A new class of antiarrhythmic-defibrillatory agents

Article abstract of DOI:10.1016/S0960-894X(01)00588-1

Novel dibenzoazepine and 11-oxo-dibenzodiazepine derivatives are shown to be effective ventricular defibrillating drug candidates. They exhibit significant in vivo defibrillatory activity with no observed changes in ECG either before or after the VF event. These compounds also exhibit antifibrillatory activity by elevating the fibrillation threshold potential, all suggesting that such drugs could be used to treat VF either by themselves or together with electrical defibrillators.

Full text of DOI:10.1016/S0960-894X(01)00588-1

Bioorganic & Medicinal Chemistry Letters 11 (2001) 2921–2926
A New Class of Antiarrhythmic-Defibrillatory Agents
Ofra Levy,a Mordechai Erez,a,* Dalia Varonb and Ehud Keinana,c,y,
*
aDepartment of Chemistry and Institute of Catalysis Science and Technology, Technion-Israel Institute of Technology,
Technion City, Haifa 32000, Israel
bDepartments of Physiology and Pharmacology, Sackler School of Medicine, Tel Aviv University, Tel Aviv, Israel
cThe Scripps Research Institute, Department of Molecular Biology and The Skaggs Institute of Chemical Biology,
10550 North Torrey Pines Road, La Jolla, CA 92037, USA
Received 11 July 2001; accepted 22 August 2001
Abstract—Novel dibenzoazepine and 11-oxo-dibenzodiazepine derivatives are shown to be effective ventricular defibrillating drug
candidates. They exhibit significant in vivo defibrillatory activity with no observed changes in ECG either before or after the VF
event. These compounds also exhibit antifibrillatory activity by elevating the fibrillation threshold potential, all suggesting that such
drugs could be used to treat VF either by themselves or together with electrical defibrillators. # 2001 Elsevier Science Ltd. All
rights reserved.
Sudden cardiac death (SCD)1 is a leading cause of
human mortality among adults, mainly among patients
suffering from either coronary heart disease2,3 or con-
gested heart failure.4 It is commonly accepted that ven-
tricular arrhythmia, such as ventricular tachycardia and
ventricular fibrillation (VF), plays the major role in
SCD. VF is fatal, unless either an external or implanted
electrical defibrillator is applied within a few minutes
from initiation. Considering the fact that 75% of VF
incidents occur while the patient is far from any profes-
sional medical aid (CPR),5 the implanted electrical defi-
brillator represents the preferred treatment. However,
this invasive approach deals only with the symptoms
and does not prevent reoccurrence of VF. Furthermore,
since the number of patients having implanted devices is
quite small, only a tiny proportion of cardiac arrest
victims are saved every year worldwide by the use of
electrical defibrillators.5 Certainly, a safe pharmaceu-
tical agent for treatment of high-risk patients is highly
desirable.4
focusing on the first strategy, no drug development
effort has been dedicated to the chemical termination of
VF. Consequently, all relevant drugs and drug candi-
dates developed so far reflect efforts to decrease the
incidence of ventricular arrhythmia that might end in
VF.6 Unfortunately, since VF may be initiated via sev-
eral different mechanisms, the design of a universal
prophylactic drug is difficult and all attempts in this
direction have gained only partial success.7 For exam-
ple, the Cardiac Arrhythmia Suppression Trial, CAST I
and II,8,9 have clearly demonstrated the limitations of
this therapeutic approach.
It has been commonly accepted that the ability of the
mammalian heart to defibrillate spontaneously is related
to its ventricular muscle mass.10 Accordingly, small
hearts defibrillate spontaneously because they do not
contain the minimal number of cells required to main-
tain fibrillation.10c Consequently, it has been assumed
that relatively large heart mass, such as the human heart
ventricles, cannot defibrillate spontaneously. Following
this conjecture no serious efforts have been directed
toward the development of VF-terminating drugs.
Nevertheless, the growing evidence for a non-fatal VF
in humans suggests that VF can convert spontaneously
into sinus rhythm.11 For example, a comparative study
of the occurrence of sustained VF (SVF) and transient
VF (TVF) in untreated mammals of various species and
ages has led to the conclusion that the heart ability to
self-defibrillate is also a function of age, with TVF
In principle, two chemical therapeutic strategies for the
treatment of VF could be envisioned. One approach
aims at prevention of VF and the other targets its ter-
mination. While drug development efforts have been
*Corresponding authors. Tel./fax: +972-4-829-3913; e-mail: tmerez
@netvision.net.il; keinan@tx.technion.ac.il
yIncumbent of the Benno Gitter & Ilana Ben-Ami chair of Bio-
technology, Technion.
0960-894X/01/$ - see front matter # 2001 Elsevier Science Ltd. All rights reserved.
PII: S0960-894X(01)00588-1

2922
O. Levy et al. / Bioorg. Med. Chem. Lett. 11 (2001) 2921–2926
ꢀ
occurring more readily in young rather than old
mammalian hearts.12
in ethanol was warmed to 65 C, the appropriate alky-
lamine was slowly added and the mixture was stirred for
1 h at this temperature and than allowed to cool to
room temperature. Work-up with 5% aq potassium
bicarbonate, and CH2Cl2, followed by recrystallization
from cold ethyl acetate, afforded the corresponding
secondary amine. The latter was dissolved in dry tolu-
ene and treated with dry HCl gas to produce the
hydrochloride 1a–g in the form of a white powder.19
Assuming that spontaneous defibrillation requires a
12a
relatively high level of intercellular synchronization,
and is enhanced by increased sympathetic activity,10d
Manoach et al.13 have been searching for chemical defi-
brillating agents that elevate extra-neuronal levels of
catecholamines in the heart. They found that several
psychotropic drugs (Scheme 1), such as dibenzoazepines
(imipramine, desipramine, and bonnecore), maprotiline,
dibenzepin and phenothiazines (chlorpromazine, mor-
icizine, and trifluoperazine), can induce defibrillation
and also increase the ventricular fibrillation threshold.14
Tricyclic antidepressants (TCAD) also decreased the
ischemic area in the heart following coronary occlu-
sion.15 Previous studies indicated that the TCAD deri-
vatives are more effective as chemical defibrillators than
the groupof phenothiazines. 16 Nevertheless, all of these
cardio-protective agents were effective only when high
doses relative to their therapeutic index were employed.
The parent system 2 was achieved in a one stepreaction
via the Ullmann–Golgber condensation (Scheme 3).20
Thus, equimolar amounts of 2-chlorobenzoic acid, 1,2-
diaminobenzene and copper powder (3 equiv) in chloro-
ꢀ
benzene and molecular sieves (3) were stirred at 130 C
for 8 h. The hot mixture was filtered, the solvent was
removed under reduced pressure, and the solid residue
was recrystallized (ethanol) to give 2 in the form of
bright yellow crystals. The latter was mixed in dry THF
with NaNH2 (2 equiv), cooled to 0 ꢀC, 3-chloro-
propanoyl chloride (1.2 equiv) was added dropwise, the
mixture was stirred at 0 ꢀC for 30 min, allowed to warm
to room temperature, washed with 5% aq potassium
bicarbonate, and extracted with CH2Cl2. The organic
layer was dried over Na2SO4, and the solvent was
removed under reduced pressure. The crude product
was crystallized from ether to give 6 in the form of a
yellow solid.21 A suspension of 6 in ethanol (50 mL) was
warmed to 65 ꢀC, alkylamine (either methylamine,
ethylamine, or isopropylamine) was added dropwise,
and the mixture was stirred at this temperature for 1 h
and then allowed to cool to room temperature. Work-
upwith aq optassium bicarbonate and CH 2Cl2, fol-
lowed by recrystallization from ethyl acetate, afforded
the free amine in the form of a white powder. The latter
was dissolved in toluene, dry HCl gas was bubbled
through the solution, and the resultant powder, 2a–c,
Following the above described indications that chemical
defibrillation could indeed be a feasible option for
treatment of VF; we have initiated a drug discovery
effort that focuses on the design and synthesis of new
defibrillatory agents. In addition to high selectivity and
an optimal therapeutic index in affecting defibrillation,
we also aimed at antiarrhythmic and antiischemic
activities. We have decided to initially focus on the two
families of drug candidates that contain the nuclei of
dibenzoazepine, 1, and 11-oxo-dibenzodiazepine, 2.
Here we report on the first compounds ever designed to
serve as ventricular defibrillating agents. These drug
candidates exhibit high defibrillatory activity with no
observed changes in ECG either before or after the VF
event. Preliminary SAR studies point at higher activity
of derivatives of 1 in comparison with those related to 2.
These studies also highlight the superiority of the amino-
hydroxyalkyl side chain over the aminoacyl and the
aminoalkyl groups. We also report on the VF initiation
prevention activity of these compounds.
22
was collected by filtration.
The seven dibenzoazepine derivatives, 1a–g, were syn-
thesized from the parent system, 3 (Scheme 2), which
was prepared from 2-nitrotoluene using the Lapworth
reaction.17 Slow addition of a benzene solution of 3-
chloropropanoyl chloride to 3, followed by reflux for 3
h, produced amide 418 in 91% yield after purification by
column chromatography. A well-stirred suspension of 4
Scheme 2.
Scheme 1.
Scheme 3.

O. Levy et al. / Bioorg. Med. Chem. Lett. 11 (2001) 2921–2926
2923
The amino alcohols 8 (Scheme 4) were obtained from 3
via epoxides 7. Thus, a mixture of 3 and NaNH2 in
benzene was refluxed for 2 h, epichlorohydrin (either
racemic or non-racemic, from Aldrich) was added
dropwise, and the mixture was refluxed for 6 h. The
solvent was removed under reduced pressure; the resi-
due was washed with 5% aq HCl and extracted with
CH2Cl2. The crude product was purified by flash chro-
carried out for each animal by induction of VF (fol-
lowed by electrical defibrillation after 90 s) before drug
administration. Thus, each animal served as its own
control. The effect of the drugs was evaluated by inject-
ing their saline solution intravenously at doses of 3, 2, 1
and 0.5 mg/kg 2-3 min before the first in a series of
electrical inductions of VF was applied. A typical
experiment is shown in Figure 1. It is important to note
that no changes could be observed in the patterns of
either the ECG or the blood pressure after the adminis-
tration of any of the compounds used in this study
either before or after the VF event.
matography to give 7 in the form of a white powder.23
A
ꢀ
suspension of 7 in isopropanol was warmed to 30 C,
and isopropyl amine (2 equiv) was added dropwise. The
mixture was stirred overnight at this temperature and
than allowed to cool to room temperature. The solvent
was removed under reduced pressure, and the residue
was recrystallized (cold ethyl acetate) to give the amino
alcohol in the form of a white powder. The latter was
dissolved in toluene; dry HCl gas was bubbled through
the solution, and the resultant powder, 8, was collected
by filtration.24
In preliminary experiments with several compounds we
found that their maximal defibrillating effect is achieved
within 10–40 min after injection. Therefore, we consider
the observation of the episode that was measured 10
min after drug administration as the representative
value for each animal. Thus, the relative activity values
presented in Table 1 refer to episodes carried out 10 min
after injection. Animals that exhibited VF duration
shorter than 90 s were designated as having TVF. Ani-
mals that failed to terminate their VF within 90 s, and
therefore required electrical treatment for defibrillation,
were defined as having SVF. The relative defibrillating
activity (shown on a qualitative scale between ++++
and 0) of a given compound was defined as the ratio
between the number of animals exhibiting TVF events
out of the total VF events.
Pharmacological investigations were performed in an in
vivo cat model. Each compound was tested in at least 3
male cats. The animals were anesthetized with sodium
pentobarbital (15–25 mg/kg, intravenous). Hearts were
exposed through midline thoracotomy, and a room air
respirator was applied through a tracheal cannula. Lead
II electrocardiogram and intra-arterial blood pressure
were recorded on a Grass Polygraph recorder. Fibrilla-
tion stimuli (a train of rectangular pulses of 2–15 V, 100
pps and duration 0.1–1 ms, for a period of 0.5 s) were
delivered through two silver needle electrodes attached
to the pericardium on the left ventricle. Strength of the
fibrillating stimuli was 1.5- to 2.0-fold the strength of
the fibrillating threshold. Control experiments were
The results in Table 1 represent a qualitative structure
activity relationship(SAR) study that points at several
interesting trends. We selected the molecular nuclei of 1
and 2 because previous studies with similar nuclei, such
as those of desipramine16 and dibenzepine,25 exhibited
various levels of defibrillating activity (Table 1).16
A
common structural feature of all these and our com-
pounds is a dihedral angle of approximately 60ꢀ
between the two benzene rings.26
As may be concluded from Table 1, the dimethylene
bridge of 1 renders this skeleton more active than the
Scheme 4.
Figure 1. Electrocardiogram (ECG, LII) and blood pressure recorded during electrically induced ventricular fibrillation 10 min after administration
of compound 1c (3 mg/kg, cat).

2924
O. Levy et al. / Bioorg. Med. Chem. Lett. 11 (2001) 2921–2926
Table 1. Relative defibrillating activity of compounds 1, 2, and 8
dosage as low as 0.5 mg/kg. This value represents the
highest chemical defibrillating activity ever reported.
Interestingly, the absolute configuration of 8c is
identical to that of nor epinephrine and epinephrine.
Compd
3 mg/kg
2 mg/kg
1 mg/kg
0.5 mg/kg
1a
1b
++++
++++
++++
+++
+
++
0
0
1c
1d
1e
1f
1g
2a
2b
2c
8a
8b
++++
++++
++++
++++
+++
++
0
0
0
0
+
In addition to the defibrillatory effect exhibited by most
of the above-described compounds, several of them
have also exhibited antifibrillatory effect, That is they
caused elevation of the VF threshold potential. Thus, in
preliminary experiments with compounds 1a, 1c, 8a,
and 8c at 2 mg/kg an increase of the VF potential (by
approximately 50%) was required in order to initiate a
fibrillation event.
0
0
0
0
0
0
0
0
0
0
0
0
++++
++++
++++
++++
++
++
+++
++
++
++++
++
++
+++
8c
Dibenzepine25
Imipramine16
Desipramine16
+++
+++
++++
0
0
+
In conclusion, we have reported here on the first com-
pounds ever designed to serve as ventricular defibrillat-
ing drugs. Several compounds, such as 1c and 8c, were
found to exhibit potent defibrillatory activity while
keeping the ECG unchanged after their administration.
These drug candidates also exhibit antifibrillatory
activity by elevating the fibrillation threshold potential.
This activity as well as the antiischemic activity of the
new compounds will be reported in due course. The
SAR studies point at higher activity of derivatives of 1
in comparison with those related to 2. These studies also
highlight the superiority of the 3-amino-2-hydroxyalkyl
side chain over the aminoacyl and the aminoalkyl
chains. The (S)-(ꢁ) enantiomer, 8c, was found to be the
most active defibrillating agent discovered to date.
These results suggest that defibrillatory drugs, such as
those described here, could be used to treat VF either by
themselves or together with electrical defibrillators.
All experiments where carried out 10 min after injection. Relative
activity (++++ represents 100% and+represents 25%) is defined
as the total TVF events out of total VF events.
amide bridge of 2. Interestingly, attachment of the side
chain onto the amide nitrogen of skeleton 2, as in the
case of dibenzepine,25 leads to significantly higher
activity than attachment to the amine nitrogen, as in the
case of 2a–c.
We focused on compounds containing side chains with
secondary amines rather than primary or tertiary
amines. Previous reports on SARs with similar defi-
brillation compounds, such as desipramine and imipra-
mine, have indicated the superiority of secondary
amines over the tertiary ones.27 Similar trends were
observed with other model systems, such as the reup-
take of noradrenaline and antidepressant activity, where
secondary amines were found to be more active than the
primary and tertiary analogues.27 Indeed, initial experi-
ments with derivatives of 1 having tertiary amine side
chains (data not shown) exhibited relatively low activ-
ity. Furthermore, the size of the alkylamino groupis
very important, with isopropylamino group (1c) show-
ing the highest activity within the molecular skeleton of
1. Small structural variations, such as switching from
tert-butylamino group( 1d) to either iso-butylamino (1f)
or to sec-butylamino (1e) analogues resulted in remarkable
decrease of activity.
Acknowledgements
We thank the Technion Foundation for partial support
of this work.
References and Notes
1. Olshausen, K. V.; Witt, T.; Pop, T.; Treese, N.; Bethge, K.;
Meyer, J. Am. J. Cardiol. 1991, 67, 381.
2. Baum, R. S.; Alvarez, H.; Cobb, L. A. Circulation 1974, 50,
1231.
3. Shargorodsky, B. M.; Braun, S.; Belhassen, B.; Laniado, S.
Cardiovas. Res. 1986, 20, 652.
Two side chains, b-aminoacyl and 3-amino-2-hydroxy-
alkyl, were used in this study. The choice of b-amino-
acyl side chain was based on previous observations of
the introduction of b-aminoacyl side chains in other
systems (e.g., in bonnecore and moricizine), which
resulted in increased antiarrhythmic activity and
decreased psychotropic activity as compared with the b-
aminoalkyl analogues.28 The choice of 3-amino-2-
hydroxyalkyl side chains was made on the basis of the
analogy to epinephrine and norepinephrine. Compar-
ison of 1c and 8a–c highlights the superiority of the 3-
amino-2-hydroxyalkyl over the aminoacyl and the ami-
noalkyl (as is the case of imipramine) side chains in our
screening model. The (S)-(ꢁ) enantiomer, 8c, was found
to be the most active defibrillating agent among the
compounds studied here, exhibiting high activity at a
4. (a) Lucchesi, B. R.; Lynch, J. J. Fed. Proc. Fed. Am. Soc.
Exp. Biol. 1986, 45, 2197. (b) Patterson, E.; Lucchesi, B. R.
Am. Heart J. 1983, 24, 129. (c) Hodeghem, L. M., Mason, J.
W. In Clinical Pharmacology; Katz, Ed.; Pergammon: New
York, 1982; pp 138–154.
5. Eisenberg, M. S. Sci. Am. 1998, 278, 86.
6. (a) Vaughan Williams E. M. In Symposium on Cardiac
Arrythmias; Sandoe, E., Flasted-Jansen, E., Olesen, K. H.,
Eds.; Sudertalje Seden: AB Astra, 1970, p. 449. (b) Vaughan
Williams, E. M. J. Clin. Pharmacol. 1984, 24, 129. (c) Vaughan
Williams, E. M. J. Clin. Pharmacol. 1991, 31, 123. (d) Task
Force of the Working Groupon Arrhythmias of the European
Society of Cardiology Circulation 1991, 84, 1831.
7. Sanna, G.; Archidiacono, R. Am, J. Cardiol 1973, 32, 982.
8. CAST Investigators N. Engl. J. Med. 1989, 321, 406.
9. CAST II Investigators N. Engl. J. Med. 1992, 327, 227.

O. Levy et al. / Bioorg. Med. Chem. Lett. 11 (2001) 2921–2926
2925
10. (a) Damiano, R. J.; Asano, T.; Smith, P. K.; Cox, J. L. J.
Am. Coll. Cardiol. 1990, 15, 730. (b) Watanabe, Y. Cardiol-
ogy. In Proceedings of the 8th World Congress of Cardiology;
Hayase, S., Mauro, S., Eds.; Expecta Medica: Amsterdam,
1979; pp. 924–929. (c) West, T. C.; Landa, J. F. Am. J. Phy-
siol. 1962, 202, 232. (d) Manoach, M.; Erez, M.; Varon, D.
Cardiol. Elderly 1993, 1, 337.
11. (a) Robinson, G. C.; Bredeck, J. F. AMA Arch. Int. Med.
1917, 20, 725. (b) Schwartz, S. P.; Orloff, J.; Fox, C. Am.
Heart J. 1949, 37, 21. (c) Ledwich, J. R.; Faye, J. E. Am. J.
Cardiol. 1969, 24, 255. (d) Dubner, S. J.; Gimeno, G. M.;
Elencwajg, B.; Leguizamon, J.; Tronge, J. E.; Quinteiro, R.
Am. Heart J. 1983, 105, 691. (e) Interian, A., Jr.; Trohman,
R. G.; Castellanos, A.; Cox, M.; Zaman, L.; Myerburg, R. J.
Am. J. Cardiol. 1987, 59, 1200. (f) Kontny, F.; Dale, J. J.
Internal Med. 1990, 227, 211.
12. (a) Manoach, M., Beker, B., Erez, M., Varon, D., Netz,
H. In Progress in Electrophysiology; Macfarlane P. W., Ed.;
Pitman Medical: London, 1979; pp. 361–365. (b) Manoach,
M.; Netz, H.; Erez, M.; Weinstock, M. Ageing 1980, 9, 112. (c)
Manoach, M.; Netz, H.; Varon, D.; Amitzur, G.; Weinstock,
M.; Kauli, N.; Assael, M. Jpn. Heart J. 1986, 27, 365. (d)
Manoach, M.; Varon, D.; Neuman, M.; Netz, H. Heart Ves-
sels 1987, 2, 56. (e) Manoach, M.; Varon, D.; Erez, M. Mol.
Cell. Biochem. 1995, 147, 181.
3.12 (m, 1H), 2.84 (b m, 7H), 2.27 (b m, 2H), 1.02 (t, J=7.4
Hz, 3H). MS (FAB) m/z 295 (MH+), HRMS (MALDI-
FTMS) expected for MH+ 295.1810, found 295.1759, expec-
ted for MNa+ 317.1630, found 317.1604. 1c: Light-yellow
solid (1.219 g, 66%), mp198.4–199.1 ꢀC, 1H NMR (D2O) d
6.97 (b m, 8H), 3.14 (m, 1H), 2.97 (m, 4H), 2.67 (m, 1H), 2.42
(m, 1H), 2.38 (m, 2H), 1.08 (d, J=6.6 Hz, 6H), 13C NMR
(D2O) d 172.12, 130.71, 130.02, 128.78, 128.42, 127.62, 127.46,
57.06, 32.89, 26.71, 20.16, 19.94. MS (FAB) m/z 309 (MH+),
HRMS (MALDI-FTMS) expected for MH+ 309.1962, found
309.1955. 1d: (280 mg, 87%), mp224.5 ꢀC, H NMR (D2O) d
1
7.24 (m, 8H), 3.39 (m, 2H), 2.85 (m, 5H), 2.51 (m, 1H), 1.26 (s,
9H). MS (FAB) m/z 323 (MH+), HRMS (MALDI-FTMS)
expected for MH+ 323.2118, found 323.2124. 1e: (264 mg,
82%), mp188.9–191 ꢀC. H NMR (D2O) d 7.23 (m, 8H), 3.35
1
(m, 2H), 2.82 (m, 4H), 2.74 (m, 2H), 1.84–1.42 (b m, 1H), 1.25
(d, J=6.5 Hz, 3H), 1.19 (m, 2H), 0.89 (t, J=6.6 Hz, 3H). MS
(FAB) m/z 323 (MH+), HRMS (MALDI-FTMS) expected for
MH+ 323.2118, found 323.2116. 1f: (241 mg, 75%), mp
194.6–195.2 ꢀC. 1H NMR (D2O) d 7.25 (m, 8H), 3.37 (m, 2H),
2.82 (m, 4H), 2.65 (d, J=6.7 Hz, 2H), 2.45 (m, 2H), 1.83 (m,
1H), 0.99 (q, J=6.6, Hz, 6H); 13C NMR (D2O) d 172.21,
130.72, 130.02, 128.91, 128.52, 127.65, 127.57, 58.06, 45.19,
32.91, 28.34, 20.42, 19.94. MS (FAB) m/z 323 (MH+), HRMS
(MALDI-FTMS) expected for MH+ 323.2118, found
323.2127. 1g: (367 mg, 67%). Mp257.7–258.3 ꢀC. H NMR d
1
13. Manoach, M.; Varon, D.; Netz, H. Heart Vessels 1987, 3,
80.
14. Manoach, M.; Varon, D.; Neuman, M.; Erez, M. Int. J.
Cardiol. 1988, 21, 211.
15. Manoach, M.; Varon, D.; Neuman, M.; Erez, M. Gen.
Pharmacol. 1988, 20, 269.
7.31–7.15 (b m, 13H), 3.85 (m, 2H), 2.94 (m, 2H), 2.82 (m,
4H), 2.47 (m, 2H). MS (FAB) m/z 357 (MH+), HRMS
(MALDI-FTMS) expected for MH+ 357.1962, found
357.1952.
20. Giani, R. P.; Borsa, M.; Parini, E.; Tonton, G. C. Synth-
esis 1985, 1, 550.
16. Erez, M.; Varon, D. Exp. Clin. Cardiol. 1997, 2, 59.
17. (a) Das, P. B.; Woodard, L. K.; Whisenant, W. F.;
Winecoff, W. F.; Boyrin, D. W. J. Med. Chem. 1970, 13, 979.
(b) Schindler, W.; Hafliger, F. Helv. Chim. Acta 1954, 59, 472.
(c) Nagarajan, K.; Shah, R. K. Indian J. Chem. 1976, 14b, 1.
18. 3-Chloro-1-(10,11-dihydrodibenzo[b,f]azepine-5-yl)-pro-
pan-1-one (4): 3-chloropropanoyl chloride (0.5 mL, 5.2 mmol)
was added dropwise to a solution of 3 (0.85 g, 4.4 mmol) in
benzene (50 mL), the mixture was refluxed for 3 h, the solvent
was removed under reduced pressure, the residue was washed
with HCl (1 N, 30 mL), and extracted with CH2Cl2. The
organic layer was dried over Na2SO4 and the crude product
was purified by flash chromatography (silica gel, hexane–ethyl
acetate 8:2) to give 4 (1.133 g, 91%) in the form of white crys-
tals, mp107.7 ꢀC. 1H NMR d 7.16 (m, 8H), 3.82 (m, 2H), 3.46
(m, 1H), 2.85 (m, 2H), 2.51 (m, 1H). MS (CI) m/z 286 (M+)
19. 1-(10,11-dihydrodibenzo[b,f]azepin-5-yl)-3-alkylamino-
propan-1-one, HCl (1a–g): A well-stirred suspension of 4 (1.71
g, 6.0 mmol) in ethanol (50 mL) was warmed to 65 ꢀC. Alky-
lamine (10 mmol) was added dropwise and the mixture was
stirred for 1 h at this temperature, then allowed to cool to
room temperature, washed with 5% aq potassium bicarbonate
and extracted with dichloromethane. For the preparation of
compounds 1d–g isopropanol was used instead of ethanol and
the mixture was refluxed for 16 h. The organic layer was dried
over Na2SO4, filtered and the solvent was removed under
reduced pressure. The crude product was recrystallized from
ethyl acetate at ꢁ20 ꢀC. The latter solid was dissolved in tolu-
ene, dry HCl was bubbled into the solution and the resultant
precipitate was filtered and dried under reduced pressure. 1a:
Light-yellow solid (1.126 g, 67%), mp158.5 ꢀC, 1H NMR
(D2O) d 6.87 (b m, 8H), 3.15 (m, 1H), 2.82 (b m, 4H), 2.47 (s,
3H), 2.24 (b m, 3H); 13C NMR (D2O) d 172.14, 130.69, 130.36,
129.23, 128.19, 127.85, 127.43, 46.22, 33.53, 30.87, 30.19. MS
(FAB) m/z 281(MH+), HRMS (MALDI-FTMS) expected for
MH+ 281.1654, found 281.1640, expected for MNa+
303.3541, found 303.1462. 1b: Light-yellow solid (1.129 g,
21. 5-(3-Chloro-propionyl)-5,10-dihydrodibenzo[b,e][1,4]-dia-
zepine-11-one, 6: white crystals (467 mg, 87%), mp211.2 ꢀC,
1H NMR (DMSO-d6) d 8.78 (s, 1H), 7.98 (s, 1H), 7.59 (s, 1H),
7.4–7.26 (m, 6H), 3.77 (m, 4H). MS (CI) m/z 301(MH+).
22. 5-(3-Alkylamino-propionyl)-5,10-dihydro-dibenzo[b,e] [1,4]-
diazepin-11-one, hydrochloride, 2a–c. A suspension of 6 (1.5
g, 5.0 mmol) in ethanol (50 mL) was warmed to 65 ꢀC, the
appropriate alkylamine (10 mmol) was added dropwise, the
mixture was stirred for 1 h at this temperature and worked up
as described above for the synthesis of 1. 2a: Light-pink solid
(627 mg, 44%), mp121 ꢀC. 1H NMR (D2O) d 7.33–7.06 (b m,
8H), 3.06 (t, J=6 Hz, 2H), 2.9 (m, 1H), 2.48 (s, 3H), 2.39 (b m,
1H). HRMS (MALDI-FTMS) expected for MH+ 296.1394,
found 296.1392. 2b: Light-yellow solid (1.023 g, 66%) mp
119.2 ꢀC, 1H NMR (D2O) d 7.62–7.09 (b m, 8H), 3.08 (t,
J=6.1 Hz, 2H), 2.86 (m, 3H), 2.38 (m, 1H), 1.06 (t, J=7.3,
3H). HRMS (MALDI-FTMS) expected for MH+ 310.1556,
found 310.1542. 2c: Light-orange solid (791 mg, 49%), mp
103–105 ꢀC. H NMR (D2O) d 7.45–7.10 (b m, 8H), 3.12 (m,
1
1H), 3.05 (t, J=6.2 Hz, 2H), 2.85 (m, 1H), 2.33 (m, 1H), 1.08 (d,
J=6.6 Hz, 6H); 13C NMR (D2O) d 172.65, 169.24, 142.21,
135.23, 134.12, 130.79, 130.09, 129.03, 128.41, 127.57, 126.96,
126.60, 122.29, 122.14, 50.86, 39.85, 29.91, 17.98. HRMS
(MALDI-FTMS) expected for MH+ 324.1707, found 324.1704.
23. Physical data of (rac) 5-oxiranylmethyl-10,11-dihydro-5H-
dibenzo[b,f]azepine, 7a: white solid (0.75 g, 45%), mp72.2 ꢀC,
1H NMR d 7.07 (m, 6H), 6.92 (m, 2H), 3.90 (dd, J=5.0, 3.0,
Hz, 2H), 3.17 (s, 4H), 3.05 (m, 1H), 2.69 (m, 1H), 2.55 (m,
1H); 13C NMR d 147.37, 133.74, 129.97, 125.77, 122.25,
119.65, 53.33, 50.16, 46.01, 31.58. MS (FAB) m/z 251 (M+).
(7b): white solid (0.95 g, 37%), mp69–70 ꢀC. (7c): white solid
(0. 82 g, 42%), mp73–74 ꢀC.
24. Physical data of 8: (rac)-1-(10,11-dihydro-dibenzo[b,f]aze-
pin-5-yl)-3-isopropylamino-propan-2-ol, HCl (8a): white solid
(580 mg, 79%), mp224.6 ꢀC. H NMR (D2O) d 7.09 (m, 6H),
1
6.91 (m, 2H), 4.00 (m, 1H), 3.81 (m, 2H), 3.15 (s, 4H), 2.80 (b
m, 2H), 2.51 (m, 1H), 0.99 (d, J=6.5 Hz, 6H). MS (CI) m/z
64%), mp165.6–166.8 ꢀC, H NMR (D2O) d 6.89 (b m, 8H),
1

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O. Levy et al. / Bioorg. Med. Chem. Lett. 11 (2001) 2921–2926
311 (MH+), HRMS (MALDI-FTMS) expected for MH+
311.2118, found 311.2124. 8b: white solid (350 mg, 65%), mp
225.9 ꢀC. [a]D20+7.05 (c 53%, H2O), ee (by HPLC)=96.7%.
8c: white solid (608 mg, 63%). Mp226.4 ꢀC. [a]D20 ꢁ7.43 (c
57%, H2O), ee (by HPLC)>99%.
26. Wilhelm, M.; Kuhn, R. Neuro-Psychopharmacology 1970,
3, 317.
27. Maxwell, R. A.; Ferris, R. M.; Burscu, J.; Chaplin
Woodward, E.; Tang, D.; Willard, K. J. Pharmacol. Exp.
Ther. 1976, 191, 418.
25. Manoach, M.; Erez, M.; Wozner, D.; Varon, D. Life
Science 1992, 51, 159.
28. Kaverina, N. V.; Skoldinov, A. P. Sov. Med. Rev. Cardiol.
1991, 3, 81.