New 1-aryl-4-(biarylmethylene)piperazines as potential atypical antipsychotics sharing dopamine D2-receptor and serotonin 5-HT1A-receptor affinities

Article abstract of DOI:10.1016/S0960-894X(01)00425-5

This paper describes the syntheses of several 1-aryl-4-(biarylmethylene)piperazines and the results of the determination of their affinity for D₂ and 5-HT_1A receptors. A selection of these compounds was evaluated in vivo, resulting in the identification of a drug candidate which is being clinically evaluated as a potential atypical antipsychotic with reduced extrapyrimidal side effects.

Full text of DOI:10.1016/S0960-894X(01)00425-5

Bioorganic & Medicinal Chemistry Letters 11 (2001) 2345–2349
New 1-Aryl-4-(biarylmethylene)piperazines as Potential Atypical
Antipsychotics Sharing Dopamine D2-Receptor and Serotonin
5-HT1A-Receptor Affinities
Rolf W. Feenstra,* Janpeter de Moes, Jos J. Hofma, Henk Kling, Wilma Kuipers,
Stephen K. Long, Martin Th. M. Tulp, Jan A. M. van der Heyden and Chris G. Kruse
Solvay Pharmaceuticals, Research Laboratories, PO Box 900, 1380 DA Weesp, The Netherlands
Received 10 May 2001; revised 15 June 2001; accepted 19 June 2001
Abstract—This paper describes the syntheses of several 1-aryl-4-(biarylmethylene)piperazines and the results of the determination
of their affinity for D2 and 5-HT1A receptors. A selection of these compounds was evaluated in vivo, resulting in the identification of
a drug candidate which is being clinically evaluated as a potential atypical antipsychotic with reduced extrapyrimidal side effects.
# 2001 Elsevier Science Ltd. All rights reserved.
Schizophrenia is a disease of which the etiology is
unknown. The disease is characterized by the so-called
positive and negative symptoms. Positive symptoms
include hallucinations and paranoia. The most char-
acteristic negative symptoms are social withdrawal and
flattening of the personality. On top of that both cogni-
tive as well as depressive symptoms may occur. After
the serendipitous discovery of chlorpromazine 1 decades
ago, several compounds, most commonly referred to as
‘neuroleptics’, have been developed which showed anti-
psychotic activity in the clinic. Of those, haloperidol 2 is
the best known example. These compounds pre-
dominantly alleviate the positive symptoms by attenu-
ating the dopaminergic neurotransmission system in the
mesolimbic area of the brain. Therapy with these types
of compounds is frequently accompanied by extra-
pyramidal side effects (EPS) resulting from a blockade
of dopaminergic activity within the motor areas of the
brain. Thus, about 20% of the treated patients suffer
from EPS, of which Parkinson like symptoms are most
common. Other side effects of these ‘typical’ neurolep-
tics include tardive dyskinesia and hyperprolactinemea.
There is a strong need for compounds which induce less
side effects and, equally important, also treat the other
than positive symptoms of schizophrenia. An example
of a successful attempt to reduce EPS and obtain
broader efficacy in treating schizophrenia is clozapine 3,
a dopamine antagonist with modest potency. Clozapine
shows affinity for several receptors, especially for ser-
otonin receptor subtypes, which may account for the
beneficial effect against negative symptoms.1,2 For this
reason, clozapine is termed an ‘atypical’ neuroleptic.
Combining dopaminergic and serotonergic actitivity
may be the way to develop atypical antipsychotics,3 a
rather recent example being risperidone 4, which is
known for binding to the dopamine D2 and serotonin
*Corresponding author. Fax: +31-294-477138; e-mail: rolf.feenstra@solvay.com
0960-894X/01/$ - see front matter # 2001 Elsevier Science Ltd. All rights reserved.
PII: S0960-894X(01)00425-5

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R. W. Feenstra et al. / Bioorg. Med. Chem. Lett. 11 (2001) 2345–2349
5-HT2A receptors. This report focuses on compounds of
type 5 which share affinity for dopamine D2 as well as
serotonin 5-HT1A receptors.
neuroleptic induced dystonia in nonhuman primates,4
and reduces the forelimb retraction time in the paw test.5
In a previous study, we described phenylpyrroles like
6,6,7 which can be considered to be conformationally
restricted derivatives of the known D2 antagonist ben-
zamides like 76 and 8;16 6 retains a high affinity for the
The rationale behind the combination D2 and 5-HT1A is
based on several preclinical data, supporting the
hypothesis that selective 5-HT1A receptor agonists are
capable of antagonizing neuroleptic-induced EPS in
animal models; for example, 8-hydroxy-2-(di-n-propyl-
amino) tetralin [8-(OH)-DPAT] is capable of antagoniz-
ing haloperidol induced catalepsy in rats, attenuates the
D2 receptor (Ki 0.42 nM). Later on, 6 turned out to be a
very potent ligand on the serotonin 5-HT1A receptor as
well (Ki 1.5 nM). To elaborate on this structural class,
we investigated the importance of the pyrrole NH
Scheme 1. Reagents and conditions.8,9 (a) Et(i-Pr)2N, KI, CH3CN, reflux; (b) LiAlH4, THF, reflux; (c) acid+DCC/HOBT, THF, 0 ꢀC, piperazine;
(d) NaBH3OAc, dimethylethyleneglycol, 80 ꢀC; (e) 3-Me-phenylboronic acid, Na2CO3/H2O, (PPh3)4Pd, toluene, 85 ꢀC.

R. W. Feenstra et al. / Bioorg. Med. Chem. Lett. 11 (2001) 2345–2349
2347
moiety of 6 by testing its biphenyl analogue compound
9. Surprisingly, 9 displayed Ki’s of 1.7 and 0.91 nM for
the D2 receptor and 5-HT1A receptor, respectively. In
conclusion, the pyrrole NH moiety is apparently not
essential for binding on the two receptors. Combining 8
and 9 resulted in the design of molecule 5b which not
only showed high affinities for the D2 and 5-HT1A
receptors (2.2 nM and 9.3 nM, respectively), but
favourable pharmacokinetic properties as well. To fur-
ther explore this molecule 5b, an additional 20 com-
pounds were synthesized and evaluated for their
pharmacological properties.
approximately 45 to 95%. Compound 5g was prepared
from 5f in 58% yield by reacting the latter with LiAlH4
in refluxing THF. 5t was prepared by reacting in THF
the biaryl carboxylic acid and DCC/HOBT at 0 ꢀC in
THF and subsequent addition of the aryl piperazine,
yielding the corresponding piperazinamide which could
be reduced with NaBH3OAc in dimethylethyleneglycol
to obtain 5t in 41%. 5u was prepared by reacting the
phenyl piperazine and O-mesyl-3-bromobenzylalcohol
yielding the corresponding N-(3-bromobenzyl) piper-
azine, the latter being cross coupled (Suzuki) to 3-
methyl-phenylboronic acid to afford the desired 5u.
Most of compounds 5 were converted into their mono-
or di-HCl salts by treatment with HCl/EtOH. The
details of the syntheses are described in the correspond-
ing patents.8,9 In Table 1 the compounds 5 are depicted.
Chemistry
The synthesis of compounds 5 is depicted in Scheme 1.
Most of the compounds 5 were prepared by reacting an
arylpiperazine and a biarylmethyl chloride, bromide or
mesylate in the presence of Et(i-Pr)2N and KI in aceto-
nitrile at reflux temperature. Yields of 5 ranged from
Results and Discussion
The affinities of compounds (5) for dopamine D2 and
the serotonin 5-HT1A receptors were measured using
Table 1.
Compound
Compound
Compound
5a
5b
5h
5i
5o
5p
5c
5j
5q
5d
5e
5k
5l
5r
5s
5f
5m
5n
5t
5g
5u

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R. W. Feenstra et al. / Bioorg. Med. Chem. Lett. 11 (2001) 2345–2349
Table 3. In vivo test results (ED50, mg/kg)
Table 2. Affinities for D2 and 5-HT1A receptors (Ki, nM)
Compounds
x HCl
D2 (nM)10
5-HT1A (nM)11
Compounds
Climbing
behaviour
(mg/kg) po
CAR (mg/kg)
ip po
0.3
LLR
(mg/kg) po
2
3
4
6
7
8
9
0
0
0
0
1
0
2
2
1
1
1
2
0
1
1
1
2
1
1
1
0
1
0
0
0
2
1
1
1.4
69
2800
270
25315
1.5
1.0
7.9
0.91
38
9.3
130
15
85
49
26
14
42
21
23
32
32
17
3.115
0.42
5.0
4.6
1.7
8.1
2.2
10
2
3
4
5b
5n
5r
5s
5t
0.2
22
32
1
0.8
0.1
0.1
0.2
0.1
0.1
7
10
>30
3
>30
>30
>20
5a
5b
5c
5d
5e
5f
5g
5h
5i
5j
5k
5l
5m
5n
5o
5p
5q
5r
5s
5t
5u
0.4
<10
20
10
4.0
1.0
0.93
8.1
18
ED50 values are based on at least three dose levels.
HT1A receptor affinity decreased. Compounds having
thienyl- instead of phenyl groups for Ar2 (5m, 5n)
showed high affinities on the D2 receptor, and some-
what lower affinities on the 5-HT1A receptor compared
to 5b.
10
6.0
2.0
2.2
1.3
12
3.0
2.9
1.8
0.47
0.41
9.3
41
200
21
7.8
16
7.6
35
In compounds 5o and 5t, effects of simple substituents
on Ar1 were studied. Introduction of a F-atom at the 6-
position (5o) lowered both affinities; a hydroxy sub-
stituent at the 4-position (5t) showed higher affinities,
especially at the D2 receptor. Compounds having a
pyridyl instead of phenyl group for Ar1 (5p–5s), showed
interesting features; all four showed comparable or
higher affinities for the D2 receptor and, in addition,
5r also displayed a comparable affinity towards the
5-HT1A receptor.
Ki values are based on three assays, each using 4–6 concentrations in
triplicate.
[3H]-spiperone10 and [3H]-8-OH-DPAT, respectively.11
In Table 2, affinities of 5 for both receptors are given
expressed as Ki (calculated from at least three indepen-
dent experiments). In the first series (i.e., 5a, 5c–5g) the
heterocyclic ring A was varied. In comparison to 5b no
improvement on D2- and 5-HT1A-receptor affinity was
established in the case of only oxygen containing het-
erocyclic rings (5a, 5d). N-Methylation (5c) turned out
to be detrimental for the 5-HT1A affinity, indicating that
the N–H function appears to be essential. Enlargement
of the heterocyclic ring of 5b by only one CH2 (5f),
resulted in an increased affinity for the D2 receptor, but
in a decreased affinity for the 5HT1A receptor. Similar
effects are encountered for 5g in which the carbonyl
function of the amide moiety in 5f is reduced to CH2.
Compound 5e, which is structurally related to 5g, shows
a smaller potency for the 5-HT1A receptor, whilst the D2
affinity is acceptable. In conclusion, the benzox-
azolinone moiety as presented in 5b is superior for
achieving high potency on both receptors.
The most interesting compounds were assayed in mod-
els relevant for antipsychotic activity: inhibition of the
apomorphine-induced climbing behavior in mice12 and
the suppression of the conditioned avoidance response
in rats.13 To assay the 5-HT1A agonistic component in
vivo, the compounds were tested for occurrence of
so-called lower lip retraction (LLR).14 The results are
given in Table 3. Compound 5n is potently active in
antagonizing apomorphine-induced climbing behavior
in mice, but no activity could be measured in the rat
(CAR and LLR). Compounds 5b and 5r show promis-
ing results in all models with ED50 values in the D2
antagonist related models below 1 mg/kg and in the
LLR model between 1 and 10 mg/kg after oral admin-
istration. Compounds 5s and 5t showed no 5-HT1A
related activity (po) in the rat models. On the basis of
broad preclinical profiling, 5b was selected for further
clinical development. More pharmacological details are
expected to be published soon.
In the second series (i.e., 5h–5u), the biphenylmethylene
part of 5b was varied by introducing substituents and
other aromatic rings. In compounds 5h–5l and 5u, effects
of simple substituents on Ar2 were studied. A F-atom at
the 40-position slightly decreased both affinities 5h; sub-
stitution at the 30-position by groups differing in elec-
tronegativity like Cl, MeO, CN and Me (5i, 5j, 5k and
5u, respectively) again gave no improvement in receptor
affinities with regard to 5b. Substitution at the 20-posi-
tion with the CN group 5l resulted in a somewhat higher
potency on the D2 receptor, but unfortunately the 5-
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