New adamantane derivatives with sigma affinity and antiproliferative activity

Article abstract of DOI:10.2174/157340612801216201

The synthesis of 4-(1-adamantyl)-4,4-diarylbutylamines 1, 5-(1-adamantyl)-5,5-diarylpentylamines 2 and 6-(1-adamantyl)-6,6- diarylhexylamines 3 is described and the σ1, σ2-receptors and sodium channels binding affinity of compounds 1 were investigated. Th

Full text of DOI:10.2174/157340612801216201

Medicinal Chemistry, 2012, 8, 569-586
569
New Adamantane Derivatives with Sigma Affinity and Antiproliferative
Activity
Stefanos Riganasa,c, Ioannis Papanastasioua, George B. Foscolos*,a, Andrew Tsotinisa, Kostas
Dimasb, Vassilios N. Kourafalosc, Andreas Eleutheriadesc, Vassilios I. Moutsosc, Humaira Khanc,
Prassa Margaritac, Stavroula Georgakopoulouc, Angeliki Zaniouc, Maria Theodoropoulouc,
Athanasios Mantelasc, Stavroula Pondikic and Alexandre Vamvakidesc
aFaculty of Pharmacy, Department of Pharmaceutical Chemistry, University of Athens, Panepistimioupoli-Zografou,
157 71 Athens, Greece
bDivision of Pharmacology, FBRAA, 11527, Athens, Greece
cAnavex Life Sciences, 27 Marathonos Avenue, 153 51 Pallini, Athens, Greece
ꢀbstract: The synthesis of 4-(1-adamantyl)-4,4-diarylbutylamines 1, 5-(1-adamantyl)-5,5-diarylpentylamines 2 and 6-(1-
adamantyl)-6,6-diarylhexylamines 3 is described and the ꢀ1, ꢀ2-receptors and sodium channels binding affinity of com-
pounds 1 were investigated. The in vitro activity of compounds 1, 2 and 3 against main cancer cell lines is significant.
One of the most active analogs, 1a, had an interesting in vivo anticancer profile against the ovarian cancer cell line
IGROV-1, which was associated with an anagelsic activity against the neuropathic pain induced by the main anticancer
drugs.
Keywords: Diaryladamantanealkanamines, synthesis, sigma-receptors affinity, sodium channels affinity, anti-proliferative ac-
tivity, in vivo anticancer profile.
INTRODUCTION
associated ER membrane (MAM) and caspases pathways,
seems to be implicated in the ꢀ1 receptor mediated apoptosis
of cancer cells [3,7]. Otherwise, in spite of caspases-
independent apoptosis pathways proposed for ꢀ2 agonists
[8], anticancer activity and caspases-dependent apoptosis of
cancer cells were found recently for ꢀ2 specific ligands [9].
Moreover, in relation to the apoptotic pathways, there is evi-
dence, that the sigma receptors modulate ion channels
[2,3,19,20], such as Ca2+, K+, Cl- and more importantly, in
relation to metastasis of cancer cells, the voltage-gated Na+
channel [21,22]. Finally, they regulate the apoptotic proc-
esses by binding to the cholesterol in the lipid rafts [23,24].
These indications might enlighten the anticancer potency of
sigma ligands. SAR studies prove that the presence of a hy-
drophobic aryl or cycloalkyl ring linked to amine via a car-
bon chain of 3-5 atoms, which might include a heteroatom, is
an essential structural requirement for affinity at the (ꢀ) re-
ceptors [25-26].
Sigma (ꢀ) receptors have been recently involved in anti-
cancer activity. Even though, they have been considered as
opioid receptors, the sigma receptors were classified as a
distinct pharmacological entity and their function was unre-
lated to the function of the opioid receptors [1-3]. Based on
the ligand selectivity in the binding assays, two subtypes, the
sigma-1 (ꢀ1) and the sigma-2 (ꢀ2) receptors, were identified
[2-4]. The ꢀ1 receptor was cloned, firstly in 1996 [5], while
ꢀ2 receptor has not been cloned until now [2,3]. ꢀ1 and ꢀ2
receptors have recently been implicated in the programmed
cell death (apoptosis) [3,6-10]. Indeed, ꢀ1 and ꢀ2 receptors
are highly expressed in cancer cells and up-regulated prior to
mitosis [11,12] suggesting important cellular functions in
cancer and putative anticancer activity for ꢀ1 antagonists
[13,14] or ꢀ2 agonists [8-10]. The former deactivate the ꢀ1
receptor activity, which is anti-apoptotic and neuroprotective
[3,6,15-17] and the latter stimulate the receptor activity,
which induces or, more likely, sensitizes cancer cells for
apoptosis [8,9,18]. Although there is considerable evidence
of antiproliferative and cytotoxic activity for ꢀ1 antagonists,
ꢀ2 putative agonists and mixed ꢀ1/ꢀ2 ligands [7-10,13], the
mechanism of their action is not yet fully clarified. Indeed, in
spite of a relative clarification of the pro-apoptotic effects of
ꢀ1 antagonists [3,6,13] more, other than mitochondrion-
In the course of our program directed towards the synthe-
sis of aminoadamantane derivatives with pharmacological
interest, we designed 4-(1-adamantyl)-4,4-diarylbutylamines
1, 5-(1-adamantyl)-5,5-diarylpentylamines 2 and 6-(1-ad-
amantyl)-6,6-diarylhexylamines 3. These include into their
scaffold two aromatic rings and a hydrophobic adamantane
moiety linked to an amine nitrogen atom. Compounds 1 were
investigated for binding affinity at both ꢀ1, ꢀ2 receptors and
Na+ channels. All the new compounds were evaluated in
vitro for the antiproliferative and cytotoxic activity in cancer
and normal cell lines and one of them (1a), in one xenograft
(ovarian).
*Address correspondence to this author at the Panepistimioupoli-Zografou,
157 71 Athens, Greece; Tel: +30 210 7274527; Fax: (+30) 210-7274747;
E-mail: gfosc@pharm.uoa.gr
1875-6638/12 $58.00+.00
© 2012 Bentham Science Publishers

570 Medicinal Chemistry, 2012, Vol. 8, No. 4
Riganas et al.
X
C
X
X
X
a
c
b
d
CH2CH=CH2
C
CH2CH2CH2OH
C
OH
C
Cl
or e
7
5
6
4
X'
X'
X'
X'
X
R
R
R
N
N
N
:
:
N
N
N
N
CH3
N
N
N
N
N
CH3
CH3
1a: X=H, X'=H,
1b: X=H, X'=H,
:
:
1f: X=CH3, X'=CH3,
R
R
R
C
CH2CH2CH2N
R
R
R
R
CH2CH3
N
N
1g: X=CH3O, X'=CH3O,
1
H
R
R
R
R
N
N
CH3
CH3
N
N
N
:
1c: X=H, X'=H,
1d: X=H, X'=H,
1e: X=H, X'=H,
:
:
:
1h: X=F, X'=F,
N
N
N
N
X'
R
R
R
R
N
N
:
CH2C6H5
1i: X=CH3, X'=H,
R
R
R
R
N
N
N
N
:
1j: X=H, X'=H
1k: X=H, X'=H
N
NH
R
R
CH3
CH3
:
Scheme 1. Reagents and conditions: a) SOCl2/CH3COCl, reflux for 30 min; b) CH2=CHCH2MgCl / THF, CuI, reflux for 4 h, then NH4Cl /
o
o
o
o
H2O at 0 C; c) BH3-THF, rt for 3h, then H2O, NaOH, H2O2 at 0 C; d) i. TsCl, Py / DCM at 0 C for 4 h, then at 10 C for 12h, ii. R2NH /
EtOH reflux for 3h; e) Tf2O, ii,6-lutidine / DCM at -10 oC for i h, ii. R2NH / THF, rt for i h.
CH2CH
CH2
CH2CH2CH2OH
CH
CH
X
X
8 X: H or CH3
9 X: H or CH3
Fig. (1).
CHEMISTRY
X=Xꢀ=CH3O, X=Xꢀ=F) without any by-product formation.
On the contrary, in the case of olefin 6 (X=Xꢀ=H and
X=CH3, Xꢀ=H), where at least one of the benzene rings was
unsubstituted, the reaction led to the formation of 1-(p-
allylbenzhydryl)adamantanes (8) as by-product (Fig. 1).
For the preparation of the butylamines 1, the appropriate
ꢀ,ꢀ-diaryl-1-adamantylmethanol 4 was used as starting mate-
rial, which was prepared by addition of the corresponding
arylmagnesiumbromide to ethyl 1-adamantanecarboxylate.
Indicativelly, ꢀ-phenyl-ꢀ-(p-tolyl)-1-adamantylmethanol (4)
(X=CH3, Xꢀ=H) was synthesized from p-tolylmagnesium
bromide and 1-adamantylphenyl ketone.
It seems that, apart from the main allylic product, p-
allylation also takes place, via a combination of the allylic
and benzhydrylic radical. The ratio of formation of these by-
products was approximately 17-20%, according to NMR
spectra analysis.
Carbinols 4 were treated with a mixture of thionyl chlo-
ride/acetyl chloride to form the corresponding chlorides 5,
which led to the 1-butene analogue 6, in the presence of al-
lylmagnesium chloride and a catalytic amount of copper (I)
iodide. The latter reaction, which proceeds through a radical
Olefins 6 were purified and then converted to 1-butanols
7 by hydroboration. Conversely, olefins 6 (X=Xꢀ=H and
X=CH3, Xꢀ=H) were used as mixtures with isomers 8. The
desired corresponding butanols 7 were separated from the
mechanism, gave the desired olefins
6 (X=Xꢀ=CH3,

New Adamantane Derivatives with Sigma Affinity
Medicinal Chemistry, 2012, Vol. 8, No. 4 571
b
c
a
C
CH2CH2CH2OMs
C
CH2CH2CH2OH
C
CH2CH2CH2C
N
10
7a
11
d,e
f
R
R
R
R
C
CH2CH2CH2CO2Et
C
CH2CH2CH2C
N
C
CH2CH2CH2CH2N
O
12
13
R
CH3
N
N
N
:
N
N
2a :
2b :
R
R
R
:
Scheme 2. Reagents and conditions: a) MsCl/Py, DCM anhydrous, rt for 12h; b) NaCN/DMSO at 60 oC for 12h; c) gas HCl/EtOH, reflux for
2h and then a few water drops, reflux for 1h; d) NaOH/EtOH-H2O, reflux for 2h and then HCl (10%) at 0 oC; e) SOCl2 reflux for 1h and then
R2NH / THF reflux for 8h; f) LiAlH4/THF reflux for 3.5h and then H2O/NaOH at 0 oC.
CO2Et
H
C
C
C
CH2CH2CH=O
C
CH2CH2CH2OH
CH2CH2
C
H
b,c
a
d
14
15
7a
R
R
C
CH2CH2CH2CH2CH2N
C
CH2CH2CH2CH2CO2Et
C CH2CH2CH2CH2CH2OH
e
f
17
R
16
N
N
N
N
N
CH3
3a:
3b:
:
:
R
R
R
o
Scheme 3. Reagents and conditions: a) PCC, DCM anhydrous, rt for 2h; b) triethyl phosphonoacetate/NaH in THF at 0 C for 30min; c) i.
aldehyde 14 in THF at 0 oC for 30min, ii NH4Cl/H2O at 0 oC; d) H2/Pd-C for 16h; e) LiAlH4/THF, rt for 1h and then H2O/NaOH at 0 oC; f) i.
TsCl/Py, rt for 1h, ii. R2NH/EtOH reflux for 5h.
benzenepropanols 9, which were formed by the hydrobora-
tion of by-products 8 (Fig. 1).
piperidine gave the respective carboxamides 13. Reduction
of these amides with LiAlH4 led to the desired pentylamines
2a and 2b.
Finally, alcohols 7 were converted to butylamines 1 via
the intermediate tosylate or trifluoromethanesulfonate. It
must be noted that the conversion to trifluoromethanesul-
fonates upon addition of the requisite secondary amines, an
SN2 substitution pathway, was followed by an E2 elimina-
tion. This elimination led to mixtures of the expected amines
1 and olefins 6, which were purified by chromatography to
give the final products 1.
For the preparation of the hexylamines 3, butanol 7a was
oxidized to butanal 14 with pyridinium chlorochromate.
Treatment of aldehyde 14 with triethyl phosphonoacetate /
o
sodium hydride at 0 C led to the Horner-Emmons product
15. Catalytic hydrogenation of ester 15 in the presence of
10% palladium on charcoal led to the saturated ester 16. The
latter was reduced with LiAlH4 to the respective hexanol 17,
which was converted to hexylamines 3 via the intermediate
tosylates.
The synthesis of the pentylamine analogs 2 was accom-
plished by the reaction sequence shown in Scheme 2. Buta-
nol 7a was mesylated to form mesylate 10, which was con-
verted to nitrile 11 by adding sodium cyanide. Alcoholysis of
cyanide 11 with an ethanolic solution of hydrogen chloride
gave ethylester 12, which was saponified to the intermediate
carboxylic acid. This was transformed to the corresponding
chloride, which coupled with 1-methylpiperazine and
RESULTS AND DISCUSSION
In vitro anti-proliferative activities of the new com-
pounds on cancer and normal cell lines are shown in Tables
1a, 1b and 1c.

572 Medicinal Chemistry, 2012, Vol. 8, No. 4
Riganas et al.
Table 1a. Summary results from the in vitro screening. *For each experimental agent: LC50 is the concentration of drug resulting in
50% lethality (50% reduction in measured protein), TGI the concentration resulting in total growth inhibition, GI50 the con-
centration resulting in growth inhibition of 50%. 5-fluorouracil (5FU) was used as reference drug.
Cancer Cell Lines
Normal Cell Lines
Colon
Renal
Prostate
Breast
Ovarian
Cmpd
Values*
LC50
TGI
GI50
LC50
TGI
GI50
LC50
TGI
GI50
LC50
TGI
GI50
LC50
TGI
GI50
LC50
TGI
GI50
LC50
TGI
GI50
LC50
TGI
GI50
LC50
TGI
GI50
LC50
TGI
GI50
LC50
TGI
GI50
LC50
TGI
GI50
8.87
6.06
3.24
9.12
6.32
3.53
100
100
9.7
6.91
4.12
9.29
6.51
3.73
55.55
7.97
2.72
100
45.35
7.16
3.8
8.7
6
8.3
5.6
8.8
5.9
8.6
5,64
3.13
9.5
8.1
5.8
8.72
6.00
3.29
8.96
6.20
3.43
100
39.22
7.42
9.5
6.5
1a
1b
1c
8.21
4.41
7.05
4.14
23.90
7.01
3.72
64.46
9.94
7.30
3.3
3.00
74
3.00
9.94
6.68
3.41
100
51
3.36
4.55
3.6
20.40
7.02
71.00
9.70
5.20
70.55
9.56
4.44
80.3
14.9
5.25
67.12
12.68
5.64
78.63
35.1
100
100
6.94
100
54.64
6.83
16.7
5.5
6.5
3.94
3.5
6.84
81.59
39.95
7.65
8.5
95.81
58.81
21.82
9.63
4.32
100
35
20.24
5.71
100
7.7
6.22
100
1d
1e
100
99.36
22.29
8.72
5.84
2.96
5.51
5.90
3.33
8.33
5.80
3.26
8.76
5.95
3.14
8.71
6.07
3.42
9.10
6.30
3.50
9.00
6.12
3.22
100
100
11.95
100
76.76
8.33
7.13
4.14
10.09
6.67
3.24
9.93
6.51
3.08
9.28
6.54
3.79
9.66
6.62
3.58
8.79
6.06
3.33
9.20
6.12
3.04
100
8.86
6.05
3.23
8.87
6.20
3.54
8.81
6.09
3.38
9.96
6.90
3.81
8.81
6.02
3.23
81.81
11.89
5.15
9.29
6.43
3.58
100
8.29
5.69
3.09
10.23
7.02
3.81
8.61
5.19
1.78
11.11
7.58
4.01
89.42
33.91
6.96
9.31
6.00
2.68
75.80
9.10
4.70
11.83
7.94
4.08
100
8.25
5.84
3.44
8.04
5.55
3.06
8.18
5.72
3.25
9.25
6.37
3.48
9.19
6.22
3.25
9.32
6.32
3.32
9.97
6.30
2.63
100
9.88
7.72
5.55
9.55
6.95
4.35
9.44
7.21
4.99
100
7.30
3.61
9.88
6.76
3.65
9.40
6.21
3.02
7.08
3.62
9.26
6.32
3.37
9.05
6.16
3.26
9.30
6.39
3.49
8.89
6.16
3.43
100
8.50
5.98
3.46
8.58
6.16
3.74
1f
1g
1h
1i
94.20
30.28
5.81
9.13
6.44
3.75
9.17
6.24
3.30
8.18
5.58
2.97
44.70
8.00
4.55
12.45
7.25
10.11
7.01
3.91
76.82
8.85
4.59
7.61
4.11
100
4.45
100
7.09
3.76
22.25
7.63
4.24
100
10.10
6.80
3.60
91.14
47.47
8.44
1j
6.56
2.67
8.37
5.90
3.42
100
22.91
6.20
9.06
5.96
2.92
100
1k
5FU
100
100
100
100
100
100
100
100
100
7.60
100
55.00
8.44
100
100
6.90
100
100
100
100
100
100
100
9.10
9.60
43.77
94.40
59.00
4.20
15.21
83.00
17.70

New Adamantane Derivatives with Sigma Affinity
Medicinal Chemistry, 2012, Vol. 8, No. 4 573
Table 1b. Summary results from the in vitro screening. *For each experimental agent: *LC50 is the concentration of drug resulting in
50% lethality (50% reduction in measured protein), TGI the concentration resulting in total growth inhibition, GI50 the con-
centration resulting in growth inhibition of 50%. 5-fluorouracil (5FU) and dacarbazine (DIC) were used as reference drug.
CNS
Liver
Melanoma
NCI-
H460
DMS
114
HL-60
(TB)
BX-
PC3
LOX-
IMVI
SK-MEL-
28
CCS
WD6
Cmpd
1a
Values*
SF268
U251
SKHep1
LC50
TGI
GI50
LC50
TGI
GI50
LC50
TGI
GI50
LC50
TGI
GI50
LC50
TGI
GI50
LC50
TGI
GI50
LC50
TGI
GI50
LC50
TGI
GI50
LC50
TGI
GI50
LC50
TGI
GI50
LC50
TGI
GI50
LC50
TGI
GI50
LC50
TGI
GI50
9.2
6.36
3.53
86.48
42.78
8.19
93.51
55.27
17.03
100
8.07
5.52
2.98
8.15
5.81
3.46
9.09
6.26
3.44
100
9.94
6.68
3.42
100
100
9.04
5.07
73.26
7.11
3.76
100
9.08
6.24
3.41
67.3
7.79
4.02
100
8.53
5.78
3.03
72.14
8.68
4.82
71.61
24.08
5.66
100
8.16
5.81
3.46
8.88
6.33
3.77
62.16
13.70
5.48
8.28
5.79
3.29
9.05
6.37
3.68
79.17
36.05
7.23
8.56
5.88
3.2
8.77
6.10
3.43
8.44
5.41
2.38
1b
1c
7.96
4.13
100
7.22
4.29
94.77
7.18
3.2
46.6
6.06
100
100
7.77
3.29
6.46
1d
1e
100
100
100
100
54.74
9.40
6.08
2.76
10.05
6.84
3.64
9.50
6.53
3.56
9.84
6.66
3.48
9.92
6.81
3.69
81.14
8.38
4.34
9.25
6.31
3.37
100
23.46
9.32
6.63
3.94
8.82
5.94
3.06
8.71
5.92
3.14
77.38
23.14
6.81
8.81
6.03
3.25
8.83
6.10
3.37
8.89
6.35
3.82
100
9.19
6.45
3.72
8.55
6.02
3.49
8.69
6.15
3.61
100
8.89
6.04
3.18
8.84
6.02
3.20
9.04
6.42
3.79
100
9.85
5.32
100
100
5.96
100
9.65
4.44
8.91
6.01
3.11
8.83
6.05
3.28
8.85
6.09
3.33
62.31
8.23
5.09
7.98
5.06
2.14
8.27
5.92
3.58
8.24
5.79
3.34
8.14
5.60
3.06
8.05
5.52
2.99
8.23
5.41
2.59
8.18
5.62
3.07
8.21
5.70
3.19
7.79
4.60
1.42
8.93
6.69
4.45
1f
1g
1h
1i
8.45
4.76
9.33
6.69
4.06
83.63
19.83
6.57
8.89
6.30
3.72
100
8.15
5.58
3.01
7.99
5.55
3.12
8.73
5.87
3.01
39.98
6.08
1.59
100
100
9.07
6.23
3.40
19.69
6.86
3.54
9.29
6.32
3.35
100
8.42
5.72
3.02
8.41
6.05
3.69
8.19
5.63
3.08
8.19
5.77
3.35
8.34
5.80
3.27
8.34
5.67
3.00
5.46
52.33
7.42
3.22
1j
1k
5FU
DIC
100
100
100
100
100
100
100
100
100
100
8.38
100
100
7.40
100
100
100
100
100
100
91.56
83.90
5.01
68.91
9.95
55.49
100
87.33
4.47

574 Medicinal Chemistry, 2012, Vol. 8, No. 4
Riganas et al.
Table 1c. Summary results from the in vitro screening. *For each experimental agent: * LC50 is the concentration of drug resulting in
50% lethality (50% reduction in measured protein), TGI the concentration resulting in total growth inhibition, GI50 the
concentration resulting in growth inhibition of 50%. 5-fluorouracil (5FU) was used as reference drug.
Colon
Prostate
Leukemia
Breast
Ovarian
Liver
Cmpd
2a
Values*
LC50
TGI
GI50
LC50
TGI
GI50
LC50
TGI
GI50
LC50
TGI
GI50
LC50
TGI
GI50
10.61
7.34
4.08
100
9.38
7.03
10.39
7.33
3.77
14.62
10.33
5.93
12.88
8.47
4.06
18.32
7.70
5.57
100
100
7.73
4.78
100
8.44
5.71
2.98
78.65
49.50
20.50
9.72
6.60
3.48
9.88
6.90
3.92
100
9.56
5.96
9.71
6.68
3.65
71.30
16.39
5.85
8.61
6.07
3.54
8.46
5.85
3.24
100
4.63
2.40
24.70
18.02
11.31
13.36
9.03
95.10
54.43
13.74
10.17
6.93
2b
3a
78.84
8.49
100
9.87
6.10
8.93
4.79
100
4.69
3.71
19.57
8.41
13.70
9.67
3b
8.99
4.49
100
5.68
5.60
100
100
100
100
100
5FU
100
100
100
100
100
100
9.60
43.77
94.40
4.20
15.21
9.95
Table 2. Affinities of the adamantane derivatives 1 for the ꢀ1, ꢀ2-receptors and for the site 2 of Na+ channels, measured by displace-
ment of [3H](+)pentazocine, [3H]1,3-di-o-tolylguanidine and [3H]batrachotoxin, respectively.
ꢀ1
ꢀ2
Sodium Channels
Cmpd.
ꢀ2 / ꢀ1
(IC50, nM)
(IC50, nM)
(IC50, μM)
1a
1c
1d
1e
1j
15
15
96
22
16
38
60
4.4
13
4
0.3
0.14
12
0.8
0.2
0.5
0.4
0.3
0.4
270
480
790
30
1k
21
Affinities of derivatives 1 for both ꢀ1, ꢀ2 receptors and
the site 2 of Na+ channels are summarized in Table 2.
Moreover, an in vivo xenograft screening study using the
ovarian cancer cell line (IGROV-1), was conducted for com-
pound 1a (Fig. 2).
well as the phenyl(s) substituted derivatives 1f, 1g, 1h and
1i, the pentylamines 2a and 2b and the hexylamines 3a and
3b, have similar anti-proliferative activities in all the cancer
cell lines. The rest of these derivatives show anti-
proliferative activities in the order: 1j > 1c > 1d, the last be-
ing quasi-inactive. According to the classic data and concep-
tions [8,9,13,14], concerning the synthesis of selective ꢀ2
agonists [8,9] and mixed ꢀ1 antagonists / ꢀ2 agonists [14], in
order to obtain anticancer efficacy [8,9,14], it could be
speculated that 1e, 1a and the derivatives, 1k and 1j might
behave as mixed ꢀ1 antagonists and weak ꢀ2 agonists.
It is clear, from Table 2, that analogs 1 exhibit significant
ꢀ1 selectivity in the order: 1j ꢁ 1k > 1e ꢁ 1a. In contrast,
derivatives 1c and 1d exhibited lower affinity for ꢀ1 vs ꢀ2
receptors. All compounds showed similar affinities (micro-
molar to sub-micromolar) for the site 2 of the Na+ channels.
According to the data presented in Table 1, 1a, 1k and 1e, as

New Adamantane Derivatives with Sigma Affinity
Medicinal Chemistry, 2012, Vol. 8, No. 4 575
A
Tumor Growth Rate
1400
Un
5T80
5Cis
30 1a
1200
1000
800
600
400
200
0
***
***
***
***
***
***
***
***
20
25
30
35
40
Da ys post inocula tion
B
Post mortem weight
ΔΤ/ΔC
C
80
5Cis
30 1a
70
60
50
40
30
20
10
Average weight
±STDV(mg)
% reduction
untreated
5T80
970±66.7
990±29.7
280±61.2
270±56.1
***
***
***
***
***
2.5 Cis
30 1a
69.76 ***
73.27 ***
***
***
***
0
20
25
30
Days post inoculation
35
40
Fig. (2). Growth of IGROV-1 (Ovarian cancer) tumors in SCID mice treated with Cisplatin (reference drug for ovarian cancer) and com-
pound 1a. (A): average tumor size (in mm3) of each mouse group (8 mice per group that is 16 tumors per group) as a function of time (in
Days); error bars represent Standard Deviation; and, (C), %ꢁꢂ/ꢁC as a function of time (in Days) for IGROV-1 xenografts. UT represents
untreated animals receiving saline; 5T80 animals treated with 5%Tween80; 2.5 CIS, animals treated with 2.5mg/kg of Cisplatin twice per
week and 30 1a, animals treated with 30mg/kg of compound 1a for 5 consecutive days. Statistical evaluation was assessed using one way
Anova followed by LSD post hoc test (cisplatin treated animals were compared to untreated animals, whereas 1a-treated animals were com-
pared to their respective controls 5T80 treated animals). Time points with significance, p ꢃ 0.05 are indicated by an asterisk (*), pꢃ0.001 by
three asterisks (***). Table B shows mean weight of tumors extracted upon completion of the experiment and percentage of reduction com-
pared to control groups. Statistical evaluation was assessed using one way Anova followed by LSD post hoc test. Values with significance, p
ꢃ 0.05 are indicated by an asterisk (*), pꢃ0.001 by three asterisks (***).
In agreement with the ꢀ1 affinities of the new derivatives
and the degree of expression of the ꢀ1 receptors in the cancer
cells [3,11-13,24] all these ligands (except 1d) exhibited
significant to high cytotoxic activity on all the studied cancer
cell lines.
mors. Compound 1a was further investigated in a xenograft
study (ovarian cancer cell line IGROV-1), which was per-
formed on mice with severe combined immune deficiency
(SCID) (Fig. 2).
Compound 1a exhibited the same activity, compared to
the reference drug cisplatin (Fig. 2). However, serious cen-
tral and peripheral painful neuropathy, usually not reversible,
is developed in most of the patients treated with therapeuti-
cal doses of cisplatin [27-29], compromising the quality of
life of cancer patients. In contrast and in good agreement
with recent experimental results, concerning the antagonism
of neuropathic pain by ꢀ1 antagonists [3,30-34] or voltage
gated sodium channels (VGSC) blockers [35-37], a putative
analgesic activity of 1a against the persistent neuropathic
pain could be anticipated by the effect obtained (Fig. 3) in
Considering the in vitro results of anti-proliferative activ-
ity of the new derivatives on cancer cell lines (colon, renal,
prostate, breast, ovarian, central nervous system, lung, leu-
kemia, pancreas, melanoma) and on normal cell lines (HU-
VEC: Human Umbilical Vein Endothelial Cells, hMSC:
Human Mesenchymal Stem Cells, NHDF: Normal Human
Dermal Fibroblasts) (Table 1a,b,c), it appears that 1a exhib-
ited some selective action against ovarian cancer cells, given
that the cytotoxic effect of 1a on the HUVEC cells could, in
vivo, also serves as an antiangiogenic factor against the tu-

576 Medicinal Chemistry, 2012, Vol. 8, No. 4
Riganas et al.
Fig. (3). Effects of orally administered (po) 1a at the dose of 100mg/kg, on Paclitaxel treated mice in the Formalin test, compared to the ref-
erence drug Gabapentin (GBP) 100mgkg ip, (GBP was administered ip since po administration of the compound exerts no analgesic effect in
the formalin test, data not shown). One way Anova followed by LSD post hoc test confirmed the expected hyperalgia of Paclitaxel treated
animals compared to the Vehicle treated group in both time intervals examined (**p<0.01 and ***p<0.001 respectively). GBP administration
in Paclitaxel pretreated animals was found to exert a mild analgesic effect in both time intervals, as indicated by their lower licking, of the
administered paw, times compared to Paclitaxel treated animals (#p<0.1 in both intervals). Administration of 1a exerted a stronger analgesic
effect in Paclitaxel treated animals: 1a Paclitaxel treated animals displayed lower licking times compared to Paclitaxel treated animals both at
0-5min (***p<0.001) and 35-40min (***p<0.001) after formalin injection (see also Experimental section).
the appropriate (formalin) test [38-40], on mice with central
and peripheral neuronal sensitization, induced by administra-
tion of paclitaxel [41], two weeks before the formalin test
[41,42]. In our knowledge for the first time, evidence is
given that an in vivo putative anticancer activity, obtained by
a mixed ꢀ1/ꢀ2 ligand with ꢀ1 preferential affinity, could be
associated with an analgesic activity against the neuropathic
pain induced by the main anticancer drugs (taxanes, plati-
nes).
EXPERIMENTAL SECTION
Binding Studies
Binding studies were carried out by CEREP (France)
with the ꢀ1 binding assay performed according to Ganapathy
et al. [43], the ꢀ2 binding assay according to Bowen et al.
[44], the sodium channel (site 2) assay according to Brown
[45].
Cell Cultures and Cell Lines
Finally, in spite of the absence of functional tests allow-
ing the study of the intrinsic activity of the new sigma
ligands and also of a clear hypothesis concerning their cyto-
toxicity against the cancer cells, the recent developments on
the role of sigma receptors of the MAM in the modulation of
apoptosis [3,6] and of the cell cycle [19] could be considered
All human cancer cell lines were obtained from the Nati-
onal Cancer Institute, NIH (Bethesda, MD, USA) with the
exception of BX-PC3 that were obtained from ATCC, the
hMSCs, NHF and HUVECs that were purchased from Lon-
za. All cell lines were adapted to propagate in RPMI 1640
medium supplemented with 5% heat-inactivated fetal calf
serum, 2 mM L-glutamine and antibiotics. The cultures were
grown in a humidified 37oC-incubator with 5% CO2 at-
mosphere.
as
a serious basic hypothesis concerning the anti-
proliferative activity of 1a.
CONCLUSION
In this work, the design and synthesis of 1-
admantyldiarylalkanamine 1, 2 and 3 were described. The
scaffold of the above compounds, which includes two aro-
matic rings and a hydrophobic adamantane moiety linked to
an amine nitrogen atom, is essential for sigma (ꢀ) receptor
affinity. The ꢀ1, ꢀ2 receptors and sodium channels binding
affinity of derivatives 1, as well as the in vitro anti-
proliferative activity of compounds 1, 2 and 3 were investi-
gated. Compound 1a was further tested on a xenograft study
(ovarian cancer cell line IGROV-1) and its anticancer activi-
ty was associated with an anagelsic potency against neuro-
pathic pain.
In Vitro Cytotoxic Activity
Cell viability was assessed at the beginning of each expe-
riment by the trypan blue dye exclusion method, and was
always greater than 95%. Cells were seeded into 96-well
microtiter plates in 100 μL of medium at a the corresponding
density (3500-30000 cells per well) and subsequently, the
plates were incubated at standard conditions for 24 h to al-
low the cells to resume exponential growth prior to addition
of the agents to be tested. Then in order to measure the cell
population, cells in one plate were fixed in situ with TCA
followed by SRB staining, as described elsewhere [46,47].
To determine the activity, each compound was dissolved in
DMSO and then was added at 10-fold dilutions (from 100 to
0.01 μM) and incubation continued for an additional period
of 48 h. The assay was terminated by addition of cold TCA
followed by SRB staining and absorbance measurement at
Xenograft studies are currently underway in order to
further investigate the activity of these compounds and
especially, in relation to their significant affinity for Na+
channels, their effects on cancer metastasis and neuropathic
pain.

New Adamantane Derivatives with Sigma Affinity
Medicinal Chemistry, 2012, Vol. 8, No. 4 577
540 nm, in an DAS plate reader, to determine the GI50, that
is, the concentration required in the cell culture to inhibit cell
growth by 50%, TGI, the concentration that is required to
completely inhibit cell growth and the LC50, the concentrati-
on that is needed in culture to kill 50% of the cellular popu-
lation as described [42, 43].
tion driven by the presumed first phase [38]. The amount of
time spent licking and biting the injected paw and leg was
recorded in 5-min intervals for 0-5 and 35-40 min after the
formalin injection.
MATERIALS AND METHODS
Melting points were determined using a Büchi capillary
apparatus and are uncorrected. IR spectra were recorded on a
In vivo Antitumor Activity
1
Perkin-Elmer 833 spectrometer. H, 13C NMR spectra were
SCID (NOD.CB17 Prkdcscid) mice were purchased from
Jackson
Laboratories/Charles
River
Laboratories
recorded on a Bruker MSL 400 spectrometer using CDCl3 as
solvent and TMS as internal standard. Carbon multiplicities
were established by DEPT experiments. 2D NMR experi-
ments (HMQC, COSY and NOESY) were performed for the
elucidation of the structures of the new compounds. Micro-
analyses were carried out by the Service Central de Micro-
analyse (CNRS) France, and the results obtained had a
maximum deviation of ±0.4% from the theoretical value.
(L’Arbresle, France). The mouse colony was maintained
under restricted flora conditions in a pathogen-free environ-
ment in type IIL-cages. Female mice, 7–9 weeks old, were
injected subcutaneously according to the British practice of
bilateral trocar implants at the axillary region. Each inocu-
lum contained 106 cells exponentially growing at the time of
harvesting. The mice were subsequently randomly divided
into groups of 10 animals per group. Treatments started
when the average tumor volume had reached about 100 mm3.
Tumor volume was calculated as described elsewhwere [48].
All administrations were intraperitoneal. Treated animals
received a single injection daily for 5 days per week throug-
hout the experiments. Tumor volume was measured with a
calliper twice per week. In addition to tumor volume, we
calculated the parameter, %ꢀT/ꢀC, where ꢀT = T ꢁ Do and
ꢀC = C ꢁ Do (Do is the average tumor volume at the begin-
ning of the treatment; T and C are the volumes of treated and
untreated tumors, respectively, at a specified day). Concur-
rently, we scored the number of tumor-free animals, number
of drug-related deaths, and average number of days required
to reach a defined tumor volume. Optimal ꢀT/ꢀC value was
used as a measure of drug activity. Losses of weight, neuro-
logical disorders and behavioral and dietary changes were
also recorded as indicators of toxicity (side effects). The ex-
periment was terminated when tumor size in untreated ani-
mals reached a volume of about 10-11% of animals’ weight.
ꢀ,ꢀ-Diphenyl-1-tricyclo[3.3.1.1.3,7]decanemethanol (4a)
Carbinol 4a was prepared by addition of phenylmagnesium
bromide to ethyl 1-adamantanecarboxylate [49]. Yield 89%.
Mp 127-128 oC (ether).
ꢀ,ꢀ-Bis(4-methylphenyl)-1-tricyclo[3.3.1.1.3,7]decaneme-
thanol (4f)
Carbinol 4f was synthesized by adding p-
tolylmagnesium bromide to ethyl 1-adamantanecarboxylate
in a similar way as for carbinol 4a. Yield 70%. Mp 144-146
1
oC (ether - n-pentane); IR (Nujol) v (OH) 3608cm-1; ꢂ-
NMR(400MHz, CDCl3) ꢃ(ppm): 1.52-1.56(m, 6H, 2, 8, 9-
H), 1.78(br.s, 6H, 4, 6, 10-H), 1.91(br.s, 3H, 3, 5, 7-H),
2.12(s, 1H, OH), 2.23(s, 6H, CH3), 6.98-7.00(d, 4H,
AA`BB`, JAB~8.5 Hz, JAA`=JBB`=0 Hz, 3, 5 -Har), 7.36-
7.38(d, 4H, AA`BB`, JAB~8.5 Hz, JAA`=JBB`=0 Hz, 2, 6-Har);
13C-NMR(100MHz, CDCl3) ꢃ(ppm): 20.88(CH3), 28.79(3, 5,
7-C), 36.92(2, 8, 9-C), 37.36(4, 6, 10-C), 40.99(1-C),
81.97(ꢀ-C), 127.79(3, 5-Car), 128.42(2, 6-Car), 135.79(1-
Car), 142.58(4-Car); Anal. Calcd for C25H30O, C: 86.65; H:
8.73. Found: C: 86.80; H: 8.54.
Statistical Analysis
Significant difference in tumor volume was determined
by one way Anova followed by LSD post hoc tests using the
SPSS for Windows (release 11.0.0, SPSS Inc., USA) soft-
ware package. A difference was considered significant if p <
0.05.
ꢀ,ꢀ-Bis(4-methoxyphenyl)-1-tricyclo[3.3.1.1.3,7]decaneme-
thanol (4g)
Formalin Test
Carbinol 4g was synthesized by adding p-anisyl-
magnesium bromide to ethyl 1-adamantanecarboxylate in a
similar way as for carbinol 4a. p-Anisylmagnesium bromide
was prepared from p-bromoanisole and magnesium turnings
in the presence of equimolar volume of THF and anhydrous
CD1 male mice weighing 34 to 40g were used. They
were kept in a room maintained at 21-22ºC with free access
to standard laboratory diet and tap water. Paclitaxel (Brystol
Myers Squibb Company) was diluted in saline and adminis-
tered at one ip injection (6mg/kg) on day 0, as adapted from
Matsumoto et al. [41]. On day 14, 1hr after oral administra-
tion (po) of the compound 1a (100mg/kg) the formalin test,
as a tonic and persistent pain model of nociception, was per-
formed. Injection of formalin into the hind paw is followed
by two phases of behavior [42]. The first phase consists of
intense licking and biting of the injected paw for the first 5
min followed by a period of little activity. The second phase
spans from 15 to 40 min after the formalin injection and in-
volves periods of licking and biting of the injected paw. The
first phase is thought to be a model of acute chemical pain,
whereas the second phase reflects a state of central sensitiza-
o
benzene. Yield 60%. Mp : 139-140 C (ether); IR (Nujol) v
1
(OH) 3481cm-1; ꢂ-NMR(400MHz, CDCl3) ꢁ 1.56-1.64(m,
6H, 2, 8, 9-H), 1.81-1.82(m, 6H, 4, 6, 10-H), 1.97(br.s, 3H,
3, 5, 7-H), 2.17(s, 1H, OH), 3.76(s, 3H, OCH3), 6.76-
6.79(~d, 4H, AA`BB`, JAB~9 Hz, JAA`=JBB`=0 Hz, 3, 5-Har),
7.44-7.46(~d, 4H, AA`BB`, JAB~9 Hz, JAA`=JBB`=0 Hz, 2, 6-
Har); 13C-NMR(100MHz, CDCl3) ꢁ 28.8(3, 5, 7-C), 36.9(2,
8, 9-C), 37.4(4, 6, 10-C), 41.1(1-C), 55.09(CH3O), 81.7(ꢀ–
C), 112.3(3, 5-Car), 129.7(2, 6-Car), 137.8(1-Car), 157.8(4-
Car); Anal. Calcd for C25H30O3, C: 79.33; H: 7.99. Found C:
79.45; H: 8.02.

578 Medicinal Chemistry, 2012, Vol. 8, No. 4
Riganas et al.
ꢀ,ꢀ-Bis(4-fluorophenyl)-1-tricyclo[3.3.1.1.3,7]decaneme-
ꢀ,ꢀ-Bis(4-methoxyphenyl)-1-tricyclo[3.3.1.1.3,7]decylmet-
thanol (4h)
hyl chloride (5g)
Carbinol 4h was synthesized by adding p-fluorophenyl-
Chloride 5g was synthesized in a similar way to chloride
5a. Yield 45%; Mp 89-90 oC (ether - n-pentane).
magnesium bromide to ethyl 1-adamantanecarboxylate in a
o
similar way as for carbinol 4a. Yield 45%; Mp 117-119 C
ꢀ,ꢀ-Bis(4-fluorophenyl)-1-tricyclo[3.3.1.1.3,7]decylmethyl
chloride (5h)
(ether- n-pentane); IR (Nujol) v (OH) 3610cm-1; 1ꢀ-
NMR(400MHz, CDCl3) ꢀ 1.52-1.62(m, 6H, 2, 8, 9-H),
1.76(br.s, 6H, 4, 6, 10-H), 1.94(br.s, 3H, 3, 5-H), 2.21(s, 1H,
OH), 6.86-6.91(t, 4H, J2ar,3ar ~ J3ar,F= 8.7 Hz, J3ar,5ar=0 Hz, 3,
5-Har), 7.42-7.46(q, 4H, J2ar,3ar=8.7 Hz, J2ar,F=5.5 Hz,
J2ar,6ar=0 Hz, 2, 6 -Har); 13C-NMR(100MHz, CDCl3) ꢀ
28.7(3, 5, 7-C), 36.8(2, 8, 9-C), 37.3(4, 6, 10-C), 41.0(1-C),
81.72(ꢁ-C), 113.8, 114.0(3, 5-Car), 130.2, 130.3(2, 6-Car),
140.9(1-Car), 162.5(4-Car); Anal. Calcd for C23H24F2O, C:
77.94; H: 6.83. Found C: 78.05; H: 6.62.
Chloride 5h was synthesized in a similar way to chloride
5a. Yield 70%; Mp 146-148 oC (ether - n-pentane).
ꢀ-(4-ꢀethylphenyl)-ꢀ-phenyl-1-tricyclo[3.3.1.1.3,7]decyl-
methyl chloride (5i)
Chloride 5i was synthesized in a similar way to chloride
5a. Yield 90% (viscous product). The product was used to
the next step as such.
ꢀ-(4-ꢀethylphenyl)-ꢀ-phenyl-1-tricyclo[3.3.1.1.3,7]decan-
emethanol (4i)
4,4-Diphenyl-4-(1-tricyclo[3.3.1.1.3,7]decyl)-1-butene (6a)
To a stirred solution of allylmagnesium chloride (2 M) in
THF (14 ml, 27 mmol), was added dropwise a solution of
chloride 5a (3 g, 9 mmol) in anhydrous THF (30 ml) in the
presence of catalytic amount of copper (I) iodide, under an
argon atmosphere. The reaction mixture was heated to reflux
for 4 h and then quenched by adding a saturated solution of
To a stirred solution of p-tolylmagnesium bromide,
which was prepared from magnesium turnings (0.8 g, 0.032
gr-at) and 4-bromotoluene (6 g, 0.035 mol) in anhydrous
diethyl ether (50 ml) was added dropwise a solution of 1-
adamantyl phenyl ketone (3.4 g, 0.014 mol) in anhydrous
diethyl ether (50 ml), under an argon atmosphere. The mix-
ture was heated to mild reflux for 1 h, then quenched by add-
ing water and a solution of HCl 10% in an ice bath. The or-
ganic layer was separated and extracted with diethyl ether.
The combined organics were washed with water, saturated
solution of Na2CO3 (10%), dried over Na2SO4 and concen-
trated jn vacuo. The residue obtained, was crystallized and
triturated with n-pentane to give 2.8 g of a solid product
o
NH4Cl at 0 C. The mixture was filtered off and the filtrate
was evaporated to remove the solvent. Water was added into
the residue and the mixture was extracted with ether. The
combined organics were washed with water, dried over
Na2SO4 and evaporated. The residue was purified by flash
column chromatography, using as eluent cyclohexane to give
1
2.84 g of an oily product (yield 92%). H-NMR spectrum
o
analysis proved that there was a mixture of butene 6a and
compound 8a. The ratio of the two isomers was 6a:8a, 5:1
(~83% of 6a). The two isomers could not be separated by
chromatography and the mixture was submitted to the next
step of hydroboration. In order to get a pure sample of
(Yield 60%). Mp 146-148 C (ether - n-pentane); IR (Nujol)
v (OH) 3651cm-1; 1ꢀ-NMR(400MHz, CDCl3) ꢀ 1.56-
1.64(m, 6H, 2, 8, 9-H), 1.84(br.s, 6H, 4, 6, 10-H), 1.97(br.s,
3H, 3, 5, 7-H), 2.21(s, 1H, OH), 2.28(s, 3H, CH3), 7.04-
7.06(d, 2H, AA`BB`, JAB = JA`B`= 8 Hz, JAA`=JBB`=0 Hz, 3, 5-
Har), 7.14-7.19(q, 1H, 4`- Har), 7.21-7.25(~t, 2H, 2`,6`-Har),
7.43-7.45(d, 2H, AA`BB`, JAB = JA`B`= 8 Hz, JAA`=JBB`=0 Hz,
2, 6-Har), 7.52-7.54(~d, 2H, 3`,5`- Har); 13C-NMR(100MHz,
CDCl3) ꢀ 20.9(CH3), 28.8(3, 5, 7-C), 36.9(2, 8, 9-C), 37.4(4,
6, 10-C), 41.0(1-C), 82.1(ꢁ-C), 126.3(4`-Car), 127.0(2`, 6`-
Car), 127.9(3, 5-Car), 128.5(3`, 5`-Car), 128.5(2, 6-Car),
135.9(1-Car), 142.5(1`-Car), 145.5(4-Car); Anal. Calcd for
C24H28O, C: 86.70; H: 8.49. Found C: 86.35; H: 8.42.
o
butene 6a, the mixture was frozen at -20 C and the crystals
o
formed, were washed with chilled n-pentane. Mp 99-101 C
(n-pentane); IR (Nujol) v (C=C) 1632cm-1; 1ꢀ-NMR
(400MHz, CDCl3) ꢀ 1.48-1.57(m, 6H, 2, 8, 9-H), 1.77(br.s,
6H, 4, 6, 10-H), 1.89(br.s, 3H, 3, 5, 7-H), 2.92- 2.93(d, 2H,
J~7 Hz, ꢂ-H), 4.68-4.78(qd, 2H, ꢁ-ꢀ), 5.40-5.47(m, 1H, ꢃ-
ꢀ),7.09-7.18( m, 6H, 2, 4, 6-Har), 7.24-7.26(m, 4H, 3, 5-
Har); 13C-NMR(100MHz, CDCl3) ꢀ 29.3(3, 5, 7-C), 37.0(2,
8, 9-C), 38.7(4, 6, 10-C), 39.9(1-C), 41.2(ꢂ-C), 58.0(ꢀ-C),
116.1(ꢁ-C), 125.3(4-Car), 126.5(2, 6-Car), 131.5(3, 5-Car),
137.2(ꢃ-C), 145.4(1-Car); Anal. Calcd for C26H30, C: 91.17;
H: 8.83. Found C: 91.07; H: 8.90.
ꢀ,ꢀ-Diphenyl-1-tricyclo[3.3.1.1.3,7]decylmethyl chloride
(5a) [49]
A mixture of carbinol 4a (5 g, 0.016 mol), thionyl chlo-
ride (30 ml) and acetyl chloride (20 ml) was heated to mild
reflux for 30 min. The excess of thionyl chloride and acetyl
chloride was evaporated under vacuum and the last traces
were removed azeotropically with anhydrous benzene. The
solid residue was recrystallized from ether, n-pentane to give
3.9 g of the product. (Yield 72%). Mp 150-152 oC.
4,4-Bis(4-methylphenyl)-4-(1-tricyclo[3.3.1.1.3,7]decyl)-1-
butene (6f)
Butene 6f was prepared from chloride 5f in a similar way
to butene 6a. It was purified by flash column chromatogra-
phy, using cyclohexane as eluent. Yield 75%; Mp 104-105
0C (n-pentane); IR (Nujol) v (C=C) 1630cm-1; 1ꢀ-NMR
(400MHz, CDCl3) ꢀ 1.58-1.72(m, 6H, 2, 8, 9-H), 1.83(br.s,
6H, 4, 6, 10-H), 1.97(br.s, 3H, 3, 5, 7-H), 2.33(s, 6H, CH3),
2.97- 2.99(d, 2H, J~ 7 Hz, ꢂ-H), 4.78-4.90(qd, 2H, ꢁ-ꢀ),
5.46-5.56(m, 1H, ꢃ-ꢀ), 7.03-7.05( d, 4H, AA`BB`, JAB~8Hz,
JAA`=JBB`~0Hz, 3, 5-Har), 7.21-7.24(d, 4H, AA`BB`,
ꢀ,ꢀ-Bis(4-methylphenyl)-1-tricyclo[3.3.1.1.3,7]decylmethyl
chloride (5f)
Chloride 5f was synthesized in a similar way to chloride
5a. Yield 74%; Mp 103-105 oC (ether - n-pentane).

New Adamantane Derivatives with Sigma Affinity
Medicinal Chemistry, 2012, Vol. 8, No. 4 579
JAB~8Hz, JAA`=JBB`~0Hz, 2, 6-Har); 13C-NMR(100MHz,
CDCl3) ꢀ 20.8(CH3), 29.4(3, 5, 7-C), 37.0(2, 8, 9-C), 38.7(4,
6, 10-C), 39.9(1-C), 41.1(ꢁ-C), 57.2(ꢀ -C), 115.9(ꢂ-C),
127.2(2, 6-Car), 131.4(3, 5-Car), 134.6(4-Car), 137.5(ꢃ-C),
142.3(1-Car); Anal. Calcd for C28H34, C: 90.75; H: 9.25.
Found C: 90.87; H: 9.17.
for 1 h. The solvent was removed under vacuum and water
was added into the residue. The resulting mixture was ex-
tracted with ether, the combined organic phases were washed
with water, dried over Na2SO4 and concentrated in vacuo to
give a residue, which was further purified by flash column
chromatography, using as eluent a mixture of cyclohex-
ane:ethyl acetate, 4:1 to give 1.1 g of crystalline butanol 9a.
(Yield 41%, calculated from pure starting material); Mp 89-
91 oC (ether); IR (Nujol) v (ꢁꢀ) 3294 cm-1; 1ꢀ-NMR
(400MHz, CDCl3) ꢀ 1.07-1.18(m, 2H, ꢃ-H), 1.50-1.57(m,
7H, 2, 8, 9-H, OH), 1.70(br.s, 6H, 4, 6, 10-H), 1.85(br.s, 3H,
3, 5, 7-H), 2.05-2.09(m, 2H, ꢁ-H), 3.35-3.39(m, 2H, ꢂ-ꢀ),
7.07-7.15( m, 6H, 2, 4, 6 -Har), 7.24-7.27(m, 4H, 3, 5-Har);
13C-NMR (100MHz, CDCl3) ꢀ 29.2(ꢃ-C), 29.3(3, 5, 7-C),
32.0(ꢁ -C), 36.9(2, 8, 9-C), 38.8(4, 6, 10-C), 40.1(1-C),
57.98(ꢀ-C), 63.4(ꢂ-C), 125.5(4-Car), 126.5(2, 6-Car),
131.2(3, 5-Car), 144.9(1-Car). Anal. Calcd for C26H32O, C:
86.62; H:8.95. Found C: 86.89; H:8.99.
4–[ꢂ-(1-Tricyclo[3.3.1.1.3,7]decyl)phenylmethyl]-ꢁ-ben-
zene propanol 8a (500 mg) was eluted in the next fractions.
Mp 71-73 oC (n-pentane); IR (Nujol) v (ꢁꢀ) 3335 cm-1; 1ꢀ-
NMR (400MHz, CDCl3) ꢀ 1.55-1.64 (complex m, 13H, 2, 4,
6, 8, 9, 10-H, OH), 1.83-1.87(m, 2H, ꢃ-H, 1.93(br.s, 3H, 3,
5, 7-H), 2.63-2.67(t, 2H, J~7.5-8Hz, ꢁ-H), 3.45(s, 1H, ꢀ-H),
3.63-3.66(t, 2H, J~6.5 Hz, ꢂ-H), 7.08-7.10(~d, 2H, AA`BB`,
JAB=JA`B`~8 Hz, JAA`=JBB`=0Hz, 2, 6-Har), 7.16-7.23(m, 1H,
4`-Har), 7.25-7.27(m, 2H, 2`, 6`-Har), 7.33-7.35(~d, 2H,
AA`BB`, JAB=JA`B`~8Hz, JAA`=JBB`=0 Hz, 3, 5-Har), 7.40-
7.43(m, 2H, 3`, 5`-Har); 13C-NMR(100MHz, CDCl3) ꢀ
28.8(3, 5, 7-C), 31.5(ꢁ-C), 34.1(ꢃ-C), 36.8(2, 8, 9-C), 41.1(1,
4, 6, 10-C), 62.4(ꢂ-C), 66.0(ꢀ-C), 125.9(4`-Car), 127.8(2`,
6`-Car), 127.9(2, 6-Car), 130.0(3, 5, 3`, 5`-Car), 139.3(1`-
Car), 139.7(1-Car), 142.3(4-Car).
4,4-Bis(4-methoxyphenyl)-4-(1-tricyclo[3.3.1.1.3,7]decyl)-
1-butene (6g)
Butene 6g was prepared from chloride 5g in a similar
way to butene 6a, which was purified by flash column chro-
matography using as eluent a mixture of ether : cyclohexane,
1:3. Yield 63%. (semisolid); IR (Nujol) v (C=C) 1635cm-1;
1ꢀ-NMR(400MHz, CDCl3) ꢀ 1.48-1.62 (m, 6H, 2, 8, 9-H),
1.79(br.s, 6H, 4, 6, 10-H), 1.95(br.s, 3H, 3, 5, 7-H), 2.93-
2.95(d, 2H, J~ 6.5 Hz, ꢁ-H), 3.79(s, 6H, CH3ꢁ), 4.76-
4.87(qd, 2H, ꢂ-ꢀ), 5.44-5.54(m, 1H, ꢃ-ꢀ),6.75-6.77(~d, 4H,
AA`BB`, JAB~9Hz, JAA`=JBB`~0Hz, 3, 5-Har), 7.23-7.25(d,
4H, AA`BB`, JAB~9Hz, JAA`=JBB`~0Hz, 2, 6 -Har); 13C-
NMR(100MHz, CDCl3) ꢀ 29.30(3, 5, 7-C), 36.97(2, 8, 9-C),
38.68(4, 6, 10-C), 40.04(1-C), 41.23(ꢁ-C), 55.04(CH3ꢁ),
56.61(ꢀ-C), 111.68(3, 5-C), 116.03(ꢂ-C), 132.35(2, 6-Car),
137.37(1-Car, ꢃ-C), 156.93(4-Car).
4,4-Bis(4-fluorophenyl)-4-(1-tricyclo[3.3.1.1.3,7]decyl)-1-
butene (6h)
Butene 6h was prepared from the chloride 5h in a similar
way to the butene 6a, which was purified by flash column
chromatography using as eluent a mixture of ether : cyclo-
o
hexane, 1:3. Yield 90%. Mp 116-118 C (n-pentane); IR
1
(Nujol) v (C=C) 1638 cm-1; ꢀ-NMR(400MHz, CDCl3) ꢀ
1.51-1.60(m, 6H, 2, 8, 9-H), 1.72(br.s, 6H, 4, 6, 10 -H),
1.91(br.s, 3H, 3, 5, 7 -H), 2.87- 2.88(d, 2H, J~ 6.5 Hz, ꢁ-H),
4.72-4.78(m, 2H, ꢂ-ꢀ), 5.37-5.42(m, 1H, ꢃ-ꢀ), 6.83-6.87(~t,
4H, J2ar,3ar ~ J3ar,F= 8.7 Hz, J3ar,5ar=0 Hz, 3, 5 -Har), 7.18-
7.21(q, 4H, J2ar,3ar=8.7 Hz, J2ar,F=5.5 Hz, J2ar,6ar=0 Hz, 2, 6-
Har); 13C-NMR(100MHz, CDCl3) ꢀ 29.2(3, 5, 7-C), 36.9(2,
8, 9-C), 38.6(4, 6, 10-C), 39.9(1-C), 41.4(ꢁ-C), 57.2(ꢀ-C),
113.2, 113.4(3, 5-Car), 116.9(ꢂ-C), 132.7, 132.8(2, 6-Car),
136.5(ꢃ-C), 140.7(1-Car), 159.4, 161.9(4-Car); Anal. Calcd
for C26H28F2, C: 82.5; H: 7.46. Found C: 82.64; H: 7.45.
ꢀ,ꢀ-Bis(4-methylphenyl)-ꢀ-(1-tricyclo[3.3.1.1.3,7]decane)
butanol (7f)
Butanol 7f was prepared in a similar way to butanol 7a
upon hydroboration of allylderivative 6f. Yield 55%. Mp 62-
64 oC (ether); IR (Nujol) v (ꢁꢀ) 3364 cm-1; 1ꢀ-
NMR(400MHz, CDCl3) ꢀ 1.10(br.s, 1H, OH), 1.17-1.20(m,
2H, ꢃ-H), 1.55-1.62(m, 6H, 2, 8, 9-H), 1.76(br.s, 6H, 4, 6,
10-H), 1.93(br.s, 3H, 3, 5, 7-H), 2.11- 2.14(m, 2H, ꢁ-H),
2.32(s, 6H, CH3) 3.48-3.51(m, 2H, ꢂ-ꢀ), 7.02-7.04(~d, 4H,
AA`BB`, JAB~8Hz, JAA`=JBB`~0Hz, 2, 6-Har), 7.21-7.23(~d,
4H, AA`BB`, JAB~8Hz, JAA`=JBB`~0Hz, 3, 5 -Har); 13C-
NMR(100MHz, CDCl3) ꢀ 20.81(CH3), 29.3(ꢃ-C), 29.4(3, 5,
7-C), 32.0(ꢁ-C), 37.0(2, 8, 9-C), 38.9(4, 6, 10-C), 40.2(1-C),
57.4(ꢀ-C), 63.7(ꢂ-C), 127.3(2, 6-Car), 131.2(3, 5-Car),
134.7(4-Car), 141.9(1-Car). Anal. Calcd for C28H36O, C:
86.54; H:9.34. Found C: 86.74; H:9.55.
4-(4-ꢀethylphenyl)-4-phenyl-4-(1-tricyclo[3.3.1.1.3,7]de-
cyl)-1-butene (6i)
Butene 6i was prepared from chloride 5i in a similar way
to butene 6a. Flash column chromatography using as eluent a
mixture of ether : cyclohexane, 1:1 gave an oily product
(yield 93%), which was found to be a mixture of isomers
6i:8i, 5:1. This mixture was used as such to the next step of
hydroboration.
ꢀ,ꢀ-Bis(4-methoxyphenyl)-ꢀ-(1-tricyclo[3.3.1.1.3,7]decane)
butanol (7g)
ꢀ,ꢀ-Diphenyl-ꢀ-(1-tricyclo[3.3.1.1.3,7]decane)butanol (7a)
To a stirred solution of a mixture of alkenes 6a:8a, 5:1 (3
g, 8.8 mmol) in anhydrous THF (20 ml) was slowly added a
solution of borane 1.0 M in anhydrous THF (9 ml, 9 mmol)
under an argon atmosphere at 0 oC. The reaction mixture was
stirred at r.t. for 3 h and then quenched by adding chilled
water until no foaming was further formed. A solution of
NaOH 10% (4 ml) and H2O2 30% (4 ml) was added drop-
Butanol 7g was prepared in a similar way to butanol 7a
upon hydroboration of allylderivative 6g Yield 55%. Mp 69-
71 oC (ether); IR (Nujol) v (ꢁꢀ) 3350cm-1; 1ꢀ-NMR
(400MHz, CDCl3) ꢀ 1.10-1.13(m, 2H, ꢃ-H), 1.28(br.s, 1H,
OH), 1.50-1.55(m, 6H, 2, 8, 9-H), 1.68(br.s, 6H, 4, 6, 10 -H),
1.86(br.s, 3H, 3, 5, 7-H), 2.02- 2.06(m, 2H, ꢁ-H), 3.41-3.44(t,
2H, J~6.4Hz, ꢂ-ꢀ), 3.73(s, 6H, CH3ꢁ), 6.69-6.71(~d, 4H,
o
wise into the latter mixture, which was heated to 50-60 C

580 Medicinal Chemistry, 2012, Vol. 8, No. 4
Riganas et al.
AA`BB`, JAB~8Hz, JAA`=JBB`~0Hz, 3, 5-Har), 7.17-7.19(~d,
4H, AA`BB`, JAB~8Hz, JAA`=JBB`~0Hz, 2, 6-Har); 13C-
NMR(100MHz, CDCl3) ꢀ 29.2(ꢁ-C), 29.4(3, 5, 7-C), 32.1(ꢂ-
C), 37.0(2, 8, 9-C), 38.8(4, 6, 10-C), 40.3(1-C), 55.1(CH3O),
56.7(ꢀ-C), 63.7(ꢃ-C), 111.8(3, 5-Car), 132.1(2, 6-Car),
137.0(1-Car), 157.0(4-Car). Anal. Calcd for C28H36O3, C:
79.96; H: 8.63. Found C: 80.29; H: 8.64.
was extracted with ether. The organic layer was thoroughly
washed with water, dried over Na2SO4 and evaporated to
give a residue, which was purified by flash column chroma-
tography, using as eluent a mixture of CHCl3:MeOH, 97:3 to
afford 700 mg of liquid product (yield 79%). Total yield
1
from butanol 7a ~75%. ꢀ-NMR(400MHz, CDCl3) ꢀ 1.04-
1.21(m, 2H, ꢁ-H), 1.54-1.62(m, 6H, 2, 8, 9-H), 1.77(br.s, 6H,
4, 6, 10-H), 1.93(br.s, 3H, 3, 5, 7-H), 2.06- 2.10(~t, 2H,
J~8Hz, ꢂ-H), 2.17-2.20(~t, 2H, J~7.6Hz, ꢃ-ꢀ), 2.24(s, 3H,
CH3), 2.20-2.53(very br.s, 8H, 2, 3, 5, 6-Hp), 7.15-7.22(m,
6H, 2, 4, 6-Har), 7.31-7.33(~d, 4H, J~7Hz, 3, 5-Har); 13C-
NMR(100MHz, CDCl3) ꢀ 23.0(ꢁ-C), 29.3(3, 5, 7-C), 35.58(ꢂ
-C), 36.9(2, 8, 9-C), 38.8(4, 6, 10-C), 40.1(1-C), 46.0(CH3),
53.2(3, 5-Cp), 55.1(2, 6-Cp) 58.2(ꢀ-C), 59.3(ꢃ-C), 125.2(4-
Car), 126.6(2, 6-Car), 131.2(3, 5-Car), 145.1(1-Car); Dihy-
ꢀ,ꢀ-Bis(4-fluorophenyl)-ꢀ-(1-tricyclo[3.3.1.1.3,7]decane)
butanol (7h)
Butanol 7h was prepared in a similar way to butanol 7a.
o
Yield 77%. Mp 59-61 C (ether); IR (Nujol) v ( ꢀ) 3335
1
cm-1; ꢀ-NMR(400MHz, CDCl3) ꢀ 1.05-1.08(m, 2H, ꢁ-H),
1.34-1.56(m, 6H, 2, 8, 9-H), 1.55(br.s, 1H, OH), 1.65(br.s,
6H, 4, 6, 10-H), 1.86(br.s, 3H, 3, 5, 7 -H), 2.03-2.07(m, 2H,
ꢂ-H), 3.41-3.45(t, 2H, J~6.5Hz, ꢃ-ꢀ), 6.81-6.89(m, 4H, 3, 5-
Har), 7.17-7.20(m, 4H, 2, 6-Har); 13C-NMR(100MHz,
CDCl3) ꢀ 29.1(ꢁ-C), 29.3(3, 5, 7-C), 32.2(ꢂ -C), 36.8(2, 8, 9-
C), 38.8(4, 6, 10-C), 40.2(1-C), 57.2(ꢀ-C), 63.41(ꢃ-C),
113.2, 113.5(3, 5-Car), 132.5(2, 6-Car), 140.4(1-Car), 159.4,
161.9(4-Car). Anal. Calcd for C26H30F2O, C: 78.76; H: 7.63.
Found C: 78.70; H: 7.60.
o
drochloride: Mp 263-265 C (EtOH-Et2O); IR (Nujol)ꢃ( ꢀ)
3401 cm-1; Anal. Calcd for C31H44Cl2N2·H2O, C: 69.77; H:
8.69; N: 5.25. Found C: 69.69; H: 8.59; N: 5.17.
4-[4,4–Diphenyl-4-(1-tricyclo[3.3.1.1.3,7]decyl)butyl]-1-
ethylpiperazine (1b)
(Trifluoromethanesulfonate method). To a stirred solu-
tion of butanol 7a (361 mg, 1 mmol) in anhydrous DCM (10
ml), was added dropwise 2,6-lutidine (180 mg, 1.7 mmol)
and trifluoromethanesulfonic anhydride (470 mg, 1.7 mmol)
ꢀ-(4-ꢀethylphenyl)-ꢀ-phenyl-ꢁ-(1-tricyclo[3.3.1.1.3,7] de-
cyl)butanol (7i)
o
at -10 C. The reaction mixture was stirred at this tempera-
Butanol 7i was synthesized by hydroboration of a mix-
ture of alkenes 6i:8i, which contains 17% of the byproduct.
Yield 54% (calculated to the pure starting material). Mp 39-
41 oC (n-ꢁꢂꢃꢄꢅꢃꢆꢇ). IR (Nujol) v ( ꢀ) 3348 cm-1; 1ꢀ-
NMR(400MHz, CDCl3) ꢀ 1.11-1.16(m, 2H, ꢈ -H), 1.27(br.s,
1H, OH), 1.53-1.56(m, 6H, 2, 8, 9-H), 1.72(br.s, 6H, 4, 6,
10-H), 1.88(br.s, 3H, 3, 5, 7-H), 2.07- 2.12(m, 2H, ꢂ-H),
2.27(s, 3H, CH3) 3.43-3.46(t, 2H, J~6.5Hz, ꢃ-ꢀ), 6.97-
6.99(~d, 2H, J~8Hz, 3, 5-Har), 7.12-7.20(~m, 5H, 2, 6, 2`,
4`, 6`-Har), 7.28-7.30(~d, 2H, J~8.5Hz, 3`, 5`-Har); 13C-
NMR(100MHz, CDCl3) ꢀ 20.81(CH3), 29.3(ꢁ-C), 29.4(3, 5,
7-C), 32.0(ꢂ-C), 37.0(2, 8, 9-C), 38.9(4, 6, 10-C), 40.2(1-C),
57.7(ꢀ-C), 63.7(ꢃ-C), 125.3(3, 5-Car), 126.6(2, 6 -Car),
127.3(2`, 6`-Car), 131.2, 131.3(3`, 4`, 5`-Car), 134.7(4-Car),
141.8(1-Car), 145.0(1`-Car). Anal. Calcd for C27H34O, C:
86.58; H: 9.15. Found C: 86.63; H: 9.13.
ture, under an argon atmosphere for 1 h. Then the solvent
was removed under vacuum, without heating and chilled
water was poured into the residue. The resulting mixture was
extracted with diethyl ether. The combined organic phase
was washed with water, dried over Na2SO4 and evaporated
under vacuum, without heating. The residue was diluted in
anhydrous THF (10 ml) and 1-ethylpiperazine (1 ml) was
added to the previous solution. The reaction mixture was
stirred at room temperature for 1 h, then the solvent was re-
moved under vacuum and water poured into the residue. The
resulting mixture was extracted with diethyl ether. The com-
bined organic phases were thoroughly washed with water
and an aqueous solution of NaHCO3, dried over Na2SO4 and
evaporated to give a residue, which was further purified by
flash column chromatography, using as eluent a mixture of
DCM:EtOAc, 2:1 to afford 218 mg of an oily product (yield
4-[4,4–Diphenyl-4-(1-tricyclo[3.3.1.1.3,7]decyl)butyl]-1-
methylpiperazine (1a)
45%). ꢀ-NMR (400MHz, CDCl3) ꢀ 0.97-1.01(t, 3H, A3X2,
1
JAX=7Hz, CH3CH2), 0.98-1.07(m, 2H, ꢁ-H), 1.48-1.55(m,
6H, 2, 8, 9-H), 1.70(br.s, 6H, 4, 6, 10-H), 1.87(br.s, 3H, 3, 5,
7 -H), 1.98-2.03(~t, 2H, J~8Hz, ꢂ-H), 2.12-2.15(~t, 2H,
J~7.8 Hz, ꢃ-ꢀ), 2.09-2.56(very br.s, 8H, 2, 3, 5, 6-Hp), 2.30-
2.35(t, 2H, A3X2, JAX=7 Hz, CH3CH2) 7.09-7.17( m, 6H, 2,
4, 6 -Har), 7.24-7.26(~d, 4H, J~7.5 Hz, 3, 5-Har); 13C-NMR
(100MHz, CDCl3) ꢀ 11.82(CH3), 23.0(ꢁ-C), 29.4(3, 5, 7-C),
36.6(ꢂ-C), 36.9(2, 8, 9-C), 38.9(4, 6, 10-C), 40.1(1-C),
52.5(3, 5-Cp), 52.6(CH2CH3), 55.0(2, 6-Cp) 58.2(ꢀ-C),
59.3(ꢃ-C), 125.3(4-Car), 126.6(2, 6-Car), 131.2(3, 5-Car),
145.1(1-Car). Dihydrochloride: Mp 229-231 oC (EtOH-
Et2O); Anal. Calcd for C32H46Cl2N2·H2O, C: 70.18; H: 8.84;
N: 5.12. Found C: 70.14; H: 8.58; N: 5.43.
(Tosylate method): To a stirred mixture of p-toluenesul-
fonyl chloride (2.51 g, 13.17 mmol) and anhydrous pyridine
(6.2 ml) in anhydrous DCM (2.5 ml) was added dropwise a
solution of butanol 7a (2.37 g, 6.58 mmol) in anhydrous
o
DCM (6 ml) at 0 C. The reaction mixture was stirred under
o
o
an argon atmosphere, at 0 C for 4 h and then at 10 C over-
night. The mixture was quenched with a solution of HCl
(10%), the organic layer was separated from the aqueous and
extracted with DCM. The combined organic phases were
washed with water and a solution of Na2CO3, dried over
Na2SO4 and evaporated under vacuum to afford 3.2 g of to-
sylate (yield ~94%), which was used to the next step without
any further purification. To a solution of the tosylate (1.03 g,
2 mmol) in absolute ethanol (10 ml) was added 1-methyl-
piperazine (4.5 ml) and the reaction mixture was heated to
reflux for 3 h. The solvent was then removed under vacuum,
water was poured into the residue and the resulting mixture
1-ꢂenzyl-4-[4,4–diphenyl-4-(1-tricyclo[3.3.1.1.3,7]decyl)
butyl]piperazine (1c)
Piperazine 1c was synthesized in a similar way to pir-
erazine 1b, using butatol 7a as starting material. Yield 75%

New Adamantane Derivatives with Sigma Affinity
Medicinal Chemistry, 2012, Vol. 8, No. 4 581
of an oily product. 1ꢀ-NMR(400MHz, CDCl3) ꢀ 0.96-
1.09(m, 2H, ꢁ-H), 1.45-1.57(m, 6H, 2, 8, 9-H), 1.69(br.s, 6H,
4, 6, 10-H), 1.86(br.s, 3H, 3, 5, 7-H), 1.99-2.02(~t, 2H,
J~7.8Hz, ꢂ-H), 2.10-2.14(~t, 2H, J~7.8Hz, ꢃ-ꢀ), 2.07-
2.51(very br.s, 8H, 2, 3, 5, 6-Hp), 3.40(s, 2H, ꢁ-H), 7.08-
7.15(m, 9H, 2, 4, 6, 2`, 4`, 6`-Har), 7.21-7.26(m, 6H, 3, 5, 3`,
5`-Har); 13C-NMR(100MHz, CDCl3) ꢀ 23.0(ꢁ-C), 29.4(3, 5,
7-C), 33.6(ꢂ-C), 36.9(2, 8, 9 -C), 38.9(4, 6, 10-C), 53.0(3, 5-
Cp), 53.2(2, 6-Cp) 57.6(ꢀ-C), 59.4(ꢃ-C), 63.0(ꢁ-C), 125.3(4-
Car), 126.5(2, 6-Car), 126.9(4`-Car), 128.1(2`, 6`-Car),
129.2(3`, 5`-Car), 131.2(3, 5-Car), 138.1(1`-Car), 145.1(1-
4-[4,4–Bis-(4-methylphenyl-4-(1-tricyclo[3.3.1.1.3,7]decyl)
butyl]-1-methylpiperazine (1f)
Piperazine 1f was synthesized in a similar way to pir-
erazine 1b using butatol 7f as starting material. Yield 34% of
1
an oily product. ꢀ-NMR(400MHz, CDCl3) ꢁ (ppm): 1.04-
1.21(m, 2H, ꢁ -H), 1.55-1.62(m, 6H, 2, 8, 9-H), 1.76(br.s,
6H, 4, 6, 10-H), 1.93(br.s, 3H, 3, 5, 7-H), 2.02- 2.06(~t, 2H,
J~4Hz, ꢂ-H), 2.18-2.22(t, 2H, J~7.5Hz, ꢃ-ꢀ), 2.25(s, 3H,
CH3-ꢃ), 2.32(s, 6H, 4ar -CH3), 2.23-2.60(very br.s, 8H, 2, 3,
5, 6-Hp), 7.01-7.03(d, 4H, AA`BB`, JAB=JA`B`=8Hz,
JAA`=JBB`=0Hz, 2, 6-Har), 7.20-7.22(d, 4H, AA`BB`,
o
Car); Difumarate: Mp 227-229 C (EtOH-Et2O); Dipicrate:
JAB=JA`B`=8Hz, JAA`=JBB`=0Hz, 3,
5
-Har); 13C-
Mp 248 oC (acetone); Anal. Calcd for C49H52N8O14, C: 60.24;
H: 5.37; Found C: 60.26; H: 5.46.
NMR(100MHz, CDCl3) ꢁ (ppm): 20.8(4ar -C), 23.0(ꢁ -C),
29.4(3, 5, 7 -C), 33.6(ꢂ-C), 37.0(2, 8, 9-C), 38.8(4, 6, 10 -C),
40.1(1-C), 45.98(CH3-N), 53.15(3, 5-Cp), 55.04(2, 6-Cp)
57.48(ꢀ-C), 59.36(ꢃ-C), 127.2(3, 5-Car), 131.1(2, 6-Car),
1-Cyclohexyl-4-[4,4–diphenyl-4-(1-tricyclo[3.3.1.1.3,7]
decyl)butyl]piperazine (1d)
o
134.5(4-Car), 142.0(1-Car); Dihydrochloride: Mp > 250 C
Piperazine 1d was synthesized in a similar way to pir-
erazine 1b using butatol 7a as starting material. Yield 66%
of an oily product. 1ꢀ-NMR(400MHz, CDCl3) ꢀ 1.05-
1.25(complex m, 7H, ꢁ -H, 2, 3, 4, 5, 6-Hc,ax), 1.54-1.61(m,
6H, 2, 8, 9-H), 1.76(br.s, 6H, 4, 6, 10-H), 1.84-1.86(m, 5H,
2, 3, 4, 5, 6-Hc,eq), 1.93(br.s, 3H, 3, 5, 7-H), 2.05-2.09(~t,
2H, J~8Hz, ꢂ-H), 2.18-2.20(m, 3H, ꢃ-ꢀ, 1-Hc,ax), 2.25-
2.43(br.s, 4H, 3, 5-Hp), 2.45-2.62(br.s, 4H, 2, 6 -Hp), 7.15-
7.22(m, 6H, 2, 4, 6-Har), 7.30-7.32(~d, 4H, J=7Hz, 3, 5 -
Har); 13C-NMR(100MHz, CDCl3) ꢁ (ppm): 23.0(ꢁ-C),
25.833, 5-Cc), 26.2(4-Cc), 28.9(2, 6-Cc), 29.4(3, 5, 7-C),
33.6(ꢂ-C), 36.9(2, 8, 9-C), 38.8(4, 6, 10-C), 40.1(1-C),
48.8(2, 6-Cp), 53.6(3, 5-Cp) 58.2(ꢀ-C), 59.5(ꢃ-C), 63.5(1-
Cc), 125.2(4-Car), 126.5(2, 6-Car), 131.2(3, 5-Car), 145.1(1-
(EtOH-Et2O); Anal. Calcd for C33H48Cl2N2·1/2H2O, C:
71.72; H: 8.93; N: 5.07. Found C: 71.59; H: 8.96; N: 5.12.
4-[4,4–Bis-(4-methoxyphenyl-4-(1-tricyclo[3.3.1.1.3,7]dec-
yl)butyl]-1-methylpiperazine (1g)
Piperazine 1g was synthesized in a similar way to pir-
erazine 1a using butatol 7g as starting material. Purification
by flash column chromatography, using as eluent a mixture
of DCM:EtOAc, 2:1 gave compound 1g as a solid. Yield
o
1
42%. Mp 30-32 C; ꢀ-NMR(400MHz, CDCl3) ꢁ (ppm):
0.96-1.04(m, 2H, ꢁ-H), 1.46-1.54(m, 6H, 2, 8, 9-H),
1.65(br.s, 6H, 4, 6, 10 -H), 1.85(br.s, 3H, 3, 5, 7-H), 1.92-
1.96(t, 2H, J~7.5- 8Hz, ꢂ-H), 2.10-2.14(t, 2H, J~7.6Hz, ꢃ-ꢀ),
2.17(s, 3H, CH3-ꢄ), 2.12-2.51(very br.s, 8H, 2, 3, 5, 6-Hp),
3.72(s, 6H, OCH3), 6.67-6.69(d, 4H, AA`BB`, JAB=JA`B`=9
Hz, JAA`=JBB`=0 Hz, 3, 5-Har), 7.14-7.17(d, 4H, AA`BB`,
o
Car); Dihydrochloride: Mp 260-262 C (EtOH-Et2O); Anal.
Calcd for C36H52Cl2N2·H2O, C: 71.85; H: 9.05; N: 4.66.
Found C: 71.50; H: 9.34; N:4.66.
JAB=JA`B`=9 Hz, JAA`=JBB`=0 Hz, 2,
6
-Har); 13C-
1-[4,4–Diphenyl-4-(1-tricyclo[3.3.1.1.3,7]decyl)butyl]piper-
azine (1e)
NMR(100MHz, CDCl3) ꢁ (ppm): 23.0(ꢁ,-C), 29.4(3, 5, 7-C),
33.7(ꢂ-C), 37.0(2, 8, 9-C), 38.8(4, 6, 10-C), 40.3(1-C),
46.0(CH3-N), 53.2(3, 5 -Cp), 55.1(2, 6-Cp, OCH3), 56.9(ꢀ-
C), 59.4(ꢃ-C), 111.8(3, 5-Car), 132.1(2, 6-Car), 137.2(1-
Car), 156.9(4-Car); Dihydrochloride: Mp 222-225 C(EtOH-
Et2O); Anal. Calcd for C33H48Cl2N2ꢄ2·H2O, C: 66.76; H:
To a stirred suspension of N-benzyl derivative 1d (1.06 g,
2 mmol) and Pd/C (10%, 950 mg) in methanol (20 ml) was
added at once ammonium formate (621 mg, 10 mmol) under
an argon atmosphere. The reaction mixture was heated at
reflux for 3 h and then cooled to r.t. The catalyst was filtered
off through Celite and the filtrate was evaporated in vacuo to
give a residue, which was purified by flash column chroma-
tography, using as eluent a mixture of CHCl3:MeOH, 9:1 to
afford 781 mg of crystalline product (Yield 89%). Mp 76-78
o
8.49; N: 4.72. Found C: 66.90; H: 8.63; N: 4.80.
4-[4,4–Bis-(4-fluorophenyl)-4-(1-tricyclo[3.3.1.1.3,7]decyl)
butyl]-1-methylpiperazine (1h)
Piperazine 1h was synthesized in a similar way to pir-
erazine 1b using butatol 7h as starting material. Yield 55%
of an oily product. 1ꢀ-NMR(400MHz, CDCl3) ꢁ (ppm):
0.94-1.01(m, 2H, ꢁ-H), 1.47-1.56(m, 6H, 2, 8, 9-H),
1.65(br.s, 6H, 4, 6, 10-H), 1.87(br.s, 3H, 3, 5, 7-H), 1.95-
1.99(~t, 2H, J~6.5= 8 Hz, ꢂ-H), 2.11-2.15(~t, 2H, J~7.5Hz,
ꢃ-ꢀ), 2.08-2.52(very br.s, 8H, 2, 3, 5, 6 -Hp), 2.19(s, 3H,
CH3), 6.82-6.87(~t, 4H, J2ar,3ar ~ J 3ar,F= 8.6 Hz, J3ar,5ar=0 Hz,
3, 5-Har), 7.17-7.20(~q, 4H, J2ar,3ar=8.6 Hz, J2ar,F=3.5 Hz,
J2ar,6ar=0 Hz, 2, 6-Har); 13C-NMR(100MHz, CDCl3) ꢁ (ppm):
23.1(ꢁ -C), 29.3(3, 5, 7-C), 33.9(ꢂ-C), 36.9(2, 8, 9-C),
38.8(4, 6, 10-C), 40.2(1-C), 46.0(CH3), 53.2(3, 5-Cp),
55.1(2, 6 -Cp), 57.4(ꢀ -C), 59.2(ꢃ-C), 113.3, 113.5(3, 5-Car),
132.4, 132.5(2-Car), 140.6(1-Car), 159.4, 161.9(4-Car); Di-
1
oC; ꢀ-NMR(400MHz, CDCl3) ꢁ (ppm): 0.97-1.00(m, 2H,
ꢁ-H), 1.46-1.56(m, 6H, 2, 8, 9 -H), 1.66(br.s, 6H, 4, 6, 10-
H), 1.83(br.s, 3H, 3, 5, 7-H), 1.96- 2.00(~t, 2H, J~7.8Hz, ꢂ-
H), 2.07-2.11(t, 2H, J~7.5Hz, ꢃ-ꢀ), 2.22(br.s, 4H, 2, 6 -Hp),
2.79-2.81(t, 4H, J~4.8Hz, 3, 5 -Hp), 2.95-3.50(very br.s, 1H,
NH), 7.06-7.16(m, 6H, 2, 4, 6-Har), 7.21-7.23(~d, 4H,
J~7.5Hz, 3, 5-Har); 13C-NMR(100MHz, CDCl3) ꢁ (ppm):
22.8(ꢂ -C), 29.4(3, 5, 7 -C), 33.5(ꢂ -C), 40.0(2, 8, 9 -C),
38.9(4, 6, 10-C), 40.2(1-C), 45.2(3, 5-Cp), 53.1(2, 6 -Cp)
58.3(ꢀ -C), 59.5(ꢃ-C), 125.3(4-Car), 126.6(2, 6-Car),
o
131.2(3, 5-Car), 145.1(1-Car); Difumarate: Mp 188-190 C
o
(EtOH-Et2O); Dipicrate: Mp >250 C (acetone); Anal. Calcd
for C42H46N8O14, C: 56.88; H: 5.23; N: 12.63. Found C:
56.59; H: 5.19; N: 12.75.
o
fumarate: Mp 219-220 C (EtOH-Et2O); Anal. Calcd for

582 Medicinal Chemistry, 2012, Vol. 8, No. 4
Riganas et al.
C39H48F2N2ꢀ8, C: 65.90; H: 6.81; N: 3.94. Found C: 65.73;
H: 6.88; N: 4.01.
261-263oC(EtOH); Anal. Calcd for C28H38ClN, C: 79.30; H:
9.05; N: 3.30. Found C: 78.98; H: 9.26; N: 3.29.
1-ꢀethyl-4-[4–(methylphenyl)-4-phenyl-4-(1-
ꢀ,ꢀ-Diphenyl-ꢀ-(1-tricyclo[3.3.1.1.3,7]decane)butanol met-
hanesulfonate (10)
tricyclo[3.3.1.1.3,7]decyl)butyl]piperazine (1i)
Piperazine 1i was synthesized in a similar way to pir-
erazine 1b using butatol 7i as starting material. Yield 51% of
an oily product. ꢁ-NMR(400MHz, CDCl3) ꢂ (ppm): 0.95-
To a stirred solution of butanol 7a (1.0 g, 2.77 mmol) in a
mixture of pyridine (1.5 ml) and anhydrous DCM (1.5 ml)
was added dropwise a solution of mesylchloride (1.35 g, 12
1
o
1.03(m, 2H, ꢀ -H), 1.45-1.53(m, 6H, 2, 8, 9-H), 1.67(br.s,
6H, 4, 6, 10 -H), 1.83(br.s, 3H, 3, 5, 7 -H), 1.95- 1.98(m, 2H,
ꢁ-H), 2.08-2.12(~t, 2H, J~8Hz, ꢂ-ꢁ), 2.04-2.52(very br.s,
8H, 2, 3, 5, 6 -Hp), 2.15(s, 3H, CH3-ꢃ), 6.92-6.94(~d, 2H,
J=8.5Hz, 3, 5 -Har), 7.04-7.13(m, 5H, 2, 6-Har, 3`, 4`, 5`-
Har), 7.22-7.24(~d, 2H, J=7.5Hz, 2`, 6`-Har); 13C-
NMR(100MHz, CDCl3) ꢂ (ppm): 20.8(CH3), 23.0(ꢀ-C),
29.4(3, 5, 7 -C), 33.6(ꢁ-C), 37.0(2, 8, 9-C), 38.9(4, 6, 10-C),
40.2(1-C), 45.9(CH3-N), 53.1(3, 5 -Cp), 55.0(2, 6-Cp)
57.9(ꢄ-C), 59.3(ꢂ -C), 125.2(4`-Car), 126.5(3`, 5`-Car),
127.3(3, 5-Car), 131.1(2, 6-Car), 134.6(4-Car), 141.9(1`-
mmol) in anhydrous DCM (1.5 ml) at 0 C. The reaction
mixture was stirred for 12h at rt, then treated with chilled
water for 30 min. The mixture was extracted with DCM. The
combined organic phases were washed with 2N HCl, 5%
NaHCO3 and water, dried over Na2SO4 and the solvent
evaporated in vacuo. The residue was further purified by
flash column chromatography, using DCM as eluent to give
1.2 g (yield almost quantitative) of a white solid. Mp 136-
o
1
138 C; ꢁ-NMR (400MHz, CDCl3) ꢄ (ppm): 1.30-1.34(m,
2H, ꢀ-H), 1.52-1.54(m, 6H, 2, 8, 9-H), 1.70(br.s, 6H, 4, 6, 10
-H), 1.88(br.s, 3H, 3, 5, 7-H), 2.12-2.16(m, 2H, ꢁ-H), 2.86(s,
3H, CH3), 3.94-3.97(t, 2H, J=6,4Hz, ꢂ-ꢁ), 7.13-7.20( m, 6H,
2, 4, 6-Har), 7.25-7.27(m, 4H, 3, 5-Har).
Car), 145.2(1-Car); Dihydrochloride: Mp
247-248 oC
(EtOH-Et2O); Anal. Calcd for C32H46Cl2N2· H2O, C: 70.18;
H: 8.83; N: 5.12. Found C: 70.54; H: 8.89; N: 5.20.
ꢀ,ꢀ-Diphenyl-1-tricyclo[3.3.1.1.3,7]decanepentanonitrile
(11)
1-[4,4–Diphenyl-4-(1-tricyclo[3.3.1.1.3,7]decyl)butyl]piper-
idine (1j)
Sodium cyanide (750 mg, 15 mmol) was added to a solu-
tion of mesylate 10 (2.1 g, 4.8 mmol) in DMSO (10 ml) and
the mixture was stirred under an argon atmosphere at 60 C
Piperidine 1j was synthesized in a similar way to pir-
erazine 1b using butatol 7a as starting material. Purification
by flash column chromatography, using as eluent a mixture
o
for 12h. After cooling the reaction mixture was poured into
chilled water and extracted with ethyl acetate. The combined
organic phases were washed with water, dried over Na2SO4
and the solvent evaporated in vacuo. The residue was further
purified by flash column chromatography using as eluent a
mixture of n-hexane : ether, 4:1, to give 1.6 g (yield 40%) of
a solid product. Mp 139-141 oC. IR (Nujol) v (CN) 2244 cm-
1
of DCM:EtOAc, 2:1 gave an oily product. Yield 40%. ꢁ-
NMR(400MHz, CDCl3) ꢂ (ppm): 1.13-1.21(m, 2H, ꢀ-H),
1.37(br.s, 2H, 4-Hp), 1.51-1.54(m, 4H, 3, 5-Hp), 1.59(m, 6H,
2, 8, 9-H), 1.77(br.s, 6H, 4, 6, 10-H), 1.93(br.s, 3H, 3, 5, 7-
H), 2.06- 2.10(~t, 2H, J~8Hz, ꢁ-H), 2.15-2.19(~t, 2H,
J~7.8Hz, ꢂ-ꢁ), 2.24(br.s, 4H, 2, 6-Hp), 7.15-7.23(m, 6H, 2,
4, 6 -Har), 7.32-7.34(d, 4H, J=7.6Hz, 3, 5 -Har); 13C-
NMR(100MHz, CDCl3) ꢂ (ppm): 22.8(ꢀ -C), 24.2(4-C),
25.6(3, 5-Cp), 29.4(3, 5-C), 33.7(ꢁ -C), 36.9(2, 8, 9-C),
38.8(4, 6, 10-C), 40.1(1-C), 54.4(2, 6 -Cp), 58.2(ꢄ-C),
60.0(ꢂ-C), 125.2(4-Car), 126.5(2, 6-Car), 131.2(3, 5-Car),
145.1(1-Car); Hydrochloride: Mp >250 oC (EtOH-Et2O);
Anal. Calcd for C31H42ClN, C: 80.22; H: 9.12; N: 3.02.
Found C: 79.95; H: 9.22; N: 3.14.
1
1; ꢁ-NMR(400MHz, CDCl3) ꢂ(ppm): 1.14-1.18(m, 2H, ꢀ-
ꢁ), 1.45-1.57(m, 6H, 2, 8, 9-H), 1.65(br.s, 6H, 4, 6, 10-H),
1.83(br.s, 3H, 3, 5, 7-H), 1.99-2.03(t, 2H, J=7Hz, ꢂ-H), 2.10-
2.14(m, 2H, ꢁ-H), 7.05-7.14(m, 6H, 2,4,6-Har), 7.18-7.21(m,
4H, 3,5-Har). 13C-NMR(100MHz, CDCl3) ꢂ (ppm): 17.6(ꢂ–
C), 22.0(ꢀ-C), 29.3(3, 5, 7-C), 35.1(ꢁ-H), 36.8(2, 8, 9-C),
38.8(4, 6, 10-C), 40.2(1-C), 58.0(ꢄ-C), 119.8(CN), 125.6(4-
Car), 126.8(2, 6-Car), 131.0(3, 5-Car), 144.3(1-Car). Anal.
Calcd for C27H31N, C: 87.75; H: 8.46; Found C: 87.90; H:
8.26;
N,N-Dimethyl-4,4–diphenyl-4-(1-tricyclo[3.3.1.1.3,7]decyl)
butylamine (1k)
Ethyl ꢀ,ꢀ-diphenyl-1-tricyclo[3.3.1.1.3,7]decanepentanoate
(12)
A solution of the tosylate of butanol 7a (580 mg, 11.3
mmol) and a solution of dimethylamine in ethanol (5.6 ml, 2
M, 11.3 mmol) was heated to reflux for 3 h. The reaction
mixture was worked up as reported for amine 1a (tosylate
method). Purification by flash column chromatography, us-
ing as eluent CHCl3 : MeOH, 9 :1, afforded 372 mg of 1k
(Yield 85%).1ꢁ-NMR (400MHz, CDCl3) ꢂ (ppm): 1.10(br.s,
2H, ꢀ-H), 1.53-1.62(br.m, 6H, 2, 8, 9-H), 1.62(br.s, 6H, 4, 6,
10-H), 1.93-1.97(m, 5H, 3, 5, 7, ꢁ-H), 2.68(s, 6H, (CH3)2ꢃ),
2.68-2.73(m, 2H, ꢂ-H), 7.16-7.28(m, 10H, 2xC6H5). 13C-
NMR(100MHz, CDCl3) ꢂ (ppm): 18.2(ꢀ-C), 28.4(3, 5, 7-C),
31.1(ꢁ-C), 35.9(2, 8, 9 -C), 38.0(4, 6, 10-C), 39.5(1 -C),
49.4(CH3-N), 57.6(ꢄ-C), 63.2(ꢂ-C), 125.0(4-Car), 126.2(2, 6
-Car), 130.0(3, 5-Car), 143.2(4-Car); Hydrochloride: Mp
Carbonitrile 11 (2.0 g, 6.4 mmol) was added to a mixture
of saturated ethanolic hydrogen chloride (15 ml) and abso-
lute ethanol (10 ml). The reaction mixture was heated to re-
flux for 2 h, water (9 drops) was then added and heating was
continued for 1 h. Ethanol was removed in vacuo, water was
added to the residue and the mixture was extracted with
ether. The organic phase was washed with water, saturated
solution of Na2CO3 (10%), dried over Na2SO4 and the sol-
vent evaporated under vacuum. The residue was further puri-
fied by flash column chromatography, using as eluent a mix-
ture of n-hexane : ether, 2:1, to give 1.5 g (yield 67%) of a
o
solid product. Mp 61-63 C. IR (Nujol) v (C=O) 1731cm-1;
1ꢁ-NMR(400MHz, CDCl3) ꢂ(ppm): 1.13-1.21(m, 2H, ꢀ-ꢁ),

New Adamantane Derivatives with Sigma Affinity
Medicinal Chemistry, 2012, Vol. 8, No. 4 583
1.14-1.71(t, 3H, A3X2, JAX=7Hz,CH3CH2), 1.48-1.55(m, 6H,
2, 8, 9-H), 1.70(br.s, 6H, 4, 6, 10-H), 1.86(br.s, 3H, 3, 5, 7-
H), 2.02-2.07(m, 2H, ꢀ-H), 2.09-2.10(~t, 2H, J=4Hz, ꢁ-H),
3.99-4.04(q, 2H, A3X2, JAX=7Hz, CH3CH2), 7.10-7.18(m,
6H, 2,4,6-Har), 7.26-7.28(m, 4H, 3,5-Har). 13C-
NMR(100MHz, CDCl3) ꢀ (ppm): 14.24(CH3), 21.3(ꢂ-C),
29.4(3, 5, 7-C), 34.9(ꢁ-H), 35.4(ꢀ-C), 36.9(2, 8, 9-C), 38.8(4,
6, 10-C), 40.2(1-C), 58.2(ꢀ-C), 60.1(CH3CH2), 125.3(4-Car),
126.6(2, 6-Car), 131.3(3, 5-Car), 144.9(1-Car), 173.6(C=O).
Anal. Calcd for C29H36O2, C: 83.61; H: 8.71. Found C:
84.00; H: 8.81.
Hp), 7.07-7.20(m, 6H, 2,4,6-Har), 7.27-7.29(m, 4H, 3,5-
Har). 13C-NMR(100MHz, CDCl3) ꢀ (ppm): 21.9(ꢂ-C),
24.5(3-Cp), 25.5(5-Cp), 26.4(4-Cp), 26.4(3, 5, 7-C), 34.5(ꢁ-
C), 35.8(ꢀ-C), 36.5(2, 8, 9-C), 38.8(4, 6, 10-C), 40.1(1-C),
42.4(2-Cp), 46.6(6-Cp), 54.6(2-Cp), 58.4(ꢀ-C), 125.3(4-
Car), 126.6(2, 6-Car), 131.3(3, 5-Car), 145.0(1-Car),
171.2(C=O). Anal. Calcd for C32H41NO C: 84.35; H: 9.07;
N: 3.07. Found C: 84.65; H: 9.05; N: 3.00.
1-Methyl-4-[5,5-diphenyl-(1-tricyclo[3.3.1.1.3,7]decyl)
pentyl]piperazine (2a)
To a stirred suspension of LiAlH4 (500 mg) in anhydrous
THF (20 ml) was added dropwise a solution of amide 13a
(500 ml, 1.06 mmol) in anhydrous THF (10 ml). The reac-
tion mixture was refluxed for 3 h, then hydrolysed by adding
1-Methyl-4-(ꢀ,ꢀ-diphenyl-1-tricyclo[3.3.1.1.3,7]decyl-
pentanoyl)piperazine (13a)
To a stirred solution of ethyl ester 12 (680 mg, 1.6 mmol)
in ethanol (10 ml) was added a solution of NaOH (2.0 g, 50
mmol) in a minimum amount of water and the mixture was
refluxed for 2 h. Ethanol was then evaporated, water was
added to the residue and the resulting mixture was acidified
with HCl 10% under cooling. The mixture was extracted
with ether and the organic phase was washed with water,
dried over Na2SO4 and concentrated in vacuo. Thionyl chlo-
ride (3 ml) was then added to the residue and the resulting
mixture was refluxed gently for 1 h. The excess of thionyl
chloride was removed in vacuo and the last traces with the
aid of anhydrous benzene. The residue was dissolved in THF
(10 ml) and the resulting solution was added dropwise to a
stirred solution of 1-methylpiperazine (3 ml) in THF (10 ml)
under cooling. The reaction mixture was refluxed for 3 h and
the solvent was removed under vacuum. Water was added to
the residue and the mixture was extracted with DCM. The
combined organic phases were washed with water, dried
over Na2SO4 and evaporated in vacuo to give a residue,
which was purified by flash column chromatography, using
as eluent a mixture of chloroform : methanol, 9:1, to give
620 mg (yield 90%) of a semisolid product. IR (Nujol) v
(C=O) 1652 cm-1; 1ꢁ-NMR(400MHz, CDCl3) ꢀ(ppm): 1.15-
1.22(m, 2H, ꢂ-ꢁ), 1.46-1.58(m, 6H, 2, 8, 9-H), 1.70(br.s, 6H,
4, 6, 10-H), 1.82(br.s, 3H, 3, 5, 7-H), 2.06-2.10(m, 4H, ꢁ, ꢂ-
H), 2.14-2.16(t, 2H, 2-Hp), 2.23-2.25(t, 2H, 6-Hp), 3.14-
3.17(t, 2H, J=5Hz, 3-Hp), 3.48-3.51(~t, 2H, 5-Hp), 7.07-
7.19(m, 6H, 2,4,6-Har), 7.27-7.29(m, 4H, 3,5-Har). 13C-
NMR(100MHz, CDCl3) ꢀ (ppm): 21.8(ꢂ-C), 29.4(3, 5, 7-C),
34.3(ꢁ-C), 35.8(ꢀ-C), 36.9(2, 8, 9-C), 38.9(4, 6, 10-C),
40.2(1-C), 41.2(5-Cp), 45.3(3-Cp), 45.9(CH3), 54.6(2-Cp),
55.0(6-Cp), 58.4(ꢀ-C), 125.3(4-Car), 126.6(2, 6-Car),
131.3(3, 5-Car), 154.0(1-Car), 171.3(C=O). Anal. Calcd for
C32H42N2O, C: 81.66; H: 8.99; N: 5.95. Found C: 81.60; H:
9.00; N: 5.99.
o
ethanol, water and a solution of NaOH 10% at 0 C. The
inorganic material was filtered and the filtrate was evapo-
rated. Water was added to the residue and the resulting mix-
ture was extracted with DCM. The combined organic phases
were washed with water, dried over Na2SO4 and concen-
trated in vacuo to give 400 mg (yield 83%)of a low mp solid.
1ꢁ-NMR(400MHz, CDCl3) ꢀ(ppm): 0.80-0.86(m, 2H, ꢀ-ꢁ),
1.31-1.35(m, 2H, ꢂ-Hp), 1.48-1.55(m, 6H, 2, 8, 9-H),
1.69(br.s, 6H, 4, 6, 10-H), 1.87(br.s, 3H, 3, 5, 7-H), 2.01-
2.05(t, 2H, J=7.5Hz, ꢃ-H), 2.11-2.15(t, 2H, J=7.5Hz, ꢁ-H),
2.21(s, 3H, CH3), 2.05-2.60(very br.s, 8H, 2, 3, 5, 6-Hp),
7.08-7.17(m, 6H, 2,4,6-Har), 7.23-7.25(m, 4H, 3,5-Har). 13C-
NMR(100MHz, CDCl3) ꢀ (ppm): 23.7(ꢀ-C), 27.7(ꢂ-C),
29.4(3, 5, 7-C), 35.8(ꢃ-C), 36.9(2, 8, 9-C), 38.8(4, 6, 10-C),
40.1(1-C), 45.9(CH3), 52.9(3,5-Cp), 54.9(2, 6-Cp), 58.3(ꢄ-
C), 58.3(ꢁ-C), 125.2(4-Car), 126.5(2, 6-Car), 131.3(3, 5-
Car), 145.2(1-Car). Dihydrochloride Mp>250 oC (EtOH-
Et2O), Anal. Calcd for C32H46Cl2N2.H2O, C: 70.05; H: 9.00;
N: 5.11. Found C: 69.74; H: 8.90; N: 5.01.
1-[5,5-diphenyl-(1-tricyclo[3.3.1.1.3,7]decyl)pentyl]piperi-
dine (2b)
Pentylamine 2b was prepared by reduction of amide 13b
with LiAlH4 in a similar way to pentylamine 2a. Yield al-
most quantitative of a viscous oil. 1ꢁ-NMR(400MHz,
CDCl3) ꢀ(ppm): 0.75-0.86(m, 2H, ꢀ-ꢁ), 1.30-1.36(m, 4H, ꢂ-
Hp, 4-Hp), 1.48-1.58(m, 10H, 2, 8, 9-H, 3, 5-Hp), 1.69(br.s,
6H, 4, 6, 10-H), 1.86(br.s, 3H, 3, 5, 7-H), 2.01-2.09(m, 4H,
ꢁ, ꢃ-H), 2.20-2.32(m, 4H, 2, 6-Hp), 7.10-7.19(m, 6H, 2,4,6-
Har), 7.24-7.26(m, 4H, 3,5-Har). 13C-NMR(100MHz,
CDCl3) ꢀ (ppm): 23.0(ꢀ-C), 23.5(4-Cp), 24.9(3,5-Cp),
28.5(3, 5, 7-C), 29.4(ꢂ-C), 35.0(ꢃ-C), 36.0(2, 8, 9-C), 37.9(4,
6, 10-C), 39.2(1-C), 53.6(2,6-Cp), 57.4(ꢄ-C), 58.3(ꢁ-C),
124.3(4-Car), 125.6(2, 6-Car), 130.4(3, 5-Car), 144.3(1-Car).
o
Hydrochloride Mp>250 C (EtOH-Et2O), Anal. Calcd for
1-(ꢀ,ꢀ-Diphenyl-1-tricyclo[3.3.1.1.3,7]decanepentanoyl)
piperidine (13b)
C32H44Cl2N.1/2H2O, C: 78.89; H: 9.31; N: 2.88. Found C:
79.20; H: 9.14; N: 2.92.
Amide 13b was prepared from the ester 12 in a similar
way to amide 13a and was purified by flash column chroma-
tography, using as eluent a mixture of chloroform : metha-
ꢁ,ꢁ-Diphenyl-1-tricyclo[3.3.1.1.3,7]decanebutanal (14)
To a solution of alcohol 7a (925 mg, 2.65 mmol) in DCM
(5.3 ml) PCC (858 mg, 3.98 mmol) was added. The reaction
mixture was stirred at r.t. for 2h, then ether was added, the
mixture was filtered through a short pad of florisil and
washed with ether. The filtrate was evaporated to afford 800
mg (yield 87%) of a white amorphous solid, which was used
o
nol, 9:1. Yield 90% of solid product. Mp 130-132 C; IR
(Nujol) v (C=O) 1638 cm-1; 1ꢁ-NMR(400MHz, CDCl3)
ꢀ(ppm): 1.16-1.21(m, 2H, ꢂ-ꢁ), 1.30(br.s, 2H, 4-Hp),
1.36(br.s 2H, 5-Hp),1.49-1.54(m, 8H, 2, 8, 9-H, 3-Hp),
1.70(br.s, 6H, 4, 6, 10-H), 1.86(br.s, 3H, 3, 5, 7-H), 2.07-
2.10(m, 4H, ꢁ, ꢀ-H), 3.09(br.s, 2H, 6-Hp), 3.40(br.s, 2H, 2-

584 Medicinal Chemistry, 2012, Vol. 8, No. 4
Riganas et al.
to the next step without further purification. Mp 156-158 oC.
ester 16 (493mg, 1.14 mmol) in anhydrous THF (10 ml). The
1
IR (KBr) v (C=O) 1717 cm-1; ꢀ-NMR(400MHz, CDCl3)
reaction mixture stirred for 1 h at rt, then hydrolysed by add-
o
ꢁ(ppm): 1.49-1.56(m, 6H, 2, 8, 9-H), 1.71-1.72(m, 6H, 4, 6,
10-H), 1.89(br.s, 3H, 3, 5, 7-H), 2.06-2.10(t, 2H, A2X2,
J=7.5Hz, ꢀ-H), 2.39-2.43(t, 2H, A2X2, J=7.5Hz, ꢁ-H), 7.10-
7.19(m, 6H, 2,4,6-Har), 7.24-7.26(m, 4H, 3,5-Har), 9.42(s,
1H,CH=O). 13C-NMR(100MHz, CDCl3) ꢁ (ppm): 27.8(ꢁ-C),
29.3(3, 5, 7-C), 36.9(2, 8, 9-C), 38.9(4, 6, 10-C), 40.7(1-C),
41.6(ꢀ-C), 57.6(ꢂ-C), 125.7(4-Car), 126.9(2, 6-Car), 131.0(3,
5-Car), 144.3(1-Car), 202.4(C=O).
ing ethanol, water and a solution of NaOH 10% at 0 C. The
inorganic material was filtered and the filtrate was evapo-
rated. Water was added to the residue and the resulting mix-
ture was extracted with ether. The combined organic phases
were washed with water, dried over Na2SO4 and concen-
trated in vacuo. The residue was further purified by flash
column chromatography, using as eluent a mixture of cyclo-
hexane : ethyl acetate, 80:20, to give 430 mg (yield 97%) of
a white foam. Mp: 99-101 oC. IR (KBr) v (C=O) 3320 cm-1;
1H-NMR (400MHz, CDCl3) ꢁ(ppm): 0.81-0.89 (m, 2H, ꢃ-H),
1.13-1.20(m, 2H, ꢂ-H), 1.32(br.s, 1H, OH), 1.33-1.39(m, 2H,
ꢀ-H), 1.49-1.58(m, 6H, 2, 8, 9- H), 1.70(br.s, 6H, 4, 6, 10-
H), 1.86(br.s, 3H, 3, 5, 7-H), 2.00-2.04(m, 2H, ꢅ-H), 3.42-
3.45(t, 2H, J=6.5Hz, ꢁ-H), 7.10-7.17(m, 6H, 2, 4, 6 -Har),
7.24- 7.26(m, 4H, 3, 5-Har). 13C-NMR (100MHz, CDCl3) ꢁ
(ppm): 25.5(ꢃ-C), 26.6(ꢂ-C), 29.4(3, 5, 7-C), 32.6(ꢀ-C),
35.9(ꢅ-C), 36.9(2, 8, 9-C), 38.9(4, 6, 10-C), 40.1(1-C),
58.3(ꢄ-C), 62.9(ꢁ-C), 125.2(4-Car), 126.5(2, 6- Car),
131.3(3,5-Car), 145.2(1-Car). Anal. Calcd for C28H36O, C:
86.54; H: 9.34. Found C: 86.68; H: 9.24.
Ethyl (E)-ꢀ,ꢀ-diphenyl-1-tricyclo[3.3.1.1.3,7]decanehex-ꢁ-
enoate (15)
To a stirred suspension of sodium hydride (136 mg, 60%
disp, 3.4 mmol) in dry THF (6 ml) was added triethyl phos-
phonoacetate (695 mg, 0.62 ml, 3.1 mmol) under an argon
0
atmosphere at 0 C. After 30 min a solution of the aldehyde
14 (1.07 g, 3.1 mmol) in dry THF (6 ml) was added into the
reaction mixture, which was then stirred for 30 more min-
utes. The reaction was quenched by adding a saturated solu-
o
tion of NH4Cl at 0 C. The mixture was extracted with ether
and the combined organic phases were washed with water,
dried over Na2SO4 and concentrated in vacuo. The residue
was further purified by flash column chromatography, using
as eluent a mixture of cyclohexane : ethyl acetate, 95:5, to
give 1.15 g (yield 87%) of a white amorphus solid unsatu-
4-[6,6-Diphenyl-6-(1-tricyclo[3.3.1.1.3,7]decyl)hexyl]-1-
methylpiperazine (3a)
To a stirred solution of hexanol 17 (384 mg, 0.99 mmol)
in a mixture of pyridine (1.5 ml) and anhydrous DCM (1.5
ml) was added dropwise a solution of p-tosylchloride (226
1
rated ester. ꢀ-NMR(400MHz, CDCl3) ꢁ(ppm):1.26-1.29(t,
3H, A3X2, J=6Hz, CH3), 1.57-1.63(m, 6H, 2, 8, 9-H), 1.75-
1.82(m, 8H, 4, 6, 10, ꢃ-H), 1.95(br.s, 3H, 3, 5, 7-H), 2.23-
2.26(~t, 2H, ꢂ-H), 4.14-4.18(q, 2H, A3X2, J=6Hz, CH2O),
5.69-5.73(d, 1H, J=13Hz, ꢁ-H), 6.84-6.90(quin, 1H, ꢀ-H),
7.19-7.26(m, 6H, 2,4,6-Har), 7.31-7.33(m, 4H, 3,5-Har).
o
mg, 1.19 mmol) in anhydrous DCM (1.5 ml) at 0 C. The
reaction mixture was stirred for 2 h at rt, then poured into
chilled water and treated for 30 min. The mixture was ex-
tracted with DCM. The combined organic phases were
washed with 2N HCl, 5% NaHCO3 and water, dried over
Na2SO4 and concentrated in vacuo. The residue was purified
by flash column chromatography, using DCM as eluent to
give 471 mg (yield 88%) of tosylate, as a white foam. The
tosylate was dissolved in ethanol (10 ml) and the resulting
solution was added dropwise to a stirred solution of 1-
methylpiperazine (3 ml) in ethanol (10 ml) under cooling.
The reaction mixture was refluxed for 5 h and the solvent
was removed in vacuo. Water was added to the residue and
the mixture was extracted with DCM. The combined organic
phases were washed with water, dried over Na2SO4 and con-
centrated in vacuo to give a residue, which was further puri-
fied by flash column chromatography, using as eluent a mix-
ture of dichloromethane : methanol, 95:5, to give 415
Ethyl ꢀ,ꢀ-diphenyl-1-tricyclo[3.3.1.1.3,7]decanehexanoate
(16)
To a solution of the olefinic ester 15 (540 mg, 1.26
mmol) in abs EtOH (40 ml) was added 10% Pd/C (60 mg)
and the suspension stirred vigorously under hydrogen at-
mosphere, for 16h at rt. The catalyst was removed by filtra-
tion through celite, and the filtrate was evaporated under
reduced pressure to give 542 mg of saturated ester 16, as a
white amorphous solid, which was used in the next step
without further purification (Yield almost quantitative). Mp
1
75-77 oC. IR (KBr) v (C=O) 1716 cm-1; ꢀ-NMR(400MHz,
CDCl3) ꢁ(ppm):0.82-0.91(m, 2H, ꢂ-H), 1.10-1.13(t, 3H,
A3X2, J=7Hz, CH3), 1.42-1.55(complex m, 8H, 2, 8, 9, ꢀ-H),
1.69(br.s, 6H, 4, 6, 10-H), 1.87(br.s, 3H, 3, 5, 7-H), 2.01-
2.05(m, 2H, ꢃ-H), 2.06-2.10(t, 2H, A2X2, J=7.6Hz, ꢁ-H),
3.96-4.01(q, 2H, A3X2, J=7Hz, CH2O), 7.07-7.18(m, 6H,
2,4,6-Har), 7.23-7.25(m, 4H, 3, 5-Har). 13C-NMR(100MHz,
CDCl3) ꢁ (ppm): 14.2(CH3), 25.4(ꢂ-C), 25.9(ꢀ-C), 29.4(3, 5,
7-C), 34.3(a-C), 35.7(ꢃ-C), 36.9(2, 8, 9-C), 38.8(4, 6, 10-C),
40.1(1-C), 41.6(ꢂ-C), 58.2(ꢄ-C), 60.1(CH2O), 125.3(4-Car),
126.9(2, 6-Car), 131.2(3, 5-Car), 145.1(1-Car), 173.7(C=O).
Anal. Calcd for C30H38O2, C: 83.67; H:8.89. Found C: 83.7;
H:8.90.
1
mg(yield 95%) of a viscous product. H-NMR (400MHz,
CDCl3) ꢁ(ppm): 0.38-0.90 (m, 2H, ꢃ-H), 1.15-1.19(m,2H, ꢂ-
H), 1.32-1.38(m,2H, ꢀ-H), 1.55-1.63(m, 6H, 2, 8, 9- H),
1.76(br.s, 6H, 4, 6, 10-H), 1.93(br.s, 3H, 3, 5, 7-H), 2.05-
2.10(m, 2H, ꢅ-H), 2.19-2.22(~t, 2H, ꢁ-H), 2.27(t, 3H, CH3),
2.01-2.65(very br.s, 8H, 2, 3, 5, 6-Hp), 7.14-7.23(m, 6H, 2,
4, 6-Har), 7.30- 7.32(m, 4H, 3, 5-Har). 13C-NMR (100MHz,
CDCl3) ꢁ (ppm): 25.6(ꢃ-C), 26.7(ꢀ-C), 28.5(ꢂ-C), 29.4(3,5,7-
C), 35.9(ꢅ-C), 37.0(2, 8, 9-C), 38.8(4, 6, 10-C), 40.1(1-C),
46.0(CH3), 53.1(3, 5-Cp), 55.0(2, 6-Cp), 58.3(ꢄ-C), 58.7(ꢁ-
C), 125.2(4-Car), 126.4(2, 6- Car), 131.3(3,5-Car), 145.2(1-
ꢂ,ꢂ-Diphenyl-1-tricyclo[3.3.1.1.3,7]decanehexanol (17)
o
Car). Dihydrochloride: Mp 245-247 C (EtOH-Et2O); Anal.
Calcd for C32H46Cl2N2.H2O, C: 70.18; H: 8.83; N: 5.12.
Found C: 70.30; H: 8.63; N: 5.22.
To a stirred suspension of LiAlH4 (185 mg, 4.26 mmol)
in anhydrous THF (20 ml) was added dropwise a solution of

New Adamantane Derivatives with Sigma Affinity
Medicinal Chemistry, 2012, Vol. 8, No. 4 585
1-[6,6-Diphenyl-6-(1-tricyclo[3.3.1.1.3,7]decyl)hexyl]piper-
idine (3b)
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A solution of tosylate (500 mg, 0.9 mmol) in ethanol (3
ml) and piperidine (3 ml) was refluxed for 5 h. The solvent
was then removed in vacuo, water was added to the residue
obtained and the mixture was extracted with DCM. The
combined organic phases were washed with water, dried
over Na2SO4 and concentrated in vacuo to give a residue,
which was further purified by flash column chromatography,
using as eluent a mixture of dichloromethane : methanol,
[11]
[12]
[13]
1
95:5, to give 415 mg (yield 99%) of a viscous product. H-
NMR (400MHz, CDCl3) ꢀ(ppm): 0.86-0.94(m, 2H, ꢀ-H),
1.14-1.21(m, 2H, ꢁ-H), 1.33-1.43(complex m, 4H, ꢂ-H, 4-
Hp), 1.52-1.63(complex m, 10H, 2, 8, 9-H, 3, 5-Hp),
1.77(br.s, 6H, 4, 6, 10-H), 1.93(br.s, 3H, 3, 5, 7-H), 2.06-
2.10(m, 2H, ꢃ-H), 2.14-2.16(~t, 2H, ꢄ-H), 2.30(br.s, 4H, 3, 5-
Hp), 7.14-7.23(m, 6H, 2, 4, 6-Har), 7.30- 7.32(m, 4H, 3, 5-
Har). 13C-NMR (100MHz, CDCl3) ꢀ (ppm): 24.4(4-Cp),
25.6(ꢀ-C), 25.9(3, 5-Cp), 26.7(ꢂ-C), 28.6(ꢁ-C), 29.4(3,5,7-
C), 35.9(ꢃ-C), 37.0(2, 8, 9-C), 38.8(4, 6, 10-C), 40.1(1-C),
54.5(2, 6-Cp), 58.3(ꢅ-C), 59.6(ꢄ-C), 125.2(4-Car), 126.4(2,
6- Car), 131.3(3,5-Car), 145.2(1-Car). Hydrochloride: Mp
[14]
[15]
[16]
o
241-242 C (EtOH-Et2O); Anal. Calcd for C32H44ClN, C:
80.38; H: 9.28; N: 2.93. Found C: 80.35; H: 9.48; N: 2.90.
ACKNOWLEDGEMENT
[17]
[18]
[19]
[20]
[21]
Dr Stefanos Riganas is idebted to National and Kapodis-
trian University of Athens for the award of a scholarship and
financial support –Support of Universities Research Groups
(2008-2009)KA 70-|4|7835 and (2009-2012)KA70|4|10311.
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Received: June 08, 2011
Revised: February 27, 2012
Accepted: March 21, 2012