Synthesis and analgesic activity of secondary amine analogues of pyridylmethylamine and positional isomeric analogues of ABT-594

Article abstract of DOI:10.1016/j.bmcl.2005.12.073

A series of highly sterically hindered secondary amine analogues of pyridylmethylamine (7a-f, 8a-c) and positional isomeric analogues of ABT-594 (9a-c) were synthesized and evaluated for their in vivo analgesic activity. The compounds 7a and 7d show potent analgesic activity and lower toxicity. Some interesting structure-activity relationships have been revealed.

Full text of DOI:10.1016/j.bmcl.2005.12.073

Bioorganic & Medicinal Chemistry Letters 16 (2006) 2013–2016
Synthesis and analgesic activity of secondary amine analogues
of pyridylmethylamine and positional isomeric analogues
of ABT-594
Chuan-Xin Zhang, Ze-Mei Ge, Tie-Ming Cheng and Run-Tao Li*
School of Pharmaceutical Sciences, Peking University, Beijing 100083, PR China
Received 8 November 2005; revised 30 November 2005; accepted 19 December 2005
Available online 18 January 2006
Abstract—A series of highly sterically hindered secondary amine analogues of pyridylmethylamine (7a–f, 8a–c) and positional
isomeric analogues of ABT-594 (9a–c) were synthesized and evaluated for their in vivo analgesic activity. The compounds 7a
and 7d show potent analgesic activity and lower toxicity. Some interesting structure–activity relationships have been revealed.
ꢀ 2005 Elsevier Ltd. All rights reserved.
Nicotine 1 produces many effects via interaction with
nicotinic cholinergic (nACh) receptors.1 There is also
considerable evidence suggesting that selective neuronal
nicotinic acetylcholine receptor (nAChR) agonists may
have therapeutic potential in CNS disorders such as
Alzheimer’s and Parkinson’s diseases, schizophrenia,
and depression.2 Antinociceptive effects of nicotine have
been known for some time, but the most important dis-
covery of the alkaloid epibatidine 2 (one of bridge
nicotinoids, isolated from South American frogs by
Daly in 1992) as a potent analgesic that acts via neuro-
nal nAChRs has stimulated renewed interest in targeting
nAChRs for analgesia.3 However, the potential thera-
peutic actions of epibatidine and older nicotinic agonists
are accompanied by evident adverse effects, such as high
toxicity, hypertension, neuromuscular paralysis, depen-
dence, and seizure.4
and has been the primary focus of high affinity ligand
design.6 To date, numerous structure–activity relation-
ship studies based on the structures of nicotine 1 and
epibatidine 2 have been performed in search of highly
efficient analgesic agents and simple structure with lower
toxicity.7
Among them, a series of representative ring-opened ana-
logues (3–5) of nicotine 1 and epibatidine 2 show that
different kinds of amines could influence the affinity
H
N
R1
R
H3C
O
N
N
N
N
Cl
N
3
2
1
Several populations of nACh receptors have been iden-
tified, the emerging diversity of nAChR subtypes sup-
porting the possibility of developing receptor subtype
selective therapeutic agents that lack or have substan-
tially reduced side effects.5 The a4b2 subtype is one of
the most abundant nAChR subtypes within the CNS
3a R = H, R1 = Me, Ki = 35 nM
3b R= R1 = Me, Ki = 21 nM
R1
N
R
R1
N R
N
N
Keywords: Nicotinic cholinergic receptor; Analgesic activity; Highly
sterically hindered secondary amine analogues of pyridylmethylamine;
Synthesis.
4
5
4a R = H, R1 = Me, Ki > 10,000 nM
4b R= R1 = Me, Ki =540 nM
4c R = Me, R1 = Et, Ki =28 nM
5a R = H, R1 = Me, Ki= 113 nM
5b R= R1 = Me, Ki =510 nM
5c R = Me, R1 = Et, Ki =1770 nM
*
Corresponding author. Tel.: +86 10 8280 1504; fax: +86 10 8271
6956; e-mail: lirt@mail.bjmu.edu.cn
0960-894X/$ - see front matter ꢀ 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmcl.2005.12.073

2014
C.-X. Zhang et al. / Bioorg. Med. Chem. Lett. 16 (2006) 2013–2016
O
H
N
N
H
N
R
N
Cl
8a ( X = H, R = cyclopentyl )
ABT-594 (6)
8b ( X = H, R = furfurylmethyl )
8c ( X = H, R =tetrahydrofurfurylmethyl )
R
N
H
X
N
H
N
( ) n
O
7a (X = H, R = cyclopentyl)
7b (X = H, R = furfurylmethyl)
7c (X = H, R =tetrahydrofurfurylmethyl)
N
Y
7d (X = Cl, R = cyclopentyl)
9a ( n = 0, Y = H )
9b ( n = 0, Y = Cl )
9c ( n = 2, Y = Cl )
7e (X = Cl, R = furfurylmethyl)
7f (X = Cl, R = tetrahydrofurfurylmethyl)
significantly.8 For 3-pyridyl ethers 3 (3-PE), the second-
ary amine (e.g., 3a) and tertiary amine (i.e., 3b) show
similar affinity for the a4b2 receptor. However, for
3-pyridylmethylamines 4 (3-PMA), the tertiary amines
(i.e., 4b and 4c) are typically favored over secondary
amines (i.e., 4a) for a4b2 receptor binding. In contrast,
for 3-pyridylbutynylamines 5 (3-PBA), the secondary
amines (e.g., 5a) bind with affinity higher than those of
corresponding tertiary amines (i.e., 5b and 5c). There-
fore, it is of interest to examine how secondary amine
analogues of 3-PMA with larger cyclic substituent influ-
ence the affinity. Also, because (R)-5-(2-azetidinylmeth-
oxy)-2-chloropyridine (ABT-594, 6) has potent
antinociceptive properties in different animal models
and demonstrates superior selectivity for neuronal
nAChRs,9 we are interested in exploring whether these
properties could remain if the ‘O’ and ‘NH’ in the mol-
ecule are exchanged. Meantime, we hope to determine
the difference between 3-pyridylmethylamines (3-PMA)
and 2-pyridylmethylamines (2-PMA) for the affinity,
because only a few papers reported the influence of the
positional isomeric chain-extended analogues of nico-
tine (1) on affinity.8c
hindered secondary amino group, as well as the chain
extended 3-pyridylamine oxacycle analogs 9a–c of
ABT-594, were synthesized and evaluated for their in vi-
vo analgesic activity. The results are reported in this
paper.
As shown in Scheme 1, the reduction of 6-chloronicoti-
nic acid with LiAlH4 gave 6-chloro-3-pyridylmetha-
nol,10 subsequent PCC oxidation affording the key
intermediate 6-chloro-3-pyridylaldehyde 10. The com-
pounds 7a–f and 8a–c were obtained by the reductive
amination of 6-chloro-3-pyridylaldehyde, 3-pyridylalde-
hyde or 2-pyridylaldehyde with the corresponding
primary amines 11 and sodium cyanoborohydride.
The synthesis of compounds 9a–c is outlined in
Scheme 2. The N-alkylation of 3-pyridylamine or
6-chloro-3-pyridylamine with epichlorohydrin (12a) or
tetrahydrofurfurylmethyl bromide (12b) was performed
under solid–liquid-phase transfer catalysis conditions
in 60–81% yields. The TBAI was used as catalyst, diox-
ane as solvent, KOH as base, and KF as activating
agent.
On the basis of the above ideas, 3-pyridylmethylamines
7 and 2-pyridylmethylamines 8 with a highly sterically
All newly synthesized compounds 7a–f, 8a–c, and 9a–c
were evaluated for their in vivo analgesic activity and
CH2OH
CHO
COOH
PCC, CH2Cl2
rt, 3h
LiAlH4, THF, 0 ˚C
Cl
N
Cl
N
Cl
N
10
CHO
R
N
H
X
N
76 - 97%
X
N
HAc / CH3OH = 1:9
NaBH3CN, rt
7a-f
RNH2
11
H
N
N
CHO
45 - 97%
HAc / CH3OH = 1:9
NaBH3CN, rt
N
R
8a-c
Scheme 1. Synthesis of secondary amine analogues of pyridylmethylamine 7a–f and 8a–c.

C.-X. Zhang et al. / Bioorg. Med. Chem. Lett. 16 (2006) 2013–2016
2015
H
N
( )
O
NH2
n
KOH(s) / TBAI
( )
O
n
+
X
dioxane, KF, refluxed 4h
60 - 81%
Y
N
N
Y
12a ( n = 0, X = Cl )
12b ( n = 2, X = Br )
9a-c
Scheme 2. Synthesis of compounds 9a–c.
Table 1. The biological activities of compounds 7a–f, 8a–c, and 9a–c
compounds 9a and 9c are devoid of any analgesic activ-
ity. So it is very important to keep the suitable distance
between two nitrogens in the molecular.
Compound
Dose
(mg/kg sc)
Inhibitory
ratea (%)b
Rate of
death (%)
Nicotine
20
10
5
—
100
88
61
0
100
50
25
0
The results of the present investigation also confirmed
that all tested compounds showed toxicity lower than
that of nicotine. Just as, the rats died in 100% at dose
of 20 mg/kg of nicotine; however, no dead rat was found
at the same dose of tested compound.
7a
7b
7c
7d
7e
20
10
20
10
20
10
20
10
20
10
20
20
20
20
20
20
20
0
50
0
0
0
56
23
66
37
46
41
35
0
0
In summary, a series of novel ring-opened secondary
pyridylmethylamine analogues of nicotine and position-
al isomeric analogues of ABT-594 have been prepared.
The highly sterically hindered secondary amine ana-
logues (7a–f) of 3-pyridylmethylamine show potent
analgesic activity and lower toxicity, especially the com-
pounds 7a and 7d. The further structure–activity rela-
tionship studies of this class of compounds might offer
the opportunity for the discovery of analgesics with
more potent activity and lower toxicity.
0
0
0
0
0
7f
0
8a
8b
8c
9a
9b
9c
0
0
0
0
0
0
0
20.5
0
0
0
a Acetic acid writhing test was used on mice.
Acknowledgments
b % inhibition = 100 À (A/B · 100), where A = incidence of writhing in
the treated group; and B = incidence of writhing in the control group,
occurring from the 5th to 10th min after administration of the
noxious agents.
This work was supported by the National Natural Sci-
ence Foundation of China (NSFC 29972005). Biological
activities were performed by National Center for Drug
Screening, Shanghai Institute of Materia Medica,
Chinese Academy of Sciences and Department of Phar-
macology, Peking University.
toxicity according to our reported method.11 The results
are summarized in Table 1.
References and notes
As shown in Table 1, all the 3-pyridylmethylamine ring-
opened nicotine analogues 7a–f displayed significantly
analgesic activity, especially the compounds 7a and 7d
showing a remarkable potency and efficacy. This result
demonstrates that higher sterically substituted second-
ary amine derivatives of 3-pyridylmethylamine are
favorable to increase the analgesic activities. Comparing
the biological results of compounds 7a–c with those of
7d–f, there is no obvious difference. Therefore, the intro-
duction of 6-chloro at pyridyl ring has little impact on
analgesic activity.
1. (a) Arneric, S. P. Neuronal Nicotinic Receptors. In Brioni,
J. D., Ed.; John Wiley and Sons: New York, 1999; (b)
Cordero, E. M.; Marubio, L. M.; Klink, R.; Changeux, J.
P. Trends Pharmacol. Sci. 2000, 21, 211.
2. (a) Arneric, S. P.; Sullivan, J. P.; Williams, M. In
Psychopharmacology: Fourth Generation of Progress;
Bloom, E., Kupfer, D. J., Eds.; Raven: New York, 1995;
p 94; (b) Leonard, S.; Adams, C.; Breese, C. R. Schizo-
phrenia Bull. 1996, 22, 431; (c) Williams, M.; Arneric, S.
Exp. Opin. Invest. Drugs 1996, 5, 1035.
3. (a) Spande, T. F.; Garraffo, H. M.; Edwards, M. W.; Yeh,
H. J. C.; Pannell, L.; Daly, J. W. J. Am. Chem. Soc. 1992,
114, 3475; (b) Daly, J. W. J. Nat. Prod. 1998, 6, 162; (c) Li,
T. C.; Qian, C. G.; Eckman, J.; Huang, D. F.; Shen, T. Y.
Bioorg. Med. Chem. Lett. 1993, 3, 2759; (d) Qian, C. G.;
Li, T. C.; Shen, T. Y.; Libertinegarahan, L.; Eckman, J.;
Biftu, T.; Ip, S. Eur. J. Pharm. 1993, 250, R13; (e) Fisher,
M.; Huangfu, D.; Shen, T. Y.; Guyenet, P. G. J.
Pharmacol. Exp. Ther. 1994, 270, 702; (f) Badio, B.; Daly,
J. W. Mol. Pharm. 1994, 45, 563.
The compounds 8a–c, the corresponding positional iso-
mers of 7a–c, completely lost the analgesic activity. It
indicates that the substituted position of aminomethyl
group in this kind of compounds is one of critical factors
influencing analgesic activity.
Among the positional isomeric analogues of ABT-594
(9a–c), only compound 9b shows weak analgesic activity
(23% analgesic activity at a dose of 20 mg/kg), and
4. (a) Sullivan, J. P.; Decker, M. W.; Brioni, J. D.;
Donnelly-Roberts, D.; Anderson, D. J.; Bannon, A. W.;

2016
C.-X. Zhang et al. / Bioorg. Med. Chem. Lett. 16 (2006) 2013–2016
Kang, C.-H.; Adams, P.; Piattoni-Kaplan, M.; Buckley,
Chem. Lett. 2002, 12, 1989; (e) Lin, N. H.; Li, Y.; He, Y.;
Holladay, M. W.; Kuntzweiler, T.; Anderson, D. J.;
Campbell, J. E.; Arneric, S. P. Bioorg. Med. Chem. Lett.
2002, 12, 1989; (f) Damaj, M. I.; Glassco, W.; Dukat, M.;
May, E. L.; Clennon, R. A.; Martin, B. R. Drug Dev. Res.
1996, 38, 177; (g) Dukat, M.; Fiedler, W.; Dumas, D.;
Damaj, I.; Martin, B. R.; Rosecrans, J. A.; James, J. R.;
Clennon, R. A. Eur. J. Med. Chem. 1996, 31, 875.
8. (a) Balboni, G.; Marastoni, M.; Merighi, M.; Borea, P. A.;
Tomatis, R. Eur. J. Med. Chem. 2000, 35, 979; (b)
Dogruer, D.; Lee, M.; Dukat, M.; Damaj, M. I.; Martin,
B. R.; Glennon, R. A. Bioorg. Med. Chem. Lett. 2004, 14,
523; (c) Cheng, Y. X.; Dukat, M.; Dowd, M.; Fiedler, W.;
Martin, B.; Damaj, M. I.; Glennon, R. A. Eur. J. Med.
Chem. 1999, 34, 177.
9. (a) Bannon, A. W.; Decker, M. W.; Holladay, M. W.;
Curzon, P.; Donnelly-Roberts, D.; Puttfarcken, P. S.;
Bitner, R. S.; Diaz, A.; Dickenson, A. H.; Porsolt, R. D.;
Williams, M.; Arneric, S. P. Science 1998, 279, 77; (b)
Holladay, M. W.; Wasicak, J. T.; Lin, N. H.; He, Y.;
Ryther, K. B.; Bannon, A. W.; Buckley, M. J.; Kim, D. J.
B.; Decker, M. W.; Anderson, D. J.; Campbell, J. E.;
Kuntzweiler, T. A.; Donnelly-Roberts, D. L.; Piattoni-
Kaplan, M.; Briggs, C. A.; Williams, M.; Arneric, S. P. J.
Med. Chem. 1998, 41, 407; (c) Kesingland, A. C.; Gentry,
C. T.; Panesar, M. S.; Bowes, M. A.; Vernier, J. M.; Cube,
R.; Walker, K.; Urban, L. Pain 2000, 86, 113.
M. J.; Gopalakrishnan, M.; Williams, M.; Arneric, S. P.
J. Pharmacol. Exp. Ther. 1994, 271, 624; (b) Bonhaus,
D. W.; Bley, K. R.; Broka, C. A.; Fontana, D. J.;
Leung, E.; Lewis, R.; Shieh, A.; Wong, E. H. F. J.
Pharmacol. Exp. Ther. 1995, 272, 1199; (c) Rao, T. S.;
Correa, L. D.; Reid, R. T.; Lloyd, G. K. Neurophar-
macology 1996, 35, 393; (d) Molina, P. E.; Ding, Y. S.;
Carroll, F. I.; Liang, F.; Volkow, N. D.; Pappas, N.;
Kuhar, M.; Abumrad, N.; Gatley, S. J.; Fowler, J. S.
Nucl. Med. Biol. 1997, 24, 743; (e) Tonder, J. E.; Olesen,
P. H. Curr. Med. Chem. 2001, 8, 651; (f) Koren, A. O.;
Horti, A. G.; Mukhin, A. G.; Gundisch, D.; Kimes, A.
S.; Dannals, R. F.; London, E. D. J. Med. Chem. 1998,
41, 3690; (g) Abreo, M. A.; Lin, N. H.; Garvey, D. S.;
Gunn, D. E.; Hettinger, A. M.; Wasicak, J. T.; Pavlik,
P. A.; Martin, Y. C.; Donnelly-Roberts, D. L.; Ander-
son, D. J.; Sullivan, J. P.; Williams, M.; Arneric, S. P.;
Holladay, M. W. J. Med. Chem. 1996, 39, 817.
5. (a) Holladay, M. W.; Dart, M. J.; Lynch, J. K. J. Med.
Chem. 1997, 40, 4169; (b) Decker, M. W.; Meyer, M. D.
Biochem. Pharmacol. 1999, 58, 917.
6. Dart, M. J.; Wasicak, J. T.; Ryther, K. B.; Schrimpf, M.
R.; Kim, K. H.; Anderson, D. J.; Sullivan, J. P.; Meyer,
M. D. Pharm. Acta Helv. 2000, 74, 115.
7. (a) Glennon, R. A.; Dukat, M. Pharm. Acta Helv. 2000,
74, 103; (b) Baraznenok, I. L.; Jonsson, E.; Claesson, A.
Bioorg. Med. Chem. Lett. 2005, 15, 1637; (c) Dong, J. C.;
Wang, X.; Li, R. T. Bioorg. Med. Chem. Lett. 2003, 13,
4327; (d) Lee, M.; Dukat, M.; Liao, L.; Flammia, D.;
Damaj, M. I.; Martin, B.; Glennon, R. A. Bioorg. Med.
10. Evans, D. A.; Scheidt, K. A.; Downey, C. W. Org. Lett.
2001, 3, 3009.
11. Li, R. T.; Cai, J. C.; Tang, X. C.; Cai, M. S. Arch. Pharm.
Pharm. Med. Chem. 1999, 332, 179.