Behavioral approach to nondyskinetic dopamine antagonists: Identification of Seroquel

Article abstract of DOI:10.1021/jm000242+

A great need exists for antipsychotic drugs which will not induce extrapyramidal symptoms (EPS) and tardive dyskinesias (TDs). These side effects are deemed to be a consequence of nonselective blockade of nigrostriatal and mesolimbic dopamine D2 receptors. Nondyskinetic clozapine (1) is a low-Potency D2 dopamine receptor antagonist which appears to act selectively in the mesolimbic area. In this work dopamine antagonism was assessed in two mouse behavioral assays: antagonism of apomorphine-Induced climbing and antagonism of apomorphine-Induced disruption of swimming. The potential for the liability of dyskinesias was determined in haloperidol-Sensitized Cebus monkeys. Initial examination of a few close cogeners of I enhanced confidence in the Cebus model as a predictor of dyskinetic potential. Considering dibenzazepines, 2 was not dyskinetic whereas 2a was dyskinetic. Among dibenzodiazepines, 1 did not induce dyskinesias whereas its N-2-(2-Hydroxyethoxy)ethyl analogue 3 was dyskinetic. The emergence of such distinctions presented an opportunity. Thus, aromatic and N-Substituted analogues of 6-(piperazin-1-yl)-11H-Dibenz[b,e]azepines and 11-(piperazin-1-yl)dibenzo[b,f][1,4]-thiazepines and -Oxazepines were prepared and evaluated. 11-(4-[2-(2-Hydroxyethoxy)ethyl]-piperazin-1-yl)dibenzo[b,f][1,4]thiazepine (23) was found to be an apomorphine antagonist comparable to clozapine. It was essentially nondyskinetic in the Cebus model. With 23 as a platform, a number of N-Substituted analogues were found to be good apomorphine antagonists but all were dyskinetic.

Full text of DOI:10.1021/jm000242+

372
J . Med. Chem. 2001, 44, 372-389
Beh a vior a l Ap p r oa ch to Non d ysk in etic Dop a m in e An ta gon ists: Id en tifica tion of
Ser oqu el
Edward J . Warawa,*,† Bernard M. Migler,‡ Cyrus J . Ohnmacht,† Ann L. Needles,† George C. Gatos,†
Frances M. McLaren,† Cynthia L. Nelson,† and Karen M. Kirkland§
Departments of Medicinal Chemistry, Pharmacology, and Drug Disposition and Metabolism, AstraZeneca Pharmaceuticals LP,
P.O. Box 15437, Wilmington, Delaware 19850-5437
Received J une 6, 2000
A great need exists for antipsychotic drugs which will not induce extrapyramidal symptoms
(EPS) and tardive dyskinesias (TDs). These side effects are deemed to be a consequence of
nonselective blockade of nigrostriatal and mesolimbic dopamine D2 receptors. Nondyskinetic
clozapine (1) is a low-potency D2 dopamine receptor antagonist which appears to act selectively
in the mesolimbic area. In this work dopamine antagonism was assessed in two mouse
behavioral assays: antagonism of apomorphine-induced climbing and antagonism of apomor-
phine-induced disruption of swimming. The potential for the liability of dyskinesias was
determined in haloperidol-sensitized Cebus monkeys. Initial examination of a few close cogeners
of 1 enhanced confidence in the Cebus model as a predictor of dyskinetic potential. Considering
dibenzazepines, 2 was not dyskinetic whereas 2a was dyskinetic. Among dibenzodiazepines, 1
did not induce dyskinesias whereas its N-2-(2-hydroxyethoxy)ethyl analogue 3 was dyskinetic.
The emergence of such distinctions presented an opportunity. Thus, aromatic and N-substituted
analogues of 6-(piperazin-1-yl)-11H-dibenz[b,e]azepines and 11-(piperazin-1-yl)dibenzo[b,f][1,4]-
thiazepines and -oxazepines were prepared and evaluated. 11-(4-[2-(2-Hydroxyethoxy)ethyl]-
piperazin-1-yl)dibenzo[b,f][1,4]thiazepine (23) was found to be an apomorphine antagonist
comparable to clozapine. It was essentially nondyskinetic in the Cebus model. With 23 as a
platform, a number of N-substituted analogues were found to be good apomorphine antagonists
but all were dyskinetic.
In tr od u ction
metabolites (DOPAC and HVA), nor is there an increase
in the number of D2 receptors.9 However, in common
with typical antipsychotics, 1 on chronic dosing in rats
induces depolarization inactivation of dopamine A10
cells, a specific effect observed with all clinically effective
antipsychotics.10,11
The use of conventional antipyschotic drugs in the
treatment of schizophrenia is associated with the oc-
currence of involuntary movements termed extrapyra-
midal symptoms (EPS) and tardive dyskinesias (TDs).
These drugs share a common pharmacological action.
As dopamine antagonists they diminish the functioning
of dopamine neurons.
Since a mechanism other than dopamine blockade for
the efficacy of 1 has not been elaborated, our initial
approach to an antipsychotic with minimal or no li-
ability to produce TDs or EPS was to identify novel
compounds12 which, comparably to 1, potentiated gnaw-
ing in mice while inhibiting apomorphine-induced climb-
ing.13 As a measure of the potential for such compounds
to induce dyskinesias, a neurochemical assessment of
striatal dopamine D2 receptor upregulation following
chronic administration to rats was made. Here, we
experienced a dichotomy. The identified antagonists
were well-tolerated, and high doses could be used unlike
the dosage of 1 which was limited by toxicity. At these
high doses, increases in striatal D2 receptor numbers
were observed whereas no increases occurred at the
highest “tolerated” dose of 1. This amibiguity was
resolved with the haloperidol-sensitized Cebus monkey
dykinesia model14 where comparable doses of the com-
pounds of interest and clozapine could be administered.
Only 1 proved to be nondyskinetic in the Cebus model,
and we concluded that the nondyskinetic characteristic
of 1 was not associated with its ability to potentiate
apomorphine stereotypy.
Clozapine1 (1) emerged as an effective antipsychotic
which does not induce TDs, is relatively free of other
EPS, and has superior efficacy2 in patients which are
refractory to other antipsychotic drugs. It is referred to
as an atypical antipsychotic. A significant obstacle to a
wider use of clozapine, however, is the increased risk
of agranulocytosis.3,4
The weak antidopaminergic effects of 1 tend to
undermine the hypothesis of a hyperdopaminergic state
in schizophrenia. For example, in rats 1 does not
antagonize5 apomorphine-induced stereotypy, a behav-
ior which constitutes a classical assay6 for dopamine
antagonists. In fact, 1 was observed to antagonize
apomorphine-induced climbing in mice while, at the
same time, eliciting gnawing.7,8 The ability of 1 to
influence striatal dopamine neurons differs from that
of typical antipsychotics. Chronic dosing of rats with 1
does not result in tolerance to increases in dopamine
* To whom correspondence should be addressed. Tel: 302-633-3300.
Fax: 302-633-3301. E-mail: kcassoc@inet.net.
† Department of Medicinal Chemistry.
In this paper, we present the results of our subse-
quent behavioral approach to identify nondyskinetic
‡ Department of Pharmacology.
§ Department of Drug Disposition and Metabolism.
10.1021/jm000242+ CCC: $20.00 © 2001 American Chemical Society
Published on Web 01/03/2001

Nondyskinetic DA Antagonists: Seroquel
J ournal of Medicinal Chemistry, 2001, Vol. 44, No. 3 373
Ta ble 1. Activity of 4-Methylpiperazin-1-yl Analogues
dose (mg/kg)
compd
X
R1
H
R2
test
route
veh + apo
2.5
5
10
20
40
80
D2 affinityd
2
CH2
H
climbinga
ip
po
22
23
23
23
22
24
23
23
22
22
25
23
22
21
0.5
23
0
9** 9**
7**
9**
20 ns
0**
2**
16*
0
3**
18
0**
3**
0**
9**
IC50 2700 nM
20
24
po + SKF525A
4
5
O
S
H
H
H
H
climbing
climbing
ip
po
19
19
25
21
23
13** 2**
13** 10**
19
3**
3**
19
27%
35%
po + SKF525A
24
climbing
ip
14** 3**
ip + SKF525A
21
21
23
18 ns
8**
18 ns
po
po + SKF525A
6
7
8
9
CH2 Cl
O
H
H
H
OH
climbing
climbing
climbing
climbing
swimmingb
climbing
swimming
ip
ip
ip
ip
ip
ip
ip
24
20
25
14
18
40%
48%
46%
Cl
Cl
H
S
CH2
19
1
18
3
7**
7**
13** 1**
0**
20**
2**
42**
1**
10
S
S
H
H
OH
F
IC50 49 nM
10** 34**
32**
Cebus monkeyc po
climbing
swimming
3/3
18
1
11
ip
ip
21
0
13
2
5** 1** IC50 963 nM
9**
3
a
b
Antagonism of apomorphine-induced climbing in mice, N ) 20; score ) mean rung height of a possible 27 rungs. Antagonism of
apomorphine-induced disruption of swimming in mice, N ) 20; score ) mean number of 180° swims. c Number of monkeys showing
dyskinesias/number of monkeys tested. dD2 affinity: % displacement of spiropiperidone at 1000 nM unless otherwise indicated. IC50
values were determined using a minimum of five concentrations of each compound in triplicate. Each value represents the mean from
two replicate experiments which differ by (5% or less. Statistics: comparison of means (drug-treated to vehicle-treated) made using
Student’s t-test *p < 0.05, **p < 0.01.
dopamine antagonists which led to the discovery of the
antipsychotic seroquel (23).15 The potential for the
liability of dyskinesias in this program was determined
in haloperidol-sensitized Cebus monkeys.16,17 Our con-
fidence in the Cebus model as a predictor of dyskinetic
potential was strengthened upon examination of a few
known close congeners of 1. Perlapine (2), a clinical
predecessor of 1, was reported to have practically no
antipsychotic efficacy.18 However, Wilks and Stanley19
found that 2 elevated the dopamine metabolite HVA in
rats and suggested that it be reevaluated in the clinical
setting. In the Cebus model, we found that 2 did not
induce any dyskinesias.
2a was reported to be a clinically effective antipsy-
chotic20 but prone to the induction of seizures. When
given to two Cebus monkeys at 20 mg/kg po, 2a induced
dyskinesias in both monkeys. Thus, in the “dibenz-
azepine” class of potential antipsychotics, there exists
a dyskinetic and a nondyskinetic agent. The potential
antipsychotic 321 produced severe dyskinesias in three
of six monkeys given 40 mg/kg po. So, in the “dibenzo-
diazepine” class there is the nondyskinetic 1 and dys-
kinetic 3. Since such distinctions exist and can be
determined by the Cebus model, an opportunity was
presented for the further identification of nondyskinetic
dopamine antagonists in the aforementioned chemical
classes.
Resu lts a n d Discu ssion
Target compounds are shown in Tables 1-4. The
assessment of dopamine antagonism was made in
rodent models. The primary assays entailed antagonism
of the effects of apomorphine in mice (see the Experi-
mental Section). Initially, this involved the antagonism
of apomorphine-induced climbing behavior. Mice treated
with apomorphine will climb to near the top of the
climbing cages and remain there during most of the
observation period. This climbing can be antagonized
in a dose-related manner with dopamine antagonists.
Later in the program, the antagonism of apomorphine-
induced disruption of swimming was also used. Mice will
normally score 16-20 swims around a circular tank in
2 min. Apomorphine-treated mice fail to swim and
remain in place, pawing the walls of the swimming
chamber, or make abortive swims. Dopamine antago-

374 J ournal of Medicinal Chemistry, 2001, Vol. 44, No. 3
Ta ble 2. Activity of Thieno[3,2-c][1]benzazepines
Warawa et al.
dose (mg/kg)
veh +
D2
compd
R
test
route
ip
apo
2.5
5
10
20
20
40
80
affinityc
12
Cl
climbinga
23
1**
2**
3**
60% at
250 nM
Cebus monkeyb
climbing
po
ip
1/2
13
H
24
21
7**
a
b
Antagonism of apomorphine-induced climbing in mice, N ) 20; score ) mean rung height of a possible 27 rungs. Number of monkeys
c
showing dyskinesias/number of monkeys tested. D2 affinity: % displacement of spiropiperidone at 1000 nM unless indicated otherwise.
Statistics: comparison of means (drug-treated to vehicle-treated) made using Student’s t-test *p < 0.05, **p < 0.01.
nists will “normalize” the swimming behavior of such
mice. We believe this new test to be more predictive of
potential antipsychotic activity in humans. The climbing
test lacks specificity since nonantipsychotics agents can
antagonize it (sedation, toxicity).
Actives in the above tests were administered at
various doses to haloperidol-sensitized Cebus monkeys
which were observed over a 6-7-h period for dyskine-
sias. With compounds prone to dykinesias, the dose
which generally evoked the most frequent reactions was
20 mg/kg po. The antagonists were also characterized
by ancillary neurochemical22 and electrophysiological23
methods. The former included the displacement of
labeled spiroperidol for D2 affinity, and the latter
invoked the reversal of amphetamine-suppression of
spontaneous cell firing.
The ability of N-methylpiperazines of the dibenz[b,e]-
azepine, dibenz[b,f][1,4]oxazepine, and dibenzo[b,f][1,4]-
thiazepine classes to antagonize apomorphine-induced
climbing in mice is shown in Table 1. Prominent here
were 2, 4, and 5, all of which bear unsubstituted
aromatic rings. The chlorinated analogues 6-8 are
substituted analogously to 1 and 2a but are essentially
inactive in the apomorphine model. These results sug-
gested the possibility that in vivo metabolites of 2, 4,
and 5 could be the active agents, formation of which is
inhibited by chlorination. From metabolic studies on
loxapine,24 it is known that the 7- and 8-positions are
hydroxylated in the rat. In mice pretreated with SKF
525A (a cytochrome P450 inhibitor),25 the ability of 2
and 4 to antagonize apomorphine-induced climbing was
essentially suppressed and that of 5 was considerably
attenuated (Table 1). After oral administration of 2 to
rats, a major metabolite was observed in extracts of
blood and urine by HPLC and the same substance was
also the major drug-related extractable component in
rat brain tissue (Kirkland, unpublished information).
This metabolite proved to be 9 (2-hydroxy 2, synthesis
of which is described herein) which antagonized apo-
morphine-induced effects to the same degree as 2. Thus,
it appears likely that 2 requires metabolism to 9 for
effective dopamine antagonism in rodents. If mammals
do not metabolize 2 to 9, then the perlapine/dopamine
hypothesis story requires reevaluation. We did not
undertake Cebus experiments to clarify this situation.
The activity of 5 in mice treated with SKF 525A
appeared not to have been completely blocked, suggest-
ing that unmetabolized 5 might have intrinsic activity.
This intrinsic level of activity was somewhat approached
by that of the 7-fluoro analogue 11 (D2 IC50 960 nM).
However, much of the activity of 5 must still be
attributed to a metabolite since 10 (7-hydroxy 5, D2 IC50
49 nM) was just as potent in the behavioral mouse
assays. Three monkeys treated with 10 at 10 mg/kg po
exhibited dyskinesias.
Replacement of the N-methyl in the thieno[3,2-c][1]-
benzazepine 2a by a 2-(2-hydroxyethoxy)ethyl moiety
gave 12 (Table 2) which was a good antagonist of
apomorphine-induced climbing but was also dyskinetic.
The deschloro analogue 13 was a much weaker antago-
nist.
Replacement of the N-methyl in 2 by a 2-(2-hydroxy-
ethoxy)ethyl moiety gave 14 which lacked potency but
was efficacious at 80 mg/kg ip (Table 3). It produced
long-lasting sedation without dyskinesias in nine sen-
sitized Cebus monkeys at 80 mg/kg po. The 2-hydroxy
analogue 15 was also only active at 80 mg/kg ip,
considerably weaker than 9, and was dyskinetic. The
3-chloro analogue 16 displayed better activity in an-
tagonizing apomorphine-induced climbing. In contra-
distinction to the thieno[3,2-c][1]benzazepine 12, seven
monkeys treated with 16 at 80 mg/kg po showed no
dyskinesias and were clearly sedated. Interest in this
series waned, however, when lethality was observed in
rats upon chronic dosing.
Of the corresponding dibenz[b,f][1,4]oxepines 17 and
18, only 17 antagonized apomorphine-induced climbing
at 40 mg/kg ip and two of three monkeys given 20 mg/
kg po exhibited moderate dyskinesias.
Replacement of the N-methyl of the inactive 8-chlorodi-
benzo[b,f][1,4]thiazepine 8 by a 2-(2-hydroxyethoxy)-
ethyl moiety gave 19 which by the ip route exhibited
the same degree of apomorphine antagonism as 16. No
dyskinesias was induced when 19 was administered at
20, 40, and 80 mg/kg po. At the highest dose, six
monkeys were clearly sedated and six were slightly
sedated. Also, 19 in rats reversed the amphetamine
suppression of A10 firing, 0.87 mg/kg iv being the
minimal effective dose to cause a 50% or greater
reversal compared to 0.50 mg/kg iv for clozapine.
Despite these good prognostications, 19 in mice by oral
administration did not antagonize the effects of apo-
morphine and in rats at 40 mg/kg po only marginally
increased DOPAC and HVA.

Nondyskinetic DA Antagonists: Seroquel
J ournal of Medicinal Chemistry, 2001, Vol. 44, No. 3 375
Ta ble 3. Activity of 4-[2-(2-Hydroxyethoxy)ethyl]piperazin-1-yl Analogues
dose (mg/kg)
compd
14
X
R1
R2
R3
H
test
route
veh + apo
10
20
40
80
D2 affinityd
22%
CH2
H
H
climbinga
ip
23
23
1
21
24
1
17
17
1
2**
10**
3**
0/9
1**
14**
po
po
po
ip
ip
po
ip
po
po
po
ip
ip
po
ip
swimmingb
Cebus monkeyc
climbing
swimming
Cebus monkey
climbing
15
16
CH2
CH2
H
OH
H
H
H
26
0.4
22
5
25%
2/3
19
Cl
23
25
0.4
6**
26
1
0/2
0**
4
2**
1**
2**
0/7
IC50 1000 nM
swimming
Cebus monkey
climbing
swimming
Cebus monkey
climbing
0/2
17
2
17
O
Cl
H
H
23
1.4
54% at 250 nM
2/3
18
19
O
S
H
H
H
H
H
23
0
23
23
1.2
17
1
8**
24
1
0/4
14*
0/4
8**
11**
8**
0**
16*
1
0/12
6**
0/2
2**
23
16%
58%
swimming
climbing
ip
ip
Cl
20
12**
25
1
0/2
16
0/2
9**
po
po
po
ip
po
ip
po
ip
po
po
ip
ip
ip
po
po
po
ip
ip
po
ip
ip
ip
ip
ip
ip
swimming
Cebus monkey
climbing
Cebus monkey
climbing
20
21
S
S
F
H
F
H
H
24
34%
H
20
23
1
14
1
IC50 560 nM
swimming
1
8**
0/2
18**
2
0
Cebus monkey
climbing
swimming
climbing
1/5
3/12
22
23
S
S
H
H
H
H
F
24
0
23
18
1.6
22
0
0**
8**
18**
0%
H
15
18
3
2/13
5**
17**
2**
14
11*
0/4
0**
31**
IC50 330 nM
19
3
1/13
27
5**
5/6
swimming
Cebus monkey
climbing
swimming
Cebus monkey
climbing
swimming
climbing
swimming
climbing
24
S
H
OH
H
25
0.3
IC50 166 nM
24%
25
S
OH
H
H
H
H
H
H
H
25
0
22
0
24
0
18
1.6
24
0
23
0
23
0
0**
15**
26
SO
SO2
27
H
swimming
climbing
swimming
Cebus monkey
clozapine
po
po
po
23
4
0/13
19
3
0/13
5**
13**
0/11
IC50 132 nM
a
b
Antagonism of apomorphine-induced climbing in mice, N ) 20; score ) mean rung height of a possible 27 rungs. Antagonism of
apomorphine-induced disruption of swimming in mice, N ) 20; score ) mean number of 180° swims. c Number of monkeys showing
dyskinesias/number of monkeys tested. Statistics: comparison of means (drug-treated to vehicle-treated) made using Student’s t-test *p
d
< 0.05, **p < 0.01. D2 affinity: % displacement of spiropiperidone at 1000 nM unless otherwise indicated. IC50 values were determined
using a minimum of five concentrations of each compound in triplicate. Each value represents the mean from two replicate experiments
which differ by (5% or less.
As measured in mouse climbing, the 8-fluorinated 20
was an antagonist comparable to 19. The profile of the
7-fluorinated 21 (D2 IC50 560 nM; A10 MED50 0.75 mg/
kg iv) was similar to that of 19, but it was dyskinetic.
The 6-fluorinated 22 was not active.
treated at 20 mg/kg po showed dyskinesias of weak
intensity which lasted 10 s in one and 20 min in the
other. The hydroxylated analogues 24 and 25 were also
evaluated. As in the case of 10, the 7-hydroxylated 24
was a potent antagonist (D2 IC50 166 nM) which induced
dyskinesias in five of six monkeys at 20 mg/kg po. The
8-hydroxylated 25 was not a dopamine antagonist.
The sulfoxide 26 and the sulfone 27 also were not
behavioral dopamine antagonists.
Following on the activity of 23, other N-substituted
analogues were investigated. Piperazines with N-sub-
stituents derived from various ethers, cyclic ethers,
Since the dibenz[b,e]azepine 14 without aromatic
substitutions had efficacy but lacked potency, the
analogous dibenzo[b,f][1,4]thiazepine 23 was synthe-
sized. As shown in Table 3, 23 (D2 IC50 330 nM) by the
oral route had comparable activity in the swimming
paradigm to that of clozapine. Moreover, this compound
was essentially nondyskinetic. Two of 13 monkeys

376 J ournal of Medicinal Chemistry, 2001, Vol. 44, No. 3
Ta ble 4. Activity of N-Substituted Analogues
Warawa et al.
dose (mg/kg)
compd
R
test
route veh + apo 2.5
5
10
20
40
80
D2 affinityd
28
-CH2CH2OH
climbinga
ip
ip
po
ip
ip
ip
ip
ip
24
0.4
24
3
2/3
6**
18** 28**
1**
IC50 1330 nM
swimmingb
Cebus monkeyc
climbing
29
30
31
-(CH2)2O(CH2)2O(CH2)2OH
-CH(CH2OCH3)2
19
0.3
22
0
20
2
14
3**
3**
12**
19
IC50 1394 nM
4%
swimming
climbing
swimming
climbing
0
21
18
5**
9**
1**
2**
0**
IC50 795 nM
swimming
Cebus monkey
climbing
ip
po
ip
0.3
22
5**
17** 28** 33**
1/2
1/2
32
19
1**
10%
swimming
ip
ip
ip
po
ip
0.2
23
0
3
0**
20** 32**
5/5
13**
33
34
-CH2CH2CH(OCH3)CH2OCH3 climbing
21
2
0/5
19
5**
8**
0**
IC50 293 nM
IC50 755 nM
swimming
Cebus monkey
climbing
21
21
0
8**
2**
1**
swimming
Cebus monkey
climbing
ip
po
ip
0.4
2
6**
2/2
22** 32**
35
36
24
21
IC50 1640 nM
swimming
climbing
ip
ip
0
21
0
0**
18
7**
4%
swimming
Cebus monkey
climbing
ip
po
ip
0
0
8**
4/4
2**
27**
37
22
14** 6**
1**
0**
50%
swimming
Cebus monkey
climbing
ip
po
ip
0
8**
13** 20** 20** 30**
2/3
38
19
21
9**
2**
7**
1**
IC50 417 nM
swimming
Cebus monkey
ip
po
0
1
7**
16** 26** 37**
2/2
a
b
Antagonism of apomorphine-induced climbing in mice, N ) 20; score ) mean rung height of a possible 27 rungs. Antagonism of
apomorphine-induced disruption of swimming in mice, N ) 20; score ) mean number of 180° swims. c Number monkeys showing
dyskinesias/number of monkeys tested. dD2 affinity: % displacement of spiropiperidone at 1000 nM unless otherwise indicated. IC50
values were determined using a minimum of five concentrations of each compound in triplicate. Each value represents the mean from
two replicate experiments which differ by (5% or less. Statistics: comparison of means (drug-treated to vehicle-treated) made using
Student’s t-test *p < 0.05, **p < 0.01.
alcohols, and combinations thereof, were prepared and
incorporated into compounds shown in Table 4. While
many of these exhibited good potency as apomorphine
antagonists, none was nondyskinetic. Some structure-
activity (SAR) features could be discerned. Branching
at the R-carbon as in 30 and 35 resulted in loss of
activity. Ethers and alcohols could be equipotent as in
31 and 34. Chiral 32 was much weaker than racemic
31, indicating a preference for the R-configuration.
were obtained by reacting the requisite imino chloride
with the appropriate piperazine. The imino chlorides
were derived from the corresponding lactams following
literature precedents using phosphorus oxychloride and
were used as either toluene or xylene extracts or were
isolated prior to dissolution. A few amidines were
prepared from imino thioethers which were obtained by
reacting the lactam with Lawsson’s reagent followed by
S-methylation with dimethyl sulfate.
The lactams in Schemes 1 and 2 were prepared from
isocyanates which were derived from anilines using
trichloromethyl chloroformate. Those in Scheme 3 were
Ch em istr y
All of the targeted compounds are amidines. Most

Nondyskinetic DA Antagonists: Seroquel
J ournal of Medicinal Chemistry, 2001, Vol. 44, No. 3 377
Sch em e 1
of 2-chloro-5-fluoronitrobenzene with thiophenoxide fol-
lowed by reduction of the nitro functionality gave aniline
50 which was processed to the lactam 51.
The preparation of the hydroxydibenzothiazepines 10,
24, and 25 from appropriately substituted nitrobenzenes
is shown in Scheme 3. Reaction of 4-benzyloxy-2-
bromonitrobenzene (46) with thiosalicylic acid using
sodium hydride in dimethylacetamide followed by treat-
ment with iodomethane gave the nitro ester 47. An
alternate procedure, in which the disodium salt of
thiosalicylic acid was generated from sodium methoxide
in methanol, taken to dryness, and then reacted with
46 in DMAC, resulted in a byproduct (10%) from ipso
displacement of the benzyloxy by sodium methoxide.
The nitro ester 52 was prepared by the sodium meth-
oxide route. Reduction of these nitro esters with stan-
nous chloride gave the anilino esters 48 and 53 which
were converted to the lactams 49 and 54 using tri-
methylaluminum. The imino chloride from 7-benzyloxy
lactam 49 was reacted with N-methylpiperazine and
debenzylated with HBr in acetic acid to 10. It was also
reacted with 1-[2-(2-hydroxyethoxy)ethyl]piperazine and
debenzylated with HBr in acetic acid which resulted in
concomitant acetylation of the alcohol functionality.
Following the sequence of hydrolysis with KOH, acidi-
fication with HCl, and basification with bicarbonate, 24
was obtained. It exhibited poor solubility, requiring a
large volume of chloroform for extraction. The 8-ben-
zyloxy lactam 54 was also reacted with 1-[2-(2-hydroxy-
ethoxy)ethyl]piperazine via the imino chloride. Follow-
ing the debenzylation and hydrolysis sequence as used
for 24, there was obtained 25 which was readily soluble
in chloroform.
prepared by intramolecular aminolysis of anilino esters.
In the preparation of the 2-hydroxydibenzazepines 9 and
15 (Scheme 1), the precursor phenolic lactam was
converted to the acetate 41 prior to reaction with POCl3.
Subsequent reaction with the piperazines gave the
amidines with concurrent removal of the acetyl.
Preparations of the monofluorinated dibenzothiaz-
epines 11 and 20-22 are indicated in Scheme 2. The
7-fluorodibenzothiazepines 11 and 21 were obtained
from 4-fluoroaniline. Ortholithiation of the tert-butoxy
carbamate using tert-butyllithium followed by sulfeny-
lation with S-phenyl benzenethiosulfonate gave car-
bamate 42 and subsequently aniline 43. 6-Fluorodiben-
zothiazepine 22 was obtained by the same process
starting from 3-fluoroaniline. Sulfenylation at the 2-po-
sition gave 55 and ultimately the aniline 56. Reaction
The other N-substituted piperazines used in our
studies were prepared from either N-benzylpiperazine
Sch em e 2

378 J ournal of Medicinal Chemistry, 2001, Vol. 44, No. 3
Warawa et al.
Sch em e 3
or N-carbethoxypiperazine as shown in Scheme 4. With
the exception of 61 which has the S-absolute configu-
ration, all the piperazines were racemates. 67 is a single
diastereomer of the cis-configuration.
Periodate oxidation of 23 gave sulfoxide 25 as two
conformational entities (TLC Rf’s 0.10 and 0.30). Heat-
ing this mixture in toluene resulted in the lower Rf
material being converted to the higher, presumably
through resonance involving the piperazine nitrogen.
withdrawal. It remains to be determined if the same
can be said for 23. The atypicality of 23 has been
demonstrated by its ability to elict long-term improve-
ment in psychotic symptoms in Parkinson’s disease
patients without causing a deterioration of the motor
symptoms.30 A particular clinical advantage of 23 over
other antipyschotics is the freedom from EPS and lack
of plasma prolactin elevation over its entire antipsy-
chotic dose range.31
Exp er im en ta l Section
Con clu sion
Melting points were determined on a Thomas-Hoover capil-
lary melting point apparatus and are uncorrected. 1H NMR
spectra were recorded on Brucker AM 300 (300 MHz), Brucker
WM 250 (250 MHz), and Brucker N80 (80 MHz) instruments,
and chemical shifts are reported in δ units with tetramethyl-
silane as an internal standard. Mass spectra were recorded
on a Kratos MS-80 instrument. Combustion analysis were
performed on a Perkin-Elmer 241 instrument. Chromato-
graphic purification refers to flash chromatography conducted
on Keiselgel 60 (230-400 mesh) supplied by E. Merck. Silica
gel GHLF (250-µm) plates supplied by Analtech were used for
thin-layer chromatography (TLC).
Gen er a l Meth od s for th e P r ep a r a tion of Requ isite
Im in o Ch lor id es. Intermediate imino chlorides were pre-
pared by refluxing the appropriate lactam with POCl3, removal
of the excess POCl3, and workup by one of two methods. In
method A, the imino chloride was isolated by extraction, the
solution was dried (MgSO4)), the solvent was removed, and the
imino chloride was redissolved in an appropriate solvent for
subsequent reaction with an appropriate piperazine. In method
B, the extraction solvent (xylene or toluene) was dried (MgSO4)
and filtered, and the solvent was concentrated to an appropri-
ate volume for use in the subsequent reaction.
It is our belief that the sensitized Cebus monkey
model is currently the most predictive test for EPS and
possibly TDs of neuroleptics. 1 does not produce dyski-
nesias in this model. We were struck by the fact that
nearly all of our apomorphine antagonists induced
unacceptable dyskinesias. Only 23 emerged with a
profile most closely resembling that of 1, and it was
progressed through additional tertiary behavioral as-
says.26 It must be noted that this behavioral profile
translated to a neurochemical22 and electrophysiologi-
cal23 profile like that of 1, both compounds showing a
prediliction for blockade of the mesolimbic (A10) D2
dopamine receptors. As shown, even the use of 23 as a
platform resulted in only dyskinetic analogues.
A nondyskinetic compound being a rarity may imply
that it is such by virtue of another pharmacological
property. Chronic administration of 1 and 23 resulted
in much smaller increases in ∆FosB-like immunoreac-
tivity in the striatum than produced by haloperidol
(dramatic increase).27 It has also been shown28 that the
acute increase of striatal Fos expression by haloperidol
can be significantly attenuated by pretreatment with 1.
Indeed, the proposal29 has been made that 1 is an
antidyskinetic agent since it shows marked efficacy in
TDs of all types and there is no rebound occurrence upon
Meth od A: 7-Ben zyloxy-11-ch lor od iben zo[b,f][1,4]th ia -
zep in e (see 10). A solution of 49, 1.84 g (5.5 mmol), 10 drops
of N,N-dimethyaniline and 20 mL of POCl3 was stirred and
heated in an oil bath at 125 °C. After 1 h, TLC analysis (2%
CH3OH-CH2Cl2) indicated the absence of 49 (Rf 0.33). Con-
centration in vacuo yielded a residue which was treated with

Nondyskinetic DA Antagonists: Seroquel
J ournal of Medicinal Chemistry, 2001, Vol. 44, No. 3 379
Sch em e 4
ethyl acetate and ice, followed by dilution with water. The
ethyl acetate extract was washed with brine and dried
(MgSO4). Remova1 of solvent in vacuo gave 1.67 g of the titled
imino chloride; TLC analysis (ibid) indicated a single compo-
nent, Rf 0.70.
1 1 -( 4 -M e t h y l p i p e r a z i n -1 -y l ) d i b e n z o [b ,f ] [ 1 ,4 ] -
th ia zep in e (5). This compound was made by the method of
Schmutz et al.33 The hydrochloride salt was prepared in ether
with ethereal HCl: mp 169-171 °C. Anal. (C18H19N3S‚2HCl‚
0.25H2O) C,H,N,Cl.
3-Ch lor o-6-(4-m et h ylp ip er a zin -1-yl)-11H -d ib en z[b,e]-
a zep in e (6). This compound was made by the procedure of
Hunziker et al.:32 mp 200-201.5 °C (lit. mp 202-204 °C). Anal.
(C19H20ClN3) C,H,N.
8-Ch lor o-11-(4-m et h ylp ip er a zin -1-yl)d ib en z[b,f][1,4]-
oxa zep in e (7). This compound was made by the procedure of
Schmutze et al.:33 mp 163.5-165 °C (lit. mp 165-166 °C); m/z
327. Anal. (C18H18ClN3O) C,H,N.
Meth od B: 3,6-Dich lor od iben z[b,e]a zep in e (see 16). A
solution of 4.0 g (16.5 mmol) of 3-chloro-5,6-dihydrodibenz-
[b,e]azepin-6-one and 1.5 mL of N,N-dimethylaniline in 60 mL
POCl3 was refluxed for 8 h. After concentration in vacuo, the
residue was partitioned between 125 mL xylene and ice/water.
The organic extract was washed with 1 N HCl, water, saline
and dried (MgSO4). This solution was concentrated to 40 mL
and used without further purification.
6-(4-Meth ylp ip er a zin -1-yl)-11H-d iben z[b,e]a zep in e (2).
This compound was made by the procedure of Hunziker et al.:
mp 135-137 °C (lit. mp 136-138 °C). Anal. (C19H21N3)
C,H,N.
11-(4-Met h ylp ip er a zin -1-yl)d ib en z[b,f][1,4]oxa zep in e
(4). The base was made by the procedure of Schmutze et al.;33
m/z 327. An ethereal solution of this base was treated with
ethereal HCl to give a white hydroscopic solid which was dried
at 60 °C at 10 mmHg: mp 160-170 °C. Anal. (C18H19N3O‚
1.5HCl‚1.5H2O) C,H,N,Cl.
8-Ch lor o-11-(4-m eth ylp ip er a zin -1-yl)d iben zo[b,f][1,4]-
th ia zep in e (8). This compound was made by the method of
Schmutz et al.33 and was isolated by column chromatography
using 5% methanol-methylene chloride: mp 162-163 °C (lit.
mp 166-167 °C). Anal. (C18H18ClN3S) H,N,C: calcd, 62.87;
found, 62.33.
2-Hyd r oxy-6-(4-m eth ylp ip er a zin -1-yl)-11H-d iben z[b,e]-
a zep in e (9). Lactam 41, 0.85 g (3.18 mmol), 0.23 g of N,N-
dimethylaniline and 6.4 mL of POCl3 were heated to reflux
for 2.5 h (method A, CH2Cl2) to give the imino chloride. TLC
32

380 J ournal of Medicinal Chemistry, 2001, Vol. 44, No. 3
Warawa et al.
analysis (2% CH3OH-CH2Cl2) indicated a single component
with Rf 0.65. This material was treated with 3.2 mL of xylene
and 0.96 g (9.54 mmol) of N-methylpiperazine and the mixture
was heated in an oil bath at 165 °C for 19 h. After cooling, the
viscous residue was stirred with ether which was then
decanted from an insoluble gum. After washing the ether
extract with water, a solid began to separate and this was
further promoted by cooling the extract in an ice bath.
Filtration and drying gave 0.46 g of a tan solid, homogeneous
by TLC (10% CH3OH-CH2Cl2) with Rf 0.45.
thiolactam (TLC, Rf 0.89, 3% MeOH-CH2Cl2), void of the
starting lactam (TLC, Rf 0.24). Flash chromatography on silica
gel with methylene chloride gave 1.30 g of an orange solid. To
0.66 g of this material in 7.4 mL dioxane was added 0.79 g of
powdered KOH in 4.5 mL methanol. This solution was treated
with 0.70 mL (7.44 mmol) of dimethyl sulfate and stirred at
ambient temperature for 70 min. The solvent was removed in
vacuo and the residue was partitioned between water and
chloroform which was dried (MgSO4). Concentration in vacuo
gave 0.66 g of a brown solid, essentially homogeneous by TLC
(20% ether-hexane, Rf 0.66): 1H NMR (80 MHz, CDCl3) 2.66
(3H, SCH3).
The above solid, 220 mg, was dissolved in ethanol and
treated with 84 mg (0.72 mmol) of fumaric acid whereupon a
solid began to form. Cooling followed by filtration gave 170
mg of a white solid. This material was recrystalized from
ethanol by effecting solution with 100 mL of hot ethanol and
concentration to 20 mL where precipation began. The resulting
solid was dried in a drying pistol over refluxing methanol at
The above imino thioether, 0.65 g (2.47 mmol), 1.23 g (7.08
mmol) of 1-[2-(2-hydroxyethoxy)ethyl]piperazine and 2 drops
of acetic acid were held at 140 °C (oil bath) for 21 h and then
partitioned between methylene chloride and water. The or-
ganic extract was washed well with water and brine, dried
(MgSO4) and concentrated in vacuo to give 0.90 g of a foam.
Purification by silica gel column chromatography using 7%
methanol-methylene chloride afforded 0.64 g of a yellow solid.
Trituration with hot petroleum ether followed by filtration and
drying in vacuo gave 0.54 g, homogeneous by TLC (8% CH3-
1
10 mTorr: 122 mg; mp 258.5-259.5 °C; H NMR (250 MHz,
CH3OH-d4) 6.91-6.94 (1H, CHdCH). Anal. (C19H21N3O‚
0.5C4H4O4‚0.25H2O) C,H,N.
7-Hydr oxy-11-(4-m eth ylpiper azin -1-yl)diben zo[b,f][1,4]-
th ia zep in e (10). The imino chloride was made from 1.00 g
(3.0 mmol) of 49, 10 drops of N,N-dimethylaniline and 8 mL
of POCl3 (method A, ethyl acetate). This solid was treated with
7 mL of xylene and 1.1 mL of N-methylpiperazine and the
solution was heated in an oil bath at 140 °C under nitrogen
for 19 h and paritioned between dilute K2CO3 and ethyl acetate
which was then dried (MgSO4). Removal of solvent in vacuo
gave 1.25 g of a glass which by TLC (10% CH3OH-CH2Cl2)
showed a major component at Rf 0.50 and a minor impurity
in the solvent front. This material was chromatographed on
42 g of silica gel using 10% methanol-methylene chloride:
1.11 g; m/z 416 (M + H)+; 1H NMR (300 MHz, CDCl3) 2.33 (s,
3H, NCH3), 4.96 (s, 2H, OCH2Ar).
To this material in 5 mL of glacial acetic acid was added 5
mL of 30% HBr in acetic acid and the flask was stoppered.
After stirring for 2 h, TLC analysis (10% CH3OH-CH2Cl2)
showed only a trace of starting material and a major compo-
nent with Rf 0.20. The content of the flask was added to 200
mL of ether. The resulting solid was collected by filtration and
dissolved in water which was made alkaline with NaHCO3 and
extracted with ethyl acetate. After drying, the solvent was
removed in vacuo to give 0.90 g. Chromatography on 50 g silica
gel with 10% methanol-methylene chloride elution gave 0.83
g of a light brown amorphous material which was triturated
with ether and dried in a drying pistol over refluxing methanol
at 5 mTorr: 0.64 g; mp 204-206 °C. Anal. (C18H19NOS) C,H,N.
7-F lu or o-11-(4-m eth ylp ip er a zin -1-yl)d iben zo[b,f][1,4]-
th ia zep in e (11). The crude imino chloride was obtained from
the reaction of 1.00 g (4.08 mmol) of lactam 45, 0.30 g of N,N-
dimethyaniline and 8.2 mL of POCl3, following method B
(toluene, 4 mL xylene). The residual xylene solution was
treated with 1.23 g (12.2 mmol) of 1-methylpiperazine and
refluxed for 17 h. The crude material was partioned between
ether and water and the ether phase was extracted with 3 N
HCl. This acidic aqueous phase was made alkaline with 20%
sodium hydroxide, extracted with ether and dried (MgSO4).
Removal of solvent in vacuo gave 0.98 g of a foam. Addition of
4 mL of ethanol resulted in complete solution and the immedi-
ate formation of white solid which was collected by filtration
and dried in vacuo in a drying pistol at 65 °C: 0.33 g; mp
127.5-128.5 °C. Anal. (C18H18FN3S) C,H,N.
1
OH-CH2Cl2, Rf 0.44): mp 107-109 °C; H NMR (250 MHz,
CDCl3) 2.55-2.70 (m, 6H), 3.60-3.80 (m, 12H), 6.85-7.20 (m,
5H). Anal. (C20H24ClN3O2S) C,H,N,Cl.
4-(4-[2-(2-H yd r oxyet h oxy)et h yl]p ip er a zin -1-yl)-10H -
t h ien o[3,2-c][1]ben za zep in e (13). Refluxing a solution of
0.38 g (1.76 mmol) of 5,10-dihydro-4H-thieno[3,2-c][1]benz-
azepin-4-one19 and 0.43 g (1.06 mmol) of 2,4-bis(4-methoxy-
phenyl)-1,3-dithia-2,4-diphosphetane 2,4-disulfide (Lawesson’s
reagent) in 10 mL toluene for 2.6 h gave the crude thiolactam
(TLC, Rf 0.86, 3% CH3OH-CH2Cl2), void of the starting lactam
(TLC, Rf 0.29). Flash chromatography on silica gel with
gradient ether-hexane (25, 50 and 100% ether) elution gave
0.28 g of a yellow solid, homogeneous by TLC (25% ether-
hexane, Rf 0.34). To 0.27 g (1.17 mmol) of this material in 3.5
mL dioxane was added 0.33 g of powdered KOH in 2.1 mL
methanol. This solution was treated with 0.33 mL (3.5 mmol)
of dimethyl sulfate and stirred at ambient temperature for 90
min. The solvent was removed in vacuo and the residue was
partitioned between water and chloroform which was dried
(MgSO4). Concentration in vacuo gave 0.29 g of a brown solid,
essentially homogeneous by TLC (10% ether-hexane, Rf
0.53): 1H NMR (80 MHz, CDCl3) 2.60 (3H, SCH3).
The above imino thioether, 0.28 g (1.14 mmol), 0.60 g (3.42
mmol) of 1-[2-(2-hydroxyethoxy)ethyl]piperazine and 2 drops
of acetic acid were held at 140 °C (oil bath) for 4 h and then
partioned between ether and water. The organic extract was
washed well with water and brine, dried (MgSO4) and con-
centrated in vacuo to give 0.39 g of a foam. Purification by
silica gel column chromatography using 8% methanol-meth-
ylene chloride afforded 0.35 g of a yellow foam, homogeneous
by TLC (8% CH3OH-CH2Cl2, Rf 0.30). Trituration with a small
amount of ether gave a solid which was collected by filtration
and dried in vacuo: 0.22 g; mp 115-118 °C; 1H NMR (250
MHz, CDCl3) 2.5-2.7 (m, 6H), 3.6-3.8 (m, 12H), 6.9-7.2 (m,
6H). Anal. (C20H25N3O2S) H,N,C: calcd, 64.66; found, 64.20.
6-(4-[2-(2-H yd r oxyet h oxy)et h yl]p ip er a zin -1-yl)-11H -
d iben z[b,e]a zep in e (14). The imino chloride, 2.00 g (8.8
mmol) prepared by method B from 5,6-dihydrodibenz[b,e]-
azepin-6-one,32 and 4.6 g (28.8 mmol) of 1-[2-(2-hydroxyethoxy)-
ethyl]piperazine in 100 mL xylene was refluxed overnight.
Solvent was removed in vacuo. The residue was extracted with
chloroform, washed with water, saline and dried (MgSO4).
Filtration and evaporation gave an oil which was purified by
chromatography with 5% methanol-methylene chloride to give
1.98 g, homogeneous by TLC.
An ethereal solution of 1.60 g was treated with ethereal HCl
to yield a salt which was dried in a drying pistol over refluxing
methanol at 10 mTorr: 1.45 g; mp 140-142 °C; m/z 365. Anal.
(C22H27N3O2‚2HCl‚H2O) C,H,N,Cl.
The ethanolic filtrate was treated with 5 mL of ethanolic
HCl and this solution was added dropwise to ether, resulting
in the formation of a white solid. This solid was collected by
filtration and dried in a drying pistol at 65 °C at 10 mTorr:
0.52 g; mp 215-218 °C. Anal. (C18H18FN3S‚2HCl‚0.75H2O)
C,H,N,Cl.
7-Ch lor o-4-(4-[2-(2-h yd r oxyeth oxy)eth yl]p ip er a zin -1-
yl)-10H-th ien o[3,2-c][1]ben za zep in e (12). Refluxing a solu-
tion of 1.68 g (6.73 mmol) of 7-chloro-5,10-dihydro-4H-thieno-
[3,2-c][1]benzazepin-4-one19 and 1.63 g (4.04 mmol) of 2,4-bis(4-
methoxyphenyl)-1,3-dithia-2,4-diphosphetane 2,4-disulfide
(Lawesson’s reagent) in 38 mL toluene for 3 h gave the crude
A fumarate was prepared by treating a solution of 0.74 g
(2.02 mmol) of base in 8 mL of hot ethanol with 125 mg (1.01
mmol) of fumaric acid. After concentration to 4 mL and cooling,

Nondyskinetic DA Antagonists: Seroquel
J ournal of Medicinal Chemistry, 2001, Vol. 44, No. 3 381
crystallization was promoted by scratching. The solid was dried
in a drying pistol over refluxing methanol at 5 mTorr: 0.75 g;
mp 154-155 °C; H NMR (250 MHz, DMSO-d6) 6.61 (0.75H,
CHdCH). Anal. (C22H27N3O2‚0.75C4H4O4) C,H,N.
The above imino thioether, 0.78 g (2.83 mmol) and 1.48 g
(8.5 mmol) of 1-[2-(2-hydroxyethoxy)ethyl]piperazine and 5
drops of acetic acid were held at 140 °C (oil bath) for 23 h and
then partioned between methylene chloride and water. The
organic extract was washed well with water and brine, dried
(MgSO4) and concentrated in vacuo to give 1.19 g of a foam.
Purification by column chromatography using 5% methanol-
methylene chloride afforded 0.93 g, homogeneous by TLC
(same solvent), Rf 0.30. An ethereal solution of this base was
treated with ethereal HCl to give a salt which was dried in a
drying pistol over refluxing methanol at 10 mTorr: 0.69 g; mp
150 °C dec; m/z 402 (M + H)+. Anal. (C21H24ClN3O3‚HCl‚H2O)
C,H,N,Cl: calcd, 15.54; found, 14.95.
11-(4-[2-(2-Hydr oxyeth oxy)eth yl]piper azin -1-yl)diben z-
[b,f][1,4]oxa zep in e (18). The crude imino chloride, from 2.49
g (11.8 mmol) of 10,11-dihydrodibenz[b,f][1,4]oxazepin-11-one
(Aldrich), 1.0 g of N,N-dimethyaniline and 43 mL of POCl3
(method B, xylene), in 70 mL xylene was treated with 2.2 g
(12.6 mmol) of 1-[2-(2-hydroxyethoxy)ethyl]piperazine and
refluxed for 10 h. On cooling, the solution was made alkaline
with 2N NaOH, diluted with ethyl acetate and the organic
extract was washed with brine and dried (MgSO4). Removal
of solvent in vacuo gave 1.52 g. Column chromatography
afforded 1.39 g of an oil which in ether was treated with
ethereal HCl to give a white precipitate which was collected
by filtration (hygroscopic) and dried in vacuo: mp 135-140
°C dec; m/z 368. Anal. (C21H25N3O3‚1.5HCl‚1.0H2O) C,H,N,Cl.
8-Ch lor o-11-(4-[2-(2-h yd r oxyeth oxy)eth yl]p ip er a zin -1-
yl)d iben zo[b,f][1,4]th ia zep in e (19). The imino chloride from
3.0 g (11.46 mmol) of 8-chloro-10(H)-dibenz[b,f][1,4]azepin-11-
one,33 0.83 mL of N,N-dimethylaniline and 22 mL of POCl3
(method B) in 20 mL xylene was treated with 6.0 g (34.3 mmol)
of 1-[2-(2-hydroxyethoxy)ethyl]piperazine and refluxed for 16.5
h. The cooled solution was partitioned between ether and water
and this extract was washed well with water and dried
(MgSO4). Removal of solvent left 4.48 g of a crude oil. Column
chromatography with 5% methanol-methylene chloride gave
2.77 g of clear viscous material. Using the same solvent, TLC
analysis exhibited Rf 0.31.
A portion, 0.87 g (2.08 mmol), and 0.24 g of fumaric acid
were dissolved in 8 mL of ethanol with heating, concentrated
to 4 mL and left at ambient temperature. The resulting solid
was collected by filtration and dried in a drying pistol over
refluxing methanol at 10 mTorr: 0.91 g; mp 133-135 °C; m/z
418 (M + H)+; 1H NMR (300 MHz, DMSO-d6) 6.62 (s, 2H, CHd
CH). Anal. (C21H24ClN3O2S‚C4H4O4) C,H,N.
1
2-Hyd r oxy-6-(4-[2-(2-h yd r oxyeth oxy)eth yl]p ip er a zin -
1-yl)-11H-d iben z[b,e]a zep in e (15). Lactam 41, 1.30 g (4.86
mmol), 0.35 g of N,N-dimethylaniline and 10 mL of POCl3 were
refluxed for 5 h (method A, CH2Cl2). The crude imino chloride
was dissolved with difficulty in 7 mL xylene and added to 2.54
g (14.58 mmol) of 1-[2-(2-hydroxyethoxy)ethyl]piperazine and
refluxed for 20 h. The cooled residue was triturated with ether
which was then decanted. Sodium bicarbonate solution was
added to the remainder. Extraction with methylene chloride
resulted in a solid separating at the interphase so the volume
of methylene chloride was increased to effect solution and it
was dried with MgSO4. Removal of solvent gave 1.48 g of a
brown residue, TLC analysis of which (10% CH3OH-CH2Cl2)
indicated a major component with Rf 0.50 and minor impurities
at both higher and lower Rf values. This crude material in hot
ethanol was treated with 0.45 g (3.88 mmol) of fumaric acid
and concentrated to 20 mL. After cooling, crystallization was
promoted by scratching The solid was collected by filtration
and dried in a drying pistol over refluxing methanol at 10
mTorr: 1.16 g; mp 194-195.5 °C; m/z 381; 1H NMR (250 MHz,
CH3OH-d4) 6.92-6.96 (1H, CHdCH). Anal. (C22H27N3O3‚
0.5C4H4O4‚0.5H2O) C,H,N.
3-Ch lor o-6-(4-[2-(2-h yd r oxyeth oxy)eth yl]p ip er a zin -1-
yl)-11H-d iben z[b,e]a zep in e (16). A solution of 4.0 g (16.5
mmol) of 3-chloro-5,6-dihydrodibenz[b,e]azepin-6-one34 and 1.5
mL of N,N-dimethylaniline in 60 mL POCl3 was refluxed for
8 h. Workup followed method B. This xylene solution was
concentrated to 40 mL, 7.19 g (41 mmol) of 1-[2-(2-hydroxy-
ethyl)ethyl]piperazine was added and refluxed for 8 h. The
cooled solution was treated with water, 10% NaOH and
extracted with ether. The ether extract was washed with water
and extracted three times with 1 N HCl. This acidic aqueous
extract was made alkaline with dilute NaOH and extracted
with ether which was washed with water, saline and dried
(MgSO4). Concentration in vacuo gave 6.16 g of a brown oil
which was purified by chromatography using 5% methanol-
methylene chloride to give 4.40 g of an oil, homogeneous by
TLC.
This oil in ether was treated with ethereal HCl to give 4.2
g of a solid. Recrystallization from acetonitrile and drying gave
3.81 g: mp 192-195 °C. Anal. (C22H26ClN3O2‚2HCl‚0.5H2O)
C,H,N.
A fumarate salt was prepared by treating a solution of 830
mg (2.08 mmol) of the base in 8 mL of ethanol with 242 mg
(2.08 mmol) of fumaric acid. This solution was warmed to
reflux, concentrated to 4 mL and left at ambient temperature.
The resulting solid was collected by filtration and dried in a
drying pistol over refluxing methanol at 10 mTorr: 830 mg;
mp 115-117 °C; m/z 400 (M + H)+; 1H NMR (300 MHz,
DMSO-d6) 6.61 (2H, CHdCH). Anal. (C22H26ClN3O2‚C4H4O4)
C,H,N.
8-Ch lor o-11-(4-[2-(2-h yd r oxyeth oxy)eth y]p ip er a zin -1-
yl)d iben z[b,f][1,4]oxa zep in e (17). Refluxing a solution of
0.94 g (3.82 mmol) of 8-chloro-10,11-dihydrodibenz[b,f][1,4]-
oxazepin-11-one34 and 0.93 g (2.3 mmol) of 2,4-bis(4-methoxy-
phenyl)-1,3-dithia-2,4-diphosphetane 2,4-disulfide (Lawesson’s
reagent) in 20 mL toluene for 1.5 h gave 1.0 g of the crude
thiolactam (TLC, Rf 0.31, 12% ether-hexane). To this material
in 12 mL dioxane was added 1.08 g of powdered KOH in 7 mL
methanol. The clear yellow solution was treated with 1.1 mL
(11.58 mmol) of dimethyl sulfate and stirred at ambient
temperature for 40 min. The solvent was removed in vacuo
and the residue was partitioned between water and chloroform
which was dried (MgSO4). Concentration in vacuo gave an oil
which solidified on standing. TLC analysis (7% ether-hexane)
indicated a major component with Rf 0.63 and several less
mobile impurities. The material was purified by column
chromatography to give 0.79 g (74%) of the imino thioether as
white solid, homogeneous by TLC: 1H NMR (250 MHz, CDCl3)
2.56 (3H, SCH3).
8-F lu or o-11-(4-[2-(2-h yd r oxyet h yl)et h yl]p ip er a zin -1-
yl)d iben zo[b,f][1,4]th ia zep in e (20). The crude imino chlo-
ride, from the reaction of 6.00 g (24.4 mmol) of lactam 43 and
1 mL of N,N-dimethyaniline with 35 mL of POCl3 (method B),
in 30 mL of xylene was treated with 12.78 g (73.3 mmol) of
1-[2-(2-hydroxyethyl)ethyl]piperazine and refluxed overnight.
The crude material was partitioned between ether and water
and the ether phase was extracted with 3 N HCl. This acidic
aqueous phase was made alkaline with 20% sodium hydroxide,
extracted with ether and dried (MgSO4). Removal of solvent
in vacuo gave 8.39 g which by TLC (5% CH3OH-CH2Cl2)
comprised a single component with Rf 0.50. This material in
50 mL of ethanol was treated with 1.30 g (11.2 mmol) of
fumaric acid. After stirring for 30 min, the resulting white solid
was collected by filtration and dried in a drying pistol at 60
°C at 20 mTorr: 8.20 g; mp 156-157 °C; m/z 401. Anal. (C21H24
FN3O2S‚0.50C4H4O4) C,H,N.
-
7-F lu or o-11-(4-[2-(2-h yd r oxyeth oxy)eth yl]p ip er a zin -1-
yl)d iben zo[b,f][1,4]th ia zep in e (21). The crude imino chlo-
ride from 4.00 g (16.31 mmol) of lactam 45, 1.18 g of N,N-
dimethylaniline and 32 mL of POCl3 (method B, toluene, 16
mL xylene) in residual xylene was treated with 8.52 g (48.93
mmol) of 1-[2-(2-hydroxyethoxy)ethyl]piperazine and refluxed
for 19 h. After partitioning between ether and water, the ether
phase was extracted with 3 N HCl. This acidic aqueous phase
was made alkaline with 20% sodium hydroxide, extracted with
ether and dried (MgSO4). Removal of solvent in vacuo gave
4.85 g of a foam which by TLC (5% CH3OH-CH2Cl2) comprised

382 J ournal of Medicinal Chemistry, 2001, Vol. 44, No. 3
Warawa et al.
a major component with Rf 0.24. This material was chromato-
graphed on silica gel using 5% methanol-methylene chloride
to give 4.52 g which was dissolved in 10 mL of ethanol and 10
mL of ethanolic HCl and stirred overnight, resulting in the
formation of a white solid. The content of the flask was added
to ethyl ether and the solid was collected by filtration and dried
in a drying pistol at 65 °C at 10 mTorr: 4.77 g; mp 213.5-
215.5 °C. Anal. (C21H24FN3O2S‚2HCl) C,H,N,Cl.
6-F lu or o-11-(4-[2-(2-h yd r oxyet h yl)et h yl]p ip er a zin -1-
yl)d iben zo[b,f][1,4]th ia zep in e (22). The crude imino chlo-
ride, from 0.30 g (1.22 mmol) of lactam 58, 0.09 g of N,N-
dimethyaniline and 25 mL of POCl3 (method B, toluene, 2 mL
xylene), in the residual xylene was treated with 0.64 g (3.66
mmol) of 1-[2-(2-hydroxyethoxy)ethyl]piperazine and refluxed
for 17 h. After partionioning between ether and water, the
ether phase was extracted with 3 N HCl. This acidic phase
was made alkaline with 20% sodium hydroxide, extracted with
ether and dried (MgSO4). Removal of solvent in vacuo gave
0.23 g of a foam. This material was chromatographed on silica
gel using 5% methanol-methylene chloride to give 0.20 g of a
pale yellow oil, homogeneous by TLC (5% CH3OH-CH2Cl2)
with Rf 0.35: 1H NMR (250 MHz, CDCl3) 2.56-2.66 (m, 6H,
N[CH2]3), 3.60-3.72 (m, 10H, N[CH2]2 and CH2OCH2CH2O),
6.68-6.71 (1H), 6.82-6.86 (1H), 7.03-7.12 (1H), 7.26-7.36
(3H), 7.54-7.58 (1H).
(MgSO4). Concentration in vacuo gave 1.93 g which by TLC
(10% CH3OH-CH2Cl2) was essentially a single component (Rf
0.42) with only minor impurities. Purification by column
chromatography on 80 g silica gel and elution with 5% CH3-
OH-CH2Cl2 gave 1.53 g of the acetate as an oil: 1H NMR (300
MHz, CDCl3) 2.04 (s, 3H, CH3), 4.18-4.21 (m, 2H, CH2OAc).
This ester, 1.52 g (3.44 mmol), and 0.62 g (9.3 mmol) of KOH
(powdered, 85%) in 16 mL of methanol was stirred at ambient
temperature for 4 h. An aliquot was treated with ethereal HCl
to yield the HCl salt which was dissolved in methanol and
applied directly to a TLC plate. Development with 10% CH3-
OH-CH2Cl2 exhibited a single component, Rf 0.30. The solvent
was then removed in vacuo and the residual potassium salt
was dissolved in 20 mL of water. Addition of 1 N HCl gave a
precipitate which dissolved upon additon of 100 mL of water.
The portionwise addition of NaHCO3 resulted in the separation
of a solid which required 850 mL of CHCl3 to effect solution.
After drying, evaporation of the solvent in vacuo gave 24 base,
1.39 g, as an amorphous solid, homogeneous by TLC (10% CH3-
OH-CH2Cl2), Rf 0.33.
A 340-mg aliquot of this phenol was dissolved in 3 mL of
ethanolic HCl and stirred at ambient temperature. After 40
min a fair amount of white solid had formed and 15 mL of
ether was added and stirring continued for 4 h. The solid was
collected by filtration, washed with ether and dried in a drying
pistol over refluxing methanol at 5 mTorr: 313 mg; mp 219-
221 °C; m/z 400 (M + H)+. Anal. (C21H25N3O3S‚2HCl‚1.2H2O)
C,H,N,Cl.
This material in ether was treated with ethereal HCl to form
the hydrochloride (hygroscopic) which was dried in a drying
pistol over refluxing methylene chloride at 10 mTorr: 0.12 g;
mp 150-160 °C dec; m/z 401. Anal. (C21H24FN3O2S‚1.6HCl‚
H2O) C,H,N: calcd, 8.79; found, 8.13.
To 0.99 g of 24 base in 25 mL of ethanol was added 10 mL
of hot ethanol containing 0.40 g of fumaric acid. This solution
was concentrated to 4 mL and allowed to cool to ambient
temperature. Refrigeration for 3 days resulted in the formation
of crystals which were collected by filtration, washed with
ether and dried in a drying pistol over refluxing methanol at
11-(4-[2-(2-Hydr oxyeth oxy)eth yl]piper azin -1-yl)diben zo-
[b,f][1,4]th ia zep in e (23). A solution of 3.0 g (13.2 mmol) of
39 and 0.5 mL of N,N-dimethylaniline in 20 mL POCl3 was
refluxed for 4 h (method B). The xylene extract was concen-
trated to 20 mL and treated with 3.2 g (18.6 mmol) of 1-[2-
(2-hydroxyethoxy)ethyl]piperazine and refluxed overnight. The
cooled solution was treated with ether and this extract was
washed well with water and extracted three times with 1 N
HCl. This acidic aqueous extract was made alkaline with dilute
NaOH and was extracted with ether and dried (MgSO4).
Removal of solvent left an oil which by TLC analysis (10% CH3-
OH-CH2Cl2) showed a major component with Rf 0.50 and a
more mobile impurity. Column chromatography with 10%
methanol-ether gave 2.9 g of a brown oil.
A portion, 2.1 g (5.47 mmol), in 20 mL of ethanol was treated
with 0.67 g (5.7 mmol) of fumaric acid. Upon heating, solution
was effected for a few minutes after which a solid began to
separate. After cooling, the solid was collected by filtration and
dried in drying pistol over refluxing methanol at 10 mTorr:
2.4 g; mp 172-173 °C; m/z 383. Anal. (C21H25N3O2S.0.5C4H4O4)
C,H,N.
7-Hyd r oxy-11-(4-[2-(2-h yd r oxyeth oxy)eth yl]p ip er a zin -
1-yl)d iben zo[b,f][1,4]th ia za p in e (24). The lactam 49, 1.84
g (5.5 mmol), 10 drops of N,N-dimethyaniline and 20 mL of
phosphorus oxychloride were heated for 1 h after which time
TLC analysis (2% CH3OH-CH2Cl2) indicated the absence of
49, Rf 0.33. Workup (method A, ethyl acetate) gave 1.67 g; TLC
(ibid) indicated a single component, Rf 0.70.
1-[2-(2-Hydroxyethoxy)ethyl]piperazine, 2.50 g (14.5 mmol),
was weighed directly into the flask containing the imino
chloride, 15 mL of xylene was added, and the mixture was
heated in an oil bath at 125 °C under nitrogen for 18 h. After
partitioning between ethyl acetate and aqueous K2CO3, the
organic phase was washed well with water, brine and dried
(MgSO4). Removal of solvent in vacuo gave 1.99 g which was
essentially a single component by TLC (5% CH3OH-CH2Cl2),
Rf 0.22.
1
10 mTorr: 1.04 g; mp 121-124 °C; H NMR (300 MHz CH3-
OH-d4) 1.14-1.19 (t, CH3CH2OH), 6.69 (s, 2H, CHdCH). Anal.
(C21H25N3O3S‚C4H4O4‚0.33C2H5OH‚0.5H2O) C,H,N.
8-Hyd r oxy-11-(4-[2-(2-h yd r oxyeth oxy)eth yl]p ip er a zin -
1-yl)d iben zo[b,f][1,4]th ia za p in e (25). The lactam 54, 1.50
g (4.52 mmol), 10 drops of N,N-dimethylaniline and 15 mL of
phosporous oxychloride were heated in an oil bath at 120 °C.
After 1 h, TLC analysis (2% CH3OH-CH2Cl2) indicated the
absence of 54, Rf 0.38. Workup (method A, ethyl acetate) gave
a brown oil; TLC (ibid) indicated a single component, Rf 0.75.
1-[2-(2-Hydroxyethoxy)ethyl]piperazine, 2.00 g (11.4 mmol),
was weighed directly into the flask containing the imino
chloride, 15 mL of xylene was added, and the mixture was
heated in an oil bath at 140 °C under nitrogen for 17 h. After
partitioning between ethyl acetate and aqueous K2CO3, the
organic phase was washed well with water, brine and dried
(MgSO4). Removal of solvent in vacuo gave 2.02 g which was
essentially a single component by TLC (10% CH3OH-CH2Cl2),
1
Rf 0.50: m/z 490 (M + H)+; H NMR (300 MHz, CDCl3) 4.98
(s, 2H, ArOCH2).
To this material in 5 mL of glacial acetic acid was added 5
mL of 30% HBr in acetic acid and the solution was stirred in
a stoppered flask for 1 h at which time TLC analysis (5% CH3-
OH-CH2Cl2) indicated the absence of starting material (Rf
0.30). The contents of the flask was added to 200 mL of ethyl
ether which resulted in an oil and suspended solid. Decanta-
tion with filtering recovered the solid which was dissolved in
water and added back to the oily residue. This aqueous
solution was made alkaline with NaHCO3 and extracted with
ethyl acetate which was washed with brine and dried (MgSO4).
Concentration in vacuo gave 1.74 g which by TLC (10% CH3-
OH-CH2Cl2) was essentially a single component (Rf 0.62) with
only minor impurities. Purification by column chromatography
on 70 g silica gel and elution with 10% CH3OH-CH2Cl2 gave
1.30 g of the acetate as an amorphous glass: 1H NMR (300
MHz, CDCl3) 2.03 (s, 3H, CH3), 2.53-2.66 (m, 6H), 3.61-3.65
(m, 8H), 4.17-4.20 (m, 2H, CH2OAc), 6.33-7.49 (m, 7H); m/z
442 (M + H)+.
To this material in 10 mL glacial acetic acid was added 10
mL of 30% HBr in acetic acid and the solution was stirred in
a stoppered flask for 1 h. The content of the flask was added
to ethyl ether and the orange HBr salt was collected by
filtration, washed with ether and dissolved in 150 mL of water.
This solution was made alkaline with NaHCO3 and extracted
with ethyl acetate which was washed with brine and dried
This acetate, 1.30 g (3.0 mmol), and 0.60 g (9.0 mmol) of
KOH (powdered, 85%) in 20 mL of methanol was stirred at

Nondyskinetic DA Antagonists: Seroquel
J ournal of Medicinal Chemistry, 2001, Vol. 44, No. 3 383
ambient temperture for 5 h. An aliquot was treated with
ethereal HCl to yield the HCl salt which was treated with
dilute NaHCO3 and extracted with CHCl3. TLC analysis (10%
CH3OH-CH2Cl2) exhibited a single component, Rf 0.20. The
solvent was then removed in vacuo and the residual potassium
salt was dissolved in water. Addition of 1 N HCl gave a
precipitate which would not completely dissolve by the addition
of more water. After the portionwise addition of NaHCO3, the
solid readily dissolved in CHCl3. After drying, evaporation of
the solvent in vacuo gave 25, 1.18 g, as an amorphous solid:
m/z 400 (M + H)+; 1H NMR (300 MHz, CH3OH-d4) 2.55-2.67
(m, 6H, N[CH2]3), 3.28-3.66 (m, 11H, N[CH2]2, CH2OCH2CH2-
OH, CH3OH), 6.35-6.47 (m, 2H), 7.14-7.50 (m, 5H).
To 1.17 g (3 mmol) of 25 base in 30 mL of ethanol was added
10 mL of hot ethanol containing 0.40 g (3.5 mmol) of fumaric
acid. This solution was concentrated to 10 mL and allowed to
cool to ambient temperature. The tan crystals were collected
by filtration, washed with ether and dried in a drying pistol
over refluxing methanol at 10 mTorr: 1.13 g; mp 205-207 °C;
1H NMR (300 MHz, CH3OH-d4) 1.03-1.07 (t, CH3CH2OH),
6.61 (s, 2H, CHdCH). Anal. (C21H25N3O3S‚C4H4O4‚0.33C2H5-
OH‚0.5H2O) C,H,N.
11-(4-[2-(2-Hydr oxyeth oxy)eth yl]piper azin -1-yl)diben zo-
[b,f][1,4]th ia zep in e Su lfoxid e (26). A solution of 1.93 g (9.0
mmol) of sodium periodate in 15 mL of water was added
dropwise over 20 min to 4.12 g (9.0 mmol) of the dihydrochlo-
ride of 23 in 20 mL of water which was cooled in an ice-water
bath. The homogeneous solution was then stirred for 22 h. An
aliquot treated with dilute sodium hydroxide and ethyl acetate
on TLC analysis (20% methanol-ether) indicated two major
components with Rf’s 0.10 and 0.30 and a minute amount of
starting material with Rf 0.47. The entire material was then
treated with dilute sodium hydroxide and extracted with ethyl
acetate which was washed with water, brine and dried
(MgSO4). Removal of solvent gave 2.70 g which was dissolved
in toluene and refluxed for 2 h. TLC analysis (ibid) showed a
major component with Rf 0.30 and minor components with Rf’s
0.10 and 0.50. Toluene was removed invacuo and the major
component was isolated by column chromatography using 20%
methanol-ether to give 1.98 g of a glassy material. This
material in 5 mL of ethanolic HCl was stirred for 10 min at
which time a voluminous precipitate formed. After dilution
with ether the solid was collected by filtation and dried in a
dyring pistol at 66 °C and 5 mTorr: 2.15 g; mp 189-191 °C;
m/z 400 (M + H)+. Anal. (C21H25N3O3S‚1.85HCl‚1.0H2O)
C,H,N,Cl.
11-(4-[2-(2-Hydr oxyeth oxy)eth yl]piper azin -1-yl)diben zo-
[b,f][1,4]th ia zep in e Su lfon e (27). A solution of 3.0 g (11.57
mmol) of 10,11-dihydrodibenzo[b,f][1,4]thiazepin-11-one sul-
fone35 and 0.5 mL of N,N-dimethylaniline in 30 mL of POCl3
was refluxed for 18 h (method B, xylene). The imino chloride
in 20 mL residual xylene was treated with 4.0 g of 1-[2-(2-
hydroxyethoxy)ethyl]piperazine and refluxed overnight. The
reaction mixture was partioned between ether and water and
the ethereal extract was washed well with water and dried
(MgSO4). Removal of solvent in vacuo gave 2.5 g, homogeneous
by TLC (5% CH3OH-CH2Cl2), Rf 0.50: m/z 415.
(56%) of white solid: mp 247-269 °C slow dec. Anal. (C19H21N3-
OS‚2HCl) C,H,N.
11-(4-[2-(2-[2-Hyd r oxyeth oxy]eth oxy)eth yl]p ip er a zin -
1-yl)d iben zo[b,f][1,4]th ia zep in e (29). To the crude imino
chloride prepared from 0.0074 mol of 39 (method B, as
described for 23) in 20 mL of xylene was added 3.25 g (0.0149
mol) of 2-[2-[2-(1-piperazinyl)ethoxy]ethoxy]ethanol37 and the
mixture stirred at reflux overnight. The mixture was added
to water, basified to pH 12 with 10% NaOH solution and
extracted with three 50-mL portions of ethyl acetate. The
combined extracts were dried (MgSO4), filtered and the solvent
removed in vacuo. The resulting yellow oil was chromato-
graphed on silica gel (ethanol:hexane, 1:9), and the proper
fractions combined to yield 1.18 g of an oil. Treatment of an
ethereal solution with ethereal HCl gave 1.02 g (27%): mp 82
°C dec. Anal. (C23H29N3O3S‚2HCl‚H2O) C,H,N.
11-(4-[2-(1,3-Dim eth oxy)pr opyl]piper azin -1-yl)diben zo-
[b,f][1,4]th ia zep in e (30). To the crude imino chloride pre-
pared from 0.0048 mol of 39 (method B, as described for 23)
in 10 mL of toluene was added 1.81 g (0.0096 mol) of N-[2-
(1,3-dimethoxy)propyl]piperazine38 and the mixture stirred at
reflux overnight. The mixture was treated with water, basified
to pH 12 with 10% sodium hydroxide and extracted with three
50-mL portions of ethyl acetate. The combined extracts were
dried (MgSO4), filtered and the solvent removed in vacuo. The
resulting brown oil was chromatographed on silica gel (hexane:
chloroform, 1:4), and the proper fractions combined to yield
1.56 g of an oil. Treatment of an etheral solution of the oil
with ethereal HCl gave 1.16 g (50%) of off-white solid: mp
130 °C dec. Anal. (C22H27N3O2S‚2HCl‚H2O) C,H,N.
11-(4-[2,3-Dim et h oxyp r op yl]p ip er a zin -1-yl)d ib en zo-
[b,f][1,4]th ia zep in e (31). To the imino chloride from 1.14 g
(0.005 mol) of 39, 5 drops of N,N-dimethylaniline and 16 mL
of POCl3 (method A, toluene) in 15 mL of xylene was added
1.88 g (0.010 mole) of 2,3-dimethoxypropylpiperazine (49) in
25 mL of xylene, the mixture refluxed for 8 h and then stirred
at room temperature overnight. The solvent was removed in
vacuo and the residue chromatographed on silica gel (ethanol:
hexane 1:19). The product was converted to the dicitrate salt
in ether and recrystallized from acetonitrile-ether: 1.71 g
(44%); mp 68 °C dec. Anal. (C22H27N3O2S‚2C6H8O7) C,H,N.
S -(+)-11-(4-[2,3-Dim e t h o xy p r op yl]p ip e r a zin -1-y l)-
d iben zo[b,f][1,4]th ia zep in e (32). A solution of 10.25 g (0.394
mol) of S-(-)-1-(2,3-dimethoxypropyl)-4-ethoxycarbonylpipera-
zine (61) and 10.7 g (0.19 mol) of potassium hydroxide in 60
mL of n-butanol was stirred at reflux for 18 h. The reaction
flask was placed in an oil bath and the n-butanol removed in
vacuo by distillation through a 4 in. Vigreaux column at
aspirator pressure. Crude product was then collected to an oil
bath temperature of 180 °C at vacuum pump pressure.
Redistillation gave 6.56 g (88%) of S-(+)-N-2,3-dimethoxypro-
27
pylpiperazine: bp 64-6 °C/0.1 mmHg; [R]D +0.49° (c ) 2,
methanol).
To the crude imino chloride prepared from 0.005 mol of 39
(method A, toluene, as described for 31) in 15 mL of toluene
was added 1.88 g (0.010 mol) of S-(+)-N-2,3-dimethoxypropy-
lpiperazine and the mixture stirred at reflux for 18 h. The
solvent was removed in vacuo and the residue chromato-
graphed on silica gel (ethyl acetate:chloroform, 1:2). The
material was converted to the hydrochloride salt in ethereal
HCl and recrystallized from acetonitrile-ether: 1.58 g (67%);
mp 110 °C dec. Anal. (C22H27N3O2S‚2HCl‚H2O) C,H,N.
A portion, 1.2 g, in ethanol was treated with ethanolic HCl
and concentrated to 5 mL. Addition of ether resulted in the
formation of a white solid which was collected by filtration and
dried in a drying pistol at 65 °C and 10 mTorr: 1.5 g; mp 168-
169 °C. Anal. (C21H25N3O4S‚HCl‚H2O) C,H,N,Cl.
11-(4-[2-Hyd r oxyeth yl]p ip er a zin -1-yl)d iben zo[b,f][1,4]-
th ia zep in e (28).36 To the crude imino chloride prepared from
0.0088 mol of 39 (method B, as described for 23) in 30 mL of
xylene was added 2.98 g (0.023 mole) of 1-piperazinylethanol
and the mixture stirred at reflux overnight. The mixture was
added to 20 mL of water, basified to pH 12 with 10% sodium
hydroxide and extracted with two 50-mL portions of ethyl
ether. The combined extracts were dried (MgSO4), filtered and
the solvent removed in vacuo. The resulting gold-colored oil
was chromatographed on silica gel (ethyl acetate), and the
proper fractions combined to yield 2.85 g of an oil. Treatment
of an etheral solution of the oil with ethereal HCl gave 2.04 g
11-(4-[3,4-Dim eth oxybu tyl]p ip er a zin -1-yl)d iben zo[b,f]-
[1,4]th ia zep in e (33). A solution of the imino chloride from
1.11 g (0.005 mol) of 39 (method B, xylene, as described for
23) in 10 mL xylene was treated with 1.98 g (0.0098 mol) of
1-(3,4-dimethoxybutyl)piperazine 64 and the mixture stirred
at reflux for 24 h. The cooled mixture was added to 10 mL of
water, basified to pH 12 with 10% NaOH. The organic layer
was washed with saturated saline solution, dried (MgSO4) and
the solvent removed to yield a brown oil. Flash chromatogra-
phy on silica gel with 5% methanol-chloroform gave 1.09 g
(54%) of base. The material in ether was treated with ethereal
HCl to yield a precipitate which was recrystallized from

384 J ournal of Medicinal Chemistry, 2001, Vol. 44, No. 3
Warawa et al.
ethanol-ethyl ether: 0.81 g; mp 68 °C dec. Anal. (C23H29N3O2‚
1.25HCl‚0.5H2O) H,N,Cl,C: calcd, 59.26; found, 59.75.
The dihydrochloride salt was recrystallized from methanol-
ethyl ether: 0.88 g (37%); mp 260 °C dec. Anal. (C22H25N3OS‚
2HCl) C,H,N.
11-(4-[2-Me t h oxy-3-h yd r oxyp r op yl]p ip e r a zin -1-yl)-
d iben zo[b,f][1,4]th ia zep in e (34). To the crude imino chloride
prepared from 0.0065 mol of 39 (method B, as described for
23) in 20 mL of toluene was added 2.29 g (0.013 mol) of 1-(2-
methoxy-3-hydroxypropyl)piperazine (66) in 10 mL of toluene
and the mixture was refluxed overnight. Water was added to
the reaction mixture which was made basic by the addition of
15% sodium hydroxide solution and extracted with ethyl
acetate. This extract was washed with three portions of 10%
hydrochloric acid. The acidic aqueous phase was made basic
with 15% sodium hydroxide and extracted with ethyl acetate
and dried (MgSO4). Removal of solvent in vacuo gave 2.34 g
of crude product. Chromatography on silica gel (ethanol-
hexane, 1:19) returned 1.81 g (72%) of pure product as a light
green oil. The oil was converted to a citrate salt in ether. The
salt was dissolved in 25 mL of distilled water, filtered and
lyophilized: 2.29 g (52%); mp 75 °C dec. Anal. (C21H25N3O2S‚
1.5C6H8O7) C,H,N.
11-(4-[1-Hyd r oxym eth yl-2-m eth oxyeth yl]p ip er a zin -1-
yl)d iben zo[b,f][1,4]th ia zep in e (35). To the crude imino
chloride prepared from 0.0040 mol of 39 (method B, as
described for 23) in 15 mL of xylene was added 0.70 g (0.004
mol) of â-methoxymethyl-1-piperazinylethanol38 and 0.55 g
(0.0040 mol) of potassium carbonate and the mixture stirred
at reflux overnight. The mixture was filtered and the solvent
removed in vacuo. The resulting gold-colored oil was chro-
matographed on silica gel (methanol:chloroform, 1:19) and the
proper fractions combined to yield an oil which was treated
with HCl in ethyl ether: 0.15 g; mp 116 °C dec. Anal.
(C21H25N3O2S‚1.5HCl‚0.5H2O) C,N,Cl,H: calcd, 6.20; found,
6.77.
11-(4-[cis-6-Hyd r oxym eth yl-1,4-d ioxa n -2-ylm eth yl]p ip -
er a zin -1-yl)d iben zo[b,f][1,4]th ia zep in e (36). To the crude
imino chloride prepared from 0.010 mol of 39 (method A,
toluene, as described for 31) in 35 mL of toluene was added
4.33 g (0.020 mol) of cis-2-piperazinylmethyl-6-hydroxymethyl-
1,4-dioxane (67) and the mixture stirred at reflux overnight.
The mixture was treated with a little 10% sodium hydroxide,
extracted with ethyl acetate, dried (MgSO4), and the solvent
removed in vacuo. The residue was chromatographed on silica
gel (ethyl acetate), the proper fractions combined and the
material converted to the hydrochloride salt with ethereal HCl.
The white solid was recrystallized from methanol-ethyl ether
and then methylene chloride-ethyl ethe: 4.05 g (81%); mp
195 °C dec. Anal. (C23H27N3O3S‚2HCl) C,H,N.
11-(4-[1,4-Dioxa n -2-ylm et h yl]p ip er a zin -1-yl)d ib en zo-
[b,f][1,4]th ia zep in e (37). To the crude imino chloride pre-
pared from 0.0038 mol of 39 (method A, as described for 31)
in 16 mL of xylene was added 1.42 g (0.020 mol) of 2-piper-
azinylmethyl-1,4-dioxane (69) and the mixture stirred at reflux
overnight. The mixture was treated with 25 mL of water,
basified to pH 12 with 10% sodium hydroxide and the phases
separated. The aqueous phase was extracted with two 50-mL
portions of ethyl acetate, the combined extract dried (MgSO4),
filtered and the solvent removed in vacuo. The resulting gold-
colored oil was chromatographed on silica gel (ethyl acetate:
chloroform, 1:2), and the proper fractions combined to yield
1.27 g of an oil. Trituration of the oil with hexane containing
a little ethyl ether returned 0.89 g (59%): mp 118-121 °C.
Anal. (C22H25N3O2S) C,H,N.
10,11-Dih yd r od ib en zo[b,f][1,4]t h ia zep in -11-on e (39).
Prepared by the method of Schmutz et al.:34 mp 256-257 °C
(lit. mp 256 °C).
2-Met h oxy-5,6-d ih yd r o-11H -d ib en z[b,e]a zep in -6-on e
(40). To 2.85 g (13.36 mmol) of 2 amino-5-methoxydiphenyl-
methane40 in 26 mL dioxane was added dropwise 0.80 mL (6.68
mmol) of trichloromethyl chloroformate and the mixture was
heated at 54 °C (oil bath) for 3 h. Dioxane was removed in
vacuo to give a residue of 3.21 g which was Kugelrohr distilled
to give the isocyanate as an oil: 2.66 g (83% yield); bp 106-
116 °C (air bath temperature) at 4-8 mTorr; TLC analysis
(1:10 ether:hexane) indicated a single component at Rf 0.54;
IR max (film) 2250(s) cm-1
.
A slurry of 1.48 g (11.08 mmol) of aluminum trichloride in
11 mL of o-dichlorobenzene was heated in an oil bath to 110
°C and a solution of 2.65 g (11.08 mmol) of the above isocyanate
in 11 mL of o-dichlorobenzene was added dropwise. The
temperature was raised to 150 °C and held for 3.5 h. Solvent
was removed using a Kugelrohr (air bath temperature 120 °C)
and water aspirator pressure. Treatment of the residue with
ice gave a tan solid which was washed well with water and
then with a little ether to give 2.62 g. This was dried in a
drying pistol over refluxing methanol at 10 mTorr: 2.54 g; mp
228.5-231.5 °C; TLC (ether:hexane, 1:1) Rf 0.20; 1H NMR (250
MHz, DMSO-d6) 3.70 (3H, CH3), 3.85 (2H, CH2), 10.22 (1H,
NH); IR max (Nujol) 3150(m), 1650(s) cm-1; m/z 239.
2-Acetoxy-5,6-dih ydr o-11H-diben z[b,e]azepin -6-on e (41).
Lactam 40, 2.52 g (10.57 mmol), in 20 mL methylene chloride
was cooled to -78 °C. Boron tribromide dimethyl sulfide, 11
mL (11 mmol), was added by syringe and the bath temperature
was allowed to increase spontaneously. Since TLC analysis
(5% CH3OH-CH2Cl2) indicated that the demethylation was
slow, additional amounts of the boron reagent were added:
15.9 mL (1.5 mmol) after 22 h and 11.1 mL (1 mmol) after a
total of 28.5 h. Since starting material was still detected after
45 h, an additional 31 mL of a 1.0 M solution of boron
tribromide in methylene chloride was added. After 3 h, no
starting material was detected. The solvent was removed in
vacuo, the residue was treated with ice and was made alkaline
with dilute sodium bicarbonate. The tan solid which separated
was collected by filtration and dried to give 2.38 g.
The above material, 2.36 g (10.48 mmol), and 2.92 mL (21
mmol) of triethylamine in 10 mL methylene chloride was
cooled to 0 °C. Acetyl chloride, 0.09 g (11.53 mmol) in 15 mL
methylene chloride was added dropwise. The solution was
stirred at ambient temperature for 1.5 h and was then treated
with water. The organic phase was dried (MgSO4) and
concentrated in vacuo to give 2.87 g of the titled compound as
a tan solid. TLC analysis (5% CH3OH-CH2Cl2) showed a
single component, Rf 0.34, and absence of starting material,
Rf 0.23: IR (Nujol) 3150(m), 1750(s), 1638(s) cm-1; m/z 267.
N -(t er t -Bu t oxyca r b on yl)-4-flu or o-2-t h iop h e n yla n i-
lin e (42). A dry three-necked flask under nitrogen was charged
with 1.61 g (7.62 mmol) of N-(tert-butoxycarbonyl)-4-fluoro-
aniline41 and 75 mL of dry THF and cooled to -76 °C. By
means of a syringe, 7.45 mL (16.76 mmol) of 2.25 M tert-
butyllithium in hexane was added dropwise. After 15 min, the
solution was allowed to warm to -22 °C, held for 1 h and cooled
again to -76 °C. S-Phenyl benzenethiosulfonate, 2.29 g (9.14
mmol), was added in one portion. The solution was stirred
overnight, allowing the bath temperature to rise spontane-
ously. After quenching with water, the THF was removed in
vacuo and the residue was extracted with ether which was
washed with brine and dried (MgSO4). Removal of solvent in
vacuo gave 2.44 g of an amber oil which by TLC (4% ether-
hexane) was composed of a major component with Rf 0.40 and
two minor impurities with lower Rf’s. This material was
purified by column chromatography, eluting with 4.5% ether-
hexane: 1.57 g (65% yield) of a yellow oil; IR (film) 3358(m),
1740 (s) cm-1; m/z 319; 1H NMR (80 MHz, CDCl3) 1.45 (s, 9H),
7.09-7.28 (m, 8H). Anal. (C17H18FNO2S) C,H,N.
11-(4-[2-T e t r a h y d o fu r a n ylm e t h y l]p ip e r a zin -1-y l)-
d iben zo[b,f][1,4]th ia zep in e (38). To the crude imino chloride
prepared from 0.0053 mol of 39 (method B, as described for
23) in 15 mL of xylene was added 1.80 g (0.0106 mol) of N-[2-
tetrahydofuranylmethyl]piperazine39 and the mixture stirred
at reflux overnight. The mixture was poured onto excess 10%
sodium hydroxide and extracted with two 50-mL portions of
ethyl acetate. The combined extracts were dried (MgSO4),
filtered and the solvent removed in vacuo. The resulting gold-
colored oil was chromatographed on silica gel (chloroform), and
the proper fractions combined to yield an oil which was further
converted to the dihydrochloride salt with HCl in ethyl ether.

Nondyskinetic DA Antagonists: Seroquel
J ournal of Medicinal Chemistry, 2001, Vol. 44, No. 3 385
4-F lu or o-2-th iop h en yla n ilin e (43). The carbamate 42,
2.90 g (9.08 mmol), in 9 mL of trifluoroacetic acid was stirred
a ambient temperature for 30 min and the solvent was
removed in vacuo. The residue was made alkaline with 10%
sodium hydroxide, extracted with ether and dried (MgSO4).
Concentration in vacuo gave 1.89 g of a yellow oil, a single
component by TLC (50% ether-hexane), Rf 0.68: IR max (film)
3448(m), 3355(m) cm-1. This material was used without
further purification.
4-F lu or o-2-(th iop h en yl)p h en yl Isocya n a te (44). A solu-
tion of 1.88 g (8.57 mmol) of 43 in 15 mL of dioxane was treated
dropwise with 0.85 g (4.28 mmol) of trichloromethyl chloro-
formate. The temperature was raised to 60 °C (oil bath) and
held for 3.5 h. TLC analysis (20% ether-hexane) showed a
major component with Rf 0.85 and a very minor impurity with
Rf 0.34. Dioxane was removed in vacuo and the residue was
Kugelrohr distilled: 1.83 g of a colorless oil; bp (air bath
temperature) 97-109 °C at 20 mTorr; IR max (film) 2260(s)
cm-1. This material was used without further purification.
7-F lu or o-10,11-d ih yd r od ib en zo[b,f][1,4]t h ia zep in -11-
on e (45). To a solution of 1.0 g (7.42 mmol) of aluminum
chloride in 50 mL of o-dichlorobenzene at 100 °C was added a
solution of 1.82 g of the crude 44 in 8 mL of the same solvent.
The temperature was raised to 150 °C, held for 6.5 h and the
solvent was removed using a Kugelrohr at 20 mmHg. The
residue was treated with ice and triturated: 1.52 g of a tan
solid; IR max (Nujol) 3150(m), 1660(s), 1645(s) cm-1. This
material was used without further purification.
4-Ben zyloxy-2-br om on itr oben zen e (46). A solution of
7.00 g (32.1 mmol) of 3-bromo-4-nitrophenol42 in 20 mL of
dimethylacetamide (DMAC) was added dropwise to a slurry
of 0.78 g (32.1 mmol) of sodium hydride in 5 mL DMAC. The
resulting homogeneous solution was warmed to 60 °C and a
solution of 5.50 g (32.1 mmol) of benzyl bromide in 5 mL DMAC
was added dropwise. After 6 h, the cooled contents were
transferred with DMAC to a single-necked flask and the
solvent was removed using a Kugelrohr at 75-100 °C (air bath
temperature) and 20 mmHg. The residue was partitioned
between ether and water and the ether extract was washed
with water, brine and dried (MgSO4). Removal of solvent in
vacuo left 9.61 g which by TLC analysis (CH2Cl2) showed a
major component at Rf 0.75 and some starting phenol at Rf
0.10. This material was chromatographed on silica gel with
methylene chloride elution: 9.11 g; mp 76-78 °C; 1H NMR
(250 MHz, CH3OH-d4) 3.58 (s, 2H, CH2), 5.40-5.44 (d, 1H, Ar),
5.75-5.76 (s, 1H, Ar), 5.84-5.87 (m, 5H, Ar), 6.40-6.44 (d,
1H, Ar); m/z 308 (M + H)+. Anal. (C13H10BrNO3) C,H,N.
was refluxed for 40 min at which time TLC analysis (40%
ether-petroleum ether) indicated the absence of the nitroben-
zene. Ethanol was removed in vacuo. The residue was treated
with ice, then water and portionwise with sodium bicarbonate
until alkaline. Ethyl acetate was added and the mixture was
filtered through Celite. The ethyl acetate extract was washed
with water, brine and dried (MgSO4). Concentration in vacuo
gave a tan solid: 4.48 g; mp 105-107 °C; homogeneous by TLC
(CH2Cl2), Rf 0.17. The analytical specimen was obtained by
drying an aliquot in a drying pistol over refluxing methanol
at 5 mTorr: m/z 366 (M + H)+. Anal. (C21H19NO3S) C,H,N.
7-Ben zyloxy-10,11-d iyd r od ib en zo[b,f][1,4]t h ia zep in -
11-on e (49). A dry three-necked flask equipped with
a
magnetic stirring bar and condenser with a nitrogen inlet was
charged with 4.39 g (12.0 mmol) of 48, 50 mL of dry methylene
chloride and was cooled in an ice-salt bath to -10 °C. By
syringe, 6.60 mL (13.2 mmol) of a 2 M solution of trimethyl-
aluminum44 in hexane was added. After 10 min the ice bath
was removed and the solution was stirred at ambient tem-
perature for 48 h. Cautiously, water was added dropwise
(gasing), followed by 25 mL of 2 N HCl. The content of the
flask was then partioned between 700 mL of water and 1500
mL of chloroform in order to get two homogeneous phases, and
the chloroform extract was washed with brine and dried
(MgSO4). Concentration in vacuo gave a solid which was
triturated with ether and air-dried: 3.66 g (91.7%) of a white
solid; mp 240-243 °C; TLC (70% ether-petroleum ether), Rf
0.22. The analytical specimen was prepared by dissolving 57
mg in 25 mL of hot ethanol and concentrating to 9 mL where
a solid began to separate. Filtration and drying in a drying
pistol over refluxing methanol at 5 mTorr gave 43 mg: mp
240-242 °C; IR (Nujol) 3160(m), 1660(s) cm-1; m/z 334 (M +
H)+. Anal. (C20H15NO2S) C,H,N.
5-F lu or o-2-th iop h en yla n ilin e (50). A solution of 1.60 g
(6.4 mmol) of 5-fluoro-2-thiophenylnitrobenzene45 in 50 mL of
ethanol was treated with 7.22 g (32.0 mmol) of stannous
chloride dihydrate43 and heated to reflux. TLC analysis (40%
toluene-petroleum ether) after 15 min indicated a single major
component with Rf 0.33 and the absence of the nitrobenzene
(Rf 0.48). The solvent was removed in vacuo and the residue
was triturated with ice. Sodium hydroxide solution (15%) was
added in portions until a pH >7, followed by the addition of
water and ethyl acetate. The resulting slurry was filtered
through Celite and the ethyl acetate extract was washed with
saline and dried (MgSO4). Concentration in vacuo gave 1.23 g
of an amber oil. TLC analysis (ibid) indicated, in addition to a
major component at Rf 0.34, two minor impurities with Rfs
0.18 and 0.09. Kugelrohr distillation removed the former as
forerun, the latter as residue, and gave 1.03 g of a pale yellow
oil, bp 100-105 °C (air bath temperature) at 10 mTorr, which
solidified on standing: mp 49-50 °C; m/z 220 (M + H)+. Anal.
(C12H10FNS) C,H,N.
8-F lu or o-10,11-d ih yd r od ib en zo[b,f][1,4]t h ia zep in -11-
on e (51). A solution of 4.68 g (21.34 mmol) of 5-fluoro-2-
thiophenylaniline (50) in 50 mL of dioxane was treated
dropwise with 2.11 g (10.67 mmol) of trichloromethyl chloro-
formate. The temperature was raised to 60 °C (oil bath) and
held for 2 h. TLC analysis (20% ether-hexane) showed a major
component with Rf 0.84, the absence of starting aniline (Rf
0.48) and a very minor impurity with a lower Rf. Dioxane was
removed in vacuo and the residue was Kugelrohr distilled to
yield 3.93 g of 5-fluoro-2-(thiophenyl)phenyl isocyanate as a
yellow oil: bp (air bath temperature) 88-101 °C at 20 mTorr;
IR (film) 2260(s), 2210(s,sh) cm-1. This material was used
without further purification.
To a solution of 2.13 g (16.0 mmol) of aluminum chloride in
16 mL of o-dichlorobenzene at 100 °C was added a solution of
3.92 g of the crude 5-fluoro-2-(thiophenyl)phenyl isocyanate
in 16 mL of the same solvent. The temperature was raised to
150 °C, held for 3.5 h and the solvent was removed using a
Kugelrohr at 20 mmHg. The residue was treated with ice and
triturated: 4.14 g of a tan solid; IR (Nujol) 3150(m), 1660(s),
1645(s) cm-1. The analytical specimen was obtained by dis-
solving 726 mg in 60 mL of hot ethanol and concentration to
4-B e n z y lo x y -2-(2 ′-c a r b o m e t h o x y )t h i o p h e n y ln i -
tr oben zen e (47). A solution of 4.62 g (30 mmol) of thiosalicylic
acid in 20 mL DMAC was added dropwise to a slurry of 1.44
g (60 mmol) of sodium hydride in 10 mL DMAC. 46, 8.30 g
(27 mmol), was added as a solid and the heterogeneous solu-
tion was warmed in an oil bath to 80 °C for 1 h. TLC analysis
(CH2Cl2) revealed the absence of the starting nitrobenzene.
The cooled solution was treated with 5.6 mL (90 mmol) of
iodomethane, the flask was stoppered and stirred at ambient
temperature for 45 h (for convenience). TLC analysis (40%
ether-petroleum ether) indicated a major component at Rf 0.35
and only two more mobile minor components. The content of
the flask was partioned between water and ethyl acetate which
was washed well with water, brine and dried (MgSO4).
Removal of solvent in vacuo gave 11.36 g of a red oil which
was heated in a Kugelrohr to give a distillate of 0.45 g, bp
130-135 °C (air bath temperature) at 5 mTorr, which was
methyl 2-thiomethylbenzoate. The residual 10.58 g was chro-
matographed on 250 g of silica gel with methylene chloride
elution: 9.60 g; mp 78-80 °C. The analytical specimen was
obtained by drying an aliquot in a drying pistol at 5 mTorr at
at ambient temperture: 1H NMR (250 MHz, CDCl3) 3.77 (s,
3H, CH3), 4.87 (s, 2H, CH2); m/z 396 (M + H)+. Anal. (C21H17
NO5S) C,H,N.
-
4-Ben zyloxy-2-(2′-car bom eth oxy)th ioph en ylan ilin e (48).
To 5.00 g (12.6 mmol) of 47 in 50 mL ethanol was added 14.26
g (63 mmol) of stannous chloride dihydrate43 and the solution

386 J ournal of Medicinal Chemistry, 2001, Vol. 44, No. 3
Warawa et al.
18 mL where a solid spontaneously formed. The resulting solid
was dried in a drying pistol over refluxing methanol at 5
mTorr: 0.57 g; mp 241-242.5 °C; homogeneous by TLC (ether:
hexane, 1:1) Rf 0.31; m/z 246 (M + H)+. Anal. (C13H8FNOS)
C,H,N.
(10.41 mmol) of 2.25 M tert-butyllithium in hexane was added
dropwise. S-Phenyl benzenethiosulfonate, 1.43 g (5.68 mmol),
was added in one portion. The solution was stirred overnight,
allowing the bath temperature to rise spontaneously. After
quenching with water, the THF was removed in vacuo and
the aqueous residue was extracted with ether which was
washed with brine and dried (MgSO4). Removal of solvent in
vacuo gave 1.53 g of an oil which slowly solidified. This
material was column chromatographed, eluting with 5%
ether-hexane: 0.84 g (56% yield) of an oil; homogeneous by
TLC (20% ether-hexane), Rf 0.45; m/z 319; 1H NMR (250 MHz,
CDCl3) 1.48 (s, 9H), 6.80-6.86 (t, 1H), 7.09-7.27 (m, 5H),
7.38-7.40 (q, 1H), 7.80 (s, 1H), 8.07-8.11 (d, 1H).
3-Flu or o-2-th ioph en ylan ilin e (56). 55, 0.83 g (2.60 mmol),
in 3 mL of trifluoroacetic acid was stirred at ambient temper-
ature for 30 min. The solvent was removed in vacuo. The
residue was made alkaline with 10% sodium hydroxide,
extracted with ether and dried (MgSO4). Concentration in
vacuo gave 0.54 g of a yellow oil which by TLC (30% ether-
hexane) was essentially a single component, Rf 0.50: IR (film)
3450(m), 3368(m) cm-1. This material was used without
further purification.
3-F lu or o-2-(th iop h en yl)p h en yl Isocya n a te (57). A solu-
tion of 0.53 g (2.42 mmol) of 56 in 5 mL of dioxane was treated
dropwise with 0.24 g (1.21 mmol) of trichloromethyl chloro-
formate. The temperature was raised to 60 °C (oil bath) and
held for 6 h. Dioxane was removed in vacuo and the residue
was Kugelrohr distilled: 0.44 g of a colorless oil; bp (air bath
temperature) 98-105 °C at 20 mTorr; IR (film) 2240(s,sh),
2210(s) cm-1; TLC analysis (15% ether-hexane) showed a
major component with Rf 0.70 and a very minor impurity with
Rf 0.30. This material was used without further purification.
6-F lu or o-10,11-d ih yd r od ib en zo[b,f][1,4]t h ia zep in -11-
on e (58). To a solution of 0.23 g (1.75 mmol) of aluminum
chloride in 4 mL of o-dichlorobenzene at 100 °C was added a
solution of 0.43 g (1.75 mmol) of 57 in 2 mL of the same solvent.
The temperature was raised to 150 °C, held for 7 h and the
solvent was removed using a Kugelrohr at 20 mmHg. The
residue was treated with ice and triturated: 0.31 g of a light
brown solid; IR (Nujol) 3165(w), 1660(s), 1650(s) cm-1. This
material was used without further purification.
1-(2,3-Dim eth oxyp r op yl)p ip er a zin e (59). A mixture of
128.6 g (0.73 mol) of phenylmethylpiperazine, 100 g (0.80 mol)
of 1-chloro-2-hydroxy-3-methoxypropane, 100.9 g (0.73 mol) of
potassium bicarbonate and 1200 mL of toluene was stirred at
reflux for 114 h and the hot solution was filtered. The salts
were dissolved in water, extracted with toluene and ethyl
ether, the organics dried (MgSO4), filtered and added to the
original toluene solution. The solvent was removed and the
residue was distilled through a 4-in. Vigreaux column to yield
186.0 g (96%) of 1-(2-hydroxy-3-methoxypropyl)-4-phenyl-
methylpiperazine, bp 160-169 °C/0.2 mmHg, which was used
in the next step without further purification.
To a stirred slurry of 33.6 g (0.7 mol) of 50% sodium hydride
dispersion in mineral oil and 500 mL of dry toluene under
nitrogen was added a solution of 186.0 g (0.70 mol) of 1-(2-
hydroxy-3-methoxypropyl)-4-phenylmethylpiperazine in 500
mL of toluene over 45 min. The reaction was stirred at reflux
for 1 h then cooled in an ice bath to 10 °C and 195 g (0.7 mol)
of methyl iodide in 150 mL of toluene was added dropwise over
50 min. After stirring under nitrogen at room temperature
overnight the mixture was treated with 250 mL of water and
stirred until all the solid had dissolved. The layers were
separated, the aqueous phase extracted twice with ethyl ether,
the organics combined, dried (MgSO4), filtered and the solvent
removed in vacuo. The oil was decanted from a small amount
of mineral oil and distilled through a 4-in. Vigreaux column
to yield 43.1 g (22%) of 1-(2,3-dimethoxypropyl)-4-phenyl-
methylpiperazine, bp 154-7 °C/0.25 mmHg, which was used
in the next step without further purification.
5-B e n z y lo x y -2-(2 ′-c a r b o m e t h o x y )t h i o p h e n y ln i -
tr oben zen e (52). To a solution of 1.59 g (39.7 mmol) of NaOH
in 30 mL of methanol was added 2.83 g (18.3 mmol) of
thiosalicylic acid and after stirring for 15 min the solvent was
removed in vacuo to give a nice solid. To this flask was added
4.83 g (18.3 mmol) of 5-benzyloxy-2-chloronitrobenzene,46
followed by 30 mL of dry DMAC, and the solution was heated
in an oil bath at 75 °C under nitrogen for 15 h. TLC analysis
(CH2Cl2) showed only a minute amount of the starting ni-
trobenzene. The cooled solution was diluted with 20 mL of
DMAC, 4.0 mL (64.2 mmol) of iodomethane was added, and
the stoppered flask was stirred over the weekend (46 h). The
content of the flask was then transferred to a single-necked
flask with DMAC and the solvent was removed by Kugelrohr
(80-100 °C at 20 mmHg). The residue was partioned between
water and ethyl acetate which was washed with brine and
dried (MgSO4). Removal of solvent in vacuo left a 7.23 g of a
solid. This material was purified by chromatography eluting
with methylene chloride to give 5.77 g (80.2% yield) which was
homogeneous by TLC (CH2Cl2), Rf 0.68, and appeared to be
light-sensitive: 1H NMR (300 MHz, CDCl3) 3.86 (s, 3H, CH3),
5.11 (s, 2H, CH2); m/z 396 (M + H)+.
5-Ben zyloxy-2-(2′-car bom eth oxy)th ioph en ylan ilin e (53).
To 5.00 g (12.6 mmol) of 52 suspended in 50 mL ethanol was
added 14.26 g (63 mmol) of stannous chloride dihydrate43 and
solution was effected by heating to 90 °C (oil bath). After 55
min TLC analysis (40% ether-petroleum ether) indicated the
absence of the nitrobenzene (Rf 0.50) and a major component
with Rf 0.42. Ethanol was removed in vacuo. The residue was
treated with ice, then water and portionwise with sodium
bicarbonate until alkaline. Dilution with ethyl acetate resulted
in a miky emulsion which was filtered through Celite. The
ethyl acetate extract was washed with water, brine and dried
(MgSO4). Concentration in vacuo gave a brown oil, 4.60 g,
homogeneous by TLC (CH2Cl2), Rf 0.40, which slowly solidified.
The analytical specimen was obtained by drying 70 mg in a
drying pistol over refluxing methanol at 5 mTorr: mp 94-96
°C; 1H NMR (300 MHz, CDCl3) 3.95 (s, 3H, CH3), 5.06 (s, 2H,
CH2); m/z 366 (M + H)+. Anal. (C21H19NO3S) C,H,N.
8-Ben zyloxy-10,11-d ih yd r od iben zo[b,f][1,4]th ia zep in -
11-on e (54). A dry three-necked flask equipped with
a
magnetic stirring bar and condenser with a nitrogen inlet was
charged with 4.28 g (12.0 mmol) of 53, 50 mL of dry methylene
chloride and was cooled in an ice-salt bath to -10 °C. By
syringe, 6.60 mL (13.2 mmol) of a 2 M solution of trimethyl-
aluminum44 in hexane was added. After 10 min the ice bath
was removed and the solution was stirred at ambient tem-
perature over the weekend. An aliquot was added to 1 N HCl
and extracted with ethyl acetate. TLC analysis (CH2Cl2)
indicated a major component with Rf 0.10 and some unreacted
53 with Rf 0.38. The solution was again cooled in an ice bath,
6 mL of 2 M trimethylaluminum in hexane was added and
the solution was stirred at ambient temperature overnight.
TLC analysis now indicated complete reaction. Cautiously,
water was added dropwise (gasing), followed by 50 mL of 1 N
HCl. The contents of the flask was then extracted with 500
mL of chloroform which was washed with brine and dried
(MgSO4). Concentration in vacuo gave a tan solid, 3.75 g. This
was dissolved in 450 mL of hot ethanol, concentrated to 50
mL and left at ambient temperature. The resulting solid was
collected by filtration and dried: 2.96 g; mp 206-208 °C; TLC
(2.5% CH3OH-CH2Cl2) Rf 0.48; 1H NMR (300 MHz, CDCl3)
5.03 (s, 2H, CH2), 8.84 (s, 1H, NH); m/z 334 (M + H)+. Anal.
(C20H15NO2S) C,H,N.
N -(t er t -B u t o x y c a r b o n y l)-3-flu o r o -2-t h i o p h e n y l-
a n ilin e (55). A dry three-necked flask equipped with a
thermometer and nitrogen inlet was charged with 1.00 g (4.73
mmol) of N-(tert-butoxycarbonyl)-3-fluoroaniline47 and 42 mL
of THF and cooled to -76 °C. By means of a syringe, 4.63 mL
A mixture of 43.0 g (0.154 mol) of 1-(2,3-dimethoxypropyl)-
4-phenylmethylpiperazine, 4.5 g of 10% Pd-C and 200 mL of
absolute ethanol was hydrogenated in a Parr apparatus at 50
°C and 50 psi for 1.5 h with theoretical uptake of hydrogen.

Nondyskinetic DA Antagonists: Seroquel
J ournal of Medicinal Chemistry, 2001, Vol. 44, No. 3 387
The catalyst was filtered through a Celite pad, the solvent
removed in vacuo and the residual oil distilled through a 4-in.
Vigreaux column: 23.6 g; bp 83-94 °C/0.3 mmHg. Redistil-
lation at 77-81 °C/0.4 mmHg returned 20.94 g (72%) of 1-(2,3-
dimethoxypropyl)piperazine. Anal. (C9H20N2O2) C,N,H: calcd,
10.71; found, 9.92.
75 mL of dry THF and 8.84 mL (0.14 mol) of iodomethane.
The mixture was stirred at 40 °C for 20 min, cooled and
cautiously treated dropwise with water until gas evolution
subsided and all solids were in solution. The mixture was
extracted with three 200-mL portions of ethyl ether, the
combined extracts were washed with saturated saline, dried
(MgSO4), filtered and the solvent removed in vacuo to yield
12.28 g (79%) of a golden oil which was used without further
purification. An analytical specimen was prepared as the
oxalate salt in ethyl ether. Anal. (C13H26N2O4‚C2H2O4) C,H,N.
1-(3,4-Dim eth oxybu tyl)p ip er a zin e (64). To a solution of
12.28 g (0.045 mol) of 63 in 68 mL of n-butanol was added
12.2 g (0.22 mol) of KOH pellets and the mixture stirred at
reflux overnight. The cooled reaction was filtered, the salts
washed with ethyl ether and the solvent removed from the
filtrate to yield an oil. Distillation through a 4-in. Vigreaux
column yielded 5.50 g (64%) of as a colorless oil: bp 68-70
°C/0.15 mmHg. An analytical specimen was prepared as the
hydrochloride salt in ethereal HCl. Anal. (C10H22N2O2‚2HCl)
C,H,N.
1-P h en ylm et h yl-4-(2-m et h oxy-3-p h en ylm et h oxyp r o-
p yl)p ip er a zin e (65). A mixture of 74.88 g (0.424 mol) of
phenylmethylpiperazine, 85.25 g (0.424 mol) of 1-chloro-2-
hydroxy-3-phenylmethoxypropane,49 58.6 g (4.24 mol) of potas-
sium carbonate and 700 mL of toluene was stirred at reflux
for 40 h. After filtration the toluene was removed in vacuo and
the residue was Kugelrohr distilled to yield crude 1-phenyl-
methyl-4-(2-hydroxy-3-phenylmethoxypropyl)piperazine: 129.3
g (90%); bp 225-230 °C/0.1 mmHg. This material was used
without further purification
The above material in 300 mL of toluene was added over
25 min to a slurry of 17.6 g (0.366 mol) of 50% sodium hydride
in mineral oil and 300 mL of toluene. The mixture heated
slowly to reflux (vigorous evolution of hydrogen occurred at
70 °C) and held there for 90 min. The solution was cooled to 5
°C, a solution of 45 mL (0.366 mol) of methyl iodide in 75 mL
of toluene was added dropwise and the mixture stirred at room
temperature overnight. After the cautious addition of 300 mL
of water and stirring for several hours the aqueous layer was
separated and extracted twice with ethyl ether. The combined
organic extract was dried (MgSO4), filtered and the solvent
removed in vacuo. The crude material was chromatographed
on silica gel (ether:hexane, 1:1): 18.35 g (12%), as a yellow
oil. Anal. (C22H30N2O2) H,N,C: calcd, 74.54; found, 74.04.
1-(2-Meth oxy-3-h yd r oxyp r op yl)p ip er a zin e (66). A mix-
ture of 16.9 g (0.48 mol) of 65, 2 g of 10% Pd-C and 250 mL
of ethanol was hydrogenated at 50 °C and 50 psi overnight.
The catalyst was filtered off and the solvent was removed in
vacuo. The residue distilled through a 4-in. Vigreaux column:
6.37 g (77%); bp 95-98 °C/0.2 mmHg. Anal. (C8H18N2O2)
C,N,H: calcd, 10.41; found, 9.80.
cis-2-P ip e r a zin ylm e t h yl-6-h yd r oxym e t h yl-1,4-d iox-
a n e (67). A mixture of 67.4 g (0.382 mol) of phenylmethylpip-
erazine, 80.7 g (0.382 mol) of 2-hydroxymethyl-6-bromomethyl-
1,4-dioxane,50 and 52.8 g of potassium carbonate in 700 mL of
toluene was stirred at reflux overnight. The salts were filtered
off, dissolved in water, the solution extracted with toluene and
the extracts combined with the toluene filtrate. The toluene
was removed in vacuo and the residual oil was Kugelrohr
distilled to yield 100.0 g (85%) of 1-phenylmethyl-4-(6-hy-
droxymethyl-1,4-dioxan-2-ylmethyl)piperazine as a pale yellow
viscous oil that was used without further purification.
A mixture of 99.5 g (0.325 mol) of 1-phenylmethyl-4-(6-
hydroxymethyl-1,4-dioxan-2-ylmethyl)piperazine, 7.5 g of 10%
Pd-C and 400 mL of absolute ethanol was hydrogenated in a
Parr apparatus at 50 °C and 50 psi for 7 h. The catalyst was
filtered through Celite and the solvent was removed in vacuo
to yield an oil with solidified. This solid was recrystallized from
a toluene-hexane-ethyl ether mixture to yield 48.9 g (70%)
of a white solid, mp 103-110 °C. The recrystallization liquor
was concentrated in vacuo and the residue was distilled
through a 4-in. Vigreaux column: 16.3 g (23%) of a viscous
yellow oil; bp 150-160 °C/0.2 Torr. 13C NMR confirmed that
the solid was essentially one isomer while the oil consisted of
S-(+)-2,2-Dim et h yl-4-[1-(4-et h oxyca r b on ylp ip er a zin -
yl)]m eth yl-1,3-d ioxola n e (60). A mixture of 14.24 g (0.090
mol) of 1-ethoxycarbonylpiperazine, 25.00 g (0.0873 mol) of
d-R,â-isopropylideneglycerol γ-tosylate, 12.06 g (0.0873 mol)
of potassium carbonate and 100 mL of toluene was stirred at
reflux for 54 h. The reaction was cooled, filtered and the
saltcake was washed well with toluene. The toluene was
removed under aspirator pressure and the residue distilled
through a 4-in. Vigreaux column: 18.07 g (79%); bp 125-131
°C/0.05 mmHg. Redistillation gave 17.12 g (72%) of analytically
pure material: bp 111-112 °C/0.1 mmHg; [R]25 +5.7° (c 3.9,
D
methanol). Anal. (C13H24N2O4) C,H,N.
S-(-)-1-(2,3-Dim et h oxyp r op yl)-4-et h oxyca r b on ylp ip -
er a zin e (61). A solution of 18.35 g (0.0674 mol) of 60 and 150
mL of absolute ethanol was treated with 100 mL of saturated
etheral HCl, the mixture refluxed for 3 h and stirred at room
temperature overnight. Since the cleavage was not complete
ether was added and the mixed hydrochloride salts filtered
off, dissolved in a small amount of methanol and treated with
saturated etheral HCl to near the cloud point. The solution
was stirred for 1 h, the solvent removed in vacuo and the
residue was recrystallized from acetonitrile to yield 16.80 g
(93%) of S-(-)-1-(2,3-dihydroxypropyl)-4-ethoxycarbonylpip-
26
erazine hydrochloride: mp 102-104 °C; [R]D -24.9° (c 2.9,
methanol).
A solution of 15.05 g (0.056 mol) of S-(-)-1-(2,3-dihydroxy-
propyl)-4-ethoxycarbonylpiperazine and 23.58 g (0.168 mol) of
methyl iodide in 65 mL of DMF was added dropwise under
nitrogen to a stirred slurry of 8.88 g (0.185 mol) of 50% sodium
hydride dispersion in mineral oil and 125 mL of THF, control-
ling the temperature at 50-60 °C by means of a water bath.
The reaction mixture was stirred at 50-55 °C for 20 min,
treated with several volumes of ether, stirred for 15 min and
filtered. The saltcake was washed well with ether, the solvent
removed in vacuo and the resulting oil was distilled through
a 4-in. Vigreaux column: 11.60 g (80%); bp 125-134 °C/0.2
mmHg. Redistillation returned 9.58 g (66%): bp 115-22 °C/
0.2 mmHg; >99.5% optical purity by NMR; [R]D26 +2.2° (c 5.08,
methanol). Anal. (C12H24N2O4) C,H,N.
4-(4-E t h oxyca r b on ylp ip er a zin ylet h yl)-2,2-d im et h yl-
(1,3)-d ioxola n e (62). To a stirred mixture of 80.0 g (0.35 mol)
of 4-methylsulfonylmethyl-2,2-dimethyl-(1,3)-dioxolane,48 48.4
g (0.35 mol) of potassium carbonate and 400 mL of dry toluene,
under nitrogen, was added dropwise 55.53 g (0.35 mol)
4-ethoxycarbonylpiperazine at ambient temperature. The mix-
ture was refluxed for 17 h, cooled, filtered and the salt cake
washed with three 150-mL portions of toluene. The solvent
was removed and the brown oil distilled through a 4-in.
Vigreaux column: 91.1 g of colorless product; bp 175-190 °C/
0.1 mmHg. Redistillation through the same column returned
76.4 g (77%) of the titled compound: bp 130-140 °C/0.25
mmHg. Anal. (C14H26N2O4) H,C: calcd, 58.72; found, 57.81;
N: calcd, 9.78; found, 9.35.
1-(3,4-Dim et h oxyb u t yl)-4-et h oxyca r b on ylp ip er a zin e
(63). A solution of 76.43 g (0.27 mol) of 62 in 500 mL of
methanol was treated with a 50-mL portion of saturated
ethereal HCl. The mixture was heated at reflux for 1.5 h and
the solvent removed in vacuo to yield a brown oil. The oil was
dissolved in 100 mL of water and basified with 10% NaOH.
Extraction with six 200-mL portions of methylene chloride and
drying over MgSO4 yielded a gold-colored oil which was
chromatographed on silica gel (5% methanol in toluene) to
yield 30.55 g (46%) of 1-(3,4-dihydroxybutyl)-4-ethoxycarbon-
ylpiperazine which was used without further purification.
A solution of 14.00 g (0.057 mol) of 1-(3,4-dihydroxybutyl)-
4-ethoxycarbonylpiperazine in 14 mL of dry THF was cau-
tiously added dropwise, under a nitrogen atmosphere, to a
stirred mixture of 6.00 g (0.125 mol) of 50% NaH/mineral oil,

388 J ournal of Medicinal Chemistry, 2001, Vol. 44, No. 3
Warawa et al.
the same isomer contaminated with 30-40% of the other
isomer. Recrystallization of the solid twice from ethyl acetate
returned a single isomer (13C NMR and TLC 20% aqueous
ammonia in methanol): mp 111-114 °C. The assignment of
the 2,6-cis-configuration was made on the basis of COSY NMR
(J H2H3 and J H2H3′ ) 10.0 and 11.3 Hz; J H6H5 and J H6H5′ ) 10.9
and 11.9 Hz) and on the existence of a NOE between H2 and
H6. Anal. (C10H20N2O3) C,H,N.
1-P h en ylm eth yl-4-(d ioxa n -2-ylm eth yl)p ip er a zin e (68).
A mixture of 11.62 g (0.066 mol) of phenylmethylpiperazine,
15.03 g (0.066 mol) of 2-iodomethyl-1,4-dioxane,51 and 9.11 g
(0.066 mol) of potassium carbonate in 200 mL of toluene was
stirred at reflux overnight. The salts were filtered off, the
toluene was removed in vacuo and the residual brown oil was
chromatographed on silica gel (methanol-toluene 1:19) to yield
16.67 g (91%) of a white solid that was used without further
purification. Recrystallization of a sample from toluene yielded
an analytical sample: mp 66-68 °C. Anal. (C16H24N2O2)
C,H,N.
to other drugs. The interval between drug treatments was at
least 2 weeks. Drug were administered orally (2 mL/kg). After
dosing, the monkey was immediately returned to its home
cage. Two observers working in 1-3-h shifts then observed
each monkey continuously for dyskinetic reactions for 6-7 h
after drug administration. Every 30 min the observer recorded
the type of reaction that had occurred and its severity (weak,
weak-to-medium, medium, medium-to-strong, or strong), and
for repetitive reactions such as tongue protrusions or licking
or biting the bars, the observer recorded the number of such
movements in 1-min time samples. Many agents were admin-
istered over a range of doses.
Dr u g Tr ea tm en ts. All drugs were administered using the
vehicle hydroxypropylmethylcellulose (0.5% w/w), Tween 80
(0.1% w/w) in distilled water.
Ack n ow led gm en t. The authors thank Chris Tyler,
J oAnne Smolka, and Dean Synder for their invaluable
technical assistance.
2-P iper azin ylm eth yl-1,4-dioxan e (69). A mixture of 13.45
g (0.049 mol) of 68, 1 g of 10% Pd-C and 200 mL of absolute
ethanol was hydrogenated in a Parr apparatus at 50 °C and
50 psi for 20 h. An additional 2 g of 10% Pd-C was added and
the mixture hydrogenated under the same condition for an
additional 10 h. The catalyst was removed by filteration
through Celite and the solvent was removed in vacuo to yield
a yellow oil. Kugelrohr distillation gave 6.59 g which solidi-
fied: mp 44-49 °C. Anal. (C9H18N2O2) H,N,C: calcd, 58.04;
found, 57.26.
An ta gon ism of Ap om or p h in e-In d u ced Clim bin g a n d
Ap om or p h in e-In d u ced Disr u p tion of Sw im m in g (a p o-
m or p h in e sw im m in g “n or m a liza tion ” test). Female Swiss-
Webster mice weighing approximately 20 g were deprived of
food for approximately 24 h and then dosed intraperitoneally
(ip), orally (po) or subcutaneously (sc) with various doses of
vehicle or a compound to be tested over a range of doses (N )
20 mice/treatment group). Thirty minutes later they were
administered apomorphine HC1 at 1.25 mg/kg sc and placed
into climbing cages. These cages were 9 cm wide, 15 cm deep
and 30 cm high. One wall had 27 horizontal rungs spaced 1
cm apart. Thirteen minutes after apomorphine each mouse
was observed continuously for 1 min and the highest and
lowest rung reached by its front paws was recorded. The mean
of these two scores was used as the score for that mouse. (The
highest and lowest potential scores were 27 and 0, respec-
tively.)
Immediately after the 1-min climbing observation period
each mouse was placed into a circular swimming tank for 2
min and the number of “swims” was counted. The height of
the tank was 15 cm and the diameter was 28 cm. A circular
obstacle, 10.5 cm in diameter and 17 cm high, was placed in
the center of the tank creating a circular swimming channel
8.75 cm wide. The water level was 5.5 cm and the water was
kept at room temperature. Marks were placed on the floor and
side of the tank 180° apart. A “swim” was scored each time a
mouse swam from one mark to the other and the median
number of swims for all the mice was used as the score for
that treatment. The mice were observed through overhead
mirrors, and the number of 180° swims was recorded for each
mouse. The mice were observed at all times for side effects of
the drugs being tested, such as salivation, tremor, stimulation,
piloerection, etc.
Dyk in esia s in Ha lop er id ol-Sen sitized Cebu s Mon k eys.
Adult female and male Cebus monkeys served as subjects.
They were dosed with 1 mg/kg of haloperidol orally, once per
week, until dyskinetic reactions occurred. These dyskinetic
reactions consisted of any one or more of the following bucco-
oral movements: repetitive tongue protrusions, repetitive
biting or licking of the bars of the cage; and the following
choreoathetoid-like movements: various twisting and/or jerk-
ing movements of the arms or legs; twisting of the torso or
neck. When these reactions occurred reliably over a period of
weeks the monkeys were considered to be “sensitized” and
could be used to test for the occurrence of dyskinetic reactions
Su p p or tin g In for m a tion Ava ila ble: Elemental analyses
for compounds 2, 4-38, 42, 46-51, 53, 54, and 59-69. This
material is available free of charge via the Internet at http://
pubs.acs.org.
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