Synthesis and binding of 6,7,8,9-tetrahydro-5H-pyrido[3,4-d]azepine and related ring-opened analogs at central nicotinic receptors

Article abstract of DOI:10.1016/S0223-5234(99)80051-8

6,7,8,9-Tetrahydro-5H-pyrido[3,4-d]azepine (5a) and its N₇-methyl derivative 5b were synthesized and evaluated as potential nicotinic acetylcholinergic receptor (nAChR) ligands. On the basis that 6,7,8,9- tetrahydro-5H-pyrido[3,4-c]azepine (4a), which binds at nAChRs with low affinity (K(i) = 1100 nM), possesses an internitrogen distance (4.6 A) that may be less than optimal, we designed compound 5a due to its similar shape but longer internitrogen distance (5.5 A). Compound 5a (K(i) = 46 nM) was found to bind with enhanced affinity. However, unlike what is seen with nornicotine/nicotine, N-methylation of 5a reduced affinity (5b; K(i) = 268 nM) rather than enhancing it. The results suggest that 5 may interact at nicotine receptors in a manner that is somewhat different from that of nicotine. Ring-opening of the pyrido[3,4-d]azepine ring led to a series of 3- (2-aminoethyl)pyridines 21 that retained the affinity of the cyclic compound. Subsequent modification, including further chain lengthening (e.g. aminopropylpyridines 22) and introduction of unsaturation, ultimately led to the development of a series of 3-(2-aminethoxy)pyridines 27. Simple N- substituted derivatives of 27 were found to bind with K(i) values of 20 to 35 nM. Because parallel structural changes in several series of related compounds did not result in parallel shifts in nAChR affinity, it is unlikely that all the investigated compounds bind in a similar fashion at these receptors. Nevertheless, some of these compounds represent novel classes of nAChR ligands.

Full text of DOI:10.1016/S0223-5234(99)80051-8

Eur. J. Med. Chem. 34 (1999) 177−190
© Elsevier, Paris
177
Laboratory note
Synthesis and binding of 6,7,8,9-tetrahydro-5H-pyrido[3,4-d]azepine and related
ring-opened analogs at central nicotinic receptors
Yun-Xing Chenga, Malgorzata Dukata, Matthew Dowda, Wolfgang Fiedlera, Billy Martinb,
Mohamed Imad Damajb, Richard A. Glennona,b*
aDepartment of Medicinal Chemistry, School of Pharmacy, Virginia Commonwealth University, Richmond, VA 23298, USA
bDepartment of Pharmacology and Toxicology, Virginia Commonwealth University, Richmond, VA 23298, USA
(Received 26 January 1998; accepted 7 August 1998)
Abstract – 6,7,8,9-Tetrahydro-5H-pyrido[3,4-d]azepine (5a) and its N7-methyl derivative 5b were synthesized and evaluated as potential
nicotinic acetylcholinergic receptor (nAChR) ligands. On the basis that 6,7,8,9-tetrahydro-5H-pyrido[3,4-c]azepine (4a), which binds at
nAChRs with low affinity (Ki = 1100 nM), possesses an internitrogen distance (4.6 Å) that may be less than optimal, we designed compound
5a due to its similar shape but longer internitrogen distance (5.5 Å). Compound 5a (Ki = 46 nM) was found to bind with enhanced affinity.
However, unlike what is seen with nornicotine/nicotine, N-methylation of 5a reduced affinity (5b; Ki = 268 nM) rather than enhancing it. The
results suggest that 5 may interact at nicotine receptors in a manner that is somewhat different from that of nicotine. Ring-opening of the
pyrido[3,4-d]azepine ring led to a series of 3-(2-aminoethyl)pyridines 21 that retained the affinity of the cyclic compound. Subsequent
modification, including further chain lengthening (e.g. aminopropylpyridines 22) and introduction of unsaturation, ultimately led to the
development of a series of 3-(2-aminethoxy)pyridines 27. Simple N-substituted derivatives of 27 were found to bind with Ki values of 20 to
35 nM. Because parallel structural changes in several series of related compounds did not result in parallel shifts in nAChR affinity, it is
unlikely that all the investigated compounds bind in a similar fashion at these receptors. Nevertheless, some of these compounds represent
novel classes of nAChR ligands. © Elsevier, Paris
nicotine receptors / nicotinic cholinergic receptors / pyrido[3,4-c]azepines / pyrido[3,4-d]azepines / 3-(2-aminoethyl)pyridines /
3-(2-aminoethoxy)pyridines
1. Introduction
mal, was not essential in order for these compounds to
bind at nAChRs. For example, the simple aminometh-
ylpyridine (AMP) 2 where R = R’ = –CH3 (i.e., 2b, Ki =
540 nM) binds, albeit with modest affinity, at nAChRs.
However, 2a (where R = R’ = –H) is devoid of affinity
(i.e., Ki > 10000 nM) whereas 2 (where R = –CH3, R’ =
–C2H5; Ki = 28 nM) binds with significantly higher
affinity and with only 10-fold lower affinity than (–)-
nicotine ((–)-1) itself (Ki = 2.3 nM) [2]. Apparently,
amine substituents can significantly influence affinity. We
have also examined several conformationally-constrained
aminomethylpyridines including naphthyridine deriva-
tives such as 3 and pyrido[3,4-c]azepines such as 4 [2].
Compound 3b (3 where R = –CH3) binds at nicotine
receptors with high affinity (Ki = 18 nM); interestingly
and surprisingly, the affinities of both 4a (Ki = 1100 nM)
and 4b (Ki = 780 nM) were significantly lower [2].
Our laboratory is currently examining nicotine acetyl-
cholinergic receptor (nAChR) ligands in an attempt to
exploit their therapeutic potential. nAChRs have been
implicated as playing roles in, for example, anxiety,
appetite control, pain and various cognitive and neuro-
logical disorders [1], and novel nicotinic cholinergic
agents may be of practical therapeutic benefit in their
treatment. We began our investigation by excising and
abbreviating the pyrrolidine portion of nicotine (1) in
order to determine the minimal structural requirements
for the binding of this agent at nAChRs [2]. It was found
that the intact pyrrolidine ring, although seemingly opti-
*Correspondence and reprints

178
Preliminary radioligand binding data indicated that 5a
binds at nAChRs with higher affinity than 4. Conse-
quently, we prepared several conformationally-flexible
(i.e., ring-opened) analogs of this compound to further
explore the role of internitrogen distance on nAChR
affinity. This investigation also involved exploration of
various N-substituents in the ring-opened analogs.
In an effort to gain an understanding of how these
agents might bind at nicotine receptors, one purpose of
the present study was to determine why the affinity of 4b
was so low relative to 3b. There are several possible
explanations: (a) the internitrogen distance in 4b might be
too short, (b) the receptors might not tolerate the added
bulk of the larger (i.e., 7-membered) ring of 4, and/or (c)
the structure of 4 might not have been correctly assigned
(it should be noted that 4b was synthesized from 4a). We
set out to test these possibilities.
2. Chemistry
We have previously prepared compound 4a via syn-
thesis and subsequent LiAlH4 reduction of 6,7,8,9-
tetrahydro-5H-pyrido[3,4-c]azepine-9-one [2]. To con-
firm the structure of this compound, we synthesized 4a
via an independent route taking advantage of a ring-
opening/rearrangement reaction reported by Kao [4].
Treatment of 7-hydroxy-8-nitrosoisoquinoline (6) with
tosyl chloride in basic aqueous acetone gave an acrylic
acid, 7, as previously described [4]. Compound 7 was
catalytically reduced to 3-(2-aminomethylpyrid-4-
yl)propionic acid (8) which was not characterized but
immediately converted to 6,7,8,9-tetrahydro-5H-
pyrido[3,4-c]azepine-7-one (9) by heating in the presence
of Al2O3 to effect cyclization. Compound 9 was reduced
using LiAlH4 to give 4a that was identical to that which
we previously reported [2].
We have previously suggested that an internitrogen
distance of 5.1 to 5.5 Å may be optimal for nAChR
binding [3]. The calculated internitrogen distances for 1
and 3 are about 4.8 Å [3]. However, the calculated
internitrogen distance in 4 is only 4.6 Å [3]; it might be
this shorter distance that accounts, at least in part, for the
reduced affinity of 4. We reasoned that shifting the
nitrogen atom of 4 by one position, to afford the
pyrido[3,4-d]azepine system 5, should increase the inter-
nitrogen distance, and that 5, although no longer an
aminomethylpyridine, might bind with enhanced affinity.
We calculated the internitrogen distance in 5 and found it
to be 5.5 Å. The second factor to be considered was that
of steric bulk. For example, 2 binds with low affinity at
nAChRs when R’ = –CH2CH2CH3, (where R = H, Ki =
2470 nM; where R = –CH3, Ki = 1140 nM) [2]; thus, the
low affinity of 4 might simply reflect the lack of bulk
tolerance associated with the amine binding site at
nicotinic receptors. Compound 5, because it shares the
bulk character of 4, might be expected to bind with low
affinity if its bulk is not tolerated; on the other hand, if 5
binds, it would suggest that internitrogen distance may be
an overriding factor. Consequently, we undertook the
synthesis and evaluation of compound 5a and its
N-methyl derivative 5b. And finally, because 4b was
synthesized from 4a, we also wished to develop a second,
independent synthesis of compound 4a in order to con-
firm the structure of this ring system.
We attempted to synthesize compound 5a using a
somewhat analogous approach, i.e., by reduction of the
corresponding azepinone 14. Ethyl (3-pyridyl)acetate
(10)
was
converted
to
ethyl
3-[(3-car-
bethoxymethyl)pyrid-4-yl]propionate (11) as previously
reported [5]; cyclization of 11 to 12 followed by hydroly-
sis and decarboxylation afforded 5,6-dihydro-7(8H)-
isoquinolin-7-one (13). However, all attempts to convert
13 to azepinone 14 were unsuccessful.
A somewhat different approach to the synthesis of 5a is
shown in figure 1. 2-(3-Pyridinyl)ethanol (15, R = H) [6]
was treated with t-butyldimethylsilyl (t-BDMS) chloride
in the presence of imidazole to give the protected alcohol
in 90% yield. The protected alcohol was reacted with
ethyl chloroformate and the resultant pyridinium salt was
next reacted with a cuprate reagent (IZnCH2CH2
COOEt/Li2CuCNCl2), followed by oxidation, to give
ester 16 in about 30% yield. The ester was converted to
amide 17 (71% yield) by treatment with an aluminum-

179
Figure 1. Conditions: (a) t-BDMS Cl, imidazole, DMF; (b) 1: ClCOOEt, THF, –78 °C → 0 °C, 2: IZnCH2CH2COOEt, CuCN/LiCl,
–78 °C, 3: xylene, S, ∆; (c) NH4Cl, AlMe3; (d) Br2/NaOMe, MeOH; (e) 1: 35% HCl, ∆, 2: TsCl, NaHCO3, THF/H2O; (f) Ph3P, DEAD,
THF, room temperature; (g) 33% HBr, HOAc, phenol. Compound 5a was converted to 5b using (CH2O)n, NaBH3CN in MeOH.
amine complex [7, 8], and Hoffmann rearrangement of 17
to 18 was accomplished using Br2/NaOMe [9]; carbamate
18 was hydrolyzed and tosylated to afford 19. Treatment
of 19 with Ph3P and diethyl azidodicarboxylate
(DEAD) [10] gave the tosylated azepine (5, R = tosyl) in
85% yield. To our knowledge, this is the first example of
the use of an intramolecular Mitsunobu reaction to
construct a medium-sized ring system. The tosyl group
was removed [11] by reaction with phenol and 33% HBr
in acetic acid to give 5a in 78% yield. Compound 5a was
methylated by reductive alkylation using sodium cy-
anoborohydride and paraformaldehyde (figure 1).
obtained by reductive amination of 21a and 22a and the
appropriate aldehyde. Compounds 22c was prepared by
amination of ethyl 3-(3-pyridyl)propionate [13, 14] with
N-ethylmethylamine in the presence of trimethylalumi-
num, followed by reduction of the corresponding amide
with alane. The 6-chloro derivative of 21c (i.e., 23) was
prepared in a similar manner from the known (6-
chloropyridin-3-yl)acetic acid [15]; following formation
of the amide using N,N’-dicyclohexylcarbodiimide
(DCC) and N-ethylmethylamine, reduction was accom-
plished with alane. Targets 24a–e (table I) were obtained
by conversion of 3-(3-pyridyl)-2-propen-1-ol (31) [16] to
its corresponding chloro derivative by reaction with
SOCl2 followed by amination with the requisite amine.
This is shown in figure 2 for compound 24c. The 2-Z
propenyl analogs 25b–d were synthesized in several steps
The free bases of compounds 21a,b and 22a,b are
known [12] and were prepared according to a literature
procedure and converted to their hydrochloride or oxalate
salts (table I). Tertiary amines 21c,d and 22d were
Figure 2. Conditions: (a) SOCl2; (b) CH3–NH–C2H5.

180
Figure 3. Conditions: (a) KHMDS, THF, –78 °C/(CF3CH2O)2POCH2COOCH3, 18-crown-6/MeCN complex; (b) DiBALH, toluene;
(c) SOCl2; (d) (CH3)2NH/H2O.
(figure 3). Methyl 3-(3-pyridyl)-Z-acrylate (33) was pre-
pared by the reaction of pyridine-3-carboxaldehyde (32)
and bis-(2,2,2-trifluoroethyl)-(methoxycarbonylmethyl)
phosphonate [17] in the presence of 18-crown-
6/acetonitrile complex [18]; hydride reduction of the
ester afforded the alcohol 34 which was converted to the
corresponding chloro compound 35 and allowed to react
with the appropriate amine (exemplified for 25b in
figure 3). Compound 25a was prepared, using a similar
strategy, from the known 3-(3-pyridyl)-2-propyn-1-
ol [19]; the alkynol was catalytically (Lindlar’s catalyst)
reduced to the corresponding 2-Z-propenol which was
then converted to its chloro derivative by reaction with
SOCl2, followed by amination with methylamine to give
25a. It might be noted that the intermediate alcohol in the
preparation of 25a (i.e., 34) is identical to the intermedi-
ate used in the synthesis of analogs 25b–d. The
2-propynyl derivatives 26a,b,d were obtained by amina-
tion of the chloro compound 37 obtained from the
reaction of 3-(3-pyridyl)-2-propyn-1-ol (36) [19] with
SOCl2 (figure 4). Compound 26c was prepared in a
similar manner from 3-(3-pyridyl)-propyn-1-yl bromide
hydrobromide [20] and N-ethylmethylamine.
Compounds 27a–e were prepared in a manner similar
to that used for the synthesis of 22c; amination of ethyl
2-[(3-pyridyl)oxy]acetate (38) [14] with the appropriate
amine in the presence of trimethylaluminum afforded
amides 39, which were reduced by alane (shown for 27e
in figure 5).
Analog 28, a positional isomer of 27a, was synthesized
from 2-chloropyridine by nucleophilic displacement of
halogen with the sodium salt of N-benzyl-N-methyl-
ethanolamine, followed by catalytic debenzylation.
Figure 4. Conditions: (a) SOCl2; (b) (CH3)2NH.

181
Table I. Physicochemical properties of aminoalkyl-, aminopropenyl-, aminopropynyl- and aminoethoxypyridines.
a
b
Method
R
R’
Yield
M.p. (°C)
Recrystallization
solvent
Empirical formula
c
c
21a
21b
21c
21d
22a
22b
22c
22d
24a
24b
24c
24d
24e
25a
25b
25c
25d
26a
26b
26c
26d
27a
27b
27c
27d
27e
–H
–CH3
–CH3
–CH3
–H
–CH3
–CH3
–CH3
–H
–CH3
–CH3
–CH3
–CH2CH2CH2CH2–
–H
–CH3
–CH3
–CH3
–H
–CH3
–CH3
–CH3
–H
–CH3
–CH3
–CH3
–CH3
–C2H5
–C3H7
–CH3
–CH3
–C2H5
–C3H7
–CH3
–CH3
–C2H5
–C3H7
83 %
67 %
61 %
61 %
83 %
71 %
49 %
80 %
76 %
71 %
56 %
74 %
50 %
39 %
51 %
63 %
24 %
62 %
20 %
60 %
80 %
50 %
83 %
54 %
53 %
80 %
188–189
205–206
135–136
156–158
151–152
138–140
89–90
155–157
125–127
156–157
120–122
145–147
128–130
164–166 (decomp.)
142–143
135–137
128–130 (decomp.)
107–110
iPrOH–MeOH
iPrOH
iPrOH
iPrOH
MeOH–EtOH
EtOH
iPrOH–acetone
iPrOH–EtOH
EtOH
EtOH
iPrOH
C8H12N2 2C2H2O4
C9H14N2 2HCl
C10H16N2 2C2H2O4
C11H18N2 2.5C2H2O4
C9H14N2 2C2H2O4
C10H16N2 2C2H2O4
C11H18N2 2C2H2O4
C12H20N2 2C2H2O4
C9H12N2 2C2H2O4
C10H14N2 2C2H2O4
C11H16N2 2.5C2H2O4
C12H18N2 2C2H2O4
C12H16N2 2C2H2O4
C9H12N2 1.4C2H2O4
C10H14N2 2C2H2O4
C11H16N2 2C2H2O4
C12H18N2 2C2H2O4
C9H10N2 C2H2O4
C10H12N2 1.8C2H2O4
C11H14N2 1.5C2H2O4
C12H16N2 2C2H2O4
C8H12N2O 2C2H2O4
C9H14N2O 2C2H2O4
C10H16N2O 2C2H2O4
C11H18N2O 2C2H2O4
C11H16N2O 2C2H2O4
d
A
A
c
c
B
A
C
C
C
C
C
D
E
E
E
F
F
G
F
B
B
B
B
B
e
f
EtOH
iPrOH
–CH3
–CH3
–C2H5
–C3H7
–CH3
–CH3
–C2H5
–C3H7
–CH3
–CH3
–C2H5
–C3H7
iPrOH–Et2O
iPrOH–Et2O
iPrOH
iPrOH–Et2O
iPrOH–Et2O
iPrOH–Et2O
iPrOH
iPrOH–Et2O
MeOH
iPrOH–MeOH
iPrOH–MeOH
iPrOH–MeOH
iPrOH–MeOH
d
149–152 (decomp.)
120–122
129–130 (decomp.)
154–155
148–150
116–118
g
f
–CH3
–CH2CH2CH2CH2–
135–136
145–146
Method: A representative example is provided in the Experimental section for each method listed. b All compounds analyzed within 0.4%
a
of theory for C, H and N. c The free bases of 21a, 21b, 22a and 22b were prepared following a known literature procedure [12] and converted
to HCl or oxalate salts. Crystallized with 0.25 mol H2O. Crystallized with 0.4 mol H2O. Crystallized with 0.5 mol H2O. Crystallized
with 1.0 mol H2O.
d
e
f
g
Figure 5. Conditions: (a) pyrrolidine, (CH3)3Al, CH2Cl2; (b) AlH3, THF.

182
3. Results and discussion
N-methyl pyridohomotropane 20, where R = –CH3 (IC50
= 1000 nM), results in a 200-fold increase in affinity [22].
We have previously suggested, given the observed differ-
ences in affinity between various N-methyl and
N-desmethyl derivatives, that these compounds may not
be binding in exactly the same manner at nAChRs [2, 3];
that is, the compounds may not utilize identical receptor
binding features and/or the amine nitrogen (or its sub-
stituents) are oriented somewhat differently upon interac-
tion with the receptor. This latter possibility is particu-
larly reinforced by the difference in affinity of 4a (Ki =
1100 nM) and its more conformationally-constrained
counterpart 20 where R = H (IC50 = 5 nM) [22] which is
simply a bridged analog of 4a.
3.1. Pyridoazepine analogs
The identity of 4a was confirmed by a new method of
synthesis. Consequently, the low affinity reported earlier
for 4 [2] cannot be due to incorrect structural assignment.
Both 5a and 5b were also successfully prepared, and
radioligand binding data were obtained for both. The
affinity of 5a (Ki = 46 ± 7 nM) was significantly higher
than that of the structurally-related aminomethylpyridine
2 where R’ = –CH2CH2CH3 (Ki = 2470 nM [2]). Thus, it
would seem that the low affinity of 4 cannot be explained
simply by the presence of the added bulk. The affinity of
5a was also higher than that of the corresponding
pyridoazepine 4a (Ki = 1100 nM). The difference in
affinity between the two structurally-related compounds
(i.e., 4a and 5a) may be related to the longer internitrogen
distance of 5a.
N-Monomethylation of nicotinic ligands can increase,
decrease, or have little influence on affinity depending
upon the particular series of agents being investigated [2,
3]. The affinity of the N-methyl derivative 5b (Ki = 268
± 44 nM) was nearly six times lower than that of 5a.
Demethylation of nicotine to nornicotine typically results
in a 10- to 20-fold decrease in affinity whereas demethy-
lation of 3b to 3a (Ki = 12330 nM), results in a 685-fold
decrease in affinity [2, 21]. Demethylation of 4b has
essentially no (i.e., less than 2-fold) effect on affinity [2].
Thus, the trend of decreasing affinity upon demethylation
seen with nicotine, 2 (where R = R’ = –CH3), and 3b
seems to end with 4, and is reversed in 5. This unusual
affinity-enhancing effect seen upon demethylation has
been noticed before; for example, demethylation of the
3.2. Conformationally-flexible analogs
3.2.1. Aminoalkylpyridines
Due to the higher affinity of 5a (Ki = 46 nM) over 4a
(Ki = 1100 nM) we examined several ring-opened, more
flexible, analogs of 5. If the aminomethylpyridines
(AMPs, 2) are viewed as ring-opened analogs of 4, then
the aminoethylpyridines(AEPs, 21) may be viewed as the
corresponding ring-opened analogs of 5. The aminopro-
pylpyridines (APPs, 22) represent chain-extended ana-
logs of 21. Binding data for 21 and 22 derivatives,
relative to 2, are shown in table II.
Table II. Nicotine receptor affinities of 3-substituted pyridine analogs; Ki values, nM (SEM).
X
a
b
c
d
e
–NRR’=
–CH2–
21 –CH2–CH2–
22 –CH2–CH2–CH2–
24 –CH=CH–CH2– (trans) 6055 (± 960)
25 –CH=CH–CH2– (cis)
26 –C≡C–CH2–
–N(CH3)H
–N(CH3)2
–N(CH3)C2H5
–N(CH3)C3H7
1-Pyrrolidinyl
30 a
2
> 10000 a
289 (± 17)
> 10000
540 a
47 (± 2)
> 10000
2775 (± 714)
2100 (± 400)
2165(± 580)
21 (± 17)
28 a
1140 a
427 (± 46)
> 10000
> 10000
> 10000
b
18 (± 1)
> 10000
> 10000
> 10000
900 (± 95)
22 (± 1)
–
–
b
5035 (± 6)
b
2870 (± 440)
2285 (± 630)
35 (± 10)
–
–
b
2240 (± 200)
138 (± 16)
27 –O–CH2–CH2–
212 (± 7)
a
Data previously reported [2].
Data unavailable; compound not prepared.
b

183
In general, analogs of the aminoethylpyridine (i.e., 21)
series were found to bind with higher affinity than the
corresponding members of the aminomethylpyridine (i.e.,
2) series, whereas members of the aminopropylpyridine
(i.e., 22) series were essentially inactive (Ki > 10000 nM).
Although the lack of affinity of the aminopropylpyridine
series of compounds might be attributable to an excessive
chain length (calculated internitrogen distance ≈ 6.9 Å),
the enhanced affinity of the aminoethylpyridine series
(calculated internitrogen distance ≈ 5.9 Å) cannot be
accounted for solely on the basis of internitrogen dis-
tance. That is, this internitrogen distance is longer than
that thought to be optimal [2]. Comparing 2a–d with
21a–d (table II) it is obvious that parallel changes in the
terminal amine substituents did not result in parallel
changes in affinity. That is, increasing the alkyl chain
length of the aminomethylpyridines by one methylene
group variously enhanced affinity by 2-fold to more than
30-fold depending upon the nature of the terminal amine.
This provides evidence that members of the two series
may not be binding in exactly the same manner. Never-
theless, in both instances, the N-ethyl-N-methyl analogs
(i.e., 2c and 21c) bind with the highest affinity.
If two series of compounds are binding in the same
manner, parallel structural changes should result in par-
allel shifts in affinity. We previously have reported that
incorporation of a 6-chloro substituent has relatively little
effect on the affinity of 2c (2c Ki = 28 nM; 6-chloro 2c Ki
= 41 nM) [2]. Consequently, we prepared and examined
the 6-chloro derivative of 21c (i.e., 23). Although 23 (Ki
= 71 ± 10 nM) binds with 4-fold lower affinity than 21c
itself (Ki = 18 nM), the change in affinity was not
sufficiently large to draw any definitive conclusions.
nM). However, the remaining members of the series, 24a,
24c, 24d, were essentially inactive (table II). Interest-
ingly, stereochemistry did not seem critical; that is, the
trans compound 24b and its cis isomer 25b bind with
nearly identical affinity (Ki = 2775 and 2100 nM, respec-
tively). The alkynyl derivative 26c (Ki = 900 nM)
(table II) was found to bind with higher affinity than its
corresponding alkyl or alkenyl counterparts (i.e., 22c and
24c, Ki > 10000 nM). Although compounds 26 generally
bind with low affinity, unsaturation again seems to
contribute to binding.
Introduction of a double or triple bond certainly
influences internitrogen distance. But, it also introduces
an electronic character to the side chain that is absent in
the aminopropylpyridine series. To examine further a
possible electronic contribution to binding we prepared a
series of aminopropylpyridines where the aromatic me-
thylene group was replaced by an ether oxygen atom (i.e.,
aminoethoxypyridines).
3.2.3. Aminoethoxypyridines
Data for the aminoethoxypyridines are shown in table
II. Some members of the pyridyl ether series, 27a–d,
were found to bind with more than 500-fold higher
affinity than the corresponding members of the amino-
propylpyridine (22) series. Interestingly, and in contrast
to what was seen with the AMP (2) series, terminal amine
substitution seemed to play a less significant role; that is,
compounds 27a–c (Ki = 35 nM, 21 nM and 22 nM,
respectively) where one of the amine substituents is
varied from H to methyl to ethyl, bind with relatively
similar affinity. This provides some additional evidence
that members of the different series of compounds are not
binding in an identical manner.
In order to determine whether the introduction of the
ether oxygen atom increases affinity by a specific receptor
interaction or whether it was more of a nonspecific effect,
such as its influence on the electronic character of the
pyridyl ring, we examined 28, a positional isomer of 27a.
Compound 28 was found to lack affinity for nicotinic
receptors (Ki > 10000 nM).
3.2.2. Aminopropenylpyridines and aminopro-
pynylpyridines
Increasing chain length by a single methylene group
(21 → 22) had a rather dramatic effect on nicotinic
receptor affinity. In an attempt to slightly shorten chain
length and to limit conformational flexibility in the
aminopropylpyridine series, unsaturation was introduced
into the chain. The first member of the series to be
examined, 24b (Ki = 2775 nM; table II), offered some
encouragement because, although it did not bind with as
high an affinity as 21b, its affinity was higher than that of
the corresponding aminopropylpyridine 22b (Ki > 10000
3.2.4. Pyrrolidine analogs
Cyclization of the terminal dimethyl groups of 2b to a
pyrrolidine ring (i.e., 2e; Ki = 30 nM) results in about a
20-fold increase in affinity, and in a compound that binds
with affinity comparable to 2c (Ki = 28 nM; table II), the

184
highest affinity member of the series [2]. This offered
another opportunity to compare several series of com-
pounds. Thus, we examined a pyrrolidinyl analog in the
trans olefinic series (i.e., 24e) and one in the pyridyl ether
series (i.e., 27e).
(2). The aminoethylpyridine series compounds (i.e., 21)
were found to bind with enhanced affinity relative to the
aminomethylpyridines and represent a novel class of
nicotinic ligands. The longer aminopropylpyridine series
compounds (i.e., 22) were, however, inactive. Introduc-
tion of unsaturation (e.g. 24/25/26) suggested possible
electronic involvement of a side chain atom, and this
ultimately led to the development of a series of pyridyl
ethers 27. The pyridyl ethers were generally found to bind
with enhanced affinity relative to the aminoalkyl analogs
(i.e., 2, 21, 22). This work supports the recent indepen-
dent claim by Abbott Laboratories that pyridyl ethers
represent high affinity nicotinic cholinergic receptor
ligands [24]. It is also quite interesting that although
A-85380 is quite similar in structure to, for example, 27a,
it binds with more than 650-fold higher affinity than the
latter.
Continued investigation of compounds such as those
described herein is certain to lead to interesting agents.
However, on the basis of the data presented above, as
well as on the results of studies by Glennon et al. [3],
Caldwell et al. [23] and Abreo et al. [24], it would appear
that parallel structural changes do not consistently lead to
parallel shifts in affinity suggesting that the different
series of compounds, or perhaps individual members
within various series, may not be binding in similar
manner at nicotinic cholinergic receptors. Results of these
same studies also indicate that agents with internitrogen
distances of > 4.8 Å represent worthwhile targets as novel
nAChR ligands.
Compound 24e (Ki = 5035 nM; table II) binds with
half the affinity of its corresponding N,N-dimethyl coun-
terpart 24b and did not represent the highest affinity
member of the series. Likewise, 27e (Ki = 212 nM; table
II) binds with 10-fold lower affinity than its N,N-
dimethyl counterpart 27b and represents the lowest affin-
ity member of the series. On the basis of these results, it
is probably safe to conclude that these agents are not
binding in an identical manner at nAChRs.
While our studies were nearing completion several
reports appeared in the literature that have a direct
bearing on our results. Caldwell et al. [23] reported that
RJR-2043 (29; R = H, R’ = –CH3), a homolog of 24a,
binds at nAChRs with high affinity (Ki = 26 nM). Abreo
and co-workers also reported on a series pyridyl
ethers [24]. For example, A-84543 (30, R = –CH3,
S-(–)-isomer; Ki = 0.15 nM) and its R-(+)-enantiomer (Ki
= 19.7 nM) bind at nAChRs with high affinity [24].
5. Experimental protocols
5.1. Chemistry
Melting points were determined with
a Tho-
4. Conclusion
mas–Hoover melting point apparatus and are uncor-
rected. Infrared spectra were obtained using a Nicolet
5ZDX spectrophotometer and proton NMR were re-
corded on a Gemini-300 instrument. Spectral data are
consistent with the assigned structures. Tetrahydrofuran
(THF) was freshly distilled from sodium/benzophenone.
Microanalysis was performed by Atlantic Microlab and
determined values are within ±0.4% of theory. Column
chromatography employed 70–230 mesh SiO2.
The chief difference between the structures of 4 and 5
is the distance between the two nitrogen atoms. Conse-
quently, 4 and 5 offer a unique set of compounds to
investigate interatom distances. The lower affinity 4
possesses an internitrogen distance of 4.6 Å whereas that
in 5 is 5.5 Å. On this basis, it was expected that
derivatives of 5 might bind with higher affinity than
derivatives of 4. This was found to be the case; compound
5a (Ki = 47 nM) binds with higher affinity than 4a (Ki =
1100 nM). Although N-monomethylation of 4a to 4b had
very little effect on affinity, it was found that
N-methylation of 5a to 5b decreased affinity by nearly
6-fold.
5.1.1.
6,7,8,9-Tetrahydro-5H-pyrido[3,4-c]azepine
oxalate 4a
Lithium aluminum hydride (0.25 g, 6.6 mmol) was
added to a solution of 9 (0.25 g, 1.5 mmol) in dry THF
(10 mL) at 0 °C; the reaction mixture was allowed to stir
at room temperature for 1 h, after which H2O (0.3 mL),
The increased affinity of 5 over 4 led to an examination
of chain-extended analogs of the aminomethylpyridines

185
10% NaOH (0.4 mL) and H2O (0.5 mL) were succes-
sively added at 0 °C. The precipitate was collected by
filtration, washed with THF (10 mL), and the combined
solution was evaporated to an oily residue. The residue in
95% EtOH (5 mL) was treated with HCl and the entire
reaction mixture was evaporated to dryness. The crude
material was triturated with Et2O to afford a hygroscopic
hydrochloride salt. The salt was converted to its free base
and treated with a solution of oxalic acid in anhydrous
Et2O to yield 0.24 g (70%) of the desired product as its
bis oxalate salt, m.p. 203–205 °C (lit. [2] 202–205 °C).
4H), 7.00 (d, 1H), 8.25 (s, 1H), 8.35 (d, 1H). Anal.
(C10H14N2•2C2H4O8) C, H, N.
5.1.4. 6,7,8,9-Tetrahydro-5H-pyrido[3,4-c]azepine-7-
one 9
7-Hydroxy-8-nitrosoisoquinoline (6) was prepared and
converted to acrylic acid 7 as described by Kao [4]; 5%
Pd/C (0.06 g) was added to a suspension of the acid
(0.42 g, 2.4 mmol) in HOAc (60 mL) and the mixture
was shaken on a Parr hydrogenator (57 psi H2) for 48 h.
The mixture was filtered, and the solid material was
washed with HOAc (2 × 10 mL). The combined HOAc
portion was evaporated under reduced pressure to afford
0.72 g of a yellow oil, which was used without further
purification or characterization. The oily residue was
neutralized by the addition of 10% NaOH; toluene
(30 mL) and Al2O3 (4.8 g) were added with stirring. The
two-phase system was heated at reflux for 20 h using a
Dean–Stark water trap. The resulting suspension was
filtered, the residue was washed with CH2Cl2/MeOH
(9:1), and the combined solutions were filtered through a
pad of SiO2. Evaporation of the solvent gave 0.10 g of 9
as a crystalline solid, m.p. 111–113 °C. 1H-NMR
(CDCl3) δ: 2.77 (t, 2H, J = 7 Hz), 3.05 (t, 2H, J = 7 Hz),
4.32 (d, 2H, J = 6 Hz), 7.01 (d, 1H, J = 5 Hz), 7.23 (br
s, 1H), 8.25 (s, 1H), 8.36 (d, 1H, J = 5 Hz). Anal.
(C9H10N2O•H2O) C, H, N.
5.1.2.
6,7,8,9-Tetrahydro-5H-pyrido[3,4-d]azepine
hydrobromide 5a
Triphenyl phosphine (0.29 g, 1.10 mmol) and 90%
DEAD (0.19 g, 0.96 mmol) were added to a stirred
solution of 19 (0.25 g, 0.78 mmol) in THF (100 mL)
under N2 at room temperature. The reaction mixture was
allowed to stir at room temperature for 2 h and was then
heated at reflux for 15 min. Solvent was evaporated under
reduced pressure and the residue was purified by column
chromatography using SiO2 (eluent: EtOAc/petroleum
ether 1:3) to give 0.20 g (85%) of 5 where R = tosyl, m.p.
121–124 °C. A solution of this material (0.10 g,
0.35 mmol) and phenol (0.30 g, 3.20 mmol) in 33% HBr
in HOAc (6 mL) was allowed to stir at room temperature
for 24 h. The HOAc was evaporated under reduced
pressure and the residue was triturated with EtOAc
(10 mL). The solvent was decanted and the resulting solid
was recrystallized from MeOH/EtOAc to give 0.06 g
(58%) of 5a, m.p. 268–270 °C (decomp.).1H-NMR
(DMSO-d6) δ: 3.25 (m, 8H), 7.78 (d, 1H), 8.61 (m, 2H).
Anal. (C9H12N2•2HBr) C, H, N.
5.1.5. 5,6-Dihydro-7(8H)-isoquinolin-7-one 13
The known compound ethyl 3-(3-carbethoxy-
methylpyrid-4-yl)propionate (11) was prepared from
ethyl 2-(3-pyridyl)acetate (10) by treatment with
ClCOOEt and IZnCH2CH2COOEt as previously reported
by Shiao et al. [5]. Sodium hydride (60%; 0.91 g,
22.4 mmol) was added to a solution of di-ester 11 (2.0 g,
7.5 mmol) in dry THF (100 mL) under N2. The resulting
reaction mixture was heated at reflux for 6 h under N2,
allowed to cool to room temperature, and 4 N HCl (5 mL)
was carefully added. THF was removed by evaporation
under reduced pressure, and the crude residue was
dissolved in 6 N HCl (30 mL); the solution was heated at
reflux for 12 h, allowed to cool to room temperature,
neutralized with solid KOH and extracted with CH2Cl2 (3
× 100 mL). The combined organic extract was dried
(MgSO4) and evaporated to dryness to give a crude
product; purification was achieved by column chroma-
tography on SiO2 (eluent: EtOAc/petroleum ether, 4:1) to
give 0.45 g (41%) of 13, m.p. 70–72 °C. Anal. (C9H9NO)
C, H, N.
5.1.3. N-Methyl-6,7,8,9-tetrahydro-5H-pyrido[3,4-d]
azepine oxalate 5b
Paraformaldehyde (28 mg, 1 mmol) and NaBH3CN
(63 mg, 1 mmol) were added to a stirred solution of 5a
(28 mg, 0.09 mmol) in MeOH (10 mL) at room tempera-
ture. This was followed by the addition of 2.5 M HCl in
MeOH (0.1 mL). The reaction mixture was allowed to stir
at room temperature for 48 h; the MeOH was evaporated
under reduced pressure and the residue was dissolved in
Et2O (30 mL). The ethereal solution was washed with
saturated NaHCO3 (5 mL), dried (K2CO3) and evapo-
rated in vacuo to give an oil which was purified by
column chromatography on SiO2 (eluent: EtOAc/MeOH
10:1) to give 14 mg (96%) of 5b as the free base. The free
base was converted to 5b by treatment with oxalic acid in
1
Et2O to give 15 mg of product, m.p. 125–127 °C. H-
NMR (CDCl3) δ: 2.35 (s, 3H), 2.60 (m, 4H), 2.90 (m,

186
5.1.6. Ethyl 3-[2-(t-butyldimethylsilyloxyethyl)pyridin-
decanted. The residue was washed with EtOAc (2 ×
50 mL), and the combined extracts were dried (MgSO4)
and evaporated to dryness to give a residue that was
purified by column chromatography (SiO2; eluent:
EtOAc/MeOH 2:1) to give 0.65 g (71%) of the desired
4-yl]propionate 16
Imidazole (2.81 g, 41.4 mmol) and t-butyl-
dimethylsilyl chloride (4.97 g, 33.1 mmol) were added to
a stirred solution of 2-(3-pyridyl)ethanol [6] (15, R = H;
3.41 g, 27.6 mmol) in DMF (50 mL). The reaction mix-
ture was allowed to stir at room temperature overnight
and was poured into ice water (100 mL). The aqueous
mixture was extracted with petroleum ether (2 ×
200 mL), and the combined organic portion was washed
well with brine, dried (MgSO4) and evaporated in vacuo
to give 5.90 g (90%) of crude 15 where R =
t-butyldimethylsilyl.
1
product, m.p. 82–84 °C. H-NMR (CDCl3) δ: 0.05 (s,
6H), 0.90 (s, 9H), 2.55 (t, 2H), 2.95 (t, 2H), 3.05 (t, 2H),
3.85 (t, 2H), 5.85 (br s, 2H), 7.15 (br s, 1H), 8.40 (m, 2H).
Anal. (C16H28N2O2Si) C, H, N.
5.1.8.
N-Tosyl-2-[3-(2-hydroxyethyl)pyridin-4-yl]-
ethylamine 19
Compound 17 (0.62 g, 2.0 mmol) was added to a
stirred solution of NaOMe (prepared by dissolving 0.18 g
of Na metal in 12 mL of MeOH) at room temperature.
After solution was complete, Br2 (0.64 g, 4.0 mmol) in
MeOH (3 mL) was added at one time. The resultant
solution was allowed to stir at room temperature for
30 min and was then heated at reflux for 30 min. The
MeOH was evaporated under reduced pressure, and the
residue dissolved in EtOAc (50 mL), and the solution
washed with brine (2 × 10 mL). The EtOAc solution was
dried (MgSO4) and evaporated in vacuo to give 0.73 g of
crude product, which was purified by column chromatog-
raphy (SiO2; eluent: MeOH/EtOAc 1:9) to give 0.43 g
(67%) of 18 and 0.15 g of 17. The above reaction was
repeated to obtain additional 18. A solution of 18 (0.50 g,
1.5 mmol) in concentrated HCl (15 mL) was heated at
reflux under N2 for 5 h. The reaction mixture was
evaporated to dryness under reduced pressure, a saturated
solution of NaHCO3 was added to adjust the pH to 8, and
again the solvent was removed by evaporation. The
residue was dissolved in absolute EtOH, and the undis-
solved material was removed by filtration. The ethanolic
solution was evaporated under reduced pressure to give a
residue (0.3 g) which was then dissolved in wet THF
(20 mL). Solid NaHCO3 (0.22 g, 2.7 mmol) and TsCl
(0.32 g, 1.8 mmol) were added to this residue and the
resultant mixture was allowed to stir at room temperature
for 1 h. The mixture was diluted by the addition of EtOAc
(100 mL) and the aqueous phase was separated. The
organic portion was dried (MgSO4) and evaporated under
reduced pressure to give 0.35 g (74%) of the desired
Ethyl 3-iodopropionate (8.0 g, 22.0 mmol) in THF
(20 mL) was added in a dropwise manner to a suspension
of freshly activated Zn powder (2.6 g, 40.0 mmol) in THF
(10 mL) at 45 °C. The reaction mixture was allowed to
stir at this temperature overnight. This solution was then
added to a stirred solution of CuCN (2.3 g, 25.0 mmol)
and LiCl (2.3 g, 50.0 mmol) in THF (50 mL) at –40 °C.
The resultant solution was allowed to slowly warm to
0 °C and was then cooled to –78 °C. The solution was
added to a suspension of the pyridinium salt [prepared
from 15 (4.1 g, 15 mmol) and ethyl chloroformate (2.2 g,
20 mmol) in THF (60 mL) at –25 °C for 30 min] at
–78 °C. The solution was then allowed to warm to room
temperature and was quenched by the addition of 5%
NH4OH solution (100 mL). The organic portion was
separated, dried (MgSO4), and the solvent was removed
in vacuo to give an intermediate which was oxidized by
boiling with sulfur (0.8 g) in xylene (25 mL) for 12 h.
The reaction mixture was filtered, the xylene was evapo-
rated, and the crude product was distilled (Kugelrohr,
150–160 °C/0.05 mmHg) to give 1.7 g (30%) of 16 as a
pale-yellow oil. Infrared (film): 1735 cm–1. 1H-NMR
(CDCl3) δ: 0.05 (s, 6H), 0.90 (s, 9H), 1.28 (t, 3H), 2.67
(t, 2H), 2.92 (t, 2H), 3.15 (t, 2H), 3.81 (t, 2H), 4.18 (q,
2H), 7.12 (d, 1H), 8.40 (d, 1H), 8.45 (s, 1H). Anal.
(C18H31NO3Si) C, H, N.
5.1.7. 3-[2-(t-Butyldimethylsilyloxyethyl)pyridin-4-yl]
propionamide 17
A solution of AlMe3 (2M, 10 mL, 20.0 mmol) in
hexane (10 mL) was added in a dropwise manner to a
stirred suspension of NH4Cl (1.1 g, 20.0 mmol) in dry
benzene (25 mL) at ice-bath temperature. After the addi-
tion was complete, the mixture was allowed to stir at
room temperature for 30 min. A solution of 16 (1.0 g,
3.0 mmol) in benzene (5 mL) was added; the reaction
mixture was allowed to stir at 50 °C for 15 h and was
subsequently cooled to room temperature, treated care-
fully with 10% HCl (2 mL), and the benzene portion
1
compound, m.p. 116–118 °C. H-NMR (CDCl3) δ: 2.42
(s, 3H), 2.85 (m, 4H), 3.20 (m, 2H), 3.86 (t, 2H), 5.80 (br
s, 1H), 6.95 (d, 1H), 7.18 (d, 2H), 7.64 (d, 2H), 8.20 (d,
1H), 8.34 (s, 1H). Anal. (C16H20N2O3S) C, H, N.
5.1.9. N-Methyl-N-n-propyl-2-(3-pyridyl)ethylamine
oxalate 21d [Method A]
Propionaldehyde (0.8 mL, 11 mmol) and then
NaBH3CN (252 mg, 4 mmol) was added to a stirred

187
solution of 21a (free base; 500 mg, 3.67 mmol) in abso-
lute EtOH (30 mL) at room temperature. Subsequently,
2.5 N HCl in MeOH (0.8 mL) was added in a dropwise
fashion. When the reaction was complete the solvent was
evaporated in vacuo and the residue was dissolved in
Et2O (100 mL), and the ethereal solution was washed
with saturated NaHCO3 (3 × 20 mL) and excess brine.
The ethereal solution was dried (K2CO3) and solvent was
evaporated in vacuo to give approximately 1 g of a
residue which on Kugelrohr distillation gave 400 mg
(61%) of the desired free base. Treatment of the free base
with an ethereal solution of oxalic acid afforded 21d after
recrystallization from iPrOH, m.p. 156–158 °C. 1H-NMR
(D2O) δ: 0.95 (s, 3H), 1.85 (m, 2H), 2.95 (s, 3H),
3.15–3.60 (m, 6H), 8.05 (m, 1H), 8.55 (d, 1H), 8.70 (d,
1H), 8.75 (s, 1H). Anal. (C11H18N2•2.5C2H2O4) C, H, N.
5.1.11. N-Ethyl-N-methyl-(6-chloropyridin-3-yl)ethyl-
amine oxalate 23
A
mixture of DCC (618 mg, 3.0 mmol), (6-
chloropyridin-3-yl)acetic acid [15] (439 mg, 2.2 mmol)
in CH2Cl2 (20 mL) was allowed to stir for 5 min at room
temperature; N-ethylmethylamine (240 mg, 4.0 mmol)
was added and the reaction mixture was allowed to stir
for an additional 48 h. The precipitated material was
removed by filtration and the filtrate was washed with 5%
HCl and then dilute NaHCO3 solution. The filtrate was
dried (Na2SO4) and the solvent was removed in vacuo to
give 500 mg of oil. Alane (1 M, 3 mL, 3.0 mmol) was
added to a solution of the crude amide (200 mg) in THF
(10 mL) at 0 °C and the reaction mixture was allowed to
stir for 1 h. Water was carefully added at 0 °C in a
dropwise manner until evolution of H2 ceased. The
mixture was diluted with Et2O (75 mL) and washed with
5% KOH (2 × 5 mL) and saturated NaCl solution
(10 mL). The organic portion was dried (K2CO3) and
evaporated to dryness in vacuo to give a crude product.
The product was purified by column chromatography
(30 g silica gel, Et2O/MeOH 12:1) to give 150 mg (85%)
of the target compound as its free base. The free base was
converted to its oxalate salt and recrystallized from
iPrOH to give 23 as a white solid, m.p. 125–127 °C.
1H-NMR (CDCl3) δ: 1.36 (m, 3H), 2.95 (s, 3H),
3.10–3.60 (m, 6H), 7.52 (d, 1H, J = 5.6 Hz), 7.84 (d, 1H,
J = 5.6 Hz), 8.32 (s, 1H). Anal. (C10H15ClN2•C2H2O4) C,
H, N.
5.1.10.
N-Ethyl-N-Methyl-3-(3-pyridyl)propylamine
oxalate 22c [Method B]
A solution of 2 M AlMe3 (7 mL, 14 mmol) in hexane
was added in a dropwise manner under N2 to a solution of
N-ethylmethylamine (0.83 g, 14 mmol) in benzene
(40 mL) at ice-bath temperature. The reaction mixture
was allowed to stir at room temperature for 30 min before
ethyl 3-(3-pyridyl)propionate [13] (1.79 g, 10 mmol) was
added. The resultant reaction mixture was heated at reflux
for 48 h, allowed to cool to room temperature, treated
with 10% HCl (2 mL) and diluted with CH2Cl2 (60 mL).
The precipitate was collected by filtration and washed
with CH2Cl2 (20 mL). The combined organic solution
was dried (Na2SO4) and the solvent was evaporated in
vacuo to give a light-yellow oil which on Kugelrohr
distillation (130–140 °C, 0.06 mm) gave 0.95 g (50%) of
the amide.
5.1.12. (E)-N-Ethyl-N-methyl-3-(3-pyridyl)-2-propenyl-
amine oxalate 24c [Method C]
Thionyl chloride (1 mL) was added to (E)-3-(3-
pyridyl)propen-1-ol (31) [16] (150 mg, 1.1 mmol) in
CH2Cl2 (10 mL) at 0 °C and the resultant solution was
heated at reflux for 1 h. Solvent and excess SOCl2 were
removed by evaporated in vacuo. The residue was dis-
solved in H2O (5 mL) and N-ethylmethylamine (304 mg,
5.15 mmol) was added; the solution was allowed to stir at
room temperature for 1 h and was then heated at reflux
for 1 h. Once the reaction mixture had attained room
temperature, it was extracted with Et2O (2 × 50 mL); the
combined ethereal extracts were dried (K2CO3) and
solvent was evaporated in vacuo to give a yellow oil
(108 mg, 56%) which was converted to an oxalate salt
A solution of 1 M AlH3 (8 mL, 8 mmol) in THF was
added under N2 to a solution of the above amide (0.95 g,
4.9 mmol) in THF (30 mL) at 0 °C. The reaction mixture
was allowed to stir at 0 °C for 1 h, and then 10% NaOH
(2 mL) was added to destroy excess AlH3. The THF
solution was diluted with Et2O (100 mL), washed with
saturated NaHCO3, dried (Na2SO4), and solvent was
evaporated in vacuo to give a light-yellow oil. The oil
was purified by column chromatography (SiO2 with
MeOH–EtOAc 1:12 as eluent) to give 0.43 g (49%) of the
desired product as the free base. The free base was
converted into an oxalate salt and recrystallized from
1
and recrystallized from iPrOH, m.p. 120–122 °C. H-
1
iPrOH/acetone, m.p. 89–90 °C. H-NMR (D2O) δ: 1.27
NMR (D2O) δ: 1.58 (t, 3H, J = 7.26 Hz), 3.12 (s, 3H),
3.53 (m, 2H), 4.23 (m, 2H), 6.90 (dt, 1H, J = 7.38 Hz,
15.45 Hz), 7.30 (d, 1H, J = 15.05 Hz), 8.28 (m, 1H), 8.95
(t, 3H, J = 7.4 Hz), 2.12 (m, 2H), 2.82 (s, 3H), 2.94 (t, 2H,
J = 7.7 Hz), 3.17 (m, 2H), 3.23 (m, 2H), 8.00 (m, 1H),
8.51 (d, 1H, J = 8.2 Hz), 8.65 (d, 1H, J = 5.9 Hz), 8.68
(s, 1H). Anal. (C11H18N2•2C2H2O4) C, H, N.
(d, 2H,
J
=
6.00 Hz), 9.11 (s, 1H). Anal.
(C11H16N2•2.5C2H2O4) C, H, N.

188
5.1.13. (Z)-N-Methyl-3-(3-pyridyl)-2-propenylamine
manner. The reaction mixture was allowed to stir for
45 min at –70 to –65 °C, and the yellow-orange mixture
was poured into saturated NH4Cl solution (100 mL) and
extracted with Et2O (5 × 75 mL). The combined organic
extracts were dried (MgSO4) and evaporated to dryness
in vacuo to give an orange oil. The oil was purified by
column chromatography (SiO2 with petroleum
ether/EtOAc 1:1 as eluent) to yield 1.26 g (74%) of ester
33 as a light-orange oil. Rf (hexanes/EtOAc) 0.3. A
solution of this acrylate ester (0.83 g, 5.1 mmol) in dry
toluene (20 mL) was added in a dropwise manner to a
hexane solution (1.0M) of DIBALH (10.7 mL,
10.7 mmol) under N2 at 0 °C. The reaction mixture was
allowed to stir at this temperature for 4.5 h and an
additional quantity of DIBALH (1 mL) was added. After
an additional 2 h, a solution of toluene (1 mL) and MeOH
(1 mL) was slowly added, followed by 2 M HCl (1 mL).
The solid aluminum salts were collected by filtration and
extracted with CH2Cl2 (10 × 50 mL). The combined
organic extracts were dried (K2CO3) and solvent was
evaporated in vacuo to give an orange oil which was
purified by column chromatography (SiO2 with petro-
leum ether/EtOAc 3:8 as eluent) to yield 0.29 g (41%) of
the alcohols an oil. The alcohol was further purified by
Kugelrohr distillation (b.p. 125 °C, 0.09 mmHg). Rf (pe-
troleum ether/EtOAc 3:8) = 0.16.
oxalate 25a [Method D]
Lindlar’s catalyst (76 mg) was added to a solution of
3-(3-pyridyl)-2-propyn-1-ol [19] (756 mg, 5.7 mmol) and
quinoline (76 mg, 0.6 mmol) in MeOH (70 mL) and the
reaction mixture was hydrogenated in a Parr apparatus at
atmospheric pressure for 18 h. The mixture was filtered
through a Celite pad and the filtrate was evaporated to
dryness in vacuo. The crude product was purified by
column chromatography (60 g silica gel, petroleum
ether/EtOAc 1:4) to yield 600 mg of an oil which was
further purified by Kugelrohr distillation (125 °C,
0.08 mm) to give 370 mg of a product that was homoge-
neous by thin-layer chromatography.
Thionyl chloride (1.07 g, 8.96 mmol) was added in a
dropwise manner to a stirred solution of the above alkene
(303 mg, 2.24 mmol) in CHCl3 (20 mL) at 0 °C under a
N2 atmosphere. The reaction mixture was allowed to stir
at room temperature for 3 h and the solvent and excess
SOCl2 were removed by evaporation in vacuo. The white
hydrochloride salt of 1-chloro-3-(3-pyridyl)-Z-2-propene
was used without further purification. An aqueous solu-
tion of methylamine (40%, 3 mL, 19 mmol) was added to
a portion of the crude salt (360 mg, 1.9 mmol). After
stirring at 70 °C for 1 h the pale yellow reaction mixture
was extracted with Et2O (10 × 30 mL) and the combined
ethereal extract was dried (K2CO3) and the solvent was
removed in vacuo to give 300 mg of a pale orange oil.
The oil was purified by column chromatography (30 g
silica gel, EtOAc/MeOH/diisopropylamine 120:60:1) to
yield 190 mg of the desired product as its free base. The
base was converted to its oxalate salt and recrystallized
from iPrOH/Et2O to afford 210 mg (39%) of 25a as a
white powder, m.p. 164–166 °C. 1H-NMR (D2O) δ: 2.70
(s, 3H), 3.95 (dd, 2H, J = 1.7 Hz, 6.9 Hz), 6.15 (dt, 1H,
J = 6.9 Hz, 11.8 Hz), 6.99 (d, 1H, J = 11.8 Hz), 8.04 (dd,
1H, J = 6.0 Hz, 8.1 Hz), 8.42 (d, 1H, J = 8.1 Hz),
8.72–8.73 (m, 2H). Anal. (C9H12N2•1.4C2H2O4) C, H, N.
Thionyl chloride (0.93 g, 7.8 mmol) was added in a
dropwise fashion to a stirred solution of alcohol 34
(0.16 g, 1.2 mmol) in anhydrous Et2O (20 mL) under N2
at 0 °C. The reaction mixture was allowed to stir at room
temperature for 1 h and was heated at reflux for 2 h.
Solvent and excess SOCl2 were removed by evaporation
in vacuo. The light-brown hydrochloride salt was isolated
and used without further purification or characterization.
An aqueous solution (40 wt.%) of NHMe2 (0.27 g,
6.0 mmol) was added in a dropwise manner to a solution
of the HCl salt in H2O (4 mL) at 0 °C. The reaction
mixture was allowed to stir at room temperature over-
night and was extracted with Et2O (5 × 25 mL). The
combined ethereal extract was dried (MgSO4) and evapo-
rated to dryness in vacuo to yield 0.16 g of an oil. The oil
was purified by column chromatography (SiO2 with
petroleum ether/EtOAc/NEt3 10:100:1 as eluent) to af-
ford about 0.1 g of product. The oxalate salt was prepared
and recrystallized from iPrOH/Et2O to give 0.13 g (51%)
5.1.14.
(Z)-N,N-Dimethyl-3-(3-pyridyl)-2-propenyl-
amine oxalate 25b [Method E]
Bis(2,2,2-trifluoroethyl)methoxycarbonylmethyl)
phosphonate [17] (3.50 g, 11.0 mmol) was added to a
solution of 18-crown-6/acetonitrile complex [18] (9.08 g,
27.7 mmol) in anhydrous THF (300 mL) under an N2
atmosphere. The reaction mixture was cooled to –70 °C
and a 0.5 M toluene solution of KHMDS (22 mL,
11.0 mmol) was added in a dropwise manner. The reac-
tion mixture was allowed to stir for an additional 20 min
and a solution of pyridine-3-carboxaldehyde (32) (1.12 g,
10.5 mmol) in dry THF (40 mL) was added in a dropwise
1
of 25b as a white powder, m.p. 142–143 °C. H-NMR
(D2O) δ: 2.71 (s, 6H), 3.89 (dd, 2H, J = 1.6 Hz, 7.0 Hz),
6.05 (dt, 1H, J = 7.0 Hz, 11.7 Hz), 6.92 (d, 1H, J =
11.7 Hz), 7.95 (dd, 1H, J = 5.9 Hz, 8.2 Hz), 8.33 (d, 1H,
J = 8.2 Hz), 8.60 (m, 2H). Anal. (C10H14N2•2C2H2O4) C,
H, N.

189
5.1.15. N-Methyl-N-n-propyl-3-(3-pyridyl)-2-propyn-
1-ylamine oxalate 26d [Method F]
stir at room temperature for another 24 h. The precipi-
tated NaCl was collected by filtration and the filtrate was
evaporated in vacuo to give a light yellow oil which, upon
Kugelrohr distillation (125–130 °C, 0.05 mm), gave 2.8 g
(57%) of the desired target pyridylethylamine. A solution
of this amine (1.5 g, 6.2 mmol) in MeOH (40 mL) was
hydrogenated at 50 psi in the presence of 20% Pd/C
(0.2 g) for 12 h in order to remove the benzyl group. The
Pd/C was removed by filtration with the aid of Celite.
Solvent was evaporated in vacuo to give 0.8 g (85%) of
the desired compound as its free base. The free base was
converted into an oxalate salt and recrystallized from an
iPrOH/MeOH mixture, m.p. 169–170 °C. 1H-NMR
(D2O) δ: 2.79 (s, 3H), 3.50 (t, 2H, J = 5.0 Hz), 4.53 (t,
2H, J = 5.0 Hz), 7.00 (d, 1H, J = 8.8 Hz), 7.13 (m, 1H),
7.87 (m, 1H), 8.12 (d, 1H, J = 5.1 Hz). Anal.
(C8H12N2O•C2H2O4) C, H, N.
Thionyl chloride (1.34 g, 11.3 mmol) was added in a
dropwise manner to a stirred solution of 3-(3-pyridyl)-2-
propyn-1-ol (36) [19] (0.50 g, 3.8 mmol) in CHCl3
(30 mL) at 0 °C under a N2 atmosphere. The reaction
mixture was allowed to stir overnight at room tempera-
ture and the solvent and excess SOCl2 were removed by
evaporation in vacuo. The white hydrochloride salt was
used in the next step without further purification.
N-Methyl-n-propylamine (2.74 g, 37.5 mmol) was
added in a dropwise manner to a stirred solution of the
above salt in H2O (15 mL) at 0 °C. The reaction mixture
was allowed to stir at 40 °C for 1.5 h and the mixture was
extracted with Et2O (5 × 40 mL). The combined ethereal
extracts were dried (K2CO3) and solvent was removed in
vacuo to yield the free base as an orange oil. The oil was
purified by Kugelrohr distillation (70–80 °C, 0.05 mm),
converted to the oxalate salt and recrystallized from
iPrOH/Et2O to give 0.96 g (80%) of 26d as a white
5.2. Radioligand binding
1
The receptor binding assay was conducted as previ-
ously reported in greater detail [2, 25]. In brief, rat brain
without cerebellum was homogenized in 10 volumes of
ice-cold 0.05 M sodium potassium phosphate buffer (pH
7.4) and centrifuged at 17500 g (4 °C) for 30 min. The
pellet was resuspended in 20 volumes of ice-cold glass-
distilled water and allowed to incubate on ice for 60 min
prior to centrifugation as described above. The final pellet
was resuspended (40 mg/mL) in buffer; [3H]nicotine was
incubated with 0.5 mL of tissue homogenate (final vol-
ume 1 mL) for 2 h at 4 °C, and samples were rapidly
filtered through Whatman GF/C filters. Specific binding
was defined as the difference in the amount of binding in
the presence and absence of 100 µM (–)-nicotine tartrate.
Following buffer wash, the filters were air-dried, placed
in scintillation vials, and radioactivity was quantified.
Following transformation of the data by the Scatchard
method, the KD and Bmax values were determined using
the program LIGAND [26]. Displacement of [3H]nico-
tine binding at 1 nM was determined in the presence of
increasing concentrations of test compound and con-
verted to percent displacement of specific binding. IC50
values were determined from a plot of the log concentra-
tion versus percent displacement and converted to Ki
values by the method of Cheng and Prusoff [27]. Ki
values were determined at least in triplicate.
powder, m.p. 129–130 °C. H-NMR (D2O) δ: 0.95 (dt,
3H, J = 7.3 Hz, 3.0 Hz), 1.76 (m, 2H), 2.99 (s, 3H),
3.19–3.32 (m, 2H), 4.35 (s, 2H), 8.02 (dd, 1H, J = 8.1 Hz,
5.5 Hz), 8.68 (d, 1H, J = 8.1 Hz), 8.77 (d, 1H, J = 5.5 Hz),
8.92 (s, 1H). Anal. (C16H18N2•2C2H2O4) C, H, N.
5.1.16.
N-Ethyl-N-methyl-3-(3-pyridyl)-2-propyn-1-
ylamine oxalate 26c [Method G]
N-Ethylmethylamine (308 mg, 5.2 mmol) was added
to a solution of 3-(3-pyridyl)-2-propyn-1-yl bromide
hydrobromide [20] (263 mg, 1 mmol) in H2O (5 mL) at
0 °C. The reaction mixture was allowed to stir at room
temperature for 2 h and was then extracted with Et2O (2
× 50 mL). The combined ethereal solution was dried
(K2CO3) and evaporated to dryness in vacuo to give
104 mg (60%) of crude product. The free base was
converted to the oxalate salt and recrystallized from
1
iPrOH, m.p. 120–122 °C. H-NMR (CD3OD) δ: 1.44 (t,
3H, J = 7.29 Hz), 3.15 (s, 3H), 3.40 (q, 2H, J = 7.29 Hz),
4.42 (s, 2H), 7.54 (dd, 1H, J = 4.95 Hz, 7.89 Hz), 8.04
(dd, 1H, J = 1.87 Hz, 7.89 Hz), 8.63 (dd, 1H, J = 1.59 Hz,
4.95
Hz),
8.76
(s,
1H).
Anal.
(C11H14N2•1.5C2H2O4•H2O) C, H, N.
5.1.17. N-Methyl-O-(2-pyridyl)aminoethanol 28
A solution of N-benzyl-N-methyl-2-(aminoethanol)
(3.5 g, 21 mmol) in THF (5 mL) was added to a refluxing
suspension of petroleum ether-washed 60% NaH (0.92 g,
23 mmol) in THF (40 mL) under N2. The reaction mix-
ture was heated at reflux for 3 h, and 2-chloropyridine
(2.4 g, 21 mmol) was added. The resultant solution was
heated under reflux for an additional 14 h and allowed to
Acknowledgements
This work was supported in part by funding from the
Technology Development Center, Virginia Center for
Innovative Technology and by NIDA grant DA 05274.

190
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