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K. M. Boy et al. / Bioorg. Med. Chem. Lett. 14 (2004) 4467–4470
SAR investigation (Fig. 1).8 Based on these early studies,
we developed a hypothesis that the angle formed between
the dialkoxyphenyl head group and the cyclohexane ring
was a determinant of potency at h-SERT and 5-HT1A
.
Specifically, we sought an optimized angle, which would
maximize both activities simultaneously.
Figure 2. ORTEP drawing of 2b with thermal ellipsoids at 40%
probability for non-H atoms and open circles for H-atoms.
We appreciated that compounds 1 sampled conforma-
tions about the cyclohexanol/aryl ring bond in solution.
We wished to add conformational constraint to this
bond to more closely match the (unknown) bound-state
conformation of the ligand. To study the issue in detail,
we envisioned two classes of molecules with fixed and
orthogonal relationships (compounds 2 and 3). In com-
pound 2, the aryl ring occupies a perpendicular (ꢀ90°)
relationship to the cyclohexanol unit, while in
compound 3, the aryl ring is fixed in a planar conforma-
tion with respect to the cyclohexene ring. Taken to-
gether, these molecules probe the binding requirements
of the h-SERT and 5-HT1A proteins.
no trans isomer detected. This was verified by single-
crystal X-ray analysis of compound 2b10 (Fig. 2).
Fused polycycles 3 were synthesized by effecting a reduc-
tive amination of 1,4-cyclohexanedione monoethylene
ketal with appropriately substituted benzylpiperazines
and benzylpiperidines. Deprotection of the ketal, fol-
lowed by enamine formation provided intermediates
14. Condensation with appropriate aryl isocyanates in
refluxing chloroform, followed by acid-mediated ring
closure provided the desired compounds 3 (Scheme 2).
Compounds 2 were synthesized starting from the
5-bromobenzo[d][1,3]dioxole-4-carbaldehyde9
Binding at the h-SERT and 5-HT1A receptors were
measured11 by published methodology12,13 (using [3H]-
citalopram and ( )-[3H]-8-hydroxydipropylaminotet-
ralin, respectively) and the data expressed as IC50 values
with the radioligand at the Kd concentration (Table 1).
Compounds 2 may be classified as dual 5-HT1A and h-
SERT modulators, the 5-HT1A activity being dominant
and in the lower-to mid-nanomolar range. Selectivities
range from ꢀ2.5-fold (2a) to ꢀ40-fold (2s, 2t). Consist-
ent with the SAR of the cyclohexanol analogs, 2-halo
substituents on the benzylpiperidine/piperazine moiety
known
(5) (Scheme 1). Silver nitrate oxidation to the corre-
sponding bromoacid and standard functional group
manipulation furnished the amide 7. Halogen–metal
exchange afforded a stable nucleophile, producing the
tertiary alcohol adduct 8 upon addition of 1,4-cyclohex-
anedione monoethylene ketal. Treatment with sodium
methoxide formed the lactone 9, which was then sub-
jected to 3M HCl and acetone to provide the ketone
10. Reductive amination with appropriately substituted
benzylpiperazines and benzylpiperidines utilizing a tita-
nium isopropoxide/sodium borohydride protocol pro-
vided the desired cis-cyclohexane spirolactones 2, with
O
O
O
O
O
O
O
O
O
n
n
n
H
N
O
O
O
a
b
c
OH
NEt2
a
b
c
Br
Br
N
Y
Br
O
N
Y
Y
5
6
7
Z
O
Z
O
O
Z
n
n
O
O
NEt2
d
e
O
11
12
13
O
HO
O
O
8
9
A
A
O
OH HN
NMe
NH
O
2
O
n
O
O
O
O
O
O
n
O
f
d
e
O
N
Y
N
Y
N
Y
NH
Y
N
10
2
Z
11
O
Z
Y
Z
Z
Z
15
14
3
Scheme 1. Reagents and conditions: (a) AgNO3, NaOH, rt, 1h; (b) i.
SOCl2, CH2Cl2, reflux, ii. HNEt2, CH2Cl2, reflux (88% from 5); (c) s-
BuLi, 1,4-cyclohexanedione monoethylene ketal, À78° C to rt; (d)
NaOMe, MeOH, (78%, two steps); (e) 3M HCl, acetone, reflux, 93%;
(f) i. Ti(Oi-Pr)4, amine, 120°C, ii. NaBH4, EtOH, (18%, two steps).
Scheme 2. Reagents and conditions: (a) 1,4-cyclohexanedione mono-
ethylene ketal, NaBH(OAc)3, THF, HOAc, 77%; (b) 3M HCl,
acetone, reflux, 100%; (c) Me2NSiMe3, p-TsOH, 100%; (d) aryl
isocyanate, CHCl3, reflux, 93%; (e) HCl, MeOH, reflux, 6%.