Potent Inhibitors for Human Glutaminyl Cyclase
Journal of Medicinal Chemistry, 2006, Vol. 49, No. 2 673
(m, 2H), 3.39-3.40 (m, 2H), 3.90-4.05 (m, 2H), 6.85 (s, 1H),
7.05-7.15 (m, 3H), 7.32-7.41 (m, 2H), 7.60 (s, 1H), 7.76 (br s,
1H), 9.41 (br s, 1H); MS m/z 279.3 (M + H)+, 211.2 ([M -
C3H3N2]•)+; ESI-FTICR-MS m/z 301.08915 ([M + Na]+, calcd for
C13H15N4SFNa+ 301.08936); HPLC (214 nm) tR 16.76 min (97.3%).
1-(3-(1H-Imidazol-1-yl)propyl)-3-(4-(dimethylamino)phenyl)-
thiourea 38: yield 0.75 g (62.1%); mp 146.5-147.0 °C; 1H NMR
δ 1.91-2.02 (m, 2H), 2.93 (s, 6H), 3.39-3.42 (m, 2H), 3.93-
4.01 (m, 2H), 6.67-6.70 (m, 2H), 6.92 (s, 1H), 7.05-7.10 (m,
2H), 7.15 (s, 1H), 7.40 (br s, 1H), 7.66 (s, 1H), 9.22 (s, 1H); MS
m/z 304.2 (M + H)+, 236.0 ([M - C3H3N2]•)+; ESI-FTICR-MS
m/z 326.14070 ([M + Na]+, calcd for C15H21N5SNa+ 326.14098);
HPLC (214 nm) tR 9.15 min (98.2%).
1-(3-(1H-Imidazol-1-yl)propyl)-3-(4-nitrophenyl)thiourea 39:
yield 0.86 g (70.2%); mp 165.0-166.0 °C; 1H NMR δ 1.91-2.05
(m, 2H), 3.30-3.51 (m, 2H), 3.95-4.05 (m, 2H), 6.85 (s, 1H),
7.15 (s, 1H), 7.62 (s, 1H), 7.73-7.76 (m, 2H), 8.12-8.13 (m, 2H),
8.31 (br s, 1H), 10.12 (br s, 1H); MS m/z 306.2 (M + H)+, 237.9
([M - C3H3N2]•)+; ESI-FTICR-MS m/z 328.08369 ([M + Na]+,
calcd for C13H15N5O2SNa+ 328.08386); HPLC (214 nm) tR 22.30
min (100%).
2H), 6.67 (dd, J ) 5.8 Hz, 2.5 Hz, 1H), 6.85-6.90 (m, 2H), 6.99-
7.07 (m, 1H), 7.15-7.25 (m, 2H), 7.62 (s, 1H), 7.86 (br s, 1H),
9.51 (s, 1H); MS m/z 291.1 (M + H)+, 223.2 ([M - C3H3N2]•)+;
ESI-FTICR-MS m/z 313.10922 ([M + Na]+, calcd for C14H18ON4-
SNa+ 313.10935); HPLC (214 nm) tR 16.40 min (98.5%).
1-(3-(1H-Imidazol-1-yl)propyl)-3-(3,4-dimethoxybenzyl)thio-
1
urea 47: yield 0.38 g (28.5%); mp:143.5-144.5 °C; H NMR δ
1H NMR δ 1.93-1.99 (m, 2H), 3.42-3.46 (m, 2H), 3.71 (s, 3H),
3.72 (s, 3H), 3.96-3.99 (m, 2H), 4.72 (s, 2H), 6.75-6.77 (m, 1H),
6.89-6.90 (m, 2H), 6.95 (s, 1H), 7.16 (s, 1H), 7.59 (br s, 1H),
7.62 (s, 1H), 9.33 (s, 1H); MS m/z 335.3 (M + H)+, 267.2 ([M -
C3H3N2]•)+; ESI-FTICR-MS m/z 357.113546 ([M + Na]+, calcd
for C16H22O2N4SNa+ 357.13556); HPLC (214 nm) tR 19.41 min
(97.3%).
1-(3-(1H-Imidazol-1-yl)propyl)-3-(2,3-dihydrobenzo[b][1,4]-
dioxin-7-yl)thiourea 48: yield 0.17 g (13.1%); mp 103.0-103.5
1
°C; H NMR δ 1.94-1.99 (m, 2H), 3.33-3.41 (m, 2H), 3.95-
3.98 (m, 2H), 4.19-4.26 (m, 4H), 6.68-6.71 (m, 1H), 6.78-6.80
(m, 1H), 6.86-6.87 (m, 2H), 7.16 (s, 1H), 7.63 (s, 2H), 9.28 (s,
1H); MS m/z 319.3 (M + H)+, 251.3 ([M - C3H3N2]•)+; ESI-
FTICR-MS m/z 341.10400 ([M + Na]+, calcd for C15H18O2N4SNa+
341.10426); HPLC (214 nm) tR 16.03 min (97.1%).
1-(3-(1H-Imidazol-1-yl)propyl)-3-(4-acetylphenyl)thiourea 40:
yield 0.98 g (81.2%); mp 170.0-171.0 °C; 1H NMR δ 1.91-2.12
(m, 2H), 2.48 (s, 3H), 3.20-3.52 (m, 2H), 3.92-4.11 (m, 2H),
6.85 (s, 1H), 7.15 (s, 1H), 7.51-7.65 (m, 3H), 7.81-7.92 (m, 2H),
8.02-8.09 (m, 1H), 9.81 (br s, 1H); MS m/z 303.2 (M + H)+,
235.1 ([M - C3H3N2]•)+; ESI-FTICR-MS m/z 325.10906 ([M +
Na]+, calcd for C15H18N4SNa+ 325.10935); HPLC (214 nm) tR
18.58 min (99.8%).
1-(3-(1H-Imidazol-1-yl)propyl)-3-(3,5-dimethoxyphenyl)thio-
1
urea 49: yield 1.18 g (92.4%); mp 142.0-143.0 °C; H NMR δ
1.95-2.01 (m, 2H), 3.42-3.49 (m, 2H), 3.61 (s, 6H), 3.97-4.00
(m, 2H), 6.25 (s, 1H), 6.59 (s, 2H), 6.87 (s, 1H), 7.17 (s, 1H), 7.62
(s, 1H), 7.83 (s, 1H), 9.47 (s, 1H); MS m/z 321.2 (M + H)+, 253.3
([M - C3H3N2]•)+; ESI-FTICR-MS m/z 343.12010 ([M + Na]+,
calcd for C15H20O2N4SNa+ 343.11992); HPLC (214 nm) tR 21.12
min (97.2%).
1-(3-(1H-Imidazol-1-yl)-propyl)-3-(4-methylsulfanyl-phenyl)-
thiourea 41: yield 1.22 g (99.5%); mp 140.0-140.5 °C; 1H NMR
δ 1.98-2.05 (m, 2H), 2.48 (s, 3H), 3.22-3.52 (m, 2H), 3.95-
4.05 (m, 2H), 6.85 (s, 1H), 7.16-7.33 (m, 5H), 7.63 (s, 1H), 7.76
(br s, 1H), 9.44 (br s, 1H); MS m/z 307.2 (M + H)+, 239.2 ([M -
C3H3N2]•)+; ESI-FTICR-MS m/z 329.08653 ([M + Na]+, calcd for
C14H18N4S2Na+ 329.08650); HPLC (214 nm) tR 22.18 min (97.8%).
1-(3-(1H-Imidazol-1-yl)propyl)-3-(4-(benzyloxy)phenyl)thio-
1-(3-(1H-Imidazol-1-yl)propyl)-3-(2,4-dimethoxyphenyl)thio-
1
urea 50: yield 1.25 g (97.6%); mp 120.0-120.5 °C; H NMR δ
1.95-2.01 (m, 2H), 3.42-3.49 (m, 2H), 3.74 (s, 3H), 3.75 (s, 3H),
3.97-3.99 (m, 2H), 6.48 (dd, J ) 6.1 Hz, 2.4 Hz, 1H), 6.60 (s,
1H), 6.87 (s, 1H), 7.15 (s, 1H), 7.31 (d, J ) 6.1 Hz, 1H), 7.47 (br
s, 1H), 7.61 (s, 1H), 8.73 (s, 1H); MS m/z 321.2 (M + H)+, 253.2
([M - C3H3N2]•)+; ESI-FTICR-MS m/z 343.12011 ([M + Na]+,
calcd for C15H20O2N4SNa+ 343.11992); HPLC (214 nm) tR 17.71
min (99.0%).
1
urea 42: yield 0.51 g (34.8%); mp 123.4-123.9 °C; H NMR δ
(CDCl3) 2.03-2.10 (m, 2H), 3.58-3.63 (m, 2H), 3.94-3.97 (m,
2H), 5.04 (s, 2H), 6.01 (s, 1H), 6.81 (br s, 1H), 6.90-6.96 (m,
4H), 7.11-7.19 (m, 2H), 7.31-7.40 (m, 5H), 7.92 (s, 1H); MS
m/z 367.2 (M + H)+, 299.3 ([M - C3H3N2]•)+; ESI-FTICR-MS
m/z 389.14028 ([M + Na]+, calcd for C20H22ON4SNa+ 389.14065);
HPLC (214 nm) tR 23.73 min (98.2%).
1-(3-(1H-Imidazol-1-yl)propyl)-3-(3,4-dimethoxyphenyl)-
urea 51. 3,4-Dimethoxyphenyl isocyanate (0.72 g, 4.0 mmol, 1.0
equiv) was added to a solution of 3-(1H-imidazol-1-yl)propan-1-
amine (0.48 mL, 4.0 mmol, 1.0 equiv) in dry acetonitrile (50 mL).
The mixture was stirred at room temperature for 8 h. After removing
the solvent, the crude product was recrystallized from EtOH: yield
1-(4-Ethoxy-phenyl)-3-(3-(1H-imidazol-1-yl)-propyl)thio-
1
1
urea 43: yield 0.87 g (71.9%); mp 126.0-126.5 °C; H NMR δ
0.59 g (48.6%); mp 114.5-115.0 °C; H NMR δ 1.81-1.86 (m,
1.28-1.32 (m, 3H), 1.94-2.01 (m, 2H), 3.41-3.45 (m, 2H), 3.93-
4.02 (m, 4H), 6.85 (s, 1H), 7.16-7.33 (m, 5H), 7.63 (s, 1H), 7.76
(br s, 1H), 9.44 (br s, 1H); MS m/z 305.2 (M + H)+, 237.2 ([M -
C3H3N2]•)+; ESI-FTICR-MS m/z 327.12504 ([M + Na]+, calcd for
C15H20ON4SNa+ 327.12500); HPLC (214 nm) tR 20.64 min
(98.4%).
2H), 3.00-3.05 (m, 2H), 3.66 (s, 3H), 3.69 (s, 3H), 3.95-3.98
(m, 2H), 6.09-6.12 (m, 1H), 6.79 (s, 2H), 6.88 (s, 1H), 7.14 (s,
1H), 7.17 (s, 1H), 7.62 (s, 1H), 8.24 (s, 1H); MS m/z 305.0 (M +
H)+, 237.3 ([M - C3H3N2]•)+; ESI-FTICR-MS m/z 327.14255 ([M
+ Na]+, calcd for C15H20O3N4SNa+ 327.14276); HPLC (214 nm)
tR 11.73 min (97.1%).
1-(3-(1H-Imidazol-1-yl)propyl)-3-(4-methoxyphenyl)thio-
urea 44: yield 0.87 g (75.3%); mp 125.0-125.5 °C; H NMR δ
1-(3-(1H-Imidazol-1-yl)propyl)-3-(3,4,5-trimethoxyphenyl)th-
iourea 52: yield 1.30 g (92.5%); mp 124.5-125.5 °C; 1H NMR δ
1.94-2.01 (m, 2H), 3.41-3.52 (m, 2H), 3.62 (s, 3H), 3.73 (s, 6H),
3.97-4.00 (m, 2H), 6.65 (s, 2H), 6.87 (s, 1H), 7.17 (s, 1H), 7.63
(s, 1H), 7.73 (br s, 1H), 9.41 (s, 1H); MS m/z 351.3 (M + H)+,
283.2 ([M - C3H3N2]•)+; ESI-FTICR-MS m/z 373.12977 ([M +
Na]+, calcd for C16H22O3N4SNa+ 373.13048); HPLC (214 nm) tR
16.85 min (98.6%).
1
1.87-2.00 (m, 2H), 3.29-3.44 (m, 2H), 3.70 (s, 3H), 3.91-4.02
(m, 2H), 6.72-6.93 (m, 3H), 7.11-7.21 (m, 3H), 7.50 (s, 1H),
7.61 (s, 1H), 9.21 (s, 1H); MS m/z 291.1 (M + H)+, 223.2 ([M -
C3H3N2]•)+; ESI-FTICR-MS m/z 313.10913 ([M + Na]+, calcd for
C14H18ON4SNa+ 313.10935); HPLC (214 nm) tR 22.83 min
(97.3%).
1-(3-(1H-Imidazol-1-yl)propyl)-3-(benzo[d][1,3]dioxol-6-yl)-
thiourea 45: yield 0.25 g (20.7%); mp 115.0-115.6 °C; 1H NMR
δ 1.99-2.03 (m, 2H), 3.42-3.44 (m, 2H), 4.08-4.15 (m, 2H), 6.01
(s, 2H), 6.67 (d, J ) 6.6 Hz, 1H), 6.90 (d, J ) 8.3 Hz, 1H), 6.95
(s, 1H), 7.25 (s, 1H), 7.45 (s, 1H), 7.68 (br s, 1H), 8.32 (br s, 1H),
9.38 (br s, 1H); MS m/z 305.2 (M + H)+, 237.2 ([M - C3H3N2]•)+;
ESI-FTICR-MS m/z 305.10642 ([M + H]+, calcd for C14H17O2N4S+
305.10667); HPLC (214 nm) tR 13.71 min (96.6%).
1-(3-(1H-Imidazol-1-yl)propyl)-3-(3,4-dimethoxyphenyl)thio-
urea 53: yield 0.66 g (51.3%); mp 160.0-161.0 °C; H NMR δ
1
1.93-1.99 (m, 2H), 3.42-3.46 (m, 2H), 3.71 (s, 3H), 3.72 (s, 3H),
3.96-3.99 (m, 2H), 6.75-6.77 (m, 1H), 6.89-6.90 (m, 2H), 6.95
(s, 1H), 7.16 (s, 1H), 7.59 (br s, 1H), 7.62 (s, 1H), 9.33 (s, 1H);
MS m/ z 321.2 (M + H)+, 253.3 ([M - C3H3N2]•)+; ESI-FTICR-
MS m/z 343.12009 ([M + Na]+, calcd for C15H20O2N4SNa+
343.11992); HPLC (214 nm) tR 14.00 min (99.8%).
1-(3-(1H-Imidazol-1-yl)propyl)-3-(3-methoxyphenyl)thio-
urea 46: yield 0.86 g (73.9%); mp 89.5-90.0 °C; 1H NMR δ 1.99-
2.05 (m, 2H), 3.42-3.46 (m, 2H), 3.71 (s, 3H), 3.97-4.01 (m,
1-(2-(1H-Imidazol-1-yl)ethyl)-3-(3,4-dimethoxyphenyl)thio-
urea 54 started from 8 (0.27 g, 2.4 mmol) and 3,4-dimethoxyphenyl
isothiocyanate (0.47 g, 2.4 mmol): yield 0.73 g (59.6%); mp