Synthesis and pharmacological evaluation of some (pyridyl)cyclopropylmethyl amines and their methiodides as nicotinic receptor ligands.

Article abstract of DOI:10.1016/S0014-827X(02)01234-X

A series of 3- and (4-pyridyl)cyclopropylmethyl amines and their quaternary ammonium derivatives have been synthesized; they can be considered as rigid analogues of nicotine. The compounds have been tested on rat cerebral cortex to measure the affinity for the central nicotinic receptor. Only the methiodides show affinity in the micromolar range. The results obtained can provide useful information on the topography of the nicotinic receptor-binding site.

Full text of DOI:10.1016/S0014-827X(02)01234-X

Il Farmaco 57 (2001) 487–496
www.elsevier.com/locate/farmac
Synthesis and pharmacological evaluation of some
(pyridyl)cyclopropylmethyl amines and their methiodides as
nicotinic receptor ligands
Luca Guandalini a, Silvia Dei a, Dina Manetti a, Maria Novella Romanelli a,*,
Serena Scapecchi a, Elisabetta Teodori a, Katia Varani b
a Dipartimento di Scienze Farmaceutiche, Uni6ersita` di Firenze, Via Gino Capponi 9, 50121 Florence, Italy
b Dipartimento di Farmacologia, Uni6ersita` di Ferrara, Via Fossato di Mortara 17-19, 44100 Ferrara, Italy
Received 25 October 2001; accepted 19 February 2002
Abstract
A series of 3- and (4-pyridyl)cyclopropylmethyl amines and their quaternary ammonium derivatives have been synthesized; they
can be considered as rigid analogues of nicotine. The compounds have been tested on rat cerebral cortex to measure the affinity
for the central nicotinic receptor. Only the methiodides show affinity in the micromolar range. The results obtained can provide
´
useful information on the topography of the nicotinic receptor-binding site. © 2002 Editions scientifiques et me´dicales Elsevier
SAS. All rights reserved.
Keywords: Nicotinic receptor ligands; Structure–activity relationships; Cyclopropyl derivatives
1. Introduction
The nicotinic pharmacophore is composed of essen-
tially two elements: an H-bond acceptor group and a
charged nitrogen atom, at a certain distance from each
other. The most common H-bond acceptor groups are
the sp2 nitrogen of a pyridyl ring or a carbonyl oxygen,
while the basic nitrogen is usually part of a ring of
different size and shape. Some important examples of
nicotinic agonists are reported in Chart 1; many other
molecules have been synthesized, in which the two
pharmacophoric elements are connected by spacers of
different length and volume (for an exhaustive review on
the structure of nicotinic ligands see ref. [8]).
Alzheimer’s disease is characterized by a deterioration
of cognitive functions, expressed by loss of memory,
impaired attention and disturbance of the language [1].
Several hypotheses have been formulated to rationalize
the origin of the disease; among them are the cholinergic
hypothesis [2] and the more recent amyloid hypothesis
[3–5]. In any case, the cholinergic system has been shown
to play a pivotal role in this disease. Both muscarinic and
nicotinic acetylcholine receptors are involved; while in
the past, researchers had focused their attention on the
development of muscarinic receptors modulators [6],
more recently interest in the synthesis of nicotinic ligands
has grown, since this kind of receptor seems to be
involved not only in Alzheimer’s disease, but also in other
important pathologies such as Parkinson’s disease,
Tourette’s syndrome and schizophrenia, as well as in the
modulation of pain [7]. Therefore, selective nicotinic
agonists may be useful drugs in several pathological
states, and at the same time could be important for the
characterization of nicotinic receptors.
(1)
* Corresponding author.
E-mail address: novella.romanelli@unifi.it (M.N. Romanelli).
´
0014-827X/02/$ - see front matter © 2002 Editions scientifiques et me´dicales Elsevier SAS. All rights reserved.
PII: S0014-827X(02)01234-X

488
L. Guandalini et al. / Il Farmaco 57 (2002) 487–496
Several nicotine analogues have been synthesized in
good affinity but probably the N-methyl group, in the
new orientation, may cause some steric hindrance in the
interaction with the receptor. In support of this hypo-
thesis, it must be noted that some bicyclic derivatives
such as epibatidine and cytisine, being rigid secondary
amines, are more active than their methylated deriva-
tives [9].
The cyclopropylmethylamines (A) (trans, Chart 2)
were, therefore, designed in which the two pharma-
cophoric elements (pyridyl ring and aliphatic nitrogen)
are connected by a spacer (cyclopropylmethyl group)
with a low hindrance to reduce untoward steric effects,
and in which the position of the nitrogen shows some
rigidity since the rotation around the cyclopropyl-
methyl bond is not completely free (Fig. 1). This
molecule could comply with the nicotinic pharma-
cophore (Fig. 2), since the distance between the pyridyl
the last decades, some of which show improved affinity
over the lead [8,9]. For instance, the racemic azetidine
analogues 2a and 2b (Chart 1) are reported to have
higher affinity than racemic nicotine (1a) and racemic
nor-nicotine (1b) [8]; moreover, in a series of enantio-
pure pyridyl ethers 3, synthesized at the Abbott labora-
tories, the replacement of the pyrrolidine with an
azetidine ring has also led to an increase in affinity [10].
These results suggest that the reduction of the confor-
mational mobility of the pyrrolidine nitrogen, by free-
zing it into a rigid 4-membered ring, gives an optimal
arrangement to the molecule; as a consequence, a ter-
tiary base is no longer required, as in nicotine, to have
,
nitrogen and the basic center (5.66 A in one of the
low-energy conformations, see Section 4) would be
similar to that reported for epibatidine [11], and the
aliphatic nitrogen could eventually be made more basic
by the introduction of one or two methyl groups, or
quaternarized. We thought it also useful to synthesize
compounds B, the 4-pyridyl isomers of A. In fact, in a
previous paper on nicotinic receptor ligands structurally
related to dimethylphenylpiperazinium iodide (DMPP),
the agonistic properties of the pyridyl derivatives 4 and
5 were reported [12]: the 4-pyridyl isomer 5 showed
analgesic activity, with lower potency but higher effi-
cacy than nicotine.
Fig. 1. Dihedral driver calculations for the cis (triangles) and trans
(squares) isomers of compound A (X=NH+3 ). The dihedral angle
(HꢀC(cy)ꢀCꢀN) is shown in the figure.
(2)
Since during modeling of compounds of the A and B
series we realized that the corresponding cyclopropy-
lamines (series C and D) would fit, even better, the
nicotinic pharmacophore (Fig. 3), we decided to include
these compounds in our synthetic program. Toward
this end, we chose a synthetic pattern that would make
cyclopropyl- and cyclopropylmethyl-amines accessible
through a common intermediate (Chart 2). Unfortu-
nately, as it will be reported in the next section, the
chosen route failed to give the cyclopropylamine series
C and D.
Fig. 2. Two different views of the overlap of epibatidine (2R isomer,
green and 2S isomer, yellow), (S)-nicotine (orange) with trans-A (red,
1R,2R-isomer).
2. Chemistry
It was anticipated that 2-(4-pyridyl)cyclopropane-
carboxylic acid ethyl ester, and its 3-pyridyl isomer,
Fig. 3. Overlap of epibatidine (2R isomer, green and 2S isomer,
yellow) with trans C (red, 1R,2S and cyano, 1S,2R isomers).

L. Guandalini et al. / Il Farmaco 57 (2002) 487–496
489
isomers (7a and 8a) but only very little cis isomer (7b
and 8b). It is interesting to notice that the cis/trans
ratio was changed after the reaction, indicating that
isomerization of the cis isomer into the apparently more
stable trans isomer has occurred. Accordingly, the reac-
tion with the more basic dimethylamine gave only the
trans isomer 9a. The trans isomers (7a, 8a, 9a), but not
the cis ones obtained in a too small quantity, were
reduced to the corresponding amines 10a, 11a, 12a with
LiAlH4. Finally, compound 12a was transformed into
the methiodide 14a.
To obtain the cis isomers of derivatives 10–12, which
would be useful for comparative purposes, we explored
a new pathway that indeed would prevent isomeriza-
tion. Thus, the mixture of esters 6 was reduced to
alcohols 13 and then transformed into amines 12. In
both these steps, however, we were unable to separate
the mixtures.
Scheme 1.
3-Vinyl-pyridine (15) [16] was obtained according to
Scheme 2, and reacted with ethyl diazoacetate to give
the ester 16 as a mixture which was separated by
chromatography; in this case separation was easier,
yielding also a suitable amount of the cis isomer. Trans-
formation of the ester 16a into the corresponding pri-
mary amide 17 occurred with isomerization, since a 1:1
mixture of cis/trans isomers was obtained. The synthe-
sis of the cyclopropylmethylamines was, therefore, per-
formed through the alcohols 18, which were
transformed only into amines 19 and the methiodides
20.
In order to try the Curtius rearrangement for the
synthesis of cyclopropylamines (general formulas C and
D, Chart 2), the ester 6, as cis/trans mixture, was
hydrolyzed to the acid 21(a,b) (Scheme 1), which was
reacted according to Ninomiya [17] without success.
The Hoffmann rearrangement of amide 7, as cis/trans
mixture, according to literature methods [18–20], af-
forded back unreacted starting material and/or compli-
cated mixtures of products, whose GC MS analysis did
not reveal the presence of the desired carbamates or
amines. Similar attempts on amide 17 were again with-
out success.
Scheme 2.
easily synthesized by reaction of vinylpyridines with
ethyl diazoacetate, could be suitable intermediates for
the synthesis of the desired compounds. Thus, 4-
vinylpyridine was reacted with ethyl diazoacetate ac-
cording to Gray [13] obtaining the ester 6 (Scheme 1) as
a 1:2 cis/trans mixture. Column chromatography af-
forded pure trans (6a) and cis (6b) isomers but the
separation was not efficient and only small amounts of
the cis isomer were obtained. The stereochemistry of
the isomers was established on the basis of their [1H]
NMR spectra that were found similar to those reported
for 2-arylcyclopropane-1-carboxylic acid derivatives
[14,15]. To overcome the difficulties met in the separa-
tion of its isomers, ester 6, as the 1:1 cis/trans mixture
deriving from column chromatography, was trans-
formed into the amides 7 and 8. However, column
chromatography separation was inefficient also in the
case of amides affording suitable quantities of the trans
3. Result and discussion
The synthesized compounds have been tested in vitro
on rat brain homogenates to evaluate their affinity for
the central nicotinic receptors using [3H]-cytisine, be-
lieved to label the a4b2 isoform of the neuronal nico-
tinic receptor, which represents up to 90% of the high
affinity agonist binding sites in rat brain [21,22]. The
cis/trans mixture of 12 (12a,b) is included to obtain
information on the activity of 12b which was not
obtained pure.

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L. Guandalini et al. / Il Farmaco 57 (2002) 487–496
Table 1
Binding affinity a of methiodides 14 and 20
N
Ki (mM)
14a (trans)
14(a,b)
20a (trans)
20b (cis)
Nicotine
\10
b
1.090.1
1.190.1
1.390.1
0.008290.0005 c
a On rat brain homogenates. The neuronal nicotinic acetylcholine
receptors were labeled by [3H]-cytisine. See ref [23] for the experimen-
tal protocol.
b As 1:2 cis:trans mixture.
c See ref [22].
Fig. 5. Two different views of the overlap of epibatidine (2R isomer,
green and 2S isomer, yellow), (S)-nicotine (orange) with 20a (red,
1R,2R isomer), 20b (magenta, 1R,2S isomer), 14a (blue, 1R,2R iso-
mer), 14b (cyan, 1S,2R isomer).
The amino derivatives 10a–12a, 12(a,b), 19a and 19b,
and the methiodide 14a did not show affinity for the
neuronal nicotinic receptor up to a concentration of 10
mM, while a Ki in the micromolar range could be
measured for the methiodides 20a and 20b, and also for
14b, which was tested only as a mixture with the
inactive trans isomer 14a; their binding affinities are
reported in Table 1. Due to the inactivity of 19, the
analogous primary and secondary amines were not
synthesized.
the bulkier trimethylammonium group, does not alter
the geometry of the low energy conformations but the
barrier for rotation around the cyclopropylꢀmethyl
bond (Fig. 4) becomes higher than in A; in addition, it
increases the distance between the pyridyl and the
,
charged nitrogen atoms, from the 5.66 and 4.62 A in
the protonated primary amines A (trans and cis respec-
,
It seems, therefore, that a permanent positive charge
is required for the interaction of this class of substance
with the receptor; although this is not a general rule
within nicotinic agonists [8], it has been noted also for
other kinds of nicotinic ligands [23–25]. The difference
between ammonium derivatives (20a, 20b and 14b) and
their corresponding amines lies in the charge distribu-
tion and the volume of the additional methyl group(s):
although there is a permanent positive charge on the
nitrogen, in an ammonium derivative this is spread on
the alkyl groups, resulting in lower partial charges with
respect to a protonated amine, where a great part of the
charge is on the hydrogen atom. Regarding the volume,
tively) to 5.98 and 5.18 A in the methiodides 20a and
20b, respectively, therefore, reducing the fitting with
epibatidine (Fig. 5). It is surprising, however, that both
isomers of 20 show the same affinity, since they occupy
very different areas.
The inactivity of 14a with respect of 14b could be
explained in terms of distance between the two nitrogen
atoms (7.01 and 5.74 A, respectively); however, it must
be noted that the former value is similar to that found
in compound 5 [12].
In conclusion, despite the fact that they appeared to
fulfil the requirements of the nicotinic pharmacophore,
our compounds lack substantial nicotinic activity thus
,
Fig. 4. Dihedral driver calculations for 20a (triangles) and 20b (squares); the dihedral angle (HꢀC(cy)ꢀCꢀN) is shown in the figure.

L. Guandalini et al. / Il Farmaco 57 (2002) 487–496
491
showing that our model of the pharmacophore is far
from being satisfactory.
14.45 (q), 22.77 (d), 24.87 (d), 60.89 (t), 124.76 (d),
146.11 (s), 149.49 (d), 170.51 (s).
4.1.2. 2-(4-Pyridyl)cyclopropanecarboxamide (7a, trans
and 7b, cis)
4. Experimental
To 6(a,b) as 1:1 cis/trans mixture (2.55 g, 13.35
mmol) dissolved in 20 ml of EtOH was added a solu-
tion of NH4Cl (0.16 g, 3 mmol) in NH4OH (90 ml, 1.75
mol). After heating in autoclave at 120 °C for 16 h, the
excess of NH3 and the solvent were evaporated in
vacuum and the solid residue treated with CHCl3 and
filtered. Evaporation of the solvent and purification by
column chromatography with CHCl3/MeOH 9:1 as
eluent gave 0.6 g of 7a (trans isomer, solid, 28% yield),
0.12 g of 7(a,b) (1:1 cis/trans mixture) and 0.03 g of 7b
(cis isomer, solid, 1% yield). IR (cis/trans) w 3340 (NH),
1660 (CON), 1610 (NH).
4.1. Chemistry
All melting points were taken on a Bu¨chi apparatus
and are uncorrected. Infrared spectra were recorded
with a Perkin–Elmer 681 spectrophotometer in Nujol
mull for solids and neat for liquids. NMR Spectra were
recorded on a Gemini 200 spectrometer (200 MHz for
1H, 50.3 MHz for 13C). Chromatographic separations
were performed on a silica gel column by gravity chro-
matography (silica gel 40, 0.063–0.200 mm; Merck) or
flash chromatography (silica gel 40, 0.040–0.063 mm;
Merck). Yields are given after purification, unless
otherwise stated. Where analyses are indicated by sym-
bols, the analytical results are within 90.4% of the
theoretical values.
Compound 7a (trans isomer) [1H] NMR (CD3OD) l
1.34–1.43 (m, 1H, CH); 1.56–1.65 (m, 1H, CH); 2.01–
2.10 (m, 1H, CH); 2.35–2.45 (m, 1H, CH); 7.21 (d,
J=6.2 Hz, 2H) and 8.39 (d, J=6.2 Hz, 2H) (aromatic
protons). [13C] NMR (CD3OD) l 15.62 (t), 23.39 (d),
25.50 (d), 121.19 (d), 148.16 (d), 151.75 (s), 174.61 (s).
M.p. 185 °C (d). Anal. C9H10N2O (C, H, N).
4.1.1. Ethyl 2-(4-pyridyl)cyclopropanecarboxylate [13]
(6a, trans and 6b, cis)
This compound was prepared according to Gray [13]:
to a solution of 1.09 g (9.55 mmol) of ethyl diazoacetate
in 20 ml of anhydrous xylene was added 1.00 g (9.51
mmol) of 4-vinylpyridine. The reaction mixture was
heated at 95 °C for 30 min, then at 115 °C for 30 min
and at 140 °C for 5 h. Removal of the solvent and
purification by column chromatography (eluting sol-
vent: petroleum ether/Et2O/abs. EtOH/CHCl3/NH4OH
200:500:40:200:2.5) gave 1.23 g (68% yield) of mixture
of cis/trans isomer in about 1:2 ratio. GC MS: (first
isomer) m/z (%) 191 (M+, 16), 162 (16), 146 (22), 118
(100), 117 (99), 108 (28), 91 (52), 65 (37); (second
isomer) m/z (%) 191 (M+, 25), 162 (20), 146 (68), 118
(71), 117 (100), 108 (17), 91 (27), 89 (22), 65 (26).
Further separation of the two isomers by column chro-
matography (using CHCl3–MeOH 99:1 as eluent) gave
0.43 g of the trans isomer 6a, 0.09 g of the cis isomer 6b
and 0.70 g of a 1:1 mixture of 6a and 6b.
Compound 7b (cis isomer) [1H] NMR (CD3OD) l
1.30–1.42 (m, 1H, CH); 1.66–1.76 (m, 1H, CH); 2.16–
2.29 (m, 1H, CH); 2.46–2.60 (m, 1H, CH); 7.33 (d,
J=4.4 Hz, 2H) and 8.37 (d, J=4.4 Hz, 2H) (aromatic
protons). [13C] NMR (CD3OD) l 9.03 (t), 22.99 (d),
23.18 (d), 124.53 (d), 147.49 (d), 148.18 (s), 172.40 (s).
M.p. 151–158 °C. Anal. C9H10N2O (C, H, N).
4.1.3. N-Methyl-2-(4-pyridyl)cyclopropanecarboxamide
(8a, trans and 8b, cis)
Starting from 1 g (5.2 mmol) of 6(a,b) as 1:1 cis/trans
mixture and MeNH2, following the procedure described
for 7, a residue was obtained which was purified by
column chromatography (CH2Cl2/MeOH 9:1 as eluent),
obtaining 0.32 g of 8a (trans isomer, oil, 35% yield),
0.34 g of 8(a,b) (6:4 cis/trans mixture, oil, 37% yield)
and 0.09 g of 8b (cis isomer, oil, 9% yield). IR (cis and
trans) w 3190 (NH), 1730 (CON).
Compound 6a (trans) [1H] NMR (CDCl3) l 1.21 (t,
J=7.1 Hz, 3H, CH3CH2); 1.23–1.32 (m, 1H, CH);
1.56–1.65 (m, 1H, CH); 1.87–1.96 (m, 1H, CH); 2.34–
2.44 (m, 1H, CH); 4.11 (q, J=7.1 Hz, 2H, CH3CH2);
6.92 (d, J=5.9 Hz, 2H) and 8.40 (d, J=5.9 Hz, 2H)
(aromatic protons). [13C] NMR (CDCl3) l 14.62 (q),
17.91 (t), 25.11 (d), 25.34 (d), 61.36 (t), 121.43 (d),
149.82 (s), 150.00 (d), 172.77 (s).
Compound 8a (trans isomer) [1H] NMR (CDCl3) l
1.21–1.34 (m, 1H, CH); 1.68–1.79 (m, 2H, 2-CH);
2.20–2.49 (m, 1H, CH); 2.86 (d, J=4.8 Hz, 3H,
NCH3); 6.18 (bs, 1H, NH); 6.99 (d, J=6.2 Hz, 2H) and
8.43 (d, J=6.2 Hz, 2H) (aromatic protons). [13C] NMR
(CDCl3) l 16.73 (t), 24.19 (d), 27.00 (q), 27.60 (d),
121.43 (d), 149.55 (d), 151.33 (s), 172.00 (s) ppm. Anal.
C10H12N2O (C, H, N).
Compound 6b (cis) [1H] NMR (CDCl3) l 0.98 (t,
J=7.1 Hz, 3H, CH3CH2); 1.31–1.42 (m, 1H, CH);
1.67–1.76 (m, 1H, CH); 2.08–2.20 (m, 1H, CH); 2.41–
2.54 (m, 1H, CH); 3.87 (q, J=7.1 Hz, 2H, CH3CH2);
7.16 (d, J=5.9 Hz, 2H) and 8.45 (d, J=5.9 Hz, 2H)
(aromatic protons). [13C] NMR (CDCl3) l 11.47 (t),
Compound 8b (cis isomer) [1H] NMR (CDCl3) l
1.28–1.39 (m, 1H, CH); 1.74–1.83 (m, 1H, CH); 1.92–
2.04 (m, 1H, CH); 2.27–2.39 (m, 1H, CH); 2.65 (d,
J=5.1 Hz, 3H, NCH3); 5.87 (bs, 1H, NH); 7.18 (d,
J=6.0 Hz, 2H) and 8.45 (d, J=6.0 Hz, 2H) (aromatic
protons). [13C] NMR (CDCl3) l 10.92 (t), 24.19 (d),

492
L. Guandalini et al. / Il Farmaco 57 (2002) 487–496
25.07 (d), 26.91 (q), 124.45 (d), 147.09 (s), 149.38 (d),
169.41 (s). Anal. C10H12N2O (C, H, N).
4.1.7. trans-N,N-Dimethyl-[(2-(4-pyridyl)cyclo-
propyl]methylamine (12a)
4.1.7.1. Method A. Starting from 0.09 g (0.7 mmol) of
9a and following the procedure described for 10a, the
title compound was obtained in 84% yield.
4.1.4. trans-N,N-Dimethyl-2-(4-pyridyl)cyclo-
propanecarboxamide (9a)
A mixture of 0.25 g (1.3 mmol) of 6(a,b) as 1:1
cis/trans mixture and Me2NH (5.9 g) in water (15 ml)
was kept in autoclave at room temperature for 5 days.
The solvent was removed, and the residue was purified
by column chromatography (CH2Cl2–MeOH 9:1 as
eluent), obtaining 0.09 g of the title compound as an oil
(32% yield). [1H] NMR (CDCl3) l 1.23–1.34 (m, 1H,
CH); 1.65–1.74 (m, 1H, CH); 2.01–2.10 (m, 1H, CH);
2.38–2.48 (m, 1H, CH); 2.97 (s, 3H, NCH3); 3.11 (s,
3H, NCH3); 6.99 (d, J=6.2 Hz, 2H) and 8.45 (d,
J=6.2 Hz, 2H) (aromatic protons) ppm. [13C] NMR
(CDCl3) l 17.29 (t), 24.21 (d), 24.81 (d), 36.32 (q),
37.69 (q), 121.47 (d), 149.95 (d), 150.93 (s), 171.18 (s)
ppm. Anal. C11H14N2O (C, H, N).
4.1.7.2. Method B. To a solution of 13a (0.21 g, 1.4
mmol) in 40 ml of CH2Cl2 was added methanesulfonyl
chloride (0.64 g, 5.5 mmol). After 2 h at room tempe-
rature the solvent and the excess of reagent were evapo-
rated; to the residue, kept at 0 °C, Me2NH in water (18
ml, 40% solution) was added and the mixture allowed
to warm to room temperature. After 4 h stirring the
solution was extracted with CHCl3. After drying and
evaporation of the solvent, purification by flash chro-
matography using CHCl3–MeOH 9:1 as first eluent, to
remove starting material and/or by-products, and then
absolute EtOH–NH4OH–CHCl3–petroleum ether
65:8:340:60 as second eluent, gave 0.12 g of the title
compound in 48% yield. [1H] NMR (CDCl3) l 0.95–
1.11 (m, 2H, CH2); 1.22–1.39 (m, 1H, CH); 1.62–1.71
(m. 1H, CH); 2.22–2.49 (m, 2H, CH2N); 2.28 (s, 6H,
CH3); 6.94 (d, J=6.2 Hz, 2H) and 8.42 (d, J=6.2 Hz,
2H) (aromatic protons). [13C] NMR (CDCl3) l 16.51
(t), 22.45 (d), 23.41 (d), 45.75 (q), 63.89 (t), 121.16 (d),
149.69 (d), 152.99 (s). Anal. C11H16N2 (C, H, N). The
oily product was transformed into the oxalate. M.p.
121–126 °C.
4.1.5. trans-2-[(4-Pyridyl)cyclopropyl]methylamine
(10a)
To a solution of 7a (0.19 g, 1.17 mmol) in anhydrous
THF under N2 atmosphere 0.09 g (2.37 mmol) of
LiAlH4 were added and the mixture was refluxed for 2
h. After the addition of water (1 ml) the organic solvent
was evaporated and the mixture extracted in CHCl3.
The organic layer was dried over sodium sulfate and
the solvent evaporated, leaving a residue that, after
purification by column chromatography (CHCl3–
MeOH–NH4OH 50:50:1 as eluent) gave 0.09 g of the
title compound as an oil (52% yield). [1H] NMR
(CDCl3) l 0.95–1.02 (m, 2H, CH2); 1.29–1.45 (m, 1H,
CH); 1.67 (bs, 2H, NH2); 1.64–1.73 (m, 1H, CH); 2.73
(d, J=6.6 Hz, 2H, CH2N); 6.93 (d, J=6.2 Hz, 2H)
and 8.40 (d, J=6.2 Hz, 2H) (aromatic protons). [13C]
NMR (CDCl3) l 16.18 (t), 21.61 (d), 28.27 (d), 46.46
(t), 121.14 (d), 149.75 (d), 153.06 (s). Anal. C9H12N2 (C,
H, N). The product was transformed into the oxalate.
M.p. 160–162 °C.
4.1.8. N,N-Dimethyl-[(2-(4-pyridyl)cyclopropyl]-
methylamine (12a,b, cis/trans mixture)
The same reaction as above (Section 4.1.7.2) per-
formed on 13(a,b) as 1:2 cis/trans mixture, gave a 1:2
mixture of cis/trans amines 12(a,b) in 62% yield. [1H]
NMR (CDCl3) l 0.78–1.42 (m, 3H, CH and CH2);
1.56–1.80 (m, 1H, CH); 2.09 (s, 33%) and 2.28 (s, 67%)
(6H, NCH3); 2.22–2.49 (m, 2H, CH2N); 6.89 (d, J=6.2
Hz, 67%) and 7.14 (d, J=6.2 Hz, 33%) (2H), 8.45-8.43
(m, 2H) (aromatic protons). This mixture was trans-
formed into the oxalate salt, which was collected as 1:2
cis:trans mixture of isomers.
4.1.6. trans-N-Methyl-[(2-(4-pyridyl)cyclopropyl]-
methylamine (11a)
4.1.9. 2-(4-Pyridyl) cyclopropanemethanol (13a, trans
and 13a,b, cis/trans mixture)
Starting from 0.35 g (2 mmol) of 8a and following
the procedure described for 10a, the title compound
was obtained in 62% yield as an oil. [1H] NMR (CDCl3)
l 0.95–1.03 (m, 2H, CH2); 1.33–1.49 (m, 1H, CH);
1.62–1.69 (m, 2H, CH and NH); 2.47 (s, 3H, NCH3);
2.64 (d, J=6.6 Hz, 2H, CH2N); 6.94 (d, J=6.0 Hz,
2H) and 8.42 (d, J=6.0 Hz, 2H) (aromatic protons).
[13C] NMR (CDCl3) l 16.16 (t), 21.72 (d), 24.89 (d),
36.45 (q), 55.93 (t), 121.03 (d), 149.53 (d), 152.92 (s).
Anal. C10H14N2 (C, H, N). The product was trans-
formed into the oxalate that was recrystallized from
absolute ethanol. M.p. 145–150 °C.
To a solution of 6a (0.43 g, 2.25 mmol) in anhydrous
THF (10 ml), kept at 0 °C, 0.08 g of LiAlH4 were
added. The mixture was heated under reflux for 3 h;
after cooling the excess hydride was destroyed with ice,
the solution was concentrated and extracted with
CHCl3. After anhydrification and removal of solvent,
the residue was purified by flash chromatography
(CHCl3/MeOH 9:1) obtaining the title compound 13a
as an oil in 98% yield. [1H] NMR (CDCl3) l 0.97–1.12
(m, 2H, CH2); 1.44–1.60 (m, 1H, CH); 1.74–1.86 (m,
1H, CH); 3.57 (dd, J=11.3 Hz and 7.0 Hz, 1H, CHO);

L. Guandalini et al. / Il Farmaco 57 (2002) 487–496
493
3.71 (dd, J=11.3 Hz and 6.2 Hz, 1H, CHO); 6.91 (d,
J=6.2 Hz, 2H) and 8.36 (d, J=6.2 Hz, 2H) (aromatic
protons). [13C] NMR (CDCl3) l 16.45 (t), 21.14 (d),
27.13 (d), 65.88 (t), 121.27 (d), 149.46 (d), 153.06 (s).
Anal. C9H11NO (C, H, N).
The same reaction, performed on 6(a,b), as 1:2 cis/
trans mixture, gave a 1:2 mixture of cis/trans alcohols
13(a,b). Due to the very close Rf values, this mixture
was not separated by chromatography. [1H] NMR
(CDCl3) l 0.88–1.25 (m, 2H, CH2); 1.42–1.69 (m),
1.74–1.82 (m) and 2.16–2.27 (m) (2H, CH); 2.87 (bs,
1H, OH), 3.21–3.31 (m) and 3.45–3.74 (m) (2H,
CH2O), 6.91 (m, 67%) and 7.12 (d, 33%) (2H, aromat-
ics), 8.32–8.41 (m, 2H, aromatics).
2H, J=6.6 Hz, CH2O); 7.24–7.30 (m, 1H); 7.56–7.61
(m, 1H) and 8.51–8.54 (m, 2H) (aromatic protons).
This compound was dissolved in anhydrous DMSO (8
ml) and treated with 2 equiv. of t-BuOK. After 1 h
stirring at room temperature, the mixture was diluted
with CHCl3 (400 ml) and extracted eight times with
H2O (a total of 360 ml). The organic solvent was
anhydrified with Na2SO4 and then removed under va-
cuum, leaving 3.21 g of a 1:1 mixture of 3-vinylpyridine
15 [16] and DMSO (68% yield). [1H] NMR (CDCl3) l
2.55 (s, 6H, DMSO); 5.36 (d, 1H, J=11.0 Hz, H-2);
5.81 (d, 1H, J=18.0 Hz, H-2); 6.69 (dd, 1H, J=11.0
Hz and 18.0 Hz, H-1); 7.23–7.28 (m, 1H, H-5%); 7.68–
7.74 (m, 1H, H-4%); 8.45–8.48 (m, 1H, H-6%); 8.60 (d,
1H, J=1.8 Hz, H-2%). This mixture was heated in
xylene (70 ml) with ethyl diazoacetate (3.5 g) at 140 °C
for 6 h. The solvent was distilled off under vacuum,
leaving a residue which was purified by column chro-
matography, obtaining 16a (trans isomer, oil, 41%
yield) and 16b (cis isomer, oil, 18% yield).
4.1.10. N,N-Dimethyl-[(2-(4-pyridyl)cyclopropyl]-
methylamine methiodide (14a, trans and 14a,b,
cis/trans mixture)
To a solution of 12a (0.12 g) in anhydrous DMF (2
ml) methyl iodide (1 equiv.) was added and the mixture
was stirred at room temperature in the dark for 3 days.
After removal of solvent, the residue was treated with
CHCl3 to remove unreacted starting material, obtaining
the title compound in 83% yield. M.p. 173–174 °C.
[1H] NMR (D2O) l 1.10–1.32 (m, 2H, CH2); 1.43–1.59
(m, 1H, CH); 1.93–2.02 (m. 1H, CH); 3.04 (s, 9H,
CH3); 3.33 (d, J=7Hz, 2H, CH2N); 7.02 (d, J=5.9
Hz, 2H) and 8.20 (d, J=5.9 Hz, 2H) (aromatic pro-
tons). [13C] NMR (D2O) l 15.20 (t), 17.51 (d), 21.43
(d), 52.97 (q), 69.35 (t), 121.43 (d), 148.20 (d), 151.57
(s). Anal. C12H19IN2 (C, H, N).
The same reaction, performed on 12(a,b) as 1:2 cis/
trans mixture, gave a 1:2 mixture of cis/trans methio-
dides 14(a,b). [1H] NMR (D2O) l 1.06–1.36 (m, 2H,
CH2); 1.40–1.65 (m, 1H, CH); 1.90–2.01 (m, trans
isomer), 2.29-2.42 (m, cis isomer) (1H, CH); 2.60–2.72
(m, cis isomer), 2.92–3.13 (m, cis isomer) and 3.30 (d,
J=7.0 Hz, trans isomer) (2H, CH2N); 2.85 (s, cis
isomer) and 3.00 (s, trans isomer) (9H, CH3); 7.01 (d,
J=5.9 Hz, trans isomer) and 7.14 (d, J=5.9 Hz, cis
isomer) (2H, aromatic protons); 8.18 (d, J=5.9 Hz,
trans isomer) and 8.25 (d, J=5.9 Hz, cis isomer) (2H,
aromatics).
Compound 16a (trans isomer): [1H] NMR (CDCl3) l
1.29 (t, J=7.1 Hz, 3H, CH3); 1.28–1.38 (m, 1H, CH);
1.60–1.70 (m, 1H, CH); 1.88–1.97 (m, 1H, CH); 2.47–
2.54 (m, 1H, CH); 4.19 (q, J=7.1 Hz, 2H, CH2O);
7.17–7.38 (m, 2H) and 8.45–8.47 (m, 2H) (aromatic
protons). [13C] NMR (CDCl3) l 14.67 (q), 17.09 (t),
23.90 (d), 24.27 (d), 61.34 (t), 123.64 (d), 133.54 (d),
136.00 (s), 148.20 (d), 148.84 (d), 173.20 (s). IR (cm−1
)
w 1730 (CON), 1190. Anal. C11H13NO2 (C, H, N).
Compound 16b (cis isomer): [1H] NMR (CDCl3) l
1.01 (t, J=7.1 Hz, 3H, CH3); 1.35–1.46 (m, 1H, CH);
1.67–1.76 (m, 1H, CH); 2.08–2.19 (m, 1H, CH); 2.47–
2.60 (m, 1H, CH); 3.90 (q, J=7.1 Hz, 2H, CH2O);
7.16–7.23 (m, 1H, H-5%); 7.56 (d, J=6.2 Hz, 1H, H-4%);
8.44 (d, J=4.8 Hz, 1H, H-6%); 8.54 (s, 1H, H-2%). [13C]
NMR (CDCl3) l 11.39 (t), 14.50 (q), 22.08 (d), 23.23
(d), 60.87 (t), 123.07 (d), 132.59 (s), 136.80 (d), 148.20
(d), 151.35 (d), 170.91 (s). IR (cm−1) w 1725 (CON),
1185. Anal. C11H13NO2 (C, H, N).
4.1.12. 2-(3-Pyridyl)cyclopropanecarboxamide (17a,
trans and 17b, cis)
A mixture of 16a (0.15 g, 0.78 mmol), ethanol (10
ml), NH4Cl (0.03 g) and NH4OH (5.3 ml) were heated
at 110 °C in autoclave for 1 day. After cooling, the
volatile material was removed under vacuum, leaving a
residue whose [1H] NMR spectrum showed the presence
of two isomeric amides in equal proportions. Chro-
matographic separation gave 17a (25% yield) and 17b
(25% yield).
4.1.11. Ethyl 2-(3-pyridyl) cyclopropanecarboxylate
(16)
A solution of 2-(3-pyridyl)ethanol (3.17 g, 0.026 mol,
obtained by reduction of the commercially available
ethyl 3-pyridylacetate according to ref. [26]), in CH2Cl2
(20 ml), was treated at 0 °C with NEt3 (3 equiv.) and
MeSO2Cl (3 equiv.). The mixture was stirred at room
temperature for 1.5 h, then was treated with NaOH 2
M and rapidly extracted with CH2Cl2. Anhydrification
and removal of the solvent gave 2-(3-pyridyl) ethyl
mesilate in quantitative yield. [1H] NMR (CDCl3) l
2.92 (s, 3H, CH3); 3.07 (t, 2H, J=6.6 Hz, CH2); 4.43 (t,
Compound 17a (trans isomer): [1H] NMR (CD3OD)
l 1.29–1.39 (m, 1H, CH); 1.52–1.61 (m, 1H, CH);
1.95–2.04 (m, 1H, CH); 2.38–2.46 (m, 1H, CH); 7.33–
7.39 (m, 1H), 7.56–7.62 (m, 1H), 8.36–8.41 (m, 2H)
(aromatics). [13C] NMR (CD3OD) l 14.64 (t), 21.63 (d),
24.34 (d), 123.51 (d), 133.74 (d), 137.13 (s), 146.18 (d),
146.94 (d), 175.02 (s). Anal. C9H10N2O (C, H, N).

494
L. Guandalini et al. / Il Farmaco 57 (2002) 487–496
Compound 17b (cis isomer): [1H] NMR (CD3OD) l
matic protons). [13C] NMR (CDCl3) l 9.85 (t), 17.42
(d), 18.13 (d), 45.74 (q), 59.27 (t), 123.11 (d), 134.82
(s), 136.55 (d), 147.44 (d), 150.93 (d). Anal. C11H16N2
(C, H, N). The oily product was transformed into the
oxalate. M.p. 95–97 °C.
1.38–1.47 (m, 1H, CH); 1.56–1.65 (m, 1H, CH);
1.90–1.99 (m, 1H, CH); 2.48–2.56 (m, 1H, CH);
7.34–7.40 (m, 1H), 7.56–7.62 (m, 1H) and 8.37–8.44
(m, 2H) (aromatic protons). [13C] NMR (CD3OD) l
13.93 (t) 20.86 (d), 21.72 (d), 121.87 (d), 132.09 (d),
135.04 (s), 144.40 (d), 145.14 (d), 173.00 (s). Anal.
C9H10N2O (C, H, N).
4.1.15. N,N-Dimethyl-[(2-(3-pyridyl)cyclopropyl]-
methylamine methiodide (20a, trans and 20b, cis)
Following the same procedure reported for 14a,
starting from 19a (0.05 g), compound 20a was ob-
tained in 77% yield, while starting from 19b (0.09 g),
20b was obtained in 74% yield.
4.1.13. 2-(3-Pyridyl)cyclopropanemethanol (18a, trans
and 18b, cis)
Following the same procedure reported for 13,
starting from 16a (0.22 g), compound 18a was ob-
tained in 87% yield. [1H] NMR (CDCl3) l 0.83–0.99
(m, 2H, CH2); 1.33–1.48 (m, 1H, CH); 1.69–1.78 (m,
1H, CH); 3.49 (dd, J=11.3 Hz and 7.0 Hz, 1H,
CHO); 3.69 (dd, J=11.3 Hz and 5.9 Hz, 1H, CHO);
4.15 (bs, 1H, OH); 7.07–7.25 (m, 2H) and 8.26–8.29
(m, 2H) (aromatic protons). [13C] NMR (CDCl3) l
14.16 (t), 19.24 (d), 25.92 (d), 65.78 (t), 123.73 (d),
133.20(d), 139.23(s), 146.65 (d), 148.13 (d). Anal.
C9H11NO (C, H, N).
The same reaction was performed on 0.54 g of 16b,
yielding 18b in 78% yield. [1H] NMR (CDCl3) l 0.82–
0.90 (m, 1H, CH); 1.06–1.18 (m, 1H, CH); 1.46–1.65
(m, 1H, CH); 2.18–2.30 (m, 2H, CH and OH); 3.25
(dd, J=11.3 Hz and 8.1 Hz, 1H, CHO); 3.46 (dd,
J=11.3 Hz and 6.2 Hz, 1H, CHO); 7.16–7.22 (m,
1H), 7.53–7.58 (m, 1H), 8.34–8.40 (m, 1H) and 8.49
(d, J=2.2 Hz, 1H, H-2%) (aromatic protons). [13C]
NMR (CDCl3) l 8.11 (t), 18.71 (d), 21.17 (d), 62.07
(t), 123.31 (d), 134.80 (s), 137.04 (d), 147.14 (d),
150.71 (d). Anal. C9H11NO (C, H, N).
Compound 20a (trans) [1H] NMR (D2O) l 1.03–
1.27 (m, 2H, CH2); 1.36–1.52 (m, 1H, CH); 1.93–2.03
(m, 1H, CH); 3.02 (s, 9H, CH3); 3.32 (d, J=7.0 Hz,
2H, CH2N); 7.18–7.25 (m, 1H), 7.38–7.43(m, 1H) and
8.18–8.22 (m, 2H) (aromatic protons). [13C] NMR
(D2O) l 13.85 (t), 16.20 (d), 19.53 (d), 52.86 (q), 69.66
(t), 124.02 (d), 134.12(d), 136.76 (s), 146.14 (d), 146.56
(d). M.p. 190 °C (dec). Anal. C12H19IN2 (C, H, N).
Compound 20b (cis) [1H] NMR (D2O) l 1.06–1.15
(m, 1H, CH); 1.27–1.38 (m, 1H, CH); 1.46–1.64 (m,
1H, CH); 2.33–2.56 (m, 2H, CH and CHN); 2.89 (s,
9H, CH3); 3.21 (dd, J=4.8 Hz and 13.5 Hz, 1H,
CHN); 7.23–7.29 (m, 1H), 7.57–7.61 (m, 1H) and
8.24–8.31 (m, 2H) (aromatic protons). [13C] NMR
(D2O) l 9.48 (t), 11.85 (d), 17.28 (d), 52.86 (q), 66.93
(t), 123.85 (d), 132.92 (s), 137.57 (d), 146.76 (d),
149.15 (d). M.p. 189 °C (dec). Anal. C12H19IN2 (C, H,
N).
4.1.16. 2-(4-Pyridyl)cyclopropanecarboxylic acid (21a,b,
cis/trans mixture)
To a solution of NaOH (0.16 g, 4.0 mmol) in etha-
nol (5 ml) 0.15 g (0.8 mmol) of 6(a,b) as 1:1 cis/trans
mixture were added and the mixture left at room
temperature for one night. The solution was treated
with 2 m of HCl 2 N; the solvent was removed under
vacuum and the solid residue was extracted with
methanol. Removal of solvent gave 0.12 g (92% yield)
of a gummy solid, which consisted in a mixture of 21a
and 21b in 55:45 ratio. [1H] NMR (D2O) l 1.58–1.86
(m, 2H); 2.16–2.27 (m, 55%) and 2.36–2.48 (m, 45%)
(1H, CH); 2.64–2.73 (m, 55%) and 2.80–2.92 (m,
45%) (1H, CH); 7.78 (d, J=6.6 Hz, 55%) and 7.94 (d,
J=6.6 Hz, 45%) (2H, aromatics); 8.61–8.66 (m, 2H,
aromatics). [13C] NMR (D2O) l 16.99 (t), 23.72 (t),
29.17 (d), 29.88 (d), 33.00 (d), 31.89 (d), 128.54 (d),
144.23 (d), 144.61 (d), 164.94 (s), 168.29 (s), 179.78
(s), 181.66 (s). Anal. C9H9NO2 (C, H, N).
4.1.14. N,N-Dimethyl-[(2-(3-pyridyl)cyclopropyl]-
methylamine (19a trans and 19b cis)
Following the same procedure reported for 12a
(Section 4.1.7.2), starting from 18a (0.15 g), com-
pound 19a was obtained in 53% yield, while starting
from 18b (0.22 g), 19b was obtained in 51% yield.
Compound 19a (trans) [1H] NMR (CDCl3) l 0.84–
1.02 (m, 2H, CH2); 1.15–1.31 (m, 1H, CH); 1.63–1.72
(m, 1H, CH); 2.26 (dd, J=12.5 Hz and 7.0 Hz, 1H,
CHN); 2.27 (s, 6H, CH3); 2.43 (dd, J=12.5 Hz and
6.2 Hz, 1H, CHN); 7.10–7.17 (m, 1H), 7.23–7.29 (m,
1H) and 8.35–8.39 (m, 2H) (aromatic protons). [13C]
NMR (CDCl3) l 15.24 (t), 20.48 (d), 22.01 (d), 45.81
(q), 64.11 (t), 123.56 (d), 132.72 (d), 138.66 (s), 147.20
(d), 148.47 (d). Anal. C11H16N2 (C, H, N). The oily
product was transformed into the oxalate. M.p. 117–
118 °C.
Compound 19b (cis) [1H] NMR (CDCl3) l 0.64–
0.77 (m, 1H, CH); 0.97–1.29 (m, 2H, CH2); 1.48–1.58
(m, 1H, CH); 2.00 (s, 6H, CH3); 1.95–2.14 (m, 2H,
CH2N); 7.02–7.08 (m, 1H), 7.32–7.36 (m, 1H), 8.27–
8.30 (m, 1H) and 8.35 (d, J=2.2 Hz, 1H, H-2%) (aro-
4.2. Pharmacology
The new compounds were tested according to the
already published protocol [23]. Amines were tested as
oxalate salts.

L. Guandalini et al. / Il Farmaco 57 (2002) 487–496
495
4.3. Molecular modeling
References
[1] S.H. Ferris, A. Kluger, Assessing cognition in Alzheimer’s di-
sease research, Alzheimer Dis. Assoc. Disord. 11 (1997) 45–49.
[2] R.T. Bartus, R.L. Dean, B. Beer, A.S. Lippa, The cholinergic
hypothesis of geriatric memory disfunction, Science 217 (1982)
408–417.
[3] C.L. Moore, M.S. Wolfe, Inhibition of beta-amyloid formation
as a therapeutic strategy, Exp. Opin. Ther. Patents 9 (1999)
135–146.
[4] R.M. Nitsch, From acetylcholine to amyloid: neurotransmitters
and the pathology of Alzheimer’s diseases, Neurodegeneration 5
(1996) 477–482.
[5] D.J. Selkoe, The origins of the Alzheimer’s diseases. A is for
amiloid, J. Am. Med. Assoc. 283 (2000) 1615–1617.
[6] F. Gualtieri, S. Dei, D. Manetti, M.N. Romanelli, S. Scapecchi,
E. Teodori, The medicinal chemistry of Alzheimer’s and
Alzheimer-like diseases with emphasis on the cholinergic hypo-
thesis, Farmaco 50 (1995) 489–503.
[7] M.W. Holladay, M.J. Dart, J.K. Lynch, Neuronal nicotinic
acetylcholine receptors as target for drug discovery, J. Med.
Chem. 40 (1997) 4169–4194.
[8] J.D. Schmitt, Exploring the nature of molecular recognition in
nicotinic acetylcholine receptors, Curr. Med. Chem. 7 (2000)
749–800.
[9] M.K. Holladay, S.A. Lebold, N.-H. Lin, Structure–activity rela-
tionships of nicotinic acetylcholine receptor agonists as potential
treatments for dementia, Drug Dev. Res. 35 (1995) 191–213.
[10] M.A. Abreo, N.H. Lin, D.S. Garvey, D.E. Gunn, A.M. Het-
tinger, J.T. Wasicak, P.A. Pavlik, Y.C. Martin, D.L. Donnelly-
Roberts, D.J. Anderson, J.P. Sullivan, M. Williams, S.P.
Arneric, M.W. Holladay, Novel 3-pyridyl ethers with sub-
nanomolar affinity for central neuronal nicotinic acetylcholine
receptors, J. Med. Chem. 39 (1996) 817–825.
The ACCELRYS package was used: compounds were
generated with InsightII and minimized with Discover
(cvff force-field). Dihedral driver calculations were per-
formed with the option ‘Torsion Force’ using a force of
100 kcal mol−1. Partial charges were not included
during minimization or dihedral driver calculations, in
order to generate all possible sterically-allowed confor-
mations; however, when included, partial charges did
not alter the energy profile of the calculations reported
in Figs. 1 and 4.
4.3.1. Conformational analysis
The energy profiles for the rotation around the cyclo-
propyl-aryl and cyclopropylꢀmethyl bonds were calcu-
lated. One dihedral angle was rotated at time from 0 to
360°, using as starting geometry for the second one that
shown in the conformation reported in Fig. 5. The
dihedral driver calculations on the cyclopropyl-pyridine
bond (dihedral HꢀC(cy)ꢀC(ar)ꢀC(ar)) gave in all cases two
minima with the same energy, located at 90 and 270°
(trans-A, trans-C), 75 and 270° (20a), 120 and 300°
(20b), 75 and 270° (14a), 60 and 240° (14b), with an
energy barrier of 5.34 (14b), 5.38 (20b), 2.13 (20a) and
2.21 (14a) kcal mol−1. The internitrogen distances in
,
the low-energy conformations were 5.66 and 6.81 A
,
,
(trans-A), 5.66 and 6.23 A (trans-C), 7.01 A (14a), 5.74
,
,
,
A (14b), 5.98 and 7.05 A (20a), 5.18 and 5.91 A (20b).
The energy profiles for the rotation around the cyclo-
propylꢀmethyl bond are reported in Figs. 1 and 4.
[11] R.A. Glennon, J.L. Herndon, M. Dukat, Epibatidine-aided stu-
dies toward definition of a nicotine receptor pharmacophore,
Med. Chem. Res. 4 (1994) 461–473.
[12] D. Manetti, A. Bartolini, P.A. Borea, C. Bellucci, S. Dei, C.
Ghelardini, F. Gualtieri, M.N. Romanelli, S. Scapecchi, E.
Teodori, K. Varani, Hybridized and isosteric analogues of N1-
acetyl-N4-dimethyl-piperazinium iodide (ADMP) and N1-
phenyl-N4-dimethyl-piperazinium iodide (DMPP) with central
nicotinic action, Bioorg. Med. Chem. 7 (1999) 457–465.
[13] A.P. Gray, H. Kraus, Cyclopropylpyridines. Synthesis and elec-
tronic interaction, J. Org. Chem. 31 (1966) 399–405.
[14] D.-J. Cho, S.-J. Jeon, H.-S. Kim, C.-S. Cho, S.-C. Shim, T.-J.
Kim, Chiral C2-symmetric bisferrocenyldiamines as ligands for
transition metal catalyzed asymmetric cyclopropanation and
aziridination, Tetrahedron: Asymmetry 10 (1999) 3833–3848.
[15] T. Ichiyanagi, M. Shimizu, T. Fujisawa, Asymmetric cyclopropa-
nation of olefins with diazoacetate using chiral copper catalysts,
Tetrahedron 53 (1997) 9599–9610.
[16] W. von, E. Doering, S.J. Rhoads, 2- and 3-Vinylpyridines as
dienophiles in the Diels–Alder reaction, J. Am. Chem. Soc. 75
(1953) 4738–4740.
[17] K. Ninomiya, T. Shioiri, S. Yamada, Phosphorus in organic
synthesis-VII. Diphenyl phosphorazidate (DPPA). A new conve-
nient reagent for a modified Curtius reaction, Tetrahedron 30
(1974) 2151–2157.
4.3.2. Superimpositions
Superimpositions were made using as fitting points
the basic nitrogen atom, the pyridyl nitrogen atom, and
the center of the aromatic ring; only low-energy confor-
mations were used. For the sake of clarity, only one
enantiomer for each compound is shown in Fig. 5. The
characteristics of the conformations reported in Fig. 5
are the following:
14a (1R,2R isomer): −97° (HꢀC(cy)ꢀC(ar)ꢀC(ar)),
,
−59° (HꢀC(cy)ꢀCꢀN), 7.01 A (NꢀN distance)
14b (1S,2R isomer): 55° (HꢀC(cy)ꢀC(ar)ꢀC(ar)), −50°
,
(HꢀC(cy)ꢀCꢀN), 5.74 A (NꢀN distance)
20a (1R,2R isomer): −97° (HꢀC(cy)ꢀC(ar)ꢀC(ar)),
,
−59° (HꢀC(cy)ꢀCꢀN), 5.98 A (NꢀN distance)
20b (1R,2S isomer): −63° (HꢀC(cy)ꢀC(ar)ꢀC(ar)), 46°
,
(HꢀC(cy)ꢀCꢀN), 5.19 A (NꢀN distance).
[18] P. Radlick, L.R. Brown, A versatile modification of the Hof-
mann rearrangement, Synthesis (1974) 290–291.
[19] H.E. Baumgarten, H.L. Smith, A. Staklis, Reaction of amines.
XVIII. The oxidative rearrangement of amides with lead tetraac-
etate, J. Org. Chem. 40 (1975) 3554–3561.
[20] S.S. Jew, H.G. Park, H.J. Park, M.S. Park, Y.S. Cho, New
method for Hofmann rearrangement, Tetrahedron Lett. 31
(1990) 1559–1562.
Acknowledgements
This research was supported by funds of the Italian
Ministry of University and Scientific Research
(MURST).

496
L. Guandalini et al. / Il Farmaco 57 (2002) 487–496
[21] C.M. Flores, S.W. Rogers, L.A. Pabreza, B.B. Wolfe, K.J.
Kellar, A subtype of nicotinic cholinergic receptor in rat brain is
composed of alpha 4 and beta 2 subunits and is up-regulated by
chronic nicotine treatment, Mol. Pharmacol. 41 (1992) 31–37.
[22] C. Ghelardini, N. Galeotti, F. Gualtieri, C. Bellucci, D. Manetti,
P.A. Borea, A. Bartolini, Antinociceptive property of the nico-
tinic agonist AG-4 in rodents, Drug Dev. Res. 41 (1997) 1–9.
[23] M.N. Romanelli, D. Manetti, S. Scapecchi, P.A. Borea, S. Dei,
A. Bartolini, C. Ghelardini, F. Gualtieri, L. Guandalini, K.
Varani, Structure-affinity relationships of a unique nicotinic
ligand: N1-dimethyl-N4-phenylpiperazinium iodide (DMPP), J.
Med. Chem. 44 (2001) 3946–3955.
[24] L. Guandalini, S. Dei, F. Gualtieri, M.N. Romanelli, S. Scapec-
chi, E. Teodori, K. Varani, Synthesis of hexahydro-[2]pyrindine
(=hexahydrocyclopenta[c]pyridine) derivatives as conformatio-
nally restricted analogs of the nicotinic ligands arecolone and
isoarecolone, Helv. Chim. Acta 85 (2002) 96–107.
[25] D. Manetti, P.A. Borea, C. Ghelardini, F. Gualtieri, M.N.
Romanelli, S. Scapecchi, G. Valle, Reduced-flexibility hybrids of
the nicotinic agonists 1,1-dimethyl-4-acetylpiperazinium iodide
and 2-(dimethylamino)methyl-5-methyl-cyclopentanone methio-
dide, Med. Chem. Res. 7 (1997) 301–312.
[26] G.T. Lowen, M.R. Almond, J.L. Rideout, Synthesis of 3-
vinylpiperidine, J. Heterocycl. Chem. 29 (1992) 1663–1665.