Non-peptide RGD surrogates which mimic a Gly-Asp β-turn: Potent antagonists of platelet glycoprotein IIb-IIIa

Article abstract of DOI:10.1021/jm9701076

Cyclic heptapeptide 1, which contains an Arg-Gly-Asp sequence, has good affinity for the platelet receptor GPIIb-IIIa and was chosen for study by ¹H NMR techniques. The key RGD sequence of this molecule was found to reside in a conformationally defined type II' Gly-Asp β-turn, and this information was used in the design of simple non-peptide RGD mimics. Disubstituted isoquinolones, bearing an acidic side chain at position 2 and a basic side chain at position 6, were prepared and were found to have modest affinity for GPIIb-IIIa. Systematic modification of the basic residue contained in these molecules yielded compounds with high affinity for GPIIb-IIIa.

Full text of DOI:10.1021/jm9701076

J . Med. Chem. 1997, 40, 2085-2101
2085
Non -P ep tid e RGD Su r r oga tes Wh ich Mim ic a Gly-Asp â-Tu r n : P oten t
An ta gon ists of P la telet Glycop r otein IIb-IIIa
Matthew J . Fisher,* Bruce Gunn, Cathy S. Harms, Allen D. Kline, J effrey T. Mullaney, Anne Nunes,
Robert M. Scarborough,† Ann E. Arfsten,† Marshall A. Skelton, Suzane L. Um, Barbara G. Utterback, and
J oseph A. J akubowski
Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, Indiana 46285
Received February 24, 1997X
Cyclic heptapeptide 1, which contains an Arg-Gly-Asp sequence, has good affinity for the platelet
receptor GPIIb-IIIa and was chosen for study by 1H NMR techniques. The key RGD sequence
of this molecule was found to reside in a conformationally defined type II′ Gly-Asp â-turn, and
this information was used in the design of simple non-peptide RGD mimics. Disubstituted
isoquinolones, bearing an acidic side chain at position 2 and a basic side chain at position 6,
were prepared and were found to have modest affinity for GPIIb-IIIa. Systematic modification
of the basic residue contained in these molecules yielded compounds with high affinity for
GPIIb-IIIa.
In tr od u ction
While several of these modified peptides have a
clinically attractive profile for parenteral use,6a the
metabolic liability of amide bonds may limit their use
as oral drugs. Accordingly, much effort has been put
into the search for non-peptide antagonists of GPIIb-
IIIa. A wide variety of non-peptide antagonists of
GPIIb-IIIa have been discovered using a number of
methods including compound screening, modification of
Activation of platelets by a variety of agonists pro-
motes binding of the plasma-proteins fibrinogen and
von Willebrand factor and leads to the formation of
platelet aggregates. This aggregation phenomenon is
mediated by membrane-associated glycoprotein (GP)
IIb-IIIa, to which fibrinogen and other adhesive ligands
bind.1-3 While platelets play a vital role in hemostasis,
uncontrolled aggregation can lead to occlusive throm-
botic disorders.4,5 Therefore, the search for agents that
can modulate platelet function has been a significant
area of pharmaceutical research.6 Inhibition of platelet
activation provides a means of controlling aggregation,
however, due to the large number of known activating
agonists, this approach has limitations. An alternative
strategy would be to inhibit the final common pathway,
the binding of fibrinogen to GPIIb-IIIa, thus controlling
aggregation irrespective of the activator.7,8
RGD peptides, and structure-based design.27-43
The
latter method relies on the use of structural information
obtained from known biological entities (either receptor
or ligand) in the design of small molecule leads. This
approach may have limitations in that the experimen-
tally determined structure may or may not represent
an active conformation. Nevertheless, such data is a
potentially powerful aid in the design of molecules which
have the desired biological activity. Compounds identi-
fied by this approach can in turn be optimized through
standard medicinal chemistry techniques. We herein
describe our approach to the rational design of GPIIb-
IIIa antagonists which utilized the elements of peptide
structural evaluation and classic medicinal chemistry.
The binding of fibrinogen to platelet GPIIb-IIIa is
known to occur through the interaction of activated
GPIIb-IIIa with at least one of two RGD (arginine-
glycine-aspartic acid) tripeptide sequences located at
positions 95-97 and 572-574 on the R-chain of
fibrinogen.9-12 The RGD motif has therefore become the
template for development of platelet aggregation inhibi-
tors, and extensive chemical modifications of this se-
quence have narrowed the functional groups required
for activity to the basic group of the arginine and the
acidic group of the aspartate.13,14 Activity is not seri-
ously affected by changing the nature of the basic
residue in the arginine moiety but the configuration and
length of the acidic side chain of the aspartate moiety,
are critical for activity.15 The above findings were
instrumental in the discovery of modified linear peptides
with enhanced activity toward GPIIb-IIIa.16 Constrain-
ing modified RGD sequences by cyclization has also led
to compounds with significantly greater affinity for
GPIIb-IIIa.17-26
Str u ctu r a l Eva lu a tion
As discussed, the RGD motif represents an attractive
template for structure-based drug design. In an effort
to understand the spatial relationship between the key
pharmacophores in this sequence, a number of small
peptide fragments have been examined by NMR. How-
ever, as linear peptides are quite flexible, little concrete
information about the active conformation was ob-
tained.44 Similar results were obtained from the NMR
analysis of a series of snake venom proteins (disinte-
grins). In these cases, the RGD motif was contained in
a long flexible loop which provided little insight into
mimetic design.45,46 Recently, small, highly active RGD-
containing cyclic peptides have been synthesized and
studied by NMR. Significant conformational detail was
obtained about the RGD triad, and this information was
successfully used in the design and synthesis of active
GPIIb-IIIa antagonists.36,37,40
We have reported the synthesis and optimization of
a variety of RGD-containing cyclic peptides with high
affinity toward GPIIb-IIIa.23 Many of these molecules
* To whom correspondence should be addressed.
† COR Therapeutics, Inc., South San Francisco, CA.
X Abstract published in Advance ACS Abstracts, May 15, 1997.
S0022-2623(97)00107-6 CCC: $14.00 © 1997 American Chemical Society

2086 J ournal of Medicinal Chemistry, 1997, Vol. 40, No. 13
Fisher et al.
F igu r e 1. Structure of cyclic peptide 1.
are heptapeptides containing a modified “RGD” se-
quence cyclized via an N-terminal mercaptopropionate
(Mpr) and a C-terminal penicillamine (Pen). We have
examined one of these peptides (1) using 1H NMR
methods with a view toward defining the conformation
of the RGD region (Figure 1). The data from these
experiments permitted proton assignment utilizing the
classical “Wu¨thrich” method.52 Spectra indicated two
complete sets of resonances with a ratio of 1:2 and were
attributed to the presence of cis/ trans isomers at the
Trp-Pro amide bond. Isomer assignment was based on
NOE’s observed across this amide bond, and integration
of the Trp aromatic proton signals revealed that the
trans form predominated. We evaluated the trans
isomer but were aware that either isomer could repre-
sent the active species.
Using the proton assignments, distance constraints
could be designated from the cross peaks in the 2D-
ROESY53 experiment, and ultimately 15 were identified
for use in subsequent calculations. All ROESY cross
peaks were assigned to either intraresidue or sequential
NOE’s, and no long-range NOE’s were observed. The
Trp-5 amide proton was found to be resistant to D2O
exchange, suggesting its involvement in hydrogen bond-
ing. While the Trp amide plays an important role in
the solution conformation, the identity of its hydrogen
bond acceptor could not be determined directly by NMR
experiments.
Given the constraints of the peptide backbone con-
nectivity and the observed NOE measurements, the
carbonyl oxygens of the Mpr, Pen, and Arg residues
were potentially accessible for hydrogen bonding to the
Trp amide proton. In order to ascertain the identity of
the acceptor, each of these possible hydrogen-bond
partners were evaluated using distance geometry cal-
culations. When the hydrogen bond was constrained
between Trp-5 and the Pen-7, the resulting structures
had large violations in backbone connectivity and NOE
constraints, thus precluding the Pen-7 carbonyl from
being the acceptor. Calculations with the Mpr and the
Arg carbonyl oxygen atoms gave structures that did not
violate any of the constraints by more than 1.0 Å,
indicating that both of these hydrogen bonds were
reasonable. Closer examination of the data, however,
revealed that conformations having a Trp-Arg hydrogen
bond were better able to satisfy all of the NOE distance
constraints and possessed lower overall energies than
structures with a Trp-Mpr hydrogen bond. As a result,
we chose to evaluate the RGD region of structures that
included a Trp-Arg hydrogen bond.
F igu r e 2. View of the type II′ â-turn structures resulting from
a Trp-Arg hydrogen bond. Shown is the backbone of the Arg-
Gly-Asp region along with the Trp amide nitrogen and proton.
the RGD triad. In all, five distinct families were
identified, with examples of type I′, II, II′, III, and III′
â-turns being observed in the minimized structures of
1; nearly half of the structures fell into the type II′
classification. To determine how well the families
satisfied the experimental constraints, each was evalu-
ated on the basis of their NOE violations. Both the type
II and II′ turns consistently satisfied the entire set of
constraints better than any of the other families. Thus
the NOE data is most consistent with a Trp-Arg
hydrogen bond and with the RGD sequence adopting a
Gly-Asp type II or II′ turn. Since a majority of the
calculated structures fell into the type II′ family, this
structure was used as the basis for design consider-
ations. The critical Gly-Asp segment of this structure
is shown in Figure 2.
The design of the inhibitors described in this report
followed directly from analysis of the structure il-
lustrated in Figure 2. Noteworthy is the fact that the
Asp and Arg side chains are flexible, but their point of
attachment to the backbone and the backbone itself
appear well ordered. The side chain of the aspartate
and the arginine residues are roughly in the same plane
and diagonally disposed across a slightly cupped Gly-
Asp â-turn. Our working hypothesis for compound
design was that the side chains of the aspartate and
arginine residues played the dominant role in binding
to GPIIb-IIIa and that other functionality found in the
RGD sequence was of lesser importance. Therefore,
non-peptide templates that would approximate the
observed â-turn and fix these key groups close to the
geometry suggested by Figure 2 were initial candidates
for synthesis.
The exact nature of the â-turn surrogate was made
apparent after studying a two-dimensional representa-
tion (Figure 3) of the partial structure shown in Figure
2. The turn itself contains 10 atoms and bears a
resemblance to a decalin ring system substituted at the
2 and 6 positions with an acidic moiety and a basic
moiety, respectively. Further analysis of this structure
indicated that the basic side chain attaches to the
pseudo A ring via an sp2 center while the acidic side
chain emanates from the pseudo B ring via an sp3
center. We therefore chose to mimic this turn with a
linearly fused 6,6 ring system in which the A ring was
aromatic and the B ring was aliphatic. Using these
considerations, we felt that an appropriately substituted
3,4-dihydro-1-oxoisoquinolone54 would make a reason-
able starting point for synthesis.
The possible types of conformations for the RGD
sequence and how well each satisfied the aforemen-
tioned constraints were determined next. The Trp-Arg
structures, which showed â-turns at the Gly-Asp posi-
tion, were classified based on the φ,ψ angles through

Non-Peptide RGD Surrogates
J ournal of Medicinal Chemistry, 1997, Vol. 40, No. 13 2087
F igu r e 3. Two-dimensional representation of the Gly-Asp â-turn shown in Figure 2 along with idealized â-turn surrogates.
Sch em e 1a
carbon congener 26 was prepared by coupling 4-cyano-
57
phenethanol with phenol 8 using Mitsunobu
condi-
tions. The nitrile moiety contained in these molecules
was transformed into a BOC-protected amidine by using
a series of transformations, namely (1) conversion to the
thioamide with H2S, (2) alkylation with methyl iodide,
(3) reaction of the intermediate thioimidate with am-
monium acetate, and (4) Boc protection of the formed
amidine to provide 22, 23, and 27.58 Removal of the
Boc and tert-butyl moieties was accomplished simulta-
neously with neat TFA to afford the desired amidino
acids 24, 25, and 28.
Compounds containing alkyl substitution at C6 were
prepared via triflate 29 as outlined in Scheme 5.
Triflate 29 was allowed to react with (4-cyanophenyl)-
acetylene59 in the presence of palladium to provide
acetylenic compound 33.60 The nitrile moiety in 33 was
transformed into a Boc-protected benzamidine 34 using
the same series of reactions previously described. Se-
lective hydrogenation of 34 with palladium on BaSO4
yielded the cis-olefin 36 while palladium on carbon
afforded the alkane 38. Bis deprotection of these
compounds with TFA provided the desired amidino
acids 35, 37, and 39. Reaction of triflate 29 with
4-cyanostyrene by the method of Heck61 afforded the
trans-olefin 30. Conversion of the nitrile 30 into the
BOC-protected amidine 32 was uneventful, and depro-
tection with TFA afforded amidino acid 32.
a
(a) BzlBr/K2CO3; (b) NaH/tert-butyl bromoacetate; (c) H2/PdC.
Ch em istr y
Isoquinolones 8 and 9 served as the foundation for
all of the compounds described in this paper. Their
synthesis is outlined in Scheme 1 and begins with
protection of the free phenol functionality of 2 and 355
with benzyl bromide which provided lactams 4 and 5.
These compounds were alkylated on nitrogen with tert-
butyl bromoacetate to give monosubstituted derivatives
6 and 7. The benzyl group was then removed with
catalytic palladium and hydrogen to afford phenols 8
and 9.
Triflate 29 also provided access to derivatives con-
taining a C6 acyl moiety (Scheme 6). Palladium-
catalyzed carbon monoxide insertion in the presence of
methanol afforded ester 40, which could be selectively
saponified with aqueous LiOH in THF to yield benzoic
acid 41. Treatment of acid 41 with oxalyl chloride and
subsequent reaction with 4-aminobenzonitrile provided
amide 47. Transformation of this material into the
desired amidino acid 49 was accomplished using the
sequence previously described for the preparation of 24.
An isoquinolone analog which contained C6 nitrogen
substitution was prepared from the acid 41 by Curtius
rearrangement.62 Treatment of 41 with diphenyl phos-
phorazidate in toluene at 85 °C smoothly effected
conversion to the corresponding isocyanate which was
not isolated but was reacted with benzyl alcohol to
provide carbamate 42. Catalytic hydrogenation over
palladium on carbon produced aniline 43, which was
allowed to react with 4-cyanobenzoic acid in the pres-
ence of EDCI to give amide 44. Transformation of this
compound into the desired amidino acid 46 was ac-
complished as for previous benzamidines.
Compounds containing a C6 ether-linked primary
alkyl amine or guanidine were prepared as outlined in
Scheme 2. In the first step, phenol 8 was allowed to
react with phthalimido bromides 10a -f (Table 1) in the
presence of K2CO3 to yield derivatives 11a -f. The
phthalimide moiety was removed with excess aqueous
hydrazine in ethanol. Treatment of the crude amine
with TFA provided amino acids 12a -f. The guanidine-
containing compounds 14a -f were obtained in a similar
manner. Removal of the phthalimide with hydrazine
followed by reaction of the crude amine with N,N′-bis-
(tert-butoxycarbonyl)-S-methoxyisothiourea afforded the
protected guanidines 13a -f.56 Complete deprotection
was accomplished with neat TFA which provided the
desired guanidino acids 14a -f as their TFA salts. Both
the amine- and the guanidine-containing compounds
were subjected to salt exchange with HCl, as their TFA
salts proved to be deliquescent. Compounds containing
C7 ether-linked alkyl guanidines were prepared from 9
in a like manner.
Incorporation of C6 ether-linked 4-alkyl piperidines
was accomplished in a similar fashion (Scheme 3).
Bromides 17a -d (Table 2) were allowed to react with
phenol 8 in the presence of K2CO3 to provide adducts
18a -d . These materials were subjected to TFA depro-
tection and salt exchange with HCl to yield piperidino
acids 19a -d .
Ether-linked benzamidine-substituted isoquinolones
were prepared as outlined in Scheme 4. Alkylation of
phenols 8 and 9 with 4-cyanobenzyl bromide in the
presence of K2CO3 provided nitriles 20 and 21. The two-
Resu lts
Compounds were evaluated for activity initially with
an ELISA assay which employed purified human plate-
let GPIIb-IIIa and measured the inhibition of fibrino-
gen binding to immobilized GPIIb-IIIa. Compounds
which displayed appropriate activity in this assay (IC50
< 1 µM) were further characterized in a functional assay
which measured the compound’s ability to inhibit the

2088 J ournal of Medicinal Chemistry, 1997, Vol. 40, No. 13
Fisher et al.
Sch em e 2a
a
(a) 10a -f/K2CO3; (b) NH2NH2; (c) TFA; (d) BocNHC(NBoc)SCH3.
Sch em e 3a
Ta ble 1. Alkylating Agents 10
a
aggregation of human platelets induced by ADP (5 µM)
in platelet-rich plasma (PRP). Peptide 1, which afforded
an IC50 of 0.035 µM in the ELISA assay and inhibited
ADP induced platelet aggregation with an IC50 of 0.3
µM, served as a benchmark throughout this study.
The first series of compounds was designed to test the
predictions afforded by the solution conformation of 1.
Four compounds were prepared (14a ,b, 15, and 16) in
which the length (four vs five atoms) and position (C6
vs C7) of the basic residue were varied (see Table 3).
Compound 14a , which contains a C6-linked arginine
isostere and represents an atom-for-atom mimic of the
â-turn depicted in Figure 2, showed modest affinity for
GPIIb-IIIa (IC50 ) 44 µM, ELISA). The C7 isomeric
compound 15 was found to be inactive at concentrations
of 100 µM in the ELISA assay. Elongation of the tether
between the guanidine moiety and the backbone sur-
rogate in each isomer by one carbon was beneficial for
both series with the C6 substitution (14b) maintaining
better overall activity. With these simple arginine
mimics, C6 substitution afforded compounds with some-
what greater affinity for GPIIb-IIIa than those with
the basic moiety attached to C7.
(a) 17a -d , K2CO3; (b) TFA.
Ta ble 2. Alkylating Agents 17
the guanidine moiety and the isoquinolone nucleus with
a chain length of four or five carbons gave modest
improvements in activity (ELISA). Introduction of
conformational constraint into this chain by incorporat-
ing a para-substituted phenyl ring (14e) increased
activity while meta substitution (14f) decreased activity
to relative to 14e. The corresponding primary amine
containing analogues 12a -f followed the same trend as
their guanidine-containing counterparts 14a -f and
afforded similar activity (Table 3). Piperidine-contain-
ing compounds displayed similar activity as evidenced
by derivatives 19a -d (Table 4). The cyclic secondary
amine construct offers an advantage in activity (ELISA)
over its amine or guanidine counterpart, and with the
chain length of four carbons, modest inhibition of
platelet aggregation (PRP) was observed.
At this point, either series could have served as a lead
for further optimization. The activity difference be-
tween 14b (C6 substitution) and 16 (C7 substitution),
while not large, did serve to focus our attention on
compounds containing a C6-linked arginine isostere. The
relationship between activity and the length of the
tether, as well as the nature of the basic group (Table
3), was examined next. Increasing the distance between
Replacing the flexible basic side chain with a benz-
amidine moiety afforded analog 24, which displayed
submicromolar activity (IC50 ) 0.6 µM) in the ELISA
(Table 5). Increasing the linkage by one methylene unit
(28) resulted in a loss of activity and suggested the

Non-Peptide RGD Surrogates
J ournal of Medicinal Chemistry, 1997, Vol. 40, No. 13 2089
Sch em e 4a
a
(a) R-Bromo-p-tolunitrile/K2CO3; (b) H2S; CH3I; NH4OAc; Boc2O; (c) TFA; (d) 4-cyanophenethyl alcohol, diethyl azodicarboxylate,
Ph3P.
Sch em e 5a
a
(a) Tf2O; (b) 4-cyanostyrene, Pd(Ph3P)4; (c) H2S, MeI, NH4OAc, Boc2O; (d) TFA; (e) (4-cyanophenyl)acetylene, Pd(Ph3P)2Cl2; (f) H2,
Pd/BaSO4; (g) H2, Pd/C.
single-carbon spacer was preferred. In order to verify
our earlier findings regarding optimum placement of the
basic side chain on the isoquinolone nucleus, the C7-
substituted isomer 25 was prepared. Activity data
(ELISA) confirmed that C7 substitution was less optimal
than C6 substitution.
was next examined (Table 5). Replacement of the ether
oxygen of 24 by a methylene provided compound 39,
which displayed a 5-fold activity increase in the ELISA
and a 25-fold increase in the aggregation assay. Ex-
change of the alkyl linker for an acetylene linker gave
linear construct 35, which provided a further modest
increase in activity (0.033 µM, ELISA; 0.52 µM, PRP).
Partial hydrogenation of 35 provided a cis linkage (37)
Since the benzamidine moiety afforded an increase
in activity, its connectivity to the isoquinolone nucleus

2090 J ournal of Medicinal Chemistry, 1997, Vol. 40, No. 13
Fisher et al.
Sch em e 6a
a
(a) CO, MeOH, Pd(Ph3P)4; (b) LiOH; (c) diphenyl phosphonazidate/BzlOH; (d) H2, Pd/C; (e) 4-cyanobenzoic acid; (f) H2S, MeI, NH4OAc,
Boc2O; (g) TFA; (h) 4-aminobenzonitrile.
Ta ble 3. Activity Data for Alkylamine- and
Ta ble 4. Activity Data for Alkylpiperidine-Containing
Guanidine-Containing Isoquinolones
Isoquinolones
ELISA
PRP
compd
X
IC50 (µM)a
IC50 (µM)b,c
19a
19b
19c
19d
CH2
55
11
6
nt
nt
nt
(CH2)2
(CH2)3
(CH2)4
ELISA
1.8
9.8
compd
X
IC50 (µM)a
As in Table 1. b Concentration required to reduce ADP-induced
a
12a
12b
12c
12d
12e
12f
14a
14b
14c
14d
14e
14f
15
(CH2)3
(CH2)4
(CH2)5
(CH2)6
48
18
28
19
12
77
44
10
9
human platelet aggregation response by 50%. The IC50 values are
expressed as the average of at least two determinations. The
average error for the IC50 determinations was (16%. c nt ) not
tested.
p-CH2(C6H4)CH2
m-CH2(C6H4)CH2
(CH2)3
These results suggested that activity was enhanced
with increased rigidity between the amidine moiety and
the supporting nucleus and that a linear or trans array
about the two linking atoms was preferred. In an effort
to further probe this area of the molecule, heteroatom-
based linkers that provided a trans geometry were
examined. Toward this end, amides 46 and 49 were
prepared. The amide analog derived from C6 carboxyl
substitution (49) was similar in potency to compound
32, again indicating that a trans orientation was
optimal, while the reversed amide (46), derived from a
C6 amine, showed a 1 order of magnitude increase in
both ELISA and aggregation assays.
(CH2)4
(CH2)5
(CH2)6
12
4
14
p-CH2(C6H4)CH2
m-CH2(C6H4)CH2
(CH2)3
<100
16
(CH2)4
46
a
Concentration required to reduce binding of fibrinogen to
purified GPIIb-IIIa by 50%. The IC50 values are expressed as
the average of at least two determinations. The average error for
the IC50 determinations was (15%.
which introduced a bend into the molecule and caused
activity to decrease by 7-fold (ELISA, 0.29 µM). The
isomeric trans compound 32, which provided a linear
relationship between the amidine and the nucleus, was
roughly equipotent with 35 in the ELISA and slightly
more active in the platelet aggregation assay.
Discu ssion
Examination of the literature reveals that consider-
able effort has been expended in the elucidation of the
topography of RGD-containing, conformationally con-

Non-Peptide RGD Surrogates
J ournal of Medicinal Chemistry, 1997, Vol. 40, No. 13 2091
Ta ble 5. Activity Data for Benzamidine Containing
Isoquinolones
basic
position
ELISA
PRP
compd
X
IC50 (µM)a
IC50 (µM)b,c
24
25
28
32
35
37
39
46
49
C6
C7
C6
C6
C6
C6
C6
C6
C6
CH2O
CH2O
(CH2)2O
trans-CHdCH
CtC
cis-CHdCH
CH2CH2
CONH
0.6
4
6
0.048
0.033
0.29
0.11
0.003
0.076
30
nt
nt
0.34
0.52
5.7
1.2
0.09
0.56
NHCO
a
See Tables 3 and 4.
strained peptides.47-51 A majority of these structural
and computational investigations63,64 concluded that the
RGD triad is conformationally defined with the arginine
and aspartate residue both held in turns separated by
glycine (see Figure 4). This turn-extended-turn confor-
mation49 of the RGD triad fixes the position of the
aspartate and the arginine side chains and imparts a
cup shape to the sequence. In general, RGD-containing
peptides which offer conformations other than the turn-
extended-turn motif show diminished activity.48 The
apparent cup shape of the RGD sequence and the turn-
extended-turn relationship have been used successfully
for the design of a γ-turn mimic37 for the aspartate
region and in the design of centrally constrained RGD
mimics like SB-20865136 and G-624940 (see Figure 4).
Our data, derived from NMR studies of peptide 1, are
consistent with the literature in that the RGD region
is conformationally defined. However, the dominant
solution conformation for the RGD triad contained in
this peptide is best described by a Gly-Asp â-turn and
not the generally observed turn-extended-turn. Never-
theless, peptide 1 afforded good activity in the GPIIb-
IIIa ELISA (0.035 µM) and aggregation assays (IC50 0.3
µM). A possible explanation for this apparent contra-
diction is that the major conformation of 1 is not a
contributor to antagonist activity and that the minor,
uncharacterized conformation maintains the active
turn-extended-turn topography. A comparison of the
potency of isoquinolones differentially substituted at the
6 and 7 positions may provide insight about the con-
formation of the RGD sequence contained in peptide 1.
In general, the compounds which are substituted at the
2 and 6 positions of the isoquinolone nucleus effectively
mimic the proposed Gly-Asp â-turn and display reason-
able activity (Tables 3-5). In comparison, analogs with
substitution at the 2 and 7 positions (15, 16, and 25),
which closely mimic the turn-extended-turn motif, are
in this series generally less active than their 2,6
disubstituted counterparts (14a ,b and 24). While it is
not possible to define with certainty the active confor-
mation of peptide 1, these data suggest that a Gly-Asp
â-turn may be responsible for the activity observed.
While the turn-extended-turn and Gly-Asp turn types
afford different placement of the critical pharmaco-
phores, it is apparent that either conformation is
conducive to binding to GPIIb-IIIa. In an effort to
rationalize this observation, it has been proposed that
the receptor may have one extended or two distinct
F igu r e 4. Shown above is a two-dimensional representation
of an RGD sequence in a “turn-extended-turn” orientation and
examples of active centrally constrained RGD mimics whose
design followed from this conformation.
F igu r e 5.
cation binding sites.65 The turn-extended-turn binding
site has been suggested to be available to compounds
like SB-208651 and G-6249 in which the acidic and basic
moieties are angularly disposed on a central constraint
(see Figure 5). It can be inferred from the literature65,66
and the results presented in this paper that the Gly-
Asp binding site accommodates compounds in which the
basic and acidic residues have a linear relationship
across a central constraint.67
One can use the above rationalization to suggest that
activities from compounds like 24 and 25 result from
each accessing a unique cation binding site on GPIIb-
IIIa, but the data from these two compounds alone is
not convincing. For either compound, the distance
between the critical pharmacophores remains relatively
constant. If the distance between the acidic and basic
residues is in fact the key determinant for activity, it is
not surprising that both compounds display activity. A
more convincing argument for an extended binding site
can, however, be made after comparing the activities
and structures of compounds 32 and 37. Compound 37
differs from compound 32 in that the cis double bond
changes the overall geometry of the molecule from linear
to bent and it forces the benzamidine moiety out of the
plane of the central constraint. These structural changes
close the distance between the acidic and basic residue
by approximately 4 Å. That 37 is only 6-fold less active
than 32 demonstrates that the GPIIb-IIIa receptor can
accommodate a variety of ligand topographies and
therefore provides additional evidence for the enlarged
binding site hypothesis.68

2092 J ournal of Medicinal Chemistry, 1997, Vol. 40, No. 13
Fisher et al.
Rigid molecules like 37, 46, 49, and 35 offer a unique
opportunity to study optimum distances and geometries
for RGD mimics which occupy the Gly-Asp binding site
in the GPIIb-IIIa receptor. Apparent from these
structures is the fact that there is a linear relationship
between the acidic and basic groups and the benz-
amidine moiety is coplanar with the central constraint.
The distance between the terminal amine of the amidine
and the carbon of the carboxylate of these four com-
pounds is roughly 16 Å. Of interest is the fact that the
central constraint chosen as a surrogate for the Gly-
Asp â-turn observed for 1 is flat. Mimicking the cup
shape of the RGD region and proper orientation of the
Asp side chain have been thought to be important
factors in the design of turn-extended-turn mimics.40
The activity displayed by these four compounds suggest
that conformational flexibility in the central constraint
is of little importance for Gly-Asp â-turn mimics.
Rather, this data indicates that relative position, dis-
tance, and a near coplanar relationship between the two
key pharmacophores are the most important factors to
consider in the design of this type of RGD mimic.
Optimization for the Gly-Asp mimic described in this
paper was accomplished by adjusting the distance of the
basic moiety from the central constraint, thereby fixing
the critical distance between the acidic and basic
moieties, and refining the nature and orientation of the
basic group. Our data indicates that there is an
optimum distance of roughly 15-16 Å between the
carbon of the carboxylate and the terminal amine of the
arginine mimic. We found that activity varies with the
nature of the basic residue, with guanidine and primary
amines providing modest activity in this series. Sub-
stituted piperidines have been shown to be effective
arginine surrogates,27 and we have found similar re-
sults. Consistent with other disclosures in the litera-
ture,34,35 the benzamidine moiety provides by far the
greatest increase in activity and its placement two
atoms removed from the backbone mimic is optimum.
Rigidification of the two-atom linkage between the
benzamidine group and the central constraint provided
further increases in activity with a linear or trans
linkage providing the most benefit. Preference for a
two-atom trans array is also seen with amide derivatives
46 and 49. The activity of amide 49 compares favorably
with that of trans olefin 32, while the reversed amide
46 shows a 1 order of magnitude increase in activity.
This data suggests that the amide linkage contained in
derivative 46 interacts favorably, possibly through a
hydrogen bond donor-acceptor relationship with comple-
mentary functionality in the receptor.
increase was obtained by optimization of only one of the
critical pharmacophores. That significant increases in
activity were made without modifying the Asp portion
of the molecule suggests that additional improvements
may still be achieved in this series. Efforts toward
optimizing the acidic pharmacophore will be reported
separately.
Exp er im en ta l Section
All starting materials were commercially available or previ-
ously reported in the literature unless noted. All reactions
were run in an atmosphere of dry nitrogen, and solvents and
reagents were used without purification with the exception of
THF which was distilled from sodium/benzophenone. Nuclear
magnetic resonance spectra for characterization of synthesis
products were recorded at 300 MHz on GE QE-300 and Bruker
AC-300 spectrometers. Chemical shifts are reported in parts
per million relative to tetramethylsilane. High-resolution
mass spectra were recorded on a VG Analytical ZAB2-SE
instrument, and FD mass spectra were recorded on a MAT-
731 instrument. Infrared spectra were recorded on a Nicolet
DX10 FT-IR spectrometer with the medium noted in the
individual experiment. Melting points were recorded on a
Thomas-Hoover melting point apparatus and are uncorrected.
Elemental analyses were performed at Lilly Research Labo-
ratories by the Physical Chemistry Department and are within
(0.4% of theory unless otherwise noted.
NMR An a lysis a n d Com p u ta tion a l In vestiga tion of
Cyclic P ep tid e 1. The samples for NMR were prepared by
dissolving the peptide into either 2H2O (MSD Isotopes) or a
mixture of H2O/2H2O (9:1) and adjusting the pH to a meter
reading of 6.0, resulting in final peptide concentrations of 10-
20 mM. The NMR experiments were carried out on a Varian
Unity 500 MHz spectrometer. The NMR probe temperature
was set to 21 °C for all the experiments.
One-dimensional spectra were recorded using 16384 com-
plex points over a spectral width of 8000 Hz. For the spectra
recorded in H2O, continuous wave presaturation was used to
suppress the solvent signal. The two-dimensional DQF-
COSY,69 TOCSY,70,71 and ROESY53 were recorded with spectral
widths of 8000 Hz in both dimensions. The number of complex
points collected in t2 was 4096, with 512 complex FID’s
collected in t1. The ROESY mixing time was 100 ms. The two-
dimensional data sets were processed on a Silicon Graphics
workstation using the software package Felix (Biosym Tech-
nologies, Inc.). Titration studies to determine residues that
were protected from solvent exchange were carried out in a
mixture of H2O/2H2O (9:1). The starting pH was 4.50, and the
pH was decreased upon additions of 0.001 M HCl.
The initial structures were generated using the distance
geometry program DGEOM (Quantum Chemistry Program
Exchange). NOE constraints were classified as either strong,
medium, or weak and were assigned upper limits of 2.5, 3.0,
or 3.5 Å with the lower limit set to the van der Waals radii.
Stereospecific assignments were not made, so NOE’s to meth-
ylene protons were included as two constraints using the
weakest intensity. In applying the hydrogen bond constraint,
a restraint (2.2 Å) was enforced between the amide proton and
the carbonyl oxygen as well as the amide nitrogen (3.3 Å) and
the carbonyl oxygen. Structures having a maximum NOE
violation error greater than 0.2 Å in the case of the Trp-Arg
hydrogen bond and 0.5 Å for the Trp-Mpr hydrogen bond were
excluded for not satisfying the NOE data.
Con clu sion
We have shown that the RGD sequence contained in
peptide 1 likely exists in a well-defined Gly-Asp type
II′ â-turn. This information was used in the design of
simple 2,6-disubstituted isoquinolone analogs with mod-
est affinity for GPIIb-IIIa. Optimization of these leads
utilized standard SAR optimization techniques and
resulted in the development of potent inhibitors of
platelet aggregation. The activity afforded by compound
46 represents a 4 order of magnitude increase relative
to the first compound in the series (14a ) and a 3-fold
increase in activity over the peptide (1) from which this
series was modeled. Notable is the fact that this activity
Distance geometry structures were annealed using XPLOR
(MSI) running on a Cray-2s supercomputer. The distance
constraints were included in the energy function, while the
electrostatic contributions were removed. Each structure was
given 15 ps of high temperature (1000 K) simulated annealing,
gradually cooled to 50 K, and then subjected to 500 steps of
minimization. The structures were then classified based on
the φ and ψ angles for RGD region using the clustering feature
in the Quanta program (MSI). In the formation of the clusters,
the lowest energy structure is taken as the nucleus of the first
cluster. Any structures with an RMSD (for the torsion angles

Non-Peptide RGD Surrogates
J ournal of Medicinal Chemistry, 1997, Vol. 40, No. 13 2093
comprising the RGD region) of no greater than 65 are grouped
into a cluster. From the remaining structures, the lowest
energy structure is taken as the nucleus of the second cluster,
and structures with an RMSD less than 65 are grouped into
the second cluster. The process is repeated until all structures
are classified. An atom by atom comparison of the RMSD’s
was performed using the COMPAR program (QCPE).
Com p ou n d Syn th esis. 7-Hyd r oxy-3,4-d ih yd r o-1-oxo-
2(1H)-isoqu in olin e (3). A mixture of 7-methoxyisoquinolone
(2.02 g, 11.4 mmol) and CH2Cl2 (25 mL) was treated with BBr3
(45.6 mL of a 1.0 M solution in CH2Cl2, 45.6 mmol) at -78 °C.
The resulting mixture was allowed to warm to room temper-
ature over 14 h. This solution was then cautiously quenched
with MeOH (11.5 mL, 285 mmol), and the resulting solution
was maintained at room temperature for 2 h. This solution
was then concentrated to dryness, and the resulting solid
material was recrystallized from H2O, providing 1.8 g (95%)
of 3 as a white solid: 1H NMR (300 MHz, CDCl3) 2.88 (t, J )
6.6 Hz, 2H), 3.47 (t, J ) 6.5 Hz, 2H), 6.93 (dd, J ) 2.6, 8.2 Hz,
1H), 7.13 (d, J ) 8.2 Hz, 1H), 7.36 (d, J ) 2.6 Hz, 1H); IR
(KBr) 3324, 3157, 1658, 1608, 1591, 1329, 1256 cm-1; MS (FD)
m/e 163; mp 195-200 °C. Anal. (C9H9NO2) C, H, N.
(t, J ) 6.6 Hz, 2H), 4.22 (s, 2H), 6.64 (d, J ) 2.3 Hz, 1H), 6.74
(dd, J ) 2.3, 8.4 Hz, 1H), 7.47 (br s, 1H), 7.90 (d, J ) 8.4 Hz,
1H); IR (KBr) 2984, 1739, 1609, 1231, 1154 cm-1; MS (FD)
m/e 278; mp 167-170 °C. Anal. (C15H19NO4) C, H, N.
7-H y d r o x y -3,4-d ih y d r o -1-o x o -2(1H )-is o q u in o lin e -
a cetic Acid 1,1-Dim eth yleth yl Ester (9). Following the
procedure outlined above, intermediate 9 was prepared in an
identical manner starting from 7: 1H NMR (300 MHz, CDCl3)
1.47 (s, 9H), 2.96 (t, J ) 6.6 Hz, 2H), 3.62 (t, J ) 6.8 Hz, 2H),
4.23 (s, 2H), 6.94 (dd, J ) 2.6, 8.1 Hz, 1H), 7.06 (d, J ) 8.2
Hz, 1H), 7.90 (d, J ) 2.7 Hz, 1H); IR (KBr) 3345, 2980, 1734,
1646, 1606, 1493, 1152 cm-1; MS (FD) m/e 278; mp 136-138
°C. Anal. (C15H19NO4) C, H, N.
2-[[4-(Br om oeth yl)ph en yl]m eth yl]-1H-isoin dole-1,3(2H)-
d ion e (10e). A mixture of R,R′-dibromo-p-xylene (5.0 g, 18.9
mmol), potassium phthalimide (3.5 g, 18.9 mmol), and DMF
(20 mL) was maintained at 100 °C for 12 h and then allowed
to cool to room temperature. This mixture was diluted with
EtOAc (200 mL) and washed with H2O (50 mL × 4). The
organic material was dried (MgSO4) and concentrated. The
crude material was purified by chromatography (silica gel
200-400 mesh, hexanes/EtOAc, 4:1), giving 1.6 g (25%) of 10e
as a white solid: 1H NMR (300 MHz, CDCl3) 4.46 (s, 2H), 4.85
(s, 2H), 7.36 (d, J ) 8.2 Hz, 2H), 7.41 (d, J ) 8.2 Hz, 2H), 7.72
(m, 2H), 7.86 (m, 2H); IR (KBr) 1767, 1718, 1433, 1391, 717
cm-1; MS (FD) m/e 329; mp 134-136 °C. Anal. (C16H12NO2-
Br) C, H, N.
6-(Ben zyloxy)-3,4-dih ydr o-1-oxo-2(1H)-isoqu in olin e (4).
A mixture of phenol 2 (1.0 g, 6.13 mmol), benzyl bromide (1.15
g, 6.75 mmol), K2CO3 (0.93 g, 6.74 mmol), and acetone (15 mL)
was maintained at reflux for 16 h. The mixture was then
allowed to cool to room temperature and was diluted with
EtOAc (100 mL). This mixture was washed with H2O (2 × 25
mL), dried (MgSO4), and concentrated. The crude residue was
recrystallized from EtOAc/hexanes, giving 1.53 g of 4 (98%)
as a white solid: 1H NMR (300 MHz, CDCl3) 2.98 (t, J ) 6.5
Hz, 2H), 3.57 (m, 2H), 5.12 (s, 2H), 5.92 (br s, 1H), 6.80 (d, J
) 2.3 Hz, 1H), 6.94 (dd, J ) 8.6 Hz, 1H), 7.40 (m, 5H), 8.03 (d,
2-[[3-(Br om oeth yl)ph en yl]m eth yl]-1H-isoin dole-1,3(2H)-
d ion e (10f). Using the procedure outlined above, 10f was
prepared in the same manner: 1H NMR (300 MHz, CDCl3) 4.45
(s, 2H), 4.83 (s, 2H), 7.30 (m, 2H), 7.37 (m, 1H), 7.45 (br s,
1H), 7.71 (m, 2H), 7.85 (m, 2H); IR (KBr) 1766, 1709, 1429,
1392, 1078 cm-1; MS (FD) m/e 329; mp 138-140 °C. Anal.
(C16H12NO2Br) C, H, N.
Gen er a l P r oced u r e for th e O-Alk yla tion of In ter m ed i-
a tes 8 a n d 9. P r ep a r a tion of 6-[[3-(1,3-Dih yd r o-1,3-d ioxa -
2H-isoin d ol-2-yl)p r op yl]oxy]-3,4-d ih yd r o-1-oxo-2(1H)-iso-
J ) 8.6 Hz, 1H); IR (KBr) 1661, 1608, 1314, 1251, 1008 cm-1
;
MS (FD) m/e 253; mp 121-124 °C. Anal. (C16H15NO2) C, H,
N.
7-(Ben zyloxy)-3,4-dih ydr o-1-oxo-2(1H)-isoqu in olin e (5).
Using the procedure described above, 5 was prepared in 75%
yield, starting from 3: 1H NMR (300 MHz, CDCl3) 2.93 (t, J
) 6.6 Hz, 2H), 3.53 (dd, J ) 2.8, 6.8 Hz, 2H), 5.11 (s, 2H), 6.18
(br s, 1H), 7.0-7.2 (m, 2H), 7.3-7.5 (m, 5H), 7.70 (d, J ) 2.6
Hz, 1H); IR (KBr) 3200, 3067, 1665, 1608, 1441, 1332, 1011
cm-1; MS (FD) m/e 253. Anal. (C16H15NO2) C, H, N.
6-(Ben zyloxy)-3,4-d ih yd r o-1-oxo-2(1H )-isoq u in olin e-
a cetic Acid 1,1-Dim eth yleth yl Ester (6). A mixture of
lactam 4 (1.0 g, 3.93 mmol), NaH (0.19 g of a 60% dispersion
in mineral oil, 4.72 mmol), and THF (15 mL) was maintained
at reflux for 2 h and then allowed to cool to room temperature.
This mixture was then treated with tert-butyl bromoacetate
(0.84 g, 4.32 mmol), and the mixture was stirred at room
temperature for 1 h. This mixture was then diluted with
EtOAc (100 mL), washed with H2O (2 × 25 mL), dried with
MgSO4, and concentrated. The crude residue was recrystal-
lized from EtOAc/hexanes, giving 1.29 g (90%) of 6 as a white
solid. 1H NMR (300 MHz, CDCl3) 1.41 (s, 9H), 3.00 (t, J ) 6.5
Hz, 2H), 3.61 (t, J ) 6.5 Hz, 2H), 4.22 (s, 2H), 5.09 (s, 2H),
6.74 (d, J ) 2.5 Hz, 1H), 6.91 (dd, J ) 2.5, 8.6 Hz, 1H), 7.36
(m, 5H), 8.02 (d, J ) 8.5 Hz, 1H); IR (KBr) 1726, 1655, 1240,
qu in olin ea cetic Acid 1,1-Dim eth yleth yl Ester (11a ).
A
mixture of 8 (0.25 g, 0.90 mmol) and 10a (0.28 g, 0.90 mmol)
was dissolved in acetone (20 mL) and then treated with K2CO3.
The resulting mixture was maintained at reflux for 12 h and
then allowed to cool to room temperature. This mixture was
diluted with EtOAc (200 mL) and then washed with H2O (2 ×
50 mL). The organic material was dried (MgSO4) and con-
centrated. The crude residue was recrystallized from EtOAc/
hexanes, which provided 0.34 g (84%) of an off-white solid: 1H
NMR (300 MHz, CDCl3) 1.45 (s, 9H), 2.20 (m, 2H), 2.94 (t, J
) 6.5 Hz, 2H), 3.58 (t, J ) 6.80 Hz, 2H), 3.89 (t, J ) 6.8 Hz,
2H), 4.04 (t, J ) 6.0 Hz, 2H), 4.19 (s, 2H), 6.53 (d, J ) 2.4 Hz,
1H), 6.65 (dd, J ) 2.5, 8.7 Hz, 1H), 7.71 (m, 2H), 7.82 (m, 2H),
7.95 (d, 8.6 Hz, 1H); IR (KBr) 1768, 1738, 1705, 1654, 1278
cm-1; MS (FD) m/e 464; mp 132-133 °C. Anal. (C26H28N2O6)
C, H, N.
6-[[4-(1,3-Dih ydr o-1,3-dioxa-2H-isoin dol-2-yl)bu tyl]oxy]-
3,4-d ih yd r o-1-oxo-2(1H)-isoqu in olin ea cetic Acid 1,1-Di-
m eth yleth yl Ester (11b). This compound was obtained from
8 and 10b following the general procedure: 1H NMR (300
MHz, CDCl3) 1.46 (s, 9H), 2.04 (m, 4H), 2.98 (t, J ) 6.5 Hz,
2H), 3.60 (t, J ) 6.6 Hz, 2H), 3.77 (t, J ) 6.6 Hz, 2H), 4.04 (m,
2H), 4.21 (s, 2H), 6.64 (s, 1H), 6.79 (dd, J ) 8.6, 2.5 Hz, 1H),
7.71 (m, 2H), 7.84 (m, 2H), 7.98 (d, J ) 8.6 Hz, 1H); mp 84-
86 °C. Anal. (C27H30N2O6) C, H, N.
6-[[5-(1,3-Dih yd r o-1,3-d ioxa -2H -isoin d ol-2-yl)p en t yl]-
oxy]-3,4-d ih yd r o-1-oxo-2(1H)-isoqu in olin ea cetic Acid 1,1-
Dim eth yleth yl Ester (11c). This compound was obtained
from 8 and 10c following the general procedure: 1H NMR (300
MHz, CDCl3) 1.47 (s, 9H), 1.82 (m, 4H), 3.00 (t, J ) 6.5 Hz,
2H), 3.61 (t, J ) 6.5 Hz, 2H), 3.73 (t, J ) 7.1 Hz, 2H), 3.98 (t,
J ) 6.4 Hz, 2H), 4.22 (s, 2H), 6.64 (s, 1H), 6.79 (d, J ) 8.7 Hz,
1H), 7.72 (m, 2H), 7.85 (m, 2H), 7.99 (d, J ) 8.6 Hz, 1H); IR
(KBr) 1736, 1702, 1663, 1277, 1158 cm-1; MS (FD) m/e 478;
mp 92-94 °C. Anal. (C28H32N2O6) C, H, N.
780 cm-1; MS (FD) m/e 367; mp 122-124 °C. Anal. (C22H25
-
NO4) C, H, N.
7-(Ben zyloxy)-3,4-d ih yd r o-1-oxo-2(1H )-isoq u in olin e-
a cetic Acid 1,1-Dim eth yleth yl Ester (7). Using the pro-
cedure outlined above, intermediate 7 was obtained in 80%
yield starting from 5: 1H NMR (300 MHz, CDCl3) 1.52 (s, 9H),
3.03 (t, J ) 6.3 Hz, 2H), 3.66 (t, J ) 6.5 Hz, 2H), 4.27 (s, 2H),
5.14 (s, 2H), 7.14 (m, 2H), 7.3-7.5 (m, 5H), 7.76 (d, J ) 1.9
Hz, 1H); IR (KBr) 1745, 1645, 1613, 1557, 1448, 1252, 1158
cm-1; MS (FAB) m/e 368; mp 119-120 °C. Anal. (C22H25NO4)
C, H, N.
6-H y d r o x y -3,4-d ih y d r o -1-o x o -2(1H )-is o q u in o lin e -
a cetic Acid 1,1-Dim eth yleth yl Ester (8). A mixture of 6
(0.13g, 0.37 mmol), Pd/C (0.14 g, 10% on carbon), and EtOAc
(5 mL) was stirred under an atmosphere of hydrogen (balloon)
for 1.5 h and then filtered. The filtrate was then concentrated,
providing 0.10 g (95%) of 8 as a pure white solid: 1H NMR
(300 MHz, CDCl3) 1.43 (s, 9H), 2.97 (t, J ) 6.6 Hz, 2H), 3.61
6-[[6-(1,3-Dih ydr o-1,3-dioxa-2H-isoin dol-2-yl)h exyl]oxy]-
3,4-d ih yd r o-1-oxo-2(1H)-isoqu in olin ea cetic Acid 1,1-Di-
m eth yleth yl Ester (11d ). This compound was obtained from
8 and 10d following the general procedure: 1H NMR (300

2094 J ournal of Medicinal Chemistry, 1997, Vol. 40, No. 13
Fisher et al.
MHz, CDCl3) 1.43 (m, 13H), 1.70 (m, 4H), 2.95 (t, J ) 6.4 Hz,
2H), 3.57 (t, J ) 6.5 Hz, 2H), 3.65 (t, J ) 7.2 Hz, 2H), 3.93 (t,
J ) 6.3 Hz, 2H), 4.18 (s, 2H), 6.60 (s, 1H), 6.75 (d, J ) 8.6 Hz,
1H), 7.67 (m, 2H), 7.78 (m, 2H), 7.95 (d, J ) 8.2 Hz, 1H); IR
(CHCl3) 2943, 1772, 1737, 1712, 1606, 1155 cm-1; MS (FD)
m/e 506. Anal. (C29H34N2O6) C, H, N.
6-[[4-[(1,3-Dih yd r o-1,3-d ioxa -2H-isoin d ol-2-yl)m eth yl]-
p h e n yl]m e t h oxy]-3,4-d ih yd r o-1-oxo-2(1H )-isoq u in o-
lin ea cetic Acid 1,1-Dim eth yleth yl Ester (11e). This com-
pound was obtained from 8 and 10e following the general
procedure: 1H NMR (300 MHz, CDCl3) 1.46 (s, 9H), 2.98 (t, J
) 6.4 Hz, 2H), 3.59 (t, J ) 6.5 Hz, 2H), 4.20 (s, 2H), 4.85 (s,
3H), 5.05 (s, 2H), 6.71 (s, 1H), 6.90 (d, J ) 8.6 Hz, 1H), 7.36
(d, J ) 8.1 Hz, 2H), 7.46 (d, J ) 8.2 Hz, 2H), 7.70 (m, 2H),
7.84 (m, 2H), 8.01 (d, J ) 8.7 Hz, 1H); IR (KBr) 1766, 1739,
1709, 1650, 1481 cm-1; MS (FD) m/e 526; mp 170-172 °C.
Anal. (C31H30N2O6) C, H, N.
6-[[3-[(1,3-Dih yd r o-1,3-d ioxa -2H-isoin d ol-2-yl)m eth yl]-
p h e n yl]m e t h oxy]-3,4-d ih yd r o-1-oxo-2(1H )-isoq u in o-
lin ea cetic Acid 1,1-Dim eth yleth yl Ester (11f). This com-
pound was obtained from 8 and 10f following the general
procedure: 1H NMR (300 MHz, CDCl3) 1.46 (s, 9H), 2.95 (t, J
) 6.4 Hz, 2H), 3.60 (t, J ) 6.5 Hz, 2H), 4.21 (s, 2H), 4.86 (s,
2H), 5.05 (s, 2H), 6.71 (s, 1H), 6.85 (dd, J ) 2.7, 8.6 Hz, 1H),
7.20-7.60 (m, 4H), 7.70 (m, 2H), 7.80 (m, 2H), 7.97 (d, J ) 8.6
Hz, 1H); IR (KBr) 1771, 1740, 1714, 1651, 1605, 1393, 1153
cm-1; MS (FD) m/e 527; mp 58-63 °C. Anal. (C31H30N2O6) C,
H, N.
(d, J ) 8.6 Hz, 1H); IR (KBr) 2943, 1713, 1650, 1611, 1482,
1277 cm-1; MS (FAB) m/e 356.8. Anal. (C17H25N2O4Cl) C, H,
N.
6-[[4-(Am in om et h yl)p h en yl]m et h oxy]-3,4-d ih yd r o-1-
oxo-2(1H)-isoqu in olin ea cetic Acid 1,1-Dim eth yleth yl Es-
ter (12e). Following the general procedure, 12e was prepared
starting from 11e: 1H NMR (300 MHz, CDCl3) 3.00 (t, J )
6.6 Hz, 2H), 3.62 (t, J ) 6.8 Hz, 2H), 4.08 (s, 2H), 4.27 (s, 2H),
5.18 (s, 2H), 6.87 (d, J ) 1.9 Hz, 1H), 6.91 (dd, J ) 1.9, 8.7
Hz, 1H), 7.49 (dd, J ) 8.1, 19.2 Hz, 4H), 7.81 (d, J ) 8.6 Hz,
1H); IR (KBr) 2932, 1724, 1625, 1604, 1483, 1185 cm-1; MS
(FAB) m/e 341. Anal. (C19H21N2O4Cl‚0.4H2O) C, H, N.
6-[[3-(Am in om et h yl)p h en yl]m et h oxy]-3,4-d ih yd r o-1-
oxo-2(1H)-isoqu in olin ea cetic Acid 1,1-Dim eth yleth yl Es-
ter (12f). Following the general procedure, 12f was prepared
starting from 11f: 1H NMR (300 MHz, CDCl3) 3.03 (t, J ) 6.6
Hz, 2H), 3.67 (t, J ) 6.5 Hz, 2H), 4.14 (s, 2H), 4.29 (s, 2H),
5.20 (s, 2H), 6.90 (d, J ) 2.3 Hz, 1H), 6.97 (dd, J ) 2.3, 8.6
Hz, 1H), 7.45 (m, 4H), 7.85 (d, J ) 8.4 Hz, 1H); IR (KBr) 2905,
1732, 1632, 1601, 1481, 1277 cm-1; MS (FAB) m/e 341. Anal.
(C19H21N2O4Cl‚0.85H2O) C, H, N.
Gen er a l P r oced u r e for th e P r ep a r a tion of Com p ou n d s
13.
6-[[3-[[N,N′-Bis[(1,1-d im et h ylet h oxy)ca r b on yl]-
am in oim in om eth yl]am in o]pr opyl]oxy]-3,4-dih ydr o-1-oxo-
2(1H)-isoqu in olin ea cetic Acid 1,1-Dim eth yleth yl Ester
(13a ). A solution of 11a (0.34 g, 0.70 mmol) and EtOH (15
mL) was treated with aqueous hydrazine (0.35 mL of an 85%
solution in H2O, 7 mmol) and maintained at 65 °C for 1 h.
The mixture was then concentrated to dryness. The crude
material was suspended in EtOAc (100 mL), and this mixture
was washed with saturated NaHCO3 (4 × 20 mL). The organic
material was then dried (MgSO4) and concentrated. The crude
material thus prepared was dissolved in CH2Cl2 (2 mL) and
then treated with N,N′-bis(tert-butoxycarbonyl)-S-methoxy-
isothiourea (0.24 g, 0.84 mmol). The resulting solution was
stirred at room temperature for 4 days. The solution was then
concentrated to dryness, and the resulting material was
purified by chromatography (silica gel 200-400 mesh, hexanes/
EtOAc, 3:1), providing 0.28 g (53%) of 13a as a clear oil: 1H
NMR (300 MHz, CDCl3) 1.46 (s, 9H), 1.50 (s, 9H), 2.05 (m,
2H), 2.98 (t, J ) 6.5 Hz, 2H), 3.62 (m, 4H), 4.09 (t, J ) 5.7 Hz,
2H), 4.21 (s, 2H), 6.78 (d, J ) 2.2 Hz, 1H), 6.85 (dd, J ) 2.3,
8.2 Hz, 1H), 7.98 (d, J ) 8.2 Hz, 1H), 8.71 (m, 1H); IR (KBr)
2980, 1725, 1640, 1611, 1325, 1130 cm-1; MS (FAB) m/e 577.
Anal. (C29H44N4O8) C, H, N.
6-[[3-[[N ,N ′-B i s [(1,1-d i m e t h y le t h o x y )c a r b o n y l]-
a m in oim in om eth yl]a m in o]bu tyl]oxy]-3,4-d ih yd r o-1-oxo-
2(1H)-isoqu in olin ea cetic Acid 1,1-Dim eth yleth yl Ester
(13b). Following the procedure employed for the preparation
of 13a , 13b was prepared in a like manner: 1H NMR (300
MHz, CDCl3) 1.46 (s, 9H), 1.48 (s, 9H), 1.49 (s, 9H), 1.90 (m,
4H), 2.99 (t, J ) 6.5 Hz, 2H), 3.50 (m, 2H), 3.60 (t, J ) 3.6 Hz,
2H), 4.01 (t, J ) 5.1 Hz, 2H), 4.21 (s, 2H), 6.64 (d, J ) 2.1 Hz,
1H), 6.80 (dd, J ) 2.2, 8.2 Hz, 1H), 7.98 (d, J ) 8.3 Hz, 1H),
8.38 (m, 1H); IR (KBr) 2984, 1735, 1723, 1640, 1609, 1155
cm-1; MS (FAB) m/e 591. Anal. (C30H46N4O8) C, H, N.
6-[[5-[[N ,N ′-B i s [[(1,1-d i m e t h y le t h o x y )c a r b o n y l]-
am in oim in om eth yl]am in o]pen tyl]oxy]-3,4-dih ydr o-1-oxo-
2(1H)-isoqu in olin ea cetic Acid 1,1-Dim eth yleth yl Ester
(13c). Following the general procedure employed for the
preparation of 13a , 13c was prepared in a like manner: 1H
NMR (300 MHz, CDCl3) 1.44 (s, 9H), 1.47 (s, 9H), 1.48 (s, 9H),
1.60 (m, 4H), 1.81 (m, 2H), 2.98 (t, J ) 6.4 Hz, 2H), 3.44 (m,
2H), 3.59 (t, J ) 6.6 Hz, 2H), 3.97 (t, J ) 6.3 Hz, 2H), 4.19 (s,
2H), 6.63 (s, 1H), 6.79 (dd, J ) 1.9, 8.6 Hz, 1H), 7.98 (d, 8.6
Hz, 1H), 8.32 (s, 1H); IR (CHCl3) 2984, 1722, 1640, 1609, 1369,
1155 cm-1; MS (FAB) m/e 605. Anal. (C31H48N4O8‚1.75H2O):
C, H, N.
Gen er a l P r oced u r e for th e P r ep a r a tion of Com p ou n d s
12a -f. 6-[(3-Am in op r op yl)oxy]-3,4-d ih yd r o-1-oxo-2(1H)-
isoqu in olin ea cetic Acid Mon oh yd r och lor id e (12a ).
A
solution of 11a (0.34 g, 0.70 mmol) in EtOH (2.5 mL) was
treated with aqueous hydrazine (0.35 mL of an 85% solution,
7.0 mmol) and then maintained at 65 °C for 1 h. This mixture
was then concentrated to dryness, and the crude residue was
partitioned between EtOAc (50 mL) and saturated aqueous
NaHCO3 (25 mL). The layers were separated, and the organic
material was washed with H2O (25 mL), dried (MgSO4), and
concentrated. The crude residue was then taken up in
anhydrous TFA and allowed to stand at room temperature for
1 h. This solution was then concentrated, the crude residue
was dissolved in 1 N aqueous HCl, and this solution was
extracted with Et2O. The remaining aqueous material was
lyophilized, providing 12a as a white, hygroscopic solid: 1H
NMR (300 MHz, CD3OD) 2.14 (m, 2H), 3.02 (t, J ) 6.4 Hz,
2H), 3.11 (t, J ) 7.1 Hz, 2H), 3.65 (t, J ) 6.6 Hz, 2H), 4.16 (t,
J ) 5.8 Hz, 2H), 4.27 (s, 2H), 6.83 (s, 1H), 6.88 (d, J ) 8.4 Hz,
1H), 7.85 (d, J ) 8.6 Hz, 1H). IR (KBr) 2882, 1628, 1600, 1488,
1200, 1029 cm-1; MS (FAB) m/e 279; mp 205-206 °C dec. Anal.
(C14H19N2O4‚1H2O) C, H, N.
6-[(4-Am in ob u t yl)oxy]-3,4-d ih yd r o-1-oxo-2(1H )-iso-
qu in olin ea cetic Acid Mon oh yd r och lor id e (12b). Follow-
ing the general procedure, 12b was prepared starting from
11b: 1H NMR (300 MHz, CD3OD) 1.87 (m, 4H), 3.01 (m, 4H),
3.66 (t, J ) 6.6 Hz, 2H), 4.09 (m, 2H), 4.28 (s, 2H), 6.81 (d, J
) 2.1 Hz, 1H), 6.87 (dd, J ) 8.6, 2.3 Hz, 1H), 7.85 (d, J ) 8.7
Hz, 1H); IR (KBr) 2936, 1723, 1633, 1485, 1021 cm-1; MS (FD)
m/e 294. Anal. (C15H21N2O4Cl‚0.25H2O) C, H, N.
6-[(5-Am in op en t yl)oxy]-3,4-d ih yd r o-1-oxo-2(1H )-iso-
qu in olin ea cetic Acid Mon oh yd r och lor id e (12c). Follow-
ing the general procedure, 12c was prepared starting from
11c: 1H NMR (300 MHz, CDCl3) 1.60 (m, 2H), 1.75 (m, 2H),
1.85 (m, 2H), 2.93 (t, J ) 6.9 Hz, 2H), 3.00 (t, J ) 6.51 Hz,
2H), 3.62 (t, J ) 6.7 Hz, 2H), 4.05 (t, J ) 6.0 Hz, 2H), 4.27 (s,
2H), 6.78 (s, 1H), 6.84 (d, J ) 8.3 Hz, 1H), 7.82 (d, J ) 8.4 Hz,
1H); IR (KBr) 2944, 1718, 1636, 1606, 1482, 1182 cm-1; MS
(FAB) m/e 307; mp 180-185 °C dec. Anal. (C16H23N2O4Cl) C,
H, N.
6-[(6-Am in oh e xyl)oxy]-3,4-d ih yd r o-1-oxo-2(1H )-iso-
qu in olin ea cetic Acid Mon oh yd r och lor id e (12d ). Follow-
ing the general procedure, 12d was prepared starting from
11d : 1H NMR (300 MHz, CD3OD) 1.46 (m, 4H), 1.65 (m, 2H),
1.81 (m, 2H), 2.92 (t, J ) 7.6 Hz, 2H), 3.02 (t, J ) 6.6 Hz, 2H),
3.66 (t, J ) 6.8 Hz, 2H), 4.05 (t, J ) 6.3 Hz, 2H), 4.28 (s, 2H),
6.79 (d, J ) 2.3 Hz, 1H), 6.85 (dd, J ) 2.3, 8.7 Hz, 1H), 7.86
6-[[3-[[N ,N ′-B i s [(1,1-d i m e t h y le t h o x y )c a r b o n y l]-
a m in oim in om eth yl]a m in o]h exyl]oxy]-3,4-d ih yd r o-1-oxo-
2(1H)-isoqu in olin ea cetic Acid 1,1-Dim eth yleth yl Ester
(13d ). Following the procedure employed for the preparation
of 13a , 13d was prepared in a like manner: 1H NMR (300
MHz, CDCl3) 1.44 (s, 9H), 1.46 (s, 9H), 1.48 (s, 9H), 1.4-1.6
(m, 4H), 1.80 (m, 2H), 2.98 (t, J ) 6.4 Hz, 2H), 3.40 (dd, J )
6.7, 12.3 Hz, 2H), 3.59 (t, J ) 6.4 Hz, 2H), 3.96 (t, J ) 6.4 Hz,

Non-Peptide RGD Surrogates
J ournal of Medicinal Chemistry, 1997, Vol. 40, No. 13 2095
2H), 4.19 (s, 2H), 6.63 (s, 1H), 6.80 (dd, J ) 1.5, 8.4 Hz, 1H),
7.97 (d, J ) 8.2 Hz, 1H), 8.29 (m, 1H); IR (KBr) 2979, 2936,
1741, 1721, 1639, 1611, 1368 cm-1; MS (FAB) m/e 619. Anal.
(C32H50N4O8) C, H, N.
MS (FAB) m/e 363; mp 146-150 °C. Anal. (C18H27N4O4Cl‚
0.25H2O) C, H, N.
6-[[4-[[(Am in oim in om e t h yl)a m in o]m e t h yl]p h e n yl]-
m eth oxy]-3,4-dih ydr o-1-oxo-2(1H)-isoqu in olin eacetic Acid
Mon oh yd r och lor id e (14e). Following the general procedure
employed for the preparation of 14a , 14e was prepared in a
like manner: 1H NMR (300 MHz, CD3OD) 3.00 (t, J ) 6.6 Hz,
2H), 3.64 (t, J ) 6.5 Hz, 2H), 4.26 (s, 2H), 4.39 (s, 2H), 5.14 (s,
2H), 6.89 (d, J ) 2.4 Hz, 1H), 6.93 (dd, J ) 2.4, 8.6 Hz, 1H),
7.35 (d, J ) 8.2 Hz, 2H), 7.45 (d, J ) 8.2 Hz, 2H), 7.81 (d, J )
8.6 Hz, 1H); IR (KBr) 3358, 3176, 1739, 1650, 1608, 1480, 1179
cm-1; MS (FAB) m/e 383. Anal. (C20H23N4O4Cl‚1H2O) C, H,
N.
6-[[4-[[[N ,N ′-B i s [(1,1-d i m e t h y le t h o x y )c a r b o n y l]-
a m in oim in om eth yl]a m in o]m eth yl]p h en yl]m eth oxy]-3,4-
d ih yd r o-1-oxo-2(1H )-isoq u in olin ea cet ic Acid 1,1-Di-
m eth yleth yl Ester (13e). Following the general procedure
employed for the preparation of 13a , 13e was prepared in a
like manner: 1H NMR (300 MHz, CDCl3) 1.41 (s, 9H), 1.42 (s,
9H), 1.43 (s, 9H), 3.01 (t, J ) 6.6 Hz, 2H), 3.62 (t, J ) 6.7 Hz,
2H), 4.23 (s, 2H), 4.64 (d, J ) 5.1 Hz, 2H), 5.09 (s, 2H), 6.75
(d, J ) 2.2 Hz, 1H), 6.90 (dd, J ) 2.2, 8.2 Hz, 1H), 7.35 (d, J
) 8.2 Hz, 2H), 7.41 (d, J ) 8.2 Hz, 2H), 8.05 (d, J ) 8.3 Hz,
1H), 8.60 (m, 1H); IR (KBr) 3061, 3020, 1732, 1622, 1606, 1575,
1484 cm-1; MS (FAB) m/e 639. Anal. (C34H46N4O8) C, H, N.
6-[[3-[[[N ,N ′-B i s [(1,1-d i m e t h y le t h o x y )c a r b o n y l]-
a m in oim in om eth yl]a m in o]m eth yl]p h en yl]m eth oxy]-3,4-
d ih yd r o-1-oxo-2(1H )-isoq u in olin ea cet ic Acid 1,1-Di-
m eth yleth yl Ester (13f). Following the general procedure
employed for the preparation of 13a , 13f was prepared in a
like manner: 1H NMR (300 MHz, CDCl3) 1.47, (s, 9H), 1.48
(s, 9H), 1.51 (s, 9H), 3.01 (t, J ) 6.6 Hz, 2H), 3.63 (t, J ) 6.4
Hz, 2H), 4.22 (s, 2H), 6.13 (d, J ) 4.8 Hz, 2H), 5.08 (s, 2H),
6.74 (d, J ) 2.5 Hz, 1H), 6.90 (dd, J ) 2.5, 8.6 Hz, 1H), 7.2-
7.4 (m, 4H), 8.01 (d, J ) 8.6 Hz, 1H), 8.65 (br s, 1H); IR (KBr)
2960, 1710, 1699, 1640, 1620, 1160 cm-1; MS (FD) m/e 369;
mp 65-71 °C. Anal. (C34H46N4O8) C, H, N.
Gen er a l P r oced u r e for th e P r ep a r a tion of An a logs
14-16. 6-[[3-[(Am in oim in om et h yl)a m in o]p r op yl]oxy]-
3,4-d ih yd r o-1-oxo-2(1H)-isoqu in olin ea cetic Acid Mon o-
h yd r och lor id e (14a ). A mixture of 13a (0.21 g, 0.36 mmol)
and anhydrous TFA (10 mL) was maintained at room tem-
perature for 1 h and then concentrated to dryness. The
resulting solid was dissolved in H2O (20 mL), and the solution
was washed with Et2O (2 × 10 mL). The aqueous material
was then treated with aqueous HCl (7.3 mL of a 1 N solution,
7.3 mmol), and the resulting solution was lyophilized, provid-
ing 0.096 g (95%) of 14a as a hygroscopic white solid: 1H NMR
(300 MHz, CD3OD) 2.05 (m, 2H), 2.99 (t, J ) 6.3 Hz, 2H), 3.40
(m, 2H), 3.63 (t, J ) 6.5 Hz, 2H), 4.11 (t, J ) 6.0 Hz, 2H), 4.27
(s, 2H), 6.82 (s, 1H), 6.88 (d, J ) 8.2 Hz, 1H), 7.40 (br s, 1H),
7.84 (d, J ) 8.4 Hz, 1H); IR (KBr) 3446, 3329, 3171, 1713,
1663, 1555, 1286 cm-1; MS (FAB) m/e 321; mp 218-220 °C
dec. Anal. (C15H21N4O4Cl) C, H, N.
6-[[3-[[(Am in oim in om e t h yl)a m in o]m e t h yl]p h e n yl]-
m eth oxy]-3,4-dih ydr o-1-oxo-2(1H)-isoqu in olin eacetic Acid
Mon oh yd r och lor id e (14f). Following the general procedure
employed for the preparation of 14a , 14f was prepared in a
like manner: 1H NMR (300 MHz, CD3OD) 3.02 (t, J ) 6.6 Hz,
2H), 3.66 (t, J ) 6.4 Hz, 2H), 4.28 (s, 2H), 4.42 (s, 2H), 5.17 (s,
2H), 6.88 (d, J ) 2.4 Hz, 1H), 6.95 (dd, J ) 2.4, 8.6 Hz, 1H),
7.29 (m, 1H), 7.40 (m, 3H), 7.84 (d, J ) 8.6 Hz, 1H); IR (KBr)
3349, 3177, 1725, 1632, 1604, 1482, 1184 cm-1; MS (FAB) m/e
383; mp 105-110 °C. Anal. (C20H23N4O4Cl‚0.6H2O) C, H, N.
7-[[3-(1,3-Dih yd r o-1,3-d ioxa -2H-isoin d ol-2-yl)p r op yl]-
oxy]-3,4-d ih yd r o-1-oxo-2(1H)-isoqu in olin ea cetic Acid 1,1-
Dim eth yleth yl Ester . Following the general procedure
employed for the preparation of 11a , the title compound was
1
prepared in a like manner: H NMR (300 MHz, CDCl3) 1.44
(s, 9H), 2.18 (m, 2H), 2.93 (t, J ) 6.5 Hz, 2H), 3.57 (t, J ) 6.5
Hz, 2H), 3.88 (t, J ) 6.8 Hz, 2H), 4.05 (t, J ) 5.9 Hz, 2H), 4.19
(s, 2H), 6.85 (dd, J ) 2.6, 8.5 Hz, 1H), 7.03 (d, J ) 8.3 Hz,
1H), 7.49 (d, J ) 2.5 Hz, 1H), 7.69 (m, 2H), 7.82 (m, 2H); IR
(CHCl3) 3019, 1738, 1713, 1653, 1395, 1153 cm-1; MS (FD)
m/e 465. Anal. (C26H28N2O6) C, H, N.
7-[[4-(1,3-Dih ydr o-1,3-dioxa-2H-isoin dol-2-yl)bu tyl]oxy]-
3,4-d ih yd r o-1-oxo-2(1H)-isoqu in olin ea cetic Acid 1,1-Di-
m eth yleth yl Ester . Following the general procedure em-
ployed for the preparation of 11a , the title compound was
1
prepared in a like manner: H NMR (300 MHz, CDCl3) 1.41
(s, 9H), 1.80 (m, 4H), 2.89 (t, J ) 6.49 Hz, 2H), 3.54 (t, J ) 6.5
Hz, 2H), 3.69 (t, J ) 6.7 Hz, 2H), 3.97 (t, J ) 5.63 Hz, 2H),
6.87 (dd, J ) 2.6, 8.2 Hz, 1H), 6.98 (d, J ) 8.3 Hz, 1H), 7.49
(d, J ) 2.5 Hz, 1H), 7.62 (m, 2H), 7.81 (m, 2H); IR (CHCl3)
1772, 1713, 1650, 1398 cm-1; MS (FD) m/e 478. Anal.
(C27H30N2O6‚0.7H2O) C, H, N.
7-[[3-[[N ,N ′-B i s [(1,1-d i m e t h y le t h o x y )c a r b o n y l]-
am in oim in om eth yl]am in o]pr opyl]oxy]-3,4-dih ydr o-1-oxo-
2(1H)-isoqu in olin ea cetic Acid 1,1-Dim eth yleth yl Ester .
Following the general procedure employed for the preparation
of 13a , the title compound was prepared in a like manner: 1H
NMR (300 MHz, CDCl3) 1.49 (s, 9H), 1.52 (s, 18H), 2.08 (m,
2H), 2.99 (t, J ) 6.6 Hz, 2H), 3.65 (m, 4H), 4.17 (t, J ) 6.3 Hz,
2H), 4.27 (s, 2H), 7.10 (m, 2H), 7.60 (m, 1H), 8.67 (m, 1H); IR
(KBr) 2977, 1741, 1726, 1639, 1480, 1368 cm-1; MS (FAB) m/e
577. Anal. (C29H44N4O8) C, H, N.
6-[[4-[(Am in oim in om eth yl)a m in o]bu tyl]oxy]-3,4-d ih y-
d r o-1-oxo-2(1H )-isoq u in olin ea cet ic Acid Mon oh yd r o-
ch lor id e (14b). Following the general procedure employed
for the preparation of 14a , 14b was prepared in a like
manner: 1H NMR (300 MHz, CD3OD) 1.95 (m, 4H), 2.95 (t, J
) 6.6 Hz, 2H), 3.22 (t, J ) 6.6 Hz, 2H), 3.59 (t, J ) 6.5 Hz,
2H), 4.21 (s, 2H), 6.73 (d, J ) 2.3 Hz, 1H), 6.81 (dd, J ) 2.4,
8.4 Hz, 1H), 7.78 (d, J ) 8.4 Hz, 1H); IR (KBr) 3344, 3170,
2935, 1739, 1667, 1630, 1608 cm-1; MS (FAB) m/e 335; mp
175-179 °C. Anal. (C16H23N4O4Cl) C, H, N.
7-[[3-[[N ,N ′-B i s [(1,1-d i m e t h y le t h o x y )c a r b o n y l]-
a m in oim in om eth yl]a m in o]bu tyl]oxy]-3,4-d ih yd r o-1-oxo-
2(1H)-isoqu in olin ea cetic Acid 1,1-Dim eth yleth yl Ester .
Following the general procedure employed for the preparation
of 13a , the title compound was prepared in a like manner: 1H
NMR (300 MHz, CDCl3) 1.44 (s, 9H), 1.46 (s, 9H), 1.47 (s, 9H),
1.80 (m, 4H), 2.94 (t, J ) 6.42 Hz, 2H), 3.42 (m, 2H), 3.57 (t,
J ) 6.5 Hz, 2H), 3.99 (t, J ) 5.9 Hz, 2H), 4.19 (s, 2H), 6.92
(dd, J ) 2.4, 8.6 Hz, 1H), 7.06 (d, J ) 8.5 Hz, 1H), 7.54 (d, J
) 2.2 Hz, 1H); IR (CHCl3) 2981, 1723, 1639, 1610, 1580, 1369
cm-1; MS (FD) m/e 591. Anal. (C30H46N4O8‚0.4H2O) C, H, N.
7-[[3-[(Am in oim in om et h yl)a m in o]p r op yl]oxy]-3,4-d i-
h yd r o-1-oxo-2(1H)-isoqu in olin ea cetic Acid Mon oh yd r o-
ch lor id e (15). Following the general procedure employed for
the preparation of 14a , 15 was prepared in a like manner: 1H
NMR (300 MHz, CD3OD) 1.95 (m, 2H), 2.87 (t, J ) 6.6 Hz,
2H), 3.29 (t, J ) 6.8 Hz, 2H), 3.55 (t, J ) 6.8 Hz, 2H), 3.98 (t,
J ) 5.9 Hz, 2H), 4.20 (s, 2H), 6.96 (dd, J ) 2.7, 8.4 Hz, 1H),
7.10 (d, J ) 8.35 Hz, 1H), 7.36 (d, J ) 2.7 Hz, 1H); IR (film)
3329, 3162, 1734, 1653, 1605, 1053 cm-1; MS (FAB) m/e 321.
Anal. (C15H21N4O4Cl‚1.5H2O) C, H, N.
6-[[5-[(Am in oim in om et h yl)a m in o]p en t yl]oxy]-3,4-d i-
h yd r o-1-oxo-2(1H)-isoqu in olin ea cetic Acid Mon oh yd r o-
ch lor id e (14c). Following the general procedure employed
for the preparation of 14a , 14d was prepared in a like
manner: 1H NMR (300 MHz, CD3OD) 1.60 (m, 4H), 1.83 (m,
2H), 3.00 (t, J ) 6.5 Hz, 2H), 3.17 (t, J ) 5.7 Hz, 2H), 3.65 (t,
J ) 6.6 Hz, 2H), 4.05 (t, J ) 6.1 Hz, 2H), 4.26 (s, 2H), 6.78 (s,
1H), 6.84 (d, J ) 8.4 Hz, 1H), 7.36 (m, 1H), 7.83 (d, J ) 8.6
Hz, 1H); IR (KBr) 3331, 3204, 2942, 1715, 1679, 1646, 1597
cm-1; MS (FD) m/e 349; mp 115-118 °C. Anal. (C17H25N4O4-
Cl) C, H, N.
6-[[4-[(Am in oim in om eth yl)a m in o]h exyl]oxy]-3,4-d ih y-
d r o-1-oxo-2(1H )-isoq u in olin ea cet ic Acid Mon oh yd r o-
ch lor id e (14d ). Following the general procedure employed
for the preparation of 14a , 14d was prepared in a like
manner: 1H NMR (300 MHz, CD3OD) 1.46-1.62 (m, 6H), 1.81
(m, 2H), 3.02 (t, J ) 6.5 Hz, 2H), 3.20 (m, 2H), 3.66 (t, J ) 6.5
Hz, 2H), 4.04 (t, J ) 6.2 Hz, 2H), 4.28 (s, 2H), 6.80 (d, J ) 2.0
Hz, 1H), 6.87 (dd, J ) 2.2, 8.6 Hz, 1H), 7.30 (m, 1H), 7.85 (d,
J ) 8.5 Hz, 1H); IR (KBr) 3447, 3346, 1736, 1669, 1608 cm-1
;

2096 J ournal of Medicinal Chemistry, 1997, Vol. 40, No. 13
Fisher et al.
7-[[4-[(Am in oim in om eth yl)a m in o]bu tyloxy]-3,4-d ih y-
d r o-1-oxo-2(1H )-isoq u in olin ea cet ic Acid Mon oh yd r o-
ch lor id e (16). Following the general procedure employed for
the preparation of 14a , 16 was prepared in a like manner: 1H
NMR (300 MHz, CD3OD) 1.91 (m, 4H) 2.95 (t, J ) 6.5 Hz,
2H), 3.24 (m, 2H), 3.63 (t, J ) 6.7 Hz, 2H), 4.03 (t, J ) 5.9 Hz,
2H), 4.29 (s, 2H), 7.01 (dd, J ) 2.5, 8.4 Hz, 1H), 7.19 (d, J )
8.5 Hz, 1H), 7.40 (m, 1H), 7.44 (d, J ) 2.5 Hz, 1H); IR (KBr)
3392, 1722, 1646, 1604, 1451 cm-1; MS (FAB) m/e 335. Anal.
(C16H23N4O4Cl) C, H, N.
Gen er a l P r oced u r e for th e P r ep a r a tion of In ter m ed i-
a tes 18a -d . P r ep a r a tion of 6-[[[N-[(Dim eth yleth oxy)-
ca r bon yl]p ip er id in -4-yl]m eth yl]oxy]-3,4-d ih yd r o-1-oxo-
2(1H)-isoqu in olin ea cetic Acid (18d ). A mixture of 9 (0.21
g, 0.74 mmol), bromide 17d (0.26 g, 0.80 mmol), K2CO3 (0.11
g, 0.80 mmol), and acetone (10 mL) was treated with a catalytic
amount of Bu4NI and maintained at reflux for 16 h. This
mixture was then diluted with EtOAc (100 mL) and washed
with H2O (2 × 25 mL). The organic material was then dried
(MgSO4) and concentrated. The crude residue was purified
by chromatography (silica gel, 240-400 mesh, hexanes/EtOAc,
1:1), providing 0.30 g (78%) of the title compound as a white
solid: 1H NMR (300 MHz, CDCl3) 1.15 (m, 2H), 1.25 (m, 2H),
1.43 (s, 9H), 1.45 (s, 9H), 1.46 (m, 3H), 1.60 (m, 2H), 1.75 (m,
2H), 2.62 (m, 2H), 2.95 (t, J ) 6.5 Hz, 2H), 3.59 (t, J ) 6.4 Hz,
2H), 3.95 (t, J ) 6.4 Hz, 2H), 4.10 (m, 2H), 4.19 (s, 2H), 6.62
(d, J ) 2.4 Hz, 1H), 6.79 (dd, J ) 2.2, 8.6 Hz, 1H), 8.01 (d, J
) 8.6 Hz, 1H); IR (KBr) 2930, 1746, 1679, 1649, 1603, 1154
cm-1; MS (FAB) m/e 517; mp 94-95 °C. Anal. (C29H44N2O6‚
0.5H2O) C, H, N.
6-[(P ip er id in -4-ylm eth yl)oxy]-3,4-d ih yd r o-1-oxo-2(1H)-
isoqu in olin ea cetic Acid Mon oh yd r och lor id e (19a ). Fol-
lowing the general procedure outlined for the preparation of
19d , 18a was deprotected with TFA in a similar fashion. The
crude TFA salt was then dissolved in H2O, treated with
aqueous HCl, and lyophilized, providing 19a as a hygroscopic
solid: 1H NMR (300 MHz, CD3OD) 1.59 (m, 2H), 2.05 (m, 3H),
3.0 (m, 4H), 3.2 (m, 2H), 3.68 (t, J ) 6.5 Hz, 2H), 3.98 (d, J )
5.9 Hz, 2H), 4.28 (s, 2H), 6.81 (d, J ) 2.3 Hz, 1H), 6.89 (dd, J
) 2.5, 8.6 Hz, 1H), 7.85 (d, J ) 8.7 Hz, 1H); IR (KBr) 2941,
2821, 1706, 1645, 1609, 1436, 1031 cm-1; MS (FAB) m/e 319.
Anal. (C17H23N2O4Cl‚0.5H2O) C, H, N.
6-[(P ip er id in -4-ylet h yl)oxy]-3,4-d ih yd r o-1-oxo-2(1H )-
isoqu in olin ea cetic Acid Hyd r och lor id e (19b). Following
the general procedure outlined for the preparation of 19d , 18b
was deprotected with TFA in a similar fashion. The crude TFA
salt was then dissolved in H2O, treated with aqueous HCl, and
lyophilized, providing 19b as a hygroscopic solid: 1H NMR (300
MHz, CD3OD) 1.48 (m, 2H), 1.81 (m, 2H), 1.95 (m, 1H), 2.04
(m, 2H), 3.00 (m, 4H), 3.40 (m, 2H), 3.66 (t, J ) 6.9 Hz, 2H),
4.12 (t, J ) 6.1 Hz, 2H), 4.28 (s, 2H), 6.83 (d, J ) 2.5 Hz, 1H),
6.89 (dd, J ) 2.5, 8.5 Hz, 1H), 7.85 (d, J ) 8.6 Hz, 1H); IR
(KBr) 2941, 1698, 1646, 1609, 1277, 1009 cm-1; MS (FAB) m/e
333. Anal. (C18H25N2O4Cl) C, H, N.
6-[(P ip er id in -4-ylp r op yl)oxy]-3,4-d ih yd r o-1-oxo-2(1H)-
isoqu in olin ea cetic Acid Hyd r och lor id e (19c). Following
the general procedure outlined for the preparation of 19d , 18c
was deprotected with TFA in a similar fashion. The crude TFA
salt was then dissolved in H2O, treated with aqueous HCl, and
lyophilized, providing 19c as a hygroscopic solid: 1H NMR (300
MHz, CD3OD) 1.20-1.45 (m, 4H), 1.65 (m, 1H), 1.80 (m, 2H),
1.98 (br d, J ) 14.5 Hz, 2H), 2.80-3.05 (m, 4H), 3.36 (br d, J
) 12.7 Hz, 2H), 3.65 (t, J ) 6.6 Hz, 2H), 4.03 (t, J ) 6.0 Hz,
2H), 4.27 (s, 2H), 6.78 (s, 1H), 6.84 (d, J ) 8.5 Hz, 1H), 7.83
(d, J ) 8.6 Hz, 1H); IR (KBr) 2951, 1781, 1745, 1652, 1602,
1190 cm-1; MS (FAB) m/e 347.1956 (347.1971 calcd for
C19H27N2O4).
6-[(4-Cya n op h en yl)m eth oxy]-3,4-d ih yd r o-1-oxo-2(1H)-
isoqu in olin ea cetic Acid 1,1-Dim eth yleth yl Ester (20). A
mixture of 8 (1.0 g, 3.60 mmol), R-bromo-p-tolunitrile (0.71 g,
3.60 mmol), K2CO3 (0.5 g, 3.60 mmol), and acetone (35 mL)
was maintained at reflux for 4 h and then allowed to cool to
room temperature. This mixture was filtered, and the filtrate
was concentrated to dryness. The crude isolate was purified
by chromatography (silica gel, 200-400 mesh, 1:1 hexanes/
EtOAc), which provided 1.38 g of 20 as a white solid: 1H NMR
(300 MHz, CDCl3) 1.51 (s, 9H), 3.05 (t, J ) 6.5 Hz, 2H), 3.66
(t, J ) 6.5 Hz, 2H), 4.26 (s 2H), 5.20 (s, 2H), 6.77 (d, J ) 1.7
Hz, 1H), 6.91 (dd, J ) 2.2, 8.7 Hz, 1H), 7.55 (d, J ) 8.1 Hz,
2H), 7.73 (d, J ) 8.0 Hz, 2H), 8.05 (d, J ) 8.6 Hz, 1H); IR
(KBr) 2110, 1737, 1651, 1604, 1153 cm-1; MS (FD) m/e 392.
Anal. (C23H30N2O4) C, H, N.
Gen er a l P r oced u r e for Con ver sion of Ar yl Nitr iles to
BOC-P r otected Am id in es. 6-[[4-[[[(1,1-d im eth yleth oxy)-
ca r b on yl]a m in o]im in om et h yl]p h en yl]m et h oxy]-3,4-d i-
h yd r o-1-oxo-2(1H)-isoqu in olin ea cetic Acid 1,1-Dim eth yl-
eth yl Ester (22). A mixture of 20 (0.38 g, 0.98 mmol),
pyridine (5.5 mL), and Et3N (0.55 mL) was saturated with
H2S(g) and allowed to stand at room temperature for 2 days.
This solution was then diluted with H2O, the resulting mixture
was extracted with EtOAc, and the extracts were concentrated.
The crude isolate was taken up in a mixture of acetone (5 mL)
and CH3I (2.5 mL) and maintained at reflux for 1 h. This
mixture was allowed to cool to room temperature and then
concentrated. The crude material was dissolved in MeOH (5
mL) and treated with NH4OAc (0.23 g, 2.9 mmol) This mixture
was maintained at 60 °C for 2 h and then concentrated. The
material thus isolated was suspended in THF/H2O (1:1, 6 mL)
and treated with K2CO3 (0.179 g, 1.30 mmol) and di-tert-butyl
dicarbonate (0.202 g, 0.95 mmol), and the resulting mixture
was stirred at room temperature for 2 h. The reaction mixture
was then diluted with EtOAc and washed with H2O. The
organic material was then concentrated to dryness, and the
crude residue was purified by chromatography (silica gel, 30:1
CHCl3/MeOH), giving 0.31 g (62%) of 22 as a white solid: 1H
NMR (300 MHz, CDCl3) 1.46 (s, 9H), 1.54 (s, 9H), 2.98 (t, J )
6-[[[N -[(Dim e t h yle t h oxy)ca r b on yl]p ip e r id in -4-yl]-
m e t h y l]o x y ]-3,4-d ih y d r o -1-o x o -2(1H )-is o q u in o lin e -
a cetic Acid (18a ). Compound 18a was prepared following
the general procedure outlined for 18d : 1H NMR (300 MHz,
CDCl3) 1.15 (m, 2H), 1.48 (s, 18H), 1.85 (m, 2H), 2.0 (m, 1H),
2.75 (m, 2H), 3.03 (t, J ) 6.5 Hz, 2H), 3.62 (t, J ) 6.4 Hz, 2H),
3.85 (d, J ) 6.3 Hz, 2H), 4.08 (m, 2H), 4.23 (s, 2H), 6.66 (d, J
) 2 Hz, 1H), 6.80 (dd, J ) 2.5, 8.7 Hz, 1H), 8.00 (d, J ) 8.6
Hz, 1H); IR (KBr) 1739, 1707, 1638, 1609, 1417, 1278 cm-1
;
MS (FD) m/e 474; mp 157-160 °C. Anal. (C26H38N2O6) C, H,
N.
6-[[[N -[(Dim e t h yle t h oxy)ca r b on yl]p ip e r id in -4-yl]-
et h yl]oxy]-3,4-d ih yd r o-1-oxo-2(1H )-isoq u in olin ea cet ic
Acid (18b). Compound 18b was prepared following the
general procedure outlined for 18d : 1H NMR (300 MHz,
CDCl3) 1.20 (m, 2H), 1.44 (s, 9H), 1.46 (s, 9H), 1.75 (m, 5H),
2.73 (m, 2H), 2.99 (t, J ) 6.6 Hz, 2H), 3.60 (t, J ) 6.4 Hz, 2H),
4.03 (t, J ) 6.1 Hz, 2H), 4.09 (m, 2H), 4.21 (s, 2H), 6.63 (d, J
) 2.4 Hz, 1H), 6.79 (dd, J ) 2.5, 8.6 Hz, 1H), 8.00 (d, J ) 8.7
Hz, 1H); IR (KBr) 2943, 1737, 1709, 1641, 1609, 1280 cm-1
;
MS (FD) m/e 488. Anal. (C27H40N2O6) C, H, N.
6-[[[N-[(Dim eth yleth oxy)ca r bon yl]p ip er id in -4-yl]p r o-
pyl]oxy]-3,4-dih yd r o-1-oxo-2(1H)-isoqu in olin ea cetic Acid
(18c). Compound 18c was prepared following the general
procedure outlined for 18d : 1H NMR (300 MHz, CDCl3) 1.0-
1.2 (m, 2H), 1.45 (s, 9H), 1.46 (s, 9H), 1.30-1.50 (m, 3H), 1.60-
1.85 (m, 4H), 2.71 (m, 4H), 3.00 (t, J ) 6.5 Hz, 2H), 3.60 (t, J
) 6.45 Hz, 2H), 3.91 (t, H ) 6.4 Hz, 2H), 4.07 (m, 2H), 4.21 (s,
2H), 6.64 (d, J ) 1.4 Hz, 1H), 6.79 (dd, J ) 2.1, 8.7 Hz, 1H),
7.99 (d, J ) 8.6 Hz, 1H); IR (KBr) 2975, 1750, 1732, 1685,
1647, 1259 cm-1; MS (FD) m/e 502; mp 113-115 °C. Anal.
(C28H42N2O6) C, H, N.
Gen er a l P r oced u r e for th e P r ep a r a tion of Com p ou n d s
19. 6-[[4-(P ip er id in -4-yl)b u t yl]oxy]-3,4-d ih yd r o-1-oxo-
2(1H)-isoqu in olin ea cetic Acid Tr iflu or oa ceta te (19d ). A
solution of 18d (0.30 g, 0.58 mmol) and anhydrous TFA was
allowed to stand at room temperature and then concentrated.
The crude residue was taken up in H2O (20 mL) and extracted
with Et2O (2 × 10 mL). The aqueous material was then
lyophilized, providing 0.24 g (90%) of 19d as a hygroscopic
solid: 1H NMR (300 MHz, DMSO) 1.14 (m, 4H), 1.45 (m, 3H),
1.81 (m, 4H), 2.80 (m, 2H), 2.94 (t, J ) 6.6 Hz, 2H), 3.25 (m,
2H), 3.58 (t, J ) 6.7 Hz, 2H), 4.02 (t, J ) 6.4 Hz, 2H), 4.16 (s,
2H), 6.83 (s, 1H), 6.86 (dd, J ) 2.2, 8.6 Hz, 1H), 7.78 (d, J )
8.6 Hz, 1H); IR (KBr) 2944, 1736, 1699, 1647, 1610, 1278 cm-1
;
MS (FAB) m/e 361. Anal. (C22H29N2O6F3‚0.5H2O) C, H, N.

Non-Peptide RGD Surrogates
J ournal of Medicinal Chemistry, 1997, Vol. 40, No. 13 2097
6.5 Hz, 2H), 3.60 (t, J ) 6.6 Hz, 2H), 4.20 (s, 2H), 5.12 (s, 2H),
6.70 (d, J ) 2.3 Hz, 1H), 6.84 (dd, J ) 2.4, 8.6 Hz, 1H), 7.43
(d, J ) 8.1 Hz, 2H), 7.86 (d, J ) 8.2 Hz, 2H), 7.91 (d, J ) 8.6
7.34 (d, J ) 8.2 Hz, 2H), 7.80 (d, J ) 8.2 Hz, 2H), 7.99 (d, J )
8.7 Hz, 1H); IR (KBr) 1737, 1650, 1620, 1604, 1278 cm-1; MS
(FAB) m/e 523; mp 146-149 °C. Anal. (C29H37N3O6) C, H, N.
6-[[4-(Am in oim in om eth yl)p h en yl]eth oxy]-3,4-d ih yd r o-
1-oxo-2(1H)-isoqu in olin ea cetic Acid Mon oh yd r och lor id e
(28). Following the general reaction outlined for the prepara-
tion of 24, 27 was deprotected with TFA, providing 28: 1H
NMR (300 MHz, CD3OD) 3.00 (t, J ) 6.7 Hz, 2H), 3.21 (t, J )
6.1 Hz, 2H), 3.65 (t, J ) 6.6 Hz, 2H), 4.28 (s, 2H), 4.33 (t, J )
6.2 Hz, 2H), 6.78 (d, J ) 2.2 Hz, 1H), 6.83 (dd, J ) 2.5, 8.7 Hz,
1H), 7.57 (d, J ) 8.4 Hz, 2H), 7.74 (d, J ) 8.3 Hz, 2H), 7.82 (d,
J ) 8.6 Hz, 1H); IR (KBr) 3354, 3075, 1697, 1628, 1601, 1485,
1280, 1249, 1187 cm-1; MS (FAB) m/e 368; mp 76-78 °C dec.
Anal. (C20H22N3O4Cl‚2H2O) C, H, N.
3,4-Dih yd r o-1-oxo-6-[[(tr iflu or om eth yl)su lfon yl]oxy]-
2(1H)-isoqu in olin ea cetic Acid 1,1-Dim eth yleth yl Ester
(29). To a solution of 8 (9.5 g, 34.2 mmol) and freshly distilled
pyridine (250 mL) was added trifluoromethanesulfonic anhy-
dride (5.8 mL, 34.2 mmol) at 0 °C. The resulting solution was
allowed to warm to room temperature and then quenched by
the addition of H2O (125 mL). The mixture was extracted with
EtOAc and the extract dried (MgSO4) and concentrated. The
crude material was purified by chromatography (silica gel, 4:1
hexanes/EtOAc) to give 11.54 g (82%) of 29 as a white solid:
1H NMR (300 MHz, CDCl3) 3.12 (t, J ) 6.5 Hz, 2H), 3.69 (t, J
) 6.5 Hz, 2H), 4.24 (s, 2H), 7.14 (d, J ) 2.2 Hz, 1H), 7.23 (dd,
J ) 2.3, 8.7 Hz, 1H), 8.20 (d, J ) 8.7 Hz, 1H); IR (CHCl3) 1660,
1425, 1250, 1153, 1141 cm-1; MS (FD) m/e 409; mp 80-82 °C.
Anal. (C16F3H18NO6S) C, H, N.
Hz, 1H); IR (CHCl3) 1738, 1648, 1611, 1479, 1276, 1156 cm-1
;
MS (FAB) m/e 510. Anal. (C28H35N3O6) C, H, N.
Gen er a l P r oced u r e for th e P r ep a r a tion of Am id in e-
Acid Der iva t ives. P r ep a r a t ion of 6-[[4-(Am in oim in o-
m et h yl)p h en yl]m et h oxy]-3,4-d ih yd r o-1-oxo-2(1H )-iso-
qu in olin ea cetic Acid Mon o(tr iflu or oa ceta te) (24.)
A
mixture of 22 (0.31 g, 0.62 mmol) and anhydrous TFA (5 mL)
was maintained at room temperature for 1 h and then
concentrated. The residue was triturated with Et2O, and the
formed solid was collected by filtration, providing 0.31 g of 22
as a white solid: 1H NMR (300 MHz, CD3OD) 3.03 (t, J ) 6.1
Hz, 2H), 3.66 (t, J ) 6.4 Hz, 2H), 4.29 (s, 2H), 5.30 (s, 2H),
6.91 (d, J ) 2.4 Hz, 1H), 6.98 (dd, J ) 2.6, 8.7 Hz, 1H), 7.70
(d, J ) 8.3 Hz, 2H), 7.81 (d, J ) 8.2 Hz, 2H), 7.86 (d, J ) 8.7
Hz, 1H); IR (KBr) 3333, 1696, 1669, 1605, 1458, 1118 cm-1
;
MS (FAB) m/e 354. Anal. (C21H20N3O6F3) C, H, N.
7-[(4-Cya n op h en yl)m eth oxy]-3,4-d ih yd r o-1-oxo-2(1H)-
isoq u in olin ea cet ic Acid 1,1-Dim et h ylet h yl E st er (21).
Following the procedure employed for the preparation of 20,
21 was prepared starting from 9 and R-bromo-p-tolunitrile:
1H NMR (300 MHz, CDCl3) 1.46 (s, 9H), 2.97 (t, J ) 6.5 Hz,
2H), 3.60 (t, J ) 6.6 Hz, 2H), 4.20 (s, 2H), 5.14 (s, 2H), 7.02
(dd, J ) 2.7, 8.3 Hz, 1H), 7.10 (d, J ) 8.3 Hz, 1H), 7.52 (d, J
) 8.2 Hz, 2H), 7.64 (m, 3H); IR (KBr) 3019, 1738, 1650, 1607,
1484, 1153 cm-1; MS (FD) m/e 392; mp 108-110 °C. Anal.
(C23H30N2O4) C, H, N.
7 -[[4 -[[[(1 ,1 -D i m e t h y l e t h o x y )c a r b o n y l ]a m i n o ]-
im in om eth yl]p h en yl]m eth oxy]-3,4-d ih yd r o-1-oxo-2(1H)-
isoq u in olin ea cet ic Acid 1,1-Dim et h ylet h yl E st er (23).
Following the general procedure employed for the preparation
6-[(4-Cya n op h e n yl)-(E )-e t h e n yl]-3,4-d ih yd r o-1-oxo-
2(1H)-isoqu in olin ea cetic Acid 1,1-Dim eth yleth yl Ester
(30). A mixture of 29 (1.0 g, 2.44 mmol), 4-cyanostyrene (0.47
g, 3.66 mmol), palladium(II) acetate (0.55 g, 0.24 mmol), tri-
o-tolylphosphine (0.149 g, 0.49 mmol), K2CO3 (1.69 g, 12.2
mmol), tetrabutylammonium iodide (0.90 g, 2.44 mmol), and
anhydrous DMF (10 mL) was maintained at 120 °C for 1.5 h.
The reaction mixture was then allowed to cool to room
temperature where it was diluted with EtOAc (150 mL) and
washed with H2O. The organic material was concentrated,
and the crude isolate was purified by chromatography (silica
gel, 3:2 hexanes/EtOAc), providing 0.51 g (53%) of 30: 1H NMR
(300 MHz, CDCl3) 1.48 (s, 9H), 3.08 (t, J ) 6.55 Hz, 2H), 3.66
(t, J ) 6.5 Hz, 2H), 4.25 (s, 2H), 7.17 (dd, J ) 16.21, 18.64 Hz,
2H), 7.33 (s, 1H), 7.49 (d, J ) 8.1 Hz, 1H), 7.62 (dd, J ) 8.4,
18.7 Hz, 4H), 8.09 (d, J ) 8.3 Hz, 1H); IR (CHCl3) 2227, 1738,
1648, 1153 cm-1; MS (FD) m/e 388. Anal. (C24H24N2O3) C, H,
N.
6 -[[4 -[[[(1 ,1 -D i m e t h y l e t h o x y )c a r b o n y l ]a m i n o ]-
im in om e t h yl]p h e n yl]-(E )-e t h e n yl]-3,4-d ih yd r o-1-oxo-
2(1H)-isoqu in olin ea cetic Acid 1,1-Dim eth yleth yl Ester
(31). Following the procedure outlined for the synthesis of
22, 31 was prepared in 30% yield, starting from 0.99 g of 30:
1H NMR (300 MHz, CDCl3) 1.48 (s, 9H), 1.56 (s, 9H), 3.07 (t,
J ) 6.5 Hz, 2H), 3.65 (t, J ) 6.4 Hz, 2H), 4.24 (s, 2H), 7.17 (s,
2H), 7.32 (s, 1H), 7.46 (d, J ) 8.2 Hz, 1H), 7.56 (d, J ) 8.5 Hz,
2H), 7.86 (d, J ) 8.4 Hz, 2H), 8.05 (d, J ) 8.0 Hz, 1H); IR
(KBr) 3391, 1744, 1642, 1653, 1608, 1283 cm-1; MS (FAB) m/e
506. Anal. (C29H30N3O5) C, H, N.
6-[[4-(Am in oim in om eth yl)p h en yl]-(E)-eth en yl]-3,4-d i-
h yd r o-1-oxo-2(1H )-isoq u in olin ea cet ic Acid Mon o(t r i-
flu or oa ceta te) (32). Following the procedure outlined for the
preparation of 24, 32 was prepared in 68% yield, starting from
0.14 g of 31: 1H NMR (300 MHz, CD3OD) 3.10 (t, J ) 6.6 Hz,
2H), 3.70 (t, J ) 6.6 Hz, 2H), 4.32 (s, 2H), 7.41 (s, 2H), 7.53 (s,
1H), 7.59 (d, J ) 8.2 Hz, 1H), 7.81 (s, 4H), 7.93 (d, J ) 8.1 Hz,
1H); IR (KBr) 3337, 3120, 1672, 1608, 1483, 1188 cm-1; MS
(FD) m/e 349. Anal. (C22H20N3O5F3‚0.2H2O) C, H, N.
6-[(4-Cya n op h en yl)et h yn yl]-3,4-d ih yd r o-1-oxo-2(1H )-
isoqu in olin ea cetic Acid 1,1-Dim eth yleth yl Ester (33). A
mixture of 29 (0.33 g, 0.79 mmol), (4-cyanophenyl)acetylene
(0.14 g, 1.11 mmol), bis(triphenylphosphine)palladium(II)
chloride (0.014 g, 0.02 mmol), anhydrous DMF (2.0 mL), and
freshly distilled Et3N (0.5 mL) was stirred at 90 °C for 1 h. At
this time, H2O (25 mL) was added and the mixture was
extracted with EtOAc (2 × 75 mL). The extracts were dried
over MgSO4 and concentrated. The crude material was
1
of 22, 23 was formed in a like manner starting from 21: H
NMR (300 MHz, CDCl3) 1.47 (s, 9H), 1.55 (s, 9H), 2.97 (t, J )
6.5 Hz, 2H), 3.61 (t, J ) 6.5 Hz, 2H), 4.22 (s, 2H), 5.13 (s, 2H),
7.06 (m, 2H), 7.47 (d, J ) 8.0 Hz, 2H), 7.65 (d, J ) 1.4 Hz,
1H), 7.85 (d, J ) 8.0 Hz, 2H); IR (KBr) 3369, 2977, 1741, 1656,
1621, 1498, 1151 cm-1; MS (FAB) m/e 510; mp 178-180 °C.
Anal. (C28H35N3O6) C, H, N.
7-[[4-(Am in oim in om eth yl)ph en yl]m eth oxy]-3,4-dih ydr o-
1-oxo-2(1H )-isoq u in olin ea cet ic Acid Mon o(t r iflu or o-
a ceta te) (25). Following the procedure employed for the
deprotection of 24, 25 was prepared in a like manner: 1H NMR
(300 MHz, CD3OD) 2.97 (t, J ) 6.5 Hz, 2H), 3.65 (t, J ) 6.5
Hz, 2H), 4.29 (s, 2H), 5.25 (s, 2H), 7.13 (m, 2H), 7.51 (d, J )
2.0 Hz, 1H), 7.68 (d, J ) 8.2 Hz, 2H), 7.79 (d, J ) 8.2 Hz, 2H);
IR (KBr) 3334, 3109, 1670, 1606, 1494, 1134 cm-1; MS (FAB)
m/e 354; mp 216-218 °C dec. Anal. (C21H20N3O6F3) C, H, N.
6-[(4-Cya n op h en yl)et h oxy]-3,4-d ih yd r o-1-oxo-2(1H )-
isoqu in olin ea cetic Acid 1,1-Dim eth yleth yl Ester (26). A
solution of phenol 8 (0.20 g, 0.72 mmol), 2-(4-cyanophenyl)-
ethanol (0.16 g, 0.72 mmol), triphenylphosphine (0.21 g, 0.79
mmol), and THF (10 mL) was treated with diethyl azodicar-
boxylate (0.14 g, 0.79 mmol) and then maintained at room
temperature for 2 h. This solution was then diluted with
EtOAc (100 mL) and washed with H2O (2 × 25 mL) and
concentrated. The residue was passed through a plug of silica
(hexanes/EtOAc, 3:2), and the residue which was obtained
after concentration was recrystallized from EtOAc/hexanes.
This purification sequence provided 0.2 g (68%) of 26 as an
off-white solid: 1H NMR (300 MHz, CDCl3) 1.42 (s, 9H), 2.94
(t, J ) 6.5 Hz, 2H), 3.10 (t, J ) 6.4 Hz, 2H), 3.56 (t, J ) 6.6
Hz, 2H), 4.17 (m, 4H), 6.59 (d, J ) 1.7 Hz, 1H), 6.74 (dd, J )
8.6, 2.1 Hz, 1H), 7.26 (s, 1H), 7.35 (d, J ) 8.1 Hz, 2H), 7.54 (d,
J ) 8.3 Hz, 2H) 7.95 (d, J ) 8.3 Hz, 1H); IR (KBr) 2220, 1736,
1724, 1654, 1613, 1236, 1152 cm-1; MS (FD) m/e 406; mp 103-
106 °C. Anal. (C24H26N2O4) C, H, N.
6 -[[4 -[[[(1 ,1 -D i m e t h y l e t h o x y )c a r b o n y l ]a m i n o ]-
im in om et h yl]p h en yl]et h oxy]-3,4-d ih yd r o-1-oxo-2(1H )-
isoq u in olin ea cet ic Acid 1,1-Dim et h ylet h yl E st er (27).
Following the general sequence employed for the preparation
1
of 22, 27 was prepared starting from 26: H NMR (300 MHz,
CDCl3) 1.46 (s, 9H), 1.54 (s, 9H), 2.98 (t, J ) 6.5 Hz, 2H), 3.13
(t, J ) 6.69 Hz, 2H), 3.59 (t, J ) 6.5 Hz, 2H), 4.20 (m, 4H),
6.62 (d, J ) 2.3 Hz, 1H), 6.79 (d, J ) 8.7 Hz, 1H), 7.26 (s, 1H),

2098 J ournal of Medicinal Chemistry, 1997, Vol. 40, No. 13
Fisher et al.
purified by chromatography (silica gel, 5:2 hexanes/EtOAc) to
give 0.17 g (57%) of 33 as an orange solid: 1H NMR (300 MHz,
CDCl3) 1.47 (s, 9H), 3.06 (t, J ) 6.5 Hz, 2H), 3.65 (t, J ) 6.8
Hz, 2H), 4.24 (s, 2H), 7.37 (br s, 1H), 7.50 (d, J ) 8.2 Hz, 1H),
7.60 (dd, J ) 8.5 Hz, 4H), 8.05 (d, J ) 8.0 Hz, 1H); IR (KBr)
2227, 1738, 1649, 1154, 832 cm-1; MS (FD) m/e 386; mp 195-
197 °C. Anal. (C24H22N2O3) C, H, N.
352.1665 (352.1661 calcd for C20H22N3O3). Anal. (C22H22N3O5‚
0.25C4H10O) C, H, N.
3,4-Dih yd r o-6-(m e t h oxyca r b on yl)-1-oxo-2(1H )-iso-
qu in olin ea cetic Acid 1,1-Dim eth yleth yl Ester (40).
A
solution of 29 (5.0 g, 12.2 mmol), DMF (25 mL), palladium(II)
acetate (0.082 g, 0.37 mmol), triphenylphosphine (0.19 g, 0.73
mmol), freshly distilled Et3N (3.4 mL, 24.4 mmol), and
anhydrous MeOH (9.9 mL) was stirred under an atmosphere
of CO (balloon) at 65 °C for 15 h. The reaction mixture was
then allowed to cool to room temperature where it was diluted
with H2O (100 mL). The resulting mixture was extracted with
EtOAc, and the combined extracts were dried (MgSO4) and
concentrated. The crude material was purified by chroma-
tography (silica gel, 1:1 hexanes/EtOAc) to provide 2.80 g (72%)
of 40 as a white solid: 1H NMR (300 MHz, CDCl3) 1.47 (s,
9H), 3.10 (t, J ) 6.5 Hz, 2H), 3.66 (t, J ) 6.5 Hz, 2H), 3.93 (s,
3H), 4.27 (s, 2H), 7.88 (s, 1H), 7.99 (d, J ) 8.1 Hz, 1H), 8.14
(d, J ) 8.0 Hz, 1H); IR (CHCl3) 1730, 1722, 1654, 1290, 1154
cm-1; MS (FD) m/e 319. Anal. (C17H21NO5) C, H, N.
6 -[[4 -[[[(1 ,1 -D i m e t h y l e t h o x y )c a r b o n y l ]a m i n o ]-
im in om et h yl]p h en yl]et h yn yl]-3,4-d ih yd r o-1-oxo-2(1H )-
isoq u in olin ea cet ic Acid 1,1-Dim et h ylet h yl E st er (34).
Following the general reaction sequence employed for the
1
synthesis of 22, 34 was prepared starting from 33: H NMR
(300 MHz, CDCl3) 1.47 (s, 9H), 1.55 (s, 9H), 3.04 (t, J ) 6.5
Hz, 2H), 3.63 (t, J ) 6.4 Hz, 2H), 4.23 (s, 2H), 7.35 (br s, 1H),
7.47 (d, J ) 8.0 Hz, 1H), 7.53 (d, J ) 8.3 Hz, 2H), 7.84 (d, J )
8.3 Hz, 2H), 8.01 (d, J ) 8.0 Hz, 1H); IR (KBr) 3400, 2990,
1640, 1620, 1150 cm-1; MS (FD) m/e 504. Anal. Calcd for
C29H33N3O5: C, 69.17; H, 6.61; N, 8.34. Found: C, 69.36; H,
6.71; N, 8.20.
6-[[4-(Am in oim in om eth y)p h en yl]eth yn yl]-3,4-d ih yd r o-
1-oxo-2(1H )-isoq u in olin ea cet ic Acid Mon o(t r iflu or o-
a ceta te) (35). Using the general procedure employed for the
deprotection of 22, 34 was treated with TFA, which provided
35: 1H NMR (300 MHz, CD3OD) 3.09 (t, J ) 6.71 Hz, 2H),
3.71 (t, J ) 6.6 Hz, 2H), 4.86 (s, 2H), 7.50 (s, 1H), 7.54 (d, J )
8.1 Hz, 1H), 7.81 (dd, J ) 8.6, 18.0 Hz, 4H), 7.96 (d, J ) 8.0
Hz, 1H); IR (KBr) 1709, 1640, 1609, 1126, 732 cm-1; MS (FAB)
m/e 348; mp 300 °C dec. Anal. (C22H18N3O5F3‚1.5H2O) C, H,
N.
6 -[[4 -[[[(1 ,1 -D i m e t h y l e t h o x y )c a r b o n y l ]a m i n o ]-
im in om e t h yl]p h e n yl]-(Z)-e t h e n yl]-3,4-d ih yd r o-1-oxo-
2(1H)-isoqu in olin ea cetic Acid 1,1-Dim eth yleth yl Ester
(36). A mixture of 34 (0.070 g, 0.18 mmol), Pd/BaSO4 (10%,
0.03 g), EtOAc (10 mL), and pyridine (2mL) was maintained
under an atmosphere of hydrogen (balloon) for 3 h and then
filtered and concentrated. The crude isolate was purified by
chromatography (silica gel, 1:1 hexanes/EtOAc) to give 0.051
g (72%) of 36 as a white solid: 1H NMR (300 MHz, CDCl3)
1.47 (s, 9H), 1.54 (s, 9H), 2.92 (t, J ) 6.65 Hz, 2H), 3.60 (t, J
) 6.5 Hz, 2H), 4.22 (s, 2H), 6.66 (s, 2H), 7.01 (s, 1H), 7.15 (d,
J ) 8.0 Hz, 1H), 7.27 (d, J ) 9.0 Hz, 2H), 7.71 (d, J ) 8.3 Hz,
2H), 7.92 (d, J ) 8.0 Hz, 1H); IR (CHCl3) 1738, 1649, 1609,
1286, 1157 cm-1; MS (FAB) m/e 506; mp 92-96 °C. Anal.
(C29H30N3O5) C, H, N.
6-[[4-(Am in oim in om eth yl)p h en yl]-(Z)-eth en yl]-3,4-d i-
h yd r o-1-oxo-2(1H )-isoq u in olin ea cet ic Acid Mon o(t r i-
flu or oa ceta te) (37). Following the procedure employed for
the synthesis of 24, 37 was prepared in 72% yield starting from
0.051 g of 36: 1H NMR (300 MHz, CD3OD) 2.97 (t, J ) 6.7
Hz, 2H), 3.67 (t, J ) 6.53 Hz, 2H), 4.87 (s, 2H), 6.82 (dd, J )
12, 19 Hz, 2H), 7.14 (m, 2H), 7.43 (d, J ) 8.4 Hz, 2H), 7.66 (d,
J ) 8.5 Hz, 2H), 7.75 (d, J ) 7.9 Hz, 1H); IR (KBr) 3101, 1761,
1666, 1606, 1428, 1183 cm-1; MS (FD) m/e 350; mp 208-210
°C. Anal. (C22H20N3O5F3) C, H, N.
6-[2-[4-[[[(1,1-Dim et h ylet h yl)ca r b on yl]a m in o]im in o-
m eth yl]p h en yl]eth yl]-3,4-d ih yd r o-1-oxo-2(1H)-isoqu in o-
lin ea cetic Acid 1,1-Dim eth yleth yl Ester (38). A mixture
of 34 (0.10 g, 0.26 mmol), Pd/C (10% on carbon, 0.1 g), and
EtOAc (10 mL) was maintained under an atmosphere of
hydrogen (balloon) for 2 h and then filtered and concentrated.
The crude isolate was purified by recrystallization from EtOAc/
hexanes, which provided 0.095 g (95%) of 38 as a white solid:
1H NMR (300 MHz, CDCl3) 1.47 (s, 9H), 1.54 (s, 9H), 2.95 (m,
6H), 3.61 (t, J ) 6.4 Hz, 2H), 4.22 (s, 2H), 6.91 (s, 1H), 7.11 (d,
J ) 8.0 Hz, 1H), 7.18 (d, J ) 8.2 Hz, 2H), 7.76 (d, J ) 8.2 Hz,
2H), 7.96 (d, J ) 8.0 Hz, 1H); IR (CHCl3) 1738, 1648, 1611,
1286, 1155 cm-1; MS (FAB) m/e 508; mp 165-168 °C. Anal.
(C29H37N3O5) C, H, N.
6-C a r b o x y -3,4-d ih y d r o -1-o x o -2(1H )-is o q u in o lin e -
a cetic Acid 1,1-Dim eth yleth yl Ester (41). A solution of 40
(2.8 g, 8.7 mmol) and THF (87 mL) was treated with aqueous
LiOH (87 mL of a 0.1 N solution, 8.7 mmol), and the resulting
solution was maintained at room temperature for 12 h. The
reaction mixture was then concentrated to half volume and
extracted with EtOAc. The remaining aqueous material was
acidified to pH 5 with 1 N HCl, and this mixture was extracted
with EtOAc. The extracts were concentrated, providing 2.2 g
of 41 as an essentially pure clear oil (85%): 1H NMR (300 MHz,
CDCl3) 1.43 (s, 9H), 3.15 (t, J ) 6.5 Hz, 2H), 3.71 (t, J ) 6.4
Hz, 2H) 4.22 (s, 2H), 7.99 (m, 3H); IR (CHCl3) 3109, 1699, 1651,
1154 cm-1; MS (FD) m/e 306. Anal. (C16H19NO5) C, H, N.
3,4-D ih y d r o -1-o x o -6-[[(p h e n y lm e t h o x y )c a r b o n y l]-
a m in o]-2(1H)-isoqu in olin ea cetic Acid 1,1-Dim eth yleth yl
Ester (42). A solution of 41 (0.20 g, 0.66 mmol) and anhy-
drous toluene (50 mL) was treated with diphenyl phosphor-
azidate (0.28 mL, 1.31 mmol) and freshly distilled Et3N (0.18
mL, 1.31 mmol), and the resulting solution was maintained
at 85 °C for 2 h. The reaction mixture was then allowed to
cool to room temperature where it was treated with benzyl
alcohol (0.14 mL, 1.31 mmol) and stirred for an additional
hour. The reaction mixture was then concentrated and the
crude isolate purified by chromatography (silica gel, 1:1
hexanes/EtOAc) to yield 0.21 g (79%) of 42 as a white solid:
1H NMR (300 MHz, CDCl3) 1.45 (s, 9H), 2.96 (t, J ) 6.5 Hz,
2H), 3.56 (t, J ) 6.5 Hz, 2H), 4.19 (s, 2H), 5.18 (s, 2H), 7.16
(dd, J ) 2.0, 8.4 Hz, 1H), 7.30 (m, 5H), 7.50 (s, 1H), 7.60 (s,
1H), 7.95 (d, J ) 2.4 Hz, 1H); IR (CHCl3) 3431, 3011, 1738,
1647, 1524 cm-1; MS (FD) m/e 410. Anal. (C16H19NO5) C, H,
N.
6-Am in o-3,4-d ih yd r o-1-oxo-2(1H )-isoq u in olin ea cet ic
Acid 1,1-Dim eth yleth yl Ester (43). A mixture of 42 (0.20
g, 0.49 mmol), EtOH (20 mL), EtOAc (20 mL), and Pd/C (0.2
g of 10% on carbon) was stirred under an atmosphere of
hydrogen (balloon) for 1 h and then filtered and concentrated,
giving 1.3 g (95%) of 43 as a white solid: 1H NMR (300 MHz,
CDCl3) 1.49 (s, 9H), 2.94 (t, J ) 6.6 Hz, 2H), 3.58 (t, J ) 6.6
Hz, 2H), 4.21 (s, 2H), 6.41 (d, J ) 1.72 Hz, 1H), 6.06 (dd, J )
1.7, 8.3 Hz, 1H), 7.89 (d, J ) 8.3 Hz, 1H); IR (CHCl3) 3008,
1737, 1640, 1621, 1607, 1154 cm-1; MS (FD) m/e 276; mp 138-
140 °C. Anal. (C15H20N2O3) C, H, N.
6-[(4-Cya n ob en zoyl)a m in o]-3,4-d ih yd r o-1-oxo-2(1H )-
isoqu in olin ea cetic Acid 1,1-Dim eth yleth yl Ester (44). A
solution of 43 (0.125 g, 0.45 mmol), anhydrous dichloro-
methane (2.5 mL), 4-cyanobenzoic acid (0.066 g, 0.45 mmol),
1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochlo-
ride (0.095 g, 0.50 mmol), and DMAP (0.01g) was maintained
at room temperature for 2 h and then diluted with EtOAc (100
mL). This mixture was washed with H2O and then concen-
trated. The crude isolate was purified by chromatography
(silica gel, 2:1 hexanes/EtOAc) to give 0.18 g (96%) of 44 as a
white solid: 1H NMR (300 MHz, CDCl3) 1.47 (s, 9H), 3.10 (t,
J ) 6.5 Hz, 2H), 3.66 (t, J ) 6.57 Hz, 2H), 4.23 (s, 2H), 7.32
(dd, J ) 2.1, 8.5 Hz, 1H), 7.80 (d, J ) 8.5 Hz, 1H), 7.85 (s,
1H), 8.02 (dd, J ) 8.5, 10.5 Hz, 4H), 8.20 (s, 1H); IR (CHCl3)
6-[2-[4-(Am in oim in om eth yl)p h en yl]eth yl]-3,4-d ih yd r o-
1-oxo-2(1H )-isoq u in olin ea cet ic Acid Mon o(t r iflu or o-
a ceta te) (39). Following the procedure outlined for the
preparation of 24, 39 was prepared in 65% yield starting from
0.06 g of 38: 1H NMR (300 MHz, CD3OD) 3.01 (m, 6H), 3.66
(t, J ) 6.5 Hz, 2H), 4.29, (s, 2H), 7.11 (m, 2H), 7.40 (d, J ) 8.3
Hz 2H), 7.70 (d, J ) 8.2 Hz, 2H), 7.79 (d, J ) 8.4 Hz, 1H); IR
(KBr) 3337, 3111, 1650, 1612, 1209, 1180 cm-1; MS (FAB) m/e

Non-Peptide RGD Surrogates
J ournal of Medicinal Chemistry, 1997, Vol. 40, No. 13 2099
3010, 2270, 1738, 1647, 1524, 1429 cm-1; MS (FD) m/e 405.
Anal. (C23H23N3O4) C, H, N.
Refer en ces
(1) Phillips, D. R.; Fitzgerald, L. A.; Charo, I. F.; Parise, L. V. The
Platelet Glycoprotein IIb/IIIa Complex. Ann. N.Y. Acad. Sci.
1987, 509, 177-187.
(2) Phillips, D. R.; Charo, I. F.; Parise, L. V.; Fitzgerald, L. A. The
Platelet Membrane Glycoprotein IIb/IIIa Complex. Blood 1988,
71, 831-843.
(3) Phillips, D. R.; Charo, I. F.; Scarborough, R. M. GPIIb-IIIa: The
Responsive Integrin. Cell 1991, 65, 359-362.
(4) Coller, B. S. Platelets and Thrombolytic Therapy. N. Engl. J .
Med. 1990, 322, 33-42.
(5) Hamm, C. W.; Bleifield, W.; Kupper, W.; Lorens, R. L.; Wever,
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Patients with Persistent Unstable Angina. J . Am. Coll. Cardiol.
1987, 10, 998-1004.
(6) For a recent reviews, see: (a) Samanen, J . Annu. Rep. Med.
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Bioorg. Med. Chem. 1995, 3, 337-360.
(7) Kroll, M. H.; Schaffer, A. I. Biochemical Mechanisms of Platelet
Activation. Blood 1989, 74, 1181-1195.
(8) Lefkovits, J .; Plow, E. F.; Topol, E. J . Platelet Glycoprotein IIb/
IIIa Receptors in Cardiovascular Medicine. N. Engl. J . Med.
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6 -[[4 -[[[(1 ,1 -D i m e t h y l e t h o x y )c a r b o n y l ]a m i n o ]-
im in om et h yl]b en zoyl]a m in o]-3,4-d ih yd r o-1-oxo-2(1H )-
isoq u in olin ea cet ic Acid 1,1-Dim et h ylet h yl E st er (45).
Following the procedure employed for the synthesis of 22,
compound 45 was prepared in 36% yield starting from 0.17 g
of 44: 1H NMR (300 MHz, CDCl3) 1.46 (s, 9H), 1.50 (s, 9H),
2.90 (t, J ) 6.2 Hz, 2H), 3.55 (t, J ) 6.3 Hz, 2H), 4.16 (s, 2H),
7.46 (m, 3H), 7.64 (d, J ) 8.2 Hz, 2H), 7.78 (m, 2H), 9.91 (br
s, 1H); IR (CHCl3) 2984, 1740, 1538, 1272, 1152 cm-1; MS
(FAB) m/e 523. Anal. (C28H34N4O6) C, H, N.
6-[[4-(Am in om eth yl)ben zoyl]am in o]-3,4-dih ydr o-1-oxo-
2(1H)-isoqu in olin ea cetic Acid Mon o(tr iflu or oa ceta te)
(46). Following the procedure employed for the synthesis of
24, 46 was prepared in 76% yield starting from 0.07 g of 45:
1H NMR (300 MHz, CD3OD) 3.09 (t, J ) 6.6 Hz, 2H), 3.72 (t,
J ) 6.6 Hz, 2H), 4.32 (s, 2H), 7.67 (m, 1H), 7.80 (br s, 1H),
7.94 (d, J ) 8.3 Hz, 3H), 8.16 (d, J ) 8.2 Hz, 2H); IR (KBr)
3354, 3007, 1634, 1538, 1196 cm-1; MS (FAB) m/e 367. Anal.
(C21H19F3N4O6) C, H, N.
6-[[(4-Cya n op h en yl)a m in o]ca r b on yl]-3,4-d ih yd r o-1-
oxoisoqu in olin ea cetic Acid 1,1-Dim eth yleth yl Ester (47).
A mixture of 41 (0.20 g, 0.66 mmol) and toluene (5 mL) was
treated with oxalyl chloride (0.07 mL, 0.78 mmol) and a
catalytic amount of DMF at room temperature. After 1 h, the
solution was concentrated to dryness, the crude residue was
taken up in CH2Cl2 (1 mL), and this solution was treated
sequentially with pyridine (1 mL) and 4-cyanoanaline (0.09
g, 0.79 mmol). The resulting mixture was stirred at room
temperature for 1 h, diluted with EtOAc (100 mL), and washed
with H2O (3 × 20 mL). The organic material was dried
(MgSO4) and concentrated. The crude residue was recrystal-
lized from EtOAc/hexanes, providing 0.26 g (80%) of 47 as a
white solid: 1H NMR (300 MHz, CDCl3) 1.44 (s, 9H), 3.06 (t,
J ) 6.5 Hz, 2H), 3.65 (t, J ) 6.5 Hz, 2H), 4.21 (s, 2H), 7.69 (m,
(9) Pytela, R.; Pierschbacher, M. D.; Ginsberg, M. H.; Plow, E. F.;
Rouslahti, E. Platelet Membrane Glycoprotein IIb/IIIa: Member
of a Family of Arg-Gly-Asp-Specific Adhesion Receptors. Science
1986, 231, 1559-1562.
(10) Hawiger, J .; Kloczewiak, M; Bednarek, M. A.; Timmons, S.
Platelet Receptor Recognition Domains on the R Chain of Human
Fibrinogen: Structure-Function Analysis. Biochemisry 1989, 28,
2909-2914.
(11) Bennett, J . S.; Shattil, S. J .; Power, S. W.; Gartner, T. K.
Interaction of Fibrinogen with Its Platelet Receptor. J . Biol.
Chem. 1988, 263, 12948-12953.
(12) Steiner, B.; Cousot, D.; Trzeciak, A.; Gillessen, D.; Hadvary, P.
Ca+2 dependant Binding of a Synthetic Arg-Gly-Asp- (RGD)
Peptide to a Single Site on the Purified Platelet Glycoprotein
IIb-IIIa complex. J . Biol. Chem. 1989, 264, 13102-13108.
(13) For leading references, see: D’Souza, S. E.; Ginsberg, M. H.;
Plow, E. F. Arginyl-glycyl-aspartic acid (RGD): A Cell Adhesion
Motif. Trends Biochem. Sci. 1991, 16, 246-250.
(14) Greenspoon, N.; Hershkoviz, R.; Alon, R.; Varon, D.; Shenkman,
B.; Marx, G.; Federman, S.; Kapustina, G.; Liker, O. Biochem-
istry 1993, 32, 1001-1008.
(15) Pierschbacher, M. D.; Ruoslahti, E. Influence of Stereochemistry
on the Sequence Arg-Gly-Asp-Xaa on Binding Specificity in Cell
Adhesion. J . Biol. Chem. 1987, 262, 17294-17298.
(16) For a review and leading references, see: (a) Nichols, A. J .;
Ruffolo, R. R. J r.; Huffman, W. F.; Proste, G.; Samanen, J .
Trends Pharmacol. Sci. 1992, 13, 413. (b) Shebuski, R. J . Annu.
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(17) Samanen, J .; Ali, F. E.; Romoff, T.; Calvo, R.; Sorenson, E.;
Bennett, D.; Berry, D.; Koster, P.; Vasko, J .; Powers, D.; Stadel,
J .; Nichols, A. Reinstatement of High Receptor Affinity in a
Peptide Fragment (RGDS) Through Conformational Constraints.
In Peptides 1990, Proceeding of the 21st European Peptide
Symposium; Giralt, E., Andreu, D., Eds.; ESCOM Science
Publishers: Leiden, 1990; pp 781-783.
(18) Samanen, J .; Ali, F.; Romoff, T.; Calvo, R.; Sorenson, E.; Vasko,
J .; Storer, B.; Berry, D.; Bennett, D.; Stroksacker, M.; Powers,
D.; Stadel, J .; Nichols, A. Development of a Small RGD Peptide
Fibrinogen Receptor Antagonist with Potent Antiaggregatory
Activity in Vitro. J . Med. Chem. 1991, 34, 3114-3125.
(19) Nutt, R. F.; Brady, S. F.; Sisko, J . T.; Ciccarone, T. M.; Colton,
C. D.; Levy, M. R.; Gould, R. J .; Shang, G.; Friedman, P. A.;
Veber, D. F. Structure and Conformation-Activity Studies Lead-
ing to Potent Fibrinogen Receptor Antagonists Containing Arg-
Gly-Asp. In Peptides 1990; Giralt, E., Andreu, D., Eds.; ESCOM
Science Publishers B.V.: Leiden, 1991; pp 784-784
(20) Ali, F. E.; Samanen, J . M.; Calvo, R.; Romoff, T.; Yellin, T.;
Vasko, J .; Powers, D.; Stadel, J .; Bennett, D.; Berry, D.; Nichols,
A. Potent Fibrinogen Receptor Antagonists Bearing Conforma-
tional Constraints. In Peptides, Chemistry and Biology, Proceed-
ings 12th American Peptide Symposium; Smith, J . A., Rivier J .
E., Eds.; ESCOM: Leiden, 1992; pp 761-762.
(21) Nutt, R. F.; Brady, S. F.; Colton, C. D.; Sisko, J . T.; Ciccarone,
T.; Levey, M. R.; Duggan, M. E.; Imagire, I. S.; Gould, R. J .;
Anderson, P. S.; Veber, D. F. Development of Novel, Highly
Selective Fibrinogen Receptor Antagonists as Potentially Useful
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pp 914-916.
4H), 7.91 (m, 3H); IR (KBr) 2222, 1730, 1679, 1529, 1319 cm-1
;
MS (FD) m/e 405; mp 220 °C dec. Anal. (C23H23N3O4) C, H,
N.
6-[[[4-[[[(1,1-D i m e t h y le t h o x y )c a r b o n y l]a m i n o ]-
im in om eth yl]ph en yl]am in o]car bon yl]-3,4-dih ydr o-1-oxo-
2(1H)-isoqu in olin ea cetic Acid 1,1-Dim eth yleth yl Ester
(48). Compound 48 was prepared following the general
procedure employed for the synthesis of 24: 1H NMR (300
MHz, CDCl3) 1.45 (s, 9H), 1.54 (s, 9H), 3.04 (m, 2H), 3.62 (t, J
) 6.4 Hz, 2H), 4.21 (s, 2H), 7.6-7.8 (m, 7H), 8.02 (m, 1H); IR
(CHCl3) 3304, 2978, 1740, 1641, 1602, 1582, 1498 cm-1; MS
(FAB) 523. Anal. (C28H34N4O5) C, H, N.
6-[[[4-(Am in oim in om et h yl)p h en yl]a m in o]ca r b on yl]-
3,4-d ih yd r o-1-oxo-2(1H)-isoqu in olin ea cetic Acid Mon o-
(tr iflu or oa ceta te) (49). Compound 49 was prepared follow-
ing the general procedure outlined for the preparation of 25:
1H NMR (300 MHz, CD3OD) 3.18 (t, J ) 6.54 Hz, 2H), 3.75 (t,
J ) 6.8 Hz, 2H), 4.35 (s, 2H), 7.8-7.9 (m, 4H), 7.9-8.1 (m,
3H); IR (KBr) 3400, 1707, 1666, 1655, 1637, 1611, 1482, 1191
cm-1; MS (FAB) m/e 367. Anal. (C21H19N4O6F3‚0.5H2O) C, H,
N.
GP IIb-IIIa ELISA. The ability of the compounds to
antagonize the binding of fibrinogen to GPIIb-IIIa was
determined by ELISA (enzyme-linked immunoadsorbent as-
say) utilizing purified human platelet GPIIb-IIIa, biotinylated
fibrinogen, alkaline phosphatase-labeled goat antibiotin, and
p-nitrophenol phosphate as previously described.72
P la telet Aggr ega tion Assa y. Assessment of functional
blockade of GPIIb-IIIa was made using ADP-induced platelet
aggregation in human platelet-rich plasma (PRP). Varying
concentrations of test compound or vehicle were incubated in
human PRP for 1 min prior to the addition of ADP (5 µM),
and the aggregation response was followed turbidometrically.73
Ack n ow led gm en t. The authors thank Michael R.
Wiley, Paul L. Ornstein, J ohn J . Masters, and David
K. Herron for invaluable discussions and advice.

2100 J ournal of Medicinal Chemistry, 1997, Vol. 40, No. 13
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