2528 J ournal of Medicinal Chemistry, 2000, Vol. 43, No. 13
Watanabe et al.
7.98 (1H, d, J ) 8.6 Hz), 8.11 (1H, br s), 8.25 (1H, dd, J ) 8.4,
1.3 Hz), 8.78 (1H, d, J ) 1.3 Hz); MS m/e (FAB) 442 (MH+).
Anal. (C22H24ClN5O3‚0.8H2O) C, H, N.
All data are expressed as mean ( SEM. The value for each
hemodynamic parameter after the injection of 13 was com-
pared with the value after the injection of vehicle by using
repeated-measures ANOVA followed by Dunn-type multiple
comparison. P values of <0.05 were considered significant.
P h a r m a cok in etic Stu d ies. The pharmacokinetics of 13
was studied in male Sprague-Dawley rats. In the iv and po
studies, 13 was dissolved in 10% lactose-phosphoric acid (pH
2). Rats were sacrificed by exsanguination under ether anaes-
thetized at 5 (iv only), 15, and 30 min and 1, 1.5 (po only), 2,
4, 6, 8, and 24 h after dosing, and blood samples (1 mL) were
collected. Plasma was obtained by centrifugation of blood at
3000g for 15 min and stored at -20 °C until analysis. The
concentration of 13 was determined by HPLC following liquid-
liquid extraction from plasma.
N6,N6-Dim eth yl-4-[(3-ch lor o-4-m eth oxyben zyl)a m in o]-
1-(4-h yd r oxyp ip er id in o)-6-p h th a la zin eca r boxa m id e Hy-
d r och lor id e (42). To a suspension of 40 (300 mg, 0.68 mmol),
dimethylamine hydrochloride (110 mg, 1.35 mmol), DCC (210
mg, 1.0 mmol), and 1-hydroxybenzotriazole (140 mg) in tri-
ethylamine (0.24 mL) and acetonitrile (10 mL) was added H2O
(1 mL), affording a clear solution. The mixture was heated at
60 °C for 8 h, during which time a precipitate was formed.
After cooling, the precipitate was filtered off, and the filtrate
was concentrated under reduced pressure. The residue was
purified by silica gel column chromatography to give the free
base (260 mg, 82%) as a yellow solid. The free base (260 mg,
0.55 mmol) was recrystallized from 1 N HCl, EtOH, EtOAc,
and IPE to give 42 (260 mg, 93%) as a yellow powder: mp
Ack n ow led gm en t. We thank Drs. S. Souda, K.
Miyake, S. Abe, T. Nagakura, and S. Suzuki for helpful
discussions and assistance during the course of this
work and the staff of Eisai Analytical Chemistry Section
for obtaining mass spectra and for elemental analysis.
1
179-184 °C (dec); H NMR (DMSO-d6) δ 1.65-1.75 (2H, m),
1.92-2.00 (2H, m), 2.94 (3H, s), 3.06 (3H, s), 3.00-3.10 (2H,
m), 3.45-3.53 (2H, m), 3.73-3.80 (1H, m), 3.85(3H, s), 4.71
(2H, d, J ) 5.6 Hz), 7.16 (1H, d, J ) 8.6 Hz), 7.44 (1H, d, J )
8.6 Hz), 7.59 (1H, bs), 8.12 (1H, dd, J ) 8.6, 1.0 Hz), 8.17 (1H,
d, J ) 8.6 Hz), 8.86 (1H, bs), 10.10 (1H, bs), 13.85 (1H,bs); MS
m/e (FAB) 470 (MH+). Anal. (C24H28ClN5O3‚HCl‚H2O) C, H,
N.
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