2-, 5-, and 6-Halo-3-(2(S)-azetidinylmethoxy)pyridines: Synthesis, affinity for nicotinic acetylcholine receptors, and molecular modeling

Article abstract of DOI:10.1021/jm980170a

3-(2(S)-Azetidinylmethoxy)pyridine (A-85380) has been identified recently as a ligad with high affinity for nicotinic acetylcholine receptors (nAChRs). Here we report the synthesis and in vitro nAChR binding of a series of 10 pyridine-modified analogues of A-85380. The novel compounds feature a halogen substituent at position 2, 5, or 6 of the 3-pyridyl fragment. Those with the substituents at position 5 or 6, as well as the 2-fluoro analogue, possess subnanomolar affinity for nAChRs in membranes from rat brain. For these ligands, K(i) values range from 11 to 210 pM, as measured by competition with (±)-[³H]epibatidine. In contrast, 2-chloro, 2-bromo, and 2-iodo analogues exhibit substantially lower affinity. AM1 quantum chemical calculations demonstrate that the bulky substituents at position 2 cause notable changes in the molecular geometry. The high-affinity members of the series and (+)-epibatidine display a tight fit superposition of low-energy stable conformers. The new ligands with high affinity for nAChRs may be of interest as pharmacological probes, potential medications, and candidates for developing radiohalogenated tracers to study nAChRs.

Full text of DOI:10.1021/jm980170a

3690
J . Med. Chem. 1998, 41, 3690-3698
2-, 5-, a n d 6-Ha lo-3-(2(S)-a zetid in ylm eth oxy)p yr id in es: Syn th esis, Affin ity for
Nicotin ic Acetylch olin e Recep tor s, a n d Molecu la r Mod elin g
Andrei O. Koren,*,† Andrew G. Horti,† Alexey G. Mukhin,† Daniela Gu¨ndisch,† Alane S. Kimes,†
Robert F. Dannals,‡ and Edythe D. London†
Brain Imaging Center, Intramural Research Program, National Institute on Drug Abuse, 5500 Nathan Shock Drive,
Baltimore, Maryland 21224, and Division of Nuclear Medicine, Department of Radiology, The J ohns Hopkins Medical
Institutions, 600 North Wolfe Street, Baltimore, Maryland 21287
Received March 19, 1998
3-(2(S)-Azetidinylmethoxy)pyridine (A-85380) has been identified recently as a ligand with high
affinity for nicotinic acetylcholine receptors (nAChRs). Here we report the synthesis and in
vitro nAChR binding of a series of 10 pyridine-modified analogues of A-85380. The novel
compounds feature a halogen substituent at position 2, 5, or 6 of the 3-pyridyl fragment. Those
with the substituents at position 5 or 6, as well as the 2-fluoro analogue, possess subnanomolar
affinity for nAChRs in membranes from rat brain. For these ligands, Ki values range from 11
to 210 pM, as measured by competition with (()-[3H]epibatidine. In contrast, 2-chloro, 2-bromo,
and 2-iodo analogues exhibit substantially lower affinity. AM1 quantum chemical calculations
demonstrate that the bulky substituents at position 2 cause notable changes in the molecular
geometry. The high-affinity members of the series and (+)-epibatidine display a tight fit
superposition of low-energy stable conformers. The new ligands with high affinity for nAChRs
may be of interest as pharmacological probes, potential medications, and candidates for
developing radiohalogenated tracers to study nAChRs.
Over the past few years, considerable efforts have
been directed toward the identification and character-
ization of ligands for nicotinic acetylcholine receptors
(nAChRs). The interest in these compounds stems in
part from accumulating evidence that agents acting at
nAChRs may have therapeutic utility in the treatment
of a variety of central nervous system (CNS) disorders,1,2
including Alzheimer’s and Parkinson’s3 diseases, atten-
tion deficit/hyperactivity disorder,4 Tourette’s syn-
drome,5 and depression.6 The therapeutic usefulness
of the prototypical agonist for nAChRs, (S)-nicotine,
however, is limited by a variety of untoward effects.
In parallel, observations of abnormalities in the
densities of nAChRs in the brains of smokers7 and
patients with various CNS disorders3 have suggested
that noninvasive in vivo imaging and quantification of
cerebral nAChRs, using such techniques as positron
emission tomography (PET) and single-photon emission
computed tomography (SPECT), could be useful in
studies of the progression of these pathological states.
The only tracer currently available for such studies8 is
the long-known (S)-[11C]nicotine,9 which shows consid-
erable nonspecific binding and rapid clearance from
brain.10 During the past few years, several promising
PET11,12 and SPECT13,14 tracers for nAChRs have been
developed. Nevertheless, none is optimal for human
subjects, and there is still a need for potent nAChR
ligands with high selectivity for CNS receptors and a
favorable in vivo profile.
F igu r e 1. Structures of A-85380 and its halogenated ana-
logues.
reported.15 These compounds include 3-pyridyl ethers
which incorporate a saturated azacyclic fragment, such
as 2-pyrrolidinyl or 2-azetidinyl. An initial report was
followed by intensive structure-activity studies of both
branches of the series.16-18 In the “pyrrolidine” branch,
these efforts led to the identification of ABT-089, an
orally bioavailable nAChR ligand19 with neuroprotec-
tive20 and cognition-enhancing21 properties. Another
pyrrolidine-based ligand, A-84543, was labeled with
carbon-11,22 and the labeled compound showed moder-
ate specific binding to nAChRs in vivo in mice.23
The parent compound of the azetidine-based series
of ligands, 3-(2(S)-azetidinylmethoxy)pyridine, A-85380
(1; Figure 1), showed a remarkable combination of
properties. It displayed exceptionally high affinity for
central nAChRs,15 almost identical to that of (()-
epibatidine (Figure 2), the most potent nAChR ligand
identified so far. However, in functional in vitro assays,
Recently, a novel series of compounds with subnano-
molar affinity for central neuronal nAChRs has been
* Address correspondence to: Andrei O. Koren, Ph.D. Tel: 410-550-
1440. Fax: 410-550-1441. E-mail: akoren@intra.nida.nih.gov.
† National Institute on Drug Abuse.
‡ The J ohns Hopkins Medical Institutions.
S0022-2623(98)00170-8 CCC: $15.00 © 1998 American Chemical Society
Published on Web 08/19/1998

Halo-3-(2(S)-azetidinylmethoxy)pyridines
J ournal of Medicinal Chemistry, 1998, Vol. 41, No. 19 3691
Sch em e 1a
F igu r e 2. Stereoisomers of epibatidine.
A-85380 was 40-fold less potent than (()-epibatidine to
activate central nAChRs and 100-fold less potent to
activate ganglionic-type nAChRs.15 Since the gangli-
onic-type nAChRs are believed to mediate at least some
untoward effects of nicotinic agonists, A-85380 may be
expected to have a wider safety margin than epibati-
dine.24 Indeed, comprehensive examination of in vitro
pharmacological properties of A-85380 suggested that
this compound may serve as a potent and highly
selective probe for the neuronal nAChRs.24 Subse-
a
(i) Diethyl azodicarboxylate, Ph3P, THF; (ii) TFA, CH2Cl2.
Sch em e 2a
3
quently H-labeled A-85380 has been identified as an
excellent tool for studying nicotinic acetylcholine recep-
tors in vitro.25 The most recently reported member of
the “azetidine” series, ABT-594,26 also showed extremely
high affinity for nAChRs and appeared to produce a non-
opioid-mediated analgesia in rodent models, with ef-
ficacy equal to that of morphine.
To gain further insight into the structure-activity
relationship for azetidine-based 3-pyridyl ether com-
pounds, we have prepared a number of pyridine-modi-
fied derivatives of A-85380 and screened them for
binding affinity for central nAChRs. In this paper, we
describe the synthesis and in vitro receptor binding
properties of a series of halogenated analogues: 2a -d ,
3a -d , and 4a ,d (Figure 1). Isomers with halogen
substituents at position 4 of the pyridine nucleus were
excluded from consideration as such derivatives are
known to be chemically unstable.27
a
(i) O-(Cyclopropylmethyl)-N,N′-dicyclohexylisourea, benzene;
(ii) KF, Kryptofix 222, DMSO; (iii) HBr, CH3COOH. For position
numbering, see Scheme 1.
Sch em e 3a
By targeting the halo derivatives we aimed at iden-
tifying nAChR ligands, which might represent suitable
candidates for developing 18F-, 76Br-, and 123/125I-labeled
probes for studying the receptors both in vivo, using
PET/SPECT, and in vitro.
Resu lts a n d Discu ssion
Ch em istr y. Throughout this report, compounds with
the a designation are fluoro derivatives, whereas the
b , c, and d designations denote, respectively, chloro,
bromo, and iodo compounds. All target compounds were
synthesized by the etherification of the respective halo-
3-pyridinols with 1-(tert-butoxycarbonyl)-2(S)-azeti-
dinemethanol under Mitsunobu conditions followed by
the removal of the protecting group (Scheme 1).
Previously unknown fluoropyridinols 8a and 10a were
synthesized via halogen exchange starting from the
available iodopyridinols 8d and 10d ,28 respectively.
Here, we employed a technique proved effective for a
bromo-to-fluoro exchange in a nonactivated pyridine
ring.11 Our initial attempts to carry out a iodo-to-fluoro
substitution directly in iodopyridinol 8d yielded only
tarlike decomposition products. In contrast, the dis-
placement did take place when the methyl ether of 8d
was brought into the reaction (data not presented),
thereby indicating the necessity of protecting the hy-
droxyl group. Eventually we found that protection with
a cyclopropylmethyl group was an adequate strategy
(Scheme 2). This group tolerated the halogen-exchange
a
(i) O-Isopropyl-N,N′-dicyclohexylisourea, benzene; (ii) aq NH3,
CuSO4; (iii) NaNO2, HF, pyridine; (iv) HBr, CH3COOH.
conditions (DMSO, 165 °C, tens of hours) and could be
removed under sufficiently mild ones (HBr-acetic acid,
room temperature, 3 h). As would be expected, com-
pound 12 was less reactive in the nucleophilic iodo-to-
fluoro displacement than isomer 11, having the iodine
atom in the vicinity of the electron-withdrawing oxygen.
One may suppose that, due to a close similarity in
structures of 11, 12 and 5d , 7d , the latter two could
also undergo the halogen-exchange nucleophilic fluori-
nation to provide a pathway to radiofluorinated ana-
logues of A-85380.
It is well-known that â-halogens in the pyridine ring
generally resist exchange fluorination, although their
displacement by a base is a practical route to 3(5)-
substituted pyridines.27 Hence we developed a strategy
for the synthesis of the previously unknown fluoro-
pyridinol 9a starting from bromopyridinol 9c (Scheme
3). The latter was protected with an isopropyl group to
give derivative 15, which was converted into amine 16

3692 J ournal of Medicinal Chemistry, 1998, Vol. 41, No. 19
Koren et al.
Ta ble 1. nAChR Binding Affinities, Distances between
Pharmacophoric Elements, Relative Energies, and
Superposition rms Deviations for (+)-Epibatidine, A-85380, and
Halogenated Analogues 2a -d , 3a -d , and 4a ,d
Sch em e 4a
∆Ed
A-Bb A-Cc (kcal/ rmse
compound
Kia (pM)
(Å)
(Å)
mol) (Å)
(+)-Epibatidine
1 (A-85380)
8.4 ( 0.2
4.47
4.39
4.81
4.27 0.18 0.00
4.43 0.33 0.09
4.13 0.59 0.21
4.24 0.63 0.34
4.32 0.88 0.40
4.36 1.52 0.42
4.40 0.42 0.09
4.39 0.32 0.09
4.36 0.25 0.09
4.35 0.24 0.09
4.37 0.35 0.09
4.40 0.36 0.09
17 ( 1
2a (R ) 2-F)f
2b (R ) 2-Cl)
2c (R ) 2-Br)
2d (R ) 2-I)
3a (R ) 5-F)
3b (R ) 5-Cl)
3c (R ) 5-Br)
3d (R ) 5-I)
4a (R ) 6-F)
4d (R ) 6-I)
46 ( 5g
(8.4 ( 0.6) × 103 h 5.10
(240 ( 10) × 103
>1 × 106
25 ( 1
5.25
5.32
4.37
4.36
4.34
4.33
4.33
4.36
a
(i) O-(Cyclopropylmethyl)-N,N′-dicyclohexylisourea, benzene;
(ii) NaSnMe3, MeOCH2CH2OMe; (iii) I2, CHCl3; (iv) HBr, CH3-
COOH.
30 ( 3
21 ( 1
11 ( 1
Sch em e 5a
25 ( 3
150 ( 8
a
Values represent mean ( SEM obtained from n independent
b
experiments where n ) 6-9, except for 2d where n ) 3. Distance
between sp3 nitrogen atom and pyridine ring nitrogen atom.
c Distance between sp3 nitrogen atom and pyridine ring centroid.
d
Energy of the stable conformer with reference to the lowest-
a
(i) NaSnMe3, MeOCH2CH2OMe; (ii) Br2, CHCl3; (iii) I2, CHCl3.
energy conformer. e rms deviation of the three pharmacophoric
elements from those of (+)-epibatidine. f For position numbering,
using a modification of a published procedure.29 The
amine, in turn, was transformed into fluoropyridine 17
via diazotization-fluorodediazonization30 in HF-pyri-
dine medium. Finally, deprotection of 17 gave the
desired fluoropyridinol 9a in a 12% overall yield. In this
synthesis, we used the isopropyl protecting group to
ensure stability of the ether bond during the fluoro-
dediazonization step, which occurs in an acidic medium
at elevated temperature (HF-pyridine, 50 °C, 1 h).
Previously unknown iodopyridinol 9d was prepared
starting from a commercially available chloropyridinol
9b. The key steps of the reaction sequence (Scheme 4)
are the synthesis of an organotin compound 19 and its
iododestannylation, which were carried out according
to a published method.31
see Scheme 1. Ki ) 150 pM against [3H]cytisine.18 Ki ) 2.5
g
h
nM against [3H]cytisine.18
dine for nAChR in rodent brain. Compared to (+)-
epibatidine, A-85380 showed somewhat lower affinity
(Ki ) 17 ( 1 pM). This pattern agrees with the findings
of an earlier work15 where Ki values for (()-epibatidine
and A-85380 (43 and 52 pM, respectively) were deter-
mined using (-)-[3H]cytisine. The discrepancy in ab-
solute values might be ascribed to an overestimation of
competitor concentrations in the assays with (-)-
[3H]cytisine due to inadequate consideration of removal
of the competitors from the incubation medium.
As seen from Table 1, most of the synthesized halo-
pyridyl ethers retained subnanomolar affinity to central
nAChRs. The apparent exceptions were 2-substituted
analogues 2b-d whose affinity diminished drastically
with an increase in the substituent size. The affinity
of the iodo compound 2d dropped into the micromolar
range. As shown below, the bulky substituents at
position 2 of the pyridine nucleus distort the molecular
conformation of the ligands and affect the intramolecu-
lar N-N distance. This parameter is believed to be
The halodestannylation was also used successively in
an alternative synthesis of compounds 6c,d (Scheme 5)
to reveal a useful precursor (21) for future development
of radiobrominated and radioiodinated analogues of
A-85380.
The syntheses of alkoxypyridines 11, 12, 15, and 18
(the first step in Schemes 2-4) were accomplished using
a modification of a published method for O-alkylation
of phenols with O-alkyl-N,N′-dicyclohexylisoureas.32
In Vitr o Recep tor Bin d in g. The binding affinity
of each ligand for nAChRs was determined by measur-
ing its ability to compete with (()-[3H]epibatidine for
specific binding sites in rat brain. Our studies showed
that the specific binding of the used radioligand to crude
synaptic membranes of rat forebrain, at concentrations
up to 1 nM, is characterized by a single population of
binding sites with Kd ) 10 ( 1 pM (n ) 6). It has been
previously found that the predominant receptor with
high affinity for [3H]nicotine, (-)-[3H]cytisine, and (()-
[3H]epibatidine in rat brain is composed of R4 and â2
subunits.33,34 Therefore, the affinities, measured in the
present work, presumably reflect interactions of ligands
primarily with the R4â2 subtype of nAChR.
crucial for high-affinity binding to nAChRs.35-37
A
relatively small fluorine substituent at position 2 causes
minimal conformational distortion. As a result, the
fluoro compound 2a showed a 2-fold lower affinity
compared to isomers 3a and 4a , which have the fluorine
atom at positions 5 and 6, respectively.
Substituents at position 6, the other R-position of the
pyridine ring, exerted a much smaller impact on the
binding affinity. Still, the iodo representative of this
series, ligand 4d , was about 1 order of magnitude less
potent than the parent compound 1.
Substitution at position 5 of the 3-pyridyl moiety had
the smallest effect on the binding affinity of the com-
pounds under consideration. Of the 5-substituted ana-
logues studied, the least potent ligand, chloro derivative
3b, showed a 2-fold lower affinity than A-85380.
Of all the synthesized ligands, the most potent one
was compound 3d , featuring an iodine atom at position
5. The affinity of 3d (Ki ) 11 ( 1 pM) was even
As shown in Table 1, competition assays yielded a Ki
value of 8.4 ( 0.2 pM for (+)-epibatidine. This result
is consistent with both recently reported33 and our own
direct measurements of the affinity of (()-[3H]epibati-

Halo-3-(2(S)-azetidinylmethoxy)pyridines
J ournal of Medicinal Chemistry, 1998, Vol. 41, No. 19 3693
somewhat higher than that of prototype 1. The emerg-
ing trend, that the presence of a bulkier substituent at
position 5 of the 3-pyridyl moiety contributes to a higher
affinity, is similar to the pattern found recently for
derivatives of A-84543.16,17 The reasons for this inter-
esting phenomenon are currently under investi-
gation.
Com p u ta tion a l Stu d ies. The pharmacophore con-
cept is one of the cornerstones of medicinal chemistry.
Deducing a pharmacophore requires identification of
chemical groups essential for a particular biological
activity and determination of their three-dimensional
arrangement that is recognized by a single receptor.
With regard to the nicotinic pharmacophore, the most
recently developed model35 suggests that the essential
groups are (A) a cationic center (e.g., a basic or quat-
ernized sp3 nitrogen atom), (B) an electronegative atom
capable of formation of a hydrogen bond (e.g., a pyridine-
like nitrogen or a carbonyl oxygen), and (C) a dummy
point or an atom to define a line along which the
hydrogen bond may form. The latter element can be
exemplified by the pyridine ring centroid or the carbonyl
carbon. Optimal distances between the three pharma-
cophoric elements were estimated35 as follows: A-B,
4.7 ( 0.3 Å; A-C, 4.0 ( 0.3 Å; B-C, 1.2 Å.
A more recent molecular modeling study36 cast some
doubt on these parameters. In that work, it was found
that the lowest-energy conformer of epibatidine had the
internitrogen (i.e., A-B) distance of 5.51 Å, a value far
beyond the range previously proposed. Since epibati-
dine is one of the most potent nAChR ligands known,
the suggestion has been made36,37 that the optimal
internitrogen distance for high-affinity binding should
be closer to 5.5 Å. Subsequently, computational stud-
ies15 assumed that in A-85380, which binds to nAChRs
almost equipotently to epibatidine, nitrogen atoms
might be even farther apart.
F igu r e 3. Superposition of 3d (solid black) on (+)-epibatidine
by the three pharmacophoric elements.
F igu r e 4. Superposition of 3d (solid black) on (-)-epibatidine
by the three pharmacophoric elements.
atom and the pyridine ring centroid) of 4.27 Å that fit
perfectly into the nicotinic pharmacophore model.35
Subsequently, higher-than-minimum-energy conform-
ers of compounds 1, 2a -d , 3a -d , and 4a ,d were
considered. We have found that molecules of parent
A-85380 and analogues 3a -d and 4a ,d have stable
conformations with the relative energies not exceeding
0.42 kcal/mol and the internitrogen distances ranging
from 4.33 to 4.39 Å (Table 1). The A-C parameters for
these conformers vary from 4.35 to 4.43 Å. Although
the obtained values do not fall exactly within the
proposed35 ranges, they are still very close to the
parameters found for epibatidine. As a result, a tight
fit superposition of each of these conformers on (+)-
epibatidine was achieved. In all cases the pyridine rings
of the overlaid structures were nearly coplanar (for
example, see Figure 3), rms deviations were below 0.1
Å (Table 1), and the maximal distance between respec-
tive superimposed points did not exceed 0.13 Å. When
superimposing the ligands on (-)-epibatidine, their
pyridine rings formed a distinct dihedral angle and the
aza fragments showed less overlap (Figure 4).
Quite different results were obtained for compounds
2a -d . A stable conformation with the distance param-
eters complying with the nicotinic pharmacophore model
was found only for the high-affinity fluoro derivative 2a .
For its chloro, bromo, and iodo analogues 2b-d , no
stable conformers could be located to have the N-N
distance shorter than 5.10, 5.25, and 5.32 Å, respec-
tively. Moreover, none of the identified conformers
could be satisfactorily superimposed on any of the
epibatidine stereoisomers (for example, see Figure 5).
These results are consistent with the lower affinities
exhibited by ligands 2b-d . As seen from superposition
of the isomeric iodo derivatives 2d and 3d (Figure 6),
the bulky substituent at position 2 of the pyridine ring
caused radical changes in the molecular geometry which
apparently are beyond the limits allowed for high-
affinity binding.
Given these findings, we decided to use molecular
modeling in order to get some idea why a substitution
at position 2, unlike one at position 5 or 6 of the
3-pyridyl fragment in A-85380, has such a profound
impact on the ligand affinity. To this end, we performed
quantum chemical calculations on molecules of com-
pounds 1, 2a -d , 3a -d , and 4a ,d using the semi-
empirical AM138 method. The calculations revealed
that the lowest-energy conformers of A-85380 and
analogues 2a -d , 3a -d , and 4a ,d had almost identical
geometries with the distance between the azetidine and
pyridine nitrogen atoms ranging from 5.50 Å (in 2b) to
5.74 Å (in 1), which could not explain the wide varia-
tions in binding affinity.
It is commonly recognized,15,35 however, that the
receptor-bound conformations of ligands may not be the
same as the lowest-energy conformations either in a
vacuum or in solution. Hence, we reexamined the
geometry of the epibatidine molecule which has been
shown to possess another stable conformer with a
shorter N-N distance.15 Our calculations substantiated
that the lowest-energy conformer of epibatidine had the
internitrogen distance of 5.50 Å. The other stable
conformer found, with a relative energy of only 0.18
kcal/mol, featured the N-N distance of 4.47 Å and the
A-C parameter (a distance between the sp3 nitrogen
In summary, our computational studies have shown
that epibatidine and the new high-affinity A-85380-
based nAChR ligands possess stable conformers featur-
ing similar spatial arrangement of pharmacophoric

3694 J ournal of Medicinal Chemistry, 1998, Vol. 41, No. 19
Koren et al.
Exp er im en ta l Section
Ch em istr y. Meth od s a n d Ma ter ia ls. Proton magnetic
resonance spectra were recorded on a Bruker AM 300 instru-
ment at 300 MHz. Chemical shifts are reported in ppm
downfield from internal tetramethylsilane at 0.00 ppm. Melt-
ing points were determined on a Mel-Temp II apparatus and
are uncorrected. Elemental analyses were performed by
Atlantic Microlab, Inc. (Norcross, GA).
High-performance liquid chromatography (HPLC) was per-
formed using a Hamilton PRP-1 column (7 × 305 mm) at flow
rate of 7 mL/min and a fixed-wavelength (254 nm) UV detector.
Flash chromatography was carried out using Merck silica gel
(grade 9385, 230-400 mesh, 60 Å) obtained from Aldrich
Chemical Co. (Milwaukee, WI).
2-Chloro-3-pyridinol (8b), 2-bromo-3-pyridinol (8c), and
5-chloro-3-pyridinol (9b) were purchased from Aldrich Chemi-
cal Co. 2-Iodo-3-pyridinol (8d ) was purchased from Lancaster
Synthesis Inc. (Windham, NH). 5-Bromo-3-pyridinol (9c),40
6-iodo-3-pyridinol (10d ),28 and 1-(tert-butoxycarbonyl)-2(S)-
azetidinemethanol15 were prepared according to the literature
procedures. All reactions were carried out under anhydrous
conditions unless otherwise noted.
F igu r e 5. Superposition of 2d (solid black) on (+)-epibatidine
by the three pharmacophoric elements.
The following abbreviations are used in the Experimental
Section: DME for ethylene glycol dimethyl ether, DMSO for
dimethyl sulfoxide, EtOAc for ethyl acetate, TFA for trifluoro-
acetic acid, THF for tetrahydrofuran, tR for retention time.
Gen er a l P r oced u r e for P r ep a r a tion of Com p ou n d s
2a -d , 3a -d , a n d 4a ,d . To a solution of an appropriate Boc-
protected compound (5a -d , 6a -d , 7a ,d ; 0.5 mmol) in CH2Cl2
(2 mL) was added TFA (2 mL), and the resulting solution was
stirred at room temperature for 3 h. The volatiles were
removed in vacuo, and the residue was purified by HPLC. The
fraction containing the desired product was concentrated in
vacuo at 40 °C using a rotary evaporator. During the evapora-
tion, HPLC-grade acetonitrile was repeatedly added to the
product for azeotropical removal of water. Finally, the product
was dried in a vacuum-desiccator over P2O5 at 0.1 mmHg.
Isolated yields ranged from 67% to 84%. The compounds were
obtained as very viscous colorless syrups.
2-F lu or o-3-(2(S)-a zetid in ylm eth oxy)p yr id in e (2a ), sa lt
w ith tr iflu or oa cetic a cid : HPLC tR 4.6 min (acetonitrile-
methanol-water-TFA, 6:4:90:0.2); 1H NMR (acetone-d6) δ
2.61 (m, 1H), 3.00 (m, 1H), 4.75-4.92 (m, 3H), 5.01 (m, 1H),
5.74 (m, 1H), 7.31 (dd, J ) 4.8, 7.9 Hz, 1H), 7.69 (ddd, J )
1.4, 7.9, 10.5 Hz, 1H), 7.81 (ddd, J ) 1.4, 1.7, 4.8 Hz, 1H).
Anal. (C9H11FN2O‚2.9C2HF3O2) C, H, N.
F igu r e 6. Superposition of 2d (solid black) on 3d by the
azetidine cycles.
elements. This arrangement agrees well with the
current nicotinic pharmacophore model. Reasons for
the lower affinity of ligands 2b-d for nAChRs can also
be rationalized within the framework of this model. We
must particularly emphasize, however, that it would be
an oversimplification to assume that the affinity for
nAChRs is determined solely by the limited set of
distance parameters examined here. It is now recog-
nized that more sophisticated models are needed to deal
with ligand volumes and regions of bulk tolerance/
intolerance.39 Nonetheless, the employed simple ap-
proach has proven to be a useful tool for interpreting
and rationalizing activity data.
Su m m a r y
2-Ch lor o-3-(2(S)-a zetid in ylm eth oxy)p yr id in e (2b), sa lt
w ith tr iflu or oa cetic a cid : HPLC tR 6.7 min (acetonitrile-
methanol-water-TFA, 6:4:90:0.2); 1H NMR (acetone-d6) δ
2.68 (m, 1H), 3.02 (m, 1H), 4.74-4.90 (m, 3H), 5.05 (m, 1H),
5.77 (m, 1H), 7.41 (dd, J ) 4.7, 8.1 Hz, 1H), 7.63 (dd, J ) 1.5,
We have shown that A-85380-based compounds, hav-
ing a halogen atom as the substituent at position 5 or 6
of the 3-pyridyl fragment, are potent nAChR ligands.
These compounds, as well as the 2-fluoro analogue,
possess subnanomolar affinity for nAChRs in mem-
branes from rat forebrain. Of these ligands, 5-iodo-3-
(2(S)-azetidinylmethoxy)pyridine shows the highest af-
finity (Ki ) 11 pM), exceeding that of A-85380 and
comparable to the affinity of (+)-epibatidine. In con-
trast, compounds with a 2-chloro-, 2-bromo-, and 2-iodo-
substituted pyridine ring exhibit substantially lower
potency. Molecular modeling studies demonstrate that
the bulky substituents at position 2 of the 3-pyridyl
moiety distort the molecular geometry common to the
high-affinity members of the series studied. For the
latter compounds, a tight fit superposition of low-energy
stable conformers on (+)-epibatidine is observed. The
high affinity of 2-fluoro, 6-fluoro, 5-bromo, and 5-iodo
analogues for nAChRs suggests that the respective
radiohalogenated compounds are worth testing as po-
tential PET/SPECT tracers. Precursors, suitable for the
syntheses of these tracers, have been developed and are
reported in the present work.
8.1 Hz, 1H), 8.05 (dd, J ) 1.5, 4.7 Hz, 1H). Anal. (C9H11
ClN2O‚2C2HF3O2) C, H, N.
-
2-Br om o-3-(2(S)-a zetid in ylm eth oxy)p yr id in e (2c), sa lt
w ith tr iflu or oa cetic a cid : HPLC tR 4.7 min (acetonitrile-
1
water-TFA, 10:90:0.2); H NMR (acetone-d6) δ 2.73 (m, 1H),
3.02 (m, 1H), 4.76 (m, 1H), 4.81-4.90 (m, 2H), 5.05 (m, 1H),
5.78 (m, 1H), 7.43 (dd, J ) 4.8, 8.1 Hz, 1H), 7.56 (dd, J ) 1.5,
8.1 Hz, 1H), 8.04 (dd, J ) 1.5, 4.8 Hz, 1H). Anal. (C9H11
BrN2O‚1.5C2HF3O2) C, H, N.
-
2-Iod o-3-(2(S)-a zetid in ylm eth oxy)p yr id in e (2d ), sa lt
w ith tr iflu or oa cetic a cid : HPLC tR 6.3 min (acetonitrile-
1
water-TFA, 10:90:0.2); H NMR (acetone-d6) δ 2.81 (m, 1H),
3.02 (m, 1H), 4.74 (m, 1H), 4.82-4.92 (m, 2H), 5.18 (m, 1H),
5.80 (m, 1H), 7.39 (dd, J ) 3.9, 8.1 Hz, 1H), 7.42 (dd, J ) 2.4,
8.1 Hz, 1H), 8.05 (dd, J ) 2.4, 3.9 Hz, 1H). Anal. (C9H11
IN2O‚3C2HF3O2) C, H, N.
-
5-F lu or o-3-(2(S)-a zetid in ylm eth oxy)p yr id in e (3a ), sa lt
w ith tr iflu or oa cetic a cid : HPLC tR 2.3 min (acetonitrile-
methanol-water-TFA, 6:4:90:0.2); 1H NMR (acetone-d6) δ
2.63 (m, 1H), 2.99 (m, 1H), 4.74-4.90 (m, 3H), 5.05 (m, 1H),
5.74 (m, 1H), 7.43 (ddd, J ) 2.2, 2.5, 10.5 Hz, 1H), 8.22 (d, J
) 2.5 Hz, 1H), 8.30 (dd, J ) 1.2, 2.2 Hz, 1H). Anal. (C9H11
FN2O‚2.8C2HF3O2) C, H, N.
-

Halo-3-(2(S)-azetidinylmethoxy)pyridines
J ournal of Medicinal Chemistry, 1998, Vol. 41, No. 19 3695
5-Ch lor o-3-(2(S)-a zetid in ylm eth oxy)p yr id in e (3b), sa lt
w ith tr iflu or oa cetic a cid : HPLC tR 5.1 min (acetonitrile-
methanol-water-TFA, 6:4:90:0.2); 1H NMR (acetone-d6) δ
2.63 (m, 1H), 2.99 (m, 1H), 4.74-4.89 (m, 3H), 5.05 (m, 1H),
5.74 (m, 1H), 7.61 (dd, J ) 1.9, 2.3 Hz, 1H), 8.1-8.6 (br, 2H).
Anal. (C9H11ClN2O‚2.5C2HF3O2) C, H, N.
5-Br om o-3-(2(S)-a zetid in ylm eth oxy)p yr id in e (3c), sa lt
w ith tr iflu or oa cetic a cid : HPLC tR 6.9 min (acetonitrile-
methanol-water-TFA, 6:4:90:0.2); 1H NMR (acetone-d6) δ
2.63 (m, 1H), 2.99 (m, 1H), 4.74-4.89 (m, 3H), 5.05 (m, 1H),
5.73 (m, 1H), 7.74 (dd, J ) 1.8, 2.6 Hz, 1H), 8.2-8.6 (br, 2H).
Anal. (C9H11BrN2O‚2.5C2HF3O2) C, H, N.
8.1 Hz, 1H), 8.01 (dd, J ) 1.4, 4.6 Hz, 1H). Anal. (C14H19-
IN2O3) C, H, N.
5-F lu or o-3-((1-(ter t-bu toxyca r bon yl)-2(S)-a zetid in yl)-
m eth oxy)p yr id in e (6a ): mp 62-63 °C; 1H NMR (acetone-
d6) δ 1.39 (s, 9H), 2.23-2.44 (m, 2H), 3.83 (m, 2H), 4.24 (m,
1H), 4.47 (m, 1H), 4.48-4.57 (m, 1H), 7.31 (ddd, J ) 2.4, 2.4,
10.9 Hz, 1H), 8.11 (d, J ) 2.4 Hz, 1H), 8.24 (dd, J ) 1.2, 2.4
Hz, 1H). Anal. (C14H19FN2O3) C, H, N.
5-Ch lor o-3-((1-(ter t-bu toxyca r bon yl)-2(S)-a zetid in yl)-
1
m eth oxy)p yr id in e (6b): mp 82-83 °C; H NMR (CDCl3) δ
1.43 (s, 9H), 2.22-2.42 (m, 2H), 3.89 (m, 2H), 4.13 (m, 1H),
4.29-4.39 (m, 1H), 4.52 (m, 1H), 7.28 (dd, J ) 1.9, 2.7 Hz,
1H), 8.20 (d, J ) 1.9 Hz, 1H), 8.25 (d, J ) 2.7 Hz, 1H). Anal.
(C14H19ClN2O3) C, H, N.
5-Iod o-3-(2(S)-a zetid in ylm eth oxy)p yr id in e (3d ), sa lt
w ith tr iflu or oa cetic a cid : HPLC tR 4.4 min (acetonitrile-
1
5-Br om o-3-((1-(ter t-bu toxyca r bon yl)-2(S)-a zetid in yl)-
m eth oxy)p yr id in e (6c): 1H NMR (CDCl3) δ 1.43 (s, 9H),
2.22-2.42 (m, 2H), 3.89 (m, 2H), 4.13 (m, 1H), 4.29-4.38 (m,
1H), 4.52 (m, 1H), 7.43 (dd, J ) 1.8, 2.6 Hz, 1H), 8.28 (d, J )
2.6 Hz, 1H), 8.29 (d, J ) 1.8 Hz, 1H). Anal. (C14H19BrN2O3)
C, H, N.
water-TFA, 10:90:0.2); H NMR (acetone-d6) δ 2.64 (m, 1H),
2.99 (m, 1H), 4.75 (m, 1H), 4.80-4.90 (m, 2H), 5.05 (m, 1H),
5.73 (m, 1H), 7.87 (dd, J ) 1.4, 2.4 Hz, 1H), 8.33-8.45 (br,
1H), 8.45-8.57 (br, 1H). Anal. (C9H11IN2O‚2.5C2HF3O2) C,
H, N.
6-F lu or o-3-(2(S)-a zetid in ylm eth oxy)p yr id in e (4a ), sa lt
w ith tr iflu or oa cetic a cid : HPLC tR 5.3 min (acetonitrile-
methanol-water-TFA, 6:4:90:0.2); 1H NMR (acetone-d6) δ
2.61 (m, 1H), 2.97 (m, 1H), 4.69-4.89 (m, 3H), 5.03 (m, 1H),
5.72 (m, 1H), 7.07 (ddd, J ) 0.5, 3.3, 9.0 Hz, 1H), 7.69 (ddd, J
) 3.3, 6.3, 9.0 Hz, 1H), 7.98 (ddd, J ) 0.5, 1.8, 3.3 Hz, 1H).
Anal. (C9H11FN2O‚1.7C2HF3O2) C, H, N.
5-Iod o-3-((1-(t er t -b u t oxyca r b on yl)-2(S )-a ze t id in yl)-
1
m eth oxy)p yr id in e (6d ): mp 65-66 °C; H NMR (CDCl3) δ
1.43 (s, 9H), 2.21-2.41 (m, 2H), 3.89 (m, 2H), 4.12 (m, 1H),
4.27-4.37 (m, 1H), 4.51 (m, 1H), 7.60 (dd, J ) 1.6, 2.7 Hz,
1H), 8.30 (d, J ) 2.7 Hz, 1H), 8.43 (d, J ) 1.6 Hz, 1H). Anal.
(C14H19IN2O3) C, H, N.
6-F lu or o-3-((1-(ter t-bu toxyca r bon yl)-2(S)-a zetid in yl)-
m eth oxy)p yr id in e (7a ): 1H NMR (acetone-d6) δ 1.39 (s, 9H),
2.22-2.43 (m, 2H), 3.83 (m, 2H), 4.21 (m, 1H), 4.42 (m, 1H),
4.47-4.57 (m, 1H), 7.02 (ddd, J ) 0.5, 3.5, 9.0 Hz, 1H), 7.61
(ddd, J ) 3.2, 6.5, 9.0 Hz, 1H), 7.93 (ddd, J ) 0.5, 1.6, 3.2 Hz,
1H). Anal. (C14H19FN2O3) C, H, N.
6-Iod o-3-(2(S)-a zetid in ylm eth oxy)p yr id in e (4d ), sa lt
w ith tr iflu or oa cetic a cid : HPLC tR 8.4 min (acetonitrile-
1
water-TFA, 12:88:0.2); H NMR (acetone-d6) δ 2.62 (m, 1H),
2.98 (m, 1H), 4.72 (m, 1H), 4.77-4.89 (m, 2H), 5.04 (m, 1H),
5.72 (m, 1H), 7.27 (dd, J ) 3.3, 8.6 Hz, 1H), 7.76 (dd, J ) 0.5,
8.6 Hz, 1H), 8.21 (dd, J ) 0.5, 3.3 Hz, 1H). Anal. (C9H11
IN2O‚2.5C2HF3O2) C, H, N.
-
6-Iod o-3-((1-(t er t -b u t oxyca r b on yl)-2(S )-a ze t id in yl)-
1
m eth oxy)p yr id in e (7d ): mp 69-70 °C; H NMR (CDCl3) δ
Gen er a l P r oced u r e for P r ep a r a tion of Com p ou n d s
5a -d , 6a -d , a n d 7a ,d . To a stirred at 0 °C solution of an
appropriate halo-3-pyridinol (8a -d , 9a -d , 10a ,d ; 2 mmol) and
1-(tert-butoxycarbonyl)-2(S)-azetidinemethanol (560 mg, 3 mmol)
in THF (8 mL) was added in one portion Ph3P (786 mg, 3
mmol) followed by the dropwise addition of neat diethyl
azodicarboxylate (522 mg, 3 mmol). The resulting solution was
allowed to warm gradually and stirred at room temperature
for 3 days. The solvent was removed under reduced pressure.
The residue was extracted with hexanes-EtOAc (80:20)
mixture (4 × 15 mL). The combined extract was washed with
10-mL portions of saturated NaHCO3 and water and dried over
anhydrous MgSO4. The solvent was removed in vacuo. The
crude material was purified by flash chromatography (hex-
anes-EtOAc, 80:20 to 60:40) to give the desired product in
61-78% yields. Compounds 5a ,d , 6c, and 7a were obtained
as colorless syrups, while 5b,c, 6a ,b,d , and 7d appeared to be
white solids.
1.41 (s, 9H), 2.21-2.41 (m, 2H), 3.88 (m, 2H), 4.10 (m, 1H),
4.26-4.36 (m, 1H), 4.50 (m, 1H), 6.97 (dd, J ) 3.2, 8.7 Hz,
1H), 7.58 (d, J ) 8.7 Hz, 1H), 8.14 (d, J ) 3.2 Hz, 1H). Anal.
(C14H19IN2O3) C, H, N.
Gen er a l P r oced u r e for P r ep a r a tion of Com p ou n d s
6c,d via Ha lod esta n n yla tion . A solution of, respectively,
bromine (80 mg, 0.5 mmol) or iodine (127 mg, 0.5 mmol) in
CHCl3 (1.5 mL) was added dropwise to a stirred solution of
21 (214 mg, 0.5 mmol) in CHCl3 (1.5 mL). The reaction
mixture was stirred for 20 min at room temperature, and then
saturated KF (2 mL) was added. The resulting mixture was
made alkaline with saturated K2CO3 and thoroughly extracted
with CHCl3. The combined extract was washed with saturated
KF, saturated Na2S2O3, and water and dried over anhydrous
MgSO4. The solvent was removed under reduced pressure.
The crude material was purified by flash chromatography
(hexanes-EtOAc, 60:40). Isolated yields were as follows: 6c,
141 mg (82%); 6d , 150 mg (77%). Properties of the compounds
were identical to those described above.
Gen er a l P r oced u r e for P r ep a r a tion of Com p ou n d s 8a ,
9a ,d , a n d 10a . A solution of HBr in acetic acid (45% w/v, 5
mL) was added dropwise to 2 mmol of an appropriate halo-3-
alkoxypyridine (13, 17, 20, or 14, respectively) while stirring
and cooling with an ice-salt bath. The resulting solution was
stirred at room temperature for 3 h (in the case of 17, at 60
°C for 72 h), neutralized by the dropwise addition of 10 M
NaOH (5.5 mL) while cooling with an ice bath, and extracted
with ether (4 × 15 mL). The combined extract was washed
with water (10 mL) and dried over anhydrous Na2SO4, and
the solvent was removed under reduced pressure. The solid
residue was purified by flash chromatography (8a , hexanes-
ether, 30:70; 9a , CH2Cl2-EtOAc, 75:25; 9d , ether; 10a ,
CH2Cl2-ether, 85:15). Isolated yields were as follows: 8a ,
61%; 9a , 36%; 9d , 78%; 10a , 55%.
2-F lu or o-3-((1-(ter t-bu toxyca r bon yl)-2(S)-a zetid in yl)-
m eth oxy)p yr id in e (5a ): 1H NMR (acetone-d6) δ 1.38 (s, 9H),
2.24-2.45 (m, 2H), 3.84 (m, 2H), 4.25 (m, 1H), 4.43-4.58 (m,
2H), 7.25 (dd, J ) 4.9, 7.9 Hz, 1H), 7.64 (ddd, J ) 1.4, 7.9,
10.5 Hz, 1H), 7.93 (ddd, J ) 1.4, 1.8, 4.9 Hz, 1H). Anal.
(C14H19FN2O3) C, H, N.
2-Ch lor o-3-((1-(ter t-bu toxyca r bon yl)-2(S)-a zetid in yl)-
1
m eth oxy)p yr id in e (5b): mp 65-66 °C; H NMR (CDCl3) δ
1.40 (s, 9H), 2.32-2.48 (m, 2H), 3.88 (m, 1H), 3.98 (m, 1H),
4.12 (m, 1H), 4.35-4.63 (m, 2H), 7.19 (dd, J ) 4.5, 8.1 Hz,
1H), 7.29 (dd, J ) 1.5, 8.1 Hz, 1H), 8.00 (dd, J ) 1.5, 4.5 Hz,
1H). Anal. (C14H19ClN2O3) C, H, N.
2-Br om o-3-((1-(ter t-bu toxyca r bon yl)-2(S)-a zetid in yl)-
m eth oxy)p yr id in e (5c): mp 67-68 °C; 1H NMR (CDCl3) δ
1.40 (s, 9H), 2.32-2.50 (m, 2H), 3.88 (m, 1H), 4.02 (m, 1H),
4.10 (m, 1H), 4.37-4.63 (m, 2H), 7.19 (dd, J ) 3.7, 8.1 Hz,
1H), 7.23 (dd, J ) 2.4, 8.1 Hz, 1H), 7.99 (dd, J ) 2.4, 3.7 Hz,
1H). Anal. (C14H19BrN2O3) C, H, N.
2-Iod o-3-((1-(t er t -b u t oxyca r b on yl)-2(S )-a ze t id in yl)-
m eth oxy)p yr id in e (5d ): 1H NMR (CDCl3) δ 1.41 (s, 9H),
2.35-2.52 (m, 2H), 3.88 (m, 1H), 4.03-4.10 (m, 2H), 4.33-
4.60 (m, 2H), 7.06 (dd, J ) 1.4, 8.1 Hz, 1H), 7.18 (dd, J ) 4.6,
2-F lu or o-3-p yr id in ol (8a ): mp 125-126 °C; 1H NMR
(acetone-d6) δ 7.14 (ddd, J ) 1.1, 4.8, 7.8 Hz, 1H), 7.42 (ddd,
J ) 1.6, 7.8, 10.6 Hz, 1H), 7.70 (ddd, J ) 1.6, 1.8, 4.8 Hz, 1H).
Anal. (C5H4FNO) C, H, N.
5-F lu or o-3-p yr id in ol (9a ): mp 167-168 °C; 1H NMR
(acetone-d6) δ 7.04 (ddd, J ) 2.4, 2.4, 10.5 Hz, 1H), 8.02 (d, J

3696 J ournal of Medicinal Chemistry, 1998, Vol. 41, No. 19
Koren et al.
) 2.4 Hz, 1H), 8.21 (dd, J ) 1.2, 2.4 Hz, 1H). Anal. (C5H4-
FNO) C, H, N.
dried over anhydrous K2CO3. The solvent was removed under
reduced pressure. The crude material was purified by flash
chromatography (hexanes-ether, 30:70) to give 0.68 g (89%)
of the title compound as a colorless liquid: 1H NMR (CDCl3)
δ 1.32 (d, J ) 6.0 Hz, 6H), 3.87 (br s, 2H), 4.50 (sept, J ) 6.0
Hz, 1H), 6.51 (dd, J ) 1.8, 2.6 Hz, 1H), 7.69 (br m, 2H). Anal.
(C8H12N2O) C, H, N.
5-Iodo-3-pyr idin ol (9d): mp 208-209 °C; 1H NMR (acetone-
d6) δ 7.62 (dd, J ) 1.6, 2.7 Hz, 1H), 8.20 (d, J ) 2.7 Hz, 1H),
8.32 (d, J ) 1.6 Hz, 1H). Anal. (C5H4INO) C, H, N.
6-F lu or o-3-p yr id in ol (10a ): mp 156-157 °C; 1H NMR
(acetone-d6) δ 6.91 (dd, J ) 3.5, 9.0 Hz, 1H), 7.40 (ddd, J )
3.2, 6.5, 9.0 Hz, 1H), 7.75 (dd, J ) 1.8, 3.2 Hz, 1H). Anal.
(C5H4FNO) C, H, N.
5-F lu or o-3-isop r op oxyp yr id in e (17). Sodium nitrite (180
mg, 2.6 mmol) was added in small portions to a solution of 16
(380 mg, 2.5 mmol) in HF-pyridine mixture (7.5 mL) in a poly-
(ethylene) reaction vessel cooled with an ice-salt bath. The
resulting solution was stirred at 0 °C for 30 min, then heated
to 50 °C, and stirred at this temperature for 1 h. The reaction
mixture was poured onto crushed ice (25 g), partially neutral-
ized with cold saturated NaHCO3, and extracted with ether
(4 × 15 mL). The combined extract was dried over anhydrous
Na2SO4, and the solvent was removed under reduced pressure.
The crude material was purified by flash chromatography
(hexanes-ether, 60:40) to give 318 mg (82%) of the title
compound as a colorless liquid: 1H NMR (CDCl3) δ 1.38 (d, J
) 6.0 Hz, 6H), 4.62 (sept, J ) 6.0 Hz, 1H), 7.07 (ddd, J ) 2.3,
2.3, 10.2 Hz, 1H), 8.16 (d, J ) 2.3 Hz, 1H), 8.21 (dd, J ) 0.7,
2.3 Hz, 1H). Anal. (C8H10FNO) C, H, N.
Gen er a l P r oced u r e for P r ep a r a tion of Com p ou n d s 11,
12, 15, a n d 18. A mixture of cyclopropanemethanol (0.79 g,
11 mmol), 1,3-dicyclohexylcarbodiimide (2.06 g, 10 mmol), and
copper(I) chloride (20 mg) was stirred at 60 °C for 6 h. (For
preparation of 15, 2-propanol (0.66 g, 11 mmol) was used
instead of cyclopropanemethanol.) The reaction mixture was
diluted with benzene (10 mL), and 10 mmol of an appropriate
halo-3-pyridinol (8d , 10d , 9c, or 9b, respectively) was added.
This mixture was heated to reflux while stirring for 24 h. A
precipitate that formed was filtered off, and the solution was
concentrated under reduced pressure. The residue was ex-
tracted with hexanes-EtOAc (80:20) mixture (4 × 20 mL). The
combined extract was washed with 20-mL portions of satu-
rated NaHCO3 and water and dried over anhydrous MgSO4.
The solvent was removed in vacuo. The crude material was
purified by flash chromatography (hexanes-EtOAc, 90:10 to
80:20) to give the desired product in 34-48% yields. Com-
pounds 11, 12, and 15 were obtained as colorless liquids, while
18 appeared to be a white solid.
5-(Tr im e t h ylst a n n yl)-3-(cyclop r op ylm e t h oxy)p yr i-
d in e (19). A solution of 18 (1.84 g, 10 mmol) in DME (6 mL)
was added dropwise to a stirred at 0 °C filtrate containing
trimethylstannyl sodium prepared according to the literature
procedure31 from trimethyltin chloride (2.5 g, 12.5 mmol) and
sodium (0.9 g, 39 mmol) in DME (10 mL). The reaction
mixture was allowed to warm to room temperature and stirred
for 3 h. The solvent was removed in vacuo at 35 °C; the
residue was extracted with ether (4 × 25 mL). After removal
of the ether, the resulting crude material was purified by flash
chromatography (hexanes-ether, 50:50) to give 1.62 g (52%)
of the title compound as a colorless liquid: 1H NMR (CDCl3)
δ 0.35 (m, 9H), 0.37 (m, 2H), 0.67 (m, 2H), 1.28 (m, 1H), 3.85
(d, J ) 7.0 Hz, 2H), 7.29 (m, 1H), 8.20 (m, 1H), 8.22 (d, J )
3.0 Hz, 1H). Anal. (C12H19NOSn) C, H, N.
1
2-Iod o-3-(cyclop r op ylm eth oxy)p yr id in e (11): H NMR
(CDCl3) δ 0.43 (m, 2H), 0.68 (m, 2H), 1.31 (m, 1H), 3.92 (d, J
) 6.6 Hz, 2H), 6.97 (dd, J ) 1.3, 8.2 Hz, 1H), 7.16 (dd, J )
4.6, 8.2 Hz, 1H), 7.99 (dd, J ) 1.3, 4.6 Hz, 1H). Anal. (C9H10
-
INO) C, H, N.
1
6-Iod o-3-(cyclop r op ylm eth oxy)p yr id in e (12): H NMR
(CDCl3) δ 0.36 (m, 2H), 0.67 (m, 2H), 1.26 (m, 1H), 3.82 (d, J
) 7.0 Hz, 2H), 6.90 (dd, J ) 3.2, 8.7 Hz, 1H), 7.57 (d, J ) 8.7
Hz, 1H), 8.09 (d, J ) 3.2 Hz, 1H). Anal. (C9H10INO) C, H, N.
5-Br om o-3-isop r op oxyp yr id in e (15): 1H NMR (CDCl3) δ
1.36 (d, J ) 6.0 Hz, 6H), 4.56 (sept, J ) 6.0 Hz, 1H), 7.34 (dd,
J ) 1.8, 2.7 Hz, 1H), 8.20 (d, J ) 2.7 Hz, 1H), 8.24 (d, J ) 1.8
Hz, 1H). Anal. (C8H10BrNO) C, H, N.
5-Iod o-3-(cyclop r op ylm eth oxy)p yr id in e (20). A solu-
tion of iodine (1.27 g, 5 mmol) in CHCl3 (15 mL) was added
dropwise to a stirred solution of 19 (1.56 g, 5 mmol) in CHCl3
(15 mL). The reaction mixture was stirred for 20 min at room
temperature, and then saturated KF (20 mL) was added. The
resulting mixture was made alkaline with saturated K2CO3
and separated. The aqueous layer was extracted with CHCl3
(3 × 15 mL). The organic layers were combined, washed with
10-mL portions of saturated KF, saturated Na2S2O3 and water,
and dried over anhydrous MgSO4. The solvent was removed
under reduced pressure. The crude material was purified by
flash chromatography (hexanes-ether, 60:40) to give 1.14 g
(83%) of the title compound as a colorless liquid: 1H NMR
(CDCl3) δ 0.36 (m, 2H), 0.67 (m, 2H), 1.27 (m, 1H), 3.83 (d, J
) 7.2 Hz, 2H), 7.53 (dd, J ) 1.6, 2.7 Hz, 1H), 8.26 (d, J ) 2.7
Hz, 1H), 8.41 (d, J ) 1.6 Hz, 1H). Anal. (C9H10INO) C, H, N.
5-(Tr im eth ylsta n n yl)-3-((1-(ter t-bu toxyca r bon yl)-2(S)-
a zetid in yl)m eth oxy)p yr id in e (21) was prepared analo-
gously to 19 starting from 3b (747 mg, 2.5 mmol). The product,
purified by flash chromatography (hexanes-EtOAc, 50:50),
was obtained as a colorless liquid: yield 470 mg (44%); 1H
NMR (CDCl3) δ 0.34 (m, 9H), 1.42 (s, 9H), 2.23-2.42 (m, 2H),
3.91 (m, 2H), 4.15 (m, 1H), 4.30-4.35 (m, 1H), 4.52 (m, 1H),
7.33 (m, 1H), 8.22 (m, 1H), 8.25 (m, 1H). Anal. (C17H28N2O3-
Sn) C, H, N.
In Vitr o Bin d in g Stu d y. Ma ter ia ls. (()-[3H]Epibatidine
(48 Ci/mmol) was obtained from New England Nuclear Corp.
(Boston, MA). 3-(2(S)-Azetidinylmethoxy)pyridine dihydro-
chloride (A-85380, 1) was purchased from Research Biochemi-
cals International (Natick, MA). All other chemicals used were
purchased from Sigma Chemical Co. (St. Louis, MO). Male
Fischer rats were obtained from Charles River Breeding
Laboratories (Wilmington, MA). Rats, shipped at age of 12
weeks, were housed in a temperature- and light-controlled
vivarium for at least 2 weeks before being used for this study.
5-Ch lor o-3-(cyclop r op ylm eth oxy)p yr id in e (18): mp 47-
48 °C; 1H NMR (CDCl3) δ 0.37 (m, 2H), 0.68 (m, 2H), 1.28 (m,
1H), 3.85 (d, J ) 7.2 Hz, 2H), 7.19 (dd, J ) 2.1, 2.6 Hz, 1H),
8.17 (d, J ) 2.1 Hz, 1H), 8.20 (d, J ) 2.6 Hz, 1H). Anal.
(C9H10ClNO) C, H, N.
Gen er a l P r oced u r e for P r ep a r a tion of Com p ou n d s 13
a n d 14. A mixture of, respectively, 11 or 12 (1.1 g, 4 mmol),
Kryptofix 222 (1.5 g, 4 mmol), and spray-dried KF (11.6 g, 200
mmol) in DMSO (80 mL) was stirred under argon at 165 °C
for 24 or 72 h, respectively. The reaction mixture was diluted
with water (160 mL) and extracted with CCl4 (3 × 40 mL).
The combined extract was washed with water (3 × 20 mL)
and dried over anhydrous MgSO4. The solvent was removed
at 35 °C under reduced pressure. The crude material was
purified by flash chromatography (hexanes-ether, 70:30) to
give the desired product as a colorless liquid in 38-46% yields.
2-Flu or o-3-(cyclopr opylm eth oxy)pyr idin e (13): 1H NMR
(acetone-d6) δ 0.38 (m, 2H), 0.63 (m, 2H), 1.29 (m, 1H), 3.97
(d, J ) 7.0 Hz, 2H), 7.22 (ddd, J ) 0.9, 4.8, 7.9 Hz, 1H), 7.53
(ddd, J ) 1.4, 7.9, 10.4 Hz, 1H), 7.70 (ddd, J ) 1.4, 1.7, 4.8
Hz, 1H). Anal. (C9H10FNO) C, H, N.
6-Flu or o-3-(cyclopr opylm eth oxy)pyr idin e (14): 1H NMR
(CDCl3) δ 0.36 (m, 2H), 0.67 (m, 2H), 1.27 (m, 1H), 3.83 (d, J
) 7.0 Hz, 2H), 6.84 (dd, J ) 3.5, 8.7 Hz, 1H), 7.33 (ddd, J )
3.2, 6.5, 8.7 Hz, 1H), 7.81 (dd, J ) 1.9, 3.2 Hz, 1H). Anal.
(C9H10FNO) C, H, N.
5-Am in o-3-isop r op oxyp yr id in e (16). A mixture of 15
(1.08 g, 5 mmol), CuSO4‚5H2O (230 mg, 0.92 mmol), and
concentrated NH4OH (7.5 mL) was heated in a high-pressure
vessel at 135 °C for 20 h while being vigorously stirred with a
Teflon-coated magnetic stirring bar. Then the mixture was
brought to pH 10 with 20% NaOH, saturated with NaCl, and
extracted with ether (2 × 20 mL). The combined extract was

Halo-3-(2(S)-azetidinylmethoxy)pyridines
J ournal of Medicinal Chemistry, 1998, Vol. 41, No. 19 3697
Mem br a n e P r ep a r a t ion . After CO2 euthanasia and
decapitation, rat forebrain was obtained by a single cut just
behind the colliculi and excluded the cerebellum and medulla.
A crude membrane fraction (P2) was isolated as previously
described41 and stored in aliquots at -70 °C for at least 16 h
but no more than 4 weeks before use. In contrast to the
original procedure,41 the pellets of the crude membrane
fraction were washed just once on the day of assay instead of
repeated washing. The pellets were homogenized in 30
volumes of a HEPES-salt solution (HSS) containing HEPES
(15 mM), NaCl (120 mM), KCl (5.4 mM), MgCl2 (0.8 mM), and
CaCl2 (1.8 mM). After centrifugation at 40000g for 10 min,
the resultant pellets were resuspended in a fresh HSS and
used for binding assay.
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Bin d in g Assa ys. Binding assays for all of the compounds
studied were carried out in HSS at 25 °C and performed in
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A systematic conformational search on molecules of com-
pounds 1, 2a -d , 3a -d , and 4a ,d was performed with three
simultaneously fixed parameters. Those were angles of rota-
tion of the respective fragments about the bonds C(azetidine)-
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Ack n ow led gm en t. The research described in this
publication was supported in part by the Intramural
Research Program of National Institute on Drug Abuse
and funding from the Office of the National Drug
Control Policy. The authors thank Dr. Michael Kassiou
for helpful discussions, Dr. J ohn L. Musachio, who
kindly provided a sample of authentic 5-bromo-3-pyri-
dinol, and Dr. Amy Newman for providing computa-
tional resources. The excellent assistance of Ms. Ger-
aldine Hill in conducting binding assays is also thankfully
acknowledged.
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