Article
Journal of Medicinal Chemistry, 2010, Vol. 53, No. 1 265
(0.66 g, 66%); mp >275 °C (dec). 1H NMR (DMSO-d6) δ 10.14
(br s, 1H), 9.93 (br s, 1H), 9.63 (d, J=6 Hz, 1H), 9.54 (s, 1H), 9.50
(br s, 1H), 9.42 (br s, 1H), 9.13 (br s, 1H), 8.59 (d, J=2.3 Hz, 1H),
8.52 (s, 1H), 8.35 (d, J=7.8 Hz, 1H), 7.91 (d, J=7.8 Hz, 1H), 7.86
(dd, J=7.8 and 7.8 Hz, 1H), 7.82 (dd, J=8.8 and 2.3 Hz, 1H),
7.42 (d, J=8.8 Hz, 1H), 4.14 (m, 2H), 4.13 (s, 3H), 1.33 (d, J=6.5
Hz, 6H), 1.31 (d, J=6.5 Hz, 6H). HPLC (method A) tR=8.24
min (100 area %). MS m/z 420.6 (MHþ of free base). Anal.
NMR (DMSO-d6) δ 11.33 (s, 1H), 10.64 (br s, 4H), 9.29 (s, 1H),
8.85 (s, 1H), 8.80 (d, J=2.4 Hz, 1H), 8.43 (d, J=8.0 Hz, 1H), 8.22
(d, J=8.0 Hz, 1H), 8.05 (dd, J=8.7 and 2.4 Hz, 1H), 7.91 (dd, J=
8.0 and 8.0 Hz, 1H), 7.40 (d, J=8.7 Hz, 1H), 4.06 (s, 4H), 3.99 (s,
4H). HPLC (method A) tR=7.51 min (100 area %). MS m/z 374.2
(MHþ of free base). Anal. (C20H19N7O 2HCl 1.7H2O 0.3EtOH)
3
3
3
C, H, N, Cl.
1-(4-Amidinophenyl)-4-(3-amidinophenyl)-1H-1,2,3-triazole
Dihydrochloride (16). White solid (0.33 g, 57%); mp 274-277 °C
(dec). 1H NMR (DMSO-d6) δ 9.80 (s, 1H), 9.62 (br s, 4H), 9.39
(br s, 4H), 8.55(s, 1H), 8.29 (d, J=8.2 Hz, 1H), 8.25 (d, J=8.8 Hz,
2H), 8.15 (d, J=8.8 Hz, 2H), 7.88 (d, J=8.2 Hz, 1H), 7.81 (dd, J=
8.2 and 8.2 Hz, 1H). HPLC (method A) tR = 5.25 min (100
area %). Anal. (C16H15N7 2HCl 1.2H2O) C, H, N, Cl.
(C23H29N7O 2HCl 1.1H2O) C, H, N, Cl.
4-[5-(4,5-Dihydro-1H-imidazol-2-yl)-2-methoxyphenyl]-1-[3-(4,5-
dihydro-1H-imidazol-2-yl)phenyl]-1H-1,2,3-triazoleDihydrochloride
3
3
1
(9). White solid (0.64 g, 69%); mp >235 °C (dec). H NMR
(DMSO-d6) δ 11.38 (br s, 2H), 10.74 (br s, 2H), 9.53 (s, 1H), 9.08 (s,
1H), 8.87 (d, J=2.3 Hz, 1H), 8.48 (d, J=8.0 Hz, 1H), 8.22 (d, J=8.0
Hz, 1H), 8.16 (dd, J=8.8 and 2.3 Hz, 1H), 7.92 (dd, J=8.0 and 8.0
Hz, 1H), 7.48 (d, J=8.8 Hz, 1H), 4.18 (s, 3H), 4.06 (s, 4H), 4.01 (s,
4H). HPLC (method A) tR=7.83 min (100 area %). MS m/z 388.8
(MHþ of free base). Anal. (C21H21N7O 2HCl 2.9H2O) C,
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3
1-(4-N-Isopropylamidinophenyl)-4-(3-N-isopropylamidino-
phenyl)-1H-1,2,3-triazole Dihydrochloride (17). White solid
(0.33 g, 45%); mp 335-336 °C (dec). 1H NMR (DMSO-d6) δ
9.84 (s, 1H), 9.70 (m, 6H), 8.40 (s, 1H), 8.28 (m, 1H), 8.24 (d,
J=8.8 Hz, 2H), 8.04 (d, J=8.8 Hz, 2H), 7.76 (m, 2H), 4.14
(m, 2H), 1.32 (d, J=6.6 Hz, 6H), 1.30 (d, J=6.6 Hz, 6H).
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3
H, N, Cl.
1-(5-Amidino-2-hydroxyphenyl)-4-(3-amidinophenyl)-1H-1,2,3-
triazole Dihydrochloride (10). Brown solid (0.30 g, 41%); mp
260 °C (dec). 1H NMR (DMSO-d6) δ 12.29 (s, 1H), 9.57 (s, 2H),
9.39 (s, 2H), 9.29 (s, 2H), 9.22 (s, 1H), 9.12 (s, 2H), 8.48 (s, 1H),
8.32 (d, J=7.7 Hz, 1H), 8.28 (s, 1H), 7.94 (d, J=8.2 Hz, 1H), 7.84
(d, J=7.7 Hz, 1H), 7.75 (dd, J=7.7 and 7.7 Hz, 1H), 7.49 (d, J=
8.2 Hz, 1H). HPLC (method A) tR=5.09 min (100 area %). MS
m/z 322.2 (MHþ of free base). Anal. (C16H15N7O 2HCl 2H2O)
HPLC (method A) tR=7.65 min (100 area %). Anal. (C22H27
N7 2HCl 0.6H2O) C, H, N, Cl.
-
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1-[4-(4,5-Dihydro-1H-imidazol-2-yl)phenyl]-4-(3-(4,5-dihydro-
1H-imidazol-2-yl)phenyl)-1H-1,2,3-triazole Dihydrochloride (18).
Off-white solid (0.34 g, 51%); mp >272 °C (dec). 1H NMR
(DMSO-d6) δ 11.1 (br s, 4H), 9.82 (s, 1H), 8.90 (s, 1H), 8.38 (d, J=
8.2 Hz, 2H), 8.29 (d, J=8.2 Hz, 1H), 8.26 (d, J=8.2 Hz, 2H), 8.10
(d, J=7.7 Hz, 1H), 7.82 (dd, J=8.2 and 7.7 Hz, 1H), 4.05 (s, 8H).
HPLC (method A) tR = 6.94 min (100 area %). Anal.
(C20H19N7 2.2HCl 1.6H2O) C, H, N, Cl.
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C, H, N, Cl.
1-(5-N-Isopropylamidino-2-hydroxyphenyl)-4-(3-N-isopropyl-
amidinophenyl)-1H-1,2,3-triazole Dihydrochloride (11). Brown
solid (0.26 g, 29%); mp >245 °C (dec). 1H NMR (DMSO-d6) δ
12.24 (s, 1H), 9.79 (d, J=7.7 Hz, 1H), 9.62 (br s, 1H), 9.60 (d, J=
7.0 Hz, 1H), 9.48 (br s, 1H), 9.28 (br s, 1H), 9.25 (s, 1H), 9.10 (br
s, 1H), 8.36 (s, 1H), 8.30 (d, J=1.8 Hz, 1H), 8.12 (s, 1H), 7.83 (d,
J=7.7 Hz, 1H), 7.74 (br s, 2H), 7.52 (d, J=8.8 Hz, 1H), 4.11 (m,
2H), 1.31 (d, J=6.4 Hz, 6H), 1.28 (d, J=6.4 Hz, 6H). HPLC
(method A) tR=7.57 min (100 area %). MS m/z 406.2 (MHþ of
free base). Anal. (C22H27N7O 2.3HCl 2.8H2O) C, H, N, Cl.
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1-(4-Amidino-2-methoxyphenyl)-4-(3-amidinophenyl)-1H-1,2,3-
triazole Dihydrochloride (19). White solid (0.55 g, 52%); mp
127-130 °C. 1H NMR (DMSO-d6) δ 9.73 (br s, 2H), 9.62 (br s,
2H), 9.44 (br s, 2H), 9.34 (br s, 2H), 9.30 (s, 1H), 8.53 (s, 1H), 8.32
(d, J=7.7 Hz, 1H), 8.02 (d, J=8.3 Hz, 1H), 7.88 (d, J=1.9 Hz,
1H), 7.86 (d, J=7.7 Hz, 1H), 7.76 (dd, J=7.7and7.7Hz, 1H), 7.66
(dd, J=8.3 and 1.9 Hz, 1H), 4.06 (s, 3H). HPLC (method A) tR=
5.89 min (100 area %). MS m/z 336.2 (MHþ of free base). Anal.
(C17H17N7O 2.2HCl 3H2O) C, H, N, Cl.
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1-[5-(4,5-Dihydro-1H-imidazol-2-yl)-2-hydroxyphenyl]-4-[3-(4,5-
dihydro-1H-imidazol-2-yl)phenyl]-1H-1,2,3-triazole Dihydrochlo-
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3
1-(4-N-Isopropylamidino-2-methoxyphenyl)-4-(3-N-isopropyl-
amidinophenyl)-1H-1,2,3-triazole Dihydrochloride (20). Off-white
solid (0.60 g, 47%); mp 80-83 °C (dec). 1H NMR (DMSO-d6) δ
9.95 (d, J=7.2 Hz, 1H), 9.81 (d, J=7.0 Hz, 1H), 9.80 (br s, 1H),
9.64 (br s, 1H), 9.40 (br s, 1H), 9.30 (s, 1H), 9.29 (br s, 1H), 8.40
(s, 1H), 8.29 (m, 1H), 7.98 (d, J=8.3 Hz, 1H), 7.78 (br s, 1H), 7.75
(m, 1H), 7.73 (dd, J=7.7 and 7.7 Hz, 1H), 7.55 (dd, J=8.3 and 1.6
Hz, 1H), 4.14 (m, 2H), 4.06 (s, 3H), 1.33 (d, J=6.2 Hz, 6H), 1.31
(d, J=6.2 Hz, 6H). HPLC (methodA) tR=7.96 min (100 area %).
MS m/z 420.2 (MHþ of free base). Anal. (C23H29N7O 2.5HCl
1
ride (12). Brown solid (0.41 g, 49%); mp 247-250 °C (dec). H
NMR (DMSO-d6) δ 12.26 (s, 1H), 11.07 (s, 2H), 10.76 (s, 2H), 9.26
(s, 1H), 8.85 (s, 1H), 8.49 (s, 1H), 8.36 (d, J=8.2 Hz, 1H), 8.18 (d,
J=8.8 Hz, 1H), 8.09 (d, J=7.7 Hz, 1H), 7.78 (dd, J=7.7 and 7.7 Hz,
1H), 7.55 (d, J=8.8 Hz, 1H), 4.04 (s, 4H), 3.98 (s, 4H). HPLC
(methodA) tR=7.00min(100area%). MSm/z374.2 (MHþ of free
base). Anal. (C20H19N7O 2.5HCl 3H2O) C, H, N, Cl.
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4-(5-Amidino-2-hydroxyphenyl)-1-(3-amidinophenyl)-1H-1,2,3-
triazole Dihydrochloride (13). Purple solid (0.23 g, 41%); mp
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3
1
>278 °C (dec). H NMR (DMSO-d6) δ 11.87 (s, 1H), 9.73 (br
3H2O) C, H, N, Cl.
s, 2H), 9.45 (br s, 2H), 9.35 (br s, 2H), 9.27 (s, 1H), 9.05 (br s, 2H),
8.68 (d, J=2.4 Hz, 1H), 8.51 (s, 1H), 8.41 (d, J=8.0 Hz, 1H), 7.98
(d, J=8.0 Hz, 1H), 7.88 (d, J=8.0 Hz, 1H), 7.78 (dd, J=8.7 and
2.4 Hz, 1H), 7.39 (d, J=8.7 Hz, 1H). HPLC (method A) tR=5.64
min (100 area %). MS m/z 322.2 (MHþ of free base). Anal.
(C16H15N7O 2HCl 1.5H2O) C, H, N, Cl.
1-[4-(4,5-Dihydro-1H-imidazol-2-yl)-2-methoxyphenyl]-4-[3-(4,5-
dihydro-1H-imidazol-2-yl)phenyl]-1H-1,2,3-triazoleDihydrochloride
(21). Off-white solid (0.82 g, 69%); mp >135 °C (dec). 1H NMR
(DMSO-d6) δ 11.24 (s, 2H), 11.08 (s, 2H), 9.38 (s, 1H), 8.91 (s, 1H),
8.35 (d, J=7.7 Hz, 1H), 8.23 (d, J=1.6 Hz, 1H), 8.10 (d, J=8.3 Hz,
1H), 8.07 (d, J=7.7 Hz, 1H), 7.88 (dd, J=8.3 and 1.6 Hz, 1H), 7.79
(dd, J=7.7 and 7.7 Hz, 1H), 4.08 (s, 3H), 4.06 (s, 4H), 4.05 (s, 4H).
HPLC(methodA) tR=7.48 min (100 area %). MS m/z388.3 (MHþ
of free base). Anal. (C21H21N7O 2.2HCl 3H2O) C, H, N, Cl.
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4-(5-N-Isopropylamidino-2-hydroxyphenyl)-1-(3-N-isopropyl-
amidinophenyl)-1H-1,2,3-triazole Dihydrochloride (14). Purple
solid (0.26 g, 37%); mp >245 °C (dec). 1H NMR (DMSO-d6) δ
11.80 (s, 1H), 9.93 (d, J=8.8 Hz, 1H), 9.76 (br s, 1H), 9.51 (d, J=
8.9 Hz, 1H), 9.38 (br s, 2H), 9.27 (s, 1H), 9.00 (br s, 1H), 8.52 (d,
J=2.2 Hz, 1H), 8.40 (s, 1H), 8.35 (d, J=8.7 Hz, 1H), 7.87 (d, J=
8.2 Hz, 1H), 7.85 (m, 1H), 7.63 (dd, J=8.8 and 2.2 Hz, 1H), 7.39
(d, J=8.8 Hz, 1H), 4.12 (m, 2H), 1.33 (d, J=6.4 Hz, 6H), 1.31 (d,
J=6.4 Hz, 6H). HPLC (method A) tR=7.97 min (100 area %).
MS m/z 406.2 (MHþ of free base). Anal. (C22H27N7O 2.4HCl
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4-(5-Amidino-2-methoxyphenyl)-1-(4-amidinophenyl)-1H-1,2,3-
triazole Dihydrochloride (22). White solid (0.53 g, 65%); mp
270-272 °C (dec). 1H NMR (DMSO-d6) δ 9.62 (br s, 2H), 9.45
(brs,4H), 9.30(s,1H), 9.20(brs, 2H), 8.72(d, J=2.2Hz, 1H), 8.35
(d, J=8.8Hz, 2H), 8.14 (d, J=8.8 Hz, 2H), 7.96 (dd, J=8.8and2.2
Hz, 1H), 7.45 (d, J=8.8 Hz, 1H), 4.12 (s, 3H). HPLC (method A)
tR=6.38 min (100 area %). Anal. (C17H17N7O 2HCl 2.1H2O
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2H2O) C, H, N, Cl.
0.2EtOH) C, H, N, Cl.
4-[5-(4,5-Dihydro-1H-imidazol-2-yl)-2-hydroxyphenyl]-1-[3-(4,5-
dihydro-1H-imidazol-2-yl)phenyl]-1H-1,2,3-triazole Dihydrochlo-
ride (15). White solid (0.19 g, 29%); mp >307 °C (dec). 1H
4-(5-N-Isopropylamidino-2-methoxyphenyl)-1-(4-N-isopropyl-
amidinophenyl)-1H-1,2,3-triazole Dihydrochloride (23). White
solid (0.18 g, 19%); mp 283-284 °C (dec). 1H NMR (DMSO-d6)