2-Aryl indole NK1 receptor antagonists: Optimisation of the 2-aryl ring and the indole nitrogen substituent

Article abstract of DOI:10.1016/S0960-894X(01)00183-4

Novel 2-aryl indole hNK₁ receptor ligands were prepared utilising palladium cross-coupling chemistry of a late intermediate as a key step. Compounds with high hNK₁ receptor binding affinity and good brain penetration (e.g., 9d) were synthesised.

Full text of DOI:10.1016/S0960-894X(01)00183-4

Bioorganic & Medicinal Chemistry Letters 11 (2001) 1237–1240
2-Aryl Indole NK1 Receptor Antagonists: Optimisation of the
2-Aryl Ring and the Indole Nitrogen Substituent
Kevin Dinnell,a,* Gary G. Chicchi,d Madhumeeta J. Dhar,c Jason M. Elliott,a
Gregory J. Hollingworth,a Marc M. Kurtz,d Mark P. Ridgill,a Wayne Rycroft,b
Kwei-Lan Tsao,d Angela R. Williamsb and Christopher J. Swaina
aDepartment of Medicinal Chemistry, Merck, Sharp and Dohme Research Laboratories,
The Neuroscience Research Centre, Terlings Park, Harlow, Essex CM20 2QR, UK
bDepartment of Pharmacology, Merck, Sharp and Dohme Research Laboratories,
The Neuroscience Research Centre, Terlings Park, Harlow, Essex CM20 2QR, UK
cDepartment of Medicinal Chemistry, Merck Research Laboratories, 126 E. Lincoln Ave, Rahway, NJ, 07065, USA
dDepartment of Biochemistry, Merck Research Laboratories, 126 E. Lincoln Ave, Rahway, NJ, 07065, USA
Received 2 November 2000; revised 29 January 2001; accepted 14 March 2001
Abstract—Novel 2-aryl indole hNK1 receptor ligands were prepared utilising palladium cross-coupling chemistry of a late inter-
mediate as a key step. Compounds with high hNK1 receptor binding affinity and good brain penetration (e.g., 9d) were synthesised.
# 2001 Elsevier Science Ltd. All rights reserved.
The human neurokinin-1 (hNK1) receptor in the central
nervous system is a potential therapeutic target for a
number of indications, including chemotherapy-induced
emesis, anxiety and depression.1ꢀ3 This wide range of
indications has led to the development of various potent
NK1 antagonists.3
group is introduced early in the synthesis. An alter-
native approach which introduced the 2-aryl group at a
later stage in the synthesis was required in order to
conveniently optimise this group. This was achieved
using palladium catalysed Suzuki coupling reactions6 of
the key 2-bromoindole 2 with commercially available
boronic acids to give compounds of type 1. The 2-bro-
moindole 2 was synthesised from the commercially
available 5-methylindole by alkylation with acrylic acid
in the presence of acetic anhydride and acetic acid followed
by amide coupling using 1-(3-dimethylaminopropyl)-3-
ethyl carbodiimide (EDC) and 1-hydroxybenzotriazole
(HOBt) with 1-(2-methoxyphenyl)piperazine. This com-
pound was then selectively brominated in the 2-position
Compound 1e was a screening hit identified from a
combinatorial library4 comprising an array of 2-aryl
indoles with pendant amide substituents at the 3-posi-
tion which showed high affinity for the hNK1 receptor
(IC50 1.0 nM).5 The high binding affinity and structural
originality of 1e as an NK1 receptor antagonist made
this an excellent starting point for a medicinal chemistry
programme. Here we report the synthesis of a new series
of compounds where the importance of the nitrogen
substituent and 2-aryl ring substitution pattern for bio-
logical activity was investigated. The Fischer indole
synthesis used to synthesise the library did allow flex-
ibility in substitution of the 2-aryl ring, however this
Scheme 1. (i) Acrylic acid, Ac2O, AcOH, 3 days, rt; (ii) 1-(2-methoxy-
phenyl)piperazine hydrochloride, EDC, HOBt, Et3N, THF; (iii)
Me3SiBr, DMSO; (iv) ArB(OH)2, Pd(dppb)Cl2, Na2CO3, DME, 80 ꢁC.
*Corresponding author. Tel.: +44-1279-440403; fax: +44-1279-
440390; e-mail: kevin_dinnell@merck.com
0960-894X/01/$ - see front matter # 2001 Elsevier Science Ltd. All rights reserved.
PII: S0960-894X(01)00183-4

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K. Dinnell et al. / Bioorg. Med. Chem. Lett. 11 (2001) 1237–1240
using bromotrimethylsilane in dimethylsulfoxide7 to
give 2 (Scheme 1). A number of analogues of type 1
were then made and their corresponding biological
activities are shown in Table 1.
The results show that deletion of the 2-aryl ring was
detrimental to hNK1 receptor binding affinity (1a) and
that a substituent in the 4-position appears optimal (1b–
h), therefore, a range of analogues with 4-substituents
(1i–n) were synthesised using similar chemistry. Com-
pound 1n was prepared from compound 1e and phenyl
boronic acid using the Suzuki reaction conditions
described in Scheme 1.
Table 1.
A range of 4-substituents, including both electron with-
drawing (4-chloro) and electron donating (4-isopropyl)
groups improve binding affinity over the lead com-
pound 1e. The size of this substituent appears to be
significant as larger groups (tert-butyl, phenyl) are less
favoured. Replacement of the 2-phenyl ring with 4-pyr-
idyl (1m) also resulted in loss of binding affinity.
a
No.
Ar
H
hNK1 IC50
(nM)
Gerbil %b
inhibition
(mg/kg iv)
1a
1b
18% at 100ꢂ7%y
6.1ꢂ1.3
Selected compounds with high binding affinity for the
hNK1 receptor were tested for CNS activity in the gerbil
foot-tapping assay.8 In this protocol, the test compound
is administered iv immediately prior to icv injection of a
NK1 receptor agonist and a percentage inhibition of
foot-tapping is measured relative to control. Compound
1j showed good activity in this assay, demonstrating it is
a brain penetrant.
1c
89ꢂ9y
1d
1e
37% at 100ꢂ9%y
1.0ꢂ0.2
In order to further improve brain penetration, a series of
compounds was synthesised to remove the indole N/H
hydrogen bond donor and reduce the polarity of the
compounds.9 N-Alkylation of the indoles was achieved
using sodium hydride and a suitable electrophile as
depicted in Scheme 2. This series was synthesised bear-
ing a 5-chloro substituent which has been shown to give
high hNK1 receptor binding affinity.10 Reduction of the
ester 4f with lithium borohydride led to the alcohol 4g
(Scheme 3). The biological results are shown in Table 2.
46% at 3
1f
82ꢂ18
1g
8.0ꢂ2.0
These results suggest that there is only a limited space
available in the binding site in this region of the mole-
cule. N-Methylation (4b) improves affinity whereas lar-
ger groups, especially those with a- or b- branching, lose
binding affinity.
1h
1i
1.5ꢂ0.6
0.60ꢂ0.16
0.2ꢂ0.10
22% at 3
1j
100% at 3
1k
1l
6.3ꢂ4.3
0.44ꢂ0.13
58% at 100ꢂ8%y
7.6ꢂ4.0
Scheme 2. (i) NaH, DMF, RX.
1m
1n
aDisplacement of [125I]-labelled substance Pfrom the cloned hNK
receptor expressed in CHO cells (n=3) unless indicated (n=4)y.5
1
bInhibition of foot-tapping by iv administration of test compound
immediately prior to icv infusion of GR73632. The duration of foot-
tapping was recorded for 5 min and is expressed as a percentage inhi-
bition of values observed in vehicle-treated animals.8
Scheme 3. (i) LiBH4, PhCH3, THF.

K. Dinnell et al. / Bioorg. Med. Chem. Lett. 11 (2001) 1237–1240
1239
Two compounds with the 2-aryl substituent bridged to
the indole nitrogen were made using intramolecular
Heck reactions (Scheme 4).
A range of compounds were then N-methylated under
standard conditions (NaH, MeI, DMF) to give the final
compounds 7 (Table 3).
Comparison of these conformationally restricted ring-
fused compounds 5 (hNK1 55% at 100 nM) and 6
(hNK1 42% at 100 nM) with their closely related non-
fused analogues (e.g., 1b and 4b) suggests that the 2-aryl
group is not coplanar with the indole in the active con-
formation. It also provides a possible explanation for
the increased affinity of 4b over 4a; increasing the steric
bulk around the indole nitrogen by methylation forces
the 2-aryl group out of coplanarity and into a more
favourable conformation for binding.
It can be seen from the results that methylation of the
indole nitrogen consistently gave compounds with high
Table 3.
a
No.
Ar
hNK1 IC50
(nM)
Gerbilb (mg/kg iv)
% Inhib. ID50
0.5
Table 2.
7e
7i
0.14ꢂ0.08
0.11ꢂ0.05y
100% at 3
100% at 3
7j
7l
0.33ꢂ0.17
0.14ꢂ0.08y
100% at 3
93% at 3
a
No.
R
hNK1 IC50 (nM)
4a
0.89ꢂ0.36
4b
4c
0.28ꢂ0.14
5.2ꢂ3.3y
aDisplacement of [125I]-labelled substance Pfrom the cloned hNK
1
receptor expressed in CHO cells (n=3) unless indicated (n=4)y.5
bInhibition of foot-tapping by iv administration of test compound
immediately prior to icv infusion of GR73632. The duration of foot-
tapping was recorded for 5 min and is expressed as a percentage inhi-
bition of values observed in vehicle-treated animals. The ID50 was cal-
culated by non-linear least-squares regression analysis of mean data.8
4d
4e
4f
103ꢂ57
96ꢂ56
Table 4.
15ꢂ7
4g
0.97ꢂ0.47
a
b
No.
Ar
hNK1 IC50
(nM)
Gerbil ID50
(mg/kg iv)
aDisplacement of [125I]-labelled substance Pfrom the cloned hNK
receptor expressed in CHO cells (n=3) unless indicated (n=4)y.5
1
9a
9b
0.92ꢂ0.11
2.9ꢂ1.7y
9c
9d
0.12ꢂ0.10
0.12ꢂ0.06
0.68
0.1
aDisplacement of [125I]-labelled substance Pfrom the cloned hNK
receptor expressed in CHO cells (n=3) unless indicated (n=4)y.5
1
bInhibition of foot-tapping by iv administration of test compound
immediately prior to icv infusion of GR73632. The duration of foot-
tapping was recorded for 5 min and percentage inhibition of values
observed in vehicle-treated animals measured. The ID50 was calculated
by non-linear least-squares regression analysis of mean data.8
.
Scheme 4. (i) R2NH HCl, HOBt, EDC, Et3N, THF; (ii) 2-bromo-
benzyl bromide, NaH, DMF; (iii) 2-bromobenzoyl chloride, NaH,
DMF; (iv) Pd(PPh3)4, KOAc, DMA, 160 ꢁC.

1240
K. Dinnell et al. / Bioorg. Med. Chem. Lett. 11 (2001) 1237–1240
In contrast to the 4-pyridyl substituted derivative 1m,
which had poor binding affinity, these results showed
that it was possible to introduce a basic centre into the
2-aryl group and achieve excellent hNK1 receptor bind-
ing affinity. In addition, compound 9d (hNK1 IC50
0.12 nM) showed excellent activity in the gerbil foot-
tapping assay (ID50 0.1 mg/kg) which represents a sig-
nificant in vivo improvement over the lead compound
1e (46% at 3 mg/kg, iv).
Scheme 5. (i) Acrylic acid, Ac2O, AcOH, 3 days, rt; (ii) NaH, DMF,
MeI; (iii) Me3SiBr, DMSO; (iv) ArSnMe3, Pd(PPh3)4, LiCl, PhMe,
110 C; (v) LiOH H2O, MeOH, H2O; (vi) 4-hydroxy-4-benzylpiper-
idine, HOBt, EDC, Et3N, THF.
In summary, a new series of 2-aryl indole hNK1 antago-
nists has been evaluated. It has been shown that by judi-
cious choice of N-substituents and 2-aryl substitution,
compounds with high binding affinity and excellent in vivo
activity may be prepared. These results were achieved
utilising a common synthetic intermediate to allow the
production of final compounds as the last step.
ꢁ
.
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benzylpiperidine was beneficial.11 The side chain, how-
ever, no longer contains a basic nitrogen, a feature
which generally conveys good physical properties and
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