New (sulfonyloxy)piperazinyldibenzazepines as potential atypical antipsychotics: Chemistry and pharmacological evaluation

Article abstract of DOI:10.1021/jm991005d

A series of 2- or 8-trifluoromethylsulfonyloxy (TfO) and 2- or 8- methylsulfonyloxy (MsO) 11-piperazinyldibenzodiazepines, -oxazepines, and - thiazepines were synthesized and evaluated in pharmacological models for their potential clozapine-like propertie

Full text of DOI:10.1021/jm991005d

J . Med. Chem. 1999, 42, 2235-2244
2235
New (Su lfon yloxy)p ip er a zin yld iben za zep in es a s P oten tia l Atyp ica l
An tip sych otics: Ch em istr y a n d P h a r m a cologica l Eva lu a tion
Yi Liao,* Bastiaan J . Venhuis, Nienke Rodenhuis, Wia Timmerman, and Håkan Wikstro¨m
Department of Medicinal Chemistry, University of Groningen, A. Deusinglaan 1, NL-9713 AV Groningen, The Netherlands
Eddie Meier
Lundbeck A/ S, Ottilliavej 9, DK-2500 Copenhagen-Valby, Denmark
Gerd D. Bartoszyk, Henning Bo¨ttcher, and Christoph A. Seyfried
Preclinical Pharmaceutical Research, Merck KGaA, D-64271 Darmstadt, Germany
Staffan Sundell
Department of Medical Biochemistry, University of Go¨teborg, Box 440, SE-405 30 Go¨teborg, Sweden
Received J anuary 7, 1999
A series of 2- or 8-trifluoromethylsulfonyloxy (TfO) and 2- or 8-methylsulfonyloxy (MsO) 11-
piperazinyldibenzodiazepines, -oxazepines, and -thiazepines were synthesized and evaluated
in pharmacological models for their potential clozapine-like properties. In receptor binding
assays, the 2-TfO analogues (18a , GMC2-83; 24, GMC3-06; and previously reported GMC1-
169, 9a ) of the dibenzazepines have profiles comparable to that of clozapine, acting on a variety
of CNS receptors except they lack M1 receptor affinity. Introduction of 2-TfO to clozapine leads
to compound 9e (GMC61-39) which has a similar binding profile as that of clozapine including
having M1 receptor affinity. Interestingly, the MsO analogues, as well as the 8-TfO analogues,
have no or weak dopaminergic and serotonergic affinities, but all 8-sulfonyloxy analogues do
have M1 affinities. In behavioral studies performed to indicate the potential antipsychotic
efficacy and the propensity to induce EPS, 2-TfO analogues blocked effectively the apomorphine-
induced climbing in mice in a dose-dependent manner with ED50 values (mg/kg) of 2.1 sc for
9a , 1.3 po for 18a , 2.6 sc for 24, and 8.2 sc for 9e. On the other hand, they showed a clear dose
separation with regard to their ED50 values (mg/kg) for indicating catalepsy in rats (>44 sc for
9a , 28 po for 18a , 30 sc for 24, and >50 sc for 9e, respectively), thus implicating a more favorable
therapeutic ratio (K/ A, ED50 climbing/ED50 catalepsy) in comparison with typical neuroleptics
such as haloperidol and isoclozapine. Furthermore, compound 18a was also demonstrated to
be an orally potent DA antagonist with an ED50 value of 0.7 mg/kg po in the ex vivo L-DOPA
accumulation model. The present study contributes to the SAR of 11-piperazinyldibenzazepines,
and the 2-TfO analogues of 11-piperazinyldibenzazepines are promising candidates as clozapine-
like atypical antipsychotics with low propensity to induce EPS.
In tr od u ction
lack of clinical efficacy in up to 30% of the therapy-
resistant patients. The atypical antipsychotic clozapine
couples a low incidence of EPS with an improved efficacy
in relief of both positive and negative symptoms as well
as an improved efficacy against treatment-resistant
schizophrenia.4-8 Still, the use of clozapine is limited
due to its propensity to induce agranulocytosis and other
side effects.9-13 For several decades, research has been
focused on studying the atypical nature of clozapine and
on developing new clozapine-like antipsychotic agents
without or with minimal EPS and other disturbing side
effects. This remains to be a great challenge today.
The neuroleptic 11-piperazinyldibenzazepines formed
a valuable chemical class for structure-activity rela-
tionship (SAR) studies.1 Some well-established repre-
sentatives of this class of compounds in the clinical
studies and practice, e.g., loxapine (1), clothiapine (2),
and isoclozapine (3), are known to be typical neurolep-
tics such as haloperidol (5) and chloropromazine (6),
while clozapine (4) is an effective atypical neuroleptic
or antipsychotic (Chart 1).1-3 The typical neuroleptics
that are used to treat schizophrenia are generally potent
dopamine (DA) receptor antagonists, especially at the
DA D2 receptor subtype, with high propensity to induce
acute or chronic motor disturbances (extrapyramidal
side effects, EPS). Other disadvantages of the typical
neuroleptics include the lack of clinical efficacy in the
negative symptoms of schizophrenia and, moreover, the
Some new classes of compounds, from either a chemi-
cal or pharmacological point of view, as new antipsy-
chotics were generated, such as remoxipride, a benza-
mide as a selective D2 antagonist;8,14 risperidone, a D2/
5-HT2 antagonist;15 and sertindole, with limbic selec-
tivity.16 However, the tricyclic piperazinyldibenzaze-
pine remains to be an interesting chemical class with
* Corresponding author: Dr. Yi Liao. Tel: +31-50-3633302. Fax:
+31-50-3636908. E-mail: y.liao@farm.rug.nl.
10.1021/jm991005d CCC: $18.00 © 1999 American Chemical Society
Published on Web 05/27/1999

2236 J ournal of Medicinal Chemistry, 1999, Vol. 42, No. 12
Ch a r t 1. Structures of Some Antipsychotics
Liao et al.
azepine skeleton of clozapine, aiming at maintaining the
interesting pharmacological profile of clozapine while
possibly avoiding some aspects of metabolism of cloz-
apine. It had been documented that clozapine and/or its
metabolites can cause a sometimes fatal agronulocyto-
sis.31 GMC1-169 (9a ) was indicated from the preclinical
pharmacological evaluation to be an atypical antipsy-
chotic agent. It has a profile similar to that of clozapine
both in vitro and in vivo; however, it lacks anticholin-
ergic properties.24,5 GMC1-169 also retains the DA D1
and D2 partial agonist-like properties of clozapine, which
may underline the atypical clinical profile of cloz-
apine.32,33 Therefore, we were encouraged to carry out
a further SAR study to evaluate the trifluoromethylsul-
fonyloxy (TfO)- or methylsulfonyloxy (MsO)-substituted
derivatives of 11-piperazinyldibenzazepine, including
not only its diazepine subclass but also the oxazepine
and thiazepine subclasses. We report here that several
2-TfO analogues of dibenzazepines appear to be inter-
esting as potential clozapine-like atypical antipsychotics.
Ch em istr y
As reported previously,24 the lactam intermediates
10a -c and 2- or 8-methoxydibenzodiazepine derivatives
13a ,b were made by following the conventional synthe-
sis of the tricyclic dibenzodiazepines with some modi-
fications in practice.34,35 O-Demethylation of compounds
10a -c and 13a ,b by aluminum chloride in ethylmer-
captan at room temperature allowed us to obtain 2- or
8-hydroxylactam intermediates 11a -c and 2- or 8-hy-
droxydibenzazepine analogues 14a ,b, respectively. Fur-
thermore, intermediates 11a -c were converted by the
appropriate agents to their sulfonic esters 12a -e, which
were eventually converted to the (sulfonyloxy)dibenzo-
diazepine derivatives 9a -e (Scheme 1). Among them,
compounds 9a ,c were reported before.24 Alternatively,
compounds 14a ,b also led to 9a -d by the formation of
the sulfonic esters. It is more efficient to convert first
the methoxylactam intermediates 10a -c to their (sul-
fonyloxy)lactam derivatives 11a -c before the formation
of the imide intermediates and then the corresponding
11-piperazinyldiazepines 9a -e.
The syntheses of 2-TfO- and 2-MsO-11-(4-methyl-
piperazinyl)dibenz[b,f][1,4]oxazepine (18a ,b) are out-
lined in Scheme 2. 2-Methoxylactam intermediate 15
was prepared according to a four-step protocol from
2-chloronitrobenzene and 2-hydroxy-4-methoxybenzal-
dehyde.36 Again, O-demethylation by aluminum chloride
in ethylmercaptan of 15 gave its hydroxy derivative 16,
which was converted to the corresponding lactam 17a
or 17b. Treatment of 17a or 17b with POCl3 in reluxing
toluene formed the corresponding imino chloride inter-
mediate, which was converted to the final product 18a
or 18b, respectively.
regard to developing new potential atypical antipsy-
chotics. A small modification of the structure can
provide very different pharmacological profiles.3,17,18
Among the newer antipsychotics that have emerged
from this approach are olanzapine (7), in which a
benzene ring of the dibenzodiazepine has been replaced
by a methylated thiophene ring,19 and seroquel (8),
which is a dibenzothiazepine derivative.20 Olanzapine
(7) has a receptor binding profile most similar to that
of clozapine. Interestingly, compounds such as 7 and 8
with similar multireceptor interactions to clozapine are
efficacious and well-tolerated antipsychotics.5
It has been demonstrated that a substituent, such as
a chlorine atom, in an aromatic ring (especially in
2-position) of the tricyclic dibenzazepine system pro-
moted neuroleptic activity. Fluorine was used in flumeza-
pine and fluperlapine,21,22 assuming to reduce the
metabolism of these drugs since some metabolites could
frequently play a role in the toxicological problems of
this class of compounds. Indeed, the halogen substituent
in different antipsychotic diarylazepine analogues has
been considered as an important structural element for
the recognition in the drug-receptor interaction.23 Its
favorable influence might be related not only to the
electron-withdrawing effect but also to the increased
lipophilicity.17
The synthesis of 2-TfO-11-(4-methylpiperazinyl)-
dibenzo[b,f][1,4]thiazepine (24) is outlined in Scheme 3.
4-Iodoanisole reacted with 2-carboxythiophenol to form
acid intermediate 19,37 which was converted to its azide
derivative 20. First, the one-pot treatment of 20 with
aluminum chloride in 1,3-dichlorobenzene under heat-
ing was conducted to generate 22 directly but in only
13-30% yield. Later, not a one-pot but two-step treat-
ment was carried out to improve the total yield (from
20 to 22) up to 80%; that is, heating of 20 alone
Several applications of the aromatic triflate function-
ality in medicinal chemistry have recently been pre-
sented.24-30 An aromatic triflate group induces less
oxidative metabolism in comparison with a hydroxy or
methoxy group due to its electron-withdrawing effect
and lipophilicity. We reported previously the introduc-
tion of the triflate substituent to the intact dibenzodi-

TfO and MsO Piperazinyldibenzazepines
J ournal of Medicinal Chemistry, 1999, Vol. 42, No. 12 2237
Sch em e 1a
a
Reagents and conditions: (a) AlCl3, EtSH, rt, 4 h; (b) PhN(SO2CF3)2, Et3N, CH2Cl2, rt, overnight; or MsCl or Tf2O, Et3N, -78 °C; (c)
i. POCl3, toluene, N,N-di-Me-aniline, reflux, 3 h, ii. N-Me-piperazine, toluene, reflux, 3 h.
Sch em e 2a
a
Reagents and conditions: (a) AlCl3, EtSH, rt, 4 h; (b) PhN(SO2CF3)2, Et3N, CH2Cl2, rt, overnight; (b)′ MeSO2Cl or Tf2O, Et3N, -78
°C 2 h; (c) i. POCl3, toluene, N,N-di-Me-aniline, reflux, 3 h, ii. N-Me-piperazine, toluene, reflux, 3 h.
Sch em e 3a
a
Reagents and conditions: (a) heat; (b) i. SOCl2, reflux 0.5 h, ii. NaN3; (c) 120 °C (oil bath), 20 min; (d) AlCl3, 1,3-dichlorobenzene, 150
°C, 20 min; (e) PhN(SO2CF3)2, Et3N, CH2Cl2, rt, overnight; (f) i. POCl3, toluene, N,N-di-Me-aniline, reflux, 3 h, ii. N-Me-piperazine, toluene,
reflux, 3 h.
generated first the isocyanate intermediate 21, which
was further treated with aluminum chloride under
heating at 150 °C (oil bath) in 1,3-dichlorobenzene for
only 20 min to give 2-hydroxylactam derivative 22. It
was assumed that the ring closure and O-demethylation
happened simultaneously. The final product 24 was
synthesized in a similar manner as described above for
its dibenzoxazapine analogue 18a .
The physicochemical properties in the lipophilicity or
hydrophobicity aspect of these dibenzazepines are in-
dicated by their calculated log P (logarithm of a partition
coefficient) values (Table 1). The smaller the log P value
as an important index of lipophilicity, the less lipophilic
a molecule. The MsO analogues and the compounds
with electron-donating substituents, like methoxy or
hydroxy, have smaller log P values in comparison with

2238 J ournal of Medicinal Chemistry, 1999, Vol. 42, No. 12
Liao et al.
Ta ble 1. Calculated log P Valuesa and Binding Affinities (IC50 Values, nM)b to Various CNS Receptors of Haloperidol and the Tested
Dibenzazepine Analoguesc
compd
log P
D1
36
D2
7.5
330
13
NT
31
920
8100
33000
43
hD2
4.9
260
34
hD3
hD4.2
5-HT2A
5-HT2C
H1
R1
18
9.2
64
NT
12
160
>1000
8700
7.1
120
240
260
1200
27
hM1
5
4
3
1
9a
9b
9c
9d
9e
13a
13b
14a
14b
18a
18b
24
3.98
3.48
3.48
3.67
3.58
1.80
3.58
1.80
4.30
2.71
2.71
2.21
2.21
3.76
1.98
4.04
10
6.5
52
110
14
55d
12 (7.8d)
12d
>1000
11
2.9
NT
34
1200
620
7400
13
21
86
81
440
100
NT
280
>1000
23
NT
NT
47
NT
720
NT
NT
NT
NT
NT
NT
120
NT
NT
5500
9.4
6.0
NT
>1000
1000
35
38
54
39
19
37
27
490
NT
460
130
11
450
120
22
NTe
64
54
6
140
NT
NT
NT
30
NT
NT
NT
NT
52
53
120
NT
NT
NT
490
NT
NT
NT
NT
150
>1000
570
43 (8d)
880d
550d
4900d
23
2100
930
22000
200
550
7400
550
9800
66
NT
NT
NT
52
NT
NT
NT
NT
29
68
12d
4300
1300
6400
40
NT
32
160d
35d
310d
48
NT
100
>1000
23
350
8
230
110
NT
3.6
a
The log P values of the neutral species of compounds in n-octanol/water system were calculated by Pallas 2.1 (CompuDrug Chemistry
b
Ltd.). Results of receptor binding assays are expressed as IC50 values in nM (logarithmic means). For the method descriptions and data
calculations, see the Experimental Section. c Binding affinities of compounds 3-5, 9a ,c, 13, a n d 14 are partly reported previously; see
ref 24. Previously reported data from a different source; see refs 24 and 43 for methodology. e NT, not tested.
d
slightly greater than 114° for 1, 117.5° for 3, and 115°
for 4. For observing the orientation of the piperazine
ring with respect to the dibenzodiazepine skeleton,
compound 18a was compared to the molecular struc-
tures of compounds 1 and 4 in the Cambridge Structures
Database (CSD).38 It was found that the orientation of
the piperazine ring was approximately the same in all
cases. Thus, it seems that the triflate group has little
or negligible influence on the 11-piperazinyldibenza-
zepine conformation. However, it might be that the
triflate group stabilizes this seemingly preferred con-
formation. As calculated by MOPAC, the slightly nega-
tively charged fluorine atom F23 (carring a charge of
-0.20) makes contact (distance of H‚‚‚F < 2.8 Å) with
four slightly positively charged H atoms (the charges
range from 0.13 to 0.25) on piperazine residue. Thus,
there is a favorable electrostatic interaction between the
triflate group and piperazine group. The further analy-
sis of the energetics of the molecule will help decide the
exact role of a triflate group. The detailed information
of compound 18a in the crystal are given as Supporting
Information.
F igu r e 1. Molecular structure of compound 18a , showing 50%
probability thermal ellipsoids for the non-H atoms and the
atom-numbering scheme.
the TfO or Cl analogues. 2-TfO-8-Cl-dibenzodiazepine
9e has a slightly increased log P value (4.30) as
compared to that of clozapine (4) and GMC1-169 (9a )
(log P ) 3.48 and 3.58, respectively). Although the TfO-
or Cl-substituted dibenzazepines are more lipophilic and
thus less aqueous soluble than their MsO, methoxy, or
hydroxy analogues with smaller log P values, their
calculated log P values are all below 5, which is
important for them to avoid absorption-permeability
alerting according to the “rule of 5” for estimating
solubility and permeability of drugs.53
To study how a triflate substituent will affect the
molecular conformation of 11-piperazinyldibenzazepines,
the molecular structure of compound 18a was deter-
mined by single-crystal X-ray analysis. To our knowl-
edge, this is the first reported single-crystal X-ray
analysis of an aryl triflate. The observed conformation
of compound 18a is shown in Figure 1. The central
seven-membered ring of 18a is in a boat conformation,
like that of loxapine (1), isoclozapine (3), and clozapine
(4).1,38 However, the dihedral angle between the planes
of the two benzene rings was found to be 124°, which is
P h a r m a cologica l Resu lts a n d Discu ssion
In Vitr o Bin d in g Stu d y. The newly synthesized
compounds 9b,d ,e, 18a ,b, and 24 were tested in vitro
for their ability to bind to the different CNS receptors
(D1, D2, 5-HT2A, 5-HT2C, H1, R1, and M1) and were
compared with our previously reported compounds
(9a ,c, 13a ,b, and 14a ,b) and the reference compounds
haloperidol (5), clozapine (4), isoclozapine (3), and
loxapine (1). Furthermore, compounds 9a ,e, 18a ,b, and
24 were tested in binding assays in vitro for their
affinities to human cloned DA D2, D3, and D4.2 receptors
and were compared with above-mentioned reference
compounds (Table 1).
From the binding profiles of the dibenzodiazepines,
it is seen that 2-substituted analogues generally show
more potent dopaminergic and serotonergic activities
than their corresponding 8-substituted analogues. The
typical neuroleptic haloperidol (5) was shown to have
high affinities at D2 and R1 receptors (IC50 ) 7.5 and
18 nM), intermediate affinities at 5-HT2A and D1 recep-
tors (IC50 ) 55 and 36 nM), and low affinities at 5-HT2C
,

TfO and MsO Piperazinyldibenzazepines
J ournal of Medicinal Chemistry, 1999, Vol. 42, No. 12 2239
Ta ble 2. Effects on Behavioral Models Indicative for Antipsychotic Activity or EPSa
c
apomorphine-induced
climbing (ED50, mg/kg)
catalepsy
(ED50, mg/kg)
∆ED50
drug
K/ Ab
5.5
(mg/kg)
haloperidol (5)
0.27 po
0.10 sc
17 po
1.5 po
1.23 po
0.15 sc
>83 po
>26.8 sc
<0.96 po
0.31 sc
0.45 sc
0.3 sc
0.25 sc
>100 po
>32.6 sce
<1.0 po
0.35 scd
0.72 scd
2.0 sc
2.5
clozapine (4)
loxapine (1)
>5.8
>5.8
<25
5.6 sc
0.04 po
0.04 (0.07d) sc
0.27 scd
1.7 scd
8.8 (or 5d)
2.7
clotiapine (2)
isoclozapine (3)
1.1
(1.8 scd)
>100 po
>44 sc
28 po
GMC1-169 (9a )
GMC2-83 (18a )
11 po
2.1 sc
1.3 po
2.2 sc
>9
>20
21.5
>89 po
>41.9 sc
26.7 po
(100 po, 32%)f
20 sc
9
17.8 sc
27.4 sc
>41.8 sc
GMC3-06 (24)
GMC61-39 (9e)
2.6 sc
8.2 sc
30 sc
>50 sc
11.5
>6.1
a
Inhibition of apomorphine-induced climbing effects in mice and catalepsy in rats was measured; see the Experimental Section and
refs 39 and 40 for details. K/ A (therapeutic ratio) ) quotient ED50 catalepsy/ED50 climbing. c ∆ED50 ) ED50 catalepsy - ED50 climbing.
b
Data from ref 1. e Data from ref 24. f Catalepsy score percent at an extremely high dose of 100 mg/kg po.
d
H1, and M1 receptors (IC50 > 1000 nM). Isoclozapine (3)
has high affinities at both DA (D1 and D2) and serotonin
(5-HT2A and 5-HT2C) receptors. Clozapine (4) showed
moderate affinities at DA (D1 and D2) receptors but high
affinities at 5-HT2A and 5-HT2C receptors. Compounds
9a ,e, 13a , 18a , and 24 showed comparable profiles to 3
and 4 in these respects. It is noteworthy that both
clozapine (4) and isoclozapine (3) showed high affinities
for M1 receptor (IC50 ) 9.4 and 6.0 nM, respectively).
The analogues with an electron-donating group at the
2- or 8-position, like compounds 13a ,b and 14a ,b, kept
this anticholinergic activity. Interestingly, the analogues
with electron-withdrawing groups at the 2-position, like
9a ,b, displayed no affinities at M1 receptors (IC50 >1000
nM), but those at the 8-position, like 9c,d , showed good
affinities at M1 receptor (IC50 ) 38 and 35 nM, respec-
tively). As a matter of fact, the 8-MsO (9d ) and 8-TfO
(9c) analogues are inactive at all the tested receptors
except for M1 receptors. Comparably, the 2-MsO ana-
logue 9b showed improved but still weak affinities to
D2, 5-HT2A, and R1 receptors. The 2-TfO analogue 9a ,
however, showed a very promising binding profile like
those of clozapine and isoclozapine except for lacking
M1 affinity. It is also noteworthy that the 2-HO ana-
logue 14a showed very good serotonergic over dopam-
inergic affinities, and in addition, this compound had a
moderate R1 binding affinity and potent M1 binding
affinity. The disubstituted analogue, 2-(trifluorometh-
ylsulfonyloxy)clozapine (9e), like compound 9a , also
showed a promising clozapine-like binding profile. In-
It is noteworthy that, after introducing 2-TfO group,
both 18a and 24 are also lacking M1 binding affinity as
does the diazepine analogue 9a .
In binding assays at human cloned DA hD2, hD3, and
hD4.2 receptors, compound 9a showed a similar profile
as clozapine (4), while compound 18a showed a similar
binding profile as loxapine (1), except for a slightly lower
hD4.2 binding affinity, as compared to those of clozapine
(4) and loxapine (1). Compound 9a showed a higher
binding affinity at the hD3 receptor than did clozapine.
Compared to clozapine, compound 9e has improved hD2
and hD3 binding affinities but a lower affinity at the
hD4.2 receptor. Compound 24 showed potent binding
affinities at hD2 and hD3 receptors but not at the hD4.2
receptor.
In other binding assays, compound 18a showed inter-
mediate affinity at histamine H1 receptors (IC50 ) 120
nM), in comparison with 23 and 47 nM for clozapine
and compound 9a , respectively. Compounds 18a and 9a
were found to have weak and negligible affinities at H3
receptors (Ki > 20 µM)39 and also at 5-HT1A and 5-HT1B
receptors (data not shown). Interestingly, compounds
9a and 18a were found to have high affinities in binding
assays at 5-HT6 and 5-HT7 receptors (data not shown;
to be published by Unelius et al.).
In Vivo P h a r m a cology. Compounds 9a ,e, 18a , and
24 were studied and compared to the reference com-
pounds 1-5 in the in vivo behavioral models for their
ability to inhibit apomorphine-induced climbing effects
in mice and, additionally, their cataleptogenic activity
in rats (Table 2). Typical antipsychotics, haloperidol (5),
loxapine (1), clothiapine (2), and isoclozapine (3), showed
the greatest antipsychotic potential on inhibition of
apomorphine-induced climbing in mice at quite low
doses under sc or po administrations. However, they
also produced catalepsy at low doses. The dose separa-
tion of these two effects, indicated by the therapeutic
ratio (K/ A, quotient ED50 catalepsy/ED50 climbing), is
determined to be small, e.g., K/ A (sc) to be 5, 2.7, 1.1,
and 2.5 for compounds 1-3 and 5, respectively. In
contrast, the atypical antipsychotic clozapine (4), at
higher doses, effectively blocked apomorphine-induced
climbing effects in mice (ED50 ) 5.6 sc and 17 po mg/
kg) and induced no catalepsy in rats up to 100 po and
terestingly, this compound had the M1 affinity (IC50
)
54 nM), although this affinity is weaker than that of
clozapine.
The 2-TfO-dibenzoxapine analogue 18a showed a
similar binding profile as its diazepine analogue 9a .
This compound had good affinities at the DA D1 and
D2, 5-HT2A, 5-HT2C, and R1 receptors. Interestingly, the
2-MsO analogue 18b lost dopaminergic affinities and
showed only low affinity at 5-HT2A receptor (IC50 ) 230
nM). Furthermore, the 2-TfO-dibenzothiazepine ana-
logue 24 showed high affinities at D2 and R1 receptors
(IC50 ) 32 and 3.6 nM for D2 and R1 receptors,
respectively) but comparably lower 5-HT2A and 5-HT2C
binding affinities (IC50 ) 110 and 280 nM, respectively).

2240 J ournal of Medicinal Chemistry, 1999, Vol. 42, No. 12
Liao et al.
Ta ble 3. Accumulation of L-DOPA Measured ex Vivo in the
Striatum of Rats
2-TfO analogue 9e (GMC61-39) has a binding profile
comparable to that of clozapine including M1 affinity.
Interestingly, the MsO analogues, as well as the 8-TfO
analogues, have no or weak dopaminergic and seroton-
ergic affinities, but all 8-sulfonyloxy analogues do have
M1 affinities. However, to postulate that the 2-TfO
analogues are potential atypical antipsychotics solely
based on their receptor binding profiles can be mislead-
ing as, for instance, isoclozapine also has a binding
profile comparable to that of clozapine but still behaves
as a typical antipsychotic in functional studies.
haloperidol (5) clozapine (4) GMC2-83 (18a )
ED50, mg/kg po
0.1
17
0.7
32.6 sc mg/kg. Thus, clozapine displayed a good EPS
separation (K/ A > 5.8 sc or po). It is worthy to note
that the therapeutic ratio discussed here is just a
preliminary indication, since the differences in phar-
macokinetics in different testing species may have an
influence on the therapeutic index of a drug.
In behavioral studies performed to indicate their
potential antipsychotic efficacy, the 2-TfO analogues
blocked the apomorpine-induced climbing effects in mice
effectively and in a dose-dependent manner like DA
antagonists, and in particular, compounds 9a , 18a , and
24 are more potent in this respect than clozapine. It is
noteworthy that compound 18a is orally very potent in
this in vivo model and also in the biochemical ex vivo
model. On the other hand, compounds 9a ,e, 18a , and
24 all displayed a clear dose separation with regard to
their ED50 values for causing catalepsy in rats versus
the ED50 values for showing presumed antipsychotic
efficacy, thus implicating a favorable therapeutic ratio
(K/ A). Since catalepsy in rats is regarded as a measure
indicative of EPS in humans, and D2 receptor antago-
nistic properties are associated with antipsychotic ac-
tion, these 2-TfO analogues (9a ,e, 18a , 24) with widely
divergent cataleptogenic versus DA antagonistic activi-
ties may be of clinical interest as clozapine-like atypical
antipsychotics with a low potential to induce EPS. Since
this unique series of compounds are structurally closely
related to clozapine but differ in binding affinities for
receptors allegedly important for antipsychotic action
and/or side effects (e.g., D2, 5-HT2A, M1), clinical study
on these compounds would help elucidate which pre-
clinical in vitro, ex vivo, and in vivo properties best
predict clozapine-like atypical antipsychotic activity.
Like clozapine (4), our previously reported compound
9a (GMC1-169) showed no cataleptogenic activity at
either sc or po administration up to 44 sc and 100 po
mg/kg doses but inhibited effectively the apomorphine-
induced climbing effects in mice at much lower doses
(ED50 ) 11 po and 2.1 sc mg/kg). Compound 18a was
shown to be a potent DA antagonist, which has very
high potency for inhibition of apomorphine-induced
climbing effects in mice, and moreover, it is orally active
(ED50 ) 1.3 mg/kg po). At an extremely high dose of
100 mg/kg po administration, it has only marginal
cataleptogenic capacity (scoring 32%), but surprisingly
and interestingly, this compound showed a catalepto-
genic activity (57%) at 30 mg/kg po in rats. ED50 values
for its cataleptogenic activities were eventually deter-
mined to be 28 po and 20 sc mg/kg. Nevertheless, these
are still quite high doses (at least 21.5- and 9-fold,
respectively, for po and sc administration) as compared
to those necessary for its antipsychotic effect. Therefore,
its therapeutic ratio (K/ A) is more favorable than that
for the typical antipsychotics including compound 1. The
2-TfO-thiazepine analogue 24 has ED50 values of 2.6 and
30 mg/kg sc for inhibition of apomorphine-induced
climbing effects in mice and catalepsy in rats, respec-
tively, therefore, also a favorable K/ A ratio (11.5).
Compound 9e, a 2-TfO analogue of clozapine itself,
showed the antipsychotic activity comparable to cloz-
apine (4) (ED50 climbing ) 8.2 and 5.6 mg/kg sc for 9e
and 4, respectively) and no cataleptogenic activity at up
to the extremly high dose of 50 mg/kg sc.
E x Vivo Bioch em ist r y. Accumulation of the dop-
amine precursor L-DOPA was measured ex vivo in the
striatum of rats after po administration of compound
18a , as compared to clozapine (4) and haloperidol (5).
In intact rats treated with the DOPA decarboxylase
inhibitor NSD1015 (m-hydroxybenzylhydrazine), com-
pound 18a increased L-DOPA accumulation in a dose-
dependent manner with ED50 values of 0.7 mg/kg po.
Compounds 4 and 5 had ED50 values of 17 and 0.1 mg/
kg po, respectively (Table 3). As drugs that mimic the
action of endogenous transmitters decrease turnover,
increased turnover indicates receptor blockade. Com-
pound 18a is thus demonstrating to be an orally potent
DA antagonist in this ex vivo biochemical model.
In summary, the pharmacological evaluation of this
new series of 2- or 8-sulfonyloxylated 11-piperazi-
nyldibenzodiazepines, -oxazepines, and thiazepines has
shown that the monosubstituted 2-TfO analogues (9a ,
GMC1-169; 18a , GMC2-83; and 24, GMC3-06) have
multireceptor binding profiles comparable to those of
clozapine and/or other parent neuroleptic diazepines.
However, there is one important difference: i.e., they
lack anticholinergic properties. The disubstituted 8-Cl-
Exp er im en ta l Section
Ch em istr y. Melting points were determined on an Elec-
trothermal digital melting point apparatus and are not cor-
rected. IR spectra were obtained on a ATI-Mattson spectrom-
eter. 1H and 13C NMR spectra were recorded on a Varian
Gemini 200 NMR spectrometer. Chemical shifts are given in
δ units (ppm) and relative to TMS or deuterated solvent.
Coupling constants (J ) are given in Hz. Mass spectra were
obtained on a Unicam 610/Automass 150 GC-MS system or
on a Finnegan 3300 system. Elemental analyses were per-
formed in the Microanalytic Laboratory, University of Gronin-
gen, and were within 0.4% of theoretical values. Merck silica
gel (Kieselgel 60, 70-230 mesh) was used for flash chroma-
tography. Chemicals used were either commercially available
(Aldrich) and used without further purification or prepared
according to the references indicated.
The syntheses of 2- or 8-methoxy-5,10-dihydro-11-oxodibenzo-
[b,e][1,4]diazepine (10a ,b), 2- or 8-hydroxy-5,10-dihydro-11-
oxodibenzo[b,e][1,4]diazepine (11a ,b), 2- or 8-(trifluorometh-
ylsulfonyloxy)-5,10-dihydro-11-oxodibenzo[b,e][1,4]diazepine
(12a ,c), 2-methoxy- or 2-hydroxy-11-(4-methylpiperazinyl)-5H-
dibenzo[b,e][1,4]diazepine (13a or 14a ), and 2- or 8-(trifluo-
romethylsulfonyloxy)-11-(4-methylpiperazinyl)-5H-dibenzo-
[b,e][1,4]diazepine (9a ,c) were described in a previous report.24
2-(Meth ylsu lfon yloxy)-11-(4-m eth yl-1-p ip er a zin yl)-5H-
d iben zo[b,e][1,4]d ia zep in e (9b). Compound 11a (226 mg,
1 mmol) in 10 mL of dichloromethane and 1 mL of triethyl-
amine was cooled to -78 °C under N2(g). To the solution was
added methanesulfonyl chloride (0.082 mL, 1.2 mmol) in 10

TfO and MsO Piperazinyldibenzazepines
J ournal of Medicinal Chemistry, 1999, Vol. 42, No. 12 2241
mL of dichloromethane dropwise under stirring. Stirring was
continued for 1 h to allow the temperature to come back to
room temperature and stopped after the disappearance of 11a
(monitored by TLC in ethyl acetate). The reaction solution was
washed with 2 N HCl (20 mL) and brine (20 mL), dried over
MgSO4, filtered, and evaporated. The residue was purified by
flash chromatography (SiO2, 9:1 to 1:1 hexanes-ethyl acetate
gradient) to afford 270 mg (89%) of intermediate 12b as a light-
yellow solid [MS (EI) m/z 304; Rf 0.8 in EtOAc], which was
used in the next step without further characterization.
Intermediate 12b (200 mg, 0.66 mmol), phosphorus oxy-
chloride (3 mL), toluene (6 mL), and N,N-dimethylaniline (0.2
mL) were combined, heated to reflux for 3 h, and then
evaporated under vacuum. The generated imino chloride
intermediate was added to 10 mL of toluene and treated with
2 mL of N-methylpiperazine under refluxing for 3 h. After
cooling to room temperature the solution was diluted with 30
mL of ethyl acetate, washed with 2 N NaOH (20 mL), and
evaporated to dryness under vacuum. The residue was purified
twice by flash chromatography (SiO2, EtOAc then 9:1 dichlo-
romethane-ethanol) and recrystallization from n-hexane/ethyl
acetate (4:1) to afford 139 mg (54%) of compound 9b: mp 188-
190 °C; IR (KBr) 3341, 2937, 2795, 1607, 1466, 1366, 1161,
2-Hyd r oxyd iben z[b,f][1,4]oxa zep in -11(10H)-on e (16).
Compound 15 (1.2 g, 5.0 mmol) in 10 mL of EtSH and 10 mL
of dichloromethane was treated with AlCl3 (5.0 g) with stirring
at room temperature for 6 h. The mixture was evaporated and
quenched with 20 mL of ice-water and then 20 mL of 4 N
aqueous HCl. White precipitate was collected, washed with
water, dried under vacuum, and characterized as the desired
product: 1.0 g, 88%; mp 233-235 °C (lit.36 mp 228-230 °C);
IR (KBr) 3281, 3192, 3057, 1672 cm-1; 1H NMR (DMSO-d6) δ
9.72 (s, 1 H), 7.25 (m, 1 H), 7.16-7.06 (m, 6 H), 6.93 (dd, 1 H,
J ) 3, 8 Hz); 13C NMR (DMSO-d6) δ 166.1, 154.8, 151.8, 131.5,
126.5, 126.0, 125.5, 121.9, 121.4, 121.2, 116.5; MS (EI) m/z 227
(M+).
2-(Tr iflu or om eth ylsu lfon yloxy)diben z[b,f][1,4]oxazepin -
11(10H)-on e (17a ). Compound 16 (1.0 g, 4.4 mmol) in 20 mL
of dichloromethane and 5 mL of triethylamine was cooled to
-78 °C and treated with triflic anhydride (1.54 mL, 7 mmol).
The mixture was stirred for 3 h to allow the temperature to
come back to room temperature, quenched with 3 mL of water,
and concentrated. The residue was flash chromatographed on
a silica gel column (hexane and ethyl acetate, 9:1 then 1:1, as
eluents) to afford 1.1 g (70%) of the title compound as a white
crystal: mp 164-166 °C; IR (KBr) 3186, 3057, 1662 cm-1; 1H
NMR (CDCl3) δ 8.87 (s, 1 H), 7.87 (d, 1 H, J ) 3.2 Hz), 7.47-
7.09 (m, 7 H); MS (EI) m/z 359 (M+). Anal. (C14H8NO4SF3) C,
H, N.
1
1144 cm-1; H NMR (CDCl3) δ 7.26-6.67 (m, 7 H), 5.03 (s, 1
H), 3.42 (m, 4 H), 3.11 (s, 3 H), 2.50 (m, 4 H), 2.36 (s, 3 H); MS
(EI) m/z 386 (M+). Anal. (C19H22N4SO3) C, H, N.
8-(Meth ylsu lfon yloxy)-11-(4-m eth yl-1-p ip er a zin yl)-5H-
d iben zo[b,e][1,4]d ia zep in e (9d ) was made from 8-hydroxy-
5,10-dihydro-11-oxodibenzo[b,e][1,4]diazepine (11b) in three
steps (total yield ca. 50-60%) in the same manner described
for compound 9b. 9d : mp 155-7 °C; IR (KBr) 3352, 1599,
Alternatively, compound 16 (250 mg, 1.1 mmol) in CH2Cl2
(10 mL) was treated with N-phenyltrifluoromethanesulfo-
nimide (540 mg, 1.5 mmol) in the presence of Et3N (1 mL) with
stirring overnight at room temperature. After evaporation the
residue was purified by flash chromatography in the same
manner described above to afford the product in 85-90% yield.
2-(Tr iflu or om eth ylsu lfon yloxy)-11-(4-m eth yl-1-p ip er -
a zin yl)d iben z[b,f][1,4]oxa zep in e (18a ). Compound 17a (1.0
g, 2.8 mmol), phosphorus oxychloride (5 mL), toluene (10 mL),
and N,N-dimethylaniline (1.0 mL) were combined and heated
to reflux for 3 h. The mixture was evaporated under vacuum
to afford the imino chloride intermediate, which was used in
the next step without further purification.
The above imino chloride in 10 mL of toluene was treated
with 5 mL of N-methylpiperazine under refluxing for 3 h. After
evaporation the residue was purified by flash chromatography
(SiO2, 9:1 hexane and ethyl acetate then pure ethyl acetate
as eluents) and recrystallization from n-hexane/ethyl acetate
(10:1) to afford 1.01 g (82%) of the title compound: mp 117-
118 °C; IR (KBr) 3070, 2941, 2793, 1610, 1566 cm-1; 1H NMR
(CDCl3) δ 7.54-7.20 (m, 7 H), 3.74 (brs, 4 H), 2.77 (brs, 4 H),
2.59 (s, 3 H); 13C NMR (CDCl3) δ 159.9, 158.2, 151.4, 145.6,
139.8, 127.2, 125.9, 125.3, 125.1, 124.7, 123.0, 120.0, 118.4 (d,
120.7, 116.1, CF3, J ) 337.5 Hz), 54.7, 47.3, 46.0; MS (EI) m/z
441 (M+). Anal. (C19H18N3O4SF3) C, H, N.
1561, 1463, 1373, 1181 cm-1 1H NMR (CDCl3) δ 7.35-7.24
;
(m, 2 H), 7.07-7.03 (m, 2 H), 6.99-6.67 (m, 3 H), 4.97 (s, 1
H), 3.47-3.41 (m, 4 H), 3.07 (s, 3 H), 2.47 (m, 4 H), 2.35 (s, 3
H); 13C NMR (CDCl3) δ 162.7, 152.4, 145.8, 141.9, 140.8, 131.9,
130.2, 123.3, 123.0, 120.1, 119.9, 119.7, 116.5, 54.8, 46.0, 45.9,
36.8; MS (EI) m/z 386 (M+). Anal. (C19H22N4SO3) C, H, N.
Syn th esis of Com p ou n d 9e. 2-Methoxy-8-chloro-11-oxo-
5H-dibenzo[b,e][1,4]diazepine (10c) was prepared in three
steps in a similar manner as described for the syntheses of
10a ,b in the literature:24,34 mp 213-216 °C (lit.40 mp 215-
217 °C).
2-H yd r oxy-8-ch lor o-11-oxo-5H -d ib e n zo[b,e][1,4]d i-
a zep in e (11c). Compound 10c was O-demethylated with AlCl3
in EtSH at room temperature in the same manner described
for compounds 10a ,b:24 mp 248-249 °C; IR (KBr) 3339, 3178,
1
1635, 1581 cm-1; H NMR (DMSO-d6) δ 9.1 (s, 1 H), 6.6 (s, 2
H), 6.4-6.1 (m, 4 H); 13C NMR (DMSO-d6) δ 173.3, 156.7,
147.1, 145.0, 136.3, 131.4, 128.8, 128.7, 125.8, 125.5, 125.2,
122.2; MS (EI) m/z 260 (M+). Anal. (C13H9N2O2Cl) C, H, N.
2-(Tr iflu or om et h ylsu lfon yloxy)-8-ch lor o-11-oxa -5H -
d iben zo[b,e][1,4]d ia zep in e (12e) was made from compound
10c by triflation with PhN(Tf)2 in a similar manner described
2-(Me t h ylsu lfon yloxy)-11-(4-m e t h yl-1-p ip e r a zin yl)-
d iben z[b,f][1,4]oxa zep in e (18b). Compound 16 (130 mg) in
20 mL of CH2Cl2 and 2 mL of triethylamine was treated with
methanesulfonyl chloride (0.4 mL) at -78 °C for 2 h. The
mixture was quenched with 4 N NaOH, extracted with
dichloromethane (2 × 20 mL), washed with 4 N HCl and brine,
dried over MgSO4, filtered, and evaporated to give the crude
lactam intermediate (17b) as a beige solid residue. The lactam
17b was converted to the product 18b in the same manner as
described previously for 18a . 18b: mp 140-142 °C; IR (KBr)
for compounds 12a ,c:24 mp 281-283 °C; IR (KBr) 1649 cm-1
;
1H NMR (CDCl3) δ 7.8 (d, 2 H), 7.6 (t, 3 H), 7.4-7.1 (m, 4 H);
13C NMR (CDCl3) δ 168.7, 149.2, 139.2, 139, 138.1, 133.6,
132.9, 130.8, 130.2, 128.8, 124.6, 123.1, 118.5 [d (121.7, 115.3),
J ) 321 Hz]; MS (EI) m/z 360 (M+).
2-(Tr iflu or om eth ylsu lfon yloxy)-8-ch lor o-11-(4-m eth yl-
1-p ip er a zin yl)-5H-d iben zo[b,e][1,4]d ia zep in e (9e). Com-
pound 9e was made from intermediate 12e in 75% yield in
the same manner described previously for compounds 9b,d :
1601, 1572, 1368, 1166 cm-1 1H NMR (CDCl3) δ 7.30 (m, 3
;
mp 121-123 °C; IR (KBr) 3636, 3281, 2941, 1611, 1567 cm-1
;
H), 7.20-6.90 (m, 4 H), 3.60 (brs, 4 H), 3.15 (s, 3 H), 2.60 (brs,
4 H), 2.58 (s, 3 H); 13C NMR (CDCl3) δ 159.4, 151.6, 145.0,
127.1, 125.9, 125.8, 124.6, 123.4, 122.6, 120.0, 54.4, 46.9, 45.7,
37.3; MS (EI) m/z 387 (M+). HRMS (EI) m/z 387.1233 (found);
calcd for C19H21N3O4S, 387.1252.
1H NMR (DMSO-d6) δ 7.6 (s, 1 H), 7.5 (dd, 1 H), 7.3 (d, 1 H),
7.2 (d, 1 H), 6.9 (s, 1 H), 3.3 (brs, 4 H), 2.4 (brs, 4 H), 2.2 (s, 3
H); 13C NMR (DMSO-d6) δ 161.2, 154.7, 144.1, 141.7, 127.6,
126.2, 125.4, 125.2, 124.5, 123.4, 123.1, 122.2, 121.3, 118.5 (d,
121.7, 115.3, J ) 321.6 Hz), 54.2, 46.9, 30.6; MS (EI) m/z 474
(M+). Anal. (C19H18N4O3SF3Cl) H, N; C: calcd, 48.06; found,
48.81. HRMS (EI) m/z 474.0756 (found); calcd for C19H21N3O4S,
474.0740.
Syn th esis of Com p ou n d 24. 2-[(4-Methoxyphenyl)thio]-
benzoic acid (19) was prepared from 2-carboxythiophenol and
4-iodoanisole according to Pelz et al.37
2-[(4-Meth oxyp h en yl)th io]ben zoyl Azid e (20). Com-
pound 19 (14 g, 53.8 mmol) was treated with 50 mL of SOCl2
and 1 mL of DMF at refuxing for 1 h. The mixture was
evaporated under vacuum, and the solid residue was dissolved
Syn th esis of Com p ou n d s 18a /b. 2-Meth oxyd iben z[b,f]-
[1,4]oxa zep in -11(10H)-on e (15) was prepared in a four-step
protocol according to ref 36: mp 168 °C (lit.36 mp 168 °C).

2242 J ournal of Medicinal Chemistry, 1999, Vol. 42, No. 12
Liao et al.
into dry acetone (100 mL). The resulting solution was added
dropwise to a cooled 30% aqueous NaN3 (60 mL) during 30
min. The suspension was stirred at 0 °C for 1 h, diluted with
water (400 mL), filtered, washed well with water, and dried
overnight under vacuum to afford 14 g of the title compound
as a fine solid: mp 72-74 °C; IR (KBr) 3294, 2995, 2937, 2843,
membranes from rat corpus striatum was described by Hyt-
tel.42,43
h -Dop a m in e D2 r ecep tor s: Incubations were carried out
in 50 mM Tris-HCl buffer, pH 7.35, containing 120 mM NaCl,
5 mM MgCl2, and 1 mM EDTA. The assay contained in a total
volume of 1 mL: 0.15 nM [3H]spiperone, specific radioactivity
3.6 TBq/mmol, and membranes of A9L cells expressing the
human D2 dopamine receptor (40-60 µg of protein/assay).
Incubations were run for 15 min at 37 °C and terminated by
rapid filtration on Whatman GF/B filters and 3 washes with
ice-cold 50 mM Tris-HCl buffer, pH 7.35 (without salts and
EDTA). Nonspecific binding was determined in the presence
of 1 mM (+)-butaclamol. Membranes containing the cloned
receptor were purchased from Receptor Biology Inc., 10000
Virginia Manaor Rd, Suite 360, Beltsville, MD 20705. Under
these conditions total binding amounted to 4000-6000 dpm/
filter and nonspecific binding to 170-300 dpm/filter; variability
of triplicates run in parallel was <10%.
h -Dop a m in e D3 r ecep t or s: A CHO cell expressing the
human dopamine D3 receptor was bought from INSERM, Paris
(P. Sokoloff). Preparation of cell membranes: Pelleted cells
(about 0.1-0.3 mL) were homogenized with a Polytron ho-
mogenizer for about 4 s at 80% of the maximal speed in 2 mL
of 10 mM Tris-HCl buffer, pH 7.4, containing 5 mM MgSO4.
The homogenate was diluted 5-fold in the same buffer and
centrifuged at 50000g for 15 min. The resulting pellet was
resuspended by gentle sonication in incubation buffer in such
a way that the amount of membranes per assay corresponded
to about 70 µg of protein. Otherwise, the procedure of hD2
receptor binding is followed, resulting in a total binding of
∼4000 dpm/filter and a nonspecific binding of ∼250 dpm/filter;
variability of triplicates run in parallel was <10%.
h -Dop a m in e D4.2 r ecep tor s: The procedure is identical
to the one used for the hD2 receptor assay except that the
amount of membranes was slightly higher, i.e., corresponding
to about 100 µg of protein/assay. Membranes of CHO-K1 cells,
expressing the human D4.2 receptor, were purchased from
Receptor Biology Inc. (address as above). Under these condi-
tions, total binding amounted to 4000-6000 dpm/filter and
nonspecific binding to 400-800 dpm/filter; variability of
triplicates run in parallel was <10%.
Ser oton in 5-HT2A r ecep tor s: Affinity at 5-HT2A receptors
in membranes from rat frontal cortex was determined using
[3H]ketanserin (0.5 nM) as radioligand as described by Klock-
ow et al.44
1
2137, 1675, 1588, 1224 cm-1; H NMR (CDCl3) δ 6.7-7.5 (m,
8 H), 3.8 (s, 3 H); 13C NMR (CDCl3) δ 159.7, 137.6, 133.8, 133.4,
131.5, 131.3, 127.8, 126.5, 126.1, 124.8, 123.7, 115.3, 115.0,
55.2; MS (EI) m/z 257 (M+ - N2). Anal. (C14H11N3SO2) C, H.
2-H y d r o x y d ib e n zo [b ,f][1,4]t h ia ze p in -11(10H )-o n e
(22): Meth od A. compound 19 (1.4 g, 4.7 mmol) in 20 mL of
dichlorobenzene was added to a suspension of AlCl3 (2.7 g) in
o-dichlorobenzene (50 mL) with stirring. The mixture was
heated to reflux for 15 min, cooled to room temperature, added
to 150 mL of CHCl3, and extracted with 4 N aqueous HCl (2
× 50 mL). The organic layer was concentrated under vacuum,
and the residue was purified by flash chromatography (SiO2,
ethyl acetate as eluent) and recrystallization from ethanol/n-
hexane to afford 240 mg (21%) of the title compound: mp 298
°C; IR (KBr) 3147, 3015, 1630, 1565 cm-1; 1H NMR (CDCl3) δ
6.8-7.5 (m, 7 H); 13C NMR (CDCl3) δ 168.7, 158.3, 140.3, 139.4,
133.3, 132.5, 130.3, 129.9, 125.6, 125.4, 123.5, 119.3, 117.8;
MS (EI) m/z 243 (M+). Anal. (C13H9NSO2) C, H, N.
Meth od B. 2-[(4-Methoxyphenyl)thio]benzoyl azide (2.85 g,
10 mmol) was dissolved in 100 mL of 1,3-dichlorobenzene and
heated with a preheated oil bath at 120 °C for 30 min with
stirring. After oil bath was removed, the mixture was first
cooled to room temperature and then to -20 °C. AlCl3 (5.35 g,
40 mmol) was added slowly to it, and the temperature was
then allowed to rise to room temperature. The mixture was
further heated at 150 °C for 20 min. After cooling to room
temperature, 100 mL of HCl saturated THF solution was
added and stirring was continued for 5 min. Water (3 mL) was
added dropwise, and the mixture was filtered. The filtrate was
evaporated, and the residue was purified by flash chromatog-
raphy (SiO2, n-hexane/EtOAc gradient) to yield 1.94 g (80%)
of the desired product.
2-(T r iflu o r o m e t h y ls u lfo n y lo x y )d ib e n zo [b ,f][1,4]-
th ia zep in -11(10H)-on e (23). Compound 22 (100 mg, 0.41
mmol) was triflated with N-phenyltrifluoromethanesulfo-
nimide in the same manner described above for compound 17a
to afford 130 mg (84%) of the title compound which was
recrystallized from ethyl acetate/n-hexane: mp 301 °C dec; IR
(KBr) 3043, 1649 cm-1 1H NMR (CDCl3) δ 7.8 (d, 1 H), 7.6
;
(m, 3 H), 7.1-7.4 (m, 4 H), 6.9 (m, 1 H); 13C NMR (CDCl3) δ
168.2, 149.2, 138.8, 138.1, 133.6, 133.0, 130.2, 129.8, 126.4,
124.8, 124.6, 123.0, 118.5 (d, 121.7, 115.3, J ) 320 Hz, CF3);
MS (EI) m/z 375 (M+). Anal. (C14H9NO4SF3) C, H, N.
Ser oton in 5-HT2C r ecep tor s: Inhibition by drugs of the
binding of 0.50 nM [3H]mesulergine to cloned rat 5-HT2C
receptors expressed in membranes from 3T3 cells was deter-
mined as described by Bøgesø et al.45
2-(T r i flu o r o m e t h y ls u lfo n y lo x y )-11-(4-m e t h y l-1-
p ip er a zin yl)d iben zo[b,f][1,4]th ia zep in e (24). Compound
23 (80 mg), phosphorus oxychloride (1 mL), toluene (1 mL),
and N,N-dimethylaniline (0.1 mL) were combined and heated
to reflux for 3 h. The mixture was evaporated under vacuum
to afford the imino chloride intermediate, which was used in
the next step without further purification.
R1 a d r en ocep tor s: Inhibition by drugs of the binding of
0.25 nM [3H]prazosin to R1 adrenoceptors in rat brain mem-
branes was determined as described by Arnt et al.46
Mu sca r in ic ch olin er gic M1 r ecep tor s: Inhibition by
drugs of the binding of 1.0 nM [3H]pirenzepine to cloned
human M1 receptors expressed in membranes from CHO-K1
cells was estimated as described by Meier et al.47
The above imino chloride in 1 mL of toluene was treated
with 1 mL of N-methylpiperazine under refluxing for 3 h. After
evaporation the residue was purified by flash chromatography
(SiO2, 9:1 hexane and ethyl acetate then pure ethyl acetate
as eluents) and recrystallization from hexane to afford 33 mg
of the title compound: mp 117 °C; IR (KBr) 3063, 2951, 1604,
Hista m in e H1 r ecep tor s: Inhibition by drugs of the
binding of 2.0 nM [3H]mepyramine to histamine H1 receptors
in rat brain membranes was determined as described by Hall
et al.48
Da ta ca lcu la tion s: Results on receptor binding study were
given as IC50 values (nM). Two complete concentration-
response curves were determined by using five concentrations
of the test drugs in triplicate (covering 3 decades). IC50 values
were estimated from hand-drawn log concentration-response
curves or computer-assisted log-logit analysis. In a series of
n determinations the variance of the log ratio (VARR) between
the double determinations is determined according to the
formula: VARR ) Σ (log R1)2/2n, where R1 is the ratio and n is
the number of observations. The VARR is equivalent to the
square of the standard deviation of the log ratio (SDR2). In case
the ratio is greater than corresponding to 2 × SDR (95%
confidence interval), further determinations were performed
and outliers discarded. For the binding analysis, the following
1
1559 cm-1; H NMR (CDCl3) δ 6.70-7.60 (m, 7 H), 3.48 (brs,
4 H), 2.45 (brs, 4 H), 2.35 (s, 3 H); 13C NMR (CDCl3) δ 169.1,
158.7, 149.0, 148.3, 140.2, 135.8, 133.8, 132,2, 129.5, 126.0,
125.5, 123.3, 122.0; 118.8 (d, 121.7, 115.8, J ) 297 Hz), 54.5,
45.6; MS (EI) m/z 457 (M+). Anal. (C19H18N3O3S2F3) C, H, N.
P h a r m a cology. 1. In Vitr o Recep tor Bin d in g Assa ys.
Dop a m in e D1 r ecep tor s: Inhibition by drugs of the binding
of 0.20 nM [3H]SCH23390 to dopamine D1 receptors in
membranes from rat corpus striatum was determined as
described by Hyttel et al.41
Dop a m in e D2 r ecep tor s: Inhibition by drugs of the
binding of 0.50 nM [3H]spiperone to dopamine D2 receptors in

TfO and MsO Piperazinyldibenzazepines
J ournal of Medicinal Chemistry, 1999, Vol. 42, No. 12 2243
serotonin-2 pKi values. J . Pharmacol. Exp. Ther. 1989, 251,
238-246.
SDR’s were obtained: D1, 1.5 (n ) 100); D2, 1.5 (n ) 100);
5-HT2A, 1.4 (n ) 30); 5-HT2C, 1.3 (n ) 100); H1, 1.5 (n ) 100);
R1, 2.0 (n ) 76); M1, 1.4 (n ) 91).16,24
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In h ibition of a p om or p h in e-in d u ced clim bin g effects
in m ice51 (fu n ction a l DA a n ta gon ism ): Climbing was
induced by injection of 1.25 mg/kg apomorphine and 2 min
later was assessed in cylindrical wire mesh cages (11.5 cm in
diameter, 15 cm in height) by scoring every 2 min for a period
of 20 min as follows: (0) no climbing behavior, (1) at least two
forelimbs on the wire mesh, (2) all four forelimbs on the wire
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Ack n ow led gm en t. We are grateful to the Research
Laboratory at Lundbeck A/S for supporting the receptor
binding assays and to the Department of CNS Research
at Merck KGaA for supporting the behavioral study,
binding assays (hD2/3/4.2 and 5-HT2A), and L-DOPA
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