Indole inhibitors of human nonpancreatic secretory phospholipase A2. 2. Indole-3-acetamides with additional functionality

J . Med. Chem. 1996, 39, 5137-5158

5137

In d ole In h ibitor s of Hu m a n Non p a n cr ea tic Secr etor y P h osp h olip a se A₂. 2.

In d ole-3-a ceta m id es w ith Ad d ition a l F u n ction a lity

Robert D. Dillard, Nicholas J . Bach,* Susan E. Draheim, Dennis R. Berry, Donald G. Carlson,

Nickolay Y. Chirgadze, David K. Clawson, Lawrence W. Hartley, Lea M. J ohnson, Noel D. J ones,

Emma R. McKinney, Edward D. Mihelich, J ennifer L. Olkowski, Richard W. Schevitz, Amy C. Smith,

David W. Snyder, Cynthia D. Sommers, and J ean-Pierre Wery

Lilly Research Laboratories, Eli Lilly and Company, Lilly Corporate Center, Indianapolis, Indiana 46285

Received J uly 5, 1996^X

As reported in our previous paper, a series of indole-3-acetamides which possessed potency

and selectivity as inhibitors of human nonpancreatic secretory phospholipase A₂(hnps-PLA₂)

was developed. The design of these compounds was based on information derived from x-ray

crystal structures determined for complexes between the enzyme and its inhibitors. We describe

here the further implementation of this structure-based design strategy and continued SAR

development to produce indole-3-acetamides with additional functionalities which provide

increased interaction with important residues within the enzyme active site. These efforts

led to inhibitors with substantially enhanced potency and selectivity.

In tr od u ction

ring system. Demethylation⁴was efficiently carried out

using boron tribromide in dichloromethane at room

temperature or below (Scheme 1), providing 4-, 5-, or

6-phenolic indoles (2), which were used to prepare

compounds with functionalities linked to these positions

of the indole ring.

The first paper in this series described the X-ray

structure-based development of an indole-3-acetic acid

lead from a screening program, into a series of indole-

3-acetamides which were potent and selective inhibitors

of hnps-PLA₂. In order to provide direction to the

continued SAR development and improve upon the

potency of this initial series of inhibitors, the available

crystal structures of sPLA₂enzyme-inhibitor complexes

were further studied. X-ray crystal structures of the

complex between a phosphonate transition state ana-

logue (TSA)²and hnps-PLA₂and of that between an

amide substrate analogue (ASA)³and a mutant porcine

PLA₂enzyme were compared to the complex between

5-methoxy-2-methyl-1H-indole-3-acetamide (1d ) and

hnps-PLA₂. Examination of these complexes indicated

that two other interactions between enzyme and inhibi-

tor noted for both ASA and TSA could be mimicked by

proper substitution on the carbocyclic portion of the

indole ring. The phosphate group in both TSA and ASA

provides an oxygen as an additional ligand for the

calcium in the active site and also a hydrogen bond to

the side chain of residue 69 (Lys 69 for hnps-PLA₂and

Tyr 69 for the mutant porcine enzyme). It was con-

cluded that an acidic group linked to the 5-position of

the indole could add these two interactions to those

already observed for 1d . This observation was the basis

for the modifications of indole-3-acetamides reported in

this paper. As new inhibitors with the additional

functionalities were prepared, X-ray crystal structures

of selected compounds, along with the determination of

their hnps-PLA₂inhibitory activity, further contributed

to our understanding of the enzyme active site, and

derivatives with substantially enhanced potency and

selectivity were obtained.

Treatment of the sodium salt of 2-ethyl-5-hydroxy-1-

(phenylmethyl)-1H-indole-3-acetamide (2g) with allyl

bromide gave the 5-allyloxy intermediate. This inter-

mediate undergoes a thermal Claisen⁵rearrangement

to providie 4-allyl-5-hydroxyindole, 2i. The exclusive

formation of the 4-allyl isomer is explicable on the basis

of the stability of the possible intermediates in the

rearrangement (Figure 1). The 4-allyl-4H-indol-5-one

retains the aromaticity of the pyrrole ring and allows

extended conjugation from the unshared pair of elec-

trons on the nitrogen through to the indol-5-one. The

other possible intermediate, 6-allyl-6H-indol-5-one, would

lose all aromaticity and retain only less significant

conjugated structures. An identical stereospecificity has

been observed for the Claisen rearrangement of a

5-(allyloxy)indole-3-glyoxamide.⁶

Indoles having a functional group linked to the

phenolic oxygen via an alkyl chain were generally

prepared by reacting the sodium salt of the phenol with

an ω-bromoalkanoate or alkylphosphonate, followed by

deesterification with aqueous sodium hydroxide, or with

trimethylsilyl bromide followed by methanol for the

phosphonates (Schemes 2 and 3). In the case of the

ethylene-linked derivative 5f, Michael addition⁷of the

phenol to an acrylic ester in the presence of mild base

afforded this derivative. The ready reversibility of this

reaction under more basic conditions required the use

of benzyl acrylate as the acceptor. This permitted

conversion of the ester to the acid using the neutral

conditions of reductive debenzylation.

Ch em istr y

In cases where the functional group was linked to the

phenolic oxygen via an arylalkyl group, compounds were

prepared by alkylation of the sodium salt of the phenol

using (bromomethyl)benzoic acid esters. Aryl-linked

derivatives were prepared by Ullman coupling of the

cuprous phenoxide⁸with iodobenzoic acid esters.

The methoxylated indole-3-acetamides (1) prepared

as described in the previous paper¹were convenient

starting materials for the syntheses of many indoles

with new substituents on the carbocyclic portion of the

^XAbstract published in Advance ACS Abstracts, December 1, 1996.

5138 J ournal of Medicinal Chemistry, 1996, Vol. 39, No. 26

Sch em e 1. Preparation of Hydroxyindoles^a

Dillard et al.

a

Reagents: (a) BBr₃, CH₂Cl₂; (b) NaH, allyl bromide, DMF; (c) N,N-dimethylaniline, heat.

with the monoalkylated compound 28. Access to the

4-aminoindoles was made via the 4-nitroindole, 21.¹The

diminished reactivity of the 3-position of 4-nitroindoles

was evidenced by its reaction with oxalyl chloride,¹¹

which required prolonged reaction time at room tem-

perature to reach completion. The 4-nitro group and

the keto group of the glyoxamide were both reduced by

low-pressure hydrogenation with palladium on barium

sulfate as catalyst to give the glycolic amide (23), which

was further reduced to the indole-3-acetamide by tri-

ethylsilane and trifluoroacetic acid.¹²Alkylation of

the amino group of 24 produced the tert-butyl ester 25

which on treatment with trifluoroacetic acid gave the

acid 26.

The all-carbon-linked carboxyl derivative 35 was

prepared as shown in Scheme 6. The crude product

from the Friedel-Crafts acylation of the N-acylindoline

using aluminum chloride and succinic anhydride¹³was

esterified and solvolyzed to the indoline 31 by heating

in ethanol containing sulfuric acid. N-Alkylation fol-

lowed by oxidation with dichlorodicyanoquinone¹⁴gave

the 5-acylindole (32) which was easily converted to the

indole-3-glyoxamide by sequential treatment with oxalyl

chloride and ammonia. It was assumed that sodium

borohydride reduction of 33 would lead to undesired

lactonization of the side chain and that proceeding to

the indole-3-acetamide by way of the indole-3-glycola-

mide would be inappropriate. Both keto functions of

the compound were efficiently reduced to methylenes

(compound 34) by use of excess triethylsilane and

trifluoroacetic acid in refluxing dichloroethane without

effect on the ester, amide, or indole functionalities.

F igu r e 1.

The (indolyloxy)alkanoic acid esters were reacted with

hydrazine to give the hydrazides 19, which were reduc-

tively cleaved to produce amides 20 (Scheme 4). Alter-

natively, for those compounds, such as 4s, containing

functional groups not compatible with the reductive

procedure, the esters were converted directly to amides

by treatment with methylchloroaluminum amide.⁹Alky-

lation of the phenoxide with bromobutyronitrile followed

by reaction with tributyltin azide¹⁰afforded the tetra-

zole 18. Reacting the phenoxide with 1,3-propyl sultone

gave the (indolyloxy)propanesulfonic acids 16a and 16b.

Functionalities linked to the indole system by a

nitrogen atom were prepared as outlined in Scheme 5.

The previously reported¹5-aminoindole 27 was reacted

with methyl acrylate in Michael fashion to give a

product which was sufficiently resistant to reversal that

it could be hydrolyzed in aqueous base to the corre-

sponding acid. Direct alkylation of the 5-aminoindole

gave substantial amounts of N,N-dialkylation along

Indole Inhibitors of hnps-PLA₂. 2

J ournal of Medicinal Chemistry, 1996, Vol. 39, No. 26 5139

Sch em e 2. Oxygen-Linked Carboxyl Functionalities^a

were easily available by the routes used for the corre-

sponding 5-substituted analogues, uncomplicated by the

additional 4- or 6-substituent.

In the first paper¹of this series, replacement of the

3-acetamide by several related functionalities was re-

ported. Schemes 10 and 11 show the synthesis of some

3-acetic acid, 3-acetic acid hydrazide, and 3-propiona-

mide derivatives with the additional functionalities of

the current series using methodologies as reported

before. The unexpected decarbonylation observed on

treatment of the 4-methoxy indole-3-glyoxamide, 79,

with boron tribromide has some precedence¹⁸in a

reported metal-catalyzed decarbonylation of glyoxylic

acid esters. A cyclic boronate intermediate is probably

involved since the decarbonylation is not observed on

reaction of the analogous 5-methoxyindole-3-glyoxam-

ides.

P h a r m a cology

The initial pharmacological evaluation of all reported

compounds was accomplished using a chromogenic

assay system, with followup testing of selected com-

pounds in the hnps-PLA₂-induced tissue contraction

assay. The specific methods employed are described in

the first paper of this series. The relative inhibitory

activities of the reported compounds, as indicated by

these two assay systems, are shown in Table 1.

Information on selectivity of the inhibitors for hnps-

PLA₂was derived from comparisons of chromogenic

assay results using different types of secretory PLA₂’s.

Relative inhibitory activities against hnps-PLA₂, human

pancreatic secretory PLA₂, and porcine pancreatic secre-

tory PLA₂are shown in Table 2.

Discu ssion

In the first paper of this series we described the

initiation of a screening program to identify potential

inhibitors of hnps-PLA₂. 5-Methoxy-2-methyl-1H-in-

dole-3-acetic acid was selected from the hits produced

by this screen for further development. This lead

compound had an IC₅₀of 13.6 µM (mole fraction 1 ×

10^-2). Using a structure-based design approach with

information gathered from X-ray crystallographic stud-

ies¹⁹of complexes between various inhibitors and hnps-

PLA₂, this lead progressed to a series of indole-3-

acetamides having a wide variety of simple substituents

at other positions of the indole nucleus. These deriva-

tives were potent inhibitors of the enzyme with IC₅₀

values as low as 120 nM (mole fraction 1 × 10^-4) in the

primary chromogenic assay screen. The compounds

reported here exhibit a further enhancement in potency,

with IC₅₀’s as low as 10 nM (mole fraction less than 1

× 10^-5).

a

Reagents: (a) NaH, BrZCO₂R³, DMF/THF; (b) K₂CO₃, benzyl

acrylate, 2-butanone, heat; (c) Ullman; (d) NaOH, EtOH/H₂O; (e)

HCl, H₂O; (f) 10% Pd/C, H₂, EtOH; (g) BBr₃, CH₂Cl₂; (h) (1) methyl

chloroformate, Et₃N, CH₂Cl₂, (2) ammonia.

Replacement of the oxygen link by a sulfur link was

accomplished by subjecting the hydroxyindoles to the

known phenol to thiophenol conversion methodology¹⁵

as illustrated in Scheme 7. The vigorous reaction

conditions involved in carrying out this conversion

prevented the early insertion of useful 3-substituents,

so the desired 3-acetamides were prepared by way of

the 3-glyoxamides subsequent to the elaboration of the

groups attached to the carbocyclic ring of the indoles.

Scheme 8 shows the route selected for the preparation

of 5,7-disubstituted indole-3-acetamides. The selective

lithiation at the 7-position¹⁶of the N-BOC-indoline 47

is an example of the ability of an acyl nitrogen function

to direct aromatic metalation even in the presence of

other good directing groups such as methoxy.¹⁷After

alkylation of the 7-lithioindoline, the N-BOC was re-

moved, the nitrogen alkylated, and the indoline oxidized

to the indole with dichlorodicyanoquinone. Demethy-

lation produced the phenol 52, which was converted to

the thiophenol 55 as described above. Both the phenol

and the thiophenol were converted to the desired

compounds, 60a and 60b, by the series of steps used

previously.

This improved activity resulted from a continuation

of a structure-based design strategy applied to the

developing SAR. X-ray crystal structures of complexes

of TSA²with hnps-PLA₂and ASA³with a mutant

porcine PLA₂enzyme were compared to the complex

between 5-methoxy-2-methyl-1H-indole-3-acetamide (1d)

and hnps-PLA₂. These comparisons¹⁹made it clear that

the indole-based inhibitor overlapped both the glycerol

backbone and one of the aliphatic side chains of the

substrate analog inhibitors very nicely, but it had no

substituent that corresponded to the phosphate head

groups of ASA and TSA. The phosphate group provides

The preparation of 4,5- and 5,6-disubstituted indole-

3-acetamides are shown in Scheme 9. These compounds

5140 J ournal of Medicinal Chemistry, 1996, Vol. 39, No. 26

Sch em e 3. Oxygen-Linked Phosphonate Functionalities^a

Dillard et al.

a

Reagents: (a) NaH, ICH₂PO₃R₂or BrZPO₃Me₂, DMF; (b) MeClAlNH₂, benzene/toluene, 50 °C; (c) (1) Me₃SiBr, CH₂Cl₂, (2) MeOH; (d)

NaOH, chromatography, HP-20 column; (e) (1) NaOH, MeOH, H₂O, heat, (2) HCl, H₂O. a. Diethyl ester instead of dimethyl ester.

Sch em e 4. Other Oxygen-Linked Functionalities^a

a

Reagents: (a) NaH, THF, 1,3-propane sultone; (b) NaH, Br(CH₂)₃CN, DMF; (c) Et₃N‚HCl, NaN₃, DMF, 105 °C; (d) hydrazine, EtOH,

heat; (e) Raney Ni, EtOH, heat; (f) MeClAlNH₂, benzene/toluene, 50 °C.

one oxygen to the coordination sphere of the catalytic

calcium while another oxygen atom hydrogen bonds to

residue 69. Consequently, the next synthetic goal for

potency improvement in the indole series of inhibitors

was to append a side chain that would emulate these

interactions.

As an initial attempt we chose to append a carboxyl-

terminated side chain to the indole nucleus. This was

synthetically attractive since numerous methoxyindoles

were available from our previous work¹and boron

tribromide treatment of these readily provided a phenol

functionality that facilitated introduction of the requi-

site appendage. Since the crystallographic information

indicated that the 5-methoxy group of 1d was positioned

in a direction which overlapped well with that portion

of the substrate analog inhibitors containing the phos-

phate head group, our first derivatives were prepared

with the carboxyl group linked to the indole 5-position.

The activity observed for a methyleneoxy linker, 7e (IC₅₀

1.79 ( 0.17 µM), was somewhat less than that observed

for 1d (IC₅₀0.84 ( 0.17 µM). Activity began to increase

with the addition of another methylene to the linker (7f,

Indole Inhibitors of hnps-PLA₂. 2

J ournal of Medicinal Chemistry, 1996, Vol. 39, No. 26 5141

Sch em e 5. Nitrogen-Linked Carboxyl Functionalities^a

a

Reagents: (a) (1) oxalyl chloride, CH₂Cl₂, (2) ammonia; (b) Pd/BaSO₄, H₂, THF/EtOH; (c) Et₃SiH, TFA; (d) Na₂CO₃, t-BuO₂CCH₂Br,

DMF; (e) TFA; (f) methyl acrylate, MeOH, room temperature; (g) NaH, Br(CH₂)₃CO₂Et, DMF; (h) (1) NaOH, EtOH, H₂O, (2) HCl, H₂O.

Sch em e 6. Carbon-Linked Carboxyl Functionalities^a

a

Reagents: (a) (1) AlCl₃, succinic anhydride, CH₂Cl₂, (2) H₂SO₄, EtOH, heat; (b) K₂CO₃, benzyl bromide, DMF, 85 °C; (c) DDQ, dioxane,

85 °C; (d) (1) oxalyl chloride, CH₂Cl₂, (2) ammonia; (e) Et₃SiH, TFA, 1,2-dichloroethane, heat; (f) (1) NaOH, EtOH, H₂O, (2) HCl, H₂O.

IC₅₀0.53 ( 0.06 µM) and peaked with the propyleneoxy

linker, 7g (IC₅₀0.15 ( 0.03 µM). Extending the chain

with a fourth methylene provided a side chain that was

too long and diminished activity (7h , IC₅₀1.15 ( 0.09

µM).

requirements of the system. The 5-[(2-carboxyphenyl)-

methylene]oxy compound 7i is larger and less flexible

than 7g, but it has the proper length to coordinate to

calcium and consequently retains good activity. Moving

the carboxy group one position on the phenyl ring, as

in 7j, provides a spatial arrangement that is more

reminiscent of 7h and leads to a corresponding loss of

activity. Replacement of the oxygen of the linker by

nitrogen, sulfur, and carbon was also accomplished. The

nitrogen substitution (29) resulted in a large decrease

in activity. Sulfur (44) and carbon (35) substitution

provided compounds that retained activity, with some

of these showing improved activity relative to their

oxygen-containing equivalents. It seems likely that this

would be a result of more precise positioning of the

carboxylate in the coordination sphere of the calcium,

but further work is required to investigate this question.

The three-dimensional structures of these inhibitors

in the active site of hnps-PLA₂suggested that position-

ing a shorter carboxy-terminated group at the 4-position

of the indole, rather than at the 5-position as described

above, would also achieve a favorable ligation of the

catalytic calcium. This was indeed demonstrated with

the synthesis of the oxyacetic acid derivative 7c (IC₅₀

0.052 ( 0.01 µM), which showed better activity than

the 5-oxybutyric acid compound 7g. Changes to 7c by

lengthening the linker (7d ), substituting nitrogen for

oxygen (26), or replacing the carboxy with amide

The X-ray structure¹⁹of 7g in the active site of hnps-

PLA₂showed that its carboxylate does coordinate to the

primary calcium as desired. However, the trigonal

array of the carboxylate’s oxygens prevented any inter-

action with Lys 69. With the expectation that a phos-

phonate would better mimic the interactions observed

for the phosphate groups of TSA and ASA, the corre-

sponding 5-propyleneoxy phosphonic acid derivative 13d

was prepared. This compound displayed improved

activity in the chromogenic assay (IC₅₀0.06 ( 0.01 µM).

A crystallographic determination of this inhibitor’s

binding to the active site¹⁹indicated a water-mediated

hydrogen bond to Lys 69 that may contribute to the

observed improvement in activity.

Systematic alterations of side chain functionality were

carried out. Amides (20d ) and sulfonic acids (16)

displayed activity similar to that of the corresponding

carboxylic acids. Interestingly, use of a tetrazole as a

carboxy replacement resulted in a large loss of activity

(18, IC₅₀2.24 ( 0.24 µM), suggesting that this anionic

heterocycle cannot substitute for the carboxylate in the

coordination sphere of the catalytic calcium. Changes

in linker atoms had effects consistent with the geometric

5142 J ournal of Medicinal Chemistry, 1996, Vol. 39, No. 26

Sch em e 7. Sulfur-Linked Functionalities^a

Dillard et al.

a

Reagents: (a) BBr₃, CH₂Cl₂; (b) NaH, dimethylthiocarbamoyl chloride, DMF; (c) phenyl ether, heat; (d) (1) NaOH, EtOH, H₂O, heat,

(2) HCl, H₂O; (e) NaH, BrZR¹, DMF or K₂CO₃, tert-butyl acrylate; (f) (1) oxalyl chloride, CH₂Cl₂, (2) ammonia; (g) (1) NaBH₄, EtOH, (2)

Et₃SiH, TFA; or Et₃SiH, TFA, dichloromethane, heat; (h) (1) NaOH, EtOH, H₂O, (2) HCl, H₂O, or (1) Me₃SiBr, CH₂Cl₂, (2) MeOH; (i)

NaOH, H₂O, HP-20 chromatography.

(20a ,b), hydrazide (19a ,b), or phosphonate (13c) groups

resulted in decreased activity. Thus, it appears that

substitution at the 4-position of the indole ring is tightly

constrained with regard to the proper positioning of a

ligand to the catalytic calcium atom.

In contrast to the 4- and 5-positions of the indole ring,

the 6-position points out of the active site. Addition of

substituents at this site would not be expected to

provide significant enhancements of activity. This is

dramatically seen in 7k and 7l, which have IC₅₀values

of greater than 5 µM. Addition of 6-alkyl groups to

compounds containing a carboxy-terminated side chain

in the 5-position had only modest effects on activity.

This is in contrast to 4-allyl substitution, as in 62c, that

leads to much diminished activity presumably by pre-

venting the 5-side chain from coordinating favorably

with the calcium.

The SAR produced by substituent changes at the 1-

and 2-positions of the indole were similar to those

observed for such changes on the structures reported

in the previous paper.¹As before, an ethyl group at the

2-position optimally fit the hydrophobic cleft in this

region of the protein. Addition of a substituent at the

7-position enhanced activity somewhat (60a , IC₅₀0.075

( 0.018 µM) compared to 7g. This probably is a

consequence of a favorable restriction on the conforma-

tional flexibility of the 1-benzyl group which has an

important role in the binding of the inhibitor through

enlarging the catalytic site by displacing His 6 in a

manner similar to that of TSA.²

1, many of these inhibitors effectively blocked hnps-

PLA₂-induced contraction of guinea pig lung pleural

strips while they showed little or no effect on the

arachidonic acid-induced contraction of the tissue at the

concentration tested. This indicates that the activity

is a result of a direct effect on the enzyme rather than

any effect as inhibitors of agents formed subsequent to

the action of the PLA₂. The results in Table 2 demon-

strate selectivity for the human, nonpancreatic enzyme

because IC₅₀values for the inhibition of this enzyme

are several hundred-fold lower than the IC₅₀values for

inhibition of human, pancreatic sPLA₂.

Su m m a r y

Addition of a tethered acidic group to either the 4- or

5-position of the indole ring has made a further im-

provement to the potency of the indole series of hnps-

PLA₂inhibitors. The most active inhibitors described

in this paper (IC₅₀of ca. 10 nM) approach the stoichio-

metric limit of the chromogenic assay (16 nM enzyme).

Additional improvement to the inherent potency of this

series was still possible, however, and these activities

are described in the following paper.

Exp er im en ta l Section

Melting points were obtained on a Thomas-Hoover Mel

Temp and are uncorrected. The NMR data were recorded on

a

QE300 instrument. The FD mass spectral data were

obtained on a VG Analytical 70-SE instrument and the FAB

spectra were recorded on a ZAB 2-SE instrument. Syntheses

of indoles 1, 8, 10, 21, 27, 36, 63, 69, 73, and 77 are described

in the preceding paper. Compound 45 was commercially

available.

The compounds described in this report displayed

excellent selectivity for hnps-PLA₂. As shown in Table

Indole Inhibitors of hnps-PLA₂. 2

J ournal of Medicinal Chemistry, 1996, Vol. 39, No. 26 5143

Sch em e 8. Oxygen- and Sulfur-Linked Functionalities: 7-Alkyl^a

a

Reagents: (a) NaCNBH₃, HOAc; (b) (BOC)₂O, THF, heat; (c) (1) n-BuLi, THF, -70 °C, (2) MeI; (d) NaOH, EtOH, H₂O, heat; (e) NaH,

benzyl bromide, DMF; (f) DDQ, dioxane, 85 °C; (g) BBr₃, CH₂Cl₂; (h) NaH, dimethylthiocarbamoyl chloride, DMF; (i) phenyl ether, 195

°C; (j) (1) NaOH, EtOH, H₂O, heat, (2) HCl, H₂O; (k) NaH, Br(CH₂)₃CO₂Et, DMF; (l) (1) oxalyl chloride, CH₂Cl₂, (2) ammonia; (m) NaBH₄,

MeOH; (n) Et₃SiH, TFA.

Sch em e 9. Oxygen-Linked Functionalities: 4- or 6-Substituted^a

a

Reagents: (a) NaH, Br(CH₂)₃X, DMF; (b) (1) NaOH, EtOH, H₂O, (2) HCl, H₂O; (c) (1) Me₃SiBr, CH₂Cl₂, (2) MeOH; (d) NaOH, H₂O,

HP-20 chromatography.

5-H yd r oxy-1-(p h en ylm et h yl)-1H -in d ole-3-a cet a m id e

(2b). A solution of 375 mg (1.23 mmol) of 1b and 5 mL of 1 M

BBr₃/CH₂Cl₂in 75 mL of CH₂Cl₂was stirred for 1.25 h and

poured into 1 N HCl. The CH₂Cl₂layer was separated, washed

with brine, and dried (Na₂SO₄). The solvent was removed at

reduced pressure to give as residue 310 mg (90% yield) of 2b,

mp 158-160 °C. Anal. (C₁₇H₁₆N₂O₂‚0.5H₂O) C, H, N.

Using the above procedure, the following hydroxyindoles (2)

were prepared from the corresponding methoxyindole (1).

4-Hydr oxy-1-(ph en ylm eth yl)-1H-in dole-3-acetam ide (2a)

(chromatography on silica gel, 50% EtOAc/hexane): yield 35%;

¹H NMR (CDCl₃) ∂ 9.50 (br s, 1H), 7.62-6.87 (m, 8H), 6.64 (d,

1H), 6.08-5.82 (m, 2H), 5.30 (s, 2H), 5.17 (s, 2H); MS (FD)

280 (M⁺).

hexane, then EtOAc): yield 66%; mp 200-208 °C; ¹H NMR

(CDCl₃) ∂ 7.35-6.92 (m, 9H), 6.81 (d, 1H), 6.60 (d, 1H), 5.27

(s, 2H), 3.78 (s, 2H), 2.31 (s, 3H); MS (FD⁺) 294 (M⁺). Anal.

(C₁₈H₁₈N₂O₂) C, H, N.

5-Hyd r oxy-2-m eth yl-1-(p h en ylm eth yl)-1H-in d ole-3-a c-

eta m id e (2d ) (chromatography on silica gel, 20% EtOAc/

hexane, then 50% EtOAc/hexane, then EtOAc): yield 80%; ¹H

NMR (CDCl₃) ∂ 7.45-6.82 (m, 8H), 6.37 (br s, 1H), 5.82 (br s,

1H), 5.57 (br s, 1H), 5.40 (s, 2H), 3.81 (s, 2H), 2.42 (s, 3H).

6-Hyd r oxy-2-m eth yl-1-(p h en ylm eth yl)-1H-in d ole-3-a c-

eta m id e (2e) (chromatography on silica gel, 5% MeOH/CH₂-

1

Cl₂): yield 45%; mp 174-179 °C; H NMR (DMSO-d₆) ∂ 8.80

(s, 1H), 7.35-7.18 (m, 4H), 7.15 (br s, 1H), 7.00 (d, 2H), 6.78

(br s, 1H), 6.61 (s, 1H), 6.51 (d, 1H), 5.25 (s, 2H), 3.39 (s, 2H),

2.25 (s, 3H); MS (FD) 294 (M⁺). Anal. (C₁₈H₁₈N₂O₂) H, N; C:

calcd, 73.45; found, 72.43.

4-Hyd r oxy-2-m eth yl-1-(p h en ylm eth yl)-1H-in d ole-3-a c-

eta m id e (2c) (chromatography on silica gel, 50% EtOAc/

5144 J ournal of Medicinal Chemistry, 1996, Vol. 39, No. 26

Sch em e 10. Indole-3-acetic Acid Hydrazides^a

Dillard et al.

a

Reagents: (a) BBr₃, CH₂Cl₂; (b) NaH, Br(CH₂)₃CO₂Et, DMF; (c) NaH, Br(CH₂)₃PO₃Me₂, DMF; (d) (1) Me₃SiBr, CH₂Cl₂, (2) MeOH; (e)

NaOH, H₂O, HP-20 chromatography; (f) (1) NaOH, EtOH, H₂O, (2) HCl, H₂O.

5.31 (s, 2H), 5.50 (s, 2H), 2.72 (q, 2H), 1.12 (t, 3H); MS (FD⁺)

Sch em e 11. Other 3-Substituents^a

308 (M⁺). Anal. (C₁₉H₂₀N₂O₂‚0.2H₂O) C, H, N.

2-Eth yl-5-h yd r oxy-6-isop r op yl-5-m eth oxy-1-(p h en ylm -

eth yl)-1H-in d ole-3-a ceta m id e (2h ) (crystallization, EtOAc/

1

hexane): yield 79%; mp 163-164 °C; H NMR (DMSO-d₆) ∂

8.57 (s, 1H), 7.32-6.96 (m, 7H), 6.85 (s, 1H), 6.82 (br s, 1H),

5.32 (s, 2H), 3.37 (s, 2H), 3.30-3.16 (m, 1H), 2.67 (q, 2H), 1.12

(d, 6H), 1.02 (t, 3H); MS (FD⁺) 350 (M⁺). Anal. (C₂₂H₂₆N₂O₂)

C, H, N.

5-Hyd r oxy-1-(p h en ylm eth yl)-2-p r op yl-1H-in d ole-3-a c-

eta m id e (2j) (chromatography on silica gel, EtOAc, then 10%

MeOH/EtOAc): yield 65%; glass; ¹H NMR (CDCl₃) ∂ 7.35-6.68

(m, 9H), 5.74 (br s, 1H), 5.46 (br s, 1H), 5.29 (s, 2H), 3.69 (s,

2H), 2.65 (t, 2H), 1.60-1.44 (m, 2H), 0.93 (t, 3H); MS (FD⁺)

322 (M⁺). Anal. (C₂₀H₂₂N₂O₂‚H₂O) C, H, N.

2-Cyclop r op yl-5-h yd r oxy-1-(p h en ylm eth yl)-1H-in d ole-

3-a ceta m id e (2k ) (crystallization, EtOAc): yield 79%; mp

174-175 °C; ¹H NMR (DMSO-d₆) ∂ 8.62 (s, 1H), 7.32-7.16 (m,

3H), 7.12 (br s, 1H), 7.04-6.96 (m, 3H), 6.86 (br s, 1H), 6.80

(d, 1H), 6.54 (dd, 1H), 5.44 (s, 2H), 3.50 (s, 2H), 1.70-1.60 (m,

1H), 0.94-0.84 (m, 2H), 0.74-0.64 (m, 2H); MS (FD⁺) 320 (M⁺).

Anal. (C₂₀H₂₀N₂O₂) C, H, N.

2-Ch lor o-5-h yd r oxy-1-(p h en ylm eth yl)-1H-in d ole-3-a c-

eta m id e (2l) (crude product).

2-Br om o-5-h yd r oxy-1-(p h en ylm eth yl)-1H-in d ole-3-a c-

eta m id e (2m ) (chromatography on silica gel, gradient, 1-4%

MeOH/CH₂Cl₂): yield 20%; oil; ¹H NMR (DMSO-d₆/D₂O) ∂

7.25-7.10 (m, 4H), 7.00 (d, 2H), 6.80 (d, 1H), 6.10 (dd, 1H),

5.30 (s, 2H), 3.40 (s, 2H); MS (FD⁺) 358 (M - 1), 360 (M + 1).

2-Br om o-6-ch lor o-5-h yd r oxy-1-(p h en ylm eth yl)-1H-in -

d ole-3-a ceta m id e (2n ) (chromatography on silica gel, gradi-

ent, 2-4% MeOH/CH₂Cl₂): yield 45%; mp 195 °C dec; ¹H NMR

(DMSO-d₆/D₂O) ∂ 7.35 (s, 1H), 7.25-7.15 (m, 3H), 6.95 (s, 1H),

6.90 (d, 2H), 5.30 (s, 2H), 3.40 (s, 2H); MS (FD) 392 (M - 1,

75), 394 (M + 1, 100). Anal. (C₁₇H₁₄BrClN₂O₂‚0.1CH₂Cl₂) C,

H, N, Br; Cl: calcd, 10.58; found, 9.49.

5-Hydr oxy-2-(m eth ylth io)-1-(ph en ylm eth yl)-1H-in dole-

3-a ceta m id e (2o) (crude product): yield 64%; wax; MS (FD⁺)

326 (M⁺). Anal. (C₁₈H₁₈N₂O₂S) C, H, N, S.

1-[(3-Ch lor op h en yl)m et h yl]-4-h yd r oxy-2-m et h yl-1H -

in d ole-3-a ceta m id e (2p ) (chromatography on silica gel,

gradient, 50% EtOAc/hexane-EtOAc): yield 48%; mp 173-

177 °C; ¹H NMR (CDCl₃) ∂ 8.65 (br s, 1H), 7.41-6.74 (m, 6H),

6.59 (d, 1H), 6.07 (br s, 1H), 5.66 (br s, 1H), 5.21 (s, 2H), 3.80

(s, 2H), 2.33 (s, 3H); MS (FD⁺) 328 (M - 1, 100), 330 (M + 1,

32). Anal. (C₁₈H₁₇ClN₂O₂) C, H, N.

a

Reagents: (a) BBr₃, CH₂Cl₂; (b) NaH, Br(CH₂)₃CO₂Et, DMF;

(c) (1) NaOH, EtOH, H₂O, (2) HCl, H₂O; (d) (1) BBr₃, CH₂Cl₂, (2)

MeSO₃H, MeOH, heat; (e) NaH, 3-chlorobenzyl bromide, DMF; (f)

(1) oxalyl chloride, CH₂Cl₂, (2) ammonia; (g) NaH, BrCH₂CO₂Me,

DMF.

2-Eth yl-4-h yd r oxy-1-(p h en ylm eth yl)-1H-in d ole-3-a ce-

ta m id e (2f) (chromatography on silica gel, EtOAc, then 5%

MeOH/EtOAc): yield 34%; foam; ¹H NMR (CDCl₃) ∂ 7.36-6.86

(m, 7H), 6.14 (br s, 1H), 5.80 (br s, 1H), 5.28 (s, 2H), 3.79 (s,

2H), 2.72 (q, 2H), 1.12 (t, 3H); MS (FD⁺) 308 (M⁺). Anal.

(C₁₉H₂₀N₂O₂) C, calcd 74.00, found 69.23; H, calcd 6.54, found

6.09; N, calcd 9.08, found 8.24.

2-Eth yl-5-h yd r oxy-1-(p h en ylm eth yl)-1H-in d ole-3-a ce-

ta m id e (2g) (chromatography on silica gel, 50% EtOAc/

hexane, then EtOAc): yield 45%; mp 174-179 °C; ¹H NMR

(CDCl₃) ∂ 7.36-6.70 (m, 9H), 5.73 (br s, 1H), 5.44 (br s, 1H),

1-[(3-Ch lor op h en yl)m eth yl]-2-eth yl-4-h yd r oxy-1H-in -

d ole-3-a cet a m id e (2q ) (chromatography on silica gel,

1

EtOAc): yield 76%; H NMR (CDCl₃) ∂ 8.75 (br s, 1H), 7.41-

6.57 (m, 7H), 5.12 (br s, 1H), 5.78 (br s, 1H), 5.25 (s, 2H), 3.81

(s, 2H), 2.73 (q, 2H), 1.15 (t, 3H); MS (FD) 343 (M - 1, 100),

345 (M + 1, 43).

1-[(3-Ch lor op h en yl)m eth yl]-2-eth yl-5-h yd r oxy-1H-in -

d ole-3-a cet a m id e (2r ) (chromatography on silica gel,

EtOAc): yield 81%; ¹H NMR (CDCl₃) ∂ 7.33-6.74 (m, 7H), 6.39

Indole Inhibitors of hnps-PLA₂. 2

J ournal of Medicinal Chemistry, 1996, Vol. 39, No. 26 5145

Ta ble 1. Inhibitory Activity against hnps-PLA₂and Arachidonic Acid

contraction of GP lung

tissue

contraction of GP lung

tissue

inhibition of human secreted

PLA₂chromogenic assay

inhibition of human secreted

PLA₂chromogenic assay

PLA₂-induced AA-induced

apparent K_B

ED₅₀(µM)

(n ) 4)

apparent K_B

ED₅₀(µM)

(n ) 4)

compd

IC₅₀(µM)

mole fraction^a(µM) (n ) 4)

compd

IC₅₀(µM)

mole fraction^a(µM) (n ) 4)

2b

2c

2d

2e

2g

2i

3.68 ( 0.15

3.0 × 10^-3

6.7 × 10^-3

8.3 × 10^-4

2.9 × 10^-3

2.8 × 10^-4

1.2 × 10^-4

2.8 × 10^-2

9.6 × 10^-5

6.9 × 10^-5

3.1 × 10^-4

4.8 × 10^-3

1.1 × 10^-3

3.7 × 10^-4

13c

13d

13e

13f

13g

13h

13i

13j

14e

15a

15h

16a

16b

18

19a

19b

19c

20a

20b

20c

20d

26

1.29 ( 0.16

0.057 ( 0.004

0.023 ( 0.005

6.13 ( 1.46

0.074 ( 0.008

0.033 ( 0.004

0.016 ( 0.01

0.022 ( 0.006

0.040 ( 0.004

3.68 ( 0.12

0.165 ( 0.040

0.195 ( 0.050

0.050 ( 0.015

2.45 (n ) 1)

0.422 ( 0.084

0.121 ( 0.056

1.27 ( 0.52

1.0 × 10^-3

4.6 × 10^-5

1.9 × 10^-5

5.0 × 10^-3

6.0 × 10^-5

2.7 × 10^-5

1.3 × 10^-5

1.8 × 10^-5

3.2 × 10^-5

3.0 × 10^-3

1.3 × 10^-4

1.6 × 10^-4

4.1 × 10^-5

2.0 × 10^-3

3.4 × 10^-4

9.8 × 10^-5

1.0 × 10^-3

2.9 × 10^-4

1.3 × 10^-4

4.7 × 10^-3

7.6 × 10^-5

5.0 × 10^-4

2.7 × 10^-3

1.5 × 10^-3

1.3 × 10^-4

4.8 × 10^-5

1.9 × 10^-5

1.8 × 10^-5

2.7 × 10^-5

4.7 × 10^-5

6.1 × 10^-5

4.1 × 10^-5

3.3 × 10^-5

1.6 × 10^-5

5.0 × 10^-4

2.7 × 10^-5

1.2 × 10^-5

8.3 × 10^-4

3.8 × 10^-4

5.6 × 10^-3

2.1 × 10^-2

1.4 × 10^-2

6.94 ( 1.03

0.85 ( 0.13

0.27 ( 0.05

>10

8.28 ( 2.34

1.02 ( 0.38

3.61 ( 0.62

0.342 ( 0.070

0.143 ( 0.031

34.0 ( 14.6

0.90 ( 0.30

0.44 ( 0.09

0.24 ( 0.05

0.26 ( 0.04

0.34 ( 0.04

>10

2j

2k

2n

2o

2p

3c

4k

4l

4n

6c

6t

6v

7a

7b

7c

7d

7e

7f

7g

7h

7i

0.118 ( 0.011

0.085 ( 0.010

0.379 ( 0.101

5.88 ( 0.95

>10

1.55 ( 0.27

0.26 ( 0.07

1.95 ( 0.17

1.38 ( 0.23

0.450 ( 0.060

0.306 ( 0.096

1.27 (n ) 1)

0.044 ( 0.008

0.052 ( 0.012

0.010 ( 0.001

0.321 ( 0.016

0.180 ( 0.007

0.052 ( 0.010

0.399 ( 0.045

1.79 ( 0.17

>10

2.5 × 10^-4

1.0 × 10^-3

3.6 × 10^-5

4.2 × 10^-5

8.1 × 10^-6

2.6 × 10^-4

1.5 × 10^-4

4.2 × 10^-5

3.2 × 10^-4

1.5 × 10^-3

4.3 × 10^-4

1.2 × 10^-4

9.3 × 10^-4

1.2 × 10^-4

1.5 × 10^-3

9.9 × 10^-3

6.5 × 10^-3

2.0 × 10^-5

1.5 × 10^-4

4.4 × 10^-4

3.6 × 10^-5

6.3 × 10^-5

5.9 × 10^-5

1.3 × 10^-4

3.2 × 10^-5

5.3 × 10^-4

5.6 × 10^-4

22.46 ( 5.95

>30

>10

0.42 ( 0.11

0.19 ( 0.02

0.14 ( 0.04

0.360 ( 0.085

0.154 ( 0.050

5.83 (n ) 1)

4.44 ( 0.95

0.37 ( 0.06

0.093 ( 0.053

0.619 ( 0.741

3.37 ( 0.46

8.22 ( 1.07

3.76 ( 0.87

2.38 ( 0.59

8.80 ( 1.95

0.72 ( 0.10

>30

>10

29a

29b

35

0.527 ( 0.056

0.152 ( 0.033

1.15 ( 0.09

0.147 ( 0.009

1.90 ( 0.40

12.21 ( 0.44

7.96 ( 0.99

1.83 (n ) 1)

0.155 ( 0.029

0.059 ( 0.027

0.023 ( 0.005

0.022 ( 0.005

0.033 ( 0.015

0.058 ( 0.006

0.075 ( 0.013

0.051 ( 0.012

0.040 ( 0.011

0.020 ( 0.003

0.612 ( 0.065

0.033 ( 0.005

0.015 ( 0.006

1.02 ( 0.15

0.332 ( 0.04

0.124 ( 0.02^b

44a

44b

44c

44d

44e

60a

60b

62a

62b

62c

62d

62e

67

7j

7k

7l

7m 0.024 ( 0.001

0.20 ( 0.04

0.52 ( 0.12

>3

>10

7n

7o

7p

7q

7r

0.189 ( 0.006

0.555 ( 0.182

0.044 ( 0.005

0.077 ( 0.018

0.073 ( 0.016

0.162 ( 0.143

0.039 ( 0.003

0.698 ( 0.15

2.74 ( 1.04

>10

0.61 ( 0.07

0.53 ( 0.07

0.63 ( 0.21

>30

>10

0.206 ( 0.05

0.202 ( 0.02

2.17 ( 0.29

1.07 ( 0.11

7s

7u

>30

>10

7w 0.654 ( 0.114

7x

7y

12e

13b

68

72

76

82

0.462 ( 0.132

6.93 ( 1.81

25.9 ( 4.2

16.8 (n ) 1)

0.683 ( 0.003

>110

0.266 (n ) 1)

0.203 ( 0.061

2.2 × 10^-4

1.7 × 10^-4

a

b

Mole fraction is the IC₅₀concentration value divided by the total lipid concentration (1230 µM). Intrinsic contractile activity was

exhibited by the compound during the incubation period.

Ta ble 2. Inhibitory Activity against Selected sPLA₂’s (µM)

human human porcine

1-([1,1′-Bip h en yl]-2-ylm eth yl)-4-h yd r oxy-2-m eth yl-1H-

in d ole-3-a cet a m id e (2s) (chromatography on silica gel,

1

EtOAc): yield 98%; H NMR (CDCl₃) ∂ 8.62 (br s, 1H), 7.70-

compd nonpancreatic PLA₂pancreatic PLA₂pancreatic PLA₂

6.43 (m, 12H), 6.06 (br s, 1H), 5.74 (br s, 1H), 5.14 (s, 2H),

3.74 (s, 2H), 2.16 (s, 3H); MS (FD) 370 (M⁺).

6t

6v

0.052 ( 0.012

0.010 ( 0.001

0.052 ( 0.010

0.399 ( 0.045

0.152 ( 0.033

0.147 ( 0.009

0.024 ( 0.001

0.189 ( 0.006

0.073 ( 0.016

1.29 ( 0.16

0.057 ( 0.004

0.023 ( 0.005

0.033 ( 0.004

0.016 ( 0.01

0.022 ( 0.006

0.050 ( 0.015

0.155 ( 0.029

0.023 ( 0.005

0.020 ( 0.003

1.02 ( 0.15

1.2

4.09(1.4)

1.4

0.02

0.014

0.15

0.61

25(18.7)

7.5

0.13

13.5

2.86

5.55

27

1-([1,1′-Bip h en yl]-2-ylm eth yl)-5-h yd r oxy-2-m eth yl-1H-

in dole-3-acetam ide (2t) (chromatography on silica gel, EtOAc,

then 5% MeOH/EtOAc): yield 85%; ¹H NMR (CDCl₃) ∂ 7.62-

6.69 (m, 12H), 6.47 (d, 1H), 6.72 (br s, 1H), 5.64 (br s, 1H),

5.15 (s, 2H), 3.66 (s, 2H), 2.15 (s, 3H); MS (FD) 371 (M⁺).

1-(Cycloh exylm eth yl)-5-h yd r oxy-2-m eth yl-1H-in d ole-

3-a ceta m id e (2u ) (crude product): yield 95%; mp 75-85 °C;

¹H NMR (DMSO-d₆) ∂ 8.54 (br s, 1H), 7.17-7.04 (br s, 2H),

6.82 (d, 1H), 6.77 (br s, 1H), 6.54 (dd, 1H), 3.84 (d, 2H), 2.29

(s, 3H), 1.80-1.45 (m, 6H), 1.25-0.90 (m, 5H); MS (FD⁺) 300

(M⁺). Anal. (C₁₈H₂₄N₂O₂) C, calcd 71.97, found 69.14; H, calcd

8.05, found 7.60; N, calcd 9.33, found 8.69.

1-Decyl-5-h ydr oxy-2-m eth yl-1H-in dole-3-acetam ide (2v)

(crude product): yield 60%; oil; ¹H NMR (DMSO-d₆) ∂ 8.54 (s,

1H), 7.08 (d, 1H), 7.06 (br s, 1H), 6.80 (d, 1H), 6.74 (br s, 1H),

6.54 (dd, 1H), 4.00 (t, 2H), 3.80 (s, 2H), 2.30 (s, 3H), 1.70-

1.50 (m, 2H), 1.36-1.16 (m, 14H), 0.82 (t, 3H); MS (FD⁺) 344

(M⁺).

7c

7d

3.66

69(76)

22.5

1.8

7g

7i

7m

7n

94

7r

15.9

73.5

67

13c

13d

13e

13h

13i

13j

16b

35

91.1

6.2

46.2

39

135

94

16

35.5

2.2

7.6

5.8

44b

62b

67

3.2

no activity

1.3

no activity

(s, 1H), 5.72 (br s, 1H), 5.48 (br s, 1H), 5.25 (s, 2H), 3.70 (s,

2H), 2.70 (q, 2H), 1.13 (t, 3H); MS (FD) 342 (M - 1, 100%),

344 (M + 1, 43%).

4-Allyl-2-eth yl-5-h yd r oxy-1-(p h en ylm eth yl)-1H-in d ole-

3-a ceta m id e (2i). To a solution of 2g (620 mg, 2.0 mmol) in

5146 J ournal of Medicinal Chemistry, 1996, Vol. 39, No. 26

Dillard et al.

10 mL of THF and 40 mL of DMF was added 90 mg (2.2 mmol)

of 60% NaH/mineral oil, and after the mixture was stirred for

0.17 h, 0.2 mL (2.3 mmol) of allyl bromide was added. After

2 h, the mixture was diluted with water and extracted with

EtOAc. The EtOAc solution was washed with brine, dried

(Na₂SO₄), and concentrated at reduced pressure. The residue

was chromatographed on silica gel, eluted with a gradient of

1-3% MeOH/CH₂Cl₂, to give 770 mg of 5-(allyloxy)-2-ethyl-1-

(phenylmethyl)-1H-indole-3-acetamide. This material (2.21

mmol) in 20 mL of N,N-dimethylaniline was heated in an oil

bath at 190 °C for 20 h. The mixture was cooled, diluted with

EtOAc, washed with 1 N HCl and brine, dried (Na₂SO₄), and

concentrated at reduced pressure. The residue was chromato-

graphed on silica gel, eluted with a gradient of 1-3% MeOH/

CH₂Cl₂, to give 295 mg (38% yield) of 2i as a wax: MS (FD⁺)

348 (M⁺). Anal. (C₂₂H₂₄N₂O₂) C, H, N.

1H), 5.35 (s, 2H), 5.10 (s, 2H), 3.75 (s, 3H), 3.40 (s, 2H), 2.25

(s, 3H); MS (FD⁺) 442 (M⁺). Anal. (C₂₇H₂₆N₂O₄‚0.4H₂O) C,

H, N.

3-[[[3-(2-Am in o-2-oxoeth yl)-2-m eth yl-1-(ph en ylm eth yl)-

1H-in d ol-5-yl]oxy]m eth yl]ben zoic a cid m eth yl ester (3j)

(chromatography on silica gel, gradient, 1-3% MeOH/CH₂Cl₂,

crystallization, CH₂Cl₂/EtOH): yield 69%; mp 147-149 °C; ¹H

NMR (DMSO-d₆) ∂ 8.05 (s, 1H), 7.85 (d, 1H), 7.70 (d, 1H), 7.50

(t, 1H), 7.30-7.10 (m, 6H), 6.95 (d, 2H), 6.75 (br s, 1H), 6.70

(dd, 1H), 5.30 (s, 2H), 5.10 (s, 2H), 3.80 (s, 3H), 3.40 (s, 2H),

2.25 (s, 3H); MS (FD⁺) 442 (M⁺). Anal. (C₂₇H₂₆N₂O₄) C, H,

N.

4-[[3-(2-Am in o-2-oxoeth yl)-2-m eth yl-1-(p h en ylm eth yl)-

1H-in d ol-6-yl]oxy]bu ta n oic a cid eth yl ester (4k ) (chro-

matography on silica gel, EtOAc, crystallization, CH₂Cl₂/

MeOH/hexane): yield 76%; mp 126-133 °C; ¹H NMR (CDCl₃)

∂ 7.41 (d, 1H), 7.34-6.94 (m, 5H), 6.81 (d, 1H), 6.75 (d, 1H),

5.69 (br s, 1H), 5.49 (br s, 1H), 5.25 (s, 2H), 4.13 (q, 2H), 3.99

(t, 2H), 3.69 (s, 2H), 2.50 (t, 2H), 2.29 (s, 3H), 2.09 (t, 2H),

1.23 (t, 3H); MS (FD⁺) 408 (M⁺). Anal. (C₂₄H₂₈N₂O₄) C, H,

N.

4-[[3-(2-Am in o-2-oxoeth yl)-2-m eth yl-1-(p h en ylm eth yl)-

1H-in d ol-4-yl]oxy]bu ta n oic Acid Eth yl Ester (4d ).

A

solution of 294 mg (1 mmol) of 4-hydroxy-2-methyl-1-(phenyl-

methyl)-1H-indole-3-acetamide (2c) in 5 mL of DMF was

treated with 40 mg (1 mmol) of 60% NaH/mineral oil, and after

1 h, 0.15 mL (1 mmol) of ethyl 4-bromobutyrate was added.

The mixture was stirred for 2 h, diluted with water, and

extracted with EtOAc. The EtOAc solution was washed with

a saturated NaCl solution, dried (MgSO₄), and concentrated

at reduced pressure. The residue was crystallized from MeOH/

hexane to give a total of 235 mg (58% yield) of 4d : mp 115-

5-[[3-(2-Am in o-2-oxoeth yl)-2-m eth yl-1-(p h en ylm eth yl)-

1H-in d ol-6-yl]oxy]p en ta n oic a cid eth yl ester (4l) (chro-

matography on silica gel, 50% EtOAc/hexane, then EtOAc):

yield 71%; mp 123-135 °C; ¹H NMR (DMSO-d₆) ∂ 7.40 (d, 1H),

7.34-6.60 (m, 9H), 5.34 (s, 2H), 4.03 (q, 2H), 3.91 (t, 2H), 3.40

(s, 2H), 2.33 (t, 2H), 2.25 (s, 3H), 1.16 (t, 3H); MS (FD⁺) 422

(M⁺). Anal. (C₂₅H₃₀N₂O₄) C, H, N.

1

116 °C; H NMR (CDCl₃) ∂ 7.38-6.90 (m, 6H), 6.87 (d, 1H),

6.52 (d, 1H), 6.02 (br s, 1H), 5.29 (s, 2H), 5.22 (br s, 1H), 4.21-

4.09 (m, 4H), 3.85 (s, 2H), 2.57 (t, 2H), 2.32 (s, 3H), 2.26-2.15

(m, 2H), 1.26 (s, 3H); MS (FD⁺) 408 (M⁺). Anal. (C₂₄H₂₈N₂O₄)

C, H, N.

Using the preceding method, the following were prepared

by reaction of the properly substituted hydroxyindole (2) (see

Scheme 2) with the appropriate bromo ester.

2-[[3-(2-Am in o-2-oxoeth yl)-1-(p h en ylm eth yl)-1H-in d ol-

4-yl]oxy]a cetic a cid m eth yl ester (3a ) (chromatography on

silica gel, 2% MeOH/EtOAc): yield 34%; oil; ¹H NMR (CDCl₃)

∂ 7.53 (br s, 1H), 7.38-7.02 (m, 9H), 6.94 (d, 1H), 6.40 (d, 1H),

5.85 (br s, 1H), 5.25 (s, 2H), 4.78 (s, 2H), 3.88 (s, 3H); MS (FD)

353 (M⁺).

2-[[3-(2-Am in o-2-oxoet h yl)-2-et h yl-1-(p h en ylm et h yl)-

1H -in d ol-4-yl]oxy]a cet ic a cid m et h yl est er (3m ) (crude

product): yield 71%; ¹H NMR (DMSO-d₆) ∂ 7.32-6.83 (m, 8H),

6.77 (br s, 1H), 6.45 (d, 1H), 5.39 (s, 2H), 4.87 (s, 2H), 3.76 (s,

3H), 3.68 (s, 2H), 2.72 (q, 2H), 1.03 (t, 3H); MS (FD⁺) 380 (M⁺).

Anal. (C₂₂H₂₄N₂O₄) C, H, N.

4-[[3-(2-Am in o-2-oxoet h yl)-2-et h yl-1-(p h en ylm et h yl)-

1H-in d ol-5-yl]oxy]bu ta n oic a cid eth yl ester (4n ) (chro-

matography on silica gel, 50% EtOAc/hexane): yield 55%; oil;

¹H NMR (CDCl₃) ∂ 7.45-6.84 (m, 8H), 6.09 (br s, 1H), 5.89 (br

s, 1H), 5.40 (s, 2H), 4.25 (q, 2H), 4.14 (t, 2H), 3.78 (s, 2H),

2.83 (q, 2H), 2.64 (t, 2H), 2.21 (t, 2H), 1.38 (t, 3H), 1.24 (t,

3H); MS (FD⁺) 422 (M⁺). Anal. (C₂₅H₃₀N₂O₄) C, H, N.

2-[[[3-(2-Am in o-2-oxoeth yl)-2-eth yl-1-(p h en ylm eth yl)-

1H-in d ol-5-yl]oxy]m eth yl]ben zoic a cid m eth yl ester (3o)

(chromatography on silica gel, gradient, 1-2% MeOH/CH₂-

4-[[3-(2-Am in o-2-oxoeth yl)-1-(p h en ylm eth yl)-1H-in d ol-

5-yl]oxy]bu ta n oic a cid eth yl ester (4b) (chromatography

on silica gel, gradient, CH₂Cl₂-3% MeOH/CH₂Cl₂): yield 66%;

1

oil; H NMR (CDCl₃) ∂ 7.35-7.25 (m, 3H), 7.15 (d, 1H), 7.10

Cl₂): yield 18%; mp 132-134 °C; H NMR (DMSO-d₆) ∂ 7.85

(d, 2H), 7.05 (s, 2H), 6.85 (dd, 1H), 6.35 (br s, 1H), 5.85 (br s,

1H), 5.20 (s, 2H), 4.15 (q, 2H), 4.05 (t, 2H), 3.65 (s, 2H), 2.60-

2.50 (m, 2H), 2.20-2.05 (m, 2H), 1.30 (t, 3H).

(d, 1H), 7.70 (d, 1H), 7.55 (t, 1H), 7.40 (t, 1H), 7.35-7.10 (m,

5H), 6.90 (d, 2H), 6.80 (br s, 1H), 6.65 (dd, 1H), 5.30 (s, 2H),

5.25 (s, 2H), 3.80 (s, 3H), 3.40 (s, 2H), 2.65 (q, 2H), 1.00 (t,

3H); MS (FD) 456 (M⁺). Anal. (C₂₈H₂₈N₂O₄) H, N; C: calcd,

73.66; found, 74.36.

4-[[3-(2-Am in o-2-oxoeth yl)-2-cyclop r op yl-1-(p h en ylm -

eth yl)-1H-in d ol-5-yl]oxy]bu ta n oic a cid m eth yl ester (3p )

(chromatography on silica gel, 3% MeOH/CH₂Cl₂): yield 23%;

oil.

2-[[3-(2-Am in o-2-oxoeth yl)-2-m eth yl-1-(p h en ylm eth yl)-

1H-in d ol-4-yl]oxy]a cetic a cid m eth yl ester (3c) (chroma-

tography on silica gel, 50%EtOAc/hexane, then EtOAc, then

2% MeOH/EtOAc): yield 76%; mp 206-208 °C; ¹H NMR

(CDCl₃) ∂ 7.34-6.92 (m, 7H), 6.89 (d, 1H), 6.22 (d, 1H), 5.29

(s, 2H), 5.22 (br s, 1H), 4.79 (s, 2H), 3.88 (s, 2H), 3.86 (s, 3H),

2.40 (s, 3H); MS (FD) 366 (M⁺). Anal. (C₂₁H₂₂N₂O₄) C, H, N.

4-[[3-(2-Am in o-2-oxoeth yl)-2-m eth yl-1-(p h en ylm eth yl)-

1H-in d ol-5-yl]oxy]bu ta n oic a cid eth yl ester (4g) (chro-

matography on silica gel, gradient, CH₂Cl₂-3% MeOH/CH₂-

Cl₂): yield 51%; oil; ¹H NMR (CDCl₃) ∂ 7.30-7.15 (m, 3H), 7.05

(d, 1H), 6.95 (d, 1H), 6.90 (d, 2H), 6.75 (dd, 1H), 6.40 (br s,

1H), 5.75 (br s, 1H), 5.25 (s, 2H), 4.10 (q, 2H), 4.00 (t, 2H),

3.65 (s, 2H), 2.50 (t, 2H), 2.25 (s, 3H), 2.15-2.00 (m, 2H), 1.25

(t, 3H).

4-[[3-(2-Am in o-2-oxoeth yl)-2-ch lor o-1-(p h en ylm eth yl)-

1H-in d ol-5-yl]oxy]bu ta n oic a cid eth yl ester (4q) (chro-

matography on silca gel, gradient, CH₂Cl₂-3% MeOH/CH₂-

1

Cl₂): yield 57%; H NMR (CDCl₃) ∂ 7.35-7.20 (m, 3H), 7.15

(dd, 1H), 7.00 (t, 2H), 6.95 (t, 1H), 6.80 (dd, 1H), 5.60 (br s,

1H), 5.65 (br s, 1H), 5.35 (d, 2H), 4.15 (q, 2H), 4.05 (t, 2H),

3.70 (s, 2H), 2.50 (t, 2H), 2.20-2.05 (m, 2H), 1.25 (t, 3H).

4-[[3-(2-Am in o-2-oxoeth yl)-2-br om o-1-(p h en ylm eth yl)-

1H-in d ol-5-yl]oxy]bu ta n oic a cid eth yl ester (4r ) (chroma-

tography on silica gel, gradient, 1-3% MeOH/CH₂Cl₂): yield

5-[[3-(2-Am in o-2-oxoeth yl)-2-m eth yl-1-(p h en ylm eth yl)-

1H-in d ol-5-yl]oxy]p en ta n oic a cid m eth yl ester (3h ) (chro-

matography on silica gel, gradient, CH₂Cl₂-2% MeOH/CH₂-

Cl₂): yield 46%; oil; ¹H NMR (CDCl₃) ∂ 7.30-7.15 (m, 3H), 7.05

(d, 1H), 6.95 (d, 1H), 6.90 (d, 2H), 6.75 (dd, 1H), 6.30 (br s,

1H), 5.70 (br s, 1H), 5.20 (s, 2H), 3.95 (t, 2H), 3.65 (s, 3H),

3.60 (s, 2H), 2.35 (t, 2H), 2.25 (s, 3H), 1.85-1.75 (m, 4H).

2-[[[3-(2-Am in o-2-oxoeth yl)-2-m eth yl-1-(ph en ylm eth yl)-

1H-in d ol-5-yl]oxy]m eth yl]ben zoic a cid m eth yl ester (3i)

(chromatography on silica gel, gradient, CH₂Cl₂-2% MeOH/

1

61%; oil; H NMR (CDCl₃) ∂ 7.30-7.15 (m, 3H), 7.05 (d, 1H),

7.00 (d, 2H), 6.95 (d, 1H), 6.75 (dd, 1H), 5.50 (br s, 2H), 5.35

(s, 2H), 4.10 (q, 2H), 3.95 (t, 2H), 2.50 (t, 2H), 2.10-2.00 (m,

2H), 1.20 (t, 3H).

4-[[3-(2-Am in o-2-oxoeth yl)-2-(m eth ylth io)-1-(p h en ylm -

eth yl)-1H-in d ol-5-yl]oxy]bu ta n oic a cid eth yl ester (4s)

(crude product, washed with EtOH/Et₂O): yield 83%; mp 109-

1

111 °C; H NMR (DMSO-d₆) ∂ 7.50 (br s, 1H), 7.40-7.25 (m,

4H), 7.20 (d, 1H), 7.10 (d, 2H), 7.00 (br s, 1H), 6.85 (dd, 1H),

5.60 (s, 2H), 4.10 (q, 2H), 4.05 (t, 2H), 3.75 (s, 2H), 2.55 (t,

2H), 2.15 (s 3H), 2.10-2.00 (m, 2H), 1.25 (t, 3H); MS (FD⁺)

440 (M⁺). Anal. (C₂₄H₂₈N₂O₄S) C, H, N.

1

CH₂Cl₂): yield 69%; mp 178-180 °C; H NMR (DMSO-d₆) ∂

7.85 (d, 1H), 7.70 (d, 1H), 7.60 (t, 1H), 7.40 (t, 1H), 7.35-7.15

(m, 5H), 7.10 (d, 1H), 6.95 (d, 2H), 6.75 (br s, 1H), 6.65 (dd,

Indole Inhibitors of hnps-PLA₂. 2

J ournal of Medicinal Chemistry, 1996, Vol. 39, No. 26 5147

2-[[3-(2-Am in o-2-oxoeth yl)-1-[(3-ch lor op h en yl)m eth yl]-

2-m et h yl-1H-in d ol-4-yl]oxy]a cet ic a cid et h yl est er (4t )

(crude product, washed with MeOH): yield 73%; mp 180-183

was added to 630 mg (1.6 mmol) of 9 and 0.3 mL (2.2 mmol)

of triethylamine in 30 mL of CH₂Cl₂, and the mixture was

stirred for 10 min. Anhydrous ammonia was bubbled into the

reaction mixture for 0.5 h, and then the mixture was washed

with water and a saturated NaCl solution, dried (Na₂SO₄) and

concentrated at reduced pressure. The residue was chromato-

graphed on silica gel, eluted with a gradient of CH₂Cl₂-3%

MeOH/CH₂Cl₂, to give after crystallization from Et₂O, 270 mg

(yield 44%) of 4e: mp 160-161 °C; ¹H NMR (DMSO-d₆) ∂

7.30-7.15 (m, 5H), 7.05 (d, 1H), 6.95 (d, 2H), 6.75 (br s, 1H),

6.65 (dd, 1H), 6.35 (br s, 1H), 5.30 (s, 2H), 4.70 (s, 2H), 4.10

(q, 2H), 3.40 (s, 2H), 2.25 (s, 3H), 1.20 (t, 3H); MS (FD⁺) 380

(M⁺). Anal. (C₂₂H₂₄N₂O₄) C, H, N.

2-[[[3-(2-Am in o-2-oxoeth yl)-1-[(3-ch lor oph en yl)m eth yl]-

2-m eth yl-1H-in d ol-4-yl]oxy]m eth yl]a cetic Acid Sod iu m

Sa lt (6t). A mixture of 155 mg (0.39 mmol) of 4t and 4 mL of

1 N NaOH in 10 mL of EtOH was heated 0.5 h and allowed to

cool, and the precipitate was filtered to give 140 mg (88% yield)

of 6t: mp >250 °C; ¹H NMR (DMSO-d₆) ∂ 9.42 (br s, 1H), 7.34-

6.82 (m, 6H), 6.38 (t, 1H), 6.31 (br s, 1H), 5.36 (s, 2H), 4.12 (s,

2H), 3.63 (s, 2H), 2.32 (s, 3H); MS (FAB+) 409 (M - 1, 100),

411 (M + 1, 45). Anal. (C₂₀H₁₈ClN₂O₄Na) C, H, N.

1

°C; H NMR (DMSO-d₆) ∂ 7.36-6.84 (m, 7H), 6.78 (br s, 1H),

6.46 (d, 1H), 5.20 (s, 2H), 4.87 (s, 2H), 3.75 (s, 3H), 3.69 (s,

2H), 2.27 (s, 3H); MS (FD⁺) 400 (M - 1, 100), 402 (M + 1, 36).

Anal. (C₂₁H₂₁ClN₂O₄) C, H, N, S.

2-[[3-(2-Am in o-2-oxoeth yl)-1-[(3-ch lor op h en yl)m eth yl]-

2-eth yl-1H-in d ol-4-yl]oxy]a cetic a cid m eth yl ester (3u )

(chromatography on silica gel, EtOAc): yield 71%; oil; ¹H NMR

(CDCl₃) ∂ 7.25-6.74 (m, 7H), 6.43 (d, 1H), 5.40 (br s, 1H), 5.27

(s, 2H), 4.81 (s, 2H), 3.89 (s, 2H), 3.88 (s, 3H), 2.84 (q, 2H),

1.16 (t, 3H); MS (FD) 415 (M - 1, 100), 417 (M + 1, 45).

2-[[3-(2-Am in o-2-oxoeth yl)-1-([1,1′-biph en yl]-2-ylm eth yl)-

2-m eth yl-1H-in d ol-4-yl]oxy]a cetic a cid m eth yl ester (3v)

(chromatography on silica gel, 50% EtOAc/hexane): yield 67%;

¹H NMR (CDCl₃) ∂ 7.66-6.90 (m, 10H), 6.78 (d, 1H), 6.47 (d,

1H), 6.40 (d, 1H), 5.16 (s, 3H), 4.80 (s, 2H), 3.86 (s, 5H), 2.28

(s, 3H); MS (FD⁺) 442 (M⁺).

4-[[3-(2-Am in o-2-oxoeth yl)-1-(cycloh exylm eth yl)-2-m eth -

yl-1H-in d ol-5-yl]oxy]bu ta n oic a cid eth yl ester (4w ) (chro-

matography on silica gel, 2% MeOH/CH₂Cl₂): yield 46%; mp

92-94 °C; MS (FD) 414 (M⁺). Anal. (C₂₄H₃₄N₂O₄) C, H, N.

4-[[3-(2-Am in o-2-oxoeth yl)-1-d ecyl-2-m eth yl-1-H-in d ol-

5-yl]oxy]bu ta n oic a cid eth yl ester (4x) (chromatography

on silica gel, 3% MeOH/CH₂Cl₂): yield 55%; mp 93-95 °C; MS

(FD⁺) 458 (M⁺). Anal. (C₂₇H₄₂N₂O₄) C, H, N.

5-[3-(Eth oxyca r bon yl)p h en oxy]-2-m eth yl-1-(p h en ylm -

eth yl)-1H-in d ole-3-a ceta m id e (4y). A mixture of 590 mg

(2.0 mmol) of 5-hydroxy-2-methyl-1-(phenylmethyl)-1H-indole-

3-acetamide (2d ), 290 mg (2.0 mmol) of CuBr, and 90 mg (2.2

mmol) of NaH (60% in mineral oil) in 40 mL of pyridine was

stirred for 10 min and then treated with 830 mg (3 mmol) of

ethyl 3-iodobenzoate at reflux for 15.5 h. The mixture was

cooled, diluted with EtOAc, washed with water, washed with

brine, dried (Na₂SO₄), and evaporated at reduced pressure. The

residue was chromatographed on silica gel, eluting with a

gradient of CH₂Cl₂-4% MeOH/CH₂Cl₂and crystallized with

Et₂O to give 4z: 120 mg (yield 14%); mp 199-200 °C; ¹H NMR

(DMSO-d₆) ∂ 10.40 (s, 1H), 8.80 (s, 1H), 8.40 (s, 1H), 8.05 (d,

1H), 7.80 (d, 1H), 7.50 (t, 1H), 7.45-7.25 (m, 3H), 7.20 (d, 1H),

7.10 (d, 2H), 7.05 (d, 1H), 6.70 (dd, 1H), 5.40 (s, 2H), 4.40 (q,

2H), 3.80 (s, 2H), 2.40 (s, 3H), 1.40 (t, 3H); MS (FD) 442 (M⁺).

Anal. (C₂₇H₂₆N₂O₄‚0.5EtOAc) C, H, N.

3-[[3-(2-Am in o-2-oxoeth yl)-2-m eth yl-1-(p h en ylm eth yl)-

1H-in dol-5-yl]oxy]pr opion ic Acid Ben zyl Ester (5f). 5-Hy-

droxy-2-methyl-1-(phenylmethyl)-1H-indole-3-acetamide (2d )

(270 mg, 0.92 mmol), 500 mg of K₂CO₃, and 1.0 mL of benzyl

acrylate in 30 mL of methyl ethyl ketone was heated to

maintain reflux for 100 h (additional benzyl acrylate was

added at various times). After cooling, the mixture was diluted

with water and extracted with EtOAc, and the EtOAc solution

was washed with a saturated NaCl solution and dried (Na₂-

SO₄). After the mixture was concentrated the residue was

chromatographed on silica gel, eluting with a gradient of CH₂-

Cl₂-7% MeOH/CH₂Cl₂to give 130 mg of 5f.

Using the preceding method, 6c was prepared from 3c and

6v was prepared from 3v.

2-[[3-(2-Am in o-2-oxoeth yl)-2-m eth yl-1-(p h en ylm eth yl)-

1H-in d ol-4-yl]oxy]a cetic a cid sod iu m sa lt (6c) (crystallized

from reaction mixture): yield 92%; mp >250 °C; ¹H NMR

(DMSO-d₆) ∂ 9.33 (br s, 1H), 7.32-6.32 (m, 8H), 6.31 (br s,

1H), 5.33 (s, 2H), 4.13 (s, 2H), 3.62 (s, 2H), 2.32 (s, 3H); MS

(FD⁺) 352 (M⁺). Anal. (C₂₀H₁₉N₂O₄Na) C, H, N.

2-[[3-(2-Am in o-2-oxoeth yl)-1-([1,1′-biph en yl]-2-ylm eth yl)-

2-m eth yl-1H-in d ol-4-yl]oxy]a cetic a cid sod iu m sa lt (6v)

(crystallized from reaction mixture): yield 75%; mp >250 °C;

¹H NMR (DMSO-d₆) ∂ 9.18 (br s, 1H), 7.40-6.80 (m, 9H), 6.65

(d, 1H), 6.38-6.26 (m, 3H), 5.21 (s, 2H), 4.11 (s, 2H), 3.61 (s,

2H), 2.21 (s, 3H); MS (FAB+) 451 (M⁺). Anal. (C₂₆H₂₃N₂O₄-

Na) C, H, N.

4-[[3-(2-Am in o-2-oxoeth yl)-2-m eth yl-1-(p h en ylm eth yl)-

1H-in d ol-6-yl]oxy]bu ta n oic Acid (7k ). A solution of 100

mg (0.245 mmol) of 4k and 2 mL of 1 N NaOH in 5 mL of

EtOH was stirred for 1.5 h, diluted with water, and extracted

with EtOAc. The aqueous layer was made acidic to pH 6 with

1 N HCl and extracted with EtOAc; the EtOAc was dried

(MgSO₄) and concentrated at reduced pressure. The residue

was crystallized from MeOH/CH₂Cl₂to give 44 mg (yield 47%)

of 7k : mp 180-184 °C; ¹H NMR (DMSO-d₆) ∂ 12.08 (br s, 1H),

7.40 (d, 1H), 7.33-7.20 (m, 3H), 7.18 (br s, 1H), 6.99 (d, 1H),

6.12 (s, 1H), 6.78 (br s, 1H), 6.64 (d, 1H), 5.34 (s, 2H), 3.93 (t,

2H), 3.41 (s, 2H), 2.37 (t, 2H), 2.25 (s, 3H); MS (FD⁺) 380 (M⁺).

Anal. (C₂₂H₂₄N₂O₄) C, H, N.

Using the procedure above or a similar procedure where the

reaction was heated at reflux in ethanol, the following conver-

sions were made: 3a to 7a ; 4b to 7b; 3c to 7c; 4d to 7d ; 4e to

7e; 4g to 7g; 3h to 7h ; 3i to 7i; 3j to 7j; 4l to 7l; 3m to 7m ; 4n

to 7n ; 3o to 7o; 3p to 7p ; 4q to 7q; 4r to 7r ; 4s to 7s; 3u to

7u ; 4w to 7w ; 4x to 7x; 4y to 7y; 4z to 7z:

2-[[3-(2-Am in o-2-oxoeth yl)-1-(p h en ylm eth yl)-1H-in d ol-

4-yl]oxy]a cetic a cid (7a ) (crude product, washed with CH₂-

Cl₂): yield 56%; mp 207-208 °C; ¹H NMR (DMSO-d₆) ∂ 7.34-

6.92 (m, 9H), 6.81 (br s, 1H), 6.42 (d, 1H), 5.33 (s, 2H), 4.72 (s,

2H), 3.64 (s, 2H); MS (FD) 339 (M⁺). Anal. (C₁₉H₁₈N₂O₄) C,

H, N.

4-[[3-(2-Am in o-2-oxoeth yl)-1-(p h en ylm eth yl)-1H-in d ol-

5-yl]oxy]b u t a n oic a cid (7b ) (crystallization, CH₂Cl₂/

EtOH): yield 46%; mp 160-163 °C; ¹H NMR (DMSO-d₆/D₂O)

∂ 7.30-7.10 (m, 4H), 7.05 (d, 2H), 7.00 (d, 1H), 6.65 (dd, 1H),

5.20 (s, 2H), 3.90 (t, 2H), 3.40 (s, 2H), 2.35 (t, 2H), 1.95-1.80

(m, 2H); MS (FD⁺) 366 (M⁺). Anal. (C₂₁H₂₂N₂O₄) C, H, N.

2-[[3-(2-Am in o-2-oxoeth yl)-2-m eth yl-1-(p h en ylm eth yl)-

1H -in d ol-4-yl]oxy]a cet ic a cid (7c) (crystallization,

MeOH): yield 57%; mp 225-227 °C; ¹H NMR (DMSO-d₆) ∂

13.19 (br s, 1H), 7.35-6.85 (m, 8H), 6.77 (br s, 1H), 6.42 (d,

1H), 5.37 (s, 2H), 4.75 (s, 2H), 3.66 (s, 2H), 2.28 (s, 3H); MS

(FD) 352 (M⁺). Anal. (C₂₀H₂₀N₂O₄) C, H, N.

2-[[3-(2-Am in o-2-oxoeth yl)-2-m eth yl-1-(p h en ylm eth yl)-

1H-in d ol-5-yl]oxy]a cetic Acid Eth yl Ester (4e). A solution

of 1.78 g (5.3 mmol) of 5-methoxy-2-methyl-1-(phenylmethyl)-

1H-indole-3-acetic acid (8) in 125 mL of CH₂Cl₂and 21 mL of

1 M boron tribromide in CH₂Cl₂was stirred for 4 h, the boron

complex was decomposed by the addition of 10 mL of methanol

over 0.5 h, and the resulting crude 5-hydroxy-2-methyl-1-

(phenylmethyl)-1H-indole-3-acetic acid was concentrated at

reduced pressure. A solution of 590 mg of this material in 30

mL of THF and 10 mL of DMSO was treated with 180 mg (4.5

mmol) of 60% NaH/mineral oil, and after 10 min, 0.25 mL (2.25

mmol) of ethyl 2-bromoacetate was added. The mixture was

stirred for 0.5 h, acidified with 1 N HCl, and extracted with

EtOAc. The EtOAc solution was washed with water and a

saturated NaCl solution, dried (Na₂SO₄), and concentrated at

reduced pressure. After chromatography on silica gel, eluted

with a gradient of CH₂Cl₂-3% MeOH/CH₂Cl₂, there was

obtained 590 mg (77% yield) of 5-(carbethoxymethoxy)-2-

methyl-1-(phenylmethyl)-1H-indole-3-acetic acid (9). While

cooling at -5 °C, 0.16 mL (2.1 mmol) of methyl chloroformate

4-[[3-(2-Am in o-2-oxoeth yl)-2-m eth yl-1-(p h en ylm eth yl)-

1H-in dol-4-yl]oxy]bu tan oic acid (7d) (crude product, washed

5148 J ournal of Medicinal Chemistry, 1996, Vol. 39, No. 26

Dillard et al.

1

with MeOH): yield 42%, mp 192-193 °C; H NMR (CDCl₃+

4-[[3-(2-Am in o-2-oxoeth yl)-2-ch lor o-1-(p h en ylm eth yl)-

1H -in d ol-5-yl]oxy]b u t a n oic a cid (7q ) (crystallization,

MeOH/CH₂Cl₂): yield 80%; mp 198-200 °C; MS (FD⁺) 400 (M

- 1, 100), 402 (M + 1, 38). Anal. (C₂₁H₂₁ClN₂O₄‚0.4CH₂Cl₂)

C, H, N.

4-[[3-(2-Am in o-2-oxoeth yl)-2-br om o-1-(p h en ylm eth yl)-

1H -in d ol-5-yl]oxy]b u t a n oic a cid (7r ) (crystallization,

EtOH/Et₂O): yield 80%; mp 184-186 °C; ¹H NMR (DMSO-

d₆) ∂ 7.60 (br s, 1H), 7.30-7.15 (m, 4H), 7.05 (d, 1H), 6.95 (d,

2H), 6.85 (br s, 1H), 6.70 (dd, 1H), 5.35 (s, 2H), 3.90 (t, 2H),

3.30 (s, 2H), 2.35 (t, 2H), 1.95-1.80 (m, 2H); MS (FD⁺) 444

(M - 1), 446 (M + 1). Anal. (C₂₁H₂₁BrN₂O₄) C, calcd 56.64,

found 42.71; H, calcd 4.75, found 3.76; N, calcd 6.29, found

4.50; Br, calcd 17.94, found 12.77; residue 17.00%.

4-[[3-(2-Am in o-2-oxoeth yl)-2-(m eth ylth io)-1-(p h en ylm -

eth yl)-1H-in d ol-5-yl]oxy]bu ta n oic a cid (7s) (crude product,

washed with EtOH/Et₂O): yield 85%; mp 187-188 °C; ¹H

NMR (DMSO-d₆) ∂ 7.40 (br s, 1H), 7.30-7.10 (m, 4H), 7.05 (s,

1H), 6.95 (d, 2H), 6.90 (br s, 1H), 6.70 (d, 1H), 5.45 (s, 2H),

3.95 (t, 2H), 3.65 (s, 2H), 2.35 (t, 2H), 2.00-1.85 (m, 2H); MS

(FD) 411 (M - 1)⁺. Anal. (C₂₂H₂₄N₂O₄S) C, H, N, S.

2-[[3-(2-Am in o-2-oxoeth yl)-1-[(3-ch lor op h en yl)m eth yl]-

2-eth yl-1H-in d ol-4-yl]oxy]a cetic a cid (7u ) (crude product,

washed with EtOAc): yield 80%; mp 216-217 °C; ¹H NMR

(DMSO-d₆) ∂ 7.34-6.74 (m, 8H), 6.46 (t, 1H), 5.41 (s, 2H), 4.75

(s, 2H), 3.67 (s, 2H), 2.74 (q, 2H), 1.04 (t, 3H); MS (FD) 401

(M - 1, 100), 403 (M + 1, 39). Anal. (C₂₁H₂₁ClN₂O₄) C, H, N.

4-[[3-(2-Am in o-2-oxoeth yl)-1-(cycloh exylm eth yl)-2-m eth -

yl-1H-in d ol-5-yl]oxy]bu t a n oic a cid (7w ) (crystallization,

MeOH): yield 28%; mp 212-214 °C; ¹H NMR (DMSO-d₆) ∂

7.25 (d, 1H), 7.20 (br s, 1H), 7.02 (d, 1H), 6.78 (br s, 1H), 6.66

(dd, 1H), 3.96 (t, 2H), 3.88 (d, 2H), 3.40 (s, 2H), 2.40 (t, 2H),

2.32 (s, 3H), 2.00-1.88 (m, 2H), 1.78-1.46 (m, 6H), 1.20-0.88

(m, 5H); MS (FD) 386 (M⁺). Anal. (C₂₂H₃₀N₂O₄) C, H, N.

4-[[3-(2-Am in o-2-oxoeth yl)-1-d ecyl-2-m eth yl-1H-in d ol-

5-yl]oxy]bu ta n oic a cid (7x) (crystallization, MeOH): yield

77%; mp 163-165 °C; ¹H NMR (DMSO-d₆) ∂ 7.25 (d, 1H), 7.20

(br s, 1H), 7.04 (d, 1H), 6.78 (br s, 1H), 6.64 (dd, 1H), 4.04 (t,

2H), 3.95 (t, 2H), 3.36 (s, 2H), 2.40 (t, 2H), 2.32 (s, 3H), 2.00-

1.88 (m, 2H), 1.66-1.50 (m, 6H), 1.36-1.16 (m, 14H), 0.86 (t,

3H); MS (FD) 430 (M⁺). Anal. (C₂₅H₃₈N₂O₄) H; C: calcd,

69.74; found, 70.63; N: calcd, 6.51; found, 6.98.

DMSO-d₆) ∂ 7.42-6.92 (m, 6H), 6.85 (d, 1H), 6.49 (d, 1H), 6.06

(br s, 1H), 5.82 (br s, 1H), 5.28 (s, 2H), 4.16 (t, 2H), 3.83 (s,

2H), 2.60-2.52 (m, 2H), 2.30 (s, 3H), 2.23-2.14 (m, 2H); MS

(FD⁺) 380 (M⁺). Anal. (C₂₂H₂₄N₂O₄) H, N; C: calcd, 69.46;

found, 68.17.

2-[[3-(2-Am in o-2-oxoeth yl)-2-m eth yl-1-(p h en ylm eth yl)-

1H-in d ol-5-yl]oxy]a cetic a cid (7e) (crude product, washed

with Et₂O): yield 90%; mp 196-198 °C; H NMR (DMSO-d₆)

∂ 7.40-7.25 (m, 5H), 7.15 (d, 1H), 7.05 (d, 2H), 6.85 (br s, 1H),

6.75 (dd, 1H), 5.40 (s, 2H), 4.65 (s, 2H), 3.50 (s, 2H), 2.35 (s,

3H); MS (FD⁺) 352 (M⁺). Anal. (C₂₀H₂₀N₂O₄) C, H, N.

4-[[3-(2-Am in o-2-oxoeth yl)-2-m eth yl-1-(p h en ylm eth yl)-

1H -in d ol-5-yl]oxy]b u t a n oic a cid (7g) (crystallization,

EtOAc): yield 38%; mp 218-221 °C; ¹H NMR (DMSO-d₆) ∂

7.35-7.20 (m, 5H), 7.10 (d, 1H), 7.00 (d, 2H), 6.80 (br s, 1H),

6.65 (dd, 1H), 5.35 (s, 2H), 3.95 (t, 2H), 3.45 (s, 2H), 2.40 (t,

2H), 2.30 (s, 3H), 2.00-1.90 (m, 2H); MS (FD⁺) 380 (M⁺). Anal.

(C₂₂H₂₄N₂O₄) C, H, N.

5-[[3-(2-Am in o-2-oxoeth yl)-2-m eth yl-1-(p h en ylm eth yl)-

1H -in d ol-5-yl]oxy]p en t a n oic a cid (7h ) (crystallization,

MeOH/CH₂Cl₂/Et₂O): yield 100%; mp 168-169 °C; H NMR

(DMSO-d₆) ∂ 7.25-7.10 (m, 5H), 7.05 (d, 1H), 6.90 (d, 2H), 6.75

(br s, 1H), 6.60 (dd, 1H), 5.25 (s, 2H), 3.90 (t, 2H), 3.35 (s, 2H),

2.15 (t, 2H), 2.15 (s, 3H), 1.75-1.55 (m, 4H); MS (FD⁺) 394

(M⁺). Anal. (C₂₃H₂₆N₂O₄) C, H, N.

2-[[[3-(2-Am in o-2-oxoeth yl)-2-m eth yl-1-(ph en ylm eth yl)-

1H-in d ol-5-yl]oxy]m eth yl]ben zoic a cid (7i) (crystallization,

1

CH₂Cl₂): yield 59%; mp 173-176 °C; H NMR (DMSO-d₆) ∂

7.90 (d, 1H), 7.70 (d, 1H), 7.55 (t, 1H), 7.40 (t, 1H), 7.35-7.15

(m, 5H), 7.10 (d, 1H), 6.95 (d, 2H), 6.75 (br s, 1H), 6.65 (dd,

1H), 5.40 (s, 2H), 5.30 (s, 2H), 3.40 (s, 2H), 2.25 (s, 3H); MS

(FD) 428 (M⁺). Anal. (C₂₆H₂₄N₂O₄‚0.4 H₂O) C, H, N.

3-[[[3-(2-Am in o-2-oxoeth yl)-2-m eth yl-1-(ph en ylm eth yl)-

1H-in d ol-5-yl]oxy]m eth yl]ben zoic a cid (7j) (crystallization,

CH₂Cl₂/EtOH): yield 72%; mp 176-179 °C; ¹H NMR (DMSO-

d₆) ∂ 8.05 (s, 1H), 7.85 (d, 1H), 7.70 (d, 1H), 7.50 (t, 1H), 7.30-

7.15 (m, 6H), 6.95 (d, 2H), 6.75 (br s, 1H), 6.70 (dd, 1H), 5.30

(s, 2H), 5.15 (s, 2H), 3.40 (s, 2H), 2.25 (s, 3H); MS (FD⁺) 428

(M⁺). Anal. (C₂₆H₂₄N₂O₄.H₂O) C, H, N.

5-[[3-(2-Am in o-2-oxoeth yl)-2-m eth yl-1-(p h en ylm eth yl)-

1H -in d ol-6-yl]oxy]p en t a n oic a cid (7l) (crystallization,

MeOH/CH₂Cl₂): yield 56%; mp 103-107 °C; ¹H NMR (DMSO-

d₆) ∂ 12.00 (br s, 1H), 7.44-6.80 (m, 10H), 5.27 (s, 2H), 3.92

(t, 2H), 3.41 (s, 2H), 2.30-2.22 (m, 2H), 2.25 (s, 3H), 1.80-

1.52 (m, 4H); MS (FD⁺) 394 (M⁺). Anal. (C₂₃H₂₆N₂O₄) C, H,

N.

2-[[3-(2-Am in o-2-oxoet h yl)-2-et h yl-1-(p h en ylm et h yl)-

1H-in d ol-4-yl]oxy]a cetic a cid (7m ) (crystallized from reac-

tion mixture): yield 95%; mp 220-222 °C; H NMR (DMSO-

5-(3-Ca r boxyp h en oxy)-2-m eth yl-1-(p h en ylm eth yl)-1H-

in d ole-3-a ceta m id e (7y) (crude product): yield 32%; amor-

phous solid; MS (FD⁺) 414 (M⁺). Anal. (C₂₅H₂₂N₂O₄‚H₂O) C,

H, N.

3-[[3-(2-Am in o-2-oxoeth yl)-2-m eth yl-1-(p h en ylm eth yl)-

1H-in d ol-5-yl]oxy]p r op ion ic Acid (7f). A mixture of 130

mg (0.29 mmol) of 5f and 0.2 g of 10% Pd/C in 100 mL of EtOH

was hydrogenated at 40 psi of hydrogen for 4.5 h. The mixture

was filtered and concentrated until the product crystallized.

The crystals were washed with Et₂O to give 80 mg (75% yield)

1

d₆) ∂ 7.32-6.40 (m, 10H), 5.38 (s, 2H), 4.75 (s, 2H), 3.66 (s,

2H), 2.74 (q, 2H), 1.05 (t, 2H); MS (FD⁺) 366 (M⁺). Anal.

(C₂₁H₂₂N₂O₄) H; C: calcd, 68.84; found, 67.52; N: calcd, 7.65;

found, 8.46.

1

of 7f; mp 201-203 °C; H NMR (DMSO-d₆) ∂ 7.30-7.10 (m,

5H), 7.05 (d, 1H), 6.90 (d, 2H), 6.75 (br s, 1H), 6.60 (dd, 1H),

5.25 (s, 2H), 3.90 (t, 2H), 3.40 (s, 2H), 2.65 (t, 2H), 2.25 (s,

3H). Anal. (C₂₁H₂₂N₂O₄‚H₂O) C, H; N: calcd, 7.29; found, 6.68.

[3-(2-Eth oxy-2-oxoeth yl)-1-(p h en ylm eth yl)-1H-in d ol-5-

yl]oxy]m eth yl]ph osph on ic Acid Dieth yl Ester (11a). 5-Hy-

droxy-1-(phenylmethyl)-1H-indole-3-acetic acid ethyl ester (10,

730 mg, 2.4 mmol) was dissolved in 20 mL of THF and 75 mL

of DMF, and 115 mg (2.8 mmol) of 60% NaH/mineral oil was

added. After 0.17 h, 1.1 g (4.0 mmol) of (iodomethyl)-

phosphonic acid dimethyl ester was added and stirring main-

tained for 5.5 h. The mixture was diluted with water and

EtOAc, and the organic layer was separated, washed with

water and brine, and dried (Na₂SO₄). The solution was

evaporated at reduced pressure and the residue chromato-

graphed on silica gel, eluting with Et₂O to give 150 mg (14%

yield) of 11a : ¹H NMR (CDCl₃) ∂ 7.35-7.00 (m, 8H), 6.85 (dd,

1H), 5.15 (s, 2H), 4.45 (d, 2H), 4.20 (q, 4H), 4.10 (q, 2H), 3.65

(s, 2H), 1.30 (t, 6H), 1.20 (t, 3H).

4-[[3-(2-Am in o-2-oxoeth yl)-2-eth yl-1-(p h en ylm eth yl)-1-

H-in d ol-5-yl]oxy]bu ta n oic a cid (7n ) (crude product, washed

with Et₂O/MeOH): yield 61%; mp 196-199 °C; ¹H NMR

(DMSO-d₆) ∂ 7.37-6.59 (m, 10H), 5.32 (s, 2H), 3.92 (t, 2H),

3.41 (s, 2H), 2.71 (q, 2H), 2.39 (t, 2H), 2.00-1.85 (m, 2H), 1.03

(t, 3H); MS (FD⁺) 394 (M⁺). Anal. (C₂₃H₂₆N₂O₄) C, H, N.

2-[[[3-(2-Am in o-2-oxoeth yl)-2-eth yl-1-(p h en ylm eth yl)-

1H-in d ol-5-yl]oxy]m eth yl]ben zoic a cid (7o) (crystalliza-

tion, CH₂Cl₂/Et₂O): yield 92%; mp ∼100 °C; ¹H NMR (DMSO-

d₆) ∂ 7.90 (d, 1H), 7.70 (d, 1H), 7.55 (t, 1H), 7.40 (t, 1H), 7.30-

7.10 (m, 6H), 6.95 (d, 2H), 6.75 (br s, 1H), 6.65 (dd, 1H), 5.35

(s, 2H), 5.25 (s, 2H), 3.35 (s, 2H), 2.65 (q, 2H), 1.00 (t, 3H);

MS (FD) 442 (M⁺). Anal. (C₂₇H₂₆N₂O₄‚0.9CH₂Cl₂) C, H, N.

4-[[3-(2-Am in o-2-oxoeth yl)-2-cyclop r op yl-1-(p h en ylm -

et h yl)-1H -in d ol-5-yl]oxy]b u t a n oic a cid (7p ) (crude

1

product): yield 15%; mp 192-196 °C; H NMR (DMSO-d₆) ∂

7.32-7.18 (m, 3H), 7.12 (d, 1H), 7.02 (br s, 1H), 7.00 (d, 2H),

6.85 (br s, 1H), 6.70 (dd, 1H), 5.45 (s, 2H), 3.96 (t, 2H), 3.54 (s,

2H), 2.90 (t, 2H), 2.00-1.86 (m, 2H), 1.70-1.60 (m, 1H), 0.98-

0.88 (m, 2H), 0.78-0.68 (m, 2H); MS (FD) 406 (M⁺). Anal.

(C₂₄H₂₆N₂O₄) C, H, N.

[3-[[3-(2-Eth oxy-2-oxoeth yl)-1-(ph en ylm eth yl)-1H-in dol-

5-yl]oxy]p r op yl]p h osp h on ic Acid Dim eth yl Ester (11b).

A solution of 10 (560 mg, 1.8 mmol) in 25 mL of THF and 75

mL of DMF was treated with 80mg (2.0 mmol) of 60% NaH/

mineral oil. After 0.17 h, 465 mg (2.0 mmol) of (3-bromopro-

Indole Inhibitors of hnps-PLA₂. 2

J ournal of Medicinal Chemistry, 1996, Vol. 39, No. 26 5149

pyl)phosphonic acid dimethyl ester was added and stirring

maintained for 3 h. The mixture was diluted with water and

EtOAc, and the organic layer was separated, washed with

water and brine, and dried (Na₂SO₄). The solution was

evaporated at reduced pressure and the residue chromato-

graphed on florisil, eluting with a gradient of 1-3% MeOH/

CH₂Cl₂, to give 590 mg (71% yield) of 11b: ¹H NMR (CDCl₃) ∂

7.30-7.20 (m, 3H), 7.10-7.05 (m, 5H), 6.75 (dd, 1H), 5.15 (s,

2H), 4.15 (q, 2H), 4.00 (t, 2H), 3.75 (s, 3H), 3.70 (s, 3H), 3.65

(s, 2H), 2.15-1.85 (m, 4H), 1.25 (t, 3H).

[[3-(2-Am in o-2-oxoeth yl)-1-(p h en ylm eth yl)-1H-in d ol-5-

yl]oxy]m eth yl]p h osp h on ic Acid Dieth yl Ester (12a ). The

phosphonic acid ester 11a (150 mg, 0.3 mmol) was dissolved

in 25 mL of toluene, and 10 mL of 0.67 M CH₃ClAlNH₂in

benzene/toluene was added. The mixture was heated at 50

°C for 1.25 h, and water and 1 N HCl were added. The mixture

was extracted with a large volume of EtOAc, and the organic

layer was washed with brine, dried (Na₂SO₄), and concentrated

at reduced pressure. The residue was chromatographed on

silica gel, eluting with a gradient of 1-3% MeOH/CH₂Cl₂, to

give 120 mg (93% yield) of 12a : ¹H NMR (CDCl₃) ∂ 7.30-7.20

(m, 3H), 7.15-7.00 (m, 5H), 6.85 (dd, 1H), 6.20 (br s, 1H), 6.00

(br s, 1H), 5.15 (s, 2H), 4.30 (d, 2H), 4.25-4.10 (m, 4H), 3.60

(s, 2H), 1.30 (t, 6H).

2H), 3.79 (s, 3H), 3.75 (s, 3H), 3.71 (s, 2H), 2.69 (t, 2H), 2.18-

1.90 (m, 4H), 1.60-1.44 (m, 2H), 0.93 (t, 3H); MS (FD⁺) 472

(M⁺). Anal. (C₂₅H₃₃N₂O₅P) C, H, N.

[3-[[3-(2-Am in o-2-oxoeth yl)-2-cyclop r op yl-1-(p h en ylm -

eth yl)-1H-in d ol-5-yl]oxy]p r op yl]p h osp h on ic a cid d im -

eth yl ester (12g) (chromatography on silica gel, gradient,

1-5% MeOH/CH₂Cl₂): yield 71%; oil; ¹H NMR (CDCl₃) ∂ 7.20-

7.05 (m, 3H), 6.95 (d, 1H), 6.90-6.80 (m, 3H), 6.70 (dd, 1H),

6.35 (br s, 1H), 5.65 (br s, 1H), 5.40 (s, 2H), 3.98 (t, 2H), 3.75

(s, 2H), 3.70 (s, 3H), 3.65 (s, 3H), 2.05-1.80 (m, 4H), 1.60-

1.50 (m, 1H), 0.90-0.80 (m, 2H), 0.65-0.60 (m, 2H).

[3-[[3-(2-Am in o-2-oxoeth yl)-2-br om o-1-(p h en ylm eth yl)-

1H-in d ol-5-yl]oxy]p r op yl]p h osp h on ic a cid d im eth yl es-

ter (12h ) (chromatography on silica gel, gradient, 1-3%

MeOH/CH₂

Cl₂, crystallization, CH₂Cl₂/Et₂O): yield 27%; mp

1

∼100 °C; H NMR (CDCl₃) ∂ 7.30-7.10 (m, 3H), 7.05 (d, 1H),

7.00 (d, 2H), 6.95 (d, 1H), 6.75 (dd, 1H), 6.15 (br s, 1H), 5.70

(br s, 1H), 5.30 (s, 2H), 3.95 (t, 2H), 3.75 (s, 3H), 3.70 (s, 3H),

3.65 (s, 2H), 2.10-1.85 (m, 4H); MS (FD⁺) 508 (M - 1), 510

(M + 1). Anal. (C₂₂H₂₆BrN₂O₅P‚0.8CH₂Cl₂) C, H, N.

[3-[[3-(2-Am in o-2-oxoeth yl)-1-[(3-ch lor oph en yl)m eth yl]-

2-eth yl-1H-in d ol-5-yl]oxy]p r op yl]p h osp h on ic a cid d im -

eth yl ester (12i) (chromatography on silica gel, EtOAc, then

10% MeOH/EtOAc): yield 40%; ¹H NMR (CDCl₃) ∂ 7.33-6.77

(m, 7H), 5.72 (br s, 1H), 5.62 (br s, 1H), 5.29 (s, 2H), 4.07 (t,

2H), 3.80 (s, 3H), 3.77 (s, 3H), 3.71 (s, 2H), 2.74 (q, 2H), 2.21-

1.94 (m, 4H), 1.16 (t, 3H); MS (FD) 493 (M - 1, 100), 491 (M

+ 1, 38).

Using the preceding method, 12b was prepared from 11b:

[3-[[3-(2-Am in o-2-oxoeth yl)-1-(ph en ylm eth yl)-1H-in dol-

5-yl]oxy]p r op yl]p h osp h on ic a cid d im et h yl est er (12b )

(chromatography on silica gel, gradient, 1-4% MeOH/CH₂-

Cl₂): yield 80%; oil.

[3-[[3-(2-Am in o-2-oxoet h yl)-1-([1,1′-b ip h en yl]-2-ylm e-

th yl)-2-m eth yl-1H-in dol-5-yl]oxy]pr opyl]ph osph on ic acid

d im eth yl ester (12j) (chromatography on silica gel, gradient,

EtOAc-10% MeOH/EtOAc): yield 34%; ¹H NMR (CDCl₃) ∂

7.58-6.73 (m, 11H), 5.62 (br s, 1H), 5.34 (br s, 1H), 5.17 (s,

2H), 4.04 (t, 2H), 3.80 (s, 3H), 3.75 (s, 3H), 3.66 (s, 2H), 2.28-

1.90 (m, 2H), 2.17 (s, 3H); MS (FD) 520 (M⁺). Anal.

(C₂₉H₃₃N₂O₅P) H, N; C: calcd, 66.91; found, 68.34.

[[[3-(2-Am in o-2-oxoeth yl)-2-m eth yl-1-(p h en ylm eth yl)-

1H-in d ol-4-yl]oxy]m eth yl]p h osp h on ic Acid Dieth yl Ester

(12c). 4-Hydroxy-2-methyl-1-(phenylmethyl)-1H-indole-3-ac-

etamide (2c, 294 mg, 1 mmol) was added to 40 mg (1 mmol) of

60% NaH/mineral oil (previously washed with hexane) in 2

mL of DMF, the mixture was stirred 0.33 h, and then 1.1 g (4

mmol) of (iodomethyl)phosphonic acid diethyl ester was added.

The mixture was stirred 72 h, 1.1 g (4 mmol) more (iodom-

ethyl)phosphonic acid diethyl ester was added, and stirring

was continued 24 h. The mixture was diluted with water and

extracted with EtOAc, and the EtOAc was washed with brine,

dried (MgSO₄), and concentrated at reduced pressure. The

residue was chromatographed on silica gel, eluting with EtOAc

and then 10% MeOH/EtOAc, to give 206 mg (yield 46%) of

12c: ¹H NMR (CDCl₃) ∂ 7.38-7.04 (m, 7H), 7.01 (d, 1H), 6.63

(d, 1H), 5.41 (s, 2H), 5.26 (br s, 1H), 4.52 (d, 2H), 4.41-4.33

(m, 4H), 3.97 (s, 2H), 2.53 (s, 3H), 1.50 (t, 6H).

[3-[[3-(2-Am in o-2-oxoeth yl)-2-eth yl-1-(p h en ylm eth yl)-

1H-in d ol-5-yl]oxy]p r op yl]p h osp h on ic Acid Dim eth yl Es-

ter (12e). 2-Ethyl-5-hydroxy-1-(phenylmethyl)-1H-indole-3-

acetamide (2g, 308 mg, 1.0 mmol) was added to 40 mg (1.0

mmol) of NaH/mineral oil (washed with hexanes) in 4 mL of

DMF, the mixture was stirred for 0.5 h, 196 mg (0.85 mmol)

of (3-bromopropyl)phosphonic acid dimethyl ester was added,

and stirring was maintained for 6.5 h. The mixture was

diluted with water and extracted with EtOAc, and the EtOAc

was washed with brine, dried (MgSO₄), and concentrated. The

residue was chromatographed on silica gel, eluting with

EtOAc, 5% MeOH/EtOAc, and then 10% MeOH/EtOAc, to give

269 mg (59% yield) of 12e: ¹H NMR (CDCl₃) ∂ 7.49-6.86 (m,

8H), 5.80 (br s, 1H), 5.48 (br s, 1H), 5.43 (s, 2H), 4.16 (t, 2H),

3.90 (s, 3H), 3.86 (s, 3H), 3.82 (s, 2H), 2.85 (q, 2H), 2.33-2.04

(m, 4H), 1.25 (t, 3H); MS (FD) 458 (M⁺).

[3-[[3-(2-Am in o-2-oxoeth yl)-2-m eth yl-1-(ph en ylm eth yl)-

1H-in d ol-5-yl]oxy]p r op yl]p h osp h on ic Acid (13d ). A solu-

tion of 100 mg (0.23 mmol) of 12d and 0.24 mL (1.8 mmol) of

bromotrimethylsilane in 2 mL of CH₂Cl₂was stirred for 18 h.

The reaction mixture was concentrated at reduced pressure,

5 mL of MeOH was added, and the mixture was stirred for

0.5 h and concentrated. The residue was crystallized from

EtOAc/MeCN/HOAc/H₂O to give 40 mg (42% yield) of 13d :

1

mp 201-203 °C; H NMR (DMSO-d₆) ∂ 7.35-6.60 (m, 10H),

5.34 (s, 2H), 4.00 (t, 2H), 3.41 (s, 2H), 2.29 (s, 3H), 2.00-1.82

(m, 2H), 1.75-1.60 (m, 2H); MS (FD⁺) 416 (M⁺). Anal.

(C₂₁H₂₅N₂O₅P) C, H, N.

Using the above procedure, the following conversions were

made: 12b,c,e-j to 13b,c,e-j.

[3-[[3-(2-Am in o-2-oxoeth yl)-1-(ph en ylm eth yl)-1H-in dol-

5-yl]oxy]p r op yl]p h osp h on ic a cid (13b ) (crystallization,

EtOAc/MeOH): yield 81%; solid; ¹H NMR (DMSO-d₆) ∂

7.35 (br s, 1H), 7.30-7.10 (m, 5H), 7.15 (d, 2H), 7.05 (d, 1H),

6.80 (br s, 1H), 6.70 (dd, 1H), 5.25 (s, 2H), 3.95 (t, 2H), 3.40

(s, 2H), 1.95-1.75 (m, 2H), 1.70-1.55 (m, 2H). Anal.

(C₂₀H₂₃N₂O₅P‚0.8H₂O) C, H, N.

[[[3-(2-Am in o-2-oxoeth yl)-2-m eth yl-1-(p h en ylm eth yl)-

1H-in d ol-4-yl]oxy]m eth yl]p h osp h on ic a cid (13c) (crystal-

lization EtOAc/MeCN/HOAc/ H₂O): yield 29%; mp 195-198

1

°C; H NMR (DMSO-d₆) ∂ 7.38 (br s, 1H), 7.32-6.86 (m, 8H),

6.80 (br s, 1H), 6.56 (d, 1H), 5.35 (s, 2H), 4.17 (d, 2H), 3.65 (s,

2H), 2.32 (s, 3H); MS (FD⁺) 388 (M⁺). Anal. (C₁₉H₂₁N₂O₅P)

C, H, N.

The following were made by the above procedure from the

appropriately substituted hydroxyindole (see Scheme 3).

[3-[[3-(2-Am in o-2-oxoeth yl)-2-m eth yl-1-(ph en ylm eth yl)-

1H-in d ol-5-yl]oxy]p r op yl]p h osp h on ic a cid d im eth yl es-

ter (12d ) (crystallization, MeOH/hexane): yield 57%; mp 136-

138 °C; ¹H NMR (CDCl₃) ∂ 7.36-6.76 (m, 9H), 5.67 (br s, 1H),

5.29 (s, 2H), 4.05 (t, 2H), 3.79 (s, 3H), 3.75 (s, 3H), 3.68 (s,

2H), 2.32 (s, 3H), 2.20-1.90 (m, 4H); MS (FD) 444 (M⁺). Anal.

(C₂₃H₂₉N₂O₅P) H, N; C: calcd, 62.15; found, 61.09.

[3-[[3-(2-Am in o-2-oxoeth yl)-2-eth yl-1-(p h en ylm eth yl)-

1H-in d ol-5-yl]oxy]p r op yl]p h osp h on ic a cid (13e) (crystal-

lization, EtOAc/MeCN/HOAc/ H₂O): yield 97%; mp 194-196

°C; ¹H NMR (DMSO-d₆) ∂ 7.41-6.57 (m, 10H), 5.33 (s, 2H),

3.98 (t, 2H), 3.42 (s, 2H), 2.81 (q, 2H), 2.00-1.82 (m, 2H), 1.75-

1.57 (m, 2H), 1.04 (t, 3H); MS (FD⁺) 430 (M⁺). Anal.

(C₂₂H₂₇N₂O₅P) C, H, N.

[3-[[3-(2-Am in o-2-oxoeth yl)-1-(p h en ylm eth yl)-2-p r op yl-

1H-in d ol-5-yl]oxy]p r op yl]p h osp h on ic a cid d im eth yl es-

ter (12f) (chromatography on silica gel, gradient, EtOAc-5%

MeOH/EtOAc): yield 60%; wax; ¹H NMR (CDCl₃) ∂ 7.32-6.74

(m, 8H), 5.81 (br s, 1H), 5.43 (br s, 1H), 5.31 (s, 2H), 4.05 (t,

[3-[[3-(2-Am in o-2-oxoeth yl)-1-(p h en ylm eth yl)-2-p r op yl-

1H-in d ol-5-yl]oxy]p r op yl]p h osp h on ic a cid (13f) (crystal-

lization, EtOAc/MeCN/HOAc/ H₂O): yield 66%; mp 213-215

°C; ¹H NMR (DMSO-d₆) ∂ 7.35-6.62 (m, 10H), 5.34 (s, 2H),

3.99 (t, 2H), 3.44 (s, 2H), 2.68 (t, 2H), 2.00-1.80 (m, 2H), 1.74-

5150 J ournal of Medicinal Chemistry, 1996, Vol. 39, No. 26

Dillard et al.

1.58 (m, 2H), 1.50-1.34 (m, 2H), 0.87 (t, 3H); MS (FD⁺) 444

(M⁺). Anal. (C₂₃H₂₉N₂O₅P) C, H, N.

[3-[[3-(2-Am in o-2-oxoeth yl)-2-cyclop r op yl-1-(p h en ylm -

et h yl)-1H -in d ol-5-yl]oxy]p r op yl]p h osp h on ic a cid (13g)

(crystallization, MeCN/ EtOAc/Et₂O): yield 94%; wax. Anal.

(C₂₃H₂₇N₂O₅P‚H₂O‚1.2 CH₂Cl₂) C, H, N.

2H), 2.55 (t, 2H), 2.25 (s, 3H), 2.05-1.90 (m, 2H). Anal.

(C₂₁H₂₄N₂O₅S) Calcd: C, 60.56; H, 5.81; N, 6.73; S, 7.70.

Found: C, 53.36; H, 5.66; N, 5.44; S, 3.30; residue, 15.32%.

Using the above procedure, 16b was prepared from 2g.

3-[[3-(2-Am in o-2-oxoet h yl)-2-et h yl-1-(p h en ylm et h yl)-

1H-in d ol-5-yl]oxy]p r op a n esu lfon ic Acid (16b) (chroma-

tography on C-18 RP column, 10% (5% HOAc/H₂O)/MeOH):

[3-[[3-(2-Am in o-2-oxoeth yl)-2-br om o-1-(p h en ylm eth yl)-

1H-in d ol-5-yl]oxy]p r op yl]p h osp h on ic a cid (13h ) (crystal-

lization, EtOAc/EtOH/CH₂Cl₂): yield 39%; mp 188-190 °C;

¹H NMR (DMSO-d₆) ∂ 7.35 (br s, 1H), 7.30-7.15 (m, 4H),

7.10-6.95 (m, 3H), 6.90 (br s, 1H), 6.70 (dd, 1H), 5.40 (s, 2H),

3.95 (t, 2H), 3.40 (s, 2H), 1.95-1.80 (m, 2H), 1.70-1.55 (m,

1

yield 60%; solid; H NMR (DMSO-d₆) ∂ 7.40 (br s, 1H), 7.30-

7.15 (m, 4H), 7.10 (s, 1H), 6.90 (d, 2H), 6.75 (br s, 1H), 6.60

(d, 1H), 5.30 (s, 2H), 4.00 (t, 2H), 3.35 (s, 2H), 2.70 (q, 2H),

2.55 (t, 2H), 2.00-1.85 (m, 2H), 0.95 (t, 3H); MS (FD⁺) 430

(M⁺). Anal. (C₂₂H₂₆N₂O₅S) H; C: calcd, 61.38; found, 56.00;

N: calcd, 6.51; found, 5.52; S: calcd, 7.45; found, 3.85; residue,

11.60%.

2H); MS (FD) 481 (M - 1), 483 (M + 1). Anal. (C₂₀H₂₂

BrN₂O₅P‚0.5CH₂Cl₂) C, H, N.

-

[3-[[3-(2-Am in o-2-oxoeth yl)-1-[(3-ch lor oph en yl)m eth yl]-

2-eth yl-1H-in d ol-5-yl]oxy]p r op yl]p h osp h on ic a cid (13i)

(crystallization, EtOAc/MeCN/HOAc/H₂O): yield 65%; mp

4-[3-(2-Am in o-2-oxoeth yl)-2-eth yl-1-(p h en yleth yl)-1H-

in d ol-5-yl]bu tyr on itr ile (17). 5-Hydroxy-2-methyl-1-(phe-

nylmethyl)-1H-indole-3-acetamide (2d , 295 mg, 1.0 mmol) was

dissolved in 25 mL of DMSO and 5 mL of THF, 45 mg (1.1

mmol) of 60% NaH/mineral oil was added, the mixture was

stirred for 10 min, 0.11 mL (1.1 mmol) of 4-bromobutyronitrile

was added, and the mixture was stirred for 2 h at 60 °C. The

mixture was cooled, diluted with water, and extracted with

EtOAc. The EtOAc solution was separated, washed with

brine, dried (Na₂SO₄), and concentrated. The residue was

chromatographed on silica gel, eluting with a gradient of CH₂-

Cl₂-2% MeOH/CH₂Cl₂, and recrystallized from CH₂Cl₂/EtOH

to give 17: 200 mg (yield 55%); mp 144-146 °C; ¹H NMR

(CDCl₃) ∂ 7.30-7.15 (m, 3H), 7.10 (d, 1H), 6.95 (d, 1H), 6.90

(d, 2H), 6.75 (dd, 1H), 6.20 (br s, 1H), 5.70 (br s, 1H), 5.25 (s,

2H), 4.05 (t, 2H), 3.65 (s, 2H), 2.55 (t, 2H), 2.30 (s, 3H), 2.15-

2.05 (m, 2H); MS (FD⁺) 361 (M⁺). Anal. (C₂₂H₂₃N₃O₂) C, H,

N.

1-(1H-Tetr a zol-5-yl)-3-[3-(2-a m in o-2-oxoeth yl)-2-m eth -

yl-1-(p h en ylm eth yl)-1H-in d ol-5-yl]p r op a n e (18). A mix-

ture of 17 (165 mg, 0.46 mmol) and 2 mL of n-Bu₃SnN₃was

heated at 95 °C for 19 h, cooled, stirred with 50 mL of CH₃-

CN, 10 mL of THF, and 20 mL of HOAc for 2 h, and washed

several times with hexane, and evaporated at reduced pres-

sure. The residue was chromatographed on silica gel, eluting

with a gradient of 3-8% MeOH/CH₂Cl₂, to give 18 [160 mg

(yield 87%)] as a glass: ¹H NMR (DMSO-d₆) ∂ 7.20-7.10 (m,

4H), 7.10 (d, 1H), 6.95 (d, 1H), 6.85 (d, 2H), 6.80 (br s, 1H),

6.60 (dd, 1H), 5.25 (s, 2H), 3.95 (t, 2H), 3.35 (s, 2H), 2.95 (t,

2H), 2.20 (s, 3H), 2.10-2.00 (m, 2H); MS (FD) 404 (M⁺). Anal.

(C₂₂H₂₄N₆O₂‚0.4H₂O) C, H, N.

1

203-205 °C; H NMR (DMSO-d₆) ∂ 7.37-6.63 (m, 9H), 5.38

(s, 2H), 3.99 (t, 2H), 3.44 (s, 2H), 2.74 (q, 2H), 2.00-1.84 (m,

2H), 1.76-1.60 (m, 2H), 1.03 (t, 3H); MS (FD⁺) 464 (M - 1,

100), 466 (M + 1, 27). Anal. (C₂₂H₂₆ClN₂O₅P) C, H, N.

[3-[[3-(2-Am in o-2-oxoet h yl)-1-([1,1′-b ip h en yl]-2-ylm e-

th yl)-2-m eth yl-1H-in dol-5-yl]oxy]pr opyl]ph osph on ic acid

(13j) (crystallization, EtOAc/MeCN/HOAc/H₂O): yield 33%;

1

mp 200-202 °C; H NMR (DMSO-d₆) ∂ 7.58-6.60 (m, 13H),

6.31 (d, 1H), 5.22 (s, 2H), 3.98 (t, 2H), 3.40 (s, 2H), 2.15 (s,

3H), 2.00-1.80 (m, 2H), 1.75-1.60 (m, 2H); MS (FD) 493 (M

+ 1). Anal. (C₂₇H₂₉N₂O₅P) C, H, N.

[3-[[3-(2-Am in o-2-oxoeth yl)-2-eth yl-1-(p h en ylm eth yl)-

1H-in d ol-5-yl]oxy]p r op yl]p h osp h on ic Acid Mon om eth yl

Ester (14e). A mixture of 162 mg (0.35 mmol) of 12e and 5

mL of 1 N NaOH in 10 mL of MeOH was heated to maintain

reflux for 5 h, diluted with water, and extracted with EtOAc.

The aqueous layer was made acidic to pH 2-3 with 1 N HCl

and extracted with EtOAc. The EtOAc solution was washed

with brine, dried (MgSO₄), and concentrated at reduced

pressure to give 120 mg (yield 77%) of 14e: oil; ¹H NMR

(DMSO-d₆) ∂ 7.36-6.62 (m, 10H), 5.36 (s, 2H), 3.99 (t, 2H),

3.56 (d, 3H), 3.33 (s, 2H), 2.72 (q, 2H), 2.00-1.66 (m, 4H), 1.04

(t, 3H); MS (FD⁺) 444 (M⁺). Anal. (C₂₃H₂₉N₂O₅P) H; C: calcd,

62.15; found, 63.15; N: calcd, 6.30; found, 4.81.

[[[3-(2-Am in o-2-oxoeth yl)-1-(p h en ylm eth yl)-1H-in d ol-

5-yl]oxy]m eth yl]p h osp h on ic Acid Disod iu m Sa lt (15a ).

A solution of 120 mg (0.28 mmol) of 12a and 0.5 mL of

trimethylsilyl bromide in 20 mL of CH₂Cl₂was stirred for 17

h and concentrated at reduced pressure. The residue was

dissolved in 10 mL of MeOH, and the mixture was stirred for

2 h and concentrated. The residue was chromatographed on

a C-18 reverse phase column, eluting with 20% (5%HOAc/

H₂O)/MeOH, then dissolved in 0.05 N NaOH and chromato-

graphed on an HP-20 column, eluting with 10% MeCN/H₂O

and then 50% MeCN/H₂O, to give 15 mg (14% yield) of 15a :

¹H NMR (DMSO-d₆) ∂ 7.30-6.95 (m, 9H), 6.75 (dd, 1H), 5.15

(s, 2H), 3.65 (d, 2H), 3.40 (s, 2H).

[3-[[3-(2-Am in o-2-oxoeth yl)-2-br om o-1-(p h en ylm eth yl)-

1H-in dol-5-yl]oxy]pr opyl]ph osph on ic Acid Disodiu m Salt

(15h ). The filtrate from the crystallization of 13h was

concentrated at reduced pressure and the residue chromato-

graphed on a C-18 reverse phase column, eluting with 5%

(5%HOAc/H₂O)/MeOH. The product was dissolved in 0.05 N

NaOH and put on a medium pressure HP-20 column, eluted

with a gradient of 10-50% MeCN/H₂O, to give 195 mg of 15h .

Anal. (C₂₀H₂₀BrN₂O₅PNa₂) C, H, Br; N: calcd, 5.42; found,

4.83.

3-[[3-(2-Am in o-2-oxoeth yl)-2-m eth yl-1-(p h en ylm eth yl)-

1H-in dol-5-yl]oxy]pr opan esu lfon ic Acid (16a). 5-Hydroxy-

2-methyl-1-(phenylmethyl)-1H-indole-3-acetamide (2d , 300 mg,

1.0 mmol) was dissolved in 50 mL of THF, 40 mg (1.0 mmol)

of 60% NaH/mineral oil was added, the mixture was stirred

for 0.25 h, 125 mg (1.0 mmol) of sultone was added, and the

mixture was stirred for 24 h. The mixture was made acidic

with 5 N HCl and then concentrated at reduced pressure. The

residue was crystallized from EtOH/water to give 145 mg (yield

35%) of 16a : mp 218-222 °C; ¹H NMR (DMSO-d₆) ∂ 7.30

(br s, 1H), 7.28-7.10 (m, 4H), 7.05 (s, 1H), 6.95 (d, 2H), 6.75

(br s, 1H), 6.60 (d, 1H), 5.25 (s, 2H), 4.00 (t, 2H), 3.40 (s,

4-(2-H yd r a zin o-2-oxoet h oxy)-2-m et h yl-1-(p h en ylm e-

th yl)-1H-in d ole-3-a ceta m id e (19a ). A mixture of 484 mg

(1.3 mmol) of 3c and 2 mL of hydrazine in 10 mL of EtOH

was heated to maintain reflux for 16 h, 10 mL of EtOH was

added, and the mixture was heated an additional 4 h and

cooled. Ethyl acetate and water were added, and the insoluble

material was filtered. The EtOAc solution was separated,

washed with brine, dried (MgSO₄), and concentrated. The

residue was combined with the precipitate above to give 435

1

mg (91% yield) of 19a : mp 207-210 °C; H NMR (DMSO-d₆)

∂ 9.57 (br s, 1H), 7.36-6.82 (m, 9H), 6.43 (d, 1H), 5.37 (s, 2H),

4.60 (s, 2H), 4.56 (br s, 2H), 3.64 (s, 2H), 2.34 (s, 3H); MS (FD⁺)

366 (M⁺). Anal. (C₂₀H₂₂N₄O₃) C, H, N.

Also by this method, the following conversions were made:

3m to 19b and 4k to 19c.

2-Eth yl-5-(4-h ydr azin o-4-oxobu toxy)-1-(ph en ylm eth yl)-

1H-in d ole-3-a ceta m id e (19b) (crude product, washed with

MeOH): yield 87%; mp 176-179 °C; ¹H NMR (DMSO-d₆) ∂

8.99 (br s, 1H), 7.32-6.62 (m, 10H), 5.35 (s, 2H), 4.17 (br s,

2H), 3.93 (t, 2H), 3.43 (s, 2H), 2.73 (q, 2H), 2.21 (t, 2H), 2.00-

1.90 (m, 2H), 1.04 (t, 3H); MS (FD) 408 (M⁺). Anal.

(C₂₃H₂₈N₄O₃) C, H, N.

6-(4-H yd r a zin o-4-oxob u t oxy)-2-m et h yl-1-(p h en ylm e-

th yl)-1H-in d ole-3-a ceta m id e (19c) (crystallization, MeOH/

1

CH₂Cl₂): yield 81%; mp 132-138 °C; H NMR (DMSO-d₆) ∂

8.96 (br s, 1H), 7.41 (d, 1H), 7.34-6.60 (m, 9H), 5.34 (s, 2H),

4.14 (br s, 2H), 3.90 (t, 2H), 3.40 (s, 2H), 2.25 (s, 3H), 2.18

(t, 2H), 1.96-1.84 (m, 2H); MS (FD⁺) 394 (M⁺). Anal.

(C₂₂H₂₆N₄O₃) C, H, N.

4-(2-Am in o-2-oxoet h oxy)-2-m et h yl-1-(p h en ylm et h yl)-

1H-in d ole-3-a ceta m id e (20a ). A mixture of 230 mg (0.63

Indole Inhibitors of hnps-PLA₂. 2

J ournal of Medicinal Chemistry, 1996, Vol. 39, No. 26 5151

mmol) of 19a and 300 mg of Raney nickel in 40 mL of EtOH

was heated to maintain reflux for 4 h. The mixture was cooled,

the EtOH was poured off the catalyst, and the catalyst was

washed twice with CH₂Cl₂. The combined solvents were

filtered and concentrated, and the residue was chromato-

graphed on silica gel, eluting with 10% MeOH/EtOAc, to give

25 mg (yield 11%) of 20a . This material melted at 190-207

°C: ¹H NMR (DMSO-d₆) ∂ 7.44-6.40 (m, 12H), 5.37 (s, 2H),

4.52 (s, 2H), 3.66 (s, 2H), 2.30 (s, 3H). Anal. (C₂₀H₂₁N₃O₃) C;

H: calcd, 6.02; found, 6.55; N: calcd, 11.96; found, 13.28.

Using the same method, the following conversions were

made: 19b to 20b and 19c to 20c.

5-(4-Am in o-4-oxobu toxy)-2-eth yl-1-(p h en ylm eth yl)-1H-

in d ole-3-a ceta m id e (20b) (chromatography on silica gel,

EtOAc, then 10% MeOH/EtOAc): yield 47%; mp 176-179 °C;

¹H NMR (DMSO-d₆) ∂ 7.38-6.62 (m, 12H), 5.36 (s, 2H), 3.93

(t, 2H), 3.43 (s, 2H), 2.73 (q, 2H), 2.43 (t, 2H), 1.98-1.85 (m,

2H), 1.03 (t, 3H); MS (FD⁺) 393 (M⁺). Anal. (C₂₃H₂₇N₃O₃) C,

H, N.

dissolved in EtOAc/H₂O. The organic phase was washed with

brine, dried over MgSO₄, and evaporated. The residue was

triturated with CH₂Cl₂and filtered to give 72 mg (yield 16%)

of 26 as its trifluoroacetic acid salt: ¹H NMR (DMSO-d₆) ∂ 7.79

(br s, 1H), 7.32-6.72 (m, 9H), 6.18 (br s, 1H), 5.35 (s, 2H),

3.94 (s, 2H), 3.64 (s, 2H), 2.78 (q, 2H), 1.00 (t, 3H); MS (FD)

355 (M⁺). Anal. (C₂₁H₂₃N₃O₃‚CF₃CO₂H) Calcd: C, 57.62; H,

5.04; N, 8.76. Found: C, 56.61; H, 5.09; N, 8.33.

3-[[3-(2-Am in o-2-oxoeth yl)-2-m eth yl-1-(p h en ylm eth yl)-

1H-in d ol-5-yl]a m in o]p r op ion ic Acid Meth yl Ester (28a ).

A solution of 147 mg (0.5 mmol) of 5-amino-2-methyl-1-

(phenylmethyl)-1H-indole-3-acetamide (27) and 2 mL of methyl

acrylate in 5 mL of MeOH was stirred for 65 h and concen-

trated at reduced pressure. The residue was a mixture of 28a

and a minor (bisalkylated) product, which were separated by

chromatography on silica gel, eluting with a gradient of

EtOAc-5% MeOH/EtOAc to give 105 mg (yield 55%) of 28a :

¹H NMR (CDCl₃) ∂ 7.38-6.85 (m, 9H), 5.77 (br s, 1H), 5.58 (br

s, 1H), 5.26 (s, 2H), 3.69 (s, 3H), 3.66 (s, 2H), 3.54 (t, 2H), 2.79

(t, 2H), 2.31 (s, 3H); MS (FD) 379 (M⁺). Anal. (C₂₂H₂₅N₃O₃)

C, H, N.

3-[[3-(2-Am in o-2-oxoeth yl)-2-m eth yl-1-(p h en ylm eth yl)-

1H-in d ol-5-yl]a m in o]p r op ion ic Acid (29a ). One milliliter

of 1 N NaOH was added to a solution of 110 mg (0.3 mmol) of

28a in 5 mL of MeOH, the mixture was stirred for 1 h, 1 mL

of 1 N NaOH was added, and the mixture was stirred for 0.5

h. Water was added, 2 mL of 1 N HCl was then added, and

the mixture was extracted with EtOAc. This was dried

(MgSO₄) and concentrated at reduced pressure to give 21mg

(20% yield) of 29a : ¹H NMR (DMSO-d₆) ∂ 7.41-7.02 (m, 8H),

6.87 (br s, 1H), 6.74 (s, 1H), 6.53 (d, 1H), 5.35 (s, 2H), 3.46 (s,

2H), 3.33 (t, 2H), 2.64 (s, 2H), 2.34 (s, 3H); MS (FD⁺) 365 (M⁺).

4-[[3-(2-Am in o-2-oxoeth yl)-2-m eth yl-1-(p h en ylm eth yl)-

1H-in d ol-5-yl]a m in o]bu ta n oic Acid (29b). To a solution

of 293 mg (1.0 mmol) of 27 in 5 mL DMF was added 420 mg

(5 mmol) of NaHCO₃and 0.15 mL (1 mmol) of ethyl 4-bro-

mobutyrate, and the mixture was heated at 80 °C for 18 h,

diluted with EtOAc, washed with water and brine, dried

(MgSO₄), and concentrated at reduced pressure. The residue

was a mixture of 28b and the bisalkylated product, which were

separated by chromatography on silica gel, eluted with a

gradient of 25-50%EtOAc/hexane, to give 76 mg (yield 14%)

of the bisalkylated product and 88 mg (0.21 mmol, yield 22%)

of 28b. This material (28b) was stirred with 1 mL of 1 N

NaOH in 2 mL of EtOH for 4 h, diluted with water, and

extracted with EtOAc. The aqueous portion was acidified to

pH 6 with 1 N HCl and then extracted with EtOAc. The

organic extract was washed with brine, dried (MgSO₄), and

evaporated at reduced pressure, and then the mixture was

stirred with EtOAc/MeCN/HOAc/H₂O for 16 h and filtered to

give 10 mg (yield 13%) of 29b: ¹H NMR (DMSO-d₆) ∂ 7.41-

7.08 (m, 8H), 6.86 (br s, 1H), 6.71 (s, 1H), 6.53 (d, 1H), 4.34 (s,

2H), 3.45 (s, 2H), 3.08 (t, 2H), 2.43 (t, 2H), 2.33 (s, 3H), 1.87

(t, 2H); MS (FD⁺) 379 (M⁺).

6-(4-Am in o-4-oxob u t oxy)-2-m et h yl-1-(p h en ylm et h yl)-

1H-in d ole-3-a ceta m id e (20c) (chromatography on silica gel,

EtOAc, then 5% MeOH/EtOAc): yield 11%; MS (FD⁺) 379

(M⁺).

5-(4-Am in o-4-oxob u t oxy)-2-(m et h ylt h io)-1-(p h en ylm -

eth yl)-1H-in d ole-3-a ceta m id e (20d ). Ten milliliters of 0.6

M (CH₃)ClAlNH₂/benzene was added to 200 mg (0.45 mmol)

of 4s in 25 mL of benzene, and the mixture was heated at 50

°C for 1.75 h. After cooling, the mixture was decomposed with

ice and 1 N HCl added. The mixture was extracted with

EtOAc, and the EtOAc solution was washed with a saturated

NaCl solution, dried (Na₂SO₄), and concentrated at reduced

pressure. The residue was crystallized from EtOH/CH₂Cl₂to

give 155 mg (yield 84%) of 20d : mp 185 °C; ¹H NMR (DMSO-

d₆) ∂ 7.40 (br s, 1H), 7.30-7.00 (m, 5H), 7.10 (d, 1H), 6.95 (d,

2H), 6.90 (br s, 1H), 6.70 (dd, 1H), 5.50 (s, 2H), 3.90 (t, 2H),

3.65 (s, 2H), 3.30 (s, 3H), 2.15 (t, 2H), 2.00-1.80 (m, 2H); MS

(FD) 411 (M⁺). Anal. (C₂₂H₂₅N₃O₃S) C; H: calcd, 6.12; found,

6.54; N: calcd, 10.21; found, 8.97; S: calcd, 7.79; found, 7.11.

3-(2-Am in o-1,2-d ioxoeth yl)-2-eth yl-4-n itr o-1-(p h en ylm -

eth yl)-1H-in d ole (22). A solution of 6.36 g (22.7 mmol) of

21 in 30 mL of CH₂Cl₂was treated with 1.98 mL (22.7 mmol)

of oxalyl chloride for 24 h, and the mixture was evaporated at

reduced pressure, diluted with 30 mL of CH₂Cl₂, treated with

ammonia gas for 15 min, and then evaporated at reduced

pressure. The residue was dissolved in EtOAc, washed with

water and brine, dried over MgSO₄, and evaporated at reduced

pressure. The residue was triturated with EtOAc/hexane and

the product removed by filtration. The filtrate was evaporated

at reduced pressure and the residue chromatographed on silica

gel, eluting with 20% EtOAc/hexane, to give additional prod-

uct. Combined product of 22 weighed 6.0 g (yield 75%): mp

207-208 °C; ¹H NMR (DMSO-d₆) ∂ 8.01 (br s, 1H), 7.96-7.84

(m, 2H), 7.65 (br s, 1H), 7.39-7.23 (m, 4H), 7.03 (d, 2H), 5.67

(s, 2H), 2.91 (q, 2H), 1.09 (t, 3H); MS (FD⁺) 351 (M⁺). Anal.

(C₁₉H₁₇N₃O₄) C, H, N.

4-(2-Meth ylin d olin -5-yl)-4-oxobu ta n oic Acid Eth yl Es-

ter (31). A solution of 10 g (57 mmol) of 1-acetyl-2-methylin-

doline (30) in 400 mL of CH₂Cl₂was treated in portions with

24 g (180 mmol) of aluminum chloride and then with 6 g (60

mmol) of succinic anhydride. The mixture was refluxed for 3

h, cooled, poured onto ice/hydrochloric acid, and extracted with

CH₂Cl₂/2-propanol (3:1). The organic phase was washed with

brine, dried over Na₂SO₄, and evaporated at reduced pressure.

The residue was dissolved in 300 mL of EtOH containing 5

mL of concentrated sulfuric acid, refluxed for 15 h, cooled,

concentrated at reduced pressure, diluted with EtOAc, washed

with aqueous NaHCO₃, dried over Na₂SO₄, and evaporated.

The residue was chromatograped on silica gel, eluting with a

gradient of 25-50% Et₂O/hexane, to give, after crystallizing

2-[[3-(2-Am in o-2-oxoet h yl)-2-et h yl-1-(p h en ylm et h yl)-

1H-in d ol-4-yl]a m in o]a cetic Acid (26). The nitro derivative

22 (6.0 g) and 1.0 g of 5% Pd/BaSO₄in 70 mL of THF and 70

mL of EtOH was hydrogenated at 60 psi for 4 h, filtered and

evaporated at reduced pressure. The residue was chromato-

graphed on silica gel, eluting with 50% EtOAc/hexane to give

a 30% yield of 4-amino-3-(3-amino-1,2-dioxoethyl)-2-ethyl-1-

(phenylmethyl)-1H-indole and a 23% yield of 23. A solution

of 969 mg (3 mmol) of 23 in 15 mL of trifluoroacetic acid was

stirred with 0.54 mL (3.3 mmol) of triethylsilane for 18 h,

triturated with EtOAc-H₂O, and filtered to give 751 mg (yield

82%) of 24 as its trifluoroacetic acid salt. A solution of 523

mg (1.7 mmol) of 24 in 5 mL of DMF and 0.28 mL (1.7 mmol)

of tert-butyl bromoacetate was stirred with 714 mg (8.5 mmol)

of NaHCO₃for 2 h, diluted with water, and extracted with

EtOAc. The organic phase was washed with brine, dried over

MgSO₄, and evaporated at reduced pressure. The residue was

chromatographed on silica gel, eluting with a gradient of 50-

1

from EtOH, 8.8 g (yield 59%) of 31: mp 92-94 °C; H NMR

(CDCl₃) ∂ 7.65 (d, 1H), 7.60 (s, 1H), 6.35 (d, 1H), 4.05 (q, 2H),

3.15 (t, 2H), 2.65 (t, 2H), 1.20 (d, 3H), 1.15 (t, 3H); MS (FD⁺)

261 (M⁺). Anal. (C₁₅H₁₉NO₃) C, H, N.

4-[2-Meth yl-1-(p h en ylm eth yl)-1H-in d ol-5-yl]-4-oxobu -

ta n oic Acid Eth yl Ester (32). A mixture of 2.8 g (11 mmol)

of the 31, 1.6 mL (14 mmol) of benzyl bromide, 2.2 g (16 mmol)

of potassium carbonate, and 125 mL of DMF was heated at

67% EtOAc/hexane, to give 410 mg (yield 57%) of 25.

A

solution of 400 mg (0.95 mmol) of 25 in 5 mL of trifluoroacetic

acid was stirred for 1 h, evaporated at reduced pressure, and

5152 J ournal of Medicinal Chemistry, 1996, Vol. 39, No. 26

Dillard et al.

85 °C for 4 h, diluted with water and extracted with EtOAc.

The organic phase was washed with brine, dried over Na₂SO₄,

and evaporated at reduced pressure. The residue was chro-

matographed on silica gel, eluting with a gradient of 20-50%

Et₂O/hexane, to give 3.5 g (yield 91%) of an oil (1-(phenylm-

ethyl)indoline derivative). This material was mixed with 2.5

g (11 mmol) of dichlorodicyanoquinone in 120 mL of dioxane,

and the mixture was heated at 85 °C for 0.5 h, cooled, diluted

with EtOAc, washed with brine, dried over Na₂SO₄, and

evaporated at reduced pressure. The residue was chromato-

graphed on fluorisil, eluting with CH₂Cl₂, to give, after

crystallizing from Et₂O, 2.1 g (yield 55%) of 32: mp 78-79

°C; ¹H NMR (CDCl₃) ∂ 8.15 (s, 1H), 7.65 (d, 1H), 7.25-7.05

(m, 4H), 6.80 (d, 2H), 6.30 (s, 1H), 5.15 (s, 2H), 4.05 (q, 2H),

3.25 (t, 2H), 2.65 (t, 2H), 2.20 (s, 3H), 1.15 (t, 3H); MS (FD⁺)

349 (M⁺). Anal. (C₂₂H₂₃NO₃‚0.5H₂O) C, H, N.

boron tribromide in 50 mL of CH₂Cl₂. The mixture was stirred

for 3 h and then evaporated at reduced pressure. The residue

was diluted with water and extracted with EtOAc, washed

with brine, dried (MgSO₄), evaporated at reduced pressure,

and then chromatographed on silica gel, eluting with 10%

EtOAc/hexane, to give 1.69 g (yield 59%) of 37b as an oil: ¹H

NMR (CDCl₃) ∂ 7.37-6.89 (m, 8H), 6.19 (s, 1H), 5.25 (s, 2H),

2.64 (q, 2H), 2.31 (s, 3H), 1.30 (t, 3H); MS (FD⁺) 265 (M⁺).

Anal. (C₁₈H₁₉NO) H, N; C: calcd, 81.47; found, 82.38.

Using the preceding method, 2-ethyl-5-methoxy-6-isopropyl-

1-(phenylmethyl)-1H-indole (36c) was converted to 37c.

2-E t h yl-5-h yd r oxy-6-isop r op yl-1-(p h en ylm et h yl)-1H -

in d ole (37c) (chromatography on silica gel, 10% EtOAc/

hexane): yield 65%; oil; ¹H NMR (CDCl₃) ∂ 7.39-6.90 (m, 8H),

6.18 (s, 1H), 5.26 (s, 2H), 3.35-3.24 (m, 1H), 2.64 (q, 2H), 1.41-

1.18 (m, 9H); MS (FD) 293 (M⁺). Anal. (C₂₀H₂₃NO) C, H, N.

5-[[(Dim eth ylam in o)th iocar bam oyl]oxy]-2-eth yl-6-m eth -

yl-1-(p h en ylm eth yl)-1H-in d ole (38b). To a solution of 1.69

g (6.4 mmol) of 37b in 20 mL of DMF was added 256 mg (6.4

mmol) of 60% NaH/mineral oil and 791 mg (6.4 mmol) of

dimethylthiocarbamoyl chloride. The mixture was stirred for

22 h, and then water and EtOAc were added. The EtOAc

extract was washed with brine, dried (MgSO₄), evaporated at

reduced pressure, and then chromatographed on silica gel,

eluting with 10% EtOAc/hexane, to give 1.78 g (yield 79%) of

38b: ¹H NMR (CDCl₃) ∂ 7.41-6.90 (m, 7H), 6.31 (s, 1H), 5.26

(s, 2H), 3.49 (s, 3H), 3.39 (s, 3H), 2.64 (q, 2H), 2.24 (s, 3H),

1.30 (t, 3H); MS (FD⁺) 352 (M⁺). Anal. (C₂₁H₂₄N₂OS) H; C:

calcd, 71.56; found, 72.07; N: calcd, 7.95; found, 7.14.

Using the preceding method, 38c was prepared from 37c.

5-[[(Dim eth yla m in o)th ioca r ba m oyl]oxy]-2-eth yl-6-iso-

p r op yl-1-(p h en ylm eth yl)-1H-in d ole (38c) (chromatography

on silica gel, 17% EtOAc/hexane): yield 73%; oil; ¹H NMR

(CDCl₃) ∂ 7.33-6.98 (m, 7H), 6.28 (s, 1H), 5.27 (s, 2H), 3.50

(s, 3H), 3.39 (s, 3H), 2.63 (q, 2H), 1.27 (t, 3H), 1.22 (d, 6H);

MS (FD⁺) 293 (M⁺). Anal. (C₂₃H₂₈N₂OS) H, N; C: calcd, 72.59;

found, 73.72.

4-[3-(2-Am in o-1,2-d ioxoet h yl)-2-m et h yl-1-(p h en ylm e-

th yl)-1H-in d ol-5-yl]-4-oxobu ta n oic Acid Eth yl Ester (33).

A solution of 790 mg (2.3 mmol) of 32 in 40 mL of CH₂Cl₂was

cooled to -5 °C and treated with 0.22 mL (2.5 mmol) of oxalyl

chloride. The cooling bath was removed, and the solution was

stirred for 0.5 h, saturated with ammonia gas, washed with

water and brine, dried over Na₂SO₄, and evaporated at reduced

pressure. The residue was chromatographed on silica gel,

eluting with a gradient of 1-3% MeOH/CH₂Cl₂, to give, after

crystallizing from Et₂O, 770 mg (yield 80%) of 33: mp 122-

123 °C; ¹H NMR (CDCl₃) ∂ 8.75 (s, 1H), 7.80 (d, 1H), 7.35-

7.05 (m, 5H), 6.90 (d, 2H), 6.55 (br s, 1H), 5.25 (s, 2H), 4.05 (q,

2H), 3.30 (t, 2H), 2.65 (t, 2H), 2.55 (t, 2H), 2.55 (s, 3H), 1.15

(t, 3H); MS (FD) 421 (M⁺). Anal. (C₂₄H₂₄N₂O₅) C, H, N.

4-[3-(2-Am in o-2-oxoeth yl)-2-m eth yl-1-(p h en ylm eth yl)-

1H-in d ol-5-yl]bu ta n oic Acid Eth yl Ester (34). A solution

of 770 mg (1.83 mmol) of 33, 5 mL of triethylsilane, 5 mL of

trifluoroacetic acid, and 40 mL of 1,2-dichloroethane was

refluxed for 23 h. After cooling, the mixture was washed with

aqueous NaHCO₃, dried over Na₂SO₄, and evaporated at

reduced pressure. The residue was chromatographed on silica

gel, eluting with EtOAc, and crystallized from Et₂O to give

5-[[(Dim et h yla m in o)ca r b a m oyl]t h io]-2-et h yl-1-(p h e-

n ylm eth yl)-1H-in d ole (39a ). A solution of 1.9 g of 38a in

50 mL of phenyl ether was refluxed for 28 h, cooled, and

chromatographed on silica gel, eluting with a gradient of 10-

40% Et₂O/hexane and crystallized from EtOH to give 1.5 g

1

450 mg (yield 63%) of 34: mp 88-90 °C; H NMR (CDCl₃) ∂

7.35 (s, 1H), 7.30-7.15 (m, 4H), 7.10 (d, 1H), 6.95 (d, 2H), 6.30

(br s, 1H), 5.70 (br s, 1H), 5.25 (q, 2H), 4.05 (q, 2H), 3.60 (s,

2H), 2.70 (t, 2H), 2.30 (t, 2H), 2.25 (s, 3H), 2.05-1.85 (m, 2H),

1.20 (t, 3H); MS (FD) 392 (M⁺). Anal. (C₂₄H₂₈N₂O₃) C, H, N.

4-[3-(2-Am in o-2-oxoeth yl)-2-m eth yl-1-(p h en ylm eth yl)-

1H-in d ol-5-yl]bu ta n oic Acid (35). A solution of 450 mg

(1.15 mmol) of 34 in 30 mL of EtOH and 2 mL of 2 N NaOH

was stirred 15 h, diluted with water, and washed with Et₂O.

The aqueous phase was acidified with 5 N HCl and extracted

with EtOAc. The organic phase was washed with brine, dried

over Na₂SO₄, and evaporated at reduced pressure. The residue

was crystallized from CH₂Cl₂/EtOH to give 300 mg (yield 72%)

of 35, mp 167-168 °C. Anal. (C₂₂H₂₄N₂O₃) H; C: calcd, 72.51;

found, 72.08; N: calcd, 7.69; found, 7.14.

1

(yield 80%) of 39a : mp 148-151 °C; H NMR (CDCl₃) ∂ 7.75

(s, 1H), 7.30-7.15 (m, 5H), 6.95 (d, 2H), 6.35 (s, 1H), 5.25 (s,

2H), 3.05 (br s, 6H), 2.65 (q, 2H), 1.30 (t, 3H); MS (FD⁺) 338

(M⁺). Anal. (C₂₀H₂₂N₂OS) C, H, N.

Using the preceding method, 38b was converted to 39b and

38c was converted to 39c.

5-[[(Dim eth yla m in o)ca r ba m oyl]th io]-2-eth yl-6-m eth yl-

1-(ph en ylm eth yl)-1H-in dole (39b) (chromatography on silica

gel, 10% EtOAc/hexane, then 20% EtOAc/hexane): yield 82%;

¹H NMR (CDCl₃) ∂ 7.75 (s, 1H), 7.45-6.90 (m, 6H), 6.31 (s,

1H), 5.30 (s, 2H), 3.29-2.92 (m, 6H), 2.66 (q, 2H), 2.47 (s, 3H),

1.31 (t, 3H); MS (FD⁺) 352 (M⁺). Anal. (C₂₁H₂₄N₂OS)H, N;

C: calcd, 71.56; found, 72.43.

5-[[(Dim eth ylam in o)th iocar bam oyl]oxy]-2-eth yl-1-(ph e-

n ylm eth yl)-1H-in d ole (38a ). A solution of 1.8 g (6.8 mmol)

of 36a in 125 mL of CH₂Cl₂was stirred with 20 mL of 1 M

boron tribromide in CH₂Cl₂for 2 h, decomposed with ice/water,

washed with brine, dried over Na₂SO₄, and evaporated at

reduced pressure. The crude 2-ethyl-5-hydroxy-1-(phenylm-

ethyl)-1H-indole (37a , 1.8 g) was dissolved in 75 mL of DMSO

and 10 mL of THF and stirred with 300 mg of NaH (60% in

mineral oil; 7.5 mmol) for 10 min and then with 930 mg (7.5

mmol) of dimethylthiocarbamoyl chloride for 2.5 h, diluted with

water, and extracted with EtOAc. The organic phase was

washed with brine, dried over Na₂SO₄, and evaporated at

reduced pressure. The residue was chromatographed on silica

gel, eluting with a gradient of 10-25% Et₂O/hexane, to give,

after crystallizing from EtOH, 1.9 g (yield 83%) of 38a : mp

5-[[(Dim eth yla m in o)ca r ba m oyl]th io]-2-eth yl-6-isop r o-

p yl-1-(p h en ylm eth yl)-1H-in d ole (39c) (chromatography on

silica gel, 10% EtOAc/hexane, then 20% EtOAc/hexane): yield

1

50%; oil; H NMR (CDCl₃) ∂ 7.75 (s, 1H), 7.34-7.22 (m, 3H),

7.18 (s, 1H), 7.02 (d, 2H), 6.28 (s, 1H), 5.31 (s, 2H), 3.59-3.44

(m, 1H), 3.17 (br s, 3H), 3.05 (br s, 3H), 2.64 (q, 2H), 1.29 (t,

3H), 1.23 (d, 6H); MS (FD⁺) 352 (M⁺). Anal. (C₂₃H₂₈N₂OS)

H, N; C: calcd, 72.59; found, 70.23.

4-[[2-Eth yl-1-(ph en ylm eth yl)-1H-in dol-5-yl]th io]bu tan o-

ic Acid Eth yl Ester (41b). A mixture of 1.5 g of 39a and 25

mL of 5 N NaOH in 125 mL of EtOH was refluxed for 5 h,

cooled, acidified with 5 N HCl, and extracted with CH₂Cl₂. The

organic phase was washed with brine, dried over Na₂SO₄, and

evaporated at reduced pressure. The residue was chromato-

graphed on silica gel, eluting with a gradient of 10-15% Et₂O/

hexane to give 930 mg (yield 84%) of 2-ethyl-5-mercapto-1-

(phenylmethyl)-1H-indole (40a ) as a glass. A solution of 400

mg (1.5 mmol) of 40a in 70 mL of DMF and 10 mL of THF

was treated with 70 mg of NaH (60% in mineral oil; 1.7 mmol)

for 5 min and then with 0.25 mL (1.8 mmol) of ethyl

4-bromobutyrate for 0.5 h, diluted with water, and extracted

1

135-138 °C; H NMR (CDCl₃) ∂ 7.35-7.20 (m, 4H), 7.15 (d,

1H), 7.00 (d, 2H), 6.85 (dd, 1H), 6.40 (s, 1H), 5.25 (s, 2H), 3.45

(s, 3H), 3.35 (s, 3H), 2.70 (q, 2H), 1.35 (t, 3H); MS (FD) 399

(M + 1)⁺. Anal. (C₂₀H₂₂N₂OS) C, H, N.

2-E t h yl-5-h yd r oxy-6-m et h yl-1-(p h en ylm et h yl)-1H -in -

d ole (37b). To a solution of 3.01 g (10.8 mmol) of 2-ethyl-5-

methoxy-6-methyl-1-(phenylmethyl)-1H-indole (36b) in 50 mL

of CH₂Cl₂was added 16 mL (16 mmol) of a 1 M solution of

Indole Inhibitors of hnps-PLA₂. 2

J ournal of Medicinal Chemistry, 1996, Vol. 39, No. 26 5153

with EtOAc. The organic phase was washed with brine, dried

over Na₂SO₄, and evaporated at reduced pressure. The residue

was chromatographed on silica gel, eluting with a gradient of

10-15% Et₂O/hexane to give 480 mg (yield 84%) of 41b as an

oil: ¹H NMR (CDCl₃) ∂ 7.75 (s, 1H), 7.35-7.15 (m, 4H), 7.10

(d, 1H), 6.95 (d, 2H), 6.35 (br s, 1H), 5.25 (s, 2H), 4.15 (q, 2H),

2.95 (t, 2H), 2.70 (q, 2H), 2.50 (t, 2H), 2.05-1.95 (m, 2H), 1.35

(t, 3H), 1.05 (t, 3H); MS (FD⁺) 381 (M⁺). Anal. (C₂₃H₂₇NO₂S)

H, N; C: calcd, 72.41; found, 73.27; S: calcd, 8.40; found, 7.96.

4-[[2-Eth yl-6-m eth yl-1-(p h en ylm eth yl)-1H-in d ol-5-yl]-

th io]bu ta n oic Acid Eth yl Ester (41c). A solution of 1.46 g

(4.1 mmol) of 39b and 20 mL of 5 N NaOH in 60 mL of EtOH

was heated at reflux for 5 h and cooled to room temperature,

water was added, and the mixture was extracted with EtOAc,

washed with brine, dried (MgSO₄), and evaporated at reduced

pressure to give 1.2 g of crude 2-ethyl-5-mercapto-6-methyl-

1-(phenylmethyl)-1H-indole (40b), which was immediately

dissolved in 20 mL of DMF and stirred with 160 mg (4 mmol)

of 60% NaH/mineral oil and 0.56 mL (4 mmol) of ethyl

bromobutyrate. The mixture was stirred for 18 h, water was

added, and the mixture was extracted with EtOAc, washed

with brine, dried (MgSO₄), concentrated, and then chromato-

graphed on silica gel, eluting with 10% EtOAc/hexane, to give

947 mg (yield 60%) of 41c as an oil: ¹H NMR (CDCl₃) ∂ 7.66

(s, 1H), 7.33-6.90 (m, 6H), 6.27 (s, 1H), 5.27 (s, 2H), 4.13 (q,

2H), 2.88 (t, 2H), 2.65 (q, 2H), 2.49 (s, 3H), 2.49-2.41 (m, 2H),

1.93 (t, 2H), 1.36-1.22 (m, 6H); MS (FD⁺) 396 (M⁺). Anal.

(C₂₄H₂₉NO₂S) H, N; C: calcd, 72.87; found, 74.72.

Using the preceding method, 39c was converted to 41d .

4-[[2-E t h yl-6-isop r op yl-1-(p h en ylm et h yl)-1H -in d ol-5-

yl]th io]bu ta n oic a cid eth yl ester (41d ) (chromatography

on silica gel, 10% EtOAc/hexane): yield 81%; oil; ¹H NMR

(CDCl₃) ∂ 7.28 (s, 1H), 7.37-7.22 (m, 3H), 7.11 (s, 1H), 7.01

(d, 1H), 5.26 (s, 1H), 5.29 (s, 2H), 4.12 (q, 2H), 3.82-3.66 (m,

1H), 2.86 (t, 2H), 2.64 (q, 2H), 2.47 (t, 2H), 2.00-1.86 (m, 2H),

1.37-1.16 (m, 12H); MS (FD⁺) 423 (M⁺).

[3-[[2-E t h yl-1-(p h en ylm et h yl)-1H-in d ol-5-yl]t h io]p r o-

p yl]p h osp h on ic Acid Dim eth yl Ester (41e). A solution of

530 mg (2.0 mmol) of 40a in 90 mL of DMF and 10 mL of THF

was treated with 70 mg (2.2 mmol) of 60%NaH/mineral oil.

The mixture was stirred for 5 min, 510 mg (2.2 mmol) of

dimethyl 3-bromopropyl phosphonate was then added, and the

mixture was stirred for 30 min. The solution was diluted with

water and EtOAc. The organic phase was washed with brine,

dried (Na₂SO₄), and then evaporated at reduced pressure. The

residue was chromatographed on silica gel, eluting with

EtOAc, to give 400 mg (yield 48%) of 41e as an oil: ¹H NMR

(CDCl₃) ∂ 7.60 (s, 1H), 7.25-7.00 (m, 5H), 6.80 (d, 2H), 6.25

(s, 1H), 5.20 (s, 2H), 3.65 (s, 3H), 3.60 (s, 3H), 2.85 (t, 2H),

2.60 (q, 2H), 1.95-1.70 (m, 4H), 1.20 (t, 3H).

washed with brine, dried over Na₂SO₄, and evaporated at

reduced pressure. The residue was chromatographed on silica

gel, eluting with a gradient of 40% Et₂O/hexane-100% Et₂O,

to give 325 mg (yield 56%) of 42b as a glass: MS (FD⁺) 452

(M⁺). Anal. (C₂₅H₂₈N₂O₄S) C, H, N, S.

4-[[3-(2-Am in o-1,2-d ioxoeth yl)-2-eth yl-6-m eth yl-1-(p h e-

n ylm eth yl)-1H-in d ol-5-yl]th io]bu ta n oic Acid Eth yl Ester

(42c). To a solution of 945 mg (2.4 mmol) of 41c in 15 mL of

CH₂Cl₂was added 0.21 mL (2.4 mmol) of oxalyl chloride. The

mixture was stirred for 3 h and then evaporated at reduced

pressure, 15 mL of CH₂Cl₂and saturated with ammonia gas

was added, and the mixture was stirred 16 h and evaporated

at reduced pressure. Water was added, and the mixture was

extracted with EtOAc, washed with brine, dried (MgSO₄),

evaporated at reduced pressure, and then chromatographed

on silica gel, eluting with 20% EtOAc/hexane, to give 620 mg

(yield 55%) of 42c as an oil: ¹H NMR (CDCl₃) ∂ 8.16 (s, 1H),

7.34-6.97 (m, 6H), 6.72 (br s, 1H), 5.77 (br s, 1H), 5.35 (s, 2H),

4.14 (q, 2H), 3.10 (q, 2H), 2.98 (t, 2H), 2.51 (t, 2H), 2.43 (s,

3H), 2.08-1.96 (m, 2H), 1.33-1.18 (m, 6H); MS (FD⁺) 466

(M⁺). Anal. (C₂₆H₃₀N₂O₄S) H; C: calcd, 66.93; found, 67.90;

N: calcd, 7.00; found, 6.34.

Using the preceding method, 41d was converted to 42d .

4-[[3-(2-Am in o-1,2-d ioxoet h yl)-2-et h yl-6-isop r op yl-1-

(p h en ylm et h yl)-1H-in d ol-5-yl]t h io]b u t a n oic a cid et h yl

ester (42d ) (chromatography on silica gel, 20% EtOAc/hexane;

1

yield 77%; oil; H NMR (CDCl₃) ∂ 8.18 (s, 1H), 7.35-7.00 (m,

6H), 6.70 (br s, 1H), 5.74 (br s, 1H), 5.39 (s, 2H), 4.14 (q, 2H),

3.67-3.55 (m, 1H), 3.10 (q, 2H), 2.98 (t, 2H), 2.51 (t, 2H), 2.08-

1.98 (m, 2H), 1.30-1.15 (m, 12H); MS (FD⁺) 494 (M⁺).

4-[[3-(2-Am in o-2-oxoet h yl)-2-et h yl-1-(p h en ylm et h yl)-

1H-in d ol-5-yl]th io]bu ta n oic Acid Eth yl Ester (43b).

A

solution of 325 mg of 42b, 2 mL of triethylsilane, and 2 mL of

trifluoroacetic acid in 40 mL of 1,2-dichloroethane was refluxed

for 18 h, cooled, washed with aqueous NaHCO₃, dried over Na₂-

SO₄, and evaporated at reduced pressure. The residue was

chromatographed on silica gel, eluting with a gradient of 1-5%

MeOH/CH₂Cl₂to give 200 mg (yield 64%) of 43b as an oil

which crystallized on standing: mp 90-92 °C; ¹H NMR

(CDCl₃) ∂ 8.15 (s, 1H), 7.30-7.15 (m, 4H), 7.10 (d, 1H), 6.95

(d, 2H), 6.90 (br s, 1H), 6.25 (br s, 1H), 5.30 (s, 2H), 4.05 (q,

2H), 3.05 (q, 2H), 2.90 (t, 2H), 2.40 (t, 2H), 1.95-1.80 (m, 2H),

1.15 (t, 6H); MS (FD⁺) 438 (M⁺). Anal. (C₂₅H₃₀N₂O₃S) C, H,

N, S.

4-[[3-(2-Am in o-2-oxoeth yl)-2-eth yl-6-m eth yl-1-(p h en yl-

m et h yl)-1H -in d ol-5-yl]t h io]b u t a n oic Acid E t h yl E st er

(43c). To a solution of 615 mg (1.32 mmol) of 42c in 15 mL of

EtOH was added 62.4 mg (1.65 mmol) of NaBH₄. The mixture

was stirred for 20 h and then evaporated at reduced pressure,

water was added, and the mixture was extracted with EtOAc,

washed with brine, dried (MgSO₄), and evaporated to give 537

mg (yield 87%) of 4-[[3-(2-amino-1-hydroxy-2-oxoethyl)-2-ethyl-

6-methyl-1-(phenylmethyl)-1H-indol-5-yl]thio]butanoic acid eth-

yl ester as an oil (532mg, 1.14 mmol). This oil was dissolved

in 20 mL of CH₂Cl₂and 0.23 mL (1.65 mmol) of triethylsilane,

and 2 mL of trifluoroacetic acid was added. The mixture was

stirred for 2 h and then evaporated at reduced pressure, water

was added, and the mixture was extracted with EtOAc,

washed with brine, dried (MgSO₄), evaporated at reduced

pressure, and then chromatographed on silica gel, eluting with

50% EtOAc/hexane, to give 290 mg (yield 56%) of 43c: mp

135-137 °C; ¹H NMR (CDCl₃) ∂ 7.60 (s, 1H), 7.33-7.22 (m,

3H), 7.07 (s, 1H), 6.97 (d, 2H), 5.71 (br s, 1H), 5.40 (br s, 1H),

5.31 (s, 2H), 4.12 (q, 2H), 3.72 (s, 2H), 2.89 (t, 2H), 2.73 (q,

2H), 2.51-2.46 (m, 2H), 2.49 (s, 3H), 1.93 (t, 2H), 1.26 (t, 3H),

1.12 (t, 3H); MS (FD⁺) 452 (M⁺). Anal. (C₂₆H₃₂N₂O₃S) C, H,

N.

3-[[3-(2-Am in o-1,2-dioxoeth yl)-2-eth yl-1-(ph en ylm eth yl)-

1H-in d ol-5-yl]th io]p r op ion ic Acid ter t-Bu tyl Ester (42a ).

To 40a (1.91g, 7.15 mmol) and 3.9 g of potassium carbonate

in 50 mL of MEK was added 1.6 mL of tert-butyl acrylate. The

mixture was heated at reflux for 24 h, diluted with water and

extracted with EtOAc. The organic phase was washed with

brine, dried (MgSO₄), and evaporated at reduced pressure. The

residue was chromatographed on silica gel, eluting with 20%

EtOAc/hexane, to give 2.47 g (6.25 mmol, yield 84%) of 41a as

an oil. This material was stirred with 0.55 mL (6.25 mmol) of

oxalyl chloride in 40 mL of CH₂Cl₂for 1 h and then evaporated

at reduced pressure. The residue was redissolved in 40 mL

of CH₂Cl₂, saturated with ammonia gas, stirred an additional

20 min, and evaporated at reduced pressure. The residue was

chromatographed on silica gel, eluting with 50% EtOAc/

hexane, to give 1.81 g (yield 62%) of 42a as an oil: ¹H NMR

(CDCl₃) ∂ 8.24 (s, 1H), 7.34-6.99 (m, 7H), 6.75 (br s, 1H), 5.71

(br s, 1H), 5.39 (s, 2H), 3.16-3.04 (m, 4H), 2.50 (t, 2H), 1.45

(s, 9H), 1.27 (t, 3H); MS (FD⁺) 466 (M⁺). Anal. (C₂₆H₃₀N₂O₄S)

C, H; N: calcd, 6.00; found, 5.21.

Using the preceding method, 42d was converted to 43d .

4-[[3-(2-Am in o-2-oxoeth yl)-2-eth yl-6-isop r op yl-1-(p h e-

4-[[3-(2-Am in o-1,2-dioxoeth yl)-2-eth yl-1-(ph en ylm eth yl)-

n ylm eth yl)-1H-in d ol-5-yl]th io]bu ta n oic a cid eth yl ester

(43d ) (crude product): yield 78%; H NMR (CDCl₃) ∂ 7.37-

1

1H-in d ol-5-yl]th io]bu ta n oic Acid Eth yl Ester (42b).

A

solution of 480 mg (1.3 mmol) of 41b in 100 mL of CH₂Cl₂was

cooled to -5 °C, and 0.14 mL (1.6 mmol) of oxalyl chloride was

added. The cooling bath was removed, and the solution was

stirred for 1 h, recooled to -5 °C, saturated with ammonia,

7.23 (m, 3H), 7.10 (s, 1H), 7.00 (d, 2H), 5.80 (br s, 1H), 5.67

(br s, 1H), 5.32 (s, 2H), 4.11 (q, 2H), 3.82-3.60 (m, 1H), 3.72

(s, 2H), 2.89 (t, 2H), 2.73 (q, 2H), 2.47 (t, 2H), 2.00-1.84 (m,

2H), 1.35-1.07 (m, 12H); MS (FD⁺) 480 (M⁺).

5154 J ournal of Medicinal Chemistry, 1996, Vol. 39, No. 26

Dillard et al.

[3-[[3-(2-Am in o-2-oxoeth yl)-2-eth yl-1-(p h en ylm eth yl)-

1H-in d ol-5-yl]th io]p r op yl]p h osp h on ic Acid Dim eth yl Es-

ter (43e). To a solution of 400 mg (1.0 mmol) of 41e in 100

mL of CH₂Cl₂at -5 °C was added 0.11 mL (1.2 mmol) of oxalyl

chloride. The cooling bath was removed, and the solution was

stirred for 1 h. After being cooled to -5 °C, the solution was

saturated with ammonia gas, washed with water, dried (Na₂-

SO₄), and evaporated at reduced pressure. The residue was

chromatographed on silica gel, eluting with a gradient of 1-5%

MeOH/CH₂Cl₂, to give 280 mg (yield 57%) of 42e, which was

dissolved in 40 mL of 1,2-dichloroethane, 2 mL of TFA, and 2

mL of triethylsilane and refluxed for 18 h. The cooled solution

was washed with a saturated NaHCO₃solution, dried (Na₂-

SO₄), and evaporated at reduced pressure. The residue was

chromatographed on silica gel, eluting with a gradient of 1-5%

MeOH/CH₂Cl₂, to give 175 mg (yield 64%) of 43e: ¹H NMR

(CDCl₃) ∂ 7.60 (s, 1H), 7.25-7.00 (m, 4H), 7.05 (d, 1H), 6.95

(d, 2H), 6.30 (br s, 1H), 5.95 (br s, 1H), 5.25 (s, 2H), 3.65 (s,

3H), 3.60 (s, 3H), 2.80 (t, 2H), 2.70 (q, 2H), 1.95-1.70 (m, 4H),

1.05 (t, 3H).

3-[[3-(2-Am in o-2-oxoet h yl)-2-et h yl-1-(p h en ylm et h yl)-

1H-in d ol-5-yl]th io]p r op ion ic Acid (44a ). To 42a (1.81 g,

3.9 mmol) in 30 mL of EtOH was added 184 mg (4.9 mmol) of

sodium borohydride. The mixture was stirred for 16 h, the

solvent was evaporated at reduced pressure, and the residue

was dissolved in EtOAc/water. The organic layer was washed

with water and with brine, dried (MgSO₄), and evaporated at

reduced pressure to give 1.34 g (3 mmol) of the R-hydroxy

intermediate. This crude product was stirred with triethyl-

silane (0.6 mL, 3.75 mmol) in trifluoroacetic acid (10 mL) for

2 h. The solvent was evaporated at reduced pressure. The

residue was dissolved in EtOAc, washed with water and brine,

dried (MgSO₄), and evaporated at reduced pressure to give 1.0

g (yield 84%) of 44a . This product was purified on a C-18

reverse phase column eluting with 10% (5% HOAc/H₂O)/

MeOH: ¹H NMR (CDCl₃) ∂ 7.66 (s, 1H), 7.33-7.20 (m, 4H),

7.14 (d, 1H), 7.08 (br s, 1H), 6.95 (d, 1H), 5.80 (br s, 1H), 5.33

(s, 2H), 3.72 (s, 2H), 3.11 (t, 2H), 2.72 (q, 2H), 2.57 (t, 2H),

1.12 (t, 2H); MS (FD) 396 (M⁺). Anal. (C₂₂H₂₄N₂O₃S) C, H,

N.

4-[[3-(2-Am in o-2-oxoet h yl)-2-et h yl-1-(p h en ylm et h yl)-

1H-in d ol-5-yl]th io]bu ta n oic Acid (44b). A mixture of 200

mg of 43b and 2 mL of 2 N NaOH in 25 mL of EtOH was

stirred for 19 h, acidified with 5 N HCl, and extracted with

EtOAc. The organic phase was washed with brine, dried over

Na₂SO₄, and concentrated. The residue was crystallized from

EtOH to give 65 mg (yield 89%) of 44b: mp 117-119 °C; MS

(FD) 410 (M⁺). Anal. (C₂₃H₂₆N₂O₃S) C, H, N.

4-[[3-(2-Am in o-2-oxoeth yl)-2-eth yl-6-m eth yl-1-(p h en yl-

m eth yl)-1H-in d ol-5-yl]th io]bu ta n oic Acid (44c). To a

solution of 280 mg (0.62 mmol) of 43c in 10 mL of MeOH was

added 4 mL of 1 N NaOH, the mixture was heated at reflux

for 1 h, water was then added,and the mixture was extracted

with EtOAc. The aqueous portion was acidified to pH 2,

extracted with EtOAc, washed with brine, dried (MgSO₄),

evaporated at reduced pressure, and then chromatographed

on silica gel, eluting with 50% EtOAc/hexane to give 214 mg

(yield 81%) of 44c: ¹H NMR (CDCl₃) ∂ 7.59 (s, 1H), 7.33-7.21

(m, 4H), 7.03 (s, 1H), 6.97 (d, 2H), 6.03 (br s, 1H), 5.30 (s, 2H),

3.72 (s, 2H), 2.91 (t, 2H), 2.72 (q, 2H), 2.49 (t, 2H), 2.44 (s,

3H), 1.96 (t, 2H), 1.11 (t, 3H); MS (FD⁺) 424 (M⁺). Anal.

(C₂₄H₂₈N₂O₃S) C, H, N.

stirred for 3 h, and evaporated at reduced pressure. The

residue, dissolved in dilute NaOH, was chromatographed on

an HP-20 column, eluting with a gradient of 5-15% MeCN/

H₂O to give 70 mg (yield 43%) of 44e as a solid: MS (FAB)

469 (M + 1 - Na)⁺, 470 (M + 2 - Na)⁺, 491 (M + 1)⁺, 492 (M

+ 2)⁺. Anal. (C₂₂H₂₅Na₂N₂O₄PS‚1.8H₂O) C, H, N.

N -(t er t -Bu t oxyca r b on yl)-5-m e t h oxy-2-m e t h ylin d o-

lin e (47). To a solution of 19 g (118 mmol) of 5-methoxy-2-

methylindole (45) in 500 mL of acetic acid at 0 °C was added

37 g (590 mmol) of sodium cyanoborohydride in portions. The

cooling bath was removed, and the reaction mixture was

stirred for 4 h and then diluted with water. The acetic acid

was evaporated at reduced pressure, the residue was made

basic with 2 N NaOH, and then the product was extracted with

Et₂O, washed with brine, dried (MgSO₄), and evaporated at

reduced pressure to give 16.9 g (104 mmol) of 5-methoxy-2-

methylindoline (46). The crude product was heated at reflux

with 27.2 g (124 mmol) of di-tert-butyl dicarbonate in 150 mL

of THF for 22 h. The solvent was evaporated at reduced

pressure, and the residue was diluted with water, extracted

with EtOAc, washed with brine, dried (MgSO₄), evaporated

at reduced pressure, and then chromatographed on silica gel,

eluting with 20% EtOAc/hexane, to give 16 g (yield 58%) of

47 as an oil: ¹H NMR (CDCl₃) ∂ 6.75-6.66 (m, 3H), 4.49 (br s,

1H), 3.78 (s, 3H), 3.34 (dd, 1H), 2.57 (br d, 1H), 1.58 (s, 9H),

1.30 (d, 3H); MS (FD⁺) 263 (M⁺). Anal. (C₁₅H₂₁NO₃) C, H, N.

N-(ter t-Bu toxyca r bon yl)-2,7-d im eth yl-5-m eth oxyin d o-

lin e (48). To a solution of 16 g (61 mmol) of 47 and 11.9 mL

(79 mmol) of N,N,N′,N′-tetramethylethylenediamine in 300 mL

of Et₂O at -78 °C was added 56 mL of a 1.3 M solution of

sec-butyllithium in cyclohexane. The mixture was stirred for

1 h, 5.7 mL (91 mmol) of methyl iodide was then added, the

cooling bath was removed, and the mixture was stirred for an

additional 16 h. Water was added, and the product was

extracted with Et₂O, washed with brine, dried (MgSO₄),

evaporated at reduced pressure, and chromatographed on

silica gel, eluting with 20% EtOAc/hexane, to give 15.4 g (yield

91%) of 48 as an oil: ¹H NMR (CDCl₃) ∂ 6.61 (s, 1H), 6.55 (s,

1H), 4.72-4.59 (m, 1H), 3.78 (s, 3H), 3.37 (dd, 1H), 2.34 (d,

1H), 2.26 (s, 3H), 1.51 (s, 9H), 1.18 (d, 3H); MS (FD⁺) 277 (M⁺).

Anal. (C₁₆H₂₃NO₃) C, H, N.

2,7-Dim eth yl-5-m eth oxy-1-(ph en ylm eth yl)in dolin e (50).

A solution of 15.7 g (56.7 mmol) of 48 in 25 mL of trifluoroacetic

acid was stirred for 17 h. The TFA was evaporated at reduced

pressure, the residue was dissolved in EtOAc/water and

neutralized with 2 N NaOH, and then the EtOAc layer was

separated, washed with brine, dried (MgSO₄), and evaporated.

The residue was chromatographed on silica gel, eluting with

20% EtOAc/hexane, to give 3.0 g (17 mmol, yield 30%) of 2,7-

dimethyl-5-methoxyindoline (49). This material was dissolved

in 15 mL of DMF and treated with 680 mg (17 mmol) of 60%

NaH/mineral oil, followed by 2 mL (17 mmol) of benzyl

bromide, and then the mixture was stirred for 1 h, diluted with

water, and extracted with EtOAc. The extract was washed

with brine, dried (MgSO₄), evaporated, and then chromato-

graphed on a silica gel column, eluting with 20% EtOAc/hexane

to give 4.1 g (yield 90%) of 50 as an oil: ¹H NMR (CDCl₃) ∂

7.53-7.20 (m, 5H), 6.59 (s, 1H), 6.49 (s, 1H), 4.29 (AB q, 2H),

3.76 (s, 3H), 3.57-3.46 (m, 1H), 3.26 (dd, 1H), 2.44 (dd, 1H),

2.26 (s, 3H), 1.14 (d, 3H); MS (FD⁺) 267 (M⁺). Anal. (C₁₈H₂₁

NO) C, H, N.

-

2,7-Dim et h yl-5-m et h oxy-1-(p h en ylm et h yl)-1H -in d ole

(51). A solution of 4.1 g (15.4 mmol) of 50 in 50 mL of dioxane

was treated with 3.5 g (15.4 mmol) of 2,3-dichloro-5,6-dicyano-

1,4-benzoquinone, and the mixture was heated at 90 °C for

15 min, diluted with water, and extracted with EtOAc. Some

insoluble material was filtered off, the EtOAc layer was

washed with brine, dried (MgSO₄), evaporated, and then

chromatographed on silica gel, eluting with 20% EtOAc/hexane

to give 3.25 g (yield 80%) of 51: mp 98-108 °C; ¹H NMR

(CDCl₃) ∂ 7.41-6.80 (m, 6H), 6.49 (s, 1H), 6.26 (s, 1H), 5.49

(s, 2H), 3.82 (s, 3H), 2.44 (s, 3H), 2.31 (s, 3H); MS (FD⁺) 265

(M⁺). Anal. (C₁₈H₁₉NO) C, H, N.

Using the preceding method, 43d was converted to 44d .

4-[[3-(2-Am in o-2-oxoeth yl)-2-eth yl-6-isop r op yl-1-(p h e-

n ylm eth yl)-1H-in d ol-5-yl]th io]bu ta n oic a cid (44d ) (crys-

tallization, EtOH/water): yield 37%; mp 138-140 °C; ¹H NMR

(CDCl₃) ∂ 7.66 (s, 1H), 7.41-7.21 (m, 3H), 7.10 (s, 1H), 7.01

(d, 2H), 6.97 (br s, 1H), 6.03 (br s, 1H), 5.33 (s, 2H), 3.73-3.57

(m, 1H), 3.66 (s, 2H), 2.89 (t, 2H), 2.69 (q, 2H), 2.47 (t, 2H),

2.00-1.88 (m, 2H), 1.23 (d, 6H), 1.12 (t, 3H); MS (FD⁺) 452

(M⁺). Anal. (C₂₆H₃₂N₂O₃S) C, H, N.

[3-[[3-(2-Am in o-2-oxoeth yl)-2-eth yl-1-(p h en ylm eth yl)-

1H-in d ol-5-yl]th io]p r op yl]p h osp h on ic Acid (44e). A solu-

tion of 175 mg (0.37 mmol) of 43e in 25 mL of CH₂Cl₂was

stirred with 0.5 mL of trimethylsilyl bromide for 19 h,

evaporated at reduced pressure, dissolved in 25 mL of MeOH,

2,7-Dim et h yl-5-h yd r oxy-1-(p h en ylm et h yl)-1H -in d ole

(52). A solution of 3.25 g (12.3 mmol) of 51 in 50 mL of CH₂-

Cl₂was treated with 18.4 mL (18.4 mmol) of a 1 M solution of

Indole Inhibitors of hnps-PLA₂. 2

J ournal of Medicinal Chemistry, 1996, Vol. 39, No. 26 5155

boron tribromide in CH₂Cl₂. The mixture was stirred for 1 h,

the solvent was evaporated, and the residue was diluted with

water, extracted with EtOAc, washed with brine, dried (Mg-

SO₄), evaporated, and then chromatographed on silica gel,

eluting with 20% EtOAc/hexane, to give 2.28 g (yield 74%) of

52: mp 113-116 °C; ¹H NMR (CDCl₃) ∂ 7.37-6.78 (m, 7H),

6.40 (s, 1H), 6.23 (s, 1H), 5.48 (s, 2H), 3.42 (s, 3H), 2.29 (s,

3H); MS (FD) 251 (M⁺). Anal. (C₁₇H₁₇NO) C, H, N.

2,7-Dim eth yl-5-[[(d im eth yla m in o)th ioca r ba m oyl]oxy]-

1-(p h en ylm eth yl)-1H-in d ole (53). To a solution of 1.7 g (6.8

mmol) of 52 in 20 mL of DMF were added 272 mg (6.8 mmol)

of 60% NaH/mineral oil and 841 mg (6.8 mmol) of dimethylth-

iocarbamoyl chloride. The mixture was stirred 72 h, water

was added, and the mixture was extracted with EtOAc,

washed with brine, dried (MgSO₄), and evaporated at reduced

pressure. The residue was stirred with EtOAc, and the

insoluble portion was filtered off to give 1.9 g (yield 83%) of

53: ¹H NMR (CDCl₃) ∂ 7.33-7.19 (m, 4H), 7.08 (s, 1H), 6.89

(d, 1H), 6.56 (s, 1H), 6.33 (s, 1H), 5.51 (s, 1H), 3.48 (s, 3H),

3.34 (s, 3H), 2.49 (s, 3H), 2.31 (s, 3H); MS (FD⁺) 338 (M⁺).

Anal. (C₂₀H₂₂N₂OS) H, N; C: calcd, 70.97; found, 68.65;

residue 2.95%.

2,7-Dim et h yl-5-[[(d im et h yla m in o)ca r b a m oyl]t h io]-1-

(p h en ylm eth yl)-1H-in d ole (54). A solution of 1.9 g (5.6

mmol) of 53 in 120 mL of phenyl ether was heated at reflux

for 16 h and cooled to room temperature, and then the entire

solution was chromatographed on silica gel, eluting with 20%

EtOAc/hexane and then 50% EtOAc/hexane, to give 1.51 g

(yield 80%) of 54: mp 171-173 °C; ¹H NMR (CDCl₃) ∂ 7.57 (s,

1H), 7.37-7.16 (m, 4H), 6.94 (s, 1H), 6.84 (d, 1H), 6.33 (s, 1H),

5.53 (s, 2H), 3.09 (br s, 3H), 3.03 (br s, 3H), 2.47 (s, 3H), 2.29

(s, 3H); MS (FD⁺) 338 (M⁺). Anal. (C₂₀H₂₂N₂OS) C, H, N.

2,7-Dim e t h yl-5-m e r ca p t o-1-(p h e n ylm e t h yl)-1H -in -

d ole (55). A solution of 744 mg (2.2 mmol) of 54 was heated

with 10 mL of 5 N NaOH in 30 mL of EtOH at reflux for 5 h

and cooled to room temperature, water was added, and the

mixture was extracted with EtOAc, washed with brine, dried

(MgSO₄), and evaporated at reduced pressure, and then

chromatographed on silica gel, eluting with 20% EtOAc/hexane

to give 545 mg (yield 93%) of 55 as an oil: ¹H NMR (CDCl₃) ∂

7.41 (s, 1H), 7.32-7.74 (m, 6H), 6.25 (s, 1H), 5.49 (s, 2H), 3.41

(s, 1H), 2.43 (s, 3H), 2.30 (s, 3H); MS (FD⁺) 267 (M⁺). Anal.

(C₁₇H₁₇NS) C, H, N.

4-[[2,7-Dim eth yl-1-(p h en ylm eth yl)-1H-in d ol-5-yl]oxy]-

bu ta n oic Acid Eth yl Ester (56a ). To a solution of 480 mg

(1.9 mmol) of 52 in 15 mL of DMF were added 76 mg (1.9

mmol) of 60% NaH/mineral oil and 0.27 mL (1.9 mmol) of ethyl

4-bromobutyrate. The mixture was stirred for 16 h, diluted

with water, extracted with EtOAc, washed with brine, dried

(MgSO₄), evaporated, and then chromatographed on silica gel,

eluting with 20% EtOAc/hexane to give 502 mg (yield 72%) of

56a as an oil: ¹H NMR (CDCl₃) ∂ 7.34-6.80 (m, 6H), 6.49 (s,

1H), 6.26 (s, 1H), 5.49 (s, 2H), 4.14 (q, 2H), 4.00 (t, 2H), 2.52

(t, 2H), 2.43 (s, 3H), 2.31 (s, 3H), 2.25-2.08 (m, 2H), 1.25 (t,

3H); MS (FD⁺) 365 (M⁺). Anal. (C₂₃H₂₇NO₃) C, H, N.

4-[[3-(2-Am in o-1-h yd r oxy-2-oxoet h yl)-2,7-d im et h yl-1-

(p h en ylm eth yl)-1H-in d ol-5-yl]oxy]bu ta n oic Acid Eth yl

Ester (58a ). To a solution of 490 mg (1.34 mmol) of 56a in

10 mL of CH₂Cl₂was added 0.12 mL (1.34 mmol)of oxalyl

chloride. The mixture was stirred for 45 min and then

evaporated at reduced pressure, 10 mL of CH₂Cl₂was added,

and the mixture was saturated with ammonia gas, stirred for

30 min, and evaporated at reduced pressure. Water was

added, and the mixture was extracted with EtOAc, washed

with brine, dried (MgSO₄), and evaporated at reduced pres-

sure. The residue was stirred with EtOAc, and the insoluble

material was filtered off to give 441 mg (1 mmol, yield 75%)

of 4-[[3-(2-amino-1,2-dioxoethyl)-2,7-dimethyl-1-(phenylmethyl)-

1H-indol-5-yl]oxy]butanoic acid ethyl ester (57a ), mp 169-171

°C. This crude product was stirred with 47.2 mg (1.25 mmol)

of sodium borohydride in 20 mL of EtOH for 24 h. The solvent

was evaporated, and the residue was dissolved in EtOAc/water.

The EtOAc layer was separated, washed with brine, dried

(MgSO₄), and evaporated at reduced pressure to give 397 mg

(yield 91%) of 58a : ¹H NMR (CDCl₃) ∂ 7.37-6.78 (m, 6H), 6.51

(s, 1H), 6.04 (br s, 1H), 5.57 (br s, 1H), 5.49 (AB q, 2H), 5.39

(d, 1H), 4.07 (q, 2H), 4.00 (t, 2H), 3.59 (d, 1H), 2.51 (t, 2H),

2.43 (s, 3H), 2.33 (s, 3H), 2.10 (t, 2H), 1.25 (t, 3H); MS (FD⁺)

438 (M⁺). Anal. (C₂₅H₃₀N₂O₅) C, H, N.

4-[[3-(2-Am in o-2-oxoeth yl)-2,7-d im eth yl-1-(p h en ylm e-

th yl)-1H-in d ol-5-yl]oxy]bu ta n oic Acid (60a ). A solution

of 389 mg (0.89 mmol) of 58a in 0.18 mL (1.1 mmol) of

triethylsilane and 3 mL of trifluoroacetic acid was stirred for

2 h and then evaporated at reduced pressure. Water was

added, and the mixture was extracted with EtOAc, washed

with brine, dried (MgSO₄), evaporated at reduced pressure,

and then chromatographed on silica gel, eluting with 50%

EtOAc/hexane, and then EtOAc, to give 235 mg (yield 63%) of

59a , which was dissolved in 10 mL of MeOH and heated 10

min at reflux with 4 mL of 1 N NaOH. Water was then added

and the mixture extracted with EtOAc. The aqueous portion

was acidified to pH 2, extracted with EtOAc, washed with

brine, dried (MgSO₄), and evaporated at reduced pressure. The

residue was stirred with EtOAc, and the insoluble product was

filtered off and vacuum-dried to give 41 mg (yield 19%) of 60a

(reaction was not complete, recovered 160 mg of 59a ): mp

1

207-209 °C; H NMR (DMSO-d₆) ∂ 7.33-6.77 (m, 8H), 6.41

(s, 1H), 5.49 (s, 2H), 3.93 (t, 2H), 3.43 (s, 2H), 2.39 (t, 2H),

2.35 (s, 3H), 2.23 (s, 3H), 1.93 (t, 2H); MS (FD⁺) 394 (M⁺). Anal.

(C₂₃H₂₆N₂O₄) C, H, N.

4-[[2,7-Dim eth yl-1-(p h en ylm eth yl)-1H-in d ol-5-yl]th io]-

bu ta n oic Acid Eth yl Ester (56b). A solution of 545 mg (2

mmol) of 55 in 10 mL of DMF was treated with 80 mg (2 mmol)

of 60% NaH/mineral oil and 0.29 mL (2 mmol) of ethyl

bromobutyrate. The mixture was stirred for 18 h, water was

added, and the mixture was extracted with EtOAc, washed

with brine, dried (MgSO₄), evaporated at reduced pressure,

and then chromatographed on silica gel, eluting with 20%

EtOAc/hexane, to give 625 mg (yield 82%) of 56b as an oil:

¹H NMR (CDCl₃) ∂ 7.51 (s, 1H), 7.34-7.21 (m, 4H), 6.91 (s,

1H), 6.84 (d, 1H), 6.31 (s, 1H), 5.51 (s, 2H), 4.12 (q, 2H), 2.92

(t, 2H), 2.48 (s, 3H), 2.47 (t, 2H), 2.33 (s, 3H), 1.93 (t, 2H),

1.26 (t, 3H); MS (FD⁺) 381 (M⁺). Anal. (C₂₃H₂₇NO₂S) H; C:

calcd, 72.41; found, 73.48; N: calcd, 3.67; found, 3.26.

4-[[3-(2-Am in o-1,2-d ioxoeth yl)-2,7-d im eth yl-1-(p h en yl-

m et h yl)-1H -in d ol-5-yl]t h io]b u t a n oic Acid E t h yl E st er

(57b). To a solution of 620 mg (1.6 mmol) of 56b in 10 mL of

CH₂Cl₂was added 0.14 mL (1.6 mmol) of oxalyl chloride. The

mixture was stirred for 1.5 h and then evaporated at reduced

pressure, 10 mL of CH₂Cl₂was added, and the mixture was

saturated with ammonia gas with stirring over 15 min and

evaporated at reduced pressure. Water was added, and the

mixture was extracted with EtOAc, washed with brine, dried

(MgSO₄), evaporated at reduced pressure, and then chromato-

graphed on silica gel, eluting with 50% EtOAc/hexane and then

EtOAc, to give 520 mg (yield 72%) of 57b as an oil: ¹H NMR

(CDCl₃) ∂ 8.08 (s, 1H), 7.37-7.25 (m, 4H), 6.99 (s, 1H), 6.91

(d, 1H), 6.79 (br s, 1H), 5.76 (br s, 1H), 5.57 (s, 2H), 4.12 (t,

2H), 2.97 (t, 2H), 2.59 (s, 3H), 2.47 (t, 2H), 2.48 (s, 3H), 1.97

(t, 2H), 1.25 (t, 3H); MS (FD⁺) 452 (M⁺). Anal. (C₂₅H₂₈N₂O₄S)

C, H, N.

4-[[3-(2-Am in o-1-h yd r oxy-2-oxoet h yl)-2,7-d im et h yl-1-

(p h en ylm eth yl)-1H-in d ol-5-yl]th io]bu ta n oic Acid Eth yl

Ester (58b). To a solution of 510 mg (1.13 mmol) of 57b in

20 mL of EtOH was added 53.4 mg (1.4 mmol) of NaBH₄. The

mixture was stirred for 16 h and then evaporated at reduced

pressure, water was added, and the mixture was extracted

with EtOAc, washed with brine, dried (MgSO₄), and evapo-

rated to give 486 mg (yield 95%) of 58b as an oil: ¹H NMR

(CDCl₃) ∂ 7.56 (s, 1H), 7.34-7.18 (m, 4H), 6.92 (s, 1H), 6.86

(d, 1H), 6.11 (br s, 1H), 5.72 (br s, 1H), 5.52 (AB q, 2H), 5.39

(d, 1H), 4.12 (q, 2H), 3.63 (d, 1H), 2.89 (t, 2H), 2.48 (s, 3H),

2.47 (t, 2H), 2.35 (s, 3H), 1.95-1.82 (m, 2H), 1.26 (t, 3H); MS

(FD⁺) 454 (M⁺). Anal. (C₂₅H₃₀N₂O₄S) C, H, N.

4-[[3-(2-Am in o-2-oxoeth yl)-2,7-d im eth yl-1-(p h en ylm e-

th yl)-1H-in d ol-5-yl]th io]bu ta n oic Acid Eth yl Ester (59b).

A solution of 475 mg (1.05 mmol) of 58b, 0.21 mL (1.3 mmol)

of triethylsilane, and 3 mL of trifluoroacetic acid was stirred

for 2 h. The solvent was evaporated at reduced pressure,

water was added to the residue, and it was extracted with

EtOAc, washed with brine, dried (MgSO₄), evaporated at

reduced pressure, and then chromatographed on silica gel,

5156 J ournal of Medicinal Chemistry, 1996, Vol. 39, No. 26

Dillard et al.

eluting with 50% EtOAc/hexane, to give 340 mg (yield 74%)

of 59b: ¹H NMR (CDCl₃) ∂ 7.48 (s, 1H), 7.41-7.16 (m, 4H),

6.95 (s, 1H), 6.83 (d, 1H), 5.67 (br s, 1H), 5.56 (s, 2H), 5.51 (br

s, 1H), 4.11 (q, 2H), 3.69 (s, 2H), 2.91 (t, 2H), 2.48 (s, 3H),

2.46 (t, 2H), 2.26 (s, 3H), 1.92 (t, 2H), 1.25 (t, 3H); MS (FD)

438 (M⁺). Anal. (C₂₅H₃₀N₂O₃S) C, H, N.

4-[[3-(2-Am in o-2-oxoeth yl)-2,7-d im eth yl-1-(p h en ylm e-

th yl)-1H-in d ol-5-yl]th io]bu ta n oic Acid (60b). To a solu-

tion of 330 mg (0.75 mmol) of 59b in 10 mL of EtOH was added

5 mL of 1 N NaOH. The mixture was heated at reflux for 20

min, water was then added, and the mixture was extracted

with EtOAc. The aqueous portion was acidified to pH 2,

extracted with EtOAc, washed with brine, dried (MgSO₄), and

evaporated at reduced pressure. The residue was stirred with

EtOAc, and the insoluble material was filtered off and vacuum-

dried to give 245 mg (yield 80%) of 60b: ¹H NMR (CDCl₃) ∂

7.45 (s, 1H), 7.33-7.16 (m, 4H), 6.91 (s, 1H), 6.83 (d, 1H), 6.66

(br s, 1H), 5.88 (br s, 1H), 5.53 (s, 2H), 3.71 (s, 2H), 2.96 (t,

2H), 2.49 (s, 3H), 2.49 (t, 2H), 2.29 (s, 3H), 1.94 (t, 2H); MS

(FD) 410 (M⁺). Anal. (C₂₃H₂₆N₂O₃S) C, H, N.

4-[[3-(2-Am in o-2-oxoet h yl)-2-b r om o-6-ch lor o-1-(p h e-

n ylm et h yl)-1H -in d ol-5-yl]oxy]b u t a n oic Acid (62b ).

A

mixture of 210 mg (0.41 mmol) of 61b and 2 mL of 2 N NaOH

in 5 mL of THF and 25 mL of EtOH was stirred for 10.5 h,

and the mixture was made acidic with 5 N HCl and extracted

with EtOAc. The EtOAc solution was washed with brine, dried

(Na₂SO₄), and concentrated at reduced pressure. The residue

was crystallized from CH₂Cl₂/EtOH to give 60 mg (yield 31%)

of 62b, mp 220 °C dec. Anal. (C₂₁H₂₀BrClN₂O₄) H, N; C:

calcd, 52.57; found, 54.03; Br: calcd, 16.65; found, 11.57; Cl:

calcd, 7.39; found, 8.96; residue, 1.35%.

[3-[[4-Allyl-3-(2-a m in o-2-oxoeth yl)-2-eth yl-1-(p h en ylm -

eth yl)-1H-in d ol-5-yl]oxy]p r op yl]p h osp h on ic Acid Diso-

d iu m Sa lt (62c). A solution of 310 mg (0.62 mmol) of 61c

and 1.0 mL (7.6 mmol) of trimethylsilyl bromide in 20 mL of

CH₂Cl₂was stirred for 18.5 h and concentrated at reduced

pressure. The residue was dissolved in 20 mL of MeOH,

stirred for 2.5 h, and concentrated. This residue was chro-

matographed on a C-18 reverse phase column, eluted with 10%

(5% HOAc/H₂

solved in 1 N NaOH and chromatographed on a HP-20 column.

O and then 25%

O)/MeOH. Material from this column was dis-

[3-[[3-(2-Am in o-2-oxoeth yl)-2-eth yl-6-isop r op yl-1-(p h e-

n ylm et h yl)-1H-in d ol-5-yl]oxy]p r op yl]p h osp h on ic Acid

Dim eth yl Ester (61a ). To a suspension of 40 mg (1 mmol)

of 60% NaH/mineral oil (previously washed with hexane) in 4

mL of DMF was added 350 mg (1mmol) of 2-ethyl-5-hydroxy-

6-isopropyl-1-(phenylmethyl)-1H-indole-3-acetamide (2h ). The

mixture was stirred for 50 min, 231 mg (1 mmol) of (3-

bromopropyl)phosphonic acid dimethyl ester was added, the

mixture was stirred an additional 4 h, water was added, and

the product was extracted with EtOAc, washed with brine,

dried (MgSO₄), and evaporated. The crystalline residue was

triturated with EtOAc/hexane, filtered, and dried to give 367

The product was eluted with 10% MeCN/H₂

MeCN/H₂O to give 165 mg (yield 52%) of 62c. Anal.

(C₂₅H₂₉N₂O₅PNa₂‚3H₂O) N; C: calcd, 52.82; found, 52.15; H:

calcd, 6.21; found, 5.50.

5-Hydr oxy-2-m eth yl-1-(ph en ylm eth yl)-1H-in dole-3-ace-

tic Acid Hyd r a zid e (64). A solution of 5-methoxy-2-methyl-

1-(phenylmethyl)-1H-indole-3-acetic acid hydrazide (63, 162

mg, 0.5 mmol) was stirred with 1.5 mL of 1 M BBr₃/CH₂Cl₂

for 3 h and poured into aqueous NaHCO₃, and the CH₂Cl₂

solution was separated, washed with brine, dried (Na₂SO₄),

and evaporated at reduced pressure. The residue was chro-

matographed on silica gel, eluting with a gradient of 2-5%

MeOH/CH₂Cl₂to give 60 mg (yield 38%) of 64: mp 216-219

°C; ¹H NMR (DMSO-d₆) ∂ 9.00 (s, 1H), 8.55 (s, 1H), 7.25-7.10

(m, 3H), 7.05 (d, 1H), 6.95 (d, 2H), 6.85 (d, 1H), 6.50 (dd, 1H),

5.25 (s, 2H), 4.10 (br s, 2H), 3.30 (s, 2H), 2.25 (s, 3H); MS (FD⁺)

309 (M⁺). Anal. (C₁₈H₁₉N₃O₂) C, H, N.

1

mg (yield 73%) of 61a : mp 143-145 °C; H NMR (DMSO-d₆)

∂ 7.32-7.20 (m, 6H), 7.09 (d, 1H), 6.98 (d, 1H), 6.80 (br s, 1H),

5.35 (s, 2H), 4.01 (t, 2H), 3.66 (s, 1H), 3.62 (s, 1H), 3.41 (s,

2H), 3.38-3.22 (m, 1H), 2.71 (q, 2H), 2.04-1.84 (m, 4H), 1.14

(d, 6H), 1.03 (t, 3H); MS (FD⁺) 500 (M⁺). Anal. (C₂₇H₃₇N₂O₅P)

C, H, N.

Using the preceding method, 61c was prepared from 2i.

[3-[[4-Allyl-3-(2-a m in o-2-oxoeth yl)-2-eth yl-1-(p h en ylm -

eth yl)-1H-in d ol-5-yl]oxy]p r op yl]p h osp h on ic Acid Dim -

et h yl E st er (61c) (chromatography on silica gel, gradient,

1-4% MeOH/CH₂Cl₂): yield 78%; ¹H NMR (CDCl₃) ∂ 7.25-

7.10 (m, 3H), 6.95 (d, 1H), 6.85 (d, 2H), 6.75 (d, 1H), 6.55 (br

s, 1H), 6.05-6.95 (br s, 1H), 5.25 (s, 2H), 4.95-4.75 (m, 2H),

3.90 (t, 2H), 3.65 (s, 5H), 3.60 (s, 3H), 2.60 (q, 2H), 2.10-1.85

(m, 4H), 1.05 (t, 3H).

4-[3-(2-Hyd r a zin o-2-oxoet h yl)-2-m et h yl-1-(p h en ylm e-

th yl)-1H-in d ol-5-yl]bu ta n oic Acid (67). A solution of 64

(310 mg, 1.0 mmol) in 25 mL of DMSO and 5 mL of THF was

treated with 45 mg (1.1 mmol) of 60%NaH/ mineral oil for 10

min and then with 0.16 mL (1.1 mmol) of ethyl 4-bromobu-

tyrate for 7.5 h. The mixture was diluted with water and

extracted with EtOAc. The EtOAc solution was washed with

brine, dried (Na₂

SO₄), and evaporated at reduced pressure. The

residue was chromatographed on silica gel, eluting with a

gradient of CH₂Cl₂-4% MeOH/CH₂Cl₂to give 65, as an oil,

320 mg (yield 75%). A solution of 290 mg of 65 in 5 mL of

THF, 25 mL of EtOH, and 2 mL of 2N NaOH was stirred for

22.5 h, diluted with water, acidified with 1 N HCl, and

extracted with EtOAc. The EtOAc solution was evaporated

at reduced pressure, and the residue was dissolved in EtOH

and precipitated by diluting with Et₂O to give 67, 50 mg (yield

18%), as an amorphous solid: ¹H NMR (DMSO-d₆/D₂O) ∂ 7.25-

7.05 (m, 4H), 7.00 (d, 1H), 6.90 (d, 2H), 6.60 (dd, 1H), 5.20 (s,

2H), 3.85 (t, 2H), 3.35 (s, 2H), 2.30 (t, 2H), 2.20 (s, 3H), 1.90-

1.75 (m, 2H). Anal. (C₂₂H₂₅N₃O₄) H; C: calcd:, 66.82; found,

66.19; N: calcd, 10.63; found, 9.32.

[3-[[3-(2-Hyd r a zin o-2-oxoeth yl)-2-m eth yl-1-(p h en ylm -

eth yl)-1H-in d ol-5-yl]oxy]p r op yl]p h osp h on ic Acid Diso-

d iu m Sa lt (68). A solution of 420 mg (1.4 mmol) of 64 in 25

mL of DMSO and 5 mL of THF was treated with 65 mg (1.6

mmol) of 60%NaH/mineral oil for 10 min and then with 370

mg (1.6 mmol) of dimethyl (3-bromopropyl)phosphonate for 3.5

h, diluted with water, and extracted with EtOAc. The EtOAc

solution was washed with brine, dried (Na₂SO₄), and evapo-

rated at reduced pressure to give the crude dimethyl ester (66),

170 mg (yield 35%). This material (0.4 mmol) was dissolved

in 20 mL of CH₂Cl₂and treated with 0.5 mL (3.9 mmol) of

Me₃SiBr for 16 h. The solvent was evaporated, and the residue

was dissolved in 25 mL of MeOH, stirred for 1 h, and

evaporated at reduced pressure. The residue, dissolved in 0.05

N NaOH, was chromatographed on an HP-20 column, eluting

with a gradient of 15-30% CH₃CN/H₂O to give 68, 105 mg

(yield 53%), as a powder: ¹H NMR (DMSO-d₆/D₂O) ∂ 7.25-

4-[[3-(2-Am in o-2-oxoet h yl)-2-b r om o-6-ch lor o-1-(p h e-

n ylm eth yl)-1H-in d ol-5-yl]oxy]bu ta n oic Acid Eth yl Ester

(61b). A solution of 235 mg (0.6 mmol) of 2-bromo-6-chloro-

5-hydroxy-1-(phenylmethyl)-1H-indole-3-acetamide (2n ) in 30

mL of DMSO and 10 mL of THF was treated with 25 mg (0.6

mmol) of 60% NaH/mineral oil, the mixture was stirred for 5

min, and then 0.1 mL (0.7 mmol) of ethyl 4-bromobutyrate was

added. The solution was heated at 60 °C for 2 h, cooled, diluted

with water, and extracted with EtOAc. The extract was

washed with water and brine, dried (Na₂SO₄), and chromato-

graphed on silica gel, eluting with a gradient of CH₂Cl₂-2%

MeOH/CH₂Cl₂, to give 210 mg (yield 69%) of 61b: ¹H NMR

(CDCl₃) ∂ 7.35-7.15 (m, 4H), 7.10-6.95 (m, 3H), 6.10 (br s,

1H), 5.85 (br s, 1H), 5.30 (s, 2H), 4.10 (q, 2H), 4.05 (t, 2H),

3.65 (s, 2H), 2.55 (t, 2H), 2.15-2.05 (m, 2H), 1.25 (t, 3H).

[3-[[3-(2-Am in o-2-oxoeth yl)-2-eth yl-6-isop r op yl-1-(p h e-

n ylm et h yl)-1H -in d ol-5-yl]oxy]p r op yl]p h osp h on ic Acid

(62a ). A solution of 350 mg (0.7 mmol) of 61a and 0.74 mL

(5.6 mmol) of trimethylsilyl bromide in 5 mL of CH₂Cl₂was

stirred for 16 h and concentrated at reduced pressure. The

residue was dissolved in 5 mL of MeOH, stirred for 2 h, and

concentrated. The residue was crystallized from EtOAc/

MeCN/HOAc/H₂O to give 330 mg (yield 100%) of 62a : mp

1

176-178 °C; H NMR (DMSO-d₆) ∂ 7.32-7.14 (m, 4H), 7.06

(s, 2H), 6.97 (d, 2H), 6.80 (br s, 1H), 5.36 (s, 2H), 4.01 (t, 2H),

3.41 (s, 2H), 3.32-3.02 (m, 1H), 2.70 (q, 2H), 2.03-1.88 (m,

2H), 1.80-1.64 (m, 2H), 1.13 (d, 6H), 1.03 (t, 3H); MS (FD⁺)

472 (M⁺). Anal. (C₂₅H₃₃N₂O₅P) H, N; C: calcd, 63.55; found,

61.98.

Indole Inhibitors of hnps-PLA₂. 2

J ournal of Medicinal Chemistry, 1996, Vol. 39, No. 26 5157

7.05 (m, 5H), 6.90 (d, 2H), 6.55 (d, 1H), 5.20 (s, 2H), 3.90 (t,

2H), 3.55 (s, 2H), 2.20 (s, 3H), 1.90-1.75 (m, 2H), 1.45-1.25

(m, 2H); MS (FAB+) 476 (M + 1 + Na), 454 (M + 1). Anal.

(C₂₁H₂₄Na₂N₃O₅P‚2.4H₂O) C, H, N.

4H), 7.04-6.88 (m, 3H), 6.66 (dd, 1H), 5.30 (s, 2H), 3.96 (t,

2H), 3.58 (s, 3H), 2.38 (s, 2H), 2.28 (s, 3H), 2.00-1.88 (m, 2H);

MS (FD⁺) 381 (M⁺). Anal. (C₂₂H₂₃NO₅) C, H, N.

3-(2-Am in o-1,2-dioxoeth yl)-1-[(3-ch lor oph en yl)m eth yl]-

2-eth yl-4-m eth oxy-1H-in d ole (79). A solution of 7.65 g (44

mmol) of 2-ethyl-4-methoxy-1H-indole (77) in 50 mL of DMF

was treated with 1.76 g (44mmol) of 60% NaH/mineral oil for

0.75 h and then with 5.6 mL (44 mmol) of 3-chlorobenzyl

chloride for 18 h. The solution was diluted with water and

extracted with EtOAc. The organic phase was washed with

brine, dried (MgSO₄), and evaporated at reduced pressure. The

residue was chromatographed on silica gel, eluting with 25%

EtOAc/hexane to give 1.6 g (yield 12%) of 78. This material

(5.3 mmol) was dissolved in 20 mL of CH₂Cl₂, and 0.5 mL of

oxalyl chloride was added. The solution was stirred for 5.5 h,

saturated with ammonia, and stirred for 18 h. The suspension

was diluted with EtOAc, the insoluble product was filtered off,

and the filtrate was concentrated at reduced pressure. The

residue was chromatographed on silica gel, eluting with 50%

EtOAc/hexane, and the product fractions were combined with

the insoluble material from above to give 1.47 g (yield 75%) of

79: mp 186-189 °C; ¹H NMR (DMSO-d₆) ∂ 7.73 (br s, 1H),

7.41 (br s, 1H), 7.36-6.88 (m, 6H), 6.68 (d, 1H), 5.54 (s, 2H),

3.78 (s, 3H), 2.88 (q, 2H), 1.07 (t, 3H); MS (FD) 370 (M - 1,

100), 372 (M + 1, 40). Anal. (C₂₀H₁₉ClN₂O₃) C, H, N.

4-(Car boxym eth oxy)-1-[(3-ch lor oph en yl)m eth yl]-2-eth -

yl-1H-in d ole-3-ca r boxa m id e (82). A solution of 503 mg

(1.35 mmol) of 79 in 20 mL of CH₂Cl₂and 6 mL of a 1 M

solution of BBr₃/CH₂Cl₂was stirred for 21 h. The solvent was

evaporated, and the residue was dissolved in EtOAc, washed

with water and brine, dried (MgSO₄), and evaporated at

reduced pressure. The residue was chromatographed on silica

gel, eluting with a gradient of 50-67% EtOAc/hexane to give

178 mg (yield 41%) of 80 as a solid. This material (0.5 mmol)

was dissolved in 15 mL of DMF and stirred with 20 mg (0.5

mmol) of 60%NaH/mineral oil for 1.5 h and and then with 0.5

mL (0.5 mmol) of methyl bromoacetate for 3 h. The solution

was diluted with water and extracted with EtOAc. The

organic phase was washed with brine, dried (MgSO₄), and

evaporated at reduced pressure. The residue was chromato-

graphed on silica gel, eluting with EtOAc, to give 73 mg (yield

43%) of 81. This material was dissolved in 6 mL of MeOH by

warming and then stirred with 2 mL of 1 N NaOH for 2 h.

The solution was diluted with water and washed with EtOAc.

The aqueous phase was acidified with 1 N HCl, extracted with

brine, dried (MgSO₄), and evaporated at reduced pressure. The

residue was triturated with CH₂Cl₂and the insoluble material

filtered to give 17 mg (yield 23%) of 82: ¹H NMR (DMSO-d₆)

∂ 8.15 (br s, 1H), 7.34-6.80 (m, 7H), 6.68 (d, 1H), 5.50 (s, 2H),

4.86 (s, 2H), 3.09 (q, 2H), 1.05 (t, 3H); MS (FD) 386 (M - 1,

100), 388 (M + 1, 9). Anal. (C₂₀H₁₉ClN₂O₄) H, N; C: calcd,

62.10; found, 61.38.

4-[[3-(3-Am in o-3-oxopr opyl)-2-m eth yl-1-(ph en ylm eth yl)-

1H-in d ol-5-yl]oxy]bu ta n oic Acid (72). A solution of 504 mg

(1.6 mmol) of 3-[5-methoxy-2-methyl-1-(phenylmethyl)-1H-

indol-5-yl]propionamide (69) in 20 mL of CH₂Cl₂and 6.3 mL

of a 1 M solution of BBr₃/CH₂Cl₂was stirred for 2.5 h. The

boron complex was decomposed with water, and the product

was extracted with EtOAc, washed with brine, dried (MgSO₄),

and evaporated at reduced pressure. The residue was chro-

matographed on silica gel, eluting with EtOAc and then 5%

MeOH/EtOAc, to give 377 mg (yield 78%) of 70 as a solid. A

solution of 170 mg (0.55 mmol) of 70 in 6 mL of DMF was

treated with 22 mg (0.55 mmol) of 60%NaH/mineral oil for 30

min and then with 0.08 mL (0.55 mmol) of ethyl 4-bromobu-

tyrate for 2.5 h, diluted with water, and extracted with EtOAc.

The organic phase was washed with brine, dried (MgSO₄), and

evaporated at reduced pressure. The residue was chromato-

graphed on silica gel, eluting with EtOAc and then 5% MeOH/

EtOAc, to give 71 mg (yield 31%) of 4-[[3-(3-amino-3-oxopropyl)-

2-methyl-1-(phenylmethyl)-1H-indol-5-yl]oxy]butanoic acid ethyl

ester (71). A solution of 65 mg (0.15 mmol) of 71 and 2 mL of

1 N NaOH in 5 mL of EtOH was stirred 1.5 h, diluted with

water, and washed with EtOAc. The aqueous phase was

acidified with 1 N HCl and extracted with EtOAc. The organic

phase was washed with brine, dried (MgSO₄), and concentrated

at reduced pressure. The residue was crystallized from MeOH

to give 55 mg (yield 93%) of 72: mp 169-171 °C; ¹H NMR

(DMSO-d₆) ∂ 12.10 (s, 1H), 7.32-6.80 (m, 9H), 5.31 (s, 2H),

4.98 (t, 2H), 2.87 (t, 2H), 2.41 (t, 2H), 2.29 (t, 2H), 2.27 (s, 3H),

2.00-1.88 (m, 2H); MS (FD⁺) 394 (M⁺). Anal. (C₂₃H₂₆N₂O₄)

C, H, N.

5-Hydr oxy-2-m eth yl-1-(ph en ylm eth yl)-1H-in dole-3-ace-

tic Acid Meth yl Ester (74). A solution of 1.78 g (5.3 mmol)

of 5-methoxy-2-methyl-1-(phenylmethyl)-1H-indole-3-acetic acid

(73) in 125 mL of CH₂Cl₂and 21 mL of a 1 M solution of BBr₃/

CH₂Cl₂was stirred for 4 h. The boron complex was decom-

posed by the addition of 10 mL of MeOH over 30 min, and the

resulting crude 5-hydroxy-2-methyl-1-(phenylmethyl)-1H-in-

dole-3-acetic acid was concentrated at reduced pressure. The

residue was dissolved in 100 mL of MeOH containing 10 mL

of methanesulfonic acid, and the mixture was stirred for 16

h, poured into water, and extracted with EtOAc. The organic

phase was washed with water, dried (Na₂SO₄), evaporated at

reduced pressure, and then chromatographed on silica gel,

eluting with a gradient of 10-30% EtOAc/toluene, to give 74,

1.30 g (yield 79%), as a wax: ¹H NMR (DMSO-d₆) ∂ 8.64 (s,

1H), 7.36-7.16 (m, 3H), 7.12 (d, 1H), 6.96 (d, 2H), 6.74 (d, 1H),

6.55 (dd, 1H), 5.36 (s, 2H), 3.58 (s, 3H), 3.30 (s, 2H), 2.26 (s,

3H), 2.00-1.88 (m, 2H); MS (FD) 309 (M⁺). Anal. (C₁₉H₁₉

NO₃) C, H, N.

-

Ack n ow led gm en t. We would like to acknowledge

our colleagues at the Shionogi Research Laboratories,

Osaka, J apan, who have collaborated with us during the

course of this research project.

4-[[3-(2-Meth oxy-2-oxoeth yl)-2-m eth yl-1-(ph en ylm eth yl)-

1H-in d ol-5-yl]oxy]bu ta n oic Acid Eth yl Ester (75).

A

solution of 0.31 g (1.0 mmol) of 74 in 15 mL of DMF and 15

mL of THF was treated with 40 mg (1.0 mmol) of 60%NaH/

mineral oil for 30 min, and then 0.143 mL (1.0 mmol) of ethyl

4-bromobutyrate was added. The mixture was stirred for 96

h, poured into water, and extracted with EtOAc. The organic

phase was washed with water, dried (Na₂SO₄), and evaporated

at reduced pressure. The residue was chromatographed on

silica gel, eluting with a gradient of toluene-10% EtOAc/

toluene to give 0.22 g (yield 52%) of 75 as an oil: ¹H NMR

(DMSO-d₆) ∂ 7.36-7.16 (m, 4H), 7.00-6.92 (m, 3H), 6.66 (dd,

1H), 5.36 (s, 2H), 4.04 (q, 2H), 3.96 (t, 2H), 3.60 (s, 3H), 3.32

(s, 2H), 2.46 (t, 2H), 2.26 (s, 3H), 2.04-1.80 (m, 2H), 1.14 (t,

3H); MS (FD) 423 (M⁺). Anal. (C₂₅H₂₉NO₅) C, H, N.

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J M960486N

Article Doi

Indole inhibitors of human nonpancreatic secretory phospholipase A2. 2. Indole-3-acetamides with additional functionality

DOI: 10.1021/jm960486n

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