Journal of Medicinal Chemistry
Article
1
the residue was purified by silica gel chromatography (hexane:ethyl
acetate = 1:1) to give 234 mg of 3 (92.1%). H NMR (400 MHz,
from 7. H NMR (400 MHz, CDCl3): δ 2.27−2.34 (m, 2H), 2.97
(s, 3H), 2.98−3.06 (m, 2H), 3.28−3.47 (m, 2H), 3.78−3.93 (m, 2H),
4.07−4.33 (m, 6H), 6.56 (d, 1H, J = 8.8 Hz), 6.75 (s, 1H), 6.80
(d, 1H, J = 6.4 Hz), 6.98 (s, 1H), 7.36 (d, 1H, J = 8.8 Hz), 7.86 (d, 1H,
J = 9.2 Hz), 8.65 (s, 1H). HRMS (FAB): m/z calcd for
C23H30N4O3ReS2 (M+), 661.1314; found, 661.1312.
1
CDCl3): δ 2.98 (d, 3H, J = 5.2 Hz), 3.84 (s, 3H), 4.78 (s, 1H), 6.47
(d, 1H, J = 8.8 Hz), 6.76 (s, 1H), 6.84 (dd, 1H, J1 = 8.8 Hz, J2 = 4.4 Hz),
7.00 (d, 1H, J = 2.4 Hz), 7.36 (d, 1H, J = 8.4 Hz), 7.87 (dd, 1H, J1 = 8.8
Hz, J2 = 2.4 Hz), 8.59 (d, 1H, J = 2.8 Hz). MS: m/z 255 (M+ + H).
2-(6-(Methylamino)pyridin-3-yl)benzofuran-5-ol (4). The same
reaction as described above to prepare 2 was used, and 218 mg of 4
5-(5-Methoxybenzofuran-2-yl)-N,N-dimethylpyridin-2-amine (9).
A mixture of 1 (360 mg, 1.5 mmol), paraformaldehyde (450 mg,
15 mmol), and sodium cyanoborohydride (284 mg, 4.5 mmol) in acetic
acid (20 mL) was stirred at room temperature overnight and then
poured into 100 mL of water. Sodium bicarbonate was added to adjust
the pH to 8−9. After a standard workup with ethyl acetate, the residue
was purified by silica gel chromatography (hexane:ethyl acetate = 3:1)
1
was obtained in a 99.0% yield from 3. H NMR (400 MHz, CDCl3):
δ 2.98 (d, 3H, J = 5.2 Hz), 4.78 (s, 1H), 6.47 (d, 1H, J = 8.8 Hz),
6.76 (s, 1H), 6.84 (dd, 1H, J1 = 8.8 Hz, J2 = 4.4 Hz), 7.00 (d, 1H, J =
2.4 Hz), 7.36 (d, 1H, J = 8.4 Hz), 7.87 (dd, 1H, J1 = 8.8 Hz, J2 =
2.4 Hz), 8.59 (d, 1H, J = 2.8 Hz). MS: m/z 241 (M+ + H).
1
to give 249 mg of 9 (62.0%). H NMR (400 MHz, CDCl3): δ 3.15
tert-Butyl 2-((3-Bromopropyl)(2-(tritylthio)ethyl)amino)ethyl
(2-(tritylthio)ethyl)carbamate (TRT-Boc-BAT-Br). To a solution of
TRT-Boc-BAT18 (399.8 mg, 0.52 mmol) in CH3CN (20 mL) were
added K2CO3 (200 mg, 1.45 mmol) and 1,3-dibromopropane (110 μL,
1.0 mmol). The mixture was heated to reflux for 18 h, and after
cooling to room temperature, evaporated dry. The residue was
redissolved in CHCl3 and washed with brine. The organic layers were
dried with Na2SO4 and evaporated dry. The crude product was chro-
matographed on silica gel (ethyl acetate:hexane = 3:7) to give 244 mg
(s, 6H), 3.85 (s, 3H), 6.59 (d, 1H, J = 8.8 Hz), 6.76 (s, 1H), 6.82 (dd,
1H, J1 = 8.8 Hz, J2 = 2.4 Hz), 7.07 (d, 1H, J = 2.4 Hz), 7.36 (d, 1H, J =
8.8 Hz), 7.86 (dd, 1H, J1 = 8.8 Hz, J2 = 2.4 Hz), 8.67 (d, 1H, J = 2.4 Hz).
MS: m/z 269 (M+ + H).
2-(6-(Dimethylamino)pyridin-3-yl)benzofuran-5-ol (10). The
same reaction as described above to prepare 2 was used, and 234 mg
1
of 10 was obtained in a 98.9% yield from 9. H NMR (400 MHz,
CDCl3): δ 3.15 (s, 6H), 4.89 (s, 1H), 6.59 (d, 1H, J = 8.8 Hz), 6.76
(s, 1H), 6.82 (dd, 1H, J1 = 8.8 Hz, J2 = 2.4 Hz), 7.07 (d, 1H, J = 2.4 Hz),
7.36 (d, 1H, J = 8.8 Hz), 7.86 (dd, 1H, J1 = 8.8 Hz, J2 = 2.4 Hz), 8.67
(d, 1H, J = 2.4 Hz). MS: m/z 255 (M+ + H).
1
of desired compound (53.0% yield). H NMR (400 MHz, CDCl3):
δ 1.37 (s, 9H), 1.71−1.73 (m, 2H), 2.25−2.42 (m, 10H), 2.87−3.03
(m, 4H), 3.90−3.93 (m, 2H), 7.14−7.29 (m, 19H), 7.38−7.40 (m,
12H). MS: m/z 887 (M+ + H).
5-(5-(3-Bromopropoxy)benzofuran-2-yl)-N,N-dimethylpyridin-2-
amine (11). To a solution of 10 (324.9 mg, 1.27 mmol) in CH3CN
(20 mL) were added K2CO3 (216 mg, 1.57 mmol) and 1,3-
dibromopropane (0.65 mL, 6.4 mmol). The mixture was heated to
reflux for 18 h, and after cooling to room temperature, evaporated dry.
The residue was redissolved in CHCl3 and washed with brine. The
organic layers were dried with Na2SO4 and evaporated dry. The crude
product was chromatographed on silica gel (ethyl acetate:hexane =
3:7) to give 275 mg of 11 (73.2% yield). 1H NMR (400 MHz,
CDCl3): δ 2.09 (t, 2H, J = 6.4 Hz), 3.09 (s, 6H), 3.60(t, 2H, J =
6.4 Hz), 4.08 (t, 2H, J = 5.8 Hz), 6.48 (s, 1H), 6.68 (s, 1H), 6.80 (d,
1H, J = 6.4 Hz), 6.96 (s, 1H), 7.33 (d, 1H, J = 8.8 Hz), 7.79 (d, 1H, J =
9.2 Hz), 8.64 (s, 1H). MS: m/z 375 (M+ + H).
tert-Butyl-2-((3-(2-(6-(dimethylamino)pyridin-3-yl)benzofuran-6-
yloxy)propyl)(2-(tritylthio)ethyl)amino)ethyl(2-(tritylthio)ethyl)-
carbamate (12). To a solution of 11 (272 mg, 0.72 mmol) and tert-
butyl 2-(tritylthio)ethyl(2-(2-(tritylthio)ethylamino)ethyl)carbamate
(TRT-Boc-BAT)18 (550 mg, 0.72 mmol) in acetonitrile (30 mL)
was added DIPEA (225 μL, 1.45 mmol). The reaction mixture was
heated to reflux for 12 h. When the solvent had evaporated, a saturated
NaCl solution was added, and after extraction with CHCl3, the organic
layers were combined, dried with Na2SO4, and evaporated dry. The crude
product was chromatographed on silica gel (ethyl acetate:hexane = 3:7)
to give 343.6 mg of 12 (45.0% yield). 1H NMR (400 MHz, CDCl3):
δ 1.26 (s, 9H), 1.61 (s, 2H), 2.16−2.30 (m, 10H), 2.77−2.87
(m, 4H), 2.97 (s, 6H), 3.81 (s, 2H), 6.40 (d, 1H, J = 9.2 Hz), 6.55
(s, 1H), 6.66 (d, 1H, J = 6.4 Hz), 6.84 (s, 1H), 7.03−7.20 (m,
19H), 7.21−7.31 (m, 12H), 7.71 (d, 1H, J = 9.2 Hz), 8.55 (s, 1H).
HRMS (FAB): m/z calcd for C67H71N4O4S2 (M+), 1059.4917; found,
1059.4910.
tert-Butyl 2-((3-(2-(6-Aminopyridin-3-yl)benzofuran-5-yloxy)-
propyl)(2-(tritylthio)ethyl)amino)ethyl(2-(tritylthio)ethyl)carbamate
(5). To a solution of 2 (18 mg, 0.08 mmol) and Boc-BAT-Br (70 mg,
0.08 mmol) in acetone (10 mL) was added cesium carbonate (31 mg,
0.10 mmol). The reaction mixture was heated to reflux for 5 h. After
evaporation of the solvent, a saturated NaCl solution was added, and
after extraction with CHCl3, the organic layers were combined, dried
with Na2SO4, and evaporated dry. The crude product was chromato-
graphed on silica gel (ethyl acetate:hexane = 1:1) to give 62 mg of 5
1
(75.2% yield). H NMR (400 MHz, CDCl3): δ 1.37 (s, 9H), 1.71−
1.73 (m, 2H), 2.25−2.42 (m, 10H), 2.87−3.03 (m, 4H), 3.90−3.93
(m, 2H), 4.80 (s, 2H), 6.55 (d, 1H, J = 8.8 Hz), 6.70 (s, 1H), 6.77 (dd,
1H, J1 = 8.8 Hz, J2 = 2.4 Hz), 6.95 (d, 1H, J = 2.8 Hz), 7.14−7.29
(m, 19H), 7.38−7.40 (m, 12H), 7.82 (J1 = 8.8 Hz, J2 = 2.4 Hz), 8.54
(d, 1H, J = 2.0 Hz). HRMS (FAB): m/z calcd for C65H66N4O4S2
(M+), 1030.4423; found, 1030.4417.
Compound 6 (Re-BAT-Bp-1). To a solution of 5 (25 mg, 0.02 mmol)
in TFA (1 mL) was added triethylsilane (0.29 mL) and mixed for
10 min, and then the solvent was removed under a stream of
nitrogen gas. The residue was resolved in 10 mL of CH2Cl2,
(Ph3P)2ReOCl3 (33 mg, 0.04 mmol), and 1 M sodium acetate in
methanol (1 mL) was added. The reaction mixture was heated to
reflux for 4 h. The mixture was filtered after cooling to room tempera-
ture. Evaporation of the solvent gave a residue which was purified with
silica gel chromatography (CHCl3:CH3OH = 10:1), to give 6.1 mg of
6 (46.0% yield). 1H NMR (400 MHz, CDCl3): δ 2.27−2.34 (m, 2H),
2.98−3.06 (m, 2H), 3.28−3.47 (m, 2H), 3.78−3.93 (m, 2H), 4.07−
4.33 (m, 6H), 6.56 (d, 1H, J = 8.8 Hz), 6.75 (s, 1H), 6.80 (d, 1H, J =
6.4 Hz), 6.98 (s, 1H), 7.36 (d, 1H, J = 8.8 Hz), 7.86 (d, 1H, J = 9.2 Hz),
8.65 (s, 1H). HRMS (FAB): m/z calcd for C22H28N4O3ReS2 (M+),
675.1471; found, 675.1469.
tert-Butyl 2-((3-(2-(6-(Methylamino)pyridin-3-yl)benzofuran-5-
yloxy)propyl)(2-(tritylthio)ethyl)amino)ethyl(2-(tritylthio)ethyl)-
carbamate (7). The same reaction as described above to prepare 5
was used, and 220.5 mg of 7 was obtained in a 70.3% yield from 4. 1H
NMR (400 MHz, CDCl3): δ 1.36 (s, 9H), 1.69−1.75 (m, 2H), 2.25−
2.40 (m, 10H), 2.87−3.03 (m, 4H), 2.97 (s, 3H), 3.89−3.93 (m, 2H),
5.03 (s, 1H), 6.44 (d, 1H, J = 8.8 Hz), 6.68 (s, 1H), 6.76 (dd, 1H, J1 =
8.8 Hz, J2 = 2.4 Hz), 6.95 (d, 1H, J = 2.8 Hz), 7.14−7.25 (m, 19H),
7.38−7.39 (m, 12H), 7.85 (J1 = 8.8 Hz, J2 = 2.4 Hz), 8.56 (d, 1H, J =
2.0 Hz). HRMS (FAB): m/z calcd for C66H68N4O4S2 (M+),
1044.4580; found, 1044.4587.
Compound 13 (Re-BAT-Bp-3). The same reaction as described
above to prepare 6 was used, and 29 mg of 13 was obtained in a 33.0%
1
yield from 12. H NMR (400 MHz, CDCl3): δ 2.27−2.34 (m, 2H),
2.98−3.06 (m, 2H), 3.16 (s, 6H), 3.28−3.47 (m, 2H), 3.78−3.93
(m, 2H), 4.07−4.33 (m, 6H), 6.56 (d, 1H, J = 8.8 Hz), 6.75 (s, 1H),
6.80 (d, 1H, J = 6.4 Hz), 6.98 (s, 1H), 7.36 (d, 1H, J = 8.8 Hz), 7.86
(d, 1H, J = 9.2 Hz), 8.65 (s, 1H). HRMS (FAB): m/z calcd for
C24H32N4O3ReS2 (M+), 675.1471; found, 675.1469.
Binding Assays Using the Aggregated Aβ Peptides in
Solution. Aβ(1−42) was purchased from Peptide Institute (Osaka,
Japan). Aggregation was carried out by gently dissolving the peptide
(0.25 mg/mL) in a buffer solution (pH 7.4) containing 10 mM
sodium phosphate and 1 mM EDTA. The solution was incubated at
37 °C for 42 h with gentle and constant shaking. A mixture containing
50 μL of Re complex (6, 8, or 13) (10−5−10−10 M in 10% EtOH),
Compound 8 (Re-BAT-Bp-2). The same reaction as described above
to prepare 6 was used, and 30.1 mg of 8 was obtained in a 26.7% yield
2284
dx.doi.org/10.1021/jm201513c | J. Med. Chem. 2012, 55, 2279−2286