Synthesis and pharmacological evaluation of several ring-contracted amantadine analogs

Article abstract of DOI:10.1016/j.bmc.2008.10.028

The synthesis of several (3-noradamantyl)amines, [(3-noradamantyl)methyl]amines, (3,7-dimethyl-1-bisnoradamantyl)amines, and [(3,7-dimethyl-1-bisnoradamantyl)methyl]amines is reported. They were evaluated against a wide range of viruses and one of them inhibited the cytopathicity of influenza A virus at a concentration similar to that of amantadine. Several of the new polycyclic amines show an interesting activity as NMDA receptor antagonists. A rimantadine analogue displayed significant trypanocidal activity. Moreover, to further characterize the pharmacology of these compounds, their effects on dopamine uptake were also assessed.

Full text of DOI:10.1016/j.bmc.2008.10.028

Bioorganic & Medicinal Chemistry 16 (2008) 9925–9936
Contents lists available at ScienceDirect
Bioorganic & Medicinal Chemistry
journal homepage: www.elsevier.com/locate/bmc
Synthesis and pharmacological evaluation of several ring-contracted
amantadine analogs
b
b
Pelayo Camps a, María D. Duque a, Santiago Vázquez a, , Lieve Naesens , Erik De Clercq ,
Francesc X. Sureda c, Marta López-Querol c, Antoni Camins d, Mercè Pallàs d, S. Radhika Prathalingam e,
John M. Kelly e, Vanessa Romero f, Dolores Ivorra f, Diego Cortés f
*
a Laboratori de Química Farmacèutica (Unitat Associada al CSIC), Facultat de Farmàcia, and Institute of Biomedicine (IBUB), Universitat de Barcelona, Av. Diagonal, 643,
Barcelona E-08028, Spain
b Rega Institute for Medical Research, Katholieke Universiteit Leuven, B-3000 Leuven, Belgium
c Unitat de Farmacologia, Facultat de Medicina i Ciències de la Salut, Universitat Rovira i Virgili, c./St. Llorenç 21, Reus E-43201, Spain
d Unitat de Farmacologia i Farmacognòsia. Facultat de Farmàcia, Institute of Biomedicine (IBUB) and CIBERNED, Universitat de Barcelona, Av. Diagonal, 643, Barcelona E-08028, Spain
e London School of Hygiene and Tropical Medicine, Department of Infectious and Tropical Diseases, Keppel Street, London WC1E 7HT, UK
f Departamento de Farmacología, Facultad de Farmacia, Universidad de Valencia, 46100 Burjassot, Valencia, Spain
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 3 June 2008
Revised 6 October 2008
Accepted 12 October 2008
Available online 17 October 2008
The synthesis of several (3-noradamantyl)amines, [(3-noradamantyl)methyl]amines, (3,7-dimethyl-1-
bisnoradamantyl)amines, and [(3,7-dimethyl-1-bisnoradamantyl)methyl]amines is reported. They were
evaluated against a wide range of viruses and one of them inhibited the cytopathicity of influenza A virus
at a concentration similar to that of amantadine. Several of the new polycyclic amines show an interest-
ing activity as NMDA receptor antagonists. A rimantadine analogue displayed significant trypanocidal
activity. Moreover, to further characterize the pharmacology of these compounds, their effects on dopa-
mine uptake were also assessed.
Keywords:
Amantadine
NMDA receptor antagonist
Influenza
Ó 2008 Elsevier Ltd. All rights reserved.
Memantine
Polycyclic cage compounds
Trypanosomiasis
1. Introduction
ity,5 5 is a MAO-B inhibitor,6 and 6 is a NMDA receptor antagonist
(Fig. 2).7
1-Adamantylamine (amantadine) and
(
a
-methyl-1-adaman-
For more than 20 years two of us (P.C. and S.V.) have worked on
a project aimed at exploring the structure and the reactivity of nor-
adamantane8 and bisnoradamantane derivatives.9 Up to now, our
work on this topic has been done from a purely synthetic point
of view. For example, we have developed several general entries
to these skeletons. However, systematic studies directed towards
the synthesis of biologically active noradamantane and bisnorada-
mantane derivatives have not yet been carried out (Fig. 3).10
tyl)methylamine (rimantadine) have prophylactic and therapeutic
activity in influenza A virus infections.1 Related adamantane deriv-
atives also show antiviral activity.2 Adamantane derivatives are
inexpensive, but resistance against the drugs develops readily
and treatment is frequently complicated by central nervous system
(CNS) side-effects. In fact, amantadine and its 3,5-dimethyl
analogue memantine are NMDA receptor antagonists and are
approved for the treatment of Parkinson’s and Alzheimer’s disease,
respectively.3 Thus, the design of new amantadine-related anti-
influenza agents without CNS side-effects is a highly desirable goal.
Amantadine, rimantadine, memantine, and related polycyclic
amines also possess trypanocidal activity (Fig. 1).4
NH2
R
NH2
Biological activity has also been found in other polycyclic cage
amines. For example, compounds 1ꢀ4 have anti-influenza activ-
R
R = H, amantadine
rimantadine
R = Me, memantine
* Corresponding author. Tel.: +34 934024533; fax: +34 934035941.
E-mail address: svazquez@ub.edu (S. Vázquez).
Figure 1. Amantadine, memantine, and rimantadine.
0968-0896/$ - see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmc.2008.10.028

9926
P. Camps et al. / Bioorg. Med. Chem. 16 (2008) 9925–9936
NH2
Hanti
Hsyn
NH2
NH2
a
b
Hα
NHEt
CH2C6H5
CH2R
Hβ
NH2
N
N
H
1
2
3
4
CH3
7
8a-f
9
ref. 13
d
c
NH2
CH2C6H5
N
O
H
5
6
CH3
CH3
N
N
Figure 2. Polycyclic cage amines with biological activity.
N
H
CH3
10
11
12
Scheme 1. Reageants and conditions: (a) aldehyde, NaBH3CN, acetic acid, meth-
anol, 18 h; 92% for 8a, R = phenyl; 79% for 8b, R = 4-methoxyphenyl; 44% for 8c,
R = 2-methoxyphenyl; 78% for 8d, R = 3-methoxyphenyl; 77% for 8e, R = 4-fluoro-
phenyl; 63% for 8f, R = 2-thienyl; (b) formaldehyde, NaBH3CN, acetic acid, aceto-
nitrile, 4 h; 91%; (c) anhyd Et3N, 1,5-dibromopentane, DMF, 60 °C, 26 h, 48%. (d) H2
(1 atm), Pd/C, ethanol, 89%.
Noradamantane
Bisnoradamantane
Figure 3. Noradamantane and bisnoradamantane.
alkylation of primary amine 7 with 1,5-dibromopentane in 51%
yield (Scheme 1).
It is well known in medicinal chemistry that when drugs con-
tain cyclic systems, it is generally worth synthesizing analogues
where the ring is opened, expanded or contracted by one unit,
because these analogues show similar activity to the parent
compound.11 Tricyclo[3.3.1.03,7]non-3-ylamine [(3-noradaman-
tyl)amine] and tricyclo[3.3.0.03,7]oct-1-ylamine [(1-bisnorada-
mantyl)amine] may be viewed as ring contracted analogs of
amantadine, featuring a skeleton with one and two carbon less
than the model, respectively. For this reason, in this paper, we de-
scribe the preparation of a series of (3-noradamantyl)amines,
(1-bisnoradamantyl)amines and related compounds as well as
the results of their antiviral, trypanocidal, NMDA receptor antago-
nist, and dopamine reuptake inhibitory activities.
Starting from the known amide 13,14 a series of 3-(noradaman-
tyl)methylamines were synthesized. Thus, reduction of amide 13
with LiAlH4 followed by acidic work-up led to the hydrochloride
of amine 14 in 90% yield. Reductive alkylation of 14 with benzalde-
hyde and NaCNBH3 in methanol gave 15 in 77% yield. Reductive
methylation of 15 followed by catalytic hydrogenation led to 19
in high yield. Reductive methylation of 14 with formic acid and
formaldehyde furnished dimethyl derivative 17 in 68% yield. Final-
ly, reaction of 14 with 1H-pyrazol-1-carboxamidine led to guani-
dine 18 in 84% yield (Scheme 2).
On the other hand, starting from the known acid 20,9g we have
prepared amines 21ꢀ23, 25ꢀ28, and 30ꢀ36 using classical meth-
ods in amine chemistry. Although the synthesis of amine 21 from
acid 20 was very low yielding using the classical Schmid’s or Cur-
tius’ reactions (14% and 24% yield, respectively), application of the
Yamada’s modification of the Curtius reaction allowed us to obtain
and fully characterize the hydrochloride of amine 21 in 73% yield.
From this amine, reductive alkylation with benzaldehyde led to
22a in 60% yield. Similarly, reductive alkylation with 2-thiophene-
carbaldehyde led to 22b in 69% yield. Reductive methylation of 22a
followed by catalytic debenzylation furnished secondary amine 28
in high yield. Dimethylated derivative 26 was obtained in 83% yield
by treating amine 21 with excess of formic acid and formaldehyde.
Finally, dibenzylated compound 27 was prepared by double alkyl-
ation of 21 with benzyl chloride in 73% yield (Scheme 3).
2. Results and discussion
2.1. Chemistry
Starting from the known amine 7,10,12 we have prepared norad-
amantane amines 8ꢀ12 using classical methods in amine chemis-
try. Thus, reductive alkylation of 7 with several aromatic aldehydes
afforded secondary amines 8a–f in moderate to high yields. Dime-
thylated derivative 10 was prepared as previously described in the
literature.13 Monomethyl derivative 12 was synthesized from 8a
by reductive alkylation followed by catalytic debenzylation in good
overall yield. Finally, piperidine derivative 11 was prepared by
a
b
e
c
CH3
N
NHCH2C6H5
NH2
Me
CH2C6H5
CONH2
13
14
17
15
16
19
f
d
H
N
CH3
N
NH
NH2
N
H
Me
18
Scheme 2. Reageants and conditions: (a) LiAlH4, THF, reflux, 15 h, 90%; (b) benzaldehyde, NaBH3CN, acetic acid, methanol, 18 h; 77%; (c) formaldehyde, NaBH3CN, acetic acid,
acetonitrile, 4 h; 96%; (d) formaldehyde, formic acid, diethyl ether, 80 °C, 10 h, 68%; (e) anhyd Et3N, 1H-pyrazol-1-carboxamidine hydrochloride, acetonitrile, reflux, 6 h, 70%;
(f) H2 (1 atm), Pd/C, ethanol, 78%.

P. Camps et al. / Bioorg. Med. Chem. 16 (2008) 9925–9936
9927
H3C
CH3
H3C
CH3
H3C
CH3
NH2
H3C
CH3
a
b
c
CH2C6H5
CH2R
N
N
H
CO2H
CH3
21
22a-b
23
20
g
e
f
d
H3C
CH3
H3C
CH3
H3C
CH3
H3C
CH3
H3C
CH3
h
CH2C6H5
NH2
CH3
CH3
O
CH3
N
N
N
H
CH2C6H5
CH3
25
26
27
28
CH3
24
Scheme 3. Reageants and conditions: (a) Diphenylphosphorylazide, Et3N, toluene, reflux, 3 h; then 6 N HCl, reflux, 24 h, 73%; (b) aldehyde, NaBH3CN, AcOH, MeOH, 18 h; 60%
for 22a, R = phenyl; 69% for 22b, R = 2-thienyl; (c) 37% aqueous formaldehyde, NaBH3CN, AcOH, CH3CN, 4 h, 88%; (d) MeLi, anhyd Et2O, 0 °C to reflux, 16 h, 19%; (e) 37%
aqueous formaldehyde, formic acid, Et2O, 80 °C, 10 h, 83%; (f) benzyl chloride, NaI, K2CO3, CH3CN, reflux, 24 h, 41%; (g) H2, Pd/C, EtOH, 89%; (h) NH2OH, NaOH, EtOH; then,
LiAlH4, Et2O, reflux, 16 h, 43%.
Moreover, reaction of 20 with methyllithium gave ketone 24 in
low yield. Reaction of 24 with hydroxylamine followed by reduc-
tion of the obtained oxime with LiAlH4 gave amine 25, a compound
that can be viewed as a ring contracted analog of the antiviral
rimantadine (Scheme 3).
Finally, reduction of the amide 29, easily available from acid 20,
with LiAlH4 followed by acidic work-up gave the hydrochloride of
amine 30 in 70% overall yield. Following a similar sequence of the
previously used with amine 21, amines 31, 32, 33, and 36 were ob-
tained in high yields. Piperidine derivative 34 was obtained by
alkylation of amine 30 with 1,5-dibromopentane in 53% yield. Fi-
nally, reaction of 30 with 1H-pyrazol-1-carboxamidine led to gua-
nidine 35 in 90% yield (Scheme 4).
cacy, toxicity, and resistance. For example, the arsenical drug mel-
arsoprol, which is used to treat late stage disease, can result in a
reactive encephalopathy which kills up to 10% of patients. In the
absence of treatment, HAT is invariably fatal and new drugs are
therefore urgently required. Recently, it was reported that the
anti-influenza virus drug rimantadine was active in vitro against
bloodstream form T. brucei, and that other aminoadamantane
derivatives had enhanced activity.4,16 To extend these observa-
tions, we have tested several new bisnoradamantanes and related
compounds for activity against bloodstream form T. brucei.
The noradamantylamines and [(3-noradamantyl)methyl]amines
described in this paper and the birnoradamantyl derivatives 21, 22a,
23, 27, 28, 32, 34, and 36 were found to have no significant activity
against cultured bloodstream from T. brucei at concentrations up
The structure of all new compounds was confirmed by elemen-
tal analysis or accurate mass measurement, IR, 1H NMR, 13C NMR,
and mass spectral data.
to 5
on growth at 5
dine analog 25 was the most active of the compounds tested and we
established its IC50 (6.02 0.36 M) and IC90 (9.48 2.64 M) val-
ues. Amine 25 was found to be slightly more active than rimantadine
(IC50 = 7.04 0.12 M; IC90 = 13.97 1.68 M) and at least 20 times
more active than amantadine (IC50 > 130 M).
l
g mLꢀ1. Compounds 26, 30, and 31 showed transient effect
l
g mLꢀ1, but cells grew to normal density. Rimanta-
2.2. Trypanocidal activity
l
l
The tsetse fly-transmitted protozoan parasite Trypanosoma bru-
cei is the causative agent of Human African Trypanosomiasis (HAT).
After a major upsurge of the disease in the late 1990s throughout
many parts of sub-Saharan Africa, annual infections have now fall-
en to 70,000 as a result of major surveillance and treatment pro-
grammes.15 However, over 60 million people remain at risk, and
in some areas death rates exceed those from HIV/AIDS and malaria.
The drugs currently available to treat HAT require administration
under medical supervision and are characterized by limited effi-
l
l
l
2.3. NMDA receptor antagonist activity
NMDA receptor antagonists are highly interesting compounds
since these receptors have been involved in several neurodegener-
ative disorders. In fact, memantine is widely used in therapeutics
to slow down the progression of Alzheimer’s disease.17
H3C
CH3
H3C
CH3
H3C
CH3
H3C
CH3
a
b
c
d
CH3
N
20
NHCH2C6H5
NH2
CH2C6H5
CONH2
e
29
30
31
32
g
h
f
H3C
CH3
H3C
CH3
Me
H3C
CH3
H3C
CH3
H
CH3
N
NH
N
N
N
H
Me
33
34
35
36
NH2
Scheme 4. Reageants and conditions: (a) SOCl2, reflux, 2 h; then NH4OH, CHCl3, rt, 15 h, 84%; (b) LiAlH4, THF, reflux, 15 h, 83%; (c) benzaldehyde, NaBH3CN, AcOH, MeOH, rt,
18 h, 68% (d) 37% aqueous formaldehyde, NaBH3CN, AcOH, CH3CN, reflux, 4 h, 70%; (e) 37% aqueous formaldehyde, formic acid, Et2O, 80 °C, 10 h, 61%; (f) Et3N, 1,5-
dibromopentane, DMF, 60 °C, 26 h, 53%; (g) Et3N, 1H-pyrazol-1-carboxamidine, CH3CN, reflux, 6 h, 90%; (h) H2, Pd/C, EtOH, 38 atm, 85%.

9928
P. Camps et al. / Bioorg. Med. Chem. 16 (2008) 9925–9936
Table 2
The activity of the different new polycyclic compounds was as-
sayed on cerebellar granule neurons loaded with the calcium-sen-
sitive probe Fura-2.18 Addition of glutamate or NMDA (100
M) in
the presence of glycine (10 M) produced a robust and stable in-
Antiviral activity against influenza virus in MDCK cells.
Cytotoxicity (MCCb in MDCK)
a
l
Compound
Antiviral EC50 in
lM
l
A/H1N1
A/H3N2
B
crease in intracellular calcium that was challenged with cumula-
tive additions of the compounds to be tested. Although all the
noradamantyl derivatives and several of the bisnoradamantyl com-
pounds were able to inhibit calcium entry through NMDA recep-
tors, none of the compounds was more potent than memantine
against glutamate- or NMDA-induced calcium increase in cerebel-
lar granule neurons (Table 1).
In general, the bisnoradamantane derivatives are more potent
as NMDA receptor antagonists than the noradamantane amines.
For example, amine 21 is 4 times more potent as NMDA receptor
antagonist than 3-noradamantylamine, 7, and the guanidine deriv-
ative 35 is 3.5 times more potent than its corresponding norada-
mantyl analog, 18.
Bisnoradamantylamines were usually more active than their
corresponding (bisnoradamantyl)methylamine analogs as exem-
plified by the pairs 21/30, 26/33, and 28/36, and alkyl substitution
causes a reduction in the potency (e.g., series 21/28/26 or 30/36/
33). The guanidine derivative 35 was the more potent compound,
being 10 times more potent than amantadine and 5 times less po-
tent than memantine. Attempts to synthesize a guanidine deriva-
tive from 21 were not successful.
7
14
196 109
36 11
77 21
29 18
26.5 22.5
52 16
2.7 1.1
0.85 1.1
NAc
NA
NA
NA
>575
>530
>100
>100
Amantadine
Rimantadine
a
EC50: compound concentration producing 50% antiviral effect, as determined by
microscopic scoring of the virus-induced cytopathic effect.
b
MCC, minimum cytotoxic concentration, or compound concentration causing
minimal changes in cell morphology.
c
NA, not active at subtoxic concentrations, or at the highest concentration tested.
line coronavirus, parainfluenza-3 virus, respiratory syncytial virus,
vesicular stomatitis virus, sindbis virus, or Punta Toro virus; or the
non-enveloped RNA viruses Coxsackievirus B4 and Reovirus-1. In
the influenza virus assays, only compounds 7 and 14, two primary
amines, displayed reasonable activity against the influenza A/
H1N1 and A/H3N2 subtypes, secondary and tertiary amines were
not active (Table 2). The antiviral data obtained by microscopy
were confirmed by a colorimetric cell viability assay (data not
shown). The highest selectivity was noted with compound 7 tested
against the A/H3N2 subtype. As anticipated, all compounds proved
to be inactive against influenza B virus, which is known to be
insensitive to amantadine and rimantadine.
2.4. Antiviral activity
2.5. Dopamine
None of the synthesized compounds was found to have antiviral
activity against the enveloped DNA viruses herpes simplex virus
(type 1 or type 2) or vaccinia virus; the enveloped RNA viruses fe-
It is known that amantadine increases extracellular dopamine
levels by antagonism of the NMDA receptor,19 although the exact
mechanism has not been fully elucidated. As several of our new
amines showed NMDA receptor antagonist activity with IC50 simi-
lar or even lower than amantadine, we have determined their ef-
fect on [3H]dopamine uptake in rat striatal synaptosomes (Table
Table 1
IC50 (l
M) values for selected polycyclic amines as NMDA antagonists.a,b
Compound
Glutamate (100
lM)
NMDA (100 lM)
3). At the concentration tested (100 lM), several of the compounds
7
8c
8d
>500
>500
>500
92 19
92 30
87 46
were able to inhibit [3H]dopamine uptake in some manner, show-
8f
9
10
11
12
15
16
18
19
21
22a
22b
25
26
28
30
384 130
>500
>500
>500
205 25
>500
>500
453 113
>500
274 68
143 62
204 13
94 29
185 69
NEd
17
36
173
45
65 15
138 16
178 25
25
71
23 2.2
70 9.3c
80 15
37 10
153 18
4
2
4
4
Table 3
Effect of compounds on dopamine uptake (at 100 lM).
Compound
[3H]Dopamine uptake, % control SEM (n = 3)
7
8a
8b
8c
8d
8e
8f
9
10
11
12
14
15
16
17
18
19
21
25
26
27
28
30
34
84.9 1.6
31.7 6.1
63.9 4.2
58.3 2.9
45.8 0.5
81.1 8.5
47.7 4.2
47.2 3.4
71.3 2.6
68.5 2.3
65.2 4.8
50.1 3.5
57.9 4.6
45.0 2.5
62.5 1.2
118.7 7.3
76.3 3.1
54.8 14.3
72.2 10.9
75.2 6.9
74.3 5.3
74.6 6.6
39.1 2.1
39.8 7.4
57.3 6.7
47.4 2.0
53.7 2.6
8
6
35
3
>500
128 39
47 15c
160 24c
7.1 0.4
92 29
31
32
35
NAe
NA
104 31
358 130
55 12
Amantadine
Memantine
1.5 0.1
a
Functional data were obtained from primary cultures of cerebellar granule
neurons using the method described in Section 4 by measuring the intracellular
calcium concentration. Cells were challenged with glutamate (2nd column) or
NMDA (3rd column) as indicated. Data shown are means SEM of at least three
separate experiments carried out on three diferent batches of cultured cells.
b
Compounds 8a, 8b, 8e, 14, 17, 23, 33, 34, and 36 were found to have low
potency as NMDA receptor antagonists (IC50 > 200 mM), while compound 27 was
found not active at the highest concentration tested.
36
c
Only 60% maximal inhibition due to insolubility in the assay buffer.
Amantadine
Memantine
d
NE, not evaluated.
e
NA, not active at the highest concentration tested.

P. Camps et al. / Bioorg. Med. Chem. 16 (2008) 9925–9936
9929
ing similar values of inhibition than amantadine or memantine.
However, it seems that no correlation exists with their potency
as antagonists at the NMDA receptor. Probably, other mechanisms
are being involved in the regulation of dopamine release, like dif-
ferent activities at D2 receptors or through inhibition at the dopa-
mine transporter.
with silica gel 60 F254 were used and spots were visualized with UV
light and/or 1% aqueous solutions of KMnO4.
4.1.2. N-Benzyl(tricyclo[3.3.1.03,7]non-3-yl)amine hydrochloride
(8aꢁHCl)
To a solution of 7ꢁHCl (600 mg, 3.46 mmol) in MeOH (10 mL),
NaBH3CN (95%, 445 mg, 6.72 mmol), AcOH (0.3 mL), and benzalde-
hyde (0.5 mL, 4.92 mmol) were added and the mixture was stirred
at room temperature for 2 h. An additional portion of NaBH3CN
(95%, 220 mg, 3.33 mmol) and benzaldehyde (0.25 mL, 2.46 mmol)
were added, the mixture was stirred at room temperature overnight
and concentrated to dryness. Water (20 mL) was added to the resi-
due, the suspension was basified with 1 N NaOH and was extracted
with EtOAc (3ꢂ 10 mL). The combined organic extracts were washed
with brine (2ꢂ 10 mL), dried with anhyd Na2SO4, filtered, and con-
centrated in vacuo. The residue was taken in EtOAc and the amine
8a was precipitated as its hydrochloride (839 mg, 92% yield) by add-
ing an excess of Et2OꢁHCl. The analytical sample of 8aꢁHCl was ob-
tained by crystallization from MeOH, mp >300 °C (dec). IR: 2942,
2757, 2656, 2600, 2428, 2363, 2340, 1458, 1425, 1331, 728,
694 cmꢀ1. 1H NMR 1.64 (dquint, J = 13.2 Hz, J0 = 2.5 Hz, 1H, 9-Hsyn),
3. Conclusions
In summary, we have synthesized and fully characterized sev-
eral (3-noradamantyl)amines, (3-noradamantyl)methylamines,
(3-bisnoradamantyl)amines, and (3-bisnoradamantyl)methylam-
ines. Although these compounds were less potent than memantine
against NMDA-induced calcium increase in cerebellar granule neu-
rons, several compounds were more potent than amantadine, the
bisnoradamantane amines being more potent than the correspond-
ing noradamantane amines. Interestingly, none of those com-
pounds showed antiviral activity, while compound 14, that
displayed reasonable activity against the influenza A/H1N1 and
A/H3N2 subtypes, showed no NMDA receptor antagonist activity.
Moreover, none of the compounds were significantly more potent,
at the tested concentration, than amantadine or memantine as
inhibitors of the dopamine uptake.
1.73 (dd, J = 11.0 Hz, J0 = 2.5 Hz, 2H, 6(8)-H ], 1.75 (overlapped dm,
a
1H, 9-Hanti), 2.04 [m, 2H, 6(8)-Hb], 2.10 [m, 2H, 2(4)-Hb], 2.14 [dd,
J = 10.5 Hz, J0 = 2.0 Hz, 2H, 2(4)-H ], 2.45 [broad s, 2H, 1(5)-H], 2.48
a
[tt, J = 7.0 Hz, J0 = 1.5 Hz, 1H, 7-H], 4.21 (s, 2H, CH2C6H5), 7.44ꢀ7.50
[complex signal, 3H, Ar-3(5)-H, and Ar-4-H], 7.55 [m, 2H, Ar-2(6)-
H]. 13C NMR 35.0 (CH2, C9), 38.8 [CH, C1(5)], 43.66 (CH, C7), 43.73
[CH2, C6(8)], 46.3 [CH2, C2(4)], 48.8 (CH2, CH2–C6H5), 71.9 (C, C3),
130.3 [CH, Ar-C3(5)], 130.6 (CH, Ar-C4), 130.9 [CH, Ar-C2(4)], 133.2
(C, Ar-C1). MS (EI), m/z (%): 228 ([M+H]+, 30), 227 (20), 185
([MꢀC3H6]Å+, 83), 184 (52), 91 (C7H7+, 100). Anal. Calcd for
C16H21NꢁHCl (263.81): C, 72.85; H, 8.41; N, 5.31; Cl, 13.44. Found:
C, 72.90; H, 8.31; N, 5.18; Cl, 13.96.
Amantadine displays both anti-influenza activity and NMDA
receptor antagonism. As selectivity is usually highly desirable in
drugs, the amines herein reported open the way for the design of
new aminopolycyclic compounds with selective anti-influenza or
NMDA receptor antagonist activity.
Interestingly, amine 25, that is 2.5 times more potent than
amantadine as NMDA receptor antagonist, also displayed trypano-
cidal activity, being slightly more active than rimantadine and at
least 21 times more active than amantadine.
Guanidine 35 is a polycyclic cage compound with selective
NMDA receptor antagonist activity (IC50 = 7.1
ral and trypanocidal activities.
lM) without antivi-
4.1.3. N-(4-Methoxybenzyl)(tricyclo[3.3.1.03,7]non-3-yl)amine
hydrochloride (8bꢁHCl)
The synthesis and pharmacological evaluation of more polycy-
clic cage amines is in progress to reach more potent and selective
derivatives.
From 7ꢁHCl (173 mg, 1.00 mmol), NaBH3CN (95%, 142 mg,
2.15 mmol), AcOH (0.3 mL), and 4-methoxybenzaldehyde
(0.18 mL, 1.48 mmol) in MeOH (7 mL) and following the above pro-
cedure, 8bꢁHCl was obtained (233 mg, 79% yield). The analytical
sample of 8bꢁHCl was obtained by crystallization from 2-propanol,
mp >300 °C (dec). IR: 2926, 2794, 2751, 2716, 2678, 2592, 2578,
2443, 1613, 1588, 1514, 1460, 1440, 1333, 1306, 1272, 1248, 1178,
4. Experimental
4.1. Chemistry
1040, 993, 826, 814, 767 cmꢀ1
.
1H NMR 1.63 (dquint, J = 13.1 Hz,
J0 = 2.5 Hz, 1H, 9-Hsyn), 1.72 [dd, J = 11.5 Hz, J0 = 2.2 Hz, 2H, 6(8)-
4.1.1. General
H ], 1.74 (overlapped dm, 1H, 9-Hanti), 2.00–2.09 [complex signal,
a
4H, 2(4)-Hb, and 6(8)-Hb], 2.12 [dd, J = 10.5 Hz, J0 = 2.2 Hz, 2H, 2(4)-
Melting points were determined in open capillary tubes. Unless
otherwise stated, NMR spectra were recorded in CD3OD in the fol-
lowing spectrometers: 1H NMR (500 MHz), 13C NMR (100.6 MHz).
Chemical shifts (d) are reported in ppm related to internal tetra-
methylsilane (TMS). Assignments given for the NMR spectra are
based on DEPT, COSY 1H/1H, and HETCOR 1H/13C (HSQC and HMBC
sequences for one bond and long range 1H/13C heterocorrelations,
respectively) and NOESY experiments for selected compounds.
For the MS and GC/MS analyses the sample was introduced directly
or through a gas chromatograph. For GC/MS analyses a 30-m col-
umn [5% diphenyl–95% dimethylpolysiloxane, conditions: 10 psi,
initial temperature: 35 °C (2 min), then heating at a range of
8 °C/min till 300 °C, then isothermic at 300 °C] was used. The elec-
tron impact (70 eV) or chemical ionization (CH4) techniques were
used. Only significant ions are given: those with higher relative ra-
tio, except for the ions with higher m/z values. Accurate mass mea-
surements were obtained using ESI technic. Absorption values in
the IR spectra (KBr) are given as wave-numbers (cmꢀ1). Column
chromatography was performed on silica gel 60 Å (35–70 mesh).
For the thin-layer chromatography (TLC) aluminum-backed sheets
H ], 2.43–2.46 [complex signal, 3H, 1(5)-H, and 7-H], 3.82 (s, 3H,
a
OCH3), 4.14 (s, 2H, CH2–C6H5), 7.01 [m, 2H, Ar-3(5)-H], 7.45 [m,
2H, Ar-2(6)-H]. 13C NMR (75.4 MHz) 35.0 (CH2, C9), 38.8 [CH,
C1(5)], 43.7 (CH, C7), 43.7 [CH2, C6(8)], 46.4 [CH2, C2(4)], 48.1
(CH2, CH2–C6H5), 55.9 (CH3, OCH3), 71.6 (C, C3), 115.6 [CH, Ar-
C3(5)], 124.9 (C, Ar-C1), 132.4 [CH, Ar-C2(6)], 162.1 (C, Ar-C4). MS
(EI), m/z (%): 257 (MÅ+, 38), 214 ([MꢀC3H7]+, 48), 121
[(CH3OC6H4CH2)+, 100]. Anal. Calcd for C17H23NOꢁ1.05 HCl (295.7):
C, 69.06; H, 8.20; N, 4.74; Cl, 12.59. Found: C, 68.69; H, 8.19; N,
4.70; Cl, 12.73.
4.1.4. N-(2-Methoxybenzyl)(tricyclo[3.3.1.03,7]non-3-yl)amine
hydrochloride (8cꢁHCl)
From 7ꢁHCl (173 mg, 1.00 mmol), NaBH3CN (95%, 142 mg,
2.15 mmol), AcOH (0.3 mL), and 2-methoxybenzaldehyde
(0.18 mL, 1.46 mmol) in MeOH (7 mL) and following the procedure
described for 8a, 8cꢁHCl was obtained (128 mg, 44% yield). The ana-
lytical sample of 8cꢁHCl was obtained by crystallization from 2-pro-
panol, mp 262ꢀ263 °C. IR: 2956, 2921, 2717, 2678, 2582, 2433,

9930
P. Camps et al. / Bioorg. Med. Chem. 16 (2008) 9925–9936
1605, 1584, 1496, 1466, 1456, 1446, 1435, 1332, 1292, 1253, 1121,
1050, 1031, 771, 752 cmꢀ1 1H NMR 1.63 (dquint, J = 13.4 Hz,
J0 = 2.5 Hz, 1H, 9-Hsyn), 1.73 [dd, J = 11.0 Hz, J0 = 2.5 Hz, 2H, 6(8)-
Anal. Calcd for C16H20NFꢁ1.1HClꢁ0.33H2O (291.45): C, 65.94; H,
7.53; N, 4.81; Cl, 13.38; F, 6.52. Found: C, 66.01; H, 7.67; N, 4.83;
Cl, 13.31; F, 6.34.
.
H ], 1.76 (overlapped dm, 1H, 9-Hanti), 1.99–2.05 [complex signal,
a
2H, 6(8)-Hb], 2.07 [dm, J = 10.5 Hz, 2H, 2(4)-Hb], 2.14 [dd, J = 10.5
4.1.7. N-(2-Thenyl)(tricyclo[3.3.1.03,7]non-3-yl)amine hydrochloride
(8fꢁHCl)
Hz, J0 = 2.5 Hz, 2H, 2(4)-H ], 2.44 [broad s, 2H, 1(5)-H], 2.49 (tt,
a
J = 6.7 Hz, J0 = 1.7 Hz, 1H, 7-H), 3.94 (s, 3H, OCH3), 4.19 (s, 2H,
CH2C6H5), 7.03 (td, J = 7.7 Hz, J0 = 1.0 Hz, 1H, Ar-5-H), 7.11 (d,
J = 8.5 Hz, 1H, Ar-3-H), 7.42 (dd, J = 7.2 Hz, J0 = 1.7 Hz, 1H, Ar-6-H),
7.46 (ddd, J = 8.4 Hz, J0 = 7.4 Hz, J00 = 1.6 Hz, 1H, Ar-4-H). 13C NMR
35.0 (CH2, C9), 38.7 [CH, C1(5)], 43.5 (CH, C7), 43.8 [CH2, C6(8)],
44.4 (CH2, CH2C6H5), 46.3 [CH2, C2(4)], 56.1 (CH3, OCH3), 71.9 (C,
C3), 112.1 (CH, Ar-C3), 121.1 (C, Ar-C1), 122.0 (CH, Ar-C5), 132.6
(CH, Ar-C6), 132.7 (CH, Ar-C4), 159.4 (C, Ar-C2). MS (EI), m/z (%):
257 (MÅ+, 35), 214 ([MꢀC3H7]+, 57), 121 ([CH3OC6H4CH2]+, 100), 91
(55). Anal. Calcd for C17H23NOꢁHCl (293.83): C, 69.49; H, 8.23; N,
4.77; Cl, 12.07. Found: C, 69.21; H, 8.29; N, 4.80; Cl, 12.32.
From 7ꢁHCl (150 mg, 0.86 mmol), NaBH3CN (95%, 125 mg,
1.89 mmol), AcOH (0.3 mL), and 2-thiophenecarbaldehyde
(0.12 mL, 1.37 mmol) in MeOH (8 mL) and following the procedure
described for 8a, 8fꢁHCl was obtained (145 mg, 66% yield). The ana-
lytical sample of 8fꢁHCl was obtained by crystallization from
EtOAc, mp 278 °C (dec). IR: 2939 2917, 2790, 2747, 2442, 1589,
1457, 1440, 1429, 1334, 1256, 1194, 1126, 984, 854, 695 cmꢀ1
.
1H NMR 1.64 (dquint, J = 13.0 Hz, J0 = 2.5 Hz, 1H, 9-Hsyn), 1.73 (dd,
J = 11.0 Hz, J0 = 2.5 Hz, 2 H, 6(8)-H ), 1.75 (overlapped dm, 1H, 9-
a
Hanti), 2.00–2.05 [m, 2H, 6(8)-Hb], 2.07 [dm, J = 10.0 Hz, 2H, 2(4)-
Hb], 2.12 [dd, J = 10.0 Hz, J0 = 2.5 Hz, 2H, 2(4)-H ], 2.44 [broad s,
a
2H, 1(5)-H], 2.46 (overlapped tt, J = 8.5 Hz, J0 = 2.0 Hz, 1H, 7-H),
4.46 (s, 2H, CH2C4H3S), 7.12 (dd, J = 5.0 Hz, J0 = 4.0 Hz, 1H, Ar-4-
H), 7.34 (dm, J = 3.5 Hz, 1H, Ar-3-H), 7.57 (dd, J = 5.0 Hz, J0 =
1.0 Hz, 1H, Ar-5-H). 13C NMR 35.0 (CH2, C9), 38.8 [CH, C1(5)],
42.6 (CH2, CH2C4H3S), 43.7 (CH, C7), 43.7 [CH2, C6(8)], 46.2 [CH2,
C2(4)], 71.8 (C, C3), 128.7 (CH, Ar-C4), 129.2 (CH, Ar-C5), 131.5
(CH, Ar-C3), 134.0 (C, Ar-C1). MS (EI), m/z (%): 233 (MÅ+, 56), 190
([MꢀC3H7]+, 78), 106 (45), 97 [(C4H3SCH2)+, 100]. Anal. Calcd for
C14H19NSꢁ1.05HClꢁ0.25H2O (276.17): C, 60.89; H, 7.50; N, 5.07; S,
11.61; Cl, 13.48. Found: C, 60.99; H, 7.59; N, 5.09; S, 11.28; Cl, 13.49.
4.1.5. N-(3-Methoxybenzyl)(tricyclo[3.3.1.03,7]non-3-yl)amine
hydrochloride (8dꢁHCl)
From 7ꢁHCl (173 mg, 1.00 mmol), NaBH3CN (95%, 142 mg,
2.15 mmol), AcOH (0.3 mL), and 3-methoxybenzaldehyde (0.18 mL,
1.45 mmol) in MeOH (7 mL) and following the procedure described
for 8a, 8dꢁHCl was obtained (228 mg, 78% yield). The analytical sam-
ple of 8dꢁHCl was obtained by crystallization from 2-propanol, mp
>257 °C (dec). IR: 3002, 2923, 2873, 2792, 2734, 2708, 2678, 2585,
2446, 1606, 1599, 1588, 1494, 1460, 1437, 1331, 1306, 1272, 1256,
1174, 1035, 851, 794 cmꢀ1 1H NMR 1.63 (dquint, J = 13.3 Hz,
.
4.1.8. N-Benzyl-N-methyl(tricyclo[3.3.1.03,7]non-3-yl)amine
hydrochloride (9ꢁHCl)
J0 = 2.6 Hz, 1H, 9-Hsyn), 1.72 (broad d, J = 11.0 Hz, 2H, 6(8)-H ), 1.74
a
(overlapped dm, 1H, 9-Hanti), 2.05 [m, 2H, 6(8)-Hb], 2.09ꢀ2.14 [com-
To a solution of 8aꢁHCl (395 mg, 1.5 mmol) in acetonitrile
(10 mL), formaldehyde (1.18 mL, 37% wt. in water solution,
15 mmol), and NaBH3CN (95%, 238 mg, 4.28 mmol) were added.
The mixture was stirred for 30 min at room temperature, AcOH
(0.3 mL) was added and the mixture was stirred at room tempera-
ture for 2 h. An additional portion of NaBH3CN (95%, 283 mg,
4.28 mmol) was added and the mixture was further stirred at room
temperature for 2 h. The mixture was concentrated to dryness, 2 N
NaOH (20 mL) was added and the suspension was extracted with
CH2Cl2 (3ꢂ 20 mL). The combined organic phases were washed
with H2O (2ꢂ 20 mL), dried with anhyd Na2SO4, filtered, and con-
centrated in vacuo. The residue was taken in EtOAc and the amine
9 was precipitated as its hydrochloride (327 mg, 91% yield) by add-
ing an excess of Et2OꢁHCl. The analytical sample of 9ꢁHCl was ob-
tained by crystallization from 2-propanol, mp 258ꢀ259 °C (dec).
IR: 3042, 2927, 2872, 2850, 2608, 2553, 2520, 2487, 2472, 2391,
1498, 1458, 1405, 1332, 994, 748, 696 cmꢀ1. 1H NMR 1.64 (dquint,
J = 13.5 Hz, J0 = 2.6 Hz, 1H, 9-Hsyn), 1.78 (dd, J = 11.5 Hz, J0 = 3.0 Hz,
plex signal, 4H, 2(4)-H , and 2(4)-Hb], 2.44 [broad s, 2H, 1(5)-H], 2.50
a
(tt, J = 1.6 Hz, J0 = 6.7 Hz, 1H, 7-H), 3.84 (s, 3H, OCH3), 4.18 (s, 2H,
CH2C6H5), 7.00 (ddd, J = 8.5 Hz, J0 = 2.5 Hz, J00 = 1.0 Hz, 1H, Ar-4-H),
7.12 (dt, J = 7.5 Hz, J0 = 1.0 Hz, 1H, Ar-6-H), 7.17 (t, J = 2.5 Hz, 1H,
Ar-2-H), 7.38 (pseudo t, J = 8.0 Hz, 1H, Ar-5-H). 13C NMR 35.0 (CH2,
C9), 38.8 [CH, C1(5)], 43.66 (CH, C7), 43.72 [CH2, C6(8)], 46.3 [CH2,
C2(4)], 48.7 (CH2, CH2C6H5), 55.9 (CH3, OCH3), 71.9 (C, C3), 116.0
(CH, Ar-C4), 116.4 (CH, Ar-C2), 122.8 (CH, Ar-C6), 131.5 (CH, Ar-
C5), 134.5 (C, Ar-C1), 161.8 (C, Ar-3). MS (EI), m/z (%): 258 ([M+H]+,
31), 257 (MÅ+, 25], 215 ([MꢀC3H6]Å+, 55), 214 ([MꢀC3H7]+, 41), 121
([CH3OC6H4CH2]+, 100], 91 (17). Anal. Calcd for C17H23NOꢁ1.1HClꢁ
0.1H2O (299.28): C, 68.23; H, 8.18; N, 4.68; Cl, 13.03. Found: C,
68.13; H, 8.34; N, 4.69; Cl, 12.91.
4.1.6. N-(4-Fluorobenzyl)(tricyclo[3.3.1.03,7]non-3-yl)amine
hydrochloride (8eꢁHCl)
From 7ꢁHCl (150 mg, 0.86 mmol), NaBH3CN (95%, 125 mg,
1.89 mmol), AcOH (0.3 mL), and 4-fluorobenzaldehyde (0.14 mL,
1.31 mmol) in MeOH (8 mL) and following the procedure described
for 8a, 8eꢁHCl was obtained (186 mg, 77% yield). The analytical sam-
ple of 8eꢁHCl was obtained by crystallization from ethyl acetate, mp
>300 °C (dec). IR: 2947, 2920, 2797, 2754, 2580, 2446, 1604, 1590,
1514, 1457, 1440, 1429, 1334, 1232, 1163, 1127, 830, 778 cmꢀ1. 1H
NMR 1.64 (dquint, J = 13.2 Hz, J0 = 2.5 Hz, 1H, 9-Hsyn), 1.73 (dd,
2 H, 6(8)-H ), 1.79 (dm, J = 13.5 Hz, 1H, 9-Hanti), 2.09–2.29 [com-
a
plex signal, 6 H, 6(8)-Hb, 2(4)-H , and 2(4)-Hb], 2.50 [broad s,
a
2 H, 1(5)-H], 2.73 (s, 3 H, N-CH3), 2.75 (tt, J = 7.0 Hz, J0 = 2.0 Hz,
1H, 7-H), 4.09 (d, J = 11.7 Hz, 1H) and 4.60 (d, J = 11.7 Hz, 1H)
(CH2–C6H5), 7.49–7.53 [complex signal, 3 H, Ar-3(5)-H and Ar-4-
H], 7.59 [m, 2 H, Ar-2(6)H]. 13C NMR 35.2 (CH2, C9), 36.5 (CH3,
NCH3), 38.8 [CH, C1(5)], 42.8 (CH, C7), 43.8 [CH2, C6(8)], 44.4
(broad signal, CH2) and 45.4 (broad signal, CH2) (C2 and C4), 58.1
(CH2, CH2C6H5), 79.9 [C, C3), 130.3 (CH, Ar-C3(5)], 131.1 (CH, Ar-
C4), 131.3 (C, Ar-C1), 132.4 [C, Ar-C2(6)]. MS (EI), m/z (%): 241
(MÅ+, 70), 199 (25), 198 ([MꢀC3H7]+, 100), 185 (40), 120 (17), 91
(96). Anal. Calcd for C17H23NꢁHCl (277.84): C, 73.49; H, 8.71; N,
5.04; Cl, 12.76. Found: C, 73.61; H, 8.74; N, 5.04; Cl, 12.99.
J = 11.0 Hz, J0 = 2.5 Hz, 2H, 6(8)-H ), 1.76 (overlapped dm,
a
1H, 9-Hanti), 2.00-2.06 [m, 2H, 6(8)-Hb], 2.08 [dm, J = 10.5 Hz, 2H,
2(4)-Hb], 2.13 [dd, J = 10.2 Hz, J0 = 1.7 Hz, 2H, 2(4)-H ], 2.45 [broad
a
s, 2H, 1(5)-H], 2.47 [overlapped tt, J = 6.7 Hz, J0 = 1.7 Hz, 1H, 7-H],
4.21 (s, 2H, CH2–C6H5), 7.22 (tt, J = 8.7 Hz, J0 = 2.2 Hz, 2H, Ar-3(5)-
H), 7.58 (m, 2H, Ar-2(6)-H). 13C NMR 35.0 (CH2, C9), 38.8 [CH,
C1(5)], 43.67 (CH, C7), 43.72 [CH2, C6(8)], 46.3 [CH2, C2(4)], 48.0
2
4.1.9. N-(Tricyclo[3.3.1.03,7]non-3-yl)piperidine hydrochloride
(11ꢁHCl)
(CH2, CH2–C6H5), 71.8 (C, C3), 117.1 [CH, d, JCF = 22.4 Hz,
3
Ar-C3(5)], 129.3 (C, Ar-C1), 133.3 [CH, d, JCF = 9.0 Hz, Ar-C2(6)],
1
164.8 (C, d, JCF = 247.7 Hz, Ar-C4). MS (EI), m/z (%): 245 (MÅ+, 32),
To a solution of 7ꢁHCl (173 mg, 1.00 mmol) in DMF (2.5 mL), an-
hyd Et3N (0.4 mL, 2.9 mmol) was added and the suspension was
203 (16), 202 ([MꢀC3H7]+, 100), 109 ([FC6H4CH2]+, 100), 106 (20).

P. Camps et al. / Bioorg. Med. Chem. 16 (2008) 9925–9936
9931
stirred at room temperature for 2 h. 1,5-Dibromopentane (0.17 mL,
1.2 mmol) was added and the mixture was heated at 60 °C for 26 h.
To the cold mixture, water (15 mL) was added and the solution was
washed with EtOAc (3ꢂ 10 mL). The aqueous phase was basified
with 2 N NaOH (5 mL) and extracted with ethyl acetate
(3ꢂ10 mL). The combined organic extracts were washed with
water (3ꢂ 10 mL), dried with anhyd Na2SO4, filtered and excess
of Et2OꢁHCl was added. The solution was concentrated in vacuo
to dryness to give 11ꢁHCl (117 mg, 48% yield). The analytical sam-
ple of 11ꢁHCl was obtained by crystallization from MeOH/Et2O, mp
>264 °C (dec). IR: 2941, 2930, 2871, 2851, 2634, 2530, 2451, 2401,
C
10H17NꢁHCl (187.71): C, 63.99; H, 9.66; N, 7.46; Cl, 18.89. Found:
C, 64.07; H, 9.66; N, 7.43; Cl, 18.97.
4.1.12. N-Benzyl[(tricyclo[3.3.1.03,7]non-3-yl)methyl]amine
hydrochloride (15ꢁHCl)
From 14ꢁHCl (500 mg, 2.67 mmol), MeOH (10 mL), NaBH3CN
(95%, 380 mg, 5.74 mmol), AcOH (0.3 mL), benzaldehyde (0.4 mL,
3.92 mmol), an additional portion of NaBH3CN (95%, 190 mg,
2.87 mmol), and benzaldehyde (0.2 mL, 1.96 mmol) and following
the procedure described for 8a, 15ꢁHCl was obtained (567 mg,
77% yield). The analytical sample of 15ꢁHCl was obtained by crys-
tallization from EtOAc, mp >277 °C (dec). IR: 2931, 2865, 2781,
1471, 1455, 1351, 1333, 1187, 1124, 1016, 992, 858, 708 cmꢀ1 1H
.
NMR 1.54 (dm, J = 13.0 Hz, 1H, 40-Hax), 1.62 (dquint, J = 13.3 Hz, 1H,
1588, 1446, 750, 700 cmꢀ1
6H, 2(4)-Hb, 6(8)-H , and 9-Hsyn and 9-Hanti], 1.76–1.81 [complex
.
1H NMR 1.58–1.70 [complex signal,
9-Hsyn), 1.72 [dd, J = 11.5 Hz, J0 = 3.0 Hz, 2H, 6(8)-H ], 1.74 (dm,
a
a
J = 13.0 Hz, 1H, 9-Hanti), 1.84-2.02 [complex signal, 9 H, 6(8)-Hb,
2(4)-Hb, 40-Heq, 30(50)-Hax, and 30(50)-Heq], 2.15 [dm, J = 10.0 Hz,
signal, 4H, 2(4)-H and 6(8)-Hb], 2.15 [t, J = 7.0 Hz, 1H, 7-H], 2.27
a
[broad s, 2H, 1(5)-H], 3.11 (s, 2H, CH2–N), 4.28 (s, 2H, CH2C6H5),
7.45–7.50 [complex signal, 3H, Ar-4-H and Ar-3(5)-H], 7.55–7.57
[m, 2H, Ar-2(6)-H]. 13C NMR 35.7 (CH2, C9), 39.0 [CH, C1(5)], 44.0
(CH, C7), 44.4 [CH2, C6(8)], 47.8 [CH2, C2(4)], 48.4 (C, C3), 53.1
(CH2, CH2C6H5), 55.9 (CH2, CH2N), 130.3 [CH, Ar-C3(5)], 130.8
(CH, Ar-C4), 131.5 [CH, Ar-C2(6)], 132.0 (C, Ar-C1). MS (EI), m/z
(%): 241 (MÅ+, 6), 240 ([MꢀH]+, 8), 150 [(C10H16N)+, 10], 120 (54),
106 [(C7H8N)+, 58), 91 [(C7H7)+, 100]. Anal. Calcd for
C17H23Nꢁ1.1HClꢁ0.1H2O (283.3): C, 72.08; H, 8.65; N, 4.94; Cl,
13.77. Found: C, 72.03; H, 8.56; N, 4.85, Cl, 13.94.
2H, 2(4)-H ], 2.44 [broad signal, 2H, 1(5)-H], 2.65 [tt, J = 6.7 Hz,
a
J0 = 1.8 Hz, 1H, 7-H], 3.05 [broad t, J = 12.0 Hz, 2H, 20(60)-Hax], 3.51
13
[d, J = 12.0 Hz, 2H, 20(60)-Heq]. C NMR 23.1 (CH2, C40), 24.6 [CH2,
C30(50)], 35.2 (CH2, C9), 38.7 [CH, C1(5)], 42.0 (CH, C7), 43.7 [CH2,
C6(8)], 44.8 [CH2, C2(4)], 51.0 [CH2, C20(60)], 78.8 (C, C3). MS (EI),
m/z (%): 205 (MÅ+, 15), 163 (14), 162 ([MꢀC3H7]+, 100), 149 (26).
Anal. Calcd for C14H23NꢁHCl (241.80): C, 69.54; H, 10.00; N, 5.79.
Found: C, 69.60; H, 10.0; N, 5.78.
4.1.10. N-Methyl(tricyclo[3.3.1.03,7]non-3-yl)amine hydrochloride
(12ꢁHCl)
4.1.13. N-Benzyl-N-methyl[(tricyclo[3.3.1.03,7]non-3-yl)methyl]amine
hydrochloride (16ꢁHCl)
A solution of 9ꢁHCl (275 mg, 0.99 mmol) and 5% Pd/C (50% in
water, 10 mg) in absolute EtOH (25 mL) was hydrogenated at
1 atm for 24 h. The suspension was filtered, the residue was
washed with EtOH, and the organic layer was concentrated in
vacuo to give a solid. Crystallization from MeOH/Et2O gave 12ꢁHCl
(165 mg, 89% yield), mp 165ꢀ166 °C. IR: 2947, 2922, 2870, 2856,
2763, 2728, 2692, 2587, 2516, 2458, 1466, 1420, 1348, 1332,
From 15ꢁHCl (465 mg, 1.67 mmol), acetonitrile (10 mL), formal-
dehyde (1.31 mL, 37% wt. in water solution, 16.7 mmol), and two
portions of NaBH3CN (95%, 314 mg, 4.75 mmol) and following the
procedure described for 9, the amine 16 was obtained (411 mg,
96% yield). Its hydrochloride was obtained by adding an excess of
Et2OꢁHCl to a solution of the amine in EtOAc, followed by concen-
tration in vacuo to dryness. The analytical sample of 16ꢁHCl was
obtained by crystallization from EtOAc, mp 251ꢀ252 °C. IR: 3042,
2924, 2865, 2698, 2641, 2550, 2530, 1458, 1423, 1337, 1085,
1311, 1258, 1160, 1111, 1094, 1060, 1018, 996, 630 cmꢀ1 1H
.
NMR 1.61 (dquint, J = 13.0 Hz, J0 = 2.5 Hz, 1H, 9-Hsyn), 1.71 (dd,
J = 12.0 Hz, J0 = 2.5 Hz, 2H, 6(8)-H ), 1.74 (overlapped m, 1H,
a
9-Hanti), 1.96–2.03 [complex signal, 6H, 6(8)-Hb, 2(4)-H , and
906, 745, 701 cmꢀ1
.
1H NMR 1.46 [d, J = 9.0 Hz, 1H, 2-H or 4-
a
a
2(4)-Hb], 2.42 [complex signal, 3H, 1(5)-H, and 7-H], 2.68 (s, 3H,
N-CH3). 13C NMR 29.1 (CH3, N-CH3), 34.9 (CH2, C9), 38.7 [CH,
C1(5)], 43.1 (CH, C7), 43.8 [CH2, C6(8)], 45.8 [CH2, C2(4)], 71.5 (C,
C3). MS (EI), m/z (%): 151 (M+, 15), 108 ([MꢀC3H7]+, 100). Anal.
Calcd for C10H17NꢁHClꢁ0.33H2O (193.66): C, 62.02; H, 9.71; N,
7.23. Found: C, 62.13; H, 9.63; N, 7.20.
H ], 1.59ꢀ1.70 [complex signal, 4H, 6-H , 8-H , 9-Hsyn, and 9-Hanti],
a
a
a
1.71ꢀ1.78 [complex signal, 3H, 4-H or 2-H , 6-Hb, and 8-Hb],
a
a
1.87 [m, 2 H, 2-Hb and 4-Hb], 2.10 [t, J = 6.7 Hz, 1H, 7-H], 2.27
(broad s, 1H) and 2.30 (broad s, 1H) (1-H and 5-H), 2.94 (s, 3 H,
CH3–N), 3.32 (d, J = 13.5 Hz, 1H, CHaN), 3.46 (d, J = 13.5 Hz, 1H,
CHbN), 4.37 (d, J = 12.2 Hz, 1H, CHaC6H5), 4.43 (d, J = 12.2 Hz, 1H,
CHbC6H5), 7.50–7.52 [complex signal, 3H, Ar-4-H and Ar-3(5)-H],
7.59 [m, 2H, Ar-2(6)H]. 13C NMR 35.5 (CH2, C9), 39.1 (CH) and
39.4 [CH, C1 and C5], 43.0 (CH3, CH3–N), 44.0 (CH2, C6, and C8),
46.0 (CH, C7), 48.6 (C, C3), 48.8 (CH2, C2, and C4), 62.8 (CH2,
CH2–C6H5), 65.1 (CH2, CH2–N), 130.4 [CH, Ar-C3(5)], 130.9 (C,
Ar-C1), 131.4 (CH, Ar-C4), 132.6 [CH, Ar-C2(6)]. MS (EI), m/z (%):
255 (MÅ+, 10), 135 (17), 134 ([C6H5CH2N(CH3)@CH2]+, 100), 120
([C6H5CH@NHCH3]+, 34), 91 [(C7H7)+, 89]. Anal. Calcd for
C18H25NꢁHCl (291.86): C, 74.07; H, 8.98; N, 4.80; Cl, 12.15. Found:
C, 74.15; H, 8.96; N, 4.81; Cl, 12.43.
4.1.11. [(Tricyclo[3.3.1.03,7]non-3-yl)methyl]amine
hydrochloride (14ꢁHCl)
To a cold (0 °C) solution of 13 (600 mg, 3.64 mmol) in anhyd
THF (50 mL), LiAlH4 (443 mg, 11.1 mmol) was added and the sus-
pension was heated under reflux for 15 h. The suspension was
cooled (ice bath), carefully basified with 10 N NaOH (10 mL), and
stirred for 1 h at room temperature. The precipitate was filtered
and washed with CH2Cl2 (3ꢂ 25 mL). The combined filtrate and
washings were dried with anhyd Na2SO4, filtered, and excess of
Et2OꢁHCl was added. The solution was concentrated in vacuo to
give a solid that was crystallized from MeOH/Et2O to give 14ꢁHCl
(613 mg, 90% yield), mp >300 °C (dec). IR: 3019, 2926, 2867,
4.1.14. N,N-Dimethyl[(tricyclo[3.3.1.03,7]non-3-yl)methyl]amine
hydrochloride (17ꢁHCl)
1597, 1499, 1384, 1337, 1116, 981, 864 cmꢀ1
.
1H NMR 1.61ꢀ1.72
To a cold (0 °C) solution of 14 (128 mg, 0.68 mmol) in Et2O
(5 mL), formaldehyde (1.38 mL, 37% wt. in water solution,
17.6 mmol) and, dropwise, formic acid (1.17 mL, 30.5 mmol) were
added and the mixture was stirred at 80 °C for 10 h. To the cold
mixture Et2O (15 mL) was added, 5 N NaOH (5 mL) was added
dropwise and the suspension was stirred at room temperature
for 15 min. The organic layer was separated and the aqueous phase
was extracted with Et2O (4ꢂ 10 mL). The combined organic phases
were dried with anhyd Na2SO4, filtered, and an excess of Et2OꢁHCl
(complex signal, 6H, 9-Hsyn, 9-Hanti, 6(8)-H , and 2(4)-Hb], 1.75
a
[dd, J = 10.5 Hz, J0 = 3.0 Hz, 2H, 2(4)-H ], 1.81 [m, 2H, 6(8)-Hb],
a
2.18 [t, J = 6.7 Hz, 1H, 7-H], 2.29 [broad signal, 2H, 1(5)-H], 3.08
(s, 2H, CH2N). 13C NMR 35.8 (CH2, C9), 38.9 [CH, C1(5)], 43.2 (CH,
C7), 44.6 [CH2, C6(8)], 47.4 [CH2, C2(4)], 48.2 (CH2, CH2N), 48.8
(C, C3). MS (EI), m/z (%): 153 (24), 152 ([M+H]+, 36], 151 (20),
135 [(C10H15)+, 53], 134 (70), 119 (29), 96 (45), 95 (59), 94 (33),
93 (57), 92 (100), 91 (58), 79 (74), 77 (40). Anal. Calcd for

9932
P. Camps et al. / Bioorg. Med. Chem. 16 (2008) 9925–9936
was added. Concentration in vacuo gave 17ꢁHCl (100 mg, 68%
yield). The analytical sample of 17ꢁHCl was obtained by crystalliza-
tion from MeOH/Et2O, mp >260 °C (dec). IR (KBr): 2930, 2915,
2868, 2847, 2681, 2570, 2468, 2360, 1471, 1413, 1338, 1306,
The organic layer was separated, the aqueous layer was washed
with Et2O (3ꢂ 5 mL) and the water was removed in a freeze–dryer
giving 21ꢁHCl as a white solid (296 mg, 73% yield). The analytical
sample was obtained by crystallization from water, mp
210ꢀ211 °C. IR: 2959, 2945, 2891, 2863, 2765, 2685, 2579, 1602,
1225, 1062, 971, 946 cmꢀ1
.
1H NMR 1.62ꢀ1.71 [complex signal,
4H, 9-Hsyn, 9-Hanti, and 6(8)-H ], 1.71ꢀ1.76 [dm, J = 10.5 Hz, 2H,
1493, 1480, 1460, 1308, 1285, 1163, 984 cmꢀ1 1H NMR 1.20 (s,
.
a
2(4)-Hb], 1.83 [m, 2H, 6(8)-Hb], 1.87 [dd, J = 10.5 Hz, J0 = 3.0 Hz,
6H, C3(7)-CH3), 1.44 [dd, J = 8.5 Hz, J0 = 3.0 Hz, 2H, 4(6)-H ],
a
2H, 2(4)-H ], 2.19 [t, J = 6.7 Hz, 1H, 7-H], 2.32 [broad signal, 2H,
1.70ꢀ1.73 [complex signal, 4H, 2(8)-H , and 2(8)-Hb], 1.75 [dd,
a
a
1(5)-H], 2.95 [s, 6H, N(CH3)2], 3.38 (s, 2H, CH2N). 13C NMR 35.7
(CH2, C9), 39.2 [CH, C1(5)], 44.1 [CH2, C6(8)], 45.5 (CH3, CH3N),
46.0 (CH, C7), 48.3 [CH2, C2(4)], 48.6 (C, C3), 67.4 (CH2, CH2N).
MS (EI), m/z (%): 179 (MÅ+, 16), 91 (7), 79 (8), 77 (7), 58
([CH2@N(CH3)2]+, 100). Anal. Calcd for C12H21Nꢁ1.05HClꢁ0.25H2O
(222.09): C, 64.90; H, 10.23; N, 6.31; Cl, 16.76. Found: C, 64.77;
H, 10.42; N, 6.32; Cl, 16.70.
J = 8.5 Hz, J0 = 3.0 Hz, 2H, 4(6)-Hb], 2.34 [t, J = 3.0 Hz, 1H, 5-H],
4.85 (s, mobile H). 13C NMR 16.4 [CH3, C3(7)-CH3], 44.1 (CH, C5),
48.1 [C, C3(7)], 53.8 [CH2, C4(6)], 56.7 [CH2, C2(8)], 61.4 (C, C1).
MS (EI), m/z (%): 152 ([M+H]+, 3), 151 (MÅ+, 2), 138 (14), 137 (12),
124 (27), 123 (25), 111 (57), 110 (88), 109 (53), 97 (81), 96
(100), 95 (70), 94 (29), 91 ([C7H7+], 23), 82 (36), 81 (30), 79 (26),
77 (36), 67 (24), 55 (44), 53 (35). Anal. Calcd for C10H17NꢁHCl
(187.71): C, 63.99; H, 9.67; N, 7.46; Cl, 18.89. Found: C, 63.71; H,
9.70; N, 7.48; Cl, 18.88.
4.1.15. N-[(Tricyclo[3.3.1.03,7]non-3-yl)methyl]guanidine
hydrochloride (18ꢁHCl)
To a cold (0 °C) solution of 14ꢁHCl (150 mg, 0.8 mmol) in acetoni-
trile (2.5 mL), anhyd Et3N (0.2 mL, 1.45 mmol), and 1H-pyrazol-1-
carboxamide hydrochloride (140 mg, 0.94 mmol) were added. The
suspension was heated at 70 °C for 6 h and cooled at 0 °C for 24 h.
The precipitate was filtered and washed with cold acetonitrile (2ꢂ
5 mL) to give 18ꢁHCl (129 mg, 70% yield). The above product was ta-
ken in EtOAc, excess Et2OꢁHCl was added, and the solvent was elim-
inated in vacuo. The analytical sample of 18ꢁHCl was obtained by
crystallization from MeOH/Et2O, mp 298ꢀ299 °C. IR (KBr): 3357,
3262, 3169, 2926, 2861, 1664, 1623, 1578, 1458, 1356, 1094,
4.1.18. N-Benzyl-3,7-dimethyl(tricyclo[3.3.0.03,7]oct-1-yl)amine
hydrochloride (22aꢁHCl)
To a solution of 21ꢁHCl (770 mg, 4.11 mmol) in MeOH (15 mL),
NaBH3CN (95%, 585 mg, 8.86 mmol), AcOH (0.3 mL), and benzalde-
hyde (653 mg, 6.16 mmol) were added, and the mixture was stir-
red at room temperature for 18 h. The solution was concentrated
to dryness, water (30 mL) was added to the residue and the mix-
ture was extracted with Et2O (3ꢂ 25 mL). The combined organic
extracts were washed with 2 N NaOH (3ꢂ 25 mL) and brine (2ꢂ
25 mL), dried (anhyd Na2SO4) and concentrated in vacuo. The res-
idue was subjected to column chromatography (silica gel; hexane/
EtOAc, 97/3) to give amine 22a (594 mg, 60% yield). An analytical
sample of 22aꢁHCl was obtained by adding an excess of Et2OꢁHCl
to a solution of 22a in EtOAc and filtration of the formed precipi-
tate, mp >258 °C (dec). IR: 2957, 2934, 2917, 2911, 2759, 2739,
2732, 2725, 2626, 2619, 2578, 2423, 1459, 1452, 1308, 1160,
690 cmꢀ1
.
1H NMR 1.61ꢀ1.68 [complex signal, 6H, 6(8)-H , 2(4)-
a
Hb, 9-Hsyn, and 9-Hanti], 1.72 [dd, J = 10.7 Hz, J0 = 2.7 Hz, 2H, 2(4)-
H ], 1.81 [m, 2H, 6(8)-Hb], 2.12 [t, J = 6.7 Hz, 1H, 7-H], 2.26 [broad
a
s, 2H, 1(5)-H], 3.30 (s, 2H, CH2N). 13C NMR (75.4 MHz) 36.1 (CH2,
C9), 38.8 [CH, C1(5)], 42.8 (CH, C7), 44.8 [CH2, C6(8)], 47.7 [CH2,
C2(4)], 49.9 (CH2, CH2N), 50.2 (C, C3), 159.1 (C, C guanidine). MS
(EI), m/z (%): 194 (12), 193 (MÅ+, 60), 150 ([MꢀC3H7]+, 24), 93 (21),
92 (30), 91 (44), 79 (36), 77 (29), 72 [(C2H6N3)+, 49], 60 ([CH6N3]Å+,
100). Anal. Calcd for C11H19N3ꢁHCl (229.75): C, 57.51; H, 8.77; N,
18.29; Cl, 15.43. Found: C, 57.65; H, 8.88; N, 18.23; Cl, 15.68.
1028, 731, 693 cmꢀ1 1H NMR 1.23 (s, 6H, C3(7)-CH3), 1.50 [dd,
.
J = 9.0 Hz, J0 = 3.0 Hz, 2 H, 4(6)-H ], 1.79 [dd, J = 9.0 Hz, J0 = 3.0 Hz,
a
2H, 4(6)-Hb], 1.82–1.86 [complex signal, 4H, 2(8)-H , and 2(8)-
a
Hb], 2.51 [t, J = 3.0 Hz, 1H, 5-H], 4.21 (s, 2H, CH2C6H5), 4.85 (s, mo-
bile H), 7.42ꢀ7.48 [complex signal, 3H, Ar-3(5)-H, and Ar-4-H],
7.52 [dd, J = 8.0 Hz, J0 = 2.0 Hz, 2H, Ar-2(6)-H]. 13C NMR 16.4 [CH3,
C3(7)-CH3], 43.6 (CH, C5), 47.8 [C, C3(7)], 49.6 (CH2, CH2–C6H5),
53.6 [CH2, C4(6)], 54.9 [CH2, C2(8)], 68.2 (C, C1), 130.3 [CH, Ar-
C3(5)], 130.6 (CH, Ar-C4), 130.8 (CH, Ar-C2(6)], 133.1 (C, Ar-C1).
MS (EI), m/z (%): 241 (MÅ+, 2), 227 (3), 226 (3), 213 (6), 200 (34),
199 (35), 91 ([C6H5CH2]+, 100). Anal. Calcd for C17H23NꢁHCl
(277.83): C, 73.49; H, 8.71; N, 5.04; Cl, 12.76. Found: C, 73.83; H,
8.78; N, 5.02; Cl, 12.92.
4.1.16. N-Methyl[(tricyclo[3.3.1.03,7]non-3-yl)methyl]amine
hydrochloride (19ꢁHCl)
From 16ꢁHCl (267 mg, 0.91 mmol), 5% Pd/C (50% in water,
10 mg), and absolute EtOH (30 mL) and following the procedure
described for 12, 19ꢁHCl (143 mg, 78% yield) was obtained after
crystallization from MeOH/Et2O, mp >224 °C (dec). IR: 2931,
2866, 2770, 2435, 1668, 1611, 1460, 1430, 1398, 1338, 1302,
1154, 1028, 732 cmꢀ1
.
1H NMR 1.61ꢀ1.73 [complex signal, 6H,
2(4)-Hb, 6(8)-H , 9-Hsyn
, and 9-Hanti], 1.75 [dd, J = 10.5 Hz,
a
J0 = 3.0 Hz, 2H, 2(4)-H ], 1.81 [m, 2H, 6(8)-Hb], 2.19 [t, J = 6.7 Hz,
4.1.19. N-(2-Thenyl)-3,7-dimethyl(tricyclo[3.3.0.03,7]oct-1-yl)amine
hydrochloride (22bꢁHCl)
a
1H, 7-H], 2.30 [broad s, 2H, 1(5)-H], 2.75 (s, 3H, CH3N), 3.16 (s,
2H, CH2–N). 13C NMR 35.0 (CH3, CH3N), 35.7 (CH2, C9), 39.0 [CH,
C1(5)], 43.7 (CH, C7), 44.5 [CH2, C6(8)], 47.7 [CH2, C2(4)], 48.5 (C,
C3), 58.6 (CH2, CH2–N). MS (EI), m/z (%): 166 (13), 165 (MÅ+, 100),
164 ([MꢀH]+, 48), 135 (20), 134 (87), 108 (54), 93 (46), 92 (86),
91 (55), 79 (60), 77 (39). Anal. Calcd for C11H19NꢁHClꢁ0.25H2O
(206.24): C, 64.06; H, 10.02; N, 6.79. Found: C, 64.02; H, 10.23;
N, 6.86.
From 21ꢁHCl (187.7 mg, 1.00 mmol), NaBH3CN (95%, 198 mg,
3 mmol), acetic acid (0.3 mL), and 2-thiophenecarbaldehyde
(0.15 mL, 1.65 mmol) in methanol (10 mL) and following the above
procedure, 22bꢁHCl (196 mg, 69% yield) was obtained. The analyt-
ical sample of 22bꢁHCl was obtained by crystallization from MeOH/
Et2O, mp >255 °C (dec). IR: 3062, 2952, 2919, 2887, 2727, 2689,
2549, 2451, 1583, 1477, 1440, 1375, 1307, 1280, 1247, 1159,
1068, 1007, 937, 855, 837, 731, 712, 701 cmꢀ1 1H NMR 1.23 (s,
.
4.1.17. 3,7-Dimethyl(tricyclo[3.3.0.03,7]oct-1-yl)amineꢁHCl
(21ꢁHCl)
6 H, C3(7)-CH3), 1.49 [dd, J = 8.5 Hz, J0 = 3.0 Hz, 2H, 4(6)-H ], 1.79
a
[dd, J = 8.5 Hz, J0 = 3.0 Hz, 2H, 4(6)-Hb], 1.84 [complex signal, 4H,
To a solution of acid 20 (389 mg, 2.16 mmol) in toluene
(6.5 mL), Et3N (0.4 mL, 2.9 mmol), and diphenylphosphorylazide
(875 mg, 3.18 mmol) were added and the mixture was heated un-
der reflux for 3 h. The cold (ice-bath) solution was washed with
cold 1 N HCl (10ꢂ 5 mL). Then, 6 N HCl (9 mL) was added to the or-
ganic solution and the mixture was heated under reflux for 24 h.
2(8)-H , and 2(8)-Hb], 2.51 [t, J = 3.0 Hz, 1H, 5-H], 4.46 (s, 2H,
a
CH2N), 4.86 (s, mobile H), 7.11 (dd, J = 5.0 Hz, J0 = 4.0 Hz, 1H, Ar-
4-H), 7.33 (dm, J = 3.5 Hz, 1H, Ar-3-H), 7.56 (dd, J = 5.0 Hz,
J0 = 1.0 Hz, 1H, Ar-5-H). 13C NMR 16.4 [CH3, C3(7)-CH3], 43.5
(CH2, CH2N), 43.6 (CH, C5), 47.8 [C, C3(7)], 53.6 [CH2, C4(6)], 54.9
[CH2, C2(8)], 68.0 (C, C1), 128.7 (CH, Ar-C4), 129.2 (CH, Ar-C5),

P. Camps et al. / Bioorg. Med. Chem. 16 (2008) 9925–9936
9933
131.4 (CH, Ar-C3), 134.0 (C, Ar-C1). MS (EI), m/z (%): 247 (MÅ+, 2),
233 (3), 219 (7), 206 (50), 205 (30), 192 (11), 97 ([C4H3SCH2]+,
100). Anal. Calcd for C15H21NSꢁ1.1HClꢁ0.1H2O (289.30): C, 62.27;
H, 7.77; N, 4.84; S, 11.08; Cl, 13.48. Found: C, 62.25; H, 7.69; N,
4.85; S, 10.95; Cl, 13.07.
tion (ice-bath) was added to a cold solution (ice bath) of concd HCl
(0.64 mmol, 7.72 mmol) and water (3.5 mL). The obtained precipi-
tate was filtered, washed with cold water (2ꢂ 2 mL) and dried in
vacuo over P4O10 to give the title oxime (135 mg, 74% yield) that
was used without further purification in the next step. IR: 3234,
2949, 2881, 1667, 1446, 1371, 1018, 918, 893, 775 cmꢀ1
.
4.1.20. N-Benzyl-N,3,7-trimethyl(tricyclo[3.3.0.03,7]oct-1-yl)amine
hydrochloride (23ꢁHCl)
4.1.21.3. 1-(3,7-Dimethyltricyclo[3.3.0.03,7]oct-1-yl)ethylamine
hydrochloride (25ꢁHCl). To a suspension of LiAlH4 (110 mg,
From a solution of 22aꢁHCl (635 mg, 2.29 mmol), acetonitrile
(15 mL), formaldehyde (1.81 mL, 37% wt. in water solution,
23 mmol), two portions of NaBH3CN (95%, 455 mg, 6.88 mmol)
and following the procedure described for 9, the amine 23
(516 mg, 88.5% yield) was obtained. An analytical sample of 23ꢁHCl
was obtained by adding an excess of Et2OꢁHCl to a solution of 23 in
EtOAc followed by filtration of the obtained precipitate, mp
>228 °C (dec). IR: 2952, 2886, 2680, 2439, 2372, 1456, 1310, 749,
2.90 mmol) in anhyd Et2O (3 mL) a solution of the above oxime
(135 mg, 0.70 mmol) in anhyd THF (2 mL) was added dropwise
and the mixture was heated under reflux for 16 h. To the cold mix-
ture, water (0.1 mL, 5.55 mmol) was added dropwise and the sus-
pension was stirred at room temperature for 1 h. The formed
precipitate was filtered through CeliteÒ and washed with Et2O
(3ꢂ 10 mL). The filtrate was dried (anhyd Na2SO4), an excess of
Et2OꢁHCl was added and the precipitate was filtered to give 25ꢁHCl
(66 mg, 44% global yield from 24), mp >278 °C (dec). IR: 2952,
2932, 2881, 2567, 1601, 1511, 1479, 1458, 1386, 1320, 1292,
705, 695 cmꢀ1
.
1H NMR 1.25 [s, 6H, C3(7)-CH3], 1.56 [dd,
J = 9.0 Hz, J0 = 3.0 Hz, 2H, 4(6)-H ], 1.83 [dd, J = 9.0 Hz, J0 = 3.0 Hz,
a
2H, 4(6)-Hb], 1.92–1.95 [complex signal, 4H, 2(8)-H , and 2(8)-
a
Hb], 2.71 (s, 3H, CH3N), 2.74 [t, J = 3.0 Hz, 1H, 5-H], 4.09 (broad sig-
nal, 1H) and 4.61 (broad signal, 1H) (CH2C6H5), 4.84 (s, mobile H),
7.49ꢀ7.51 [complex signal, 3H, Ar-3(5)-H and Ar-4-H], 7.53ꢀ7.56
[m, 2H, Ar-2(6)-H]. 13C NMR 16.5 [CH3, C3(7)-CH3], 37.2 (CH3,
CH3N), 43.3 (CH, C5), 47.6 (CH2, CH2C6H5), 53.5 [CH2, C4(6)], 53.7
[CH2, C2(8)], 58.7 [C, C3(7)], 76.2 (C, C1), 130.3 [CH, Ar-C3(5)],
131.1 (CH, Ar-C4), 131.2 (C, Ar-C1), 132.1 [CH, Ar-C2(6)]. MS (EI),
m/z (%): 255 (MÅ+, 3), 254 ([MꢀH]+, 3), 240 (7), 226 (7), 213 (82),
212 (28), 91 ([C6H5CH2]+, 100). Anal. Calcd for C18H25Nꢁ0.95HCl
(290.04): C, 74.54; H, 9.02; N, 4.83; Cl, 11.61. Found: C, 74.63; H,
9.13; N, 4.84; Cl, 11.60.
1202, 1162, 1062 cmꢀ1 1H NMR 1.192 (s, 3H) and 1.195 (s, 3H)
.
[C3-CH3 and C7-CH3], 1.32 [d, J = 7.0 Hz, 3H, CH3CH], 1.38ꢀ1.60
(complex signal, 8H, methylene protons), 2.26 [t, J = 3.0 Hz, 1H,
5-H], 3.54 (q, J = 7.0 Hz, 1H, CHN), 4.86 (s, mobile H). 13C NMR
16.4 (CH3, CH3CH), 16.8 (CH3) and 16.9 (CH3) (C3-CH3 and C7-
CH3), 42.1 (CH, C5), 48.4 (C) and 48.5 (C) (C3 and C7), 51.3 (CH,
CHN), 54.5 (CH2) and 54.6 (CH2) (C4 and C6), 54.7 (C, C1), 55.2
(CH2) and 55.4 (CH2) (C2 and C8). MS (EI), m/z (%): 179 (MÅ+, 2),
178 ([MꢀH]+, 3), 164 (36), 147 (50), 122 (36), 121 (77), 119 (37),
109 (45), 108 (32), 107 (100), 106 (63), 105 (73), 93 (34), 91
(76), 83 (69), 80 (30), 79 (46), 77 (36), 70 (51). Anal. Calcd for
C12H21Nꢁ1.05HClꢁ0.1H2O (219.39): C, 65.70; H, 10.22; N, 6.38; Cl,
16.97. Found: C, 65.53; H, 10.49; N, 6.36; Cl, 16.86.
4.1.21. 1-(3,7-Dimethyltricyclo[3.3.0.03,7]oct-1-yl)ethylamine
hydrochloride (25ꢁHCl)
4.1.21.1. 1-(3,7-Dimethyltricyclo[3.3.0.03,7 ]oct-1-yl)-1-ethanone
(24). To a suspension of Li2CO3 (189 mg, 2.55 mmol) in H2O (40
mL) solid 20 (900 mg, 5.00 mmol) was added and the resulting sus-
pension was stirred for 48 h at room temperature. The water of the
resulting solution was removed in a freeze–dryer giving the lith-
ium salt of 20 as a white solid. This salt was added to anhyd
Et2O (20 mL) and the resulting suspension was cooled to 0 °C.
Methyllithium (18.8 mL, 1.6 M in Et2O, 30 mmol) was added drop-
wise and the suspension was heated under reflux for 18 h. To the
cold (ice-bath) mixture, water (15 mL) was added dropwise, and
the mixture was further stirred for 15 min. The organic layer was
separated and the aqueous phase was extracted with Et2O (3ꢂ
15 mL). The combined organic phases were dried (anhyd Na2SO4)
and concentrated in vacuo at room temperature to give ketone
24 (382 mg, 43% yield; 57% yield based on unrecovered starting
material). The aqueous layer was made acidic and extracted with
CH2Cl2 (4ꢂ 10 mL). The combined organic phases were dried (an-
hyd Na2SO4), and concentrated in vacuo to give starting acid 20
(223 mg). IR: 2956, 2885, 1716, 1699, 1438, 1360, 1302,
4.1.22. N,N-3,7-Tetramethyl(tricyclo[3.3.0.03,7]oct-1-yl)amine
hydrochloride (26ꢁHCl)
From amine 21 (151 mg, 1.0 mmol) in Et2O (5 mL), formalde-
hyde (1.8 mL, 37% wt. in water solution, 22.8 mmol), and formic
acid (1.5 mL, 39 mmol) and following the procedure described for
17, the amine 26 was obtained as its hydrochloride. The analytical
sample of 26ꢁHCl (180 mg, 83.5% yield) was obtained by crystalli-
zation from MeOH/Et2O, mp 173ꢀ174 °C. IR 2999, 2955, 2933,
2886, 2628, 2569, 2540, 2518, 2468, 1472, 1455, 1439, 1312,
1054 cm–1 1H NMR 1.22 [s, 6 H, C3(7)-CH3], 1.51 [dm, J = 9.0 Hz,
.
2H, 4(6)-H ], 1.75 [dd, J = 9.0 Hz, J0 = 3.0 Hz, 2H, 4(6)-Hb], 1.81 [m,
a
4H, 2(8)-H2], 2.59 [t, J = 3.0 Hz, 1H, 5-H], 2.88 (s, 6H, (CH3)2N).
13C NMR 16.5 [CH3, C3(7)-CH3], 40.8 (CH3, (CH3)2N), 42.5 (CH,
C5), 47.7 [C, C3(7)], 53.2 [CH2, C2(8)], 53.5 [CH2, C4(6)], 75.4 (C,
C1). MS (EI), m/z (%): 179 (MÅ+, 2), 178 ([MꢀH]+, 4), 164 (14), 150
(18), 138 (22), 137 (100), 136 (79), 123 (46), 122 (45), 108 (35),
77 (24), 55 (35). Anal. Calcd for C12H21NꢁHCl (215.77): C, 66.80;
H, 10.28; N, 6.49; Cl, 16.43. Found: C, 66.81; H, 10.30; N, 6.41; Cl,
16.65.
1220 cmꢀ1 1H NMR (300 MHz) 1.18 (s, 6H, C3(7)-CH3), 1.37 [dd,
.
J = 8.5 Hz, J0 = 3.6 Hz, 2H, 4(6)-H ], 1.56ꢀ1.62 [complex signal,
4.1.23. N,N-Dibenzyl-3,7-dimethyl(tricyclo[3.3.0.03,7]oct-1-yl)amine
hydrochloride (27ꢁHCl)
a
4H, 2(8)-H and 4(6)-Hb], 1.70 [dm, J = 7.8 Hz, 2(8)-Hb], 2.16 (d,
a
J = 0.6 Hz, 3H, CH3CO), 2.60 [t, J = 3.0 Hz, 1H, 5-H]. MS (EI), m/z
(%): 178 (MÅ+, 3), 163 ([MꢀCH3]+, 7), 136 (11), 135 ([C10H15]+, 23),
123 (20), 122 (31), 107 (21), 95 (41), 93 (27), 43 ([CH3CO]+, 100).
Accurate mass measurement (ESI+) calcd for [C12H18O+H]+:
179.1430. Found: 179.1431.
A
mixture of 21ꢁHCl (178 mg, 0.95 mmol), K2CO3 (1.03 g,
7.5 mmol), benzyl chloride (0.29 mL, 2.5 mmol) and NaI (100 mg,
0.67 mmol) in acetonitrile (10 mL) was heated under reflux for
24 h. The mixture was concentrated in vacuo and EtOAc (30 mL)
was added to the residue. The organic solution was washed with
water (2ꢂ 20 mL), dried (anhy Na2SO4) and concentrated in vacuo.
The residue was subjected to column chromatography (silica gel;
hexane/EtOAc, 99:1) to give amine 27 (130 mg, 41% yield). An ana-
lytical sample of 27ꢁHCl was obtained by adding an excess of
Et2OꢁHCl to a solution of 27 in EtOAc and filtration of the formed
precipitate, mp 191ꢀ192 °C. IR: 3034, 2959, 2920, 2887, 2864,
4.1.21.2. 1-(3,7-Dimethyltricyclo[3.3.0.03,7]oct-1-yl)-1-ethanone oxi-
me. To a solution of ketone 24 (168 mg, 0.94 mmol) in ethanol
(1 mL), hydroxylamine hydrochloride (103 mg, 1.49 mmol), water
(0.1 mL), and powdered NaOH (190 mg, 4.75 mmol) were added
and the mixture was heated under reflux for 5 min. The cold solu-

9934
P. Camps et al. / Bioorg. Med. Chem. 16 (2008) 9925–9936
2806, 2674, 2590, 2546, 1526, 1482, 1457, 1420, 1400, 1312, 1162,
1014, 921, 859, 742, 692 cmꢀ1 1H NMR 1.25 (s, 6H, C3(7)-CH3),
(72), 80 (33), 79 (60), 77 (40). Anal. Calcd for C11H17NO (179.26):
C, 73.70; H, 9.56; N, 7.81. Found: C, 73.64; H, 9.55; N, 7.74.
.
1.55 [broad d, J = 9.0 Hz, 2H, 4(6)-H ], 1.86 [dd, J = 9.0 Hz,
a
J0 = 3.0 Hz, 2H, 4(6)-Hb], 2.05 [s, 4H, 2(8)-H2], 2.73 [t, J = 3.0 Hz,
1H, 5-H], 4.38 [d, J = 13.5 Hz, 2H) and 4.60 [d, J = 13.5 Hz, 2H)
(CH2C6H5)], 4.86 (s, mobile H), 7.23 [dm, J = 8.0 Hz, 4H, Ar-2(6)-
H], 7.34 [tm, J = 7.5 Hz, 4H, Ar-3(5)-H], 7.39 (tt, J = 7.5 Hz,
J0 = 2.0 Hz, 2H, Ar-4-H). 13C NMR 16.5 [CH3, C3(7)-CH3], 44.2 (CH,
C5), 47.3 [C, C3(7)], 53.6 [CH2, C4(6)], 54.5 [CH2, C2(8)], 58.4
(CH2, CH2C6H5), 78.0 (C, C1), 130.2 [CH, Ar-C3(5)], 130.9 (CH, Ar-
C4), 131.9 [CH, Ar-C2(6)], 132.0 (C, Ar-C1). MS (EI), m/z (%): 331
[MÅ+, 1], 316 (2), 289 (43), 198 ([(C6H5CH2)2NH2]+, 10), 91
([C6H5CH2]+, 100). Anal. Calcd for C24H29Nꢁ1.4HCl (382.55): C,
75.34; H, 8.01; N, 3.66; Cl, 12.99. Found: C, 75.34; H, 8.10; N,
3.60; Cl, 13.09. Accurate mass measurement (ESI+) calcd for
[C24H29N+H]+: 332.2372. Found: 332.2382.
4.1.26. [(3,7-Dimethyltricyclo[3.3.0.03,7]oct-1-yl)methyl]amine
hydrochloride (30ꢁHCl)
To a cold (0 °C) solution of 29 (570 mg, 3.18 mmol) in anhyd
THF (70 mL), LiAlH4 (388 mg, 9.72 mmol) was added and the sus-
pension was heated under reflux for 15 h. The suspension was
cooled (ice bath), carefully basified with 10 N NaOH (5 mL) and
stirred for 1 h at room temperature. The precipitate was filtered
and washed with CH2Cl2 (3ꢂ 25 mL). The combined filtrate and
washings were dried (anhyd Na2SO4) and excess of Et2OꢁHCl was
added. The solution was concentrated in vacuo to give a solid that
was crystallized from MeOH/Et2O to give 30ꢁHCl (534 mg, 83%
yield), mp >270 °C (dec). IR 2952, 2881, 1600, 1505, 1480, 1457,
1389, 1322, 1292 cmꢀ1 1H NMR 1.19 (s, 6 H, C3(7)-CH3), 1.39
.
[dd, J = 8.0 Hz, J0 = 4.0 Hz, 2 H, 4(6)-H ], 1.43 [dd, J = 8.0 Hz,
a
J0 = 4.0 Hz, 2H, 2(8)-H ], 1.49 [dm, J = 7.5 Hz, 2H, 2(8)-Hb], 1.62
a
4.1.24. N-3,7-Trimethyl(tricyclo[3.3.0.03,7]oct-1-yl)amine hydrochloride
(28ꢁHCl)
[dd, J = 8.0 Hz, J0 = 3.0 Hz, 2H, 4(6)-Hb], 2.20 [t, J = 3.0 Hz, 1H, 5-
H], 3.19 (s, 2 H, CH2N), 4.85 (s, mobile H). 13C NMR (75.4 MHz)
16.8 [CH3, C3(7)-CH3], 42.8 (CH, C5), 43.8 (CH2, CH2N), 48.6 [C,
C3(7)], 49.7 (C, C1), 54.6 [CH2, C4(6)], 56.7 [CH2, C2(8)]. MS (EI),
m/z (%): 166 (1), 165 (MÅ+, 1), 152 (3), 151 (3), 148 (8), 136 (26),
135 ([C10H15]+, 46), 133 (30), 107 (82), 106 (41), 105 (43), 93
(100), 92 (38), 91 (91), 79 (49), 77 (51), 71 (41). Anal. Calcd for
C11H19NꢁHClꢁ0.5H2O (210.75): C, 62.69; H, 10.04; N, 6.65; Cl,
16.82. Found: C, 62.38; H, 9.71; N, 6.58, Cl, 16.55.
A mixture of 23ꢁHCl (390 mg, 1.33 mmol) and 10% Pd/C (50% in
water, 10 mg) in absolute EtOH (80 mL) was hydrogenated at
38 atm and 100 °C for 24 h. The suspension was filtered, the resi-
due was washed with EtOH and the organic layer was concentrated
in vacuo to give a solid. Crystallization from MeOH/Et2O gave
28ꢁHCl (240 mg, 89% yield). An analytical sample of 28ꢁHCl was ob-
tained by crystallization from THF, mp 167ꢀ168 °C. IR (KBr) 2961,
2939, 2807, 2739, 2521, 2431, 2392, 2370, 1458, 1310, 1161, 1099,
1077, 878 cmꢀ1
.
1H NMR 1.22 [s, 6H, C3(7)-CH3], 1.47 [dd,
4.1.27. N-Benzyl[(3,7-dimethyltricyclo[3.3.0.03,7]oct-1-yl)methyl]amine
hydrochloride (31ꢁHCl)
J = 8.5 Hz, J0 = 2.0 Hz, 2H, 4(6)-H ], 1.75-1.79 [complex signal, 6 H,
a
4(6)-Hb, 2(8)-H and 2(8)-Hb], 2.47 [t, J = 2.5 Hz, 1H, 5-H], 2.69 (s,
a
From 30ꢁHClꢁ0.5H2O (500 mg, 2.37 mmol), MeOH (10 mL),
NaBH3CN (95%, 335 mg, 5.3 mmol), AcOH (0.3 mL), and benzalde-
hyde (395 mg, 3.68 mmol) and following the procedure described
for 22a, 31ꢁHCl (489 mg, 68% yield) was obtained, mp >270 °C
(dec). IR: 2948, 2880, 2781, 2371, 1586, 1478, 1447, 1420, 1382,
3H, CH3–N), 4.85 (s, mobile H). 13C NMR (75.4 MHz) 16.5 [CH3,
C3(7)-CH3], 30.1 (CH3, CH3–N), 43.0 (CH, C5), 47.7 [C, C3(7)], 53.6
[CH2, C4(6)], 54.4 [CH2, C2(8)], 68.1 (C, C1). MS (EI), m/z (%): 165
(MÅ+, 1), 164 ([MꢀH]+, 8), 150 ([MꢀCH3]+, 24), 136 (33), 124 (23),
123 (100), 122 (76), 109 (56), 108 (44), 94 (27). Anal. Calcd for
C11H19NꢁHClꢁ0.15H2O (204.44): C, 64.63; H, 10.01; N, 6.85. Found:
C, 64.71; H, 9.92; N, 6.86.
1355, 1321, 1289, 1237, 1084, 1025, 748, 698 cmꢀ1 1H NMR 1.18
.
(s, 6H, 3(7)-CH3), 1.37 [dd, J = 8.5 Hz, J0 = 3.5 Hz, 2H, 4(6)-H ],
a
1.44 [dd, J = 8.0 Hz, J0 = 3.5 Hz, 2H, 2(8)-H ], 1.49 [dm, J = 8.0 Hz,
a
2H, 2(8)-Hb], 1.61 [dd, J = 8.5 Hz, J0 = 3.0 Hz, 2H, 4(6)-Hb], 2.18 [t,
J = 3.0 Hz, 1H, 5-H], 3.25 (s, 2H, CH2N), 4.26 (s, 2H, CH2C6H5),
4.86 (s, mobile H), 7.46–7.50 [complex signal, 3H, Ar-3(5)-H and
Ar-4-H], 7.55 [m, 2H, Ar-2(6)-H]. 13C NMR 16.7 [CH3, C3(7)-CH3],
43.5 (CH, C5), 48.6 [C, C3(7)], 48.9 (C, C1), 51.4 (CH2, CH2N), 53.1
(CH2, C6H5CH2), 54.6 [CH2, C4(6)], 57.1 [CH2, C2(8)], 130.3 [CH,
Ar-C3(5)], 130.8 (CH, Ar-C4), 131.4 [CH, Ar-C2(6)], 132.1 (C, Ar-
C1). MS (EI), m/z (%): 255 (MÅ+, 3), 254 ([MꢀH]+, 2), 199 (10), 120
([C6H5CH2+NH@CH2], 67), 93 (18), 91 ([C6H5CH2]+, 100). Anal. Calcd
for C18H25NꢁHClꢁ0.05 H2O (292.76): C, 73.85; H, 8.99; N, 4.78; Cl,
12.11. Found: C, 73.58; H, 8.91; N, 4.70; Cl, 12.47.
4.1.25. (3,7-Dimethyltricyclo[3.3.0.03,7]oct-1-yl)carboxamide (29)
A solution of acid 20 (1.12 g, 6.22 mmol) in thionyl chloride
(18 mL, 0.24 mmol) was heated under reflux for 2 h. The excess
thionyl chloride was removed under vacuum, the residue was ta-
ken in toluene (5 mL) and evaporated to dryness (twice). The oily
yellow residue (1.16 g) was dissolved in CHCl3, the solution was
cooled to 0 °C and NH4OH (60 mL, 25% aqueous solution) was
added dropwise. After stirring for 15 h at room temperature, the
suspension was extracted with CH2Cl2 (4ꢂ 30 mL). The aqueous
layer was made acidic with concd HCl and extracted with EtOAc
(3ꢂ 30 mL). The combined EtOAc extracts were dried (anhyd
Na2SO4) and concentrated in vacuo to give the starting acid 20
(438 mg). The combined CH2Cl2 extracts were washed with brine
(2ꢂ 30 mL), dried (anhyd Na2SO4), and concentrated in vacuo to
give amide 29 (572 mg, 51% yield, 84% yield taking into account
the recovered starting acid). An analytical sample of 29 was
obtained by crystallization from EtOAc, mp 105ꢀ106 °C. IR, 3458,
3410, 3348, 3298, 3199, 3000, 2950, 2883, 1655, 1613, 1478,
4.1.28. N-Benzyl-N-methyl[(3,7-dimethyltricyclo[3.3.0.03,7]oct-
1-yl)methyl]amine hydrochloride (32ꢁHCl)
From a solution of 31ꢁHCl (400 mg, 1.37 mmol), acetonitrile
(10 mL), formaldehyde (1.08 mL, 37% wt. in water solution,
13.7 mmol) and two portions of NaBH3CN (95%, 272 mg, 4.11 mmol)
and following the procedure described for 9, the amine 32 (260 mg,
70.5% yield) was obtained. Its hydrochloride was obtained by adding
an excess of Et2OꢁHCl to a solution of the amine in EtOAc followed by
concentration to dryness in vacuo. The analytical sample of 32ꢁHCl
was obtained by crystallization from EtOAc, mp 215ꢀ216 °C. IR:
3030, 3011, 2946, 2879, 2862, 2695, 2635, 2512, 1478, 1455, 1070,
917, 906, 746, 697 cmꢀ1. 1H NMR 1.18 [s, 6H, C3(7)-CH3], 1.40 [dd,
1397, 1304, 1160, 790 cmꢀ1 1H NMR (CDCl3) 1.17 (s, 6H, C3(7)-
.
CH3), 1.37 [dd, J = 8.5 Hz, J0 = 3.5 Hz, 2H, 4(6)-H ], 1.61 [dd,
a
J = 7.5 Hz, J0 = 3.5 Hz, 2H, 2(8)-H ], 1.62 [dd, J = 8.5 Hz, J0 = 3.5 Hz,
a
2H, 4(6)-Hb], 1.70 [dm, J = 11.5 Hz, 2H, 2(8)-Hb], 2.56 [t, J = 3.0 Hz,
1H, 5-H], 5.50 (broad signal, 1H), 5.72 (broad signal, 1H) (CONH2).
13C NMR (CDCl3) 16.3 [CH3, C3(7)-CH3], 43.5 (CH, C5), 47.9 [C,
C3(7)], 53.5 [CH2, C4(6)], 54.5 (C, C1), 57.1 [CH2, C2(8)], 177.9 (C,
CO). MS (EI), m/z (%): 179 (MÅ+, 4), 164 (5), 138 (24), 135
([C10H15]+, 21), 124 (39), 123 (42), 95 (100), 93 (38), 91 (34), 81
J = 8.5 Hz, J0 = 3.5 Hz, 2H, 4(6)-H ], 1.45-1.60 [complex signal, 4H,
a
2(8)-H , and 2(8)-Hb], 1.62 [dd, J = 8.5 Hz, J0 = 3.0 Hz, 2H, 4(6)-Hb],
a
2.16 [t, J = 3.0 Hz, 1H, 5-H], 2.89 (s, 3H, CH3N), 3.43 (d, J = 13.5 Hz,
1H) and 3.54 (d, J = 13.5 Hz, 1H) (CH2N), 4.33 (d, J = 12.5 Hz, 1H)

P. Camps et al. / Bioorg. Med. Chem. 16 (2008) 9925–9936
9935
and 4.43 (d, J = 12.5 Hz, 1H) (CH2C6H5), 7.49–7.52 [complex signal,
3H, Ar-3(5)-H and Ar-4-H], 7.57 [m, 2H, Ar-2(6)-H]. 13C NMR 16.6
[CH3, C3(7)-CH3], 42.4 (CH3, CH3–N), 44.8 (CH, C5), 48.5 [C, C3(7)],
48.7 (C, C1), 54.4 [CH2, C4(6)], 57.8 [CH2, C2(8)], 60.3 (CH2, CH2N),
62.3 (CH2, CH2C6H5), 130.4 [CH, Ar-C3(5)], 130.8 (C, Ar-C1), 131.3
(CH, Ar-C4), 132.5 [CH, Ar-C2(6)]. MS (EI), m/z (%): 269 (MÅ+, 7),
213 (15), 134 (87), 120 (13), 107 (10), 93 (15), 92 (13), 91
([C6H5CH2]+, 100). Anal. Calcd for C19H27NꢁHCl (305.89): C, 74.60;
H, 9.23; N, 4.58; Cl, 11.59. Found: C, 74.51; H, 9.26; N, 4.55; Cl, 11.74.
J = 2.5 Hz, 1H, 5-H], 3.41 (s, 2H, CH2N), 4.86 (s, mobile H). 13C
NMR 16.9 [CH3, C3(7)-CH3], 42.7 (CH, C5), 45.6 (CH2, CH2N), 48.5
[C, C3(7)], 51.5 (C, C1), 54.8 [CH2, C4(6)], 56.9 [CH2, C2(8)], 158.9
(C, C guanidine). MS (EI), m/z (%): 209 (9), 208 ([M+H]+, 9), 195
(5), 194 (5), 167 (14), 166 (15), 154 (12), 153 (12), 148 (17), 133
(31), 119 (22), 107 (81), 106 (42), 105 (48), 93 (83), 92 (38), 91
(100), 79 (46), 77 (66), 75 (39), 74 (38), 63 (47), 62 (68), 61 (48).
Anal. Calcd for C12H21N3ꢁHClꢁ1.5H2O (270.80): C, 53.22; H, 9.30;
N, 15.52. Found: C, 53.37; H, 9.03; N, 15.52.
4.1.29. N,N-Dimethyl[(3,7-dimethyltricyclo[3.3.0.03,7]oct-1-
yl)methyl]amine hydrochloride (33ꢁHCl)
4.1.32. N-Methyl[(3,7-dimethyltricyclo[3.3.0.03,7]oct-1-yl)methyl]amine
hydrochloride (36ꢁHCl)
From a cold (0 °C) solution of 30ꢁHCl (80 mg, 0.48 mmol) in Et2O
(5 mL), formaldehyde (1.0 mL, 37%wt. in water solution, 12.7 mmol)
and formic acid (0.85 mL, 22 mmol) and following the procedure de-
scribed for 17, 33ꢁHCl was obtained. The analytical sample of 33ꢁHCl
(68 mg, 61% yield) was obtained by crystallization from THF, mp
>250 °C. IR (KBr): 2952, 2884, 2691, 1479, 1412, 1316, 1211, 1136,
973, 948 cmꢀ1. 1H NMR 1.20 [s, 6H, C3(7)-CH3], 1.43 [dd, J = 8.5 Hz,
From 32ꢁHCl (200 mg, 0.65 mmol), 10% Pd/C (50% in water,
10 mg) and absolute ethanol (25 mL) and following the procedure
described for 28, 36ꢁHCl (120 mg, 85% yield) was obtained after
crystallization from MeOH/Et2O, mp >255 °C. IR: 2952, 2880,
2764, 1588, 1458, 1427, 1385, 1325, 1292, 1088, 1022, 806 cmꢀ1
.
1H NMR 1.19 [s, 6H, C3(7)-CH3], 1.40 [dd, J = 8.5 Hz, J0 = 3.5 Hz,
2H, 4(6)-H ], 1.43-1.46 [dd, J = 7.5 Hz, J0 = 3.5 Hz, 2H, 2(8)-H ],
J0 = 3.5 Hz, 2H, 4(6)-H ], 1.52 [dd, J = 7.5 Hz, J0 = 3.5 Hz, 2H, 2(8)-
a
a
a
1.50 [dm, J = 7.5 Hz, 2H, 2(8)-Hb], 1.61 [dd, J = 8.5 Hz, J0 = 3.0 Hz,
2H, 4(6)-Hb], 2.22 [t, J = 3.0 Hz, 1H, 5-H], 2.74 (s, 3H, CH3N), 3.27
(s, 2H, CH2N), 4.86 (s, mobile H). 13C NMR 16.7 [CH3, C3(7)-CH3],
34.8 (CH3, CH3N), 43.2 (CH, C5), 48.6 [C, C3(7)], 54.0 (CH2, CH2N),
54.6 [CH2, C4(6)], 57.0 [CH2, C2(8)]. The signal corresponding to
C1 was not observed. MS (EI), m/z (%): 179 (MÅ+, 4), 165 (5), 164
(4), 148 (6), 147 (6), 136 (15), 135 ([C10H15]+, 34), 134 (32), 133
(27), 124 (26), 123 (29), 107 (71), 106 (35), 105 (44), 93 (100),
92 (38), 91 (97), 79 (42), 77 (56). Anal. Calcd for
C12H21NꢁHClꢁ0.5H2O (224.77): C, 64.12; H, 10.31; N, 6.23. Found:
C, 64.22; H, 10.24; N, 6.35.
H ], 1.57 [dm, J = 7.5 Hz, 2H, 2(8)-Hb], 1.65 [dd, J = 8.5 Hz,
a
J0 = 3.0 Hz, 2H, 4(6)-Hb], 2.25 [t, J = 3.0 Hz, 1H, 5-H], 2.93 (s, 6H,
(CH3)2N), 3.47 (s, 2H, CH2N), 4.85 (s, mobile H). 13C NMR 16.6 [CH3,
C3(7)-CH3], 44.7 (CH, C5), 45.1 (CH3, CH3N), 48.5 [C, C3(7)], 54.5
[CH2, C4(6)], 57.7 [CH2, C2(8)], 62.5 (CH2, CH2N). The signal corre-
sponding to C1 was not observed. MS (EI), m/z (%): 193 (MÅ+, 3),
137 (5), 107 (7), 93 (12), 91 (11), 58 ([Me2NCH2]+, 100). Anal. Calcd
for C13H23Nꢁ1.6HCl (251.67): C, 62.04; H, 9.85; N, 5.57. Found: C,
62.23; H, 10.16; N, 5.76. Accurate mass measurement (ESI+) calcd
for [C13H23N+H]+: 194.1903. Found: 194.1909.
4.1.30. N-[(3,7-Dimethyltricyclo[3.3.0.03,7]oct-1-yl)methyl]piperidine
hydrochloride (34ꢁHCl)
4.2. Trypanosoma brucei culturing and drug test
From 30ꢁHCl (201 mg, 1.00 mmol), DMF (2.5 mL), anhyd Et3N
(0.4 mL, 2.9 mmol), 1,5-dibromopentane (0.17 mL, 1.2 mmol) and
following the procedure described for 11, 34ꢁHCl (111 mg, 41%
yield) was obtained. The analytical sample of 34ꢁHCl was obtained
by crystallization from 2-propanol, mp >265 °C (dec). IR: 2948,
2879, 2857, 2644, 2580, 2534, 1477, 1455, 1438, 1376, 1318,
Cultures of bloodstream form T. brucei (strain 427) were main-
tained at 37 °C in modified Iscove’s medium (pH 7.4).20 Trypanoci-
dal activity was assessed by growing parasites for 48 h in the
presence of various drug concentrations and determining the levels
which inhibited growth by 50% (IC50) and 90% (IC90). In the case of
untreated cultures (volume 4 mL), cell densities increased from
0.25 ꢂ 105 to 1 ꢂ 106 cells mLꢀ1 over this period. Experiments
were performed in triplicate. Cell densities at each drug concentra-
tion were determined using a hemocytometer (Weber Scientific
International Ltd), and drug sensitivity was expressed as a percent-
age of growth of control cells.
950 cmꢀ1 1H NMR 1.20 [s, 6H, C3(7)-CH3], 1.43 [dd, J = 8.5 Hz,
.
J0 = 3.5 Hz, 2H, 4(6)-H ], 1.52 [dd, J = 7.5 Hz, J0 = 3.5 Hz, 3 H, 2(8)-
a
H ], 1.50–1.55 (overlapped m, 1H, 40-Hax], 1.57 [dm, J = 7.5 Hz,
a
2H, 2(8)-Hb], 1.65 [dd, J = 9.0 Hz, J0 = 3.0 Hz, 2 H, 4(6)-Hb], 1.75–
1.97 [broad signal, 5 H, 40-Heq, 30(50)-Hax, and 30(50)-Heq], 2.24 [t,
J = 2.5 Hz, 1H, 5-H], 3.02 [broad signal, 2 H, 20(60)-Hax], 3.42 (s,
2 H, CH2N), 3.53 [broad signal, 2 H, 20(60)-Heq], 4.85 (s, mobile H).
13C NMR 16.6 [CH3, C3(7)-CH3], 22.5 (CH2, C40), 23.8 [CH2,
C30(50)], 45.1 (CH, C5), 48.4 [C, C3(7)], 49.4 (C, C1), 54.5 [CH2,
C4(6)], 55.3 [CH2, C20(60)], 58.1 [CH2, C2(8)], 61.5 (CH2, CH2N). MS
(EI), m/z (%):233 (MÅ+, 9), 177 (14), 98 ([C5H10NCH2]+, 100), 93
(13), 91 (13), 84 ([C5H10N]+, 17). Anal. Calcd for C16H27NꢁHCl
(269.86): C, 71.21; H, 10.46; N, 5.19; Cl, 13.14. Found: C, 71.19;
H, 10.45; N, 5.17; Cl, 13.12.
4.3. NMDA receptor antagonist activity
The functional assay of antagonist activity at NMDA receptors
was performed using primary cultures of cerebellar granule neu-
rons, which were prepared according to established protocols.18
Cells were grown on 10 mm poly-
and used for the experiments after 7–14 days in vitro. Cells were
loaded with 6 M Fura-2 AM (Invitrogen-Molecular Probes) for
L-lysine coated glass cover slips,
4.1.31. N-[(3,7-dimethyltricyclo[3.3.0.03,7]oct-1-yl)methyl]guanidine
hydrochloride (35ꢁHCl)
l
45 min. Afterwards, the coverslip was mounted on a quartz cuvette
containing a Locke–Hepes buffer using a special holder. Measure-
ments were performed using a PerkinElmer LS-50B fluorometer
equipped with a fast-filter accessory, under mild agitation and at
37 °C. Analysis from each sample was recorded real-time during
From a solution of 30ꢁHCl (150 mg, 0.74 mmol), acetonitrile
(2.5 mL), anhyd Et3N (0.2 mL, 1.45 mmol) and 1H-pyrazol-1-car-
boxamidine hydrochloride (130 mg, 0.89 mmol) and following
the procedure described for 18, 35ꢁHCl (139 mg, 77% yield) was ob-
tained. The analytical sample of 35ꢁHCl was obtained by crystalli-
zation from MeOH/Et2O, mp 214ꢀ215 °C. IR: 3600–3000 (max at
3376, 3247, 3170), 2948, 2879, 1646, 1456, 1354, 1319, 1291,
1200 s. After stimulation with NMDA or glutamate (100
lM, in
the presence of 10 M glycine), increasing cumulative concentra-
l
tions of the compound to be tested were added. The percentages
of inhibition at every tested concentration were analyzed using a
non-linear regression curve fitting (variable slope) by using the
software GraphPad Prism 4.0.
1160 cmꢀ1
.
1H NMR 1.18 [s, 6H, C3(7)-CH3], 1.37 [dd, J = 7.5 Hz,
J0 = 3.5 Hz, 2H, 4(6)-H ], 1.39-1.46 [complex signal, 4H, 2(8)-H
a
a
and 2(8)-Hb], 1.61 [dd, J = 7.5 Hz, J0 = 3.0 Hz, 2H, 4(6)-Hb], 2.12 [t,

9936
P. Camps et al. / Bioorg. Med. Chem. 16 (2008) 9925–9936
Snyder, J. A.; Watts, J. C. J. Med. Chem. 1971, 14, 535; (c) Tilley, T. W.; Levitan, P.;
4.4. Antiviral evaluation
Kramer, M. J. J. Med. Chem. 1979, 22, 1009; (d) Kolocouris, N.; Foscolos, G. B.;
Kolocouris, A.; Marakos, P.; Pouli, N.; Fytas, G.; Ikeda, S.; De Clercq, E. J. Med.
Chem. 1994, 37, 2896; (e) Kolocouris, N.; Kolocouris, A.; Foscolos, G. B.; Fytas,
G.; Neyts, J.; Padalko, E.; Balzarini, J.; Snoeck, R.; Andrei, G.; De Clercq, E. J. Med.
Chem. 1996, 39, 3307; (f) Van Derpoorten, K.; Balzarini, J.; De Clercq, E.;
Poupaert, J. H. Biomed. Pharmacother. 1997, 51, 464; (g) Scholtissek, C.; Quack,
G.; Klenk, H. D.; Webster, R. G. Antiviral Res. 1998, 37, 83; (h) Burstein, M. E.;
Serbin, A. V.; Khakhulina, T. V.; Alymova, I. V.; Stotskaya, L. L.; Bogdan, O. P.;
Manukchina, E. E.; Jdanov, V. V.; Sharova, N. K. Antiviral Res. 1999, 41, 135; (i)
Stylianakis, I.; Kolocouris, A.; Kolocouris, N.; Fytas, G.; Foscolos, G. B.; Padalko,
E.; Neyts, J.; De Clercq, E. Bioorg. Med. Chem. Lett. 2003, 13, 1699; (j) El-Emam, A.
A.; Al-Deeb, O. A.; Al-Omar, M.; Lehmann, J. Bioorg. Med. Chem. 2004, 12, 5107.
3. (a) Danysz, W.; Parsons, C. G.; Kornhuber, J.; Schmidt, W. J.; Quack, G. Neurosci.
Biobehav. Rev. 1997, 21, 455; (b) Palmer, G. C. Curr. Drug Targets 2001, 2, 241.
4. (a) Kelly, J. M.; Miles, M. A.; Skinner, A. C. Antimicrob. Agents Chemother. 1999,
43, 985; (b) Kelly, J. M.; Quack, G.; Miles, M. A. Antimicrob. Agents Chemother.
2001, 45, 1360.
The antiviral activity of the compounds was determined in
established cell culture assays using a selection of DNA and RNA
viruses, including three subtypes of influenza virus [A/Puerto
Rico/8/34 (H1N1); A/Hong Kong/7/87 (H3N2) and B/Hong Kong/
5/72].21 The compounds’ inhibitory effect on virus replication as
well as their cytotoxicity were monitored by microscopical exam-
ination, and confirmed by the colorimetric MTS cell viability assay.
4.5. Dopaminergic evaluation
4.5.1. Synaptosomal preparation
Female Wistar rats (200–250 g) were used throughout. Briefly,
rats were killed by decapitation and the striatum was dissected
and homogenized in 10 volumes (w/v) of 0.32 M sucrose using a
Potter–Elvejhem. The resulting crude synaptosomal preparation
was centrifuged at 1000g for 10 min. The supernatant was stored
and the pellet was resuspended in 10 volumes of 0.32 M sucrose
and recentrifuged. The two supernatants were combined and the
mixture centrifuged at 16,000g for 30 min. The resultant pellet
was suspended in 10 volumes of ice-cold Krebs medium. Protein
concentrations were determined using the Bradford protein assay.
5. (a) Martínez, A. G.; Vilar, E. T.; Fraile, A. G.; Cerezo, S. D.; Herrero, M. E. R.; Ruiz,
P. M.; Subramanian, L. R.; Gancedo, A. G. J. Med. Chem. 1995, 38, 4474; (b)
Miller, J. A.; Ullah, G. M.; Welsh, G. M.; Hall, A. C. Tetrahedron Lett. 2001, 42,
7503; (c) Gregory, W. A. U.S. Patent 3 558 704, 1971.; (d) Aigami, K.; Inamoto,
Y.; Takaishi, N.; Fujikura, Y.; Takatsuki, A.; Tamura, G. J. Med. Chem. 1976, 19,
536.
6. Zhou, J. J. P.; Li, J.; Upadhyaya, S.; Eaton, P. E.; Silverman, R. B. J. Med. Chem.
1997, 40, 1165.
7. (a) Geldenhuys, W. J.; Malan, S. F.; Bloomquist, J. R.; Marchand, A. P.; van der
Schyf, C. J. Med. Res. Rev. 2005, 25, 21; (b) Geldenhuys, W. J.; Malan, S. F.;
Bloomquist, J. R.; van der Schyf, C. J. Bioorg. Med. Chem. 2007, 15, 1525.
8. (a) Camps, P.; Muñoz-Torrero, D. Tetrahedron Lett. 1994, 35, 3187; (b) Camps,
P.; Font-Bardia, M.; Muñoz-Torrero, D.; Solans, X. Liebigs Ann. 1995, 523; (c)
Camps, P.; Muñoz-Torrero, D.; Muñoz-Torrero, V. Tetrahedron Lett. 1995, 36,
1917.
4.5.2. [3H]DA uptake assay
[3H]Dopamine uptake was evaluated on aliquots of the synapto-
somal preparation. After a 10 min preincubation at 37 °C in Krebs
9. (a) Camps, P.; Figueredo, M. Can. J. Chem. 1984, 62, 1184; (b) Camps, P.; Iglesias,
C.; Rodríguez, M. J.; Grancha, M. D.; Gregori, M. E.; Lozano, R.; Miranda, M. A.;
Figueredo, M.; Linares, A. Chem. Ber. 1988, 121, 647; (c) Camps, P.; Estiarte, M.
A.; Vázquez, S.; Pérez, F. Synth. Commun. 1995, 25, 1287; (d) Camps, P.; Font-
Bardia, M.; Pérez, F.; Solans, X.; Vázquez, S. Angew. Chem., Int. Ed. Engl. 1995, 34,
912; (e) Camps, P.; Luque, F. J.; Orozco, M.; Pérez, F.; Vázquez, S. Tetrahedron
Lett. 1996, 37, 8605; (f) Camps, P.; Lukach, A.; Vázquez, S. Tetrahedron 2001, 57,
2419; (g) Camps, P.; Lukach, A.; Pujol, X.; Rossi, R. A. J. Org. Chem. 2001, 66,
5366; (h) Camps, P.; Pujol, X.; Vázquez, S. Tetrahedron 2002, 58, 10081; (i)
Ayats, C.; Camps, P.; Duque, M. D.; Font-Bardia, M.; Muñoz, M. R.; Solans, X.;
Vázquez, S. J. Org. Chem. 2003, 68, 8715; (j) Camps, P.; Muñoz, M. R.; Vázquez, S.
J. Org. Chem. 2005, 70, 1945; (k) Camps, P.; Fernández, J. A.; Font-Bardia, M.;
Solans, X.; Vázquez, S. Tetrahedron 2005, 61, 3593; (l) Ayats, C.; Camps, P.; Font-
Bardia, M.; Muñoz, M. R.; Solans, X.; Vázquez, S. Tetrahedron 2006, 62, 7436;
(m) Camps, P.; Muñoz, M. R.; Vázquez, S. Tetrahedron 2006, 62, 7645; (n) Ayats,
C.; Camps, P.; Fernández, J. A.; Vázquez, S. Chem. Eur. J. 2007, 13, 1522; (o)
Camps, P.; Colet, G.; Delgado, S.; Muñoz, M. R.; Pericàs, M. A.; Solà, Ll.; Vázquez,
S. Tetrahedron 2007, 63, 4669; (p) Ayats, C.; Camps, P.; Font-Bardia, M.; Solans,
X.; Vázquez, S. Tetrahedron 2007, 63, 8027.
buffer containing 10 lM pargyline (to block metabolism of dopa-
mine by monoamine oxidase), [3H]dopamine (47 Ci/mmole, Amer-
sham) was added to a final 0.5 nM concentration. Ten minute
incubations were stopped by dilution into ice-cold Krebs medium.
Samples were filtered rapidly through Grade 30 fiberglass filters
(Schleicher & Schuell) using a Brandel cell harvester (model M-
24, Biochemical Research and Development Laboratories, Inc.). Fil-
ters were washed twice with 3 mL cold Krebs medium and dried.
Non-specific [3H]DA uptake was determined in duplicate samples
in the presence of 10 lM nomifensine (dopamine uptake inhibi-
tor). Filters were placed into scintillation mixture (Optiphase ‘Hi-
safe’ 2, Perkin-Elmer) and radioactivity was determined by
scintillation spectrometry.
10. We found a patent that claimed antiviral activity for some bisnor- and nor-
adamantane derivatives, but activity details are not given. See, Hoover, J. R.
E. U.S. Patent 3496228, 1970. For the anti-influenza activity of 7 see Ref.
2g.
Acknowledgments
11. Patrick, G. L. An Introduction to Medicinal Chemistry; Oxford University Press:
Oxford, 2005. pp 204–205.
12. Jawdosiuk, M.; Kovacic, P. Synth. Commun. 1983, 13, 53.
13. Casanova, J.; Devi, P. Synth. Commun. 1993, 23, 245.
14. Okazaki, T.; Isobe, H.; Kitagawa, T.; Takeuchi, K. Bull. Chem. Soc. Jpn. 1996, 69,
2053.
Financial support from Ministerio de Educación y Ciencia (P.C.
and S.V.: Project CTQ2005-02192; F.X.S. and M.P.: Project SAF
2006-13092-C02-01; A.C.: Project SAF2005-01604; D.C. and D.I.:
Project SAF 2007-63142), the Centros de Investigación Biomédica
en Red de Enfermedades Neuro-degenerativas (CIBERNED) and
Comissionat per a Universitats i Recerca (P.C. and S.V.: Project
2005-SGR-00180, F.X.S., M.P., and A.C.: Project 2005-SGR-00893)
is gratefully acknowledged. M.D.D. thanks to the Ministerio de Edu-
cación y Ciencia (FPU Program). S.R.P. and J.M.K. acknowledge Well-
come Trust for support.
15. Barret, M. P. Lancet 2006, 367, 1377.
16. (a) Kolocouris, N.; Zoidis, G.; Foscolos, G. B.; Fytas, G.; Prathalingam, R.; Kelly, J.
M.; Naesens, L.; De Clercq, E. Bioorg. Med. Chem. Lett. 2007, 17, 4358; (b)
Papanastasiou, I.; Tsotinis, A.; Kolocouris, N.; Prathalingam, R.; Kelly, J. M. J.
Med. Chem. 2008, 51, 1496.
17. Robinson, D. M.; Keating, G. M. Drugs 2006, 66, 1515.
18. Canudas, A. M.; Pubill, D.; Sureda, F. X.; Verdaguer, E.; Camps, P.; Muñoz-
Torrero, D.; Jiménez, A.; Camins, A.; Pallàs, M. Exp. Neurol. 2003, 180, 123.
19. Mizoguchi, K.; Yokoo, H.; Yoshida, M.; Tanaka, T.; Tanaka, M. Brain Res. 1994,
662, 255.
References and notes
20. Hirumi, H.; Hirumi, K. J. Parasitol. 1989, 75, 985.
21. (a) De Clercq, E.; Cools, M.; Balzarini, J.; Márquez, V. E.; Borcherding, D. R.;
Borchardt, R. T.; Drach, J. C.; Kitaoka, S.; Konno, T. Antimicrob. Agents Chemother.
1989, 33, 1291; (b) Setaki, D.; Tataridis, D.; Stamatiou, G.; Kolocouris, A.;
Foscolos, G. B.; Fytas, G.; Kolocouris, N.; Padalko, E.; Neyts, J.; De Clercq, E.
Bioorg. Chem. 2006, 34, 248.
1. (a) Aoki, F. Textbook of Influenza. In Nicholson, K. G., Webster, R. G., Hay, A. J.,
Eds.; Blackwell Science: Oxford, 1998; pp 457–476; (b) De Clercq, E. Nat. Rev.
Drug Discovery 2006, 5, 1015.
2. (a) Geluk, H. W.; Schut, J.; Schlatmann, J. L. M. A. J. Med. Chem. 1969, 12, 712; (b)
Aldrich, P. E.; Hermann, E. C.; Meier, W. E.; Paulshock, M.; Prichard, W. W.;