Design and synthesis of piperazinylpyrimidinones as novel selective 5-HT2C agonists

Article abstract of DOI:10.1016/j.bmcl.2009.07.133

This Letter reports the design and synthesis of several novel series of piperazinyl pyrimidinones as 5-HT_2C agonists. Several of the compounds presented exhibit good in vitro potency and selectivity over the closely related 5-HT_2A an

Full text of DOI:10.1016/j.bmcl.2009.07.133

Bioorganic & Medicinal Chemistry Letters 19 (2009) 5346–5350
Contents lists available at ScienceDirect
Bioorganic & Medicinal Chemistry Letters
journal homepage: www.elsevier.com/locate/bmcl
Design and synthesis of piperazinylpyrimidinones as novel selective
5-HT2C agonists
a,
a
a
b
Mark D. Andrews a, , Martin P. Green , Charlotte M. N. Allerton , David V. Batchelor , Julian Blagg ,
*
*
Alan D. Brown a, David W. Gordon a, Gordon McMurray c, Daniel J. Millns a, Carly L. Nichols a, Lesa Watson a
a Department of Medicinal Chemistry, Pfizer Global Research and Development, Sandwich Laboratories, Sandwich, Kent CT13 9NJ, UK
b Cancer Research UK Centre for Cancer Therapeutics, The Institute for Cancer Research, Haddow Laboratories, 15 Cotswold Road, Sutton, Surrey SM2 5NG, UK
c Department of Discovery Biology, Pfizer Global Research and Development, Sandwich Laboratories, Sandwich, Kent CT13 9NJ, UK
a r t i c l e i n f o
a b s t r a c t
Article history:
This Letter reports the design and synthesis of several novel series of piperazinyl pyrimidinones as 5-HT2C
agonists. Several of the compounds presented exhibit good in vitro potency and selectivity over the clo-
sely related 5-HT2A and 5-HT2B receptors. Compound 11 was active in in vivo models of stress urinary
incontinence.
Received 30 June 2009
Revised 27 July 2009
Accepted 28 July 2009
Available online 6 August 2009
Ó 2009 Elsevier Ltd. All rights reserved.
Keywords:
5-HT2C
Agonist
Pyrimidinone
CNS penetration
Serotonin (5-hydroxytryptamine, 5-HT) is a neurotransmitter
involved in a diverse range of physiological functions, mediated
by at least 14 distinct 5-HT receptors distributed widely in the cen-
tral and peripheral nervous systems. The 5-HT2 receptor subfamily
associated with pulmonary hypertension and valvulopathy.5 Addi-
tionally, the 5-HT2C receptor is expressed primarily in the brain,
and compounds would therefore have to be able to cross the
blood–brain barrier in order to achieve in vivo efficacy.
comprises three subtypes, namely 5-HT2A, 5-HT2B and 5-HT2C
.
A number of series of 5-HT2C agonists have been reported in the
literature, which have a heterocyclic core substituted by a pipera-
zine and a pendant aromatic ring, for example, the agonists 16 and
2.7 Our strategy was to retain the overall architecture of these ago-
nists whilst incorporatingpolarity into the core, as it was anticipated
that this might provide agonists with improved overall profiles.8
These receptors exhibit 46–50% sequence homology and belong
to the large family of seven-transmembrane domain G protein-
coupled receptors.1 The 5-HT2C receptor is reported to have a num-
ber of potential therapeutic uses including treatment of urinary
incontinence, obesity, sexual dysfunction, schizophrenia and
depression2 and while a number of agents are reported to be in
clinical development,3 no selective 5-HT2C agonist is currently ap-
proved for any of the proposed indications. Our goal was to identify
potent and selective 5-HT2C agonists for potential use in the treat-
ment of urinary incontinence (improving both bladder and ure-
thral function) and sexual dysfunction.
A key challenge was to identify agonists of the 5-HT2C receptor
with selectivity over the closely related receptors 5-HT2A and 5-
HT2B, as agonism of these receptors is associated with undesirable
physiological outcomes. Activation of the 5-HT2A receptor is
thought to cause hallucinogenic effects, platelet aggregation and
an increase in peripheral vasoconstriction.4 5-HT2B agonism is
Cl
O
CF3
N
O
N
N
O
N
N
O
O
N
O
N
N
N
N
N
H
1, BVT-2938
2
3
N
H
N
H
Earlier work had identified the pyridazinone template, exempli-
fied by compound 3, which was potent, metabolically stable and
free of the mutagenic liability seen with compound 2.9 This series
did however show efflux in an MDCK-mdr1 cell line, a model
which indicates affinity for P-gp efflux transporters and a potential
for reduced CNS penetration.10
* Corresponding authors. Tel.: +44 1304648831; fax +44 1304651987 (M.D.A.),
tel.: +44 1304649037; fax +33 1304651987 (M.P.G.).
E-mail addresses: mark.d.andrews@pfizer.com (M.D. Andrews), martin.x.-
green@pfizer.com (M.P. Green).
0960-894X/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmcl.2009.07.133

M. D. Andrews et al. / Bioorg. Med. Chem. Lett. 19 (2009) 5346–5350
5347
Table 2
SAR of ether linked series
In this Letter we disclose novel pyrimidinone templates 4–6,
their activity at the 5-HT2C receptor and their potential to provide
improved CNS penetration, as measured by their MDCK-mdr1 ef-
O
O
N
flux ratio.
N
N
Cl
R1
N
N
N
Me
R2
Me
N
O
HN
O
HN
O
O
O
N
N
R
R
10
9
N
N
N
N
Me
R2
Compound
R
5-HT2C
EC50 (nM) Emax (%)
Log D7.4 HLM Cli
L/min/mg)
N
N
O
(
l
N
H
R1
N
H
N
H
4
5
6
9a
9b
9c
9d
9e
9f
9g
9h
9i
2-CF3
2-Cl
2-Me
3-CF3
3-Cl
3-CN
4-CF3
4-Cl
2-Me, 5-F
2-Me, 5-Cl 160
2-Cl, 5-F
3-CN
2-Cl, 5-F
30
73
72
61
60
49
66
63
—
1.4
0.8
0.8
1.3
1.0
0.3
1.1
0.8
1.0
1.5
1.0
0.4
1.4
14
11
<7
228
487
493
319
>10,000
>10,000
46
<7
<7
8
<7
<7
<7
<7
<7
<7
The 5-HT2C agonist activity of target compounds (Tables 1 and
2) was evaluated by measuring the ability to induce a fluorescent
based calcium mobilisation signal in a FLIPR assay employing re-
combinant CHO K1 cells expressing the human 5-HT2C receptor.11
Agonist activity at the 5-HT2A and 5-HT2B receptors was measured
in similar recombinant cell-based systems expressing the human
receptors.11
—
84
84
48
77
46
9j
9k
10a
10b
361
112
103
The pyrimidinones 4 were designed as more polar analogues of
pyrazines such as 1 and, encouragingly, the simple phenyl ana-
logue 4a was found to be a 5-HT2C agonist, albeit relatively weak
(EC50 = 1020 nM) (Table 1). Even more encouraging was the fact
that 4a showed a reduced efflux ratio in the MDCK-mdr1 assay rel-
ative to compound 3 (1.6 vs 3.4), indicating lower P-gp affinity.
Changing the length of the spacer between the pendant phenyl ring
and the pyrimidinone core (7a,b) abolished the 5-HT2C agonist
activity, as did, surprisingly, meta or para substitution of the phe-
nyl ring with a fluorine (4c,d). para-Chloro substitution was toler-
ated, while a meta-chloro group gave a fourfold increase in potency
(4f,g). A significant increase in potency was given by ortho-substi-
tution with either a fluorine (4b) or a chlorine (4e), giving agonists
with sub 100 nM potency. Potency could also be increased sixfold
by (2R)-methyl substitution of the piperazine ring (4h). Disap-
pointingly however, compounds from this series that were tested
for 5-HT2B activity showed significant agonism. Given the risks
associated with this, despite the encouraging potency and MDCK-
mdr1 flux, work on series 4 was discontinued in order to focus
on pyrimidinones 5 and 6 as analogues of compound 2.
Me
O
N
N
O
N
N
Cl
N
N
R
N
H
7a, R = Ph
7b, R = OCH2Ph
8
N
H
The 2-piperazinyl pyrimidinone 5 showed no 5-HT2C agonism at
all, in contrast to the corresponding 4-piperazinyl isomer 6b,
Table 1
SAR of pyrimidinones 4–8
Compound R1
R2
Log D7.4 HLM Cli
L/min/mg)
MDCK-mdr1 efflux ratio
5-HT2C
5-HT2A % agonism @ 10
lM
5-HT2B % agonism @ 10 lM
(
l
EC50 (nM) Emax (%)
3
—
H
—
H
H
H
H
H
H
H
1.4
0.7
0.45
0.8
0.7
1.0
1.2
—
15
26
—
—
—
27
—
—
16
<7
<7
<7
<7
<10
24
18
29
—
3.4
1.6
—
—
—
—
—
—
—
47
1020
77
>10,000
>10,000
56
262
899
163
>10,000
275
96
262
26
21
26
64
>10,000
>10,000
21
45
77
92
—
50
44
39
—
—
58
—
—
—
—
13
57
58
76
27
50
45
—
<10
57
35
—
—
46
—
—
—
—
<5
<5
<5
13
<5
<5
6
—
—
<5
4a
4b
4c
4d
4e
4f
4g
4h
5
6a
6b
6c
6d
6e
6f
6g
7a
7b
8
o-F
m-F
p-F
o-Cl
m-Cl
p-Cl
H
—
83
86
91
84
—
43
59
50
59
46
59
59
—
Me 0.9
—
H
—
H
H
1.3
0.6
1.2
—
3.4
4.0
—
3.7
3.1
3.5
—
—
—
4.3
m-Cl
H
m-Cl
o-Cl
o-Me
Me 1.0
Me 1.6
Me 1.6
Me 1.4
o-CF3 Me 1.8
—
—
—
—
—
—
—
—
1.9
—
30
—
50
—
16
See Ref. 11 for complete details of assay conditions. Values (EC50, Emax) are geometric or arithmetic means of two or more experiments. Differences of <2-fold should not be
considered significant.

5348
M. D. Andrews et al. / Bioorg. Med. Chem. Lett. 19 (2009) 5346–5350
which had significant agonist activity with an EC50 of 96 nM. One
potential reason for this marked difference is the inability of the
piperazine ring in 5 to sit in the same plane as the pyrimidinone
ring due to a steric clash with the N3 methyl group. This is consis-
tent with behaviour we have observed in other related series
(unpublished results) where the piperazine and pendant aromatic
group have a meta relationship on the heterocyclic core. In con-
trast, with the piperazine and pendant aromatic group having an
ortho relationship (4) the piperazine ring clearly does not need to
sit in the same plane as the core as these compounds still have
good 5-HT2C activity.
Encouragingly, 6b had excellent metabolic stability in human li-
ver microsomes (HLM) and was completely devoid of 5-HT2B agon-
ism up to 10 lM. Slightly disappointingly, 6b had an MDCK-mdr1
efflux ratio of 4.0 indicating some affinity for P-gp. While incorpo-
rating a methyl group on the piperazine ring of the simple phenyl
analogue caused no increase in potency (6c vs 6a), in the case of 6b
the corresponding methyl piperazine 6d was approximately four-
fold more potent. However this also increased the activity at 5-
O
5-HT2C EC50 (Emax) 9 nM (41%)
5-HT2A EC50 > 1.5 µM
N
5-HT2B EC50 >10 µM
N
N
CF3
HLM 27 µL/min/mg
N
H
O
hERG Ki > 13 µM
MDCK-mdr1 AB/BA 13/41 x10-6 cms-1
11
Compound 11 was selective over 5-HT2A and 5-HT2B, was mod-
erately stable in human liver microsomes and had no measurable
affinity for the potassium hERG channel. In order to assess mem-
brane permeability, the transit performance across MDCK-mdr1
cells was measured. An efflux ratio of 3.2 suggested some affinity
for P-gp transporters and therefore that some impairment of CNS
penetration might be expected for this compound. In addition, 11
was screened for off-target pharmacology against a panel of recep-
tors, enzymes and ion channels (CEREP, BioprintTM) and was shown
to have a very clean profile, with moderate binding affinities for
only the 5-HT1B (210 nM) and dopamine D3 receptors (480 nM).
11 was also found to have weak binding affinity (1–5 lM) for the
HT2A (76% at 10 lM) and introduced a low level of 5-HT2B agonism.
5-HT4E, b2 and M3 receptors and the Ca2+ (L-Verapamil site) ion
channel.
Moving the chloro group from the meta to the ortho position (6e)
eliminated the 5-HT2B activity and reduced the 5-HT2A activity
whilst retaining potency at 5-HT2C. Metabolic stability was re-
duced however, with HLM turnover increasing to 24 lL/min/mg.
ortho-Substitution with methyl or trifluoromethyl (6f,g) gave com-
In light of these encouraging data, 11 was screened in a suitable
pre-clinical in vivo model of urethral function in the anaesthetised
dog.13 Compound 11 significantly increased urethral pressure in
two animals when infused intravenously, evoking a 20–30% in-
crease in peak urethral pressure (considered clinically meaningful)
over measured free plasma concentrations of 19–53 nM. In one
animal a cerebro spinal fluid (CSF) sample was obtained and the ra-
tio of CSF/free plasma concentrations was found to be 0.34, sug-
gesting that CNS penetration was only slightly impaired.
Pyrimidinones 4 and 7 were synthesised starting from the pri-
mary amines 12 (Scheme 1). Treatment with thiocarbonyldi-
2(1H)-pyridone followed by quenching with aqueous ammonia
generated the corresponding primary thioureas.14 These were then
cyclised to the pyrimidinones 13 by treatment with ethyl acetoac-
etate and base in ethanol at reflux. The 2-mercapto pyrimidinones
pounds with very similar profiles.
Varying the pyrimidinone N3-substituent from methyl to ethyl
was also investigated (8). While this gave an excellent pharmacol-
ogy profile (potent 5-HT2C agonism and excellent selectivity over
5-HT2A/2B) it also resulted in increased HLM turnover and MDCK-
mdr1 efflux.
The identification of potent and selective leads from the 4-pip-
erazinyl series 6 was encouraging, but some of the more potent
compounds from this series were relatively lipophilic and were
predicted to have poor metabolic stability. With these issues in
mind, we set out to identify a more polar expression of this series,
with the aim of identifying compounds with improved metabolic
stability. Replacement of the benzylic methylene with oxygen re-
duces the lipophilicity of the template, and analogues from this
ether series were synthetically accessible in a one-pot sequence
from a readily available intermediate 23 (Scheme 4).12
A small set of analogues was synthesised with a view to probing
the effect of substitution of the phenyl ring (Table 2). ortho-Substi-
tution with lipophilic groups was found to give good levels of po-
tency. For example, 9a (o-CF3) met our objectives in terms of
potency, although metabolic stability was compromised. meta Sub-
stitution was tolerated, but para substitution with various groups
resulted in complete loss of 5-HT2C activity. In an attempt to fine
tune the properties, a number of ortho and meta disubstituted com-
pounds were made. SAR seemed not to be additive and was there-
fore unpredictable, but a number of 2,5-disubstituted analogues,
for example, 9i and 9j, retained good potency and stability. All
compounds from this series were selective over 5-HT2B, with no
O
S
O
O
Me
a,b
+
NH2
R
N
N
R
N
N
12
13
SH
e
c,d
R = Ph
R = OCH2Ph
O
Me
O
Me
O
N
N
R
N
N
TBDPS
R2
N
N
N
N
H
7a,b
15
Boc
f,g,h
H
N
R2
agonism seen at 10 lM.
O
Me
It was subsequently found that substitution of the pyrimidinone
nitrogen with ethyl (10a and 10b) resulted in a threefold increase
in 5-HT2C potency and, in spite of the increase in lipophilicity com-
pared with the N-methyl analogue, there was no apparent reduc-
tion in stability in human liver microsomes (HLM).
R1
O
N
N
N
14
R2
4a-h
N
Boc
N
H
In an attempt to identify more potent compounds from the ser-
ies some methylpiperazinyl analogues were prepared and profiled.
In the case of compound 11, this led to a threefold increase in po-
tency, in comparison with the des-methyl analogue. This increase
in lipophilicity resulted in a reduction in metabolic stability, how-
ever, 11 represented the best balance of potency and metabolic
stability from the series and was more fully profiled.
Scheme 1. Synthesis of pyrimidinones 4 and 7. Reagents and conditions: (a) CH2Cl2,
0 °C to room temperature then NH4OH (79–91%); (b) ethyl acetoacetate, DBU, EtOH,
reflux (63–69%); (c) (COCl)2, cat. DMF, CH2Cl2, room temperature then reflux (80%);
(d) piperazine 14, K2CO3, EtCN, 100 °C (92–97%); (e) (COCl)2, cat. DMF, CH2Cl2, room
temperature then reflux followed by piperazine (58–75%); (f) NH4F, MeOH (98%);
(g) phenol, polymer supported PPh3, t-butyl azodicarboxylate, toluene, CH3CN; (h)
4 M HCl in dioxane (30–56% over two steps).

M. D. Andrews et al. / Bioorg. Med. Chem. Lett. 19 (2009) 5346–5350
5349
MeO2C
O
O
O
O
N
O
N
R'
O
R'
O
a, b
c
NH
N
N
N
a
Cl
Cl
N
Cl
N
N
HS
Cl
HN
Cl
23
24, R'=Me
25, R'=Et
16
9, R'=Me
10, R'=Et
R
R
O
N
17
N
O
N
O
b,c
N
N
HN
Cl
f, g
d, e
Cl
N
CF3
N
N
CF3
5
O
HN
O
26
11
Scheme 2. Synthesis of pyrimidinone 5. Reagents and conditions: (a) N-meth-
ylthiourea, DBU, EtOH, reflux; (b) (COCl)2, cat. DMF, CH2Cl2, room temperature then
reflux; (c) piperazine CH2Cl2 (35% over three steps).
Scheme 4. Synthesis of the ether series 9–11. Reagents and conditions: (a) phenol,
Cs2CO3 (2 equiv), DMF, room temperature; (b) MeI or EtI, then evaporate; (c)
piperazine, ethanol, 45 °C (30–50% over three steps); (d) ortho-trifluoromethylphe-
nol, Cs2CO3 (2 equiv), DMF, room temperature; (e) MeI (45% over two steps); (f)
Boc-(R)-3-methylpiperazine; NEt3, DMSO 120 °C (72%); (g) 4 M HCl in dioxane
(80%).
13 were converted to the corresponding chloro compounds by
treatment with oxalyl chloride and catalytic DMF; in the case of
the pyrimidinones 7 the chloro compounds were not isolated but
treated directly with piperazine to generate the desired products,
which were isolated by column chromatography. For the pyrimid-
inones 4, the intermediate chloro compound was isolated by col-
umn chromatography before being reacted with the appropriate
Boc-protected piperazine 14 to generate the protected intermedi-
ates 15. Deprotection of the silyl protecting group with ammonium
fluoride was followed by a Mitsunobu reaction to introduce the
substituted phenyl group. Finally, Boc deprotection with 4 M HCl
in dioxane generated the desired products 4.
was chlorinated with POCl3 to give the dichloropyrimidines 19.
Displacement of one of the chlorines with the appropriate Boc-pro-
tected piperazine 14 gave the chloropyrimidines 20. Hydrolysis to
the corresponding pyrimidinone was achieved using K+TMSOÀ in
DMSO at 100 °C. Alkylation using methyl tosylate (R@Me) or ethyl
iodide (R@Et) gave a roughly 1:2 mixture of the O- and N-alkyl-
ation products, 21 and 22, respectively. Boc deprotection then gave
the desired pyrimidinones 6 and 8.
Pyrimidinone 5 was synthesised in a three-step sequence
starting from the b-dicarbonyl compound 16 (Scheme 2).15 Cyclisa-
tion with N-methylthiourea generated the 2-mercapto pyrimidi-
none 17 which was converted to the corresponding chloro
compound with oxalyl chloride and catalytic DMF. Treatment with
piperazine then allowed isolation of the pyrimidinone 5 by column
chromatography.
The 4-piperazinyl pyrimidinones 6 and 8 were synthesised in a
six-step sequence starting from the amidines 18 (Scheme 3).16
Cyclisation with diethyl malonate under basic conditions gave
the corresponding pyrimidine dione in moderate yield, which
Compounds from the ether series 9 and 10 could easily be ac-
cessed in parallel, using a one-pot, three-step sequence from the
known precursor 23 (Scheme 4).12 Addition of 23 to the appropri-
ate phenol and 2 equiv of caesium carbonate in DMF at room tem-
perature, was followed by addition of iodomethane or iodoethane
to give 24 or 25, respectively. Removal of the solvent by evapora-
tion was followed by addition of piperazine in ethanol and warm-
ing to 45 °C. Once the reaction was complete, the solvent was
removed and products 9 or 10 were isolated by column chroma-
tography (typical yields 30–50%). Compound 11 was made using
a similar route, except that intermediate 26 was isolated and puri-
fied before being heated with Boc-protected (R)-3-methylpipera-
zine in DMSO. The Boc-protected intermediate was then
deprotected with HCl in dioxane.
Cl
NH
R1
N
a,b
R1
NH2
N
Cl
Acknowledgments
18
19
We thank Eugene Gbekor and the Primary Pharmacology Group
for screening data, Dominique Westbrook for urethral pressure
data and Peter Bungay (PDM) for additional studies.
c
OR3
Cl
d,e (R3=Me)
d,f (R3=Et)
N
N
R1
R1
References and notes
N
N
N
N
NBoc
R2
1. Hoyer, D.; Martin, G. Neuropharmacology 1997, 36, 419.
2. (a) Bishop, M. J.; Nilsson, B. M. Exp. Opin. Ther. Patents 2003, 13, 1691; (b)
Ramage, A. G. Br. J. Pharmacol. 2006, 147, S120.
NBoc
R2
21
20
+
3. (a) Wang, Y.; Serradell, N.; Bolos, J. Drugs Future 2007, 32, 766; (b) Smith, B. M.;
Smith, J. M.; Tsai, J. H.; Schultz, J. A.; Gilson, C. A.; Estrada, S. A.; Chen, R. R.;
Park, D. M.; Prieto, E. B.; Gallardo, C. S.; Sengupta, D.; Dosa, P. I.; Covel, J. A.; Ren,
A.; Webb, R. R.; Beeley, N. R. A.; Martin, M.; Morgan, M.; Espitia, S.; Saldana, H.
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2008, 325, 577; (d) Ramamoorthy, P. S.; Beyer, C.; Brennan, J.; Dunlop, J.; Gove,
S.; Grauer, S.; Harrison, B. L.; Lin, Q.; Malberg, J.; Marquis, K.; Mazandarani, H.;
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O
O
N
R3
R3
N
N
g
R1
R1
N
N
N
NBoc
NH
R2
R2
22
6a-g (R3=Me)
8 (R3=Et)
Scheme 3. Synthesis of pyrimidinones
CH2(CO2Et)2, NaOEt, EtOH, reflux (27–51%); (b) POCl3, Et4NCl, EtCN, reflux (97–
100%); (c) piperazine 14, Pr2NEt, THF, reflux (79–82%); (d) KOTMS, DMSO, 100 °C
(27–58%); (e) MeOTs, K2CO3, DMF, 80 °C (29–50% of 22 and 11–37% of 21); (f) EtI,
6 and 8. Reagents and conditions: (a)
i
4. (a) Nichols, D. E. Pharmacol. Ther. 2004, 101, 131; (b) Villalon, C. M.; Centurion,
D. Naunyn-Schmiedeberg’s Arch. Pharmacol. 2007, 376, 45.
K2CO3, acetone, reflux; (g) 4 M HCl in dioxan (80–100%).

5350
M. D. Andrews et al. / Bioorg. Med. Chem. Lett. 19 (2009) 5346–5350
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G. A. WO patent 117169, 2008.
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