Journal of Medicinal Chemistry
Article
8
6
1
.31 (d, J = 5.24 Hz, 1H), 7.40 (dd, J = 5.2, 1.2 Hz, 1H), 7.25 (m, 1H),
.73 (d, J = 8.0 Hz, 1H), 6.65 (d, J = 8.4 Hz, 1H), 4.83 (d, J = 8.0 Hz,
H), 3.90 (m, 4H), 3.67 (m, 1H), 3.34 (m, 2H), 3.05 (m, 2H), 2.86
(m, 1H), 6.74 (d, J = 8.00 Hz, 1H), 6.66 (d, J = 8.12 Hz, 1H), 4.87 (d,
J = 7.64 Hz, 1H), 4.08 (s, 3H), 3.88−3.70 (m, 2H), 3.36−3.32 (m,
2H), 3.12−3.05 (m, 2H), 2.87 (m, 1H), 2.47 (m, 2H), 2.02−1.89 (m,
1H), 1.74 (m, 1H), 1.62 (m, 1H), 1.46−1.35 (m, 2H), 1.09 (m, 1H),
(
m, 1H), 2.45 (m, 2H), 1.90 (m, 1H), 1.78 (m, 1H), 1.58 (m, 1H),
1
3
1
1
1
1
2
.43 (m, 2H), 1.08 (m, 1H), 0.67 (m, 1H), 0.59 (m, 1H), 0.52 (m,
0.68 (m, 1H), 0.60 (m, 1H), 0.52 (m, 1H), 0.42 (m, 1H); C NMR
H), 0.41 (m, 1H); 13C NMR (100 MHz, DMSO-d ) δ 164.10,
(100 MHz, DMSO-d ) δ 162.95, 155.65, 153.65, 152.38, 142.15,
6
6
63.63, 147.53, 144.34, 141.98, 141.24, 129.49, 120.52, 119.26, 117.86,
14.55, 108.25, 89.51, 69.60, 61.59, 56.61, 53.51, 51.27, 46.39, 45.51,
9.23, 27.23, 23.47, 22.94, 5.63, 5.02, 2.54. MS m/z found 478.2 (M +
141.28, 129.68, 121.76, 120.60, 119.26, 117.97, 92.59, 89.91, 69.71,
61.45, 56.92, 56.69, 51.27, 46.49, 45.68, 29.52, 27.29, 23.58, 23.00,
+
21.18, 5.72, 5.10, 2.63. MS m/z found 478.6 (M + H) . IR (diamond,
+
−1
−1
H) . IR (diamond, cm ) ν 3390.5, 3172.6, 3116.7, 1659.7, 1617.9,
cm ) ν 3068.3, 1655.7, 1525.6, 1503.5, 1319.4, 1255.5, 1125.2,
max
max
1
547.9, 1422.0, 1372.2, 1329.2, 1276.0, 1131.8, 1033.6, 919.4, 859.7,
1032.1, 1006.7, 800.7. Mp 225 °C, dec.
8
N.
11.6. Mp 244−248 °C, dec. Anal. (C H N O ·2HCl·2.5H O) C, H,
17-Cyclopropylmethyl-3,14β-dihydroxy-4,5α-epoxy-6β-[2′-
(pyridine-4″-yl)acetamido]morphinan (10). The title compound
was obtained following the general procedure as a yellow solid, in 44%
yield. [α]25 −115.30° (c 1.0, MeOH). H NMR (300 MHz, CDCl ) δ
27
31
3
5
2
1
7-Cyclopropylmethyl-3,14β-dihydroxy-4,5α-epoxy-6β-{[4′-
1
(
3′-chloropyridyl)]carboxamido}morphinan (6). The title com-
D
3
pound was obtained following the general procedure as a light yellow
8.32 (d, J = 5.1 Hz, 2H), 7.45 (d, J = 7.5 Hz, 1H), 7.18 (d, J = 5.1 Hz,
2H), 6.69 (d, J = 8.1 Hz, 1H), 6.54 (d, J = 7.8 Hz, 1H), 4.59 (d, J = 7.2
Hz, 1H), 3.87 (m, 1H), 3.68 (d, J = 15.0 Hz, 1H), 3.48 (d, J = 15.6 Hz,
1H), 3.05 (m, 2H), 2.62 (m, 2H), 2.38 (d, J = 6.0 Hz, 2H), 2.17 (d, J =
6.9 Hz, 2H), 1.81 (m, 2H), 1.58−1.28 (m, 3H), 0.84 (m, 1H), 0.55 (d,
J = 8.1 Hz, 2H), 0.14 (d, J = 4.5 Hz, 2H); 13C NMR (75 MHz,
solid, in 68% yield. [α]25 −155.77° (c 1.0, MeOH). H NMR (300
1
D
MHz, CDCl ) δ 8.61 (m, 1H), 8.51 (d, J = 4.8 Hz, 1H), 7.56 (d, J =
3
9.3 Hz, 1H), 7.39 (m, 1H), 6.72 (d, J = 8.4 Hz, 1H), 6.57 (d, J = 8.1
Hz, 1H), 4.51 (d, J = 6.6 Hz, 1H), 4.04 (m, 1H), 3.10 (d, J = 5.7 Hz,
1
2
H), 3.04 (d, J = 18.3 Hz, 1H), 2.63 (m, 2H), 2.38 (d, J = 6.6 Hz, 2H),
.18 (d, J = 8.1 Hz, 2H), 1.90 (m, 1H), 1.74−1.62 (m, 2H), 1.54−1.47
CD OD) δ 171.8, 150.1 (×2), 147.7, 143.7, 142.0, 132.5, 126.3 (×2),
3
1
(
m, 2H), 0.82 (m, 1H), 0.54 (m, 2H), 0.14 (m, 2H); H NMR (300
125.3, 120.2, 118.7, 93.2, 71.8, 63.8, 60.3, 53.3, 49.0, 45.5, 43.2, 31.8,
+
MHz, CD OD) δ 8.62 (m, 1H), 8.54 (d, J = 4.5 Hz, 1H), 7.50 (m,
31.4, 25.7, 23.7, 10.3, 4.7, 4.3. MS m/z found 462.3 (M + H) . IR
3
−1
1H), 6.62 (m, 2H), 4.51 (d, J = 7.8 Hz, 1H), 3.83 (m, 1H), 3.13 (m,
(KBr, cm ) νmax 3398.9, 3243.8, 3069.3, 1660.3, 1640.0, 1556.9,
1501. 8, 1317. 8, 1130. 3. Mp 210 °C, dec. Anal.
2H), 2.68 (m, 2H), 2.41 (m, 2H), 2.17 (m, 2H), 1.94 (m, 1H), 1.76
(
m, 1H), 1.58 (m, 2H), 1.39 (m, 1H), 0.87 (m, 1H), 0.54 (m, 2H),
(C27H N O ·2HCl·2H O) C, H, N.
31 3 4 2
0
1
6
.16 (m, 2H); 13C NMR (75 MHz, CD OD) δ 167.0, 150.8, 149.1,
17-Cyclopropylmethyl-3,14β-dihydroxy-4,5α-epoxy-6β-[3′-
(pyridine-4″-yl)propanamido]morphinan (11). The title com-
pound was obtained following the general procedure as a yellow solid,
3
45.1, 143.7, 142.1, 132.5, 129.8, 125.4, 124.2, 120.3, 120.7, 92.8, 71.8,
3.7, 60.3, 53.8, 49.0, 45.5, 31.8, 31.4, 25.5, 23.7, 10.3, 4.7, 4.4. MS m/z
+
−1
25
1
found 482.4 (M + H) . IR (KBr, cm ) ν 3198.6, 1653.9, 1498.7,
1
in 49% yield. [α]
CDCl
D
−102.63° (c 1.5, MeOH). H NMR (400 MHz,
max
317. 8, 1123. 9, 1033. 4. Mp 230 °C, dec. Anal.
3
) δ 8.47 (m, 2H), 7.14 (m, 3H), 6.71 (d, J = 8.0 Hz, 1H), 6.53
(
C H ClN O ·2HCl·H O) C, H, N.
(d, J = 8.0 Hz, 1H), 4.30 (d, J = 6.4 Hz, 1H), 3.84 (m, 1H), 3.07 (d, J
= 5.6 Hz, 1H), 3.00 (d, J = 18.4 Hz, 1H), 2.94 (t, J = 7.4 Hz, 2H), 2.58
(m, 2H), 2.48 (t, J = 7.6 Hz, 2H), 2.35 (d, J = 6.4 Hz, 2H), 2.11 (m,
2H), 1.69 (m, 1H), 1.61−1.54 (m, 2H), 1.43 (m, 2H), 0.86 (m, 1H),
2
1
6
28
3
4
2
7-Cyclopropylmethyl-3,14β-dihydroxy-4,5α-epoxy-6β-{[4′-
(
3′-bromopyridyl)]carboxamido}morphinan (7). The title com-
pound was obtained following the general procedure as a light yellow
solid, in 51% yield. [α]25 −141.16° (c 1.0, MeOH). H NMR (300
1
0.52 (d, J = 8.0 Hz, 2H), 0.12 (d, J = 4.8 Hz, 2H). Hydrochloride salt:
D
1
MHz, CDCl ) δ 8.71 (m, 1H), 8.53 (d, J = 5.1 Hz, 1H), 7.48 (d, J =
H NMR (400 MHz, DMSO-d ) δ 9.36 (brs, 1H, exchangeable), 8.82
6
3
9
(
=
.0 Hz, 1H), 7.29 (d, J = 4.5 Hz, 1H), 6.71 (d, J = 8.1 Hz, 1H), 6.56
d, J = 8.4 Hz, 1H), 4.52 (d, J = 6.6 Hz, 1H), 4.03 (m, 1H), 3.09 (d, J
5.7 Hz, 1H), 3.03 (d, J = 18.6 Hz, 1H), 2.65 (m, 2H), 2.36 (d, J =
(brs, 1H, exchangeable), 8.55 (d, J = 4.4 Hz, 2H), 8.22 (d, J = 7.6 Hz,
1H, exchangeable), 7.44 (d, J = 5.2 Hz, 2H), 6.72 (d, J = 8.0 Hz, 1H),
6.63 (d, J = 8.0 Hz, 1H), 6.17 (brs, 1H, exchangeable), 4.51 (d, J = 8.0
Hz, 1H, C −H), 3.83 (m, 1H, C −H), 3.45−3.20 (m, 3H, buried in
6
.0 Hz, 2H), 2.17 (d, J = 8.1 Hz, 2H), 1.89 (m, 1H), 1.74−1.61 (m,
5
6
2
H), 1.53−1.46 (m, 2H), 0.82 (m, 1H), 0.53 (d, J = 7.5 Hz, 2H), 0.13
water peak), 3.10−2.97 (m, 2H), 2.91 (t, J = 7.4 Hz, 2H), 2.84 (m,
1H), 2.48−2.32 (m, 4H), 1.64 (m, 2H), 1.44 (m, 2H), 1.32 (m, 1H),
1.06 (m, 1H), 0.67 (m, 1H), 0.58 (m, 1H), 0.50 (m, 1H), 0.40 (m,
(
d, J = 4.5 Hz, 2H); 13C NMR (75 MHz, CD OD) 168.0, 153.2, 149.5,
3
1
6
47.5, 143.7, 142.1, 132.5, 125.4, 124.3, 120.3, 119.0, 118.7, 92.8, 71.8,
1H); 13C NMR (100 MHz, DMSO-d ) δ 170.44, 146.83 (×2), 141.92,
3.7, 60.3, 53.8, 49.0, 45.5, 31.8, 31.4, 25.5, 23.7, 10.3, 4.7, 4.4. MS m/z
6
+
−1
found 526.6 (M + H) . IR (KBr, cm ) ν 3398.9, 1653.9, 1550.4,
1
141.03, 139.0, 129.49, 124.73 (×2), 120.54, 119.26, 117.72, 89.72,
max
505. 2, 1330. 7, 1123. 9. Mp 235 °C, dec. Anal.
69.49, 61.46, 56.52, 50.44, 46.28, 45.41, 35.33, 30.30, 29.15, 27.14,
+
(
C H BrN O ·2HCl·2H O) C, H, N.
23.45, 22.81, 5.55, 5.03, 2.46. MS m/z found 476.4 (M + H) . IR
26
28
3
4
2
−1
1
7-Cyclopropylmethyl-3,14β-dihydroxy-4,5α-epoxy-6β-{[4′-
(diamond, cm ) ν 3065.4, 1652.1, 1556.5, 1501.4, 1463.3, 1319.1,
max
(
3′-methylpyridyl)]carboxamido}morphinan (8). The title com-
1159.8, 1128.6. Mp 205 °C, dec. Anal. (C H N O ·2HCl·0.5H O)
28
33
3
4
2
pound was obtained following the general procedure as a white solid,
C, H, N.
in 88% yield. [α]25 −141.45° (c 1.0, MeOH). H NMR (300 MHz,
1
D
17-Cyclopropylmethyl-3,14β-dihydroxy-4,5α-epoxy-6β-{2′-
[(pyridine-4″-yl)carboxamido]acetamido}morphinan (12). The
title compound was obtained following the general procedure as a
CDCl ) δ 8.53 (m, 2H), 7.23 (d, J = 5.4 Hz, 1H), 6.87 (d, J = 9.0 Hz,
3
1
H), 6.78 (d, J = 7.8 Hz, 1H), 6.62 (d, J = 7.8 Hz, 1H), 4.48 (d, J = 5.7
white solid, in 74% yield. [α]25 −126.34° (c 1.0, MeOH). H NMR
1
Hz, 1H), 4.12 (m, 1H), 3.14 (d, J = 5.7 Hz, 1H), 3.07 (d, J = 18.9 Hz,
D
1
1
(
H), 2.67 (m, 2H), 2.43 (s, 3H), 2.39 (m, 2H), 2.22 (m, 2H), 1.89 (m,
H), 1.69 (m, 2H), 1.55 (m, 2H), 0.85 (m, 1H), 0.56 (m, 2H), 0.16
(300 MHz, CDCl ) δ 8.55 (d, J = 4.5 Hz, 2H), 8.41 (m, 1H,
3
exchangeable), 7.74 (d, J = 6.9 Hz, 1H, exchangeable), 7.64 (d, J = 4.8
Hz, 2H), 6.67 (d, J = 7.8 Hz, 1H), 6.53 (d, J = 8.1 Hz, 1H), 4.57 (d, J
= 6.6 Hz, 1H), 4.28 (m, 1H), 4.08 (d, J = 13.2 Hz, 1H), 3.82 (m, 1H),
3.03 (m, 2H), 2.58 (m, 2H), 2.35 (d, J = 5.1 Hz, 2H), 2.11 (m, 2H),
1.89 (m, 1H), 1.60 (m, 2H), 1.37 (m, 2H), 0.81 (m, 1H), 0.52 (d, J =
m, 2H); 13 C NMR (75 MHz, CDCl ) δ 167.5, 151.3, 147.0, 143.6,
3
1
5
43.0, 140.3, 131.1, 130.8, 124.1, 121.1, 119.3, 118.3, 92.0, 70.5, 62.3,
9.4, 53.6, 51.4, 47.6, 44.1, 29.7, 24.0, 22.7, 16.7, 9.5, 4.2, 3.9. MS m/z
+
−1
found 462.2 (M + H) . IR (KBr, cm ) ν 3424.8, 1653.9, 1544.0,
1
max
505. 2, 1317. 8, 1130. 3. Mp 211 °C, dec. Anal.
7.5 Hz, 2H), 0.11 (d, J = 3.9 Hz, 2H); 13C NMR (75 MHz, CDCl ) δ
3
(
C H N O ·2HCl·0.2H O) C, H, N.
169.5, 166.0, 150.2 (×2), 142.5, 140.7, 140.3, 131.3, 124.4, 121.5 (×2),
27
31
3
4
2
1
7-Cyclopropylmethyl-3,14β-dihydroxy-4,5α-epoxy-6β-{[4′-
3′-methoxylpyridyl)]carboxamido}morphinan (9). The title
compound was obtained following the general procedure as a light
119.5, 117.8, 92.5, 70.5, 62.4, 59.3, 52.1, 47.8, 44.2, 43.6, 30.9, 30.2,
+
(
24.7, 22.8, 9.6, 4.2, 4.0. MS m/z found 505.7 (M + H) . IR (KBr,
−
1
cm ) ν 3398.9, 1653.9, 1544.0, 1498.7, 1317.8, 1246.7, 1123.9. Mp
max
2
5
yellow solid, in 60% yield. [α]
Hydrochloride salt: H NMR (400 MHz, DMSO-d ) δ 8.88 (brs,
1
−145.47° (c 0.5, MeOH).
215 °C, dec. Anal. (C H N O ·2HCl·3H O) C, H, N.
D
28 32
4
5
2
1
6
17-Cyclopropylmethyl-3,14β-dihydroxy-4,5α-epoxy-6β-[(2′-
H), 8.76 (brs, 1H), 8.71 (d, J = 8.16 Hz, 1H), 8.54 (brs, 1H), 7.80
pyridazine)carboxamido]morphinan (13). The title compound
1
0125
dx.doi.org/10.1021/jm301247n | J. Med. Chem. 2012, 55, 10118−10129