Cationic Diphenylisoxazole Anitprotozoal ActiVity
Journal of Medicinal Chemistry, 2007, Vol. 50, No. 10 2477
3-(4-Amidino-2-nitrophenyl)-5-(3-amidinophenyl)isoxazole di-
m/z 351 (MH+ of free base); HPLC (method A) tR 4.35 min (100
area % at 254 nm). Anal. (C17H14N6O3‚2HCl‚H2O) C, H, N, Cl.
hydrochloride (27) was prepared from nitrile 72l (0.78 g, 2.47
1
mmol) to give a white solid (0.26 g, 25%): mp 236 °C (dec); H
5-(5-Amidino-2-chlorophenyl)-3-(3-amidinophenyl)isox-
azole dihydrochloride (36) was prepared from nitrile 72q (0.50
g, 1.64 mmol) to give a white solid (0.33 g, 58%): mp 347 °C
(dec); 1H NMR δ 9.67 (s, 2H), 9.62 (s, 2H), 9.38 (s, 2H), 9.32 (s,
2H), 8.48 (d, J ) 8.8 Hz, 2H), 8.35 (d, J ) 7.1 Hz, 1H), 7.99 (m,
4H), 7.83 (t, J ) 7.7 Hz, 1H); HPLC (method A) tR 4.68 min
(100 area % at 254 nm). Anal. (C17H14N5OCl‚2HCl‚0.3H2O) C,
H, N, Cl.
5-(5-Amidino-2-methoxyphenyl)-3-(3-amidinophenyl)isox-
azole dihydrochloride (37) was prepared from nitrile 50i (0.19 g,
0.64 mmol) to give a white solid (0.12 g, 46%): mp 240 °C (dec);
1H NMR δ 9.66 (s, 2H), 9.47 (s, 2H), 9.34 (s, 2H), 9.18 (s, 2H),
8.47 (m, 2H), 8.34 (d, J ) 8.2 Hz, 1H), 8.06 (d, J ) 8.8 Hz, 1H),
8.00 (d, J ) 7.7 Hz, 1H), 7.81 (t, J ) 7.7 Hz, 1H), 7.77 (s, 1H),
7.52 (d, J ) 8.8 Hz, 1H), 4.12 (s, 3H); HPLC (method A) tR 4.63
min (100 area % at 254 nm). Anal. (C18H17N5O2‚2HCl‚0.7H2O)
C, H, N, Cl.
NMR δ 10.0-9.20 (br s, 8H), 8.63 (s, 1H), 8.48 (s, 1H), 8.35 (d,
J ) 8.2 Hz, 1H), 8.28 (d, J ) 7.7 Hz, 1H), 8.14 (d, J ) 8.2 Hz,
1H), 8.02 (d, J ) 7.7 Hz, 1H), 7.85 (dd, J ) 8.2 and 8.2 Hz, 1H),
7.73 (s, 1H); HPLC (method A) tR 3.92 min (100 area % at 254
nm). Anal. (C17H14N6O3‚2HCl‚0.8H2O) C, H, N, Cl.
3-(4-Amidino-2-chlorophenyl)-5-(3-amidinophenyl)isox-
azole dihydrochloride (28) was prepared from nitrile 72m (0.77
g, 2.47 mmol) to give a white solid (0.34 g, 33%): mp 210 °C
1
(dec); H NMR δ 9.58 (br s, 8H), 8.54 (s, 1H), 8.32 (d, J ) 7.7
Hz, 1H), 8.21 (s, 1H), 8.03 (d, J ) 7.7 Hz, 1H), 8.02 (d, J ) 8.2
Hz, 1H), 7.99 (d, J ) 8.2 Hz, 1H), 7.85 (dd, J ) 8.2 and 8.2 Hz,
1H), 7.80 (s, 1H); HPLC (method A) tR 4.41 min (100 area % at
254 nm). Anal. (C17H14ClN5O‚2HCl‚1.1H2O) C, H, N, Cl.
3-(4-Amidino-2-methoxyphenyl)-5-(3-amidinophenyl)isox-
azole dihydrochloride (29) was prepared from nitrile 72n (1.00
g, 3.32 mmol) to give a white solid (0.29 g, 22%): mp 288 °C
1
(dec); H NMR δ 9.69 (br s, 4H), 9.43 (br s, 4H), 8.52 (s, 1H),
3-(5-Amidino-2-nitrophenyl)-5-(3-amidinophenyl)isoxazole di-
8.30 (d, J ) 7.7 Hz, 1H), 8.03 (d, J ) 8.2 Hz, 1H), 8.00 (d, J )
7.7 Hz, 1H), 7.82 (dd, J ) 7.7 and 7.7 Hz, 1H), 7.74 (s, 2H), 7.59
(d, J ) 8.2 Hz, 1H), 4.08 (s, 3H); HPLC (method A) tR 4.42 min
(100 area % at 265 nm). Anal. (C18H17N5O2‚2HCl‚H2O) C,
H, N, Cl.
hydrochloride (38) was prepared by from nitrile 50j (0.24 g, 0.76
1
mmol) to give a white solid (0.08 g, 25%): mp 220 °C (dec); H
NMR δ 9.81 (s, 2H), 9.61 (s, 2H), 9.52 (s, 2H), 9.33 (s, 2H), 8.39
(m, 3H), 8.25 (m, 2H), 8.00 (d, J ) 8.2 Hz, 1H), 7.87 (t, J ) 7.7
Hz, 1H), 7.72 (s, 1H); MS m/z 351 (MH+ of free base); HPLC
(method A) tR 4.11 min (97.6 area % at 254 nm). Anal.
(C17H14N6O3‚2HCl‚H2O) C, H, N, Cl.
5-(5-Amidino-2-methoxyphenyl)-3-(4-amidino-2-nitrophenyl)-
isoxazole dihydrochloride (30) was prepared from nitrile 72o (0.70
g, 2.03 mmol) to give a white solid (0.10 g, 11%): mp 260 °C
(dec); 1H NMR δ 9.70-9.20 (br s, 8H), 8.62 (s, 1H), 8.48 (d, J )
1.6 Hz, 1H), 8.34 (d, J ) 8.2 Hz, 1H), 8.19 (d, J ) 8.2 Hz, 1H),
8.10 (dd, J ) 8.8 and 1.6 Hz, 1H), 7.52 (d, J ) 8.8 Hz, 1H), 7.48
(s, 1H), 4.10 (s, 3H); HPLC (method A) tR 4.51 min (100 area %
at 254 nm). Anal. (C18H16N6O4‚2HCl‚0.8H2O) C, H, N, Cl.
3-(4-Amidino-2-methoxyphenyl)-5-(5-amidino-2-methoxyphe-
nyl)isoxazole dihydrochloride (31) was prepared from nitrile 72p
(0.78 g, 2.35 mmol) to give a white solid (0.36 g, 35%): mp 330
3-(5-Amidino-2-chlorophenyl)-5-(3-amidinophenyl)isox-
azole dihydrochloride (39) was prepared from nitrile 72r (0.60 g,
1.96 mmol) to give a light yellow solid (0.39 g, 48%): mp 239-
1
140 °C; H NMR δ 9.66 (s, 4H), 9.40 (s, 4H), 8.50 (s, 1H), 8.30
(d, J ) 8.2 Hz, 1H), 8.26 (d, J ) 2.2 Hz, 1H), 8.04 (dd, J ) 8.2
and 2.2 Hz, 1H), 8.00 (m, 2H), 7.84 (dd, J ) 8.7 and 7.7 Hz, 1H),
7.80 (s, 1H); HPLC (method A) tR 4.69 min (100 area % at 254
nm). Anal. (C17H14N5O‚2HCl‚1.5H2O‚0.3EtOH) C, H, N, Cl.
3-(5-Amidino-2-methoxyphenyl)-5-(3-amidinophenyl)isox-
azole dihydrochloride (40) was prepared from nitrile 50k (0.34
g, 1.13 mmol) to give a light yellow solid (0.15 g, 33%): mp 210
°C (dec); 1H NMR δ 9.64 (s, 2H), 9.42 (s, 2H), 9.35 (s, 2H), 9.12
(s, 2H), 8.47 (s, 1H), 8.33 (d, J ) 2.2 Hz, 1H), 8.30 (d, J ) 8.8
Hz, 1H), 8.06 (dd, J ) 8.2 and 2.2 Hz, 1H), 7.98 (d, J ) 7.7, 2H),
7.83 (t, J ) 7.7 Hz, 1H), 7.71 (s, 1H), 7.50 (d, J ) 8.8 Hz, 1H),
4.05 (s, 3H); HPLC (method A) tR 4.46 min (100 area % at 254
nm). Anal. (C18H17N5O2‚2HCl‚0.6H2O) C, H, N, Cl.
3,5-Bis(5-amidino-2-methoxyphenyl)isoxazole dihydrochlo-
ride (41) was prepared from nitrile 72s (0.70 g, 2.11 mmol) to
give a light yellow solid (0.34 g, 44%): mp 240 °C (dec); 1H NMR
δ 9.54 (s, 2H), 9.50 (s, 2H), 9.28 (s, 2H), 9.23 (s, 2H), 8.45 (d, J
) 2.2 Hz, 1H), 8.31 (d, J ) 2.2 Hz, 1H), 8.09 (dd, J ) 8.8 and 2.2
Hz, 2H), 7.50 (t, J ) 8.8 Hz, 2H), 7.43 (s, 1H), 4.11 (s, 3H), 4.03
(s, 3H); HPLC (method A) tR 5.19 min (96.0 area % at 254 nm).
Anal. (C19H19N5O3‚2.1HCl‚2.2H2O) C, H, N, Cl.
1
°C (dec); H NMR δ 9.63 (br s, 2H), 9.48 (br s, 2H), 9.34 (br s,
2H), 9.18 (br s, 2H), 8.44 (d, J ) 2.2 Hz, 1H), 8.06 (dd, J ) 8.9
and 2.2 Hz, 1H), 8.02 (d, J ) 8.1 Hz, 1H), 7.72 (d, J ) 1.3 Hz,
1H), 7.57 (dd, J ) 8.1 and 1.3 Hz, 1H), 7.52 (d, J ) 8.9 Hz, 1H),
7.41 (s, 1H), 4.11 (s, 3H), 4.05 (s, 3H); HPLC (method A) tR
5.01 min (100 area % at 254 nm). Anal. (C19H19N5O3‚2HCl) C, H,
N, Cl.
3,5-Bis(3-amidinophenyl)isoxazole dihydrochloride (32) was
prepared from nitrile 50g (0.58 g, 2.15 mmol) to give a white solid
(0.40 g, 62%): mp 365-367 °C; 1H NMR δ 9.60 (br s, 4H), 9.32
(d, J ) 6.8 Hz, 4H), 8.42 (br s, 2H), 8.27 (d, J ) 7.7 Hz, 2H), 7.99
(d, J ) 7.7 Hz, 2H), 7.96 (s, 1H), 7.86 (t, J ) 7.7 Hz, 1H), 7.85
(t, J ) 7.7 Hz, 1H); HPLC (method A) tR 3.92 min (98.8 area %
at 254 nm). Anal. (C17H15N5O‚2HCl‚2H2O) C, H, N, Cl.
3,5-Bis[3-(N-isopropylamidino)pheny]isoxazole dihydrochlo-
ride (33) was prepared from nitrile 50g (0.58 g, 2.15 mmol) to
1
give a white solid (0.33 g, 42%): mp 260 °C (dec); H NMR δ
3,5-Bis[5-(N-isopropyl)amidino-2-methoxyphenyl]isoxazole di-
hydrochloride (42) was prepared from nitrile 72s (0.70 g, 2.11
9.83 (br s, 2H), 9.65 (br s, 2H), 9.29 (d, J ) 4.1 Hz, 2H), 8.29 (br
s, 2H), 8.24 (d, J ) 7.7 Hz, 2H), 7.98 (s, 1H), 7.86 (m, 4H), 4.09
(m, 2H), 1.31 (d, J ) 6.6 Hz, 12H); MS m/z 390.5 (MH+ of free
base); HPLC (method A) tR 5.83 min (100 area % at 254 nm).
Anal. (C23H27N5O‚2HCl‚1.5H2O‚0.2EtOH) C, H, N, Cl.
3,5-Bis[3-(2-imidazolinyl)phenyl]isoxazole dihydrochloride
(34) was prepared from nitrile 50g (0.58 g, 2.15 mmol) to give a
white solid (0.37 g, 54%): mp 373-374 °C; 1H NMR δ 11.02 (s,
4H), 8.74 (s, 2H), 8.28 (d, J ) 7.1 Hz, 2H), 8.19 (d, J ) 7.7 Hz,
2H), 8.01 (s, 1H), 7.91 (m, 2H), 4.06 (s, 8H); HPLC (method A)
tR 5.00 min (100 area % at 254 nm). Anal. (C21H19N5O‚2HCl‚
0.5H2O) C, H, N, Cl.
1
mmol) to give a white solid (0.33 g, 30%): mp 185 °C (dec); H
NMR δ 9.70 (m, 2H), 9.57 (d, J ) 10.9 Hz 2H), 9.18 (d, J ) 13.2
Hz, 2H), 8.31 (d, J ) 2.2 Hz, 1H), 8.20 (d, J ) 2.2 Hz, 1H), 7.95
(dd, J ) 8.8 and 2.2 Hz, 2H), 7.47 (d, J ) 8.8 Hz, 2H), 7.44 (s,
1H), 4.11 (m, 2H), 4.09 (s, 3H), 4.02 (s, 3H), 1.29 (m, 12H); HPLC
(method A) tR 7.07 min (100 area % at 254 nm). Anal. (C25H31N5O3‚
2.4HCl‚1.6H2O‚0.2EtOH) C, H, N, Cl.
3,5-Bis[5-(2-imidazolinyl)-2-methoxyphenyl]isoxazole dihy-
drochloride (43) was prepared by from nitrile 72s (0.70 g, 2.11
1
mmol) to give a white solid (0.44 g, 42%): mp 210 °C (dec); H
5-(5-Amidino-2-nitrophenyl)-3-(3-amidinophenyl)isoxazole di-
hydrochloride (35) was prepared from nitrile 50h (0.42 g, 1.33
mmol) to give a white solid (0.05 g, 9%): mp 222 °C (dec); H
NMR δ 9.83 (s, 2H), 9.60 (s, 2H), 9.55 (s, 2H), 9.30 (s, 2H), 8.48
(s, 1H), 8.40 (s, 1H), 8.39 (d, J ) 8.2 Hz, 1H), 8.26 (m, 2H), 8.00
(d, J ) 7.7 Hz, 1H), 7.84 (t, J ) 7.7 Hz, 1H), 7.82 (s, 1H); MS
NMR δ 10.95 (s, 2H), 10.91 (s, 2H), 8.67 (d, J ) 2.2 Hz, 1H),
8.54 (d, J ) 2.2 Hz, 1H), 8.33 (dd, J ) 8.8 and 2.2 Hz, 2H), 7.54
(t, J ) 8.8 Hz, 2H), 7.47 (s, 1H), 4.12 (s, 3H), 4.04 (s, 3H), 4.01
(s, 4H), 4.00 (s, 4H); HPLC (method A) tR 6.16 min (100 area %
at 254 nm). Anal. (C23H23N5O3‚2.2HCl‚2.5H2O‚0.1EtOH) C, H,
N, Cl.
1