Design, synthesis, and trypanocidal activity of new aminoadamantane derivatives

Article abstract of DOI:10.1021/jm7014292

To develop functionalized adamantanes for treating African trypanosomiasis, we report on the synthesis of new 1-alkyl-2-aminoadamantanes 1a-i, 1-alkyltricyclo[3.3.1.1^3,7]decan-2-guanylhydrazones 2a-g, and their congeneric thiosemicarbazones 3a,

Full text of DOI:10.1021/jm7014292

1496
J. Med. Chem. 2008, 51, 1496–1500
Design, Synthesis, and Trypanocidal Activity of New Aminoadamantane Derivatives
Ioannis Papanastasiou,† Andrew Tsotinis,† Nicolas Kolocouris,*,† S. Radhika Prathalingam,‡ and John M. Kelly‡
Faculty of Pharmacy, Department of Pharmaceutical Chemistry, UniVersity of Athens, Panepistimioupoli-Zografou, 157 71 Athens, Greece, and
Department of Infectious and Tropical Diseases, London School of Hygiene and Tropical Medicine, London WC1E 7HT, U.K.
ReceiVed NoVember 13, 2007
To develop functionalized adamantanes for treating African trypanosomiasis, we report on the synthesis of
new 1-alkyl-2-aminoadamantanes 1a-i, 1-alkyltricyclo[3.3.1.13,7]decan-2-guanylhydrazones 2a-g, and their
congeneric thiosemicarbazones 3a,b. The potency of these compounds against Trypanosoma brucei was
compared to that of amantadine and rimantadine and found to be substantially higher. The most active
analogues, 1c, 1d, 2c, 2g, and 3b, illustrate the synergistic effect of the lipophilic character of the C1 side
chain and the C2 functionality on trypanocidal activity.
Introduction
melarsoprol resistance or in patients who have relapsed after
melarsoprol monotherapy, eflornithine is used. More recently,
a combination of melarsoprol and nifurtimox has also been
shown to be effective.6
Sleeping sickness or African trypanosomiasis is a parasitic
disease of humans and animals caused by protozoa of the genus
Trypanosoma and transmitted by the tsetse fly. The disease is
endemic in several regions of Sub-Saharan Africa, covering
about 36 countries and 60 million people. It is estimated that
50 000-70 000 people are currently infected, the number having
declined somewhat in recent years.1 Three major epidemics have
occurred in the past hundred years, one from 1896 to 1906 and
the others in 1920 and 1970. The disease had practically
disappeared between 1960 and 1965, but since then, screening
and effective surveillance have been relaxed and the disease
has reappeared in endemic form in several foci over the past
30 years.2
Trypanosoma brucei is an extracellular parasite and replicates
in the bloodstream of infected individuals, where it avoids
immune destruction by a complex system of antigenic variation.3
As a result, there is little prospect of an effective vaccine.
Symptoms begin with fever, headaches, and joint pains, and as
the disease progresses, the lymph nodes often swell consider-
ably. Other presentations include anemia and endocrine, cardiac,
and kidney disorders. The disease enters its critical stage when
the parasite passes through the blood-brain barrier, and the
resulting symptoms give the disease its name. Besides confusion
and reduced coordination, the sleep cycle is disturbed with bouts
of fatigue punctuated with manic periods progressing to daytime
slumber and nighttime insomnia. Damage caused in this
neurological phase can be irreversible. In addition to the bite
of the tsetse fly, the disease can also be contracted by congenital
transmission, laboratory-acquired infection, and blood transfusion.
Without treatment, African trypanosomiasis is invariably fatal,
with progressive mental deterioration leading to coma and death.
However, current drug regimes are unsatisfactory for reasons
that include lack of efficacy, toxic side effects, and the need
for administration under medical supervision. The standard
treatment for first stage disease is intravenous pentamidine (T.b.
gambiense) or intravenous suramin (T.b. rhodesiense). For late
stage disease, intravenous melarsoprol is given at 2.2 mg/kg
daily for 10 consecutive days.4 Alternative first line therapies
include intravenous eflornithine (difluoromethylornithine) 50
mg/kg every 6 h for 14 days (T.b. gambiense).5 In areas with
Pentamidine has been used since 1939. During the 1950s, it
was widely used as a prophylactic agent in West Africa, leading
to a sharp decline in infection rates. At the time, it was thought
that eradication of the disease was at hand. The organoarsenical
melarsoprol (Arsobal) was developed in the 1940s and is
effective for patients with second stage sleeping sickness.
However, 3-10% of those injected have reactive encephalopa-
thy (convulsions, progressive coma, or psychotic reactions), and
those that survive can suffer brain damage. Despite this, because
of its effectiveness, melarsoprol is still widely used and
resistance is increasing. Eflornithine, the most modern treatment,
was developed in the 1970s by Albert Sjoerdsmanot and
underwent clinical trials in the 1980s. The drug was approved
by the U.S. Food and Drug Administration in 1990, but
guaranteed production remains a problem.
Recently, we discovered that bloodstream form T. brucei are
sensitive to the antiviral drug amantadine (I, Figure 1) and its
congener rimantadine (II, Figure 1) and that the potency of these
drugs is pH dependent, a factor that could be related to the
mechanism of action.7,8 Derivatives of these compounds (III-V,
Figure 1)8 were found to have potential as trypanocidal agents.8
For example, analogue V (1-adamantyl-4-aminocyclohexane)
(IC50 ) 0.33 µM) was 400 times more potent than amantadine
and 20-fold more active than rimantadine. Moreover, as a
general trend, we found a correlation between the lipophilicity
of derivatives and their trypanocidal activity.
Over the past 15 years we have sought to develop adamantane
derivatives with antiviral properties.9–11 In extending this work,
we describe the synthesis of 1-alkyl-2-aminoadamantanes 1,
1-alkyltricyclo[3.3.1.13,7]decan-2-guanylhydrazones 2 and their
respective thiosemicarbazones 3 (Figure 2) and report the
activity of these compounds against T. brucei. The design of
analogues 1 was based on our earlier findings, which link
lipophilicity with trypanocidal action.8 The rationale behind the
synthesis of 2 and their bioisosters 3 resided in the reported
antitrypanosome potency of heterocyclic guanylhydrazones and
thiosemicarbazones.12
* To whom correspondence should be addressed. Phone: 30 210 7274809.
Fax: 30 210 7274747. E-mail: kolocouris@pharm.uoa.gr.
Chemistry
†
The synthesis of analogues 1a-h is shown in Scheme 1.
Protoadamantanone 4,13 prepared by a modification of the
University of Athens.
‡
London School of Hygiene and Tropical Medicine.
10.1021/jm7014292 CCC: $40.75
2008 American Chemical Society
Published on Web 02/19/2008

Brief Articles
Journal of Medicinal Chemistry, 2008, Vol. 51, No. 5 1497
The ethylation of primary amines, such as 1a-e to their
congeners 1f-h by the solvent (ethanol), has been scarcely
reported in the literature and only in cases where the reaction
is run at high temperatures.15 It is noteworthy that at 120 °C
and after 5 h of hydrogenation only the secondary amines 1f-h
were detected in the reaction mixture. Moreover, their formation,
albeit partial, was also evident at temperatures below 80 °C. A
possible explanation for the observed ethylation of amines 1a-e
resides in the disproportionation of the solvent (ethanol), which,
under the specific reaction conditions, is rendered sufficiently
electrophilic.
The guanylhydrazones 2 were prepared by heating the
respective ketones (Scheme 2) with an ethanolic solution of
aminoguanidine hydrochloride; the latter was prepared by
acidifying (concentrated HCl) an ethanolic suspension of
aminoguanidine bicarbonate. For the synthesis of guanylhydra-
zone 2f, the organometallic reagent used was phenyllithium,
whereas for 2g it was phenylmagnesium bromide.
The thiosemicarbazones 3 were prepared by heating the
respective ketones 9 with an ethanolic solution of thiosemicar-
bazide (Scheme 3).
Results and Discussion
The 18 new adamantane derivatives were tested for activity
against bloodstream form T. brucei. The aminoadamantane
analogues (1a-i) allowed us to explore the synergism of the
amino and alkyl/aryl moieties. From Table 1, it can be seen
that increasing the size of the alkyl chain from n-hexyl (1a) to
n-dodecyl (1d, 1h) leads to an enhancement in potency.
Analogues 1d and 1h are ∼280- and 15-fold more active than
amantadine and rimantadine, respectively. However, the intro-
duction of a tetradecyl at the 1 position of 2-aminoadamantane
(1e) or a benzylic group (compound 1i) leads to a decrease in
activity. A difference in potency was also noticed between the
Figure 1. Structures of amantadine (I), rimantadine (II), and ami-
noadamantane derivatives with trypanocidal activity (III-V).8 The
concentrations that inhibit growth of bloodstream form T. brucei in
Vitro by 50% are indicated.
primary amines 1c and 1d (1c, IC90 ) 0.67 µM; 1d, IC90
0.67 µM) and their respective N-ethyl congeners 1g (IC90
)
)
1.65 µM) and 1h (IC90 ) 1.06 µM). Taking amantadine and
rimantadine as the basic structures, these results nicely illustrate
the effect of adding alkyl and phenyl groups at C1 and
converting the C2 amine from primary to secondary.
Comparison of the 1-amino derivatives (1a-i) with their
guanylhydrazone congeners (2a-g) shows that the nature of
the C2 substitution is even more important in the latter series
(Table 2). Compound 2c (R ) C8H17) is an exceptionally potent
adamantane derivative, being 1460- and 77-fold more active
than amantadine and rimantadine, respectively, and warrants
further investigation. Interestingly, this activity was reduced by
approximately 10-fold by lengthening the alkyl group from
n-decyl (2c) to n-dodecyl (2e). Another derivative that displayed
considerable trypanocidal activity was 2g (R ) Ph), which was
323- and 17-fold more potent than amantadine and rimantadine,
respectively. The differences between the 1-amino derivatives
(1a-i) and guanylhydrazones (2a-g) demonstrate that the latter
compounds show an enhanced activity that is not linked to the
degree of lipophilicity of the R group and/or its aliphatic or
aromatic nature but to the characteristic stereoelectronic features
of the guanylhydrazone component.
This hypothesis is further strengthened by the trypanocidal
activity data obtained for thiosemicarbazones 3a and 3b (Table
3), which are structurally related to guanylhydrazones (2a-g).
Thus, compound 3a (R ) C4H9; IC90 ) 5.64 µM) is ∼3-fold
less potent than its aminoadamantane congener 1a (R ) C4H9;
IC90 ) 1.73 µM) while 3b (R ) C12H25; IC90 ) 0.54 µM) is 4
times as active as 1e (R ) C12H25; IC90 ) 1.98 µM). However,
Figure 2. Structures of the new adamantane derivatives 1a-i, 2a-g,
and 3a,b.
literature method from the reaction of 1-adamantanol with iodine
and lead tetraacetate,14 was treated with the appropriate lithiated
acetylene to give the corresponding tertiary alcohol 5 as an endo/
exo isomeric (1:1) mixture in 82–95% yield. Alcohols 5 were
in turn hydrogenated under Adams’ conditions to the respective
endo/exo saturated products 6, which on treatment with formic
acid were converted to formates 7 via a C2-C3 to C4
metathesis. Saponification of the in situ formed esters 7 gave
the respective secondary alcohols 8 in 91–96% yield, and these
were then oxidized under Jones reaction conditions to the
corresponding 1-alkyl-2-ones 9. Treatment of ketones 9 with
hydroxylamine hydrochloride in the presence of sodium acetate
led to the formation of the respective oximes 10, which on
hydrogenation over Raney Ni catalyst were converted to a
mixture of amines, 1a-e and 1f-h; the yield of the latter was
found to increase upon heating and prolonged hydrogenation.
Amine 1i was obtained from ketone 4 by lithiation with
phenyllithium followed by the sequence of the reactions
described above.

1498 Journal of Medicinal Chemistry, 2008, Vol. 51, No. 5
Brief Articles
Scheme 1. Synthesis of the New Adamantane Derivatives 1a-ha
a Reagents and conditions: (a) RCt CH, n-BuLi, THF; (b) H2O; (c) H2/PtO2, EtOH, room temp; (d) HCOOH, reflux, 30 min; (e) NaOH/EtOH, ∆; (f)
CrO3, aqueous H2SO4 (8 N), acetone, 15 °C; (g) H2NOH·HCl, AcONa, EtOH; (h) H2/Raney Ni, EtOH, 80 °C.
Table 2. Trypanocidal Activity of
Scheme 2. Synthesis of the New Adamantane Derivatives 2a-e
(n ) 2), 2f (n ) 0), and 2g (n ) 1)a
1-Alkyltricyclodecan-2-guanylhydrazonesa
compd
1-alkyl side chain
IC50 (µM)
IC90 (µM)
2a
2b
2c
2e
2f
C6
C8
C10
C14
Ph
>6.0
>6.0
0.09 ( 0.02
0.84 ( 0.50
2.12 ( 0.09
0.41 ( 0.06
0.11 ( 0.00
1.30 ( 0.50
2.81 ( 0.03
0.47 ( 0.01
2g
PhCH2
a Derivatives 2a-g were tested against in vitro bloodstream form T.
brucei (pH 7.4) as outlined in the Supporting Information. The lengths or
nature of the 1-alkyl side chains is indicated. IC50 and IC90 data are the
mean of triplicate experiments ( SEM.
a Reagents and conditions: (a) aminoguanidine bicarbonate, HCl, EtOH, ∆.
Scheme 3. Synthesis of the New Adamantane Derivatives 3a,ba
Table 3. Trypanocidal Activity of
1-Alkyl-tricyclodecan-2-thiosemicarbazonesa
compd
1-alkyl side chain
IC50 (µM)
IC90 (µM)
3a
3b
C6
C14
2.81 ( 0.09
0.42 ( 0.04
5.64 ( 0.54
0.54 ( 0.02
a Derivatives 3a and 3b were tested against in vitro bloodstream form
T. brucei (pH 7.4) (Supporting Information). The lengths of the 1-alkyl
side chains are indicated. IC50 and IC90 data are the mean of triplicate
experiments ( SEM.
a Reagents and conditions: (a) thiosemicarbazide, EtOH, ∆.
Table 1. Trypanocidal Activity of 1-Alkyl-2-aminoadamantanesa
The five most active adamantane analogues identified in
this report, 1c, 1d, 2c, 2g, and 3b, illustrate the synergistic
effect on antitrypanosome activity of the lipophilic character
of the C1 side chain and C2 functionality. Continuing
attempts to define the characteristics of adamantane-based
structures required for effective activity against T. brucei are
currently underway. This would be greatly facilitated if the
target of these adamantine analogues in the trypanosome
could be identified. Our current model is that these drugs
probably block/perturb a parasite membrane-localized ion
channel/transporter, since this is the only known mechanism
by which this class of compound are therapeutically effective.
Channel blocking activity is the basis for the anti-influenza
virus properties of aminoadamantanes and is also the mech-
anism behind their effects on neurodegenerative disorders.
Respectively, this involves blockage of the M2 proton
channel16 and the transmembrane channel in the N-methyl-
D-aspartate receptor.17 The activity of amantadine against
hepatitis C virus is also mediated by blocking of an ion
channel, in this instance that formed by the viral encoded
protein p7.18
compd
1-alkyl side chain
IC50 (µM)
IC90 (µM)
amantadine
rimantadine
>132.4
>132.4
7.04 ( 0.27
1.32 ( 0.00
0.80 ( 0.36
0.48 ( 0.03
0.47 ( 0.02
0.92 ( 0.05
2.07 ( 0.03
>2
13.97 ( 1.67
1.73 ( 0.03
1.06 ( 0.46
0.67 ( 0.09
0.67 ( 0.00
1.98 ( 0.05
2.65 ( 0.00
1a
1b
1c
1d
1e
1i
C6
C8
C10
C12
C14
PhCH2
C6
1f
1g
1h
C10
C12
1.09 ( 0.28
0.59 ( 0.05
1.65 ( 0.28
1.06 ( 0.02
a Several 2-aminoadamantane derivatives were tested for in vitro activity
against bloodstream form T. brucei (pH 7.4), and the concentrations that
inhibited growth by 50% (IC50) and 90% (IC90) were calculated (Supporting
Information). The lengths or nature of the 1-alkyl side chains is indicated.
The derivatives contained primary (1a-e) or N-ethyl substituted (1f-i)
amino groups at the 2 position. IC50 and IC90 data are the mean of triplicate
experiments ( SEM.
the activity of the more lipophilic compound 3b is 10 times
higher than that of 3a. Both thiosemicarbazones were consider-
ably more active than amantadine and rimantadine, 3b being
respectively 315- and 17-fold more potent.

Brief Articles
Journal of Medicinal Chemistry, 2008, Vol. 51, No. 5 1499
The requisite 1-substituted-2-adamantanone (1.28 mmol) was then
added, and the mixture was refluxed for 5 h. The solvent was
evaporated in vacuo, and the residue obtained was treated with Et2O/
n-pentane. The precipitate formed was filtered, washed with
n-pentane, and dried to give the desired compound.
Experimental Section
General Procedure for the Preparation of 1-Alkyltricyclo-
[3.3.1.13,7]decan-2-amines 1a-e and N-Ethyl-1-alkyltricyclo-
[3.3.1.13,7]decan-2-amines 1f-h. A solution of the appropriate
ketoxime (1.63 mmol) in absolute EtOH (50 mL) under H2 (55
psi) in the presence of Raney Ni was heated at 80–100 °C for 4–5
h. The resulting suspension was filtered through Celite, and the
filtrate was concentrated in vacuo to give a liquid product, which
was flash-chromatographed (eluent Et2O) to give the title amines.
Both primary amines 1a-e and their N-ethyl congeners 1f-h were
treated with an HCl saturated ethanolic solution. The solvent was
evaporated, and n-pentane (1c), acetone (1b,d,e,h), ether (1a), or
water (1f,g) was added to the resulting residue, which was chilled
to 0 °C. The precipitate formed was filtered, washed with n-pentane,
acetone, ether, or water and dried to give the hydrochloride salts
of the title amines.
1-Hexyltricyclo[3.3.1.13,7]decan-2-guanylhydrazone (2a).
Yield 92%. Mp 173 °C (hydrochloride salt, EtOH/Et2O). IR (free
1
base, nujol) νmax 3441, 3315, 2588, 2425, 1598 cm-1. H NMR
(400 MHz, CDCl3) δ 0.87 (t, J ) 6.8 Hz, 3H, CH3), 1.27–1.44 (m,
10H, (CH2)5), 1.59–1.97 (m, 12H, H4–10), 3.70 (bs, 1H, H3-
adamantane), 4.82 (bs, 4H, NHC(dNH)NH2). 13C NMR (50 MHz,
CDCl3) δ 13.2 (CH3), 21.8 (C5′), 22.4 (C2′), 27.4 (C5,7), 29.6 (C3′),
30.3 (C3), 31.1 (C4′), 35.4 (C6), 37.2 (C4,10), 37.3 (C1′), 40.9 (C1),
43.2 (C8,9), 157.2 (CdN), 168.0 (NHC(dNH)NH2). Anal.
(C17H31N4Cl) C, H.
1-Octyltricyclo[3.3.1.13,7]decan-2-guanylhydrazone (2b). Yield
85%. Mp 177 °C (hydrochloride salt, EtOH/Et2O). Anal. (C19-
H35N4Cl) C, H.
1-Hexyltricyclo[3.3.1.13,7]decan-2-amine (1a). This compound
was obtained in 45% yield following the general method by
hydrogenating ketoxime 10 at 55 psi for 4 h at 100 °C. Mp 128 °C
(hydrochloride salt, Et2O). 1H NMR (400 MHz, CDCl3) δ 0.81 (t,
J ) 6.9 Hz, 3H, CH3), 0.91–1.19 (m, 10H, (CH2)5), 1.31–1.82 (m,
13H, H3–10), 2.66 (s, 1H, H2-adamantane). 13C NMR (50 MHz,
CDCl3) δ 14.0 (CH3), 21.8 CH3CH2NH), 28.5 (C7), 30.2 (C4), 30.7
(C4), 31.9 (C3), 35.5 (C3), 35.7 (C1), 36.8 (C1), 37.6 (C9), 37.8 (C6),
39.8 (C10), 41.1 (C8), 57.2 (C2). Anal. (C16H30NCl) C, H.
1-Decyltricyclo[3.3.1.13,7]decan-2-amine (1c). This compound
was obtained in 31% yield following the general method by
hydrogenating ketoxime 10 at 55 psi for 5 h at 80 °C. Mp 101 °C
(hydrochloride salt, EtOH/Et2O/n-pentane).
1-Decyltricyclo[3.3.1.13,7]decan-2-guanylhydrazone (2c). Yield
94%. Mp 133 °C (hydrochloride salt, EtOH/Et2O). Anal. (C21H39-
N4Cl) C, H.
1-Dodecyltricyclo[3.3.1.13,7]decan-2-guanylhydrazone (2d).
Yield 78%. Mp 172 °C (hydrochloride salt, EtOH/Et2O). Anal.
(C23H43N4Cl) C, H.
1-Tetradecyltricyclo[3.3.1.13,7]decan-2-guanylhydrazone (2e).
Yield 85%. Mp 98 °C (hydrochloride salt, EtOH/Et2O/n-pentane).
1-Phenyltricyclo[3.3.1.13,7]decan-2-guanylhydrazone (2f).
Yield 96%. Mp 251 °C (hydrochloride salt, EtOH/Et2O).
1-Benzyltricyclo[3.3.1.13,7]decan-2-guanylhydrazone (2g).
Yield 78%. Mp >255 °C (hydrochloride salt, EtOH/Et2O).
General Procedure for the Preparation of 1-Alkyltricyclo-
[3.3.1.13,7]decan-2-thiosemicarbazones 3a,b. A mixture of the
appropriate ketone 10 (1.28 mmol) and thiosemicarbazide (0.12 g,
1.28 mmol) in absolute EtOH (15 mL) was refluxed for 5 h. The
resulting suspension was concentrated in vacuo to 1/3 of its original
value, the solution chilled (0 °C), and the resulting precipitate
filtered and washed with cold EtOH to give the title compounds.
1-Hexyltricyclo[3.3.1.13,7]decan-2-thiosemicarbazone (3a).
Yield 82%. Mp 173 °C (hydrochloride salt, EtOH). IR (nujol) νmax
3416, 3254, 3148 cm-1. 1H NMR (400 MHz, CDCl3) δ 0.80 (t, J
) 6.4 Hz, 3H, CH3), 1.21–1.37 (m, 10H, (CH2)5), 1.58–1.94 (m,
12H, H4–10), 3.13 (s, 1H, H3-adamantane).
1-Dodecyltricyclo[3.3.1.13,7]decan-2-amine (1d). This com-
pound was obtained in 53% yield following the general method by
hydrogenating ketoxime 10 at 55 psi for 2 h at 105 °C. Mp 73 °C
(hydrochloride salt, methanol-acetone).
N-Ethyl-1-hexyltricyclo[3.3.1.13,7]decan-2-amine (1f). This
compound was obtained in 23% yield following the general method
by hydrogenating ketoxime 10 at 55 psi for 4 h at 100 °C. Mp 137
°C (hydrochloride salt, Et2O/n-pentane). 1H NMR (400 MHz,
CDCl3) δ 0.81 (t, J ) 6.8 Hz, 3H, CH3), 1.03 (t, J ) 7.0 Hz, 3H,
CH3CH2NH), 1.12–1.32 (m, 10H, (CH2)5), 1.33–1.86 (m, 13H,
H
3–10), 2.39 (bs, 1H, H2-adamantane), 2.45 (m, 1H, CH3CH2NH),
2.66 (m, 1H, CH3CH2NH). 13C NMR (50 MHz, CDCl3) δ 14.1
(CH3), 15.7 (CH3CH2NH), 21.8 (C5), 22.6 (C2′), 28.2 (C5), 28.4
(C7), 30.2 (C4), 30.6 (C3), 31.0 (C4‘), 31.9 (C3′), 35.6 (C1), 37.4
(C9), 38.1 (C1′), 39.8 (C10), 41.7 (C8), 42.0 (CH3CH2NH), 63.6
(CHNHCH2CH3). Anal. (C18H34NCl) C, H.
1-Tetradecyltricyclo[3.3.1.13,7]decan-2-thiosemicarbazone
(3b). Yield 89%. Mp 108 °C (hydrochloride salt, EtOH). IR (nujol)
νmax 3424, 3255, 3143 cm-1. Anal. (C25H45N3S) C, H.
Supporting Information Available: Experimental details of
the synthesis of the compounds described in this paper; NMR,
IR, and 2-D NMR spectra of selective compounds; elemental
analysis data for key target molecules; and pharmacological
assay. This material is available free of charge via the Internet
at http://pubs.acs.org.
N-Ethyl-1-decyltricyclo[3.3.1.13,7]decan-2-amine (1g). This
compound was obtained in 43% yield following the general method
by hydrogenating ketoxime 10 at 55 psi for 5 h at 80 °C. Yield
43%. Mp 69 °C (hydrochloride salt, H2O).
N-Ethyl-1-dodecyltricyclo[3.3.1.13,7]decan-2-amine (1h). This
compound was obtained in 30% yield following the general method
by hydrogenating ketoxime 10 at 55 psi for 2 h at 105 °C. Mp 105
°C (hydrochloride salt, acetone).
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1-Benzyltricyclo[3.3.1.13,7]decan-2-amine (1i). 1-Benzylada-
mantan-2-one oxime (3.40 mmol) in absolute EtOH (25 mL) under
H2 (55 psi) in the presence of Raney Ni was heated at 90 °C for
8 h. The resulting suspension was filtered through Celite, and the
filtrate was concentrated in vacuo to give 0.63 g of a viscous liquid
product, which was treated with an HCl saturated ethanolic solution.
The solvent was evaporated, and water was added to the resulting
residue, which was chilled to 0 °C. The precipitate formed was
filtered, washed with water, and dried to give the hydrochloride
salt of the title amine. Yield 82%. Mp >255 °C (hydrochloride
salt, EtOH/Et2O).
General Procedure for the Preparation of 1-Alkyltricyclo-
[3.3.1.13,7]decan-2-guanylhydrazones 2a-g. A suspension of
aminoguanidine bicarbonate (0.17 g, 1.28 mmol) in absolute EtOH
(15 mL) was cautiously acidified with concentrated HCl until the
mixture became soluble (pH ∼2) and CO2 gas ceased to evolve.

1500 Journal of Medicinal Chemistry, 2008, Vol. 51, No. 5
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