Journal of Medicinal Chemistry
Article
s, 4H), 2.56 (t, J = 6.3 Hz, 2H), 2.70 (t, J = 5.4 Hz, 2H), 2.78 (t, J = 5.4
Hz, 2H), 3.42−3.64 (m, 4H), 3.72 (s, 3H), 3.77 (s, 3H), 3.79 (s, 3H),
5.55 (s, 2H), 6.43 (s, 1H), 6.54 (s, 1H), 6.83−6.95 (m, 3H), 7.31 (t, J
= 8.4 Hz, 1H), 7.54−7.67 (m, 5H), 7.69 (s, 1H). HR-MS (ESI, [M +
H]+) calcd for C32H37N5O4 + H, 556.2918; found, m/z 556.2917.
N-(4-(6,7-Dimethoxy-3,4-dihydroisoquinolin-2(1H)-yl)butyl)-4-
(1-(4-methoxybenzyl)-1H-1,2,3-triazol-4-yl)benzamide (48c) was
prepared from 47c (150 mg, 0.64 mmol) and 15b (169 mg, 0.64
mmol) as described above for 24a. The crude product was purified by
silica gel column chromatography eluting with ethyl acetate/methanol
(5/1, v/v) to afford 48c as a white solid (266 mg, 75% yield), mp
(oxalate salt): >250 °C. HR-MS (ESI, [M + H]+) calcd for
C28H38N6O4 + H, 523.3027; found, m/z 523.3023.
N-(4-(6,7-Dimethoxy-3,4-dihydroisoquinolin-2(1H)-yl)butyl)-2-
methoxy-5-(4-(1-methyl-1H-imidazol-5-yl)-1H-1,2,3-triazol-1-yl)-
benzamide (60b) was prepared from 59b (40 mg, 0.14 mmol) and
15b (36 mg, 0.14 mmol) as described above for 24a. The crude
product was purified by silica gel column chromatography eluting with
dichloromethane/methanol (10/1, v/v) to afford 60b as a colorless
1
grease (21 mg, 27% yield), mp (oxalate salt): 176−178 °C. H NMR
(300 MHz, CDCl3): δ 1.73 (br s, 4H), 2.52−2.62 (m, 2H), 2.70−2.79
(m, 2H), 2.79−2.88 (m, 2H), 3.52−3.60 (m, 4H), 3.83 (s, 3H), 3.84
(s, 3H), 3.98 (s, 3H), 4.02 (s, 3H), 6.49 (s, 1H), 6.58 (s, 1H), 7.15 (d,
J = 9.0 Hz, 1H), 7.33 (s, 1H), 7.55 (s, 1H), 7.97−8.09 (m, 2H), 8.12
(s, 1H), 8.44 (d, J = 3.0 Hz, 1H). HR-MS (ESI, [M + H]+) calcd for
C29H35N7O4 + H, 546.2823; found, m/z 546.2820.
1
(oxalate salt): 175−176 °C. H NMR (300 MHz, CDCl3): δ 1.64−
1.76 (m, 4H), 2.57 (t, J = 6.3 Hz, 2H), 2.75 (t, J = 5.4 Hz, 2H), 2.84 (t,
J = 5.4 Hz, 2H), 3.47 (d, J = 3.3 Hz, 2H), 3.59 (s, 2H), 3.81 (s, 3H),
3.83 (s, 3H), 3.84 (s, 3H), 5.47 (s, 2H), 6.52 (s, 1H), 6.59 (s, 1H),
6.90 (d, J = 8.7 Hz, 2H), 7.20−7.28 (m, 2H), 7.32 (br s, 1H), 7.65 (br
s, 4H), 7.91 (s, 1H). HR-MS (ESI, [M + H]+) calcd for C32H37N5O4 +
H, 556.2918; found, m/z 556.2917.
N-(4-(6,7-Dimethoxy-3,4-dihydroisoquinolin-2(1H)-yl)butyl)-5-
(4-((2-(2-fluoroethoxy)ethoxy)methyl)-1H-1,2,3-triazol-1-yl)-2-
methoxybenzamide (60c) was prepared from 59c (206 mg, 0.61
mmol) and 15b (160 mg, 0.61 mmol) as described above for 24a. The
crude product was purified by silica gel column chromatography
eluting with dichloromethane/methanol (10/1, v/v) to afford 60c as a
yellow grease (135 mg, 38% yield), mp (oxalate salt): 107−109 °C. 1H
NMR (300 MHz, CDCl3): δ 1.72 (br s, 4H), 2.52−2.62 (m, 2H),
2.68−2.78 (m, 2H), 2.79−2.87 (m, 2H), 3.46−3.60 (m, 4H), 3.66−
3.80 (m, 6H), 3.83 (s, 3H), 3.84 (s, 3H), 4.00 (s, 3H), 4.51 (t, J = 4.0
Hz, 1H), 4.67 (t, J = 4.0 Hz, 1H), 4.78 (s, 2H), 6.49 (s, 1H), 6.58 (s,
1H), 7.10 (d, J = 9.0 Hz, 1H), 7.95−8.02 (m, 2H), 8.06 (s, 1H), 8.38
(d, J = 2.7 Hz, 1H). HR-MS (ESI, [M + H]+) calcd for C30H40FN5O6
+ H, 586.3035; found, m/z 586.3043.
5-Azido-N-(4-(6,7-dimethoxy-3,4-dihydroisoquinolin-2(1H)-
yl)butyl)-2-(2-fluoroethoxy)benzamide (64). 63 (1.11 g, 2
mmol), sodium azide (260 mg, 4 mmol), N,N′-dimethylethylenedi-
amine (25 mg, 0.3 mmol), copper(I) iodide (380 mg, 2 mmol) and
sodium ascorbate (20 mg, 0.1 mmol) were added to 10 mL DMF with
stirring and heated at 80 °C overnight. After cooling, 60 mL water was
added. The mixture was extracted with ethyl acetate (60 mL × 3). The
organic layer was washed with brine (180 mL), dried with anhydrous
sodium sulfate, and concentrated under reduced pressure. The crude
product was purified by silica gel column chromatography eluting with
dichloromethane/methanol (10/1, v/v) to afford 64 as a brown solid
(474 mg, 50.2% yield), mp 45.2−46.3 °C. 1H NMR (300 MHz,
CDCl3): δ 1.60−1.80 (m, 4H), 2.84−2.96 (m, 2H), 3.40−3.62 (m,
8H), 3.90 (s, 6H), 4.26 (t, J = 4.2 Hz, 1H), 4.36 (t, J = 4.2 Hz, 1H),
4.71 (t, J = 4.2 Hz, 1H), 4.87 (t, J = 4.2 Hz, 1H), 6.62 (s, 1H), 6.69 (d,
J = 8.6 Hz, 1H), 7.56 (s, 1H), 6.78 (dd, J = 8.6, 2.4 Hz, 1H), 7.83 (br s,
1H), 8.45 (d, J = 2.4 Hz, 1H).
N-(4-(6,7-Dimethoxy-3,4-dihydroisoquinolin-2(1H)-yl)butyl)-3-
(1-(3-methoxybenzyl)-1H-1,2,3-triazol-4-yl)benzamide (48d) was
prepared from 47d (168 mg, 0.54 mmol) and 15b (144 mg, 0.54
mmol) as described above for 24a. The crude product was purified by
silica gel column chromatography eluting with ethyl acetate/methanol
(5/2. v/v) to afford 48d as a yellow solid (99 mg, 33% yield), mp
1
(oxalate salt): 133−135 °C. H NMR (300 MHz, CDCl3): δ 1.65 (br
s, 4H), 2.61 (br s, 2H), 2.78 (t, J = 5.4 Hz, 4H), 3.46−3.68 (m, 4H),
3.79 (s, 3H), 3.80 (s, 3H), 3.83 (s, 3H), 5.54 (s, 2H), 6.43 (s, 1H),
6.52 (s, 1H), 6.84 (t, J = 1.2 Hz, 1H), 6.89 (t, J = 1.8 Hz, 1H), 6.91 (d,
J = 8.4 Hz, 1H), 7.24 (t, J = 8.4 Hz, 1H), 7.31 (t, J = 8.4 Hz, 1H), 7.45
(br s, 1H), 7.55 (d, J = 8.4 Hz, 1H), 7.74 (s, 1H), 7.91 (d, J = 8.4, 1H),
8.13 (s, 1H). HR-MS (ESI, [M + H]+) calcd for C32H37N5O4 + H,
556.2926; found, m/z 556.2917.
5-Cyano-N-(4-(6,7-dimethoxy-3,4-dihydroisoquinolin-2(1H)-yl)-
butyl)-2-(prop-2-ynyloxy)benzamide (52) was prepared from 51
(180 mg, 0.896 mmol) and 15b (236 mg, 0.896 mmol) as described
above for 24a. The crude product was purified by silica gel column
chromatography eluting with ethyl acetate/methanol (4/1, v/v) to
afford 52 as a pale yellow oil (114 mg, 28.5% yield). For the in vitro
binding experiments, the free base was converted into the
corresponding oxalate salt, mp (oxalate salt): 166.6−168.6 °C. 1H
NMR (300 MHz, CDCl3): δ 1.72 (br s, 4H), 2.55 (t, J = 6.6 Hz, 2H),
2.69 (m, 2H), 2.70 (s, 1H), 2.79 (t, J = 5.4 Hz, 2H), 3.51 (t, J = 5.4
Hz, 2H), 3.53 (s, 2H), 3.82 (s, 3H), 3.83 (s, 3H), 5.08 (s, 2H), 6.48 (s,
1H), 6.56 (s, 1H), 7.08 (d, J = 8.7 Hz, 1H), 7.68 (dd, J = 8.7, 2.1 Hz,
1H), 7.85 (t, J = 5.4 Hz, 1H), 8.78 (d, J = 2.1 Hz, 1H). Anal.
(C26H29N3O4·1.5H2C2O4) C, H, N.
5-Cyano-N-(4-(6,7-dimethoxy-3,4-dihydroisoquinolin-2(1H)-yl)-
butyl)-2-((1-(2-fluoroethyl)-1H-1,2,3-triazol-4-yl)methoxy)-
benzamide (53) was prepared from 52 (80 mg, 0.179 mmol) and 43a
(39.8 mg, 0.447 mmol) as described above for 22a, as a white solid (72
mg, 75% yield), mp: 147.3−148.1 °C. 1H NMR (300 MHz, CDCl3): δ
1.60 (br s, 4H), 2.49 (t, J = 5.4 Hz, 2H), 2.66 (t, J = 5.4 Hz, 2H), 2.76
(t, J = 5.4 Hz, 2H), 3.43 (t, J = 5.4 Hz, 2H), 3.50 (s, 2H), 3.83 (s, 3H),
3.84 (s, 3H), 4.60 (t, J = 4.5 Hz, 1H), 4.67 (t, J = 4.5 Hz, 1H), 4.68 (t,
J = 5.4 Hz, 1H), 4.83 (t, J = 5.4 Hz, 1H), 5.33 (s, 2H), 6.49 (s, 1H),
6.56 (s, 1H), 7.18 (d, J = 8.4 Hz, 1H), 7.67 (dd, J = 8.4, 2.3 Hz, 1H),
7.83 (s, 1H), 8.04 (t, J = 5.4 Hz, 1H), 8.38 (d, J = 2.3 Hz, 1H). Anal.
(C28H33FN6O4) C, H, N.
N-(4-(6,7-Dimethoxy-3,4-dihydroisoquinolin-2(1H)-yl)butyl)-5-
(4-((dimethylamino)methyl)-1H-1,2,3-triazol-1-yl)-2-methoxyben-
zamide (60a) was prepared from 59a (140 mg, 0.51 mmol) and 15b
(134 mg, 0.51 mmol) as described above for 24a. The crude product
was purified by silica gel column chromatography eluting with
dichloromethane/methanol (10/1, v/v) to afford 60a as a colorless
grease (75 mg, 28% yield). 1H NMR (300 MHz, CDCl3): δ 1.70 (br s,
4H), 2.32 (s, 6H), 2.55 (t, J = 5.4 Hz, 2H), 2.70 (t, J = 5.4 Hz, 2H),
2.80 (t, J = 5.4 Hz, 2H), 3.44−3.56 (m, 4H), 3.69 (s, 2H), 3.82 (s,
3H), 3.83 (s, 3H), 3.99 (s, 3H), 6.49 (s, 1H), 6.57 (s, 1H), 7.09 (d, J =
9.0 Hz, 1H), 7.92−8.04 (m, 3H), 8.38 (d, J = 3.0 Hz, 1H). Mp
N-(4-(6,7-Dimethoxy-3,4-dihydroisoquinolin-2(1H)-yl)butyl)-5-
(4-((dimethylamino)methyl)-1H-1,2,3-triazol-1-yl)-2-(2-
fluoroethoxy)benzamide (65) was prepared from 64 (90 mg, 0.19
mmol) and 3-dimethylamino-1-propyne (16 mg, 0.19 mmol) as
described above for 22a, as a yellow grease (35 mg, 33% yield), mp
1
(oxalate salt): >250 °C. H NMR (300 MHz, CDCl3): δ 1.60−1.80
(m, 4H), 2.42 (s, 6H), 2.60−2.72 (m, 2H), 2.90−3.14 (m, 2H), 3.26−
3.38 (m, 2H), 3.50−3.59 (m, 2H), 3.70−3.78 (m, 2H), 3.83 (s, 3H),
3.84 (s. 3H), 4.15 (s, 2H), 4.36 (t, J = 4.2 Hz, 1H), 4.46 (t, J = 4.2 Hz,
1H), 4.79 (t, J = 4.2 Hz, 1H), 4.95 (t, J = 4.2 Hz, 1H), 6.51 (s, 1H),
6.59 (s, 1H), 6.61 (s, 1H), 7.09 (d, J = 8.7 Hz, 1H), 8.00 (dd, J = 8.7,
2.7 Hz, 1H), 8.16 (s, 1H), 8.42 (d, J = 2.7 Hz, 1H). HR-MS (ESI, [M
+ H]+) calcd for C29H39N6O4 + H, 555.3090; found, m/z 555.3096.
Sigma Receptor Binding Assays. The compounds were
dissolved in DMSO or ethanol and then diluted in 50 mM Tris-HCl
buffer containing 150 mM NaCl and 100 mM EDTA at pH 7.4 prior
to performing the σ1 and σ2 receptor binding assays. The procedures
for isolating the membrane homogenates and performing the σ1 and σ2
receptor binding assays have been previously described in detail.63
Briefly, the σ1 receptor binding assays were conducted in 96-well
plates using guinea pig brain membrane homogenates (∼300 μg of
protein) and ∼5 nM (+)-[3H]pentazocine (34.9 Ci/mmol, Perki-
nElmer, Boston, MA). The total incubation time was 90 min.
Nonspecific binding was determined from samples that contained 10
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dx.doi.org/10.1021/jm5001453 | J. Med. Chem. 2014, 57, 4239−4251