Aminimides as potential CNS acting agents. I. Design, synthesis, and receptor binding of 4′-aryl aminimide analogues of clozapine as prospective novel antipsychotics

Article abstract of DOI:10.1071/CH07197

A series of substituted 1-[4-(8-chloro-5H-dibenzo[b,e][1,4]diazepin-11-yl)- 1-methylhexahydropyrazin-1-ium]-1-aminimide derivatives were designed on the basis of the physicochemical properties of the aminimide functional group and synthesized as potential antipsychotic agents for the treatment of schizophrenia. The target compounds were readily prepared in two steps from clozapine (8-chloro-11-(4-methylpiperazino)-5H-dibenzo[b,e][1,4]diazepine) and involved N-acylation of a common hydrazinium salt intermediate by an acyl chloride or activated ester in the presence of a strong base. The aminimides were tested for in vitro activity at the dopamine D₄ and serotonin 5-HT_2A receptors and were found to possess modest affinity for both receptor systems. CSIRO 2007.

Full text of DOI:10.1071/CH07197

Full Paper
CSIRO PUBLISHING
www.publish.csiro.au/journals/ajc
Aust. J. Chem. 2007, 60, 673–684
Aminimides as Potential CNS Acting Agents. I. Design,
Synthesis, and Receptor Binding of 4ꢀ-Aryl Aminimide
Analogues of Clozapine as Prospective
Novel Antipsychotics
Ben Capuano,A Ian T. Crosby,A,D Edward J. Lloyd,A Juliette E. Neve,A,B
and David A. TaylorC
ADepartment of Medicinal Chemistry, Victorian College of Pharmacy, Monash University,
381 Royal Parade, Parkville, Vic. 3052, Australia.
BCurrent address: Natural Product Discovery, Eskitis Institute for Cell and Molecular Therapies,
Griffith University, Nathan, Qld 4111, Australia.
CDepartment of Pharmaceutical Biology, Victorian College of Pharmacy, Monash University,
381 Royal Parade, Parkville, Vic. 3052, Australia.
DCorresponding author. Email: ian.crosby@vcp.monash.edu.au
A series of substituted 1-[4-(8-chloro-5H-dibenzo[b,e][1,4]diazepin-11-yl)-1-methylhexahydropyrazin-1-ium]-1-amin-
imide derivatives were designed on the basis of the physicochemical properties of the aminimide functional group and
synthesized as potential antipsychotic agents for the treatment of schizophrenia. The target compounds were readily
prepared in two steps from clozapine (8-chloro-11-(4-methylpiperazino)-5H-dibenzo[b,e][1,4]diazepine) and involved
N-acylation of a common hydrazinium salt intermediate by an acyl chloride or activated ester in the presence of a strong
base. The aminimides were tested for in vitro activity at the dopamine D4 and serotonin 5-HT2A receptors and were found
to possess modest affinity for both receptor systems.
Manuscript received: 12 June 2007.
Final version: 25 July 2007.
Introduction
Cl
H
N
HO
Schizophrenia is a debilitating mental illness that severely
impairs one’s perception of reality, and damages a variety of
emotional, behavioural, and cognitive functions.[1] This most
common form of psychosis afflicts about 1% of the population.
The symptoms of schizophrenia are divided into two distinct
classifications; positive (delusions, hallucinations, and disorga-
nized behaviour) and negative (social and emotional withdrawal,
affective flattening).[2] For further elaboration on the complex
disease state of schizophrenia, see cited reviews.[2–4]
Antipsychotic drugs are divided into two clinical classes,
namely; typical (effective in treating positive symptoms and tend
to induce Parkinsonian type side-effects) and atypical (effective
intreatingbothpositiveandnegativesymptoms, andarevirtually
devoid of dose-limiting side-effects).[5] Fig. 1 depicts four com-
mercially available antipsychotic agents commonly prescribed
for the treatment of schizophrenia.
Cl
N
N
N
O
Clozapine
(Clozaril)
Haloperidol
(Serenace)
N
H3C
F
O
N
H
N
S
N
H3C
F
N
CH3
N
N
N
N
Risperidone
(Risperdal)
Olanzapine
(Zyprexa)
O
Clozapine, the prototype atypical antipsychotic, causes no
extrapyramidal side effects (EPS) and is effective against both
positive and negative symptoms. Clozapine has weak dopamine
D2 receptor affinity, and significantly greater dopamine D4.4
(the most common polymorphic variant of the D4 receptor)
and serotonin 5-HT2A receptor affinities. Clozapine is unfor-
tunately hampered by a 1–2% incidence of agranulocytosis[2]
(a life-threatening blood disorder) which mandates expensive
H3C
Fig. 1. Clinically prescribed antipsychotic agents.
hematological monitoring. As a consequence, clozapine is gen-
erally administered for the treatment of refractory schizophrenia.
The clinical model for antipsychotic activity we have selected
is directed towards compounds with a potential dual action.
© CSIRO 2007
10.1071/CH07197
0004-9425/07/090673

674
B. Capuano et al.
Primarily, the clozapine-like profile of high D4.4 and 5-HT2A
receptor affinity is postulated for the improvement of posi-
tive and negative symptoms, respectively, and reduced striatal
D2 affinity to minimize EPS liability. Because of clozap-
ine’s almost ideal therapeutic profile, structural analogues have
been synthesized as biological probes to further explore this
model.[2,6]
character of aminimides is reported to result in enhanced
solubility in protic, aprotic, and non-polar media.[9,10] This inter-
esting property led us to consider the use of aminimides in
clozapine-like molecules of general structure 2 (Fig. 2), in order
to address some of the limitations of our compounds. Here we
report the design, synthesis, and preliminary pharmacological
evaluation of these aminimide-based clozapine analogues.
The general structure (1) for the 4ꢀ-arylmethyl clozapine ana-
logues investigated in the previous study[6] essentially contains
the tricyclic nucleus of clozapine and an additional substituted
aromatic ring attached to the distal nitrogen by a methylene
spacer. The reported analogues (2) have replaced the methylene
spacer with an aminimide functional group and the aryl por-
tion (Ar) of the aminimide acyl moiety is represented by: (a) a
monosubstituted phenyl ring that includes a variety of electron-
withdrawing and electron-releasing groups (phenyl analogues,
2a–y); (b) a catechol-based moiety (2z and 2aa); and (c) a
5-substituted indol-2-yl group connected by the 2-position
(9, 10).
In a previous study, the synthesis of a series of 4ꢀ-arylmethyl
clozapine analogues of general structure 1 (Fig. 2), were reported
along with their affinities at the D4.4 and 5-HT2A receptors.[6]
From this research, it was concluded that the introduction of
an N-arylmethyl group into the structure of clozapine, although
affording compounds with respectable affinity, appears not to
have a superior effect on binding at the receptors of interest com-
pared with clozapine. In addition, incorporation of a substituted
arylmethyl group into the structure of clozapine increased the
lipophilicity and reduced the aqueous solubility to a level diffi-
cult to use in assays, therefore indicating potential bioavailability
issues. Recently, there have been reports describing the use of the
aminimide moiety in azole antifungals,[7] and peptidomimetic
inhibitors of elastase[8] and HIV-1 protease.[9] The zwitterionic
Chemistry
Our recent communication on the chemistry of benzoyl
azides[11] showed that direct synthesis of the desired series of
aminimide analogues from clozapine was not feasible. A con-
venient and flexible synthesis was consequently developed for
all of the target aminimides, in two steps from clozapine (4).
Clozapine (4) was readily synthesized from the key intermedi-
ate lactam (3) and N-methylpiperazine in the presence of the
Lewis acid, titanium tetrachloride (Scheme 1).
The general approach used for all aminimides involved initial
N-amination of 4 with O-mesitylenesulfonylhydroxylamine[12]
to produce the hydrazinium salt (5), followed by N-acylation
of 5 with an appropriate acylating agent (Scheme 1). Com-
pounds 2a–u and 2z were formed by N-acylation of 5 with the
H
N
H
N
Cl
Cl
N
N
N
N
O
ꢁ
N
4ꢀ
1
2
ꢁ
N
N
ꢂ
Aryl
CH3
Aryl
X
H
CH2
X
Fig. 2. General substituted arylmethyl (1) and aryl aminimide analogues
(2) of clozapine at physiological pH.
H
N
H
N
Cl
Cl
(ii)
N
N
N
N
ꢂ
SO3
4
ꢁ
N
N
H3C
CH3
H2N
H3C
CH3
5
CH3
O
O
(i)
Cl
OH, TBTU
X
O
(iii)
(iii)
H
N
6v
6a–u, 7
CH3
Cl
NH
H
N
H
N
O
3
Cl
Cl
N
N
N
N
O
O
2a–u, 2z
2v
ꢁ
N
ꢁ
N
N
N
X
CH3
CH3
ꢂ
ꢂ
O
CH3
Scheme 1. Reagents and conditions: (i) TiCl4, N-methylpiperazine, 1,4-dioxan, reflux, 2 h. (ii) MesSO3NH2, CH2Cl2,
0◦C, 10 min. (iii) NaH, DMF, −15◦C to room temp., 8 h.

4ꢀ-Aryl Aminimide Analogues of Clozapine
675
appropriately substituted benzoyl chloride (6a–u, 7, Scheme 1)
in 33–64% yield. Compound 2v was synthesized in 38%
yield by N-acylation of 5 with an activated (hydroxybenzotria-
zolyl, HOBt) ester (6v) prepared from 4-acetylbenzoic acid and
O-benzotriazol-1yl-N,N,Nꢀ,Nꢀ-tetramethyluronium tetrafluoro-
borate (TBTU). The 5-methoxyindolyl aminimide analogue (9)
was prepared from 5 and the corresponding indolecarboxylic
acid and TBTU (Scheme 2, 34% yield). The hydroxy ana-
logues 2w–y, 2aa, and 10 were prepared by BBr3-mediated de-
etherification of their corresponding methoxyphenyl analogues
(2q–s), the methylenedioxy ether (2z), and 5-methoxyindolyl
compounds (9), respectively (Scheme 3) in 42–79% yield.
Structural assignment of the aminimides was achieved from
their NMR analyses and mass spectrometric data. The X-ray
crystal structure of 2g (Fig. 3) has also been published,[13]
which gave insight into structural features associated with the
aminimide functional group (a group not well parameterized in
molecular modelling packages) and its incorporation into the
structure of clozapine.
Receptor Binding Studies
Details of the in vitro assays for the synthesized compounds
are described in the Experimental section. Tables 1 and 2 list
preliminary percentage inhibition of radioligand at a compound
concentration of 10−6 M for the dopamine D4.4 and serotonin
5-HT2A receptors for all test compounds. All affinities were
below that of clozapine, which recorded 54 and 90% inhibition
at D4.4 and 5-HT2A receptors, respectively, at a concentration of
10−6 M.
The affinities of the phenyl analogues for D4.4 receptors in
mammalian CHO-K1 cells, calculated as a percentage inhibi-
tion using [3H]spiperone as the competing radioligand, ranged
from −14 to 40% at 10−6 M (Table 1), with the 4-fluorophenyl
compound (2d) displaying the greatest affinity. The affinities
of the phenyl analogues for 5-HT2A receptors in rat cerebral
cortex (percentage inhibition, [3H]ketanserin) ranged from 6
to 53% at 10−6 M (Table 1), with the 3,4-dihydroxyphenyl
(catechol) compound 2aa exhibiting the highest affinity. The
affinities for the indolyl analogues 8, 9 for the D4.4 receptor
were poor with 9 and 14% inhibition, respectively (Table 2).
Our interest in the crystal structure of 2g was to examine
the effect of the aminimide substituent on the geometries of
the piperazine ring and the tricyclic nucleus, relative to clozap-
ine. The tricyclic portion of 2g is in a similar conformation to
that observed for the parent compound, clozapine (4),[14] which
shows the buckled nature of the dibenzodiazepine nucleus with
the central seven-membered heterocycle in a boat conformation.
As was observed for clozapine (4), the piperazine ring of 2g
adopts a chair conformation.The methyl group of 2g assumes an
equatorial orientation as is observed with clozapine. This obser-
vation supports the axial orientation of the 4-chlorobenzimide
group for the solution structure, which was deduced by the cor-
relations observed in the nuclear Overhauser effect (NOESY)
spectrum of 2g (Fig. 4). NOes are observed between the +N-
methyl proton resonance and both the axial and equatorial H2ꢀ
andH6ꢀ protonresonances, whichindicatesthatthemethylgroup
lies equatorial and the (4-chlorobenzoyl)amide group axial. A
further nOe observed between the H2ꢀꢀ/H6ꢀꢀ proton resonance
(δ 7.93) and resonances of H2ꢀb/H6ꢀb (δ 4.43) and H3ꢀ/H5ꢀ (δ
3.87) provides further evidence for the axial 4-chlorobenzimide
group. The 4-chlorobenzimide moiety also shows features simi-
lar to those reported for other aminimides.[15,16] The N–N bond
is similar to a single bond in length.There is also charge delocal-
ization from the nitrogen onto the carbonyl oxygen atom of the
molecule, which is supported by the characteristic aminimide
H
N
H
N
Cl
Cl
(i)
N
N
N
N
O
O
ꢁ
ꢁ
N
N
R1
N
R2
N
CH3
CH3
C
ꢂ
ꢂ
2q: 2-OCH3
2r: 3-OCH3
2s: 4-OCH3
2w: 2-OH
2x: 3-OH
2y: 4-OH
C
R1 ꢃ H3CO
R
2 ꢃ HO
HO
HO
O
O
C
C
2z
9
2aa
10
H
N
H
N
C
C
H3CO
HO
Scheme 3. Reagents and conditions: (i) BBr3, CH2Cl2, −78◦C, 1 h, room
infrared resonance (−OC=N) at 1554 cm−1
.
temp.
H
N
H
N
Cl
Cl
N
N
N
N
(i)
O
ꢁ
O
H
N
9
H
N
N
ꢁ
5
N
N
OH, TBTU
CH3
ꢂ
H2N
CH3
ꢂ
SO3
8
H3CO
H3CO
H3C
CH3
CH3
Scheme 2. Reagents and conditions: (i) NaH, DMF, −15◦C to room temp., 8 h.

676
B. Capuano et al.
Similarly, compound 8 showed poor dopaminergic affinity at
the D4.4 receptor. A notable result was the 5-HT2A receptor
affinity of compound 9, which showed a very respectable affin-
ity corresponding to 67% inhibition. This result is gratifying
as it demonstrates relatively enhanced recognition of the
5-HT2A receptor by the incorporation of a serotonin-like moi-
ety (5-hydroxyindol-2-yl), and may be useful in establishing
further structure–activity relationships. Overall, the synthesized
compounds all showed mild binding affinity for both the D4.4
and 5-HT2A receptors with none exhibiting affinity superior to
that of clozapine, or the corresponding substituted arylmethyl
compounds published previously.[6] As a result, no compounds
assayed met the criteria of greater than 50% inhibition at both
receptors, to warrant Ki determination.
H7
Cl1
C8
H6
C9
C7
H4
C6
C10
H8
C3
H3
H5
C5
C4
C1
Conclusions
C11
N2
H2
C2
N1
Several aminimide analogues of clozapine were synthesized and
evaluated in vitro for their affinity for the dopamine D4.4 and
serotonin 5-HT2A receptors. All of the compounds showed a
marked reduction in binding at the two receptor systems when
compared with clozapine, thus indicating minimal potential for
atypical antipsychotic activity. The reduced affinities, in gen-
eral for the aminimide analogues, may reflect the introduced
aromatic moiety’s axial disposition in contrast to the equatorial
disposition of the original series. Further work will focus on
the biochemical effects of extending the alkyl spacer between
the aminimide functional group and the newly introduced aryl
moiety.
C13
H1
C12
H16
N3
Cl4
H9
C14
H10
C17
H15
H14
C16
H13
H17
H11
C26
C15
N4
C18
H12
Cl3
N5
H20
C21
H18
C19
O1
H19
H21
C22
C23
C24
Experimental
C20
General
C25
H23
Melting points were determined using a Reichert Micro-melting
point apparatus and are uncorrected. Microanalyses were car-
ried out by Chemical and Micro Analytical Services Pty Ltd,
Melbourne, Australia, or the Chemistry Department, Univer-
sity of Queensland. Infrared spectra were recorded using a
Hitachi 270-30 infrared spectrometer as potassium bromide
Cl2
H22
Fig. 3. ORTEP view of 2g (50% probability displacement ellipsoids).
Cl
8
H
HN
N
H
4ꢀ
H
N
1
H
H
CH3
N
ꢁ
ꢂ
H
O
N
ꢁ
NCH3
H
H
2g
H2ꢄ, H6ꢄ
H1
H9
Cl
H5
H3ꢀ, H5ꢀ
H2ꢀb, H6ꢀb
H2ꢀa, H6ꢀa
ppm
3.0
3.5
4.0
4.5
5.0
8.0
7.5
7.0
6.5
6.0
5.5
5.0
4.5
4.0
3.5 ppm
Fig. 4. 300 MHz 1H–1H NOESY spectrum of 2g. Some nOe correlations (arrows) have been omitted for clarity.

4ꢀ-Aryl Aminimide Analogues of Clozapine
677
Table 1. Preliminary binding studies
Table 2. Preliminary binding studies
H
H
N
N
Cl
Cl
N
N
N
N
O
O
2a–z, 2aa
ꢁ
N
ꢁ
N
H
N
8: R = CH3
9: R = H
N
ꢂ
N
X
CH3
CH3
ꢂ
RO
Compound
X
Binding affinity percentage
inhibition [% I] at 10−6 M
A
A
Compound
R
Binding affinity percentage
inhibition [% I] at 10−6 M
D4.4
5-HT2A
[3H]spiperone
[3H]ketanserin
A
A
D4.4
5-HT2A
Clozapine
2a
2b
2c
2d
2e
2f
2g
2h
2i
2j
2k
2l
2m
2n
2o
2p
2q
2r
2s
2t
2u
2v
2w
2x
—
H
2-F
3-F
4-F
2-Cl
3-Cl
4-Cl
54
−14
3
90
47
3
[3H]spiperone
[3H]ketanserin
Clozapine
8
9
—
CH3
H
54
14
9
90
17
67
2
12
34
21
19
12
42
18
21
14
24
9
40
−13
20
14
17
5
ADetermined in duplicate by MDS PANLABS (Taiwan).
2-Br
3-Br
4-Br
mesh) was used for column chromatography. Preparative TLC
was performed on glass plates (Merck ART 5717). Solvents
were purified by literature methods.[17,18] Hexane refers to the
hydrocarbon fraction boiling between 60 and 80◦C.
−13
2-CH3
3-CH3
4-CH3
2-CF3
3-CF3
4-CF3
2-OCH3
3-OCH3
4-OCH3
2-COCH3
3-COCH3
4-COCH3
2-OH
3-OH
4-OH
3
2
12
−1
3
29
16
8
8-Chloro-11-(4-methylpiperazino)-
5H-dibenzo[b,e][1,4]diazepine 4
−18
25
12
28
−7
10
14
28
11
23
33
17
To a solution of 1-methylpiperazine (3.43 mL, 3.10 g,
30.8 mmol) in anhydrous dioxan (30 mL) under nitrogen was
added a solution of titanium tetrachloride in toluene (1.0 M,
6.76 mL, 6.76 mmol), which resulted in an immediate deep green
coloration (titanium–amine complex). The reaction mixture was
heated to 50–55◦C and a hot solution of 17 (1.50 g, 6.15 mmol)
in anhydrous dioxan (20 mL) was added.The mixture was heated
to reflux for 2 h, cooled, and evaporated to dryness. The brown
coloured residue was partitioned between ethyl acetate (200 mL)
andaqueoussodiumhydroxide(2 M, 50 mL)andfilteredthrough
a bed of Celite. The organic layer was separated and the aque-
ous phase extracted with ethyl acetate (2 × 100 mL).The organic
fractions were combined, washed with water (2 × 50 mL), dried
over anhydrous sodium sulfate, and evaporated to dryness. The
resulting oily yellow residue was purified by flash chromatogra-
phy (ethyl acetate followed by 85/15 ethyl acetate/methanol) to
afford a bright yellow foam (1.97 g, 98%), which recrystallized
from acetone/water to afford 4 (1.76 g, 88%) as brilliant yellow
prisms, mp 181–183◦C [lit.[19] 183–184◦C]. δH (CDCl3) 2.35
(3H, s, CH3N), 2.52 (4H, br s, H3ꢀ, H5ꢀ), 3.49 (4H, br s, H2ꢀ,
H6ꢀ), 5.00 (1H, s, H5), 6.61 (1H, d, J 8.5, H6), 6.80–6.83 (2H,
m, H4, H7), 7.01 (1H, app td, J 7.5, 1, H2), 7.07 (1H, d, J 2.5,
H9), 7.24–7.30 (2H, m, H1, H3). δC (CDCl3) 46.0 (CH3N), 47.2
(C2ꢀ, C6ꢀ), 55.0 (C3ꢀ, C5ꢀ), 120.0 (C6), 120.1 (C4), 123.0 (C2),
123.1 (C7), 123.5 (C11a), 126.8 (C9), 129.1 (C8), 130.3 (C1),
131.9 (C3), 140.4 (C5a), 141.8 (C9a), 152.8 (C4a), 162.8 (C11).
m/z (+ESI, 30V) 329 (35%, M[37Cl]H+), 327 (100%, MH+).
33
10
13
29
22
26
22
6
2y
2z
2aa
8
13
53
3,4-OCH2O–
3,4-diOH
ADetermined in duplicate by MDS PANLABS (Taiwan).
(KBr) disks for solids, as thin films of liquids (neat) between
sodium chloride plates, and as chloroform (CHCl3) solutions
of gums. UV-Vis spectra were recorded as ethanolic solutions
with a Pharmacia Biotech Ultraspec 2000 UV-VIS spectro-
meter utilising Swift II software. 1H and 13C NMR spectra
were obtained on a Bruker DPX-300 and a Bruker DRX-500
spectrometer. Chemical shifts are reported in δ units relative
to internal tetramethylsilane (TMS) or the deuterated solvent.
13C NMR spectra were recorded at 75.5 MHz on a Bruker
DPX-300 spectrometer or, where stated, at 125.72 MHz on
a Bruker DRX-500 spectrometer. The NOESY, homonuclear
(1H/1H) correlation spectroscopy (DQFCOSY and gradient
COSY), and inverse heteronuclear (1H/13C) correlation spec-
troscopy (HMQC and gradient HMBC) were obtained by the
standard Bruker pulse sequences for the structural assignment
of some NMR spectra. Mass spectra were recorded on a JEOL
JMS-DX300 or a Micromass platform II mass spectrometer
in positive ion electrospray mode. High-resolution mass spec-
tra (HRMS) were recorded with a Bruker Bio Apex II FTICR
mass spectrometer. Silica gel (Kieselgel 60 silica gel 230–400
1-Amino-4-(8-chloro-5H-dibenzo[b,e][1,4]diazepin-
11-yl)-1-methylhexahydropyrazin-1-ium-2,4,6-
trimethyl-1-benzenesulfonate 5
A
solution of O-mesitylenesulfonylhydroxylamine[20]
(0.66 g, 3.1 mmol) was added dropwise to a solution of 4 (1.0 g,

678
B. Capuano et al.
3.1 mmol) in dichloromethane (15 mL) in ice and after the addi-
tion was complete the mixture was left to stir for a further
20 min. Hexane (20 mL) was added to precipitate the product
(1.59 g, 95%), which was collected by filtration. Recrystal-
lization from ethyl acetate/methanol gave 5 as bright yellow
needles (1.36 g, 82%), mp 183–184◦C. (Found: C 59.4, H 6.2, N
13.0. C27H32ClN5O3S requires C 59.8, H 6.0, N 12.9%.) νmax
(KBr)/cm−1 3312, 1568. λmax/nm (ε/M−1 cm−1) 205 (77 600),
226 (74 100), 260 (18 200), 296 (9330). δH (d4-methanol) 2.27
(3H, s, ArCH3), 2.67 (6H, s, 2 ×ArCH3), 3.47 (3H, s, CH3N+),
3.55–3.63 (2H, m, H3ꢀa, H5ꢀa), 3.71–3.76 (2H, m, H3ꢀb, H5ꢀb),
3.80–3.84 (2H, m, H2ꢀa, H6ꢀa), 3.93 (2H, br m, H2ꢀb, H6ꢀb),
6.88 (1H, d, J 8.5, 1H, H6), 6.92 (2H, s, H3ꢀꢀ, H5ꢀꢀ), 6.95 (1H,
dd, J 8.5, 2.5, H7), 7.03 (1H, d, J 2.5, H9), 7.07 (1H, br d, J 8,
H4), 7.12 (1H, app br t, J 8, H2), 7.38 (1H, br d, J 7.5, H1), 7.43
(1H, app td, J 8, 1.5, H3). δC (d4-methanol) 21.0 (ArCH3), 24.4
(2 ×ArCH3), 42.9 (C3ꢀ, C5ꢀ), 58.4 (CH3N+), 64.3 (C2ꢀ, C6ꢀ),
121.7 (C4), 121.8 (C6), 123.6 (C11a), 124.5 (C2), 125.4 (C7),
127.5 (C9), 129.8 (C8), 131.1 (C1), 131.9 (C3ꢀꢀ, C5ꢀꢀ), 134.1
(C3), 138.3 (C2ꢀꢀ, C6ꢀꢀ), 140.3 (C1ꢀꢀ), 141.0 (C4ꢀꢀ), 142.6 (C5a),
143.2 (C9a), 155.6 (C4a), 164.0 (C11). m/z (+ESI, 70V) 344
(13%, M[37Cl]+), 342 (40%, M+), 272 (28), 270 (80), 258 (20),
256 (60), 245 (25), 243 (100), 229 (20), 227 (60).
dd, J 8.5, 2.5, H7), 7.01 (1H, app td, J 7.5, 1, H2), 7.07 (1H, d,
J 2.5, H9), 7.25 (1H, dd, J 7.5, 1.5, H1), 7.30–7.38 (4H, m, H3,
H3ꢀꢀ, H4ꢀꢀ, H5ꢀꢀ), 8.00 (2H, dd, J 7, 2, H2ꢀꢀ, H6ꢀꢀ). δC (CDCl3)
42.7 (C3ꢀ, C5ꢀ), 53.5 (CH3N+), 62.1 (C2ꢀ, C6ꢀ), 120.46 (C4),
120.51 (C6), 122.9 (C11a), 123.6 (C2), 124.2 (C7), 127.2 (C9),
127.7 (C2ꢀꢀ, C6ꢀꢀ), 127.9 (C3ꢀꢀ, C5ꢀꢀ), 129.5 (C8), 129.7 (C4ꢀꢀ),
130.2 (C1), 132.8 (C3), 139.0 (C1ꢀꢀ), 140.6 (C5a), 141.4 (C9a),
153.3 (C4a), 162.3 (C11), 170.4 (CO). m/z (+ESI, 70V) 448
(35%, M[37Cl]H+), 446 (100%, MH+), 402 (10), 400 (30), 329
(12), 327 (40), 298 (30), 296 (100), 272 (27), 270 (80).
1-[4-(8-Chloro-5H-dibenzo[b,e][1,4]diazepin-11-yl)-
1-methylhexahydropyrazin-1-ium]-
1-(2-fluoro)benzimide 2b
Purifiedbyflashchromatography(85/15, chloroform/propan-
2-ol), yellow needles (CHCl3), yield 48%, mp 226–
227◦C. (Found: C 63.6, H 4.9, N 14.7, MH+ 464.1647.
C25H23ClFN5O·0.5H2O requires C 63.5, H 5.1, N 14.8%,
MH+ 464.1648.) νmax (KBr)/cm−1 3268, 1608, 1560. λmax/nm
(ε/M−1 cm−1) 229 (32 400), 259 (20 400), 295 (10 700). δH
(CDCl3) 3.25 (2H, m, H2ꢀa, H6ꢀa), 3.60 (3H, s, CH3N+), 3.96
(4H, br m, H3ꢀ, H5ꢀ), 4.45 (2H, m, H2ꢀb, H6ꢀb), 4.99 (1H, br s,
H5), 6.63 (1H, d, J 8.5, H6), 6.83 (1H, br d, J 8, H4), 6.88 (1H,
dd, J 8.5, 2.5, H7), 7.03 (1H, ddd, J 8, 7.5, 1, H2), 7.00–7.05
(1H, m, H3ꢀꢀ), 7.07 (1H, d, J 2.5, H9), 7.11 (1H, app td, J 7.5, 1,
H5ꢀꢀ), 7.26 (1H, dd, J 8, 1, H1), 7.25–7.27 (1H, m, H4ꢀꢀ), 7.32
(1H, app td, J 7.5, 1.5, H3), 7.69 (1H, ddd, J 7.5, 6, 1.5, H6ꢀꢀ). δC
(CDCl3) 42.6 (C3ꢀ, C5ꢀ), 53.4 (CH3N+), 61.8 (C2ꢀ, C6ꢀ), 116.2
(d, J 23, C3ꢀꢀ), 120.49 (C6), 120.52 (C4), 122.8 (C11a), 123.5
(C2), 123.8 (d, J 4, C5ꢀꢀ), 124.1 (C7), 127.0 (C9), 128.0 (d, J 15,
C1ꢀꢀ), 129.3 (C8), 130.1 (C1), 130.2 (d, J 9, C4ꢀꢀ), 130.5 (d, J 4,
C6ꢀꢀ), 132.7 (C3), 140.6 (C5a), 141.4 (C9a), 153.2 (C4a), 160.5
(d, J 252, C2ꢀꢀ), 162.2 (C11), 169.2 (d, J 11.5, CO). m/z (+ESI,
70V) 466 (35%, M[37Cl]H+), 464 (100%, MH+).
General Procedure for the Synthesis of Aminimides:
N-Acylation Using Acid Chlorides
The aminimides 2a–u and 2z were prepared from 1-amino-
4-(8-chloro-5H-dibenzo[b,e][1,4]diazepin-11-yl)-1-methylhexa-
hydropyrazin-1-ium-2,4,6-trimethyl-1-benzenesulfonate
5
(100 mg, 0.18 mmol) and the corresponding substituted acyl
chloride (0.22 mmol) in the presence of sodium hydride
(0.74 mmol), and isolated as yellow crystalline solids. The gen-
eral method exemplified for the synthesis of 1-[4-(8-chloro-5H-
dibenzo[b,e][1,4]diazepin-11-yl)-1-methylhexahydropyrazin-1-
ium]-1-benzimide 2a is described below.
1-[4-(8-Chloro-5H-dibenzo[b,e][1,4]diazepin-11-yl)-
1-methylhexahydropyrazin-1-ium]-
1-(3-fluoro)benzimide 2c
1-[4-(8-Chloro-5H-dibenzo[b,e][1,4]diazepin-11-yl)-
1-methylhexahydropyrazin-1-ium]-1-benzimide 2a
Purifiedbyflashchromatography(85/15, chloroform/propan-
2-ol), yellow needles (CHCl3), yield 48%, mp 193–194◦C.
(Found: C 64.6, H 5.1, N 14.7. C25H23ClFN5O requires C 64.7,
H 5.0, N 15.1%.) νmax (KBr)/cm−1 3262, 1605, 1566. λmax/nm
(ε/M−1 cm−1) 229 (32 400), 261 (21 400), 295 (10 700). δH (d6-
DMSO) 3.48 (2H, br m, H2ꢀa, H6ꢀa), 3.50 (2H, br m, H3ꢀa, H5ꢀa),
3.50 (3H, s, CH3N+), 3.77 (2H, br m, H3ꢀb, H5ꢀb), 4.21 (2H, m,
H2ꢀb, H6ꢀb), 6.87–6.90 (3H, m, H6, H7, H9), 7.00 (1H, app t, J
7.5, H2), 7.01 (1H, d, J 8, H4), 7.04 (1H, s, H5), 7.14 (1H, ddd,
J 9, 7.5, 2.5, H4ꢀꢀ), 7.28–7.31 (1H, m, H1, H5ꢀꢀ), 7.36 (1H, app
t, J 8, H3), 7.58 (1H, dd, J 10.5, 1.5, H2ꢀꢀ), 7.71 (1H, d, J 7.5,
H6ꢀꢀ). δC (d6-DMSO) 42.0 (C3ꢀ, C5ꢀ), 51.7 (CH3N+), 60.7 (C2ꢀ,
C6ꢀ), 113.7 (d, J 22, C2ꢀꢀ), 115.6 (d, J 21, C4ꢀꢀ), 120.4 (C4), 120.7
(C6), 122.4 (C11a), 122.5 (C2), 123.1 (C7), 123.2 (C6ꢀꢀ), 125.7
(C9), 126.7 (C8), 129.2 (d, J 8, C5ꢀꢀ), 129.9 (C1), 132.4 (C3),
141.4 (C5a), 142.3 (C9a), 142.3 (d, J 6, C1ꢀꢀ), 154.1 (C4a), 161.8
(d, J 242, C3ꢀꢀ), 162.2 (C11), 166.2 (CO). m/z (+ESI, 30V) 466
(35%, M[37Cl]H+), 464 (100%, MH+).
Sodium hydride (29.8 mg, 0.74 mmol, 60% dispersion in oil)
was washed with anhydrous hexane, dried under a continuous
stream of dry nitrogen and cooled to −15◦C (dry ice-benzyl
alcohol). A cooled solution of 1-amino-4-(8-chloro-5H-
dibenzo[b,e][1,4]diazepin-11-yl)-1-methylhexahydropyrazin-1-
ium 2,4,6-trimethyl-1-benzenesulfonate 5 (100 mg, 0.18 mmol),
and benzoyl chloride (25.7 µL, 0.22 mmol) in anhydrous N,N-
dimethylformamide (4 mL) was added dropwise to the dry
sodium hydride with stirring over 5 min. The mixture was then
maintained at −15◦C for 7 h and then allowed to warm to
room temperature overnight. The solvent was removed under
vacuum to afford an orange solid, which was resuspended in
ethyl acetate, and a white solid removed by filtration. The fil-
trate was concentrated and the resulting residue purified by
flash chromatography (10/1, ethyl acetate/methanol) to afford
a bright yellow solid (68.2 mg, 85%). Recrystallization from
acetone/water gave 2a (51 mg, 64%) as bright yellow micro-
needles, mp 229–230◦C. (Found: C 67.4, H 5.5, N 15.4, MH+
446.1745. C25H24ClN5O requires C 67.3, H 5.4, N 15.7%,
MH+ 446.1742.) νmax (KBr)/cm−1 3264, 1586, 1560. λmax/nm
(ε/M−1 cm−1) 226 (30 900), 259 (19 100), 297 (9300). δH
(CDCl3) 3.24 (2H, br m, H2ꢀa, H6ꢀa), 3.59 (3H, s, CH3N+),
3.91 (4H, br m, H3ꢀ, H5ꢀ), 4.45 (2H, m, H2ꢀb, H6ꢀb), 4.93 (1H,
s, H5), 6.63 (1H, d, J 8.5, H6), 6.82 (1H, d, J 8, H4), 6.87 (1H,
1-[4-(8-Chloro-5H-dibenzo[b,e][1,4]diazepin-11-yl)-
1-methylhexahydropyrazin-1-ium]-
1-(4-fluoro)benzimide 2d
Purifiedbyflashchromatography(85/15, chloroform/propan-
2-ol), fine yellow needles (CHCl3/hexane), yield 46%, mp

4ꢀ-Aryl Aminimide Analogues of Clozapine
679
219–220◦C. (Found: C 64.8, H 5.0, N 14.9. C25H23ClFN5O
requires C 64.7, H 5.0, N 15.1%.) νmax (KBr)/cm−1 3274, 1605,
1572. λmax/nm (ε/M−1 cm−1) 228 (3600), 260 (23 400), 296
(11 500). δH (CDCl3) 3.27 (2H, br m, H2ꢀa, H6ꢀa), 3.58 (3H, s,
CH3N+), 3.88 (4H, br m, H3ꢀ, H5ꢀ), 4.41 (2H, m, H2ꢀb, H6ꢀb),
4.94 (1H, s, H5), 6.63 (1H, d, J 8.5, H6), 6.82 (1H, dd, J 8, 1,
H4), 6.87 (1H, dd, J 8.5, 2.5, H7), 7.00 (2H, br d, J 9, H3ꢀꢀ, H5ꢀꢀ),
7.03 (app td, J 7.5, 1, H2), 7.07 (1H, d, J 2.5, H9), 7.24 (1H,
dd, J 8, 1.5, H1), 7.32 (1H, app td, J 8, 1, H3), 8.00 (2H, dd, J
7.5, 5, H2ꢀꢀ, H6ꢀꢀ). δC (CDCl3) 42.8 (C3ꢀ, C5ꢀ), 53.5 (CH3N+),
62.2 (C2ꢀ, C6ꢀ), 114.7 (d, J 22, C3ꢀꢀ, C5ꢀꢀ), 120.6 (C4, C6), 123.0
(C11a), 123.7 (C2), 124.3 (C7), 127.3 (C9), 129.5 (C8), 129.8
(d, J 8, C2ꢀꢀ, C6ꢀꢀ), 130.2 (C1), 132.9 (C3), 135.2 (C1ꢀꢀ), 140.8
(C5a), 141.5 (C9a), 153.5 (C4a), 162.5 (C11), 164.2 (d, J 256,
C4ꢀꢀ), 169.5 (CO). m/z (+ESI, 30 V) 466 (33%, M[37Cl]H+),
464 (100%, MH+).
1-[4-(8-Chloro-5H-dibenzo[b,e][1,4]diazepin-11-yl)-
1-methylhexahydropyrazin-1-ium]-
1-(4-chloro)benzimide 2g
Purified by flash chromatography (10/1, ethyl acetate/
methanol), fine yellow needles (CHCl3/hexane), yield 40%,
mp 168–170◦C. (Found: C 61.4, H 4.8, N 14.0, MH+
480.1358. C25H23Cl2N5O requires C 61.4, H 4.9, N 14.3%,
MH+ 480.1352.) νmax (KBr)/cm−1 3264, 1600, 1554. λmax/nm
(ε/M−1 cm−1) 229 (22 400), 259 (15 100), 294 (6800). δH
(CDCl3) 3.23 (2H, br m, H2ꢀa, H6ꢀa), 3.54 (3H, s, CH3N+),
3.87 (4H, m, H3ꢀ, H5ꢀ), 4.43 (2H, m, H2ꢀb, H6ꢀb), 4.98 (1H, br
s, H5), 6.63 (1H, d, J 8.5, H6), 6.82 (1H, d, J 8, H4), 6.86 (1H, dd,
J 8.5, 2.5, H7), 7.01 (1H, app t, J 8, H2), 7.06 (1H, d, J 2.5, H9),
7.23 (1H, d, J 8, H1), 7.28 (2H, d, J 8.5, H3ꢀꢀ, H5ꢀꢀ), 7.31 (1H,
app t, J 8, H3), 7.93 (2H, d, J 8.5, H2ꢀꢀ, H6ꢀꢀ). δC (CDCl3) 42.6
(C3ꢀ, C5ꢀ), 53.4 (CH3N+), 62.1 (C2ꢀ, C6ꢀ), 120.5 (C4), 120.6
(C6), 122.8 (C11a), 123.6 (C2), 124.3 (C7), 127.2 (C9), 128.0
(C3ꢀꢀ, C5ꢀꢀ), 129.2 (C2ꢀꢀ, C6ꢀꢀ), 129.5 (C8), 130.1 (C1), 132.8
(C3), 135.7 (C4ꢀꢀ), 137.2 (C1ꢀꢀ), 140.6 (C5a), 141.3 (C9a), 153.3
(C4a), 162.3 (C11), 169.1 (CO). m/z (+ESI, 30V) 484 (15%,
M[37Cl, 37Cl]H+), 482 (70%, M[37Cl, 35Cl]H+), 480 (100%,
MH+).
1-[4-(8-Chloro-5H-dibenzo[b,e][1,4]diazepin-11-yl)-
1-methylhexahydropyrazin-1-ium]-
1-(2-chloro)benzimide 2e
Purified by flash chromatography (10/1, ethyl acetate/
methanol), yellow rosettes (CHCl3/hexane), yield 39%, mp
158–159◦C. (Found: C 61.5, H 4.8, N 14.0, MH+ 480.1370.
C25H23Cl2N5O·0.5H2O requires C 61.4, H 4.9, N 14.3%,
MH+ 480.1370.) νmax (KBr)/cm−1 3308, 1604, 1560. λmax/nm
(ε/M−1 cm−1) 231 (20 400), 260 (12 600), 295 (7100). δH
(CDCl3) 3.22 (2H, br m, H2ꢀa, H6ꢀa), 3.57 (3H, s, CH3N+),
3.97 (4H, m, H3ꢀ, H5ꢀ), 4.41 (2H, m, H2ꢀb, H6ꢀb), 5.04 (1H, br
s, H5), 6.63 (1H, d, J 8.5, H6), 6.83 (1H, d, J 8, H4), 6.86 (1H,
dd, J 8.5, 2.5, H7), 7.03 (1H, app t, J 7.5, H2), 7.06 (1H, d, J
2.5, H9), 7.16–7.22 (2H, m, H3ꢀꢀ, H5ꢀꢀ), 7.26 (1H, dd, J 7.5, 1,
H1), 7.29–7.34 (2H, m, H3, H4ꢀꢀ), 7.47–7.50 (1H, m, H6ꢀꢀ). δC
(CDCl3) 42.8 (C3ꢀ, C5ꢀ), 53.5 (CH3N+), 62.1 (C2ꢀ, C6ꢀ), 120.47
(C4), 120.52 (C6), 122.9 (C11a), 123.6 (C2), 124.2 (C7), 126.7
(C5ꢀꢀ), 127.1 (C9), 129.1 (C3ꢀꢀ), 129.5 (C8), 129.7 (C6ꢀꢀ), 130.0
(C4ꢀꢀ), 130.2 (C1), 131.6 (C1ꢀꢀ), 132.8 (C3), 139.8 (C2ꢀꢀ), 140.6
(C5a), 141.4 (C9a), 153.3 (C4a), 162.2 (C11), 171.6 (CO). m/z
(+ESI, 30V) 484 (15%, M[37Cl, 37Cl]H+), 482 (70%, M[37Cl,
35Cl]H+), 480 (100%, MH+).
1-[4-(8-Chloro-5H-dibenzo[b,e][1,4]diazepin-11-yl)-
1-methylhexahydropyrazin-1-ium]-
1-(2-bromo)benzimide 2h
Purifiedbyflashchromatography(85/15, chloroform/propan-
2-ol), fine yellow needles (CHCl3), yield 36%, mp 203–204◦C.
(Found: C 57.2, H 4.5, N 13.2, MH+ 524.0847. C25H23ClBrN5O
requires C 57.2, H 4.4, N 13.3%, MH+ 523.0848.) νmax
(KBr)/cm−1 3256, 1614, 1550. λmax/nm (ε/M−1 cm−1) 228
(32 400), 260 (17 400), 295 (9800). δH (CDCl3) 3.24 (2H, br
m, H2ꢀa, H6ꢀa), 3.60 (3H, s, CH3N+), 4.01 (4H, m, H3ꢀ, H5ꢀ),
4.43 (2H, m, H2ꢀb, H6ꢀb), 4.96 (1H, s, H5), 6.63 (1H, d, J 8.5,
H6), 6.83 (1H, d, J 8, H4), 6.87 (1H, dd, J 8.5, 2.5, H7), 7.04
(1H, app t, J 8, H2), 7.07 (1H, d, J 2.5, H9), 7.12 (1H, app td, J 8,
2, H5ꢀꢀ), 7.23–7.29 (2H, m, H1, H4ꢀꢀ), 7.32 (1H, app td, J 8, 1.5,
H3), 7.47 (1H, dd, J 7.5, 1.5, H3ꢀꢀ), 7.52 (1H, dd, J 8, 1, H6ꢀꢀ).
δC (CDCl3) 42.9 (C3ꢀ, C5ꢀ), 53.4 (CH3N+), 62.1 (C2ꢀ, C6ꢀ),
120.5 (C4), 120.6 (C6), 120.8 (C2ꢀꢀ), 123.0 (C11a), 123.8 (C2),
124.3 (C7), 127.3 (C9, C5ꢀꢀ), 129.3 (C6ꢀꢀ), 129.6 (C8), 129.8
(C3ꢀꢀ), 130.3 (C1), 132.2 (C1ꢀꢀ), 132.9 (C3), 133.2 (C4ꢀꢀ), 140.7
(C5a), 141.5 (C9a), 153.5 (C4a), 162.3 (C11), 172.6 (CO). m/z
(+ESI, 30V) 528 (30%, M[81Br, 37Cl]H+), 526 (100%, M[81Br,
35Cl]H+; M[79Br, 37Cl]H+), 524 (70%, MH+), 329 (10), 327
(30), 263 (40).
1-[4-(8-Chloro-5H-dibenzo[b,e][1,4]diazepin-11-yl)-
1-methylhexahydropyrazin-1-ium]-
1-(3-chloro)benzimide 2f
Purified by flash chromatography (95/5/1, dichloromethane/
ethanol/ammonia), yellow rosettes (CHCl3/hexane), yield 44%,
mp 218–218.5◦C. (Found: C 62.2, H 4.9, N 14.5. C25H23Cl2N5O
requires C 62.5, H 4.8, N 14.6%.) νmax (KBr)/cm−1 3280, 1604,
1562. λmax/nm (ε/M−1 cm−1) 230 (21 900), 260 (18 600), 299
(8700). δH (CDCl3) 3.25 (2H, br m, H2ꢀa, H6ꢀa), 3.57 (3H, s,
CH3N+), 3.89 (4H, m, H3ꢀ, H5ꢀ), 4.45 (2H, m, H2ꢀb, H6ꢀb), 4.94
(1H, br s, H5), 6.63 (1H, d, J 8.5, H6), 6.83 (1H, d, J 8, H4),
6.88 (1H, dd, J 8.5, 2.5, H7), 7.02 (1H, br app t, J 7.5, H2), 7.07
(1H, d, J 2.5, H9), 7.25 (1H, br d, J 7.5, H1), 7.29–7.35 (3H, m,
H3, H4ꢀꢀ, H5ꢀꢀ), 7.88 (1H, br d, J 7.5, H6ꢀꢀ), 8.00 (1H, br s, H2ꢀꢀ).
δC (CDCl3) 42.6 (C3ꢀ, C5ꢀ), 53.3 (CH3N+), 62.2 (C2ꢀ, C6ꢀ),
120.5 (C4, C6), 122.8 (C11a), 123.4 (C2), 124.2 (C7), 125.9
(C2ꢀꢀ), 127.1 (C9), 128.0 (C6ꢀꢀ), 129.1 (C5ꢀꢀ), 129.3 (C8), 129.5
(C4ꢀꢀ), 130.1 (C1), 132.7 (C3), 133.8 (C3ꢀꢀ), 134.2 (C1ꢀꢀ), 140.8
(C5a), 141.3 (C9a), 153.4 (C4a), 162.3 (C11), 168.7 (CO). m/z
(+ESI, 30V) 484 (14%, M[37Cl, 37Cl]H+), 482 (67%, M[37Cl,
35Cl]H+), 480 (100%, MH+).
1-[4-(8-Chloro-5H-dibenzo[b,e][1,4]diazepin-11-yl)-
1-methylhexahydropyrazin-1-ium]-
1-(3-bromo)benzimide 2i
Purifiedbyflashchromatography(85/15, chloroform/propan-
2-ol), yellow needles (CHCl3/hexane), yield 33%, mp 213–
214◦C. (Found: C 57.0, H 4.4, N 13.0. C25H23ClBrN5O requires
C 57.2, H 4.4, N 13.3%.) νmax (KBr)/cm−1 3276, 1604, 1554.
λmax/nm(ε/M−1 cm−1)230(35 500), 262(22 400), 300(10 200).
δH (CDCl3) 3.25 (2H, br m, H2ꢀa, H6ꢀa), 3.56 (3H, s, CH3N+),
3.86 (4H, br m, H3ꢀ, H5ꢀ), 4.41 (2H, m, H2ꢀb, H6ꢀb), 4.96 (1H,
br s, H5), 6.62 (1H, d, J 8.5, H6), 6.82 (1H, d, J 8, H4), 6.87 (1H,
dd, J 8.5, 2.5, H7), 7.01 (1H, app t, J 7.5, H2), 7.07 (1H, d, J
2.5, H9), 7.18–7.25 (2H, m, H1, H5ꢀꢀ), 7.31 (1H, br app t, J 7.5,
H3), 7.48 (1H, br d, J 7, H4ꢀꢀ), 7.93 (1H, d, J 7, H6ꢀꢀ), 8.16 (1H,
s, H2ꢀꢀ). δC (CDCl3) 42.7 (C3ꢀ, C5ꢀ), 53.4 (CH3N+), 62.1 (C2ꢀ,

680
B. Capuano et al.
C6ꢀ), 120.5 (C4, C6), 122.2 (C3ꢀꢀ), 122.9 (C11a), 123.6 (C2),
124.3 (C7), 126.4 (C6ꢀꢀ), 127.2 (C9), 129.5 (C8, C5ꢀꢀ), 130.2
(C1), 130.9 (C2ꢀꢀ), 132.6 (C4ꢀꢀ), 132.8 (C3), 140.6 (C5a), 141.1
(C1ꢀꢀ), 141.4 (C9a), 153.3 (C4a), 162.3 (C11), 168.8 (CO). m/z
(+ESI, 30V) 528 (30%, M[81Br, 37Cl]H+), 526 (100%, M[81Br,
35Cl]H+; M[79Br, 37Cl]H+), 524 (80%, MH+), 264 (80).
(3H, s, CH3N+), 3.91 (4H, m, H3ꢀ, H5ꢀ), 4.47 (2H, m, H2ꢀb,
H6ꢀb), 4.93 (1H, br s, H5), 6.63 (1H, d, J 8.5, H6), 6.83 (1H, br
d, J 8, H4), 6.87 (1H, dd, J 8.5, 2.5, H7), 7.02 (1H, app td, J 7.5,
1, H2), 7.07 (1H, d, J 2.5, H9), 7.18 (1H, app t, J 7.5, H5ꢀꢀ), 7.21
(1H, br d, J 7.5, H4ꢀꢀ), 7.24 (1H, dd, J 8, 1.5, H1), 7.32 (1H, app
td, J 8, 1.5, H3), 7.79–7.82 (2H, m, H2ꢀꢀ, H6ꢀꢀ). δC (CDCl3) 21.6
(ArCH3), 42.7 (C3ꢀ, C5ꢀ), 53.5 (CH3N+), 62.2 (C2ꢀ, C6ꢀ), 120.5
(C4, C6), 122.8 (C11a), 123.5 (C2), 124.2 (C7), 125.0 (C6ꢀꢀ),
127.1 (C9), 127.9 (C2ꢀꢀ), 128.4 (C5ꢀꢀ), 129.4 (C8), 130.1 (C1),
132.7 (C3), 133.7 (C4ꢀꢀ), 137.4 (C3ꢀꢀ), 138.3 (C1ꢀꢀ), 140.7 (C5a),
141.3 (C9a), 153.3 (C4a), 162.3 (C11), 170.6 (CO). m/z (+ESI,
30V) 462 (35%, M[37Cl]H+), 460 (100%, MH+).
1-[4-(8-Chloro-5H-dibenzo[b,e][1,4]diazepin-11-yl)-
1-methylhexahydropyrazin-1-ium]-
1-(4-bromo)benzimide 2j
Purifiedbyflashchromatography(85/15, chloroform/propan-
2-ol), yellow needles (CHCl3/hexane), yield 44%, mp 176.5–
178◦C. (Found: C 53.7, H 4.4, N 12.2, MH+ 524.0851.
C25H23ClBrN5O·2H2O requires C 53.5, H 4.8, N 12.5%, MH+
524.0848.) νmax (KBr)/cm−1 3228, 1604, 1584, 1544. λmax/nm
(ε/M−1 cm−1) 230 (30 200), 261 (21 400), 299 (8700). δH
(CDCl3) 3.25 (2H, br m, H2ꢀa, H6ꢀa), 3.57 (3H, s, CH3N+),
3.85 (4H, m, H3ꢀ, H5ꢀ), 4.41 (2H, m, H2ꢀb, H6ꢀb), 4.94 (1H, s,
H5), 6.63 (1H, d, J 8.5, H6), 6.82 (1H, dd, J 8, 1, H4), 6.87 (1H,
dd, J 8.5, 2.5, H7), 7.02 (1H, app td, J 8, 1, H2), 7.07 (1H, d, J 2.5,
H9), 7.24 (1H, dd, J 8, 1.5, H1), 7.32 (1H, app td, J 8, 1.5, H3),
7.45 (2H, d, J 8.5, H3ꢀꢀ, H5ꢀꢀ), 7.88 (1H, d, J 8.5, H2ꢀꢀ, H6ꢀꢀ). δC
(CDCl3) 42.5 (C3ꢀ, C5ꢀ), 53.4 (CH3N+), 62.0 (C2ꢀ, C6ꢀ), 120.5
(C4, C6), 122.8 (C11a), 123.6 (C2), 124.1 (C4ꢀꢀ), 124.3 (C7),
127.1 (C9), 129.5 (C8, C2ꢀꢀ, C6ꢀꢀ), 130.2 (C1), 131.0 (C3ꢀꢀ, C5ꢀꢀ),
132.8 (C3), 137.8 (C1ꢀꢀ), 140.6 (C5a), 141.3 (C9a), 153.3 (C4a),
162.3 (C11), 169.3 (CO). m/z (+ESI, 30V) 528 (30%, M[81Br,
37Cl]H+), 526 (100%, M[81Br, 35Cl]H+; M[79Br, 37Cl]H+), 524
(80%, MH+).
1-[4-(8-Chloro-5H-dibenzo[b,e][1,4]diazepin-11-yl)-
1-methylhexahydropyrazin-1-ium]-
1-(4-methyl)benzimide 2m
Purified by flash chromatography (95/5/0.1, ethyl acetate/
methanol/triethylamine), brightyellowneedles(CHCl3/hexane),
yield 47%, mp 162–164◦C. (Found: C 66.7, H 5.7, N 14.4,
MH+ 460.1901. C26H26ClN5O·0.5H2O requires C 66.6, H 5.7,
N 14.4%, MH+ 460.1899.) νmax (KBr)/cm−1 3220, 1614, 1554.
λmax/nm (ε/M−1 cm−1) 230 (25 700), 262 (13 500), 295 (6500).
δH (CDCl3) 2.35 (3H, s, ArCH3), 3.22 (2H, br m, H2ꢀa, H6ꢀa),
3.58 (3H, s, CH3N+), 3.90 (4H, m, H3ꢀ, H5ꢀ), 4.44 (2H, m, H2ꢀb,
H6ꢀb), 4.99 (1H, br s, H5), 6.62 (1H, d, J 8.5, H6), 6.82 (1H, d, J
8, H4), 6.87 (1H, dd, J 8.5, 2.5, H7), 7.00 (1H, app t, J 7.5, H2),
7.07 (1H, d, J 2.5, H9), 7.13 (2H, d, J 8, H3ꢀꢀ, H5ꢀꢀ), 7.22 (1H, d, J
7.5, H1), 7.32 (1H, app t, J 7.5, H3), 7.90 (2H, d, J 8, H2ꢀꢀ, H6ꢀꢀ).
δC (CDCl3) 21.5 (ArCH3), 42.7 (C3ꢀ, C5ꢀ), 53.5 (CH3N+), 62.1
(C2ꢀ, C6ꢀ), 120.5 (C4, C6), 122.9 (C11a), 123.6 (C2), 124.2
(C7), 127.3 (C9), 127.8 (C2ꢀꢀ, C6ꢀꢀ), 128.6 (C3ꢀꢀ, C5ꢀꢀ), 129.5
(C8), 130.2 (C1), 132.7 (C3), 136.2 (C1ꢀꢀ), 139.5 (C4ꢀꢀ), 140.7
(C5a), 141.4 (C9a), 153.4 (C4a), 162.3 (C11), 170.3 (CO). m/z
(+ESI, 30V) 462 (35%, M[37Cl]H+), 460 (100%, MH+).
1-[4-(8-Chloro-5H-dibenzo[b,e][1,4]diazepin-11-yl)-
1-methylhexahydro-pyrazin-1-ium]-
1-(2-methyl)benzimide 2k
Purified by flash chromatography (9/1, chloroform/propan-
2-ol), bright yellow needles (CHCl3/hexane), yield 56%, mp
144–145◦C. (Found: C 65.1, H 5.8, N 14.3, MH+ 460.1898.
C26H26ClN5O·H2O requires C 65.3, H 5.9, N 14.6%, MH+
460.1899.) νmax (KBr)/cm−1 3224, 1604, 1564. λmax/nm
(ε/M−1 cm−1) 230 (25 700), 259 (15 100), 298 (8100). δH
(CDCl3) 2.51 (3H, s, ArCH3), 3.26 (2H, br m, H2ꢀa, H6ꢀa), 3.62
(3H, s, CH3N+), 3.92 (4H, m, H3ꢀ, H5ꢀ), 4.48 (2H, m, H2ꢀb,
H6ꢀb), 4.96 (1H, br s, H5), 6.63 (1H, d, J 8.5, H6), 6.83 (1H, d, J
8, H4), 6.88 (1H, dd, J 8.5, 2.5, H7), 7.04 (1H, app t, J 7.5, H2),
7.05 (1H, d, J 2.5, H9), 7.13–7.17 (3H, m, H3ꢀꢀ, H4ꢀꢀ, H5ꢀꢀ), 7.25
(1H, d, J 7.5, H1), 7.31 (1H, app t, J 7.5, H3), 7.50 (1H, br d, J 7,
H6ꢀꢀ). δC (CDCl3) 20.6 (ArCH3), 42.8 (C3ꢀ, C5ꢀ), 53.3 (CH3N+),
61.9 (C2ꢀ, C6ꢀ), 120.5 (C4, C6), 122.9 (C11a), 123.6 (C2), 124.3
(C7), 125.5 (C5ꢀꢀ), 127.2 (C9), 128.3 (C3ꢀꢀ, C6ꢀꢀ), 129.5 (C8),
130.2 (C1), 130.7 (C4ꢀꢀ), 132.8 (C3), 135.8 (C2ꢀꢀ), 139.8 (C1ꢀꢀ),
140.7 (C5a), 141.4 (C9a), 153.4 (C4a), 162.2 (C11), 174.3 (CO).
m/z (+ESI, 30V) 462 (30%, M[37Cl]H+), 460 (100%, MH+),
327 (30).
1-[4-(8-Chloro-5H-dibenzo[b,e][1,4]diazepin-11-yl)-
1-methylhexahydropyrazin-1-ium]-
1-(2-trifluoromethyl)benzimide 2n
Purified by flash chromatography (4/1, chloroform/propan-
2-ol), yellow/orange needles (CHCl3/hexane), yield 51%, mp
206–208◦C. (Found: MH+ 514.1612. C26H23ClF3N5O requires
MH+ 524.1616.) νmax (KBr)/cm−1 3260, 1612, 1570. λmax/nm
(ε/M−1 cm−1) 228 (27 500), 261 (17 000), 295 (9100). δH
(CDCl3) 3.28 (2H, br m, H2ꢀa, H6ꢀa), 3.58 (3H, s, CH3N+),
3.91 (4H, br m, H3ꢀ, H5ꢀ), 4.41 (2H, m, H2ꢀb, H6ꢀb), 4.97 (1H,
s, H5), 6.65 (1H, d, J 8, H6), 6.85 (1H, d, J 8, H4), 6.87 (1H, dd,
J 8.5, 2, H7), 7.06 (1H, app t, J 7.5, H2), 7.08 (1H, d, J 2, H9),
7.28 (1H, d, J 7.5, H1), 7.33 (1H, app td, J 7.5, 1, H3), 7.39 (1H,
app t, J 8, H4ꢀꢀ), 7.51 (1H, app t, J 7.5, H5ꢀꢀ), 7.61 (1H, br d, J 8,
H6ꢀꢀ), 7.64 (1H, br d, J 8, H3ꢀꢀ). δC (CDCl3) 42.8 (C3ꢀ, C5ꢀ), 52.8
(CH3N+), 61.8 (C2ꢀ, C6ꢀ), 120.5 (C4, C6), 122.6 (C11a), 123.5
(C2), 124.1 (C7), 125.1 (q, J 277, CF3), 126.3 (q, J 4, C3ꢀꢀ),
127.0 (C9), 127.2 (q, J 30, C2ꢀꢀ), 128.0 (C4ꢀꢀ), 129.2 (C8), 129.6
(C6ꢀꢀ), 130.0 (C1), 131.7 (C5ꢀꢀ), 132.7 (C3), 139.7 (C1ꢀꢀ), 140.7
(C5a), 141.3 (C9a), 153.3 (C4a), 162.1 (C11), 172.2 (CO). m/z
(+ESI, 30V) 536 (20%, MNa+), 516 (33%, M[37Cl]H+), 514
(100%, MH+), 327 (50).
1-[4-(8-Chloro-5H-dibenzo[b,e][1,4]diazepin-11-yl)-
1-methylhexahydropyrazin-1-ium-1]-
1-(3-methyl)benzimide 2l
Purified by flash chromatography (4/1, chloroform/propan-
2-ol), bright yellow needles (CHCl3/hexane), yield 55%, mp
214–215◦C. (Found: C 67.7, H 5.7, N 15.0, MH+ 460.1898.
C26H26ClN5O requires C 67.9, H 5.7, N 15.2%, MH+
460.1899.) νmax (KBr)/cm−1 3284, 1610, 1564. λmax/nm
(ε/M−1 cm−1) 228 (30 200), 261 (19 100), 294 (9500). δH
(CDCl3) 2.36 (3H, s, ArCH3), 3.25 (2H, br m, H2ꢀa, H6ꢀa), 3.59
1-[4-(8-Chloro-5H-dibenzo[b,e][1,4]diazepin-11-yl)-
1-methylhexahydropyrazin-1-ium]-
1-(3-trifluoromethyl)benzimide 2o
Purifiedbyflashchromatography(85/15, chloroform/propan-
2-ol), yellow/orange needles (CHCl3/hexane), yield 61%, mp

4ꢀ-Aryl Aminimide Analogues of Clozapine
681
181–183◦C. (Found: C 60.5, H 4.8, N 13.6. C26H23ClF3N5O
requires C 60.8, H 4.5, N 13.6%.) νmax (KBr)/cm−1 3216, 1604,
1566. λmax/nm (ε/M−1 cm−1) 227 (27 500), 257 (11 700), 296
(5500). δH (CDCl3) 3.27 (2H, br m, H2ꢀa, H6ꢀa), 3.58 (3H, s,
CH3N+), 3.87 (4H, br m, H3ꢀ, H5ꢀ), 4.42 (2H, m, H2ꢀb, H6ꢀb),
4.97 (1H, s, H5), 6.62 (1H, d, J 8.5, H6), 6.82 (1H, d, J 8, H4),
6.87 (1H, dd, J 8.5, 2.5, H7), 7.02 (1H, app t, J 7.5, H2), 7.07
(1H, d, J 2.5, H9), 7.24 (1H, dd, J 7.5, 1, H1), 7.33 (1H, app td,
J 7.5, 1, H3), 7.44 (1H, app t, J 7.5, H5ꢀꢀ), 7.60 (1H, d, J 7.5,
H4ꢀꢀ), 8.18 (1H, d, J 7.5, H6ꢀꢀ), 8.29 (1H, br s, H2ꢀꢀ). δC (CDCl3)
42.6 (C3ꢀ, C5ꢀ), 53.3 (CH3N+), 62.0 (C2ꢀ, C6ꢀ), 120.48 (C4),
120.54 (C6), 122.7 (C11a), 123.6 (C2), 124.2 (C7), 124.5 (q, J
278, CF3), 124.6 (C2ꢀꢀ), 126.3 (C4ꢀꢀ), 127.1 (C9), 128.3 (C5ꢀꢀ),
129.4 (C8), 130.1 (C1), 130.5 (q, J 32, C3ꢀꢀ), 131.0 (C6ꢀꢀ), 132.8
(C3), 139.6 (C1ꢀꢀ), 140.7 (C5a), 141.2 (C9a), 153.3 (C4a), 162.3
(C11), 168.6 (CO). m/z (+ESI, 30V) 516 (35%, M[37Cl]H+),
514 (100%, MH+), 501 (28), 499 (70).
1-[4-(8-Chloro-5H-dibenzo[b,e][1,4]diazepin-11-yl)-
1-methylhexahydropyrazin-1-ium]-
1-(3-methoxy)benzimide 2r
Purifiedbyflashchromatography(9/1, chloroform/propan-2-
ol), yellow rosettes (CHCl3/hexane), yield 61%, mp 208–209◦C.
(Found: C 65.6, H 5.6, N 14.5, MH+ 476.1854. C26H26ClN5O2
requires C 65.6, H 5.5, N 14.7%, MH+ 476.1848.) νmax
(KBr)/cm−1 3296, 1602, 1564. λmax/nm (ε/M−1 cm−1) 230
(24 500), 262 (17 000), 299 (9500). δH (CDCl3, 500 MHz) 3.28
(2H, br m, H2ꢀa, H6ꢀa), 3.61 (3H, s, CH3N+), 3.84 (3H, s,
OCH3), 3.91 (4H, m, H3ꢀ, H5ꢀ), 4.48 (2H, m, H2ꢀb, H6ꢀb), 4.99
(1H, s, H5), 6.63 (1H, d, J 8.5, H6), 6.82 (1H, d, J 8, H4), 6.87
(1H, dd, J 8.5, 2.5, H7), 6.93 (1H, br dd, J 8, 2, H4ꢀꢀ), 7.01 (1H,
app t, J 7.5, H2), 7.07 (1H, d, J 2.5, H9), 7.23 (1H, d, J 7.5, H1),
7.34 (1H, br app t, J 8, H3), 7.43 (1H, app t, J 8, H5ꢀꢀ), 7.60 (1H,
br s, H2ꢀꢀ), 7.68 (1H, br d, J 7.5, H6ꢀꢀ). δC (CDCl3) 42.8 (C3ꢀ,
C5ꢀ), 53.6 (CH3N+), 55.7 (OCH3), 62.4 (C2ꢀ, C6ꢀ), 112.9 (C2ꢀꢀ),
116.5 (C4ꢀꢀ), 120.2 (C6ꢀꢀ), 120.6 (C4, C6), 123.1 (C11a), 123.7
(C2), 124.3 (C7), 127.3 (C9), 128.9 (C5ꢀꢀ), 129.4 (C8), 130.3
(C1), 132.9 (C3), 139.9 (C1ꢀꢀ), 140.7 (C5a), 141.6 (C9a), 153.4
(C4a), 159.7 (C3ꢀꢀ), 162.2 (C11), 170.6 (CO). m/z (+ESI, 30V)
498 (20%, MNa+), 478 (38%, M[37Cl]H+), 476 (100%, MH+).
1-[4-(8-Chloro-5H-dibenzo[b,e][1,4]diazepin-11-yl)-
1-methylhexahydropyrazin-1-ium]-
1-(4-trifluoromethyl)benzimide 2p
Purifiedbyflashchromatography(85/15, chloroform/propan-
2-ol), yellow/orange rosettes (CHCl3/hexane), yield 45%, mp
159–161◦C. (Found: C 58.5, H 4.6, N 13.1, MH+ 514.1613.
C26H23ClF3N5O·H2O requires C 58.7, H 4.7, N 13.2%,
MH+ 514.1616.) νmax (KBr)/cm−1 3288, 1604, 1552. λmax/nm
(ε/M−1 cm−1) 228 (28 800), 260 (20 400), 299 (9100). δH
(CDCl3) 3.27 (2H, br m, H2ꢀa, H6ꢀa), 3.57 (3H, s, CH3N+),
3.87 (4H, br m, H3ꢀ, H5ꢀ), 4.41 (2H, m, H2ꢀb, H6ꢀb), 5.00 (1H,
s, H5), 6.63 (1H, d, J 8.5, H6), 6.82 (1H, d, J 8, H4), 6.87 (1H,
dd, J 8.5, 2.5, H7), 7.01 (1H, app t, J 7.5, H2), 7.07 (1H, d, J 2.5,
H9), 7.23 (1H, d, J 8, H1), 7.31 (1H, app td, J 7.5, 1.5, H3), 7.58
(2H, d, J 8, H3ꢀꢀ, H5ꢀꢀ), 8.11 (2H, d, J 8, H2ꢀꢀ, H6ꢀꢀ). δC (CDCl3)
42.7 (C3ꢀ, C5ꢀ), 53.4 (CH3N+), 62.1 (C2ꢀ, C6ꢀ), 120.5 (C4, C6),
122.9 (C11a), 123.6 (C2), 124.3 (C7), 124.6 (q, J 274, CF3),
124.8 (C3ꢀꢀ, C5ꢀꢀ), 127.2 (C9), 128.1 (C2ꢀꢀ, C6ꢀꢀ), 129.5 (C8),
130.1 (C1), 131.4 (q, J 32, C4ꢀꢀ), 132.8 (C3), 140.6 (C5a), 141.3
(C9a), 142.5 (C1ꢀꢀ), 153.3 (C4a), 162.3 (C11), 168.9 (CO). m/z
(+ESI, 30V) 516 (35%, M[37Cl]H+), 514 (100%, MH+).
1-[4-(8-Chloro-5H-dibenzo[b,e][1,4]diazepin-11-yl)-
1-methylhexahydropyrazin-1-ium]-
1-(4-methoxy)benzimide 2s
Purifiedbyflashchromatography(4/1, chloroform/propan-2-
ol), yellow needles (CHCl3/hexane), yield 45%, mp 159–160◦C.
(Found: C 64.0, H 5.4, N 14.3, MH+ 476.1848. C26H26ClN5O2
requires C 64.4, H 5.6, N 14.4%, MH+ 476.1848.) νmax
(KBr)/cm−1 3224, 1606, 1566. λmax/nm (ε/M−1 cm−1) 231
(20 400), 258 (19 100), 297 (7100). δH (CDCl3) 3.23 (2H, br
m, H2ꢀa, H6ꢀa), 3.58 (3H, s, CH3N+), 3.90 (3H, s, OCH3), 3.90
(4H, br m, H3ꢀ, H5ꢀ), 4.43 (2H, m, H2ꢀb, H6ꢀb), 4.92 (1H, s, H5),
6.62 (1H, d, J 8.5, H6), 6.82 (1H, br d, J 8, H4), 6.84 (2H, d, J 9,
H3ꢀꢀ, H5ꢀꢀ), 6.87 (1H, dd, J 8.5, 2.5, H7), 7.01 (1H, app td, J 8, 1,
H2), 7.07 (1H, d, J 2.5, H9), 7.23 (1H, dd, J 8, 1.5, H1), 7.31 (1H,
app td, J 8, 1.5, H3), 7.96 (2H, d, J 9, H2ꢀꢀ, H6ꢀꢀ). δC (CDCl3)
42.3 (C3ꢀ, C5ꢀ), 53.2 (CH3N+), 55.2 (OCH3), 61.7 (C2ꢀ, C6ꢀ),
112.9 (C3ꢀꢀ, C5ꢀꢀ), 120.2 (C4, C6), 122.5 (C11a), 123.3 (C2),
123.9 (C7), 126.8 (C9), 128.9 (C2ꢀꢀ, C6ꢀꢀ), 129.1 (C8), 129.9
(C1), 131.1 (C1ꢀꢀ), 132.5 (C3), 140.3 (C5a), 141.0 (C9a), 152.9
(C4a), 160.7 (C4ꢀꢀ), 162.0 (C11), 169.8 (CO). m/z (+ESI, 30V)
478 (35%, M[37Cl]H+), 476 (100%, MH+).
1-[4-(8-Chloro-5H-dibenzo[b,e][1,4]diazepin-11-yl)-
1-methylhexahydropyrazin-1-ium]-
1-(2-methoxy)benzimide 2q
Purified by flash chromatography (4/1, chloroform/propan-
2-ol), yellow needles (CHCl3/hexane), yield 48%, mp 163.5–
165◦C. (Found: C 65.8, H 5.5, N 14.5. C26H26ClN5O2 requires
C 65.6, H 5.6, N 14.7%.) νmax (KBr)/cm−1 3262, 1614, 1587,
1563. λmax/nm (ε/M−1 cm−1) 226 (24 500), 260 (13 500), 299
(7400). δH (CDCl3) 3.16 (2H, br m, H2ꢀa, H6ꢀa), 3.59 (3H, s,
CH3N+), 3.85 (3H, s, OCH3), 4.03 (4H, m, H3ꢀ, H5ꢀ), 4.46 (2H,
m, H2ꢀb, H6ꢀb), 4.95 (1H, s, H5), 6.63 (1H, d, J 8.5, H6), 6.82
(1H, d, J 8, H4), 6.85 (1H, dd, J 8.5, 2.5, H7), 6.86 (1H, d, J 8,
H3ꢀꢀ), 6.89 (1H, app t, J 8, H5ꢀꢀ), 7.03 (1H, app t, J 7.5, H2), 7.07
(1H, d, J 2.5, H9), 7.23 (1H, app td, J 8, 1.5, H4ꢀꢀ), 7.25 (1H, br d,
J 8, H1), 7.32 (1H, app td, J 8, 1.5, H3), 7.43 (1H, dd, J 7.5, 1.5,
H6ꢀꢀ). δC (CDCl3) 42.8 (C3ꢀ, C5ꢀ), 53.5 (CH3N+), 56.1 (OCH3),
61.9 (C2ꢀ, C6ꢀ), 111.8 (C3ꢀꢀ), 120.6 (C4, C6, C1ꢀꢀ, C5ꢀꢀ), 123.1
(C11a), 123.7 (C2), 124.2 (C7), 127.3 (C9), 129.3 (C6ꢀꢀ), 129.5
(C8, C4ꢀꢀ), 130.3 (C1), 132.8 (C3), 140.7 (C5a), 141.5 (C9a),
153.4 (C4a), 157.2 (C2ꢀꢀ), 162.3 (C11), 170 (CO). m/z (+ESI,
30V) 478 (35%, M[37Cl]H+), 476 (100%, MH+).
1-[4-(8-Chloro-5H-dibenzo[b,e][1,4]diazepin-11-yl)-
1-methylhexahydropyrazin-1-ium]-
1-(2-acetyl)benzimide 2t
Purifiedbyflashchromatography(85/15, chloroform/propan-
2-ol), pale yellow needles (CHCl3/hexane), yield 43%, mp
221–222◦C. (Found: C 66.4, H 5.3, N 14.2. C27H26ClN5O2
requires C 66.5, H 5.4, N 14.4%.) νmax (KBr)/cm−1 3364, 1680,
1604, 1552. λmax/nm (ε/M−1 cm−1) 229 (30 200), 261 (17 800),
299 (9100). δH (CDCl3, 500 MHz) 2.56 (3H, s, COCH3), 3.25
(2H, br m, H2ꢀa, H6ꢀa), 3.57 (3H, s, CH3N+), 3.88 (4H, m, H3ꢀ,
H5ꢀ), 4.36 (2H, m, H2ꢀb, H6ꢀb), 4.94 (1H, s, H5), 6.65 (1H, d,
J 8.5, H6), 6.84 (1H, br d, J 7.5, H4), 6.88 (1H, dd, J 8.5, 2.5,
H7), 7.04 (1H, app td, J 7.5, 1, H2), 7.07 (1H, d, J 2.5, H9), 7.26
(1H, dd, J 7.5, 1, H1), 7.33 (1H, app td, J 7.5, 1, H3), 7.35–7.39
(2H, m, H4ꢀꢀ, H6ꢀꢀ), 7.41 (1H, app td, J 7, 2, H5ꢀꢀ), 7.80 (1H,

682
B. Capuano et al.
dd, J 7, 2, H3ꢀꢀ). δC (CDCl3) 26.7 (COCH3), 42.0 (C3ꢀ, C5ꢀ),
53.0 (CH3N+), 61.8 (C2ꢀ, C6ꢀ), 120.3 (C4, C6), 122.5 (C11a),
123.4 (C2), 124.0 (C7), 126.2 (C6ꢀꢀ), 126.8 (C9), 128.6 (C3ꢀꢀ),
128.7 (C4ꢀꢀ), 129.1 (C8), 129.7 (C5ꢀꢀ), 129.9 (C1), 132.5 (C3),
137.8(C1ꢀꢀ), 138.0 (C2ꢀꢀ), 140.2(C5a), 141.0(C9a), 153.0(C4a),
161.9 (C11), 170.9 (CO), 198.2 (CH3CO). m/z (+ESI, 30V) 510
(30%, MNa+) 490 (35%, M[37Cl]H+), 488 (100%, MH+).
exemplified for the synthesis of 1-[(4-acetyl)benzimide]-4-(8-
chloro-5H-dibenzo[b,e][1,4]diazepin-11-yl)-1-methylhexahydr-
opyrazin-1-ium (2v) is described below.
1-[4-(8-Chloro-5H-dibenzo[b,e][1,4]diazepin-11-yl)-
1-methylhexahydropyrazin-1-ium]-
1-(4-acetyl)benzimide 2v
A solution of 5 (167 mg, 0.31 mmol), 4-acetylbenzoic acid
(46 mg, 0.28 mmol), and TBTU (108 mg, 0.34 mmol) in anhy-
drous N,N-dimethylformamide (4 mL) was stirred at room tem-
perature for 1 h under an atmosphere of nitrogen. The reaction
mixture was cooled to −15◦C and then added to sodium hydride
(45 mg, 1.1 mmol, 60% dispersion in oil), which had been previ-
ously washed with anhydrous hexane and cooled to −15◦C. The
reaction mixture was maintained at −15◦C for a further 2 h and
then allowed to warm to room temperature overnight. The sol-
vent was removed under vacuum to afford a brown gum, which
was resuspended in ethyl acetate, and a brown solid removed by
filtration. The filtrate was concentrated and the resulting residue
purified by flash chromatography (9/1, chloroform/propan-2-ol)
to afford a bright yellow powder (70 mg, 50%). Recrystallization
from dichloromethane/hexane gave 2v (52 mg, 38%) as yel-
low micro-needles, mp 178–180◦C. (Found: C 66.4, H 5.6, N
14.0, MH+ 488.1849. C27H26ClN5O2 requires C 66.4, H 5.4,
N 14.4%, MH+ 488.1848.) νmax (KBr)/cm−1 3464, 1680, 1606,
1564. λmax/nm (ε/M−1 cm−1) 232 (32 400), 261 (19 100), 295
(9500). δH (CDCl3) 2.60 (3H, s, COCH3), 3.27 (2H, br m, H2ꢀa,
H6ꢀa), 3.57 (3H, s, CH3N+), 3.85 (4H, br m, H3ꢀ, H5ꢀ), 4.42
(2H, m, H2ꢀb, H6ꢀb), 4.96 (1H, s, H5), 6.65 (1H, d, J 8, H6),
6.83–6.88 (2H, m, H4, H7), 7.00 (1H, app t, J 7.5, H2), 7.06
(1H, d, J 2.5, H9), 7.23 (1H, br d, J 7.5, H1), 7.31 (1H, app
td, J 8, 1.5, H3), 7.92 (2H, d, J 8, H3ꢀꢀ, H5ꢀꢀ), 8.08 (2H, d, J
8, H2ꢀꢀ, H6ꢀꢀ). δC (CDCl3) 26.7 (COCH3), 42.2 (C3ꢀ, C5ꢀ), 53.0
(CH3N+), 61.8 (C2ꢀ, C6ꢀ), 120.3 (C4, C6), 122.4 (C11a), 123.3
(C2), 124.0 (C7), 126.8 (C9), 127.6, 127.8 (C2ꢀꢀ, C3ꢀꢀ, C5ꢀꢀ, C6ꢀꢀ),
129.1 (C8), 129.8 (C1), 132.5 (C3), 137.9 (C1ꢀꢀ), 140.4 (C5a),
141.0 (C9a), 143.1 (C4ꢀꢀ), 153.1 (C4a), 162.2 (C11), 168.9 (CO),
198.2 (CH3CO). m/z (+ESI, 30V) 490 (40%, M[37Cl]H+), 488
(100%, MH+).
1-[4-(8-Chloro-5H-dibenzo[b,e][1,4]diazepin-11-yl)-
1-methylhexahydropyrazin-1-ium]-
1-(3-acetyl)benzimide 2u
Purifiedbyflashchromatography(85/15, chloroform/propan-
2-ol), pale yellow needles (CHCl3/hexane), yield 50%, mp
159–160◦C. (Found: C 63.0, H 5.5, N 13.3, MH+ 488.1848.
C27H26ClN5O2·1.5H2O requires C 63.0, H 5.7, N 13.6%, MH+
488.1848.) νmax (KBr)/cm−1 3364, 1680, 1604, 1552. λmax/nm
(ε/M−1 cm−1) 230 (17 800), 260 (17 000), 298 (14 100). δH
(CDCl3) 2.65 (3H, s, COCH3), 3.28 (2H, br m, H2ꢀa, H6ꢀa),
3.60 (3H, s, CH3N+), 3.89 (4H, m, H3ꢀ, H5ꢀ), 4.44 (2H, m,
H2ꢀb, H6ꢀb), 5.00 (1H, s, H5), 6.65 (1H, d, J 8.5, H6), 6.84 (1H,
d, J 8, H4), 6.86 (1H, dd, J 8.5, 2.5, H7), 7.02 (1H, app t, J
7.5, H2), 7.06 (1H, d, J 2.5, H9), 7.25 (1H, d, J 7.5, H1), 7.33
(1H, app t, J 8, H3), 7.44 (1H, app t, J 7.5, H5ꢀꢀ), 7.99 (1H,
d, J 7.5, H6ꢀꢀ), 8.24 (1H, d, J 7.5, H4ꢀꢀ), 8.59 (1H, s, H2ꢀꢀ). δC
(CDCl3) 27.0 (COCH3), 42.6 (C3ꢀ, C5ꢀ), 53.3 (CH3N+), 62.0
(C2ꢀ, C6ꢀ), 120.5 (C4, C6), 123.3 (C11a), 123.5 (C2), 124.2 (C7),
127.0 (C9), 127.9 (C2ꢀꢀ), 128.2 (C5ꢀꢀ), 129.2 (C6ꢀꢀ), 129.3 (C8),
130.1 (C1), 132.1 (C4ꢀꢀ), 132.7 (C3), 136.9 (C1ꢀꢀ), 139.3 (C3ꢀꢀ),
140.7 (C5a), 141.2 (C9a), 153.3 (C4a), 162.2 (C11), 169.1 (CO),
198.7 (CH3CO). m/z (+ESI, 30V) 490 (35%, M[37Cl]H+), 488
(100%, MH+).
1-[4-(8-Chloro-5H-dibenzo[b,e][1,4]diazepin-11-yl)-
1-methylhexahydropyrazin-1-ium]-
1-(3,4-methylenedioxy)benzimide 2z
Purifiedbyflashchromatography(85/15, chloroform/propan-
2-ol), yellow micro-needles (CHCl3/hexane), yield 48%, mp
165–167◦C. (Found: C 63.4, H 4.9, N 14.3. C26H24ClN5O3
requires C 63.7, H 4.9, N 14.3%.) νmax (KBr)/cm−1 3348, 1608,
1566, 1548. λmax/nm (ε/M−1 cm−1) 231 (26 900), 260 (22 400),
295 (14 800). δH (CDCl3) 3.27 (2H, br m, H2ꢀa, H6ꢀa), 3.57 (3H,
s, CH3N+), 3.88 (4H, br m, H3ꢀ, H5ꢀ), 4.42 (2H, m, H2ꢀb, H6ꢀb),
4.91 (1H, s, H5), 5.94 (2H, s, H2ꢀꢀ), 6.62 (1H, d, J 8.5, H6), 6.77
(1H, d, J 8, H7ꢀꢀ), 6.82 (1H, d, J 8, H4), 6.87 (1H, dd, J 8.5, 2.5,
H7), 7.02 (1H, app t, J 7.5, H2), 7.07 (1H, d, J 2.5, H9), 7.23
(1H, br d, J 7.5, H1), 7.32 (1H, app td, J 7.5, 1, H3), 7.51 (1H, br
s, H4ꢀꢀ), 7.58 (1H, dd, J 8, 1, H6ꢀꢀ). δC (CDCl3) 42.8 (C3ꢀ, C5ꢀ),
53.6 (CH3N+), 62.2 (C2ꢀ, C6ꢀ), 101.3 (C2ꢀꢀ), 107.7 (C4ꢀꢀ), 108.5
(C7ꢀꢀ), 120.6 (C4, C6), 122.1 (C6ꢀꢀ), 123.0 (C11a), 123.6 (C2),
124.3 (C7), 127.2 (C9), 130.2 (C1), 132.8 (C3), 133.5 (C5ꢀꢀ),
140.9 (C5a), 141.5 (C9a), 147.4 (C3ꢀꢀa), 149.0 (C7ꢀꢀa), 153.5
(C4a), 162.4 (C11), 169.8 (CO). m/z (+ESI, 30V) 492 (35%,
M[37Cl]H+), 490 (100%, MH+), 329 (20), 327 (60).
1-[4-(8-Chloro-5H-dibenzo[b,e][1,4]diazepin-11-yl)-
1-methylhexahydropyrazin-1-ium]-
1-(5-methoxy-1H-indol-2-yl)carbonylimide 9
Purifiedbyflashchromatography(85/15, chloroform/propan-
2-ol), fine yellow micro-crystals (CH2Cl2/hexane), yield 34%,
mp 209–212◦C. (Found: C 63.3, H 5.4, N 15.2, MH+ 515.1962.
C28H27ClN6O2·H2O requires C 63.3, H 5.4, N 15.2%, MH+
515.1597.) νmax (KBr)/cm−1 3446, 1611, 1572. λmax/nm
(ε/M−1 cm−1) 232 (30 900), 264 (15 800), 295 (22 900). δH
(CDCl3) 3.16 (2H, br m, H2ꢀa, H6ꢀa), 3.60 (3H, s, CH3N+),
3.83 (4H, br m, H3ꢀ, H5ꢀ), 3.83 (3H, s, OCH3), 4.32 (2H, m,
H2ꢀb, H6ꢀb), 5.03 (1H, s, H5), 6.63 (1H, d, J 8.5, H6), 6.82 (1H,
dd, J 8, 1, H4), 6.84 (1H, dd, J 8.5, 2.5, H7), 6.86 (1H, dd, J 9,
2.5, H6ꢀꢀ), 6.90 (1H, d, J 2.5, H3ꢀꢀ), 7.00 (1H, app td, J 7.5, 1, H2),
7.06 (1H, d, J 2.5, H4ꢀꢀ), 7.08 (1H, d, J 2.5, H9), 7.18 (1H, br d,
J 8, H1), 7.22 (1H, d, J 9, H7ꢀꢀ), 7.30 (1H, app td, J 7.5, 1.5, H3),
9.28 (1H, br s, H1ꢀꢀ). δC (CDCl3) 42.2 (C3ꢀ, C5ꢀ), 53.6 (CH3N+),
55.9 (OCH3), 62.1 (C2ꢀ, C6ꢀ), 102.4 (C3ꢀꢀ), 102.7 (C4ꢀꢀ), 112.2
(C7ꢀꢀ), 113.6 (C6ꢀꢀ), 120.6 (C4, C6), 122.7 (C11a), 123.5 (C2),
124.2 (C7), 127.0 (C9), 128.8 (C3ꢀꢀa), 129.2 (C8), 130.4 (C1),
131.1 (C2ꢀꢀ), 132.7 (C3), 136.8 (C7ꢀꢀa), 140.7 (C5a), 141.2 (C9a),
153.2 (C4a), 154.1 (C5ꢀꢀ), 162.3 (C11), 165.3 (CO). m/z (+ESI,
General Method: N-Acylation Using Acyl Acids (2v, 9)
The following compounds were prepared by acylation
of 1-amino-4-(8-chloro-5H-dibenzo[b,e][1,4]diazepin-11-yl)-
1-methylhexahydropyrazin-1-ium2,4,6-trimethyl-1-benzenesul-
fonate (5), in the presence of sodium hydride, with a hydroxy-
benzotriazolyl active ester.The activated ester was prepared from
TBTU and the appropriate carboxylic acid. The general method

4ꢀ-Aryl Aminimide Analogues of Clozapine
683
30V) 537 (45%, MNa+) 517 (35%, M[37Cl]H+), 515 (100%,
MH+).
(1H, app td, J 8, 1.5, H2), 7.05 (1H, br d, J 8, H4), 7.27–7.32
(4H, m, H1, H2ꢀꢀ, H5ꢀꢀ, H6ꢀꢀ), 7.35 (1H, br app t, J 8, H3), 9.09
(1H, br s, OH). δC (d6-DMSO) 42.3 (C3ꢀ, C5ꢀ), 51.7 (CH3N+),
60.6 (C2ꢀ, C6ꢀ), 114.4 (C2ꢀꢀ), 115.8 (C4ꢀꢀ), 117.9 (C6ꢀꢀ), 120.5
(C4), 120.8 (C6), 122.4 (C11a), 122.5 (C2), 123.1 (C7), 125.7
(C9), 126.7 (C8), 128.0 (C5ꢀꢀ), 129.9 (C1), 132.4 (C3), 141.0
(C1ꢀꢀ), 141.4 (C5a), 142.3 (C9a), 154.1 (C4a), 156.9 (C3ꢀꢀ), 162.3
(C11), 167.9 (CO). m/z (+ESI, 30V) 464 (35%, M[37Cl]H+),
462 (100%, MH+).
General Method: De-etherification of Aminimides 2w–y,
2aa, 10
The following hydroxy-substituted aminimides were prepared
from their respective methyl ethers (100 mg, 0.21 mmol) by
boron tribromide (4 equiv.) in dichloromethane and isolated as
yellow crystalline solids.The general method exemplified for the
synthesis of 1-[4-(8-chloro-5H-dibenzo[b,e][1,4]diazepin-11-
yl)-1-methylhexahydropyrazin-1-ium]-1-(2-hydroxy)benzimide
2w is described below.
1-[4-(8-Chloro-5H-dibenzo[b,e][1,4]diazepin-11-yl)-
1-methylhexahydropyrazin-1-ium]-
1-(4-hydroxy)benzimide 2y
Purifiedbyflashchromatography(85/15, chloroform/propan-
2-ol), fine yellow needles (CHCl3), yield 42%, mp 195–
196◦C. (Found: MH+ 462.1693. C25H24ClN5O2 requires MH+
462.1691.) νmax (KBr)/cm−1 3328, 1716, 1614, 1548. λmax/nm
(ε/M−1 cm−1) 232 (23 400), 254 (22 400), 298 (7600). δH (d4-
methanol) 3.47 (2H, br m, H2ꢀa, H6ꢀa), 3.53 (3H, s, CH3N+),
3.69 (2H, br m, H3ꢀb, H5ꢀb), 3.87 (2H, br m, H3ꢀa, H5ꢀa), 4.28
(2H, m, H2ꢀb, H6ꢀb), 6.74 (2H, d, J 8.5, H3ꢀꢀ, H5ꢀꢀ), 6.81 (1H, d,
J 8.5, H6), 6.87 (1H, dd, J 8.5, 2.5, H7), 6.99 (1H, d, J 2.5, H9),
7.00 (1H, d, J 7.5, H4), 7.05 (1H, app t, J 7.5, H2), 7.31 (1H,
br d, J 7.5, H1), 7.35 (1H, app td, J 7.5, 1.5, H3), 7.76 (2H, d, J
8.5, H2ꢀꢀ, H6ꢀꢀ). δC (d4-methanol)43.8(C3ꢀ, C5ꢀ), 56.0(CH3N+),
63.0 (C2ꢀ, C6ꢀ), 115.5 (C3ꢀꢀ, C5ꢀꢀ), 121.6 (C4), 121.7 (C6), 124.0
(C11a), 124.4 (C2), 125.1 (C7), 127.5 (C9), 129.8 (C1ꢀꢀ), 130.4
(C2ꢀꢀ, C6ꢀꢀ), 130.9 (C8), 131.3 (C1), 133.9 (C3), 142.9 (C5a),
143.4 (C9a), 155.5 (C4a), 160.5 (C4ꢀꢀ), 164.5 (C11), 172.3 (CO).
m/z (+ESI, 30V) 464 (35%, M[37Cl]H+), 462 (100%, MH+).
1-[4-(8-Chloro-5H-dibenzo[b,e][1,4]diazepin-11-yl)-
1-methylhexahydropyrazin-1-ium]-
1-(2-hydroxy)benzimide 2w
A solution of boron tribromide in dichloromethane (1.0 M,
850 µL, 0.85 mmol) was added at −78◦C, under an atmo-
sphere of nitrogen, to a solution of 1-[4-(8-chloro-5H-
dibenzo[b,e][1,4]diazepin-11-yl)-1-methylhexahydropyrazin-1-
ium]-1-(2- methoxy)benzimide 2q (100 mg, 0.21 mmol) in
anhydrous dichloromethane (10 mL). The reaction mixture was
maintained at −78◦C for 1 h and then allowed to warm to
room temperature overnight. Saturated brine solution (10 mL)
was added and the reaction mixture stirred for a further
20 min. Saturated sodium bicarbonate solution (50 mL) was then
added and the reaction mixture extracted with ethyl acetate
(3 × 30 mL). The combined organic extracts were washed with
water (50 mL), dried over anhydrous sodium sulfate, and con-
centrated under vacuum. The resulting residue was purified by
flash chromatography (85/15, chloroform/propan-2-ol) to afford
a bright yellow foam (81 mg, 81%). Recrystallization from
chloroform/hexane gave 2w (61 mg, 63%) as yellow rosettes, mp
184–186◦C. (Found: MH+ 462.1696. C25H24ClN5O2 requires
MH+ 462.1691.) νmax (KBr)/cm−1 3600–3100, 3286, 1608,
1563. λmax/nm (ε/M−1 cm−1) 231 (29 500), 263 (17 000), 297
(12 600). δH (CDCl3) 3.30 (2H, m, H2ꢀa, H6ꢀa), 3.60 (3H, s,
CH3N+), 3.79 (4H, m, H3ꢀ, H5ꢀ), 4.38 (2H, m, H2ꢀb, H6ꢀb),
4.91 (1H, s, H5), 6.62 (1H, d, J 8.5, H6), 6.80 (1H, br d, J 8,
H3ꢀꢀ), 6.81 (1H, d, J 8, H4), 6.86–6.89 (2H, m, H7, H5ꢀꢀ), 7.00
(1H, app t, J 7.5, H2), 7.05 (1H, d, J 2.5, H9), 7.21 (1H, br d, J
7.5, H1), 7.26 (1H, app td, J 8, 2, H4ꢀꢀ), 7.31 (1H, app td, J 7.5,
1.5, H3), 7.91 (1H, dd, J 8, 2, H6ꢀꢀ), 12.64 (1H, br s, OH). δC
(CDCl3) 42.3 (C3ꢀ, C5ꢀ), 54.1 (CH3N+), 62.2 (C2ꢀ, C6ꢀ), 116.4
(C3ꢀꢀ), 118.4 (C5ꢀꢀ), 120.3 (C1ꢀꢀ), 120.6 (C4, C6), 122.5 (C11a),
123.6 (C2), 124.3 (C7), 127.0 (C9), 129.1 (C6ꢀꢀ), 129.3 (C8),
130.0 (C1), 132.0 (C4ꢀꢀ), 132.8 (C3), 140.7 (C5a), 141.1 (C9a),
153.3 (C4a), 159.5 (C2ꢀꢀ), 162.1 (C11), 171.0 (CO). m/z (+ESI,
30V) 464 (35%, M[37Cl]H+), 462 (100%, MH+).
1-[4-(8-Chloro-5H-dibenzo[b,e][1,4]diazepin-11-yl)-
1-methylhexahydropyrazin-1-ium]-
1-(3,4-dihydroxy)benzimide 2aa
Purified by flash chromatography (9/1, ethyl acetate/
methanol), yellow-brown foam, yield 79%, mp 194–198◦C
(dec.). (Found: MH+ 478.1645. C25H24ClN5O3 requires MH+
478.1640.) νmax (KBr)/cm−1 3464, 3364, 1614, 1566. λmax/nm
(ε/M−1 cm−1) 232 (19 100), 258 (15 800), 295 (9100). δH (d4-
methanol) 3.55 (2H, br m, H2ꢀa, H6ꢀa), 3.55 (3H, s, CH3N+),
3.69 (4H, br m, H3ꢀ, H5ꢀ), 4.34 (2H, m, H2ꢀb, H6ꢀb), 6.78 (1H,
d, J 8.5, H5ꢀꢀ), 6.83 (1H, d, J 8.5, H6), 6.89 (1H, dd, J 8.5, 2.5,
H7), 7.02 (1H, d, J 2.5, H9), 7.06–7.16 (2H, m, H2, H4), 7.29
(1H, dd, J 8.5, 2, H6ꢀꢀ), 7.36–7.40 (2H, m, H1, H3), 7.42 (1H,
d, J 2, H2ꢀꢀ). δC (d4-methanol) 43.2 (C3ꢀ, C5ꢀ), 53.6 (CH3N+),
63.0 (C2ꢀ, C6ꢀ), 115.3 (C2ꢀꢀ), 115.6 (C5ꢀꢀ), 121.0 (C6ꢀꢀ), 121.6
(C4), 121.8 (C6), 124.0 (C11a), 124.4 (C2), 125.0 (C7), 127.5
(C9), 129.4 (C8), 131.3 (C1), 131.5 (C1ꢀꢀ), 133.9 (C3), 142.9
(C5a), 143.4 (C9a), 145.6 (C3ꢀꢀ), 148.5 (C4ꢀꢀ), 155.6 (C4a), 164.6
(C11), 171.1 (CO). m/z (+ESI, 30V) 480 (35%, M[37Cl]H+),
478 (100%, MH+).
1-[4-(8-Chloro-5H-dibenzo[b,e][1,4]diazepin-11-yl)-
1-methylhexahydropyrazin-1-ium]-
1-(3-hydroxy)benzimide 2x
1-[4-(8-Chloro-5H-dibenzo[b,e][1,4]diazepin-11-yl)-
1-methylhexahydropyrazin-1-ium]-
1-(5-hydroxyindol-1H-2-yl)carbonylimide 10
Purifiedbyflashchromatography(85/15, chloroform/propan-
2-ol), fine yellow needles (CHCl3/MeOH), yield 66%, mp
236–237◦C. (Found: C 62.7, H 5.3, N 14.3, MH+ 462.2697.
C25H24ClN5O2·H2O requires C 62.6, H 5.5, N 14.6, MH+
462.1691.) νmax (KBr)/cm−1 3328, 3250, 1614, 1554. λmax/nm
(ε/M−1 cm−1) 229 (15 800), 261 (9800), 295 (6200). δH (d6-
DMSO) 3.48 (6H, br m, H3ꢀ, H5ꢀ, H2ꢀa, H6ꢀa), 3.48 (3H, s,
CH3N+), 4.21 (2H, m, H2ꢀb, H6ꢀb), 6.68 (1H, br dd, J 8, 1.5,
H4ꢀꢀ), 6.87–6.90 (3H, m, H6, H7, H9), 7.00 (1H, s, H5), 7.01
Purified by flash chromatography (4/1, chloroform/propan-
2-ol), amorphous tan coloured solid, yield 60%, mp 184–186◦C
(dec.). (Found: MH+ 501.1781. C27H25ClN6O2 requires MH+
501.1800.) νmax (KBr)/cm−1 3464, 3364, 1614, 1566. λmax/nm
(ε/M−1 cm−1) 229 (31 600), 263 (18 200), 297 (20 400). δH (d4-
methanol) 3.46 (2H, m, H2ꢀa, H6ꢀa), 3.55 (3H, s, CH3N+), 3.78
(2H, m, H3ꢀ, H5ꢀ), 4.26 (2H, m, H2ꢀb, H6ꢀb), 6.72 (1H, dd, J 9,
2.5, H6ꢀꢀ), 6.74 (1H, br s, H3ꢀꢀ), 6.80 (1H, d, J 8.5, H6), 6.86 (1H,

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B. Capuano et al.
dd, J 8.5, 2.5, H7), 6.91 (1H, d, J 2.5, H4ꢀꢀ), 6.99 (1H, d, J 2.5,
H9), 6.99 (1H, br d, J 7.5, H4), 7.04 (1H, br app t, J 7.5, H2),
7.22 (1H, d, J 9, H7ꢀꢀ), 7.30 (1H, br d, J 8, H1), 7.35 (1H, app td,
J 7.5, 1, H3). δC (d4-methanol) 43.2 (C3ꢀ, C5ꢀ), 53.8 (CH3N+),
63.2 (C2ꢀ, C6ꢀ), 103.4 (C3ꢀꢀ), 105.8 (C4ꢀꢀ), 113.2 (C7ꢀꢀ), 114.5
(C6ꢀꢀ), 121.6 (C4), 121.7 (C6), 124.0 (C11a), 124.4 (C2), 125.0
(C7), 127.5 (C9), 129.8 (C8), 130.0 (C3ꢀꢀa), 131.3 (C1), 133.0
(C7ꢀꢀa), 133.9 (C3), 137.5(C2ꢀꢀ), 142.9(C5a), 143.3(C9a), 151.7
(C5ꢀꢀ), 155.5 (C4a), 164.5 (C11), 167.0 (CO). m/z (+ESI, 30V)
503 (35%, M[37Cl]H+), 501 (100%, MH+), 327 (20), 225 (20),
126 (35).
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Receptor Binding Assays
Receptor affinities were determined by MDS Panlabs, Taiwan,
by the ability of the tested compounds to displace selective radio-
ligands.All assayed compounds were dissolved in dimethyl sulf-
oxide to a stock concentration of 10 × 10−3 M, and then diluted
with assay buffer to a final concentration of 10−6 M. The assays
were carried out using the following: (i) for dopamine D4.4
;
human recombinant (mammalian CHO-K1 cells), [3H]spiperone
(0.3 × 10−9 M) as radioligand, and haloperidol (10 × 10−6 M) as
reference compound for non-specific binding; (ii) for serotonin
5-HT2A; rat cortex, [3H]ketanserin (0.5 × 10−9 M) as radio-
ligand, and ketanserin (1 × 10−6 M) as reference compound for
non-specific binding. The binding results are expressed as the
percentage inhibition of specific binding at a concentration of
1 × 10−6 M for the tested compound and represent the mean
of duplicate tubes with a maximum standard error in the mean
of 5.
Acknowledgement
The receipt of a Monash Graduate Scholarship (J.E.N.) for support of this
research is gratefully acknowledged.
References
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