1- Or 3-(3-amino-2-hydroxy-1-phenyl propyl)-1,3-dihydro-2H-benzimidazol-2- ones: Potent, selective, and orally efficacious norepinephrine reuptake inhibitors

Article abstract of DOI:10.1021/jm900888c

Sequential structural modifications of the aryloxypropanamine template (e.g., atomoxetine, 2) led to a novel series of 1-(3-amino-2-hydroxy-1-phenyl propyl)-1,3-dihydro-2H-benzimidazol-2-ones as selective norepinephrine reuptake inhibitors (NRIs). In general, this series of compounds potently blocked the human norepinephrine transporter (hNET) while exhibiting selectivity at hNET against both the human serotonin (hSERT) and dopamine transporters (hDAT). Numerous compounds (e.g., 19-22) had low nonamolar hNET potency with IC ₅₀ values of 7-10 nM and excellent selectivity (>500 fold) at hNET over hSERT and hDAT. Several compounds, such as 20 and 22, were tested in a telemetric rat model of ovariectomized-induced thermoregulatory dysfunction and were efficacious at oral doses of 3 mg/kg in reducing the tail skin temperature. In addition, compound 20 was also studied in the rat hot plate and spinal nerve ligation (SNL) models of acute and neuropathic pain, respectively, and was orally efficacious at doses of 3-10 mg/kg.

Full text of DOI:10.1021/jm900888c

J. Med. Chem. 2009, 52, 5703–5711 5703
DOI: 10.1021/jm900888c
1- or 3-(3-Amino-2-hydroxy-1-phenyl propyl)-1,3-dihydro-2H-benzimidazol-2-ones: Potent, Selective,
and Orally Efficacious Norepinephrine Reuptake Inhibitors†,‡
Puwen Zhang,*,§ Eugene A. Terefenko,§ Jenifer Bray, Darlene Deecher, Andrew Fensome,§ Jim Harrison,# Callain Kim,§
Elizabeth Koury, Lilly Mark,# Casey C. McComas,§ Cheryl A. Mugford,^ Eugene J. Trybulski,§ An T. Vu,§
Garth T. Whiteside,# and Paige E. Mahaney§
§Chemical Sciences and Musculoskeletal Biology and ^Drug Safety and Metabolism , Wyeth Research, S-2250B, 500 Arcola Road, Collegeville,
Pennsylvania 19426, and #Neurosciences, Wyeth Research, CN 8000, Princeton, New Jersey 08543
Received June 17, 2009
Sequential structural modifications of the aryloxypropanamine template (e.g., atomoxetine, 2) led to a
novel series of 1-(3-amino-2-hydroxy-1-phenyl propyl)-1,3-dihydro-2H-benzimidazol-2-ones as selec-
tive norepinephrine reuptake inhibitors (NRIs). In general, this series of compounds potently blocked
the human norepinephrine transporter (hNET) while exhibiting selectivity at hNET against both the
human serotonin (hSERT) and dopamine transporters (hDAT). Numerous compounds (e.g., 19-22)
had low nonamolar hNET potency with IC50 values of 7-10 nM and excellent selectivity (>500 fold) at
hNET over hSERT and hDAT. Several compounds, such as 20 and 22, were tested in a telemetric rat
model of ovariectomized-induced thermoregulatory dysfunction and were efficacious at oral doses of
3 mg/kg in reducing the tail skin temperature. In addition, compound 20 was also studied in the rat hot
plate and spinal nerve ligation (SNL) models of acute and neuropathic pain, respectively, and was orally
efficacious at doses of 3-10 mg/kg.
Introduction
major depression and anxiety disorders.5-7 Additionally,
clinical evidence also suggested that reboxetine may have
efficacy in the treatment of chronic pain such as fibromyalgia
and chronic low back pain.8 Atomoxetine (2), another selec-
tive NRI, has been approved for attention deficit hyperacti-
vity disorder (ADHD).9 Considerable research has also fo-
cused on the development of SNRIs.2,3 These efforts have led
to the marketed drugs such as duloxetine (3) and milnacip-
ran (4), which are both prescribed for treatment of MDD
and fibromyalgia.10-13 Duloxetine has also been approved
for diabetic neuropathy14 and stress urinary incontinence
(SUI).15
The serotonin (SERTa), norepinephrine (NET), and dopa-
mine transporters (DAT) are integral membrane proteins that
uptake 5-hydroxytryptamine (5-HT, serotonin), norepinephr-
ine (NE), and dopamine (DA), respectively, into presynaptic
cells from the synaptic cleft and play a critical role in regulat-
ing the physiological functions of these neurotransmitters.1,2
Monoamine neurotransmitter deficiency has been implicated
in a number of neurological disorders making transpor-
ter inhibitors potential treatment for a wide range of CNS
diseases. Since the early 1980s, numerous monoamine reup-
take inhibitors, including selective serotonin reuptake inhi-
bitors (SRIs), norepinephrine reuptake inhibitors (NRIs),
and dual serotonin and norepinephrine reuptake inhibitors
(SNRIs), have been developed for the treatment of psychiatric
disorders.3,4 Selective SRIs and NRIs such as fluoxetine and
reboxetine (1) have been used to treat symptoms including
†Presented in preliminary form at the 236th ACS National Meeting,
Philadelphia, PA, August 17-21, 2008, MEDI-184.
‡This manuscript is dedicated to the memory of Dr. Ronald L.
Magolda.
*To whom correspondence should be addressed. Phone: (484) 865-
3856. Fax: (484) 865-9398. E-mail: Zhangp@wyeth.com.
a Abbreviations: NE, norepinephrine; NET, norephinephrine trans-
porter; NRI, norepinephrine reuptake inhibitor; 5-HT, serotonin;
SERT, serotonin transporter; SRI, serotonin reuptake inhibitor; SNRI,
serotonin and norepinephrine reuptake inhibitor; DA, dopamine; DAT,
dopamine transporter; hNET, human norepinephrine transporter;
hSERT, human serotonin transporter; hDAT, human dopamine trans-
porter; MDD, major depressive disorder; SUI, stress urinary inconti-
nence; ADHD, attention deficit hyperactivity disorder; SAR,
There is still considerable effort16-27 focused on the devel-
opment of novel NRIs and SNRIs with improved metabolic
and pharmacologic properties (treatment onset, response
rate, or efficacy) to address unmet medical needs arising
from existing therapy.28 In our effort to develop selective
NRIs, we discovered a novel series of monoamine reuptake
structure-activity relationship; AUC, area under the curve; Cmax
,
maximum concentration; OVX, ovariectomized; TST, tail-skin tem-
perature; SNL, spinal nerve ligation.
r
2009 American Chemical Society
Published on Web 09/01/2009
pubs.acs.org/jmc

5704 Journal of Medicinal Chemistry, 2009, Vol. 52, No. 18
Zhang et al.
Scheme 1. Synthesis of 1-(3-Amino-2-hydroxy-1-phenylpropyl)-benzimidazolonesa
a Reagents and conditions: (a) R1NH2, DMF, rt, N2 or PhNH2, KOt-Bu, DMF, rt, N2, 50-80%; (b) NaBH4, MeOH, THF, Pd/C; or H2 (∼30 psi),
MeOH, Pd/C, rt, 40-90%; (c) CDI, THF, rt, N2, 40-80%; (d) ((2R,3R)-3-phenyloxiran-2-yl)methanol or ((2R,3R)-3-(3-fluorophenyl)oxiran-
2-yl)methanol, NaH, Ti(Oi-Pr)4, DMF, rt, 60-80%; (e) TsCl, pyridine, rt; then R2NH2, EtOH, rt, 4-60% for two steps.
inhibitors, the 1-amino-3-(1H-indol-1-yl)-3-phenylpropan-
2-ols (e.g., 5), which were identified by combining virtual
and focused screening efforts with a rational drug design
approach.29 Although several compounds from this series
demonstrated good hNET potency and selectivity at hNET
over hSERT and hDAT, they did not meet our criteria for
advancement to development. To further explore the SAR
of the propanolamine scaffold, we decided to elaborate
the pendent heterocycles by replacing the indole with other
benzene-fused heterocycles. Gratifyingly, the substitution of
indole for benzimidazolone and oxindole moieties led to two
novel series of potent, selective, and orally active NRIs. In this
report, we will discuss the synthesis and SAR of benzimida-
zolone based propanolamines (9-24) and the in vivo activities
of several lead compounds. The oxindole based propanola-
mines is the subject of a separate reportand willbedisclosed in
the due course.
which were subsequently treated with an alcoholic solution of
alkyl amines to furnish target compounds 9-24. Compounds
9-24 were finally converted to their hydrochloride salt prior
to in vitro and in vivo testing.
Results and Discussion
Successful discovery of numerous CNS drugs including
fluoxetine, duloxetine, and atomoxetine from the aryloxypro-
panamine scaffold provides a testament that the propanamine
scaffold serves as a good drug-like template for CNS drug
discovery. However, little has been reported31 on the intro-
duction of a β-hydroxyl group on the propanamine chain even
though it is present in the structure of NE, inferring its
significance in the evolution process. In addition, we reasoned
thata hydroxyl group reduces the lipophilicity and might have
a favorable impact on the ADMET properties of the propa-
nolamines.32 With these notions, we decided to select the lead
compounds that possessed the β-hydroxyl group on the
propanamine chain for our NRI program. Our initial effort
on the indole and aniline based propanolamine templates led
to two new series of selective NRIs or SNRIs,29,33 and the
SAR trends uncovered from these studies have laid a founda-
tion for further SAR expansion. Consequently, our effort
on the benzimidazolones was centered on the 3-position of
benzimidazolinones while maintaining the preferred stereo-
chemistry and SAR of the pendent phenyl group defined from
the previous studies.29,33 The new 1-(3-amino-2-hydroxy-1-
phenylpropyl)-benzimidazol-2-ones (9-24) were evaluated
in vitro for their ability to inhibit both the uptake of NE
in MDCK-Net6 cells stably transfected with human NET
(hNET) and 5-HT in JAR cells natively expressing the human
serotonin transporter (hSERT).20 Compounds were then
assayed for inhibition of radioligand binding to the human
dopamine transporter (hDAT).20 The results of these studies
are summarized in Table 1.
Chemistry
The preparation of 1-(3-amino-2-hydroxy-1-phenylpro-
pyl)-benzimidazolones is illustrated in Scheme 1. Substituted
1-fluoro-2-nitrobenzenes 6 were treated with an appropriate
alkylamine or aniline followed by palladium mediated reduc-
tion of the nitro moiety using either sodium borohydride or
hydrogen to afford benzene-1,2-diamines. The diamines were
immediately used in the next step in which they were subjected
to a ring closure via 1,10-carbonyldiimidazole (CDI) to give
benzimidazolones 7a-l. With the key headpieces 7 in hand,
the epoxide ring-opening of either ((2R,3R)-3-phenyloxi-
ran-2-yl)methanol or ((2R,3R)-3-(3-fluorophenyl)oxiran-2-
yl)methanol by benzimidazolones 7 was readily achieved in
a regio- and stereospecific fashion to furnish the propane-1,2-
diols 8a-o. Ring-opening of the epoxide proved to be very
sluggish and yielded minimal propane-1,2-diol product in the
absence of titanium isopropoxide. The ((2R,3R)-3-(3-fluoro-
phenyl)oxiran-2-yl)methanol was readily prepared in high
enantiomeric excess using a Sharpless epoxidation protocol.30
The least hindered terminal hydroxyl group in diols 8a-o
were selectively activated and converted into their tosylates,
Examining the inhibition profiles of the analogues with
different N-substituents (R1) indicated that the size of the R1
group had a significant impact on the hNET potency. The
smaller methyl group (R1 = Me) resulted in compound 9 with

Article
Journal of Medicinal Chemistry, 2009, Vol. 52, No. 18 5705
Table 1. Inhibitory Activities of 1-(3-Amino-2-hydroxy-1-phenylpropyl)-benzimidazolones at hNET, hSERT, and hDATa
hNET IC50
(nM)b
hNET binding
IC50 (nM)b
hSERT %inh
at 1 μM, %c
hDAT %inh
at 10 μM, %d
compd
R1
R2
X
Y
clogPh
1
3.2 ( 0.5
3.1
(242)e
3.26
3.26
3.94
2.82
2.03
2.56
3.09
2.87
3.27
2.95
3.50
2.83
2.83
3.36
3.14
2.70
2.97
3.28
4.13
3.67
(S,S)-126
2
(5200)e
(>10000)e
3.1 ( 0.3
(48)e
(358)e
15
5
28 ( 11.0
257.0 ( 32.5
17.5 ( 1.8
18.6 ( 2.1
13.4 ( 1.3
56 ( 4.8
42.5 ( 5.3
66.7 ( 8.0
36.7 ( 4.5
13.8 ( 1.6
39.4 ( 5.3
7.8 ( 1.2
19f
14
9
Me
Et
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Et
H
H
H
H
H
H
H
H
H
H
H
H
F
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
H
16.8 ( 4.4
10.8 ( 2.7
90.0 ( 19.0
4
-19
6
n-Pr
i-Pr
t-Bu
c-Bu
c-Pent
Et
H
15
19
H
19
3f
H
1
H
5
6
20
H
46 (2369)e
32
6-F
7-F
6-F
7-F
H
30
29
Et
11.4 ( 5.6
-5
n-Pr
i-Pr
Et
44 (8316)e
6 (>10000)e
15 (>10000)e
8 (>10000)e
19 (6318)e
NDg
16
12
7.4 ( 1.0
10.4 ( 0.8
6.9 ( 0.8
91.9 ( 18.8
>1000
6.4 ( 1.7
4.1 ( 1.3
-2
11
Et
7-F
7-F
7-F
6-F
F
i-Pr
Ph
F
27
11f
NDg
F
i-Pr
H
NDg
a Inhibition of norepinephrine uptake in MDCK-Net6 cells, natively expressing human norepinephrine transporter (hNET). Desipramine (IC50 = 3.4
( 1.6 nM) was used as a standard. b Inhibition of [3H] nisoxetine binding to MDCK-Net6 cells stably transfected with hNET. Desipramine (Ki = 2.1 (
0.6 nM) was used as a standard. 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. d Inhibition of [3H]WIN-35,428 binding to membranes from CHO cells expressing recombinant human
dopamine transporter (hDAT). Mazindol (Ki = 22.1 ( 6.5 nM) was used as a standard. e Values in the parentheses are IC5 (nM). f Percent inhibition
measured at a concentration of 1 μM. g ND: not determined. h Calculated logP by Daylight engine V 4.81.
moderate hNET potency (IC50 = 257.0 nM). Replacing the
methyl group with a larger ethyl or propyl group (10-12) led
to compounds with greater than 10-fold increase in the hNET
potency (IC50 = 13.4-18.6 nM for 10-12 vs 257 nM for 9).
However, further increasing the size of R1 to t-butyl, c-butyl,
and c-pentyl groups caused a slight decrease in hNET potency
(13-15, IC50 = 36.7-66.7 nM) compared to their ethyl and
propyl analogues. Analogues with a 6-fluorine substitution
(16 and 18, IC50 = 36.7, 39.4 nM)) weremarginally less potent
at hNET compared to their des-fluorine congeners 10 and 11
(IC50 = 17.5, 18.6 nM). However, the 7-fluorine substituted
compounds, 17 and 19, had similar hNET potency as their
unsubstituted analogues 10 and 12. Consistent with previous
SAR observation,33 the meta-fluoro analogues, 21-22, were
among the most potent analogues from this new series with
IC50 values of 6.9-10.4 nM. Compound 23, with a phenyl
groupat the R1 position, was significantly less potent at hNET
than its alkyl substituted analogues 21 and 22 (IC50 = 91.9 vs
6.9-10.4 nM). This finding is quite surprising because phenyl
substituted analogues from the corresponding des-hydroxy
propanamine series were more potent at hNET than their
alkyl substituted analogues.27 Ethylamino analogue 24 was
significantly less potent at hNET, consistent with previous
SAR observation on propanamine series.27,33
NE uptake functional assay. For example, compound 20 had
similar IC50 values from these functional and binding assays
(7.4 vs 6.4 nM).
As illustrated in Table 1, inhibition of both hSERT and
hDAT by benzimidazolone analogues was marginal. All
compounds that were examined exhibited less than 50%
inhibition of [3H]WIN-35,428 binding to hDAT at a concen-
tration of 10 μM indicating excellent hNET selectivity over
hDAT. For the hNET selectivity versus hSERT, the com-
poundstested from thisseries hadgoodtoexcellentselectivity.
Among the most potent analogues, compounds 19-22 ex-
hibited excellent hNET selectivity over hSERT (>900 fold)
which was similar to that of (S,S)-reboxetine (1) but better
than those of atomoxetine (2) and lead compounds from
aniline and indole-based propanolamines.29,33 In addition,
these compounds possess desirable drug-like molecular pro-
perties such as polar surface area (PSA, <70)34 and clogP
(<4), which are expected to be beneficial to the PK and the in
vivo efficacy described below.32,35
Neurotransmitters NE and 5-HT have been reported to
stimulate areas of the hypothalamus that play an important
role in temperature regulation.36,37 SRIs and SNRIs have
been shown preclinically and clinically to restore thermore-
gulatory dysfunction caused by the hormone depletion.38-42
More recently, we reported that a selective NRI from a series
of cyclohexanol ethylpiperazines significantly reduced the tail
skin temperature (TST) in a telemetric rat model of ovariec-
tomized (OVX)-induced thermoregulatory dysfunction.20
A selected group of compounds were also tested for their
inhibition of [3H] nisoxetine binding to whole MDCK-Net6
cells stably transfected with hNET. In general, the binding
affinity was consistent with the potency determined from the

5706 Journal of Medicinal Chemistry, 2009, Vol. 52, No. 18
Zhang et al.
To examine the effects of benzimidazolone based propanola-
mines on temperature homeostasis, compounds 10, 19, 20,
and 22 were evaluated in the telemetric rat model.43,44 As
illustrated in Table 2, all four compounds significantly re-
ducedTST with maximum temperature reduction between 1.8
and 3.7ꢀC. Itisnoteworthy thatpropanolamine, 22, ata lower
dosewas moreefficaciousin bothTST reduction andduration
than the ethylpiperazine we previously reported.20 Also no-
tably, the meta-fluorine substituted analogues 20 and 22 were
more efficacious in the telemetric rat model than their des-
fluorine congeners 10 and 19 despite having similar hNET
potency (IC50 = 7-17 nM). For example, both 20 and 22 had
greater mean and maximum reduction in TSTaswellaslonger
duration than those of 10 and 19.
In an effort to establish a pharmacodynamic-pharmaco-
kinetic relationship, the pharmacokinetic properties of com-
pounds 10 and 22 were examined (Table 3). After oral
administration, compounds 10 and 22 had good bioavailabil-
ity, rapid absorption with maximum concentration achieved
within 2 h, and a moderate terminal half-life. The pharmaco-
kinetic findings were consistent with the rapid onset and
moderate duration of activities observed in the telemetric rat
model. However, compound 10 had a higher clearance and
consequentlylower maximum concentration(Cmax) and smal-
ler area under the curve (AUC) than those of 22. These results
may in part explain why compound 10 was less efficacious in
the telemetric rat model than 22 for both duration and TST
reduction.
drugs with greater NRI versus SRI activity are more effective
for the treatment of pain than drugs with only SRI acti-
vity.49,50 To investigate the effect of benzimidazolone based
propanolamines on pain, compound 20 was characterized in
both acute and neuropathic pain models.
The activity of 20 was evaluated in the rat hot plate assay of
acute analgesia. In the hot plate assay,51,52 rats are placed on a
metal plate maintained at a temperature of 52 ꢀC. The latency
to exhibit a nocifensive response, defined as hind paw lift,
flutter, licking, orescape behavior, was measured witha cutoff
of 30 s set to avoid tissue damage. Compound 20 was
administered orally in 0.5% methylcellulose plus 2% Tween
in water and was observed to significantly increase latency at
10 mg/kg 1, 3, and 5 h postdosing (Figure 1). This data
suggests that 20 may be efficacious in treating acute pain at
these doses.
The activity of compound 20 was also evaluated in a rat
spinal nerve ligation (SNL) model of neuropathic pain.
Briefly, in this model,53,54 surgery was performed to tightly
ligate the left L5 spinal nerve. Assessment of mechanical
thresholds was then measured as the hind paw withdrawal
threshold to a noxious mechanical stimulus as determined
usingthe pawpressure technique (Randall-Selitto). The cutoff
was set at 250 g and the end point taken is complete paw
withdrawal. Thresholds were evaluated prior to surgery and
reassessed three to four weeks after SNL surgery. Compound
20 was administered orally in 0.5% methylcellulose plus 2%
Tween in water and the ability to reverse SNL-induced
mechanical hyperalgesia with this agent was assessed. Com-
pound 20 significantly and dose-dependently reversed
A number of neurotransmitters have been implicated in the
modulation of nociceptive processing. NE is a major compo-
nent of the endogenous descending pain inhibitory system
from the rostral ventral medulla to the spinal cord and a
reduced level of endogenous NE activity at both the spine and
supra-spine may in part cause chronic pain.45-48 Consequen-
tially, it is believed that NRIs attenuate pain by blocking
reuptake of NE leading to increased postsynaptic NE levels
and sustained activation of the descending pain inhibitory
pathway. In addition, clinical observations also suggest that
Table 2. Oral Activity of 10, 19, 20, and 22 at 3 mg/kg in a Teleme-
tric Rat Model of Ovariectomized-Induced Thermoregulatory Dys-
functiona
onset of duration of mean reduction maximum reduction
in TST, ꢀC
compd activity, h action, h
in TST, ꢀC
10
19
20
22
1.0
1.0
1.0
1.0
3.5
1.0
5.0
6.0
-1.57
-1.61
-2.03
-2.44
-1.82
-2.09
-2.62
-3.73
a Compound was dosed (po, 3 mg/kg) via % Tween-80 /0.5%
methylcellulose in water vehicle. The onset of an effect was defined as
the first half-hour interval of two consecutive significant (p < 0.05) half-
hour intervals following any number of nonsignificant half-hour inter-
vals. The treatment effect will be considered to have ended when two
consecutive nonsignificant half-hour intervals follow any number of
significant half-hour intervals. Mean temperature change is calculated
from half-hour TST averages obtained over the treatment duration.
Figure 1. Oral activity of compound 20 on hot plate latency. Male
Sprague-Dawley rats (180-210 g, n = 9-10/group). The hot plate
was set at 52 ꢀC and cut off was set at 30 s. Latency to nocifensive
response was measured. 20 was administered orally as a solution of
0.5% methylcellulose plus 2% Tween in water (vehicle). Morphine
as a positive control was administered (sc) as a solution in 0.9%
saline. Data shown are means ( SEM * indicates a p value of e0.05
vs vehicle (ANOVA).
Table 3. Female Sprague-Dawley (SD) Rat Pharmacokinetic Parameters of Compounds 10 and 22 after Intravenous and Oral Administrationsa
dose (mg/kg)
compd
Clp (mL/min/kg)
Cmax (ng/mL)
Tmax (h)
t1/2 (h)
AUC0-inf (h ng/mL)
3
F%
5 (iv)
10
22
10
22
54 ( 16
24 ( 5.7
3.6 ( 1.4
2.3 ( 0.9
3.4 ( 1.0
3.9 ( 0.9
1645 ( 582
3651 ( 806
1845 ( 360
7076 ( 3801 3802
10 (po)
306 ( 1233
1121 ( 527
1.1 ( 0.9
0.5 ( 0.0
56
97
a 2% Tween-80/0.5% methylcellulose in water and 20% of DMSO in PEG200 were used as vehicles for oral and intravenous administrations,
respectively. Three rats were used in each study.

Article
Journal of Medicinal Chemistry, 2009, Vol. 52, No. 18 5707
perature, and the reaction mixture stirred at room temperature
under nitrogen. After 18 h, the reaction mixture was poured into
a saturated aqueous solution of sodium chloride (50 mL) and
extracted with ethyl acetate (2 ꢀ 50 mL). The organic layer was
dried over anhydrous sodium sulfate, concentrated in vacuo,
and the residue was purified via flash column chromato-
graphy (silica, 1% ethyl acetate in hexane) to give t-butyl-(2-
nitrophenyl)-amine as an orange oil (1.27 g, 93%). MS (ES) m/z
195.2 ([M þ H]þ). 1H NMR (DMSO-d6) δ 8.25 (s, 1H), 8.08 (dd,
J = 1.69, 8.71 Hz, 1H), 7.52 (s, 1H), 7.27 (dd, J = 1.30, 8.84 Hz,
1H), 6.68 (ddd, J = 1.17, 6.95, 8.51 Hz, 1H), 1.47 (s, 9H).
To a solution of t-butyl-(2-nitrophenyl)-amine (1.27 g, 6.5
mmol), 5% palladium on carbon (0.5 g), and sodium boro-
hydride (0.49 g, 13.1 mmol) in THF (20 mL) was added
methanol (10 mL) in a dropwise manner. After addition and
stirring for additional 30 min, the reaction mixture was filtered
through a pad of celite and the filtrate was poured into a
saturated aqueous solution of ammonium chloride (50 mL)
and extracted with ethyl acetate (2 ꢀ 50 mL). The organic layer
was dried over anhydrous magnesium sulfate and concentrated
in vacuo to give N-t-butyl-benzene-1,2-diamine, which was used
in the next step without further purification. A solution of N-t-
butyl-benzene-1,2-diamine (1.1 g, 6.7 mmol) and 1,10-carbonyl-
diimidazole (1.63 g, 10 mmol) in anhydrous THF (50 mL) was
stirred at room temperature for 12 h. The reaction mixture was
then poured into a 1N aqueous solution of hydrochloric acid
(50 mL) and extracted with ethyl acetate (2 ꢀ 50 mL). The
organic layer was dried over anhydrous sodium sulfate and
concentrated in vacuo. The crude product was purified via flash
column chromatography (silica, 50% ethyl acetate in hexane) to
give 1-t-butyl-1,3-dihydro-benzimidazol-2-one55 as an off-white
solid (0.66 g, 53% for two steps). MS (ES) m/z 191.1 ([M þ H]þ).
1H NMR (400 MHz, DMSO-d6) δ 10.71 (s, 1H), 7.39 (d, J =
7.02 Hz, 1H), 6.87-6.95 (m, 3H), 1.69 (s, 9H). Similar procedure
was used to prepare other benzimidazolones that were not
commercially available.
Figure 2. Oral activity of compound 20 on SNL-induced mechan-
ical hyperalgesia. Male Sprague-Dawley rats (238-304 g, 9-10/
group), 3 weeks postsurgery. Threshold to paw withdrawal was
measured. 20 was administered orally as a suspension of 0.5%
methylcellulose plus 2% Tween in water. Gabapentin was used as a
positive control and administered (ip) as a solution in 0.9% saline.
Data shown are means ( SEM * indicates a p value of e0.05 vs
SNL/vehicle (ANOVA).
mechanical hyperalgesia at 3 and 10 mg/kg, suggesting it may
be efficacious in treating neuropathic pain (Figure 2).
Conclusion
A new series of 1-(3-amino-2-hydroxy-1-phenylpropyl)-
benzimidazol-2-ones was discovered and evaluated as mono-
amine reuptake inhibitors and for oral efficacy toward alle-
viating the dysfunction associated with NE deficiency.
Amongthemost potentanalogues, 20and22exhibited similar
hNET potency to reboxetine (1) and atomoxetine (2) and
excellent selectivity at hNET versus hSERT and hDAT.
Notably, several lead compounds had good pharmacokinetic
profiles and exhibited significant efficacy in reducing the tail
skin temperature in the telemetric rat model. In addition,
compound 20 was also orally efficacious in the rat hot plate
and SNL models, suggesting its potential to treat acute and
neuropathic pain.
1-Ethyl-1,3-dihydro-benzimidazol-2-one (7b).56 MS (ES) m/z
163.2 ([M þ H]þ). 1H NMR (DMSO-d6) δ 10.79 (br s, 1H), 7.12
(d, J = 7.02 Hz, 1H), 6.76-7.06 (m, 3H), 3.82 (q, J = 7.28 Hz,
2H), 1.19 (t, J = 7.15 Hz, 3H).
1-Propyl-1,3-dihydro-2H-benzimidazol-2-one (7c).57 MS (ES)
1
m/z 177.1 ([M þ H]þ). H NMR (DMSO-d6) δ 10.78 (s, 1H),
7.11 (d, J = 5.98 Hz, 1H), 6.91-7.03 (m, 3H), 3.74 (t, J = 7.15
Hz, 2H), 1.55-1.77 (m, 2H), 0.86 (t, J = 7.41 Hz, 3H).
1-Isopropyl-1,3-dihydro-2H-benzimidazol-2-one (7d).58 MS (ES)
1
m/z 176.9 ([M þ H]þ). H NMR (DMSO-d6) δ 10.77 (s, 1H),
7.13-7.34 (m, 1H), 6.82-7.08 (m, 3H), 4.56 (t, J = 7.02 Hz, 1H),
1.43 (d, J = 7.02 Hz, 6H).
Experimental Section
1H NMR spectra were recorded on a Varian INOVA 400 or
Varian INOVA 500 instrument. Chemical shifts are reported in δ
values (parts per million, ppm) relative to an internal standard of
tetramethylsilane in CDCl3 or DMSO-d6. Electrospray (ESI)
mass spectra were recorded using a Hewlett-Packard 5989B MS
engine or Waters Alliance-ZMD mass spectrometer. Electron
impact ionization (EI, EE = 70 eV) mass spectra were recorded
on a Finnigan Trace mass spectrometer. Analytical thin-layer
chromatography (TLC) was carried out on precoated plates
(silica gel, 60 F-254), and spots were visualized with UV light
and stained in iodine. Preparative HPLC purifications were
performed on a preparative Gilson HPLC system using a Com-
biPrep Pro C18 column with acetonitrile (0.1% TFA) and water
(0.1% TFA) as solvents at a flow rate of 20 mL/min. Solvents
were purchased as anhydrous grade and were used without
further purification. Compound purity was assessed by 1H
NMR and an analytical HPLC method as described in Support-
ing Information. Biological results were obtained on compounds
of >95% chemical purity as determined by the above methods.
1-t-Butyl-1,3-dihydro-benzimidazol-2-one (7e). To a solution
of 1-fluoro-2-nitro-benzene (1 g, 7.1 mmol) in DMF (15 mL)
was added t-butyl amine (0.82 mL, 7.81 mmol) at room tem-
1-Cyclobutyl-1,3-dihydro-2H-benzimidazol-2-one (7f). MS (ES)
m/z 189 ([M þ H]þ). 1H NMR (DMSO-d6) δ 10.75 (s, 1H),
7.22-7.31 (m, 1H), 6.85-6.98 (m, 3H), 4.75 (dd, J = 8.32, 9.36
Hz, 1H), 2.66-2.85 (m, 2H), 2.11-2.28 (m, 2H), 1.64-1.88
(m, 2H).
1-Cyclopentyl-1,3-dihydro-benzimidazol-2-one (7g). MS (ESI)
1
m/z 203 ([M þ H]þ). H NMR (DMSO-d6) δ 10.80 (s, 1H),
7.08-7.15 (m, 1H), 6.92-7.02 (m, 3H), 4.71 (t, J = 8.58 Hz,
1H), 1.96-2.10 (m, 2H), 1.81-1.96 (m, 4H), 1.58-1.73 (m, 2H).
1-Ethyl-5-fluoro-1,3-dihydro-2H-benzimidazol-2-one (7h).59 MS
(ES) m/z 181.2 ([M þ H]þ). 1H NMR (DMSO-d6) δ 10.96 (s, 1H),
7.06-7.18 (m, 1H), 6.73-6.89 (m, 2H), 3.81 (q, J = 7.02 Hz, 2H),
1.18 (t, J = 7.15 Hz, 3H).
1-Ethyl-4-fluoro-1,3-dihydro-2H-benzimidazol-2-one (7i). MS
(ES) m/z 181.2 ([M þ H]þ). 1H NMR (DMSO-d6) δ 11.36 (br s,
1H), 7.01 (td, J = 2.21, 3.70 Hz, 2H), 6.78-6.94 (m, 1H), 3.83 (q,
J = 7.19 Hz, 2H), 1.19 (t, J = 7.15 Hz, 3H).
5-Fluoro-1-propyl-1,3-dihydro-benzimidazol-2-one (7j).60 MS
(ES) m/z 195.2 ([M þ H]þ). 1H NMR (DMSO-d6) δ
10.96 (s, 1H), 7.03-7.16 (m, 1H), 6.75-6.87 (m, 2H), 3.73 (t,
J = 7.15 Hz, 2H), 1.54-1.71 (m, 2H), 0.85 (t, J = 7.41
Hz, 3H).

5708 Journal of Medicinal Chemistry, 2009, Vol. 52, No. 18
4-Fluoro-1-isopropyl-1,3-dihydro-benzimidazol-2-one (7k). MS
Zhang et al.
(60% ethyl acetate in hexane) to give 1-t-butyl-3-[(1S,2S)-2,
3-dihydroxy-1-phenyl-propyl]-1,3-dihydro-2H-benzimidazol-2-
one as an oil (0.6 g, 50%). MS (ES) m/z 341.2 ([M þ H]þ). 1H
NMR (, DMSO-d6) δ 7.52 (d, J = 7.28 Hz, 2H), 7.44-7.48 (m,
1H), 7.27-7.33 (m, 2H), 7.22-7.26 (m, 1H), 7.08-7.15 (m, 1H),
6.89-6.97 (m, 2H), 5.33 (d, J = 8.32 Hz, 1H), 5.21 (d, J = 5.72
Hz, 1H), 4.66-4.75 (m, 1H), 4.60-4.66 (m, 1H), 3.32-3.36 (m,
2H), 1.72 (s, 9H).
1-Cyclobutyl-3-[(1S,2S)-2,3-dihydroxy-1-phenyl-propyl]-1,3-di-
hydro-2H-benzimidazol-2-one (8f). MS (ES) m/z 339.2 ([M þ
H]þ). 1H NMR (DMSO-d6) δ 7.51-7.57 (m, 2H), 7.27-7.37 (m,
3H), 7.19-7.26 (m, 2H), 6.95-7.05 (m, 2H), 5.33 (d, J = 8.58
Hz, 1H), 5.20 (d, J = 5.98 Hz, 1H), 4.86 (t, J = 8.97 Hz, 1H),
4.73 (dd, J = 5.59, 8.45 Hz, 1H), 4.63-4.68 (m, 1H), 3.34-3.37
(m, 2H), 2.75-2.89 (m, 2H), 2.23-2.35 (m, 2H), 1.84-1.95 (m,
1H), 1.74-1.84 (m, 1H).
1-Cyclopentyl-3-[(1S,2S)-2,3-dihydroxy-1-phenylpropyl]-1,3-di-
hydro-2H-benzimidazol-2-one (8g). MS (ES) m/z 352.9 ([M þ
H]þ). 1H NMR (DMSO-d6) δ 7.55 (d, J = 7.28 Hz, 2H),
7.13-7.36 (m, 5H), 6.99 (dd, J = 6.63, 7.93 Hz, 2H), 5.34 (d,
J = 8.06 Hz, 1H), 5.21 (d, J = 5.98 Hz, 1H), 4.69-4.82 (m, 2H),
4.66 (t, J = 5.46 Hz, 1H), 3.33-3.38 (m, 2H), 2.01 (d, J = 7.80
Hz, 2H), 1.90 (br s, 4H), 1.58-1.71 (m, 2H).
3-[(1S,2S)-2,3-Dihydroxy-1-phenylpropyl]-1-ethyl-5-fluoro-1,3-
dihydro-2H-benzimidazol-2-one (8h). MS (ES) m/z 331.1 ([M þ
H]þ). 1H NMR (DMSO-d6) δ 7.53-7.60 (m, 2H), 7.28-7.34 (m,
2H), 7.14-7.27 (m, 3H), 6.81-6.89 (m, 1H), 5.34 (d, J = 8.06
Hz, 1H), 5.20 (d, J = 5.72 Hz, 1H), 4.69-4.76 (m, 1H), 4.66 (t,
J = 5.59 Hz, 1H), 3.86 (q, J = 7.28 Hz, 2H), 3.33-3.44 (m, 2H),
1.15-1.22 (m, 3H).
3-[(1S,2S)-2,3-Dihydroxy-1-phenylpropyl]-1-ethyl-4-fluoro-1,
3-dihydro-2H-benzimidazol-2-one (8i). MS (ES) m/z 331.1 ([M þ
H]þ). 1H NMR (DMSO-d6) δ 7.47 (d, J = 7.54 Hz, 2H),
7.28-7.35 (m, 2H), 7.19-7.28 (m, 1H), 6.99-7.09 (m, 2H),
6.82-6.94 (m, 1H), 5.50 (d, J = 8.84 Hz, 1H), 5.16 (d, J = 6.24
Hz, 1H), 4.77 (br s, 1H), 4.65 (t, J = 5.46 Hz, 1H), 3.82-3.94 (m,
2H), 3.34-3.46 (m, 2H), 1.20 (t, J = 7.15 Hz, 3H).
3-[(1S,2S)-2,3-Dihydroxy-1-(3-fluorophenyl)-propyl]-1-ethyl-
4-fluoro-1,3-dihydro-2H-benzimidazol-2-one (8m). MS (ES) m/z
349.1 ([M þ H]þ). 1H NMR (DMSO-d6) δ 7.23-7.36 (m, 2H),
7.18 (d, J = 7.80 Hz, 1H), 6.92-7.08 (m, 3H), 6.78-6.90 (m,
1H), 5.45 (d, J = 9.36 Hz, 1H), 5.20 (d, J = 6.50 Hz, 1H),
4.65-4.73 (m, 1H), 4.63 (t, J = 5.46 Hz, 1H), 3.75-3.89 (m,
2H), 3.31-3.37 (m, 2H), 1.10-1.17 (m, 3H).
1-t-Butyl-3-[(1S,2R)-2-hydroxy-3-(methylamino)-1-phenylpro-
pyl]-1,3-dihydro-2H-benzimidazol-2-one hydrochloride (13). A
solution of 1-t-butyl-3-[(1S,2S)-2,3-dihydroxy-1-phenyl-pro-
pyl]-1,3-dihydro-2H-benzimidazol-2-one (0.55 g, 1.6 mmol)
and p-toluenesulfonyl chloride (0.37 g, 1.9 mmol) in anhydrous
pyridine (5 mL) was stirred at room temperature under nitrogen
for 12 h. The reaction was poured into a cold 1N aqueous
solution of hydrochloric acid (50 mL) and extracted with ethyl
acetate (2 ꢀ 50 mL). The organic layer was dried over anhydrous
sodium sulfate, filtered, and concentrated to give (2S,3S)-to-
luene-4-sulfonic acid 3-(3-t-butyl-2-oxo-2,3-dihydro-benzimi-
dazol-1-yl)-2-hydroxy-3-phenyl-propyl ester, which was taken
up in methanol (10 mL) and added a 2N solution of methyla-
mine in methanol (4 mL, 8 mmol). The reaction mixture was
stirred for 12 h at room temperature in a sealed tube and
partitioned between a saturated aqueous solution of sodium
bicarbonate (50 mL) and ethyl acetate (80 mL). The organic
layer was separated, dried over anhydrous sodium sulfate,
filtered, and concentrated in vacuo. The residue was purified
via flash column chromatography (silica, 20% MeOH in
dichloromethane) to give 1-t-butyl-3-[(1S,2R)-2-hydroxy-3-
methylamino-1-phenylpropyl]-1,3-dihydro-2H-benzimidazol-2-
one as a clear oil. The free base was dissolved in a minimum
amount of ethanol and treated with a 2N ethereal solution of
hydrochloric acid (1 mL) and stirred for 1 h. The ethanol was
removed in vacuo, and the clear oil was triturated with diethyl
1
(ES) m/z 195.2 ([M þ H]þ). H NMR (DMSO-d6) δ 11.34 (s,
1H), 7.11 (d, J = 8.06 Hz, 1H), 6.97 (td, J = 5.20, 8.19 Hz, 1H),
6.87 (dd, J = 8.58, 10.40 Hz, 1H), 4.48-4.65 (m, 1H), 1.43 (d, J =
7.02 Hz, 6H).
5-Fluoro-1-isopropyl-1,3-dihydro-2H-benzimidazol-2-one (7l).61
1
MS (ES) m/z 195.1 ([M þ H]þ). H NMR (DMSO-d6) δ 10.94
(br s, 1H), 7.22 (dd, J = 4.68, 8.58 Hz, 1H), 6.76-6.84 (m, 2H),
4.40-4.66 (m, 1H), 1.42 (d, J = 7.02 Hz, 6H).
4-Fluoro-1-phenyl-1H-benzo[d]imidazol-2(3H)-one (7m). To a
solution of 2,6-difluoronitrobenzene (2.0 g, 6.28 mmol) and
aniline (1.15 mL, 12.6 mmol) in dry DMF (10 mL) was added
potassium t-butoxide (1.40 g, 12.5 mmol) in portions. After 16 h
at room temperature, the reaction mixture was poured into a
saturated aqueous ammonium chloride solution (50 mL) and
extracted with dichloromethane (2 ꢀ 50 mL). The combined
organic layers were washed with water (50 mL), dried over
anhydrous magnesium sulfate, filtered, and concentrated under
reduced pressure to afford crude 3-fluoro-2-nitro-N-phenylani-
line (1.15 g, 78%), which was used in the next step without
further purification. A mixture of 3-fluoro-2-nitro-N-phenyla-
niline (1.15 g, 4.9 mmol) and palladium on charcoal (10%,
200 mg) in methanol (30 mL) was hydrogenated (50 psi H2) in a
Parr shaker apparatus. After 2 h, the catalyst was removed by
filtration through a pad of celite and the celite washed with fresh
methanol (20 mL). The combined methanol layers were con-
centrated under reduced pressure and the residue purified
by column chromatography (silica, 1:0 to 9:1 hexanes:ethyl
acetate) to afford 3-fluoro-N-1-phenylbenzene-1,2-diamine
1
(0.47 g, 47%). MS (ES) m/z 203.2 ([M þ H]þ). H NMR (400
MHz, DMSO-d6) δ 7.22 (s, 1H), 7.10 (tt, J = 2.17 and 7.3 Hz,
2H), 6.81 (d, J = 7.94 Hz, 1H), 6.75-6.65 (m, 5H), 6.50-6.44
(m, 1H) and 4.63 (br s, 1H).
To a stirred solution of 3-fluoro-N-1-phenylbenzene-1,2-dia-
mine (0.247 g, 1.22 mmol) in dry THF (10 mL) was added
carbonyl diimidazole (0.21 g, 1.3 mmol) under nitrogen. After
30 min, 4-dimethylaminopyridine (catalytic amount) was added
and the reaction stirred overnight. After 16 h, a further portion
of carbonyl diimidazole was added (0.21 g, 1.3 mmol) and
stirring continued. After 48 h, the reaction mixture was diluted
with ethyl acetate (50 mL) and extracted with sodium hydroxide
solution (2N, 2 ꢀ 25 mL). The combined basic extracts were
washed with ethyl acetate (2 ꢀ 20 mL) and then acidified
(hydrochloric acid, pH 1). The product was collected by filtra-
tion and was then washed with water, hexanes, and air-dried
to afford 4-fluoro-1-phenyl-1H-benzo[d]imidazol-2(3H)-one
(0.117 g, 42%) as a white solid. MS (ES) m/z 228.9 ([M þ H]þ).
1H NMR (400 MHz, DMSO-d6) δ 11.71 (br s, 1H), 7.59-7.52
(m, 4H), 7.45 (tt, J = 1.54 and 7.04 Hz, 1H), 7.03-6.95 (m, 2H)
and 6.81 (dt, J = 1.66 and 7.18 Hz, 1H).
The intermediates 8a-o were prepared according to the
general procedure as described for compound 8e. Most com-
pounds were not characterized and used in the next step.
The selected examples that were characterized are reported
herein.
1-t-Butyl-3-[(1S,2S)-2,3-dihydroxy-1-phenyl-propyl]-1,3-
dihydro-2H-benzimidazol-2-one (8e). A mixture of 1-t-butyl-1,
3-dihydro-benzimidazol-2-one (0.66 g, 3.5 mmol) and sodium
hydride (60% dispersion in mineral oil, 0.15 g, 3.8 mmol) in
anhydrous DMF (4 mL) was stirred for 10 min under nitrogen at
room temperature. A solution of [(2R,3R)-3-phenyloxiran-2-
yl]methanol (1.07 g, 7.1 mmol) and titanium isopropoxide (2.14
mL, 7.1 mmol) in anhydrous DMF (4 mL) that was aged for
20 min was then added, and the mixture was stirred at room
temperature under nitrogen. After 18 h, the mixture was parti-
tioned between a 1N aqueous solution of hydrochloric acid
(50 mL) and ethyl acetate (2 ꢀ 50 mL). The organic layer was
separated, washed with saturated sodium bicarbonate (50 mL),
dried over anhydrous sodium sulfate, filtered, and concen-
trated in vacuo. The residue was purified via silica gel column

Article
Journal of Medicinal Chemistry, 2009, Vol. 52, No. 18 5709
ether/dichloromethane to afford 1-t-butyl-3-[(1S,2R)-2-hydro-
xy-3-(methylamino)-1-phenylpropyl]-1,3-dihydro-2H-benzimi-
dazol-2-one hydrochloride as a white solid (0.027 g, 4.7% for
two steps). HRMS: calcd for C21H27N3O2 þ Hþ, 354.2176;
found (ESI, [M þ H]þ), 354.2179. 1H NMR (DMSO-d6) δ 8.51
(br s, 2H), 7.52-7.58 (m, 2H), 7.46-7.51 (m, 1H), 7.32-7.39 (m,
2H), 7.24-7.31 (m, 1H), 7.12-7.19 (m, 1H), 6.93-7.00 (m, 2H),
6.05 (d, J = 6.76 Hz, 1H), 5.29 (d, J = 8.84 Hz, 1H), 5.12 (br s,
1H), 2.83-3.04 (m, 2H), 2.54-2.60 (m, 3H), 1.73 (s, 9H).
Following this general procedure, analogues 9-12 and 14-24
were prepared and characterized as follows.
1-[(1S,2R)-2-Hydroxy-3-(methylamino)-1-phenylpropyl]-3-me-
thyl-1,3-dihydro-2H-benzimidazol-2-one hydrochloride (9). MS
(ES) m/z 312.3 ([M þ H]þ). HRMS: calcd for C18H21N3O2 þ
Hþ, 312.17065; found (ESI, [M þ H]þ), 312.17. 1H NMR
(DMSO-d6) δ 8.69 (br s, 1H), 8.58 (br s, 1H), 7.53-7.58 (m,
2H), 7.31-7.37 (m, 2H), 7.25-7.31 (m, 1H), 7.20-7.24 (m, 1H),
7.13-7.17 (m, 1H), 6.98-7.09 (m, 2H), 6.05 (m, 1H), 5.31 (d,
J = 8.84 Hz, 1H), 5.09-5.23 (m, 1H), 3.36 (br s, 3H), 2.99-3.08
(m, 1H), 2.86-2.96 (m, 1H), 2.55 (t, J = 8.00 Hz, 3H).
(ddd, J = 2.47, 8.58, 10.01 Hz, 1H), 6.02 (d, J = 6.50 Hz, 1H),
5.26 (d, J = 8.58 Hz, 1H), 5.01-5.20 (m, 1H), 3.83 (q, J = 7.02 Hz,
2H), 2.83-3.03 (m, 2H), 2.42-2.45 (m, 3H), 1.12-1.20 (m, 3H).
1-Ethyl-4-fluoro-3-[(1S,2R)-2-hydroxy-3-(methylamino)-1-phe-
nylpropyl]-1,3-dihydro-2H-benzimidazol-2-one Hydrochloride
(17). MS (ES) m/z 344.2 ([M þ H]þ). HRMS: calcd for
C19H22FN3O2 þ Hþ, 344.17688; found (ESI, [M þ H]þ),
1
344.1768. H NMR (DMSO-d6) δ 8.72 (br s, 1H), 8.60 (br s,
1H), 7.45 (d, J = 7.54 Hz, 2H), 7.32-7.39 (m, 2H), 7.25-7.32
(m, 1H), 7.04-7.13 (m, 2H), 6.91 (ddd, J = 1.43, 7.86, 12.02 Hz,
1H), 6.02 (d, J = 7.54 Hz, 1H), 5.38 (d, J = 9.62 Hz, 1H),
5.06-5.17 (m, 1H), 3.91 (q, J = 7.19 Hz, 2H), 3.08 (br s, 1H),
2.98 (br s, 1H), 2.54-2.60 (m, 3H), 1.22 (t, J = 7.15 Hz, 3H).
5-Fluoro-3-[(1S,2R)-2-hydroxy-3-(methylamino)-1-phenylpro-
pyl]-1-propyl-1,3-dihydro-2H-benzimidazol-2-one Hydrochloride
(18). MS (ES) m/z 358.2 ([M þ H]þ). HRMS: calcd for
C20H24FN3O2 þ Hþ, 358.19253; found (ESI, [M þ H]þ),
1
358.1895. H NMR (DMSO-d6) δ 8.53-8.71 (m, 2H), 7.58 (d,
J = 8.06 Hz, 2H), 7.33-7.39 (m, 2H), 7.27-7.33 (m, 1H),
7.17-7.23 (m, 2H), 6.85-6.92 (m, 1H), 6.07 (d, J = 6.50 Hz,
1H), 5.31 (d, J = 8.58 Hz, 1H), 5.10-5.20 (m, 1H), 3.81 (t, J =
6.89 Hz, 2H), 2.84-3.08 (m, 2H), 2.56 (t, J = 5.07 Hz, 3H), 1.66
(q, J = 7.02 Hz, 2H), 0.84 (t, J = 7.28 Hz, 3H).
1-Ethyl-3-[(1S,2R)-2-hydroxy-3-(methylamino)-1-phenylpro-
pyl]-1,3-dihydro-2H-benzimidazol-2-one hydrochloride (10). MS
(ES) m/z 326.2 ([M þ H]þ). HRMS: calcd for C19H23N3O2 þ
1
Hþ, 326.18630; found (ESI, [M þ H]þ), 326.1845. H NMR
4-Fluoro-3-[(1S,2R)-2-hydroxy-3-(methylamino)-1-phenylpro-
pyl]-1-isopropyl-1,3-dihydro-2H-benzimidazol-2-one Hydrochlo-
ride (19). MS (ES) m/z 358.4 ([M þ H]þ). HRMS: calcd for
C20H24FN3O2 þ Hþ, 358.19253; found (ESI, [M þ H]þ),
(DMSO-d6) δ 8.51 (br s, 2H), 7.53-7.58 (m, 2H), 7.33-7.38 (m,
2H), 7.28-7.31 (m, 1H), 7.19-7.24 (m, 2H), 6.96-7.09 (m, 2H),
6.06 (d, J = 7.02 Hz, 1H), 5.30 (d, J = 8.84 Hz, 1H), 5.07-5.18
(m, 1H), 3.81-3.96 (m, 2H), 2.87-3.10 (m, 2H), 2.54-2.59 (m,
3H), 1.22 (t, J = 7.15 Hz, 3H).
1
358.19347. H NMR (DMSO-d6) δ 8.74 (br s, 1H), 8.60 (br s,
1H), 7.42-7.48 (m, 2H), 7.25-7.37 (m, 3H), 7.21 (d, J = 7.28
Hz, 1H), 7.05 (td, J = 4.94, 8.19 Hz, 1H), 6.90 (dd, J = 8.58,
11.96 Hz, 1H), 6.02 (br s, 1H), 5.34-5.43 (m, 1H), 5.06-5.16 (m,
1H), 4.65 (quin, J = 6.95 Hz, 1H), 2.91-3.11 (m, 2H), 2.56 (t,
J = 5.46 Hz, 3H), 1.45 (d, J = 4.68 Hz, 6H).
1-[(1S,2R)-2-Hydroxy-3-(methylamino)-1-phenylpropyl]-3-pro-
pyl-1,3-dihydro-2H-benzimidazol-2-one hydrochloride (11).
HRMS: calcd for C20H25N3O2 þ Hþ, 340.20195; found (ESI,
1
[M þ H]þ), 340.2007. H NMR (DMSO-d6) δ 8.45-8.68 (m,
1-Ethyl-3-[1-(3-fluoro-phenyl)-2-hydroxy-3-methylamino-pro-
pyl]-1,3-dihydro-benzimidazol-2-one Hydrochloride (20). MS
(ES) m/z 344.2 ([M þ H]þ). HRMS: calcd for C19H22FN3O2 þ
Hþ, 344.17688; found (ESI, [M þ H]þ), 344.178. 1H NMR
(DMSO-d6) δ 8.54-8.84 (m, 2H), 7.26-7.47 (m, 4H), 7.19-7.26
(m, 1H), 7.00-7.19 (m, 3H), 6.13 (d, J = 6.76 Hz, 1H), 5.35 (d,
J = 8.84 Hz, 1H), 5.05-5.23 (m, 1H), 3.90 (q, J = 7.19 Hz, 2H),
2.99 (br s, 2H), 2.54-2.60 (m, 3H), 1.22 (t, J = 7.15 Hz, 3H).
1-Ethyl-4-fluoro-3-[(1S,2R)-2-hydroxy-3-(methylamino)-1-(3-
fluorophenyl)-propyl]-1,3-dihydro-2H-benzimidazol-2-one Hy-
drochloride (21). MS (ES) m/z 362.1 ([M þ H]. HRMS: calcd
for C19H21F2N3O2 þ Hþ, 362.16746; found (ESI, [M þ H]þ),
362.1666. 1H NMR (DMSO-d6) δ 8.57-8.81 (m, 2H), 7.26-7.49
(m, 2H), 7.02-7.25 (m, 4H), 6.87-6.98 (m, 1H), 6.11 (d, J =
7.80 Hz, 1H), 5.40 (d, J = 9.62 Hz, 1H), 5.01-5.16 (m, 1H), 3.91
(q, J = 7.11 Hz, 2H), 2.90-3.12 (m, 2H), 2.54-2.60 (m, 3H),
1.22 (t, J = 7.15 Hz, 3H).
4-Fluoro-3-[(1S,2R)-1-(3-fluorophenyl)-2-hydroxy-3-(methyl-
amino)-propyl]-1-isopropyl-1,3-dihydro-2H-benzimidazol-2-one
Hydrochloride (22). MS (ES) m/z 376.2 ([M þ H]þ). HRMS:
calcd for C20H23F2N3O2 þ Hþ, 376.18311; found (ESI, [M þ
H]þ), 376.1845. 1H NMR (DMSO-d6) δ 8.67 (br s, 1H), 8.55 (br
s, 1H), 7.40 (td, J = 6.24, 8.06 Hz, 1H), 7.31 (d, J = 10.40 Hz,
1H), 7.11-7.26 (m, 3H), 7.03-7.10 (m, 1H), 6.93 (dd, J = 8.45,
12.09 Hz, 1H), 6.08 (d, J = 7.80 Hz, 1H), 5.33-5.45 (m, 1H),
5.01-5.16 (m, 1H), 4.57-4.72 (m, 1H), 2.89-3.13 (m, 2H),
2.54-2.61 (m, 3H), 1.46 (d, J = 4.16 Hz, 6H).
2H), 7.50-7.58 (m, 2H), 7.32-7.39 (m, 2H), 7.25-7.32 (m, 1H),
7.21 (d, J = 8.32 Hz, 2H), 6.95-7.10 (m, 2H), 6.08 (d, J = 7.02
Hz, 1H), 5.30 (d, J = 8.58 Hz, 1H), 5.06-5.21 (m, 1H),
3.78-3.87 (m, 2H), 2.99 (d, J = 3.64 Hz, 2H), 2.53-2.60 (m,
3H), 1.61-1.73 (m, 2H), 0.85 (t, J = 7.41 Hz, 3H).
1-[(1S,2R)-2-Hydroxy-3-(methylamino)-1-phenylpropyl]-3-iso-
propyl-1,3-dihydro-2H-benzimidazol-2-one hydrochloride (12).
MS (ES) m/z 340.3 ([M þ H]þ). HRMS: calcd for C20-
H25N3O2 þ Hþ, 340.20195; found (ESI, [M þ H]þ), 340.2012.
1H NMR (DMSO-d6) δ 8.57 (br s, 2H), 7.55 (d, J = 7.54 Hz,
2H), 7.25-7.39 (m, 4H), 7.18-7.24 (m, 1H), 6.96-7.06 (m, 2H),
6.07 (d, J = 6.76 Hz, 1H), 5.30 (d, J = 8.58 Hz, 1H), 5.13 (d, J =
8.84 Hz, 1H), 4.65 (quin, J = 6.89 Hz, 1H), 2.85-3.04 (m, 2H),
2.56 (m, 3H), 1.46 (d, J = 7.02 Hz, 6H).
1-Cyclobutyl-3-[(1S,2R)-2-hydroxy-3-(methylamino)-1-phenyl-
propyl]-1,3-dihydro-2H-benzimidazol-2-one hydrochloride (14).
MS (ES) m/z 352.2 ([M þ H]þ). HRMS: calcd for C21-
H25N3O2 þ Hþ, 352.202; found (ESI, [M þ H]þ), 352.207. 1H
NMR (DMSO-d6) δ 8.56 (br s, 2H), 7.50-7.63 (m, 2H),
7.31-7.40 (m, 3H), 7.21-7.31 (m, 2H), 6.98-7.08 (m, 2H),
6.04 (d, J = 7.02 Hz, 1H), 5.30 (d, J = 8.84 Hz, 1H), 5.06-5.22
(m, 1H), 4.86 (m, 1H), 3.01 (m, 1H), 2.76-2.91 (m, 3H), 2.56 (s,
3H), 2.22-2.37 (m, 2H), 1.72-1.97 (m, 2H).
1-Cyclopentyl-3-[(1S,2R)-2-hydroxy-3-(methylamino)-1-phenyl-
propyl]-1,3-dihydro-2H-benzimidazol-2-one hydrochloride (15).
1
MS (ESI) m/z 366 ([M þ H]þ). H NMR (DMSO-d6) δ 8.68
(br s, 1H), 8.56 (br s, 1H), 7.55 (d, J = 7.28 Hz, 2H), 7.32-7.38
(m, 2H), 7.19-7.31 (m, 3H), 6.98-7.07 (m, 2H), 6.06 (d, J =
8.00 Hz, 1H), 5.31 (d, J = 8.84 Hz, 1H), 4.78 (t, J = 8.45 Hz,
1H), 3.34-3.42 (m, 1H), 2.99 (br s, 2H), 2.56 (t, J = 5.33 Hz,
3H), 1.86-2.10 (m, 6H), 1.60-1.72 (m, 2H).
4-Fluoro-3-[(1S,2R)-1-(3-fluorophenyl)-2-hydroxy-3-(methyl-
amino)propyl]-1-phenyl-1,3-dihydro-2H-benzimidazol-2-one Hy-
drochloride (23). HRMS: calculated for C23H21F2N3O2 þ Hþ,
1
410.16746; found (ESI, [M þ H]þ), 410.1662. H NMR (400
MHz, DMSO-d6) δ 8.70 (br s, 1H), 8.57 (br s, 1H), 7.57-7.52
(m, 4H), 7.47-7.43 (m, 1H), 7.40-7.33 (m, 2H), 7.26 (d, J =
7.82 Hz, 1H), 7.12 (dt, J = 2.18 and 8.58 Hz, 1H), 7.05-6.95 (m,
2H), 6.81 (dd, J = 0.89 and 7.68 Hz, 1H), 6.05 (d, J = 7.94 Hz,
1H), 5.42 (d, J = 9.36 Hz. 1H), 5.09-5.07 (m, 1H), 3.25-3.20
(m, 1H), 3.02-2.98 (m, 1H) and 2.53 (br s, 3H).
1-Ethyl-5-fluoro-3-[(1S,2R)-2-hydroxy-3-(methylamino)-1-phe-
nylpropyl]-1,3-dihydro-2H-benzimidazol-2-one hydrochloride
(16). MS (ES) m/z 344.2 ([M þ H]þ). HRMS: calcd for C19H22-
1
FN3O2 þ Hþ, 344.17688; found (ESI, [M þ H]þ), 344.175. H
NMR (DMSO-d6) δ 8.56 (br s, 2H), 7.48-7.61 (m, 2H), 7.28-
7.35 (m, 2H), 7.21-7.28 (m, 1H), 7.13-7.20 (m, 2H), 6.85

5710 Journal of Medicinal Chemistry, 2009, Vol. 52, No. 18
3-[(1S,2R)-3-(Ethylamino)-2-hydroxy-1-phenylpropyl]-5-flu-
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oro-1-isopropyl-1,3-dihydro-2H-benzimidazol-2-one
Hydro-
chloride (24). MS (ESI) m/z 372.21 ([M þ H]þ). HRMS: calcd
for C21H26FN3O2 þ Hþ, 372.20818; found (ESI, [M þ H]þ),
372.2099. 1H NMR (DMSO-d6) δ 8.42-8.62 (m, 2H), 7.53-7.62
(m, 2H), 7.34-7.41 (m, 2H), 7.27-7.34 (m, 2H), 7.21 (dd, J =
2.34, 9.36 Hz, 1H), 6.81-6.91 (m, 1H), 6.04 (d, J = 6.50 Hz,
1H), 5.27 (d, J = 8.32 Hz, 1H), 5.08-5.19 (m, 1H), 4.62 (quin,
J = 7.02 Hz, 1H), 2.84-3.07 (m, 4H), 1.44 (d, J = 7.02 Hz, 6H),
1.13-1.19 (m, 3H).
Acknowledgment. The authors wish to thank the Discov-
ery Analytical Chemistry group for compound analysis.
We also thank our management Drs. Ronald Magolda,
Magid Abou-Gharbia, and Menelas Pangalos for their
support.
Supporting Information Available: Analytical HPLC purity
data of all tested compounds, synthetic procedures for ((2R,3R)-
3-(3-fluorophenyl)oxiran-2-yl)methanol, and ((2R,3R)-3-phe-
nyloxiran-2-yl)methanol. This material is available free of
charge via the Internet at http://pubs.acs.org.
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