Synthesis of conformationally constrained adamantane imidazolines with trypanocidal activity

Article abstract of DOI:10.1002/jhet.5570450524

(Chemical Equation Presented) Aiming at the development of new adamantano building blocks for treating African trypanosomiasis, we report on the synthesis of spiro adamantane 2-imidazolines 8a-f and 9a-c, and their congeneric 5-(1-adamantyl)imidazolines 1

Full text of DOI:10.1002/jhet.5570450524

Sep-Oct 2008
1401
Synthesis of Conformationally Constrained Adamantane
Imidazolines with Trypanocidal Activity
Ioannis Papanastasiou1, Andrew Tsotinis1, George B. Foscolos1*, S. Radhika
Prathalingam2, John M. Kelly2
1Faculty of Pharmacy, Department of Pharmaceutical Chemistry, University of Athens,
Panepistimioupoli-Zografou, 157 71 Athens, Greece.
2Department of Infectious and Tropical Diseases, London School of Hygiene and Tropical Medicine,
London WC1E 7HT, U.K.
tsotinis@pharm.uoa.gr
Received February 29, 2008
N
R'
N
N
R'
R
N
R
H
14a-f, 15a,b
8a-f, 9a-c
Aiming at the development of new adamantano building blocks for treating African trypanosomiasis, we
report on the synthesis of spiro adamantane 2-imidazolines 8a-f and 9a-c, and their congeneric 5-(1-
adamantyl)imidazolines 14 and 15. The potency of these compounds against Trypanosoma brucei was
compared to that of rimantadine and found, in the case of compound 14e, to be three fold higher. Together
with the other active compounds, 14b and 15b, which were equipotent to rimantadine, the new molecules
illustrate the synergistic effect of the lipophilic character of adamantane and the C1 amidine functionality
on trypanocidal activity.
J. Heterocyclic Chem., 45, 1401 (2008).
INTRODUCTION
with substituted aminoadamantane derivatives identified
compounds with enhanced potency (compounds 3-5,
Figure 1), and we showed that this increased trypanocidal
activity could be correlated with hydrophobic
substitutions to the adamantane ring [4,5].
Human African Trypanosomiasis (HAT) is endemic in
several areas of Sub-Saharan Africa. Current estimates are
that 70,000 individuals are infected, the number having
fallen from 450,000 within the last 10 years as a result of
co-ordinated public health campaigns [1]. HAT is caused
by tsetse fly transmitted protozoan parasites of the
Trypanosoma brucei species complex, and is invariably
fatal unless treated. For more than fifty years,
pentamidine and suramin have been the drugs of choice
against first stage disease [2]. However, these compounds
are unable to cross the blood brain barrier and are
therefore ineffective against second stage HAT, which
occurs once the parasites has accessed the central nervous
system. The arsenical melarsoprol (Mel B, Asorbal) and
eflornithine (Ornidyl) are the only drugs routinely used
against this stage of the disease. New drugs are urgently
required since melarsoprol is extremely toxic and
eflornithine is only effective against T.b. gambiense and is
relatively expensive.
NH2 .HCl
NH2 .HCl
NH2.HCl
H
C
NH2.HCl
CH3
NH2 .HCl
()2
1
2
4
3
5
Figure 1. Structures of trypanocidal aminoadamantanes [4]. The
concentrations that inhibited growth of bloodstream form T. brucei by
50% (IC50) were established as follows: (1) 7.04 μM; (2) > 132 μM; (3)
0.52 μM; (4) 0.62 μM; (5) 0.33 μM.
To explore further the potential of this class of
compound against T. brucei, these observations have
prompted us to synthesise adamantane 2-imidazolines 8
and 9 (Schemes 1 and 2), and their 1-substituted
congeners 14 and 15 (Scheme 3). These compounds
combine two distinct structural components: amidine
moieties, which have been widely shown to display
trypanocidal activity, attached to adamantane, a lipophilic
molecule which could facilitate passage of the new
derivatives across the blood brain barrier.
We have reported that bloodstream forms of
Trypanosoma brucei are susceptible to the anti-influenza
virus drug rimantadine, and to a lesser extent amantadine
[3] (compounds 1 and 2, Fig. 1). This could have
relevance for drug development against HAT, since both
compounds readily cross the blood brain barrier and are
well absorbed from the gastrointestinal tract. Further tests

1402
I. Papanastasiou1, A. Tsotinis, G. B. Foscolos, S. R. Prathalingam, J. M. Kelly
Vol 45
Scheme 2
RESULTS AND DISCUSSION
The synthetic route followed for the preparation of
spiroadamantanimidazolines 8 and 9 is illustrated in
Scheme 1.
NH, I
SCH
NH
CH2 NH2
NH2
S
b
a
N
H
N
H
11
10
7a
N
Scheme 1
R
9c: R=H
9d: R=CH3
c
N
N
H
1
5
CH3
N
C
N
CH2NH2
NHR
1'
4
8 '
7'
3
R'
a
2 '
2
b
9'
N
NHR
Reagents and Conditions: (a) CS2, H2O/EtOH, reflux 1 h and then HCl
(35%), reflux 7 h; (b) CH3I, i-PrOH, reflux 2 h; (c) CH3NH2 or
(CH3)2NH, i-PrOH, 130-140 oC, 50 psi, 40 h.
10 '
3'
6'
5'
4 '
R
7a: R=H
7b: R=CH3
6a: R=H
6b: R=CH3
8a: R=H; R'=H
8b: R=H; R'=CH3
8c: R=CH3; R'=H
8d: R=CH3; R'=CH3
8e: R=H; R'=C6H5
8f: R=CH3; R'=C6H5
Scheme 3
c
1
N
3'
5
2 '
1 '
3
N
4'
1'
C
N
a
CH2 NH2
NHR
1 0'
9'
4
b
8 '
7 '
4
5 '
NH2
CH
3
N
CH
2'
R
2
1
N
5
2
9 '
NHR
6'
7'
8'
1 0'
H
3'
13a: R=H
13b: R=CH
12a: R=H
6'
5'
R
4'
R
3
12b: R=CH
c
3
9a: R=H
9b: R=CH3
14a: R=H; R'=H
14b: R=H; R'=CH
3
3'
9'
14c: R=CH ; R'=H
2 '
1 '
3
4'
3
N
1 0'
4
14d: R=CH ; R'=CH
o
5 '
3
3
Reagents and Conditions: (a) H2/PtO2, gas HCl/EtOH, 55 psi, 90 C, 1.5
NH2
1
N
5
2
14e: R=H; R'=C H
6'
7'
6
5
8'
H
h
and then aq. NaOH; (b) formamidine acetate or acetamidine
hydrochloride or benzamidine hydrochloride, EtOH, r.t., 30-48 h; (c)
BrCN, CH2Cl2, 0 oC and then r.t., 70 h.
14f: R=CH ; R'=C H
3
6
5
R
15a: R=H
15b: R=CH
3
Catalytic hydrogenation of the hydrochloride salts of ꢀ-
aminonitriles 6 [7] under Adams’ conditions provided the
corresponding hydrochloride diamines 7 [8]. These were
converted to their respective bases by adding a solution of
NaOH. Condensation of diamines 7 with formamidine
acetate, acetamidine hydrochloride or benzamidine hydro-
chloride [7] led to the spiroimidazolines 8, whereas
condensation of diamines 7 with cyanogen bromide gave
aminospiroimidazolines 9. The methylamino- and the
dimethylaminoderivatives 9c and 9d were obtained by
cyclizing the diamines 7 with carbon disulfide [8] in the
presence of conc. HCl to give the thione 10. S-
methylation of thione 10 with methyl iodide gave the S-
methyl derivative 11. Displacement of methyl mercaptan
by methylamine or dimethylamine in i-PrOH under
pressure and heating gave amines 9c and 9d (Scheme 2).
The 2-alkyl and 2-amino-5-(1-adamantyl)imidazolines 14
and 15 were prepared from the nitriles 12 [9] in a similar
way as imidazolines 8 and 9 (Scheme 3).
o
Reagents and Conditions: (a) H2/PtO2, gas HCl/EtOH, 55 psi, 90 C,
1.5 h and then aq. NaOH; (b) formamidine acetate or acetamidine
hydrochloride or benzamidine hydrochloride, EtOH; (c) BrCN,
CH2Cl2, 0 oC and then r.t., 70 h.
14a-f and 15a,b, respectively), we observed a range of
trypanocidal activity. For example, compounds 14a and
15a inhibited parasite growth by approximately 50% at 5
μg/ml, whereas 14d and 14f displayed no activity. The
most active compounds tested were 14b, c, e and 15 b
(Table 1). Of these, 14e was found to be at least three
times as effective at killing bloodstream form T. brucei as
rimantadine, with an IC50 close to 2 μM. The results
presented in this paper show that exocyclic imidazolines
have significant activity against bloodstream form T.
brucei. Other adamantane 2-imidazoline derivatives that
we tested exhibited little effect. In the absence of
information on the biological target, it is difficult to be
definitive about the physicochemical parameters
responsible for this lack of activity. The degree of
lipophilicity may be one factor, although it could be that
the rigidness of the spiro arrangement, in relation to the
bulk of adamantane skeleton, hinders the approach
towards the biological target. The adamantane imida-
zoline with the greatest trypanocidal activity was a 2-alkyl
derivative (14e), which we found to be three fold more
effective than rimantadine. By exploring the properties of
other derivatives of this class, it should be possible to
identify compounds that display significantly higher
activity.
The new adamantane derivatives were initially screened
for activity against bloodstream form T. brucei at 5 μg/ml
(15–20 μM).
With the exception of the methylaminospiroimidazoline
derivative (compound 9c), none of the spiroadamantan-
imidazolines (compounds 8a-f, 9a, b, d) had any
significant effect on the parasite at this concentration.
Compound 9c, on the other hand, completely blocked
parasite growth. However, it was ineffective at 1 μg ml-1
and was not assessed further at this stage. With the 2-alkyl
and 2-amino-5(1-adamantyl)imidazolines (compounds

Sep-Oct 2008 Synthesis of Conformationally Constrained Adamantane Imidazolines with Trypanocidal Activity 1403
Table 1
determined. In these experiments, which were performed at least
in triplicate, the densities of untreated cultures increased from
0.25 x 105 to 4 x 106 cells ml-1. After determination of cell
densities at each drug concentration with a hemocytometer
(Weber Scientific International Ltd.), drug sensitivity was
expressed as a percentage of growth of control cells.
Trypanocidal activity of 2-alkyl (14b, c, e) and 2-amino-5-(1-
adamantyl)imidazoline (15b)
Compound
ꢀC50 (μM)
14ba
14ca
7.40 ± 2.28
11.55 ± 0.36
2.13 ± 0.51
6.27 ± 2.04
7.04 ± 0.27
3,5-Dihydrospiro[imidazole-4,2'-tricyclo[3.3.1.1.3,7]decane]
(8a). To a solution of diamine 7a (650 mg, 3.6 mmol) in
absolute ethanol (20 ml) was added formamidine acetate (427
mg, 4.1 mmol). The solution was stirred under an argon
atmosphere at ambient temperature for 48 h. The solvent was
then evaporated under vacuum and the residue was treated with
4% HCl (50 ml). The mixture was taken up with ethyl acetate,
made alkaline with 4% NaOH (50 ml), and extracted with ethyl
acetate. The organic phase was washed with brine, dried
(Na2SO4) and concentrated in vacuo to give 380 mg (56%) of
imidazoline 8a, which was then converted to its fumarate salt;
mpfumarate 161-163 oC (EtOH-Et2O). 1H nmr (DMSO-d6, 400
MHz): ꢀ 1.58-1.75 (m, 12H, 1', 3', 4'eq, 5', 6', 7', 8', 9'eq, 10'-H),
1.99-2.03 (br d, 2H, 4'ax, 9'ax-H), 3.66 (s, 2H, 5-H), 6.42 (s, 2H,
CH= fumarate), 8.34 (s, 1H, 2-H); 13C nmr (DMSO-d6, 50
MHz): ꢀ 25.8 (5'-C), 26.2 (7'-C), 32.3 (4', 9'-C), 33.2 (8', 10'-C),
36.5 (1', 3'-C), 37.0 (6'-C), 54.2 (5-C), 69.6 (4,2'-C), 135.6 (CH=
fumarate), 155.6 (2-C), 168.6 (C=O fumarate). Anal. Calcd. for
C16H22N2O4 (306.4): C, 62.73%; H, 7.24%. Found: C, 62.48%;
H, 7.39%.
14eb
15bc
rimantadineb
Derivatives were tested for in vitro activity against bloodstream form T.
brucei (pH 7.4) and the concentrations that inhibited growth by 50%
(IC50) were calculated. Data are the mean of triplicate experiments +
SEM. The value obtained with rimantadine is shown for comparison.
a fumarate salt; b hydrochloride salt; c hydrobromide salt.
The design of more effective derivatives would be
greatly aided if their target in the trypanosome could be
identified. Channel blocking activity is the only known
mechanism for the therapeutic activity of amantadine and
its derivatives. Targets of these compounds include the
hepatitis C virus encoded protein p7 [10], the potassium
channel of the PBCV-1 chlorella virus [11] and the
transmembrane channel of the N-methyl-D-aspartate
receptor [12]. In the case of influenza virus A infected
cells, the most studied system, the target is the virus-
encoded M2 proton channel. Whether the main antiviral
activity results from physical blockage of the channel, or
by an allosteric effect mediated by binding of the drug to
a site external to the channel, remains to be resolved
[13,14]. It seems reasonable, by analogy with other cases,
to assume that the mechanism of action of these
compounds in trypanosomes involves blockage/
3,5-Dihydro-2-methylspiro[imidazole-4,2'-tricyclo[3.3.1.1.3,7]-
decane] (8b). Imidazoline 8b was prepared by following the
procedure used for the synthesis of 8a, by reacting diamine 7a
with acetamidine hydrochloride. Yield 56%; mpfumarate 170-172
oC (EtOH-Et2O); 1H nmr (DMSO-d6, 400 MHz): ꢀ 1.56-1.75 (m,
12H, 1', 3', 4'eq, 5', 6', 7', 8', 9'eq, 10'-H ), 1.99-2.03 (br d, 2H, 4'ax,
9'ax-H), 2.15 (s, 3H, CH3), 3.62 (s, 2H, 5-H), 6.38 (s, 2H, CH=
fumarate); 13C nmr (DMSO-d6, 50 MHz): ꢀ 12.4 (CH3), 25.8 (5'-
C), 26.2 (7'-C), 32.3 (4', 9'-C), 33.2 (8', 10'-C), 36.5 (1', 3'-C),
37.0 (6'-C), 54.1 (5-C), 69.5 (4,2'-C), 135.6 (CH= fumarate),
165.6 (2-C), 168.6 (C=O fumarate). Anal. Calcd. for C17H24N2O4
(320.4): C, 63.73%; H, 7.55%. Found: C, 63.40%; H, 7.81%.
3,5-Dihydro-3-methylspiro[imidazole-4,2'-tricyclo[3.3.1.1.3,7]-
decane] (8c). Imidazoline 8c was prepared by following the
procedure used for the synthesis of 8a, by reacting diamine 7b
with formamidine acetate. Yield 82%; mpfumarate 158-160 oC
perturbation of
a parasite membrane-localized ion
channel/transporter. This would correlate with our
observations that drug potency appears to be associated an
increase in the lipophilic nature of side chains on the
adamantane ring [4,5].
1
(EtOH-Et2O); H nmr (DMSO-d6, 400 MHz): ꢀ 1.60-1.99 (m,
EXPERIMENTAL
12H, 1', 3', 4'eq, 5', 6', 7', 8', 9'eq, 10'-H ), 2.19-2.22 (br d, 2H, 4'ax,
9'ax-H), 3.39 (s, 3H, CH3), 3.76 (s, 2H, 5-H), 6.42 (s, 2H, CH=
fumarate), 8.20 (s, 1H, 2-H); 13C nmr (DMSO-d6, 50 MHz): ꢀ
26.1 (5', 7'-C), 32.6 (4', 9'-C), 35.0 (8', 10'-C), 35.5 (1', 3'-C),
38.0 (CH3), 38.1 (6'-C), 55.8 (5-C), 72.2 (4,2'-C), 135.2 (CH=
fumarate), 159.2 (2-C), 167.9 (C=O fumarate). Anal. Calcd. for
C17H24N2O4 (320.4): C, 63.73%; H, 7.55%. Found: C, 63.61%;
H, 7.59%.
General
Melting points were determined on a Büchi 530 apparatus and
are uncorrected. Infrared (ir) spectra were recorded on a Perkin-
Elmer 833 spectrophotometer. H NMR spectra were taken in
1
Deuteriochloroform or DMSO-d6 and recorded on a Bruker DRX
400 (400 MHz) spectrometer, and the spectra are reported in ꢀ.
13C NMR spectra were taken at 50 MHz or 100 MHz on a
Bruker AC 200 or Bruker DRX 400 spectrometer, respectively.
Tetramethylsilane was used as internal standard. Microanalyses
were carried out by the Service Central de Microanalyse
(CNRS) France, and the results obtained had a maximum
deviation of ±0.4% from the theoretical value.
Bloodstream-form T. brucei (strain 427) were cultured in 25
cm3 flasks at 37 C in modified Iscove’s medium (pH 7.4) [6].
To establish the extent of activity, parasites were grown for 3
days in the presence of test compounds and the concentrations
which inhibited growth by 50% (IC50) and 90% (IC90) were
3,5-Dihydro-2,3-dimethylspiro[imidazole-4,2'-tricyclo-
[3.3.1.1.3,7]decane] (8d). Imidazoline 8d was prepared by
following the procedure used for the synthesis of 8a, by reacting
diamine 7b with acetamidine hydrochloride. The reaction
mixture was stirred under an argon atmosphere at 65-70o for 30
o
h. Yield 42%; mp 40-41o (mpfumarate 65-67 C, resolidifies at 110
o
oC and melts again at 144-146 C); ir (Nujol): 3419 (H2O) cm-1;
1H nmr (deuteriochloroform, 400 MHz, free base): ꢀ 1.56-1.73
(m, 8H, 4'eq, 8', 9'eq, 10'-H ), 1.84-1.87 (m, 7H, 1', 3', 5', 6', 7'-H,
2-CH3), 2.26-2.30 (br d, 2H, 4'ax, 9'ax-H), 3.15 (s, 3H, N-CH3),
3.54 (s, 2H, 5-H); 13C nmr (deuteriochloroform, 100 MHz, free
o

1404
I. Papanastasiou1, A. Tsotinis, G. B. Foscolos, S. R. Prathalingam, J. M. Kelly
Vol 45
base): ꢀ 16.1 (2-CH3), 26.8 (5'-C), 27.0 (7'-C), 33.2 (4', 9'-C),
35.0 (N-CH3), 35.8 (8', 10'-C), 36.8 (1', 3'-C), 39.0 (6'-C), 64.3
(5-C), 68.9 (4,2'-C), 164.1 (2-C). Anal. Calcd. for C18H26N2O4
(fumarate) x 1 H2ꢀ (352.4): C, 61.34%; H, 8.01%. Found: C,
61.02%; H, 8.01%.
C13H22N3Br (300.2): C, 52.01%; H, 7.38%. Found: C, 51.80%;
H, 7.60%.
1,5-Dihydrospiro[imidazole-4,2'-tricyclo[3.3.1.1.3,7]decan]-
2(3H)-thione (10). To a suspension of diamine 7a (850 mg, 4.7
mmol) in a solution of EtOH:H2O (10 ml, 8/2) was added carbon
disulfide (400 mg, 5.3 mmol) and the reaction mixture was
heated at reflux for 1 h. To the refluxing mixture 2 drops of HCl
(~35%) were added and heating was continued for 7 h. Then, the
suspension was left stirring at ambient temperature for 24 h.
Water was poured onto the mixture, which was filtered and the
residue was washed with water to give 1.01 g (97%) of 10 as an
3,5-Dihydro-2-phenylspiro[imidazole-4,2'-tricyclo[3.3.1.1.3,7]-
decane] (8e). Imidazoline 8e was prepared by following the
procedure used for the synthesis of 8d, by reacting diamine 7a
with benzamidine hydrochloride. Yield 52%; mp 127-129 oC
(mpfumarate 218-220 oC (dec) (EtOH-Et2O). 1H nmr
(deuteriochloroform, 400 MHz, free base): ꢀ 1.69-1.89 (m, 14H,
adamantane-H), 3.78 (s, 2H, 5-H), 5.22 (brs, 1H, 3-H), 7.31-7.39
(m, 3H, 3, 4, 5-Harom), 7.71-7.72 (m, 2H, 2, 6-Harom); 13C nmr
(deuteriochloroform, 100 MHz, free base): ꢀ 26.5 (5'-C), 26.9
(7'-C), 34.1 (4', 9'-C), 34.1 (8', 10'-C), 37.2 (1', 3'-C), 37.5 (6'-C),
64.7 (5-C), 71.9 (4,2'-C), 126.9 (2, 6-Carom), 128.4 (3, 5-Carom),
130.4 (4-Carom), 130.9 (1-Carom), 161.9 (2-C). Anal. Calcd. for
C22H26N2O4 (fumarate) (382.4): C, 69.09%; H, 6.85%. Found: C,
68.85%; H, 6.97%.
o
1
off-white solid; mp 209-211 C; H nmr (deuteriochloroform,
400 MHz): ꢀ 1.60-1.83 (m, 14H, adamantane H ), 3.54 (s, 2H, 5-
H), 6.68 (s, 1H, 3-H), 7.02 (s, 1H, 1-H); 13C nmr (deuterio-
chloroform, 50 MHz): ꢀ 26.1 (5'-C), 26.3 (7'-C), 33.2 (4', 9'-C),
35.1 (8', 10'-C), 36.5 (1', 3'-C), 37.2 (6'-C), 54.6 (5-C), 68.4
(4,2'-C), 181.0 (2-C). Anal. Calcd. for C12H18N2S (222.4): C,
64.82%; H, 8.16%. Found: C, 64.61%; H, 8.33%.
3,5-Dihydro-2-methylthiospiro[imidazole-4,2'-tricyclo-
[3.3.1.1.3,7]decane]hydroiodide (11). To a suspension of thione
10 (2.0 g, 9.0 mmol) in i-PrOH (15 ml) was added dropwise
methyl iodide (1.42 g, 10.0 mmol). The reaction mixture was
heated at reflux for 2 h, the solvent evaporated to half of its
initial volume and anhydrous ether was added. The precipitate
formed was removed by filtration to give 2.1 g (64%) of salt 11;
mp 214-215 oC (EtOH-Et2O). Anal. Calcd. for C13H21N2IS
(364.3): C, 42.86%; H, 5.81%. Found: C, 42.63%; H, 5.98%.
3,5-Dihydro-N-methylspiro[imidazole-4,2'-tricyclo[3.3.1.1.3,7]-
decan]]-2-amine (9c). To a suspension of salt 11 (2.5 g, 6.8
mmol) in i-PrOH (20 ml) in an autoclave was added a solution
of methylamine (2.5 g, 80.6 mmol) in i-PrOH (40 ml). The
3,5-Dihydro-3-methyl-2-phenylspiro[imidazole-4,2'-
tricyclo[3.3.1.1.3,7]decane] (8f). Imidazoline 8f was prepared by
following the procedure used for the synthesis of 8d, by reacting
diamine 7b with benzamidine hydrochloride. Yield 58%; mp 83-
o
o
85 C; mpfumarate 187-188 C (dec) (EtOH - Et2O); mppicrate 180-
o
1
182 C (dec) (MeOH-Et2O); H nmr (deuteriochloroform, 400
MHz, free base): ꢀ 1.68-1.73 (m, 6H, 4'eq, 6', 8'eq, 9'eq, 10'eq-H),
1.82-1.93 (m, 6H, 1', 3', 5', 7', 8'ax, 10'ax-H), 2.25-2.28 (br d, 2H,
4'ax, 9'ax-H), 3.00 (s, 3H, CH3), 3.77 (s, 2H, 5-H), 7.34-7.41 (m,
3H, 3, 4, 5-Harom), 7.62-7.65(m, 2H, 2, 6-Harom); 13C nmr
(deuteriochloroform, 100 MHz, free base): ꢀ 27.0 (5'-C), 27.2
(7'-C), 33.7 (4', 9'-C), 35.2 (8', 10'-C), 35.2 (1', 3'-C), 35.4
(CH3), 38.4 (6'-C), 64.2 (5-C), 68.9 (4, 2'-C), 128.2 (2, 6-Carom),
128.9 (3, 5-Carom), 130.0 (4-Carom), 132.2 (1-Carom), 168.8 (2-C).
Anal. Calcd. for C25H27N5O7 (picrate) (509.5): C, 58.93%; H,
5.34%. Found: C, 58.69%; H, 5.50%.
o
reaction mixture was heated at 130-140 C under a pressure of
50 psi for 40 h. The solvent was then evaporated under vacuum
and the residue dissolved in 4% HCl (50 ml). The solution was
taken up with ether and made alkaline with a solution of 4%
NaOH (50 ml). The aqueous layer was extracted with
chloroform, the organic phase was decolorized by adding
activated charcoal, dried (Na2SO4) and evaporated to give 940
mg (74%) of imidazoline 9c; mp 238-239 oC (CH2Cl2-n-
pentane), mphydrochloride 247-248 oC (EtOH-Et2O); 1H nmr
(deuteriochloroform, 400 MHz, free base): ꢀ 1.62-1.85 (m, 12H,
1', 3', 4'eq, 5', 6', 7', 8', 9'eq, 10'-H ), 1.98-2.01 (br d, 2H, 4'ax, 9'ax-
H), 2.94 (s, 3H, CH3), 3.54 (s, 2H, 5-H); 13C nmr (deuterio-
chloroform, 50 MHz, free base): ꢀ 26.0 (5'-C), 26.4 (7'-C), 29.1
(CH3), 33.2 (4', 9'-C), 34.0 (8', 10'-C), 36.9 (1'-C), 37.1 (6'-C),
52.5 (5-C), 66.4 (4, 2'-C), 77.2 (3'-C), 158.4 (2-C). Anal. Calcd.
for C13H22N3Cl (hydrochloride) (255.8): C, 61.04%; H, 8.67%.
Found: C, 61.40%; H, 8.70%.
3,5-Dihydro-N,N-dimethylspiro[imidazole-4,2'-tricyclo-
[3.3.1.1.3,7]decan]]-2-amine (9d). To a suspension of salt 11
(1.7 g, 4.6 mmol) in i-PrOH (40 ml) in an autoclave was added a
solution of dimethylamine (9.0 ml, 33% in absolute ethanol) and
the reaction mixture was heated at 100 oC under a pressure of 50
psi for 30 h. Following the work up as described for the
preparation of 9c, imidazoline 9d was obtained as a pale yellow
liquid (400 mg, 37%), which was then converted to the fumarate
salt, mp 208-209 oC (EtOH-Et2O); 1H nmr (DMSO-d6, 400
MHz): ꢀ 1.46-1.50 (br d, 2H, 4'eq, 9'eq -H), 1.66-1.69 (m, 1', 3', 5',
6', 7', 8', 10'-H), 2.12-2.16 (br d, 2H, 4'ax, 9'ax-H), 2.95 (s, 6H,
2ꢀCH3), 3.43 (s, 2H, 5-H), 5.62 (br s, 1H, 3-H), 6.32 (s, 2H,
CH= fumarate), 8.08 (s, 1H, CO2H); 13C nmr (DMSO-d6, 50
MHz): ꢀ 25.2 (5'-C), 25.6 (7'-C), 31.3 (4', 9'-C), 33.1 (8', 10'-C),
3,5-Dihydrospiro[imidazole-4,2'-tricyclo[3.3.1.1.3,7]decan]-
2-amine hydrobromide (9a). To a solution of diamine 7a (670
mg, 4.0 mmol) in dichloromethane (10 ml) was added dropwise
a solution of cyanogen bromide (530 mg, 5.0 mmol) in
dichloromethane (30 ml) under ice cooling. The reaction mixture
was stirred at ambient temperature for 70 h, and the solvent was
then evaporated under vacuum to leave a residue, which was
triturated with anhydrous ether. The crystalline compound
formed was filtered and dried to give 560 mg (49%) of salt 9a;
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1
mp 174-176 C (EtOH- Et2O); H nmr (DMSO-d6, 400 MHz): ꢀ
1.64-1.80 (m, 12H, 1', 3', 4'eq, 5', 6', 7', 8', 9'eq, 10'-H ), 1.90-1.93
(brd, 2H, 4'ax, 9'ax-H), 3.46 (s, 2H, 5-H), 7.36 (br s, 2H, NH2),
7.94 (s, 1H, 3-H), 8.78 (s, 1H, 1-H); 13C nmr (DMSO-d6, 50
MHz): ꢀ 25.8 (5'-C), 26.2 (7'-C), 32.8 (4', 9'-C), 33.5 (8', 10'-C),
36.4 (1', 3'-C), 37.0 (6'-C), 52.2 (5-C), 66.5 (4,2'-C), 157.9 (2-
C). Anal. Calcd. for C12H20N3Br (286.2): C, 50.36%; H, 7.04%.
Found: C, 50.16%; H, 7.34%.
3,5-Dihydro-3-methylspiro[imidazole-4,2'-tricyclo[3.3.1.1.3,7]-
decan]-2-amine hydrobromide (9b). Imidazoline 9b was
prepared by the procedure used for the synthesis of 9a, using
diamine 7b as starting material. Yield 79%; mp > 240 oC (EtOH-
1
Et2O); H nmr (DMSO-d6, 400 MHz): ꢀ 1.61-1.93 (m, 12H, 1',
3', 4'eq, 5', 6', 7', 8', 9'eq, 10'-H), 2.20-2.23 (br d, 2H, 4'ax, 9'ax-H),
3.19 (s, 3H, CH3), 3.42 (s, 2H, 5-H), 7.83 (br s, 2H, NH2), 7.88
(s, 1H, 3-H); 13C nmr (DMSO-d6, 50 MHz): ꢀ 26.4 (5', 7'-C),
32.5 (4', 9'-C), 34.1 (CH3), 35.0 (1', 3'-C), 35.6 (8', 10'-C), 38.4
(6'-C), 51.6 (5-C), 70.2 (4, 2'-C), 158.8 (2-C). Anal. Calcd. for

Sep-Oct 2008 Synthesis of Conformationally Constrained Adamantane Imidazolines with Trypanocidal Activity 1405
35.8 (1', 3'-C), 36.6 (6'-C), 38.0 (2ꢀCH3), 51.9 (5-C), 67.0 (4, 2'-
C), 134.9 (CH= fumarate), 157.3 (2-C), 167.8 (C=O fumarate).
Anal. Calcd. for C18H27N3O4 (349.4): C, 61.87%; H, 7.79%.
Found: C, 61.90%; H, 7.90%.
used for 8a, by reacting diamine 13a with benzamidine
hydrochloride. The reaction mixture was stirred under an argon
o
atmosphere at 65-70 ºC for 21 h. Yield 77%, mp 127-129 C;
o
mphydrochloride 205-207 C (dec) (acetone-Et2O); mpfumarate 214-216
4,5-Dihydro-5(1-tricyclo[3.3.1.1.3,7]decyl)-1H-imidazole (14a).
Imidazoline 14a was prepared by the method employed for the
synthesis of 8a, by the reacting diamine 13a with formamidine
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1
oC (dec) (EtOH-Et2O); mppicrate 151-153 C (MeOH-Et2O); H
nmr (deuteriochloroform, 400 MHz, free base): ꢀ 1.39-1.50 (m,
6H, 2´, 8´, 9´-H), 1.56-1.67 (m, 6H, 4´, 6´, 10´-H), 1.93 (br s,
3H, 3´, 5´, 7´-H), 3.44-3.49 (t, J = 9.5 Hz, 1H, 5-H), 3.68-3.70
(d, J = 9.5 Hz, 2H, 4-H), 4.20 (s, 1H, 1-H), 7.32-7.34 (m, 3H, 3,
4, 5- Harom), 7.70-7.72 (m, 2H, 2, 6-Harom); 13C nmr (deuterio-
chloroform, 100 MHz, free base): ꢀ 28.1 (3´, 5´, 7´-C), 35.4 (1´-
C), 37.1 (4´, 6´, 10´-C), 38.3 (2´, 8´, 9´-C), 52.3 (4-C), 69.5 (5-
C), 127.0 (2, 6-Carom), 128.3 (3, 5-Carom), 130.5 (1, 4-Carom), 163.5
(2-C). Anal. Calcd. for C25H27N5O7 (picrate) (509.5): C, 58.93%;
H, 5.34%. Found: C, 58.69%; H, 5.50%.
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1
acetate. Yield 60%; mpfumarate 179-180 C (EtOH-Et2O); H nmr
(DMSO-d6, 400 MHz): ꢀ 1.29-1.48 (m, 6H, 2´, 8´, 9´-H), 1.53-
1.63 (m, 6H, 4´, 6´, 10´-H), 1.91 (br s, 3´, 5´, 7´-H), 3.60-3.75
(m 3H, 4-H, 5-H), 6.40(s, 2H, CH= fumarate), 8.36 (s, 2H, 2-H),
10.22 (br s, 2H, 2ꢀCO2H); 13C nmr (DMSO-d6, 50 MHz): ꢀ 27.5
(3´, 5´, 7´-C), 35.0 (1´-C), 36.5 (4´, 6´, 10´-C), 36.8 (2´, 8´, 9´-
C), 44.1 (4-C), 66.2 (5-C), 135.3 (CH= fumarate), 157.2 (2-C),
168.1 (C=O fumarate). Anal. Calcd. for C17H24N2O4 (320.4): C,
63.73%; H, 7.55%. Found: C, 64.01%; H, 7.85%.
4,5-Dihydro-1-methyl-2-phenyl-5(1-tricyclo[3.3.1.1.3,7]-
decyl)-1H-imidazole (14f). Imidazoline 14f was prepared by the
method used for the synthesis of 8a, by reacting diamine 13b
with benzamidine hydrochloride. The reaction mixture was
4,5-Dihydro-2-methyl-5(1-tricyclo[3.3.1.1.3,7]decyl)-1H-
imidazole (14b). Imidazoline 14b was prepared by the method
used for the synthesis of 8a, by reacting diamine 13b with
acetamidine hydrochloride. The solution was stirred under an
o
stirred under an argon atmosphere at 65-70 C for 24 h. Yield
o
o
o
argon atmosphere at 40 C for 7 h and then at room temperature
70%. mp 75-77 C; mpfumarate 130-132 C (EtOH-Et2O); mppicrate
179-181 oC (MeOH-Et2O); 1H nmr (deuteriochloroform, 400
MHz, free base): ꢀ 1.46-1.54 (m, 6H, 2´, 8´, 9´-H), 1.59-1.68 (m,
6H, 4´, 6´, 10´-H), 1.94 (br s, 3H, 3´, 5´, 7´-H), 2.80 (s, 3H,
CH3), 2.88-2.93 (t, J = 8.0 Hz, 1H, 5-H), 3.76-3.79 (d, J = 8.0
Hz, 2H, 4-H), 7.32-7.34 (m, 3H, 3, 4, 5-Harom), 7.59-7.62(m, 2H,
2, 6-Harom). 13C nmr (deuteriochloroform, 100 MHz, free base): ꢀ
28.1 (3´, 5´, 7´-C), 37.2 (4´, 6´, 10), 37,4 (2´, 8´, 9´-C), 39.4 (1´-
C), 40.4 (CH3), 54.4 (4-C), 74.6 (5-C), 128.2 (2, 6-Carom), 128.6
(3, 5-Carom), 130.0 (4-Carom), 131.4 (1-Carom), 168.9 (2-C). Anal.
Calcd. for C26H29N5O7 (picrate) (523.5): C, 59.65%; H, 5.58%.
Found: C, 59.91%; H, 5.86%.
o
for 42 h. Yield 60%; mpfumarate 150-152 C (EtOH-Et2O); 1H nmr
(DMSO-d6, 400 MHz): ꢀ 1.30-1.48 (br q, 6H, 2´, 8´, 9´-H), 1.54-
1.64 (m, 6H, 4´, 6´, 10´-H), 1.91 (br s, 3H, 3´, 5´, 7´-H), 2.13 (s,
3H, CH3), 3.59-3.72 (m 3H, 4-H, 5-H), 6.36 (s, 2H, CH=
fumarate); 13C nmr (DMSO-d6, 100 MHz): ꢀ 12.1 (CH3), 27.5
(3´, 5´, 7´-C), 35.0 (1´-C), 36.5 (4´, 6´, 10´-C), 37.8 (2´, 8´, 9´-
C), 44.3 (4-C), 66.4 (5-C), 135.6 (CH= fumarate), 167.4 (2-C),
168.4 (C=O fumarate). Anal. Calcd. for C18H26N2O4 (334.4): C,
64.65%; H, 7.84%. Found: C, 64.29%; H, 7.81%.
4,5-Dihydro-1-methyl-5(1-tricyclo[3.3.1.1.3,7]decyl)-1H-
imidazole (14c). Imidazoline 14c was prepared by the method
used for 8a, by reacting diamine 13b with formamidine acetate.
The reaction mixture was stirred under an argon atmosphere at
4,5-Dihydro-5(1-tricyclo[3.3.1.1.3,7]decyl)-1H-imidazole-2-amine
hydrobromide (15a). Imidazoline 15a was prepared from diamine
13a by the method used for 9a. Yield 89%, mphydrobromide 240-241o
(EtOH-Et2O); 1H nmr (DMSO-d6, 400 MHz, hydrobromide): ꢀ
1.28-1.44 (m, 6H, 2´, 8´, 9´-H), 1.53-1.64 (m, 6H, 4´, 6´, 10´-H),
1.91 (br s, 3´, 5´, 7´-H), 3.38-3.49 (m 3H, 4-H, 5-H), 7.49 (s, 2H,
NH2), 7.81 (s, 1H, 1-H), 8.20 (s, 1H, 3-H); 13C nmr (DMSO-d6, 100
MHz, hydrobromide): ꢀ 27.5 (3´, 5´, 7´-C), 35.0 (1´-C), 36.5 (4´, 6´,
10´-C), 37.1 (2´, 8´, 9´-C), 42.4 (4-C), 63.9 (5-C), 159.5 (2-C). Anal.
Calcd. for C13H22N3Br (hydrobromide) (300.2): C, 52.01%; H,
7.38%. Found: C, 51.66%; H, 7.55%.
o
40-45 C for 10 h and then at ambient temperature for 24 h.
Yield 75%; mpfumarate 166-168 Co (EtOH-Et2O); 1H nmr (DMSO-
d6, 400 MHz): ꢀ 1.40-1.55 (m, 6H, 2´, 8´, 9´-H), 1.60 (m, 6H,
4´, 6´, 10´-H), 1.91 (br s, 3H, 3´, 5´, 7´-H), 3.08 (s, 3H, CH3),
3.44-3.49 (t, J = 10.0 Hz 1H, 5-H), 3.72-3.74 (d, J = 10.0 Hz,
2H, 4-H), 6.42 (s, 2H, CH= fumarate), 8.01 (s, 2H, 2-H); 13C
nmr (DMSO-d6, 100 MHz): ꢀ 27.6 (3´, 5´, 7´-C), 36.4 (1´, 4´, 6´,
10´-C), 37.4 (CH3, 2´, 8´, 9´-C), 48.2 (4-C), 71.1 (5-C), 135.3
(CH= fumarate), 160.0 (2-C), 167.9 (C=O fumarate). Anal.
Calcd. for C18H26N2O4 (334.4): C, 64.65%; H, 7.84%. Found: C,
64.39%; H, 7.93%.
4,5-Dihydro-1-methyl-5(1-tricyclo[3.3.1.1.3,7]decyl)-1H-
imidazole-2-amine hydrobromide (15b). Imidazoline 15a was
prepared from diamine 13b by the method used for the synthesis
4,5-Dihydro-1,2-dimethyl-5(1-tricyclo[3.3.1.1.3,7]decyl)-1H-
imidazole (14d). Imidazoline 14d was prepared by following
the procedure employed for the synthesis 8a, by reacting
diamine 13b with acetamidine hydrochloride. The reaction
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1
of 9a. Yield 69%; mphydrobromide > 250 C (EtOH-Et2O); H nmr
(DMSO-d6, 400 MHz, hydrobromide): ꢀ 1.44-1.53 (m, 6H, 2´,
8´, 9´-H), 1.61-1.69 (m, 6H, 4´, 6´, 10´-H), 1.97 (br s, 3´, 5´, 7´-
H), 2.99 (s, 3H, CH3), 3.38-3.41 (m, 1H, 5-H), 3.49-3.50 (m, 2H,
4-H), 7.86 (s, 1H, 3-H), 7.89 (s, 2H, NH2); 13C nmr (DMSO-d6,
100 MHz): ꢀ 27.5 (3´, 5´, 7´-C), 35.8 (CH3, 1´-C), 36.4 (4´, 6´,
10´-C), 37.1 (2´, 8´, 9´-C), 41.8 (4-C), 70.2 (5-C), 159.9 (2-C).
Anal. Calcd. for C14H24N3Br (hydrobromide) (314.3): C,
53.51%; H, 7.70%. Found: C, 53.32%; H, 7.90%.
o
mixture was stirred under an argon atmosphere at 65-70 C for
o
o
28.5 h. Yield 55%; mp 94-96 C; mpfumarate 132-134 C (EtOH-
Et2O); mppicrate 168-170 oC (MeOH-Et2O); 1H nmr (deuterio-
chloroform, 400 MHz, free base): ꢀ 1.38-1.52 (m, 6H, 2´, 8´, 9´-
H), 1.57-1.67 (m, 6H, 4´, 6´, 10´-H), 1.87 (s, 3H, 1-CH3), 1.93
(br s, 3H, 3´, 5´, 7´-H), 2.82 (s, 3H, 2-CH3), 2.84-2.89 (m, 1H, 5-
H), 3.49-3.60 (m, 2H, 4-H); 13C NMR (deuteriochloroform, 100
MHz, free base): ꢀ 14.8 (1-CH3), 28.1 (3´, 5´, 7´-C), 36.9 (1´-C),
36.1 (4´, 6´, 10´-C), 37.2 (2-CH3), 38.3 (2´, 8´, 9´-C), 53.7 (4-C),
73.4 (5-C), 166.0 (2-C). Anal. Calcd. for C21H27N5O7 (picrate)
(461.5): C, 54.66%; H, 5.90%. Found: C, 54.75%; H, 5.70%.
4,5-Dihydro-2-phenyl-5(1-tricyclo[3.3.1.1.3,7]decyl)-1H-
imidazole (14e). Imidazoline 14e was prepared by the method
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