3-amino-1-[(n-hexylamino)-
(thiocarbonyl)]-1H-1,2,4-triazole (1:1, 3.13 g, 29%) was ob-
tained. Further purification with HPLC (CH3CN/H2O, 1/1)
and recrystallization from hexane and AcOEt, 1d was obtained
as colorless crystals: mp 122-123 °C; IR (KBr, cm-1) 3400,
1628, 1515; 1H-NMR (DMSO-d6) δ 0.86 (t, 3H, J ) 6.9 Hz CH3),
1.22-1.36 (m, 6H, CH2), 1.61 (quint, 2H, J ) 7.2 Hz, CH2),
3.56 (t, 2H, J ) 7.2 Hz, CH2), 7.61 (s, 1H, CH), 8.18 (brs, 2H,
NH2), 10.02 (brs, 1H, NH).
5-Am in o-1-[[(3-et h oxyp r op yl)a m in o](t h ioca r b on yl)]-
1H-1,2,4-tr ia zole (1e). The procedure used for the prepara-
tion of 1a (method A) was repeated with 3-ethoxypropyl
isothiocyanate as a starting material. After purification with
column chromatography on silica gel (CHCl3/MeOH, 20/1), a
mixture of 1e and 3-amino-1-[[(3-ethoxypropyl)amino](thio-
carbonyl)]-1H-1,2,4-triazole (69:31, 5.41 g, 50%) was obtained.
Purification with HPLC (CH3CN/H2O, 2/3) and recrystalliza-
tion from hexane and CHCl3 gave colorless crystals: mp 137-
139 °C; IR (KBr, cm-1) 3320, 3060, 2920, 1638, 1507; 1H-NMR
(DMSO-d6) δ 1.12 (t, 3H, J ) 7.0 Hz, CH3), 1.86 (quint, 2H, J
) 6.5 Hz, CH2), 3.42 (q, 2H, J ) 7.0 Hz, CH2), 3.44 (t, 2H, J )
6.5 Hz, CH2), 3.63 (t, 2H, J ) 6.5 Hz, CH2), 7.61 (s, 1H, CH),
8.18 (brs, 2H, NH2), 10.02 (brs, 1H, NH).
5-Am in o-1-[(cycloh exyla m in o)(th ioca r bon yl)]-1H-1,2,4-
tr ia zole (1f). The procedure used for the preparation of 1a
(method A) was repeated with cyclohexyl isothiocyanate as a
starting material. After purification with column chromatog-
raphy on silica gel (hexane/AcOEt, 1/1) and recrystallization
from hexane and AcOEt, 1f was obtained as colorless crystals
(2.26 g, 14%): mp 168-170 °C; IR (KBr, cm-1) 3380, 3270,
1633, 1562, 1505; 1H-NMR (DMSO-d6) δ 1.13 (t q, 1H, J )
3.4, 12.6 Hz, CH), 1.30 (t q, 2H, J ) 3.4, 12.6 Hz, CH), 1.51 (d
q, 2H, J ) 3.4, 11.7 Hz, CH), 1.60 (d t, 1H, J ) 12.8, 3.3 Hz,
CH), 1.73 (d t, 2H, J ) 13.5, 3.1 Hz, CH), 1.85 (d d, 2H, J )
2.9, 12.2 Hz, CH), 4.16 (brs, 1H, CH), 7.62 (s, 1H, CH), 8.18
(brs, 2H, NH2), 9.62 (brs, 1H, NH).
5-Am in o-1-[(m eth yla m in o)(th ioca r bon yl)]p yr a zole (4).
The procedure used for the preparation of 1a (method A) was
repeated with 3-aminopyrazole as a starting material. The
crude product obtained was purified by column chromatogra-
phy on silica gel (hexane/AcOEt, 10/1 to 1/2) to give a colorless
1
oil (2.03 g, 27%): IR (KBr, cm-1) 3270, 1600, 1520; H-NMR
(DMSO-d6) δ 3.04 (d, 3H, J ) 4.7 Hz, CH3), 5.40 (d, 1H, J )
1.7 Hz, CH), 7.33 (brs, 2H, NH2), 7.36 (d, 1H, J ) 1.7 Hz, CH),
9.99 (brs, 1H, NH).
5-Am in o-1-[(m et h yla m in o)(t h ioca r b on yl)]-1H -t et r a -
zole (5). The procedure used for the preparation of 1a
(method A) was repeated with 5-amino-1H-tetrazole as a
starting material. The crude product obtained was purified
by column chromatography on silica gel (CHCl3/MeOH, 20/1)
to give a mixture of 5 and 5-amino-2-[(methylamino)(thiocar-
bonyl)]tetrazole (10:1, 234 mg, 3.9%) as a white powder: IR
(KBr, cm-1) 3320, 3170, 1640, 1553; 1H-NMR (DMSO-d6) δ 3.08
(d, 3H, J ) 4.2 Hz, CH3), 6.03 (brs, 2H, NH2), 10.70 (brs, 1H,
NH).
3-Am in o-N-m eth ylp yr a zole-4-ca r both ioa m id e (7a ). A
mixture of 6a (3.6 g, 25.7 mmol) and phosphorus pentasulfide
(8.5 g, 38.3 mmol) in pyridine (50 mL) was stirred at 80 °C
overnight. After careful addition of 28% aqueous ammonia
solution (50 mL), the mixture was stirred at 80 °C for 4 h.
After the reaction, a solution of CHCl3-MeOH (1:1, 300 mL)
was added. The organic layer was collected by decantation
and concentrated under reduced pressure. Purification with
column chromatography on silica gel (CHCl3/MeOH, 20/1 to
10/1) and recrystallization from CHCl3 and MeOH gave white
crystals (600 mg, 15%): mp 235-237 °C; IR (KBr, cm-1) 3450,
1
3300, 3100, 1585, 1560, 1525; H-NMR (DMSO-d6) δ 3.01 (d,
3H, J ) 4.5 Hz, CH3), 6.85 (brs, 2H, NH2), 7.76 (s, 1H, CH),
5-Am in o-1-[(p h en yla m in o)(th ioca r bon yl)]-1H-1,2,4-tr i-
a zole (1g). The procedure used for the preparation of 1a
(method A) was repeated with phenyl isothiocyanate as a
starting material. After the reaction, the precipitated white
solid was collected and recrystallization from MeOH gave 1g
as colorless crystals (0.21 g, 2.7%): mp 146-148 °C dec; IR
9.24 (s, 1H, NH), 11.84 (brs, 1H, NH).
4-Am in o-N-m et h ylim id a zole-5-ca r b ot h ioa m id e (7b ).
The procedure used for preparation of 7a was repeated with
6b as a starting material. The residue obtained was chro-
matographed on silica gel (CHCl3/MeOH, 20/1 to 10/1) and
recrystallized from CHCl3 and MeOH to give dark brown
crystals (1.1 g, 33%): mp 202-204 °C; IR (KBr, cm-1) 3300,
1
(KBr, cm-1) 3290, 3240, 3060, 1638, 1503; H-NMR (DMSO-
d6) δ 7.31 (t, 1H, J ) 7.2 Hz, CH), 7.41-7.50 (m, 4H, CH),
7.71 (s, 1H, CH), 8.26 (brs, 2H, NH2), 11.50 (brs, 1H, NH).
5-Am in o-1-[(ben zyla m in o)(th ioca r bon yl)]-1H-1,2,4-tr i-
a zole (1h ). The procedure used for the preparation of 1a
(method A) was repeated with benzyl isothiocyanate as a
starting material. After recrystallization from EtOH, 1h was
obtained as white crystals (3.99 g, 36%): mp 157-158 °C; IR
(KBr, cm-1) 3380, 3270, 3070, 1633, 1618, 1512; 1H-NMR
(DMSO-d6) δ 4.81 (s, 2H, CH2), 7.25 (t t, 1H, J ) 1.8, 6.8 Hz,
CH), 7.30-7.36 (m, 4H, CH), 7.66 (s, 1H, CH), 8.20 (brs, 2H,
NH2), 10.54 (brs, 1H, NH).
1
3200, 1610, 1540; H-NMR (DMSO-d6) δ 3.01 (d, 3H, J ) 4.8
Hz, CH3), 6.72 (brs, 2H, NH2), 7.11 (s, 1H, CH), 9.05 (brs, 1H,
NH), 11.47 (brs, 1H, NH).
3-Am in o-N-m et h ylt h iop h en e-2-ca r bot h ioa m id e (7c).
The procedure used for preparation of 7a was repeated with
6c as a starting material. The residue obtained was chro-
matographed on silica gel (AcOEt/hexane, 1/4 to 1/2) to give a
brown oil (0.35 g, 51%): IR (KBr, cm-1) 3300, 1590, 1520; 1H-
NMR (DMSO-d6) δ 3.00 (d, 3H, J ) 4.4 Hz, CH3), 6.63 (d, 1H,
J ) 5.5 Hz, CH), 7.43 (d, 1H, J ) 5.5 Hz, CH), 7.57 (brs, 2H,
NH2), 8.75 (m, 1H, NH).
2-Am in o-N-m eth ylben zen eca r both ioa m id e (7d ). The
procedure used for the preparation of 7a was repeated using
6d as a starting material. A mixture of 6d (2.0 g, 13.6 mmol)
and phosphorus pentasulfide (3.03 g, 13.6 mmol) in pyridine
(8 mL) was stirred at reflux for 1.5 h. After addition of H2O,
5-Am in o-1-[[(5-h yd r oxyp en tyl)a m in o](th ioca r bon yl)]-
1H-1,2,4-tr ia zole (1i). The procedure used for the prepara-
tion of 1a (method A) was repeated with 5-hydroxypentyl
isothiocyanate as
a starting material. Purification with
column chromatography on silica gel (CHCl3/MeOH, 10/1) and
recrystallization from CHCl3 gave white crystals (19%): mp
108-109 °C; IR (KBr, cm-1) 3290, 3130, 2940, 2880, 1634,
1521; 1H-NMR (DMSO-d6) δ 1.27-1.36 (m, 2H, CH2), 1.45
(quint, 2H, J ) 6.5 Hz, CH2), 1.62 (quint, 2H, J ) 7.4 Hz, CH2),
a precipitated yellow solid was collected by filtration.
A
suspension of the solid obtained in benzene (150 mL) and H2O
(15 mL) was stirred at reflux for 15.5 h. The benzene layer