Imidazo[1,2-a]pyridine Antiprotozoal Agents
J ournal of Medicinal Chemistry, 2004, Vol. 47, No. 14 3663
127.4, 123.8, 123.3, 118.8, 117.0, 111.4, 111.0, 110.3, 109.3,
97.1, 16.3. MS (m/z, rel int); 324 (M+, 100), 295 (7), 222 (8),
194 (15), 162 (15). High-resolution mass calcd for C20H12N4O:
324.10111. Observed: 324.10070.
243-246 °C. 1H NMR (D2O/DMSO-d6); δ 1.90 (s, 3 × CH3),
7.61-7.69 (m, 2H), 7.89-7.94 (m, 6H), 8.13 (s, 2H), 8.62 (s,
1H), 9.12 (s, 1H). MS (m/z, rel int); 354 (M+, 10), 321 (100),
311 (90), 296 (35). Anal. (C21H18N6‚3.0AcOH‚2.5H2O) C, H, N.
2-(3-Br om op h en yl)-im id a zo[1,2-a ]p yr id in e-6-ca r bon i-
tr ile (9b). The same procedure described for 9a was used,
employing 3-bromophenacyl bromide instead of 4-bromophen-
acyl bromide. Yield 64%, mp 205-206.5 °C. 1H NMR (DMSO-
d6); δ 7.43-7.47 (m, 1H), 7.52-7.58 (m, 2H), 7.75-7.78 (m,
1H), 8.03 (s, 1H), 8.22 (s, 1H), 8.61-8.65 (m, 1H), 9.37 (s, 1H).
13C NMR; δ 144.6, 144.1, 135.2, 134.3, 130.9, 128.3, 125.1,
124.7, 122.2, 117.5, 116.9, 111.2, 97.2. MS (m/z, rel int); 298
(M+, 100), 161 (10). Anal. (C14H8BrN3) C, H.
N-Hydr oxy-2-{5-[4-(N-h ydr oxyam idin o)-ph en yl]-fu r an -
2-yl}-8-m e t h yl-im id a zo[1,2-a ]p yr id in e -6-ca r b oxa m i-
d in e (5b). The same procedure described for 5a was used
starting with 4b. Yield 92%, mp 255-258 °C. 1H NMR (DMSO-
d6); δ 2.54 (s, 3H), 5.91 (br s, 4H), 6.99 (d, J ) 3.6 Hz, 1H),
7.15 (d, J ) 3.6 Hz, 1H), 7.41 (s, 1H), 7.78 (d, J ) 8.7 Hz, 2H),
7.83 (d, J ) 8.7 Hz, 2H), 8.36 (s, 1H), 8.68 (s, 1H), 9.73 (s,
1H), 9.79 (s, 1H). 13C NMR; δ 152.0, 150.4, 149.4, 148.7, 145.2,
136.4, 132.0, 130.3, 125.8, 125.1, 123.0, 121.9, 119.1, 110.1,
108.9, 108.4, 16.7. Anal. (C20H18N6O3‚0.5H2O) C, H.
2-(4′-Cya n ob ip h en yl-3-yl)-im id a zo[1,2-a ]p yr id in e-6-
ca r bon itr ile (10b). The same procedure described for 4a was
2-[5-(4-Am id in op h en yl)-fu r a n -2-yl]-8-m eth yl-im id a zo-
[1,2-a ]p yr id in e-6-ca r boxa m id in e Aceta te Sa lt (8b). The
same procedure described for 8a was used, starting with 5b.
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used, starting with 9b. Yield 61%, mp 290-292 °C. H NMR
(DMSO-d6); δ 7.48-7.63 (m, 2H), 7.74-7.78 (m, 2H), 7.92-
7.99 (m, 4H), 8.08 (d, J ) 7.8 Hz, 1H), 8.36 (s, 1H), 8.64 (s,
1H), 9.33 (s, 1H). 13C NMR; δ 146.7, 145.0, 144.9, 139.6, 135.0,
134.5, 133.6, 130.5, 128.4, 127.8, 126.9, 125.7, 125.2, 119.5,
118.2, 117.8, 111.7, 110.9, 97.9. MS (m/z, rel int); 320 (M+, 100),
297 (3), 217 (5), 190 (8), 160 (10). High-resolution mass calcd.
for C21H12N4: 320.10620. Observed: 320.10619. Anal. (C21H12N4)
C, H.
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Yield 68%, mp 229-231 °C. H NMR (D2O/DMSO-d6); δ 1.84
(s, 3 × CH3), 2.58 (s, 3H), 7.02 (d, J ) 3.6 Hz, 1H), 7.24 (d, J
) 3.6 Hz, 1H), 7.48 (s, 1H), 7.82-7.92 (m, 4H), 8.40 (s, 1H),
8.89 (s, 1H). Anal. (C20H18N6O-3.0AcOH-1.35H2O) C, H, N.
2-(4-Br om op h en yl)-im id a zo[1,2-a ]p yr id in e-6-ca r bon i-
tr ile (9a ). The same procedure described for 3a was used,
employing 4-bromophenacyl bromide instead of 2-bromo-1-(5-
bromofuran-2-yl)-ethanone (2). Yield 67%, mp 262-264 °C. 1H
NMR (DMSO-d6); δ 7.73 (d, J ) 8.4 Hz, 2H), 7.76 (d, J ) 9.6
Hz, 1H), 7.87 (d, J ) 9.6 Hz, 1H), 7.97 (d, J ) 8.4 Hz, 2H),
8.69 (s, 1H), 9.48 (s, 1H). Anal. (C14H8BrN3) C, H.
N-H yd r oxy-2-[4′-(N-h yd r oxya m id in o)-b ip h en yl-3-yl]-
im id a zo[1,2-a ]p yr id in e-6-ca r boxa m id in e (11b). The same
procedure described for 5a was used, starting with 10b. Yield
94%, mp 252-254 °C. 1H NMR (DMSO-d6); δ 5.89 (s, 2H), 5.98
(s, 2H), 7.52-7.58 (m, 3H), 7.67 (d, J ) 8.1 Hz, 1H), 7.78 (d, J
) 8.7 Hz, 2H), 7.83 (d, J ) 8.7 Hz, 2H), 8.00 (d, J ) 7.8 Hz,
1H), 8.31 (s, 1H), 8.57 (s, 1H), 8.81 (s, 1H), 9.72 (s, 1H), 9.86
(s, 1H). 13C NMR; δ 150.5, 148.5, 144.6, 144.5, 140.3, 139.9,
134.3, 132.4, 129.3, 126.3, 125.9, 124.8, 123.9, 123.6, 123.2,
119.0, 115.8, 110.1. Anal. (C21H18N6O2‚2.0H2O) C, H.
2-(4′-Am idin obiph en yl-3-yl)-5,6,7,8-tetr ah ydr o-im idazo-
[1,2-a ]p yr id in e-6-ca r boxa m id in e Aceta te Sa lt (13b). The
same procedure described for 7 was used, starting with 11b.
Yield 65%, mp 236-238 °C. 1H NMR (D2O/DMSO-d6); δ 1.90-
2.17 (br s, 3 × CH3 + 3H), 2.79 (br s, 1H), 3.03 (br s, 1H), 4.11
(br s, 1H), 4.33 (br s, 1H), 7.48 (t, J ) 7.5 Hz, 1H), 7.57 (d, J
) 8.1 Hz, 1H), 7.71 (s, 1H), 7.79 (d, J ) 7.5 Hz, 1H), 7.90-
7.96 (m, 4H), 8.09 (s, 1H). Anal. (C21H22N6-3.0AcOH‚2.85H2O‚
0.25EtOH) C, H, N.
2-(4′-Cya n ob ip h en yl-4-yl)-im id a zo[1,2-a ]p yr id in e-6-
ca r bon itr ile (10a ). The same procedure described for 4a was
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used, starting with 9a . Yield 78%, mp 276-278 °C. H NMR
(DMSO-d6); δ 7.51 (d, J ) 9.0 Hz, 1H), 7.76 (d, J ) 9.0 Hz,
1H), 7.87 (d, J ) 7.8 Hz, 2H), 7.92-7.98 (m, 4H), 8.14 (d, J )
7.8 Hz, 2H), 8.58 (s, 1H), 9.33 (s, 1H). 13C NMR; δ 145.6, 144.2,
143.9, 137.9, 134.3, 133.2, 132.8, 127.5, 127.4, 126.6, 125.0,
118.8, 117.4, 117.1, 110.9, 110.0, 97.1. MS (m/z, rel int); 320
(M+, 100), 293 (5), 217 (8), 190 (8), 160 (10). High-resolution
mass calcd. for C21H12N4: 320.10620. Observed: 320.10275.
Anal. (C21H12N4‚0.25H2O) C, H, N.
N-H yd r oxy-2-[4′-(N-h yd r oxya m id in o)-b ip h en yl-4-yl]-
im id a zo[1,2-a ]p yr id in e-6-ca r boxa m id in e Hyd r och lor id e
Sa lt (11a ). The same procedure described for 5a was used
starting with 10a . Free base yield 97%, mp 300-302 °C. 1H
NMR (DMSO-d6); δ 5.86 (s, 2H), 5.94 (s, 2H), 7.55 (s, 2H),
7.72-7.80 (m, 6H), 8.07 (d, J ) 8.1 Hz, 2H), 8.47 (s, 1H), 8.80
(s, 1H), 9.69 (s, 1H), 9.83 (s, 1H). 13C NMR; δ 150.4, 148.5,
144.6, 144.4, 139.9, 138.7, 133.0, 132.3, 126.8, 126.16, 126.11,
125.9, 124.0, 123.2, 119.0, 115.8, 110.0. (11a , hydrochloride
salt), mp 291-293 °C. Anal. (C21H18N6O2‚3.0HCl‚1.9H2O‚
0.25EtOH) C, H, N.
2-(4′-Am id in obip h en yl-3-yl)-im id a zo[1,2-a ]p yr id in e-6-
ca r boxa m id in e Aceta te Sa lt (14b). The same procedure
described for 8a was used, starting with 11b. Yield 57%, mp
233-235 °C. 1H NMR (D2O/DMSO-d6); δ 1.87 (s, 3 × CH3),
7.55-7.69 (m, 4H), 7.72-7.92 (m, 4H), 8.05 (d, J ) 7.5 Hz,
1H), 8.33 (s, 1H), 8.56 (s, 1H), 9.03 (s, 1H). Anal. (C21H18N6‚
3.0AcOH‚0.9H2O) C, H, N.
N-Met h oxy-2-[4′-(N-m et h oxya m id in o)-b ip h en yl-4-yl]-
im id a zo[1,2-a ]p yr id in e-6-ca r boxa m id in e Hyd r och lor id e
Sa lt (12). The same procedure described for 6 was used
starting with 11a . Free base yield 48%, mp 224-226 °C
(SiO2: hexanes/EtOAc; 2:8). 1H NMR (DMSO-d6); δ 3.77 (s,
3H), 3.79 (s, 3H), 6.12 (s, 2H), 6.23 (s, 2H), 7.50-7.59 (m, 2H),
7.77 (s, 4H), 7.81 (d, J ) 8.4 Hz, 2H), 8.09 (d, J ) 8.4 Hz, 2H),
8.50 (s, 1H), 8.83 (s, 1H). 13C NMR; δ 150.6, 148.8, 144.6, 144.5,
140.3, 138.5, 133.0, 131.4, 126.8, 126.2, 126.1, 126.0, 124.5,
123.2, 118.1, 115.8, 110.0, 60.6, 60.5. MS (m/z, rel int); 414
(M+, 60), 384 (10), 367 (50), 320 (100), 294 (10). High-resolution
mass calcd. for C23H22N6O2: 414.18042. Observed: 414.18122.
(12, hydrochloride salt), mp 234-236 °C. Anal. (C23H22N6O2‚
3.0HCl‚1.4H2O‚0.25EtOH) C, H, N.
2-(3-Br om op h en yl)-8-m eth yl-im id a zo[1,2-a ]p yr id in e-6-
ca r bon itr ile (9c). The same procedure described for 9b was
used, employing 6-amino-5-methylnicotinonitrile instead of
6-amino-nicotinonitrile. Yield 70%, mp 168-169.5 °C. 1H NMR
(DMSO-d6); δ 2.55 (s, 3H), 7.36 (s, 1H), 7.43 (t, J ) 7.8 Hz,
1H), 7.55 (d, J ) 7.8 Hz, 1H), 8.01 (d, J ) 7.8 Hz, 1H), 8.20 (s,
1H), 8.57 (s, 1H), 9.20 (s, 1H). MS (m/z, rel int); 312 (M+, 60),
175 (100), 135 (10). Anal. (C15H10BrN3) C, H.
2-(4′-Cya n obip h en yl-3-yl)-8-m eth yl-im id a zo[1,2-a ]p y-
r id in e-6-ca r bon itr ile (10c). The same procedure described
for 4a was used, starting with 9c. Yield 78%, mp 236-238
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°C. H NMR (DMSO-d6); δ 2.56 (s, 3H), 7.34 (s, 1H), 7.60 (t, J
) 7.8 Hz, 1H), 7.73 (d, J ) 7.8 Hz, 1H), 7.97 (s, 4H), 8.10 (d,
J ) 7.8 Hz, 1H), 8.34 (s, 1H), 8.64 (s, 1H), 9.21 (s, 1H). 13C
NMR; δ 145.2, 144.7, 144.3, 138.7, 133.8, 132.8, 131.9, 129.6,
127.6, 127.5, 126.9, 126.1, 124.3, 122.8, 118.8, 117.1, 111.4,
110.1, 96.9, 16.3. Anal. (C22H14N4) C, H.
2-(4′-Am idin obiph en yl-4-yl)-5,6,7,8-tetr ah ydr o-im idazo-
[1,2-a ]p yr id in e-6-ca r boxa m id in e Aceta te Sa lt (13a ). The
same procedure described for 7 was used starting with 11a .
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Yield 85%, mp 240-242 °C. H NMR (D2O/DMSO-d6); δ 2.03
N-Hyd r oxy-2-[4′-(N-h yd r oxya m id in o)-bip h en yl-3-yl]-8-
m eth yl-im id a zo[1,2-a ]p yr id in e-6-ca r boxa m id in e (11c).
The same procedure described for 5a was used, starting with
(br s, 3 × CH3 + 3H), 2.86 (br s, 1H), 3.03 (br s, 1H), 4.16 (br
s, 1H), 4.36 (br s, 1H), 7.57 (s, 1H), 7.75-7.77 (m, 2H), 7.85-
7.91 (m, 6H). Anal. (C21H22N6‚3.0AcOH‚1.5H2O) C, H, N.
2-(4′-Am id in obip h en yl-4-yl)-im id a zo[1,2-a ]p yr id in e-6-
ca r boxa m id in e a ceta te sa lt (14a ). The same procedure
described for 8a was used, starting with 11a . Yield 81%, mp
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10c. Yield 97%, mp 193-195 °C. H NMR (DMSO-d6); δ 2.56
(s, 3H), 5.89 (s, 2H), 5.93 (s, 2H), 7.39 (s, 1H), 7.55 (t, J ) 7.8
Hz, 1H), 7.66 (d, J ) 7.8 Hz, 1H), 7.77 (d, J ) 9 Hz, 2H), 7.83
(d, J ) 9 Hz, 2H), 8.02 (d, J ) 7.8 Hz, 1H), 8.29 (s, 1H), 8.56