3-(4-piperidinyl)- and 3-(8-aza-bicyclo[3.2.1]oct-3-yl)-2-phenyl-1H-indoles as bioavailable h5-HT(2A) antagonists

Article abstract of DOI:10.1016/S0960-894X(00)00559-X

A series of 3-(4-piperidinyl)- and 3-(8-aza-bicyclo[3.2.1]oct-3-yl)-2-phenyl-1H-indoles have been prepared and evaluated as ligands for the h5-HT(2A) receptor. 3-(8-Phenethyl-8-aza-bicyclo[3.2.1]oct-3-yI)-2-phenyl-1H-indole is a high-affinity (1.2nM), selective (>800 fold over h5-HT(2C) and hD₂ receptors) antagonist at the h5-HT(2A) receptor with oral bioavailability in rats. (C) 2000 Elsevier Science Ltd.

Full text of DOI:10.1016/S0960-894X(00)00559-X

Bioorganic & Medicinal Chemistry Letters 10 (2000) 2701±2703
3-(4-Piperidinyl)- and 3-(8-Aza-bicyclo[3.2.1]oct-3-yl)-2-phenyl-
1H-indoles as Bioavailable h5-HT2A Antagonists
James Crawforth,* Simon Goodacre, Robert Maxey, Sylvie Bourrain, Smita Patel,
Rosemarie Marwood, Desmond O'Connor, Richard Herbert, Peter Hutson and
Michael Rowley
Merck Sharp & Dohme Research Laboratories, The Neuroscience Research Centre, Terlings Park, Eastwick Road, Harlow,
Essex CM20 2QR, UK
Received 26 June 2000; revised 21 August 2000; accepted 15 September 2000
AbstractÐA series of 3-(4-piperidinyl)- and 3-(8-aza-bicyclo[3.2.l]oct-3-yl)-2-phenyl-1H-indoles have been prepared and evaluated
as ligands for the h5-HT2A receptor. 3-(8-Phenethyl-8-aza-bicyclo[3.2.l]oct-3-yI)-2-phenyl-1H-indole is a high-anity (1.2 nM),
selective (>800 fold over h5-HT2C and hD2 receptors) antagonist at the h5-HT2A receptor with oral bioavailability in rats. # 2000
Elsevier Science Ltd. All rights reserved.
Since the introduction of chlorpromazine, the treatment
of psychoses with neuroleptic drugs has become well
established. It is widely accepted that schizophrenia is
related to excessive dopaminergic activity in the CNS
and the typical antipsychotic haloperidol 1 acts by
blocking central D2 receptors.1
Although this compound is e€ective for the treatment of
the positive symptoms of schizophrenia, it is ine€ective
against negative symptoms. Dopamine D2 blockade is
also associated with the occurrence of extrapyramidal
side e€ects (EPS), observed with these compounds.
Atypical antipsychotics such as sertindole 2 show a
greater ecacy in the treatment of the negative symp-
toms of schizophrenia, and a reduced liability for
EPS.1,2 This atypical nature is regarded as a con-
sequence of their preferential activity through the h5-
HT2 rather than the hD2 receptor. Until recently, there
were no selective 5-HT2A antagonists, but MDL-100907
3 has recently been disclosed as a very selective 5-HT2A
antagonist in phase III clinical trial for schizophrenia.3
Our studies with a series of 2-phenyl tryptamine deriva-
tives4 indicated that it is possible to obtain compounds
in this series that display good anity and selectivity for
the h5-HT2A receptor over h5-HT2C and hD2 receptors,
as exempli®ed by the piperidine derivative 4 (Table 1). It
is not entirely clear what the e€ect in schizophrenia of
binding to h5-HT2C receptors may be, so if it were to be
an undesired e€ect this may represent a useful result.
This compound, however, su€ered from a poor phar-
macokinetic pro®le, with an oral bioavailability in rats
of less than 5%. As a continuation of our study of
2-phenyl tryptamine derivatives, we sought to investi-
gate the amine moiety of 4 in order to improve its a-
nity and pharmacokinetic parameters. In this letter, we
describe the synthesis and receptor binding anities of
compounds where the tryptamine side chain has been
constrained within a ring.
*Corresponding author. Tel.: +44-1279-440-436; fax: +44-1279-440-
390; e-mail: james_crawforth@merck.com
0960-894X/00/$ - see front matter # 2000 Elsevier Science Ltd. All rights reserved.
PII: S0960-894X(00)00559-X

2702
J. Crawforth et al. / Bioorg. Med. Chem. Lett. 10 (2000) 2701±2703
The piperidinyl derivatives 6±10 were prepared from
2-phenyl indole in three steps as described in Scheme 1.
Reaction of 4-piperidone with the indole under acidic
conditions,5 followed by reduction of the tetra-
hydropyridine 5 gave the piperidine 6. This could be
alkylated with the appropriate alkyl halide to give
compounds 7±10.
Scheme 1.
Scheme 2.
The 8-aza-bicyclo derivatives 13±18 were synthesised as
shown in Scheme 2. Condensation of 2-phenyl indole
with tropanone or nortropanone under acidic reaction
conditions gave 11 and 12 in 82 and 50% yields,
respectively. Attempted reduction of the double bonds
in 11 or 12 using either transfer hydrogenation or under
increased pressure of hydrogen proved troublesome,
extended reaction times being required for product for-
mation. Reduction with triethylsilane and tri-
¯uoroacetic acid a€orded the desired amines as a
mixture of isomers in the ratio of 1:1 and 6:1 for the
NMe and NH case, respectively, that were separable by
¯ash chromatography to give 13±16. The structures
The imidazolidinone 10 shows binding anity compar-
able to the methyl analogue 7, and had a slightly
improved selectivity pro®le. In pharmacokinetic studies,
this compound had oral bioavailability in rats and dogs
of 40 and 33%, respectively. A substantial improvement
in anity and selectivity was seen with the phenethyl
compound 9, displaying subnanomolar h5-HT2A a-
nity, very good selectivity and an oral bioavailability of
12% in rats. In rat liver microsomes, compound 4 was
metabolised at the indole 6-position and the para-posi-
tion of the 2-phenyl ring. Compound 9 was also meta-
bolised at the para-position of the 2-phenyl ring, and at
the para-position of the phenethyl benzene ring.
1
were con®rmed by H NMR NOE experiments. Alky-
lation of 14 and 16 with phenethyl bromide then gave 17
and 18.
In order to investigate the role of the amine nitrogen in
the possible recognition process for P450 enzymes, we
decided to increase the bulk around the basic nitrogen
atom by construction of the aza-bicyclo ring system
typi®ed by 14. This showed an improved binding anity
at h5-HT2A receptors compared to 6 (Table 2) and a
much higher hD2 selectivity as a result of this improved
anity. For the methyl analogues 13 and 15, there is
little di€erence between the pro®les of the two isomers.
However, in the phenethyl analogues the isomer 17
retains high h5-HT2A anity and displays a better
selectivity window over h5-HT2C and hD2 receptors
Constraining the tryptamine side chain into the piper-
idyl ring in compounds 6, 7 gave some loss in h5-HT2A
anity compared to 4 (Table 1). Encouragingly,
however, this compound did retain some selectivity over
h5-HT2C and hD2 receptors. Alkylation on the amine
nitrogen with a benzyl moiety gave 8, which exhibited a
further loss in h5-HT2A anity. This drop in binding
may be due to the reduction in the pKa of the basic
nitrogen.

J. Crawforth et al. / Bioorg. Med. Chem. Lett. 10 (2000) 2701±2703
2703
Table 1. Piperidinesa
Table 2. Azabicyclesa
Selectivityb
Ki (nM)
Selectivityb
Ki (nM)
c
d
e
c
d
e
No.
R
h5-HT2A
h5-HT2C
hD2
No.
R
h5-HT2A
h5-HT2C
hD2
4
2.7
100
330
14
1.8
200
1055
6
7
8
9
12.1
7.8
28
30
30
130
205
2
13
15
17
18
1.1
1.5
1.2
2.6
70
45
1190
960
30
0.5
160
690
860
60
1080
170
10
7.3
160
250
aBinding anities are quoted as Ki values and are the geometric mean
of at least two experiments.
bRatio of the Ki (nM) values h5-HT2C/h5-HT2A, and hD2/h5-HT2A
.
cDisplacement of [3H]-ketanserin from CHO cells stably expressing h5-
HT2A receptors.6
aBinding anities are quoted as Ki values and are the geometric mean
of at least two experiments.
dDisplacement of [3H]-mesulergine from Chinese hamster ovary
(CHO) cells stably expressing h5-HT2C receptors.7
eDisplacement of [3H]-spiperone from CHO cells stably expressing
hD2 receptors.8
bRatio of the Ki (nM) values h5-HT2C/h5-HT2A, and hD2/h5-HT2A
.
cDisplacement of [3H]-ketanserin from CHO cells stably expressing h5-
HT2A receptors.6
dDisplacement of [3H]-mesulergine from Chinese hamster ovary
(CHO) cells stably expressing h5-HT2C receptors.7
eDisplacement of [3H]-spiperone from CHO cells stably expressing
hD2 receptors.8
than 18. Compound 17 also demonstrated oral bio-
availability in rat of 18%.
experiments, and Russell Mortishire-Smith and Ute
Gerhard for spectroscopic studies.
In summary, by constraining the tryptamine side chain
into a piperidine ring, we were able to retain moderate
h5-HT2A anity relative to the initial 2-phenyl trypta-
mine lead 4. Adding a phenethyl side chain gave 9 with
an improvement in anity, and this compound shows
an oral bioavailability in rats of 12%. Inclusion of an
azabicyclo ring system gave 17, which retains good anity
and excellent selectivity over h5-HT2C and hD2 recep-
tors, with an oral bioavailability in rat of 18%. Com-
pounds 9 and 17 are antagonists at the h5-HT2A
receptor: in h5-HT2A CHO cells, 1 mM of each alone
had no e€ect, but antagonised the 5-HT (1 mM)
mediated accumulation of inositol phosphates.6,7
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Acknowledgements
We are indebted to Nicola Szeto, Paul Stevens and Eli-
zabeth Norris for performing the oral bioavailability