Synthesis of novel triplet drugs with 1,3,5-trioxazatriquinane skeletons and their pharmacologies. 3: Synthesis of novel triplet drugs with the bis(epoxymethano) or bis(dimethylepoxymethano) structure (double-capped triplet)

Article abstract of DOI:10.1016/j.bmcl.2012.10.023

Novel double-capped triplet drugs, which have one pharmacophore unit and two epoxymethano or dimethylepoxymethano structures (termed cap or diMe-cap structures, respectively) were synthesized. Key intermediate oxazoline 16 derived from acetone enabled the

Full text of DOI:10.1016/j.bmcl.2012.10.023

Bioorganic & Medicinal Chemistry Letters 22 (2012) 7551–7554
Contents lists available at SciVerse ScienceDirect
Bioorganic & Medicinal Chemistry Letters
journal homepage: www.elsevier.com/locate/bmcl
Synthesis of novel triplet drugs with 1,3,5-trioxazatriquinane skeletons
and their pharmacologies. 3: Synthesis of novel triplet drugs with
the bis(epoxymethano) or bis(dimethylepoxymethano) structure
(double-capped triplet)
⇑
Naohisa Wada, Hideaki Fujii, Koji Koyano, Shigeto Hirayama, Takashi Iwai, Toru Nemoto, Hiroshi Nagase
School of Pharmacy, Kitasato University, 5-9-1 Shirokane, Minato-ku, Tokyo 108-8641, Japan
a r t i c l e i n f o
a b s t r a c t
Article history:
Novel double-capped triplet drugs, which have one pharmacophore unit and two epoxymethano or dime-
thylepoxymethano structures (termed cap or diMe-cap structures, respectively) were synthesized. Key
intermediate oxazoline 16 derived from acetone enabled the effective synthesis of double-capped trip-
lets. SYK-134 (7a) and SYK-135 (8a) with N-cyclopropylmethyl substituent and cap structures showed
Received 30 August 2012
Revised 29 September 2012
Accepted 4 October 2012
Available online 13 October 2012
selectivities for the
the opioid receptor. The double-capped triplet drugs with diMe-cap structures preferred the
independently of their N-substituents. SYK-385 (19b), one of the -selective double-capped triplet drugs,
showed the highest selectivity for the receptor among the reported -selective nonpeptide ligands.
Ó 2012 Elsevier Ltd. All rights reserved.
j
opioid receptor. On the other hand, the N-Me series exhibited selectivities for
l
l
receptor
Keywords:
l
Cap structure
DiMe-cap structure
Double-capped triplet
Opioid
l
l
Oxazoline
Many twin drugs have been reported.1,2 Symmetrical twin
drugs can simultaneously fit into the symmetrical binding sites
of a protein complex to afford increased activity, whereas nonsym-
metrical twin drugs may bind to each individual binding site to
give dual action.3 However, twin drugs can act in only one mode,
either with an increase of activity or with a dual action. The advent
of a rigid triplet drug (trimer drug) containing three pharmaco-
phore units in a single molecule is expected to provide the ability
to deliver both increased activity and dual actions. Recently, we
have reported a synthetic method for rigid symmetrical and non-
symmetrical triplet drugs 1 with the 1,3,5-trioxazatriquinane skel-
eton that, depending on the substituents, carried three identical
and nonidentical morphinan units, respectively (Fig. 1).4,5 Among
the synthesized triplet drugs, the symmetrical triplet drug KNT-
93 (R1, R2 = Me, R3, R4 = OH) showed about 56-fold more potent
analgesic effects than did morphine in an acetic acid writhing test,5
indicating that triplet drugs would be useful tools for pharmaco-
logical investigation. We also synthesized capped homotriplet
drugs 2, which have two identical pharmacophore units and the
epoxymethano structure (termed ‘cap structure’).6 One of the syn-
thesized capped triplet drugs, KNT-123 (R3, R4 = OH, R5 = Me)
gands.6 For the comparison with pharmacological effects induced
by triplet drugs 1 or capped triplet drugs 2, we considered the
importance of the synthesis of the corresponding double-capped
triplet drugs 7 and 8 (Scheme 1), which have a pharmacophore unit
and two cap structures. Double-capped triplet drugs 7 and stereo-
isomer 8 were expected to provide insights into the effect of the
R1
R4
N
R3
H
R3
H
O
R2
R5
O
N
N
O
R4
N
O
O
R3
R4
N
O
O
O
O
O
R4
O
R4
R3
R3
N
R5
N
2
R1
1
R1, R2 = Me, CPM
R3 = H, OH
R4 = OMe, OH
showed the highest selectivity for the
l
opioid receptor over the
-selective nonpeptide li-
j
opioid receptor among the reported
l
R5 = Me, CPM, CBM, i-Bu
Figure 1. Structures of symmetrical or nonsymmetrical triplet drugs 1 and capped
homotriplets 2. The cap structure is depicted in blue. CPM: cyclopropylmethyl,
CBM: cyclobutylmethyl
⇑
Corresponding author.
E-mail address: nagaseh@pharm.kitasato-u.ac.jp (H. Nagase).
0960-894X/$ - see front matter Ó 2012 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.bmcl.2012.10.023

7552
N. Wada et al. / Bioorg. Med. Chem. Lett. 22 (2012) 7551–7554
OH
OH
OH
OH
O
O
R1
N
N
N
N
R1
R1
R1
i), ii)
iii)
N
N
N
O
O
+
O
O
O
O
O
O
O
O
OH
OMe
OMe
OR2
OR2
3a-d
4a-d
5a-d (R2 = Me)
7a-d (R2 = H)
6a-d (R2 = Me)
8a-d (R2 = H)
iv)
iv)
a: R1 = CPM, b: R1 = Me, c: R1 = i-Bu, d: R1 = Bn
Scheme 1. Reagents and conditions: (i) TosMIC, K2CO3, MeOH, rt; (ii) 2 M HCl, 60 °C, then glycolaldehyde dimer, HMDS, NH4Cl, AcONa, MeOH, rt, 4a: 50% from 3a, 4b: 67%
from 3b, 4c: 86% from 3c, 4d: 45% from 3d; (iii) glycolaldehyde dimer, CSA, CHCl3, rt, 5a: 18%, 6a: 45%, 5b: 21%, 6b: 21%, 5c: 21%, 6c: 20%, 5d: 27%, 6d: 37%; (iv) n-PrSH, t-
BuOK, DMF, 130 °C, 7a: 60%, 8a: 62%, 7b: 81%, 8b: 69%, 7c: 86%, 8c: 36%, 7d: 71%, 8d: 70%. CPM: cyclopropylmethyl, TosMIC: p-toluenesulfonylmethyl isocyanide, HMDS:
hexamethyldisilazane, CSA: camphorsulfonic acid.
10.1 %
Me
Me
N
Me
Me
Me
Me
OH
5.01 ppm
i), ii)
iii)
H4.84 ppm
O
OH
Me
O
H
1.94 ppm
HO
HO
H
O
CHO
H
O
O
H
H
Me
4.58 ppm
N
N
S
14
15
16
N
R
N
O
H
O
O
O
Scheme 3. Reagents and conditions: (i) TosMIC, K2CO3, MeOH, rt; (ii) 2 M HCl, THF,
rt; (iii) NH4Cl, AcONa, MeOH, reflux, 71% from 14.
H
O
OMe
OMe
6a
As shown in Scheme 1, we achieved the synthesis of the double-
capped triplet drugs 7 and 8 with various N-substituents. However,
this method required the stepwise synthesis of each oxazoline 4 for
the respective double-capped triplet drugs 7 and 8. Therefore, we
attempted to develop a more efficient one-pot synthesis using
oxazoline 10 composed from two glycolaldehyde units. The reac-
5a
NOESY
NOE
Figure 2. Observed NOESY and NOE in compounds 5a and 6a, respectively.
1,3,5-trioxazatriquinane skeleton on the pharmacological proper-
ties. Herein, we report the synthesis of double-capped triplet drugs
7 and 8 and their pharmacologies.
tion of oxazoline 10 with
a-hydroxyaldehyde derived from 3
would then directly provide double-capped triplets 5 and 6. How-
ever, our attempt to synthesize oxazoline 10 furnished a complex
product mixture (Scheme 2). This outcome may have resulted from
Synthesis of double-capped triplet drugs 7 and 8 stemmed
from naltrexone methyl ether (3a) or the related compounds
3b–d (Scheme 1). Naltrexone methyl ether (3a) was treated with
p-toluenesulfonylmethyl isocyanide (TosMIC) in the presence of
labile intermediate 11. Iminoalcohol 11 with hydrogens at the
a-
position of the hydroxy group would be in equilibrium among
11, aminoenol 12, and aminoaldehyde 13 (Scheme 2). Inspired
with this result, we planned to synthesize new targets 19 and 20.
K2CO3, and then 2 M HCl.6 The thus obtained
a-hydroxyaldehyde
was converted into oxazoline 4a by the treatment with glycolalde-
hyde dimer in 50% yield from 3a. The reaction of oxazoline 4a with
glycolaldehyde dimer afforded the mixture of double-capped trip-
lets 5a and 6a in 18% and 45% yield, respectively. NOESY and NOE
experiments determined that the configuration of the methine
moiety of 1,3,5-trioxazatriquinane skeleton in 5a and 6a was R
and S, respectively (Fig. 2). O-Demethylation of 5a and 6a was con-
ducted by treatment with n-PrSH and t-BuOK to give the corre-
sponding phenolic compounds 7a (SYK-134) and 8a (SYK-135) in
respective 60% and 62% yields. The other double-capped triplet
drugs 7b–d and 8b–d with N-Me, i-Bu, or Bn substituents were
prepared from the corresponding compounds 3b–d in the same
manner (Scheme 1).
For the purpose, we attempted to synthesize
15 which lacked -protons (Scheme 3). Acetone (14) was con-
verted into -hydroxyaldehyde 15 by the procedure described
a-hydroxyaldehyde
a
a
above. The treatment of 15 with NH4Cl in the presence of AcONa
provided oxazoline 16 in 71% yield from 14.
With oxazoline 16 in hand, we then reacted 16 with
a-hydroxyaldehyde derived from naltrexone methyl ether (3a) to
afford the other double-capped triplets 17a and 18a in 15% and
21% yield, respectively (Scheme 4). The obtained double-capped
triplets 17a and 18a have two dimethylepoxymethano structures
(hereafter termed ‘dimethylcap (diMe-cap) structure’). The config-
uration of the methine moiety of the 1,3,5-trioxazatriquinane
Me
Me
Me
Me
OH
OH
O
O
N
N
R1
R1
OH
N
CHO
OH
9
i)
N
N
i) - iii)
O
O
+
3a-d
O
O
O
O
O
10
Me
Me
Me
Me
OR2
OR2
17a-d (R2 = Me)
19a-d (R2 = H)
18a-d (R2 = Me)
20a-d (R2 = H)
i)
iv)
iv)
NH2
OH
a: R1 = CPM, b: R1 = Me, c: R1 = i-Bu, d: R1 = Bn
NH
NH2
complex mixture
OH
11
O
13
Scheme 4. Reagents and conditions: (i) TosMIC, K2CO3, MeOH, rt; (ii) 2 M HCl,
60 °C; (iii) oxazoline 16, CSA, CHCl3, reflux, 17a: 15% from 3a, 18a: 21% from 3a,
17b: 17% from 3b, 18b: 27% from 3b, 17c: 22% from 3c, 18c: 48% from 3c, 17d: 35%
from 3d, 18d: 48% from 3d; (iv) BBr3, CH2Cl2, À78 °C to rt, 19a: 86%, 20a: 93%, 19b:
quant., 20b: 83%, 19c: quant., 20c: 91%, 19d: 94%, 20d: 63%.
12
Scheme 2. Reagents and conditions: (i) glycolaldehyde dimer, NH4Cl, AcONa,
MeOH, rt.

N. Wada et al. / Bioorg. Med. Chem. Lett. 22 (2012) 7551–7554
7553
Table 1
Binding affinities of synthesized double-capped triplet drugs for opioid receptorsa
Compound
N-Substituent
Configuration
Ki (nM)
j
Selectivity
l Selectivity
lb
dc
jd
l
/
j
d/j
d/
l
j/l
7a (SYK-134)
8a (SYK-135)
19a (SYK-342)
20a (SYK-341)
7b (SYK-379)
8b (SYK-380)
19b (SYK-385)
20b (SYK-386)
7c (SYK-381)
8c (SYK-382)
19c (SYK-394)
20c (SYK-395)
7d (SYK-368)
8d (SYK-369)
19d (SYK-396)
20d (SYK-397)
CPM
R
S
R
S
R
S
R
S
R
S
R
S
R
S
R
S
8.65
6.85
2.14
5.35
2.34
2.38
1.85
2.67
99.1
85.7
88.1
134
99.8
78.6
71.8
22.0
171
3.86
5.95
7.89
24.2
2.24
1.15
0.271
0.221
25.9
13.2
9.10
0.909
1.57
11.5
11.5
33.6
4.11
73.1
55.9
42.8
3.66
0.798
9.89
>11.4
4.04
0.446
0.869
3.69
4.52
46.6
Me
i-Bu
Bn
109
0.0214
<0.0024
<0.0019
<0.0027
<0.099
<0.086
<0.088
<0.134
133
>1000
>1000
>1000
>1000
>1000
>1000
>1000
>1000
>1000
>1000
>1000
<0.133
<0.079
<0.0098
<0.079
<0.848
>420
>541
>375
>10.1
>11.7
>11.4
>7.46
79.1
9.78
79.1
848
>1000
541
>1000
84.0
>1000
>1000
e
—
<0.541
e
e
e
e
>1000
581
450
—
—
—
—
<0.581
<0.450
<0.084
0.145
>2.22
>1.72
>2.22
e
—
—
e
e
e
e
>1000
—
—
—
a
b
c
Binding assays were carried out in duplicate (
[3H] DAMGO was used.
j
: cerebellum of guinea pig,
l
and d: whole brain without cerebellum of mouse).
[3H] DPDPE was used.
d
e
[3H] U-69,593 was used.
Selectivity was not calculated as both Ki values were over 1000 nM.
O
(A)
OH
OH
O
O
(B)
N
N
HO
HO
N
N
O
O
O
O
O
O
O
O
C-ring
OH
O
O
O
OH
OH
H
N
O
NMe
C-ring
HO
HO
O
N
N
N
6
N
5
SYK-140
KNT-152
repulsion
O
O
4
Figure 3. Structures of capped homotriplet drugs SYK-140 and KNT-152.
OH
OH
Figure 4. Proposed active conformation of SYK-134 (7a) and SYK-135 (8a) (A) and
nalfurafine (B) binding to the receptor. The green sphere indicates a hydrogen
bond accepting pharmacophore.
skeleton in 17a and 18a was determined by NOE and NOESY exper-
iments. Double-capped triplets 17a and 18a were demethylated
with BBr3 to give the corresponding phenolic compounds 19a
and 20a in 86% and 93% yield, respectively. The other double-
capped triplet drugs 19b–d and 20b–d with diMe-cap structures
were prepared in the same manner (Scheme 4).
The binding affinities of the prepared double-capped triplet
drugs for the opioid receptors were evaluated with competitive
binding assays (Table 1). The assays were performed by a previ-
ously reported procedure.7 In the capped homotriplet drugs with
N-cyclopropylmethyl (CPM) substituents, the configuration of the
methine moiety of 1,3,5-trioxazatriquinane skeleton had an
j
compounds with N-CPM group. As a result, double-capped triplet
drugs with the N-Me substituent showed
l selectivity. This substi-
tuent effect was also observed in other morphinan derivatives.8–11
Among compounds with N-Me substituent, SYK-385 (19b) was the
most selective for the
123,6 which was a capped homotriplet drug with an N-Me group
and was reported to show the highest selectivity for the receptor
-selective nonpeptide li-
l receptor and was more selective than KNT-
l
over the
j receptor among the reported l
gands.12–15 The affinities of compounds with bulky substituents (i-
Bu or Bn group) on the nitrogen were very low.
extreme effect on the binding affinities: the affinities (Ki
38.33 nM, Ki (d) = >1000 nM, Ki ) = 247.2 nM) of SYK-140
(R-isomer, Fig. 3) were much worse than those (Ki ) = 0.480
) = 2.752 nM) of KNT-152 (S-isomer,
(l) =
(j
SYK-134 (7a) and SYK-385 (19b), which were the most selective
(l
compounds for the
j
and
l
receptor, respectively, were assessed
S-binding assay in human
nM, Ki (d) = 16.15 nM, Ki (j
for functional activity in the [35S]GTP
c
Fig. 3).6 In contrast, double-capped triplet drugs with the N-CPM
group demonstrated sufficient binding to each type of opioid
receptor independently of their configurations.
receptor transfected CHO cells. Procedures similar to those previ-
ously reported16 were used. Both compounds showed agonist
activities: SYK-134 (7a): EC50
SYK-385 (19b): EC50 ) = 6.0 nM, Emax
The selectivity of SYK-134 (7a) and SYK-135 (8a) can be inter-
(j
) = 25.0 nM, Emax
(j)
17 = 70.0%;
SYK-134 (7a) and SYK-135 (8a) with cap structures showed
selectivities, whereas SYK-341 (20a) and SYK-342 (19a) with
diMe-cap structures exhibited selectivities. SYK-134 (7a)
(R-isomer) was more selective for the receptor than SYK-135
(8a) (S-isomer), while SYK-342 (19a) (R-isomer) was more selective
for the receptor over the d receptor than SYK-341 (20a) (S-isomer).
On the other hand, the affinities for the receptor of compounds
with an N-Me substituent were extremely decreased, whereas
their affinities for the receptor were increased compared to the
j
(l
(l)
17 = 79.1%.
j
l
preted in terms of their possible conformation: the dipole-dipole
repulsion between 4,5-epoxy moiety and the cap structure would
raise the 1,3,5-trioxazatriquinane structure to the upper side of
the C-ring (Fig. 4A), which would resemble the active conformation
j
l
j
of nalfurafine18–21 (Fig. 4B) for binding to the
to our 3D-pharmacophore model of
j
receptor. According
j
agonists,20,21 the 6-amide
l

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N. Wada et al. / Bioorg. Med. Chem. Lett. 22 (2012) 7551–7554
side chain of nalfurafine is one of the important pharmacophores
and functions as a hydrogen bond acceptor. The oxygen of the
cap structure in SYK-134 (7a) and SYK-135 (8a) may also function
as a hydrogen bond acceptor. As a result, SYK-134 (7a) and SYK-
References and notes
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135 (8a) would exert
esting that the diMe-cap structure increased and decreased the
affinities for the and receptor, respectively, to exhibit selec-
tivity in both the N-CPM and N-Me series. These phenomena indi-
cate that the receptor binding site, with which the cap or diMe-
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stricted compared to the receptor.
j selectivity and j agonist activity. It is inter-
l
j
l
j
l
Concerning the symmetrical triplet drugs with three identical
pharmacophore units, the 1,3,5-trioxazatriquinane skeleton
seemed to mainly function as a spacer because the binding profiles
of the triplets resembled that of each pharmacophore unit. On the
other hand, the 1,3,5-trioxazatriquinane skeleton in the double-
capped triplets effected the binding profiles of the triplets; the
11. Yamamoto, N.; Fujii, H.; Nemoto, T.; Nakajima, R.; Momen, S.; Izumimoto, N.;
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selectivity for the
SYK-135 (8a), while SYK-385 (19b) was obtained the selectivity
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j receptor was provided to SYK-134 (7a) and
12.
13.
14.
15.
A l antagonist, cyprodime: Schmidhammer, H.; Jennewein, H. K.; Krassnig, R.;
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l
In conclusion, novel double-capped triplet drugs with cap or
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l
Antagonists, 6-heterocyclic substituted naltrexamine derivatives: Li, G.;
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and cap structures, showed
N-Me series exhibited selectivities. The double-capped triplet drugs
with diMe-cap structures preferred the receptor independently
of their N-substituents. SYK-385 (19b), one of the -selective
double-capped triplet drugs, showed the highest selectivity for
the receptor among the reported -selective nonpeptide ligands.
j selectivities. On the other hand, the
A
l agonist, morphine: Toll, L.; Berzetei-Gurske, I. P.; Polgar, W. E.; Brandt, S.
l
R.; Adapa, I. D.; Rodriguez, L.; Schwartz, R. W.; Haggart, D.; O’Brien, A.; White,
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l
l
j and l
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Acknowledgments
19. Nagase, H.; Watanabe, A.; Nemoto, T.; Yamaotsu, N.; Hayashida, K.; Nakajima,
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We acknowledge the financial supports from Shorai Foundation
for Science and Uehara Memorial Foundation. We also acknowl-
edge the Institute of Instrumental Analysis of Kitasato University,
School of Pharmacy for its facilities.