1-Aryl-3,4-dihydro-1H-quinolin-2-one derivatives, novel and selective norepinephrine reuptake inhibitors

Article abstract of DOI:10.1016/j.bmcl.2005.07.038

A novel series of 1-aryl-3,4-dihydro-1H-quinolin-2-ones have been discovered as potent and selective norepinephrine reuptake inhibitors. Efficient synthetic routes have been developed which allow for the multi-gram preparation of both final targets and ad

Full text of DOI:10.1016/j.bmcl.2005.07.038

Bioorganic & Medicinal Chemistry Letters 15 (2005) 4432–4437
1-Aryl-3,4-dihydro-1H-quinolin-2-one derivatives, novel
and selective norepinephrine reuptake inhibitors
Christopher D. Beadle,a John Boot,a Nicholas P. Camp,a,* Nancy Dezutter,b
Jeremy Findlay,a Lorna Hayhurst,a John J. Masters,c
Roberta Penariola and Magnus W. Waltera
aEli Lilly and Company Ltd, Lilly Research Centre, Erl Wood Manor, Windlesham, Surrey, GU20 6PH, UK
b
´
Lilly Development Centre, Parc Scientifique de Louvain-la-Neuve, Rue Granbonpre 11, 1348 Mont-Saint-Guibert, Belgium
cLilly Research Laboratories, Eli Lilly and Company, Lilly Corporate Center, Indianapolis, IN 46285, USA
Received 13 May 2005; revised 6 July 2005; accepted 14 July 2005
Abstract—A novel series of 1-aryl-3,4-dihydro-1H-quinolin-2-ones have been discovered as potent and selective norepinephrine
reuptake inhibitors. Efficient synthetic routes have been developed which allow for the multi-gram preparation of both final targets
and advanced intermediates for SAR expansion.
Ó 2005 Elsevier Ltd. All rights reserved.
1. Introduction
O
A number of major affective disorders have been suc-
R
cessfully treated in the clinic by drugs that target mono-
O
O
amine reuptake inhibition.1 Selective serotonin reuptake
inhibitors (SSRIs), such as fluoxetine 1 (ProzacTM), are
currently in use for the treatment of depression.
O
O
S
N
H
N
N
H
H
Increasing evidence suggests that norepinephrine (NE)
plays a key role in the central nervous system2 and
inhibitors of the norepinephrine transporter (NET) are
currently in clinical use for the treatment of depression
and attention-deficit/hyperactivity disorder (ADHD).
Lilly recently introduced atomoxetine 2 (StratteraTM),
a selective norepinephrine reuptake inhibitor (NERI)
for the treatment of ADHD.3 Reboxetine 3 (Edro-
naxTM), another selective NERI, is marketed in Europe
for the treatment of depression.4 In addition to these
selective inhibitors, new generation dual serotonin and
norepinephrine reuptake inhibitors have emerged.
Duloxetine 4 (CymbaltaTM), a member of this group,
has been shown to improve potency and accelerate the
3 Reboxetine
4 Duloxetine
1 R = 4-CF3 (Fluoxetine)
2 R = 2-Me (Atomoxetine)
Figure 1. Selective and dual monoamine reuptake inhibitors.
onset of action of antidepressant activity.5 Thus, there is
continued interest in biogenic amine reuptake inhibitors
with both selective and mixed activity profiles (Fig. 1).
These varied approaches offer the potential to bring
more effective treatments to a wider patient population.
2. Inhibitor design
Fluoxetine 1, atomoxetine 2, reboxetine 3, and duloxe-
tine 4, all contain a 3-aryloxypropylamine structural
motif. Whilst this structural feature has previously been
used to obtain potent inhibitors of biogenic amine
transporters,6 we wished to explore alternative chemical
Keywords: Monoamine reuptake inhibitors; Selective norepinephrine
reuptake
inhibitor;
SAR;
Norepinephrine;
Quinolin-2-one;
Pharmacophore.
*
Corresponding author. Tel.: +44 01276 483 983; fax: +44 012 76 483
525; e-mail: Camp_Nicholas@lilly.com
0960-894X/$ - see front matter Ó 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmcl.2005.07.038

C. D. Beadle et al. / Bioorg. Med. Chem. Lett. 15 (2005) 4432–4437
4433
i
N
O
N
H
O
5
6
Figure 2. Proposed pharmacophore for NET inhibition.
ii
H
N
Cl
H
H
N
n
n
N
n
n
iii
N
N
O
O
N
N
O
n=1-3
10 n=1, 11 n=2, 12 n=3
7 n=1, 8 n=2, 9 n=3
Figure 3. Identification of 1-aryl-3,4-dihydro-1H-quinolin-2-ones.
Scheme 1. Reagents and conditions: (i) bromobenzene (3 equiv.), CuI
(0.2 equiv.), trans-cyclohexane-1,2-diamine (0.2 equiv.), K2CO3 (2.1
equiv.), dioxane, 125 °C, 80%; (ii) (a) LiHMDS (1.1 equiv.), THF,
À78 °C, 30 min, (b) Cl-(CH2)n-Br (1.1 equiv.), THF, À78 °C to rt; (iii)
aq MeNH2 (40%), EtOH, 100 °C, 3 h; (n = 1, 7% steps ii and iii; n = 2,
42% steps ii and iii; n = 3, 28% steps ii and iii).
scaffolds. Based upon findings from an in-house high-
throughput screen, we proposed the following pharma-
cophore for NET inhibition (Fig. 2). This pharmaco-
phore consisted of a basic amine linked by a flexible
chain to a ring system flanked by two nitrogen-linked
aromatics.
An improved synthetic route was then developed to the
3-carbon spacer, providing access to multi-gram quanti-
ties of final products (Scheme 2) and also advanced
intermediates that could be used for SAR expansion
(Scheme 3).
Herein, we report a novel series of 1-aryl-3,4-dihydro-
1H-quinolin-2-ones7 (Fig. 3) and describe their synthe-
ses and SAR. Amongst this series, we reveal a number
of analogues as potent and selective inhibitors of the
NET transporter.
Using the previously described alkylation conditions, 1-
phenyl-3,4-dihydro-1H-quinolin-2-one 6 was converted
to the allyl derivative 13 in excellent yield using allyl
bromide as the alkylating reagent. Hydroboration of
13 using 9-BBN, followed by an oxidative work up, gave
3. Chemistry
Our initial synthetic route involved a novel application
of the Buchwald reaction for the N-arylation of amides
(Scheme 1).8 Treatment of commercially available 3,4-
dihydro-1H-quinolin-2-one 5 with excess bromobenzene
or iodobenzene, in refluxing 1,4-dioxane using catalytic
copper (I) iodide and a trans-cyclohexane-1,2-diamine
ligand, gave 1-phenyl-3,4-dihydro-1H-quinolin-2-one 6
in 80% yield.9
R
i
N
O
N
O
The best general conditions for mono-alkylation of
1-phenyl-3,4-dihydro-1H-quinolin-2-one
6
13 R=H
6
involved
treatment with lithium hexamethyldisilazide (LiHMDS)
at À78 °C in tetrahydrofuran, followed by addition
of the electrophile.10 In the first instance, we employed
ii, iii
R
R
1-bromo-2-chloroethane,
1-bromo-3-chloropropane,
N
OMs
and 1-bromo-4-chlorobutane, which provided the corre-
sponding chloro derivatives 7, 8, and 9. These crude
intermediates could then be converted to final products
by displacement reactions using aqueous methylamine
in refluxing ethanol. Purification of the crude amines
with an SCX-2 cartridge provided 10, 11, and 12, the
2, 3, and 4-carbon spacer analogues, respectively. Whilst
this 3-step synthetic route gave a rapid entry to the final
products, yields for the 2-carbon spacer were poor (7%
over two steps). In addition, yields for alkylations
involving these dihaloalkanes dropped dramatically
upon scale up.
H
iv
N
N
O
O
11
14
Scheme 2. Reagents and conditions: (i) (a) LiHMDS (1.1 equiv.),
THF, À78 °C, 30 min, (b) allyl bromide (1.1 equiv.), THF, À78 °C
to rt; (ii) (a) 9-BBN (2.5 equiv.), THF, 0 °C to rt overnight, (b)
EtOH, NaOH (aq), 0 °C, H2O2 (aq), 5–10 °C, (c) rt to reflux 90 min,
70% over steps i and ii; (iii) MsCl (1.1 equiv.), NEt3 (1.5 equiv.),
THF, rt, 3 h, 100%; (iv) aq MeNH2 (40%), EtOH, 60 °C, 2 h, 81%.

4434
C. D. Beadle et al. / Bioorg. Med. Chem. Lett. 15 (2005) 4432–4437
R
R
R
N
N
H
i, ii
i
ii, iii
N
O
N
H
O
O
N
O
N
O
O
5
15
Y
20-33
16
17
MeO
R=H or CH3
MeO
X
Scheme 3. Reagents and conditions: (i) arylhalide (3 equiv.), CuI (0.2
equiv.), trans-cyclohexane-1,2-diamine (0.2 equiv.), K2CO3 (2.1
equiv.), dioxane, 125 °C; (ii) TFA, DCM, rt 2 h; yields typically
>80% for steps i and ii.
iv, v, vi
R
R
N
N
vii, viii
H
the primary alcohol intermediate in 70% over the two
steps. Clean conversion of the alcohol to the corre-
sponding mesylate 14 was achieved in quantitative yield
using methanesulfonyl chloride and triethylamine in tet-
rahydrofuran at room temperature. The mesylate was
reacted with aqueous methylamine in ethanol for 2 h
at 60 °C to give the amine product 11 (R@H) in good
yield. In addition, mesylate 14 served as a versatile inter-
mediate for exploring the SAR around the amine substi-
tuent. The same synthetic sequence could be used to
explore the effect of alkyl substitution in the 3-position
(e.g., R@CH3, etc.) (Table 3). In this case, alkylation
with the appropriate alkyl halide is carried out, prior
to alkylation with allyl bromide. These derivatives are
then converted to final products using the previously de-
scribed chemistry in Scheme 2. In this manner, final
products containing methyl, ethyl, n-propyl, i-propyl,
and n-butyl in the 3-position were all prepared.
N
H
O
O
O
N
O
15
18
R=CH3
MeO
Scheme 4. Reagents and conditions: (i) NaH (1.3 equiv.), DMF, 4-
methoxy benzyl chloride (1.3 equiv.), 10 °C to rt, 85%; (ii) LiHMDS,
(1.1 equiv.), THF, À78 °C, 30 min, MeI (1.1 equiv.) 100%; (iii) (a)
LiHMDS (1.1 equiv.), THF, À78 °C, 30 min, (b) allyl bromide (1.1
equiv.), À78 °C to rt, 100%; (iv) (a) 9-BBN (2.5 equiv.), THF, 0 °C to
rt overnight, (b) EtOH, NaOH (aq), 0 °C, H2O2 (aq), 5–10 °C, (c) rt to
reflux 90 min, 84%; (v) MsCl (1.1 equiv.), NEt3 (1.5 equiv.), THF, rt
3 h, 96%; (vi) aq MeNH2 (40%.), EtOH, 60 °C, 2 h; (vii) TFA, anisole,
65 °C, 3 h, 77% over steps vi and vii; (viii) boc anhydride, THF, 100%;
53% overall yield over steps i to viii.
R
R
X
N
N
i
N
H
O
N
O
O
O
O
O
To explore the SAR around the southern N-aromatic
ring, a multi-gram synthesis of advanced intermediate
15 was required. With this in hand, the aforementioned
Buchwald reaction could be used to access a range of
N-arylated final products (Scheme 3, Table 2).
H
15
X =Cl or Br
Scheme 5. Reagents and conditions: (i) N-chlorosuccinimide or N-
bromosuccinimide, DMF, 0 °C to rt overnight, 96%.
Finding a suitable nitrogen-protecting group for 3,4-
dihydro-1H-quinolin-2-one 5 proved to be critical in
the synthesis of the desired advanced intermediate 15
(Scheme 4). 3,4-Dihydro-1H-quinolin-2-one 5 was suc-
cessfully N-protected with both tert-butoxycarbonyl
(boc) and benzyl groups, but the former failed to give
the desired alkylation reaction and the latter proved
impossible to remove. For this reason, the more labile
4-methoxybenzyl group was chosen and the reaction
of 5 with sodium hydride in dimethylformamide, fol-
lowed by treatment with 4-methoxybenzyl chloride,
provided the protected analogue 16 in 85% yield.
The same previously described dialkylation procedure
provided allyl derivative 17 in quantitative yield. This
was converted into amine 18 using the hydroboration,
mesylation, and amination sequence. Removal of the
4-methoxybenzyl protecting group was achieved in
excellent yield using modified conditions involving
neat trifluoroacetic acid and one equivalent of anisole
at 65 °C.11 A final nitrogen protection step using boc
anhydride gave multi-gram quantities of 15 (R@CH3)
in a respectable 53% overall yield for all eight steps.
This exact route worked for R@H, but with consider-
ably lower yields.
In addition, treatment of 15 with N-chlorosuccinimide
or N-bromosuccinimide in dimethylformamide provided
the monosubstituted halides in the 6-position of the
aromatic ring in excellent yield (Scheme 5). These inter-
mediates were used in combination with the southern
N-aromatic SAR and also offered potential as metabo-
lism blockers (Table 4).
6-Fluoro-3,4-dihydro-1H-quinolin-2-one was prepared
from 1-hydroxy-3,4-dihydro-1H-quinolin-2-one using
literature methods.12
4. SAR
All target compounds were tested initially as racemates
for reuptake inhibition at the norepinephrine (NET),
serotonin (SERT), and dopamine transporters (DAT).13
Table 1 shows the effect of chain length upon NET reup-
take inhibition. The 2-carbon spacer (n = 1) racemate 10
was separated into its enantiomers 10a and 10b using

C. D. Beadle et al. / Bioorg. Med. Chem. Lett. 15 (2005) 4432–4437
4435
Table 1. Inhibition of monoamine reuptake for norepinephrine, serotonin, and dopamine for compounds 10–12 and 19
H
R
N
n
N
O
Compound
n
R
Stereochemistry
Ki (nM)a
SERT
NET
DAT
10a
10b
11
1
1
2
2
2
3
2
H
Isomer-1
Isomer-2
Racemate
Isomer-1
Isomer-2
Racemate
Racemate
38
54
10
8
5
6
4
3
>100 (1 1%)b
>100 (9 11%)b
>100 (À0.3 6%)b
>100 (5 4%)b
>100 (4 4%)b
>100 (À3 3%)b
>100 (9 0.1%)b
>200 (13 1%)c
>200 (9 4%)c
>200 (24 7%)c
>200 (11 1%)
>200 (5 1%)c
>200 (12 3%)c
>200 (10 4%)c
H
H
11a
11b
12
H
H
190 11
>200 (53 3%)c
44
H
Me
19
1
a Values are means of at least three experiments, rounded off to the nearest whole number.
b Percentage displacement at 100 nM.
c Percentage displacement at 1000 nM. Radio-ligands [3H]-WIN35,428 (DAT); [3H]-citalopram (SERT); [3H]-nisoxetine (NET). For full details of
assay conditions, see Ref. 10. Minimum significant ratio (MSR): NET: 2.5; SERT: 3.0; DAT: 1.6. NET, SERT, and DAT binding data for
fluoxetine 1, atomoxetine 2, and duloxetine 4 has recently been published.14
chiral HPLC.15 Both isomers possessed modest NET
potency. The 3-carbon spacer (n = 2) racemate 11 had
potent activity and was separated into its enantiomers
11a and 11b using the same HPLC technique.15 The fast-
er eluting isomer 1 was found to be 20-fold more NET
active than isomer 2 and selective over SERT and
DAT. This NET selectivity is generally maintained
throughout this series. The absolute stereochemistry of
11a is unknown. The 4-carbon spacer 12 (n = 3) showed
poor NET affinity. In addition, the initial synthesis al-
lowed for the incorporation of an alkyl substituent in
the 3-position. The racemic methyl analogue (R@CH3)
19 had moderate NET activity.
Before embarking on further SAR studies for this new
series, profiling data for our initial hit 11a were collect-
ed, including an examination of its physicochemical
properties. The measured logD of the molecule high-
Table 2. Inhibition of monoamine reuptake for norepinephrine, serotonin, and dopamine for compounds 20–33
R
N
H
Western
N-aromatic
N
O
Y
Southern
N-aromatic
Compound
Y
R
Ki (nM)a
SERT
NET
DAT
11-rac
20-rac
21-rac
19-rac
22-rac
23-rac
24-rac
25-rac
26-rac
27-rac
28-rac
29-rac
30-rac
31-rac
32-rac
33-rac
H
3-F
H
10
18
4
1
>100 (0 6%)b
>100 (9 1%)b
>100 (7 2%)b
>100 (9 0.1%)b
>100 (9 2%)b
>100 (7 2%)b
>100 (8 1%)b
>100 (15 6%)b
>100 (3 2%)b
>100 (1 1%)b
>100 (12 2%)b
>100 (5 5%)b
>100 (8 3%)b
>100 (11 1%)b
>100 (9 3%)b
>100 (10 1%)b
>200 (24 7%)c
>200 (10 0.2%)c
>200 (64 2%)c
>200 (10 4%)c
>200 (9 2%)c
>200 (5 5%)c
>200 (50 3%)c
>200 (19 3%)c
>200 (9 6%)c
>200 (12 1%)c
>200 (3 8%)c
>200 (2 1%)c
H
3-Cl
H
H
79 11
44
146 14
Me
Me
H
1
3-Me
4-F
4-Cl
92
21
3
3
2
1
H
4-Me
4-Et
H
H
150 41
1430 285
4-CF3
4-Me
4-iPr
H
Me
Me
H
9
2
>200 (18 1%)c
3,4-DiCl
3,4-DiF
3,5-DiF
3,5-DiCl
62
77
6
8
13
3
Me
Me
Me
>200 (50 3%)c
>200 (19 1%)c
>200 (41 6%)c
165 25
>200 (39% 0.2)c
a Values are means of at least three experiments, rounded off to the nearest whole number.
b %-displacement at 100nM.
c Percentage displacement at 1000 nM; rac (racemate).

4436
C. D. Beadle et al. / Bioorg. Med. Chem. Lett. 15 (2005) 4432–4437
Table 3. Inhibition of monoamine reuptake for norepinephrine, serotonin, and dopamine for compounds 34–35
R
N
H
N
O
Compound
R
Ki (nM)a
NET
SERT
DAT
11-rac
19-rac
34-rac
35-rac
H
10
44
10
7
4
1
1
1
>100 (À0.3 6%)b
>100 (9 0.1%)b
>100 (12 3%)b
>100 (51 2%)b
>200 (24 7%)c
>200 (10 4%)c
>200 (6 0.2%)c
>200 (3 3%)c
Me
Et
n-Pr
a Values are means of at least three experiments, rounded off to the nearest whole number.
b Percentage displacement at 100 nM.
c Percentage displacement at 1000 nM; rac (racemate).
lighted its inherent hydrophilicity (logD = À0.48) and
suggested poor brain penetration.16 The goal, therefore,
was to maintain this desired in vitro NET potency,
whilst increasing the overall lipophilic nature of the mol-
ecule. This strategy should ultimately increase the rate of
brain penetration and with this in mind the various SAR
domains of the molecule were studied.
implying size constraints. Mono-substitution with a 4-
fluoro group 23 in the same ring reduced NET activity,
whilst the corresponding 4-chloro derivative 24 was tol-
erated. NET potency was increased with both the
4-methyl analogues 25 and 28, suggesting a preference
for a small lipophilic substituent in this position.
Increasing the size of the alkyl group to ethyl 26 or iso-
propyl 29 caused a reduction in NET activity as did the
electron-withdrawing CF3 analogue 27. Using this
Buchwald chemistry, the synthesis of analogues contain-
ing 2-substituents was unsuccessful, probably due to ste-
ric constraints. With these limitations in mind, only the
3,4- and 3,5-dihalo analogues were prepared. Whilst 3,4-
difluorosubstitution 31 was tolerated, the corresponding
3,4-dichloro analogue 30 caused a modest reduction in
NET activity. Unsurprisingly, the 3,4-dichloro analogue
30 possessed good DAT potency. In the case of the 3,5-
disubstituted analogues, the 3,5-difluoro analogue 32
caused a reduction in NET activity, whilst a greater
reduction in activity was observed with the 3,5-dichloro
derivative 33.
Using mesylate 14 a limited set of analogues containing
various amine substituents were prepared. Replacement
of the methylamine group in 11 by its tertiary amine
counterpart and by larger alkyl groups all resulted in a
reduction of NET affinity. Therefore, the first attempt
to increase logD, whilst maintaining NET potency,
was unsuccessful.
Table 2 shows the effect of substitution in the southern
N-aromatic ring. Mono-substitution in the 3-position
of the southern N-aromatic ring with a fluoro group
20 was tolerated, whilst a 3-chloro 21 and 3-methyl
group 22 both caused a reduction in NET affinity,
Table 4. Inhibition of monoamine reuptake for norepinephrine, serotonin, and dopamine for compounds 36–43
R
X
N
H
Western
N-aromatic
N
O
Y
Southern
N-aromatic
Compound
X
Y
R
Ki (nM)a
NET
SERT
>100 (11 2%)b
DAT
36-rac
37-rac
38-rac
39-rac
40-rac
41-rac
42-rac
43-rac
H
H
H
H
F
4-Me
4-Me
4-Me
4-Me
4-Me
4-Me
4-Me
4-Me
Et
17
11
1
>200 (11 0.1%)c
>200 (9 1%)c
>200 (7 5%)c
>200 (18 3%)c
>200 (5 3%)c
>200 (7 5%)c
N.D
n-Pr
i-Pr
n-Bu
H
1
160
5
150 30
N.D
N.D
>100 (45 3%)b
>100 (15 2%)b
>100 (15 2%)b
128 10
8
5
6
2
1
2
Cl
Cl
Cl
H
Me
Et
43 12
47
5
>200 (3 3%)c
a Values are means of at least three experiments, rounded off to the nearest whole number.
b Percentage displacement at 100 nM.
c Percentage displacement at 1000 nM; rac (racemate); N.D (not determined).

C. D. Beadle et al. / Bioorg. Med. Chem. Lett. 15 (2005) 4432–4437
4437
2. Southwick, S. M.; Bremner, J. D.; Rasmusson, A.;
Morgan, C. A.; Arnsten, A.; Charney, D. S. Biol.
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3. Bymaster, F. P.; Katner, J. S.; Nelson, D. L.; Hemrick-
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Morin, S. M.; Gehlert, D. R.; Perry, K. W. Neuropsycho-
pharmacology 2002, 27, 699.
Table 3 shows the effect of steric bulk in the 3-position
within a series of straight chain alkyl analogues. Replac-
ing the hydrogen in the 3-position 11 with a methyl sub-
stituent 19 resulted in a 4-fold drop in NET activity.
However, increasing the size of the alkyl substituent to
ethyl 34 and n-propyl 35 brought the NET activity back,
with these analogues being comparable to 11 (R@H).
This approach proved successful in increasing the over-
all lipophilic nature of the molecules with the n-propyl
analogue 35 having a predicted logD of 1.117
4. Scates, A. C.; Doraiswamy, P. M. Ann. Pharmacother.
2000, 34, 1302.
5. Schatzberg, A. F. J. Clin. Psychiatry 2003, 64, 30.
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Mahadevan, S.; Mitchell, S. N.; Rathmell, R. E.; Rich-
ards, S. J.; Simmonds, R. G.; Wallace, L.; Whatton, M. A.
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7. A related series of 5-membered ring analogues have been
described: Canas-Rodriguez, A.; Leeming, P. R. J. Med.
Chem. 1972, 15, 762.
With the increase in potency obtained with analogues
containing a 4-methyl substituent on the southern N-ar-
omatic rings 25 and 28, a combination with the previ-
ously described 3-alkyl SAR was attempted (Table 4).
Potent NET activity was observed with the ethyl 36,
n-propyl 37, and n-butyl analogues 39, although this
combination did not give an additive boost to activity
versus the corresponding unsubstituted analogues 34
and 35. In this series of compounds, the branched iso-
propyl analogue 38 was not tolerated. Halogen substitu-
tion in the 6-position of the western N-aromatic ring 40
and 41 was tolerated. As before, the combination SAR
failed to be additive with analogues 42 and 43 possessing
moderate NET activity.
8. Klapars, A.; Antilla, J. C.; Huang, X.; Buchwald, S. L.
J. Am. Chem. Soc. 2001, 123, 7727.
9. During the course of this work, a microwave-assisted
Goldberg reaction was reported: Lange, J. H. M.;
Hofmeyer, L. J. F.; Hout, F. A. S.; Osnabrug, S. J. M.;
Verveer, P. C.; Kruse, C. G.; Feenstra, R. W. Tetrahedron
Lett. 2002, 43, 1101.
10. For full experimental details see: Camp, N. P.; Penariol,
R.; Beadle, C. D. WO2004096773..
11. Couture, A.; Deniau, E.; Grandclaudon, P.; Lebrun, S.
Synlett 1997, 12, 1475.
12. Kikugawa, Y.; Matsumoto, K.; Mitsui, K.; Sakamoto, T.
J. Chem. Soc. Chem. Comm. 1992, 12, 921.
5. Summary
13. NET assay: Gobel, J.; Saussy, D. L.; Goetz, A. J.
Pharmacol. Toxicol. Methods 1999, 42, 237; SERT/DAT
assay: Ramamoorthy, S.; Giovanetti, E.; Qian, Y.; Blakely,
R. J. Biol. Chem. 1998, 273, 2458.
14. Bymaster, F. P.; Beedle, E. E.; Findlay, J.; Gallagher, P.
T.; Krushinski, J. H.; Mitchell, S.; Robertson, D. W.;
Thompson, D. C.; Wallace, L.; Wong, D. T. Bioorg. Med.
Chem. Lett. 2003, 13, 4477.
A novel series of 1-aryl-3,4-dihydro-1H-quinolin-2-ones
has been discovered as potent and selective NET reup-
take inhibitors. Efficient syntheses of these analogues
have been developed, allowing for the preparation of
multi-gram quantities of final products and advanced
intermediates for SAR determination. The strategy to
increase the lipophilic nature of this series was success-
ful (measured logD increased from À0.48 for the origi-
nal hit 11a to 1.8 for analogue 43). There were
limitations within this SAR and often increasing lipo-
philicity within this series resulted in a reduction in
NET activity. However, substitution in the 3-position
with straight chain alkyl groups provided molecules
with both increased lipophilic character and good
NET potency.
15. 10a was obtained after separation by chiral HPLC on a
Chiralcel-OJ(3624) semi-preparative column using
a
gradient of 50% heptane, 50% isopropanol, and 0.2%
dimethylethyl amine as eluent (e.e. 100%), sample
concentration 0.5 mg/ml 1.0 ml/min, sample solvent:
50% heptane, 50% isopropanol, and 0.2 dimethylethyl
amine, Rt = 18.39 min. 10b was obtained after separation
by chiral HPLC using the same conditions;
Rt = 22.02 min (e.e. 98%). 11a was obtained after
separation by chiral HPLC on a Chiralcel-OJ(3624)
semi-preparative column using a gradient of 85% hep-
tane, 15% ethanol, and 0.2% dimethylethyl amine as
eluent (e.e. 96%), sample concentration 0.2 mg/ml 1.0 ml/
min, sample solvent: 50% heptane, 50% isopropanol,
Rt = 18.6 min. 11b was obtained after separation by
chiral HPLC using the same conditions; Rt = 20.79 min
(e.e. 91%).
Acknowledgments
We thank the analytical and DCSG groups at Erl Wood
for providing support, and Dr. Peter Gallagher and
Anne Marie Welsh for helpful advice.
16. Gulyaeva, N.; Zaslavsky, A.; Lechner, P.; Chlenov, M.;
McConnell, O.; Chait, A.; Kipnis, V.; Zaslavsky, B. Eur.
J. Med. Chem. 2003, 38, 391.
References and notes
1. Bymaster, F. P.; McNamara, R. K.; Tran, P. V. Exp.
Opin. Invest. Drugs 2003, 12, 531.
17. Predicted logDÕs were determined using the ACDLabs
software package version 7.0.