Synthesis and NMDA-receptor affinity of ring and side chain homologous dexoxadrol derivatives.

Article abstract of DOI:10.1002/ardp.200300821

The regioselectivity during transacetalization of benzophenone dimethyl acetal (4) with butane-1, 2, 4-triol (5) is controlled by the reaction conditions. Thermo-dynamic control leads predominantly to the 1, 3-dioxolane 6 whereas kinetic control favors the six-membered acetal 7. The amines 2a-e and 3a-e are synthesized from the alcohols 6 and 7 and are investigated in receptor binding studies with radioligands for their affinity to the phencyclidine binding site of the NMDA-receptor. In both series the primary amines 2a and 3a show the highest NMDA-receptor affinity (2a: Ki=3.38 microM; 3a: Ki=1.45 microM). The NMDA receptor slightly prefers the 1, 3-dioxane derivatives 3a and 3b compared to 2a and 2b (factor 2-3). Low interactions of the amines 3a and 3b with various receptor and reuptake systems indicate selectivity for the NMDA receptor. Surprisingly, the piperidine derivative 2e binds with high affinity at sigma1-receptors and, therefore, represents a novel lead compound for high affinity sigma1-receptor ligands.

Full text of DOI:10.1002/ardp.200300821

Arch. Pharm. Pharm. Med. Chem. 2004, 337, 67−75
NMDA-Receptor Affinity of Dexoxadrol Derivatives 67
Marion Aepkers,
Bernhard Wünsch
Synthesis and NMDA-Receptor Affinity of Ring
and Side Chain Homologous Dexoxadrol
Derivatives
Institut für Pharmazeutische
und Medizinische Chemie,
Westfälische
The regioselectivity during transacetalization of benzophenone dimethyl acetal
(4) with butane-1,2,4-triol (5) is controlled by the reaction conditions. Thermo-
dynamic control leads predominantly to the 1,3-dioxolane 6 whereas kinetic con-
trol favors the six-membered acetal 7. The amines 2aϪe and 3aϪe are synthe-
sized from the alcohols 6 and 7 and are investigated in receptor binding studies
with radioligands for their affinity to the phencyclidine binding site of the NMDA-
receptor. In both series the primary amines 2a and 3a show the highest NMDA-
receptor affinity (2a: Ki = 3.38 µM; 3a: Ki = 1.45 µM). The NMDA receptor
slightly prefers the 1,3-dioxane derivatives 3a and 3b compared to 2a and 2b
(factor 2Ϫ3). Low interactions of the amines 3a and 3b with various receptor
and reuptake systems indicate selectivity for the NMDA receptor. Surprisingly,
the piperidine derivative 2e binds with high affinity at σ1-receptors and, there-
fore, represents a novel lead compound for high affinity σ1-receptor ligands.
Wilhelms-Universität,
Münster, Germany
Keywords: Dexoxadrol homologues; NMDA-receptor antagonists; Structure/
affinity relationships; Regioselective acetalization
Received: June 6, 2003; Accepted September 12, 2003 [FP821]
DOI 10.1002/ardp.200300821
Introduction
agents with different indications including stroke, epi-
lepsy, Morbus Parkinson, and Morbus Alzheimer
[4Ϫ6]. Thereby, a moderate affinity to the PCP-binding
site of the NMDA receptor seems crucial; it results in
inhibition of overactivation, but maintains the normal
activity of the NMDA receptor.
Originally, dexoxadrol (1) was developed as an anaes-
thetic drug [1]. During the clinical evaluation it became
obvious that non tolerable postanaesthetic side reac-
tions, e.g. retrograde amnesia and psychotomimetic
effects, are associated with the use of dexoxadrol.
Therefore, the clinical development of dexoxadrol
was terminated.
Stimulated by the high affinity NMDA-receptor antago-
nist dexoxadrol (1), we planned the synthesis and
pharmacological evaluation of two series of homo-
logues. The first series comprises ligands with an in-
creased distance between the oxygen heterocycle and
the basic amino moiety (compare 2). In the second
series the five-membered 1,3-dioxolane ring is en-
larged to an unsymmetrically substituted 1,3-dioxane
ring (compare 3). According to reported structure/affin-
In the mid 1980s the “PCP-receptor” was postulated
as the target system for phencyclidine (PCP) and re-
lated compounds. It was found that dexoxadrol inter-
acted with the PCP-receptor with high affinity [2],
which was later recognized as a binding site within the
NMDA (N-methyl-D-aspartate) receptor-associated
ion channel [3].
The physiological activation of the NMDA receptor is
important for the development of neurons and thus for
processes like learning and memory. However, an
overstimulation of the NMDA receptor leads to an in-
creased Ca2+-ion influx into neurons which results in
neuronal damage (excitotoxicity). Therefore, com-
pounds blocking the excessive influx of Ca2+-ions into
neurons are of major interest as neuroprotective
Correspondence:
Pharmazeutische und Medizinische Chemie der Westfälischen
Wilhelms-Universität Münster, Hittorfstraße 58Ϫ62,
Bernhard
Wünsch,
Institut
für
D-48149 Münster, Germany. Phone: +49 251 833-3311, Fax:
+49 251 833-2144; e-mail: Wuensch@uni-muenster.de
Figure 1.
 2004 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim

68 Aepkers and Wünsch
Arch. Pharm. Pharm. Med. Chem. 2004, 337, 67−75
ity studies the complete piperidine ring is not essential
for receptor binding [7].
Table 1. Regioselectivity during acetalization of benzo-
phenone dimethyl acetal (4) with butane-1,2,4-triol (5).
Therefore, simple amino substituents replace the
piperidine nucleus of dexoxadrol in the ligands within
this series (see Figure 1).
Entry
Temp
Reaction time
Ratio 6:7
1
2
3
66°C
66°C
20°C
3 h
2 h
10 d
89 : 11
73 : 27
41 : 59
Chemistry
At first the acetalization of benzophenone with butane-
1,2,4-triol (5) was carefully investigated, since it rep-
resents the key step to obtain cyclic acetals with differ-
ent ring sizes. However, the direct acetalization of
benzophenone with butane-1,2,4-triol (5) failed to give
cyclic acetals. Therefore, benzophenone was trans-
formed into its dimethyl acetal 4 [8], which smoothly
reacted with the triol 5. Heating of a mixture of 4, 5,
p-toluenesulfonic acid and THF for 3 h led to the 1,3-
dioxolane 6 and the 1,3-dioxane 7 in the ratio 89 : 11
(entry 1, Table 1; Scheme 1). The regioisomeric [9]
acetals 6 and 7 were separated by flash chromatogra-
phy and characterized spectroscopically. The ratio of
6 : 7 in the crude product was determined by inte-
to the thermodynamically more stable five-membered
dioxolane 6.
1
Therefore, the H NMR spectrum of 8 has to be re-
corded immediately after dissolving the sample in
CDCl3 or in another solvent (e.g. [D6]-acetone). Since
in the following equilibrium attempts the product ratio
was spectroscopically determined by 1H NMR (solvent
CDCl3), the signals of 8 were usually not found.
With the cyclic acetals 6 and 7 in hand the position of
the equilibrium was determined. For this purpose
p-toluenesulfonic acid was added to solutions of puri-
fied acetals 6 and 7 in THF, respectively, and both mix-
tures were heated to reflux. After 20 h the reactions
were terminated and the mixtures were analyzed by
1H NMR spectroscopy. The 1H NMR spectra of the
products showed the 1,3-dioxolane 6 and the 1,3-di-
oxane 7 in ratios of 93 : 7 and 89 : 11, respectively.
This result is in agreement with the general rule that
thermodynamic control during the reaction of polyols
with ketones favors formation of five-membered
acetals [10, 11].
1
gration of characteristic signals in the H NMR spec-
trum (4.35 ppm (4-H of 6), 4.03 ppm (6-Hax of 7)).
In order to increase the amount of the minor re-
gioisomer 7 attempts with milder reaction conditions
for the transacetalization of the benzophenone acetal
4 with the triol 5 were carried out. Indeed, after short-
ening of the reaction time (2 h, THF reflux) the ratio of
6 : 7 was shifted in favor of the 1,3-dioxane (6 : 7 =
73 : 27; entry 2, Table 1). Further improvement was
achieved by performing the transacetalization at room
temperature leading predominantly to the six-mem-
bered 1,3-dioxane 7 with a ratio of 6 : 7 = 41 : 59 after
10 days (entry 3, Table 1). These results demonstrate
that the ratio of regioisomeric acetals of polyols can be
shifted in favor of the thermodynamically less stable
regioisomer by kinetic control of the transacetalization.
Scheme 1.
Next, the obtained alcohols 6 and 7 were transformed
into the amines 2 and 3. For this purpose the alcohols
6 and 7 were activated with tosyl chloride to give the
tosylates 9 and 11, which underwent nucleophilic sub-
stitution. SN2 reaction of the tosylates 9 and 11 with
NaN3 succeeded by refluxing dimethylformamide to
yield the azides 10 and 12, which were catalytically
After transacetalization of a large amount of the di-
methyl acetal 4 with the triol 5, a third acetalic product
could be isolated in 2.3% yield, which was identified
as the corresponding seven-membered acetal 8. Re-
cording of the 1H NMR spectrum of 8 in a CDCl3 solu-
tion revealed fast isomerization of the 1,3-dioxepane 8
 2004 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim

Arch. Pharm. Pharm. Med. Chem. 2004, 337, 67−75
NMDA-Receptor Affinity of Dexoxadrol Derivatives 69
Scheme 2. (a) TosCl, NEt3, CH2Cl2, 4 °C, 48 h, 96%.
(b) NaN3, DMF, 155 °C, 2.5 h, 87%. (c) H2, Pd/C, THF,
1 bar, 20 °C, 1.5 h, 88%. (d) RRЈNH, CH3OH or EtOH,
20 °C, 4Ϫ6 d. 2b: 93%; 2c: 91%; 2d: 90%; 2e: 88%.
Scheme 3. (a) TosCl, NEt3, CH2Cl2, 4 °C, 48 h, 74%.
(b) NaN3, DMF, 155 °C, 9 h, 91%. (c) H2, Pd/C, THF,
1 bar, 20 °C, 4 h, 98%. (d) RRNH, CH3OH or EtOH,
65 °C or 78 °C, 8Ϫ24 h 3b: 88%; 3c: 91%; 3d: 92%;
3e: 96%.
hydrogenated with H2 and Pd/C to provide the primary
amines 2a and 3a (Schemes 2 and 3).
The secondary amines 2b, c and 3b, c were prepared
by substitution of the tosylates 9 and 11 with the pri-
mary amines methylamine and butan-1-amine,
respectively. Reaction of the tosylates 9 and 11 with
the secondary amines dimethylamine and piperidine
led to the tertiary amines 2d, e and 3d, e, respectively.
Whereas substitution of the (1,3-dioxolan-4-yl)ethyl to-
sylate 9 with amines took place at room temperature
affording high yields of 2bϪe (88Ϫ93%), the anal-
ogous substitution of the (1,3-dioxan-4-yl)methyl tosyl-
ate 11 required heating of the reaction mixture to
65Ϫ78°C to complete the transformation (88Ϫ96%
yield).
Receptor binding studies
The affinity of the amines 2a؊e and 3aϪe to the
phencyclidine binding site of the NMDA receptor was
Table 2. Affinities of the amines 2 and 3 to the phencyclidine binding site of the NMDA receptor.
Compd.
NR2
Ki SEM [µM]
Compd.
NR2
Ki SEM [µM]
2a
2b
2c
2d
2e
dexoxadrol
NH2
3.38 0.29a
12.9 0.24a
16.7
3a
3b
3c
3d
NH2
1.45 0.09a
3.95 0.21a
18.9
29.8
36.8
NHMe
NHBu
NMe2
N(CH2)5
NHMe
NHBu
NMe2
N(CH2)5
30.1
19.9
3e
0.023 0.0034a
(S)-ketamine
0.11 0.011a
a
For compounds with Ki-values lower than 15 µM three independent experiments (n = 3) were performed.
 2004 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim

70 Aepkers and Wünsch
Arch. Pharm. Pharm. Med. Chem. 2004, 337, 67−75
determined in competition experiments with a radio-
ligand. In the assay pig brain cortex preparations were
used. [3H]-(+)-MK-801, which binds with high affinity
and selectivity to the phencyclidine binding site of the
NMDA receptor, was employed as radioligand. Non-
specific binding was determined in the presence of a
large excess of non-tritiated (+)-MK-801 [12, 13].
of the methylamine 3b for the phencyclidine binding
site of the NMDA receptor is high. With exception of
the 5-HT1A-receptor, the primary amine 3a also dis-
plays very low affinity to the investigated receptor and
reuptake systems indicating very high selectivity for
the phencyclidine binding site of the NMDA receptor.
However, an unexpected high affinity of the primary
amine 3a to the 5-HT1A-receptor (IC50 = 29 nM) (entry
6, Table 3) was found, which even exceeds the NMDA-
receptor affinity.
The NMDA-receptor affinities of the amines 2 and 3
are summarized in Table 2. In both series the primary
amines 2a and 3a display the highest NMDA-receptor
affinity. The secondary amines with a methyl (2b, 3b)
or butyl (2c, 3c) residue at the nitrogen atom show
reduced NMDA-receptor affinity whereas interactions
of the tertiary amines 2d, e and 3d, e with the NMDA
receptor are quite low.
Tertiary amines with a phenyl residue in a definite dis-
tance often display high affinity to σ1-receptors [14,
15]. Therefore, the tertiary amines 2d, e and 3d, e
were investigated for their σ1-receptor affinity. In the
assay guinea pig brain homogenates were used as re-
ceptor source and the 1-selective ligand [3H]-(+)-
pentazocine was employed as radioligand [16, 17]. In
the initial screening 1 µM solutions of the test com-
pounds were incubated with the receptor preparation
and the radioligand and the radioactivity trapped on
the filters was determined. With exception of the pip-
eridine derivative 2e the binding of the radioligand was
very high indicating low competition (see Table 4).
Therefore, a complete competition curve was recorded
only for the piperidine 2e Ϫ the most promising σ1-
ligand. Thereby a Ki-value of 39.3 nM 3.3 nM (SEM,
n = 3) was found. Thus, the piperidine 2e represents
a novel lead structure for the development of high af-
finity, selective σ1-ligands.
The NMDA-receptor affinity of the primary amine 3a
of the 1,3-dioxane series is higher by the factor 2.3
compared to the NMDA-receptor affinity of the corre-
sponding primary amine 2a of the 1,3-dioxolane
series. A similar relationship is observed among the
methylamines: The 1,3-dioxane derivative 3b shows
a lower Ki-value than the 1,3-dioxolane derivative 2b
(factor 3.3). Altogether, within both series of dexoxad-
rol homologues, novel NMDA-receptor antagonists are
found with affinity in the range of 1Ϫ5 µM.
Since ligands with moderate NMDA-receptor affinity
are of interest because of their potentially low side ef-
fects, the receptor binding profile of the most promis-
ing ligands 3a and 3b was determined by screening
these ligands in several receptor and reuptake assays.
The results in Table 3 point out that interactions of the
methylamine 3b with the investigated receptor and re-
uptake systems are very low. Obviously, the selectivity
Conclusion
Table 3. Affinities of the primary amine 3a and the methylamine 3b to various receptor and reuptake systems.
Entry
Receptor system (radioligand)
IC50 (µM)
3a
3b
1
2
3
4
5
6
7
8
9
10
11
12
13
NMDA, glutamate (CGP-39,653)
NMDA, glycine (MDL 105,519)
NMDA, polyamine (ifenprodil)
histamine H1 (mepyramine)
>10
>10
>10
>10
>10
0.029
>10
>10
>10
>10
>10
>10
>10
>10
>10
>10
>10
>10
>1
dopamine D1 (SCH 23,390)
serotonin 5-HT1A (5-OH DPAT)
serotonin 5-HT2A (ketanserin)
serotonin 5-HT3 (GR 65,630)
noradrenaline α1 (prazosine)
noradrenaline α2 (idazoxane)
serotonin reuptake (serotonin)
noradrenaline reuptake (noradrenaline)
dopamine reuptake (dopamine)
5.8
>10
>10
>10
>10
2.2
8.6
 2004 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim

Arch. Pharm. Pharm. Med. Chem. 2004, 337, 67−75
NMDA-Receptor Affinity of Dexoxadrol Derivatives 71
trometer (Varian), δ in ppm related to tetramethylsilane, coup-
ling constants are given with 0.5 Hz resolution; the assign-
ments of 13C and 1H NMR signals were supported by 2D
NMR techniques.
Table 4. Affinities of the amines 2d, e and 3d, e for
σ1-receptors.
Compd.
% bindinga
Benzophenone dimethyl acetal (4)
The synthesis reported in ref. [8] was slightly modified: A
solution of benzophenone (18.2 g, 100 mmol), trimethyl or-
thoformiate (12.0 mL, 110 mmol) and p-toluenesulfonic acid
monohydrate (0.95 g, 5 mmol) in methanol (150 mL) was
stirred for 16 h at room temperature (r.t.). The product was
filtered and recrystallized from methanol. Colorless solid
(methanol), mp 105.6Ϫ107.0°C (ref. [8] 107Ϫ108°C), yield
17.8 g (78%). C15H16O2 (228.29). 1H NMR (CDCl3): δ [ppm] =
3.14 (s, 6H, OCH3), 7.19Ϫ7.33 (m, 6H, arom. Hmeta and
2d
2e
3d
3e
70.0
9.6
77.0
72.0
In the table the binding of the radioligand [3H]-(+)-
pentazocine to σ1-receptors in the presence of 1 µM
of the test compounds is given.
a
Hpara), 7.49Ϫ7.53 (m, 4H, arom. Hortho). Ϫ IR (KBr): ν
˜
[cmϪ1] = 2828 (OCH3), 1093, 1062 (C-O).
We have shown that homologization of the oxygen
heterocycle or the distance between the amine and
the oxygen heterocycle of the lead structure dexoxad-
rol provides novel NMDA-receptor antagonists with
µM-affinity levels. The NMDA-receptor affinities of the
most promising ligands (2a, 3a, 3b) are considerably
lower than the NMDA-receptor affinity of the lead com-
pound dexoxadrol. However, the moderate affinity of
these NMDA-receptor antagonists together with their
high receptor selectivity should cause little side effects
in vivo. Therefore, further variations of acetalic NMDA-
receptor antagonists are in progress.
2-(2,2-Diphenyl-1,3-dioxolan-4-yl)ethan-1-ol (6), and (2,2-Di-
phenyl-1,3-dioxan-4-yl)methanol (7), and 2,2-Diphenyl-1,3-di-
oxepan-5-ol (8)
A solution of benzophenone dimethyl acetal (4, 4.57 g, 20
mmol) and racemic butanetriol 5 (2.12. g, 20 mmol) in THF
(50 mL) was dried with Na2SO4. Then a dried (Na2SO4) solu-
tion of p-toluenesulfonic acid monohydrate (0.033 mol/L, 30
mL, 1 mmol) in THF was added and the mixture was heated
at reflux for 4 h. Then, Na2SO4 was separated, Et2O (50 mL)
was added and the mixture was washed with a saturated
solution of NaHCO3 (100 mL). The organic layer was dried
(MgSO4), filtered. and concentrated in vacuo. A 1H NMR
spectrum was recorded and the mixture of regioisomers was
separated by fc (8 cm, petroleum ether : ethyl acetate =
7 : 3, fractions 35 mL).
Acknowledgments
6 (Rf = 0.13): Colorless oil, yield 1.86 g (34%). C17H18O3
(270.3), calcd. C 75.5 H 6.71 found C 75.5 H 6.77. Ϫ MS
(EI): m/z (%) = 270 (M, 0.4), 193 (M Ϫ Ph, 65), 182 (Ph2CO,
74), 105 (PhCO, 100). Ϫ 1H NMR (CDCl3): δ [ppm] = 1.85
(dtd, J = 14.2/6.0/4.8 Hz, 1H, CH2CH2OH), 1.95 (ddt, J =
14.2/7.8/5.8 Hz, 1H, CH2CH2OH), 2.03 (s, broad, 1H, OH),
3.77 (dd, J = 7.8/7.1 Hz, 1H, 5-H), 3.83 (t, J = 5.8 Hz, 2H,
CH2CH2OH), 4.16 (dd, J = 7.8/6.6 Hz, 1H, 5-H), 4.35 (qd, J =
7.1/4.9 Hz, 1H, 4-H), 7.26Ϫ7.38 (m, 6H, arom. Hmeta and
Financial support of this work by the Deutsche For-
schungsgemeinschaft, the Fonds der Chemischen In-
dustrie, and the Wissenschaftliche Gesellschaft Frei-
burg is gratefully acknowledged. Thanks are also due
to the Degussa AG, Upjohn/Pharmacia for donation of
chemicals and reference compounds. Performance of
the receptor screening (Table 3) by Dr. Christoph A.
Seyfried, Department of CNS Research, Merck KGaA,
Darmstadt, is gratefully acknowledged.
Hpara), 7.47Ϫ7.54 (m, 4H, arom. Hortho). Ϫ IR (film): ν
˜
[cmϪ1] = 3410 (O-H), 2944 (C-H), 2883 (C-H), 1070 (s, C-O),
755, 700 (aryl).
7 (Rf = 0.20: Colorless oil, yield 1.0 g (19%). C17H18O3
(270.3), calcd. C 75.5 H 6.71 found C 75.3 H 6.81. Ϫ MS
(EI): m/z (%) = 270 (M, 0.9), 239 (M Ϫ CH2OH, 6), 193 (M Ϫ
Ph, 52), 182 (Ph2CO, 66), 105 (PhCO, 100). Ϫ 1H NMR
(CDCl3): δ [ppm] = 1.34 (dtd, J = 12.9/2.4/1.7 Hz, 1H, 5-
Hequat.), 1.99 (dtd, J = 12.9/12.0/5.9 Hz, 1H, 5-Haxial), 2.19 (s,
broad, 1H, OH), 3.68 (dd, J = 11.7/6.1 Hz, 1H, CH2OH), 3.74
(dd, J = 11.7/3.7 Hz, 1H, CH2OH), 4.03 (td, J = 11.5/2.7 Hz,
Experimental
Chemistry, general
Unless otherwise noted, moisture sensitive reactions were
conducted under dry nitrogen. Ϫ Petroleum ether used refers
to the fraction boiling at 40Ϫ60°C. Ϫ Thin layer chromatogra-
phy (tlc): Silica gel 60 F254 plates (Merck, Darmstadt, Ger-
many). Ϫ Flash chromatography (fc) [18]: Silica gel 60,
0.040Ϫ0.063 mm (Merck); parentheses include: Diameter of
the column [cm], eluent, fraction size [mL], Rf. Ϫ Melting
points: Melting point apparatus SMP 2 (Stuart Scientific), un-
corrected. Ϫ Elemental analyses: Elemental Analyzer 240
(Perkin-Elmer) and Vario EL (Elementaranalysesysteme
GmbH). Ϫ MS: MAT 312, MAT 8200, MAT 44, and TSQ 7000
(Finnigan); EI = electron impact, CI = chemical ionization. Ϫ
High resolution MS (HR-MS): MAT 8200 (Finnigan). Ϫ IR: IR
spectrophotometer 1605 FT-IR (Perkin-Elmer). Ϫ 1H NMR
(300 MHz), 13C NMR (75 MHz): Unity 300 FT NMR spec-
1H, 6-Haxial), 4.06Ϫ4.16 (m, 2H, 4-Haxial
,
6-Hequat.),
7.19Ϫ7.34 (m, 4H, arom. Hmeta), 7.38Ϫ7.45 (m, 2H, arom.
Hpara), 7.47Ϫ7.57 (m, 4H, arom. Hortho). Ϫ IR (film): ν
˜
[cmϪ1] = 3394 (O-H), 2951 (C-H), 2878 (C-H), 1101, 1024
(C-O), 750, 702 (aryl).
8 (Rf = 0.26): Colorless solid, mp 107.0Ϫ108.0°C, yield 0.123
g (2.3%). C17H18O3 (270.3), calcd. C 75.5 H 6.71 found C
75.5 H 6.78. Ϫ MS (EI): m/z (%) = 270 (M, 1.4), 240 (M Ϫ
H2O, 17), 193 (M Ϫ Ph, 27), 182 (Ph2CO, 83), 105 (PhCO,
69). Ϫ 1H NMR (CDCl3 at once): δ [ppm] = 1.79 (dtd, J =
14.9/3.2/2.4 Hz, 1H, 6-H), 1.93 (dddd, J = 14.3/8.3/6.3/3.9
 2004 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim

72 Aepkers and Wünsch
Arch. Pharm. Pharm. Med. Chem. 2004, 337, 67−75
Hz, 1H, 6-H), 2.49 (s, broad, 1H, OH), 3.74Ϫ3.80 (m, 4H, 4-
H, 7-H), 3.90 (qd, J = 3.9/2.0 Hz, 1H, 5-H), 7.19Ϫ7.35 (m,
6H, arom. Hmeta and Hpara), 7.58Ϫ7.64 (m, 4H, arom. Hortho).
(MϪPh, 24), 105 (PhCO, 85), 87 (O-CH2-CH-(CH2)2-NH2,
69). Ϫ MS (CI): m/z (%) = 270 (M + H, 50), 192 (M Ϫ Ph, 15),
88 (O-CH2-CH-(CH2)2-NH2 + H, 100). Ϫ 1H NMR (CDCl3): δ
[ppm] = 1.19 (s, broad, 2H, NH2), 1.72 (dtd, J = 13.7/7.2/
4.9 Hz, 1H, CH2CH2NH2), 1.86 (dtd, J = 13.7/7.2/6.4 Hz, 1H,
CH2CH2NH2), 2.85 (dt, J = 12.5/7.0 Hz, 1H, CH2CH2NH2),
2.92 (ddd, J = 12.5/7.3/6.4 Hz, 1H, CH2CH2NH2), 3.71 (t, J =
7.5 Hz, 1H, 5-H), 4.14 (dd, J = 7.6/6.7 Hz, 1H, 5-H), 4.26
(tdd, J = 7.3/6.7/4.9 Hz, 1H, 4-H), 7.26Ϫ7.37 (m, 6H, arom.
Hmeta and Hpara), 7.49Ϫ7.55 (m, 4H, arom. Hortho). Ϫ IR (film):
Ϫ
1H NMR ([D6]-acetone): δ [ppm] = 1.67Ϫ1.77 (m, 1H, 6-
H), 1.90Ϫ2.00 (m, 1H, 6-H), 2.96 (s, 1H, OH), 3.62 (ddd, J =
12.4/8.1/2.6 Hz, 1H, 7-H), 3.60Ϫ3.74 (m, 1H, 5-H), 3.81 (ddd,
J = 12.4/7.0/2.9 Hz, 1H, 7-H), 3.84Ϫ3.90 (m, 2H, 4-H),
7.17Ϫ7.24 (m, 2H, arom. Hpara), 7.26Ϫ7.33 (m, 4H, arom.
Hmeta), 7.58Ϫ7.64 (m, 4H, arom Hortho). Ϫ 13C NMR ([D6]-
acetone): δ [ppm] = 38.7 (1C, C-6), 59.5 (1C, C-7), 67.9
(1C, C-5), 69.0 (1C, C-4), 104.2 (1C, C-2), 127.0 (4C, arom.
CHortho), 128.1 (2C, arom. CHpara), 128.7 (4C, arom. CHmeta),
145.0 (1C, arom. Cquart.), 145.1 (1C, arom. Cquart.). Ϫ IR
ν [cmϪ1] = 3367 (N-H), 2941, 2879 (C-H), 1590 (N-H), 1087,
˜
1067 (C-O), 754, 702 (aryl).
(KBr): ν [cmϪ1] = 3444 (O-H), 2942 (C-H), 1083 (C-O).
2-(2,2-Diphenyl-1,3-dioxolan-4-yl)-N-methylethan-1-amine
(2b)
˜
2-(2,2-Diphenyl-1,3-dioxolan-4-yl)ethyl tosylate (9)
The tosylate 9 (0.43 g, 1.0 mmol) was dissolved in a solution
of methylamine in ethanol (7.5 mL, 8.03 M, 60 mmol CH3NH2)
and the mixture was stirred for 4 d at room temperature. The
solvent was evaporated in vacuo and the residue was dis-
solved in CH2Cl2 (10 mL). The organic layer was washed with
a saturated solution of NaHCO3 (2 ϫ 10 mL) and water (10
mL), dried (MgSO4), filtered, and concentrated in vacuo to
yield pure methylamine 2b. Pale yellow oil, yield 0.264 g
A solution of 6 (1.35 g, 5 mmol) and triethylamine (0.84 mL,
6 mmol) in CH2Cl2 (15 mL) was cooled in an ice bath. A solu-
tion of p-toluenesulfonyl chloride (1.91 g, 10 mmol) in CH2Cl2
(10 mL) was slowly added and the reaction mixture was
stirred at 4°C for 48 h. The mixture was concentrated in
vacuo and the residue was purified by fc (6 cm, petroleum
ether : ethyl acetate = 4 : 1, fractions 20 mL, Rf = 0.28).
Colorless solid, mp 59Ϫ63°C, yield 2.04 g (96%). C24H24O5S
(424.51), calcd. C 67.9 H 5.70 found C 68.0 H 5.69. Ϫ MS
(EI): m/z (%) = 424 (M, 1.6), 347 (M Ϫ Ph, 95), 155 (tos, 14),
105 (PhCO, 100). Ϫ 1H NMR (CDCl3): δ [ppm] = 1.96 (“q”,
J = 6.4 Hz, 2H, CH2CH2Otos), 2.45 (s, 3H, PhCH3), 3.68 (dd,
J = 7.9/6.4 Hz, 1H, 5-H), 4.07 (dd, J = 7.9/6.4 Hz, 1H, 5-H),
4.21 (t, J = 6.4 Hz, 2H, CH2CH2Otos), 4.24 (“quint”, J = 6.4
Hz, 1H, 4-H), 7.26Ϫ7.36 (m, 8H, arom. Hmeta, Hpara and 3-H,
5-H (tos)), 7.39Ϫ7.46 (m, 4H, arom. Hortho), 7.79 (d, J = 8.3
(93.3%).
C18H21NO2 (283.37). Ϫ HR-MS (for M Ϫ
CH2NHCH3): calcd. 239.1072 found 239.1071. Ϫ MS (EI):
m/z (%) = 283 (M, 0.2), 239 (M Ϫ CH2NHCH3, 2.8), 206 (M
Ϫ Ph, 4), 105 (PhCO, 42), 101 (O-CH2-CH-(CH2)2-NH-CH3,
81). Ϫ 1H NMR (CDCl3): δ [ppm] = 1.63 (s, 1H, NH), 1.78
(dddd, J = 13.7/7.6/6.7/5.2 Hz, 1H, CH2CH2NH), 1.92 (dtd,
J = 13.7/7.3/6.4 Hz, 1H, CH2CH2NH), 2.43 (s, 3H, NHCH3),
2.71 (dt, J = 11.9/7.0 Hz, 1H, CH2CH2NH), 2.79 (ddd, J =
11.9/7.6/6.4 Hz, 1H, CH2CH2NH), 3.71 (dd, J = 7.6/6.7 Hz,
1H, 5-H), 4.14 (dd, J = 7.6/7.0 Hz, 1H, 5-H), 4.25 (qd, J = 7.0/
5.2 Hz, 1H, 4-H), 7.26Ϫ7.37 (m, 6H, arom. Hmeta and Hpara),
Hz, 2H, arom. 2-H, 6-H (tos)). Ϫ IR (KBr): ν [cmϪ1] = 2928
˜
(C-H), 2860 (C-H), 1356, 1182 (SO2), 1096 (C-O), 838 (aryl),
750, 704 (aryl).
7.48Ϫ7.54 (m, 4H, arom. Hortho). Ϫ IR (film): ν [cmϪ1] = 3322
˜
(N-H), 2939, 2882 (C-H), 2793 (C-H), 1087, 1069 (C-O), 753,
701 (aryl).
4-(2-Azidoethyl)-2,2-diphenyl-1,3-dioxolane (10)
N-[2-(2,2-Diphenyl-1,3-dioxolan-4-yl)ethyl]butan-1-amine
(2c)
A solution of 9 (0.47 g, 1.1 mmol) and NaN3 (0.72 g, 11 mmol)
in DMF (15 mL) was heated to reflux for 2.5 h. The solvent
was removed in vacuo (< 10 mbar, < 60°C) and the residue
was dissolved in Et2O (10 mL). The suspension was washed
with saturated solutions of NaHCO3 (10 mL) and NaCl (10
mL), dried (MgSO4), filtered, and concentrated in vacuo.
Further purification of 10 was unnecessary. Colorless oil,
yield 0.28 g (87%). C17H17N3O2 (295.34), calcd. C 69.1 H
5.80 N 14.23 found C 69.1 H 5.82 N 14.55. Ϫ MS (EI): m/z
(%) = 295 (M, 1.1), 218 (MϪPh, 62), 182 (Ph2CO, 13), 105
(PhCO, 100). Ϫ 1H NMR (CDCl3): δ [ppm] = 1.85 (dtd, J =
14.0/7.6/4.6 Hz, 1H, CH2CH2N3), 1.94 (ddt, J = 14.0/7.9/6.1
Hz, 1H, CH2CH2N3), 3.50 (t, broad, J = 6.9 Hz, 2H,
CH2CH2N3), 3.75 (dd, J = 7.9/6.7 Hz, 1H, 5-H), 4.15 (dd, J =
7.9/6.7 Hz, 1H, 5-H), 4.29 (dtd, J = 7.9/6.7/4.6 Hz, 1H, 4-H),
7.27Ϫ7.38 (m, 6H, arom. Hmeta and Hpara), 7.47Ϫ7.55 (m,
A solution of 9 (0.21 g, 0.50 mmol) and butan-1-amine (2.0
mL, 20 mmol) in methanol (5 mL) was stirred for 6 d at room
temperature. The mixture was concentrated in vacuo and the
residue was dissolved in CH2Cl2 (10 mL). The CH2Cl2 layer
was washed with a saturated solution of NaHCO3 (2 ϫ 10
mL), dried (MgSO4), filtered, and concentrated in vacuo to
afford pure butylamine 2c. Pale yellow solid, mp 46Ϫ48°C,
yield 0.15 g (91%). C21H27NO2 (325.45). Ϫ HR-MS (for
MϪCH2CH2CH3): calcd. 282.1494 found 282.1494. Ϫ MS
(EI): m/z (%) = 325 (M, 0.8), 282 (M Ϫ CH2CH2CH3, 5.5),
248 (M Ϫ Ph, 14), 143 (O-CH2-CH-(CH2)2-NH-C4H9, 88), 100
((CH2)2-NH-C4H9, 95). Ϫ 1H NMR (CDCl3): δ [ppm] = 0.91 (t,
J = 7.3 Hz, 3H, NHCH2CH2CH2CH3), 1.33 (sext, J = 7.3 Hz,
2H, NHCH2CH2CH2CH3), 1.45 (quint, J = 7.3 Hz, 2H,
NHCH2CH2CH2CH3), 1.48 (s, broad, 1H, NH), 1.78 (dddd,
J = 13.2/7.8/6.8/5.4 Hz, 1H, CH2CH2NH), 1.92 (dtd, J = 13.2/
7.3/6.3 Hz, 1H, CH2CH2NH), 2.59 (t, J = 7.3 Hz, 2H,
NHCH2CH2CH2CH3), 2.73 (ddd, J = 11.7/7.3/6.8 Hz, 1H,
CH2CH2NH), 2.82 (ddd, J = 11.7/7.8/6.3 Hz, 1H, CH2CH2NH),
3.71 (dd, J = 7.8/7.3 Hz, 1H, 5-H), 4.13 (dd, J = 7.8/6.3 Hz,
1H, 5-H), 4.24 (tdd, J = 7.3/6.3/5.4 Hz, 1H, 4-H), 7.26Ϫ7.37
(m, 6H, arom. Hmeta and Hpara), 7.48Ϫ7.54 (m, 4H, arom.
4H, arom. Hortho). Ϫ IR (film): ν [cmϪ1] = 2943 (C-H), 2882
˜
(C-H), 2097 (N3), 1089 (C-O), 756, 703 (aryl).
2-(2,2-Diphenyl-1,3-dioxolan-4-yl)ethan-1-amine (2a)
A mixture of 10 (0.15 g, 0.5 mmol), Pd/C (10%, 7.5 mg) and
THF (10 mL) was stirred under hydrogen atmosphere (1 bar)
for 1.5 h at room temperature. The mixture was filtered with
Celite AFA and the solvent was evaporated in vacuo to af-
ford the pure primary amine 2a. Colorless oil, yield 0.12 g
(88%). C17H19NO2 (269.34). Ϫ HR-MS: calcd. 269.1416
found 269.1417. Ϫ MS (EI): m/z (%) = 269 (M, 0.6), 192
Hortho). Ϫ IR (film): ν [cmϪ1] = 3345 (N-H), 2930, 2873 (C-H),
˜
1085 (C-O), 756, 702 (aryl).
 2004 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim

Arch. Pharm. Pharm. Med. Chem. 2004, 337, 67−75
NMDA-Receptor Affinity of Dexoxadrol Derivatives 73
2-(2,2-Diphenyl-1,3-dioxolan-4-yl)-N,N-dimethylethan-1-
amine (2d)
2H, arom. 3-H, 5-H (tos)), 7.84 (d, J = 8.8 Hz, 2H, arom. 2-
H, 6-H (tos)). Ϫ IR (KBr): ν [cmϪ1] = 2970 (C-H), 2878 (C-H),
˜
1361, 1174 (SO2), 1102 (C-O), 832 (aryl), 748, 709 (aryl).
The tosylate 9 (0.43 g, 1.0 mmol) was dissolved in a solution
of dimethylamine in ethanol (10.8 mL, 5.6 M, 60 mmol
(CH3)2NH2) and the mixture was stirred for 4 d at room tem-
perature. The mixture was concentrated in vacuo and the
residue was dissolved in CH2Cl2 (10 mL). The CH2Cl2 layer
was washed with a saturated solution of NaHCO3 (2 ϫ 10
mL) and water (10 mL), dried (MgSO4), filtered, and concen-
trated in vacuo to yield the pure dimethylamine 2d. Pale yel-
low oil, yield 0.27 g (90%). C19H23NO2 (297.40). Ϫ HR-MS:
calcd. 297.1729 found 297.1721. Ϫ MS (CI): m/z (%) = 298
(M + H, 100), 116 (O-CH2-CH-(CH2)2-N(CH3)2, 66). Ϫ 1H
NMR (CDCl3): δ [ppm] = 1.74 (ddt, J = 13.4/9.5/5.8 Hz, 1H,
4-(Azidomethyl)-2,2-diphenyl-1,3-dioxane (12)
A solution of 11 (0.21 g, 0.50 mmol) and NaN3 (0.33 g, 5
mmol) in DMF (10 mL) was heated to reflux for 9 h. The sol-
vent was evaporated in vacuo (< 10 mbar, < 60°C) and the
residue was dissolved in Et2O (5 mL). The suspension was
washed with a saturated solution of NaHCO3 (5 mL) and
water (5 mL). The organic layer was dried (MgSO4), filtered
and concentrated in vacuo. Further purification of 12 was un-
necessary. Colorless oil, yield 0.134 g (91%). C17H17N3O2
(295.34), calcd. C 69.1 H 5.80 N 14.23 found C 69.6 H 5.74
N 13.86. Ϫ MS (EI): m/z (%) = 295 (M, 13), 239 (M Ϫ CH2N3,
50), 218 (M Ϫ Ph, 100), 105 (PhCO, 82). Ϫ 1H NMR (CDCl3):
δ [ppm] = 1.38 (dtd, J = 12.8/2.4/1.8 Hz, 1H, 5-Hequat.), 1.94
dtd, J = 12.8/11.6/5.8 Hz, 1H, 5-Haxial), 3.21 (dd, J = 12.8/3.4
Hz, 1H, CH2N3), 3.50 (dd, J = 12.8/7.6 Hz, 1H, CH2N3), 4.06
(td, J = 11.6/2.4 Hz, 1H, 6-Haxial), 4.12 (ddd, J = 11.6/5.8/1.8
Hz, 1H, 6-Hequat.), 4.18 (dddd, J = 11.6/7.6/3.4/2.4 Hz, 1H, 4-
Haxial), 7.16Ϫ7.32 (m, 4H, arom. Hmeta), 7.38Ϫ7.44 (m, 2H,
CH2CH2N), 1.92 (dddd,
J = 13.4/9.2/7.0/5.5 Hz, 1H,
CH2CH2N), 2.22 (s, 6H, N(CH3)2), 2.36 (ddd, J = 12.2/9.2/
6.1 Hz, 1H, CH2CH2N), 2.48 (ddd, J = 12.2/9.5/5.5 Hz, 1H,
CH2CH2N), 3.71 (dd, J = 7.3/7.0 Hz, 1H, 5-H), 4.14 (dd, J =
7.3/6.4 Hz, 1H, 5-H), 4.22 (quint, J = 6.5 Hz, 1H, 4-H),
7.26Ϫ7.36 (m, 6H, arom. Hmeta and Hpara), 7.48Ϫ7.54 (m,
4H, arom. Hortho). Ϫ IR (film): ν [cmϪ1] = 2944, 2863 (C-H),
˜
2817, 2765 (C-H), 1088, 1068 (C-O), 753, 701 (aryl).
arom. Hpara), 7.53Ϫ7.59 (m, 4H, arom. Hortho). Ϫ IR (film): ν
˜
1-[2-(2,2-Diphenyl-1,3-dioxolan-4-yl)ethyl]piperidine (2e)
[cmϪ1] = 2967 (C-H), 2879 (C-H), 2095 (N3), 1102 (C-O), 749,
704 (aryl).
A mixture of 9 (0.21 g, 0.50 mmol), piperidine (2.0 mL, 20
mmol) and methanol (5 mL) was stirred at room temperature
for 3 d. The mixture was concentrated in vacuo and the resi-
due was dissolved in CH2Cl2 (10 mL). The CH2Cl2 layer was
washed with a saturated solution of NaHCO3 (10 mL) and
water (10 mL), dried (MgSO4), filtered, and concentrated in
vacuo to yield the pure piperidine 2e. Colorless oil, yield 0.15
g (88%). C22H27NO2 (337.46), calcd. C 78.3 H 8.06 N 4.15
found C 78.1 H 8.12 N 4.11.- MS (EI): m/z (%) = 337 (M, 0.6),
260 (M Ϫ Ph, 14), 155 (O-CH2-CH-(CH2)2-N(CH2)5, 71), 98
1-(2,2-Diphenyl-1,3-dioxan-4-yl)methanamine (3a)
A mixture of 12 (97.5 mg, 0.33 mmol), ), Pd/C (10%, 5 mg)
and THF (10 mL) was stirred under a hydrogen atmosphere
(1 bar) for 4 h at room temperature. The mixture was filtered
with Celite AFA and the solvent was evaporated in vacuo to
afford the pure primary amine 3a. Colorless oil, yield 86.7
mg (98%). C17H19NO2 (269.34). Ϫ HR-MS: calcd. 269.1416
found 269.1417. Ϫ MS (EI): m/z (%) = 269 (M, 2), 239 (M Ϫ
CH2NH2, 100), 192 (M Ϫ Ph, 18), 105 (PhCO, 83). Ϫ MS
(CI): m/z (%) = 270 (M + H, 22), 239 (M Ϫ CH2NH2, 35), 88
(O(CH2)2CHCH2NH2 + H, 62). Ϫ 1H NMR (CDCl3): δ [ppm] =
1.37 (dtd, J = 12.8/2.7/1.8 Hz, 1H, 5-Hequat.), 1.45 (s, broad,
2H, NH2), 1.91 (dtd, J = 12.8/11.9/5.8 Hz, 1H, 5-Haxial), 2.83
(dd, J = 13.1/4.0 Hz, 1H, CH2NH2), 2.92 (dd, J = 13.1/7.0 Hz,
1H, CH2NH2), 3.95 (dddd, J = 11.9/7.0/4.0/2.7 Hz, 1H, 4-
Haxial), 4.03 (td, J = 11.6/2.7 Hz, 1H, 6-Haxial), 4.10 (ddd, J =
11.6/5.8/1.8 Hz, 1H, 6-Hequat.), 7.18Ϫ7.32 (m, 4H, arom.
Hmeta), 7.38Ϫ7.43 (m, 2H, arom. Hpara), 7.50Ϫ7.58 (m, 4H,
(CH2-N(CH2)5, 100).
1.41Ϫ1.48 (m, 2H, 4-Hpip.), 1.54Ϫ1.62 (m, 4H, 3-Hpip., 5-
pip.), 1.80 (ddt, J = 13.2/9.5/5.9 Hz, 1H, CH2CH2N), 1.96
Ϫ δ [ppm] =
1H NMR (CDCl3):
H
(dddd, J = 13.2/9.5/6.6/5.1 Hz, 1H, CH2CH2N), 2.33Ϫ2.43
(m, 4H, 2-Hpip., 6-Hpip.), 2.38 (ddd, J = 12.5/9.5/6.2 Hz, 1H,
CH2CH2N), 2.52 (ddd, J = 12.5/9.5/5.1 Hz, 1H, CH2CH2N),
3.72 (dd, J = 7.0/6.6 Hz, 1H, 5-Hdiox.), 4.15 (dd, J = 7.0/6.6
Hz, 1H, 5-Hdiox.), 4.20 (qd, J = 6.6/5.9 Hz, 1H, 4-Hdiox.),
7.27Ϫ7.37 (m, 6H, arom. Hmeta and Hpara), 7.48Ϫ7.54 (m,
4H, arom. Hortho). Ϫ IR (film): ν [cmϪ1] = 2934 (C-H), 2769
˜
(C-H), 1085 (C-O), 760, 705 (aryl).
arom. Hortho). Ϫ IR (film): ν [cmϪ1] = 3374 (N-H), 2952, 2875
˜
(C-H), 1593 (N-H), 1101, 1026 (C-O), 749, 707 (aryl).
(2,2-Diphenyl-1,3-dioxan-4-yl)methyl tosylate (11)
1-(2,2-Diphenyl-1,3-dioxan-4-yl)-N-methylmethanamine (3b)
A solution of 7 (1.35 g, 5 mmol) and triethylamine (0.84 mL,
6 mmol) in CH2Cl2 (15 mL) was cooled in an ice bath. A solu-
tion of p-toluenesulfonyl chloride (1.91 g, 10 mmol) in CH2Cl2
(10 mL) was slowly added and the reaction mixture was
stirred at 4°C for 48 h. The mixture was concentrated in
vacuo and the residue was purified by fc (6 cm, petroleum
ether : ethyl acetate = 4 : 1, fractions 30 mL, Rf = 0.35).
Colorless solid, mp 70Ϫ74°C, yield 1.56 g (74%). C24H24O5S
(424.51), calcd. C 67.9 H 5.70 found C 68.0 H 5.76. Ϫ MS
(EI): m/z (%) = 424 (M, 2.8), 347 (M Ϫ Ph, 83), 155 (Tos, 23),
105 (PhCO, 100). Ϫ 1H NMR (CDCl3): δ [ppm] = 1.39 (dtd,
J = 12.7/2.4/2.0 Hz, 1H, 5-Hequat.), 1.83 (dtd, J = 12.7/11.7/
5.9 Hz, 1H, 5-Haxial), 2.44 (s, 3H, PhCH3), 4.00 (td, J = 11.7/
2.4 Hz, 1H, 6-Haxial), 4.07 (ddd, J = 11.5/5.9/2.0 Hz, 1H, 6-
Hequat.), 4.08 (dd, J = 10.3/3.9 Hz, 1H, CH2Otos), 4.19 (dd,
J = 10.3/6.8 Hz, 1H, CH2Otos), 4.24 (dddd, J = 11.7/6.8/3.9/
2.4 Hz, 1H, 4-Haxial), 7.19Ϫ7.33 (m, 6H, arom. Hmeta and
The tosylate 11 (0.21 g, 0.50 mmol) was dissolved in a solu-
tion of methylamine in ethanol (5 mL, 8.03 M, 40 mmol
CH3NH2) and the mixture was heated to reflux for 8 h. The
mixture was concentrated in vacuo and the procedure was
repeated four times. After complete transformation the resi-
due was dissolved in CH2Cl2 (10 ml) and washed with a satu-
rated solution of NaHCO3 (2 ϫ 10 mL) and water (10 mL),
dried (MgSO4), filtered, and concentrated in vacuo to yield
pure methylamine 3b. Colorless oil, yield 0.125 g (88%).
C18H21NO2 (283.37). Ϫ HR-MS: calcd. 283.1572 found
283.1573. Ϫ MS (EI): m/z (%) = 283 (M, 2.7), 239 (M Ϫ
CH2NHCH3, 48), 206 (M Ϫ Ph, 4), 105 (PhCO, 96), 101 (O-
1
(CH2)2-CH-CH2-NH-CH3, 42). Ϫ H NMR (CDCl3): δ [ppm] =
1.28 (dtd, J = 12.8/2.4/1.8 Hz, 1H, 5-Hequat.), 1.84 (dtd, J =
12.8/11.6/6.1 Hz, 1H, 5-Haxial), 2.04 (s, broad, 1H, NH), 2.42
(s, 3H, NHCH3), 2.58 (dd, J = 12.2/3.7 Hz, 1H, CH2NH), 2.77
(dd, J = 12.2/7.9 Hz, 1H, CH2NH), 3.93 (td, J = 11.6/2.4 Hz,
Hpara), 7.36Ϫ7.42 (m, 4H, arom. Hortho), 7.48 (d, J = 8.8 Hz,
 2004 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim

74 Aepkers and Wünsch
Arch. Pharm. Pharm. Med. Chem. 2004, 337, 67−75
1H, 6-Haxial), 3.99 (ddd, J = 11.6/6.1/1.8 Hz, 1H, 6-Hequat.),
4.06 (dddd, J = 11.6/7.9/3.7/2.4 Hz, 1H, 4-Haxial), 7.07Ϫ7.21
(m, 4H, arom. Hmeta), 7.27Ϫ7.33 (m, 2H, arom. Hpara),
and water (10 mL), dried (MgSO4), filtered, and concentrated
in vacuo to afford pure piperidine 3e. Pale yellow oil, yield
0.163 g (96%). C22H27NO2 (337.46), calcd. C 78.3 H 8.06 N
4.15 found C 78.1 H 8.17 N 4.38. Ϫ MS (EI): m/z (%) = 337
(M, 4), 260 (M Ϫ Ph, 11), 155 (O-(CH2)2-CH-CH2-N(CH2)5,
63), 98 (CH2-N(CH2)5, 100). Ϫ 1H NMR (CDCl3): δ [ppm] =
1.42Ϫ1.50 (m, 2H, 4-Hpip.), 1.49 (dtd, J = 12.8/2.6/1.8 Hz,
1H, 5-Hequat.), 1.57Ϫ1.65 (m, 4H, 3-Hpip., 5-Hpip.), 1.86 (dtd,
J = 12.8/11.7/5.9 Hz, 1H, 5-Haxial), 2.44 (dd, J = 13.2/5.1 Hz,
1H, CH2N), 2.49 (dt, J = 11.4/5.5 Hz, 2H, 2-Hpip., 6-Hpip.), 2.57
(dt, J = 11.4/5.5 Hz, 2H, 2-Hpip., 6-Hpip.), 2.70 (dd, J = 13.2/
6.2 Hz, 1H, CH2N), 4.04 (td, J = 11.4/2.6 Hz, 1H, 6-Haxial),
4.10 (ddd, J = 11.4/5.9/1.8 Hz, 1H, 6-Hequat.), 4.12 (dddd, J =
11.7/6.2/5.1/2.6 Hz, 1H, 4-Haxial), 7.16Ϫ7.31 (m, 4H, arom.
7.38Ϫ7.47 (m, 4H, arom. Hortho). Ϫ IR (film): ν [cmϪ1] = 3334
˜
(N-H), 2948, 2877 (C-H), 2795 (C-H), 1102, 1028 (C-O), 749,
707 (aryl).
N-[(2,2-Diphenyl-1,3-dioxan-4-yl)methyl]butan-1-amine (3c)
A solution of 11 (0.21 g, 0.50 mmol) and butan-1-amine (4.0
mL, 40 mmol) in methanol (5 mL) was heated to reflux for 24
h. The solvent methanol and the excess of butan-1-amine
were evaporated in vacuo and the residue was dissolved in
CH2Cl2 (10 mL). The CH2Cl2 layer was washed with a satu-
rated solution of NaHCO3 (2 ϫ 10 mL), dried (MgSO4), fil-
tered and concentrated to yield pure butylamine 3c. Colorless
H
meta), 7.37Ϫ7.43 (m, 2H, arom. Hpara), 7.50Ϫ7.61 (m, 4H,
arom. Hortho). Ϫ IR (film): ν [cmϪ1] = 2932 (C-H), 2779 (C-H),
˜
solid, mp 42Ϫ44°C, yield 0.148
g (91%). C21H27NO2
1099 (C-O), 755, 707 (aryl).
(325.45), calcd. C 77.5 H 8.30 N 4.30 found C 77.3 H 8.35
N 4.13. Ϫ MS (EI): m/z (%) = 325 (M, 3), 248 (M Ϫ Ph,
8), 239 (M Ϫ CH2NHC4H9, 35), 143 (O-(CH2)2-CH-CH2-NH-
C4H9, 51), 105 (PhCO, 70). Ϫ 1H NMR (CDCl3): δ [ppm] =
0.95 (t, J = 7.3 Hz, 3H, NHCH2CH2CH2CH3), 1.36Ϫ1.43 (m,
Receptor binding studies
General
Teflon-glass-homogenizer: PotterS (B. Braun Biotech Inter-
national). Ϫ Rotor/stator homogenizer: Ultraturrax T25 basic
(Ika Labortechnik). Ϫ Centrifuge: High speed refrigerating
centrifuge model J2-HS (Beckman). Ϫ Filter: Whatman glass
fiber filters GF/B and GF/C presoaked in 1% (NMDA assay)
or 0.5% (1-assay) polyethylene imine (in water) for 2 h at 4°C
before use. Ϫ Filtration was performed with a Brandel 24-
well cell harvester. Ϫ Scintillation cocktail: Rotiszint eco plus
(Roth). Ϫ Liquid scintillation analyzer: Tri-Carb 2100 TR
(Canberra Packard), counting efficiency 66%. Ϫ All experi-
ments were carried out in triplicate. Ϫ IC50-values were deter-
mined from competition experiments with at least 6 concen-
trations of test compounds and were calculated with the
curve-fitting program GraphPad Prism 3.0 (GraphPad
Software) by nonlinear regression analysis. Ϫ Ki-values were
calculated according to Cheng and Prusoff [19]; KD ((+)-MK-
801) = 2.26 nM; KD ((+)-pentazocine) = 2.90 nM; for com-
pounds with high affinity (low Ki-values) mean values SEM
from at least three independent experiments are given.
1H, 5-Hequat.), 1.39 (sext,
NHCH2CH2CH2CH3), 1.55 (quint,
J
=
J
7.3 Hz, 2H,
= 7.3 Hz, 2H,
NHCH2CH2CH2CH3), 1.92 (dtd, J = 12.5/11.6/5.8 Hz, 1H, 5-
Haxial), 1.97 (s, broad, 1H, NH), 2.66 (dt, J = 11.3/7.3 Hz, 1H,
NHCH2CH2CH2CH3), 2.72 (dt,
J = 11.3/7.3 Hz, 1H,
NHCH2CH2CH2CH3), 2.72 (dd, J = 12.2/3.7 Hz, 1H, CH2NH),
2.90 (dd, J = 12.2/7.9 Hz, 1H, CH2NH), 4.02 (td, J = 11.6/2.7
Hz, 1H, 6-Haxial), 4.08 (ddd, J = 11.6/5.8/1.8 Hz, 1H, 6-
Hequat.), 4.14 (dddd, J = 11.6/7.9/3.7/2.4 Hz, 1H, 4-Haxial),
7.17Ϫ7.30 (m, 4H, arom. Hmeta), 7.36Ϫ7.42 (m, 2H, arom.
H
para), 7.47Ϫ7.56 (m, 4H, arom. Hortho). Ϫ IR (film): ν
˜
[cmϪ1] = 3351 (N-H), 2956, 2928, 2872 (C-H), 1099, 1025
(C-O), 751, 706 (aryl).
1-(2,2-Diphenyl-1,3-dioxan-4-yl)-N,N-dimethylmethanamine
(3d)
The tosylate 11 (0.21 g, 0.50 mmol) was dissolved in a solu-
tion of dimethylamine in ethanol (7.2 mL, 5.6 M, 40 mmol
(CH3)2NH2) and heated to reflux for 13 h. The volatile compo-
nents were removed in vacuo and the residue was dissolved
in CH2Cl2 (10 mL). The CH2Cl2 layer was washed with a satu-
rated solution of NaHCO3 (2 ϫ 10 mL), dried (MgSO4), fil-
tered, and concentrated in vacuo to afford pure dimethyl-
amine 3d. Colorless oil, yield 0.137 g (92%). C19H23NO2
(297.40). Ϫ HR-MS: calcd. 297.1729 found 297.1730. Ϫ MS
(EI): m/z (%) = 297 (M, 8), 239 (M Ϫ CH2N(CH3)2, 24), 220
(M Ϫ Ph, 13), 115 (O-(CH2)2-CH-CH2-N(CH3)2, 74), 105
(PhCO, 76). Ϫ 1H NMR (CDCl3): δ [ppm] = 1.46 (dtd, J =
12.7/2.4/2.0 Hz, 1H, 5-Hequat.), 1.88 (dtd, J = 12.7/11.2/6.3
Hz, 1H, 5-Haxial), 2.35 (s, 6H, N(CH3)2), 2.42 (dd, J = 13.2/
4.9 Hz, 1H, CH2N), 2.68 (dd, J = 13.2/6.8 Hz, 1H, CH2N),
4.05 (td, J = 11.2/2.4 Hz, 1H, 6-Haxial), 4.08 (ddd, J = 11.2/
6.3/2.0 Hz, 1H, 6-Hequat.), 4.05Ϫ4.15 (m, 1H, 4-Haxial),
7.16Ϫ7.32 (m, 4H, arom. Hmeta), 7.38Ϫ7.44 (m, 2H, arom.
Investigation of the affinity for the phencyclidine binding site
of the NMDA receptor [12, 13]
[3H]-(+)-MK-801 binding to pig brain cortex membrane prep-
arations was performed according to standard radioligand
binding assays, which were slightly modified as described be-
low.
Preparation of the tissue: Fresh pig cortex was homogenized
with a potter (500 rpm, 10 up-and-down strokes) in 10 vol-
umes of cold 0.32 M sucrose. The suspension was centri-
fuged at 1000 g for 10 min at 4°C. The supernatant was
separated and centrifuged at 10000 g for 20 min at 4°C. The
pellet was resuspended in buffer (5 mM Tris acetate with 1
mM EDTA, pH 7.5) with an Ultraturrax (8000 rpm) and centri-
fuged at 20000 g (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 [20] using bovine serum albumin as standard, and
subsequently the preparation was frozen (Ϫ83°C) in 5 mL
portions of about 1 mg protein/mL.
H
para), 7.52Ϫ7.61 (m, 4H, arom. Hortho). Ϫ IR (film): ν
˜
[cmϪ1] = 2944, 2874 (C-H), 2823, 2767 (C-H), 1099, 1026
(C-O), 754, 706 (aryl).
1-[(2,2-Diphenyl-1,3-dioxan-4-yl)methyl]piperidine (3e)
A solution of 11 (0.21 g, 0.50 mmol) and piperidine (4.0 mL,
40 mmol) in methanol (5 mL) was heated to reflux for 20 h.
The volatile components were evaporated in vacuo and the
residue was dissolved in CH2Cl2 (10 mL). The CH2Cl2 layer
was washed with a saturated solution of NaHCO3 (10 mL)
Performance of the assay: The test was performed with the
radioligand [3H]-(+)-MK-801 (832.5 GBq/mmol; (NEN TM Life
Science Products, Zaventem, Belgium). The thawed mem-
brane preparation (about 100 µg of the protein) was incu-
bated with various concentrations of test compounds, 2 nM
 2004 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim

Arch. Pharm. Pharm. Med. Chem. 2004, 337, 67−75
NMDA-Receptor Affinity of Dexoxadrol Derivatives 75
[3H]-(+)-MK-801, and buffer (5 mM Tris-acetate, 1 mM EDTA,
pH 7.5) in a total volume of 500 µL for 90 min at 25°C. The
incubation was terminated by rapid filtration through pre-
soaked Whatman GF/C filters (1% polyethylene imine in
water for 3 h at 4°C) using a cell harvester. After washing
four times with 2 mL of cold buffer 3 mL of scintillation cocktail
were added to the filters. After at least 8 h bound radioactivity
trapped on the filters was counted in a liquid scintillation ana-
lyzer. Nonspecific binding was determined with 10 µM (+)-
MK-801.
[3] D. Lodge in Excitatory Amino Acid Receptors Ϫ Design
of Agonists and Antagonists, (Eds. P. Krogsgaard-
Larsen, J. J. Hansen), Ellis Harwood Ltd., Chichester,
1992, pp 201Ϫ215.
[4] E. H. F. Wong, J. A. Kemp, Annu. Rev. Pharmacol. Tox-
icol. 1991, 31, 401Ϫ425.
[5] K. Yamada, T. Nabeshima, Drug News Persp. 1991,
524Ϫ529.
[6] H. Bräuner-Osborne, J. Egebjerg, E. O. Nielsen, U.
Madsen, P. Krogsgaard-Larsen, J. Med. Chem. 2000,
43, 2609Ϫ2645.
Investigation of the σ1-receptor affinity [16, 17]
[3H]-(+)-Pentazocine binding to guinea pig brain membrane
preparations was performed according to standard radioli-
gand binding assays [17], which were slightly modified as de-
scribed below.
[7] A. Thurkauf, M. V. Mattson, S. Richardson, S. Mirsad-
eghi, P. L. Ornstein, E. A. Harrison, Jr., K. C. Rice, A. E.
Jacobson, J. A. Monn, J. Med. Chem. 1992, 35,
1323Ϫ1329.
Membrane preparation: Thawed guinea pig brains (Dunkin
Harley, Harlan-Sera-Lab, Loughborough, UK) were homo-
genized with an Ultraturrax (8000 rpm) in 10 volumes of cold
0.32 M sucrose. The homogenate was centrifuged at 1000
g for 10 min at 4°C. The supernatant was separated and
centrifuged at 22000 g for 20 min at 4°C. The pellet was
resuspended in 10 volumes of buffer (50 mM Tris HCl, pH
7.4) with an Ultraturrax (8000 rpm), incubated for 30 min at
25°C and centrifuged at 22000 g (20 min, 4°C). The pellet
was resuspended in buffer, the protein concentration was de-
termined according to the method of Bradford [20] using bov-
ine serum albumin as standard, and subsequently the prep-
aration was frozen (Ϫ83°C) in 5 mL portions of about 2 mg
protein/mL.
[8] D. Seebach, A. K. Beck, R. Dahinden, M. Hoffmann, F.
N. M. Kuehnle, Croat. Chem. Acta 1996, 69, 459Ϫ484.
[9] Herein, the products formed by reaction of OH-groups
in different positions (1,2-; 1,3-; 1,4-) are termed re-
gioisomers.
[10] A.I. Meyers, J. P. Lawson, D. G. Walker, R. J. Linder-
man, J. Org. Chem. 1986, 51, 5111Ϫ5123.
[11] R. Brückner, Reaktionsmechanismen: Organische Reak-
tionen, Stereochemie, moderne Synthesemethoden,
Spektrum Akademischer Verlag, Heidelberg 1996, p
257f.
[12] R. M. McKernan, S. Castro, J. A. Poat, E. H. F. Wong,
J. Neurochem. 1989, 52, 777Ϫ785.
Performance of the assay: The test was performed with the
radioligand [ring-1,3-3H]-(+)-pentazocine (1036 GBq/mmol;
NENTM Life Science Products). The thawed membrane prep-
aration (about 150 µg of the protein) was incubated with vari-
ous concentrations of test compounds, 3 nM [3H]-(+)-penta-
zocine and buffer (50 mM Tris HCl, pH 7.4) in a total volume
of 500 µL for 150 min at 37°C. The incubation was terminated
by rapid filtration through presoaked Whatman GF/B filters
using a cell harvester. After washing four times with 2 mL of
cold buffer 3 mL of scintillation cocktail were added to the
filters. After at least 8 h bound radioactivity trapped on the
filters was counted in a liquid scintillation analyzer. Non-
specific binding was determined with 10 µM haloperidol.
[13] G. Höfner, K. T. Wanner, J. Rec. Sign. Transd. Res.
1996, 16, 297Ϫ313.
[14] C. Kaiser, J. J. Pontecorvo, R. E. Mewshaw, Neuro-
transmissions, 1991, 1Ϫ5.
[15] B. R. de Costa, L. Radesca, L. Di Paolo, W. D. Bowen,
J. Med. Chem. 1992, 35, 38Ϫ47.
[16] C. A. Maier, B. Wünsch, J. Med. Chem. 2002, 45,
438Ϫ448.
[17] D. L. DeHaven-Hudkins, L. C. Fleissner, F. Y. Ford-Rice,
Eur. J. Pharmacol. Mol. Pharmacol. Sect. 1992, 227,
371Ϫ378.
References
[18] W. Still, M. Kahn, A. Mitra, J. Org. Chem. 1978, 43,
2923Ϫ2925.
[1] W. R. Hardie, J. Hidalgo, I. F. Halverstadt, R. E. Allen,
J. Med. Chem. 1966, 9, 127Ϫ136.
[19] Y. Cheng, W. H. Prusoff, Biochem. Pharmacol. 1973,
22, 3099Ϫ3108.
[2] L. G. Mendelsohn, G. A. Kerchner, V. Kalra, D. M. Zim-
mermann, J. D. Leander, Biochem. Pharmacol. 1984,
33, 3529Ϫ3535.
[20] M. Bradford, Anal. Biochem. 1976, 72, 248Ϫ254.
 2004 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim