7-Azaindole derivatives as potential partial nicotinic agonists

Article abstract of DOI:10.1016/j.bmcl.2007.10.101

We have investigated a series of 7-azaindoles as potential partial agonists of the α4β2 nicotinic acetylcholine receptor (nAChR). Three series of 7-azaindole derivatives have been synthesized and evaluated for rat brain neuronal nicotinic receptor affinity and functional activity. Compound (+)-51 exhibited the most potent nAChR binding (K_i = 10 nM). Compound 30A demonstrated both moderate binding affinity and partial agonist potency, thus representing a promising lead for the indications of cognition and smoking cessation.

Full text of DOI:10.1016/j.bmcl.2007.10.101

Available online at www.sciencedirect.com
Bioorganic & Medicinal Chemistry Letters 18 (2008) 188–193
7-Azaindole derivatives as potential partial nicotinic agonists
Axel R. Stoit,* Arnold P. den Hartog, Harry Mons, Sjoerd van Schaik, Nynke Barkhuijsen,
Cees Stroomer, Hein K. A. C. Coolen, Jan Hendrik Reinders, Tiny J. P. Adolfs,
Martina van der Neut, Hiskias Keizer and Chris G. Kruse
Solvay Pharmaceuticals, Research Laboratories, C.J. van Houtenlaan 36, 1381 CP Weesp, The Netherlands
Received 5 September 2007; revised 25 October 2007; accepted 27 October 2007
Available online 1 November 2007
Abstract—We have investigated a series of 7-azaindoles as potential partial agonists of the a4b2 nicotinic acetylcholine receptor
(nAChR). Three series of 7-azaindole derivatives have been synthesized and evaluated for rat brain neuronal nicotinic receptor affin-
ity and functional activity. Compound (+)-51 exhibited the most potent nAChR binding (Ki = 10 nM). Compound 30A demon-
strated both moderate binding affinity and partial agonist potency, thus representing a promising lead for the indications of
cognition and smoking cessation.
ꢀ 2007 Elsevier Ltd. All rights reserved.
Nicotinic acetylcholine receptors (nAChRs) are a sub-
type of acetylcholine-operated receptors and are mem-
bers of the superfamily of ligand-gated ion channel
receptors.1 Pentameric combinations of multiple a and
b subunits lead to a large number of nicotinic receptors
in the brain, complicating their study.2 The nAChR are
involved in a wide range of physiological and pathophys-
iological processes. The numerous neuronal nAChRs
subtypes are located at neurons throughout the CNS,
where they are involved in a number of processes con-
nected to cognitive functions, learning and memory, re-
ward, motor control, and analgesia.2 Equally
important to the overall contribution of nAChRs to cho-
linergic neurotransmission are the roles of presynaptic
and preterminal nAChRs as autoreceptors and heterore-
ceptors regulating the synaptic release of acetylcholine
and other neurotransmitters including dopamine, nor-
epinephrine, serotonin, glutamate, and c-aminobutyric
acid. Because of their modulatory influence on these neu-
rotransmitter systems, neuronal nAChRs have been pro-
posed as potential therapeutic targets for the treatment
of pain, epilepsy, and a wide range of neuron-degenera-
tive and psychiatric disorders such as Alzheimer’s
disease, Parkinson’s disease, schizophrenia, anxiety,
depression and the treatment of smoking cessation.3–5
The invention of TC-2403,6 as a moderately potent nic-
otinic receptor agonist exhibiting some functional pref-
erence for a4b2 over other a/b, a7, and muscle-type
nAChRs, and the finding of TC-1734,7 as a partial ago-
nist on nicotinic receptor subtype a4b2 showing im-
proved short- and long-term memory in rodent
models,8 encouraged us to synthesize 7-azaindole9,10
derivatives (I–III, Fig. 1). It was envisaged that these
conformationally restricted analogs of trans-meta-nico-
tine (TC-2403) would result in compounds with the tra-
ditional pharmacophoric elements for nAChR agonists,
consisting of a charged nitrogen and a hydrogen bond
acceptor,11 with distinctive distance/angle geometries.12
An elegant example, which illustrates such a rigidifica-
tion strategy, is varenicline, acting as a selective partial
agonist of the a4b2 nAChR, displaying 30–60% of the
in vivo efficacy of nicotine, and effectively blocking the
H
H
N
N
O
N
NH
N
N
N
TC-2403
Varenicline
TC-1734
H
N
R
N
N
H
R
N
N
H
N
N
N
H
NH
H
Keywords: Azaindole derivatives; Partial agonist; Nicotinic acetylcho-
line receptor; Cognition; Smoke cessation.
II
I
III
*
Figure 1.
Corresponding author. E-mail: axel.stoit@solvay.com
0960-894X/$ - see front matter ꢀ 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmcl.2007.10.101

A. R. Stoit et al. / Bioorg. Med. Chem. Lett. 18 (2008) 188–193
189
in vivo response to nicotine.4b This compound was ap-
proved by the FDA for smoking cessation in 2006.
a
b
OH
CH2Ph
N
N
N
N
N
SO2Ph
SO2Ph
13
14
The investigation of the novel 7-azaindole derivatives
(I–III) as putative partial nicotinic agonists is presented
in this paper, and their synthetic routes are described in
Schemes 1–7.
c
d
OH
OH
CH2Ph
H
N
N
N
N
N
N
H
H
15
16
Commercially available 7-azaindole 1 (Scheme 1) was
reacted with 1-benzyl-piperidin-3-one 2 under basic con-
ditions to yield the piperidin-3-ol compound 3.9 Benzyl
group deprotection with ammonium formate and palla-
dium hydroxide resulted in 4, which was dehydrated to 5
under acidic conditions. Hydrogenation gave the desired
3-piperidin-3-yl-1H-pyrrolo[2,3-b]pyridine 6.
e
f or g
H
H
N
N
N
N
N
N
H
H
18
17
4
h
i
N+
O
N
O
N
N
H
6
N
O
N
H
O
N
19
20
O
N
21
N
The synthesis of 6-chloro-3-piperidin-3-yl-1H-pyrrolo-
[2,3-b]pyridine 12 is depicted in Scheme 2. Compound
6 was reacted with di-tert-butyl-dicarbonate to generate
the piperidine N-Boc protected analog 8 (in a two-step
sequence), thereby facilitating the synthesis of the N-
oxide 9. Regioselective chlorination occurred at the C-
6 position of 7-azaindole N-oxide 9 and was achieved
by a Reissert–Henze type reaction, effectively assisted
Boc
Boc
O
Boc
Cl
N
+
Cl
N
N
N
R
R
N
22A, R = COOMe
22B, R = H
23A, R = COOMe
N
Boc 23B, R = H
Boc
j
j
Cl
(-)-24
k
Cl
N
N
N
N
H
H
(+)-24
24
25
N
H
N
H
O
HO
N
a
b
CH2Ph
+
N
Scheme 3. Reagents and conditions: (a) 1—LDA/THF, ꢀ10 ꢁC, 0.5 h;
2—1-benzyl-piperidin-3-one, THF, ꢀ30 ꢁC, 2 h (23%); (b) 2 N NaOH in
MeOH, reflux, 2 h (66%); (c) NH4HCO2, Pd(OH)2, MeOH, reflux, 1 h
(80%); (d) 6 N HCl, reflux, 18 h (92%); (e) H2, 50 psi, Pd(OH)2, MeOH,
rt, 1 h (84%); (f) chiral column23; (g) 1—(BOC)2O, N(Et)3, CH2Cl2,
reflux, 0.25 h; 2—2 N NaOH/MeOH, rt, 0.5 h (87%); (h) m-ClPBA,
dimethoxyethane, rt, 0.25 h (87%); (i) HMDS, methyl chloroformate,
THF, reflux, 1.5 h (34% (22 A) and 44% (23A)); (j) 1—2 N NaOH in
MeOH, rt, 18 h; 2—HCl/EtOH, reflux, 1 h (31%); (k) chiral column.24
N
N
CH2Ph
N
N
H
H
2
1
3
HO
NH
NH
NH
d
c
N
N
N
N
N
N
H
H
H
6
4
5
Scheme 1. Reagents and conditions: (a) NaOEt/EtOH, rt, 72 h (75%);
(b) NH4HCO2, Pd(OH)2, MeOH, reflux, 2 h (88%); (c) HCl/EtOH,
reflux, 1 h (44%); (d) H2, 50 psi, Pd(OH)2, HCl/MeOH, rt, 1 h (55%).
by hexamethyldisilazane (HMDS).13 Thus, the N-1-
methoxycarbonyl compound 10, obtained from this
N
NH
a
Boc
b
N
N
N
N
H
Boc
6
7
N
N
N
Boc
Boc
d
c
e
Boc
N
N
N
N
H
Cl
N
N
H
O
9
10
8
MeO
O
N
NH
f
Boc
Cl
N
N
Cl
N
N
H
H
11
12
Scheme 2. Reagents and conditions: (a) (Boc)2O, N(Et)3, CH2Cl2, reflux, 0.25 h; (b) 2 N NaOH/MeOH, rt, 0.5 h (55% overall); (c) m-CPBA,
dimethoxyethane, rt, 0.25 h (95%); (d) HMDS, methyl chloroformate, THF, rt, 0.5 h (59%); (e) 2 N NaOH/MeOH, rt, 18 h (95%); (f) HCl/EtOH,
reflux, 1 h (76%).

190
A. R. Stoit et al. / Bioorg. Med. Chem. Lett. 18 (2008) 188–193
a
a
a
b
c
O
N
N
H
N
N
F
N
F
F
N
NH2
F
N
N
O
H
H
27
26
S
O
S
HO
HO
O
O
43
42
O
41
O
O
Si(CH3)3
b
c
I
O
e
d
O
N
N
N
N
N
SO2Ph
S
O
O
SO2Ph
F
N
N
H
O
13
28
F
N
N
O
Li+
O
H
44
45
d
N
N
N
N
H
N
H
N
f
H
SO2Ph
29A
30A
F
N
N
F
N
N
H
e, c
d
46
35
O
O
13 + 27
29A/B
N
N
H
N
N
N
H
N
H
SO2Ph
29B
30B
Scheme 6. Reagents and conditions: (a) NH4OH, 9.2 bar, 125 ꢁC
(90%)18; (b) ethyl chloroformate, K2CO3, CH3CN, 40 ꢁC, 96 h (66%);
(c) 1—n-BuLi/THF, TMEDA, ꢀ78 ꢁC, 2 h, 2—I2, ꢀ78 ꢁC, 1 h (70%);
(d) TMSA, CuI, PdCl2(PPH3)2, N(Et)3, 100 ꢁC, 10 h (42%); (e) CuI,
DMF, 150 ꢁC, 0.5 h (58%); (f) 2 N NaOH/MeOH (99%).
f
g
N
N
N
N
N
N
H
SO2Ph
CH3
CH3
32A/B, (A = R-isomer, B = S-isomer)
31A/B
Scheme 4. Reagents and conditions: (a) SO2Cl2, Pyridine, CH2Cl2,
ꢀ78 ꢁC, 1 h15 (35%); (b) 1—LDA/THF, ꢀ10 ꢁC, 0.5 h; 2—(R)-
sulfamidate, THF, ꢀ78 ꢁC and then ꢀ20 ꢁC, 2 h; (c) 1 N HCl, EtOH,
THF, 80 ꢁC, 18 h (44% overall); (d) KOH, hydrazine monohydrate, 2-
(2-hydroxy-ethoxy)-ethanol, 100 ꢁC, 1 h (66%)25; (e) 1—LDA/THF,
ꢀ10 ꢁC, 0.5 h; 2—(S)-sulfamidate, THF, ꢀ20 ꢁC, 2 h; (f) 37% aqueous
formaldehyde, NaBH(OAc)3, dichloroethane, rt, 1 h (90%); (g) KOH,
hydrazine monohydrate, 2-(2-hydroxy-ethoxy)-ethanol, 100 ꢁC, 1 h
(80%).26
O
Boc
b
a
N
OH
+
Boc
N
N
N
N
N
SO2Ph
SO2Ph
47
48
13
c
d
OH
Boc
N
H
N
N
N
N
NH
H
49
50
a, b, c, d
e
R
N
N
R
N
N
N
(-)-51
(+)-51
H
H
H
e
33 , R = Cl
34 , R = Br
35 , R = F
36A/B , R = Cl (A = R-isomer, B = S-isomer)
37A/B , R = Br
N
N
H
NH
38A/B , R = F
51
Scheme 7. Reagents and conditions: (a) 1—LDA/THF, ꢀ10 ꢁC, 0.5 h;
2—CeCl3, THF, ꢀ70 to 10 ꢁC, 0.25 h; (3) compound 47, THF, ꢀ30 ꢁC,
2 h (58%); (b) KOH, hydrazine monohydrate, 2-(2-hydroxy-ethoxy)-
ethanol, 100 ꢁC, 1 h (84%); (c) 38% HCl/H2O (1:1), reflux, 12 h (58%);
(d) H2, 50 psi, Pd(OH)2, MeOH, rt, 2 h (59%); (e) chiral column.28a
f, g
Br
N
N
N
MeO
N
N
N
H
H
H
Boc
39
40
Scheme 5. Reagents and conditions: (a) 1—NaH/THF, 0 ꢁC, 1 h; 2—
benzenesulfonyl chloride, 0 ꢁC, 1 h (resp. 80%, 95% and 89%); (b) 1—
LDA/THF, ꢀ78 ꢁC, 1 h; 2—(R or S)-sulfamidate, THF, ꢀ78 to 30 ꢁC,
2 h; (c) 1 N HCl, EtOH, THF, 80 ꢁC, 18 h (resp., 31%, 48% and 30%);
(d) 2 N NaOH, isopropanol, 100 ꢁC, 3 h (resp., 58%, 76% and 57%); (e)
1—(BOC)2O, N(Et)3, CH2Cl2, reflux, 0.25 h; 2—2 N NaOH/MeOH,
rt, 0.5 h (79% overall); (f) NaOMe, Cu(I)Br, DMF, MeOH (56%); (g)
HCl/EtOH, reflux, 1 h (80%).27
(Scheme 3). After basic hydrolysis of the N-1-phenylsul-
fonyl group (15), the preferred sequence to 17 was ben-
zyl group deprotection (16), subsequently followed by
dehydration under acidic conditions. Hydrogenation
yielded 2-piperidin-3-yl-1H-pyrrolo[2,3-b]pyridine 18.
Furthermore, by the sequence described in Scheme 3,
starting material 18 was converted into the N-oxide 20
which was exposed to methyl chloroformate and
HMDS.13 Surprisingly, the subsequent Reissert–Henze
reaction afforded a mixture of 6- and 4-substituted prod-
ucts (22A and 23A). We attributed the non-selectivity of
this reaction to steric and electronic influences of the
piperidine ring on the adjacent carbamate and carbonate
group in intermediate 21, decreasing the reactivity of the
6-position relative to the 4-position. Purification by chro-
matography and subsequent basic hydrolysis (22B,23B),
followed by removal of the N-Boc protecting group,
yielded the corresponding 6- and 4-chloro-2-piperidin-
3-yl-1H-pyrrolo[2,3-b]pyridines (24,25).
reaction, was converted to compound 11 under basic
conditions. Acidic deprotection of the N-Boc completed
the synthesis of 12.
Scheme 3 highlights the synthesis of 2-(3-piperidyl)
substituted azaindoles. The phenylsulfonyl group as
Directing Metalation Group (DMG) at the N-1-position
of azaindole analogs enabled the lithiation of the 2-posi-
tion and thereby the synthesis of C-2 derivatives.14 The
C-2 lithio derivative of 13, prepared on multigram scale
by a-metalation (1,1 equiv LDA, THF, ꢀ10 ꢁC), was
trapped with 1-benzyl-piperidin-3-one (2) to afford 14

A. R. Stoit et al. / Bioorg. Med. Chem. Lett. 18 (2008) 188–193
191
Table 1. Radioligand [3H]cytisine binding for 7-azaindole analogs29
5-(R)-[3,3,0]-1-Aza-2-thia-3-oxabicyclooctane-2,2-di-oxide
(26, Scheme 4) and the corresponding 5-(S)-analog (27)15
were employed as enantiomerically pure starting materi-
als for the synthesis of 30A and 30B (Scheme 4).
Compound
Kia (nM)
Compound
Kia (nM)
6
12
2950
2950
10,000
na
36A
36B
147
3715
691
na
( )-18
(+)-18
(ꢀ)-18
( )-24
(ꢀ)-24
(+)-24
25
37A
37B
The 2-lithio derivative of 13 was reacted with (R)-sul-
famidate 26 to produce the lithium-sulfonate 28, which
was subsequently hydrolyzed to generate 29A. Various
methods were tried for the removal of the N-1-phenyl-
sulfonyl group. After considerable experimentation, we
found that potassium hydroxide in di-ethylene glycol,
in the presence of hydrazine, improved the reaction rate
and yields of 30A.25a The (S)-isomer 30B was obtained
starting from 13 and the (S)-sulfamidate 27. Reductive
methylation of 29A (29B) resulted in 31A (31B). Basic
deprotection of the N-1-phenylsulfonyl group completed
the synthesis of 32A (32B).
1995
na
38A
38B
316
1995
na
na
40
3460
na
( )-51
(ꢀ)-51
(+)-51
(ꢀ)-Nicotine
TC-2403
TC-1734
16
251
10
30A
30B
125
2750
2511
691
7
32A
32B
266,35
117,35
na, not active.
a Values are the average of three experiments. The assay-to-assay
maximum variability in the series was 3-fold. More common vari-
ability was 2-fold.
Scheme 5 illustrates the preparation of the halogen and
methoxy derivatives of 30A/B. The procedure described
above (Scheme 4, using the chiral sulfamidates 26 and
27) was used to convert the N-1-phenylsulfonyl14 pro-
tected derivatives of 33,13 34,13 and 35 (Scheme 6) to
the corresponding compounds 36A/B, 37A/B, and 38A/
B16 (Scheme 5). The 6-bromo derivate 37A was con-
verted to its N-Boc protected analog 39 (as described
in Scheme 1) which was treated with NaOMe in the
presence of copper(I) bromide.17 Subsequent deprotec-
tion of the N-Boc yielded (R)-6-methoxy-2-pyrrolidin-
2-ylmethyl-1-H-pyrrolo[2,3-b]pyridine (40).
(18 and 6) displayed low binding affinity. Electron-
withdrawing substitution in heterocyclic nicotine deriv-
atives has previously been reported to increase binding
affinity3 and/or improve subtype selectivity in terms of
functional activity.32 Interestingly, the 6-chloro ana-
logs 12 and (+)-24 exhibited the same affinity com-
pared to their hydrogen analogs (6 and (ꢀ)-18).
Moreover, replacement of the piperidine ring ((ꢀ)-
18) to a (methylene)-pyrrolidine ring, i.e., 30A and
(+)-5128a,b resulted in a 16-fold and 200-fold affinity
increase, respectively.
Surprisingly, and to the best of our knowledge, the syn-
thesis of 6-fluoro-7-azaindole (35) has not been pub-
lished yet. We envisioned a straightforward synthesis
of 35 from commercially available 2,6-difluoro-pyridine
41, which was converted to 2-amino-6-fluoro-pyridine
42.18 Different DMG groups were examined (for exam-
ple the 2,2-dimethyl-propanamide),17,19 the ethyl-carba-
mate20 being essential for the regioselective iodination of
compound 43 to generate the unknown (6-fluoro-3-
iodo-pyridin-2-yl)-carbamic acid ethyl ester (44). Subse-
quent Sonogashira chemistry (45) and ring closure in the
presence of copper(I) iodide21 afforded compound 46.
Cleavage of the N-1-carbamate generated the desired
6-fluoro-7-azaindole 35.
Demethylation of nicotine analogs typically reduced
affinity for the nicotinic receptors, but the extent of
the reduction depended on the particular nicotine ana-
log being examined.31 N-Demethylation of compound
32B decreased affinity by 4-fold (30B), however
demethylation of compound 32A increased the affinity
by ca. 20-fold (30A), indicating a lack of bulk toler-
ance in this vicinity with respect to the R-isomer
(30A).
The 6-fluoro substituted (R)-analog (38A) and its 6-
chloro counterpart (36A) displayed comparable affinity
(with respect to 30A). The 6-bromo substituted (R)-ana-
log (37A) and the 6-methoxy (R)-analog (40) displayed a
decreased or negligible binding affinity, suggesting unfa-
vorable interactions between the receptor and the
ligand.
The preparation of 2-pyrrolidin-3-yl-1H-pyrrolo[2,3-b]-
pyridine (51) is depicted in Scheme 7. The C-2 lithio
derivative of 13 underwent a cerium-mediated reaction22
with 3-oxo-pyrrolidin-1-carboxylic acid tert-butyl ester
(47) to yield the corresponding tertiary alcohol (48). Ba-
sic hydrolysis of the phenylsulfonyl group resulted in
compound 49. Acidic deprotection of the N-Boc and
subsequent dehydration generated 50. Hydrogenation
completed the synthesis of 51. Chromatographic separa-
tion of the isomers could be achieved using a chiral
column.28a
All active compounds were subsequently evaluated in an
in vitro functional assay,30 the best compounds being
(+)-5128b and 30A.25b Thus, the presence of agonist or
partial agonist activity was detected by comparing the
effects of compounds at 10 nM and 1 lM to the response
elicited by 10 lM nicotine. In parallel, responses of test
compounds were determined in the presence of the aspe-
cific nicotine receptor antagonist mecamylamine, to ex-
clude the involvement of other than nicotinergic
mechanisms. Second, antagonist effects were assessed
in a similar paradigm that measured the compounds’
ability (10 lM) to inhibit the current evoked by 1 lM
nicotine.
The binding affinities of the 7-azaindole analogs at the
rat neuronal nicotinic receptors in the brain were
determined using [3H]cytisine displacement experi-
ments (Table 1).29 We can readily observe that the
2- and 3-azaindole substituted piperidine derivatives

192
A. R. Stoit et al. / Bioorg. Med. Chem. Lett. 18 (2008) 188–193
14. (a) Desarbre, E.; Coudret, S.; Meheust, C.; Merour, J.-Y.
Tetrahedron 1997, 53, 3637; (b) Lefoix, M.; Daillant, J.-P.;
Merour, J.-Y.; Gillaizeau, I.; Coudret, G. Synthesis 2005,
20, 3581.
We found that compound 30A was a partial agonist,
displaying 62% of the in vitro efficacy of nicotine. In
addition, compound 30A blocked the nicotine re-
sponse in vitro (70%). We found that compound
30A has a favorable metabolic stability and brain pen-
etration25b in spite of it modest oral availability. Thus,
on the basis of its satisfactory binding affinity for the
CNS nAChR and his partial agonistic activity in com-
bination with its acceptable pharmacokinetics, we re-
gard compound 30A as a promising lead for the
indications of cognition and smoking cessation.
15. Lowe, G.; Reed, M. Tetrahedron Asymmetry 1990, 1, 885.
16. Analytical data for (a); (R)-6-Chloro-1H-pyrrolo[2,3-
25
b]pyridine (36A): ½aꢁD ꢀ 48 (c1, toluene). 1H NMR
(400 MHz, CDCl3): d 11.0–10.0 (br s, 1H), 7.52 (d,
J = 8 Hz, 1H), 7.01 (d, J = 8 Hz, 1H), 6.16 (s, 1H), 3.50–
3.42 (m, 1H), 3.02–2.90 (m, 3H), 2.81–2.73 (m, 1H), 1.95–
1.85 (m, 1H), 1.82–1.64 (m, 2H), 1.43–1.33 (m, 1H); (b)
(R)-6-bromo-2-pyrrolidin-2-ylmethyl-1H-pyrrolo[2,3-b]pyri-
25
dine (37A): ½aꢁD ꢀ 50 (c 1, toluene), which was converted
to its (amorphous) salt (free base/fumaric acid (1:1)),1H
NMR (400 MHz, DMSO-d6): d N1–H invisible, 7.82 (d,
J = 8 Hz, 1H), 7.18 (d, J = 8 Hz, 1H), 6.49 (s, 2H), 6.38 (s,
1H), 3.82–3.72 (m, 1H), 3.27–3.05 (m, 4H), 2.09–1.80 (m,
3H), 1.70–1.60 (m, 1H); (c) (R)-6-fluoro-2-pyrrolidin-2-
Acknowledgment
Mr Jan Hoogendoorn is acknowledged for the chiral
preparative HPLC separation of 18, 24, and 51.
25
ylmethyl-1H-pyrrolo[2,3-b]pyridine (38A): ½aꢁD ꢀ 38 (c1,
toluene), which was converted to its (amorphous) salt (free
base/fumaric acid (1:1)), 1H NMR (400 MHz, DMSO-d6):
d 12.2–11.7 (br s, 1H), 8.0 (br t, J = 8 Hz, 1H), 6.76 (br d,
J = 8 Hz, 1H), 6.51 (s, 2H), 6.37 (s, 1H), 3.83–3.74 (m,
1H), 3.26–3.03 (m, 4H), 2.10–1.79 (m, 3H), 1.71–1.61 (m,
1H).
References and notes
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2. Jensen, A. A.; Frolund, B.; Liljefors, T. J. Med. Chem.
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17. Mazeas, D.; Guillaumet, G.; Viaud, M.-C. Heterocycles
1999, 50, 1065.
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23. Separation of the enantiomerically pure isomers was
achieved using a chiral column (Chiralpak AD 20 lm,
250 · 4.6, MeOH/EtOH 1:1, 2 ml/min, d = 220 nm. Ana-
25
lytical data for (+)-18: Rt 5.6 min, ½aꢁD þ 4 (c1, toluene).
25
Analytical data for (ꢀ)-18: Rt 8.3 min, ½aꢁD ꢀ 4 (c1,
toluene).
24. Separation of the enantiomerically pure isomers was
achieved using a chiral column (Chiralpak AD-H 5 lm,
250 · 4.6, 100% EtOH + 0.1% diethylamine, 0.5 ml/min,
d = 220 nm. Analytical data for (ꢀ)-24: Rt 18.4 min,
25
½aꢁD ꢀ 10 (c1, toluene). Analytical data for (+)-24: Rt
7. Gatto, G. J.; Bohme, G. A.; Caldwell, W. S.; Letchworth,
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try 2002, 26, 913.
25
25.2 min, ½aꢁD þ 10 (c1, toluene).
25
25. (a) Analytical data for 30A: ½aꢁD ꢀ 50 (c1, toluene), which
was reacted with 1 equiv of fumaric acid in EtOH and
concentrated. Recrystallization from EtOH/ethyl acetate
afforded a solid (free base/fumaric acid (1:1)), mp >163 ꢁC
1
(decomposition). H NMR (400 MHz, DMSO-d6): d 11.7
(br s, 1H), 8.13 (dd, J = 5 Hz, 2 Hz, 1H), 7.84 (dd,
J = 8 Hz, 2 Hz, 1H), 7.0 (dd, J = 8 Hz, 5 Hz, 1H), 6.51 (s,
2H), 6.32 (s, 1H), 3.85–3.77 (m, 1H), 3.26–3.04 (m, 4H),
2.09–1.80 (m, 3H), 1.71–1.61 (m, 1H).; (b) The P-glyco-
protein transport factor33 of the compound was also
performed in vitro, being 1.2. Determination of the
metabolic stability was performed in vitro (human liver
homogenate34); t1/2 being 266 min. Iv/po studies (rat)
reveal a bioavailability of 11.3% and a brain-plasma ratio
of 3.7. Cmax following po administration was reached after
0.5–1 h with levels in brain of 280–290 ng/g and 70–
120 ng/ml in plasma.
9. Mewshaw, R. E.; Meagher, K. L.; Zhou, P.; Zhou, D.;
Shi, X.; Scerni, R.; Smith, D.; Schechter, L. E.; Andree, T.
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A. A. EP0870768, October 14, 1998.
11. Beers, W. H.; Reich, E. Nature (Lond) 1970, 225, 917.
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13. Minakata, S.; Komatsu, M.; Ohshiro, Y. Synthesis 1992,
661.

A. R. Stoit et al. / Bioorg. Med. Chem. Lett. 18 (2008) 188–193
193
25
26. Analytical data for 32A: ½aꢁD þ 44 (c 1, toluene).
30. In vitro [3H]dopamine release. Dopamine release was
measured using rat striatal slices, as described by Stoof
et al. (Brain Res., 1980, 196, 276). Test compounds or
epibatidine was added together with the K+ pulse to the
medium at t = 50 (10 nM) and t = 90 min (1 lM) for
5 min. In parallel, responses of test compound were
determined in the presence of the aspecific nicotine
receptor antagonist mecamylamine (0.1 lM) or the specific
a4b2 n-acetylcholine receptor antagonist DHBE (1 lM).
Effects of test compounds were calculated as percentages
of the control group. Mecamylamine or DHBE sensitive
release was expressed as percentage inhibition of evoked
[3H]dopamine release in response to test compound.
Within each assay, each test compound was replicated
using 2–3 chambers; replicates were averaged.
31. Ferretti, G.; Dukat, M.; Giannella, M.; Piergentili, A.;
Pigini, M.; Quaglia, W.; Damaj, M. I.; Martin, B. R.;
Glennon, R. A. J. Med. Chem. 2002, 45, 4724.
32. Carroll, F. I. Bioorg. Med. Chem. Lett. 2004, 14, 1889.
33. Schinkel, A. H.; Wagenaar, E.; van Deemter, L.; Mol, C.
A. A. M.; Borst, P. J. Clin. Invest. 1995, 96, 1698.
34. Di, L.; Kerns, E. H.; Hong, Y.; Kleintop, T. A.; Mc
Connel, O. J.; Huryn, D. M. J. Biomol. Screening 2003, 8,
453.
25
27. Analytical data for 40: ½aꢁD ꢀ 12 (c 1, MeOH).
28. (a) Separation of the enantiomerically pure isomers was
achieved using a chiral column (Chiralpak AD 20 lm,
250 · 4.6, 20% MeOH, 20% EtOH, 60% heptane, 2 ml/
min, d = 220 nm. Analytical data for (ꢀ)-51: Rt, 6.0 min,
25
½aꢁD ꢀ 10 (c1, MeOH). Analytical data for (+)-51: Rt
25
7.9 min, ½aꢁD þ 12 (c1, MeOH). Both isomers were reacted
with 1 equiv of fumaric acid in MeOH and concentrated to
afford the salt of the title compound. Mp 130–133 ꢁC (free
base/fumaric acid (1:1.5)). 1H NMR (400 MHz, DMSO-
d6): d 11.7 (br s, 1H), 8.08 (dd, J = 5 Hz, 2 Hz, 1H), 7.78
(dd, J = 8 Hz, 2 Hz, 1H), 6.95 (dd, J = 8 Hz, 5 Hz, 1H),
6.4 (s, 3H), 6.27 (br s, 1H), 3.63–3.53 (m, 2H), 3.33–3.15
(m, 3H), 2.36–2.25 (m, 1H), 2.08–1.97 (m, 1H).; (b)
Compound (+)-51 was a full agonist, displaying the same
in vitro efficacy as nicotine. The P-glycoprotein transport
factor33 for compound (+)-51 was also determined
in vitro, being 2. Determination of the metabolic stability
was determined in vitro (human liver homogenate)34; t1/2
being 134 min.
29. Affinity for neuronal nicotinic receptors was determined
using rat brain membranes and [3H]cytisine at CEREP, by
the receptor binding assay described by Pabreza et al.:
‘[3H]cytisine binding to nicotinic cholinergic receptors in
brain’ Mol. Pharmacol. 1991, 39, 9.
35. Radioligand [3H]-L-nicotine binding in membranes from
rat cerebral cortex.