Novel σ receptor ligands. Part 2. SAR of spiro[[2]benzopyran-1,4′-piperidines] and spiro[[2]benzofuran-1,4′-piperidines] with carbon substituents in position 3

Article abstract of DOI:10.1021/jm020889p

Several spiro[[2]benzopyran-1,4′-piperidines] and spiro[[2]benzofuran-1,4′-piperidines] were synthesized and evaluated for their binding properties for σ₁ and σ₂ receptors. The key step for the introduction of a one carbon residue is the reaction of the cyclic methyl acetals 2a and 3a with trimethylsilyl cyanide to yield the nitriles 5 and 20. The reaction of the lactols 2b and 3b with stabilized phosphoranes affords spiropiperidines with a two carbon residue in position 3. In agreement with previously reported σ₁ and σ₂ receptor binding data, the investigated spiro compounds display higher affinity for σ₁ vs σ₂ receptors. Compounds with a cyano group in position 3 of the spirocycle show high σ₁ receptor affinity and selectivity. The spirobenzopyran nitrile 5 and the homologous spirobenzofuran nitriles 20 and 23 show almost identical σ₁ affinities, whereas the spirobenzopyran nitrile 13 with a methylene spacer is 10-fold less potent. Among the reported compounds, 1′-benzyl-3,4-dihydrospiro[[2]benzopyran-1,4′-piperidinel -3-carbonitrile 5 represents the most potent σ₁ receptor ligand with a K_i value of 1.54 nM and a σ₁/σ₂ selectivity ratio of 1030.

Full text of DOI:10.1021/jm020889p

J . Med. Chem. 2002, 45, 4923-4930
4923
Novel σ Recep tor Liga n d s. P a r t 2. SAR of Sp ir o[[2]ben zop yr a n -1,4′-p ip er id in es]
a n d Sp ir o[[2]ben zofu r a n -1,4′-p ip er id in es] w ith Ca r bon Su bstitu en ts in
P osition 3
Christoph A. Maier and Bernhard Wu¨nsch*
Pharmazeutisches Institut der Universita¨t Freiburg, Albertstrasse 25, D-79104 Freiburg i. Br., Germany
Received March 25, 2002
Several spiro[[2]benzopyran-1,4′-piperidines] and spiro[[2]benzofuran-1,4′-piperidines] were
synthesized and evaluated for their binding properties for σ1 and σ2 receptors. The key step
for the introduction of a one carbon residue is the reaction of the cyclic methyl acetals 2a and
3a with trimethylsilyl cyanide to yield the nitriles 5 and 20. The reaction of the lactols 2b and
3b with stabilized phosphoranes affords spiropiperidines with a two carbon residue in position
3. In agreement with previously reported σ1 and σ2 receptor binding data, the investigated
spiro compounds display higher affinity for σ1 vs σ2 receptors. Compounds with a cyano group
in position 3 of the spirocycle show high σ1 receptor affinity and selectivity. The spirobenzopyran
nitrile 5 and the homologous spirobenzofuran nitriles 20 and 23 show almost identical σ1
affinities, whereas the spirobenzopyran nitrile 13 with a methylene spacer is 10-fold less potent.
Among the reported compounds, 1′-benzyl-3,4-dihydrospiro[[2]benzopyran-1,4′-piperidine]-3-
carbonitrile 5 represents the most potent σ1 receptor ligand with a Ki value of 1.54 nM and a
σ1/σ2 selectivity ratio of 1030.
Ch a r t 1
In tr od u ction
σ Receptors were originally classified as subtypes of
the opioid class of receptors.1 Because most of the σ
receptor-mediated effects are not sensitive to the opioid
antagonist naloxone, this classification was discarded.2
Later, it became clear that σ receptors are a new family
of receptors consisting of σ1 and σ2 subtypes.3 Recently,
the σ1 receptor has been cloned.4-6 The amino acid
sequence displays no homology to any other known
mammalian protein but shows 30% identity to the yeast
enzyme sterol C8-C7 isomerase.7 The cloned receptor
is likely to possess one transmembrane domain. The σ2
receptor has not been cloned yet. At present, neuro-
steroids such as progesterone are thought to be the
endogenous ligands for σ1 receptors.8 The biochemical
and physiological role of σ receptors and the mechanism
of signal transduction are not completely understood so
far.9 Yet, they seem to be involved in pathophysiological
processes such as psychosis, depression, and uncon-
trolled cell proliferation. Therefore, potential applica-
tions of σ receptor ligands are, for example, in the
treatment of psychosis, depression, acute and chronic
neurodegeneration, and cancer.10 Some compounds are
already in clinical trials for the treatment of psychosis
(e.g., BMY-14802)11 and depression (e.g., E-5842).12 The
well-known highly potent antipsychotic haloperidol
turned out to be a highly potent σ receptor ligand
(compare Table 1).
of the prepared spiropiperidines 1 regarding σ1 and σ2
receptors. Compounds with the benzyl residue in posi-
tion 1′ of the spiropiperidine ring system revealed the
highest σ1 receptor affinity. Some compounds with
appropriate substituents in position 3, especially 2a and
3a with the methoxy group, displayed high σ1/σ2 selec-
tivities (compare Tables 1 and 2).13 As a continued effort
to further characterize the structure-affinity relation-
ships within this class of compounds, we modified the
substituents in position 3 of the spiro compounds 1.
Herein, we report on the preparation and in vitro
evaluation of novel spiropiperidines 4 (n ) 0, 1) with
carbon-carbon connected residues in position 3 and the
benzyl group in position 1′.
Ch em istr y
In Part 1,13 we described the synthesis of novel spiro-
[[2]benzopyran-1,4′-piperidines] 1 (n ) 1) and spiro[[2]-
benzofuran-1,4′-piperidines] 1 (n ) 0) with different
oxygen substituents connected to position 3 and various
residues in position 1′ (e.g., m ) 0-4, compare Chart
1). We also discussed structure-affinity relationships
Recently, we described the synthesis of the spiro[[2]-
benzopyran-1,4′-piperidines] 2a ,b.13 Proceeding from
both compounds, we synthesized a second series of com-
pounds containing one or two carbon residues in position
3 of the spirocyclic ring system. The introduction of a
one carbon residue succeeded by the reaction of 2a with
trimethylsilyl cyanide in the presence of the Lewis acid
boron trifluoride diethyl ether complex (BF3‚Et2O)14 at
-25 °C to afford the nitrile 5 in 23% yield and the
* To whom correspondence should be addressed. Tel: +49-761-203-
6320. Fax: +49-761-203-6321. E-mail: bernhard.wuensch@pharmazie.
uni-freiburg.de.
10.1021/jm020889p CCC: $22.00 © 2002 American Chemical Society
Published on Web 10/02/2002

4924 J ournal of Medicinal Chemistry, 2002, Vol. 45, No. 22
Maier and Wu¨nsch
Sch em e 1a
Sch em e 2a
a
Reagents and conditions: (a) Ph3PdCHCO2Et (10), CH3CN,
reflux. (b) NaOtBu, CH2Cl2, room temperature (50%). (c) Ph3Pd
CHCO2Et (10), toluene, reflux (67%). (d) (EtO)2P(O)CH2CN,
Cs2CO3, THF, reflux (77%). (e) DIBAL, toluene, -78 °C; NH4Cl
(42%).
Sch em e 3a
a
Reagents and conditions: (a) Trimethylsilyl cyanide, BF3‚Et2O,
CH2Cl2, -25 °C (5, 23%) or trimethylsilyl cyanide, tetracyano-
ethylene, CH3CN, reflux (5, 30%). (b) EtOH, H2SO4, reflux (60%).
(c) LiAlH4, Et2O, -15 °C (31%). (d) DIBAL, toluene, -78 °C and
then NH4Cl (14%). (e) LiAlH4, Et2O, -15 °C (33%).
alkene 613 in 44% yield (Scheme 1). To prevent the
elimination of methanol that leads to the formation of
the benzopyran 6 and to improve the yield of 5, we
looked for alternative methods. Instead of BF3‚Et2O, the
neutral catalyst tetracyanoethylene was used.15 In this
case, heating of the reaction mixture for a prolonged
time was necessary for completion of the transforma-
tion. The yield of 5 could be improved from 23 to 30%.
The nitrile 5 was transformed into the ester 7 in 60%
yield by refluxing in a mixture of concentrated H2SO4
and ethanol. The synthesis of the methanol derivative
8 succeeded in two ways. Reduction of the ester 7 with
LiAlH4 afforded 8 in 31% yield. It was also possible to
reduce 5 with diisobutylaluminum hydride (DIBAL)16
in toluene to give the unstable aldehyde 9, which was
subsequently reduced with LiAlH4, leading to 8 (33%
yield).
The introduction of a two carbon residue in position
3 of the spirocyclic system was possible starting from
the lactol 2b (Scheme 2). Thus, 2b was refluxed with
ethoxycarbonylmethylene triphenylphosphorane (10)17
in acetonitrile. Under these conditions, two products
were isolated, the R,â-unsaturated ester 11 and the
cyclized ester 12. Sodium tert-butoxide catalyzed the
intramolecular Michael reaction of 11 to yield the spiro
compound 12. If the reaction of 2b with the Wittig
reagent 10 was conducted in toluene at reflux temper-
ature, the only product obtained was 12 in 67% yield.
This tandem reaction comprises the three steps ring
opening of the lactol to afford the hydroxyaldehyde,
Wittig reaction, and intramolecular Michael addition.
The ethanenitrile 13 was prepared by the Horner-
a
Reagents and conditions: (a) LiAlH4, Et2O, -15 °C (96%). (b)
CH3SO2Cl, Et3N, CH2Cl2, -10 °C. (c) LiAlH4, THF, reflux (40%, 2
steps). (d) CH3NH2, EtOH, room temperature (99%). (e) LiAlH4,
Et2O, CH2Cl2, -35 °C (40%).
Emmons variation of the Wittig reaction using diethyl
cyanomethylphosphonate in tetrahydrofuran (THF) and
cesium carbonate as base.18 The nitrile 13 was trans-
formed into the aldehyde 14 by reduction with DIBAL
in 42% yield.
The ester 12 was converted into the alcohol 15 by
reduction with LiAlH4 in diethyl ether (Scheme 3). The
hydroxy group of 15 was removed in two steps.19
Activation of 15 with methanesulfonyl chloride afforded
the mesylate 16, and subsequent nucleophilic substitu-

Novel σ Receptor Ligands
J ournal of Medicinal Chemistry, 2002, Vol. 45, No. 22 4925
Sch em e 4a
Sch em e 5a
a
Reagents and conditions: (a) Trimethylsilyl cyanide, tetra-
cyanoethylene, CH3CN, reflux (68%). (b) EtOH, H2SO4, reflux
(39%). (c) LiAlH4, Et2O, -15 °C (75%).
a
Reagents and conditions: (a) Ph3PdCHCN, Cs2CO3, toluene,
reflux (76%). (b) Ph3PdCHCO2Et (10), Cs2CO3, toluene, reflux
(88%). (c) LiAlH4, Et2O, -15 °C (75%).
tion with LiAlH4 led to the ethyl derivative 17. An
amino group was introduced by aminolysis of the ester
12 to yield the amide 18, which was reduced with
LiAlH4 to give the secondary amine 19.
an excess of nontritiated 1,3-di(o-tolyl)guanidine re-
sulted in the nonspecific binding of the radioligand.13
The introduction of carbon residues in position 3 of
the spiro[[2]benzofuran-1,4′-piperidines] was performed
in a similar way to the spirobenzopyrans (Scheme 4).
Treatment of the cyclic methyl acetal 3a with trimeth-
ylsilyl cyanide and tetracyanoethylene in acetonitrile
provided the nitrile 20. Tetracyanoethylene was used
because the yield of the nitrile 5 in the spirobenzopyran
series was higher using tetracyanoethylene than with
BF3‚Et2O. In contrast to the spirobenzopyran analogue
2a , elimination of methanol is not possible so that no
side product can arise; therefore, the yield was more
than doubled (68% for 20 vs 30% for 5). The nitrile 20
was transformed into the ester 21 by refluxing with
EtOH/H2SO4. The ester 21 was subsequently reduced
with LiAlH4 to yield the methanol derivative 22.
Resu lts a n d Discu ssion
The σ receptor affinities of the spiro[[2]benzopyran-
1,4′-piperidines] with various substituents R in position
3 are shown in Table 1. For comparison, the Ki values
of two compounds (2a ,b) described in Part 113 are
included in Table 1. Additionally, the Ki values of the
three reference compounds haloperidol, ditolylguani-
dine, and BMY-14802 are given.
Ta ble 1. σ Receptor Affinities of Spiro[[2]benzopyran-1,4′-
piperidines] with Various Substituents R in Position 3
Proceeding from the lactol 3b, reaction with the
Wittig reagent cyanomethylene triphenylphosphorane
directly yielded the ethanenitrile 23. An R,â-unsatur-
ated nitrile analogous to 11 was not detected, as the
base cesium carbonate was added (Scheme 5). To obtain
the ester 24, the lactol 3b was reacted with the Wittig
reagent 10. The ester 24 was reduced with LiAlH4 to
afford the alcohol 25.
Ki ( SEM (nM)a
σ1/σ2
compd
R
σ1
σ2
selectivity
2a
2b
5
13
7
12
8
15
17
18
19
14
OCH3
OH
CN
CH2CN
CO2Et
1.29 ( 0.18b 3500 ( 352b
2710
236
1030
295
1130
124
292
668
333
200
29
2.17 ( 0.40b
1.54 ( 0.31
15.9 ( 4.04
513 ( 71.6b
1590 ( 388
4700 ( 129
9.33 ( 2.08 10 540 ( 2190
183 ( 25.9 22 700 ( 1730
CH2CO2Et
CH2OH
CH2CH2OH
CH2CH3
7.16 ( 0.66
12.7 ( 2.60
11.7 ( 2.55
2089 ( 606
8460 ( 280
3900 ( 1270
Recep tor Bin d in g Stu d ies
The σ receptor affinities of the spiropiperidines were
determined in radioligand binding experiments. In the
σ1 assay, homogenates of guinea pig brains were used
as receptor material. The σ1 selective compound [3H]-
(+)-pentazocine was employed as radioligand, and the
nonspecific binding was determined in the presence of
a large excess of haloperidol.13 A rat liver membrane
preparation served as a source for σ2 receptors in the
σ2 assay. Because a σ2 selective radioligand is not
available, the nonselective radioligand [3H]ditolylguani-
dine was employed in the presence of nonradiolabeled
(+)-pentazocine (100 nM) for selective masking of σ1
receptors. Performing the σ2 assay in the presence of
CH2CONHCH3 170 ( 17.2 34 000 ( 7480
CH2CH2NHCH3 148 ( 0.33
4360 ( 1100
9910 ( 3260
CH2CHO
55.1 ( 12.8
180
haloperidol
2.20 ( 0.31
34.2 ( 2.3
63.9 ( 10.8
391 ( 62
16
0.4
1.5
ditolylguanidine 164 ( 47
BMY-14802 265 ( 32
a
Ki values ( SEM from three independent experiments. Ra-
dioligands and tissues used for receptor binding studies were as
follows: σ1, [3H]-(+)-pentazocine (guinea pig brain); σ2, [3H]-
ditolylguanidine in the presence of 100 nM (+)-pentazocine (rat
b
liver). Ref 13.
Generally, the σ2 receptor affinities of all of the
investigated spiropiperidines are lower than their σ1

4926 J ournal of Medicinal Chemistry, 2002, Vol. 45, No. 22
Maier and Wu¨nsch
receptor affinities. Among the test compounds with a
one carbon residue in position 3, the nitrile 5 displays
the highest affinity to σ1 (Ki ) 1.54 nM) and σ2 (Ki )
1590 nM) receptors. The σ1 affinity is somewhat lower
as compared to the methoxy derivative 2a , but the σ1/
σ2 selectivity is still very high (1030-fold). In comparison
with 5, the homologous ethanenitrile 13 is about 10-
fold less potent at σ1 receptors (Ki ) 15.9 nM). Trans-
formation of the homologous nitriles 5 and 13 into their
ethyl esters 7 and 12 led to a reduced σ1 and σ2 receptor
affinity, respectively. However, the σ1/σ2 selectivity of
the ester 7 is still very high (1130-fold). Reduction of
the ester moieties of 7 and 12 afforded the smaller
alcohols 8 (Ki ) 7.16 nM) and 15 (Ki ) 12.7 nM), respec-
tively, with increased σ1 receptor affinities. The lactol
2b without a methylene spacer moiety shows an even
smaller Ki value (2.17 nM). Apparently, the σ1 receptor
affinity is diminished by an increase of the substituent’s
volume in position 3. The ethyl derivative 17 (R )
CH2CH3, Ki ) 11.7 nM) displays an almost 10-fold lower
affinity for σ1 receptors than the bioisosteric methoxy
derivative 2a (R ) OCH3, Ki ) 1.29 nM). The methanol
derivative 8 (R ) CH2OH) with the hydroxymethyl
group in position 3 binds σ1 receptors less effectively
than the methoxy counterpart 2a . These observations
indicate that the presence and the position of the oxygen
atom in the C-3 substituent are important for high σ1
receptor affinity. On the other hand, the σ2 receptor
affinities of 2a , 8, and 17 are quite similar.
receptor affinity of the spirobenzofurans (Ki ) 2.18 and
2.16 nM, respectively). Surprisingly, the additional
methylene spacer group of 23 does not influence con-
siderably the interaction with σ1 receptors. In this case,
the cyano group is decisive for high σ1 receptor affinity.
The σ1 receptor affinities of the nitriles 20 and 23 are
somewhat decreased in comparison with the methoxy
derivative 3a (Ki ) 1.14 nM).
The difference in receptor affinity of the homologous
esters 21 (Ki ) 8.95 nM) and 24 (Ki ) 15.1 nM) is much
lower than in the 2-benzopyran series. The acetic acid
ester 24 is 12-fold more potent than the corresponding
derivative 12 of the spirobenzopyran series. In the
2-benzofuran series as well as in the 2-benzopyran
series, the nitriles show good σ1 receptor affinities,
which are decreased in the corresponding esters. The
σ1 affinity is improved again when the esters are
reduced to the respective alcohols. The homologous
alcohols 3b (Ki ) 7.33 nM), 22 (Ki ) 5.66 nM), and 25
(Ki ) 7.27 nM) display very similar σ1 affinities, whereas
in the 2-benzopyran series a significant decrease in σ1
receptor binding is observed with insertion of methylene
spacer groups between the spiropiperidine and the
hydroxy group (compounds 2b, 8, and 15, Table 1). The
σ2 receptor affinities of the 2-benzofurans are generally
lower than their σ1 receptor affinities, but they tend to
be higher as compared to the corresponding 2-benzopy-
ran derivatives.
Con clu sion
The σ1 receptor affinities of ester 12 (Ki ) 183 nM)
and amide 18 (Ki ) 170 nM) are almost identical. The
secondary amine 19 displays a somewhat higher σ1
affinity (Ki ) 148 nM) as compared to the ester 12 and
the amide 18. The acetaldehyde derivative 14 (Ki ) 55.1
nM) exhibits a 4-fold lower affinity for σ1 receptors than
the ethanol derivative 15.
In this paper, we have presented novel spiropi-
peridines with carbon substituents in position 3. Some
of these compounds display high affinity and selectivity
for σ1 receptors. In particular, the compounds 5, 20, and
23 bearing a cyano group bind with high affinity to σ1
receptors. The carbonitrile 5 reveals the highest σ1
affinity and additionally very high σ1 selectivity. A
distance of one or two carbon atoms between the cyano
group and the phenyl moiety of the spirocyclic 2-ben-
zopyrans or 2-benzofurans seems to be the optimum for
σ1 receptor binding. The σ receptor binding profiles of
the nitriles 5 and 20 are similar to those of the
corresponding methoxy derivatives 2a and 3a ,13 respec-
tively. These results demonstrate the remarkable simi-
larity of the methoxy and the cyano moiety within this
class of σ receptor ligands. In contrast to the acetalic
methoxy derivatives 2a and 3a , the nitriles 5 and 20
represent stable compounds, which are not hydrolyzed
or isomerized in acidic solvents.
Ta ble 2. σ Receptor Affinities of Spiro[[2]benzofuran-1,4′-
piperidines] with Various Substituents R in Position 3
Ki ( SEM (nM)a
σ1/σ2
compd
R
σ1
σ2
selectivity
3a
3b
20
23
21
24
22
25
OCH3
OH
CN
CH2CN
CO2Et
CH2CO2Et
CH2OH
1.14 ( 0.22b,c 1280 ( 137c
1130
104
352
768
796
449
349
348
7.33 ( 0.60c
2.18 ( 0.45b
2.16 ( 0.50
8.95 ( 1.57
15.1 ( 3.45
5.66 ( 1.13
761 ( 13.0c
766 ( 149
1660 ( 424
7130 ( 1390
6770 ( 2000
1980 ( 857
2530 ( 427
Exp er im en ta l Section
Gen er a l. Moisture sensitive reactions were conducted
under dry nitrogen. THF, Et2O, and toluene were distilled from
sodium/benzophenone ketyl, CH2Cl2 from CaH2, and CH3CN
from P2O5 prior to use. Thin-layer chromatography (TLC) was
conducted with Merck silica gel 60 F254 plates. Flash chroma-
tography20 was conducted with Merck silica gel 60, 0.040-
0.063 mm, and the terms in parentheses for flash chromato-
graphy include the following: diameter of the column (cm),
eluent, fraction size (mL), Rf. Melting points were determined
with an SMP 2 (Stuart Scientific) and are uncorrected.
Elemental analyses were conducted with an VarioEL (Elemen-
taranalysesysteme GmbH). The mass spectrometer used was
model 5989A (Hewlett-Packard) and models MAT 312, MAT
8200, MAT 44, and TSQ 7000 (Finnigan). The ionization
method used was electron impact (EI) at 70 eV. IR spectra
CH2CH2OH 7.27 ( 0.43
a
Ki values ( SEM from three independent experiments, except
when specified. Radioligands and tissues used for receptor binding
studies were as follows: σ1, [3H]-(+)-pentazocine (guinea pig brain);
σ2, [3H]-ditolylguanidine in the presence of 100 nM (+)-pentazocine
b
(rat liver). Four independent experiments. c Ref 13.
The σ receptor affinities of the five-membered 2-ben-
zofuran derivatives are shown in Table 2. For compari-
son, the Ki values of two compounds (3a ,b) described
in Part 113 are additionally listed in Table 2. The
homologous nitriles 20 and 23 reveal the highest σ1

Novel σ Receptor Ligands
J ournal of Medicinal Chemistry, 2002, Vol. 45, No. 22 4927
were obtained from a Perkin-Elmer 1605 FT-IR spectropho-
0.19 mmol) was dissolved in Et2O (5 mL) under nitrogen. This
solution was cooled to -15 °C, and a solution of LiAlH4 (1 M
in THF, 0.29 mL, 0.29 mmol) was slowly added. After 1 h, the
mixture was hydrolyzed by addition of H2O. The salts were
filtered off and washed with EtOAc. The organic layer was
dried (Na2SO4) and concentrated under reduced pressure. The
crude product was purified by flash chromatography (1 cm,
petroleum ether:EtOAc 1:1, 5 mL, Rf ) 0.03) to afford a
colorless oil, yield 19 mg (31%).
1
tometer, and wavenumbers are given in cm-1. H NMR (300
MHz) and 13C NMR (75 MHz) spectra were recorded on a
Varian Unity 300 NMR spectrometer operating at 27 °C.
Chemical shifts (δ) are reported in ppm downfield from
tetramethylsilane. Coupling constants (J ) are given with 0.5
Hz resolution. The assignments of 1H NMR and 13C NMR
signals were supported by two-dimensional (2D) NMR tech-
niques (correlation spectroscopy, COSY).
1′-Ben zyl-3,4-d ih yd r osp ir o[[2]ben zop yr a n -1,4′-p ip er i-
din e]-3-car bon itr ile (5) an d 1′-Ben zylspir o[[2]ben zopyr an -
1,4′-p ip er id in e] (6).13 Tetracyanoethylene (13 mg, 0.1 mmol)
was dissolved in CH3CN (1 mL) under nitrogen. Then, a
solution of 2a (108 mg, 0.33 mmol) in CH3CN (1 mL) was added
and the mixture was stirred at room temperature for 5 min.
Trimethylsilyl cyanide (0.1 mL) was then added, and the
reaction mixture was refluxed. Six further portions of tri-
methylsilyl cyanide (0.1 mL each) were added over a period of
15 h. When the reaction was completed, the solvent was
removed under reduced pressure, and the residue was dis-
solved in CH2Cl2. Then, some silica gel was added and the
suspension was concentrated under reduced pressure. The
residue was purified by flash chromatography (2 cm, petroleum
ether:EtOAc ) 3:1, 10 mL).
Fraction 1 (Rf ) 0.16) contained 613 (42 mg, 42%) as a
colorless oil, which solidified on standing; fraction 2 contained
the nitrile 5 (Rf ) 0.05) as a colorless oil, yield 32 mg (30%).
IR (film): ν˜ (cm-1) ) 2938, 2817 (C-H); 2214 (CtN); 1097,
1044 (C-O); 732, 700 (C-H). 1H NMR (CDCl3): δ (ppm) 1.85-
2.01 (m, 3 H, N(CH2CH2)2), 2.20 (td, J ) 12.8, 4.3 Hz, 1 H,
N(CH2CH2)2), 2.43 (td, J ) 11.0, 2.7 Hz, 1 H, N(CH2CH2)2),
2.54 (td, J ) 12.5, 2.3 Hz, 1 H, N(CH2CH2)2), 2.71-2.84 (m, 2
H, N(CH2CH2)2), 3.03 (dd, J ) 15.9, 3.4 Hz, 1 H, ArCH2CH),
3.27 (dd, J ) 15.9, 9.8 Hz, 1 H, ArCH2CH), 3.56 (d, J ) 13.1
Hz, 1 H, NCH2Ph), 3.61 (d, J ) 13.1 Hz, 1 H, NCH2Ph), 4.71
(dd, J ) 9.8, 3.4 Hz, 1 H, ArCH2CH), 7.11 (d, J ) 7.0 Hz, 1 H,
arom), 7.14-7.42 (m, 8 H, arom). 13C NMR (CDCl3): δ (ppm)
33.4 (1 C, ArCH2CH), 36.1 (1 C, N(CH2CH2)2), 38.3 (1 C,
N(CH2CH2)2), 48.9 (1 C, N(CH2CH2)2), 49.0 (1 C, N(CH2CH2)2),
58.3 (1 C, ArCH2CH), 63.2 (1 C, NCH2Ph), 76.1 (1 C, ArCO),
118.6 (1 C, CN), 125.5 (1 C, arom CH), 126.9 (1 C, arom CH),
127.0 (1 C, arom CH), 127.4 (1 C, arom CH), 128.2 (2 C, arom
CH), 128.6 (1 C, arom CH), 129.2 (2 C, arom CH), 129.8 (1 C,
arom C), 138.5 (1 C, arom C), 140.2 (1 C, arom C). MS (EI):
m/z 318 [M+], 227 [M+ - CH2Ph], 91 [CH2Ph+]. HRMS: calcd
for C21H22N2O, 318.1732; found, 318.1733.
P r oced u r e 2. Compound 5 (94 mg, 0.28 mmol) was dis-
solved in anhydrous toluene (5 mL) under nitrogen. This
solution was cooled to -78 °C, and a solution of DIBAL (1 M
in cyclohexane, 0.45 mL, 0.45 mmol) was slowly added. After
1.5 h at -78 °C, a saturated aqueous solution of NH4Cl (3 mL)
was added. This mixture was stirred for 1 h at room temper-
ature. Then, an aqueous solution of NaOH (2 M) was added
to give pH 10 and the mixture was extracted with EtOAc. The
organic layer was dried (Na2SO4) and concentrated under
reduced pressure at 30 °C. The crude product was purified by
flash chromatography (1 cm, petroleum ether:EtOAc ) 3:2, 5
mL, Rf ) 0.06) to afford a colorless oil, yield 13 mg (14%). The
aldehyde 9 was immediately reduced to yield the alcohol 8.
1′-Ben zyl-3,4-d ih yd r osp ir o[[2]ben zop yr a n -1,4′-p ip er i-
d in e]-3-ca r ba ld eh yd e (9). IR (film): ν˜ (cm-1) 2923, 2814 (C-
H); 1738 (CdO); 1107, 1074, 1046 (C-O); 756, 734, 699 (C-
H). 1H NMR (CDCl3): δ (ppm) 1.77 (dd, J ) 13.7, 2.4 Hz, 1 H,
N(CH2CH2)2, 1.87-2.05 (m, 2 H, N(CH2CH2)2, 2.25 (td, J )
13.1, 4.9 Hz, 1 H, N(CH2CH2)2), 2.42 (td, J ) 11.0, 3.7 Hz, 1
H, N(CH2CH2)2), 2.59 (td, J ) 12.2, 2.1 Hz, 1 H, N(CH2CH2)2),
2.70-2.83 (m, 2 H, N(CH2CH2)2), 2.84-2.90 (m, 2 H, ArCH2-
CH), 3.59 (s, 2 H, NCH2Ph), 4.17 (dd, J ) 8.5, 6.4 Hz, 1 H,
ArCH2CH), 7.07-7.40 (m, 9 H, arom), 9.84 (s, 1 H, CHO).
Compound 9 (6 mg, 0.019 mmol) was dissolved in Et2O (4
mL) under nitrogen. This solution was cooled to -15 °C, and
a solution of LiAlH4 (1 M in THF, 0.03 mL, 0.03 mmol) was
slowly added. After 1 h, the mixture was hydrolyzed by
addition of 2 drops of H2O. The salts were filtered off and
washed with Et2O. The organic layer was removed under
reduced pressure. The crude product was purified by flash
chromatography (0.8 cm, petroleum ether:EtOAc ) 1:1, 5 mL,
Rf ) 0.03) to afford a colorless oil, yield 2 mg (33%).
Com p ou n d 8. IR (film): ν˜ (cm-1) 3430 (O-H); 2924, 2812
1
(C-H); 1104, 1047 (C-O); 757, 699 (C-H). H NMR (CDCl3):
δ (ppm) 1.72 (dd, J ) 13.4, 2.7 Hz, 1 H, N(CH2CH2)2, 1.91 (td,
J ) 12.6, 4.3 Hz, 1 H, N(CH2CH2)2, 2.08 (dd, J ) 14.3, 2.7 Hz,
1 H, N(CH2CH2)2, 2.25 (td, J ) 12.5, 4.6 Hz, 1 H, N(CH2CH2)2),
2.36 (td, J ) 12.5, 2.7 Hz, 1 H, N(CH2CH2)2), 2.47 (dd, J )
11.6, 2.7 Hz, 1 H, N(CH2CH2)2), 2.57 (dd, J ) 15.9, 2.7 Hz, 1
H, ArCH2CH), 2.72-2.83 (m, 2 H, N(CH2CH2)2), 2.80 (dd, J )
15.9, 11.3 Hz, 1 H, ArCH2CH), 3.59 (s, 2 H, NCH2Ph), 3.69
(dd, J ) 11.3, 7.0 Hz, 1 H, CHCH2OH), 3.81 (dd, J ) 11.3, 3.1
Hz, 1 H, CHCH2OH), 3.88-3.98 (m, 1 H, ArCH2CHCH2OH),
7.09 (d, J ) 7.3 Hz, 1 H, arom), 7.12-7.41 (m, 8 H, arom). MS
(EI): m/z 323 [M+], 232 [M+ - CH2Ph], 91 [CH2Ph+]. HRMS:
calcd for C21H25NO2, 323.1885; found, 323.1876.
Eth yl 1′-Ben zyl-3,4-d ih yd r osp ir o[[2]ben zop yr a n -1,4′-
p ip er id in e]-3-ca r boxyla te (7). A solution of 5 (84 mg, 0.26
mmol) in EtOH (3 g), H2O (65 mg), and concentrated H2SO4
(1 g) was refluxed for 11.5 h. Then, an aqueous solution of
NaOH (3 M) was added to give pH 10 and the mixture was
extracted with CH2Cl2. The organic layer was dried (Na2SO4),
and the solvent was removed under reduced pressure. The
crude product was purified by flash chromatography (1 cm,
petroleum ether:EtOAc ) 3:1, 10 mL, Rf ) 0.06) to afford a
colorless oil, yield 58 mg (60%). IR (film): ν˜ (cm-1) ) 2939,
2816 (C-H); 1743 (CdO); 1112, 1045 (C-O); 741, 699 (C-H).
1H NMR (CDCl3): δ (ppm) 1.33 (t, J ) 7.3 Hz, 3 H, OCH2CH3),
1.81 (dd, J ) 13.7, 2.8 Hz, 1 H, N(CH2CH2)2, 1.94 (dd, J )
12.2, 4.3 Hz, 1 H, N(CH2CH2)2, 2.02 (dd, J ) 14.3, 2.8 Hz, 1
H, N(CH2CH2)2, 2.21 (td, J ) 12.5, 4.9 Hz, 1 H, N(CH2CH2)2),
2.44 (td, J ) 11.9, 3.1 Hz, 1 H, N(CH2CH2)2), 2.60 (td, J )
11.3, 2.4 Hz, 1 H, N(CH2CH2)2), 2.66-2.81 (m, 2 H, N(CH2-
CH2)2), 2.94 (dd, J ) 15.9, 3.4 Hz, 1 H, ArCH2CH), 3.08 (dd, J
) 15.9, 11.3 Hz, 1 H, ArCH2CH), 3.55 (d, J ) 12.8 Hz, 2 H,
NCH2Ph), 3.60 (d, J ) 12.8 Hz, 2 H, NCH2Ph), 4.24-4.31 (m,
2 H, OCH2CH3), 4.35 (dd, J ) 11.3, 3.4 Hz, 1 H, ArCH2CH),
7.10 (d, J ) 7.0 Hz, 1 H, arom), 7.12-7.40 (m, 8 H, arom). MS
(EI): m/z 365 [M+], 274 [M+ - CH2Ph], 91 [CH2Ph+]. HRMS:
Eth yl (E)-4-[2-(1-Ben zyl-4-h yd r oxyp ip er id in -4-yl)p h en -
yl]bu t-2-en oate (11) an d Eth yl 2-(1′-Ben zyl-3,4-dih ydr ospi-
r o[[2]ben zop yr a n -1,4′-p ip er id in ]-3-yl)a ceta te (12). P r o-
ced u r e 1. A solution of the lactol 2b (93 mg, 0.30 mmol) and
Ph3PdCHCO2Et (10) (157 mg, 0.45 mmol) in CH3CN (3 mL)
was refluxed for 40 h. The solvent was removed under reduced
pressure. The residue was purified by flash chromatography
(2 cm, petroleum ether:EtOAc ) 1:2, 10 mL). Fraction 1 (Rf )
0.26) contained compound 12 as colorless oil (6 mg, 5%),
fraction 3 (Rf ) 0.05) contained the R,â-unsaturated ester 11
as colorless oil (36 mg, 31%), and fraction 2 contained a
mixture of 11 and 12 (53 mg, 46%).
P r oced u r e 2. A mixture of 11 (36 mg, 0.09 mmol) and
NaOtBu (3 mg) in CH2Cl2 (2 mL) was stirred for 24 h at room
temperature. A saturated aqueous solution of NaCl (2 mL) was
added, and the mixture was extracted with CH2Cl2. The
organic layer was dried (Na2SO4) and concentrated under
reduced pressure. Flash chromatography (1 cm, petroleum
calcd for C23H27NO3, 365.1991; found, 365.1993. Anal. (C23H27
-
NO3) N; C: calcd, 75.6; found, 75.1; H: calcd, 7.45; found, H
8.15.
(1′-Ben zyl-3,4-d ih yd r osp ir o[[2]ben zop yr a n -1,4′-p ip er i-
d in ]-3-yl)m eth a n ol (8). P r oced u r e 1. Compound 7 (69 mg,

4928 J ournal of Medicinal Chemistry, 2002, Vol. 45, No. 22
Maier and Wu¨nsch
ether:EtOAc ) 1:1, 5 mL, Rf ) 0.10) afforded 12 as colorless
oil, yield 17 mg (50%).
ArCH2CH (2 H), CHCH2CHO (1 H)), 3.57 (s, 2 H, NCH2Ph),
4.27-4.37 (m, 1 H, CHCH2CHO), 7.07 (d, J ) 6.7 Hz, 1 H,
arom), 7.12-7.41 (m, 8 H, arom), 9.93 (t, J ) 2.2 Hz, 1 H,
CHCH2CHO). MS (EI): m/z 335 [M+], 244 [M+ - CH2Ph], 91
[CH2Ph+]. HRMS: calcd for C22H25NO2, 335.1885; found,
335.1883.
P r oced u r e 3. A solution of the lactol 2b (217 mg, 0.70
mmol) and Ph3PdCHCO2Et (10) (489 mg, 1.4 mmol) in
anhydrous toluene (10 mL) was refluxed for 32 h. The solvent
was removed under reduced pressure. The residue was purified
by flash chromatography (2 cm, petroleum ether:EtOAc ) 2:1,
10 mL, Rf ) 0.07) to afford 12 as colorless oil, yield 179 mg
(67%).
2-(1′-Ben zyl-3,4-d ih yd r osp ir o[[2]b en zop yr a n -1,4′-p i-
p er id in ]-3-yl)eth a n ol (15). Compound 12 (200 mg, 0.53
mmol) was dissolved in Et2O (5 mL) under nitrogen. This
solution was cooled to -15 °C, and a solution of LiAlH4 (1 M
in THF, 1.3 mL, 1.3 mmol) was slowly added. After 2 h, the
mixture was hydrolyzed by addition of H2O and subsequently
extracted with EtOAc. The organic layer was dried (Na2SO4)
and concentrated under reduced pressure. The crude product
(207 mg) was purified by flash chromatography (2 cm, petro-
leum ether:EtOAc ) 1:1, 16 mL, Rf ) 0.03) to afford a colorless
oil, yield 170 mg (96%). Compound 15 was converted into the
hydrochloride in the usual manner to obtain 15‚HCl as
colorless needles, mp 221 °C (Et2O/CH3OH).
Com p ou n d 11. IR (film): ν˜ (cm-1) 3430 (O-H); 2934, 2829
(C-H); 1727 (CdO); 1158, 1037 (C-O); 749, 700 (C-H). 1H
NMR (CDCl3): δ (ppm) 1.27 (t, J ) 7.0 Hz, 3 H, OCH2CH3),
1.97 (dd, J ) 14.3, 2.5 Hz, 2 H, N(CH2CH2)2), 2.19 (td, J )
12.5, 4.3 Hz, 2 H, N(CH2CH2)2), 2.54 (td, J ) 11.6, 2.4 Hz, 2
H, N(CH2CH2)2), 2.77 (br d, J ) 11.3 Hz, 2 H, N(CH2CH2)2),
3.25 (dd, J ) 7.0, 1.5 Hz, 2 H, ArCH2CHdCH), 3.58 (s, 2 H,
NCH2Ph), 4.16 (q, J ) 7.3 Hz, 2 H, OCH2CH3), 5.98 (dt, J )
15.6, 7.2 Hz, 1 H, (E)-ArCH2CHdCH), 7.18-7.44 (m, 9 H,
arom), 7.48 (br d, J ) 15.9 Hz, 1 H, (E)-ArCH2CHdCH).
Com p ou n d 12. IR (film): ν˜ (cm-1) 2928, 2819 (C-H); 1735
IR (base, film): ν˜ (cm-1) 3394 (O-H); 2939, 2821 (C-H);
1094, 1049 (C-O); 741, 700 (C-H). 1H NMR (base, CDCl3): δ
1
(CdO); 1219, 1044 (C-O); 742, 699 (C-H). H NMR (CDCl3):
(ppm) 1.71 (dd,
J ) 13.4, 2.7 Hz, 1 H, N(CH2CH2)2),
δ (ppm) 1.33 (t, J ) 7.0 Hz, 3 H, OCH2CH3), 1.69 (dd, J )
13.4, 2.44 Hz, 1 H, N(CH2CH2)2), 1.88 (td, J ) 12.5, 4.4 Hz, 1
H, N(CH2CH2)2), 2.09 (dd, J ) 14.0, 2.4 Hz, 1 H, N(CH2CH2)2),
2.19 (td, J ) 12.8, 4.3 Hz, 1 H, N(CH2CH2)2), 2.33 (td, J )
12.2, 1.5 Hz, 1 H, N(CH2CH2)2), 2.45 (td, J ) 12.5, 2.1 Hz, 1
H, N(CH2CH2)2), 2.55-2.83 (m, 6 H, CHCH2COO (2 H), N(CH2-
CH2)2 (2 H), ArCH2CH (2 H)), 3.54 (s, 2 H, NCH2Ph), 4.11-
4.31 (m, 3 H, ArCH2CH (1 H), OCH2CH3 (2 H)), 7.06 (d, J )
7.3 Hz, 1 H, arom), 7.11-7.41 (m, 8 H, arom). MS (EI): m/z
379 [M+], 302 [M+ - Ph], 288 [M+ - CH2Ph], 91 [CH2Ph+].
Anal. (C24H29NO3) C, H, N.
1.84-2.01 (m, 3 H, N(CH2CH2)2 (1 H), CH2CH2OH (2 H)), 2.08
(dd, J ) 14.2, 4.5 Hz, 1 H, N(CH2CH2)2), 2.22 (td, J ) 13.1,
4.4 Hz, 1 H, N(CH2CH2)2), 2.30-2.44 (m, 2 H, N(CH2CH2)2),
2.61 (dd, J ) 15.9, 2.7 Hz, 1 H, ArCH2CH), 2.72-2.83 (m, 2
H, N(CH2CH2)2,), 2.83 (dd, J ) 15.9, 11.3 Hz, 1 H, ArCH2CH),
3.57 (s, 2 H, NCH2Ph), 3.89 (t, J ) 5.5 Hz, 2 H, CH2CH2OH),
3.96-4.05 (m, 1 H, ArCH2CH), 7.04 (d, J ) 7.0 Hz, 1 H, arom),
7.10-7.40 (m, 8 H, arom). MS (base, EI): m/z 337 [M+], 246
[M+ - CH2Ph], 91 [CH2Ph+]. Anal. (C22H27ClNO2) C, H, N.
1′-Ben zyl-3-eth yl-3,4-d ih yd r osp ir o[[2]ben zop yr a n -1,4′-
p ip er id in e] (17). A solution of 15 (55 mg, 0.16 mmol) and
Et3N (25 mg, 0.25 mmol) in CH2Cl2 (5 mL) was cooled to -10
°C, and CH3SO2Cl (22 mg, 0.20 mmol) was added. After 2 h at
-10 °C, an aqueous solution of NaOH (0.5 M) was added to
the mixture to give pH 10. Then, it was extracted with
CH2Cl2. The organic layer was dried (Na2SO4) and concen-
trated under reduced pressure. The crude product contained
the mesylate 16, which was immediately reduced.
2-(1′-Ben zyl-3,4-d ih yd r osp ir o[[2]b en zop yr a n -1,4′-p i-
p er id in ]-3-yl)eth yl Meth a n esu lfon a te (16). IR (film): ν˜
(cm-1) 2923 (C-H); 1356, 1174 (ROSO2CH3); 1114, 1046
(C-O); 741, 701 (C-H). 1H NMR (CDCl3): δ (ppm) 1.68 (dd, J
) 13.4, 2.4 Hz, 1 H, N(CH2CH2)2), 1.84-2.28 (m, 5 H,
N(CH2CH2)2 (3 H), CH2CH2OSO2CH3 (2 H), 2.35 (br t, J ) 11.9
Hz, 1 H, N(CH2CH2)2), 2.47 (br t, J ) 11.9 Hz, 1 H, N(CH2-
CH2)2), 2.63 (dd, J ) 15.9, 3.4 Hz, 1 H, ArCH2CH), 2.68-2.82
(m, 2 H, N(CH2CH2)2), 2.74 (dd, J ) 15.9, 10.4 Hz, 1 H, ArCH2-
CH), 3.01 (s, 3 H, ROSO2CH3), 3.59 (s, 2 H, NCH2Ph), 3.91
(tt, J ) 10.1, 3.1 Hz, 1 H, ArCH2CH), 4.42-4.57 (m, 2 H,
CH2CH2OSO2CH3), 7.05 (d, J ) 7.3 Hz, 1 H, arom), 7.10-7.43
(m, 8 H, arom).
2-(1′-Ben zyl-3,4-d ih yd r osp ir o[[2]b en zop yr a n -1,4′-p i-
p er id in ]-3-yl)eth a n en itr ile (13). A mixture of the lactol 2b
(55 mg, 0.18 mmol), (EtO)2P(O)CH2CN (48 mg, 0.27 mmol),
and Cs2CO3 (59 mg, 0.18 mmol) in THF (10 mL) was refluxed
for 22 h. Then, H2O (5 mL) was added and the mixture was
extracted with CH2Cl2. The organic layer was dried (Na2SO4),
and the solvent was removed under reduced pressure. The
residue was purified by flash chromatography (2 cm, petroleum
ether:EtOAc ) 1:2, 10 mL, Rf ) 0.26) to afford a colorless oil,
which solidified on standing, mp 84 °C, yield 46 mg (77%).
IR (film): ν˜ (cm-1) 2931, 2818 (C-H); 2252 (CtN), 1103,
1
1073 (C-O); 741, 700 (C-H). H NMR (CDCl3): δ (ppm) 1.72
(dd, J ) 13.4, 2.7 Hz, 1 H, N(CH2CH2)2), 1.88-2.09 (m, 2 H,
N(CH2CH2)2), 2.23 (td, J ) 12.8, 4.6 Hz, 1 H, N(CH2CH2)2),
2.48-2.61 (m, 2 H, N(CH2CH2)2), 2.67-2.89 (m, 6 H, CHCH2-
CN (2 H), N(CH2CH2)2 (2 H), ArCH2CH (2 H)), 3.60 (s, 2 H,
NCH2Ph), 4.04-4.14 (m, 1 H, ArCH2CH), 7.08 (d, J ) 7.0 Hz,
1 H, arom), 7.15-7.43 (m, 8 H, arom). MS (EI): m/z 332 [M+],
241 [M+ - CH2Ph], 91 [CH2Ph+]. HRMS: calcd for C22H24N2O,
332.1889; found, 332.1890.
2-(1′-Ben zyl-3,4-d ih yd r osp ir o[[2]b en zop yr a n -1,4′-p i-
p er id in ]-3-yl)a ceta ld eh yd e (14). Compound 13 (25 mg,
0.075 mmol) was dissolved in anhydrous toluene (3 mL) under
nitrogen. This solution was cooled to -78 °C, and a solution
of DIBAL (1 M in cyclohexane, 0.15 mL, 0.15 mmol) was slowly
added. After 2.5 h at -78 °C, a saturated aqueous solution of
NH4Cl (3 mL) was added. This mixture was stirred for 30 min
at room temperature. An aqueous solution of NaOH (2 M) was
added to give pH 10, and the mixture was extracted with
CH2Cl2. The organic layer was dried (Na2SO4), and the solvent
was removed under reduced pressure at 30 °C. The crude
product was purified by flash chromatography (1 cm, petro-
leum ether:EtOAc ) 1:1, 5 mL, Rf ) 0.08) to afford a colorless
oil, yield 11 mg (42%).
The crude product 16 (58 mg) was dissolved in THF (4
mL). Then, a solution of LiAlH4 (1 M in THF, 1 mL, 1 mmol)
was added and the mixture was refluxed for 2 d. Then, H2O
was added and the salts were filtered off and washed with
CH2Cl2. The solvent was removed under reduced pressure, and
the residue was purified by flash chromatography (0.8 cm,
petroleum ether:EtOAc ) 1:1, 5 mL, Rf ) 0.2) to afford a
colorless oil, yield 18 mg (40%).
Com p ou n d 17. IR (film): ν˜ (cm-1) 2924, 2813 (C-H); 1067,
1
1046 (C-O); 755, 734, 698 (C-H). H NMR (CDCl3): δ (ppm)
1.07 (t, J ) 7.5 Hz, 3 H, CH2CH3), 1.59-1.75 (m, 3 H,
N(CH2CH2)2 (1 H), CH2CH3 (2 H)), 1.88 (td, J ) 14.0, 4.4 Hz,
1 H, N(CH2CH2)2), 2.05 (dd, J ) 14.0, 2.7 Hz, 1 H, N(CH2CH2)2),
2.23 (td, J ) 13.1, 4.6 Hz, 1 H, N(CH2CH2)2), 2.44 (td, J )
11.0, 2.7 Hz, 1 H, N(CH2CH2)2), 2.56 (td, J ) 11.3, 2.7 Hz, 1
H, N(CH2CH2)2), 2.63-2.80 (m, 4 H, N(CH2CH2)2 (2 H), ArCH2-
CH (2 H)), 3.59 (s, 2 H, NCH2Ph), 3.57-3.68 (m, 1 H, CHCH2-
CH3), 7.06 (d, J ) 7.0 Hz, 1 H, arom), 7.13 (td, J ) 6.7, 2.1
Hz, 1 H, arom), 7.17-7.41 (m, 7 H, arom). MS (EI): m/z 321
[M+], 230 [M+ - CH2Ph], 91 [CH2Ph+]. HRMS: calcd for
IR (film): ν˜ (cm-1) 2927, 2816 (C-H); 1725 (HCdO); 1110,
1
1052 (C-O); 742, 701 (C-H). H NMR (CDCl3): δ (ppm) 1.69
(dd, J ) 13.4, 2.4 Hz, 1 H, N(CH2CH2)2), 1.93 (td, J ) 14.3,
4.5 Hz, 1 H, N(CH2CH2)2), 2.08 (dd, J ) 14.6, 2.7 Hz, 1 H,
N(CH2CH2)2), 2.22 (td, J ) 12.2, 4.6 Hz, 1 H, N(CH2CH2)2),
2.33 (td, J ) 12.2, 2.7 Hz, 1 H, N(CH2CH2)2), 2.45 (td, J )
11.3, 2.4 Hz, 1 H, N(CH2CH2)2), 2.65 (ddd, J ) 16.2, 4.0, 1.8
Hz, 1 H, CHCH2CHO), 2.71-2.88 (m, 5 H, N(CH2CH2)2 (2 H),
C
22H27NO, 321.2093; found, 321.2092.

Novel σ Receptor Ligands
J ournal of Medicinal Chemistry, 2002, Vol. 45, No. 22 4929
2-(1′-Ben zyl-3,4-d ih yd r osp ir o[[2]b en zop yr a n -1,4′-p i-
p er id in ]-3-yl)-N-m eth yla ceta m id e (18). Compound 12 (97
mg, 0.25 mmol) was stirred for 11 d in a solution of CH3NH2
in EtOH (3 M, 3 mL) at room temperature. The solvent was
removed under reduced pressure, and the crude product was
purified by flash chromatography (2 cm, EtOAc:acetone ) 9:1,
10 mL, Rf ) 0.03) to afford a colorless oil, yield 90 mg (99%).
Compound 18 was converted into the hydrochloride in the
usual manner to obtain 18‚HCl as colorless crystals, mp
88-90 °C (Et2O/CH3OH).
IR (base, film): ν˜ (cm-1) 3298 (N-H); 2937, 2820 (C-H);
1648 (amide I); 1561 (amide II); 1097, 1049 (C-O); 740, 700
(C-H). 1H NMR (base, CDCl3): δ (ppm) 1.70 (dd, J ) 13.4,
2.5 Hz, 1 H, N(CH2CH2)2), 1.89 (td, J ) 12.8, 4.5 Hz, 1 H,
N(CH2CH2)2), 2.03-2.12 (m, 1 H, N(CH2CH2)2), 2.20-2.33 (m,
2 H, N(CH2CH2)2 (1 H), N(CH2CH2)2 (1 H)), 2.39 (dd, J ) 11.0,
2.1 Hz, 1 H, N(CH2CH2)2), 2.46 (dd, J ) 14.3, 8.2 Hz, 1 H,
ArCH2CH), 2.57 (dd, J ) 14.3, 3.5 Hz, 1 H, ArCH2CH),
2.64-2.85 (m, 4 H, N(CH2CH2)2 (2 H), CH2CONH (2 H)), 2.87
(d, J ) 4.9 Hz, 3 H, CONHCH3), 3.56 (s, 2 H, NCH2Ph), 4.12-
4.23 (m, 1 H, ArCH2CH), 6.18 (br s, 1 H, CONHCH3), 7.06 (d,
J ) 7.0 Hz, 1 H, arom), 7.11-7.40 (m, 8 H, arom). MS (EI):
m/z 364 [M+], 273 [M+ - CH2Ph], 91 [CH2Ph+]. HRMS: calcd
for C23H28N2O2, 364.2151; found, 364.2152.
63.3 (1 C, NCH2Ph), 68.8 (1 C, ArCHCN), 88.1 (1 C, ArCO),
118.4 (1 C, CN), 121.4 (1 C, arom CH), 122.0 (1 C, arom CH),
127.1 (1 C, arom CH), 128.2 (2 C, arom CH), 128.8 (1 C, arom
CH), 129.2 (2 C, arom CH), 129.8 (1 C, arom C), 133.8 (1 C,
arom C), 138.3 (1 C, arom C), 145.5 (1 C, arom C). MS
(EI): m/z 304 [M+], 227 [M+ - Ph], 213 [M+ - CH2Ph], 91
[CH2Ph+]. HRMS: calcd for C20H20N2O, 304.1576; found,
304.1573. Anal. (C20H20N2O) C, H, N; C: calcd, 78.9; found,
78.4.
Eth yl 1′-Ben zyl-3H-spir o[[2]ben zofu r an -1,4′-piper idin e]-
3-ca r boxyla te (21). A solution of 20 (101 mg, 0.33 mmol) in
EtOH (3 g), H2O (68 mg), and concentrated H2SO4 (1.1 g) was
refluxed for 7.5 h. Then, an aqueous solution of NaOH (3 M)
was added to give pH 10 and the mixture was extracted with
CH2Cl2. The organic layer was dried (Na2SO4), and the solvent
was removed under reduced pressure. The crude product was
purified by flash chromatography (2 cm, petroleum ether:
EtOAc ) 2:1, 10 mL, Rf ) 0.06) to afford a colorless oil, yield
46 mg (39%).
IR (film): ν˜ (cm-1) 2943, 2811 (C-H); 1755 (CdO); 1196,
1
1075 (C-O); 755, 700 (C-H). H NMR (CDCl3): δ (ppm) 1.29
(t, J ) 7.0 Hz, 3 H, OCH2CH3), 1.75 (dd, J ) 13.7, 2.4 Hz, 1 H,
N(CH2CH2)2), 1.98-2.11 (m, 2 H, N(CH2CH2)2), 2.19 (td, J )
13.4, 4.3 Hz, 1 H, N(CH2CH2)2), 2.60 (td, J ) 11.9, 3.1 Hz, 1
H, N(CH2CH2)2), 2.71 (td, J ) 11.6, 4.3 Hz, 1 H, N(CH2CH2)2),
2.98 (br d, J ) 11.3 Hz, 2 H, N(CH2CH2)2), 3.71 (s, 2 H, NCH2-
Ph), 4.22 (q, J ) 7.0 Hz, 2 H, OCH2CH3), 5.66 (s, 1 H,
ArCHCO), 7.18 (dd, J ) 6.1, 1.5 Hz, 1 H, arom), 7.27-7.42
(m, 8 H, arom). MS (EI): m/z 351 [M+], 260 [M+ - CH2Ph], 91
[CH2Ph+]. HRMS: calcd for C22H25NO3, 351.1834; found,
351.1833.
2-(1′-Ben zyl-3,4-d ih yd r osp ir o[[2]b en zop yr a n -1,4′-p i-
p er id in ]-3-yl)-N-m eth yleth a n a m in e (19). The amide 18 (35
mg, 0.096 mmol) was dissolved in anhydrous Et2O (4 mL) and
some drops of CH2Cl2. The solution was cooled to -35 °C, and
a solution of LiAlH4 (1 M in THF, 0.15 mL, 0.15 mmol) was
slowly added. The mixture was stirred for 5 h at room
temperature. Then, H2O was added and the precipitate was
sucked off and washed with EtOAc. The organic layer was
dried (Na2SO4) and concentrated under reduced pressure. The
crude product was purified by flash chromatography (1 cm,
CH3OH:ammonia ) 98:2, 5 mL, Rf ) 0.05) to afford a colorless
oil, yield 13 mg (40%).
(1′-Ben zyl-3H-sp ir o[[2]ben zofu r a n -1,4′-p ip er id in ]-3-yl)-
m eth a n ol (22). Compound 21 (35 mg, 0.1 mmol) was dissolved
in Et2O (5 mL) under nitrogen. This solution was cooled to
-15 °C, and a solution of LiAlH4 (1 M in THF, 0.2 mL, 0.2
mmol) was slowly added. After 30 min, the mixture was
hydrolyzed by addition of some H2O. The salts were filtered
off and washed with EtOAc. The organic layer was concen-
trated under reduced pressure. The crude product was purified
by flash chromatography (1 cm, petroleum ether:EtOAc ) 1:1,
5 mL, Rf ) 0.04) to afford a colorless oil, yield 23 mg (75%).
IR (film): ν˜ (cm-1) 3424 (N-H); 2939, 2812 (C-H); 1095,
1
1046 (C-O); 751, 701 (C-H). H NMR (CDCl3): δ (ppm) 1.68
(dd, J ) 13.4, 2.7 Hz, 2 H, N(CH2CH2), (1 H), NH (1 H)), 1.82
(q, J ) 6.7 Hz, 2 H, CHCH2CH2NH), 1.90 (dd, J ) 12.5, 4.6
Hz, 1 H, N(CH2CH2)2), 2.03 (dd, J ) 13.7, 2.1 Hz, 1 H,
N(CH2CH2)2), 2.23 (td, J ) 12.8, 4.3 Hz, 1 H, N(CH2CH2)2),
2.34 (td, J ) 12.5, 2.7 Hz, 1 H, N(CH2CH2)2), 2.49 (s, 3 H,
NHCH3), 2.49 (td, J ) 14.0, 2.7 Hz, 1 H, N(CH2CH2)2), 2.61
(dd, 15.9, 3.1 Hz, 1 H, ArCH2CH), 2.68-2.88 (m, 5 H, N(CH2-
CH2)2 (2 H), CHCH2CH2NH (2 H), ArCH2CH (1 H)), 3.59 (s, 2
H, NCH2Ph), 3.77-3.88 (m, 1 H, ArCH2CH), 7.05 (d, J ) 7.0
Hz, 1 H, arom), 7.10-7.42 (m, 8 H, arom). MS (EI): m/z 350
[M+], 259 [M+ - CH2Ph], 91 [CH2Ph+]. HRMS: calcd for
IR (film): ν˜ (cm-1) 3386 (O-H); 2917, 2812 (C-H); 1050
(C-O); 745, 699 (C-H). 1H NMR (CDCl3): δ (ppm) 1.71 (br d,
J ) 13.7 Hz, 2 H, N(CH2CH2)2), 1.95 (td, J ) 13.4, 4.3 Hz, 1
H, N(CH2CH2)2), 2.15 (td, J ) 13.1, 4.3 Hz, 1 H, N(CH2CH2)2),
2.49 (br t, J ) 11.3 Hz, 2 H, N(CH2CH2)2), 2.80-2.91 (m, 2 H,
N(CH2CH2)2), 3.61 (s, 2 H, NCH2Ph), 3.76 (dd, J ) 11.6, 5.8
Hz, 1 H, CHCH2OH), 3.95 (dd, J ) 11.6, 3.4 Hz, 1 H, CHCH2-
OH), 5.27-5.32 (m, 1 H, ArCHCH2OH), 7.15-7.21 (m, 2 H,
arom), 7.25-7.41 (m, 7 H, arom). MS (EI): m/z 309 [M+], 218
[M+ - CH2Ph], 91 [CH2Ph+]. HRMS: calcd for C20H23NO2,
309.1729; found, 309.1729. Anal. (C20H23NO2) C, N; H: calcd,
7.49; found, 8.16.
2-(1′-Ben zyl-3H-sp ir o[[2]ben zofu r a n -1,4′-p ip er id in ]-3-
yl)eth a n en itr ile (23). A mixture of 3b (78 mg, 0.26 mmol),
Ph3PdCHCN (159 mg, 0.53 mmol), and Cs2CO3 (20 mg) in
anhydrous toluene (10 mL) was refluxed for 40 h. The solvent
was removed under reduced pressure. The residue was purified
by flash chromatography (2 cm, petroleum ether:EtOAc ) 2:1,
10 mL, Rf ) 0.08) to afford a colorless oil, which solidified on
standing, mp 113 °C, yield 64 mg (76%).
IR (film): ν˜ (cm-1) 2942, 2811 (C-H); 2252 (CtN); 1050
(C-O); 741, 698 (C-H). 1H NMR (CDCl3): δ (ppm) 1.69 (dd, J
) 13.7, 2.7 Hz, 1 H, N(CH2CH2)2), 1.85 (dd, J ) 13.7, 2.7 Hz,
1 H, N(CH2CH2)2), 1.97 (td, J ) 13.0, 4.6 Hz, 1 H, N(CH2CH2)2),
2.16 (td, J ) 13.4, 4.4 Hz, 1 H, N(CH2CH2)2), 2.40-2.57 (m, 2
H, N(CH2CH2)2), 2.81-2.92 (m, 4 H, N(CH2CH2)2 (2 H),
ArCHCH2CN (2 H)), 3.62 (s, 2 H, NCH2Ph), 5.43 (t, J ) 5.5
Hz, 1 H, ArCHCH2CN), 7.19 (dd, J ) 5.5, 2.8 Hz, 1 H, arom),
7.25-7.41 (m, 8 H, arom). 13C NMR (CDCl3): δ (ppm) 26.1 (1
C, CH2CN), 37.4 (1 C, N(CH2CH2)2), 38.2 (1 C, N(CH2CH2)2),
49.7 (1 C, N(CH2CH2)2), 49.9 (1 C, N(CH2CH2)2), 63.3 (1 C,
NCH2Ph), 76.8 (1 C, ArCHCH2CN), 85.5 (1 C, ArCO), 116.9 (1
C, CN), 121.2 (2 C, arom CH), 127.0 (1 C, arom CH), 128.2 (3
C
23H30N2O, 350.2358; found, 350.2364.
1′-Ben zyl-3H -sp ir o[[2]b en zofu r a n -1,4′-p ip er id in e]-3-
ca r bon it r ile (20). Tetracyanoethylene (33 mg, 0.26 mmol)
was dissolved in CH3CN (2 mL) under nitrogen. Then, a
solution of 3a (403 mg, 1.3 mmol) in CH3CN (2 mL) was added
and the mixture was stirred for 5 min. Trimethylsilyl cyanide
(0.4 mL) was added, and the mixture was refluxed. Two
additional portions of trimethylsilyl cyanide (0.3 mL each) were
added within a period of 4 h. When the reaction was completed,
the solvent was removed under reduced pressure and the
residue was dissolved in CH2Cl2. Then, some silica gel was
added and the suspension was concentrated under reduced
pressure. The residue was purified by flash chromatography
(3 cm, petroleum ether:EtOAc ) 4:1, 20 mL, Rf ) 0.05) to afford
a colorless oil, which solidified on standing, mp 114-115 °C,
yield 268 mg (68%).
IR (film): ν˜ (cm-1) 2944, 2813(C-H); 1044 (C-O); 741, 699
(C-H), (no CtN-valence vibration). 1H NMR (CDCl3): δ (ppm)
1.72 (ddd, J ) 13.4, 5.2, 2.5 Hz, 1 H, N(CH2CH2)2), 1.92-2.18
(m, 3 H, N(CH2CH2)2), 2.45 (td, J ) 11.3, 2.7 Hz, 1 H, N(CH2-
CH2)2), 2.53 (td, J ) 11.9, 3.1 Hz, 1 H, N(CH2CH2)2), 2.83-
2.94 (m, 2 H, N(CH2CH2)2), 3.63 (s, 2 H, NCH2Ph), 5.86 (s, 1
H, ArCH), 7.18-7.22 (m, 1 H, arom), 7.24-7.47 (m, 8 H, arom).
13C NMR (CDCl3): δ (ppm) 36.9 (1 C, N(CH2CH2)2), 37.2 (1 C,
N(CH2CH2)2), 49.6 (1 C, N(CH2CH2)2), 49.9 (1 C, N(CH2CH2)2),

4930 J ournal of Medicinal Chemistry, 2002, Vol. 45, No. 22
Maier and Wu¨nsch
(2) Tam, S. W. Naloxone-inaccessible sigma receptor in rat central
nervous system. Proc. Natl. Acad. Sci. U.S.A. 1983, 80, 6703-
6707.
(3) Quirion, R.; Bowen, W. D.; Itzhak, Y.; J unien, J . L.; Musacchio,
J . M.; Rothman, R. B.; Su, T.-P.; Tam, W.; Taylor, D. P. A
proposal for the classification of sigma binding sites. Trends
Pharmacol. Sci. 1992, 13, 85-86.
C, arom CH), 128.8 (1 C, arom CH), 129.3 (2 C, arom CH),
138.2 (1 C, arom C), 138.3 (1 C, arom C), 146.0 (1 C, arom C).
MS (EI): m/z 318 [M+], 227 [M+ - CH2Ph], 91 [CH2Ph+].
HRMS: calcd for C21H22N2O, 318.1732; found, 318.1733.
Eth yl 2-(1′-Ben zyl-3H-sp ir o[[2]ben zofu r a n -1,4′-p ip er i-
d in ]-3-yl)a ceta te (24). A mixture of 3b (266 mg, 0.90 mmol),
Ph3PdCHCO2Et (10) (627 mg, 1.8 mmol), and Cs2CO3 (50 mg)
in anhydrous toluene (20 mL) was refluxed for 15 h. The
solvent was removed under reduced pressure. The residue was
purified by flash chromatography (3 cm, petroleum ether:
EtOAc ) 3:1, 20 mL, Rf ) 0.05) to afford a colorless oil, yield
289 mg (88%).
(4) Hanner, M.; Moebius, F. F.; Flandorfer, A.; Knaus, H.-G.;
Striessnig, J .; Kempner, E.; Glossmann, H. Purification, mole-
cular cloning, and expression of the mammalian sigma1-binding
site. Proc. Natl. Acad. Sci. U.S.A. 1996, 93, 8072-8077.
(5) Kekuda, R.; Prasad, P. D.; Fei, Y.-J .; Leibach, F. H.; Ganapathy,
V. Cloning and Functional Expression of the Human Type 1
Sigma Receptor (hSigmaR1). Biochem. Biophys. Res. Commun.
1996, 229, 553-558.
(6) Seth, P.; Fei, Y.-J .; Li, H. W.; Huang, W.; Leibach, F. H.;
Ganapathy, V. Cloning and Functional Characterization of a σ
Receptor from Rat Brain. J . Neurochem. 1998, 70, 922-931.
(7) Moebius, F. F.; Striessnig, J .; Glossmann, H. The mysteries of
sigma receptors: new family members reveal a role in cholesterol
synthesis. Trends Pharmacol. Sci. 1997, 18, 67-70.
(8) Bastianetto, S.; Monnet, F.; J unien, J .-L.; Quirion, R. Steroidal
Modulation of Sigma Receptor Function. In Contemporary
Endocrinology: Neurosteroids: A New Regulatory Function in the
Nervous System; Baulieu, E.-E., Robel, P., Schumacher, M., Eds.;
Humana Press: Totowa, 1999; pp 191-205.
IR (film): ν˜ (cm-1) 2941, 2811 (C-H); 1735 (CdO); 1162,
1
1045 (C-O); 744, 699 (C-H). H NMR (CDCl3): δ (ppm) 1.28
(t, J ) 7.3 Hz, 3 H, OCH2CH3), 1.64-1.76 (m, 2 H, N(CH2CH2)2),
1.95 (td, J ) 12.8, 4.6 Hz, 1 H, N(CH2CH2)2), 2.10 (td, J )
13.4, 4.4 Hz, 1 H, N(CH2CH2)2), 2.48 (br t, J ) 11.6 Hz, 2 H,
N(CH2CH2)2), 2.74 (d, J ) 6.7 Hz, 2 H, ArCHCH2CO), 2.79-
2.88 (m, 2 H, N(CH2CH2)2), 3.60 (s, 2 H, NCH2Ph), 4.21 (q, J
) 7.3 Hz, 2 H, OCH2CH3), 5.61 (t, J ) 6.7 Hz, 1 H, ArCHCH2-
CO), 7.12-7.19 (m, 1 H, arom), 7.23-7.40 (m, 8 H, arom). MS
(EI): m/z 365 [M+], 274 [M+ - CH2Ph], 91 [CH2Ph+]. HRMS:
calcd for C23H27NO3, 365.1991; found, 365.1989. Anal. (C23H27
-
NO3) N; C: calcd, 75.4; found, 74.9; H: calcd, 7.45; found, 8.17.
2-(1′-Ben zyl-3H-sp ir o[[2]ben zofu r a n -1,4′-p ip er id in ]-3-
yl)eth a n ol (25). Compound 24 (130 mg, 0.36 mmol) was
dissolved in Et2O (5 mL) under nitrogen. This solution was
cooled to -15 °C, and a solution of LiAlH4 (1 M in THF, 0.89
mL, 0.89 mmol) was slowly added. After 30 min, the mixture
was allowed to warm to room temperature, and after another
30 min, some H2O was added. The mixture was extracted with
EtOAc. The organic layer was dried (Na2SO4) and concentrated
under reduced pressure. The crude product was purified by
flash chromatography (1 cm, petroleum ether:EtOAc ) 1:1, 5
mL, Rf ) 0.03) to afford a colorless oil, yield 86 mg (75%).
Compound 25 was converted into the hydrochloride in the
usual manner to obtain 25‚HCl as colorless crystals, mp 216
°C (Et2O/CH3OH).
(9) Walker, J . M.; Bowen, W. D.; Walker, F. O.; Matsumoto, R. R.;
De Costa, B.; Rice, K. C. Sigma Receptors: Biology and Function.
Pharmacol. Rev. 1990, 42, 353-402.
(10) Bowen, W. D. Sigma receptors: recent advances and new clinical
potentials. Pharm. Acta Helv. 2000, 74, 211-218.
(11) (a) Monograph BMY-14802-1. Drugs Future 1987, 12, 752-753.
(b) Monograph BMY-14802. Drugs Future 1995, 20, 821-822.
(12) Guitart, X.; Ballarin, M.; Codony, X.; Dordal, A.; Farre´, A. J .;
Frigola, J .; Merce`, R. Drugs Future 1999, 24, 386-392.
(13) Maier, C. A.; Wu¨nsch, B. Novel Spiropiperidines as Highly
Potent and Subtype Selective σ-Receptor Ligands. Part 1. J . Med.
Chem. 2002, 45, 438-448.
(14) Cohen, N.; Schaer, B.; Saucy, G.; Borer, R.; Todaro, L.; Chiu,
A.-M. Lewis Acid Mediated Nucleophilic Substitution Reactions
of 2-Alkoxy-3,4-dihydro-2H-1-benzopyrans: Regiochemistry and
Utility in the Synthesis of 3,4-Dihydro-2H-1-benzopyran-2-
carboxylic Acids. J . Org. Chem. 1989, 54, 3282-3292.
(15) Miura, T.; Masaki, Y. Carbon-carbon bond formation and
reduction of aldehydes, ketones and acetals with silylated
nucleophiles catalysed by tetracyanoethylene. J . Chem. Soc.,
Perkin Trans. 1 1995, 2155-2158.
(16) Stevenson, G. I.; Huscroft, I.; MacLeod, A. M.; Swain, C. J .;
Cascieri, M. A.; Chicchi, G. G.; Graham, M. I.; Harrison, T.;
Kelleher, F. J .; Kurtz, M.; Ladduwahetty, T.; Merchant, K. J .;
Metzger, J . M.; MacIntyre, D. E.; Sadowski, S.; Sohal, B.; Owens,
A. P. 4,4-Disubstituted Piperidine High-Affinity NK1 Antago-
nists: Structure-Activity Relationships and in Vivo Activity.
J . Med. Chem. 1998, 41, 4623-4635.
(17) Subrahmanyam, D.; Renuka, B.; Kumar, G. S.; Vandana, V.;
Deevi, D. S. 9-Deoxopodophyllotoxin derivatives as anti-cancer
agents. Bioorg. Med. Chem. Lett. 1999, 9, 2131-2134.
(18) Bloch, R.; Seck, M. Optically active five-membered oxygen-
containing rings, a synthesis of (+)-Eldanolide. Tetrahedron
1989, 45, 3731-3740.
IR (base, film): ν˜ (cm-1) 3411 (O-H); 2940, 2819 (C-H);
1050 (C-O); 744, 700 (C-H). 1H NMR (base, CDCl3):
δ
(ppm) 1.69-1.80 (m, 2 H, N(CH2CH2)2), 1.85-1.99 (m, 2 H,
N(CH2CH2)2 (1 H), CH2CH2OH (1 H)), 2.09-2.26 (m, 2 H,
N(CH2CH2)2 (1 H), CH2CH2OH (1 H)), 2.34-2.50 (m, 2 H,
N(CH2CH2)2), 2.79-2.92 (m, 3 H, N(CH2CH2)2 (2 H), OH (1
H)), 3.58 (s, 2 H, NCH2Ph), 3.81-3.98 (m, 2 H, CH2CH2OH),
5.41 (dd, J ) 8.9, 3.1 Hz, 1 H, ArCH), 7.09-7.19 (m, 2 H,
arom), 7.25-7.40 (m, 7 H, arom). MS (base, EI): m/z 323
[M+], 232 [M+ - CH2Ph], 91 [CH2Ph+]. Anal. (C21H26ClNO2)
C, H, N.
P h a r m a cology. σ1 and σ2 receptor binding assays were
conducted as previously reported.13 The σ1 binding assay was
performed using a guinea pig brain membrane preparation as
receptor material and [3H]-(+)-pentazocine as the radioligand.
Nonspecific binding was determined with 10 µM haloperidol.21
The σ2 receptor affinity was determined using rat liver
membrane preparations with the radioligand [3H]ditolylguani-
dine in the presence of 100 nM (+)-pentazocine to mask σ1
binding sites. Nonspecific binding was determined with 10 µM
ditolylguanidine.22,23 Ki values were calculated according to
Cheng and Prusoff24 and represent data from at least three
independent experiments, each performed in triplicate. The
results are given as mean ( standard error of the mean (SEM).
(19) Rossi, R.; Salvadori, P. A. Synthesis of Both Enantiomers of
6-Methyl-3-octanone, a Component of the Alarm Pheromone of
Ants in the Genus Crematogaster. Synthesis 1979, 209-210.
(20) Still, W. C.; Kahn, M.; Mitra, A. Rapid Chromatographic
Technique for Preparative Separations with Moderate Resolu-
tion. J . Org. Chem. 1978, 43, 2923-2925.
(21) DeHaven-Hudkins, D. L.; Fleissner, L. C.; Ford-Rice, F. Y.
Characterization of the binding of [3H](+)-pentazocine to σ
recognition sites in guinea pig brain. Eur. J . Pharmacol. 1992,
227, 371-378.
(22) Mach, R. H.; Smith, C. R.; Childers, S. R. Ibogaine Possesses a
Selective Affinity for σ2 Receptors. Life Sci. 1995, 57, PL 57-
62.
(23) Hellewell, S. B.; Bruce, A.; Feinstein, G.; Orringer, J .; Williams,
W.; Bowen, W. D. Rat liver and kidney contain high densities of
σ1 and σ2 receptors: characterization by ligand binding and
photoaffinity labeling. Eur. J . Pharmacol. Mol. Pharmacol. Sect.
1994, 268, 9-18.
Ack n ow led gm en t . We thank the Deutsche For-
schungsgemeinschaft, the Fonds der Chemischen In-
dustrie, and the Wissenschaftliche Gesellschaft Freiburg
for financial support. Thanks are also due to Degussa
AG, J anssen-Cilag GmbH, and Bristol-Myers Squibb for
donation of chemicals and reference compounds.
(24) Cheng, Y.; Prusoff, W. H. Relationship between the inhibition
constant (Ki) and the concentration of inhibitor which causes
50% inhibition (IC50) of an enzymatic reaction. Biochem. Phar-
macol. 1973, 22, 3099-3108.
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J M020889P