5830
Y. Ida et al. / Bioorg. Med. Chem. 20 (2012) 5810–5831
5.1.143. 80-Amino-6,7-didehydro-3-methoxy-17-
methylquinolino[20,30:6,7]morphinan-14b-ol (32d)
Compound 32d was prepared from compound 23d according to
the procedure used to prepare compound 32a. Yield, 36%; a yellow
amorphous solid.
5.2. Pharmacology
5.2.1. Opioid receptor binding assay
Mouse whole brain without cerebellum and guinea pig cerebel-
lum membranes were prepared as described previously.31 The
l
, d
opioid receptor binding assays were performed with
[3H]DAMGO, [3H]DPDPE ([D-Pen2,5]-Enkephalin) or [3H]U69,593.
Nonspecific binding was measured in the presence of 1 M unla-
IR (KBr): 3437, 2930, 1592, 1497, 1273, 1044 cmꢀ1
.
1H NMR
or j
(300 MHz, CDCl3) d: 1.35–1.46 (1H, m), 2.19–2.31 (2H, m),
2.41–2.48 (1H, m), 2.44 (3H, s), 2.88–3.08 (4H, m), 3.25 (1H, d,
J = 18.3 Hz), 3.54 (1H, d, J = 17.4 Hz), 3.64 (3H, s), 3.67 (1H, d,
J = 17.4 Hz), 4.63 (1H, br s), 6.60 (1H, dd, J = 2.7, 8.4 Hz), 6.80
(1H, dd, J = 1.2, 7.5 Hz), 6.90 (1H, d, J = 2.4 Hz), 6.94 (1H, dd,
J = 1.2, 8.1 Hz), 7.00 (1H, d, J = 8.4 Hz), 7.16 (1H, t, J = 7.8 Hz),
7.55 (1H, s), two protons (NH2) were not observed. 13C NMR
(75 MHz, CDCl3) d: 24.0, 36.0, 36.6, 39.3, 40.5, 42.9, 45.6, 55.0,
61.8, 69.5, 109.0, 111.4, 111.5, 115.3, 126.0, 127.5, 127.6,
128.1, 128.3, 135.0, 136.9, 141.3, 143.1, 154.3, 158.1.
l
beled DAMGO, DPDPE or U-69,593. Ki value was calculated accord-
ing to the Cheng–Prusoff equation.32
Acknowledgments
This work was supported by JSPS KAKENHI (23790139) [Grant-
in-Aid for Young Scientists (B)]. We also acknowledge the Institute
of Instrumental Analysis of Kitasato University, School of Pharmacy
for its facilities.
HRMS (ESI) Calcd for
402.2180.
C
25H28N3O2 [M+H]+: 402.2182. Found:
References and notes
5.1.144. 6,7-Didehydro-80-(N,N-dimethylamino)-3-methoxy-17-
methylquinolino[20,30:6,7]morphinan-14b-ol (33d)
Compound 33d was prepared from compound 32d according to
the procedure used to prepare compound 33a. Yield, 94%; a yellow
oil.
1. Dhawan, B. N.; Cesselin, F.; Raghubir, R.; Reisine, T.; Bradley, P. B.; Portoghese,
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IR (neat): 3409, 2936, 1499, 1273, 1043, 752 cmꢀ1 1H NMR
.
(300 MHz, CDCl3) d: 1.35–1.46 (1H, m), 2.19–2.31 (2H, m),
2.40–2.48 (1H, m), 2.44 (3H, s), 2.87–3.02 (4H, m), 3.09 (6H, s),
3.25 (1H, d, J = 18.0 Hz), 3.59 (1H, d, J = 17.1 Hz), 3.61 (3H, s),
3.77 (1H, d, J = 17.1 Hz), 6.60 (1H, dd, J = 2.7, 8.4 Hz), 6.94 (1H,
d, J = 2.7 Hz), 6.97 (1H, dd, J = 1.2, 7.4 Hz), 6.99 (1H, d,
J = 8.4 Hz), 7.17 (1H, dd, J = 1.3, 8.1 Hz), 7.26 (1H, t, J = 7.8 Hz),
7.59 (1H, s),
a
proton (OH) was not observed. 13C NMR
(75 MHz, CDCl3) d: 24.0, 35.9, 36.6, 39.7, 40.7, 42.9, 44.5 (2C),
45.6, 54.9, 61.7, 69.5, 111.0, 112.1, 114.3, 119.9, 125.4, 127.46,
127.51, 128.3, 128.5, 135.4, 140.8, 141.3, 149.6 154.6, 158.1.
HRMS (ESI) Calcd for
430.2504.
C
27H32N3O2 [M+H]+: 430.2495. Found:
5.1.145. 6,7-Didehydro-80-(N,N-dimethylamino)-17-
methylquinolino[20,30:6,7]morphinan-3,14b-diol (34d)
Compound 34d was prepared from compound 33d according to
the procedure used to prepare compound 24a. Yield, 87%; a yellow
oil.
13. Nagase, H.; Kawai, K.; Hayakawa, J.; Wakita, H.; Mizusuna, A.; Matsuura, H.;
Tajima, C.; Takezawa, Y.; Endoh, T. Chem. Pharm. Bull. 1998, 46, 1695.
14. Nagase, H.; Yajima, Y.; Fujii, H.; Kawamura, K.; Narita, M.; Kamei, J.; Suzuki, T.
Life Sci. 2001, 68, 2227.
IR (neat): 3348, 2937, 1446, 1280, 1051, 754 cmꢀ1 1H NMR
.
(300 MHz, CDCl3) d: 1.16–1.26 (1H, m), 2.07–2.21 (2H, m), 2.36–
2.42 (1H, m), 2.41 (3H, s), 2.82–3.06 (4H, m), 2.99 (6H, s), 3.18
(1H, d, J = 18.0 Hz), 3.50 (1H, d, J = 17.4 Hz), 3.67 (1H, d,
J = 17.4 Hz), 6.45 (1H, dd, J = 2.4, 8.4 Hz), 6.69 (1H, d, J = 2.4 Hz),
6.85 (1H, d, J = 8.4 Hz), 6.97 (1H, dd, J = 1.2, 7.5 Hz), 7.13 (1H, dd,
J = 1.2, 7.8 Hz), 7.22 (1H, t, J = 7.8 Hz), 7.55 (s, 1H), two protons
(OH) were not observed. 13C NMR (75 MHz, CDCl3) d: 23.9, 35.8,
36.3, 39.2, 40.4, 43.0, 44.6 (2C), 45.6, 61.7, 69.4, 112.6, 113.6,
114.7, 120.3, 125.3, 126.8, 127.7, 128.3, 128.5, 135.7, 140.6,
141.2, 149.6, 154.7, 155.0. HRMS (ESI) Calcd for C26H30N3O2
[M+H]+: 416.2338. Found: 416.2318.
15. Takemori, A. E.; Sultana, M.; Nagase, H.; Portoghese, P. S. Life Sci. 1992, 50,
1491.
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Chem. Lett. 2010, 20, 6302.
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49, 2081.
25. Yamamoto, N.; Fujii, H.; Nemoto, T.; Nakajima, R.; Momen, S.; Izumimoto, N.;
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5.1.146. 6,7-Didehydro-80-(N,N-dimethylamino)-17-
methylquinolino[20,30:6,7]morphinan-3,14b-diol hydrochloride
(SYK-363)
SYK-363 was prepared from compound 34d according to the
procedure used to prepare SYK-27.
Yield, quant.; a pale yellow amorphous solid. Mp: 234–236 °C
(dec). Anal. Calcd for C26H29N3O2ꢁ2.0HClꢁ1.7H2O: C, 60.16; H,
6.68; N, 8.10. Found: C, 60.21; H, 6.74; N, 8.14.