Use of conformationally restricted benzamidines as arginine surrogates in the design of platelet GPIIb-IIIa receptor antagonists

Article abstract of DOI:10.1021/jm970020k

The use of 5,6-bicyclic amidines as arginine surrogates in the design of a novel class of potent platelet glycoprotein IIb-IIIa receptor (GPIIb-IIIa) antagonists is described. The additional conformational restriction offered by the bicyclic nucleus results in 20-400-fold increases in potency compared to the freely flexible, acyclic benzamidine counterpart. The design, synthesis, structure-activity relationships (SAR), and in vitro activity of this novel class of GPIIb-IIIa antagonists are presented.

Full text of DOI:10.1021/jm970020k

J . Med. Chem. 1997, 40, 2843-2857
2843
Use of Con for m a tion a lly Restr icted Ben za m id in es a s Ar gin in e Su r r oga tes in th e
Design of P la telet GP IIb-IIIa Recep tor An ta gon ists1
Daniel J . Sall,*,† Ann E. Arfsten,§ J olie A. Bastian,† Michael L. Denney,† Cathy S. Harms,†
J efferson R. McCowan,† J ohn M. Morin, J r.,† J ack W. Rose,§ Robert M. Scarborough,*,§ Mark S. Smyth,§
Suzane L. Um,† Barbara G. Utterback,† Robert T. Vasileff,† J ames H. Wikel,† Virginia L. Wyss,† and
J oseph A. J akubowski†
Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, Indiana 46285, and COR Therapeutics, Inc.,
South San Francisco, California 94080
Received J anuary 10, 1997X
The use of 5,6-bicyclic amidines as arginine surrogates in the design of a novel class of potent
platelet glycoprotein IIb-IIIa receptor (GPIIb-IIIa) antagonists is described. The additional
conformational restriction offered by the bicyclic nucleus results in 20-400-fold increases in
potency compared to the freely flexible, acyclic benzamidine counterpart. The design, synthesis,
structure-activity relationships (SAR), and in vitro activity of this novel class of GPIIb-IIIa
antagonists are presented.
In tr od u ction
The process of platelet aggregation,2 and its role in
the acute thrombotic events, that can result from
mechanical or natural rupture of atherosclerotic plaques
have been well characterized.3 Disruption of an arterial
atherosclerotic plaque, either spontaneously or following
balloon angioplasty, exposes collagen and von Wille-
brand factor (vWF) at the site of damage and promotes
platelet adhesion. As a consequence, the bound plate-
lets become activated and undergo conformational
changes that result in the activation of glycoprotein IIb-
IIIa (GPIIb-IIIa) receptors on the platelet surface.
GPIIb-IIIa binds plasma fibrinogen, which due to its
multivalent structure results in the cross-linking of
F igu r e 1. General structure of 5,6-bicyclic amidino acids (B)
as platelet GPIIb-IIIa receptor antagonists.
platelets and consequently in platelet aggregation. This
nuclear spacers connected to an acidic aspartate isostere
process of aggregation at the site of plaque rupture may
(Figure 1). We chose to investigate the potential utility
ultimately lead to arterial occlusion with the clinical
of amidine-substituted 5,6-bicyclic heterocycles as re-
sequela of myocardial infarction or stroke. In an
stricted benzamidine analogs. This analysis resulted
attempt to modulate aggressive aggregation processes
in a series of antagonists represented by general struc-
and thus identify therapies to prevent such vaso-
ture B in which a 5,6-bicyclic arginine isostere is
occlusive disorders, antagonists of the GPIIb-IIIa recep-
connected via an acyclic or cyclic nuclear linker to an
tor have been proposed as potential therapeutic agents.
acidic side chain (as the aspartate surrogate). In this
Early macromolecular approaches, including monoclonal
report, we describe in detail the design, synthesis,
structure-activity relationships (SAR), and pharmaco-
antibodies directed to GPIIb-IIIa4 as well as peptide-
based antagonists of the receptor,5 have shown great
logical properties of this novel series of potent GPIIb-
promise as acute parenteral antithrombotic agents.
IIIa antagonists.
More recently, the pharmaceutical strategy has focused
on the design of small molecule, orally active antago-
nists for the chronic and/or prophylactic treatment of
Ch em istr y
arterial thrombosis.
As direct comparators for the 5,6-bicyclic series, the
freely flexible, acyclic benzamidino acids 4a -c were
prepared according to the conditions outlined in Scheme
1. Alkylation of anilines la ,b or phenol 1c using tert-
butyl bromoacetate afforded esters 2a -c. Deprotection
(TFA) to the corresponding acids followed directly by
condensation with tert-butyl 7-aminoheptanoate gave
the nitrile amides 3a -c. Coupling reagents, such as
DCC and CDI, could be used in the coupling reaction;
however, the water soluble carbodiimide 1-[3-(dimethy-
lamino)propyl]-3-ethylcarbodiimide hydrochloride (EDC)
was commonly employed due to the ease of workup.
Using this reagent, the crude product was isolated in
sufficient homogeneity to allow purification by simple
recrystallization. Nitrile to amidine conversion en route
The binding of fibrinogen to GPIIb-IIIa is mediated
in part by receptor recognition of the tripeptide sequence
Arg-Gly-Asp (RGD).6 Accordingly, small molecules that
are able to mimic the RGD sequence can act as antago-
nists of fibrinogen binding, thereby blocking platelet
aggregation.7 A number of potent and selective peptide-
based and small molecule RGD mimics have been
reported that use benzamidines as an arginine sur-
rogate.8 These surrogates have generally been ap-
pended to a variety of acyclic, monocyclic, and bicyclic
* To whom correspondence should be addressed.
† Eli Lilly and Company.
§ COR Therapeutics, Inc.
X Abstract published in Advance ACS Abstracts, August 1, 1997.
S0022-2623(97)00020-4 CCC: $14.00 © 1997 American Chemical Society

2844 J ournal of Medicinal Chemistry, 1997, Vol. 40, No. 18
Sall et al.
Sch em e 1a
Sch em e 3a
a
Reagents: (a) phthalic anhydride; (b) (COCl)2, DMSO, TEA;
(c) alkyl phosphonate, KO-t-Bu or NaH; (d) 10% Pd/C, H2; (e)
NH2NH2.
a
Reagents: (a) tert-butyl bromoacetate, K2CO3; (b) TFA, anisole;
sponding acids which were either commercially avail-
able or prepared according to previously published
methods. During the preparation of nitrile amide 6h
(R2 ) tert-butyl), a variety of attempts were made to
couple acid 5 with the dipeptide side chain derived from
γ-amino-n-butyric acid and glycine. Unfortunately, only
poor yields of the coupled product (6h ) were realized,
necessitating the more linear approach of condensing
acid 5 with ethyl γ-amino-n-butyrate, subsequent sa-
ponification of the ester, and coupling of the resulting
acid with glycine tert-butyl ester. Nitrile to amidine
conversion en route to products 7a -r again was ac-
complished using either Pinner conditions10 or the
thioamide/thioimidate route.9 Attempts to improve the
efficiency of the synthetic routes through the large scale
preparation of Boc- or Cbz-protected 5-amidinoindole-
2-carboxylate met with limited success due to poor yields
in the amidine-forming reaction.
(c) EDC, DMAP, DIEA, tert-butyl 7-aminoheptanoate; (d) H2S, pyr;
(e) MeI; (f) NH4OAc; (g) Boc2O, K2CO3; (h) TFA, anisole; (i) EtOH,
HCl gas; (j) NH3; (k) NaOH.
Sch em e 2
The syntheses of substituted side chains 13a -c and
18a -e, which were required for the preparation of
amidino acids 7k -m and 7n -r , respectively, are de-
picted in Schemes 3 and 4. The R-substituted deriva-
tives 13a -c were derived from 5-amino-1-pentanol (8;
Scheme 3) which was protected as the corresponding
phthalimide 9 and subsequently oxidized under Swern
conditions12 to afford the common aldehyde 10. Hor-
ner-Emmons reaction13 with the appropriate alkyl
phosphonates yielded the R,â-unsaturated esters 11a -c
as a mixture of geometrical isomers. The isomers were
not generally separated but were taken on directly.
Hydrogenation to the saturated esters 12a -c and
subsequent deprotection using hydrazine afforded amino
esters 13a -c which were condensed directly with acid
5 to give nitrile amides 7k -m (Scheme 2).
Amino ester side chains containing substituents at
the position â to the carboxylate (18a -e) were prepared
according to Scheme 4, beginning with commercially
available 5-aminovaleric acid (14). Protection of the
primary amine using benzyl chloroformate and subse-
quent derivatization of the carboxylate afforded the Cbz-
protected Weinreb amide 15,14 which was used as a
common intermediate. Treatment with the appropriate
commercially available Grignard or alkyllithium re-
agents afforded ketones 16a -e. In the case where R )
hexyl (16d ), it was necessary to generate the appropri-
ate Grignard reagent from 1-bromohexane. Condensa-
tion of ketones 16a -e with tert-butyl diethylphospho-
to products 4a -c was accomplished by one of two
methods. In the conversion of 3a ,c to amidino acids
4a ,c, respectively, the well-documented three-step pro-
cedure, which proceeds via the thioamide/thioimidate
intermediates, was employed.9 Attempts to convert
nitrile 3b to the corresponding thioamide using this
methodology were unsuccessful, necessitating the use
of Pinner conditions to effect nitrile to amidine conver-
sion.10 In either route, the intermediate amidino ester
products were protected as the N-Boc derivatives to
facilitate purification. Deprotection of the Boc-protected
amidino esters afforded the desired amidino acids
4a -c.
Preparation of the target molecules used to study the
SAR of the acidic side chain portion of structure B is
shown in Scheme 2. Indole acid (5),11 used as the
precursor to a common amidine-substituted 5,6-bicyclic
nucleus, was condensed with a variety of structurally
diverse amino ester side chains to afford the nitrile
amide derivatives 6a -r . In most cases, the required
amino ester side chains were derived from the corre-

Benzamidines for GPIIb-IIIa Receptor Antagonists
J ournal of Medicinal Chemistry, 1997, Vol. 40, No. 18 2845
Sch em e 4a
Sch em e 6a
a
Reagents: (a) NaOEt, diethyl oxalate; (b) Zn, HOAc; (c) NaOH.
Sch em e 7a
a
Reagents: (a) benzyl chloroformate, K2CO3; (b) isobutyl chlo-
roformate, NH(OMe)Me‚HCl, N-methylmorpholine; (c) RLi or
RMgBr; (d) tert-butyl diethylphosphonoacetate, KO-t-Bu; (e) 10%
Pd/C, H2.
Sch em e 5a
a
Reagents: (a) POCl3, DMF; (b) NaClO2, NaH2PO4.
Sch em e 8a
a
Reagents: (a) KOH, DMSO, MeI; (b) KOH, DMSO, benzyl
bromide; (c) LiOH.
noacetate gave the corresponding R,â-unsaturated esters
17a -e as mixtures of geometrical isomers. Hydrogena-
tion of the carbon-carbon double bond and simulta-
neous hydrogenolysis of the Cbz protecting group was
effected under conditions of catalytic hydrogenation,
resulting in the corresponding amino esters 18a -e.
Direct condensation with acid 5 gave nitrile amides
7n -r (Scheme 2).
In order to explore the SAR of the bicyclic component
and the relative amidine position on general structure
B, a variety of cyano-substituted 5,6-bicyclic acids were
prepared using either literature methods or the routes
depicted in Schemes 5-9. Condensation of the resulting
acids with the appropriate amino ester side chains and
conversion of the resulting nitrile amides to the desired
amidino acids are shown in Scheme 10.
The N-methyl- and N-benzylindole-2-carboxylic acids
were derived from 5-cyanoindole-2-carboxylate (5)11 as
depicted in Scheme 5. In the case of the N-methyl
derivative, simultaneous N-methylation/esterification of
acid 5 using potassium dimsylate and excess methyl
iodide afforded the N-methyl methyl ester 19 which was
subsequently hydrolyzed to give the N-methyl acid 20.
The N-benzyl acid 21 was prepared in a similar fashion
with the exception that quenching the dianion of 5 with
a single equivalent of benzyl bromide afforded the
N-benzyl acid as the primary product.
Preparation of the 2,6-disubstituted indole nucleus
was accomplished using the Riessert indole synthesis15
similar to Kermack’s original conditions (Scheme 6).16
Benzylic deprotonation of tolunitrile 22, which was
prepared according to literature methods,17 and quench-
ing the anion with diethyl oxalate afforded the indole
precursor 23. Reduction of the nitro group followed by
a
Reagents: (a) methyl R-bromoacetate, K2CO3, NaI; (b) NaOMe;
(c) CuCN, CuI, 160 °C; (d) LiOH.
in situ cyclization afforded the indole product 24 which
was saponified to give the desired 6-cyanoindole-2-
carboxylate (25).
The 3,5- and 3,6-disubstituted indole nuclei were
prepared from 5-cyanoindole (26) and 6-cyanoindole
(27), respectively (Scheme 7). While 5-cyanoindole was
commercially available, the 6-cyano derivative was
prepared according to the method of Batcho et al.18
Regioselective formylation at the C-3 position (28 and
29) and subsequent oxidation using isobutylene as a
chlorine scavenger19 afforded the requisite 5-cyano- and
6-cyanoindole-3-carboxylic acids (30 and 31).
The synthesis of 5-cyanobenzofuran-2-carboxylate was
modeled from the literature20 and is described in
Scheme 8. Alkylation of commercially available 5-bro-
mosalicylaldehyde (32) with methyl R-bromoacetate
afforded aldehyde 33 which was subjected to base-
induced ring closure and in situ dehydration to give
methyl 5-bromobenzofuran-2-carboxylate (34). Limited
attempts at combining the base-induced alkylation and
ring closure reactions into a single step resulted in
substantially reduced yields compared to the two-step
procedure and were not pursued further. Bromide
displacement using copper(I) cyanide and copper(I)
iodide21 at elevated temperatures afforded the requisite
methyl 5-cyanobenzofuran-2-carboxylate (35). Saponi-
fication afforded the corresponding 5-cyanobenzofuran-
2-carboxylate (36).

2846 J ournal of Medicinal Chemistry, 1997, Vol. 40, No. 18
Sall et al.
Sch em e 9a
Sch em e 10
a
Reagents: (a) NaH; (b) CO2 (1900 psi), 175 °C; (c) EtOH,
H2SO4; (d) NaH, chloromethyl methyl ether; (e) LiAlH4; (f) MnO2;
(g) p-TosOH, dioxane, H2O; (h) ethyl R-bromoacetate, K2CO3, NaI;
(i) DBU; (j) CuCN, CuI, 135 °C; (k) NaOH.
The synthesis of the regioisomeric 2,6-disubstituted
benzofuran derivative paralleled that of 36 with the
exception that it was first necessary to prepare the
requisite 4-bromosalicylaldehyde as shown in Scheme
9. Kolbe-Schmitt22 carbonylation of sodium 3-bro-
mophenoxide regiospecifically afforded salicylic acid
derivative 38 which was subsequently esterified to 39.
Initially, direct conversion of ester 39 to salicylaldehyde
42 was attempted through a two-step reduction/oxida-
tion sequence using LiAlH4 and MnO2. While reduction
to the primary alcohol proceeded smoothly, the desired
aldehyde product from the oxidation reaction could not
be extracted from the manganese complexes. Accord-
ingly, the phenol was protected as the methoxymethyl
(MOM) derivative 40 which was subjected to the same
two-step reduction/oxidation sequence to afford benzal-
dehyde 41. Acid-catalyzed deprotection of the MOM
group afforded the requisite 4-bromosalicylaldehyde
(42). Alkylation with ethyl R-bromoacetate to afford
derivative 43, cyclization/dehydration to give bromoben-
zofuran 44, nitrile formation to give ethyl 5-cyanoben-
zofuran-2-carboxylate (45), and subsequent saponifica-
tion afforded 6-cyanobenzofuran-2-carboxylate (46).
Elaboration of the nitrile-substituted, 5,6-bicyclic
acids 20, 21, 25, 30, 31, 36, 46, and 4723 into the desired
amidino acid products 56-63 parallels the preparation
of indole derivatives 7a -r and is depicted in Scheme
10. Condensation of the aromatic acids with the ap-
propriate amino ester gave nitrile amides 48-55. In
certain instances, the 5,6-bicyclic acids such as 30 and
36 were coupled to amino ester side chains of varying
length (51a ,b and 53a -c, respectively). Conversion to
the desired amidino acids 56-63 was accomplished by
the thioamide/thioimidate route9 or using Pinner condi-
tions.10 During the preparation of product 56, conver-
sion of nitrile 48 to the corresponding thioamide using
H2S proceeded without incident. Upon treatment of the
thioamide with methyl iodide in refluxing acetone,
however, the only product isolated was starting nitrile
48, necessitating the use of Pinner conditions.
Sch em e 11a
a
Reagents: (a) PCl5, p-toluenesulfonamide; (b) Na, (CO2Et)2,
EtOH; (c) NaH, MeI; (d) Zn, HOAc; (e) LiOH; (f) EDC, DMAP,
DIEA, methyl 7-aminoheptanoate hydrochloride; (g) H2S, pyridine,
TEA; (h) MeI; (i) NH4OAc; (j) di-tert-butyl dicarbonate, K2CO3; (k)
LiOH; (l) TFA, anisole.
66 and subsequently with MeI, afforded the Riessert
substrate 67. Reductive cyclization afforded the requi-
site 3-methylindole nucleus (68) which was saponified
to acid 69. Elaboration to nitrile amide 70 and subse-
quently to amidino acid 71 followed from previously
described conditions.
Preparation of the amidinoindazole derivative began
with nitrosation of 6-cyanoindole (27) to afford the
3-formylindazole nucleus (72; Scheme 12).25 Oxidation
with sodium chlorite and monobasic sodium phosphate
using isobutylene as a chlorine scavenger19 afforded
6-cyanoindazole-3-carboxylate (73), which was elabo-
rated to amidino acid 75 using the methods described
above.
The preparation of the 2,3-dihydrobenzofuran deriva-
tive is depicted in Scheme 13, beginning with the
preparation of the 5-cyano-2,3-dihydrobenzofuran-2-
carboxylate nucleus according to the general methods
of Edwards et al.26 Alkylation of commercially available
5-bromosalicylaldehyde (76) with ethyl bromoacetate
Preparation of analog 71 began with the synthesis of
the 3-methylindole nucleus which was accomplished
using the Riessert indole synthesis15 as shown in
Scheme 11. Treatment of commercially available 3-meth-
yl-4-nitrobenzoic acid (64) with phosphorous pentachlo-
ride and p-toluenesulfonamide gave the tolunitrile
derivative 65.24 Sequential bis alkylation at the benz-
ylic position, first using diethyl oxalate to give derivative

Benzamidines for GPIIb-IIIa Receptor Antagonists
J ournal of Medicinal Chemistry, 1997, Vol. 40, No. 18 2847
Sch em e 12a
Ta ble 1. Antagonism of Platelet GPIIb-IIIa by
2,5-Disubstituted Indole Amidines 7a -d
µ
µ
a
Reagents: (a) NaNO2, HCl; (b) NaClO2, NaH2PO4; (c) EDC,
tert-butyl 7-aminoheptanoate, DMAP, DIEA; (d) H2S, pyridine,
TEA; (e) MeI; (f) NH4OAc; (g) di-tert-butyl dicarbonate, K2CO3;
(h) TFA, anisole.
Sch em e 13a
endopeptidases, initial efforts focused on the use of
5-amidinoindole as the restricted bicyclic unit.29 In an
attempt to mimic the critical distance between the
guanidyl- and carboxyl-binding sites in receptor-bound
RGD sequences, acidic side chains of varying length
were appended via an amide bond to the 2-position of
the indole nucleus (7a -d ; Table 1). Amidino acid 7c
was at least 10-fold more potent than the other deriva-
tives in both the purified receptor binding assay (ELISA)
and the platelet aggregation assay (PRP), suggesting
that the eight-atom tether between the indole nucleus
and the acidic carboxylate provides the best approxima-
tion of the spatial relationship between guanidyl- and
carboxyl-binding sites. The strict spatial requirements
governing this series is evidenced by the fact that
shortening or lengthening the acidic side chain by a
single carbon-carbon bond (1.4 Å) causes at least a 10-
fold decrease in potency. The lower activity of deriva-
tives 7a -d in the functional (PRP) versus ELISA assays
could be due to multiple factors including plasma
protein or lipid binding and/or the high fibrinogen
concentrations present in the PRP assay.
It has been documented that conformational defini-
tion in the central region of RGD mimics enhances their
potency against GPIIb-IIIa.30 To assess whether the
additional conformational restriction offered by the
indole nucleus compared to benzamidine enhances the
activity of this series, the acyclic derivative 4b was
prepared and its activity compared to the bicyclic
counterpart 7c (Table 2). Amidine 7c is 34- and 17-
fold more potent than its acyclic counterpart 4b in the
ELISA and PRP assays, respectively. A number of
plausible explanations might explain the greater activ-
ity of the bicyclic series: One, the indole nucleus might
provide additional π-stacking within that region of
GPIIb-IIIa, or two, the electronic character of the indole
nitrogen (7c) is sufficiently different from that of the
aniline (4b) resulting in enhanced interaction within
GPIIb-IIIa. Alternatively, the indole nucleus may
induce a preferred geometrical relationship between the
amidine, hydrogen bond-donating NH, and acidic side
chain. Figure 2 shows the molecular overlays of low-
energy models of the cyclic indole analog 7c and the
acyclic benzamidine 4b.31 There is a significant energy
penalty for acyclic derivative 4b to adopt the conforma-
a
Reagents: (a) ethyl bromoacetate, K2CO3, NaI; (b) NaBH4; (c)
SOCl2, pyridine; (d) NaH; (e) CuI, CuCN, 160 °C; (f) LiOH; (g)
EDC, tert-butyl 7-aminoheptanoate, DMAP, DIEA; (h) H2S, pyri-
dine, TEA; (i) MeI; (j) NH4OAc; (k) di-tert-butyl dicarbonate,
K2CO3; (l) TFA, anisole.
and catalytic NaI afforded phenoxyacetate 77. Selective
reduction of the aldehyde, followed by treatment of the
resulting alcohol with thionyl chloride in pyridine,
afforded the benzylic chloride 78. Base-induced, in-
tramolecular displacement of the chloride afforded the
cyclized 2,3-dihydrobenzofuran nucleus (79). Conver-
sion to nitrile 80 and subsequent saponification gave
5-cyano-2,3-dihydrobenzofuran-2-carboxylate (81) which
was elaborated to amidino acid 83 following previously
described methodology.
Resu lts a n d Discu ssion
The ability of the amidino acids 4a -c, 7a -r , 56-63,
71, 75, and 83 to block the binding of fibrinogen to the
platelet GPIIb-IIIa receptor was measured in two assay
systems. Antagonism of fibrinogen binding to a purified
receptor preparation was determined using an enzyme-
linked immunosorbent assay (ELISA),27 while functional
inhibition was measured by the compounds’ ability to
attenuate ADP-induced (fibrinogen-mediated) platelet
aggregation in human platelet-rich plasma (PRP).28
The initial goal in this study was to design a novel
class of nonpeptidyl mimics of the RGD sequence with
a restricted benzamidine isostere whose structure would
be amenable to the rapid exploration of the SAR of the
series. In that indole amidines have been previously
employed as probes for the specificity pocket of arginine

2848 J ournal of Medicinal Chemistry, 1997, Vol. 40, No. 18
Sall et al.
Ta ble 2. Comparison of Indole Amidine 7c to Its Benzamidine
Analog 4b: Effects of Conformational Restriction in the Basic
Component of RGD Mimics
Ta ble 3. Effect of Side Chain Modifications on Antagonism of
Platelet GPIIb-IIIa: Indole Amidines 7e-j
µ
µ
11.02, respectively, it is unlikely that the enhanced
potency of analog 7c is due to differences in basicity.
Having identified a nonpeptidyl RGD mimic (7c) with
modest activity against GPIIb-IIIa, we turned our
attention to exploring the SAR in an effort to enhance
the potency of the series. In an attempt to better
represent the peptidic nature of the physiological ligands
for GPIIb-IIIa, the introduction of hydrogen bond donor/
acceptor groups in the acidic side chain was undertaken.
Derivative 7e (Table 3) was explored to determine the
role of the amide NH, whereas agents 7f-h were
prepared to make the acidic side chain of lead structure
7c better resemble the peptidyl backbone of the RGD
sequence. Removal of the hydrogen bond-donating
capacity of the amide NH through N-methylation (7e)
resulted in a 2-fold increase in activity in the ELISA
suggesting that a H-bond donor at this site is not critical
for good potency in the series. Since molecular modeling
studies32 show that the N-Me has little impact on the
conformational biases of the acidic side chain, the
increase in activity suggests the occurrence of a lipo-
philic interaction between the methyl group and the
receptor. Incorporation of hydrogen bond donor/accep-
tor pairs in the form of amide bonds was not tolerated
at the N- and C-terminal ends of the acidic side chain
(7f,h , respectively), resulting in 14- and 11-fold losses
in potency in the ELISA. Internal placement of the
amide bond (agent 7g) results in a derivative which
contains the identical atom spacing as is present
between the Gly-Asp amide bond and the â-carboxyl of
F igu r e 2. (Top) Structure overlay of a low-energy conforma-
tion for a model of the indole 7c in green and a low-energy
conformation of the acyclic benzamidine 4b in blue. The
minimized energy for 7c was -12.03 kcal/mol; the minimized
energy for 4b was -22.15 kcal/mol. (Bottom) Edge view of the
structure overlay of the low-energy conformations depicted in
the top panel with the superimposition of the heteroatoms and
the methyl group representing the amidine moiety. The acyclic
benzamidine undergoes a deformation of the methylene group
in order to meet the shorter heteroatom distances of the indole
compound. The energy of this conformation of 4b was -8.82
kcal/mol. The energy difference of 13.33 kcal/mol represents
the energy penalty for the acyclic series to assume the proposed
preferred geometrical relationships of the heteroatom interac-
tions offered by the indole analog 7c.
tion of cyclic analog 7c which may explain the 34-fold
difference in activity between the two. Since the pKa
of the amidines in derivatives 7c and 4b are 12.17 and

Benzamidines for GPIIb-IIIa Receptor Antagonists
J ournal of Medicinal Chemistry, 1997, Vol. 40, No. 18 2849
Ta ble 4. Effects of Hydrophobic Substitution Proximal to the
Terminal Carboxylate: Indole Amidines 7k -r
F igu r e 3. Effect of serum albumin on GPIIb-IIIa antagonism
by indole amidines 7c,n -r .
Since the literature suggests that the preferred absolute
stereochemistry at the site of substitution is series
dependent,8a,36a,37 we initially chose to prepare deriva-
tives 7k -r in racemic form to gauge the impact of
substituents adjacent to the carboxylate in this particu-
lar series. The incorporation of any alkyl substituents
at the position R to the terminal carboxylate decreased
activity in both the ELISA and the functional assay (e.g.,
7k -m ). In contrast, lipophilic substituents at the
â-position, regardless of size, were well tolerated. The
fact that both small (methyl, 7n ) and large (phenyl, 7r )
lipophilic groups modestly enhanced the activity of the
series in the ELISA assay suggests the presence of an
ill-defined binding site in that region of the receptor.
While increases in activity were observed for agents
7n -r in the ELISA, similar increases were not observed
in the functional assay (PRP; Table 4), in which the
methyl and phenyl substituents had either a neutral
or a negative impact on aggregation. The disparity
between the ELISA and PRP data may indicate that
the introduction of lipophilic substituents enhances the
binding of these agents to various plasma constituents
in the PRP assay, decreasing the effective concentration
of the compound. To investigate this possibility, the
effect of elevated levels of a representative plasma
constituent on the ability of agents 7n -r to antagonize
the GPIIb-IIIa receptor was measured (Figure 3). In
this case, bovine serum albumin (BSA) was used as a
surrogate for human serum albumin (HSA). While
increased levels of BSA in the ELISA (4.5%, w/v) had
little impact on the activity of the unsubstituted deriva-
tive 7c, the dose-response curves for the â-substituted
analogs 7n -r were shifted. For compounds 7n -p the
degree of shift was directly proportional to the size of
the substituent, with the butyl, hexyl, and phenyl
derivatives all suffering similar losses in potency of
approximately 85%. The data would suggest that while
lipophilic substituents at the position â to the free
carboxylate enhanced the inherent ability of this series
to antagonize GPIIb-IIIa (ELISA), the value of such
structural manipulations would appear limited due to
increased interactions with various protein constituents
in physiologically relevant media. Accordingly, the
Asp in the RGD sequence. While incorporation of the
amide group at this position was tolerated, it did not
add to the overall activity of the series.
Derivative 7c possesses a freely flexible acidic side
chain, capable of binding in more than a single confor-
mation. To assess the impact of conformational restric-
tion, a phenyl ring was incorporated into the flexible
side chain in order to reduce the number of conforma-
tional degrees of freedom. In an energy-minimized
conformation, the distance from the amide nitrogen to
the carboxylate carbon is 8.9 Å in the lead structure 7c.
Both the phenylacetic acid (7i) and the phenylpropionic
acid (7j) derivatives (7.8 and 9.5 Å, respectively) were
prepared in order to approximate this distance.33 Un-
fortunately, this met with little success as agent 7c was
20- and 6-fold more potent in the ELISA than analogs
7i,j, respectively. Phenoxyacetic34 and phenylpropi-
onic35 acids have been previously used as Asp surrogates
in the design of very potent GPIIb-IIIa receptor antago-
nists, suggesting that unless agents 7i,j bind to the
receptor in a different orientation, the potency loss is
not likely due to steric effects. It is possible that either
the amide to carboxylate distances in derivatives 7i,j
do not provide an accurate enough approximation of the
six-carbon tether present in analog 7c or a freely flexible
side chain within this particular series of GPIIb-IIIa
receptor antagonists is required for tight binding.
The impact of lipophilic substituents proximal to the
carboxylate in nonpeptidal GPIIb-IIIa receptor antago-
nists has been previously studied.36 To probe for the
presence of a lipophilic binding site proximal to the
carboxylate in the bound orientation of compound 3c
and to examine the effects of additional lipophilic
interactions on the activity of this series, R- and
â-substituted carboxylate derivatives (7k -m and 7n -
r , respectively) were prepared and evaluated (Table 4).

2850 J ournal of Medicinal Chemistry, 1997, Vol. 40, No. 18
Sall et al.
Ta ble 5. Effects of Nuclear Modifications on Antagonism of
Platelet GPIIb-IIIa: Amidines 56, 57, 61b, 63, 71, 75, and 83
Ta ble 6. Antagonism of Platelet GPIIb-IIIa by Regioisomeric
Indole Amidines 58-60
through increased lipophilic interactions surrounding
the 5,6-bicyclic nucleus. However, the opposite trends
in activity between the ELISA and PRP data suggest
that the usefulness of such structural manipulations
might again be limited due to enhanced interactions
with plasma components.
The critical tether length between the indole nucleus
and the terminal carboxylate was well characterized
through the study of derivatives 7a -d . Regioisomeric
derivatives 58-60 (Table 6) were prepared to determine
the optimal substitution pattern between the basic
amidine and the acidic side chain. While the inter-
atomic distances between indole atom pairs C-2/C-5 (7c),
C-2/C-6 (58), and C-3/C-6 (60) are all similar (4.5, 4.5,
and 4.2 Å, respectively), the interatomic distance be-
tween C-3 and C-5 (59a ) is only 3.7 Å.33 The one carbon
homolog 59b was prepared in an attempt to compensate
for this 0.8 Å discrepancy. In both assays, the 2,6- and
3,6-disubstituted regioisomers (58 and 60, respectively)
displayed greater potency than the parent compound
7c, while neither of the 3,5-disubstituted analogs (59a,b)
displayed detectable activity in either assay. Perhaps
the lack of potency for derivatives 59a ,b indicates that
the 3,5-disubstitution pattern does not allow a suitable
approximation of the critical distance between the
guanidyl- and carboxyl-binding sites within the GPIIb-
IIIa receptor. The distance between the sites of sub-
stitution and the geometrical relationship in regioiso-
mers 7c, 58, and 60 are nearly identical. However,
derivatives 58 and 60 bind with a 5-fold higher affinity
than agent 7c, suggesting the presence of a preferred
spatial orientation between the amidine and the indole
N-H.
The benzofuran, benzo[b]thiophene, and indazole
derivatives 61b, 63, and 75, respectively (Table 5), were
prepared to study the impact of incorporating hydrogen
bond acceptor atoms in the B-ring of the 5,6-bicyclic
nucleus. The benzo[b]thiophene analog 63 displayed
similar activity to the indole 7c, consistent with the fact
that a hydrogen bond donor at this site is not required
for receptor binding. On the other hand, the benzofuran
(61b) and indazole (75) derivatives exhibited improve-
ment in their ability both to bind to purified GPIIb-IIIa
(ELISA) and to inhibit ADP-induced platelet aggrega-
tion (PRP). The 17- and 34-fold increases in potency in
preparation of enantiomeric pairs to assess stereochem-
ical effects of â-substituents was not pursued.
The inability to enhance the functional activity of the
lead structure 7c through structural manipulation of
the acidic side chain prompted us to direct our attention
to studying the SAR surrounding the 5,6-bicyclic indole
ring. Two immediate sites for exploration were the N-1
and C-3 atoms, resulting in the preparation and evalu-
ation of derivatives 56, 57, and 71 (Table 5). Compound
71, which possesses a lipophilic methyl group at C-3,
was only 2.5- and 1.5-fold less active than agent 7c in
the ELISA and PRP assays, respectively. N-Methyla-
tion (56) of the indole N-H reduces activity in the ELISA
and PRP assays by 4- and 2.5-fold, respectively. Func-
tionalization as the N-benzyl derivative (57), however,
restores activity in the ELISA, indicating that a hydro-
gen bond donor in this region is not an absolute
requirement for good potency. The ELISA activity of
57 relative to the N-methyl derivative 56 indicates that
it may in fact be possible to enhance receptor affinity

Benzamidines for GPIIb-IIIa Receptor Antagonists
J ournal of Medicinal Chemistry, 1997, Vol. 40, No. 18 2851
Ta ble 7. Modifications to the Benzofuran Series: Amidines
61a -c and 62
Ta ble 8. Comparison of 5,6-Bicyclic Amidines 58 and 61b to
Their Acyclic Counterparts 4b and 4c, Respectively
µ
µ
µ
µ
Ta ble 9. Inhibition of Adhesive Protein Binding to Platelet
GPIIb-IIIa and the Vitronectin Receptor (Rvâ3) by Amidino
Acids 60, 61b, and 75
the ELISA observed for the benzofuran and indazole
analogs, respectively (61b and 75), suggests that a
hydrogen bond acceptor in this region is optimal for
tight binding. Since neither the benzofuran oxygen nor
the indazole N-2 are geometrically disposed to allow
intramolecular hydrogen bonding to the side chain
amide NH, the increased activity observed for analogs
61b and 75 may be due to intermolecular hydrogen
bonding with the receptor and not to an altered side
chain orientation. Saturation of analog 61b to the 2,3-
dihydrobenzofuran derivative 83 resulted in a 20-fold
loss in potency in the ELISA. Changes in the physical
chemical properties of the molecule as a result of
saturating the benzofuran nucleus could be responsible
for the reduced activity of analog 83, including disrup-
tion of the planarity of the five-member ring, modified
H-bonding capacity of the benzofuran and 2,3-dihy-
drobenzofuran oxygen, and differences in the pKbs of
the amidines. Data for the clinical agent from Searle
(SC54701A) is included in Table 5 as a comparator.8b
It had been shown earlier that strict spatial and
geometrical relationships between the amidine, the
indole N-H, and the acidic side chain governed the
activity of the amidinoindole series of antagonists. To
probe whether these same geometrical and spatial
constraints applied to the benzofuran series, which now
contains a hydrogen bond acceptor in the B-ring of the
5,6-bicyclic system, agents 61a ,c and 62 were prepared
and evaluated (Table 7). Similar to the indole series,
strict spatial requirements govern the activity of the
benzofuran class as evidenced by the fact that either
increasing or decreasing the length of the tether con-
necting the terminal carboxylate to the amide nitrogen
by only one carbon (61a ,c, respectively) causes 57- and
83-fold losses in potency, respectively. In contrast to
the indole series, however, the 2,5-disubstitution pattern
(61b) is preferred over the 2,6-array (62), indicating that
the correct geometrical relationship between the ami-
dine, the acidic side chain, and the hydrogen bond-
accepting oxygen atom is also critical for tight binding
to GPIIb-IIIa.
µ
µ
series, derivatives 4a ,c were compared to their re-
stricted partners 58 and 61b, respectively (Table 8). In
both cases, the additional conformational constraints
offered by the 5,6-bicyclic nucleus resulted in enhanced
potency, confirming that conformationally restricted
benzamidines can exhibit advantages over benzamidine
itself.
The RGD motif is also recognized by other integrins
such as the vitronectin receptor (Rvâ3), and therefore,
mimics of the RGD sequence can serve as antagonists
of receptors other than GPIIb-IIIa. As representatives
from this study, amidinoindole 60, benzofuran 61b, and
indazole 75 were studied and found to bind selectively
to the GPIIb-IIIa receptor, failing to compete with
vitronectin for binding to its receptor (Rvâ3) at concen-
trations as high as 100 µM (Table 9).27
The systematic SAR around a novel class of nonpep-
tidyl RGD mimics containing constrained benzamidine
surrogates that act as potent and selective platelet
GPIIb-IIIa antagonists has been described. The an-
tagonists were derived from 5,6-bicyclic amidines which
permitted the study of specific spatial and geometrical
relationships between critical structural elements. The
ability to define the orientation between amidine, acidic
side chain, and hydrogen bond donor atoms led to
increased potency. While a large number of nonpeptidyl
GPIIb-IIIa antagonists have utilized benzamidine as an
arginine surrogate, this study would suggest that the
bicyclic nuclei can offer distinct advantages in terms of
in vitro potency. The limitation of this series in its
current form is the poor oral bioavailability of the free
amidino acids, indicating that the use of prodrugs and/
or formulations may be necessary to achieve useful
plasma levels following oral administration.
The 34-fold difference in potency (ELISA) observed
between indole amidine 7c and its acyclic counterpart
4b suggested that additional conformational restriction
in the basic component of RGD mimics leads to en-
hanced interactions at the receptor. To determine if this
trend holds true for other members of the 5,6-bicyclic

2852 J ournal of Medicinal Chemistry, 1997, Vol. 40, No. 18
Sall et al.
Dim eth yleth yl Ester (3a ). A solution of 18.0 g (77.5 mmol)
of tert-butyl ester 2a in 225 mL of CH2Cl2 was treated with
84.0 mL (773 mmol) of anisole, and the mixture was cooled to
0 °C. The solution was treated with 59.0 mL (766 mmol) of
TFA in a dropwise manner, the cold bath was removed, and
the reaction was allowed to stir at ambient temperature until
no starting ester could be detected by TLC (24 h). The reaction
was concentrated in vacuo and the oil poured into saturated
aqueous NaHCO3. The basic mixture was washed twice with
EtOAc and acidified to ∼pH 3 with 5 N aqueous HCl, resulting
in the precipitation of the desired acid. The acid was filtered
and dried to afford 12.41 g of a solid.
Exp er im en ta l Section
The syntheses of analogs 4a , 7c,k ,n , 58, 61b, and 75 are
described below. The experimental techniques employed to
prepare the intermediates leading up to and including final
products 4b,c, 7a ,b,d -j,l-m ,o-r , 56, 57, 59a ,b, 60-63, 71,
75, and 83 pattern those described below and are included in
the Supporting Information with the appropriate physical
chemical data.
Melting points were determined on a Thomas-Hoover capil-
lary melting point apparatus calibrated with known com-
pounds and are uncorrected. Proton nuclear magnetic reso-
nance spectra (1H NMR) were obtained on a General Electric
QE-300 spectrometer using either deuterated dimethyl sul-
foxide in the absence (DMSO-d6) or presence (DMSO-d6/TFA)
of trifluoroacetic acid or deuterated chloroform (CDCl3) as the
solvent, and chemical shifts are reported in parts per million
(ppm) relative to dimethyl sulfoxide (DMSO; 2.49 ppm) or
chloroform (CHCl3; 7.25 ppm). Infrared spectra (IR) were run
either as solutions in CHCl3 or as pellets in KBr and were
recorded on a Nicolet 510P spectrometer. Field desorption
mass spectra (FDMS) were obtained on a VG Analytical
VG70SE mass spectrometer. Fast atom bombardment high-
resolution mass spectra (FAB-HRMS) were obtained on a VG
Analytical VGZAB-2SE mass spectrometer. Combustion analy-
A solution of 1.60 g (9.08 mmol) of the preceding acid in 50
mL of CH2Cl2 was treated with 1.70 g (9.87 mmol) of 4-(di-
methylamino)pyridine, 6.30 mL (36.2 mmol) of N,N-diiso-
propylethylamine, and 2.75 g (13.7 mmol) of tert-butyl 7-
aminoheptanoate. The mixture was treated with 3.50 g (18.3
mmol) of 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hy-
drochloride, and the reaction stirred at ambient temperature
until all of the starting acid had been consumed (∼15 h). The
mixture was washed sequentially with 1 N aqueous citric acid
(1×), H2O (1×), 1 N aqueous NaOH (1×), and H2O (1×). The
organic layer was dried over Na2SO4, filtered, and concentrated
in vacuo to afford 4.16 g of a solid. Purification by flash
chromatography (SiO2; 25% hexanes in EtOAc) afforded 2.40
g (6.66 mmol, 52% over two steps) of nitrile amide 3a as a
solid: 1H NMR (DMSO-d6) δ 7.90 (t, J ) 5.5 Hz, 1H), 7.25-
7.19 (m, 1H), 6.92 (d, J ) 7.3 Hz, 1H), 6.84-6.76 (m, 2H), 6.46
(t, J ) 5.9 Hz, 1H), 3.63 (d, J ) 5.9 Hz, 2H), 3.08-2.99 (m,
2H), 2.11 (t, J ) 7.3 Hz, 2H), 1.46-1.29 (m, 13H), 1.23-1.12
(m, 4H); IR (CHCl3) 3409, 2936, 2232, 1719, 1670, 1606, 1152
cm-1; FDMS m/e 359 (M+). Anal. (C20H29N3O3) C, H, N.
ses were performed on
a Control Equipment Corp. 440
elemental analyzer and were within 0.4% of the calculated
values. Medium pressure liquid chromatography (MPLC) was
performed using PrepPak silica gel cartridges on a Waters
Prep LC/System 500A. Flash chromatography was performed
over silica gel 60 (230-400 mesh ASTM). Preparative cen-
trifugal thin-layer chromatography (PCTLC) was performed
on a Harrison Model 7924 chromatotron with Merck silica gel
60 PF254 containing CaSO4‚0.5H2O binder. All reactions
requiring anhydrous conditions and/or an inert atmosphere
were performed under a positive N2 flow. Reverse phase
chromatography was performed on a Ranin Rabbit chroma-
tography system equipped with HDX pumps and using a
NovaPak C18 (41.4 × 300) column. Ethyl 4-aminobutyrate
hydrochloride and 5-cyanoindole were purchased from Aldrich
Chemical Co. (Milwaukee, WI).
The ability of the amidino acids prepared in this study to
antagonize the GPIIb-IIIa receptor was measured in two
different assay systems. Antagonism in a purified receptor
binding assay was determined by an ELISA (enzyme-linked
immunosorbent assay) using purified human platelet GPIIb-
IIIa, biotinylated fibrinogen, alkaline phosphatase-labeled goat
antibiotin, and p-nitrophenyl phosphate, as previously re-
ported.27 Functional inhibition of the GPIIb-IIIa receptor was
reflected in the compounds’ ability to antagonize ADP-induced
(fibrinogen-mediated) platelet aggregation in human platelet-
rich plasma (PRP).28 The vitronectin receptor binding assay
was run using purified human placenta Rvâ3 (VnR), biotiny-
lated vitronectin, alkaline phosphatase-labeled goat antibiotin,
and p-nitrophenol phosphate, as previously reported.27 Ad-
enosine diphosphate, alkaline phosphatase-labeled goat anti-
biotin, and bovine serum albumin (BSA) were purchased from
Sigma Chemical Co. (St. Louis, MO). p-Nitrophenol phosphate
was purchased from Bio-Rad (Hercules, CA).
Glycin e, N-(3-Cya n op h en yl)-, 1,1-Dim eth yleth yl Ester
(2a ). A solution of 20.0 g (169.2 mmol) of 3-aminobenzonitrile
(1a ) in 400 mL of DMF was treated with 60.0 g (434 mmol) of
K2CO3 followed by 12.8 mL (86.7 mmol) of tert-butyl bromoac-
etate. The mixture was heated at 80 °C for 16 h, cooled, and
filtered. The solvent was removed in vacuo and the residue
partitioned between EtOAc and H2O. The organic layer was
separated and the aqueous layer extracted twice with EtOAc.
The combined organic layers were dried over Na2SO4, filtered,
and concentrated in vacuo to give an oil. Purification by MPLC
(SiO2; 10% EtOAc in hexanes) afforded 19.45 g (83.7 mmol,
49%) of ester 2a as an oily solid: 1H NMR (DMSO-d6) δ 7.26-
7.18 (m, 1H), 6.94-6.82 (m, 2H), 6.42 (t, J ) 6.2 Hz, 2H), 3.80
(d, J ) 6.2 Hz, 2H), 1.37 (s, 9H); IR (CHCl3) 3412, 2989, 2231,
1734, 1605, 1370, 1156 cm-1; FDMS m/e 232 (M+). Anal.
(C13H16N2O2) C, H, N.
Non a n oic Acid , 9-[[3-(Am in oim in om eth yl)p h en yl]a m i-
n o]-8-oxo-, Mon o(tr iflu or oa ceta te) (4a ). A solution of 2.00
g (5.56 mmol) of nitrile amide 3a in 100 mL of a 10% TEA in
pyridine mixture was treated with a stream of H2S(g) for 5 min.
The reaction was stirred at ambient temperature until TLC
analysis indicated the absence of starting nitrile (40 h). The
mixture was concentrated in vacuo, and the oil was subjected
to flash chromatography (2.5% MeOH in CHCl3) to afford 1.20
g (3.05 mmol, 55%) of the corresponding thioamide. The
thioamide (1.10 g, 2.80 mmol) was dissolved in 30 mL of
acetone, and the solution was treated with 4.56 g (32.1 mmol,
11 equiv) of MeI. The reaction was heated to reflux for 1 h
and evaporated in vacuo. The resulting residue was recon-
stituted in 5 mL of MeOH, and a solution of 0.43 g (5.60 mmol,
2 equiv) of NH4OAc in 5 mL of MeOH was added. The mixture
was heated to reflux for 2 h and concentrated in vacuo, and
the resulting oil was taken up in 50 mL of a 1:1 THF:H2O
mixture. The solution was treated with 1.60 g (11.2 mmol, 4
equiv) of K2CO3 followed by 2.44 g (11.2 mmol, 4 equiv) of di-
tert-butyl dicarbonate. The reaction was stirred for 72 h and
was diluted with 50 mL of EtOAc and 50 mL of brine. The
organic layer was separated, dried over Na2SO4, filtered, and
evaporated in vacuo. The resulting oil was subjected to MPLC
(25% EtOAc in hexanes) to afford 0.70 g (1.46 mmol, 29% from
nitrile amide 3a ) of the corresponding Boc-protected amidino
tert-butyl ester as an oil: 1H NMR (CDCl3) δ 7.24-7.19 (m,
2H), 7.14-7.08 (m, 1H), 6.76-6.67 (m, 2H), 4.73-4.64 (m, 1H),
3.76 (br s, 2H), 3.26-3.18 (m, 2H), 2.13 (t, J ) 7.4 Hz, 2H),
1.57-1.37 (m, 22H), 1.29-1.14 (m, 4H); IR (CHCl3) 2982, 1718,
1666, 1607, 1584, 1524, 1295, 1162 cm-1; FDMS m/e 477 (M
+ 1). Anal. (C25H40N4O5‚0.5H2O) C, H, N.
A mixture of 0.60 g (1.30 mmol) of the Boc-protected amidino
tert-butyl ester in 5 mL of anisole was treated with 10 mL of
TFA. The reaction was stirred at ambient temperature until
TLC analysis indicated the complete disappearance of starting
material (16 h). The mixture was concentrated in vacuo and
the resulting oil triturated with Et2O to afford the trifluoro-
acetate salt of amidino acid 4a as a solid in 73% yield (21%
overall yield from nitrile amide 3a ): 1H NMR (DMSO-d6) δ
11.99 (br s, 1H), 9.14 (br s, 2H), 9.10 (br s, 2H), 7.97-7.85 (m,
1H), 7.26 (t, J ) 7.6 Hz, 1H), 6.97-6.78 (m, 3H), 6.41-6.28
(m, 1H), 3.68 (s, 2H), 3.10-2.97 (m, 2H), 2.15 (t, J ) 7.2 Hz,
2H), 1.54-1.13 (m, 8H); IR (KBr) 3355, 3111, 1728, 1672, 1641,
Non a n oic Acid , 9-[(3-Cya n op h en yl)a m in o]-8-oxo-, 1,1-

Benzamidines for GPIIb-IIIa Receptor Antagonists
J ournal of Medicinal Chemistry, 1997, Vol. 40, No. 18 2853
1206, 1131, 724 cm-1; FDMS m/e 321 (M + 1). Anal.
(C16H24N4O3‚CF3CO2H) C, H, N.
dried over MgSO4, filtered, and concentrated in vacuo to afford
29.0 g of an oil. Purification by MPLC (15% then 25% EtOAc
in hexanes) afforded 20.19 g (87.4 mmol, 95%) of aldehyde
10: 1H NMR (CDCl3) δ 9.74 (s, 1H), 7.85-7.78 (m, 2H), 7.73-
7.64 (m, 2H), 3.75-3.63 (m, 2H), 2.55-2.46 (m, 2H), 1.78-
Hep ta n oic Acid , 7-[[(5-Cya n o-1H-in d ol-2-yl)ca r bon yl]-
a m in o]-, Eth yl Ester (6c). A solution of 2.75 g (14.8 mmol)
of 5-cyanoindole-2-carboxylate11 in 100 mL of CH2Cl2 was
treated with 3.50 g (28.6 mmol) of 4-(dimethylamino)pyridine,
4.00 mL (23.0 mmol) of N,N-diisopropylethylamine, and 4.00
g (19.1 mmol) of ethyl 7-aminoheptanoate hydrochloride.38 The
mixture was treated with 3.70 g (19.3 mmol) of 1-[3-)-
dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride, and
the reaction stirred at ambient temperature until all of the
starting acid had been consumed (∼48 h). The mixture was
washed sequentially with 1 N aqueous citric acid (50 mL), H2O
(50 mL), 1 N aqueous NaOH (50 mL), and H2O (50 mL). The
organic layer was dried over Na2SO4, filtered, and concentrated
in vacuo to afford 4.10 g of a paste. Recrystallization from
EtOAc/hexanes afforded 3.25 g (9.52 mmol, 64%) of 6c as a
white solid: 1H NMR (DMSO-d6) δ 12.11 (s, 1H), 8.61 (t, J )
5.5 Hz, 1H), 8.21 (s, 1H), 7.58-7.46 (m, 2H), 7.23 (s, 1H), 4.01
(q, J ) 7.0 Hz, 2H), 3.36-3.20 (m, 2H), 2.30-2.22 (m, 2H),
1.67-1.44 (m, 4H), 1.35-1.24 (m, 4H), 1.13 (t, J ) 7.0 Hz, 3H);
1.60 (m, 4H); IR (CHCl3) 3026, 1773, 1713, 1398, 1051 cm-1
;
FDMS m/e 231 (M+). Anal. (C13H13NO3) C, H, N.
2-Hep ta n oic Acid , 7-(1,3-Dih yd r o-1,3-d ioxo-2H-isoin -
d ol-2-yl)-2-m eth yl-, Eth yl Ester (11a ). To a 0 °C mixture
of 3.60 g (32.5 mmol, 1.5 equiv) of potassium tert-butoxide in
100 mL of THF was added 7.70 g (32.5 mmol) of triethyl
2-phosphonopropionate in a dropwise manner. After stirring
at 0 °C for 15 min, a solution of 5.0 g (21.6 mmol, 1 equiv) of
aldehyde 10 in 10 mL of THF was added dropwise. The
reaction was stirred at ambient temperature until TLC
analysis indicated complete consumption of starting aldehyde
10 (1 h). The mixture was quenched by the careful addition
of 100 mL of brine. Ethyl acetate (100 mL) was added, the
layers were separated, and the aqueous phase was extracted
with 50 mL of EtOAc. The combined organic layers were
washed with 100 mL of H2O, dried over MgSO4, filtered, and
concentrated in vacuo to afford 8.35 g of an oil. Purification
by MPLC (1% MeOH in CHCl3) afforded 8.85 g (15.4 mmol,
71%) of product 11a as an oil: 1H NMR (CDCl3) δ 7.89-7.83
(m, 2H), 7.76-7.68 (m, 2H), 5.93-5.86 (m, 1H), 4.19 (q, J )
7.2 Hz, 2H), 3.70 (t, J ) 7.2 Hz, 2H), 2.57-2.46 (m, 2H), 1.88
(d, J ) 1.0 Hz, 3H), 1.77-1.66 (m, 2H), 1.53-1.42 (m, 2H),
1.30 (t, J ) 7.2 Hz, 3H); IR (CHCl3) 3015, 2934, 1772, 1711,
1398, 1230 cm-1; FDMS m/e 315 (M+). Anal. (C18H21NO4) C,
H, N.
IR (KBr) 3345, 3225, 2219, 1703, 1637, 1565, 1333, 1275 cm-1
;
FDMS m/e 341 (M+). Anal. (C19H23N3O3) C, H, N.
P r ep a r a t ion of H ep t a n oic Acid , 7-[[5-(Am in oim in o-
m eth yl)-1H-in d ol-2-yl]a m in o]- (7c). Nitrile amide 6c was
converted to the corresponding amidino ester using Pinner
conditions.10 A solution of 1.50 g (4.18 mmol) of nitrile amide
6c in 250 mL of EtOH was treated with a stream of HCl gas
for 30 min. The reaction vessel was sealed, and the solution
was stirred until 1H NMR indicated complete conversion to
the imino ether (48 h). The reaction was concentrated in
vacuo, reconstituted in EtOH, and evaporated in vacuo again.
The residue was taken up in 250 mL of EtOH, and the mixture
was treated with a stream of NH3 gas for 30 min. The vessel
was sealed, and the contents were stirred until analysis by
1H NMR revealed the complete consumption of imino ether
(24 h). The reaction was concentrated in vacuo to afford 820
mg (2.08 mmol, 50%) of the corresponding amidino ester
hydrochloride as a white solid.
A 260 mg (0.65 mmol) sample of the amidino ester hydro-
chloride was taken up in 13 mL of THF and treated with 13.0
mL of 0.10 N aqueous LiOH. The reaction was stirred for 16
h, the THF was removed in vacuo, and the aqueous layer was
acidified to pH 4 with 1 N aqueous HCl. The resulting solid
was filtered, dried, and purified by reverse phase chromatog-
raphy (0.5% NH3CO2H and 30% MeOH in H2O) to afford 151
mg (0.46 mmol, 32% over two steps) of the formate salt of
amidino acid 7c: 1H NMR (DMSO-d6) δ 11.86 (s, 1H), 9.10
(br s, 2H), 8.55 (br s, 2H), 8.20 (s, 1H), 7.62-7.55 (m, 2H),
7.24 (s, 1H), 3.40 (t, J ) 7.0 Hz, 2H), 2.29 (t, J ) 7.3 Hz, 2H),
1.70-1.55 (m, 4H), 1.47-1.34 (m, 4H); IR (KBr) 3315, 1642,
1543, 1407, 1334, 744 cm-1; FAB-HRMS m/e C17H23N4O3 calcd
331.1770, found 331.1774. Anal. (C17H22N4O3) C, H, N.
2H-Isoin d ole-2-p en ta n ol, 1,3-Dih yd r o-1,3-d ioxo- (9). A
mixture of 14.4 g (97.2 mmol) of phthalic anhydride and 10 g
(96.6 mmol) of 5-amino-1-pentanol (8) was heated at 130 °C
for 16 h. The reaction was allowed to cool to room temperature
and concentrated in vacuo. The crude oil was purified by
MPLC (2% MeOH in CHCl3) to afford 21.42 g (91.9 mmol, 94%)
of phthalimide 9 as an oil: 1H NMR (CDCl3) δ 7.84-7.78 (m,
2H), 7.72-7.65 (m, 2H), 3.67 (t, J ) 7.1 Hz, 2H), 3.62 (t, J )
6.5 Hz, 2H), 2.13-2.04 (br s, 1H), 1.75-1.57 (m, 4H), 1.47-
1.38 (m, 2H); IR (CHCl3) 3019, 2943, 1772, 1711, 1439, 1398,
1367, 1052 cm-1; FDMS m/e 234 (M + 1). Anal. (C13H15NO3)
C, H, N.
2H-Isoin d ole-2-h ep ta n oic Acid , r-Meth yl-1,3-d ih yd r o-
1,3-d ioxo-, Eth yl Ester (12a ). A solution of 4.80 g (15.2
mmol) of R,â-unsaturated ester 11a in 30 mL of glacial HOAc
was treated with 0.50 g of 10% Pd/C which had been prewetted
with the same solvent. The mixture was hydrogenated at an
initial pressure of 50 psi for 7 h. The reaction was filtered
through Celite and concentrated in vacuo to afford 4.1 g (12.9
mmol, 85%) of product 12a in analytically pure form as an
oil: 1H NMR (CDCl3) δ 7.89-7.82 (m, 2H), 7.74 (m, 2H), 4.11
(q, J ) 7.1, 2H), 3.67 (t, J ) 7.2 Hz, 2H), 2.44-2.35 (m, 1H),
1.74-1.60 (m, 4H), 1.39-1.28 (m, 4H), 1.24 (t, J ) 7.1 Hz, 3H),
1.12 (d, J ) 7.0 Hz, 3H); IR (CHCl3) 2940, 1771, 1711, 1468,
1398, 1372, 1187 cm-1; FDMS m/e 317 (M+). Anal. (C18H23
-
NO4) C, H, N.
Hep ta n oic Acid , 7-[[(5-Cya n o-1H-in d ol-2-yl)ca r bon yl]-
a m in o]-2-m eth yl-, Eth yl Ester (6k ). A solution of 4.10 g
(13.0 mmol) of phthalimido ester 12a in EtOH (150 mL) was
treated with 6.30 mL (6.50 g, 130 mmol) of hydrazine hydrate
and the mixture heated to reflux for 1 h. The reaction was
allowed to cool and concentrated in vacuo. The residue was
partitioned between Et2O and 1 N aqueous NaOH. The
organic layer was separated, washed with 1 N aqueous NaOH,
dried over Na2SO4, filtered, and evaporated in vacuo to afford
1.90 g of crude amino ester 13a which was used in the
subsequent reaction without purification.
Amino ester 13a was coupled to 5-cyanoindole-2-carboxy-
late11 according to the conditions used in the preparation of
6c to afford product 6k in 40% yield (from 12a ) following
recrystallization from EtOAc: mp 144-145 °C; 1H NMR
(CDCl3) δ 10.65 (br s, 1H), 8.03 (s, 1H), 7.59-7.48 (m, 2H),
6.95 (d, J ) 1.6 Hz, 1H), 6.51-6.43 (m, 1H), 4.15 (q, J ) 7.2
Hz, 2H), 3.55-3.46 (m, 2H), 2.49-2.38 (m, 1H), 1.76-1.62 (m,
3H), 1.52-1.31 (m, 5H), 1.25 (t, J ) 7.2 Hz, 3H), 1.15 (d, J )
6.8 Hz, 3H); IR (CHCl3) 3446, 2939, 2224, 1723, 1653, 1553,
1328, 1216 cm-1; FDMS m/e 355 (M+). Anal. (C20H25N3O3)
C, H, N.
Hep ta n oic Acid , 7-[[[5-(Am in oim in om eth yl)-1H-in d ol-
2-yl]ca r bon yl]a m in o]-2-m eth yl-, Mon o(tr iflu or oa ceta te)
(7k ). Nitrile amide 6k was processed according to conditions
used in the conversion of 3a to 4a to afford amidino indole 7k
in 24% yield following reverse phase chromatography (20%
CH3CN in H2O): mp 266-268 °C; 1H NMR (DMSO-d6/TFA) δ
12.07 (br s, 1H), 9.12 (br s, 2H), 8.75 (br s, 2H), 8.58 (t, J )
5.6 Hz, 1H), 8.19 (s, 1H), 7.62-7.53 (m, 2H), 7.27 (s, 1H), 3.31-
3.22 (m, 2H), 2.34-2.22 (m, 1H), 1.58-1.47 (m, 4H), 1.39-
1.22 (m, 4H), 1.00 (d, J ) 7.0 Hz, 3H), no carboxyl OH
2H-Isoin d ole-2-p en ta n a l, 1,3-Dih yd r o-1,3-d ioxo- (10). A
-78 °C solution of 12.0 mL (17.5 g, 138 mmol) of oxalyl chloride
in 200 mL of CH2Cl2 was treated with a solution of 16.3 mL
(18.0 g, 230 mmol) of DMSO in 100 mL of CH2Cl2 in a dropwise
manner. After stirring at -78 °C for 5 min, a solution of 21.4
g (92.0 mmol) of alcohol 9 in 100 mL of CH2Cl2 was added
dropwise. The reaction was stirred at -78 °C for 15 min when
64.0 mL (46.5 g, 460 mmol) of Et3N was added in one portion.
The cold bath was removed, and the reaction was allowed to
reach 0 °C before 200 mL of H2O was added. The organic layer
was separated, washed with 1 N aqueous HCl (2 × 100 mL),

2854 J ournal of Medicinal Chemistry, 1997, Vol. 40, No. 18
Sall et al.
observed; IR (KBr) 3239, 2937, 1713, 1657, 1529, 1193, 1114,
804, 723 cm-1; FDMS m/e 345 (M + 1); FAB-HRMS m/e
C18H25N4O3 calcd 345.1972, found 345.1896. Anal. (C18H24N4O3‚
CF3CO2H) C, H, N.
(7n ). Nitrile amide 6n was processed according to the condi-
tions used in the conversion of 3a to 4a to afford amidinoindole
7n in 92% yield following trituration of the crude product with
hot EtOAc: 1H NMR (DMSO-d6) δ 12.11 (s, 1H), 11.98 (br s,
1H), 9.15 (s, 2H), 8.89 (s, 2H), 8.65 (t, J ) 5.6 Hz, 1H), 8.22 (s,
1H), 7.64-7.52 (m, 2H), 7.29 (d, J ) 1.8 Hz, 1H), 3.35-3.23
(m, 2H), 2.26-2.15 (m, 1H), 2.06-1.93 (m, 1H), 1.88-1.76 (m,
1H), 1.57-1.44 (m, 2H), 1.40-1.13 (m, 4H), 0.87 (d, J ) 6.5
Hz, 3H); IR (CHCl3) 3330, 3220, 3068, 2942, 1706, 1651, 1569,
1534, 1332, 1190, 1150, 808, 722 cm-1; FDMS m/e 345 (M +
1). Anal. (C18H24N4O3‚CF3CO2H) C, H, N.
Ben zen ep r op a n oic Acid , 4-Cya n o-2-n itr o-r-oxo-, Eth yl
Ester (23). A solution of 30.60 g (188.0 mmol) of tolunitrile
2217 and 20.0 g (1.37 mol) of diethyl oxalate in 300 mL of EtOH
was treated with a solution of NaOEt (generated by dissolving
11.30 g (283.0 mmol) of sodium metal in 300 mL of EtOH),
and the mixture was stirred at ambient temperature for 16 h.
The reaction was neutralized with 56.6 mL of 5 N aqueous
HCl. The EtOH was removed in vacuo, and the resulting
aqueous layer was extracted with CH2Cl2 (500 mL). The
organic layer was washed with H2O, dried over MgSO4,
filtered, and concentrated in vacuo. The oil was placed under
high vacuum to remove excess diethyl oxalate resulting in a
solid. Purification by MPLC (CHCl3) afforded 43.45 g (165.3
mmol, 88%) of product 23 as a yellow solid: 1H NMR (CDCl3)
δ 8.45 (d, J ) 8.3 Hz, 1H), 8.19 (d, J ) 1.6 Hz, 1H), 7.85 (dd,
J ) 8.3, 1.5 Hz, 1H), 7.03 (d, J ) 1.1 Hz, 1H), 6.93 (s, 1H),
4.44 (q, J ) 7.0 Hz, 2H), 1.43 (t, J ) 7.0 Hz, 3H); IR (CHCl3)
3438, 3027, 2238, 1708, 1535, 1258 cm-1; FDMS m/e 262 (M+).
Anal. (C12H10N2O5) C, H, N.
1H -In d ole-2-ca r b oxylic Acid , 6-Cya n o-, E t h yl E st er
(24). Water (180 mL) was added to a solution of 12.1 g (46.2
mmol) of 23 in 180 mL of glacial AcOH, and the mixture was
heated to 75 °C. Zinc dust (230.5 g, 462 mmol) was carefully
added in portions to the hot mixture, and after complete
addition the reaction was stirred at 75 °C for 1 h. The mixture
was cooled, filtered, and concentrated in vacuo. The residue
was partitioned between H2O and EtOAc. The organic layer
was separated, washed with H2O, dried over MgSO4, filtered,
and concentrated in vacuo to give a solid. Purification by
MPLC (10% EtOAc in hexanes) afforded 3.60 g (16.8 mmol,
36%) of indole 24 as a white solid: 1H NMR (DMSO-d6) δ 12.25
(s, 1H), 8.10 (s, 1H), 7.73 (d, J ) 8.6 Hz, 1H), 7.64 (d, J ) 8.5
Hz, 1H), 7.19 (d, J ) 1.9 Hz, 1H), 4.32 (q, J ) 7.0 Hz, 2H),
1.32 (t, J ) 7.0 Hz, 3H); IR (CHCl3) 3451, 3025, 2225, 1710,
1322, 1247 cm-1; FDMS m/e 214 (M+). Anal. (C12H10N2O2)
C, H, N.
1H-In d ole-2-ca r boxylic Acid , 6-Cya n o- (25). A solution
of 7.90 g (37.0 mmol) of ester 24 in 200 mL of EtOH was
treated with 22 mL of 5 N aqueous NaOH (111 mmol). The
reaction was heated to reflux for 3 h. The mixture was cooled
and neutralized with 22 mL of 5 N aqueous HCl (111 mmol).
The mixture was concentrated in vacuo and the residue
partitioned between EtOAc and H2O. The organic layer was
separated, washed with brine, dried over Na2SO4, and con-
centrated in vacuo to a solid. Recrystallization from toluene/
MeOH afforded 3.10 g (16.6 mmol, 45%) of acid 25 as a white
solid: 1H NMR (DMSO-d6) δ 13.21 (br, 1H), 12.31 (s, 1H),
7.89-7.80 (m, 2H), 7.37 (d, J ) 8.3 Hz, 1H), 7.18 (s, 1H); IR
(KBr) 3293, 2234, 1707, 1530, 1247, 1205 cm-1; FDMS m/e 186
(M+). Anal. (C10H6N2O2) C, H, N.
Ca r b a m ic Acid , [5-(Met h oxym et h yla m in o)-5-oxo-
p en tyl]-, P h en ylm eth yl Ester (15). A -15 °C solution of
55.0 g (0.22 mol) of 5-(carbobenzyloxyamino)valeric acid (14)
and 55.4 g (0.26 mol) of 4-methylmorpholine in 500 mL of CH2-
Cl2 was treated with 35.9 g (0.26 mol) of isobutyl chloroformate
in a dropwise manner. After stirring for 45 min, 53.4 g (0.55
mol) of N,O-dimethylhydroxylamine hydrochloride was added
in one portion. The reaction was stirred at -15 °C for an
additional 3 h at which time it was quenched by the dropwise
addition of 500 mL of saturated aqueous NaHCO3. The two
layers were separated, and the organic layer was dried over
MgSO4, filtered, and evaporated in vacuo. Purification by
MPLC (40% EtOAc in hexanes) afforded 30.5 g (0.10 mol, 40%)
of amide 15 as a colorless oil: 1H NMR (CDCl3) δ 7.38-7.29
(m, 5H), 5.09 (s, 2H), 5.05-4.94 (m, 1H), 3.67 (s, 3H), 3.28-
3.14 (m, 5H), 2.44 (t, J ) 6.8 Hz, 2H), 1.74-1.52 (m, 4H); IR
(CHCl3) 3453, 3012, 2941, 1717, 1649, 1516, 1237, 1000 cm-1
;
FDMS m/e 295 (M + 1). Anal. (C15H22N2O4) C, H, N.
Ca r b a m ic Acid , (5-Oxoh exyl)-, P h en ylm et h yl E st er
(16a ). A -78 °C solution of 8.00 g (272. mmol) of Weinreb
amide 15 in THF (200 mL) was treated with 80.0 mL of MeLi
(1.4 M in Et2O, 112 mmol) in a dropwise manner. After
complete addition, the mixture was stirred at -78 °C for 0.5
h and then at 0 °C for 0.5 h. The reaction was cooled to -78
°C and quenched by the dropwise addition of saturated
aqueous NH4Cl (50 mL). The two layers were separated, and
the organic phase was dried over Na2SO4 and filtered. Evapo-
ration of the solvent in vacuo afforded 6.10 g of an oil.
Purification by flash chromatography (15% EtOAc in hexanes)
afforded 4.25 g (17.0 mmol, 63%) of ketone 16a : 1H NMR
(DMSO-d6) δ 7.38-7.21 (m, 6H), 4.98 (s, 2H), 2.95 (q, J ) 6.2
Hz, 2H), 2.39 (t, J ) 7.1 Hz, 2H), 2.04 (s, 3H), 1.48-1.32 (m,
4H); IR (CHCl3) 3454, 2945, 1715, 1516, 1235 cm-1; FDMS
m/e 249 (M+). Anal. (C14H19NO3) C, H, N.
2-Hep ten oic Acid , 3-Meth yl-7-[[(p h en ylm eth oxy)ca r -
bon yl]a m in o]-, 1,1-Dim eth yleth yl ester (17a ). A -10 °C
slurry of 7.40 g (193 mmol) of NaH (60% dispersion in oil) in
400 mL of THF was treated with 47.0 g (185 mmol) of tert-
butyl diethylphosphonoacetate. The temperature of the mix-
ture was allowed to rise to 0 °C, and the mixture was stirred
for 2 h before a solution of 22.0 g (88.0 mmol) of ketone 16a in
75 mL of THF was added dropwise. The reaction was stirred
at ambient temperature for 2 h and was quenched by the
addition of saturated aqueous NH4Cl (100 mL). The mixture
was diluted with H2O and EtOAc, and the layers were
separated. The organic layer was dried over MgSO4, filtered,
and concentrated in vacuo to afford an oil. Purification by
flash chromatography (15% EtOAc in hexanes) afforded 25.81
g (74.3 mmol, 84%) of R,â-unsaturated ester 17a as an oil: IR
(CHCl3) 3453, 2979, 1710, 1646, 1516, 1455, 1369, 1144 cm-1
;
FDMS m/e 348 (M + 1). Anal. (C20H29NO4) C, H, N.
Hep ta n oic Acid , 3-Meth yl-7-[[(5-cya n o-1H-in d ol-2-yl)-
ca r bon yl]a m in o]-, 1,1-Dim eth yleth yl Ester (6n ). A solu-
tion of 7.30 g (21.0 mmol) of R,âunsaturated ester 17a in
EtOAc (25 mL) was added to a slurry of 10% Pd/C (3.00 g) in
10 mL of EtOAc. The mixture was hydrogenated at atmo-
spheric pressure until TLC indicated the complete consump-
tion of starting material (18 h). The reaction was filtered and
concentrated in vacuo to afford the crude amino ester 18a
which was taken onto the next step without purification.
Amino ester 18a was directly coupled to indole acid 5
according to the conditions used in the preparation of 3a to
afford nitrile ester 6n as a white solid in 38% yield following
flash chromatography (40% EtOAc in hexanes): 1H NMR
(CDCl3) δ 10.60 (s, 1H), 8.03 (s, 1H), 7.58-7.47 (m, 2H), 6.98
(d, J ) 1.6 Hz, 1H), 6.61 (t, J ) 5.7 Hz, 1H), 3.61-3.52 (m,
2H), 2.27-2.05 (m, 2H), 2.03-1.91 (m, 1H), 1.75-1.63 (m, 2H),
1.57-1.26 (m, 13H), 0.96 (d, J ) 6.6 Hz, 3H); IR (CHCl3) 3446,
Hep ta n oic Acid , 7-[[(6-Cya n o-1H-in d ol-2-yl)ca r bon yl]-
a m in o]-, 1,1-Dim eth yleth yl Ester (50). Employing the
conditions used in the preparation of 3a , acid 25 and tert-butyl
7-aminoheptanoate were coupled to afford nitrile amide 50 in
59% yield following recrystallization from EtOAc/hexanes: 1H
NMR (CDCl3) δ 12.27 (s, 1H), 7.85 (s, 1H), 7.72 (d, J ) 8.4 Hz,
1H), 7.35 (dd, J ) 8.1, 1.1 Hz, 1H), 6.94 (d, J ) 1.8 Hz, 1H),
6.55 (t, J ) 5.4 Hz, 1H), 3.62-3.53 (m, 2H), 2.24 (t, J ) 7.3
Hz, 2H), 1.78-1.59 (m, 4H), 1.51-1.38 (m, 13H); IR (CHCl3)
3451, 2938, 2224, 1719, 1653, 1546, 1321, 1152 cm-1; FDMS
m/e 369 (M+). Anal. (C21H27N3O3) C, H, N.
3012, 2936, 2224, 1716, 1653, 1554, 1369, 1327, 1156 cm-1
;
Hep ta n oic Acid , 7-[[[6-(Am in oim in om eth yl)-1H-in d ol-
2-yl]ca r bon yl]a m in o]-, Mon o(tr iflu or oa ceta te) (58). Ni-
trile amide 50 was processed by the conditions used in the
conversion of 3a to 4a to afford amidino acid 58 as the
FDMS m/e 383 (M+). Anal. (C22H29N3O3) C, H, N.
Hep ta n oic Acid , 3-Meth yl-7-[[[5-(a m in oim in om eth yl)-
1H-in d ol-2-yl]ca r bon yl]a m in o]-, Mon o(tr iflu or oa ceta te)

Benzamidines for GPIIb-IIIa Receptor Antagonists
J ournal of Medicinal Chemistry, 1997, Vol. 40, No. 18 2855
trifluoroacetate salt in 35% overall yield following trituration
with hot EtOAc: 1H NMR (DMSO-d6) δ 12.21 (s, 1H), 11.97
(br s, 1H), 9.22 (br s, 2H), 8.90 (br s, 2H), 8.65 (t, J ) 5.5 Hz,
1H), 7.87 (s, 1H), 7.82 (d, J ) 8.4, 1H), 7.39 (d, J ) 8.4 Hz,
1H), 7.21 (s, 1H), 3.34-3.23 (m, 2H), 2.18 (t, J ) 7.3 Hz, 2H),
1.59-1.41 (m, 4H), 1.37-1.24 (m, 4H); IR (KBr) 3467, 3354,
3098, 1717, 1667, 1567, 1532, 1195, 1132, 839 cm-1; FDMS
m/e 331 (M + 1). Anal. (C17H22N4O3‚CF3CO2H) C, H, N.
Acetic Acid , (4-Br om o-2-for m ylp h en oxy)-, Eth yl Ester
(33). A slurry of 2.01 g (10.0 mmol) of 4-bromosalicylaldehyde
(32), 1.52 g (11.0 mmol) of K2CO3, and 0.30 g (2.00 mmol) of
NaI in 3 mL of DMF was treated with 1.25 mL (1.84 g, 11.0
mmol) of ethyl bromoacetate in a dropwise manner. The
reaction was stirred at ambient temperature for 15 h, filtered,
and concentrated in vacuo. The residue was taken up in 50
mL of EtOAc, and the mixture was washed with H2O (3 × 25
mL). The organic layer was dried over Na2SO4, filtered, and
evaporated in vacuo to give 3.25 g of an oil. Purification by
flash chromatography (10% EtOAc in hexanes) afforded 2.90
g (10.0 mmol, quantitative) of 33 as an oil: 1H NMR (CDCl3)
δ 10.32 (s, 1H), 7.83-7.72 (m, 2H), 7.18 (d, J ) 8.8 Hz, 1H),
4.99 (s, 2H), 4.15 (q, J ) 7.1 Hz, 2H), 1.19 (t, J ) 7.1 Hz, 3H);
IR (CHCl3) 3029, 1757, 1690, 1593, 1481, 1393, 1182, 1128
cm-1; FDMS m/e 286, 288 (M+). Anal. (C11H11BrO4) C, H.
2-Ben zofu r a n ca r boxylic Acid , 5-Br om o-, Meth yl Ester
(34). A 0 °C solution of 300 mg (1.04 mmol) of aldehyde 33 in
8 mL of MeOH was treated with 75 mg (1.4 mmol) of NaOMe
and the resulting mixture heated to reflux for 15 min. The
reaction was cooled and treated with 5 mL of 1 N aqueous
citric acid. The MeOH was evaporated in vacuo, and the
aqueous layer was extracted with EtOAc (3 × 20 mL). The
combined organic extracts were dried over Na2SO4, filtered,
and concentrated in vacuo to give 285 mg of a white solid. The
solid was taken up in MeOH and the solution treated with a
stream of HCl gas. After stirring for 2 h at ambient temper-
ature, the mixture was evaporated in vacuo. The solid was
recrystallized from hexanes/EtOAc to afford 195 mg (0.76
mmol, 74%) of benzofuran 34 as a white solid: 1H NMR
(CDCl3) δ 7.99 (d, J ) 1.4 Hz, 1H), 6.74-6.60 (m, 2H), 3.87 (s,
3H), no carboxyl OH observed; IR (CHCl3) 1726, 1572, 1430,
1297, 1219, 1088, 975, 809 cm-1; FDMS m/e 254, 256 (M+).
Anal. (C10H7BrO3) C, H.
2-Ben zofu r a n ca r boxylic Acid , 5-Cya n o-, Meth yl Ester
(35). A mixture of 700 mg (2.74 mmol) of bromide 34, 525 mg
(2.76 mmol) of CuI, and 500 mg (5.60 mmol) of CuCN in 10
mL of DMF was heated to 155 °C for 16 h. The mixture was
cooled, filtered over Celite, and concentrated in vacuo. The
residue was partitioned between 50 mL of EtOAc and 50 mL
of H2O. The organic layer was separated, dried over Na2SO4,
filtered, and evaporated in vacuo to give 755 mg of a yellow
solid. Recrystallization from hexanes/EtOAc afforded 495 mg
(2.46 mmol, 90%) of nitrile 35 as a light yellow solid: 1H NMR
(CDCl3) δ 8.37 (s, 1H), 7.99-7.92 (m, 2H), 7.83 (s, 1H), 3.90
(s, 3H); IR (CHCl3) 2229, 1717, 1584, 1302, 1238, 1123, 913,
824, 764 cm-1; FDMS m/e 201 (M+). Anal. (C11H7NO3) C, H,
N.
2-Ben zofu r a n ca r boxylic Acid , 5-Cya n o- (36). The title
compound was prepared in 53% yield from methyl ester 35 by
following the procedure described for the preparation of acid
25: 1H NMR (DMSO-d6) δ 13.90 (br s, 1H), 8.32 (s, 1H), 7.02-
7.84 (m, 2H), 7.71 (s, 1H); IR (KBr) 3418, 2235, 1692, 1578,
1425, 1207, 829 cm-1; FDMS m/e 187 (M+). Anal. (C10H5NO3)
C, H, N.
Nitrile amide 53b was processed under the conditions used
in the conversion of 3a to 4a to afford amidino acid 61b in
41% overall yield following trituration with EtOAc: 1H NMR
(DMSO-d6) δ 11.97 (s, 1H), 9.35 (s, 2H), 9.15 (s, 2H), 8.84 (t, J
) 5.1 Hz, 1H), 8.26 (s, 1H), 7.94-7.79 (m, 2H), 7.67 (s, 1H),
3.35-3.19 (m, 2H), 2.17 (t, J ) 7.3 Hz, 2H), 1.60-1.41 (m, 4H),
1.38-1.17 (m, 4H); IR (KBr) 3321, 3109, 2938, 1672, 1647,
1538, 1456, 1206, 1190, 1132 cm-1; FDMS m/e 332 (M + 1).
Anal. (C17H21N3O4‚CF3CO2H) C, H, N.
1H-In d a zole-3-ca r boxylic a cid , 6-Cya n o- (73). To a
slurry of 3.00 g (21.1 mmol) of 6-cyanoindole (27)18 in a solution
of 14.6 g (211 mmol) of NaNO2 in 200 mL of H2O was slowly
added 32 mL of 6 N aqueous HCl until pH < 2. After stirring
for 3 h, the solution was extracted with EtOAc (5 × 300 mL).
The combined organic layers were dried over MgSO4, filtered,
and concentrated in vacuo to afford 3.40 g of crude 3-formyl-
6-cyanoindazole (72). The aldehyde was not purified but was
directly oxidized according to the methods used in the syn-
thesis of 30 to afford 2.58 g (13.8 mmol, 65% overall yield from
27) of 73: 1H NMR (DMSO-d6) δ 14.34 (br s, 1H), 13.26 (br s,
1H), 8.28 (s, 1H), 8.20 (d, J ) 8.6 Hz, 1H), 7.58 (d, J ) 8.4 Hz,
1H); IR (KBr) 3167, 3129, 2221, 1737, 1695, 1491, 1233, 1167,
824 cm-1; FDMS m/e 187 (M+). Anal. (C9H5N3O2) C, H, N.
H ep t a n oic
Acid ,
7-[[(6-Cya n o-1H -in d a zol-3-yl)-
ca r bon yl]a m in o]-, 1,1-Dim eth yleth yl Ester (74). Employ-
ing the conditions used in the preparation of 3a , nitrile amide
74 was prepared from acid 73 and tert-butyl 7-aminohep-
tanoate in 27% yield following PCTLC (gradient of 10-40%
EtOAc in hexanes): 1H NMR (DMSO-d6) δ 14.11 (s, 1H), 8.54
(t, J ) 5.4 Hz, 1H), 8.30 (d, J ) 8.4 Hz, 1H), 8.24 (s, 1H), 7.54
(d, J ) 8.5 Hz, 1H), 3.30-3.19 (m, 2H), 2.14 (t, J ) 7.2 Hz,
2H), 1.56-1.20 (m, 17H); IR (KBr) 3367, 3155, 2227, 1730,
1641, 1553, 1366, 1153 cm-1; FDMS m/e 371 (M + 1). Anal.
(C20H26N4O3) C, H, N.
Hep ta n oic Acid , 7-[[[6-(Am in oim in om eth yl)-1H-in d a -
zol-3-yl]ca r bon yl]a m in o]-, Mon o(tr iflu or oa ceta te) (75).
Nitrile amide 74 was processed under the conditions used in
the conversion of 3a to 4a to afford amidino acid 75 in 21%
overall yield following trituration with hot EtOAc: 1H NMR
(DMSO-d6) δ 14.23 (s, 1H), 12.02 (br, 1H), 9.50 (br s, 2H), 9.11
(br s, 2H), 8.54 (t, J ) 5.6 Hz, 1H), 8.42 (d, J ) 8.2 Hz, 1H),
8.18 (s, 1H), 7.64 (d, J ) 8.5 Hz, 1H), 3.29-3.49 (m, 2H), 2.28
(t, J ) 4.8 Hz, 2H), 1.62-1.49 (m, 4H), 1.46-1.32 (m, 4H); IR
(KBr) 3361, 3122, 1704, 1667, 1537, 1210, 1194, 1150, 723
cm-1; FAB-HRMS m/e C16H22N5O3 calcd 332.1723, found
332.1716 (M + 1). Anal. (C16H21N5O3‚CF3CO2H) C, H, N.
Ack n ow led gm en t. We are grateful to Dr. Ting Su
of COR Therapeutics, Inc. for her support and consulta-
tion during the course of this project. We would like to
thank the Physical Chemistry Department (Lilly Re-
search Laboratories) for their careful characterization
of the compounds reported in this manuscript. In
particular, we are grateful to J im Gillam and Bob
Brickley for their mass spectral work and to J im
Schwarz for the infrared spectra that are reported.
Su p p or tin g In for m a tion Ava ila ble: Experimental pro-
cedures, physical chemical data, and analytical data for all
synthetic intermediates and final products of this study (41
pages). Ordering information is given on any current mast-
head page.
H ep t a n oic Acid , 7-[[(5-Cya n o-2-b en zofu r a n yl)ca r -
bon yl]a m in o]-, Meth yl Ester (53b). Employing the condi-
tions used in the preparation of 3a , nitrile amide 53b was
prepared from acid 36 and methyl 7-heptanoate as a white
solid in 48% yield following flash chromatography (0% then
10% THF in CH2Cl2): 1H NMR (DMSO-d6) δ 8.81 (t, J ) 5.7
Hz, 1H), 8.32 (s, 1H), 7.87-7.81 (m, 2H), 7.57 (s, 1H), 3.52 (s,
3H), 3.28-3.16 (m, 2H), 2.24 (t, J ) 7.4 Hz, 2H), 1.54-1.43
(m, 4H), 1.29-1.20 (m, 4H); IR (KBr) 3369, 2932, 2853, 2226,
1717, 1675, 1599, 1532, 1462, 1435, 1278, 1201, 1124, 822
cm-1; FDMS m/e 328 (M+). Anal. (C18H20N2O4), C, H, N.
Hep ta n oic Acid , 7-[[[5-(Am in oim in om eth yl)-2-ben zo-
fu r a n yl]ca r bon yl]Am in o]-, Mon o(tr iflu or oa ceta te) (61b).
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(31) Molecular modeling was done on a Silicon Graphics workstation
using QUANTA96, version 96.1008, from Molecular Simulations
Inc., San Diego, CA. Conformations were generated by an
exhaustive grid scan of all torsions at 45° increments followed
by 1000 steps of the adopted-basic Newton Raphson energy
minimization method. For computer modeling purposes, the
amidine moiety was represented by a methyl group and the
aliphatic side chain was truncated to a methyl group. The acyclic
compound model of 4b contained seven torsion angles resulting
in 4096 conformations which were minimized and analyzed. The
model for the cyclic compound 7c contained four torsion angles
resulting in 256 conformations which were minimized and
analyzed.
(32) Low-energy conformations of the N-H and N-Me derivatives
(7c,e) were generated using the software package QUANTA,
version 4.1.1 (Molecular Simulations, Inc., San Diego, CA) using
a SGI Indigo R4000 workstation.
(33) Interatomic distances were measured using Macromodel (version
4.0) on an Antares Silicon Graphics workstation R4400 using
molecular structures which had been minimized with the MM3
force field.
J M970020K