Synthesis and activity of novel 1- or 3-(3-amino-1-phenyl propyl)-1,3-dihydro-2H-benzimidazol-2-ones as selective norepinephrine reuptake inhibitors

Article abstract of DOI:10.1016/j.bmcl.2008.10.026

A series of novel 1- or 3-(3-amino-1-phenyl propyl)-1,3-dihydro-2H-benzimidazol-2-ones as selective norepinephrine reuptake inhibitors was discovered. Several compounds such as 15 and 20 showed good hNET potency. Compounds 15 and 20 also displayed excellent selectivity at hNET that appeared superior to those of reboxetine and atomoxetine (4 and 5).

Full text of DOI:10.1016/j.bmcl.2008.10.026

Bioorganic & Medicinal Chemistry Letters 18 (2008) 6067–6070
Contents lists available at ScienceDirect
Bioorganic & Medicinal Chemistry Letters
journal homepage: www.elsevier.com/locate/bmcl
Synthesis and activity of novel 1- or 3-(3-amino-1-phenyl propyl)-1,3-dihydro-
2H-benzimidazol-2-ones as selective norepinephrine reuptake inhibitors
a
a
a
a
a
Puwen Zhang a, , Eugene A. Terefenko , Casey C. McComas , Paige E. Mahaney , An Vu , Eugene Trybulski ,
*
Elizabeth Koury b, Grace Johnston b, Jenifer Bray b, Darlene Deecher b
a Chemical and Screening Sciences, Wyeth Research, 500 Arcola Road, Collegeville, PA 19426, USA
b Women’s Health and Musculoskeletal Biology, Wyeth Research, 500 Arcola Road, Collegeville, PA 19426, USA
a r t i c l e i n f o
a b s t r a c t
Article history:
A series of novel 1- or 3-(3-amino-1-phenyl propyl)-1,3-dihydro-2H-benzimidazol-2-ones as selective
norepinephrine reuptake inhibitors was discovered. Several compounds such as 15 and 20 showed good
hNET potency. Compounds 15 and 20 also displayed excellent selectivity at hNET that appeared superior
to those of reboxetine and atomoxetine (4 and 5).
Received 17 September 2008
Revised 6 October 2008
Accepted 7 October 2008
Available online 11 October 2008
Ó 2008 Elsevier Ltd. All rights reserved.
Keywords:
Norepinephrine reuptake inhibitor
NRI
Serotonin reuptake inhibitor
Dopamine reuptake inhibitor
3-(3-Amino-1-phenyl propyl)-1,3-dihydro-
2H-benzimidazol-2-ones
The serotonin (SERT), norepinephrine (NET), and dopamine
transporters (DAT) are integral membrane proteins that uptake
5-hydroxytryptamine (5-HT, serotonin), norepinephrine (NE), and
dopamine (DA), respectively, from the synaptic cleft and play a
critical role in regulating the physiological functions of these neu-
rotransmitters.1,2 Monoamine neurotransmitter deficiency has
been implicated in a number of neurological disorders thus making
transporters an important target for drug development. In the last
two decades, numerous selective serotonin reuptake inhibitors
(SRIs) and norepinephrine reuptake inhibitors (NRIs) have been
developed for the treatment of psychiatric disorders.3,4 For exam-
ple, selective SRIs such as fluoxetine (1), paroxetine (2), and citalo-
pram (3) have been used extensively to treat symptoms including
depression and panic disorders. Whereas fewer selective NRIs have
been approved for CNS diseases. Reboxetine (4), a racemic mixture,
has been developed for the treatment of major depressive disorder
(MDD).5,6 Clinical evidences also suggested that reboxetine may
have efficacy in the treatment of chronic pain such as fibromyalgia
and chronic low back pain.7 Atomoxetine (5), another selective
NRI, has been approved for attention deficit hyperactivity disorder
(ADHD).8 In addition, considerable research has focused on devel-
opment of compounds that include both the inhibition of 5-HT and
NE reuptake.2,3 These efforts have led to the development of com-
pounds such as venlafaxine,9 desvenlafaxine,10 and duloxetine
(6)11 that are dual 5-HT and NE reuptake inhibitors (SNRI). Venla-
faxine, desvenlafaxine, and duloxetine are marketed for treatment
of MDD.12–15 Duloxetine has also been approved for diabetic neu-
ropathy,16 fibromyalgia,17 and stress urinary incontinence (SUI).18
H
Me
N
N
Me
F
F3C
O
Me
O
N
H
O
O
NC
F
O
1
2
3
S
Me
Me
O
N
O
NH
O
N
H
H
O
O
Me
4
5
6
Although numerous monoamine transporter inhibitors are
clinically available, there is still considerable interest19–27 in devel-
oping novel compounds with improved metabolic and pharmaco-
logical (treatment onset and response rate or efficacy) properties.
* Corresponding author. Tel.: +1 484 865 3856; fax: +1 484 865 9398.
E-mail address: ZhangP@wyeth.com (P. Zhang).
0960-894X/$ - see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmcl.2008.10.026

6068
P. Zhang et al. / Bioorg. Med. Chem. Lett. 18 (2008) 6067–6070
Our interest in understanding the role of NE in CNS disorders and
its therapeutic potentials7,28 led us to undertake a program to de-
velop selective NRIs. In a previous report, we disclosed a series of
3-(1H-indol-1-yl)-3-arylpropan-1-amines (e.g., 7) that was de-
signed to capture the NRI pharmacophore of the aryloxypropanam-
ines (e.g., atomoxetine 4). To our surprise, these compounds
displayed dual acting NE and 5-HT reuptake inhibition.29,30 In an
effort to expand the SAR of this series and identify new compounds
selective for NET we further elaborated the indole ring and de-
signed oxindole and benzimidazolone based propanamines. Inter-
estingly, replacement of the indole moiety by oxindoles and
benzimidazolones had a marked effect on the NET selectivity over
SERT and led to two new series of selective NRIs. Results of oxin-
dole analogs were recently disclosed.31 Herein we report the syn-
thesis and in vitro activities of benzimidazolone based
propanamines and their analog (8–27).
The new 1- or 3-(3-amino-1-phenylpropyl)-benzimidazol-2-ones
(8–26) and (R)-3-(3-(methylamino)-1-phenylpropyl)benzo[d]thia-
zol-2(3H)-one (27) were evaluated in vitro for their ability to inhi-
bit both the uptake of NE in MDCK-Net6 cells stably transfected
with human NET (hNET) and 5-HT in JAR cells stably transfected
with the human serotonin transporter (hSERT).23 Selected com-
pounds were then assayed for inhibition of radioligand binding
to the human dopamine transporter (hDAT).23 The results of these
studies are summarized in Tables 1 and 2.
Since a majority of compounds from the indole series did not
show a stereochemical preference for NET potency,30 we decided
to start with the (R)-enantiomers for the structure–activity rela-
tionship of the benzimidazolone-derived propanamines. The inhib-
itory activities of these compounds at human NET, SERT, and DAT
are listed in Table 1. Examining inhibition activities of the analogs
with different N-substituents (R3) indicated that the size and nat-
ure of the R3 group had significant impact on hNET potency. The
smaller methyl and larger cyclopentyl and cyclohexyl substitutions
at the R3 position resulted in compounds (8, 18, and 19) with mod-
erate hNET potency (IC50 = 201–463 nM). However, the intermedi-
ate sized ethyl (10), n-propyl (14), and i-propyl (15) analogs had
increased potency with IC50 values ranging from 22–44 nM. The
cyclopropyl analog 13 (166 nM) showed moderate hNET potency
and was >5-fold less potent than its propyl congeners 14 and 15.
The most potent compounds evaluated at hNET from this series
were 20 and 21 (IC50 < 10 nM) in which a phenyl moiety was at-
tached to the benzimidazolone at the R3 position. Fluorination on
the benzimidazolone and/or pendent phenyl ring did not signifi-
cantly change the hNET potency. For example, compounds 10
and 12 had similar hNET potency with IC50 values of 44 and
19 nM, respectively, in the hNET functional assay. Fluorinated 21
also had similar hNET potency comparable to its des-fluorine ana-
log 20 (IC50 = 6 and 9 nM). Consistent with the previous SAR
trend,30 methylamino compound 16 was more potent at hNET than
its dimethylamino analog 17. In addition, compound 10 was signif-
icantly more potent at hNET than its unsubstituted and ethyl ana-
logs (9 and 11) indicating methyl substitution is preferred on the
propanamine. Benzothiazolone analog 27 showed moderate po-
tency with a hNET IC50 value of 121 nM.
Y
X
R1
*
N
R2
*
Me
N
N
N
H
N
R3
O
8-26
7
The preparation of 1- or 3-(3-amino-1-phenylpropyl)-ben-
zimidazol-2-ones is illustrated in Scheme 1. Substituted 1-fluoro-
2-nitrobenzenes 28 were treated with an appropriate alkylamine
or aniline followed by a palladium-mediated reduction of the nitro
moiety to afford benzene-1,2-diamines 29. Ring closure of com-
pounds 29 to generate benzimidazolones 30 was achieved using
1,10-carbonyldiimidazole (CDI). With the key headpiece 30 in hand,
it was attached to 3-chloro-1-phenylpropane to deliver 31 via Mit-
snobu’s coupling protocol by replacing the hydroxyl group of (R)-
or (S)-3-chloro-1-phenylpropan-1-ol. (S)-3-Chloro-1-(3-fluoro-
phenyl)propan-1-ol was not commercially available and was pre-
pared by reducing 3-chloro-1-(3-fluorophenyl)propan-1-one with
BH3 in the presence of catalytic (R)-2-methyl-CBS-oxazaborolidine
following Corey’s conditions.32 Compounds 31 were subjected to
an alcoholic solution of alkyl amines in the presence of potassium
iodide to furnish target compounds 8–26. Compound 27 was pre-
pared in a similar fashion as described for 8–26 starting from com-
mercially available benzo[d]thiazol-2(3H)-one.
In general, hSERT and hDAT inhibition by benzimidazolone ana-
logs as illustrated in Table 1 were weak. For the hDAT-binding
affinity, all compounds that were examined had <50% inhibition
of [3H]WIN-35,428 binding to hDAT at a concentration of 10
lM
indicating excellent hNET selectivity over hDAT. For the hNET
selectivity against hSERT, the ratio derived from the hSERT vs.
hNET IC50 ranged from 16 to >400 indicating improved selectivity
compared to those of the indole leads such as 7.30 Among the most
potent analogs were compounds 15 and 20 of which their hNET
selectivity over hSERT (>300-fold) were superior to those of
reboxetine and atomoxetine (16- and 81-fold).
To determine the stereochemical preference of the benzimidazo-
lone series, the selected (S)-enantiomers of corresponding potent
NRIs from this series were prepared and their inhibition activities
at monoamine transporters are listed in Table 2. When compared
to their (R)-enantiomers, the (S)-enantiomers examined were signif-
icantly less potent at hNET. For example, (S)-24 (21% inhibition at
X
X
X
H
N
NO2
F
NH2
a, b
c
O
N
R3
NHR3
28
29
30
Y
Y
X
X
1 lM) and 26 (IC50 = 215 nM) were over 20-fold less potent than
d
e
R1
*
*
15 (IC50 = 22 nM) and 20 (IC50 = 9 nM). In contrast to the hNET po-
tencytrend, the(S)-enantiomers evaluatedhadgreaterorequivalent
hSERT potency compared to their (R)-enantiomers. For example,
compound 16 and 25 had similar hSERT potency with IC50 values
of 1208 and 1408 nM, respectively while (S)-26 (IC50 = 273 nM)
was about 10-fold more potent than 20 (IC50 = 2995 nM). Finally,
three (S)-enantiomers tested had similar hDAT-binding affinity
compared to their (R)-enantiomers suggesting that stereochemistry
may not play a major role in their binding to hDAT.
Cl
N
N
R2
N
N
R3
N
R3
O
O
31
8-26
Scheme 1. Synthesis of 1- or 3-(3-amino-1-phenylpropyl)-benzimidazol-2-ones.
Reagents and conditions: (a) R3NH2, THF, rt, sealed tube, 70–95%; when R3 = Aryl, n-
BuLi, THF, ꢀ78 to 0 °C, 30–60%; (b) NaBH4, Pd/C (10%), THF/MeOH, rt, N2, 50–90% or
H2, Pd/C (10%), EtOH, rt, >90%; (c) CDI, THF, rt, 60–90%; (d) (R)- or (S)-3-chloro-1-
arylpropan-1-ol, DIAD, Ph3P, THF, rt, N2; 30–70%; (e) KI, MeOH, NHR1R2, 30–80%.

P. Zhang et al. / Bioorg. Med. Chem. Lett. 18 (2008) 6067–6070
6069
Table 1
Inhibitory activities of (R)-1- or 3-(3-amino-1-phenylpropyl)-benzimidazol-2-ones and reference compounds at hNET, hSERT and hDAT
Y
X
R2
N
N
R1
N
N
H
N
S
O
O
R3
8-21
27
R1
R2
R3
hNET IC50 (nM)
hSERT IC50 (nM)
hSERT IC50/hNET IC50
hDAT% inh. at 10 l
Md (%)
a
b
c
Compound
X
Y
4
5
7
8
9
3
3
47
242
48
81
16
7
327
H
H
H
H
F
H
H
H
F
H
H
H
H
F
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
Me
H
H
H
H
Me
H
Me
Et
Me
Et
Et
Et
Et
463
51%e
44
10%e
12
4
10
11
12
13
14
15
16
17
18
19
20
21
27
4311
98
27%e
19
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
28%e
4565
3100
2%e,f
14
7
3
11
5
c-Pro
n-Pro
i-Pro
i-Pro
i-Pro
c-Pent
c-Hex
Ph
166
32
22
28
97
ꢁ450g
40
30
1208
F
27%e
201
311
9
H
H
H
F
16%e
20%e
2995
483
22
24
33
333
80
16
20-F-Ph
6
121
1910
36
a
Inhibition of norepinephrine uptake in MDCK-Net6 cells, stably transfected with human norepinephrine transporter (hNET). Desipramine (IC50 = 3.4 1.6 nM) was used
as a standard.
b
c
Inhibition of serotonin uptake in JAR cells, stably transfected with human Serotonin transporter (hSERT). Fluoxetine (IC50 = 9.4 3.1 nM) was used as a standard.
Unitless value as a ratio in which higher numbers represent relatively greater NET selectivity.
d
Inhibition of [3H]WIN-35,428 binding to membranes from CHO cells expressing recombinant human dopamine transporter (hDAT). Mazindol (22.1 6.5 nM) was used as
a standard.
e
Percent inhibition measured at a concentration of 1
Fifty-three percent inhibition was observed at a concentration of 10
Estimated value based on 53% inhibition at 10 lM.
l
M.
f
lM.
g
(R)-enantiomers from this series were more potent at hNET than
their (S)-analogs. (R)-enantiomers also demonstrated improved
hNET selectivity against hSERT. Several compounds such as 15
and 20 showed good hNET potency and excellent selectivity
against hSERT and hDAT.
Table 2
Inhibitory activities of (S)-1- or 3-(3-amino-1-phenylpropyl)-benzimidazol-2-ones at
hNET, hSERT, and hDAT
X
N
N
Acknowledgments
H
N
O
R3
The authors thank Drs. Ron Magolda and Magid Abou-Gharbia
for their support and the assistance of the Department of Analytical
Chemistry for analytical data.
Compound
X
R3
hNET IC50 (nM)
hSERT IC50 (nM)
hDAT% inh. at
10
a
b
l
Mc (%)
22
23
24
25
26
H
H
H
F
c-Pro
n-Pro
i-Pro
i-Pro
Ph
25%d
627
166
5
References and notes
21%d
1053
215
1408
273
31
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