Synthesis of 4-(aminoalkyl) substituted 1,3-dioxanes as potent NMDA and σ receptor antagonists

Article abstract of DOI:10.1016/j.ejmech.2011.02.070

Elongation of the distance between the oxygen heterocycle and the basic amino moiety or ring expansion of the oxygen heterocycle of the NMDA receptor antagonists dexoxadrol and etoxadrol led to compounds with promising NMDA receptor affinity. Herein the c

Full text of DOI:10.1016/j.ejmech.2011.02.070

European Journal of Medicinal Chemistry 46 (2011) 2157e2169
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European Journal of Medicinal Chemistry
journal homepage: http://www.elsevier.com/locate/ejmech
Original article
Synthesis of 4-(aminoalkyl) substituted 1,3-dioxanes as potent NMDA
and receptor antagonists
s
*
Tina Utech, Jens Köhler, Bernhard Wünsch
Institut für Pharmazeutische und Medizinische Chemie, Westfälischen Wilhelms-Universität Münster, Hittorfstraße 58-62, D-48149 Münster, Germany
a r t i c l e i n f o
a b s t r a c t
Article history:
Elongation of the distance between the oxygen heterocycle and the basic amino moiety or ring expansion
of the oxygen heterocycle of the NMDA receptor antagonists dexoxadrol and etoxadrol led to compounds
with promising NMDA receptor affinity. Herein the combination of both structural features, i.e. elon-
gation of the O-heterocycle e amine distance with a 1,3-dioxane ring is envisaged. The synthesis of
aminoethyl-1,3-dioxanes 13, 22, 23 and 29 was performed by transacetalization of various acetals with
pentane-1,3,5-triol, activation of the remaining free OH moiety with tosyl chloride and subsequent
nucleophilic substitution. The corresponding 3-aminopropyl derivatives 33e35 were prepared by
substitution of the tosylates with KCN and LiAlH4 reduction. The highest NMDA receptor affinity was
found for 1,3-dioxanes with a phenyl and an ethyl residue at the acetalic position (23) followed by
diphenyl (22) and monophenyl derivatives (13). Generally the NMDA affinity of primary amines is higher
than the NMDA affinity of secondary and tertiary amines. Altogether the primary amine 23a (Ki ¼ 24 nM)
represents the most promising NMDA receptor antagonist of this series exceeding the NMDA affinity of
the mono-homologues (2-aminoethyl)-1,3-dioxolanes (3,4) and (aminomethyl)-1,3-dioxanes (5,6).
Whereas the primary amine 23a turned out to be selective against s1 and s2 receptors the benzylamine
13d was identified as potent (Ki ¼ 19 nM) and selective s1 antagonist, which showed extraordinarily high
antiallodynic activity in the capsaicin assay.
Received 3 December 2010
Received in revised form
25 February 2011
Accepted 26 February 2011
Available online 5 March 2011
Keywords:
1,3-Dioxanes
NMDA receptor antagonists
PCP binding site
Dexoxadrol homologues
Structureeaffinity relationships
s
Receptor affinity
Ó 2011 Elsevier Masson SAS. All rights reserved.
1. Introduction
uncontrolled activation of several Ca2þ-dependent processes and at
the end in damage of neuronal cells (excitotoxicity) [5]. Compounds
The excitatory amino acid neurotransmitter (S)-glutamate
mediates its effects through two types of receptors, which are
termed ionotropic and metabotropic receptors. Herein we report on
novel ligands interacting with the NMDA (N-methyl-D-aspartate)
receptor, which represents the pharmacologically best character-
ized subtype of the ionotropic receptor class [1].
The NMDA receptor is a ligand gated ion channel, which controls
the passage of cations across neuronal membranes. In addition to
the control of Naþ-influx and Kþ-outflow the NMDA receptor is
responsible for the influx of Ca2þ-ions into neurons, which renders
it unique among the ionotropic glutamate receptors. The manifold
mechanisms controlling the Ca2þ-flow through the ion channel are
the origin for synaptic plasticity and long term potentiation, which
can be considered as cellular correlates for learning and memory
[2e4].
blocking the excessive influx of Ca2þ-ions through the NMDA
receptor associated ion channel into neurons are of major interest
as neuroprotective agents, which may be used for the therapy of
cerebral ischemia, stroke, epilepsy and trauma (brain injury).
Furthermore, permanent increased activation of NMDA receptors is
discussed to be involved in the development of chronic neurode-
generative disorders like Parkinson’s disease, Alzheimer’s disease,
amyotrophic lateral sclerosis and alcohol dependence. Conse-
quently, the NMDA receptor represents a promising target for the
development of novel drugs for the therapy of acute and chronic
neurological disorders [3,4,6,7].
There are several binding sites on the receptor protein for the
modulation of the Ca2þ-influx and thus the NMDA receptor activity.
The respective binding sites are termed according to their proto-
typical ligands, binding sites for (S)-glutamate, glycine, polyamines,
Zn2þ, Mg2þ, Hþ and phencyclidine (1-(1-phenylcyclohexyl)piperi-
dine, PCP) [3,8,9].
However, overactivation of NMDA receptors leads to an
increased influx of Ca2þ-ions into neurons resulting in an
We are particularly interested in ligands interacting with the PCP
binding site, which is located within the cation channel. Since
ligands can only interact with this binding site after opening of the
* Corresponding author. Tel.: þ49 251 8333311; fax: þ49 251 8332144.
E-mail address: wuensch@uni-muenster.de (B. Wünsch).
0223-5234/$ e see front matter Ó 2011 Elsevier Masson SAS. All rights reserved.
doi:10.1016/j.ejmech.2011.02.070

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T. Utech et al. / European Journal of Medicinal Chemistry 46 (2011) 2157e2169
ion channel, compounds of this type are termed “open-channel
blockers”. Open-channel blockers are uncompetitive NMDA
receptor antagonists and inhibit the influx of Ca2þ-ions into the
neuron [3,8,9].
stereochemistry representatives of both types of homologues
interact with NMDA receptors in a promising range [18] (see Fig. 1).
Therefore the idea came up to combine the side chain homo-
logation and the ring expansion in one molecule. Herein we report on
the synthesis and biological evaluation of double homologous 4-(2-
aminoehtyl)-1,3-dioxanes with the general structure 7.
In the mid 1960s piperidine derivatives with an acetalic
substituent in position
2 were synthesized by Hardie and
coworkers [10]. These studies led to the enantiomerically pure
compounds dexoxadrol (1) and etoxadrol (2, Fig. 1), which were
clinically evaluated as analgesic and anesthetic drugs [11,12].
Unfortunately the clinical evaluation of both compounds had to be
stopped, because psychotomimetic side effects, unpleasant dreams
and aberrations were observed [13,14]. After detection and char-
acterization of the NMDA receptor, it was shown that both
compounds dexoxadrol and etoxadrol were blocking the ion
channel by interaction with the PCP binding site [15,16]. The cor-
responding Ki-values are 112 nM [17] (23 nM [18]) for dexoxadrol
and 107 nM [17] (20 nM [18]) for etoxadrol.
2. Chemistry
For the synthesis of 2-aminoethyl substituted 1,3-dioxanes of
type 7 pentane-1.3,5-triol (8) was required as central starting
compound. According to literature the triol 8 was synthesized by
reduction of dimethyl 3-oxoglutarate with LiAlH4 [27]. However,
the isolation of the triol 8 was very difficult due to its high polarity.
The yield and the purity of the triol 8 were considerably improved
by a modified work-up procedure, which led to the pure triol 8 in
43% isolated yield.
In literature some structure-affinity relationship studies dealing
with these structurally and stereochemically interesting heterocy-
clic systems are reported [17e26]. It has been shown that the
complete piperidine ring is not necessary for high NMDA receptor
affinity, since 1,3-dioxolane derivatives bearing simple primary
(aminomethyl) or secondary amines (methylaminomethyl) as
piperidine substructures are also potent NMDA receptor antago-
nists. However, there are only few studies concerning the size of the
oxygen heterocycle and the distance between the oxygen hetero-
cycle and the basic amino group of the piperidine ring or its
surrogate [17e21]. Recently we have reported on the synthesis and
biological evaluation of side chain and ring homologues of dexox-
adrol and etoxadrol. In the first type of homologues 3 and 4 the
distance between the oxygen heterocycle and the basic amino
group is enlarged to two methylene moieties (three bond lengths).
The second type of homologues 5 and 6 contains a six-membered
1,3-dioxane ring instead of five-membered 1,3-dioxolane ring of 1
and 2. Depending on the substitution pattern and the
Pentanetriol 8 reacted with benzaldehyde dimethyl acetal (9) to
afford stereoselectively the thermodynamically favored cis-
configured 1,3-dioxane 10 (Scheme 1). The cis-configuration of 10
was proved by an NOE experiment showing the axial orientation of
the protons in 2- and 4-position. After conversion of the primary
alcohol 10 into the tosylate 11, nucleophilic substitution with
various amines led to the secondary and tertiary amines 13bed.
The primary amine 13a was obtained by hydrogenation (H2, Pd/C)
of the azide 12, which was prepared by nucleophilic substitution of
the tosylate 11 with NaN3. The final amines 13aed were prepared
and tested as racemic mixtures.
Transacetalization of benzophenone dimethyl acetal (14) and
propiophenone dimethyl acetal (15) with pentanetriol 8 provided
the 1,3-dioxanes 16 and 17, respectively (Scheme 2).
In case of the non-symmetric acetal 15 only the diastereomer
trans-17 with an axially oriented phenyl residue and an equatorially
oriented ethyl moiety was obtained. The stereodescriptor trans
refers to the relative orientation of the phenyl and 2-hydroxyethyl
O
H
N
OH
OH
H
OH
O
(a)
8
X
O
O
Ph
R
+
H
Ph-CH(OCH3)2
9
1: R = Ph (dexoxadrol)
2: R = Et (etoxadrol)
10: X = OH
11: X = OTos
12: X = N3
(b)
(c)
O
O
R
NH2
12
11
O
H
(d)
(e)
NH2
O
R
O
O
O
O
NH2
NR2
Ph
Ph
3: R = Ph ((Ki = 3260 nM))
4: R = Et (Ki = 69 nM)
5: R = Ph (Ki == 717 nM)
6: R = Et (Ki = 257 nM)
13a
13b-d
13
NR2
b
c
d
NHCH3
N(CH3)2
NHBn
O
R1
O
NR2
R2
Scheme 1. Reagents and reaction conditions: (a) p-TosOH, THF, 12 h, reflux, 57%. (b)
p-TosCl, pyridine, CH2Cl2, 15 h, 0e20 ꢀC, 67%. (c) NaN3, DMF, 2 h, reflux, 74%. (d) H2,
1 bar, Pd/C, THF, 1 h, rt, 96%. (e) MeNH2/EtOH or Me2NH/EtOH or BnNH2/toluene, 12 h,
reflux, 13b (56%), 13c (51%), 13d (67%).
7
Fig. 1. Development of mono and double homologues of the potent NMDA receptor
antagonists dexoxadrol and etoxadrol.

T. Utech et al. / European Journal of Medicinal Chemistry 46 (2011) 2157e2169
2159
in case of trans-17, since the axially oriented phenyl group can
adopt an orientation, which is perpendicular to the 1,3-dioxane
plane. The free rotation of the axially oriented phenyl moiety of
trans-17 is considerably restricted, which results in minimized
interactions between the ortho-protons and the axially oriented
protons at 4- and 6-position [28e30].
OO
O
R1
OH
OCH3
Ph
R1
(a)
(b)
8
+
OCH3
The secondary and tertiary amines 22bed and 23bed were
prepared by activation of the alcohols 16 and 17 with tosyl chloride
and subsequent nucleophilic substitution. Nucleophilic substitu-
tion of the tosyloxy group of 18 and 19 with NaN3 provided the
corresponding azides 20 and 21, which were reduced with H2 in the
presence of Pd/C to yield the primary amines 22a and 23a,
respectively.
14: R1 = Ph
15: R1 = Et
16: R1 = Ph
17: R1 = Et
O
O
(c)
R1
O
R1
OTos
N3
O
In order to replace the phenyl residues of 22a or the phenyl and
ethyl residues of 23a by a bulky non-aromatic moiety, the
adamantane derivative 29a was envisaged (Scheme 3). The
synthesis of 29a [31] started with acetalization of adamantanone
(24) with methanol and subsequent transacetalization of the
resulting dimethyl acetal 25 with pentanetriol 8 to afford the 1,3-
dioxane 26 in 52% yield. Tosylation and subsequent substitution
with NaN3 converted the alcohol 26 into the azide 28, which was
reduced with H2 and Pd/C to give the primary amine 29a.
Since some of the primary amines, in particular the primary
amine 23a, showed high NMDA receptor affinity (see Table 1) the
homologous primary amines 33ae35a should be included into this
study. The homologization was achieved by substitution of the
tosylates 11, 18 and 19 with KCN and subsequent reduction of the
respective nitriles 30e32 with LiAlH4 (Scheme 4).
Ph
Ph
20: R1 = Ph
18: R1 = Ph
21: R1 = Et
19: R1 = Et
(e)
(d)
O
O
O
O
R1
R1
NR2
NH2
Ph
Ph
22b-d: R1 = Ph
23b-d: R1 = Et
22a:R1 = Ph
23a:R1 = Et
During the selectivity tests unexpected high s1 receptor affini-
ties of the benzaldehyde derivatives 13ae13d and 33a were found.
Therefore the corresponding homologous secondary and tertiary
amines 33be33d were also prepared and evaluated pharmaco-
logically. The synthesis of the propylamines 33be33d started with
alcohol 36, which was accessible by regioselective trans-
acetalization of benzaldehyde dimethyl acetal (9) with racemic
butane-1,2,4-triol [32,33]. After Swern oxidation [34] of the alcohol
22, 23 NR2
b
c
d
NHCH3
N(CH3)2
NHBn
Scheme 2. Reagents and reaction conditions: (a) p-TosOH, THF, 12 h, reflux, 16 (73%),
17 (70%). (b) p-TosCl, pyridine, CH2Cl2, 0e20 ꢀC, 18 (79%), 19 (56%). (c) NaN3, DMF, 2 h,
reflux, 20 (69%), 21 (65%). (d) MeNH2/EtOH or Me2NH/EtOH or BnNH2/toluene, 3e12 h,
reflux, 22b (41%), 22c (80%), 22d (65%), 23b (44%), 23c (44%), 23d (71%). (e) H2, 1 bar,
Pd/C, EtOAc or MeOH, rt, 22a (82%), 23a (93%).
36, aldehyde 37 was converted via a Wittig reaction into the a,b-
unsaturated ester 38. Hydrogenation and subsequent LiBH4
reduction of the saturated ester 39 gave the propanol 40, which was
transformed into the secondary and tertiary amines 33be33d via
nucleophilic substitution of the tosylate 41 (Scheme 5).
residues (Fig. 2). The relative configuration of trans-17 was proved
by NOE experiments. Irradiation with the resonance frequencies of
the axial protons at 6-position (3.80 ppm) and at 4-position
(3.96 ppm) led to an increased signal of the aromatic protons at
7.38e7.40 ppm, respectively. These effects are only possible when
the phenyl moiety adopts the axial position.
OCH3
OCH3
O
(b)
(a)
The diastereomer trans-17 appears to be energetically favored
over cis-17, since it was formed under thermodynamically
controlled conditions. The higher stability of trans-17 is explained
with steric interactions (Fig. 2). In case of cis-17 strong interactions
between the axially oriented ethyl moiety and the axially oriented
protons at 4- and 6-position result. These interactions are reduced
24
25
O
O
O
O
(e)
X
NH2
26: X = OH
27: X = OTos
28: X = N3
29a
(c)
(d)
Fig. 2. Possible diastereomeric 1,3-dioxanes derived from propiophenone and
pentanetriol 8. The stereodescriptors cis and trans define the relative orientation of
the 2-hydroxyethyl and phenyl moieties.
Scheme 3. Reagents and reaction conditions: (a) MeOH, HC(OMe)3, p-TosOH, 12 h,
reflux, 82%. (b) 8, p-TosOH, THF, 12 h, reflux, 52%. (c) p-TosCl, NEt3, CH2Cl2, 15 h,
0e20 ꢀC, 92%. (d) NaN3, DMF, 2 h, reflux, 53%. (e) H2, 1 bar, Pd/C, MeOH, 1 h, rt, 97%.

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T. Utech et al. / European Journal of Medicinal Chemistry 46 (2011) 2157e2169
receptors. A concentration of 10 mM of non-tritiated ditolylguani-
11,18,19
dine was used for the determination of non-specific binding.
(a)
3.2. Results and discussion
O
O
(b)
Table 1 clearly shows that 1,3-dioxanes with only one phenyl
substituent at the acetalic 2-position (13aed) do not interact
significantly with the phencyclidine binding site of the NMDA
receptor. Introduction of two phenyl residues (22a,b) as in dexox-
adrol leads to slightly increased NMDA receptor affinity. The most
promising compounds of this series are the etoxadrol derived
propiophenone derivatives 23 bearing a phenyl and an ethyl
residue at 2-position. Replacement of the phenyl and ethyl moieties
of 23a with a lipophilic, sterically demanding but non-aromatic
substituent (29a) was not tolerated by the NMDA receptor.
The same trend Ph,Et > Ph,Ph > Ph,H was observed for 4-(amino-
ethyl)-1,3-dioxolanes 3 and 4 and 4-(aminomethyl)-1,3-dioxanes 5
and 6 [18].
R1
R1
CN
O
O
NH2
R2
R2
30-32
33a-35a
30, 33a: R1 = Ph, R2 = H
31, 34a: R1 = R2 = Ph
32, 35a: R1 = Et, R2 = Ph
Scheme 4. Reagents and reaction conditions: (a) KCN, DMSO or DMF, 5e6 h, reflux, 30
(68%), 31 (81%), 32 (53%). (b) LiAlH4, THF, 2 h, 0 ꢀC, 33a (45%), 34a (89%), 35a (57%).
3. Pharmacology
The primary amine 23a represents the most potent NMDA
receptor antagonist (Ki ¼ 24 nM) of these double homologous
etoxadrol derivatives. The secondary amine 23b with a small
methyl residue at the N-atom and the tertiary amine 23c with two
methyl moieties show 6-fold and 30-fold reduced NMDA receptor
affinities, respectively. Introduction of a large lipophilic benzyl
residue at the N-atom (23d) leads to almost complete loss of NMDA
receptor affinity. The mono-homologous 4-(aminoethyl)-1,3-diox-
olanes 3,4 and 4-(aminomethyl)-1,3-dioxanes 5,6 show the same
tendency of NH2 > NHCH3 > N(CH3)2 [18,21].
Generally it was found that double-homologous aminoethyl
substituted 1,3-dioxanes, e.g. 23a (Ki ¼ 24 nM), which are derived
from etoxadrol, show higher NMDA receptor affinities than their
mono-homologous 4-(aminoethyl)-1,3-dioxolanes (e.g. (S,S)-4,
Ki ¼ 69 nM) and 4-(aminomethyl)-1,3-dioxanes (e.g. (S,S)-6,
Ki ¼ 257 nM). However, a further homologization of the aminoethyl
derivatives to aminopropyl derivatives 33ae35a led to considerably
reduced NMDA receptor affinities.
3.1. Receptor binding studies
The affinities of the 2-aminoethyl and 3-aminopropyl 1,3-diox-
anes to the phencyclidine binding site of the NMDA receptor were
determined in competition experiments with the radioligand [3H]-
(þ)-MK-801, which interacts with the ion channel binding site with
high affinity and selectivity. In the assay membrane preparations
from pig brain cortex were used as receptor material. Non-specific
binding was determined by saturation of the specific binding sites
with a large excess of non-tritiated (þ)-MK-801 [35e37].
There are several compounds interacting both with the phen-
cyclidine binding site of the NMDA receptor and with
[26,38,39]. Therefore in the past the enigmatic receptor has been
regarded to be identical with the phencyclidine binding site of the
NMDA receptor [40]. This hypothesis was disproved by further
investigations demonstrating the
receptor [41,42]. The cross reactivity of ligands with both receptor
types prompted us to investigate the receptor affinities of the
s receptors
s
s receptor to be an unique
s
Due to the cross reactivity of NMDA and
s ligands the s1 and s2
amines in addition to their NMDA receptor affinities.
affinities of all amines were determined (see Table 1). In the
benzaldehyde (13), benzophenone (22) and propiophenone (23)
series the benzylamines 13d, 22d and 23d represent the most
potent s1 ligands, respectively. The s1 affinity of the benzylamines
can be correlated with the size of the substituent in 2-position:
Replacement of one of the phenyl residues in 2-position of 22d with
an ethyl residue (23d) led to a 10-fold increase of s1 affinity and the
1,3-dioxane 13d with a proton at 2-position shows the highest s1
affinity of this series (Ki ¼ 19 nM). Elongation of the side chain of
In the s1 assay homogenates of guinea pig brains were used as
receptor material. The s1 selective ligand [3H]-(þ)-pentazocine was
employed as radioligand, and the non-specific binding was deter-
mined by saturation of the specific binding sites with a large excess
of haloperidol [43,44]. The s2 assay was performed with rat liver
membrane preparations and the non-selective radioligand [3H]-
ditolylguanidine. In order to gain s2 selectivity an excess of the s1
selective ligand (þ)-pentazocine was added to occupy the s1
O
O
O
O
O
O
(a)
(b)
(c)
CO2Et
CH=O
Ph
Ph
Ph
OH
36
37
38
O
O
O
O
O
(d)
(f)
CO2Et
Ph
Ph
O
Ph
(e)
NR2
X
40: X = OH
41: X = OTos
39
33b-d
33
NR2
b
c
d
NHCH3
N(CH3)2
NHBn
Scheme 5. (a) (COCl)2, DMSO, CH2Cl2, NEt3, ꢁ78 ꢀC. (b) Ph3P]CHCO2Et, CH2Cl2, 3 h, rt, 62% (from 36). (c) H2, 1.5 bar, Pd/C, EtOAc, 4 h, 88%. (d) LiBlH4, THF, 4 h, 0 ꢀC, 55%. (e) p-TosCl,
NEt3, CH2Cl2, 1 h, 0 ꢀC, 56%. (f) MeNH2/EtOH or Me2NH/EtOH or BnNH2/toluene, 12 h, reflux, 33b (58%), 33c (36%), 33d (76%).

T. Utech et al. / European Journal of Medicinal Chemistry 46 (2011) 2157e2169
2161
Table 1
NMDA, s1 and s2 receptor affinities of 4-aminoalkyl-1,3-dioxanes.
Compd.
R1
R2
n
NR2
Ki ꢂ SEM [nM] (n ¼ 3)
NMDA
s1
s2
13a
13b
13c
13d
22a
22b
22c
22d
23a
23b
23c
23d
29a
33a
33b
33c
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Et
Et
Et
Et
H
H
H
H
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
1
1
1
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
NH2
>10
>10
>10
>10
m
m
m
m
M
M
M
M
165 ꢂ 20
449 ꢂ 29
1650 ꢂ 60
19 ꢂ 1.0
>10
>10
m
m
M
M
NHCH3
N(CH3)2
NHBn
NH2
NHCH3
N(CH3)2
NHBn
NH2
NHCH3
N(CH3)2
NHBn
NH2
1830 ꢂ 93
92 ꢂ 40
2350 ꢂ 180
>10
>10
mM
M
>10
>10
>10
m
m
m
M
M
M
6870 ꢂ 230
m
>10
>10
m
m
M
M
660 ꢂ 82
320 ꢂ 12
955 ꢂ 145
856 ꢂ 109
511 ꢂ 28
27 ꢂ 2.0
2750 ꢂ 230
24 ꢂ 2.0
154 ꢂ 6.0
713 ꢂ 83
>10
>10
>10
m
m
m
M
M
M
>10
>10
>10
>10
>10
>10
>10
m
m
m
m
m
m
m
M
M
M
M
M
M
M
903 ꢂ 190
Adamantane
1250 ꢂ 30
167 ꢂ 13
327 ꢂ 51
1220 ꢂ 340
164 ꢂ 15
175 ꢂ 45
6450 ꢂ 73
>10
mM
Ph
Ph
Ph
Ph
Ph
Et
H
H
H
H
Ph
Ph
NH2
581 ꢂ 90
NHCH3
N(CH3)2
NHBn
NH2
6320 ꢂ 1460
>10 mM
33d
34a
35a
3890 ꢂ 2000
>10
mM
NH2
7670 ꢂ 830
542 ꢂ 170
Dexoxadrol
Etoxadrol
Phencyclidine
(þ)-Pentazcoine
Ditolylguanidine
19 ꢂ 2.5
22 ꢂ 3.9
28 ꢂ 4.6
3.5 ꢂ 0.2
64 ꢂ 11
the benzylamine 13d by one methylene moiety led to the propyl-
amine 33d with 10-fold decreased s1 affinity.
analgesic activity up to a dose of 32 mg/kg body weight, the benz-
aldehyde derivative 13d was extremely potent. Doses of 1.0 and
0.50 mg/kg led to 100% analgesia and a dose of 0.25 mg/kg showed
still more than 70% analgesia. Even at the very low dose of 0.125 mg/
kg around 10% analgesic activity was observed. The high anti-
allodynic potency indicates 13d to be a s1 receptor antagonist [45].
With exception of the benzylamine 13d (Ki ¼ 92 nM) the s2
affinities of the amines are generally rather low.
Since the NMDA receptor prefers primary amines and the s1
receptor benzylamines, both ligand types are selective over the
other receptor types. E.g. the most potent NMDA receptor antago-
nist 23a shows a 40-fold selectivity against the s1 receptor and
>400-fold selectivity against the s2 subtype. On the other hand the
most promising s1 ligands 13d and 23d do not interact significantly
with NMDA receptors. However, the selectivity against the s2
subtype differs considerably. Whereas the potent s1 ligand 23d
shows a 33-fold selectivity over the s2 receptor, only 5-fold selec-
tivity over the s2 subtype was observed for 13d. Despite the
moderate selectivity against the s2 subtype 13d reveals an excel-
lent selectivity over more than 60 other targets [45].
4. Conclusion
A series of aminoethyl and aminopropyl substituted 1,3-diox-
anes, which are considered as ring and side chain homologues of
the NMDA antagonists dexoxadrol and etoxadrol, has been
synthesized and pharmacologically evaluated. The most potent
NMDA antagonists result, when the acetalic position is substituted
with a phenyl and an ethyl residue. Primary amines are more
potent than secondary amines and these are more potent than
tertiary amines. The most promising NMDA antagonist 23a
(Ki ¼ 24 nM) exceeds the NMDA affinity of the mono-homologues 4
(aminoethyl-1,3-dioxolane) and 6 (aminomethyl-1,3-dioxane). 23a
reveals an excellent selectivity over s1 and s2 receptors.
Surprisingly this study did not only lead to the characterization
of the novel NMDA antagonist 23a but also to the identification of
the s1 antagonist 13d. The benzylamine 13d represents a very
potent (Ki ¼ 19 nM) and selective s1 ligand, which shows extraor-
dinarily high antiallodynic activity in the capsaicin assay.
3.3. Analgesic activity
The high s1 affinity of the benzylamines 13d and 23d stimulated
an in vivo study with these ligands. Sensitization by subplantar
capsaicin injection was used to assess the effect of the s1 ligands
13d and 23d on mechanical allodynia. Subplantar capsaicin
(8-methyl-N-vanillylnon-6-enamide) injection initially evokes
a nocifensive behavior that is characterized by lifting and guarding
the injected paw and typically lasts up to 5 min following injection.
Afterwards hypersensitivity to both thermal and mechanical
stimuli is evidenced [46,47].
5. Experimental
Mice were treated with the s1 ligands 13d and 23d 30 min before
capsaicin injection into the mid-plantar surface of the right hind
paw. Withdrawal latencies to mechanical stimuli by a von Frey
filament (1 g) were determined 15 min after capsaicin injection.
Whereas the propiophenone derivative 23d did not show any
5.1. Chemistry
5.1.1. General
Petroleum ether used refers to the fraction boiling at 40e60 ꢀC.
Thin layer chromatography (tlc): Silica gel 60 F254 plates (Merck).

2162
T. Utech et al. / European Journal of Medicinal Chemistry 46 (2011) 2157e2169
Flash chromatography (fc): Silica gel 60, 0.040e0.063 mm (Merck);
parentheses include: diameter of the column [cm], height of SiO2
column, eluent, fraction size [mL], Rf-value. Melting points: Melting
point apparatus SMP 2 (Stuart Scientific), uncorrected. Elemental
analyses: Elemental Analyzer Vario EL (Elementaranalysesysteme
GmbH). MS: MAT 312, MAT 8200, MAT 44, and TSQ 7000 (Fin-
nigan); EI ¼ electron impact, CI ¼ chemical ionization. High reso-
lution MS (HRMS): MAT 8200 (Finnigan). IR: IR spectrophotometer
1600 FT-IR and 2000 FT-ATR-IR (PerkineElmer). 1H NMR
(300 MHz), 13C NMR (75 MHz): Unity 300 FT NMR spectrometer
(10 mL). The mixture was stirred for 15 h at rt. The solvent was
removed in vacuo and the residue was purified by fc (5 cm, 15 cm,
petroleum ether:EtOAc ¼ 7:3, 20 mL, Rf ¼ 0.40). Colorless solid, mp
78 ꢀC, yield 2.3 g (67%). C19H22SO5 (362.5). Anal. calcd. C 62.96, H
6.12, S 8.85; found C 62.86, H 6.11, S 8.57. MS (EI): m/z (%) ¼ 362 [M,
~
100], 155 [tos, 46], 105 [PhCO, 86]. IR (ATR, neat):
n
(cmꢁ1) ¼ 2966,
2870 (CeH), 1357, 1175 (SO2), 1096, 1021 (CeO), 780, 743 (ArCeH).
1H NMR (CDCl3):
d
(ppm) ¼ 1.48 (dtd, J ¼ 13.4/2.7/1.5 Hz, 1H, 5-Heq),
1.77 (qd, J ¼ 13.4/5.1 Hz, 1H, 5-Hax), 1.91 (dt, J ¼ 10.1/4.3 Hz, 2H,
CH2eCH2eOtos), 2.37 (s, 3H, PheCH3), 3.91e3.99 (m, 2H, 4-Hax and
6-Heq), 3.92 (td, J ¼ 12.5/2.7 Hz, 1H, 6-Hax), 4.16 (dt, J ¼ 10.1/4.8 Hz,
1H, CH2eCH2eOtos), 4.21e4.29 (m, 1H, CH2eCH2eOtos), 5.37 (s,
1H, 2-Hax), 7.26e7.38 (m, 7H, Harom, 3-HPhCH3 and 5-HPhCH3), 7.78
(d, J ¼ 8.2 Hz, 2H, 2-HPhCH3 and 6-HPhCH3).
(Varian),
d in ppm related to tetramethylsilane, coupling constants
are given with 0.5 Hz resolution; the assignments of 13C and of 1
NMR signals were supported by 2D NMR techniques.
H
5.1.2. Pentane-1,3,5-triol (8) (synthesis modified according to
Ref. [27])
5.1.5. cis-4-(2-Azidoethyl)-2-phenyl-1,3-dioxane (12)
Under ice-cooling a solution of dimethyl 3-oxoglutarate (11.5 g,
66 mmol) in THF (100 mL) was added dropwise to a suspension of
LiAlH4 (5.4 g, 140 mmol) in THF (100 mL) and the reaction mixture
was stirred under reflux for 48 h. Excess of LiAlH4 was destroyed
with water (100 mL) at rt, H2SO4 (25%) was added until the
precipitate was dissolved completely (pH 1) and the mixture was
heated to reflux for further 17 h. THF was evaporated in vacuo,
water (300 mL) was added and the mixture was alkalized (pH 10)
with NH3 (25%). The resulting precipitate of Al(OH)3 was removed
by suction through a filter paper with a sufficient amount of sand
on top of it and washed with water. The filtrate was concentrated in
vacuo, the dry residue was suspended in ethanol (100 mL) and the
mixture was heated to reflux for 17 h. Insoluble Li2SO4 was filtered
off at 50 ꢀC and washed with ethanol (100 mL). The organic layer
was removed in vacuo and the residue was distilled in a Kugelrohr
apparatus under high vacuum. Colorless oil, bp 160e210 ꢀC,
0.14 mbar. The crude material was purified by fc (8 cm, 15 cm,
A mixture of tosylate 11 (150 mg, 0.41 mmol) and NaN3 (130 mg,
2.0 mmol) in DMF (10 mL) was heated to reflux for 2 h. After cooling
down excess of DMF was evaporated in vacuo. The residue was
purified by fc (2 cm, 15 cm, petroleum ether:EtOAc ¼ 19:1, 2 mL,
Rf ¼ 0.32). Colorless oil, yield 71 mg (74%). C12H15N3O2 (233.3).
HRMS (EI): calcd. for C12H14N3O2 232.1086; found 232.1086. MS (EI):
m/z (%) ¼ 232 [MeH, 32], 105 [PhCO, 100]. MS (CI): m/z (%) ¼ 234
~
[MH, 100]. IR (ATR, film):
n
(cmꢁ1) ¼ 2951, 2875 (CeH), 2093 (N3),
1099,1018 (CeO), 782, 749 (ArCeH).1H NMR (CDCl3):
d
(ppm) ¼ 1.53
(dtd, J ¼ 13.1/2.4/1.5 Hz,1H, 5-Heq),1.76 e 1.98 (m, 3H, CH2eCH2eN3
and 5-Hax), 3.44 (ddd, J ¼ 12.5/6.7/2.1 Hz, 1H, CH2eCH2eN3), 3.53
(ddd, J ¼ 12.5/6.1/2.7 Hz,1H, CH2eCH2eN3), 3.89 (td, J ¼ 11.6/2.7 Hz,
1H, 6-Hax), 3.95e4.04 (m, 1H, 4-Hax), 4.28 (ddd, J ¼ 11.6/5.1/1.5 Hz,
1H, 6-Heq), 5.52 (s, 1H, 2-Hax), 7.32e7.40 (m, 3H, Harom), 7.47e7.50
(m, 2H, Harom).
5.1.6. cis-2-(2-Phenyl-1,3-dioxan-4-yl)-ethan-1-amine (13a)
EtOAc:MeOH ¼ 4:1, 30 mL, Rf ¼ 0.21) and
a
second Kugelrohr
A mixture of azide 12 (30 mg, 0.12 mmol) and Pd/C (6 mg, 5%)
in THF (5 mL) was stirred under H2 (balloon) for 1 h at rt. The
mixture was filtered over CeliteÒ. Since the filtrate contained
traces of the catalyst Pd/C the solvent was removed in vacuo, the
residue was dissolved in methanol (2 mL) and the filtration over
CeliteÒ was repeated. The filtrate was concentrated in vacuo. Pale
yellow oil, yield 24 mg (96%). C12H17NO2 (207.3). HRMS (EI): calcd.
for C12H17NO2 207.1254; found 207.1259. Anal. calcd. C 69.54, H
8.26, N 6.76; found C 69.10, H 8.57, N 6.30. MS (EI): m/z (%) ¼ 207
distillation. Colorless oil, bp 190e210 ꢀC, 0.12 mbar, yield 3.39 g
(43%). C5H12O3 (120.1). MS (EI): m/z (%) ¼ 121 [MH, 100]. IR (ATR,
~
film):
n
(cmꢁ1) ¼ 3294 (OeH), 2938 (CeH), 1041 (CeO). 1H NMR
(CD3OD):
d
(ppm) ¼ 1.60e1.74 (m, 4H, CH2eCHeCH2), 3.70 (t,
J ¼ 6.6 Hz, 4H, CH2eOH), 3.88 (tt, J ¼ 8.1/4.5 Hz, 1H, CH2eCHeCH2).
5.1.3. cis-2-(2-Phenyl-1,3-dioxan-4-yl)ethan-1-ol (10)
A solution of pentane-1,3,5-triol (8, 700 mg, 5.8 mmol), benz-
aldehyde dimethyl acetal (9, 1.2 mL, 8.0 mmol) and p-toluene-
sulfonic acid (20 mg, 0.1 mmol) in THF (20 mL) was heated to reflux
for 12 h. The solvent was removed in vacuo, the residue was dis-
solved in Et2O (15 mL) and the mixture was extracted with a satu-
rated solution of NaHCO3 (5 mL). The Et2O layer was dried (MgSO4),
concentrated in vacuo and the residue was purified by fc (4 cm,
petroleum ether:EtOAc ¼ 60:40, 20 mL, Rf ¼ 0.25). Colorless oil,
yield 681 mg (57%). C12H16O3 (208.3). HRMS: calcd. for C12H16O3
208.1093; found 208.1099. Anal. calcd. C 69.21, H 7.74; found C
[M, 1], 163[MþeCH2CH2NH2, 9], 101[MePhCO, 100]. IR (ATR, film):
~
n
(cmꢁ1) ¼ 3367 (NH2), 2920, 2852 (CeH), 1662 (NH2), 1101, 1023
(CeO), 748, 727 (ArCeH). 1H NMR (CDCl3):
d
(ppm) ¼ 1.50 (dtd,
J ¼ 13.7/2.4/1.5 Hz, 1H, 5-Heq), 1.67 (dddd, J ¼ 13.7/11.9/11.2/4.3 Hz,
1H, 5-Hax), 1.75e1.92 (m, 4H, CH2eCH2eNH2), 2.87 (t, J ¼ 6.9 Hz,
2H, CH2eCH2eNH2), 3.93e4.01 (m, 1H, 4-Hax), 3.96 (td, J ¼ 11.6/
2.7 Hz, 1H, 6-Hax), 4.26 (ddd, J ¼ 11.6/4.8/1.2 Hz, 1H, 6-Heq), 5.51 (s,
1H, 2-Hax), 7.28e7.38 (m, 3H, Harom), 7.45e7.49 (m, 2H, Harom).
68.86, H 8.06. MS (EI): m/z (%) ¼ 208 [M, 59], 177 [MeCH2OH, 8],
5.1.7. cis-N-Methyl-2-(2-phenyl-1,3-dioxan-4-yl)ethan-1-amine (13b)
Tosylate 11 (100 mg, 0.27 mmol) was added to an ethanolic
solution of methylamine (8 M, 5 mL, 40 mmol). The mixture was
heated to reflux for 12 h. After cooling down the excess of methyl-
amine and ethanol was evaporated in vacuo. The yellow residue was
dissolved in CH2Cl2 (10 mL) and the solution was washed with
a saturated solution of NaHCO3 (2 ꢃ 10 mL). The organic layer was
dried over MgSO4, filtered and evaporated in vacuo. The residue was
purifiedbyfc (2 cm,15 cm, CH2Cl2:MeOH ¼ 8:1, 5 mL, Rf ¼ 0.29). Pale
yellow oil, yield 33 mg (56%). C13H19NO2 (221.3). HRMS (EI): calcd.
for C13H19NO2 221.1415; found 221.1415. MS (EI): m/z (%) ¼ 221 [M,
(cmꢁ1) ¼ 3427 (OH), 2942, 2877
~
105 [PhCO, 100]. IR (ATR, film):
n
(CeH), 1167, 1090 (CeO), 757, 735 (ArCeH). 1H NMR (CDCl3):
d
(ppm) ¼ 1.52 (dq, J ¼ 13.4/2.4 Hz, 1H, 5-Heq), 1.77e1.99 (m, 4H,
CH2eCH2eOH and 5-Hax), 3.81 (ddd, J ¼ 11.5/6.1/4.8 Hz, 1H,
CH2eCH2eOH), 3.86 (ddd, J ¼ 11.5/6.4/4.8 Hz, 1H, CH2eCH2eOH),
3,97 (td, J ¼ 11.3/2.4 Hz, 1H, 6-Hax), 4.12 (ddt, J ¼ 11.2/5.8/2.4 Hz, 1H,
4-Hax), 4.27 (ddd, J ¼ 11.3/5.2/1.8 Hz, 1H, 6-Heq), 5.53 (s, 1H, 2-Hax),
7.32e7.39 (m, 3H, Harom), 7.45e7.48 (m, 2H, Harom).
5.1.4. cis-[2-(2-Phenyl-1,3-dioxan-4-yl)ethyl] p-toluenesulfonate (11)
A cold solution of p-toluenesulfonyl chloride (3.6 g, 19 mmol) in
CH2Cl2 (10 mL) was added slowly to a cold solution of alcohol 10
(2.0 g, 9.6 mmol) and pyridine (9.5 mL, 9.6 mmol) in CH2Cl2
3], 177 [MeCH2eNHCH3, 3], 115 [Oe(CH2)2eCHe(CH2)2eNHCH3,
~
58], 105 [PhCO, 33], 44 [eCH2eNHCH3, 100]. IR (ATR, film):
n
(cmꢁ1) ¼ 3390 (NeH); 2953, 2852 (CeH); 2732 (NHCH3),1098,1020

T. Utech et al. / European Journal of Medicinal Chemistry 46 (2011) 2157e2169
2163
(CeO), 749 (ArCeH). 1H NMR (CDCl3):
d
(ppm) ¼ 1.52 (dtd, J ¼ 13.1/
Rf ¼ 0.36). Colorless solid, mp 61 ꢀC, yield 332 mg (73%). C18H20O3
(284.4). Anal. calcd. C 76.03, H 7.10; found C 75.89, H 7.00. MS (EI):
m/z (%) ¼ 284 [M, 2], 239 [MeCH2CH2OH, 2], 207 [MePh, 100], 105
2.7/1.8 Hz, 1H, 5-Heq), 1.74e1.87 (m, 1H, 5-Hax), 1.87e2.02 (m, 3H,
CH2eCH2eNHCH3), 2.48 (s, 3H, NHCH3), 2.80e2.89 (m, 2H,
CH2eCH2eNHCH3), 3.89e4.03 (m, 1H, 4-Hax), 3.96 (td, J ¼ 11.9/
2.4 Hz, 1H, 6-Hax), 4.24 (ddd, J ¼ 11.9/4.8/1.2 Hz, 1H, 6-Heq), 5.51 (s,
1H, 2-Hax), 7.32e7.38 (m, 3H, Harom), 7.45e7.49 (m, 2H, Harom).
þ
(cmꢁ1) ¼ 3294 (OH), 2954, 2934, 2874
~
[PhCO ,64]. IR (ATR, neat):
n
(CeH), 1096, 1025 (CeO), 768, 746 (ArCeH). 1H NMR (CDCl3):
d
(ppm) ¼ 1.39 (dq, J ¼ 12.8/2.3 Hz, 1H, 5-Heq), 1.76e1.85 (m, 1H 5-
Hax), 1.88e2.01 (m, 2H, CH2eCH2eOH), 2.14 (dd, J ¼ 6.1/4.7 Hz, 1H,
CH2eCH2eOH), 3.90e3.96 (m, 2H, CH2eCH2eOH), 4.04 (dt, J ¼ 11.6/
2.5 Hz, 1H, 6-Hax), 4.08 (td, J ¼ 11.6/2.1 Hz, 1H, 6-Heq), 4.12e4.20 (m,
1H, 4-Hax), 7.17e7.30 (m, 4H, Harom), 7.36e7.48 (m, 4H, Harom),
7.53e7.54 (m, 2H, Harom).
5.1.8. cis-N,N-Dimethyl-2-(2-phenyl-1,3-dioxan-4-yl)ethan-1-
amine (13c)
Tosylate 11 (100 mg, 0.27 mmol) was added to an ethanolic
solution of dimethylamine (5.6 M, 5 mL, 28 mmol) and the mixture
was heated to reflux for 12 h. After cooling down the excess of
dimethylamine and ethanol was evaporated in vacuo. The yellow
residuewas dissolved in CH2Cl2 (10 mL) and the mixturewas washed
with a saturated solution of NaHCO3 (2 ꢃ 10 mL). The organic layer
was dried over MgSO4, filtered and evaporated in vacuo. The residue
was purified by fc (2 cm,15 cm, CH2Cl2:MeOH ¼ 8:1, 5 mL, Rf ¼ 0.19).
Pale yellow oil, yield 32 mg (51%). C14H21NO2 (235.30). HRMS (EI):
calcd. for C14H21NO2 235.1570; found 235.1572. MS (EI): m/z (%) ¼
5.1.11. trans-2-(2-Ethyl-2-phenyl-1,3-dioxan-4-yl)ethan-1-ol (17)
Propiophenone dimethyl acetal 15 (324.5 mg, 1.8 mmol) and
p-toluenesulfonic acid (20 mg, 0.1 mmol) were added to a solution
of pentane-1,3,5-triol (8, 115 mg, 0.9 mmol) in THF (10 mL). The
mixture was heated to reflux for 12 h. The mixture was concentrated
in vacuo, the residue was dissolved in Et2O and the solution was
extracted with a saturated solution of NaHCO3 (5 mL). The Et2O layer
was dried over MgSO4, evaporated in vacuo and the residue was
purified by fc (4 cm, 15 cm, petroleum ether:EtOAc ¼ 6:4, 10 mL,
Rf ¼ 0.36). Colorless oil, yield 150 mg (70%). C14H20O3 (236.4). Anal.
calcd. C 71.16, H 8.53; found C 70.99, H 8.25. MS (CI): m/z (%) ¼ 237
235 [M, 4.5],129 [MePhCHO, 40],105 [PhCO,13], 58 [eCH2eN(CH3)2,
~
100]. IR (ATR, film):
n
(cmꢁ1) ¼ 2950, 2858 (CeH), 2766 (N(CH3)2),
1101,1025 (CeO), 749 (ArCeH).1H NMR (CDCl3):
d
(ppm) ¼ 1.53 (dtd,
J ¼ 13.1/2.4/1.2 Hz,1H, 5-Heq),1.69e1.94 (m,1H, 5-Hax),1.82e1.94 (m,
2H, CH2eCH2eN(CH3)2), 2.29 (s, 6H, N(CH3)2), 2.51 (t, J ¼ 7.4 Hz, 2H,
CH2eCH2eN(CH3)2), 3.89e3.98 (m, 1H, 4-Hax), 3.96 (td, J ¼ 11.3/
2.4 Hz, 1H, 6-Hax), 4.25 (ddd, J ¼ 11.3/5.2/1.2 Hz, 1H, 6-Heq), 5.51 (s,
1H, 2-Hax), 7.31e7.38 (m, 3H, Harom), 7.45e7.49 (m, 2H, Harom).
þ
~
[MH, 100], 135 [PhCOC2H5 þ H , 54]. EA: IR (ATR, film):
n
(cmꢁ1) ¼
3420 (OH), 2942, 2877 (CeH), 1166, 1099 (CeO), 757, 736 (ArCeH).
1H NMR (CDCl3):
d
(ppm) ¼ 0.81 (t, J ¼ 7.4 Hz, 3H, CH2eCH3), 1.27
(dq, J ¼ 12.8/2.4 Hz,1H, 5-Heq),1.66e1.90 (m, 3H, CH2eCH2eOH and
5-Hax), 1.75 (q, J ¼ 7.4 Hz, 2H, CH2eCH3), 2.55 (s broad, 1H,
CH2eCH2eOH), 3.80 (td, J ¼ 12.2/2.4 Hz, 1H, 6-Hax), 3.85e3.90 (m,
1H, 6-Heq), 3.89 (t, J ¼ 5.4 Hz, 2H, CH2eCH2eOH), 3.92e4.00 (m, 1H,
4-Hax), 7.28e7.33 (m, 1H, Harom), 7.36e7.43 (m, 4H, Harom).
5.1.9. cis-N-Benzyl-2-(2-phenyl-1,3-dioxan-4-yl)ethan-1-amine
(13d)
A solution of tosylate 11 (400 mg, 1.10 mmol) and freshly
distilled benzylamine (0.15 mL, 2 mmol) in toluene (5 mL) was
heated to reflux for 12 h. After cooling down the mixture was
concentrated in vacuo. The residue was dissolved in CH2Cl2 (10 mL)
and the solution was washed with a saturated solution of NaHCO3
(2 ꢃ 10 mL). The organic layer was dried (MgSO4), evaporated in
vacuo and the residue was purified by fc (2 cm, 15 cm,
CH2Cl2:MeOH ¼ 80:10, 2 mL, Rf ¼ 0.31). Pale yellow oil, yield
220 mg (67%). C19H23NO2 (297.4). HRMS (EI): calcd. for C19H23NO2
297.1729; found 297.1728. MS (EI): m/z (%) ¼ 297 [M, 2], 191 [Oe
5.1.12. [2-(2,2-Diphenyl-1,3-dioxan-4-yl)ethyl] p-toluenesulfonate
(18)
A cold solution of p-toluenesulfonyl chloride (260 mg,1.4 mmol)
in CH2Cl2 (10 mL) was added slowly to a cold solution of alcohol 16
(200 mg, 0.70 mmol) and pyridine (0.6 mL, 0.8 mmol) in CH2Cl2
(10 mL). The mixture was stirred for 4 h at rt. CH2Cl2 was evaporated
in vacuo and the residue was purified by fc (2 cm, 15 cm, petroleum
ether:EtOAc ¼ 7:3, 5 mL, Rf ¼ 0.46). Colorless solid, mp 108 ꢀC, yield
245 mg (79%). C25H26O5S (438.5). Anal. calcd. C 68.47, H 5.97, S 7.31;
(CH2)2eCHe(CH2)2eNHBn, 60], 120 [CH2eNHBn, 36], 91 [tropy-
~
lium, 100]. IR (ATR, film):
n
(cmꢁ1) ¼ 2769 (CeH), 1112, 1000 (CeO),
found C 68.24, H 5.88, S 6.94. MS (EI): m/z (%) ¼ 438 [M, 3], 361
751, 663 (ArCeH). 1H NMR (CDCl3):
d
(ppm) ¼ 1.52 (dtd, J ¼ 13.1/2.4/
[MePh, 100], 155 [tos, 9], 105 [PhCO, 70]. IR (ATR, neat):
n
(cmꢁ1) ¼
~
1.2 Hz, 1H, 5-Heq), 1.77 (dddd, J ¼ 13.1/11.9/11.2/4.6 Hz, 1H, 5-Hax),
1.82e1.96 (m, 3H, CH2eCH2eNHBn), 2.83 (t, J ¼ 6.7 Hz, 2H,
CH2eCH2eNHBn), 3.81 (s, 2H, NHCH2Bn), 3.94e4.03 (m, 1H, 4-Hax),
3.97 (td, J ¼ 11.6/2.7 Hz,1H, 6-Hax), 4.27 (ddd, J ¼ 11.6/4.8/1.2 Hz,1H,
6-Heq), 5.52 (s, 1H, 2-Hax), 7.22e7.39 (m, 8H, Harom), 7.47e7.50 (m,
2H, Harom).
2956, 2892 (CeH), 1094, 1019 (CeO), 780, 747 (ArCeH). 1H NMR
(CDCl3):
d
(ppm) ¼ 1.34 (dq, J ¼ 12.8/2.4 Hz, 1H, 5-Heq), 1.82 (dtd,
J ¼ 12.8/11.6/5.7 Hz, 1H, 5-Hax), 1.90e1.97 (m, 2H, CH2eCH2eOtos),
2.45 (s, 3H, ePheCH3), 3.97 (td, J ¼ 11.6/2.4 Hz, 1H, 6-Hax),
4.02e4.12 (m, 2H, 4-Hax and 6-Heq), 4.24 (dt, J ¼ 9.1/5.2 Hz, 1H,
CH2eCH2eOtos), 4.50 (ddd, J ¼ 9.7/5.2/4.6 Hz, 1H, CH2eCH2eOtos),
7.16e7.31 (m, 4H, Harom), 7.33e7.51 (m, 8H, Harom, 3-HPhCH3 and
5-HPhCH3), 7.48 (d, J ¼ 8.2 Hz, 2H, 2-HPhCH3 and 6-HPhCH3).
For the preparation of the hydrochloride 13d.HCl the amine 13d
(100 mg, 0.34 mmol) was dissolved in Et2Oabs (2 mL) and a solution
of HCl in Et2O was added slowly until no further precipitate was
formed. The solid was separated and recrystalized with iPr2O.
Colorless solid, mp 177 ꢀC (iPr2O), yield 44 mg (39%). Anal. calcd. C
68.35, H 7.25, N 4.19; found C 68.09, H 7.39, N 3.88.
5.1.13. trans-[2-(2-Ethyl-2-phenyl-1,3-dioxan-4-yl)ethyl]
p-toluenesulfonate (19)
A cold solution of p-toluenesulfonyl chloride (1.3 g, 7.0 mmol) in
CH2Cl2 (5 mL) was added slowly to a cold solution of alcohol 17
(1.0 g, 4.2 mmol) and pyridine (5.7 mL, 8 mmol) in CH2Cl2 (15 mL).
The mixture was stirred for 2 h at 0 ꢀC and for 12 h at rt. CH2Cl2 was
evaporated in vacuo and the residue was purified by fc (3 cm,15 cm,
petroleum ether:EtOAc ¼ 7:3, 10 mL, Rf ¼ 0.39). Colorless solid, mp
80 ꢀC, yield 900 mg (56%). C21H26O5S (390.5). Anal. calcd. C 64.59, H
6.71, S 8.21; found C 64.58, H 6.62, S 7.95. MS (EI): m/z (%) ¼ 390 [M,
5.1.10. 2-(2,2-Diphenyl-1,3-dioxan-4-yl)ethan-1-ol (16)
Benzophenone dimethyl acetal (14, 913 mg, 4.0 mmol) was
added to a solution of pentane-1,3,5-triol (8, 340 mg, 2.8 mmol)
and p-toluenesulfonic acid (86.1 mg, 0.5 mmol) in THF (10 mL). The
mixture was heated to reflux for 12 h. The solvent was removed in
vacuo, the residue was dissolved in Et2O and the solution was
extracted with a saturated solution of NaHCO3 (5 mL). The Et2O
layer was dried (MgSO4), concentrated in vacuo and the residue
was purified by fc (4 cm, petroleum ether:EtOAc ¼ 60:40, 10 mL,
0.5], 361 [MeC2H5, 100], 155 [tos, 16], 105 [PhCO, 54]. IR (ATR, film):
~
n
(cmꢁ1) ¼ 2968, 2886 (CeH); 1356, 1188 (SO2): 1090, 1016 (CeO);
765, 726 (ArCeH). 1H NMR (CDCl3):
d
(ppm) ¼ 0.75 (t, J ¼ 7.6 Hz, 3H,

2164
T. Utech et al. / European Journal of Medicinal Chemistry 46 (2011) 2157e2169
CH2eCH3), 1.22 (dq, J ¼ 12.8/2.4 Hz, 1H, 5-Heq), 1.66 (q, J ¼ 7.6 Hz,
2H, CH2eCH3), 1.59e1.73 (m, 1H, 5-Hax), 1.79e1.86 (m, 2H,
CH2eCH2eOtos), 2.45 (s, 3H, PheCH3), 3.78 (td, J ¼ 12.5/2.4 Hz, 1H,
6-Hax), 3.81 (ddd, J ¼ 12.5/5.4/1.8 Hz, 1H, 6-Heq), 3.76e3.87 (m, 1H,
4-Hax), 4.19 (dt, J ¼ 9.7/5.1 Hz, 1H, CH2eCH2eOtos), 4.38 (ddd,
J ¼ 9.7/7.6/6.3 Hz, 1H, CH2eCH2eOtos), 7.26e7.41 (m, 7H, Harom, 3-
HPhCH3 and 5-HPhCH3), 7.81 (d, J ¼ 8.2 Hz, 2H, 2-HPhCH3 and 6-
5.1.17. 2-(2,2-Diphenyl-1,3-dioxan-4-yl)-N-methylethan-1-amine
(22b)
Tosylate 18 (100 mg, 0.23 mmol) was dissolved in an ethanolic
solution of methylamine (8 M, 5 mL, 40 mmol) and the mixture was
heated to reflux for 12 h. After cooling down it was concentrated in
vacuo. The pale yellow residue was dissolved in CH2Cl2 (10 mL), the
mixture was washed with
a saturated solution of NaHCO3
HPhCH3). 1H NMR (C6D6):
d
(ppm) ¼ 0.52 (dq, J ¼ 12.2/2.1 Hz, 1H, 5-
(2 ꢃ10 mL), dried (MgSO4), filtered and concentrated in vacuo. The
residue was purified by fc (2 cm, 15 cm, CH2Cl2:MeOH ¼ 8:1, 2 mL,
Rf ¼ 0.16). Pale yellow oil, yield 28 mg (41%). C19H23NO2 (297.4).
HRMS: calcd. for C19H23NO2 297.1729; found 297.1728. MS (EI): m/z
Heq), 0.90 (t, J ¼ 7.3 Hz, 3H, CH2eCH3), 1.31 (qd, J ¼ 12.5/5.2 Hz, 1H,
5-Hax), 1.38e1.47 (m, 2H, CH2eCH2eOtos), 1.81 (s, 3H, PheCH3),
1.86 (q, J ¼ 7.3 Hz, 2H, CH2eCH3), 3.43 (td, J ¼ 11.5/2.7 Hz, 1H, 6-
Hax), 3.50e3.63 (m, 2H, 4-Hax and 6-Heq), 3.98 (dt, J ¼ 10.1/5.2 Hz,
1H, CH2eCH2eOtos), 4.34 (ddd, J ¼ 10.1/7.6/5.5 Hz, 1H,
CH2eCH2eOtos), 6.69 (d, J ¼ 7.9 Hz, 2H, 3-HPhCH3 and 5-HPhCH3),
7,13e7.18 (m, 1H, Harom), 7.31 (t, J ¼ 7.6 Hz, 2H, Harom), 7.44 (d,
J ¼ 7.1 Hz, 2H, Harom), 7.78 (d, J ¼ 8.2 Hz, 2H, 2-HPhCH3 and 6-HPhCH3).
(%) ¼ 297 [M, 1], 220 [MePh, 5], 115 [O(CH2)2CH(CH2)2NHCH3, 100],
~
105 [PhCO, 56]. IR (ATR, film):
n
(cmꢁ1) ¼ 3328 (NeH); 2953, 2875
(CeH), 2732 (NHCH3), 1098, 1020 (CeO), 768, 749 (ArCeH). 1H NMR
(CDCl3):
d
(ppm) ¼ 1.40 (dq, J ¼ 12.8/2.4 Hz, 1H, 5-Heq), 1.92 (dddd,
J ¼ 12.8/11.9/11.2/5.7 Hz, 1H, 5-Hax), 2.01e2.12 (m, 2H,
CH2eCH2eNHCH3), 2.63 (s, 3H, NHCH3), 3.04 (ddd, J ¼ 11.9/6.4/
5.5 Hz, 1H, CH2eCH2eNHCH3), 3.20 (ddd, J ¼ 11.9/6.1/5.5 Hz, 1H,
CH2eCH2eNHCH3), 3.99 (td, J ¼ 11.5/2.4 Hz, 1H, 6-Hax), 4.02e4.09
(m, 2H, 4-Hax and 6-Heq), 7.19e7.31 (m, 4H, Harom), 7.37e7.48 (m,
6H, Harom). A signal for the NH-proton is not seen in the spectrum.
As described for the preparation of 13d.HCl the hydrochloride 22b.
HCl was prepared from 22b (20 mg, 0.07 mmol). Colorless solid, mp
164 ꢀC, yield 10 mg (42%).
5.1.14. 4-(2-Azidoethyl)-2,2-diphenyl-1,3-dioxane (20)
A mixture of tosylate 18 (80 mg, 0.18 mmol) and NaN3 (113 mg,
1.8 mmol) in DMF (5 mL) was heated to reflux for 2 h. After cooling
downDMFwasevaporatedinvacuoandtheresiduewaspurifiedbyfc
(2 cm,15 cm, petroleum ether:EtOAc ¼ 7:3, 5 mL, Rf ¼ 0.60). Colorless
oil, yield 38 mg (69%). C18H19N3O2 (309.4). Anal. calcd. C 69.88, H 6.19,
N 13.60; found C 69.40, H 6.14, N 13.94. MS (EI): m/z (%) ¼ 309 [M,12],
~
232 [MePh, 100], 182 [(Ph)2CO, 31]. IR (ATR, film):
n
(cmꢁ1) ¼ 2951,
2875 (CeH), 2091 (N3), 1097, 1023 (CeO), 762, 746 (ArCeH). 1H NMR
5.1.18. 2-(2,2-Diphenyl-1,3-dioxan-4-yl)-N,N-dimethylethan-1-
amine (22c)
(CDCl3):
d
(ppm) ¼ 1.42 (dq, J ¼ 12.8/2.4 Hz, 1H, 5-Heq), 1.78 (dddd,
J ¼ 12.8/11.9/10.1/3.4 Hz,1H, 5-Hax),1.83e2.02(m, 2H, CH2eCH2eN3),
3.63 (t, J ¼ 7.2 Hz, 2H, eCH2eCH2eN3), 4.03 (td, J ¼ 11.3/2.4 Hz,1H, 6-
Hax), 4.05e4.13 (m, 2H, 4-Hax and 6-Heq), 7.17e7.32 (m, 4H, Harom),
7.38e7.62 (m, 4H, Harom), 7.80e7.83 (m, 2H, Harom).
Tosylate 18 (100 mg, 0.23 mmol) was dissolved in an ethanolic
solution of dimethylamine (5.6 M, 7 mL, 39.2 mmol) and the
mixture was heated to reflux for 4 h. After cooling down dime-
thylamine and ethanol were evaporated in vacuo. The yellow
residue was dissolved in CH2Cl2 (10 mL) and the mixture was
extracted with a saturated solution of NaHCO3 (2 ꢃ 10 mL). The
organic layer was dried over MgSO4, filtered and evaporated in
vacuo. The crude product was purified by fc (3 cm, 15 cm,
CH2Cl2:MeOH ¼ 8:1, 2 mL, Rf ¼ 0.21). Pale yellow oil, yield 57 mg
(80%). C20H25NO2 (311.4). HRMS: calcd. for C20H25NO2 311.1893;
found 311.1893. MS (EI): m/z (%) ¼ 311 [M, 1], 234 [MePh, 2], 176
5.1.15. trans-4-(2-Azidoethyl)-2-ethyl-2-phenyl-1,3-dioxane (21)
A mixture of tosylate 19 (43 mg, 0.26 mmol) and NaN3 (113 mg,
1.8 mmol) in DMF (5 mL) was heated to reflux for 2 h. After cooling
down DMF was evaporated in vacuo. The residue was purified by fc
(2 cm, 15 cm, petroleum ether:EtOAc ¼ 9:1, 5 mL, Rf ¼ 0.41). Color-
less oil, yield 45 mg (65%). C14H19N3O2 (261.3). HRMS (CI): calcd. for
C12H14N3O2 232.1084; found 232.1086. Anal. calcd. C 64.35, H 7.33,
N 16.08; found C 64.23, H 7.56, N 15.82. MS (CI): m/z (%) ¼ 262
[MePheCH2e N(CH3)2, 2],105 [PhCO, 31], 58 [eCH2eN(CH3)2, 100].
~
IR (ATR, film):
n
(cmꢁ1) ¼ 2947, 2869 (CeH), 2815, 2763 (N(CH3)2),
[MHþ, 100], 232 [MeC2H5, 40], 184 [MePh, 6], 105 [PhCO, 1]. IR
1097, 1025 (CeO), 760, 745 (ArCeH). 1H NMR (CDCl3):
d
(ppm) ¼
~
(ATR, film):
n
(cmꢁ1) ¼ 2973, 2876 (CeH), 2093 (N3), 1090, 1025
1.41 (dq, J ¼ 12.8/2.4 Hz, 1H, 5-Heq), 1.75 (dtd, J ¼ 12.8/11.9/2.4 Hz,
1H, 5-Hax), 1.82e1.98 (m, 2H, CH2eCH2eN(CH3)2), 2.34 (s, 6H, N
(CH3)2), 2.58 (ddd, J ¼ 11.9/9.1/6.1 Hz, 1H, CH2eCH2eN(CH3)2), 2.68
(ddd, J ¼ 11.9/9.4/5.5 Hz, 1H, CH2eCH2eN(CH3)2), 3.99 (td, J ¼ 11.3/
2.4 Hz, 1H, 6-Hax), 4.03e4.16 (m, 2H, 4-Hax and 6-Heq), 7.15e7.30
(m, 4H, Harom), 7.35e7.41 (m, 2H, Harom), 7.49e7.54 (m, 4H, Harom).
As described for the preparation of 13d.HCl the hydrochloride 22c.
HCl was prepared from 22c (57 mg, 0.20 mmol). Colorless solid, mp
94 ꢀC, yield 46 mg (65%).
(CeO), 756, 745 (ArCeH). 1H NMR (CDCl3):
d
(ppm) ¼ 0.78 (t,
J ¼ 7.4 Hz, 3H, CH2eCH3), 1.26 (dq, J ¼ 12.8/2.4 Hz, 1H, 5-Heq),
1.67e1.86 (m, 3H, 5-Hax and CH2eCH2eN3), 1.72 (q, J ¼ 7.4 Hz, 2H,
CH2eCH3), 3.50e3.53 (m, 2H, CH2eCH2eN3), 3.77 (td, J ¼ 11.6/
2.7 Hz, 1H, 6-Hax), 3.75e3.82 (m, 1H, 4-Hax), 3.85 (ddd, J ¼ 11.6/5.5/
1.8 Hz, 1H, 6-Heq), 7.24e7.41 (m, 5H, Harom).
5.1.16. 2-(2,2-Diphenyl-1,3-dioxan-4-yl)ethan-1-amine (22a)
A mixture of azide 20 (85 mg, 0.2 mmol) and Pd/C (51 mg, 5%) in
EtOAc (3 mL) was stirred under a H2 atmosphere (balloon) for 12 h
at rt. The mixture was filtered over CeliteÒ and the filtrate was
concentrated in vacuo. Pale yellow oil, yield 52 mg (82%).
C18H21NO2 (283.4). HRMS: calcd. for C18H21NO2 283.1578; found
283.1572. MS (EI): m/z (%) ¼ 283 [M, 5], 239 [MeCH2CH2NH2, 4],
5.1.19. N-Benzyl-2-(2,2-diphenyl-1,3-dioxan-4-yl)ethan-1-amine
(22d)
A mixture of tosylate 18 (200 mg, 0.45 mmol) and freshly
distilled benzylamine (0.10 mL, 0.9 mmol) in toluene (5 mL) was
heated to reflux for 5 h. After cooling down excess of benzylamine
and toluene was evaporated in vacuo. The yellow residue was dis-
solved in CH2Cl2 (10 mL) and the mixture was extracted with
a saturated solution of NaHCO3 (2 ꢃ 10 mL). The organic layer was
dried over MgSO4, filtered and concentrated in vacuo. The residue
was purified by fc (2 cm, 15 cm, EtOAc, 5 mL, Rf ¼ 0.22). Pale yellow
oil, yield 110 mg (65%). C25H27NO2 (373.5). Anal. calcd. C 80.39, H
7.29, N 3.75; found C 79.90, H 7.08, N 3.56. MS (EI): m/z (%) ¼ 373 [M,
þ
~
206 [M ePh, 36], 105 [PhCO, 100]. IR (ATR, film):
n
(cmꢁ1) ¼ 3420
(NeH); 2928, 2855 (CeH); 1728 (NeH); 1096, 1024 (CeO); 749, 712
(ArCeH). 1H NMR (CDCl3):
d
(ppm) ¼ 1.39 (dq, J ¼ 12.8/2.1 Hz,1H, 5-
Heq), 1.66 (dddd, J ¼ 12.7/11.2/10.3/3.6 Hz, 1H, 5-Hax), 1.73 (s broad,
2H, eNH2), 1.82e1.98 (m, 2H, CH2eCH2eNH2), 2.98 (dt, J ¼ 12.5/
7.3 Hz, 1H, CH2eCH2eNH2), 3.05 (ddd, J ¼ 12.5/7.9/6.1 Hz, 1H,
CH2eCH2eNH2), 3.95e4.09 (m, 2H, 4-Hax and 6-Heq), 4.02 (td,
J ¼ 11.3/2.1 Hz, 1H, 6-Hax), 7.18e7.30 (m, 4H, Harom), 7.36e7.41 (m,
2H, Harom), 7.49e7.54 (m, 4H, Harom).
5], 296 [MePh, 9], 191 [Oe(CH2)2eCHe(CH2)2eNHeBn, 90] 105
~
[PhCO, 75], 91 [tropylium, 100]. IR (ATR, film):
n
(cmꢁ1) ¼ 3325

T. Utech et al. / European Journal of Medicinal Chemistry 46 (2011) 2157e2169
2165
(NeH), 2952, 2876 (CeH); 2816 (CHeNHBn); 1101,1026 (CeO); 766,
744 (ArCeH). 1H NMR (CDCl3):
(ppm) ¼ 1.37 (dq, J ¼ 13.1/2.1 Hz,
the residue was dissolved in CH2Cl2 (10 mL) and the solution was
extracted with a saturated solution of NaHCO3 (2 ꢃ 10 mL). The
organic layer was dried over MgSO4, filtered and evaporated
in vacuo. The residue was purified by fc (2 cm, 15 cm,
CH2Cl2:MeOH ¼ 8:1, 3 mL, Rf ¼ 0.15). Pale yellow oil, yield 30 mg
(44%). C16H25NO2 (263.4). HRMS (EI): calcd. for C16H25NO2
263.1886; found 263.1885. MS (EI): m/z (%) ¼ 263 [M, 0.6], 234
d
1H, 5-Heq), 1.74 (dtd, J ¼ 13.1/11.3/4.1 Hz, 1H, 5-Hax), 1.86e1.93 (m,
2H, CH2eCH2eNHBn), 2.93 (td, J ¼ 6.7/1.5 Hz, 2H, CH2eCH2eNHBn),
3.84 (d, J ¼ 14.0 Hz, 1H, NHeCH2ePh), 3.85 (d, J ¼ 14.3 Hz, 1H,
NHeCH2ePh), 4.00 (td, J ¼ 11.3/2.4 Hz,1H, 6-Hax), 4.02e4.09 (m, 2H,
4-Hax and 6-Heq), 7.14e7.28 (m, 6H, Harom), 7.31e7.38 (m, 6H, Harom),
7.46e7.50 (m, 3H, Harom). A signal for the NH-proton is not seen in
the spectrum. As described for the preparation of 13d.HCl, the
hydrochloride 22d$HCl was prepared from 22d (100 mg,
0.27 mmol). Colorless solid, mp 157 ꢀC, yield 54 mg (49%).
[MeC2H5, 1], 186 [MePh, 4], 129 [Oe(CH2)2eCHe(CH2)2eN(CH3)2,
~
33], 58 [eCH2eN(CH3)2,100]. IR (ATR, film):
n
(cmꢁ1) ¼ 2968, (CeH),
2715 (N(CH3)2), 1026, 1011 (CeO), 756, 726 (ArCeH). 1H NMR
(CDCl3):
d
(ppm) ¼ 0.76 (t, J ¼ 7.6 Hz, 3H, CH2eCH3), 1.26 (dq,
J ¼ 12.8/1.9 Hz, 1H, 5-Heq), 1.58e1.83 (m, 3H, CH2eCH2eN(CH3)2
and 5-Hax), 1.70 (q, J ¼ 7.6 Hz, 2H, CH2eCH3), 2.30 (s, 6H, N(CH3)2),
2.46 (ddd, J ¼ 11.9/9.4/6.1 Hz, 1H, CH2eCH2eN(CH3)2), 2.57 (ddd,
J ¼ 11.9/9.7/5.5 Hz, 1H, CH2eCH2eN(CH3)2), 3.71 (td, J ¼ 11.3/2.4 Hz,
1H, 6-Hax), 3.81 (ddd, J ¼ 11.3/5.5/1.8 Hz, 1H, 6-Heq), 3.69e3.75 (m,
1H, 4-Hax), 7.22e7.38 (m, 5H, Harom). As described for the prepara-
tion of 13d.HCl the hydrochloride 23c$ HCl was prepared from 23c
(20 mg, 0.06 mmol). Colorless solid, mp 165 ꢀC, yield 7.0 mg (41%).
5.1.20. trans-2-(2-Ethyl-2-phenyl-1,3-dioxan-4-yl)ethan-1-amine
(23a)
A mixture of azide 21 (40 mg, 0.15 mmol), Pd/C (5%, 16 mg) and
methanol (3 mL) was stirred under a H2 atmosphere (balloon) for
1 h at rt. The mixture was filtered over CeliteÒ and the filtrate was
concentrated in vacuo. Pale yellow oil, yield 32.6 mg (93%).
C14H21NO2 (235.3). HRMS (EI): calcd. for C14H21NO2 235.1572;
found 235.1572. MS (EI): m/z (%) ¼ 235 [M, 6.11]; 206 [MeC2H5, 52],
(cmꢁ1) ¼ 3355 (NH2), 2940, 2871
5.1.23. trans-N-Benzyl-2-(2-ethyl-2-phenyl-1,3-dioxan-4-yl)ethan-
1-amine (23d)
~
105 [PhCO, 100]. IR (ATR, film):
n
(CeH), 1663 (NH2), 1092, 1025 (CeO), 756, 727 (ArCeH). 1H NMR
(CDCl3):
d
(ppm) ¼ 0.79 (t, J ¼ 7.5 Hz, 3H, CH2eCH3), 1.25 (dq,
A solution of tosylate 19 (300 mg, 0.78 mmol) and freshly
distilled benzylamine (0.10 mL, 1.4 mmol) in toluene (10 mL) was
heated to reflux for 5 h. After cooling down the mixture was
concentrated in vacuo, the residue was dissolved in CH2Cl2 (10 mL)
and the solution was extracted with a saturated solution of NaHCO3
(2 ꢃ10 mL). The organic layer was dried over MgSO4, filtered and
evaporated in vacuo. The crude product was purified by fc (2 cm,
15 cm, EtOAc, 10 mL, Rf ¼ 0.28). Pale yellow oil, yield 180 mg (71%).
C21H27NO2 (325.5). HRMS (EI): calcd. for C21H27NO2 325.2042;
found 325.2041. MS (EI): m/z (%) ¼ 325 [M, 0.8]; 191 [Oe
J ¼ 12.8/2.1 Hz, 1H, 5-Heq), 1.56 (dtd, J ¼ 12.5/11.2/3.9 Hz, 1H, 5-Hax),
1.64e1.81 (m, 4H, CH2eCH2eNH2),1.73 (q, J ¼ 7.5 Hz, 2H, CH2eCH3),
2.87 (dt, J ¼ 12.5/7.0 Hz, 1H, CH2eCH2eNH2), 2.94 (ddd, J ¼ 12.5/7.3/
6.4 Hz, 1H, CH2eCH2eNH2), 3.75e3.91 (m, 2H, 4-Hax and 6-Heq),
3.76 (td, J ¼ 11.2/2.4 Hz, 1H, 6-Hax), 7.25e7.32 (m, 1H, Harom),
7.33e7.41 (m, 4H, Harom).
5.1.21. trans-2-(2-Ethyl-2-phenyl-1,3-dioxan-4-yl)-N-methylethan-
1-amine (23b)
Tosylate 19 (100 mg, 0.26 mmol) was dissolved in an ethanolic
solutionofmethylamine(8.0 M, 5 mL, 40 mmol)andthemixturewas
heated to reflux for 3 h. After cooling down the mixture was
concentrated in vacuo. The yellow residue was dissolved in CH2Cl2
(10 mL) and the mixture was extracted with a saturated solution of
NaHCO3 (2 ꢃ 10 mL). Theorganic layerwasdried overMgSO4, filtered
and evaporated in vacuo. The residue was purified by fc (2 cm,15 cm,
CH2Cl2:MeOH ¼ 8:1, 3 mL, Rf ¼ 0.1). Pale yellow oil, yield 30 mg
(44%). C15H23NO2 (249.4). HRMS (CI): calcd. for C15H24NO2 250.1806;
found 250.1807. MS (EI): m/z (%) ¼ 249 [Mþ, 1], 220 [MþeC2H5, 63],
172 [MþePh, 51], 105 [PhCO, 20], 77 [Ph, 10]. MS (CI): m/z (%) ¼ 250
(CH2)2eCHe(CH2)2eNHBn, 100], 120 [CH2eNHBn, 81], 106 [NHBn,
~
54], 91 [tropylium, 95]. IR (ATR, film):
n
(cmꢁ1) ¼ 3456 (NH), 2926
(CeH), 1489 (NH); 1092 (CeO); 756, 699 (ArCeH). 1H NMR (CDCl3):
d
(ppm) ¼ 0.79 (t, J ¼ 7.6 Hz, 3H, CH2eCH3), 1.25 (dq, J ¼ 12.8/2.4 Hz,
1H, 5-Heq), 1.61e1.88 (m, 3H, CH2eCH2eNHBn and 5-Hax), 1.73 (q,
J ¼ 7.6 Hz, 2H, CH2eCH3), 1.95 (s broad, 1H, CH2eCH2eNHBn), 2.86
(td, J ¼ 6.7/2.9 Hz, 2H, CH2eCH2eNHBn), 3.73e3.90 (m, 2H, 4-Hax
and 6-Heq), 3.77 (td, J ¼ 12.2/2.4 Hz, 1H, 6-Hax), 3.86 (d, J ¼ 15.8 Hz,
1H, eNHeCH2ePh), 3.87 (d, J ¼ 15.8 Hz, 1H, NHeCH2ePh)
7.26e7.39 (m, 10H, Harom). As described for the preparation of
13d.HCl the hydrochloride 23d$HCl was prepared from 23d (50 mg,
0.15 mmol). Colorless solid, mp 155 ꢀC, yield 26 mg (48%).
þ
(cmꢁ1) ¼ 3325 (NeH), 2953, 2875 (CeH),
~
[MH ,100]. IR (ATR, film):
n
2732 (NHCH3),1098,1020 (CeO), 768, 749 (ArCeH).1H NMR (CDCl3):
d
(ppm) ¼ 0.79 (t, J ¼ 7.3 Hz, 3H, CH2eCH3), 1.25 (dq, J ¼ 12.8/1.9 Hz,
5.1.24. Adamantan-2-one dimethyl acetal (25) [31]
1H, 5-Heq), 1.50 (s broad, 1H, NHCH3), 1.61 (dddd, J ¼ 12.5/11.9/11.5/
5.2 Hz, 1H, 5-Hax), 1.67e1,86 (m, 2H, CH2eCH2eNHCH3), 1.72 (q,
J ¼ 7.3 Hz, 2H, CH2eCH3), 2.46 (s, 3H, CH2eCH2eNHCH3), 2.72 (dt,
J ¼ 11.5/7.1 Hz, 1H, CH2eCH2eNHCH3), 2.78 (ddd, J ¼ 11.5/7.6/6.1 Hz,
1H, CH2eCH2eNHCH3), 3.73 (td, J ¼ 11.5/2.1 Hz,1H, 6-Hax), 3.83 (ddd,
J ¼ 11.5/5.5/1.5 Hz, 1H, 6-Heq), 3.69e3.78 (m, 1H, 4-Hax), 7.25e7.40
(m, 5H, Harom). Direct fc purification of the product without extract-
ing the mixture with a saturated solution of NaHCO3 led to a salt of
amine 23b and p-toluenesulfonic acid. Colorless solid, (Rf ¼ 0.14), mp
134 ꢀC, yield 78 mg (74%). Anal. calcd. C 62.09, H 7.41, N 3.32, S 7.60;
found C 61.84, H 7.40, N 3.22, S 7.32. As described for the preparation
of 13d.HCl, the hydrochloride 23b$HCl was prepared from 23b
(15 mg, 0.06 mmol). Colorless solid, mp 148 ꢀC, yield 7.0 mg (41%).
A mixture of adamantan-2-one (24, 2.0 g, 13.3 mmol), methanol
(10 mL), trimethyl ortho formate (1.6 mL, 12 mmol) and p-tolue-
nesulfonic acid (100 mg, 0.5 mmol) was heated to reflux for 12 h.
The solvent was removed in vacuo, the residue was dissolved in
Et2O (5 mL) and the mixture was extracted with a saturated solution
of NaHCO3 (5ꢃ). The Et2O layer was dried (MgSO4) and concen-
trated in vacuo. Colorless solid, mp 184 ꢀC, yield 2.1 g (82%).
C12H20O2 (196.3). 1H NMR (CDCl3):
d
(ppm) ¼ 1.58e1.65 (m, 6H,
HAdam), 1.79e1.90 (m, 6H, HAdam), 1.97e2.10 (m, 2H, 1-HAdam and 3-
HAdam), 3.15 (s, 6H, (OCH3)2). For further analytical data see Ref. [31].
5.1.25. 2-(Spiro[adamantan-2,20-[1,3]dioxan]-40-yl)ethanol (26)
A mixture of triol 8 (330 mg, 2.7 mmol), acetal 25 (580 mg,
3 mmol), THF (10 mL) and p-toluenesulfonic acid (10 mg,
0.16 mmol) was heated to reflux for 12 h. The solvent was removed
in vacuo, the residue was dissolved in Et2O and the mixture was
extracted with a saturated solution of NaHCO3 (5ꢃ). The Et2O layer
was dried (MgSO4), concentrated in vacuo and the residue was
purified by fc (2 cm, petroleum ether:EtOAc ¼ 6:4, 5 mL, Rf ¼ 0.43).
5.1.22. trans-[2-(2-Ethyl-2-phenyl-1,3-dioxan-4-yl)]-N,N-
dimethylethan-1-amine (23c)
Tosylate 19 (102 mg, 0.26 mmol) was dissolved in an ethanolic
solution of dimethylamine (5.6 M, 5 mL, 28 mmol) and the mixture
was stirred for 12 h at rt. The mixture was concentrated in vacuo,

2166
T. Utech et al. / European Journal of Medicinal Chemistry 46 (2011) 2157e2169
Colorless solid, mp 54 ꢀC, yield 396 mg (52%). C15H24O3 (252.35).
2.02e2.05 (m, 1H, 1-HAdam), 2.73e2.94 (m, 3H, 3-HAdam and
CH2eCH2eNH2), 3.78 (ddd, J ¼ 11.9/5.5/1.5 Hz, 1H, 6-Heq),
3.91e4.03 (m, 1H, 4-Hax), 3.96 (td, J ¼ 11.9/2.7 Hz, 1H, 6-Hax).
Anal. calcd. C 71.40, H 9.59; found C 71.32, H 9.43. MS (EI): m/z (%) ¼
~
252 [M, 34], 207 [MeCH2CH2OH, 73],150 [C10H14O,100]. IR (neat):
n
(cmꢁ1) ¼ 3443 (OH); 2932 (CeH); 1099 (CeO). 1H NMR (CDCl3):
d
(ppm) ¼ 1.40 (dtd, J ¼ 13.1/2.7/1.5 Hz, 1H, 5-Heq), 1.54e1.84 (m,
5.1.29. cis-3-(2-Phenyl-1,3-dioxan-4-yl)propanenitrile (30)
14H, 5-Hax, CH2eCH2eOH and 11HAdam), 1.90e2.08 (m, 2H, HAdam),
2.55 (dd, J ¼ 5.8/4.8 Hz, 1H, CH2eCH2eOH), 2.81 (s broad, 1H, 3-
HAdam), 3.75 (ddd, J ¼ 12.2/5.5/1.5 Hz, 1H, 6-Heq), 3.76e3.83 (m, 2H,
CH2eCH2eOH), 3.98 (td, J ¼ 12.2/2.7 Hz, 1H, 6-Hax), 4.14 (ddt,
J ¼ 11.9/4.8/2.7 Hz, 1H, 4-Hax).
A mixture of tosylate 11 (100 mg, 0.27 mmol) and KCN (156 mg,
2.7 mmol) in DMSO (15 mL) was heated to reflux for 5 h and then
stirred for 12 h at rt. DMSO was evaporated in vacuo. The oily
residue was dissolved in petroleum ether:EtOAc (9:1, 10 mL) and
the mixture was washed with a saturated solution of NaHCO3
(2 ꢃ 20 mL). The organic layer was dried over MgSO4 and evapo-
rated in vacuo. Colorless oil, yield 40 mg (68%). C13H15NO2 (217.3).
HRMS (EI): calcd. for C13H15NO2 217.1098; found 217.1102. Anal.
calcd. C 71.87, H 6.96, N 6.45; found C 71.44, H 7.43, N 6.17. MS (EI):
5.1.26. [2-(Spiro[adamantan-2,20-[1,3]dioxan]-40-yl)ethyl]
p-toluenesulfonate (27)
A cold solution of p-toluenesulfonyl chloride (514 mg, 2.7 mmol)
in CH2Cl2 (5 mL) was added slowly to a cold solution of alcohol 26
(350 mg, 1.4 mmol) and NEt3 (1.4 mL, 1.4 mmol) in CH2Cl2 (15 mL).
The mixture was stirred for 2 h at 0 ꢀC and for 12 h at rt. Then the
mixture was concentrated in vacuo and the residue was purified by
fc (2 cm, 15 cm, petroleum ether:EtOAc ¼ 7:3, 10 mL, Rf ¼ 0.35).
Colorless solid, mp 93 ꢀC, yield 521 mg (92%). C22H30O5S (406.5).
Anal. calcd. C 64.99, H 7.44, S 7.88; found C 64.78, H 7.39, S 8.03. MS
m/z (%) ¼ 217[M, 45], 177[MþeCH2CN, 22], 105 [PhCO, 100]. IR (ATR,
~
film):
n
(cmꢁ1) ¼ 2924 (CeH), 2245 (CN), 1062 (CeO), 749, 727
(ArCeH). 1H NMR (CDCl3):
d
(ppm) ¼ 1.56 (dtd, J ¼ 13.1/2.4/1.5 Hz,
1H, 5-Heq), 1.84 (dddd, J ¼ 13.1/11.9/11.3/5.1 Hz, 1H, 5-Hax),
1.89e1.96 (m, 2H, CH2eCH2eCN), 2.52 (ddd, J ¼ 10.6/9.1/6.4 Hz, 1H,
CH2eCH2eCN), 2.57 (ddd, J ¼ 10.6/9.4/7.6 Hz, 1H, CH2eCH2eCN),
3.96e4.04 (m, 1H, 4-Hax), 3.98 (td, J ¼ 11.9/2.4 Hz, 1H, 6-Hax), 4.29
(ddd, J ¼ 11.9/5.1/1.5 Hz, 1H, 6-Heq), 5.53 (s, 1H, 2-Hax), 7.33e7.40
(m, 3H, Harom), 7.45e7.49 (m, 2H, Harom).
(EI): m/z (%) ¼ 406 [M, 5], 207 [MeCH2CH2Otos, 25], 199
~
[eCH2CH2Otos, 86]. IR (neat):
n
(cmꢁ1) ¼ 2908 (CeH), 1360, 1188
(SO2), 1097, 1063 (CeO), 778, 721 (ArCeH). 1H NMR (CDCl3):
d
(ppm) ¼ 1.38 (dtd, J ¼ 12.8/2.7/1.5 Hz, 1H, 5-Heq), 1.47e1.90 (m,
5.1.30. 3-(2,2-Diphenyl-1,3-dioxan-4-yl)propanenitrile (31)
15H, 5-Hax, CH2eCH2eOtos and 12HAdam), 2.02e2.05 (m, 1H, 1-
HAdam), 2.44 (s, 3H, PhCH3), 2.71 (s broad, 1H, 3-HAdam), 3.76 (ddd,
J ¼ 11.9/5.8/1.5 Hz, 1H, 6-Heq), 3.93 (td, J ¼ 11.9/2.7 Hz, 1H, 6-Hax),
3.95e4.03 (m, 1H, 4-Hax), 4.11e4.19 (m, 1H, CH2eCH2eOtos), 4.20
(ddd, J ¼ 10.3/9.4/4.8 Hz, 1H, CH2eCH2eOtos), 7.34 (d, J ¼ 7.9 Hz,
2H, 3-HPhCH3 and 5-HPhCH3), 7.78 (d, J ¼ 8.2 Hz, 2H, 2-HPhCH3 and 6-
A mixture of tosylate 18 (650 mg, 1.78 mmol) and KCN (1.1 g,
17 mmol) in DMSO (15 mL) was heated to reflux for 5 h. Then
excess of DMSO was evaporated in vacuo. The yellow residue was
dissolved in petroleum ether:EtOAc (9:1, 10 mL) and the mixture
was extracted with a saturated solution of NaHCO3 (2 ꢃ 20 mL). The
organic layer was dried over MgSO4 and evaporated in vacuo.
Colorless solid, mp 135 ꢀC, yield 421 mg (81%). C19H19NO2 (293.4).
HRMS (EI): calcd. for C19H19NO2 293.1412; found 293.1415. Anal.
calcd. C 77.79, H 6.53, N 4.77; found C 77.74, H 6.50, N 4.66. MS (EI):
HPhCH3). 13C NMR (CDCl3):
d
(ppm) ¼ 21.6 (1C, OeSO2ePhCH3), 27.1,
27.46, 31.26, 32.94, 33.03, 33.50, 33.55, 5.98, 36.31, 36.57, 39.2 (11C,
CH2eCH2eO, C-5Diox and 9CAdam), 58.2 (1C, C-6Diox), 62.9 (1C, C-
4Diox), 66.8 (1C, CH2eCH2eO), 100.4 (1C, C-2Diox), 124.5 (2C, C-3arom
and C-5arom), 126.2 (2C, C-2arom and C-6arom), 133.1 (1C, C-4arom),
144.7 (1C, C-1arom). The assignment of the signals was supported by
HETCOR spectra.
m/z (%) ¼ 293 [M, 5], 216 [MePh, 100] 182 [(Ph)2CO, 6]. IR (ATR,
~
neat):
n
(cmꢁ1) ¼ 2925 (CeH), 2246 (CN), 1097 (CeO), 799, 745
(ArCeH). 1H NMR (CDCl3):
d
(ppm) ¼ 1.46 (dq, J ¼ 13.0/2.1 Hz, 1H, 5-
Heq), 1.86e2.09 (m, 3H, 5-Hax and CH2eCH2eCN), 2.67 (ddd,
J ¼ 11.8/6.9/5.6 Hz, 1H, CH2eCH2eCN), 2.76 (ddd, J ¼ 11.8/7.3/5.5 Hz,
1H, CH2eCH2eCN), 4.05e4.13 (m, 1H, 4-Hax), 4.06 (td, J ¼ 11.5/
2.5 Hz, 1H, 6-Hax), 4.12 (dt, J ¼ 11.5/1.8 Hz, 1H, 6-Heq), 7.20e7.46 (m,
4H, Harom), 7.41e7.46 (m, 2H, Harom), 7.50e7.55 (m, 4H, Harom).
5.1.27. 40-(2-Azidoethyl)spiro[adamantan-2,20-[1,3]dioxane] (28)
Tosylate 27 (250 mg, 1.62 mmol) was dissolved in DMF (10 mL)
and after addition of NaN3 (313 mg, 5 mmol) the mixture was
heated to reflux for 2 h. After cooling down it was concentrated in
vacuo. The residue was purified by fc (2 cm, 15 cm, petroleum
ether:EtOAc ¼ 8:2, 5 mL, Rf ¼ 0.74). Colorless oil, yield 150 mg
(53%). C15H23N3O2 (277.4). HRMS (EI): calcd. for C15H23N3O2
277.1787; found 277.1790. MS (CI): m/z (%) ¼ 278 [MH, 19], 151
5.1.31. trans-3-(2-Ethyl-2-phenyl-1,3-dioxan-4-yl)propanenitrile
(32)
A mixture of tosylate 19 (100 mg, 0.25 mmol) and KCN (150 mg,
2.5 mmol) in DMF (5 mL) was heated to reflux for 6 h. Then DMF
was evaporated in vacuo. The oily residue was purified by fc (2 cm,
15 cm, petroleum ether:EtOAc ¼ 7:3, 2 mL, Rf ¼ 0.55). Colorless oil,
yield 33 mg (53%). C15H19NO2 (245.3). HRMS (EI): calcd. for
þ
[C10H15O , 17]. IR (film):
(CeO). 1H NMR (CDCl3):
n
(cmꢁ1) ¼ 2909 (CeH), 2090 (N3), 1099
~
d
(ppm) ¼ 1.42 (dtd, J ¼ 12.8/2.9/1.5 Hz, 1H,
5-Heq), 1.53e1.83 (m, 15H, 5-Hax
, CH2eCH2eN3, 12HAdam),
1.97e2.05 (m, 1H, 10-HAdam), 2,76 (s broad, 1H, 30-HAdam), 3.36e3.50
(m, 2H, CH2eCH2eN3), 3.78 (ddd, J ¼ 11.7/5.5/1.5 Hz, 1H, 6-Heq),
3.93e4.03 (m, 1H, 4-Hax), 3.96 (td, J ¼ 11.7/2.9 Hz, 1H, 6-Hax).
C13H14NO2 216.1026; found: 216.1024. Anal. calcd. C 73.44, H 7.81, N
~
5.71; found C 73.18, H 8.30, N 5.53. IR (ATR, film):
n
(cmꢁ1) ¼ 2970
(CeH), 2246 (CN), 1091 (CeO), 819, 757 (ArCeH). MS (EI): m/z (%) ¼
216 [MeC2H5, 100], 168 [MePh, 23], 105 [PhCO, 88]. MS (CI): m/z
5.1.28. 2-(Spiro[adamantan-2,20-[1,3]dioxan]-40-yl)ethan-1-amine
(29a)
A mixture of azide 28 (80 mg, 0.25 mmol), Pd/C (5%, 23 mg) and
methanol (3 mL) was stirred under a H2 atmosphere (balloon) for
1 h at rt. The mixture was filtered over CeliteÒ and the filtrate was
concentrated in vacuo. Pale yellow oil, yield 70 mg (97%).
C15H25NO2 (251.36). HRMS (EI): calcd. for C15H25NO2 251.1884;
(%) ¼ 246 [MH, 100]. 1H NMR (CDCl3):
d
(ppm) ¼ 0.80 (t, J ¼ 7.3 Hz,
3H, CH2eCH3), 1.29 (dq, J ¼ 12.8/2.4 Hz, 1H, 5-Heq), 1.65e1.93 (m,
3H, CH2eCH2eCN and 5-Hax), 1.74 (q, J ¼ 7.3 Hz, 2H, CH2eCH3),
2.51e2.69 (m, 2H, CH2eCH2eCN), 3.77e3.91 (m, 2H, 4-Hax and 6-
Heq), 3.79 (td, J ¼ 11.9/2.7 Hz, 1H, 6-Hax), 7.25e7.42 (m, 5H, Harom).
5.1.32. cis-3-(2-Phenyl-1,3-dioxan-4-yl)propan-1-amine (33a)
Under N2 at 0 ꢀC a solution of LiAlH4 in THF (1 M, 0.1 mL,
0.1 mmol) was added to a solution of 30 (42 mg, 0.19 mmol) in Et2O
(5 mL). The mixture was stirred for 2 h at 0 ꢀC. Then one equivalent
of water was added. The mixture was dried over MgSO4, filtered
found 251.1885. MS (EI): m/z (%) ¼ 251 [M, 0.5], 101 [eO(CH2)2CH
(CH2)2NH2, 100]. IR (film):
n
(cmꢁ1) ¼ 3362 (NH2), 2907 (CeH), 1062
~
(CeO). 1H NMR (CDCl3):
d
(ppm) ¼ 1.39 (dtd, J ¼ 13.1/2.7/1.5 Hz, 1H,
5-Heq), 1.52e1.85 (m, 17H, 5-Hax
, CH2eCH2eNH2, 12HAdam),

T. Utech et al. / European Journal of Medicinal Chemistry 46 (2011) 2157e2169
2167
and evaporated in vacuo. Pale yellow oil, yield 18 mg (45%).
C13H19NO2 (221.3). HRMS (EI): calcd. for C13H18NO2 220.1335; found
220.1337. MS (EI): m/z (%) ¼ 220 [MeH, 7], 115 [MePhCHO, 65], 105
3H, COOCH2CH3), 1.86 (dtd, J ¼ 13.4/2.4/1.2 Hz, 1H, 5-Heq), 1.93
(dddd, J ¼ 13.4/12.2/11.5/4.8 Hz, 1H, 5-Hax), 4.02 (td, J ¼ 11.5/2.7 Hz,
1H, 6-Hax), 4.2 (q, J ¼ 7.1 Hz, 2H, COOCH2CH3), 4.32 (ddd, J ¼ 11.5/
4.8/1.2 Hz, 1H, 6-Heq), 4.52e4.56 (m, 1H, 4-Hax), 5.59 (s, 1H, 2-Hax),
6.13 (dd, J ¼ 15.8/1.8 Hz, 1H, CH]CHeCO), 6.96 (dd, J ¼ 15.8/3.9 Hz,
1H, CH]CHeCO), 7.34e7.41 (m, 3H, Harom), 7.49e7.53 (m, 2H,
Harom).
þ
~
[PheCO, 54]. MS (CI): m/z (%) ¼ 222 [MH , 100]. IR (ATR, film):
n
(cmꢁ1) ¼ 3368 (NH2), 2924 (CeH), 1022 (CeO), 804, 748 (ArCeH).
1H NMR (CDCl3):
d
(ppm) ¼ 1.34 (s broad, 2H, CH2eCH2eCH2eNH2),
1.51 (dtd, J ¼ 13.4/2.4/1.5 Hz, 1H, 5-Heq), 1.56e1.76 (m, 4H,
CH2eCH2eCH2eNH2), 1.80 (dddd, J ¼ 13.4/11.9/11.2/5.1 Hz, 1H, 5-
Hax), 2.72 (t, J ¼ 6.4 Hz, 2H, CH2eCH2eCH2eNH2), 3.77e3.87 (m,1H,
4-Hax), 3.94 (td, J ¼ 11.6/2.4 Hz, 1H, 6-Hax), 4.25 (ddd, J ¼ 11.6/5.2/
1.5 Hz, 1H, 6-Heq), 5.49 (s, 1H, 2-Hax), 7.27e7.37 (m, 3H, Harom), 7.47
(dd, J ¼ 7.9/1.5 Hz, 2H, Harom).
5.1.36. Ethyl 3-(cis-2-phenyl-1,3-dioxan-4-yl)propanoate (39)
The a,b-unsaturated ester 38 (1.56 g, 6.0 mmol) was dissolved in
EtOAc (5 mL) and Pd/C (5%, 0.3 mg) was added. The mixture was
shaken for 4 h under an H2 atmosphere (1.5 bar). The mixture was
filtered over CeliteÒ and the filtrate was concentrated in vacuo. The
residue was purified by fc (3 cm, 15 cm, petroleum ether:-
EtOAc ¼ 7:3, 10 mL, Rf ¼ 0.42). Colorless oil, yield 1.4 g (88%).
C15H20O4 (264.3). Anal. calcd. C 68.16, H 7.63; found C 68.04, H 7.51.
5.1.33. 3-(2,2-Diphenyl-1,3-dioxan-4-yl)propan-1-amine (34a)
Under N2 at 0 ꢀC a solution of LiAlH4 in THF (1 M, 0.3 mL,
0.3 mmol) was added to a solution of 31 (19 mg, 0.06 mmol) in Et2O
(3 mL). The mixture was stirred for 2 h at 0 ꢀC. Then one equivalent
of water was added. The mixture was dried over MgSO4, filtered and
concentrated in vacuo. Colorless oil, yield 16 mg (89%). C19H23NO2
(297.4). HRMS (EI): calcd. for C19H20O2 280.1462; found 280.1463.
MS (EI): m/z (%) ¼ 280 [MeNH3, 3], 105 [PheCO, 100]. MS (CI): m/z
þ
~
MS (EI): m/z (%) ¼ 264 [M , 25],105 [PhCO,100]. IR (film):
n
(cmꢁ1) ¼
2959 (CeH),1731 (C]O),1092 (CeO), 752 (ArCeH).1H NMR (CDCl3):
d
(ppm) ¼ 1.24 (t, J ¼ 7.3 Hz, 3H, COOCH2CH3), 1.27 (dtd, J ¼ 13.1/2.4/
1.5 Hz, 1H, 5-Heq), 1.84 (dddd, J ¼ 13.1/12.2/11.3/4.8 Hz, 1H, 5-Hax
)
1.93 (q, J ¼ 7.3 Hz, 2H, CH2eCH2eCOOEt), 2.49e2.53 (m, 2H,
CH2eCH2eCOOEt), 3.84e3.94 (m, 1H, 4-Hax), 3.96 (td, J ¼ 11.3/
2.4 Hz, 1H, 6-Hax), 4.12 (q, J ¼ 7.3 Hz, 2H, COOCH2CH3), 4.27 (ddd,
J ¼ 11.3/4.8/1.5 Hz, 1H, 6-Heq), 5.21 (s, 1H, 2-Hax), 7.33e7.39 (m, 3H,
Harom), 7.47e7.56 (m, 2H, Harom).
þ
(%) ¼ 298 [MH , 100]. IR (ATR, film): (cmꢁ1) ¼ 3368 (NH2), 2925
~
n
(CeH), 1097 (CeO), 799, 745 (ArCeH). 1H NMR (CDCl3):
d
(ppm) ¼
1.39 (dq, J ¼ 12.8/2.1 Hz, 1H, 5-Heq), 1.53e1.93 (m, 7H, 5-Hax, NH2,
CH2eCH2eCH2eNH2), 2.77 (t, J ¼ 6.8 Hz, 2H, CH2eCH2eCH2eNH2),
3.89 (ddt, J ¼ 11.5/7.0/2.4 Hz, 1H, 4-Hax), 4.00 (td, J ¼ 11.5/2.4 Hz, 1H,
6-Hax), 4.08 (ddd, J ¼ 11.5/4.8/1.8 Hz, 1H, 6-Heq), 7.14e7.29 (m, 4H,
Harom), 7.31e7.41 (m, 2H, Harom), 7.49e7.54 (m, 4H, Harom).
5.1.37. cis-3-(2-Phenyl-1,3-dioxan-4-yl)propan-1-ol (40)
Under N2 at 0 ꢀC a solution of LiBH4 in THF (2 M, 3.2 mL,
6.4 mmol) was added to a solution of ester 39 (1.8 g, 6.4 mmol) in
Et2O (15 mL). After stirring for 4 h at 0 ꢀC one equivalent of water
was added. The mixture was dried over Na2SO4, filtered and
concentrated in vacuo. The residue was purified by fc (4 cm, 15 cm,
petroleum ether:EtOAc ¼ 6:4, 10 mL, Rf ¼ 0.20). Colorless oil, yield
784 mg (55%). C13H18O3 (222.3). Anal. calcd. C 70.30, H 8.20; found C
5.1.34. trans-3-(2-Ethyl-2-phenyl-1,3-dioxan-4-yl)propan-1-amine
(35a)
Under N2 at 0 ꢀC a solution of LiAlH4 in THF (1 M, 0.1 mL,
0.1 mmol) was added to a solution of 32 (36 mg, 0.14 mmol) in Et2O
(5 mL). The mixture was stirred for 2 h at 0 ꢀC. Then one equivalent
of water was added. The mixture was dried over MgSO4, filtered
and evaporated in vacuo. Pale yellow oil, yield 20 mg (57%).
C15H23NO2 (249.4). HRMS (EI): calcd. for C13H18NO2 220.1337;
found 220.1337. MS (EI): m/z (%) ¼ 220 [MeC2H5, 71], 115
[NH2(CH2)3CH(CH2)2O, 55], 105 [PheCO, 80], 77 [Ph, 28]. MS (CI):
70.þ04,
H
7.93. MS (EI): m/zm/z (%) ¼ 222 [Mþ, 12], 163
~
[M e(CH2)3OH, 19], 105 [PheCO, 100]. IR (film):
n
(cmꢁ1) ¼ 3425
(OH), 2946 (CeH), 1104 (CeO), 753, 699 (ArCeH). 1H NMR (CDCl3):
d
(ppm) ¼ 1.46 (dtd, J ¼ 13.4/2.4/1.2 Hz,1H, 5-Heq),1.62e1.71 (m, 5H,
CH2eCH2eCH2eOH), 1.80 (dddd, J ¼ 13.1/12.2/11.3/4.8 Hz, 1H, 5-
Hax), 3.58e3.63 (m, 2H, CH2eCH2eCH2eOH), 3.78e3.85 (m, 1H, 4-
Hax), 3.90 (td, J ¼ 11.3/2.4 Hz, 1H, 6-Hax), 4.21 (ddd, J ¼ 11.3/4.8/
1.2 Hz, 1H, 6-Heq), 5.46 (s, 1H, 2-Hax), 7.23e7.33 (m, 3H, Harom),
7.39e7.44 (m, 2H, Harom).
þ
~
m/z (%) ¼ 250 [MH , 100]. IR (ATR, film):
n
(cmꢁ1) ¼ 3367 (NH2),
2928 (CeH), 1092 (CeO), 804, 757 (ArCeH). 1H NMR (CDCl3):
d
(ppm) ¼ 0.79 (t, J ¼ 7.3 Hz, 3H, CH2eCH3), 1.27 (dq, J ¼ 12.8/2.4 Hz,
1H, 5-Heq), 1.42e1.77 (m, 5H, 5-Hax, CH2eCH2eCH2eNH2), 1.71 (s
broad, 2H, CH2eCH2eCH2eNH2), 1.72 (q, J ¼ 7.3 Hz, 2H, CH2eCH3),
2.75 (t, J ¼ 6.8 Hz, 2H, CH2eCH2eCH2eNH2), 3.60e3.69 (m, 1H, 4-
Hax), 3.76 (td, J ¼ 11.3/2.4 Hz, 1H, 6-Hax), 3.87 (ddd, J ¼ 11.3/5.2/
1.8 Hz, 1H, 6-Heq), 7.27e7.31 (m, 1H, Harom), 7.34e7.38 (m, 4H,
Harom).
5.1.38. cis-[3-(2-Phenyl-1,3-dioxan-4-yl)propyl] p-toluenesulfonate
(41)
A cold solution of p-toluenesulfonyl chloride (400 mg, 2.1 mmol)
in CH2Cl2 (5 mL) was added slowly to a cold solution of alcohol 40
(235 mg, 1.0 mmol) and NEt3 (1.6 mL, 1.4 mmol) in CH2Cl2 (15 mL).
The mixture was stirred for 1 h at 0 ꢀC and then it was stored for 12 h
at 3e5 ꢀC. The mixture was concentrated in vacuo and the residue
was purified by fc (2 cm, 15 cm, petroleum ether:EtOAc ¼ 7:3, 2 mL,
Rf ¼ 0.32). Colorless oil, yield 198 mg (50%). C20H24O5S (376.5). Anal.
5.1.35. Ethyl (E)-3-(cis-2-phenyl-1,3-dioxan-4-yl)prop-2-enoate (38)
Under N2 CH2Cl2 (20 mL) was cooled down to ꢁ78 ꢀC. Oxalyl
chloride (0.1 mL, 1.1 mmol) was added. The mixture was stirred for
2 min before DMSO (0.15 mL, 2.2 mmol) was added. 10 min later
a solution of the alcohol 36 (195 mg, 1.0 mmol) in CH2Cl2 (10 mL)
was added and the mixture was stirred for 15 min at ꢁ78 ꢀC. NEt3
(0.7 mL, 5 mmol) was added and the mixture was stirred for 15 min
at rt (formation of aldehyde 37). Then a solution of ethox-
ycarbonylmethylenetriphenylphosphorane (552 mg, 1.5 mmol) in
CH2Cl2 (5 mL) was added and the mixture was stirred for 3 h at rt.
The mixture was concentrated in vacuo and the residue was puri-
fied by fc (4 cm, 15 cm, petroleum ether:EtOAc ¼ 7:3, 20 mL,
Rf ¼ 0.43). Only the (E)-Isomer was isolated. Colorless oil, yield
calcd. C 63.81,þH 6.43, S 8.52; found C 63.40, H 6.48, S 8.40. MS (EI): m/
~
z (%) ¼ 376 [M , 58],105[PhCO, 64]. IR (film):
n
(cmꢁ1) ¼ 2952 (CeH),
1470, 1206 (SO2): 1007 (CeO), 817 (ArCeH). 1H NMR (CDCl3):
d
(ppm) ¼ 1.46 (dtd, J ¼ 13.1/2.4/1.2 Hz,1H, 5-Heq),1.59e1.67 (m, 2H,
CH2eCH2eCH2eOtos),1.74e1.97 (m, 2H, CH2eCH2eCH2eOtos),1,75
(dddd, J ¼ 13.1/12.5/11.3/4.8 Hz, 1H, 5-Hax), 2.44 (s, 3H, PhCH3), 3.78
(ddt, J ¼ 12.2/6.1/2.4 Hz, 1H, 4-Hax), 3.93 (td, J ¼ 11.3/2.7 Hz, 1H, 6-
Hax), 4.04 (dt, J ¼ 9.7/6.4 Hz, 1H, CH2eCH2eCH2eOtos), 4.12 (ddd,
J ¼ 9.7/6.4/5.1 Hz, 1H, CH2eCH2eCH2eOtos), 4.25 (ddd, J ¼ 11.3/4.8/
1.2 Hz, 1H, 6-Heq), 5.45 (s, 1H, 2-Hax), 7.30e7.38 (m, 5H, Harom, 3-
HPhCH3 and 5-HPhCH3), 7.42e7.46 (m, 2H, Harom), 7.78 (d, J ¼ 8.2 Hz,
2H, 2-HPhCH3 and 6-HPhCH3).
162 mg (62%). C15H18O4 (262.2). MS (EI): m/z (%) ¼ 262 [Mþ, 6]. IR
~
(film):
n
(cmꢁ1) ¼ 2976 (CeH), 1738 (C]O), 1661 (C]C), 10,965
(CeO), 756 (ArCeH). 1H NMR (CDCl3):
d
(ppm) ¼ 1.29 (t, J ¼ 7.1 Hz,

2168
T. Utech et al. / European Journal of Medicinal Chemistry 46 (2011) 2157e2169
5.1.39. cis-N-Methyl-3-(2-phenyl-1,3-dioxan-4-yl)propan-1-amine
(33b)
cooling centrifuge model J2-HS (Beckman). Filter: Whatman glass
fiber filters GF/B and GF/C, presoaked in 1% (NMDA assay) or 0.5%
Tosylate 41 (280 mg, 0.27 mmol) was dissolved in an ethanolic
solution of methylamine (8 M, 5 mL, 40 mmol) and the mixture was
heated to reflux for 12 h. After cooling down the mixture was
concentrated in vacuo. The residue was dissolved in CH2Cl2 (10 mL)
and the solution was extracted with a saturated solution of NaHCO3
(2 ꢃ10 mL). The organic layer was dried over MgSO4, filtered and
evaporated in vacuo. Pale yellow oil, yield 37 mg (58%). C14H21NO2
(235.4). HRMS (CI): calcd. for C14H21NO2 236.1375; found 236.1373.
MS (EI): m/z (%) ¼ 129 [MþePhCHO, 9], 105 [PhCO, 33]. MS (CI): m/z
(
s1 assay) polyethylenimine (in water) for 2 h at 4 ꢀC before use.
Filtration was performed with a Brandel 24-well cell harvester.
Scintillation cocktail: Rotiscint Eco Plus (Roth). Liquid scintillation
analyzer: TriCarb 2100 TR (Canberra Packard), counting efficiency
65%. All experiments were carried out in triplicates. IC50-values
were determined in competition experiments with at least 6
concentrations of test compounds and were calculated with the
program GraphPad PrismÒ 3.0 (GraphPad Software) by nonlinear
regression analysis. Ki-values were calculated according to Cheng
and Prusoff [48]. The Ki-values are given as mean value ꢂ SEM from
three independent experiments.
þ
~
(%) ¼ 236 [MH , 100]. IR (film):
n
(cmꢁ1) ¼ 3435(NeH), 2954 (CeH),
2742 (NHCH3), 1045 (CeO), 735 (ArCeH). 1H NMR (CDCl3):
d
(ppm) ¼ 1.41 (dtd, J ¼ 13.1/2.4/1.2 Hz, 1H, 5-Heq), 1.58e1.67 (m,
3H, CH2eCH2eCH2eNHCH3), 1.74 (dddd, J ¼ 13.1/12.5/11.2/4.8 Hz,
1H, 5-Hax), 1.82e1.98 (m, 2H, CH2eCH2eCH2eNHCH3), 2.34 (s, 3H,
NHCH3), 2.92 (q, J ¼ 7.3 Hz, 2H, CH2eCH2eCH2eNHCH3), 3.77e3.85
(m, 1H, 4-Hax), 3.88 (td, J ¼ 11.9/2.4 Hz, 1H, 6-Hax), 4.19 (ddd,
J ¼ 11.9/4.8/1.2 Hz, 1H, 6-Heq), 5.46 (s, 1H, 2-Hax), 7.30e7.36 (m, 3H,
Harom), 7.43e7.47 (m, 2H, Harom).
5.2.2. Investigation of the affinity towards the phencyclidine
binding site of the NMDA receptor
[3H]-(þ)-MK-801 binding to pig brain cortex membrane prep-
arations was performed according to standard radioligand binding
assays [18,21], which were slightly modified as described below.
5.2.2.1. Preparation of the tissue. Fresh pig brain cortex was
homogenized with a potter (500 rpm, 10 up-and-down strokes) in
10 volumes of cold 0.32 M sucrose. The suspension was centrifuged
at 1000g for 10 min at 4 ꢀC. The supernatant was separated and
centrifuged at 10,000g for 20 min at 4 ꢀC. The pellet was resus-
pended in buffer (5 mM Triseacetate with 1 mM EDTA, pH 7.5) with
an Ultraturrax (8000 rpm) and centrifuged at 20,000g (20 min,
4 ꢀC). This procedure was repeated twice. The final pellet was
resuspended in buffer, the protein concentration was determined
according to the method of Bradford [49] using bovine serum
albumin as standard, and subsequently the preparation was frozen
(ꢁ83 ꢀC) in 5 mL portions of about 1 mg protein/mL.
5.1.40. cis-N,N-Dimethyl-3-(2-phenyl-1,3-dioxan-4-yl) propan-1-
amine (33c)
Tosylate 41 (100 mg, 0.26 mmol) was dissolved in an ethanolic
solution of dimethylamine (5.6 M, 5 mL, 28 mmol) and the mixture
was heated to reflux for 12 h. After cooling down the mixture was
concentrated in vacuo. The residue was dissolved in CH2Cl2 (10 mL)
and the mixture was extracted with a saturated solution of NaHCO3
(2 ꢃ10 mL). The organic layer was dried over MgSO4, filtered and
evaporated in vacuo. Pale yellow oil, yield 23 mg (36%). C15H23NO2
(249.4). HRMS (EI): calcd. for C15H22NO2 248.1646; found 248.1650.
MS (EI): m/z (%) ¼ 248 [MþeH, 100], 105 [PhCO, 38]. MS (CI): m/z
þ
~
(%) ¼ 250 [MH , 100]. IR (film):
n
(cmꢁ1) ¼ 2935 (CeH), 2764 (N
(CH3)2), 1045 (CeO), 749 (ArCeH). 1H NMR (CDCl3):
d
(ppm) ¼ 1.52
5.2.2.2. Performance of the assay. The test was performed with the
radioligand [3H]-(þ)-MK-801 (832.5 GBq/mmol; NENÔ Life Science
(dtd, J ¼ 13.1/2.4/1.5 Hz, 1H, 5-Heq), 1.57e1.74 (m, 4H,
CH2eCH2eCH2eN(CH3)2), 1.82 (dddd, J ¼ 13.1/12.5/11.3/4.8 Hz, 1H,
5-Hax), 2.23 (s, 6H, N(CH3)2), 2.30 (t, J ¼ 7.1 Hz, 2H,
CH2eCH2eCH2eN(CH3)2), 3.84 (ddt, J ¼ 12.2/7.1/2.4 Hz, 1H, 4-Hax),
3.96 (td, J ¼ 11.3/2.4 Hz, 1H, 6-Hax), 4.27 (ddd, J ¼ 11.3/4.8/1.5 Hz,
1H, 6-Heq), 5.51 (s, 1H, 2-Hax), 7.31e7.38 (m, 3H, Harom), 7.49 (dd,
J ¼ 7.6/1.8 Hz, 2H, Harom).
Products). The thawed membrane preparation (about 100 mg of the
protein) was incubated with various concentrations of test
compounds, 2 nM [3H]-(þ)-MK-801, and buffer (5 mM
Triseacetate, 1 mM EDTA, pH 7.5) in a total volume of 500 mL for
90 min at 25 ꢀC. The incubation was terminated by rapid filtration
through presoaked Whatman GF/C filters using a cell harvester.
After washing four times with 2 mL of cold buffer 3 mL of scintil-
lation cocktail were added to the filters. After at least 8 h bound
radioactivity trapped on the filters was counted in a liquid scintil-
5.1.41. cis-N-Benzyl-3-(2-phenyl-1,3-dioxan-4-yl)propan-1-amine
(33d)
A solution of tosylate 41 (100 mg, 0.26 mmol) and freshly
distilled benzylamine (0.30 mL, 0.40 mmol) in toluene (5 mL) was
heated to reflux for 12 h. After cooling down the mixture was
concentrated in vacuo and the residue was purified by fc (2 cm,
15 cm, ethyl acetate: 2 mL, Rf ¼ 0.12). Pale yellow oil, yield 62 mg
(76%). C20H25NO2 (311.4). HRMS (EI): calcd. C20H25NO2 311.1884;
lation analyzer. Non-specific binding was determined with 10
(þ)-MK-801.
mM
5.2.3. Investigation of the s1 receptor affinity
[3H]-(þ)-Pentazocine binding to guinea pig brain membrane
preparations was performed according to standard radioligand
binding assays [43,44], which were slightly modified as described
below.
found 311.1885. MS (EI): m/z (%) ¼ 311 [Mþ, 3], 206 [MþeNHBn, 34],
~
120 [CH2eNHBn, 77], 91 [tropylium, 100]. IR (film):
n
(cmꢁ1) ¼ 3393
(NH), 2924 (CeH), 1026 (CeO), 744, 698 (ArCeH). 1H NMR (CDCl3):
d
(ppm) ¼ 1.51 (dtd, J ¼ 13.1/2.4/1.2 Hz,1H, 5-Heq),1.56e1.74 (m, 5H,
5.2.3.1. Membrane preparation. Thawed guinea pig brains (Dunkin
Hartley, Harlan-Sera-Lab) were homogenized with an ultraturrax
(8000 rpm) in 10 volumes of cold 0.32 M sucrose. The homogenate
was centrifuged at 1000g for 10 min at 4 ꢀC. The supernatant was
separated and centrifuged at 22,000g for 20 min at 4 ꢀC. The pellet
was resuspended in 10 volumes of buffer (50 mM TriseHCl, pH 7.4)
with an ultraturrax (8000 rpm), incubated for 30 min at 25 ꢀC and
centrifuged at 22,000g (20 min, 4 ꢀC). The pellet was resuspended
in buffer, the protein concentration was determined according to
the method of Bradford [49] using bovine serum albumin as stan-
dard, and subsequently the preparation was frozen (ꢁ83 ꢀC) in
5 mL portions of about 2 mg protein/mL.
CH2eCH2eCH2eNHBn), 1.80 (dddd, J ¼ 13.1/12.5/11.6/4.8 Hz, 1H, 5-
Hax), 2.68 (t, J ¼ 6.4 Hz, 2H, CH2eCH2eCH2eNHBn), 3.77e3.88 (m,
1H, 4-Hax), 3.79 (s, 2H, NHCH2Ph), 3.95 (td, J ¼ 11.6/2.4 Hz, 1H, 6-
Hax), 4.26 (ddd, J ¼ 11.6/4.8/1.2 Hz, 1H, 6-Heq), 5.50 (s, 1H, 2-Hax),
7.21e7.39 (m, 8H, Harom), 7.49 (dd, J ¼ 7.5/2.1 Hz, 2H, Harom).
5.2. Receptor binding studies
5.2.1. General
Homogenizer: PotterÒS (B. Braun Biotech International). Ultra-
turrax: EuroturraxÒ T20 (Ika Labortechnik). Centrifuge: High speed

T. Utech et al. / European Journal of Medicinal Chemistry 46 (2011) 2157e2169
2169
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