A novel series of 2,5-substituted tryptamine derivatives as vascular 5HT(1B/1D) receptor antagonists

J . Med. Chem. 1997, 40, 2347-2362

2347

A Novel Ser ies of 2,5-Su bstitu ted Tr yp ta m in e Der iva tives a s Va scu la r 5HT_1B/1D

Recep tor An ta gon ists

Gerard P. Moloney,*^,†Alan D. Robertson,^‡Graeme R. Martin,^§Steven MacLennan,^§Neil Mathews,^∇

Susan Dodsworth,^∇Pang Yih Sang,^∇Cameron Knight,^|and Robert Glen

Department of Medicinal Chemistry, Victorian College of Pharmacy, Monash University, 381 Royal Parade,

Parkville, Victoria 3052, Australia, AMRAD, 576 Swan Street, Richmond, Victoria 3121, Australia, Department of

Molecular Pharmacology, Neurobiology Unit, Roche Bioscience, 3401 Hillview Avenue, R2-101, Palo Alto, California 94304,

Department of Medicinal Chemistry, GlaxoWellcome Research Group, Gunnels Road, Stevenage,

Hertsfordshire SG1 2NY, U.K., Astra Pharmaceuticals, P.O. Box 428, Abbotsford, Victoria 3067, Australia, and

Tripos Inc., 1699 South Hanley Road, St. Louis, Missouri 63144

Received August 9, 1996^X

The design, synthesis, and activity of a novel series of 2,5-substituted tryptamine derivatives

at vascular 5HT_1B-like receptors is described. Several important auxiliary binding sites of the

5HT_1B-like receptor have been proposed following various modifications to the 2-substituent

and especially to the methylene- or ethylene-linked 5-side chain. Careful design of new

molecules based on a proposed pharmacophoric model of the 5HT_1B-like receptor has resulted

in the discovery of ethyl 3-[2-(dimethylamino)ethyl]-5-[2-(2,5-dioxo-1-imidazolidinyl)ethyl]-1H-

indole-2-carboxylate (40), a highly potent, silent, competitive, and selective antagonist which

shows affinity at the vascular 5HT_1B-like receptors only. Changes to the size of the 2-ester

substituent have a significant effect on affinity at the 5HT_1B-like receptor and other receptors.

Prudent placement of the carbonyl substituent in the heterocycle of the 5-side chain is crucial

for good affinity and selectivity over the 5HT_2Aand other receptors. Several key structural

and electronic features were identified which are crucial for producing antagonism within a

tryptamine-based series. An electron deficient indole ring system appears essential in order

to achieve antagonism, and this is achieved by the inclusion of electron-withdrawing groups

at the 2-position of the indole ring. The molecule displacement within the receptor resulting

from the inclusion of the bulky 2-substituents also enhances antagonism as this results in the

removal of the π electon density of the indole ring from the region of the receptor normally

occupied by the indole ring of 5HT. There also appears to be a structural requirement on the

side chain incorporating the protonatable nitrogen, and this is achieved by the inclusion of the

bulky 2-ester group which neighbors the 3-ethylamine side chain.

In tr od u ction

antimigraine drugs, leading to the development of

5HT_1B/1Dreceptor selective agonists such as sumatriptan

(GR43175)^6-8and more recently zolmitriptan,⁹rizatrip-

tan, eletriptan, avitriptan, and others.^10,11

Fourteen subtypes of serotonin (5HT) receptors or-

ganized into seven distinct receptor classes, 5HT₁-

5HT₇, are now recognized.^1-3In some cases, i.e., 5ht_1E

,

Until recently, efforts to characterize vascular 5HT_1B

-

5ht_1F, 5ht₅, and 5ht₆, only the genes encoding putative

serotonin receptor proteins have been identified, and

although the recombinant proteins are functionally

active when transfected 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.⁴The most

diverse of the 5HT receptor classes is the 5HT₁class,

comprising 5HT_1A, 5HT_1B(formally 5HT_1Dâ),⁵5HT_1D

(formally 5HT_1DR),⁵5ht_1E, and 5ht_1Fsubtypes. In ad-

dition, a well-characterized 5HT receptor mediating

vasoconstriction has long been recognized. Increasing

evidence indicates that this receptor is 5HT_1B, but in

the absence of ligands to make a definitive classification,

it is referred to here as 5HT_1B-like. Among these

subtypes, the 5HT_1Band 5HT_1Dreceptors have attracted

considerable attention as putative targets for novel

like receptors have been frustrated by the lack of

selectivity of the available antagonists, e.g., metergoline

and methiothepin. A series of benzanilides,¹²exempli-

fied by GR127935, have been described as potent

antagonists at 5HT_1Band 5HT_1Dreceptors and have

been shown to block both peripheral and central re-

sponses mediated by both of these receptor types.¹³

However, this compound is not a silent antagonist and

behaves as a partial agonist at recombinant human

5HT_1Band 5HT_1Dreceptors.¹⁴Moreover, the drug

exhibits pseudoirreversible pharmacodynamics, making

it less than ideal for the quantitative study of 5HT_1B

and 5HT_1Dreceptors.¹³

Examination of molecules developed as selective

5HT_1B/1Dreceptor agonists, e.g., sumatriptan,^6-8,15,16

MSD compounds,^17,18and zolmitriptan,⁹together with

work carried out in our laboratories have given some

insight into the requirements for conversion of these

potent agonists into antagonists. A program was initi-

ated in our laboratories with the objective of identifying

a novel series of potent and selective antagonists of the

vascular 5HT_1B-like receptor as potential new drugs for

the prophylactic treatment of various cardiovascular

disease states including cerebral vasospasm following

* To whom correspondence should be addressed.

^†Monash University.

^‡AMRAD.

^§Roche Bioscience.

^∇GlaxoWellcome Research Group.

^|Astra Pharmaceuticals.

Tripos Inc.

^XAbstract published in Advance ACS Abstracts, J une 15, 1997.

2348 J ournal of Medicinal Chemistry, 1997, Vol. 40, No. 15

Moloney et al.

F igu r e 1. Four target tryptamine derivatives (1-4) designed

as antagonists and zolmitriptan, a known selective and potent

5HT_1B/1Dagonist.

subarachnoid hemorrhage, Raynaud’s syndrome, angina

pectoris, and intermittent claudication.¹⁹Selective

5HT_1B/1Dantagonists will also be useful as tools to study

the physiological function of these receptors. The target

molecule profile was one of a potent, silent, reversible

antagonist with 100-fold selectivity over other mono-

amine receptors and a pharmacokinetic profile consis-

tent with the potential therapeutic applications outlined

earlier.

Structure-activity relationships obtained from non-

selective antagonists identified from previous work in

our laboratories and from existing antagonists sug-

gested that for tryptamine analogues an electron defi-

cient aromatic system was important for antagonism.

Moreover there appeared to be an association between

antagonism and a conformational restriction of some

nature on the 3-ethylamine side chain.²⁰A consider-

ation of the factors affecting selectivity and efficacy

described elsewhere²¹led to the identification of the

tryptamine analogues 1-4 as primary targets, Figure

1. The structure of these compounds is based on

zolmitriptan, a selective partial 5HT_1B/1Dreceptor ago-

nist.^9,21

The proposed compounds differ from zolmitriptan in

the electron-withdrawing groups attached to the indole

in the 2-position. These substituents have been located

in this position as this would create an electron deficient

indole system while simultaneously conferring a con-

formational restriction on the ethylamine side chain.

Biological results for these compounds were encouraging

in that a series of silent, competitive antagonists were

produced from selective agonists by incorporation of an

electron-withdrawing group at the 2-position; however,

potency and selectivity were not up to the desired level.

In the design of a novel series of 5HT ligands, we

utilized computer graphics and computational chemis-

try. A theoretical model of the binding mode of high-

affinity ligands to the vascular 5HT_1B-like receptor has

been postulated²¹based on the common pharmacophoric

points displayed by a large number of diverse ligands

with affinity at 5HT_1B/1Dreceptors. This pharmaco-

phore model was constructed using the active analogue

approach.^21,22The elucidation of a series of common

distance constraints between functional groups led to

the hypothesis that a combination of a protonated

amine, an aromatic center, a hydrophobic volume, a

hydrogen-bonding acceptor site, and a donor-acceptor

site could be occupied and result in affinity for the

F igu r e 2. Theoretical 5HT_1B-like receptor model using zolmi-

triptan as a reference. The amine-binding site is represented

by the blue sphere, the aromatic binding site by the green

sphere, the hydrogen-bonding site by the red sphere, and the

selectivity volume in yellow.

vascular 5HT_1B-like receptor. In addition, a “selectivity

volume” was deduced which, if occupied, resulted in

selectivity for 5HT_1B/1Dreceptors over 5HT_2Areceptors.

A representation of the pharmacophore model is de-

picted in Figure 2.

Given the spatial distribution of the common phar-

macophore points, it is possible to perform conforma-

tional analysis and least-squares fitting of novel com-

pounds to the desired pharmacophoric points and hence

suggest a binding mode for new compounds. The

principal binding points were deduced to be the proto-

nated amine and the hydrogen bond acceptor. In some

cases, due to the conformational and geometric con-

straints present in some molecular structures, this mode

of least-squares fitting results in displacement of the

aromatic center of the indole (if present) from the

aromatic site occupied by, for example, zolmitriptan. It

was observed that in such cases the affinity of the

compound could be high while its efficacy was greatly

reduced. An extensive quantitative investigation of this

effect (to be published elsewhere) implied that confor-

mational constriction of the relationships between the

protonated amine, hydrogen-bonding acceptor, and aro-

matic center would result in a displacement of the

aromatic center from the volume normally occupied by

the aromatic center in zolmitriptan and result in a loss

of efficacy. Subsequent investigations narrowed the

region which appears to be responsible for efficacy down

to the double bond (π-density) region of the pyrrole of

the indole indicated in Figure 3.

It thus appears that in order to design high-affinity

antagonists occupation of the protonated amine site and

the hydrogen-bonding site in addition to the aromatic

center would be good for affinity while π-electron density

in the region normally occupied by the indole double

bond should be avoided to prevent an agonist response.

The substitution in the 2-position of the indole causes

restriction in the conformational flexibility of the eth-

ylamine side chain, and in addition, we hypothesized

that there may be a restriction in the size of substituents

in the 2-position that could be accommodated by the

Tryptamines as 5HT_{1B/ 1D}Receptor Antagonists

J ournal of Medicinal Chemistry, 1997, Vol. 40, No. 15 2349

Sch em e 1^a

a

Reagents: (a) HNO₃/H₂SO₄; (b) SOCl₂, CH₃OH; (c) CH₃OH,

NaBH₄; (d) COCl₂; (e) H₂, 10% Pd-C, EtOH.

Sch em e 2^a

Figu r e 3. Overlay of zolmitriptan and the displaced tryptamine

derivative 1. The π-density region is indicated.

F igu r e 4. Series of 2,5-substituted tryptamine derivatives

investigated with variation in structure occurring in the

2-ester substituent and the 5-linked heterocycle.

a

Reagents: (a) NaNO₂, HCl, NaOH; (b) PPE, CHCl₃or p-

5HT_1B-like receptor. Bulk in this region may cause a

displacement of the indole away from its usual position

(as seen in 1, Figure 3) resulting in loss of occupancy of

the π-electron density region necessary to elicit an

agonist response. The inclusion of this receptor es-

sential volume explained the loss of agonism upon

substitution of bulky substituents in the 2-position. If

suitable modifications are made to the remainder of the

molecule such that it can still accommodate the prin-

cipal pharmacophoric binding points, then an antagonist

toluenesulfonic acid, CHCl₃.

and selectivity and to explore the pharmacophore of the

5HT_1B-like recognition site.

Syn th etic Ch em istr y

The tryptamine derivatives 1-4 were prepared from

the aniline derivative 10 (Scheme 1). Nitration of

phenylalanine followed by reaction with thionyl chloride

and methanol gave the methyl ester intermediate 7. The

ester functionality was reduced to a methyl alcohol

group with sodium borohydride. Cyclization of the

alcohol and neighboring amine group with phosgene

gave the oxazolidinone derivative 9 which was converted

to the aniline derivative 10 by hydrogenation of the nitro

group in the presence of 10% palladium on carbon.

The â-keto ester 11 or amide 11′ required for the

J app-Klingemann indole formation^23,24was prepared

by alkylation of ethyl acetoacetate²⁵or acetoacetamide

respectively with 3-(dimethylamino)propyl chloride hy-

drochloride, Scheme 2. Diazotization of the aniline

derivative 10 followed by reaction with the prepared

â-keto ester or amide afforded the hydrazone intermedi-

ate 12. A number of different catalysts were used in

attempts to force the final indole ring closure. Cycliza-

may be obtained which has high affinity for the 5HT_1B

like receptor.

-

Examination of the tryptamine derivatives 1-4 in the

pharmacophore model suggested that the molecules may

better accommodate the pharmacophore binding points

if the 5-side chain is increased in length hence allowing

for more conformational freedom. A further series of

compounds 5 were synthesized incorporating this change,

Figure 4.

We describe in this paper the design, synthesis, and

5HT_1B-like activity of a series of 2,5-substituted tryp-

tamine derivatives 5 and related analogues. Changes

to the 2-substituent, the length of the linking chain (n),

and the nature of the 5-linked heterocycle as well as

the 3-side chain incorporating the protonatable nitrogen

have been performed in an attempt to improve potency

2350 J ournal of Medicinal Chemistry, 1997, Vol. 40, No. 15

Moloney et al.

Sch em e 3^a

Sch em e 5^a

a

Reagents: (a) (CH₃)₃SiBr, DMSO.

Sch em e 4^a

a

Reagents: (a) Ph₃P, DIAD, THF, 0 °C; (b) H₂, 10% Pd-C.

Sch em e 6^a

a

Reagents: (a) Na, EtOH; (b) 60% HBr; (c) KOH, H₂O,

CH₃NCO, HCl; (d) H₂, Pd-C (10%), EtOH; (e) SOCl₂, CH₃OH; (f)

CH₃OH, NaBH₄; (g) COCl₂; (h) H₂, Pd-C (10%), EtOH.

a

Reagents: (a) THF, Et₃N; (b) 5 N NaOH, THF; (c) H₂, Pd-C

(10%), EtOH.

tion with polyphosphate ester in chloroform effected the

formation of the indole and simultaneously dehydrated

the amide to the required nitrile 1. Cyclization of the

hydrazone with p-toluenesulfonic acid gave the indole

amide 2 and the indole ester 3, Scheme 2.

The 2-bromo-substituted derivative 4 was prepared

from the 2-unsubstituted tryptamine compound zolmi-

triptan by treatment with trimethylsilyl bromide, Scheme

3.

Oth er An ilin e In ter m ed ia tes Requ ir ed for In -

d ole Syn th esis. A 5-ethylene-linked analogue of the

2-ester indole derivative 3 was prepared from the higher

homologue of p-nitrophenylalanine which was obtained

by a conventional amino acid synthesis, Scheme 4.

4-Nitrophenethyl bromide was coupled with diethyl

acetoamidomalonate to give the diester derivative 13.

Refluxing in 60% HBr resulted in loss of CO₂and

formation of the amino acid 14 which was reacted on

in an analogous way to that described in Scheme 1 to

afford the oxazolidinone derivative 18. The aniline

derivative required to form a carbon-linked hydantoin

derivative was also synthesized from the amino acid 14.

Reaction with methyl isocyanate afforded the hydantoin

derivative 19 which was converted to the aniline deriva-

tive 20 by hydrogenation in the presence of 10% pal-

ladium on carbon.

The hydantoin derivatives 26-30 were synthesized

as shown in Scheme 5. Reaction of p-nitrophenethyl

alcohol and the appropriate hydantoin derivative under

Mitsunobu conditions^26-28afforded the nitro intermedi-

ates 21-25. Hydrogenation at room temperature and

atmospheric pressure afforded the desired aniline de-

rivatives 26-30.

An oxazolidinone derivative (35) connected through

the nitrogen was synthesized according to Scheme 6.

p-Nitrophenethylamine was reacted with 2-chloroethyl

chloroformate to give the amido halide 31. Cyclization

with NaOH followed by hydrogenation of the nitro group

afforded the desired N-linked oxazolidinone aniline

derivative 35. The lactam aniline derivative 36 was

Tryptamines as 5HT_{1B/ 1D}Receptor Antagonists

J ournal of Medicinal Chemistry, 1997, Vol. 40, No. 15 2351

Sch em e 7^a

Sch em e 8^a

a

Reagents: (a) NaNO₂, H₂O, NaOAc; (b) n-BuOH; (c) NaC-

NBH₃, CH₂O.

synthesized in a similar manner to 35 using instead

4-chlorobutyryl chloride in the alkylation step.

Conversion of all the aniline derivatives to the cor-

responding 2-substituted tryptamine derivatives pro-

ceeded as described in Scheme 2. Hydrazone formation

followed the same reaction conditions as those utilized

in the synthesis of compounds 1-3; however, cyclization

of the hydrazone intermediates was achieved by stirring

in hot ethanol in the presence of sulfuric acid. A series

of methyl ester derivatives was obtained by refluxing

the hydrazone intermediate in hot methanol in the

presence of sulfuric acid. The isopropyl ester and the

cyclohexyl ester derivatives were formed by heating the

appropriate tryptamine 2-ethyl ester derivative in iso-

propyl alcohol or cyclohexanol, respectively, in the

presence of titanium tetraisopropoxide. Table 2 outlines

the tryptamine derivatives synthesized.

a

Reagents: (a) K₂CO₃, DMF; (b) H₂, Pd-C (10%); (c) HCl,

NaNO₂, NaOH; (d) EtOH (or MeOH), cH₂SO₄; (e) (CH₃)₂CHOH,

Ti(i-OPr)₄.

Sch em e 9^a

In an attempt to improve the yields of the 2,5-

substituted tryptamine derivatives, the thiazolidinone

derivative 57 was synthesized in a different manner to

the other tryptamine derivatives. The aniline derivative

30 was reacted with diethyl chloropropylmalonate²⁹

under J app-Klingemann conditions to give the hydra-

zone derivative 58, Scheme 7. Cyclization was achieved

by heating the hydrazone in butanol to give the

tryptamine intermediate 59 which was converted to the

dimethyl derivative 57 by reaction with formaldehyde

and sodium cyanoborohydride.

a

Reagents: (a) LiAlH₄, Et₂O; (b) PCl₅, CHCl₃; (c) Na, MeOH.

3-P ip er id in e Der iva tives. A series of 3-piperidine

derivatives was prepared in a slightly different manner

to the corresponding 3-ethylamine derivatives. The

substituted â-keto ester 69 containing a piperidine side

chain could not be obtained in a manner analogous to

that used to synthesize the diketone 11 shown in

Scheme 2. Ethyl acetoacetate could not be persuaded

to accept the piperidine alkyl halide as an electrophile,

Scheme 9.

The desired â-keto ester was finally prepared by

alkylation of ethyl acetoacetate with 4-picolyl chloride

followed by quaternization with methyl iodide and

hydrogenation of the aromatic ring under reduced

pressure, Scheme 10.

A series of lower homologue 5-ethylene-linked tryp-

tamine derivatives was synthesized as outlined in

Scheme 8. Reaction of p-nitrobenzyl bromide with the

hydantoin derivative gave the required nitro hydantoin

derivatives 60 and 61. The nitro group was reduced

with hydrogen in the presence of 10% palladium on

carbon, and the resulting aniline derivative was reacted

with the diketone under J app-Klingemann conditions

to give the desired hydrazone intermediate. Cyclization

to form the 2-substituted tryptamine derivative was

achieved by heating the hydrazone intermediate in

ethanol and concentrated sulfuric acid. Heating of the

ethyl ester in isopropyl alcohol in the presence of

titanium tetraisopropoxide gave the desired isopropyl

ester derivative 68. The lower homologue compounds

investigated are shown in Table 5.

J app-Klingemann coupling of the diketone 69 with

the aniline derivative 10 afforded the hydrazone inter-

mediate 72 which was cyclized with p-toluenesulfonic

acid in toluene to give the 3-piperidine analogue 73,

Scheme 11.

A series of higher homologues of the 3-piperidine

derivative 73 were synthesized in a slightly different

2352 J ournal of Medicinal Chemistry, 1997, Vol. 40, No. 15

Moloney et al.

Sch em e 10^a

Sch em e 12^a

a

Reagents: (a) Na, EtOH; (b) MeI, ether; (c) H₂, PtO₂, 50 atm.

Sch em e 11^a

a

Reagents: (a) HCl, NaNO₂, NaOH; (b) EtOH, cH₂SO₄; (c) MeI,

THF; (d) NaBH₄, MeOH; (e) H₂, Pd (10%).

Ta ble 1

a

pK_B

compd

no.

5HT_1B-like,

RbSV

5HT_2A

RbA

,

R¹

CN

CONH₂

CO₂Et

Br

1

2

3

4

4.8

4.6

<4.5

5.66

<5.0

4.75

6.12

5.86

a

Affinity (pK_B) -log₁₀K_B, the dissociation equilibrium con-

a

stant) estimates for novel compounds at the vascular 5HT_1B-like

and 5HT_2Areceptors in the rabbit saphenous vein (RbSV) and

aorta (RbA), respectively. Affinity values are the means of at least

three separate estimates. Standard errors are omitted for clarity

but in all cases were e0.2 log₁₀unit.

Reagents: (a) HCl, NaNO₂, NaOH; (b) p-toluenesulfonic acid,

toluene.

manner, Scheme 12. The pyridine diketone derivative

70 was reacted directly with the aniline derivative to

afford a pyridine hydrazone intermediate (74) which

was cyclized in hot ethanol in the presence of sulfuric

acid to give a 2-ethyl ester indole intermediate (76).

Quaternization with methyl iodide followed by reduction

with sodium borohydride afforded a tetrahydropyridine

derivative (78). Reduction with hydrogen in the pres-

ence of 10% palladium on carbon gave the 3-piperidine

derivative 79, Scheme 12. Table 6 shows the 3-tetrahy-

dropyridine and 3-piperidine derivatives investigated.

ecule from that predicted for zolmitriptan and the

concomitant loss of occupancy of the selectivity volume.

These compounds did however serve as good leads on

which to base a potency and selectivity optimization

program. Previous work in our laboratories suggested

that the bulk of the 2-substituent resulted in displace-

ment of the molecule from its preferred mode of binding

within the receptor. Early modifications to take ad-

vantage of this displacement and maintain affinity

involved the inclusion of a 5-ethylene linker between

the 5-heterocycle and the indole ring allowing an

increase in the degrees of freedom of the 5-side chain

and allowing the molecule to more easily adopt a

favorable conformation. From these preliminary results

it was also apparent that the nitrile was poorly tolerated

and that the ester group afforded significantly higher

affinity. A large range of 2,5-substituted tryptamine

derivatives incorporating a variety of heterocyclic ring

systems connected to the 5-position of the indole group

by an ethylene linker chain were investigated.

Resu lts a n d Discu ssion

Str u ctu r e-Activity Rela tion sh ip s. Table 1 shows

biological data for the 2-substituted tryptamine deriva-

tives 1-4. It was encouraging to note that a highly

selective agonist (zolmitriptan) had been converted to

an antagonist by a simple structural manipulation.

Clearly however the level of activity was modest, and a

relative increase in affinity for the 5HT_2Areceptor was

observed consistent with the displacement of the mol-

Tryptamines as 5HT_{1B/ 1D}Receptor Antagonists

J ournal of Medicinal Chemistry, 1997, Vol. 40, No. 15 2353

Ta ble 2

Table 2 shows biological results for this series of

compounds. This series of 5-ethylene-linked tryptamine

derivatives was a considerable improvement over the

methylene-linked oxazolidinone derivatives of Table 1

with up to 40-fold increase in affinity at the 5HT_1B-like

receptor in some cases. All the compounds were silent,

competitive antagonists with the ethyl ester substituent

at the 2-position affording more potent analogues than

the methyl ester group. The best compounds with both

good affinity at the 5HT_1B-like receptor and selectivity

over 5HT_2Aare the hydantoin derivatives 40 and 44,

the phthalimide derivatives 55 and 56, and the thiazo-

lidinedione 57. 40 was comprehensively investigated

and found to be a silent, competitive antagonist at the

5HT_1B-like receptor. The compound was also found to

have good selectivity over other monoamine receptor

subtypes, Table 3.

a

compd

no.

The affinity for 40 for amine-binding sites in the brain

has also been examined, and the results are shown in

Table 4. 40 has little affinity for any well-recognized

brain receptor including other 5HT receptors. Thus 40

appears to be unique in its ability to discriminate

between vascular 5HT receptors and central 5HT recep-

tors. This has not been reported before and clearly calls

into question the use of the appellant 1D for the 5HT

receptor on the saphenous vein. This is not a species

differentiation as has been demonstrated. 40 has been

shown to antagonize the constrictor effects of 5HT in

the human saphenous vein (pK_B) 7.4), in the dog

saphenous vein (pK_B) 6.96), and in the rabbit femoral

artery (pK_B) 7.24). The differences in affinity are

ascribed to species differentiation and not different

receptors. The lack of significant interaction with any

of the recognized central binding sites suggests that

there may not be a requirement to minimize the central

penetration of these antagonists.

Preliminary studies in conscious beagle dogs showed

that 40 is well absorbed after oral dosing (10 mg/kg, po)

with oral bioavailability of at least 40%. Pharmacoki-

netic studies revealed 40 to undergo rapid metabolism

in plasma exhibiting a half-life of t_1/2)15 min in rat

plasma and t_1/2) 12 min in mouse plasma. However

40 was shown to survive longer in both human and dog

plasma (t_1/2) ∼2 h in both human and dog). The short

plasma half-life of 40 precluded further development of

the compound.

The proposed mode of binding of 40 is shown in Figure

5. Following displacement of the molecule in order to

accommodate the bulky 2-ethyl ester group, 40 is still

able to access the amine-binding site, the aromatic

binding site, and the hydrogen-bonding site, while the

methylene protons of the 5-ethylene-linking chain can

insert into the “selectivity site”.

The biological results for the lower homologues of the

hydantoin series shown in Table 5 were less encourag-

ing with all compounds investigated failing to reach our

desired pK_Blevel of 7.0. Evidence from earlier work in

our laboratories had suggested that conformational

restriction of the 3-substituent aided the ability of these

molecules to take up an antagonist binding mode.

Indeed that was one reason for siting the electron-

withdrawing group on the 2-position of the indole. This

conformational restriction can be enhanced by preparing

a series of 3-piperidine and 3-tetrahydropyridine deriva-

tives. Previous work in our department in a research

a

Affinity (pK_B) -log₁₀K_B, the dissociation equilibrium con-

stant) estimates for novel compounds at the vascular 5HT_1B-like

and 5HT_2Areceptors in the rabbit saphenous vein (RbSV) and

aorta (RbA), respectively. Affinity values are the means of at least

three separate estimates. Standard errors are omitted for clarity

but in all cases were e0.2 log₁₀unit.

2354 J ournal of Medicinal Chemistry, 1997, Vol. 40, No. 15

Moloney et al.

Ta ble 3

Ta ble 5

receptor type^a

5HT_1B-like 5HT_2B5HT₇5HT_2AR₁

7.42 <5.0 5.50 5.80 5.43 <5.0 <5.0 <5.0

Affinity (pK_B) -log₁₀K_B, the dissociation equilibrium con-

R₂

H₁

M₃

40

a

stant) estimates for novel compounds at the vascular 5HT_1B-like

receptor in rabbit saphenous vein (RbSV). Affinity at the 5HT_2A

receptors was measured in the rabbit aorta (RbA), at the 5HT_2B

receptors in the endothelium intact rabbit jugular vein, and at

the 5HT₇receptor in the endothelium denuded rabbit jugular vein.

Affinity for both R₁and H₁was measured in the rabbit thoracic

aorta and M₃in the guinea pig trachea. Affinity values are the

means of at least three separate estimates. Standard errors are

omitted for clarity but in all cases were e0.2 log₁₀unit.

a

compd

no.

Ta ble 4

receptor type^a

5HT_1A5HT_1D5HT_2A5HT_2CD₁

D₂

R₁

R₂

â

40 5.03

5.0

5.1

5.26 4.49 4.97 4.95 5.25 4.34

a

Affinity (pK_i) for 5HT_1A, 5HT_2A, 5HT_2C, D₁, D₂, R₁, R₂, and â

was measured in rat cortex homogenates. 5HT_1Dis obtained from

a calf caudate homogenate. Affinity values are the means of at

least three separate estimates. Standard errors are omitted for

clarity but in all cases were e0.2 log₁₀unit.

a

Affinity (pK_B) -log₁₀K_B, the dissociation equilibrium con-

stant) estimates for novel compounds at the vascular 5HT_1B-like

and 5HT_2Areceptors in the rabbit saphenous vein (RbSV) and

aorta (RbA), respectively. Affinity values are the means of at least

three separate estimates. Standard errors are omitted for clarity

but in all cases were e0.2 log₁₀units.

tency and the desired selectivity over 5HT_2Aand other

receptor types.

Con clu sion s

A series of novel, highly potent and selective vascular

5HT_1B-like receptor antagonists have been developed

which are orally bioavailable. The compounds are in

general tryptamine based with methyl or ethyl ester

substituents at the 2-position and 5-methylene- and

5-ethylene-linked heterocyclic ring systems. In particu-

lar several compounds including 40 and the dimethyl-

hydantoin analogue 44 were identified which differen-

tiated between the central 5HT_1B-like receptors and the

vascular 5HT_1B-like receptors. The less than desirable

pharmacokinetics of the 2-ester tryptamine series pre-

cluded further development of compounds from this

group, and future work which will be reported at a later

date will be directed toward stable isosteres of the ester

group.

F igu r e 5. Proposed mode of binding of 40. The amine-binding

site is represented by the blue sphere, the aromatic binding

site by the green sphere, the hydrogen-bonding site by the red

sphere, and the selectivity volume in yellow.

program directed toward the discovery of compounds for

the treatment of migraine had shown that replacement

of the 3-ethylamine side chain with a cyclic structure

produced compounds with slightly higher potency for

the 5HT_1B-like receptor and with a longer half-life as

the cyclic structures were less liable to oxidation by

monoamine oxidases. The biological results for the

compounds investigated shown in Table 6 clearly indi-

cate that in the case of 2-substituted indole compounds,

the bulky cyclic 3-substituents were not well tolerated,

the best compound being 82 (pK_B) 6.42).

Steric restrictions clearly appear to further constrict

the 2-substituent possibly in an unfavorable conforma-

tion for binding (out of the plane of the indole) and

appeared to result in a loss of affinity. Thus from the

variegated series of 2-ester-5-substituted tryptamine

derivatives investigated as 5HT_1B-like antagonists, the

more potent and selective compounds were those from

the 3-ethylamine group. In particular 40 and its related

dimethylhydantoin analogue 44 showed excellent po-

Exp er im en ta l Section

Biological Meth ods: 1. Rabbit Saph en ou s Vein (RbSV)

P r ep a r a tion . The vascular 5HT_1B-like receptor affinities of

compounds were assessed using ring preparations of rabbit

saphenous vein.³⁰Vessels were removed from male New

Zealand white rabbits killed by injecting pentobarbitone (80

mg/kg, iv) followed by exsanguination. After removing adher-

ing connective tissue, ring segments (4-5 mm) were prepared

and mounted between parallel tungsten wires. Tissues were

suspended in 20 mL organ baths containing Krebs-Henseleit

buffer at 37 °C, pH 7.4, and constantly gassed with 95% O₂:

5% CO₂. The Kreb-Henseleit solution used had the following

composition (mM): NaCl 118.41, NaHCO₃25.00, KCl 4.75,

KH₂PO₄1.19, MgSO₄1.19, glucose 11.10, and CaCl₂2.50. 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 R-adrenorecep-

Tryptamines as 5HT_{1B/ 1D}Receptor Antagonists

J ournal of Medicinal Chemistry, 1997, Vol. 40, No. 15 2355

Ta ble 6

Recep tor Bin d in g Assa ys. Competition binding assays

were performed to determine drug affinity (pK_ior pIC₅₀) at

the various receptors described. Briefly the appropriate

radioligand (∼K_D) and a wide range of test drug concentrations

(in duplicate) were incubated with the relevant receptor

preparation (brain homogenate or cell membranes) for 30 min

at 27 °Csconditions determined previously to satisfy mass-

action conditions. The assay buffer comprised 50 mM TRIS-

HCl, 5 mM CaCl₂, 0.1% (w/v) ascorbate, and 10 mM pargyline.

Nonspecific binding was defined using an excess of cold 5HT.

Incubations were terminated by rapid filtration and washing

with ice-cold buffer. Specifically bound radiolabel was mea-

sured by liquid scintillation spectroscopy.

a

compd

no.

Ch em ica l Meth od s: Gen er a l Dir ection s. Computa-

tional chemistry was performed on a Silicon Graphics Iris

Indigo II workstation using the Sybyl³¹molecular modeling

software.

Unless otherwise stated, all ¹H 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) spectrometer, a Kratos MS50 (FAB)

mass spectrometer, or a J oel J MX DX-300 double focusing

instrument. Melting points were determined on a Gallencamp

melting point apparatus 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 and pyridine were stored over sodium hydrox-

ide. All solutions were dried over MgSO₄or Na₂SO₄and

concentrated on a Buchi rotary evaporator. Flash chroma-

tography was performed on silica gel (Merck Kieselgel 60 F₂₅₄).

Infrared 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 theoretical

values unless otherwise stated. HPLC was performed on a

Waters Millenium system comprising a 490E multiwavelength

detector, a 600 controller, and 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.

a

Affinity (pK_B) -log₁₀K_B, the dissociation equilibrium con-

stant) estimates for novel compounds at the vascular 5HT_1B-like

and 5HT_2Areceptors in the rabbit saphenous vein (RbSV) and

aorta (RbA), respectively. Affinity values are the means of at least

three separate estimates. Standard errors are omitted for clarity

but in all cases were e0.2 log₁₀unit.

tors, saphenous veins were simultaneously exposed to phe-

noxybenzamine (0.3 µM). After 30 min, excess inhibitors were

removed by several exchanges of the organ bath buffer and

the tissues challenged with 5HT (1 µM) to determine viability.

In the saphenous vein a cumulative concentration-effect (E/

[A]) curve to 5HT was constructed followed by washout and

after 60 min recovery by a second curve to the test compound.

When the test compound failed to produce agonism, it was

evaluated as a 5HT antagonist, potency being determined as

an apparent pK_B. When the test produced vascular contrac-

tion, potency estimates were determined as p[A]₅₀and intrinsic

activity (R) values determined from the ratio: test maximum

response/5HT maximum.

2. Ra bbit F em or a l Ar ter y (RbF A) P r ep a r a tion . Rings

(2 mm) of rabbit femoral artery were exposed to pargyline (500

µM) for 30 min 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 5HT as a reference) was

constructed to determine vascular 5HT_1B-like agonist activity.

Krebs solution containing prazosin, mepyramine, and spiper-

one (0.3 µM each) was used throughout to block possible effects

mediated by R₁adrenergic, H₁histaminergic, and 5HT_2A

serotonergic receptor activation, respectively.

4-Nitr op h en yla la n in e (6).²¹To a stirring mixture of

phenylalanine (20.0 g, 0.095 mol) in concentrated sulfuric acid

(27.8 mL, 0.28 mol) at 0 °C was gradually added concentrated

nitric acid (5.55 mL, 0.095 mol) over 45 min. The reaction

mixture was then stirred for a further 30 min at room

temperature and poured onto ice/water (1.0 L), and stirring

continued for a further 30 min. The yellow emulsion was

extracted with ethyl acetate; the combined extracts were dried,

filtered, and concentrated under vacuum. The solid was

recrystallized from ethanol to give 9.8 g (53%) of 6 as yellow

crystals (mp dec > 230 °C). Anal. (C₉H₁₀N₂O₄‚1.0H₂O) C, H,

N.

(S)-Meth yl 4-Nitr op h en yla la n a te Hyd r och lor id e (7).²¹

To a stirring solution of anhydrous methanol (50 mL) at -10

°C was added thionyl chloride (7.25 mL, 0.1 mol). The amino

acid 6 (9.8 g, 0.05 mol) was added as a solid, and the reaction

mixture was allowed to stir up to room temperature over 3 h.

The mixture was warmed to 40 °C for 1 h and then cooled and

the solvent removed under reduced pressure. The residue was

taken up in water and extracted with ethyl acetate (3 × 50

mL). The extract was dried, and the filtrate was concentrated

under vacuum to give 9.96 g (76%) of 7 as a white solid.

Recrystallization of a small amount from ethanol afforded 7

as white needles (mp 227-228 °C): MS m/z (M⁺) 224; ¹H NMR

δ 3.3 (2H, m, CH₂), 3.7 (3H, s, OCH₃), 4.4 (1H, t, CH), 7.1 (2H,

d, H3, H5, J ) 7.2 Hz), 8.2 (2H, d, H2, H6, J ) 7.2 Hz), 8.8

(3H, s, NH₃⁺).

3. Ra bbit Aor ta (RbA) P r ep a r a tion . Rings (3 mm) of

rabbit thoracic aorta were exposed to pargyline (500 µM) for

30 min during which they were tensioned twice to 3.0 g.

Exposure to ^L-phenylephrine (L-Phe; 10 µM) enabled tissue

viability to be assessed and provided a reference contracture

for subsequent data analysis. Following washout tissues were

exposed to novels (30 µM) for 60 min prior to a cumulative

E/[A] curve to ^L-Phe being constructed.

(S)-2-Am in o-3-(4-n itr op h en yl)p r op a n ol (8).²¹To a solu-

tion of sodium borohydride (4.93 g, 0.13 mol) in ethanol/water

(1:1) (70 mL) was added dropwise a solution of the amino ester

2356 J ournal of Medicinal Chemistry, 1997, Vol. 40, No. 15

Moloney et al.

7 (8.0 g, 0.031 mol) in ethanol/water (70 mL) at 0 °C. The

mixture was refluxed for 4 h and then allowed to cool to room

temperature. The solvent was decanted from the gray pre-

cipitate, and the ethanol was then removed under vacuum.

The remaining water was extracted with ethyl acetate (3 ×

50 mL) and the organic layer washed with brine and then

water, dried, and concentrated. The yellow solid was recrys-

tallized from ethanol to give 3.88 g (65%) of 8 as yellow crystals

(mp 141-142 °C): ¹H NMR δ 2.52 (2H, m, CH₂O), 2.88 (2H,

m, CH₂Ph), 3.22 (3H, m, CH, NH₂), 4.61 (1H, s, OH), 7.5 (2H,

d, H3, H5, J ) 7.3 Hz), 8.15 (2H, d, H2, H6, J ) 7.3 Hz).

Meth od 1: Gen er a l P r oced u r e for F or m a tion of th e

Oxa zolid in on e Rin g of (S)-4-(4-Nitr oben zyl)-1,3-oxa zo-

lid in -2-on e (9)²¹a n d Rela ted Com p ou n d 17. The amino

alcohol 8 (3.57 g, 0.018 mol) was suspended in toluene (55 mL)

and cooled to 0 °C, and an aqueous potassium hydroxide

solution (0.2 M, 41 mL) was added dropwise with stirring. To

this solution was gradually added phosgene in toluene (1.25

M, 46 mL, 0.0576 mol) at 0 °C. The resulting solution was

allowed to stir up to room temperature, and stirring continued

for 2 h. A yellow solid was filtered off and dried over

phosphorus pentoxide under vacuum. The compound was

recrystallized from ethanol to give 2.97 g (75%) of 9 as yellow

solution of potassium hydroxide (0.43 g, 7.6 mmol) in water

(1.0 mL) was added to a solution of the diketone 11 (0.92 g,

4.25 mmol) in ice (3.88 g). This solution was stirred for 30

min and then added at once to the diazonium salt solution.

The solution was left to stir for 30 min at 0-5 °C. Concen-

trated hydrochloric acid (0.33 mL) and ice (1.95 g) were then

added, and the solution stirred at 10-15 °C overnight. The

red suspension was basified with 2 N NaOH solution, extracted

with CHCl₃, dried, and concentrated to give 0.9 g of a crude

residue which was reacted on without further purification.

5-(Dim et h yla m in o)-2-[[4-[(2-oxo-1,3-oxa zolid in -4-yl)-

m eth yl]p h en yl]h yd r a zin -2-ylid en e]p en ta n a m id e (12′). A

stirring solution of 10 (1.0 g, 5.21 mmol) in concentrated

hydrochloric acid (0.55 mL, 5.21 mmol) and ice (2.6 g) was

cooled to -2 °C. A solution of sodium nitrite (0.36 g, 5.21

mmol) in ice water (0.5 mL) was added dropwise keeping the

temperature below 0 °C, and the solution was stirred for 30

min. Meanwhile a solution of potassium hydroxide (0.52 g,

9.3 mmol) in water (1.4 mL) was added to a solution of the

amide 11′ (0.97 g, 5.21 mmol) in ice (4.8 g). This solution was

stirred for 30 min and then added at once to the hydrazine

solution. The solution was left to stir for 30 min at 0-5 °C.

Concentrated hydrochloric acid (0.4 mL) and ice (2.4 g) were

then added, and the solution stirred up to room temperature

for 2 h. The red suspension was then basified with 2 N NaOH,

extracted with CHCl₃, dried, and concentrated to give a crude

residue (0.86 g, 47%) which was reacted on without further

purification.

1

crystals: MS m/z 222 (M + 1)⁺; H NMR δ 4.0 (2H, m, CH₂-

Ph), 4.13 (1H, m, CH), 4.3 (2H, m, CH₂O), 7.55 (2H, d, H3,

H5, J ) 7.2 Hz), 7.74 (1H, s, NH), 8.16 (2H, d, H2, H6, J ) 7.3

Hz). Anal. (C₁₀H₁₀N₂O₄) C, H, N.

Meth od 2: Gen er a l Hyd r ogen a tion P r oced u r e for th e

P r epar ation of th e An ilin e Der ivative (S)-4-(4-Am in oben -

zyl)-1,3-oxa zolid in -2-on e (10) a n d Rela ted Com p ou n d s

18, 20, 26-29, 35, 36, 62, a n d 63. A suspension of 9 (2.9 g,

13 mmol) in a mixture of ethanol (76 mL), water (60 mL), and

2 N HCl (12 mL) was hydrogenated at room temperature and

atmospheric pressure over 10% palladium on carbon (0.39 g)

overnight. The catalyst was filtered through Celite and

washed with ethanol (2 × 15 mL) and the solvent removed

under vacuum. The remaining residue was azeotropically

dried with absolute ethanol (50 mL) and further dried under

vacuum to give 2.37 g (79%) of 10 as a white solid: MS m/z

(S)-2-[2-Cya n o-5-[(2-oxo-1,3-oxa zolid in -4-yl)m et h yl]-

1H-in d ol-3-yl]d im eth yleth yla m in e (1). The crude hydra-

zone 12′ (0.4 g, 1.06 mmol) and polyphosphoric ester (5.7 g) in

CHCl₃(10 mL) were heated to reflux for 1 h. The reaction

mixture was poured onto ice water, extracted with chloroform

(3 × 300 mL), dried, and concentrated. The residue was

purified by flash chromatography eluting with CH₂Cl₂:EtOH:

NH₃(240:8:1) to give 30 mg (8%) of 1 as an off-white powder.

The solid was further purified by preparative HPLC to afford

the acetate salt of 1 as a white lyophylate: t_R13.1 min; IR

CN stretch 2218; MS m/z 313 (M + 1)⁺; ¹H NMR δ 2.6 (6H, s,

2 × NCH₃), 2.72 (2H, m, CH₂NMe₂), 2.95 (2H, m, 5-CH₂), 3.12

(2H, m, 3-CH₂), 4.2 (3H, m, CH₂O, CH), 7.25 (1H, d, H6, J )

8.1 Hz), 7.32 (1H, d, H7, J ) 8.2 Hz), 7.59 (1H, s, H4); found

1

193 (M + 1)⁺; H NMR δ 4.0 (3H, m, CH₂Ph, CH), 4.28 (2H,

m, CH₂O), 7.32 (4H, m, H2, H3, H5, H6), 7.8 (1H, s, NH), 10.3

(3H, br s, NH₃⁺).

M

⁺312.3710, C₁₇H₂₀N₄O₂requires M⁺312.3714. Anal. Calcd

Meth od 3: Gen er a l P r oced u r e for F or m a tion of th e

â-Keto Ester Eth yl 2-Acetyl-5-(dim eth ylam in o)pen tan oate

(11).²⁴A sodium ethoxide solution was generated from

absolute ethanol (175 mL) and sodium (9.2 g, 0.4 mol). To

this stirring solution was added a solution of ethyl acetoacetate

(26.0 g, 0.2 mol) and absolute ethanol (20 mL), and stirring

continued for 1 h. A solution of (N,N-dimethylamino)propyl

chloride hydrochloride (31.6 g, 0.2 mol) in absolute ethanol (50

mL) was gradually added and the resulting suspension re-

fluxed for 18 h. The solution was cooled and the solvent

removed under vacuum. Water (80 mL) was added and then

extracted with ethyl acetate (3 × 100 mL). The organic extract

was dried and concentrated to give a yellow oil. Purification

was achieved by flash chromatography (CH₂Cl₂:EtOH:NH₃,

120:8:1) to give 10.8 g (25%) of 11 as a light yellow oil: MS

(C₁₇H₂₀N₄O₂‚2.0CH₃CO₂H‚3.0H₂O): C, 51.8; H, 7.0; N, 11.7.

Found: C, 51.9; H, 6.3; N, 12.5.

Meth od 5: Gen er a l Meth od for In d ole F or m a tion

Usin g p-Tolu en esu lfon ic Acid . (S)-2-[2-Am id o-5-[(2-oxo-

1,3-oxa zolid in -4-yl)m eth yl]-1H-in d ol-3-yl]d im eth yleth yl-

a m in e (2). Hydrated p-toluenesulfonic acid monohydrate (0.6

g, 3.15 mmol) was dried by refluxing in toluene (20 mL) and

then distilling off the toluene. A solution of dry p-toluene-

sulfonic acid in dry toluene (20 mL) was then added to the

crude hydrazone 12′ (0.43 g, 12.4 mmol) and refluxed for 6 h.

The toluene was evaporated, and the black residue was

partially purified by flash chromatography eluting with CH₂-

Cl₂:EtOH:NH₃(90:8:1). Further purification was achieved

with preparative HPLC to give 25 mg (6%) of the acetate salt

of 2 as a white lyophylate: MS m/z 331 (M + 1⁺); found M⁺

1

m/z 215 (M⁺); H NMR δ 1.17 (3H, t, CH₃, J ) 7.1 Hz), 1.76

1

330.3872, C₁₇H₂₂N₄O₃requires M⁺330.3867; H NMR (CH₃-

(2H, m, CH₂CH₂), 2.1 (6H, s, 2 × NCH₃), 2.19 (3H, s, CH₃CO),

2.26 (2H, t, CH₂Cd, J ) 6.5 Hz), 3.8 (2H, t, CH₂N, J ) 6.4

Hz), 4.02 (2H, q, CH₂, J ) 7.1 Hz), 5.01 (1H, s, OH).

OH-d₄) δ 2.7 (6H, s, 2 × NCH₃), 2.96 (2H, m, CH₂NMe₂), 3.16

(2H, m, 5-CH₂), 3.4 (2H, m, 3-CH₂), 4.21 (2H, m, CH₂O), 4.38

(1H, m, CH), 7.19 (1H, d, H6, J ) 8.4 Hz), 7.39 (1H, d, H7, J

) 8.3 Hz), 7.52 (1H, s, H4). Anal. (C₁₇H₂₂N₄O₃‚1.0CH₃-

CO₂H‚0.9H₂O) C, H, N.

(S)-Eth yl 3-[2-(Dim eth yla m in o)eth yl]-5-[(2-oxo-1,3-ox-

a zolid in -4-yl)m et h yl]-1H-in d ole-2-ca r boxyla t e (3). The

crude hydrazone 12 (0.14 g, 0.4 mmol) and polyphosphoric

ester (2.5 g) in CHCl₃(8 mL) was heated to reflux for 8 h. The

reaction mixture was cooled, poured onto ice water, basified

to pH 8 with sodium hydrogen carbonate, and extracted with

ethyl acetate. The organic layer was dried and concentrated

to give a crude gum which was partially purified using flash

chromatography eluting with CH₂Cl₂:EtOH:NH₃(60:8:1). Fur-

ther purification by preparative HPLC afforded 25 mg (20%)

of the acetate salt of 3 as a white lyophylate: MS m/z 360 (M

+ 1)⁺; found M⁺359.4249, C₁₉H₂₅N₃O₄requires M⁺359.4252;

2-Acetyl-5-(d im eth yla m in o)p en ta m id e (11′): method 3

(using ethyl acetoacetamide), 4.65 g (13%), bp 190 °C (2

mmHg); MS m/z 187 (M + 1)⁺; ¹H NMR δ (CDCl₃) 1.4-1.9

(4H, m, 2 × CH₂), 2.2 (9H, s, 2 × NCH₃, CH₃CO), 3.4 (2H, t,

CH₂N, J ) 6.1 Hz), 5.7 (1H, br s, NH), 6.5 (1H, br s, NH).

Meth od 4: Gen er a l Meth od for th e F or m a tion of Eth yl

5-(Dim eth yla m in o)-2-[[4-[(2-oxo-1,3-oxa zolid in -4-yl)m e-

th yl]p h en yl]h yd r a zin -2-ylid en e]p en ta n oa te (12) a n d Re-

la ted Hyd r a zon e In ter m ed ia tes Requ ir ed for th e Syn -

th esis of th e In d ole Der iva tives 48 a n d 49. A stirring

solution of 10 (0.97 g, 4.25 mmol) in concentrated hydrochloric

acid (0.45 mL, 4.25 mmol) and ice (2.2 g) was cooled to -2 °C.

A solution of sodium nitrite (0.29 g, 4.25 mmol) in ice water

(0.5 mL) was added dropwise keeping the temperature below

0 °C, and the solution was stirred for 30 min. Meanwhile a

Tryptamines as 5HT_{1B/ 1D}Receptor Antagonists

J ournal of Medicinal Chemistry, 1997, Vol. 40, No. 15 2357

¹H NMR δ 1.49 (3H, t, CH₂CH₃, J ) 7.0 Hz), 2.48 (6H, s, 2 ×

NCH₃), 2.7 (2H, m, CH₂NMe₂), 3.0 (2H, m, 5-CH₂) 3.38 (2H,

m, 3-CH₂), 4.25 (2H, q, CH₂CH₃, J ) 7.0 Hz), 4.44 (3H, m,

CH₂O, CH), 7.22 (1H, m, H6), 7.45 (1H, d, H7, J ) 8.0 Hz),

7.61 (1H, d, H4, J ) 8.0 Hz). Anal. Calcd (C₁₉H₂₅N₃O₄‚1.3H₂O):

C, 59.6; H, 7.2; N, 11.0. Found: C, 59.5; H, 6.4; N, 11.4.

4-(4-Nitr op h en eth yl)-1,3-oxa zolid in -2-on e (17): method

1, pale yellow crystals (53%); MS m/z 236 (M⁺); ¹H NMR

(CDCl₃) δ 1.9 (2H, m, CH₂Ph), 2.8 (2H, m, CH₂CH), 3.9 (1H,

m, CH), 4.1 (1H, m, CH_AO), 4.52 (1H, m, CH_BO), 7.0 (1H, s,

NH), 7.38 (2H, d, H3, H5, J ) 8.5 Hz), 8.18 (2H, d, H2, H6, J

) 8.5 Hz).

4-(4-Am in op h en eth yl)-1,3-oxa zolid in -2-on e h yd r och lo-

r id e (18): method 2, (85%); MS m/z 206 (M⁺); ¹H NMR δ 1.75

(2H, m, CH₂Ph), 2.53 (2H, m, CH₂CH), 3.75 (1H, m, CH), 3.95

(1H, m, CH_AO), 4.4 (1H, m, CH_BO), 7.3 (4H, m, H2, H3, H5,

H6), 7.86 (1H, s, NH), 10.3 (3H, br s, NH₃⁺).

(S)-2-[2-Br om o-5-[(2-oxo-1,3-oxa zolid in -4-yl)m et h yl]-

1H-in d ol-3-yl]d im eth yleth yla m in e (4). Trimethylsilyl bro-

mide (0.4 mL, 3.1 mmol) was added to dimethyl sulfoxide (5.0

mL) and stirred for 15 min under nitrogen. A solution of the

zolmitriptan^9,21(147 mg, 0.5 mmol) in dimethyl sulfoxide (2.0

mL) was added, and the resulting solution was stirred for 50

min at room temperature. The reaction mixture was poured

onto ice water, adjusted to pH 9 with aqueous ammonium

hydroxide, and then extracted with dichloromethane (4 × 20

mL), and the combined organic phases were washed with brine

(3 × 10 mL). After drying, concentration gave a gummy solid

which was dissolved in dichloromethane and filtered. Con-

centration in vacuo gave 65 mg (35%) of a pale gum. Further

purification was achieved by preparative HPLC to afford 28

mg (13%) of the acetate salt of 4 as a beige lyophylate: t_R9.25

1-Meth yl-4-[(4-n itr op h en yl)eth yl]im id a zolid in e-2,5-d i-

on e (19). The amino acid 14 (2.8 g, 12.5 mmol) was added to

a solution of potassium hydroxide (0.84 g, 15 mmol) in water

(25 mL). The solution was cooled to 0 °C, and methyl

isocyanate (0.86 g, 0.89 mL, 15 mmol) was added over 15 min

at 0 °C. The solution was stirred at 60-70 °C for 2 h after

which the urea was filtered off. The filtrate was acidifed with

concentrated hydrochloric acid and then filtered. The uncy-

clized hydantoic acid was collected and washed with water.

The solid was suspended in concentrated HCl/water (1:1) (15

mL) and refluxed for 2 h. The solution was then cooled, diluted

with water, filtered, washed with water, and dried in vacuo

to give 2.63 g (80%) of 19 as a white powder: MS m/z 264 (M

+ 1)⁺.

1

min; MS m/z 366 (M + 1)⁺; H NMR δ 2.2 (6H, s, 2 × NCH₃),

2.42 (2H, m, CH₂NMe₂), 2.74 (2H, m, 5-CH₂), 2.8 (2H, m,

3-CH₂), 4.0 (3H, m, CH₂O, CH), 6.95 (1H, d, H6, J ) 7.9 Hz),

7.18 (1H, d, H7, J ) 7.8 Hz), 7.34 (1H, s, H4), 7.7 (1H, s,

NHCO), 11.5 (1H, s, NH).

1-Met h yl-4-[(4-a n ilin o)et h yl]im id a zolid in e-2,5-d ion e

(20):²¹method 2, 2.38 g (92%); MS m/z 234 (M + 1)⁺.

E t h yl

2-(N-Acet a m id o)-2-(ca r b oxyet h yl)-4-(4-n it r o-

p h en yl)bu ta n oa te (13). To a stirring solution of sodium (5.0

g, 0.22 mol) dissolved in dry ethanol (600 mL) was added

diethyl acetamidomalonate (47.2 g, 0.22 mol). The resulting

solution was stirred for 5 min and then heated to reflux. To

this solution was added dropwise 4-nitrophenethyl bromide

(50.0 g, 0.22 mol) in dry ethanol (225 mL). The resulting

solution was refluxed overnight and then allowed to cool. The

solution was concentrated under vacuum to a smaller volume

and the resultant precipitate filtered and dried to afford 54.9

g (55%) of 13 as white crystals: MS m/z 366 (M⁺); ¹H NMR δ

1.16 (6H, t, 2 × CH₂CH₃, J ) 7.1 Hz), 1.92 (3H, s, COCH₃),

2.5 (4H, m, CH₂CH₂), 4.12 (4H, q, 2 × CH₂, J ) 7.1 Hz), 7.41

(2H, d, H3, H5, J ) 8.9 Hz), 8.14 (2H, d, H2, H6, J ) 8.8 Hz),

8.32 (1H, s, NH). Anal. (C₁₇H₂₂N₂O₇‚0.23H₂O) C, H, N.

2-Am in o-4-(4-n itr op h en yl)bu tyr ic Acid (14). A solution

of the diester 13 (17.0 g, 46.5 mM) in 60% hydrobromic acid

(150 mL) was gently refluxed for 3 h. The solution was cooled

and concentrated under vacuum, the residue dissolved in water

(150 mL), and the solution adjusted to pH 7 with 5 N NaOH.

The precipitate was filtered, washed with water, and dried

under vacuum over phosphorus pentoxide to give 9.8 g (94%)

of 14: MS m/z 224 (M⁺); ¹H NMR δ 2.81 (2H, m, CH₂Ph), 3.16

(2H, m, CH₂), 3.3 (1H, m, CH, blanketed by HDO peak), 7.5

(2H, d, H3, H5, J ) 8.3 Hz), 8.18 (2H, d, H2, H6, J ) 8.5 Hz).

Meth yl 2-Am in o-4-(4-n itr op h en yl)bu tyr a te (15). Thi-

onyl chloride (10.4 g, 87.5 mmol) was added dropwise to a

stirring solution of methanol (50 mL) at -10 °C under

nitrogen. The amino acid 14 (9.8 g, 43.8 mmol) was gradually

added and the reaction mixture allowed to stir up to room

temperature overnight. The methanol was removed under

vacuum; the solid was washed with diethyl ether, filtered, and

dried to give 6.98 g (58%) of the hydrochloride salt of 15 as a

white solid: MS m/z 239 (M + 1)⁺; ¹H NMR δ 2.2 (2H, m, CH₂-

Ph), 2.9 (2H, m, CH₂), 3.75 (3H, s, OCH₃), 4.02 (1H, m, CH),

7.55 (2H, d, H3, H5, J ) 9.0 Hz), 8.2 (2H, d, H2, H6, J ) 9.2

Hz), 8.88 (3H, s, NH₃⁺).

E t h yl 3-[2-(Dim et h yla m in o)et h yl]-5-[2-(2,5-d ioxo-1-

m e t h yl-4-im id a zolid in yl)e t h yl]-1H -in d ole -2-c a r b o x -

yla te (47).²¹The previously prepared hydrazone was used

crude. Water was azeotroped off by distillation of TsOH‚H₂O

in toluene. The TsOH/toluene solution was added to the crude

hydrazone and refluxed for 2 h. The solution was cooled and

the toluene evaporated under reduced pressure. The residue

was dried and then purified by flash chromatography eluting

with CH₂Cl₂:EtOH:NH₃(100:8:1) to give an orange solid.

Further purification with preparative HPLC gave 30 mg (4%)

of the acetate salt 47 as a white lyophylate: MS m/z 401 (M

1

+ 1)⁺; H NMR (CH₃OH-d₄) δ 1.42 (3H, t, CH₂CH₃, J ) 7.2

Hz), 1.91 (3H, s, CH₃CO₂H), 2.15 (2H, m, CH₂CH), 2.69 (6H,

s, 2 × NCH₃), 2.8 (5H, m, CH₂NMe₂, NCH₃), 3.1 (2H, m,

5-CH₂), 3.45 (2H, m, 3-CH₂), 4.1 (1H, m, CH), 4.45 (2H, q, CH₂-

CH₃, J ) 7.1 Hz), 7.2 (1H, d, H6, J ) 8.0 Hz), 7.38 (1H, d, H7,

J ) 8.2 Hz), 7.53 (1H, s, H4). Anal. (C₂₁H₂₈N₄O₄‚1.0CH₃-

CO₂H‚0.4H₂O) C, H, N.

Meth od 6: Gen er a l Meth od for In d ole F or m a tion To

Affor d Meth yl 3-[2-(Dim eth yla m in o)eth yl]-5-[2-(2-oxo-

1,3-oxa zilid in -4-yl)eth yl]-1H-in d ole-2-ca r boxyla te (48).

To a solution of the crude ethyl ester hydrazone (0.45 g, 1.15

mmol) prepared by method 4 in methanol (45 mL) was added

dropwise concentrated hydrochloric acid (0.9 mL). The reac-

tion mixture was stirred at 80 °C under nitrogen for 24 h. The

solution was cooled, the solvent evaporated, water added (40

mL), and the pH adjusted to 9 with potassium carbonate. The

aqueous layer was extracted with ethyl acetate, dried, and

filtered and the solvent evaporated under reduced pressure

to give an orange solid which was purified by column chro-

matography eluting with CH₂Cl₂:EtOH:NH₃(80:8:1) to give

the product as a yellow solid. Further purification with

preparative HPLC afforded 30 mg (8%) of 48 as the acetate

salt: MS m/z 360 (M + 1⁺); ¹H NMR δ 1.74-1.9 (4H, m, CH₂-

CH, CH₂NMe₂), 2.25 (6H, s, 2 × NCH₃), 2.44 (2H, m, 5-CH₂),

2.68 (2H, m, 3-CH₂), 3.75 (1H, m, CH), 3.88 (3H, s, OCH₃),

3.95 (1H, m, CH_AO), 4.31 (1H, m, CH_BO), 7.12 (1H, d, H6, J )

7.9 Hz), 7.21 (1H, d, H7, 8.0 Hz), 7.44 (1H, s, H4), 7.8 (1H, s,

NHCO), 11.43 (1H, s, NH); found M⁺359.1811, C₁₉H₂₅N₃O₄

requires M⁺359.4252.

2-Am in o-4-(4-n itr op h en yl)bu ta n ol (16). A solution of 15

(6.98 g, 25.4 mmol) in ethanol/water (1:1) (75 mL) was added

dropwise to a stirring solution of sodium borohydride (3.95 g,

0.1 mol) in ethanol/water (1:1) (75 mL) at room temperature.

The reaction mixture was refluxed for 4 h and then allowed

to cool. The ethanol was removed under vacuum, and the

remaining aqueous layer was extracted with ethyl acetate,

washed with brine, dried, and filtered and the solvent removed

to give 3.4 g (64%) of 16 as a yellow powder: MS m/z 211 (M

Eth yl 3-[2-(d im eth yla m in o)eth yl]-5-[2-(2-oxo-1,3-oxa -

zilid in -4-yl)eth yl]-1H-in d ole-2-ca r boxyla te (49): method

6 (using ethanol as solvent), white powder (free base) (17%)

1

(mp 190-192 °C); MS m/z 373 (M⁺); H NMR δ 1.36 (3H, t,

CH₂CH₃, J ) 7.4 Hz), 1.78 (2H, m, CH₂CH), 2.21 (6H, s, 2 ×

NCH₃), 2.42 (2H, m, CH₂NMe₂), 2.69 (2H, m, 5-CH₂), 3.18 (2H,

m, 3-CH₂), 3.75 (1H, m, CH), 3.94 (1H, m, CH_AO), 4.30 (1H,

m, CH_BO), 4.31 (2H, q, CH₂CH₃, J ) 7.3 Hz), 7.1 (1H, dd, H6,

1

+ 1)⁺; H NMR δ 1.56 (2H, m, CH₂Ph), 2.7 (4H, m, CH₂CH,

CH₂O), 3.2 (1H, m, CH), 7.48 (2H, d, H3, H5, J ) 8.2 Hz),

8.13 (2H, d, H2, H6, J ) 8.3 Hz).

2358 J ournal of Medicinal Chemistry, 1997, Vol. 40, No. 15

Moloney et al.

J ) 8.3 Hz), 7.3 (1H, d, H7, J ) 8.2 Hz), 7.42 (1H, s, H4), 7.82

(1H, s, NH), 11.36 (1H, s, NH). Anal. (C₂₀H₂₇N₃O₄‚0.25H₂O)

C, H, N.

the amine salt as a white solid: MS m/z 237 (M + 1)⁺; ¹H NMR

δ 2.67 (2H, t, CH₂N, J ) 8.9 Hz), 3.4 (3H, br s, NH₃⁺), 3.66

(2H, t, CH₂Ph, J ) 8.7 Hz), 4.18 (2H, s, CH₂S), 4.88 (1H, br s,

NH), 6.5 (2H, d, H2, H6, J ) 7.8 Hz), 6.82 (2H, d, H3, H5, J

) 7.9 Hz). Anal. (C₁₁H₁₂N₂O₂S‚0.27H₂O) C, H, N.

Meth od 7: Gen er a l P r oced u r e for th e P r ep a r a tion of

N-Lin k ed Im id a zolid in e-2,5-d ion es. 5,5-Dim et h yl-3-[2-

(4-n itr op h en yl)eth yl]im id a zolid in e-2,4-d ion e (22). To a

solution of dry DMF (60 mL) were added 5,5-dimethylhydan-

toin (3.83 g, 0.029 mol), p-nitrophenethyl alcohol (5.0 g, 0.029

mol), and triphenylphosphine (7.84 g, 0.029 mol). The solution

was stirred under nitrogen at 0 °C for 15 min; then diisopropyl

azodicarboxylate (6.04 g, 6.2 mL, 0.029 mol) was added

dropwise over 30 min with the temperature maintained at 0

°C. The solution was then allowed to warm up to room

temperature overnight. The reaction mixture was poured onto

ice water (250 mL) and stirred for 2 h. The white solid was

filtered and recrystallized from ethanol to give 4.64 g (54%) of

N-[(2-Ch lor oeth oxy)ca r bon yl]-2-(4-n itr op h en yl)eth yl-

a m in e (31). To (4-nitrophenyl)ethylamine hydrochloride (2.5

g, 0.012 mol) in THF (200 mL) were added 2-chloroethyl

chloroformate (1.78 g, 0.012 mol) and triethylamine (1.21 g,

0.012 mol), and the solution was stirred at room temperature

for 48 h. The solution was evaporated under vacuum, the solid

was taken up in ethyl acetate, and the salts were filtered off.

The filtrate was evaporated under reduced pressure to give

1

1.87 g (61%) of 31 as yellow crystals: MS m/z 272 (M⁺); H

NMR δ 2.54 (2H, swamped by DMSO peak, CH₂N), 2.85 (2H,

m, CH₂Ph), 3.73 (2H, m, CH₂Cl), 4.2 (2H, m, CH₂O), 7.39 (1H,

t, NH), 7.5 (2H, d, H3, H5, J ) 8.7 Hz), 8.16 (2H, d, H2, H6,

J ) 8.7 Hz).

1

22 as white needles (mp 159-160 °C): MS m/z 277 (M⁺); H

NMR δ 1.16 (6H, s, 2 × CH₃), 2.9 (2H, m, CH₂N), 3.63 (2H, m,

CH₂Ph), 7.43 (2H, d, H3, H5, J ) 8.7 Hz), 8.13 (2H, d, H2,

H6, J ) 8.7 Hz), 8.2 (1H, s, NH); found M⁺277.1058,

C₁₃H₁₅N₃O₄requires M⁺277.2798. Anal. Calcd (C₁₃H₁₅N₃O₄):

C, 56.3; H, 5.4; N, 15.1. Found: C, 56.9; H, 5.5; N, 14.3.

3-[2-(4-Nitr op h en yl)eth yl]im id a zolid in e-2,4-d ion e (21):

method 7, white crystals from ethanol (60%); MS m/z 250 (M⁺);

¹H NMR δ 2.95 (2H, t, CH₂N, J ) 7.1 Hz), 3.62 (2H, t, CH₂Ph,

J ) 7.1 Hz), 3.85 (2H, s, CH₂CO), 7.47 (2H, d, H3, H5, J ) 8.4

Hz), 8.0 (1H, s, NH), 8.12 (2H, d, H2, H6, J ) 8.3 Hz).

N-[2-(4-Nitr op h en yl)eth yl]su ccin im id e (23): method 7,

white crystals, 3.89 g (51%); MS m/z 249 (M + 1)⁺; ¹H NMR δ

2.58 (4H, s, 2 × CH₂CO), 2.93 (2H, t, CH₂N, J ) 7.26 Hz),

3.63 (2H, t, CH₂Ph, J ) 7.2 Hz), 7.48 (2H, d, H3, H5, J ) 8.67

Hz), 8.14 (2H, d, H2, H6, J ) 8.7 Hz); found M⁺248.2123,

C₁₂H₁₂N₂O₄requires 248.2383.

N-[2-(4-Nit r op h en yl)et h yl]-1,3-oxa zolid in -2-on e (33).

To a stirring solution of 31 (2.0 g, 7.34 mmol) in THF (25 mL)

was added 5 N NaOH (4.4 mL). The solution was refluxed

overnight and cooled, the solvent evaporated, and the residue

purified by flash chromatography eluting with chloroform/

methanol (95:5). The resulting yellow solid was recrystallized

from ethanol to give 1.3 g (75%) of yellow crystals (mp 128-

130 °C): MS m/z 236 (M⁺); ¹H NMR δ 2.95 (2H, t, CH₂N, J )

7.3 Hz), 3.47 (2H, t, CH₂Ph, J ) 7.4 Hz), 3.55 (2H, dd, CH₂-

CH₂O), 4.21 (2H, dd, CH₂O), 7.57 (2H, d, H3, H5, J ) 8.6 Hz),

8.18 (2H, d, H2, H6, J ) 8.6 Hz). Anal. (C₁₁H₁₂N₂O₄) C, H,

N.

N-[2-(4-Am in op h en yl)eth yl]-1,3-oxa zolid in -2-on e (35):

method 2, white foam, 1.03 g (97%); MS m/z 207 (M + 1)⁺; ¹H

NMR δ 2.8 (2H, t, CH₂N, J ) 7.2 Hz), 3.4-3.55 (4H, m, CH₂N,

CH₂Ph), 4.22 (2H, dd, CH₂O), 7.21 (2H, d, H2, H6, J ) 8.4

Hz), 7.31 (2H, d, H3, H5, J ) 8.4 Hz). Anal. (C₁₁H₁₄N₂O₂‚

1.0HCl‚1.5H₂O) C, H, N.

N-[2-(4-Nitr op h en yl)eth yl]p h th a lim id e (24): method 7,

white needles from ethanol, 5.64 g (64%) (mp 202-204 °C);

1

MS m/z 297 (M + 1)⁺; H NMR δ 3.07 (2H, t, CH₂N, J ) 6.9

Hz), 3.87 (2H, t, CH₂Ph, J ) 7.0 Hz), 7.5 (2H, d, H3, H5, J )

8.5 Hz), 7.82 (4H, m, 4 × PhthAr), 8.1 (2H, d, H2, H6, J ) 8.5

Hz). Anal. (C₁₆H₁₂N₂O₄‚0.1H₂O) C, H, N.

N-[2-(4-Nitr oph en yl)eth yl]-4-ch lor obu tylam ide (32). To

a solution of (4-nitrophenyl)ethylamine hydrochloride (1.0 g,

4.93 mmol) in THF (100 mL) was added 4-chlorobutyryl

chloride (0.696 g, 4.93 mmol) followed by triethylamine (0.8

g, 4.93 mmol). The solution was stirred at room temperature

for 48 h and then evaporated under reduced pressure, water

added, and the water layer extracted with ethyl acetate. The

organic layer was dried, filtered, and evaporated under

reduced pressure to give a yellow solid which was purified by

flash chromatography eluting with CH₂Cl₂:EtOH:NH₃(150:8:

1). The resulting yellow solid was recrystallized from ethanol

to give 0.7 g (52%) of 32 as soft white crystals (mp 72-74 °C):

3-[2-(4-Nitr op h en yl)eth yl]th ia zolid in e-2,4-d ion e (25):

method 7, white crystals from ethanol, 0.5 g (75%); MS m/z

1

267 (M + 1)⁺; H NMR δ 3.0 (2H, t, CH₂N, J ) 8.4 Hz), 3.8

(2H, t, CH₂Ph, J ) 8.4 Hz), 4.2 (2H, s, CH₂S), 7.5 (2H, d, H3,

H5, J ) 8.0 Hz), 8.16 (2H, d, H2, H6, J ) 8.0 Hz).

3-(4-Am in op h en et h yl)im id a zolid in e-2,4-d ion e

(26):

method 2, cream solid (94%) (mp 257-259 °C); MS m/z 219

1

(M⁺); H NMR δ 2.44 (2H, t, CH₂N, J ) 6.9 Hz), 3.17 (2H, t,

CH₂Ph, J ) 7.0 Hz), 3.46 (2H, s, CH₂O), 6.84 (4H, m, H2, H3,

H5, H6), 7.61 (1H, s, NH). Anal. (C₁₁H₁₃N₃O₂‚0.2H₂O) C, H,

N.

1

MS m/z 271 (M + 1)⁺; H NMR δ 1.87 (2H, m, CH₂CH₂CH₂),

2.16 (2H, t, CH₂CO, J ) 7.0 Hz), 2.84 (2H, t, CH₂N, J ) 6.9

Hz), 3.34 (2H, m, CH₂Ph, blanketed by water peak), 3.54 (2H,

t, CH₂Cl, J ) 6.5 Hz), 7.48 (2H, d, H3, H5, J ) 7.0 Hz), 7.97

(1H, t, NH), 8.14 (2H, d, H2, H6, J ) 8.3 Hz). Anal.

(C₁₂H₁₅N₂O₃Cl‚0.5H₂O) C, H, N.

3-(4-Am in op h en eth yl)-5,5-d im eth ylim id a zolid in e-2,4-

d ion e (27): method 2, white needles, 2.05 g (45%) (mp 268-

1

270 °C); MS m/z 247 (M⁺); H NMR δ 0.78 (6H, s, 2 × CH₃),

2.46 (2H, t, CH₂N, J ) 7.0 Hz), 3.18 (2H, t, CH₂Ph, J ) 6.9

Hz), 6.84 (4H, m, H2, H3, H5, H6), 7.74 (1H, s, NH). Anal.

(C₁₇H₁₃N₃O₂‚1.0HCl) C, H, N.

N-[2-(4-Nitr op h en yl)eth yl]-2-p yr r olid in on e (34). The

alkyl halide 32 (1.79 g, 6.59 mmol) was added to a solution of

5 N NaOH (7.0 mL, 32.9 mmol) in THF (160 mL), and the

resulting solution was refluxed for 24 h. The solution was

cooled, concentrated, and diluted with water (50 mL). The

aqueous layer was extracted with ethyl acetate, dried, and

filtered and the solvent evaporated under reduced pressure

to give an orange residue which was purified by flash chro-

matography eluting with CH₂Cl₂:EtOH:NH₃(300:8:1) to give

342 mg (22%) of the desired lactam as a white solid: MS m/z

235 (M + 1)⁺; ¹H NMR δ 1.88 (2H, m, CH₂CH₂CH₂), 2.18 (2H,

t, CH₂CO, J ) 7.8 Hz), 2.93 (2H, t, CH₂N, J ) 7.2 Hz), 3.34

(2H, m, CH₂Ph, blanketed by water peak), 3.5 (2H, t, CH₂O, J

) 7.2 Hz), 7.54 (2H, d, H3, H5, J ) 8.5 Hz), 8.19 (2H, d, H2,

H6, J ) 8.5 Hz). Anal. (C₁₂H₁₄N₂O₃‚0.3H₂O) C, H, N.

N-[2-(4-Am in oph en yl)eth yl]-2-pyr r olidin on e (36): meth-

od 2, white solid, 294 mg (90%); MS m/z 205 (M + 1)⁺; ¹H NMR

δ 1.83 (2H, m, CH₂CH₂CH₂), 2.10 (2H, t, CH₂CO, J ) 7.9 Hz),

2.71 (2H, t, CH₂N, J ) 7.3 Hz), 3.23 (2H, t, CH₂Ph, J ) 7.1

Hz), 3.5 (2H, m, CH₂NH, blanketed by water peak), 7.18 (2H,

d, H2, H6, J ) 8.5 Hz), 7.25 (2H, d, H3, H5, J ) 8.5 Hz), 9.87

(3H, br s NH₃⁺). Anal. (C₁₂H₁₆N₂O‚1.25H₂O) C, H, N.

N-(4-Am in op h en eth yl)su ccin im id e (28): method 2, hy-

drochloride salt as white needles from ethanol, 3.52 g (87%);

MS m/z 219 (M + 1)⁺; ¹H NMR δ 2.54 (4H, s, 2 × CH₂CO),

2.71 (2H, t, CH₂N, J ) 7.7 Hz), 3.5 (2H, t, CH₂Ph, J ) 7.8

Hz), 7.1 (2H, d, H2, H6, J ) 8.3 Hz), 7.17 (2H, d, H3, H5, J )

8.3 Hz), 9.33 (3H, br s, NH₃⁺). Anal. (C₁₂H₁₄N₂O₂‚1.0HCl) C,

H, N.

N-(4-Am in oph en eth yl)ph th alim ide (29): method 2, white

needles of the hydrochloride salt from ethanol, 3.81 g (62%)

(mp dec > 270 °C); MS m/z 266 (M⁺); ¹H NMR δ 2.95 (2H, m,

CH₂N), 3.75 (2H, m, CH₂Ph), 7.11 (4H, m, 4 × PhthAr), 7.7

(4H, s, H2, H3, H5, H6), 9.32 (3H, br s, NH₃⁺). Anal.

(C₁₆H₁₄N₂O₂‚1.0HCl) C, H, N.

3-(4-Am in op h en eth yl)th ia zolid in e-2,4-d ion e (30). The

thiazolidinone 25 (5.0 g, 18.8 mmol) was hydrogenated at room

temperature and atmospheric pressure over 10% palladium

on carbon (0.5 g) in acetic acid (100 mL) for 48 h. The catalyst

was removed over Celite and the filtrate concentrated to a light

brown powder which was triturated with ethyl acetate/diethyl

ether (1:5) and isolated by filtration to give 3.73 g (67%) of

Tryptamines as 5HT_{1B/ 1D}Receptor Antagonists

J ournal of Medicinal Chemistry, 1997, Vol. 40, No. 15 2359

Eth yl 3-[2-(d im eth yla m in o)eth yl]-5-[2-(2,5-d ioxo-1-im -

id a zolid in yl)eth yl]-1H-in d ole-2-ca r boxyla te (40): method

6 (using ethanol as solvent), cream solid (40%) (mp 210-211

the acetate salt of 39 as a white lyophylate; MS m/z 373 (M +

1)⁺; t_R9.51 min; ¹H NMR (CH₃OH-d₄) δ 1.9 (3H, s, CH₃CO₂H),

2.88 (6H, s, 2 × NCH₃), 3.08 (2H, m, CH₂NMe₂), 3.22 (2H, m,

CH₂N), 3.53 (2H, m, 5-CH₂), 3.83 (2H, m, 3-CH₂), 4.0 (2H, s,

CH₂NH), 7.22 (1H, d, H6, J ) 8.0 Hz), 7.53 (1H, d, H7, J )

8.1 Hz), 7.62 (1H, s, H4). Anal. (C₁₉H₂₄N₄O₄‚1.0CH₃CO₂H‚

2.0H₂O) C, H, N.

1

°C); MS m/z 387 (M + 1)⁺; H NMR δ 1.35 (3H, t, CH₃CH₂, J

) 7.6 Hz), 2.25 (6H, s, 2 × NCH₃), 2.49 (2H, m, CH₂NMe₂,

under DMSO peak), 2.9 (2H, t, CH₂N, J ) 6.9 Hz), 3.15 (3H,

m, 5-CH₂), 3.6 (2H, t, 3-CH₂, J ) 6.8 Hz), 3.85 (2H, s, CH₂-

NH), 4.4 (2H, q, CH₂CH₃, J ) 7.4 Hz), 7.1 (1H, d, H6, J ) 8.4

Hz), 7.35 (1H, d, H7, J ) 8.5 Hz), 7.4 (1H, s, H4), 7.95 (1H, s,

NHCO), 11.4 (1H, s, NH). Anal. (C₂₀H₂₆N₄O₄‚0.25H₂O) C, H,

N.

Meth yl 3-[2-(d im eth yla m in o)eth yl]-5-[2-(4,4-d im eth yl-

2,5-d ioxo-1-im id a zolid in yl)et h yl]-1H -in d ole-2-ca r b oxy-

la te (43): method 6, 56 mg (22%); MS m/z 401 (M + 1)⁺; found

1

M⁺400.21106, C₂₁H₂₈N₄O₄requires M⁺400.4777; H NMR δ

Ben zyl 3-[2-(Dim eth yla m in o)eth yl]-5-[2-(2,5-d ioxo-1-

1.15 (6H, s, 2 × CH₃), 2.21 (6H, s, 2 × NCH₃), 2.43 (2H, m,

CH₂NMe₂), 2.91 (2H, m, CH₂N), 3.1 (2H, m, 5-CH₂), 3.57 (2H,

m, 3-CH₂), 3.85 (3H, s, OCH₃), 7.06 (1H, d, H6, J ) 7.6 Hz),

7.31 (2H, m, H7, H4), 8.11 (1H, s, NH), 11.45 (1H, s, NH).

E t h yl 3-[2-(Dim et h yla m in o)et h yl]-5-[2-(4,4-d im et h yl-

2,5-d ioxo-1-im id a zolid in yl)et h yl]-1H -in d ole-2-ca r b oxy-

la t e (44) (Met h od 6, u sin g et h a n ol a s solven t ). To the

required hydrazone intermediate (277 mg, 0.64 mmol) in

ethanol (25 mL) was added concentrated H₂SO₄(0.62 mL). The

reaction mixture was gently refluxed at 90 °C overnight. The

solution was cooled, the solvent evaporated, water added (40

mL), and the pH adjusted to 9 with potassium carbonate. The

aqueous layer was extracted with ethyl acetate, dried, and

filtered and the solvent evaporated under reduced pressure

to give an orange powder which was further purified by flash

chromatography eluting with CH₂Cl₂:EtOH:NH₃(110:8:1).

Recrystallization from ethanol gave 143 mg (54%) of 44 as a

yellow powder (mp 142-144 °C): MS m/z 415 (M + 1)⁺; found

M⁺414.2267, C₂₂H₃₀N₄O₄requires M⁺414.5046; ¹H NMR δ

1.09 (6H, s, 2 × CH₃), 1.3 (3H, t, CH₂CH₃, J ) 7.5 Hz), 2.18

(6H, s, 2 × NCH₃), 2.38 (2H, m, CH₂NMe₂), 2.87 (2H, m,

CH₂N), 3.06 (2H, m, 5-CH₂), 3.56 (2H, m, 3-CH₂), 4.31 (2H, q,

CH₂CH₃, J ) 7.5 Hz), 7.03 (1H, m, H6), 7.28 (2H, m, H7, H4),

8.11 (1H, s, NHCO), 11.4 (1H, s, NH).

im id a zolid in yl)eth yl]-1H-in d ole-2-ca r boxyla te (42).

A

mixture of 40 (962 mg, 2.49 mmol) and titanium tetraisopro-

poxide (0.24 mL, 0.87 mmol) in benzyl alcohol (20 mL) was

heated to 100 °C for 24 h. The solution was concentrated in

vacuo to give a brown gum which was purified by flash

chromatography eluting with CH₂Cl₂:EtOH:NH₃(200:8:1) to

give 1.1 g (98%) of 42 as a yellow solid (mp 163-170 °C,

1

softens): MS m/z 449 (M + 1)⁺; H NMR δ 2.15 (6H, s, 2 ×

NCH₃), 2.45 (2H, m, CH₂NMe₂), 2.92 (2H, m, CH₂N), 3.19 (2H,

m, 5-CH₂), 3.62 (2H, m, 3-CH₂), 3.88 (2H, s, CH₂CO), 5.38 (2H,

s, CH₂O), 7.11 (1H, d, H6, J ) 8.0 Hz), 7.4 (7H, m, H7, H4, 5

× ArH), 7.95 (1H, s, NHCO), 11.4 (1H, s, NH). Anal.

(C₂₅H₂₈N₄O₄‚0.75H₂O) C, H, N.

3-[2-(Dim eth yla m in o)eth yl]-5-[2-(2,5-d ioxo-1-im id a zo-

lid in yl)eth yl]-1H-in d ole-2-ca r boxylic Acid (37). A mix-

ture of 42 (137 mg, 0.3 mmol) and 10% palladium on carbon

(30 mg) in ethyl acetate (10 mL) and ethanol (10 mL) was

hydrogenated overnight at room temperature and atmospheric

pressure. The catalyst was filtered through Celite, concen-

trated, and triturated with dichloromethane to give 86 mg

(79%) of 37 as a white powder: MS m/z 359 (M + 1)⁺; ¹H NMR

δ 2.81 (6H, s, 2 × NCH₃), 2.95 (2H, m, CH₂NMe₂), 3.41 (4H,

m, CH₂N, 5-CH₂), 3.75 (2H, m, 3-CH₂), 3.83 (2H, s, CH₂NH),

7.1 (1H, d, H6, J ) 8.3 Hz), 7.3 (1H, d, H7, J ) 8.1 Hz), 7.45

(1H, s, H4); t_R8.06 min.

Isop r op yl 3-[2-(d im eth yla m in o)eth yl]-5-[2-(2,5-d ioxo-

1-im id a zolid in yl)et h yl]-1H -in d ole-2-ca r b oxyla t e (41):

method 6 (using 2-propanol as solvent), white powder (40%)

(mp 202-203 °C); MS m/z 401 (M + 1)⁺; found M⁺400.2145,

C₂₁H₂₈N₄O₄requires M⁺401.4777; ¹H NMR δ 1.34 (6H, d, CH-

(CH₃)₂, J ) 6.3 Hz), 2.25 (6H, s, 2 × NCH₃), 2.44 (2H, m, CH₂-

NMe₂), 2.9 (2H, m, CH₂N), 3.18 (2H, m, 5-CH₂), 3.59 (2H, m,

3-CH₂), 5.2 (1H, m, CH, J ) 6.3 Hz), 7.1 (1H, d, H6, J ) 8.1

Hz), 7.3 (1H, s, H4), 7.4 (1H, m, H6), 7.94 (1H, s, NHCO), 11.35

(1H, s, NH). Anal. (C₂₁H₃₂N₄O₄‚0.3H₂O) C, H, N.

Isopr opyl 3-[2-(dim eth ylam in o)eth yl]-5-[2-(4,4-dim eth yl-

2,5-d ioxo-1-im id a zolid in yl)et h yl]-1H -in d ole-2-ca r b oxy-

la te (45): method 6 (using isopropyl alcohol as solvent), 25

mg (13%); MS m/z 429 (M + 1)⁺; found M⁺428.24236,

C₂₃H₃₂N₄O₄requires M⁺428.5315; ¹H NMR δ 1.13 (6H, s, 2 ×

NCH₃), 1.36 (6H, d, CH(CH₃)₂, J ) 6.2 Hz), 2.92 (2H, m, CH₂-

NMe₂), 3.18 (2H, m, CH₂N), 3.41 (2H, m, 5-CH₂), 3.62 (2H, m,

3-CH₂), 5.18 (1H, m, CH, J ) 6.2 Hz), 7.1 (1H, m, H6), 7.35

(1H, d, H7, J ) 8.4 Hz), 7.54 (1H, s, H4), 8.18 (1H, s, NH),

10.2 (1H, br s, NH⁺CH₃), 11.61 (1H, s, NH). Anal. Calcd (C₂₃

-

H₃₂N₄O₄‚1.0HCl‚3.0H₂O): C, 53.2; H, 7.5; N, 10.8. Found: C,

52.87; H, 6.81; N, 10.47.

Cycloh exyl 3-[2-(d im et h yla m in o)et h yl]-5-[2-(4,4-d i-

m et h yl-2,5-d ioxo-1-im id a zolid in yl)et h yl]-1H -in d ole-2-

ca r boxyla te (46): method 6 (using cyclohexanol as solvent),

light brown powder purified by flash chromatography eluting

with CH₂Cl₂:EtOH:NH₃(250:8:1), 60 mg (27%); MS m/z 469

(M + 1)⁺; found M⁺468.2749, C₂₆H₃₆N₄O₄requires M⁺

Meth od 8: Gen er a l P r oced u r e for th e F or m a tion of

Meth yl 5-(Dim eth yla m in o)-2-[[4-[2-(2,5-d ioxo-1-im id a zo-

lidin yl)eth yl]ph en yl]h ydr azin -2-yliden e]pen tan oate (38).

To a stirring solution of 26 (1.0 g, 3.91 mmol) in ethanol (2.0

mL) and water (6.5 mL) was added concentrated HCl (0.78

mL, 7.42 mmol). The solution was cooled to 0 °C, and a

solution of sodium nitrite (0.54 g, 7.82 mmol) in water (2.5

mL) was added. The solution was stirred for 10 min; then the

excess sodium nitrite was destroyed with urea (0.29 g, 4.8

mmol). Meanwhile the diketone 11 (0.79 g, 3.91 mmol) was

stirred with sodium acetate trihydrate (2.77 g, 20 mmol) and

ice (3.5 g). The diazonium salt was added quickly to the

diketone solution, and the reaction mixture was stirred for 1.5

h up to room temperature. Concentrated HCl (100 µL) was

added, and the solution stirred a further 20 min. The solution

was adjusted to pH 9 with 10% NaOH and stirred for a further

10 min. The solution was extracted with ethyl acetate, dried,

filtered, and evaporated to give an orange gum. Purification

was achieved with flash chromatography eluting with CH₂-

Cl₂:EtOH:NH₃(100:8:1). Recrystallization from ethanol af-

forded 0.77 g (51%) of 38 as orange needles (mp 158-160 °C):

MS m/z 389 (M⁺); ¹H NMR δ 1.75 (2H, m, CH₂), 2.12 (6H, s, 2

× NCH₃), 2.28 (2H, m, CH₂), 2.6 (2H, m, CH₂), 2.72 (2H, m,

CH₂), 3.55 (2H, m, CH₂), 3.59 (3H, s, OCH₃), 3.85 (2H, s, CH₂-

NH), 7.12 (4H, m, H2, H3, H5, H6), 7.97 (1H, s, NH), 10.1

(1H, s, NH). Anal. (C₁₉H₂₇N₅O₄‚0.65H₂O) C, H, N.

1

468.5962; H NMR δ 1.13 (6H, s, 2 × CH₃), 1.2-1.9 (10H, m,

cyclohexyl methylenes), 2.21 (6H, s, 2 × NCH₃), 2.4 (2H, m,

CH₂NMe₂), 2.9 (2H, m, CH₂N), 3.2 (2H, m, 5-CH₂), 3.6 (2H,

m, 3-CH₂), 4.9 (1H, m, CH), 7.06 (1H, d, H6, J ) 8.3 Hz), 7.32

(2H, m, H7, H4), 8.12 (1H, s, NHCO), 11.36 (1H, s, NH). Anal.

Calcd (C₂₆H₃₆N₄O₄‚1.1H₂O): C, 63.96; H, 7.83; N, 11.4.

Found: C, 63.95, H, 7.49; N, 10.9.

Eth yl 3-[2-(d im eth yla m in o)eth yl]-5-[2-(2,5-d ioxo-1-p yr -

r olid in yl)eth yl]-1H-in d ole-2-ca r boxyla te (52): method 6

(using ethanol as solvent), light brown powder (8%); MS m/z

386 (M + 1)⁺; found M⁺385.1974, C₂₁H₂₇N₃O₄requires M⁺

385.4631; ¹H NMR δ 1.4 (3H, t, CH₂CH₃, J ) 7.2 Hz), 2.59

(10H, br s, 2 × NCH₃, 2 × CH₂CO), 2.84-2.96 (4H, m, CH₂-

NMe₂, CH₂N), 3.4 (2H, m, 5-CH₂), 3.7 (2H, m, 3-CH₂), 4.36

(2H, q, CH₂CH₃, J ) 7.2 Hz), 7.15 (2H, m, H6, H7), 7.62 (1H,

s, H4), 8.63 (1H, s, NH).

Eth yl 5-(d im eth yla m in o)-2-[[4-[2-(N-p h th a lim id o)eth -

yl]p h en yl]h yd r a zin -2-ylid en e]p en ta n oa te (54): method 8,

light brown powder purified by flash chromatography eluting

with CH₂Cl₂:EtOH:NH₃(180:8:1), 220 mg (20%); MS m/z 451

(M + 1)⁺; ¹H NMR δ 2.1 (3H, t, CH₂CH₃, J ) 6.9 Hz), 2.49

(2H, m, CH₂CH₂CH₂), 2.9 (6H, s, 2 × NCH₃), 3.39 (2H, m, CH₂-

NMe₂), 3.71 (2H, m, CH₂Cd), 4.29 (2H, m, CH₂N), 4.6 (2H, m,

Met h yl 3-[2-(d im et h yla m in o)et h yl]-5-[2-(2,5-d ioxo-1-

im idazolidin yl)eth yl]-1H-in dole-2-car boxylate (39): meth-

od 6, purification by preparative HPLC gave 70 mg (8%) of

2360 J ournal of Medicinal Chemistry, 1997, Vol. 40, No. 15

Moloney et al.

CH₂Ph), 5.0 (2H, q, CH₂CH₃, J ) 6.9 Hz), 7.9 (4H, m, H2, H3,

H5, H6), 8.6 (4H, s, 4 × PhthArH), 11.4 (1H, s, NH).

Meth yl 3-[2-(d im eth yla m in o)eth yl]-5-[2-(N-p h th a lim -

id o)eth yl]-1H-in d ole-2-ca r boxyla te (55): method 6, white

crystals from ethanol, 50 mg (53%); MS m/z 420 (M + 1)⁺; ¹H

NMR δ 2.07 (6H, s, 2 × NCH₃), 2.21 (2H, m, CH₂NMe₂), 2.97

(4H, m, CH₂N, 5-CH₂) 3.79 (5H, m, 3-CH₂, OCH₃), 7.07 (1H,

d, H6, J ) 7.9 Hz), 7.24 (2H, m, H7, H4), 7.57 (4H, s, 4 ×

PhthArH), 11.4 (1H, s, NH); found M⁺419.1851, C₂₄H₂₅N₃O₄

requires M⁺419.4802.

washed with butanol and diethyl ether, and dried in vacuo to

give 764 mg (38%) of the product as a brown powder: MS m/z

376 (M + 1)⁺; m/z 375 (M⁺); ¹H NMR δ 1.4 (3H, t, CH₂CH₃, J

) 7.6 Hz), 2.88 (2H, m, CH₂NH₂), 3.0 (2H, m, CH₂N), 3.36 (2H,

m, 5-CH₂, blanketed by water peak), 3.77 (2H, m, 3-CH₂), 4.21

(2H, s, CH₂S), 4.38 (2H, q, CH₂CH₃, J ) 7.5 Hz), 7.12 (1H, d,

H6, J ) 7.9 Hz), 7.38 (1H, d, H7, J ) 8.0 Hz), 7.5 (1H, s, H4),

8.05 (2H, s, NH₂), 11.7 (1H, s, NH). Anal. (C₁₈H₂₁N₃O₄S‚

1.0HCl) C, H, N.

E t h yl 3-[2-(Dim et h yla m in o)et h yl]-5-[2-(2,4-d ioxo-3-

th ia zolid in yl)eth yl]-1H-in d ole-2-ca r boxyla te (57). Form-

aldehyde (0.1 mL, 1.27 mmol) in methanol (1.0 mL) was added

dropwise to a solution of the amine hydrochloride 59 (238 mg,

0.58 mmol), sodium cyanoborohydride (44 mg, 0.69 mmol), and

glacial acetic acid (166 µL, 2.89 mmol) in methanol (10 mL).

The solution was stirred for 3 h and concentrated and the

residue purified by flash chromatography eluting with CH₂-

Cl₂:EtOH:NH₃(100:8:1) to give 143 mg (61%) of the product

as a brown foam: MS m/z 404 (M + 1)⁺; ¹H NMR δ 1.38 (3H,

t, CH₃CH₂, J ) 6.0 Hz), 2.25 (6H, s, 2 × NCH₃), 2.45 (2H, m,

CH₂NMe₂), 2.9 (2H, m, CH₂N), 3.18 (2H, m, 5-CH₂), 3.7 (2H,

m, 3-CH₂), 4.13 (2H, s, CH₂S), 4.32 (2H, q, CH₂CH₃, J ) 6.2

Hz), 7.1 (1H, d, H6, J ) 8.4 Hz), 7.3 (1H, d, H7, J ) 8.4 Hz),

7.4 (1H, s, H4), 11.4 (1H, s, NH). Anal. (C₂₀H₂₅N₃O₄S‚0.5H₂O)

C, H, N.

Meth od 9: Gen er a l P r oced u r e for th e P r ep a r a tion of

th e 5-Meth ylen e-Lin k ed Hyd a n toin Der iva tives 60 a n d

61. 4-[(2,5-Dioxo-1-im id a zolid in yl)m eth yl]n itr oben zen e

(60). To a solution of hydantoin (9.25 g, 0.093 mol) in DMF

(100 mL) was added potassium carbonate (12.8 g, 0.093 mol).

The solution was stirred under nitrogen for 30 min; then

p-nitrobenzyl bromide (22.0 g, 0.102 mol) was gradually added.

The solution was stirred overnight at room temperature under

nitrogen. The reaction mixture was poured onto water (300

mL), extracted with ethyl acetate, dried, and evaporated to

give a white solid. Recrystallization from ethyl acetate gave

8.91 g (84%) of 60 as white crystals (mp 215-217 °C): MS

m/z 205 (M⁺); ¹H NMR δ 4.0 (2H, s, CH₂NH), 4.6 (2H, s, CH₂-

Ph), 7.53 (2H, d, H3, H5, J ) 9.0 Hz), 8.2 (3H, m, H2, H6,

NH). Anal. (C₁₀H₉N₃O₄) C, H, N.

E t h yl 3-[2-(d im et h yla m in o)et h yl]-5-[2-(N-p h t h a lim -

id o)eth yl]-1H-in d ole-2-ca r boxyla te (56): method 6 (using

ethanol as solvent), white powder from ethyl acetate, 70 mg

(67%); MS m/z 434 (M + 1)⁺; found M⁺433.1999, C₂₅H₂₇N₃O₄

1

requires M⁺433.5071; H NMR δ 1.28 (3H, t, CH₂CH₃, J )

7.2 Hz), 2.07 (6H, s, 2 × NCH₃), 2.19 (2H, m, CH₂NMe₂), 2.94

(4H, m, CH₂N, 5-CH₂), 3.79 (2H, m, 3-CH₂), 4.28 (2H, q, CH₂-

CH₃, J ) 7.1 Hz), 7.07 (1H, m, H6), 7.24 (2H, m, H7, H4), 7.76

(4H, s, 4 × PhthArH), 11.34 (1H, s, NH). Anal. Calcd (C₂₅

-

H₂₇N₃O₄‚0.5H₂O): C, 67.8; H, 6.33; N, 9.4. Found: C, 67.8;

H, 7.17; N, 8.7.

Meth yl 5-(d im eth yla m in o)-2-[[4-[2-(2-oxo-1,3-oxa zili-

din -4-yl)eth yl]ph en yl]h ydr azin -2-yliden e]pen tan oate (50):

method 8, purified by flash chromatography eluting with CH₂-

Cl₂:EtOH:NH₃(30:8:1) to give 253 mg (31%) of the hydrazone

1

as an orange powder; MS m/z 377 (M + 1)⁺; H NMR δ 1.66

(2H, m, CH₂CH₂CH₂), 2.18 (6H, s, 2 × NCH₃), 2.6 (2H, m, CH₂-

NMe₂), 2.75 (2H, m, CH₂Cd), 3.3-3.36 (4H, m, OCH₂CH₂N,

PhCH₂CH₂N), 3.5 (2H, m, CH₂Ph), 3.75 (3H, s, OCH₃), 4.2 (2H,

m, CH₂O), 7.17 (4H, m, H2, H3, H5, H6), 10.62 (1H, s, NH).

Anal. Calcd (C₁₉H₂₈N₄O₄‚0.1CH₃CH₂OH): C, 60.6; H, 7.57; N,

14.69. Found: C, 61.14; H, 7.57; N, 14.17.

Meth yl 3-[2-(d im eth yla m in o)eth yl]-5-[2-(2-oxo-1,3-oxa -

zolid in -3-yl)eth yl]-1H-in d ole-2-ca r boxyla te (51): method

6, purification by flash chromatography eluting with CH₂Cl₂:

EtOH:NH₃(90:8:1) gave 51 as an orange powder; conversion

to the hydrochloride salt with 0.2 N methanolic HCl gave 130

1

mg (54%) of 51 as white crystals; MS m/z 360 (M + 1)⁺; H

NMR δ 2.2 (6H, s, 2 × NCH₃), 2.92 (2H, m, CH₂NMe₂), 2.96

(2H, m, CH₂N), 3.15 (2H, m, 5-CH₂), 3.35-3.55 (2H, m, 3-CH₂),

3.86 (3H, s, OCH₃), 4.17 (2H, m, CH₂O), 7.15 (1H, d, H6, J )

8.1 Hz), 7.35 (1H, d, H7, J ) 8.0 Hz), 7.5 (1H, s, H4), 11.45

(1H, s, NH). Anal. Calcd (C₁₉H₂₅N₃O₄‚1.0HCl‚1.3H₂O): C,

54.42; H, 6.8; N, 10.02. Found: C, 54.02; H, 6.24; N, 9.69.

Eth yl 3-[2-(d im eth yla m in o)eth yl]-5-[2-(2-oxo-1-p yr r o-

lid in yl)eth yl]-1H-in d ole-2-ca r boxyla te (53): method 6 (us-

ing ethanol as solvent), purification by flash chromatography

eluting with CH₂Cl₂:EtOH:NH₃(80:8:1) gave 53 as a glassy

orange solid; conversion to the hydrochloride salt gave 7.0 mg

(34%) of a light yellow powder; MS m/z 372 (M + 1)⁺; found

4-[(4,4-Dim eth yl-2,5-d ioxo-1-im id a zolid in yl)m eth yl]n i-

tr oben zen e (61): method 9, 7.53 g (68%) (mp 233-235 °C);

1

MS m/z 263 (M⁺); H NMR δ 1.3 (6H, s, 2 × CH₃), 4.6 (2H, s,

CH₂Ph), 7.47 (2H, d, H3, H5, J ) 8.7 Hz), 8.2 (2H, d, H2, H6,

J ) 8.7 Hz), 8.4 (1H, s, NH). Anal. (C₁₂H₁₃N₃O₄) C, H, N.

4-[(2,5-Dioxoim id a zolid in -3-yl)m et h yl]a n ilin e

(62):

method 2, 5.0 g (97%) (mp 261-263 °C); MS m/z 205 (M⁺); ¹H

NMR δ 4.0 (2H, s, CH₂NH), 4.5 (2H, s, CH₂Ph), 7.25 (2H, d,

H2, H6, J ) 8.5 Hz), 7.3 (2H, d, H3, H5, J ) 8.5 Hz), 8.1 (1H,

s, NH), 9.0 (3H, br s, NH₃⁺). Anal. (C₁₀H₁₁N₃O₂) C, H, N.

4-[(4,4-Dim et h yl-2,5-d ioxoim id a zolid in -3-yl)m et h yl]-

a n ilin e (63): method 2, 7.0 g (87%) (mp dec > 200 °C, softens

M

⁺371.2207, C₂₁H₂₉N₃O₃‚HCl requires M⁺371.4795; ¹H NMR

δ 1.41 (3H, t, CH₂CH₃, J ) 6.6 Hz), 1.93 (2H, m, CH₂CH₂-

CH₂), 2.19 (2H, m, CH₂CO), 2.54 (6H, s, 2 × NCH₃), 2.88 (4H,

m, 2 × CH₂N), 3.35-3.5 (4H, m, 5-CH₂, 3-CH₂, blanketed by

water peak), 4.4 (2H, q, CH₂CH₃, J ) 7.1 Hz), 7.21 (1H, d,

H6, J ) 8.2 Hz), 7.41 (1H, d, H7, J ) 8.3 Hz), 7.6 (1H, s, H4),

11.7 (1H, s, NH).

1

at 85-90 °C); MS m/z 233 (M⁺); H NMR δ 1.28 (6H, s, 2 ×

CH₃), 4.5 (2H, s, CH₂Ph), 7.21 (4H, m, H2, H3, H5, H6), 8.4

(1H, s, NH). Anal. (C₁₂H₁₅N₃O₂‚HCl) C, H, N.

Meth yl 3-[2-(d im eth yla m in o)eth yl]-5-[(2,5-d ioxo-1-im -

idazolidin yl)m eth yl]-1H-in dole-2-car boxylate (64): method

6, 20 mg (12%); MS m/z 359 (M + 1)⁺; found M⁺358.1614,

C₁₈H₂₂N₄O₄requires M⁺358.1641; ¹H NMR δ 2.07 (6H, s, 2 ×

NCH₃), 2.45 (2H, m, CH₂NMe₂), 3.13 (2H, m, CH₂N), 3.86 (3H,

s, OCH₃), 3.93 (2H, s, 3-CH₂), 4.6 (2H, s, CH₂NH), 7.19 (1H,

d, H6, J ) 8.4 Hz), 7.33 (1H, d, H7, J ) 8.4 Hz), 7.6 (1H, s,

H4), 8.1 (1H, s, NH), 11.5 (1H, s, NH).

Eth yl 3-[2-(d im eth yla m in o)eth yl]-5-[(2,5-d ioxo-1-im id -

a zolid in yl)m eth yl]-1H-in d ole-2-ca r boxyla te (65): method

6 (using ethanol as solvent), 37 mg (19%); MS m/z 373 (M +

1)⁺; ¹H NMR δ 1.34 (3H, t, CH₂CH₃, J ) 7.5 Hz), 2.13 (2H, m,

CH₂NMe₂), 2.25 (6H, s, 2 × NCH₃), 2.5 (2H, m, CH₂N), 3.9

(2H, s, 3-CH₂), 4.37 (2H, q, CH₂CH₃, J ) 7.5 Hz), 4.6 (2H, s,

CH₂NH), 7.2 (1H, d, H6, J ) 8.5 Hz), 7.38 (1H, d, H7, J ) 8.5

Hz), 7.6 (1H, s, H4), 8.1 (1H, s, NH), 11.6 (1H, s, NH). Anal.

(C₁₉H₂₄N₄O₄‚0.8H₂O) C, H, N.

Eth yl 5-Ch lor o-2-[[4-[2-(2,4-d ioxo-3-th ia zolid in yl)eth -

yl]p h en yl]h yd r a zin -2-ylid en e]p en t a n oa t e (58). Potas-

sium hydroxide (0.5 g, 8.93 mmol) in ethanol (6 mL) was added

to a solution of diethyl chloropropylmalonate²⁹(1.86 mL, 8.54

mmol) in ethanol (6 mL), and the solution was stirred at room

temperature for 3 h under nitrogen. The acetate salt of 30

(1.94 g, 6.57 mmol) was dissolved in water (15 mL) and

concentrated HCl (1.97 mL, 19.7 mmol). Sodium nitrite (906

mg, 13.1 mmol) in water (4 mL) was added dropwise at 0 °C,

and the solution was stirred for 24 h up to room temperature.

The reaction mixture was diluted with water, extracted with

dichloromethane, washed with 2 N NaOH and then water, and

dried. The organic layer was concentrated to give ∼2.0 g of

58 as a red oil which was used without further purification.

Eth yl 3-(2-Am in oeth yl)-5-[2-(2,4-d ioxo-3-th ia zolid in yl)-

eth yl]-1H-in d ole-2-ca r boxyla te (59). The crude hydrazone

58 (2.0 g, 4.86 mmol) was heated in butanol (25 mL) and 2

drops of water for 18 h at reflux. The solution was allowed to

cool to room temperature and the product isolated by filtration,

Met h yl 3-[2-(d im et h yla m in o)et h yl]-5-[(4,4-d im et h yl-

2,5-d ioxo-1-im id a zolid in yl)m eth yl]-1H-in d ole-2-ca r boxy-

la te (66): method 6, 115 mg (44%); MS m/z 387 (M + 1)⁺; ¹H

NMR δ 1.28 (6H, s, 2 × CH₃), 2.19 (6H, s, 2 × NCH₃), 2.4 (2H,

Tryptamines as 5HT_{1B/ 1D}Receptor Antagonists

J ournal of Medicinal Chemistry, 1997, Vol. 40, No. 15 2361

m, CH₂NMe₂), 3.1 (2H, m, CH₂N), 3.8 (3H, s, OCH₃), 4.6 (2H,

s, 3-CH₂), 7.16 (1H, d, H6, J ) 8.4 Hz), 7.34 (1H, d, H7, J )

8.4 Hz), 7.5 (1H, s, H4), 8.4 (1H, s, NH), 11.6 (1H, s, NH). Anal.

(C₂₀H₂₆N₄O₄‚0.5H₂O) C, H, N.

Eth yl 3-[2-(d im eth yla m in o)eth yl]-5-[(4,4-d im eth yl-2,5-

d ioxo-1-im id a zolid in yl)m e t h yl]-1H -in d ole -2-ca r b ox-

yla te (67): method 6 (using ethanol as solvent), 61 mg (23%)

(mp 192-194 °C); MS m/z 401 (M + 1)⁺; ¹H NMR δ 1.28 (6H,

s, 2 × CH₃), 1.3 (3H, t, CH₂CH₃, J ) 6.6 Hz), 2.2 (6H, s, 2 ×

NCH₃), 2.48 (2H, m, CH₂NMe₂), 3.2 (2H, m, CH₂N), 4.32 (2H,

q, CH₂CH₃, J ) 6.8 Hz), 4.6 (2H, s, 3-CH₂), 7.2 (1H, d, H6, J

) 8.4 Hz), 7.35 (1H, d, H7, J ) 8.5 Hz), 7.5 (1H, s, H4), 8.4

(1H, s, NH), 11.5 (1H, s, NH). Anal. (C₂₁H₂₈N₄O₄‚0.2H₂O) C,

H, N.

Isop r op yl 3-[2-(d im eth yla m in o)eth yl]-5-[(4,4-d im eth yl-

2,5-d ioxo-1-im id a zolid in yl)m eth yl]-1H-in d ole-2-ca r boxy-

la te (68): method 6 (using 2-propanol as solvent), 14 mg

(24%); MS m/z 415 (M + 1)⁺; found M⁺414.2250, C₂₂H₃₀N₄O₄

requires M⁺414.2267; ¹H NMR (CH₃OH-d₄) δ 1.46 (12H, m, 2

× CH₃, CH(CH₃)₂), 2.46 (6H, s, 2 × NCH₃), 2.7 (2H, m, CH₂-

NMe₂), 3.35 (2H, m, CH₂N), 4.7 (2H, m, 3-CH₂), 5.3 (1H, m,

CH(CH₃)₂), 7.31 (1H, d, H6, J ) 8.2 Hz), 7.42 (1H, d, H7, J )

8.1 Hz), 7.7 (1H, s, H4).

Eth yl 2-Acetyl-3-(4-p yr id in yl)p r op a n oa te (70). Sodium

(9.2 g, 0.4 mol) was dissolved in dry ethanol (130 mL); then

ethyl acetoacetate (26.0 g, 0.2 mol) in dry ethanol (130 mL)

was added dropwise. The solution was stirred for 30 min; then

4-picolylchloride hydrochloride (32.8 g, 0.2 mol) in dry ethanol

(250 mL) was added dropwise over 30 min. The resulting

solution was stirred at room temperature overnight. The

solvent was removed under reduced pressure, and the oily

residue was taken up in water (100 mL), extracted with ethyl

acetate, dried, filtered, and evaporated to give a yellow oil

which was purified by flash chromatrography eluting with

hexane:ethyl acetate (8:2) to give 14.1 g (32%) of the diketone

as a light yellow oil: MS m/z 222 (M + 1)⁺; ¹H NMR δ 1.1

(3H, t, CH₃, J ) 7.2 Hz), 2.2 (3H, s, CH₃CO), 3.05 (2H, m,

CH₂CH), 4.1 (3H, m, CH₂CH₃, CHCH₂), 7.2 (2H, d, H2, H6, J

Eth yl 3-(4-p yr id in yl)-2-[[4-[2-(2,5-d ioxo-1-im id a zolid in -

yl)eth yl]ph en yl]h ydr azin -2-yliden e]pr opan oate (74): meth-

od 8, purification by flash chromatography gave 950 mg (58%)

of the hydrazone; recrystallization from ethanol gave the

hydrazone as yellow needles (mp 192-193 °C); MS m/z 410

(M + 1)⁺; ¹H NMR δ 1.2 (3H, t, CH₂CH₃, J ) 6.9 Hz), 2.75

(2H, m, CH₂N), 3.52 (2H, m, CH₂Ph), 3.83 (2H, s, CH₂Pyr),

4.0 (2H, s, CH₂NH), 4.16 (2H, q, CH₂CH₃, J ) 7.1 Hz), 7.15

(6H, m, 6 × ArH), 7.8 (1H, s, NHPh), 8.45 (2H, d, 2 × CHN),

10.3 (1H, s, NH). Anal. (C₂₁H₂₃N₅O₄‚0.12H₂O) C, H, N.

Eth yl 3-(4-p yr id in yl)-5-[2-(2,5-d ioxo-1-im id a zolid in yl)-

eth yl]-1H-in d ole-2-ca r boxyla te (76): method 6 (using etha-

nol as solvent), white crystals purified by flash chromatogra-

phy eluting with CH₂Cl₂:EtOH:NH₃, 226 mg (94%) (mp 243-

245 °C); MS m/z 393 (M + 1)⁺; ¹H NMR δ 1.21 (3H, t, CH₂CH₃,

J ) 6.8 Hz), 2.88 (2H, m, CH₂N), 3.57 (2H, m, 5-CH₂), 3.82

(2H, s, CH₂NH), 4.26 (2H, q, CH₂CH₃, J ) 6.6 Hz), 7.2 (1H, d,

H6, J ) 8.0 Hz), 7.3 (1H, s, H4), 7.5 (3H, m, H7, H3′, H5′),

7.96 (1H, s, NH), 8.64 (2H, d, 2 × CHN, J ) 6.3 Hz), 12.1 (1H,

s, NH). Anal. (C₂₁H₂₀N₄O₄‚0.7H₂O) C, H, N.

Eth yl 3-[4-(N-m eth yliod o)p yr id in yl]-5-[2-(2,5-d ioxo-1-

im idazolidin yl)eth yl]-1H-in dole-2-car boxylate (77): meth-

od 10 (using THF instead of ether), yellow crystals from

ethanol, 88 mg (59%) (mp 225-226 °C); MS m/z 407 (M + 1)⁺;

¹H NMR δ 1.3 (3H, t, CH₂CH₃, J ) 6.7 Hz), 2.9 (2H, m, CH₂N),

3.58 (2H, m, 5-CH₂), 3.82 (2H, s, CH₂NH), 4.3 (2H, q, CH₂-

CH₃, J ) 6.8 Hz), 4.36 (3H, s, NCH₃), 7.25 (1H, d, H6, J ) 8.4

Hz), 7.48 (1H, s, H4), 7.55 (1H, d, H7, J ) 8.3 Hz), 7.94 (1H,

s, NH), 8.27 (2H, d, H3′, H5′, J ) 6.4 Hz), 8.93 (2H, d, H2′,

H6′, J ) 6.6 Hz). Anal. (C₂₂H₂₃N₄O₄I‚1.0H₂O) C, H, N.

Meth od 11: Gen er a l P r oced u r e for Red u ction of a n

N-Meth ylp yr id in e Rin g to a n N-Meth yltetr a h yd r op yr i-

d in e Der iva tive. Eth yl 3-(N-Meth yltetr a h yd r op yr id in -

4-yl)-5-[2-(2,5-d ioxo-1-im id a zolid in yl)eth yl]-1H-in d ole-2-

ca r boxyla te (78). The indole 77 (42 mg 0.078 mmol) was

dissolved in methanol (5 mL) and cooled to ∼5 °C. Sodium

borohydride (12.0 mg, 0.32 mmol) was gradually added, and

the solution was stirred for 30 min. The reaction mixture was

diluted with water, extracted with ethyl acetate, dried, and

evaporated under reduced pressure to give 32 mg (100%) of

78 as a yellow powder (mp 94 °C): MS m/z 410 (M⁺); ¹H NMR

δ 1.35 (3H, t, CH₂CH₃, J ) 6.9 Hz), 2.31 (3H, s, NCH₃), 2.4-

2.6 (4H, m, 2 × CH₂), 2.85 (2H, m, CH₂N), 3.05 (2H, m, CH₂),

3.52 (2H, m, 5-CH₂), 3.82 (2H, s, CH₂NH), 4.27 (2H, q, CH₂-

CH₃, J ) 7.1 Hz), 5.61 (1H, m, CHd), 7.07 (1H, d, H6, J ) 8.5

Hz), 7.28 (1H, s, H4), 7.32 (1H, d, H7, J ) 8.6 Hz), 7.95 (1H,

s, NH), 11.57 (1H, s, NH). Anal. (C₂₂H₂₆N₄O₄‚1.0HCl‚0.5H₂O)

C, H, N.

) 6.6 Hz), 8.45 (2H, d, H3, H5, J ) 6.5 Hz). Anal. (C₁₂H₁₅

NO₃‚0.65H₂O) C, H, N.

-

Meth od 10: Gen er a l P r oced u r e for Meth yla tion of th e

P yr id in e Nitr ogen Usin g Meth yl Iod id e. Eth yl 2-Acetyl-

3-[N-(m eth yliod o)p yr id in -4-yl]p r op a n oa te (71). A solu-

tion of the diketone 70 (3.0 g, 13.5 mmol) and methyl iodide

(2.3 g, 16.2 mmol) in dry diethyl ether (80 mL) was stirred at

room temperature under nitrogen for 18 h. The solvent was

decanted off to leave an orange precipitate which was washed

with ether and dried under vacuum to give 2.5 g (51%) of 71

as an orange solid: MS m/z 236 (M + 1)⁺; found M⁺235.1239,

C₁₃H₁₇NO₃requires M⁺235.2828; ¹H NMR δ 1.18 (3H, t,

CH₂CH₃, J ) 6.8 Hz), 2.27 (3H, s, CH₃CO), 3.35 (2H, m,

CHCH₂), 4.1 (2H, q, CH₂CH₃, J ) 6.8 Hz), 4.3 (3H, s, NCH₃),

4.4 (1H, m, CHCH₂), 8.0 (2H, d, H2, H6, J ) 8.3 Hz), 8.88

(2H, d, H3, H5, J ) 8.4 Hz). Anal. (C₁₃H₁₈NO₃I‚1.0H₂O) C,

H, N.

Eth yl 3-(N-Meth ylp ip er id in -4-yl)-5-[2-(2,5-d ioxo-1-im -

id a zolid in yl)eth yl]-1H-in d ole-2-ca r boxyla te (79). A stir-

ring suspension of the tetrahydropyridine derivative 78 (25

mg, 61.0 mmol) and 10% palladium on carbon (10 mg) in

methanol (10 mL) was hydrogenated overnight at room tem-

perature and atmospheric pressure. The suspension was

filtered through Celite and the solvent evaporated under

reduced pressure to give a yellow residue which was purified

by preparative HPLC to give 6.0 mg (21%) of 79 as the acetate

salt: MS m/z 413 (M + 1)⁺; found M⁺412.2071, C₂₂H₂₈N₄O₄‚

1.0CH₃CO₂H requires M⁺412.4887; ¹H NMR δ 1.35 (3H, t,

CH₂CH₃, J ) 6.9 Hz), 1.61 (2H, m, CH₂), 1.95 (2H, m, CH₂),

2.22 (3H, s, NCH₃), 2.85 (6H, m, 2 × CH₂, CH₂N), 3.6 (3H, m,

5-CH₂, CH), 3.95 (2H, s, CH₂NH), 4.3 (2H, q, CH₂CH₃, J ) 7.0

Hz), 7.05 (1H, dd, H6, J ) 8.1 Hz), 7.37 (1H, d, H7, J ) 8.3

Hz), 7.5 (1H, s, H4), 7.95 (1H, s, NH), 11.35 (1H, s, NH); t_R11

min.

Eth yl 2-Acetyl-3-(N-m eth ylp ip er id in -4-yl)p r op a n oa te

(69). A mixture of 71 (2.16 g, 5.9 mmol) in ethanol (50 mL)

in the presence of platinum oxide (135 mg) was hydrogenated

at room temperature and 50 atm overnight. The catalyst was

filtered through Celite and the solvent removed under vacuum

to give 2.1 g (95%) of a yellow gum which was dried and stored

1

under vacuum: MS m/z 242 (M + 1)⁺; H NMR δ 1.2 (3H, t,

CH₂CH₃, J ) 7.3 Hz), 1.3-1.9 (6H, m, 3 × CH₂), 2.25 (3H, s,

CH₃CO), 2.77 (3H, s, NCH₃), 2.9 (1H, m, CHCH₂), 3.45 (4H,

m, 2 × CH₂N), 3.7 (1H, m, CHCH₂), 4.2 (2H, q, CH₂CH₃, J )

7.2 Hz).

(S)-Eth yl 3-(N-m eth ylp ip er id in -4-yl)-5-[(2-oxo-1,3-oxa -

zilidin -4-yl)m eth yl]-1H-in dole-2-car boxylate (73): method

5, purification by preparative HPLC afforded 222 mg (27%) of

73 as the acetate salt; t_R12 min; MS m/z 386 (M + 1)⁺; found

M⁺385.1988, C₂₁H₂₇N₃O₄requires M⁺385.4631; ¹H NMR δ

1.4 (3H, t, CH₂CH₃, J ) 7.1 Hz), 1.7-2.4 (8H, m, 4 × CH₂),

2.4 (3H, s, NCH₃), 3.82 (1H, m, CH₂CHCH₂), 4.38 (3H, m, CH₂-

CH₃, CHNH), 4.2 (2H, m, CH₂O), 7.1 (1H, d, H6, J ) 8.2 Hz),

7.38 (1H, d, H7, J ) 8.4 Hz), 7.85 (1H, s, H4), 8.55 (1H, s,

NH).

Isop r op yl 3-(4-P yr id in yl)-5-[2-(2,5-d ioxo-1-im id a zoli-

d in yl)eth yl]-1H-in d ole-2-ca r boxyla te (80) (Meth od 6, u s-

in g 2-p r op a n ol a s solven t). The required hydrazone was

synthesized from the aniline hydrochloride 22 and the â-keto

ester 70. The hydrazone was purified by flash chromatography

eluting with CHCl₃:MeOH (97:3) and was used directly to form

the indole derivative 80, 60 mg (33%): MS m/z 435 (M + 1)⁺;

¹H NMR δ 1.04 (6H, s, 2 × CH₃), 1.19 (6H, d, CH(CH₃)₂, J )

6.3 Hz), 2.9 (2H, m, CH₂N), 3.5 (2H, m, 5-CH₂), 5.1 (1H, m,

CH), 7.14 (1H, d, H6, J ) 8.2 Hz), 7.2 (1H, s, H4), 7.46 (3H,

2362 J ournal of Medicinal Chemistry, 1997, Vol. 40, No. 15

Moloney et al.

(11) Martin, G. R. Serotonin Receptor Involvement in the Pathogen-

esis and Treatment of Migraine. In Blue Books on Neurology;

Silberstein, S., Goadsby, P. J ., Eds.; in press.

(12) (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.

(13) Skingle, M.; Sleight, A. J .; Feniuk, S. Effects of the 5HT_1D

receptor antagonist GR127935 on extracellular levels of 5HT in

the guinea-pig frontal cortex as measured by microdialysis.

Neuropharmacology 1995, 34, 377-382.

(14) Walsh, D. M.; Beattie, D. T.; Connor, H. E. The activity of 5HT_1D

receptor ligands at cloned human 5HT_1DRand 5HT_1Dâreceptors.

Eur. J . Pharmacol. 1995, 287, 79-84.

(15) (a) Feniuk, W.; Humphrey, P. P. A. Development of a highly

selective 5HT₁receptor agonist, sumatriptan, for the treatment

of migraine. Drug Dev. Res. 1992, 26, 235-240. (b) Ferrari, M.

D.; Saxena, P. R. On serotonin and migraine: a clinical and

pharmacological review. Cephalgia 1993, 13, 151-165. (c) Fer-

rari, M. D.; Saxena, P. R. Clinical and experimental effects of

sumatriptan in humans. Trends Pharmacol. Sci. 1993, 14, 129-

133.

m, H7, H3′, H5′), 8.1 (1H, s, NH), 8.62 (2H, d, H2′, H6′, J )

5.1 Hz), 12.0 (1H, s, NH). Anal. (C₂₄H₂₆N₄O₄‚0.75H₂O) C, H,

N.

Isop r op yl 3-(N-Met h ylt et r a h yd r op yr id in -4-yl)-5-[2-

(4,4-dim eth yl-2,5-dioxo-1-im idazolidin yl)eth yl]-1H-in dole-

2-ca r boxyla te (81). The methyl iodide quaternary salt of 80

was synthesized by method 9 and reacted on without purifica-

tion via method 10 to give 40 mg (52%) of the desired

1

tetrahydropyridine derivative 81: MS m/z 453 (M + 1)⁺; H

NMR δ 1.1 (6H, s, 2 × CH₃), 1.28 (6H, d, CH(CH₃)₂, J ) 6.3

Hz), 2.28 (3H, s, NCH₃), 2.38 (2H, m, CH₂), 2.56 (2H, m, CH₂),

2.86 (2H, m, CH₂N), 3.0 (2H, m, CH₂), 3.54 (2H, m, 5-CH₂),

5.1 (1H, m, CH(CH₃)₂), 5.6 (1H, s, CHd), 7.0 (1H, d, H6, J )

8.1 Hz), 7.2 (1H, s, H4), 7.3 (1H, d, H7, J ) 8.1 Hz), 8.1 (1H,

s, NH), 11.5 (1H, s, NH). Anal. (C₂₅H₃₂N₄O₄‚1.0H₂O) C, H,

N.

E t h yl

3-(N-Met h ylt et r a h yd r op yr id in -4-yl)-5-[2-(N-

p h th a lim id o)eth yl]-1H-in d ole-2-ca r boxyla te (82). The

required hydrazone was synthesized by method 7, indole

closure was achieved using method 6, and the pyridine

nitrogen was methylated using method 9. Reduction of the

N-methylated pyridine ring to a tetrahydropyridine substitu-

ent was achieved using method 10. In each reaction the

intermediates were not isolated and purified but were reacted

on greater than 90% pure to ultimately afford 63 mg (23%) of

82 as an orange solid after purification by flash chromatog-

raphy eluting with CH₂Cl₂:EtOH:NH₃(150:8:1): MS m/z 458

(16) (a) Ward, T. J . 5-HT₁-like and 5-HT_1D-Agonists as treatment for

migraine Curr. Opin. Ther. Pat. 1993, 3, 417-423 (b) Macor, J .

E.; Blank, D. H.; Post, R. J .; Ryan, K. The synthesis of a

conformationally restricted analog of the anti-migraine drug

sumatriptan. Tetrahedron. Lett. 1992, 33, 8011-8014. (c) King,

F. D.; Brown, M. A.; Gaster, L. M.; Kaumann, A. J .; Medhurst,

A. D.; Parker, S. G.; Parsons, A. A.; Patch, T. L.; Raval, P. (+/-)-

3-Amino-6-carboxamido-1,2,3,4-tetrahydrocarbazole: a confor-

mationally restricted analogue of 5-carboxamidotryptamine with

selectivity for the serotonin 5HT_1Dreceptor. J . Med. Chem. 1993,

36, 1918-1919.

(17) Street, L. J .; Baker, R.; Castro, J . L.; Chambers, M. S.; Guiblin,

A. R.; Hobbs, S. C.; Matassa, V. G.; Reeve, A. J .; Beer, M. S.;

Middlemiss, D. N.; Noble, A. J .; Stanton, J . A.; Scholey, K.;

Hargreaves, R. J . Synthesis and serotonergic activity of 5-(oxa-

diazolyl)tryptamines: potent agonists for 5HT_1Dreceptors. J .

Med. Chem. 1993, 36, 1529-1538.

(18) Castro, J . L.; Baker, R.; Guiblin, A. R.; Hobbs, S. C.; J enkins,

M. R.; Russell, M. G. N.; Beer, M. S.; Stanton, J . A.; Scholey,

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1

(M + 1)⁺; H NMR δ 1.28 (3H, t, CH₂CH₃, J ) 6.9 Hz), 1.76

(2H, m, CH₂), 2.26 (3H, s, NCH₃), 2.8 (2H, m, CH₂), 2.95 (2H,

m, CH₂N), 3.6 (2H, m, CH₂), 3.8 (2H, m, 5-CH₂), 4.25 (2H, q,

CH₂CH₃, J ) 6.7 Hz), 6.1 (1H, t, CHd), 7.1 (1H, d, H6, J )

8.2 Hz), 7.3 (1H, d, H7, J ) 8.3 Hz), 7.6 (1H, s, H4), 7.8 (4H,

s, Phth Ar), 11.5 (1H, s, NH); found M⁺457.2016, C₂₇H₂₇N₃O₄

requires M⁺457.2002.

Ack n ow led gm en t. The authors acknowledge the

support of The Wellcome Foundation Ltd. and Wellcome

Australia (now GlaxoWellcome Australia).

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J M9605849

Article Doi

A novel series of 2,5-substituted tryptamine derivatives as vascular 5HT(1B/1D) receptor antagonists

DOI: 10.1021/jm9605849

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Full text of DOI:10.1021/jm9605849

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