Synthesis and pharmacological profile of a series of 2,5-substituted-N,N-dimethyltryptamine derivatives as novel antagonists for the vascular 5-HT1B-like receptor

Article abstract of DOI:10.1039/a903328i

The coronary 5-HT_1B-like receptor has been implicated in vasospasm and it is postulated that a 5-HT_1B-like antagonist may block the detrimental action of 5-HT whilst not interfering with normal blood vessel function. The synthesis and pharmacological profile of a novel series of 2-(N-heteroaryl)carboxamido-5-substituted-N,N-dimethyltryptamine derivatives as silent (as judged by the inability of angiotensin II to unmask 5-HT_1B-like receptor mediated agonist activity in the rabbit femoral artery), competitive and selective 5-HT_1B-like receptor antagonists is described. Modifications to the 2-carboxamido sidechain as well as the 5-ethylene linked heterocycle are explored. N-Furfuryl-5-[2-(N-phthalimido)ethyl]-3-[2-(dimethylamino)ethyl]-1H-indole-2- carboxamide (34) was discovered which fulfilled our in vitro selection criteria and which had a favourable pharmacokinetic profile. Compound 34 showed good affinity (pK_B = 7.38) for the vascular 5-HT_1B-like receptor and greater than 125 fold selectivity over α₁-adrenoceptor affinity. The selectivity of 34 and related compounds for the 5-HT_1B-like receptor over other receptor subtypes is discussed and a mode of binding for this class of compound to a pharmacophore model is proposed. The Royal Society of Chemistry 1999.

Full text of DOI:10.1039/a903328i

View Online / Journal Homepage / Table of Contents for this issue
Synthesis and pharmacological profile of a series of 2,5-
substituted-N,N-dimethyltryptamine derivatives as novel
antagonists for the vascular 5-HT1B-like receptor
Gerard P. Moloney,*a Graeme R. Martin,b Neil Mathews,c Heather Hobbs,c Susan Dodsworth,c
Pang Yih Sang,c Cameron Knight,a Miles Maxwellc and Robert C. Glend
a Department of Medicinal Chemistry, Victorian College of Pharmacy (Monash University),
381 Royal Parade Parkville, Victoria, 3052 Australia. Fax: (03) 99039634;
E-mail: Gerard.Moloney@vcp.monash.edu.au
b Molecular Pharmacology Department, Neurobiology Unit, Roche Bioscience,
3401 Hillview Avenue, R2-101, Palo Alto CA94304 USA
c Department of Medicinal Chemistry, GlaxoWellcome Research Group, Gunnels Wood Road,
Stevenage, Hertfordshire, UK SG1 2NY
d Tripos Inc., 1699 South Hanley Road, St Louis, MO 63144, USA
Received (in Cambridge, UK) 26th April 1999, Accepted 29th July 1999
The coronary 5-HT1B-like receptor has been implicated in vasospasm and it is postulated that a 5-HT1B-like
antagonist may block the detrimental action of 5-HT whilst not interfering with normal blood vessel function.
The synthesis and pharmacological profile of a novel series of 2-(N-heteroaryl)carboxamido-5-substituted-N,N-
dimethyltryptamine derivatives as silent (as judged by the inability of angiotensin II to unmask 5-HT1B-like receptor
mediated agonist activity in the rabbit femoral artery), competitive and selective 5-HT1B-like receptor antagonists is
described. Modifications to the 2-carboxamido sidechain as well as the 5-ethylene linked heterocycle are explored.
N-Furfuryl-5-[2-(N-phthalimido)ethyl]-3-[2-(dimethylamino)ethyl]-1H-indole-2-carboxamide (34) was discovered
which fulfilled our in vitro selection criteria and which had a favourable pharmacokinetic profile. Compound 34
showed good affinity (pKB = 7.38) for the vascular 5-HT1B-like receptor and greater than 125 fold selectivity over α1-
adrenoceptor affinity. The selectivity of 34 and related compounds for the 5-HT1B-like receptor over other receptor
subtypes is discussed and a mode of binding for this class of compound to a pharmacophore model is proposed.
We recently reported a series of 2-ester-5-(2-ethyl-1-dioxo-
Introduction
imidazolidinyl)-N,N-dimethyltryptamine derivatives as the first
silent (as judged by the inability of angiotensin II to unmask
5-HT1B-like receptor mediated agonist activity in the rabbit
femoral artery), competitive and selective antagonists for the
vascular 5-HT1B-like receptors.25 We also reported the discovery
of some stable 2-N-(benzyl)carboxamido-5-(2-ethyl-1-dioxo-
imidazolidinyl)-N,N-dimethyltryptamine derivatives with simi-
lar pharmacological profiles.26 Further to this work we now
report on a related series of tryptamine derivatives with a range
of heterocyclic 2-N-carboxamido substituents. The objective of
our research program was to develop a novel, silent (as judged
by the inability of angiotensin II to unmask 5-HT1B-like recep-
tor mediated agonist activity in the rabbit femoral artery) and
highly selective antagonist at vascular 5-HT1B-like receptors
with good oral bioavailability, a plasma half-life of at least 4
hours and low central penetration. Compounds were sought
which had high potency (pKB > 7.0) and ideally 100 fold select-
ivity over other receptor subtypes, in particular the α1-
adrenoceptor so as to avoid hypotensive effects. It has been
postulated that a compound fitting our biological profile may
be a useful agent for the treatment of vasospastic disease states
including Raynaud’s phenomenon,27–30 variant angina,31,32 and
intermittent claudication.33–38 Present therapies for vasospastic
angina include calcium channel blockers and nitrates which are
non-specific and suffer from tolerance problems and cause
peripheral vasodilation which can lead to hypotension and
headaches. Neither of these treatments is effective in all
patients, nor all the time in the same patient and so there is a
need for a selective treatment with a low side effect profile, and a
silent (as judged by the inability of angiotensin II to unmask
Our knowledge and understanding of the serotonin (5-HT)
receptor family has continued to grow in recent years and it is
now divided into seven major families based on pharmaco-
logical properties, second messenger coupling and sequence
data.1–3 Receptors 5-HT1, 5-HT2, 5-HT3 and 5-HT4 4–9 comprise
the main classes although gene products encoding other
putative receptors such as 5-ht5, 5-ht6 and 5-HT7 have been
identified from cloning studies.10–12 The 5-HT1D receptor has
attracted considerable interest since it has been shown to be
widely distributed in the central nervous system (CNS).13 Vas-
cular 5-HT1 receptors very similar to the 5-HT1B-like receptors
in the brain have been identified in vascular smooth muscle and
mediate contraction.14 Studies by Weinshank and co-workers
have identified two populations of human 5-HT1D receptors:
5-HT1Dα and 5-HT1Dβ receptors.15 There have been a number
of selective 5-HT1D agonists for vascular 5-HT1D receptors
reported recently including sumatriptan,16 zolmitriptan,17,18
MSD AH 2508619 and other related tryptamine derivatives.20,21
A series of benzanilides,22 have been described as potent
antagonists at 5-HT1B and 5-HT1D receptors and have been
shown to block both peripheral and central responses mediated
by both of these receptor types.23 However, this compound is
not a silent (as judged by the inability of angiotensin II to
unmask 5-HT1B-like receptor mediated agonist activity in
the rabbit femoral artery) antagonist and behaves as a partial
agonist at recombinant human 5-HT1B and 5-HT1D receptors.24
Moreover, the drug exhibits pseudo-irreversible pharmaco-
dynamics, making it less than ideal for the quantitative study of
5-HT1B and 5-HT1D receptors.23
J. Chem. Soc., Perkin Trans. 1, 1999, 2713–2723
This journal is © The Royal Society of Chemistry 1999
2713

View Online
5-HT1B-like receptor mediated agonist activity in the rabbit
femoral artery) competitive and selective vascular 5-HT1B-like
receptor antagonist may provide this.
We describe in this paper the synthesis, 5-HT1B-like receptor
activity and selectivity profile of a series of 2-N-carboxamido-
5-substituted-N,N-dimethyltryptamine analogs 1 and related
coupling of the tryptamine-2-carboxylic acid with the desired
methylamine derivative using TBTU and DIPEA in DMF gave
the desired 2-N-carboxamido tryptamine 1.
A range of methylene linked heterocyclic groups R1 were
incorporated into the 2-sidechain to explore the effect of
increased polarity within this series. It was of interest to explore
a range of 5-membered heteroaromatic groups and observe the
effect substituents of different sizes had on potency and select-
ivity at the vascular 5-HT1B-like receptor.
The heterocyclic methylamine derivatives required for
the amide coupling were prepared in a variety of ways. The
oxadiazole derivatives 13 and 14 were synthesized by coupling
a previously formed oxime41 with tert-butyloxycarbonyl pro-
tected glycine ethyl ester 8 (Scheme 2). Deprotection of the
analogs. To explore the pharmacophore we have studied
changes to the amide moiety R1 and the heterocyclic moiety R3
connected to the 5-position of the indole. Potential modes of
binding to the pharmacophore model for several of the key
compounds are discussed.
Results and discussion
Synthesis
The synthesis of the 2-N-carboxamido-5-substituted trypt-
amine derivatives proceeded via a Japp Klingemann indole
synthesis as previously reported,39,40 (Scheme 1). The desired
Scheme 2 Reagents: (a) Boc2O, CH2Cl2; (b) NaOCH3, MeOH; (c) 3 Å
sieves, NaH, THF; (d) TFA.
amines 11 and 12 with TFA afforded the desired methylamine
derivatives 13 and 14 as TFA salts.41
The isoxazole methylamine derivative 18 was synthesized via
the method of Pevarello and Varasi (Scheme 3).42 The bromo-
Scheme 1 Reagents: (a) NaNO2, HCl, NaOH; (b) concentrated
H2SO4, EtOH; (c) benzyl alcohol, Ti(iOPr)4; (d) H2, Pd–C (10%);
(e) TBTU, DIPEA, R1NH2, DMF.
tryptamine derivatives were obtained in a 5-step pathway
starting from a previously synthesized 4-substituted aniline
derivative 2.25,26 Reaction with the β-keto ester 3 under basic
conditions gave the hydrazone 4 which could be isolated and
crystallized. Refluxing in ethanol in the presence of concen-
trated sulfuric acid gave the 2-ethyl ester tryptamine 5 which
was then converted to the benzyl ester 6 by heating in benzyl
alcohol in the presence of titanium tetraisopropoxide. Follow-
ing trans-esterification, the 2-benzyl ester derivative was
converted to the tryptamine-2-carboxylic acid 7 under hydro-
genation conditions in the presence of 10% palladium on
carbon at room temperature and atmospheric pressure. Amide
Scheme 3 Reagents: (a) H2O, NaHCO3, CH2Cl2; (b) Br2; (c) KHCO3,
EtOAc; (d) 25% NH4OH.
2714
J. Chem. Soc., Perkin Trans. 1, 1999, 2713–2723

View Online
nitrile oxide 16 was formed by reaction of glyoxylic acid and
hydroxylamine.43,44 A 1,3-dipolar cycloaddition–elimination44
of dibromoformaldoxime (16) with 2,3-dichloroprop-1-ene
gave 5-chloromethyl-3-bromoisoxazole (17)42 in good yield.
Reaction of the alkyl chloride with 25% NH4OH afforded the
desired methylamino isoxazole 18.45
The 3-ethyl ester isoxazole derivative 22 was synthesized by
coupling of tert-butyloxycarbonyl protected propargylamine
(prop-2-ynylamine) 19 with an ethyl oximino acetate derivative
20 (Scheme 4).46 The oximino acetate 20 was previously formed
Fig. 1 Theoretical 5-HT1B-like receptor model using N-benzyl-3-[2-
(dimethylamino)ethyl]-5-[2-(4,4-dimethyl-2,5-dioxoimidazolidin-1-yl)-
ethyl]-1H-indole-2-carboxamide (24)26 as a reference and with methy-
sergide as background.
Scheme
4
Reagents: (a) Boc2O, CH2Cl2; (b) concentrated HCl,
NaNO2, H2O; (c) THF, Et3N, Et2O; (d) TFA.
of the molecule to orient so as to accurately interact with the
remaining pharmacophoric sites.
by reaction of the ethyl ester of glycine with hydrochloric acid
and sodium nitrite at ~5 ЊC. Deprotection of the intermediate
isoxazole 21 with TFA afforded the desired aminomethyl
isoxazole derivative 22 as the TFA salt.
A variety of heterocycles were incorporated onto the 5-
sidechain to explore this area of the receptor including a range
of hydantoin derivatives as well as several phthalimide deriv-
atives (Table 1). The synthesis of these heterocyclic systems has
been described previously.25,26,47 The combination of the polar
5-membered heteroaromatic 2-N-carboxamido substituents
and the various 5-ethylene linked heterocycles should afford
more information about the vascular 5-HT1B-like pharmaco-
phore.
It was of interest to us to investigate the possibility of
replacing the phenyl ring of the 2-N-carboxamido side chain
with a range of heteroaromatic groups. Different hetero-
aromatic ring systems may result in molecules adopting varied
conformations within the receptor and in turn have an impact
on the compounds’ pharmacological profiles. We also investi-
gated a range of hydantoin-based ring systems in the 5-side-
chain to assess the effect of subtle changes to the relative
positions of important functional groups such as the hydantoin
carbonyl groups on 5-HT1B-like receptor potency.
Several pyridylmethylamido tryptamine derivatives were
examined including 25 (pKB = 5.89), 26 (pKB = 6.44), 28
(pKB = 6.54) and 29 (pKB = 6.38). The biological results indicate
that the inclusion of the nitrogen atom in the aromatic group of
the 2-N-carboxamido sidechain is not well tolerated with affin-
ity dropping by at least 0.5 log units relative to the 2-(N-benzyl)-
carboxamido analog 24 (pKB = 7.09).26 It would appear that the
differing electronic nature of the pyridyl group has a detri-
mental effect on 5-HT1B-like receptor affinity a result which
reflects the importance of the aromatic group of the 2-N-carb-
oxamido sidechain in 5-HT1B-like receptor binding.
A range of 2-furfurylamide derivatives were investigated.
It would be expected that the slightly smaller 5-membered
heteroaromatic group would result in a different conformation
within the 5-HT1B-like receptor relative to 24 which has a
2-(N-benzyl)carboxamido sidechain. Two compounds showed
acceptable affinity at the 5-HT1B-like receptor, 34 (pKB = 7.38)
containing a 5-ethylene linked phthalimide group and 36
(pKB = 7.16) incorporating an N-benzyl substituted hydantoin
group in the 5-sidechain. Both these compounds exhibited
improved vascular 5-HT1B-like receptor affinity relative to the
2-(N-benzyl)carboxamido tryptamine analogs.26
Activity
The compounds synthesized and their biological results are
shown in Table 1.
In an effort to explain the biological results we have referred
to a theoretical 5HT1B-like receptor model which we have
described previously.18,25,26,47 This pharmacophore was con-
structed using the active analogue approach.18,48 We have
hypothesized that if the proposed important binding sites are
occupied then the molecule will have high affinity and selectiv-
ity for the vascular 5-HT1B-like receptor. The binding sites we
refer to are a protonated amine site, an aromatic centre, a
hydrophobic region, a hydrogen bonding acceptor site and a
hydrogen bond donor–acceptor site and a ‘selectivity’ site for
5-HT1B-like receptor over 5-HT2A illustrated in Fig. 1.
As has been previously reported there is a spatial restriction
on the size of the 2-carboxamido sidechain on the indole ring
and bulkier groups result in steric interaction with the recep-
tor.25 We have postulated that in order to accommodate the
large 2-substituent the molecule occupies a different position
within the receptor or is ‘displaced’ resulting in the aromatic
portion of the 2-sidechain occupying the aromatic binding site.
The flexibility of the 5-ethyl linking chain allows the remainder
All other analogs containing hydantoin-based groups linked
to the 5-position of the indole ring exhibited pKB’s < 7.0. It
appears that the furan ring is able to substitute for the phenyl
ring and bind at the aromatic binding site although with less
J. Chem. Soc., Perkin Trans. 1, 1999, 2713–2723
2715

View Online
Table 1
5-HT1B
like
-
5-HT1B
like
-
Com-
α1
Com-
α1
pound
RbSVa RbTAa
pound
RbSVa RbTAa
Number R1
R2
R3
(pKB)
(pKB)
Number R1
R2
R3
(pKB)
(pKB)
2716
J. Chem. Soc., Perkin Trans. 1, 1999, 2713–2723

View Online
Table 1 (Contd.)
5-HT1B
-
5-HT1B
like
-
Com-
like
α1
Com-
α1
pound
RbSVa RbTAa
pound
RbSVa RbTAa
Number R1
R2
R3
(pKB)
(pKB)
Number R1
R2
R3
(pKB)
(pKB)
a Affinity (pKB : Ϫlog10KB, the dissociation equilibrium constant) estimates for novel compounds at the vascular 5-HT1B-like receptor in the rabbit
saphenous vein (RbSV). α1-Adrenoceptor affinity was measured in the rabbit thoracic aorta (RbTA) using phenylephrine as agonist. Affinity values
are the means of at least 3 separate estimates. Standard errors are omitted for clarity, but in all cases were ≤0.2 log10 units. In each case affinity
estimates were determined using the Gaddum–Schild equation and 5-HT as the receptor agonist. b Both compound 2426 and 5747 have been
previously described.
Four 2-carboxamidomethylthiophene derivatives were
investigated. As with the furfurylamide derivatives there was
a decrease in overall affinity compared with the corresponding
2-(N-benzyl)-carboxamido tryptamine derivatives though the
decrease was less. The compound with highest affinity from this
group was 49 (pKB = 7.25) with an hydantoin moiety in the
5-sidechain. However, it exhibited ~20 fold selectivity over α1-
adrenoceptor affinity. The phthalimide compound 46 (pKB =
7.22) had slightly lower affinity but superior selectivity (~60
fold) over α1-adrenoceptor affinity. It may be that substitution
of the phenyl ring with a thiophene group has produced the
required hydrophobic interaction but without steric hindrance.
Three 2-carboxamidomethyloxadiazole tryptamine deriv-
atives 50–52 were investigated and only one of the compounds
had a pharmacological profile comparable to the corresponding
2-(N-benzyl)carboxamido tryptamine analog. The phthalimide
containing analog 52 (pKB = 7.23) has similar potency to the
2-(N-benzyl)carboxamido analog 57 (pKB = 7.33) and similar
selectivity over α1-adrenoceptor affinity (~1.78 fold), Table 1.
Four 2-N-carboxamidomethylisoxazole derivatives 53–56
were investigated. All four compounds showed low 5-HT1B-like
receptor affinity and poor selectivity for the 5-HT1B-like
receptor over α1-adrenoceptor affinity. One possible explan-
ation for the poor biological profile observed for 53–56 is the
extra size of the heteroaromatic groups containing the 3-bromo
and 3-ethyl ester groups and the subsequent effect these groups
have on the overall configuration of the molecules within the
5-HT1B-like receptor.
Fig. 2 Proposed conformation of 34 fitted to the 5-HT1B-like receptor
pharmacophore model.
potency than a phenyl ring. The improved potency of 34 and
36 may be due to the ability of the fused phenyl ring of
the phthalimide group and the methyl-linked phenyl group
of the N-benzylhydantoin ring system respectively to interact
with a previously unreported hydrophobic pocket within the
pharmacophore model. The proposed mode of binding of 34 is
shown in Fig. 2.
In the conformation proposed in Fig. 2, the 3-ethylamine
nitrogen can interact accurately with the amine binding site.
The amide bond is slightly twisted from planarity but still ener-
getically favourable allowing the furan ring to occupy the aro-
matic binding site. The 5-ethyl linked phthalimide sidechain is
flexible and it is proposed that within the active site the
sidechain adopts a conformation to allow one of the carbonyl
groups to interact with the hydrogen bonding site. This con-
formation also allows for the other carbonyl of the hydantoin
to interact with the proposed secondary hydrogen bonding
site.18,25 The selectivity site shown in yellow is occupied by part
of the indole ring.
Conclusion
In this study we have identified a novel series of 2-N-carb-
oxamido-5-substituted-N,N-dimethyltryptamine derivatives as
antagonists for the vascular 5-HT1B-like receptor. N-Furfuryl-
5-[2-(N-phthalimido)ethyl]-3-[2-(dimethylamino)ethyl]-1H-
indole-2-carboxamide (34) exhibited high 5-HT1B-like receptor
affinity (pKB = 7.38) and showed that the furfurylamido group
can successfully replace the 2-(N-benzyl)carboxamide group
and interact with the proposed aromatic binding site. From this
series, the phthalimide moiety in the 5-sidechain provided the
most potent compounds. Analog 36 with an N-benzyl substi-
tuted hydantoin ring in the 5-sidechain also showed high 5-
It was interesting to note the considerable decrease in
potency observed for the N-methyl derivative 44 (pKB = 5.0)
compared with 32 (pKB = 6.75). The N-methyl group appears
to cause steric hindrance between the 2 and 3-sidechains not
allowing the groups to take up optimal positions for binding.
J. Chem. Soc., Perkin Trans. 1, 1999, 2713–2723
2717

View Online
HT1B-like receptor affinity (pKB = 7.16). These results appear to
indicate there may be a hydrophobic binding region in the
pharmacophore previously unrecognised.26 All other substi-
tuted hydantoin derivatives investigated resulted in compounds
with relatively low 5-HT1B-like receptor affinity (pKB’s < 7.0).
These results indicate a size restriction in this region of the
pharmacophore. Compounds such as 34 may prove to be useful
pharmacological probes for the vascular 5-HT1B-like receptor.
α1-Adrenoceptor activity was determined in tissues exposed to
pargyline (500 µM for 30 minutes) during which they were ten-
sioned twice to a resting force of 3.0 g. Exposure to -phenyl-
ephrine (-Phe, 10 µM) enabled tissue viability to be assessed
and provided a reference contracture for subsequent data
analysis. Following washout tissues were exposed to novel com-
pounds (30 µM) for 60 minutes prior to a cumulative E/[A]
curve to -Phe being constructed.
Chemical methods
Experimental
Computational chemistry was performed on a Silicon Graphics
Iris Indigo II using the Sybyl51 molecular modelling soft-
ware.
Biological methods
Definition: ‘Intrinsic activity’: the maximum effect of the test
agonist relative to a standard (usually a full agonist).
1
Unless otherwise stated, all H NMR spectra were recorded
at 200 MHz on a Bruker AC 200 spectrometer or at 300 MHz
on a Bruker AM 300 spectrometer. Chemical shifts are in δ/ppm
relative to TMS. Deuterated dimethyl sulfoxide (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 Kratos MS50 (FAB) mass spectrometer
or a JEOL JMS DX-300 double focussing instrument. Melting
points were determined on a Gallenkamp melting point appar-
atus and are uncorrected. Methanol and ethanol were distilled
from iodine and magnesium and stored over type 3 Å molecular
sieves. Anhydrous THF was freshly distilled over potassium and
benzophenone. Anhydrous DMF, ether and toluene were stored
over type 4 Å molecular sieves. Triethylamine, diisopropylethyl-
amine and pyridine were stored over sodium hydroxide. All
solutions were dried over MgSO4 or Na2SO4 and concen-
trated on a Buchi rotary evaporator. Flash chromatography
was performed on silica gel (Merck Kieselgel 60 F254). Infra
red spectra were run in KBr disks on a Bruker IFS66 FTIR
spectrometer. Microanalysis were performed on a VG Plat-
form spectrometer and are within 0.4% of the theoretical
values unless otherwise stated. HPLC was performed on a
Rabbit saphenous vein (RbSV) preparation. The vascular
5-HT1B-like receptor affinities of compounds were assessed
using ring preparations of rabbit saphenous vein.49 Vessels were
removed from male New Zealand White rabbits killed by inject-
ing pentobarbitone (80 mg kgϪ1, iv) followed by exsanguin-
ation. After removing adhering connective tissue, ring segments
(4–5 mm) were prepared and mounted between parallel tung-
sten wires. Tissues were suspended in 20 mL organ baths con-
taining Krebs–Henseleit buffer at 37 ЊC, pH 7.4 and constantly
gassed with 95% O2–5% CO2. The Kreb–Henseleit solution
used had the following composition: (mM) NaCl 118.41,
NaHCO3 25.00, KCl 4.75, KH2PO4 1.19, MgSO4 1.19, glucose
11.10 and CaCl2 2.50. After application of a passive force (2 g)
tissues were exposed to pargyline (500 µM) to inactivate
monoamine oxidase. In order to prevent the direct or indirect
activation of α1-adrenoceptors, saphenous veins were simul-
taneously exposed to phenoxybenzamine (0.3 µM). After 30
minutes, excess inhibitors were removed by several exchanges of
the organ bath buffer and the tissues challenged with 5-HT (1
µM) to determine viability. In the saphenous vein a cumulative
concentration-effect (E/[A]) curve to 5-HT was constructed fol-
lowed by washout and after 60 minute recovery, by a second
curve to the test compound. When the test compound failed to
produce agonism, it was evaluated as a 5-HT antagonist,
potency being determined as an apparent pKB. When the test
produced vascular contraction, potency estimates were deter-
mined as p[A]50 and intrinsic activity (α) values determined
from the ratio test maximum response/5-HT maximum.
Waters Millenium system comprising
a
490E multi-
wavelength detector, 600 controller, a series 600 pump with a
717 Plus autosampler. A Zorbax 4.6 mm × 250 mm, 5 µm
column was used for analytical work while a 22.4 mm × 250
mm, 7 µm C18 column was used for preparative work. A
10% H2O–AcCN (10–90% gradient elution) (A)–0.1
M
NH4OAc (pH 4) (90–10%) (B) solvent system was used. The
following chemical abbreviation definitions were used: DIAD
diisopropyl azodicarboxylate; TBTU O-benzothiazol-1-yl-
N,N,NЈ,NЈ,-tetramethyluronium tetrafluoroborate; DIPEA
diisopropylethylamine; NaCNBH3 sodium cyanoborohydride;
KtBuO potassium tert-butoxide; CH2O formaldehyde; Ph3P
triphenylphosphine; TEA triethylamine; TFA trifluoroacetic
acid; Et3N triethylamine and SOCl2 thionyl chloride.
Rabbit femoral artery (RbFA) preparation. Rings (2 mm) of
rabbit femoral artery were used to determine whether or not
novel compounds behaved as ‘silent (as judged by the inability
of angiotensin II to unmask 5-HT1B-like receptor mediated
agonist activity in the rabbit femoral artery) antagonists’ i.e.
were essentially devoid of agonist properties. This is possible in
this preparation, since concomitant exposure to spasmogens
such as thromboxane A2 or angiotensin II unmasks activity at
5-HT1B-like receptors that might not otherwise manifest agonist
ligands with very low intrinsic efficacy.50 Rings (2 mm) of rabbit
femoral artery were exposed to pargyline (500 µM) for 30
minutes during which time they were progressively tensioned to
2.6 g. The tissues were exposed to 80 mM KCl to assess tissue
viability and provide a reference contracture for subsequent
data analysis. After washout, angiotension II was titrated to
provide a contraction equivalent to ~45% of the KCl response.
Once this was achieved a cumulative E/[A] curve to the novel
compound (or 5-HT as a reference) was constructed to deter-
mine vascular 5-HT1B-like agonist activity. Krebs solution con-
taining prazosin, mepyramine and spiperone (0.3 µM of each)
was used throughout to block possible effects mediated by α1-
adrenergic, H1 histaminergic and 5-HT2A serotonergic receptor
activation respectively.
N-(3-Pyridylmethyl)-3-[2-(dimethylamino)ethyl]-5-[2-(4,4-
dimethyl-2,5-dioxoimidazolidin-1-yl)ethyl]-1H-indole-2-carb-
oxamide (25). Method 1: 3-aminomethylpyridine (14.5 µL, 0.14
mmol) was added to a stirred solution of 3-[2-(dimethyl-
amino)ethyl]-5-[2-(4,4-dimethyl-2,5-dioxoimidazolidin-1-yl)-
ethyl]-1H-indole-2-carboxylic acid 2326 (50 mg, 0.13 mmol) and
TBTU (46 mg, 0.14 mmol) in DMF (5 mL). DIPEA (27 µL,
0.16 mmol) was added and the solution was stirred at room
temperature for 3 h. The reaction was concentrated under
reduced pressure and the residue purified by column chrom-
atography eluting with CH2Cl2–EtOH–NH3 (150:8:1) to give
1
48 mg (73%) of 25 as a white foam. MS m/z 477 (M ϩ 1)ϩ; H
NMR δ 1.19 (6H, s, 2 × CH3), 2.13 (6H, s, 2 × NCH3), 2.54
(2H, m, CH2NMe2, under DMSO), 2.95 (2H, t, CH2N, J 6.3
Hz), 3.08 (2H, m, 5-CH2), 3.62 (2H, m, 3-CH2), 4.55 (2H, d,
CH2NH), 7.05 (1H, d, H6), 7.32 (4H, m, H7, H4, 2 × ArH), 8.1
(1H, s, NH), 8.53 (2H, d, 2 × ArH), 9.79 (1H, t, NH), 11.17
(1H, s, NH); Found Mϩ 476.25311. C26H32N6O3 requires Mϩ
476.25359. HPLC retention time = 12.5 min.
Rabbit aorta (RbA) preparation. Rings (3 mm) of rabbit thor-
acic aorta were used to assay for activity at α1-adrenoceptors.
2718
J. Chem. Soc., Perkin Trans. 1, 1999, 2713–2723

View Online
N-(4-Pyridylmethyl)-3-[2-(dimethylamino)ethyl]-5-[2-(4,4-
dimethyl-2,5-dioxoimidazolidin-1-yl)ethyl]-1H-indole-2-carb-
oxamide (26). Method 1: cream powder, 10.5 mg (11%); MS
NCH3), 2.22 (2H, m, CH2NMe2), 2.84 (2H, m, CH2N), 2.93
(2H, m, 5-CH2), 3.78 (2H, m, 3-CH2), 4.44 (2H, d, CH2NH,
J 5.7 Hz), 6.25 (1H, d, CH᎐C, J 3.0 Hz), 6.35 (1H, d, CH᎐C,
J 3.0 Hz), 7.01 (1H, d, H6, J 8.4 Hz), 7.2 (2H, m, H7, H4),
7.74 (4H, m, 4 × ArH), 8.05 (1H, s, NH), 9.8 (1H, t, NH), 11.15
(1H, s, NH); Found Mϩ 484.21094. C28H28N4O4 requires Mϩ
484.21106.
᎐
᎐
1
m/z 476 (Mϩ); H NMR δ 1.2 (6H, s, 2 × CH3), 2.19 (6H, s,
2 × NCH3), 2.6 (2H, m, CH2NMe2, under DMSO), 2.98 (2H, t,
CH2N, J 6.3 Hz), 3.12 (2H, m, 5-CH2), 3.67 (2H, m, 3-CH2), 4.6
(2H, d, CH2NH), 7.09 (1H, d, H6), 7.38 (4H, m, H7, H4,
2 × ArH), 8.16 (1H, s, NH), 8.53 (2H, d, 2 × ArH), 9.77 (1H, t,
NH), 11.25 (1H, s, NH); Found Mϩ 476.25436. C26H32N6O3
requires Mϩ 476.25359. HPLC retention time = 12.01 min.
N-Furfuryl-5-[2-(1-benzyl-2,5-dioxoimidazolidin-4-yl)ethyl]-
3-[2-(dimethylamino)ethyl]-1H-indole-2-carboxamide
(36).
Method 1 (using furfurylamine and 3-[2-(dimethylamino)-
ethyl]-5-[2-(1-benzyl-2,5-dioxoimidazolidin-4-yl)ethyl]-1H-
indole-2-carboxylic acid 35):47 yellow powder, 30 mg (79%); MS
m/z 528 (M ϩ 1)ϩ; 1H NMR δ 1.93 (6H, s, 2 × NCH3), 2.22 (2H,
m, CH2NMe2), 2.84 (2H, m, CH2N), 2.93 (2H, m, 5-CH2), 3.78
(2H, m, 3-CH2), 4.44 (2H, d, CH2NH, J 5.7 Hz), 6.25 (1H, d,
CH᎐C, J 3.0 Hz), 6.35 (1H, d, CH᎐C, J 3.0 Hz), 7.01 (1H, d,
N-(2-Pyridylmethyl)-5-[2-(4-phenyl-4-methyl-2,5-dioxo-
imidazolidin-1-yl)ethyl]-3-[2-(dimethylamino)ethyl]-1H-indole-
2-carboxamide (28). Method 1 (using 3-[2-(dimethylamino)-
ethyl]-5-[2-(4-phenyl-4-methyl-2,5-dioxoimidazolidin-1-yl)-
ethyl]-1H-indole-2-carboxylic acid 27).26 White lyophilate, 50
1
mg (83%) (mp 75–77 ЊC); MS m/z 539 (M ϩ 1)ϩ; H NMR
᎐
᎐
δ 1.5 (3H, s, CH3), 2.49 (2H, m, CH2NMe2, under DMSO), 2.79
(6H, s, 2 × NCH3), 2.95 (2H, t, CH2N, J 6.3 Hz), 3.1 (2H, m, 5-
CH2), 3.3 (2H, m, 3-CH2), 4.59 (2H, d, CH2NH, J 5.2 Hz),
6.99–7.78 (12H, m, 12 × ArH); Found Mϩ 538.27054. C31H34-
N6O3 requires Mϩ 538.26924. HPLC retention time = 11.0 min.
H6, J 8.4 Hz), 7.2 (2H, m, H7, H4), 7.74 (4H, m, 4 × ArH), 8.05
(1H, s, NH), 9.8 (1H, t, NH), 11.15 (1H, s, NH); Found Mϩ
527.25198. C30H33N5O4 requires Mϩ 527.25325.
N-Furfuryl-5-[2-(1,3,4-trioxo-2,3,5,6,10,10a-hexahydro-1H,
H-acenaptho[1,8a-c]pyrrolyl)ethyl]-3-[2-(dimethylamino)ethyl]-
1H-indole-2-carboxamide (38). Method 1 (using furfurylamine
N-(2-Pyridylmethyl)-3-[2-(dimethylamino)ethyl]-5-[2-(4,4-
dimethyl-2,5-dioxoimidazolidin-1-yl)ethyl]-1H-indole-2-carb-
oxamide (29). Method 1: purification by HPLC afforded 39 mg
(42%) of the acetate salt of 29 as a white powder (mp 75–77 ЊC)
(Found C, 59.93; H, 6.99; N, 14.97. C26H32N6O3ؒ1.25H2Oؒ
1.0CH3CO2H requires C, 63.14; H, 6.94; N, 15.03%); MS m/z
476 (Mϩ); 1H NMR δ 1.15 (6H, s, 2 × CH3), 1.9 (3H, s,
CH3CO2H), 2.09 (6H, s, 2 × NCH3), 2.49 (2H, m, CH2NMe2,
under DMSO), 2.95 (2H, m, CH2N), 3.05 (2H, m, 5-CH2), 3.3
(2H, m, 3-CH2, under water peak), 3.6 (2H, m, CH2Hyd), 4.6
(2H, d, CH2NHCO), 7.0 (1H, d, H6), 7.3 (4H, m, H7, H4,
2 × PyrH), 7.8 (1H, m, PyrH), 8.15 (1H, s, NH), 8.5 (1H, d,
PyrH), 9.8 (1H, t, NH), 11.2 (1H, s, NH). Anal. (C26H32N6O3ؒ
1.25H2Oؒ1.0CH3CO2H) C, H, N.
and
3-[2-(dimethylamino)ethyl]-5-[2-(1,3,4-trioxo-2,3,5,6,10,
10a-hexahydro-1H,
H-acenaptho[1,8a-c]pyrrolyl)ethyl]-1H-
indole-2-carboxylic acid 37):47 yellow powder, 13.5 mg (47%);
MS m/z 579 (M ϩ 1)ϩ; 1H NMR δ 1.59 (3H, s, CCH3), 2.04 (6H,
s, 2 × NCH3), 2.45 (2H, m, CH2NMe2), 2.59 (3H, s, NCH3),
2.97 (4H, m, CH2N, 5-CH2), 3.71 (2H, m, 3-CH2), 4.51 (2H, d,
CH NH, J 5.4 Hz), 6.34 (1H, m, CH᎐C), 6.41 (1H, m, CH᎐C),
᎐
᎐
2
7.01 (3H, m, H6, 2 × ArH), 7.24 (5H, m, 5 × ArH), 7.6 (1H, m,
CH-O), 9.9 (1H, t, NH), 11.71 (1H, s, NH); Found Mϩ
578.24901. C34H34N4O5 requires Mϩ 578.25292.
N-Furfuryl-5-[2-(4-phenyl-4-methyl-2,5-dioxoimidazolidin-1-
yl)ethyl]-3-[2-(dimethylamino)ethyl]-1H-indole-2-carboxamide
(39). Method 1 (using furfurylamine and 3-[2-(dimethylamino)-
ethyl]-5-[2-(4-phenyl-4-methyl-2,5-dioxoimidazolidin-1-yl)-
ethyl]-1H-indole-2-carboxylic acid 27):26 HCl salt of 39 as a
white lyophilate, 34 mg (58%); MS m/z 528 (M ϩ 1)ϩ; 1H NMR
δ 1.23 (3H, s, CH3), 2.82 (6H, s, 2 × NCH3), 2.92 (2H, m,
CH2NMe2), 3.15 (4H, s, CH2N, 5-CH2), 3.68 (2H, m, 3-CH2),
4.51 (2H, d, CH NH, J 4.9 Hz), 6.36 (1H, m, CH᎐C), 6.43 (1H,
N-Furfuryl-5-[2-(2,5-dioxoimidazolidin-1-yl)ethyl]-3-[2-
(dimethylamino)ethyl]-1H-indole-2-carboxamide (31). Method 1
(using furfurylamine and 3-[2-(dimethylamino)ethyl]-5-[2-(2,5-
dioxoimidazolidin-1-yl)ethyl]-1H-indole-2-carboxylic
acid
30).26 HCl salt of 31 as a yellow lyophilate, 33 mg (53%); MS
m/z 438 (M ϩ 1)ϩ; 1H NMR δ 2.07 (6H, s, 2 × NCH3), 2.49 (2H,
m, CH2NMe2, under DMSO), 2.86 (2H, t, CH2N, J 8.1 Hz),
3.01 (2H, t, 5-CH2, J 6.0 Hz), 3.15 (2H, m, 3-CH2), 3.83 (2H, s,
᎐
2
m, CH᎐C), 7.03 (1H, d, H6, J 9.0 Hz), 7.27 (6H, m, H7,
᎐
5 × ArH), 7.46 (1H, s, CHO), 8.62 (1H, m, NHMe2), 8.7 (1H, s,
NH), 9.71 (1H, t, NH), 11.44 (1H, s, NH); Found Mϩ
527.25123. C30H33N5O4 requires Mϩ 527.25325.
HydCH ), 4.53 (2H, d, CH NH, J 5.1 Hz), 6.33 (1H, d, CH᎐C,
᎐
2
2
J 3.3 Hz), 6.41 (1H, d, CH᎐C, J 1.8 Hz), 7.0 (1H, dd, H6, J 1.5,
᎐
8.4 Hz), 7.3 (2H, m, H7, H4), 7.98 (1H, s, CH᎐C), 8.3 (1H, s,
᎐
NH), 9.92 (1H, t, NH, J 4.8 Hz), 11.24 (1H, s, NH); Found Mϩ
437.20630. C23H27N5O4ؒHCl requires Mϩ 437.20661. HPLC
retention time = 11.97 min.
N-Furfuryl-5-[2-(4-phenyl-3,4-dimethyl-2,5-dioxoimidazol-
idin-1-yl)ethyl]-3-[2-(dimethylamino)ethyl]-1H-indole-2-carbox-
amide (41). Method 1 (using furfurylamine and 3-[2-(dimethyl-
amino)ethyl]-5-[2-(4-phenyl-3,4-dimethyl-2,5-dioxoimidazol-
idin-1-yl)ethyl]-1H-indole-2-carboxylic acid 40):26 HCl salt of
41 as a fluffy white solid, 50 mg (66%) (Found C, 58.39; H, 5.88;
N, 10.72. C31H35N5O4ؒ1.0HCl requires C, 59.0; H, 6.60; N,
11.10%); MS m/z 542 (M ϩ 1)ϩ; 1H NMR δ 1.59 (3H, s, CCH3),
2.04 (6H, s, 2 × NCH3), 2.45 (2H, m, CH2NMe2), 2.59 (3H, s,
NCH3), 2.97 (4H, m, CH2N, 5-CH2), 3.71 (2H, m, 3-CH2), 4.51
N-Furfuryl-5-[2-(4,4-dimethyl-2,5-dioxoimidazolidin-1-
yl)ethyl]-3-[2-(dimethylamino)ethyl]-1H-indole-2-carboxamide
(32). Method 1: pale yellow solid, 81 mg (42%); MS m/z 466
(M ϩ 1)ϩ; 1H NMR δ 1.13 (3H, s, 2 × CH3), 2.06 (6H, s,
2 × NCH3), 2.85 (2H, m, CH2NMe2), 2.9 (2H, m, CH2N), 3.0
(2H, m, 5-CH2), 3.6 (2H, m, 3-CH2, J 6.9 Hz), 4.5 (2H, d,
CH NH, J 5.1 Hz), 6.34 (1H, d, CH᎐C, J 3.0 Hz), 6.41 (1H, d,
(2H, d, CH NH, J 5.4 Hz), 6.34 (1H, m, CH᎐C), 6.41 (1H, m,
᎐
2
᎐
2
CH᎐C, J 2.8 Hz), 7.0 (1H, d, H6, J 8.4 Hz), 7.28 (2H, m, H7,
CH᎐C), 7.01 (3H, m, H6, 2 × ArH), 7.24 (5H, m, 5 × ArH), 7.6
᎐
᎐
H4), 7.6 (1H, s, CHO), 8.1 (1H, s, NH), 9.9 (1H, t, NH), 11.2
(1H, s, NH); Found Mϩ 465.23897. C25H31N5O4 requires Mϩ
465.23760.
(1H, m, CHO), 9.9 (1H, t, NH), 11.19 (1H, s, NH). Anal.
(C31H35N5O4ؒ1.0HCl) C, H, N.
N-Furfuryl-5-[2-(4,4-diphenyl-2,5-dioxoimidazolidin-1-yl)-
ethyl]-3-[2-(dimethylamino)ethyl]-1H-indole-2-carboxamide
(43). Method 1 (using furfurylamine and 3-[2-(dimethylamino)-
ethyl]-5-[2-(4,4-diphenyl-2,5-dioxoimidazolidin-1-yl)ethyl]-1H-
indole-2-carboxylic acid 42):26 HCl salt of 43 as a fluffy white
solid, 27 mg (33%) (Found C, 55.89; H, 5.30; N, 9.12. C35H35-
N-Furfuryl-5-[2-(phthalimido)ethyl]-3-[2-(dimethylamino)-
ethyl]-1H-indole-2-carboxamide (34). Method 1 (using fur-
furylamine and 3-[2-(dimethylamino)ethyl]-5-[2-(phthalimido)-
ethyl]-1H-indole-2-carboxylic acid 33):47 yellow powder, 22 mg
(59%); MS m/z 485 (M ϩ 1)ϩ; 1H NMR δ 1.93 (6H, s, 2 ×
J. Chem. Soc., Perkin Trans. 1, 1999, 2713–2723
2719

View Online
N5O4ؒ2.0HClؒ5.0H2O requires C, 55.84; H, 6.29; N, 9.30%);
MS m/z 590 (M ϩ 1)ϩ; 1H NMR δ 2.02 (6H, s, 2 × NCH3), 2.47
(2H, m, CH2NMe2), 2.80 (2H, m, NCH2), 2.90 (2H, m, 5-CH2),
3.73 (2H, m, 3-CH2), 4.51 (2H, d, CH2NH, J 5.4 Hz), 6.34 (1H,
N-(2-Methylthienyl)-5-[2-(4-phenyl-3,4-dimethyl-2,5-dioxo-
imidazolidin-1-yl)ethyl]-3-[2-(dimethylamino)ethyl]-1H-indole-
2-carboxamide (48). Method 1 (using methylaminothiophene
and
3-[2-(dimethylamino)ethyl]-5-[2-(4-phenyl-3,4-dimethyl-
m, CH᎐C), 6.42 (1H, m, CH᎐C), 6.95 (1H, d, H6, J 8.4 Hz),
2,5-dioxoimidazolidin-1-yl)ethyl]-1H-indole-2-carboxylic acid
40):26 HCl salt of 48 as a fluffy white solid, 51 mg (71%) (Found
C, 59.30; H, 6.11; N, 10.87. C31H35N5O3ؒ1.0HClؒ1.75H2O
requires C, 59.5; H, 6.11; N, 10.87%); MS m/z 558 (M ϩ 1)ϩ; 1H
NMR δ 1.58 (3H, s, CH3), 2.04 (6H, s, 2 × NCH3), 2.47 (2H, m,
CH2NMe2), 2.58 (3H, s, NCH3), 2.98 (4H, m, 5-CH2, NCH2),
3.72 (2H, m, 3-CH2), 4.68 (2H, d, CH2NH, J 5.7 Hz), 6.98 (5H,
᎐
᎐
7.01–7.29 (13H, m, 12 × ArH, CH-O), 9.43 (1H, s, NH), 9.92
(1H, t, NH), 11.19 (1H, s, NH). Anal. (C35H35N5O4ؒ2.0HClؒ
5.0H2O) C, H, N.
N-Furfuryl-N-methyl-5-[2-(4,4-dimethyl-2,5-dioxoimidazol-
idin-1-yl)ethyl]-3-[2-(dimethylamino)ethyl]-1H-indole-2-carbox-
amide (44). Method 2: to a solution of 32 (59 mg, 0.11 mmol) in
dry THF (3.0 mL) was added sodium hydride (4.3 mg, 0.11
mmol) and the solution was stirred at room temperature under
nitrogen for 1.5 h. Dimethyl sulfate (11.0 µL, 0.11 mmol) was
added and the reaction mixture stirred overnight. The solution
was evaporated under reduced pressure and the residue sus-
pended in water and extracted with ethyl acetate. The organic
layer was dried, filtered and the solvent reduced in vacuo to give
a yellow solid which was purified by flash chromatography elut-
ing with CH2Cl2–EtOH–NH3 (300:8:1) to give 15.6 mg (30%)
of 44 as a yellow solid which was converted to the HCl salt.
Rf = 0.26 (CH2Cl2–EtOH–NH3, 150:8:1); MS m/z 480 (M ϩ
1)ϩ; 1H NMR ((CD3)2CO) δ 1.25 (6H, s, 2 × CH3), 2.10 (6H, s,
2 × NCH3), 2.5 (2H, m, CH2NMe2), 2.8 (3H, s, NCH3), 3.43
(4H, m, CH2N, 5-CH2), 3.7 (2H, m, 3-CH2), 4.55 (2H, d,
CH NH, J 5.3 Hz), 6.35 (2H, m, 2 × CH᎐C), 7.25 (1H, d, H6,
m, H6, H7, 2 × CH᎐C, 1 × ArH), 7.24 (6H, m, H4, CHS,
᎐
4 × ArH), 10.03 (1H, t, NHCH2, J 5.4 Hz), 11.25 (1H, s, NH).
Anal. (C31H35N5O3ؒ1.0HClؒ1.75H2O) C, H, N.
N-(Methylthienyl)-5-[2-(2,5-dioxoimidazolidin-1-yl)ethyl]-3-
[2-(dimethylamino)ethyl]-1H-indole-2-carboxamide
(49).
Method 1 (using methylaminothiophene and 3-[2-(dimethyl-
amino)ethyl]-5-[2-(2,5-dioxoimidazolidin-1-yl)ethyl]-1H-
indole-2-carboxylic acid 30):26 HCl salt of 49 as an off-white
powder, 30.3 mg (48%); MS m/z 454 (M ϩ 1)ϩ; 1H NMR δ 2.08
(6H, s, 2 × NCH3), 2.48 (2H, m, CH2NMe2, under DMSO),
2.87 (2H, m, CH2N, J 8.1 Hz), 3.01 (2H, m, 5-CH2, J 5.7 Hz),
3.57 (2H, m, 3-CH2, J 6.9 Hz), 3.83 (2H, s, HydCH2), 4.67 (2H,
d, CH2NH, J 5.7 Hz), 7.04 (3H, m, H6, H2Ј, H3Ј), 7.3 (3H, m,
H7, H4, H4Ј), 7.97 (1H, s, NH), 10.02 (1H, t, NH, J 5.1 Hz),
11.24 (1H, s, NH); Found Mϩ 453.18346. C23H27N5O3SؒHCl
requires Mϩ 453.18151. HPLC retention time = 12.77 min.
᎐
2
J 8.1 Hz), 7.45 (2H, m, H7, H4), 7.53 (1H, s, CHO), 10.3 (1H,
br s, NH), 10.65 (1H, br s, NH); Found Mϩ 479.25431. C26H33-
N5O4 requires Mϩ 479.25325.
(N-tert-Butyloxycarbonyl)glycine ethyl ester (8). Glycine ethyl
ester (13.9 g, 0.1 mol) was combined with a mixture of water
(191 mL), dioxane (350 mL) and 1 M NaOH (190 mL). To this
mixture was added di-tert-butyl dicarbonate (24.0 g, 0.2 mol)
dropwise while maintaining the mixture at 0–5 ЊC. The solution
was stirred overnight at room temperature. Dioxane–water was
removed under reduced pressure and the remaining residue was
extracted with ethyl acetate, dried and the solvent evaporated
under reduced pressure to give an oil which was distilled to give
N-Furfuryl-N-methyl-5-[2-(3,4,4-trimethyl-2,5-dioxoimidazol-
idin-1-yl)ethyl]-3-[2-(dimethylamino)ethyl]-1H-indole-2-carb-
oxamide (45). Method 2: purification by flash chromatography
eluting with CH2Cl2–EtOH–NH3 (300:8:1) gave 11.5 mg (22%)
of 45 as a yellow solid which was converted to the HCl
salt. Rf = 0.21 (CH2Cl2–EtOH–NH3, 150:8:1); MS m/z 494
1
(M ϩ 1)ϩ; H NMR ((CD3)2CO) δ 1.21 (6H, s, 2 × CH3), 2.06
1
(6H, s, 2 × NCH3), 2.6 (2H, m, CH2NMe2), 2.81 (3H, s, NCH3),
3.0 (4H, m, CH2N, 5-CH2), 3.7 (2H, m, 3-CH2), 3.87 (3H, s,
NCH3), 4.61 (2H, d, NHCH2, J 5.34 Hz), 6.4 (2H, m,
the 11.5 g (56%) of 8 as a clear oil. MS m/z 204 (M ϩ 1)ϩ; H
NMR δ 1.17 (3H, t, CH2CH3, J 7.1 Hz), 1.38 (9H, s, 3 × CH3),
3.59 (2H, d, CH2NH, J 6.2 Hz), 4.07 (2H, q, CH2CH3, J 7.3
Hz), 7.17 (1H, br t, NH).
2 × CH᎐C), 7.15 (1H, d, H6, J 8.0 Hz), 7.35 (2H, m, H7, H4),
᎐
7.5 (1H, s, CHO), 10.45 (1H, br s, NH); Found Mϩ 493.27268.
C27H35N5O4 requires Mϩ 493.26890.
(N-tert-Butyloxycarbonyl)-3-methyl-1,2,4-oxadiazol-5-yl-
methylamine (11). Method 3: the oxime 9 (1.44 g, 19.0 mmol)
was added to a stirred suspension of powdered 3 Å sieves (3.0 g)
in THF (200 mL) under nitrogen. After 15 min sodium hydride
(1.3 g, 32.0 mmol) was added and stirring continued for a
further 40 min. The amino acid 8 (2.0 g, 9.7 mmol) in THF
(40 mL) was added and the reaction mixture was refluxed over-
night. The reaction mixture was cooled, filtered over Celite and
the solvent removed under reduced pressure. The resulting oil
was partitioned between CH2Cl2 and water. The combined
organic extracts were dried and the solvent removed. The crude
product was purified by column chromatography eluting with
CH2Cl2–EtOH–NH3 (300:8:1) to give 1.14 g (55%) of 11 as a
pale yellow oil. MS m/z 214 (M ϩ 1)ϩ; 1H NMR δ 1.38 (9H, s,
3 × CH3), 2.3 (3H, s, CH3), 4.36 (2H, d, CH2NH), 7.61 (1H, br
t, NH).
N-(2-Methylthienyl)-5-[2-(phthalimido)ethyl]-3-[2-(dimethyl-
amino)ethyl]-1H-indole-2-carboxamide (46). Method 1 (using
methylaminothiophene and 3-[2-(dimethylamino)ethyl]-5-[2-
(phthalimido)ethyl]-1H-indole-2-carboxylic acid 33):47 yellow
1
powder, 23 mg (55%); MS m/z 501 (M ϩ 1)ϩ; H NMR δ 1.97
(6H, s, 2 × NCH3), 2.26 (2H, m, CH2NMe2), 2.85 (2H, m,
CH2N), 2.95 (2H, m, 5-CH2), 3.8 (2H, t, 3-CH2, J 6.9 Hz), 4.65
(2H, d, CH NH, J 5.7 Hz), 6.96 (1H, m, CH᎐C), 7.04 (2H,
᎐
2
m, CH᎐C, H6), 7.23 (2H, m, H7, H4), 7.39 (1H, m, CH-S),
᎐
7.79 (4H, s, PhthH), 9.9 (1H, t, NHCH2, J 5.4 Hz), 11.12 (1H,
s, NH); Found Mϩ 500.19050. C28H28N4O3S requires Mϩ
500.18821.
N-(2-Methylthienyl)-5-[2-(1-benzyl-2,5-dioxoimidazolidin-
4-yl)ethyl]-3-[2-(dimethylamino)ethyl]-1H-indole-2-carbox-
amide (47). Method 1 (using methylaminothiophene and 3-[2-
(dimethylamino)ethyl]-5-[2-(1-benzyl-2,5-dioxoimidazolidin-4-
yl)ethyl]-1H-indole-2-carboxylic acid 35):47 Yellow powder, 20
mg (37%); MS m/z 544 (M ϩ 1)ϩ; 1H NMR δ 1.8 (2H, m,
CH2CH), 2.07 (6H, s, 2 × NCH3), 2.51 (2H, m, CH2NMe2
under DMSO), 2.69 (2H, m, 5-CH2), 3.01 (2H, m, 3-CH2), 4.1
(1H, m, CH), 4.48 (2H, s, CH2Ph), 4.67 (2H, d, CH2NH, J 5.4
Hz), 7.02 (3H, m, 3 × ArH), 7.28 (8H, m, 8 × ArH), 8.52 (1H,
s, NH), 10.02 (1H, t, NH), 11.19 (1H, s, NH); Found Mϩ
543.23164. C30H33N5O3S requires Mϩ 543.23041.
(N-tert-Butyloxycarbonyl)-3-ethyl-1,2,4-oxadiazol-5-yl-
methylamine (12). Method
3
(using N-hydroxypropan-
imidamide 10): bp 150 ЊC at 0.1 mmHg (145 ЊC at 0.05
mmHg).41 MS m/z 203 (Mϩ).
3-Methyl-1,2,4-oxadiazolymethylamine41 (13). Method 4: to
the N-protected oxadiazole derivative 11 (0.34 g, 1.6 mmol) was
added 1,4-dioxane (24 mL) and 1 M HCl (28 mL). The mixture
was allowed to stir at room temperature for 2 h. The solvent was
removed under vacuum and the resultant oil was triturated with
2720
J. Chem. Soc., Perkin Trans. 1, 1999, 2713–2723

View Online
acetonitrile to afford white crystals. Conversion to the HCl salt
and recrystallisation from acetonitrile afforded 0.11 g (61%) of
the HCl salt of 13 as white crystals (mp 177 ЊC (dec)) (Found C,
31.93; H, 5.25; N, 27.41. C4H7N3Oؒ1.0HClؒ0.3H2O requires C,
N-[5-(3-Bromo)-1,2-oxazol-5-ylmethyl]-3-[2-(dimethyl-
amino)ethyl]-5-[2-(2,5-dioxoimidazolidin-1-yl)ethyl]-1H-indole-
2-carboxamide (53). Method 1 (using 3-[2-(dimethylamino)-
ethyl]-5-[2-(2,5-dioxoimidazolidin-1-yl)ethyl]-1H-indole-2-
carboxylic acid 30):26 HCl salt of 53 as a white lyophilate, 8.5
mg (12%); MS m/z 517, 519 (M ϩ 1)ϩ, (Mϩ3)ϩ; 1H NMR δ 2.14
(6H, s, 2 × NCH3), 2.48 (2H, m, CH2NMe2, under DMSO),
2.86 (2H, m, CH2N, J 7.0 Hz), 3.03 (2H, m, 5-CH2), 3.56 (2H,
m, 3-CH2, J 6.6 Hz), 3.82 (2H, s, HydCH2), 4.6 (2H, d, CH2NH,
1
31.8; H, 5.39; N, 27.83%); MS m/z 114 (M ϩ 1)ϩ; H NMR
δ 2.3 (3H, s, CH3), 4.45 (2H, s, CH2), 8.67 (3H, s, NH3ϩ).
Anal. (C4H7N3Oؒ1.0HClؒ0.3H2O) C, H, N.
3-Ethyloxadiazolymethylamine (14). Method 4: HCl salt of
14, 120 mg (70%); mp 160–162 ЊC (lit.,41 mp 158–161 ЊC); MS
m/z 127 (Mϩ) (Found C, 36.10; H, 5.99; N, 25.44. C5H9N3Oؒ
1.0HCl requires C, 35.80; H, 5.84; N, 24.86).
J 5.1 Hz), 6.74 (1H, s, CH᎐CBr), 7.05 (1H, m, H6), 7.31 (2H, m,
᎐
H7, H4), 7.98 (1H, s, NH), 10.17 (1H, t, NHCH2, J 5.0 Hz),
11.31 (1H, s, NH); Found Mϩ 516.10881. C22H25N6O4BrؒHCl
requires Mϩ 516.11206. HPLC retention time = 12.56 min.
N-[5-(3-Methyl)-1,2,4-oxadiazolymethyl)-3-[2-(dimethyl-
amino)ethyl]-5-[2-(4,4-dimethyl-2,5-dioxoimidazolidin-1-yl)-
ethyl]-1H-indole-2-carboxamide (50). Method 1 (using 3-[2-
(dimethylamino)ethyl]-5-[2-(4,4-dimethyl-2,5-dioxoimidazol-
idin-1-yl)ethyl]-1H-indole-2-carboxylic acid 23):26 HCl salt of
50 as a yellow lyophilate, 51.7 mg (92%); MS m/z 482 (M ϩ 1)ϩ;
1H NMR δ 1.12 (6H, s, 2 × CH3), 2.16 (6H, s, 2 × NCH3), 2.31
(3H, s, OxadCH3), 2.53 (2H, m, CH2NMe2), 2.91 (2H, t, CH2N,
J 7.5 Hz), 3.02 (2H, t, 5-CH2, J 5.7 Hz), 3.59 (2H, t, 3-CH2,
J 6.9 Hz), 4.76 (2H, d, CH2NH, J 5.4 Hz), 7.0 (1H, dd, H6, J
1.5, 6.9 Hz), 7.27 (2H, m, H7, H4), 8.11 (1H, s, NH), 10.31 (1H,
t, NH, J 5.7 Hz), 11.29 (1H, s, NH); Found Mϩ 481.25404
C24H31N7O4ؒHCl requires Mϩ 481.24378. HPLC retention
time = 10.81 min.
N-[5-(3-Bromo)-1,2-oxadiazol-5-ylmethyl]-3-[2-(dimethyl-
amino)ethyl]-5-[2-(4,4-dimethyl-2,5-dioxoimidazolidin-1-yl)-
ethyl]-1H-indole-2-carboxamide (54). Method 1 (using 3-[2-
(dimethylamino)ethyl]-5-[2-(4,4-dimethyl-2,5-dioxoimidazol-
idin-1-yl)ethyl]-1H-indole-2-carboxylic acid 23):26 HCl salt of
54 as a white solid, 15 mg (21%); MS m/z 545, 547 (M ϩ 1)ϩ,
(Mϩ3)ϩ; 1H NMR δ 1.06 (6H, s, 2 × CH3), 2.14 (6H, s,
2 × NCH3), 2.49 (2H, m, CH2NMe2, under DMSO), 2.91 (2H,
t, CH2N, J 6.9 Hz), 3.02 (2H, m, 5-CH2), 3.59 (2H, m, 3-CH2,
J 6.9 Hz), 4.66 (2H, d, CH NH, J 5.4 Hz), 6.74 (1H, s, CH᎐C),
᎐
2
7.01 (1H, d, H6, J 8.4 Hz), 7.27 (2H, m, H7, H4), 8.11 (1H, s,
NH), 10.15 (1H, t, NH, J 5.1 Hz), 12.75 (1H, s, NH); Found Mϩ
544.14126. C24H29N6O4BrؒHCl requires Mϩ 544.14126. HPLC
retention time = 13.83 min.
N-[5-(3-Methyl)-1,2,4-oxadiazol-5-ylmethyl)-3-[2-(dimethyl-
amino)ethyl]-5-[2-(4-methyl-4-phenyl-2,5-dioxoimidazolidin-1-
yl)ethyl]-1H-indole-2-carboxamide (51). Method 1 (using 3-[2-
(dimethylamino)ethyl]-5-[2-(4-methyl-4-phenyl-2,5-dioxoimid-
azolidin-1-yl)ethyl]-1H-indole-2-carboxylic acid 27):26 HCl salt
of 51 as a yellow lyophilate, 24 mg (35%); MS m/z 544
(M ϩ 1)ϩ; 1H NMR δ 1.53 (3H, s, HydCH3), 2.15 (6H, s,
2 × NCH3), 2.32 (3H, s, OxadCH3), 2.49 (2H, m, CH2NMe2,
under DMSO), 2.91 (2H, m, CH2N), 2.99 (2H, m, 5-CH2), 3.65
(2H, m, 3-CH2), 4.77 (2H, d, CH2NH, J 5.1 Hz), 6.98 (1H, d,
H6, J 8.1 Hz), 7.28 (7H, m, H7, H4, 5 × ArH), 8.75 (1H,
s, NH), 10.3 (1H, t, NH), 11.23 (1H, s, NH); Found Mϩ
543.25337. C29H33N7O4ؒHCl requires Mϩ 543.25940. Rf = 0.37
CH2Cl2–EtOH–NH3 (80:8:1).
N-(tert-Butyloxycarbonyl)propargylamine (19). To an ice
cooled solution of propargylamine (5.0 g, 0.09 mol) and tri-
ethylamine (12.7 mL, 0.09 mol) in diethyl ether (70 mL) was
added Boc2O in diethyl ether (30 mL). The resulting solution
was stirred at room temperature overnight. The reaction mix-
ture was washed with saturated ammonium chloride (150 mL)
followed by water then dried. The solvent was evaporated under
reduced pressure to give a yellow oil which was distilled (bp
170 ЊC at 14 mmHg) to give the propargylamine derivative 19
as a clear oil. 13.9 g (90%); MS m/z 155 (Mϩ); 1H NMR δ 1.36
(9H, s, 3 × CH ), 1.45 (1H, s, CH᎐C), 3.67 (2H, d, CH NH,
᎐
3
2
J 5.7 Hz), 7.22 (1H, br s, NH).
Ethyl 2-chloro-2-hydroxyiminoacetate (20).46 Glycine ethyl
ester (20 g, 0.143 mol) was dissolved in water (30 mL) and
cooled to ~5 ЊC. Concentrated HCl (16.3 mL, 0.14 mol) was
added to the stirring solution. After a further 5 min stirring,
sodium nitrite (9.87 g, 0.14 mol) in water (15 mL) was added. A
further equivalent of concentrated HCl (16.3 mL) was added
followed by another equivalent of sodium nitrite (9.87 g) in
water (15 mL). Following evolution of a brown gas, stirring was
continued for 1 h. A white precipitate was filtered off and the
filtrate was left to sit in the fridge overnight after which a
second crop of the desired compound was filtered. The com-
pound was dried to give 8.0 g (36%) of the desired oximino ester
as a white crystalline solid (Mp 79–80 ЊC, lit.,46 mp 80 ЊC); MS
m/z 152, 154 (M ϩ 1)ϩ, (Mϩ3)ϩ (3:1); 1H NMR δ 1.26 (3H, t,
CH3, J 7.2 Hz), 4.29 (2H, q, CH2, J 7.2 Hz), 13.5 (1H, s, OH);
Found Mϩ 151.00362. C4H6NO3Cl requires Mϩ 151.00306.
N-[5-(3-Methyl)-1,2,4-oxadiazol-5-ylmethyl)-3-[2-(dimethyl-
amino)ethyl]-5-[2-(phthalimido)ethyl]-1H-indole-2-carbox-
amide (52). Method 1 (using 3-[2-(dimethylamino)ethyl]-5-[2-
(phthalimido)ethyl]-1H-indole-2-carboxylic acid 33):47 HCl salt
of 52 as a white lyophilate, 14 mg (23%); MS m/z 501 (M ϩ 1)ϩ;
1H NMR δ 2.07 (6H, s, 2 × NCH3), 2.27 (3H, s, OxadCH3),
2.49 (2H, m, CH2NMe2, under DMSO), 2.98 (4H, m, CH2N,
5-CH2), 3.38 (2H, m, 3-CH2), 4.74 (2H, d, CH2NH, J 5.7
Hz), 7.06 (1H, d, H6, J 6.6 Hz), 7.28 (2H, m, H7, H4), 7.8
(4H, s, 4 × ArH), 10.32 (1H, t, NH, J 5.4 Hz), 11.29 (1H,
s, NH); Found Mϩ 500.21297. C27H28N6O4ؒHCl requires Mϩ
500.21720. Rf = 0.7, CH2Cl2–EtOH–NH3 (80:8:1).
Dibromoformaldoxime (16).42,43,45 Yellow solid, 19.8 g (45%)
(mp 68–70 ЊC, lit.,42 65–66 ЊC) (Found C, 5.37; H, 0.43; N, 6.41.
CHNOBr2 requires C, 5.37; H, 0.70; N, 6.72%); MS m/z 197
(Mϩ) 203 (1:3:1); 1H NMR δ 12.83 (1H, s, OH). Anal.
(CHNOBr2ؒ0.3H2O) C, H, N.
Ethyl [N-(tert-butyloxycarbonyl)-5-aminomethyl]isoxazole-3-
carboxylate (21). Ethyl 2-chloro-2-hydroxyiminoacetate 20 (5.0
g, 0.033 mol) was dissolved in THF (35 mL). A solution of the
N-protected propargylamine 19 (5.86 g, 0.038 mol) and tri-
ethylamine (5.27 mL, 0.038 mol) in diethyl ether (140 mL) was
added dropwise at room temperature. The solution was left to
stir at room temperature overnight. The ether solution was
washed with dilute ammonium chloride solution followed by
water then dried. The ether was evaporated under reduced pres-
sure to give a yellow oil which was dried under vacuum. Purifi-
cation by column chromatography eluting with chloroform–
5-Chloromethyl-3-bromoisoxazole (17).42 Yellow oil, 6.19 g
(80%); MS m/z 197 (M ϩ 1)ϩ; 1H NMR δ 4.63 (2H, s, CH2Cl),
6.43 (1H, s, CH᎐C).
᎐
5-Aminomethyl-3-bromoisoxazole (18).42 Yellow crystals, 417
1
mg (70%) (mp 117–118 ЊC); MS m/z 176 (M ϩ 1)ϩ; H NMR
δ 3.75 (2H, s, CH ), 6.53 (1H, s, CH᎐C), 9.74 (2H, s, NH );
᎐
2
2
Found Mϩ 176.00451. C4H5N2OBr requires Mϩ 175.95852.
J. Chem. Soc., Perkin Trans. 1, 1999, 2713–2723
2721

View Online
6 P. R. Hartig, H. T. Kao, M. Macchi, N. Adham, J. Zgombick,
R. Weinshank and T. Branchek, Neuropsychopharmacology, 1990, 3,
335.
7 A. Frazer, S. Maayani and B. B. Wolfe, Annu. Rev. Pharmacol.
Toxicol., 1990, 30, 307.
8 A. W. Schmidt and S. J. Peroutka, FASEB J., 1989, 3, 2242.
9 S. J. Peroutka, Trends. Neurosci., 1988, 11, 496.
hexane (1:1) followed by chloroform to afford 1.42 g (16%) of
1
21 as a viscous yellow oil. MS m/z 271 (M ϩ 1)ϩ; H NMR δ
1.28 (3H, t, CH3, J 7.0 Hz), 1.37 (9H, s, 3 × CH3), 4.33 (4H, m,
CH CH , CH NH), 6.62 (1H, s, CH᎐C), 7.57 (1H, t, NH, J 5.5
᎐
2
3
2
Hz).
10 H. Matthes, U. Boschert, N. Amliaky, R. Grailhe, J. Plassat,
F. G. Muscatelli and R. Hen, Mol. Pharmacol., 1993, 43, 313.
11 F. J. Monsma, Y. Shen, R. P. Ward, M. W. Hamblin and D. R.
Sibley, Mol. Pharmacol., 1993, 43, 320.
12 Y. Shen, F. J. Monsma, M. A. Metcalf, P. A. Jose, M. W. Hamblin
and D. R. Sibley, J. Biol. Chem., 1993, 268, 18200.
13 C. Waeber, P. Schoeffter, D. Hoyer and J. M. Palacios, Neurochem.
Res., 1990, 15, 567.
14 P. P. A. Humphrey, W. Feniuk, M. J. Perren, H. E. Connor, A. W.
Oxford, I. H. Coates and D. Butina, Br. J. Pharmacol., 1988, 94,
1123.
15 R. L. Weinshank, J. Zgombick, M. J. Macchi, T. A. Branchek and
P. R. Hartig, Proc. Natl. Acad. Sci. U.S.A., 1992, 89, 3630.
16 (a) M. D. Ferrari and P. R. Saxena, Trends. Pharmacol. Sci., 1993,
14, 129; (b) K. L. Dechant and S. P. Clissold, Drugs, 1992, 43, 776.
17 R. C. Glen, A. P. Hill, G. R. Martin and A. D. Robertson, Headache,
1994, 34, 307.
Ethyl 5-aminomethylisoxazole-3-carboxylate (22). A stirring
solution of the ester 21 (416 mg, 1.5 mmol) in dichloromethane
(7.5 mL) was cooled to 0 ЊC. TFA (1.5 mL, 2.22 g, 19.4 mmol)
was added dropwise and the solution was allowed to stir up to
room temperature over 5 h. The solvent was then evaporated
under reduced pressure and diethyl ether (20 mL) was added.
The oil solidified and was then filtered and washed several times
with ether. The solid was dried under vacuum to afford 341 mg
(80%) of the trifluoroacetate salt of the 22 as an off-white solid.
MS m/z 171 (M ϩ 1)ϩ; Found Mϩ 170.06914. C7H10N2O3ؒCF3-
1
CO2H requires Mϩ 170.06895; H NMR δ 1.32 (3H, t, CH3,
J 8.7 Hz), 4.37 (4H, m, 2 × CH ), 6.96 (1H, s, CH᎐C), 8.41 (3H,
᎐
2
br s, NH3ϩ).
N-[5-(3-Ethoxycarbonyl)isoxazol-5-ylmethyl]-3-[2-(dimethyl-
amino)ethyl]-5-[2-(4,4-dimethyl-2,5-dioxoimidazolidin-1-yl)-
ethyl]-1H-indole-2-carboxamide (55). Method 1 (using 3-[2-
(dimethylamino)ethyl]-5-[2-(4,4-dimethyl-2,5-dioxoimidazol-
idin-1-yl)ethyl]-1H-indole-2-carboxylic acid 23):26 HCl salt of
55 as a yellow lyophilate, 44 mg (63%); MS m/z 539 (M ϩ 1)ϩ;
1H NMR δ 1.14 (6H, s, 2 × CH3), 1.29 (3H, t, CH2CH3, J 7.2
Hz), 2.84 (6H, s, 2 × NCH3), 2.94 (2H, m, CH2NMe2), 3.23
(2H, m, CH2N), 3.36 (2H, m, 5-CH2), 3.62 (2H, m, 3-CH2), 4.35
(2H, q, CH2CH3, J 7.2 Hz), 4.72 (2H, d, CH2NH, J 5.4 Hz),
18 R. C. Glen, G. R. Martin, A. P. Hill, R. M. Hyde, P. M. Woollard,
J. A. Salmon, J. Buckingham and A. D. Robertson, J. Med. Chem.,
1995, 38, 3566.
19 L. J. Street, R. Baker, J. L. Castro, M. S. Chambers, A. R. Guiblin,
S. C. Hobbs, V. G. Matassa, A. J. Reeve, M. S. Beer, D. N.
Middlemiss, A. J. Noble, J. A. Stanton, K. Scholey and R. J.
Hargreaves, J. Med. Chem., 1993, 36, 1529.
20 J. L. Castro, R. Baker, A. R. Guiblin, S. C. Hobbs, M. R. Jenkins,
M. G. N. Russell, M. S. Beer, J. A. Stanton, K. Scholey, R. J.
Hargreaves, M. I. Graham and V. G. Matassa, J. Med. Chem., 1994,
37, 3023.
21 J. E. Macor, D. H. Blank, C. B. Fox, L. A. Lebel, M. E. Newman,
R. J. Post, K. Ryan, A. W. Schmidt, D. W. Schultz and B. K. Koe,
J. Med. Chem., 1994, 37, 2509.
6.84 (1H, s, CH᎐C), 7.09 (1H, d, H6, J 8.4 Hz), 7.34 (2H, d,
᎐
H7, J 8.4 Hz), 7.5 (1H, s, H4), 8.17 (1H, s, NH), 9.09 (1H, t,
NHCH2, J 5.4 Hz), 9.85 (1H, br s, NH(ϩ)Me2), 11.63 (1H, s,
NH); Found Mϩ 538.25134. C27H34N6O6ؒHCl requires Mϩ
538.25398.
22 (a) European Patent EP 0 533 266 A1, 1992; (b) European Patent
EP 0 533 267 A1, 1992; (c) European Patent EP 0 533 268 A1,
1992.
23 J. W. Clitherow, D. I. Scopes, M. Skingle, C. C. Jordan, W. Feniuk,
I. B. Campbell, M. C. Carter, E. W. Collington, H. E. Connor,
G. A. Higgins, D. Beattie, H. A. Kelly, W. L. Mitchell, A. W. Oxford,
A. H. Wadsworth and M. B. Tyers, J. Med. Chem., 1994, 37, 2253.
24 D. M. Walsh, D. T. Beattie and H. E. Connor, Eur. J. Pharmacol.,
1995, 287, 79.
25 G. P. Moloney, A. D. Robertson, G. R. Martin, S. MacLennan,
N. Mathews, S. Dodsworth, Pang Yih Sang, C. Knight and R. C.
Glen, J. Med Chem., 1997, 40, 2347.
26 G. P. Moloney, G. R. Martin, N. Mathews, H. Hobbs, S. Dods-
worth, Pang Yih Sang, C. Knight, M. Williams, M. Maxwell and
R. C. Glen, J. Med Chem., 1998, submitted.
27 A. Maseri, Circulation, 1990, I1–I3.
28 D. J. Fitzgerald, L. Roy, F. Catella and G. A. Fitzgerald, New. Engl.
J. Med., 1986, 315, 983.
N-[5-(3-Ethoxycarbonyl)isoxazol-5-ylmethyl]-3-[2-(dimethyl-
amino)ethyl]-5-[2-(2,5-dioxoimidazolidin-1-yl)ethyl]-1H-
indole-2-carboxamide (56). Method 1 (using 3-[2-(dimethyl-
amino)ethyl]-5-[2-(2,5-dioxoimidazolidin-1-yl)ethyl]-1H-
indole-2-carboxylic acid 30).26 HCl salt of 56 as a yellow
lyophilate, 30 mg (40%); MS m/z 511 (M ϩ 1)ϩ; 1H NMR δ 1.29
(3H, t, CH2CH3, J 7.2 Hz), 2.15 (6H, s, 2 × NCH3), 2.49 (2H,
m, CH2NMe2, under DMSO), 2.87 (2H, m, CH2N), 3.05 (2H,
m, 5-CH2), 3.58 (2H, m, 3-CH2), 3.82 (2H, s, HydCH2), 4.34
(2H, q, CH2CH3, J 7.3 Hz), 4.72 (2H, d, CH2NH, J 5.4 Hz),
6.78 (1H, s, CH᎐C), 7.03 (1H, d, H6, J 7.2 Hz), 7.33 (2H, m,
᎐
H7, H4), 7.97 (1H, s, NH), 10.12 (1H, t, NHCH2, J 5.0 Hz),
11.28 (1H, s, NH); Found Mϩ 510.22144. C25H30N6O6ؒHCl
requires Mϩ 510.22268.
29 P. B. Bradley, G. Engel, W. Feniuk, J. R. Fozard, P. P. A. Humphrey,
D. N. Middlemiss, E. J. Mylecharane, B. P. Richardson and
P. R. Saxena, Neuropharmacology, 1986, 25, 563.
30 A. L. Scherbel and J. N. Harrison, Angiology, 1959, 10, 29.
31 E. P. McFadden, J. G. Clarke, G. J. Davies, J. C. Kaski, A. W and
M. A. Maseri, New. Engl. J. Med., 1991, 324, 648.
32 P. Golino, F. Piscione, J. T. Willerson, M. Cappelli-Bigazzi,
A. Focaccio, B. Villari, C. Indolfi, E. Russolillo, M. Condorelli
and M. Chiariello, New. Engl. J. Med., 1991, 324, 641.
33 D. D. Heistad, M. L. Armstrong, M. L. Marcus, D. J. Piegors and
A. L. Mark, Circ. Res., 1984, 54, 711.
Acknowledgements
The authors acknowledge the support of The Wellcome
Foundation Ltd and Wellcome Australia (now GlaxoWellcome
Australia).
34 A. Verheyen, F. Lauwers, E. Vlaminckx, L. Wouters and F. De
Clerck, Abstracts of the 5th Meeting of the Belgian Cardiology
Society, pA7, 1987.
35 N. K. Hollenberg, K. Monteiro and T. Sandor, J. Pharmacol. Exp.
Ther., 1988, 244, 1164.
36 R. G. Schaub, K. M. Meyers and R. D. Sande, J. Lab. Clin. Med.,
1977, 90, 645.
References
1 G. A. Glennon and M. Dukat, Serotonin Receptor Subtypes,
in Psychopharmacology: The Fourth Generation of Progress;
ed. F. Bloom and M. Kupfer, Raven Press: New York, 1994; pp. 415–
429.
2 (a) G. R. Martin and P. P. A. Humphrey, Neuropharmacology, 1994,
33, 261; (b) D. Hoyer, D. E. Clarke, J. R. Fozard, P. R. Hartig, G. R.
Martin, E. J. Mylecharane, P. R. Saxena and P. Humphrey,
Pharmacol. Rev., 1994, 46, 157.
37 F. De Clerck, W. Loots, A. Jageneau and A. Nevelsteen, Drug. Dev.
Res., 1986, 8, 149.
38 C. Orlandi, J. L. Blackshear and N. K. Hollenberg, Microvasc. Res.,
1986, 32, 121.
39 R. R. Phillips, Org. React., 1959, 10, 143.
40 F. R. Japp and P. Klingemann, in Methoden der organischen Chemie,
(Houben-Weyl-Muller) Bd. X/3, S.523, Thieme-Verlag, Stuttgart
1965.
3 F. Saudou and R. Hen, Med. Chem. Res., 1994, 4, 16.
4 P. P. A. Humphrey, P. Hartig and D. A. Hoyer, Trends Pharmacol.
Sci., 1993, 14, 233.
5 D. Julius, Annu. Rev. Neurosci., 1991, 14, 335.
2722
J. Chem. Soc., Perkin Trans. 1, 1999, 2713–2723

View Online
Dodsworth, Pang Yih Sang, C. Knight, M. Maxwell and R. C. Glen,
J. Chem. Soc., Perkin Trans. 1, 1999, 2699.
41 E. B. Cantrell and D. M. Zimmerman, Eli Lilly and Co, European
Patent, EP 0 506 478 A1, 1992.
42 P. Pevarello and M. Varasi, Synth. Commun., 1992, 22, 1939.
43 D. M. Vyas, Y. Chiang and T. W. Doyle, Tetrahedron Lett., 1984, 25,
487.
44 (a) P. Grunanger and P. Vita Finzi, Isoxazoles. Part 1 in The
Chemistry of Heterocyclic Compounds, ed. E. C. Taylor, Wiley,
New York, 1990; pp. 196–207; (b) M. C. Ashraf, T. J. Burrowes and
W. R. Jackson, Aust. J. Chem., 1976, 29, 2643; (c) G. Stagno
D’Alcontres and G. Lo Vecchio, Gazz. Chim. Ital., 1960, 90, 1239.
45 A. R. Gagneux, F. Hafliger, C. H. Eugster and R. Good,
Tetrahedron Lett., 1965, 2077.
48 G. R. Marshall, C. D. Barry, H. E. Bosshard, R. A. Dammkoehler
and D. A. Dunn, The Conformational Parameter in Drug-Design:
Active Analogue Approach, Computer Assisted Drug Design; ACS
Symposium series 112, American Chemical Society: Washington
DC, 1979.
49 G. R. Martin and S. J. MacLennan, Naunyn – Schmiedebergs. Arch.
Pharmacol., 1990, 342, 111.
50 S. J. MacLennan and G. R. Martin, Br. J. Pharm., 1992, 107, 418.
51 Sybyl 6.1 molecular modelling package. Tripos Associates, St Louis
MO 63144, U.S.A. 1992.
46 G. S. Skinner, J. Am. Chem. Soc., 1924, 46, 731.
47 G. P. Moloney, G. R. Martin, N. Mathews, H. Hobbs, S.
Paper 9/03328I
J. Chem. Soc., Perkin Trans. 1, 1999, 2713–2723
2723