Novel benzothiazolin-2-one and benzoxazin-3-one arylpiperazine derivatives with mixed 5HT1(A)/D2 affinity as potential atypical antipsychotics

Article abstract of DOI:10.1021/jm970298c

Since it was known that 5HT properties (5HT(1A) agonism or 5HT(2A) antagonism) combined with D₂ antagonism may lead to atypical antipsychotic drugs, a series of 19 benzothiazolin-2-one and benzoxazin-3-one derivatives possessing the arylpiperaz

Full text of DOI:10.1021/jm970298c

2010
J . Med. Chem. 1998, 41, 2010-2018
Novel Ben zoth ia zolin -2-on e a n d Ben zoxa zin -3-on e Ar ylp ip er a zin e Der iva tives
w ith Mixed 5HT1A/D2 Affin ity a s P oten tia l Atyp ica l An tip sych otics
Thierry Taverne,† Ousmane Diouf,† Patrick Depreux,† J acques H. Poupaert,‡ Daniel Lesieur,†
Be´atrice Guardiola-Lemaˆıtre,§ Pierre Renard,§ Marie-Claire Rettori,§ Daniel-Henri Caignard,*,§ and
Bruno Pfeiffer§
Institut de Chimie Pharmaceutique, 3 rue du Professeur Laguesse, BP 83, F-59006 Lille Cedex, France, Ecole de Pharmacie,
Universite´ Catholique de Louvain, Avenue E. Mounier 73, B-1200 Bruxelles, Belgium, and ADIR et Cie, 1 rue Carle Hebert,
F-92415 Courbevoie Cedex, France
Received May 7, 1997
Since it was known that 5HT properties (5HT1A agonism or 5HT2A antagonism) combined with
D2 antagonism may lead to atypical antipsychotic drugs, a series of 19 benzothiazolin-2-one
and benzoxazin-3-one derivatives possessing the arylpiperazine moiety was prepared, and their
binding profiles were investigated. All tested compounds displayed very high affinities for
the 5HT1A and D2 receptors. Therefore, further pharmacological studies were carried out on
selected compounds (24, 27, 30, 46, and 47). This evaluation in rats clearly revealed potent
antipsychotic properties along with a decrease of extrapyramidal side effects. These derivatives
are currently under preclinical development.
Sch em e 1
In tr od u ction
Schizophrenia is a group of illnesses that occurs in
approximately 1% of the adult population. The schizo-
phrenia is characterized by a spectrum of symptoms
that typically include disordered thought, social with-
drawal, and hallucinations. So far, there is no known
cure, and the disease is chronic and generally progres-
sive. However, the introduction of the neuroleptic
phenothiazine chlorpromazine in 1952 initiated the area
of pharmacotherapy in psychiatric medicine and has led
to the marketing of dozens of clinically diverse antip-
sychotic drugs, belonging to different chemical families
(i.e. thioxanthenes, butyrophenones, diphenylbutylpip-
eridines, etc.).1
Nevertheless, currently available antipsychotics drugs
have several limitations. First, they are ineffective in
many patients (neuroleptic nonresponders). Second,
even when patients do respond, some aspects of psy-
chopathology may benefit more than others: in many
patients, positive symptoms may be alleviated while
negative or deficit remain unresponsive.2 Negative
symptoms include alogia, flattened affect, anhedonia,
asociability, and attentional impairment.3,4 Third, clas-
sical antipsychotic drugs exhibit unwanted extrapyra-
midal side effects (EPS) and tardive dyskinesia.5
During the past few years, a second generation of
antipsychotic agents has emerged; the term “atypical
neuroleptic” originates from the clinical observation that
the dibenzazepine clozapine exhibits antipsychotic ac-
tivity in the absence of debilitating, short (e.g. dystonia)
or long term (e.g. tardive dyskinesia) extrapyramidal
side effects.6
weak dopamine D2 receptor antagonism in vitro and in
vivo,8 but potentially important activities at other
dopaminergic (D1, D4) receptors, at serotoninergic (5HT2A
5HT3, 5HT2C), adrenergic (R1, R2), histaminergic (H1),
and muscarinic receptors.9-12
,
However, treatment with clozapine is associated with
an increased risk of agranulocytosis,13 which strongly
limits its therapeutic use.
This finding with clozapine led to a major search for
other pharmacological agents with mixed serotoninergic
and dopaminergic activities such as risperidone14
(Scheme 1), olanzapine,15 or mixed 5HT1A agonists/D2
antagonists such as RWJ -3779616 (Scheme 1).
Previous works in our laboratory17-20 have estab-
lished the bioisosteric equivalency of benzoxazolin-2-one
and pyrocatechol. This concept led to the synthesis of
amino ketones, amino alcohols, and amine derivatives
of 6-(2-aminoethyl)benzoxazolin-2-one which exhibited
high affinity for adrenergic and dopaminergic receptors.
The expected advantages resulting from this bioisosteric
Clozapine (Scheme 1) generally considered as the
reference drug is characterized by a dual dopaminergic
and serotoninergic mechanism of action:7 a relatively
† Institut de Chimie Pharmaceutique.
‡ Universite´ Catholique de Louvain.
§ ADIR et Cie.
S0022-2623(97)00298-7 CCC: $15.00 © 1998 American Chemical Society
Published on Web 05/15/1998

Potential Atypical Antipsychotics
J ournal of Medicinal Chemistry, 1998, Vol. 41, No. 12 2011
Sch em e 2
Sch em e 4a
Sch em e 3a
a
(i) AlCl3/DMF, BrCH2COCl; (ii) (C2H5)3SiH, CF3CO2H; (iii)
arylpiperazine, acetone, (C2H5)3N; (iv) NaOH, methanol; (v) ethyl
bromoacetate, sodium ethanolate DMSO; (vi) Cl(CH2)3COCl, PPA;
(vii) acetone, HBr.
6-halogenoalkyl 11-16 derivatives were obtained as
previously described.24-26 Compounds 11-16 were then
reacted with the desired arylpiperazines in dry acetone
in the presence of triethylamine to give the arylethy-
lamino (17, 19-21, and 23-25), the arylpropylamino
(26 and 27), and the arylbutylamino (28-31) com-
pounds. Phenolic compounds 18 and 22 were obtained
by acidic cleavage of the corresponding methoxy ethers
19 and 24. 4-Methylbenzoxazin-3-one derivatives 44
and 45 were obtained as shown in Scheme 4. Com-
pounds 33 and 34 were synthesized by previously
described procedures.19,20 Compounds 35 and 36 were
obtained by using the same conditions which were
employed for the preparation of compounds 17, 19-21,
and 23-25. The heterocycle cleavage was carried out
in aqueous medium in the presence of NaOH and led
to o-aminophenols 37 and 38. A one-pot reaction using
sodium ethanolate, dimethyl sulfoxide, and ethyl bro-
moacetate gave the final compounds 44 and 45. The
synthetic approach employed for the preparation of the
butylamino homologues is summarized in Scheme 4.
The bromo ketone 42 was obtained from 3-methylben-
zoxazolinone 32 according a previously described pro-
cedure.27 Reduction of the ketone carbonyl group of
compound 42 was carried out with the triethylsilane-
trifluoroacetic acid reagent.28 Condensation reaction
with arylpiperazines was performed in dry acetone in
the presence of triethylamine to give compounds 46 and
47.
a
(i) AlCl3/DMF; BrCH2COCl or Cl(CH2)2COCl; (ii) (C2H5)3SiH,
CF3CO2H; (iii) PPA, Cl(CH2)3COCl; (iv) acetone, HBr; (v) arylpip-
erazine, acetone, (C2H5)3N.
replacement were increases of the chemical stability and
duration of action. On the basis of the well-established
advantages of mixed 5HT1A/D2 ligands in the search for
atypical antipsychotics, we therefore combined the
intrinsic D2 affinity of these compounds with the phe-
nylpiperazine pharmacophore, known as one of the most
potent 5HT1A pharmacophores.21-23 These arylpipera-
zine derivatives showed important psychotropic and
analgesic properties involving interaction at central
serotonin (5HT) and dopamine (D2) receptors. To
increase the CNS activity and the metabolic stability,
we therefore decide to replace the benzoxazolinone
heterocycle with its sulfur bioisostere and with its
benzoxazin-3-one homologue (structures A and B in
Scheme 2). This article reports their synthesis and
pharmacological evaluation as mixed 5HT1A/D2 receptor
ligands and atypical antipsychotic agents.
Ch em istr y
Scheme 3 illustrates the procedures used to synthe-
size benzothiazolin-2-one derivatives 17, 19-21, and
23-31. From benzothiazolin-2-one (1) or 3-methylben-
zothiazolin-2-one (2), 6-halogenoacyl 3-6, and 9-10 and
P h a r m a cologica l Resu lts a n d Discu ssion
Affinities (IC50’s, nM) for 5HT1A, 5HT1B, 5HT2A
5HT2C, D2, and R1 receptors were determined for com-
,

2012 J ournal of Medicinal Chemistry, 1998, Vol. 41, No. 12
Taverne et al.
Ta ble 1. Structures and Binding Assays Results (IC50 ( SEM in nM) of Compounds of General Structure A
compd
n
R
Y
5-HT1A
5-HT1B
5-HT2A
5-HT2C
90 ( 10
520 ( 110
300 ( 25
60 ( 7
D2
R1
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
2
2
2
2
2
2
2
2
2
3
3
4
4
4
4
H
H
H
H
CH3
CH3
CH3
CH3
CH3
H
CH3
H
H
H
3 ( 0.06
0. 7 (0.09
0.3 ( 0.09
3 ( 0.7
300 ( 25
260 ( 50
20 ( 4
600 ( 180
200 ( 39
31 ( 4
40 ( 15
100 ( 15
27 ( 6
10 ( 4
60 ( 7
1000 ( 120
71 ( 22
1000 ( 120
40 ( 9
200 ( 40
6 ( 0.5
7 ( 4
0.77 ( 0.07
57 ( 4
2-OH
530 ( 200
300 ( 50
200 ( 35
70 ( 7
2-OCH3
3-CF3
H
0.6 ( 0.2
90 ( 10
>100
0.7 ( 0.08
0.2 ( 0.03
40 ( 7
2000 ( 300
2000 ( 260
2-OH
1100 ( 15
200 ( 27
500 ( 75
600 ( 110
290 ( 80
910 ( 170
150 ( 25
570 ( 20
1000 ( 120
400 ( 38
3 ( 1
4-F
3000 ( 420
300 ( 55
70 ( 8
30 ( 4
10 ( 3
400 ( 60
1 ( 0.3
6 ( 3
0.82 * 0.1
45 ( 9
30 ( 4
200 ( 22
160 ( 25
20 ( 5
2-OCH3
3-CF3
2-OCH3
2-OCH3
2-OCH3
3-CF3
2-OCH3
3-CF3
2 ( 0.3
4000 ( 440
>10000
99 ( 15
560 ( 29
320 ( 50
11000 ( 700
240 ( 10
1 ( 0.1
11 ( 3
61 ( 5
3 ( 0.7
360 ( 95
200 ( 10
400 ( 36
300 ( 30
1000 ( 49
2500 ( 290
>10000
0.2 ( 0.02
43 + 9
CH3
CH3
0.8 ( 0.07
2 ( 0.6
10 ( 2
50 ( 8
140 ( 30
1.2 ( 0.1
clozapine
haloperidol
150 ( 40
1500 ( 100
10 ( 3
>10000
30 ( 5
Ta ble 2. Structures and Binding Assays Results (IC50 ( SEM in nM) of Compounds of General Structure B
compd
n
Y
5-HT1A
5-HT1B
5-HT2A
5-HT2C
D2
R1
44
45
46
47
2
2
4
4
2-OCH3
3-CF3
2-OCH3
3-CF3
0.2 ( 0.03
0.7 ( 0.04
0.8 ( 0.09
0.6 ( 0.07
180 ( 50
600 ( 50
620 ( 100
840 ( 150
620 ( 35
1200 ( 400
360 ( 50
3 ( 1
0.5 ( 0.05
85 ( 5
460 ( 135
150 ( 15
5.2 ( 2
8 ( 3
20 ( 4
280 ( 65
800 ( 190
30 ( 2
Ta ble 3. R1/5-HT1A and D2/5-HT1A Selectivity Ratios
compd R1/5-HT1A D2/5-HT1A compd R1/5-HT1A D2/5-HT1A
affinity obtained with 24 is 5-fold less than that
observed with its oxygene analogue, confering to the
benzothiazolin-2-one derivatives a best 5-HT1A versus
R1 selectivity ratio. Pharmacomodulations concerning
the nitrogen substituent of the heterocyclic pivotal
template, the length of the hydrocarbon chain linking
this heterocycle with the arylpiperazine moiety, and the
nature and place of the substitution group of the
arylpiperazine moiety were studied. It was anticipated
that the diverse number of synthesized compounds could
lead to the selection of compounds presenting high and
selective affinities for both the 5HT1A and D2 receptors
and low affinity for R1 sites. Comparison of the results
obtained with the N-methyl derivatives (21, 22, 24, 25,
27, 30, and 31) with their nonmethylated analogues (i.e.
17, 18, 19, 20, 26, 28, and 29, respectively) leads to the
following observations:
(1) The two classes of compounds retain high and
similar affinities at 5HT1A and D2 sites (0.1 to 1 nM at
5HT1A sites and 1 to 1000 nM at D2 receptors).
(2) The N-methyl derivatives generally possess lower
affinities at the other 5HT receptors (i.e. 5HT2A and
5HT2C). This can be observed when 17 or 18 are
compared with 21 or 22.
17
18
19
20
21
22
23
24
25
26
33
39
33
27
28
29
30
31
44
45
46
47
2
4.1
1.05
37.5
100
2.5
123
251
50
2.3
3.85
1.33
12.5
25
15
214
6.25
13.3
2
30
20
1429
355
25
20
200
0.75
5
400
0.09
0.55
pounds of general structures A and B (Tables 1 and 2).
The selectivity ratios R1/5HT1A and D2/5HT1A are re-
ported in Table 3.
The expected affinities were associated with an ago-
nist character at 5HT1A receptors and an antagonist one
at D2 sites. The 5HT1A agonism should lead to anti-
anxiety properties comparable to those observed with
buspirone and when associated with a D2 blockade to
antipsychotic properties with less extrapyramidal side
effects. Thus, the combination of high and selective
5HT1A affinity with D2 affinity lends support to the
“atypical” profile of the potentially antipsychotic com-
pounds.
Structure-affinity relationships were first studied in
the benzothiazolinonic series. Replacement of benzox-
azolin-2-one with its sulfur analogue (i.e. compound 24)
has led to the same binding profile. The obtained
5-HT1A and 5-HT1B affinities are quite similar. The R1
(3) The undesirable R1 affinity is lower in most cases
with the N-methyl compounds as for example 19, 28,
29 compared with 24, 30, 31. N-Methylation seems to
have no or negligible influence on the D2 affinity.
The length of the hydrocarbon linking chain bearing
the arylpiperazine was modified since the high and

Potential Atypical Antipsychotics
J ournal of Medicinal Chemistry, 1998, Vol. 41, No. 12 2013
undesirable R1 affinity of compounds 17-25 could be
related to the arylethylamino structure. No significant
modification concerning the R1 affinity with compounds
bearing three and four methylene units (26-31) was
observed as shown when 19 and 24 are compared with
26 and 30. Nevertheless, this result is not surprising
since it is well-known that the arylpiperazine is also a
good structure for R1 affinity.29 On the other hand, the
length of the hydrocarbon side chain seems to influence
D2 affinity. Compounds with a 4-butylamino side chain
(30 and 31) are respectively more potent at D2 sites than
their ethylamino homologues 24 and 25. Finally, varia-
tion of the number of methylene units has no or
negligible influence on 5HT1A affinity. The nature of
the substituent on the arylpiperazine pharmacophore
is of importance for the 5HT1A, D2, and R1 affinities: no
substitution leads to compounds with high 5HT1A af-
finity (17 and 21) but with a low D2 affinity. The (o-
methoxyphenyl)piperazino derivatives (19, 28, and 30)
exhibit better 5HT1A, D2, and R1 affinity than their
m-trifluoromethyl analogues (20, 29, and 31, respec-
tively). In most cases D2 and R1 affinity of nonsubsti-
tuted and 3-CF3 arylpiperazines is lower than that of
the other substituted compounds. The (o-hydroxyphe-
nyl)piperazines (18 and 22) exhibit high 5HT1A and D2
affinities. Replacement of the benzothiazolin-2-one
heterocycle with the benzoxazin-3-one moiety (com-
pounds 44-47, Table 2) leads to high combined 5HT1A
(0.2-0.8) and D2 (3-8) affinity, except for compound 45
(D2 ) 150).
Compounds 24, 30, and 47 were tested for their ability
to antagonize the effects of a low dose of a direct D2
dopaminergic agonist, apomorphine, in mice.
Compounds 24 and 47 completely blocked the stereo-
typies and the climbing at the dose of 1 mg/kg ip (100%
of antagonism), while compound 30 was active at the
dose of 8 mg/kg ip (100% of antagonism), indicating that
the tested compounds behave like D2 antagonists. It
must be noted that none of these compounds were able
to reduce the apomorphine-induced hypothermia since
they intrinsically induced hypothermia in mice; tested
in the same conditions, haloperidol (0.25 mg/kg ip)
completely abolished both stereotypies and climbing
(100% of antagonism), and significantly reduced the
apomorphine-induced hypothermia (2.2 °C, p < 0.01).
Some of the synthesized compounds were examined
for potential antipsychotic activity. Compounds 22, 24,
27, 28, 30, 46, and 47 were tested for their ability to
antagonize the hyperlocomotion induced by d-amphet-
amine in mice. The compounds were tested at two doses
which weakly reduced the spontaneous locomotor activ-
ity. All the tested compounds significantly antagonized
the d-amphetamine induced hyperlocomotion. The doses
which reduced by approximately 50% the locomotion in
comparison with the amphetamine treated animals
were 0.25 mg/kg ip for compound 46 (46% of antago-
nism, p < 0.01), 0.50 mg/kg ip for compound 30 (54% of
antagonism, p < 0.05), 1 mg/kg ip for compounds 24 and
27 (respectively 57% and 52% of antagonism, p < 0.01),
2 mg/kg ip for compound 22 (56% of antagonism, p <
0.01), and 4 mg/kg ip for compounds 28 and 47 (respec-
tively 68% and 61%, p < 0.01). In the same experimen-
tal conditions, clozapine reduced by 48% (p < 0.01) and
haloperidol by 67% (p < 0.01) the amphetamine-induced
hyperactivity, at the respective doses of 4 and 0.125 mg/
kg ip.
As a general remark concerning compounds of general
structure A and B, it can be stated that they possess a
multireceptorial binding profile and most of them suffer
from a lack of selectivity and specificity. They repre-
sent, however, precious pharmacological tools for the
studies of 5HT receptors and in particular for a better
knowledge of the pharmacological activities generally
related to 5HT1A receptors.
In addition, compounds 24 and 46 were also tested
in rats, using the same paradigm. After oral adminis-
tration, both compounds significantly (p < 0.05) reduced
the hyperactivity by 50% at the doses of 2 and 4 mg/kg
po, respectively 63% and 58% of antagonism for com-
pounds 24 and 46; the antagonism was complete (103%
and 108%) at the respective doses of 8 and 16 mg/kg po
for compounds 24 and 46 (p < 0.01). In comparison,
haloperidol completely blocked the hyperactivity (p <
0.001) at the dose of 1 mg/kg po (179% of antagonism).
These behavioral tests predictive of an antipsychotic
activity were based on the dopaminergic hypothesis of
schizophrenia.
The nature of the interactions with 5HT1A, 5HT2A, D2,
and R1 receptors was determined for some of the
synthesized compounds. Compounds 24, 25, 28, 30, and
47 were tested for their ability to induce forepaw
treading in rats, indicating a stimulation of the 5HT1A
receptors subtypes. None of these compounds behave
in vivo in rats like 5HT1A agonists since they were
unable to induce forepaw treading at doses active in
models predictive of an antipsychotic activity; in the
same conditions, the 5-HT1A agonist, 8-OH-DPAT, at the
dose of 8 mg/kg ip, induced forepaw treading (77% of
the maximal possible score, p < 0.001).
Nevertheless, the same compounds, i.e. 24, 25, 28, 30,
and 47, showed clear antagonist action at 5HT2A recep-
tor subtype since they significantly inhibited the head-
twich response induced by 5-hydroxytryptophan (5HTP)
in mice. The antagonism was nearly complete at the
dose of 1 mg/kg ip for compounds 24 and 28 (respectively
94% and 83% of antagonism, p < 0.01), at the dose of 4
mg/kg ip for compound 25 (91% of antagonism, p < 0.01)
and at the dose of 8 mg/kg ip for compounds 30 and 47
(respectively 78% and 97% of antagonism, p < 0.01).
Tested in the same conditions, the 5-HT2 antagonist,
cyproheptadine, at the dose of 16 mg/kg ip, produced
an antagonism of 83% (p>0.05).
Some of the synthesized compounds were tested for
their ability to antagonize the scratching induced by
mescaline, a serotonergic compound, in mice.
Compound 18 (2 and 4 mg/kg ip), 24 (0.25 and 1 mg/
kg ip), 26 (4 mg/kg ip), 27 (2 mg/kg ip), 46 (1 mg/kg ip),
and 47 (2 and 8 mg/kg ip) significantly (p < 0.05)
reduced the scratching induced by mescaline (Table 4).
In comparison, at the dose of 4 mg/kg ip, the atypical
antipsychotic drug clozapine completely blocked the
scratching induced by mescaline, in accordance with the
interaction with serotoninergic receptors.
Five compounds were tested in the tail suspension
test (TST) which allows to screen different psychotropic
drugs including antidepressants, anxiolytics, and neu-
roleptics. In this test derived from the forced swim test,

2014 J ournal of Medicinal Chemistry, 1998, Vol. 41, No. 12
Ta ble 4. In Vivo Antagonism of the Effects of Mescaline in Mice
Taverne et al.
18
24
47
26
27 46
clozapine
4
dose (mg/kg ip)
2
4
0.25
1
4
2
1
2
8
antagonism of mescaline-induced scratching (% vs controls)a 71% ** 97*** 92*** 100*** 96** 73* 81* 60 ns 87** 99***
a
*p < 0.05. **p < 0.01. ***p < 0.001. n ) 10 animals per group.
Ta ble 5. Tail Suspension Test in Mice
18
24
26
30
46
haloperidol
clozapine
dose (mg/kg ip)
4
1
4
8
1
0.5
+65***
4
duration of immobility (% vs controls)a
+92**
+89***
+99**
+36*
+124**
+90***
a
*p < 0.05. **p < 0.01. ***p < 0.001. n ) 10 animals per group.
Ta ble 6. In Vivo Antagonism of the Effects of SKF 10047 and of PCP by Compound 24 in Rats
24
haloperidol
dose (mg/kg po)
0.5
39*
12
2
8
1
2
antagonism of SKF 10047-induced hypermotility (% vs controls)a
antagonism of PCP-induced stereotypies (% vs controls)a
56**
2
71****
21
94***
87***
a
*p < 0.05. **p < 0.01. ***p < 0.001. n ) 12 animals per group.
Ta ble 7. Effects of Compound 24 on Sidman Avoidance Performance in Rats
24
haloperidol
clozapine
dose (mg/kg po)
8
16
-38**
+23.8 ns
+18.5 ns
32
-78***
+87.8***
+63.6**
1
32
number of avoidance responses (% change from control)a
number of shocks (absolute change from control)a
number of escape failure (absolute change from control)a
-12 ns
+7.3 ns
+5.8 ns
-86***
+99.7***
+84.6***
-62**
+71.1**
+53.8*
a
*p < 0.05. **p < 0.01. ***p < 0.001. n ) 10 animals per group.
neuroleptics increased the duration of immobility while
they had no clear effects on the power of movements
(Table 5).
number of escape failures (i.e. decrease in the ability of
animals to escape shocks). For comparison, haloperidol
decreased the avoidance response and increased the
escape failure at low doses.
To qualify a putative antipsychotic agent as atypical,
its low propensity to induce extrapyramidal side effects
(EPS) has to be demonstrated.
Compounds 24 and 47 were tested at pharmacological
doses (1 and 2 mg/kg ip, respectively) and at high doses
(32 and 64 mg/kg ip) in rats for their potential ability
to induce catalepsy indicative of EPS production in
human.
Both compounds did not induce catalepsy in rats at
doses active in models predictive of an antipsychotic
activity. Compound 24 increased significantly catalepsy
at the dose of 32 mg/kg while compound 47 was devoid
of any catalepsigenic effects.
The amphetamine-induced stereotypies are thought
to result from dopaminergic activation in the striatum.
Compounds 24 and 30 which were previously shown to
antagonize the hyperactivity induced by d-amphetamine
(resulting from DA activation in the limbic system) were
tested for their ability at the same dose to block the
stereotypies induced by amphetamine.
Compound 24 neither blocked the stereotypies in-
duced by amphetamine in mice (0.25 and 1 mg/kg ip)
nor those induced in rats (8 mg/kg PO); these doses were
previously found active on amphetamine-induced hy-
perlocomotion.
The different arylpiperazine derivatives tested thus
showed clear activity in different tests predictive of an
antipsychotic activity: these models were based on the
dopaminergic and the serotonergic hypothesis of schizo-
phrenia. Compounds 24, 25, 30, and 31 were tested for
their sedative potential using an interaction test with
the barbital-induced sleep. Compounds 24 (2 mg/kg ip)
and 25 (16 mg/kg ip) weakly increased the duration of
the sleep, respectively 50% and 70% (ns) of increase in
comparison with barbital treated animals (non signifi-
cant). On the contrary, compounds 30 and 31 dramati-
cally increased the duration of sleep (+400% for com-
pound 30 at the dose of 8 mg/kg ip and +360% for
compound 31 at the doses of 64 mg/kg ip, p < 0.001).
This latter effect was similar to the one induced by the
typical antipsychotic haloperidol at the dose of 0.5 mg/
kg ip (Table 6).
Compound 24 seems very promising since it was
active at low doses and was interestingly devoid of clear
sedative effects at dose active in these models and thus
was tested in other models, based on the σ and the
NMDA hypothesis of schizophrenia.
Compound 24 showed a clear dose dependent antago-
nism of the hyperlocomotion induced by the σ agonist,
SKF 10047, and of the stereotypies induced by the
phencyclidine (PCP).
Finally compound 24 was investigated after oral
administration in rats to evaluate its effects in the
Sidman avoidance test.
Compound 24 dose-dependently decreased the num-
ber of avoidance responses (Table 7). This effect was
associated only at the highest dose with a significant
increase in the number of shocks received and in the
Con clu sion
We have designed and synthesized novel original
ligands with mixed affinities for the 5HT1A and D2
receptors for which the expected profiles were indeed
obtained. Moreover, we have obtained potent and
selective pharmacological tools in the field of central

Potential Atypical Antipsychotics
J ournal of Medicinal Chemistry, 1998, Vol. 41, No. 12 2015
3-Meth yl-6-(2-(4-(3-tr iflu or om eth ylp h en yl)p ip er a zin -
1-yl)eth yl)ben zoth ia zolin -2-on e Hyd r och lor id e (25). Re-
crystallized from absolute EtOH (50% yield): mp 236-237 °C;
1H NMR (DMSO-d6) δ 3.20-3.85 (m, 12H, CH2CH2 + pipera-
zine); 3.40 (s, 3H, NCH3); 7.00-7.55 (m, 7H, aromatic); 11.30
(s, 1H, NH+). Anal. (C21H22F3N3OS‚1HCl) C, H, N.
5HT1A ligands. Five compounds (24, 27, 30, 46, and 47)
which could be qualified as potential “atypical” antip-
sychotics emerged in this series as they do not induce
any (or only a low level of) cataleptic behavior which is
indicative of EPS.
6-(3-(4-(2-Me t h o x y p h e n y l)p ip e r a zin -1-y l)p r o p y l)-
ben zoth ia zolin -2-on e Hyd r och lor id e (26). Recrystallized
from absolute EtOH (65% yield): mp 224-225 °C; H NMR
Exp er im en ta l Section
1
Ch em istr y. Compounds were characterized by elemental
analyses and IR and 1H NMR spectra. IR spectra were
recorded on a Perkin-Elmer 297 spectrophotometer, using KBr
(DMSO-d6) δ 2.05 (m, 2H, CH2); 2.65 (t, J ) 7.30 Hz, 2H,
ArCH2); 3.15 (m, 6H, CH2N(CH2)2); 3.50 (m, 4H, (CH2)2N); 3.80
(s, 3H, OCH3); 7.00-7.50 (m, 7H, aromatic); 11.10 (s, 1H, NH+);
11.95 (s, 1H, NH). Anal. (C21H25N3O2S‚1HCl) C, H, N.
3-Me t h yl-6-(3-(4-(2-m e t h oxyp h e n yl)p ip e r a zin -1-yl)-
p r op yl)ben zoth ia zolin -2-on e Hyd r och lor id e (27). Re-
crystallized from absolute EtOH (40% yield): mp 214-216 °C;
1H NMR (DMSO-d6) δ 2.10 (m, 2H, CH2); 2.70 (t, J ) 7.30 Hz,
2H, ArCH2); 3.10 (m, 6H, CH2N(CH2)2); 3.40 (s, 3H, NCH3);
3.50 (m, 4H, (CH2)2N); 3.80 (s, 3H, OCH3) 7.00-7.60 (m, 7H,
aromatic); 11.25 (s, 1H, NH+). Anal. (C22H27N3O2S‚1HCl) C,
H, N.
6-(4-(4-(2-M e t h o x y p h e n y l)p i p e r a z i n -1-y l)b u t y l)-
ben zoth ia zolin -2-on e (28). Recrystallized from toluene (55%
yield): mp 125-127 °C; 1H NMR (DMSO-d6) δ 1.60-1.80 (m,
4H, CH2CH2); 2.30-2.50 (m, 2H, ArCH2); 3.00-3.40 (m, 10H,
CH2N + piperazine); 3.80 (s, 3H, OCH3); 6.80-7.60 (m, 7H,
aromatic); 11.90 (s, 1H, NH). Anal. (C22H27N3O2S) C, H, N.
6-(4-(4-(3-Tr iflu or om eth ylp h en yl)p ip er a zin -1-yl)bu tyl-
)ben zoth ia zolin -2-on e (29). Recrystallized from 95% EtOH
(46% yield): mp 129-130 °C; 1H NMR (DMSO-d6) δ 1.40-
1.60 (m, 4H, CH2CH2); 2.40-2.50 (m, 4H, ArCH2 + CH2N);
3.00-3.40 (m, 8H, piperazine); 7.00-7.50 (m, 7H, aromatic);
11.80 (s, 1H, NH). Anal. (C22H24F3N3OS) C, H, N.
3-Me t h yl-6-(4-(4-(2-m e t h oxyp h e n yl)p ip e r a zin -1-yl)-
bu tyl)ben zoth ia zolin -2-on e Hyd r och lor id e (30). Recrys-
tallized from absolute EtOH (48% yield): mp 228-230 °C; 1H
NMR (DMSO-d6) δ 1.50-2.00 (m, 4H, CH2CH2); 2.50-3.00 (m,
4H, NCH2 + ArCH2); 3.30-3.70 (m, 11H, NCH3 + piperazine);
3.80 (s, 3H, OCH3); 6.80-7.50 (m, 7H, aromatic); 11.20 (s, 2H,
NH+). Anal. (C2H29N3O2S‚2HCl) C, H, N.
3-Meth yl-6-(4-(4-(3-tr iflu or om eth yl)p h en ylp ip er a zin -
1-yl)bu tyl)ben zoth ia zolin -2-on e Hyd r och lor id e (31). Re-
crystallized from toluene (67% yield): mp 182-184 °C; 1H
NMR (DMSO-d6) δ 1.10-1.40 (m, 4H, CH2CH2); 1.60-2.00 (m,
4H, NCH2 + ArCH2); 3.20-3.70 (m, 11H, NCH3 + piperazine);
6.90-7.70 (m, 7H, aromatic); 13.40 (s, 2H, NH+). Anal.
(C23H26F3N3OS‚2HCl) C, H, N.
tablets; the frequencies are expressed in cm-1. The H NMR
1
spectra were obtained on a Bru¨cker WP 80 SY (80 MHz)
spectrometer, with Me4Si as the internal standard and with
CDCl3 or DMSO-d6 as solvent; the chemical shifts are reported
in δ units and the coupling constants in hertz. Melting points
were determined using a Bu¨chi SMP-20 apparatus and are
uncorrected. Elemental analyses were determined by the
CNRS center of analysis in Vernaison (France). Elemental
analyses were within 0.4% of the theoretical values. Com-
pounds 3-16, 32-34, and 39-42 were prepared according to
published procedures.18,19,25,28
Gen er a l P r oced u r e for th e Syn th esis of th e Ar ylp ip -
er a zin oa lk ylben zoth ia zolin -2-on e (17, 19-21, 23-31) or
ben zoxa zolin -2-on e (35, 36) Der iva tives. The method
adopted for the synthesis of 6-(2-(4-phenylpiperazin-1-yl)ethyl)-
benzothiazolin-2-one hydrochloride (17) is described. A stirred
solution of 2.60 g (0.01 mol) of 6-(2-bromoethyl)benzothiazolin-
2-one (11), 0.96 g (0.01 mol) of 1-phenylpiperazine, and 1.01
g (0.01 mol) of triethylamine in 150 mL of dry acetone was
heated under reflux for 72h and then concentrated in vacuo.
The residue was triturated in 50 mL of a 5% aqueous solution
of HCl. The resulting precipitate was filtered, washed with
H2O, treated with a 10% aqueous solution of Na2CO3, and
extracted with EtOAc. The combined organic layers were
dried (K2CO3) and evaporated. The resulting residue was
dissolved in absolute ethanol, and dry HCl was bubbled into
the solution. The formed solid was filtered, dried, and
recrystallized from 95% EtOH to give 2.25 g of 17 (60% yield):
mp >250 °C; 1H NMR (DMSO-d6) δ 3.00-4.10 (m, 12H, CH2-
CH2 + piperazine); 6.80-7.50 (m, 8H, aromatic); 11.80 (s, 1H,
NH+); 12.00 (s, 1H, NH). Anal. (C19H21N3OS‚1HCl‚1/2H2O) C,
H, N.
6-(2-(4-(2-M e t h o x y p h e n y l)p i p e r a z i n -1-y l)e t h y l)-
ben zoth ia zolin -2-on e Hyd r och lor id e (19). Recrystallized
from H2O (70% yield): mp >250 °C; 1H NMR (DMSO-d6) δ
2.20 (m, 12H, CH2CH2 and piperazine moiety); 3.75 (s, 3H,
OCH3); 6.80-7.50 (m, 7H, aromatic); 11.80 (s, 2H, NH + NH+).
Anal. (C20 H23N3O2S‚1HCl) C, H, N.
6-(2-(4-(3-Tr iflu or om eth ylp h en yl)p ip er a zin -1-yl)eth yl-
)ben zoth ia zolin -2-on e (20). Recrystallized from 1-propanol
to give 1.83 g (45% yield): mp 132 °C; H NMR (DMSO-d6) δ
2.39-3.50 (m, 12H, CH2CH2 + piperazine); 6.96-7.60 (m, 7H,
aromatic); 11.75 (s, 1H, NH). Anal. (C20 H20F3N3OS) C, H,
N.
3-Met h yl-6-(2-(4-p h en yl)p ip er a zin -1-yl)et h yl)b en zo-
th ia zolin -2-on e Hyd r och lor id e (21). Recrystallized from
95% EtOH (77% yield): mp 226-228 °C; 1H NMR (DMSO-d6)
δ 3.20-3.30 (m, 8H, CH2CH2N(CH2)2); 3.35-3.40 (m, 7H,
N(CH2)2 + NCH3); 7.00-7.60 (m, 8H, aromatic); 11.00 (s, 1H,
NH+). Anal. (C20H23N3OS‚1HCl) C, H, N.
3-Me t h yl-6-(2-(4-(2-m e t h oxyp h e n yl)p ip e r a zin -1-yl)-
eth yl)ben zoxa zolin -2-on e (35). Recrystallized from cyclo-
hexane (65% yield): mp 137-138 °C; 1H NMR (CDCl3) δ 2.80
(m, 8H, CH2CH2N(CH2)2); 3.15 (m, 4H, (CH2)2N); 3.40 (s, 3H,
NCH3); 3.90 (s, 3H, OCH3); 6.80-7.20 (m, 7H, aromatic). Anal.
(C21H25N3O3) C, H, N.
1
3-Meth yl-6-(2-(4-(3-tr iflu or om eth ylp h en yl)p ip er a zin -
1-yl)eth yl)ben zoxa zolin -2-on e (36). Recrystallized from
1
cyclohexane (70% yield): mp 110 °C; H NMR (CDCl3) δ 2.70
(m, 8H, CH2CH2N(CH2)2); 3.30 (m, 4H, (CH2)2N); 3.40 (s, 3H,
NCH3); 6.90-7.30 (m, 7H, aromatic). Anal. (C21H22F3N3O2)
C, H, N.
Syn th esis of th e 6-(2-(4-(2-h yd r oxyp h en yl)p ip er a zin -
1-yl)eth yl)ben zoth ia zolin -2-on e Der iva tives (18, 22). The
method adopted for the synthesis of 6-(2-(4-(2-hydroxyphenyl)-
piperazin-1-yl)ethyl)benzothiazolin-2-one (18) is described. A
stirred solution of 4.00 g (0.01 mol) of 6-(2-(4-(2-methoxyphe-
nyl)piperazin-1-yl)ethyl)benzothiazolin-2-one hydrochloride (19)
in 100 mL of a 47% aqueous solution of HBr was heated under
reflux for 48 h. The formed precipitate was filtered, washed
with acetone, and dissolved in 100 mL of H2O. The solution
was made basic with a 20% aqueous solution of NaOH and
extracted with CHCl3. The organic layer was washed with
H2O, dried over CaCl2, and evaporated in vacuo. The residue
was dissolved in dry acetone, and HCl was bubbled to give
the hydrochloride salt which was filtered, dried, and recrystal-
lized from absolute EtOH to give 1.76 g of pure 18 (45%
3-Meth yl-6-(2-(4-(4-flu or op h en yl)p ip er a zin -1-yl)eth yl)-
ben zoth ia zolin -2-on e Hyd r och lor id e (23). Recrystallized
from absolute EtOH (45% yield): mp 232-235 °C; H NMR
1
(DMSO-d6) δ 3.25-3.80 (m, 12H, ArCH2CH2 piperazine); 3.40
(s, 3H, NCH3); 6.70-7.60 (m, 7H, aromatic); 11.90 (s, 2H,
NH+). Anal. (C20H22FN3OS‚2HCl) C, H, N.
3-Me t h yl-6-(2-(4-(2-m e t h oxyp h e n yl)p ip e r a zin -1-yl)-
eth yl)ben zoth ia zolin -2-on e Hyd r och lor id e (24). Recrys-
tallized from MeOH (55% yield): mp >250 °C; 1H NMR
(DMSO-d6) δ 3.10-3.60 (m, 12H, CH2CH2 + piperazine); 3.40
(s, 3H, NCH3); 3.85 (s, 3H, OCH3); 6.95-7.60 (m, 7H, aro-
matic); 11.30 (s, 1H, NH+). Anal. (C21H25N3O2S‚1HCl) C, H,
N.

2016 J ournal of Medicinal Chemistry, 1998, Vol. 41, No. 12
Taverne et al.
yield): mp 164-166 °C; 1H NMR (DMSO-d6) δ 3.00-3.30 (m,
8H, CH2CH2N(CH2)2); 3.50 (m, 4H, (CH2)2N)); 5.80 (s, 1H, NH);
6.75-7.50 (m, 7H, aromatic); 11.20 (s, 1H, OH); 12.00 (s, 1H,
NH+). Anal. (C19H21N3O2S‚1HCl) C, H, N.
3-Me t h yl-6-(2-(4-(2-h yd r oxyp h e n yl)p ip e r a zin -1-yl)-
eth yl)ben zoth ia zolin -2-on e h yd r och lor id e (22). Recrys-
tallized from absolute EtOH (64% yield): mp > 260 °C; 1H
NMR (DMSO-d6) δ 3.10-3.60 (m, 12H, CH2CH2 + piperazine);
3.40 (s, 3H, NCH3); 6.05 (s, 1H, OH); 7.00-7.60 (m, 7H,
aromatic); 11.50 (s, 1H, NH+). Anal. (C21 H25N3O2S‚1HCl) C,
H, N.
Gen er a l P r oced u r e for th e Syn th esis of th e Am i-
n op h en ol Der iva tives (37, 38). The method adopted for the
synthesis of 5-(2-(4-(2-methoxyphenyl)piperazin-1-yl)ethyl)-2-
(methylamino)phenol (37) is described. A mixture of 36.7 g
(0.1 mol) of 3-methyl-6-(2-(4-(2-methoxyphenyl)piperazin-1-yl)-
ethyl)benzoxazolin-2-one (35), 300 mL of 10% aqueous solution
of NaOH, and 150 mL of MeOH was heated under reflux for
3 h. After filtration, the filtrate was made acidic with a 6 N
aqueous solution of HCl and filtered. The filtrate was then
made basic with a 10% aqueous solution of Na2CO3; the
resulting precipitate was filtered, washed with H2O, dried, and
recrystallized from toluene to give 19.40 g of pure 37 (57%
yield): mp 172-174 °C; 1H NMR (DMSO-d6) δ 2.40-2.60 (m,
8H, CH2CH2N(CH2)2); 2.65 (s, 3H, NCH3); 3.00 (m, 4H,
N(CH2)2); 3.75 (s, 3H, OCH3); 6.35-7.90 (m, 7H, aromatic); 9.10
(s, 1H, OH). Anal. (C20H27N3O2) C, H, N.
OCH3); 4.60 (s, 2H, COCH2O); 6.80-7.10 (m, 7H, aromatic).
Anal. (C24H31N3O3) C, H, N.
7-(4-(4-(3-Tr iflu or om eth ylph en yl)piper azin -1-yl)bu tyl)-
4-m eth yl-3-oxo-2,3-d ih yd r o[1,4]ben zoxa zin e (47). Start-
ing from 43, compound 47 was synthesized using the same
procedure as for 17. The hydrochloride salt was obtained by
bubbling HCl in dry acetone, and recrystallization from
absolute EtOH yielded 3.40 g of pure material (70% yield): mp
1
205 °C; H NMR (DMSO-d6) δ 1-60 (m, 4H, CH2CH2); 2.75-
3.50 (m, 15H, ArCH2 + CH2 piperazine + NCH3); 4.60 (s, 2H,
COCH2O); 6.90-7.40 (m, 7H, aromatic); 11.10 (s, 1H, NH+).
Anal. (C24H28F3N3O2‚1HCl) C, H, N.
Bin d in g Stu d ies. 5HT1A Recep tor . Binding was deter-
mined using membranes prepared from bovine hippocampus.
The receptor was labeled with 0.5 nM [3H]-8-hydroxydipropy-
laminotetralin (8-OH-DPAT) by incubation at 25 °C for 30 min
with 11 concentrations of the test compounds (10-9-10-4 M).
Nonspecific binding was determined using 10-5 M buspirone.30
Competition experiments were analyzed using the iterative
nonlinear least-squares curve-fitting program Inplot 4, graph-
pad; IC50 values were calculated using the Cheng-Prusoff
equation.31
5HT1B Recep tor . Binding was determined using mem-
branes prepared from rat frontal cortex. The receptor was
labeled with 2 nM [3H]-5-hydroxytryptamine by incubation at
25 °C for 30 min. Nonspecific binding was determined using
10-5 M propranolol.32 Competition experiments were analyzed
using the iterative nonlinear least-squares curve-fitting pro-
gram Inplot 4, graphpad; IC50 values were calculated using
the Cheng-Prusoff equation.31
5-(2-(4-(3-Tr iflu or om eth ylp h en yl)p ip er a zin -1yl)eth yl)-
2-m eth yla m in op h en ol (38). Recrystallized from MeOH
(59% yield): mp 158-161 °C; 1H NMR (DMSO-d6) δ 3.45-
3.75 (m, 11H, CH2CH2N(CH2)2 + NCH3); 4.20 (m, 4H, N(CH2)2);
4.50 (s, 1H, NH); 7.30-8.50 (m, 7H, aromatic); 9.00 (s, 1H,
OH). Anal. (C20H24N3O) C, H, N.
5HT2A Recep tor . Binding was determined using mem-
branes prepared from bovine frontal cortex. The receptors was
labeled with 0.8 nM [3H]ketanserin by incubation for 30 min
at 37 °C. Nonspecific binding was determined using 10-5
M
7-(4-Br om ob u t yl)-4-m e t h yl-3-oxo-2,3-d ih yd r o[1,4]-
ben zoxa zin e (43). 42 (12.50 g, 0.08 mol) was dissolved in
CF3COOH (70 mL), and under stirring at room temperature,
triethylsilane (39.90 mL, 0.25 mol) was added dropwise. After
20 h, the mixture was poured onto ice. The resulting precipi-
tate was filtered, washed with H2O, dried, and recrystallized
from cyclohexane to give 17.90 g of pure 43 (60% yield): mp
spiperone.33 Competition experiments were analyzed using the
iterative nonlinear least-squares curve-fitting program Inplot
4, graphpad; IC50 values were calculated using the Cheng-
Prusoff equation.31
5HT2C Recep tor . Binding was determined using mem-
branes prepared from pig choroid plexus. The receptor was
labeled with 1.2 nM [3H]-N-methylmesulergine by incubation
at 25 °C for 30 min. Nonspecific binding was determined using
10-5 M mianserine.34 Competition experiments were analyzed
using the iterative nonlinear least-squares curve-fitting pro-
gram Inplot 4, graphpad; IC50 values were calculated using
the Cheng-Prusoff equation.31
D2 Recep tor . Binding was determined using membranes
prepared from bovine striatum. The receptor was labeled with
1.2 nM [3H]raclopride by incubation at 25 °C for 30 min with
11 concentrations of the test compounds (10-9-10-4 M).
Nonspecific binding was determined using 10-5 M spiper-
one.35,36 Competition experiments were analyzed using the
iterative nonlinear least-squares curve-fitting program Inplot
4, graphpad; IC50 values were calculated using the Cheng-
Prusoff equation.31
r1 Recep tor . Binding was determined using membranes
prepared from bovine frontal cortex. The receptor was labeled
with 0.5 nM [3H]prazosin by incubation at 25 °C for 40 min
with 11 concentrations of the test compounds (10-9-10-4 M).
Nonspecific binding was determined using 10-5 M phentola-
mine.37 Competition experiments were analyzed using the
iterative nonlinear least-squares curve-fitting program Inplot
4, graphpad; IC50 values were calculated using the Cheng-
Prusoff equation.31
1
41-42 °C; H NMR (DMSO-d6) δ 1.75 (m, 4H, CH2CH2); 2.50
(t, J ) 6.00 Hz, 2H, ArCH2); 3.50 (t, J ) 6.00 Hz, 2H, CH2Br);
4.60 (s, 2H, COCH2O); 6.80-7.20 (m, 3H, aromatic). Anal.
(C13H16BrNO2) C, H, N.
Gen er a l P r oced u r e for th e Syn th esis of th e 3-Oxo-2,3-
dih ydr o[1,4]ben zoxazin e Der ivatives (44, 45). The method
adopted for the synthesis of 7-(2-(4-(2-methoxyphenyl)piper-
azin-1-yl)ethyl)-4-methyl-3-oxo-2,3-dihydro[1,4]benzoxazine (44)
is described. 37 (3.40 g, 0.01 mol) was dissolved in DMSO (120
mL). Under stirring, 0.68 g (0.01 mol) of sodium ethanolate
was added and then dropwise 1.10 mL (0.01 mol) of ethyl
bromoacetate. The mixture was stirred at room temperature
for 3 h and then poured onto ice water and extracted with
EtOAc. The organic layer was dried over K2CO3, filtered, and
evaporated in vacuo. The resulting oil was recrystallized from
absolute EtOH to give 1.10 g of pure 44 (30% yield): mp 117-
119 °C; 1H NMR (DMSO-d6) δ 3.10-3.40 (m, 11H, CH2CH2N-
(CH2)2 + NCH3); 3.60 (m, 4H, N(CH2)2); 3.80 (s, 3H, OCH3);
4.65 (s, 2H, COCH2O); 6.90-7.10 (m, 7H, aromatic). Anal.
(C22H27N3O3) C, H, N.
7-(2-(4-(3-Tr iflu or om eth ylph en yl)piper azin -1-yl)eth yl)-
4-m eth yl-3-oxo-2,3-d ih yd r o[1,4]ben zoxa zin e Hyd r och lo-
r id e (45). Recrystallized from acetone (30% yield): mp 241-
243 °C; 1H NMR (DMSO-d6)
δ 3.00-3.50 (m, 11H,
CH2CH2N(CH2)2 + NCH3); 3.60-4.00 (m, 4H, N(CH2)2); 4.70
(s, 2H, COCH2O); 6.90-7.10 (m, 7H, aromatic); 11.50 (s, 1H,
NH+). Anal. (C22H24F3N3O2‚1HCl) C, H, N.
7-(4-(4-(2-Meth oxyph en yl)piper azin -1-yl)bu tyl)-4-m eth -
yl-3-oxo-2,3-d ih yd r o[1,4]ben zoxa zin e (46). Starting from
43, compound 46 was synthesized using the same procedure
as for 17 and recrystallized from absolute EtOH to give 2.80
g of pure material (70% yield): mp 90-92 °C; 1H NMR (DMSO-
d6) δ 1.50 (m, 4H, CH2CH2); 2.45-2.70 (m, 8H, ArCH2 + CH2N-
(CH2)2); 3.25 (s, 3H, NCH3); 3.40 (m, 4H, (CH2)2N); 3.80 (s, 3H,
Na tu r e of th e In ter a ction w ith Recep tor s. In Vivo
5HT Beh a vor ia l Syn d r om e in Ra ts. Wistar rats (n ) 6)
are injected with the test compound immediately before test
and are scored for the intensity of forepaw treading on a scale;
The intensity of forepaw treading is expressed as percentage
of the maximal possible score. The 5HT1A agonist 8-OH-DPAT
induces forepaw treading and is used as a reference com-
pound.37
An ta gon ism of h ea d tw itch es induced by L-5-hydrox-
ytryptophane (5HTP) in mice indicates classical antiserotonin-

Potential Atypical Antipsychotics
J ournal of Medicinal Chemistry, 1998, Vol. 41, No. 12 2017
ergic activities.38 Swiss mice were injected with the test
compound before an injection of 5HTP (400 mg/kg ip). The
number of head twiches occurring in a 10 min period starting
10 min after the injection of 5HTP is counted. Cyproheptadine
was used as reference compound.
An ta gon ism of a low d ose of a p om or p h in e in m ice
indicates a classical antidopaminergic activity.39 The intensity
of apomorphine (1 mg/kg sc) induced stereotypies, climbing,
and the rectal temperature were measured 30 min after
apomorphine. Haloperidol was used as a reference compound.
Th e in ter a ction w ith r1 a d r en ocep tor s was assessed in
vitro on rabbit thoracic aorta.40,41 Compounds were tested for
their ability to antagonize the contractile effect of phenyleph-
rine (antagonistic effect) or for their ability to induce a
contractile effect (agonistic effect) which can be blocked with
prazosin.
An ta gon ism of d -Am p h eta m in e-In d u ced Hyp er a ctiv-
ity in Mice a n d Ra ts. Locomotor activity was measured in
Plexiglass chambers. Swiss mice or Wistar rats were pre-
treated with d-amphetamine (4 mg/kg ip) followed by vehicle
or test compounds 30 min after. Data were recorded for 30
min.42 Treatment group means were compared with a Stu-
dent’s t test.
Ster eotyp ies In d u ced by d -Am p h eta m in e in Mice a n d
Ra ts. Swiss mice were pretreated with d-amphetamine (4 mg/
kg ip) and were scored for the intensity of stereotypies on a
4-point scale 30 min later; Wistar rats receive the same dose
of d-amphetamine but observations were carried out every 10
min until the disappearance of the stereotypies.
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Handbook of neurochemistry; Plenum: New York, 1985; pp 331-
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(2) Kane, J . M. Newer antipsychotic drugs. A review of their
pharmacology and therapeutic potential. Drugs 1993, 46, 585-
593.
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