Synthesis and cannabinoid activity of 1-substituted-indole-3-oxadiazole derivatives: Novel agonists for the CB1 receptor

Article abstract of DOI:10.1016/j.ejmech.2007.04.007

An exploratory chemical effort has been undertaken to develop a novel series of compounds as selective CB₁ agonists. It is hoped that compounds of this type will have clinical utility in pain control, and cerebral ischaemia following stroke or traumatic head injury. We report here medicinal chemistry studies directed towards the investigation of a series of 1-substituted-indole-3-oxadiazoles as potential CB₁ agonists. Crown Copyright

Full text of DOI:10.1016/j.ejmech.2007.04.007

Available online at www.sciencedirect.com
European Journal of Medicinal Chemistry 43 (2008) 513e539
http://www.elsevier.com/locate/ejmech
Original article
Synthesis and cannabinoid activity of 1-substituted-indole-3-oxadiazole
derivatives: Novel agonists for the CB1 receptor
b
c
a
Gerard P. Moloney a, , James A. Angus , Alan D. Robertson , Martin J. Stoermer ,
*
Michael Robinson a, Christine E. Wright b, Ken McRae a, Arthur Christopoulos d
a Department of Medicinal Chemistry, Victorian College of Pharmacy (Monash University), 381 Royal Parade Parkville, Victoria, 3052, Australia
b Cardiovascular Therapeutics Unit, Department of Pharmacology, University of Melbourne, Victoria, 3010, Australia
c AMRAD Corporation Limited (now known as Zenyth Therapeutics Limited) 576 Swan Street, Richmond, Victoria, 3121, Australia
d Drug Discovery Laboratory, Department of Pharmacology, Monash University, Victoria, 3800, Australia
Received 12 December 2006; received in revised form 6 April 2007; accepted 12 April 2007
Available online 6 May 2007
Abstract
An exploratory chemical effort has been undertaken to develop a novel series of compounds as selective CB1 agonists. It is hoped that com-
pounds of this type will have clinical utility in pain control, and cerebral ischaemia following stroke or traumatic head injury.
We report here medicinal chemistry studies directed towards the investigation of a series of 1-substituted-indole-3-oxadiazoles as potential
CB1 agonists.
Crown Copyright Ó 2007 Published by Elsevier Masson SAS. All rights reserved.
Keywords: Cannabinoid CB1 receptors; CB1 agonists; Pain control; Aminoalkylindoles; Design; Synthesis
1. Introduction
Anandamide (1) and a range of other structurally unrelated
cannabinoid agonists have been shown to block the N-type
calcium channel. Given that blockade of these channels by
certain conotoxin peptides has already demonstrated clinical
potential for the treatment of neuropathic pain [7], there is
considerable and ongoing interest for the development of
more tractable, organic small molecules that can achieve the
same therapeutic effect without the difficulties associated
with the use of peptides as therapeutic agents. Not surpris-
ingly, a number of studies have already investigated analogues
of anandamide as one means for achieving such a goal [8e13].
Molecular modeling studies have been performed on ananda-
mide [14] and these and other studies have resulted in a pro-
posed conformation of anandamide (1) for activity at the
CB1 receptor Chart 1 [15,16].
There are two cannabinoid receptors designated neuronal
(CB1) and peripheral (CB2) and both have recently been
cloned [1,2]. Activation of both receptors leads to inhibition
of adenylate cyclase and activation of mitogen-activated pro-
tein kinases. Activation of CB1 receptors also leads to the
gating of a variety of ion channels, including the inhibition
of N-type voltage dependent calcium channels. As a conse-
quence of these cellular effects, together with the distribution
of the receptors in neuronal tissues, cannabinoid CB1 agonists
have been suggested to offer significant therapeutic potential
in the management of glaucoma, motor dysfunction, appetite
stimulation, emesis and, in particular, the treatment of chronic
neuropathic pain [3e5]. In 1992, it was discovered that the en-
dogenous ligand for the CB1 receptor is anandamide [6].
In recent times it has been demonstrated that the activity of
a series of aminoalkylindole (AAI) antinociceptive agents,
originally designed as non-ulcerogenic, non-steroidal antiin-
flammatory drugs (NSAIDS) is associated with a second
mechanism of action manifested by potent activity at
* Corresponding author. Tel.: þ613 99039623; fax: þ613 99039651.
E-mail address: gerard.moloney@vcp.monash.edu.au (G.P. Moloney).
0223-5234/$ - see front matter Crown Copyright Ó 2007 Published by Elsevier Masson SAS. All rights reserved.
doi:10.1016/j.ejmech.2007.04.007

514
G.P. Moloney et al. / European Journal of Medicinal Chemistry 43 (2008) 513e539
O
HO
N
H
OH
H
N
O
1
1
Chart 1.
inhibiting electrically induced contractions of mouse vas def-
erens (MVD) [12,17e20]. Studies on WIN-55,212-2 (2), pra-
vadoline (3), and related compounds have shown that
compounds from this structurally unrelated indole based series
(relative to the non-classical cannabinoids or to anandamide
(1) and other arachadonic acid derivatives) are capable of pro-
ducing pharmacological responses in a fashion resembling the
profile exhibited by (ꢀ)-D9-THC. Additionally the AAI drug
class produces its cannabimimetic actions in a stereoselective
manner as shown by the results for the optical isomers of
WIN-55,212-2 [21].
WIN-55,212-2 (CB1, IC50 ¼ 2.0 nM) (2), pravadoline (CB1,
IC50 ¼ 453 nM) (3), and (4-methoxyphenyl)(3-morpholino-
methyl)-2,3-dihydro-1H-pyrrolo[1,2-a]indol-9-yl)methanone
(4) [15] (CB1, IC50 ¼ 0.32 nM) are all potent CB1 receptor ag-
onists, Chart 2 [2,17,22]. The key structural features for potent
cannabinoid activity in this series are a 3-keto group, an aryl or
bicyclic (naphthyl) substituent at the 3-position, a small (H or
CH3) substituent at the 2-position and an ethylene linked mor-
pholine group at the 1-position. Molecular modeling studies
have been performed to develop a pharmacophore and to com-
pare AAI structures with those of classical cannabinoids [23].
Within this work a CB1 antagonist WIN-54,461 (5) (or bromo-
pravadoline) was also identified. A separate group identified
a related compound AM630 (6) (or iodopravadoline) which
is also found to be a competitive cannabinoid receptor antag-
onist [24].
AM630 (6), Chart 3 behaved as a competitive antagonist of
CP-55940 (8), WIN-55,212-2 (2), and anandamide (1) produc-
ing rightward shifts in the log concentration response curves of
these cannabinoid receptor agonists and of (ꢀ)-D9-THC that
was concentration-dependent, essentially parallel and not ac-
companied by any decrease in the size of maximal response.
AM630 (6) was markedly more potent as an antagonist of
(ꢀ)-D9-THC and CP-55940 (8) (Kd ¼ 14.0 and 17.3 nM, re-
spectively) than as an antagonist of WIN-55,212-2 (2) or anan-
damide (36.5 and 278.8 nM, respectively). These differences
in dissociation constants imply that the mouse vas deferens
may contain more than one type of cannabinoid receptor.
The data also indicate that the receptors for which AM630
(6) has the highest affinity may not be CB1 cannabinoid recep-
tors as the CB1-selective antagonist, SR141716A (7) is known
to be equally potent in attenuating the inhibitory effects of CP-
55940 (8) and anandamide (1) on the twitch response of the
mouse vas deferens (Chart 4).
In 1993, a human peripheral cannabinoid (CB2) receptor
was disclosed [22]. Several workers have put forward the hy-
pothesis that a selective and potent ligand for the CB2 receptor
would show therapeutically useful effects [19]. Gallant and
colleagues submitted a large number of compounds to in vitro
H3CO
H3CO
O
O
O
CH3
CH3
N
N
N
O
N
N
N
O
O
O
2
3
4
Chart 2.

G.P. Moloney et al. / European Journal of Medicinal Chemistry 43 (2008) 513e539
H3CO
515
The indole-3-oxadiazole derivatives were then alkylated with
1-(2-chloroethyl)morpholine hydrochloride, 1-(2-chloroethyl)-
pyrrolidine hydrochloride, 2-bromo-1-(4-morpholinyl)-1-etha-
none or other alkyl halides to afford the desired target
molecules, Scheme 2. In our current study we have reported
the synthesis and testing of one indole based compound with
an alternative to the 3-oxadiazole substituent and that is
1-(2-(4-morpholino)ethyl)-3-aceto-1H-indole (54), which has
an aceto group at the 3-position and this indole derivative
was synthesized by alkylation of 3-indolyl acetate with
4-(2-chloroethyl)morpholine hydrochloride.
H3CO
O
O
CH3
CH3
N
I
N
Br
N
N
3. Results and discussion
The compounds investigated and their biological data are
shown in Table 1. In order to explain the biological data we re-
ferred to our theoretical receptor model for the CB1 receptor,
shown in Fig. 1. using the preferred conformation of the canna-
binoid mimetic HU210 (11) fitted to the proposed CB1 receptor
model. The theoretical receptor model is composed of four
binding sites. To build our theoretical CB1 receptor model we
compared potential commonality between aminoalkylindoles
and other cannabinoids. We initially built the structure for anan-
damide (1) and minimised the proposed conformation ananda-
mide adopts for binding to the CB1 receptor. We then
recognized that when HU210 and anandamide (1) were com-
pared it was possible to overlay the phenolic hydroxyl of
HU210 with the amido ethyl alcohol of anandamide (binding
site 1). Binding site 1 is represented by the red1 sphere and is
a hydrogen bonding site, which the phenolic group of HU210
can interact with, Fig. 1. Binding site 2 is represented by the pur-
ple sphere in Fig. 1. and the 9-hydroxymethyl group of HU210
interacts with this binding site and is an important binding site
for the aminoalkylindole series [12,19,20] and our novel indole-
3-oxadiazole series. Binding site 3 is a hydrogen bonding site
and is represented by the orange sphere, Fig. 1 and is accessed
by the pyran oxygen of HU210 and the amide carbonyl of anan-
damide (1), Fig. 2. Binding site 4 is represented by the large
elongated yellow space and is a hydrophobic binding site,
Fig. 1 and is the binding site which the aliphatic side chain of
HU210 and (ꢀ)-D9-THC can interact with as does the aliphatic
side chain of anandamide (1), Fig. 2. A low energy conforma-
tion of HU210 and binding sites 1e4 are shown in Fig. 1.
The proposed conformation anandamide (1) adopts for
binding to the CB1 receptor and the binding sites 1e4 are
shown in Fig. 2.
O
O
Bromopravadoline
AM630
6
WIN-54,461.
5
Chart 3.
binding assays on the cannabinoid receptors. These com-
pounds included a series of analogues selected through a topo-
logical similarity search using WIN-55,212-2 (2) as the
template [17,18]. This work led to the discovery of a range
of N1-benzoyl and N1-naphthoyl indole analogues [17,18].
Two of the more potent compounds from this work included
L-768,242 (9) and L-759,787 [12] (10) (Ki ¼ 12 and 8.5 nM,
respectively, for the CB2 receptor) Chart 5.
They exhibit good selectivity over the CB1 receptor (CB1/
CB2 ¼ 160 for L-768,242 (9) and 103 for L-759,787 (10)).
In conjunction with the synthesis of novel compounds as po-
tential CB1 agonists, we have performed preliminary modeling
studies in an attempt to build up a pharmacophore for the CB1
receptor. A comparison was made between the aminoalkylin-
doles, anandamide (1) and the classical and non-classical can-
nabinoids. We extrapolated from work carried out by Thomas
and coworkers [15] using the proposed conformation ananda-
mide adopts for binding. Chart 6 illustrates the four proposed
important binding sites within the CB1 pharmacophore using
anandamide, (ꢀ)-D9-THC, HU210 (11) and WIN-55,212-2
(2). The proposed binding sites are a hydrogen bond donor/ac-
ceptor site (1), and two further hydrogen bonding sites (2) and
(3) and a hydrophobic pocket (4). The pharmacophore is fur-
ther illustrated in Figs. 1e4. The proposed mode of binding of
a low energy conformer of HU210 (11) and anandamide (1)
are shown in Figs. 1 and 2, respectively.
Our current series of indole-3-oxadiazole compounds were
modelled on the aminoalkyl indole series [23]. In our current
study a decision was made to replace the indole-3-linking
group with an oxadiazole group, which is of the appropriate
size to allow the phenyl group of the attached benzyl group
to occupy a similar position in the CB1 receptor like the
keto linked phenyl group of the aminoalkylindole series. The
2. Synthetic chemistry
The amideoxime derivatives required for the synthesis of
the oxadiazole derivatives were prepared from nitrile deriva-
tives, Scheme 1. Reaction with hydroxylamine hydrochloride
in the presence of triethylamine afforded the amideoximes in
good yield. Reaction of the amideoxime with indole-3-carbox-
ylic acid afforded the desired indole-3-oxadiazoles, Scheme 2.
1
For interpretation of the references to colour in text, the reader is referred
to the web version of this article.

516
G.P. Moloney et al. / European Journal of Medicinal Chemistry 43 (2008) 513e539
O
OH
N
HO
NH
OH
N
N
Cl
Cl
Cl
SR141716A
CP55940.
7
8
Chart 4.
1,2,4-oxadiazole group also has an oxygen group ideally
placed to act as a hydrogen bond acceptor if this is the function
of the ketone oxygen of the aminoalkylindole series. The ox-
adiazole group is a stable bioisosteric replacement for ester
and amide groups [19,25e27]. In our previous work in the se-
rotonin area we successfully replaced the ester group with
a 1,2,4-oxadiazole moiety while successfully retaining the de-
sired pharmacological profile [29].
We have retained an alkyl linked morpholine side chain at-
tached to the indole nitrogen because the literature suggests
that the nitrogen of the morpholine ring is important for rea-
sonable CB1 potency.
As a part of our study to investigate important structural
features in an effort to establish structureeactivity relation-
ships within our 1H-indole-3-oxadiazole series, the aminoal-
kylindole series of compounds and other cannabinoid
mimetics we decided to study the hydrophobic pocket which
we have designated as binding site 4, Chart 6. The hydropho-
bic pocket looks interesting as a variety of functional groups
within the different classes of cannabinoid ligands have been
used to interact with this binding site including a variety of
substituted phenyl groups [30].
Several changes were made to the oxadiazole-3-aromatic
group in our efforts to investigate whether CB1 affinity could
be enhanced with changes to this position of the molecule. We
have investigated benzyl, phenyl, biphenyl, phenethyl and thio-
phene groups as well as varying substitution within the benzyl
series. A comparison of compounds containing these aromatic
groups attached to the 1,2,4-oxadiazole group revealed that
the best aromatic groups were the benzyl group and the phe-
nethyl group. From the benzyl series we can compare four com-
pounds 37 (96.6% inhibition at 1.0 mM), 38 (pKb ¼ 7.2), 48
(pKb ¼ 5.6) and 50 (100% inhibition at 1.0 mM). The one com-
pound we synthesized and evaluated from the phenethyl series
was 1-(2-morpholin-4-yl-ethyl)-3-(3-phenethyl-[1,2,4]oxadia-
zol-5-yl)-1H-indole (53) (90% inhibition at 1.0 mM). It was in-
teresting and informative to observe that the biphenyl derivative
41 was essentially inactive (11.4% inhibition at 1.0 mM).and the
compounds, which contained more flexible aromatic substitu-
ents exhibited good CB1 affinity. Our molecular modeling stud-
ies revealed that the biphenyl group was unable to access the
hydrophobic pocket while the oxadiazole oxygen interacted
with the hydrogen bonding site (binding site 1), Chart 6. It
was also interesting to observe that replacement of the benzyl
group with a methyl thiophene group to produce 45 (81% inhi-
bition at 1.0 mM) resulted in an indole-3-oxadiazole derivative
with good CB1 affinity. Compound 45 was expected to have
good CB1 potency as our modeling studies suggested that the
thiophene moiety would be able to orientate itself so as to easily
access the hydrophobic pocket while the other binding sites
were being interacted with. It was not surprising to observe
that an alternative aromatic group could interact successfully
with the hydrophobic pocket given that we have witnessed
that the aliphatic side chains of anandamide (1), (ꢀ)-D9-THC
and HU210 (11) interact with the hydrophobic pocket and the
naphthyl groups of WIN-55212-2 (2) and L-759,787 (10)
[12,17,18] interact with the hydrophobic pocket. The biological
results presented in Table 1 confirm that the inclusion of a
2-naphthyl group attached to the 1,2,4-oxadiazole enhances
CB1 affinity. A proposed conformation and mode of interaction
Fig. 1.

G.P. Moloney et al. / European Journal of Medicinal Chemistry 43 (2008) 513e539
517
Fig. 4.
N
CN
a
OH
NH2
R
R
Reagent: (a) NH2OH
Scheme 1.
H
N
H
N
a
OH
O
N
O
N
Fig. 2.
R
with the CB1 receptor for 56, (95.6% inhibition at 1.0 mM) is
shown in Fig. 3. Published research conducted on the aminoal-
kylindole series [27,28] revealed the potency of derivatives con-
taining a naphthyl group which have ability to interact
b
R
N
O
N
N
R
Reagents: (a) CDI, amideoxime, THF. (b) NaH, DMF, alkyl halide.
Fig. 3.
Scheme 2.

518
G.P. Moloney et al. / European Journal of Medicinal Chemistry 43 (2008) 513e539
Table 1
Compound number
Structure
CB1 (MVD)a,b
CB1 (binding)c
CB2 (binding)c
O
OH
N
H
Anandamide 1
pKB ¼ 8.52
Anandamide
OH
OH
CP-55940 8
HO
CP 55940
OH
HO
HU210 11
IC50 ¼ 3.22 mM
O
HU210
OH
(ꢀ)-D9-THC
pKB ¼ 8.74
O
THC
O
CH3
N
WIN-55212 2
pKB ¼ 8.6
IC50 ¼ 0.43 mM
IC50 ¼ 2200 nM
O
N
O
O
N
H3C
N
H
N
N
Cl
Cl
SR141716A 7
pKB ¼ 8.4e8.6
IC50 ¼ 3.92 nM
Cl
N
O
N
N
37
pKB ¼ 7.0
IC50 ¼ 2.62 nM
IC50 ¼ 1.1 mM
N
O
N
N
38
pKB ¼ 7.2
N
O
N

G.P. Moloney et al. / European Journal of Medicinal Chemistry 43 (2008) 513e539
519
Table 1 (continued)
Compound number
Structure
CB1 (MVD)a,b
CB1 (binding)c
CB2 (binding)c
N
O
N
O
N
39
22.4% inhibition at 1.0 mM
N
O
N
O
N
40
pKB ¼ 6.47
IC50 ¼ 0.25 mM
IC50 ¼ 4.03 mM
N
N
O
N
O
N
41
11.4% inhibition at 1.0 mM
IC50 ¼ 1.52 mM
14% inhibition at 10.0 mM
N
N
O
N
O
N
42
43
44
ꢀ5.29% inhibition at 1.0 mM
17% inhibition at 1.0 mM
44.3% inhibition at 1.0 mM
Inactive
N
O
N
O
N
O
N
N
O
Inactive
N
O
N
O
N
N
O
Inactive
N
O
(continued on next page)

520
G.P. Moloney et al. / European Journal of Medicinal Chemistry 43 (2008) 513e539
Table 1 (continued)
Compound number
Structure
CB1 (MVD)a,b
CB1 (binding)c
CB2 (binding)c
N
O
S
N
N
45
81% inhibition at 1.0 mM
IC50 ¼ 6.8 mM
N
O
N
N
O
N
N
46
Inactive
Inactive
O
47
46.8% inhibition at 1.0 mM
Inactive
N
O
N
N
48
49
50
pKB ¼ 5.6 (partial agonist)
39.2% inhibition at 1.0 mM
58% inhibition at 1.0 mM
IC50 ¼ 5.6 mM
N
N
O
OCH3
N
N
IC50 ¼ 2.8 mM
N
O
N
O
Br
N
N
IC50 ¼ 6.2 mM
N
O

G.P. Moloney et al. / European Journal of Medicinal Chemistry 43 (2008) 513e539
521
Table 1 (continued)
Compound number
Structure
CB1 (MVD)a,b
CB1 (binding)c
CB2 (binding)c
Cl
N
O
N
51
ꢀ21% inhibition at 1.0 mM
Inactive
O
N
N
O
N
O
N
52
100% inhibition at 1.0 mM
IC50 ¼ 8.8 mM
N
N
O
N
53
90% inhibition at 1.0 mM
IC50 ¼ 6.8 mM
N
N
O
Cl
N
O
N
54
95% inhibition at 1.0 mM
IC50 ¼ 7.4 mM
N
N
O
O
HN
N
O
N
55
15.8% inhibition at 1.0 mM
IC50 ¼ 6.1 mM
O
N
O
N
N
56
95.6% inhibition at 1.0 mM
O
N
N
(continued on next page)

522
G.P. Moloney et al. / European Journal of Medicinal Chemistry 43 (2008) 513e539
Table 1 (continued)
Compound number
Structure
CB1 (MVD)a,b
CB1 (binding)c
CB2 (binding)c
N
N
57
78.6% inhibition at 1.0 mM
O
N
N
O
OCH2CH3
N
N
58
41.6% inhibition at 1.0 mM. Non-specific
O
N
O
OH
N
N
59
53.6% inhibition at 1.0 mM. Non-specific
O
N
O
N
60
81.8% inhibition at 1.0 mM
N
CH3
O
O
a
MVD e mouse vas deferens bioassay.
Affinity (pKB ¼ ꢀlog10
b
KB the dissociation equilibrium constant) estimates for novel compounds at the CB1 receptor in the mouse vas deferens (MVD). Stan-
dard errors are omitted for clarity but in all cases were ꢁ0.2 log10 units.
c
IC50 ¼ negative logarithm of the concentration of compound required to inhibit 50% of the specific binding of the radioligand. Affinity values are the means of
at least four different estimates. Negative values connote stimulation rather than inhibition.
intimately with the hydrophobic pocket. Other classes of canna-
binoid ligands that possess a naphthyl group have been reported,
which interacts with the hydrophobic pocket such as the N1-
naphthoyl indole derivative L-759,787 [17,18], Chart 5. In our
current study we investigated two compounds, which contained
an oxadiazole-3-methyl naphthyl group including (57), (78.6%
inhibition), which contains a 1-ethyl linked pyrrole group as
does the benzyl oxadiazole derivative (38). The second com-
pound we investigated, which contains an oxadiazole-3-methyl
naphthyl group was 3-[3-(2-methylnaphthyl)-[1,2,4]oxadiazol-
5-yl]-1-(2-morpholin-4-yl-ethyl)-1H-indole (56), (95.6% inhi-
bition), which contains a 1-ethyl linked morpholine group. A

G.P. Moloney et al. / European Journal of Medicinal Chemistry 43 (2008) 513e539
523
O
the hydrophobic pocket. The general substitution of the benzyl
group did not enhance CB1 affinity. The 4-bromobenzyl ana-
logue 50 (58% inhibition at 1.0 mM) showed decreased CB1
affinity compared with the unsubstituted analogues 37 and
38. A similar situation was observed for the 4-methoxybenzyl
derivative 49 (39% inhibition at 1.0 mM). Clearly substitution
on the benzyl group was not detrimental to CB1 affinity illus-
trated by the potency of the 2-chlorobenzyl derivative 54
(95.0% inhibition at 1.0 mM). The choice of inclusion of
a chloro substituent at the 2-position of the benzyl group
was based on the favourable CB1 affinity observed for the
chloro substituted N1-benzoyl indole derivative L-768,242
(9), Chart 5 [17,18].
O
N
N
H3CO
CH3
CH3
N
N
O
O
Cl
One of the most potent compounds from the indole-3-
oxadiazole series was 3-(3-benzyl-[1,2,4]oxadiazol-5-yl)-1-
(2-pyrrolidin-1-yl-ethyl)-1H-indole (38), which possesses an
1-ethyl linked pyrrolidine group. The pyrrolidine nitrogen
can interact with the hydrogen bonding site (binding site 3),
Fig. 4.
Cl
L-768,242
L-759,787
10
9
Chart 5.
Molecular modeling studies indicate that as the ethyl link-
ing side chain orientates to allow the pyrrolidine nitrogen to
interact with the hydrogen bonding site (binding site 2) the ox-
adiazole oxygen is able to interact with another hydrogen
bonding site (binding site 1), which allows the attached benzyl
group to interact with the proposed hydrophobic pocket,
Fig. 4. When 38 adopts a conformation to interact with
these proposed CB1 binding sites the p electrons of the
indole ring are able to interact with an extra binding site pro-
posed for the pyran oxygen of HU210 (binding site 3), Chart 6.
proposed conformation and mode of interaction with the CB1 re-
ceptor is shown for 56 in Fig. 3.
The importance of the hydrophobic pocket for good CB1
potency is further illustrated with the total inactivity observed
for the indole-2-substituted indole derivative 46. When the
2-indole substituted analogue 46 adopts a conformation that
allows the oxadiazole oxygen to interact with the hydrogen
bonding site, the attached benzyl group is unable to access
1
1
OH
HO
HN
O
3
O
3
4
4
9
(–)-Δ -THC
Anandamide (1)
2
2
O
HO
1
N
1
CH3
O
OH
N
O
O
3
3
4
4
HU-210 (11)
WIN-55212 (2).
Chart 6.

524
G.P. Moloney et al. / European Journal of Medicinal Chemistry 43 (2008) 513e539
3-[3-Benzyl-[1,2,4]oxadiazol-5-yl]-1-(2-morpholin-4-yl-ethyl)-1
H-indole (37) was one of the first indole-3-oxadiazole deriva-
tives designed, synthesized and evaluated. Like many of the
compounds from our indole-3-oxadiazole series 37 possesses
a 1-ethyl linked morpholine moiety. The 1-ethyl linked
morpholine moiety was incorporated into the design of the
indole-3-oxadiazole series based on the structureeactivity
relationships of the aminoalkylindole series previously pub-
lished [27]. Compound 37 exhibited good affinity for the
CB1 receptor (96.6% inhibition) indicating that 37 was able
to interact with the important binding sites within the CB1
receptor including the hydrogen bonding site (binding site 3)
that the morpholine nitrogen was able to interact with.
In the process of investigating a variety of indole based
compounds incorporating an oxadiazole moiety at the 3-posi-
tion of the indole in order to supply the molecule with the ap-
propriate functionality to interact with the hydrogen bonding
site (binding site 1) and to act as a suitable linking moiety be-
tween the central indole nucleus and the hydrophobic group,
we investigated several compounds with a ketone bridging
group between the indole ring at the 3-position and the oxadia-
zole group. The poor CB1 affinity of (3-benzyl-1,2,4-oxadia-
zol-5-yl)(1-(2-morpholinoethyl)-1H-indol-3-yl)methanone (39)
(18% inhibition at 1.0 mM) and [1-(2-morpholin-4-yl-ethyl)-
1H-indol-3-yl]-(3-phenyl-[1,2,4]oxadiazol-5-yl)-methanone
(44) (44% inhibition at 1.0 mM) indicates that the presence of
the keto bridging group between the indole ring and the oxa-
diazole moiety is detrimental to interaction with the CB1 bind-
ing sites as the oxygen of the bridging ketone preferentially
interacts with the hydrogen bonding site (binding site 1),
which results in the terminal aromatic group not being able
to access the hydrophobic pocket accurately.
sites is illustrated when we observe the highly potent cannabi-
noid mimetic HU210 (11), which has the pyran ring oxygen to
interact with the extra binding site (binding site 3) and is able to
interact with all the proposed binding sites 1e4, Fig. 1.
An examination of some of the compounds from the vari-
ous classes of CB1 agonists including the aminoalkylindoles
and our novel 1-substituted-1H-indole-3-oxadiazole deriva-
tives reveals an area of space between the indole nitrogen
and the morpholine nitrogen or the pyrrolidine nitrogen (bind-
ing site 2). There may be a requirement for hydrophobicity
in this region. It is interesting to compare the aminoalkylin-
doles and our novel 1-substituted-1H-indole-3-oxadiazole de-
rivatives with (ꢀ)-D9-THC and HU210. This proposed
hydrophobic region may be where the six membered rings
of (ꢀ)-D9-THC and HU210 are placed when these compounds
are interacting with the CB1 receptor. The good CB1 potency
of 3-(3-benzyl-[1,2,4]oxadiazol-5-yl)-1-pentyl-1H-indole (52)
may be partially explained by the ability of the 1-pentyl side
chain to interact with this proposed hydrophobic region near
the indole nitrogen.
For 37 and 38 the 1-ethyl linking chain may be in this area.
It was of interest to us to design new compounds with different
functionality in this area of the molecule. To investigate this
region of the receptor we synthesized 2-[3-(3-benzyl-[1,2,4]
oxadiazol-5-yl)-indol-1-yl]-1-morpholin-4-yl-ethanone (43),
2-{3-[3-(2-chlorobenzyl)-[1,2,4]oxadiazol-5-yl]-indol-1-yl}-
1-morpholin-4-yl-ethanone (51) and 1-morpholin-4-yl-2-
[3-(3-phenyl-[1,2,4]oxadiazol-5-yl)-indol-1-yl]-ethanone (42).
When a comparison is made with the unsubstituted analogues
37, 54 and 40 it became clear that inclusion of a carbonyl
group in this region within these classes of molecules was det-
rimental to CB1 potency.
The biological results presented in Table 1 reveal that there
are CB1 binding sites that must be interacted with in order for
the compound to exhibit good CB1 potency and there are less
important binding sites. This observation is evident when we
observe that 3-(3-benzyl-[1,2,4]oxadiazol-5-yl)-1-pentyl-1H-
indole (52), exhibits 100% inhibition at 1.0 mM. Compound
52 has a pentyl chain attached to the indole nitrogen and thus
has no attached heterocyclic ring system containing a protonat-
able nitrogen such as a morpholine or pyrrolidine ring to inter-
act with the hydrogen bonding site (binding site 2). An
examination of the expected conformation 52 adopts to interact
with the CB1 receptor reveals that the oxadiazole oxygen can
interact with binding site 1, the benzyl group can interact
with the hydrophobic pocket and the p electrons of the indole
ring system is able to interact with the extra binding site (bind-
ing site 3), Chart 6. Clearly interaction with the hydrogen bond-
ing site (binding site 2) is not a requirement for optimal CB1
affinity. This proposal on the relative importance of the CB1 re-
ceptor binding sites appears to be confirmed when an inspec-
tion is made on the preferred conformations of potent
cannabinoids such as anandamide (1), Fig. 2 and (ꢀ)-D9-
THC. An inspection of anandamide (1) and (ꢀ)-D9-THC
reveals that both molecules do not possess functionality to
interact with the hydrogen bonding site (binding site 2). The
importance of being able to access all the CB1 receptor binding
Inclusion of a carbonyl group into the 1-ethyl linking chain
of 40 resulted in the formation of 42, which has been con-
verted from a potent CB1 inhibitor (83%) to a compound
with no significant potency at all (ꢀ5.29%). (4-(2-(3-(2-Chlor-
obenzyl)-1,2,4-oxadiazol-5-yl)-1H-indol-1-yl)ethyl)morpho-
line (54) is a potent inhibitor (95%) and conversion to the
carbonyl analogue 51 results in a significant decrease in
potency (21%). 3-[3-Benzyl-[1,2,4]oxadiazol-5-yl]-1-(2-mor-
pholin-4-yl-ethyl)-1H-indole (37) is one of the compounds
we first designed and synthesized within the oxadiazole family
and 37 exhibited good potency (96.6% inhibition). Compound
43 the carbonyl analogue of 37 exhibited only 17% inhibition
at the same concentration.
Clearly the inclusion of a carbonyl group in the 1-ethyl
linking chain neighbouring the morpholine nitrogen impedes
the ease with which the morpholine or pyrrolidine nitrogen
can interact with the proposed hydrogen bonding site in the
position (binding site 2).
In a second effort to explore the proposed hydrophobic re-
gion between the indole nitrogen and the proposed hydrogen
bonding site (binding site 2) we synthesized the two com-
pounds which have the 1-ethyl morpholine or 1-ethyl pyrroli-
dine side chain replaced with either a pentanoic acid side
chain (59) or an ethyl pentanoate side chain (58) substituent
attached to the indole nitrogen. Inspection of the biological

G.P. Moloney et al. / European Journal of Medicinal Chemistry 43 (2008) 513e539
525
results for 58 and 59 reveals that both compounds do exhibit
CB1 potency but not as potent as 38, which possesses a 1-ethyl
pyrrolidine side chain. Molecular modeling studies suggest
that the pentanoic acid and the ethyl pentanoate side chains
are not able to adopt a conformation to easily access the hy-
drogen bonding site 2 while interacting with binding site 1.
It is possible that the terminal carboxylic and ethyl carboxylate
groups are detrimental to good CB1 affinity given that the un-
substituted 1-pentyl analogue 52 displays high CB1 potency.
the high affinity agonist [3H]WIN-55212-2. Since this com-
pound labels both CB1 and CB2, single affinity estimates
would only be associated with compounds that showed no
selectivity between the two subtypes in the rat spleen assay.
In contrast biphasic binding curves in the spleen character-
ised by two affinity constants represent the profile of com-
pounds showing selectivity for one receptor subtype over
another. In order to determine the order of selectivity, the
high and low affinity values obtained for these compounds
in the spleen binding assays were compared to the single af-
finity estimates obtained for the cerebellum (CB1) assays.
Compounds for which the high affinity binding constant
from the spleen correlated with the binding affinity constant
from the cerebellum were concluded to be CB1-selective. In
contrast, compounds for which the low affinity binding con-
stant from the spleen correlated the binding affinity constant
from the cerebellum were concluded to be CB2-selective
and the high affinity constant from the spleen experiments
was then taken as the measure of affinity for the CB2
receptor.
4. Conclusions
In this study we have identified a novel series of indole-
3-oxadiazole derivatives as agonists of the CB1 receptor.
3-(3-Benzyl-[1,2,4]oxadiazol-5-yl)-1-(2-pyrrolidin-1-yl-ethyl)-
1H-indole (38) exhibited high CB1 receptor affinity (pKB ¼
7.2) and showed that the 1,2,4-oxadiazole group can success-
fully replace the keto linking group common to the aminoalkyl
indole series [23] and interact with the hydrogen bonding site
designated as binding site 1, Chart 6. From this series the pyr-
rolidine ring system linked to the 1-ethyl side chain provided
the most potent compound. Compounds 37, 40 and 45 incor-
porating a morpholine moiety and compound 48 containing
a piperidine moiety were also potent indicating that a ring sys-
tem containing a basic nitrogen in the correct position would
allow for interaction with binding site 2. The biological results
presented in Table 1 support our proposed CB1 binding sites
shown in Chart 6 and by the individual figures for specific
compounds, Figs. 1e4. Although we have not rigorously in-
vestigated additional properties of these compounds, such as
ability to cross the blood brain barrier and their addictive
potential (or lack thereof), the in vitro profile of compounds
such as (3-benzyl-5-(1-(2-pyrrolidin-1-yl)ethyl)-1H-indol-3-yl)-
1,2,4-oxadiazole (38) suggests at the very least that we have
identified useful pharmacological probes for the CB1 receptor.
Functional activity of the compounds was assayed using the
mouse electrically-stimulated vas deferens bioassay, a measure
of CB1 receptor function [35,36]. Compounds showing appre-
ciable activity in this assay and the ability to be antagonised by
the CB1-selective antagonist, SR141716A (7), were deemed to
be CB1 agonists. The remaining compounds were classed as
cannabinoid ligands. CB2 functionality may be investigated
using assays, such as those described in (US 6,013,648) [37].
5.1.2. Radioligand binding assays
5.1.2.1. Rat cerebellum. Sprague Dawley rats of either sex
(200e300 g) were killed by gassing with 80% CO2 in O2
and decapitation, and the entire brain excised rapidly and
placed in ice-cold triseHCl buffer (tris 50 mM, MgCl2
3 mM, EGTA 0.2 mM, pH to 7.4 with HCl). On ice the cere-
bellum was dissected away from the rest of the brain, weighed
and homogenised (PT-DA 1205/2EC Polytron Aggregate; Kin-
ematica, Luzernstrasse Switzerland) in 10 volumes of ice-cold
TriseHCl (buffer, Fullerton, CA, USA) and centrifuged at
31,000g for 15 min at 4 ꢂC. Subsequently, the supernatant
was discarded, the pellet then suspended in 20 volumes of
buffer and assayed for protein content using the method of
Bradford [38] in a Novaspec II spectrometer (Pharmacia Bio-
tech) with bovine serum albumen (BSA, Homosafe BSA, c/o
‘ScimaR’ Templestowe, Australia) as a standard. The homog-
enate was then recentrifuged and the final pellet resuspended
in triseHCl buffer at a protein concentration of 5 mg/mL
and stored in 500 mL aliquots at ꢀ80 ꢂC until used in the bind-
ing assay.
5. Experimental section
5.1. Biological methods
5.1.1. Pharmacological studies
The affinity of compounds at cannabinoid receptors is
routinely assessed using ligand binding assays. Radioligand
binding assays were conducted using rat cerebellum or rat
spleen. The rationale for this approach is as follows: The
rat cerebellum expresses predominantly, if not exclusively
the CB1 receptor subtype [31,32]. Thus binding constants
obtained from these studies using the CB1-selective antago-
nist [3H]SR141716A are characterised by a single affinity
value, as only one receptor type is labeled. This was found
to be the case for all compounds tested thus the derived
values represent binding affinity constants for the CB1 re-
ceptor. The rat spleen possesses both CB1 and CB2 subtypes
of cannabinoid receptor, with the latter being the predomi-
nating subtype [33,34]. Because of the lack of the general
availability of a CB2-selective antagonist we utilised instead
5.1.2.2. Rat spleen. Sprague Dawley rats (200e300 g) were
killed by gassing with 80% CO2 in O2 and decapitation and
the spleen excised rapidly and placed in ice-cold triseHCl
buffer (tris 50 mM, MgCl2 3 mM, EGTA 0.2 mM, pH 7.4).
The spleen was weighed and diced using a scalpel before ho-
mogenisation in 10 volumes of triseHCl buffer. The

526
G.P. Moloney et al. / European Journal of Medicinal Chemistry 43 (2008) 513e539
homogenate was then made up to 20 volumes and centrifuged
(12,600g, 5 min, 4 ꢂC) and the supernatant was retained and
centrifuged (23,800g, 20 min, 4 ꢂC). The pellet was resus-
pended in 10 volumes of buffer and assayed for protein con-
tent using the method of Bradford [38] with BSA as
standard. The homogenate was then recentrifuged and the final
pellet resuspended in triseHCl buffer at a protein concentra-
tion of 5 mg/mL and stored in 500 mL aliquots at ꢀ80 ꢂC until
used for the binding assay.
stretched by 0.5 g force and allowed to equilibrate for
10 min. The tissues were stimulated (grass S88 stimulator)
to contract using trains of electrical field stimulation of three
pulses (4 Hz), 0.5 ms duration, 100 V (80% maximal voltage)
every 20 s for 10 min. This electrical stimulation period was
applied before and after both antagonist and agonist addition.
Output from the transducer amplifier were recorded on a flat
bed recorder (Gould BS 272, Cleveland, OH, USA) All drugs
were dissolved in dimethyl sulfoxide (DMSO, Sigma, St
Louis, MO, USA) and allowed to equilibrate with the tissue
for 30 min before the responses to field stimulation were as-
sessed. Drug effects were measured as the percentage decrease
of the pre-drug twitch force. In experiments where only a sin-
gle drug concentration was tested, the resulting effect was ex-
pressed as a percentage of that observed in the presence of
vehicle. Binding data and data in the mouse vas deferens assay
for some compounds are summarised in Table 1.
5.1.2.3. Radioligand binding protocol. Ligand binding assays
were performed in polypropylene tubes in a total volume of
1.0 mL containing triseHCl buffer, a final concentration of
1.0 mg/mL BSA, and varying concentrations of drugs. Tubes
contained 30.0 mg of membrane protein and incubation was
started by the addition of 100 mL of either 0.5 nM
[3H]SR141716A or 0.2 nM [3H]WIN-55,212-2. Experiments
were carried out in triplicate at 30 ꢂC for 90 min with non-spe-
cific binding being defined as radioligand binding in the pres-
ence of 1.0 mM unlabelled WIN-55,212-2. Incubations were
terminated by rapid filtration with an M-24 Cell Harvester
(Brandel; Gaithersburg, MD, USA) using ice-cold triseHCl
buffer containing 0.5 mg/mL BSA. Filters (Wattman GR/B)
were soaked for 2 h prior to filtering in a solution of trise
HCl buffer containing 3.0 mg/mL BSA and 0.5% w/w polye-
thyleneimine (PEI). Filters were left to dry thoroughly before
placement into scintillation vials with 5.0 mL of scintillation
cocktail (Ultima Gold LSC-cocktail; Packard Bioscience, Me-
ridian, CT, USA) being added. Vials were left to stand over-
night before the radioactivity was determined using a Model
1409 DSA Liquid Scintillation counter (EG&E Wallac,
Gaithersburg, Maryland, USA).
5.2. Chemical methods: general directions
Computational chemistry was performed on a Silicon
Graphics Iris indigo II using the Sybyl [40] molecular model-
ing software.
Unless otherwise stated, all 1H NMR spectra were recorded
at 300 MHz on a Bruker AM 300 spectrometer. Chemical
shifts are in D ppm relative to TMS. Deuterated dimethyl-
sulphoxide (99.9%) was used as solvent unless otherwise
stated. Mass spectra and high resolution mass spectra
(HRMS) were obtained on a Kratos Concept IS (EIMS), a Kra-
tos MS50 (FAB) mass spectrometer or a Joel JMX DX-300
double focussing instrument. Melting points were determined
on a Gallencamp melting point apparatus and are uncorrected.
Methanol and ethanol were distilled from iodine and magne-
˚
5.1.2.4. Data analysis. The resulting radioligand binding
curves were analysed by nonlinear regression using the
program PRISM 3.0 (Graphpad Software, San Diego, CA) in
order to derive ligand affinity estimates for the cannabinoid
receptor(s).
sium and stored over type 3 A molecular sieves. Anhydrous
THF was freshly distilled over potassium and benzophenone.
Anhydrous DMF, diethyl ether and toluene were stored over
˚
type 4 A molecular sieves. Triethylamine, diisopropylethyl-
amine and pyridine were stored over sodium hydroxide. All
solutions were dried over MgSO4 or Na2SO4 and concentrated
on a Buchi rotary evaporator. Column chromatography was
performed on silica gel (Merck Kieselgel 60 F254). Infra Red
spectra were run in KBr discs on a Bruker IFS66 FTIR spec-
trometer. Microanalyses were performed on a VG Platform
spectrometer and are within 0.4% of the theoretical values un-
less otherwise stated. HPLC was performed on a Waters Mil-
lenium system comprising a 490E multi-wavelength detector,
600 controller, a series 600 pump with a 717 plus autosampler.
A Zorbax 4.6 mm ꢃ 250 mm, 5 mm column was used for ana-
lytical work while a 22.4 mm ꢃ 250 mm, 7 mm C18 column
was used for preparative work. A 10% H2O/AcCN (10e90%
gradient elution) (A)/0.1 M NH4OAc (pH 4) (90e10%) (B)
solvent system was used.
5.1.2.5. Drugs and chemicals. [3H]SR141716A (Amersham
Pharmacia Biotech Piscataway, NJ, USA), [3H]WIN-55212-2
(Du Pont), Bio-Rad protein assay dye reagent concentrate
(Bio-Rad, Hercules, CA, USA), ethylglycol-bis(b-aminethyl
ether)-N,N,N0,N0-tetraacetic acid (EGTA; Sigma Chemical
Co., St Louis, MO, USA) and Tris Ultrapure (ICN Biomedi-
cals Inc, Ohio, USA). All other reagents were obtained from
Sigma Chemical Co.
5.1.3. Mouse isolated vas deferentia
Swiss white mice (35e50 g) were killed by exposure to
80% CO2 in O2 and exsanguination. Mouse vas deferentia
were dissected with capsular connective tissue intact and set
up in 20 mL organ baths at 37 ꢂC in Mg2þ-free physiological
salt solution [39]. The upper (epididymal) end was attached to
an isometric force transducer (Grass FTO3C) and lower (pros-
tatic) end tied to a fixed support between two parallel field
electrodes (5 mm apart, 5 mm long). The tissue was initially
5.2.1. N-Hydroxy-2-(4-methoxyphenyl)acetamidine (11) [41]
A mixture of (4-methoxyphenyl)acetonitrile (2.0 g, 14.0 mmol)
and hydroxylamine hydrochloride (1.94 g, 28.0 mmol) in ethanol
(25.0 mL) was treated with triethylamine (4.4 mL) and heated at

G.P. Moloney et al. / European Journal of Medicinal Chemistry 43 (2008) 513e539
527
reflux for 16 h after which the solvent was evaporated under re-
duced pressure. Sodium carbonate solution (10%, 100.0 mL)
was added and the solution extracted with ethyl acetate. The
combined ethyl acetate extracts were dried, filtered and evaporated
under reduced pressure to afford a green solid, which was recrystal-
lised from ethyl acetate/hexane to afford (1.43 g, 57.0%) the de-
sired N-hydroxy-2-(4-methoxy-phenyl)-acetamidine (11) as pale
green prisms. M.p. ¼ 109e111þꢂC, (lit [42] m.p. ¼ 108e
109 ꢂC), M.S. m/z 181 (M þ 1) . 1H NMR (DMSO-d6) D
(10%) was added and the solution extracted with hot ethyl ac-
etate. The combined ethyl acetate extracts (900.0 mL) were
evaporated under reduced pressure to an approximate volume
of 100.0 mL and the ethyl acetate was allowed to cool to room
temperature and white crystals crystallised out to afford
(2.85 g, 48.0%) the desired N-hydroxyisonicotinamidine (14)
as fine white needles. M.p. ¼ 175e176 ꢂC, (lit [41] m.p. ¼
1
178e179 ꢂC), M.S. m/z 138 (M þ 1)þ. H NMR (DMSO-d6)
D 5.97 (2H, s, NH2), AA0BB0 system: 7.63 (2H, d, JAB
þ
00
3.17 (2H, s, CH2), 3.7 (3H, s, CH3), 5.29 (2H, s, NH2), AA0BB0
JAB ¼ 5.0 Hz, H-3 ), 8.56 (2H, d, JAB þ JAB ¼ 5.0 Hz,
0
0
00
system: 6.83 (2H, d, JAB þ JAB ¼ 8.3 Hz, H-3 ), 7.17 (2H, d,
H-200), 10.03 (1H, s, OH).
0
JAB þ JAB ¼ 8.3 Hz, H-2 ), 8.83 (1H, s, OH). 13C NMR
00
0
(DMSO-d6) D 36.33, 55.02, 113.5, 129.7, 129.8, 152.3, 157.8.
5.2.5. N-Hydroxybenzamidine (15) [45]
A mixture of benzonitrile (4.4 g, 42.7 mmol) and hydroxyl-
amine hydrochloride (2.97 g, 42.7 mmol) in ethanol (40.0 mL)
was treated with triethylamine (13.0 mL) and heated at reflux
for 24 h after which the solvent was evaporated under reduced
pressure. Sodium carbonate solution (10%, 100.0 mL) was
added and the solution extracted with ethyl acetate. The com-
bined ethyl acetate extracts were dried, filtered and evaporated
under reduced pressure to afford viscous colourless oil, which
was purified with column chromatography eluting with (chlo-
roform/methanol) (9/1) to afford (3.5 g, 60.0%) the desired
N-hydroxybenzamidine (15) as a cream coloured powder.
M.p. ¼ 75e77 ꢂC, (lit [45] m.p. ¼ 79e80 ꢂC), 1H NMR
(DMSO-d6) D 5.7 (2H, s, NH2), 7.34 (3H, m, 3 ꢃ ArH),
7.65 (2H, m, 2 ꢃ ArH), 9.59 (1H, s, OH).
5.2.2. N-Hydroxy-2-phenyl-acetamidine (12) [42]
A mixture of phenylacetonitrile (5.0 g, 42.7 mmol) and hy-
droxylamine hydrochloride (4.97 g, 71.5 mmol) in ethanol
(75.0 mL) was treated with triethylamine (13.0 mL) and
heated at reflux for 24 h after which the solvent was evapo-
rated under reduced pressure. Sodium carbonate solution
(10%) was added and the solution extracted with ethyl acetate.
The combined ethyl acetate extracts were dried, filtered and
evaporated under reduced pressure to afford yellow oil, which
on standing crystallised to afford a yellow crystalline solid,
which was purified with column chromatography eluting
with (chloroform/methanol) (9/1) to afford (4.94 g, 77.0%)
the desired N-hydroxy-2-phenyl-acetamidine (12) as a cream
powder. M.p. ¼ 63e64 ꢂC, (lit [42] m.p. ¼ 67 ꢂC), M.S. m/z
1
151 (M þ 1)þ. H NMR (CDCl3) D 3.47 (2H, s, CH2), 4.45
5.2.6. N-Hydroxy-2-(thiophen-2-yl)acetamidine (16) [43,45]
Sodium metal (380.0 mg, 17.0 mmol) was added in small
pieces to methanol (12.0 mL), and once cooled, was treated
with a solution of hydroxylamine hydrochloride (1.14 g,
16.0 mmol) in methanol (20.0 mL). The reaction mixture
was stirred at room temperature for 40 min and filtered. The
filtrate was treated with thiophene-2-acetonitrile (1.74 mL,
16.0 mmol) and heated at gentle reflux for 48 h after which
the methanol was evaporated under reduced pressure to afford
a residue, which was purified with column chromatography
eluting with (chloroform/methanol) (19/1) to afford (1.07 g,
49%) the desired N-hydroxy-2-(thiophen-2-yl)acetamidine
(16) as a cream solid. M.p. ¼ 77 ꢂC (lit [45] m.p. ¼ 80 ꢂC),
(2H, s, NH2), 6.88 (1H, s, OH), 7.22e7.38 (5H, m, 5 ꢃ ArH).
5.2.3. N-Hydroxy-2-naphthalen-2-yl-acetamidine (13) [43]
A mixture of naphthalene-2-acetonitrile (2.34 g, 14.0 mmol)
and hydroxylamine hydrochloride (1.94 g, 28.0 mmol) in
ethanol (40.0 mL) was treated with triethylamine (4.4 mL)
and heated at reflux for 24 h after which the solvent was evap-
orated under reduced pressure. Sodium carbonate solution
(10%) was added and the solution extracted with ethyl acetate.
The combined ethyl acetate extracts were dried, filtered and
evaporated under reduced pressure to afford a yellow powder,
which was recrystallised from ethyl acetate/hexane to afford
(910.0 mg, 32.0%) the desired N-hydroxy-2-naphthalen-2-yl-
acetamidine (13) as a cream powder. M.p. ¼ 117e119 ꢂC,
1
M.S. m/z 157 (M þ 1)þ. H NMR (DMSO-d6) D 3.45 (2H,
s, CH2), 5.37 (2H, s, NH2), 6.9 (2H, m, 2 ꢃ ArH), 7.3 (1H,
1
M.S. m/z 201 (M þ 1)þ. H NMR (DMSO-d6) D 3.46 (2H,
m, ArH), 8.89 (1H, s, OH).
s, CH2), 5.45 (2H, s, NH2), 7.4e7.5 (3H, m, 3 ꢃ ArH),
7.77e7.89 (4H, m, 4 ꢃ ArH), 8.97 (1H, s, OH). 13C NMR
(DMSO-d6) D 37.36, 125.4, 126.0, 126.8, 127.3, 127.4,
127.4, 127.5, 131.8, 133.0, 135.6, 152.0. Found C, 71.95, H,
6.1, N, 13.95%, C12H12N2O requires C, 71.98, H, 6.04, N,
13.99%.
5.2.7. N-Hydroxy-2-(4-nitrophenyl)acetamidine (17) [43]
Sodium metal (741.0 mg, 32.23 mmol) was added in small
pieces to methanol (20.0 mL), and once cooled, was treated
with a solution of hydroxylamine hydrochloride (2.1 g,
30.3 mmol) in methanol (40.0 mL). The mixture was stirred
at room temperature for 40 min and filtered. The filtrate was
treated with (4-nitrophenyl)acetonitrile (4.91 g, 30.3 mmol)
and heated at gentle reflux for 48 h after which the solvent
was evaporated under reduced pressure. The residue was
purified by flash chromatography eluting with (chloroform/
methanol) (19/1) to afford (2.9 g, 49.0%) the desired N-
hydroxy-2-(4-nitrophenyl)acetamidine (17) as a green powder.
5.2.4. N-Hydroxyisonicotinamidine (14) [44]
A mixture of 4-cyanopyridine (4.48 g, 43.0 mmol) and hy-
droxylamine hydrochloride (2.97 g, 43.0 mmol) in ethanol
(60.0 mL) was treated with triethylamine (13.0 mL) and
heated at reflux for 24 h after which the solvent was evapo-
rated under reduced pressure. Sodium carbonate solution

528
G.P. Moloney et al. / European Journal of Medicinal Chemistry 43 (2008) 513e539
M.p. ¼ 154e156 ꢂC, M.S. m/z 196 (M þ 1)þ. 1H NMR
(DMSO-d6) D 3.43 (2H, s, CH2), 5.46 (2H, s,00NH2), AA0BB0
5.2.11. N-Hydroxy-2-(2-methoxyphenyl)acetamidine
(21) [43,47]
0
system: 7.54 (2H, d, JAB þ JAB ¼ 8.7 Hz, H-2 ), 8.15 (2H, d,
Sodium metal (160.0 mg, 6.79 mmol) was added in small
pieces to methanol (5.0 mL), and once cooled, was treated
with a solution of hydroxylamine hydrochloride (470.0 mg,
6.79 mmol) in methanol (8.0 mL). The mixture was stirred
at room temperature for 40 min and filtered. The filtrate was
treated with (2-methoxyphenyl)acetonitrile (1.0 g, 6.79 mmol)
and heated at gentle reflux for 16 h after which the solvent
was evaporated under reduced pressure to afford a residue,
which was purified with column chromatography eluting
with (chloroform/methanol) (19/1) to afford (570.0 mg,
47.0%) the desired 2-(2-methoxyphenyl)-N-hydroxyacetami-
00
0
JAB þ JAB ¼ 8.7 Hz, H-3 ), 8.93 (1H, s, OH).
5.2.8. 2-(4-Bromophenyl)-N-hydroxy-acetamidine
(18) [43,46]
Sodium metal (590.0 mg, 25.6 mmol) was added in small
pieces to methanol (20.0 mL), and once cooled, was treated
with a solution of hydroxylamine hydrochloride (1.77 g,
25.5 mmol) in methanol (40.0 mL). The mixture was stirred
at room temperature for 40 min and filtered. The filtrate was
treated with 2-(4-bromophenyl)-N-hydroxyacetamidine (5.0 g,
25.5 mmol) and heated at gentle reflux for 16 h after which
the solvent was evaporated under reduced pressure to afford
a residue, which was purified with column chromatography
eluting with (chloroform/methanol) (19/1) to afford (1.9 g,
33.0%) the desired 2-(4-bromophenyl)-N-hydroxy-acetami-
dine (18) as a pale yellow powder. M.p. ¼ 132e134 ꢂC,
dine (21) as a yellow oil. M.S. m/z 181 (M þ 1)þ. H NMR
1
(CDCl3) D 3.48 (2H, s, CH2), 3.88 (3H, s, OCH3), 4.77 (2H,
s, NH2), 6.95e6.88 (2H, m, 2 ꢃ ArH), 7.21e7.27 (2H, m,
2 ꢃ ArH), 7.3e7.9 (1H, br s, OH). Found C, 59.8, H, 6.68,
N, 15.4%, C9H12N2O2 requires C, 59.99, H, 6.71, N, 15.55%.
1
M.S. m/z 229/231 (M þ 1)þ. H NMR (DMSO-d6) D 3.22
(2H, s, CH2), 5.4 (2H, s, NH2), AA0BB0 system: 7.21 (2H,
m, H-200), 7.47 (2H, m, H-300), 8.89 (1H, s, OH).
5.2.12. 2-(4-Chlorophenyl)-N-hydroxyacetamidine
(22) [42,43]
Sodium metal (150.0 mg, 6.6 mmol) was added in small
pieces to methanol (5.0 mL), and once cooled, was treated
with a solution of hydroxylamine hydrochloride (460.0 mg,
6.6 mmol) in methanol (8.0 mL). The mixture was stirred at
room temperature for 40 min and filtered. The filtrate was
treated with (4-chlorophenyl)acetonitrile (1.0 g, 6.6 mmol)
and heated at gentle reflux for 16 h after which the solvent
was evaporated under reduced pressure to afford a residue,
which was purified with column chromatography eluting
with (chloroform/methanol) (19/1) to afford (200.0 mg,
16.0%) the desired 2-(4-chlorophenyl)-N-hydroxyacetamidine
(22) as a yellow powder. M.p. ¼ 103e104 ꢂC, M.S. m/z 185,
5.2.9. 2-(2-Chlorophenyl)-N-hydroxyacetamidine (19) [43]
Sodium metal (450.0 mg, 19.8 mmol) was added in small
pieces to methanol (15.0 mL), and once cooled, was treated
with a solution of hydroxylamine hydrochloride (1.38 g,
19.8 mmol) in methanol (40.0 mL). The mixture was stirred
at room temperature for 40 min and filtered. The filtrate was
treated with 2-chlorobenzylcyanide (3.0 g, 19.8 mmol) and
heated at gentle reflux for 16 h after which the solvent was
evaporated under reduced pressure to afford a residue, which
was purified with column chromatography eluting with (chlo-
roform/methanol) (19/1) to afford (1.05 g, 58.0%) the desired
2-(2-chlorophenyl)-N-hydroxyacetamidine (19) as a whiþte
powder. M.p. ¼ 112e114 ꢂC, M.S. m/z 185/187 (M þ 1) .
1H NMR (DMSO-d6) D 3.42 (2H, s, CH2), 5.45 (2H, s,
NH2), 7.22e7.28 (2H, m, 2 ꢃ ArH), 7.33e7.41 (2H, m,
2 ꢃ ArH), 8.98 (1H, s, OH). Found: (M þ 1)þ ¼ 185.0474,
C8H9ClN2O requires (M þ 1)þ ¼ 185.0476.
1
187 (M þ 1)þ. H NMR (CDCl3) D 3.56 (2H, s, CH2), 5.3
(3H, s, NH2 þ OH), AA0BB0 system: 7.23 (2H, d, JAB
þ
00
00
0
0
JAB ¼ 8.4 Hz, H-2 ), 7.34 (2H, d, JAB þ JAB ¼ 8.7 Hz, H-3 ).
5.2.13. N-Hydroxy-3-phenyl-propionamidine (23) [43,48]
Sodium metal (880.0 mg, 38.0 mmol) was added in small
pieces to methanol (40.0 mL), and once cooled, was treated
with a solution of hydroxylamine hydrochloride (2.65 g,
38.0 mmol) in methanol (20.0 mL). The mixture was stirred
at room temperature for 40 min and filtered. The filtrate was
treated with hydrocinnamonitrile (5.0 g, 38.0 mmol) and
heated at gentle reflux for 24 h after which the solvent was
evaporated under reduced pressure to afford a residue, which
was purified with column chromatography eluting with (chlo-
roform/methanol) (19/1) to afford (3.73 g, 60.0%) the desired
N-hydroxy-3-phenyl-propionamidine (23) as a viscous yellow
5.2.10. 2-(2,4-Dichlorophenyl)-N-hydroxyacetamidine
(20) [43]
Sodium metal (120.0 mg, 5.2 mmol) was added in small
pieces to methanol (4.0 mL), and once cooled, was treated
with a solution of hydroxylamine hydrochloride (370.0 mg,
5.38 mmol) in methanol (8.0 mL). The mixture was stirred
at room temperature for 40 min and filtered. The filtrate was
treated with 2,4-dichlorophenylacetonitrile (1.0 g, 5.38 mmol)
and heated at gentle reflux for 16 h after which the solvent
was evaporated under reduced pressure to afford a residue,
which was purified with column chromatography eluting
with (chloroform/methanol) (19/1) to afford (500.0 mg,
42.0%) the desired 2-(2,4-dichlorophenyl)-N-hydroxyacetami-
dine (20) as a yellow powder. M.S. m/z 219/221/223 (M þ 1)þ.
1H NMR (CDCl3) D 3.57 (2H, s, CH2), 4.55 (1H, s, OH), 5.42
(2H, s, NH2), 7.24e7.43 (3H, m, 3 ꢃ ArH).
1
oil. M.S. m/z 165 (M þ 1)þ. H NMR (CDCl3) D 2.46 (2H, t,
J ¼ 7.8 Hz, CH2), 2.89 (2H, t, J ¼ 7.8 Hz, CH2), 4.49 (2H, s,
NH2), 7.16e7.35 (5H, m, 5 ꢃ ArH), 7.92 (1H, s, OH).
Found: (M þ 1)þ ¼ 165.102, C9H12N2O requires (M þ 1)þ ¼
165.1022.

G.P. Moloney et al. / European Journal of Medicinal Chemistry 43 (2008) 513e539
529
5.2.14. N-Hydroxy-2-biphenylacetamidine (24) [43,49]
for an additional 30 min, the amidoxime/sieves/sodium hy-
dride mixture was added in one portion to the acid/CDI mix-
ture and the resulting mixture was heated at gentle reflux for
24 h. The solvent was evaporated under reduced pressure
and the residue partitioned between ethyl acetate and sodium
bicarbonate solution (5%). The entire mixture was filtered
through a sintered glass funnel and the phases separated.
The aqueous portion was extracted with ethyl acetate and
the combined ethyl acetate extracts were dried, filtered and
evaporated under reduced pressure to afford an oily black
solid, which was purified with column chromatography eluting
with chloroform to afford (124.0 mg, 14.0%) the desired
5-(1H-indol-3-yl)-3-(thiophen-2-ylmethyl)-1,2,4-oxadiazole
A mixture of biphenyl-4-carbonitrile (1.0 g, 5.58 mmol)
and hydroxylamine hydrochloride (769.0 mg, 11.16 mmol) in
ethanol (10.0 mL) was treated with triethylamine (1.76 mL)
and heated at reflux for 16 h after which the solvent was evap-
orated under reduced pressure. Sodium carbonate solution
(10%) was added and the solution extracted with ethyl acetate.
The combined ethyl acetate extracts were dried, filtered and
evaporated under reduced pressure to afford a white solid,
which was purified with column chromatography eluting
with (chloroform/methanol) (95/5) to afford (695.0 mg,
60.0%) the desired N-hydroxy-2-biphenyl-acetamidine (24)
as a white powder. M.S. m/z 213 (M þ 1)þ. 1H NMR
(DMSO-d6) D 5.7 (2H, s, NH2), 6.93 (1H, m, ArH), 7.26
(1H, m, ArH), 7.36 (2H, m, 2 ꢃ ArH), 7.57 (2H, m,
2 ꢃ ArH), 7.6 (1H, m, ArH), 7.65 (2H, d, J ¼ 8.2 Hz,
2 ꢃ ArH), 9.54 (1H, s, OH). Found C, 73.58, H, 5.69, N,
13.18%, C13H12N2O requires C, 73.6, H, 5.66, N, 13.19%.
1
(26) as a black powder. M.S. m/z 282 (M þ 1)þ. H NMR
(CDCl3) D 4.37 (2H, m, CH2), 6.98 (1H, dd, J ¼ 3.6,
5.1 Hz, H-400), 7.07 (1H, m, H-300), 7.23 (1H, dd, J ¼ 1.2,
5.1 Hz, H-500), 7.3e7.39 (2H, m, 2 ꢃ ArH), 7.44e7.5 (1H,
m, ArH), 8.06 (1H, d, J ¼ 2.7 Hz, ArH), 8.3e8.33 (1H, m,
ArH), 8.64 (1H, br s, NH). Found: (M þ 1)þ ¼ 282.0688,
C15H11N3OS requires (M þ 1)þ ¼ 282.0696.
5.2.15. 3-Benzyl-5-(1H-indol-3-yl)-1,2,4-oxadiazole (25)
[43]
Indole-3-carboxylic acid (820.0 mg, 5.1 mmol) and carbon-
yldiimidazole (914.0 mg, 5.6 mmol) were stirred in anhydrous
DME (20.0 mL) for 16 h. To a stirred solution of N-hydroxy-
2-phenyl-acetamidine (766.0 mg, 5.1 mmol) in anhydrous
5.2.17. 5-(1H-Imidazol-4-yl)-3-(thiophen-2-ylmethyl)-1,2,4-
oxadiazole (27)
Imidazole-4-carboxylic acid (247.2 mg, 2.2 mmol) and
carbonyldiimidazole (395.0 mg, 2.42 mmol) were stirred in
anhydrous DME (8.0 mL) for 16 h. To a stirred solution of
N-hydroxy-2-phenyl-acetamidine (331.2 mg, 2.2 mmol) in an-
hydrous DME (8.0 mL), was added crushed molecular sieves
˚
DME (20.0 mL), was added crushed molecular sieves (3A,
900.0 mg). The mixture was stirred at room temperature for
30 min and sodium hydride (60%, 205.0 mg, 5.1 mmol) was
added. After stirring at room temperature for an additional
30 min, the amidoxime/sieves/sodium hydride mixture was
added in one portion to the acid/CDI mixture and the resulting
mixture was heated at gentle reflux for 24 h. The solvent was
evaporated under reduced pressure and the residue partitioned
between ethyl acetate (50.0 mL) and sodium bicarbonate solu-
tion (5%, 50.0 mL). The entire mixture was filtered through
a sintered glass funnel and the phases separated. The aqueous
portion was extracted with ethyl acetate (2 ꢃ 20.0 mL), and
the combined organic extracts were dried, filtered and evapo-
rated under reduced pressure to afford an oily yellow solid,
which was recrystallised from ethyl acetate/hexane to afford
(720.0 mg, 51.0%) the desired 3-benzyl-5-(1H-indol-3-yl)-
1,2,4-oxadiazole (25) as white crystals. M.p. ¼ 198e199 ꢂC,
˚
(3 A, 360.0 mg). The mixture was stirred at room temperature
for 30 min and sodium hydride (60%, 88.2 mg, 2.2 mmol) was
added. After stirring at room temperature for an additional
30 min, the imidamide/sieves/sodium hydride mixture was
added in one portion to the acid/CDI mixture and the resulting
mixture was heated at gentle reflux for 24 h. The solvent was
evaporated under reduced pressure and the residue partitioned
between ethyl acetate and sodium bicarbonate solution (5%).
The entire mixture was filtered through a sintered glass
funnel and the phases separated. The aqueous phase was
extracted with ethyl acetate and the combined ethyl acetate
extracts were dried, filtered and evaporated under reduced
pressure to afford an yellow solid, which was purified with
column chromatography eluting with (chloroform/methanol)
(9/1) to afford (469.0 mg, 94.0%) the desired 5-(1H-imida-
zol-4-yl)-3-(thiophen-2-ylmethyl)-1,2,4-oxadiazole (27) as
1
M.S. m/z 276 (M þ 1)þ. H NMR (CDCl3) D 4.16 (2H, s,
CH2), 7.21e7.48 (8H, m, 8 ꢃ ArH), 8.02 (1H, m, ArH), 8.28
(1H, m, ArH), 8.7 (1H, s, NH). Found C, 74.15, H, 4.7, N,
15.2%, C17H13N3O requires C, 74.17, H, 4.76, N, 15.26%.
1
a cream powder. M.S. m/z 227 (M þ 1)þ. H NMR (DMSO-
d6) D 4.09 (2H, s, CH2), 7.02 (1H, s, NH), 7.19e7.35 (5H,
m, 5 ꢃ ArH), 7.92 (1H, s, ArH), 8.08 (1H, s, ArH). Found:
(M þ 1)þ ¼ 227.0923, C12H10N4O requires (M þ 1)þ ¼
2227.0927.
5.2.16. 5-(1H-Indol-3-yl)-3-(thiophen-2-ylmethyl)-1,2,4-
oxadiazole (26) [43]
1H-Indole-3-carboxylic acid (505.5 mg, 3.13 mmol) and
carbonyldiimidazole (562.0 mg, 3.44 mmol) were stirred in
anhydrous DME (15.0 mL) for 16 h. To a stirred solution of
N-hydroxy-2-thiophen-2-yl-acetamidine (470.0 mg, 3.13 mmol)
in anhydrous DME (15.0 mL), was added crushed molecular
5.2.18. 3-(4-Bromobenzyl)-5-(1H-indol-3-yl)-1,2,4-oxadiazole
(28) [43]
1H-Indole-3-carboxylic acid (350.0 mg, 2.17 mmol) and
carbonyldiimidazole (389.0 mg, 2.38 mmol) were stirred in
anhydrous THF (20.0 mL) for 16 h. To a stirred solution of
4-bromobenzylamido oxime (1.0 g, 4.37 mmol) in anhydrous
˚
sieves (3 A, 500.0 mg). The mixture was stirred at room tem-
perature for 30 min and sodium hydride (60%, 126.0 mg,
3.13 mmol) was added. After stirring at room temperature
˚
THF (20.0 mL) was added crushed molecular sieves (3 A,

530
G.P. Moloney et al. / European Journal of Medicinal Chemistry 43 (2008) 513e539
1.1 g). The mixture was stirred at room temperature for 30 min
and sodium hydride (60%, 175.0 mg, 4.38 mmol) was added.
After stirring at room temperature for an additional 30 min,
the amidoxime/sieves/sodium hydride mixture was added in
one portion to the acid/CDI mixture and the resulting mixture
was heated at gentle reflux for 24 h. The solvent was evapo-
rated under reduced pressure and the residue partitioned be-
tween ethyl acetate and sodium bicarbonate solution (5%).
The entire mixture was filtered through a sintered glass funnel
and the phases separated. The aqueous portion was extracted
with ethyl acetate and the combined organic extracts were
dried, filtered and evaporated under reduced pressure to afford
an yellow solid, which was purified with column chromatogra-
phy eluting with (chloroform/methanol) (9/1) to afford
(46.0 mg, 6.0%) the desired 3-(4-bromobenzyl)-5-(1H-indol-
3-yl)-1,2,4-oxadiazole (28) as a black solid. M.S. m/z 354/
Found:
(M þ 1)þ ¼ 306.11643.
(M þ 1)þ ¼ 306.12449
C18H15N3O2
requires
5.2.20. 3-(2-Chlorobenzyl)-5-(1H-indol-3-yl)-1,2,4-oxadiazole
(30) [43]
1H-Indole-3-carboxylic acid (440.0 mg, 2.71 mmol) and
carbonyldiimidazole (480.0 mg, 2.98 mmol) were stirred in
anhydrous DME (8.0 mL) under an atmosphere of nitrogen
at 80 ꢂC for 2 h. To a stirred solution of N-hydroxy-2-(2-chlor-
ophenyl)acetamidine (500.0 mg, 2.71 mmol) in anhydrous
˚
DME (8.0 mL), was added crushed molecular sieves (3 A,
550.0 mg). The mixture was stirred at room temperature for
30 min and sodium hydride (60%, 108.0 mg, 2.71 mmol)
was added. After stirring at room temperature for an additional
30 min, the amidoxime/sieves/sodium hydride mixture was
added in one portion to the acid/CDI mixture and the resulting
mixture was stirred at 80 ꢂC for 10 min followed by heating at
gentle reflux for 18 h. After this the reaction mixture was al-
lowed to cool to room temperature and the solvent was evap-
orated under reduced pressure and the residue was taken up in
water. The aqueous solution was extracted with ethyl acetate.
The combined ethyl acetate extracts were washed with brine
and water and dried, filtered and evaporated under reduced
pressure to afford an off white residue, which was purified
with column chromatography eluting with (chloroform/metha-
nol) (95/5) to afford (182.3 mg, 36.0%) the desired 3-(2-chlor-
obenzyl)-5-(1H-indol-3-yl)-1,2,4-oxadiazole (30) as a pale
brown powder. M.S. m/z 310/312 (M þ 1)þ. 1H NMR (CDCl3)
D 4.31 (2H, s, CH2), 7.2e7.48 (7H, m, 7 ꢃ ArH), 8.05 (1H,
m, ArH), 8.28 (1H, s, ArH), 8.67 (1H, s, NH). Found:
(M þ 1)þ ¼ 310.0744, C17H12ClN3O requires (M þ 1)þ ¼
310.0747. Found C, 65.9, H, 3.86, N, 13.52%, C17H12ClN3O re-
quires C, 65.92, H, 3.9, N, 13.57%.
1
356 (M þ 1)þ. H NMR (DMSO-d6) D 4.12 (2H, s, CH2),
7.25 (3H, m, 3 ꢃ ArH), AA0BB0 system: 7.34 (2H, d,
00
0
0
JAB þ JAB ¼ 8.4 Hz, H-2 ), 7.53 (2H, d, JAB þ JAB ¼ 8.4 Hz,
H-300), 8.04 (1H, m, ArH), 8.31 (1H, s, ArH), 12.17 (1H, s,
NH). Found: (M þ 1)þ ¼ 354.0223, C17H12BrN3O requires
(M þ 1)þ ¼ 354.0236.
5.2.19. 5-(1H-Indol-3-yl)-3-(4-methoxybenzyl)-1,2,4-oxadiazole
(29) [43]
1H-Indole-3-carboxylic acid (89.0 mg, 0.55 mmol) and car-
bonyldiimidazole (99.0 mg, 0.61 mmol) were stirred in anhy-
drous THF (10.0 mL) under an atmosphere of nitrogen at
room temperature for 2 h. To a stirred solution of N-hydroxy-
2-(4-methoxyphenyl)acetamidine (200.0 mg, 1.11 mmol) in
anhydrous THF (10.0 mL), was added crushed molecular
˚
sieves (3 A, 250.0 mg). The mixture was stirred at room tem-
perature for 30 min and sodium hydride (60%, 44.0 mg,
1.11 mmol) was added. After stirring at room temperature
for an additional 30 min, the amidoxime/sieves/sodium hy-
dride mixture was added in one portion to the acid/CDI mix-
ture and the resulting mixture was heated at gentle reflux for
4 h After this the reaction mixture was allowed to cool to
room temperature and the solvent was evaporated under re-
duced pressure and the residue was taken up in water. The
aqueous solution was extracted with ethyl acetate. The com-
bined ethyl acetate extracts were washed with brine and water
and dried, filtered and evaporated under reduced pressure to
afford an off white residue, which was purified with column
chromatography eluting with (chloroform/methanol) (95/5)
to afford (41.0 mg, 24.3%) the desired 5-(1H-indol-3-yl)-3-
(4-methoxybenzyl)-1,2,4-oxadiazole (29) as a grey solid.
5.2.21. 5-(1H-Indol-3-yl)-3-phenethyl-1,2,4-oxadiazole
(31) [43]
1H-Indole-3-carboxylic acid (980.0 mg, 6.08 mmol) and
carbonyldiimidazole (1.09 g, 6.7 mmol) were stirred in an-
hydrous DME (25.0 mL) under an atmosphere of nitrogen
at 80 ꢂC for 2 h. To a stirred solution of phenethylamidoox-
ime (1.0 g, 6.08 mmol) in anhydrous DME (25.0 mL) was
˚
added crushed molecular sieves (3 A, 1.0 g). The mixture
was stirred at room temperature for 30 min and sodium hy-
dride (60%, 240.0 mg, 6.08 mmol) was added. After stirring
at room temperature for an additional 30 min, the amidox-
ime/sieves/sodium hydride mixture was added in one portion
to the acid/CDI mixture and the resulting mixture was
stirred at 80 ꢂC for 10 min followed by heating at gentle re-
flux for 18 h. After this the reaction mixture was allowed to
cool to room temperature and the solvent was evaporated
under reduced pressure and the residue was taken up in wa-
ter. The aqueous solution was extracted with ethyl acetate.
The combined ethyl acetate extracts were washed with brine
and water and dried, filtered and evaporated under reduced
pressure to afford a pink residue, which was purified with
column chromatography eluting with chloroform to afford
1
M.S. m/z 306 (M þ 1)þ. H NMR (DMSO-d6) D 3.72 (3H,
0
s, CH3), 4.04 (2H, s, CH2), 6.89 (2H, d, JAB þ JAB ¼ 8.7 Hz,
H-200), 7.3-7.23 (4H, m, 4 ꢃ ArH), 7.51e7.53 (1H, m, ArH),
8.04 (1H, m, ArH), 8.3 (1H, s, ArH), 12.13 (1H, s, NH). 13C
NMR (methanol-d4) D 32.26, 55.84, 102.2, 113.4, 115.3,
121.6, 123.1, 124.5, 126.2, 129.4, 131.1, 138.4, 160.4,
170.9, 175.2. Found: (M þ 1)þ ¼ 306.1245, C18H15N3O2 re-
quires (M þ 1)þ ¼ 306.1243. Found C, 70.8, H, 4.92, N,
13.74%, C18H15N3O2 requires C, 70.81, H, 4.95, N, 13.76%.

G.P. Moloney et al. / European Journal of Medicinal Chemistry 43 (2008) 513e539
531
(326.3 mg, 18.65%) the desired 5-(1H-indol-3-yl)-3-phenethyl-
1,2,4-oxadiazole (31) as a pale pink powder. M.S. m/z 290
(M þ 1)þ. 1H NMR (CDCl3) D 3.16 (4H, m, 2 ꢃ CH2),
7.18e7.4 (7H, m, 7 ꢃ ArH), 7.43e7.53 (1H, m, ArH), 8.06
(1H, d, J ¼ 3.0 Hz, ArH), 8.28e8.37 (1H, m, ArH), 8.67
(1H, s, NH). Found: (M þ 1)þ ¼ 290.1279, C18H15N3O requires
(M þ 1)þ ¼ 290.1288. Found C, 74.7, H, 6.25, N, 13.72%,
C18H15N3O requires C, 74.73, H, 6.27, N, 13.76%.
for 4 h. After this the reaction mixture was allowed to cool
to room temperature and the reaction mixture was allowed
to stir at room temperature for 18 h. After this the solvent
was evaporated under reduced pressure and the residue was
taken up in water. The aqueous solution was extracted with
ethyl acetate. The combined ethyl acetate extracts were
washed with brine and water and dried, filtered and evaporated
under reduced pressure to afford a yellow residue, which was
purified with column chromatography eluting with (chloro-
form/methanol) (99/1) to afford (308.6 mg, 31.0%) the desired
(3-benzyl-[1,2,4]oxadiazol-5-yl)(1H-indol-3-yl)methanone (33)
as a yellow powder. M.p. ¼ 223e225 ꢂC, M.S. m/z 304
5.2.22. 3-(Biphenyl-4-yl)-5-(1H-indol-3-yl)-1,2,4-oxadiazole
(32) [43]
1H-Indole-3-carboxylic acid (49.4 mg, 0.31 mmol) and
carbonyldiimidazole (54.7 mg, 0.34 mmol) were stirred in
anhydrous THF (15.0 mL) for 16 h. To a stirred solution of
N-hydroxy-2-biphenyl-acetamidine (130.0 mg, 0.61 mmol) in
anhydrous THF (15.0 mL) was added crushed molecular
1
(M þ 1)þ. H NMR (DMSO-d6) D 4.28 (2H, s, CH2), 7.3e
7.51 (7H, m, 7 ꢃ ArH), 7.6 (1H, m, ArH), 8.25 (1H, m,
ArH), 8.75 (1H, s, ArH), 12.5 (1H, s, NH). Found C, 71.08,
H, 4.32, N, 13.46%, C18H13N3O2 requires C, 71.28, H, 4.32,
N, 13.85%.
˚
sieves (3 A, 100.0 mg). The mixture was stirred at room tem-
perature for 30 min and sodium hydride (60%, 24.6 mg,
0.61 mmol) was added. After stirring at room temperature
for an additional 30 min, the amidoxime/sieves/sodium hy-
dride mixture was added in one portion to the acid/CDI mix-
ture and the resulting mixture was heated at gentle reflux for
24 h. After this the solvent was evaporated under reduced pres-
sure and the residue partitioned between ethyl acetate and so-
dium bicarbonate solution (5%). The entire mixture was
filtered through a sintered glass funnel and the phases sepa-
rated. The aqueous portion was extracted with ethyl acetate
and the combined ethyl acetate extracts were dried, filtered
and evaporated under reduced pressure to afford an off white
solid, which was purified with column chromatography eluting
with (chloroform/methanol) (9/1) to afford a white solid,
which was recrystallised from ethyl acetate/hexane to afford
(78.0 mg, 75.4%) the desired 3-(biphenyl-4-yl)-5-(1H-indol-
3-yl)-1,2,4-oxadiazole (32) as white crystals. M.p. ¼ 236e
238 ꢂC, M.S. m/z 338 (M þ 1)þ. 1H NMR (DMSO-d6) D
7.16e7.19 (2H, m, 2 ꢃ ArH), 7.29 (1H, m, ArH), 7.36 (2H,
m, 2 ꢃ ArH), 7.43e7.46 (2H, m, 2 ꢃ ArH), 7.63 (2H, d,
J ¼ 6.0 Hz, 2 ꢃ ArH), 7.76 (2H, d, J ¼ 6.0 Hz, 2 ꢃ ArH),
8.06e8.12 (3H, m, 3 ꢃ ArH), 8.31 (1H, s, H-2). Found C,
78.3, H, 4.5, N, 12.44%, C22H15N3O requires C, 78.32, H,
4.48, N, 12.46%. Found: (M þ 1)þ ¼ 338.12672, C22H15N3O
requires (M þ 1)þ ¼ 338.12151.
5.2.24. 5-(1H-Indol-3-yl)-3-phenyl-1,2,4-oxadiazole
(34) [43,50]
1H-Indole-3-carboxylic acid (376.0 mg, 2.33 mmol) and
carbonyldiimidazole (416.0 mg, 2.57 mmol) were stirred in
anhydrous THF (8.0 mL) under an atmosphere of nitrogen at
room temperature for 30 min. To a stirred solution of N-hy-
droxy-2-phenyl-acetamidine (635.0 mg, 4.67 mmol) in anhy-
drous DME (8.0 mL), was added crushed molecular sieves
˚
(3 A, 770.0 mg). The mixture was stirred at room temperature
for 30 min and sodium hydride (60%, 187.0 mg, 4.67 mmol)
was added. After stirring at room temperature for an additional
30 min, the amidoxime/sieves/sodium hydride mixture was
added in one portion to the acid/CDI mixture and the resulting
mixture was stirred at 80 ꢂC for 10 min followed by heating at
gentle reflux for 18 h. After this the reaction mixture was al-
lowed to cool to room temperature and the solvent was evap-
orated under reduced pressure and the residue was taken up in
water. The aqueous solution was extracted with ethyl acetate.
The combined ethyl acetate extracts were washed with brine
and water and dried, filtered and evaporated under reduced
pressure to afford an off white solid, which was purified
with column chromatography eluting with chloroform to af-
ford to afford a white solid, which was recrystallised from
ethyl acetate/hexane to afford (400.0 mg, 65.61%) the desired
5-(1H-indol-3-yl)-3-phenyl-1,2,4-oxadiazole (34) as fineþwhite
crystals. M.p. ¼ 172e173 ꢂC, M.S. m/z 262 (M þ 1) . 1H
NMR (DMSO-d6) D 7.3 (2H, m, 2 ꢃ ArH), 7.6 (4H, m,
4 ꢃ ArH), 8.14 (2H, m, 2 ꢃ ArH), 8.23 (1H, m, ArH), 8.43
(1H, s, ArH), 12.27 (1H, s, NH). Found C, 73.54, H, 4.2, N,
16.06%, C16H11N3O requires C, 73.56, H, 4.24, N, 16.08%.
5.2.23. (3-Benzyl-[1,2,4]oxadiazol-5-yl)(1H-indol-3-yl)-
methanone (33)
Indole-3-glyoxylic acid (630.0 mg, 3.33 mmol) and carbon-
yldiimidazole (590.0 mg, 6.7 mmol) were stirred in anhydrous
THF (20.0 mL) under an atmosphere of nitrogen at room tem-
perature for 2 h. To a stirred solution of benzylamidooxime
(1.0 g, 6.66 mmol) in anhydrous THF (20.0 mL) was added
5.2.25. (1H-Indol-3-yl)(3-phenyl-1,2,4-oxadiazol-5-yl)-
methanone (35)
˚
crushed molecular sieves (3 A, 1.1 g). The mixture was stirred
at room temperature for 30 min and sodium hydride (60%,
266.0 mg, 6.66 mmol) was added. After stirring at room tem-
perature for an additional 30 min, the amidoxime/sieves/so-
dium hydride mixture was added in one portion to the acid/
CDI mixture and the resulting mixture was stirred at room
temperature for 30 min followed by heating at gentle reflux
Indole-3-glyoxylic acid (274.0 mg, 1.44 mmol) and carbon-
yldiimidazole (259.0 mg, 1.59 mmol) were stirred in anhy-
drous THF (10.0 mL) under an atmosphere of nitrogen at
room temperature for 2 h. To a stirred solution of phenylami-
dooxime (394.0 mg, 2.89 mmol) in anhydrous THF (10.0 mL)
˚
was added crushed molecular sieves (3 A, 479.0 mg). The

532
G.P. Moloney et al. / European Journal of Medicinal Chemistry 43 (2008) 513e539
mixture was stirred at room temperature for 30 min and so-
dium hydride (60%, 116.0 mg, 2.89 mmol) was added. After
stirring at room temperature for an additional 30 min, the ami-
doxime/sieves/sodium hydride mixture was added in one por-
tion to the acid/CDI mixture and the resulting mixture was
stirred at room temperature for 30 min followed by heating
at gentle reflux for 4 h. After this the reaction mixture was al-
lowed to cool to room temperature and the solvent was evap-
orated under reduced pressure and the residue was taken up in
water. The aqueous solution was extracted with ethyl acetate.
The combined ethyl acetate extracts were washed with brine
and water and dried, filtered and evaporated under reduced
pressure to afford a yellow solid, which was purified with
column chromatography eluting with (chloroform/methanol)
(95/5) to afford (185.0 mg, 44.15%) the desired (1H-indol-3-yl)
(3-phenyl-1,2,4-oxadiazol-5-yl)methanone (35) as a yellow
powder. M.p. ¼ 258e260 ꢂC, M.S. m/z 290 (M þ 1)þ. 1H
NMR (DMSO-d6) D 7.31 (2H, m, 2 ꢃ ArH), 7.56e7.7 (4H, m,
4 ꢃ ArH), 8.17 (2H, m, 2 ꢃ ArH), 8.3 (2H, m, 2 ꢃ ArH), 8.98
(1H, s, ArH), 12.11 (1H, s, NH). Found C, 70.54, H, 3.81, N,
14.5%, C17H11N3O2 requires C, 70.56, H, 3.84, N, 14.53%.
(5.0 mL) was added sodium hydride (60%, 79.0 mg,
1.97 mmol). The mixture was stirred at room temperature
for 30 min and 4-(2-chloroethyl)morpholine hydrochloride
(157.0 mg, 0.84 mmol) was added. The reaction mixture was
stirred at room temperature for 30 min and at 100 ꢂC for
16 h after which the reaction mixture was allowed to cool to
room temperature and the solvent was then evaporated under
reduced pressure to a yellow residue, which was taken up in
water. The aqueous phase was basified with potassium carbon-
ate and the basic aqueous phase was extracted with ethyl ace-
tate. The combined ethyl acetate extracts were dried, filtered
and evaporated under reduced pressure to afford a yellow
solid, which was purified with column chromatography eluting
with (dichloromethane/ethanol/ammonia) (250/5/1) to afford
(52.0 mg, 14.9%) the desired 4-(2-(3-(3-benzyl-[1,2,4]oxadia-
zol-5-yl)-1H-indol-1-yl)ethyl)morpholine (37) as a yellow
powder. M.S. m/z 389 (M þ 1)þ. 1H NMR (DMSO-d6) D
2.42 (4H, m, 2 ꢃ NCH2), 2.71 (2H, t, J ¼ 5.7 Hz, CH2), 3.49
(4H, m, 2 ꢃ OCH2), 4.13 (2H, s, CH2), 4.4 (2H, t,
J ¼ 6.0 Hz, CH2), 7.25e7.36 (7H, m, 7 ꢃ ArH), 7.67 (1H, d,
J ¼ 8.1 Hz, ArH), 8.05 (1H, d, J ¼ 6.9 Hz, H-5), 8.41 (1H, s,
H-2). H.p.l.c. retention time ¼ 5.39 min; (10% B/90% D) to
(100% B) over 20 min (B ¼ 90% CH3CN/10% H2O)
(D ¼ 0.05% aqueous TFA).
5.2.26. 5-(1H-Indol-3-yl)-3-(naphthalene-2-ylmethyl)-1,2,4-
oxadiazole (36) [43]
1H-Indole-3-carboxylic acid (80.0 mg, 0.49 mmol) and car-
bonyldiimidazole (89.0 mg, 0.54 mmol) were stirred in anhy-
drous THF (15.0 mL) under an atmosphere of nitrogen at
room temperature for 2 h. To a stirred solution of N-hydroxy-
2-(2-naphthalen-2-yl)acetamidine (200.0 mg, 0.55 mmol) in
anhydrous THF (15.0 mL), was added crushed molecular
5.2.28. 3-Benzyl-5-(1-(2-pyrrolidin-1-yl)ethyl)-1H-indol-3-yl)-
1,2,4-oxadiazole (38) [43]
To a stirred solution of 3-(3-benzyl-[1,2,4]oxadiazol-5-yl)-
1H-indole (120.0 mg, 0.43 mmol) in anhydrous DMF (2.0 mL)
was added sodium hydride (60%, 38.0 mg, 0.95 mmol). The
mixture was stirred at room temperature for 30 min and 1-(2-
chloroethyl)pyrrolidine hydrochloride (81.0 mg, 0.5 mmol)
was added. The reaction mixture was stirred at room temper-
ature for 30 min and at 100 ꢂC for 24 h after which the solvent
was evaporated under reduced pressure. Sodium carbonate so-
lution (10%, 30.0 mL) was added and the solution was ex-
tracted with ethyl acetate. The combined ethyl acetate
extracts were dried, filtered and evaporated under reduced
pressure to afford a yellow residue, which was purified by
column chromatography eluting with (chloroform/methanol)
(19/1), to afford (116.0 mg, 72.0%) the desired 3-benzyl-5-(1-
(2-pyrrolidin-1-yl)ethyl)-1H-indol-3-yl)-1,2,4-oxadiazole (38)
˚
sieves (3 A, 500.0 mg). The mixture was stirred at room tem-
perature for 30 min and sodium hydride (60%, 40.0 mg,
0.5 mmol) was added. After stirring at room temperature for
an additional 30 min, the amidoxime/sieves/sodium hydride
mixture was added in one portion to the acid/CDI mixture
and the resulting mixture was heated to gentle reflux for 4 h.
After this the reaction mixture was allowed to cool to room
temperature and the solvent was evaporated under reduced
pressure and the residue was taken up in water. The aqueous
solution was extracted with ethyl acetate. The combined ethyl
acetate extracts were washed with brine and water and dried,
filtered and evaporated under reduced pressure to afford a yel-
low residue, which was purified with column chromatography
eluting with (chloroform/methanol) (95/5) to afford
(140.0 mg, 86.7%) the desired 5-(1H-indol-3-yl)-3-(naphtha-
lene-2-ylmethyl)-1,2,4-oxadiazole (36) as a yellow powder.
1
as a viscous yellow oil. M.S. m/z 373 (M þ 1)þ. H NMR
(methanol-d4) D 1.64 (4H, m, 2 ꢃ CH2), 2.39 (4H, m,
2 ꢃ CH2), 2.71 (2H, t, J ¼ 6.9 Hz, CH2), 4.01 (2H, s, CH2),
4.14 (2H, t, J ¼ 6.9 Hz, CH2), 7.1e7.38 (8H, m, 8 ꢃ ArH),
7.94 (1H, s, H-2), 8.06 (1H, m, H-4). 13C NMR (methanol-
d4) D 22.81, 31.53, 45.21, 53.59, 54.68, 100.0, 110.1, 120.5,
121.8, 123.0, 125.1, 126.5, 128.2, 128.6, 132.4, 135.9,
136.4, 169.1, 173.3. Found C, 70.7, H, 6.5, N, 14.24%,
C23H24N4O$1H2O requires C, 70.74, H, 6.66, N, 14.27%.
1
M.S. m/z 326 (M þ 1)þ. H NMR (DMSO-d6) D 3.62 (2H,
s, CH2), 7.25 (3H, m, 3 ꢃ ArH), 7.4e7.51 (3H, m,
3 ꢃ ArH), 7.7e7.81 (4H, m, 4 ꢃ ArH), 8.02 (1H, m, ArH),
8.29 (1H, s, ArH), 12.0 (1H, s, NH). Found C, 77.48, H,
4.64, N, 12.9%, C21H15N3O requires C, 77.52, H, 4.65, N,
12.91%.
5.2.29. (3-Benzyl-1,2,4-oxadiazol-5-yl)(1-(2-morpholinoethyl)-
5.2.27. 4-(2-(3-(3-Benzyl-[1,2,4]oxadiazol-5-yl)-1H-indol-1-yl)-
ethyl)morpholine (37) [43]
1H-indol-3-yl)methanone (39)
To
a
stirred solution of (1H-indol-3-yl)-(3-phenyl-
To a stirred solution of 3-[3-benzyl-[1,2,4]oxadiazol-5-yl]-
1H-indole (247.0 mg, 0.89 mmol) in anhydrous DMF
[1,2,4]oxadiazol-5-yl)-methanone (100.0 mg, 0.33 mmol) in
anhydrous DMF (10.0 mL) was added sodium hydride (60%,

G.P. Moloney et al. / European Journal of Medicinal Chemistry 43 (2008) 513e539
533
29.0 mg, 0.73 mmol). The mixture was stirred at room temper-
ature for 30 min and 4-(2-chloroethyl)morpholine hydrochlo-
ride (61.0 mg, 0.33 mmol) was added. The reaction mixture
was stirred at room temperature for 30 min and at 100 ꢂC
for 4 h after which the reaction mixture was allowed to cool
to room temperature and the solvent was then evaporated un-
der reduced pressure to afford a yellow residue. The yellow
residue was taken up in water and the aqueous solution was
basified with potassium carbonate. The basic aqueous solution
was extracted with ethyl acetate. The combined ethyl acetate
extracts were dried, filtered and evaporated under reduced
pressure to afford a yellow solid, which was purified with col-
umn chromatography eluting with (chloroform/methanol) (95/
5) to afford (120.0 mg, 87.6%) the desired 3-benzyl-5-(1-[2-
(morpholine-4-yl)ethyl]-3-indoloyl)oxadiazole (39) as a yellow
powder. M.S. m/z 417 (M þ 1)þ. 1H NMR (DMSO-d6) D 2.42
(4H, t, J ¼ 4.5 Hz, 2 ꢃ CH2), 2.69 (2H, t, J ¼ 6.0 Hz, CH2),
3.49 (4H, t, J ¼ 4.5 Hz, 2 ꢃ CH2), 4.27 (2H, s, CH2), 4.44
(2H, t, J ¼ 6.0 Hz, CH2), 7.28e7.39 (7H, m, 7 ꢃ ArH),
7.68e7.74 (1H, m, H-7), 8.23e8.29 (1H, s, H-2). Found C,
69.2, H, 5.78, N, 14.4%, C24H24N4O3 requires C, 69.21, H,
5.81, N, 13.45%.
4-(2-chloroethyl)morpholine hydrochloride (28.0 mg, 0.15 mmol)
was added. The reaction mixture was stirred at room tempera-
ture for 30 min and at 100 ꢂC for 18 h after which the solvent
was evaporated under reduced pressure. Sodium carbonate solu-
tion (10%) was added and the solution was extracted with ethyl
acetate. The combined ethyl acetate extracts were dried, filtered
and evaporated under reduced pressure to afford a white solid,
which was recrystallised from ethyl acetate/hexane to afford
(45.0 mg, 67.5%) the desired 4-(2-(3-(3-biphenyl-4-yl)-1,2,4-
oxadiazol-5-yl)-1H-indol-1-yl)ethyl)morpholine (41) as white
crystals. M.p. ¼ 138e140 ꢂC, M.S. m/z 451 (M þ 1)þ.
1H NMR (DMSO-d6) D 2.57 (4H, m, 2 ꢃ CH2), 2.8 (2H, t, J ¼
6.3 Hz, CH2), 3.6 (4H, m, 2 ꢃ CH2), 4.53 (2H, t, J ¼ 6.2 Hz,
CH2), 7.41 (1H, m, ArH), 7.45 (1H, m, ArH), 7.59 (2H, m, 2 ꢃ
ArH), 7.77e7.86 (3H, m, 3 ꢃ ArH), 7.98 (2H, d, J ¼ 8.4 Hz,
2 ꢃ ArH), 8.26 (2H, d, J ¼ 8.3 Hz, 2 ꢃ ArH), 8.27e8.28 (1H, m,
ArH), 8.62 (1H, s, H-2). Found C, 74.63, H, 5.86, N, 12.11%,
C28H26N4O2 requires C, 74.65, H, 5.82, N, 12.44%. Found:
(M þ 1)þ ¼ 451.21302, C28H26N4O2 requires (M þ 1)þ ¼
451.20558. Retention time ¼ 27.51 min (Isocratic 50 B/50 D
(B ¼ CH3CN/H2O 9/1) (D ¼ 0.05% TFA in H2O).
5.2.32. 1-Morpholino-2-(3-phenyl-1,2,4-oxadiazol-5-yl)-
1H-indol-1-yl)ethanone (42)
5.2.30. 4-(2-(3-(3-Phenyl-1,2,4-oxadiazol-5-yl)-1H-indol-1-yl)-
ethyl)morpholine (40) [43]
To a stirred solution of 3-(3-phenyl-[1,2,4]oxadiazol-5-yl)-
1H-indole (121.0 mg, 0.46 mmol) in anhydrous DMF (5.0 mL)
was added sodium hydride (60%, 37.1 mg, 0.93 mmol). The
mixture was stirred at room temperature for 30 min and 2-
bromo-1-(4-morpholinyl)-1-ethanone (96.4 mg, 0.46 mmol)
was added. The reaction mixture was stirred at room temper-
ature for 30 min and at 80 ꢂC for 9 h after which the reaction
mixture was allowed to cool to room temperature and the sol-
vent was then evaporated under reduced pressure to afford
a yellow residue. The yellow residue was taken up in water
and the aqueous solution was basified with sodium carbonate.
The basic aqueous solution was the extracted with ethyl ace-
tate. The combined ethyl acetate extracts were dried, filtered
and evaporated under reduced pressure to afford a yellow
solid, which was purified with column chromatography eluting
with (chloroform/methanol) (95/5) to afford (60.0 mg, 20.5%)
the desired 1-morpholino-2-(3-phenyl-1,2,4-oxadiazol-5-yl)-
To a stirred solution of 3-(3-phenyl-[1,2,4]oxadiazol-5-yl)-
1H-indole (100.0 mg, 0.38 mmol) in anhydrous DMF
(5.0 mL) was added sodium hydride (60%, 34.0 mg,
0.84 mmol). The mixture was stirred at room temperature
for 30 min and 1-(2-chloroethyl)morpholine hydrochloride
(71.3 mg, 0.38 mmol) was added. The reaction mixture was
stirred at room temperature for 30 min and at 100 ꢂC for 2 h
after which the reaction mixture was allowed to cool to
room temperature and the solvent was then evaporated under
reduced pressure to afford a yellow residue. Sodium carbonate
solution (10%, 30.0 mL) was added and the aqueous solution
was extracted with ethyl acetate. The combined ethyl acetate
extracts were dried, filtered and evaporated under reduced
pressure to afford a yellow solid, which was recrystallised
from ethyl acetate/hexane to afford (130.0 mg, 90.9%) the de-
sired 4-(2-(3-(3-phenyl-1,2,4-oxadiazol-5-yl)-1H-indol-1-yl)
ethyl)morpholine (40) as yelþlow crystals. M.p. ¼ 144e
146 ꢂC, M.S. m/z 375 (M þ 1) . 1H NMR (DMSO-d6) D
2.52 (4H, t, J ¼ 4.5 Hz, 2 ꢃ CH2), 2.78 (2H, t, J ¼ 6.3 Hz,
CH2), 3.55 (4H, t, J ¼ 4.5 Hz, 2 ꢃ CH2), 4.49 (2H, t,
J ¼ 6.3 Hz, CH2), 7.33e7.44 (2H, m, 2 ꢃ ArH), 7.58e7.69
(3H, m, 3 ꢃ ArH), 7.76 (1H, m, ArH), 8.16 (2H, m,
2 ꢃ ArH), 8.26 (1H, m, ArH), 8.56 (1H, s, ArH). Found C,
70.57, H, 5.9, N, 14.92%, C22H22N4O2 requires C, 70.57, H,
5.92, N, 14.96%.
1H-indol-1-yl)ethanone (42) as
a
whþite powder.
M.p. ¼ 174e175 ꢂC, M.S. m/z 389 (M þ 1) . 1H NMR
(DMSO-d6) D 3.6 (6H, s, 3 ꢃ CH2), 3.71 (2H, s, CH2), 5.39
(2H, s, CH2), 7.33 (2H, m, 2 ꢃ ArH), 7.59 (4H, m,
4 ꢃ ArH), 8.12 (2H, m, 2 ꢃ ArH), 8.22 (1H, m, ArH), 8.39
(1H, s, ArH). Found C, 67.59, H, 5.16, N, 14.4%,
C22H20N4O3 requires C, 68.03, H, 5.19, N, 14.42%.
5.2.33. 2-(3-(3-Benzyl-1,2,4-oxadiazol-5-yl)-1H-indol-1-yl)-
1-morpholinoethanone (43)
5.2.31. 4-(2-(3-(3-Biphenyl-4-yl)-1,2,4-oxadiazol-5-yl)-1H-
indol-1-yl)ethyl)morpholine (41) [43]
To a stirred solution of 3-(3-biphenyl-[1,2,4]oxadiazol-5-yl)-
1H-indole (50.0 mg, 0.15 mmol) in anhydrous DMF (5.0 mL)
was added sodium hydride (60%, 14.0 mg, 0.33 mmol).
The mixture was stirred at room temperature for 30 min and
To a stirred solution of 3-(3-benzyl-[1,2,4]oxadiazol-5-yl)-
1H-indole (125.0 mg, 0.38 mmol) in anhydrous DMF (5.0 mL)
was added sodium hydride (60%, 30.5 mg, 0.76 mmol). The
mixture was stirred at room temperature for 30 min and 2-
bromo-1-(4-morpholinyl)-1-ethanone (79.5 mg, 0.38 mmol)
was added. The reaction mixturewas stirred at room temperature

534
G.P. Moloney et al. / European Journal of Medicinal Chemistry 43 (2008) 513e539
for 30 min and at 80 ꢂC for 8 h after which the reaction mixture
was allowed to cool to room temperature and the solvent was
then evaporated under reduced pressure to afford a yellow resi-
due. The yellow residue was taken up in water and the aqueous
solution was basified with potassium carbonate. The basic aque-
oussolutionwas thenextracted withethylacetate. Thecombined
ethyl acetate extracts were dried, filtered and evaporated under
reduced pressure to afford a yellow solid, which was purified
with column chromatography eluting with (chloroform/
methanol) (95/5) toafford(80.7 mg, 44.12%) the desired 2-(3-(3-
benzyl-1,2,4-oxadiazol-5-yl)-1H-indol-1-yl)-1-morpholinoetha-
none (43) as white needles. M.p. ¼ 172e174 ꢂC, M.S. m/z
stirred at room temperature for 30 min and at 100 ꢂC for
22 h after which the reaction mixture was allowed to cool to
room temperature and the solvent was then evaporated under
reduced pressure to afford brown oil. The brown oil was par-
titioned between aqueous sodium carbonate solution (10%,
30.0 mL) and ethyl acetate (30.0 mL). The ethyl acetate ex-
tract was then dried, filtered and evaporated under reduced
pressure to afford brown oil, which was purified with column
chromatography eluting with (chloroform/methanol) (98/2) to
afford (127.0 mg, 43.13%) the desired 4-(2-(3-(3-(thiophen-2-
ylmethyl)-1,2,4-oxadiazol-5-yl)-1H-indol-1-yl)ethyl)morpho-
1
line (45) as a yellow gum. M.S. m/z 395 (M þ 1)þ. H NMR
1
403 (M þ 1)þ. H NMR (DMSO-d6) D 3.44 (2H, s, CH2),
(MeOH-d4) D 2.5 (2H, m, CH2), 2.58 (2H, m, CH2), 2.81
(2H, t, J ¼ 6.3 Hz, CH2), 3.63 (2H, t, J ¼ 4.8 Hz, CH2), 3.69
(2H, m, CH2), 4.34 (2H, s, CH2), 4.45 (2H, m, CH2), 6.91
(1H, m, ArH), 7.05, (1H, d, J ¼ 3.6 Hz, ArH), 7.27e7.34
(3H, m, 3 ꢃ ArH), 7.58 (1H, d, J ¼ 7.8 Hz, ArH), 8.17 (1H,
m, ArH), 8.23 (1H, s, H-2). Found: (M þ 1)þ ¼ 395.1516,
C21H22N4O2S requires (M þ 1)þ ¼ 395.1536.
3.59 (4H, s, 2 ꢃ CH2), 3.69 (2H, s, CH2), 4.13 (2H, s,
CH2), 5.34 (2H, s, CH2), 7.2e7.41 (7H, m, 7 ꢃ ArH), 7.53
(1H, m, ArH), 8.05 (1H, m, ArH), 8.27 (1H, s, ArH). Found
C, 68.58, H, 5.49, N, 13.8%, C23H22N4O3 requires C, 68.64,
H, 5.51, N, 13.92%.
5.2.34.
1,2,4-oxadiazol-5-yl)methanone (44)
To stirred solution of (1H-indol-3-yl)-(3-phenyl-
(1-(2-Morpholinoethyl)-1H-indol-3-yl)(3-phenyl-
5.2.36. 4-(2-(3-(3-Benzyl-1,2,4-oxadiazol-5-yl)-1H-indol-1-yl)-
ethyl)morpholine (46)
a
[1,2,4]oxadiazol-5-yl)-methanone (75.5 mg, 0.26 mmol) in an-
hydrous DMF (5.0 mL) was added sodium hydride (60%,
30.3 mg, 0.76 mmol). The mixture was stirred at room temper-
ature for 30 min and 4-(2-chloroethyl)morpholine hydrochlo-
ride (48.6 mg, 0.26 mmol) was added. The reaction mixture
was stirred at room temperature for 30 min and at 100 ꢂC
for 8 h after which the reaction mixture was allowed to cool
to room temperature and the solvent was then evaporated un-
der reduced pressure to afford a yellow residue. The yellow
residue was taken up in water and the aqueous solution was
basified with potassium carbonate. The basic aqueous solution
was then extracted with ethyl acetate. The combined ethyl ac-
etate extracts were dried, filtered and evaporated under re-
duced pressure to afford a yellow solid, which was purified
with column chromatography eluting with (chloroform/metha-
nol) (95/5) to afford (27.0 mg, 25.76%) the desired (1-(2-mor-
pholinoethyl)-1H-indol-3-yl)(3-phenyl-1,2,4-oxadiazol-5-yl)
methanone (44) as a yellow powder. M.p. ¼ 132e133 ꢂC,
To a stirred solution of 2-(3-benzyl-[1,2,4]oxadiazol-5-yl)-
1H-indole (230.0 mg, 0.84 mmol) in anhydrous DMF
(5.0 mL) was added sodium hydride (60%, 74.0 mg,
1.9 mmol). The mixture was stirred at room temperature for
30 min and 4-(2-chloroethyl)morpholine hydrochloride
(171.0 mg, 0.92 mmol) was added. The reaction mixture was
stirred at room temperature for 30 min and at 100 ꢂC for
24 h after which the reaction mixture was allowed to cool to
room temperature and the solvent was then evaporated under
reduced pressure to afford an off white residue. The residue
was taken up in water and the aqueous solution was basified
with potassium carbonate. The basic aqueous solution was ex-
tracted with ethyl acetate. The combined ethyl acetate extracts
ware then dried, filtered and evaporated under reduced pres-
sure to afford an off white solid, which was purified with col-
umn chromatography eluting with (chloroform/methanol) (98/
2) to afford (193.0 mg, 60.0%) the desired 4-(2-(3-(3-
benzyl-1,2,4-oxadiazol-5-yl)-1H-indol-1-yl)morpholine (46) as
a cream powder. M.S. m/z 389 (M þ 1)þ. 1H NMR (CDCl3) D
2.35 (4H, m, 2 ꢃ CH2), 2.63 (2H, m, CH2), 3.53 (4H, m,
2 ꢃ CH2), 4.15 (2H, s, CH2), 4.78 (2H, m, CH2), 7.18 (1H,
dd, J ¼ 7.2, 7.8 Hz, ArH), 7.22e7.5 (8H, m, 8 ꢃ ArH), 7.7
(1H, d, J ¼ 8.1 Hz, ArH). 13C NMR (CDCl3) D 32.34, 42.21,
53.68, 57.58, 66.76, 109.2, 110.3, 121.0, 122.4, 123.7, 125.1,
126.9, 127.1, 128.6, 129.0, 135.5, 138.9, 169.5, 170.0. Found
C, 65.0, H, 6.55, N, 13.15%, C23H24N4O2$2H2O requires C,
65.08, H, 6.59, N, 13.19%. Found: (M þ 1)þ ¼
389.1956, C23H24N4O2 requires (M þ 1)þ ¼ 389.1972.
1
M.S. m/z 403 (M þ 1)þ. H NMR (DMSO-d6) D 2.49 (4H, t,
J ¼ 4.5 Hz, 2 ꢃ CH2), 2.73 (2H, t, J ¼ 5.9 Hz, CH2), 3.52
(4H, t, J ¼ 4.5 Hz, 2 ꢃ CH2), 4.51 (2H, t, J ¼ 5.9 Hz, CH2),
7.21 (1H, m, ArH), 7.38 (2H, m, ArH), 7.64 (2H, m,
2 ꢃ ArH), 7.74, (1H, d, J ¼ 7.2 Hz, ArH), 8.18 (2H, m,
2 ꢃ ArH), 8.32 (1H, d, J ¼ 7.8 Hz, ArH), 9.08 (1H, s, ArH).
Found C, 68.22, H, 5.63, N, 13.2%, C23H22N4O3$0.1H2O re-
quires C, 68.27, H, 5.49, N, 13.8%.
5.2.35. 4-(2-(3-(3-(Thiophen-2-ylmethyl)-1,2,4-oxadiazol-5-yl)-
1H-indol-1-yl)ethyl)morpholine (45) [43]
To a stirred solution of 5-(1H-indol-3-yl)-3-(thiophen-2-yl-
methyl)-1,2,4-oxadiazole (210.0 mg, 0.75 mmol) in anhydrous
DMF (5.0 mL) was added sodium hydride (60%, 66.0 mg,
1.6 mmol). The mixture was stirred at room temperature for
30 min and 4-(2-chloroethyl)morpholine hydrochloride
(139.0 mg, 0.75 mmol) was added. The reaction mixture was
5.2.37. 4-(2-(4-(3-Benzyl-1,2,4-oxadiazol-5-yl)-1H-imidazol-1-
yl)ethyl)morpholine and 4-(2-(5-(3-benzyl-1,2,4-oxadiazol-5-
yl)-1H-imidazol-1-yl)ethyl)morpholine (1/1 mixture) (47)
To a stirred solution of 3-benzyl-5-(1H-imidazol-4-yl)-
[1,2,4]oxadiazole (102.0 mg, 0.45 mmol) in anhydrous DMF
(3.0 mL) was added sodium hydride (60%, 40.0 mg,

G.P. Moloney et al. / European Journal of Medicinal Chemistry 43 (2008) 513e539
535
1.0 mmol). The mixture was stirred at room temperature for
30 min and 4-(2-chloroethyl)morpholine hydrochloride
(92.0 mg, 0.49 mmol) was added. The reaction mixture was
stirred at room temperature for 30 min and at 100 ꢂC for
24 h after which the reaction mixture was allowed to cool to
room temperature and the solvent was then evaporated under
reduced pressure to afford an off white residue. The residue
was taken up in water and the aqueous solution was basified
with potassium carbonate. The basic aqueous solution was ex-
tracted with ethyl acetate. The combined ethyl acetate extracts
were then dried, filtered and evaporated under reduced pres-
sure to afford an off white solid, which was purified with col-
umn chromatography eluting with (chloroform/methanol) (9/1)
to afford (80.6 mg, 52.67%) the desired 4-(2-(4-(3-benzyl-1,2,
4-oxadiazol-5-yl)-1H-imidazol-1-yl)ethyl)morpholine and 4-(2-
(5-(3-benzyl-1,2,4-oxadiazol-5-yl)-1H-imidazol-1-yl)ethyl)mor-
pholine (1/1 mixture, 47) as a colourless solid. M.S. m/z 340
(M þ 1)þ. H.p.l.c. retention time ¼ 21.39 min; (Isocratic 20
B/80 D (B ¼ 90% CH3CN/10% H2O) (D ¼ 0.05% aqueous
TFA).
room temperature and the solvent was then evaporated under
reduced pressure to a yellow residue, which was taken up in
water. The aqueous phase was basified with potassium carbon-
ate and the basic aqueous phase was extracted with ethyl ace-
tate. The combined ethyl acetate extracts were dried, filtered
and evaporated under reduced pressure to afford a yellow
solid, which was purified with column chromatography eluting
with (chloroform/methanol) (95/5) to afford (45.0 mg, 84.3%)
the desired 4-(2-(3-(3-(4-methoxybenzyl)-1,2,4-oxadiazol-5-yl)-
1H-indol-1-yl)ethyl)morpholine (49) as a yellow powder. M.S.
m/z 419 (M þ 1)þ. 1H NMR (DMSO-d6) D 2.42 (4H, t,
J ¼ 4.2 Hz, 2 ꢃ CH2), 2.7 (2H, t, J ¼ 6.0 Hz, CH2), 3.5 (4H,
t, J ¼ 4.5 Hz, 2 ꢃ CH2), 3.82 (3H, s, OCH3), 4.04 (2H, s,
CH2), 4.4 (2H, t, J ¼ 6.0 Hz, CH2), 6.89 (2H, d, J ¼ 8.7 Hz,
2 ꢃ ArH), 7.27 (2H, d, J ¼ 8.7 Hz, 2 ꢃ ArH), 7.3 (2H, m,
2 ꢃ ArH), 7.66 (1H, d, J ¼ 7.5 Hz, ArH), 8.05 (1H, d, J ¼
8.1 Hz, ArH), 8.39 (1H, s, H-2). Found: (M þ 1)þ ¼
419.20616, C24H26N4O3 requires (M þ 1)þ ¼ 419.20049.
5.2.40. 4-(2-(3-(3-(4-Bromobenzyl)-1,2,4-oxadiazol-5-yl)-
1H-indol-1-yl)ethyl)morpholine (50) [43]
5.2.38. 3-Benzyl-5-1-(2-(piperidine-1-yl)ethyl)-1H-indol-3-yl)-
1,2,4-oxadiazole (48) [43]
To a stirred solution of 3-[3-(4-bromobenzyl)-[1,2,4]oxa-
diazol-5-yl]-1H-indole (200.0 mg, 0.54 mmol) in anhydrous
DMF (10.0 mL) was added sodium hydride (60%, 47.0 mg,
1.18 mmol). The mixture was stirred at room temperature
for 30 min and 1-(2-chloroethyl)morpholine hydrochloride
(100.0 mg, 0.54 mmol) was added. The reaction mixture was
stirred at room temperature for 30 min and at 100 ꢂC for 4 h
after which the reaction mixture was allowed to cool to
room temperature and the solvent was then evaporated under
reduced pressure to a yellow residue, which was taken up in
water. The aqueous phase was basified with potassium carbon-
ate and the basic aqueous phase was extracted with ethyl ace-
tate. The combined ethyl acetate extracts were dried, filtered
and evaporated under reduced pressure to afford a yellow
solid, which was purified with column chromatography eluting
with (chloroform/methanol) (95/5) to afford (217.3 mg,
87.0%) the desired 4-(2-(3-(3-(4-bromobenzyl)-1,2,4-oxadia-
zol-5-yl)-1H-indol-1-yl)ethyl)morpholine (50) as a yellow
solid. M.S. m/z 467 (M þ 1)þ 1H NMR (CDCl3) D 2.52
(2H, s, CH2), 2.82 (2H, s, CH2), 3.7 (2H, s, CH2), 4.09 (2H,
s, CH2), 4.33 (2H, s, CH2), 7.29 (2H, d, J ¼ 8.1 Hz,
2 ꢃ ArH), 7.25e7.5 (2H, m, H-5, H-6), 7.46 (1H, d,
J ¼ 8.1 Hz, H-2), 8.0 (1H, s, H-2), 8.27 (1H, d, J ¼ 5.4 Hz,
H-4). H.p.l.c. retention time ¼ 16.7 min; (10% B/90% D) to
(100% B) over 20 min (B ¼ 90% CH3CN/10% H2O)
(D ¼ 0.05% aqueous TFA).
To a stirred solution of 3-(3-benzyl-[1,2,4]oxadiazol-5-yl)-
1H-indole (180.0 mg, 0.65 mmol) in anhydrous DMF (5.0 mL)
was added sodium hydride (60%, 58.0 mg, 1.43 mmol). The
mixture was stirred at room temperature for 30 min and 1-(2-
chloroethyl)piperidine hydrochloride (132.0 mg, 0.72 mmol)
was added. The reaction mixturewas stirred at room temperature
for 30 min and at 100 ꢂC for 16 h after which the reaction mix-
ture was allowed to cool to room temperature and the solvent
was then evaporated under reduced pressure to afford a yellow
residue. The residue was taken up in aqueous sodium carbonate
solution (5%, 10.0 mL) and the basic aqueous solution was ex-
tracted with ethyl acetate. The combined ethyl acetate extracts
were then dried, filtered and evaporated under reduced pressure
to afford a yellow oil, which was purified with column chroma-
tography eluting with (chloroform/methanol) (9/1) to afford
(175.7 mg, 70.0%) the desired 3-benzyl-5-1-(2-(piperidine-1-
yl)ethyl)-1H-indol-3-yl)-1,2,4-oxadiazole (48) as a yellow oil.
1
M.S. m/z 387 (M þ 1)þ. H NMR (CDCl3) D 1.35e1.51 (2H,
m, CH2), 1.51e1.75 (4H, m, 2 ꢃ CH2), 2.45 (4H, m, 2 ꢃ CH2),
2.74 (2H, t, J ¼ 6.9 Hz, CH2), 4.16 (2H, s, CH2), 4.29 (2H, t,
J ¼ 6.9 Hz, CH2), 7.2e7.47 (8H, m, 8 ꢃ ArH), 8.0 (1H, s,
H-2), 8.27 (1H, m, H-4). Found: (M þ 1)þ ¼ 387.2175,
C24H26N4O requires (M þ 1)þ ¼ 387.2179.
5.2.39. 4-(2-(3-(3-(4-Methoxybenzyl)-1,2,4-oxadiazol-5-yl)-
1H-indol-1-yl)ethyl)morpholine (49) [43]
5.2.41. 2-(3-(3-(2-Chlorobenzyl)-1,2,4-oxadiazol-5-yl)-1H-
indol-1-yl)-1-morpholinoethanone (51)
To a stirred solution of 3-[3-(4-methoxybenzyl)-[1,2,4]oxa-
diazol-5-yl]-1H-indole (40.0 mg, 0.13 mmol) in anhydrous
DMF (10.0 mL) was added sodium hydride (60%, 12.0 mg,
0.29 mmol). The mixture was stirred at room temperature
for 30 min and 1-(2-chloroethyl)morpholine hydrochloride
(132.0 mg, 0.72 mmol) was added. The reaction mixture was
stirred at room temperature for 30 min and at 100 ꢂC for
16 h after which the reaction mixture was allowed to cool to
To a stirred solution of 3-(3-(2-chlorobenzyl)-[1,2,4]oxa-
diazol-5-yl)-1H-indole (50.0 mg, 0.16 mmol) in anhydrous
DMF (5.0 mL) was added sodium hydride (60%, 14.0 mg,
0.36 mmol). The mixture was stirred at room temperature
for 30 min and 2-bromo-1-(4-morpholinyl)-1-ethanone
(34.0 mg, 0.16 mmol) was added. The reaction mixture was
stirred at room temperature for 30 min and at 100 ꢂC for

536
G.P. Moloney et al. / European Journal of Medicinal Chemistry 43 (2008) 513e539
15 h after which the reaction mixture was allowed to cool to
room temperature and the solvent was then evaporated under
reduced pressure to afford a grey residue. The grey residue
was taken up in water and the aqueous solution was basified
with potassium carbonate. The basic aqueous solution was
the extracted with ethyl acetate. The combined ethyl acetate
extracts were dried, filtered and evaporated under reduced pres-
sure to afford a grey solid, which was purified with column
chromatography eluting with (chloroform/methanol) (95/5)
to afford (18.0 mg, 25.5%) the desired 2-(3-(3-(2-chloroben-
zyl)-1,2,4-oxadiazol-5-yl)-1H-indol-1-yl)-1-morpholinoetha-
18 h after which the reaction mixture was allowed to cool to
room temperature and the solvent was then evaporated under
reduced pressure to afford a yellow residue. Water was added
to the residue and the aqueous solution was basified with po-
tassium carbonate. The basic aqueous solution was then ex-
tracted with ethyl acetate. The combined ethyl acetate
extracts were dried, filtered and evaporated under reduced
pressure to afford a yellow solid, which purified with column
chromatography eluting with (chloroform/methanol) (95/5) to
afford (296.0 mg, 85.0%) the desired 4-(2-(3-(3-phenethyl-
1,2,4-oxadiazol-5-yl)-1H-indol-1-yl)ethyl)morpholine (53) as
1
1
none (51) as a grey solid. M.S. m/z 437 (M þ 1)þ. H NMR
yellow needles. M.S. m/z 403 (M þ 1)þ. H NMR (CDCl3)
(CDCl3) D 3.51 (2H, m, CH2), 3.68 (6H, m, 3 ꢃ CH2), 4.3
(2H, s, CH2), 4.96 (2H, s, CH2), 7.22e7.24 (2H, m,
2 ꢃ ArH), 7.32e7.43 (3H, m, 3 ꢃ ArH), 7.94 (1H, s, ArH),
8.28 (1H, m, ArH). Found: (M þ 1)þ ¼ 437.13723 and
439.13431, C23H21ClN4O2 requires (M þ 1)þ ¼ 437.13022
and 439.13022. H.p.l.c. retention time ¼ 21.0 min; (50% A/
50% B) (A ¼ 90% CH3CN/10% H2O) (B ¼ 0.05% aqueous
TFA.
D 2.5 (4H, t, J ¼ 4.7 Hz, 2 ꢃ CH2), 2.82 (2H, t, J ¼ 6.6 Hz,
CH2), 3.08e3.24 (4H, m, 2 ꢃ CH2), 3.7 (4H, t, J ¼ 4.7 Hz,
2 ꢃ CH2), 4.31 (2H, t, J ¼ 6.6 Hz, CH2), 7.18e7.47 (8H, m,
8 ꢃ ArH), 8.03 (1H, s, ArH), 8.31 (1H, m, ArH). Found:
(M þ 1)þ ¼ 403.2125, C24H26N4O2 requires (M þ 1)þ ¼
403.2129.
5.2.44. 4-(2-(3-(3-(2-Chlorobenzyl)-1,2,4-oxadiazol-5-yl)-
1H-indol-1-yl)ethyl)morpholine (54) [43]
5.2.42. 3-Benzyl-5-(1-pentyl-1H-indol-3-yl)-1,2,4-oxadiazole
(52) [43]
To a stirred solution of 3-[3-(2-chlorobenzyl)-[1,2,4]oxa-
diazol-5-yl]-1H-indole (70.0 mg, 0.23 mmol) in anhydrous
DMF (12.0 mL) was added sodium hydride (60%, 20.0 mg,
0.5 mmol). The mixture was stirred at room temperature
for 30 min and 4-(2-chloroethyl)morpholine hydrochloride
(42.1 mg, 0.23 mmol) was added. The reaction mixture was
stirred at room temperature for 30 min and at 100 ꢂC for
15 h after which the reaction mixture was allowed to cool
to room temperature and the solvent was then evaporated un-
der reduced pressure to a yellow residue, which was taken up
in water. The aqueous phase was basified with potassium car-
bonate and the basic aqueous phase was extracted with ethyl
acetate. The combined ethyl acetate extracts were dried, fil-
tered and evaporated under reduced pressure to afford a yel-
low solid, which was purified with column chromatography
eluting with (chloroform/methanol) (95/5) to afford
(12.1 mg, 12.6%) the desired 4-(2-(3-(3-(2-chlorobenzyl)-
1,2,4-oxadiazol-5-yl)-1H-indol-1-yl)ethyl)morpholine (54) as
To a stirred solution of 3-(3-benzyl-[1,2,4]oxadiazol-5-yl)-
1H-indole (100.0 mg, 0.36 mmol) in anhydrous DMF
(5.0 mL) was added sodium hydride (60%, 16.0 mg,
0.4 mmol). The mixture was stirred at room temperature
for 30 min and 1-bromopentane (50.0 mL, 0.65 mmol) was
added. The reaction mixture was stirred at room temperature
for 30 min and at 100 ꢂC for 18 h after which the reaction
mixture was allowed to cool to room temperature and the
solvent was then evaporated under reduced pressure to afford
an off white residue. Water was added to the residue and the
aqueous solution was basified with potassium carbonate. The
basic aqueous solution was then extracted with ethyl acetate.
The combined ethyl acetate extracts were dried, filtered and
evaporated under reduced pressure to afford an off white
solid, which was purified with column chromatography elut-
ing with chloroform to afford (59.0 mg, 85.0%) the desired
3-benzyl-5-(1-pentyl-1H-indol-3-yl)-1,2,4-oxadiazole (52) as
colourless needles. M.S. m/z 346 (M þ 1)þ. 1H NMR
(CDCl3) D 1.04 (3H, t, J ¼ 6.9 Hz, CH2), 1.44 (4H, s,
2 ꢃ CH2), 2.0 (2H, tt, J ¼ 7.2, 7.2 Hz, CH2), 4.25 (2H, t,
J ¼ 7.2 Hz, CH2), 4.31 (2H, s, CH2), 7.37e7.61 (8H, m,
8 ꢃ ArH), 8.04 (1H, s, ArH), 8.43 (1H, m, ArH). Found C,
76.46, H, 6.68, N, 12.14, C22H23N3O requires C, 76.49, H,
6.71, N, 12.16%.
1
a yellow solid. M.S. m/z 423 (M þ 1)þ. H NMR (MeOH-
d4) D 2.0 (4H, m, 2 ꢃ CH2), 2.07 (2H, m, CH2), 2.38 (2H,
m, CH2), 2.61 (4H, m, 2 ꢃ CH2), 2.97 (2H, s, CH2), 5.84
(1H, m, ArH), 5.99 (2H, m, 2 ꢃ ArH), 6.1 (3H, m,
3 ꢃ ArH), 6.35 (1H, d, J ¼ 8.1 Hz, ArH), 6.87 (1H, d,
J ¼ .5 Hz, ArH), 6.95 (1H, s, H-2). Found C, 65.28, H,
5.46, N, 13.22%, C23H23ClN4O2 requires C, 65.32, H, 5.48,
N, 13.25%.
5.2.43. 4-(2-(3-(3-Phenethyl-1,2,4-oxadiazol-5-yl)-1H-indol-1-
yl)ethyl)morpholine (53) [43]
5.2.45. 4-((3-(3-Benzyl-1,2,4-oxadiazol-5-yl)-1H-indol-1-yl)-
methyl)oxazolidine-2-one (55)
To a stirred solution of 3-(3-phenethyl-1,2,4-oxadiazol-5-
yl)-1H-indole (250.0 mg, 0.86 mmol) in anhydrous DMF
(10.0 mL) was added sodium hydride (60%, 76.0 mg,
1.9 mmol). The mixture was stirred at room temperature for
30 min and 4-(2-chloroethyl)morpholine hydrochloride
(161.0 mg, 0.86 mmol) was added. The reaction mixture was
stirred at room temperature for 30 min and at 100 ꢂC for
To a stirred solution of 3-[3-benzyl-[1,2,4]oxadiazol-5-yl]-
1H-indole (123.0 mg, 0.45 mmol) in anhydrous DMF
(12.0 mL) was added sodium hydride (60%, 17.0 mg,
0.45 mmol). The mixture was stirred at room temperature
for 30 min and 5-(chloromethyl)oxazolidinone (60.6 mg,
0.45 mmol) was added. The reaction mixture was stirred at
room temperature for 30 min and at 100 ꢂC for 4 h after which

G.P. Moloney et al. / European Journal of Medicinal Chemistry 43 (2008) 513e539
537
the reaction mixture was allowed to cool to room temperature
and the solvent was then evaporated under reduced pressure to
a white residue, which was taken up in water. The aqueous
phase was extracted with ethyl acetate. The combined ethyl
acetate extracts were dried, filtered and evaporated under re-
duced pressure to afford a white solid, which was purified
with column chromatography eluting with (chloroform/
methanol) (9/1) to afford (41.8 mg, 25.0%) the desired 4-
((3-(3-benzyl-1,2,4-oxadiazol-5-yl)-1H-indol-1-yl)methyl)
oxazolidine-2-one (55) as a yellow solid. M.S. m/z 375
mixture was allowed to cool to room temperature and the sol-
vent was then evaporated under reduced pressure to yellow
oil, which was taken up in water. The aqueous phase was ba-
sified with potassium carbonate and the basic aqueous phase
was extracted with ethyl acetate. The combined ethyl acetate
extracts were dried, filtered and evaporated under reduced
pressure to afford yellow oil, which was purified with column
chromatography eluting with (chloroform/methanol) (99/1) to
afford (12.2 mg, 15.9%) the desired 4-(2-(3-(3-(naphthalene-
2-ylmethyl)-1,2,4-oxadiazol-5-yl)-1H-indol-1-yl)ethyl)mor-
1
1
(M þ 1)þ. H NMR (DMSO-d6) D 3.78 (2H, d, CH2), 3.86
pholine (57) as a yellow powder. M.S. m/z 423 (M þ 1)þ. H
(2H, d, CH2), 4.12 (2H, s, CH2), 4.82 (1H, m, CH), 7.23e
7.26 (3H, m, 3 ꢃ ArH), 7.36 (2H, m, 2 ꢃ ArH), 7.52 (2H,
m, 2 ꢃ ArH), 8.05 (1H, m, ArH), 8.31 (1H, s, H-2). Found
C, 67.32, H, 4.82, N, 14.5%, C21H18N4O3 requires C, 67.37,
H, 4.85, N, 14.96%.
NMR (methanol-d4) D 1.45 (4H, m, 2 ꢃ CH2), 1.7e1.75 (4H,
m, 2 ꢃ CH2), 4.29 (2H, t, J ¼ 6.6 Hz, CH2), 4.59 (2H, s,
CH2), 7.29 (4H, m, 4 ꢃ ArH), 7.46e7.62 (6H, m, 6 ꢃ ArH),
7.85 (2H, m, ArH), 8.19 (1H, m, ArH). Found C, 76.72, H,
6.1, N, 13.2%, C27H26N4O requires C, 76.75, H, 6.2, N,
13.26%.
5.2.46. 4-(2-(3-(3-(Naphthalene-2-ylmethyl)-1,2,4-oxadiazol-
5-yl)-1H-indol-1-yl)ethyl)morpholine (56) [43]
5.2.48. Ethyl 5-(3-(3-(naphthalen-2-ylmethyl)-1,2,4-oxadiazol-
5-yl)-1H-indol-1-yl)pentanoate (58) [43]
To a stirred solution of 3-[3-(2-naphthalene)-[1,2,4]oxadia-
zol-5-yl]-1H-indole (125.7 mg, 0.38 mmol) in anhydrous
DMF (5.0 mL) was added sodium hydride (60%, 30.9 mg,
0.77 mmol). The mixture was stirred at room temperature
for 30 min and 4-(2-chloroethyl)morpholine hydrochloride
(71.9 mg, 0.38 mmol) was added. The reaction mixture was
stirred at room temperature for 30 min and at 100 ꢂC for
15 h after which the reaction mixture was allowed to cool to
room temperature and the solvent was then evaporated under
reduced pressure to a yellow residue, which was taken up in
water. The aqueous phase was basified with potassium carbon-
ate and the basic aqueous phase was extracted with ethyl ac-
etate. The combined ethyl acetate extracts were dried, filtered
and evaporated under reduced pressure to afford a yellow
solid, which was purified with column chromatography elut-
ing with (chloroform/methanol) (95/5) to afford (90.0 mg,
53.0%) the desired 4-(2-(3-(3-(naphthalene-2-ylmethyl)-
1,2,4-oxadiazol-5-yl)-1H-indol-1-yl)ethyl)morpholine (56) as
a yellow powder. M.S. m/z 439 (M þ 1)þ. 1H NMR
(DMSO-d6) D 2.4 (4H, m, 2 ꢃ CH2), 2.68 (2H, m, CH2),
3.48 (4H, m, 2 ꢃ CH2), 4.38 (2H, t, J ¼ 6.3 Hz, CH2), 4.59
(2H, s, CH2), 7.27 (2H, m, 2 ꢃ ArH), 7.49e7.66 (6H, m,
6 ꢃ ArH), 7.86 (1H, d, J ¼ 7.5 Hz, ArH), 7.94 (1H, d,
J ¼ 7.2 Hz, ArH), 8.01 (1H, d, J ¼ 77.2 Hz, ArH), 8.2 (1H,
d, J ¼ 78.4 Hz, ArH), 8.37 (1H, s, H-2). Found C, 73.92, H,
5.96, N, 12.8%, C27H26N4O2 requires C, 73.95, H, 5.98, N,
12.78%.
To a stirred solution of 3-[3-(2-naphthalene)-[1,2,4]oxa-
diazol-5-yl]-1H-indole (39.4 mg, 0.12 mmol) in anhydrous
DMF (5.0 mL) was added sodium hydride (60%, 5.0 mg,
0.12 mmol). The mixture was stirred at 60 ꢂC for 60 min
then allowed to cool to room temperature and 5-bromovaler-
ate (25.3 mg, 0.12 mmol) was added. The reaction mixture
was stirred at room temperature for 30 min and at 110 ꢂC
for 18 h after which the reaction mixture was allowed to
cool to room temperature and the solvent was then evapo-
rated under reduced pressure to afford white oil, which was
taken up in water. The aqueous phase was extracted with
ethyl acetate. The combined ethyl acetate extracts were
dried, filtered and evaporated under reduced pressure to af-
ford white oil, which was purified with column chromatogra-
phy eluting with (chloroform/methanol) (95/5) to afford
(30.0 mg, 54.6%) the desired ethyl 5-(3-(3-(naphthalen-2-yl-
methyl)-1,2,4-oxadiazol-5-yl)-1H-indol-1-yl)pentanoate (58)
as an off white oil. M.S. m/z 454 (M þ 1)þ. 1H NMR
(MeOH-d4) D 1.14 (3H, t, J ¼ 7.2 Hz, CH3), 1.53 (2H, m,
CH2), 1.84 (2H, m, CH2), 4.05 (2H, q, J ¼ 6.9 Hz, CH2),
4.21 (2H, m, CH2), 4.56 (2H, s, CH2), 7.19e7.3 (4H, m,
4 ꢃ ArH), 7.42e7.56 (6H, m, 6 ꢃ ArH), 7.8 (1H, d,
J ¼ 8.1 Hz, ArH), 7.87 (1H, d, J ¼ 7.8 Hz, ArH), 8.1 (1H,
s, ArH), 8.21 (1H, m, ArH). H.p.l.c. retention time ¼
21.51 min; (50% B/50% D) (B ¼ 90% CH3CN/10% H2O)
(D ¼ 0.05% H3PO4 in water).
5.2.47. (3-Naphthalen-2-ylmethyl)-5-(1-(2-(pyrrolidine-1-yl)-
ethyl)-1H-indol-3-yl)-1,2,4-oxadiazole (57) [43]
5.2.49. 5-(3-(3-(Naphthalene-2-ylmethyl)-1,2,4-oxadiazol-
5-yl)-1H-indol-1-yl)pentanoic acid (59) [43]
To a stirred solution of 3-[3-(2-naphthalene)-[1,2,4]oxadia-
zol-5-yl]-1H-indole (58.9 mg, 0.18 mmol) in anhydrous DMF
(5.0 mL) was added sodium hydride (60%, 25.0 mg,
0.18 mmol). The mixture was stirred at 60 ꢂC for 30 min
then allowed to cool to room temperature and 4-(2-chloroe-
thyl)pyrrolidine hydrochloride (31.7 mg, 0.19 mmol) was
added. The reaction mixture was stirred at room temperature
for 30 min and at 110 ꢂC for 18 h after which the reaction
3-[3-(2-Methylnaphthyl)-5-(ethyl-N-pentanoate)indol-3-yl)
oxadiazole (10.9 mg, 0.024 mmol) was dissolved in metha-
nolic potassium hydroxide (potassium hydroxide (2.0 mg), an-
hydrous methanol (5.0 mL)) and the reaction mixture was
stirred at room temperature for 12 h. After this the methanol
was evaporated under reduced pressure to grey gum, which
was taken up in water. The aqueous phase was acidified
with dilute hydrochloric acid and then extracted with ethyl

538
G.P. Moloney et al. / European Journal of Medicinal Chemistry 43 (2008) 513e539
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acetate. The combined ethyl acetate extracts were dried, fil-
tered and evaporated under reduced pressure to afford a grey
gum, which was purified with column chromatography eluting
with (chloroform/methanol) (95/5) to afford (8.0 mg, 72.2%)
the desired 5-(3-(3-(naphthalene-2-ylmethyl)-1,2,4-oxadiazol-
5-yl)-1H-indol-1-yl)pentanoic acid (59) as a grey gum. M.S.
m/z 426 (M þ 1)þ. 1H NMR (MeOH-d4) D 0.9 (2H, m,
CH2), 1.62 (2H, m, CH2), 1.92 (2H, m, CH2), 2.3 (2H, m,
CH2), 4.58 (2H, s, CH2), 7.25e7.31 (4H, m, 4 ꢃ ArH),
7.46e7.51 (2H, m, 2 ꢃ ArH), 7.52e7.55 (4H, m, 4 ꢃ ArH),
7.82 (2H, d, J ¼ 8.1 Hz, 2 ꢃ ArH), 7.88 (2H, d, J ¼ 8.7 Hz,
2 ꢃ ArH), 8.11 (1H, m, ArH), 8.13 (1H, s, ArH), 8.22 (1H,
m, ArH). H.p.l.c. retention time ¼ 2.53 min; (100% B)
(B ¼ 90% CH3CN/10% H2O).
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5.2.50. 1-(2-Morpholinoethyl)-1H-indol-3-yl acetate (60)
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drous DMF (10.0 mL) and sodium hydride (60% dispersion,
437.6 mg, 11.4 mmol) was added and the reaction mixture
was stirred at room temperature for 30 min. After this 4-(2-
chloroethyl)morpholine hydrochloride (1.06 g, 5.7 mmol)
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with chloroform to afford (1.1 g, 67.0%) the desired 1-(2-(4-
morpholino)ethyl)-3-aceto-1H-indole (60) as a purple solid.
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1
M.S. m/z 189 (M þ 1)þ. H NMR (DMSO-d6) D 2.41 (4H, t,
J ¼ 4.5 Hz, 2 ꢃ CH2), 2.48 (2H, t, J ¼ 6.0 Hz, CH2), 3.55
(4H, t, J ¼ 4.5 Hz, 2 ꢃ CH2), 3.66 (2H, t, J ¼ 6.0 Hz, CH2),
7.24 (2H, m, 2 ꢃ ArH), 7.69 (2H, m, 2 ꢃ ArH), 8.44 (1H, s,
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(B ¼ 90% CH3CN/10% H2O).
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Acknowledgement
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The authors acknowledge the support of AMRAD and the
Australian Research Council.
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