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E. Honda et al. / Bioorg. Med. Chem. Lett. 24 (2014) 3898–3902
basic amino group of compound 23a was expected to be fixed
around the suitable region against the aromatic ring. The cyclic
compound 23a showed more potency on NE and DA reuptake inhi-
bition than acyclic compound 5 (Table 1, entry 1). These results
encouraged us to further optimize the 1-aryl-1,4-diazepan-2-one
derivatives.
N
NH
HCl
O
Me
23j-
S
TRI activity and metabolic stability of synthesized 1-aryl-1,4-
diazepan-2-one derivatives were shown in Table 1. Initially, com-
pound 23b without a substituent on the 1,4-diazepan-2-one ring
was synthesized as a benchmark. Interestingly, compound 23b
had more potent TRI activity but had reduced metabolic stability
compared with the spiro-cyclopropane analog 23a (Table 1, entries
1 and 2). A major site of metabolism (SOM) was predicted at the 6-
and 7-positions of compound 23b by MetaSite13 analysis (Fig. 3a),
which explained the differences in metabolic stability between
compounds 23a and 23b. On the basis of these results, smaller sub-
stituents than cyclopropane, such as methyl or fluorine groups,
were introduced at the 6-position of compound 23b to increase
TRI activity while maintaining metabolic stability. As the result,
both 6-methyl derivative 23c and 6,6-difuloro derivative 23d
showed good metabolic stability but showed reduced TRI activity
(Table 1, entries 3 and 4). These results indicated that substituents
at the 6-position were not suitable for the enhancements of TRI
activities and that suitable pKa values were required for TRI activity
(pKa value; 23d = 4.2, 23b = 7.9).
Two other approaches were considered for the improvement of
metabolic stability on the basis of the results of MetaSite analyses,
(i) direct and/or indirect block of SOMs and (ii) direct and/or
indirect block of site of structure contribution (Fig. 3a–c). Thus,
the 7-methyl derivative 23e (i), the 5-methyl derivative 23f (i/ii),
the 4-methyl derivative 23g (ii), and the 3-methyl derivative 23h
(ii) were synthesized. Introduction of a substituent at the 3-posi-
tion showed the most balanced results for both metabolic stability
and TRI activity (Table 1, entries 5–8). Through further optimiza-
tion of substituents at the 3-position, ethyl group was identified
as a good substituent (Table 1, entry 9). Next, the 3,4-dichloro-
phenyl group at 1-position was replaced with a 2-naphthyl group
according to the common knowledge of the efficacy of 2-naphthyl
group with TRI activity.14 The resulting 2-naphthyl derivatives 23j
and 23k showed high TRI activities, and the 3-methyl derivative
23j showed excellent metabolic stability (Table 1, entries 10 and
11). Finally, the optical resolution of the racemate 28 was
performed by chiral HPLC to obtain the two enantiomers 28-S
and 28-R. The eutomer 23j-S, which was derived from 28-S by
salt formation, showed both good TRI activity and metabolic
stability.
Figure 1. ORTEP drawing of 23j-S; thermal ellipsoids are drawn at 30% probability.
CCDC for compound 23j-S contains the supplementary crystallographic data for this
Letter (CCDC No.: 964884). These data can be obtained free of charge from The
of the Boc group, cyclization, deprotection of the benzyl group, and
then salt formation. The 4-methyl derivative 23g was derived from
23a by reductive alkylation and then salt formation. Optical reso-
lution of the free base 28 was performed by chiral HPLC. Acidic
treatment of the two enantiomers 28-S and 28-R gave the final
products 23j-S and 23j-R. Absolute configuration of 23j-S was
determined by single crystal X-ray structure analysis, and an
ORTEP drawing of 23j-S is demonstrated in Figure 1.
The outline of design of the 1-aryl-1,4-diazepan-2-one deriva-
tive 23a is shown in Figure 2. Amitifadine and Milnacipran have
characteristic rigid structures among reported uptake inhibitors,
because it was considered that relative distance between aromatic
ring and basic amino group was important for TRI activity. In par-
ticular, Milnacipran showed a relatively lower risk of CYP2D6 and
hERG inhibition. The amide moiety of Milnacipran is unique among
antidepressants, and it may play an important role in the avoid-
ance of the common liabilities of CAD structures due to its low
lipophilicity.
Amitifadine and Milnacipran have the same core structure A,
which was created by the cleavage of bond ‘a’ of Amitifadine or
by the removal of diethylamide of Milnacipran. The other cleavage
of bond ‘b’ of Amitifadine led to the other type of core structure B,
which will provide a new structure by insertion of an amide moiety
such as transformation into Milnacipran from structure A. Subse-
quently, compound 5 was designed by appropriate relocation of
three key components, the benzene ring, the amide moiety, and
the basic amine groups, such as Milnaciplan or Amitifadine.
Compound 5 showed potential to achieve TRI activity, and its
IC50 values of serotonin transporter (SERT), norepinephrine trans-
porter (NET), and dopamine transporter (DAT) were 1100, 120,
and 880 nM, respectively. Finally, the compound 23a was designed
by cyclization in order to enhance TRI activity, and because the
Removal of
amide
Cl
Cl
O
NH2
Clevage
of bond 'a'
NEt2
H2N
A
Milnacipran
Cl
Cl
Cl
N
NH
HCl
a
b
O
Cl
N
23a
H
Amitifadine
Cyclization
Clevage
of bond 'b'
Insertion of
amide
Cl
Cl
Cl
N
O
NH2 HCl
Me
Cl
NH2
5
B
Figure 2. Design of a novel core structure.
Honda, Eiji
