Synthesis and pharmacological evaluation of (2-oxaadamant-1-yl)amines

Article abstract of DOI:10.1016/j.bmc.2009.02.007

The synthesis of several (2-oxaadamant-1-yl)amines is reported. They were evaluated as NMDA receptor antagonists and several of them were more active than amantadine, but none was more potent than memantine. None of the tested compounds displayed antivira

Full text of DOI:10.1016/j.bmc.2009.02.007

Bioorganic & Medicinal Chemistry 17 (2009) 3198–3206
Contents lists available at ScienceDirect
Bioorganic & Medicinal Chemistry
journal homepage: www.elsevier.com/locate/bmc
Synthesis and pharmacological evaluation of (2-oxaadamant-1-yl)amines
María D. Duque a, Pelayo Camps a, Lenuta Profire a, Silvia Montaner a, Santiago Vázquez a,
,
*
Francesc X. Sureda b, Jordi Mallol b, Marta López-Querol b, Lieve Naesens c, Erik De Clercq c,
S. Radhika Prathalingam d, John M. Kelly d
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 Unitat de Farmacologia, Facultat de Medicina i Ciències de la Salut, Universitat Rovira i Virgili, c./St. Llorenç 21, Reus E-43201, Spain
c Rega Institute for Medical Research, Katholieke Universiteit Leuven, B-3000 Leuven, Belgium
d London School of Hygiene and Tropical Medicine, Department of Infectious and Tropical Diseases, Keppel Street, London WC1E 7HT, United Kingdom
a r t i c l e i n f o
a b s t r a c t
Article history:
The synthesis of several (2-oxaadamant-1-yl)amines is reported. They were evaluated as NMDA receptor
antagonists and several of them were more active than amantadine, but none was more potent than
memantine. None of the tested compounds displayed antiviral activity. Two of the derivatives showed
a significant level of trypanocidal activity.
Received 22 November 2008
Revised 5 February 2009
Accepted 6 February 2009
Available online 13 February 2009
Ó 2009 Elsevier Ltd. All rights reserved.
Keywords:
NMDA
Memantine
Amantadine
Adamantane
NGP1-01
Trypanosoma
Cage compounds
1. Introduction
explore the biological profile of (2-oxaadamant-1-yl)amine
derivatives.
1-Adamantylamine (amantadine) and its 3,5-dimethyl ana-
logue, memantine, are NMDA receptor antagonists approved for
the treatment of Parkinson’s and Alzheimer’s disease, respec-
tively.1 Amantadine also has prophylactic and therapeutic activi-
ties in influenza A virus infections2, and related adamantane
derivatives show antiviral activity.3 Moreover, amantadine,
memantine, and related polycyclic amines possess trypanocidal
properties.4
In this paper, we report the synthesis of several (2-oxaadamant-
1-yl)amines and related compounds and their pharmacological
evaluation as NMDA receptor antagonists, and antivirals and try-
panocidals agents.
2. Results and discussion
2.1. Chemistry
It is well known in medicinal chemistry that substitution of a
methylene unit in a bioactive compound for an oxygen atom usu-
ally leads to analogues showing similar activity to the parent com-
pound.5 Indeed, NGP1-01, a brain-permeable, oxa-polycyclic cage
amine, is a dual action uncompetitive NMDA receptor antagonist
and blocker of L-type calcium-channels. In addition, several exper-
iments have shown that NGP1-01 has neuroprotective activity
(Fig. 1).6
Starting from the known diketone 1,7 we have prepared amines
2ꢀ4, 7, 8, and 10ꢀ15 using classical methods in amine chemistry
(see Scheme 1).
H
N
R
NH2
Based on the interesting and widely observed biological activity
of amantadine, memantine, and NGP1-01, we therefore sought to
R
O
R = H, amantadine
R = Me, memantine
NGP1-01
* Corresponding author. Tel.: +34 934024533; fax: +34 934035941.
E-mail address: svazquez@ub.edu (S. Vázquez).
Figure 1. Amantadine, memantine, and NGP1-01 structures.
0968-0896/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmc.2009.02.007

M. D. Duque et al. / Bioorg. Med. Chem. 17 (2009) 3198–3206
3199
Secondary amines 2a and 2b were obtained in high yields fol-
lowing a known general procedure that involves reductive amina-
tion of diketone 1.8 Thus, reaction of 1 with benzylamine followed
by reduction with LiAlH4 led to amine 2a in 58% yield. Similarly,
reductive amination of 1 with phenethylamine furnished amine
2b in 51% yield. Reductive alkylation of amines 2a,b with formal-
dehyde and sodium cyanoborohydride afforded tertiary amines
3a,b in high yields. Hydrogenolysis of the benzyl group of amines
2a and 3a led to 7 and 4, respectively. Finally, alkylation of 2a with
benzyl chloride led to 8 in 85% yield.
Alcohols of general structure 5 were prepared using a general
method developed some time ago by our group.9 Several attempts
to carry out the substitution of the hydroxyl group of 5 by a wide
range of amines led to the recovery of the starting material. More-
over, the attempted Ritter reaction of 5c with acetonitrile in acidic
medium led to the known enone 6 in high yield.9c However, reac-
tion of 5a–c with aqueous hydrazine led to hydrazines 9a–c in high
Catalytic hydrogenation of 9a,b furnished amines 10a,b in high
yields. Surprisingly, 9c led to a mixture of the expected amine 10c
and the cyclohexyl derivative 10d in the ratio of 3:4. Both products
were separated by column chromatography. Reductive methyla-
tion of amines 10a and 10b with formaldehyde and sodium cyano-
borohydride afforded tertiary amines 11a and 11b, respectively. In
a similar way, reductive alkylation of 10b with acetaldehyde or
benzaldehyde led to amines 12 and 13, respectively. Finally, sec-
ondary amine 15 was synthesized from benzylamine 13 by reduc-
tive alkylation followed by catalytic debenzylation in good overall
yield.
The structure of all new compounds was confirmed by elemen-
tal analysis or by accurate mass measurement, IR, 1H NMR, 13C
NMR, and mass spectral data.
2.2. NMDA receptor antagonist activity
yields, probably due to the
ity of hydrazine. Even though the reaction failed in the case of 5d.
a
-effect ensuring a higher nucleophilic-
In the last years there has been an intensive research on the
development of new NMDA receptor antagonists, since this sub-
H
H
H
Heq
Hax
O
3
4
a
b
O2
c
O
O
10
7
O
5
1
9
R1
R1
NH
Hanti
N
N
H
6
Heq
Me
8
Me
Hsyn
Hax
2a, R1 = C6H5CH2
2b, R1 = C6H5CH2CH2
3a, R1 = C6H5CH2
3b, R1 = C6H5CH2CH2
1
4
c
ref. 9
d
H
R3
H
C6H5
O
O
e
O
O
CH2C6H5
N
OH
NH2
CH2C6H5
5a, R3 = Me
5b, R3 = Et
5c, R3 = C6H5
5d, R3 = t-Bu
8
6
7
f
R3
R3
O
R3
g
h
O
O
Me
N
NHNH2
NH2
Me
9a, R3 = Me
10a, R3 = Me
11a, R3 = Me
11b, R3 = Et
9b, R3 = Et
10b, R3 = Et
9c, R3 = C6H5
10c, R3 = C6H5
10d, R3 = c-Hex
i
j
Et
Et
Et
Et
c
b
O
Et
N
O
O
O
CH2C6H5
Me
Me
N
N
H
N
H
Et
CH2C6H5
12
13
14
15
Scheme 1. Reagents and conditions: (a) Benzylamine or phenethylamine, anhyd THF, reflux, 30 min; then, LiAlH4, anhyd Et2O, reflux, 6 h; 58% for 2a, 51% for 2b; (b)
formaldehyde, NaBH3CN, AcOH, acetonitrile, 4 h; 99% for 3a, 88% for 3b, 86% for 14; (c) H2 (38 atm), 100 °C, Pd/C, EtOH, 24 h; 59% for 4, 70% for 7, 85% for 15; (d) benzyl
chloride, K2CO3, NaI, acetonitrile, reflux; 18 h, 85%; (e) acetonitrile, H2SO4, reflux, 18 h; 90%; (f) hydrazine hydrate, concd HCl, reflux, 18 h; 84% for 9a, 45% for 9b, 62% for 9c;
(g) H2 (1 atm), PtO2, EtOH, 4 days; 58% for 10a, 48% for 10b, 29% for 10c and 42% for 10d; (h) HCO2H, CH2O 37% aq, 80 °C, 10 h; 51% for 11a, 27% for 11b; (i) acetaldehyde,
NaBH3CN, acetic acid, MeOH, 18 h, 73%; (j) benzaldehyde, NaBH3CN, AcOH, acetonitrile, 4 h, 79%.

3200
M. D. Duque et al. / Bioorg. Med. Chem. 17 (2009) 3198–3206
Table 1
supervision, and in many cases, a lack of efficacy. New drugs to
IC50 (l
M) values for (2-oxaadamant-1-yl)amines as NMDA antagonistsa,b
combat this important disease are urgently needed. A range of ada-
mantylamine compounds have trypanocidal activity.4 We there-
fore investigated whether this property also extended to (2-
oxaadamant-1-yl)amine derivatives.
All the new derivatives described in this paper were tested for
potency against cultured bloodstream form T. brucei. As was the
case with the NMDA receptor antagonism, the presence of a substi-
tution at the C-3 position in the 2-oxadamantane nucleus was
found to be essential for trypanocidal activity. Of these com-
pounds, the tertiary amines 11a,b were found to be the most ac-
Compound
Glutamate (100
lM)
NMDA (100
83
226 37
94 13
55 12
lM)
10b
10c
10d
11b
12
15
223 52
350 108
>500
6
106 10
22
7
14
32
92 29
3
9
108 17
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 the experimental section 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 different batches of cultured
cells.
tive. Amine 11b had an IC50 = 10.92 0.21
l
M and an IC90 = 15.54
M, while the trimethyl derivative 11a had an IC50 = 3.97
M and an IC90 = 6.82 0.84 M. Amine 11a was the most
1.14
0.75
l
l
l
potent compound tested, being approximately twice as active as
rimantadine (IC50 = 7.04 0.12 M; IC90 = 13.97 1.68 M), and
at least 30 times more active than amantadine (IC50 > 130 M).
l
l
b
Compounds 2a, 2b, 3a, 3b, 4, 7, 8, 9a, 10a, 11a, 13, and 14 were found to have
l
low potency as glutamate (IC50 > 500
lM) and NMDA receptor antagonists
(IC50 > 200 M). Hydrazines 9b and 9c were not evaluated.
l
Amines 2a,b, 3a,b, 4, 7, and 8, which lack the C3 substitution,
had no activity at concentrations up to 5 mg mLꢀ1. The primary
and secondary amines 10a–d, 13, and 15 also displayed no signif-
icant trypanocidal properties, even though they do carry a substi-
tution at this position.
Several adamantane derivatives have previously been shown to
have trypanocidal properties; however the oxanalogues reported
here are the first heteroadamantanes to show significant activity
against bloodstream form T. brucei.4
type of receptors has been involved in the apoptotic process that
develops during neurodegenerative diseases. Memantine is a
non-competitive and low affinity blocker that acts selectively on
NMDA receptors that is being used in Alzheimer’s disease to slow
down its progression.10
The activity of the different (2-oxaadamant-1-yl)amines was as-
sayed on cerebellar granule neurons loaded with the calcium-sen-
sitive probe Fura-2.11 Addition of glutamate or NMDA (100
l
M) in
3. Conclusions
the presence of glycine (10
lM) produced a robust and stable in-
crease in intracellular calcium that was challenged with cumula-
tive additions of the compounds to be tested. The data presented
in Table 1 indicate that the presence of a substituent in C-3 in
the 2-oxaadamantane nucleus is essential for NMDA receptor
antagonism. Thus, primary amine 7 and all its N-alkylated and N-
dialkylated derivatives (2a,b, 3a,b, 4, and 8) are inactive as it is
the case of the methyl derivatives 10a and 11a. Phenyl derivative
10c is only a weak NMDA receptor antagonist while more lipo-
philic amines 10b and 10d show a similar potency than amanta-
dine. Further enhancement in potency was achieved by
alkylation of 10b, the most active derivative being 12, a tertiary
amine that is seven times more potent than amantadine, but still
ten times less potent than memantine. Contrary to our expecta-
tions, all the benzyl derivatives were found to be inactive. This is
in striking contrast with NGP1-01 that features a benzyl group
essential for NMDA receptor antagonism, and with previous work
by our groups that found that benzylated ring-contracted ana-
logues of amantadine showed NMDA receptor antagonism.12
In summary, we have synthesized and fully characterized sev-
eral (2-oxaadamant-1-yl)amines. The presence of a substitution at
the C-3 position is essential for NMDA receptor antagonism.
Although 11b, 12, and 15 were more potent than amantadine
against NMDA-induced calcium increase in cerebellar granule
neurons, they were less potent than memantine. In contrast with
the model compound NGP1-01, all our benzyl derivatives were
devoid of NMDA receptor antagonism activity. None of the tested
compounds showed antiviral activity. Two tertiary amines, 11a
and 11b, displayed a significant level of trypanocidal activity;
11a was twice as active as rimantadine. The mechanism by which
adamantylamine derivatives kill trypanosomes is unknown, but it
has been hypothesized by analogy with the known properties of
this class of compound that it may involve channel blocking
activity.4 The data obtained with the trimethyl amine 11a now
provides a basis for exploring if related derivatives have enhanced
activity.
The synthesis and pharmacological evaluation of more polycy-
clic cage amines are in progress.
2.3. Antiviral activity
4. Experimental
4.1. Chemistry
Primary amines 7, 10c, and 10d and secondary amines 2a, 4,
and 15 were tested for antiviral activity. None of the tested com-
pounds displayed activity against the enveloped DNA viruses her-
pes simplex virus (type 1 or type 2) or vaccinia virus; the
enveloped RNA viruses feline coronavirus, parainfluenza-3 virus,
respiratory syncytial virus, vesicular stomatitis virus, sindbis virus,
or Punta Toro virus; or the non-enveloped RNA viruses Coxsackie-
virus B4 and Reovirus-1. Also none of the compounds was found to
be active against influenza virus A/H1N1, A/H3N2, or B.
4.1.1. General
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 (75.4 MHz).
Chemical shifts (d) are reported in ppm are related to internal tet-
ramethylsilane (TMS). Assignments given for the NMR spectra are
based on DEPT, COSY 1H/1H, HETCOR 1H/13C (HSQC and HMBC se-
quences 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-meter
column [5% diphenyl-95% dimethylpolysiloxane, conditions: 10
2.4. Trypanocidal activity
Protozoan parasites of the Trypanosoma brucei species complex
are the causative agents of African trypanosomiasis, a disease that
is invariably fatal unless treated. However, current drugs are char-
acterized by toxicity, the need for administration under medical

M. D. Duque et al. / Bioorg. Med. Chem. 17 (2009) 3198–3206
3201
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
abundance, except for the ions with higher m/z values. Accurate
mass measurements were obtained using ESI technic. Absorption
values in the IR spectra (KBr) are given as wave-numbers (cmꢀ1).
Only the more intense bands are given. Column chromatography
was performed on silica gel 60 Å (35–70 mesh). For the thin layer
chromatography (TLC), aluminum-backed sheets with silica gel 60
F254 were used and spots were visualized with UV light and/or 1%
aqueous solutions of KMnO4.
4.1.4. N-Benzyl-N-methyl(2-oxaadamant-1-yl)amine, 3a
To a solution of 2aꢁHCl (838 mg, 3.00 mmol) in acetonitrile
(20 mL), formaldehyde (2.36 mL, 37 wt % in water solution,
30 mmol) and NaBH3CN (595 mg, 9.00 mmol) were added. The
mixture was stirred for 30 min at room temperature, acetic acid
(0.6 mL) was added and the mixture was stirred at room tem-
perature for 2 h. An additional portion of NaBH3CN (595 mg,
9.00 mmol) was added and the mixture was further stirred at
room temperature for 2 h. The mixture was concentrated to dry-
ness, 2 N NaOH (30 mL) was added and the suspension was ex-
tracted with CH2Cl2 (3 ꢂ 45 mL). The combined organic phases
were washed with H2O (2 ꢂ 30 mL), dried with anhyd Na2SO4,
filtered, and concentrated in vacuo to give 3a (765 mg, 99%
yield) as a white solid. The analytical sample was obtained by
crystallization from CH2Cl2, mp 60ꢀ61 °C (dec.). IR 2929, 2897,
2838, 1456, 1442, 1381, 1323, 1190, 994, 972, 957, 856,
4.1.2. N-Benzyl(2-oxaadamant-1-yl)amine hydrochloride,
2aꢁHCl
To a solution of diketone 1 (6.00 g, 39.4 mmol) in anhyd THF
(200 mL), benzylamine (4.29 g, 40.0 mmol) was added and the
solution was refluxed for 30 min. After cooling (ice-bath), this solu-
tion was added dropwise while stirring vigorously to a suspension
of LiAlH4 (3.00 g, 79.0 mmol) in anhyd diethyl ether (80 mL). The
mixture was stirred for 6 h at 40 °C and then, while cooling with
an ice-bath, 1 N NaOH (19 mL) was added dropwise. The precipi-
tate formed was filtered through CeliteÒ, the clear filtrate was
dried with anhyd Na2SO4, filtered, and concentrated in vacuo to
give an oily residue (9.29 g). The residue was dissolved in acetone
(120 mL), concd HCl (6 mL) was added and the solution was cooled
at 4 °C, whereupon 2a precipitated as its hydrochloride. Crystalli-
zation from 2-propanol gave pure 2aꢁHCl (6.39 g, 58% yield), mp
257ꢀ259 °C (lit.8b 253ꢀ255 °C). IR 2927, 2852, 2712, 2606, 2457,
2408, 2377, 1569, 1456, 1323, 1206, 1194, 1126, 1093, 1008,
747 cmꢀ1 1H NMR 1.55 [dm, J = 13.5 Hz, 2H, 4(10)-Hax], 1.67
.
[broad d, J = 12.0 Hz, 2H, 8(9)-Hax], 1.78 (dm, J = 13.5 Hz, 1H, 6-
Hsyn), 1.82 (dm, J = 13.5 Hz, 1H, 6-Hanti), 1.90 [dm, J = 13.5 Hz,
2H, 4(10)-Heq], 2.16 [dm, J = 12.0 Hz, 2H, 8(9)-Heq], 2.26 [broad
s, 2H, 5(7)-H], 2.29 (s, 3H, CH3–N), 3.81 (s, 2H, CH2–C6H5),
4.17 (broad s, 1H, 3-H), 4.86 (broad signal, mobile H), 7.19
(tm, J = 7.5 Hz 1H, Ar-Hpara), 7.28 (tm, J = 7.5 Hz, 2H, Ar-Hmeta),
7.32 (dm, J = 7.5 Hz, 2H, Ar-Hortho). 13C NMR (50.3 MHz) 28.5
[CH, C5(7)], 33.8 (CH3, CH3–N), 35.3 (CH2, C6), 35.4 [CH2,
C4(10)], 38.4 [CH2, C8(9)], 53.0 (CH2, CH2–C6H5), 70.2 (CH, C3),
85.4 (C, C1), 126.3 (CH, Cpara), 128.07 (CH) and 128.12 (CH) (Cme-
and Cortho), 141.5 (C, Cipso). MS (EI), m/z (%): 257 (MÅ+, 27), 214
ta
(15), 200 (42), 163 (41), 120 (19), 91 (100). Anal. Calcd for
C17H23NO (257.37): C, 79.33; H, 9.01; N, 5.44. Found: C, 79.25;
H, 9.11; N, 5.38.
994, 754, 739, 695 cmꢀ1 1H NMR 1.78 [dm, J = 12.5 Hz, 2H,
.
4(10)-Hax], 1.90 (dquint, J = 14.0 Hz, J0 = 2.5 Hz, 1H, 6-Hsyn), 1.97
(dtt, J = 14.0 Hz, J0 = 2.5 Hz, J00 = 1.5 Hz, 1H, 6-Hanti), 2.01–2.06 [com-
plex signal, 4H, 4(10)-Heq and 8(9)-Hax], 2.14 [dm, J = 11.5 Hz, 2H,
8(9)-Heq], 2.40 [broad s, 2H, 5(7)-H], 4.26 (s, 2H, CH2–C6H5), 4.39
(broad s, 1H, 3-H), 4.86 (broad signal, mobile H), 7.42–7.49 (com-
plex signal, 3H, Ar-Hmeta and Ar-Hpara) 7.50 (m, 2 H, Ar-Hortho).
13C NMR 29.4 [CH, C5(7)], 35.0 (CH2, C6), 35.1 [CH2, C4(10)], 37.8
[CH2, C8(9)], 45.1 (CH2, CH2–C6H5), 73.6 (CH, C3), 86.6 (C, C1),
130.2 (CH, Cmeta), 130.4 (CH, Cpara), 131.1 (CH, Cortho), 132.9 (C, Cipso).
MS (EI), m/z (%): 243 (MÅ+, 26), 200 (9), 186 (36), 149 (26), 106 (16),
91 (100). Anal. Calcd for C16H21NOꢁHCl (279.81): C, 68.68; H, 7.92;
N, 5.01; Cl, 12.67. Found: C, 68.51; H, 8.10; N, 5.00; Cl, 12.70.
4.1.5. N-Methyl-N-(2-phenylethyl)(2-oxaadamant-1-yl)amine
hydrochloride, 3b
To a solution of 2bꢁHCl (257 mg, 1.00 mmol) in acetonitrile
(10 mL), formaldehyde (0.78 mL, 37 wt % in water solution,
10 mmol) and NaBH3CN (188 mg, 3.00 mmol) were added. The
mixture was stirred for 30 min at room temperature, acetic acid
(0.3 mL) was added and the mixture was stirred at room tempera-
ture for 2 h. An additional portion of NaBH3CN (188 mg, 3.00 mmol)
was added and the mixture was further stirred at room tempera-
ture for 2 h. The mixture was concentrated to dryness, 2 N NaOH
(10 mL) was added and the suspension was extracted with CH2Cl2
(3 ꢂ 15 mL). The combined organic phases were washed with H2O
(2 ꢂ 10 mL), dried with anhyd Na2SO4, filtered, and concentrated
in vacuo to give 3b (239 mg, 88% yield) as a white solid. Its hydro-
chloride was obtained by adding an excess of Et2OꢁHCl to a solution
of the amine in EtOAc. The analytical sample of 16ꢁHCl was obtained
by crystallization from EtOAc, mp 211ꢀ212 °C. IR 2956, 2915, 2855,
2596, 2417, 1481, 1467, 1454, 1411, 1376, 1210, 1086, 1027, 996,
4.1.3. N-(2-Phenylethyl)(2-oxaadamant-1-yl)amine
hydrochloride, 2bꢁHCl
From
1
(3.00 g, 19.7 mmol), phenethylamine (2.55 g,
21.1 mmol) in anhyd THF (100 mL) and following the above proce-
dure, the amine 2b was obtained as its hydrochloride (2.94 g, 51%
yield), mp 256–259 °C (2-propanol). IR 2934, 2855, 2721, 2674,
2617, 2419, 1604, 1467, 1455, 1324, 1209, 1192, 1093, 1018,
749, 699 cmꢀ1 1H NMR (3b free base) 1.54 [dm, J = 13.0 Hz, 2H,
.
1001, 784, 725, 698 cmꢀ1
.
1H NMR 1.74 [dm, J = 14.0 Hz, 2H,
4(10)-Hax], 1.59 [dm, J = 12.0 Hz, 2H, 8(9)-Hax], 1.74 (dquint,
J = 13.0 Hz, J0 = 2.0 Hz, 2H, 6-Hsyn), 1.80 (dquint, J = 13.0 Hz,
J0 = 2.0 Hz, 2H, 6-Hanti), 1.88 [dm, J = 13.0 Hz, 2H, 4(10)-Heq], 2.07
[dm, J = 12.0 Hz, 2H, 8(9)-Heq], 2.23 [broad s, 2H, 5(7)-H], 2.47 (s,
3H, CH3–N), 2.79 (m, 2H, CH2–C6H5), 2.89 (m, 2H, CH2–N), 4.14
(broad s, 1H, 3-H), 4.86 (broad signal, mobile H), 7.18 (tm,
J = 7.5 Hz, 1H, Ar-Hpara), 7.20 (dm, J = 7.5 Hz, 2H, Ar-Hortho), 7.27
(tm, J = 7.5 Hz, 2H, Ar-Hmeta). 13C NMR (50.3 MHz) (3b free base)
28.4 [CH, C5(7)], 34.0 (CH3, CH3–N), 35.3 (CH2, C6), 35.4 [CH2,
C4(10)], 36.1 (CH2, CH2C6H5), 38.0 [CH2, C8(9)], 51.6 (CH2, CH2N),
69.9 (CH, C3), 85.4 (C, C1), 125.7 (CH, Ar-Cpara), 128.2 (CH) and
128.7 (CH) (Ar-Cortho and Ar-Cmeta), 140.9 (C, Ar-Cipso). MS (EI), m/z
(%): 228 (2), 214 (2), 181 (13), 180 ([MꢀCH2C6H5]+, 100), 137
(49). Anal. Calcd for C18H25NOꢁHCl (307.86): C, 70.23; H, 8.51; N,
4.55; Cl, 11.52. Found: C, 70.19; H, 8.59; N, 4.54; Cl, 11.80.
4(10)-Hax], 1.87 (dquint, J = 13.0 Hz, J0 = 2.5 Hz, 1H, 6-Hsyn), 1.95
(overlapped dm, 1H, 6-Hanti), 1.96–2.03 [complex signal, 4H,
4(10)-Heq and 8(9)-Hax], 2.06 [dm, J = 11.0 Hz, 2H, 8(9)-Heq], 2.38
[broad s, 2H, 5(7)-H], 2.99 (m, 2H, CH2–C6H5), 3.28 (m, 2H,
CH2N), 4.33 (broad s, 1H, 3-H), 4.86 (broad signal, mobile H),
7.27 (tm, J = 7.5 Hz, 1H, Ar-Hpara), 7.29 (dm, J = 7.5 Hz, 2H, Ar-
Hortho), 7.35 (tm, J = 7.5 Hz, 2H, Ar-Hmeta). 13C NMR (50.3 MHz)
29.3 [CH, C5(7)], 33.6 (CH2, CH2C6H5), 34.9 (CH2, C6), 35.0 [CH2,
C4(10)], 37.7 [CH2, C8(9)], 42.4 (CH2, CH2NH), 73.5 (CH, C3), 86.3
(C, C1), 128.2 (CH, Cpara), 129.7 (CH, Cortho), 130.0 (CH, Cmeta),
137.8 (C, Cipso). MS (EI), m/z (%): 257 (MÅ+, 1), 200 (10), 167 (12),
166 (100), 137 (54), 105 (22), 104 (27). Anal. Calcd for
C17H23NOꢁHCl (293.84): C, 69.49; H, 8.23; N, 4.77; Cl, 12.07. Found:
C, 69.21; H, 8.31; N, 4.71; Cl, 11.98.

3202
M. D. Duque et al. / Bioorg. Med. Chem. 17 (2009) 3198–3206
4.1.6. N-Methyl(2-oxaadamant-1-yl)amine hydrochloride,
4ꢁHCl
35.2 (CH2, C6), 35.3 [CH2, C4(10)], 40.2 [CH2, C8(9)], 51.9 (CH2,
CH2–C6H5), 70.2 (CH, C3), 86.4 (C, C1), 126.1 (CH, Cpara), 127.84
(CH) and 127.88 (CH) (Cmeta and Cortho), 142.2 (C, Cipso). MS (EI),
m/z (%): 333 (MÅ+, 11), 276 (11), 242 (20), 148 (15), 106 (36), 91
(100). Anal. Calcd for C23H27NO (333.47): C, 82.84; H, 8.16; N,
4.20. Found: C, 82.59; H, 8.19; N, 4.12.
A mixture of 3a (765 mg, 2.97 mmol) and 10% Pd/C (50% in
water, 200 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 to the combined organic filtrates
an excess of Et2OꢁHCl was added. Evaporation of the solvents from
the filtrate in vacuo followed by crystallization from MeOH/Et2O
gave 4ꢁHCl (357 mg, 59% yield), mp 226–230 °C. IR 2928, 2856,
2750, 2694, 2416, 2372, 1467, 1209, 1157, 1097, 1078, 1023,
4.1.9. (3-Methyl-2-oxaadamant-1-yl)hydrazine hydrochloride,
9aꢁHCl
A mixture of alcohol 5a (10.5 g, 62.5 mmol), hydrazine hydrate
(68.5 mL, 98% aq solution, 1.38 mol), and concd HCl (2.2 mL) was
refluxed for 18 h. The suspension was cooled (ice-bath) and the so-
lid hydrazine was filtered off and dried under reduced pressure. Its
hydrochloride (11.5 g, 84% yield) was obtained by adding an excess
of Et2OꢁHCl to a solution of the hydrazine in EtOAc (10 mL). The
analytical sample of 9aꢁHCl was obtained by crystallization from
MeOH/Et2O, mp 181ꢀ183 °C. IR 3180, 2923, 2681, 1690, 1611,
998 cmꢀ1 1H NMR 1.75 [dm, J = 12.5 Hz, 2H, 4(10)-Hax], 1.88
.
(dquint, J = 13.0 Hz, J0 = 2.5 Hz, 1H, 6-Hsyn), 1.95 (overlapped dm,
1H, 6-Hanti), 1.97 [overlapped dm, 4H, 8(9)-Heq and 8(9)-Hax],
1.99 [overlapped dm, 2H, 4(10)-Heq], 2.39 [broad s, 2H, 5(7)-H],
2.64 (s, 3H, CH3–N). 4.33 (broad s, 1H, 3-H), 4.86 (broad signal, mo-
bile H). 13C NMR (50.3 MHz) 25.5 (CH3, CH3–N), 29.2 [CH, C5(7)],
34.9 (CH2, C6), 35.0 [CH2, C4(10)], 37.4 [CH2, C8(9)], 73.4 (CH,
C3), 85.6 (C, C1). MS (CI, CH4), m/z (%): 169 (18), 168 ([M+H]+,
51), 167 (20), 125 (30), 112 (21), 111 (100), 110 (44), 75 (23), 74
(79), 73 (44), 72 (48), 59 (32). Anal. Calcd for
C10H17NOꢁ1.05HClꢁ0.25H20 (210.04): C, 57.18; H, 8.90; N, 6.67;
Cl, 17.72. Found: C, 57.36; H, 8.77; N, 6.76; Cl, 17.65.
1528, 1509, 1497, 1383, 1106, 1077, 943, 839 cmꢀ1 1H NMR 1.16
.
(s, 3H, CH3–C3), 1.60 [dm, J = 13.5 Hz, 2H, 4(10)-Hax], 1.63 [over-
lapped dm, 2H, 4(10)-Heq], 1.66 [overlapped dm, J = 12.5 Hz, 2H,
8(9)-Hax], 1.74 [dm, J = 12.5 Hz, 2H, 8(9)-Heq], 1.79 [complex signal,
2H, 6-Hanti and 6-Hsyn], 2.31 [m, 2H, 5(7)-H], 4.86 (s, mobile H). 13
C
NMR 29.0 (CH3, C3-CH3), 29.7 [CH, C5(7)], 34.9 (CH2, C6), 37.5 [CH2,
C8(9)], 41.4 [CH2, C4(10)], 74.8 (C, C3), 84.3 (C, C1). MS (EI), m/z (%):
183 (12), 182 (MÅ+, 100), 167 (16), 164 (22), 151 (47), 125 (43), 109
(38), 107 (31), 100 (22), 96 (20), 95 (34), 93 (94), 91 (26), 81 (35),
79 (25), 77 (22), 74 (30), 72 (47), 67 (31), 55 (31). Accurate mass
measurement (ESI+) calcd for [C10H18N2O+H]+: 183.1491. Found:
183.1493.
4.1.7. (2-Oxaadamant-1-yl)amine hydrochloride, 7ꢁHCl
A mixture of 2aꢁHCl (2.20 g, 7.87 mmol) and 10% Pd/C (50% in
water, 100 mg) in absolute EtOH (300 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 combined organic filtrates
were concentrated in vacuo to give a solid. 2 N NaOH (25 mL)
was added to the residue which was then extracted with EtOAc
(3 ꢂ 25 mL). The combined organic extracts were dried with anhyd
Na2SO4, filtered, and concentrated in vacuo to give a residue that
was sublimed at 60 °C/2 Torr to give amine 7. Its hydrochloride
(1.05 g, 70% yield) was obtained by adding an excess of a solution
of HCl in MeOH to the amine, followed by concentration in vacuo.
The analytical sample of 7ꢁHCl was obtained by crystallization from
MeOH, mp > 218 °C (dec.). IR 3034, 2945, 2851, 2789, 2744, 2697,
2631, 2563, 1578, 1502, 1384, 1359, 1329, 1304, 1211, 1156, 1016,
996 cmꢀ1. 1H NMR 1.74 [d, J = 13.0 Hz, 2H, 4(10)-Hax], 1.86 (dquint,
J = 13.5 Hz, J0 = 2.5 Hz, 1H, 6-Hsyn), 1.95 (overlapped dm, 1H, 6-Han-
ti), 1.96 [s, 4H, 8(9)-Hax and 8(9)-Heq], 1.98 [overlapped dm, 2H,
4(10)-Heq], 2.35 [broad s, 2H, 5(7)-H], 4.28 (broad s, 1H, 3-H),
4.86 (broad signal, mobile H). 13C NMR 29.2 [CH, C5(7)], 34.7
(CH2, C6), 35.0 [CH2, C4(10)], 39.5 [CH2, C8(9)], 73.0 (CH, C3),
82.3 (C, C1). MS (EI), m/z (%): 153 (MÅ+, 30), 136 (10), 110 (25),
96 (100), 95 (17), 94 (29), 85 (29), 67 (29), 60 (37), 59 (68), 57
(76). Anal. Calcd for C9H15NOꢁHCl (189.68): C, 56.99; H, 8.50; N,
7.38; Cl, 18.69. Found: C, 57.08; H, 8.61; N, 7.22; Cl, 18.54.
4.1.10. (3-Ethyl-2-oxaadamant-1-yl)hydrazine hydrochloride,
9bꢁHCl
From 5b (5.60 g, 30.7 mmol), hydrazine hydrate (33.5 mL, 98%
aq solution, 0.68 mol), and concentrated HCl (1.1 mL) and follow-
ing the procedure described for 9a, the hydrazine 9b was obtained
as its hydrochloride (3.20 g, 45% yield). The analytical sample of
9bꢁHCl was obtained by crystallization from 2-propanol/hexane,
mp 199ꢀ200 °C. IR 3176, 2914, 2852, 2682, 1609, 1529, 1515,
1442, 1383, 1206, 1138, 1079, 978, 956, 942, 839 cmꢀ1 1H NMR
.
0.91 (t, J = 7.5 Hz, 3H, CH3–CH2), 1.50 (q, J = 7.5 Hz, 2H, CH3–CH2),
1.58 [dm, J = 12.5 Hz, 2H, 4(10)-Hax], 1.62 [dm, J = 12.5 Hz, 2H,
4(10)-Heq], 1.67 [dm, J = 11.5 Hz, 2H, 8(9)-Hax], 1.74 [dm,
J = 11.5 Hz, 2H, 8(9)-Heq], 1.81 [complex signal, 2H, 6-Hanti and 6-
Hsyn], 2.33 [m, 2H, 5(7)-H], 4.86 (s, mobile H). 13C NMR 7.4 (CH3,
CH2CH3), 29.6 [CH, C5(7)], 35.3 (CH2, C6), 35.4 (CH2, CH2CH3),
37.8 [CH2, C8(9)], 38.9 [CH2, C4(10)], 77.0 (C, C3), 84.2 (C, C1).
MS (EI), m/z (%): 196 (MÅ+, 100), 178 (16), 167 (55), 165 (50), 125
(42), 107 (61), 95 (60), 93 (28), 91 (25), 81 (34), 79 (71), 74 (38),
72 (48), 67 (30), 57 (27), 55 (33). Accurate mass measurement
(ESI+) calcd for [C11H20N2O+H]+: 197.1648. Found: 197.1644.
4.1.8. N,N-Dibenzyl(2-oxaadamant-1-yl)amine, 8
A suspension of 2aꢁHCl (280 mg, 1.00 mmol), K2CO3 (690 mg,
5.00 mmol), benzyl chloride (0.14 mL, 1.25 mmol), and NaI
(50 mg, 0.33 mmol) in acetonitrile (10 mL) was heated under reflux
for 18 h. To the cold mixture, CH2Cl2 (20 mL) was added and the
solution was washed with water (2 ꢂ 20 mL). The organic layer
was dried with anhyd Na2SO4, filtered, and concentrated in vacuo.
The residue was crystallized from EtOAc to give amine 8 (283 mg,
85% yield), mp 155–157 °C. IR 2932, 2922, 2851, 1600, 1493, 1449,
4.1.11. (3-Phenyl-2-oxaadamant-1-yl)hydrazine hydrochloride,
9cꢁHCl
From 5c (1.85 g, 8.04 mmol), hydrazine hydrate (8.8 mL, 98% aq
solution, 0.18 mol), and concentrated HCl (0.3 mL) and following
the procedure described for 9a, the hydrazine 9c was obtained as
its hydrochloride (1.39 g, 62% yield). The analytical sample of
9bꢁHCl was obtained by crystallization from methanol, mp
203ꢀ204 °C. IR 3219, 2948, 2851, 2669, 1573, 1514, 1209, 996,
1382, 1321, 1198, 1158, 1122, 986, 959, 864, 746, 736, 699 cmꢀ1
.
1H NMR 1.54 [dm, J = 12.5 Hz, 2H, 4(10)-Hax], 1.59 [dm,
J = 12.0 Hz, 2H, 8(9)-Hax], 1.72 (broad d, J = 12.5 Hz, 1H, 6-Hsyn),
1.76 (broad d, J = 12.5 Hz, 1H, 6-Hanti), 1.90 (dm, J = 12.5 Hz, 2H,
4(10)-Heq], 2.14 [dm, J = 12.0 Hz, 2H, 8(9)-Heq], 2.18 [broad s, 2H,
5(7)-H], 4.01 (s, 4H, CH2–C6H5), 4.21 (broad s, 1H, 3-H), 4.86 (broad
signal, mobile H), 7.12 (t, J = 7.5 Hz, 2H, Ar-Hpara), 7.20 (t, J = 7.5 Hz,
4H, Hmeta), 7.30 (d, J = 7.5 Hz, 4H, Hortho). 13C NMR 28.5 [CH, C5(7)],
865, 754, 702 cmꢀ1 1H NMR 1.78 [dm, J = 12.5 Hz, 2H, 8(9)-Hax],
.
1.85 [dm, J = 12.5 Hz, 2H, 4(10)-Hax], 1.86–1.92 [complex signal,
3H, 8(9)-Heq and 6-Hanti], 1.98 (dm, J = 13.5 Hz, 1H, 6-Hsyn), 2.07
[dm, J = 12.5 Hz, 2H, 4(10)-Heq], 2.45 [m, 2H, 5(7)-H], 4.86 (s, mo-
bile H), 7.22 (tm, 1H, J = 7.5 Hz, Ar-Hpara), 7.32 (tm, J = 7.5 Hz, 2H,
Ar-Hmeta), 7.52 (dm, J = 7.5 Hz, 2H, Ar-Hortho). 13C NMR
(100.6 MHz) 30.0 [CH, C5(7)], 34.8 (CH2, C6), 37.6 [CH2, C8(9)],

M. D. Duque et al. / Bioorg. Med. Chem. 17 (2009) 3198–3206
3203
41.7 [CH2, C4(10)], 78.1 (C, C3), 85.1 (C, C1), 125.3 (CH, Ar-Cortho),
127.9 (CH, Ar-Cpara), 129.1 (CH, Ar-Cmeta), 147.9 (C, Ar-Cipso). MS
(EI), m/z (%): 245 (14), 244 (M+, 76), 213 (32), 171 (13), 169 (15),
156 (17), 155 (100), 129 (20), 125 (31), 105 (23), 95 (29), 91
(34), 77 (37), 72 (29). Anal. Calcd for C15H20N2OꢁHCl (280.80): C,
64.16; H, 7.54; N, 9.98; Cl, 12.63. Found: C, 64.03; H, 7.42; N,
9.86; Cl, 12.51.
NaOH was added till basic pH. The suspension was extracted with
EtOAc (5 ꢂ 10 mL). The combined organic phases were dried with
anhyd Na2SO4, filtered, and concentrated in vacuo to give a mixture
of 10c and 10d. Column chromatography of this mixture (silica gel,
hexane/EtOAc mixtures) gave amine 10d (hexane/EtOAc, 8/2,
454 mg, 43% yield) and amine 10c (hexane/EtOAc, 6/4, 311 mg,
29% yield). Their hydrochlorides were obtained by adding excess
of a solution of HCl in Et2O to a solution of the corresponding
amine in EtOAc. 10cꢁHCl, mp 254ꢀ260 °C (dec.). IR 2920, 2859,
4.1.12. (3-Methyl-2-oxaadamant-1-yl)amine hydrochloride,
10aꢁHCl
1502, 1232, 1028, 758, 699 cmꢀ1
.
1H NMR 1.86ꢀ1.92 [complex
A mixture of 9aꢁHCl (6.70 g, 30.6 mmol) and PtO2 (20 mg) in
absolute EtOH (200 mL) was hydrogenated at 1 atm and room tem-
perature for 4 days. The suspension was filtered, the residue was
washed with absolute EtOH, and the combined organic filtrates
were concentrated in vacuo to dryness. The obtained white residue
was taken in water (100 mL), the solution was basified with 2 N
NaOH, and was extracted with EtOAc (5 ꢂ 80 mL). The combined
organic extracts were dried with anhyd Na2SO4, and concentrated
in vacuo to dryness. The residue was taken in the minimum
amount of AcOEt and the solution was treated with an excess of
a solution of HCl in Et2O. The precipitate was filtered and washed
with Et2O to give 10aꢁHCl (3.60 g, 58% yield). The analytical sample
of 10aꢁHCl was obtained by crystallization from MeOH, mp
268ꢀ269 °C. IR 2966, 2924, 2852, 1582, 1516, 1379, 1235, 1060,
signal, 3H, 4(10)-Hax and 6-Hanti], 1.98–2.05 [complex signal, 5H,
8(9)-Hax, 8(9)-Heq and 6-Hsyn], 2.14 [dd, J = 12.7 Hz, J0 = 2.5 Hz, 2H,
4(10)-Hec], 2.51 [m, 2H, 5(7)-H], 4.86 (s, mobile H), 7.24 (tt, J = 7.5 Hz,
J0 = 1.5 Hz, 1H, Ar-Hpara), 7.33 (tm, J = 7.5 Hz, 2H, Ar-Hmeta), 7.46 (dm,
J = 7.5 Hz, 2H, Ar-Hortho). 13C NMR (100.6 MHz) 30.1 [CH, C5(7)],
33.9 (CH2, C6), 39.0 [CH2, C8(9)], 41.3 [CH2, C4(10)], 79.0 (C, C3),
83.9 (C, C1), 125.0 (CH, Ar-Cortho), 128.1 (CH, Ar-Cpara), 129.2 (CH,
Ar-Cmeta), 147.2 (C, Ar-Cipso). MS (EI), m/z (%): 230 (18), 229
(MÅ+,100), 212 (26), 170 (36), 155 (24), 129 (41), 110 (78), 105
(28), 91 (23), 77 (38), 57 (40). Anal. Calcd for C15H19NOꢁHCl
(265.78): C, 67.79; H, 7.58; N, 5.27; Cl, 13.34. Found: C, 67.60; H,
7.70; N, 5.14; Cl, 13.37; 10dꢁHCl, mp 255ꢀ256 °C. IR 2930, 2914,
2852, 1495, 1227, 1060, 1019 cmꢀ1 1H NMR 1.04 [dq, J = 2.5 Hz,
.
J0 = 12.5 Hz, 2H, 20(60)-Hax], 1.15 [overlapped tq, J = 3.5 Hz,
J0 = 13.0 Hz, 1H, 40-Hax), 1.15–1.25 [overlapped m, 2H, 30(50)-Hax],
1.30 [overlapped tt, J = 12.5 Hz, J0 = 3.0 Hz, 1H, 10-H], 1.65ꢀ1.70
[complex signal, 5H, 40-Heq, 4(10)-Hax and 4(10)-Heq], 1.77ꢀ1.92
[complex signal, 10H, 20(60)-Heq, 30(50)-Heq, 6-Hanti, 6-Hsyn, 8(9)-
Hax and 8(9)-Heq], 2.39 [broad s, 2H, 5(7)-H], 4.86 (s, mobile H).
13C NMR (100.6 MHz) 27.3 [CH2, C20(60)], 27.7 [CH2, C40 and
C30(50)], 29.8 [CH, C5(7)], 34.7 (CH2, C6), 36.5 [CH2, C4(10)], 39.3
[CH2, C8(9)], 49.3 (CH, C10), 80.0 (C, C3), 83.2 (C, C1). MS (EI), m/z
(%): 235 (MÅ+,28), 218 (11), 177 (12), 176 (60), 153 (18), 152
(100), 110 (56), 94 (38). Anal. Calcd for C15H25NOꢁHCl (271.83):
C, 66.28; H, 9.64; N, 5.15; Cl, 13.04. Found: C, 66.67; H, 9.95; N,
5.01; Cl, 12.63.
1038, 1005 cmꢀ1 1H NMR 1.18 (s, 3H, CH3–C3), 1.66 [dm,
.
J = 14.0 Hz, 2H, 4(10)-Hax], 1.70 [dm, J = 14.0 Hz, 2H, 4(10)-Heq],
1.81 [complex signal, 2H, 6-Hanti and 6-Hsyn], 1.85 [dm,
J = 11.5 Hz, 2H, 8(9)-Heq], 1.90 [dd, J = 11.5 Hz, J0 = 2.5 Hz, 2H,
8(9)-Hax], 2.38 [broad s, 2H, 5(7)-H], 4.86 (s, mobile H). 13C NMR
28.9 (CH3, C3–CH3), 29.8 [CH, C5(7)], 34.0 (CH2, C6), 38.9 [CH2,
C8(9)], 40.9 [CH2, C4(10)], 75.8 (C, C3), 83.2 (C, C1). MS (EI), m/z
(%): 168 (9), 167 (MÅ+, 73), 152 (33), 150 (27), 124 (27), 110
(100), 109 (37), 108 (68), 106 (21), 94 (28), 93 (49), 85 (72), 81
(37), 67 (22), 60 (21), 59 (47), 57 (66). Anal. Calcd for
C10H17NOꢁHClꢁ0.25H2O (208.22): C, 57.69; H, 8.96; N, 6.73; Cl,
17.03. Found: C, 57.78; H, 8.92; N, 7.01; Cl, 17.34.
4.1.13. (3-Ethyl-2-oxaadamant-1-yl)amine hydrochloride,
10bꢁHCl
4.1.15. N,N-Dimethyl(3-methyl-2-oxaadamant-1-yl)amine
hydrochloride, 11aꢁHCl
From 9bꢁHCl (2.00 g, 8.60 mmol) and PtO2 (5 mg) in absolute
EtOH (200 mL) and following the procedure described for 10a,
the amine 10b was obtained as its hydrochloride (900 mg,
48% yield). The analytical sample of 10bꢁHCl was obtained by
crystallization from MeOH, mp 218ꢀ219 °C. IR 2934, 2854,
1588, 1507, 1461, 1377, 1345, 1302, 1279, 1057, 1015,
To a cold (0 °C) solution of 10a (410 mg, 2.45 mmol) in Et2O
(8 mL), formaldehyde (4.85 mL, 37 wt % in water solution,
61 mmol) and formic acid (3.8 mL, 98 mmol) were added drop-
wise, and the mixture was stirred at 80 °C for 10 h. The mixture
was allowed to cool to room temperature, it was diluted with
Et2O (15 mL), 5 N NaOH (5 mL) was added dropwise, and the
suspension was stirred at room temperature for 15 min. The or-
ganic layer was separated and the aqueous phase was extracted
with Et2O (4 ꢂ 25 mL). The combined organic phases were dried
with anhyd Na2SO4, filtered, and an excess of a solution of HCl in
Et2O was added. Concentration in vacuo of this solution gave
11aꢁHCl. The analytical sample of 11aꢁHCl (300 mg, 51% yield)
was obtained by crystallization from MeOH/Et2O, mp
174ꢀ175 °C. IR 2963, 2912, 2856, 2654, 2556, 2519, 2458,
1488, 1471, 1450, 1438, 1410, 1378, 1240, 1155, 1033, 1021,
988 cmꢀ1 1H NMR 0.91 (t, J = 7.8 Hz, 3H, CH3CH2), 1.48 (q,
.
J = 7.8 Hz, 2H, CH3CH2), 1.62 [dm, J = 12.5 Hz, 2H, 4(10)-Hax],
1.70 [dm, J = 12.5 Hz, 2H, 4(10)-Heq], 1.82 [complex signal, 2H,
6-Hanti and 6-Hsyn], 1.85 [dm, J = 11.5 Hz, 2H, 8(9)-Heq], 1.91
[dd, J = 11.5 Hz, J0 = 2.5 Hz, 2H, 8(9)-Hax], 2.39 [broad s, 2H,
5(7)-H], 4.86 (s, mobile H). 13C NMR 7.2 (CH3, CH3CH2), 29.7
[CH, C5(7)], 34.4 (CH2, C6), 35.3 (CH2, CH3CH2), 38.5 [CH2,
C4(10)], 39.1 [CH2, C8(9)], 77.9 (C, C3), 83.2 (C, C1). MS (EI),
m/z (%): 182 (15), 181 (MÅ+, 76), 166 (11), 164 (31), 152 (79),
124 (39), 123 (37), 122 (69), 120 (20), 110 (100), 95 (35), 94
(55), 93 (63), 85 (81), 81 (33), 59 (43), 57 (82). Anal. Calcd
for C11H19NOꢁHCl (217.74): C, 60.68; H, 9.26; N, 6.43; Cl,
16.28. Found: C, 60.78; H, 9.43; N, 6.44; Cl, 16.26.
916 cmꢀ1 1H NMR 1.22 (s, 3H, CH3–C3), 1.69 [overlapped dm,
.
2H, 4(10)-Hax], 1.71 [overlapped dm, 2H, 4(10)-Heq], 1.82 [com-
plex signal, 2H, 6-Hanti and 6-Hsyn], 1.85 [dm, J = 11.0 Hz, 2H,
8(9)-Heq], 2.05 [dd, J = 11.0 Hz, J0 = 2.0 Hz, 2H, 8(9)-Hax], 2.46
[m, 2H, 5(7)-H], 2.83 [s, 6H, (CH3)2N]. 13C NMR 28.7 (CH3, C3–
CH3), 30.2 [CH, C5(7)], 34.1 (CH2, C6), 34.4 [CH2, C8(9)], 36.9
[CH3, (CH3)2N], 40.7 [CH2, C4(10)], 77.2 (C, C3), 91.8 (C, C1).
MS (EI), m/z (%): 196 (10), 195 (MÅ+, 76), 180 (24), 152 (17),
138 (81), 122 (18), 113 (35), 109 (17), 98 (21), 88 (17), 87
(100), 85 (32), 72 (34). Anal. Calcd for C12H21NOꢁHClꢁ0.5H2O
(240.77): C, 59.86; H, 9.63; N, 5.82; Cl, 14.72. Found: C, 60.04;
H, 9.32; N, 5.88; Cl, 14.73.
4.1.14. (3-Phenyl-2-oxaadamant-1-yl)amine hydrochloride,
10cꢁHCl and (3-cyclohexyl-2-oxaadamant-1-yl)amine
hydrochloride, 10dꢁHCl
From 9cꢁHCl (1.30 g, 4.63 mmol) and PtO2 (5 mg) in absolute
EtOH (60 mL) and following the procedure described for 10a, a
mixture of amines 10c and 10d was obtained as their hydrochlo-
rides. The mixture was diluted with water (25 mL) and then 2 N

3204
M. D. Duque et al. / Bioorg. Med. Chem. 17 (2009) 3198–3206
4.1.16. N,N-Dimethyl(3-ethyl-2-oxaadamant-1-yl)amine
hydrochloride, 11bꢁHCl
and benzaldehyde (0.42 mL, 4.12 mmol) were added, and the
mixture was stirred at room temperature for 2 h. An additional
portion of NaBH3CN (95%, 190 mg, 2.87 mmol) and benzaldehyde
(0.21 mL, 2.06 mmol) was added, the mixture was stirred at
room temperature for 16 h, and then it was concentrated in va-
cuo to dryness. Water (30 mL) was added to the residue, the sus-
pension was basified with 1 N NaOH, and was extracted with
EtOAc (4 ꢂ 15 mL). The combined organic extracts were washed
with brine (2 ꢂ 25 mL), dried with anhyd Na2SO4, filtered, and
concentrated in vacuo. The residue was taken in EtOAc and
13ꢁHCl (451 mg, 79% yield) was precipitated by adding an excess
of a solution of HCl in Et2O. The analytical sample of 13ꢁHCl was
obtained by crystallization from MeOH/Et2O, mp 213ꢀ214 °C. IR
2922, 2851, 2725, 2656, 2619, 2414, 1566, 1463, 1056, 1042,
To a cold (0 °C) solution of 10b (300 mg, 1.65 mmol) in Et2O
(5 mL), formaldehyde (3.5 mL, 37 wt % in water solution,
42.7 mmol) and formic acid (2.85 mL, 74 mmol) were added drop-
wise, and the mixture was stirred at 80 °C for 10 h. The cold mix-
ture was diluted with Et2O (15 mL), 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 (4 ꢂ 15 mL). The combined organic phases
were dried with anhyd Na2SO4, filtered, and treated with an excess
of Et2OꢁHCl. Concentration of the above mixture in vacuo gave
11bꢁHCl. The analytical sample of 11bꢁHCl (110 mg, 27% yield)
was obtained by crystallization from MeOH/Et2O, mp
129ꢀ130 °C. IR 2963, 2934, 2859, 2572, 2376, 1467, 1438, 1378,
1007, 988, 749, 690 cmꢀ1
.
1H NMR 0.96 (t, J = 7.5 Hz, 3H,
1297, 1150, 1040, 1022, 972, 938 cmꢀ1
.
1H NMR 0.93 (t,
CH3CH2), 1.56 (q, J = 7.5 Hz, 2H, CH3CH2), 1.67 [dm, J = 12.5 Hz,
2H, 4(10)-Hax], 1.77 [dm, J = 12.5 Hz, 2H, 4(10)-Heq], 1.87 [broad
signal, 2H, 6-Hanti and 6-Hsyn], 1.98 [dm, J = 11.5 Hz, 2H, 8(9)-
Hax], 2.04 [dm, J = 11.5 Hz, 2H, 8(9)-Heq], 2.46 [m, 2H, 5(7)-H],
4.25 [s, 2H, NCH2], 4.86 (s, mobile H), 7.42-7.50 (complex signal,
5H, Ar-H). 13C NMR 7.2 (CH3, CH3CH2), 29.9 [CH, C5(7)], 34.7
(CH2, C6), 35.2 (CH2, CH3CH2), 37.3 [CH2, C8(9)], 38.6 [CH2,
C4(10)], 45.1 (CH2, NCH2), 78.7 (C, C3), 87.6 (C, C1), 130.2 (CH,
Ar-Cortho), 130.4 (CH, Ar-Cpara), 131.1 (CH, Ar-Cmeta), 133.0 (C,
Ar-Cipso). MS (EI), m/z (%): 272 (15), 271 (MÅ+, 71), 242 (39),
200 (22), 160 (20), 149 (62), 91 (C7H7+, 100). Anal. Calcd for
C18H25NOꢁ1.1HCl (311.51): C, 69.40; H, 8.44; N, 4.50; Cl, 12.52.
Found: C, 69.38; H, 8.38; N, 4.43; Cl, 12.29.
J = 7.5 Hz, 3H, CH3CH2), 1.53 (q, J = 7.5 Hz, 2H, CH3CH2), 1.64
[ddm, J = 13.0 Hz, J0 = 2.0 Hz, 2H, 4(10)-Hax], 1.73 [broad d,
J = 13.0 Hz, 2H, 4(10)-Heq], 1.84 [overlapped signal, 2H, 6-Hanti
and 6-Hsyn], 1.85 [overlapped broad d, 2H, 8(9)-Heq], 2.05 [broad
dd, J = 11.5 Hz, J0 = 2.5 Hz, 2H, 8(9)-Hax], 2.48 [broad s, 2H, 5(7)-
H], 2.83 [s, 6H, (CH3)2N], 4.85 (s, mobile H). 13C NMR 7.2 (CH3,
CH3CH2), 30.1 [CH, C5(7)], 34.6 [CH2, C6 and C8(9)], 35.1 (CH2,
CH3CH2), 36.8 [CH3, (CH3)2N], 38.4 [CH2, C4(10)], 79.3 (C, C3),
91.8 (C, C1). MS (EI), m/z (%): 209 (MÅ+, 60), 180 (59), 152 (25),
138 (39), 122 (27), 113 (33), 88 (16), 87 (100), 72 (25). Accurate
mass measurement (ESI+) calcd for [C13H23NO+H]+: 210.1852.
Found: 210.1859.
4.1.17. N,N-Diethyl(3-ethyl-2-oxaadamant-1-yl)amine
hydrochloride, 12ꢁHCl
4.1.19. N-Benzyl-N-methyl(3-ethyl-2-oxaadamant-1-yl)amine
hydrochloride, 14ꢁHCl
To a solution of 10bꢁHCl (350 mg, 1.60 mmol) in methanol
(20 mL), NaBH3CN (95%, 200 mg, 3.20 mmol), AcOH (0.6 mL), and
acetaldehyde (0.56 mL, 9.6 mmol) were added and the mixture
was stirred at room temperature for 2 h. An additional portion of
NaBH3CN (95%, 100 mg, 1.60 mmol) and acetaldehyde (0.26 mL,
4.8 mmol) was added, the mixture was stirred at room temperature
for 16 h, and then it was concentrated in vacuo to dryness. Water
(30 mL) was added to the residue, the suspension was basified with
NaHCO3 (saturatedaqueoussolution), and wasextractedwith EtOAc
(3 ꢂ 15 mL). The combined organic extracts were dried with anhyd
Na2SO4, filtered, and concentrated in vacuo. The residue was taken
in EtOAc and 12ꢁHCl (320 mg, 73% yield) was precipitated by adding
an excess of a solution of HCl in Et2O. The analytical sample of 12ꢁHCl
was obtained by crystallization from MeOH/Et2O, mp 195ꢀ196 °C.
IR 2972, 2933, 2855, 2645, 2579, 2484, 1458, 1446, 1377, 1033,
To a solution of 13ꢁHCl (90 mg, 0.29 mmol) in acetonitrile
(10 mL), formaldehyde (0.23 mL, 37 wt % in water solution,
0.29 mmol) and NaBH3CN (95%, 55 mg, 0.83 mmol) were added.
The mixture was stirred at room temperature for 30 min, AcOH
(0.2 mL) was added and the mixture was stirred at room tem-
perature for 2 h. An additional portion of NaBH3CN (95%,
55 mg, 0.83 mmol) was added and the mixture was further stir-
red at room temperature for 16 h. The mixture was concentrated
in vacuo to dryness, 1 N NaOH (15 mL) was added, and the sus-
pension was extracted with CH2Cl2 (5 ꢂ 10 mL). The combined
organic phases were washed with H2O (2 ꢂ 10 mL), dried with
anhyd Na2SO4, filtered, and concentrated in vacuo to give the
amine 14. The amine was taken in EtOAc and was precipitated
as its hydrochloride (80 mg, 86% yield) by adding an excess of
a solution of HCl in Et2O. The analytical sample of 14ꢁHCl was
obtained by crystallization from MeOH/Et2O, mp 165ꢀ166 °C.
IR 2969, 2921, 2853, 2472, 2353, 1458, 1033, 1024, 972, 938,
1014, 975, 949 cmꢀ1 1H NMR 0.93 (t, J = 7.5 Hz, 3H, CH3CH2C3),
.
1.38 (t, J = 7.5 Hz, 6H, (CH3CH2)2N), 1.53 (q, J = 7.5 Hz, 2H,
CH3CH2C3), 1.64 [dm, J = 13.0 Hz, 2H, 4(10)-Hax], 1.75 [dm,
J = 13.0 Hz, 2H, 4(10)-Heq], 1.82 (overlapped dm, 1H, 6-Hanti), 1.85
(overlapped dm, 1H, 6-Hsyn), 1.94 [dm, J = 12.5 Hz, 2H, 8(9)-Heq],
2.09 [dm, J = 12.5 Hz, 2H, 8(9)-Hax], 2.47 [tm, J = 2.5 Hz, 2H, 5(7)-
H], 3.06 (broad signal, 2H) and 3.59 (broad signal, 2H) [diastereotop-
ic (CH3CH2)2N]. 13C NMR (100.6 MHz) 7.2 (CH3, CH3CH2C3), 12.1
[CH3, (CH3CH2)2N], 30.2 [CH, C5(7)], 34.6 (CH2, C6), 35.2 (CH2,
CH3CH2C3), 35.4 [CH2, C8(9)], 38.4 [CH2, C4(10)], 45.4 [CH2,
(CH3CH2)2N], 79.3 (C, C3), 93.9 (C, C1). MS (EI), m/z (%): 238 (16),
237 (MÅ+, 59), 222 (14), 209 (19), 208 (74), 180 (30), 166 (48), 150
(23), 126 (31), 115 (100), 100 (54). Anal. Calcd for C15H27NOꢁHCl
(273.85): C, 65.79; H, 10.31; N, 5.11; Cl, 12.95. Found: C, 65.64; H,
10.50; N, 5.13; Cl, 13.01.
750, 702 cmꢀ1 1H NMR 0.99 (t, J = 7.5 Hz, 3H, CH3CH2), 1.60
.
(q, J = 7.5 Hz, 2H, CH3CH2), 1.69 (dm, J = 12.5 Hz, 2H, 4-Hax and
10-Hax,), 1.77ꢀ1.84 (broad signal, 2H, 4-Heq and 10-Heq), 1.87
(overlapped dm, 1H, 6-Hanti), 1.89 (overlapped dm, 1H, 6-Hsyn),
1.94ꢀ2.08 [broad signal, 2H, 8-Hax and 9-Hax], 2.14ꢀ2.25 [broad
signal,
2H,
8-Heq
and
9-Heq],
2.53
[broad
s,
2H, 5(7)-H], 2.71 (s, 3H, NCH3), 3.93 (broad d, 1H, J = 8.0 Hz)
and 4.85 (overlapped signal, 1H) (NCH2Bn), 4.86 (s, mobile H),
7.50 (complex signal, 5H, Ar-H). 13C NMR 7.3 (CH3, CH3CH2),
30.3 [CH, C5(7)], 33.5 (CH3, CH3N), 34.2 (CH2) and 35.8 (CH2)
(diastereotopic C8 and C9), 34.7 (CH2, C6), 35.2 (CH2, CH3CH2),
38.3 (CH2) and 38.5 (CH2) (diastereotopic C4 and C10), 54.7
(CH2, NCH2), 79.8 (C, C3), 93.3 (C, C1), 130.3 (CH, Ar-Cortho),
131.0 (CH, Ar-Cpara), 131.5 (C, Ar-Cipso), 132.4 (CH, Ar-Cmeta).
MS (EI), m/z (%): 286 (14), 285 (MÅ+, 64), 256 (41), 228 (16),
214 (21), 174 (20), 163 (82), 91 (100). Anal. Calcd for
C19H27NOꢁHClꢁ0.4H2O (332.74): C, 69.34; H, 8.82; N, 4.26; Cl,
10.77. Found: C, 69.39; H, 8.73; N, 4.18; Cl, 11.05.
4.1.18. N-Benzyl(3-ethyl-2-oxaadamant-1-yl)amine
hydrochloride, 13ꢁHCl
To
a
solution of 10bꢁHCl (400 mg, 1.84 mmol) in MeOH
(10 mL), NaBH3CN (95%, 393 mg, 5.93 mmol), AcOH (0.3 mL),

M. D. Duque et al. / Bioorg. Med. Chem. 17 (2009) 3198–3206
3205
4.1.20. N-Methyl(3-ethyl-2-oxaadamant-1-yl)amine
hydrochloride, 15ꢁHCl
were determined using a hemocytometer (Weber Scientific Inter-
national Ltd), and drug sensitivity was expressed as a percentage
of growth of control cells.
A mixture of 14ꢁHCl (390 mg, 1.21 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 res-
idue was washed with EtOH, and the combined organic filtrates
were treated with an excess of a solution of HCl in Et2O. The
solution was concentrated in vacuo and the residue was crystal-
lized from MeOH/Et2O to give the analytical sample of 15ꢁHCl
(240 mg, 85% yield), mp 155ꢀ156 °C. IR 2968, 2931, 2848,
2706, 2592, 1561, 1474, 1118, 1068, 1057, 1028, 991,
Acknowledgments
P.C., F.X.S. and S.V. gratefully acknowledge financial support
from Ministerio de Educación y Ciencia (P.C. and S.V.: Project
CTQ2005-02192; F.X.S.: Project SAF 2006-13092-C02-01) and
Comissionat per a Universitats i Recerca (P.C. and S.V.: Project
2005-SGR-00180, F. X. S.: Project 2005-SGR-00893). M.D.D. thanks
the Ministerio de Educación y Ciencia (FPU Program). L.P. thanks the
European Commision for a Marie Curie Fellowship. S.R.P. and J.M.K.
acknowledge Wellcome Trust for support.
972 cmꢀ1 1H NMR 0.92 (t, J = 7.5 Hz, 3H, CH3CH2), 1.50 (q,
.
J = 7.5 Hz, 2H, CH3CH2), 1.63 [dm, J = 12.5 Hz, 2H, 4(10)-Hax],
1.72 [dm, J = 12.5 Hz, 2H, 4(10)-Heq], 1.84 [s, 2H, 6-Hanti and 6-
Hsyn], 1.87 [dm, J = 13.0 Hz, 2H, 8(9)-Hax], 1.91 [dm, J = 13.0 Hz,
2H, 8(9)-Heq], 2.43 [broad s, 2H, 5(7)-H], 2.63 (s, 3H, NCH3).
13C NMR (100.6 MHz) 7.1 (CH3, CH3CH2), 25.5 (CH3, NCH3),
29.8 [CH, C5(7)], 34.6 (CH2, C6), 35.2 (CH2, CH3CH2), 37.0 [CH2,
C8(9)], 38.6 [CH2, C4(10)], 78.5 (C, C3), 86.5 (C, C1). MS (EI,
CH4), m/z (%): 196 (11), 195 (MÅ+, 84), 180 (11), 166 (69), 138
(26), 124 (56), 108 (37), 99 (62), 95 (31), 74 (28), 73 (100), 71
(51). Anal. Calcd for C12H21NOꢁ1.1HClꢁ0.5H2O (242.60): C,
59.41; H, 9.58; N, 5.77; Cl, 15.34. Found: C, 59.41; H, 9.89; N,
6.11; Cl, 15.61.
References and notes
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l
45 min. Afterwards, the coverslip was mounted on a quartz cuvette
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