Substituted 1-phenyl-2-cyclopropylmethylamines with high affinity and selectivity for sigma sites

Article abstract of DOI:10.1016/S0968-0896(00)00072-9

A series of 1-phenyl-2-cyclopropylmethylamines structurally related to (+)- and (-)-MPCB were synthesized and their binding affinities for σ₁, σ₂, opioid and dopamine (D₂) receptors were evaluated. Substitution of the cis-N-normetazocine with different aminic moieties provided compounds with high affinity and selectivity for σ binding sites with respect to opioid and dopamine (D₂) receptors. The observed increase in σ₂ affinity as compared to the parent (+)-MPCB, supports the idea that the particular stereochemistry of (+)-cis-N-normetazocine affects σ₁ selectivity but does not affect σ₁ affinity. The (±)-cis isomers of methyl 2-[(1-adamantylamino)methyl]-1-phenylcyclopropane-1-carboxylate (18) displayed a higher affinity and selectivity for the σ₁ and σ₂ receptor subtypes compared to the (±)-trans 19. Interestingly, the enantiomer (-)-cis 18 displayed a preference for σ₁ receptor subtype whereas the (+)-cis 18 did for σ₂. These results prompt us to synthesize compounds with modification of nitrogen and carboxyl groups. The compounds obtained showed high affinities and selectivity for σ sites. Moreover, modifications of carboxyl groups provided compounds with the highest affinities in the series. In particular, compound 25 with reverse-type ester showed a K(i) of 0.6 and 4.05nM for σ₁ and σ₂ binding sites, respectively. Copyright (C) 2000 Elsevier Science Ltd.

Full text of DOI:10.1016/S0968-0896(00)00072-9

Bioorganic & Medicinal Chemistry 8 (2000) 1503±1513
Substituted 1-Phenyl-2-cyclopropylmethylamines with High
Anity and Selectivity for Sigma Sites
Giuseppe Ronsisvalle,a,* Agostino Marrazzo,a Orazio Prezzavento,a Lorella Pasquinucci,a
Barbara Falcucci,b Rosanna Di Torob and Santi Spampinatob
aDepartment of Pharmaceutical Sciences, University of Catania, Viale Andrea Doria 6, 95125 Catania, Italy
bDepartment of Pharmacology, University of Bologna, Via Irnerio 48, 40126 Bologna, Italy
Received 5 May 1999; accepted 2 March 2000
AbstractÐA series of 1-phenyl-2-cyclopropylmethylamines structurally related to (+)- and ( )-MPCB were synthesized and their
binding anities for s1, s2, opioid and dopamine (D2) receptors were evaluated. Substitution of the cis-N-normetazocine with
di€erent aminic moieties provided compounds with high anity and selectivity for s binding sites with respect to opioid and
dopamine (D2) receptors. The observed increase in s2 anity as compared to the parent (+)-MPCB, supports the idea that the
particular stereochemistry of (+)-cis-N-normetazocine a€ects s1 selectivity but does not a€ect s1 anity. The (Æ)-cis isomers of
methyl 2-[(1-adamantylamino)methyl]-1-phenylcyclopropane-1-carboxylate (18) displayed a higher anity and selectivity for the s1
and s2 receptor subtypes compared to the (Æ)-trans 19. Interestingly, the enantiomer ( )-cis 18 displayed a preference for s1
receptor subtype whereas the (+)-cis 18 did for s2. These results prompt us to synthesize compounds with modi®cation of nitrogen
and carboxyl groups. The compounds obtained showed high anities and selectivity for s sites. Moreover, modi®cations of car-
boxyl groups provided compounds with the highest anities in the series. In particular, compound 25 with reverse-type ester
showed a Ki of 0.6 and 4.05 nM for s1 and s2 binding sites, respectively. # 2000 Elsevier Science Ltd. All rights reserved.
Introduction
demonstrate that (+) enantiomers of opiate ligands,
such as (+)-pentazocine and (+)-SKF 10,047, have a
higher anity for s1 over s2 subtypes. Other s ligands,
such as haloperidol and DTG [1,3-di-2-(tolyl)guani-
dine], do not discriminate between s1 and s2 sites.
Sigma (s) receptors are characterized as nonopiate sites
which bind certain benzomorphan opioids with high
anity.1 The investigation of ligands for s site receptors
has been the object of several studies designed to eluci-
date their physiological role. Sigma receptors are widely
distributed within the central nervous system2 and per-
ipheral tissue3 of many species. Moreover, s sites are
expressed in a wide variety of human and rodent tumor
cell lines. It has been proposed that s receptors may
represent potential targets for diagnostic tumor imaging
agents.4 In addition, the binding anity of typical and
atypical antipsychotic drugs for s sites and the possible
modulation on release and biosynthesis of several neu-
rotransmitters5,6 suggests their potential involvement as
neuromodulators in a€ective disorders, schizophrenia
and motor control.7 11
The isolation and cloning of guinea pig liver and human
placental s1 sites have been reported.13,14 The cloned
protein is not related to any known mammalian protein,
but it is similar to a fungal protein involved in cholesterol
biosynthesis.15,16 The proteins corresponding to the s2
site have not been cloned, but a recent report suggests
that they are distinct macromolecules with a particular
mode of association with the cell membrane.17
Several studies on structure±anity relationships for
several classes of s ligands, such as benzomorphans,
phenylalkylamines, guanidines and derivatives of
U50,488 have been reported.18 Recently, we reported
the synthesis and binding anities of 20-methoxy-
carbonyl-20-phenyl-10-cyclopropylmethyl normetazocine
derivatives (MPCB, Fig. 1)19 21 in order to investigate
k-opioid selective ligands that discriminate between
opioid and s1 binding sites. In these studies, we
observed that the two diastereoisomers, ( )-MPCB and
At present, there are pharmacological data which sup-
port the existence of at least two s subtypes, namely s1
and s2.12 This conclusion is based on studies which
*Corresponding author. Tel.: +39-95-3367-22; fax: +39-95-3367-22;
e-mail: ggrmedch@mbox.unict.it
0968-0896/00/$ - see front matter # 2000 Elsevier Science Ltd. All rights reserved.
PII: S0968-0896(00)00072-9

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G. Ronsisvalle et al. / Bioorg. Med. Chem. 8 (2000) 1503±1513
Figure 1. Chemical structures of ( )-MPCB, (+)-MPCB and compounds 14±19. a The ( ) and (+) are related to cis-N-normetazocine nucleus; b cis
and trans are related to cyclopropane ring.
(+)-MPCB, possess high selectivity for k-opioid and
s1 binding sites, respectively. Speci®cally, ( )-MPCB
exhibited a binding anity of 240 nM for the k-opioid
receptors, >1000 nM for s1 sites and >25,000 nM for
m- and d-opioid receptors, while (+)-MPCB showed
binding anity of 66.7 nM for s1 sites and >1000 nM
for k-, m- and d-opioid receptors.
and biological evaluation of these analogues are repor-
ted herein.
Chemistry
Our retrosynthetic analysis of the synthesis of com-
pounds 14±26 is shown in Figure 2. In order to obtain
the halogen or tosyl intermediate we started from
lactone 1. Subsequently, the nucleophilic displace-
ment with the appropriate amines provided the ®nal
compounds.
To further evaluate the structure±activity relationships
of MPCB analogues with respect to anity and selec-
tivity for the s receptor subtypes, we synthesized a new
series of 1-methoxycarbonyl-1-phenyl-2-cyclopropyl-
methylamines in which the cis-N-normetazocine nucleus
has been substituted with the 1,2,3,4-tetrahydroiso-
quinoline 14, N,N-dicyclohexylamine 15, N-methyl-
N(2-piperidin-1-ylethyl)amine 16, N-ethyl-N-(2-piper-
idin-1-ylethyl)amine 17 and 1-adamantanamine 18±19
moieties (Fig. 1). To obtain further insight into the
requirements of s1 and s2 recognition sites, we also
synthesized the enantiomers of methyl cis-2-[(1-adam-
antylamino)methyl]-1-phenylcyclopropane-1-carboxylate
(20 and 21) and some cis-1-phenyl-2-cyclopropylmethyl
derivatives (22±26) with modi®cation on the nitrogen
substituent and/or on the carboxylic group. The syntheses
Speci®cally, the lactone (Æ)-1 and acid (Æ)-5 were pre-
pared as reported in the literature.22 Enantiomers 3 were
obtained by treatment of lactone (Æ)-1 with R-(+)-a-
methylbenzylamine, followed by ¯ash chromatographic
separation of the two diastereoisomeric amides 2
(Scheme 1). The subsequent hydrolysis of 2 with 1N
H2SO4 in dioxane/H2O gave the expected enantiomers
(+)- and ( )-3. Con®gurational assignment of 3 was
1
based on previously reported H NOE NMR data and
molecular mechanic calculations on the individual dia-
stereoisomeric acid derivatives of MPCB.19 21 In addi-
tion, compound 4 was synthesized in racemic form by

G. Ronsisvalle et al. / Bioorg. Med. Chem. 8 (2000) 1503±1513
1505
Figure 2. Retrosynthetic analysis and strategy for the synthesis of compounds 14±26.
Scheme 1. Synthesis of methyl or ethyl cis-2-(bromomethyl)-1-phenylcyclopropanecarboxylate 4a±b. Reagents and conditions: (i) (R)-(+)-a-
methylbenzylamine; dry toluene; 2-hydroxypiridine; re¯ux; 24 h; (ii) ¯ash chromatography; (iii) 1N H2SO4 in dioxane/H2O; 85 ꢀC; 16 h; (iv) HBr/
CH3COOH (33%); 80 ꢀC; 2 h; (v) benzene; SOCl2; ROH/3N HCl; 5 h.
Scheme 2. Synthesis of methyl (Æ)-trans-2-([(4-methylphenyl)sulfonyl]oxymethyl)-1-phenylcyclopropanecarboxylate (Æ)-7. Reagents and conditions:
(i) CH3OH/HCl; re¯ux; 4 h; (ii) CH2Cl2; p-toluensulfonyl chloride; pyridine; 12 h.
treatment of lactone 1 with HBr/CH3COOH (33%) and
subsequent esteri®cation of the bromoacid derivatives
with SOCl2 and methanol or ethanol/3N HCl.
tosyl chloride and pyridine in CH2Cl2 a€orded ester
(Æ)-7 in an 80% overall yield (Scheme 2). Compound 9
was obtained in a good yield by treatment of chloro-
methyl ester 8, synthesized as reported in the literature,22
with alane±N,N-dimethylethylamine complex (Scheme
3). The same reaction with the bromomethyl and ethyl
ester derivatives of 8 (compound 4) provided low yields
The syntheses of tosyl and chloro esters (Æ)-7 and (Æ)-
10 are shown in Schemes 2 and 3. Esteri®cation with
anhydrous HCl/CH3OH and subsequent treatment with

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G. Ronsisvalle et al. / Bioorg. Med. Chem. 8 (2000) 1503±1513
Scheme 3. Synthesis of (Æ)-cis-[2-(chloromethyl)-1-phenylcyclopropyl]methanol (Æ)-9 and (Æ)-cis-[2-(chloromethyl)-1-phenylcyclopropyl]methyl
acetate (Æ)-10. Reagents and conditions: (i) benzene; ZnCl2; SOCl2; CH3OH/3N HCl; 5 h; (ii) THF; C2H5N(CH3)2 AlH3; 0 ꢀC; 2.5 h; THF; acetyl
.
chloride; 4-dimethylaminopyridine; r.t; 20 h.
Scheme 4. Synthesis of amines 11a±b and 13. Reagents and conditions: (i) H2O; r.t; 2 h; (ii) EtOCHO; re¯ux; 12 h; (iii) THF; LiAlH4; 40 ꢀC; 5 h.
of expected compounds. The simple acylation of 9 with
commercially available acetyl chloride in anhydrous
THF provided compound 10.
moderate to high anity for s1 and s2 sites and negli-
gible anity for the opioid and dopaminergic D2
receptors. The data reported in Table 1 con®rm the high
steric and structural tolerability of the s1 binding sites.
In general, substitution of the (+)-cis-N-normetazocine
nucleus of MPCB with 1,2,3,4-tetrahydroisoquinoline
(14), N,N-dicyclohexyl (15), N-methyl-N-(2-piperidin-1-
ylethyl)amine (16) and N-ethyl-N-(2-piperidin-1-yl-
ethyl)amine (17) provided compounds with similar
binding anities. A notable increase in binding anity
was obtained by substitution of the (+)-cis-N-norme-
tazocine moiety of (+)-MPCB with 1-adamantan-
Synthesis of the amine component of the target struc-
tures is shown in Scheme 4. The amines 11a and 11b
were obtained by the reaction of 1-(2-chloroethyl)-
piperidine with methyl- or ethylamine in water.23,24 The
formylation of 1-adamantanamine with ethyl formate
and subsequent reduction of amide 12 with LiAlH4
produced the N-methyladamantan-1-amine 13.25 27
Nucleophilic substitution of the cyclopropylphenyl deri-
vatives with the appropriate amine provided the ®nal
compounds 14±26 (Tables 1 and 2) as shown in Scheme 5.
amine (18). This compound displayed
a 20-fold
increase in anity for the s1 subtypes as compared to
(+)-MPCB.
With regard to stereochemical considerations, the cis
racemic mixture (18) displayed a higher anity for the
s1 and s2 receptor subtypes than did the trans racemic
mixture (19). Moreover, the cis enantiomers ( )-18 and
Results and Discussion
The binding data for compounds 14±19 and 20±26 are
reported in Tables 1 and 2. All compounds showed

G. Ronsisvalle et al. / Bioorg. Med. Chem. 8 (2000) 1503±1513
1507
Table 1. Binding anities [KiÆSEM (nM)] of ( )-MPCB, (+)-MPCB and compounds 14±19
Compound
R
[3H](+)Pentaz (s1)
[3H]DTG (s2)
[3H]Nalox (opioid)
[3H]Spirop (D2)
>10,000
(
)-MPCB
>10,000
>10,000
378Æ12
(+)-MPCB
66.7Æ2.2
3980Æ42
>10,000
>10,000
(Æ)-14
(Æ)-15
61Æ4.2
141.7Æ12.7
204.3Æ31.5
5000<IC50<10,000
>10,000
>10,000
>10,000
93.2Æ3.5
(Æ)-16
61.4Æ1.7
32.9Æ0.8
5000<IC50<10,000
>10,000
(Æ)-17
(Æ)-18
34Æ0.8
3Æ0.4
80.8Æ1.5
23Æ6.4
>10,000
5000<IC50<10,000
>10,000
>10,000
>10,000
>10,000
>10,000
>10,000
NDc
(
)-18
4Æ0.7
35Æ0.4
(+)-18
(Æ)-19a
DTGb
234Æ21.4
226Æ13.7
59Æ1.3
39.4Æ3.9
135Æ11.4
31.7Æ1.7
>10,000
5000<IC50<10,000
NDc
atrans con®guration.
b1,3-Di(2-tolyl)guanidine.
cNot detected.
(+)-18 showed di€erent binding pro®les for the s1 and
s2 sites (Table 1). In particular, the levo-isomer ( )-18
was more selective for s1 whereas the dextro-isomer
(+)-18 was selective for s2 sites.
with 1-adamantylmethanamine (20), (1-adamantyl)-
ethylamino (21) or N-methyladamantanamine (22)
resulted in decreased s1 anity and an increased s2
anity.
As reported in Table 2, modi®cation on the amino moiety
of compound 18, by substitution of 1-adamantanamine
These results seem to provide evidence that a small
increase of distance between adamantane nucleus and

1508
G. Ronsisvalle et al. / Bioorg. Med. Chem. 8 (2000) 1503±1513
Table 2. Binding anities [KiÆSEM (nM)] of compounds 20±26
Compound
R
R
[3H](+)Pentaz (s1)
11.5Æ3.7
[3H]DTG (s2)
12.7Æ4.8
[3H]Nalox (opioid)
>10,000
[3H]Spirop (D2)
(Æ)-20
COOCH3
5000<IC50<10,000
(Æ)-21
(Æ)-22
(Æ)-23
(Æ)-24
(Æ)-25
(Æ)-26
COOCH3
COOCH3
99.3Æ10
12Æ1.2
45.2Æ1.5
11.2Æ0.8
35.8Æ3.7
2.22Æ1.0
4.05Æ0.5
7.4Æ0.9
>10,000
>10,000
>10,000
>10,000
>10,000
>10,000
>10,000
>10,000
>10,000
>10,000
>10,000
>10,000
COOC2H5
CH2OH
1.29Æ0.4
5.3Æ1.2
0.6Æ0.04
2.5Æ1.3
CH2OCOCH3
CH2OCOCH3
Scheme 5. Synthesis of ®nal compounds 14±26. Reagents and conditions: (i) DMF; NaHCO3; 70 ꢀC; 8 h.
nitrogen atom or the increase of lipophilic bulk for s1
was critical, but it improves s2 anity.
Conclusion
In this study we have reported the synthesis and binding
anities with respect to s1, s2, opioid and dopamine
D2 receptors of a new series of 1-phenyl-2-cyclo-
propylmethylamine derivatives structurally related to
MPCB.
Modi®cation of the carboxyester group (23±26) pro-
vided compounds with a very high anity for s1 and s2
sites. In particular, compound 23 with carboxyethylester
displayed a reduced s2 anity with an improved selec-
tivity compared to (Æ)-18. Moreover, compounds 25
and 26 with reverse-type ester showed the highest a-
nity of the series and a preference for s1 with respect to
s2 sites.
Substitution of the cis-N-normetazocine nucleus with
1-adamantanamine provided compounds with higher
anity and selectivity for s sites than opioid and
dopamine (D2) receptors.
The substitution of the carboxyester with hydroxy-
methylenic group provided compound 24 with a reverse
s1 and s2 preference and the highest anity of the ser-
ies for s2 binding sites.These data seem to suggest that
an increase of lipophilic bulk and the presence of the
carboxyester group on this position are opportune for
s1 binding sites but not for s2. However, in order to
evaluate the stereoelectronic e€ects on s1 and s2 recep-
tor sites other studies are in progress.
Stereochemical analysis of the cyclopropane ring
revealed that the cis-isomers display enhanced binding
pro®le as compared to the trans-isomers and the ( )-cis
and (+)-cis enantiomers exhibit opposite selectivity for
s1 and s2 sites respectively. This observation supports
current evidence which suggests s1 and s2 are pharma-
cologically di€erent. Moreover, the equal or higher a-
nity of the racemic mixture 18 for s sites with respect to

G. Ronsisvalle et al. / Bioorg. Med. Chem. 8 (2000) 1503±1513
1509
enantiomers ( )-18 and (+)-18 might suggest a favor-
able allosteric modulation, as reported in several
studies.28 30
The second fraction was ( )-2: 32% yield; mp 101±
20
d
102 ꢀC; Rf 0.23; ‰aŠ
44ꢀ; (HPLC) rt=6.71 (cyclo-
hexane:ethyl acetate 57:43); anal. (C19H21NO2) C, H, N.
In addition, with compounds 20±26, we have evaluated
structural modi®cations to nitrogen substituent and to
the carboxylic group with respect to compound (Æ)-18.
(1R,2S)- and (1S,2R)-2-Oxo-1-phenyl-3-oxabicyclo[3.1.0]-
hexane (3). Compound (+)- or ( )-2 (20 g, 67.7 mmol)
was added to a solution of 1N H2SO4 (140 mL) in
dioxane/H2O. The mixture was stirred at 85 ꢀC for 16 h.
After cooling the mixture was diluted with H2O (50 mL)
and subsequently extracted with CH2Cl2 (3Â100 mL).
The combined organic extracts were washed with H2O
and brine, dried with anhydrous Na2SO4 and the
solvents were evaporated in vacuo to give the desired
lactones 3. (+)-3: 1.16 g, 100%; mp 55±56 ꢀC; Rf 0.65
(ethyl acetate:cyclohexane 6:4); IR (KBr): n(CˆO) 1754
The binding data showed that these structural mod-
i®cations gave compounds 23±26 with the highest a-
nity for s receptors and a€orded new insight into the
design of speci®c and high anity ligands for either s1
or s2 receptor subtypes.
cm 1; ‰aŠ20+78ꢀ; MS: m/z 174 [M]+; anal. (C11H10O2)
d
Materials and Methods
Chemistry
C, H. ( )-3: 1.16 g, 100%; mp 54±55 ꢀC; Rf 0.65 (ethyl
1
acetate:cyclohexane 6:4); IR (KBr): n(CˆO) 1754 cm
;
d
20
‰aŠ
76ꢀ; MS: m/z 174 [M]+; anal. (C11H10O2) C, H.
Reagents were purchased from Aldrich Chemicals Co.
unless otherwise speci®ed. Melting points were deter-
mined on a Buchi 530 capillary apparatus and are
uncorrected. Analytical thin-layer chromatography
(TLC) was performed on pre-coated silica gel 60 F254
aluminum sheets (Merck); visualization was accom-
plished under UV or in an iodine chamber. Merck silica
gel 60, 230±400 mesh, was used for ¯ash column chro-
matography. 1H NMR and 13C NMR spectra were
recorded on a Varian Unity INOVA (200 MHz) spec-
trometer with TMS as an internal standard. Optical
rotations were determined in MeOH (c=1) with a Perkin±
Elmer 241 polarimeter. Infrared spectra were recorded
on a 1600 FT-IR Perkin±Elmer instrument and are
consistent with the assigned structures. Elemental ana-
lyses were measured on an elemental analyzer (Model
1106, Carlo Erba). Analyses are indicated by symbols of
the elements. Analytical results obtained for those
elements were within Æ0.4% of the theoretical values.
Molecular weights of the obtained products were
determined by EI MS (70 eV) on a Kratos 2S RFA
spectrometer using a Tektronix 4205 computer system.
Analytical HPLC was carried out on a Waters Model
600-E, using a spherisorb column 10 SIL 10 mm,
25 cmÂ0.46 cm silica gel, ¯ow 3 mL/min, l=254 nm.
Methyl (+)-(1R,2S)-2-(bromomethyl)-1-phenylcyclopro-
panecarboxylate (4a). Compound 3 (1.24 g, 7.11 mmol)
was added to a solution of hydrogen bromide in 33%
acetic acid (12 mL) and the resulting mixture was stirred
at 80 ꢀC for 2 h. After cooling to 40 ꢀC, the reaction
mixture was poured into an ice-H2O bath to obtain the
(1R,2S)-2-(bromomethyl)-1-phenylcyclopropanecarb-
oxylic acid as a white precipitate which was ®ltered and
dried in vacuo [1.66 g, 91%; mp 148 ꢀC; IR (KBr): n
1
(CˆO) 1665; H NMR (CDCl3) d 1.61 (dd, 1H J=4.8,
9.0 Hz), 1.88 (dd, 1H, J=4.8, 7.0 Hz), 2.12±2.22 (m,
1H), 3.72 (dd, 1H, J=10.2, 11.4 Hz), 3.94 (dd, 1H,
J=5.6, 11.4 Hz), 5.28 (br s, 1H), 7.29±7.50 (m, 5H)].
Subsequently, SOCl2 (1.24 mL, 16.9 mmol) was added
to a solution of (1R,2S)-2-(bromomethyl)-1-phenyl-
cyclopropanecarboxylic acid (1.66 g, 6.5 mmol) in anhy-
drous benzene (8 mL) at 0 ꢀC. After heating to re¯ux for
5 h, the reaction was cooled to 0ꢀ C and a solution of
3N CH3OH/HCl (2.76 mL) was added dropwise and
allowed to stir overnight at room temperature. The
mixture was evaporated in vacuo and the residue dis-
solved in Et2O, washed with a solution of 4% NaHCO3
and dried over anhydrous Na2SO4. The solvent was
then evaporated in vacuo to give the desired ester (+)-
4a (1.67 g, 88%): mp 53±55 ꢀC; Rf 0.57 (toluene:chloro-
1
(1R,2S)-2-(Hydroxymethyl)-1-phenyl-N-[(1R)-1-phenyl-
ethyl]cyclopropanecarboxamide and (1S,2R)-2-(hydroxy-
methyl)-1-phenyl-N-[(1R)-1-phenylethyl]cyclopropanecar-
boxamide (2). R(+)-a-Methylbenzylamine (8.8 mL,
78 mmol) and 2-hydroxypyridine (3.24 g, 34 mmol) were
added to a solution of (Æ)-cis-2-oxo-1-phenyl-3-oxa-
bicyclo[3.1.0]hexane (1) (6 g, 34 mmmol) in dry toluene
(20 mL). The mixture was heated to re¯ux for 24 h.
After evaporation in vacuo the residue was dissolved in
CH2Cl2 and washed with 0.5N HCl (4Â20 mL) and then
with H2O. After drying with anhydrous Na2SO4, the
solvent was evaporated and the diastereoisomers (+)-
and ( )-2 were separated by ¯ash chromatography
using cyclohexane:ethyl acetate (60:40).
form 8:2); IR (KBr): n(CˆO) 1716 cm
;
1H NMR
(CDCl3) d 1.52 (dd, 1H J=4.6, 8.5 Hz), 1.78 (dd, 1H,
J=4.6, 7.5 Hz), 2.05±2.12 (m, 1H), 3.72 (dd, 1H, J=10.0,
11.2 Hz), 3.80 (s, 3H), 3.89 (dd, 1H, J=5.6, 11.2 Hz),
7.29±7.50 (m, 5H). 13C NMR (CDCl3) d 22.32, 27.54,
38.36, 38.91, 50.51, 118.30, 125.32, 128.65, 138.41,
173.61; MS: m/z 269 [M]+; anal. (C12H13BrO2) C, H.
The following compounds were prepared using the
above procedure.
Methyl (-)-(1R,2S)-2-(bromomethyl)-1-phenylcyclopropa-
necarboxylate (4a). (1.61 g, 85%); mp 53±55 ꢀC; Rf 0.57
1
(toluene:chloroform 8:2); IR (KBr): n(CˆO) 1716 cm
;
MS: m/z 269 [M]+; anal. (C12H13BrO2) C, H.
The ®rst eluted fraction was (+)-2: 33% yield; mp 74±
d
75 ꢀC; Rf 0.33; ‰aŠ20+96ꢀ; (HPLC) rt=5.22 (cyclo-
Methyl (Æ)-cis-2-(bromomethyl)-1-phenylcyclopropane-
carboxylate (4a). (1.65 g, 87%); mp 53±55 ꢀC; Rf 0.57
hexane:ethyl acetate 57:43), anal. (C19H21NO2) C, H, N.

1510
G. Ronsisvalle et al. / Bioorg. Med. Chem. 8 (2000) 1503±1513
1
(toluene:chloroform 8:2); IR (KBr): n(CˆO) 1716 cm
MS: m/z 269 [M]+; anal. (C12H13BrO2) C, H.
;
J=4.8, 8.8 Hz), 1.85 (dd, 1H, J=4.8, 7.0 Hz), 2.00±2.12
(m, 1H), 3.66 (s, 3H),3.79 (dd, 1H, J=10.0, 11.2 Hz),
3.99 (dd, 1H, J=5.6, 11.2 Hz), 7.26±7-50 (m, 5H). 13C
NMR (CDCl3) d 23.02, 28.44, 38.36, 37.98, 49.31, 50.25
120.42, 127.11, 129.45, 138.11, 173.7; 1H NMR (CDCl3)
d 1.52 (dd, 1H J=4.6, 8.5 Hz), 1.78 (dd, 1H, J=4.6,
7.5 Hz), 2.05±2.12 (m, 1H), 3.72 (dd, 1H, J=10.0,
11.2 Hz), 3.80 (s, 3H), 3.89 (dd, 1H, J=5.6, 11.2 Hz),
7.29±7.50 (m, 5H). 13C NMR (CDCl3) d 22.32, 27.54,
38.36, 38.91, 50.51, 118.30, 125.32, 128.65, 138.41,
173.61; MS: m/z 224 [M]+; anal. (C12H13ClO2) C, H.
Ethyl (Æ)-cis-2-(bromomethyl)-1-phenylcyclopropanecar-
boxylate (4b). (1.61, 80%); mp 60±61 ꢀC; Rf 0.57 (tolu-
ene:chloroform 8:2); IR (KBr): n(CˆO) 1714 cm 1; H
1
NMR (CDCl3) d 1.30 (t, 3H, J=7.0), 2.09±2.31 (m,
2H), 2.35±2.40 (m, 1H), 3.42±3.50 (m, 2H) 3.98 (q, 2H,
J=7.0), 7.28±7.55 (m, 5H). 13C NMR (CDCl3) d 13.20,
22.18, 27.79, 39.59, 39.71, 60.32, 121.32, 125.32, 128.34,
135.22, 174.32. MS: m/z 283 [M]+; anal. (C13H15BrO2)
C, H.
(Æ)-cis-[2-(Chloromethyl)-1-phenylcyclopropyl]methanol
(9). A solution of compound 8 (1 g, 4.45 mmol) in
anhydrous THF (5 mL) was added dropwise to a 0.5 M
solution of alane±N,N-dimethylethylamine complex
(9 mL, 4.48 mmol) in anhydrous THF (10 mL) at 0 ꢀC
under a nitrogen atmosphere. The reaction mixture was
stirred for 2.5 h and quenched with a H2O:THF (1:1)
solution to give a white precipitate. The mixture was
dissolved in 1N HCl and extracted with Et2O
(3Â30 mL). The organic extracts were dried with anhy-
drous Na2SO4 and concentrated under reduced pres-
sure. The crude product was puri®ed by ¯ash
chromatography using cyclohexane:ethyl acetate (9:1)
to obtain 668 mg of compound 9 (0.66 g, 76%); mp 30±
Methyl (Æ)-trans-2-(hydroxymethyl)-1-phenylcyclopro-
panecarboxylate (6). A solution of cis-2-(hydroxy-
methyl)-1-phenylcyclopropanecarboxylic acid 5 (353mg,
1.83 mmol) in 3N HCl in CH3OH (10 mL) was heated to
re¯ux for 4 h. HCl gas was bubbled through the reaction
mixture until the reaction was complete. The solvent
was evaporated and the residue dissolved in CHCl3 and
washed with a solution of 4% NaHCO3. The organic
layer was dried over anhydrous Na2SO4 and con-
centrated under reduced pressure to give the solid pro-
duct 6. (0.34 g, 98%); mp 69±70 ꢀC; Rf 0.6 (ethyl acetate:
1
cyclohexane 7:3); IR (KBr): n(CˆO) 1715 cm
;
1H
NMR (CDCl3) d 1.50 (dd, 1H, J=7.6, 8.5 Hz), 1.80 (dd,
1H, J=7.6, 7.9 Hz), 1.95±2.05 (m, 1H), 3.52 (s, 3H),
3.62 (dd, 1H, J=4.5, 9.5 Hz), 3.89 (dd, 1H, J=4.5,
11.2 Hz), 4.78 (br s, 1H) 7.29±7.50 (m, 5H). 13C NMR
(CDCl3) d 20.12, 26.44, 34.63, 51.11, 60.22, 124.23,
127.05, 128.41, 138.90 173.41; MS: m/z 206 [M]+; anal.
(C12H14O3) C, H.
31 ꢀC; Rf 0.6 (cyclohexane:ethyl acetate 5:5); H NMR
1
(CDCl3) d 0.92 (dd, 1H, J=7.2, 8.3 Hz), 1.15 (dd, 1H,
J=7.7, 8.3 Hz), 1.34±1.63 (m, 1H), 3.40±3.46 (m, 2H),
3.98±4.15 (m, 2H), 4.51 (br s, 1H), 7.29±7.52 (m, 5H).
13C NMR (CDCl3) d 18.22, 25.54, 37.46, 48.05, 68.45,
121.72, 125.35, 128.32, 142.91; MS: m/z 196 [M]+; anal.
(C11H13ClO) C, H.
Methyl (Æ)-trans-2-([(4-methylphenyl)sulfonyl]oxymeth-
yl)-1-phenylcyclopropanecarboxylate (7). With vigorous
stirring pyridine (3.5 mL) and p-toluensulfonyl chloride
(700 mg, 3.67 mmol) were added to a solution of methyl
(Æ)-trans-2-(hydroxymethyl)-1-phenylcyclopropanecarb-
oxylate (6) (376.5 mg, 1.82 mmol) in CH2Cl2 (10 mL)
cooled to 0 ꢀC. After 12 h, the reaction was quenched
with ice, dissolved in Et2O (40 mL) and washed with a
solution of 2N HCl and then with a solution of 4%
NaHCO3. The ether solution was dried over anhydrous
Na2SO4 and concentrated under reduced pressure to
give a crude product that was used without further
puri®cation.
(Æ)-cis-[2-(Chloromethyl)-1-phenylcyclopropyl]methyl
acetate (10). A solution of (Æ)-cis-[2-(chloromethyl)-1-
phenylcyclopropyl]methanol (9) (668 mg, 3.4 mmol) and
4-dimethylaminopyridine (250 mg, 2.03 mmol) was
added under vigorous stirring to a solution of acetyl
chloride (2 mL, 28.1 mmol) in anhydrous THF at room
temperature. After 20 h, the reaction was quenched with
brine (10 mL) and extracted with Et2O (3Â20 mL). The
organic extracts were washed with a 4% solution of
NaHCO3, dried over anhydrous Na2SO4 and con-
centrated under reduced pressure. Subsequently, the
crude product was puri®ed by ¯ash chromatography
eluting with cyclohexane:ethyl acetate (9.5:0.5) to pro-
vide 780 mg of compound 10. Yield 96%; mp 68±70 ꢀC;
Rf 0.58 (cyclohexane:ethyl acetate, 9:1); IR (KBr):
Methyl (Æ)-cis-2-(chloromethyl)-1-phenylcyclopropane-
carboxylate (8).22 A catalytic amount of ZnCl2 and
SOCl2 (2.7 mL, 36.7 mmol) was added dropwise to a
solution of compound (Æ)-1 (2.06 g, 11.9 mmol) in 4 mL
of dry benzene at 0 ꢀC. After heating to re¯ux for 5 h,
the reaction mixture was cooled to 0 ꢀC and a solution
of 3N HCl in CH3OH (3 mL) was added dropwise and
allowed to stir overnight at room temperature. The
mixture was evaporated in vacuo and the residue dis-
solved in Et2O, washed with a solution of 4% NaHCO3
and dried over anhydrous Na2SO4. The solvent was
evaporated in vacuo to provide an oil which was puri®ed
by ¯ash chromatography using cyclohexane:toluene
(6:4) to give the desired ester 8 (2.19 g, 82%); mp 43±
45 ꢀC; Rf 0.52 (toluene:chloroform 8:2); IR (KBr):
1
n(CˆO) 1730 cm 1; H NMR (CDCl3) d 0.89 (dd, 1H,
J=7.4, 8.3 Hz), 1.02 (dd, 1H, J=7.8, 8.3 Hz), 1.31±1.40
(m, 1H), 2.2 (s, 3H), 3.38±3.45 (m, 2H), 4.48±4.70 (m,
2H), 7.15±7.55 (m, 5H). 13C NMR (CDCl3) d 18.33,
22.35, 27.03, 35.21, 47.32, 70.22, 122.12, 124.88,128.66,
141.12, 169.89; MS: m/z 238 [M]+; anal. (C13H15ClO2)
C, H.
N-Methyl-N-(2-piperidin-1-ylethyl)amine (11a). A solution
of 1-(2-chloroethyl)-piperidine hydrochloride (11.9 g,
64 mmol) in H2O (50 mL) was added dropwise to a
solution of 40% methylamine in water (50 mL) at room
temperature under vigorous stirring. After 2 h, NaOH
(20.2 g, 5.06 mol) was added to the reaction mixture.
1
n(CˆO) 1715 cm 1; H NMR (CDCl3) d 1.53 (dd, 1H

G. Ronsisvalle et al. / Bioorg. Med. Chem. 8 (2000) 1503±1513
1511
The aqueous solution was then extracted with Et2O and
dried over anhydrous Na2SO4. After solvent evapora-
tion under reduced pressure, the crude product was
puri®ed by ¯ash chromatography eluting with CHCl3:
CH3OH:30% ammonia solution (8:1.8:0.2) to give
7.05 g of the amine 11a. A portion of the product was
dissolved in Et2O and treated with a solution of H2C2O4
to obtain the oxalate salt as a white solid. The analyti-
cally pure sample was obtained by recrystallization from
methanol (7.1 g, 78%); mp 192±194 ꢀC; Rf 0.23 (CHCl3:
126.85, 127.63, 127.79, 128.52, 128.82, 129.49, 130.14,
131.86, 139.53, 164.30, 172.11; MS: m/z 321 [M]+; anal.
.
(C21H23NO2 0.9H2C2O4 0.5H2O) C, H, N.
.
The following compounds were prepared using the
above procedure.
Methyl (Æ)-cis-2-[(dicyclohexylamino)methyl]-1-phenyl-
cyclopropanecarboxylate (15). (0.2 g, 30%); mp 147±
149 ꢀC; 1H NMR (DMSO-d6) d 0.85±1.85 (m, 23H),
2.96±3.03 (m, 2H), 3.18 (dd, 1H, J=5.0, 12.6 Hz), 3.29
(dd, 1H, J=8.9, 12.6 Hz), 3.52 (s, 3H), 6.20 (br s, 2H),
7.42±7.79 (m, 5H); 13C NMR (DMSO-d6) d 20.54,
22.47, 24.82, 26.33, 28.81, 35.54, 45.73, 50.82, 62.41,
CH3OH:30% ammonia solution 8:1.8:0.2); MS m/z 142
+
.
.
[M] ; anal. (C8H18N2 H2C2O4 H2O) C, H, N.
Using the above mentioned procedure, the N-ethyl-N-
(2-piperidin-1-ylethyl)amine (11b) was prepared in 87%
yield; mp 230±232 ꢀC (oxalate salt); Rf 0.25 (CHCl3:
126.52, 127.32, 132.61, 139.44, 168.31, 172.12; MS: m/z
+
.
.
369 [M] ; anal. (C24H35NO2 0.5H2C2O4 2H2O) C, H,
N.
CH3OH:30% ammonia solution 8:1.8:0.2); MS m/z 156
+
.
[M] ; anal. (C9H20N2 H2C2O4 0.5H2O) C, H, N.
.
Methyl (Æ)-cis-2-{[methyl(2-piperidin-1-ylethyl)amino]-
methyl}-1-phenylcyclopropanecarboxylate (16). (0.15 g,
40%); mp 210±212 ꢀC; 1H NMR (DMSO-d6) d 1.41 (dd,
1H, J=4.2, 7.5 Hz), 1.45±1.95 (m, 8H), 2.49 (s, 3H),
2.83±3.22 (m, 10H), 3.56 (s, 3H), 6.50 (br s, 4H), 7.28±
7.34 (m, 5H); 13C NMR (DMSO-d6) d 20.44, 21.61,
22.79, 24.41, 33.76, 40.66, 50.43, 51.79, 52.65, 52.79,
1-Adamantylformamide (12). A solution of 1-adamanta-
namine (500 mg, 3.3 mmol) in ethyl formate (EtOCHO)
(50 mL) was stirred and re¯uxed for 12 h. The EtOCHO
was evaporated under reduced pressure and the product
was recrystallized from n-hexane/ethyl acetate (592 mg,
100%); mp 138±139 ꢀC; MS: m/z 179 [M]+; anal.
(C11H17NO) C, H, N.
55.00, 127.51, 128.53, 130.09, 139.94, 163.87, 172.26;
+
.
MS: m/z 330 [M] ; anal. (C20H30N2O2 1.8H2C2O4
H2O) C, H, N.
.
N-Methyladamantan-1-amine (13). A solution of 1-ada-
mantylformamide (12) (588 mg, 3.27 mmol) in anhy-
drous THF was added dropwise to a suspension of
LiAlH4 (624 mg, 16,4 mmol) in anhydrous THF. The
reaction was stirred at 40 ꢀC for 5 h and then quenched
with H2O (3 mL) at 7 ꢀC. After ®ltration, the white
precipitate was triturated and washed with Et2O
(40 mL). The organic mixture was dried over Na2SO4
and evaporated in vacuo. The residue was dissolved in
C2H5OH and a solution of C2H5OH/HCl was added.
Evaporation under reduced pressure gave N-methyl-
adamantan-1-amine hydrochloride which was crystal-
lized from ethanol (0.51 g, 95% ); mp 242±244 ꢀC; MS:
m/z 165 [M]+; anal. (C11H19N.HCl.0.2H2O) C, H, N.
Methyl (Æ)-cis-2-{[ethyl(2-piperidin-1-ylethyl)amino]-
methyl}-1-phenylcyclopropanecarboxylate (17). (0.2 g,
90%); mp 166±168 ꢀC; H NMR (DMSO-d6) d 1.11 (t,
1
3H, J=6.8 Hz), 1.41 (dd, 1H, J=5.4, 8.8 Hz), 1.42±1.97
(m, 8H), 2.87±3.35 (m, 12H), 3.55 (s, 3H), 6.05 (br s,
3H), 7.21±7.45 (m, 5H); 13C NMR (DMSO-d6) d 9.98,
20.68, 21.62, 22.88, 24.34, 33.82, 46.78, 47.12, 50.81,
51.79, 5275, 52.94, 127.58, 128.58, 130.19, 139.97,
164.05, 172.39; MS: m/z 344 [M]+; anal. (C21H32N2
.
.
O2 1.5H2C2O4 1.5H2O) C, H, N.
Methyl (Æ)-cis-2-[(1-adamantylamino)methyl]-1-phenyl-
cyclopropanecarboxylate (18). (70 mg, 15%); mp 248±
1
Methyl 2-[3,4-dihydroisoquinolin-2(1H)-ylmethyl]-1-phe-
nylcyclopropanecarboxylate (14). NaHCO3 (168 mg,
2 mmol) and compound 4a (150 mg, 0.66 mmol) were
added to a solution of 1,2,3,4-tetrahydroisoquinoline
hydrochloride (170 mg, 1 mmol) in DMF (7 mL). The
reaction mixture was stirred at 70 ꢀC for 8 h. The solvent
was evaporated under reduced pressure and the residue
was dissolved in CHCl3 and washed with a solution of
4% NaHCO3. The mixture was dried over anhydrous
Na2SO4, evaporated in vacuo and the crude product
was puri®ed by ¯ash chromatography with CHCl3:
cyclohexane:EtOH (6:4.5:0.5). Compound 14 was then
dissolved in THF and treated with a solution of H2C2O4
in THF to give the oxalate salt as a white solid. The
analytically pure sample was obtained by recrystalliza-
tion from methanol/diethyl ether (127 mg, 60%); mp
160±165 ꢀC; 1H NMR (DMSO-d6) d 1.54 (dd, 1H,
J=4.4, 7.0 Hz), 1.68 (t, 1H, J=4.4 Hz), 2.02 (m, 1H),
3.09±3.55 (m, 6H), 3.56 (s, 3H, OCH3), 4.28 (s, 2H), 5.8
(br s, 2H), 7.18±7.38 (m, 9H); 13C NMR (DMSO-d6) d
20.76, 23.21, 25.67, 38.84, 49.23, 52.67, 52.78, 54.41,
250 ꢀC; H NMR (DMSO-d6) d 1.48 (dd, 1H, J=4.0,
9.2 Hz), 1.51±198 (m, 14H), 2.05±2.20 (m, 4H), 3.12 (dd,
1H, J=7.5, 12.6 Hz), 3.50 (dd, 1H, J=5.5, 12.6 Hz),
3.60 (s, 3H), 4.80 (br s, 2H), 7.20±7.45 (m, 5H); 13C
NMR (DMSO-d6) d 19.85, 23.31, 28.35, 34.22, 35.88,
38.08, 46.25, 52.98, 61.01, 127.41, 128.61, 130.80,
139.35, 165.50, 172.19; MS: m/z 339 [M]+; anal.
.
.
(C22H29NO2 0.5H2C2O4 1.5H2O) C, H, N.
Methyl (Æ)-trans-2-[(1-adamantylamino)methyl]-1-phenyl-
cyclopropanecarboxylate (19). (95 mg, 18%); mp 252±
254 ꢀC; 1H NMR (DMSO-d6) d 1.40±1.85 (m, 14H),
1.85±2.22 (m, 4H), 2.84±3.00 (m, 2H), 3.55 (s, 3H), 4.65
(br s, 3H), 7.25±7.47 (m, 5H); 13C NMR (DMSO-d6) d
19.87, 23.21, 28.89, 33.60, 35.06, 37.49, 39.24, 52.43,
55.95, 127.66, 128.31, 131.25, 134.38, 164.51, 173.20;
+
.
MS: m/z 339 [M] ; anal. (C22H29NO2 H2C2O4) C, H, N.
Methyl ( )-(1S,2R)-2-[(1-adamantylamino)methyl]-1-
phenylcyclopropanedcarboxylate [( )-18]. (89 mg, 22%);
20
mp 248±250 ꢀC; ‰aŠ
50ꢀ; 1H NMR (DMSO-d6) d 1.45

1512
G. Ronsisvalle et al. / Bioorg. Med. Chem. 8 (2000) 1503±1513
(dd, 1H, J=4.0, 9.1 Hz), 1.50±2.00 (m, 14H), 2.08±2.25
(m, 4H), 3.14 (dd, 1H, J=7.2, 12.1 Hz), 3.53 (dd, 1H,
J=5.4, 12.1 Hz), 3.61 (s, 3H), 5.5 (br s, 2H), 7.27±7.45
(m, 5H); 13C NMR (DMSO-d6) d 20.58, 23.31, 27.98,
34.50, 35.66, 38.40, 45.91, 51.02, 60.92, 126.33, 128.03,
131.00, 139.02, 166.48, 172.20; MS: m/z 339 [M]+; anal.
20.47, 24.57, 28.72, 34.18, 35.38, 36.93, 37.88, 56.68,
60.50, 127.39, 130.41, 139.80, 164.48, 171.95; MS: m/z
+
.
353 [M] ; anal. (C23H31NO2 H2C2O4) C, H, N.
(Æ)-cis-{2-[(1-Adamantylamino)methyl]-1-phenylcyclopro-
pyl}methanol (24). (0.18 g 76%); mp 282±283 ꢀC; 1H
NMR (DMSO-d6) d 1.05 (dd, 1H, J=5.0, 8.6 Hz), 1.11
(dd, 1H, J=5.5, 8.6 Hz), 1.46 (m, 1H) 1.58 (m, 6H), 1.87
(m, 6H), 2.14 (m, 3H), 3.11 (dd, 1H, J=6.4, 12.2 Hz),
3.29 (dd, 1H, J=5.1, 12.2 Hz), 3.53 (d, 1H, J=11.6 Hz),
4.10 (d, 1H, J=11.6 Hz), 5.60 (br s, 3H), 7.15±7.45
(m, 5H); 13C NMR (DMSO-d6) d 17.51, 20.28, 28.42,
.
(C22H29NO2 0.6H2C2O4) C, H, N.
Methyl (+)-(1R,2S)-2-[(1-adamantylamino)methyl]-1-
phenylcyclopropanecdarboxylate [(+)-18]. (80 mg, 18%);
20
mp 105±112 ꢀC; ‰aŠ +49ꢀ; 1H NMR (DMSO-d6) d
1.47 (dd, 1H, J=4.1, 9.1 Hz), 1.50±2.00 (m, 14H), 2.08±
2.25 (m, 4H), 3.14 (dd, 1H, J=7.2, 12.1 Hz), 3.50 (dd,
1H, J=5.4, 12.1 Hz), 3.59 (s, 3H), 6.2 (br s, 2H), 7.28±
7.50 (m, 5H); 13C NMR (DMSO-d6) d 19.98, 23.10,
28.01, 33.98, 35.00, 39.65, 46.00, 51.32, 61.22, 126.15,
31.72, 35.21, 37.79, 40.12, 55.94, 64.74, 126.29, 128.01,
+
.
128.72, 143.93; MS: m/z 311 [M] ; anal. (C21H29NO2
.
HCl 0.2H2O) C, H, N.
128.32, 131.50, 139.10, 165.98, 172.50; MS: m/z 339
+
(Æ)-cis-{2-[(1-Adamantylamino)methyl]-1-phenylcyclopro-
pyl}methyl acetate (25). (97 mg, 28%); mp 210±211 ꢀC;
1H NMR (DMSO-d6) d 1.09 (dd, 1H, J=7.6, 8.2 Hz),
1.25 (dd, 1H, J=7.4, 8.2 Hz), 1.41 (m, 1H), 1.50±1.78
(m, 6H), 1.80±1.95 (m, 6H), 1.97 (s, 3H) 2.05±2.22 (m,
3H), 2.90 (dd, 1H, J=5.6, 12.5 Hz), 3.42 (dd, 1H,
J=8.7, 12.5 Hz), 4.30 (d, 1H, J=12.4 Hz), 4.38 (d, 1H,
J=12.4 Hz), 5.00 (br s, 3H), 7.18±7.41 (m, 5H); 13C
NMR (DMSO-d6) d 17.66, 21.10, 21.50, 28.78, 29.51,
35.43, 37.88, 40.91, 56.71, 67.52, 127.16, 128.69, 128.75,
142.94, 165.19, 170.92; MS: m/z 353 [M]+; anal. (C23
.
[M] ; anal. (C22H29NO2 0.7H2C2O4 2H2O) C, H, N.
.
Methyl (Æ)-cis-2-{[(1-adamantylmethyl)amino]methyl}-
1-phenylcyclopropanecarboxylate (20). (120 mg, 57%);
mp 210±212 ꢀC; H NMR (DMSO-d6) d 1.41 (dd, 1H,
1
J=4.6, 8.7 Hz), 1.46±1.80 (m, 13H), 1.82±2.10 (m, 4H),
2,6 (s, 2H) 3.22 (dd, 1H, J=5.0, 12.6 Hz), 3.45 (dd, 1H,
J=9.0, 12.6 Hz), 3.60 (s, 3H), 5.8 (br s, 3H), 7.27±7.45
(m, 5H); 13C NMR (DMSO-d6) d 19.80, 23.71, 27.08,
35.95, 37.80, 39.45, 44.71, 45.80, 52.75, 60.97, 127.44,
.
.
128.29, 130.41, 139.61, 164.27, 172.09; MS: m/z 353
+
H31NO2 H2C2O4 0.4H2O) C, H, N.
.
[M] ; anal. (C23H31NO2 H2C2O4 0.2H2O) C, H, N.
.
(Æ)-cis-(2-{[1-Adamantyl(methyl)amino]methyl}-1-phenyl-
cyclopropyl)methyl acetate (26). (110 mg, 15%); mp
132±133 ꢀC; 1H NMR (DMSO-d6) d 1.10 (dd, 1H,
J=7.3, 8.3 Hz), 1.28 (dd, 1H, J=7.0, 8.3 Hz), 1.40 (m,
1H), 1.50±1.90 (m, 12H), 1.99 (s, 3H), 2.10±2.32 (m,
3H), 2.73 (s, 3H), 2.92 (dd, 1H, J=5.8, 12.8 Hz), 3.44
(dd, 1H, J=8.5, 12.8 Hz), 4.33 (d, 1H, J=12.7 Hz), 4.41
(d, 1H, J=12.7 Hz), 5.50 (br s, 3H), 7.20±7.44 (m, 5H);
13C NMR (DMSO-d6) d 17.36, 20.98, 21.32, 28.80,
29.32, 32.00, 35.27, 36.90, 40.05, 55.80, 68.52, 127.51,
Methyl (Æ)-cis-2-({[1-(1-adamantyl)ethyl]amino}methyl)-
1-phenylcyclopropanecarboxylate (21). (125 mg, 66%);
mp 190±191 ꢀC; 1H NMR (DMSO-d6) (1:1 diastereo-
isomeric mixture) d 1.14 (d, 3H, J=6.6 Hz), 1.16 (d, 3H,
J=6.6 Hz), 1.40 (dd, 1H, J=4.0, 8.8 Hz) 1.45±1.80 (m,
13H), 1.84±2.10 (m, 4H), 2.83 (q, 1H, J=6.6 Hz), 3.10±
3.30 (m, 1H), 3.35±3.45 (m, 1H), 3.57 (s, 3H), 3.58 (s,
3H), 5.4 (br s, 3H), 7.20±7.45 (m, 5H); 13C NMR
(DMSO-d6) (1:1 diastereoisomeric mixture) d 10.28,
10.57, 20.06, 21.23, 23.68, 24.07, 2752, 33.20, 34.21,
34.81, 34.87, 36.11, 36.92, 43.96, 44.91, 52.57, 52.58,
61.59, 62.47, 127.31, 128.05, 128.18, 129.95, 130.26,
139.43, 139.54, 164.53, 172.01; MS: m/z 367 [M]+; anal.
128.44, 128.81, 141.09, 164.12, 171.32; MS: m/z 367
+
.
[M] ; anal. (C24H33NO2 H2C2O4 1.5H2O) C, H, N.
.
.
(C22H29NO2 H2C2O4) C, H, N.
Biological Evaluation
Methyl (Æ)-cis-2-{[1-adamantyl(methyl)amino]methyl}-
1-phenylcyclopropanecarboxylate (22). (135 mg, 42%);
Radioligand binding assays
mp 181±184 ꢀC; H NMR (DMSO-d6) d 1.51 (dd, 1H,
Sigma1 binding assays were carried out on guinea pig
brain membranes prepared by the method described by
Matsumoto et al.31 and the protein content was eval-
uated.32 The binding assay was performed as described
by DeHaven et al.33 Each tube contained 500 mg of
membrane protein, 3 nM [3H]-pentazocine (31.6 Ci/
mmol; the value of the apparent dissociation constant
(Kd) was 4.3Æ0.8 nM, n=3). Non-speci®c binding was
determined by addition of 10 mM haloperidol. The
reaction was performed for 150 min at 37 ꢀC and termi-
nated by ®ltering the solution through Whatman GF/B
glass ®lters that were presoaked in a 0.5% polyethyl-
enimine solution.
1
J=4.1, 8.8 Hz), 1.60±1.78 (m, 7H), 1.82±2.23 (m, 10H),
2.75 (s, 3H), 3.25±3.50 (m, 2H), 3.58 (s, 3H), 5.40 (br s,
2H), 7.22±7.45 (m, 5H); 13C NMR (DMSO-d6) d 20.65,
23.75, 28.92, 32.38, 34.10, 35.07, 35.52, 46.81, 52.62,
62.97, 127.31, 128.19, 130.07, 139.31, 164.63, 172.04;
+
.
MS: m/z 353 [M] ; anal. (C23H31NO2 0.5H2C2O4
1.5H2O) C, H, N.
.
Ethyl (Æ)-cis-2-[(1-adamantylamino)methyl]-1-phenyl-
cyclopropanecarboxylate (23). (98 mg, 35%); mp 210±
ꢀ
1
212 C; H NMR (DMSO-d6) d 1.07 (t, 3H, J=7 Hz),
1.49 (dd, 1H, J=4.0, 8.8 Hz), 1.54±2.00 (m, 13H), 2.10±
2.22 (m, 4H), 3.12 (dd, 1H, J=7.4, 12.7 Hz), 3.46 (dd,
1H, J=5.8, 12.7 Hz), 4.00 (q, 2H, J=7 Hz), 5.00 (br s,
3H), 7.20±7.42 (m, 5H); 13C NMR (DMSO-d6) d 14.26,
Sigma2 binding assays were carried out on guinea pig
brain membranes prepared as described by Mach et al.34

G. Ronsisvalle et al. / Bioorg. Med. Chem. 8 (2000) 1503±1513
1513
These were incubated with 3 nM [3H]-DTG [1,3-di-2-
(tolyl)-guanidine] (35 Ci/mmol; Kd=9.9Æ0.8 nM; n=3)
in the presence of 100 nM (+)-NANM (N-allyl-norm-
etazocine) to mask sigma1 receptor sites. Incubations
were carried out in 50 mM Tris±HCl (pH 8.0) for
120 min at room temperature and assays were termi-
nated by the addition of ice-cold 10 mM Tris±HCl (pH
8.0) followed by ®ltration through Whatman GF/B
glass ®bers. Non-speci®c binding was evaluated in the
presence of 5 mM DTG.
8. Walker, J. M.; Bowen, W. D..; Patrick, S. L.; Williams, W.
E.; Mascarella, S. W.; Bai, X.; Carroll, F. I. Eur. J. Pharmacol.
1993, 231, 61.
9. Mach, R. H.; Smith, C. R.; al-Nabulsi, I.; Whurrett, B. R.;
Wheeler, K. T. Cancer Res. 1997, 57, 156.
10. Moltzen, E. K.; Perregaard, J.; Meier, E.; Sanchez, C.;
Arnt, J.; Nielsen, J. B. Twelfth International Symposium on
Medicinal Chemistry; Basel, Switzerland, 13±17 September
1992, Abstract P-105.A.
11. Debonnel, G.; de Montigny, C. Life Sci. 1996, 58, 721.
12. Quirion, R.; Bowen, W. D.; Itzhak, Y.; Junien, J. L.;
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Taylor, D. P. Trends in Pharmacol. Sci. 1992, 13, 85.
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Total opioid receptor binding was assessed on rat brain
membranes prepared as previously reported19 and incu-
bated in the presence of [3H]-naloxone (55.5 Ci/mmol;
Kd=6.6Æ0.7 nM; n=3). Non-speci®c binding was eval-
uated in the presence of 10 mM naloxone. Binding assays
for the k-opioid receptor were carried out on mem-
branes obtained from guinea pig cerebella using [3H]-
U69,593 (62 Ci/mmol; Kd=1.98Æ0.4; n=3) in the pre-
sence of 300 nM d-Ala,2 N-MePhe,4 Gly-ol5-enkephalin
and 300 nM d-Ala2-d-Leu5-enkephalin to block the m
and d receptors.
14. Kekuda, R.; Prasad, P. D.; Fei, Y.; Leibach, F. H.; Gana-
pathy, V. Biochem. Biophys. Res. Comm. 1996, 229, 553.
15. Moebius, F. F.; Bermoser, K.; Reiter, R. J.; Hanner, M.;
Glossmann, H. Biochem. 1996, 35, 16871.
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Pharmacol. Sci. 1997, 18, 67.
17. Torrence-Campbell, C.; Bowen, W. D. Eur. J. Pharmacol.
1996, 304, 201.
18. De Costa, B. R.; He, X. S. In Sigma Receptors; Itzhak, Y.,
Ed.; Academic: San Diego, CA, 1994; Chapter 3, pp 45±111.
19. Ronsisvalle, G.; Pasquinucci, L.; Pappalardo, M. S.;
Vittorio, F.; Fronza, G.; Romagnoli, C.; Pistacchio, E.;
Spanpinato, S.; Ferri, S. J. Med. Chem. 1993, 36, 1860.
20. Ronsisvalle, G.; Prezzavento, O.; Pasquinucci, L.; Marrazzo,
A.; Vittorio, F.; Gomez-Vidal, J. A.; Carboni, L.; Spanpinato,
S. Life Sci. 1995, 16, 1487.
Dopaminergic (D2) receptor binding assays were per-
formed using 0.5 nM [3H]-spiroperidol (18.5 Ci/mmol;
Kd=0.5Æ0.08 nM; n=3) and rat striatal membranes
as reported by Briley and Langer.35 Non-speci®c bind-
ing assays were measured in the presence of 10 mM
haloperidol.
21. Ronsisvalle, G.; Prezzavento, O.; Pasquinucci, L.;
Pappalardo, M. S.; Marrazzo, A.; Vittorio, F.; Carboni, L.;
Spanpinato, S. IL FARMACO 1997, 52 (6±7), 471.
22. Casadio, S.; Bonnaud, B.; Mouzin, G.; Cousse, H. Boll.
Chim. Farm. 1978, 117, 331.
Inhibition constants (Ki values) for test compounds
were calculated using the EBDA/LIGAND program,36
purchased from Elsevier/Biosoft.
23. Yang, D.; Soulier, J.; Sicsic, S.; Mathe-Allainmat, M.;
Bremont, B.; Croci, T.; Cardamone, R.; Aureggi, G.; Langlois,
M. J. Med. Chem. 1997, 40, 608.
Acknowledgements
24. Watanabe, T.; Kinoyama, I.; Kakefuda, A.; Okazaki, T.;
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We thank Italian MURST and CNR for ®nancial sup-
port. The authors would also like to thank Dr. Salva-
tore Di Marco for the elemental analyses.
26. Shokova, E.; Mousolou, T.; Luzikov, Y.; Kovalev, V.
Synthesis 1997, 1034.
27. Aldrich, P. E.; Hermann, E. C.; Meier, W. E.; Paulshock,
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