Spirocyclic NK1 antagonists II: [4.5]-spiroethers

Article abstract of DOI:10.1016/S0960-894X(02)00509-7

A series of novel spiroether-based neurokinin-1 (NK₁) antagonists is described. The effect of modifications to the spiroether ring and aromatic substituents are discussed, leading to the identification of compounds with high affinity and excellent CNS penetration.

Full text of DOI:10.1016/S0960-894X(02)00509-7

Bioorganic & Medicinal Chemistry Letters 12 (2002) 2719–2722
Spirocyclic NK1 Antagonists II: [4.5]-Spiroethers
Brian J. Williams,a,* Margaret A. Cascieri,c Gary G. Chicchi,c
Timothy Harrison,a Andrew P. Owens,a Simon N. Owen,a
Nadia M. J. Rupniak,b David F. Tattersall,b Angela Williamsb
and Christopher J. Swaina
aDepartment of Medicinal Chemistry, Merck Sharp & Dohme Research Laboratories,
The Neuroscience Research Centre, Terlings Park, Eastwick Road, Harlow, Essex, UK
bDepartment of Pharmacology, Merck Sharp & Dohme Research Laboratories,
The Neuroscience Research Centre, Terlings Park, Eastwick Road, Harlow, Essex, UK
cDepartment of Biochemistry, Merck Research Laboratories, Rahway, NJ 07065, USA
Received 2 May 2002; revised 18 June 2002; accepted 28 June 2002
Abstract—A series of novel spiroether-based neurokinin-1 (NK1) antagonists is described. The effect of modifications to the spiro-
ether ring and aromatic substituents are discussed, leading to the identification of compounds with high affinity and excellent CNS
penetration.
# 2002 Elsevier Science Ltd. All rights reserved.
The use of neurokinin-1 (NK1) antagonists for the
treatment of depression represents a breakthrough dis-
covery and provides the first novel therapeutic approach
to this disease for many years.1 In our previous paper2 we
described a conformational approach to the design of NK1
antagonists in which [5.5] and [4.5]-spiroketals 1 were used
as structural scaffolds to dispose key elements of the NK1
antagonist pharmacophore. The conformational pref-
erence of the spirocycle was influenced by stereoelectronic
stabilization afforded by the anomeric effect.3
We hypothesised that [4.5]spiroether equivalents 2 may
have improved acid stability than the corresponding spiro-
ketal even in the absence of a proximal basic nitrogen
atom. It was not clear, however, whether this change, that
of removing one of the anomeric oxygen atoms, would
result in compounds with a similar overall conformation
and hence retention of high affinity for the NK1 receptor.
In this communication we describe the synthesis and
NK1 antagonist activity of these [4.5]-spiroethers.
The spiropiperidines 2 were synthesized diastereoselec-
tively and in homochiral form from the resolved cis
(3S)-hydroxy-(2S)-phenylpiperidine 3.4 This route relied
on the stereoselective addition of the Grignard reagent 4
(Scheme 1) to homochiral N-protected (2S)-ketone 5
(Scheme 2).5a,6,9 Preparation of the Grignard reagent 4
required very careful activation of the magnesium to
allow formation at low to ambient temperatures in
order to prevent self condensation via attack of the
formed organometallic reagent on the allylic phenyl
ether system.7 Initially the Grignard reagent was trans-
metallated to the zincate 7,7 however similar yield and
chiral purity of the product 6 was obtained with either
organometallic species when the addition to the ketone 5
was performed slowly at 0ꢀC. Palladium mediated cycli-
zation of the allyl system 6 under basic conditions gave
excellent yields of the exocyclic allylic ether 8. Ozonolysis
*Corresponding author. Fax:+44-1279-440390; e-mail: brian_williams@
merck.com
0960-894X/02/$ - see front matter # 2002 Elsevier Science Ltd. All rights reserved.
PII: S0960-894X(02)00509-7

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B. J. Williams et al. / Bioorg. Med. Chem. Lett. 12 (2002) 2719–2722
Table 1. hNK1 Binding affinity of 3-styryl[4.5]-spiroether NK1
antagonists
Scheme 1. Reagents and conditions: (i) PhOH, NaH; (ii) Mg, 20 ꢀC,
THF; (iii) ZnBr2.
Compd
R
R0
NK1 IC50
(nM)a
Gerbil foot
tappingb
(ID50 mg/k iv)
13
14
2-OMe
2-OMe
H
5-OCF3
49
0.35
ND
0.2
15
2-OMe
0.08
0.1
aDisplacement of [125I]-labelled substance P from the cloned human
receptor expressed in CHO cells (ref 11). Values are IC50s and are
means of three experiments.
bFoot-tapping induced by the central infusion of an NK1-selective
agonist (GR 73632) (ref 12). Inhibition of foot tapping 5 min after
intravenous administration of antagonist.
Table 2. hNK1 Binding affinity of [4.5]-spiroether NK1 antagonists
Scheme 2. Reagents and conditions: (i) Boc2O, DCM; (ii) DMSO,
(COCl)2; (iii) Et3N, ꢁ40 to 0 ꢀC, ref 9; (iv) 4 or 7, THF, 0 ꢀC; (v) nBuLi
in hexanes, ZnCl2, THF; ((Ph)3P)4Pd; (vi) O3, DCM, MeOH, ꢁ80 ꢀC;
(vii) Me2S, rt, 16 h; (viii) NaHMDS, ꢁ80 ꢀC, 1 h, 9, ꢁ80 ꢀCꢁrt, THF.
Compd
R
R0
NK1 IC50
(nM)a
Gerbil foot
tappingb
(ID50 mg/k iv)
16
17
18
H
2-OMe
2-OMe
H
H
133
6.5
0.30
ND
ND
0.3
5-OCF3
19
2-OMe
0.11
0.1
aDisplacement of [125I]-labelled substance P from the cloned human
.
receptor expressed in CHO cells (ref 11). Values are IC50s and are
means of three experiments.
bFoot-tapping induced by the central infusion of an NK1-selective
agonist (GR 73632) (ref 12). Inhibition of foot tapping 5 min after
intravenous administration of antagonist.
Scheme 3. Reagents and conditions: (i) (nBu)6Sn2, ((Ph)3P)4Pd, LiCl,
Li2CO3, 60 ꢀC, 16 h,THF; (ii) Ar-Br, ((Ph)3P)4Pd, LiCl, toluene, 90 ꢀC,
20 h; (iii) TFA; (iv) H2, Pd/C; (v) Ar-B(OH)2, ((Ph)3P)4Pd.
hydrogenation which occurred from the more exposed
face, gave the desired epimer 2 with good facial selec-
tivity.5 The presence or absence of the Boc- protecting
group during the hydrogenation step had little influence
on the epimeric ratio of the hydrogenation (3-S: 3-R
95:5). 1H NMR evidence confirmed the oxygen sub-
stituent adopts an axial conformation with respect to
the piperidine ring in spiroethers 2 as desired.
to the ketone and regioselective enol triflate formation
with 2-[N,N-bis(trifluoromethylsulfonyl)amino]-5-chloro-
pyridine8 (9) gave the enol triflate 10 as a single regio-
isomer in 88% yield.
Formation of the vinyl stannane 11 (Scheme 3) was
achieved by reaction of 10 with hexabutylditin and cat-
alytic palladium (0). Subsequent palladium catalysed
cross coupling with the appropriate aryl bromide10
afforded the styrene derivatives 12. Alternatively, Suzuki
coupling of the triflate 10 with phenylboronic acid pro-
vided access directly to the styrene derivative 12 (R=H).
Deprotection under acidic conditions, followed by
This synthesis strategy gives access to the
(3S,5R,6S)aryl- substituted [4.5]spiropiperidines with
good diastereo and enantio control. We have recently
reported5 conditions which enhance and extend this
synthetic approach and which provide access to epimers
from both (3S)aryl and (3R)aryl- series.

B. J. Williams et al. / Bioorg. Med. Chem. Lett. 12 (2002) 2719–2722
2721
The NK1 tachykinin activity11 of these compounds was
next determined. Comparable activity was seen for both
the unsaturated derivatives (Table 1) and the saturated
3-aryl bicycles (Table 2). The unsubstituted 3-phenyl
[4.5]bicycle 16 showed weak affinity for the NK1 recep-
tor (Table 2), however introduction of a 2-methoxy
substituent (17) improved affinity 20 fold (IC50 6.5 nM).
Table 4. Anti-emetic response (ferret) of 18 and 19 after intravenous
and oral routes of administration
Compd
Inhibition of emetic responsea ID90 mg/kg
iv
po
18
19
1
0.2
3
1
aCompounds were administered iv or po following emetogen challenge
after 3 min (iv experiments) or 60 min (po experiments) (see ref 13).
Drug vehicle (control) was PEG 300 (iv experiment) or 0.5% Metho-
cell (po experiment).
The 2,5-aryl substitution pattern, which was found pre-
viously to be optimal in the spiroketal series,2 again
provided high affinity NK1 antagonists in the spiroether
series. Incorporation of 5-trifluoromethoxy group or
5-trifluoromethyltetrazol-1-yl afforded high affinity
compounds 18 (IC50 0.30 nM) and 19 (IC50 0.11 nM)
respectively.
triazolinone 21 and imidazole 22 substituents retained
high in vitro affinity comparable to 19. However, com-
pounds 20 and 21 showed a significantly attenuated
response in vivo as shown by inhibition of the foot-tap-
ping response in gerbils.
The ability of key compounds to block central NK1
receptors was assessed by their ability to inhibit the
foot-tapping in gerbils immediately following central
administration of GR73632.12 Excellent inhibitory
activity was seen 5 min after intravenous administration
of both 19 (ID50 0.1 mg/kg) and 18 (ID50 0.3 mg/kg)
indicating rapid penetration of these compounds into
the CNS.
Preclinical studies in ferrets have demonstrated that the
retching and vomiting induced by emetogens such as
cisplatin can be attenuated by pre-administration of an
NK1 receptor antagonist.13 Inhibition of the emetic
response (Table 4) was seen after oral administration of
18 (po ID90 3mg/kg ) and 19 (po ID90 1 mg/kg)) sug-
gesting that these compounds were well absorbed and
had excellent CNS penetration. Compound 19 had a
favorable pharmacokinetic profile in two additional
species (bioavailability F=16%, t1/2 1.7 h rat and
F=79%, t1/2 2.7 h dog).
Table 3 shows the effect on activity of incorporating
additional N-substituents to compounds 18 and 19.
Although the affinity of the triazole 20 was reduced
marginally compared with the unsubstituted 18, the
Table 3. hNK1 Binding affinity of [4.5]-spiroether NK1 antagonists
In conclusion, compounds from the [4.5]-spiropiper-
idine series and the structurally related [4.5]-spiroketal
series2 show similar solution conformations (NMR)
despite the absence of an anomeric effect in the former
class. [4.5]Spiroethers are high affinity antagonists at the
NK1 receptor. They have been shown to have rapid
CNS penetration (gerbil foot tapping) after intravenous
administration and are active orally in the ferret against
emesis induced by cisplatin treatment.
Compd
R
X
NK1 IC50
(nM)a
Gerbil foot
tappingb
(% inhib or
ID50 mg/kg iv)
Acknowledgements
18
20
–OCF3
–OCF3
H
0.30
0.89
0.3
The authors would like to thank M. Kurtz for re-titrat-
ing the compounds for publication and to R. Herbert
and S. Thomas for NMR studies and H. Verrier for
chiral hplc determination of enantiomeric excess.
(45% inhib@1 mg/kg)
19
21
22
H
0.11
0.10
0.11
0.1
(6% inhib@1 mg/kg)
0.5
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bFoot-tapping induced by the central infusion of an NK1-selective
agonist (GR 73632) (ref 12). Inhibition of foot tapping 5 min after
intravenous administration of antagonist.

2722
B. J. Williams et al. / Bioorg. Med. Chem. Lett. 12 (2002) 2719–2722
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