Synthesis of quinolinomorphinan-4-ol derivatives as δ opioid receptor agonists

Article abstract of DOI:10.1016/j.bmc.2011.11.047

The previously reported morphinan derivative SN-28 showed high selectivity and agonist activity for the δ opioid receptor. In the course of examining the structure-activity relationship of SN-28 derivatives, the derivatives with the 4-hydroxy group (SN-24

Full text of DOI:10.1016/j.bmc.2011.11.047

Bioorganic & Medicinal Chemistry 20 (2012) 949–961
Contents lists available at SciVerse ScienceDirect
Bioorganic & Medicinal Chemistry
journal homepage: www.elsevier.com/locate/bmc
Synthesis of quinolinomorphinan-4-ol derivatives as d opioid receptor agonists
Yoshihiro Ida a, Toru Nemoto a, Shigeto Hirayama a, Hideaki Fujii a, Yumiko Osa a, Masayuki Imai b,
Takashi Nakamura b, Toshiyuki Kanemasa b, Akira Kato b, Hiroshi Nagase a,
⇑
a School of Pharmacy, Kitasato University, 5-9-1, Shirokane, Minato-ku, Tokyo 108-8641, Japan
b Pain & Frontier, Discovery Research Laboratories, Shionogi & Co., Ltd, 1405, Gotanda, Koka-cho, Koka, Shiga 520-3423, Japan
a r t i c l e i n f o
a b s t r a c t
Article history:
The previously reported morphinan derivative SN-28 showed high selectivity and agonist activity for the
d opioid receptor. In the course of examining the structure–activity relationship of SN-28 derivatives, the
derivatives with the 4-hydroxy group (SN-24, 26, 27) showed higher selectivities for the d receptor over
Received 15 November 2011
Revised 22 November 2011
Accepted 22 November 2011
Available online 1 December 2011
the
l receptor than the corresponding SN-28 derivatives with the 3-hydroxy group (SN-11, 23, 28). Deriv-
atives with the 4-hydroxy group showed potent agonist activities for the d receptor in the [35S]GTP
c
S
binding assay. Although the 17-cyclopropylmethyl derivative (SN-11) with a 3-hydroxy group showed
the lowest selectivity for the d receptor among the morphinan derivatives, the agonist activity toward
the d receptor was the most potent for candidates with the 3-hydroxy group.
Ó 2011 Elsevier Ltd. All rights reserved.
Keywords:
Opioid
Naltrexone
Analgesics
d Receptor
1. Introduction
also reported the highly selective d-agonist, (ꢀ)-TAN-67,17,18 which
was designed from the d-selective antagonist, naltrindole (NTI)16,19
Three types of opioid receptors (
l, d,
j
) are now well estab-
by removing postulated accessory sites,20 that is, the 4,5-epoxy ring
and the 10-methylene bridge and converting the indole structure to
a quinoline (Fig. 3).
lished not only by pharmacological studies, but also through
molecular biological studies.1 For the past three decades, consider-
able efforts have been expended to obtain an opioid
j
-selective
In an earlier effort to synthesize novel d opioid receptor ago-
nists, we reviewed the accessory sites of the 4,5-epoxymorphinan
skeleton.21 This study led us to conclude that only the 4,5-epoxy
ring would be an accessory site. We subsequently reported a novel
d-agonist, SN-28 (Fig. 4), which showed about 15 times and 334
times more potent agonist activities than (ꢀ)-TAN-67 and SNC80,
respectively, and had almost equivalent selectivity to (ꢀ)-TAN-67
in in vitro assays.21 The discovery of SN-28 led us to investigate
the structure–activity relationships for SN-28 derivatives to obtain
more selective agonists for the d receptor. Usually, the 3-hydroxy
group and the 17-nitrogen of the morphinan derivatives have been
considered as the key functionalities that play important roles for
associations between the drug molecule and the receptor site.22,23
The influences of the transposition of the 3-hydroxy group to
the 4-position have already been examined in NTI derivatives,
agonist without undesirable morphine-like side effects like addic-
tion. In 1982, U-50,488H was discovered to be a highly selective
j
-agonist by researchers at Upjohn (now merged with Pfizer).2–4
Since then, numerous research groups modified the structure of
U-50,488H and succeeded in preparing more selective and potent
j
-agonists. However, all these compounds have structures similar
to that of U-50,488H, with the [N–C–C–N (sp2)] pharmacophore
sequence (Fig. 1), and showed severe aversion like psychotomi-
metic effects.5–7 We recently reported a novel
j-agonist, TRK-820
(nalfurafine hydrochloride) which has a structure quite different
from U-50,488H (Fig. 1).8–10
TRK-820 showed neither addiction nor aversion and was
launched in Japan as an antipruritic agent for kidney dialysis
patients in 2009.10,11 This is the first opioid drug that does not cause
addiction. Now that we have obtained a selective j-agonist without
morphine-like side effects and aversion, our next target was a highly
selective and potent d-agonist. Nonpeptide d-opioid agonists
BW373U86,12 SNC80,13,14 and OMI15,16 were described (Fig. 2). We
OH
Cl
Cl
O
O
N
N
N
CH3
O
·HCl
O
CH3
N
OH
TRK-820
Abbreviations: CPM, cyclopropylmethyl; CBM, cyclobutylmethyl; c-Pen,
cyclopentyl.
U-50,488H
⇑
Corresponding author. Tel.: +81 3 5791 6372; fax: +81 3 3442 5707.
E-mail address: nagaseh@pharm.kitasato-u.ac.jp (H. Nagase).
Figure 1. The structures of U-50,488H and TRK-820.
0968-0896/$ - see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmc.2011.11.047

950
Y. Ida et al. / Bioorg. Med. Chem. 20 (2012) 949–961
O
O
Et2N
Et2N
H
N
N
H
OH
H3C
OH
OCH3
N
N
N
CH3
CH3
N
H
O
H3C
H3C
OH
OMI
SNC80
BW373U86
Figure 2. The structures of BW373U86, SNC80, and OMI.
H
OH
H
OH
N
N
(a)
H3C
N
(b)
O
O
N
O
N
O
O
O
N
N
H
O
OCH3
OCH3
OCH3
N
OH
TAN-67
OH
4
3
5
NTI
H
H
Figure 3. The structures of TAN-67 and NTI.
N
(c)
(d)
O
N
OCH3
OR
8
4'
9
H
5'
8'
H
H3C 17
7
6
H
6
6'
7'
R
R
7
R = CH3:
14
N
N
N
(e)
13
16
10
11
15
R = H: SN-11
N
5
N
N
OH
12
4
H
N
H
1
3
OH
SN-28
OH
2
N
(f)
(d)
2
1
6
N
O
Figure 4. The structures of SN-28 and compounds 1 and 2.
OR
OCH3
R = CH3: 9
R = H: SN-23
8
(e)
which influenced the affinity and the selectivity for the d recep-
tor.24 NTI derivatives with the 4-hydroxy group or 3-methoxy
group showed lower binding affinity and selectivity for the d recep-
tor than NTI itself, NTI derivatives with the 3-hydroxy group, or the
4-methoxy group. The conversion of 17-substituents was also
examined in NTI and TAN-67 derivatives.15,17,25 In NTI derivatives,
the 17-cyclopropylmethyl (CPM) derivative showed the highest
binding affinity and high selectivity for the d receptor. On the other
hand, although the 17-methyl derivative showed the highest selec-
tivity for the d receptor in TAN-67 derivatives, the 17-CPM deriva-
tive showed highest affinity for the d receptor.
However, as the roles of the 3-hydroxy group and the 17-sub-
stituents have not yet been examined in SN-28 derivatives, we
especially focused on the influence of the 17-substituents and
the position of the hydroxy group in the phenol ring on the selec-
tivities and agonistic activities for the d receptor. So, we synthe-
sized 3-hydroxy derivatives 1 and 4-hydroxy variants 2 with
various 17-substituents (Fig. 4). Herein, we report the synthesis
of SN-28 derivatives and their pharmacologies.
Scheme 1. Reagents and conditions: (a) SOCl2, pyridine, 0 °C to rt, 71%; (b) PtO2, H2,
CH3OH, rt; (c) 2 M HCl, 50 °C, 63% (2 steps from compound 4); (d) 2-aminobenz-
aldehyde, CH3SO3H, C2H5OH, reflux, 96% (7), 98% (9); (e) BBr3, CH2Cl2, 0 °C to rt, 97%
(SN-11), 84% (SN-23); (f) 48% HBr, CH3OH, PtO2, H2, rt, 32%.
amount of CH3SO3H in C2H5OH.17 The methoxy groups in the
resulting compounds 7 and 9 were demethylated with BBr3 in
CH2Cl2 to afford SN-11 and SN-23, respectively (Scheme 1).32
The 17-CPM group of compound
5 was converted to a
17-methyl group by a previously reported method.33,34 The result-
ing 17-methyl derivative 11 was converted to SN-28 as shown in
Scheme 2.17,32
To examine the influence of 17-substituents on the selectivities
for the d receptor, we converted the 17-CPM substituent to benzyl
(SYK-259), phenethyl (SYK-260), cyclobutylmethyl (CBM) (SYK-
261), and cyclopentylmethyl (c-Pen-methyl) (SYK-262) substitu-
ents. These derivatives were synthesized from compound 10 by
the reported method (Scheme 3).35
To obtain the morphinan derivatives with a 4-hydroxy group
(SN-24, 26, 27), compound 28 without a 3-hydroxy group, which
was derived from naltrexone,36 was transformed into the 14-H
compound 31 according to a previously reported method (Scheme
4).29 The resulting compound 31 was hydrolyzed to compound 32.
17-Isobutyl derivative 33 was obtained by the reductive cleavage
of the 17-cyclopropyl moiety in compound 31.30,31 17-Methyl
derivative 36 was obtained by the same method as shown in
Scheme 2 (Scheme 4). The resulting compounds 32, 33, and 36
were converted to SN-27, 24, and 26, respectively, by the reductive
cleavage of the 4,5-epoxy ring with zinc in acetic acid28,37 followed
by the formation of a quinoline ring with 2-aminobenzaldehyde in
2. Results
2.1. Chemistry
Three compounds (SN-11, SN-23, and SN-28) with different
17-substituents (CPM, isobutyl, methyl groups) were synthesized
(Schemes 1 and 2). The 14-OH-morphinan 3 was synthesized from
naltrexone by the reported method,26–28 and 14-H-morphinan 6
was synthesized from 3 in three steps (Scheme 1).29 The 17-isobu-
tyl derivative 8 was obtained by the reductive cleavage of the
17-cyclopropyl moiety in compound 6.30,31 Compounds 7 and 9
were synthesized from the respective morphinan derivatives 6
and 8 with 2-aminobenzaldehyde in the presence of a catalytic
the presence of
(Scheme 4).
a catalytic amount of CH3SO3H in C2H5OH

Y. Ida et al. / Bioorg. Med. Chem. 20 (2012) 949–961
951
H
H
H
H
R
H3C
H3C
N
N
N
N
O
d)
O
(a)
c)
b)
O
N
O
O
OCH3
R = Troc: 10
11
OCH3
OCH3
OR
13
5
R = CH3:
R = H: SN-28
12
e)
R = CH3:
Scheme 2. Reagents and conditions: (a) Troc-Cl, K2CO3, (CHCl2)2, reflux, 53%; (b) LiAlH4, THF, 0 °C to rt, 65%; (c) 2 M HCl, 80 °C, 79%; (d) 2-aminobenzaldehyde, CH3SO3H,
C2H5OH, reflux, 95%; (e) BBr3, CH2Cl2, 0 °C to rt, 78%.
H
H
H
Troc
R
N
HN
N
(a)
(b) or (c) or (d)
or (e)
O
O
O
O
O
O
OCH3
OCH3
OCH3
10
14
R = benzyl: 15
R = phenethyl: 16
R = CBM: 17
R = c-Pen-methyl: 18
H
H
H
R
R
R
N
(f)
(g)
N
(h)
N
O
OCH3
N
N
OCH3
OH
R = benzyl: SYK-259
R = benzyl: 19
R = phenethyl: 20
R = CBM: 21
R = benzyl: 23
R = phenethyl: SYK-260
R = CBM: SYK-261
R = phenethyl: 24
R = CBM: 25
R = c-Pen-methyl: SYK-262
R = c-Pen-methyl: 22
R = c-Pen-methyl: 26
Scheme 3. Reagents and conditions: (a) 12 M KOH, DMSO, reflux, quant.; (b) BnBr, K2CO3, DMF, rt, 88%; (c) PhCH2CHO, NaBH(OAc)3, CH2Cl2, rt, 91%; (d) CBM-Br, K2CO3, DMF,
60 °C, 65%; (e) cyclopentanecarbaldehyde, AcOH, NaBH(OAc)3, CH2Cl2, rt, 90%; (f) 2 M HCl, 80 °C, 82% (19), quant. (20), quant. (21), quant. (22); (g) 2-aminobenzaldehyde,
CH3SO3H, C2H5OH, reflux, 86% (23), 90% (26); (h) BBr3, CH2Cl2, 0 °C to rt, 88% (SYK-259), 76% (SYK-260: two steps), 38% (SYK-261: two steps), 93% (SYK-262).
To compare the pharmacological profiles of the compounds
with and without a 4,5-epoxy ring, the 4,5-epoxymorphinan deriv-
ative (SN-25) was also synthesized from compound 4029 by the
same method as that shown in Scheme 1 (Scheme 5).
17-phenethyl) showed lower affinities for the d receptor than
SN-11 (with 17-CPM), and SYK-261 (with 17-CBM), 262 (with
17-c-Pen-methyl) which showed almost equivalent affinities for
the d receptor as SN-11.
With regard to the functional assay, the 3-OH-morphinan deriv-
atives (SN-11, 23, and 28) showed very high agonist activities for
the d receptor (Table 2) with EC50 values = 0.018, 0.06, and
0.047 nM, respectively. They displayed over 10 times greater
potency than (ꢀ)-TAN-67 (EC50 = 0.70 nM) and SNC80
(EC50 = 15.7 nM), compounds which are widely used as nonpeptide
d agonists. The 4-OH-morphinan derivatives (SN-24, 26, and 27)
also showed potent d agonist activities (EC50 = 2.34, 1.77, and
0.19 nM, respectively). Although these three activities were lower
than those of the corresponding 3-OH-morphinan derivatives, only
SN-27 (with the 17-CPM functionality) showed more potent activ-
ity than (ꢀ)-TAN-67. All these tested compounds showed sufficient
full agonistic activities compared to endogeneous opioid peptide
methionine–enkephalin (Met–enk).
2.2. Pharmacology
Table 1 shows the binding affinities and selectivities of the syn-
thesized compounds toward opioid
poses of comparison, the results of d antagonist NTI and d agonist
l, d, and j receptors. For pur-
(ꢀ)-TAN-67 are also described. The standard d antagonist, NTI (
l
j
/
/
d = 81.5, /d = 197.3,
j
/d = 48.3) and agonist, (ꢀ)-TAN-67
(l
d = 508.7) also showed high selectivity for the d receptor in this
binding assay. The 4-OH-morphinan derivatives, SN-24, 26, and
27, showed higher selectivities for the d receptor than the corre-
sponding 3-OH-morphinan derivatives (SN-23, 28, and 11).
SN-24 showed high
l
/d selectivity and
j
/d selectivity, SN-26
/d selectiv-
showed high /d selectivity, and SN-27 showed high
j
l
ity. In the 3-OH-morphinan derivatives with different 17-substitu-
ents, SYK-259-262 showed lower selectivities for the d receptor
than SN-28, whose selectivity for the d receptor was comparable
with that of NTI. In the 17-CPM derivatives, including SN-25 with
the 4,5-epoxy ring, SN-27 showed the best selectivity for the d
3. Discussion
We synthesized a series of SN-28 derivatives and compared
them with SN-28 for d-selectivity and agonist activity to clarify
the SAR of 17-substituents and the position of the hydroxy group
in the phenol ring. The 4-OH-morphinan derivatives (SN-24, 26,
receptor [SN-27 (with
a 4-hydroxy group) > SN-25 (with a
4,5-epoxy ring) > SN-11 (with a 3-hydroxy group)]. On the other
hand, the 3-OH-morphinan derivatives, SN-11, 23, and 28, showed
high affinities for the d receptor. Although SN-24, 26, and 27 with
the 4-hydroxy group showed sufficient affinities for the d receptor,
their affinities were lower than those of the 3-OH-morphinan
derivatives SN-11, 23, and 28. In compounds with the different
17-substituents, SYK-259 (with 17-benzyl) and 260 (with
and 27) showed higher
l/d selectivities than the corresponding
3-OH-morphinan derivatives (SN-11, 23, and 28). Previously
reported SN-11 bearing a 17-CPM group21 showed the most potent
agonist activity among these compounds, but the selectivity was
low. This tendency of SN-11 was also observed in the series of
TAN-67 derivatives.17 Although the potent agonistic activity of

952
Y. Ida et al. / Bioorg. Med. Chem. 20 (2012) 949–961
OH
OH
OH
N
N
N
(a)
(b)
O
O
N
O
O
O
O
O
N
N
OH
naltrexone
N
28
27 Ph
OH
H
H
N
O
N
O
N
(d)
O
O
N
(c)
(e)
(f)
O
O
O
O
O
O
O
29
30
31
32
H
H
N
O
N
(g)
O
O
O
O
h)
31
33
H
R
N
H
O
O
H3C
(f)
N
O
O
O
34
35
R = Troc:
R = CH3:
36
(i)
H
H
R
H
R
R
N
N
N
(j)
(k)
N
O
O
O
OH
OH
R = CPM: SN-27
R = isobutyl: SN-24
R = CH3: SN-26
R = CPM: 32
R = isobutyl:
R = CH3: 36
37
R = CPM:
R = isobutyl: 38
39
33
R = CH3:
Scheme 4. Reagents and conditions: (a) 5-chloro-1-phenyl-1H-tetrazole, K2CO3, DMF, rt, quant.; (b) 10% Pd/C, AcOH, H2, 70 °C, 90%; (c) (CH2OH)2, p-toluenesulfonic acid
monohydrate, toluene, reflux, 89%; (d) SOCl2, pyridine, 0 °C to rt, 73%; (e) PtO2, CH3OH, H2, rt, quant.; (f) 2 M HCl, 80 °C, 85% (32), 81% (36); (g) 48% HBr, CH3OH, PtO2, H2, rt,
44%; (h) Troc-Cl, K2CO3, (CHCl2)2, reflux, 80%; (i) LiAlH4, THF, 0 °C to rt, quant.; (j) Zn, AcOH, reflux, quant. (37), 81% (38), 94% (39); (k) 2-aminobenzaldehyde, CH3SO3H,
C2H5OH, reflux, 86% (SN-27), 78% (SN-24), 78% (SN-26) .
H
H
H
N
N
(a)
(b)
N
O
N
O
N
O
O
OCH3
OCH3
OH
SN-25
40
41
Scheme 5. Reagents and conditions: (a) 2-aminobenzaldehyde, CH3SO3H, C2H5OH, reflux, 77%; (b) BBr3, CH2Cl2, 0 °C to rt, 40%.
CPM derivatives may result from the electron-donating property of
(SN-28) showed the most balanced and highest selectivity for the
d receptor, as well as the 17-methyl compound in KNT-127 (a po-
tent d opioid receptor agonist) derivatives.35
the CPM group,39 the CPM derivative with a 4-hydroxy group (SN-
27) showed very high selectivity for the d receptor. With regard to
the role of 17-nitrogen substituent, the order of
l
/d selectivity in 4-
The binding affinities of 4-OH-morphinan derivatives (SN-24,
26, and 27) were lower than those of the corresponding 3-OH-mor-
phinan derivatives (SN-11, 23, and 28). Likewise, the d-agonist
activities of 4-OH morphinan derivatives were less potent than
3-OH morphinan derivatives. However, SN-27 (with a 4-OH substi-
OH-morphinan derivatives (SN-24, 26, and 27) is ranked as fol-
lows: SN-27 (CPM) > SN-24 (isobutyl) > SN-26 (methyl). On the
other hand, in the corresponding 3-OH-morphinan derivatives
(SN-11, 23, and 28), the order of
l/d selectivity is ranked as fol-
lows: SN-23 (isobutyl) > SN-28 (methyl) > SN-11 (CPM). These re-
sults suggest that the influence of 17-substituents on the
selectivities for the d receptor is quite different between the 4-
tuent) showed not only 2.8 times higher l/d selectivity but also 3.7
times more potent activity than (ꢀ)-TAN-67. As shown in Table 2
and 3-OH morphinan derivatives (SN-11, 23, and 28) showed very
high agonist activities for the d receptor. To the best of our knowl-
edge, SN-11 was one of the most potent d-agonists. These results
suggest that the 4-hydroxy group may be related to the selectivity
OH- and 3-OH-morphinan derivatives. Considering the
j/d selec-
tivity ratio, in the derivatives with some 17-substituents [(Table
1); SN-11, 23, 28, and SYK-259-262], the 17-methyl compound

Y. Ida et al. / Bioorg. Med. Chem. 20 (2012) 949–961
953
Table 1
The binding affinities and selectivities of SN-11, 23–28, SYK-259–262 for opioid
l
, d and
j
receptorsa
Compounds
17-Substituents
The position of hydroxy group
Affinity (Ki, nM)
Selectivity
l
d
j
l
/d
j/d
NTI
23.6
284.1
0.77
23.6
322.8
13.0
51.8
147.8
11.5
23.2
76.9
12.5
6.31
20.1
0.29
1.44
0.19
0.19
1.22
0.43
1.00
0.27
0.14
0.29
12.4
4.68
0.12
0.35
14.0
732.5
0.36
4.41
516.2
14.8
263.4
17.5
10.2
14.3
50.0
17.9
81.5
197.3
4.1
48.3
508.7
1.9
(ꢀ)-TAN-67
SN-11
SN-23
SN-24
SN-25c
SN-26
SN-27
SN-28
CPM
3-OH
3-OH
4-OH
3-OH
4-OH
4-OH
3-OH
3-OH
3-OH
3-OH
3-OH
3-OH
Isobutyl
Isobutyl
CPM
Methyl
CPM
Methyl
Methyl
Benzyl
Phenethyl
CBM
124.3
264.6
30.2
51.8
547.6
82.4
81.3
6.2
23.2
423.1
34.4
263.4
64.8
72.9
50.2
4.0
b
SN-28
SYK-259b
SYK-260b
SYK-261b
SYK-262b
2.7
54.6
57.7
3.8
9.26
10.2
1.07
3.54
c-Pen-methyl
a
Ref. 21 Evaluated by ability of each compound to displace [3H]DAMGO (
guinea pig cerebrum ( ).
Evaluated by ability of each compound to displace [3H]DAMGO (
l
), [3H]DADLE (d), and [3H]U-69,593 (
j) binding to membranes of rat cerebrum (l and d) or the
j
b
l
), [3H]DPDPE (d), and [3H]U-69,593 (
j) binding to membranes of mouse whole brain without cerebellum
(
l
and d) or the guinea pig cerebellum (j).
4,5-Epoxymorphinan derivative.
c
Table 2
d Agonist activities of SN-11, 23, 24, and 26–28a
Compounds
EC50 (nM)
Compounds
17-substituents
The position of hydroxy group
EC50 (nM)
(ꢀ)-TAN-67
SNC80
0.7
15.7b
1.03
SN-11
SN-23
SN-24
SN-26
SN-27
SN-28
CPM
3-OH
3-OH
4-OH
4-OH
4-OH
3-OH
0.018
0.06
2.34
1.77
0.19
0.047
Isobutyl
Isobutyl
Methyl
CPM
[Met5]-enkephalin
Methyl
a
Membranes were incubated with [35S] GTP
cS and GDP with the compound. The d human recombinant cell membrane (HEK-293) was used in this assay. (ꢀ)-TAN-67 and
[Met5]-enkephalin were used as the standard d agonists.
b
Ref. 38
for the d receptor while the 3-hydroxy group may be related to the
potent agonist activity for the d receptor. This is the first report that
the 4-OH derivatives with the quinolinomorphinan skeleton
showed higher selectivities for the d receptor than the 3-OH
derivatives.
values (ppm) related to tetramethylsilane (TMS). Mass spectra
(MS) were obtained on a JMS-AX505HA or JMS-700 MStation and
JMS-100LP instrument by applying a fast atom bombardment
(FAB) ionization method or an electrospray ionization (ESI) meth-
od. Elemental analyses were determined with a Yanako MT-5
and JM10 for carbon, hydrogen, and nitrogen. The progress of the
reaction was determined on Merck Silica Gel Art. 5715. Column
chromatographies were carried out using Kanto Silica Gel 60 N
4. Conclusion
(40–100 lm).
SN-28 derivatives with the 4-hydroxy group (SN-24, 26, 27)
showed higher selectivities for the d receptor over the
l receptor
5.1.1. 17-Cyclopropylmethyl-8,14-dehydro-3-methoxy-
than the corresponding morphinan derivatives with the 3-hydroxy
group (SN-11, 23, 28). This is the first report that the 4-OH deriva-
tives with the quinolinomorphinan skeleton showed higher selec-
tivities for the d receptor than the 3-OH derivatives. Moreover the
4-OH-morphinan derivatives showed high agonist activities for
the d receptor. Among them, the 17-CPM derivative (SN-27) showed
the highest selectivity for the d receptor; on the other hand, although
the 17-CPM derivative (SN-11) with a 3-hydroxy group showed the
lowest selectivity for the d receptor in the morphinan derivatives, its
agonist activity for the d receptor was the most potent.
morphinan-6-spiro-20-(10,30-dioxolane) (4)
To a stirred solution of 3 (7 g, 18.2 mmol) in pyridine (70 mL) was
added SOCl2 (10.3 mL, 141 mmol) and stirred at 0 °C under an Ar
atmosphere. After 10 min, the reaction mixture was stirred at rt
for 19 h. The reaction mixture was evaporated in vacuo. The result-
ing mixture was basified (pH 9) with saturated NaHCO3 aqueous
solution, and extracted with CHCl3 three times. The combined or-
ganic extracts were washed with brine, dried over Na2SO4, and evap-
orated in vacuo. The residue was chromatographed on silica gel
(200 g, CHCl3/MeOH = 25/1) to give 4 (4.7 g, 71%) as a brown amor-
phous solid. IR (film): 2910, 1609, 1500 cmꢀ1 1H NMR (CDCl3,
;
5. Experimental
5.1. Chemistry
400 MHz) d: 0.05–0.16 (2H, m), 0.44–0.55 (2H, m), 0.83–0.95 (1H,
m), 1.30 (1H, d, J = 12.0 Hz), 2.10 (1H, dd, J = 1.6, 14.0 Hz), 2.11
(1H, d, J = 14.0 Hz), 2.20–2.47 (6H, m), 2.50 (1H, dd, J = 6.4,
12.4 Hz), 2.77 (1H, dd, J = 2.0, 15.6 Hz), 2.87 (1H, dd, J = 6.0,
17.6 Hz), 3.65 (1H, d, J = 6.0 Hz), 3.76 (3H, s), 3.87–3.93 (2H, m),
3.94–4.08 (2H, m), 5.57 (1H, t, J = 3.8 Hz), 6.68 (1H, dd, J = 2.8,
8.0 Hz), 6.70 (1H, d, J = 2.8 Hz), 6.97 (1H, d, J = 8.0 Hz). MS (ESI) m/
z = 368 [M+H]+. HRMS (ESI) Calcd for C23H30NO3 [M+H]+:
368.2226; Found 368.2212.
Melting points were determined on a Yanako MP-500P melting
point apparatus and were uncorrected. Infrared (IR) spectra were
recorded on a JASCO FT/IR-460Plus. Nuclear magnetic resonance
(NMR) spectra were recorded on a Varian Mercury-300 or Varian
NMR System-400 for 1H NMR. Chemical shifts were reported as d

954
Y. Ida et al. / Bioorg. Med. Chem. 20 (2012) 949–961
5.1.2. 17-Cyclopropylmethyl-3-methoxymorphinan-6-spiro-20-
(10,30-dioxolane) (5)
To a stirred solution of 4 (4.3 g, 11.7 mmol) in MeOH (90 mL)
was added PtO2 (800 mg, 3.5 mmol) and stirred at rt under a H2
atmosphere. After 20 h with stirring, the reaction mixture was fil-
terated and evaporated in vacuo. The residue was used for the next
reaction without purification.
IR (film): 2919, 1608, 1497 cmꢀ1 1H NMR (CDCl3, 400 MHz) d:
;
0.03–0.12 (2H, m), 0.40–0.48 (2H, m), 0.82–0.94 (1H, m), 1.46 (1H,
d, J = 12.4 Hz), 1.85 (1H, dt, J = 4.4, 12.8 Hz), 2.18 (1H, dt, J = 2.8,
12.4 Hz), 2.43 (2H, dt, J = 2.8, 12.8 Hz), 2.51 (1H, dd, J = 5.6,
12.8 Hz), 2.66–2.77 (2H, m), 2.81 (1H, dd, J = 6.0, 17.6 Hz), 2.86–
2.96 (2H, m), 3.01 (1H, d, J = 18.4 Hz), 3.50 (1H, dd, J = 3.2,
6.0 Hz), 3.84 (1H, d, J = 17.6 Hz), 6.59 (1H, dd, J = 2.4, 8.0 Hz), 6.91
(1H, d, J = 2.4 Hz), 6.91 (1H, d, J = 8.0 Hz), 7.18–7.27 (2H, m),
7.36–7.42 (1H, m), 7.48 (1H, m), 7.61 (1H, dd, J = 2.0, 7.2 Hz), a pro-
ton (OH) was not observed. MS (ESI) m/z = 397 [M+H]+. HRMS (ESI)
Calcd for C27H29N2O [M+H]+: 397.2280. Found 397.2262.
(SN-11)
5.1.3. 17-Cyclopropylmethyl-3-methoxymorphinan-6-one (6)
The solution of 5 (30 mg, 0.08 mmol) in 2 M HCl (1.5 mL) was
stirred at 80 °C under an Ar atmosphere. After 1 h with stirring,
the reaction mixture was basified (pH 9) with saturated NaHCO3
aqueous solution, and extracted with CHCl3 three times. The com-
bined organic extracts were washed with brine, dried over Na2SO4,
and evaporated in vacuo. The residue was purified by preparative
TLC (CHCl3/MeOH = 10/1) to give 6 (63% from compound 4 in 2
Mp 224–226 °C (dec); Anal. Calcd for C27H28N2Oꢁ2HClꢁ1.5H2O:
C, 65.32; H, 6.70; N, 5.64. Found: C, 65.10; H, 6.80; N, 5.69.
5.1.6. 17-Isobutyl-3-methoxymorphinan-6-one (8)
steps) as a colorless oil. IR (neat): 2920, 1712, 1502 cmꢀ1
;
1H
To a stirred solution of 6 (100 mg, 0.27 mmol) in MeOH (2 mL)
were added 48% HBr (2.4 mL) and PtO2 (320 mg, 0.11 mmol), and
stirred at rt under a H2 atmosphere. After 21 h with stirring, the
reaction mixture was filterated and evaporated in vacuo. The
resulting mixture was basified (pH 9) with saturated NaHCO3
aqueous solution, and extracted with CHCl3 three times. The com-
bined organic extracts were washed with brine, dried over Na2SO4,
and evaporated in vacuo. The residue was purified by preparative
TLC (CHCl3/MeOH = 10/1) to give 8 (29 mg, 32%) as a colorless
NMR (CDCl3, 400 Hz) d: 0.06–0.15 (2H, m), 0.47–0.53 (2H, m),
0.80–0.92 (1H, m), 1.45 (1H, d, J = 12.4 Hz), 1.55 (1H, dq, J = 4.8,
13.2 Hz), 1.76–1.87 (1H, m), 1.92 (1H, dt, J = 2.8, 12.4 Hz), 2.02
(1H, dt, J = 2.8, 12.4 Hz), 2.22 (1H, td, J = 2.4, 14.4 Hz), 2.26–2.40
(3H, m), 2.39 (1H, d, J = 14.4 Hz), 2.48 (1H, dd, J = 6.0, 12.6 Hz),
2.56 (1H, dd, J = 6.0, 18.4 Hz), 2.69 (1H, m), 2.91 (1H, d,
J = 18.4 Hz), 3.09 (1H, dd, J = 2.0, 14.4 Hz), 3.29 (1H, dd, J = 3.2,
6.0 Hz), 3.73 (3H, s), 6.65 (1H, dd, J = 2.8, 8.4 Hz), 6.77 (1H, d,
J = 2.8 Hz), 6.95 (1H, d, J = 8.4 Hz). MS (ESI) m/z = 326 [M+H]+. HRMS
(ESI) Calcd for C21H28NO2 [M+H]+: 326.2120; Found 326.2120.
oil. IR (neat): 2951, 1713, 1502 cmꢀ1 1H NMR (CDCl3, 400 MHz)
;
d: 0.92 (3H, d, J = 6.8 Hz), 0.93 (3H, d, J = 6.8 Hz), 1.43 (1H, td,
J = 2.4, 12.0 Hz), 1.56 (1H, dq, J = 4.8, 13.2 Hz), 1.68–1.86 (2H, m),
1.91 (1H, dt, J = 3.2, 12.0 Hz), 2.08 (1H, dt, J = 2.8, 12.0 Hz), 2.20–
2.34 (4H, m), 2.38 (1H, m), 2.40 (1H, d, J = 14.4 Hz), 2.44–2.51
(1H, m), 2.59 (1H, dd, J = 6.4, 18.4 Hz), 2.96 (1H, d, J = 18.8 Hz),
3.00 (1H, s), 3.12 (1H, dd, J = 2.4, 14.4 Hz), 3.76 (3H, s), 6.68 (1H,
dd, J = 2.8, 8.4 Hz), 6.79 (1H, d, J = 2.8 Hz), 6.98 (1H, d, J = 8.4 Hz).
MS (ESI) m/z = 328 [M+H]+. HRMS (ESI) Calcd for C21H30NO2
[M+H]+: 328.2277. Found 328.2284.
5.1.4. 17-Cyclopropylmethyl-6,7-didehydro-3-methoxy-
quinolino[20,30:6,7]morphinan (7)
To a stirred solution of 6 (40 mg, 0.12 mmol) in ethanol (2 mL)
were added methanesulfonic acid (30 lL, 0.43 mmol) and
2-aminobenzaldehyde (60 mg, 0.49 mmol) and refluxed under an
Ar atmosphere. After 20 h with stirring, the reaction mixture was
basified (pH 9) with saturated NaHCO3 aqueous solution, and ex-
tracted with CHCl3 three times. The combined organic extracts
were washed with brine, dried over Na2SO4, and evaporated in va-
cuo. The residue was purified by preparative TLC (CHCl3/
MeOH = 10/1) to give 7 (42.8 mg, 96%) as a colorless oil. IR (neat):
5.1.7. 6,7-Didehydro-17-isobutyl-3-methoxy-quinolino-
[20,30:6,7]morphinan (9)
Compound 9 was prepared from compound 8 according to the
procedure used to prepare compound 7. Yield, 98%; a colorless
2914, 1609, 1496 cmꢀ1 1H NMR (CDCl3, 400 MHz) d: 0.13–0.22
;
oil. IR (neat): 2916, 1608, 1496 cmꢀ1 1H NMR (CDCl3, 400 MHz)
;
(2H, m), 0.51–0.62 (2H, m), 0.89–1.02 (1H, m), 1.69 (1H, d,
J = 12.4 Hz), 2.06 (1H, dt, J = 4.4, 12.4 Hz), 2.19 (1H, dt, J = 2.8,
12.4 Hz), 2.43–2.59 (3H, m), 2.67–2.86 (3H, m), 2.96 (1H, dd,
J = 6.0, 17.2 Hz), 3.03 (1H, d, J = 18.8 Hz), 3.12 (1H, d, J = 17.6 Hz),
3.48 (1H, dd, J = 3.2, 6.0 Hz), 3.62 (3H, s), 3.96 (1H, d, J = 17.6),
6.59 (1H, dd, J = 2.8, 8.4 Hz), 6.91 (1H, d, J = 2.8 Hz), 6.97 (1H, d,
J = 8.4 Hz), 7.36 (1H, dt, J = 0.8, 8.0 Hz), 7.54–7.62 (3H, m), 7.95
(1H, d, J = 9.2 Hz). MS (ESI) m/z = 411 [M+H]+. HRMS (ESI) Calcd
for C28H31N2O [M+H]+: 411.2436. Found 411.2457.
d: 0.94 (3H, d, J = 6.4 Hz), 0.96 (3H, d, J = 6.4 Hz), 1.65 (1H, m),
1.73–1.85 (1H, m), 2.00 (1H, dt, J = 2.4, 12.0 Hz), 2.22 (1H, dt,
J = 2.4, 12.0 Hz), 2.33 (2H, d, J = 7.2 Hz), 2.43–2.52 (1H, m), 2.53
(1H, dt, J = 3.2, 12.0 Hz), 2.72 (1H, dd, J = 12.8, 16.8 Hz), 2.81 (1H,
dd, J = 6.0, 18.4 Hz), 2.93 (1H, dd, J = 6.0, 17.2 Hz), 3.06 (1H, d,
J = 17.2 Hz), 3.11 (1H, d, J = 17.2 Hz), 3.12–3.17 (1H, m), 3.63 (3H,
s), 3.96 (1H, d, J = 17.6 Hz), 6.59 (1H, dd, J = 2.4, 8.4 Hz), 6.91 (1H,
d, J = 17.2 Hz), 6.99 (1H, d, J = 8.4 Hz), 7.37 (1H, dt, J = 1.2, 7.2 Hz),
7.54–7.63 (3H, m), 7.96 (1H, dd, J = 0.8, 8.4 Hz). MS (ESI) m/
z = 413 [M+H]+. HRMS (ESI) Calcd for C28H33N2O [M+H]+:
413.2580. Found 413.2574.
5.1.5. 17-Cyclopropylmethyl-6,7-didehydro-quinolino[20,30:6,7]-
morphinan-3-ol hydrochloride (SN-11)
To a stirred solution of 7 (45 mg, 0.11 mmol) in CH2Cl2 (4.5 mL)
was added 1 M BBr3 in CH2Cl2 (660 lL, 0.66 mmol) at 0 °C under an
5.1.8. 6,7-Didehydro-17-isobutyl-quinolino[20,30:6,7]-
morphinan-3-ol hydrochloride (SN-23)
A free base of SN-23 was prepared from compound 9 according
to the procedure used to prepare the free base of SN-11. Yield, 84%;
a white solid.
Ar atmosphere and stirred at rt. After 1 h with stirring, the reaction
mixture was basified (pH 9) with 25% ammonia aqueous solution,
and extracted with CHCl3 three times. The combined organic
extracts were washed with brine, dried over Na2SO4, and evapo-
rated in vacuo. The residue was purified by preparative TLC
(CHCl3/MeOH = 10/1) to give a free base of SN-11 (42 mg, 97%) as
a white amorphous solid. To a solution of the free base of SN-11
(42 mg, 0.089 mmol) in CHCl3 was added dropwise HCl–MeOH.
After evaporation, to the residue was added AcOEt to give a white
solid. Filtration followed by drying the solid gave SN-11 (32 mg,
64%) as a white solid.
(Free base of SN-23)
IR (film): 2918, 1609, 1497 cmꢀ1 1H NMR (CDCl3, 400 MHz) d:
;
0.94 (3H, d, J = 6.4 Hz), 0.95 (3H, d, J = 6.4 Hz), 1.50 (1H, m), 1,71–
1.91 (2H, m), 2.24 (1H, dt, J = 2.4, 12.4 Hz), 2.33 (2H, d,
J = 7.2 Hz), 2.40–2.48 (1H, m), 2.53 (1H, dt, J = 2.4, 12.4 Hz), 2.70
(1H, dd, J = 12.4, 17.2 Hz), 2.79 (1H, dd, J = 6.0, 18.4 Hz), 2.96 (1H,
dd, J = 6.8, 17.6 Hz), 2.96 (1H, d, J = 17.6 Hz), 3.05 (1H, d,
J = 18.4 Hz), 3.13 (1H, s), 3.88 (1H, d, J = 17.6 Hz), 6.61 (1H, dd,
(Free base of SN-11)

Y. Ida et al. / Bioorg. Med. Chem. 20 (2012) 949–961
955
J = 2.4, 8.4 Hz), 6.94 (1H, d, J = 8.4 Hz), 6.97 (1H, d, J = 2.4 Hz), 7.20–
7.28 (2H, m), 7.45–7.55 (2H, m), 7.60 (1H, s), a proton (OH) was not
observed. MS (ESI) m/z = 399 [M+H]+. HRMS (ESI) Calcd for
dt, J = 5.2, 12.8 Hz), 2.44–2.60 (2H, m), 2.49 (3H, s), 2.73 (1H, dd,
J = 12.4, 17.0 Hz), 2.81 (1H, dd, J = 6.4, 18.6 Hz), 2.95 (1H, dd,
J = 6.4, 17.4 Hz), 3.08 (1H, d, J = 17.4 Hz), 3.12 (1H, d, J = 18.8 Hz),
3.13–3.20 (1H, m), 3.62 (3H, s), 3.97 (1H, d, J = 17.4 Hz), 6.60 (1H,
dd, J = 2.8, 8.4 Hz), 6.91 (1H, d, J = 2.8 Hz), 7.00 (1H, d, J = 8.4 Hz),
7.37 (1H, dt, J = 1.2, 8.0 Hz), 7.53–7.64 (3H, m), 7.97 (1H, d,
J = 8.0 Hz). MS (ESI) m/z = 371 [M+H]+. HRMS (ESI) Calcd for
C
27H31N2O [M+H]+: 399.2436. Found 399.2419.
(SN-23)
SN-23 was prepared from the free base of SN-23 according to
the procedure used to prepare SN-11. Yield, 77%. A white solid.
Mp 216–218 °C (dec); Anal. Calcd for C27H30N2Oꢁ2HClꢁ1.5H2O: C,
65.06; H, 7.08; N, 5.62. Found: C, 65.00; H, 7.34; N, 5.62.
C
25H27N2O [M+H]+: 371.2123. Found 371.2107.
5.1.13. 6,7-Didehydro-17-methyl-quinolino[20,30:6,7]-
morphinan-3-ol hydrochloride (SN-28)
A free base of SN-28 was prepared from compound 13 according
to the procedure used to prepare the free base of SN-11. Yield, 78%;
a yellow solid. SN-28 was prepared from the free base of SN-28
according to the procedure used to prepare SN-11. Yield, 80%; a
white solid.
5.1.9. 3-Methoxy-17-(2,2,2-trichloroethoxycarbonyl)-
morphinan-6-spiro-20-(10,30-dioxolane) (10)
To a stirred solution of 5 (2.1 g, 5.7 mmol) in tetrachloroethane
(10 mL) were added K2CO3 (1.8 g, 12.5 mmol) and Troc-Cl (1.6 mL,
11.4 mmol) and refluxed under an Ar atmosphere. After 4 h with
stirring, the reaction mixture was added 1 M HCl and extracted
with CHCl3 three times. The combined organic extracts were
washed with brine, dried over Na2SO4, and evaporated in vacuo.
The residue was chromatographed on silica gel (150 g, Hexane/
AcOEt = 5/1) to give 10 (1.47 g, 53%) as a yellow oil. IR (neat):
(Free base of SN-28)
IR (film): 2910, 1607, 1496 cmꢀ1 1H NMR (CDCl3, 400 MHz) d:
;
1.52 (1H, d, J = 12.4 Hz), 1.85 (1H, dt, J = 4.8, 12.6 Hz), 2.25 (1H, dt,
J = 2.8, 12.4 Hz), 2.38–2.54 (2H, m), 2.43 (3H, s), 2.64–2.95 (4H, m),
3.09 (1H, d, J = 18.4 Hz), 3.18 (1H, dd, J = 2.8, 6.0 Hz), 3.85 (1H, d,
J = 17.6 Hz), 6.60 (1H, dd, J = 2.8, 8.2 Hz), 6.92 (1H, d, J = 2.8 Hz),
6.93 (1H, d, J = 8.2 Hz), 7.17–7.25 (2H, m), 7.34–7.44 (1H, m),
7.48 (1H, s), 7.56–7.63 (1H, m), a proton (OH) was not observed.
MS (ESI) m/z = 357 [M+H]+. HRMS (ESI) Calcd for C24H25N2O
[M+H]+: 357.1967. Found 357.1957.
2947, 1712, 1426 cmꢀ1 1H NMR (CDCl3, 400 MHz) d: 1.38–1.80
;
(8H, m), 2.54–2.78 (3H, m), 3.10–3.19 (1H, m), 3.74–3.81 (1H,
m), 3.79 (3H, s), 3.81–3.90 (3H, m), 3.91–3.98 (1H, m), 4.49 (1H,
s), 4.70 (1H, d, J = 12.0 Hz), 4.77 (0.5H, d, J = 12.0 Hz), 4.86 (0.5H,
d, J = 12.0 Hz), 6.73 (1H, dd, J = 2.4, 8.4 Hz), 6.85 (1H, d,
J = 2.8 Hz), 6.99 (0.5H, d, J = 8.4 Hz), 7.00 (0.5H, d, J = 8.4 Hz). MS
(ESI) m/z = 512 [M+Na]+. HRMS (ESI) Calcd for C22H26Cl3NNaO5
[M+Na]+: 512.0774. Found 512.0773.
(SN-28)
Mp 239–242 °C (dec); Anal. Calcd for C24H24N2Oꢁ1.5HClꢁ1.7H2O:
C, 65.25; H, 6.59; N, 6.34. Found: C, 65.09; H, 6.61; N, 6.34.
5.1.10. 3-Methoxy-17-methylmorphinan-6-spiro-20-(10,30-
dioxolane) (11)
5.1.14. 3-Methoxymorphinan-6-spiro-20-(10,30-dioxolane) (14)
To a stirred solution of 10 (1.3 g, 2,65 mmol) in DMSO (8 mL)
was added 12 M KOH (8 mL) and stirred at 120 °C under an Ar
atmosphere. After 3 h with stirring, to the reaction mixture was
added saturated NH4Cl aqueous solution and then basified (pH 9)
with saturated NaHCO3 aqueous solution, and extracted with
CHCl3/2-propanol = 2:1 three times. The combined organic extracts
were washed with brine, dried over Na2SO4, and evaporated in va-
cuo. The residue was chromatographed on silica gel (20 g, ammo-
nia saturated CHCl3/MeOH = 10/1) to give 14 (0.9 g, quant.) as a
To a stirred suspension of LiAlH4 (40 mg, 1.00 mmol) in THF
(1 mL) was added a solution of 10 (119 mg, 0.24 mmol) in THF
(2 mL) at 0 °C under an Ar atmosphere and stirred at rt. After 1 h
with stirring, AcOEt and saturated Na2SO4 aqueous solution were
added to the solution, filterated, and evaporated in vacuo. The res-
idue was purified by preparative TLC (CHCl3/MeOH = 10/1) to give
11 (52.1 mg, 65%) as a colorless oil. IR (neat): 2931, 1612, 1497 cm
ꢀ1; 1H NMR (CDCl3, 400 MHz) d: 1.38 (1H, td, J = 2.4, 12.4 Hz), 1.43–
1.54 (2H, m), 1.57 (1H, d, J = 14.0 Hz), 1.60–1.74 (3H, m), 1.86 (1H,
td, J = 3.6, 12.0 Hz), 2.02 (1H, dt, J = 3.2, 12.4 Hz), 2.39–2.47 (1H, m),
2.41 (3H, s), 2.59 (1H, dd, J = 2.4, 14.0 Hz), 2.65 (1H, dd, J = 5.6,
18.4 Hz), 2.91–3.00 (2H, m), 3.71–3.80 (1H, m), 3.76 (3H, s),
3.80–3.87 (2H, m), 3.89–3.96 (1H, m), 6.68 (1H, dd, J = 2.8,
8.4 Hz), 6.81 (1H, d, J = 2.8 Hz), 6.98 (1H, d, J = 8.4 Hz). MS (ESI)
m/z = 330 [M+H]+. HRMS (ESI) Calcd for C20H28NO3 [M+H]+:
330.2068. Found 330.2054.
yellow oil. IR (neat): 2940, 1612, 1496 cmꢀ1 1H NMR (CDCl3,
;
400 MHz) d: 1.33–1.45 (2H, m), 1.46–1.63 (2H, m), 1.58 (1H, d,
J = 14.0 Hz), 1.67 (1H, dt, J = 4.0, 12.8 Hz), 1.70–1.80 (2H, m), 2.30
(1H, s), 2.50 (1H, dt, J = 3.2, 12.8 Hz), 2.56 (1H, dd, J = 2.4,
14.4 Hz), 2.64 (1H, ddd, J = 1.6, 4.8, 16.4 Hz), 2.72 (1H, d,
J = 17.6 Hz), 3.14 (1H, dd, J = 6.0, 17.6 Hz), 3.14–3.19 (1H, m),
3.74–3.80 (1H, m), 3.77 (3H, s), 3.81–3.88 (2H, m), 3.91–3.97
(1H, m), 6.70 (1H, dd, J = 2.4, 8.4 Hz), 6.82 (1H, d, J = 2.4 Hz), 7.00
(1H, d, J = 8.4 Hz). MS (ESI) m/z = 316 [M+H]+. HRMS (ESI) Calcd
for C19H26NO3 [M+H]+: 316.1913. Found 316.1922.
5.1.11. 3-Methoxy-17-methylmorphinan-6-one (12)
Compound 12 was prepared from compound 11 according to the
procedure used to prepare compound 6. Yield, 79%; a white solid. IR
(KBr): 2923, 1701, 1503 cmꢀ1
;
1H NMR (CDCl3, 400 MHz) d: 1.47
5.1.15. 17-Benzyl-3-methoxymorphinan-6-spiro-20-(10,30-
dioxolane) (15)
To a stirred solution of 14 (100 mg, 0.32 mmol) in DMF (1 mL)
were added K2CO3 (220 mg, 1.59 mmol) and BnBr (120 lL,
(1H, d, J = 12.0 Hz), 1.58 (1H, dq, J = 4.8, 13.2 Hz), 1.79–1.88 (1H,
m), 1.90 (1H, dt, J = 4.8, 12.4 Hz), 2.09 (2H, dt, J = 3.2, 12.0 Hz),
2.20–2.30 (2H, m), 2.33–2.48 (2H, m), 2.43 (3H, s), 2.57 (1H, dd,
J = 6.0, 18.4 Hz), 2.98–3.07 (2H, m), 3.11 (1H, dd, J = 2.4, 14.0 Hz),
3.75 (3H, s), 6.68 (1H, dd, J = 2.4, 8.4 Hz), 6.79 (1H, d, J = 2.4 Hz),
7.00 (1H, d, J = 8.4 Hz). MS (ESI) m/z = 286 [M+H]+. HRMS (ESI) Calcd
for C18H24NO2 [M+H]+: 286.1807. Found 286.1809.
0.95 mmol), and stirred at rt under an Ar atmosphere. After 4 h
with stirring, the reaction mixture was evaporated in vacuo. The
resulting mixture was basified (pH 9) with saturated NaHCO3
aqueous solution and extracted with CHCl3 three times. The com-
bined organic extracts were washed with brine, dried over Na2SO4,
and evaporated in vacuo. The residue was chromatographed on sil-
ica gel (20 g, Hexane/AcOEt = 1/1) to give 15 (113 mg, 88%) as a
5.1.12. 6,7-Didehydro-3-methoxy-17-methyl-quinolino-
[20,30:6,7]morphinan (13)
Compound 13 was prepared from compound 12 according to
the procedure used to prepare compound 7. Yield, 95%; a yellow
yellow oil. IR (neat): 2918, 1611, 1496 cmꢀ1 1H NMR (CDCl3,
;
400 MHz) d: 1.37 (1H, td, J = 2.8, 12.0 Hz), 1.44–1.53 (2H, m),
1.61 (1H, d, J = 14.0 Hz), 1.65–1.79 (3H, m), 1.83–1.94 (1H, m),
2.06 (1H, dt, J = 3.2, 12.0 Hz), 2.44 (1H, ddd, J = 1.6, 4.8, 12.0 Hz),
oil. IR (neat): 2908, 1608, 1496 cmꢀ1 1H NMR (CDCl3, 400 MHz)
;
d: 1.69 (1H, d, J = 12.0 Hz), 2.02 (1H, dt, J = 5.2, 12.6 Hz), 2.25 (1H,

956
Y. Ida et al. / Bioorg. Med. Chem. 20 (2012) 949–961
2.62 (1H, dd, J = 2.4, 14.0 Hz), 2.67 (1H, dd, J = 5.2, 18.4 Hz), 2.94–
3.00 (1H, m), 3.05 (1H, d, J = 17.6 Hz), 3.63 (1H, d, J = 13.2 Hz),
3.75 (1H, d, J = 13.2 Hz), 3.75–3.82 (1H, m), 3.80 (3H, s), 3.83–
3.91 (2H, m), 3.92–4.01 (1H, m), 6.73 (1H, dd, J = 2.4, 8.4 Hz),
6.86 (1H, d, J = 2.4 Hz), 7.05 (1H, d, J = 8.4 Hz), 7.22–7.73 (2H, m),
7.29–7.39 (3H, m). MS (ESI) m/z = 406 [M+H]+. HRMS (ESI) Calcd
for C26H32NO3 [M+H]+: 406.2382. Found 406.2364.
(1H, dt, J = 4.0, 12.0 Hz), 1.98–2.09 (1H, m), 2.31–2.50 (3H, m), 2.60
(1H, dd, Jv2.4, 14.0 Hz), 2.62 (1H, dd, J = 5.2, 12.8 Hz), 2.92 (1H, d,
J = 17.6 Hz), 2.92–2.98 (1H, m), 3.74–3.80 (1H, m), 3.77 (3H, s),
3.80–3.89 (2H, m), 3.90–3.98 (1H, m), 6.68 (1H, dd, J = 2.8,
8.4 Hz), 6.82 (1H, d, J = 2.8 Hz), 6.98 (1H, d, J = 8.4 Hz). MS (ESI)
m/z = 398 [M+H]+. HRMS (ESI) Calcd for C25H36NO3 [M+H]+:
398.2695. Found 398.2686.
5.1.16. 3-Methoxy-17-phenethylmorphinan-6-spiro-20-(10,30-
dioxolane) (16)
To a stirred solution of 14 (100 mg, 0.32 mmol) in CH2Cl2 (5 mL)
were added 50% solution of phenylacetaldehyde (240 lL,
5.1.19. 17-Benzyl-3-methoxymorphinan-6-one (19)
Compound 19 was prepared from compound 15 according to the
procedure used to prepare compound 6. Yield, 82%; a white amor-
phous solid. IR (film): 2909, 1712, 1610, 1502 cmꢀ1; 1H NMR (CDCl3,
400 MHz) d: 1.45 (1H, d, J = 12.4 Hz), 1.56 (1H, dq, J = 4.8, 13.2 Hz),
1.73–1.83 (1H, m), 1.91 (1H, dt, J = 4.8, 12.4 Hz), 2.16 (1H, dt,
J = 3.2, 12.4 Hz), 2.20–2.28 (1H, m), 2.29–2.54 (4H, m), 2.62 (1H,
dd, J = 6.4, 18.0 Hz), 3.04–3.17 (3H, m), 3.68 (1H, d, J = 13.6 Hz),
3.77 (1H, d, J = 13.6 Hz), 3.77 (3H, s), 6.72 (1H, dd, J = 2.4, 8.6 Hz),
6.82 (1H, d, J = 2.4 Hz), 7.05 (1H, d, J = 8.4 Hz), 7.23–7.29 (2H, m),
7.31–7.42 (3H, m). MS (ESI) m/z = 362 [M+H]+. HRMS (ESI) Calcd
for C24H28NO2 [M+H]+: 362.2120. Found 362.2129.
0.95 mmol) in 2-propanol solution and NaBH(OAc)3 (270 mg,
1.27 mmol), and stirred at rt under an Ar atmosphere. After 6 h
with stirring, the reaction mixture was basified (pH 9) with satu-
rated NaHCO3 aqueous solution and extracted with CHCl3 three
times. The combined organic extracts were washed with brine,
dried over Na2SO4, and evaporated in vacuo. The residue was chro-
matographed on silica gel (20 g, Hexane/AcOEt = 1/1-CHCl3/
MeOH = 10/1) to give 16 (122 mg, 91%) as a white amorphous so-
lid. IR (film): 2921, 1611, 1496 cmꢀ1 1H NMR (CDCl3, 400 MHz)
;
d: 1.41 (1H, m), 1.45–1.56 (2H, m), 1.59 (1H, d, J = 14.0 Hz), 1.66
(1H, dt, J = 4.8, 12.6 Hz), 1.69–1.79 (2H, m), 1.85 (1H, td, J = 3.2,
11.6 Hz), 2.02 (1H, dt, J = 2.8, 12.0 Hz), 2.54–2.84 (7H, m), 2.94
(1H, d, J = 18.0 Hz), 3.06 (1H, dd, J = 2.8, 5.6 Hz), 3.72–3.81 (1H,
m), 3.77(3H, s), 3.82–3.89 (2H, m), 3.90–3.99 (1H, m), 6.68 (1H,
dd, J = 2.4, 8.4 Hz), 6.83 (1H, d, J = 2.4 Hz), 6.97 (1H, d, J = 8.4 Hz),
7.16–7.23 (2H, m), 7.25–7.31 (3H, m). MS (ESI) m/z = 420 [M+H]+.
5.1.20. 3-Methoxy-17-phenethylmorphinan-6-one (20)
Compound 20 was prepared from compound 16 according to
the procedure used to prepare compound 6. Yield, quant; a color-
less oil. IR (neat): 2928, 1712, 1609, 1501 cmꢀ1 1H NMR (CDCl3,
;
400 MHz) d: 1.49 (1H, d, J = 12.8 Hz), 1.58 (1H, dq, J = 4.8,
13.2 Hz), 1.78–1.88 (1H, m), 1.94 (1H, dt, J = 4.8, 12.8 Hz), 2.14
(1H, dt, J = 3.2, 12.4 Hz), 2.20–2.46 (4H, m), 2.62 (1H, dd, J = 6.0,
18.4 Hz), 2.62–2.70 (1H, m), 2.71–2.88 (4H, m), 3.00 (1H, d,
J = 18.4 Hz), 3.13 (1H, dd, J = 2.0, 14.0 Hz), 3.17 (1H, dd, J = 2.8,
5.6 Hz), 3.76 (3H, s), 6.69 (1H, dd, J = 2.8, 8.4 Hz), 6.82 (1H, d,
J = 2.8 Hz), 7.00 (1H, d, J = 8.4 Hz), 7.18–7.26 (3H, m), 7.27–7.33
(2H, m). MS (ESI) m/z = 376 [M+H]+. HRMS (ESI) Calcd for
HRMS (ESI) Calcd for
420.2526.
C
27H34NO3 [M+H]+: 420.2539. Found
5.1.17. 17-Cyclobutylmethyl-3-methoxymorphinan-6-spiro-20-
(10,30-dioxolane) (17)
To a stirred solution of 14 (100 mg, 0.32 mmol) in DMF (1 mL)
were added K2CO3 (310 mg, 2.22 mmol) and (bromomethyl)cyclo-
C
25H30NO2 [M+H]+: 376.2250. Found 376.2261.
butane (150
l
L, 1.27 mmol), and stirred at 60 °C under an Ar atmo-
5.1.21. 17-Cyclobutylmethyl-3-methoxymorphinan-6-one (21)
Compound 21 was prepared from compound 17 according to
the procedure used to prepare compound 6. Yield, quant.; a color-
sphere. After 24 h with stirring, the reaction mixture was
evaporated in vacuo. The resulting mixture was basified (pH 9)
with saturated NaHCO3 aqueous solution and extracted with CHCl3
three times. The combined organic extracts were washed with
brine, dried over Na2SO4, and evaporated in vacuo. The residue
was purified by preparative TLC (CHCl3/MeOH = 10/1) to give 17
less oil. IR (neat): 2928, 1713, 1610, 1502 cmꢀ1 1H NMR (CDCl3,
;
400 MHz) d: 1.41 (1H, d, J = 12.4 Hz), 1.54 (1H, dq, J = 5.2,
13.4 Hz), 1.61–1.75 (2H, m), 1.75–1.95 (4H, m), 1.98–2.12 (3H,
m), 2.22–2.23 (2H, m), 2.23–2.62 (7H, m), 2.98 (1H, d,
J = 18.4 Hz), 3.00 (1H, d, J = 8.4 Hz), 3.08 (1H, dd, J = 2.0, 14.4 Hz),
3.74 (3H, s), 6.66 (1H, dd, J = 2.4, 8.4 Hz), 6.77 (1H, d, J = 2.4 Hz),
6.97 (1H, d, J = 8.4 Hz). MS (ESI) m/z = 340 [M+H]+. HRMS (ESI)
Calcd for C22H30NO2 [M+H]+: 340.2277. Found 340.2271.
(79 mg, 65%) as a colorless oil. IR (neat): 2936, 1611, 1497 cmꢀ1
;
1H NMR (CDCl3, 400 MHz) d: 1.30–1.38 (1H, m), 1.40–1.53 (2H,
m), 1.57 (1H, d, J = 14.4 Hz), 1.60–1.92 (8H, m), 1.93–2.12 (3H,
m), 2.40–2.62 (5H, m), 2.63 (1H, dd, J = 6.4, 18.0 Hz), 2.92–2.98
(1H, m), 2.94 (1H, d, J = 18.0 Hz), 3.72–3.79 (1H, m), 3.76 (3H, s),
3.80–3.86 (2H, m), 3.89–3.96 (1H, m), 6.68 (1H, dd, J = 2.8,
8.4 Hz), 6.81 (1H, d, J = 2.8 Hz), 6.98 (1H, d, J = 8.4 Hz). MS (ESI)
m/z = 384 [M+H]+. HRMS (ESI) Calcd for C24H34NO3 [M+H]+:
384.2539. Found 384.2548.
5.1.22. 17-Cyclopentylmethyl-3-methoxymorphinan-6-one (22)
Compound 22 was prepared from compound 18 according to
the procedure used to prepare compound 6. Yield, quant.; a color-
less oil. IR (neat): 2945, 1713, 1610, 1502 cmꢀ1 1H NMR (CDCl3,
;
400 MHz) d: 1.15–1.28 (2H, m), 1.41 (1H, d, J = 12.4 Hz), 1.46–
1.64 (5H, m), 1.68–1.84 (3H, m), 1.86 (1H, dt, J = 4.8, 12.4 Hz),
1.98–2.10 (2H, m), 2.17–2.28 (2H, m), 2.30–2.52 (5H, m), 2.55
(1H, dd, J = 6.4, 18.4 Hz), 2.96 (1H, d, J = 18.4 Hz), 3.04 (1H, dd,
J = 3.2, 5.6 Hz), 3.08 (1H, dd, J = 1.6, 14.2 Hz), 3.73 (3H, s), 6.65
(1H, dd, J = 2.4, 8.4 Hz), 6.78 (1H, d, J = 2.4 Hz), 6.96 (1H, d,
J = 8.4 Hz). MS (ESI) m/z = 354 [M+H]+. HRMS (ESI) Calcd for
5.1.18. 17-Cyclopentylmethyl-3-methoxymorphinan-6-spiro-20-
(10,30-dioxolane) (18)
To a stirred solution of 14 (150 mg, 0.48 mmol) in CH2Cl2
(20 mL) were added cyclopentanecarbaldehyde (200
lL,
1.90 mmol), acetic acid (220 L, 3.80 mmol), and NaBH(OAc)3
l
(1 g, 4.76 mmol), and stirred at rt under an Ar atmosphere. After
1 h with stirring, the reaction mixture was basified (pH 9) with sat-
urated NaHCO3 aqueous solution and extracted with CHCl3 three
times. The combined organic extracts were washed with brine,
dried over Na2SO4, and evaporated in vacuo. The residue was chro-
matographed on silica gel (15 g, ammonia saturated CHCl3) to give
18 (169 mg, 90%) as a colorless oil. IR (neat): 2944, 1612, 1497 cm
ꢀ1; 1H NMR (CDCl3, 400 MHz) d: 1.14–1.28 (2H, m), 1.31–1.38 (1H,
m), 1.43–1.64 (7H, m), 1.64–1.79 (5H, m), 1.79–1.86 (1H, m), 1.96
C
23H32NO2 [M+H]+: 354.2433. Found 354.2447.
5.1.23. 17-Benzyl-6,7-didehydro-3-methoxy-quinolino-
[20,30:6,7]morphinan (23)
Compound 23 was prepared from compound 19 according to
the procedure used to prepare compound 7. Yield, 86%; a white
amorphous solid. IR (film): 2908, 1608 cmꢀ1 1H NMR (CDCl3,
;
400 MHz) d: 1.64–1.70 (1H, m), 2.00 (1H, dt, J = 4.5, 12.0 Hz),

Y. Ida et al. / Bioorg. Med. Chem. 20 (2012) 949–961
957
2.29 (1H, dt, J = 3.0, 12.0 Hz), 2.45–2.60 (2H, m), 2.70 (1H, dd,
J = 12.0, 17.0 Hz), 2.77–2.91 (2H, m), 3.13 (1H, d, J = 18.0 Hz),
3.16–3.23 (2H, m), 3.64 (3H, s), 3.72 (1H, d, J = 13.5 Hz), 3.81 (1H,
d, J = 13.5 Hz), 3.98 (1H, d, J = 17.5 Hz), 6.63 (1H, dd, J = 2.5,
8.0 Hz), 6.94 (1H, d, J = 2.5 Hz), 7.04 (1H, d, J = 8.0 Hz), 7.27–7.31
(1H, m), 7.33–7.45 (5H, m), 7.54–7.60 (3H, m), 7.96–8.00 (1H,
m). MS (ESI) m/z = 447 [M+H]+. HRMS (FAB) Calcd for C31H31N2O
[M+H]+: 447.2436. Found 447.2417.
SN-11. Yield, 76% (2 steps from 20); a white solid. SYK-260 was
prepared from the free base of SYK-260 according to the procedure
used to prepare SN-11. Yield, 95%; a yellow solid.
(Free base of SYK-260)
IR (KBr): 3423, 2909, 1607 cmꢀ1 1H NMR (CDCl3, 400 MHz) d:
;
1.53–1.60 (1H, m), 1.83–1.94 (1H, m), 2.26–2.35 (1H, m), 2.44–
2.53 (1H, m), 2.67–2.86 (6H, m), 2.87–3.02 (3H, m), 3.09 (1H, d,
J = 18.0 Hz), 3.30–3.35 (1H, m), 3.92 (1H, d, J = 17.5 Hz), 6.64 (1H,
dd, J = 2.5, 8.0 Hz), 6.96 (1H, d, J = 8.0 Hz), 6.97 (1H, d, J = 2.5 Hz),
7.14–7.31 (7H, m), 7.41–7.46 (1H, m), 7.51–7.54 (1H, m), 7.56–
7.60 (1H, m), a proton (OH) was not observed. MS (ESI) m/z = 447
[M+H]+. HRMS (FAB) Calcd for C31H31N2O [M+H]+: 447.2436. Found
447.2414.
5.1.24. 6,7-Didehydro-3-methoxy-17-phenethyl-
quinolino[20,30:6,7]morphinan (24)
Compound 24 was prepared from compound 20 according to
the procedure used to prepare compound 7. The crude compound
was chromatographed on silica gel, but could not be purified com-
pletely. The resulting compound 24 was used for the next reaction
without further purification.
(SYK-260)
Mp 229–232 °C (dec). Anal. Calcd for C31H30N2Oꢁ2HClꢁ0.4H2O:
C, 70.69; H, 6.28; N, 5.32. Found: C, 70.77; H, 6.58; N, 5.32.
5.1.25. 17-Cyclobutylmethyl-6,7-didehydro-3-methoxy-
quinolino[20,30:6,7]morphinan (25)
5.1.29. 17-Cyclobutylmethyl-6,7-didehydro-
quinolino[20,30:6,7]morphinan-3-ol hydrochloride (SYK-261)
A free base of SYK-261 was prepared from compound 25
according to the procedure used to prepare the free base of
SN-11. Yield, 38% (2 steps from 21); a white crystal. SYK-261 was
prepared from the free base of SYK-261 according to the procedure
used to prepare SN-11. Yield, 98%; a yellow solid.
Compound 25 was prepared from compound 21 according to
the procedure used to prepare compound 7. The crude compound
was chromatographed on silica gel, but could not be purified com-
pletely. The resulting compound 25 was used for the next reaction
without further purification.
(Free base of SYK-261)
5.1.26. 17-Cyclopentylmethyl-6,7-didehydro-3-methoxy-
quinolino[20,30:6,7]morphinan (26)
Mp 225–229 °C. IR (KBr): 2923, 1492 cmꢀ1 1H NMR (CDCl3,
;
400 MHz) d: 1.56–1.97 (7H, m), 2.03–2.16 (2H, m), 2.16–2.26
(1H, dt, J = 2.5, 12.0 Hz), 2.40–2.47 (1H, m), 2.50–2.73 (4H, m),
2.73–2.79 (1H, m), 2.96 (1H, dd, J = 6.5, 17.0 Hz), 3.06 (1H, d,
J = 17.0 Hz), 3.09 (1H, d, J = 17.0 Hz), 3.11–3.17 (1H, m), 3.90 (1H,
d, J = 17.0 Hz), 6.57 (1H, dd, J = 2.5, 8.0 Hz), 6.89 (1H, d,
J = 2.5 Hz), 6.95 (1H, d, J = 8.0 Hz), 7.28–7.33 (1H, m), 7.35–7.40
(1H, m), 7.52–7.57 (1H, m), 7.62–7.69 (2H, m), a proton (OH) was
not observed. MS (ESI) m/z = 411 [M+H]+. HRMS (FAB) Calcd for
Compound 26 was prepared from compound 22 according to
the procedure used to prepare compound 7. Yield, 90%; a white
amorphous solid. IR (film): 2947, 1609, 1496 cmꢀ1
;
1H NMR
(CDCl3, 400 MHz) d: 1.19–1.34 (2H, m), 1.48–1.69 (5H, m), 1.72–
1.84 (2H, m), 1.97 (1H, dt, J = 4.8, 12.6 Hz), 2.04–2.14 (1H, m),
2.20 (1H, dt, J = 3.2, 12.4 Hz), 2.48–2.53 (3H, m), 2.58 (1H, dd,
J = 3.2, 12.0 Hz), 2.72 (1H, dd, J = 12.4, 16.8 Hz), 2.78 (1H, dd,
J = 6.4, 18.4 Hz), 2.90 (1H, dd, J = 6.4, 17.2 Hz), 3.07 (1H, d,
J = 18.4 Hz), 3.09 (1H, d, J = 17.6 Hz), 3.19 (1H, dd, J = 2.4, 6.0 Hz),
3.62 (3H, s), 3.95 (1H, d, J = 17.6 Hz), 6.58 (1H, dd, J = 2.8, 8.4 Hz),
6.91 (1H, d, J = 2.8 Hz), 6.98 (1H, d, J = 8.4 Hz), 7.36 (1H, dt,
J = 1.2, 8.0 Hz), 7.53–7.58 (3H, m), 7.96 (1H, d, J = 9.2 Hz). MS
(ESI) m/z = 439 [M+H]+. HRMS (ESI) Calcd for C30H35N2O [M+H]+:
439.2749. Found 439.2731.
C
28H31N2O [M+H]+: 411.2436. Found 411.2451.
(SYK-261)
Mp 231–235 °C (dec). Anal. Calcd for C28H30N2Oꢁ2HClꢁ0.8H2O:
C, 67.55; H, 6.80; N, 5.63. Found: C, 67.62; H, 6.89; N, 5.69.
5.1.30. 17-Cyclopentylmethyl-6,7-didehydro-
quinolino[20,30:6,7]morphinan-3-ol hydrochloride (SYK-262)
A free base of SYK-262 was prepared from compound 26
according to the procedure used to prepare the free base of SN-
11. Yield, 93%; a white amorphous solid. SYK-262 was prepared
from the free base of SYK-262 according to the procedure used to
prepare SN-11. Yield, 92%; a white solid.
5.1.27. 17-Benzyl-6,7-didehydro-
quinolino[20,30:6,7]morphinan-3-ol hydrochloride (SYK-259)
A free base of SYK-259 was prepared from compound 23
according to the procedure used to prepare the free base of SN-
11. Yield, 88%; a white solid. SYK-259 was prepared from the free
base of SYK-259 according to the procedure used to prepare SN-11.
Yield, 88%; a yellow solid.
(Free base of SYK-262)
IR (film): 2947, 1608, 1496 cmꢀ1 1H NMR (CDCl3, 400 MHz) d:
;
(Free base of SYK-259)
1.10–1.29 (2H, m), 1.34–1.42 (1H, m), 1.44–1.64 (4H, m), 1.66–1.82
(3H, m), 1.96–2.10 (1H, m), 2.18 (1H, dt, J = 3.2, 12.0 Hz), 2.32–2.59
(4H, m), 2.62–2.96 (4H, m), 3.05 (1H, d, J = 18.8 Hz), 3.15–3.25 (1H,
m), 3.83 (1H, d, J = 17.2 Hz), 6.61 (1H, dd, J = 2.0, 8.4 Hz), 6.92 (1H,
d, J = 8.4 Hz), 6.93 (1H, d, J = 2.0 Hz), 7.16–7.25 (2H, m), 7.36–7.43
(1H, m), 7.46 (1H, s), 7.56–7.64 (1H, m), a proton (OH) was not ob-
served. MS (ESI) m/z = 425 [M+H]+. HRMS (ESI) Calcd for
IR (KBr): 2907, 1608 cmꢀ1 1H NMR (CDCl3, 400 MHz) d: 1.42–
;
1.50 (1H, m), 1.76–1.88 (1H, m), 2.28–2.37 (1H, m), 2.44–2.60 (2H,
m), 2.67 (1H, dd, J = 12.0, 17.0 Hz), 2.76–2.90 (2H, m), 2.96 (1H, d,
J = 18.0 Hz), 3.15–3.22 (2H, m), 3.76 (1H, d, J = 13.5 Hz), 3.79 (1H,
d, J = 13.5 Hz), 3.88 (1H, d, J = 17.5 Hz), 6.65 (1H, dd, J = 2.5,
8.0 Hz), 6.96 (1H, d, J = 2.5 Hz), 6.98 (1H, d, J = 8.0 Hz), 7.17–7.24
(2H, m), 7.27–7.38 (3H, m), 7.42–7.47 (3H, m), 7.51–7.57 (2H, m),
a proton (OH) was not observed. MS (ESI) m/z = 433 [M+H]+. HRMS
(FAB) Calcd for C30H29N2O [M+H]+: 433.2280. Found 433.2324.
(SYK-259)
C
29H33N2O [M+H]+: 425.2593. Found 425.2584.
(SYK-262)
Mp 226–228 °C (dec); Anal. Calcd for C29H32N2Oꢁ2HClꢁH2O: C,
67.57; H, 7.04; N, 5.43. Found: C, 67.72; H, 7.13; N, 5.43.
Mp 233–237 °C (dec). Anal. Calcd for C30H28N2Oꢁ2HClꢁ0.4H2O:
C, 70.28; H, 6.06; N, 5.46. Found: C, 70.33; H, 6.23; N, 5.39.
5.1.31. 17-Cyclopropylmethyl-4,5
phenyl-1H-tetrazol-5-yloxy)morphinan-6-one (27)
To stirred solution of naltrexone hydrochloride (5 g,
13.2 mmol) in DMF (50 mL) were added K2CO3 (4.5 g, 33.1 mmol)
and 5-chloro-1-phenyl-1H-tetrazol (2.6 g, 14.6 mmol), and stirred
at rt under an Ar atmosphere. After 42 h with stirring, the reaction
a-epoxy-14b-hydroxy-3-(1-
5.1.28. 6,7-Didehydro-17-phenethyl-
a
quinolino[20,30:6,7]morphinan-3-ol hydrochloride (SYK-260)
A free base of SYK-260 was prepared from compound 24
according to the procedure used to prepare the free base of

958
Y. Ida et al. / Bioorg. Med. Chem. 20 (2012) 949–961
mixture was evaporated in vacuo. To the resulting mixture was
added water and extracted with CHCl3 three times. The combined
organic extracts were washed with brine, dried over Na2SO4, and
evaporated in vacuo. The residue was chromatographed on silica
gel (200 g, CHCl3/MeOH = 20/1) to give 27 (6.8 g, quant) as a yellow
oil. IR (neat): 2997, 1628, 1602, 1456 cmꢀ1 1H NMR (CDCl3,
;
400 MHz) d: 0.08–0.17 (2H, m), 0.49–0.55 (2H, m), 0.85–0.94
(1H, m), 1.70–1.78 (1H, m), 2.00 (1H, dt, J = 4.8, 12.4 Hz), 2.03–
2.13 (1H, m), 2.43 (2H, d, J = 6.4 Hz), 2.40–2.49 (1H, m), 2.60 (1H,
dt, J = 3.6, 12.8 Hz), 2.72 (1H, dd, J = 6.4, 18.4 Hz), 2.78–2.85 (1H,
m), 3.17 (1H, d, J = 18.4 Hz), 3.67–3.74 (2H, m), 3.82–3.91 (2H,
m), 4.14–4.21 (1H, m), 4.58 (1H, s), 5.48 (1H, dd, J = 1.6, 6.8 Hz),
6.56 (1H, dd, J = 2.4, 7.6 Hz), 6.63 (1H, dd, J = 2.4, 7.6 Hz), 6.98
(1H, t, J = 7.6 Hz). MS (ESI) m/z = 352 [M+H]+. HRMS (ESI) Calcd
for C22H26NO3 [M+H]+: 352.1913. Found 352.1906.
oil. IR (neat): 3529, 2938, 1725, 1540, 1240, 1058 cmꢀ1 1H NMR
;
(CDCl3, 300 MHz) d: 0.09–0.24 (2H, m), 0.49–0.66 (2H, m), 0.80–
0.95 (1H, m), 1.63 (1H, dt, J = 3.5, 14.5 Hz), 1.65 (1H, dd, J = 2.5,
10.5 Hz), 1.92 (1H, ddd, J = 2.5, 3.0, 14.5 Hz), 2.16 (1H, dt, J = 4.0,
12.0 Hz), 2.31 (1H, dt, J = 3.0, 14.5 Hz), 2.38–2.51 (3H, m), 2.64
(1H, dd, J = 6.0, 18.5 Hz), 2.74 (1H, dd, J = 4.5, 12.0 Hz), 3.04 (1H,
dt, J = 5.0, 13.5 Hz), 3.12 (1H, d, J = 18.5 Hz), 3.23 (1H, d,
J = 6.0 Hz), 4.72 (1H, s), 6.75 (1H, d, J = 8.5 Hz), 7.16 (1H, d,
J = 8.5 Hz), 7.50 (1H, dt, J = 1.5, 7.5 Hz), 7.59 (2H, ddd, J = 2.5, 7.5,
8.0 Hz), 7.89 (2H, ddd, J = 1.5, 2.5, 8.0 Hz), a proton (OH) was not
observed. MS (ESI) m/z = 486 [M+H]+. HRMS (ESI) Calcd for
C27H28N5O4 [M+H]+: 486.2141. Found 486.2148.
5.1.35. 17-Cyclopropylmethyl-4,5
a-epoxymorphinan-6-spiro-
20-(10,30-dioxolane) (31)
Compound 31 was prepared from compound 30 according to the
procedure used to prepare compound 5. Yield, quant.; a white amor-
phous solid. IR (film): 2951, 1632, 1609, 1457 cmꢀ1; 1H NMR (CDCl3,
400 MHz) d: 0.12–0.20 (2H, m), 0.50–0.58 (2H, m), 0.83–0.97 (1H,
m), 1.08–1.21 (1H, m), 1.49–1.70 (4H, m), 1.95 (1H, dt, J = 3.6,
11.6 Hz), 2.16 (1H, dt, J = 3.2, 12.0 Hz), 2.24–2.48 (3H, m), 2.52 (1H,
dd, J = 6.0, 12.4 Hz), 2.76–2.85 (1H, m), 2.93 (1H, d, J = 18.8 Hz),
3.45 (1H, s), 3.73–3.81 (1H, m), 3.85–3.93 (2H, m), 4.10–4.18 (1H,
m), 4.43 (1H, s), 6.61 (1H, dd, J = 2.4, 7.6 Hz), 6.66 (1H, dd, J = 2.4,
7.6 Hz), 7.05 (1H, t, J = 7.6 Hz). MS (ESI) m/z = 354 [M+H]+. HRMS
(ESI) Calcd for C22H28NO3 [M+H]+: 354.2069. Found 354.2079.
5.1.32. 17-Cyclopropylmethyl-4,5a-epoxy-14b-
hydroxymorphinan-6-one (28)
To a stirred solution of 27 (4.8 g, 9.9 mmol) in AcOH (50 mL) was
added 10% Pd/C(1.8 g, 16.80 mmol) and stirred at 70 °C under a H2
atmosphere. After 19 h with stirring, the reaction mixture was fil-
trated and evaporated in vacuo. The resulting mixture was basified
(pH 9) with 4 M NaOH aqueous solution and extracted with CHCl3
three times. The combined organic extracts were washed with brine,
dried over Na2SO4, and evaporated in vacuo. The residue was chro-
matographed on silica gel (150 g, ammonia saturated CHCl3) to give
28 (2.88 g, 90%) as a brown amorphous solid. IR (film): 2928, 1726,
5.1.36. 17-Cyclopropylmethyl-4,5a-epoxymorphinan-6-one (32)
Compound 32 was prepared from compound 31 according to
the procedure used to prepare compound 6. Yield, 85%; a white
crystal. Mp 187.7–188.4 °C; IR (KBr): 2923, 1721, 1455 cmꢀ1 1H
;
1455 cmꢀ1
;
1H NMR (CDCl3, 400 MHz) d: 0.03–0.12 (2H, m), 0.42–
NMR (CDCl3, 400 MHz) d: 0.03–0.12 (2H, m), 0.42–0.50 (2H, m),
0.75–0.87 (1H, m), 1.09–1.25 (1H, m), 1.64–1.71 (1H, m), 1.75–
1.83 (1H, m), 1.97–2.09 (2H, m), 2.25–2.36 (4H, m), 2.43 (1H, dd,
J = 6.4, 12.6 Hz), 2.56 (1H, ddd, J = 2.8, 4.0, 12.8 Hz), 2.68–2.79
(1H, m), 2.89 (1H, d, J = 19.2 Hz), 3.41 (1H, dd, J = 2.4, 5.4 Hz),
4.56 (1H, s), 6.60 (1H, dd, J = 2.4, 7.6 Hz), 6.68 (1H, dd, J = 2.4,
7.6 Hz), 6.97 (1H, t, J = 7.6 Hz). MS (ESI) m/z = 310 [M+H]+. HRMS
(ESI) Calcd for C20H24NO2 [M+H]+: 310.1807. Found 310.1814.
0.53 (2H, m), 0.74–0.86 (1H, m), 1.38–1.45 (1H, m), 1.46–1.58 (1H,
m), 1.80 (1H, td, J = 2.4, 13.6 Hz), 1.98–2.08 (1H, m), 2.15–2.24 (1H,
m), 2.28–2.40 (3H, m), 2.57–2.66 (1H, m), 2.62 (1H, dd, J = 4.8,
12.0 Hz), 2.96 (1H, dt, J = 3.2, 14.4 Hz), 3.03 (1H, d, J = 18.8 Hz),
3.13 (1H, d, J = 5.6 Hz), 4.55 (1H, d, J = 2.0 Hz), 5.02 (1H, br s), 6.61
(1H, dd, J = 1.6, 8.0 Hz), 6.65 (1H, dd, J = 1.6, 8.0 Hz), 6.97 (1H, dt,
J = 2.4, 8.0 Hz). MS (ESI) m/z = 326 [M+H]+. HRMS (ESI) Calcd for
C
20H24NO3 [M+H]+: 326.1756. F. Found 326.1766.
5.1.37. 4,5a-Epoxy-17-isobutylmorphinan-6-one (33)
5.1.33. 17-Cyclopropylmethyl-4,5
a
-epoxy-14b-
Compound 33 was prepared from compound 31 according to
the procedure used to prepare compound 8. Yield, 44%; a colorless
oil. IR (neat): 2941, 1723, 1455 cmꢀ1; 1H NMR (CDCl3, 400 MHz) d:
0.90 (3H, d, J = 6.4 Hz), 0.92 (3H, d, J = 6.4 Hz), 1.22 (1H, dq, J = 4.8,
12.8 Hz), 1.66–1.86 (3H, m), 2.03 (1H, dt, J = 4.8, 12.0 Hz), 2.15 (1H,
dt, J = 3.2, 12.0 Hz), 2.20–2.30 (2H, m), 2.31–2.43 (3H, m), 2.51–
2.64 (2H, m), 2.97 (1H, d, J = 18.8 Hz), 3.16 (1H, dd, J = 2.8,
5.2 Hz), 4.59 (1H, s), 6.67 (1H, dd, J = 0.8, 7.6 Hz), 6.64 (1H, dd,
J = 0.8, 7.6 Hz), 7.04 (1H, t, J = 7.6 Hz). MS (ESI) m/z = 312 [M+H]+.
hydroxymorphinan-6-spiro-20-(10,30-dioxolane) (29)
To a stirred solution of 28 (2.8 g, 8.60 mmol) in toluene (40 mL)
were added p-toluenesufonic acid monohydrate (2.5 g, 12.9 mmol)
and ethylene glycol (3 mL, 51.62 mmol), and refluxed under an Ar
atmosphere. After 13 h with stirring, the reaction mixture was
evaporated in vacuo. The resulting mixture was basified (pH 9)
with saturated NaHCO3 aqueous solution and extracted with CHCl3
three times. The combined organic extracts were washed with
brine, dried over Na2SO4, and evaporated in vacuo. The residue
was chromatographed on silica gel (100 g, CHCl3/MeOH/25% NH3
aqueous solution = 500/9/1) to give 29 (2.8 g, 89%) as a brown
HRMS (ESI) Calcd for
312.1957.
C
20H26NO2 [M+H]+: 312.1964. Found
amorphous solid. IR (film): 3412, 2953, 1634, 1457 cmꢀ1
;
1H
5.1.38. 4,5a-Epoxy-17-(2,2,2-trichloroethoxycarbonyl)-
NMR (CDCl3, 400 MHz) d: 0.09–0.18 (2H, m), 0.49–0.57 (2H, m),
0.78–0.92 (1H, m), 1.37–1.44 (1H, m), 1.49–1.63(3H, m), 2.11
(1H, dt J = 4.0 12.0 Hz), 2.19–2.33 (2H, m), 2.38 (2H, d, J = 6.4 Hz),
2.58–2.69 (2H, m), 3.06 (1H, d, J = 18.8 Hz), 3.09–3.12 (1H, m),
3.72–3.79 (1H, m), 3.83–3.97 (2H, m), 4.12–4.20 (1H, m), 4.53
(1H, s), 6.60 (1H, dd, J = 2.4, 8.0 Hz), 6.67 (1H, dd, J = 2.4, 8.0 Hz),
7.06 (1H, t, J = 8.0 Hz), a proton (OH) was not observed. MS (ESI)
m/z = 392 [M+Na]+. HRMS (ESI) Calcd for C22H27NNaO4 [M+Na]+:
392.1838. Found 392.1847.
morphinan-6-spiro-20-(10,30-dioxolane) (34)
Compound 34 was prepared from compound 31 according to
the procedure used to prepare compound 10. Yield, 80%; a white
amorphous solid. IR (film): 2950, 1711, 1455, 1422 cmꢀ1 1H
;
NMR (CDCl3, 400 MHz) d: 1.12 (0.5H, dt, J = 3.2, 12.4 Hz), 1.16
(0.5H, dt, J = 3.2, 12.4 Hz), 1.46–1.70 (3H, m), 1.71–1.86 (2H, m),
2.07–2.16 (1H, m), 2.71–2.97 (2H, m), 2.97 (1H, dd, J = 5.6,
18.4 Hz), 3.72–3.82 (1H, m), 3.84–3.93 (2H, m), 3.97–4.07 (1H,
m), 4.10–4.19 (1H, m), 4.43 (1H, s), 4.68 (1H, dd, J = 4.8, 8.0 Hz),
4.73 (1H, d, J = 12.0 Hz), 4.79 (0.5H, d, J = 12.0 Hz), 4.87 (0.5H, d,
J = 12.0 Hz), 6.65 (1H, dd, J = 3.2, 7.6 Hz), 6.70 (1H, dd, J = 3.2,
7.6 Hz), 7.10 (1H, t, J = 7.6 Hz). MS (ESI) m/z = 496 [M+Na]+. HRMS
5.1.34. 17-Cyclopropylmethyl-8,14-didehydro-4,5
a-
epoxymorphinan-6-spiro-20-(10,30-dioxolane) (30)
Compound 30 was prepared from compound 29 according to
the procedure used to prepare compound 4. Yield, 73%; a brown
(ESI) Calcd for
496.0462.
C
21H22Cl3NNaO5 [M+Na]+: 496.0461. Found

Y. Ida et al. / Bioorg. Med. Chem. 20 (2012) 949–961
959
5.1.39. 4,5
dioxolane) (35)
a
-Epoxy-17-methylmorphinan-6-spiro-20-(10,30-
1H NMR (CDCl3, 400 MHz) d: 1.74 (1H, dq, J = 4.8, 13.2 Hz), 1.84–
2.02 (3H, m), 2.15 (1H, dt, J = 3.6, 12.0 Hz), 2.25 (1H, td, J = 2.4,
14.0 Hz), 2.32–2.46 (2H, m), 2.44 (3H, s), 2.48–2.59 (2H, m), 2.76
(1H, dd, J = 6.0, 18.8 Hz), 3.02 (1H, d, J = 18.8 Hz), 3.09 (1H, dd,
J = 3.2, 5.4 Hz), 4.46 (1H, dd, J = 2.0, 13.2 Hz), 6.59 (1H, dd, J = 0.4,
7.6 Hz), 6.60 (1H, dd, J = 0.4, 7.6 Hz), 6.92 (1H, t, J = 7.6 Hz), a pro-
ton (OH) was not observed. MS (ESI) m/z = 272 [M+H]+. HRMS
(ESI) Calcd for C17H22NO2 [M+H]+: 272.1651. Found 272.1658.
Compound 35 was prepared from compound 34 according to
the procedure used to prepare compound 11. Yield, quant.; a yel-
low oil. IR (neat): 2928, 1631, 1607, 1455 cmꢀ1 1H NMR (CDCl3,
;
400 MHz) d: 1.17 (1H, dq, J = 3.6, 12.8 Hz), 1.48–1.56 (2H, m),
1.59–1.69 (2H, m), 1.89 (1H, dt, J = 4.8, 12.4 Hz), 2.21 (1H, dt,
J = 4.0, 12.4 Hz), 2.23–2.30 (1H, m), 2.37–2.46 (1H, m), 2.42 (3H,
s), 2.53 (1H, ddd, J = 1.2, 4.8, 12.4 Hz), 3.03 (1H, d, J = 18.8 Hz),
3.13 (1H, dd, J = 2.4, 5.2 Hz), 3.73–3.80 (1H, m), 3.85–3.91 (2H,
m), 4.10–4.18 (1H, m), 4.42 (1H, s), 6.61 (1H, dd, J = 0.4, 7.6 Hz),
6.68 (1H, dd, J = 0.4, 7.6 Hz), 7.05 (1H, t, J = 7.6 Hz). MS (ESI) m/
z = 314 [M+H]+. HRMS (ESI) Calcd for C19H24NO3 [M+H]+:
314.1756. Found 314.1762.
5.1.44. 17-Cyclopropylmethyl-6,7-didehydro-quinolino-
[20,30:6,7]morphinan-4-ol (SN-27)
A free base of SN-27 was prepared from compound 37 according
to the procedure used to prepare compound 7. Yield, 86%; a color-
less oil. SN-27 was prepared from the free base of SN-27 according
to the procedure used to prepare SN-11. Yield, 74%; a white solid.
(Free base of SN-27)
5.1.40. 4,5a-Epoxy-17-methylmorphinan-6-one (36)
Compound 36 was prepared from compound 35 according to
IR (neat): 2920, 1579, 1459 cmꢀ1 1H NMR (CDCl3, 400 MHz) d:
;
the procedure used to prepare compound 6. Yield, 81%; a white
0.31–0.20 (2H, m), 0.50–0.57 (2H, m), 0.90–1.01 (1H, m), 2.01 (1H,
dt, J = 4.4, 12.8 Hz), 2.20 (1H, d, J = 12.8 Hz), 2.28 (1H, dt, J = 2.4,
12.8 Hz), 2.45–2.60 (3H, m), 2.82–2.95 (3H, m), 2.99 (1H, dd,
J = 6.0, 19.2 Hz), 3.07–3.16 (2H, m), 3.49–3.56 (1H, m), 5.34 (1H,
d, J = 16.0 Hz), 6.48 (1H, d, J = 7.6 Hz), 6.62 (1H, d, J = 7.2 Hz),
6.68–6.77 (2H, m), 6.80 (1H, t, J = 8.0 Hz), 7.04 (1H, dt, J = 0.8,
6.4 Hz), 7.41 (1H, d, J = 7.6 Hz), 7.60 (1H, s), a proton (OH) was
not observed. MS (ESI) m/z = 397 [M+H]+. HRMS (ESI) Calcd for
crystal. Mp 199.3–200.4 °C; IR (KBr): 2919, 1717, 1457 cmꢀ1 1H
;
NMR (CDCl3, 400 MHz) d: 1.10–1.23 (1H, m), 1.64–1.82 (2H, m),
2.00 (1H, dt, J = 4.4, 12.0 Hz), 2.11 (1H, dt, J = 3.2, 12.0 Hz), 2.24–
2.35 (3H, m), 2.36 (3H, s), 2.44–2.57 (2H, m), 3.00 (1H, d,
J = 18.8 Hz), 3.13 (1H, dd, J = 2.8, 5.2 Hz), 4.56 (1H, s), 6.63 (1H,
dd, J = 0.4, 7.6 Hz), 6.68 (1H, dd, J = 0.4, 7.6 Hz), 6.98 (1H, t,
J = 7.6 Hz). MS (ESI) m/z = 270 [M+H]+. HRMS (ESI) Calcd for
C
17H20NO2 [M+H]+: 270.1490. Found 270.1504.
C
27H29N2O [M+H]+: 397.2280. Found 397.2293.
(SN-27)
5.1.41. 17-Cyclopropylmetyl-4-hydroxymorphinan-6-one (37)
To a stirred solution of 32 (70 mg, 0.23 mmol) in acetic acid
(1 mL) was added zinc (75 mg, 1.13 mmol) and was refluxed under
an Ar atmosphere. After 4 h with stirring, the reaction mixture was
filtrated and evaporated in vacuo. The resulting mixture was basi-
fied (pH 9) with saturated NaHCO3 aqueous solution and extracted
with CHCl3 three times. The combined organic extracts were
washed with brine, dried over Na2SO4, and evaporated in vacuo.
The residue was purified by preparative TLC (ammonia saturated
CHCl3/MeOH = 20/1) to give 37 (89 mg, quant) as a colorless oil.
Mp 229–231 °C (dec); Anal. Calcd for C27H28N2Oꢁ2HClꢁ1.3H2O:
C, 65.80; H, 6.67; N, 5.68. Found: C, 65.91; H, 6.63; N, 5.69.
5.1.45. 6,7-Didehydro-17-isobutyl-quinolino[20,30:6,7]-
morphinan-4-ol hydrochloride (SN-24)
A free base of SN-24 was prepared from compound 38 according
to the procedure used to prepare compound 7. Yield, 78%; a color-
less oil. SN-24 was prepared from the free base of SN-24 according
to the procedure used to prepare SN-11. Yield, 47%; a yellow solid.
(Free base of SN-24)
IR (neat): 3278, 2923, 1698, 1580, 1460 cmꢀ1
;
1H NMR (CDCl3,
IR (neat): 2919, 1579, 1458 cmꢀ1 1H NMR (CDCl3, 400 MHz) d:
;
400 MHz) d: 0.07–0.16 (2H, m), 0.49–0.57 (2H, m), 0.84–0.96
(1H, m), 1.76 (1H, dq, J = 4.8, 13.2 Hz), 1.84–2.01 (3H, m), 2.05
(1H, dt, J = 3.2, 12.2 Hz), 2.24–2.40 (4H, m), 2.49 (1H, dd, J = 7.2,
13.6 Hz), 2.55 (1H, dd, J = 6.0, 13.0 Hz), 2.73 (1H, dd, J = 6.0,
18.8 Hz), 2.82 (1H, d, J = 12.4 Hz), 2.92 (1H, d, J = 18.8), 3.31 (1H,
dd, J = 3.2, 5.6 Hz), 4.46 (1H, dd, J = 2.0, 13.4 Hz), 6.58 (1H, dd,
J = 2.4, 7.2 Hz), 6.67 (1H, dd, J = 2.4, 7.2 Hz), 6.91 (1H, t,
J = 7.6 Hz). MS (ESI) m/z = 312 [M+H]+. HRMS (ESI) Calcd for
0.97 (3H, d, J = 6.4 Hz), 0.99 (3H, d, J = 6.4 Hz), 1.78–1.90 (1H, m),
1.98 (1H, dt, J = 2.8, 12.4 Hz), 2.15 (1H, d, J = 12.8 Hz), 2.22–2.43
(3H, m), 2.53 (1H, br s), 2.60–2.70 (1H, m), 2.86 (1H, dd, J = 11.6,
18.0 Hz), 2.93 (1H, d, J = 16.4 Hz), 3.00 (1H, dd, J = 6.0, 18.4 Hz),
3.05–3.23 (3H, m), 5.30 (1H, d, J = 16.0 Hz), 6.47 (1H, dd,
J = 7.2 Hz), 6.60 (1H, d, J = 8.4 Hz), 6.62–6.76 (2H, m), 6.80 (1H, t,
J = 8.0 Hz), 7.01 (1H, dt, J = 1.2, 8.0 Hz), 7.40 (1H, d, J = 8.0 Hz),
7.61 (1H, s), a proton (OH) was not observed. MS (ESI) m/z = 399
[M+H]+. HRMS (ESI) Calcd for C27H31N2O [M+H]+: 399.2436. Found
399.2425.
C
20H26NO2 [M+H]+: 312.1964. Found 312.1953.
5.1.42. 4-Hydroxy-17-isobutylmorphinan-6-one (38)
(SN-24)
Compound 38 was prepared from compound 33 according to
the procedure used to prepare compound 37. Yield, 81%; a pink
Mp 223–225 °C (dec); Anal. Calcd for C27H30N2Oꢁ2HClꢁ2H2O: C,
63.90; H, 7.15; N, 5.52. Found: C, 63.89; H, 7.20; N, 5.60.
amorphous solid. IR (film): 3289, 2950, 1697, 1582, 1461 cmꢀ1
;
1H NMR (CDCl3, 400 MHz) d: 0.91 (3H, d, J = 6.4 Hz), 0.93 (3H, d,
J = 6.4 Hz), 1.68–1.85 (3H, m), 1.85–1.96 (2H, m), 2.08 (1H, dt,
J = 2.8, 12.0 Hz), 2.20–2.35 (5H, m), 2.44 (1H, dd, J = 6.8, 13.6 Hz),
2.47–2.56 (1H, m), 2.71 (1H, dd, J = 6.0, 18.8 Hz), 2.95 (1H, d,
J = 18.8 Hz), 2.95–3.03 (1H, m), 4.44 (1H, dd, J = 2.4, 13.2 Hz), 6.60
(1H, dd, J = 0.8, 7.6 Hz), 6.73 (1H, dd, J = 0.8, 7.6 Hz), 6.91 (1H, t,
J = 7.6 Hz), a proton (OH) was not observed. MS (ESI) m/z = 314
[M+H]+. HRMS (ESI) Calcd for C20H28NO2 [M+H]+: 314.2120. Found
314.2135.
5.1.46. 6,7-Didehydro-17-methyl-quinolino[20,30:6,7]-
morphinan-4-ol hydrochloride (SN-26)
A free base of SN-26 was prepared from compound 39 according
to the procedure used to prepare compound 7. Yield, 78%; a color-
less oil. SN-26 was prepared from the free base of SN-26 according
to the procedure used to prepare SN-11. Yield, 65%; a white solid.
(Free base of SN-26)
IR (neat): 2910, 1579, 1459 cmꢀ1 1H NMR (CDCl3, 400 MHz) d:
;
1.97 (1H, dt, J = 4.4, 12.8 Hz), 2.16–2.24 (1H, m), 2.32 (1H, dt,
J = 2.8, 12.0 Hz), 2.45 (3H, s), 2.50 (1H, ddd, J = 2.8, 7.2, 11.6 Hz),
2.60 (1H, dd, J = 2.8, 11.6 Hz), 2.84–2.94 (1H, m), 2.91 (1H, d,
J = 16.0 Hz), 2.98 (1H, dd, J = 6.8, 19.2 Hz), 3.08 (1H, dd, J = 6.8,
17.2 Hz), 3.12–3.22 (2H, m), 5.37 (1H, d, J = 16.0 Hz), 6.46 (1H, d,
J = 7.6 Hz), 6.64 (1H, d, J = 7.6 Hz), 6.69–6.80 (2H, m), 6.81 (1H, t,
5.1.43. 4-Hydroxy-17-methylmorphinan-6-one (39)
Compound 39 was prepared from compound 36 according to
the procedure used to prepare compound 37. Yield, 94%; a brown
amorphous solid IR (film): 3270, 2937, 1703, 1580, 1459 cmꢀ1
;

960
Y. Ida et al. / Bioorg. Med. Chem. 20 (2012) 949–961
J = 7.6 Hz), 7.03 (1H, dt, J = 1.2, 7.6 Hz), 7.40 (1H, d, J = 8.0 Hz), 7.59
(1H, s), a proton (OH) was not observed. MS (ESI) m/z = 357
[M+H]+. HRMS (ESI) Calcd for C24H25N2O [M+H]+: 357.1967. Found
357.1962.
or
j
opioid receptor binding assays were performed with
-Pen2,5]-Enkephalin) or [3H]U69,593.
[3H]DAMGO, [3H]DPDPE ([
D
Nonspecific binding was measured in the presence of 1 mM unla-
beled DAMGO, DPDPE or U-69,593. Ki value was calculated accord-
ing to the Cheng–Prusoff equation .41
(SN-26)
Mp 241–242 °C (dec); Anal. Calcd for C24H24N2Oꢁ2HClꢁ2.5H2O:
C, 60.76; H, 6.59; N, 5.90. Found: C, 61.00; H, 6.80; N, 5.95.
Acknowledgments
5.1.47. 17-Cyclopropylmethyl-6,7-didehydro-4,5
a-epoxy-3-
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.
methoxy-quinolino[20,30:6,7]morphinan (41)
Compound 41 was prepared from compound 40 according to
the procedure used to prepare compound 7. The crude compound
was chromatographed on silica gel, but could not be purified com-
pletely. The resulting compound 41 was used for the next reaction
without further purification.
References and notes
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(Free base of SN-25)
IR (KBr): 3652 cmꢀ1 1H NMR (CD3COCD3, 400 MHz) d: 0.08–
;
0.17 (2H, m), 0.41–0.51 (2H, m), 0.81–0.92 (1H, m), 1.83–1.89
(1H, m), 2.04–2.08 (1H, m), 2.13 (1H, dt, J = 4.5, 12.0 Hz), 2.29–
2.41 (2H, m), 2.48 (1H, dd, J = 6.5, 18.0 Hz), 2.50 (1H, dd, J = 6.5,
12.0 Hz), 2.58–2.64 (1H, m), 2.73–2.84 (2H, m), 3.01 (1H, d,
J = 18.0 Hz), 3.25–3.31 (1H, m), 3.62 (1H, dd, J = 2.5, 6.5 Hz), 5.55
(1H, s), 6.56 (1H, d, J = 8.0 Hz), 6.60 (1H, d, J = 8.0 Hz), 7.53 (1H,
ddd, J = 1.0, 7.0, 7.5 Hz), 7.69 (1H, ddd, J = 1.0, 7.0, 7.5 Hz),
7.78–7.82 (1H, m), 7.90–7.93 (1H, m), 8.01–8.05 (1H, m). MS
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(SN-25)
Mp 235–240 °C (dec). Anal. Calcd for C27H26N2O2ꢁ2HClꢁ1.2H2O:
C, 64.21; H, 6.07; N, 5.55. Found: C, 64.25; H, 6.33; N, 5.36.
5.2. Pharmacology
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5.2.1. [35S]GTP
cS binding assay
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d Human recombinant cell (HEK-293) membrane, which was
purchased from PerkinElmer, was incubated in 0.5 mL of assay buf-
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cS (PerkinElmer). Nonspecific binding
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l
, d or
j
opioid receptor bind-
-Ala2, N-Me-Phe4,
ing assays were performed with [3H]DAMGO ([
D
Gly5-ol]-Enkephalin), [3H]DADLE ([
D-Ala2, D-Leu5]-Enkephalin) or
[3H]U69,593 (N-methyl-2-phenyl-N-[(5R,7S,8S)-7-(pyrrolidin-1-
yl)-1-oxaspiro[4.5]dec-8-yl]acetamide). Nonspecific binding was
measured in the presence of 20 mM unlabeled levallorphan for
l,
d opioid receptor binding assay and 1 mM unlabeled U-69,593
for
j opioid receptor binding assay. Ki value was calculated accord-
ing to the Cheng–Prusoff equation.41
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Mouse whole brain without cerebellum and guinea pig cerebel-
lum membranes were prepared as described previously.42 The
l, d

Y. Ida et al. / Bioorg. Med. Chem. 20 (2012) 949–961
961
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(b)
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(a) Nagase, H.; Yamamoto, N.; Nemoto, T.; Yoza, K.;
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