Synthesis and serotonergic activity of a series of 2-(JV-benzyl)carboxamido-5-substituted-N,N-dimethyltryptamine derivatives: Novel antagonists for the vascular 5-HT1B-like receptors

Article abstract of DOI:10.1039/a903141c

The synthesis and vascular 5-HT,B-like receptor activity of a novel series of 2-(Ar-benzyl)carboxamido-5-substitutedA-4W-dimethyltryptamine derivatives is described. Modifications to the 5-ethylene linked heterocycle are explored. Compounds such as N-benzyl-5-[2-(phthalimido)ethyl]-3-[2-(dimethylamino)ethyl]-l//-indole-2- carboxamide 22 (pA'B = 7.33), tfie 2-aminobenzyl analogue 24 (pA_1B = 7.19), which both contain a phthalimide group, and A-4-benzyl-S[2-(l-benzyl-2,5-dioxoimidazolidin-4-yl)ethyl]-3-[2-(dimethylamino) ethyl]-l//-indole-2-carboxamide 81 (pATB = 7.05), which incorporates an N-benzylhydantoin moiety, have good 5-HT1B-like affinity and indicate that there may be a hydrophobic binding pocket within the vascular 5-HT1B-like receptor previously not considered. Compounds including N-benzyl-3-[2-(dimethylamino)ethyl]-5-[2-(2,4-dioxo-l,3-thiazolidinyl)ethyl]-l// -indole-2-carboxamide 39 (pA_1B = 7.35) and the dimethyl analogue 46 (pA_1B = 7.48) which contain a 2,4-thiazolidinedione moiety have good vascular 5-HT_1B-like receptor affinity and show that the sulfur atom is well tolerated. Compound 61 which includes a methylsulfonyl substituent on the 1-nitrogen of the hydantoin ring system has the highest recorded 5-HT_1B-like affinity for this series (pA_1B = 7.54) and it is proposed that this functional group can interact with a secondary hydrogen bonding region within the receptor. Compounds 22, 24,39,46,61 and 81 also exhibited good selectivity over the a,-adrenoceptors. The most selective compound from this series is 46 which contains a 5,5-dimethylthiazolidine-2,4-dione group and which is 66-fold selective over the a,-adrenoceptors. This finding is consistent with the previous discovery that 5,5-dimethyl substitution on the hydantoin group in a related series of compounds afforded superior selectivity for 5-HT_1B-like receptors over a,-adrenoceptors and other 5-HT receptors, in particular 5-HT_2A receptors, relative to unsubstituted hydantoin analogues. The selectivity of these compounds for the vascular 5-HT_1B-like receptor is discussed. Structure-activity relationship indicated a significant steric requirement of the 5-HT_1B-like receptor subtype. Potential modes of binding for several of the compounds to a vascular 5-HT_1B-like receptor pharmacophore model are also proposed. The Royal Society of Chemistry 1999.

Full text of DOI:10.1039/a903141c

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Synthesis and serotonergic activity of a series of 2-(N-benzyl)-
carboxamido-5-substituted-N,N-dimethyltryptamine derivatives:
novel antagonists for the vascular 5-HT1B-like receptors
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 Maxwelld and Robert C. Glene
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 Systems Pharmacology Unit, GlaxoWellcome Research Group, Gunnels Wood Road,
Stevenage, Hertfordshire, UK SG1 2NY
e Tripos Inc., 1699 South Hanley Road, St Louis, MO 63144, USA
Received (in Cambridge, UK) 20th April 1999, Accepted 29th July 1999
The synthesis and vascular 5-HT1B-like receptor activity of a novel series of 2-(N-benzyl)carboxamido-5-substituted-
N,N-dimethyltryptamine derivatives is described. Modifications to the 5-ethylene linked heterocycle are explored.
Compounds such as N-benzyl-5-[2-(phthalimido)ethyl]-3-[2-(dimethylamino)ethyl]-1H-indole-2-carboxamide 22
(pKB = 7.33), the 2-aminobenzyl analogue 24 (pKB = 7.19), which both contain a phthalimide group, and N-benzyl-5-
[2-(1-benzyl-2,5-dioxoimidazolidin-4-yl)ethyl]-3-[2-(dimethylamino)ethyl]-1H-indole-2-carboxamide 81 (pKB = 7.05),
which incorporates an N-benzylhydantoin moiety, have good 5-HT1B-like affinity and indicate that there may be
a hydrophobic binding pocket within the vascular 5-HT1B-like receptor previously not considered. Compounds
including N-benzyl-3-[2-(dimethylamino)ethyl]-5-[2-(2,4-dioxo-1,3-thiazolidinyl)ethyl]-1H-indole-2-carboxamide
39 (pKB = 7.35) and the dimethyl analogue 46 (pKB = 7.48) which contain a 2,4-thiazolidinedione moiety have good
vascular 5-HT1B-like receptor affinity and show that the sulfur atom is well tolerated. Compound 61 which includes
a methylsulfonyl substituent on the 1-nitrogen of the hydantoin ring system has the highest recorded 5-HT1B-like
affinity for this series (pKB = 7.54) and it is proposed that this functional group can interact with a secondary
hydrogen bonding region within the receptor. Compounds 22, 24, 39, 46, 61 and 81 also exhibited good selectivity
over the α1-adrenoceptors. The most selective compound from this series is 46 which contains a 5,5-dimethyl-
thiazolidine-2,4-dione group and which is 66-fold selective over the α1-adrenoceptors. This finding is consistent
with the previous discovery that 5,5-dimethyl substitution on the hydantoin group in a related series of compounds
afforded superior selectivity for 5-HT1B-like receptors over α1-adrenoceptors and other 5-HT receptors, in particular
5-HT2A receptors, relative to unsubstituted hydantoin analogues. The selectivity of these compounds for the
vascular 5-HT1B-like receptor is discussed. Structure–activity relationship indicated a significant steric requirement
of the 5-HT1B-like receptor subtype. Potential modes of binding for several of the compounds to a vascular
5-HT1B-like receptor pharmacophore model are also proposed.
5-HT1Dβ),8 5-HT1D (formally 5-HT1Dα),8 5-ht1E and 5-ht1F sub-
types. Increasing evidence has indicated that the 5-HT1B recep-
Introduction
Serotonin (5-hydroxytryptamine, 5-HT) was discovered over 50
years ago1 and continues to generate interest as one of the most
attractive targets for medicinal chemists. The search for novel
agonists and antagonists of 5-HT has become increasingly
inviting as new receptor subtypes within the 5-HT family of
receptors continue to be discovered.2–5 Serotonin receptors have
been classified into seven distinct receptor classes, 5-HT1 to 5-
HT7.3,4,6 Within these classes, fourteen different 5-HT receptor
subtypes have been identified.3,4,6 In some cases i.e. 5-ht1E, 5-
ht1F, 5-ht5 and 5-ht6 only the gene products encoding putative
serotonin receptor proteins have been identified and although
the recombinant proteins are functionally active when trans-
fected into a mammalian host cell, true physiological roles have
not been demonstrated. For this reason, these gene products are
provisionally referred to using a lower case notation.7 The
5-HT1 class is diverse and comprises 5-HT1A, 5-HT1B (formally
tor is likely to be the 5-HT receptor mediating vasoconstriction,
but in the absence of ligands to make a definitive classification,
it is referred to here as 5-HT1B-like. The 5-HT1B and 5-HT1D
receptors have attracted considerable attention in recent
times as putative targets for novel antimigraine drugs, leading
to the development of 5-HT1B/1D receptor agonists such as
sumatriptan (GR 43175)9–11 and more recently zolmitriptan,12,13
rizatriptan, eletriptan, avitriptan and others.14–18
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 receptor mediated agonist activity in the
rabbit femoral artery) and highly selective antagonist at vascu-
lar 5-HT1B-like receptors with good oral bioavailability, a
plasma half-life of at least 4 hours and low central penetration.
Such a compound may have potential as a prophylactic treat-
ment for unstable angina,19,20 Raynaud’s syndrome21–24 and a
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variety of other vasospastic conditions in which a patho-
physiological role for 5-HT has been implicated.
Recently, a class of benzanilides,25 have been reported to
block both the 5-HT1B and 5-HT1D receptors in the periphery
and the central nervous system (CNS) vascular and central
responses mediated by both of these receptor types.25,26 How-
ever, studies have shown that these compounds behave as
partial agonists at recombinant human 5-HT1B and 5-HT1D
receptors.27 We recently reported
a series of 2-ester-5-
substituted tryptamine derivatives28 as well as some structurally
related 2,N-benzylcarboxamido-5-(2-ethyldioxoimidazolidin-1-
yl)-N,N-dimethyltryptamine analogues29 which are both highly
potent and selective antagonists for the vascular 5-HT1B-like
receptors. We describe in this paper the synthesis, 5-HT1B-like
activity and receptor selectivity profile of a related series
of 2-(N-benzyl)carboxamido-5-substituted-N,N-dimethyltrypt-
amine derivatives 1. To explore the pharmacophore of the vas-
Chart 1
tryptamine series we report here was also shown to possess a
favourable pharmacokinetic profile comparable with 3.29
Results and discussion
Synthesis
The 2,5-substituted tryptamine derivatives described here were
synthesised using several different methods as previously out-
lined.28,29 The synthesis of the nitro intermediates 4–8 followed
the Mitsunobu procedure30,31 used in the synthesis of a series of
hydantoin derivatives previously reported (Scheme 1).28,29
The nitro intermediates 4–8 were converted to the aniline
derivatives 9–13 by hydrogenation at room temperature and
atmospheric pressure in the presence of 10% palladium on
carbon (Scheme 1). The aniline derivatives 9 and 10 as well as
the commercially available norbornene derivative 14 were con-
verted to the tryptamine target molecules via a Japp Klinge-
mann indole synthesis32,33 (Scheme 2). Diazotisation of the
aniline derivative followed by reaction with the β-keto ester 1528
afforded the hydrazone intermediate 16. Cyclization of the
hydrazone to form the tryptamine 17 was achieved by refluxing
with ethanol in the presence of a catalytic amount of concen-
trated H2SO4. The ethyl ester was then converted to a 2-benzyl
ester derivative by refluxing in benzyl alcohol in the presence
of titanium tetraisopropoxide. Following transesterification the
2-benzyl ester was converted to the tryptamine-2-carboxylic
acid under hydrogenation conditions in the presence of
palladium on carbon (10%) at room temperature and atmos-
pheric pressure. Amide coupling of the tryptamine-2-carb-
cular 5-HT-like recognition site we have studied variations to
the heterocycle R1 connected to the 5-position of the indole
group by an ethylene linking chain. We have studied the mode
of binding of several of the compounds to a pharmacophore
model and attempt to explain changes in potency and selectiv-
ity in terms of changes in structure.
We report the discovery of several compounds, in particular
22, 24, 39, 41, 46, 61 and 81 (Table 1) which have com-
parable potency to ethyl 3-[2-(dimethylamino)ethyl]-5-[2-(2,5-
dioxoimidazolidin-1-yl)ethyl]-1H-indole-2-carboxylate
(2)28
and N-benzyl-3-(2-dimethylaminoethyl)-5-[2-(4,4-dimethyl-2,5-
dioxoimidazolidin-1-yl)ethyl]-1H-indole-2-carboxamide (3)29
(Chart 1).
The 2-(N-benzyl)carboxamido-5-substituted-N,N-dimethyl-
Scheme 1 Reagents: (a) Ph3P, DIAD, THF, 0 ЊC; (b) H2, Pd–C (10%), EtOH.
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oxylic acid with benzylamine derivative using TBTU and
DIPEA in DMF afforded the desired 2-(N-benzyl)carboxamido
tryptamine 18 (Scheme 2).
Scheme 4 Reagents: (a) KtBuO, MeI.
Scheme 2 Reagents: (a) NaNO2, HCl, NaOH; (b) conc. H2SO4, EtOH;
(c) Ti(iOPr)4, benzyl alcohol; (d) H2, Pd–C (10%); (e) TBTU, DMF,
DIPEA.
The remaining tryptamine derivatives were synthesised by the
general method outlined in Scheme 3. Reaction of the aniline
Scheme 5 Reagents: (a) SOCl2, EtOH; (b) ClSO2N᎐C᎐O, tBuOH,
᎐
᎐
TEA; (c) Ph3P, DEAD, DMF; (d) CH2Cl2, TFA; (e) NaOH.
tection of the amine with trifluoroacetic acid in dichlorometh-
ane followed by cyclization using sodium hydroxide gave the
1,2,5-thiadiazolidin-3-one 1,1-dioxide intermediate 52. This
nitro intermediate was then reacted on as described in Scheme 3
to afford 56.
The N-methylsulfonyl hydantoin derivative 57 required for
the synthesis of 61 was synthesised by reacting the hydantoin
intermediate 8 with methanesulfonyl chloride as shown in
Scheme 6.
Scheme 3 Reagents: (a) NaNO2, SnCl2ؒ2H2O; (b) EtOH, H2O; (c)
AcOH, MeOH, CH2O, NaCNBH3.
derivative with sodium nitrite and tin chloride dihydrate
afforded the hydrazine intermediate 34 which was then reacted
with the α-ketoamide 3528 under Fischer conditions34 to afford
the tryptamine intermediate 36. Dimethylation of the 3-ethyl-
amine nitrogen afforded the desired tryptamine molecule 18.
The 5,5-dimethyl thiazolidinedione intermediate 42 required
for the synthesis of the tryptamine derivative 46 was syn-
thesised from reaction of the unsubstituted thiazolidinedione
derivative 6 with potassium tert-butoxide and methyl iodide
(Scheme 4). The 5,5-dimethyl thiazolidinedione derivative 42
was reacted further under the conditions described in Scheme 3
to give the desired tryptamine compound 46.
The 2-(4-nitrophenyl)ethyl-4,4-dimethyl-1,2,5-thiadiazolidin-
3-one 1,1-dioxide intermediate 52 required for the synthesis of
the tryptamine derivative 56 was prepared as shown in Scheme
5. 2-Aminoisobutyric acid 47 was ethyl esterified with thionyl
chloride in ethanol. Reaction of the amine with chlorosulfonyl-
isocyanate and 2-methylpropan-2-ol in dichloromethane gave
49 which was Mitsunobu coupled to p-nitrophenethyl alcohol
to give the Boc protected phenethylamine derivative 50. Depro-
Scheme 6 Reagents: (a) methanesulfonyl chloride, Et3N, toluene.
The ‘rotated’ hydantoin derivative 65 required for the syn-
thesis of 69 was synthesised as shown in Scheme 7. This com-
pound incorporates a 5-ethylene linked hydantoin sidechain
connected through the 1-nitrogen. The 3-nitrogen of 5,5-
dimethylhydantoin was protected with a methylene linked mor-
pholine group by reaction with morpholine and formaldehyde
to give 62. The protected hydantoin derivative was then reacted
with sodium hydride followed by p-nitrophenethyl bromide
to give the p-nitrophenethyl derivative 64. Deprotection with
sodium hydroxide gave the desired p-nitrophenethyl analogue 65
connected through the 1-nitrogen. Conversion of the nitro
derivative 65 to the desired N-benzylamido tryptamine deriva-
tive 69 then proceeded as outlined in Scheme 3.
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Scheme 7 Reagents: (a) CH2O, MeOH; (b) NaH, DMF; (c) NaOH.
The aniline intermediates required for the synthesis of the
N-benzyl hydantoin derivative 81 and the N-methyl analogue
84 were prepared as outlined in Scheme 8. 4-Nitrophenethyl
Fig. 1 Theoretical 5-HT1B-like receptor model using ethyl 3-[2-(di-
methylamino)ethyl]-5-[2-(2,5-dioxoimidazolidin-1-yl)ethyl]-1H-indole-
2-carboxylate (2),28 N-benzyl-3-[2-(dimethylamino)ethyl]-5-[2-(4,4-
dimethyl-2,5-dioxoimidazolidin-1-yl)ethyl]-1H-indole-2-carboxamide
(3)29 as a reference with methysergide as background.
potency and selectivity. The compounds studied and their
biological results are shown in Table 1.
Several compounds with favourable pharmacological profiles
were discovered from the 2-(N-benzyl)carboxamido tryptamine
series previously reported including 3 (Table 1).29 It was inter-
esting to observe in this previous study that subtle changes to
substitution at the 4-position of the hydantoin ring resulted in
significant changes to affinity and selectivity for the 5-HT1B-like
receptor.29 In particular, increased selectivity was observed for
compounds incorporating a dimethyl hydantoin moiety com-
pared with an unsubstituted hydantoin group. This was consist-
ent with the observation that hydrophobicity in this region
13
increased affinity and selectivity for 5-HT1D
.
In the present
study we wished to investigate a range of heterocyclic systems
which could be used to replace the hydantoin group linked to
the 5-position of the indole ring and ideally enhance potency
and selectivity for the 5-HT1B-like receptor. Information from a
range of compounds could also help to elucidate important
pharmacophoric points within our 5-HT1B-like receptor model.
In order to explain the biological data we referred to our
theoretical receptor model for the vascular 5-HT1B-like receptor
shown in Fig. 1. The theoretical receptor model is composed of
a protonated amine, an aromatic binding site, a hydrogen-bond
acceptor site, a ‘selectivity’ site for 5-HT1B-like over 5-HT2A, a
hydrophobic site and an additional hydrogen bonding donor/
acceptor site with associated inter-group distances. It was gen-
erated using systematic conformational searching of a series of
analogues having a range of affinities and efficacies at both the
5-HT1B-like and 5-HT2A receptors.12,13 This model proved to be
qualitatively predictive for both affinity and selectivity and
enabled the design of analogues having both affinity and selec-
tivity at 5-HT1B-like receptors.28,29 Compounds which were
selective for the 5-HT1B-like receptor over 5-HT2A were found to
have occupied the ‘selectivity site’ with some part of the
molecule.13,28,29
Scheme 8 Reagents: (a) Na, EtOH; (b) 60% HBr; (c) KOH, H2O,
R1NCO, HCl; (d) H2, Pd–C (10%), EtOH.
bromide was coupled with diethyl acetamidomalonate 70 to
give the diester derivative 71. Refluxing in 60% HBr resulted in
loss of CO2 and formation of the amino acid 72. Reaction with
methyl isocyanate or benzyl isocyanate afforded the nitro
hydantoin derivatives 73 and 74 which were reduced to the anil-
ine derivatives 75 and 76 under hydrogenation conditions in the
presence of 10% palladium on carbon. The aniline intermedi-
ates 75 and 76 were then converted to the tryptamine derivatives
81 and 84 respectively via the Japp Klingemann indole synthesis
(Scheme 2).
Activity
Earlier studies towards vascular 5-HT1B-like antagonists
involved the investigation of a series of 2-(N-benzyl)carbox-
amido tryptamine derivatives containing a range of hydantoin
ring systems connected to the 5-position of the indole ring.29
A
series of tryptamine derivatives with a range of heterocycles
replacing the hydantoin ring system are the focus of this study.
The primary reason for this study was to investigate the effects
of differing substitution in this region of the receptor on
The important pharmacophoric points are illustrated using
ethyl 3-[2-(dimethylamino)ethyl]-5-[2-(2,5-dioxoimidazolidin-
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Table 1
5-HT1B
-
5-HT1B
like
RbSVa RbTAa
(pKB) (pKB)
-
Com-
pound
Number
like
Com-
α1
RbSVa α1 RbTAa
pound
R1
R2
(pKB)
(pKB)
Number R1
R2
a Affinity (pKB: Ϫlog10KB, the dissociation equilibrium constant) estimates for novel compounds at the vascular 5-HT1B-like receptors 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 Compounds 85 and 86 have been previously
described.29
1-yl)ethyl]-1H-indole-2-carboxylate (2)28 and N-benzyl-3-
[2-(dimethylamino)ethyl]-5-[2-(4,4-dimethyl-2,5-dioxoimidazol-
idin-1-yl)ethyl]-1H-indole-2-carboxamide (3)29 and methy-
sergide. The distances between each site are shown in angstroms.
Methysergide (pA50/α = 6.7/0.64 at 5-HT1B) was one of the
structures used to deduce the theoretical model as it had
restricted conformational freedom about the ethylamine
sidechain.13 A large range of structures were used to deduce the
relative positions of pharmacophoric groups.13 Methysergide is
shown here as a reference structure for comparison purposes.
Compound 3 is a previously selective 5-HT1B-like receptor
antagonist which can interact with the binding sites of the
theoretical 5-HT1B-like receptor model in a similar manner
to the compounds of the present study.
Several compounds containing a phthalimide moiety were
investigated. The results indicate that the phthalimide group
does appear to enhance affinity within the 2-(N-benzyl)carbox-
amido tryptamine series. In particular the 2-amino substituted
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Fig. 2 The phthalimide derivative 22 fitted to the pharmacophore
model with methysergide as background.
Fig. 3 Compound 61 overlaid on the vascular 5-HT1B-like receptor
pharmacophore model. The selectivity site is shown in yellow.
benzylamide derivatives 23 (pKB = 6.73) and 24 (pKB = 7.19)
showed higher potency relative to the hydantoin analogues 85
(pKB = 6.19) and 86 (pKB = 6.72) Table 1.29 Fig. 2 shows the
proposed mode of binding for the phthalimide derivative 22 to
the pharmacophore model using methysergide as background.
As postulated previously there appears to be a spatial restric-
tion on the size of the 2-substituent on the indole ring, the
receptor not tolerating large substituents at this position.28 We
therefore hypothesised that there was a steric interaction
between the sidechain in the 2-position and the receptor and
that the molecule is displaced by the steric interaction in order
to accommodate the large 2-substituent. This would result in
important functional groups not occupying optimal positions
for binding at the proposed auxiliary binding sites.13,28
Following displacement of the molecule to accommodate the
2-benzylamido sidechain, the benzylamide phenyl group could
potentially occupy the proposed aromatic binding site. The
5-ethylene linking chain could orientate so as to allow one of
the carbonyls to interact with the hydrogen binding site while
the other carbonyl group could interact with the secondary
hydrogen binding site.13 Another explanation for the enhanced
affinity is that the fused aromatic ring of the phthalimide group
may access a previously unrecognised hydrophobic pocket in
the pharmacophore in the region between the protonated amine
hydrogen bonding site and the secondary hydrogen bonding
site.
because of the extra hydrogen-bonding capabilities of the sulf-
onamide oxygens which may allow an additional hydrogen
bonding interaction with the secondary hydrogen bonding site,
Fig. 3. The NHSO2CH3 substituent in this position confers
high affinity in the hydantoin series also (refer to 14 in Glen
et al.13)
The tryptamine derivative 69 with an hydantoin group con-
nected through the 1-nitrogen had reduced affinity and selectiv-
ity. This observation is likely to be due to the altered relative
position of the carbonyl groups of the hydantoin ring and the
subsequent ability of the group to optimally interact with one
of the hydrogen bonding sites.
The tryptamine derivatives 81 and 84 both include 5-ethylene
linked hydantoin ring systems connected through the 5-carbon
of the hydantoin ring. The hydantoin 81 had good affinity
(pKB = 7.05) and reasonable selectivity for the 5-HT1B-like
receptor over α1-adrenoceptor affinity. The change in position
of one of the carbonyl groups of the hydantoin ring (relative to
the hydantoin derivatives connected through the 3-nitrogen)
appears to be well tolerated. These results may reflect the flexi-
bility of the 5-ethylene linking chain and the ability of the
sidechain to position the attached heterocycle in an optimal
position for good interaction.
Conclusions
The tetrahydrosuccinimide-like substituent of 29 resulted in
poor affinity indicating that a size restriction exists for an ideal
biological profile. The benzyl linked succinimide containing
derivative 33 had poor affinity for the vascular 5-HT1B-like
receptor. It appears the inclusion of the benzyl group linking
the indole ring to the succinimide-norbornene group does not
allow for optimal interaction of the molecule with the receptor.
The two thiazolidinone derivatives 39 and 46 had excellent
affinity at the 5-HT1B-like receptor and approximately 66 fold
selectivity over α1-adrenoceptor activity. The sulfur atom
appears to enhance binding possibly by accessing a hydro-
phobic region smaller than the phenyl ring of the phthalimide
which may be advantageous and additionally by altering the
exocyclic ring angles of the hydrogen bonding ketone.
The tryptamine derivative 41 which contains a pyrimidine
ring in place of the five membered hydantoin ring system had
good affinity at the 5-HT1B-like receptor (pKB = 7.07). This sub-
tle structural change and relative movement of key functional-
ity including the carbonyl groups within the active site appears
to be well tolerated as the carbonyl groups can still access the
hydrogen bonding sites.
This work has culminated in the discovery of a novel series of
2-(N-benzyl)carboxamido tryptamine derivatives which are
potent, 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 receptor. The biological results for 22
and 24 indicate that a phthalimide group in the 5-sidechain
enhances 5-HT1B-like receptor affinity. The two thiazolidine-
dione derivatives 39 and 46 exhibited favourable 5-HT1B-
like affinity indicating that the sulfur atom is well tolerated.
Dimethyl substitution on the thiazolidinedione moiety
increased both affinity and selectivity consistent with the trend
observed for a 5,5-dimethyl hydantoin analogue investigated
previously.28,29 The high affinity recorded for 61 containing an
N-methylsulfonyl group was explained in terms of the ability of
the sulfonyl atom to interact with the secondary hydrogen
bonding site13 giving further credibility to the proposed 5-
HT1B-like receptor pharmacophore. Compounds such as 22, 39,
46 and 61 will be useful biological probes for the vascular
5-HT1B-like receptor.
The dioxothiazolidine derivative 56 showed poor 5-HT1B-like
affinity (pKB = 6.29). It would appear that the two extra oxygens
in the five membered ring system are not well tolerated. The
N-methylsulfonyl substituted hydantoin derivative 61 had the
highest recorded vascular 5-HT1B-like affinity possibly for this
series. The sulfonamide moiety appears to enhance affinity
Experimental
Biological methods
Definition: ‘Intrinsic activity’: the maximum effect of the test
agonist relative to a standard (usually a full agonist).
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Rabbit saphenous vein (RbSV) preparation. The vascular
5-HT1B-like receptor affinities of compounds were assessed
using ring preparations of rabbit saphenous vein.35 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 minutes 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.
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, diethyl ether, benzene and
toluene were stored over type 4 Å molecular sieves. Triethyl-
amine, diisopropylethylamine and pyridine were stored over
sodium hydroxide. All solutions were dried over MgSO4 or
Na2SO4 and concentrated 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. Microanalyses were performed on a
VG Platform spectrometer and are within 0.4% of the theor-
etical values unless otherwise stated. HPLC was performed on a
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 triethyl-
amine; TFA trifluoroacetic acid; Et3N triethylamine and SOCl2
thionyl chloride. RT = HPLC retention time.
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.36 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.
Benzyl 5-[2-(phthalimido)ethyl]-3-[2-(dimethylamino)ethyl]-
1H-indole-2-carboxylate (20). Method 1: A mixture of the ethyl
ester 1729 (68.0 mg, 0.16 mmol) and titanium tetraisopropoxide
(16.4 µL, 0.05 mmol) in benzyl alcohol (3.0 mL) was heated to
100 ЊC for 18 h. The solution was concentrated in vacuo to give
a brown gum which was purified by flash chromatography elut-
ing with CH2Cl2–EtOH–NH3 (200:8:1) to give 70 mg (90%) of
1
20 as a white solid. MS m/z 496 (Mϩ); H NMR δ 2.0 (6H, s,
2 × NCH3), 2.20 (2H, m, CH2NMe2), 2.98 (4H, m, 5-CH2,
3-CH2), 3.83 (2H, t, CH2Phth, J 7.0 Hz), 5.35 (2H, s, CH2O),
7.12 (1H, d, H6, J 8.7 Hz), 7.3–7.5 (7H, m, H7, H4, 5 × ArH),
7.79 (4H, s, 4 × PhthH), 11.45 (1H, s, NH); Found Mϩ
495.21576. C30H29N3O4 requires Mϩ 495.21580.
5-[2-(Phthalimido)ethyl]-3-[2-(dimethylamino)ethyl]-1H-
indole-2-carboxylic acid (21). Method 2: To a solution of the
benzyl ester 20 (65 mg, 0.13 mmol) in ethanol (10 mL) was
added 10% palladium on carbon (33 mg) and the suspension
was hydrogenated at room temperature and atmospheric pres-
sure for 48 h. The suspension was filtered through Celite and
washed with ethanol. The filtrate was evaporated under reduced
pressure to give 21 as a white powder which was reacted on
Rabbit aorta (RbA) preparation. Rings (3 mm) of rabbit thor-
acic aorta were used to assay for activity at α1-adrenoceptors.
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.
1
without further purification. MS m/z 406 (M ϩ 1)ϩ; H NMR
δ 2.35 (6H, s, 2 × NCH3), 2.49 (2H, m, CH2NMe2), 2.97 (2H, m,
5-CH2), 3.06 (2H, m, 3-CH2), 3.79 (2H, m, CH2Phth), 6.96 (1H,
d, H6), 7.22 (2H, m, H7, H4), 7.8 (4H, m, 4 × ArH), 10.8 (1H, s,
NH).
N-Benzyl-5-[2-(phthalimido)ethyl]-3-[2-(dimethylamino)-
ethyl]-1H-indole-2-carboxamide (22). Method 3: a solution of
the carboxylic acid 21 (31.6 mg, 0.8 mmol), benzylamine (9.2
mg, 0.86 mmol) and TBTU (27.5 mg, 0.086 mmol) in DMF
(33.0 mL) was stirred for 1 h. DIPEA (16.3 µL, 0.094 mmol)
was added and the resulting solution was stirred at room tem-
perature under nitrogen overnight. The solvent was evaporated
Chemical methods: general directions
Computational chemistry was performed on a Silicon Graphics
Iris indigo II using the Sybyl37 molecular modelling software.
1
Unless otherwise stated, all H NMR spectra were recorded
at 200 MHz on a Bruker AC 200 spectrometer or at 300 MHz
J. Chem. Soc., Perkin Trans. 1, 1999, 2699–2711
2705

View Article Online
under reduced pressure and the residue taken up in water (10
mL) and extracted with ethyl acetate. The organic layer was
dried, filtered and evaporated under reduced pressure to give a
yellow solid which was further purified by flash chromato-
graphy eluting with CH2Cl2–EtOH–NH3 (200:8:1) to give 26
mg (67%) of 22 as a yellow powder (Mp 142–143 ЊC); MS m/z
triturated with diethyl ether. The solid was recrystallised from
ethanol–ether and dried under vacuum to give 6.37 g (97%) of
10 as white crystals (Mp 177–180 ЊC) (Found C, 62.49; H, 5.60;
N, 6.37. C22H20N2O3ؒ1.0HClؒ1.44H2O requires C, 62.49; H,
1
5.45; N, 6.63%); MS m/z 361 (M ϩ 1)ϩ; H NMR δ 1.78 (2H,
m, CH2), 2.25 (1H, m, CH), 2.31 (1H, m, CH), 2.79 (2H, m,
CH2N), 3.39 (2H, m, CH2), 3.57 (2H, m, CH2), 3.95 (1H, s,
CH), 7.1 (4H, m, H2, H3, H5, H6), 7.48 (3H, m, 3 × ArH), 9.6
(3H, br s, NH3ϩ); Anal. (C22H20N2O3ؒ1.0HClؒ1.44 H2O) C, H,
N.
1
494 (Mϩ); H NMR δ 1.93 (6H, s, 2 × NCH3), 2.25 (2H, m,
CH2NMe2), 2.88 (2H, m, 5-CH2), 3.0 (2H, m, 3-CH2), 3.85 (2H,
t, CH2Phth, J 7.0 Hz), 5.0 (2H, d, CH2NHCO), 7.0 (1H, d, H6),
7.3 (2H, m, H7, H4), 7.5–7.6 (4H, m, 4 × ArH), 7.9–8.2 (4H, m,
3 × ArH, NH), 9.7 (1H, t, NH), 11.2 (1H, s, NH); Found Mϩ
494.23456. C30H30N4O3 requires Mϩ 494.23179.
Ethyl 5-(dimethylamino)-2-{4-[2-(1,3,4-trioxo-2,3,5,6,10,10a-
hexahydro-1H,4H-acenaptho[1,8a-c]pyrrolyl)ethyl]phenyl}-
hydrazin-2-ylidenepentanoate (25). Method 6: a stirring solution
of the amine 10 (2.0 g, 5.0 mmol) in concentrated hydrochloric
acid (1.05 mL, 9.5 mmol), ethanol (6.6 mL) and water (10.0
mL) was cooled to 0 ЊC. A solution of sodium nitrite (0.35 g,
5.0 mmol) in water (3.1 mL) was added dropwise keeping the
temperature at ~0 ЊC and the solution was stirred for 30 min.
Meanwhile, a solution of sodium acetate trihydrate (3.52 g, 25.9
mmol) in water (4.5 mL) was added to a solution of the
diketone 1528 (1.08 g, 5.0 mmol) in ethanol (4.5 mL). This solu-
tion was stirred for 30 min and then added at once to the diazo-
nium salt solution. The solution was left to stir for 30 min at
0–5 ЊC then allowed to stir at 10–15 ЊC overnight. The orange
suspension was basified with 2 M NaOH solution, extracted
with CHCl3, dried and concentrated to give 1.5 g of a crude
residue which was purified by column chromatography eluting
with CH2Cl2–EtOH–NH3 (150:8:1) to give 1.1 g (40%) of 25 as
an orange powder. MS m/z 545 (M ϩ 1)ϩ; 1H NMR δ 1.27 (3H,
t, CH2CH3, J 7.2 Hz), 1.64 (2H, t, CH2, J 6.3 Hz), 1.75 (2H, m,
CH2), 2.11 (6H, s, 2 × NCH3), 2.25 (2H, m, CH2), 2.52 (2H, m,
CH2), 2.69 (2H, m, CH2), 2.72 (1H, m, CH), 2.83 (1H, m, CH),
3.31 (2H, m, CH2), 3.53 (2H, m, CH2), 3.94 (1H, s, CH), 4.12
(2H, q, CH2CH3, J 7.3 Hz), 6.87 (2H, d, H2, H6, J 8.4 Hz), 6.95
(2H, d, H3, H5, J 8.1 Hz), 7.41–7.55 (3H, m, 3 × ArH), 10.55
(1H, s, NH); Found Mϩ 544.26844. C31H36N4O5 requires Mϩ
544.26857.
N-(4-Aminobenzyl)-3-[2-(dimethylamino)ethyl]-5-[2-(phthal-
imido)ethyl]-1H-indole-2-carboxamide (23). Method 3 (using
4-aminobenzylamine): yellow solid, 40 mg (63%) (Found
C, 66.81; H, 5.83; N, 12.54. C30H31N5O3ؒ1.0HCl requires C,
1
65.99; H, 5.86; N, 12.83%); MS m/z 510 (M ϩ 1)ϩ; H NMR
δ 1.89 (6H, s, 2 × NCH3), 2.23 (2H, m, CH2NMe2), 2.86 (2H, t,
5-CH2, J 6.8 Hz), 2.98 (2H, t, 3-CH3, J 7.2 Hz), 3.82 (2H, m,
CH2Hyd), 4.3 (2H, d, CH2NHCO, J 5.4 Hz), 4.9 (2H, s, NH2),
6.5 (2H, d, H2Ј, H6Ј, J 8.4 Hz), 6.97 (2H, d, H3Ј, H5Ј, J 8.4 Hz),
7.0 (1H, d, H6, J 8.4 Hz), 7.23 (2H, m, H7, H4), 7.8 (4H, s,
4 × Phth-H), 9.51 (1H, t, NH, J 5.7 Hz), 9.5 (1H, s, NH), 11.15
(1H, s, NH); Found Mϩ 509.23919. C30H31N5O3 requires Mϩ
509.24269; Anal. (C30H31N5O3ؒ1.0HCl) C, H, N. RT = 15.77
min.
N-(2-Aminobenzyl)-3-[2-(dimethylamino)ethyl]-5-[2-(phthal-
imido)ethyl]-1H-indole-2-carboxamide (24). Method 3 (using
2-aminobenzylamine): yellow lyophilate, 45 mg (72%) (Found
C, 56.74; H, 5.77; N, 10.58. C30H31N5O3ؒ2.0HClؒ3.0H2O
requires C, 56.63; H, 6.13; N, 11.01%); MS m/z 510 (M ϩ 1)ϩ;
1H NMR δ 1.92 (6H, s, 2 × NCH3), 2.22 (2H, m, CH2NMe2,
J 6.0 Hz), 2.88 (2H, m, 5-CH2), 2.97 (2H, t, 3-CH2, J 6.6 Hz),
3.82 (2H, t, CH2Hyd, J 6.6 Hz), 4.34 (2H, d, CH2NHCO, J 5.4
Hz), 5.12 (2H, s, NH2), 6.51 (1H, m, ArH, J 8.1 Hz), 6.61 (1H,
d, ArH, J 7.2 Hz), 7.0 (3H, m, 2 × ArH, H6), 7.23 (2H, m, H7,
H4), 7.79 (4H, s, 4 × PhthH), 9.65 (1H, t, NH, J 5.7 Hz), 11.2
(1H, s, NH); Found Mϩ 509.23919. C30H31N5O3ؒ1.0HCl
requires Mϩ 509.24269; Anal. (C30H31N5O3ؒ2.0HClؒ3.0H2O) C,
H, N. RT = 17.52 min.
Ethyl
5-[2-(1,3,4-trioxo-2,3,5,6,10,10a-hexahydro-1H,4H-
acenaptho[1,8a-c]pyrrolyl)ethyl]-3-[2-(dimethylamino)ethyl]-
1H-indole-2-carboxylate (26). Method 7: to a solution of the
ethyl ester hydrazone 25 (1.1 g, 2.0 mmol) in ethanol (100 mL)
was added dropwise concentrated hydrochloric acid (2.35 mL).
The reaction was gently refluxed under nitrogen for 24 h. The
solution was cooled, the solvent evaporated under reduced
pressure, water added (30 mL) and the pH adjusted to 9 with
potassium carbonate. The aqueous layer was extracted with
ethyl acetate, dried, filtered and the solvent evaporated under
reduced pressure to give an orange solid which was purified
by column chromatography eluting with CH2Cl2–EtOH–NH3
(80:8:1) to give 0.26 g (25%) of 26 as a white powder. MS m/z
528 (M ϩ 1)ϩ; 1H NMR δ 1.34 (3H, t, CH2CH3, J 7.2 Hz), 1.71
(2H, m, CH2), 2.19 (1H, m, CH), 2.21 (6H, s, 2 × NCH3), 2.25
(1H, m, CH), 2.39 (2H, m, CH2), 2.65 (3H, m, CH2, CH), 2.84
(3H, m, CH2, CH), 3.6 (2H, m, CH2), 3.9 (1H, s, CH), 4.33 (2H,
q, CH2CH3, J 7.3 Hz), 6.9 (1H, d, H7, J 8.4 Hz), 7.18 (1H, d,
H6, J 8.1 Hz), 7.23 (1H, s, H4), 7.37 (2H, m, 2 × ArH), 7.5 (1H,
m, ArH), 11.34 (1H, s, NH); Found Mϩ 527.24446. C32H33N3O5
requires Mϩ 527.24202.
2-(4-Nitrophenethyl)-2,3,5,6,10,10a-hexahydro-1H,4H-
acenaptho[1,8a-c]pyrrole-1,3,4-trione (5). Method 4: 4-nitro-
phenethyl alcohol (3.33 g, 20 mmol) was dissolved in DMF (50
mL) and the succinimide derivative 10 (4.8 g, 20 mmol) was
added. To the stirring solution was added triphenylphosphine
(5.2 g, 20 mmol) and the solution was cooled to 0 ЊC. A solution
of diisopropyl azodicarboxylate (4.02 g, 20 mmol) in DMF (20
mL) was added dropwise over 20 min and then the solution was
stirred up to room temperature overnight. The solution was
poured onto ice–water (250 mL) and stirring continued for 3 h
to form a yellow gum. The solvent was decanted off and the
yellow solid recrystallised from ethanol to give 6.06 g (78%) of
1
5 as yellow crystals (Mp 175–177 ЊC); MS m/z 390 (Mϩ); H
NMR δ 1.75 (2H, m, CH2), 2.23 (2H, m, CH2), 2.7 (1H, m,
CH), 2.94 (2H, m, CH2N), 3.11 (1H, m, CH), 3.64 (2H, m,
CH2), 3.92 (1H, s, CH), 7.23 (2H, d, H3, H5, J 8.5 Hz), 7.48
(3H, m, 3 × ArH), 7.93 (2H, d, H2, H6, J 8.0 Hz).
2-(4-Aminophenethyl)-2,3,5,6,10,10a-hexahydro-1H,4H-
acenaptho[1,8a-c]pyrrole-1,3,4-trione (10). Method 5: a suspen-
sion of the nitro intermediate 5 (5.9 g, 15 mmol) in a mixture
of ethanol (125 mL), water (96 mL) and 2 M HCl (7.6 mL) was
hydrogenated at room temperature and atmospheric pressure
over 10% palladium on carbon (0.45 g) overnight. The catalyst
was filtered through Celite, washed with ethanol (2 × 15 mL)
and the solvent removed under vacuum. The remaining residue
was azeotropically dried with absolute ethanol (50 mL) and
Benzyl 5-[2-(1,3,4-trioxo-2,3,5,6,10,10a-hexahydro-1H,4H-
acenaptho[1,8a-c]pyrrolyl)ethyl]-3-[2-(dimethylamino)ethyl]-
1H-indole-2-carboxylate (27). Method 1: yellow powder, 84 mg
(43%); MS m/z 590 (M ϩ 1)ϩ; 1H NMR δ 1.7 (2H, m, CH2), 2.1
(6H, s, 2 × NCH3), 2.4 (2H, m, CH2), 3.06 (4H, m, 2 × CH2),
3.2 (4H, m, 2 × CH2), 3.3 (2H, m, CH2, under water peak), 3.6
(2H, m, CH2NCO), 3.8 (1H, s, CH), 5.37 (2H, s, CH2O), 6.9–7.5
(11H, m, H7, H4, 8 × ArH), 11.47 (1H, s, NH); Found Mϩ
589.25654. C36H35N3O5 requires Mϩ 589.25767.
2706
J. Chem. Soc., Perkin Trans. 1, 1999, 2699–2711

View Article Online
5-[2-(1,3,4-Trioxo-2,3,5,6,10,10a-hexahydro-1H,4H-
acenaptho[1,8a-c]pyrrolyl)ethyl]-3-[2-(dimethylamino)ethyl]-
1H-indole-2-carboxylic acid (28). Method 2: White powder, 36
mg (59%); MS m/z 500 (M ϩ 1)ϩ; Found Mϩ 500.21807.
C29H30N3O5 requires Mϩ 500.21854.
and recrystallisation from ethanol gave 1.7 g (98%) of the 37 as
1
a white solid. MS m/z 252 (M ϩ 1)ϩ; H NMR δ 2.73 (2H, t,
CH2N, J 7.3 Hz), 3.65 (2H, t, CH2Ph, J 7.2 Hz), 10.22 (3H, br s,
NH3ϩ).
N-Benzyl-3-[2-(dimethylamino)ethyl]-5-[2-(2,4-dioxo-1,3-
thiazolidin-3-yl)ethyl]-1H-indole-2-carboxamide (39). Method
9: a refluxing solution of the hydrazine 37 (1.7 g, 5.9 mmol) in
ethanol (40 mL) and water (4 mL) was treated dropwise with a
solution of the benzylamide 35 (1.86 g, 6.6 mmol) in ethanol
(20 mL) and reflux continued for 4 h. The solution was concen-
trated under reduced pressure and partitioned between 2 M
HCl and ethyl acetate. The aqueous phase was neutralised (2 M
NaOH) and extracted with ethyl acetate. The organic phase was
dried and concentrated under reduced pressure to afford 198
mg (8%) of the primary amine intermediate 38 as an orange
gum which was reacted on without further purification.
Method 10: A solution of the 38 (198 mg, 4.5 mmol) in meth-
anol (34 mL) was treated with acetic acid (0.12 mL, 2.1 mmol),
formaldehyde (0.08 mL) followed by sodium cyanoborohydride
(33 mg, 0.5 mmol) and the solution was stirred overnight. The
reaction mixture was quenched with water and extracted with
CH2Cl2. The organic phase was concentrated under reduced
pressure to afford a yellow oil which was purified by column
chromatography eluting with CH2Cl2–EtOH–NH3 (300:8:1)
afforded 20 mg (10%) of 39 as a white solid. MS m/z 465
N-Benzyl 5-[2-(1,3,4-trioxo-2,3,4,6,10,10a-hexahydro-1H,4H-
acenaptho[1,8a-c]pyrrolyl)ethyl]-3-[2-(dimethylamino)ethyl]-
1H-indole-2-carboxamide (29). Method 3: yellow powder, 10.4
mg (42%); MS m/z 589 (M ϩ 1)ϩ; 1H NMR δ 1.7 (2H, m, CH2),
2.0 (6H, s, 2 × NCH3), 2.47 (2H, m, CH2), 2.7–3.2 (8H, m,
4 × CH2), 3.59 (3H, m, CH, CH2), 4.51 (2H, d, CH2NH, J 5.4
Hz), 6.86 (1H, d, H6), 7.1–7.7 (10H, m, H7, H4, 8 × ArH), 9.71
(1H, m, NH), 11.14 (1H, s, NH); Found Mϩ 588.27473. C36H36-
N4O4 requires Mϩ 588.27366.
Ethyl
5-(dimethylamino)-2-{3-[4-(4-azatricyclo[5.2.1.02,6]-
dec-8-en-4-yl)phenyl]propyl}hydrazin-2-ylidenepentanoate (30).
Method 6: orange solid, 0.91 g (61%); MS m/z 529 (M ϩ 1)ϩ; 1H
NMR δ 1.25 (3H, t, CH3CH2, J 7.3 Hz), 1.58 (2H, s, CH2), 1.64
(2H, m, CH2), 2.11 (2H, m, CH2), 2.14 (6H, s, 2 × NCH3), 2.54
(2H, m, CH2), 3.46 (2H, s, CH2), 3.88 (2H, s, CH2), 4.26 (2H, q,
CH CH , J 6.9 Hz), 6.19 (2H, s, CH᎐CH), 6.99 (2H, d, H2, H6,
᎐
2
3
J 8.1 Hz), 7.09 (4H, s, 4 × ArH), 7.25 (2H, d, H3, H5, J 8.0 Hz),
10.63 (1H, s, NH).
1
(M ϩ 1)ϩ; H NMR δ 2.08 (6H, s, 2 × NCH3), 2.49 (2H, m,
Ethyl
3-[2-(dimethylamino)ethyl]-5-{3-[4-(4-azatricyclo-
CH2, under DMSO peak), 2.9 (2H, m, CH2NMe2), 3.08 (2H, m,
CH2), 3.75 (2H, m, CH2Hyd), 4.13 (2H, s, CH2), 4.5 (2H, d,
CH2NHCO), 7.05 (1H, d, H6, J 7.8 Hz), 7.3–7.5 (7H, m, H7,
H4, 5 × ArH), 9.8 (1H, t, NH), 11.42 (1H, s, NH); Found Mϩ
464.18877. C25H28N4O3S requires Mϩ 464.18821. RT = 19.33
min.
[5.2.1.02,6]dec-8-en-4-yl)phenyl]propyl}-1H-indole-2-carboxylate
(31). Method 7: yellow powder, 0.80 g (93%); MS m/z 512
(M ϩ 1)ϩ; 1H NMR δ 1.25 (3H, t, CH3CH2, J 6.3 Hz), 1.51 (2H,
s, CH2), 2.08 (2H, s, 2 × CH), 2.14 (6H, s, 2 × NCH3), 2.40 (2H,
m, CH2), 2.43 (2H, s, CH2), 3.08 (2H, m, CH2), 3.24 (4H, s,
2 × CH2), 3.88 (2H, s, CH2), 4.26 (2H, q, CH2CH3, J 6.2 Hz),
6.12 (2H, s, CH᎐CH), 6.9–7.5 (7H, m, 7 × ArH), 11.34 (1H, s,
NH).
᎐
3-(4-Nitrophenethyl)-5-methyl-1,2,3,4-tetrahydropyrimidine-
2,4-dione (7). Method 4: trituration with diethyl ether gave 1.9 g
(28%) of an off-white solid which was reacted on without
further purification. 1H NMR δ 1.78 (3H, s, CH3), 2.98 (2H, m,
CH2Ph), 4.05 (2H, t, CH2N), 7.45–7.65 (5H, m, 5 × ArH), 8.16
(3H, m, 3 × ArH), 10.86 (1H, d, NH).
Benzyl
3-[2-(dimethylamino)ethyl]-5-{3-[4-(4-azatricyclo-
[5.2.1.02,6]dec-8-en-4-yl)phenyl]propyl}-1H-indole-2-carboxylate
(32). Method 1: yellow solid, 780 mg (80%); MS m/z 574
(M ϩ 1)ϩ; 1H NMR δ 1.57 (2H, s, CH2), 2.1 (6H, s, 2 × NCH3),
2.41 (2H, m, CH2), 3.14 (2H, m, CH2), 3.3 (2H, m, CH2 under
HDO peak), 3.44 (2H, s, CH2), 4.01 (2H, s, CH2), 5.43 (2H, s,
CH2), 6.2 (2H, s, CH2O), 6.96–7.5 (12H, m, 12 × ArH), 11.5
(1H, s, NH); Found Mϩ 573.26241. C36H35N3O4 requires Mϩ
573.26276.
3-(4-Aminophenethyl)-5-methyl-1,2,3,4-tetrahydropyrimidine-
2,4-dione (12). Method 5: white solid, 1.0 g (59%). Mp = 208–
1
210 ЊC; MS m/z 245 (M)ϩ; H NMR δ 1.74 (3H, s, CH3), 2.78
(2H, t, CH2Ph, J 8.6 Hz), 3.95 (2H, t, CH2N, J 8.3 Hz), 7.28
(4H, m, H2, H3, H5, H6), 10.3 (2H, br s, NH2), 10.95 (1H, d,
CH).
N-Benzyl-3-[2-(dimethylamino)ethyl]-5-{3-[4-(3,5-dioxo-4-
azatricyclo[5.2.1.02,6]dec-8-en-4-yl)phenylpropyl}-1H-indole-2-
carboxamide (33). Method 2, method 3: white lyophilate, 3.5
mg (21%); MS m/z 573 (M ϩ 1)ϩ; 1H NMR δ 2.0 (6H, s,
2 × NCH3), 3.06 (2H, m, CH2), 3.1–3.5 (8H, m, 4 × CH2, -CH2-,
2 × CH), 4.07 (2H, m, 2 × CH2), 4.51 (2H, d, CH2NH, J 5.4
Hz), 6.9–7.6 (12H, m, 12 × ArH), 9.13 (1H, t, NH), 11.48
(1H, s, NH); Found Mϩ 572.27568. C36H36N4O3 requires Mϩ
572.27874.
N-Benzyl-3-(2-aminoethyl)-5-[2-(2,6-dioxo-5-methyl-1,2,3,6-
tetrahydropyrimidin-1-yl)ethyl]-1H-indole-2-carboxamide (40).
Method 8, method 9: purification by HPLC afforded 200 mg
(16%) of the acetate of salt of 40 as an off-white solid. MS m/z
446 (M ϩ 1)ϩ; 1H NMR δ 1.78 (3H, s, CH3), 1.89 (3H, s,
CH3CO2H), 2.09 (6H, S, 2 × NCH3), 2.48 (2H, m, CH2NMe2,
under DMSO peak), 2.88 (2H, m, 5-CH2), 3.08 (2H, m, 3-CH2),
4.05 (2H, m, CH2Hyd), 4.55 (2H, d, CH2NHCO), 7.08 (1H, d,
H6), 7.28–7.4 (8H, m, H7, H4, 5 × ArH, NH), 9.7 (1H, t, NH),
11.23 (1H, s, NH). RT = 14.21 min.
3-[2-(4-Hydrazinophenyl)ethyl]-1,3-thiazolidine-2,4-dione
(37). Method 8: A solution of the acetate salt of the amine 1128
(1.77 g, 5.9 mmol) in water (7.9 mL) was treated with concen-
trated HCl (15.3 mL) and cooled to Ϫ5 ЊC. A solution of
sodium nitrite (0.4 g, 10.0 mmol) in water (4.2 mL) was added
dropwise and stirring continued at 0 ЊC for 1 h. A solution of
tin chloride dihydrate (7.75 g, 34.4 mmol) in concentrated HCl
(12.8 mL) was added dropwise and stirring continued at room
temperature overnight. The suspension was concentrated under
reduced pressure and the residue resuspended in water. The
aqueous phase was washed with dichloromethane and brought
to pH 2.5. Filtration and concentration under reduced pressure
afforded a solid which was triturated with ethanol. Filtration
N-Benzyl-3-[2-(dimethylamino)ethyl]-5-[2-(2,6-dioxo-5-
methyl-1,2,3,6-tetrahydropyrimidin-1-yl)ethyl]-1H-indole-2-
carboxamide (41). Method 10: purification by HPLC afforded
41 as a white solid (Found C, 57.45; H, 6.37; N, 11.32.
C27H31N5O3ؒ1.0CH3CO2Hؒ4.0H2O requires C, 57.52; H, 7.10;
1
N, 11.57%); MS m/z 473 (M)ϩ; H NMR δ 1.78 (3H, s, CH3),
1.89 (3H, s, CH3CO2H), 2.09 (6H, S, 2 × NCH3), 2.48 (2H, m,
CH2NMe2, under DMSO peak), 2.88 (2H, m, 5-CH2), 3.08 (2H,
m, 3-CH2), 4.05 (2H, m, CH2Hyd), 4.55 (2H, d, CH2NHCO),
7.08 (1H, d, H6), 7.28–7.4 (8H, m, H7, H4, 5 × ArH, NH), 9.7
(1H, t, NH), 11.23 (1H, s, NH); Found Mϩ 473.24305. C27H31-
J. Chem. Soc., Perkin Trans. 1, 1999, 2699–2711
2707

View Article Online
N5O3 requires Mϩ 473.24269; Anal. (C27H31N5O3ؒ1.0CH3-
CO2Hؒ4.0 H2O) C, H, N. RT = 15.41 min.
11.2 (1H, s, NH); Found Mϩ 492.22109. C27H32N4O3S requires
Mϩ 492.21951; Anal. (C27H32N4O3Sؒ0.6H2O) C, H, N.
Ethyl 2-aminoisobutyrate (48). A solution of 2-amino-
isobutyric acid 47 (9.0 g, 93 mmol) in ethanol (100 mL) was
treated with thionyl chloride (20 mL, 0.27 mol) and heated at
reflux for 16 h. The solution was concentrated under reduced
pressure and triturated with ethyl acetate–ethanol to afford 11.3
g (75%) of 48 as a white crystalline solid which was reacted on
without further purification.
5,5-Dimethyl-3-[2-(4-nitrophenyl)ethyl]-1,3-thiazolidine-2,4-
dione (42). A solution of 3-[2-(4-nitrophenyl)ethyl]-1,3-thiazol-
idine-2,4-dione 6 (5.0 g, 18.8 mmol) in THF (200 mL) was
cooled to Ϫ78 ЊC. Potassium tert-butoxide (8.4 g, 75.0 mmol)
was added and the solution stirred at Ϫ78 ЊC for 0.5 h. Methyl
iodide (10.7 g, 4.6 mL, 75.0 mmol) was added and the solution
allowed to warm gradually to room temperature. The reaction
was quenched with aqueous ammonium chloride and extracted
with dichloromethane. The organic layer was concentrated
under reduced pressure and purified by flash chromatography
eluting with petrol–ethyl acetate (4:1) to afford 3.7 g (67%) of
42 as white needles. MS m/z 295 (M ϩ 1)ϩ; 1H NMR δ (CDCl3)
1.59 (6H, s, 2 × CH3), 3.05 (2H, t, CH2N), 3.8 (2H, t, CH2-
Ph), 7.35 (2H, d, H3, H5, J 8.7 Hz), 8.13 (2H, d, H2, H6, J 8.7
Hz).
Ethyl
2-[N-(tert-butyloxycarbonyl)aminosulfonamido]-2-
methylpropanoate (49). A solution of chlorosulfonyl isocyanate
(4.4 g, 34.0 mmol) in dichloromethane (77 mL) was added to a
solution of butan-2-ol (5.5 mL) in dichloromethane (30 mL)
at 0 ЊC. This solution was warmed to room temperature
and added to a stirring solution of the amino ester 48 (5.0 g,
31.0 mmol) in dichloromethane (15 mL) and triethylamine
(5.0 mL, 36 mmol) was then added. The solution was stirred
at room temperature for 3 h. The solution was then diluted
with dichloromethane, washed with 2 M HCl and water. Con-
centration of the solution under reduced pressure afforded 5.0 g
(58%) of 49 as a white solid which was reacted on without
further purification.
5,5-Dimethyl-3-[2-(4-aminophenyl)ethyl]-1,3-thiazolidine-2,4-
dione (43). A solution of 42 (3.7 g, 12.6 mmol) in ethanol (200
mL) was treated with concentrated HCl (12.6 mL) and 10%
palladium on charcoal (200 mg) and stirred under an atmos-
phere of hydrogen at room temperature overnight. The solution
was filtered through Celite and concentrated under reduced
pressure to afford 3.15 g (83%) of 43 as a pale orange solid
which was reacted on without further purification.
Ethyl 2-methyl-2-[N-(4-nitrophenylethyl)-N-(tert-butyloxy-
carbonyl)aminosulfonamido]propanoate (50). A solution of 49
(4.5 g, 16.2 mmol) and triphenylphosphine (4.76 g, 18.1 mmol)
in dry DMF (30 mL) was treated under nitrogen with diethyl
azodicarboxylate (3.75 mL, 23.8 mmol) and stirred in the dark
for 1 h. A solution of p-nitrophenethyl alcohol (2.7 g, 16.2
mmol) was added dropwise and stirring continued for 3 days.
The solution was concentrated under reduced pressure and the
residue purified by flash chromatography eluting with petrol–
ethyl acetate (8:1) to give 5.58 g (75%) of 50 as a pale yellow
powder. 1H NMR δ (CDCl3) 1.3 (3H, t, CH2CH3), 1.48 (9H, s,
3 × CH3), 1.54 (6H, s, 2 × CH3), 3.05 (2H, t, CH2Ph), 3.88 (2H,
m, CH2N), 4.23 (2H, q, CH2CH3), 6.3 (1H, s, NH), 7.38 (2H, d,
H3, H5), 8.14 (2H, d, H2, H6).
5,5-Dimethyl-3-[2-(4-hydrazinophenyl)ethyl]-1,3-thiazolidine-
2,4-dione (44). Method 8: a suspension of the amine 43 (3.0 g,
10.0 mmol) in water (13.3 mL) was treated with concentrated
HCl (24.4 mL) and cooled to Ϫ5 ЊC. A solution of sodium
nitrite (0.68 g, 10.0 mmol) in water (6.5 mL) was added drop-
wise and stirring continued at 0 ЊC for 1 h. A solution of tin
chloride dihydrate (11.1 g, 50.0 mmol) in concentrated HCl
(19.8 mL) was added dropwise and stirring continued at room
temperature overnight. The suspension was concentrated under
reduced pressure and the residue resuspended in water. The
aqueous phase was washed with dichloromethane and brought
to pH 2.5. Filtration and concentration under reduced pressure
afforded a solid which was triturated with ethanol. Filtration
and concentration gave 1.8 g (57%) of 44 as an orange solid
which was reacted on without further purification.
Ethyl 2-methyl-2-[(4-nitrophenyl)ethylaminosulfonamido]pro-
panoate (51). Method 11: a solution of 49 (5.5 g, 1.2 mmol) in
dichloromethane (20 mL) was treated with a solution of TFA
(20 mL) in dichloromethane (20 mL) at 0 ЊC and stirred for 1 h
then left at 4 ЊC overnight. The solution was concentrated
under reduced pressure to give a yellow oil which was triturated
with ether to afford a pale yellow solid. Recrystallisation from
ether afforded 3.71 g (86%) of 51 as a pale yellow powder. MS
m/z 359 (Mϩ); 1H NMR δ (CDCl3) 1.28 (3H, t, CH2CH3), 1.48
(6H, s, 2 × CH3), 2.98 (2H, t, CH2Ph), 3.4 (2H, m, CH2N), 4.2
(2H, q, CH2CH3), 4.45 (1H, s, NH), 4.95 (1H, s, NH), 7.38 (2H,
d, H3, H5), 8.15 (2H, d, H2, H6) (Found C, 44.01; H, 5.69; N,
11.24. C14H21N3O6Sؒ1.25H2O requires C, 44.01; H, 6.15; N,
11.00%); Found Mϩ 359.11564. C14H21N3O6S requires Mϩ
359.11511.
N-Benzyl-3-(2-aminoethyl)-5-[2-(5,5-dimethyl-2,4-dioxo-1,3-
thiazolidin-3-yl)ethyl]-1H-indole-2-carboxamide (45). Method
9: a solution of the hydrazine 44 (1.5 g, 5.3 mmol) in ethanol
(20 mL) and water (2.0 mL) was heated to ~90 ЊC and the α-
ketoamide 35 (1.0 g, 3.5 mmol) was added portionwise over 1 h.
The solution was heated to reflux for 4 h and then stirred at
room temperature overnight. The solution was concentrated
under reduced pressure and the residue purified using flash
chromatography eluting with CH2Cl2–EtOH–NH3 (150:8:1) to
give 240 mg (15%) of 45 as an off-white solid (Found C, 63.04;
H, 5.95; N, 11.74. C25H28N4O3Sؒ0.65H2O requires C, 63.03; H,
6.16; N, 11.77%); MS m/z 465 (M ϩ 1)ϩ; 1H NMR δ 1.5 (6H, s,
2 × CH3), 2.82–3.08 (6H, m, 3 × CH2), 3.79 (2H, m, CH2), 4.5
(2H, d, CH2NHCO), 7.0 (1H, d, H6), 7.22–7.35 (9H, m, H7,
H4, 5 × ArH, NH2), 10.5 (1H, m, NH), 11.16 (1H, s, NH);
Anal. (C25H28N4O3Sؒ0.65H2O) C, H, N.
2-(4-Nitrophenyl)ethyl-(4,4-dimethyl-1,2,5-thiadiazolidin-3-
one 1,1-dioxide) (52). The ethyl ester intermediate 51 (3.5 g, 9.7
mmol) was treated with an aqueous solution of 1.6 M sodium
hydroxide (500 mL) and stirred at room temperature for 2 h
prior to quenching with 10 M HCl until the solution reached
pH 1. The precipitate was isolated by filtration to give 2.15 g
(70%) of 52 as a white solid (Found C, 43.80; H, 4.82; N, 12.75.
C12H15N3O5S requires C, 43.75; H, 5.16; N, 12.75%), MS m/z
N-Benzyl-3-[2-(dimethylamino)ethyl]-5-[2-(5,5-dimethyl-2,4-
dioxo-1,3-thiazolidin-3-yl)ethyl]-1H-indole-2-carboxamide (46).
Method 10: pale yellow powder (Found C, 64.43; H, 6.41; N,
11.11. C27H32N4O3Sؒ0.6H2O requires C, 64.44; H, 6.60; N,
11.14%); MS m/z 493 (M ϩ 1)ϩ; 1H NMR δ 1.45 (6H, s,
2 × CH3), 2.05 (6H, s, 2 × NCH3), 2.49 (2H, m, CH2NMe2,
under DMSO peak), 2.93 (2H, m, 5-CH2), 3.03 (2H, t, 3-CH2),
3.82 (2H, t, CH2Hyd), 4.53 (2H, d, CH2NHCO), 6.99 (1H, d,
H6), 7.22–7.39 (7H, m, H7, H4, 5 × ArH), 9.67 (1H, t, NH),
1
313 (Mϩ); H NMR δ (CDCl3) 1.31 (6H, s, 2 × CH3), 3.0 (2H,
m, CH2Ph), 3.8 (2H, t, CH2N), 7.5 (2H, d, H3, H5), 8.15 (2H, d,
H2, H6); Anal. (C12H15N3O5S) C, H, N.
2-(4-Aminophenyl)ethyl-4,4-dimethyl-1,2,5-thiadiazolidin-3-
one 1,1-dioxide (53). Method 5: cream powder (Found C, 57.46;
H, 6.03; N, 14.59. C12H17N3O3S requires C, 50.84; H, 6.05; N,
2708
J. Chem. Soc., Perkin Trans. 1, 1999, 2699–2711

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14.83%), MS m/z 284 (M ϩ 1)ϩ; 1H NMR δ (CDCl3) 1.35 (6H,
s, 2 × CH3), 2.72 (2H, m, CH2Ph), 3.58 (2H, t, CH2N), 4.87
(1H, s, NH), 6.47 (2H, d, H2, H6), 6.86 (2H, d, H3, H5); Anal.
(C12H17N3O3S) C, H, N.
(3H, s, SO2CH3), 4.39 (2H, s, HydCH2), 7.15 (2H, d, H2, H6),
7.25 (2H, d, H3, H5).
3-(4-Hydrazinophenethyl)-1-methylsulfonylimidazolidine-2,4-
dione (59). Method 8: white solid, 60 mg (69%); MS m/z 312
1
(Mϩ); H NMR δ 2.76 (2H, m, CH2N), 3.09 (2H, t, CH2Ph),
2-(4-Hydrazinophenyl)ethyl-4,4-dimethyl-1,2,5-thiadiazolidin-
3-one 1,1-dioxide (54). Method 8: a solution of the amine 53
(1.0 g, 3.53 mmol) in water (4.7 mL) was treated with concen-
trated HCl (8.6 mL) and cooled to Ϫ5 ЊC. A solution of sodium
nitrite (0.24 g, 3.5 mmol) in water (3.0 mL) was added dropwise
and stirred at Ϫ5 ЊC for 1 h. A solution of tin chloride dihydrate
(3.9 g, 17.3 mmol) in concentrated HCl (7.0 mL) was added
dropwise and the solution stirred at room temperature for 4 h.
The reaction mixture was concentrated in vacuo and resus-
pended in water. The aqueous phase was washed with CH2Cl2
and adjusted to pH 2.5 with 2 M NaOH. Concentration under
reduced pressure afforded a white solid which was triturated
with ethanol and filtered. Concentration of the ethanol
afforded 1.2 g (100%) of the hydrazine hydrochloride 54 as
a pale yellow solid which was reacted on without further
purification.
3.32 (3H, s, SO2CH3), 4.38 (2H, s, HydCH2), 6.92 (2H, d, H2,
H6), 7.11 (2H, d, H3, H5).
N-Benzyl-3-[2-aminoethyl]-5-[2-(3-methylsulfonyl-2,5-dioxo-
imidazolidin-1-yl)ethyl]-1H-indole-2-carboxamide (60). Method
9: white solid, 50 mg (10%); MS m/z 498 (M ϩ 1)ϩ; H NMR
1
δ 2.9 (4H, m, CH2NMe2, 5-CH2), 3.03 (2H, m, 3-CH2), 3.32
(3H, s, CH3SO2), 3.65 (2H, m, CH2NH2), 4.39 (2H, s, HydCH2),
4.52 (2H, d, CH2NH, J 5.2 Hz), 7.03 (1H, d, H6), 7.3 (7H, m,
H7, H4, 5 × ArH), 10.55 (1H, t, NH), 11.2 (1H, s, NH).
N-Benzyl-3-[2-(dimethylamino)ethyl]-5-[2-(3-methylsulfonyl-
2,5-dioxoimidazolidin-1-yl)ethyl]-1H-indole-2-carboxamide
(61). Method 10: purification by HPLC afforded 10 mg (18%)
of the acetate salt of 61 as a white lyophilate; MS m/z 526
(M ϩ 1)ϩ; H NMR δ 1.9 (2.5H, s, CH3CO2H), 2.08 (6H, s,
1
2 × NCH3), 2.55 (2H, m, CH2NMe2), 2.93 (2H, m, 5-CH2), 3.05
(2H, m, 3-CH2), 3.31 (3H, s, CH3SO2), 3.65 (2H, m, CH2Hyd),
4.37 (2H, s, COCH2N), 4.55 (2H, d, CH2NHCO, J 5.4 Hz), 7.01
(1H, d, H6), 7.33 (7H, m, H7, H4, 5 × ArH), 9.75 (1H, t, NH),
11.24 (1H, s, NH); Found Mϩ 525.20645. C26H31N5O5Sؒ
1.0CH3CO2H requires Mϩ 525.20459.
N-Benzyl-5-[2-(4,4-dimethyl-1,1,3-trioxo-1,2,5-thiadiazol-
idin-2-yl)ethyl]-3-(2-aminoethyl)-1H-indole-2-carboxamide (55).
Method 9: a solution of the hydrazine hydrochloride 54 (1.0 g,
3.0 mmol) in ethanol (12 mL) and water (1.2 mL) was heated to
reflux. The α-ketoamide 35 (0.95 g, 3.3 mmol) was added
portion-wise and the solution was refluxed for 6 h. Concen-
tration under reduced pressure and flash chromatography elut-
ing with CH2Cl2–EtOH–NH3 (150:8:1) afforded 285 mg (20%)
of 55 as a pale gum. 1H NMR δ 1.25 (6H, s, 2 × CH3), 2.95 (4H,
m, CH2NMe2, 3-CH2), 3.12 (2H, m, 5-CH2), 3.6 (2H, m, CH2N,
under water peak), 4.51 (2H, d, NHCH2Ph), 7.1 (1H, d, H6),
7.15–7.35 (7H, m, H7, H4, 5 × CH2), 9.8 (1H, m, NH), 11.2
(1H, br s, NH).
1-(4-Nitrophenethyl)-5,5-dimethylimidazolidine-2,4-dione
(65). Morpholine (0.05 mol, 4.37 mL) was added to a chilled
solution of 5,5-dimethylhydantoin (6.4 g, 0.05 mol) in meth-
anol (50 mL). Formaldehyde (4.1 mL, 0.05 mol) was added and
the solution stirred for 2 h. The solution was concentrated to a
white solid which was azeotroped with benzene, washed with
petrol and dried in vacuo to give 11.2 g (98%) of 62. A portion
of the solid (5.5 g, 24 mmol) was dissolved in dry DMF (100
mL) chilled to 0 ЊC and sodium hydride (970 mg, 60% disp, 55.0
mmol) was added portion wise. The suspension was stirred at
room temperature until evolution of H2 ceased after which 4-
nitrophenethyl bromide 63 (5.52 g, 0.05 mol) was gradually
added and the reaction mixture was stirred under nitrogen
overnight. The solution was concentrated under reduced pres-
sure to give a black oil which was stirred with 2 M NaOH (75
mL) and THF (25 mL) for 1.5 h. The solution was acidified to
pH 1 with 2 M HCl and extracted with CH2Cl2 (3 × 50 mL).
The combined organic phases were dried, concentrated and
triturated with ethanol to give 1.19 g (18%) of 65 as a pale
cream solid. (Mp 186–187 ЊC) which was reacted on without
further purification. HPLC retention time = 14.38 min.
N-Benzyl-5-[2-(4,4-dimethyl-1,1,3-trioxo-1,2,5-thiadiazol-
idin-2-yl)ethyl]-3-[2-(dimethylamino)ethyl]-1H-indole-2-carb-
oxamide (56). Method 10: purification by HPLC afforded 110
mg (41%) of the acetate salt of 56 as a white lyophilate (Found
C, 57.36; H, 6.28; N, 12.20. C26H33N5O4Sؒ1.0H2Oؒ0.5CH3-
CO2H requires C, 57.41; H, 6.71; N, 12.40%); MS m/z 512
(M ϩ 1)ϩ; 1H NMR δ 1.35 (6H, s, 2 × CH3), 1.9 (1.5H, s,
CH3CO2H), 2.1 (6H, s, 2 × NCH3), 2.55 (2H, m, CH2NMe2),
3.05 (4H, m, 5-CH2, 3-CH2), 3.75 (2H, t, CH2Hyd), 4.5 (2H, d,
CH2), 7.1 (1H, d, H6), 7.3–7.4 (8H, m, H7, H4, 5 × ArH, NH),
9.7 (1H, t, NH), 11.2 (1H, s, NH); Found Mϩ 511.22575.
C26H33N5O4S requires Mϩ 511.22533; Anal. (C26H33N5O4Sؒ
1.0H2Oؒ0.5CH3CO2H) C, H, N. HPLC retention time = 17.08
min.
1-(4-Hydrazinophenethyl)-5,5-dimethylimidazolidine-2,4-
1
dione (67). Method 5: MS m/z 248 (M ϩ 1)ϩ; H NMR δ 1.19
3-(4-Nitrophenethyl)-1-methylsulfonylimidazolidine-2,4-dione
(57). Methanesulfonyl chloride (1.38 g, 0.93 mL, 12.0 mmol)
was added dropwise to a suspension of the hydantoin derivative
829 (2.5 g, 10.0 mmol) and triethylamine (2.0 g, 20.0 mmol) in
toluene (50 mL). The solution was stirred at room temperature
under nitrogen for 6 h. A further equivalent of triethylamine
(1.39 mL) was added and the solution was stirred overnight. A
solid was filtered off and the remaining filtrate was evaporated
to dryness under reduced pressure. The solid residue was tritur-
ated with ethanol and water then filtered and eventually dried
under vacuum to give 1.89 g (59%) of 57. MS m/z 327 (Mϩ); 1H
NMR δ 3.0 (2H, t, CH2N), 3.36 (3H, s, SO2CH3), 3.7 (2H, t,
CH2), 4.39 (2H, s, HydCH2), 7.5 (2H, d, H3, H5, J 8.7 Hz), 8.18
(2H, d, H2, H6, J 8.7 Hz).
(6H, s, 2 × CH3), 2.95 (2H, t, CH2N, J 7.1 Hz), 3.42 (2H, t,
CH2Ph, J 7.1 Hz), 7.25 (2H, d, H3, H5, J 8.3 Hz), 7.35 (2H, d,
H2, H6, J 8.3 Hz), 10.8 (1H, s, NH). RT = 8.29 min. Method 8:
The amine hydrochloride 66 (3.9 g, 13.7 mmol) prepared from
the nitro intermediate 65 via method 2 was dissolved in water
(24 mL) and cooled to Ϫ5 ЊC. Concentrated HCl (43 mL) was
added dropwise maintaining the temperature at 0–5 ЊC. NaNO2
(0.95 g, 13.8 mmol) in water (12 mL) was added dropwise at
Ϫ2 ЊC. The solution was stirred for 30 min after which the
diazonium salt formed was added dropwise to a solution of tin
chloride dihydrate (13.0 g, 57.7 mmol) in concentrated HCl (35
mL) over 30 min at ~0 ЊC. The solution was allowed to warm to
room temperature then concentrated under reduced pressure,
redissolved in water and basified to pH 3 with 2 M NaOH. The
suspension was filtered and the filtrate concentrated to give 3.87
g (94%) of 67 as a cream solid which was reacted on without
further purification. HPLC retention time = 7.87 min.
3-(4-Aminophenethyl)-1-methylsulfonylimidazolidine-2,4-
dione (58). Method 5: yellow solid, 579 mg (32%); MS m/z 297
(Mϩ); 1H NMR δ 2.85 (2H, t, CH2N), 3.05 (2H, t, CH2Ph), 3.32
J. Chem. Soc., Perkin Trans. 1, 1999, 2699–2711
2709

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N-Benzyl-5-[2-(5,5-dimethyl-2,4-dioxoimidazolidin-1-yl)-
ethyl]-3-[2-aminoethyl]-1H-indole-2-carboxamide (68). Method
9: the α-ketoamide 35 (617 mg, 21.7 mmol) was added to a
stirred suspension of hydrazine hydrochloride 67 (650 mg, 22.0
mmol) in ethanol–water (1:1) (25 mL). The solution was stirred
for 15 min at room temperature then heated to reflux for 4 h.
Concentration under reduced pressure and flash chromato-
graphy eluting with CH2Cl2–EtOH–NH3 (60:8:1) gave 189 mg
(20%) of 68 as a pale foam which was reacted on without
further purification.
10.63 (1H, s, NH); Found (M ϩ 1)ϩ 494.27664. C27H36N5O4
requires (M ϩ 1)ϩ 494.27673. Anal. (C27H35N5O4ؒ0.1H2O) C,
H, N.
Ethyl 5-[2-(1-benzyl-2,5-dioxoimidazolidin-4-yl)ethyl]-3-[2-
(dimethylamino)ethyl]-1H-indole-2-carboxylate (78). Method 7:
1
yellow powder, 0.32 g (58%); MS m/z 477 (M ϩ 1)ϩ; H NMR
δ 1.34 (3H, t, CH2CH3, J 6.9 Hz), 1.88 (2H, m, CH2Hyd),
2.21 (6H, s, 2 × NCH3), 2.45 (2H, m, CH2NMe2), 2.71 (2H, m,
5-CH2), 3.1 (2H, t, 3-CH2), 4.1 (1H, m, CH), 4.36 (2H, q,
CH2CH3, J 7.0 Hz), 4.5 (2H, s, NCH2Ph), 7.09 (1H, d, H6, J 8.6
Hz), 7.2–7.4 (7H, m, H7, H4, 5 × ArH), 8.5 (1H, s, NH), 9.77
(1H, t, NH), 11.4 (1H, s, NH); Found Mϩ 476.24520.
C27H32N4O4 requires Mϩ 476.24236.
N-Benzyl-5-[2-(5,5-dimethyl-2,4-dioxoimidazolidin-1-yl)-
ethyl]-3-[2-(dimethylamino)ethyl]-1H-indole-2-carboxamide
(69). Method 10: white powder, 35 mg (20%). MS m/z 476
1
(M ϩ 1)ϩ; H NMR δ 1.15 (6H, s, 2 × CH3), 2.05 (6H, s, 2 ×
Benzyl 5-[2-(1-benzyl-2,5-dioxoimidazolidin-4-yl)ethyl]-3-[2-
(dimethylamino)ethyl]-1H-indole-2-carboxylate (79). Method 1:
purification by column chromatography eluting with CH2Cl2–
EtOH–NH3 (150:8:1) gave 0.18 g (60%) of 79 as a yellow
NCH3), 2.55 (2H, m, CH2NMe2), 2.95 (2H, m, CH2), 3.06 (2H,
m, 5-CH2), 3.39 (2H, m, 3-CH2), 4.52 (2H, d, CH2NHCO), 7.1
(1H, d, H6, J 7.5 Hz), 7.3 (1H, s, NH), 7.35–7.41 (2H, m, H7,
H4), 9.75 (1H, t, NH), 11.17 (1H, s, NH); Found Mϩ 475.25689.
C27H33N5O3 requires Mϩ 475.25834. HPLC retention time =
15.19 min.
1
powder. MS m/z 539 (M ϩ 1)ϩ; H NMR δ 1.98–2.01 (2H, m,
CH2Hyd), 2.2 (6H, s, 2 × NCH3), 2.48 (2H, m, CH2NMe2), 2.71
(2H, m, 5-CH2), 3.13 (2H, t, 3-CH2, J 8.1 Hz), 4.1 (1H, m, CH),
4.5 (2H, m, NCH2Ph), 5.36 (2H, s, OCH2Ph), 7.09 (1H, d, H6,
J 8.7 Hz), 7.2–7.5 (12H, m, H7, H4, 10 × ArH), 8.51 (1H, s,
NH), 11.5 (1H, s, NH); Found (M ϩ 1)ϩ 539.26580. C32H35-
N4O4 requires (M ϩ 1)ϩ 539.26583.
1-Benzyl-4-[(4-nitrophenyl)ethyl]imidazolidine-2,5-dione (74).
The amino acid 7229 (2.8 g, 12.5 mmol) was added to a solution
of potassium hydroxide (0.84 g, 15.0 mmol) in water (25 mL).
The solution was cooled to 0 ЊC and benzyl isocyanate (1.99 g,
1.85 mL, 15 mmol) was added over 20 min maintaining the
temperature at 0 ЊC. The solution was stirred at 60–70 ЊC for 2 h
after which the urea was filtered off. The filtrate was acidified
with concentrated HCl then filtered. The uncyclised hydantoic
acid was collected and washed with water. The solid was sus-
pended in concentrated HCl–water (1:1) (15 mL) and refluxed
for 2 h. The solution was then cooled, diluted with water, fil-
tered, washed with water and dried in vacuo to give 4.23 g (83%)
of 74 as a white powder which was reacted on without further
5-[2-(1-Benzyl-2,5-dioxoimidazolidin-4-yl)ethyl]-3-[2-
(dimethylamino)ethyl]-1H-indole-2-carboxylic
acid
(80).
Method 2: white solid, 93 mg (95%); MS m/z 449 (M ϩ 1)ϩ; 1H
NMR δ 1.8–2.0 (2H, m, CH2Hyd), 2.52 (6H, s, 2 × NCH3), 2.68
(2H, m, CH2NMe2), 2.98 (2H, m, 5-CH2), 3.15 (2H, m, 3-CH2),
4.1 (1H, m, CH), 4.5 (2H, s, CH2Ph), 6.99 (1H, d, H6, J 8.0
Hz), 7.3 (7H, m, H7, H4, 5 × ArH), 8.5 (1H, s, NH), 11.0 (1H,
s, NH); Found (M ϩ 1)ϩ 449.21845. C25H28N4O4 requires (M ϩ
1)ϩ 449.21888.
1
purification. MS m/z 339 (M ϩ 1)ϩ; H NMR δ 1.83 (1H, m,
CHA), 2.01 (1H, m, CHAЈ), 2.8 (2H, m, CH2Ph), 4.12 (1H, m,
CH), 4.54 (2H, s, NCH2Ph), 7.28 (5H, m, 5 × ArH), 7.51 (2H,
d, H3, H5), 8.15 (2H, d, H2, H6), 8.49 (1H, s, NH).
N-Benzyl-5-[2-(1-benzyl-2,5-dioxoimidazolidin-4-yl)ethyl]-3-
[2-(dimethylamino)ethyl]-1H-indole-2-carboxamide
(81).
Method 3: purification by column chromatography eluting with
CH2Cl2–EtOH–NH3 (100:8:1) gave 30 mg (77%) of 81 as a
yellow powder. MS m/z 538 (M ϩ 1)ϩ; 1H NMR δ 1.7–1.9 (2H,
m, CH2Hyd), 2.02 (6H, s, 2 × NCH3), 2.5 (2H, m, CH2NMe2),
2.69 (2H, m, 5-CH2), 3.03 (2H, m, 3-CH2, J 6.9 Hz), 4.1 (1H, m,
CH), 4.5 (4H, m, HydCH2Ph, CONHCH2Ph), 7.02 (1H, d, H6,
J 8.1 Hz), 7.3 (12H, m, H7, H4, 10 × ArH), 8.5 (1H, s, NH),
9.77 (1H, t, NH), 11.2 (1H, s, NH); Found Mϩ 537.27126.
C32H35N5O3 requires Mϩ 537.27399.
1-Benzyl-4-[2-(4-anilino)ethyl]imidazolidine-2,5-dione (76).
Method 5: 3.68 g (85%); MS m/z 310 (M ϩ 1)ϩ; 1H NMR δ 1.84
(1H, m, CHA), 2.02 (1H, m, CHAЈ), 2.65 (2H, m, CH2Ph), 4.09
(1H, m, CH), 4.5 (2H, s, NCH2Ph), 7.3 (9H, m, 9 × ArH), 8.5
(1H, s, NH), 10.2 (3H, br s, NH3ϩ).
Ethyl
5-(dimethylamino)-2-{4-[2-(1-benzyl-2,5-dioxoimid-
(77).
azolidin-4-yl)ethyl]phenyl}hydrazin-2-ylidenepentanoate
Method 6: to a stirring solution of 76 (1.59 g, 4.59 mmol) in
ethanol (6.0 mL) and water (9.1 mL) was added concentrated
HCl (0.96 mL, 8.68 mmol). The solution was cooled to 0 ЊC and
a solution of sodium nitrite (0.32 g, 4.59 mmol) in water
(2.8 mL) was added and the solution was stirred for 10 min.
Meanwhile a solution of the diketone 15 (0.98 g, 4.59 mmol) in
ethanol (4.0 mL) was stirred with sodium acetate trihydrate (3.2
g, 23.6 mmol) and ice (4.0 g). The diazonium salt was added
quickly to the diketone solution and the reaction was stirred for
5.0 h up to room temperature. The solution was adjusted to pH
9 with 10% NaOH and stirred for a further 10 min. The solu-
tion was extracted with ethyl acetate, dried, filtered and evapor-
ated under reduced pressure to give an orange gum. Purification
by flash chromatography eluting with CH2Cl2–EtOH–NH3
(200:8:1) afforded 0.57 g (26%) of 77 as a yellow powder (Mp
142–143 ЊC) (Found C, 65.20; H, 6.89; N, 13.82. C27H35-
N5O4ؒ0.10H2O requires C, 65.46; H, 7.16; N, 14.13%); MS m/z
494 (M ϩ 1)ϩ; 1H NMR δ 1.24 (3H, t, CH2CH3, J 7.2 Hz), 1.64
(2H, m, CH2), 2.0 (2H, m, CH2), 2.1 (2H, m, CH2), 2.14 (6H, s,
2 × NCH3), 2.5 (4H, m, 2 × CH2), 4.0 (1H, m, CH), 4.1 (2H, q,
CH2CH3, J 7.0 Hz), 4.6 (2H, d, NCH2Ph, J 4.4 Hz), 7.09 (4H, s,
H2, H3, H5, H6), 7.24–7.34 (5H, m, 5 × ArH), 8.5 (1H, s, NH),
Benzyl 3-[2-(dimethylamino)ethyl]-5-[2-(1-methyl-2,5-dioxo-
imidazolidin-4-yl)ethyl]-1H-indole-2-carboxylate (82). Method
1: (from ethyl 3-[2-(dimethylamino)ethyl]-5-[2-(2,5-dioxo-1-
methylimidazolidin-4-yl)ethyl]-1H-indole-2-carboxylate28,29):
1
white solid, 51 mg (79%); MS m/z 463 (M ϩ 1)ϩ; H NMR
δ 1.90 (2H, m, CH2CH), 2.0 (6H, s, 2 × NCH3), 2.39 (2H, m,
CH2NMe2), 2.72 (2H, m, 5-CH2), 2.76 (3H, s, NCH3), 3.13 (2H,
m, 3-CH2), 3.96 (1H, m, CH), 5.36 (2H, s, CH2O), 7.12 (1H, d,
H6, J 8.2 Hz), 7.3–7.5 (7H, m, H7, H4, 5 × ArH), 8.38 (1H, s,
NH), 11.42 (1H, s, NH).
3-[2-(Dimethylamino)ethyl]-5-[2-(1-methyl-2,5-dioxoimid-
azolidin-4-yl)ethyl]-1H-indole-2-carboxylic acid (83). Method 2:
1
white solid, 35 mg (87%); MS m/z 373 (M ϩ 1)ϩ; H NMR
δ 1.87 (2H, m, CH2), 2.28 (6H, s, 2 × NCH3), 2.68 (2H, t,
CH2NMe2, J 7.8 Hz), 2.77 (3H, s, NCH3), 3.16 (2H, m, 3-CH2),
3.3 (2H, m, 5-CH2), 3.97 (1H, m, CH), 6.94 (1H, d, H6, J 8.7
Hz), 7.24 (1H, m, H7), 7.32 (1H, s, H4).
N-Benzyl-3-[2-(dimethylamino)ethyl]-5-[2-(1-methyl-2,5-
dioxoimidazolidin-4-yl)ethyl]-1H-indole-2-carboxamide
(84).
Method 3: HCl salt of 84 as a white lyophilate, 14 mg (55%);
2710
J. Chem. Soc., Perkin Trans. 1, 1999, 2699–2711

View Article Online
MS m/z 462 (M ϩ 1)ϩ; 1H NMR δ 1.83 (2H, m, CH2CH), 2.03
(6H, s, 2 × NCH3), 2.48 (2H, m, CH2NMe2 under DMSO), 2.68
(2H, t, 5-CH2, J 8.1 Hz), 2.73 (3H, s, NCH3), 3.01 (2H, m,
16 S. J. Peroutka and B. G. McCarthy, Eur. J. Pharmacol., 1989, 163,
133.
17 E. Hamel, Current Drugs: Serotonin ID Research Alert, 1996, 1, 19.
18 G. R. Martin, Serotonin Receptor Involvement in the Pathogenesis
and Treatment of Migraine, in: Blue Books on Neurology, eds
S. Silberstein and P. J. Goadsby, Butterworth-Heinemann, 1997.
19 E. P. McFadden, J. G. Clarke, G. J. Davies, J. C. Kaski, A. W and
M. A. Maseri, New Eng. J. Med., 1991, 324, 648.
3-CH2,
J 6.3 Hz), 3.97 (1H, m, CH), 4.5 (2H, d,
CH2NHCO, J 5.7 Hz), 7.04 (1H, d, H6, J 8.7 Hz), 7.27 (7H, m,
H7, H4, 5 × ArH), 8.3 (1H, s, NH), 9.76 (1H, t, NH, J 5.7
Hz), 11.24 (1H, s, NH); Found Mϩ 461.24319. C26H31N5O3ؒ
1.0HCl requires Mϩ 461.24269; Rf = 0.46 CH2Cl2–EtOH–NH3
(60:8:1).
20 P. Golino, F. Piscione, J. T. Willerson, M. Cappelli-Bigazzi,
A. Focaccio, B. Villari, C. Indolfi, E. Russolillo, M. Condorelli and
M. Chiariello, New Eng. J. Med., 1991, 324, 641.
21 A. Maseri, Circulation, 1990, I1-I3.
22 D. J. Fitzgerald, L. Roy, F. Catella and G. A. Fitzgerald, New Engl. J.
Med., 1986, 315, 983.
Acknowledgements
23 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.
The authors acknowledge the support of The Wellcome
Foundation Ltd and Wellcome Australia (now GlaxoWellcome
Australia).
24 A. L. Scherbel and J. N. Harrison, Angiology, 1959, 10, 29.
25 (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;
(d) J. W. Clitherow, D. I. C. 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,
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26 M. Skingle, A. J. Sleight and S. Feniuk, Neuropharmacology, 1995,
34, 377.
27 D. M. Walsh, D. T. Beattie and H. E. Connor, Eur. J. Pharmacol.,
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