Discovery of 1-(3,4-dichlorophenyl)-N,N-dimethyl-1,2,3,4- tetrahydroquinolin-4-amine, a dual serotonin and dopamine reuptake inhibitor

Article abstract of DOI:10.1016/j.bmcl.2010.10.086

The present work describes a series of novel tetrahydroquinoline amines that potently inhibit the in vitro reuptake of serotonin and dopamine (dual reuptake inhibitors). The compounds are structurally related to a series we disclosed previously, but are i

Full text of DOI:10.1016/j.bmcl.2010.10.086

Bioorganic & Medicinal Chemistry Letters 21 (2011) 520–523
Contents lists available at ScienceDirect
Bioorganic & Medicinal Chemistry Letters
journal homepage: www.elsevier.com/locate/bmcl
Discovery of 1-(3,4-dichlorophenyl)-N,N-dimethyl-1,2,3,4-tetrahydroquinolin-4-
amine, a dual serotonin and dopamine reuptake inhibitor
⇑
Liming Shao , Jianguo Ma, Fengjiang Wang, Scott C. Malcolm, Michael C. Hewitt, Una C. Campbell,
Nancy A. Spicer, Larry W. Hardy, Rudy Schreiber , Kerry L. Spear, Mark A. Varney à
Discovery and Early Clinical Research, Sunovion Pharmaceuticals Inc., 84 Waterford Drive, Marlborough, MA 01752, USA
a r t i c l e i n f o
a b s t r a c t
Article history:
The present work describes a series of novel tetrahydroquinoline amines that potently inhibit the in vitro
reuptake of serotonin and dopamine (dual reuptake inhibitors). The compounds are structurally related
to a series we disclosed previously, but are improved with respect to cytochrome P-450 enzyme (CYP)
and potassium ion channel Kv11.1 (hERG) inhibition and synthetic accessibility. The detailed synthesis
and in vitro activity and ADME profile of the compounds is described, which represent a previously
undisclosed dual reuptake inhibitor chemotype.
Received 9 August 2010
Revised 15 October 2010
Accepted 18 October 2010
Available online 28 October 2010
Keywords:
Depression
Ó 2010 Elsevier Ltd. All rights reserved.
Antidepressant
Monoamine transporter
The monoamine hypothesis of depression postulates that
deficits in serotonin, norepinephrine and dopamine in the central
nervous system underlie the disease, and is supported by the clin-
ical efficacy of marketed selective serotonin reuptake inhibitors
(SSRIs) and serotonin and norepinephrine reuptake inhibitors
(SNRIs) in alleviating symptoms of depression.1 Efforts towards
the discovery of a single agent that would simultaneously elevate
all three monoamines, a triple reuptake inhibitor (TRI), have been
driven by a desire to improve the efficacy, onset of the action
and adverse effect profile of SSRIs and SNRIs.2,3 The benefit of add-
ing a dopamine component is supported by the finding of linkages
between deficits in mesocorticolimbic dopaminergic function and
anhedonia.4 In addition, dopamine reuptake inhibitors (e.g.,
buproprion) and dopamine agonists (e.g., pramipexole) are already
used clinically as antidepressants5 and to augment the effects of
traditional antidepressants in treatment refractory patients.6
The TRI theory was reduced to practice preclinically with
DOV-21,9477 and DOV-216,303.8 Both compounds potently inhib-
ited the three monamine transporters (IC50 for hSERT, hNET and
hDAT for DOV-21,947 = 12, 23, 96 nM and for DOV-216,303 = 14,
20, 78 nM, respectively), and exhibited antidepressant-like activity
in the rat forced swim and mouse tail suspension tests (Fig. 1).
Although the overall clinical picture for TRIs is still mixed,9,10
DOV Pharmaceuticals produced a positive Phase II clinical result
for a TRI in 2005. DOV-216,303 was shown in a multicenter, active
comparator Phase II study of patients with moderate to severe ma-
jor depressive disorder (n = 67) to be safe and as effective as
citalopram.11
Cl
Cl
Cl
Cl
N
H
N
H
DOV-216,303
DOV-21,947
racemic
(+)-(3,4-dichlorophenyl)-3-
azabicyclo[3.3.0]-hexane
Figure 1. Structures of DOV-216,303 and 21,947.
H
N
H
N
CH3
N
Cl
Cl
⇑
Corresponding author.
E-mail addresses: liming.shao@sunovion.com, lshao@fas.harvard.edu (L. Shao).
Present address: Evotec, Schnacokenburgallee 114, Hamburg 22525, Germany.
Present address: Cortex Pharmaceuticals, 15231 Barranca Parkway, Irvine, CA
Cl
2
Cl
1
à
92618, USA.
Figure 2. Transformation of tetrahydronaphthalene to tetrahydroquinoline.
0960-894X/$ - see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmcl.2010.10.086

L. Shao et al. / Bioorg. Med. Chem. Lett. 21 (2011) 520–523
521
In a previous communication12 we detailed the synthesis and
the in vitro and in vivo profile of compounds such as 1, which were
potent triple reuptake inhibitors against the serotonin, norepi-
nephrine and dopamine transporters (Fig. 2). The compounds were
also active in the mouse tail suspension test13 (10 mg/kg p.o.), an
in vivo model widely used to assess antidepressant-like activity.
On the negative side, the compound series also showed some inhi-
bition of CYP2D6 and the hERG potassium channel, and we sought
to minimize those undesired activities in a subsequent compound
series. Our present work focused on an additional modification to
the scaffold to create tetrahydroquinolines 2 (Fig. 2). Structure 2
retained the basic amine and lipophilic aromatic features present
in 1, but was simplified by removing the second stereogenic center.
Our goal was to determine the in vitro profile of compounds such
as 2 to determine if the desired potent reuptake inhibitory activi-
ties could be retained while minimizing the detrimental CYP2D6
and hERG inhibitory activities.
The first step in the synthesis of our potential triple reuptake
inhibitors was palladium catalyzed coupling of 1-iodo-3,4-dichlo-
rophenyl benzene to N-Boc protected tetrahydroquinoline 3, which
proceeded in good yield to give the desired racemic phenyl tetra-
hydroquinolines (Scheme 1). Chiral separation on a Chiral Technol-
ogies AD column provided pure fast moving enantiomer 5 (FME)
and slow moving enantiomer 6 (SME). A similar reaction scheme
with the b-amino tetrahydroquinoline 7 provided compounds 8
(FME) and 9 (SME) as pure enantiomers.
NHBoc
N
NHBoc
N
1. Pd(OAc)2, PtBu3, KOtBu,
Toluene, 70 C, overnight
I
NHBoc
º
75%
+
+
Cl
N
H
2. Chiral Separation
(AD Column)
Cl
Cl
Cl
Cl
3
4
Cl
5 (FME)
6 (SME)
NHBoc
1. Pd(OAc)2, PtBu3, KOtBu,
NHBoc
Cl
I
NHBoc
Toluene, 70 ºC, overnight
N
N
73%
+
+
N
H
Cl
2. Chiral Separation
(AD Column)
Cl
Cl
Cl
Cl
7
4
8 (FME)
9 (SME)
Scheme 1. Synthesis of tetrahydroquinolines 5, 6, 8, and 9.
NHBoc
NH2
N
N
N
HCHO, HCO2H
HCl
CH2Cl2 MeOH
N
-
NaB(CN)H3, MeOH
91%
40%
Cl
Cl
Cl
Cl
Cl
10
Cl
5
11
NaH, MeI
THF
94%
NH2
N
NH
N
N
N
NH
N
NBoc
TMSOTf, 2,6-lutidine
CH2Cl2
93%
N
Cl
Cl
14
Cl
Cl
Cl
Cl
Cl
15
Cl
16
Cl
Cl
12
13
Scheme 2. Synthesis of compounds 10, 11, 13, and 14–16.

522
L. Shao et al. / Bioorg. Med. Chem. Lett. 21 (2011) 520–523
NHBoc
Cl
NH2
N
HCHO, HCO H
2
TFA, CH Cl
2
2
N
N
NaB(CN)H , MeOH
3
N
92%
90%
Cl
Cl
Cl
Cl
Cl
8
17
18
NaH, MeI
THF
94%
NH
Cl
NH2
N
NBoc
Cl
NH
TFA, CH Cl
N
N
N
2
2
N
N
90%
Cl
Cl
Cl
Cl
Cl
Cl
Cl
Cl
21
22
23
19
20
Scheme 3. Synthesis of compounds 17, 18, 20, and 21–23.
Starting from the b-amino tetrahydroquinoline 8, deprotection
using TFA in CH2Cl2 provided primary amine 17, which was dime-
thylated (formic acid, sodium cyanoborohydride) to give dimethyl
amine 18 (Scheme 3). Alternatively, methylation of the N-Boc
starting material 8 provided compound 19, which was deprotected
to give monomethyl amine 20. A similar reaction sequence using
the enantiomeric starting material 9 provided compounds 21–23.
Table 1 details the in vitro data for the novel tetrahydroquino-
lines for inhibition of human recombinant serotonin,14 norepi-
nephrine,15 and dopamine16 transporters using published
methods.
For the first series of compounds, inhibition at SERT was best for
the dimethyl amines (compounds 11 and 16), and most of the com-
pounds showed modest inhibition at NET. Compound 14 was an
exception, showing an IC50 of 138 nM at NET. For inhibition at
DAT, the compounds were generally potent inhibitors, with the
exception of compound 11, which selectively inhibited SERT. The
Table 1
IC50 values at inhibition of human recombinant SERT, NET and DAT transporters for
tetrahydroquinolines
Compound
IC50 (nM)
NE
5-HT
DA
72
246
5033
39
12
8
16
605
122
177
465
100
309
1
10
11
13
14
15
16
17
18
20
21
22
23
107
650
3
73
926
7141
934
138
601
1184
2597
1857
1005
1849
1246
3091
20
116
132
7
2550
436
985
2400
128
5558
standouts in the a-amino-tetrahydroquinolines series from a triple
reuptake perspective were primary amine 14, which was below
200 nM at SERT and NET and below 20 nM on DAT, and dimethyl
amine 16, which was a potent dual dopamine serotonin reuptake
inhibitor (DSRI).
In general, SERT inhibition was weak in the b-amino-tetrahydro-
quinoline series, with only compound 22 showing an IC50 <200 nM.
Inhibition at DAT was significant for the mono and dimethyl amines
in the second series, while none of the b-amino-tetrahydroquino-
Elaboration of the amines in 5 and 6 was straightforward and is
shown in Scheme 2. Removal of the Boc protecting group using HCl
gave primary amine 10, which was dimethylated under reductive
amination conditions using formic acid and sodium cyanoborohy-
dride to give dimethyl amine 11. Alternatively, alkylation of the
N-Boc starting material 5 gave methyl amine 12, which was depro-
tected using TMSOTf in CH2Cl2 to give monomethyl amine 13. A
similar reaction scheme using chiral amine 6 as starting material
provided compounds 14–16.
lines showed inhibition at NET below 1 lM.
Table 2
In vitro microsomal stability, CYP and hERG inhibition for selected compounds
Compound
Microsomal stability t1/2 (min)
CYP450 inhibition IC50
2C19
(l
M)
2D6
hERG IC50 (lM)
Human
Mouse
1A
2C9
3A4
14
13
15
16
22
>300
199
>300
>300
237
201
22
>300
.300
20
>25
>25
>25
>25
n.t.*
>25
>25
>25
.25
>25
14.1
19
>25
n.t.
4.87
3
1.5
6.02
0.10
>25
>25
>25
>25
n.t.
3.5
7.8
3.25
8.6
n.t.
n.t.
*
n.t., not tested.

L. Shao et al. / Bioorg. Med. Chem. Lett. 21 (2011) 520–523
523
The in vitro microsomal stability, CYP and hERG inhibition
profiles of series one compounds 13–16 and series two compound
22 are shown in Table 2. All of the compounds showed excellent
stability in the human microsomal stability assay, with half-lives
greater than 200 min in most cases. The CYP inhibition profile of
the series one compounds was similar or slightly improved com-
communications will detail the in vivo efficacy profile of this novel
class of dual reuptake inhibitors.
References and notes
1. Hirschfeld, R. M. J. Clin. Psychiatry 2000, 61, 4.
pared to initial lead 1 (CYP2D6 IC50 = 2.78
amine 13 showing an IC50 at CYP2D6 of almost 5
amine 16 showing an IC50 of 6.02 M. Inhibition at the hERG potas-
sium channel was also reduced for the series one compounds, with
compound 13 and 16 showing IC50’s of 7.8 and 8.6 M, respec-
lM), with primary
2. British Association for Psychopharmacology. Evidence based guidelines for
treating depressive disorders with antidepressants: a revision of the 2000
British Association for Psychopharmacology guidelines [online]. available from
URL: http://www.bap.org.uk.
lM, and dimethyl
l
3. Paul, I. A. Pharma. News 2001, 8, 33.
l
4. D’Aquila, P. S.; Collu, M.; Gessa, G. L.; Serra, G. Eur. J. Pharmacol. 2000, 405, 365.
5. Corrigan, M. H.; Denahan, A. Q.; Wright, C. E.; Ragual, R. J.; Evans, D. L. Depress.
Anxiety 2000, 11, 58.
6. Sporn, J.; Ghaemi, S. N.; Sambur, M. R.; Rankin, M. A.; Recht, J.; Sachs, G. S.;
Rosenbaum, J. F.; Fava, M. Ann. Clin. Psychiatry 2000, 12, 137.
7. Skolnick, P.; Popik, P.; Janowsky, A.; Beer, B.; Lippa, A. S. Eur. J. Pharmacol. 2003,
461, 99.
8. (a) Beer, B.; Stark, J.; Krieter, P.; Czobor, P.; Beer, G.; Lippa, A.; Skolnick, P. J. Clin.
Pharmacol. 2004, 44, 1360; (b) Skolnick, P.; Popik, P.; Janowsky, A.; Beer, B.;
Lippa, A. S. Life Sci. 2003, 73, 3175.
9. Graff, O.; Learned, S.; Roychowdhury, S. M.; Moate, R.; Morrison, D.; Lavergne,
A; Krishnan, K. R.; Archer, G.; Modell, J.; Alexander, R.; Ratti, E. ACNP Poster
2009.
tively. The only compound tested from series 2, monomethyl
amine 22, showed good stability in the human microsomal stabil-
ity assay, but also showed potent inhibition against CYP2D6
(IC50 = 100 nM). No other isoforms were tested for compound 22
due to the significant CYP2D6 inhibition.
The a- and b-amino tetrahydroquinolines described in the pres-
ent work are a significant synthetic improvement over the b-amino
tetrahydronaphthalenes described in our initial work. With only
one chiral center, the synthesis was comparably easier, eliminating
the need to separate the mixtures of diastereomers present in any
work using tetralone precursors. The series one tetrahydroquino-
line-4-amines showed better CYP2D6 and hERG inhibition profiles,
which should reduce the potential for cardiac toxicity (hERG) and
drug–drug interactions (CYP2D6), while maintaining potent reup-
take inhibition against the serotonin and dopamine transporters.
The loss of norepinephrine reuptake inhibition may improve the
safety profile of this class of compounds; the NE transporter is ex-
pressed in heart tissue and the clinical effects of NE reuptake inhib-
itors on heart function is an area of active research.17 Future
10. Sepracor Inc. Press Release, July 1, 2009.
11. DOV Pharmaceutical Press Release, September 27, 2005.
12. Shao, L.; Wang, F.; Malcolm, S. C.; Ma, J.; Hewitt, M. C.; Campbell, U.; Varney, M.
Bioorg. Med. Chem. 2010, doi:10.1016/j.bmc.2010.10.034.
13. Steru, L.; Chermat, R.; Thierry, B.; Simon, P. Psychopharmacology 1985, 85, 367.
14. Gu, H.; Wall, S.; Rudnick, G. J. Biol. Chem. 1994, 269, 7124.
15. Galli, A.; DeFelice, L. J.; Duke, B. J.; Moore, K. R.; Blakely, R. D. J. Exp. Biol. 1995,
198, 2197.
16. Pristupa, Z. B.; Wilson, J. M.; Hoffman, B. J.; Kish, S. J.; Niznik, H. B. Mol.
Pharmacol. 1994, 45, 125.
17. Vincent, S.; Bieck, P. R.; Garland, E. M.; Loghin, C.; Bymaster, F. P.; Black, B. K.;
Gonzales, C.; Potter, W. Z.; Robertson, D. Circulation 2004, 109, 3202.