Novel 3,7-diheterabicyclo[3.3.1]nonanes that possess predominant class III antiarrhythmic activity in 1-4 day post infarction dog models: X-ray diffraction analysis of 3-[4-(1H-imidazol-1-yl)benzoyl]-7-isopropyl-3,7-diazabicyclo[3.3.1]nonane dihydroperchl

Article abstract of DOI:10.1021/jm950772j

Several 3,7-diheterabicyclo[3.3.1]nonanes (DHBCNs) were prepared and screened in the Harris dog model for their ability to abolish pace-induced and sustained ventricular tachycardia (SVT) or prevent induction of ventricular tachycardia. In addition, an el

Full text of DOI:10.1021/jm950772j

J . Med. Chem. 1996, 39, 2559-2570
2559
Novel 3,7-Dih eter a bicyclo[3.3.1]n on a n es Th a t P ossess P r ed om in a n t
Cla ss III An tia r r h yth m ic Activity in 1-4 Da y P ost In fa r ction Dog
Mod els: X-r a y Diffr a ction An a lysis of
3-[4-(1H-Im id a zol-1-yl)ben zoyl]-7-isop r op yl-3,7-d ia za bicyclo[3.3.1]n on a n e
Dih yd r op er ch lor a te
Gregory L. Garrison,† K. Darrell Berlin,*,† Benjamin J . Scherlag,*,‡ Ralph Lazzara,‡ Eugene Patterson,‡
Tamas Fazekas,‡ Subbiah Sangiah,*,§ Chun-Lin Chen,§ F. D. Schubot, and Dick van der Helm*,
Departments of Chemistry and Physiological Sciences, Oklahoma State University, Stillwater, Oklahoma 74078,
Department of Medicine, University of Oklahoma Health Science Center, Oklahoma City, Oklahoma 73104, and
Department of Chemistry, University of Oklahoma, Norman, Oklahoma 73019
Received October 16, 1995X
Several 3,7-diheterabicyclo[3.3.1]nonanes (DHBCNs) were prepared and screened in the Harris
dog model for their ability to abolish pace-induced and sustained ventricular tachycardia (SVT)
or prevent induction of ventricular tachycardia. In addition, an electrophysiological examination
was made in the infarcted hearts of each animal to determine if more than one class activity
was present. The examples exhibited predominately class III antiarrhythmic activity via a
prolongation of the ventricular effective refractory period (VERP) in the models, although there
may well be an underlying class Ib action present as exemplified by the ability of several of
the agents to slow conduction in the myocardial infarcted dog hearts. 3-[4-(1H-Imidazol-1-
yl)benzoyl]-7-isopropyl-3,7-diazabicyclo[3.3.1]nonane dihydroperchlorate displayed powerful
class III activity in the model systems while several other DHBCNs exhibited various degrees
of class III action. An X-ray diffraction analysis revealed that this compound has a
3,7-diazabicyclo[3.3.1]nonane bicyclic unit in a chair-chair conformation.
In tr od u ction
membrane action potential duration (APD) and refrac-
4
toriness without affecting cardiac conduction, i.e., Vmax
.
Sudden cardiac death (SCD) is a leading cause of
mortality in which ventricular arrhythmias are believed
to play a major role.1 Prevention and control of ven-
tricular tachycardias (VT)/ventricular fibrillation (VF)
have very significant therapeutic importance. Patients
who suffer from ischemic heart disease or congestive
heart failure experience the majority of potentially
lethal arrhythmias. Clinical evidence and many indi-
vidual studies have concluded that most life-threatening
arrhythmias are due to reentry.2
In the last decade, new antiarrhythmic agents (AAA)
have been prepared which differed greatly in activity.
Such agents have been designated as having class I-IV
activity.3 These classifications were assigned somewhat
arbitrarily, but they are commonly associated with the
following properties.3 A class I agent must slow con-
duction of the cardiac impulse by blocking the fast Na+
channel, as evidenced by a significant reduction of the
upstroke of the transmembrane action potential (Vmax).3
Side effects with class I agents are proarrhythmia and
negative inotropism along with certain gastrointestinal
and CNS difficulties. Class II agents (â-blockers)
antagonize the effects of catecholamines on cardiac
tissue. A reduction in SCD has also been associated
with some class II agents. Side effects include negative
inotropic and chronotropic properties that severely
restrict their useage.3 Class III agents prolong trans-
APD prolongation can result from a block of outward
K+ current or from an increase of the inward ion
current.4,5 Class IV agents are calcium channel antago-
nists and usually have minimal or no class I-III
actions.3 Several derivatives of the 3,7-diheterabicyclo-
[3.3.1]nonane (DHBCN) family, such as 1 in Chart 1,
have class I activity (i.e., class Ib).6
Lidocaine (2) has been the agent of choice in the
treatment of lethal arrhythmias.7 Several agents pos-
sess class II and class III activity such as propranolol
(3) and sematilide (4), respectively, as shown in Chart
1.8 Tedisamil (5) is related to 1 and is a recently
reported antiarrhythmic agent possessing class III
activity.9
Class I AAA, as mentioned earlier, are prescribed
worldwide for the prevention of arrhythmias. These
agents often reduce the frequency of premature ven-
tricular contractions (PVC) but are rather poor in
controlling life-threatening VT and VF. Results of the
cardiac arrhythmia suppression trials (CAST) have
clearly shown that the negative side effects can out-
weigh the clinical benefit of certain potent class I
agents.10 One recent approach for the development of
new antiarrhythmic agents has been to introduce prop-
erties into a single molecule which induce actions in at
least two different classes. For example, it was re-
ported11 that when certain features of propranolol (3)
and sematilide (4) were combined to give 6, an increased
therapeutic index was realized compared to 3 and 4
individually in terms of preventing programmed, elec-
trical stimulation-induced reentrant ventricular tachy-
cardia (PES-VT) in dogs (Chart 2).11 (()-Sotatol (7)
exhibits both class II and class III activity.12 An
* To whom correspondence should be addressed.
† Department of Chemistry, Oklahoma State University.
‡ Department of Medicine, University of Oklahoma Health Science
Center.
§ Department of Physiological Sciences, Oklahoma State University.
Department of Chemistry, University of Oklahoma. Address
inquiries on the X-ray data to this author.
X Abstract published in Advance ACS Abstracts, J une 1, 1996.
S0022-2623(95)00772-2 CCC: $12.00 © 1996 American Chemical Society

2560 J ournal of Medicinal Chemistry, 1996, Vol. 39, No. 13
Ch a r t 1. Selected Antiarrhythmic Agents
Garrison et al.
Sch em e 2
Ch a r t 2. Antiarrhythmics with Combined Class Actions
yields. The corresponding solid hydroperchlorates 11
and 12 were easily prepared using perchloric acid. In
all of our work to date, we have only isolated monosalts
of members of the family of 3,7-diheterabicyclo[3.3.1]-
nonanes. Tedisamil (5) is a dihydrochloride, but the
exact conditions for its preparation have not been
published to the best of our knowledge. We have no
explanation for the formation of the monosalts in our
present work, although space-filling models imply that
the “bite” area between the heteroatoms is highly
congested when one nitrogen is protonated.
Sch em e 1
It had been noted earlier that certain N-aroyl deriva-
tives of DHBCNs exhibited inhibitory activity with
guinea pig myocardial Na+,K+-ATPase.6i It was ratio-
nalized that selected N-substituents on such systems
might induce more than one class action in the antiar-
rhythmic agent. Reduction of ketone 136 (Scheme 2) to
amine 14,6 followed by debenzylation of the latter, gave
key intermediate 15.6c,13 Using modified Schotten-
Baumann conditions, the reaction of amine 15 with
4-nitrobenzoyl chloride produced benzamide 16 (97%).
Acidification of a solution of 16 with HCl(g) generated
hydrochloride 17. Conversion of the nitro group in 16
to an amino function using TiCl3 gave benzamide 18
which was treated with HCl(g) to give the corresponding
hydrochloride 19. Sulfonylation of benzamide 18 with
methanesulfonyl chloride/pyridine led to sulfonamide 20
which was converted to the hydroperchlorate and the
hydrochlorides 21 and 22, respectively.
Amidation of 15 in aqueous methylene chloride pro-
duced benzamide 23 (Scheme 3) which was converted
to its corresponding hydroperchlorate 24. Nucleophilic
aromatic substitution of 24 using imidazole, K2CO3,
DMSO, and 18-C-6 gave amide 25 containing an imi-
dazole moiety in the para position of the phenyl ring.
Acidification of benzamide 25 with perchloric acid gave
dihydroperchlorate 26.
objective of the present work was to determine if
multiclass antiarrhythmic action could be induced into
certain members of 3,7-diheterabicyclo[3.3.1]nonanes
(DHBCNs).
Ch em istr y
The preparation of several novel 3,7-diheterabicyclo-
[3.3.1]nonanes has been achieved by the methods out-
lined below in Schemes 1-6. A modified double-
Mannich condensation (Scheme 1) using piperidin-4-
ones 8a nd 8b in the presence of HCl, glacial acetic acid,
paraformaldehyde, and the appropriate primary amine
led to ketones 9a and 9b. It has been observed6a,b that
an additional equivalent of paraformaldehyde added
during the reaction can increase the yields of product
to above 70%. Wolff-Kishner reduction of ketones 9a
and 9b gave amines 10a and 10b, respectively, in high
Masking of the carbonyl groups in ketones 9a and 9b

Novel 3,7-Diheterabicyclo[3.3.1]nonanes
J ournal of Medicinal Chemistry, 1996, Vol. 39, No. 13 2561
Sch em e 3
Sch em e 6
hygroscopic as might be expected.
X-r a y Cr ysta llogr a p h ic An a lysis of 26
In view of the paucity of simple model systems in the
family of DHBCNs14 and the fact that 26 exhibited such
powerful class III activity, it was deemed of value to
subject crystals of 26 to an X-ray diffraction analysis.
An ORTEP plot of the molecule is shown in Figure 1.
The bicyclo[3.3.1]nonane system of 26 assumes a chair-
chair (CC) conformation (Figure 3) as found in 16a and
other related structures.13b,15 It was observed that
hydrogen atoms were bonded to N(3) and N(22) in 26.
Both hydrogens refined with normal temperature fac-
tors. The molecule is therefore a dication, and the
positive charges are neutralized by two perchlorate
anions in the crystal structure. The geometry of N(3)
is near tetrahedral (the average of the three C-N-C
angles is 112.8°). The configuration of N(7) is ap-
proximately planar.
Sch em e 4
Despite the large R groups attached to the nitrogen
atoms, the bicyclo[3.3.1]nonane system assumes a chair-
chair (CC) conformation in the solid state. As seen in
Figure 2, however, both chairs are significantly flattened
due to the repulsion of the two nitrogen atoms and the
large R groups. The interplanar angles 2/3 and 4/5 are
137.9° and 133.1° (Figure 3), respectively, and are much
larger than the ideal angle of 120°. This suggests
considerable strain within the system. It is clearly
noticeable that the plane containing the N(7) adopts a
smaller angle than that containing N(3). This obser-
vation indicates that the group on N(7) requires less
space in the bicyclo[3.3.1]nonane unit than the atoms
attached to N(3). The chair-chair arrangement may
be critical for maximum antiarrhythmic activity in
DHBCNs as illustrated in the one published work in
this area.6g
Sch em e 5
Although the N(3)-N(7) distance of 2.91 Å is slightly
shorter than the 3.0 Å observed for a (CC) system with
a CH2 group at the 3-position and an NH2 group at the
7-position,16 there are several indications that no in-
tramolecular hydrogen bonding occurs between H(3) and
N(7) (see Figures 1-3). The relevant N(7)-HN(3) bond
angle is only 121.7° and clearly bent instead of being
linear or close to linear as expected for a hydrogen bond.
For comparison, the corresponding angle in 7-hydroxy-
â-isosparteine is 163°.17 Furthermore, the nonbonded
N(7)‚‚‚H(3) distance in 26 is 2.39 Å, which is much
longer than the counterpart (1.84 Å) found in the spar-
teine derivative. One reason for the “apparent lack of
a hydrogen bond” might lie in the involvement of the
lone pair on N(7) via delocalization into the N-C(O)
linkage of the amide bond, resulting in a very short
N(7)-C(13) bond distance of 1.357(3) Å as compared
with a “normal C-N bond”. Moreover, the increased
double bond character of the N(7)-C(13) bond likely
flattens the ring with a simultaneous increase in the
H(3)‚‚‚N(7) distance. A similar effect was observed in
with 1,2-ethanedithiol and p-tolunenesulfonic acid (PTSA
in Scheme 4) led to thioketals 27a and 27b in good
yields. The respective hydroperchlorates 28 and 29
were then prepared with perchloric acid in standard
fashion.
Debenzylation of amine 10b gave the key secondary
amine 30 which, with an appropriate aroyl chloride, led
to benzamides 31 and 32 (Scheme 5). Treatment of
these compounds with perchloric acid resulted in forma-
tion of salts 33 and 34, respectively. In addition to and
because of the strong antiarrhythmic activity displayed
by 1,6a,f an evaluation of the activity of the corresponding
hydrochloride 37 was deemed worthwhile since no study
has been reported in this family of heterocyclic salts
with respect to the influence of the anion on antiar-
rhythmic action. Known ketone 356a,b and amine 366a,b
were prepared, and 36 with HCl(g) gave salt 37 (Scheme
6). Highly purified salt 37 did not appear to be

2562 J ournal of Medicinal Chemistry, 1996, Vol. 39, No. 13
Garrison et al.
15-oxasparteine perchlorate hemihydrate,20 and two
other sparteine derivatives.16,21 All C-C bonds in 26
lie between 1.52 and 1.53 Å. The C(6)-N(7) bond [1.477
(4) Å] and the N(7)-C(8) bond [1.484 (3) Å] are mark-
edly shorter than the C(2)-N(3) and N(3)-C(4) bonds
with respective values of 1.520 (4) and 1.495 (4) Å.
This is due to the positive charge on N(3). Similar
results have been noted for the other compounds cited
above.
The substituent on N(7) consists of three noninter-
acting π-systems, namely the CdO group, the phenyl
ring, and the imidazolium ion. These π systems do not
lie in a common plane and thus do not interact. Indeed,
the CdO plane and the phenyl ring are rotated from
one another around the common bond by 45.6 (1)°. The
plane of the imidazolium ring is rotated by an angle of
28.2 (2)° from the plane of the phenyl ring.
The imidazolium ring is linked to the phenyl ring by
N(20). Both N(20) and N(22) are completely planar
coordinated since the sum of the three bond angles
around them is 360.0° and 359.8°, respectively. Such
angles imply that the lone pairs on the two nitrogen
atoms participate in the ring bonding, but several bond
distances suggest that the six available π-electrons are
not entirely delocalized. The C-N bonds range from
1.310 (4) Å for the C(21)-N(22) bond to 1.387 (3) Å for
the N(20)-C(24) bond. In addition, the C(23)-C(24)
bond distance of 1.330 (4) Å is comparatively short,
suggesting an almost completely localized double bond.
A comparable situation has been found with the corre-
sponding bond in imidazolium sulfate (1.335 Å)22 and
in 1,3-diphenylimidazolium perchlorate (1.339 Å).23 In
the reported deuterated imidazolium hydrogen maleate,
the similar bond seems unusually long at 1.358 Å and
may be due to the fact that the measurement was done
by neutron diffraction.24
F igu r e 1. ORTEP drawing of 26.
F igu r e 2. Schematic drawing of 26.
The present work supports our previous prediction6g
that the chair-chair form of selected members of the
DHBCN family could well exhibit useful antiarrhythmic
activity. Confirmation of the chair-chair form in 26 is
exemplary in this respect, although the exact mecha-
nism by which antiarrhythmic effects occur remains to
be uncovered.
P h a r m a cologica l Resu lts
Only a few antiarrhythmic properties of a small
number of DHBCNs have appeared in the litera-
ture.6,13a,b,15,25 The compounds (Table 1) in the current
study were examined in anesthetized mongrel dogs
24-96 h following the occlusion of the left anterior
descending coronary artery. This occusion results in a
myocardial infarction with a surviving rim of epicar-
dium that serves as the substrate for inducible, sus-
tained ventricular tachycardia (SVT). A 12-lead elec-
trocardiogram (ECG) was monitored throughout. In-
duction of SVT (SVT is defined as a series of ventricular
beats which are usually uniform and at a rate of 250
beats/min or more and lasting 30 s or more) was
initiated using programmed electrical stimulation (PES)
in the baseline state followed with the test agents at
doses of 3 and 6 mg/kg administered intravenously
(iv). The agent’s ability to terminate or prevent the
induction of SVT was measured in all experiments.
Lidocaine (2) (Table 1) was used as the standard for
comparison purposes since it is currently the agent of
F igu r e 3. Interplanar angles in the bicyclo[3.3.1]nonane
system 26.
the X-ray crystal structure of anhydrous (+)-lupanine
perchlorate with a length of 1.362 (5) Å for the corre-
sponding bond.18 This implies that the slightly short-
ened N(3)‚‚‚N(7) distance merely results from ring strain
imposed on the structure by angles within the bicyclic
unit.
The N(3)H group, however, forms a hydrogen bond
to O(P2) of one perchlorate group. No further hydrogen
bonding of atoms in 26 with perchlorate groups was
observed. The N(22)-H(22) group, which is where the
second positive charge is located, forms a strong inter-
molecular hydrogen bond with O(25).
Bond distances in the bicyclo[3.3.1]nonane portion
of 26 agree well with those reported for anhydrous
lupanine perchlorate,18 the monohydrate of (+)-lupanine
perchlorate,19 (+)-lupanine hydrochloride dihydrate,18

Novel 3,7-Diheterabicyclo[3.3.1]nonanes
J ournal of Medicinal Chemistry, 1996, Vol. 39, No. 13 2563
Ta ble 1. Selected Antiarrhythmic Properties of 2, 26, 28, 31, and 34
HRb
MBPc
QT intervald
AH intervale
HV intervalf
VERPg
post
compda
preh
posti
pre
post
pre
post
pre
post
pre
post
pre
2 (lidocaine)
NEj
148
154
125
120
NE
105
94
61
88
92
84
84
76
98
83
NE
196
236
215
NE
NE
288
270
250
NE
NE
57
56
60
65
NE
66
75
68
70
NE
32
30
NE
NE
NE
37
40
NE
NE
142
144
140
170
170
167
187
180
220
190
26
28
31
34
110
105
105
111
a
Antiarrhythmic properties are compared to lidocaine (2) using doses (3 and 6 mg/kg) in which SVT was noninducible in the DHBCN
system while lidocaine only reduced the rate of the VT. The limits on the above values were (5%. HR ) heart rate (beats/min). c MBP
b
d
) mean blood pressure (mmHg). QT interval ) time (ms) required for the ventricular myocardium to undergo depolarization and
repolarization. e AH interval ) (ms) measures A-V nodal conduction time. f HV interval ) (ms) measures His-Purkinje conduction time.
g
h
i
VERP ) (ms) ventricular effective refractory period. Pre ) drug free; measurements before administration of agent. Post ) post
j
drug; measurements after the administration of agent. NE ) no effect.
Ta ble 2. Certain Antiarrhythmic Properties of Selected Agents 1, 11, 17, 19, 21, 22, 29, and 37
HRb
MBPc
post
OT intervald
AH intervale
HV intervalf
VERPg
NSVT,h
mg/kg
compda
preh
posti
pre
pre
post
pre
NE
post
NE
pre
post
pre
post
1
11
17
19
21
22
29
37
162
130
130
130
150
150
148
162
162
110
100
115
150
150
148
165
98
130
95
100
70
95
105
99
120
37
75
77
50
95
105
105
NEi
220
220
210
NE
260
260
220
30
35
40
50
142
160
160
180
163
230
230
220
3
3
6
6
6
6
3
3
NMj
60
55
75
65
NM
NM
NE
NE
NE
NE
NE
NE
NE
NE
NE
NE
NE
NE
NE
NE
NE
30
35
a
Antiarrhythmic properties of test compounds were compared to lidocaine (3 and 6 mg/kg iv) in that lidocaine (2) only reduced the rate
of the VT and possessed only class Ib. The limits on the above values were (5%. HR ) heart rate (beats/min). c MBP ) mean blood
b
pressure (mmHg). QT interval ) time (ms) elapsed for the ventricular myocardium to undergo depolarization and repolarization. e AH
d
interval ) (ms) measures A-V nodal conduction time. f HV interval ) (ms) measures His-Purkinje conduction time. VERP ) (ms)
g
h
i
ventricular effective refractory period. NSVT ) nonsustained ventricular tachycardia; SVT not inducible at indicated dosage. NE ) no
j
effect. NM ) not measured.
choice for the treatment of SVT26 in acute stages of
myocardial infarction.
The other eight agents examined showed good class
Ib antiarrhythmic activity while their effects on the
class III parameters were modest to weak (Table 2).
After the administration (3 mg/kg iv) of 11, a marked
drop in the MBP and the HR was observed. This agent
had no effect on any of the class III parameters
measured. Interestingly, compounds 17 and 19 pos-
sessed similar action (decreased MBP and HR; class IV
action) but with varying degrees of effect on the class
III action parameters (Table 2). It should be noted that
the hydroperchlorate 1 increased the VERP while the
corresponding hydrochloride 37 had no effect. Interest-
ingly, the hydroperchlorate 21 produced a decrease in
MBP while the hydrochloride 22 had no effect. These
are the first examples of two different salts of single
DHBCNs which have demonstrated ability to exert
varying degrees of influence on such cardiovascular
parameters.
Agents 17 and 19 abolished SVT at the 6 mg/kg dose
level with no pronounced effect seen at 3 mg/kg.
Compound 17 decreased the MBP (95 to 70 mmHg) with
fast recovery and induced a lowering of HR (130 to 110
beats/min) which had a lasting effect of 2 h. Amide 17
also prolonged HV (35-50 ms), VERP (160-230 ms),
and QT (220-260 ms). Similar properties were ob-
served with dihydroperchlorate 19, but the effects were
less pronounced.
The DHBCN agents tested in the present study
possess class III antiarrhythmic activity in these dog
models (Table 1). The effects on the class III parameters
varied between agents nearly all of which abolished the
VT at doses of 3 and 6 mg/kg. Specifically, four
compounds (26, 28, 31, and 34) exhibited the most
significant antiarrhythmic activity. The most active
compound was dihydroperchlorate 26. This agent
slightly reduced the MBP, but the effect was short
lasting. However, salt 26 markedly reduced the HR and
prolonged the VERP, AH, HV, and the QT intervals.
From the data obtained, it was tentatively concluded
that this agent possessed predominately class III anti-
arrhythmic activity.15c
Tedisamil (5), a known K+ current blocker,9 and
thioketal 28 show some structural similarities. How-
ever, 28 cannot be considered a close analogue of
tedisamil due to the observed activity differences from
those reported for 5.9 For example, after administration
of 28, the MBP increased while the HR was reduced
with a prolongation of the VERP, HV, and QT interval
(Table 1). SMVT was found to be noninducible after 3
and 6 mg/kg doses of 28, and SVT was terminated with
6 mg/kg iv. These studies suggested that 28 is not only
capable of preventing but also capable of terminating
PES-induced SMVT.
Two other compounds (31 and 34) were found to
exhibit excellent antiarrhythmic activity. Both amides
possess similar activities with some variation in the
degree of effectiveness in terms of the class III param-
eters measured. One interesting property of 34 is the
simultaneous lowering of the HR and the MBP which
suggests that these agents may possess Ca2+ channel
blocking action (class IV AAA).9
Discu ssion a n d Con clu sion s
A comparison of hydroperchlorate 1 and hydrochloride
37 revealed related activities but not identical. Salt 1
induced a significant prolongation of the HV interval
(30-40 ms) and the VERP (142-163 ms) while prolon-
gation by 37 of the HV interval (30-35 ms) was less
pronounced and there was no effect on the VERP.
Agent 1 prevented electrically induced sustained mono-

2564 J ournal of Medicinal Chemistry, 1996, Vol. 39, No. 13
Garrison et al.
analytical instrument model ZAB-2SE. Elemental analyses
were performed by Galbraith Laboratories, Knoxville, TN
37921.
morphic ventricular tachycardia (SMVT) in two of the
six dogs tested. Salt 1, however, did markedly slow the
rate of SMVT in the other four dogs while 37 had no
effect. These slight differences in activities may be due
to an effect by the different anions, namely chloride
versus perchlorate. Only very slight differences were
noted in activity between 21 and 22.
Syntheses were performed under an atmosphere of N2 at
room temperature (RT) unless otherwise specified. The fol-
lowing compounds required distillation prior to use: benzoyl
chloride (bp 46 °C/1.0 mmHg, Eastman), benzylamine (bp 57-
59 °C/4.25 mmHg, Lancaster), 4-chlorobenzoyl chloride (bp 40
°C/10 mmHg, Aldrich), 1,2-ethanedithiol (bp 144-146 °C,
Aldrich), 4-fluorobenzoyl chloride (82 °C/20 mmHg, Aldrich),
N-benzyl-4-piperidinone (bp 134 °C/7.0 mmHg, Aldrich), N-iso-
propyl-4-piperidinone (bp 100-101 °C/27 mmHg, Lancaster),
and pyridine (114 °C, Fisher). Precursors 13-15 were pre-
pared by procedures reported previously.6c Reagent grade
solvents were used without further purification, and chro-
matographic separations were performed on silica gel (Davisil
62, 60-200 mesh, Davison Chemical) and alumina (neutral,
70-230 mesh, Merck). CAUTION: Although no difficulties
were encountered with the hydroperchlorates, careful precau-
tions should always be exercised in all handling operations.
3,7-Diisopr opyl-3,7-diazabicyclo[3.3.1]n on an -9-on e (9a).
A mixture of isopropylamine (8.87 g, 150.0 mmol), HCl (37%,
7.39 g, 75.0 mmol), glacial acetic acid (9.01 g, 150.0 mmol),
and paraformaldehyde (9.46 g, 315.0 mmol) in deoxygenated
(dry N2 was bubbled through the solvent for 2 h) H3COH (125
mL) was stirred at reflux (15 min) under N2. A solution of
N-isopropyl-4-piperidinone (8a , 21.18 g, 150.0 mmol) in glacial
acetic acid (9.01 g, 150.0 mmol) was added dropwise over 1.5
h, and this was followed by a period of boiling (23 h). After
the initial 10 h of heating, another equivalent of paraformal-
dehyde (9.46 g, 315.0 mmol) was added in one portion to the
mixture after which reflux was continued (13 h). After cooling
to RT, the solution was concentrated under vacuum and gave
an orange oil which was redissolved in H2O (150 mL). Extracts
(ether, 2 × 100 mL) thereof were discarded. The aqueous layer
was chilled (5 °C) and made basic (pH ∼12, NaOH pellets).
Extraction (H2CCl2, 3 × 75 mL) gave a solution which was
dried (Na2SO4), filtered, and concentrated to give a viscous,
reddish-orange oil. Distillation of the oil on a molecular still
(110-120 °C/10-5 mmHg) gave 22.53 g (67.3%) of a light yellow
Most of the agents tested in Tables 1 and 2 demon-
strate physiological properties which are consistent with
a predominant class III antiarrhythmic action. Some
evidence for class I action was also observed, especially
in the significant prolongation of the HV intervals
(slowing of conduction in the His-Purkinje system) by
26, 28, and 37.
The underlying feature of these agents, however, is
a class Ib antiarrhythmic action which may well be
associated with the heterobicyclic unit present in these
molecules. Indeed, such class Ib activity was shown
previously to be the major antiarrhythmic property of
agent BRB-I-28 (1) in dog models as well as in tissues.6a,f
The fact that a chair-chair form exhibited improved
antiarrhythmic activity over a chair-boat form with two
isomeric DHBCN systems previously reported6g may
also be an important parameter as could be the nature
of the heteroatom and substituent(s) attached thereto.
Moreover, polar, geminal hydroxyl groups at C(9) re-
sulted in a near lack of any antiarrhythmic activity in
certain systems previously investigated.6a,b Conse-
quently, it appears that hydrophobic groups may be
preferred at C(9) as well as on the heteroatoms for
optimum antiarrhythmic activity. This is reminiscent
of the structure in tedisamil (5) which has a nonpolar
five-membered ring fused in a spiro arrangement at the
9-position.9 It is interesting to note that the torsional
angle of C(6)-N(7)-C(13)-C(14) is 177.1 (2)° in 26
while in the sulfur relative 1 the angle is 169.7 (4)°. It
should be recalled that the 3-position in 1 is comparable
to the 7-position in 26, both rings containing these
positions being slightly flattened. One might speculate
that the nature of the group attached to nitrogen might
be quite variable, and yet the system could retain good
antiarrhythmic properties if a certain conformation
around nitrogen were maintained.6 This supposition
has support from the observation that the selenium
analog13 of 1 clearly possesses strong antiarrhythmic
activity. The corresponding selenium system is also
flattened at the end of the molecule holding the sele-
nium atom. Consequently, manipulation of selected
N-substituted groups at the 3- or 7-position of the
DHBCN unit may well be the key to multiclass antiar-
rhythmic activity in these systems. Work is continuing
to explore the biological properties of these heterocyclics.
1
oil, 9a : IR (film) 1735 (CdO) cm-1; H NMR (DCCl3) δ 1.02
(d, J ) 6.5 Hz, 12 H, CH3 isopropyl), 2.58 [m, 2 H, H(1,5)],
2.87 [m, 6 H, H(2,4,6,8)ax, C-H isopropyl], 3.04 [dd, J ) 10.1
Hz, 4 H, H(2,4,6,8)eq]; 13C NMR (DCCl3) ppm 17.90, 18.02 (CH3,
isopropyl), 46.82 [C(1,5)], 53.17 (C-H isopropyl), 53.27, 53.36
[C(2,4,6,8)], 215.18 [C(9)]. Anal. (C13H24N2O) C, H, N.
7-Ben zyl-3-(cyclopr opylm eth yl)-3,7-diazabicyclo[3.3.1]-
n on a n -9-on e (9b). A mixture of (aminomethyl)cyclopropane
(4.44 g, 62.4 mmol), HCl (37%, 3.07 g, 31.2 mmol), glacial acetic
acid (3.75 g, 62.4 mmol), and paraformaldehyde (3.94 g, 131.04
mmol) in deoxygenated (N2 bubbled in for 2 h) CH3OH (125
mL) was stirred at reflux for 15 min under N2. A solution of
N-benzyl-4-piperidinone (8b, 11.8 g, 62.4 mmol) and glacial
acetic acid (3.75 g, 62.4 mmol) was added dropwise over 1.5 h.
After 10 h at reflux, the mixture was treated with additional
paraformaldehyde (3.94 g, 131.04 mmol) in one portion.
Heating at reflux was continued (19 h). Upon cooling to RT,
the solution was concentrated under vacuum and gave a
orange oil which was dissolved in H2O (100 mL). Extracts
(ether, 2 × 75 mL) of the aqueous solution were discarded.
The aqueous layer was cooled (5 °C) and made basic (pH ∼12,
NaOH pellets). Extraction (H2CCl2, 3 × 75 mL) gave a solution
which was dried (Na2SO4), filtered, and concentrated to a
viscous, reddish-orange oil. Distillation of the oil (175-190
°C/10-5 mmHg) gave 13.54 g (76.3%) of 9b as an light yellow
oil which solidified upon standing at -10 °C, mp 56.0-57.5
°C. A portion of this solid was recrystallized (pentane) to give
an analytical sample: mp 58.5-59.5 °C; IR (KBr) 3005 (C-H,
Exp er im en ta l Section
Ma ter ia ls a n d Meth od s. Ch em istr y. Melting points
were obtained on a Thomas-Hoover melting point apparatus
or on an Electrothermal IA9100 digital melting point ap-
paratus and were uncorrected. IR spectra were recorded on
a Perkin-Elmer 681 (KBr pellets or films). All NMR spectra
were taken either on a Varian XL-300 NMR spectrometer with
1H and 13C being observed at 299.94 and 75.43 MHz, respec-
tively, or on a XL-400 NMR unit with 1H, 13C, and 15N being
observed at 399.99, 100.6, and 41.2 MHz, respectively. Chemi-
cal shifts for 1H and 13C NMR spectra were reported in δ or
ppm downfield from TMS [(CH3)4Si)] for 1H and 13C and from
NH3(l) for 15N. Mass spectral data were recorded on a VG
cyclopropyl), 1740 (CdO), 1495 (ArCdC), cm-1 1H NMR
;
(DCCl3) δ 0.12 [m, 2 H, cyclopropyl], 0.51 [m, 2 H, cyclopropyl],
0.89 [m, 1 H, (C-H), cyclopropyl], 2.32 (d, J ) 9.8 Hz, 2 H,
CH2-cyclopropyl), 2.59 [m, 2 H, H(1,5)], 2.81 [dd, J ) 10.8 Hz,
J ) 5.6 Hz, 2 H, H(6,8)ax], 2.94 [dd, J ) 10.8 Hz, J ) 6.8 Hz,
2 H, H(2,4)ax], 3.04 [dd, J ) 10.8 Hz, J ) 3.2 Hz, 2 H, H(6,8)eq],
3.12 [dd, J ) 10.8 Hz, J ) 3.2 Hz, 2 H, H(2,4)eq], 3.57 (s, 2 H,
CH2Ph), 7.38-7.22 (m, 5 H, Ar-H); 13C NMR (DCCl3) ppm 3.76

Novel 3,7-Diheterabicyclo[3.3.1]nonanes
J ournal of Medicinal Chemistry, 1996, Vol. 39, No. 13 2565
(CH2, cyclopropyl), 8.53 (CH, cyclopropyl), 46.76 [C(1,5)], 58.19
[C(2,4)], 58.36 [C(6,8)], 61.11 (CH2Ph), 61.85 (CH2-cyclopropyl),
127.08, 128.22, 128.66, 138.54 (Ar-C), 214.85 (CdO); 15N NMR
(DCCl3) ppm 36.17 [N(7)], 37.74 [N(3)]; MS (EI) data calcd
C18H24N2O m/ z (M+) 284.1188, found 284.1190. Anal.
(C18H24N2O) C, H, N.
mixture was allowed to stir (15 min) at 0-5 °C. A white
precipitate formed and was filtered and washed (cold ether,
30 mL). The solid was recrystallized (H3COH, 30 mL), and
the resulting white needles were collected, washed (cold H3-
COH, 25 mL), and dried (80 °C/0.2 mmHg) to give 3.63 g
(72.3%) of salt 12: mp 211-212 °C; IR (KBr) 3560 (O-H), 3400
1
(N-H), 1090 (Cl-O) cm-1; H NMR (D3CCN) δ 1.14 (d, J ) 6.2
3,7-Diisopr opyl-3,7-diazabicyclo[3.3.1]n on an e (10a). To
a solution of ketone 9a (5.90 g, 20.3 mmol) in triethylene glycol
(60 mL) was added KOH pellets (85%, 13.89 g, 210.9 mmol)
and anhydrous hydrazine (95%, 3.55 g, 105.19 mmol). The
stirred mixture was heated at 160-170 °C for 4 h under N2
via the use of a jacketed flask containing boiling tetralin (bp
207 °C). Cooling of the solution to RT (1 h) was followed by
addition of ice-cold H2O (100 mL). Extraction (ether, 4 × 50
mL) was followed by washing of the combined extracts with
10% NaOH (100 mL) and saturated NaCl (100 mL) and then
drying (Na2SO4). Filtration and concentration of the solution
gave a light yellow oil 10a (4.48 g, 81.1%) which was placed
on a vacuum pump overnight (RT/0.2 mmHg). IR analysis of
the compound showed no carbonyl absorption as present in
the starting material 9a , and thus the crude product 10a was
used without further purification to prepare salt 12.
Hz, 12 H, CH3 isopropyl), 1.80 [bs, 2 H, H(1,5)], 2.21 [bs, 2 H,
H(9)], 2.97 (d, J ) 11.9 Hz, 4 H, ring protons), 3.19 (m, 2 H,
C-H isopropyl), 3.28 (d, J ) 12.2 Hz, 4 H, ring protons); 13C
NMR (D3CCN) ppm 17.11 (CH3 isopropyl), 28.56 [C(1,5)],
31.41 [C(9)], 54.26 [C(2,4 6,8)], 56.13 (C-H isopropyl); the
compound proved slightly hygroscopic; MS (EI) data calcd
C13H27N2ClO4 m/ z (M+) 210.2096, found 210.2096. Anal.
Calcd for C13H27N2O4Cl: C, 50.24; H, 8.76; N, 9.01. Anal.
Calcd for C13H27N2O4Cl‚0.2H2O: C, 49.66; H, 8.78; N, 8.91.
Found: C, 49.33; H, 8.52; N, 9.31.
3-(4-Nitr oben zoyl)-7-isop r op yl-3,7-d ia za bicyclo[3.3.1]-
n on a n e (16). To a mixture of amine 156c (3.82 g, 22.70 mmol)
in H2CCl2 (25 mL) and 10% NaOH (22.76 g, 56.80 mmol) was
added dropwise 4-nitrobenzoyl chloride (4.63 g, 24.90 mmol)
in H2CCl2 (15 mL) over a period of 15 min. Stirring of the
mixture was continued for 3 h under N2. To the heterogeneous
mixture was added H2O (100 mL) in one portion, and two
layers were separated. Further extracts (H2CCl2, 3 × 50 mL)
of the aqueous layer were combined, dried (Na2SO4), filtered,
and concentrated under vacuum to give a viscous yellow oil
which solidified. This yellow solid was dissolved in ether, and
the solution was filtered. The filtrate was concentrated under
vacuum and then placed on vacuum pump overnight (RT/0.2
mmHg) to give 6.79 g (94.3%) of a light yellow solid 16: mp
7-Ben zyl-3-(cyclopr opylm eth yl)-3,7-diazabicyclo[3.3.1]-
n on a n e (10b). To a solution of ketone 9b (9.53 g, 33.51 mmol)
in triethylene glycol (100 mL) were added KOH pellets (85%,
17.7 g, 268.08 mmol) and hydrazine (95%, 4.52 g, 134.04
mmol). The stirred mixture was heated at 160-170 °C for 4
h under N2 in a jacketed flask containing boiling tetralin (bp
207 °C). Cooling of the solution to RT (1 h) was followed by
addition of ice-cold H2O (100 mL). Combined extracts (ether,
4 × 80 mL) of the suspension were first washed with 10%
NaOH (80 mL) and saturated NaCl (80 mL) and then dried
(Na2SO4). Filtration and concentration under vacuum gave a
light yellow oil 10b (8.99 g, 98.2%) which was placed on a
vacuum pump overnight (RT/0.2 mmHg): IR (film) 3090 (Ar-
119-120 °C; IR (KBr) 3090, (Ar-H), 1635 (NCdO) cm-1 1H
;
NMR (DCCl3) δ 0.56 (d, J ) 6.7 Hz, 3 H, CH3 isopropyl), 0.69
(d, J ) 6.7 Hz, 3 H, CH3 isopropyl), 1.34 [m, 2 H, H(9)ax, H(5)],
1.61 [bs, 1 H, H(1)], 2.04-2.32 [m, 3 H, ring protons], 2.67
(dd, J ) 11.2 Hz, 2 H, ring protons), 2.94 (dd, J ) 12.9 Hz, 1
H, ring proton), 3.20 (d, J ) 12.9 Hz, 1 H, ring proton), 3.39
(d, J ) 11.2 Hz, 1 H, ring proton), 7.13 (d, 2 H, Ar-H), 7.85 (d,
2 H, Ar-H); 13C NMR (DCCl3) ppm 15.89, 19.46 (CH3 isopropyl),
28.81 29.57 [C(1,5)], 32.04 [C(9)], 46.55 [C(2)], 51.79, 52.31,
54.26, 54.85 [C(4,6,8), C-H isopropyl], 123.52, 127.60, 143.91,
147.62 (Ar-C), 167.58 (NCdO); MS (EI) data calcd C17H23N3O3
m/ z (M+) 317.1739, found 317.1750. Anal. (C17H23N3O3) C,
H, N.
1
H) 735 and 700 (monophenyl) cm-1; H NMR (DCCl3) δ 0.14
[m, 2 H, cyclopropyl], 0.51 [m, 2 H, cyclopropyl], 0.94 [m, 1 H,
(CH), cyclopropyl], 1.52 [dd, J ) 19.8 Hz, 2 H, H(9)], 1.91 [m,
2 H, H(1,5)], 2.20 (d, J ) 6.6 Hz, 2 H, CH2-cyclopropyl), 2.33
[dd, J ) 10.7 Hz, J ) 3.6 Hz, 2 H, H(6,8)ax], 2.41 [dd, J ) 10.8
Hz, J ) 4.8 Hz, 2 H, H(2,4)ax], 2.76 [d, J ) 10.5 Hz, 2 H,
H(6,8)eq], 2.85 [d, J ) 10.5 Hz, 2 H, H(2,4)eq], 3.49 (s, 2 H, Ar-
CH2), 7.21-7.45 (m, 5 H, Ar-H); 13C NMR (DCCl3) ppm 3.90
(CH2, cyclopropyl), 8.72 (CH, cyclopropyl), 29.43 [C(9)], 30.22
[C(1,5)], 57.68 [C(2,4)], 57.90 [C(6,8)], 62.75 (Ar-CH2), 64.04
(CH2-cyclopropyl), 126.38, 127.92, 128.62, 139.74 (Ar-C). IR
and 13C NMR spectra confirmed the absence of the carbonyl
group, and thus the oil was used without further purification
to prepare salt 11 and secondary amine 30.
3-(4-Nitr oben zoyl)-7-isop r op yl-3,7-d ia za bicyclo[3.3.1]-
n on a n e Hyd r och lor id e (17). Gaseous HCl was generated
in a standard setup with a collection flask containing solid
NaCl. The H2SO4 (∼15 mL) was added dropwise (1 mL/min),
and the HCl gas generated was passed through a CaCl2 drying
tube. Into a flask equipped with a magnetic stirrer and an
ice bath was bubbled HCl(g) to a chilled (5 °C) solution of
amide 16 (2.5 g, 7.88 mmol) in ether (75 mL) over a 15 min
period. The mixture was allowed to stir (15 min) at 0-5 °C.
A white precipitate formed and was filtered and washed (cold
7-Ben zyl-3-(cyclopr opylm eth yl)-3,7-diazabicyclo[3.3.1]-
n on a n e Hyd r op er ch lor a te (11). To a chilled (5 °C) solution
of amine 10b (4.41 g, 16.3 mmol) in dry ether (150 mL) was
added HClO4 (60%, 3.41 g, 20.4 mmol) dropwise over a period
of 15 min. The mixture was allowed to stir (15 min) at 0-5
°C. A white precipitate formed and was filtered and washed
(cold ether, 30 mL). The solid was recrystallized (H3COH, 30
mL), and the resulting white needles were collected and
washed with cold H3COH (25 mL) and dried (80 °C/0.2 mmHg)
to give 4.3 g (71.1%) of salt 11: mp 190-191 °C; IR (KBr) 3060
(Ar-H), 1100 (Cl-O), 735 and 710 (monophenyl) cm-1; 1H NMR
(DMSO-d6) δ 0.46 [m, 2 H, cyclopropyl], 0.62 [m, 2 H,
cyclopropyl], 1.07 [m, 1 H, (CH), cyclopropyl], 1.64 [d, J ) 11.4
Hz, 1 H, H(9)ax], 1.77 [d, J ) 11.4 Hz, 1 H, H(9)eq], 2.42 [d, J
) 11.1 Hz, 2 H, H(6,8)ax], 2.85 (d, J ) 7.2 Hz, 2 H, CH2-
cyclopropyl), 3.09 [m, 4 H, H(2,4)ax, H(6,8)eq], 3.54 [bs, 4 H,
CH2-Ar, H(2,4)eq], 7.31-7.43 (m, 5 H, Ar-H); 13C NMR (DMSO-
d6) ppm 3.87 (CH2, cyclopropyl), 6.07 (CH, cyclopropyl), 27.46
[C(6)], 29.58 [C(1,5)], 57.01, 56.84 [C(2,4,6,8)], 60.56 (CH2-Ar),
61.49 (NCH2-cyclopropyl), 127.57, 128.39, 129.32, 136.49 (Ar-
C); 15N NMR (DMSO-d6) ppm 49.22 [N(7)], 55.18 [N(3)]; MS
(EI) data calcd C18H26N2 (HClO4) m/ z (M+) 270.2096 (-HClO4),
found 270.2093. Anal. (C18H27ClN2O4) C, H.
ether-30 mL). The solid was recrystallized (H3
COH/ether, 1:1,
60 mL), and the white needles were washed (cold ether, 25
mL) and dried (80 °C/0.2 mmHg) to give 2.09 g (74.9%) of salt
17: mp 258-259 °C; IR (KBr) 3400 (N-H), 1660 (NCdO) cm-1
1H NMR (D2O) δ 1.44 (d, J ) 6.1 Hz, 6 H, CH3 isopropyl), 2.03
[bs, 2 H, H(9)], 2.52 [bs, 2 H, H(1,5)], 3.39-3.67 (m, 9 H, ring
protons, C-H isopropyl), 4.45 (s, 1 H, N-H), 7.71 (d, 2 H, Ar-
H), 8.36 (d, 2 H, Ar-H); 13C NMR (D2O) ppm 19.82 (bs, CH3
isopropyl), 29.36 [bs, C(1,5,9)], 49.42, 54.01 [bs, C(2,4,6,8)],
63.38 (C-H isopropyl), 126.89, 130.73, 143.84, 151.10 (Ar-C),
175.77 (NCdO); MS (EI) data calcd C17H23N3O3 (HCl) m/ z
(M+) 317.1739 (-HCl), found 317.1734. Anal. (C17H24N3O3-
Cl) C, H, N.
;
3-(4-Am in oben zoyl)-7-isopr opyl-3,7-diazabicyclo[3.3.1]-
n on a n e (18). To amide 16 (9.17 g, 28.90 mmol) in AcOH/
H2O (1:1, 100 mL) was added in one portion TiCl3 (12% in HCl,
195.0 g, 202.3 mmol), and the mixture was stirred at RT (7
min). The deep purple solution was basified (pH ∼12-20%,
NaOH) until a dark blue color persisted. Extractions (H2CCl2,
4 × 90 mL) were washed with H2O (2 × 100 mL) and brine
(100 mL). After drying (Na2SO4), the solution was filtered and
concentrated to give 7.34 g (86.2%) of an off-white solid 18:
3,7-Diisop r op yl-3,7-d ia za bicyclo[3.3.1]n on a n e Hyd r o-
p er ch lor a te (12). To a chilled (5 °C) solution of amine 10a
(3.4 g, 16.16 mmol) in dry ether (50 mL) was added HClO4
(60%, 3.4 g, 20.2 mmol) dropwise over a period of 15 min. The

2566 J ournal of Medicinal Chemistry, 1996, Vol. 39, No. 13
Garrison et al.
mp 149-150 °C; IR (KBr) 3220 (N-H), 1640 (NCdO) cm-1; 1H
NMR (DCCl3) δ 0.98 (bs, 6 H, CH3 isopropyl), 1.67 [m, 3 H,
H(5), H(9)], 1.91 [s, 1 H, H(1)], 2.41 (bs, 2 H, ring proton), 2.59
(m, 1 H, C-H isopropyl), 2.72 (s, 1 H, ring proton), 3.02 (bs, 2
H, ring protons), 3.31 (d, 1 H, ring proton), 3.83 (bs, 3 H, NH2,
ring proton), 4.70 (bd, 1 H, ring proton), 6.62 (d, 2 H, Ar-H),
7.19 (d, 2 H, Ar-H); 13C NMR (DCCl3) ppm 16.81, 18.79 (CH3
isopropyl), 29.15, 29.79 [C(1,5)], 32.25 [C(9)], 46.61 [C(2)],
52.59, 54.22 [C(4,6,8), C-H isopropyl], 114.10, 127.21, 128.68,
147.18 (Ar-C), 170.47 (NCdO). Anal. (C17H25N3O) C, H, N.
3-(4-Am in oben zoyl)-7-isopr opyl-3,7-diazabicyclo[3.3.1]-
n on a n e Dih yd r och lor id e (19). Amide 18 (2.0 g, 6.96 mmol)
in ether (75 mL) was chilled (5 °C). HCl gas (generated as
described for 17) was bubbled into the system (10 min). The
resulting white precipitate was filtered and washed with cold
ether (10 mL). Recrystallization (H3COH/ether, 1:1, 20 mL)
was followed by filtering and drying (80 °C/0.2 mmHg) to afford
salt 19 (1.58 g, 70.2%): mp 209-210 °C; IR (KBr) 3560 (O-H),
3400 (N-H), 3160 (NH2), 1630 (NCdO) cm-1; 1H NMR (D2O) δ
1.45 (d, J ) 6.0 Hz, 6 H, CH3 isopropyl), 2.03 [bs, 2 H, H(9)],
2.49 [bs, 2 H, H(1,5)], 3.40-3.67 (m, 9 H, ring protons, C-H
isopropyl), 4.63 (s, 2 H, N-H), 7.62 (m, 4 H, Ar-H); 13C NMR
(D2O) ppm 18.83 (bs, CH3 isopropyl), 29.84 [C(1,5)], 30.14
[C(9)], 52.19, 55.26 [bs, C(2,4,6,8)], 63.65 (C-H isopropyl),
124.20, 131.59, 135.29, 139.39 (Ar-C), 177.42 (NC)O); MS (EI)
calcd C17H25N3O (2 HCl) m/ z (M+) 287.1998 (-2HCl), found
287.2013. Anal. Calcd (C17H27Cl2N3O): C, 63.05; H, 8.09.
Anal. Calcd (C17H27Cl2N3O‚0.9H2O): C, 54.23; H, 7.71.
Found: C, 54.56; H, 7.62.
3-[4-[(Meth ylsu lfon yl)a m in o]ben zoyl]-7-isop r op yl-3,7-
d ia za bicyclo[3.3.1]n on a n e Hyd r och lor id e (22). Into a
chilled (5 °C) solution of sulfonamide 20 (3.18 g, 8.70 mmol)
in H3COH (75 mL) was bubbled HCl gas over a period of 15
min, and the resulting mixture was stirred for an additional
15 min. Filtration of the precipitate was followed by dissolving
in H3COH (10 mL). To this solution was added ether (∼35
mL) to reach the cloud point, and the resulting solution was
allowed to cool to RT. The precipitate was filtered and dried
(80 °C/0.2 mmHg) to give 1.13 g (33.8%) of 22: mp 203-204
°C; IR (KBr) 3575 (O-H), 3420 (N-H), 3240 (N-H), 1720
(NCdO) cm-1; 1H NMR (DMSO-d6) δ 1.43 (d, J ) 6.5 Hz, 6 H,
CH3 isopropyl), 1.82 [m, 2 H, H(9)], 2.36 [bs, 2 H, H(1,5)], 3.11
(s, 3 H, SO2CH3), 3.29 (m, 5 H, ring protons, C-H isopropyl),
3.35 (d, J ) 13.1 Hz, 2 H, ring protons), 3.60 (d, J ) 13.1 Hz,
2 H, ring protons), 7.32 (d, 2 H, Ar-H), 7.94 (d, 2 H, Ar-H),
9.72 (bs, 1 H, N-H); 13C NMR (DMSO-d6) ppm 16.92 (CH3
isopropyl), 25.21 [C(1,5 9)], 43.81 (SO2CH3), 50.65, 51.72
[C(2,4,6,8)], 61.09 (C-H isopropyl), 117.56, 123.77, 130.62,
143.01 (Ar-C), 165.66 (NCdO); MS (EI) data C18H27N3O3S
(HCl) m/ z (M+) 365.1773 (-HCl), found 365.1754. Anal.
Calcd (C18H28ClN3O3S): C, 53.79; H, 7.02. Anal. Calcd
(C18H28ClN3O3S‚2.5H2O): C, 48.37; H, 7.44. Found: C, 48.46;
H, 7.37.
3-(4-Flu or oben zoyl)-7-isopr opyl-3,7-diazabicyclo[3.3.1]-
n on a n e (23). To amine 15 (2.53 g, 15.03 mmol) and NaOH
(10% aqueous, 15.07 g, 37.58 mmol) in H2CCl2 (25 mL) was
added a solution of 4-fluorobenzoyl chloride (2.62 g, 16.54
mmol) in H2CCl2 (15 mL) dropwise over a period of 0.5 h under
N2. The mixture was stirred (3 h). Addition of H2O (50 mL)
was followed by extraction with H2CCl2 (3 × 50 mL). Com-
bined extracts were dried (Na2SO4), filtered, and concentrated
under vacuum to give a light yellow oil, which was flash
chromatographed on neutral alumina (50 g) with hexane/ethyl
acetate (60:40) as the eluent. The filtrate was concentrated
under vacuum and placed on a vacuum pump overnight (RT/
0.2 mmHg) to give 3.88 g (89.0%) of amide 23 as a white
3-[4-[(Meth ylsu lfon yl)a m in o]ben zoyl]-7-isop r op yl-3,7-
d ia za bicyclo[3.3.1]n on a n e (20). To a chilled (5 °C) solution
of amide 18 (3.0 g, 10.44 mmol) and pyridine (0.87 g, 10.96
mmol) in H2CCl2 (20 mL) was added dropwise methanesulfonyl
chloride (1.18 g, 10.34 mmol) in H2CCl2 (10 mL) over a 15-
min period. When the addition was complete, the mixture was
allowed to stir at RT overnight. Filtration of the mixture
removed pyridine hydrochloride, and the filtrate was trans-
ferred to a separatory funnel. Extraction (1 N NaOH, 4 × 40
mL) was followed by neutralization (pH ∼7, HOAc) of the
aqueous phase, and the remaining organic layer was discarded.
This neutral solution was extracted (H2CCl2, 4 × 40 mL), dried
(Na2SO4), and filtered. After concentration in vacuo, there was
obtained 3.46 g (90.6%) of an off-white solid 20: mp 89-91
°C; IR (KBr) 3140 (N-H), 1610 (NCdO) cm-1; 1H NMR (DCCl3)
δ 0.97 (d, J ) 6.1 Hz, 3 H, CH3 isopropyl), 1.08 (d, J ) 6.1 Hz,
3 H, CH3 isopropyl), 1.69 [bs, 1 H, H(5)], 1.79 [bd, 2 H, H(9)],
1.98 [bs, 1 H, H(1)], 2.42 (d, J ) 11.3 Hz, 1 H, ring proton),
2.51 (d, J ) 11.3 Hz, 1 H, ring proton), 2.60 (m, 1 H, C-H
isopropyl), 2.74 (d, J ) 11.3 Hz, 1 H, ring proton), 3.03 (m, 5
H, ring protons, SO2CH3), 3.32 (d, J ) 13.0 Hz, 1 H, ring
proton), 3.78 (d, J ) 13.0 Hz, 1 H, ring proton), 4.76 (d, J )
13.0 Hz, 1 H, ring proton), 7.21-7.30 (q, 4 H, Ar-H); 13C NMR
(DCCl3) ppm 16.26, 1916 (CH3 isopropyl), 28.89, 29.55 [C(1,5)],
32.05 [C(9)], 39.18 (SO2CH3), 46.76 [C(2)], 52.11, 52.52, 54.19,
54.54 [C(4,6,8), C-H isopropyl], 119.80, 128.05, 128.16, 133.22,
138.21 (Ar-C), 169.63 (NCdO). Sulfonamide 20 was used
without further purification to prepare salts 21 and 22.
3-[4-[(Meth ylsu lfon yl)a m in o]ben zoyl]-7-isop r op yl-3,7-
d ia za bicyclo[3.3.1]n on a n e Hyd r op er ch lor a te (21). Sul-
fonamide 20 (3.1 g, 8.48 mmol) was dissolved in EtOH (95%,
50 mL), and the resulting solution was chilled (5 °C). With
stirring, HClO4 (60%, 1.77 g, 10.60 mmol) in EtOH (5 mL) was
added dropwise over a period of 15 min, and stirring was
continued (10 min). The white precipitate formed was filtered
and recrystallized (warm H2O, 25 mL) to give 1.97 g (49.9%)
of white platelets of 21: mp 267-268 °C; IR (KBr) 3120 (N-
solid: mp 87-88 °C; IR (KBr) 1630 (NCdO), 750 cm-1 1H
;
NMR (DCCl3) δ 0.96 (d, J ) 5.9 Hz, 3 H, CH3 isopropyl), 1.07
(d, J ) 5.9 Hz, 3 H, CH3 isopropyl), 1.71 [m, 3 H, H(9), H(5)],
1.95 [s, 1 H, H(1)], 2.41-2.72 (m, 4 H, ring protons, C-H
isopropyl), 3.03 (d, J ) 12.7 Hz, 2 H, ring protons), 3.31 (d, J
) 12.7 Hz, 1 H, ring proton), 3.72 (d, J ) 12.7 Hz, 1 H, ring
proton), 4.74 (d, J ) 12.7 Hz, 1 H, ring proton), 7.08 (m, 2 H,
Ar-H), 7.36 (m, 2 H, Ar-H); 13C NMR (DCCl3) ppm 16.26, 19.18
(CH3 isopropyl), 28.97, 29.69 [C(1,5)], 32.16 [C(9)], 46.59
[C(2)], 52.12, 52.49, 54.65 [C(4,6,8), C-H isopropyl], 114.96,
115.25, 128.77, 128.88, 133.60, 133.64 (Ar-C), 161.04, 164.33
(J ) 248.2 Hz, ArC-F), 169.07 (NCdO); 15N NMR (DCCl3)
ppm 40.78 [N(7)], 119.65 [N(3)]; MS (EI) data C17H23N2OF
m/ z (M+) 290.1794, found 290.1790. Anal. Calcd (C17H23N2-
OF) C, H, N.
3-(4-Flu or oben zoyl)-7-isopr opyl-3,7-diazabicyclo[3.3.1]-
n on a n e Hyd r op er ch lor a te (24). To a chilled (5 °C) solution
of amide 23 (1.0 g, 3.44 mmol) in ether (25 mL) was added
dropwise HClO4 (60%, 0.72 g, 4.30 mmol) over a period of 5
min. The precipitate was filtered and washed (cold ether).
Recrystallization (H3COH) of the precipitate was followed by
filtration and drying (80 °C/0.2 mmHg) to give 1.03 g (76.3%)
of salt 24 as white platelets: mp 246-247 °C; IR (KBr) 3120
1
(N-H), 1625 (NCdO) cm-1; H NMR (D3CCN) δ 1.38 (d, J )
6.5 Hz, 6 H, CH3 isopropyl), 1.81 [bd, 1 H, H(5)], 2.29 [bd, 3
H, H(5,9)], 3.34 (m, 5 H, ring protons, C-H isopropyl), 3.52 (bd,
4 H, ring protons), 7.17 (t, 2 H, Ar-H), 7.38 (m, 2 H, Ar-H); 13
C
NMR (D3CCN) ppm 16.72 (CH3 isopropyl), 27.89 [C(1,5)], 28.99
[C(9)], 50.34, 53.52 [bs, C(2,4,6,8)], 60.96 (C-H isopropyl),
116.29, 116.59, 118.01, 118.36, 130.65, 130.77, 132.78, 132.82
(Ar-C), 162.59, 165.88 (J ) 247.6 Hz, ArC-F), 174.13 (NCdO);
MS (EI) data C17H23N2OF (HClO4) m/ z (M+) 290.1855 (-HC-
lO4), found 290.1853. Anal. (C17H24ClN2O5F) C, H.
3-[4-(1H -Im id a zol-1-yl)b e n zoyl]-7-isop r op yl-3,7-d i-
a za bicyclo[3.3.1]n on a n e (25). To a solution of amide 23
(3.35 g, 11.54 mmol) in DMSO (15 mL) was added imidazole
(1.18 g, 17.30 mmol), potassium carbonate (anhydrous,1.67 g,
12.12 mmol), and 18-crown-6 (100 mg). The stirred mixture
was heated at 110 °C for 45 h under N2 in a jacketed flask
H), 1630 (NCdO), 1100 (Cl-O) cm-1 1H NMR (DMSO-d6) δ
;
1.32 (dd, J ) 6.1 Hz, 2 H, CH3 isopropyl), 1.69-1.87 [dd, 2 H,
H(9)], 2.24 [m, 2 H, H(1,5)], 3.06 (s, 3 H, SO2CH3), 3.18-3.55
(m, 9 H, ring protons, C-H isopropyl), 7.24 (bd, 2 H, Ar-H),
7.37 (bd, 2 H, Ar-H), 7.93 (bs, 1 H, N-H), 10.05 (s, 1 H, CH3-
SO2N-H); 13C NMR (DMSO-d6) ppm 26.48 (CH3 isopropyl),
27.59 [C(1,5,9)], 59.53 [bs, C-H isopropyl, C(2,4,6,8), CH3SO2],
118.12, 128.81, 130.60, 139.53 (Ar-C), 172.62 (NCdO); MS (EI)
data C18H27N3SO3 (HClO4) m/ z (M+) 365.1773 (-HClO4), found
365.1775. Anal. (C18H28ClN3SO7) C, H, N, S.

Novel 3,7-Diheterabicyclo[3.3.1]nonanes
J ournal of Medicinal Chemistry, 1996, Vol. 39, No. 13 2567
containing boiling toluene. Cooling the solution to RT was
followed by the addition of chilled H2O. Combined extracts
(H2CCl2, 4 × 40 mL) of the suspension were washed with H2O
(80 mL) and saturated NaCl (80 mL); the solution was then
dried (Na2SO4). Filtration and concentration gave a light
yellow solid [dried overnight at RT/0.2 mmHg]. Flash chro-
matography (neutral alumina) of the crude solid in solution
using ethyl acetate/hexane (2:3) caused the starting material
to be eluted first. With a more polar solvent system [EtOAc/
H3COH (30:1)], product 25 was isolated (1.35 g, 35.1%) as an
off white solid. This solid was sensitive to air and became
gummy when exposed to the atmosphere: IR(film) 3400 (N-
was used as was done for 27a . After addition of ketone 9b
(6.0 g, 21.09 mmol), 1,2-ethanedithiol (19.87 g, 210.9 mmol),
p-toluenesulfonic acid (9.63 g, 50.6 mmol), and benzene (120
mL), the resulting mixture was heated at reflux (30 h).
Benzene was removed through the Dean-Stark trap, and the
resulting oil was dissolved in H2O (100 mL). The aqueous
layer was extracted (ether, 2 × 50 mL), and these extracts
were discarded. Basification of the aqueous solution (pH ∼12,
aqueous 10% NaOH) followed. This new solution was ex-
tracted (ether, 4 × 75 mL), and the extracts were then washed
with NaOH (1 N, 90 mL) and saturated NaCl (90 mL). After
drying (Na2SO4), the organic solution was evaporated in vacuo
to afford 6.44 g (84.7%) of 27b, a light yellow oil: IR (film)
1
H), 1620 (NCdO) cm-1; H (DCCl3) δ 0.96-1.14 (dd, J ) 5.9
1
Hz, 6 H, CH3 isopropyl), 1.68 [bd, 1 H, H(9)], 1.81 [bs, 2 H,
H(1,5)], 2.02 [bs, 1 H, H(9)], 2.45 (d, J ) 10.8 Hz, 1 H, ring
proton), 2.57 (d, J ) 10.8 Hz, 1 H, ring proton), 2.63 (m, 1 H,
C-H isopropyl), 2.77 (d, J ) 10.8 Hz, 1 H, ring proton), 3.09
(d, J ) 12.4 Hz, 2 H, ring protons), 3.38 (d, J ) 12.4 Hz, 1 H,
ring proton), 3.76 (d, J ) 12.4 Hz, 1 H, ring proton), 4.79 (d,
J ) 12.4 Hz, 1 H, ring proton), 7.22 (s, 1 H, C-H imidazole),
7.32 (s, 1 H, C-H imidazole), 7.41-7.54 (dd, 4 H, Ar-H), 7.89
(s, 1 H, C-H imidazole); 13C NMR (DCCl3) ppm 16.33, 19.41
(CH3 isopropyl), 29.03, 29.78 [C(1,5)], 32.26 [C(9)], 46.72 [C(2)],
52.15, 52.61, 54.38, 54.82 [C(4,6,8), C-H isopropyl], 118.07 (C-H
imidazole), 121.15, 128.54 (Ar-C), 130.60, 135.44 (C-H imida-
zole), 136.91, 137.43 (Ar-C), 168.80 (NCdO). Due to its
extreme hygroscopic nature, benzamide 25 was converted
directly to the dihydroperchlorate 26.
3-[4-(1H -Im id a zol-1-yl)b e n zoyl]-7-isop r op yl-3,7-d i-
a za bicyclo[3.3.1]n on a n e Dih yd r op er ch lor a te (26). To a
flask was added amide 25 (1.44 g, 4.25 mmol) in 40 mL of
ether/H3COH (50:50) which was chilled (5 °C). To this new
solution was added perchloric acid (60%, 1.56 g, 9.56 mmol),
and immediately a white precipitate formed. The heteroge-
neous mixture was stirred an additional 15 min at 5 °C. After
filtering, the solid was recrystallized (H3COH, 35 mL), and
this solution was allowed to stand at room temperature. The
solid which formed was filtered and dried (80 °C/0.2 mmHg)
to give white needles (1.14 g, 60.9%) of 26: mp 262-263 °C;
IR (KBr) 3200 (N-H), 1645 (NCdO), 1100 (Cl-O) cm-1; 1H NMR
(DMSO-d6) δ 1.33 (d, J ) 5.8 Hz, 6 H, CH3 isopropyl), 1.71-
1.92 [bd, 2 H, H(9)], 2.34-2.41 [bs, 2 H, H(1,5)], 3.23 [m, 5 H,
H(2,4,6,8)ax, C-H isopropyl], 3.23-3.97 [m, 4 H, H(2,4,6,8)eq],
3.94 (bs, 1 H, N-H), 7.66 (d, 2 H, Ar-H), 7.94 (s, 1 H, C-H
imidazole), 7.96 (d, 2 H, Ar-H), 8.32 (s, 1 H, C-H imidazole),
9.20 (s, 1 H, C-H imidazole); 13C NMR (DMSO-d6) ppm 26.42
[C(1,5)], 27.36 [C(9)], 59.64 [C(2,4,6,8), C-H isopropyl], 120.63,
121.35, 122.01, 128.74, 135.27, 137.49 (Ar-C), 171.49 (NCdO);
MS (EI) data C20H6N4O (2HClO4) m/z (M+) 338.2106 (-2HC-
lO4), found 338.2099. Anal. (C20H28Cl2N4O9) C, H, N.
3010 (Ar-H) cm-1; H NMR (DCCl3) δ 0.14 [m, 2 H, cyclopro-
pyl], 0.51 [m, 2 H, cyclopropyl], 0.92 [m, 1 H, (CH), cyclopropyl],
2.15 [m, 2 H, H(1,5)], 2.27 (d, J ) 5.5 Hz, 2 H, CH2-cyclopropyl),
2.73-2.84 (m, 8 H, ring protons), 3.14 (s, 4 H, SCH2), 3.53 (s,
2 H, Ar-CH2), 7.24-7.46 (m, 5 H, Ar-H); 13C NMR (DCCl3) ppm
3.83 (CH2, cyclopropyl ring), 8.60 (CH, cyclopropyl ring), 37.93,
37.98 [C(1,5)], 43.51 (SCH2), 56.56 [C(2,4)], 56.67 [C(6,8)], 61.68
(CH2-Ar), 62.49 (CH2-cyclopropyl), 71.91 [C(9)], 126.60, 128.02,
128.62, 139.34 (Ar-C). Thioketal 27b was used without further
purification to prepare salt 29.
3,7-Diisopr opyl-9,9-(1,3-dith iolan -2-yl)-3,7-diazabicyclo-
[3.3.1]n on a n e Hyd r op er ch lor a te (28). Thioketal 27a (8.06
g, 26.82 mmol) in dry ether (100 mL) was cooled (0-5 °C). To
the stirred solution was added HClO4 (60%, 5.61 g, 33.52
mmol) dropwise over a period of 15 min. After an additional
15 min of stirring at 5 °C, the solution deposited a white
precipitate which was filtered and washed with cold ether (25
mL). Recrystallization (H3COH, 50 mL) afforded, after drying
(80 °C/0.2 mmHg, P2O5), hydroperchlorate 28 as white needles
(3.15 g, 29.3%): mp 222.0-223.0 °C; IR (KBr) 2980 and 2920
1
(aliphatic C-H) cm-1; H NMR (DCCl3) δ 1.18 (d, J ) 6.4 Hz,
12 H, CH3 isopropyl), 2.31 [bs, 2 H, H(1,5)], 3.32-3.57 [m, 15
H, N-H, H(2,4,6,8)ax-eq, C-H isopropyl, S-CH2]; 13C NMR
(DCCl3) ppm 16.78 (CH3 isopropyl), 39.29 [C(1,5)], 41.23 (S-
CH2), 52.29 [C(2,4,6,8)], 54.64 (C-H isopropyl), 70.22 [C(9)].
Anal. (C15H29ClN2S2O4) C, H, N, S.
7-Ben zyl-3-(cyclop r op ylm et h yl)-9,9-(1,3-d it h iola n -2-
yl)-3,7-d ia za bicyclo[3.3.1]n on a n e Hyd r op er ch lor a te (29).
Thioketal 27b (6.44 g, 17.86 mmol) was dissolved in dry ether
(100 mL), and the solution was cooled (0-5 °C). To the stirred
mixture was added dropwise perchloric acid (60%, 3.73 g, 22.32
mmol) over a period of 15 min. After an additional 15 min of
stirring at 5 °C, a white precipitate formed and was filtered
and washed with cold ether (25 mL). Recrystallization (H3-
COH, 50 mL) afforded, after drying (80 °C, 0.2 mmHg, P2O5),
hydroperchlorate 29 (3.34 g, 40.6%) as white needles: mp
1
147.5-149.0 °C; IR (KBr) 3010 (Ar-H), 1100 (Cl-O) cm-1; H
3,7-Diisopr opyl-9,9-(1,3-dith iolan -2-yl)-3,7-diazabicyclo-
[3.3.1]n on a n e (27a ). A flask was equipped with a magnetic
stirrer, a condenser with a N2 inlet, a Dean-Stark trap, and
a heating mantle. After addition of ketone 9a (8.0 g, 35.66
mmol), 1,2-ethanedithiol (33.59 g, 356.6 mmol), p-toluene-
sulfonic acid (16.28 g, 85.58 mmol), and benzene (200 mL),
the resulting mixture was heated at reflux (40 h). Benzene
was then removed through the Dean-Stark trap, and the
resulting oil was dissolved in H2O (100 mL). The aqueous
layer was extracted (ether, 2 × 100 mL), the extracts being
discarded. Basification (pH ∼12, 10% NaOH) was followed
by extraction (ether, 4 × 75 mL) and washing with NaOH (1
N, 90 mL) and then with brine (90 mL). After the solution
was dried (Na2SO4), evaporation under vacuum afforded 8.06
g (75.2%) of a light yellow oil 27a : IR (film) 2905 and 2800
(aliphatic C-H) cm-1; 1H NMR (DCCl3) δ 1.03 (d, J ) 12.5 Hz,
12 H, CH3 isopropyl), 2.26 [bs, 2 H, H(1,5)], 2.62 (d, 4 H, ring
protons), 2.77 (m, 2 H, C-H isopropyl), 2.89 (d, J ) 12.7 Hz, 4
H, ring protons), 3.08 (s, 4 H, S-CH2); 13C NMR (DCCl3) ppm
17.97 (CH3 isopropyl), 37.39 [C(1,5)], 43.11 (S-CH2), 51.20
[C(2,4,6,8)], 53.21 (C-H isopropyl), 70.89 [C(9)]. Spectral
analyses (IR and 13C NMR) of the oil did not show the presence
of a carbonyl group as present in 9a , and thus the thioketal
was used without purification to prepare 28.
NMR (DCCl3) δ 0.59 [m, 2 H, cyclopropyl ring], 0.68 [m, 2 H,
cyclopropyl], 0.98 (m, 1 H, C-H cyclopropyl), 2.26 [bs, 2 H,
H(1,5)], 3.01 [m, 4 H, H(2,4)ax, CH2-cyclopropyl], 3.31-3.46 [m,
8 H, H(6,8)ax, H(2,4)eq, SCH2], 3.73 (s, 2 H, Ar-CH2), 3.92 [d, J
) 13.1 Hz, 2 H, H(6,8)eq], 7.28-7.45 (m, 5 H, Ar-H); 13C NMR
(DCCl3) ppm 4.29 (CH2, cyclopropyl), 6.10 (CH, cyclopropyl),
39.19, 39.35 (SCH2), 41.73 [C(1,5)], 56.12 [C(2,4)], 56.92
[C(6,8)], 60.96 (Ar-CH2), 60.99 (CH2-cyclopropyl), 69.42 [C(9)],
128.04, 128.57, 129.89, 135.09 (Ar-C); MS (EI) data C20H28N2S2
(HClO4) m/ z (M+) 360.1694 (-HClO4), found 360.1703. Anal.
(C20H29ClN2O4S2) C, H, N, S.
3 -(C y c l o p r o p y l m e t h y l )-3 ,7 -d i a z a b i c y c l o [3 .3 .1 ]-
n on a n e (30). The system was initially flushed with N2 for a
period of 15 min. Palladium-on-carbon (Alfa, 10%, 0.997 g,
30 mg of catalyst/mmol of the amine) was added in one portion,
and the system was flushed with N2. Dry and deoxygenated
H3COH (90 mL) was slowly poured over the catalyst (CAU-
TION: catalyst can ignite in the presence of air). To the
stirred solution were added amine 10b (8.99 g, 33.24 mmol)
and anhydrous HCO2NH4 (5.24 g, 83.1 mmol), and the result-
ing mixture was boiled under N2 (30 min). Cooling of the
mixture to RT and filtering through a Celite pad was followed
by concentration of the resulting solution to give an off-white,
viscous oil. The oil was dissolved in H2O (100 mL) and made
basic (pH ∼12, 10% NaOH pellets). Combined extracts (CCl4,
4 × 60 mL) of the aqueous solution were dried (Na2SO4),
7-Ben zyl-3-(cyclop r op ylm et h yl)-9,9-(1,3-d it h iola n -2-
yl)-3,7-d ia za bicyclo[3.3.1]n on a n e (27b). An identical setup

2568 J ournal of Medicinal Chemistry, 1996, Vol. 39, No. 13
filtered, and concentrated in vacuo to give a yellow oil 30 (5.50
Garrison et al.
1090 (Cl-O) cm-1; H NMR (D3CCN) δ 0.51 [d, J ) 3.2 Hz, 2
H, cyclopropyl], 0.82 [d, J ) 3.6 Hz, 2 H, cyclopropyl], 1.18
(m, 1 H, C-H cyclopropyl), 1.85 [bd, 1 H, H(9)], 2.33 [bs, 3 H,
H(1,5,9)], 3.03 (d, J ) 6.2 Hz, 2 H, CH2 cyclopropyl), 3.29 (m,
4 H, ring protons), 3.74 (bs, 2 H, ring protons), 4.09 (bs, 2 H,
ring protons), 7.36 (d, 2 H, Ar-H), 7.48 (d, 2 H, Ar-H); 13C NMR
(D3CCN) ppm 4.94, 6.40 (cyclopropyl CH2), 27.89 [C(1,5)], 29.05
[C(9)], 57.42, 63.98, 64.08 [C(2,4,6,8), CH2-cyclopropyl], 118.37,
129.67, 129.79, 129.95, 135.08, 136.29 (Ar-C), 173.85 (NCdO);
MS (EI) data C18H23ClN2O (HClO4) m/ z (M+) 318.1499 (-HC-
lO4), found 318.1500. Anal. (C18H24Cl2N2O5) C, H.
1
g, 91.8%): IR (film) 3300 (N-H), 3010 (CH2 cyclopropyl) cm-1
;
1H NMR (DCCl3) δ 0.13 [m, 2 H, cyclopropyl], 0.52 [m, 2 H,
cyclopropyl], 0.87 [m, 1 H, (CH), cyclopropyl], 1.64 [m, 2 H,
H(1,5)], 1.82 [m, 2 H, H(9)], 2.07 (d, J ) 6.6 Hz, 2 H, CH2-
cyclopropyl), 2.31 [d, J ) 11.1 Hz, 2 H, H(6,8)ax], 2.94 [d, J )
13.8 Hz, 2 H, H(2,4)ax], 3.09 [d, J ) 13.2 Hz, 2 H, H(6,8)eq],
3.17 [d, J ) 11.1 Hz, 2 H, H(2,4)eq], 4.09 [bs, 1 H, (N-H)]; 13C
NMR (DCCl3) ppm 3.76 (CH2, cyclopropyl), 8.76 (CH, cyclo-
propyl), 29.87 [C(9)], 33.23 [C(1,5)], 52.45 [C(6,8)], 59.51
1
[C(2,4)], 64.32 (CH2-cyclopropyl). The H NMR spectrum was
devoid of aromatic protons, and thus the oil was used without
further purification to prepare amides 31 and 32.
3-Ben zoyl-7-(cyclopr opylm eth yl)-3,7-diazabicyclo[3.3.1]-
n on a n e Hyd r op er ch lor a te (34). To a cooled (5 °C), stirred
solution of amide 32 (7.15 g, 25.14 mmol) in dry ether (120
mL) was added dropwise a solution of HClO4 (60%, 5.26 g,
31.43 mmol) over a 10-min period, followed by stirring for an
additional 10 min. Filtered salt 34 (a white solid) was washed
with dry, cold ether (60 mL). The white solid was dissolved
(H3COH, 160 mL) and filtered hot and then allowed to cool to
RT. Filtration and drying (0.2 mmHg/80 °C) afforded 6.30 g
(65.1%) of pure salt 34: mp 236.0-237.0 °C; IR (KBr) 3150
3-(4-Ch lor ob e n zoyl)-7-(cyclop r op ylm e t h yl)-3,7-d i-
a za bicyclo[3.3.1]n on a n e (31). To a mixture of amine 30
(4.03 g, 22.35 mmol) in H2CCl2 (25 mL) and 10% NaOH (22.41
g, 55.88 mmol) was added dropwise a solution of 4-chloroben-
zoyl chloride (4.30 g, 24.59 mmol) in H2CCl2 (15 mL) over a
period of 30 min. Stirring of the mixture was continued for
an additional 3 h under N2. To the heterogeneous mixture
was added H2O (100 mL), and two layers were separarated.
Extracts (H2CCl2, 3 × 50 mL) of the aqueous layer were
combined, dried (Na2SO4), filtered, and concentrated under
vacuum to give a viscous yellow oil. Flash chromatography
of the oil was accomplished on neutral alumina (50 g) using
hexanes/ethyl acetate (60:40) as the eluent. The filtrate was
concentrated and then placed under vacuum overnight (RT/
0.2 mmHg) to give 4.18 g (83.1%) of an off-white solid 31: mp
67-68 °C; IR (KBr) 3005 (Ar-H), 1635 (NCdO) cm-1; 1H NMR
(DCCl3) δ 0.12 [m, 2 H, cyclopropyl], 0.54 [m, 2 H, cyclopropyl],
0.91 [m, 1 H, (CH), cyclopropyl], 1.73 [m, 3 H, H(5), H(9)], 2.02
[m, 2 H, H(1), CH2-cyclopropyl], 2.24 [m, 3 H, H(4)ax, H(6)ax,
CH2-cyclopropyl], 2.96 [d, J ) 10.5 Hz, 1 H, H(6)eq], 3.03 [d, J
) 13.2 Hz, 1 H, H(2)ax], 3.28 [m, 2 H, H(8)ax, H(4)eq], 3.75 [d,
J ) 13.2 Hz, 1 H, H(8)eq], 4.83 [d, J ) 13.2 Hz, 1 H, H(2)eq],
7.39 (s, 4 H, Ar-H); 13C NMR (DCCl3) ppm 3.21, 4.43 (CH2
cyclopropyl), 8.29 (CH cyclopropyl), 29.01 [C(1)], 29.41 [C(5)],
32.10 [C(9)], 46.59 [C(2)], 52.16, 58.10, 58.38 [C(4,6,8)], 64.25
(NCH2-cyclopropyl), 128.15, 128.28, 134.40, 135.90 (Ar-C),
169.06 (NCdO); 15N NMR (DCCl3) ppm 40.55 [N(7)], 119.74
[N(3)]; MS (EI) data (C18H23ClN2O) m/ z (M+) 318.1499, found
318.1498. Anal. (C18H23ClN2O) C, H, N.
3-Ben zoyl-7-(cyclopr opylm eth yl)-3,7-diazabicyclo[3.3.1]-
n on a n e (32). In flask were placed the amine 30 (5.50 g, 30.51
mmol) and NaOH (10%, 30.60 g, 76.28 mmol) in H2CCl2 (25
mL). A solution of benzoyl chloride (4.72 g, 33.56 mmol) in
H2CCl2 (15 mL) was added dropwise over a period of 0.5 h
under N2. The mixture was allowed to stir an additional 3 h.
Addition of H2O (50 mL) was followed by extraction with H2-
CCl2 (3 × 50 mL). Combined extracts were dried (Na2SO4),
filtered, and concentrated in vacuo to give a yellow oil. Flash
chromatography of the oil was performed on neutral alumina
(50 g) with ethyl acetate as the eluent. The filtrate was
concentrated under vacuum and then dried under vacuum
overnight (RT/0.2 mmHg) to give 7.15 g (82.4%) of amide 32
as an oil: IR (film) 3005 (Ar-H), 1630 (NCdO) cm-1; 1H NMR
(DCCl3) δ 0.11 [bd, 2 H, cyclopropyl], 0.49 [m, 2 H, cyclopropyl],
0.92 (m, 2 H, cyclopropyl C-H), 1.74 [m, 3 H, H(5,9)], 1.98 [bs,
2 H, H(1), CH2 cyclopropyl], 2.23 [bs, 3 H, H(4,6)ax, CH2
cyclopropyl], 2.94 [d, 1 H, H(6)eq], 3.01 [d, 1 H, H(2)ax], 3.28
[m, 2 H, H(8)ax, H(4)eq], 3.78 [d, J ) 12.2 Hz, 1 H, H(8)eq], 4.79
[d, J ) 12.1 Hz, 1 H, H(2)eq], 7.38 (m, 5 H, Ar-H); 13C NMR
(DCCl3) ppm 2.85, 4.11 (cyclopropyl CH2), 7.95 (cyclopropyl
C-H), 28.64, 29.01 [C(1,5)], 31.72 [C(9)], 46.02 [C(2)], 51.74,
57.71, 57.98 [C(4,6,8)], 63.84 (CH2 cyclopropyl), 126.13, 127.64,
128.07, 137.20 (Ar-C), 169.68 (NCdO). Benzamide 32 was
used without further purification to prepare salt 34.
1
(N-H), 1630 (NCdO), 1095 (Cl-O) cm-1; H NMR (D3CCN) δ
0.52 [d, J ) 3.1 Hz, 2 H, cyclopropyl], 0.81 [d, J ) 2.7 Hz, 2 H,
cyclopropyl], 1.19 (m, 1 H, cyclopropyl C-H), 1.83 [bd, 1 H,
H(1)], 2.24 [bd, 3 H, H(5,9)], 2.98 (d, J ) 6.2 Hz, 2 H, CH2
cyclopropyl), 3.21 (m, 4 H, ring protons), 3.71 (bs, 2 H, ring
protons), 4.08 (bs, 2 H, ring protons), 7.41 (m, 5 H, Ar-H); 13
C
NMR (D3CCN) ppm 5.27 (cyclopropyl CH2), 26.45 [C(1,5)],
27.76 [C(9)], 62.56 [C(2,4,6,8), CH2-cyclopropyl], 126.95, 128.22,
129.33, 136.98 (Ar-C), 172.69 (NCdO);
15N NMR (DMSO-d6)
ppm 50.05 [N(7)], 108.49 [N(3)]; MS (EI) data C18
H24N2O
(HClO4) m/ z (M+) 284.1888 (-HClO4), found 284.1888. Anal.
(C18H25ClN2O5) C, H.
7-Ben zyl-3-th ia -7-a za bicyclo[3.3.1]n on a n e Hyd r och lo-
r id e (37). Gaseous HCl was generated in a collection flask
from solid NaCl as described for 17. The HCl(g) generated
was bubbled into a cooled (5 °C, ice bath) solution of amine 36
(5.00 g, 20.20 mmol) in ether (150 mL) over a 15 min period.
The mixture was allowed to stir an additional 15 min at 0-5
°C. A white precipitate formed and was filtered and washed
with cold ether (30 mL). The solid was recrystallized (H3COH/
ether, 1:1, 60 mL), and the white solid collected was washed
with cold ether (25 mL) and dried (80 °C/0.2 mmHg) to give
3.31 g (60.7%) of salt 37: mp 246.0-247.0 °C; IR (KBr) 3040
1
(Ar-H) cm-1; H NMR (DMSO-d6) δ 1.84 [m, 2 H, H(9)], 2.38
[m, 2 H, H(1,5)], 2.71 [d, J ) 11.9 Hz, 2 H, H(6,8)ax], 3.13 [d,
J ) 11.9 Hz, 2 H, H(2,4)ax], 3.36 [bs, 2 H, H(6,8)eq], 3.60 [d, J
) 10.3 Hz, 2 H, H(2,4)eq], 4.29 (d, 2 H, CH2Ph), 7.61-7.49 (Ar-
H), 9.25 (bs, 1 H, N-H); 13C NMR (DMSO-d6) ppm 25.96
[C(1,5)], 28.65 [C(9)], 30.91 [C(2,4)], 56.41 [C(6,8)], 60.82 (CH2-
Ph), 129.21, 129.82, 130.19, 130.43 (Ar-C); MS (EI) data C14H20
-
NSCl m/ z (M+) 233.1238, found 233.1239. Anal. (C14H20NSC)
C, H, N.
Electr op h ysiology. The techniques and overall approach
have been previously described in detail.6g For the sake of
completeness, a summary of the methodology follows. Mongrel
dogs, weighing about 12-25 kg, were anesthetized with
sodium pentobarbital (∼30 mg/kg), after which a full 12 lead
electocardiogram (ECG) was recorded for baseline establish-
ment. A left thoracotomy was performed at the 4th intercostal
space, and the heart was exposed through an opening in the
pericardium. Dissection followed of the left anterior descend-
ing coronary artery approximately 5-8 mm from its origin,
and a silk ligature was employed to interupt flow partially.
After 20 min, the vessel was completely ligated in order to
produce an anteroseptal myocardial infarction. After repair
of the thoracotomy, the animal was allowed to recover for 24-
96 h.
After the period of recovery and after induction of anesthesia
with sodium pentobarbital, standard ECG leads V2-V6 re-
vealed QS patterns indicative of an anterior wall myocardial
infarction. The heart was exposed through the original
thoracotomy incision. Composite electrodes were secured to
the area overlying the infarct zone (anterior wall) and a normal
zone (posterior wall) to obtain local electrical recordings during
induced ventricular arrhythmias. One His bundle electrogram
3-(4-Ch lor ob e n zoyl)-7-(m e t h ylcyclop r op yl)-3,7-d i-
a za bicyclo[3.3.1]n on a n e Hyd r op er ch lor a te (33). To a
cooled (5 °C, ice bath) solution of amide 31 (1.0 g, 3.14 mmol)
in ether (30 mL) was added HClO4 (60%, 0.66 g, 3.92 mmol)
dropwise over a period of 15 min. The suspension was stirred
an additional 10 min at this temperature followed by filtration.
A white solid produced was recrystallized (H3COH, 25 mL)
and dried (80 °C/0.2 mmHg) to give 0.93 g (70.9%) 33 as white
needles: mp 231-232 °C; IR (KBr) 3180 (N-H), 1620 (NCdO),

Novel 3,7-Diheterabicyclo[3.3.1]nonanes
J ournal of Medicinal Chemistry, 1996, Vol. 39, No. 13 2569
Ta ble 3. Crystal Data, Data Collection, and Refinement
Parameters for 26
Ack n ow led gm en t. We (K.D.B., B.J .S., E.P., R.L.)
gratefully acknowledge partial support of this research
by grants from the OCAST(ARO-51)/Presbyterian Foun-
dation. We gratefully acknowledge partial support of
this work through a J ohnson Fellowship and a Conoco
Fellowship (G.L.G.), the College of Arts and Sciences of
the Oklahoma State University (K.D.B.), and a grant
from the Department of Veterans Affairs (B.J .S.).
Grateful acknowledgment is also extended to the Na-
tional Science Foundation for grants to upgrade the
XL300 NMR spectrometer (DMB-8603684) and to pur-
chase the XL-400 NMR spectrometer (CHE-89718150).
We are also very grateful to the Oklahoma MOST grant
(1506) program for partial funding to upgrade the XL-
300 NMR spectometer and the Oklahoma OCAST grant
(FMG-3478) program for partial funding for the XL-400
NMR spectrometer. We (D.v.d.H., F.D.S.) gratefully
thank NIH for partial support with a grant (NCI-17562).
formula
Mr
C20H28O9N4Cl2
539.1
space group
P21/a
cell dimensions
a (Å)
b
c
10.796(4)
12.842(9)
17.475(8)
97.10(4)
2404.2
â
V (Å3)
z
4
Dx (gm cm-3
radiation
µ, cm-1
)
1.488
Cu KR
28.10
163 K
150
-13 to +13
0 to 16
0 to 22
(1.30 + 0.20) tan θ
(4.50 + 0.86) tan θ
75
temperature
2θmax (deg)
h range
k
l
scan width (deg)
aperature
Tmax (s)
Su p p or tin g In for m a tion Ava ila ble: Complete tables of
crystallographic data, atom coordinates, anisotropic thermal
parameters, bond lengths, angles, and intermolecular dis-
tances (8 pages). Ordering information is given on any current
masthead page.
monitors
2 h
max variation
total reflections
no. of obsd
reflections (I > 2σ(I))
R
7.4%
4909
3802
0.048
0.055
0.02
1.73
429
Refer en ces
Rω
(∆/σ)max
(1) Olshausen, K. V.; Witt, T.; Pop, T.; Treese, N.; Sethge, K.; Meyer,
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Raven Press: New York, 1987; pp 11-47.
S
no. of parameters
max density (e/Å3)
(diff. map)
min density
0.49
-0.38
(3) (a) Vaughan Williams, E. M. Significance of Classifying Anti-
arrhythmic Actions Since the CAST. J . Clin. Pharmacol. 1991,
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Gambit: A New Approach to the Classification of Anti-arrhyth-
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nisms. Circulation 1991, 84 (4), 1831-1851.
from the aortic root and central aortic blood pressure were
continuously monitored during the experiments as were Lead
II and V2.
Ventricular pacing was initiated via pacing pulses from an
electrical stimulator (S-88 Grass Stimulator) to the right
ventricle. Three-beat bursts, at rates of 240-390/min, were
employed to induce ventricular arrhythmias. The generation
of ventricular ecotopic beats lasting at least 30 s, or more than
100 consecutive ectopic beats, was accepted as having created
sustained ventricular tachycardia.
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A
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used to determine the inducibility of lack thereof. Thirty
minutes after administration of the agent, the same pacing
procedure was utilized to ascertain the dissipation of the effect
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Previous work6a revealed the tests were unaffected by the use
of ethanol alone.
Cr ystallogr aph ic Exper im en tal Data for 26. The bicyclo-
[3.3.1]nonane 26 was recrystallized by means of slow vapor
diffusion in an ethanol/water solution. The crystals were
monoclinic, space group P21/a. More complete information
about data collection and cell parameters are given in Table
3. Data collection was accomplished with a Nonius CAD-4
diffractometer equipped with a nitrogen low-temperatrure
device. The cell dimensions were determined by a least square
fit to (2θ of 48 reflections. The structure was solved by
direct methods using the program SHELXS.27 No absorption
correction was performed.
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of a better fit.

2570 J ournal of Medicinal Chemistry, 1996, Vol. 39, No. 13
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