8-[2-(4-Aryl-1-piperazinyl)ethyl]-2H-1,4-benzoxazin-3(4H)-ones: Dual-acting 5-HT1 receptor antagonists and serotonin reuptake inhibitors-Part II

Article abstract of DOI:10.1016/j.bmcl.2009.02.056

8-[2-(4-Aryl-1-piperazinyl)ethyl]-2H-1,4-benzoxazin-3(4H)-ones have been identified as highly potent 5-HT_1A/B/D receptor antagonists with and without additional SerT activity and a high degree of selectivity over hERG potassium channels. Modula

Full text of DOI:10.1016/j.bmcl.2009.02.056

Bioorganic & Medicinal Chemistry Letters 19 (2009) 2338–2342
Contents lists available at ScienceDirect
Bioorganic & Medicinal Chemistry Letters
journal homepage: www.elsevier.com/locate/bmcl
8-[2-(4-Aryl-1-piperazinyl)ethyl]-2H-1,4-benzoxazin-3(4H)-ones: Dual-acting
5-HT1 receptor antagonists and serotonin reuptake inhibitors—Part II
b
b
b
b
Steven M. Bromidge a, , Barbara Bertani , Manuela Borriello , Andrea Bozzoli , Stefania Faedo ,
Massimo Gianotti b, Laurie J. Gordon a, Matthew Hill a, Valeria Zucchelli b,
Jeannette M. Watson a, Laura Zonzini b
*
a Neurosciences CEDD, GlaxoSmithKline, New Frontiers Science Park, Third Avenue, Harlow, Essex CM19 5AW, UK
b Neurosciences CEDD, GlaxoSmithKline, Medicines Research Centre, Via A. Fleming 4, Verona 37135, Italy
a r t i c l e i n f o
a b s t r a c t
Article history:
8-[2-(4-Aryl-1-piperazinyl)ethyl]-2H-1,4-benzoxazin-3(4H)-ones have been identified as highly potent
5-HT1A/B/D receptor antagonists with and without additional SerT activity and a high degree of selectivity
over hERG potassium channels. Modulation of the different target activities gave compounds with a range
of profiles suitable for further in vivo characterization.
Received 21 November 2008
Revised 12 February 2009
Accepted 13 February 2009
Available online 20 February 2009
Ó 2009 Elsevier Ltd. All rights reserved.
Keywords:
5-HT1A/1B/1D antagonists
Serotonin reuptake inhibitors
5-HT1 autoreceptors
hERG
Antidepressant
Over the past decades, a wealth of pre-clinical and clinical evi-
dence has confirmed a link between extracellular levels of seroto-
nin (5-HT) and a plethora of psychiatric indications, in particular
anxiety and depression.1 In fact, enhanced serotonergic neuro-
transmission has become the unifying mechanism of action of
modern day antidepressants and the selective serotonin reuptake
inhibitors (SSRIs) have become established as the most effective
antidepressant agents in current clinical use.2 Despite the success
of SSRIs, one undesirable characteristic is a long latency to thera-
peutic onset which is hypothesized to be due to the requirement
for desensitisation of 5-HT1 autoreceptors to maintain increased
5-HT levels.3
5-HT1 autoreceptors are located on both cell bodies (5-HT1A and
5-HT1D receptor subtypes) and nerve terminals (5-HT1B and 5-HT1D
receptor subtypes).4 They are widely distributed in the brain and in
addition to SerT are known to have a major role in the control of
synaptic 5-HT levels.4 Blockade of 5-HT1A/B/D autoreceptors, with
or without concomitant SerT inhibition, rapidly increases brain
5-HT levels and consequently should provide a fast onset of antide-
pressant/anxiolytic action relative to current therapies.5
inhibitory activity (Fig. 1).6 Modulation of the balance between the
different target affinities allowed us to identify compounds with
interesting in vitro and in vivo profiles. Unfortunately, the further
progression of these molecules into development was precluded by
the finding that they had significant binding affinity for human
ether-a-go-go-related gene (hERG) potassium channels.7 For in-
stance 1 had a pKi of 7.2 in a hERG binding assay (Table 1) which
translated to potent functional inhibition of hERG tail current in
whole cell electrophysiology studies8 (pEC50 8.1). Inhibition of
hERG in vitro is associated to increases in the QT interval prolonga-
tion in vivo and the induction of potentially life-threatening ven-
tricular arrhythmias in the clinic (Torsades de Pointes).9
Therefore, the removal or reduction of hERG affinity became a
key requirement in order to identify compounds which could be
further progressed into development. This Letter reports a success-
N
N
R1
N
We recently disclosed
a series of 6-[2-(4-aryl-1-piperazi-
N
O
nyl)ethyl]-2H-1,4-benzoxazin-3(4H)-ones as potent 5-HT1A/B/D
receptor antagonists some of which had additional hSerT reuptake
R1 = H SB-744185
R1 = Me
O
1
2
* Corresponding author. Tel.: +44 1279 627031; fax: +44 1279 622790.
E-mail address: steve.bromidge@gsk.com (S.M. Bromidge).
Figure 1.
0960-894X/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmcl.2009.02.056

S. M. Bromidge et al. / Bioorg. Med. Chem. Lett. 19 (2009) 2338–2342
2339
Table 1
a,b
Functional activity (f-pKi or pEC50
)
for human 5-HT1A/B/D receptors with intrinsic activity (IA) and SerT and hERG binding affinities (pKi)b: substitution of the benzoxazinone
R
N
N
N
6
O
N
7
O
8
*
Compdc
Sub
R
f-pKi or pEC50
pKib
a,b
5-HT1A (I.A.)
5-HT1B (I.A.)
5-HT1D (I.A.)
hSerT
hERG
*
1
2
3
4
5
6
6
6
8
8
7
7
H
Me
H
Me
H
Me
10.2 (0.0)
10.1 (0.3)
9.6 (0.0)
9.8 (0.0)
9.6 (0.0)
<5.5 (0.0)
6.6 (0.0)
8.7 (0.3)
9.0 (0.0)
8.4 (0.0)
7.5 (0.3)
9.3 (0.6)
8.9
7.7
6.5
8.0
7.0
6.8
7.2
6.1
5.6
5.4
7.0
5.5
10.0 (0.0)
10.3 (0.0)
9.5 (0.0)
9.1 (0.0)
8.3 (0.0)
*
8.2 (0.4)
a
Data from the agonist mode (pEC50)* are reported for those compounds with intrinsic activity (IA) P 0.4 in this mode (i.e., partial or full agonists), whereas, for those
compounds with IA <0.4 in the agonist mode (i.e., antagonists) data from the antagonist mode is reported (f-pKi).
b
Each determination lies within 0.3 log units of the mean with a minimum of three replicates. See text for radioligands and assay details.
c
Compounds were characterized and purity assessed using 1H NMR and LCMS.
ful strategy to this end and further exploration of the structure-
activity relationships (SAR) in this novel series.
alternative procedure outlined in Scheme 2 in which the cyclopro-
pyl group was introduced prior to the formation of the benzoxaz-
inone system.
The synthesis of the 6-substituted compounds 1 and 2 has been
previously described.6 The 8-substituted ethyl linked analogues 3,
4, 12–15 (Tables 1 and 3) were prepared according to Scheme 1 by
Claisen rearrangement of 22 (CARE—violently exothermic on large
scale >5 g) followed by construction of the benzoxazinone ring and
then osmylation of 25 to the key aldehyde 26 followed by reduc-
tive amination with the appropriate quinolinyl piperazine.10 The
homologated analogues 16–20 were prepared similarly from the
NH– or N-methylbenzoxazinone-8-(3-propanal) 28 itself prepared
by hydroboration of 25 to the primary alcohol 27 followed by
Dess–Martin oxidation.
The 7-substituted compounds 5 and 6 (Table 1) were prepared
according to Scheme 3. Thus, commercially available 3-hydroxy-4-
nitrobenzaldehyde was alkylated with methyl bromoacetate to af-
ford 32 which was converted to the enol ether 33. Reduction of the
nitro moiety and concomitant cyclisation afforded the benzoxazi-
none 34 which was hydrolysed directly to the key aldehyde 35
or alternatively methylated and then hydrolysed to afford the cor-
responding N-methyl analogue 36. Reductive amination of 35 and
36 with 2-methyl-5-(1-piperazinyl)-quinoline afforded the target
compounds 5 and 6.
Compounds 7, 8 and 10 (Table 2) were prepared as 4 according
to Scheme 1 by alkylation of 25 with the appropriate alkylating
agent in place of MeI at room temperature (41–77% yield). The
difluoromethyl analogue 11 was prepared similarly using chlorodi-
fluoromethane at À60 °C for 5 h then 16 h at room temperature
(28% yield).11 The cyclopropyl analogue 9 was prepared by the
The affinities of the compounds for the reuptake site of the
hSerT, stably expressed in epithelial pig kidney (LLCPK) cells, were
assessed by displacement of [3H]-citalopram binding either by fil-
tration or proximity assays.10 The affinities of the compounds for
hERG potassium channels, stably expressed in Chinese hamster
ovary (CHO) cells, were assessed by displacement of [3H]-dofetilide
NO2
OH
NO2
O
NO2
OH
NO2
(i)
(ii)
(iii)
(iv)
OMe
O
21
O
22
23
24
R1
N
H
N
n = 1 R1 = H (vi)
R1 = Me (v), (vi)
O
R3
O
O
O
25
26
N
N
n = 2 R1 = H (vii)
(ix)
N
R1 = Me (v), (vii)
(
)n
O
R2
R1
N
R1
N
O
N
R1
O
O
3-4, 12-15 n = 1
16-20 n = 2
(viii)
O
O
O
27
28
O
HO
Scheme 1. Reagents and conditions: (i) allyl bromide, K2CO3, acetone, reflux, overnight (100%); (ii) 200 °C, 3 h (45%); (iii) BrCH2CO2Me, K2CO3, acetone, reflux, 4 h (100%); (iv)
iron powder, NH4Cl, MeOH/H2O, 80 °C, 5 h (68%); (v) 60% NaH, MeI, DMF, 0 °C to rt, 4 h (66%); (vi) 4% OsO4 aq solution, NaIO4, THF/H2O, rt, 4 h (52–67%); (vii) Sia2BH, THF,
0 °C, 3 h; 3 N NaOH, 30% H2O2, THF/EtOH, 0 °C to 50 °C, 2 h (30%); (viii) Dess–Martin, DCM, rt, 3 h (54%) (ix) 7-R1-2-methyl-5-[3-R2-1-piperazinyl]quinoline, NaHB(OAc)3, 1,2-
DCE, rt, 6 h (26–83%).

2340
S. M. Bromidge et al. / Bioorg. Med. Chem. Lett. 19 (2009) 2338–2342
Table 2
Functional activity (f-pKi or pEC50
ring of 4
)
a,b for human 5-HT1A/B/D receptors with intrinsic activity (IA) and SerT and hERG binding affinities (pKi)b: N-substitution of the benzoxazinone
N
N
O
R1
N
O
N
Compdc
R1
f-pKia,b
pKib
5-HT1A (I.A.)
5-HT1B (I.A.)
5-HT1D (I.A.)
hSerT
hERG
4
7
8
9
10
11
Me
Et
iPr
9.8 (0.0)
9.9 (0.3)
9.2 (0.0)
10.0 (0.0)
9.2 (0.0)
9.3 (0.0)
8.4 (0.0)
8.4 (0.0)
8.3 (0.0)
8.3 (0.0)
8.2 (0.0)
7.8 (0.0)
9.5 (0.0)
9.7 (0.0)
9.6 (0.0)
9.8 (0.0)
9.5 (0.0)
9.4 (0.0)
8.0
7.7
6.8
6.9
6.7
7.2
5.4
5.1
5.3
5.8
5.8
6.4
cPr
CH2cPr
CHF2
a–c
see Table 1.
NO2
OH
N
N
NH
(iii)
N
O
O
(i)
N
O
(v)
(iv)
N
O
O
(ii)
OH
29
O
N
23
9
30
31
O
Scheme 2. Reagents and conditions: (i) Fe, CH3COOH, reflux 1 h, 69%; (ii) [(1-ethoxycyclopropyl)oxy]trimethylsilane, CH3COOH, NaBH(OAc)3, MeOH, reflux 3 h, 37%; (iii) (a)
chloroacetyl chloride, sodium bicarbonate, water/MEK (1:1), from 0 °C to reflux 4.5 h; (b) K2CO3, DMF, reflux overnight, 63%; (iv) OsO4 4% sol. in H2O, NaIO4, THF/ H2O, rt 3 h,
52%; (v) 2-methyl-5-(1-piperazinyl)quinoline, NaBH(OAc)3, 1,2-DCE, rt, overnight, 100%.
H
NO2
O
N
O
NO2
O
NO2
OH
(i)
(ii)
(iii)
OMe
H
OMe
O
H
O
O
O
34
MeO
O
33
MeO
32
R1
N
O
R1 = H (v)
(vi)
R1
N
N
N
R1 = Me (iv), (v)
O
N
O
5
R1 = H
35 R1 = H
36 R1 = Me
O
O
6
R1 = Me
Scheme 3. Reagents and conditions: (i) BrCH2CO2Me, K2CO3, MEK, reflux, 6 h (72%); (ii) Ph3P+CH2OMeClÀ , 18-Crown-6, THF, reflux, 6 h (71%, E/Z: 80:20); (iii) iron powder,
NH4Cl, MeOH/water, reflux, 2 h (66%); (iv) NaH 60%, MeI, THF, rt, 3 h (88%); (v) 10% HCl , THF, rt, overnight (80%); (vi) 2-methyl-5-(1-piperazinyl)quinoline, NaBH(OAc)3, 1,2-
DCE, from 0 °C to rt, overnight, (70%).
binding by proximity assays.12 Compounds were screened against
human-5-HT1A/B/D receptors in a dose response GTPgS functional
assay using Scintillation Proximity Detection (LEADSeekerTM) in
both agonist and antagonist mode, that is, in absence and presence
of 5-HT, respectively. Compounds with intrinsic activity (IA) in the
agonist mode P 0.4 relative to 5-HT were classified as partial or
full agonists and only the agonist data is reported (pEC50) whereas
compounds with IA <0.4 in the agonist mode were classified as
antagonists and data from the antagonist mode is reported as a
functional pKi (f-pKi).13 In general, the data from the 5-HT1A/1D
functional assays correlated well with displacement binding data6
which we had previously employed, however, for the 5-HT1B as-
says the f-pKi values were generally 0.5–1.0 log lower although
the rank order was in general maintained.14
nist potencies and low IA, had 15-fold reduced hSerT affinity
relative to 1 (Table 1).6b Interestingly, 2 also showed 10-fold re-
duced hERG affinity relative to 1 which was somewhat surprising
since the increased lipophilicity of 2 might be expected to result
in higher hERG affinity.15 This finding led us to hypothesise a spe-
cific binding interaction between the lactam N–H and the hERG
channel and to investigate the effect of transposing the substitu-
tion point of the linker to different positions of the benzoxazinone
ring in an attempt to selectively disrupt interaction with the hERG
channel whilst maintaining the key target interactions.
Encouragingly, the 8-substituted analogues 3 and 4 were found
to have similar or improved pan 5-HT1A/B/D antagonist potencies
with no intrinsic activity (IA) relative to 1 and 2 with significantly
reduced hERG affinities (40- and 5-fold, respectively). Unexpect-
edly, the SAR for hSerT was reversed in the 8-substituted compared
to the 6-substituted series. Thus, whereas the 6-substituted NH
analogue 1 had 15-fold higher hSerT affinity than the corresponding
We previously concluded that the lactam N–H of 1 was a key
pharmacophoric requirement for hSerT binding since the corre-
sponding N-methyl analogue 2, despite potent 5-HT1A/B/D antago-

S. M. Bromidge et al. / Bioorg. Med. Chem. Lett. 19 (2009) 2338–2342
2341
Table 3
a,b
Functional activity (f-pKi or pEC50
)
for human 5-HT1A/B/D receptors with intrinsic activity (IA) and SerT and hERG binding affinities (pKi)b: SAR studies on 4
R3
n
N
N
N
O
R1
O
R2
N
*
Compdc
n
R1
R2
R3
f-pKi or pEC50
pKib
a,b
5-HT1A (I.A.)
5-HT1B (I.A.)
5-HT1D (I.A.)
hSerT
hERG
4
1
1
1
1
1
2
2
2
2
2
Me
Me
Me
Me
Me
Me
Me
Me
Me
H
H
H
H
H
F
9.8 (0.0)
9.5 (0.0)
9.4 (0.0)
9.7 (0.0)
9.7 (0.0)
8.8 (0.0)
8.7 (0.0)
8.2 (0.0)
8.8 (0.0)
8.5 (0.3)
8.4 (0.0)
8.6 (0.0)
7.8 (0.0)
8.6 (0.0)
8.7 (0.0)
9.5 (0.0)
9.4 (0.0)
8.8 (0.0)
10.1 (0.0)
9.5 (0.0)
8.5 (0.0)
9.2 (0.0)
7.8 (0.0)
8.4 (0.0)
9.4 (0.3)
8.0
5.4
5.0
4.9
5.4
5.5
5.3
5.2
5.2
5.5
6.2
12
13
14
15
16
17
18
19
20
R-Me
S-Me
H
R-Me
H
R-Me
H
R-Me
H
8.3 (1)
7.9 (1)
8.1
F
8.7
*
H
H
F
F
H
7.2 (0.5)
7.6 (0.4)
9.4 (1)
9.3 (1)
9.5
9.1
7.4
*
6.1 (0.0)
6.8 (0.0)
*
7.8 (0.4)
a–c
see Table 1.
NMe analogue 2, the 8-substituted NH analogue 3 showed 30-fold
lower hSerT affinity compared to its corresponding NMe analogue
4. Therefore, 3 and 4 have distinct pharmacological profiles
(5-HT1A/B/D antagonists with an additional hSerT component in
the case of the latter) both of which are of potential therapeutic
utility with low potential hERG/QT risk.
Results in the 7-substituted series were less promising. The 7-
substituted NH-benzoxazinone 5 demonstrated potent 5-HT1A/D
antagonism, partial agonism at 5-HT1B and comparable hERG affin-
ity to 1 but 100-fold reduced hSerT affinity. In contrast, the corre-
sponding NMe analogue 6 demonstrated low hERG and hSerT
affinities and although some 5-HT1B/D activity was maintained 5-
HT1A activity was lost.
On the basis of the very encouraging results obtained for the 8-
substituted analogue 4 we undertook a limited targeted explora-
tion at several key positions in the molecule. Increasing the size
of the benzoxazinone N-alkyl substituent 7–11 in general main-
tained potent 5-HT1A/B/D antagonist activities and similar or
slightly increased hERG affinities but reduced hSerT activity (Table
2).
Methyl substitution at the alpha position of piperazine ring was
undertaken to probe the effect on hERG and hSerT activities (Table
3). Introduction of R-Me into alpha position of piperazine 12 had
minimal effect on 5-HT1A/B/D antagonist potencies, relative to 4,
but afforded a modest increase in hSerT affinity together with a
modest reduction in hERG affinity thereby further enhancing selec-
tivity. The corresponding S-enantiomer 13 maintained a reason-
able overall profile but had reduced 5-HT1B/D potencies and hSerT
compared to 12 and consequently lower selectivity over hERG.
Introduction of F into the 7-position of the quinoline 14 was well
tolerated and in combination with the R-Me piperazine 15 gave a
potent and balanced target profile with >1000-fold selectivity over
hERG affinity.
Extending the ethyl linker to propyl afforded interesting phar-
macological profiles with a very distinct balance of target activities
(16, 17, 18 and 19). In general, 5-HT1A/D antagonist potencies were
reduced by an order of magnitude (IA = 0) whilst 5-HT1B potencies
were more dramatically reduced and in some cases partial agonism
emerged (16, 17). Conversely, hSert affinities were significantly in-
creased to subnanomolar levels with consistently low hERG affin-
ities. Interestingly, the NH analogue 15 afforded a similar 5-HT1A/
B/D profile to the corresponding NMe analogue 11 with 100-fold re-
duced hSerT but 10-fold increased hERG affinity.
A number of compounds with a range of interesting pharmaco-
logical profiles and acceptable selectivity over hERG were pro-
gressed to in vivo rat pharmacokinetic studies (Table 4). The
‘selective’ 5-HT1A/B/D antagonist 3 demonstrated good oral bio-
availability combined with low blood clearance, a good half-life
and high brain exposure. Compounds with additional hSerT activ-
ity were also identified which were suitable for further in vivo
study (e.g., 4, 13, 14 and 16). However, although these gave good
brain exposure, they were more rapidly cleared in rat than 3 result-
ing in modest half-lives and in addition demonstrated higher
intrinsic clearance in human liver microsomes. The metabolic sta-
bilization of these compounds will be the subject of future
publications.
In conclusion, 8-[2-(4-aryl-1-piperazinyl)alkyl]benzoxazinones
have been identified as potent 5-HT1A/B/D receptor antagonists with
Table 4
Rat pharmacokinetic profile for compounds 1–4, 13, 14 and 16
Compound
Cli rat; huma mL/min/g liver
CLbb (mL/min/kg)
Vss (L/kg)
t
(h)
Fpo (%)
Br:Bl
½
1
2
3
4
13
14
16
1.3; <0.5
0.8; 1.1
0.7; 1.0
1.0; 2.4
1.1; 3.5
0.8; 3.2
1.4; 2.1
5
8
8
29
44
21
55
2.0
2.7
3.4
1.7
1.9
2.1
5.2
5.1
4.4
5.2
1.0
0.8
1.4
1.5
68
59
63
26
31
41
ND
1.6
2.2
0.7
1.5
1.9
1.1
2.9
a
Intrinsic clearance in liver microsomes.
In vivo data determined by 0.5 mg/kg iv and 1 mg/kg po administration in rat.
b

2342
S. M. Bromidge et al. / Bioorg. Med. Chem. Lett. 19 (2009) 2338–2342
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