1-Phenyl-8-azabicyclo[3.2.1]octane ethers: A novel series of neurokinin (NK1) antagonists

Article abstract of DOI:10.1016/j.bmcl.2005.12.069

1-Phenyl-8-azabicyclo[3.2.1]octane ethers are NK₁ receptor antagonists. Substitution at the 6-exo-position led to high affinity NK ₁ antagonists with a prolonged duration of action in vivo. Incorporation of an α-methyl substituent in

Full text of DOI:10.1016/j.bmcl.2005.12.069

Bioorganic & Medicinal Chemistry Letters 16 (2006) 2008–2012
1-Phenyl-8-azabicyclo[3.2.1]octane ethers: A novel series
of neurokinin (NK1) antagonists
Ian T. Huscroft,a,* Emma J. Carlson,b Gary G. Chicchi,c Marc M. Kurtz,c Clare London,a
Piotr Raubo,a Alan Wheeldonb and Janusz J. Kulagowskia
aDepartment of Medicinal Chemistry, Merck Sharp & Dohme Research Laboratories, The Neuroscience Research Centre,
Terlings Park, Harlow, Essex CM20 2QR, UK
bDepartment of in vivo Neuroscience, Merck Sharp & Dohme Research Laboratories, The Neuroscience Research Centre,
Terlings Park, Harlow, Essex CM20 2QR, UK
cDepartment of Biochemistry, Merck Research Laboratories, 126 E.Lincoln Avenue, Rahway, NJ 07065, USA
Received 18 November 2005; revised 19 December 2005; accepted 19 December 2005
Available online 18 January 2006
Abstract—1-Phenyl-8-azabicyclo[3.2.1]octane ethers are NK1 receptor antagonists. Substitution at the 6-exo-position led to high
affinity NK1 antagonists with a prolonged duration of action in vivo. Incorporation of an a-methyl substituent in the pendent benzyl
ether side chain gave compounds with increased selectivity over the hERG channel.
Ó 2006 Elsevier Ltd. All rights reserved.
Research at Merck into selective non-peptide NK1
antagonists Òculminated in the identification of Aprepit-
ant (Emend )1 as a potent, orally active drug suitable
for the treatment of both the acute and delayed phases
of chemotherapy induced nausea and vomiting.2
bromo-3-hydroxypyridine (Scheme 1). 1,3-Dipolar
cycloaddition of the betaine 3 with phenyl vinyl sulfone
afforded the cycloadduct 4 as the predominant epimer.
Hydrogenation of the double bond followed by reduc-
Since 1991, when the first non-peptidic NK1 receptor
antagonist was reported by Pfizer,3 numerous selective
and structurally diverse NK1 antagonists have been
identified (e.g., 1).4 As part of our effort in this area,
we have been actively investigating conformationally
restricted piperidine derivatives (e.g., 2) of known NK1
receptor antagonists (Fig. 1).
The key synthetic transformation used in the prepara-
tion of analogues of 2 and a related benzylamine series5
was a [3 + 2] cycloaddition reaction6 (Schemes 1 and 2).
C-6 bridge substituents were introduced using this meth-
odology. Herein, we will focus on the preparation of tet-
razoles as the C-6 substituent (Schemes 2 and 3).
1-Benzyl-3-hydroxy-2-phenylpyridinium bromide 3 was
prepared in two steps from commercially available 2-
Keywords: NK1 receptor antagonist; Drug design and synthesis.
*
Corresponding author. Tel.: +44 1279 440434; fax: +44 1279
440288; e-mail: ian_huscroft@merck.com
Figure 1.
0960-894X/$ - see front matter Ó 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmcl.2005.12.069

I. T. Huscroft et al. / Bioorg. Med. Chem. Lett. 16 (2006) 2008–2012
2009
Scheme 1. Reagents and conditions: (i) PhB(OH)2, Pd(PPh3)4, NaHCO3, toluene, H2O; (ii) benzyl bromide, toluene; (iii) phenyl vinyl sulfone, 1,4-
dioxane, Et3N; (iv) separation of cycloadducts, SiO2; (v) Pd/C, H2, EtOH; (vi) NaBH4, MeOH, THF; (vii) 3,5-bis(trifluoromethyl)benzylbromide,
NaH, THF; (viii) Na(Hg), MeOH, THF; (ix) 3,5-bis(trifluoromethyl)benzoyl chloride, Et3N, DMAP, DCM; (x) dimethyl titanocene, toluene; (xi)
lithium naphthalenide, THF, À78 °C.
Scheme 2. Reagents and conditions: (i) acrylonitrile, 1,4-dioxane, Et3N; (ii) separation of cycloadducts, SiO2; (iii) Pd/C, H2, EtOH; (iv) NaBH4,
MeOH, THF; (v) 3,5-bis(trifluoromethyl)benzyl bromide, NaH, THF; (vi) NaN3, NH4Cl, DMF; (vii) MeI, K2CO3, DMF; (viii) regioisomer
separation, SiO2; (ix) 3,5-bis(trifluoromethyl)benzoyl chloride, Et3N, DMAP, DCM; (x) dimethyl titanocene, toluene; (xi) diastereomer separation,
SiO2.
tion of the ketone to the exo-alcohol 5 and alkylation
with 3,5-bis(trifluoromethyl)benzyl bromide afforded
the ether 6 from which the N-benzyl and phenyl sulfone
groups were successively removed to give 7 and 8.
in the gerbil foot-tapping assay (Table 1). We reasoned
that the polar phenyl sulfone fragment found in 11
would not be optimal for good brain penetration and
hence sought to replace this group in subsequent
compounds.
Esterification of the exo-alcohol 5 with 3,5-bis(trifluoro-
methyl)benzoyl chloride was followed by formation of
the enol ether 9 using the conditions developed by Peta-
sis.7 Hydrogenation and diastereomer separation gave
the a-methylbenzyl derivatives 11 and 12. Unsubstituted
compounds 13 and 14 were prepared in an analogous
fashion from 10 following reductive removal of the
phenyl sulfone from 5 (Scheme 1). Compound 11
(hNK1 0.6 nM) displayed only modest brain penetration
1,3-Dipolar cycloaddition of the betaine 3 with acryloni-
trile followed by chromatographic separation of the cyc-
loadducts and elaboration analogous to that described
in Scheme 1 gave the 6-exo-cyano alcohol 15. The 6-
endo-cyano analogue, 15a, was also isolated and utilized
subsequently (Scheme 3). Alkylation with 3,5-bis(trifluo-
romethyl)benzyl bromide followed by tetrazole forma-
tion, alkylation and N-benzyl deprotection gave the

2010
I. T. Huscroft et al. / Bioorg. Med. Chem. Lett. 16 (2006) 2008–2012
Scheme 3. Reagents and conditions: (i) TBSOTf, Et3N, DCM; (ii) NaN3, Et3NÆHCl, DMF; (iii) MEM-Cl, K2CO3, DMF; (iv) regioisomer
separation, SiO2, 24:24a = 1:1.5; (v) nBuLi, (PhSO)2NF, THF, 25:25a = 1:1; (vi) HCl, Et2O, MeOH; (vii) 3,5-bis(trifluoromethyl)benzyl bromide,
NaH, THF; (viii) PPh3, DEAD, THF, MeOH; (ix) Pd/C, H2, EtOH; (x) 3,5-bis(trifluoromethyl)phenyl diazo acetic acid methyl ester, Rh2(OAc)4,
DCE; (xi) LiBH4, Et2O; (xii) PPh3, I2, imidazole, DCM.
isomeric tetrazoles 16 and 17 (Scheme 2). Introduction
of an a-methylbenzyl substituent was achieved by ester-
ification of the exo-alcohol 15 with 3,5-bis(trifluoro-
methyl)benzoyl chloride followed by tetrazole
formation, alkylation and chromatographic regioisomer
separation. Formation of the enol ethers 18 and 19 was
carried out as described previously. Subsequent hydro-
genation and diastereomer separation gave the isomeric
pairs of a-methylbenzyl ethers, 20 and 21; 22 and 23
(Scheme 2).
quired. Rhodium (II) catalysed insertion of alcohol 25
with [3,5-bis(trifluoromethyl)phenyl]-diazo acetic acid
methyl ester11 yielded a 3.4:1 ratio of isomers with the
preferred (b) isomer the major product. Chromato-
graphic separation of the isomers followed by reduction
of the methyl ester and iodination of the resulting alco-
hol gave 27. Elaboration of 27 via MEM deprotection,
tetrazole N-methylation and hydrogenation resulted in
the desired a-methylbenzyl ether 28.
The data in Table 1 reveal that substitution at the 6-po-
sition of the bicyclic[3.2.1] ring system is tolerated. Com-
pound 7 bearing a 6-exo-phenylsulfonyl group shows
similar binding affinity for the hNK1 receptor as the par-
ent 8. Substitution of the pendent benzyl ether shows the
b-diasteromer 13 to be more potent than the a-analogue
14 (hNK1 IC50 200 nM). However, substitution at the
benzylic position on its own does not improve affinity
relative to the parent, 8. Interestingly, a combination
of 6-substituent coupled with an a-methylbenzyl frag-
ment gives rise to a more potent compound, 11.
Fluorine is commonly incorporated into biologically ac-
tive compounds since it gives rise tominimal steric impact,
whilst its electronegativity influences pKa.8 We wished to
examine the effect of reducing pKa on the hERG channel
liability.9 Elaboration of 15a gave the regioisomers 24 and
24a after chromatography (Scheme 3). Tetrazole deriva-
tives bearing a fluorine atom at the 6-endo-position were
prepared by fluorination of 24 with N-fluorobenzenesulf-
onamide. During the course of this transformation, epi-
merization of the C-6 position was observed. Removal
of the TBS group revealed the diastereomeric fluorides
25 and 25a. Etherification of 25 followed by removal of
the MEM group, regioselective tetrazole N-2 methylation
under Mitsunobu10 conditions and hydrogenation yield-
ed the fluorinated benzylether 26.
The N-2 methyl tetrazole derivative 17 exhibits high
affinity for the hNK1 receptor. The ability of 17 to occu-
py central hNK1 receptors in vivo was studied further.
Foot-tapping in gerbils is induced after central infusion
of the NK1 agonist GR 73632. This is a centrally medi-
ated response; dosing immediately prior to the agonist
challenge (GFTt=0) demonstrates that a compound is
brain penetrant. Dosing with 17 twenty-four hours prior
to the agonist challenge demonstrates duration of action
Hydrogenation of either of the enol ethers 18 or 19
resulted in variable ratios of epimers, typically with
the undesired (a) isomer predominant. Hence, an alter-
nate synthesis towards the a-methylbenzyl ethers was re-

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2011
Table 1. NK1 receptor binding, hERG channel activity and gerbil foot-tapping results for the azabicyclic series
R1
R2
R3
hERG Kib (nM)
Gerbil foot tapping ID50
mg/kg ivc
a
hNK1 IC50 (nM)
Compound
t = 0 h
t = 24 h
8
7
H
H
H
H
H
H
3
300
1300
H
PhSO2
H
PhSO2
2.8
4.2
0.6
13
11
Me
Me
1930
100
39% at 3
0.3
17
16
22
20
26
28
H
H
H
H
H
F
1.0
9.0
0.5
1.2
1.5
0.4
0.6
H
1250
Me
Me
H
1800
0.4
0.2
1.1
2800
0.8
>10,000
>5000
11% at 3
23% at 3
Me
F
Data are geometric means of 3–6 determinations.
a Displacement of [125I]-labelled substance P from the cloned hNK1 receptor expressed in CHO cells.12
b Displacement of [35S]-labelled MK-499 from the cloned receptor expressed in HEK cells.13
c Inhibition of GR 73632 induced foot-tapping in gerbils.14 Where an ID50 value was not determined, % inhibition at 3 mg/kg is quoted.
(GFTt=24h). Despite the excellent in vivo properties of
17, it is compromised by its hERG liability. In compar-
ison the N-1 methyl tetrazole, 16 displayed a lower
potency for the hERG channel although coupled with
lower affinity for the target receptor. Installation of an
a-methyl group (20 and 22) in the pendent bis(trifluoro-
methyl)benzyl ether resulted in an increase in hNK1
affinity over the corresponding unsubstituted analogues
(16 and 17). Both 20 and 22 retain excellent brain pene-
tration, duration of action and interestingly, an increase
in selectivity over hERG channel activity in both the N-
1 and N-2 methyl tetrazoles. There was a particularly
striking eighteen-fold reduction observed in the N-2
methyl tetrazole analogue 22 over the unsubstituted
derivative 17. Introduction of a fluorine atom (26 and
28) at the C-6 position of the azabicyclic ring maintained
the hNK1 affinity observed in the des-fluoro analogues
17 and 22 but dramatically increases the selectivity over
the hERG channel. Unfortunately, however, this was
accompanied by a reduction in the duration of action
in vivo (Table 1).
In conclusion, we have identified and evaluated a novel
series of NK1 receptor ligands. Introduction of a tetra-
zole moiety at the 6-exo-position of the 8-azabi-
cyclo[3.2.1]octane core led to the identification of 17
which showed both rapid CNS penetration and extend-
ed duration of action in vivo.
Introduction of an a-methyl substituent into the pen-
dent benzyl ether side chain attenuated the hERG activ-
ity whilst maintaining efficacy in the gerbil foot-tapping
assay. Finally we found that modulating the pKa of the
azabicycle significantly affected the hERG affinity in
vitro. However, incorporation of the fluorine atom
resulted in a reduction of efficacy in vivo.

2012
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9. Inhibition of the hERG channel is implicated as the
References and notes
underlying cause of cardiac disfunctions such as QT
interval prolongation and Torsades de Pointes: Finlayson,
K.; Withel, H. J.; McCulloch, J.; Sharkey, J. Eur. J.
Pharmacol. 2004, 500, 129.
1. Hale, J. J.; Mills, S. G.; MacCoss, M.; Finke, P. E.;
Cascieri, M. A.; Sadowski, S.; Ber, E.; Chicchi, G. G.;
Kurtz, M.; Metzger, J.; Eirmann, G.; Tsou, N. N.;
Tattersall, F. D.; Rupniak, N. M. J.; Williams, A. R.;
Rycroft, W.; Hargreaves, R.; MacIntyre, D. E. J. Med.
Chem. 1998, 41, 4607.
2. Dando, T. M.; Perry, C. M. Drugs 2004, 64, 777.
3. Snider, R. M.; Constantine, J. W.; Lowe, J. A., III; Longo,
K. P.; Lebel, W. S.; Woody, H. A.; Drozda, S. E.; Desai,
M. C.; Vinick, F. J.; Spencer, R. W.; Hess, H. J. Science
1991, 251, 435.
4. Harrison, T.; Wiliams, B. J.; Swain, C. J.; Ball, R. G.
Bioorg. Med. Chem. Lett. 1994, 4, 2545.
5. Thomson, C. G.; Carlson, E.; Chicchi, G. G.; Kulagowski,
J. J.; Kurtz, M. M.; Swain, C. J.; Tsao, K. C.; Wheeldon,
A. Bioorg. Med. Chem. Lett., in press.;
10. Purchase, C. F.; White, A. D. Synth. Commun. 1996, 26,
2687.
11. Lewis, R. T.; Ladduwahetty, T.; Merchant, K. J.; Keown,
L. E.; Hitzel, L.; Verrier, H.; Stevenson, G. I.; MacLeod,
A. M. J. Org. Chem. 2000, 65, 2615.
12. Cascieri, M. A.; Ber, E.; Fong, T. M.; Sadowski, S.;
Bansal, A.; Swain, C. J.; Seward, E. M.; Frances, B.;
Burns, D.; Strader, C. D. Mol. Pharmacol. 1992, 42,
458.
13. Cooper, L. C.; Carlson, E.; Castro, J. C.; Chicchi, G.;
Dinnell, K.; Di Salvo, J.; Elliott, J. M.; Hollingworth,
G. J.; Kurtz, M. M.; Ridgill, M. P.; Rycroft, W.; Tsao,
K.; Swain, C. J. Bioorg. Med. Chem. Lett. 2002, 12,
1759.
6. Kozikowski, A. P.; Araldi, G. L.; Ball, R. G. J. Org.
Chem. 1997, 62, 503.
7. Petasis, N. A.; Bzowej, E. I. J. Am. Chem. Soc. 1990, 112,
6392.
8. Welch, J. T.; Eswarakrishnan, S. In Fluorine in Bioorganic
Chemistry; John Wiley & Sons: New York, 1991; p 1.
14. Rupniak, N. M. J.; Tattersall, F. D.; Williams, A. R.;
Rycroft, W.; Carlson, E. J.; Casieri, M. A.; Sadowski, S.;
Ber, E.; Hale, J. J.; Mills, S. G.; MacCoss, M.; Seward, E.;
Huscroft, I.; Owen, S.; Swain, C. J.; Hill, R. G.;
Hargreaves, R. J. Eur. J. Pharmacol. 1997, 326, 201.