Indole inhibitors of human nonpancreatic secretory phospholipase A2. 3. Indole-3-glyoxamides

Article abstract of DOI:10.1021/jm960487f

The preceding papers of this series detail the development of functionalized indole-3-acetamides as inhibitors of hnps-PLA₂. We describe here the extension of the structure-activity relationship to include a series of indole-3-glyoxamide derivatives. Functionalized indole-3-glyoxamides with an acidic substituent appended to the 4- or 5-position of the indole ring were prepared and tested as inhibitors of hnps-PLA₂. It was found that the indole-3-glyoxamides with a 4-oxyacetic acid substituent had optimal inhibitory activity. These inhibitors exhibited an improvement in potency over the best of the indole-3-acetamides, and LY315920 (6m) was selected for evaluation clinically as an hnps-PLA₂ inhibitor.

Full text of DOI:10.1021/jm960487f

J . Med. Chem. 1996, 39, 5159-5175
5159
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. 3.
In d ole-3-glyoxa m id es
Susan E. Draheim, Nicholas J . Bach,* Robert D. Dillard, 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, 1996X
The preceding papers of this series detail the development of functionalized indole-3-acetamides
as inhibitors of hnps-PLA2. We describe here the extension of the structure-activity
relationship to include a series of indole-3-glyoxamide derivatives. Functionalized indole-3-
glyoxamides with an acidic substituent appended to the 4- or 5-position of the indole ring were
prepared and tested as inhibitors of hnps-PLA2. It was found that the indole-3-glyoxamides
with a 4-oxyacetic acid substituent had optimal inhibitory activity. These inhibitors exhibited
an improvement in potency over the best of the indole-3-acetamides, and LY315920 (6m ) was
selected for evaluation clinically as an hnps-PLA2 inhibitor.
In tr od u ction
As detailed in the preceding papers of this series,
variation of the indole 3-substituent had been explored
in developing the structure-activity relationship (SAR)
of the indole hnps-PLA2 inhibitors. The preferred
3-substituent was a 3-acetamide functionality, and our
reported modifications of this group had generally
F igu r e 1. Chromogenic assay results of methoxy-substituted
resulted in diminished activity. The exception was the
3-glyoxamide derivatives, some of which had shown
activity similiar to their 3-acetamide counterparts.
Chromogenic assay results comparing methoxy-substi-
tuted indole-3-acetamides and -3-glyoxamides are shown
in Figure 1. There were obvious differences between
4- and 5-methoxy substitution of the indoles having a
3-glyoxamide substituent in place of the 3-acetamide.
Applying the SAR information gained in the previous
papers of this series, we sought to further elaborate
these indole-3-glyoxamides to include an acidic sub-
stituent appended at an optimal length for interaction
with the calcium in the enzyme active site.
acetamides and glyoxamides.
to give the O-alkylated products (4). The glyoxamide
group was then introduced into the 3-position by reac-
tion with oxalyl chloride in dichloromethane, followed
by treatment with ammonia gas. The ester of the 4- or
5-substituent was hydrolyzed, providing the free acid
or its sodium salt (6).
The 5-allyl-4-hydroxyindole 3u was prepared by treat-
ment of the 4-hydroxyindole 3m with NaH and allyl
bromide in DMF to give an intermediate O-allyl product,
which, when refluxed in N,N-dimethylaniline, gave the
Claisen rearrangement3 product 3u . This product was
then treated with sodium hydride and ethyl bromoac-
etate, and the resulting O-alkylated product (4u ) was
treated with oxalyl chloride and ammonia as above to
give 5u . Hydrogenation of the 5-allyl group of 5u gave
the 5-propyl compound 5a b. Basic hydrolysis of 5u and
5a b gave 6u and 6a b, respectively.
The amide 4a a was prepared from 4m , which was
first heated with hydrazine in ethanol to give the
hydrazide and then was reduced to the amide by
refluxing in ethanol with Raney nickel catalyst. Treat-
ment of 4a a with oxalyl chloride and ammonia as above
gave 5a a .
For the preparation of compound 5a c, the reaction
sequence was altered. 2-Ethyl-5-methoxy-1H-indole 1g
was reacted with oxalyl chloride and ammonia prior to
alkylation of the indole nitrogen. With the usual
sequence, some 1,3-dialkylation was often seen. The
3-glyoxylindole 7 was cleanly N-alkylated with sodium
hydride and benzyl bromide in DMF. Subsequent boron
tribromide demethylation and alkylation of the resulting
hydroxy indole with tert-butyl 4-bromobutyrate, followed
by trifluoroacetic acid deprotection, gave 6a c. This
As the SAR of this series developed, the exceptional
potency of the compounds brought into question whether
the chromogenic assay was adequate to differentiate
them. A deoxycholate/phosphatidylcholine (DOC/PC)
mixed micelle system, which allowed accurate deter-
minination of IC50 values for inhibitors with a mole
fraction below 10-5, was implemented.
Ch em istr y
Substituted indoles with a 3-glyoxamide functionality
and an acidic group appended to a 4- or 5-oxygen
substituent were prepared starting with 4- or 5-meth-
oxyindoles (1) (Scheme 1). The sodium salt of 1 was
first reacted with an alkyl halide to give the N-alkylated
product (2) or with an acyl halide to give the N-acylated
product (2q). Boron tribromide demethylation2 of 2
gave the hydroxy indoles (3), which were treated with
sodium hydride and an ω-bromoalkanoic ester in DMF
X Abstract published in Advance ACS Abstracts, December 1, 1996.
S0022-2623(96)00487-6 CCC: $12.00 © 1996 American Chemical Society

5160 J ournal of Medicinal Chemistry, 1996, Vol. 39, No. 26
Sch em e 1. Oxygen-Linked Functionalitiesa
Draheim et al.
a
Reagents: (a) NaH, R1X, DMF; (b) BBr3, CH2Cl2; (c) NaH, BrR4, DMF; (d) 1 oxalyl chloride, CH2Cl2, (2) ammonia; (e) 1 NaOH, ROH,
H2L, (2) HCl, H2O; (f) TFA, CH2Cl2; (g) allyl bromide, NaH; (h) PhNMe2, heat; (i) (1) H2NNH2, (2) RaNi; (j) H2, Pd/C; (k) NaOH, MeOH;
(l) PhSO2Cl, NaH, DMF.
reaction sequence, however, was not useful for the
preparation of the 4-functionalized indoles, because the
boron tribromide demethylation of 4-methoxy indoles
having a 3-glyoxamide functionality can lead to the
decarbonylation described in the previous paper of this
series.

Indole Inhibitors of hnps-PLA2. 3
J ournal of Medicinal Chemistry, 1996, Vol. 39, No. 26 5161
Sch em e 2. Enantiomeric Oxygen-Linked Carboxyl Functionalitiesa
a
Reagents: (a) NaH, A or B, DMF; (b) LiOCH2Ph, THF, 0 °C; (c) 1 oxalyl chloride, (2) ammonia; (d) H2, Pd/C, EtOH; (e) MeOMgBr,
MeOH, THF; (f) NaH, (R)- or (S)-CH3CH(Cl)CO2CH3, DMF.
Sch em e 3. Sulfur-Linked Carboxyl Functionalitiesa
a
Reagents: (a) NaH, dimethylthiocarbamoyl chloride, DMF; (b) phenyl ether, heat; (c) (1) NaOH, H2O, EtOH, (2) HCl, H2O; (d) NaH,
BrCH2CO2tBu or Br(CH2)3CO2Et, DMF; (e) (1) oxalyl chloride, CH2Cl2, (2) ammonia; (f) TFA.
The 1-benzoyl group of 5q is extremely labile to base,
providing 8, which was a useful starting material for
other indoles that could not be prepared by our usual
route, such as the 1-(phenylsulfonyl)indole 6a d and the
N-unsubstituted indole 6a e.
4z by treatment with MeOMgBr5 in MeOH/THF, and
then the 3-glyoxamide functionality was added to give
5z. The optical rotation of this product was -80.5°. As
a standard for comparison, the sodium salt of 3m was
alkylated with the pure S- and R-enantiomers of methyl
2-chloropropionate, resulting in inversion of the optical
center to give the R- and S-isomers of 4z, and these
isomers were carried on to the 3-glyoxamide compounds,
5z. Optical rotations were measured for each of these
5z isomers and found to be -13.3° for the R-isomer and
+13.9° for the S-isomer. The low rotation of these two
samples indicates that some racemization occurred
during the alkylation procedure, but the direction of
rotation allowed assignment of the R- and S-isomers of
5z, 6y, and 6z.
The racemic compounds (dl)-6y and (dl)-6z (Scheme
1) were prepared as single enantiomers in Scheme 2.
Acylation of the lithium salt of (S)-4-benzyl-2-oxazoli-
dine by 2-bromopropionyl bromide provided a mixture
of diastereomers (A and B), which were separated by
chromatography. Compounds 3c and 3m were each
alkylated separately with A and B in DMF at room
temperature. These alkylation reactions gave some
minor racemization, but the individual diastereomers
were readily separable by chromatography. Both dia-
stereomers of 9a and one of the diastereomers of 9b
were converted to their benzyl esters by treatment with
lithium benzyl oxide in THF,4 the 3-glyoxamide func-
tionality was then added, and hydrogenation of the
benzyl esters provided the single enantiomers of 6y and
6z.
The preparation of 4- or 5-mercaptoindoles, and their
elaboration to indole 3-glyoxamides with an acidic group
appended to the sulfur is shown in Scheme 3. The
oxygen to sulfur conversion of the 4- and 5-hydroxyin-
doles 3m and 3a g was accomplished by the dialkyl
thiocarbamate conditions reported by Newman et al.6
The mercaptoindoles were S-alkylated and then treated
To establish the absolute configuration of these enan-
tiomers, the other diastereomer of 9b was converted to

5162 J ournal of Medicinal Chemistry, 1996, Vol. 39, No. 26
Sch em e 4. Nitrogen-Linked Carboxyl Functionalitiesa
Draheim et al.
(Scheme 6). Bromination of the indoline with bromine
and silver salts in H2SO410 followed by N-alkylation gave
a mixture of the 4- and 6-bromoindolines, 33a and 33b.
The bromine was subjected to halogen-metal exchange
using n-butyllithium, and the mixture of lithio deriva-
tives was reacted with DMF to give 34a and 34b, which
were separable by chromatography. Wittig reaction of
the aldehyde 34a with methyl (triphenylphosphora-
nylidene)acetate gave the indoline 35, which could be
oxidized by DDQ11 to the indole 36. Compound 36 and
compound 38 (obtained by hydrogenation of 36) were
each treated with oxalyl chloride and ammonia and then
with aqueous base to give 39 and 40, respectively.
P h a r m a cology
All compounds were evaluated in the chromogenic
assay system described in the previous papers of this
series. The most interesting compounds were tested for
potency and selectivity in secondary assays that used
either hnps-PLA2 or arachidonic acid to stimulate a
contraction of guinea pig lung pleural strips. These
results are summarized in Table 1.
a
Reagents: (a) H2, 5% Pt/C, EtOH; (b) NaHCO3, BrCH2CO2Me,
The exceptional potency of a number of these inhibi-
tors raised some questions with regard to the meaning
of the chromogenic assay results. The concentration of
hnps-PLA2 in this system is 16 nM, and many of the
IC50 values determined for the indole-3-glyoxamide
inhibitors are at or below this concentration. In par-
ticular, a number of the most potent compounds dis-
played half-maximal inhibition within experimental
error of 8 nM. This concentration is exactly half that
of the enzyme in the assay and suggests that the
stoichiometric limit may have been attained.
To address this concern, we used a slightly modified
deoxycholate/phosphatidyl choline (DOC/PC) assay that
had been developed for the evaluation of patient samples
of hnps-PLA2.12 The lipid concentration in this assay
(4 mM) is higher than that of the chromogenic (1.23
mM), and less enzyme was required (3 nM). These
differences allow accurate determination of IC50 values
below 10-5 mole fraction. The use of mole fraction
terminology in the description of inhibitory constants
is important for the PLA2 enzymes since they operate
on aggregated substrate.13 Briefly, an IC50 presented
in molar terms for any inhibitor will vary depending
on the concentration of lipid used in the assay. This
makes it difficult to compare inhibitors evaluated in
different assays. However, if the IC50 determined for a
compound is divided by the lipid concentration that is
being used in the assay, a dimensionless number results
that is independent of the lipid concentration and may
be used to compare results generated under quite
different conditions. The symbol commonly used to
express the mole fraction for 50% inhibition is Ìi50.
DMF; (c) (1) oxalyl chloride, CH2Cl2, (2) ammonia.
with oxalyl chloride and ammonia as above, and the
ester products were hydrolyzed to give 15 and 17.
An early attempt to produce 4-aminoindole-3-glyoxa-
mide derivatives with an acidic substituent on the
amino nitrogen is depicted in Scheme 4. Catalytic
hydrogenation of the 4-nitro group of 18 provided the
4-aminoindole, 19, which was treated with 1 equiv of
methyl bromoacetate to give 20a , or with an excess to
give the N,N-dialkylated product 21. Reaction of 20a
with oxalyl chloride occurred exclusively at the 4-amino
group with no reaction at the 3-position of the indole.
This reflects the exceptional nucleophilicity of a 4-amino
substituent consequent to the enhanced electron density
at this position of the indole system. No catalyst was
required for the subsequent cyclization to 22. Similar
observations have been made with anilines having
exceptional electron density due to multiple oxygen
substituents.7 Treatment of 21 with oxalyl chloride
produced compounds 22 and 23. These were presumed
to have been formed from the intermediate shown,
which leads to 23 by a Fries8 type rearrangement and
to 22 by a von Braun9 dealkylation, followed by an
internal cyclization.
As shown in Scheme 5, hydrogenation of a 4-nitroin-
dole with the 3-glyoxamide functionality already in
place provided the 4-aminoindole-3-glyoxamide 25, which
was readily converted to the ester 26 and to the desired
N-acetic acid compound 27. Treatment of the 4-N-
alkylated indole-3-glyoxamide 26 with oxalyl chloride
and ammonia resulted in acylation of the 4-nitrogen,
but the electron density of the carbocyclic ring of the
indole was so diminished by the 3-acyl group that the
spontaneous cyclization seen with compound 22 did not
occur. Only compound 28 was isolated.
A significant number of the indole-3-glyoxamide
inhibitors were evaluated in the DOC/PC assay (Table
1). For those compounds whose IC50 values had not
dropped below the 16 nM concentration of PLA2 in the
chromogenic assay, there was generally excellent agree-
ment between the Ìi50’s observed in the two assays.
Representative examples are 6f, 6g, and 6k . For some
compounds at the stoichiometric limit of the chromoge-
nic assay, such as 6h , 6i, 6j, and 6p , comparable results
were obtained in the DOC/PC assay when mole fraction
comparisons were made. The most potent compounds,
such as 6d , 6m , 6n , and 6o, had truly “bottomed out”
N,N-Disubstituted indole-3-glyoxamides with an N-
acetyl group in addition to the N-acidic substituent on
the 4-nitrogen were prepared by acylation of 20a and
20b with acetic anhydride and then further elaborated
to the 3-glyoxamides as described previously.
Indole-3-glyoxamides with an acidic group attached
to the 4-position of the indole via an all-carbon chain
(39 and 40) were prepared from 2-methylindoline

Indole Inhibitors of hnps-PLA2. 3
J ournal of Medicinal Chemistry, 1996, Vol. 39, No. 26 5163
Sch em e 5. Nitrogen-Linked Carboxyl Functionalitiesa
a
Reagents: (a) H2, Pd/BaSO4, EtOH; (b) NaHCO3, BrCH2CO2Me, DMF; (c) (1) NaOH, H2O, EtOH, (2) HCl, H2O; (d) (1) oxalyl chloride,
CH2Cl2, (2) ammonia; (e) methyl acrylate, MeOH; (f) Ac2O, CH2Cl2.
Sch em e 6. Carbon-Linked Carboxyl Functionalitiesa
a
Reagents: (a) Ag2SO4, H2SO4, Br2; (b) K2CO3, benzyl bromide, DMF, 85 °C; (c) (1) n-BuLi, THF, -75 °C, (2) DMF; (d) Ph3PdCHCO2Me,
THF; (e) DDQ, dioxane, 95 °C; (f) (1) oxalyl chloride, CH2Cl2, (2) ammonia; (g) 10% Pd/C, H2, EtOH; (h) (1) NaOH, H2O, EtOH, (2) HCl,
H2O.
in the chromogenic assay. As shown in Table 1, these
inhibitors were 3-6-fold more potent in the DOC/PC
assay than had been indicated by the chromogenic
numbers. The best inhibitors show Ìi50 values of 10-6
or below. This improved potency was reflected in
generally improved activity in the tissue bath secondary
assay (Table 1).
mole fraction values generated for a pair of 2-ethyl-1-
(phenylmethyl)-1H-indole-3-glyoxamides with an acidic
substituent appended at an optimal length for interac-
tion with the calcium in the enzyme active site (deter-
mined in the preceding paper) showed the indole-3-
glyoxamide with a 4-oxyacetic acid substituent, 6m (1.8
× 10-6), was approximately 100-fold more active than
6a c (1.7 × 10-4), which has a 5-oxybutanoic acid
substituent. The carboxy group of the 4-substituent and
the carboxamido group of the glyoxamide, which provide
ligands for the calcium in the active site, are held in a
distinct relation to each other in the 4-substituted
glyoxamides. This arrangement is apparently very
suitable for the geometry of the ligand shell. The
5-substituted analogues require a longer alkyl chain for
the carboxy ligand to reach the calcium in the enzyme
active site and therefore have more conformational
flexibility.
Discu ssion
The structure-activity relationship of the indole-3-
acetamide hnps-PLA2 inhibitors discussed in the pre-
ceding papers1 was extended to include a series of
indole-3-glyoxamides. The information gained from the
3-acetamide SAR and the X-ray crystal structures14 of
the 3-acetamide inhibitors in the enzyme active site was
applied. Indole-3-glyoxamides with an acidic group
linked by a carbon chain to a 4- or 5-heteroatom
substituent on the indole ring, or directly linked to the
indole by an all-carbon chain, were prepared. In
general, the 4-substituted indole-3-glyoxamides were
significantly more active than the corresponding aceta-
mides, while the 5-substituted indole-3-glyoxamides
were somewhat less active.
The most potent inhibitors were substituted with a
3-glyoxamide and 4-oxyacetic acid function. The opti-
mal substitution at the 1-position of these indoles
mimicked the SAR of the indole-3-acetamides. Com-
pounds with a benzyl, substituted benzyl, or a long alkyl
chain at the 1-position showed the best activity, while
compounds with a 1-benzoyl or 1-benzenesulfonyl were
Within the glyoxamide series, 4-substitution was
generally preferred over 5-substitution. Comparison of

5164 J ournal of Medicinal Chemistry, 1996, Vol. 39, No. 26
Draheim et al.
Ta ble 1. Inhibitory Activity Against hnps-PLA2 and Arachidonic Acid
inhibition of human secreted PLA2
contraction of GP lung tissue
chromogenic assay
DOC/PC assay
PLA2-induced
apparent KB (µM) (n ) 4)
AA-induced
ED50 (µM) (n ) 4)
compd
IC50 (µM)
mole fractiona
IC50 (µM)
mole fraction
5a a
6a
6b
6c
6d
6e
6f
6g
6h
6i
6j
6k
6l
6m
6n
6o
6p
6q
0.124 ( 0.013
62.0 ( 2.9
1.0 × 10-4
4.8 × 10-2
8.0 × 10-5
8.9 × 10-6
5.0 × 10-6
7.3 × 10-6
3.6 × 10-5
2.5 × 10-5
5.0 × 10-6
7.3 × 10-6
7.3 × 10-6
1.3 × 10-5
6.5 × 10-6
7.3 × 10-6
5.0 × 10-6
3.3 × 10-6
5.8 × 10-6
6.6 × 10-5
6.7 × 10-5
2.3 × 10-5
5.0 × 10-6
1.3 × 10-3
2.0 × 10-4
2.1 × 10-5
3.8 × 10-5
8.1 × 10-6
8.9 × 10-6
1.5 × 10-4
8.9 × 10-6
1.1 × 10-4
1.7 × 10-3
1.7 × 10-4
2.3 × 10-5
1.3 × 10-3
6.5 × 10-6
1.2 × 10-4
4.0 × 10-5
8.1 × 10-4
0.096 ( 0.015
0.011 ( 0.004
0.006 ( 0.001
0.009 ( 0.001
0.043 ( 0.003
0.030 ( 0.003
0.006 ( 0.001
0.009 ( 0.004
0.009 ( 0.002
0.015 ( 0.004
0.008 ( 0.003
0.009 ( 0.001
0.006 ( 0.002
0.004 ( 0.001
0.007 ( 0.002
0.081 ( 0.009
0.082 ( 0.014
0.028 ( 0.010
0.006 ( 0.002
1.62 ( 0.085
0.243 ( 0.075
0.025 ( 0.002
0.046 ( 0.001
0.010 ( 0.002
0.011 ( 0.002
0.188 ( 0.055
0.011 ( 0.001
0.141 ( 0.030
2.07 ( 0.12
0.019
0.003
0.008
0.150
0.074
0.022
0.017
0.025
0.045
0.018
0.007
0.006
0.004
0.025
0.039
4.8 × 10-6
7.5 × 10-7
2.0 × 10-6
3.8 × 10-5
1.9 × 10-5
5.5 × 10-6
4.3 × 10-6
6.3 × 10-6
1.1 × 10-5
4.5 × 10-6
1.8 × 10-6
1.5 × 10-6
1.0 × 10-6
6.3 × 10-6
9.8 × 10-6
0.14 ( 0.07
>10
>10
0.068 ( 0.01
0.11 ( 0.02
0.077 ( 0.01
0.128 ( 0.04
0.100 ( 0.02
0.154 ( 0.05
0.061 ( 0.01
0.083 ( 0.01
0.057 ( 0.01
0.052 ( 0.01
0.11 ( 0.01
0.34 ( 0.12
>30
>30
>30
>30
>30
>30
>10
>30
5 ( 1
6r
6s
6t
6u
0.041
0.023
1.0 × 10-5
5.8 × 10-6
0.075 ( 0.01
>10
6v
6w
(dl)-6x
(dl)-6y
(R)-6y
(S)-6y
(dl)-6z
(S)-6z
6a b
6a c
6a d
6a e
6a f
15
0.029
0.026
0.009
0.006
0.136
0.013
7.3 × 10-6
6.5 × 10-6
2.3 × 10-6
1.5 × 10-6
3.4 × 10-5
3.3 × 10-6
0.143 ( 0.02
0.293 ( 0.04
0.145 ( 0.04
>30
>30
>30
0.21 ( 0.09
>30
0.210 ( 0.046
0.028 ( 0.013
1.600 ( 0.200
0.008 ( 0.001
0.145 ( 0.008
0.049 ( 0.01
1.0 ( 0.28
0.316 ( 0.12
3.41 ( 0.64
0.124 ( 0.029
0.008
0.210
2.0 × 10-6
5.3 × 10-5
3.16 ( 0.5
17
27
31a
31b
39
>100
>100
46
3.6 × 10-2
1.2 × 10-4
40
0.145 ( 0.006
0.614 ( 0.18
a
Mole fraction is the IC50 concentration value divided by the total lipid concentration (chromogenic assay, 1230 µM; DOC/PC assay,
4000 µM).
less active. Ortho- or meta-substitution of the benzyl
The indole-3-glyoxamides with a sulfur-linked acidic
functionality are an isolated example where 5-substitu-
tion is preferred over 4-substitution. The 4-thioacetic
acid compound, 15 (0.145 µM), was less potent than the
5-thiobutanoic acid derivative 17 (0.049 µM) in the
chromogenic assay. Both were much less potent than
6m .
was preferred; in particular, compounds with an o-
phenyl or o-benzyl substituent were very active. The
optimal indole 2-substituent also paralleled the indole-
3-acetamide SAR. An ethyl group was generally best,
but compounds with a 2-methyl or 2-cyclopropyl group
were also very active.
An additional 5-substituent such as the 5-allyl or
5-propyl group of 6u and 6a b caused a large loss of
activity compared to 6m , presumably a consequence of
steric interference with the positioning of the 4-sub-
stituent. The additional 6-methyl substituent of 6a f
caused no loss of activity.
Replacing the oxygen linker of the oxyacetic acid of
6m with a nitrogen (27) caused a large decrease in
activity in the chromogenic assay (1.6 µM). To test
whether this loss of activity was due to the basic
nitrogen, an acetyl group was added (31a and 31b), but
these compounds showed even poorer activity, possibly
due to steric considerations. Compounds with the
4-acidic substituent appended via an all-carbon chain
(39 and 40) were also less active than the oxyacetic acid
compounds.
Substitution on the R-carbon of the oxyacetic acid
(6w -z) was well tolerated. Even groups as large as a
phenethyl substituent or dimethyl substitution of the
R-carbon retained considerable activity. When the
enantiomers of the R-methyl compound, 6y, were pre-
pared and tested, the R-isomer was 20-fold more potent
than the S-isomer. The decreased activity of the S-
isomer might be explained by steric compression result-
ing from the R-methyl group eclipsing the indole 5-hy-
drogen to achieve optimal binding of the carboxyl group
with the catalytic calcium.
Compound 6m was cocrystallized with hnps-PLA2 and
was examined by X-ray crystallography.15 The X-ray
crystal structure of this complex revealed several in-
teractions between 6m and the enzyme active site. The
carboxyl group of the 4-substituent and the carboxamide
carbonyl of the 3-glyoxamide both function as ligands
for the calcium in the active site. The carboxamide

Indole Inhibitors of hnps-PLA2. 3
J ournal of Medicinal Chemistry, 1996, Vol. 39, No. 26 5165
Ta ble 2. Inhibition of Selected PLA2’s
doline (32). Syntheses of 4-methoxy-2-methyl-1H-indole (1c),
2-ethyl-4-methoxy-1H-indole (1d ), 4-methoxy-2-propyl-1H-in-
dole (1e), 2-cyclopropyl-4-methoxy-1H-indole (1f), and 2-ethyl-
5-methoxy-1H-indole (1g) are described in the first paper of
this series, as are compounds 2b, 2m , and 2p . Compounds
3a g, 16, 18, and 24 are described in the preceding paper.
5-Meth oxy-1-(p h en ylm eth yl)-1H-in d ole (2a ). A solution
of 940 mg (6.0 mmol) of 5-methoxy-1H-indole (1a ) in 10 mL of
DMF was stirred with 255 mg of NaH (60% in mineral oil; 6.4
mmol) for 5 min and then with 800 mg (6.3 mmol) of benzyl
chloride for 1 h. The solution was 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
5% EtOAc/hexane, to give 2a : 1.21 g (yield 85%); mp 64-67
°C; MS (FD) 237 (M+). Anal. (C16H15NO) C, H, N.
The following compounds were prepared from 1 by the above
procedure (utilizing the appropriate alkyl or acyl halide) and
purified by the method indicated.
4-Meth oxy-2-m eth yl-1-(p h en ylm eth yl)-1H-in d ole (2c)
(chromatography on silica gel, 20% EtOAc/hexane): yield 84%;
mp 96-116 °C; 1H NMR (CDCl3) ∂ 7.32-6.92 (m, 7H), 6.85 (d,
1H), 6.53 (d, 1H), 5.29 (s, 2H), 3.96 (s, 3H), 2.36 (s, 3H); MS
(FD+) 251 (M+). Anal. (C17H17NO) C, H, N.
1-([1,1′-Bip h en yl]-2-ylm eth yl)-4-m eth oxy-2-m eth yl-1H-
in d ole (2d ) (chromatography on silica gel, 16% EtOAc/
hexane): yield 80%; oil; 1H NMR (CDCl3) ∂ 7.56-6.96 (m, 10H),
6.73 (d, 1H), 6.56-6.40 (m, 2H), 5.16 (s, 2H), 3.95 (s, 3H), 2.23
(s, 3H); MS (FD+) 327 (M+). Anal. (C23H21NO) C; H: calcd,
6.46; found, 5.66; N: calcd, 4.28; found, 3.83.
1-([1,1′-Bip h en yl]-3-ylm eth yl)-4-m eth oxy-2-m eth yl-1H-
in d ole (2e) (chromatography on silica gel, 20% EtOAc/hex-
ane): yield 76%; mp 127-131 °C; 1H NMR (CDCl3) ∂ 7.66-
7.00 (m, 9H), 6.89 (d, 2H), 6.53 (d, 1H), 6.45 (br s, 1H), 5.35
(s, 2H), 3.98 (s, 3H), 2.39 (s, 3H); MS (FD+) 327 (M+). Anal.
(C23H21NO) H, N; C: calcd, 84.37; found, 83.30.
1-([1,1′-Bip h en yl]-4-ylm eth yl)-4-m eth oxy-2-m eth yl-1H-
in d ole (2f) (chromatography on silica gel, 20% EtOAc/hex-
ane): yield 80%; mp 118-123 °C; 1H NMR (CDCl3) ∂ 7.70-
7.00 (m, 10H), 6.89 (d, 1H), 6.55 (d, 1H), 6.45 (br s, 1H), 5.32
(s, 2H), 3.96 (s, 3H), 2.39 (s, 3H); MS (FD+) 327 (M+). Anal.
(C23H21NO) C, H, N.
1-[(4-F lu or op h en yl)m et h yl]-4-m et h oxy-2-m et h yl-1H -
in d ole (2g) (chromatography on silica gel, 20% EtOAc/
hexane): yield 82%; mp 104-108 °C; 1H NMR (CDCl3) ∂ 7.21-
6.86 (m, 5H), 6.82 (d, 1H), 6.52 (d, 1H), 6.42 (s, 1H), 5.23 (s,
2H), 3.94 (s, 3H), 2.33 (s, 3H); MS (FD+) 269 (M+). Anal.
(C17H16FNO) H, N; C: calcd, 75.82; found, 73.82.
IC50 (µM)
human
nonpancreatic
PLA2
human
pancreatic
PLA2
porcine
pancreatic
PLA2
compd
6c
6d
6e
6f
6i
6l
6m
6o
6p
39
40
0.011 ( 0.004
0.006 ( 0.001
0.009 ( 0.001
0.043 ( 0.003
0.009 ( 0.004
0.008 ( 0.003
0.009 ( 0.001
0.004 ( 0.001
0.007 ( 0.002
46
0.761
0.364
0.57
1.09
1.2
0.015
0.097
0.007
0.78
0.228
0.062
0.390
>100
>100
0.048
0.003
0.145 ( 0.006
hydrogen bonds to His 48. The ketone carbonyl of the
glyoxamide appears to interact with Phe 106 of the
enzyme. The indole itself fits well into the space
normally occupied by the substrate. The sum of all
these observable interactions between the inhibitor and
the enzyme accounts for the exceptional potency of these
indole-3-glyoxamide derivatives as inhibitors of hnps-
PLA2.
As shown in Table 1, the hydrolytic activity of hnps-
PLA2 in the in vitro assays is inhibited by the more
active compounds at mole fractions in the 10-6 range.
This level of potency is at the stoichiometric limit of the
chromogenic assay and approaches the stoichiometric
limit of the DOC/PC assay. These compounds displayed
potent inhibition against hnps-PLA2 challenge in the
tissue-based assay, with KB values below 100 nM, while
selectivity in the control tissues challenged with arachi-
donic acid remained high. This indicates that inhibition
of the hnps-PLA2-induced contractile response is a
consequence of direct inhibition of the enzyme rather
than inhibition at some point subsequent to the action
of the PLA2.
Table 2 compares IC50 values generated for the indole-
3-glyoxamides as inhibitors of human nonpancreatic
secretory PLA2 relative to their inhibition of pancreatic
secretory PLA2 enzymes. The indole-3-glyoxamide de-
rivatives show increased potency against the pancreatic
enzymes as compared to the indole-3-acetamides, but
still exhibit selectivity for human nonpancreatic secre-
tory PLA2.
On the basis of consideration of the combination of
chemical, physical, and pharmacological characteristics,
LY315920 (6m ) has been chosen for clinical evaluation
as an inhibitor of hnps-PLA2.
1-[(2,6-Dich lor op h en yl)m et h yl]-4-m et h oxy-2-m et h yl-
1H -in d ole (2h ) (chromatography on silica gel, 20%
EtOAc/hexane): yield 84%; mp 154-157 °C; 1H NMR (CDCl3)
∂ 7.41-7.17 (m, 3H), 6.95 (t, 1H), 6.73 (d, 1H), 6.48 (d, 1H),
6.37 (br s, 1H), 5.50 (s, 2H), 3.92 (s, 3H), 2.39 (s, 3H); MS (FD+)
319 (M - 1, 100), 321 (M + 1, 75). Anal. (C17H15Cl2NO) H,
N; C: calcd, 63.77; found, 67.16.
4-Me t h oxy-2-m e t h yl-1-[(1-n a p h t h yl)m e t h yl]-1H -in -
d ole (2i) (chromatography on silica gel, 20% EtOAc/hexane):
1
yield 97%; oil; H NMR (CDCl3) ∂ 8.21-7.16 (m, 6H), 7.02 (t,
1H), 6.79 (d, 1H), 6.59-6.47 (m, 2H), 6.37 (d, 1H), 5.75 (s, 2H),
Su m m a r y
4.00 (s, 3H), 2.34 (s, 3H); MS (FD+) 301 (M+). Anal. (C21H19
NO) C, H, N.
-
The application of structure-based drug design meth-
odology to a screening hit has resulted in the identifica-
tion of clinical candidate LY315920. This inhibitor is
6500-fold more potent than the lead compound, achiev-
ing near stoichiometric inhibition of hnps-PLA2 through
optimized tight-binding interactions at the enzyme’s
catalytic site.
1-[(2-Ch lor op h en yl)m et h yl]-4-m et h oxy-2-m et h yl-1H -
in d ole (2j) (chromatography on silica gel, 20% EtOAc/hex-
1
ane): yield 85%; mp 150-157 °C; H NMR (CDCl3) ∂ 7.42 (d,
1H), 7.18 (br t, 1H), 7.13-6.98 (m, 2H), 6.80 (d, 1H), 6.56 (d,
1H), 6.48 (s, 1H), 6.27 (d, 2H), 5.33 (s, 2H), 3.96 (s, 3H), 2.32
(s, 3H). Anal. (C17H16ClNO) C, H, N.
4-Met h oxy-2-m et h yl-1-[(2-m et h ylp h en yl)m et h yl]-1H -
in d ole (2k ) (chromatography on silica gel, 20% EtOAc/
hexane): yield 62%; mp 126-146 °C; 1H NMR (CDCl3) ∂ 7.26-
6.94 (m, 4H), 6.75 (d, 1H), 6.53 (d, 1H), 6.48 (br s, 1H), 6.25
(d, 1H), 5.21 (s, 2H), 3.96 (s, 3H), 2.41 (s, 3H), 2.30 (s, 3H);
MS (FD+) 265 (M+). Anal. (C18H19NO) H; C: calcd, 81.47;
found, 77.56; N: calcd, 5.28; found, 4.37.
Exp er im en ta l Section
Melting points were obtained on a Thomas-Hoover Mel
Temp apparatus 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
Compounds 1a and 1b, 5-methoxy-1H-indole and 4-methoxy-
1H-indole, were commercially available, as was 2-methylin-
a
ZAB 2-SE instrument.
4-Meth oxy-2-m eth yl-1-n -octyl-1H-in d ole (2l) (chroma-
tography on silica gel, 20% EtOAc/hexane): yield 76%; oil; 1H
NMR (CDCl3) ∂ 7.07 (t, 1H), 6.90 (d, 1H), 6.49 (d, 1H), 6.33 (s,

5166 J ournal of Medicinal Chemistry, 1996, Vol. 39, No. 26
Draheim et al.
1H), 4.02 (t, 2H), 3.92 (s, 3H), 2.41 (s, 3H), 1.82-0.84 (m, 15H);
MS (FD+) 273 (M+). Anal. (C18H27NO) C, H, N.
1H), 6.52 (d, 1H), 6.38 (s, 1H), 5.25 (s, 2H), 4.95 (s, 1H), 2.36
(s, 3H); MS (FD+) 255 (M+).
1-([1,1′-Bip h en yl]-2-ylm et h yl)-2-et h yl-4-m et h oxy-1H -
in d ole (2n ) (chromatography on silica gel, 20% EtOAc/
hexane): yield 37%; oil; MS (FD+) 273 (M+).
1-[(2,6-Dich lor op h en yl)m et h yl]-4-h yd r oxy-2-m et h yl-
1H -in d ole (3h ) (chromatography on silica gel, 20%
EtOAc/hexane): yield 83%; oil; H NMR (CDCl3) ∂ 7.41-7.19
1
(m, 3H), 6.89 (t, 1H), 6.71 (d, 1H), 6.47 (d, 1H), 6.31 (br s, 1H),
5.49 (s, 2H), 4.82 (br s, 1H), 2.40 (s, 3H); MS (FD+) 305 (M -
1, 100), 307 (M + 1, 90). Anal. (C16H13Cl2NO) C, H, N.
4-H yd r oxy-2-m e t h yl-1-[(1-n a p h t h yl)m e t h yl]-1H -in -
d ole (3i) (chromatography on silica gel, 20% EtOAc/hexane):
2-Eth yl-4-m eth oxy-1-[(2-[ph en ylm eth yl]ph en yl)m eth yl]-
1H -in d ole
(2o)
(chromatography
on
silica
gel,
1
20%EtOAc/hexane): yield 68%; oil; H NMR (CDCl3) ∂ 7.45-
6.93 (m, 9H), 6.52 (dd, 2H), 6.43 (br s, 1H), 6.22 (d, 1H), 5.21
(s, 2H), 4.16 (s, 3H), 3.98 (s, 2H), 2.39 (q, 2H), 1.18 (t, 3H);
MS (FD) 355 (M+). Anal. (C25H25NO) C, H, N.
1
yield 71%; oil; H NMR (CDCl3) ∂ 8.14 (d, 1H), 7.94 (d, 1H),
7.75 (d, 1H), 7.72-7.21 (m, 3H), 6.96 (t, 1H), 6.76 (d, 1H), 6.55
(d, 1H), 6.47 (s, 1H), 6.37 (d, 1H), 5.75 (s, 2H), 4.94 (s, 1H),
2.35 (s, 3H); MS (FD+) 287 (M+).
1-Ben zoyl-2-eth yl-4-m eth oxy-1H-in d ole (2q) (chroma-
tography on silica gel, 20% EtOAc/hexane): yield 43%; oil; 1H
NMR (CDCl3) ∂ 7.41 (d, 2H), 7.31-7.08 (m, 3H), 6.93 (t, 1H),
6.66-6.51 (m, 2H), 6.50 (d, 1H), 3.95 (s, 3H), 2.84 (q, 2H), 1.29
(t, 3H).
1-([1,1′-Bip h en yl]-2-ylm eth yl)-4-m eth oxy-2-p r op yl-1H-
in d ole (2r ) (chromatography on silica gel, 20% EtOAc/
hexane): yield 65%; oil; 1H NMR (CDCl3) ∂ 7.57-7.10 (m, 8H),
7.02 (t, 1H), 6.75 (d, 1H), 6.50 (dd, 2H), 6.42 (s, 1H), 5.16 (s,
2H), 3.96 (s, 3H), 2.49 (t, 2H), 1.74-1.58 (m, 2H), 0.93 (t, 3H);
MS (FD+) 355 (M+).
1-[(2-Ch lor op h en yl)m et h yl]-4-h yd r oxy-2-m et h yl-1H -
in d ole (3j) (chromatography on silica gel, 20% EtOAc/hex-
1
ane): yield 55%; oil; H NMR (CDCl3) ∂ 7.43 (d, 1H), 7.21 (t,
1H), 7.12-7.00 (m, 1H), 6.98 (t, 1H), 6.77 (d, 1H), 6.55 (d, 1H),
6.42 (s, 1H), 6.30 (d, 1H), 5.33 (s, 2H), 4.89 (br s, 1H), 2.33 (s,
3H); MS (FD) 271 (M - 1, 100), 273 (M + 1, 33). Anal. (C16H14
ClNO) C, H, N.
-
4-H yd r oxy-2-m et h yl-1-[(2-m et h ylp h en yl)m et h yl]-1H -
in d ole (3k ) (chromatography on silica gel, 20% EtOAc/
hexane): yield 43%; mp 156-166 °C; 1H NMR (CDCl3) ∂ 7.41-
6.90 (m, 4H), 6.74 (d, 1H), 6.52 (d, 1H), 6.40 (s, 1H), 6.28 (d,
1H), 5.20 (s, 2H), 4.88 (s, 1H), 2.41 (s, 3H), 2.32 (s, 3H); MS
(FD) 251 (M+). Anal. (C17H17NO) H, N; C: calcd, 81.24; found,
80.61.
2-Cyclop r op yl-4-m e t h oxy-1-(p h e n ylm e t h yl)-1H -in -
d ole (2s) (chromatography on silica gel, 20% EtOAc/hexane):
1
yield 45%; oil; H NMR (CDCl3) ∂ 7.42-7.00 (m, 6H), 6.92 (d,
1H), 6.60 (d, 1H), 6.40 (s, 1H), 5.54 (s, 2H), 4.04 (s, 3H), 1.90-
1.79 (m, 1H), 1.00-0.89 (m, 2H), 0.82-0.70 (m, 2H); MS (FD)
277 (M+).
1-([1,1′-Biph en yl]-2-ylm eth yl)-2-cyclopr opyl-4-m eth oxy-
1H -in d ole (2t ) (chromatography on silica gel, 20%
EtOAc/hexane): yield 52%; MS (FD) 353 (M+).
4-Hyd r oxy-2-m eth yl-1-n -octyl-1H-in d ole (3l) (chroma-
tography on silica gel, 20% EtOAc/hexane): yield 59%; oil; 1H
NMR (CDCl3) ∂ 7.04-6.93 (m, 1H), 6.88 (d, 1H), 6.48 (d, 1H),
6.25 (br s, 1H), 4.80 (br s, 1H), 4.02 (t, 2H), 2.41 (s, 3H), 1.74
(br t, 2H), 1.67-1.22 (m, 10H), 0.87 (t, 3H); MS (FD) 259 (M+).
Anal. (C17H25NO) C, H, N.
1-([1,1′-Bip h en yl]-2-ylm eth yl)-2-eth yl-4-h yd r oxy-1H-in -
d ole (3n ) (chromatography on silica gel, 20% EtOAc/hex-
ane): yield 69%; oil; 1H NMR (CDCl3) ∂ 7.70-7.20 (m, 8H),
7.08 (t, 1H), 6.84 (d, 1H), 6.64 (t, 2H), 6.49 (s, 1H), 5.29 (s,
2H), 4.99 (s, 1H), 2.66 (q, 2H), 1.39 (t, 3H); MS (FD) 327 (M+).
2-Eth yl-4-h ydr oxy-1-[[2-(ph en ylm eth yl)ph en yl]m eth yl]-
1H-in d ole (3o) (chromatography on silica gel, 20% EtOAc/
hexane, then 50% EtOAc/hexane): yield 38%; oil; 1H NMR
(CDCl3) ∂ 7.41-7.00 (m, 8H), 6.89 (t, 1H), 6.50 (t, 2H), 6.37
(br s, 1H), 6.23 (d, 1H), 5.11 (s, 2H), 4.88 (br s, 1H), 4.17 (s,
2H), 2.39 (q, 2H), 1.21 (t, 3H); MS (FD) 341 (M+).
2-Eth yl-4-h yd r oxy-1-(p h en ylm eth yl)-1H-in d ole (3m ).
To a solution of 3.1 g (11.7 mmol) of 2m in 40 mL of CH2Cl2
was added 47 mL of a 1 M solution of BBr3 in CH2Cl2. The
mixture was stirred for 4 h, and the solvent was evaporated
at reduced pressure. The residue was dissolved in EtOAc/
water, and the organic phase was separated, washed with
brine, dried over MgSO4, and evaporated at reduced pressure.
The residue was chromatographed on silica gel, eluting with
20% EtOAc/hexane, to give 3m : 1.58 g (yield 54%); mp 86-
90 °C: 1H NMR (CDCl3) ∂ 7.41-6.94 (m, 6H), 6.85 (d, 1H),
6.53 (d, 1H), 6.41 (s, 1H), 5.33 (s, 2H), 4.98 (s, 1H), 2.71 (q,
2H) 1.35 (t, 3H); MS (FD+) 251 (M+). Anal (C17H17NO) C, H,
N.
The following compounds were prepared utilizing the above
procedure.
1-[(3-Ch lor op h en yl)m eth yl]-2-eth yl-4-h yd r oxy-1H-in -
d ole (3p ) (chromatography on silica gel, EtOAc, then 5%
5-Hyd r oxy-1-(p h en ylm eth yl)-1H-in d ole (3a ) (chroma-
tography on silica gel, gradient, 20-100% Et2O/hexane): yield
41%; 1H NMR(CDCl3) ∂ 7.45-7.25(m, 4H), 7.25-7.05(m, 4H),
6.85(dd, 1H), 6.55(d, 1H), 5.65(br s, 1H), 5.25(s, 2H).
4-H yd r oxy-1-(p h en ylm et h yl)-1H -in d ole (3b ) (crude
product): yield 100%.
1
MeOH/EtOAc): yield 40%; oil; H NMR (CDCl3) ∂ 7.27-6.94
(m, 4H), 6.80 (d, 2H), 6.53 (d, 1H), 6.42 (s, 1H), 5.25 (s, 2H),
5.00 (s, 1H), 2.67 (q, 2H), 1.34 (t, 3H); MS (FD+) 285 (M - 1,
100), 287 (M + 1, 30).
1-Ben zoyl-2-eth yl-4-h yd r oxy-1H-in d ole (3q) (chroma-
tography on silica gel, 20% EtOAc/hexane, then 50%
4-Hyd r oxy-2-m eth yl-1-(p h en ylm eth yl)-1H-in d ole (3c)
(chromatography on silica gel, 20% EtOAc/hexane): yield 49%;
1
EtOAc/hexane): yield 52%; mp 91-110 °C; H NMR (CDCl3)
1
mp 125-127 °C; H NMR (CDCl3) ∂ 7.45-6.94 (m, 6H), 6.83
∂ 8.11 (d, 1H), 7.73 (d, 1H), 7.68-7.58 (m, 1H), 7.49 (t, 3H),
6.85 (t, 1H), 6.60-6.44 (m, 3H), 2.85 (q, 2H), 1.26 (t, 3H); MS
(FD) 265 (M+). Anal. (C17H15NO2) H; C: calcd, 76.96; found,
74.04; N: calcd, 5.28; found, 4.45.
(d, 1H), 6.52 (d, 1H), 6.39 (s, 1H), 5.29 (s, 2H), 4.97 (s, 1H),
2.38 (s, 3H); MS (FD) 237 (M+). Anal. (C16H15NO) C, H, N.
1-([1,1′-Bip h en yl]-2-ylm eth yl)-4-h yd r oxy-2-m eth yl-1H-
in d ole (3d ) (chromatography on silica gel, 20% EtOAc/
hexane): yield 55%; oil; 1H NMR (CDCl3) ∂ 7.60-7.15 (m, 8H),
6.94 (t, 1H), 6.72 (d, 1H), 6.55-6.45 (m, 2H), 6.34 (s, 1H), 5.16
(s, 2H), 4.99 (s, 1H), 2.25 (s, 3H); MS (FD) 313 (M+). Anal.
(C22H19NO) C, H, N.
1-([1,1′-Bip h en yl]-2-ylm eth yl)-4-h yd r oxy-2-p r op yl-1H-
in d ole (3r ) (chromatography on silica gel, 20% EtOAc/hexane,
1
then 50% EtOAc/hexane): yield 71%; oil; H NMR (CDCl3) ∂
7.61-7.12 (m, 8H), 6.96 (t, 1H), 6.75 (d, 1H), 6.52 (dd, 2H),
6.38 (s, 1H), 5.18 (s, 2H), 4.90 (br s, 1H), 2.50 (t, 2H), 1.72-
1.53 (m, 2H), 0.94 (t, 3H); MS (FD+) 341 (M+).
1-([1,1′-Bip h en yl]-3-ylm eth yl)-4-h yd r oxy-2-m eth yl-1H-
in d ole (3e) (chromatography on silica gel, 20% EtOAc/
hexane): yield 87%; oil; 1H NMR (CDCl3) ∂ 7.66-6.82 (m, 11H),
6.52 (d, 1H), 6.39 (s, 1H), 5.33 (s, 2H), 5.00 (s, 1H), 2.40 (s,
3H); MS (FD+) 313 (M+).
2-Cyclop r op yl-4-h yd r oxy-1-(p h e n ylm e t h yl)-1H -in -
d ole (3s) (chromatography on silica gel, 20% EtOAc/hexane):
1
yield 52%; oil; H NMR (CDCl3) ∂ 7.34-6.90 (m, 6H), 6.80 (d,
1H), 6.47 (d, 1H), 6.22 (br s, 1H), 5.42 (s, 2H), 4.82 (br s, 1H),
1.82-1.77 (m, 1H), 0.90-0.82 (m, 2H), 0.74-0.66 (m, 2H); MS
(FD) 263 (M+).
1-([1,1′-Bip h en yl]-4-ylm eth yl)-4-h yd r oxy-2-m eth yl-1H-
in d ole (3f) (chromatography on silica gel, 20% EtOAc/hex-
1
ane): yield 77%; oil; H NMR (CDCl3) ∂ 7.65-6.97 (m, 10H),
1-([1,1′-Biph en yl]-2-ylm eth yl)-2-cyclopr opyl-4-h ydr oxy-
1H -in d ole (3t ) (chromatography on silica gel, 20%
6.86 (d, 1H), 6.52 (d, 1H), 6.39 (br s, 1H), 5.32 (s, 2H), 4.90 (br
s, 1H), 2.41 (s, 3H); MS (FD+) 313 (M+).
1
EtOAc/hexane): yield 29%; oil; H NMR (CDCl3) ∂ 7.52-7.08
1-[(4-Flu or op h en yl)m eth yl]-4-h yd r oxy-2-m eth yl-1H-in -
d ole (3g) (chromatography on silica gel, 20% EtOAc/hexane):
(m, 6H), 6.91 (t, 1H), 6.67 (d, 1H), 6.52 (d, 1H), 6.45 (d, 2H),
6.17 (s, 1H), 5.30 (s, 2H), 4.79 (s, 1H), 1.70-1.49 (m, 1H), 0.80-
0.66 (m, 2H), 0.62-0.52 (m, 2H); MS (FD) 263 (M+).
1
yield 84%; oil; H NMR (CDCl3) ∂ 7.08-6.90 (m, 5H), 6.82 (d,

Indole Inhibitors of hnps-PLA2. 3
J ournal of Medicinal Chemistry, 1996, Vol. 39, No. 26 5167
2-[[2-Meth yl-1-(p h en ylm eth yl)-1H-in d ol-4-yl]oxy]a ce-
tic Acid Meth yl Ester (4c). A solution of 530 mg (2.2 mmol)
of 3c in 20 mL of DMF was stirred with 88 mg of NaH (60%
in mineral oil; 2.2 mmol) for 40 min and then with 0.2 mL of
methyl bromoacetate for 17 h. The solution was diluted with
water and extracted with EtOAc. The organic phase was
washed with water, dried over MgSO4, and evaporated at
reduced pressure. The residue was chromatographed on silica
gel, eluting with 20%EtOAc/hexane, to give 4c: 597 mg (yield
88%); mp 140-145 °C; 1H NMR (CDCl3) ∂ 7.32-6.86 (m, 7H),
6.50 (s, 1H), 6.41 (d, 1H), 5.30 (s, 2H), 4.80 (s, 2H), 3.83 (s,
3H), 2.36 (s, 3H); MS (FD) 309 (M+). Anal. (C19H19NO3) C,
H, N.
1H NMR (CDCl3) ∂ 7.33-6.95 (m, 4H), 6.80 (d, 1H), 6.55 (s,
1H), 6.42 (d, 1H), 6.25 (d, 1H), 5.22 (s, 2H), 4.82 (s, 2H), 3.82
(s, 3H), 2.42 (s, 3H), 2.32 (s, 3H); MS (FD+) 323 (M+). Anal.
(C20H21NO3) C, H, N.
2-[(2-Met h yl-1-n -oct yl-1H -in d ol-4-yl)oxy]a cet ic a cid
m et h yl est er (4l) (chromatography on silica gel, 20%
EtOAc/hexane): yield 82%; mp 66-68 °C; 1H NMR (CDCl3) ∂
7.07-6.92 (m, 2H), 6.41 (d, 2H), 4.77 (s, 2H), 4.02 (t, 2H), 3.81
(s, 3H), 2.41 (s, 3H), 1.74 (br t, 2H), 1.45-1.21 (m, 10H), 0.88
(t, 3H); MS (FD+) 331 (M+). Anal. (C20H29NO3) H, N; C: calcd,
72.47; found, 73.36.
2-[[2-E t h yl-1-(p h en ylm et h yl)-1H -in d ol-4-yl]oxy]a ce-
tic a cid m eth yl ester (4m ) (chromatography on silica gel,
20% EtOAc/hexane): yield 69%; mp 89-92 °C; 1H NMR
(CDCl3) ∂ 7.30-6.85 (m, 7H), 6.53 (s, 1H), 6.42 (d, 1H), 5.30
(s, 2H), 4.81 (s, 2H), 3.82 (s, 3H), 2.67 (q, 2H), 1.33 (t, 3H);
MS (FD+) 323 (M+). Anal. (C20H21NO3) C, H, N.
2-[[1-([1,1′-Biph en yl]-2-ylm eth yl)-2-eth yl-1H-in dol-4-yl]-
oxy]a cetic a cid m eth yl ester (4n ) (chromatography on silica
gel, 20% EtOAc/hexane): yield 59%; 1H NMR (CDCl3) ∂ 7.74-
7.23 (m, 9H), 7.11 (t, 1H), 6.91 (d, 1H), 6.64 (s, 1H), 6.53 (dd,
1H), 5.30 (s, 2H), 4.93 (s, 2H), 3.96 (s, 3H), 2.66 (q, 2H), 1.41
(t, 3H); MS (FD) 399 (M+).
The following compounds were prepared by the procedure
above (utilizing the appropriate ester alkyl halide) and purified
by the indicated method.
4-[[1-(P h en ylm eth yl)-1H-in d ol-5-yl]oxy]bu ta n oic a cid
eth yl ester (4a ) (chromatography on silica gel, gradient, 15-
1
50% Et2O/hexane): yield 40%; H NMR (CDCl3) ∂ 7.40-7.30
(m, 3H), 7.25-7.10 (m, 5H), 6.90 (dd, 1H), 6.55 (d, 1H), 5.25
(s, 2H), 4.15 (q, 2H), 4.10 (t, 2H), 3.70 (t, 2H), 2.15-195 (m,
2H), 1.20 (t, 3H).
2-[[1-(P h en ylm eth yl)-1H-in dol-4-yl]oxy]acetic acid ter t-
bu tyl ester (4b) (chromatography on silica gel, gradient, 10-
20% Et2O/hexane): yield 12%.
2-[[1-([1,1′-Bip h 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 (4d ) (chromatography on
silica gel, 20% EtOAc/hexane): yield 77%; mp 99-101 °C; 1H
NMR (CDCl3) ∂ 7.62-7.09 (m, 8H), 6.97 (t, 1H), 6.77 (d, 1H),
6.54-6.45 (m, 2H), 6.41 (d, 1H), 5.16 (s, 2H), 4.80 (s, 2H), 3.83
(s, 3H), 2.23 (s, 3H); MS (FD) 385 (M+). Anal. (C25H23NO3)
C, H, N.
2-[[1-([1,1′-Bip h en yl]-3-ylm eth yl)-2-m eth yl-1H-in d ol-4-
yl]oxy]a cetic a cid m eth yl ester (4e) (chromatography on
silica gel, 20% EtOAc/hexane): yield 79%; mp 99-102 °C; 1H
NMR (CDCl3) ∂ 7.57-6.84 (m, 11H), 6.53 (s, 1H), 6.44 (d, 1H),
5.35 (s, 2H), 4.82 (s, 2H), 3.82 (s, 3H), 2.40 (s, 3H); MS (FD)
385 (M+). Anal. (C25H23NO3) C, H, N.
2-[[1-([1,1′-Bip h en yl]-4-ylm eth yl)-2-m eth yl-1H-in d ol-4-
yl]oxy]a cetic a cid m eth yl ester (4f) (chromatography on
silica gel, 20% EtOAc/hexane): yield 63%; mp 164-167 °C;
1H NMR (CDCl3) ∂ 7.62-6.90 (m, 11H), 6.53 (s, 1H), 6.43 (d,
1H), 5.33 (s, 2H), 4.82 (s, 2H), 3.82 (s, 3H), 2.40 (s, 3H); MS
(FD+) 385 (M+). Anal. (C25H23NO3) H, N; C: calcd, 77.90;
found, 78.83.
2-[[2-Eth yl-1-[[2-(p h en ylm eth yl)p h en yl]m eth yl]-1H-in -
d ol-4-yl]oxy]a cetic a cid m eth yl ester (4o) (chromatography
on silica gel, 20% EtOAc/hexane): yield 65%; mp 109-114 °C;
1H NMR (CDCl3) ∂ 7.41-7.16 (m, 7H), 7.02 (t, 1H), 6.90 (t,
1H), 6.57 (d, 1H), 6.49 (s, 1H), 6.39 (d, 1H), 6.22 (d, 1H), 5.11
(s, 2H), 4.80 (s, 2H), 4.16 (s, 2H), 3.80 (s, 3H), 2.37 (q, 2H),
1.19 (t, 3H); MS (FD+) 413 (M+). Anal. (C27H27NO3) H, N; C:
calcd, 78.42; found, 80.14.
2-[[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 (4p ) (chromatography on silica
1
gel, 20% EtOAc/hexane): yield 65%; mp 85-90 °C; H NMR
(CDCl3) ∂ 7.25-6.75 (m, 6H), 6.56 (s, 1H), 6.43 (d, 1H), 5.27
(s, 2H), 4.83 (s, 2H), 3.83 (s, 3H), 2.66 (q, 2H), 1.35 (t, 3H);
MS (FD+) 357 (M - 1, 100), 359 (M + 1, 40). Anal. (C20H20
-
ClNO3) H; C: calcd, 67.13; found, 64.41; N: calcd, 3.91; found,
3.10.
2-[(1-Ben zoyl-2-eth yl-1H-in dol-4-yl)oxy]acetic acid ter t-
bu t yl est er (4q) (chromatography on silica gel, 20%
EtOAc/hexane): yield 63%; oil; 1H NMR (CDCl3) ∂ 8.11 (d, 1H),
7.75-7.43 (m, 4H), 6.89 (t, 1H), 6.71 (s, 1H), 6.49 (dd, 1H),
4.75 (s, 2H), 2.83 (q, 2H), 1.49 (s, 3H), 1.28 (t, 3H); MS (FD+)
379 (M+). Anal. (C23H25NO4) C, H, N.
2-[[1-([1,1′-Bip h en yl]-2-ylm eth yl)-2-p r op yl-1H-in d ol-4-
yl]oxy]a cetic a cid m eth yl ester (4r ) (chromatography on
silica gel, 20% EtOAc/hexane): yield 56%; oil; 1H NMR (CDCl3)
∂ 7.59-7.11 (m, 8H), 6.98 (t, 1H), 6.80 (d, 1H), 6.50 (s, 1H),
6.49 (d, 1H), 6.41 (d, 1H), 5.16 (s, 2H), 4.81 (s, 2H), 3.82 (s,
3H), 2.49 (t, 2H), 1.66 (q, 2H), 0.94 (t, 3H); MS (FD) 413 (M+).
2-[[2-Cyclopr opyl-1-(ph en ylm eth yl)-1H-in dol-4-yl]oxy]-
a cetic a cid m eth yl ester (4s) (chromatography on silica gel,
20% EtOAc/hexane): yield 63%; oil; 1H NMR (CDCl3) ∂ 7.33-
6.33 (m, 9H), 5.41 (s, 2H), 4.75 (s, 2H), 3.80 (s, 3H), 1.80-1.67
(m, 1H), 0.90-0.78 (m, 2H), 0.74-0.66 (m, 2H); MS (FD) 335
(M+).
2-[[1-([1,1′-Bip h en yl]-2-ylm eth yl)-2-cyclop r op yl-1H-in -
d ol-4-yl]oxy]a cetic a cid m eth yl ester (4t) (chromatography
on silica gel, 20% EtOAc/hexane): yield 59%; oil; 1H NMR
(CDCl3) ∂ 7.51-6.29 (m, 13H), 5.28 (s, 2H), 4.74 (s, 2H), 3.76
(s, 3H), 1.63-1.49 (m, 1H), 0.74-0.66 (m, 2H), 0.62-0.49 (m,
2H); MS (FD) 411 (M+).
4-[[1-([1,1′-Bip h en yl]-2-ylm eth yl)-2-m eth yl-1H-in d ol-4-
yl]oxy]bu ta n oic a cid eth yl ester (4v) (chromatography on
silica gel, 20% EtOAc/hexane): yield 51%; oil; 1H NMR (CDCl3)
∂ 7.57-6.41 (m, 13H), 5.16 (s, 2H), 4.14 (q, 2H), 3.49 (t, 2H),
2.52 (t, 2H), 2.23 (s, 3H), 2.27-2.16 (m, 2H), 1.29 (t, 3H); MS
(FD) 427 (M+).
2-[[2-Eth yl-1-(p h en ylm eth yl)-1H-in d ol-4-yl]oxy]-2-m e-
th ylp r op ion ic a cid m eth yl ester (4w ) (chromatography on
silica gel, 20% EtOAc/hexane): yield 49%; 1H NMR (CDCl3) ∂
7.34-6.85 (m, 7H), 6.48 (s, 1H), 6.40 (d, 1H), 5.29 (s, 2H), 4.27
(q, 2H), 2.67 (q, 2H), 1.93 (s, 3H), 1.69 (s, 3H), 1.33 (t, 3H),
1.25 (t, 3H); MS (FD+) 365 (M+).
2-[[1-[(4-Flu or oph en yl)m eth yl]-2-m eth yl-1H-in dol-4-yl]-
oxy]a cetic a cid m eth yl ester (4g) (chromatography on silica
gel, 20% EtOAc/hexane): yield 81%; mp 92-98 °C; H NMR
1
(CDCl3) ∂ 7.02-6.82 (m, 6H), 6.50 (s, 1H), 6.42 (d, 1H), 5.25
(s, 2H), 4.81 (s, 2H), 3.82 (s, 3H), 2.34 (s, 3H); MS (FD+) 327
(M+). Anal. (C19H18FNO3) N; C: calcd, 69.71; found, 70.83;
H: calcd, 5.54; found, 6.00.
2-[[1-[(2,6-Dich lor op h en yl)m eth yl]-2-m eth yl-1H-in d ol-
4-yl]oxy]a cetic a cid m eth yl ester (4h ) (chromatography on
silica gel, 20% EtOAc/hexane): yield 39%; mp 168-169 °C;
1H NMR (CDCl3) ∂ 7.41-7.18 (m, 3H), 6.92 (t, 1H), 6.76 (d,
1H), 6.45 (s, 1H), 6.39 (d, 1H), 5.50 (s, 2H), 4.76 (s, 2H), 3.81
(s, 3H), 2.41 (s, 3H); MS (FD+) 377 (M - 1, 100), 379 (M + 1,
70). Anal. (C18H17Cl2NO3) C, H, N.
2-[[2-Meth yl-1-[(1-n aph th yl)m eth yl]-1H-in dol-4-yl]oxy]-
a cetic a cid m eth yl ester (4i) (chromatography on silica gel,
20% EtOAc/hexane): yield 45%; mp 167-171 °C; 1H NMR
(CDCl3) ∂ 8.11 (d, 1H), 7.92 (d, 1H), 7.74 (d, 1H), 7.68-7.54
(m, 2H), 7.23 (t, 1H), 6.95 (t, 1H), 6.81 (d, 1H), 6.59 (s, 1H),
6.44 (d, 1H), 6.36 (d, 1H), 5.76 (s, 2H), 4.82 (s, 2H), 3.85 (s,
3H), 2.35 (s, 3H); MS (FD+) 359 (M+). Anal. (C23H21NO3) H,
N; C: calcd, 76.86; found, 77.95.
2-[[1-[(2-Ch lor oph en yl)m eth yl]-2-m eth yl-1H-in dol-4-yl]-
oxy]a cetic a cid m eth yl ester (4j) (chromatography on silica
gel, 20% EtOAc/hexane): yield 91%; mp 138-141 °C; 1H NMR
(CDCl3) ∂ 7.41 (d, 1H), 7.18 (t, 1H), 7.08-6.94 (m, 2H), 6.82
(d, 1H), 6.55 (s, 1H), 6.43 (d, 1H), 6.25 (d, 1H), 5.33 (s, 2H),
4.80 (s, 2H), 3.82 (s, 3H), 2.33 (s, 3H); MS (FD+) 343 (M - 1,
100), 345 (M + 1, 60). Anal. (C19H18ClNO3) C, H, N.
2-[[2-Met h yl-1-[(2-m et h ylp h en yl)m et h yl]-1H -in d ol-4-
yl]oxy]a cetic a cid m eth yl ester (4k ) (chromatography on
silica gel, 20% EtOAc/hexane): yield 63%; mp 151-154 °C;
d l-2-[[2-E t h yl-1-(p h en ylm et h yl)-1H -in d ol-4-yl]oxy]-4-
p h en ylbu ta n oic a cid m eth yl ester ((d l)-4x) (chromatog-

5168 J ournal of Medicinal Chemistry, 1996, Vol. 39, No. 26
Draheim et al.
raphy on silica gel, 50% EtOAc/hexane): yield 86%; oil; 1H
NMR (CDCl3) ∂ 7.45-6.80 (m, 12H), 6.53 (s, 1H), 6.34 (d, 1H),
5.27 (s, 2H), 4.88-4.74 (m, 1H), 4.23 (q, 2H), 3.10-2.82 (m,
2H), 2.67 (q, 2H), 2.49-2.25 (m, 2H), 1.33 (t, 3H), 1.25 (t, 3H);
MS (FD) 441 (M+). Anal. (C29H31NO3) C, H, N.
d l-2-[[2-Met h yl-1-(p h en ylm et h yl)-1H -in d ol-4-yl]oxy]-
p r op ion ic a cid m eth yl ester ((d l)-4y) (chromatography on
silica gel, 20% EtOAc/hexane): yield 74%; 1H NMR (CDCl3) ∂
7.37-6.84 (m, 7H), 6.50 (s, 1H), 6.41 (d, 1H), 5.26 (s, 2H), 4.94
(q, 1H), 3.75 (s, 3H), 2.34 (s, 3H), 1.71 (d, 3H); MS (FD+) 323
(M+).
d l-2-[[2-Eth yl-1-(p h en ylm eth yl)-1H-in d ol-4-yl]oxy]p r o-
p ion ic a cid m eth yl ester ((d l)-4z) (chromatography on silica
gel, 20% EtOAc/hexane): yield 56%; 1H NMR (CDCl3) ∂ 7.35-
6.84 (m, 7H), 6.57 (s, 1H), 6.40 (d, 1H), 5.30 (s, 2H), 4.95 (q,
1H), 3.78 (s, 3H), 2.69 (q, 2H), 1.74 (d, 3H), 1.34 (t, 3H); MS
(FD+) 337 (M+).
2-[[5-Allyl-2-eth yl-1-(p h en ylm eth yl)-1H-in d ol-4-yl]oxy]-
a cetic Acid Eth yl Ester (4u ). A solution of 1.0 g (4 mmol)
of 3m in 10 mL of THF and 75 mL of DMF was stirred with
200 mg of NaH (60% in mineral oil; 5 mmol) for 10 min, and
then with 0.4 mL (4.6 mmol) of allyl bromide for 2 h. The
solution was 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 5-10%
Et2O/hexane to give 4-(allyloxy)-2-ethyl-1-(phenylmethyl)-1H-
indole. This material was heated at reflux in 20 mL of N,N-
dimethylaniline for 19 h, cooled, diluted with EtOAc, washed
with 1 N HCl, H2O, and brine, dried (Na2SO4), and concen-
trated. The residue was chromatographed on silica gel, eluting
with a gradient of 10-40% Et2O/hexane to give 5-allyl-2-ethyl-
4-hydroxy-1-(phenylmethyl)-1H-indole (3u ), 1.0 g (yield 86%).
This material (3.4 mmol) was dissolved in 60 mL of DMF and
10 mL of THF, 150 mg of NaH (60% in mineral oil; 3.7 mmol)
was added, the mixture was stirred for 15 min, 0.4 mL (3.6
mmol) of ethyl bromoacetate was added, and stirring was
continued for an additional 2.5 h. The solution was diluted
with water and extracted with EtOAc. The organic phase was
washed with brine, dried (Na2SO4), and evaporated at reduced
pressure. The residue was chromatographed on silica gel,
eluting with a gradient of 15-20% Et2O/hexane, to give 780
mg (yield 61%) of 4u : 1H NMR (CDCl3) ∂ 7.45-7.30 (m, 3H),
7.25-7.00 (m, 4H), 6.50 (s, 1H), 6.25-6.00 (m, 1H), 5.35 (s,
2H), 5.25-5.10 (m, 2H), 4.95 (s, 2H), 4.45 (q, 2H), 3.75 (d, 2H),
2.80 (q, 2H), 1.45 (t, 6H).
(R)-2-[[2-Eth yl-1-(ph en ylm eth yl)-1H-in dol-4-yl]oxy]pr o-
p ion ic Acid Meth yl Ester ((R)-4z). To a solution of 1.0 g
(3 mmol) of 3m in 75 mL of DMF was added 180 mg of NaH
(60% in mineral oil; 4.4 mmol), the mixture was stirred for 5
min, and then 0.5 mL (4.7 mmol) of methyl (S)-(-)-2-chloro-
propionate was added. The solution was stirred for 1 h and
then diluted with EtOAc and water. 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 20-50% Et2O/hexane, to give
1.36 g (yield 100%) of (R)-4z; oil; 1H NMR (CDCl3) ∂ 7.20-
7.10 (m, 3H), 6.95-6.80 (m, 3H), 6.75 (d, 1H), 6.50 (s, 1H),
6.35 (d, 1H), 5.15 (s, 2H), 4.95 (q, 1H), 3.70 (s, 3H), 2.60 (q,
2H), 1.65 (d, 3H), 1.25 (t, 3H).
2-[[2-Eth yl-1-(p h en ylm eth yl)-1H-in d ol-4-yl]oxy]a ceta -
m id e (4a a ). A solution of 560 mg (1.73 mmol) of 4m , 2 mL of
hydrazine, and 10 mL of EtOH was refluxed for 1 h, cooled,
diluted with water, and extracted with EtOAc. The organic
phase was washed with brine, dried over MgSO4, and evapo-
rated at reduced pressure to give 2-[[2-ethyl-1-(phenylmethyl)-
1H-indol-4-yl]oxy]acetic acid hydrazide: 390 mg (yield 70%);
mp 159-161 °C; 1H NMR (DMSO-d6) ∂ 9.34 (br s, 1H), 7.34-
6.88 (m, 7H), 6.55 (s, 1H), 6.47 (d, 1H), 5.38 (s, 2H), 4.57 (s,
2H), 4.39 (d, 2H), 2.66 (q, 2H), 1.25 (t, 3H); MS (FD+) 323 (M+).
A mixture of this material (1.2 mmol), ca. 0.5 g of Raney nickel
catalyst, and 10 mL of EtOH was refluxed for 2 h and cooled,
and the solution was decanted. The solids were washed with
CH2Cl2 by decantation, and the combined organics were
evaporated at reduced pressure. The residue was chromato-
graphed on silica gel, eluting with EtOAc, to give 4a a : 255
mg (yield 69%); mp 190-192 °C: 1H NMR (DMSO-d6) ∂ 7.49
(br s, 1H), 7.42 (br s, 1H), 7.33-6.87 (m, 7H), 6.52 (s, 1H),
6.42 (d, 1H), 5.34 (s, 2H), 4.48 (s, 2H), 2.63 (q, 2H), 1.24 (t,
3H); MS (FD+) 308 (M+). Anal. (C19H20N2O2) H, N; C: calcd,
74.01; found, 74.61.
2-[[3-(2-Am in o-1,2-d ioxoet h yl)-1-([1,1′-b ip h en yl]-3-yl-
m eth yl)-2-m eth yl-1H-in d ol-4-yl]oxy]a cetic a cid m eth yl
ester (5e). A solution of 1.0 g (2.6 mmol) of 4e in 15 mL of
CH2Cl2 was stirred for 80 min with 0.23 mL (2.6 mmol) of
oxalyl chloride. The solution was saturated with ammonia,
evaporated at reduced pressure, and partitioned between
EtOAc and water. The organic phase was washed with brine,
dried over MgSO4, and evaporated at reduced pressure. The
residue was chromatographed on silica gel, eluting with
1
EtOAc, to give 791 mg of 5e: yield 82%; mp 175-179 °C; H
NMR (DMSO-d6) ∂ 7.72 (br s, 1H), 7.62-7.34 (m, 9H), 7.22 (d,
1H), 7.08 (t, 1H), 6.93 (d, 1H), 6.59 (d, 1H), 5.59 (s, 2H), 4.77
(s, 2H), 3.71 (s, 3H), 2.57 (s, 3H); MS (FD+) 456 (M+). Anal.
(C27H24N2O5) C, H, N.
The following compounds were prepared using the above
procedure and the indicated purification method.
4-[[3-(2-Am in o-1,2-d ioxoeth yl)-1-(p h en ylm eth yl)-1H-in -
d ol-5-yl]oxy]bu ta n oic a cid eth yl ester (5a ) (crystallized
from CH2Cl2/EtOH): yield 84%; mp 168-170 °C; 1H NMR
(DMSO-d6) ∂ 8.75 (s, 1H), 8.05 (br s, 1H), 7.70 (s, 2H), 7.45 (d,
1H), 7.35-7.15 (m, 5H), 6.85 (dd, 1H), 5.45 (s, 2H), 4.10-3.85
(m, 4H), 2.45 (t, 3H), 2.05-1.90 (m, 3H), 1.15 (t, 3H); MS (FD+)
408 (M+). Anal. (C23H24N2O5) C, H, N.
2-[[3-(2-Am in o-1,2-d ioxoeth yl)-1-(p h en ylm eth yl)-1H-in -
d ol-4-yl]oxy]a cetic a cid m eth yl ester (5b) (chromatogra-
phy on silica gel, Et2O): yield 41%; 1H NMR (CDCl3) ∂ 8.70 (s,
1H), 7.30 (br s, 1H), 7.20-7.10 (m, 3H), 7.05-6.95 (m, 3H),
6.80 (d, 1H), 6.55 (d, 1H), 5.85 (br s, 1H), 5.20 (s, 2H), 4.55 (s,
2H), 1.35 (s, 9H).
2-[[3-(2-Am in o-1,2-d ioxoeth yl)-2-m eth yl-1-(p h en ylm e-
t h yl)-1H-in d ol-4-yl]oxy]a cet ic a cid m et h yl est er (5c)
(crude product filtered): yield 93%; mp 202-215 °C; 1H NMR
(DMSO-d6) ∂ 7.98 (br s, 1H), 7.71 (br s, 2H), 7.40-7.02 (m,
6H), 6.58 (d, 1H), 5.50 (s, 2H), 4.76 (s, 2H), 3.70 (s, 3H), 2.51
(s, 3H); MS (FD) 380 (M+).
2-[[3-(2-Am in o-1,2-d ioxoet h yl)-1-([1,1′-b ip h en yl]-2-yl-
m eth yl)-2-m eth yl-1H-in d ol-4-yl]oxy]a cetic a cid m eth yl
ester (5d ) (crude product filtered): yield 99%; mp 144-148
1
°C; H NMR (DMSO-d6) ∂ 7.74 (br s, 1H), 7.63-7.21 (m, 9H),
(S)-2-[[2-Eth yl-1-(ph en ylm eth yl)-1H-in dol-4-yl]oxy]pr o-
p ion ic Acid Meth yl Ester ((S)-4z). Using reaction condi-
tions identical to those above, 3m was reacted with methyl
(R)-(+)-2-chloropropionate to give a 90% yield of (S)-4z; oil;
1H NMR data is identical to that given for (R)-4z.
(R)-2-[[2-Eth yl-1-(ph en ylm eth yl)-1H-in dol-4-yl]oxy]pr o-
p ion ic Acid Meth yl Ester ((R)-4z) (alternate preparation).
A solution of 450 mg (1.0 mmol) of (R,S)-9b in 5 mL of THF
and 5 mL of MeOH was added to a solution of 2 mmol of
MeOMgBr (from MeOH and 3 M PhMgBr/Et2O) in 25 mL of
MeOH at 0-5 °C. The solution was stirred, cooled for 20 min,
and then diluted with EtOAc and water. 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 15-20% Et2O/hexane to
give (R)-4z: 240 mg (yield 71%); oil; 1H NMR data is identical
to that given above for (R)-4z.
7.05 (t, 1H), 6.92 (d, 1H), 6.57 (d, 1H), 6.42 (d, 1H), 5.38 (s,
2H), 4.77 (s, 2H), 3.72 (s, 3H), 2.55 (s, 3H); MS (FD+) 443 (M+).
2-[[3-(2-Am in o-1,2-d ioxoet h yl)-1-([1,1′-b ip h en yl]-4-yl-
m eth yl)-2-m eth yl-1H-in d ol-4-yl]oxy]a cetic a cid m eth yl
ester (5f) (crystallized from EtOAc): yield 94%; mp 215-217
°C; 1H NMR (DMSO-d6) ∂ 7.73 (br s, 1H), 7.67-7.04 (m, 12H),
6.58 (d, 1H), 5.55 (s, 2H), 4.78 (s, 2H), 3.70 (s, 3H), 2.55 (s,
3H); MS (FD+) 456 (M+). Anal. (C27H24N2O5) C, H, N.
2-[[3-(2-Am in o-1,2-d ioxoeth yl)-1-[(4-flu or op h en yl)m e-
th yl]-2-m eth yl-1H-in d ol-4-yl]oxy]a cetic a cid m eth yl es-
ter (5g) (chromatography on silica gel, EtOAc): yield 70%;
1
mp 178-180 °C; H NMR (DMSO-d6) ∂ 7.72 (br s, 1H), 7.39
(br s, 1H), 7.26-7.02 (m, 6H), 6.57 (d, 1H), 5.49 (s, 2H), 4.76
(s, 2H), 3.70 (s, 3H), 2.49 (s, 3H); MS (FD+) 398 (M+). Anal.
(C21H19N2O5) H, N; C: calcd, 63.31; found, 62.31; residue
0.85%.

Indole Inhibitors of hnps-PLA2. 3
J ournal of Medicinal Chemistry, 1996, Vol. 39, No. 26 5169
2-[[3-(2-Am in o-1,2-d ioxoeth yl)-1-[(2,6-d ich lor op h en yl)-
m eth yl]-2-m eth yl-1H-in d ol-4-yl]oxy]a cetic a cid m eth yl
ester (5h ) (chromatography on silica gel, EtOAc): yield 88%;
4.74 (s, 2H), 3.79 (s, 3H), 2.74 (t, 2H), 1.47 (q, 2H), 0.89 (t,
3H); MS (FD) 484 (M+).
2-[[3-(2-Am in o-1,2-d ioxoet h yl)-2-cyclop r op yl-1-(p h e-
n ylm eth yl)-1H-in d ol-4-yl]oxy]a cetic a cid m eth yl ester
1
mp 200-202 °C; H NMR (DMSO-d6) ∂ 7.68 (br s, 1H), 7.59-
1
7.41 (m, 3H), 7.35 (br s, 1H), 6.97 (t, 1H), 6.79 (d, 1H), 6.51 (d,
1H), 5.67 (s, 2H), 4.73 (s, 2H), 3.68 (s, 3H), 2.50 (s, 3H); MS
(5s) (crude product filtered): yield 73%; H NMR (DMSO-d6)
∂ 7.76 (br s, 1H), 7.47 (br s, 1H), 7.37-7.00 (m, 7H), 6.57-
6.41 (m, 1H), 5.59 (s, 2H), 4.74 (s, 2H), 3.69 (s, 3H), 1.89-1.74
(m, 1H), 1.04-0.90 (m, 2H), 0.53-0.43 (m, 2H); MS (FD) 406
(M+).
2-[[3-(2-Am in o-1,2-d ioxoet h yl)-1-([1,1′-b ip h en yl]-2-yl-
m eth yl)-2-cyclopr opyl-1H-in dol-4-yl]oxy]acetic acid m eth -
yl ester (5t) (chromatography on silica gel, EtOAc): yield 59%;
1H NMR (DMSO-d6) ∂ 7.75 (br s, 1H), 7.59-7.20 (m, 9H), 7.07
(t, 1H), 6.96 (d, 1H), 6.51 (d, 1H), 6.46 (d, 1H), 5.48 (s, 2H),
4.74 (s, 2H), 3.70 (s, 3H), 1.63-1.49 (m, 1H), 0.74-0.67 (m,
2H), 0.32-0.25 (m, 2H); MS (FD) 482 (M+).
(FD+) 448 (M - 1, 100), 450 (M + 1, 90). Anal. (C21H18
Cl2N2O5) C, H, N.
-
2-[[3-(2-Am in o-1,2-d ioxoeth yl)-2-m eth yl-1-[(1-n a p h th -
yl)m eth yl]-1H-in d ol-4-yl]oxy]a cetic a cid m eth yl ester
(5i) (chromatography on silica gel, EtOAc): yield 95%; mp
188-190 °C; 1H NMR (DMSO-d6) ∂ 8.34 (d, 1H), 8.04 (d, 1H),
7.86 (d, 1H), 7.79 (br s, 1H), 7.78-7.61 (m, 3H), 7.45 (br s,
1H), 7.36 (t, 1H), 7.16-7.04 (m, 2H), 6.66-6.60 (m, 2H), 6.28
(d, 1H), 6.05 (s, 2H), 4.84 (s, 2H), 3.76 (s, 3H), 2.53 (s, 3H);
MS (FD+) 430 (M+). Anal. (C25H22N2O5) C, H, N.
2-[[3-(2-Am in o-1,2-d ioxoeth yl)-1-[(2-ch lor op h en yl)m e-
th yl]-2-m eth yl-1H-in d ol-4-yl]oxy]a cetic a cid m eth yl es-
ter (5j) (chromatography on silica gel, EtOAc): yield 71%; mp
2-[[5-Allyl-3-(2-a m in o-1,2-d ioxoet h yl)-2-et h yl-1-(p h e-
n ylm eth yl)-1H-in d ol-4-yl]oxy]a cetic a cid eth yl ester (5u )
(chromatography on silica gel, gradient, 20-50% Et2O/hex-
ane): yield 73%; mp 149-151 °C; MS (FD+) 448 (M+); Anal.
(C26H28N2O5) C, H, N.
4-[[3-(2-Am in o-1,2-d ioxoet h yl)-1-([1,1′-b ip h en yl]-2-yl-
m eth yl)-2-m eth yl-1H-in d ol-4-yl]oxy]bu ta n oic a cid eth yl
ester (5v) (chromatography on silica gel, EtOAc): yield 71%;
1H NMR (CDCl3) ∂ 7.57-6.53 (m, 13H), 5.72 (br s, 1H), 5.18
(s, 2H), 4.20-4.07 (m, 4H), 2.57 (t, 2H), 2.39 (s, 3H), 2.25-
2.10 (m, 2H), 1.29 (t, 3H); MS (FD) 498 (M+).
2-[[3-(2-Am in o-1,2-dioxoeth yl)-2-eth yl-1-(ph en ylm eth yl)-
1H-in d ol-4-yl]oxy]-2-m eth ylp r op ion ic a cid m eth yl ester
(5w ) (chromatography on silica gel, EtOAc): yield 48%; oil;
1H NMR (CDCl3) ∂ 7.38-6.97 (m, 6H), 6.82 (d, 2H), 6.36 (d,
1H), 5.53 (br s, 1H), 5.34 (s, 2H), 4.27-4.08 (m, 4H), 2.90 (q,
2H), 1.74 (s, 6H), 1.31-1.16 (m, 5H); MS (FD+) 436 (M+). Anal.
(C25H28N2O5) H; C: calcd, 68.79; found, 67.97; N: calcd, 6.42;
found, 5.99.
1
198-200 °C; H NMR (CDCl3) ∂ 7.44 (d, 1H), 7.36-7.06 (m,
3H), 6.86 (d, 1H), 6.63 (br s, 1H), 6.57 (d, 1H), 6.41 (d, 1H),
5.57 (br s, 1H), 5.40 (s, 2H), 4.78 (s, 2H), 3.80 (s, 3H), 2.55 (s,
3H); MS (FD+) 414 (M - 1, 100), 416 (M + 1, 57). Anal.
(C21H19ClN2O5) C, H, N.
2-[[3-(2-Am in o-1,2-dioxoeth yl)-2-m eth yl-1-[(2-m eth ylph e-
n yl)m eth yl]-1H-in d ol-4-yl]oxy]a cetic a cid m eth yl ester
(5k ) (chromatography on silica gel, EtOAc): yield 89%; mp
1
212-213 °C; H NMR (CDCl3) ∂ 7.36-7.00 (m, 4H), 6.84 (d,
1H), 6.61 (br s, 1H), 6.58 (d, 1H), 6.38 (d, 1H), 5.49 (br s, 1H),
5.27 (s, 2H), 4.79 (s, 2H), 3.78 (s, 3H), 2.51 (s, 3H), 2.43 (s,
3H); MS (FD+) 394 (M+). Anal. (C22H22N2O5) C, H, N.
2-[[3-(2-Am in o-1,2-d ioxoeth yl)-2-m eth yl-1-n -octyl-1H-
in d ol-4-yl]oxy]a cetic a cid m eth yl ester (5l) (chromatog-
1
raphy on silica gel, EtOAc): yield 77%; mp 143-144 °C; H
NMR (CDCl3) ∂ 7.14 (t, 1H), 6.98 (d, 1H), 6.57 (br s, 1H), 6.55
(d, 1H), 5.53 (br s, 1H), 4.74 (s, 2H), 4.07 (t, 2H), 3.75 (s, 3H),
2.59 (s, 3H), 1.77 (br t, 2H), 1.49-1.23 (m, 10H), 0.89 (t, 3H);
MS (FD+) 402 (M+). Anal. (C22H30N2O5) C, H, N.
d l-2-[[3-(2-Am in o-1,2-d ioxoe t h yl)-2-e t h yl-1-(p h e n yl-
m eth yl)-1H-in d ol-4-yl]oxy]-4-p h en ylbu ta n oic a cid m eth -
1
yl ester ((d l)-5x) (crude product): yield 100%; oil; H NMR
2-[[3-(2-Am in o-1,2-dioxoeth yl)-2-eth yl-1-(ph en ylm eth yl)-
1H-in d ol-4-yl]oxy]a cetic a cid m eth yl ester (5m ) (crystal-
lized from EtOAc): yield 96%; mp 172-187 °C; 1H NMR-
(DMSO-d6) ∂ 7.72(br s, 1H), 7.45-7.00(m, 8H), 6.57(d, 1H),
5.51(s, 2H), 4.76(s, 2H), 3.68(s, 3H), 2.90(q, 2H), 1.08(t, 3H);
MS(FD+) 394(M+).
2-[[3-(2-Am in o-1,2-d ioxoet h yl)-1-([1,1′-b ip h en yl]-2-yl-
m eth yl)-2-eth yl-1H-in d ol-4-yl]oxy]a cetic a cid m eth yl es-
ter (5n ) (chromatography on silica gel, EtOAc): yield 92%;
1H NMR (DMSO-d6) ∂ 7.74 (br s, 1H), 7.66-7.19 (m, 9H), 7.07
(t, 1H), 6.96 (d, 1H), 6.57 (d, 1H), 6.49 (d, 1H), 5.37 (s, 2H),
4.76 (s, 2H), 3.71 (s, 3H), 2.70 (q, 2H), 0.92 (t, 3H); MS (FD)
470 (M+).
(CDCl3) ∂ 7.41-6.92 (m, 11H), 6.83 (d, 1H), 6.61 (br s, 1H),
6.44 (d, 1H), 5.55 (br s, 1H), 5.34 (s, 2H), 4.84-4.71 (m, 1H),
4.15 (q, 2H), 3.00-2.74 (m, 4H), 2.49-2.33 (m, 2H), 1.34-1.07
(m, 6H); MS (FD) 512 (M+). Anal. (C31H32N2O5) H; C: calcd,
72.64; found, 70.15; N: calcd, 5.47; found, 6.27.
(d l)-2-[[3-(2-Am in o-1,2-d ioxoeth yl)-2-m eth yl-1-(p h en yl-
m eth yl)-1H-in d ol-4-yl]oxy]p r op ion ic a cid m eth yl ester
((d l)-5y) (chromatography on silica gel, EtOAc): yield 90%;
1
mp 175 °C; H NMR (DMSO-d6) ∂ 7.79 (br s, 1H), 7.40 (br s,
1H), 7.38-7.00 (m, 7H), 6.42 (d, 1H), 5.49 (s, 2H), 4.70 (q, 1H),
3.63 (s, 3H), 2.46 (s, 3H), 1.58 (d, 3H); MS (FD+) 394 (M+).
Anal. (C22H22N2O5) C, H, N.
d l-2-[[3-(2-Am in o-1,2-d ioxoe t h yl)-2-e t h yl-1-(p h e n yl-
m eth yl)-1H-in d ol-4-yl]oxy]p r op ion ic a cid m eth yl ester
((d l)-5z) (chromatography on silica gel, EtOAc): yield 94%;
2-[[3-(2-Am in o-1,2-d ioxoet h yl)-2-et h yl-1-[[2-(p h en yl-
m et h yl)p h en yl]m et h yl]-1H -in d ol-4-yl]oxy]a cet ic a cid
m eth yl ester (5o) (crystallized from EtOAc): yield 59%; mp
1
oil; H NMR (CDCl3) ∂ 7.37-7.00 (m, 6H), 6.85 (d, 1H), 6.66
1
161-163 °C; H NMR (CDCl3) ∂ 7.43-6.98 (m, 10H), 6.55 (t,
(br s, 1H), 6.48 (d, 1H), 5.49 (br s, 1H), 5.35 (s, 2H), 4.92 (q,
1H), 3.74 (s, 3H), 2.92 (q, 2H), 1.71 (d, 3H), 1.23 (t, 3H); MS
2H), 6.38 (d, 1H), 5.45 (br s, 1H), 4.74 (s, 2H), 4.18 (s, 2H),
3.78 (s, 3H), 2.64 (q, 2H), 1.00 (t, 3H); MS (FD+) 484 (M+).
Anal. (C29H28N2O5) C, H, N.
(FD
+) 408 (M+). Anal. (C23H24N2O5) C, H, N.
(R)-2-[[3-(2-Am in o-1,2-d ioxoet h yl)-2-et h yl-1-(p h en yl-
m eth yl)-1H-in d ol-4-yl]oxy]p r op ion ic a cid m eth yl ester
((R)-5z) (from oxazolidinone route) (crystallized from
Et2O/hexane): yield 61%; mp 153-155 °C; MS (FD) 408 (M+);
Anal. (C23H24N2O5‚0.3Et2O) C, H, N.
(R)-2-[[3-(2-Am in o-1,2-d ioxoet h yl)-2-et h yl-1-(p h en yl-
m eth yl)-1H-in d ol-4-yl]oxy]p r op ion ic a cid m eth yl ester
((R)-5z) (from methyl chloropropionate route) (crystallized
from Et2O/hexane): yield 88%; mp 153-155 °C; MS (FD) 408
(M+); optical rotation at 589 nm -13.3° (MeOH). Anal.
(C23H24N2O5) C, H, N.
2-[[3-(2-Am in o-1,2-d ioxoeth yl)-1-[(3-ch lor op h en yl)m e-
th yl]-2-eth yl-1H-in d ol-4-yl]oxy]a cetic a cid m eth yl ester
(5p ) (crystallized from EtOAc): yield 86%; mp 173-185 °C;
1H NMR (DMSO-d6) ∂ 7.73 (br s, 1H), 7.45-6.56 (m, 8H), 5.55
(s, 2H), 4.77 (s, 2H), 3.72 (s, 3H), 2.90 (q, 2H), 1.08 (t, 3H);
MS (FD+) 428 (M - 1, 100), 430 (M + 1, 40).
2-[[3-(2-Am in o-1,2-d ioxoeth yl)-1-ben zoyl-2-eth yl-1H-in -
d ol-4-yl]oxy]a cetic a cid ter t-bu tyl ester (5q) (chromatog-
raphy on silica gel, 50% EtOAc/hexane): yield 32%; mp 152-
1
155 °C; H NMR (CDCl3) ∂ 7.82 (d, 1H), 7.70 (t, 1H), 7.54 (t,
2H), 7.34-7.24 (m, 1H), 6.94 (t, 1H), 6.77 (br s, 1H), 6.52 (d,
1H), 6.42 (d, 1H), 5.49 (br s, 1H), 4.59 (s, 2H), 3.01 (q, 2H),
1.48 (s, 9H), 1.26 (t, 3H); MS (FD) 450 (M+). Anal. (C25H26N2O6)
H, N; C: calcd, 66.66; found, 69.84.
2-[[3-(2-Am in o-1,2-d ioxoet h yl)-1-([1,1′-b ip h en yl]-2-yl-
m eth yl)-2-p r op yl-1H-in d ol-4-yl]oxy]a cetic a cid m eth yl
ester (5r ) (chromatography on silica gel, EtOAc): yield 70%;
foam; 1H NMR (CDCl3) ∂ 7.58-7.21 (m, 9H), 7.07 (t, 1H), 6.80
(d, 1H), 6.63 (d, 1H), 6.53 (d, 1H), 5.49 (br s, 1H), 5.21 (s, 2H),
(S)-2-[[3-(2-Am in o-1,2-d ioxoet h yl)-2-et h yl-1-(p h en yl-
m eth yl)-1H-in d ol-4-yl]oxy]p r op ion ic a cid m eth yl ester
((S)-5z) (crystallized from Et2O/hexane): yield 81%; mp 157-
159 °C; MS (FD) 408 (M+); optical rotation at 589 nm +13.9°
(MeOH) Anal. (C23H24N2O5) C, H, N.
2-[[3-(2-Am in o-1,2-dioxoeth yl)-2-eth yl-1-(ph en ylm eth yl)-
1H -in d ol-4-yl]oxy]a cet a m id e (5a a ) (crude product fil-
tered): yield 70%; mp >230 °C; 1H NMR (DMSO-d6) ∂ 8.07
(br s, 1H), 7.70 (br s, 1H), 7.51 (br s, 1H), 7.39 (br s, 1H), 7.36-

5170 J ournal of Medicinal Chemistry, 1996, Vol. 39, No. 26
Draheim et al.
7.08 (m, 5H), 7.03 (d, 2H), 6.54 (dd, 1H), 5.55 (s, 2H), 4.47 (s,
2H), 2.94 (q, 2H), 1.08 (t, 3H); MS (FD+) 394 (M+). Anal.
(C21H21N3O4) C, H, N.
2-[[3-(2-Am in o-1,2-d ioxoet h yl)-1-([1,1′-b ip h en yl]-3-yl-
m eth yl)-2-m eth yl-1H-in d ol-4-yl]oxy]a cetic Acid (6e). A
mixture of 956 mg (2.1 mmol) of 5b, 10 mL of 1 N NaOH, and
30 mL of MeOH was refluxed for 40 min, cooled, concentrated,
and stirred with EtOAc and water. Filtration afforded the
sodium salt of 6e: 403 mg (yield 41%); mp >250 °C; 1H NMR
(DMSO-d6) ∂ 8.47 (br s, 1H), 7.64-7.32 (m, 8H), 7.28 (br s,
1H), 7.07 (d, 1H), 7.01 (t, 1H), 6.90 (d, 1H), 6.48 (d, 1H), 5.56
(s, 2H), 4.16 (s, 2H), 2.52 (s, 3H); MS (FAB) 465.2 (M + Na +
1)+. Anal. (C26H21N2O5Na) C, H, N. The filtrate was acidified
and extracted with EtOAc. The organic phase was washed
with brine, dried over MgSO4, concentrated at reduced pres-
sure, and filtered to give 6e: 346 mg (yield 37%); mp 236-
238 °C: 1H NMR (DMSO-d6) ∂ 12.88 (br s, 1H), 7.77 (br s, 1H),
7.64-7.32 (m, 9H), 7.22 (d, 1H), 7.09 (t, 1H), 6.93 (d, 1H), 6.56
(d, 1H), 5.59 (s, 2H), 4.67 (s, 2H), 2.58 (s, 3H); MS (FD) 443
(M+). Anal. (C26H22N2O5) C, H, N.
2-[[3-(2-Am in o-1,2-dioxoeth yl)-2-eth yl-1-(ph en ylm eth yl)-
5-p r op yl-1H-in d ol-4-yl]oxy]a cetic Acid Eth yl Ester (5a b).
A mixture of 380 mg (0.85 mmol) of 5u , 0.2 g of 10% Pd/C, 50
mL of THF, and 50 mL of EtOH was stirred under 1 atm of
H2 for 6.5 h, filtered, and evaporated at reduced pressure. The
residue was chromatographed on silica gel, eluting with Et2O,
1
to give 5a b: 255 mg (yield 67%); mp 152-153 °C; H NMR
(CDCl3) ∂ 7.20-7.05 (m, 3H), 6.95-6.80 (m, 3H), 6.75 (d, 1H),
6.65 (br s, 1H), 6.15 (br s, 1H), 5.15 (s, 1H), 4.40 (s, 2H), 4.05
(q, 2H), 2.80 (q, 2H), 2.55 (t, 2H), 1.75-1.55 (m, 2H), 1.05 (t,
6H), 0.85 (t, 3H); MS (FD+) 420 (M+). Anal. (C26H30N2O5) C,
H, N.
4-[[3-(2-Am in o-1,2-dioxoeth yl)-2-eth yl-1-(ph en ylm eth yl)-
1H-in d ol-5-yl]oxy]bu ta n oic Acid ter t-Bu tyl Ester (5a c).
A solution of 4.1 g (23.4 mmol) of 2-ethyl-5-methoxyindole (1g)
in 200 mL of CH2Cl2 was stirred with 2.2 mL (25 mmol) of
oxalyl chloride for 10 min and then poured into 500 mL of THF
saturated with ammonia at 0-5 °C. The mixture was ex-
tracted with CH2Cl2/2-propanol (3:1). The organic layer was
washed with brine, dried over Na2SO4, and evaporated at
reduced pressure to give 3.0 g (yield 52%) of 3-(2-amino-1,2-
dioxoethyl)-2-ethyl-5-methoxy-1H-indole (7). This material
(12.2 mmol) was dissolved in 25 mL of THF and 125 mL of
DMSO and stirred with 520 mg of NaH (60% in mineral oil;
13 mmol) for 15 min, and then with 1.6 mL (13 mmol) of benzyl
bromide for 45 min. The solution was diluted with water and
extracted with EtOAc. The organic phase was washed with
water, dried over Na2SO4, and evaporated at reduced pressure.
The residue was chromatographed on silica gel, eluting with
a gradient of 0-4% MeOH/CH2Cl2, to give 1.6 g (yield 40%) of
3-(2-amino-1,2-dioxoethyl)-2-ethyl-5-methoxy-1-(phenylmethyl)-
1H-indole. A solution of 1.3 g (4.0 mmol) of this material in
100 mL of CH2Cl2 was stirred with 16 mL of 1 M BBr3/CH2Cl2
for 1.5 h. The mixture was decomposed with ice/water and
the organic layer washed with brine, dried over Na2SO4, and
evaporated at reduced pressure. The residue was chromato-
graphed on silica gel, eluting with a gradient of 1-3% MeOH/
CH2Cl2, to give 440 mg of 3-(2-amino-1,2-dioxoethyl)-2-ethyl-
5-hydroxy-1-(phenylmethyl)-1H-indole. A solution of 355 mg
(1.1 mmol) of this material in 10 mL of THF and 40 mL of
DMF was stirred with 50 mg of NaH (60% in mineral oil; 1.2
mmol) for 10 min, and then with 290 mg (1.3 mmol) of tert-
butyl 4-bromobutyrate for 5 h. The solution was 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 0-2% MeOH/CH2Cl2, to give
5a c: 460 mg (yield 90%); mp 101-104 °C: 1H NMR (CDCl3)
∂ 7.65 (d, 1H), 7.30-7.20 (m, 3H), 7.05-6.95 (m, 4H), 6.75 (dd,
1H), 6.50 (br s, 1H), 5.25 (s, 2H), 4.00 (t, 2H), 3.05 (q, 2H),
2.40 (t, 2H), 2.10-1.95 (m, 2H), 1.45 (s, 9H), 1.15 (t, 3H); MS
(FD+) 464 (M+). Anal. (C27H32N2O5) H, N; C: calcd, 69.81;
found, 70.54.
The following compounds were prepared using the above
procedure.
2-[[3-(2-Am in o-1,2-d ioxoeth yl)-2-m eth yl-1-(p h en ylm e-
th yl)-1H-in d ol-4-yl]oxy]a cetic a cid (6c): yield 69%; mp
1
218-220 °C; H NMR (DMSO-d6) ∂ 12.88 (br s, 1H), 7.75 (br
s, 1H), 7.43 (br s, 1H), 7.34-7.07 (m, 7H), 6.55 (d, 1H), 5.50
(s, 2H), 4.66 (s, 2H), 2.51 (s, 3H); MS (FD+) 366 (M+). Anal.
(C20H18N2O5) H; C: calcd, 65.57; found, 63.31; N: calcd, 7.65;
found, 6.91.
2-[[3-(2-Am in o-1,2-d ioxoet h yl)-1-[(1,1′-b ip h en yl)-2-yl-
m eth yl]-2-m eth yl-1H-in d ol-4-yl]oxy]a cetic a cid (6d ) (so-
1
d iu m sa lt): yield 69%; mp >255 °C; H NMR (DMSO-d6) ∂
8.33 (br s, 1H), 7.66-7.21 (m, 9H), 6.97 (t, 1H), 6.76 (d, 1H),
6.46 (d, 1H), 6.40 (d, 1H), 5.33 (s, 2H), 4.16 (s, 2H), 2.32 (s,
3H); MS (FAB) 465.2 (M + Na + 1)+. Anal. (C26H21N2O5Na)
C, H, N.
6d : yield 15%; mp 228-231 °C; 1H NMR (DMSO-d6) ∂ 7.80
(br s, 1H), 7.72-7.25 (m, 9H), 7.07 (t, 1H), 6.93 (d, 1H), 6.57
(d, 1H), 6.43 (d, 1H), 5.39 (s, 2H), 4.68 (s, 2H), 2.38 (s, 3H);
MS (FD+) 442 (M+). Anal. (C26H22N2O5) C, H, N.
2-[[3-(2-Am in o-1,2-d ioxoet h yl)-1-([1,1′-b ip h en yl]-4-yl-
m eth yl)-2-m eth yl-1H-in d ol-4-yl]oxy]a cetic a cid (6f) (so-
1
d iu m sa lt): yield 74%; mp >250 °C; H NMR (DMSO-d6) ∂
8.40 (br s, 1H), 7.66-7.32 (m, 7H), 7.28 (br s, 1H), 7.14 (d,
1H), 7.08-6.98 (m, 2H), 6.48 (dd, 1H), 5.52 (s, 2H), 4.17 (s,
2H), 2.47 (s, 3H); MS (FAB) 465.2 (M + Na + 1)+. Anal.
(C26H21N2O5Na) C, H, N.
6f: yield 4%; mp 228-232 °C; 1H NMR (DMSO-d6) ∂ 12.90
(br s, 1H), 7.78 (br s, 1H), 7.66-7.06 (m, 12H), 6.56 (d, 1H),
5.56 (s, 2H), 4.67 (s, 2H), 2.56 (s, 3H); MS (FD) 443 (M+). Anal.
(C26H22N2O5) C, H, N.
2-[[3-(2-Am in o-1,2-d ioxoeth yl)-1-[(4-flu or op h en yl)m e-
th yl]-2-m eth yl-1H-in d ol-4-yl]oxy]a cetic a cid (6g): yield
81%; mp 244-247 °C; 1H NMR (DMSO-d6) ∂ 12.88 (br s, 1H),
7.75 (br s, 1H), 7.43 (br s, 1H), 7.20-7.04 (m, 6H), 6.55 (d,
1H), 5.50 (s, 2H), 4.66 (s, 2H), 2.49 (s, 3H); MS (FD) 384 (M+).
Anal. (C20H17FN2O5) C, H, N.
2-[[3-(2-Am in o-1,2-d ioxoeth yl)-1-[(2,6-d ich lor op h en yl)-
m eth yl]-2-m eth yl-1H-in dol-4-yl]oxy]acetic acid (6h ): yield
86%; mp 236-239 °C; 1H NMR (DMSO-d6) ∂ 12.90 (br s, 1H),
7.74 (br s, 1H), 7.60-7.40 (m, 4H), 7.00 (t, 1H), 6.81 (d, 1H),
6.51 (d, 1H), 5.72 (s, 2H), 4.65 (s, 2H), 2.50 (s, 3H); MS (FD+)
434 (M - 1, 100), 436 (M + 1, 70). Anal. (C20H16Cl2N2O5) C,
H, N.
2-[[3-(2-Am in o-1,2-d ioxoet h yl)-1-(p h en ylsu lfon yl)-2-
eth yl-1H-in dol-4-yl]oxy]acetic acid ter t-Bu tyl Ester (5ad).
A solution of 148 mg (0.33 mmol) of 5q, 2 mL of 1 N NaOH,
and 9 mL of MeOH was stirred at room temperature for 2 min
and then diluted with EtOAc and water. The organic phase
was washed with brine, dried over MgSO4, evaporated at
reduced pressure, and then crystallized from MeOH to give
91 mg (yield 80%) of 8. This material (82 mg, 0.24 mmol) was
dissolved in 5 mL of DMF, treated with 10 mg (0.24 mmol) of
60% NaH/mineral oil, and stirred for 1.5 h. Benzenesulfonyl
chloride (0.3 mL, 0.24 mmol) was added, and the solution was
stirred for 20 h. The solution was diluted with water and
extracted with EtOAc. The organic phase was washed with
brine, dried over MgSO4, evaporated at reduced pressure, and
then chromatographed on silica gel, eluting with 50% EtOAc/
hexane and then 66% EtOAc/hexane, to give 35 mg (yield 30%)
of 5a d : 1H NMR (CDCl3) ∂ 7.88-7.80 (m, 3H), 7.58 (t, 1H),
7.48 (t, 2H), 7.23 (t, 1H), 6.80 (br s, 1H), 6.58 (d, 1H), 5.72 (br
s, 1H), 4.51 (s, 2H), 3.09 (q, 2H), 1.44 (s, 9H), 1.35 (t, 3H); MS
(FD+) 486 (M+).
2-[[3-(2-Am in o-1,2-d ioxoeth yl)-2-m eth yl-1-[(1-n a p h th -
yl)m eth yl]-1H-in d ol-4-yl]oxy]a cetic a cid (6i): yield 75%;
1
mp 233-235 °C; H NMR (DMSO-d6) ∂ 12.92 (br s, 1H), 8.32
(d, 1H), 8.02 (d, 1H), 7.85 (d, 1H), 7.80 (br s, 1H), 7.74-7.60
(m, 2H), 7.48 (br s, 1H), 7.32 (t, 1H), 7.02 (d, 2H), 6.57 (t, 1H),
6.25 (d, 1H), 6.00 (s, 2H), 4.69 (s, 2H), 2.46 (s, 3H); MS (FD+)
416 (M+). Anal. (C24H20N2O5) C, H, N.
2-[[3-(2-Am in o-1,2-d ioxoeth yl)-1-[(2-ch lor op h en yl)m e-
th yl]-2-m eth yl-1H-in d ol-4-yl]oxy]a cetic a cid (6j): yield
79%; mp 223-226 °C; 1H NMR (DMSO-d6) ∂ 12.90 (br s, 1H),
7.77 (br s, 1H), 7.56 (d, 1H), 7.45 (br s, 1H), 7.32 (t, 1H), 7.21
(t, 1H), 7.10-7.00 (m, 2H), 6.56 (d, 1H), 6.32 (d, 1H), 5.54 (s,
2H), 4.66 (s, 2H), 2.46 (s, 3H); MS (FD+) 400 (M - 1, 100), 402
(M + 1, 35). Anal. (C20H17ClN2O5) C, H, N.
2-[[3-(2-Am in o-1,2-dioxoeth yl)-2-m eth yl-1-[(2-m eth ylph e-
n yl)m eth yl]-1H-in d ol-4-yl]oxy]a cetic a cid (6k ): yield 57%;

Indole Inhibitors of hnps-PLA2. 3
J ournal of Medicinal Chemistry, 1996, Vol. 39, No. 26 5171
1
mp 235-238 °C; H NMR (DMSO-d6) ∂ 12.90 (br s, 1H), 7.77
yield 28%; mp 205-208 °C; 1H NMR (DMSO-d6) ∂ 12.08 (br s,
1H), 7.77 (br s, 1H), 7.60-7.20 (m, 9H), 7.04 (t, 1H), 6.85 (d,
1H), 6.64 (d, 1H), 6.40 (d, 1H), 5.34 (s, 2H), 4.04 (t, 2H), 2.41
(t, 2H), 2.32 (s, 3H), 2.06-1.95 (m, 2H); MS (FD) 468 (M+).
Anal. (C28H26N2O5) C, H, N.
(br s, 1H), 7.45 (br s, 1H), 7.25 (d, 1H), 7.15 (t, 1H), 7.10-6.97
(m, 3H), 6.56 (dd, 1H), 6.06 (d, 1H), 5.45 (s, 2H), 4.68 (s, 2H),
2.44 (s, 6H); MS (FD+) 380 (M+). Anal. (C21H20N2O5) C, H,
N.
2-[[3-(2-Am in o-1,2-d ioxoeth yl)-2-m eth yl-1-n -octyl-1H-
in d ol-4-yl]oxy]a cetic a cid (6l): yield 82%; mp 195-196 °C;
1H NMR (DMSO-d6) ∂ 7.74 (br s, 1H), 7.41 (br s, 1H), 7.22-
7.08 (m, 2H), 6.56 (d, 1H), 4.66 (s, 2H), 4.18 (t, 2H), 2.57 (s,
3H), 1.75-1.62 (m, 2H), 1,41-1.18 (m, 10H), 0.84 (t, 3H); MS
(FD+) 388 (M+). Anal. (C21H28N2O5) C, H, N.
2-[[3-(2-Am in o-1,2-dioxoeth yl)-2-eth yl-1-(ph en ylm eth yl)-
1H-in d ol-4-yl]oxy]-2-m eth ylp r op ion ic a cid (6w ): yield
13%; mp 114-116 °C; 1H NMR (DMSO-d6) ∂ 12.87 (br s, 1H),
7.86 (br s, 1H), 7.56 (br s, 1H), 7.36-6.96 (m, 7H), 7.32 (dd,
1H), 5.50 (s, 2H), 2.82 (q, 2H), 1.61 (s, 6H), 1.07 (t, 3H); MS
(FD+) 408 (M+). Anal. (C23H24N2O5) C, H, N.
2-[[3-(2-Am in o-1,2-dioxoeth yl)-2-eth yl-1-(ph en ylm eth yl)-
1H-in d ol-4-yl]oxy]a cetic a cid (6m ): yield 74%; mp 230-
d l-2-[[3-(2-Am in o-1,2-d ioxoe t h yl)-2-e t h yl-1-(p h e n yl-
m eth yl)-1H-in d ol-4-yl]oxy]-4-p h en ylbu ta n oic a cid (6x):
yield 51%; mp 180-182 °C; 1H NMR (DMSO-d6) ∂ 12.70 (br s,
1H), 8.04 (br s, 1H), 7.64 (br s, 1H), 7.37-7.00 (m, 7H), 6.40
(d, 1H), 5.53 (s, 2H), 4.65 (dd, 1H), 3.96-3.78 (m, 4H), 2.40-
2.36 (m, 1H), 2.20-2.04 (m, 1H), 1.10 (t, 3H); MS (FD) 484
(M+). Anal. (C29H28N2O5) C, H, N.
d l-2-[[3-(2-Am in o-1,2-d ioxoeth yl)-2-m eth yl-1-(p h en yl-
m eth yl)-1H-in d ol-4-yl]oxy]p r op ion ic a cid ((d l)-6y): yield
50%; mp 201-204 °C; 1H NMR (DMSO-d6) ∂ 12.72 (br s, 1H),
7.89 (br s, 1H), 7.53 (br s, 1H), 7.36-7.00 (m, 7H), 6.44 (d,
1H), 5.50 (s, 2H), 4.84 (q, 1H), 2.48 (s, 3H), 1.37 (d, 3H); MS
(FD) 380 (M+). Anal. (C21H20N2O5) H, N; C: calcd, 66.31;
found, 65.63.
d l-2-[[3-(2-Am in o-1,2-d ioxoe t h yl)-2-e t h yl-1-(p h e n yl-
m eth yl)-1H-in d ol-4-yl]oxy]p r op ion ic a cid ((d l)-6z): yield
56%; mp 185-187 °C; 1H NMR (DMSO-d6) ∂ 12.73 (br s, 1H),
7.90 (br s, 1H), 7.52 (br s, 1H), 7.38-7.00 (m, 7H), 6.48-6.40
(m, 1H), 5.51 (s, 2H), 4.84 (q, 1H), 2.96-2.80 (m, 2H), 1.58 (d,
3H), 1.08 (t, 3H); MS (FD+) 394 (M+). Anal. (C22H22N2O5) C,
H, N.
2-[[3-(2-Am in o-1,2-dioxoeth yl)-2-eth yl-1-(ph en ylm eth yl)-
5-p r op yl-1H-in d ol-4-yl]oxy]a cetic a cid (6a b): yield 56%;
mp 138 °C; MS (FD+) 422 (M+). Anal. (C24H26N2O5‚1.2 H2O)
C, H, N.
4-[[3-(2-Am in o-1,2-d ioxoeth yl)-1-(p h en ylm eth yl)-1H-in -
d ol-5-yl]oxy]bu ta n oic Acid (6a ). A solution of 450 mg (1.1
mmol) of compound 5a in 50 mL of THF and 50 mL of 5 N
HCl was stirred for 16h. and then extracted with EtOAc. 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 2%MeOH/CH2Cl2, to give
recovered 5a , 110 mg, and then eluting with EtOAc to give
6a : 190 mg (yield 46%); mp 193-195 °C: 1H NMR (DMSO-
d6) ∂ 12.05 (br s, 1H), 8.80 (s, 1H), 8.05 (br s, 1H), 7.70 (d,
1H), 7.40 (d, 1H), 7.30-7.15 (m, 5H), 6.85 (dd, 1H), 5.70 (s, 1H),
5.45 (s, 2H), 3.95 (t, 2H), 2.35 (t, 2H), 1.95-1.85 (m, 2H); MS
(FD+) 380 (M+). Anal. (C21H20N2O5) H; C: calcd, 66.31; found,
60.82; N: calcd, 7.36; found, 6.64.
1
234 °C; H NMR (DMSO-d6) ∂ 7.80 (br s, 1H), 7.43 (br s, 1H),
7.38-7.00 (m, 7H), 6.55 (dd, 1H), 5.52 (s, 2H), 4.67 (s, 2H),
2.91 (q, 2H), 1.09 (t, 3H); MS (FD) 380 (M+). Anal.
(C21H20N2O5) C, H, N.
2-[[3-(2-Am in o-1,2-d ioxoet h yl)-1-([1,1′-b ip h en yl]-2-yl-
m eth yl)-2-eth yl-1H-in d ol-4-yl]oxy]a cetic a cid (6n ): yield
59%; mp 211-214 °C; 1H NMR (DMSO-d6) ∂ 12.90 (br s, 1H),
7.74 (br s, 1H), 7.58-7.46 (m, 5H), 7.41 (br s, 1H), 7.36-7.20
(m, 3H), 7.05 (t, 1H), 6.93 (d, 1H), 6.52 (dd, 1H), 5.37 (s, 2H),
4.65 (s, 2H), 2.71 (q, 2H), 0.93 (t, 3H); MS (FD) 456 (M+). Anal.
(C27H24N2O5) C, H, N.
2-[[3-(2-Am in o-1,2-d ioxoet h yl)-2-et h yl-1-[(2-(p h en yl-
m et h yl)p h en yl]m et h yl]-1H -in d ol-4-yl]oxy]a cet ic a cid
(6o): yield 86%; mp 245-246 °C; 1H NMR (DMSO-d6) ∂ 12.92
(br s, 1H), 7.75 (br s, 1H), 7.46-7.20 (m, 8H), 7.07 (t, 1H), 6.98
(t, 1H), 6.67 (d, 1H), 6.52 (d, 1H), 6.04 (d, 1H), 5.37 (s, 2H),
4.67 (s, 2H), 4.24 (s, 2H), 2.60 (q, 2H), 0.90 (t, 3H); MS (FD+)
470 (M+). Anal. (C28H26N2O5) C, H, N.
2-[[3-(2-Am in o-1,2-d ioxoeth yl)-1-[(3-ch lor op h en yl)m e-
th yl]-2-eth yl-1H-in d ol-4-yl]oxy]a cetic a cid (6p ) (sod iu m
1
sa lt): yield 61%; mp >250 °C; H NMR (DMSO-d6) ∂ 8.51 (br
s, 1H), 7.37-7.30 (m, 2H), 7.27 (br s, 1H), 7.14 (s, 1H), 7.05-
6.85 (m, 3H), 6.48 (d, 1H), 5.51 (s, 2H), 4.14 (s, 2H), 4.84 (q,
2H), 1.06 (t, 3H); MS (FAB) 437.1 (M + Na)+. Anal. (C21H18
-
ClN2O5Na) Calcd. C, 57.74; H, 4.15; N, 6.41. Found: C, 58.36;
H, 4.61; N, 5.57.
6p : yield 14%; mp 210-213 °C; 1H NMR (DMSO-d6) ∂ 12.90
(br s, 1H), 7.77 (br s, 1H), 7.44 (br s, 1H), 7.36-7.32 (m, 2H),
7.26 (s, 1H), 7.09 (d, 2H), 6.94-6.87 (m, 1H), 6.56 (t, 1H), 5.55
(s, 2H), 4.69 (s, 2H), 2.90 (q, 2H), 1.67 (t, 3H); MS (FD+) 414
(M - 1, 100), 416 (M + 1, 30). Anal. (C21H19ClN2O5) C, H, N.
2-[[3-(2-Am in o-1,2-d ioxoeth yl)-1-ben zoyl-2-eth yl-1H-in -
d ol-4-yl]oxy]a cetic a cid (6q): yield 63%; mp 194-196 °C;
1H NMR (DMSO-d6) ∂ 7.97 (br s, 1H), 7.86-7.61 (m, 6H), 7.01
(t, 1H), 6.64 (d, 1H), 6.34 (d, 1H), 4.70 (s, 2H), 2.82 (q, 2H),
1.17 (t, 3H); MS (FD+) 394 (M+). Anal. (C21H18N2O6) C, H,
N.
2-[[3-(2-Am in o-1,2-d ioxoet h yl)-1-([1,1′-b ip h en yl]-2-yl-
m eth yl)-2-p r op yl-1H-in d ol-4-yl]oxy]a cetic a cid (6r ): yield
88%; foam; H NMR (DMSO-d6) ∂ 12.87 (br s, 1H), 7.74 (br s,
1H), 7.60-7.45 (m, 4H), 7.41 (br s, 1H), 7.36-7.20 (m, 4H),
7.07 (t, 1H), 6.96 (d, 1H), 6.52 (t, 2H), 5.38 (s, 2H), 4.65 (s,
2H), 2.65 (br t, 2H), 1.32 (br q, 2H), 0.77 (t, 3H); MS (FD+)
470 (M+). Anal. (C28H26N2O5) H; C: calcd, 71.47; found, 69.58;
N: calcd, 5.95; found, 5.53.
2-[[3-(2-Am in o-1,2-d ioxoeth yl)-1-(p h en ylm eth yl)-1H-in -
d ol-5-yl]oxy]a cetic Acid (6b). A solution of 180 mg (0.44
mmol) of 5b in 30 mL of CH2Cl2 and 5 mL of TFA was stirred
for 1 h and evaporated at reduced pressure, and the residue
was crystallized with EtOH/Et2O to give 6b: 155 mg (yield
100); mp 225-227 °C; MS (FD) 352 (M+). Anal. (C19H16N2O5)
C, H, N.
1
The following compounds were prepared utilizing the above
procedure.
2-[[3-(2-Am in o-1,2-d ioxoet h yl)-2-cyclop r op yl-1-(p h e-
n ylm eth yl)-1H-in d ol-4-yl]oxy]a cetic a cid (6s): yield 80%;
4-[[3-(2-Am in o-1,2-dioxoeth yl)-2-eth yl-1-(ph en ylm eth yl)-
1H-in d ol-5-yl]oxy]bu ta n oic a cid (6a c): yield 64%; mp 173-
1
mp 246-249 °C; H NMR (DMSO-d6) ∂ 7.81 (br s, 1H), 7.51
1
(br s, 1H), 7.39-7.02 (m, 7H), 6.59-6.48 (m, 1H), 5.59 (s, 2H),
4.65 (s, 2H), 1.90-1.75 (m, 1H), 1.08-0.90 (m, 2H), 0.51-0.43
(m, 2H); MS (FD) 392 (M+). Anal. (C22H20N2O5) C, H, N.
2-[[3-(2-Am in o-1,2-d ioxoet h yl)-1-([1,1′-b ip h en yl]-2-yl-
175 °C; H NMR (DMSO-d6) ∂ 8.15 (s, 1H), 7.75 (s, 1H), 7.50
(d, 1H), 7.35 (d, 1H), 7.35-7.15 (m, 3H), 7.05-6.90 (m, 2H),
6.80 (dd, 1H), 5.45 (s, 2H), 3.95 (t, 2H), 3.00 (q, 2H), 2.35 (t,
2H), 2.05-1.85 (m, 2H), 1.05 (t, 3H); MS (FD+) 408 (M+). Anal.
(C23H24N2O5‚0.3H2O) C, H, N.
2-[[3-(2-Am in o-1,2-d ioxoet h yl)-1-(p h en ylsu lfon yl)-2-
eth yl-1H-in d ol-4-yl]oxy]a cetic a cid (6a d ): yield 40%; mp
202-204 °C; 1H NMR (DMSO-d6) ∂ 7.98 (d, 3H), 7.82-7.64
(m, 5H), 7.28 (t, 1H), 6.75 (d, 1H), 4.66 (s, 2H), 3.04 (q, 2H),
1.26 (t, 3H); MS (FD+) 430 (M+). Anal. (C20H18N2O7S) H, N;
C: calcd, 55.81; found, 56.96.
2-[[3-(2-Am in o-1,2-d ioxoet h yl)-2-et h yl-1H -in d ol-4-yl]-
oxy]a cetic a cid (6a e): yield 58%; mp 244-246 °C; 1H NMR
(DMSO-d6) ∂ 7.76 (br s, 1H), 7.40 (br s, 1H), 7.09-6.98 (m,
2H), 6.49 (dd, 1H), 4.64 (s, 2H), 2.89 (q, 2H), 1.26 (t, 3H); MS
(FD+) 290 (M+). Anal. (C14H14N2O5) C, H, N.
m et h yl)-2-cyclop r op yl-1H -in d ol-4-yl]oxy]a cet ic
a cid
1
(6t): yield 62%; mp 172-174 °C; H NMR (DMSO-d6) ∂ 7.76
(br s, 1H), 7.59-7.19 (m, 9H), 7.07 (t, 1H), 6.96 (d, 1H), 6.48
(t, 2H), 5.49 (s, 2H), 4.65 (s, 2H), 1.59-1.49 (m, 1H), 0.75-
0.66 (m, 2H), 0.33-0.25 (m, 2H); MS (FD) 468 (M+). Anal.
(C28H24N2O5) C, H, N.
2-[[3-(2-Am in o-1,2-d ioxoet h yl)-5-a llyl-2-et h yl-1-(p h e-
n ylm eth yl)-1H-in d ol-4-yl]oxy]a cetic a cid (6u ): yield 90%;
mp 165 °C; MS (FD+) 420 (M+). Anal. (C24H24N2O5) C, H; N:
calcd, 6.66; found 6.12.
4-[[3-(2-Am in o-1,2-d ioxoet h yl)-1-([1,1′-b ip h en yl]-2-yl-
m eth yl)-2-m eth yl-1H-in d ol-4-yl]oxy]bu ta n oic a cid (6v):

5172 J ournal of Medicinal Chemistry, 1996, Vol. 39, No. 26
Draheim et al.
P r ep a r a tion of (S)-N-((S)-2-br om op r op ion yl)-4-(p h e-
n ylm et h yl)-2-oxa zolid in on e (A) a n d (S)-N-((R )-2-b r o-
m op r op ion yl)-4-(p h en ylm eth yl)-2-oxa zolid in on e (B). To
1.8 g (10.2 mmol) of (S)-(-)-4-benzyl-2-oxazolidine in 150 mL
of THF at -75 °C was added 6.4 mL of n-butyllithium (1.6 M
in hexane; 1.2 mmol) and then 1.1 mL (10.5 mmol) of
2-bromopropionyl bromide. The solution was stirred for 20
min, diluted with EtOAc, and washed with an aqueous
NaHCO3 solution and brine, dried over Na2SO4, and evapo-
rated at reduced pressure. The residue was chromatographed
on silica gel, eluting with a gradient of 15-50% Et2O/hexane
to give 1.6 g (yield 50%) each of A and B.
(S)-N-[(R)-2-[[2-Met h yl-1-(p h en ylm et h yl)-1H -in d ol-4-
yl]oxy]p r op ion yl]-4-(p h e n ylm e t h yl)-2-oxa zolid in on e
((R,S)-9a ). To a solution of 455 mg (2 mmol) of 3c in 70 mL
of DMF was added 90 mg of NaH (60% in mineral oil; 2.2
mmol). The mixture was stirred for 5 min, and then 0.5 mL
(4.7 mmol) of A dissolved in 15 mL of THF was added. The
solution was stirred for 1 h and then diluted with EtOAc and
water. 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 20-
50% Et2O/hexane, to give 1.3 g (yield 100) of (R,S)-9a .
The following compounds were prepared by the procedure
above: (S,S)-9a from 3c and B; (R,S)-9b from 3m and A; and
(S,S)-9b from 3m and B.
(S)-2-[[3-(2-Am in o-1,2-d ioxoeth yl)-2-m eth yl-1-(p h en yl-
m eth yl)-1H-in d ol-4-yl]oxy]p r op ion ic a cid ((S)-6y): yield
38%; foam; MS (FD+) 380 (M+); optical rotation at 589 nm
+31.3° (MeOH, cloudy). Anal. (C21H20N2O5‚1.3H2O) C, H, N.
4-[[(Dim eth yla m in oth io)ca r bon yl]oxy]-2-eth yl-1-(p h e-
n ylm eth yl)-1H-in d ole (10). A solution of 1.0 g (4 mmol) of
3m in 20 mL of DMF was stirred with 180 mg of NaH (60% in
mineral oil; 4.5 mmol) for 30 min and then with 556 mg (4.5
mmol) of dimethylthiocarbonyl chloride for 17 h. The solution
was 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 chromato-
graphed on silica gel, eluting with 33% EtOAc/hexane, to give
10: 1.08 g (yield 80%); mp 127-130 °C: 1H NMR (DMSO-d6)
∂ 7.32-6.95 (m, 7H), 6.68 (d, 1H), 6.14 (s, 1H), 5.42 (s, 2H),
3.40 (d, 6H), 2.68 (q, 2H), 1.22 (t, 3H); MS (FD) 339 (M+). Anal.
(C20H22N2OS) H, N; C: calcd, 70.97; found, 71.89.
4-[[(Dim eth yla m in o)ca r bon yl]th io]-2-eth yl-1-(p h en yl-
m eth yl)-1H-in d ole (11). A mixture of 1.07 g (3.17 mmol) of
10 and 25 mL of diphenyl ether was refluxed for 24 h, cooled,
and chromatographed on silica gel, eluting with a gradient of
20% EtOAc/hexane and then 50% EtOAc/hexane, to give 11:
864 mg (yield 81%); mp 111-113 °C; 1H NMR (CDCl3) ∂ 7.31-
6.93 (m, 8H), 6.44 (s, 1H), 5.31 (s, 2H), 3.21 (br s, 3H), 3.06
(br s, 3H), 2.69 (q, 2H), 1.34 (t, 3H); MS (FD) 338 (M+). Anal.
(C20H22N2OS) C, H, N.
(S)-N-[(S)-2-[[2-Meth yl-1-(ph en ylm eth yl)-1H-in dol-4-yl]-
oxy]p r op ion yl]-4-(p h en ylm eth yl)-2-oxa zolid in on e ((S,S)-
9a ) (chromatography on silica gel, gradient, 20-50%
Et2O/hexane): yield 34%.
2-Eth yl-4-m er ca p to-1-(p h en ylm eth yl)-1H-in d ole (12). A
mixture of 850 mg (2.5 mmol) of 11, 30 mL of EtOH, and 10
mL of 5 N NaOH was refluxed for 3 h, cooled, 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 20% EtOAc/hexane, to give 12: 323 mg (yield
48%); oil: 1H NMR (CDCl3) ∂ 7.33-6.90 (m, 8H), 6.39 (s, 1H),
5.30 (s, 2H), 3.53 (s, 1H), 2.69 (q, 2H), 1.34 (t, 3H); MS (FD+)
267 (M+). Anal. (C17H17NS) C, H, N.
2-[[2-E t h yl-1-(p h en ylm et h yl)-1H -in d ol-4-yl]t h io]a ce-
tic Acid ter t-Bu tyl Ester (13). A solution of 439 mg (1.64
mmol) of 12 in 10 mL of DMF was saturated with nitrogen,
66 mg of NaH (60% in mineral oil; 1.64 mmol) was added, the
solution was stirred for 20 min, 0.26 mL (1.64 mmol) of tert-
butyl bromoacetate was added, and the mixture was stirred
an additional 1 h. The solution was diluted with water and
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 20% EtOAc/
hexane, to give 13: 476 mg (yield 76%); oil: 1H NMR (CDCl3)
∂ 7.33-6.92 (m, 8H), 6.53 (s, 1H), 5.31 (s, 2H), 3.66 (s, 2H),
2.66 (q, 2H), 1.34 (s, 9H), 1.32 (t, 3H); MS (FD) 382 (M+). Anal.
(C23H27NO2S) C, H, N.
2-[[3-(2-Am in o-1,2-dioxoeth yl)-2-eth yl-1-(ph en ylm eth yl)-
1H-in d ol-4-yl]th io]a cetic Acid ter t-Bu tyl Ester (14). To
a solution of 443 mg (1.16 mmol) of 13 in 10 mL of CH2Cl2
was added 0.17 mL (1.9 mmol) of oxalyl chloride. The solution
was stirred for 1 h, and then ammonia gas was bubbled into
the solution for 10 min. The solvent was evaporated at
reduced pressure, and the residue was diluted with EtOAc and
water. The organic phase was washed with brine, dried over
MgSO4, and evaporated at reduced pressure. The residue was
chromatographed on silica gel, eluting with 20% EtOAc/hexane
and then 50% EtOAc/hexane, to give 14: 477 mg (yield 91%):
1H NMR (CDCl3) ∂ 7.36-7.00 (m, 9H), 5.57 (br s, 1H), 5.38 (s,
2H), 3.50 (s, 2H), 2.86 (q, 2H), 1.27 (s, 9H), 1.21 (t, 3H); MS
(FD) 452 (M+). Anal. (C25H28N2O4S) C, H, N.
2-[[3-(2-Am in o-1,2-dioxoeth yl)-2-eth yl-1-(ph en ylm eth yl)-
1H-in d ol-4-yl]th io]a cetic Acid (15). To a solution of 454
mg (1.0 mmol) of 14 in 15 mL of CH2Cl2 was added 2 mL of
trifluoroacetic acid. This mixture was stirred for 1.5 h, the
solvent was evaporated at reduced pressure, and the residue
was diluted with EtOAc and water. The organic phase was
washed with brine, dried over MgSO4, and evaporated at
reduced pressure. The solid residue was stirred with CH2Cl2/
Et2O, filtered, and dried to give 15: 322 mg (yield 81%); mp
210-213 °C: 1H NMR (CDCl3) ∂ 12.60 (br s, 1H), 8.03 (br s,
1H), 7.68 (br s, 1H), 7.40-7.12 (m, 6H), 7.03 (d, 2H), 5.53 (s,
2H), 3.64 (s, 2H), 2.82 (q, 2H), 1.07 (t, 3H); MS (FD) 396 (M+).
Anal. (C21H20N2O4S) C, H, N.
(S)-N-[(R)-2-[(2-Eth yl-1-(p h en ylm eth yl)-1H-in d ol-4-yl)-
oxy]p r op ion yl]-4-(p h en ylm eth yl)-2-oxa zolid in on e ((R,S)-
9b ) (chromatography on silica gel, gradient, 20-50%
1
Et2O/hexane): yield 89%; foam; H NMR(CDCl3) ∂ 7.45-7.10
(m, 8H), 7.05-6.85 (m, 3H), 6.80 (d, 1H), 6.65 (s, 1H), 6.20 (d,
1H), 6.15 (q, 1H), 5.25 (s, 2H), 4.75-4.55 (m, 1H), 4.10 (q, 2H),
3.15 (dd, 1H), 2.75 (dd, 1H), 3.65 (q, 2H), 1.85 (d, 3H), 1.30 (t,
3H); MS (FD+) 482 (M+); optical rotation at 589 nm +16.6°
(MeOH). Anal. (C30H30N2O4) C, H, N.
(S)-N-[(S)-2-[[2-Eth yl-1-(p h en ylm eth yl)-1H-in d ol-4-yl]-
oxy]p r op ion yl]-4-(p h en ylm eth yl)-2-oxa zolid in on e ((S,S)-
9b ) (chromatography on silica gel, gradient, 20-50%
Et2O/hexane): yield 89%; foam; 1H NMR identical to that given
for (R,S)-9b; MS (FD+) 482 (M+); optical rotation at 589 nm
+63.2° (MeOH). Anal. (C30H30N2O4) C, H, N.
(S)-2-[[3-(2-Am in o-1,2-d ioxoet h yl)-2-et h yl-1-(p h en yl-
m eth yl)-1H-in d ol-4-yl]oxy]p r op ion ic Acid ((S)-6z). To a
solution of 480 mg (1.0 mmol) of (S,S)-9b in 15 mL of THF
was added a solution of 4 mmol of LiOCH2Ph (from n-BuLi
and PhCH2OH) in 70 mL of THF at -5 °C. The mixture was
stirred with cooling for 2.5 h and then diluted with EtOAc/
water. The organic phase was washed with brine, dried (Na2-
SO4), and evaporated at reduced pressure to give 365 mg (yield
90%) of (S)-2-[[2-ethyl-1-(phenylmethyl)-1H-indol-4-yl]oxy]pro-
pionic acid benzyl ester: 1H NMR (CDCl3) ∂ 7.40 (s, 1H), 7.35-
7.20 (m, 8H), 7.05-6.95 (m, 2H), 6.90 (d, 1H), 6.60 (s, 1H),
6.45 (d, 1H), 5.30 (s, 2H), 5.25 (s, 2H), 5.05 (q, 1H), 2.70 (q,
2H), 1.80 (d, 3H), 1.35 (t, 3H). This material (0.9 mmol) in 30
mL of CH2Cl2 was stirred for 30 min with 0.12 mL (1.4 mmol)
of oxalyl chloride. The solution was washed with brine, dried
(Na2SO4), and evaporated at reduced pressure to give the
indole-3-glyoxamide derivative, 380 mg (yield 87%), as an oil:
1H NMR (CDCl3) ∂ 7.35-7.15 (m, 8H), 7.05-6.90 (m, 3H), 6.80
(d, 1H), 6.70 (br d, 2H), 6.40 (d, 1H), 5.30 (s, 2H), 5.15 (s, 2H),
2.90 (m, 2H), 1.70 (d, 3H), 1.15 (t, 3H). This material (0.79
mmol), 0.2 g of 10% Pd/C, and 50 mL of EtOH were stirred
under 1 atm of H2 for 2.5 h, filtered, and evaporated at reduced
pressure to give (S)-6z: 200 mg (yield 65%); foam: MS (FD+)
394 (M+); optical rotation at 589 nm +49.5° (MeOH). Anal.
(C22H22N2O5) H, N; C: calcd, 66.99; found, 63.23.
The following compounds were prepared utilizing the above
procedure.
(R)-2-[[3-(2-Am in o-1,2-d ioxoeth yl)-2-m eth yl-1-(p h en yl-
m eth yl)-1H-in d ol-4-yl]oxy]p r op ion ic a cid ((R)-6y): yield
81%; mp 196-198 °C; MS (FD) 380 (M+); optical rotation at
589 nm -65.8° (MeOH, cloudy). Anal. (C21H20N2O5‚0.3H2O)
C, H, N.

Indole Inhibitors of hnps-PLA2. 3
J ournal of Medicinal Chemistry, 1996, Vol. 39, No. 26 5173
4-[[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]bu ta n oic Acid (17). A solution of 240
mg (0.53 mmol) of 16 in 20 mL of THF, 60 mL of EtOH, and
5 mL of 2 N NaOH was stirred for 2.5 h, acidified with 1 N
HCl, and extracted with EtOAc. The organic solution was
washed with brine, dried over Na2SO4, and evaporated at
reduced pressure. The residue was crystallized from CH2Cl2/
Et2O to give 17: 135 mg (yield 58%); mp 135-138 °C; MS
(FD+) 424 (M+). Anal. (C23H24N2O4S‚0.5H2O) C, H, N, S.
4-Am in o-2-eth yl-1-(p h en ylm eth yl)-1H-in d ole (19). To
a solution of 1.77 g (6.32 mmol) of 18 in 50 mL of EtOH was
added 175 mg of 5% Pt/C. The mixture was hydrogenated for
2 h at an initial pressure of 60 psi of hydrogen. The catalyst
was filtered, and the solvent was evaporated at reduced
pressure. The residue was chromatographed on silica gel,
eluting with 20% EtOAc/hexane, to give 19: 1.16 g (yield 73%);
1H NMR (CDCl3) ∂ 7.35-6.90 (m, 6H), 6.70 (d, 1H), 6.41 (d,
1H), 6.27 (s, 1H), 5.26 (s, 2H), 4.00 (br s, 2H), 2.66 (q, 2H),
1.31 (t, 3H); MS (FD) 250 (M+). Anal. (C17H18N2) C, H, N.
2-[[2-Eth yl-1-(p h en ylm eth yl)-1H-in d ol-4-yl]a m in o]a ce-
tic Acid Meth yl Ester (20a ). A mixture of 500 mg (2 mmol)
of 19, 840 mg (10 mmol) of NaHCO3, 5 mL of DMF, and 0.2
mL (2.1 mmol) of methyl bromoacetate was stirred for 16 h,
diluted with water, and extracted with EtOAc. The organic
phase was washed with brine, dried over MgSO4, and evapo-
rated at reduced pressure. The residue was chromatographed
on silica gel, eluting with 20% EtOAc/hexane, to give 20a : 416
mg (yield 65%); oil; 1H NMR (CDCl3) ∂ 7.41-6.90 (m, 6H), 6.70
(d, 1H), 6.33 (s, 1H), 6.19 (d, 1H), 5.26 (s, 2H), 4.71 (br s, 2H),
4.10 (s, 2H), 3.82 (s, 3H), 2.66 (q, 2H), 1.33 (t, 3H); MS (FD+)
322 (M+). Anal. (C20H22N2O2) C, H, N.
Compound 23 was obtained in 43% yield: 1H NMR (CDCl3) ∂
7.69 (d, 1H), 7.18-7.11 (m, 3H), 6.63 (dd, 2H), 6.56 (br s, 1H),
6.34 (s, 1H), 6.31 (d, 1H), 5.70 (s, 1H), 5.46 (s, 2H), 4.45 (s,
4H), 3.80 (s, 6H), 2.74 (q, 2H), 1.34 (t, 3H); MS (FD+) 465 (M+).
4-Am in o-3-(2-a m in o-1,2-d ioxoeth yl)-2-eth yl-1-(p h en yl-
m eth yl)-1H-in d ole (25). A mixture of 6.0 g (17.1 mmol) of
24, 1.0 g of 5% Pd/BaSO4, 70 mL of THF, and 70 mL of EtOH
was shaken under hydrogen at an initial pressure of 60 psi
for 4 h, filtered, and evaporated at reduced pressure. The
residue was chromatographed on silica gel, eluting with 50%
EtOAc/hexane to separate a mixture of 4-amino-2-ethyl-R-oxy-
1-(phenylmethyl)-1H-indole-3-acetamide; 1.28 g (yield 23%),
and 25, 1.66 g (yield 30%): 1H NMR (CDCl3) ∂ 7.33-7.25 (m,
3H), 7.00 (t, 3H), 6.66 (br s, 1H), 6.56 (d, 1H), 6.48 (d, 1H),
5.72 (br s, 1H), 5.33 (s, 2H), 5.21 (br s, 2H), 2.96 (q, 2H), 1.24
(t, 3H); MS (FD+) 321 (M+). Anal. (C19H19N3O2) H; C: calcd,
71.01; found, 68.50; N: calcd, 13.08; found, 11.88.
2-[[3-(2-Am in o-1,2-dioxoeth yl)-2-eth yl-1-(ph en ylm eth yl)-
1H-in d ol-4-yl]a m in o]a cetic Acid Meth yl Ester (26).
A
mixture of 250 mg (0.78 mmol) of 25, 327 mg (3.9 mmol) of
NaHCO3, 0.07 mL (0.78 mmol) of methyl bromoacetate, and 4
mL of DMF was heated at 60 °C for 1 h, stirred for an
additional 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 solid residue was
stirred with EtOAc, filtered, and dried to give 26: 185 mg
1
(yield 60%); oil; H NMR (CDCl3) ∂ 7.56 (br t, 1H), 7.33-7.25
(m, 2H), 7.08 (t, 1H), 7.00 (dd, 2H), 6.62 (br s, 1H), 6.55 (d,
1H), 6.23 (d, 1H), 5.60 (br s, 1H), 5.33 (s, 2H), 4.06 (d, 2H),
3.80 (s, 3H), 2.97 (q, 2H), 1.23 (t, 3H); MS (FD+) 393 (M+).
Anal. (C22H23N3O4) C, H, N.
2-[[3-(2-Am in o-1,2-dioxoeth yl)-2-eth yl-1-(ph en ylm eth yl)-
1H-in d ol-4-yl]a m in o]a cetic a cid (27). A solution of 190 mg
(0.48 mmol) of 26 and 5 mL of 1 N NaOH in 15 mL of MeOH
was heated at reflux for 20 min, stirred an additional 1 h,
diluted with water, acidified with 1 N HCl, and extracted with
EtOAc. The organic phase was washed with brine, dried over
MgSO4, and evaporated at reduced pressure. The residue was
3-[[2-Eth yl-1-(p h en ylm eth yl)-1H-in d ol-4-yl]a m in o]p r o-
p ion ic Acid Meth yl Ester (20b). A mixture of 500 mg (2
mmol) of 19, 1.5 mL (16.5 mmol) of methyl acrylate, and 5
mL of MeOH was stirred for 72 h and then evaporated at
reduced pressure. The residue was chromatographed on silica
gel, eluting with 20% EtOAc/hexane to separate 19 (317 mg;
63% recovered starting material) from 20b: 186 mg (yield
28%); oil: 1H NMR (CDCl3) ∂ 7.37-6.91 (m, 6H), 6.66 (d, 1H),
6.32 (d, 1H), 6.24 (s, 1H), 5.25 (s, 2H), 3.70 (s, 3H), 3.63 (t,
2H), 2.74 (t, 2H), 2.66 (q, 2H), 1.31 (t, 3H); MS (FD+) 336 (M+).
Anal. (C21H24N2O2) H, N; C: calcd,74.97; found, 72.31.
N-[(Met h oxyca r b on yl)m et h yl]-2-[[2-et h yl-1-(p h en yl-
m et h yl)-1H-in d ol-4-yl]a m in o]a cet ic Acid Met h yl E st er
(21). A mixture of 119 mg (0.48 mmol) of 19, 201 mg (2.4
mmol) of NaHCO3, 5 mL of DMF, and 0.11 mL (1.2 mmol) of
methyl bromoacetate was stirred for 72 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 20% EtOAc/hexane, to give 21: 124 mg (yield
66%); oil; 1H NMR (CDCl3) ∂ 7.31-7.02 (m, 6H), 6.82 (d, 1H),
6.47 (d, 1H), 6.26 (s, 1H), 5.26 (s, 2H), 4.40 (s, 4H), 3.77 (s,
6H), 2.66 (q, 2H), 1.31 (t, 3H); MS (FD) 394 (M+).
2,3-Dioxo-7-eth yl-1-[(m eth oxycar bon yl)m eth yl]-6-(ph e-
n ylm eth yl)ben zo[1,2-b:3′,4′-b′]d ip yr r ole (22). To a solution
of 410 mg (1.27 mmol) of 20a in 10 mL of CH2Cl2 was added
0.11 mL (1.27 mmol) of oxalyl chloride. The solution was
stirred for 2.5 h, ammonia gas was bubbled into the solution
for 15 min, and then the reaction mixture was stirred an
additional 15 min. The solvent was evaporated at reduced
pressure, and the residue was diluted with EtOAc and water.
The organic phase was washed with brine, dried over MgSO4,
and evaporated at reduced pressure. The residue was chro-
matographed on silica gel, eluting with 20% EtOAc/hexane,
to give 22: 161 mg (yield 32%): 1H NMR (CDCl3) ∂ 7.39 (d,
1H), 7.30 (t, 1H), 6.96 (dd, 1H), 6.83 (d, 1H), 6.25 (s, 1H), 5.27
(s, 2H), 4.80 (s, 2H), 3.80 (s, 3H), 2.66 (q, 2H), 1.32 (t, 3H);
MS (FD+) 376 (M+). Anal. (C22H20N2O4) C, H, N.
1
crystallized from MeOH to give 96 mg (yield 53%) of 27; H
NMR (DMSO-d6) ∂ 8.25 (br s, 1H), 7.79 (br s, 1H), 7.35-6.94
(m, 6H), 6.63 (d, 1H), 6.52 (d, 1H), 5.49 (s, 2H), 3.93 (s, 2H),
3.00 (q, 2H), 1.11 (t, 3H); MS (FAB) 380.2 (M+). Anal.
(C21H21N3O4) C, H, N.
N-(2-Am in o-1,2-d ioxoeth yl)-2-[[3-(2-a m in o-1,2-d ioxoet-
h yl)-2-eth yl-1-(p h en ylm eth yl)-1H-in d ol-4-yl]a m in o]a ce-
tic Acid Meth yl Ester (28). To a solution of 140 mg (0.36
mmol) of 26 in 5 mL of CH2Cl2 was added 0.03 mL (0.36 mmol)
of oxalyl chloride. The solution was stirred for 19 h, ammonia
gas was bubbled into the solution for 15 min, and then the
reaction mixture was stirred for an additional 1 h. The solvent
was evaporated at reduced pressure, and the residue was
chromatographed on silica gel, eluting with EtOAc, to give
28: 61 mg (yield 38%); 1H NMR (CDCl3) ∂ 7.49-6.96 (m, 10H),
6.20 (br s, 1H), 5.59 (br s, 1H), 5.40 (s, 2H), 4.89 (d, 1H), 3.78
(d, 1H), 3.70 (s, 3H), 3.08-2.86 (m, 2H), 1.33-1.19 (m, 3H);
MS (FD+) 464 (M+).
N-Acet yl-2-[[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 Meth yl Ester (29a ). A solution of 137
mg (0.43 mmol) of 20a and 0.5 mL of acetic anhydride in 10
mL of CH2Cl2 was stirred for 1 h. The solvent was evaporated
at reduced pressure, and the residue was diluted with EtOAc/
water. The organic phase was washed with brine, dried
(MgSO4), and evaporated at reduced pressure. The residue
was chromatographed on silica gel, eluting with 50% EtOAc/
hexane, to give 29a : 130 mg (yield 83%); MS (FD+) 364 (M+).
N-Acet yl-3-[[2-et h yl-1-(p h en ylm et h yl)-1H -in d ol-4-yl]-
a m in o]p r op ion ic Acid Meth yl Ester (29b). Using reaction
conditions identical to those above, 20b was reacted with acetic
anhydride to give a 92% yield of 29b: 1H NMR (CDCl3) ∂ 7.37-
6.84 (m, 8H), 6.24 (s, 1H), 5.32 (s, 2H), 4.33-4.23 (m, 1H),
4.03-3.90 (m, 1H), 3.58 (s, 3H), 2.75-2.63 (m, 4H), 1.84 (s,
3H), 1.33 (t, 3H); MS (FD+) 378 (M+).
N-[(Meth oxyca r bon yl)m eth yl]-2-[[7-(2-a m in o-1,2-d iox-
oet 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 Meth yl Ester (23). Using reaction conditions
identical to those above, 21 was reacted with oxalyl chloride
and then ammonia to give a mixture of 22 and 23, which were
separated by chromatography on silica gel, eluting with 20%
N-Acetyl-2-[[3-(2-a m in o-1,2-d ioxoeth yl)-2-eth yl-1-(p h e-
n ylm eth yl)-1H-in d ol-4-yl]a m in o]a cetic Acid Meth yl Es-
ter (30a ). To a solution of 130 mg (0.36 mmol) of 29a in 2
mL of CH2Cl2 was added 0.16 mL (1.8 mmol) of oxalyl chloride.
The solution was stirred for 4 h, and ammonia gas was bubbled
1
EtOAc/hexane, then 50% EtOAc/hexane, and then EtOAc. H
NMRdata of compound 22 is identical to that given above.

5174 J ournal of Medicinal Chemistry, 1996, Vol. 39, No. 26
Draheim et al.
into the solution for 30 min. The solvent was evaporated, and
the residue was diluted with EtOAc and water. The organic
phase was washed with brine, dried over MgSO4, and evapo-
rated at reduced pressure. The residue was chromatographed
on silica gel, eluting with 50% EtOAc/hexane, to give 30a : 90
2H), 6.85 (s, 1H), 4.45 (d, 1H), 4.25 (d, 1H), 3.90-3.75 (m, 1H),
3.30-3.20 (m, 1H), 2.75-2.65 (m, 1H), 1.35 (d, 3H).
3-[2-Meth yl-1-(p h en ylm eth yl)in d olin -4-yl]a cr ylic Acid
Meth yl Ester (35). A solution of 1.3 g (5.3 mmol) of 34a and
2.0 g (6 mmol) of methyl (triphenylphosphoranylidene)acetate
in 100 mL of THF was refluxed for 19h, cooled, diluted with
EtOAc, washed with water, washed with brine, dried over Na2-
SO4, and evaporated at reduced pressure. The residue was
chromatographed on silica gel, eluting with a gradient of
2-10% Et2O/hexane to give 35: 1.1 g (yield 69%); oil; 1H NMR
(CDCl3) ∂ 7.75 (d, 1H), 7.40-7.25 (m, 5H), 7.05 (t, 1H), 6.90
(d, 1H), 6.40 (d, 1H), 6.35 (d, 1H), 4.45 (d, 1H), 4.25 (d, 1H),
3.85 (s, 3H), 3.85-3.75 (m, 1H), 3.45-3.35 (m, 1H), 2.85-2.75
(m, 1H), 1.35 (d, 3H).
3-[2-Meth yl-1-(ph en ylm eth yl)-1H-in dol-4-yl]acr ylic Acid
Meth yl Ester (36). A solution of 465 mg (1.5 mmol) of 35
and 410 mg (1.8 mmol) of dichlorodicyanoquinone in 50 mL of
dioxane was heated at 85 °C for 15 min, cooled, poured into
aqueous NaHCO3, and extracted with EtOAc. The organic
phase was washed with brine, dried over Na2SO4, and evapo-
rated at reduced pressure. The residue was chromatographed
on silica gel, eluting with a gradient of 15-20% Et2O/hexane
to give the indole 36: 320 mg (yield 69%); oil; 1H NMR (CDCl3)
∂ 8.20 (d, 1H), 7.35 (d, 1H), 7.30-7.15 (m, 4H), 7.10 (d, 1H),
7.00 (d, 2H), 6.70 (s, 1H), 6.65 (d, 1H), 5.25 (s, 2H), 3.85 (s,
3H), 2.40 (s, 3H).
1
mg (yield 57%); foam; H NMR (CDCl3) ∂ 7.43-7.16 (m, 6H),
7.05 (d, 2H), 6.73 (br s, 1H), 5.57 (br s, 1H), 5.40 (s, 2H), 4.90
(d, 1H), 3.72 (s, 3H), 2.93 (q, 2H), 1.98 (s, 3H), 1.25 (t, 3H);
MS (FD+) 435 (M+).
N-Acetyl-3-[[3-(2-a m in o-1,2-d ioxoeth yl)-2-eth yl-1-(p h e-
n ylm eth yl)-1H-in d ol-4-yl]a m in o]p r op ion ic Acid Meth yl
Ester (30b). Using reaction conditions identical to those
above, 29b was reacted with oxalyl chloride and then ammonia
to give a 27% yield of 30b: 1H NMR (CDCl3) ∂ 7.39-7.14 (m,
5H), 7.07 (d, 2H), 6.96 (d, 1H), 6.80 (br s, 1H), 5.75 (br s, 1H),
5.40 (s, 2H), 4.59-4.49 (m, 1H), 3.56 (s, 3H), 3.24-3.12 (m,
1H), 3.07-2.86 (m, 2H), 2.71-2.59 (m, 1H), 2.48-2.34 (m, 1H),
2.00 (s, 3H), 1.25 (t, 3H); MS (FD+) 449 (M+).
N-Acetyl-2-[[3-(2-a m in o-1,2-d ioxoeth yl)-2-eth yl-1-(p h e-
n ylm eth yl)-1H-in d ol-4-yl]a m in o]a cetic Acid (31a ). A so-
lution of 85 mg (0.2 mmol) of 30a and 1 mL of 1 N NaOH in
5 mL of MeOH was stirred for 1.5 h, diluted with water,
acidified with 1 N HCl, and extracted with EtOAc. The organic
phase was washed with brine, dried over MgSO4, and evapo-
rated at reduced pressure. The residue was dissolved in
MeOH, and insoluble material was filtered off. The filtrate
contained 34 mg (yield 40%) of 31a : 1H NMR (CDCl3) ∂ 7.48-
6.82 (m, 10H), 5.40 (s, 2H), 4.89 (d, 1H), 3.80 (d, 1H), 2.94 (q,
2H), 1.96 (s, 3H), 1.23 (t, 3H); MS (FD+) 421 (M+). Anal.
(C23H23N3O5) H; C: calcd, 65.49; found 64.66; N: calcd, 9.97;
found, 9.19.
N-Acetyl-3-[[3-(2-a m in o-1,2-d ioxoeth yl)-2-eth yl-1-(p h e-
n ylm eth yl)-1H-in d ol-4-yl]a m in o]p r op ion ic Acid (31b).
Using reaction conditions identical to those above, 30b was
hydrolyzed to give a 73% yield of 31b: 1H NMR (CDCl3) ∂
7.36-7.12 (m, 6H), 7.06 (d, 2H), 6.98 (d, 1H), 6.44 (br s, 1H),
5.39 (s, 2H), 4.51-4.47 (m, 1H), 3.25-3.15 (m, 1H), 3.02-2.85
(m, 2H), 2.74-2.59 (m, 1H), 2.49-2.34 (m, 1H), 1.98 (s, 3H),
1.23 (t, 3H); MS (FD+) 435 (M+). Anal. (C24H25N3O5) H, N;
C: calcd, 66.19; found, 61.01.
4-F or m yl-2-m eth yl-1-(p h en ylm eth yl)in d olin e (34a ). To
150 mL of H2SO4 cooled in ice/water was added in portions 30
mL (0.23 mol) of 2-methylindoline, 32, followed by 37.4 g (0.12
mol) of Ag2SO4. The cooling bath was removed, and the
mixture was stirred to give a complete solution, cooled in ice/
water, and treated dropwise with 20 mL (0.21 mol) of bromine
at a temperature below 15 °C. After being left to stand at room
temperature overnight, it was poured on ice, made basic with
NaOH, and extracted with EtOAc. The organic phase was
washed with brine and dried (Na2SO4). The solvent was
evaporated, and the residue was chromatographed on silica
gel, eluting with a gradient of 20-50% Et2O/hexane to give
32 g of a mixture of 32, 4-bromo-2-methylindoline, and
6-bromo-2-methylindoline. This mixture was stirred with 50
g of K2CO3, 25 mL of benzyl bromide, and 200 mL of DMF,
heated at 85 °C for 5 h, then cooled, diluted with water, and
extracted with EtOAc. The organic phase was washed with
brine, dried (Na2SO4), and evaporated at reduced pressure. The
residue was chromatographed on silica gel, eluting with a
gradient of 5-10% Et2O/hexane to give 42.7 g of a mixture of
4-bromo-2-methyl-1-(phenylmethyl)indoline (33a) and 6-bromo-
2-methyl-1-(phenylmethyl)indoline (33b). This mixture (0.14
mol) was dissolved in 500 mL of THF, cooled to -75 °C, and
treated slowly with 100 mL of n-butyllithium (1.6 M in hexane;
0.16 mol) and then with 14 mL (0.18 mol) of DMF by rapid
dropwise addition. The cooling bath was removed and the
solution stirred for 2 h, diluted with water, and extracted with
EtOAc. The organic phase was washed with brine, dried (Na2-
SO4), and evaporated at reduced pressure. The residue was
chromatographed on silica gel, eluting with a gradient of
5-15% Et2O/hexane to give 4-formyl-2-methyl-1-(phenyl-
methyl)indoline (34a ) [1.33 g (yield 4%); oil; 1H NMR (CDCl3)
∂ 10.10 (s, 1H), 7.40-7.20 (m, 5H), 7.15 (t, 1H), 7.10 (d, 1H),
6.50 (d, 1H), 4.45 (d, 1H), 4.25 (d, 1H), 3.95-3.8 (m, 1H), 3.75-
3.65 (m, 1H), 3.05-2.95 (m, 1H), 1.35 (d, 3H)] and 6-formyl-
2-methyl-1-(phenylmethyl)indoline (34b): 16.6 g, 47%; oil; 1H
NMR (CDCl3) ∂ 9.85 (s, 1H), 7.40-7.20 (m, 5H), 7.20-7.10 (m,
3-[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-4-yl]a cr ylic Acid Meth yl Ester (37).
A
solution of 350 mg (1.1 mmol) of 36 in 50 mL of CH2Cl2 was
stirred with 0.11 mL (1.2 mmol) of oxalyl chloride for 45 min,
saturated with ammonia, washed with brine, dried over Na2-
SO4, and evaporated at reduced pressure. The residue was
chromatographed on silica gel, eluting with Et2O and then
EtOAc, to give 37 which crystallized when mixed with CDCl3:
325 mg (yield 73%); mp 181-183 °C: MS (FD) 377 (M + 1)+.
Anal. (C22H20N2O4‚0.2 CDCl3) C, H, N.
3-[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-4-yl]p r op ion ic Acid Meth yl Ester (38). A
mixture of 170 mg (0.56 mmol) of 36, 0.2 g of 10% Pd/C, 25
mL of THF, and 25 mL of MeOH was stirred under 1 atm of
H2 for 2.5 h, filtered, and evaporated at reduced pressure. The
residue was dissolved in 30 mL of CH2Cl2, stirred with 0.1 mL
of oxalyl chloride for 1 h, saturated with ammonia, washed
with brine, dried (Na2SO4), and evaporated at reduced pres-
sure. The residue was chromatographed on silica gel, eluting
with Et2O and then EtOAc, to give 38: 185 mg (yield 88%);
mp 147-149 °C; MS (FD) 379 (M + 1)+. Anal. (C22H22N2O4)
C, H, N.
3-[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-4-yl]a cr ylic Acid (39). A solution of 300 mg
(0.8 mmol) of 37 and 4 mL of 2 N NaOH in 10 mL of THF and
30 mL of EtOH was stirred for 15.5 h, acidified with 1 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 CDCl3 to give
39: 135 mg (yield 46%): MS (FD+) 362 (M+). Anal.
(C21H18N2O4‚0.35 CDCl3) C, H, N.
3-[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-4-yl]p r op ion ic Acid (40). Using reaction
conditions identical to those above, 38 was hydrolyzed to give
a 60% yield of 40: MS (FD+) 364 (M+). Anal. (C21H20N2O4‚0.2
CDCl3) C, H; N: calcd, 7.21; found, 6.72.
DOC/P C P h osp h olip a se A2 In h ibition Assa y. Aliquots
of 10 µL of test compound solutions in DMSO were added to
20 µL (10 ng) of enzyme in 25 mM Tris.HCl (pH 8) with 0.25
mg/mL BSA and 150 µL of assay buffer containing 50mM Tris
(pH 8), 0.2 M NaCl, 2 mM CaCl2, and 1 mg/mL fatty acid free
BSA (Sigma, no. A7030). To each tube was added 20 µL of a
freshly prepared, iced 10× concentrated stock solution of the
PC and bile salt, which had been sonicated and concocted such
that the final 200 µL reaction volume would contain 3 mM
DOC/1 mM total PC and approximately 100 000 cpm of [14C]-
PC. To prepare the lipid substrate, aliquots of labeled PC (1-
palmitoyl-2[14C]-oleoylphosphatidyl choline: Amersham, no.
CFA656) and 100 mM stock cold PC (Sigma, no. P3017) in
chloroform, and 100 mM DOC (sodium salt of deoxycholic
acid: Sigma, no. D6750) in ethanol were mixed, dried under

Indole Inhibitors of hnps-PLA2. 3
J ournal of Medicinal Chemistry, 1996, Vol. 39, No. 26 5175
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a N2 stream, and then reconstituted in 10 mM Tris with 0.2
mM NaCl, before sonicating for 10 min. The assay tubes were
incubated for 1 h in a 40 °C water bath. The reaction was
stopped with 1.5 mL of Doles 2-propanol/heptane/0.5 M H2-
SO4 at 40:10:1 (v/v) with 1 mg/mL palmitic acid. The mixtures
were then heated for 1 min at 60 °C before 1 mL of H2O and
1.25 mL of heptane were added and mixed thoroughly. After
the two phases were allowed to separate, the upper phase was
transferred to 1 mL of heptane containing 150 mg of dried
silica (100-200 mesh) and mixed again before centrifugation
for 5 min at 1500g. The supernatant was removed for
scintillation counting of the liberated [14C]oleic acid. The
degree of inhibition was compared to diluent controls, and the
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Ack n ow led gm en t. We would like to acknowledge
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J M960487F