Synthesis and activity of 1-(3-amino-1-phenylpropyl)indolin-2-ones: A new class of selective norepinephrine reuptake inhibitors

Article abstract of DOI:10.1016/j.bmcl.2008.08.060

Norepinephrine and serotonin play an important role in a wide variety of biological processes and are implicated in a number of neurological disorders. A novel class of 1-(3-amino-1-phenylpropyl)indolin-2-ones was designed and synthesized that displays po

Full text of DOI:10.1016/j.bmcl.2008.08.060

Bioorganic & Medicinal Chemistry Letters 18 (2008) 4929–4931
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Bioorganic & Medicinal Chemistry Letters
journal homepage: www.elsevier.com/locate/bmcl
Synthesis and activity of 1-(3-amino-1-phenylpropyl)indolin-2-ones: A new
class of selective norepinephrine reuptake inhibitors
a
a
a
a
Casey C. McComas a, , An T. Vu , Paige E. Mahaney , Stephen T. Cohn , Andrew Fensome ,
Michael A. Marella a, Lisa Nogle a, Eugene J. Trybulski a, Fei Ye a, Puwen Zhang a, Peter Alfinito b, Jenifer Bray b,
Grace Johnston b, Elizabeth Koury b, Darlene C. Deecher b
*
a Chemical and Screening Sciences, Wyeth Research, 500 Arcola Road, S2227A, 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:
Norepinephrine and serotonin play an important role in a wide variety of biological processes and are
implicated in a number of neurological disorders. A novel class of 1-(3-amino-1-phenylpropyl)indolin-
2-ones was designed and synthesized that displays potent norepinephrine reuptake inhibition while
maintaining high selectivity (>100-fold) against the human serotonin and dopamine transporters.
Ó 2008 Elsevier Ltd. All rights reserved.
Received 30 July 2008
Revised 14 August 2008
Accepted 18 August 2008
Available online 22 August 2008
This manuscript is dedicated to the memory
of Dr. Ronald L. Magolda.
Norepinephrine (NE), serotonin (5-HT), and dopamine (DA) are
essential monoamine neurotransmitters in both the central and
peripheral nervous system and are involved in regulation of a wide
variety of physiological functions.1 There are a number of neuro-
logical disorders thought to be associated with monoamine neuro-
transmitter deficiency thus making this system an important
target for drug development.
Selective serotonin reuptake inhibitors (SSRIs) such as fluoxe-
tine (1), paroxetine (2), and sertraline have been used extensively
to treat depression (Fig. 1). More recently, considerable research
has focused on development of compounds that include both the
inhibition of serotonin and norepinephrine reuptake.2,3 These ef-
forts have led to the development of compounds such as duloxe-
tine (3), which is
a potent serotonin and norepinephrine
reuptake inhibitor (Table 1).
Figure 1.
Duloxetine is marketed for major depressive disorder (MDD)
and shows efficacy in the treatment of chronic pain disorders
and stress urinary incontinence (SUI).4 Desvenlafaxine also inhibits
the reuptake of both serotonin and norepinephrine and is approved
for the treatment of MDD.5 Alternatively, selective norepinephrine
reuptake inhibitors, such as atomoxetine (4), nisoxetine (5), and
reboxetine (6) have been developed for the treatment of MDD
and attention deficit hyperactivity disorder (ADHD).6,7 These com-
pounds show selectivity ratios ranging from 16 for atomoxetine (4)
to 81 for reboxetine (6).
the extracellular concentration of NE in the synaptic cleft resulting
in increased downstream cellular signaling.8 Neurological disor-
ders such as depression, pain, and vasomotor symptoms are
thought to result from fluctuations in the levels of 5-HT and NE
in the brain and in particular the cortical, hippocampal and hypo-
thalamic regions. Our interest in understanding the role of NE in
these disorders led us to undertake a program to develop selective
NE reuptake inhibitors (NRIs). Previously we disclosed a series of 3-
(1H-indol-1-yl)-3-arylpropan-1-amines (7) that displayed dual
acting NE and 5-HT reuptake inhibition.9 In an effort to improve
the chemical stability of this series we designed a 1-(3-amino-1-
phenylpropyl)indolin-2-one scaffold leading to compounds with
the core structure 8 (Fig. 2). The use of an indolin-2-one headpiece
offered the additional advantage of greater versatility with respect
Norepinephrine reuptake inhibitors (NRIs) exert their effects by
binding to the norepinephrine transporter (NET) protein located
presynaptically. This binding interaction results in an increase in
* Corresponding author. Tel.: +1 484 865 8724; fax: +1 484 865 9398.
E-mail address: mccomac@wyeth.com (C.C. McComas).
0960-894X/$ - see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmcl.2008.08.060

4930
C. C. McComas et al. / Bioorg. Med. Chem. Lett. 18 (2008) 4929–4931
Table 1
manner to give the enantiomeric 1-(3-amino-1-phenylpro-
pyl)indolin-2-one (S)-18a.
Inhibition of monoamine reuptake at the hNET and hSERT of compounds within the
aryloxypropanamine class
An enantioselective synthesis was designed in order to assign
the stereochemistry at the benzylic position and eliminate the
need for an HPLC resolution step (Scheme 2). Reduction of 3-
chloro-1-phenylpropan-1-one (15) with BH3 in the presence of cat-
alytic (R)-2-methyl-CBS-oxazaborolidine provided the (S)-alcohol
in 94.6% e.e. which could be recrystallized to give 16 in 99.4% e.e.
and 77% yield. The alcohol was displaced with 3,3-dimethyloxin-
dole under Mitsunobu conditions to generate 17. This reaction pro-
ceeded with clean inversion of stereochemistry with no observed
racemization. Finally, substitution of the chloride with methyl-
amine yielded 1-(3-amino-1-phenylpropyl)-indolin-2-one (R)-
14a in >99.8% e.e. after recrystallization of the HCl salt. Either enan-
tiomer of 1-(3-amino-1-phenylpropyl)-indolin-2-one could be ac-
cessed by this route depending on the isomer of the CBS catalyst
used.
Compounds 14, 18, 19, and 20 were evaluated in vitro for the
ability to inhibit both the uptake of NE in MDCK-Net6 cells stably
transfected with human NET and 5-HT in JAR cells stably transfec-
ted with the human serotonin transporter (hSERT). Selected com-
pounds were then assayed for inhibition of radioligand binding
to the human dopamine transporter (hDAT). The experimental
methods for these biochemical assays have been detailed previ-
ously.10 The results of these studies are summarized in Table 2.
The promise of this series was immediately apparent upon eval-
uation of the unsubstituted analog 14a that showed moderate
hNET potency but was highly selective against hSERT. The enantio-
meric compound 18a was only weakly active and revealed the
strong eutomer/distomer property of this series. Encouraged by
this result, the nitrogen R-group was varied but even minor
changes resulted in a loss of activity. Previous SAR indicated that
fluorination of the 7-position of the heterocyclic ring and the 3-po-
sition of the pendant aryl ring improved activity.11 Following this
observed trend, synthesis of 14b and 14c led to greater than 10-
fold improvement in hNET potency while maintaining excellent
selectivity over hSERT (selectivity ratio of 182 and >157, respec-
tively). Addition of chlorine to the pendant aryl ring (14d and
14e) led to a 2-fold increase in hNET activity but also led to approx-
imately a 10-fold increase in hSERT potency. Addition of a second
fluorine to the aryl ring (14f) showed the same improvement in
activity (7 nM) while maintaining high selectivity over hSERT
(selectivity ratio 192). Expansion of the gem-dimethyl group to a
spirocyclohexyl group at the 3,3-position of the oxindole was
briefly explored. Compounds 19a and 19b demonstrated that an
increase in steric bulk about the 3-position of the heterocycle
was well tolerated and even showed a modest improvement in
potency. The S-enantiomers (20a and 20b) also showed the same
a
b
c
Compound
hNET IC50 (nM) hSERT IC50 (nM) hSERT IC50/hNET IC50
Fluoxetine (1)
Paroxetine (2)
(S)-Duloxetine (3)
Atomoxetine (4)
Nisoxetine (5)
Reboxetine (6)
563
100
4
10
2
3
48
277
242
0.02
0.02
0.75
16
3
6
46
3
81
a
Inhibition of norepinephrine uptake in MDCK-Net6 cells, stably transfected
with human NET.
b
Inhibition of serotonin uptake in JAR cells, stably transfected with human SERT.
Unitless value as a ratio in which higher numbers represent relatively greater
c
NET selectivity.
to substitution at the 3-position of the heterocycle. Introduction of
an indolin-2-one revealed a dramatic effect of functionality about
the 2 and 3 position of the heterocycle on NE selectivity and led
to the discovery of a new series of 1-(3-amino-1-phenylpro-
pyl)indolin-2-ones which are potent and selective NRIs.
Initially,
a racemic synthesis of 1-(3-amino-1-phenylpro-
pyl)indolin-2-ones (Scheme 1) was developed. Alkylation of oxin-
dole at the 3-position provided 10 followed by N-alkylation with
benzyl bromide to generate 11. Installation of an ethanol sidechain
was accomplished by treatment with butyllithium and (2-bromo-
ethoxy)-t-butyl-dimethyl-silane followed by removal of the silyl
group with TBAF. At this stage the racemic mixture of alcohols
was resolved by preparative chiral HPLC to give enantiomers 12
and 13. Alcohol 13 was then converted to the tosylate which was
displaced with methylamine to give 1-(3-amino-1-phenylpro-
pyl)indolin-2-one (R)-14a. Alcohol 12 was treated in a similar
Figure 2. 1-(3-amino-1-phenylproplyl)indolin-2-ones.
Scheme 2. Enantioselective synthesis of 1-(3-amino-1-phenylproplyl)indolin-2-
Scheme 1. Synthesis of 1-(3-amino-1-phenylproplyl)indolin-2-ones.
ones.

C. C. McComas et al. / Bioorg. Med. Chem. Lett. 18 (2008) 4929–4931
4931
Table 2
Characterization of compounds 14, 18, 19, and 20 at the human norepinephrine, serotonin, and dopamine transporters
a
b
c
Compound
X
Y
Z
hNET IC50 (nM)
hSERT IC50 (nM)
hSERT IC50/hNET IC50
hDAT % inhib @ 1 lM
7
H
H
F
F
H
F
H
H
F
H
F
H
H
H
Cl
Cl
F
H
F
F
F
F
47
175
14
19
7
327
7
44%
3%
7%
0%
10%
0%
0%
3%
20%
26%
1%
14a
14b
14c
14d
14e
14f
18a
19a
19b
20a
20b
>3000
2550
>3000
290
>17
182
>157
41
F
H
6
7
330
55
H
1350
1950
>3000
>3000
1150
1750
192
<0.65
>115
>56
<0.38
<0.58
>3000
26
53
>3000
>3000
0%
a
Inhibition of norepinephrine uptake in MDCK-Net6 cells, stably transfected with human NET. Desipramine (IC50 = 3.9 0.5 nM) was used as standard.
Inhibition of serotonin uptake in JAR cells, stably transfected with human SERT. Fluoxetine (IC50 = 10.3 1.7 nM) was used as a standard.
Unitless value as a ratio in which higher numbers represent relatively greater NET selectivity.
b
c
loss of hNET activity observed previously and even displayed a
modest selectivity for hSERT. Although not anticipated to be active
at DAT, these compounds were evaluated for their dopamine trans-
porter binding activity and showed very weak affinity for the DA
transporter. In general compounds 14 and 19 were potent NRIs
and showed excellent selectivity against the 5-HT and DA
trasporters.
References and notes
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Med. Chem. Lett. 2003, 13, 4477; (e) Trybulski, E. J.; Mahaney, P. E.; Gavrin, L. K.;
Vu, A. T.; Stack, G.; Cohn, S.; Jenkins, D. J.; Sabatucci, J. P.; Ye, F.; Webb, M. B.;
Sipe, K.; Leiter, J.; Johnston, G. H.; Burroughs, K.; Cosmi, S.; Leventhal, L.; Zhang,
Y.; Mugford, C.; Platt, B.; Deecher, D. C. Abstracts of Papers 234th ACS National
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In summary, a medicinal chemistry program focused on the de-
sign of potent and selective NRIs successfully identified a new class
of
a 1-(3-amino-1-phenylpropyl)indolin-2-ones that represent
some of the most selective hNET ligands reported to date. Com-
pounds 14d, 14e, and 14f in particular, showed excellent potency
at the hNET and remarkable selectivity over hSERT and hDAT.
Additionally, compounds 14d, 14e, and 14f have low TPSA (ꢀ32)
and are therefore anticipated to cross the blood-brain barrier effi-
ciently.12 These compounds will be further profiled in in vivo mod-
els of neurological disorders and dysfunction thought to be
associated with NE deficiency. The synthesis and characterization
of additional compounds is ongoing in an effort to identify potent
and selective NRIs that may have utility in treating various neuro-
logical disorders.
10. Mahaney, P.; Gavrin, L. K.; Trybulski, E. J.; Vu, A. T.; Johnston, G. H.; Bray, J. A.;
Burroughs, K.; Cosmi, S.; Leventhal, L.; Koury, E.; Zhang, Y.; Mugford, C. A.; Ho,
D. M.; Rosenzweig-Lipson, S.; Platt, B.; Deecher, D. C. J. Med Chem. 2008, 51,
4038.
11. For synthesis of fluorinated oxindoles see: Fensome, A.; Adams, W. R.; Adams,
A. L.; Berrodin, T. J.; Cohen, J.; Huselton, C.; Illenberger, A.; Kern, J. C.; Hudak, V.
A.; Marella, M. A.; Melenski, E. G.; McComas, C. C.; Mugford, C. A.; Slayden, O.
D.; Yudt, M.; Zhang, Z.; Zhang, P.; Zhu, Y.; Winneker, R. C.; Wrobel, J. E. J. Med.
Chem. 2008, 51, 1861.
Acknowledgments
The authors thank the members of the Discovery Analytical
Chemistry group at Wyeth, especially Diane Andraka, Scott Brec-
ker, Rebecca Dooley, Dr. Christopher Petucci, and Dr. Oliver McCon-
nell for compound analysis. We also thank Dr. Ron Magolda and Dr.
Magid Abou-Gharbia for their encouragement and support.
12. Hitchcock, S. A.; Pennington, L. D. J. Med. Chem. 2006, 49, 7559.