3-(2-Pyrrolidin-1-ylethyl)-5-(1,2,3,6-tetrahydropyridin-4-yl)-1H-indole derivatives as high affinity human 5-HT1B/1D ligands

Article abstract of DOI:10.1016/j.bmcl.2003.11.023

A series of 3-(2-pyrrolidin-1-ylethyl)-5-(1,2,3,6-tetrahydropyridin-4-yl)- 1H-indole derivatives (2) has been prepared using parallel synthesis techniques, and their structure-activity relationships studied. High affinity human 5-HT_1B/1D (h5-HT_1B/1D) ligands have been identified.

Full text of DOI:10.1016/j.bmcl.2003.11.023

Bioorganic & Medicinal Chemistry Letters 14 (2004) 727–729
3-(2-Pyrrolidin-1-ylethyl)-5-(1,2,3,6-tetrahydropyridin-4-yl)-1H-
indole derivatives as high affinity human 5-HT1B/1D ligands
Ian Egle,* Neil MacLean, Lidia Demchyshyn, Louise Edwards, Abdelmalik Slassi
and Ashok Tehimy
NPS Pharmaceuticals Inc., 6850 Goreway Dr., Mississauga, Ontario, Canada L4V 1V7
Received 16 September 2003; revised 12 November 2003; accepted 13 November 2003
Abstract—A series of 3-(2-pyrrolidin-1-ylethyl)-5-(1,2,3,6-tetrahydropyridin-4-yl)-1H-indole derivatives (2) has been prepared using
)
parallel synthesis techniques, and their structure–activity relationships studied. High affinity human 5-HT1B/1D (h5-HT1B/1D
ligands have been identified.
# 2003 Elsevier Ltd. All rights reserved.
Migraine is a serious and debilitating disease with pro-
found economic impacts. Over 200 million people
worldwide suffer from at least occasional migraine
attacks. The experience of these episodes varies, but can
typically be characterized by intense unilateral headache
pain, often accompanied by secondary symptoms
including nausea and vomiting, photophobia, and pho-
nophobia.1,2 The prototypical pharmacotherapy for
migraine is sumatriptan. It is a mixed h5-HT1B/1D
receptor agonist, with Ki values of 3.4 and 7.7 nM at the
h5-HT1D and h5-HT1B receptors, respectively.3 Suma-
triptan is contraindicated in patients with coronary
heart disease, as it can cause coronary artery constric-
tion leading to angina-like effects.4,5 It also possesses
poor oral bioavailability and a limited half-life, leading
to a tendency for the migraine attack to reoccur. These
liabilities have left room for the introduction of several
new antimigraine triptans. While these have shown sig-
nificant improvement in bioavailability and duration of
action, the majority of them have still been shown to
contract the human coronary artery in vitro,6 and up
to 40% of all attacks and up to 25% of all patients do
not respond to any of these drugs.7
the vasoconstrictive effects of the triptans, as many of
these drugs are potent 5-HT1B agonists. Both 5-HT1B
and 5-HT1D are found in human trigeminal ganglia.
Electrical stimulation of the trigeminal nerves induces
release of neuropeptides such as calcitonin gene-related
peptide (CGRP). CGRP levels are found to be elevated
during a migraine attack, and these levels are normal-
ized by sumatriptan. Subsequently, plasma protein
extravasation into the dura occurs, resulting in vasodi-
lation, inflammation and pain. Although still under
debate,8,9 this neurogenic hypothesis has been the
impetus for the search for h5-HT1D agonists that are
4
selective over h5-HT1B
.
Our efforts in the field of h5-HT1D selective agonists led
to the discovery of ALX-0646 (1). This potent and
selective ligand has a Ki of 8ꢀ1and 610 ꢀ147 nM for
h5-HT1D and h5-HT1B respectively, with a h5-HT1B/h5-
HT1D ratio of 76.10,11 It is currently in development for
the acute treatment of migraine.12
There are abundant levels of functional 5-HT1B recep-
tors in vascular smooth muscle. This has led to the
hypothesis that activity at this receptor might underlie
* Correspondence author. Tel.: +1-905-677-0831; fax: +1-905-677-
9595; e-mail: iegle@npsp.com
Present address: Memory Pharmaceuticals Corp., 100 Philips Park-
way, Montvale, New Jersey 07645, USA.
As a continuation of our efforts in this field,13 this paper
relates the results of one of our endeavors to determine
the effect of changing both the N,N-dialkylethylamine
y
0960-894X/$ - see front matter # 2003 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmcl.2003.11.023

728
I. Egle et al. / Bioorg. Med. Chem. Lett. 14 (2004) 727–729
Scheme 1. (a) Oxalyl chloride, DMF, CH2Cl2, then pyrrolidine; (b) LiAlH4, THF, Á; (c) NaHMDS, TBSCl, DMF, 0 ꢁC; (d) tBuLi, THF, ꢂ78 ꢁC,
then N-Boc-4-piperidone; (e) 30% TFA/CH2Cl2, Á; (f) RNCO, CH2Cl2, or RNCS, CH2Cl2, or RSO2Cl, Et3N, CH2Cl2.
Table 1. Binding profile of series 2 at the cloned human h5-HT1B and h5-HT1D receptors
Compd
X
R
h5-HT1D Ki (nM)a
h5-HT1B Ki (nM)a
Ki (h5-HT1B)/
Ki(h5-HT1D
)
Sumatriptan
3.43
7.73
2a
2b
2c
2d
2e
2f
2g
2h
2i
SO2
SO2
SO2
SO2
4-MeOPh
1-Napthyl
4-ClPh
4-MePh
Ph
4-ClPh
cyclohexyl
1-Adamantyl
Ph
4-MeOPh
4-MePh
1-Napthyl
Cyclohexyl
1-Adamantyl 70
Ph
11ꢀ0
1
ꢀ40
40
0
13
15
12
12
21
27ꢀ0
41 ꢀ100
110ꢀ20
9.3ꢀ0.7
12ꢀ2
1
ꢀ20
40
SO2
21ꢀ2
440ꢀ150
82ꢀ1
NHCO
NHCO
NHCO
NHCO
NHCO
NHCO
NHCO
NHCS
NHCS
NHCS
NHCS
NHCS
NHCS
NHCS
H
6.1ꢀ2.6
29ꢀ9
8
1
1
ꢀ0
64ꢀ6
40ꢀ3
44ꢀ12
63ꢀ20
65ꢀ13
38ꢀ8
ꢀ20
30
4.4
29ꢀ7
2.2
4.6
5.6
7.4
7.6
3.5
5.9
7.2
3.0
9.3
4.4
8.6ꢀ1.0
7.8ꢀ0.4
8.5ꢀ0.6
8.8ꢀ0.0
11ꢀ0
2j
2k
2l
2m
2n
2o
2p
2q
2r
2s
8
29ꢀ11
9.5ꢀ0.3
12ꢀ2
68ꢀ9
36ꢀ8
58ꢀ8
32ꢀ4
95ꢀ16.0
4-ClPh
4-MeOPh
4-MePh
1-Napthyl
6.2ꢀ1.5
7.4ꢀ0.6
16ꢀ2
74ꢀ6
760ꢀ40
10
a Ki values are reported as the mean of two independent determinationsꢀSEM.
substituent at position 3 of the indole nucleus, and the
substituent on the nitrogen of the tetrahydropyridine
ring of 1, yielding compounds of the general structure 2.
Compounds for this study were prepared from 5-bro-
moindole as illustrated in Scheme 1. 5-Bromoindole (3)
was acylated at the 3-position with oxalyl chloride, and the
intermediate acid chloride was trapped in situ with pyrro-
lidine to provide the a-carbonyl amide 4.14 Following
reduction with excess of LiAlH4 and protection of the
indole nitrogen,15 lithium-halogen exchange and trap-
ping with N-Boc-4-piperidone yielded the tertiary alco-
hol 7.16 Treatment of this compound with
trifluoroacetic acid (TFA) simultaneously eliminated the
alcohol, and removed the TBDMS and t-butoxy-
carbonyl protecting groups to provide the key inter-
mediate 8,17 from which all of the compounds in this

I. Egle et al. / Bioorg. Med. Chem. Lett. 14 (2004) 727–729
729
series could be synthesized using standard parallel
synthesis acylation techniques.18
8. Humphrey, P. P. A.; Goadsby, P. J. Cephalalgia 1994, 14,
401.
9. Longmore, J.; Dowson, A. J.; Hill, R. G. Curr. Opin.
CPNS Invest. Drugs 1999, 1, 39.
10. Isaac, M.; Slassi, M. Idrugs 2001, 4, 189.
11. Slassi, A.; Isaac, M.; Arora, J. Exp. Opin. Ther. Patents
2001, 11, 625.
12. Kamboj, R. IBC’s 3rd Annual Conference on Migraine:
Novel Drugs and Therapeutic Development. Philadel-
phia, PA, USA 1999.
13. Egle, I.; MacLean, N.; Demchyshyn, L.; Edwards, L.; Slassi,
A.; Tehim, A. Bioorg. Med. Chem. Lett. 2003, 13, 3419.
14. Slassi, A.; Edwards, L.; O’Brien, A.; Meng, C. Q.; Xin, T.;
Seto, C.; Lee, D. K. H.; MacLean, N.; Hynd, D.; Chen,
C.; Wang, H.; Kamboj, R.; Rakhit, S. Bioorg. Med.
Chem. Lett. 2000, 10, 1707.
The affinities of the compounds 2a–s and the inter-
mediate 8 for the cloned human 5-HT1B and 5-HT1D
receptors are depicted in Table 1.19 All final compounds
reported here exhibited good affinity for the h5-HT1D
receptor, with Ki values ranging from 6.1to 29 nM for
compounds 2f and 2h respectively. Selectivity over h5-
HT1B was modest however, the best compound having
an h5-HT1B/h5-HT1D ratio of 21:1 (compound 2e). As a
result, functional activity of this class of ligands was not
investigated.
There was no significant difference between the ureas
and thioureas, while the sulphonamides were typically
less potent but more selective. The affinities of the com-
pounds were not found to be particularly sensitive to
the nature of the lipophilic R group, however aromatic
groups were somewhat preferred over aliphatic groups.
Smaller alkyl groups provided compounds with weak
affinity (% inhibition data only, not shown), suggesting
that the substituent at this position might be interacting
with a hydrophobic pocket within the receptor. Com-
pound 8, where the substituent on the nitrogen was
merely a hydrogen atom, exhibited an order of magni-
tude drop in affinity for both receptors.
15. Slassi, A.; Arora, J.; Tehim, A. WO Patent 2000004019,
2000.
16. A solution of 6 (1.07 g, 2.63 mmol) in anhydrous THF (20
mL) was chilled in a dry ice/acetone bath. A 1.7 M solu-
tion of t-butyllithium in pentane (3.8 mL, 6.56 mmol) was
added dropwise. After 1h a solution of 4-oxopiperidine-1-
carboxylic acid t-butyl ester (1.12 g, 5.65 mmol) in THF
(10 mL) was added dropwise. The reaction was warmed to
room temperature. After 2 h the reaction was quenched
with pH 7 buffer and extracted with EtOAc. The organic
phase was washed with water and brine, dried (MgSO4),
filtered, and concentrated. Column chromatography (1%
NH4OH, 4% MeOH, 95% CH2Cl2) provided 7 (0.67 g,
48%) as a yellow oil. 7: 1H NMR (300 MHz, CDCl3) d
0.55 (s, 6H), 0.91 (s, 9H), 1.48 (s, 9H), 1.78–1.83 (m, 5H),
1.95–2.18 (m, 3H), 2.61 (s, 4H), 2.74 (t, 2H), 2.90 (t, 2H),
3.30 (t, 2H), 4.00 (br s, 2H), 6.98 (s, 1H), 7.28 (d, 1H),
7.42 (d, 1H), 7.70 (s, 1H).
In summary, a series of highly affinitive h5-HT1B/1D
ligands has been identified using parallel synthesis tech-
niques. Several compounds with nanomolar affinity for
the h5-HT1D receptor were developed.
17. Indole 7 (0.67 g, 1.27 mmol) was dissolved in CH2Cl2 (7
mL) and trifluoroacetic acid (3 mL). The solution was
refluxed for 21h, then cooled and washed with 1M
NaOH. The organic phase was dried (MgSO4), filtered,
and concentrated. Column chromatography (1% NH4OH,
2% MeOH, 97% CH2Cl2) provided 8 (113 mg, 30%) as an
References and notes
1
off-white solid. 8: H NMR (300 MHz, CDCl3) d 1.85 (t,
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4H), 2.50 (t, 2H), 2.59 (t, 4H), 2.80 (t, 2H), 2.99 (t, 2H),
3.15 (t, 2H), 3.58 (t, 2H), 6.13 (s, 1H), 7.02 (s, 1H), 7.23–
7.31(m, 2H), 7.62 (s, 2H), 7.97 (br s, 1H).
18. As a representative procedure, 8 (20 mg, 0.068 mmol) was
dissolved in anhydrous CH2Cl2 (2 mL). 1-Napthyl isocya-
nate (9.7 mL, 11 mg, 0.068 mmol) was added. After 4 h a
drop of methanol was added and the reaction mixture was
concentrated to provide 2l in quantitative yield. 2l: 1H
NMR (300 MHz, CDCl3) d 1.81 (s, 4H), 2.62 (s, 4H), 2.75
(s, 2H), 2.83 (t, 2H), 3.04 (t, 2H), 3.85 (t, 2H), 4.30 (s, 2H),
6.09 (s, 1H), 6.76 (s, 1H), 7.01 (s, 1H), 7.28–7.33 (m, 1H),
7.42–7.58 (m, 2H), 7.60–7.69 (m, 2H), 7.76 (d, 1H), 7.82–
7.95 (m, 2H), 8.22 (s, 1H).
6. Massen Van Den Brink, A.; Reekers, M.; Bax, W. A.;
Ferrari, M. D.; Saxena, P. R. Circulation 1998, 98, 25.
7. Diener, H.-C.; Limmroth, V. Exp. Opin. Investig. Drugs
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19. Audinot, V.; Newman-Tancredi, A.; Millan, M. J. Neuro-
pharmacology 2001, 40, 57.