Design and synthesis of novel opioid ligands with an azabicyclo[2.2.2] octane skeleton and their pharmacologies

Article abstract of DOI:10.1016/j.bmcl.2012.03.001

A novel opioid ligand possessing a stable and cyclic imine 16 and its derivatives with an azabicyclo[2.2.2]octane skeleton were synthesized. The imine 16 showed higher affinity for the μ receptor than compound 21 with an oxabicyclo[2.2.2]octane skeleton.

Full text of DOI:10.1016/j.bmcl.2012.03.001

Bioorganic & Medicinal Chemistry Letters 22 (2012) 2689–2692
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Bioorganic & Medicinal Chemistry Letters
journal homepage: www.elsevier.com/locate/bmcl
Design and synthesis of novel opioid ligands with
an azabicyclo[2.2.2]octane skeleton and their pharmacologies
Yoshikazu Watanabe a,b, Shota Kitazawa a, Hideaki Fujii a, Toru Nemoto a, Shigeto Hirayama a,
Hiroshi Nagase a,
⇑
a School of Pharmacy, Kitasato University, 5-9-1, Shirokane, Minato-ku, Tokyo 108-8641, Japan
b Discovery Research Laboratories, Nippon Chemiphar Co., Ltd, 1-22, Hikokawado, Misato-shi, Saitama 341-0005, Japan
a r t i c l e i n f o
a b s t r a c t
Article history:
A novel opioid ligand possessing a stable and cyclic imine 16 and its derivatives with an azabicy-
Received 9 February 2012
Revised 1 March 2012
Accepted 2 March 2012
Available online 8 March 2012
clo[2.2.2]octane skeleton were synthesized. The imine 16 showed higher affinity for the
compound 21 with an oxabicyclo[2.2.2]octane skeleton. Azabicyclo[2.2.2]octane derivative 18d with a
l receptor than
cyclopropylmethyl group on the 8-nitrogen showed the highest affinity for the
thesized derivatives.
l receptor among the syn-
Ó 2012 Elsevier Ltd. All rights reserved.
Keywords:
Opioid
Naltrexone
Azabicyclo[2.2.2]octane skeleton
l
Receptor
Three types of opioid receptors (
l, d,
j) are now well estab-
over that of TRK-820 (Ki = 0.23 nM). The higher affinity of KNT-63
lished not only by pharmacological studies but also by molecular
for the
j
receptor supported our hypothesis that the C-ring may
biological studies.1 Narcotic addiction is believed to be derived
from
drug targets for analgesics without addiction. To obtain ideal anal-
gesics without addiction and other side effects derived from the
receptor, we have synthesized various kinds of naltrexone deriva-
tives2,3 and have reported selective ligands for the d and
recep-
selective agonists,
l receptor type, and therefore j and d types are promising
O
l
j
O
H
tors.4,5 Quite recently, one of our designed
j
OH
14
O
N Me
6
O
TRK-820 (Fig. 1),4a,b,e was launched in Japan as an antipruritic for
patients undergoing dialysis.
Me
N
14
N
N
C
In a previous report,4c,d we postulated that the C-ring in
TRK-820 was in the boat form in its active conformation and the
amide side chain in TRK-820 would orient toward the upper side
of the C-ring in the morphinan skeleton by an interaction between
the 14-OH group and the amide group (Fig. 1). On the basis of our
working hypothesis that the amide orientation in the active con-
formation of TRK-820 would significantly influence the affinity
O
O
O
OH
TRK-820
OH
active conformation
of TRK-820
O
O
R1
8 N
and selectivity for the
j receptor, we designed and synthesized
NH
OH
NH
OH
KNT-63 having
a
novel oxabicyclo[2.2.2]octane skeleton4d
O
14
7
7
(Fig. 1). The orientation of the amide side chain in KNT-63 is fixed
toward the upper side of the C-ring by the oxabicyclo[2.2.2]octane
skeleton similar to the postulated active orientation of that of TRK-
820. This orientation of the amide side chain may account for the
N
C
N
O
O
OH
OH
improved affinity of KNT-63 for the
j receptor (Ki = 0.11 nM) even
1
KNT-63
⇑
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. Structures of TRK-820, KNT-63, and designed derivatives 1 with an
azabicyclo[2.2.2]octane skeleton, and active conformation of TRK-820.
0960-894X/$ - see front matter Ó 2012 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmcl.2012.03.001

2690
Y. Watanabe et al. / Bioorg. Med. Chem. Lett. 22 (2012) 2689–2692
assume the boat form in the active conformation of TRK-820, pro-
moted by an interaction between the 14-OH and the amide group.
The newly designed derivatives with an azabicy-
OH
N
N
1
O
OMe
i)
O
O
clo[2.2.2]octane skeleton have a nitrogen atom at the 8-position
whereas KNT-63 possesses an oxygen atom (Fig. 1). The nitrogen
atom can introduce an extra alkyl or acyl group (R1) on the 8-nitro-
gen. Moreover, the extra nitrogen functionality may afford addi-
tional ionic interactions with the opioid receptor. Thus, the
derivatives with an azabicyclo[2.2.2]octane skeleton were ex-
pected to show interesting structure–activity relationships that
differed from those of KNT-63 derivatives. This report outlines
OMe
OH
Naltrexone
Troc
2
NH2
N
O
N
O
N
OMe
ii)
O
O
O
our attempts to synthesize derivatives
1 with an azabicy-
clo[2.2.2]octane skeleton. We also describe our investigations of
their pharmacologies.
To obtain the designed compounds 1, we synthesized a key
intermediate 14-aminonaltrexone derivative 6 from naltrexone
via 17-(cyclopropylmethyl)northebaine (2)6–9 by a modification
of the previously reported method10 (Scheme 1).
OMe
OMe
4
3
NH2
NH2
N
N
O
O
iii)
iv)
O
O
O
To obtain 8 with an azabicyclo[2.2.2]octane skeleton, we at-
tempted to prepare epoxyester 7 as an intermediate under the same
conditions as for synthesis of KNT-63.4d,11,12 The amine 6 was trea-
ted with ethyl chloroacetate in the presence of NaH in THF; how-
ever, this approach gave only a complex mixture of products
(Scheme 2). Alternatively, we attempted to synthesize aldehyde 9
from amine 6 by use of p-toluenesulfonylmethyl isocyanide (Tos-
MIC)13,14 (Scheme 3). We predicted that aldehyde 9 would convert
to 10 and then further cyclize to provide derivative 11 with an aza-
bicyclo[2.2.2]octane skeleton. Contrary to our expectations, the
treatment of amine 6 with TosMIC at rt in the presence of K2CO3
and subsequent hydrolysis with 2 M HCl gave a novel cyclic imine
12, but not aldehyde 9. The unexpected imine 12 could be stably
isolated in 86% by silica gel column chromatography. The reduction
of imine 12 with NaBH4 provided amine 13 with an azabicyclo-
[2.2.2]octane skeleton. The 3-methoxy group in the amine 13 could
be easily demethylated with BBr3 to afford 14. On the other hand,
the O-demethylation of imine 12 under usual acidic or basic condi-
tions furnished complex mixtures. Therefore, imine 16 was pre-
pared from amine 6 by the O-demethylation and subsequent
TosMIC treatment (23% in two steps, Scheme 4).
OMe
OMe
5
6
Scheme 1. Reagents and conditions: (i) TrocNHOH, NaIO4, 0.5 M AcONa, AcOEt,
0 °C–rt, 86%; (ii) ethylene glycol, CSA, CH2Cl2, rt, then Zn, (NH4)2CO3, 100 °C, 74%;
(iii) H2, 10% Pd/C, MeOH, rt, 88%; (iv) 2 M HCl, 100 °C, 86%.
NH2
14
NH2
14
COOEt
N
N
O
i)
O
O
O
OMe
OMe
7
6
COOEt
7
OH
8
HN
N
We next synthesized the azabicyclo[2.2.2]octane derivatives
with an acyl or alkyl group at the 8-position. We also prepared
a 14-aminonaltrexone derivative 20 without an azabicyclo
[2.2.2]octane skeleton to evaluate the effect of the azabicy-
clo[2.2.2]octane structural motif on the binding affinities to the
opioid receptors (Table 1). These derivatives were synthesized
by acylation or alkylation of the amino group in 13 or 6, with
subsequent O-demethylation (Schemes 5 and 6).
O
OMe
8
Scheme 2. Reagents and conditions: (i) ethyl chloroacetate, NaH, THF, 0 °C–rt.
COOEt
NH2
NH2
NH2
COOEt
HN
N
N
CHO
OH
N
N
OH
O
i), ii)
O
O
OH
O
O
OMe
OMe
OMe
OMe
6
9
10
11
N
HN
HN
N
OH
N
OH
N
OH
iv)
iii)
O
O
O
OMe
OMe
OH
14
12
13
Scheme 3. Reagents and conditions: (i) TosMIC, K2CO3, rt; (ii) 2 M HCl, MeOH, rt, 86% from 6; (iii) NaBH4, MeOH, 0 °C, 54%; (iv) BBr3, CH2Cl2, 0 °C–rt, 34%.

Y. Watanabe et al. / Bioorg. Med. Chem. Lett. 22 (2012) 2689–2692
NH2 NH2
2691
NH2
NHMe
NHMe
N
N
N
N
N
O
O
O
O
O
i)
O
O
O
O
O
ii)
i)
OMe
OH
OMe
OMe
OH
20
6
15
6
19
N
Scheme 6. Reagents and conditions: (i) MeI, K2CO3, DMF, rt, 74%; (ii) BBr3, CH2Cl2,
0 °C–rt, 83%.
N
OH
ii), iii)
O
O
OH
N
OH
16
O
Scheme 4. Reagents and conditions: (i) BBr3, CH2Cl2, 0 °C–rt, 80%; (ii) TosMIC,
K2CO3, rt; (iii) 2 M HCl, MeOH, rt, 23% from 15.
OH
21
Table 1
Figure 2. Structure of 21 with oxabicyclo[2.2.2]octane skeleton.
Binding affinities of oxabicyclo and azabicyclo[2.2.2]octane derivatives for the opioid
receptorsa
(Fig. 2).15,16 The assays were performed by previously reported
procedures.5e
Compound
Affinity (Ki, nM)
Selectivity
lb
dc
jd
d/
l
j
/l
All the azabicyclo[2.2.2]octane derivatives strongly bound to
the
l receptor. Among them, the affinity of 14 for the l receptor
21
14
16
18a
18b
18c
18d
20
0.41
0.28
0.28
0.097
0.90
0.45
0.049
0.27
9.39
13.5
6.12
2.28
10.1
12.1
0.74
2.49
0.47
0.86
1.42
0.29
0.34
9.91
0.19
0.35
22.9
48.4
21.7
23.5
11.3
27.0
15.1
1.15
3.09
5.03
3.00
0.38
22.2
3.91
1.31
was stronger than that of 21 with an oxabicyclo[2.2.2]octane skel-
eton. The azabicyclo[2.2.2]octane derivative 14 also showed higher
l
selectivity than 21, indicating that the conversion of the oxygen
atom (compound 21) to the nitrogen atom (compound 14) in-
creased the selectivity. The lower selectivity ( = 1.15) of
21 would stem from the absence of the amide side chain which
may play an important role in binding to the receptor ( ad-
dress). Although the imine 16 showed the same affinity for the
l
j
j/l
9.20
a
j
j
Binding assays were carried out in duplicate (
j
: cerebellum of guinea pig, l and
d: whole brain without cerebellum of mouse).
l
[3H] DAMGO was used.
b
receptor as the amine 14, its selectivity for the
the d receptor was lower and its selectivity for the
the
With respect to 18a with a Me group on the 8-nitrogen, the
binding affinity for the receptor was stronger than that of 14
without a substituent on the 8-nitrogen. Compound 18d with an
8-cyclopropylmethyl (CPM) group showed the highest affinity for
the
l
receptor over
[3H] DPDPE was used.
c
l
receptor over
[3H] U-69,593 was used.
d
j receptor was higher than that of 14.
l
R
HN
N
N
OH
N
OH
l receptor among the synthesized compounds. The high affin-
ities of 8-alkyl derivatives (18a and 18d) may arise from the high
electron density on the 8-nitrogen due to the electron donating
property of the 8-alkyl groups. The CPM group has been reported
to be a stronger electron donor than the Me group.17–19 Therefore,
18d with a CPM group would be expected to show higher affinity
O
i) or ii)
O
OMe
OMe
13
17a (R = Me), i)
17b
(R = benzoyl), ii) 95%
17c (R = cyclopropanecarbonyl), ii) 95%
for the
l
receptor than 18a with a Me group. In contrast, the bind-
opioid receptor of 18b and 18c, which have the
iii)
17d
(R = CPM)
ing affinities for
l
electron withdrawing benzoyl and cyclopropanecarbonyl groups,
respectively, were lower than those of 18a and 18d. These results
indicated again that the electron density on the 8-nitrogen could
R
N
N
OH
affect the binding affinity for the
On the other hand, the 14-amino compound 20 lacking a bicy-
clic system showed almost the same affinity for the opioid recep-
tor as 14 with an azabicyclo[2.2.2]octane skeleton, although the
l receptor type.
iv)
17
O
l
l
OH
selectivities of 20 were lower than those of 14. These results sug-
gested that the fixed orientation of the lone electron pair or sub-
18a (R = Me), 87%
18b (R = benzoyl), 79%
stituents at the 8-nitrogen could play an important role in the
selectivity.
l
18c (R = cyclopropanecarbonyl), 87%
18d
(R = CPM), 64%
These novel bicyclic compounds, which can possess various 8-
substituents, are expected to be new lead compounds to study
opioid receptors. We are now undertaking the synthesis of azabicy-
clo[2.2.2]octane derivatives 1 with an amide side chain at the
7-position which are expected to show improved affinities and
Scheme 5. Reagents and conditions: (i) MeI, K2CO3, DMF, rt, 90%; (ii) RCOCl, Et3N,
CH2Cl2, rt; (iii) LiAlH4, THF, 0 °C–rt, 90%; (iv) BBr3, CH2Cl2, 0 °C–rt.
The binding affinities of these synthesized derivatives for the
opioid receptors were evaluated with competitive binding assays.
The obtained Ki values, shown in Table 1, are compared with the
values obtained for oxabicyclo[2.2.2]octane derivative 21
selectivities for the
j receptor. The synthesis of the compounds 1
with a 7-amide side chain and their pharmacologies will be the
subject of a future report.

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Y. Watanabe et al. / Bioorg. Med. Chem. Lett. 22 (2012) 2689–2692
Hasebe, K.; Nakajima, M.; Mochizuki, H.; Nagase, H. Bioorg. Med. Chem. 2011,
In conclusion, we synthesized the novel stable and cyclic imine
19, 1205.
16, which was the key intermediate for synthesis of the derivatives
with an azabicyclo[2.2.2]octane skeleton. Cyclic amine 14 with the
basic azabicyclo[2.2.2]octane skeleton and imine 16 showed higher
affinities for the
ative 21. With these new compounds, we have defined some
important structural determinants that favor binding to the
receptor. The presence of an electron donating group at the 8-
nitrogen significantly increased the affinities for the receptor,
5. d Agonists: (a) Nagase, H.; Kawai, K.; Hayakawa, J.; Wakita, H.; Mizusuna, A.;
Matsuura, H.; Tajima, C.; Takezawa, Y.; Endoh, T. Chem. Pharm. Bull. 1998, 46,
1695; (b) Nagase, H.; Yajima, Y.; Fujii, H.; Kawamura, K.; Narita, M.; Kamei, J.;
Suzuki, T. Life Sci. 2001, 68, 2227; (c) Nagase, H.; Osa, Y.; Nemoto, T.; Fujii, H.;
Imai, M.; Nakamura, T.; Kanemasa, T.; Kato, A.; Gouda, H.; Hirono, S. Bioorg.
Med. Chem. Lett. 2009, 19, 2792; (d) Nagase, H.; Nemoto, T.; Matsubara, A.;
Saito, M.; Yamamoto, N.; Osa, Y.; Hirayama, S.; Nakajima, M.; Nakao, K.;
Mochizuki, H.; Fujii, H. Bioorg. Med. Chem. Lett. 2010, 20, 6302; (e) Ida, Y.;
Nemoto, T.; Hirayama, S.; Fujii, H.; Osa, Y.; Imai, M.; Nakamura, T.; Kanemasa,
T.; Kato, A.; Nagase, H. Bioorg. Med. Chem. 2012, 20, 949.
l receptor than the oxabicyclo[2.2.2]octane deriv-
l
l
whereas, the presence of an electron withdrawing group decreased
them. Moreover, the fixation of the orientation of lone electron pair
or alkyl substituent by the azabicyclo[2.2.2]octane skeleton may
6. Bartels-Keith, J. R. J. Chem. Soc. C 1966, 617.
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l selectivities.
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We acknowledge the Institute of Instrumental Analysis of
Kitasato University, School of Pharmacy for its facilities.
deprotection of thioacetal can provide
a-hydroxyaldehyde. However, the
reaction required air- and moisture-sensitive n-BuLi, malodorous 1,3-dithiane,
and the low reaction temperature (À78 °C). Therefore, we developed a new
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