Structure-activity relationships of a series of novel (piperazinylbutyl)thiazolidinone antipsychotic agents related to 3-[4-[4-(6- fluorobenzo[b]thien-3-yl)-1-piperazinyl]butyl]-2,5,5-trimethyl-4- thiazolidinone maleate

Article abstract of DOI:10.1021/jm960268u

HP-236 (3-[4-[4-(6-Fluorobenzo[b]thien-3-yl)-1-piperazinyl]butyl]- 2,5,5-trimethyl-4-thiazolidinone maleate; P-9236) (54) displayed a pharmacological profile indicative of potential atypical antipsychotic activity. A series of piperazinyl butyl thiazolidi

Full text of DOI:10.1021/jm960268u

4044
J . Med. Chem. 1996, 39, 4044-4057
Str u ctu r e-Activity Rela tion sh ip s of a Ser ies of Novel
(P ip er a zin ylbu tyl)th ia zolid in on e An tip sych otic Agen ts Rela ted to
3-[4-[4-(6-F lu or oben zo[b]th ien -3-yl)-1-p ip er a zin yl]bu tyl]-2,5,5-tr im eth yl-4-
th ia zolid in on e Ma lea te
Nicholas J . Hrib,*,† J ohn G. J urcak,† Deborah E. Bregna,‡ Kendra L. Burgher,‡ Harold B. Hartman,§
Sharon Kafka,‡ Lisa L. Kerman,§ Sam Kongsamut,§ J oachim E. Roehr,§ Mark R. Szewczak,‡
Ann T. Woods-Kettelberger,‡ and Roy Corbett‡
Neuroscience Therapeutic Area, Hoechst Marion Roussel, Inc., Bridgewater, New J ersey 08876
Received April 5, 1996X
HP-236 (3-[4-[4-(6-Fluorobenzo[b]thien-3-yl)-1-piperazinyl]butyl]-2,5,5-trimethyl-4-thiazolidi-
none maleate; P-9236) (54) displayed a pharmacological profile indicative of potential atypical
antipsychotic activity. A series of piperazinyl butyl thiazolidinones structurally related to this
compound were prepared and evaluated in vitro for dopamine D2 and serotonin 5HT2 and 5HT1A
receptor affinity. The compounds were examined in vivo in animal models of potential
antipsychotic activity and screened in models predictive of extrapyramidal side effect (EPS)
liability. The synthesis of these compounds, details of their structure-activity relationships,
and discovery of a new lead, compound 50, as well as further development of the profiles of
compounds 50 and 54 are described.
In tr od u ction
It has been observed that clozapine and other antip-
sychotic drugs which show a reduced propensity for the
development of EPS have demonstrated a higher affin-
ity for the 5HT2 receptor than the D2 receptor in rat
membrane preparations.9 This has resulted in the
hypothesis that a combination of serotonin 5HT2 and
dopamine D2 receptor antagonism in a proper ratio is
one way to achieve atypical antipsychotic activity. The
ratio of activities at these receptors has been advanced
as one explanation for the atypical profile of clozapine.10
Clozapine shows affinity for a number of other recep-
tors as well. For example, its affinity for the serotonin
5HT1A receptor is higher than that for the D2 receptor.
The 5HT1A receptor has been implicated in the activity
of atypical antipsychotic agents.11 The 5HT1A agonists
8-OH-DPAT, buspirone, and ipsapirone have been found
to reverse haloperidol-induced catalepsy,12 and in fact
a combination of 5HT1A agonism and D2 antagonism was
the basis for the design of a series of potential atypical
antipsychotic agents.13
A number of new antipsychotic agents which have
been reported to show a profile predictive of atypical
antipsychotic activity in animal models act via the
mehanism of combined dopamine D2 and serotonin 5HT2
antagonism. These compounds include risperidone,14
sertindole,15 and iloperidone (HP 873).16 Recently, we
reported the synthesis and pharmacological profile of a
new potential atypical antipsychotic agent, (3-[4-[4-(6-
fluorobenzo[b]thien-3-yl)-1-piperazinyl]butyl]-2,5,5-tri-
methyl-4-thiazolidinone maleate (P-9236; HP-236) (com-
pound 54). This compound demonstrated a profile of
potential atypical antipsychotic activity in a number of
animal models.17 The electrophysiological profile of 54
was also strongly indicative of atypicality.17,18
A series of compounds structurally related to 54,
designed for both D2 and 5HT2 receptor antagonism,
was prepared by varying both the arylpiperazine
moiety and the substituents on the thiazolidinone ring
(Table 1). We expected that the arylpiperazine moiety
would impart the dopamine D2 antagonist activity
Schizophrenia is a complex and devastating disease,
with a worldwide lifetime prevalence of almost 1% of
the general population.1 The disease exhibits a variety
of symptoms, and in fact it is still not known whether
the many symptoms of schizophrenia are the product
of a single or a multiple disease entity.2 Traditionally,
the symptoms have been loosely grouped into positive
and negative syndromes.3 The positive symptoms of
schizophrenia include psychotic symptoms such as hal-
lucinations and delusions. The negative symptoms, for
example apathy, lack of motivation, and social with-
drawal, can persist after positive symptoms have been
allieviated and hinder the patient’s complete return to
society. Recently, models of the disease have appeared
which distinguish dissociative thought processes and
cognitive impairment as a distinct third cluster of
symptoms whose therapeutic response parallels that of
the positive symptoms.4
Compounds which inhibit postsynaptic dopaminergic
neurotransmission have been effective in the treatment
of schizophrenia.5,6 However, most of these agents are
typical, i.e., they show some propensity for the develop-
ment of extrapyramidal side effects (EPS), either acutely
(dystonia, pseudo-Parkinsonism) or on chronic admin-
istration (Tardive Dyskinesia).7 In addition, few of
these agents have shown efficacy against the negative
symptom cluster. Clozapine, an atypical antipsychotic,
is almost totally devoid of EPS liability and was reported
to be effective in the treatment of both positive and
negative symptoms. However, a small percentage of
clozapine patients are at risk for the development of
agranulocytosis, a potentially fatal blood disorder. In
the United States, treatment with clozapine is restricted
to a small, closely-monitored population of treatment-
refractory patients.8
* Author to whom correspondence should be addressed.
† Medicinal Chemistry.
‡ In Vivo Biology.
§ In Vitro Biology.
X Abstract published in Advance ACS Abstracts, August 15, 1996.
S0022-2623(96)00268-3 CCC: $12.00 © 1996 American Chemical Society

Novel (Piperazinylbutyl)thiazolidinone Antipsychotic Agents
J ournal of Medicinal Chemistry, 1996, Vol. 39, No. 20 4045
Ta ble 1

4046 J ournal of Medicinal Chemistry, 1996, Vol. 39, No. 20
Ta ble 1 (Continued)
Hrib et al.
as haloperidol decrease social interaction behavior in
this model, while atypical agents such as clozapine
increase this behavior.
We present here the synthesis, in vitro, and in vivo
evaluation of these compounds, and also the identifica-
tion and profiling of a new lead in this series, compound
50, as well as further evaluation of compound 54.
F igu r e 1. (Piperazinylbutyl)thiazolidinones.
required of an antipsychotic agent and confer serotonin
5HT2 antagonist activity as well. This property of
arylpiperazines and -piperidines had been shown in a
number of antipsychotic series investigated in these and
other laboratories.16,32 Variations on the thiazolidinone
ring, which were expected to impart subtle changes in
activity, in fact sometimes produced dramatic differ-
ences in otherwise similar molecules. Many of these
compounds demonstrate a potent ability to inhibit
apomorphine-induced climbing in mice (CMA), an ani-
mal model predictive of potential antipsychotic activity.
Also, some compounds have shown more potent activity
in this limbically-mediated behavioral assay (CMA) vs
a striatally-mediated assay, namely the inhibition of
apomorphine-induced stereotypies in the rat (APO-S).
Such a ratio of activities in these two in vivo assays may
be indicative of a reduced propensity for a compound to
cause extrapyramidal side effects.9,10
Ch em istr y
The synthesis of the target compounds 1-60 can be
divided into three parts: (A) the synthesis of a substi-
tuted 4-thiazolidinone, (B) the preparation of an arylpip-
erazine, and (C) the coupling of these components.
A. P r ep a r a tion of 3-(4-Ha lobu tyl)-4-th ia zolid i-
n on es. The condensation of thioglycolamide with either
formaldehyde or 2,2-dimethoxypropane provided the
4-thiazolidinones 61a and 61b,20 respectively. The
intermediate 2-methyl-4-thiazolidinone 61c, previously
prepared by another method,21 was synthesized by
treating methyl thioglycolate with acetaldehyde-am-
monia trimer. The 4-thiazolidinones 61a -c were alky-
lated with 1,4-dibromobutane to give the 2-substituted
3-(4-bromobutyl)-4-thiazolidinones 62a -c. The 5-mono-
substituted intermediates were prepared by reacting
compounds 62a or 62b with 1 equiv of lithium bis-
(trimethylsilyl)amide followed by an alkylating agent
to provide compounds 62d , 62e, and 62m . The 5,5-
disubstituted and spiro-substituted intermediates were
synthesized by adding 2 equiv of lithium bis(trimeth-
In addition, some compounds were tested in an
animal model predictive for the potential efficacy of an
antipsychotic agent against the negative symptom of
social withdrawal.19 Typical antipsychotic agents such

Novel (Piperazinylbutyl)thiazolidinone Antipsychotic Agents
J ournal of Medicinal Chemistry, 1996, Vol. 39, No. 20 4047
Sch em e 1a
a
Reagents: (a) formalin (61a ) or 2,2-dimethoxypropane (61b); (b) acetaldehyde-ammonia trimer (61c); (c) NaH, Br(CH2)4Br; (d)
LiN(TMS)2, alkylating agents; (e) DAST (see Experimental Section for details).
ylsilyl)amide to a solution of compounds 62a -c and an
alkylating agent to yield compounds 62f-l. Treatment
of 62m with (dimethylamido)sulfur trifluoride (DAST)
provided compound 62n (Scheme 1).
gously to the literature procedure22 to provide 3-hy-
droxy-6-chloro-1,2-benzisothiazole, 65a . Conversion of
this compound to the 3,6-dichloro-1,2-benzisothiazole
65b followed by displacement of the 3-chloride with
piperazine provided the desired intermediate het-
eroarylpiperazine 66 (Scheme 2).
Two routes to the 1-aryl-2-carbalkoxy-3-hydroxyindole
intermediates which are required for the preparation
of the 3-piperazinyl-1-phenylindole systems are shown
in Schemes 3 and 4. The first method proceeds via
treatment of benzoic acids 67 with formaldehyde to form
the benzoxazines 68, which are opened by treatment
with potassium cyanide to provide cyano acids 69.
These intermediates are converted to diacids 70a ,b.23
For the preparation of 1-(6-fluoro-1-phenyl-1H-indol-3-
yl)piperazine, we utilized an alternative route which
avoided the use of potassium cyanide. The Ullmann
reaction of N-phenylglycine and 2-chloro-4-fluorobenzoic
acid provided the intermediate diacid 70c in one step.24
B. P r ep a r a tion of Bicyclic Heter oa r ylp ip er a -
zin es. Literature methods were adopted for the prepa-
ration of the 3-piperazinyl derivatives of the 1,2-
benzisothiazole22 and N-phenylindole23-25 systems, with
the following exceptions. For the preparation of 1-(6-
chloro-1,2-benzisothiazol-3-yl)piperazine, the requisite
3-hydroxy-6-chloro-1,2-benzisothiazole was prepared as
follows. Ullman coupling of benzyl mercaptan and 2,4-
dichlorobenzoic acid generated the 2-(benzylthio)-4-
chlorobenzoic acid, 63a . This compound was converted
to the corresponding acid chloride 63b which was then
treated with chlorine gas, oxidatively cleaving the
S-benzyl group to provide an intermediate sulfuryl
chloride 64. This solution was then added dropwise to
ammonium hydroxide, stirred, and then acidified analo-

4048 J ournal of Medicinal Chemistry, 1996, Vol. 39, No. 20
Hrib et al.
Sch em e 2a
a
Reagents: (a) benzyl mercaptan, K2CO3, CuCl; (b) SOCl2; (c) Cl2(g), CCl4; (d) (1) NH4OH, (2) 6 N HCl; (e) POCl3, PCl5; (f) piperazine.
Sch em e 3a
a
Reagents: (a) formalin, ethanol; (b) KCN, H2O; (c) aqueous NaOH; (d) N-phenylglycine; (e) NaOH, MeI (see ref 23 for experimental
details).
These compounds were converted to diesters 71. Dieck-
mann cyclization of diesters 71 as described in the
literature provided the 2-hydroxy-3-carbomethoxyin-
doles 72.23 These compounds were converted to the
3-piperiazinyl-1-phenylindoles 73 following literature
procedures as illustrated in Scheme 4.25
lustrated for the preparation of the 6-fluoro derivative
74a .26 In a variation of the literature procedure, de-
carbomethoxylation was carried out using N-methylpip-
erazine to provide 75a . Displacement of the amino
group with piperazine provided the desired intermediate
benzo[b]thienylpiperazine 76a (Scheme 5).
The 1-benzo[b]thien-3-ylpiperazine systems were pre-
pared using literature methods to prepare the interme-
diate 3-aminobenzo[b]thiophene-2-carboxylates as il-
The piperazine derivatives of quinoline, isoquinoline,
and benzothiazole were prepared by displacement of the
corresponding chlorides, which were commercially avail-

Novel (Piperazinylbutyl)thiazolidinone Antipsychotic Agents
J ournal of Medicinal Chemistry, 1996, Vol. 39, No. 20 4049
Sch em e 4a
a
Reagents: (a) NaOMe, MeOH; (b) MgCl2-6H2O, then piperazine (see ref 25 for details).
Sch em e 5a
This behavior is mediated by the limbic dopaminergic
pathway, which has been associated with the therapeu-
tic effects of antipsychotic agents. Compounds which
showed potency in this assay using intraperitoneal (ip)
administration were then evaluated orally (po) in the
CMA assay to assess oral bioavailability. Additionally,
compounds which demonstrated activity in CMA were
examined for their ability to inhibit apomorphine-
induced stereotypy in rats (APO-S).29 This is a behav-
ioral assay mediated by activation of the nigrostriatal
dopamine system, a pathway which has been linked to
potential EPS liability.30,31 Therefore, an agent which
demonstrates potential atypical antipsychotic activity
should be active in the climbing-mouse assay and weak
or inactive in inhibiting agonist-induced rat stereotypy
(Table 4). Indeed, while haloperidol is potently active
in both these assays, clozapine and risperidone display
only weak activity in the stereotypy model even at high
doses relative to their effective dose in the CMA assay.
a
Reagents: (a) methyl thioglycolate, LiOH-H2O; (b) N-meth-
ylpiperazine; (c) piperazine, N-methylpiperidone.
Sch em e 6a
Str u ctu r e-Activity Con sid er a tion s
In the CMA assay, compounds with a simple mono-
cyclic arylpiperazine moiety were in general less potent
than compounds which possessed a bicyclic [5,6]-fused
heteroaryl-3-piperazine system. (This has been ob-
served in other series of antipsychotic agents from these
laboratories.)32 Quinolyl, isoquinolyl, and 2-benzothia-
zolyl substituents also provided less potent targets.
Therefore, much of our overall effort was devoted to
discovering which bicyclic [5,6]-fused system would
produce the optimal pharmacological profile. It was
discovered that the most potent dopamine D2 affinity
was found in compounds possessing the 1,2-benzisothia-
zol-3-ylpiperazine substituent (compound 35, 15.7 nM)
and the (6-fluorobenzo[b]thien-3-yl)piperazine substitu-
ent (compound 53, 14 nM). The former substituent was
also found in the compound with the highest 5HT2
affinity (28, 1.34 nM). Like clozapine, many members
of the series possessed higher affinity for the serotonin
5HT2 and/or 5HT1A receptors than for the D2 receptor,
possibly predictive of potential atypical antipsychotic
activity.9 Of the compounds demonstrating good activ-
ity in the CMA assay, ratios of D2/5HT2 affinity were
highest with compounds 28 (ratio 41), 27 (ratio 16), 54
(ratio 19), and 50 (ratio 7.3). We were aware that the
serotonin 5HT2 receptor binding studies using rat
membrane do not distinguish between the recently
characterized 5HT2 subtypes. Thus, we also evaluated
a
Reagents: (a) K2CO3, CH3CN.
able or were prepared via literature methods. The
monocyclic arylpiperazines were commercially available.
C. Cou p lin g. The arylpiperazines were alkylated
(Scheme 6) with the substituted 3-(4-bromobutyl)-4-
thiazolidinones 62a -n to give the target compounds
1-60 (Table 1).
Resu lts a n d Discu ssion
Compounds in this series were evaluated in vitro for
affinity at the dopamine D2 receptor (Table 2). Concur-
rently, targets were screened for potential antipsychotic
activity in a behavioral model, the inhibition of apo-
morphine-induced climbing in mice (CMA)27,28 (Table 3).

4050 J ournal of Medicinal Chemistry, 1996, Vol. 39, No. 20
Hrib et al.
Ta ble 2. In Vitro Receptor Affinity (IC50, µmol, and 95% Confidence Limits)
a
b
c
compd no.
D2
IC50, µmol
5HT2
IC50, µmol
5HT1A
IC50, µmol
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
0.514
0.786
0.548
0.304
0.15
7.49
2.43
1.96
1.13
1.64
1.61
1.77
12.6
3.75
2.64
1.84
0.778
0.916
0.652
2.21
2.23
0.835
8.76
(0.295-0.895)
(0.583-1.059)
(0.309-0.972)
(0.233-0.397)
(0.09-0.252)
(5.69-9.86)
(1.46-4.05)
(1.52-2.53)
(0.86-1.49)
(1.28-2.11)
(0.84-3.09)
(1.03-3.06)
(6.8-23.2)
0.010
0.022
0.011
0.018
0.002
0.139
0.009
0.034
(0.008-0.013)
(0.016-0.030)
(0.008-0.014)
(0.011-0.028)
(0.001-0.003)
(0.106-0.183)
(0.005-0.017)
(0.025-0.044)
0.588
0.492
0.503
(0.354-0.979)
(0.272-0.887)
(0.31-0.817)
0.090
0.569
(0.043-0.188)
(0.456-0.711)
0.007
0.061
0.013
0.140
0.026
0.012
0.038
0.083
0.006
0.023
0.057
0.010
(0.005-0.008)
(0.048-0.078)
(0.010-0.017)
(0.073-0.269)
(0.015-0.045)
(0.009-0.016)
(0.028-0.051)
(0.053-0.131)
(0.005-0.007)
(0.017-0.032)
(0.035-0.092)
(0.008-0.012)
(1.92-7.32)
(1.44-4.85)
(1.0-3.38)
0.439
0.414
(0.247-0.781)
(0.244-0.701)
(0.449-1.349)
(0.69-1.217)
(0.376-1.131)
(1.24-3.93)
(1.33-3.75)
(0.613-1.136)
(4.08-18.82)
(5.5-30)
(0.133-0.38)
(0.113-0.332)
(0.068-0.110)
(0.043-0.071)
1.28
(0.56-2.94)
12.9
0.140
0.011
0.007
0.011
0.008
0.007
0.324
0.017
0.003
0.012
0.052
0.002
(0.106-0.183)
(0.006-0.019)
(0.004-0.013)
(0.008-0.014)
(0.004-0.014)
(0.006-0.010)
(0.137-0.764)
(0.011-0.029)
(0.001-0.005)
(0.010-0.016)
(0.029-0.094)
(0.001-0.003)
0.224
0.193
0.086
0.055
0.007
0.012
0.005
0.001
0.002
0.271
0.0035
(0.003-0.014)
(0.006-0.022)
(0.004-0.007)
(0.0007-0.002)
(0.001-0.004)
(0.066-1.12)
0.286
0.201
0.136
0.029
0.697
0.016
(0.068-1.21)
(0.124-0.326)
(0.103-0.181)
(0.022-0.038)
(0.432-1.125)
(0.009-0.026)
(0.0018-0.0066)
0.0189
1.11
0.003
(0.0151-0.0236)
(0.36-3.42)
(0.001-0.008)
>20
0.154
0.029
0.671
0.191
0.131
0.20
(0.09-0.239)
(0.021-0.039)
0.341-1.322)
0.142-0.258)
(0.112-0.153)
(0.168-0.239)
(0.0001-24.9)
(0.431-2.76)
(0.204-0.622)
(0.279-0.781)
(0.067-0.174)
(0.158-0.377)
(0.154-2.42)
(0.285-3.191)
(0.131-0.36)
(0.206-0.993)
(0.007-0.3)
0.0096
0.018
1.06
(0.0053-0.018)
(0.009-0.036)
(0.22-5.18)
(0.154-0.561)
(0.023-0.119)
(0.045-0.766)
(0.03-0.53)
(0.010-1.28)
(0.0494-0.1949)
(0.020-0.098)
(0.116-0.173)
(0.009-0.028)
(0.392-0.858)
(0.101-0.168)
(0.093-0.411)
(0.041-0.267)
(0.008-0.013)
(0.026-0.12)
(0.62-3.79)
(0.394-1.044)
(0.248-0.803)
(0.046-0.158)
(4.13-17.15)
(1.28-4.14)
0.003
0.002
0.969
1.73
2.33
2.55
3.05
8.08
11.7
(0.002-0.004)
(0.001-0.003)
(0.529-1.78)
(1.27-2.35)
(1.29-4.20)
(1.97-3.31)
(0.22-7.63)
(0.068-9.58)
(9.20-15.0)
0.294
0.053
0.186
0.126
0.119
0.0981
0.045
0.142
0.016
0.58
0.131
0.196
0.105
0.01
0.056
1.54
0.059
1.09
0.356
0.467
0.108
0.244
0.611
0.954
0.218
0.453
0.014
1.21
9.03
(7.06-11.6)
0.002
0.776
0.189
0.102
0.091
(0.001-0.002)
(0.322-1.86)
(0.145-0.245)
(0.067-0.156)
(0.041-0.203)
(0.38-3.82)
(2.18-10.27)
0.061
0.855
0.332
0.153
0.629
0.367
1.37
1.01
7.079
0.95
(0.031-0.119)
(0.362-2.019)
(0.176-0.624)
(0.121-0.193)
(0.479-0.826)
(0.225-0.601)
(1.05-1.80)
(0.74-1.39)
(4.94-10.13)
(0.75-1.22)
4.73
0.641
0.446
0.085
8.42
8.43
(6.46-11)
2.31
clozapine
haloperidol
risperidone
1.61
0.033
0.037
(1.24-2.07)
(0.024-0.045)
(0.024-0.047)
0.072
0.129
0.0026
(0.055-0.094)
(0.07-0.239)
(0.0019-0.0042)
a
Dopamine D2 binding determined in rat striatum using [3H]spiperone as ligand. IC50 values determined from seven-point concentration
curves done in duplicate. Serotonin 5HT2 binding determined in rat cortex using [3H]spiperone as ligand. IC50 values determined from
seven-point concentration curves done in duplicate. c Serotonin 5HT1A binding determined in rat hippocampus using [3H]-8-OH-DPAT as
ligand. IC50 values determined from seven-point concentration curves done in duplicate.
b
the affinity of lead compounds 50 and 54 for the cloned
human 5HT2A receptor (Table 7).
substituents; however, tetrasubstitution at the 2- and
5-positions decreased the CMA potency.
The two most potent compounds in the CMA assay,
33 (ED50 ) 0.127 mg/kg ip) and 52 (ED50 ) 0.2 mg/kg
ip), shared as a common structural feature a 5-(1-
hydroxy-1-methylethyl) substituent on the 4-thiazoli-
dinone moiety. With regard to CMA potency, the
thiazolidinone system was tolerant to up to three
In the benzisothiazolyl series, chlorine substitution
at the 6-position decreased D2 and, in particular, 5HT2
receptor affinity and also reduced potency in the CMA
assay (cf. compound 30 vs 29 and 39 vs 38). Oxidation
of the sulfur of the benzisothiazole moiety also reduced
D2 affinity and CMA potency (cf. compound 36 vs 35).

Novel (Piperazinylbutyl)thiazolidinone Antipsychotic Agents
J ournal of Medicinal Chemistry, 1996, Vol. 39, No. 20 4051
Ta ble 3. Potential for Antipsychotic Activity: Inhibition of Apomorphine-Induced Climbing in Mice
compd no.
ED50, mg/kg ipa
ED50, mg/kg po
compd no.
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
ED50, mg/kg ip
ED50, mg/kg po
1
2
3
4
5
6
7
8
9
>20b
0.127 (0.116-0.14)
4.5 (4.0-5.0)
0.6 (0.52-0.69)
0.99 (0.8-1.24)
-44% at 10
4.4 (3.9-4.9)
12 (10.7-13.2)
10.7 (9.0-12.5)
>20
>20
10.3 (9.0-12.0)
>20
>20
19.3 (18.4-20.3)
>20
16.7 (15.7-17.7)
14.3 (13.2-15.6)
>20
>20
17.1 (14.9-20.3)
5.1 (4.4-6.6)
0.99 (0.88-1.1)
30.3 (28.6-32.1)
6.8 (2.2-11.4)
-38% at 14.5
2.3 (1.4-3.8)
2.22 (2.09-2.36)
4. (4.1-5.6)
2.946 (2.566-3.313)
1.349 (1.203-1.506)
1.55 (1.33-1.80)
4.617 (4.094-5.145)
1.03 (0.95-1.12)
10.21 (9.213-11.391)
4.191 (3.692-4.698)
8.8 (7.9-10.0)
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
2.7 (2.4-3.1)
13.8 (12.9-14.8)
>20
>20
>20
>20
1.44 (1.24-1.63)
>20
-17% at 7
15.4 (13.8-17.3)
>20
15.5 (12.8-19.0)
>10
>20
>20
>20
>20
>20
3.5 (3.066-3.956)
5.04 (4.415-5.669)
0.2 (0.182-0.218)
0.92 (0.07-11.7)
2.8 (2.5-3.1)
6.1 (1.1-34.3)
-27% at 25
1.3 (1.1-1.4)
2.6 (1.2-5.6)
15.43 (14.4-16.6)
>20
>20
>20
>20
>20
>20
2.94 (2.75-3.15)
1.43 (1.23-1.63)
23.2 (20.8-25.4)
30.5 (27.9-33.6)
60
clozapine
haloperidol
risperidone
9.10 ( 1.77 (6)c
23.2 (21.1-25.9)
0.28 (0.27-0.29)
0.28 (0.25-0.3)
12.69 (11.32-14.46)
0.194 ( 0.056 (2)c
>20
0.062 (0.047-0.077)
2.91 (2.59-3.29)
14.9 (12.5-17.8)
a
b
ED50 and 95% confidence limits. ED50 was not determined but is greater than screening dose reported. c ED50 ( SEM (n).
Ta ble 4. Potential for Atypical Antipsychotic Activity in Vivo
In the benzo[b]thien-3-yl series, again, the presence
of a 6-chloro substituent produced compounds with
reduced D2 affinity and CMA potency (cf. compounds
55 vs 54 and 49 vs 50). With regard to the desired in
vivo profile, the best ratios of CMA/APO-S activity (and
thus potential for atypicality) were found in this series,
in compounds 50, 52, 53, and 54. Compound 54 (HP
236) demonstrated one of the higher ratios of D2/5HT2
affinity (21.7) and an almost equally greater preference
for the 5HT1A receptor over the D2 receptor (17.5).
Compound 50 showed a ratio of 7.28. However, com-
pound 52 showed only a modest preference for either
5HT2 (4.31) or 5HT1A (4.9) over D2, and compound 53
had an almost equal affinty for D2 and 5HT2. Because
of the structural resemblance of compound 50 to com-
pound 54, and their similar pharmacological profiles,
as well as the good D2/5HT2 ratio observed, we examined
the electrophysiological profile of compound 50 in the
chronic single-unit assay.33 On chronic administration,
atypical antipsychotic agents have been shown to reduce
the number of active dopamine neurons only in the A
10 (ventral tegmental) dopaminergic pathway, associ-
ated with mood and behavior and thus with the thera-
peutic effects of antipsychotics. Typical agents such as
haloperidol depress dopamine activity in both the A 10
and the A 9 (nigrostriatal) pathway, the latter being
associated with motor control and therefore EPS li-
ability. Like clozapine and compound 54, compound 50
also displayed an atypical profile in this assay, as shown
in Table 5.
inhibition of
apomorphine-induced
climbing (mouse)
(ED50, mg/kg ip)a
inhibition of apomorphine-
induced stereotypy (rat)
(ED50, mg/kg, or %
compd no.
27
28
29
32
33
34
35
37
38
39
40
41
42
43
45
activity at dose, ip)
2.94 (2.75-3.15)
1.43 (1.23-1.63)
(30.5 (27.9-33.6)) (po)
2.91 (2.59-3.29)
0.127 (0.116-0.14)
4.5 (4.0-5.0)
0.6 (0.52-0.69)
(30.3 (28.6-32.1))(po)
0.99 (0.88-1.1)
2.946 (2.566-3.313)
1.349 (1.203-1.506)
1.55 (1.33-1.80)
4.617 (4.094-5.145)
1.03 (0.95-1.12)
4.191 (3.692-4.698)
8.8 (7.9-10.0)
0% at 20, 17% at 40b
8.9 (7.0-11.3)
0% at 20, 40% at 40
3.3 (2.2-5.0)
2.3 (1.6-3.1)
0% at 40,50% at 80
90% at 10
10% at 20, 100% at 30
100% at 10
0% at 20, 80% at 40
19.6 (19.6-22.5)
7.1 (5.6-9.0)
0% at 40, 67% at 80
16.4 (10.0-26.7)
41.7 (32.1-54.3)
27.4 (17.2-43.8)
20% at 50, 50% at 60
33% at 40, 50% at 80
10% at 2.5, 40% at 5
0% at 10
46
50
51
52
53
54
3.5 (3.066-3.956)
5.04 (4.415-5.669)
0.2 (0.182-0.218)
0.92 (0.07-11.7)
2.8 (2.5-3.1)
61.4 (54.2-69.6)
33% at 40
0.6 (0.40-0.80)
3.2 (2.1-4.8)
clozapine
9.10 ( 1.77 (6)c
haloperidol 0.194 ( 0.056 (2)c
risperidone 0.062 (0.047-0.077)
a
b
ED50 and 95% confidence limits. ED50 was not determined
but is greater than screening dose reported. c ED50 ( SEM (n).
The series of compounds bearing an N-phenylindole
piperazine moiety did not demonstrate high affinity for
the 5HT1A receptor. In this series, the presence of a
fluorine at the 6-position of the indole ring reduced both
D2 affinity and CMA potency (cf. compound 44 vs 42).
However, no correlation was observed between the
presence of a 4-fluorine on the pendant phenyl ring and
CMA potency.
For optimal effectiveness, an antipsychotic agent
should have efficacy for both the positive and negative
symptomatology of schizophrenia. One setback in the
development of these agents has been the lack of reliable
preclinical assays to predict a compound’s effectiveness
for treating negative symptoms. To address this issue,

4052 J ournal of Medicinal Chemistry, 1996, Vol. 39, No. 20
Ta ble 5. Chronic Single Unit Sampling of Compounds 54 and 50a
Hrib et al.
compd no.
dose, mg/kg ip
n
no. of A 10 neurons
% change
no. of A 9 neurons
% change
vehicle
haloperidol
vehicle
clozapine
vehicle
54
vehicle
54
vehicle
50
10
10
11
6
10
12
10
10
10
10
10
10
10.4 ( 0.8
6.8 ( 0.7
9.0 ( 0.8
6.2 ( 0.9
10.0 ( 0.4
13.7 ( 0.6
12.3 ( 0.56
14 ( 0.77
11.1 ( 0.57
14.7 ( 1.09
10.8 ( 0.51
9.5 ( 0.83
10.8 ( 0.51
9.9 ( 0.99
0.5
20
-35**
-79**
-34**
-57**
-27**
-39**
-30*
37*
14
8.8 ( 0.4
1.8 ( 0.3
10.4 ( 0.73
6.8 ( 0.67
9.2 ( 0.85
4.0 ( 0.3
10
20
32
10.3 ( 0.62
7.5 ( 0.72
10.3 ( 0.62
6.3 ( 0.68
10
-12
-8
vehicle
50
20
a
*p < 0.05 vs vehicle. **p < 0.01 vs vehicle. Duration was 21 days. Number of units/12 tracks ((SEM).
Ta ble 6. Effects of Antipsychotic Agents and Test Compounds on Social Interaction and on Total Activity in Ratsa
social interaction
total activity
drug
dose, mg/kg ip
X + SEM
% change
X + SEM
% change
vehicle
haloperidol
haloperidol
vehicle
clozapine
clozapine
vehicle
50
vehicle
50
50
vehicle
54
54
95.8 ( 2.0
77.2 ( 7.7*
65.6 ( 6.1*
108.3 ( 6.8
123.3 ( 7.9
151.3 ( 9.0*
96.0 ( 3.4
144.8 ( 3.9
129.2 ( 9.0
112.3 ( 4.4*
172.0 ( 3.9
140.3 ( 7.5*
146.3 ( 7.5*
145.4 ( 4.5
146.4 ( 3.6
130.4 ( 4.6
106.3 ( 3.7
82.1 ( 4.7*
142.0 ( 5.4
144.3 ( 5.4
96.0 ( 4.8*
0.05
0.125
-19
-32
-11
-22
5.0
10.0
+14
+40
-18
-15
1.25
108.0 ( 6.4
93.4 ( 4.4
+13
+1
2.5
5.0
106.5 ( 4.3
97.3 ( 6.1
100.0 ( 3.4
114.0 ( 3.7
109.1 ( 4.6
+14
+5
-18
-36
1.25
2.5
+14
+9
+1
-32
a
*p < 0.05 compared with vehicle control.
we developed a preclinical assay for the negative
symptoms of social withdrawal in schizophrenic pa-
tients, namely, the social interaction test in rodents.19
The atypical antipsychotic agent clozapine increased
social interaction behavior, while the typical antipsy-
chotic agent haloperidol decreased this behavior in
rodents. The present results show that both compounds
50 and 54 had a pharmacological profile similar to
clozapine in this animal model for negative symptoms
(Table 6). Compound 50 at 1.25 and 2.5 mg/kg in-
creased social interaction behavior by 13% and 14%,
respectively, while compound 54 at 1.25 mg/kg increased
social interaction behavior by 14%. These compounds
increased social behavior at doses similar to those that
produced efficacy in other preclinical antipsychotic
screening assays such as the CMA assay. The mecha-
nism of action responsible for these effects of compounds
50 and 54 remains uncertain; however, the present
studies show that these compounds have high affinity
for the 5HT1A receptor. Previous studies have demon-
strated that clozapine also has affinity for this receptor
subtype.19 In addition, the selective 5HT1A agonist
8-OH-DPAT also increased social interaction behavior
in rats. Finally, the clinical observation that the 5HT1A
agonist buspirone was effective in reducing stress-
induced psychosocial deficits in chronic schizophrenic
patients34,35 supports these preclinical findings that
antipsychotic agents with affinity for the 5HT1A receptor
subtype would be beneficial in treating the negative
symptom of social withdrawal. Therefore the in vitro
binding profile and in vivo activity of compounds 50 and
54 suggest a pharmacological profile with efficacy for
both the positive and negative symptoms of schizophre-
nia. While we have not carried out experiments to
determine the functional activity of compounds 50 and
54 at this receptor, the previously mentioned observa-
tions lead us to expect that these compounds would also
be agonists at the 5HT1A receptor.
Recently it has been shown that clozapine shows a
high affinity for the human dopamine D4 receptor
subtype.36 The atypical profile of clozapine has been
attributed to its affinity for this receptor, since plasma
levels of clozapine at therapeutic doses have been
associated with the level of D4 affinity, not D2 affin-
ity.37,38 Very recently olanzapine, an antipsychotic
currently under clinical investigation which has shown
an atypical profile preclinically, has also demonstrated
an affinity for the dopamine D4 receptor subtype.39
These observations led us to investigate the dopamine
D4 affinity of selected compounds in this series vs
standard antipsychotic agents clozapine and haloperidol
and the clinical compound olanzapine (Table 7). We
discovered that compounds 50 and 54 also show high
affinity for the human D4 receptor subtype. Thus the
atypical profile of compounds 50 and 54 in behavioral
and electrophysiological models might also be attributed
to a higher affinity for dopamine D4 receptors than for
dopamine D2 receptors.
Con clu sion s
A series of (piperazinylbutyl)thiazolidinones was pre-
pared and submitted for biological evaluation. Many
members of this series displayed a higher affinity for
the serotonin 5HT2 receptor than for dopamine D2
receptor. This biochemical profile is consistent with
potential atypical antipsychotic activity.
In vivo, many compounds in this series showed
potential antipsychotic activity in an animal model,
namely the inhibition of apomorphine-induced mouse
climbing. In addition, some compounds also displayed
a potential for atypicality in animal models in vivo.

Novel (Piperazinylbutyl)thiazolidinone Antipsychotic Agents
J ournal of Medicinal Chemistry, 1996, Vol. 39, No. 20 4053
Ta ble 7. Affinity for Cloned Human Dopamine D 4.2 Receptora,b and Cloned Human 5HT2A Receptorc
rat 5HT2
human D4.2
human D4.2
human 5HT2A
human 5HT2A
compd no.
clozapine
rat D2 (IC50, µM)
1.61 (1.24-2.07)
(IC50, µM)
(IC50, µM)
(Ki, µM)
(IC50, µM)
(Ki, µM)
0.072 (0.055-0.094) 0.058 (0.024-0.144)
0.006 (0.004-0.01)
0.158 (0.115-0.219) 0.047 (0.036-0.062) 0.173 (0.116-0.260)
0.01
0.012 (0.008-0.018)
0.288 (0.205-0.404)
0.009 (0.004-0.019)
0.017 (0.012-0.026)
0.008 (0.006-0.012)
0.005
0.108
0.004
0.008
0.004
haloperidol 0.033 (0.024-0.045) 0.129 (0.07-0.239)
olanzapine
54
50
0.001
0.029
0.005
0.117
1.212 (0.384-3.826) 0.056 (0.026-0.12)
0.954 (0.285-3.191) 0.131 (0.101-0.168) 0.713 (0.341-1.492)
0.029 (0.023-0.043)
a
b
IC50 and 95% confidence limits. Human D2 receptor in CHO cells. c Serotonin 5HT2A receptor in BEK cells.
crystalline solid: mp 147-150 °C; 1H NMR (DMSO-d6) δ 11.3
(br s, 1 H), 8.20-8.05 (m, 2 H), 7.65-7.40 (m, 2 H), 4.78 (br s,
1 H), 4.40-4.25 (m, 2 H), 4.17-3.93 (m, 2 H), 3.73 (s, 1 H),
3.70-3.07 (m, 12 H), 1.83-1.43 (m, 4 H), 1.32 (s, 3 H), 1.19 (s,
3 H); mass spectrum (EI, 70 eV) M+ 434. Anal. (C21H29N4O2S2‚-
HCl) C, H, N.
These compounds were more active in behavioral assays
mediated by the limbic dopaminergic system (inhibition
of apomorphine-induced mouse climbing) than in assays
mediated by the nigrostriatal dopaminergic system
(inhibition of apomorphine-induced stereotypy in rats).
The lead compounds in this series, 50 and 54, also
showed an atypical profile in electrophysiological assays
and increased social interaction in rats, an indication
of potential efficacy against the negative symptoms of
schizophrenia. Leading compounds from this series
were selected for toxicological evaluation and additional
preclinical studies.
3-[4-[4-(6-Ch lor o-1,2-ben zisoth iazol-3-yl)-1-piper azin yl]-
bu tyl]-1-th ia -3-a za sp ir o[4.5]d eca n -4-on e Hyd r och lor id e
(39). A mixture of 3-(4-bromobutyl)-1-thia-3-azaspiro[4.5]-
decan-4-one (62k ) (2.7 g, 7.9 mmol), 1-(6-chloro-1,2-ben-
zisothiazol-3-yl)piperazine (66) (2.0 g, 7.9 mmol), K2CO3 (2.2
g, 15.8 mmol), and NaI (200 mg) in 100 mL of dry CH3CN was
heated to 80 °C with stirring under N2. After 8 h the mixture
was cooled to room temperature, the CH3CN was removed in
vacuo, and the residue was partitioned between Et2O/H2O. The
organic phase was dried over MgSO4, filtered, and concen-
trated in vacuo. The residue was chromatographed on silica
using EtOAc as eluent to provide 2.64 g of a clear oil. This
product was taken up in Et2O/CH2Cl2 and the HCl salt
precipitated out by the addition of HCl in Et2O. The salt was
recrystallized from Et2O/CH2Cl2 to provide 1.56 g (3.02 mmol,
38.2%) of product as a white solid: mp 202-205 °C; homoge-
neous by TLC (silica, 0.1:9.9:90 NH4OH:CH3OH:EtOAc, Rf )
0.55); 1H NMR (CDCl3) δ 12.8 (br s, 1 H), 7.82 (d, J ) 1.7 Hz,
1 H), 7.72 (d, J ) 8.8 Hz, 1 H), 7.36 (dd, J ) 1.8 and 8.7 Hz,
1 H), 4.27 (s, 2 H), 4.17-3.93 (m, 4 H), 3.61-3.34 (m, 4 H),
3.24-3.00 (m, 4 H), 2.17-1.12 (m, 14 H); mass spectrum (EI,
70 eV) M+ ) 478. Anal. (C23H31N4OS2Cl‚HCl) C, H, N.
3-[4-[4-(6-Flu or o-1-ph en yl-1H-in dol-3-yl)-1-piper azin yl]-
bu tyl]-2,5,5-tr im eth yl-4-th ia zolid in on e Dih yd r och lor id e
(44). A mixture of 3-(4-bromobutyl)-2,5,5-trimethyl-4-thiazo-
lidinone (62f) (1.66 g, 5.92 mmol), 1-(6-fluoro-1-phenyl-1H-
indol-3-yl)piperazine (1.75 g, 5.92 mmol), K2CO3 (2.50 g, 18.1
mol), NaI (150 mg), and acetonitrile (100 mL) was heated at
60 °C under nitrogen. After 22.5 h, the dark mixture was
filtered, the inorganics were washed with dichloromethane (50
mL), and the filtrate was concentrated under reduced pressure.
The residue was taken up in dichloromethane (100 mL),
washed with 5% NaOH (60 mL) and H2O (60 mL), and dried
(Na2SO4). Concentration in vacuo gave a dark viscous liquid.
Chromatography on silica gel (7.5% methanol in dichlo-
romethane eluent) afforded a viscous liquid (Rf ) 0.37, 10%
methanol in dichloromethane). The dihydrochloride salt of this
amine was prepared and recrystallized from ethanol to yield
Exp er im en ta l Section
All structures are supported by their IR (Perkin-Elmer 547)
and 1H NMR (Varian XL-200) spectra. Melting points were
determined on a Thomas-Hoover capillary apparatus and are
uncorrected. Mass spectra were determined on a Finnigan
4000 GC-MS equipped with an INCOS data system. Elemen-
tal analyses were performed by Oneida Research Services, Inc.,
Whitesboro, NY, or Robertson Microlit Laboratories, Inc.,
Madison, NJ . Analyses were performed routinely only on
target compounds and selected intermediates.
3-[4-[4-(2-Meth oxyp h en yl)-1-p ip er a zin yl]bu tyl]-1-th ia -
3-a za sp ir o[4.4]n on a n -4-on e Dih yd r och lor id e (5). A mix-
ture of 3-(4-bromobutyl)-1-thia-3-azaspiro[4.4]nonan-4-one (62i)-
(4.60 g, 15.7 mmol), 1-(2-methoxyphenyl)piperazine (3.33 g,
17.3 mmol), K2CO3 (5.42 g, 39.3 mmol), NaI (310 mg), and CH3-
CN (200 mL) was heated at 65 °C (bath temperature) under
nitrogen. After 6 h, TLC analysis (silica gel, 40% ethyl acetate/
hexanes) showed the starting bromide, Rf ) 0.46, to be
consumed. The mixture was cooled to room temperature, ethyl
acetate (150 mL) was added, and the inorganics were filtered.
The filtrate was concentrated in vacuo to a residue which was
taken up into methylene chloride (200 mL), washed with H2O
(100 mL) and brine (100 mL), and dried (Na2SO4). Concentra-
tion in vacuo gave an amber liquid which was purified by
chromatography on silica gel, eluting with 5% methanol in
methylene chloride, yielding 5.78 g of a liquid. The liquid was
dissolved in hot ether/ethanol and the solution made acidic
with ethereal HCl, yielding, after slow cooling, 3.43 g of fine
white crystals: mp 144 °C (begin decomposition); 1H NMR
(CDCl3) δ 13.6 (br s, 1 H), 8.24 (d, J ) 7.6 Hz, 1 H), 7.47 (t, J
) 8.0 Hz, 1 H), 7.10-7.01 (m, 2 H), 5.18-5.06 (m, 2 H), 4.56-
4.28 (m with a s at 4.33, 4 H), 4.08 (s, 3 H), 3.67-3.52 (m, 4
H), 3.45 (t, J ) 6.7 Hz, 2 H), 3.33-3.14 (m, 2 H), 2.37-2.15
(m, 2 H), 2.07-1.59 (m, 10 H); mass spectrum (EI, 70 eV) M+
403. Anal. (C22H33N3O2S‚2HCl) C, H, N.
3-[4-[4-(1,2-Ben zisoth ia zol-3-yl)-1-p ip er a zin yl]bu tyl]-5-
(1-h yd r oxy-1-m eth yleth yl)-4-th ia zolid in on e Hyd r och lo-
r ide (33). A mixture of 3-(4-bromobutyl)-5-(2-hydroxyisopropyl)-
4-thiazolidinone (62m ) (4.00 g, 13.5 mmol), 3-piperazinyl-1,2-
benzisothiazole hydrochloride (3.80 g, 14.9 mmol), K2CO3 (8.00
g, 57.9 mmol), NaI (450 mg), and acetonitrile (200 mL) was
heated at 80 °C under nitrogen. After 17 h the mixture was
filtered, the insolubles were washed with dichloromethane, and
the filtrate was concentrated in vacuo. The residue was taken
up in dichloromethane (200 mL), washed with 5% NaOH (100
mL) and H2O (100 mL), and dried. Evaporation of the solvent
at reduced pressure gave a viscous brown liquid. The crude
product was chromatographed on silica gel. Elution with 8%
methanol in dichloromethane gave 5.06 g of an amber liquid.
The HCl salt of the amine was prepared. Recrystallization
from ethanol/ethyl acetate afforded 2.26 g (35.6%) of a fine
1
1.46 g (43.5%) of a beige powder: mp 207-210 °C; H NMR
(DMSO-d6) δ 11.4 (br s, 1 H), 7.75 (dd, J ) 5.5 and 8.8 Hz, 1
H), 7.70-7.50 (m, 4 H), 7.49-7.23 (m with a dd at 7.31), 7.00
(ddd, J ) 2.2, 9.1, and 9.1 Hz, 1 H), 6.52 (br s), 4.82 (q, J )
6.0 Hz), 3.77-3.07 (m, 12 H), 1.90-1.33 (m with a d at 1.49
and two s at 1.47 and 1.44, 13 H); mass spectrum (EI, 70 eV)
M+ 494. Anal. (C22H30FN4OS‚2HCl) C, H, N.
3-(4-(4-(6-Flu or oben zo[b]th ioph en e-3-yl)-1-piper azin yl)-
bu tyl)-2-m eth yl-3-a za sp ir o[4.4]n on a n -4-on e Ma lea te (50).
A mixture of 3-(4-bromobutyl)-2-methyl-3-azaspiro[4.4]nonan-
4-one (62j) (5.00 g, 16.3 mmol), 1-(6-fluorobenzo[b]thien-3-yl)-
piperazine (4.55 g, 19.3 mmol), K2CO3 (8.00 g, 57.9 mmol), NaI
(0.400 g), and acetonitrile was heated at 80 °C under nitrogen
for 2.5 h and then at room temperature for an additional 64
h. The mixture was filtered, the insolubles were washed with
dichloromethane, and the filtrate was concentrated under
reduced pressure. The residue was taken up in dichlo-
romethane (250 mL), washed successively with 5% NaOH (125
mL), H2O (125 mL), and then brine (125 mL), dried (Na2SO4),
and concentrated under reduced pressure to a viscous brown
liquid. The liquid was chromatographed on silica gel, eluting
with 5% methanol in dichloromethane, to afford 5.90 g (78.4%)

4054 J ournal of Medicinal Chemistry, 1996, Vol. 39, No. 20
Hrib et al.
of a beige solid, mp 85-89 °C. The maleic acid salt of this
amine was prepared and recrystallized from 2-propanol to yield
4.38 g of an off-white solid: mp 174-176 °C; 1H NMR (CDCl3,
200 MHz) δ 7.57 (dd, J ) 5.0 and 8.9 Hz, 1 H), 7.49 (dd, J )
2.3 and 8.8 Hz, 1 H), 6.73 (s, 1 H), 6.29 (s, 2 H), 4.65 (q, J )
6.1 Hz, 1 H), 3.80-3.00 (m, 12 H), 2.43-2.16 (m, 2 H), 2.03-
1.58 (m, 10 H), 1.54 (d, J ) 6.1 Hz, 3 H); mass spectrum (70
eV, EI) M+ 401. Anal. (C24H32FN3OS2‚C4H4O4) C, H, N.
3-[4-[4-(6-F lu or oben zo[b]th ien -3-yl)-1-p ip er a zin yl]bu -
tyl]-2,5,5-tr im eth yl-4-th ia zolid in on e Ma lea te (54). A mix-
ture of 3-(4-bromobutyl)-2,5,5-trimethyl-4-thiazolidinone (62f)
(4.00 g, 14.3 mmol), 1-(6-fluorobenzo[b]thien-3-yl)piperazine
(3.71 g, 15.7 mmol), K2CO3 (6.00 g, 43.4 mmol), NaI (400 mg),
and acetonitrile was heated at 50 °C under nitrogen. After
16 h, the mixture was filtered, the insolubles were washed with
dichloromethane (100 mL), and the filtrate was concentrated
in vacuo. The residue was taken up in dichloromethane (200
mL), washed with 5% NaOH (100 mL), H2O (100 mL), and
dried over Na2SO4. The dichloromethane was removed in
vacuo and the resulting viscous liquid chromatographed on
silica gel, eluting with 5% methanol in dichloromethane, to
give 3.40 g of a viscous amber liquid (Rf ) 0.58, 10% methanol
in dichloromethane). The maleic acid salt of the amine was
prepared and recrystallized from ethanol to afford 2.09 g
(26.5%) of a white solid: mp 170-171 °C; 1H NMR (CDCl3,
200 MHz) δ 7.60 (dd, 1 H, J ) 5.0, 8.8 Hz), 7.50 (dd, 1 H, J )
2.3, 8.7 Hz), 7.15 (ddd, 1 H, J ) 2.3, 8.8, and 8.8 Hz), 6.73 (s,
1 H), 6.30 (s, 2 H), 4.66 (q, 1 H, J ) 6.1 Hz), 3.73-3.16 (m, 12
H), 1.87-1.65 (m, 4 H), 1.57-1.52 (two s superimposed on d,
9 H); mass spectrum (EI, 70 eV) M+ 435. Anal. (C22H30N3-
FOS2‚C4H4O4) C, H, N.
was added over a period of 0.5 h. The resulting cloudy yellow
reaction was allowed to warm to -45 °C, at which temperature
1 N HCl (250 mL) was added. The resulting aqueous mixture
was extracted with ether (4 × 110 mL). The combined extracts
were washed with brine (250 mL), dried (Na2SO4), and
concentrated to a dark brown liquid. The liquid was chro-
matographed on silica gel (elution with 40% ethyl acetate in
hexanes) to give 3.34 g (57.5%) of a faint yellow liquid (Rf )
0.49). The liquid was distilled using a short-path distillation
apparatus at 0.20 mmHg (bath temperature 120-140 °C) to
give 2.35 g (40.4%) of a clear oil: 1H NMR (CDCl3) δ 4.32 (s,
2 H), 3.54-3.36 (m, 4 H), 2.40-2.16 (m, 2 H), 2.00-1.60 (m,
10 H). Mass spectrum (Br79 and Br81, EI, 70 eV) M+ 291 and
293. Anal. (C11H18BrNOS) C, H, N.
3-(4-Br om obu tyl)-5-(1-h yd r oxy-1-m eth yleth yl)-4-th ia -
zolid in on e (62m ). To a solution of 3-(4-bromobutyl)-4-
thiazolidinone (62a ) (10.0 g, 42 mmol) and tetrahydrofuran
(200 mL) cooled to -78 °C under nitrogen was added rapidly
a solution of lithium bis(trimethylsilyl)amide (44 mmol) and
tetrahydrofuran (44 mL) followed immediately by acetone (10
mL, 0.137 mol). The resulting solution was stirred at -78 °C
for 20 min and removed from the cold bath, and 0.5 N HCl
(250 mL) was added. The aqueous mixture was placed under
reduced pressure to remove some of the tetrahydrofuran. The
resulting mixture was extracted with ether (3 × 125 mL). The
combined extracts were washed with brine (200 mL), dried
(Na2SO4), and concentrated to a viscous brown liquid. The
liquid was chromatographed on silica gel, eluting with 50-
100% ethyl acetate in hexanes, to afford 8.96 g (72.0%) of an
amber oil (Rf ) 0.37, silica gel, 50% ethyl acetate/hexanes).
The oil was dried at 0.2 mmHg for 48 h: 1H NMR (CDCl3) δ
4.40-4.27 (m, 2 H), 3.85 (br s, 1 H), 3.60-3.28 (m, 4 H), 2.00-
1.65 (m, 4 H), 1.29 (s, 3 H), 1.27 (s, 3 H); mass spectrum (Br79
and Br81, EI, 70 eV) M+ 296 and 298. Anal. (C10H18BrNO2S)
C, H, N.
3-(4-Br om obu tyl)-5-(1-flu or o-1-m eth yleth yl)-4-th ia zo-
lid in on e (62n ). To a -67 °C solution of (dimethylamido)-
sulfur trifluoride (3.15 g, 23.7 mmol) and dichloromethane (100
mL) under nitrogen was added a solution of 3-(4-bromobutyl)-
5-(1-hydroxy-1-methylethyl)-4-thiazolidinone (62m ) (7.01 g,
23.7 mmol) and dichloromethane (30 mL) dropwise over a
period of 35 min. The resulting solution was allowed to warm
to ambient temperature over a period of 80 min. Cold H2O
(75 mL) was added, and the layers were separated. The
organic layer was washed successively with H2O (75 mL) and
then brine (100 mL), dried (NaSO4), and concentrated to a
yellow-orange liquid. The liquid was purified by chromatog-
raphy on silica gel, eluting with 40-60% ethyl acetate in
hexanes, to give 6.01 g (85.1%) of a yellow oil. A 2.07 g sample
of oil was distilled using a molecular still (120 °C/0.20 mmHg)
to give 1.75 g of a clear liquid (Rf ) 0.46, silica gel, 40% ethyl
acetate/hexanes): 1H NMR (CDCl3, 200 MHz) δ 4.42 (d, J ) 7
Hz, 1 H), 4.23 (d, J ) 7 Hz, 1 H), 3.88 (d, J ) 15 Hz, 1 H),
3.60-3.27 (m, 4 H), 1.98-1.40 (m with two d (each 21 Hz), 10
H); mass spectrum (Br79 and Br81, CI, 70 eV) M+ 298 and 300.
Anal. (C10H17BrFNOS) C, H, N.
2-(Ben zylth io)-4-ch lor oben zoic Acid (63a ). A mixture
of 2,4-dichlorobenzoic acid (91.0 g, 476 mmol), benzyl mercap-
tan (58.6 mL, 500 mmol), K2CO3 (131 g, 829 mmol), and CuCl
(1.0 g) in 700 mL of sieve-dried DMF was heated with stirring
to 120 °C under N2. After 18 h the mixture was allowed to
cool to room temperature and filtered, and the residual solids
were triturated with DMF, decanted, and combined with the
filtrate. This DMF phase was diluted with 800 mL of H2O,
and the pH was adjusted with 6 N HCl to pH 1 with
precipitation of a white solid. The solid was collected, washed
with H2O, and recrystallized from acetone/H2O to provide 84.42
g (303.6 mmol, 63.8%) of a white solid: mp 205-208 °C;
homogeneous by TLC (silica, EtOAc, Rf ) 0.34); 1H NMR
(DMSO-d6) δ 13.2 (br s, 1 H), 7.89 (d, J ) 8.4 Hz, 1 H), 7.53-
7.20 (m, 7 H), 4.27 (s, 2 H); mass spectrum (EI, 70 eV) M+
278. Anal. (C14H11ClO2S) C, H.
3-(4-Br om obu tyl)-2-m eth yl-4-th ia zolid in on e (62c). To
a stirred suspension of 2-methyl-4-thiazolidinone (61c) (20 g,
171 mmol) in 500 mL of anhydrous dimethylformamide under
N2 was added in one portion KOH (19.1 g, 342 mmol). Stirring
was continued for 30 min, providing a yellow solution. At this
time, 1,4-dibromobutane (61 mL, 513 mmol) was added in one
portion. After 1 h, TLC (silica, EtOAc) showed no remaining
starting material. The mixture was quenched in 600 mL
water, and the aqueous phase was extracted exhaustively with
EtOAc. The organic extracts were combined and dried over
MgSO4, filtered, and concentrated in vacuo. Chromatography
of the residue using a 3:1 hexanes/EtOAc eluent provided 16
g (63.6 mmol, 37%) of the product as an oil, homogeneous by
TLC (silica, 2:1 hexanes/EtOAc, Rf ) 0.27): 1H NMR (CDCl3)
δ 4.75 (q, J ) 6 Hz, 1 H), 3.85-3.40 (m, 5 H), 3.20-3.01 (m, 1
H), 1.91-1.57 (m, 4 H), 1.54 (d, J ) 6 Hz, 3 H); mass spectrum
(Br79 and Br81, EI, 70 eV) M+ 251 and 253. Anal. (C18H14
BrNOS) C, H, N.
-
3-(4-Br om obu tyl)-2,5,5-tr im eth yl-4-th iazolidin on e (62f).
To a -73 °C solution of 2-methyl-3-(4-bromobutyl)-4-thiazoli-
dinone (62c) (6.00 g, 23.8 mmol), methyl iodide (11.0 g, 77.4
mmol), and THF (50 mL) under nitrogen was added lithium
bis(trimethylsilyl)amide (50.0 mmol) in THF (50 mL) at a rate
to maintain the internal temperature <-55 °C. The resulting
amber solution was stirred at <-55 °C for 10 min and then
allowed to warm to -40 °C, at which temperature 1 N HCl
(250 mL) was added. The aqueous mixture was extracted with
25% benzene/ether (3 × 125 mL). The combined extracts were
washed with brine (200 mL), dried (Na2SO4), and concentrated
to a brown liquid which was chromatographed on silica gel,
eluting with a 35-65% gradient of ethyl acetate in hexanes,
yielding 5.07 g (76%) of a liquid, Rf ) 0.37 (30% ethyl acetate
in hexanes). The liquid was distilled to give 3.80 g of a clear
liquid: bp 109-114 °C at 0.20 mmHg; 1H NMR (CDCl3) δ 4.68
(q, J ) 6 Hz, 1 H), 3.77-3.60 (m, 1 H), 3.45 (t, J ) 6 Hz, 2 H),
3.28-3.03 (m, 1 H), 1.93-1.60 (m, 4 H), 1.55-1.51 (two singlets
superimposed on a doublet, 9 H); mass spectrum (Br79 and
Br81, 70 eV, EI) M+ 279 and 281. Anal. (C10H18BrNOS) C, H,
N.
3-(4-Br om ob u t yl)-1-t h ia -3-a za sp ir o[4.4]n on a n -4-on e
(62i). To a -76 °C solution of 3-(4-bromobutyl)-4-thiazolidi-
none (62a ) (4.75 g, 19.9 mmol) and THF (120 mL) under
nitrogen was added lithium bis(trimethylsilyl)amide (20.3
mmol) in THF (20.3 mL) rapidly, immediately followed by 1,4-
diiodobutane (15.5 g, 50.0 mmol). After 12 min, a solution of
lithium bis(trimethylsilyl)amide (62.0 mmol) in THF (62 mL)
2-(Ben zylth io)-4-ch lor oben zoic Acid Ch lor id e (63b). A
mixture of 2-(benzylthio)-4-chlorobenzoic acid (3a ) (42.08 g, 150
mmol) and thionyl chloride (13.24 mL, 180 mmol) in 200 mL
of toluene and 2 mL of DMF was heated to reflux with stirring.
After 3 h, no starting material remained by TLC, and the

Novel (Piperazinylbutyl)thiazolidinone Antipsychotic Agents
J ournal of Medicinal Chemistry, 1996, Vol. 39, No. 20 4055
mixture was allowed to cool to room temperature. Addition
of 700 mL of hexane caused the precipitation of a yellow solid
which was collected and air-dried. This provided the desired
acid chloride which was used without further purification: 1H
NMR (DMSO-d6) δ 8.00-7.77 (m, 1 H), 7.57-7.19 (m, 7 H),
4.26 (s, 2 H).
dichloromethane) Rf ) 0.31. Recrystallization of the solid from
ether/hexanes gave 8.65 g of a fluffy white solid: mp 157-
158 °C; 1H NMR (CDCl3) δ 7.57 (dd, J ) 5.0 and 8.9 Hz, 1 H),
7.39 (dd, J ) 2.3 and 8.7 Hz, 1 H), 7.09 (ddd, J ) 2.3, 8.8, and
8.8 Hz, 1 H), 5.89 (br s, 2 H), 3.87 (s, 3 H); mass spectrum (EI,
70 eV) M+ 225. Anal. (C10H8FNO2S) C, H, N.
3-Hyd r oxy-6-ch lor o-1,2-ben zisoth ia zole (65a ). 2-(Ben-
zylthio)-4-chlorobenzoic acid chloride (20 g, 67.6 mmol) was
stirred in 250 mL of CCl4. Chlorine gas was bubbled into the
stirred mixture until all acid chloride was gone by TLC
(approximately 1 h). This solution was added dropwise to a
stirred solution of ammonium hydroxide (250 mL), which
caused the precipitation of a gummy solid. Stirring was
continued for a further 1 h, and then the mixture was carefully
acidified to pH 3 with 6 N HCl. The solid precipitate was
collected and dried to provide 12.3 g (66.7 mmol) of product,
which was used without further purification: 1H NMR (DMSO-
d6) δ 8.19 (s, 1 H), 8.00-7.77 (m, 2 H), 7.48 (d, J ) 8 Hz, 1 H).
3,6-Dich lor o-1,2-ben zisoth ia zole (65b). A mixture of
3-hydroxy-6-chloro-1,2-benzisoxazole (65a ) (3.6 g, 19.4 mmol)
and PCl5 (4.4 g) in POCl3 (5 mL) was heated to 120 °C with
stirring. After 2 h no starting material remained. The
mixture was cooled to room temperature, poured into ice water,
and extracted with CH2Cl2. The organic phase was drawn off,
dried over MgSO4, filtered, and concentrated in vacuo. The
residue was purified by being washed through a short pad of
silica gel using hexane as eluent. The fractions containing
desired product were combined and concentrated in vacuo to
provide the product as a fluffy, yellow-white solid. The yield
was 3.8 g (18.7 mmol): 1H NMR (CDCl3) δ 8.03-7.87 (m, 2
H), 7.49 (d, J ) 9 Hz, 1 H); mass spectrum (EI, 70 eV) M+
203.
1-(6-Ch lor o-1,2-ben zisoth ia zol-3-yl)-3-p ip er a zin e (66).
A mixture of 3,6-dichloro-1,2-benzisothiazole (2.96 g, 14.6
mmol) and piperazine (12.54 g, 146 mmol) in 150 mL of
chlorobenzene was heated to reflux with stirring for 18 h. The
mixture was allowed to cool to room temperature, diluted with
Et2O, and partitioned between organics and water. The
organic phase was separated, dried over MgSO4, filtered, and
concentrated in vacuo to provide 2.0 g of the desired product
as a waxy solid: 1H NMR (CDCl3) δ 7.83-7.78 (d superimposed
on s, 3 H), 7.31 (d, J ) 8.3 Hz, 1 H), 3.54-3.40 (m, 4 H), 3.17-
3.03 (m, 4 H), 1.84 (br s, 1 H). Anal. (C15H12NO4) C, H, N.
2-[(Car boxym eth yl)ph en ylam in o]-4-flu or oben zoic Acid
(70c). A mixture of 2-chloro-4-fluorobenzoic acid (11.5 g, 66.1
mmol), N-phenylglycine (12.0 g, 79.4 mmol), K2CO3 (41.5 g,
300 mmol), CuCl (0.82 g, 9.1 mmol), and N-methylpyrrolidi-
none (130 mL) was heated under nitrogen between 135 and
152 °C. After 0.5 h the mixture was diluted with H2O (600
mL), made basic, and extracted with ether (2 × 300 mL). The
aqueous layer was acidified with concentrated HCl and
extracted with ether (3 × 300 mL). The combined extracts
were washed successively with H2O (350 mL) and then brine
(350 mL), dried (Na2SO4), and concentrated to a brown foam.
Trituration of the foam with dichloromethane/hexane gave 7.24
g of a beige solid. Recrystallization from dichloromethane gave
2.83 g (14.8%) of a white fibrous solid: mp 120-122 °C dec;
1H NMR (DMSO-d6) δ 12.8 (br s, 2 H), 7.98 (dd, J ) 6.8 and
9.4 Hz, 1 H), 7.27-7.05 (m, 4 H), 6.72 (t, J ) 7.3 Hz, 1 H),
6.48 (d, J ) 7.8 Hz, 2 H), 4.36 (s, 2 H); mass spectrum (EI, 70
eV) M+ 289. Anal. (C15H12NO4) C, H, N.
1-(6-Flu or oben zo[b]th ien -3-yl)-piper azin e Maleate (76a).
A mixture of methyl-6-fluoro-3-aminobenzo[b]thiophene-2-
carboxylate (74a ) (20.11 g, 89.3 mmol), 1-methylpiperazine
(13.10 g, 180 mmol), and 1-methyl-2-pyrrolidinone (100 mL)
was heated at 176 °C under nitrogen for 2 h. The resulting
dark solution was diluted with H2O (400 mL) and extracted
with ether (3 × 200 mL). The combined extracts were washed
with H2O and brine and dried (sodium sulfate). Concentration
under reduced pressure gave 9.32 g of crude 3-amino-6-
fluorobenzo[b]thiophene (75a ) as a brown liquid (Rf ) 0.39,
50% ethyl acetate in hexanes, silica gel). A mixture of the
crude intermediate (75a , 9.32 g), piperazine (15.0 g, 174 mmol),
and 1-methyl-2-pyrrolidinone (100 mL) was heated between
186 and 192 °C under nitrogen for 14 h. The black mixture
was cooled, diluted with H2O (500 mL), and extracted with
ether (3 × 200 mL). The combined extracts were washed
successively with H2O (250 mL) and then brine (250 mL) and
dried (potassium carbonate). Concentration under reduced
pressure gave a brown liquid. Chromatography of the crude
product on silica gel (eluting with 30% methanol in dichlo-
romethane) gave 3.03 g of a yellow viscous liquid (Rf ) 0.22,
30% methanol in dichloromethane, silica gel). The free amine
was taken up in 2-propanol (20 mL), and a solution of maleic
acid (1.49 g, 12.8 mmol) in 2-propanol (20 mL) was added.
Concentration under reduced pressure of the resulting mixture
gave a brown solid (4.52 g). Recrystallization from methanol/
ethyl acetate afforded 2.72 g (8.80%) of off-white crystals: mp
173-175 °C; 1H NMR (DMSO-d6) δ 20.1 (br s, 1 H), 8.80 (br s,
2 H), 7.90-7.80 (m, 2 H), 7.28 (ddd, J ) 2.4, 9.0, and 9.0 Hz,
1 H), 7.07 (s, 1 H), 6.04 (s, 2 H), 3.43-3.13 (m, 8 H); mass
spectrum (EI, 70 eV) M+ 236. Anal. (C12H13FN2S‚C4H4O4) C,
H, N.
In Vitr o Stu d ies. Receptor binding assays in rat mem-
brane preparations were performed according to previously
reported procedures.40
(A) [3H]Sp ip er on e Bin d in g to Hu m a n Dop a m in e D4
Sites Tr a n sfected in to CHO Cells (D4.7 Va r ia n t fr om
Recep tor Biology, In c.). A competitive receptor binding
assay was conducted using membranes expressing human
dopamine D4 receptors (the D4.7 isoform) obtained from Recep-
tor Biology Inc. (Baltimore, MD) and [3H]spiperone (0.5 nM;
specific activity 113 Ci/mmol) as the labeled ligand. Specific
binding is defined using 10 µM haloperidol. The incubation
buffer contained 50 mM Tris-HCl, 120 mM NaCl, 5 mM KCl,
1 mM MgCl2, and 2 mM CaCl2 (pH 7.7). Compounds of
interest were incubated with D4 membranes and [3H]spiperone
at 37 °C for 25 min; incubation was terminated by vacuum
filtration through GF/B glass fiber filters and washed with 50
mM Tris buffer containing no salts (pH adjusted to 7.7 with
HCl). Filters were presoaked in 50 mM Tris buffer containing
0.05% polyethylenimine. Ki values were calculated from two
to four displacement curves (nine concentrations) in duplicate.
(B) [3H]Meth ylsp ip er on e Bin d in g to Hu m a n 5HT2A
Sites Exp r essed in BHK Cells. Competitive receptor bind-
ing assays are run using membranes obtained from BHK cells
expressing the human serotonin 5HT2A receptor. This cell line
was created by the Molecular Neurobiology Group of Hoechst
Marion Roussel. Briefly 0.8 nM [3H]methylspiperone (NEN
no. 856, 82 Ci/mmol) is used to label the sites and 10 µM
methysergide maleate (RBI M-137) is used to define nonspe-
cific binding. The incubation buffer is 50 mM Tris-HCl (pH
7.7) containing 120 mM NaCl, 5 mM KCl, 2 mM CaCl2, and 1
mM MgCl2. Compounds of interest (100 µL/eight concentra-
tions 1.0-0.0003 µM) are incubated with 5HT2A membranes
(750 µL/50-80 µg) and 0.8 nM [3H]methylspiperone (150 µL)
at 37 °C for 30 min in 96 cube-tube styrene plates. Incubation
is terminated by vacuum filtration (Tomtech Harvester Mach
III) through presoaked Packard GF/B Unifilters treated with
0.05% polyethylenimine. Filters are washed with ice-cold 50
mM Tris-HCl containing no salts. Lastly, filter plates are
counted in a Packard TopCount MicroPlate Scintillator.
Meth yl 3-Am in o-6-flu or oben zo[b]th iop h en e-2-ca r box-
yla te (74a ). To a mixture of 2,4-difluorobenzonitrile (229 g,
1650 mmol), lithium hydroxide monohydrate (104 g, 2480
mmol), and dimethylformamide (802 mL) at -10 °C was added
methyl thioglycolate (210 g, 1980 mmol) over 7 h via a syringe
pump. The reaction was diluted with water (4.0 L), and 73.5
g of crude methyl 3-amino-6-fluorobenzo[b]thiophene-2-car-
boxylate, prepared by a similar procedure, was added to the
mixture. The pH of the slurry was raised from 8.5 to 9.4 by
the addition of lithium hydroxide monohydrate over 3 h. The
white solid was collected by filtration, washed with water (2.0
L), and dried to afford 286 g (64.4%) of a white solid. A 20.0
g sample of crude product was purified by filtration through
silica gel with methanol/dichloromethane followed by chroma-
tography on silica gel, eluting with 50% dichloromethane/
hexanes, to yield 12.9 g of a white solid, TLC (silica gel,

4056 J ournal of Medicinal Chemistry, 1996, Vol. 39, No. 20
Hrib et al.
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then observed for climbing behavior for 30 min. ED50 values
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(B) Ap om or p h in e-In d u ced Ster eotyp y in Ra ts. The
procedure is a modification of J anssen et al.29 Male Wistar rats
(150-250 g) were dosed ip with distilled water or test
compounds (6-10/dose group). After 50 min, apomorphine (1.5
mg/kg sc) was administered, and the rats were placed in
individual opaque plastic cages (40 × 22 × 18 cm). After 10
min, the rats were observed for the presence of continuous
stereotyped licking or sniffing behavior.
(C) Socia l In ter a ction in Ra ts. The procedure is a
modification of that used by File41 and Gardner and Guy.42
Pairs of male Wistar rats (200-275 g) were placed in an arena
(45 × 45 × 40 cm) and allowed to acclimate for 8 min on two
consecutive days. On the third day, rats naive to one another
were assigned to treatment groups, six pairs per treatment
group, and the rats received test drug or vehicle. After 30 or
60 min, the appropriate rats were paired and placed in the
test arena for observation of social interaction behavior (time
spent sniffing partner, climbing over partner, following part-
ner, mutual grooming, etc.) for 5 min. Social interaction time
(in seconds) and total activity (counts per body leingth of
movement) for the test groups were compared to control, and
statistical significance was determined by a one-way ANOVA
and Duncan’s multiple range test.
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Dop a m in e Neu r on Sa m p lin g. Single unit studies were
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Ack n ow led gm en t. We wish to thank Anastasia
Linville and J ason Karns of the Physical Methods
Department for spectroscopic data. We wish to thank
Betina Spahl of the HMR Library and Information
Center for her invaluable assistance with literature
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