Synthesis and structure-activity relationships of 8-azabicyclo[3.2.1]octane benzylamine NK1 antagonists

Article abstract of DOI:10.1016/j.bmcl.2005.11.026

A series of 8-azabicyclo[3.2.1]octane amine hNK₁ antagonists has been investigated and structure-activity relationships of the benzylamine and 6-exo substituents described. Acidic substituents at C6 give a series of high affinity compounds for

Full text of DOI:10.1016/j.bmcl.2005.11.026

Bioorganic & Medicinal Chemistry Letters 16 (2006) 811–814
Synthesis and structure–activity relationships of
8-azabicyclo[3.2.1]octane benzylamine NK1 antagonists
Christopher G. Thomson,a,* Emma Carlson,b Gary G. Chicchi,c Janusz J. Kulagowski,a
Marc M. Kurtz,c Christopher J. Swain,a Kwei-Lan C. Tsaoc and Alan Wheeldonb
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 Immunology, Merck Research Laboratories, 126 E.Lincoln Ave, Rahway, NJ 07065, USA
Received 20 October 2005; revised 7 November 2005; accepted 7 November 2005
Available online 22 November 2005
Abstract—A series of 8-azabicyclo[3.2.1]octane amine hNK1 antagonists has been investigated and structure–activity relationships
of the benzylamine and 6-exo substituents described. Acidic substituents at C6 give a series of high affinity compounds for hNK1
with selectivity over the hERG channel.
Ó 2005 Elsevier Ltd. All rights reserved.
The action of the mammalian tachykinin, substance P,
at the human neurokinin-1 (hNK1) receptor has been
implicated in inflammatory conditions such as
migraine,1 rheumatoid arthritis,2 asthma3 and
inflammatory bowel disease,4 as well as mediation of
the emetic reflex.5 Hence, non-peptide antagonists for
the hNK1 receptor in the central nervous system are
potential therapeutic agents for these indications.
hNK1 antagonists, a two carbon bridge was appended
to the positions adjacent to the endocyclic nitrogen, to
give a series of 8-azabicyclo[3.2.1]octanes such as 1b.
Synthesis of this series centres upon a [3+2] cycloaddition
reaction (Scheme 1) givingthe azabicyclic core with varied
substitution on the bridge. This core can be readily mod-
ified to give ethers via reduction of the ketone produced
followed by alkylation or amines by reductive amination.
Both C6 and C7, exo and endo isomers at the bridge are
formed in the cycloaddition, but these are separable by
CP-122721
1b
Compound CP-122721 is a high affinity antagonist at
hNK1 (hNK1 IC50 0.14 nM).6 To explore conformation-
ally restrained piperidine derivatives of CP-122721 as
Keywords: Bicyclic diamine; Azabicyclo[3.2.1]octane; NK1 antagonist;
Substance P; Selectivity.
*
Scheme 1. Reagents: (i) PhCH2Br, toluene, followed by ion exchange;
(ii) vinyl-R, 1,4-dioxane; (iii) Pd/C, MeOH, EtOAc, H2; (iv)
PhCH2NH2, TsOH, toluene; (v) NaBH4, MeOH.
Corresponding
christopher_thomson@merck.com
author.
Tel.:
+44
1279440563; e-mail:
0960-894X/$ - see front matter Ó 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmcl.2005.11.026

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C. G. Thomson et al. / Bioorg. Med. Chem. Lett. 16 (2006) 811–814
chromatography and crystallisation. Early studies of
structure–activity relationships (SAR) in a related ether
series7 showed the 6-substituted compounds to have
higher affinity than 7-substituted isomers at hNK1. The
reaction was carried out in an analogous manner using
2-(4-fluorophenyl)-3-hydroxypyridine to give the corre-
sponding 4-fluorophenyl bicyclic core, in an attempt to
block metabolism at the 4-position of the phenyl group.
This had little effect on binding to hNK1 or hERG
receptors.
Studies showed that the C2 amine gave higher affinity
compounds if exo to the bicyclic core. Reduction of
the imine formed from condensation of benzylamine
and the ketone with sodium borohydride gave an exclu-
sively exo-benzylamine rather than the exo/endo mixture
obtained by reduction with sodium cyanoborohydride.
Scheme 3. Reagents: (i) Pd/C, NH4O2CH, EtOH; (ii) ArCHO,
NaBH(OAc)3, DCE; (iii) Na/Hg, Na2HPO4, MeOH.
Bicyclic diamines substituted with 6-exo cyano, tert-butyl
ester and phenyl sulfone groups could be obtained using
this methodology, and these were further manipulated
to give a range of functionalities such as tetrazole and
hydroxymethyl at C6 (Scheme 2).
The benzyl-protecting groups were removed by hydrog-
enolysis (Scheme 3) and the less sterically hindered
exo-amine reacted with a substituted benzaldehyde by
reductive amination to yield the target compounds. In
the case of the phenyl sulfone derivative, removal of
the benzyl groups first, followed by reductive cleavage
of the carbon–sulfur bond of 2a, provided the most
efficient route to 2b.
The tert-butyl ester group could be carried through the
synthesis to give a late stage intermediate (3) (Scheme
4). This could be deprotected to give the diamino acid
(4), which was further elaborated to give acyl sulfona-
mides and amides. The primary amide was reduced
to the amino methyl compound, and this reacted with
sulfonyl chlorides to give sulfonamides. Attempts to
convert the 6-hydroxymethyl compound (5a) to the
corresponding halide or mesylate, followed by displace-
ment by sulfonamides, resulted in very poor yields.
Scheme 4. Reagents: (i) TFA, DCM; (ii) N,N0-carbonyldiimidazole,
Et3N, NH3, THF; (iii) N,N0-carbonyldiimidazole, Et3N, RSO2NH2,
THF; (iv) BH3ÆSMe2, toluene; (v) RSO2Cl, NaOH, DCM, H2O.
The diamino acid (6) could be used to form 1,2,4-triazol-
3-one on the bridge by condensation with semicarbaz-
ide, followed by cyclisation under basic conditions
(Scheme 5). The benzyl groups were removed, and the
exo-amine reductively alkylated as in Scheme 3 to give
5e.
Scheme 5. Reagents and condition: (i) semicarbazide HCl, BOP-Cl,
Et3N, DCM; (ii) 1 M aqueous NaOH, reflux.
high affinity at the hNK1 receptor in other series, were
explored (Table 1).
Initially, a number of substitution patterns on the
benzylamine side chain, which are known6,8,9 to exhibit
The bicyclic core followed the trend displayed by CP-
122721 and analogues by requiring 2,5-disubstitution
on the benzylamine for maximum affinity, with 2-meth-
oxy (1b) or cyclopropoxy (1c) 5-trifluoromethoxy
compounds giving sub-nanomolar affinity. These
compounds showed significant binding to the hERG
channel,12 however. This could be alleviated in 1d with
a 2-chloro substituent, reducing the hERG affinity to a
micromolar level, but to the detriment of hNK1 affinity.
Therefore, the benzylamine substitution in 1c was
chosen to continue SAR studies in this series.
Scheme 2. Reagents: (i) NaN3, Et3NÆHCl, NMP; (ii) DIBAL-H,
toluene.

C. G. Thomson et al. / Bioorg. Med. Chem. Lett. 16 (2006) 811–814
813
Table 1.
Table 2.
a
Compound
Ar
hNK1 IC50
(nM)
hERG Kib
(nM)
a
Compound
R
H
X
H
hNK1 IC50
(nM)
hERG Kib
(nM)
1c
0.10
0.11
0.09
0.24
1.0
360
CP-122721c
0.14
1800
5a
5b
5c
4
H
F
F
F
H
270
420
1a
1b
3
—
190
0.13
240
CO2H
4800
>6000
5d
0.65
1c
1d
0.10
360
5e
5f
F
F
0.61
1.2
5800
>5000
2.1
1400
5g
F
0.27
>6000
Values represent geometric means of three determinations.
a Displacement of [125I]-labelled substance P from the cloned receptor
expressed in CHO cells.10
Values represent geometric means of three determinations.
a Displacement of [125I]-labelled substance P from the cloned receptor
expressed in CHO cells.10
b Displacement of [35S]-labelled MK-499 from the cloned channel
expressed in HEK cells.11
b Displacement of [35S]-labelled MK-499 from the cloned channel
expressed in HEK cells.11
c CP-122721 is a single enantiomer. All 8-azabicyclo[3.2.1]octanes are
racemic.
A wide variety of substituents are tolerated at the 6-exo
position (Table 2) showing that both large and polar
groups give compounds of high hNK1 affinity and can
also modulate hERG affinity. It was not until intermedi-
ate 4 was profiled that it became apparent that acidic
groups in this position maintain the good hNK1 affinity,
but have a marked effect on hERG.
the compounds bearing acidic substituents were inactive
in this assay, indicating a potential lack of brain
penetration.
A series of 8-azabicyclo[3.2.1]octane benzylamines has
been explored leading to high affinity hNK1 ligands.
Inhibition of the hERG channel can be significantly
reduced by substitution at the 6-position with acidic
groups, whilst maintaining this high hNK1 affinity.
However, substitution with these acidic groups also
abolishes in vivo activity.
The acidic heterocycles 5d and 5e show improved selectiv-
ity for hNK1 over hERG, as does the acidic methyl acyl
sulfonamide, 5f. Replacement of the methyl with phenyl
gave the highest affinity and the most selective compound
from the series, the phenyl acyl sulfonamide, 5g.
References and notes
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gerbil foot-tap assay,13 a measure of NK1 activity in the
brain. Compounds 1c and 5a showed activity, with an
ID50 of 2.6 and 1.1 mg/kg, respectively. Unfortunately,
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