New platelet fibrinogen receptor glycoprotein IIb-IIIa antagonists: Orally active series of N-alkylated amidines with a 6,6-bicyclic template

Article abstract of DOI:10.1021/jm9801859

The design, synthesis, and pharmacological evaluation of (S)-(-)-ethyl [6-[4-(morpholino-formimidoyl)benzamido]-3,4-dihydro-2H-1-benzopyran-3- yl]acetate hydrochloride ((S)-4·HCl, MS-180), an orally active glycoprotein IIb-IIIa (GPIIb-IIIa) antagonist, are reported. Pharmacophore mapping of amidino and carboxyl groups of already known GPIIb-IIIa antagonists led to the synthesis of nine amidino acids containing 6,6-bicyclic ring skeletons (10a-i). Among them, the compounds 10a,c,e having an amide bond and 1,2,3,4- tetrahydronaphthalene or 3,4-dihydro-2H-1-benzopyran skeleton showed marked inhibitions with IC₅₀ values of 46-57 nM in human platelet aggregation assay in vitro, but low oral activities. N-Alkylation of the amidino group coupled with the ester prodrug approach afforded MS-180 ((S)-4·HCl), which generates in vivo the corresponding carboxylic acid (S)-3 as an active species. In vitro, (S)-3 inhibited ADP-induced aggregation of guinea pig, dog, and human platelets (IC₅₀ = 110, 253, and 35 nM, respectively) and inhibited the binding of fibrinogen to immobilized GPIIb-IIIa of human platelets (IC₅₀ = 0.12 nM). After oral administration of MS-180 ((S)4·HCl) to fasted beagle dog, ex vivo inhibition of platelet aggregation was observed. The maximal inhibitions were observed 2-4 h after dosing with dose dependency (60% inhibition at a dose of 1 mg/kg, 85% at 3 mg/kg, and 100% at 10 mg/kg, respectively) and the extent of the inhibitions paralleled the plasma concentration of the active species (S)-3. On the basis of these studies, we selected MS-180 ((S)-4·HCl) as a candidate for clinical evaluation as a drug for the treatment and prevention of thrombosis in patients.

Full text of DOI:10.1021/jm9801859

4036
J . Med. Chem. 1998, 41, 4036-4052
New P la telet F ibr in ogen Recep tor Glycop r otein IIb-IIIa An ta gon ists:
Or a lly Active Ser ies of N-Alk yla ted Am id in es w ith a 6,6-Bicyclic Tem p la te
Kunio Okumura,* Toshiyuki Shimazaki, Yoji Aoki, and Hiroyuki Yamashita
Pharmaceuticals Section, Life Sciences Laboratory, Performance Materials R&D Center, Mitsui Chemicals Inc.,
1144, Togo, Mobara-shi, Chiba 297-0017, J apan
Eishi Tanaka and Shinichi Banba
Computational Science Department, Performance Materials R&D Center, Mitsui Chemicals Inc.,
1144, Togo, Mobara-shi, Chiba 297-0017, J apan
Kouhei Yazawa, Kenji Kibayashi, and Hitoshi Banno
Institute of Biological Science, Mitsui Pharmaceuticals Inc., 1900-1, Togo, Mobara-shi, Chiba 297-0017, J apan
Received March 24, 1998
The design, synthesis, and pharmacological evaluation of (S)-(-)-ethyl [6-[4-(morpholino-
formimidoyl)benzamido]-3,4-dihydro-2H-1-benzopyran-3-yl]acetate hydrochloride ((S)-4‚HCl,
MS-180), an orally active glycoprotein IIb-IIIa (GPIIb-IIIa) antagonist, are reported. Phar-
macophore mapping of amidino and carboxyl groups of already known GPIIb-IIIa antagonists
led to the synthesis of nine amidino acids containing 6,6-bicyclic ring skeletons (10a -i). Among
them, the compounds 10a ,c,e having an amide bond and 1,2,3,4-tetrahydronaphthalene or 3,4-
dihydro-2H-1-benzopyran skeleton showed marked inhibitions with IC50 values of 46-57 nM
in human platelet aggregation assay in vitro, but low oral activities. N-Alkylation of the amidino
group coupled with the ester prodrug approach afforded MS-180 ((S)-4‚HCl), which generates
in vivo the corresponding carboxylic acid (S)-3 as an active species. In vitro, (S)-3 inhibited
ADP-induced aggregation of guinea pig, dog, and human platelets (IC50 ) 110, 253, and 35
nM, respectively) and inhibited the binding of fibrinogen to immobilized GPIIb-IIIa of human
platelets (IC50 ) 0.12 nM). After oral administration of MS-180 ((S)-4‚HCl) to fasted beagle
dog, ex vivo inhibition of platelet aggregation was observed. The maximal inhibitions were
observed 2-4 h after dosing with dose dependency (60% inhibition at a dose of 1 mg/kg, 85%
at 3 mg/kg, and 100% at 10 mg/kg, respectively) and the extent of the inhibitions paralleled
the plasma concentration of the active species (S)-3. On the basis of these studies, we selected
MS-180 ((S)-4‚HCl) as a candidate for clinical evaluation as a drug for the treatment and
prevention of thrombosis in patients.
In tr od u ction
Lamifiban10 are now under clinical trials for intravenous
treatment of acute thrombus disorders. The latest
tendency has focused on orally active GPIIb-IIIa an-
While platelets play a vital role in homeostasis,
uncontrolled platelet aggregation leads to thrombus
formation and causes thrombotic disorders such as
myocardial infarction, transient ischemic attacks, un-
stable angina, stroke, and peripheral arterial disease.1,2
Platelets are activated by a variety of agonists including
adenosine diphosphate (ADP), collagen, epinephrine,
platelet-activating factor (PAF), thrombin, and throm-
boxane A2, and the final common stage resulting in
platelet aggregation is the binding of fibrinogen to
GPIIb-IIIa on the surface of activated platelets.3-6
Inhibition of platelet aggregation at the activation stage
has proven difficult due to the many activation path-
ways available to platelets. Therefore, inhibition of the
binding of fibrinogen to GPIIb-IIIa on the surface of
activated platelets, the final stage of platelet aggrega-
tion, has become an attractive strategy. In fact, GPIIb-
IIIa monoclonal antibody Reo-Pro7 is now available for
use in patients undergoing percutaneous transluminal
coronary angioplasty (PTCA) who are at high risk for
abrupt artery closure. In addition, a number of GPIIb-
IIIa antagonists such as Integrelin,8 Tirofiban,9 and
tagonists useful for chronic thrombotic disorders.
A
number of the orally active antagonists represented by
Xemilofiban,11 Orbofiban,12 and Ro 48-365713 are now
under clinical trials.14
Herein, we describe our approach for an orally active
GPIIb-IIIa antagonist, designed with the aid of phar-
macophore mapping of known GPIIb-IIIa antagonists,
synthesis, and quantitative structure-activity relation-
ships (QSAR) using comparative molecular field analy-
sis (CoMFA).15 From these studies, we obtained an
orally active series of N-alkylated amidines with a 6,6-
bicyclic ring template, culminating with the discovery
of MS-180 ((S)-4‚HCl) with a morpholinoformimidoyl
group.
Dr u g Design
P h a r m a cop h or e Ma p p in g of Kn ow n GP IIb-IIIa
An ta gon ists. Since the three-dimensional structure of
GPIIb-IIIa is unknown, we designed several lead com-
pounds from the structures of already known GPIIb-
S0022-2623(98)00185-X CCC: $15.00 © 1998 American Chemical Society
Published on Web 09/10/1998

New GPIIb-IIIa Antagonists
J ournal of Medicinal Chemistry, 1998, Vol. 41, No. 21 4037
Ch a r t 1
to match the extracted parameters and synthesized nine
compounds that have different bond forms and 6,6-
bicyclic templates as spacers (Figure 2).
Ch em istr y
The newly designed GPIIb-IIIa antagonists 10a -i
were prepared following the general procedure depicted
in Scheme 1. Cyano compound 11 was treated with
ethanolic HCl and reacted with ammonium acetate to
give the corresponding amidine 12, which was hydro-
lyzed to afford amidino acid 10.
The synthesis of (2-naphthalenyl)acetate and (1,2,3,4-
tetrahydro-2-naphthalenyl)acetate intermediates of 11
is depicted in Scheme 2. 2-Oxo-1,2,3,4-tetrahydronaph-
thalene intermediate 15 was prepared from 1-oxo-
1,2,3,4-tetrahydronaphthalene derivative 13 (13a,c were
commercially available, 13b was synthesized following
the method of Gerlach et al.24) following a modification
of the ketone transposition procedure described by
Nichols et al.25 Reduction of the carbonyl group of 13
with NaBH4, followed by dehydration in the presence
of strongly acidic ion-exchange resin (Amberlyst 15) or
pyridinium p-toluenesulfonate (PPTS), gave olefin 14.
Epoxidation of 14 with 3-chloroperbenzoic acid followed
by treatment with ZnI2 gave 15, which was converted
to 17 following a modification of the procedure described
by Strasser et al.26 Horner-Emmons reaction with
appropriate phosphonates gave (3,4-dihydro-2-naphtha-
lenyl)acetate 16 with a small amount of olefin isomer
R,â-unsaturated ester. This mixture was taken on
directly without separation. Hydrogenation of 16 cata-
lyzed by Pd/C gave (1,2,3,4-tetrahydro-2-naphthalenyl)-
acetate 17. The nitro group of 16a was also converted
to the amino group in this hydrogenation condition.
Compound 17 was converted to several types of 6,6-
bicyclic ring intermediates of 11. According to the
method of Xue et al.,27 the amino group of 17a was
protected by Boc and N-methylated with NaH/MeI in
DMF to afford 18. Cleavage of the Boc protecting group
of 18 gave the N-methyl derivative 19. The methyl ester
of 17b was selectively hydrolyzed to afford monoacid 20.
The methyl ether of 17c was cleaved to afford phenol
derivative 21, which was converted to triflate 22.
Naphthol derivative 23 was synthesized from 16c via
dehydrogenation with p-chloranil26 and cleavage of the
methyl ether.
IIIa antagonists using computed pharmacophore map-
ping. Chart 1 illustrates our approach to MS-180 ((S)-
4‚HCl). The structural features of known GPIIb-IIIa
antagonists are (1) two functional groups (amidino or
guanidino group and carboxyl group) essential for its
activity and (2) a spacer which correctly positions the
two functional groups. Then, to search the spatial
parameters of the two functional groups vital for the
activity, we performed pharmacophore mapping using
five compounds (Chart 2).16-20 Alignments of all com-
pounds were achieved by using the DISCO21 module of
SYBYL version 6.3,22 and the ring structure of DMP 728
(7)18 obtained from the Cambridge Structure Database
was used as a template structure.23 The superimposed
structures of known GPIIb-IIIa antagonists obtained
from DISCO analysis are shown in Figure 1.
Parameter definitions and pharmacophoric features
of the known GPIIb-IIIa antagonists extracted from
alignments are summarized in Table 1. The distance
between carbon of cationic amidino or guanidino group
(C1) and carbon of anionic carboxyl group (C2) ranged
from 13.5 to 14.5 Å (distance a). The distance between
amidino group-substituted atom (A) and carboxyl group-
substituted atom (B) ranged from 11.5 to 13.0 Å
(distance b). The R defined as angle C1-A-B ranged
from 150° to 170°, and the â defined as C2-B-A ranged
from 85° to 110°, respectively. We designed compounds
Ch a r t 2. Known GPIIb-IIIa Antagonists Used in Pharmacophore Mapping

4038 J ournal of Medicinal Chemistry, 1998, Vol. 41, No. 21
Okumura et al.
F igu r e 1. Alignment of the known GPIIb-IIIa antagonists using hydrogen-devoid backbone-type representation. The carbons of
compounds 5-9 are shown in white, violet, orange, cyan, and yellow, respectively. Compound 10a , whose carbons are shown in
green, was also aligned with these antagonists.
Ta ble 1. Parameter Definition and Extracted Parameters of
Known GPIIb-IIIa Antagonists
distance, Å
angle, deg
compd
a
b
R
â
5a
6b
7c
8d
9e
13.66
13.90
14.19
13.85
13.89
11.78
12.35
12.44
12.46
12.31
156.84
166.32
165.50
156.02
166.81
105.75
88.96
106.28
87.82
91.00
F igu r e 2. Newly designed compounds to match extracted
parameters.
a
b
d
See ref 16. See ref 17. c See ref 18. See ref 19. e See ref 20.
To prepare 17a as a key intermediate, an improved
synthetic method was developed (Scheme 3). Compound
13a was converted to the R,â-unsaturated acid 24 by
aldol condensation with glyoxylic acid in the presence
of H2SO4. Hydrogenation of nitro, keto, and olefin
groups of 24 catalyzed by Pd/C in the presence of H2-
SO4 accomplished the one-step conversion to 17a . Ac-
cording to this procedure, ethyl (6-amino-3,4-dihydro-
2H-1-benzopyran-3-yl)acetate (27) was also synthesized
in two steps from 6-nitro-4-oxo-3,4-dihydro-2H-1-ben-
zopyran (25).
28 gave 29. N-Alkylation of 29 with ethyl bromoacetate,
followed by hydrogenation catalyzed by Pd/C, afforded
30.
Cyano compounds 11a -i were synthesized as shown
in Scheme 5. Amide compounds 11a -d were prepared
by acylation of amino compounds 17a , 19, 27, and 30,
respectively, with 4-cyanobenzoyl chloride. Compound
11e was prepared from 20. Treatment of 20 with
(COCl)2 in the presence of a catalytic amount of DMF,
followed by the reaction with 4-aminobenzonitrile in the
presence of Et3N and 4-(dimethylamino)pyridine, af-
forded 11e. Ether type compounds 11f,g were synthe-
sized from 21 and 23, respectively, by reaction with
p-cyanobenzyl bromide. Compounds 11h ,i were syn-
thesized via palladium catalyzed coupling with orga-
Ethyl (7-amino-1,2,3,4-tetrahydro-2-isoquinolinyl)ac-
etate (30), an intermediate of 11d , was synthesized as
shown in Scheme 4. Nitration at the 7-position of
1,2,3,4-tetrahydroisoquinoline (28) with KNO3/H2SO4-

New GPIIb-IIIa Antagonists
J ournal of Medicinal Chemistry, 1998, Vol. 41, No. 21 4039
Sch em e 1. General Procedure for the Preparation of
Amidino Acid 10
Sch em e 3. Synthesis of 6,6-Bicyclic Intermediates
(Step 2): Convergent Synthesis of 17a and Ethyl
(6-Amino-2H-1-benzopyran-3-yl)acetate (27)a
a
Reagents: (a) glyoxylic acid, H2SO4; (b) H2, Pd/C, H2SO4,
EtOH.
Sch em e 4. Synthesis of 6,6-Bicyclic Intermediates
(Step 3): Ethyl (7-Amino-1,2,3,4-tetrahydro-2-
isoquinolinyl)acetate (30)a
a
Reagents: (a) KNO3, H2SO4; (b) ethyl bromoacetate, Et3N; (c)
H2, Pd/C.
32 with tri-n-butyltin hydride, followed by palladium-
catalyzed coupling29 with triflate 22 gave (E)-olefin 11h .
Compound 11i was obtained by hydrogenation of 11h .
N-Alkylated amidino acids 34a -e, 36, and (RS)-3
were synthesized from 11a ,c (Scheme 6). Cyano com-
pound 11 was converted to the corresponding imidate,
which was treated with appropriate amines to afford a
series of N-alkylated amidino esters 33a -e, 35, and
(RS)-4. Hydrolysis of each ester gave corresponding
N-alkylated amidino acids 34a -e, 36, and (RS)-3.
MS-180 ((S)-4‚HCl) and corresponding carboxylic acid
(S)-3 were synthesized as enantiomerically pure forms
via optical resolution using chiral HPLC (Scheme 7).
Methyl [6-(N-Boc-amino)-3,4-dihydro-2H-1-benzopyran-
3-yl]acetate ((RS)-37), which was prepared from 26 in
two steps: (1) hydrogenation in the presence of Pd/C
and H2SO4 and (2) protection as the Boc derivative, was
resolved on large scale using CHIRALCEL-OD (Daicel
Chemical Industries, Ltd.). The absolute configuration
of the enantiomer that has the longer retention time
was determined to be the (S)-form by single-crystal
X-ray crystallographic analysis of the amide 39 obtained
from N-(4-nitrophenylsulfonyl)-L-phenylalanine. Treat-
ment of (S)-37 with ethanolic HCl afforded (S)-27, which
was converted to MS-180 ((S)-4‚HCl) and its acid (S)-3.
Enantiomeric purities of (S)-4 and (S)-3 were deter-
mined as greater than 99% ee by chiral HPLC analysis.
According to the same procedure, (R)-4 and (R)-3 were
synthesized from (R)-37.
Sch em e 2. Synthesis of 6,6-Bicyclic Intermediates
(Step 1)a
a
Reagents: (a) NaBH4, MeOH; (b) Amberlyst 15 or PPTS,
Resu lts a n d Discu ssion
azeotrope; (c) m-CPBA; (d) ZnI2; (e) ethyl (diethylphosphoryl)ac-
etate or t-butyl P,P-dimethylphophonoacetate, NaH; (f) H2, Pd/C;
(g) Boc2O; (h) NaH, MeI; (i) HCl; (j) NaOH; (k) TMSCl, NaI; (l)
Tf2O, pyridine; (m) p-chloranil.
Am idin o Acid Der iva tives with 6,6-Bicyclic Tem -
p la te. The synthesized compounds 10a -i were evalu-
ated for their abilities to inhibit in vitro ADP-induced
platelet aggregation of guinea pig and human platelet-
rich plasma (PRP). The results are given as IC50 values
and are shown in Table 2. These compounds showed
IC50 values of 230-18000 nM in guinea pig PRP and
46-1500 nM in human PRP with the exception of
nostannane.29 4-Ethynylbenzonitrile (32) was synthe-
sized from p-cyanophenol (31) in three steps: (1)
conversion to the triflate, (2) Pd(0)-Cu(I)-catalyzed
coupling with (trimethylsilyl)acetylene,30 and (3) desi-
lylation with potassium fluoride. Hydrostannation of

4040 J ournal of Medicinal Chemistry, 1998, Vol. 41, No. 21
Sch em e 5. Synthesis of Key Intermediates 11a -ia
Okumura et al.
a
Reagents: (a) 4-cyanobenzoyl chloride, Et3N; (b) (COCl)2, DMF; (c) 4-aminobenzonitrile, Et3N; (d) 4-cyanobenzyl bromide, K2CO3; (e)
Tf2O, pyridine, (f) (trimethylsilyl)acetylene, Pd(PPh3)4, CuI, n-PrNH2; (g) KF; (h) n-Bu3SnH, AIBN; (i) 22, Pd(PPH3)4, LiCl, DMF; (j) H2,
Pd/C.
Sch em e 6. Synthesis of N-Alkylated Amidinesa
a
Reagents: (a) saturated HCl/EtOH; (b) appropriate amine, EtOH; (c) NaOH.
compound 10g. Compounds 10a ,c,e showed especially
marked inhibitions of platelet aggregation in human
PRP.
known GPIIb-IIIa antagonists. Using the default CoM-
FA settings, which included both steric and electrostatic
fields, we observed the cross-validated r2 (q2) of 0.398
with five principal components. The choice of CoMFA
options was tried to minimize the standard error of
prediction rather than simply maximizing the q2 value.
This resulted in using a smaller number of partial least-
squares (PLS) principal components, and that was
appropriate for our small data set. The final model,
which includes both steric and electrostatic fields, with
three principal components was obtained using grid box
translation from SYBYL’s default position 1.0 Å in the
Z direction relative to the orientation of our aligned
Then, to elucidate the quantitative structure-activity
relationships (QSAR) with the present compounds,
comparative molecular field analysis (CoMFA)15 was
performed. The inhibitory potencies of platelet ag-
gregation in guinea pig were used for the CoMFA study.
For the convenience of the CoMFA study, an IC50 value
of 2 × 106 nM was substituted for the inhibitory potency
of compound 10g, for which the experimental IC50 value
was greater than 106 nM. Molecular alignments were
achieved by using the alignment rule above-defined for

New GPIIb-IIIa Antagonists
J ournal of Medicinal Chemistry, 1998, Vol. 41, No. 21 4041
Sch em e 7. Synthesis of Optically Active 3 and 4a
a
Reagents: (a) H2, Pd/C, H2SO4, MeOH; (b) Boc2O; (c) separation by chiral HPLC, CHIRALCEL-OD; (d) HCl, MeOH; (e)
N-(p-nitrophenylsulfonyl)-L-phenylalanyl chloride, Et3N, DMAP; (f) HCl, EtOH; (g) 4-cyanobenzoyl chloride, Et3N; (h) saturated HCl/
EtOH; (i) morpholine; (j) NaOH.
Ta ble 2. In Vitro Inhibition of ADP-Induced Platelet
the receptor will increase their activity relative to the
non-amide compounds 10f,h ,i. The yellow contour
Aggregation with 10a -ia
located around the N-methyl group of 10b indicates the
area in which the N-methyl group is detrimental to the
affinity at the receptor. This result suggests compound
10b is more unfavorable to interact with the receptor
than amide compounds 10a ,c,e. Among them, com-
pound 10e, which showed marked inhibitions of platelet
aggregation in vitro, was not selected for further inves-
tigation due to its short half-life (<30 min) in guinea
pig after intravenous administration.
IC50,b nM
compd
guinea pigc
humand
10a
10b
10c
10d
10e
10f
10g
10h
10i
370
1800
480
6600
230
18000
>106
5000
2500
57
200
49
290
46
The oral profiles of the representative compound 10a
and ester prodrugs 12a ,c were assessed by platelet
aggregation assay in guinea pig (Table 3). The inhibi-
tion of ex vivo ADP-induced platelet aggregation was
measured at 1 h after oral administration of these
compounds to guinea pigs (dose: 37 µmol/kg). Though
amidino acid 10a showed only a weak inhibition (8%),
ester prodrugs 12a ,c showed moderate enhancement of
inhibitory potency (41% and 40% inhibitions, respec-
tively). Consequently, we selected 12a ,c as lead com-
pounds and attempted to improve the oral profiles
focused on the modification of the amidino group.
1500
nte
nte
370
a
Expressed as the average of at least two determinations.
Concentration required to inhibit by 50%. c Inhibition of guinea
b
d
pig PRP aggregation induced by 5 µM ADP. Inhibition of human
PRP aggregation induced by 5 µM ADP. e nt, not tested.
structure. This model had the cross-validated q2 values
of 0.637 and r2 values of 0.993. The contour map of the
CoMFA model is shown in Figure 3. Because the
molecules used in this study have the same benzamidine
and carboxylic acid units, we could not get any informa-
tion around these functional groups. The blue contour
located around one side on the 6,6-bicyclic ring indicates
an area in which electron-deficient groups increase the
affinity. This result suggested that 10g, which has the
electron-rich naphthalene ring, is unfavorable to bind
with the receptor site. The red contours located around
the oxygen atom of the amide bond and the blue
contours located around the hydrogen of the amide bond
indicate the electrostatic interaction with the amide
bond and the receptor. When compounds 10a ,c,e
containing an amide bond reach the receptor site, the
electrostatic interaction between the amide bond and
N-Alk yla ted Am id in e Der iva tives. We modified
the amidino groups of 10a ,c to the N-alkylated amidino
groups. The in vitro activities of the N-alkylated
amidino acids 34a -e, 36, and (RS)-3 were assessed by
the inhibition of the ADP-induced platelet aggregation
of guinea pig and human PRP and the inhibition of the
fibrinogen binding to human immobilized GPIIb-IIIa
(Table 4). The N-alkylated amidino acids possessed
almost the same inhibitory potencies of platelet ag-
gregation and of fibrinogen binding compared with the
parent amidino acids 10a ,c. The results of the fibrino-
gen binding assay clearly showed that N-alkylated
amidino acids themselves bind to the GPIIb-IIIa. We
next assessed oral profiles of N-alkylated amidino esters
33a -e, 35, and (RS)-4. The inhibition of ex vivo ADP-
induced platelet aggregation in guinea pig was mea-

4042 J ournal of Medicinal Chemistry, 1998, Vol. 41, No. 21
Okumura et al.
F igu r e 3. Steric and electrostatic CoMFA field from the analysis of ADP-induced platelet aggregation of guinea pig without
cross-validation. Compounds 10a -i are shown inside the field. Favoring activity: yellow, less bulky; blue, positive charge; red,
negative charge (contribution level 80%).
Ta ble 3. Ex Vivo Inhibition of ADP-Induced Platelet
Aggregation by Oral Administration of 10a and 12a ,ca and
Solubility in Saline
Ta ble 4. In Vitro Inhibition of ADP-Induced Platelet
Aggregation and Fibrinogen Binding by 10a ,c, 34a -e, 36, and
(RS)-3a
compd
R
A
inhibition,b %
sol,c mg/mL
IC50,b nM
10a
12a
12c
H
C2H5
C2H5
CH2
CH2
O
8
41
40
ndd
0.26
0.41
guinea
pigc
fibrinogen
bindinge
compd
R
A
humand
10a
10c
34a
34b
34c
34d
34e
36
NH2
NH2
CH2
O
CH2
370
480
170
490
300
620
190
350
230
57
49
68
0.12
0.073
0.13
0.26
0.16
0.20
0.15
0.13
0.098
a
b
Data are expressed as the average of three animals. Percent
inhibition of ex vivo platelet aggregation induced by 5 µM ADP 1
h after oral administration (dose: 37 µmol/kg). c The solubility of
the compounds in saline was determined by UV spectrophotom-
CH3(CH2)2NH
H2CdCHCH2NH CH2
HCtCCH2NH
(2-furyl)CH2NH
morpholino
ntf
100
ntf
80
CH2
CH2
CH2
O
d
etry. nd, not determined.
sured at 1 h after oral administration (37 µmol/kg) of
these compounds (Table 5). Excepting 33a ,b, these
N-alkylated amidines showed stronger inhibition (>90%)
than the parent amidines 12a ,c.
HCtCCH2NH
78
66
(RS)-3 morpholino
O
See footnotes a-d in Table 2. e Inhibition of fibrinogen
a-d
binding to immobilized human GPIIb-IIIa. f nt, not tested.
Next, we estimated plasma concentrations of the
corresponding carboxylic acids 34a -e, 36, and (RS)-3
at 1 h after oral administration of N-alkylated amidino
esters 33a -e, 35, and (RS)-4 in guinea pig (Table 5).
Compounds 33e, 35, and (RS)-4 showed high plasma
concentrations of the corresponding N-alkylated acids
compared with 33a -d . Furthermore, since we could not
find amidino acid 10a or 10c in plasma, the active
species in vivo must be the N-alkylated amidino acids
themselves. Although the mechanism underlying the
improvement of the oral profile by N-alkylated amidine
is not clear, we assumed that the lack of oral activity of
10a , 12a ,c, 33a ,b was due to poor oral absorption.
Features of these compounds which we considered to
contribute to the lack of oral absorption included poor
aqueous solubility. Compounds 33e, 35, and (RS)-4
showed good aqueous solubility (Table 5). These com-
pounds also showed good oral activity, supporting the
importance of good aqueous solubility for oral absorption

New GPIIb-IIIa Antagonists
J ournal of Medicinal Chemistry, 1998, Vol. 41, No. 21 4043
Ta ble 5. Ex Vivo Inhibition of ADP-Induced Platelet
Aggregation, Plasma Concentration of the Active Species by
Oral Administration of N-Alkylated Amidino Esters,a and
Solubility in Saline
inhibition,b plasma level,c
sol,d
mg/mL
compd
R
A
%
µM
33a
33b
33c
33d
33e
35
CH3(CH2)2NH
CH2
3
21
99
91
98
99
99
<0.18
0.38
1.0
0.85
7.3
nde
nde
1.50
1.06
>200
106
H2CdCHCH2NH CH2
HCtCCH2NH CH2
(2-furyl)CH2NH CH2
morpholino
HCtCCH2NH
CH2
O
O
3.8
8.4
(RS)-4 morpholino
>200
a,b
See footnotes a and b in Table 3. c Concentration of active
species in plasma 1 h after oral administration (dose: 37 µmol/
d
kg). ,eSee footnotes c and d in Table 3.
Ta ble 6. Comparison of the Enantiomers of 3 by in Vitro
Profilea
F igu r e 4. Effect of MS-180 ((S)-4‚HCl) upon oral administra-
tion in conscious dogs (n ) 4). Data are expressed as mean (
SE: (a) inhibition of ADP-induced ex vivo platelet aggregation;
(b) plasma concentration of the active species (S)-3 determined
by bioassay. Legend: (O) 1 mg/kg, (0) 3 mg/kg, (4) 10 mg/kg.
IC50,b nM
compd
guinea pigc
humand
fibrinogen bindinge
(S)-3
(R)-3
110
4400
35
360
0.12
2.6
extent of the inhibitions declined in parallel with the
a-d
See footnotes a-d in Table 2. e See footnote e in Table 4.
plasma concentration of (S)-3.
Con clu sion
in these series. Finally, we selected (RS)-4 as a promis-
ing compound, because it had the highest plasma
concentration.
In this paper, we have reported our approach to orally
active GPIIb-IIIa antagonists: namely, design with the
aid of pharmacophore mapping of amidino and carboxyl
groups of known GPIIb-IIIa antagonists, synthesis, and
quantitative structure-activity relationships using CoM-
FA. We obtained compounds 10a ,c,e containing amide
bonds and the 1,2,3,4-tetrahydronaphthalene or 3,4-
dihydro-2H-1-benzopyran skeleton that showed potent
inhibition of platelet aggregation in vitro but had weak
oral activities. In an attempt to improve the oral
profiles of these compounds, N-alkylated amidino esters
(33a -e, 35, and (RS)-4) were prepared. These com-
pounds showed good oral activities with regard to the
inhibition of ex vivo platelet aggregation in guinea pig
or dog, with the in vivo hydrolysis to the corresponding
acids. N-Alkylated amidino acids (34a -e, 36, and (RS)-
3), the active species of the corresponding ester, showed
in vitro antiplatelet activities similar to those of the
parent amidino acids 10a ,c. Among these N-alkylated
amidino esters, (RS)-4 was selected as the most promis-
ing compound by virtue of it having the highest plasma
concentration of the active species at 1 h after oral
administration in guinea pig (8.4 µM of (RS)-3 at a dose
of 37 µmol/kg). The two enantiomers of (RS)-3 were
compared with regards to their in vitro profile, and the
(S)-form was found to be the active enantiomer. On the
basis of these studies, optically active (S)-4‚HCl (MS-
180) was selected as a candidate for clinical evaluation
The in vitro antiplatelet activity of each enantiomer
of (RS)-3, the active species of (RS)-4, was compared
by determining the ability to inhibit ADP-induced
platelet aggregation of guinea pig and human PRP and
the ability to inhibit binding of fibrinogen to immobilized
human GPIIb-IIIa (Table 6). (S)-3 was found to be more
active than (R)-3 (10.3-fold in human PRP, 44-fold in
guinea pig PRP, and 21.7-fold in binding assay) and
considered to be the active enantiomer. (S)-3 also
showed in vitro inhibition of ADP-induced platelet
aggregation in beagle dog (IC50 ) 253.3 nM), and the
oral profile of the prodrug (S)-4 was evaluated in dog.
P h a r m a cology of MS-180 ((S)-4‚HCl). The anti-
platelet activity of (S)-4‚HCl (MS-180) was assessed by
oral administration of the solid compound in gelatin
capsules at a dose of 1, 3, or 5 mg/kg to fasted conscious
male dogs (n ) 4). After administration, plasma
samples were drawn at specified time points, and the
derived PRP was evaluated for the extent of ADP-
induced platelet aggregation and plasma concentrations
of (S)-3 (Figure 4). Maximal inhibitions and highest
concentrations of (S)-3 were observed within 2-4 h after
administration. The maximal inhibitions of ADP-
induced platelet aggregation have dose dependency
(60.2% inhibition at a dose of 1 mg/kg, 84.9% at 3 mg/
kg, and 101.8% at 10 mg/kg, respectively), and the

4044 J ournal of Medicinal Chemistry, 1998, Vol. 41, No. 21
Okumura et al.
mg (48%) of 11e as a white solid: mp 176-177 °C. Anal.
(C24H26N2O3) C, H, N.
as a drug for the treatment and prevention of throm-
bosis in patients.
Eth yl [7-[(4-Cya n op h en yl)m eth oxy]-1,2,3,4-tetr a h yd r o-
2-n a p h th a len yl]a ceta te (11f). A mixture of 21 (2.20 g, 9.4
mmol), 4-cyanobenzyl bromide (3.7 g, 18.8 mmol), and K2CO3
(3.0 g, 21.7 mmol) in 2-butanone (20 mL) was refluxed for 3 h.
After concentration in vacuo, the mixture was diluted with
EtOAc and washed with brine three times. The organic phase
was dried over MgSO4, filtered, and concentrated in vacuo to
afford an oil, which was purified by column chromatography
(SiO2, n-hexane/EtOAc ) 3/1) to afford 2.83 g (95%) of 11f as
a white solid: mp 71-72 °C. Anal. (C22H23NO3) C, H, N.
Eth yl [7-[(4-Cya n op h en yl)m eth oxy]-2-n a p h th a len yl]-
a ceta te (11g). Synthesized from 23 in 48% yield following a
similar procedure described for the preparation of 11f: mp
100-101 °C. Anal. (C22H19NO3) C, H, N: calcd, 4.05; found,
3.63.
E t h yl (E)-[7-[2-(4-Cya n op h en yl)et h en yl]-1,2,3,4-t et -
r a h yd r o-2-n a p h t h a len yl]a cet a t e (11h ). To a mixture of
acetylene 32 (3.0 g, 23.5 mmol), tri-n-butyltin hydride (7.4 g,
25.4 mmol), and toluene (10 mL) was added 2,2′-azobis-
(isobutyronitrile) (2.0 mg, 0.012 mmol) at room temperature.
The mixture was stirred for 1 h at 100 °C and concentrated in
vacuo to afford vinylstannane, which was dissolved in DMF
(80 mL). To this were added triflate 22 (6.6 g, 18.0 mmol),
LiCl (2.56 g, 60.4 mmol), and Pd(PPh3)4 (0.52 g, 0.45 mmol).
The mixture was stirred for 3 h at 70 °C and concentrated in
vacuo to afford an oily residue, which was dissolved in
diisopropyl ether and washed with aqueous 5% potassium
fluoride solution twice. The organic phase was dried over
MgSO4 and concentrated in vacuo. Purification by column
chromatography (SiO2, n-hexane/EtOAc ) 7/1) gave 4.23 g
(68%) of 11h as a pale-yellow solid: mp 99-100 °C. Anal.
(C23H23NO2) C, H, N.
Eth yl [7-[2-(4-Cya n op h en yl)eth yl]-1,2,3,4-tetr a h yd r o-
2-n a p h th a len yl]a ceta te (11i). A mixture of 11h (610 mg,
1.76 mmol) and 10% Pd/C (400 mg) in EtOH (20 mL) was
stirred under H2 atmosphere at room temperature. After
completion of the hydrogenation, the catalyst was removed by
filtration. The filtrate was concentrated in vacuo and purified
by column chromatography (SiO2, n-hexane/EtOAc ) 5/1) to
afford 540 mg (88%) of 11i as a white solid: mp 30-32 °C.
Anal. (C23H25NO2) C, H, N.
Exp er im en ta l Section
Ch em istr y. Melting points were determined on a Bu¨chi
535 melting point apparatus. Proton magnetic resonance
spectra (1H NMR) were obtained on a J EOL EX-270 (270 MHz)
or GX-400 (400 MHz) spectrometer using either deuterated
dimethyl sulfoxide (DMSO-d6) or deuterated chloroform (CDCl3)
as the solvent, and chemical shifts are reported in parts per
million (ppm) downfield from tetramethylsilane (TMS). Car-
bon magnetic resonance spectra (13C NMR) were obtained on
a J EOL EX-90 (22.40 MHz) or GX-400 (100.4 MHz) spectrom-
eter using either DMSO-d6 or CDCl3 as the solvent, and
chemical shifts are reported in ppm downfield from TMS.
Infrared spectra (IR) were recorded on a J ASCO IR 7300
spectrometer. Mass (MS) spectra were recorded on a HITA-
CHI M-80B (CI) or a Micromass QUATTRO-II (ESI) spectrom-
eter. Elemental analyses were determined on a Perkin-Elmer
CHN2400 elemental analyzer. The optical rotations were
recorded on a J ASCO DIP-730 polarimeter. High-performance
liquid chromatography (HPLC) was performed on a Shimadzu
LC-10A or LC-6A HPLC system.
All reactions requiring anhydrous conditions and/or inert
atmosphere were carried out under a nitrogen atmosphere.
The reactions were monitored by thin-layer chromatography
(TLC) analysis by using Merck Kiesel gel 60F254 TLC plates.
Silica gel column chromatographies were carried out on silica
gel 60 purchased from E. Merck. Reverse-phase column
chromatographies were carried out on Chromatorex ODS silica
gel purchased from Fuji-Silysia Chemical Ltd.
Eth yl [7-(4-Cyan oben zam ido)-1,2,3,4-tetr ah ydr o-2-n aph -
th a len yl]a ceta te (11a ). To an ice-cooled solution of 17a
(15.26 g, 65.4 mmol) and Et3N (7.62 g, 75.3 mmol) in CHCl3
(200 mL) was added 4-cyanobenzoyl chloride (11.8 g, 71.2
mmol) by portions. The mixture was stirred for 2 h at 0 °C
and washed with 5% aqueous NaOH solution (2 × 100 mL),
water (50 mL), 0.6 N HCl (150 mL), and brine (50 mL)
successively. The organic phase was dried over Na2SO4,
filtered, and concentrated in vacuo. Purification by column
chromatography (SiO2, CHCl3/EtOAc ) 20/1) afforded 20.7 g
(88%) of 11a as a white solid: mp 140-142 °C. Anal.
(C22H22N2O3) C, H, N.
E t h yl [7-(4-Am id in ob en za m id o)-1,2,3,4-t et r a h yd r o-2-
n a p h th a len yl]a ceta te Hyd r och lor id e (12a ‚HCl). Anhy-
drous hydrogen chloride was bubbled into an ice-cooled
suspension of 11a (1.79 g, 4.93 mmol) in EtOH (20 mL) for 30
min. The mixture was stirred for 4 h at room temperature
and concentrated in vacuo. The residual solid was rinsed with
isopropyl ether, dried under reduced pressure, and dissolved
in 30 mL of EtOH. To this solution was added ammonium
acetate (1.04 g, 13.5 mmol), and the mixture was stirred for
20 h. The resulting precipitate was collected by filtration and
treated with ethanolic HCl to afford 1.31 g (64%) of 12a ‚HCl
as a white solid: mp 207-210 °C; IR (KBr) 2924, 1733, 1671,
1614, 1596, 1542, 1506, 1413, 1334, 1155 cm-1; 1H NMR (270
MHz, DMSO-d6) δ 10.38 (s, 1H), 9.54 (s, 2H), 9.30 (s, 2H), 8.16
(d, 2H, J ) 8.6 Hz), 7.97 (d, 2H, J ) 8.6 Hz), 7.53-7.50 (m,
2H), 7.06 (d, 1H, J ) 8.9 Hz), 4.10 (q, 2H, J ) 7.3 Hz), 2.86-
2.75 (m, 3H), 2.52-2.35 (m, 3H), 2.15-2.05 (m, 1H), 1.91-
Eth yl [7-(4-Cyan o-N-m eth ylben zam ido)-1,2,3,4-tetr ah y-
d r o-2-n a p h th a len yl]a ceta te (11b). Synthesized from 19 in
66% yield using a similar procedure described for the prepara-
tion of 11a as a colorless oil. Anal. (C23H24N2O3) H; C: calcd,
73.38; found, 72.97. N: calcd, 7.44; found, 6.65.
E t h yl [6-(4-Cya n ob en za m id o)-3,4-d ih yd r o-2H -1-b en -
zop yr a n -3-yl]a ceta te (11c). Synthesized from 27 in 98%
yield using a similar procedure described for the preparation
of 11a as
(C21H20N2O4) C, H, N.
a pale-yellow solid: mp 166-168 °C. Anal.
Eth yl [7-(4-Cya n oben za m id o)-1,2,3,4-tetr a h yd r o-2-iso-
qu in olin yl]acetate Hydr och lor ide (11d‚HCl). A free amine
of the title compound was prepared from 30‚2HCl using a
similar procedure described for the preparation of 11a . Treat-
ment of the free amine with 4 N HCl in 1,4-dioxane afforded
the 11d ‚HCl salt (60% yield from 30‚2HCl): mp 205-207 °C.
Anal. (C21H21N3O3 and HCl) C, H, N.
ter t-Bu t yl [7-[N-(4-Cya n op h en yl)ca r b a m oyl]-1,2,3,4-
tetr a h yd r o-2-n a p h th a len yl]a ceta te (11e). To a mixture of
20 (0.70 g, 2.4 mmol) and (COCl)2 (2.18 g, 17.2 mmol) in
toluene (5.0 mL) was added DMF (20 µL). The mixture was
stirred for 1 h and concentrated in vacuo to afford a pale-yellow
solid, which was dissolved in THF (5.0 mL). To this were
added 4-aminobenzonitrile (350 mg, 2.94 mmol), pyridine (1.0
g, 12.6 mmol), and 4-(dimethylamino)pyridine (50 mg, 0.4
mmol). The mixture was stirred for 12 h at room temperature.
After addition of CHCl3 (100 mL), the mixture was washed
with 1 N HCl, saturated NaHCO3 solution, and brine succes-
sively. The organic phase was dried over Na2SO4, filtered, and
concentrated in vacuo. Purification of the residue by column
chromatography (SiO2, n-hexane/EtOAc ) 3/1) afforded 473
1.87 (m, 1H), 1.49-1.34 (m, 1H), 1.22 (t, 3H, J ) 7.3 Hz); 13
C
NMR (22.4 MHz, DMSO-d6) δ 172.0, 165.1, 163.9, 139.3, 136.3,
135.6, 131.6, 130.3, 128.6, 128.1 (2C), 128.0 (2C), 120.7, 118.4,
59.7, 40.0, 35.0, 30.9, 28.5, 27.6, 14.1; CI-MS m/e 380 (M +
1)+. Anal. (C22H25N3O3 and 0.95HCl plus H2O) C, H, N, Cl.
Eth yl [7-(4-Am id in o-N-m eth ylben za m id o)-1,2,3,4-tet-
r a h yd r o-2-n a p h t h a len yl]a cet a t e H yd r och lor id e (12b ‚
HCl). Following the procedure described for the preparation
of 12a ‚HCl, the title compound was prepared in 53% yield from
the nitrile 11b as a white solid: mp 187-189 °C; IR (KBr)
2977, 1732, 1683, 1622, 1503, 1437, 1394, 1313, 1286, 1250,
1155, 1102, 1028, 861, 770, 722 cm-1 1H NMR (270 MHz,
;
DMSO-d6) δ 9.42 (br s, 2H), 9.26 (br s, 2H), 7.73 (d, 2H, J )
8.2 Hz), 7.49 (d, 2H, J ) 8.2 Hz), 6.96-6.85 (m, 3H), 4.08 (q,

New GPIIb-IIIa Antagonists
J ournal of Medicinal Chemistry, 1998, Vol. 41, No. 21 4045
a white solid: mp 209-210 °C; IR (KBr) 1732, 1671, 1195,
2H, J ) 7.1 Hz), 3.34 (s, 3H), 2.76-2.68 (m, 3H), 2.88-2.23
(m, 3H), 2.10-1.95 (m, 1H), 1.86-1.81 (m, 1H), 1.41-1.26 (m,
1H), 1.20 (t, 3H, J ) 7.1 Hz); 13C NMR (22.4 MHz, DMSO-d6)
δ 171.8, 168.1, 165.0, 141.6, 141.2, 136.7, 134.5, 129.3, 128.2
(2C), 128.1, 127.7 (2C), 127.0, 124.5, 60.0, 39.9, 38.0, 34.6, 30.6,
28.1, 27.6, 14.1. Anal. (C23H27N3O3 and 1.1HCl) C, H, N, Cl.
1
1163, 1128, 837 cm-1; H NMR (270 MHz, DMSO-d6) δ 9.45
(s, 2H), 9.27 (s, 2H), 7.91-7.71 (m, 6H), 7.64 (s, 1H), 7.36 (d,
1H, J ) 2.3 Hz), 7.27 (t, 1H, J ) 2.1 Hz), 7.24 (t, 1H, J ) 2.5
Hz), 5.38 (s, 2H), 4.09 (q, 2H, J ) 7.1 Hz), 3.79 (s, 2H), 1.19 (t,
3H, J ) 7.1 Hz); 13C NMR (22.4 MHz, DMSO-d6) δ 171.0, 165.5,
156.0, 143.1, 134.1, 132.6, 129.2 (2C), 128.3 (2C), 127.6 (2C),
127.5, 127.3, 126.6, 125.5, 118.4, 107.3, 68.3, 60.2, 40.5, 14.0.
Anal. (C22H22N2O3 and HCl) C, H, N, Cl.
Eth yl [6-(4-Am id in oben za m id o)-3,4-d ih yd r o-2H-1-ben -
zop yr a n -3-yl]a ceta te Hyd r och lor id e (12c‚HCl). Following
the procedure described for the preparation of 12a ‚HCl, the
title compound was prepared in 63% yield from the nitrile 11c
as a pale-yellow solid: mp 238-240 °C; IR (KBr) 3290, 3077,
1706, 1687, 1651, 1560, 1500, 1426, 1299, 1260, 1176, 1094,
Eth yl (E)-[7-[2-(4-Am id in op h en yl)eth en yl]-1,2,3,4-tet-
r a h yd r o-2-n a p h t h a len yl]a cet a t e H yd r och lor id e (12h ‚
HCl). Following the procedure described for the preparation
of 12a ‚HCl, the title compound was prepared in 77% yield from
the nitrile 11h as an yellow solid: mp 234-236 °C; IR (KBr)
3124, 2920, 1724, 1671, 1604, 1540, 1491, 1293, 1265, 1155,
1028, 856, 829, 691 cm-1 1H NMR (270 MHz, DMSO-d6) δ
;
10.33 (s, 1H), 9.53 (br s, 2H), 9.28 (br s, 2H), 8.16 (d, 2H, J )
8.2 Hz), 7.96 (d, 2H, J ) 8.2 Hz), 7.52 (d, 1H, J ) 2.3 Hz),
7.47 (dd, 1H, J ) 2.3, 8.6 Hz), 6.75 (d, 1H, J ) 8.6 Hz), 4.18
(d, 1H, J ) 10.9 Hz), 4.11 (q, 2H, J ) 7.1 Hz), 3.85-3.78 (m,
1H), 2.93-2.86 (m, 1H), 2.52-2.33 (m, 4H), 1.21 (t, 3H, J )
7.1 Hz); 13C NMR (22.4 MHz, DMSO-d6) δ 171.4, 165.1, 163.6,
150.4, 139.3, 131.6, 130.2, 128.1 (2C), 127.9 (2C), 122.2, 120.7,
120.3, 115.9, 68.8, 59.9, 35.3, 30.2, 28.7, 14.0; ESI-MS m/e 382
(M + 1)+. Anal. (C21H23N3O4 and 1.12HCl) C, H, N, Cl.
1066, 1029, 972, 873, 838, 705 cm-1 1H NMR (270 MHz,
;
DMSO-d6) δ 9.42 (br s, 2H), 9.23 (br s, 2H), 7.88 (d, 2H, J )
8.2 Hz), 7.80 (d, 2H, J ) 8.2 Hz), 7.43 (d, 1H, J ) 16.5 Hz),
7.37-7.34 (m, 2H), 7.29 (d, 1H, J ) 16.5 Hz), 7.11 (d, 1H, J )
7.9 Hz), 4.10 (q, 2H, J ) 7.1 Hz), 2.91-2.78 (m, 3H), 2.52-
2.36 (m, 3H), 2.20-2.05 (m, 1H), 1.95-1.83 (m, 1H), 1.50-
1.39 (m, 1H), 1.21 (t, 3H, J ) 7.1 Hz); 13C NMR (22.4 MHz,
DMSO-d6) δ 171.9, 165.0, 142.7, 136.5, 135.9, 133.8, 131.9,
129.1, 128.6 (2C), 127.5, 126.4 (2C), 125.7 (2C), 124.2, 59.7,
40.0, 34.8, 30.9, 28.3, 28.1, 14.1. Anal. (C23H26N2O2 and
1.2HCl plus 0.2H2O) C, H, N, Cl.
E t h yl [7-(4-Am id in ob en za m id o)-1,2,3,4-t et r a h yd r o-2-
isoqu in olin yl]a ceta te Dih yd r och lor id e (12d ‚2HCl). Fol-
lowing the procedure described for the preparation of 12a ‚HCl,
the title compound was prepared in 60% yield from the nitrile
11d ‚HCl as a white solid: mp 172-173 °C; IR (KBr) 1869,
1748, 1676, 1617, 1601, 1542, 1508, 1489, 1421, 1303, 1216,
Eth yl [7-[2-(4-Am idin oph en yl)eth yl]-1,2,3,4-tetr ah ydr o-
2-n a p h th a len yl]a ceta te Hyd r och lor id e (12i‚HCl). Fol-
lowing the procedure described for the preparation of 12a ‚HCl,
the title compound was prepared in 68% yield from the nitrile
11i as a white solid: mp 149-151 °C; IR (KBr) 3124, 2925,
1
1072, 1018, 862, 700 cm-1; H NMR (270 MHz, DMSO-d6) δ
10.70 (s, 1H), 9.61 (br s, 2H), 9.38 (br s, 2H), 8.21 (d, 2H, J )
8.2 Hz), 8.00 (d, 2H, J ) 8.2 Hz), 7.74 (s, 1H), 7.71 (d, 1H, J
) 8.4 Hz), 7.24 (d, 1H, J ) 8.4 Hz), 4.52 (br s, 2H), 4.36 (br s,
2H), 4.27 (q, 2H, J ) 7.1 Hz), 3.75-3.25 (broad peak, 3H),
3.20-2.90 (broad peak, 2H), 1.28 (t, 3H, J ) 7.1 Hz); 13C NMR
(22.4 MHz, DMSO-d6) δ 165.6, 165.0, 164.1, 138.9, 137.4, 130.3,
128.7, 128.1 (5C), 126.7, 120.2, 118.0, 61.7, 54.2, 52.5, 49.6,
24.4, 13.8. Anal. (C21H24N4O3 and 2HCl plus H2O) C, H, N,
Cl.
1728, 1671, 1614, 1541, 1490, 1187, 1155, 1019, 834, 705 cm-1
;
1H NMR (270 MHz, DMSO-d6) δ 9.33 (br s, 2H), 9.14 (br s,
2H), 7.77 (d, 2H, J ) 8.2 Hz), 7.48 (d, 2H, J ) 8.2 Hz), 6.96-
6.93 (m, 3H), 4.09 (q, 2H, J ) 7.1 Hz), 2.99-2.71 (m, 7H), 2.45-
2.33 (m, 3H), 2.14-2.03 (m, 1H), 1.95-1.80 (m, 1H), 1.45-
1.30 (m, 1H), 1.20 (t, 3H, J ) 7.1 Hz); 13C NMR (22.4 MHz,
DMSO-d6) δ 171.9, 165.4, 148.3, 138.0, 135.3, 133.3, 128.9 (2C),
128.7, 128.5, 128.0 (2C), 125.7, 125.3, 59.7, 40.1, 36.7, 36.0,
34.9, 31.0, 28.5, 27.8, 14.1. Anal. (C23H28N2O2 and 1.05HCl)
C, H, N, Cl.
Eth yl [7-[N-(4-Am id in op h en yl)ca r ba m oyl]-1,2,3,4-tet-
r a h yd r o-2-n a p h t h a len yl]a cet a t e H yd r och lor id e (12e‚
HCl). Following the procedure described for the preparation
of 12a ‚HCl, the title compound was prepared in 75% yield from
the nitrile 11e as a white solid: mp 219-220 °C; IR (KBr)
3294, 3056, 1732, 1674, 1655, 1609, 1518, 1499, 1476, 1320,
1245, 1186, 1167, 1028, 934, 856, 754 cm-1; 1H NMR (270 MHz,
CDCl3) δ 10.57 (s, 1H), 9.27 (br s, 2H), 8.99 (br s, 2H), 8.03 (d,
2H, J ) 8.9 Hz), 7.86 (d, 2H, J ) 8.9 Hz), 7.74-7.71 (m, 2H),
7.25 (d, 1H, J ) 8.6 Hz), 4.10 (q, 2H, J ) 7.1 Hz), 2.92-2.82,
(m, 3H), 2.58-2.48 (m, 1H), 2.40 (d, 2H, J ) 6.9 Hz), 2.20-
2.05 (m, 1H), 1.94-1.90 (m, 1H), 1.53-1.42 (m, 1H), 1.21 (t,
3H, J ) 7.1 Hz); 13C NMR (22.4 MHz, DMSO-d6) δ 171.8, 165.9,
164.8, 144.4, 140.4, 135.7, 131.4, 128.9 (2C), 128.7, 128.5,
125.2, 121,7, 119.6 (2C), 59.7, 39.9, 34.7, 30.7, 28.1 (2C), 14.1.
Anal. (C22H25N3O3 and 1.05HCl) C, H, N, Cl.
[7-(4-Am id in ob en za m id o)-1,2,3,4-t et r a h yd r o-2-n a p h -
th a len yl]a cetic Acid Hyd r och lor id e (10a ‚HCl). To a
suspension of 12a ‚HCl (1.04 g, 2.5 mmol) in EtOH (10 mL)
was added 2 N NaOH (4.0 mL) at room temperature. The
mixture was stirred for 20 h at room temperature and
concentrated in vacuo. The resulting residue was suspended
in H2O, and the mixture was acidified with 2 N HCl. Purifica-
tion by reverse-phase column chromatography (Chromatorex-
ODS, 0.1 N HCl/MeCN ) 30/70) afforded 0.63 g (70%) of 10a ‚
HCl as a white solid: mp 236-238 °C; IR (KBr) 3397, 3250,
1721, 1661, 1545, 1506, 1486, 1335, 1315, 1019, 864, 829, 778,
1
703 cm-1; H NMR (270 MHz, DMSO-d6) δ 12.11 (br s, 1H),
10.37 (s, 1H), 9.54 (br s, 2H), 9.29 (br s, 2H), 8.17 (d, 2H, J )
8.6 Hz), 7.97 (d, 2H, J ) 8.6 Hz), 7.53-7.50 (m, 2H), 7.05 (d,
1H, J ) 8.9 Hz), 2.84 (dd, 1H, J ) 4.6, 16.5 Hz), 2.78-2.75
(m, 2H), 2.45 (dd, 1H, J ) 10.2, 16.5 Hz), 2.30-2.27 (m, 2H),
Eth yl [7-[(4-Am id in op h en yl)m eth oxy]-1,2,3,4-tetr a h y-
dr o-2-n aph th alen yl]acetate Hydr och lor ide (12f‚HCl). Fol-
lowing the procedure described for the preparation of 12a ‚HCl,
the title compound was prepared in 68% yield from the nitrile
11f as a white solid: mp 161-162 °C; IR (KBr) 3152, 2916,
2.20-2.10 (m, 1H), 1.95-1.85 (m, 1H), 1.50-1.34 (m, 1H); 13
C
NMR (22.4 MHz, DMSO-d6) δ 173.5, 165.0, 163.8, 139.3, 136.3,
135.7, 131.7, 130.2, 128.6, 128.1 (2C), 128.0 (2C), 120.7, 118.3,
40.2, 35.1, 30.7, 28.5, 27.6; ESI-MS m/e 352 (M + 1)+. Anal.
(C20H21N3O3 and 1.05HCl plus H2O) C, H, N, Cl.
1722, 1671, 1615, 1502, 1260, 1160, 1068, 1031, 834, 726 cm-1
;
1H NMR (270 MHz, DMSO-d6) δ 9.40 (br s, 2H), 9.19 (br s,
2H), 7.84 (d, 2H, J ) 8.6 Hz), 7.64 (d, 2H, J ) 8.6 Hz), 6.97 (d,
1H, J ) 8.2 Hz), 6.75 (dd, 1H, J ) 8.2, 2.6 Hz), 6.71 (d, 1H, J
) 2.6 Hz), 5.19 (s, 2H), 4.08 (q, 2H, J ) 7.1 Hz), 2.79 (dd, 1H,
J ) 16.5, 4.6 Hz), 2.70-2.64 (m, 2H), 2.45-2.32 (m, 3H), 2.12-
1.98 (m, 1H), 1.90-1.80 (m, 1H), 1.44-1.29 (m, 1H), 1.20 (t,
3H, J ) 7.1 Hz); 13C NMR (22.4 MHz, DMSO-d6) δ 171.9, 165.4,
155.8, 143.6, 136.7, 129.5, 128.2 (3C), 127.4 (2C), 127.0, 114.5,
112.7, 68.1, 59.7, 40.0, 35.1, 30.9, 28.6, 27.3, 14.1. Anal.
(C22H26N2O3 and 1.1HCl) C, H, N, Cl.
[7-(4-Am id in o-N-m eth ylben za m id o)-1,2,3,4-tetr a h yd r o-
2-n a p h th a len yl]a cetic Acid Hyd r och lor id e (10b‚HCl).
Following the procedure described for the preparation of 10a ‚
HCl, the title compound was prepared in 40% yield from the
ester 12b‚HCl as a white solid: mp 175-177 °C; IR (KBr)
3055, 1683, 1624, 1506, 1437, 1387, 1290, 1159, 1101, 1017,
1
856, 716 cm-1; H NMR (270 MHz, DMSO-d6) δ 12.01 (br s,
1H), 9.37 (br s, 2H), 9.18 (br s, 2H), 7.70 (d, 2H, J ) 8.2 Hz),
7.49 (d, 2H, J ) 8.2 Hz), 6.97 (s, 1H), 6.93 (d, 1H, J ) 7.9 Hz),
6.86 (d, 1H, J ) 7.9 Hz), 3.34 (s, 3H), 2.79-2.67 (m, 3H), 2.37-
2.22 (m, 3H), 2.10-1.90 (m, 1H), 1.88-1.82 (m, 1H), 1.37-
1.28 (m, 1H); 13C NMR (22.4 MHz, DMSO-d6) δ 173.4, 168.1,
E t h yl [7-[(4-Am id in op h en yl)m et h oxy]-2-n a p h t h a len -
yl]a ceta te Hyd r och lor id e (12g‚HCl). Following the pro-
cedure described for the preparation of 12a ‚HCl, the title
compound was prepared in 89% yield from the nitrile 11g as

4046 J ournal of Medicinal Chemistry, 1998, Vol. 41, No. 21
Okumura et al.
165.0, 141.6, 141.2, 136.8, 134.6, 129.3, 128.2 (2C), 128.1, 127.7
(2C), 127.0, 124.5, 40.3, 38.0, 34.7, 30.5, 28.3, 27.7. Anal.
(C21H23N3O3 and 1.05HCl plus H2O) C, H, N Cl.
1H, J ) 2.0, 5.0 Hz), 7.23 (dd, 1H, J ) 2.2, 5.7 Hz), 5.38 (s,
2H), 3.71 (s, 2H); 13C NMR (22.4 MHz, DMSO-d6) δ 172.5,
165.5, 155.9, 143.1, 134.1, 133.2, 129.1, 128.3 (2C), 127.6 (2C),
127.4 (2C), 127.2, 126.6, 125.7, 118.3, 107.3, 68.2, 40.9. Anal.
(C20H18N2O3 and HCl plus 0.2H2O) C, H, N, Cl.
[6-(4-Am idin oben zam ido)-3,4-dih ydr o-2H-1-ben zopyr an -
3-yl]a cetic Acid Hyd r och lor id e (10c‚HCl). Following the
procedure described for the preparation of 10a ‚HCl, the title
compound was prepared in 55% yield from the ester 12c‚HCl
as a pale-yellow solid: mp >250 °C; IR (KBr) 3375, 3280, 1704,
1676, 1652, 1538, 1504, 1321, 1256, 1220, 1032, 860, 810, 717
cm-1; 1H NMR (270 MHz, DMSO-d6) δ 12.28 (br s, 1H), 10.34
(s, 1H), 9.54 (br s, 2H), 9.30 (br s, 2H), 8.16 (d, 2H, J ) 8.6
Hz), 7.97 (d, 2H, J ) 8.6 Hz), 7.51 (d, 1H, J ) 2.3 Hz), 7.47
(dd, 1H, J ) 2.3, 8.6 Hz), 6.75 (d, 1H, J ) 8.6 Hz), 4.18 (d, 1H,
J ) 10.6 Hz), 3.82 (dd, 1H, J ) 6.9, 10.6 Hz), 2.92-2.85 (m,
1H), 2.58-2.49 (m, 1H), 2.38-2.23 (m, 3H); 13C NMR (22.4
MHz, DMSO-d6) δ 172.9, 165.0, 163.6, 150.4, 139.3, 131.4,
130.1, 128.1 (2C), 127.9 (2C), 122.2, 120.9, 120.2, 115.8, 68.9,
35.5, 30.2, 28.5; ESI-MS m/e 354 (M + 1)+. Anal. (C19H19N3O4
and 1.2HCl plus 1.3H2O) C, H, N, Cl.
[7-(4-Am id in oben za m id o)-1,2,3,4-tetr a h yd r o-2-isoqu in -
olin yl]a cetic Acid Dih yd r och lor id e (10d ‚2HCl). Follow-
ing the procedure described for the preparation of 10a ‚HCl,
the title compound was prepared in 60% yield from the ester
12d ‚2HCl as a white solid: mp 241-243 °C; IR (KBr) 3336,
3090, 1671, 1653, 1617, 1542, 1508, 1398, 1318, 910, 865, 837,
696 cm-1; 1H NMR (270 MHz, DMSO-d6) δ 10.50 (s, 1H), 9.54
(br s, 2H), 9.47 (br s, 2H), 8.18 (d, 2H, J ) 8.4 Hz), 7.98 (d,
2H, J ) 8.4 Hz), 7.62-7.59 (m, 2H), 7.14 (d, 1H, J ) 8.9 Hz),
5.30-3.20 (broad peak, 1H), 4.02 (s, 2H), 3.58 (s, 2H), 3.13-
3.10 (m, 2H), 2.95-2.92 (m, 2H); 13C NMR (22.4 MHz, DMSO-
d6) δ 170.0, 165.1, 164.0, 139.1, 136.6, 132.7, 130.5, 128.7, 128.1
(4C), 127.9, 119.2, 118.1, 57.7, 53.8, 49.8, 26.9. Anal.
(C19H20N4O3 and 1.85HCl plus H2O) C, H, N, Cl.
(E)-[7-[2-(4-Am idin oph en yl)eth en yl]-1,2,3,4-tetr ah ydr o-
2-n a p h th a len yl]a cetic Acid Hyd r och lor id e (10h ‚HCl).
Following the procedure described for the preparation of 10a ‚
HCl, the title compound was prepared in 66% yield from the
ester 12h ‚HCl as a pale-yellow solid: mp >260 °C; IR (KBr)
3326, 3179, 3071, 1710, 1676, 1605, 1541, 1508, 1475, 1436,
1389, 1234, 1149, 967, 947, 836, 718 cm-1; 1H NMR (270 MHz,
DMSO-d6) δ 12.17 (s, 1H), 9.40 (br s, 2H), 9.21 (br s, 2H), 7.87
(d, 2H, J ) 8.6 Hz), 7.80 (d, 2H, J ) 8.6 Hz), 7.43 (d, 1H, J )
16.5 Hz), 7.40-7.34 (m, 2H), 7.29 (d, 1H, J ) 16.5 Hz), 7.11
(d, 1H, J ) 7.9 Hz), 2.93-2.78 (m, 3H), 2.52-2.42 (m, 1H),
2.30 (d, 2H, J ) 7.3 Hz), 2.18-2.02 (m, 1H), 1.98-1.83 (m,
1H), 1.49-1.34 (m, 1H); 13C NMR (22.4 MHz, DMSO-d6) δ
173.5, 165.0, 142.7, 136.6, 136.0, 133.7, 131.9, 129.0, 128.5
(2C), 127.4, 126.4 (3C), 125.7, 124.2, 40.3, 34.9, 30.7, 28.4, 28.1.
Anal. (C21H22N2O2 and HCl) C, H, N, Cl.
[7-[2-(4-Am id in op h e n yl)e t h yl]-1,2,3,4-t e t r a h yd r o-2-
n a p h th a len yl]a cetic Acid Hyd r och lor id e (10i‚HCl). Fol-
lowing the procedure described for the preparation of 10a ‚HCl,
the title compound was prepared in 88% yield from the ester
12i‚HCl as a white solid: mp 219-221 °C; IR (KBr) 3104,
2913, 1708, 1685, 1614, 1489, 1242, 1157, 835, 765, 669 cm-1
;
1H NMR (270 MHz, DMSO-d6) δ 12.14 (s, 1H), 9.34 (br s, 2H),
9.16 (br s, 2H), 7.77 (d, 2H, J ) 8.2 Hz), 7.49 (d, 2H, J ) 8.2
Hz), 6.96-6.93 (m, 3H), 3.00-2.71 (m, 7H), 2.39 (dd, 1H, J )
10.2, 16.5 Hz), 2.29-2.25 (m, 2H), 2.12-1.98 (m, 1H), 1.95-
1.80 (m, 1H), 1.45-1.30 (m, 1H); 13C NMR (22.4 MHz, DMSO-
d6) δ 173.5, 165.4, 148.2, 138.0, 135.4, 133.4, 128.9 (2C), 128.6,
128.5, 128.0 (2C), 125.6, 125.3, 40.3, 36.6, 35.9, 35.0, 30.8, 28.6,
27.8. Anal. (C21H24N2O2 and 1.05HCl) C, H, N, Cl.
[7-[N-(4-Am idin oph en yl)car bam oyl]-1,2,3,4-tetr ah ydr o-
2-n a p h th a len yl]a cetic Acid Hyd r och lor id e (10e‚HCl).
Following the procedure described for the preparation of 10a ‚
HCl, the title compound was prepared in 79% yield from the
ester 12e‚HCl as a white solid: mp >250 °C; IR (KBr) 3397,
3135, 2925, 1716, 1671, 1663, 1654, 1608, 1521, 1496, 1490,
Meth yl 5,6-Dih yd r o-2-n a p h th oa te (14b). To an ice-
cooled solution of 13b24 (15.7 g, 77 mmol) in a mixture of
methanol (20 mL) and THF (40 mL) was added NaBH4 (3.1 g,
42.0 mmol) by portions. The mixture was stirred for 1 h at
room temperature, neutralized with 1 N HCl, and extracted
with ether. The organic phase was washed with brine, dried
over MgSO4, filtered, and concentrated in vacuo. Purification
of the residue by column chromatography (SiO2, n-hexane/
EtOAc ) 3/1) afforded 15.1 g (95%) of methyl 8-hydroxy-
5,6,7,8-tetrahydro-2-naphthoate.
The preceding alcohol (14.47 g, 70.1 mmol) was dissolved
in benzene (200 mL), and Amberlyst 15 (5.0 g) was added. The
mixture was refluxed for 3 h, filtered, and concentrated in
vacuo to afford an oily residue. Purification by column
chromatography (SiO2, n-hexane/EtOAc ) 7/1) afforded 11.7
g (89%) of 14b as a colorless oil. Anal. (C12H12O2) C, H.
Meth yl 7-Oxo-5,6,7,8-tetr a h yd r o-2-n a p h th oa te (15b).
To a solution of 14b (10.2 g, 54.1 mmol) in benzene (140 mL)
was added 3-chloroperbenzoic acid (12.0 g, 69.5 mmol) by
portions. The mixture was stirred for 2 h at room temperature.
The reaction was quenched with aqueous Na2SO3 solution, and
the mixture was extracted with benzene. The organic phase
was dried over Na2SO4, filtered, and concentrated in vacuo.
Purification by column chromatography (SiO2, n-hexane/EtOAc
) 4/1) afforded 10.5 g (95%) of methyl 7,8-epoxy-5,6,7,8-
tetrahydro-2-naphthoate.
A mixture of the preceding epoxide (10.4 g, 50.9 mmol) and
ZnI2 (19.2 g, 60.2 mmol) in benzene (200 mL) was stirred for
1 h at room temperature. After addition of water, the mixture
was extracted with benzene. The organic phase was dried over
Na2SO4, filtered, and concentrated in vacuo. Purification of
the residue by column chromatography (SiO2, n-hexane/EtOAc
) 5/1) gave 9.55 g (92%) of 15b as a white solid: mp 56-58
°C.
Meth yl 7-[(ter t-Bu toxyca r bon yl)m eth yl]-5,6-d ih yd r o-
2-n a p h th oa te (16b). To an ice-cooled solution of tert-butyl
P,P-dimethylphosphonoacetate (12.4 g, 55.3 mmol) in benzene
(100 mL) was added NaH (1.26 g, 52.5 mmol) by portions, and
the mixture was stirred for 30 min at room temperature. To
1409, 1331, 1255, 1190, 846, 750 cm-1 1H NMR (270 MHz,
;
DMSO-d6) δ 12.15 (br s, 1H), 10.58 (s, 1H), 9.30 (br s, 2H),
9.05 (br s, 2H), 8.04 (d, 2H, J ) 8.9 Hz), 7.87 (d, 2H, J ) 8.9
Hz), 7.74-7.71 (m, 2H), 7.23 (d, 1H, J ) 8.6 Hz), 2.97 (dd, 1H,
J ) 10.3, 4.1 Hz), 2.90-2.83 (m, 2H), 2.58-2.48 (m, 1H), 2.34-
2.30 (m, 2H), 2.15-2.05 (m, 1H), 1.98-1.92 (m, 1H), 1.54-
1.39 (m, 1H); 13C NMR (22.4 MHz, DMSO-d6) δ 173.5, 165.9,
164.8, 144.4, 140.5, 135.8, 131.4, 128.9 (2C), 128.7, 128.4,
125.1, 121.7, 119.6 (2C), 40.2, 34.9, 30.6, 28.2 (2C). Anal.
(C20H21N3O3 and 1.1HCl plus 1.6H2O) C, H, N, Cl.
[7-[(4-Am id in op h en yl)m et h oxy]-1,2,3,4-t et r a h yd r o-2-
n a p h th a len yl]a cetic Acid Hyd r och lor id e (10f‚HCl). Fol-
lowing the procedure described for the preparation of 10a ‚HCl,
the title compound was prepared in 79% yield from the ester
12f‚HCl as a white solid: mp 249-250 °C; IR (KBr) 3379,
3263, 3105, 2925, 1718, 1669, 1502, 1261, 1161, 1025, 867, 832,
802 cm-1; 1H NMR (270 MHz, DMSO-d6) δ 12.14 (s, 1H), 9.40
(br s, 2H), 9.20 (br s, 2H), 7.84 (d, 2H, J ) 8.6 Hz), 7.64 (d,
2H, J ) 8.6 Hz), 6.97 (d, 1H, J ) 8.2 Hz), 6.75 (dd, 1H, J )
8.2, 2.6 Hz), 6.71 (d, 1H, J ) 2.6 Hz), 5.19 (s, 2H), 2.78 (dd,
1H, J ) 4.3, 16.5 Hz), 2.70-2.66 (m, 2H), 2.39 (dd, 1H, J )
10.4, 16.5 Hz), 2.28-2.25 (m, 2H), 2.12-1.98 (m, 1H), 1.95-
1.80 (m, 1H), 1.43-1.28 (m, 1H); 13C NMR (22.4 MHz, DMSO-
d6) δ 173.5, 165.4, 155.7, 143.6, 136.8, 129.5, 128.2 (3C), 127.3
(2C), 126.9, 114.4, 112.7, 68.0, 40.3, 35.2, 30.7, 28.7, 27.4.
Anal. (C20H22N2O3 and HCl plus H2O) C, H, N, Cl.
[7-[(4-Am id in op h en yl)m et h oxy]-2-n a p h t h a len yl]a ce-
tic Acid Hyd r och lor id e (10g‚HCl). Following the procedure
described for the preparation of 10a ‚HCl, the title compound
was prepared in 68% yield from the ester 12g‚HCl as a white
solid: mp >260 °C; IR (KBr) 3362, 3219, 3096, 2921, 1710,
1691, 1674, 1632, 1616, 1512, 1486, 1392, 1265, 1222, 1202,
1167, 1124, 1039, 1016, 841, 726, 670 cm-1; 1H NMR (270 MHz,
DMSO-d6) δ 12.40 (s, 1H), 9.42 (s, 2H), 9.25 (s, 2H), 7.88-
7.70 (m, 6H), 7.62 (s, 1H), 7.35 (d, 1H, J ) 2.5 Hz), 7.26 (dd,

New GPIIb-IIIa Antagonists
J ournal of Medicinal Chemistry, 1998, Vol. 41, No. 21 4047
this was added a solution of 15b (9.4 g, 46.0 mmol) in THF
(30 mL). The mixture was stirred for an additional 2 h at room
temperature. After addition of 1 N HCl (100 mL), the mixture
was extracted with toluene. The organic phase was washed
with saturated aqueous NaHCO3 and brine, dried over Na2-
SO4, filtered, and concentrated in vacuo. Purification by
column chromatography (SiO2, n-hexane/isopropyl ether ) 1/6)
gave 12.16 g (87%) of a mixture of 16b and its olefin isomer,
which was used for the next reaction without further purifica-
tion. An analytical pure 16b was afforded by flash chroma-
tography (SiO2, n-hexane/isopropyl ether ) 8/1) as a colorless
solid: mp 60-61 °C. Anal. (C18H22O4) C, H.
Met h yl 7-[(ter t-Bu t oxyca r b on yl)m et h yl]-5,6,7,8-t et -
r a h yd r o-2-n a p h th oa te (17b). A mixture of 16b (9.1 g, 30.0
mmol) and 10% Pd/C (0.70 g) in MeOH (50 mL) was stirred at
0.1 MPa of H2 atmosphere for 2 h. Filtration and evaporation
of the filtrate gave 8.88 g (29.2 mmol, 97%) of 17b as a white
solid: mp 54-55 °C. Anal. (C18H24O4) C, H.
6-Meth oxy-1,2-d ih yd r on a p h th a len e (14c). To an ice-
cooled solution of 50.3 g (0.285 mol) of 13c in a mixture of
MeOH (50 mL) and THF (250 mL) was added NaBH4 (10.6 g,
0.280 mol). The mixture was stirred for 2 h at room temper-
ature. The reaction mixture was neutralized with 3 N HCl
solution, concentrated in vacuo, and extracted with ether twice.
The combined organic phases were dried over MgSO4, filtered,
and concentrated in vacuo to afford an oil, which was passed
through a pad of silica gel. Concentration in vacuo gave a
crude alcohol (51.1 g).
Eth yl [7-(N-Meth yl-ter t-bu toxyca r ba m oyl)-1,2,3,4-tet-
r a h yd r o-2-n a p h th a len yl]a ceta te (18). A mixture of 17a
(5.83 g, 25.0 mmol) and di-tert-butyl dicarbonate (6.0 g, 27.5
mmol) in 1,4-dioxane (30 mL) was stirred for 20 h at room
temperature and concentrated in vacuo to afford an oily
residue, which was crystallized by addition of n-hexane.
Recrystallization from a mixture of n-hexane and EtOAc (5:1)
afforded 5.74 g (69%) of Boc-aniline derivative as a white
solid: mp 112-114 °C.
To a solution of the preceding Boc-aniline derivative (0.67
g, 2.0 mmol) in DMF (10 mL) was added NaH (57 mg, 2.4
mmol), and the mixture was stirred for 5 min. To this was
added 0.57 g (4.0 mmol) of methyl iodide, and the mixture was
stirred for 18 h at room temperature. After removal of the
solvent, the mixture was diluted with H2O and extracted with
EtOAc twice. The combined organic phases were dried over
MgSO4, filtered, and concentrated in vacuo. The residual oil
was purified by column chromatography (SiO2, n-hexane/
EtOAc ) 10/1) to afford 0.67 g (96%) of 18 as a colorless oil.
Anal. (C20H29NO4) C, H, N.
Eth yl [7-(N-Meth yla m in o)-1,2,3,4-tetr a h yd r o-2-n a p h -
th a len yl]a ceta te Hyd r och lor id e (19‚HCl). Into an ice-
cooled solution of 18 (3.0 g, 8.63 mmol) in EtOH (30 mL) was
bubbled HCl for 15 min. The mixture was stirred for 3 h at
room temperature and concentrated in vacuo to afford 2.47 g
(quantitative) of 19‚HCl, which was used for the next reaction
without further purification: mp 138-140 °C.
7-[(ter t-Bu toxyca r bon yl)m eth yl]-5,6,7,8-tetr a h yd r o-2-
n a p h th oic Acid (20). To a solution of 17b (10.8 g, 35.5 mmol)
in MeOH (100 mL) was added 2.5 N NaOH (20 mL). The
mixture was stirred for 20 h at room temperature and
concentrated in vacuo. The resulting residue was suspended
with H2O and acidified by 3 N HCl. The mixture was extracted
with EtOAc. The organic phase was washed with brine, dried
over MgSO4, and concentrated in vacuo to afford a residue.
Purification by column chromatography (SiO2, CHCl3/MeOH
) 1/20) gave 6.62 g (64%) of 20 as a white solid: mp 125-126
°C. Anal. (C17H22O4) C, H.
A mixture of the preceding alcohol (51.1 g) and pyridinium
p-toluenesulfonate (3.60 g, 14.3 mmol) in toluene (500 mL) was
refluxed for 3 h. The mixture was washed with aqueous
NaHCO3, aqueous NaHSO4, and brine successively. The
organic phase was dried over Na2SO4, filtered, and concen-
trated in vacuo to afford an oily residue. Distillation (82-85
°C at 30 Pa) gave 39.0 g (0.243 mol, 85% from 13c) of 14c as
an oil. Anal. (C11H12O) H; C: calcd, 82.46; found, 82.01.
7-Meth oxy-2-oxo-1,2,3,4-tetr a h yd r on a p h th a len e (15c).
To an ice-cooled mixture of 14c (35.0 g, 218 mmol), 10%
aqueous NaHCO3 (200 mL), and toluene (300 mL) was added
of 3-chloroperbenzoic acid (50.0 g, 289 mmol). The mixture
was vigorously stirred for 2 h at room temperature. The
reaction was quenched with 10% aqueous Na2SO3 solution. The
organic phase was separated, dried over Na2SO4, filtered, and
concentrated in vacuo. Purification by column chromatogra-
phy (SiO2, n-hexane/EtOAc ) 3/1) afforded 36.5 g (207 mmol,
95%) of 1,2-epoxy-7-methoxy-1,2,3,4-tetrahydronaphthalene as
a colorless oil.
Eth yl (7-Hyd r oxy-1,2,3,4-tetr a h yd r o-2-n a p h th a len yl)-
a ceta te (21). To a mixture of NaI (6.04 g, 40.0 mmol) and
TMSCl (4.44 g, 40.0 mmol) in MeCN (100 mL) was added 7.70
g (31.0 mmol) of 17c, and the mixture was refluxed for 6 h.
The reaction was quenched by addition of 10% Na2SO3
solution. The mixture was extracted with ether twice, and the
combined organic phases were dried over MgSO4 and concen-
trated in vacuo. Purification by column chromatography (SiO2,
n-hexane/EtOAc ) 5/1) gave 3.96 g (55%) of 21 as a colorless
oil.
To a suspension of ZnI2 (7.9 g, 24.8 mmol) in benzene (300
mL) was dropwise added the above epoxide (13.0 g, 73.9 mmol).
The mixture was refluxed for 3 h and washed with H2O. The
organic phase was dried over MgSO4, filtered, and concen-
trated in vacuo to afford a residual oil. Purification of column
chromatography (SiO2, CHCl3) afforded 9.6 g (74%) of 15c as
a colorless oil.
E t h yl [7-[(Tr iflu or om et h yl)su lfon yloxy]-1,2,3,4-t et -
r a h yd r o-2-n a p h th a len yl]a ceta te (22). To an ice-cooled
solution of 21 (4.0 g, 17.5 mmol) and pyridine (20.0 g, 253
mmol) in CHCl3 (50 mL) was slowly added trifluoromethane-
sulfonic anhydride (6.37 g, 22.5 mmol). The mixture was
stirred for 2 h at 0 °C. After addition of 2 N HCl, the mixture
was extracted with CHCl3. The organic phase was washed
with aqueous NaHCO3 solution and brine, dried over MgSO4,
filtered, and concentrated in vacuo. Purification of the residue
by column chromatography (SiO2, n-hexane/EtOAc ) 7/1) gave
6.6 g (quantitative) of 22 as a colorless oil.
Eth yl (7-Hyd r oxy-2-n a p h th a len yl)a ceta te (23). A mix-
ture of 16c (6.60 g, 26.8 mmol) and p-chloranil (8.57 g, 34.8
mmol) in xylene (50 mL) was refluxed for 1.5 h and concen-
trated in vacuo. Purification of the residue by column chro-
matography (SiO2, n-hexane/EtOAc ) 15/1) gave 3.11 g (48%)
of ethyl (7-methoxy-2-naphthalenyl)acetate as a pale-yellow
solid: mp 68-69 °C. Anal. (C15H16O3) C, H.
Following the procedure described for the preparation of 21,
the preceding ether was converted to 23 in 49% yield as a white
solid: mp 132-134 °C. Anal. (C14H14O3) C, H.
(7-Nitr o-1-oxo-1,2,3,4-tetr a h yd r o-2-n a p h th ylid en e)a ce-
tic Acid (24). A mixture of 13a (5.0 g, 26.5 mmol), 40%
glyoxylic acid (15.0 g, 81.0 mmol), and H2SO4 (3.2 g, 32.6 mmol)
in 1,4-dioxane (10 mL) was refluxed for 5 h. After addition of
water (10 mL), the mixture was cooled to room temperature.
Eth yl (7-Meth oxy-3,4-d ih yd r o-2-n a p h th a len yl)a ceta te
(16c). To a solution of ethyl (diethylphosphoryl)acetate (13.5
g, 60.1 mmol) in 1,2-dimethoxyethane (200 mL) was added
NaH (1.44 g, 60 mmol) by portions at room temperature, and
the mixture was stirred for 1 h at room temperature. After
addition of 15c (9.6 g, 54.5 mmol), the mixture was stirred for
3 h at room temperature, poured onto ice-water, and extracted
with EtOAc twice. The combined organic phases were dried
over Na2SO4, filtered, and concentrated in vacuo to afford an
oil, which was purified by column chromatography (SiO2,
n-hexane/EtOAc ) 10/1) to give 9.6 g (60%) of 16c with a small
amount of olefin isomer, ethyl (7-methoxy-1,2,3,4-tetrahydro-
2-naphthalenylidene)acetate. An analytical pure 16c was
afforded by flash chromatography (SiO2, n-hexane/isopropyl
ether ) 10/1) as a colorless oil.
Eth yl (7-Meth oxy-1,2,3,4-tetr a h yd r o-2-n a p h th a len yl)-
a ceta te (17c). According to the procedure described for the
preparation of 17b, the title compound was prepared from 16c
in 95% yield as a colorless oil.

4048 J ournal of Medicinal Chemistry, 1998, Vol. 41, No. 21
Okumura et al.
The resulting precipitate was collected by filtration and
washed with water and MeOH successively. Recrystallization
from 1,4-dioxane gave 4.1 g (63%) of 24 as a pale-yellow solid:
mp 204-206 °C. Anal. (C12H9NO5) C, H, N.
7/1) gave 7.4 g (98%) of 32 as a white solid: mp 156-157 °C.
Anal. (C9H5N) C, N; H: found, 4.52; calcd, 3.96.
Eth yl [7-[4-[N-(n -P r op yl)a m id in o]ben za m id o]-1,2,3,4-
tetr a h yd r o-2-n a p h th a len yl]a ceta te Hyd r och lor id e (33a ‚
HCl). Anhydrous HCl was bubbled into an ice-cooled suspen-
sion of 11a (2.45 g, 6.76 mmol) in EtOH (20 mL) for 30 min.
The mixture was stirred for 4 h at room temperature and
concentrated in vacuo. The residual solid was triturated with
isopropyl ether, dried under reduced pressure, and dissolved
in EtOH (18 mL). To this was added n-propylamine (0.81 g,
13.6 mmol), and the mixture was stirred for 20 h at room
temperature. The resulting precipitate was collected by filtra-
tion and treated with ethanolic HCl to afford 2.8 g (89%) of
33a ‚HCl as a white solid: mp 250 °C; IR (KBr) 3328, 3212,
3043, 2931, 1727, 1675, 1626, 1596, 1538, 1508, 1420, 1157,
Eth yl (7-Am in o-1,2,3,4-tetr a h yd r o-2-n a p h th a len yl)a c-
eta te (17a ). A mixture of 24 (5.0 g, 18.1 mmol), H2SO4 (2.13
g, 21.7 mmol), and 10% Pd/C (1.0 g) in EtOH (50 mL) was
placed in an autoclave. The mixture was stirred under H2
atmosphere (1.0 MPa) for 20 h at 60 °C and filtered. The
filtrate was neutralized with 20% NaOH and concentrated in
vacuo to afford an oily residue, which was dissolved in CHCl3
(50 mL) and washed with H2O. The organic phase was dried
over Na2SO4 and concentrated in vacuo. Purification by
column chromatography (SiO2, n-hexane/EtOAc ) 3/1) gave
2.10 g (50%) of 17a as solid: mp 45-47 °C.
(E)-(6-Nitr o-4-oxo-3,4-dih ydr o-2H-1-ben zopyr an -3-ylide-
n e)a cetic Acid (26). Following the procedure described for
the preparation of 24, the title compound was prepared from
25 in 61% yield as a yellow solid: mp 193-194 °C. Anal.
(C11H7NO6) C, H, N.
1
1026, 831, 714 cm-1; H NMR (270 MHz, DMSO-d6) δ 10.36
(s, 1H), 10.10-9.20 (broad peak, 3H), 8.16 (d, 2H, J ) 8.4 Hz),
7.88 (d, 2H, J ) 8.4 Hz), 7.53-7.50 (m, 2H), 7.06 (d, 1H, J )
8.6 Hz), 4.10 (q, 2H, J ) 7.3 Hz), 3.40 (t, 2H, J ) 7.2 Hz),
2.85-2.75 (m, 3H), 2.49-2.35 (m, 3H), 2.15-2.05 (m, 1H),
1.91-1.87 (m, 1H), 1.75-1.62 (m, 2H), 1.49-1.39 (m, 1H), 1.21
(t, 3H, J ) 7.3 Hz), 0.98 (t, 3H, J ) 7.3 Hz); 13C NMR (22.4
MHz, DMSO-d6) δ 171.9, 163.9, 162.2, 138.7, 136.3, 135.6,
131.6, 131.3, 128.6, 128.2 (2C), 127.9 (2C), 120.8, 118.4, 59.7,
44.3, 40.0, 35.0, 30.9, 28.5, 27.6, 20.7, 14.1, 11.1. Anal.
(C25H31N3O3 and HCl) C, H, N, Cl.
Eth yl (6-Am in o-3,4-d ih yd r o-2H-1-ben zop yr a n -3-yl)a c-
eta te (27). Following the procedure described for the prepa-
ration of 17a , the title compound was prepared from 26 in 74%
yield: mp 57-58 °C. Anal. (C13H17NO3) C, H, N.
Eth yl (7-Am in o-1,2,3,4-tetr a h yd r o-2-isoqu in olin yl)a c-
eta te Dih yd r och lor id e (30‚2HCl). A mixture of 2928 (2.89
g, 13.5 mmol), ethyl bromoacetate (2.25 g, 13.5 mmol), and
Et3N (2.83 g, 27.9 mmol) in EtOH (20 mL) was refluxed for 5
h and concentrated in vacuo. After addition of water, the
mixture was extracted with EtOAc twice. The combined
organic phases were dried over Na2SO4, filtered, and concen-
trated in vacuo to afford a residue. Purification by column
chromatography (SiO2, n-hexane/EtOAc ) 3/1) gave a free
amine, which was treated with 4 N HCl in 1,4-dioxane to afford
2.14 g (57%) of ethyl (7-nitro-1,2,3,4-tetrahydro-2-isoquinoli-
nyl)acetate hydrochloride as a hygroscopic solid: mp 174-177
°C.
A mixture of the preceding nitro compound (2.0 g, 6.65
mmol) and 10% Pd/C (1.0 g) in EtOH (40 mL) was vigorously
stirred under H2 atmosphere for 2 h at room temperature.
After removal of the catalyst by filtration, the filtrate was
concentrated in vacuo to afford a residue. Treatment of the
residue with 4 N HCl in 1,4-dioxane gave 2.0 g (100%) of 30‚
2HCl as a hygroscopic solid, which was immediately used for
the next reaction without purification.
4-Eth yn ylben zon itr ile (32). To an ice-cooled mixture of
11.9 g (0.10 mol) of 4-hydroxybenzonitrile (31) and Et3N (12.1
g, 0.10 mol) in CH2Cl2 (100 mL) was dropwise added trifluo-
romethanesulfonic anhydride (30.9 g, 0.109 mol). The mixture
was stirred at ambient temperature for 1 h, and aqueous
NaHCO3 solution was added. The mixture was extracted with
CH2Cl2. The organic phase was washed with aqueous NaHSO4
solution and brine successively, dried over Na2SO4, filtered,
and concentrated in vacuo. Purification by column chroma-
tography (SiO2, n-hexane/EtOAc ) 10/1) gave 20.0 g (80%) of
the 4-cyanophenyl trifluoromethanesulfonate as a colorless oil.
A mixture of the preceding triflate (18.3 g, 77.8 mmol),
(trimethylsilyl)acetylene (15.2 g, 154.7 mmol), CuI (2.83 g, 14.9
mmol), Pd(PPh3)4 (5.0 g, 4.3 mmol), and n-propylamine (14.0
g, 0.236 mol) in benzene (200 mL) was stirred at room
temperature for 3 h. The reaction mixture was washed with
saturated aqueous NH4Cl solution three times. The organic
phase was dried over Na2SO4, filtered, and concentrated in
vacuo. Purification by column chromatography (SiO2, n-
hexane/CHCl3 ) 3/1) afforded 15.1 g (97%) of 4-[2-(trimethyl-
silyl)ethynyl]benzonitrile as a white solid: mp 107-108 °C.
Anal. (C12H13NSi) C, H, N.
Eth yl [7-[4-[N-(2-P r open yl)am idin o]ben zam ido]-1,2,3,4-
tetr a h yd r o-2-n a p h th a len yl]a ceta te Hyd r och lor id e (33b‚
HCl). The title compound was prepared from 11a and
allylamine in 85% yield following the procedure described for
the preparation of 33a ‚HCl: mp 248-250 °C; IR (KBr) 3329,
3050, 2931, 1725, 1673, 1623, 1597, 1539, 1508, 1420, 1331,
1263, 1159, 1025, 830, 714 cm-1; 1H NMR (DMSO-d6) δ 10.38
(s, 1H), 10.19 (br s, 1H), 9.72 (br s, 1H), 9.25 (br s, 1H), 8.17
(d, 2H, J ) 8.6 Hz), 7.92 (d, 2H, J ) 8.6 Hz), 7.53-7.50 (m,
2H), 7.05 (d, 1H, J ) 8.9 Hz), 6.00-5.89 (m, 1H), 5.38-5.26
(m, 2H), 4.16-4.06 (m, 4H), 2.80-2.75 (m, 3H), 2.47-2.35 (m,
3H), 2.20-2.05 (m, 1H), 1.91-1.87 (m, 1H), 1.46-1.40 (m, 1H),
1.21 (t, 3H, J ) 7.1 Hz); 13C NMR (22.4 MHz, DMSO-d6) δ
171.9, 163.8, 162.1, 138.8, 136.4, 135.5, 131.5 (2C), 131.0,
128.6, 128.3 (2C), 127.9 (2C), 120.8, 118.4, 117.2, 59.7, 44.4,
40.0, 35.0, 30.9, 28.5, 27.6, 14.1; CI-MS m/e 420 (M + 1)+. Anal.
(C25H29N3O3 and HCl) C, H, N, Cl.
Eth yl [7-[4-[N-(2-P r opyn yl)am idin o]ben zam ido]-1,2,3,4-
tetr a h yd r o-2-n a p h th a len yl]a ceta te Hyd r och lor id e (33c‚
HCl). The title compound was prepared from 11a and
propargylamine in 82% yield following the procedure described
for the preparation of 33a ‚HCl: mp 203-205 °C; IR (KBr)
3422, 3236, 3043, 1721, 1671, 1617, 1541, 1506, 1418, 1333,
1269, 1158, 1028, 858, 713 cm-1; 1H NMR (270 MHz, DMSO-
d6) δ 10.45 (br s, 1H), 10.36 (s, 1H), 9.93 (br s, 1H), 9.46 (br s,
1H), 8.16 (d, 2H, J ) 8.2 Hz), 7.89 (d, 2H, J ) 8.6 Hz), 7.52-
7.49 (m, 2H), 7.05 (d, 1H, J ) 8.9 Hz), 4.37-4.35 (m, 2H), 4.10
(q, 2H, J ) 7.1 Hz), 3.50 (s, 1H), 2.86-2.75 (m, 3H), 2.45-
2.35 (m, 3H), 2.20-2.13 (m, 1H), 1.91-1.87 (m, 1H), 1.46-
1.42 (m, 1H), 1.22 (t, 3H, J ) 7.1 Hz); 13C NMR (22.4 MHz,
DMSO-d6) δ 171.9, 163.8, 162.3, 139.0, 136.3, 135.6, 131.5,
130.7, 128.6, 128.3 (2C), 127.9 (2C), 120.7, 118.3, 77.2, 75.9,
59.6, 39.9, 35.0, 32.1, 30.9, 28.4, 27.6, 14.1; CI-MS m/e 418 (M
+ 1)+. Anal. (C25H27N3O3 and 1.03HCl plus 0.1H2O) C, H, N,
Cl.
E t h yl [7-[4-[N-(2-F u r ylm et h yl)a m id in o]b en za m id o]-
1,2,3,4-t et r a h yd r o-2-n a p h t h a len yl]a cet a t e H yd r och lo-
r id e (33d ‚HCl). The title compound was prepared from 11a
and furfurylamine in 55% yield following the procedure
described for the preparation of 33a ‚HCl: mp 240-242 °C;
IR (KBr) 3316, 3032, 1732, 1678, 1622, 1596, 1539, 1507, 1420,
1337, 1258, 1205, 1149, 1018, 826, 744 cm-1 1H NMR (270
;
A mixture of 12.2 g (59.7 mmol) of the preceding silylacety-
lene and KF (15.0 g, 258 mmol) in acetonitrile (120 mL) was
refluxed for 4 h. After addition of water, the mixture was
extracted with ether twice. The combined organic phases were
dried over MgSO4, filtered, and concentrated in vacuo. Puri-
fication by column chromatography (SiO2, n-hexane/EtOAc )
MHz, DMSO-d6) δ 10.48 (br s, 1H), 10.39 (s, 1H), 9.90 (br s,
1H), 9.61 (br s, 1H), 8.17 (d, 2H, J ) 8.2 Hz), 7.90 (d, 2H, J )
8.2 Hz), 7.70 (s, 1H), 7.53-7.50 (m, 2H), 7.05 (d, 1H, J ) 8.9
Hz), 6.48-6.46 (m, 2H), 4.77 (s, 2H), 4.10 (q, 2H, J ) 7.1 Hz),
2.85-2.75 (m, 3H), 2.44-2.35 (m, 3H), 2.20-2.05 (m, 1H),
1.91-1.87 (m, 1H), 1.46-1.39 (m, 1H), 1.21 (t, 3H, J ) 7.1

New GPIIb-IIIa Antagonists
J ournal of Medicinal Chemistry, 1998, Vol. 41, No. 21 4049
Hz); 13C NMR (22.4 MHz, DMSO-d6) δ 171.9, 163.9, 162.3,
148.3, 143.2, 138.9, 136.4, 135.6, 131.5, 130.8, 128.6, 128.4
(2C), 128.0 (2C), 120.9, 118.5, 110.6, 109.2, 59.7, 40.0, 39.5,
35.1, 30.9, 28.5, 27.6, 14.1; ESI-MS m/e 460 (M + 1)+. Anal.
(C27H29N3O4 and HCl) C, H, N, Cl.
[7-[4-[N-(2-P r op en yl)a m id in o]b en za m id o]-1,2,3,4-t et -
r ah ydr o-2-n aph th alen yl]acetic Acid Hydr och lor ide (34b‚
HCl). Following the procedure described for the preparation
of 10a ‚HCl, the title compound was prepared in 49% yield from
the ester 33b‚HCl: mp >250 °C; IR (KBr) 3263, 3089, 1693,
1653, 1538, 1501, 1439, 1389, 1318, 1236, 1155, 1063, 985, 939,
864, 823, 719, 692 cm-1; 1H NMR (270 MHz, DMSO-d6) δ 10.38
(s, 1H), 10.20-9.20 (broad peak, 2H), 8.18 (d, 2H, J ) 8.6 Hz),
7.93 (d, 2H, J ) 8.6 Hz), 7.53-7.50 (m, 2H), 7.05 (d, 1H, J )
8.6 Hz), 6.00-5.90 (m, 1H), 5.38-5.25 (m, 2H), 4.15 (d, 2H, J
) 5.3 Hz), 2.88-2.75 (m, 3H), 2.46-2.27 (m, 3H), 2.20-2.05
(m, 1H), 1.94-1.89 (m, 1H), 1.45-1.39 (m, 1H); 13C NMR (22.4
MHz, DMSO-d6) δ 173.5, 163.9, 162.1, 138.8, 136.3, 135.7,
131.6, 131.5, 131.0, 128.6, 128.3 (2C), 128.0 (2C), 120.8, 118.4,
117.2, 44.5, 40.3, 35.2, 30.8, 28.6, 27.6. Anal. (C23H25N3O3
and 1.1HCl plus 0.7H2O) C, H, N, Cl.
[7-[4-[N-(2-P r op yn yl)a m id in o]b en za m id o]-1,2,3,4-t et -
r a h yd r o-2-n a p h th a len yl]a cetic Acid Hyd r och lor id e (34c‚
HCl). Following the procedure described for the preparation
of 10a ‚HCl, the title compound was prepared in 91% yield from
the ester 33c‚HCl: mp 247-249 °C; IR (KBr) 3284, 3046, 1690,
1654, 1628, 1612, 1538, 1503, 1391, 1335, 1318, 1249, 1156,
863, 721, 692 cm-1; 1H NMR (270 MHz, DMSO-d6) δ 10.48 (br
s, 1H), 10.36 (s, 1H), 9.94 (br s, 1H), 9.46 (br s, 1H), 8.17 (d,
2H, J ) 8.4 Hz), 7.90 (d, 2H, J ) 8.4 Hz), 7.52-7.49 (m, 2H),
7.05 (d, 1H, J ) 8.9 Hz), 4.36 (dd, 2H, J ) 2.4, 5.4 Hz), 3.49 (t,
1H, J ) 2.4 Hz), 2.86-2.75 (m, 3H), 2.44-2.30 (m, 3H), 2.20-
2.05 (m, 1H), 1.91-1.87 (m, 1H), 1.46-1.39 (m, 1H); 13C NMR
(22.4 MHz, DMSO-d6) δ 173.5, 163.8, 162.2, 139.0, 136.3, 135.7,
131.6, 130.6, 128.6, 128.4 (2C), 128.0 (2C), 120.8, 118.4, 77.3,
75.9, 40.3, 35.1, 32.2, 30.7, 28.5, 27.6; ESI-MS m/e 390 (M +
1)+. Anal. (C23H23N3O3 and 1.05HCl plus 0.5H2O) C, H, N,
Cl.
[7-[4-[N-(2-F u r ylm et h yl)a m id in o]b en za m id o]-1,2,3,4-
t et r a h yd r o-2-n a p h t h a len yl]a cet ic Acid Hyd r och lor id e
(34d ‚HCl). Following the procedure described for the prepa-
ration of 10a ‚HCl, the title compound was prepared in 81%
yield from the ester 33d ‚HCl: mp 172-174 °C; IR (KBr) 3035,
2924, 1702, 1672, 1624, 1596, 1541, 1507, 1419, 1339, 1151,
1018, 860, 815, 746, 705 cm-1; 1H NMR (270 MHz, DMSO-d6)
δ 12.10-11.90 (broad peak, 1H), 10.60-10.40 (broad peak, 1H),
10.36 (s, 1H), 1.00-9.40 (broad peak, 2H), 8.15 (d, 2H, J )
8.2 Hz), 7.88 (d, 2H, J ) 8.2 Hz), 7.72-7.71 (m, 1H), 7.51-
7.48 (m, 2H), 7.06 (d, 1H, J ) 8.2 Hz), 6.59 (d, 1H, J ) 2.9
Hz), 6.49 (dd, 1H, J ) 1.7, 2.9 Hz), 4.74 (s, 2H), 2.87-2.75 (m,
3H), 2.46-2.27 (m, 3H), 2.20-2.05 (m, 1H), 1.93-1.89 (m, 1H),
1.48-1.37 (m, 1H); 13C NMR (22.4 MHz, DMSO-d6) δ 173.5,
163.9, 162.3, 148.3, 143.2, 138.9, 136.3, 135.7, 131.6, 130.8,
128.6, 128.4 (2C), 128.0 (2C), 120.9, 118.5, 110.6, 109.2, 40.2,
39.3, 35.1, 30.8, 28.5, 27.7; ESI-MS m/e 432 (M + 1)+. Anal.
(C25H25N3O4 and HCl plus 0.2H2O) C, H, N, Cl.
Eth yl [7-[4-(Mor ph olin ofor m im idoyl)ben zam ido]-1,2,3,4-
tetr a h yd r o-2-n a p h th a len yl]a ceta te Hyd r och lor id e (33e‚
HCl). The title compound was prepared from 11a and
morpholine in 75% yield following the procedure described for
the preparation of 33a ‚HCl: mp 242-244 °C; IR (KBr) 3023,
1731, 1668, 1613, 1535, 1505, 1418, 1322, 1266, 1159, 1114,
1
1068, 1019, 869, 704 cm-1; H NMR (270 MHz, DMSO-d6) δ
10.35 (s, 1H), 9.70 (br s, 2H), 8.18 (d, 2H, J ) 8.2 Hz), 7.77 (d,
2H, J ) 8.2 Hz), 7.51-7.49 (m, 2H), 7.05 (d, 1H, J ) 8.9 Hz),
4.10 (q, 2H, J ) 7.1 Hz), 3.76-3.31 (broad peak, 8H), 2.86-
2.75 (m, 3H), 2.44-2.35 (m, 3H), 2.20-2.05 (m, 1H), 1.91-
1.87 (m, 1H), 1.49-1.38 (m, 1H), 1.21 (t, 3H, J ) 7.1 Hz); 13
C
NMR (22.4 MHz, DMSO-d6) δ 172.0, 164.0, 163.2, 137.8, 136.5,
135.7, 131.4 (2C), 128.4 (5C), 120.8, 118.5, 65.2 (2C), 59.7, 48.4
(2C), 40.0, 35.1, 30.9, 28.5, 27.6, 14.1; CI-MS m/e 450 (M +
1)+. Anal. (C26H31N3O4 and 1.03HCl plus 0.2H2O) C, H, N,
Cl.
E t h yl [6-[4-[N-(2-P r op yn yl)a m id in o]b en za m id o]-3,4-
dih ydr o-2H-1-ben zopyr an -3-yl]acetate Hydr och lor ide (35‚
HCl). The title compound was prepared from 11c and
propargylamine in 65% yield following the procedure described
for the preparation of 33a ‚HCl: mp 247-249 °C; IR (KBr)
3226, 3044, 1729, 1667, 1621, 1551, 1501, 1327, 1255, 1217,
1
1158, 1031, 856, 822, 760 cm-1; H NMR (270 MHz, DMSO-
d6) δ 10.51 (br s, 1H), 10.35 (s, 1H), 9.96 (br s, 1H), 9.50 (br s,
1H), 8.16 (d, 2H, J ) 8.2 Hz), 7.90 (d, 2H, J ) 8.2 Hz), 7.51 (d,
1H, J ) 2.3 Hz), 7.47 (dd, 1H, J ) 2.3, 8.9 Hz), 6.75 (d, 1H, J
) 8.9 Hz), 4.38-4.36 (m, 2H), 4.18 (d, 1H, J ) 10.9 Hz) 4.11
(q, 2H, J ) 7.1 Hz), 3.85-3.78 (m, 1H), 3.51 (s, 1H), 2.92-
2.85 (m, 1H), 2.55-2.33 (m, 4H), 1.21 (t, 3H, J ) 7.1 Hz); 13
C
NMR (22.4 MHz, DMSO-d6) δ 171.4, 163.6, 162.3, 150.4, 139.1,
131.6, 130.6, 128.4 (2C), 127.9 (2C), 122.2, 120.7, 120.3, 115.8,
77.3, 75.9, 68.8, 59.9, 35.3, 32.2, 30.2, 28.7, 14.0; CI-MS m/e
420 (M + 1)+. Anal. (C24H25N3O4 and HCl) C, H, N, Cl.
Eth yl [6-[4-(Mor p h olin ofor m im id oyl)ben za m id o]-3,4-
d ih yd r o-2H -1-b en zop yr a n -3-yl]a cet a t e H yd r och lor id e
((RS)-4‚HCl). The title compound was prepared from 11c and
morpholine in 61% yield following the procedure described for
the preparation of 33a ‚HCl: mp 251-253 °C; IR (KBr) 3432,
3218, 3028, 1730, 1662, 1619, 1538, 1499, 1422, 1252, 1221,
1
1110, 1019, 702 cm-1; H NMR (400 MHz, DMSO-d6) δ 10.41
(s, 1H), 9.82 (br s, 1H), 9.78 (s, 1H), 8.19 (d, 2H, J ) 8.3 Hz),
7.76 (d, 2H, J ) 8.3 Hz), 7.55 (d, 1H, J ) 2.5 Hz), 7.49 (dd,
1H, J ) 2.5, 8.8 Hz), 6.75 (d, 1H, J ) 8.8 Hz), 4.18 (d, 1H, J
) 10.7 Hz), 4.11 (q, 2H, J ) 7.1 Hz), 3.95-3.20 (m, 9H), 2.92-
2.86 (m, 1H), 2.56-2.35 (m, 4H), 1.21 (t, 3H, J ) 7.1 Hz); 13
C
[7-[4-(Mor p h olin ofor m im id oyl)ben za m id o]-1,2,3,4-tet-
r a h yd r o-2-n a p h th a len yl]a cetic Acid Hyd r och lor id e (34e‚
HCl). Following the procedure described for the preparation
of 10a ‚HCl, the title compound was prepared in 55% yield from
the ester 33e‚HCl: mp 243-245 °C; IR (KBr) 3278, 3025, 1716,
1684, 1635, 1593, 1542, 1420, 1340, 1266, 1119, 1013, 872, 718
NMR (100.4 MHz, DMSO-d6) δ 171.6, 163.9, 163.5, 150.6,
138.1, 131.8, 131.5, 128.6 (2C), 128.4 (2C), 122.3, 120.9, 120.4,
116.0, 69.0, 65.7, 64.9, 60.1, 49.9, 47.2, 35.5, 30.4, 28.9, 14.2;
CI-MS m/e 452 (M + 1)+. Anal. (C25H29N3O5 and HCl) C, H,
N, Cl.
1
[7-[4-[N-(n -P r opyl)am idin o]ben zam ido]-1,2,3,4-tetr ah y-
d r o-2-n a p h t h a len yl]a cet ic Acid H yd r och lor id e (34a ‚
HCl). Following the procedure described for the preparation
of 10a ‚HCl, the title compound was prepared in 85% yield from
the ester 33a ‚HCl: mp >250 °C; IR (KBr) 3340, 3142, 1706,
1673, 1623, 1593, 1538, 1508, 1418, 1336, 1251, 1167, 1016,
cm-1; H NMR (270 MHz, DMSO-d6) δ 10.36 (s, 1H), 10.10-
9.40 (broad peak, 2H), 8.18 (d, 2H, J ) 8.6 Hz), 7.76 (d, 2H, J
) 8.6 Hz), 7.52-7.50 (m, 2H), 7.05 (d, 1H, J ) 8.9 Hz), 3.76-
3.33 (m, 8H), 2.87-2.75 (m, 3H), 2.46-2.28 (m, 3H), 2.20-
2.03 (m, 1H), 1.93-1.89 (m, 1H), 1.49-1.34 (m, 1H); 13C NMR
(22.4 MHz, DMSO-d6) δ 173.6, 164.0, 163.2, 137.8, 136.3, 135.7,
131.6, 131.4, 128.4 (5C), 120.8, 118.4, 65.2 (2C), 48.5 (br s, 2C),
40.2, 35.1, 30.8, 28.6, 27.6. Anal. (C24H27N3O4 and 1.05HCl
plus 0.5H2O) C, H, N, Cl.
921, 860, 829, 710 cm-1 1H NMR (270 MHz, DMSO-d6) δ
;
12.30-11.80 (broad peak, 1H), 10.41 (s, 1H), 10.02 (br s, 1H),
9.65 (br s, 1H), 9.33 (br s, 1H), 8.18 (d, 2H, J ) 8.2 Hz), 7.91
(d, 2H, J ) 8.2 Hz), 7.54-7.52 (m, 2H), 7.05 (d, 1H, J ) 8.2
Hz), 3.42 (t, 2H, J ) 7.1 Hz), 2.87-2.75 (m, 3H), 2.46-2.28
(m, 3H), 2.15-2.05 (m, 1H), 1.93-1.89 (m, 1H), 1.76-1.63 (m,
2H), 1.46-1.33 (m, 1H), 0.98 (t, 3H, J ) 7.2 Hz); 13C NMR
(22.4 MHz, DMSO-d6) δ 173.5, 163.9, 162.0, 138.7, 136.3, 135.7,
131.6, 131.2, 128.6, 128.3 (2C), 127.9 (2C), 120.8, 118.4, 44.2,
40.3, 35.1, 30.8, 28.6, 27.6, 20.8, 11.1. Anal. (C23H27N3O3 and
1.15HCl plus 0.5H2O) C, H, N, Cl.
[7-[4-[N-(2-P r op yn yl)a m id in o]ben za m id o]-3,4-d ih yd r o-
2H-1-ben zop yr a n -3-yl]a cetic Acid Hyd r och lor id e (36‚
HCl). Following the procedure described for the preparation
of 10a , the title compound was prepared in 75% yield from
the ester 35‚HCl: mp 173-175 °C; IR (KBr) 3493, 3425, 3365,
3257, 2126, 1717, 1680, 1647, 1619, 1549, 1497, 1425, 1251,
1218, 1155, 1129, 1031, 861, 827, 697 cm-1; 1H NMR (270 MHz,
DMSO-d6) δ 12.27 (s, 1H), 10.49 (br s, 1H), 10.33 (s, 1H), 9.95

4050 J ournal of Medicinal Chemistry, 1998, Vol. 41, No. 21
Okumura et al.
(br s, 1H), 9.48 (br s, 1H), 8.16 (d, 2H, J ) 8.2 Hz), 7.90 (d,
2H, J ) 8.2 Hz), 7.50-7.44 (m, 2H), 6.75 (d, 1H, J ) 8.6 Hz),
4.36 (s, 2H), 4.20-4.16 (m, 1H), 3.85-3.78 (m, 1H), 3.82 (s,
1H), 2.92-2.86 (m, 1H), 2.57-2.23 (m, 4H); 13C NMR (22.4
MHz, DMSO-d6) δ 172.9, 163.6, 162.3, 150.5, 139.0, 131.5,
130.6, 128.3 (2C), 127.9 (2C), 122.3, 120.9, 120.3, 115.8, 77.3,
75.9, 69.0, 35.5, 32.2, 30.3, 28.6; CI-MS m/e 392 (M + 1)+. Anal.
(C22H21N3O4 and HCl) C, H, N, Cl.
dried over MgSO4 and concentrated in vacuo to afford a crude
amide. Purification by column chromatography (SiO2, CHCl3/
EtOAc ) 7/1) gave 1.12 g (64%) of 39. Recrystallization from
2-propanol gave an analytically pure sample as a yellow
solid: mp 141-143 °C. Anal. (C27H27N3O8S) C, H, N.
Eth yl (S)-(6-Am in o-3,4-d ih yd r o-2H-1-ben zop yr a n -3-yl)-
a ceta te ((S)-27). To a solution of HCl (approximately 50 g)
in absolute EtOH (200 mL) was added (S)-37 (20.0 g, 62.2
mmol) by portions. The mixture was stirred for 4 h at 60 °C
and concentrated in vacuo. The residue was dissolved in
absolute EtOH (350 mL), and H2SO4 (3.5 g) was added. The
mixture was refluxed for 4 h, neutralized by 10% K2CO3
solution, and concentrated in vacuo. The residual solid was
diluted with CHCl3, and the organic phase was separated,
dried over MgSO4, filtered, and concentrated in vacuo. Puri-
fication of the residue by column chromatography (SiO2,
CHCl3/MeOH ) 100/3) afforded 11.5 g (79%) of (S)-27 as a pale-
[6-[4-(Mor ph olin ofor m im idoyl)ben zam ido]-3,4-dih ydr o-
2H-1-ben zop yr a n -3-yl]a cetic Acid Hyd r och lor id e ((RS)-
3‚HCl). Following the procedure described for the preparation
of 10a ‚HCl, the title compound was prepared in 50% yield from
the ester (RS)-4‚HCl: mp 245-247 °C; IR (KBr) 3423, 3229,
3030, 1715, 1663, 1621, 1540, 1499, 1424, 1256, 1220, 1112
cm-1 1H NMR (400 MHz, DMSO-d6) δ 12.60-12.00 (broad
;
peak, 1H), 10.30 (s, 1H), 9.79 (br s, 2H), 8.16 (d, 2H, J ) 8.6
Hz), 7.76 (d, 2H, J ) 8.2 Hz), 7.53-7.43 (m, 2H), 6.75 (d, 1H,
J ) 8.6 Hz), 4.18 (d, 1H, J ) 9.8 Hz), 3.85-3.32 (m, 9H), 2.90-
2.86 (m, 1H), 2.57-2.26 (m, 4H); 13C NMR (100.4 MHz, DMSO-
d6) δ 173.2, 163.9, 163.5, 150.7, 138.1, 131.8, 131.6, 128.6 (2C),
128.4 (2C), 122.4, 121.1, 120.5, 116.1, 69.2, 65.6, 65.1, 49.9,
47.2, 35.8, 30.5, 28.8; ESI-MS m/e 424 (M + 1)+. Anal.
(C23H25N3O5 and HCl) C, H, N, Cl.
yellow solid: mp 75-76 °C; [R]20 -26.5° (c 1.02, MeOH).
D
Anal. (C13H17NO2) C, H, N.
Eth yl (R)-(6-a m in o-3,4-d ih yd r o-2H-1-ben zop yr a n -3-yl)-
a ceta te ((R)-27): mp 75-76 °C; [R]20D +26.1° (c 1.03, MeOH).
Anal. (C13H17NO2) C, H, N.
E t h yl (S)-[6-(4-Cya n ob en za m id o)-3,4-d ih yd r o-2H -1-
ben zop yr a n -3-yl]a ceta te ((S)-11c). According to the pro-
cedure for the preparation of 11c, the title compound was
prepared from (S)-27 in 93% yield as a pale-yellow solid: mp
Meth yl [6-(ter t-Bu toxyca r boxa m id o)-3,4-d ih yd r o-2H-
1-ben zop yr a n -3-yl]a ceta te ((RS)-37). According to a simi-
lar hydrogenation procedure in MeOH described for the
preparation of 17a , methyl (6-amino-3,4-dihydro-2H-1-ben-
zopyran-3-yl)acetate was prepared from 26 in 62% yield as a
white solid: mp 107-109 °C. Anal. (C12H15NO3) C, H, N.
To a solution of the preceding amino compound (21.6 g, 97.6
mmol) in EtOAc (100 mL) was added di-tert-butyl dicarbonate
(22.7 g, 104.1 mmol). The mixture was stirred for 6 h at room
temperature and washed with 10% citric acid (2 × 50 mL) and
brine (50 mL). The organic phase was dried over Na2SO4 and
concentrated in vacuo to afford an oily residue. Purification
by column chromatography (SiO2, n-hexane/EtOAc ) 5/1)
followed by trituration from n-hexane gave 28.1 g (90%) of
(RS)-37 as a white solid: mp 86-88 °C. Anal. (C17H23NO5)
C, H, N.
Op tica l Resolu tion of (RS)-37 by Ch ir a l HP LC. Pre-
parative HPLC was performed on a Shimadzu LC-8A system.
(RS)-37 (500 mg/injection) was submitted to semipreparative
HPLC containing a CHIRALCEL-OD column (20 mm i.d. ×
300 mm), eluted (20 mL/min) at 20 °C with a mixture of
n-hexane/EtOH (5/1), and detected at 254 nm. The first peak
at 10.2 min was collected to afford (R)-37 (210-220 mg/
injection) as a white solid: mp 84-85 °C; [R]20D +22.6° (c 1.05,
MeOH). Anal. (C17H23NO5) C, H, N.
148-149 °C; [R]20 -25.9° (c 1.00, 1,4-dioxane). Anal.
D
(C21H20N2O4) C, H, N.
E t h yl (R)-[6-(4-cya n ob en za m id o)-3,4-d ih yd r o-2H -1-
ben zop yr a n -3-yl]a ceta te ((R)-11c): mp 148-149 °C; [R]20
D
+25.5° (c 0.99, 1,4-dioxane). Anal. (C21H20N2O4) C, H, N.
Eth yl (S)-[6-[4-(Mor p h olin ofor m im id oyl)ben za m id o]-
3,4-d ih yd r o-2H -1-b en zop yr a n -3-yl]a cet a t e H yd r och lo-
r id e (MS-180, (S)-4‚HCl). Following the procedure described
for the preparation of 33a ‚HCl, the title compound was
prepared in 90% yield from the nitrile (S)-11c as a pale-yellow
solid: mp 242-244 °C; [R]20 -14.5° (c 1.0, MeOH). The
D
enantiomeric purity was found to be greater than 99.5% ee by
HPLC analysis on CHIRAL-AGP column (ChromTech AB,
Ha¨gelsten, Sweden; 4.0 mm i.d. × 100 mm) with a flow rate
of 0.9 mL/min at 25 °C and a mobile phase of 0.01 M KH2PO4
(pH 7.0) and 1 mM N,N-dimethyloctylamine. Anal. (C25H29
-
N3O5 and HCl) C, H, N, Cl.
Eth yl (R)-[6-[4-(m or p h olin ofor m im id oyl)ben za m id o]-
3,4-d ih yd r o-2H-1-ben zop yr a n -3-yl]a ceta te h yd r och lor id e
((R)-4‚HCl): mp 242-244 °C; [R]20 +14.0° (c 1.0, MeOH).
D
Anal. (C25H29N3O5 and HCl) C, H, N, Cl.
(S)-[6-[4-(Mor p h olin ofor m im id oyl)ben za m id o]-3,4-d i-
h yd r o-2H-1-ben zop yr a n -3-yl]a cetic Acid Hyd r och lor id e
((S)-3‚HCl). Following the procedure described for the prepa-
ration of 10a ‚HCl, the title compound was prepared in 92%
yield from the ester (S)-4‚HCl as a yellow solid: mp 242-244
The second peak at 22.6 min was collected to afford (S)-37
(205-214 mg/injection) as a white solid: mp 84-85 °C; [R]20
D
-22.1° (c 0.98, MeOH). Anal. (C17H23NO5) C, H, N.
Enantiomeric purities of (R)-37 and (S)-37 were found to
be greater than 99.5% ee by analytical HPLC (CHIRALCEL-
OD (4.6 mm i.d. × 250 mm), n-hexane/EtOH ) 5/1, 0.7 mL/
min, 35 °C, 254 nm).
°C; [R]25 -9.3° (c 1.0, H2O). Enantiomeric purity of (S)-3‚
D
HCl was found to be greater than 99.5% ee by HPLC analysis
on CHIRAL-AGP column (4.0 mm i.d. × 100 mm) with a flow
rate of 0.7 mL/min at 30 °C and a mobile phase of 0.01 M KH2-
PO4 (pH 5.6). Anal. (C23H25N3O5 and HCl plus 1.05H2O) C,
H, N, Cl.
Met h yl
[6-[2(S)-[(4-Nit r op h en ylsu lfon yl)a m in o]-3-
p h en ylp r op a n a m id o]-3,4-d ih yd r o-2H-1-ben zop yr a n -3(S)-
yl]a ceta te (39). To a solution of HCl (22 g) in EtOH (180
mL) was added (S)-37 (15.0 g, 48.5 mmol) at room tempera-
ture. The mixture was stirred for 5 h at room temperature
and concentrated in vacuo to afford a white solid, which was
dissolved in CHCl3 (100 mL). The solution was washed with
aqueous NaHCO3 solution and extracted with CHCl3. The
organic phase was dried over MgSO4 and concentrated in vacuo
to afford 10.14 g (94%) of methyl (S)-(6-amino-3,4-dihydro-2H-
1-benzopyran-3-yl)acetate.
To a solution of 0.70 g (3.16 mmol) of the preceding aniline,
0.9 mL (12.2 mmol) of triethylamine, and 60 mg (0.49 mmol)
of 4-(dimethylamino)pyridine in 10 mL of CHCl3 was added
1.4 g (3.8 mmol) of N-(4-nitrophenylsulfonyl)-L-phenylalanyl
chloride (Tokyo Chemical Industry Co. Ltd.) at room temper-
ature, and the mixture was stirred for 12 h at room temper-
ature. After addition of aqueous NaHCO3 solution, the
mixture was extracted with CHCl3. The organic phase was
(R)-[6-[4-(Mor p h olin ofor m im id oyl)ben za m id o]-3,4-d i-
h yd r o-2H-1-ben zop yr a n -3-yl]a cetic a cid h yd r och lor id e
((R)-3‚HCl): mp 242-244 °C; [R]25 +9.1° (c 1.0, H2O). Anal.
D
(C23H25N3O5 and HCl plus H2O) C, H, N, Cl.
Com p u ta tion a l Meth od s. Molecu la r Mod elin g a n d
P h a r m a cop h or e Ma p p in g. All molecular modeling studies
were performed on
a Silicon Graphics IMPACT R10000
graphic workstation using the molecular modeling software
package SYBYL version 6.3 from TRIPOS Associates (St.
Louis, MO). Geometry optimization was carried out using
TRIPOS force field31 with Gasteiger-Hu¨ckel charge.32 Con-
formational databases were developed for each compound
using the Random Search evaluation subroutine33 of SYBYL
6.3. In each case, the energy cutoff for conformers was
designated as 292.88 kJ /mol. Each search resulted in a
molecular database that was representative of the conforma-

New GPIIb-IIIa Antagonists
J ournal of Medicinal Chemistry, 1998, Vol. 41, No. 21 4051
tional space that each analogue occupies within the specified
energy window. The DISCO algorithm was used to find
multipoint pharmacophoric models.
at room temperature. After the plate was washed, 200 µL of
o-phenylenediamine (0.4 mg/mL in 0.05 M citrate-phosphate
buffer (pH 5.0), containing 0.012% H2O2) was added to develop
color for 20-40 min. The reaction was terminated by addition
of 0.3 M H2SO4 (50 µL), and absorbance at 490 nm was
measured. The difference between total (in the absence of the
inhibitor) and nonspecific (in the presence of 500 µg/mL
fibrinogen) binding was designated as specific binding. IC50
values were determined from the dose-response curves of the
inhibition percent plotted against the log-concentration of the
test compounds.
Ex Vivo In h ibition Stu d ies in Gu in ea P ig. Test com-
pounds (Tables 3 and 5) suspended or dissolved in saline
containing 0.5% Tween 80 were orally administered (37 µmol/
kg) to male guinea pigs starved overnight. The guinea pigs
were anesthetized with pentobarbital 1 h after the administra-
tion. Blood sample was collected by venipuncture, and PPP
and PRP were obtained as described above. The platelet count
of PRP was adjusted to 3.0 × 108 platelets/mL by the addition
of PPP. The PRP (270 µL) was preincubated for 2 min in the
aggregometer, and successively aggregation was measured by
addition of 30 µL of ADP (final concentration 5 µM). Three
vehicle-treated animals were used as a control group at each
experiment. The percentage inhibition of platelet aggregation
in drug-treated animals was determined by comparison with
the aggregation in the control group.
The concentration of the active species in PPP was esti-
mated by a bioassay as described by Salyers et al.38 with
modifications. PPP from treated guinea pigs was diluted with
PPP from nontreated donor guinea pigs and mixed with PRP
from nontreated donors. Platelet aggregation was determined
as described above. The concentration of active species in PPP
was estimated by comparing the aggregation observed with a
standard curve prepared using PPP spiked with known
amounts of the active species of administered prodrug.
Ex Vivo Stu d ies in Dog. MS-180 ((S)-4‚HCl) was orally
administered by capsule to conscious beagle dogs starved
overnight. Blood samples (4.5 mL) were withdrawn via
venipuncture into plastic syringes containing 0.5 mL of 3.8%
trisodium citrate at predetermined times before and after
dosing. PRP and PPP were prepared by centrifuging blood
samples. Aggregation was induced by the addition of 30 µL
of ADP (final concentration 200 µM) to 270 µL of the PRP,
and the percent inhibition for individual dogs was calculated
by comparing the aggregation of predosing sample.
The concentration of the active species ((S)-3) was estimated
from the inhibition of fibrinogen binding to GPIIb-IIIa. After
2-fold dilution of PPP with TBS, an equal volume of MeCN
was added, and the mixture was centrifuged at 19000g for 5
min. The supernatant was removed and further diluted with
TBS containing 0.5% BSA. The inhibitory activity of the
supernatant to fibrinogen-GPIIb-IIIa binding was determined
as described above. The concentration of (S)-3 in PPP was
estimated using the standard curve of inhibition established
with PPP from untreated dogs that had been spiked with
known amounts of (S)-3. Reliability of this assay method was
confirmed by the result that concentrations of (S)-3 measured
both by this method and by HPLC were almost identical in
plasma of four dogs to which MS-180 ((S)-4‚HCl) had been
orally administered at 5 mg/kg.
CoMF A a n d P LS Regr ession An a lysis. CoMFA studies
were carried out using the QSAR option of SYBYL version 6.3.
The partial atomic charges used in CoMFA were computed
using the semiempirical method PM3 implemented in MO-
PAC93.34 Single-point calculations were performed on the
geometries previously optimized with SYBYL/TRIPOS force
field. The steric and electrostatic probe-ligand interaction
energies (kJ /mol) were calculated with the Lennard-J ones and
Coulomb potential functions of the TRIPOS force field using
a carbon sp3 probe atom, having a 1.0 charge. The steric and
electrostatic energies were truncated at 125.52 kJ /mol. The
dimensions of CoMFA lattice were determined through an
automatic procedure, featured by the SYBYL/CoMFA routine,
which extends the lattice walls beyond the dimensions of each
structure by 4.0 Å in all directions. The lattice spacing was
set to a value of 2.0 Å. The PLS regression analysis were
performed with the SYBYL/QSAR routine at default setting.
P h a r m a cology. In Vitr o In h ibition of P la telet Ag-
gr ega tion . The inhibition of platelet aggregation was deter-
mined as essentially described by Nicholsonl et al.35 Venous
blood was obtained from anesthetized male guinea pigs or male
healthy human volunteers. Blood was anticoagulated by
addition of 3.8% sodium citrate (1/9 ) citrate/blood). Platelet-
rich plasma (PRP) was prepared by centrifugation at 120g for
15 min. The remaining blood was centrifuged at 1200g for 15
min, and platelet-poor plasma (PPP) was removed. The
platelet count in PRP was adjusted to 2.5-3.0 × 108 platelets/
mL with PPP. After incubation of PRP (240 µL) at 37 °C for
2 min in an aggregometer (hema tracer 1, NKK Co., J apan),
30 µL of test compound (Table 2, 4, and 6) or vehicle was added
to PRP. A further 2 min later, 30 µL of ADP (final concentra-
tion 5 µM) was added to induce platelet aggregation. The
inhibition percentage was obtained by comparing the maxi-
mum aggregation of treated PRP with that of the control, and
then a test compound concentration giving a 50% inhibition
(IC50) value was estimated.
In h ibition of F ibr in ogen Bin d in g to Im m obilized Hu -
m a n GP IIb-IIIa . The binding of fibrinogen to immobilized
GPIIb-IIIa was performed using a modification of the method
of Charo et al.36 GPIIb-IIIa was extracted from concentrated
and lyophilized human platelets (Organon Teknika Co.) sus-
pended in 10 mM Tris-HCl, 150 mM NaCl, 1% Triton X-100,
1 mM CaCl2, 10 µM leupeptin, and 1 mM phenylmethane-
sulfonyl fluoride (pH 7.4). The suspension was incubated for
1 h at 4 °C, and centrifuged at 30000g for 15 min. GPIIb-IIIa
was purified from the supernatant using concanavalin A-
Sepharose, heparin-Sepharose, and Sephacryl S-300 according
to the method of Phillips et al.37 Human fibrinogen (glade L,
KabiVitrum) was further purified by Sepharose CL-6B gel
chromatography and lysine-Sepharose affinity chromatogra-
phy. Purified fibrinogen was incubated with NHC-LC-biotin
(Pierce Co.), and then the mixture was dialyzed against Tris-
buffered saline (TBS; 20 mM Tris-HCl, 150 mM NaCl, 1 mM
CaCl2, 1 mM MgCl2, pH 7.4) to obtain biotinylated fibrinogen.
Protein concentrations of the GPIIb-IIIa and the biotinylated
fibrinogen preparations were determined by Bradford’s method
(Bio-Rad).
Ack n ow led gm en t. We would like to thank the
members of M.C. Research Center, Inc. for their careful
characterization of the compounds reported in this
manuscript. In particular, we are grateful to Takatoshi
Mitsuishi for his helpful information about the charac-
terization of compounds and to Dr. Masayoshi Maehara
for the X-ray crystallographic analysis and NMR spectra
that are reported.
Su p p or tin g In for m a tion Ava ila ble: 1H and 13C NMR
spectra for compounds 11a -i, 14b,c, 15b,c, 16b,c, 17a -c, 18-
24, 26, 27, 30, 32, (RS)-37, and 39; X-ray crystallographic
analysis data of compound 39 (18 pages). Ordering informa-
tion is given on any current masthead page.
A 96-well microtiter plate was coated with 100 µL/well of
purified GPIIb-IIIa diluted to 1.5 µg/mL with TBS containing
0.0005% Triton X-100 for 24 h at 4 °C. After the plate was
washed with a washing solution (TBS containing 0.01% Tween
20), TBS containing 3.5% bovine serum albumin (BSA; 200
µL/well) was added and incubated for 1 h at room temperature.
The test compound (Tables 4 and 6) was dissolved in DMSO
at 10 mM, further diluted with TBS, and mixed with an equal
volume of biotinylated fibrinogen (2 µg/mL) in TBS containing
1% BSA. After the plate was washed, the mixture (100 µL/
well) was added and incubated for 24 h at room temperature.
The plate was thereafter washed, and peroxidase-labeled
streptavidin (Amersham) diluted 3000 times with TBS (100
µL/well) was added. The mixture was incubated for 30 min

4052 J ournal of Medicinal Chemistry, 1998, Vol. 41, No. 21
Okumura et al.
Antiplatelet and Antithrombotic Efficacy of DMP 728, a Novel
Platelet GPIIb/IIIa Receptor Antagonist. Circulation 1994, 89,
3-12.
Refer en ces
(1) Fitzgerald, D. J .; Roy, L.; Catella, F.; Fitzgerald, G. A. Platelet
Activation in Unstable Coronary Disease. N. Engl. J . Med. 1986,
315, 983-989.
(2) Scharf, R. E.; Harker, L. A. Thrombosis and Atherosclerosis:
Regulatory Role of Interactions Among Blood Components and
Endothelium. Blut 1987, 55, 131-144.
(3) Peerschke, E. I.; Zucker, M. B.; Grant, R. A.; Egan, J . J .; J ohnson,
M. M. Correlation between Fibrinogen Binding to Human
Platelets and Platelet Aggregability. Blood 1980, 55, 841-847.
(4) Pytela, R.; Pierschbacher, M. D.; Ginsberg, M. H.; Plow, E. F.;
Ruoslahti, E. Platelet Membrane Glycoprotein IIb/IIIa: Member
of a Family of Arg-Gly-Asp-Specific Adhesion Receptors. Science
1986, 231, 1559-1562.
(19) Nicholson, N. S.; Panzer-Knodle, S. G.; Salyers, A. K.; Taite, B.
B.; Szalony, J . A.; Haas, N. F.; King, L. W.; Zablocki, J . A.; Keller,
B. T.; Broschat, K.; Engleman, V. W.; Herin, M.; J acqmin, P.;
Feigen, L. P. SC-54684A: An Orally Active Inhibitor of Platelet
Aggregation. Circulation 1995, 91, 403-410.
(20) Himmelsbach, F.; Austel, V.; Guth, B.; Linz, G.; Mu¨ller, T. H.;
Piper, H.; Seewaldt-Becker, E.; Weisenberger, H. Design of
Highly Potent Nonpeptidic Fibrinogen Receptor Antagonists.
Eur. J . Med. Chem. 1995, 30, 243s-254s.
(21) Diaz-Arauzo, H.; Kohler, K.; Hagen, T.; Cook, J . Synthetic and
Computer Assisted Analysis of Pharamacophore for Agonists at
Benzodiazepin Receptors. Life Sci. 1991, 49, 207-216.
(22) Tripos Associates, 1699 South Hanley Rd., Suite 303, St. Louis,
MO 63144.
(23) Bach, A. C., II; Eyermann, C. J .; Gross, J . D.; Bower, M. J .;
Harlow, R. L.; Weber, P. C.; DeGrado, W. F. Structural Studies
of a Family of High Affinity Ligands for GPIIb/IIIa. J . Am. Chem.
Soc. 1994, 116, 3207-3219.
(24) Gerlach, U.; Wollmann, T. Synthesis of Benzoic and Tetralone
Carboxylic Acid Esters from Phenols by Palladium Catalyzed
Alkoxy/Aryloxy. Carbonylation. Tetrahedron Lett. 1992, 33,
5499-5502.
(25) Nichols, D. E.; Cassady, J . M.; Persons, P. E.; Yeung, M. C.;
Clemens, J . A.; Smalstig, E. B. Synthesis and Evaluation of N,N-
Di-n-propyltetrahydrobenz[f]indol-7-amine and Related Conge-
ners as Dopaminergic Agonists. J . Med. Chem. 1989, 32, 2128-
2134.
(5) Hawiger, J .; Kloczewiak, M.; Bednarek, M. A.; Timmons, S.
Platelet Receptor Recognition Domains on the R Chain of Human
Fibrinogen: Structure-Function Analysis. Biochemistry 1989,
28, 2909-2914.
(6) Bennet, J . S.; Shattil, S. J .; Power, J . W.; Gartner, T. K.
Interaction of Fibrinogen with Its Platelet Receptor. J . Biol.
Chem. 1988, 263, 12948-12953.
(7) Drug Data Rep. 1995, 17, 446-447.
(8) Tcheng, J . E.; Ellis, S. G.; Kleiman, N. S.; Harrington, R. A.;
Mick, M. J .; Navetta, F. I.; Worley, S.; Smith, J . E.; Kereiakes,
D. J .; Kitt, M. M.; Miller, J . A.; Sigmon, K. N.; Califf, R. M.;
Topol, E. J . Outcome of Patients Treated with the GP IIb-IIIa
Inhibitor Integrelin During Coronary Angioplasty: Results of
the IMPACT Study. Circulation 1993, 88, I-595, Abstract 3200.
(9) Barret, J . S.; Murphy, G.; Peerlinck, K.; De Lepeleire, I.; Gould,
R. J .; Panebianco, D.; Hand, E.; Deckmyn, H.; Vermylen, J .;
Arnout, J . Pharmacokinetics and Pharmacodynamics of MK-383,
a Selective Non-Peptide Platelet Glycoprotein-IIb/IIIa Receptor
Antagonist, in Healthy Men. Clin. Pharmacol. Ther. 1994, 56,
377-388.
(26) Strasser, M.; Cooper, P.; Dewald, B.; Payne, T. Design and
Synthesis of 5-Lipoxygenase Inhibitors. Helv. Chim. Acta 1988,
71, 1156-1176.
(27) Xue, C.-B.; Wityak, J .; Sielecki, T. M.; Pinto, D. J .; Batt, D. G.;
Cain, G. A.; Sworin, M.; Rockwell, A. L.; Roderick, J . J .; Wang,
S.; Orwat, M. J .; Frietze, W. E.; Bostrom, L. L.; Liu, J .; Higley,
C. A.; Rankin, F. W.; Tobin, A. E.; Emmett, G.; Lelka, G. K.;
Sze, J . Y.; Di Meo, S. V.; Mousa, S. A.; Thoolen, M. J .; Racanelli,
A. L.; Hausner, E. A.; Reilly, T. M.; DeGrado, W. F.; Wexler, R.
R.; Olson, R. E. Discovery of an Orally Active Series of Isoxazo-
line Glycoprotein IIb/IIIa Antagonists. J . Med. Chem. 1997, 40,
2064-2084.
(28) Ajao, J . F.; Bird, C. W. The Preparation and Oxidative Dimer-
ization of 2-Acetyl-7-hydroxy-1,2,3,4-tetrahydroisoquinoline. A
New Approach to Tetrahydroisoqinoline Synthesis. J . Heterocycl.
Chem. 1985, 22, 329-331.
(29) Echavarren, A. M.; Stille, J . K. Palladium-Catalyzed Coupling
of Aryl Triflates with Organostannanes. J . Am. Chem. Soc. 1987,
109, 5478-5486.
(30) Chen, Q.-Y.; Yang, Z.-Y. Palladium-Catalyzed Reaction of Phenyl
Fluoroalkanesulfonates with Alkynes and Alkenes. Tetrahedron
Lett. 1986, 27, 1171-1174.
(31) Clark, M.; Cramer, R. D., III; Opdenbosch, N. V. Validation of
the General Purpose Tripos 5.2 Force Field. J . Comput. Chem.
1989, 10, 982-1012.
(32) Gasteiger, J .; Marsili, M. Iterative Partial Equalization of
Orbital. Electronegativity-a Rapid Access to Atomic Charges.
Tetrahedron 1980, 36, 3219-3228.
(33) Saunders, M. Stochastic Exploration of Molecular Mechanics
Energy Surface. Hunting for the Global Minimum. J . Am. Chem.
Soc. 1987, 109, 3150-3152.
(34) Stewart, J . J . P. Optimization of Parameters for Semiempirical
Methos I. Methodol. J . Comput. Chem. 1989, 10, 209-220.
(35) Nicholson, N. S.; Panzer-Knodle, S. G.; Salyers, A. K.; Taite, B.
B.; King, L. W.; Miyano, M.; Gorczynski, R. J .; Williams, M. H.;
Zupec, M. E.; Tjoeng, F. S.; Adams, S. P.; Feigen, L. P. In Vitro
and In Vivo Effects of a Peptide Mimetic(SC-47643) of RGD as
an Antiplatelet and Antithrombotic Agent. Thromb. Res. 1991,
62, 567-578.
(36) Charo, I. F.; Nannizzi, L.; Phillips, D. R.; Hsu, M. A.; Scarbor-
ough, R. M. J . Biol. Chem. 1991, 25, 1415-1421.
(37) Phillips, D. R.; Fitzgerald, L.; Parise, L.; Steiner, B. Platelet
Membrane Glycoprotein IIb-IIIa Complex: Purification, Char-
acterization, and Reconstitution into Phospholipid Vesicles. In
Methods in Enzymology; Hawigar, J . J ., Eds.; Academic Press
Inc.: San Diego, 1992; Vol. 215, pp 244-263.
(10) The´roux, P.; Kouz, S.; Knudtson, M. L.; Kells, C.; Nasmith, J .;
Roy, L.; Dalle Ave, S.; Steiner, B.; Xiao, Z.; Rapold, H. J . A
Randomized Double-Blind Controlled Trial with the Non-Pep-
tidic Platelet GP IIb/IIIa Antagonist Ro 44-9883 in Unstable
Angina. Circulation 1994, 90, I-232, Abstract 1243.
(11) Zablocki, J . A.; Rico, J . G.; Garland, R. B.; Rogers, T. E.;
Williams, K.; Schretzman, L. A.; Rao, S. A.; Bovy, P. R.; Tjeong,
F. S.; Lindmark, R. J .; Toth, M. V.; Zupec, M. E.; McMackins,
D. E.; Adams, S. P.; Miyano, M.; Markos, C. S.; Milton, M. N.;
Paulson, S.; Herin, M.; J acqmin, P.; Nicholson, N. S.; Panzer-
Knodle, S. G.; Haas, N. F.; Page, J . D.; Szalony, J . A.; Taite, B.
B.; Salyers, A. K.; King, L. W.; Campion, J . G.; Feigen, L. P.
Potent in Vitro and in Vivo Inhibitors of Platelet Aggregation
Based Upon the Arg-Gly-Asp Sequence of Fibrinogen. (Ami-
nobenzamidino)succinyl (ABAS) Series of Orally Active Fibrino-
gen Receptor Antagonists. J . Med. Chem. 1995, 38, 2378-2394.
(12) Abood, N. A.; Flynn, D. L.; Garland, R. B.; Schretzman, L. A.;
Williams, K.; Zablocki, J . A.; Hockerman, S. L. 1-Amidinophenyl
Pyrrolidones Piperidinones Azetinones as Platelet Aggregation
Inhibitors. Int. Pat. Appl. WO94/22820, Oct 13, 1994.
(13) Weller, T.; Alig, L.; Beresini, M.; Blackburn, B.; Bunting, S.;
Hadva´ry, P.; Mu¨ller, M. H.; Knopp, D.; Levet-Trafit, B.; Lipari,
M. T.; Modi, N. B.; Mu¨ller, M.; Refino, C. J .; Schmitt, M.;
Scho¨nholzer, P.; Weiss, S.; Steiner, B. Orally Active Fibrinogen
Receptor Antagonists. 2. Amidoximes as Prodrugs of Amidines.
J . Med. Chem. 1996, 39, 3139-3147.
(14) Raddatz, P.; Gante, J . Recent Developments in Glycoprotein IIb/
IIIa Antagonists. Exp. Opin. Ther. Pat. 1995, 5 (11), 1163-1183.
(15) Cramer, R. D., III; Patterson, D. E.; Bunce, J . D. Comparative
Molecular Field Analysis (CoMFA). 1. Effect of Shape on Binding
of Steroids to Carrier Proteins. J . Am. Chem. Soc. 1988, 110,
5959-5967.
(16) Eldred, C. D.; Evans, B.; Hindley, S.; J udkins, B. D.; Kelly, H.
A.; Kitchin, J .; Lumley, P.; Porter, B.; Ross, B. C.; Smith, K. J .;
Taylor, N. R.; Wheatcroft, J . R. Orally Active Non-Peptide
Fibrinogen Receptor (GpIIb/IIIa) Antagonists: Identification of
4-[4-[4-(Aminoiminomethyl)phenyl]-1-piperazinyl]-1-piperidine-
acetic Acids as a Long-Acting, Broad-Spectrum Antithrombotic
Agent. J . Med. Chem. 1994, 37, 3882-3885.
(17) Sugihara, H.; Fukushi, H.; Miyawaki, T.; Imai, Y.; Terashita,
Z.; Kawamura, M.; Fujisawa, Y.; Kita, S. Novel Non-Peptide
Fibrinogen Receptor Antagonists. 1. Synthesis and Glycoprotein
IIb-IIIa Antagonistic Activities of 1,3,4-Trisubstituted 2-Oxopip-
erazine Derivatives Incorporating Side-Chain Functions of the
RGDF Peptide. J . Med. Chem. 1998, 41, 489-502.
(18) Mousa, S. A.; Bozarth, J . M.; Forsythe, M. S.; J ackson, S. M.;
Leamy, A.; Diemer, M. M.; Kapil, R. P.; Knabb, R. M.; Mayo, M.
C.; Pierce, S. K.; De Grado, W. F.; Thoolen, M. J .; Reilly, T. M.
(38) Salyers, A. K.; Szalony, J . A.; Taite, B. B.; Haas, N. F.; Mehrotra,
D. V.; Feigen, L. P.; Nicholson, N. S. A New Method for
Measurement of Plasma Concentration of Orally Active Glyco-
protain IIb/IIIa Antagonists. Thromb. Res. 1994, 75, 409-417.
J M9801859