GPIIb/IIIa integrin antagonists with the new conformational restriction unit, trisubstituted β-amino acid derivatives, and a substituted benzamidine structure

Article abstract of DOI:10.1021/jm980126v

Ethyl N-[3-(2-fluor-4-(thiazolidin-3-y](imino)methyl)benzoyl)amino-2,2- dimethylpentanoyl]piperidine-4-acetate 40 (NSL-96184) is a highly potent and orally active fibrinogen receptor antagonist, which is characterized by the presence of the trisubstituted β-amino acid residue, 3-ethyl-2,2-dimethyl- β-alanine. This compound was developed on the basis of the SAR study of N- [3-N-4-amidinobenzoyl)amino-2,2-dimethyl-3-phenylpropionyl]piperidine-4- acetic acid 1 (NSL-95301) with the derivatization focused on the central trisubstituted β-amino acid unit as well as the basic amidinobenzoyl unit, and the esterification of the carboxyl group for prodrug composition. Compound 1, which was reported in our previous study, was discovered by the application of combinatorial chemistry. The molecular modeling study suggests that the trisubstituted β-amino acid unit is responsible for fixing the molecule to its active conformation. Compound 40 showed an excellent profile in the in vitro and in vivo studies for its human platelet aggregation inhibitory activity and oral availability in guinea pigs. This oral availability largely depends on the modification of the amidino group with a cyclic secondary amine, i.e., thiazolidine in 40. In in vivo studies, the onset of the antiplatelet action of 40 is very fast after oral administration, whereas its duration of action is relatively short. These results suggest that 40 has an excellent therapeutic potential, especially for antithrombotic treatment in the acute phase. 3-Substituted-2,2-dimethyl- β-amino acid residues would serve as new and useful linear templates to restrict the conformational flexibility of peptidomimetics.

Full text of DOI:10.1021/jm980126v

J . Med. Chem. 1998, 41, 2345-2360
2345
GP IIb/IIIa In tegr in An ta gon ists w ith th e New Con for m a tion a l Restr iction Un it,
Tr isu bstitu ted â-Am in o Acid Der iva tives, a n d a Su bstitu ted Ben za m id in e
Str u ctu r e
Yoshio Hayashi,* J un Katada, Takeo Harada, Akira Tachiki, Kiyoko Iijima, Yoshimi Takiguchi,
Michiko Muramatsu, Hiroshi Miyazaki, Tohru Asari, Takeo Okazaki, Yoshimi Sato, Emiko Yasuda, Mako Yano,
Isao Uno, and Iwao Ojima†
Life Science Research Center, Advanced Technology Research Laboratories, Nippon Steel Corporation,
3-35-1 Ida, Nakahara-ku, Kawasaki 211-0035, J apan, and Department of Chemistry, State University of New York at
Stony Brook, New York 11794-3400
Received February 25, 1998
Ethyl N-[3-(2-fluoro-4-(thiazolidin-3-yl(imino)methyl)benzoyl)amino-2,2-dimethylpentanoyl]pi-
peridine-4-acetate 40 (NSL-96184) is a highly potent and orally active fibrinogen receptor
antagonist, which is characterized by the presence of the trisubstituted â-amino acid residue,
3-ethyl-2,2-dimethyl-â-alanine. This compound was developed on the basis of the SAR study
of N-[3-(N-4-amidinobenzoyl)amino-2,2-dimethyl-3-phenylpropionyl]piperidine-4-acetic acid 1
(NSL-95301) with the derivatization focused on the central trisubstituted â-amino acid unit
as well as the basic amidinobenzoyl unit, and the esterification of the carboxyl group for prodrug
composition. Compound 1, which was reported in our previous study, was discovered by the
application of combinatorial chemistry. The molecular modeling study suggests that the
trisubstituted â-amino acid unit is responsible for fixing the molecule to its active conformation.
Compound 40 showed an excellent profile in the in vitro and in vivo studies for its human
platelet aggregation inhibitory activity and oral availability in guinea pigs. This oral availability
largely depends on the modification of the amidino group with a cyclic secondary amine, i.e.,
thiazolidine in 40. In in vivo studies, the onset of the antiplatelet action of 40 is very fast
after oral administration, whereas its duration of action is relatively short. These results
suggest that 40 has an excellent therapeutic potential, especially for antithrombotic treatment
in the acute phase. 3-Substituted-2,2-dimethyl-â-amino acid residues would serve as new and
useful linear templates to restrict the conformational flexibility of peptidomimetics.
In tr od u ction
Undesired platelet aggregation and subsequent throm-
bosis are suspected to play an important role in various
vasoocclusive diseases such as unstable angina, myo-
cardial infarction, transient ischemic attacks and
stroke.1-3 The effective drugs to prevent such irregular
platelet aggregation are in serious demand. The fi-
brinogen receptor, glycoprotein (GP) IIb/IIIa, has re-
cently been one of the major targets for the development
of antagonists. Since the binding of fibrinogen to GPIIb/
IIIa is the final and common pathway for platelet
aggregation through the cross-linking of platelets, these
antagonists are likely to serve as a new class of
antithrombotic agents.4,5 In this binding process, it is
F igu r e 1. Superimpositioning study of the lower energy
conformations of 1.
known that (i) the RGD sequence(s) in fibrinogen is
responsible for the recognition of GPIIb/IIIa and (ii) the
guanidino group of the Arg residue and the â-carboxylic
acid of the Asp residue in the RGD sequence are the
essential functionalities in this recognition.5-14 There-
fore, most of the fibrinogen receptor antagonists have
initially been designed to reproduce the three-dimen-
sional conformation of the RGD sequence(s) in fibrino-
gen by adjusting the distance between these two func-
tional groups.15
Combinatorial chemistry should be an efficient tool
for discovering GPIIb/IIIa antagonists,16-18 since previ-
ous studies regarding the antagonistic effects of RGD
peptides against the GPIIb/IIIa receptor provided in-
formation about the active conformation of the antago-
nistic molecules.19-24 In our previous study16 using
three-component combinatorial approach, we have re-
ported a potent non-peptide GPIIb/IIIa antagonist 1
(NSL-95301) (Figure 1), wherein the space between the
basic moiety and the acidic moiety was adjusted to the
* To whom correspondence should be addressed. Tel: +81-44-797-
1313. Fax: +81-44-752-6351. E-mail: yhayashi@Lab1.nsc.co.jp.
† State University of New York at Stony Brook.
S0022-2623(98)00126-5 CCC: $15.00 © 1998 American Chemical Society
Published on Web 06/03/1998

2346 J ournal of Medicinal Chemistry, 1998, Vol. 41, No. 13
Hayashi et al.
Sch em e 1a
a
(a) LiN(SiMe3)2, THF, -20 °C; (b) (CH3)2C(Li)COOEt, THF, -70 °C; (c) 6 N HCl, room temperature; or KOH, THF, reflux; (d) R2X,
NaH, THF; (e) Et3N, DMF; (f) BOP reagent, DIEA, CH2Cl2; (g) H2S, Et3N, pyridine; (h) MeI, acetone, reflux; (i) CH3COONH4, MeOH,
reflux; (j) Pd(OH)2, 90% aqueous MeOH containing 2% AcOH; or LiOH, 80% aqueous MeOH.
proper distance. This molecule is unique for its trisub-
stituted â-amino acid residue serving as the central core
unit.
In this paper, we describe the development of a potent
and orally active GPIIb/IIIa antagonist based on the
conformational analysis and the SAR study of 1 and
further modification of the amidine group of the an-
for the synthesis of â-substituted-R,R-dimethyl-â-alanine
tagonist molecule.
4, the corresponding lactam 3, which was prepared by
convenient ester-imine condensation25 with N-(tri-
methylsilyl)imines of 2 and lithium enolate of ethyl
Ch em istr y
Analogues of 1, in which the â-position of the central
â-amino acid is varied, were generally synthesized by
the methods shown in Schemes 1 and 2. In Scheme 1,
isobutyrate, was hydrolyzed in 6 N HCl or with KOH
in THF. Compound 4 was coupled with N-hydroxysuc-
cinimide ester of 4-cyanobenzoic acid (7) in the presence

GPIIb/ IIIa Integrin Antagonists
J ournal of Medicinal Chemistry, 1998, Vol. 41, No. 13 2347
Sch em e 2a
a
(a) (Boc)2O, 10% Na2CO3, dioxane; (b), benzyl, methyl, or ethyl piperidine-4-acetate, HATU, DIEA, CH2Cl2; (c) TFA, anisole; 0 °C; (d)
2-halo-4-cyanobenzoic acid, WSCD‚HCl, HOBt, DMF; (e) H2S, Et3N, pyridine; (f) MeI, acetone, reflux; (g) CH3COONH4, MeOH, reflux;
(h) Pd(OH)2, 90% aqueous MeOH containing 2% AcOH; or LiOH, 80% aqueous MeOH; (i) amine, MeOH, reflux; (j) LiOH, 80% aqueous
MeOH.
Sch em e 3a
of triethylamine to give amide 8, which was coupled
with benzyl or methyl piperidine-4-acetate 9 using the
BOP reagent26 in the presence of N,N-diisopropylethyl-
amine (DIEA) to give 10. Subsequent amidination27 of
the nitrile group of 10 provided 11. The biologically
active form of compounds 18-33 was obtained as a
trifluoroacetic acid salt by hydrogenolysis of the benzyl
protecting group with 20% palladium hydroxide on
carbon or saponification of methyl ester with LiOH and
the subsequent reverse phase HPLC purification. In
the synthesis of 29 and 31, the phenolic hydroxyl group
a
at the â-position of central â-alanine analogues was
protected with a benzyl group and deprotected at the
final step of the synthesis via hydrogenolysis with the
benzyl protecting group for the terminal carboxylic acid.
This benzyl protection for the phenolic hydroxyl group
was introduced by preparing â-(3- or 4-benzyloxy)-
phenyl-R,R-dimethyl-â-alanine (4n or 4l) via hydrolysis
of the corresponding â-lactam. In the synthesis of 32
and 33, â-lactam 3 was alkylated with methyl iodide in
the presence of NaH or propargyl bromide in the
presence of NaH and HMPA, respectively. For the
synthesis of 18, â-methyl-R,R-dimethyl-â-alanine (4a )
was synthesized from corresponding â-lactam 3a , which
was prepared from bis(trimethylsilyl)formamide on the
basis of the method of Uyehara et al.28
In the synthesis of compound 34-43 (Scheme 2),
t-Boc-protected â-substituted-R,R-dimethyl-â-alanine de-
rivative 12 was coupled with benzyl, methyl, or ethyl
piperidine-4-acetate by O-(7-azabenzotriazol-1-yl)-1,1,3,3-
tetramethyluronium hexafluorophosphate (HATU)29 to
give 13. After the deprotection of the t-Boc group of 13
by TFA in the presence of anisole, coupling with
2-chloro-4-cyanobenzoic acid for 34 or 2-fluoro-4-cy-
anobenzoic acid30 for 35-43 by 1-ethyl-3-(3-dimethyl-
(a) (R)-(+)-1-(1-Naphthyl)ethylamine, HATU, DIEA, CH2Cl2;
(b) SiO2 chromatography; (c) 6 N HCl, reflux; (d) (Boc)2O, 10%
Na2CO3, dioxane; (e) see Scheme 2.
aminopropyl)carbodiimide hydrochloride (WSCD‚HCl)31
in the presence of 1-hydroxybenzotriazole (HOBt)32 was
carried out to give 14. In the synthesis of 34-37,
amidination of 14 and subsequent cleavage of the
protecting group for the terminal carboxyl group were
performed by the same method shown in Scheme 1. For
the modification of the amidino group in 38-43, corre-
sponding secondary amine was used in the final step of
the above-mentioned amidination method. The biologi-
cally active form of compounds 38-43 was obtained as
a trifluoroacetic acid salt by saponification of ethyl ester
with LiOH and the subsequent reverse phase HPLC
purification.
The synthesis of two individual enantiomers of the
racemic 40 is outlined in Scheme 3 for the (R)-enanti-
omer. (R)-(+)-3-[N-(t-Boc-amino)-2,2-dimethylpentanoyl]-
1-(1-naphthyl) ethylamine (15-R) was obtained by the
separation of diastereomers of 15 prepared from 3-(N-
t-Boc)amino-2,2-dimethylpentanoic acid (12b) by column
chromatography; the absolute configuration of 15-R was

2348 J ournal of Medicinal Chemistry, 1998, Vol. 41, No. 13
Hayashi et al.
1 shows, the introduction of a relatively small alkyl
group such as methyl (18), ethyl (19), and n-propyl (20)
increases the activity as compared to that of 1. n-Butyl
analogue 23 and isobutyl analogue 24 are also 3 times
as active as 1, but isopropyl analogue 21, 2-propenyl
analogue 22, and normal pentyl analogue 25 do not
show improved activity as compared to 1 in the platelet
aggregation inhibitory assay.
Accordingly, this SAR study indicates that the re-
placement of the phenyl group of 1 with an alkyl
substituent retains or improves inhibitory activity for
platelet aggregation, and the bulkiness of the alkyl
â-substituents has a rather small (less than a factor of
2 in the platelet aggregation assay) effect on the
biological activity. Compounds with an aromatic sub-
stituent such as 4-chlorophenyl (28) at the â-position
are less potent. However, 2-naphthyl (27), 3-chlorophe-
nyl (30), and 2-phenylethyl (26) are tolerated.
The effect of the introduction of hydroxyphenyl
group as the â-substituent on the activity is worth
mentioning. As Table 1 shows, while 4-hydroxyphenyl
analogue 29 only possesses virtually the same activity
as 1, 3-hydroxyphenyl analogue 31 exhibits more than
3-fold better activity than 1. This may imply that there
is a basic residue in the GPIIb/IIIa binding site which
can form a hydrogen bonding with the 3-hydroxyphenyl
group, enhancing the binding of 31 to the receptor.
F igu r e 2. Superimpositioning study of the lower energy
conformations of 16.
determined by X-ray crystallographic analysis. Com-
pound 15-R was hydrolyzed and converted into the
corresponding t-Boc-protected amino acid 12b-R, and
the biologically active form of 40-R was obtained as a
trifluoroacetic acid salt by the same procedure described
in Scheme 2. In the same manner, the (S)-enantiomer
40-S was prepared from 15-S.
Resu lts a n d Discu ssion
Molecu la r Mod elin g. Molecular modeling studies
of 1 and the related compound 16 have revealed unique
conformational characteristics of 1 (Figure 1). First,
this molecule exhibits a cup-shaped conformation with
the amidino group and the carboxyl group protruding
at each end of the molecule. Second, the phenyl group
at the â-position is oriented perpendicular to the pseudo
plane including the amidinophenyl group and the pip-
eridine ring. Third, this compound is quite rigid despite
its linear structure, fixing the spatial distance between
the amidino group and the carboxyl group. This cup-
shaped conformation with considerable rigidity can be
ascribed to the correlated and restricted movements of
the phenyl group at the â-position, the gem-dimethyl
group at the R-position and the piperidine ring to avoid
steric repulsion among these three moieties. Especially,
the existence of a substituent at the â-position appears
to be very important to maintain such rigidity. In fact,
compound 16, which has no substituent at the â-posi-
tion, showed much greater conformational flexibility as
compared to 1 (Figure 2). Compound 1 is a potent
antagonist of the GPIIb/IIIa receptor on platelets ((+)-1
shows the IC50 value of 0.092 µM [human PRP/collagen],
but the antagonistic activity of (-)-form is more than
300 times less than that of (+)-form),16 whereas 16
shows a weaker activity (10 times less active based on
the ELISA GPIIb/IIIa binding assay, if we consider the
chimeric structure of 1) as shown in Table 1. These
results suggest that the potent activity of 1 is ascribed
to the fixation of the molecule to its bioactive conforma-
tion preferable for the binding to GPIIb/IIIa. This
hypothesis is also supported by the fact that 17, bearing
an (E)-olefin moiety at the C3-C4 position to freeze the
free rotation around the C3-C4 bond, shows almost the
same activity as that of 1.33
Next, we carried out further optimization of 19 in
order to improve antiplatelet activity and pharmacoki-
netic properties. Analogue 19 was chosen based on the
fact that the plasma half-life (T1/2â) of 19 was slightly
longer than those of its analogues with comparable in
vitro potency. Compound 19 is a hydrophilic compound
containing the amidine group, carboxylic acid, and two
amide bonds. This hydrophilicity may restrict wide
tissue distribution and the binding to plasma proteins,
resulting in high clearance rate of this compound.
Hence, modification of 19 was carried out to increase
hydrophobicity, especially modification of a secondary
amide bond with N-alkylation and an introduction of
an hydrophobic functional group such as halogen to an
aromatic ring. As Table 1 shows, the modification of
the amide nitrogen of the central â-amino acid residue
by the introduction of an N-methyl group (32) or an
N-propargyl group (33) decreases antiplatelet activity.
The introduction of a fluorine atom at the meta position
of the amidinobenzoyl group (35-37) not only slightly
Str u ctu r e-Activity Rela tion sh ip s. On the basis
of these findings, we have synthesized and looked at the
SAR of a series of analogues 18-31 in which the
â-substituent of the trisubstituted â-amino acid residue
is varied. Results are summarized in Table 1. As Table

GPIIb/ IIIa Integrin Antagonists
J ournal of Medicinal Chemistry, 1998, Vol. 41, No. 13 2349
Ta ble 1. Structure-Activity Relationships of the Analogues of 1
platelet aggregationa
GPIIb/IIIa ELISA
IC50 (nM)
T1/2â
(min)
compd
R1
R2
R3
IC50 (µM)
1
16c
17c
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
phenyl (NSL-95301)
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
Cl
F
0.23 ( 0.035b
0.57 ( 0.032
0.31 ( 0.087
0.082 ( 0.007
0.085 ( 0.005
0.082 ( 0.007
0.15 ( 0.036
0.17 ( 0.061
0.082 ( 0.011
0.081 ( 0.009
0.16 ( 0.036
0.16 ( 0.020
0.38 ( 0.219
0.66 ( 0.163
0.22 ( 0.017
0.25 ( 0.072
0.076 ( 0.012
0.30 ( 0.038
1.4 ( 0.22
25.3 ( 3.5
125 ( 25
36.0 ( 7.5
5.3 ( 0.78
5.0 ( 0.60
5.1 ( 0.98
8.6 ( 2.4
13.0 ( 1.2
3.8 ( 0.52
2.7 ( 0.25
22.3 ( 7.9
47.3 ( 4.0
21.0 ( 3.7
34.7 ( 2.3
23.7 ( 5.2
31.3 ( 5.0
2.6 ( 0.43
21.3 ( 2.0
363 ( 55
32
H
nad
nad
H
Me
Et
n-Pr
i-Pr
2-propenyl
n-Bu
i-Bu
n-pentyl
2-phenylethyl
2-naphthyl
4-Cl-phenyl
4-OH-phenyl
3-Cl-phenyl
3-OH-phenyl
phenyl
53
78
54
48
56
62
55
31
46
51
72
63
150
65
85
90
75
84
89
78
H
H
H
H
H
H
H
H
H
H
H
H
H
Me
propargyl
H
H
H
H
n-Bu
phenyl
Me
Et (NSL-96173)
n-Bu
0.37 ( 0.036
0.076 ( 0.009
0.062 ( 0.023
0.081 ( 0.012
27.3 ( 5.9
4.3 ( 0.50
2.7 ( 0.23
5.7 ( 1.2
F
F
a
b
Collagen (5 µg/mL)-induced platelet aggregation using human platelet-rich plasma. Values are means ( SEM of three experiments.
c See refs 16 and 33. na ) not applicable.
d
increases the activity, but also prolongs the plasma half-
life, while replacement with a chlorine atom at the same
position (34) does not improve the activity as compared
to 1. These results may be due to the strong hydropho-
bic effect of a fluorine atom without affecting conforma-
tion, since a fluorine atom can possess similar atom
space as a hydrogen atom.
duction of cyclic secondary amine structure)35 were
investigated by modifying the ethyl ester of 36. As
shown in Table 2, the introduction of cyclic secondary
amine structure at one of the amidino nitrogens resulted
in the improved pharmacokinetic properties in most
compounds tested, represented by the prolonged T1/2â
values or high Cmax values, after po administration.
Further, despite the modification of the amidino group,
which is one of the essential pharmacophores of these
compounds, their antagonistic activities were not al-
tered. Although the mechanism underlying the im-
provement of pharmacokinetic properties by dialkyla-
tion is not clear, it can be attributed to the increased
hydrophobicity at the amidino group which is positively
charged in physiological conditions. Dialkylation at the
amidino group may increase the permeability through
the cell barrier such as epithelium of gastrointestinal
tract and endothelium of blood vessels, probably by
masking the positive charge or affecting the basicity.
Analogue 36 (NSL-96173) is a potent platelet ag-
gregation inhibitor in vitro, possessing the longest
plasma stability in this series. However, even by the
introduction of the fluorine atom, this analogue showed
only a limited bioavailability after po administration in
guinea pigs (data not shown). One reason for this low
oral bioavailability may be due to the fact that the
amidino group exists in its ionic form in the acidic
condition of stomach and even in the weak basic
condition of intestine due to its strong basicity, and this
lasting ionic form prevents the absorption through a
passive transport from the intestine, which is generally
dependent on the hydrophobicity of the molecule. The
terminal carboxylic acid may also have a higher rate of
dissociation in intestine. However, these free basic and
acidic groups are thought to be critical to induce the
activity. To improve oral bioavailability, we modified
the amidino group by alkylation to increase hydropho-
bicity. The carboxylic acid was also blocked by ester
formation as prodrugs. However, the esterification of
36 to provide the corresponding methyl, ethyl, isopropyl,
and benzyl esters as a prodrug brought about only slight
improvement in oral bioavailability regardless of the
nature of the esters (data not shown).
As shown in Table 2, the active form, i.e., free
carboxylic acid form, of 40 (NSL-96184) with a thiazo-
lidine group at one of the amidino nitrogens not only
exhibits most potent activity (IC50 45 nM, human PRP/
collagen), but also possesses a high Cmax value (1.2 µg/
mL) in rats after oral administration (10 mg/kg). The
presence of a heteroatom within the ring structure such
as oxygen in morpholine (38) and sulfur in thiazolidine
(40) seems to be important in the increase of the Cmax
value, because 39 with no heteroatom in the ring
structure shows very low Cmax value compared to those
of 38 and 40. These results suggest that the modifica-
tion of amidino or guanidino group by introducing cyclic
secondary amines can be one of the useful approaches
Since monoalkylation of the amidino group signifi-
cantly decreased the antiplatelet activity in our pre-
liminary study,34 the effects of dialkylation (the intro-

2350 J ournal of Medicinal Chemistry, 1998, Vol. 41, No. 13
Ta ble 2. Modification of Amidino Group for Oral Bioavailability
Hayashi et al.
reported to have an oral bioavailability of more than
20% in dogs, we used SC-54684A as a reference com-
pound for evaluation of 40.36 Racemic SC-54684A, when
administered orally at the same dose (10 mg/kg) as that
used for 40, showed less than 70% inhibition for ex vivo
platelet aggregation in the guinea pig at its maximum
(Figure 3). The plasma half-life of the active form of
40 after intravenous administration to the guinea pig
(1 mg/kg) was found to be relatively short with a T1/2â
value of 1.8 h. Since most sulfur containing drugs are
metabolized via the S-oxidation pathway in vivo, cata-
lyzed by cytochrome P450 or flavin-containing monooxy-
genase (FMO), this relatively short half-life may be due
to the oxidative metabolism of the thiazolidine group
in 40.37 However, in this experiment using HPLC
analysis for the detection of the biologically active form
of 40 in plasma, we could not observe any other
metabolite. The other possibility is that the active form
of 40 is quickly excreted from the circulation without
metabolism due to its relatively hydrophilic structure.
F igu r e 3. Effects of 40 and SC-54684A on ex vivo platelet
aggregation in guinea pigs.
to improve pharmacokinetic properties in GPIIb/IIIa
antagonists.
To evaluate pharmacological and pharmacodynamic
properties of 40, ex vivo platelet aggregation was
examined by the oral administration of 40 in guinea
pigs. As shown in Figure 3, the 10 mg/kg oral admin-
istration of 40 results in the complete inhibition of ex
vivo platelet aggregation over 3 h. It is noteworthy that
the onset of the antiplatelet activity was very rapid and
almost the maximum inhibition was observed even at
the 30 min period after the administration, the earliest
time point of the experiment. Since SC-54684A was
These encouraging results prompted us to synthesize
two individual enantiomers of the racemic 40. Both
synthetic enantiomers were subjected to in vitro activity
assay (human PRP/collagen). We have found that only

GPIIb/ IIIa Integrin Antagonists
J ournal of Medicinal Chemistry, 1998, Vol. 41, No. 13 2351
with heparin as an anticoagulant at 1, 5, 10, 30, 45, 60, 120,
and 180 min after the intravenous administration. These
samples were centrifuged, and plasma concentrations of each
compound were determined by HPLC. In most of the com-
pounds tested here, plasma concentration declined biexponen-
tially and T1/2â values were calculated from the exponential
curve fitted by the least-squares methods.
Mea su r em en t of Cm a x Va lu es. Male Sprague-Dawley
rats (190-210 g) were fasted overnight with water ad libitum.
Each compound was suspended in 2% arabic gum solution and
was administered po (10 mg/kg). Blood samples were collected
from the jugular vein at 30, 60, and 120 min after the
administration, and plasma concentrations of the active form
were determined by HPLC. Prodrug form was not detected
in plasma. Cmax value was defined as the maximum plasma
concentration of the active form achieved at these three time
points.
Ex Vivo Stu d y in Gu in ea P igs. Male hartley guinea pigs
(170-250 g), fasted for 24 h, were used for ex vivo platelet
aggregation study. 40 or SC-54684A was dissolved in distilled
water and administered orally at a dose of 10 mg/kg. Blood
samples were collected at selected times after the administra-
tion for 6 h from the abdominal artery under anesthesia with
pentobarbital, and PRP was prepared by centrifugation.
Inhibition of collagen (10 mg/mL)-induced platelet aggregation
was determined by comparing the responses in the samples
from drug-administered animals with those of vehicle control
group at each time point. Mean ( SEM (n ) 3).
Ch em istr y. 1H NMR and 13C NMR spectra were recorded
on J EOL GSX270J or EX-400 spectrometer. These spectra
were recorded with tetramethylsilane (δ ) 0.0 for 1H); CD3-
OD (δ ) 49.8 for 13C); CDCl3 (δ ) 77.0 for 13C); (CD3)2SO (δ )
39.5 for 13C) as internal reference. Mass spectra (electrospray
ionization, methanol as the mobile phase) were analyzed with
Finnigan SSQ 7000 spectrometer. High-resolution fast atom
bombardment mass spectra were analyzed with J EOL J MS-
DX303 spectrometer. HPLC was carried out using a J asco
system (800 series) equipped with a UV/VIS detector and an
integrator. The solvent system used for analytical HPLC was
a binary system, water containing 0.1% TFA and acetonitrile
containing the same TFA as the organic modifier. The column
used for analytical chromatography had dimensions of 4.6 ×
250 mm (Wakosil-II 5C18 HG). The analytical conditions for
K′ values are (a) a linear gradient with 10% to 40% acetonitrile
in 0.1% TFA over 60 min at a flow rate of 1.0 mL/min, (b) a
linear gradient with 10% to 55% acetonitrile in 0.1% TFA over
30 min at a flow rate of 1.0 mL/min. HPLC on a semiprepara-
tive scale was performed with a reverse phase column (Waters,
µBondasphere 19 × 150 mm, 10 µm, C-18) employing the same
binary solvent system used for analytical HPLC at a flow rate
of 17 mL/min on a Waters system (600E series). GRGDS was
purchased from the Peptide Institute Inc.
40-R is a highly potent platelet aggregation inhibitor
(IC50 22 nM) while 40-S shows poor activity (IC50 3100
nM).
In conclusion, the active form of 40-R is a highly
potent antagonist of the platelet fibrinogen receptor
GPIIb/IIIa, effectively inhibiting platelet aggregation in
vitro. This compound is characterized by the presence
of the trisubstituted â-amino acid residue, 3-ethyl-2,2-
dimethyl-â-alanine, which is responsible for fixing the
molecule to its active conformation. In vivo assay
results clearly show that 40 is orally active in guinea
pigs. The onset of antiplatelet action is very fast,
whereas its duration of action is relatively short. These
results suggest that 40 may have an excellent thera-
peutic potential, especially for antithrombotic treatment
in the acute phase.
Exp er im en ta l Section
Con for m a tion a l An a lysis. All the conformational analy-
ses were carried out on Macromodel ver. 5.5d. The 10000
Monte Carlo conformational search steps were performed with
AMBER* force field UA minimization. Conformers whose
steric energy was within 10 kJ from global minima were
subjected to the superimpositioning study. The distance
constraint factor has been set between center carbon atom of
the amidine and center carbon atom of the carboxylic acid to
be larger than 12 Å.
In Vitr o P la telet Aggr ega tion . Platelet aggregation
studies were performed in platelet-rich plasma (PRP) obtained
from human volunteers. Blood was drawn into plastic syringes
containing 1/10 volume of 3.8% trisodium citrate. PRP was
prepared by centrifugation of citrated whole blood at 160g for
15 min at room temperature. PRP was removed, and the
platelet count was determined. Platelet-poor plasma was
obtained by centrifugation of the remaining blood at 2000g for
15 min. Saline or sample solution of various concentrations
was added to PRP at 37 °C 1 min prior to the initiation of
platelet aggregation. Platelet aggregation was initiated with
5 µg/mL collagen, and the aggregation was measured in an
aggregometer (NBS Hematracer-601, Nikoh Bioscience Co.,
Ltd., Tokyo) as an increase in light transmission. Platelet
aggregation is presented as the percent inhibition of the rate
of platelet aggregation compared to control samples, and IC50
values were calculated from dose-inhibition curves. Through-
out the platelet aggregation assay, GRGDS peptide was used
as a reference compound, and we confirmed that the IC50
values of this peptide did not significantly vary with PRPs from
different blood donors (470 ( 23 µM; mean ( SEM from five
different donors).
Solid -P h a se Bin d in g Assa y. The inhibitory effects of each
compound on the interaction of fibrinogen and its receptor,
GPIIb/IIIa, were evaluated using a competitive enzyme-linked
immunosorbent assay. Briefly, a 96-well plate (MAXISORP,
Nunc) was coated with 5 µg/mL human GPIIb/IIIa solution
(Enzyme Research Lab., Inc.) overnight at 4 °C. The plate
was washed with wash buffer containing 50 mM Tris, 100 mM
NaCl, 2 mM CaCl2, and 0.02% NaN3 (pH 7.4) and was blocked
with wash buffer supplemented with 35 mg/mL bovine serum
albumin (Fraction V, Sigma) for 3 h at room temperature.
Ninety microliters of human fibrinogen solution (30 µg/mL,
Calbiochem Co., CA) and 10 µL of the inhibitor solution were
added to each well, and the plate was incubated for 3 h at
room temperature. After the plate was washed three times
with wash buffer, bound fibrinogen was detected using alkaline
phosphatase-conjugated goat anti-human fibrinogen antibody
(EY Laboratories, Inc., CA).
Gen er al P r ocedu r e A for â-Lactam P r epar ation : 4-Eth -
yl-3,3-d im eth yl-2-a zetid in on e (3b). To 14 mL (66 mmol)
of 1,1,1,3,3,3-hexamethyldisilazane in 20 mL of dry tetrahy-
drofuran was added 40 mL (66 mmol) of 1.65 M n-butyllithium
in hexane at 0 °C over 10-min period. The mixture was stirred
at 0 °C for 20 min, and the solvent was removed in vacuo until
a white precipitate appeared. To the resulting slurry was
added dropwise a solution of 4.0 mL (55 mmol) of propional-
dehyde in 15 mL of tetrahydrofuran at -20 °C over 5-min
period. The resulting solution of trimethylsilyl imine was used
directly in the following reaction. To 9.1 mL (65 mmol) of
diisopropylamine in 30 mL of tetrahydrofuran was added 36.4
mL (60 mmol) of 1.65 M n-butyllithium in hexane at -70 °C.
The mixture was stirred at -70 °C for 20 min followed by the
addition of 6.7 mL (50 mmol) of ethyl isobutyrate in 10 mL of
tetrahydrofuran over a 10-min period. The solution was
stirred at -70 °C for 60 min followed by addition of the solution
of trimethylsilyl imine via cannula at a rate such that the
temperature did not exceed -50 °C. The mixture was stirred
at -70 °C for 60 min, allowed to warm to room temperature,
and stirred for an additional 18 h. Then 100 mL of saturated
aqueous NH4Cl was added to the reaction mixture, and the
Mea su r em en t of P la sm a Ha lf-Life. Male Hartley guinea
pigs (400-500 g) were anesthetized with urethane (1.0 g/kg,
ip), and a cannula was inserted into the left carotid artery.
Each compound was dissolved in saline and administered
intravenously (1 mg/kg) via a right jugular vein. Blood
samples (0.3 mL) were collected through the arterial cannula

2352 J ournal of Medicinal Chemistry, 1998, Vol. 41, No. 13
Hayashi et al.
mixture was extracted three times with 50 mL of diethyl ether.
The combined organic layers were washed with saturated
NaCl, dried over Na2SO4, and concentrated in vacuo. The
residual pale yellow oil was applied to a silica gel column (5
× 50 cm) and eluted with EtOAc-hexane (1:4) to give 3.33 g
(53%) of azetidinone 3b as a pale-yellow oil: 1H NMR (270
MHz, CDCl3) δ 0.95 (t, J ) 8.0 Hz, 3H), 1.18 (s, 3H), 1.32 (s,
3H), 1.56 (m, 2H), 3.22 (dd, J ) 6.0, 9.0 Hz, 1H), 6.01 (br s,
1H); MS (ESI) m/z 128 (M + H)+.
Compounds 3c-n were prepared according to the general
procedure A described for 3b starting from the corresponding
aldehydes 2. 3a was prepared from bis(trimethylsilyl)forma-
mide based on the method of Uyehara et al.28
4-n -P r op yl-3,3-d im eth yl-2-a zetid in on e (3c): 42% yield
from n-butylaldehyde; mp 70-71 °C; 1H NMR (270 MHz,
CDCl3) δ 0.92 (t, J ) 7.0 Hz, 3H), 1.17 (s, 3H), 1.31 (s, 3H),
1.25-1.64 (m, 4H), 3.27 (dd, J ) 6.0, 8.0 Hz, 1H), 5.92 (br s,
1H); MS (ESI) m/z 142 (M + H)+.
4-Isop r op yl-3,3-d im eth yl-2-a zetid in on e (3d ): 55% yield
from isobutylaldehyde; mp 94-96 °C; 1H NMR (270 MHz,
CDCl3) δ 0.89 (d, J ) 6.0 Hz, 3H), 0.93 (d, J ) 6.0 Hz, 3H),
1.23 (s, 3H), 1.31 (s, 3H), 1.75 (m, 1H), 2.90 (d, J ) 10.0 Hz,
1H), 5.85 (br s, 1H); MS (ESI) m/z 142 (M + H)+.
N-Meth yl-4-p h en yl-3,3-d im eth yl-2-a zetid in on e (5o). To
a solution of 4-phenyl-3,3-dimethyl-2-azetidinone25 (1.75 g, 10
mmol) in tetrahydrofuran (40 mL) was added 0.48 g (12 mmol)
of sodium hydride (60% in mineral oil) in portions, and the
mixture was stirred at 0 °C for 15 min. To this mixture was
added dropwise 0.74 mL (12 mmol) of MeI, and the mixture
was allowed to warm to room temperature and stirred for an
additional 2 h. Then, 50 mL of saturated aqueous NH4Cl was
added to the reaction mixture, and the mixture was extracted
two times with 50 mL of EtOAc. The combined organic layers
were washed with saturated NaCl, dried over Na2SO4, and
concentrated in vacuo. The residual oil (2.1 g) was chromato-
graphed over 150 g of silica gel and eluted with EtOAc-hexane
(1:2) to give 1.9 g (quant) of 5o as an oil: 1H NMR (270 MHz,
CDCl3) δ 0.76 (s, 3H), 1.43 (s, 3H), 2.86 (s, 3H), 4.31 (s, 1H),
7.14-7.23 (m, 2H), 7.28-7.50 (m, 3H); MS (ESI) m/z 212 (M
+ Na)+.
N -(2-P r o p a r g y l)-4-n -b u t y l-3,3-d im e t h y l-2-a ze t id i-
n on e (5p ). This compound was prepared from 3f and prop-
argyl bromide following the procedure described for 5o, but
HMPA (3 mL) was added to the reaction mixture. The crude
product (2.5 g) was chromatographed over 70 g of silica gel
and eluted with EtOAc-hexane (1:5) to give 1.6 g (quantita-
tive) of 5p as an oil: 1H NMR (270 MHz, CDCl3) δ 0.93 (t, J )
6.8 Hz, 3H), 1.17 (s, 3H), 1.27 (s, 3H), 1.20-1.78 (m, 6H), 2.26
(t, J ) 2.4 Hz, 1H), 3.35 (t, J ) 6.4 Hz, 1H), 3.76 (dd, J ) 2.4,
17.6 Hz, 1H), 4.21 (dd, J ) 2.4, 17.6 Hz, 1H); MS (ESI) m/z
194 (M + H)+.
4-(2-P r open yl)-3,3-dim eth yl-2-azetidin on e (3e): 82% yield
from crotonaldehyde; 1H NMR (270 MHz, CDCl3) δ 1.10 (s,
3H), 1.32 (s, 3H), 1.75 (dd, J ) 1.4, 7.3 Hz, 3H), 3.77 (d, J )
7.3 Hz, 1H), 5.41-5.51 (m, 1H), 5.64-5.74 (m, 1H), 5.84 (br s,
1H); MS (ESI) m/z 140 (M + H)+.
Gen er a l P r oced u r e B for th e P r ep a r a tion of 8: 3-(N-
4-Cya n oben zoyl)a m in o-2,2-d im eth ylp en ta n oic Acid (8b).
A mixture of 4-ethyl-3,3-dimethyl-2-azetidinone (3b) (2.0 g,
15.7 mmol) and 6 N HCl (100 mL) was stirred at room
temperature for 24 h. The solution was condensed under
reduced pressure, and then toluene (30 mL) was added to the
residue and evaporated twice to give 2.3 g (81%) of a hydro-
chloride salt of 3-amino-2,2-dimethylpentanoic acid (4b) as a
white solid: mp 216-218 °C; 1H NMR (270 MHz, D2O) δ 0.84
(t, J ) 7.0 Hz, 3H), 1.06 (s, 3H), 1.10 (s, 3H), 1.38 (m, 1H),
1.63 (m, 1H), 3.16 (dd, J ) 3.0, 10.0 Hz, 1H); MS (ESI) m/z
146 (M + H)+. To a solution of this material (1.0 g, 5.5 mmol)
in DMF (40 mL) were added triethylamine (1.7 mL, 12.1 mmol)
and N-succinimidyl-4-cyanobenzoate (1.6 g, 6.6 mmol) at 0 °C,
and the resulting mixture was stirred at room temperature
for 17 h. The solvent was removed by evaporation, and the
residue was dissolved in EtOAc (50 mL). The organic phase
was washed with 5% citric acid and saturated NaCl, dried over
Na2SO4, and concentrated in vacuo. The resulting powder was
recrystallized from EtOAc with ether-hexane (1:1): yield 1.32
4-n -Bu tyl-3,3-d im eth yl-2-a zetid in on e (3f): 53% yield
from n-valeraldehyde; mp 59-60 °C; 1H NMR (270 MHz,
CDCl3) δ 0.93 (t, J ) 6.0 Hz, 3H), 1.17 (s, 3H), 1.31 (s, 3H),
1.21-1.64 (m, 6H), 3.28 (dd, J ) 6.0, 8.0 Hz, 1H), 5.87 (br s,
1H); MS (ESI) m/z 156 (M + H)+.
4-Isobu tyl-3,3-d im eth yl-2-a zetid in on e (3g): 15% yield
1
from isovaleraldehyde; mp 101-102 °C; H NMR (270 MHz,
CDCl3) δ 0.93 (d, J ) 4.4 Hz, 3H), 0.96 (d, J ) 4.4 Hz, 3H),
1.16 (s, 3H), 1.31 (s, 3H), 1.37-1.50 (m, 2H), 1.54-1.68 (m,
1H), 3.39 (dd, J ) 3.4, 8.3 Hz, 1H), 5.80 (br s, 1H); MS (ESI)
m/z 156 (M + H)+.
4-n -P en tyl-3,3-d im eth yl-2-a zetid in on e (3h ): 52% yield
1
from 1-hexanal; H NMR (270 MHz, CDCl3) δ 0.90 (m, 3H),
1.17 (s, 3H), 1.31 (s, 3H), 1.22-1.40 (m, 6H), 1.43-1.62 (m,
2H), 3.29 (dd, J ) 5.8, 3.0 Hz, 1H), 5.96 (br s, 1H); MS (ESI)
m/z 170 (M + H)+.
4-(2-P h en yleth yl)-3,3-d im eth yl-2-a zetid in on e (3i): 35%
1
yield from 3-phenylpropionaldehyde; mp 83-85 °C; H NMR
(270 MHz, CDCl3) δ 1.17 (s, 3H), 1.30 (s, 3H), 1.71-1.98 (m,
2H), 2.53-2.75 (m, 2H), 3.29 (dd, J ) 4.0, 8.0 Hz, 1H), 5.52
(br s, 1H), 7.09-7.31 (m, 5H); MS (ESI) m/z 204 (M + H)+.
4-(2-Naph th yl)-3,3-dim eth yl-2-azetidin on e (3j): 87% yield
from 2-naphthaldehyde; mp 160-162 °C; 1H NMR (270 MHz,
CDCl3) δ 0.79 (s, 3H), 1.53 (s, 3H), 4.66 (s, 1H), 6.36 (br s,
1H), 7.31-7.34 (m, 1H), 7.47-7.53 (m, 2H), 7.72 (s, 1H), 7.82-
7.86 (m, 3H); MS (ESI) m/z 226 (M + H)+.
1
g (87%); mp 157-160 °C; H NMR (270 MHz, CDCl3) δ 0.94
(t, J ) 7.3 Hz, 3H), 1.27 (s, 3H), 1.29 (s, 3H), 1.14 (ddq, J )
10.7, 14.0, 7.3 Hz, 1H), 1.83 (ddq, J ) 2.0, 14.0, 7.3 Hz, 1H),
4.06 (dt, J ) 2.0, 10.7 Hz, 1H), 7.44 (d, J ) 10.7 Hz, 1H), 7.75
(d, J ) 8.8 Hz, 2H), 7.94 (d, J ) 8.8 Hz, 2H); 13C NMR (67.5
MHz, CDCl3) δ 10.8, 23.0, 23.6, 24.1, 45.3, 57.7, 114.3, 117.8,
127.4, 132.0, 138.5, 165.2, 178.9; MS (ESI) m/z 297 (M + Na)+.
Compounds 4a ,c,d ,f-n , 6o,p , and 8a -p were prepared
according to the general procedure B described for 8b starting
from the appropriate intermediates (3a -n and 5o,p ).
3-Am in o-2,2-d im eth ylbu ta n oic a cid (4a ) (h yd r och lo-
r id e): 88% yield from 3a ; 1H NMR (270 MHz, D2O) δ 1.05 (s,
3H), 1.09 (s, 3H), 1.10 (d, J ) 6.8 Hz, 3H), 3.38 (q, J ) 6.8 Hz,
1H); MS (ESI) m/z 132 (M + H)+.
3-(N-4-Cyan oben zoyl)am in o-2,2-dim eth ylbu tan oic acid
(8a ): 76% yield from 4a ; 1H NMR (270 MHz, CDCl3) δ 1.28 (d,
J ) 6.4 Hz, 3H), 1.33 (s, 3H), 1.34 (s, 3H), 4.31 (dq, J ) 6.4,
9.8 Hz, 1H), 7.16 (d, J ) 9.8 Hz, 1H), 7.75 (d, J ) 8.8 Hz, 2H),
7.88 (d, J ) 8.8 Hz, 2H); MS (ESI) m/z 259 (M - H)-.
3-Am in o-2,2-d im eth ylh exa n oic a cid (4c) (h yd r och lo-
r id e): 98% yield from 3c; mp 208-210 °C; 1H NMR (270 MHz,
D2O) δ 0.74 (t, J ) 7.0 Hz, 3H), 1.07 (s, 3H), 1.10 (s, 3H), 1.04-
1.57 (m, 4H), 3.23 (dd, J ) 2.0, 10.0 Hz, 1H); MS (ESI) m/z
160 (M + H)+.
4-(4-Ch lor oph en yl)-3,3-dim eth yl-2-azetidin on e (3k): 67%
yield from 4-chlorobenzaldehyde; mp 127-128 °C; 1H NMR
(270 MHz, CDCl3) δ 0.77 (s, 3H), 1.46 (s, 3H), 4.48 (s, 1H),
6.13 (br s, 1H), 7.20 (d, J ) 8.3 Hz, 2H), 7.36 (d, J ) 8.3 Hz,
2H); MS (ESI) m/z 210 (M + H)+.
4-(4-Ben zyloxyp h en yl)-3,3-d im eth yl-2-a zetid in on e (3l):
94% yield from 4-benzyloxybenzaldehyde; 1H NMR (270 MHz,
CDCl3) δ 0.70 (s, 3H), 1.39 (s, 3H), 4.45 (s, 1H), 5.07 (s, 2H),
7.00 (d, J ) 8.8 Hz, 2H), 7.17 (d, J ) 8.8 Hz, 2H), 7.26-7.43
(m, 5H); MS (ESI) m/z 282 (M + H)+.
4-(3-Ch lor op h en yl)-3,3-d im eth yl-2-a zetid in on e (3m ):
87% yield from 3-chlorobenzaldehyde; mp 120-121 °C; 1H
NMR (270 MHz, CDCl3) δ 0.80 (s, 3H), 1.47 (s, 3H), 4.48 (s,
1H), 6.41 (br s, 1H), 7.14 (dt, J ) 7.0, 2.0 Hz, 1H), 7.30 (s,
1H), 7.22-7.35 (m, 2H); MS (ESI) m/z 210 (M + H)+.
4-(3-Ben zyloxyph en yl)-3,3-dim eth yl-2-azetidin on e (3n ):
47% yield from 3-benzyloxybenzaldehyde; 1H NMR (270 MHz,
CDCl3) δ 0.77 (s, 3H), 1.44 (s, 3H), 4.46 (s, 1H), 5.07 (s, 2H),
6.11 (br s, 1H), 6.80-6.95 (m, 3H), 7.25-7.46 (m, 6H); MS
(ESI) m/z 282 (M + H)+.
3-(N-4-Cyan oben zoyl)am in o-2,2-dim eth ylh exan oic acid
(8c): 67% yield from 4c; mp 234-235 °C; 1H NMR (270 MHz,

GPIIb/ IIIa Integrin Antagonists
J ournal of Medicinal Chemistry, 1998, Vol. 41, No. 13 2353
CDCl3) δ 0.91 (t, J ) 7.3 Hz, 3H), 1.28 (s, 3H), 1.29 (s, 3H),
1.26-1.46 (m, 3H), 1.69 (m, 1H), 4.12 (m, 1H), 7.41 (d, J ) 9.8
3-(N -4-Cya n ob e n zoyl)a m in o-2,2-d im e t h yl-3-(4-ch lo-
r op h en yl)p r op ion ic a cid (8k ): 87% yield from 4k ; mp 272-
1
Hz, 1H), 7.74 (d, J ) 8.8 Hz, 2H), 7.93 (d, J ) 8.8 Hz, 2H); 13
C
273 °C; H NMR (270 MHz, DMSO-d6) δ 1.09 (s, 3H), 1.13 (s,
NMR (67.5 MHz, CDCl3) δ 13.6, 19.5, 23.1, 24.2, 32.9, 45.4,
55.9, 114.3, 117.8, 127.4, 132.0, 138.5, 165.0, 179.0; MS (ESI)
m/z 289 (M + H)+.
3H), 5.48 (d, J ) 9.8 Hz, 1H), 7.39 (d, J ) 8.8 Hz, 2H), 7.45 (d,
J ) 8.8 Hz, 2H), 7.91 (d, J ) 8.3 Hz, 2H), 7.98 (d, J ) 8.3 Hz,
2H), 8.88 (d, J ) 9.8 Hz, 1H); MS (ESI) m/z 355 (M - H)-.
3-Am in o-2,2-d im e t h yl-3-(4-b e n zyloxyp h e n yl)p r op i-
on ic a cid (4l) (h yd r och lor id e): 92% yield from 3l; mp 142-
3-Am in o-2,2-dim eth yl-4-m eth ylpen tan oic acid (4d) (h y-
1
d r och lor id e): 97% yield from 3d ; mp 218 °C; H NMR (270
1
MHz, D2O) δ 0.75 (d, J ) 7.0 Hz, 3H), 0.86 (d, J ) 7.0 Hz,
3H), 1.09 (s, 3H), 1.14 (s, 3H), 2.02 (m, 1H), 3.12 (d, J ) 3.0
Hz, 1H); MS (ESI) m/z 160 (M + H)+.
145 °C; H NMR (270 MHz, D2O) δ 1.19 (s, 3H), 1.26 (s, 3H),
4.41 (s, 1H), 5.10 (s, 2H), 7.05 (d, J ) 8.8 Hz, 2H), 7.29-7.44
(m, 7H); MS (ESI) m/z 298 (M + H)+.
3-(N-4-Cyan oben zoyl)am in o-2,2-dim eth yl-4-m eth ylpen -
ta n oic a cid (8d ): 85% yield from 4d ; mp 148-150 °C; 1H
NMR (270 MHz, CDCl3) δ 0.86 (d, J ) 6.8 Hz, 3H), 1.00 (d, J
) 6.8 Hz, 3H), 1.33 (s, 3H), 1.36 (s, 3H), 2.21 (dsep, J ) 3.4,
6.8 Hz, 1H), 4.19 (dd, J ) 3.4, 10.3 Hz, 1H), 7.57 (d, J ) 10.3
3-(N-4-Cya n ob en zoyl)a m in o-2,2-d im et h yl-3-(4-b en zy-
loxyp h en yl)p r op ion ic a cid (8l): 77% yield from 4l; mp 147-
149 °C; 1H NMR (270 MHz, CDCl3) δ 1.19 (s, 3H), 1.47 (s, 3H),
5.01 (s, 2H), 5.11 (d, J ) 9.3 Hz, 1H), 6.90 (d, J ) 8.8 Hz, 2H),
7.27 (d, J ) 8.8 Hz, 2H), 7.22-7.42 (m, 5H), 7.70 (d, J ) 8.4
Hz, 2H), 7.90 (d, J ) 8.4 Hz, 2H), 8.44 (d, J ) 9.3 Hz, 1H); MS
(ESI) m/z 429 (M + H)+.
3-Am in o-2,2-dim eth yl-3-(3-ch lor oph en yl)pr opion ic acid
(4m ) (h yd r och lor id e): 98% yield from 3m ; mp 232-233 °C;
1H NMR (270 MHz, D2O) δ 1.12 (s, 3H), 1.31 (s, 3H), 4.50 (s,
1H), 7.33 (dt, J ) 7.0, 2.0 Hz, 1H), 7.41-7.52 (m, 3H); MS
(ESI) m/z 228 (M + H)+.
3-(N -4-Cya n ob e n zoyl)a m in o-2,2-d im e t h yl-3-(3-ch lo-
r op h en yl)p r op ion ic a cid (8m ): 92% yield from 4m ; mp 160-
163 °C; 1H NMR (400 MHz, CDCl3) δ 1.19 (s, 3H), 1.28 (s, 3H),
5.34 (s, 1H), 7.27-7.34 (m, 3H), 7.44 (s, 1H), 7.83 (d, J ) 8.4
Hz, 2H), 7.90 (dt, J ) 8.4, 1.6 Hz, 2H); MS (ESI) m/z 379 (M
+ H)+.
3-Am in o-2,2-d im e t h yl-3-(3-b e n zyloxyp h e n yl)p r op i-
on ic a cid (4n ) (h yd r och lor id e): 51% yield from 3n ; 1H NMR
(270 MHz, CD3OD) δ 1.15 (s, 3H), 1.22 (s, 3H), 4.43 (s, 1H),
5.07 (s, 2H), 6.72-6.88 (m, 2H), 6.92-7.08 (m, 2H), 7.13-7.41
(m, 5H); MS (ESI) m/z 300 (M + H)+.
Hz, 1H), 7.77 (d, J ) 8.8 Hz, 2H), 7.95 (d, J ) 8.8 Hz, 2H); 13
C
NMR (67.5 MHz, CDCl3) δ 16.6, 22.0, 23.0, 26.0, 29.2, 44.6,
60.8, 115.1, 117.9, 127.6, 132.5, 138.4, 166.1, 182.8; MS (ESI)
m/z 311 (M + Na)+.
3-Am in o-2,2-d im eth ylh ep ta n oic a cid (4f) (h yd r och lo-
r id e): 99% yield from 3f; mp 194-195 °C; 1H NMR (270 MHz,
D2O) δ 0.69 (t, J ) 7.0 Hz, 3H) 1.07 (s, 3H), 1.10 (s, 3H), 1.12-
1.32 (m, 4H), 1.37 (m, 1H), 1.55 (m, 1H), 3.22 (dd, J ) 10.0,
2.0 Hz, 1H); MS (ESI) m/z 174 (M + H)+.
3-(N-4-Cyan oben zoyl)am in o-2,2-dim eth ylh eptan oic acid
1
(8f): 41% yield from 4f; mp 204-206 °C; H NMR (270 MHz,
CDCl3) δ 0.88 (t, J ) 6.8 Hz, 3H), 1.14-1.48 (m, 4H), 1.19 (s,
3H), 1.22 (s, 3H), 1.48-1.65 (m, 2H), 4.40 (m, 1H), 7.83 (d, J
) 10.0 Hz, 2H), 7.96 (d, J ) 10.0 Hz, 2H); MS (ESI) m/z 303
(M + H)+.
3-Am in o-2,2-d im eth yl-5-m eth ylh exa n oic a cid (4g) (h y-
d r och lor id e): quantitative yield from 3g; mp 224-226 °C;
1H NMR (270 MHz, D2O) δ 0.73 (d, J ) 7.0 Hz, 3H), 0.77 (d,
J ) 7.0 Hz, 3H), 1.07 (s, 3H), 1.10 (s, 3H), 1.17-1.45 (m, 2H),
1.48 (m, 1H), 3.28 (dd, J ) 2.0, 10.0 Hz, 1H); MS (ESI) m/z
174 (M + H)+.
3-(N-4-Cya n ob en zoyl)a m in o-2,2-d im et h yl-3-(3-b en zy-
loxyp h en yl)p r op ion ic a cid (8n ): 43% yield from 4n ; mp
1
180-181 °C; H NMR (270 MHz, CDCl3) δ 1.18 (s, 3H), 1.45
3-(N-4-Cyan oben zoyl)am in o-2,2-dim eth yl-5-m eth ylh ex-
a n oic a cid (8g): 41% yield from 4g; mp 188-190 °C; 1H NMR
(270 MHz, CD3OD) δ 0.90 (d, J ) 6.8 Hz, 3H), 0.94 (d, J ) 6.8
Hz, 3H), 1.17 (s, 3H), 1.21 (s, 3H), 1.10-1.41 (m, 3H), 4.49-
4.58 (m, 1H), 7.83 (d, J ) 8.7 Hz, 2H), 7.92 (d, J ) 8.7 Hz,
2H); MS (ESI) m/z 303 (M + H)+.
3-Am in o-2,2-d im eth ylocta n oic a cid (4h ) (h yd r och lo-
r id e): 90% yield from 3h ; mp 152-154 °C; 1H NMR (270 MHz,
D2O) δ 0.70-0.76 (m, 3H), 1.12 (s, 3H), 1.14 (s, 3H), 1.08-
1.29 (m, 5H), 1.33-1.49 (m, 2H), 1.52-1.66 (m, 1H), 3.26 (dd,
J ) 3.8, 14.0 Hz, 1H); MS (ESI) m/z 188 (M + H)+.
3-(N-4-Cya n oben zoyl)a m in o-2,2-d im eth ylocta n oic a cid
(8h ): 20% yield from 4h ; mp 149-150 °C; 1H NMR (270 MHz,
CDCl3) δ 0.87 (t, J ) 6.4 Hz, 3H), 1.15-1.38 (m, 6H), 1.18 (s,
3H), 1.22 (s, 3H), 1.47-1.60 (m, 2H), 4.39 (dd, J ) 4.3, 9.2 Hz,
1H), 7.84 (d, J ) 8.4 Hz, 2H), 7.93 (d, J ) 8.4 Hz, 2H); MS
(ESI) m/z 339 (M + Na)+.
(s, 3H), 5.02 (s, 2H), 5.11 (d, J ) 9.3 Hz, 1H), 6.80-6.98 (m,
2H), 7.17-7.43 (m, 6H), 7.72 (d, J ) 8.3 Hz, 2H), 7.87 (d, J )
8.3 Hz, 2H), 8.17 (br t, J ) 8.0 Hz, 1H); MS (ESI) m/z 451 (M
+ Na)+.
3-(N-Meth yl)am in o-2,2-dim eth yl-3-ph en ylpr opion ic acid
(6o) (h yd r och lor id e): 96% yield from 5o; mp 228-229 °C;
1H NMR (270 MHz, D2O) δ 1.10 (s, 3H), 1.25 (s, 3H), 2.47 (s,
3H), 4.31 (s, 1H), 7.30-7.38 (m, 5H); MS (ESI) m/z 208 (M +
H)+.
3-[(N-4-Cyan oben zoyl)-(N-m eth yl)]am in o-2,2-dim eth yl-
3-p h en ylp r op ion ic a cid (8o): 61% yield from 6o; mp 176-
177 °C; 1H NMR (270 MHz, CD3OD) δ 1.43 (s, 3H), 1.48 (s,
3H), 2.76 (s, 3H), 5.27 (s, 1H), 7.15-7.55 (m, 5H), 7.60 (d, J )
7.8 Hz, 2H), 8.31 (d, J ) 7.8 Hz, 2H); MS (ESI) m/z 359 (M +
Na)+.
3-(N-P r opar gyl)am in o-2,2-dim eth ylh eptan oic acid (6p)
(h yd r och lor id e): 98% yield from 5p ; 1H NMR (270 MHz, CD3-
OD) δ 0.97 (t, J ) 6.8 Hz, 3H), 1.34 (s, 3H), 1.36 (s, 3H), 1.18-
1.82 (m, 6H), 3.30 (t, J ) 2.4 Hz, 1H), 3.43 (t, J ) 5.9 Hz, 1H),
4.06 (d, J ) 2.4 Hz, 2H); MS (ESI) m/z 212 (M + H)+.
3-Am in o-2,2-d im eth yl-4-h exen oic Acid (4e). A mixture
of 4-(2-propenyl)-3,3-dimethyl-2-azetidinone 3e (1.5 g, 10.7
mmol) and KOH (0.67 g, 11.8 mmol) in THF (50 mL) was
refluxed for 72 h. The solution was condensed under reduced
pressure, toluene (30 mL) was added to the residue, and the
mixture was evaporated twice to give 2.30 g (99%) of 4e as a
3-Am in o-2,2-d im eth yl-5-p h en ylp en ta n oic a cid (4i) (h y-
1
d r och lor id e): 99% yield from 3i; mp 202-203 °C; H NMR
(270 MHz, D2O) δ 1.02 (s, 3H), 1.06 (s, 3H), 1.69 (m, 1H), 1.82
(m, 1H), 2.47 (m, 1H), 2.68 (m, 1H), 3.22 (br d, J ) 9.0 Hz,
1H), 7.02-7.23 (m, 5H); MS (ESI) m/z 222 (M + H)+.
3-Am in o-2,2-dim eth yl-3-(2-n aph th yl)pr opion ic acid (4j)
(h yd r och lor id e): 99% yield from 3j; mp 254 °C; 1H NMR (270
MHz, D2O) δ 1.09 (s, 3H), 1.22 (s, 3H), 4.59 (s, 1H), 7.33-7.37
(m, 1H), 7.46-7.51 (m, 2H) 7.79-7.87 (m, 4H); MS (ESI) m/z
244 (M + H)+.
1
white solid: mp 187 °C dec; H NMR (270 MHz, D2O) δ 0.98
3-(N-4-Cya n oben zoyl)a m in o-2,2-d im eth yl-3-(2-n a p h th -
yl)p r op ion ic a cid (8j): 83% yield from 4j; mp 207-208 °C;
1H NMR (400 MHz, CD3OD) δ 1.23 (s, 3H), 1.33 (s, 3H), 5.53
(s, 1H), 7.41-7.43 (m, 2H), 7.52 (dd, J ) 8.4, 1.6 Hz, 1H), 7.74
(t, J ) 1.8 Hz, 1H), 7.74-7.80 (m, 4H), 7.86-7.89 (m, 3H);
MS (ESI) m/z 373 (M + H)+.
3-Am in o-2,2-dim eth yl-3-(4-ch lor oph en yl)pr opion ic acid
(4k ) (h yd r och lor id e): 98% yield from 3k ; mp 251-252 °C;
1H NMR (270 MHz, CD3OD) δ 1.21 (s, 3H), 1.30 (s, 3H), 4.54
(s, 1H), 7.45 (s, 4H); MS (ESI) m/z 228 (M + H)+.
(s, 3H), 1.10 (s, 3H), 1.65 (br d, J ) 6.8 Hz, 3H), 3.36 (d, J )
7.8 Hz, 1H), 5.33-5.42 (m, 1H), 5.53-5.65 (m, 1H); MS (ESI)
m/z 158 (M + H)+.
3-(N-4-Cya n ob en zoyl)a m in o-2,2-d im et h yl-4-h exen oic
1
a cid (8e): 38% yield from 4e; mp 172-174 °C; H NMR (270
MHz, CDCl3) δ 1.31 (s, 3H), 1.37 (s, 3H), 1.71 (dd, J ) 1.4, 6.2
Hz, 3H), 4.64 (br t, J ) 9.2 Hz, 1H), 5.38 (ddd, J ) 1.4, 7.8,
15.1 Hz, 1H), 5.81 (dt, J ) 6.2 Hz, 15.1 Hz, 1H), 7.29 (br d, J
) 9.2 Hz, 1H), 7.76 (d, J ) 8.3 Hz, 2H), 7.90 (d, J ) 8.3 Hz,
2H); MS (ESI) m/z 285 (M - H)-.

2354 J ournal of Medicinal Chemistry, 1998, Vol. 41, No. 13
Hayashi et al.
Gen er a l P r oced u r e C for P r ep a r a tion of 10: Ben zyl
N-[3-(N-4-Cya n oben zoyl)a m in o-2,2-d im eth ylp en ta n oyl]-
p ip er id in e-4-a ceta te (10b). To a solution of 8b (0.5 g, 1.82
mmol) and benzyl piperidine-4-acetate (2.2 g, 5.47 mmol) in
CH2Cl2 (30 mL) were added benzotriazol-1-yloxy-tris(dimethy-
lamino)phosphonium hexafluorophosphate (BOP reagent, 0.9
g, 2.0 mmol) and DIEA (0.36 mL, 2.0 mmol), and the mixture
was stirred at room temperature for 18 h. After the solvent
was removed in vacuo, the residue was dissolved in EtOAc
(50 mL), washed with 5% citric acid, 5% sodium bicarbonate,
and saturated NaCl, dried over Na2SO4, and concentrated in
vacuo. The residual oil (0.78 g) was applied to a silica gel
column (2.2 × 25 cm) and eluted with EtOAc-hexane (1:4 to
Hz, 3H), 1.15-1.45 (m, 6H) 1.33 (s, 3H), 1.41 (s, 3H), 1.70 (br
s, 2H), 1.79 (d, J ) 12.8 Hz), 2.04-2.13 (m, 1H), 2.31 (d, J )
7.6 Hz, 2H), 2.80 (br s, 2H), 4.04 (dt, J ) 2.8, 6.8 Hz, 1H),
4.38 (br d, J ) 11.6 Hz, 2H), 5.12 (s, 2H), 7.30-7.38 (m, 5H),
7.71 (d, J ) 8.0 Hz, 2H), 7.90 (d, J ) 8.0 Hz, 2H); MS (ESI)
m/z 540 (M + Na)+.
Meth yl N-[3-(N-4-cya n oben zoyl)a m in o-2,2-d im eth yl-5-
m eth ylh exa n oyl]p ip er id in e-4-a ceta te (10g): 33% yield
from 8g; 1H NMR (270 MHz, CDCl3) δ 0.90 (d, J ) 6.3 Hz,
3H), 0.96 (d, J ) 6.3 Hz, 3H), 1.07-1.29 (m, 3H), 1.34 (s, 3H),
1.40 (s, 3H), 1.33-1.44 (m, 2H), 1.70-1.86 (m, 2H), 1.97-2.15
(m, 1H), 2.27 (d, J ) 6.8 Hz, 2H), 2.71-2.92 (m, 2H), 3.68 (s,
3H), 4.10 (dt, J ) 2.4, 10.3 Hz, 1H), 4.38 (br d, J ) 12.7 Hz,
2H), 7.66 (d, J ) 10.3 Hz, 1H), 7.72 (d, J ) 8.8 Hz, 2H), 7.89
(d, J ) 8.8 Hz, 2H), MS (ESI) m/z 442 (M + H)+.
1
1:1) to give 0.60 g (67%) of 10b as an oil; H NMR (270 MHz,
CDCl3) δ 0.94 (t, J ) 7.8 Hz, 3H), 1.07-1.30 (m, 2H), 1.33 (s,
3H), 1.41 (s, 3H), 1.63-1.86 (m, 4H), 1.98-2.17 (m, 1H), 2.31
(d, J ) 6.8 Hz, 2H), 2.69-2.92 (m, 2H), 3.95 (dt, J ) 3.9, 9.8
Hz, 1H), 4.36 (br d, J ) 12.7 Hz, 2H), 5.12 (s, 2H), 7.35 (m,
5H), 7.67-7.76 (m, 1H), 7.72 (d, J ) 8.3 Hz, 2H), 7.90 (d, J )
8.3 Hz, 2H); 13C NMR (67.5 MHz, CDCl3) δ 11.7, 23.9, 24.5,
24.6, 31.9, 32.2, 33.1, 40.7, 46.2, 62.1, 66.3, 114.7, 118.1, 127.6,
128.2, 128.3, 128.6, 132.3, 135.8, 138.8, 165.5, 171.9, 175.4;
MS (ESI) m/z 512 (M + Na)+.
Compounds 10a ,c-p were prepared according to the general
procedure C described for 10b starting from the appropriate
intermediates (8a -p ) by coupling with benzyl piperidine-4-
acetate for 10c,d ,f,h -l,n ,o or methyl piperidine-4-acetate for
10a ,e,g,m ,p .
Met h yl N-[3-(N-4-cya n ob en zoyl)a m in o-2,2-d im et h yl-
bu ta n oyl]p ip er id in e-4-a ceta te (10a ): 98% yield from 8a ; 1H
NMR (270 MHz, CDCl3) δ 1.09-1.35 (m, 2H), 1.34 (d, J ) 6.2
Hz, 3H), 1.35 (s, 3H), 1.40 (s, 3H), 1.73-1.87 (m, 2H), 1.96-
2.13 (m, 1H), 2.26 (d, J ) 7.3 Hz, 2H), 2.72-2.89 (m, 2H), 3.67
(s, 3H), 4.10-4.20 (m, 1H), 4.37 (br d, J ) 13.5 Hz, 2H), 7.71
(d, J ) 8.4 Hz, 2H), 7.88 (d, J ) 8.4 Hz, 2H), 7.92 (d, J ) 9.5
Hz, 1H); MS (ESI) m/z 422 (M + Na)+.
Ben zyl N-[3-(N-4-cya n ob en zoyl)a m in o-2,2-d im et h yl-
h exa n oyl]p ip er id in e-4-a ceta te (10c): 25% yield from 8c; mp
113-114 °C; 1H NMR (270 MHz, CDCl3) δ 0.19 (t, J ) 7.3 Hz,
3H), 1.08-1.46 (m, 4H), 1.33 (s, 3H), 1.41 (s, 3H), 1.55-1.85
(m, 4H), 1.98-2.16 (m, 1H), 2.31 (d, J ) 7.3 Hz, 2H), 2.68-
2.89 (m, 2H), 4.03 (dt, J ) 3.0, 10.3 Hz, 1H), 4.36 (br d, J )
13.2 Hz, 2H), 5.12 (s, 2H), 7.35 (m, 5H), 7.67-7.76 (m, NH),
7.72 (d, J ) 8.3 Hz, 2H), 7.89 (d, J ) 8.3 Hz, 2H); 13C NMR
(67.5 MHz, CDCl3) δ 14.0, 20.4, 24.5, 24.7, 31.9, 32.2, 33.1,
33.3, 40.7, 46.2, 60.3, 66.3, 114.7, 118.1, 127.6, 128.2, 128.3,
128.6, 132.3, 135.8, 138.8, 165.3, 171.9, 175.5; MS (ESI) m/z
526 (M + Na)+.
Ben zyl N-[3-(N-4-cya n oben zoyl)a m in o-2,2-d im eth yl-4-
m eth ylp en ta n oyl]p ip er id in e-4-a ceta te (10d ): 15% yield
from 8d ; 1H NMR (270 MHz, CDCl3) δ 0.93 (d, J ) 6.4 Hz,
3H), 1.02 (d, J ) 6.4 Hz, 3H), 1.08-1.27 (m, 2H), 1.30 (s, 3H),
1.40 (s, 3H), 1.75-1.88 (m, 2H), 1.97-2.18 (m, 2H), 2.33 (d, J
) 6.8 Hz, 2H), 2.69-2.95 (m, 2H), 4.11 (dd, J ) 5.4, 9.8 Hz,
1H), 4.45 (br d, J ) 13.2 Hz, 2H), 5.12 (s, 2H), 7.35 (m, 5H),
7.75 (d, J ) 8.3 Hz, 2H), 7.84-7.93 (m, 1H), 7.92 (d, J ) 8.3
Hz, 2H); 13C NMR (67.5 MHz, CDCl3) δ 19.3, 22.7, 24.3, 24.6,
29.9, 31.7, 32.0, 33.0, 40.6, 46.6, 62.5, 66.3, 114.6, 118.0, 127.6,
128.1, 128.2, 128.4, 132.3, 135.6, 138.6, 166.1, 172.1, 175.9;
MS (ESI) m/z 504 (M + H)+.
Meth yl N-[3-(N-4-cya n oben zoyl)a m in o-2,2-d im eth yl-4-
h exen oyl]p ip er id in e-4-a ceta te (10e): 78% yield from 8e; mp
105-108 °C; 1H NMR (270 MHz, CDCl3) δ 1.07-1.42 (m, 2H),
1.35 (s, 3H), 1.37 (s, 3H), 1.68 (d, J ) 4.9 Hz, 3H), 1.73-1.87
(m, 2H), 1.98-2.14 (m, 1H), 2.27 (d, J ) 6.8 Hz, 2H), 2.69-
2.90 (m, 2H), 3.68 (s, 3H), 4.32-4.77 (m, 3H), 5.68-5.76 (m,
2H), 7.72 (d, J ) 8.4 Hz, 2H), 7.90 (d, J ) 8.4 Hz, 2H), 8.08 (d,
J ) 12.6 Hz, 1H); 13C NMR (67.5 MHz, CDCl3) δ 17.8, 24.1,
24.5, 31.9, 32.2, 33.0, 40.5, 44.9, 45.1, 45.7, 51.5, 63.2, 114.7,
118.2, 127.7, 128.9, 130.0, 132.3, 138.8, 164.4, 172.5, 175.2;
MS (ESI) m/z 448 (M + Na)+.
Ben zyl N-[3-(N-4-cya n oben zoyl)a m in o-2,2-d im eth yloc-
1
ta n oyl]p ip er id in e-4-a ceta te (10h ): 76% yield from 8h ; H
NMR (400 MHz, CDCl3) δ 0.75 (t, J ) 7.0 Hz, 3H), 1.03-1.35
(m, 8H), 1.24 (s, 3H), 1.32 (s, 3H), 1.52-1.66 (m, 2H), 1.70 (br
d, J ) 13.2 Hz, 2H), 1.94-2.03 (m, 1H), 2.22 (d, J ) 8.4 Hz,
2H), 2.71 (br s, 2H), 3.96 (dt, J ) 2.8, 10.4 Hz, 1H), 4.29 (d, J
) 12.4 Hz, 2H), 5.03 (s, 2H), 7.21-7.29 (m, 5H), 7.62 (d, J )
8.4 Hz, 2H), 7.81 (d, J ) 8.4 Hz, 2H); MS (ESI) m/z 532 (M +
H)+.
Ben zyl N-[3-(N-4-cya n oben zoyl)a m in o-2,2-d im eth yl-5-
p h en ylp en ta n oyl]p ip er id in e-4-a ceta te (10i): 66% yield
from all of the crude product of 8i obtained in the previous
step; mp 162-164 °C; 1H NMR (400 MHz, CDCl3) δ 0.76-0.89
(m, 1H), 1.05 (br dd, J ) 12.0, 11.0 Hz, 2H), 1.24 (s, 3H), 1.27
(s, 3H), 1.64-1.72 (m, 2H), 1.83-2.11 (m, 3H), 2.21 (d, J )
6.8 Hz, 1H), 2.47-2.57 (m, 1H), 2.57-2.69 (m, 2H), 4.03 (dt, J
) 9.6, 0.3 Hz), 4.18-4.29 (m, 2H), 5.04 (s, 2H), 7.05-7.12 (m,
3H), 7.15-7.19 (m, 2H), 7.25-7.29 (m, 5H), 7.64 (d, J ) 8.0
Hz, 2H), 7.80 (d, J ) 8.0 Hz, 2H); 13C NMR (100 MHz, CDCl3)
δ 24.3, 24.5, 24.6, 31.8, 32.2, 33.0, 33.2, 33.5, 40.6, 44.9, 46.3,
60.0, 65.2, 66.3, 125.8, 127.0, 127.7, 128.2, 128.3, 128.5, 128.6,
132.3, 135.8, 138.6, 141.8; MS (ESI) m/z 588 (M + Na)+.
Ben zyl N-[3-(N-4-cya n oben zoyl)a m in o-2,2-d im eth yl-3-
(2-n a p h th yl)p r op ion yl]p ip er id in e-4-a ceta te (10j): 45%
yield from 8j; 1H NMR (400 MHz, CDCl3) δ 0.67-0.72 (m,
0.5H), 0.72-1.35 (m, 3.5H), 1.35-1.50 (m, 3H), 1.50-1.76 (m,
1H), 1.83-1.92 (m, 1H), 2.02-2.09 (m, 1.4H), 2.14-2.24 (m,
0.6H), 2.48-2.93 (m, 2H), 2.57-2.63 (m, 2H), 4.10-4.35 (br s,
2H), 4.97-5.06 (m, 1H), 5.06-5.20 (m, 2H), 7.15-7.89 (m,
16H), 13C NMR (100 MHz, CDCl3) δ 23.0, 24.8, 25.4, 25.5, 25.9,
26.7, 27.1, 31.7, 32.0, 32.8, 33.2, 33.9, 36.2, 36.3, 38.8, 40.2,
41.0, 45.4, 45.5, 46.3, 46.9, 47.0, 51.7, 61.3, 63.7, 66.0, 66.2,
67.1, 114.7, 118.1, 125.1, 126.0, 126.1, 126.2, 126.7, 127.1,
127.4, 127.5, 127.6, 127.7, 127.8, 128.0, 128.05, 128.1, 128.2,
128.4, 128.5, 128.6, 132.2, 132.3, 132.7, 132.8, 133.0, 135.0,
135.7, 136.0, 136.1, 136.8, 136.9, 138.4, 164.2, 164.3, 171.8,
172.5, 175.6, 177.0; MS (ESI) m/z 588 (M + H)+.
Ben zyl N-[3-(N-4-cya n oben zoyl)a m in o-2,2-d im eth yl-3-
(4-ch lor op h en yl)p r op ion yl]p ip er id in e-4-a cet a t e (10k ):
1
45% yield from 8k ; H NMR (270 MHz, CDCl3) δ 0.89-1.15
(m, 2H), 1.22 (s, 3H), 1.42 (s, 3H), 1.69 (br t, J ) 13.6 Hz, 2H),
1.88-2.07 (m, 1H), 2.20 (d, J ) 6.8 Hz, 2H), 2.68 (br q, J )
12.0 Hz, 2H), 4.13-4.38 (m, 2H), 4.93 (d, J ) 8.8 Hz, 1H), 5.04
(s, 2H), 7.18 (d, J ) 8.4 Hz, 2H), 7.34 (d, J ) 8.4 Hz, 2H),
7.15-7.37 (m, 5H), 7.64 (d, J ) 8.0 Hz, 2H), 7.83 (d, J ) 8.0
Hz, 2H), 8.97 (d, J ) 8.8 Hz, 1H); 13C NMR (67.5 MHz, CDCl3)
δ 25.2, 26.2, 31.7, 32.2, 32.9, 40.6, 45.4, 45.5, 46.6, 63.5, 66.3,
114.9, 118.1, 127.7, 128.2, 128.3, 128.6, 130.6, 132.3, 133.4,
135.7, 138.0, 138.2, 164.4, 171.8, 175.5; MS (ESI) m/z 594 (M
+ Na)+.
Ben zyl N-[3-(N-4-cya n oben zoyl)a m in o-2,2-d im eth yl-3-
(4-ben zyloxyph en yl)pr opion yl]piper idin e-4-acetate (10l):
49% yield from 8l; 1H NMR (270 MHz, CDCl3) δ 0.97-1.37
(m, 2H), 1.31 (s, 3H), 1.48 (s, 3H), 1.63-1.84 (m, 2H), 1.94-
2.18 (m, 1H), 2.26 (d, J ) 6.8 Hz, 2H), 2.56-2.84 (m, 2H),
4.17-4.41 (m, 2H), 5.00 (d, J ) 8.8 Hz, 1H), 5.02 (s, 2H), 5.11
(s, 2H), 6.89 (d, J ) 8.8 Hz, 2H), 7.22-7.52 (m, 12H), 7.69 (d,
J ) 8.3 Hz, 2H), 7.91 (d, J ) 8.3 Hz, 2H), 8.94 (d, J ) 8.8 Hz,
1H); MS (ESI) m/z 666 (M + Na)+.
Ben zyl N-[3-(N-4-cya n ob en zoyl)a m in o-2,2-d im et h yl-
h ep ta n oyl]p ip er id in e-4-a ceta te (10f): 58% yield from 8f;
mp 104-107 °C; 1H NMR (400 MHz, CDCl3) δ 0.86 (t, J ) 6.0

GPIIb/ IIIa Integrin Antagonists
J ournal of Medicinal Chemistry, 1998, Vol. 41, No. 13 2355
Meth yl N-[3-(N-4-cya n oben zoyl)a m in o-2,2-d im eth yl-3-
(3-ch lor op h en yl)p r op ion yl]p ip er id in e-4-a cet a t e (10m ):
65% yield from 8m ; 1H NMR (400 MHz, CDCl3) δ 1.01 (br dd,
J ) 11.1, 25.2 Hz, 1H), 1.16 (ddd, J ) 4.0, 12.4, 25.2 Hz, 1H),
1.33 (s, 3H), 1.51 (s, 3H), 1.70 (br d, J ) 16.0 Hz, 1H), 1.79 (br
d, J ) 16.4 Hz, 1H), 1.96-2.10 (m, 1H), 2.23 (d, J ) 6.8 Hz,
2H), 2.71 (dd, J ) 10.8, 1.2 Hz, 1H), 2.67-2.86 (m, 1H), 3.67
(s, 3H), 4.33 (br s, 2H), 4.99 (d, J ) 9.2 Hz, 1H), 7.23-7.25
(m, 2H), 7.30-7.36 (m, 1H), 7.46 (s, 1H), 7.72 (d, J ) 8.4 Hz,
2H), 7.92 (d, J ) 8.4 Hz, 2H); 13C NMR (100 MHz, CDCl3) δ
25.3, 26.5, 31.8, 32.1, 32.9, 40.4, 45.4, 46.7, 51.5, 63.5, 114.9,
118.1, 127.6, 127.75, 127.82, 129.0, 129.4, 132.4, 134.1, 138.2,
141.6, 164.4, 172.5, 175.6; MS (ESI) m/z 518 (M + Na)+.
of 19 (TFA salt) as a white fluffy powder: 1H NMR (400 MHz,
CD3OD) δ 0.89-0.99 (m, 3H), 1.12-1.26 (m, 2H), 1.27 (s, 3H),
1.30 (s, 3H), 1.53-1.70 (m, 2H), 1.84 (br t, J ) 14.8 Hz, 2H),
2.00-2.14 (m, 1H), 2.21-2.30 (m, 2H), 2.75-3.10 (br, 2H), 4.47
(m, 1H), 4.55 (br d, J ) 13.6 Hz, 2H), 7.89 (d, J ) 8.4 Hz, 2H),
7.99 (d, J ) 8.4 Hz, 2H); 13C NMR (100 MHz, CD3OD) δ 12.7,
27.1, 24.6, 25.0, 34.0, 34.1, 35.1, 42.3, 47.5, 130.1, 133.1, 144.9,
168.8, 170.5, 176.8, 177.1; MS (ESI) m/ z 417 (M + H)+; HRMS
(FAB) calcd for C22H33N4O4 (M + H)+ 417.2501, found 417.2473;
HPLCa K′ 8.49. Anal. (C22H32N4O4‚CF3COOH‚H2O) C, H, N.
Compounds 18 and 20-33 were prepared according to the
general procedure D described for 19 starting from the
appropriate intermediates (10a -p ). However, in compounds
18, 22, 24, 30, and 33, methyl ester for the protection of
carboxylic acid was removed by the procedure described for
18.
Ben zyl N-[3-(N-4-cya n oben zoyl)a m in o-2,2-d im eth yl-3-
(3-ben zyloxyp h en yl)p r op ion yl]p ip er id in e-4-a ceta te(10n ):
1
60% yield from 8n ; H NMR (270 MHz, CDCl3) δ 0.84-1.38
(m, 2H), 1.33 (s, 3H), 1.48 (s, 3H), 1.72 (br t, J ) 10.7 Hz, 2H),
1.92-2.12 (m, 1H), 2.25 (d, J ) 6.8 Hz, 2H), 2.54-2.73 (m,
2H), 4.11-4.38 (m, 2H), 4.99 (d, J ) 8.8 Hz, 1H), 5.06 (s, 2H),
5.10 (s, 2H), 6.87 (dd, J ) 3.0, 8.5 Hz, 1H), 6.95-7.09 (m, 2H),
7.17-7.43 (m, 11H), 7.66 (d, J ) 8.3 Hz, 2H), 7.90 (d, J ) 8.3
Hz, 2H), 8.94 (d, J ) 8.8 Hz, 1H); MS (ESI) m/z 666 (M +
Na)+.
N-[3-(N-4-Amidinobenzoyl)amino-2,2-dimethylbutanoyl]-
p ip er id in e-4-a cetic Acid (18). All of the crude product of
11a (0.68 g), which was prepared according to the general
procedure D for 19 from 10a (0.60 g, 1.5 mmol), was dissolved
in 80% aqueous MeOH (10 mL). To the solution was added
LiOH (54 mg, 2.25 mmol), and the mixture was stirred at room
temperature for 30 min. After solvent was removed in vacuo,
the residue was dissolved in 1 N AcOH (3 mL) and purified
over preparative reverse phased HPLC (µBondasphere 5C18
100 Å, 19 × 150 mm) eluted in a linear gradient with 9% to
14% acetonitrile in 0.1% TFA over 15 min at a flow rate of 17
mL/min) to give 18 (TFA salt) as a white fluffy powder (0.36
g, 46%): 1H NMR (400 MHz, CD3OD) δ 1.00-1.25 (m, 2H),
1.18-1.22 (m, 3H), 1.41-1.46 (m, 3H), 1.60-1.63 (m, 3H),
1.68-1.95 (m, 2H), 2.00-2.14 (m, 1H), 2.19-2.29 (m, 2H),
2.64-2.70 (m, 1H), 3.09-3.20 (m, 1H), 3.29-3.31 (m, 3H),
3.46-3.52 (m 1H), 4.23-4.30 (m, 1H), 4.55-4.65 (m, 1H),
7.81-7.99 (m, 4H); 13C NMR (100 MHz, CD3OD) δ 14.5, 14.7,
15.1, 25.7, 25.8, 26.4, 26.8, 33.6, 33.7, 34.4, 34.9, 35.0, 35.1,
42.17, 42.24, 43.3, 43.4, 44.0, 44.1, 58.1, 58.3, 129.5, 129.66,
129.71, 130.2, 133.0, 134.5, 142.8, 168.6, 168.7, 168.8, 176.8,
177.0; MS (ESI) m/ z 403 (M + H)+; HRMS (FAB) calcd for
Ben zyl N-[3-[(N-4-cya n ob en zoyl)-(N-m et h yl)]a m in o-
2,2-d im e t h yl-3-p h e n ylp r op ion yl]p ip e r id in e -4-a ce t a t e
1
(10o): 98% yield from 8o; H NMR (270 MHz, CDCl3) δ 1.53
(s, 3H), 1.57 (s, 3H), 1.53-1.82 (m, 4H), 1.94 (br s, 1H), 2.13
(d, J ) 6.8 Hz, 2H), 2.53-2.90 (m, 2H), 2.67 (s, 3H), 4.48 (br
t, J ) 13.6 Hz, 2H), 5.08 (s, 2H), 5.06-5.20 (m, 1H), 7.24-
7.50 (m, 10H), 7.53 (d, J ) 7.8 Hz, 2H), 7.74 (d, J ) 7.8 Hz,
2H); MS (ESI) m/z 574 (M + Na)+.
Meth yl N-[3-[(N-4-cyan oben zoyl)-(N-pr opar gyl)]am in o-
2,2-d im et h ylh ep t a n oyl]p ip er id in e-4-a cet a t e (10p ): 52%
yield from all of the crude product of 8p obtained in the
previous step; 1H NMR (270 MHz, CDCl3) δ 0.80-0.98 (m, 3H),
1.38 (s, 3H), 1.41 (s, 3H), 1.08-1.58 (m, 8H), 1.64-1.92 (m,
2H), 1.96-2.16 (m, 1H), 2.18-2.31 (m, 3H), 2.70-3.04 (m, 2H),
3.65 (s, 3H), 3.92-4.18 (m, 2H), 4.55-4.76 (m, 2H), 5.20 (br d,
J ) 11.2 Hz, 1H), 7.73 (d, J ) 8.3 Hz, 2H), 7.93 (d, J ) 8.3 Hz,
2H); MS (ESI) m/z 502 (M + Na)+.
C
21H31N4O4 (M + H)+ 403.2345, found 403.2380. Anal.
(C21H30N4O4‚2CF3COOH) C, H, N.
N -[3-(N -4-Am id in ob e n zoyl)a m in o-2,2-d im e t h ylh e x-
a n oyl]p ip er id in e-4-a cetic a cid (20): 32% yield from 10c;
1H NMR (400 MHz, CD3OD) δ 0.90-0.97 (m, 3H), 1.15-1.36
(m, 3H), 1.27 (s, 3H), 1.31 (m, 3H), 1.36-1.47 (m, 2H), 1.58-
1.71 (m, 1H), 1.76-1.89 (m, 2H), 1.97-2.13 (m, 1H), 2.19-
2.28 (m, 2H), 4.48-4.63 (m, 3H), 7.83-7.92 (m, 2H), 7.94-
8.02 (m, 2H); 13C NMR (100 MHz, CD3OD) δ 15.0, 22.0, 24.1,
24.6, 34.1, 35.2, 42.4, 56.8, 130.8, 133.1, 141.9, 168.7, 170.2,
176.8, 177.1; MS (ESI) m/ z 431 (M + H)+; HRMS (FAB) calcd
for C23H35N4O4 (M + H)+ 431.2658, found 431.2652; HPLCa
K′ 10.69. Anal. (C23H34N4O4‚CF3COOH‚1.5H2O) C, H, N.
Gen er a l P r oced u r e D for P r ep a r a tion of Com p ou n d
1 An a logu es. N-[3-(N-4-Am id in ob en zoyl)a m in o-2,2-d i-
m eth ylp en ta n oyl]p ip er id in e-4-a cetic Acid (19). A solu-
tion of the nitrile 10b (245 mg, 0.5 mmol) in pyridine (40 mL)
was bubbled with 10% H2S/N2 gas for 15 min in the presence
of triethylamine (1 mL) and allowed to stand at room temper-
ature for 24 h. The solvent was removed by evaporation, and
then toluene (30 mL) was added to the residue and evaporated
twice. The resulting yellow powder and MeI (1.2 mL) were
dissolved in acetone (20 mL) and refluxed for 1 h. After
evaporation, to the residual pale yellow oil was added am-
monium acetate (0.6 g) in MeOH (25 mL), and the mixture
was refluxed for 1.5 h. The solvent was removed by evapora-
tion, and the residue was dissolved in CHCl3. The mixture
was washed with saturated NaCl, dried over anhydrous Na2-
SO4, and concentrated under reduced pressure. The residual
oil (0.78 g) was applied to a silica gel column (1.5 × 18 cm)
and eluted with CHCl3-MeOH (10:1) to give 80 mg (32%) of
11b as an oil: 1H NMR (400 MHz, CDCl3) δ 0.84 (t, J ) 7.0
Hz, 3H), 1.07-1.22 (m, 2H), 1.28 (s, 3H), 1.24 (s, 3H), 1.53-
2.07 (m, 5H), 2.28 (d, J ) 7.2 Hz, 2H), 2.58-2.96 (m, 2H), 4.09
(t, J ) 6.8 Hz, 1H), 4.34 (d, J ) 12.0 Hz, 2H), 5.10 (s, 2H),
7.28-7.37 (m, 5H), 7.83 (d, J ) 8.4 Hz, 2H), 7.92 (d, J ) 8.4
Hz, 2H), 8.18 (br s, 3H); MS (ESI) m/z 507 (M + H)+. To a
solution of 11b (40 mg, 0.079 mmol) in 20 mL of 90% aqueous
MeOH containing 2% AcOH was added 10 mg of 20% Pd(OH)2
on carbon, and the mixture was stirred at room temperature
for 15 min under atmospheric hydrogen pressure. After the
catalyst was filtered off and the filtrate was concentrated
under reduced pressure, the residue was dissolved in 1 N
AcOH and purified over preparative reverse phased HPLC
(µBondasphere 5C18 100 Å, 19 × 150 mm) eluted in a linear
gradient with 20% to 30% acetonitrile in 0.1% aqueous TFA
over 20 min at a flow rate of 17 mL/min) to give 21 mg (64%)
N-[3-(N-4-Am id in oben zoyl)a m in o-2,2-d im eth yl-4-m et-
h yp en ta n oyl]p ip er id in e-4-a cetic a cid (21): 38% yield from
1
10d ; H NMR (400 MHz, CD3OD) δ 0.97 (d, J ) 5.6 Hz, 6H),
1.17-1.32 (m, 6H), 1.28 (m, 6H), 1.83-1.92 (m, 2H), 1.96-
2.13 (m, 2H), 2.27 (d, J ) 6.8 Hz, 2H), 2.73-3.09 (br s, 2H),
4.45 (br t, J ) 8.8 Hz, 1H), 4.48-4.73 (m, 2H), 7.90 (d, J ) 7.2
Hz, 2H), 8.01 (d, J ) 7.2 Hz, 2H); MS (ESI) m/ z 431 (M +
H)+; HRMS (FAB) calcd for C23H35N4O4 (M + H)+ 431.2658,
found 431.2626; HPLCa K′ 9.72. Anal. (C23H34N4O4‚1.5CF3-
COOH‚H2O) C, H, N.
N-[3-(N-4-Am id in oben zoyl)a m in o-2,2-d im eth yl-4-h ex-
en oyl]p ip er id in e-4-a cetic a cid (22): 31% yield from 10e;
1H NMR (400 MHz, CD3OD) δ 1.13-1.27 (m, 2H), 1.32 (s, 6H),
1.70 (d, J ) 5.2 Hz, 3H), 1.82 (br d, J ) 12.4 Hz, 2H), 1.96-
2.09 (m, 1H), 2.24 (d, J ) 6.8 Hz, 2H), 2.60-3.04 (m, 2H), 4.47
(br d, J ) 13.2 Hz, 2H), 4.87 (br d, J ) 7.2 Hz, 1H), 5.64 (ddd,
J ) 1.6, 7.2, 15.2 Hz, 1H), 5.73 (dq, J ) 5.2, 15.2 Hz, 1H),
7.87 (d, J ) 8.8 Hz, 2H), 7.97 (d, J ) 8.8 Hz, 2H); MS (ESI)
m/ z 429 (M + H)+; HRMS (FAB) calcd for C23H33N4O4 (M +
H)+ 429.2501, found 429.2524; HPLCa K′ 9.89. Anal.
(C23H32N4O4‚1.5CF3COOH) C, H, N.
N -[3-(N -4-Am id in ob e n zoyl)a m in o-2,2-d im e t h ylh e p -
ta n oyl]p ip er id in e-4-a cetic a cid (23): 24% yield from 10f;

2356 J ournal of Medicinal Chemistry, 1998, Vol. 41, No. 13
Hayashi et al.
1H NMR (400 MHz, CD3OD) δ 0.89 (t, J ) 6.8 Hz, 3H), 1.13-
1.43 (m, 6H), 1.27 (s, 3H), 1.30 (s, 3H), 1.49 (br dd, J ) 6.9,
13.8 Hz, 1H), 1.64 (br dd, J ) 11.1, 22.0 Hz, 1H), 1.86 (br t, J
) 12.8 Hz, 2H), 2.01-2.12 (m, 1H), 2.25 (d, J ) 6.8 Hz, 2H),
2.77-3.08 (br, 2H), 4.52-4.61 (m, 3H), 7.89 (d, J ) 8.0 Hz,
2H), 7.99 (d, J ) 8.0 Hz, 2H); MS (ESI) m/ z 445 (M + H)+;
HRMS (FAB) calcd for C24H37N4O4 (M + H)+ 445.2814, found
445.2792; HPLCa K′ 13.31. Anal. (C24H36N4O4‚CF3-
COOH‚1.5H2O) C, H, N.
(s, 1H), 6.74 (d, J ) 6.8 Hz, 2H), 7.25 (d, J ) 8.8 Hz, 2H), 7.87
(d, J ) 8.8 Hz, 2H), 7.95 (d, J ) 8.8 Hz, 2H); MS (ESI) m/ z
481 (M + H)+; HRMS (FAB) calcd for C26H33N4O5 (M + H)+
481.2450, found 481.2448; HPLCa K′ 8.45.
(C26H32N4O5‚1.5CF3COOH‚0.5H2O) C, H, N.
Anal.
N-[3-(N-4-Am idin oben zoyl)am in o-2,2-dim eth yl-3-(3-ch lo-
r op h en yl)p r op ion yl]p ip er id in e-4-a cetic a cid (30): 20%
1
yield from 10m ; H NMR (400 MHz, CD3OD) δ 1.08 (br dd, J
) 22.0, 8.0 Hz, 1H), 1.22 (ddd, J ) 2.8, 12.4, 24.4 Hz, 1H),
1.30 (s, 3H), 1.36 (s, 3H), 1.81 (br s, 2H), 1.97-2.10 (m, 1H),
2.14-2.25 (m, 2H), 2.80-3.03 (br m, 2H), 4.51 (br d, J ) 13.2
Hz, 2H), 5.56 (s, 1H), 7.29-7.34 (m, 2H), 7.39 (dt, J ) 6.8, 1.6
Hz, 1H), 7.52 (s, 1H), 7.89 (dt, J ) 8.4, 2.0 Hz, 2H), 7.96 (dt,
J ) 8.4, 2.0 Hz, 2H); MS (ESI) m/ z 499 (M + H)+; HRMS
(FAB) calcd for C26H32ClN4O4 (M + H)+ 499.2111, found
499.2095; HPLCa K′ 17.02. Anal. (C26H31ClN4O4‚1.5CF3-
COOH‚0.5H2O) C, H, N.
N-[3-(N-4-Am id in ob en zoyl)a m in o-2,2-d im et h yl-5-m e-
th yh exa n oyl]p ip er id in e-4-a cetic a cid (24): 23% yield from
1
10g; H NMR (400 MHz, CD3OD) δ 0.92 (d, J ) 7.2 Hz, 3H),
0.94 (d, J ) 6.0 Hz, 3H), 1.11-1.35 (m, 3H), 1.52-1.63 (m,
1H), 1.69 (ddd, J ) 3.2, 11.2, 14.4 Hz, 1H), 1.84 (br d, J )
12.8 Hz, 2H), 1.97-2.11 (m, 1H), 2.25 (d, J ) 7.2 Hz, 2H),
2.80-3.05 (br s, 2H), 4.48-4.61 (m, 2H), 4.70 (br t, J ) 8.8
Hz, 1H), 7.88 (dt, J ) 8.8, 2.0 Hz, 2H), 7.98 (dt, J ) 8.8, 2.0
Hz, 2H); MS (ESI) m/ z 445 (M + H)+; HRMS (FAB) calcd for
C24H37N4O4 (M + H)+ 445.2814, found 445.2788; HPLCa K′
10.95. Anal. (C24H36N4O4‚1.5CF3COOH‚0.5H2O) C, H, N.
N-[3-(N-4-Am id in oben zoyl)a m in o-2,2-d im eth yl-3-(3-h y-
dr oxyph en yl)pr opion yl]piper idin e-4-acetic acid (31): 27%
1
yield from 10n ; H NMR (400 MHz, CD3OD) δ 1.05 (dq, J )
1.6, 8.8 Hz, 1H), 1.23 (dq, J ) 1.6, 12.4 Hz, 1H), 1.32 (s, 3H),
1.36 (s, 3H), 1.79 (br t, J ) 11.0 Hz, 2H), 1.92-2.07 (m, 1H),
2.13-2.24 (m, 2H), 2.77-2.98 (m, 2H), 4.48 (br d, J ) 13.2
Hz, 2H), 5.46 (s, 1H), 6.71 (dd, J ) 1.2, 9.6 Hz, 1H), 6.85 (t, J
) 1.2 Hz, 1H), 6.89 (br d, J ) 7.6 Hz, 1H), 7.14 (t, J ) 7.6 Hz,
1H), 7.88 (d, J ) 8.8 Hz, 2H), 7.96 (d, J ) 8.8 Hz, 2H); 13C
NMR (100 MHz, CD3OD) δ 25.6, 26.3, 33.9, 35.1, 42.3, 47.7,
62.1, 116.4, 117.5, 121.7, 130.1, 130.9, 133.2, 141.8, 142.2,
159.2, 168.9, 176.8, 177.1; MS (ESI) m/ z 481 (M + H)+; HRMS
(FAB) calcd for C26H33N4O5 (M + H)+ 481.2450, found 481.2440;
HPLCa K′ 9.20. Anal. (C26H32N4O5‚CF3COOH‚1.5H2O) C, H,
N.
N-[3-(N-4-Am id in ob en zoyl)-(N-m et h yl)]a m in o-2,2-d i-
m eth yl-3-p h en ylp r op ion yl]p ip er id in e-4-a cetic a cid (32):
17% yield from 10o; 1H NMR (400 MHz, CD3OD) δ 1.28-1.60
(m, 2H), 1.55 (s, 3H), 1.57 (s, 3H), 1.64-1.75 (m, 2H), 1.85-
2.00 (m, 1H), 2.06 (m, 2H), 2.71 (s, 3H), 2.60-3.05 (m, 2H),
4.49 (br t, J ) 13.5 Hz, 2H), 5.06 (m, 1H), 7.28-7.50 (m, 5H),
7.67 (d, J ) 7.6 Hz, 2H), 7.90 (d, J ) 7.6 Hz, 2H); 13C NMR
(100 MHz, CD3OD) δ 26.8, 27.3, 33.7, 34.9, 38.0, 42.3, 47.5,
48.1, 62.8, 129.2, 130.0, 130.4, 130.5, 131.3, 131.7, 138.9, 144.1,
163.0, 168.8, 174.9, 176.7; MS (ESI) m/ z 479 (M + H)+; HRMS
(FAB) calcd for C27H35N4O4 (M + H)+ 479.2658, found 479.2678;
HPLCa K′ 13.01. Anal. (C27H34N4O4‚1.5CF3COOH) C, H, N.
N-[3-(N-4-Am id in ob en zoyl)-(N-p r op a r gyl)]a m in o-2,2-
d im et h ylh ep t a n oyl]p ip er id in e-4-a cet ic a cid (33): 14%
yield from 10p ; 1H NMR (270 MHz, CD3OD) δ 0.95 (t, J ) 6.8
Hz, 3H), 1.08-1.68 (m, 8H), 1.36 (s, 3H), 1.42 (s, 3H), 1.77-
1.98 (m, 2H), 1.98-2.13 (m, 1H), 2.25 (d, J ) 6.8 Hz, 2H), 2.68
(t, J ) 2.2 Hz, 1H), 2.76-3.09 (m, 2H), 4.06 (dd, J ) 25.5, 2.2
Hz, 1H), 4.15 (dd, J ) 25.5, 2.2 Hz, 1H), 4.58-4.74 (m, 2H),
5.27 (br d, J ) 16.1 Hz, 1H), 7.67 (d, J ) 8.8 Hz, 2H), 7.90 (d,
J ) 8.8 Hz, 2H); MS (ESI) m/ z 483 (M + H)+; HRMS (FAB)
calcd for C27H39N4O4 (M + H)+ 483.2971, found 483.2984;
HPLCa K′ 14.66. Anal. (C27H38N4O4‚1.4CF3COOH) C, H, N.
N-[3-(N-4-Am idin oben zoyl)am ino-2,2-dim eth yloctan oyl]-
p ip er id in e-4-a cetic a cid (25): 39% yield from 10h ; 1H NMR
(400 MHz, CD3OD) δ 0.88 (t, J ) 7.0 Hz, 3H), 1.15-1.52 (m,
9H), 1.26 (s, 3H), 1.30 (s, 3H), 1.57-1.69 (m, 1H), 1.85 (br t, J
) 12.4 Hz, 2H), 2.02-2.13 (m, 1H), 2.25 (d, J ) 6.8 Hz, 2H),
2.70-3.09 (m, 2H), 4.52-4.61 (m, 3H), 7.89 (dt, J ) 6.8, 2.0
Hz, 2H), 7.99 (dt, J ) 6.8, 2.0 Hz, 2H); MS (ESI) m/ z 459 (M
+ H)+; HRMS (FAB) calcd for C25H39N4O4 (M + H)+ 459.2971,
found 459.2991; HPLCa K′ 15.53. Anal. (C25H38N4O4‚1.4CF3-
COOH) C, H, N.
N-[3-(N-4-Am id in oben zoyl)a m in o-2,2-d im eth yl-5-p h e-
n ylp en ta n oyl]p ip er id in e-4-a cetic a cid (26): 17% yield from
10i; 1H NMR (400 MHz, CD3OD) δ 0.77-0.97 (br s, 1H), 0.97-
1.13 (m, 1H), 1.13-1.28 (m, 6H), 1.62-1.78 (m, 2H), 1.83-
1.96 (m, 1H), 1.96-2.11 (m, 1H), 2.18 (d, J ) 6.8 Hz, 2H),
2.41-2.57 (m, 2H), 2.68-2.87 (m, 2H), 4.38 (br t, J ) 14.4 Hz,
2H), 4.58 (br t, J ) 11.2 Hz, 1H), 7.15-7.21 (m, 3H), 7.27 (t,
J ) 7.2 Hz, 2H), 7.92 (d, J ) 7.2 Hz, 2H), 8.04 (d, J ) 7.2 Hz,
2H); 13C NMR (100 MHz, CD3OD) δ 23.9, 24.4, 33.7, 33.9, 34.3,
34.6, 35.0, 42.2, 55.0, 128.1, 130.1, 130.4, 130.9, 133.1, 141.9,
143.6, 168.8, 170.5, 176.8; MS (ESI) m/ z 493 (M + H)+; HRMS
(FAB) calcd for C28H37N4O4 (M + H)+ 493.2814, found 493.2827;
HPLCa K′ 14.71. Anal. (C28H36N4O4‚1.3CF3COOH) C, H, N.
N-[3-(N-4-Am id in ob en zoyl)a m in o-2,2-d im et h yl-3-(2-
n a p h th yl)p r op ion yl]p ip er id in e-4-a cetic a cid (27): 32%
1
yield from 10j; H NMR (400 MHz, CD3OD) δ 0.95-1.08 (m,
1H), 1.16-1.29 (m, 1H), 1.36 (s, 3H), 1.41 (m, 3H), 1.79 (br t,
J ) 12.8 Hz, 2H), 1.92-2.07 (m, 1H), 2.07-2.17 (m, 2H), 2.53-
3.07 (br, 1H), 2.99 (br t, J ) 13.2 Hz, 1H), 4.55 (br d, J ) 13.6
Hz, 2H), 5.76 (s, 1H), 7.42-7.53 (m, 2H), 7.59 (d, J ) 8.4 Hz,
1H), 7.81-7.87 (m, 3H), 7.87-7.91 (m, 3H), 7.99 (d, J ) 6.8
Hz, 2H); MS (ESI) m/ z 515 (M + H)+; HRMS (FAB) calcd for
C
30H35N4O4 (M + H)+ 515.2658, found 515.2668; HPLCa K′
18.56. Anal. (C30H34N4O4‚1.5CF3COOH) C, H, N.
N-[3-(N-4-Am idin oben zoyl)am in o-2,2-dim eth yl-3-(4-ch lo-
r op h en yl)p r op ion yl]p ip er id in e-4-a cetic a cid (28): 33%
yield from 10k ; 1H NMR (400 MHz, CD3OD) δ 1.09 (q, J )
12.4 Hz, 1H), 1.22 (q, J ) 12.4 Hz, 1H), 1.29 (s, 3H), 1.35 (s,
3H), 1.81 (br d, J ) 12.0 Hz, 2H), 1.94-2.07 (m, 1H), 2.14-
2.25 (m, 2H), 2.75-3.00 (m, 2H), 4.51 (br d, J ) 12.0 Hz, 2H),
5.56 (s, 1H), 7.33 (d, J ) 8.4 Hz, 2H), 7.44 (d, J ) 8.4 Hz, 2H),
7.89 (d, J ) 8.8 Hz, 2H), 7.96 (d, J ) 8.8 Hz, 2H); 13C NMR
(100 MHz, CD3OD) δ 25.2, 25.7, 33.9, 34.0, 35.0, 42.3, 47.7,
61.6, 130.0, 130.2, 132.3, 133.2, 135.4, 139.6, 141.7, 169.0,
176.6, 176.8; MS (ESI) m/ z 499 (M + H)+; HRMS (FAB) calcd
for C26H32ClN4O4 (M + H)+ 499.2111, found 499.2086; HPLCa
K′ 12.29. Anal. (C26H31ClN4O4‚1.5CF3COOH) C, H, N.
Gen er a l P r oced u r e E for P r ep a r a tion of Boc-P r otect-
ed â-Ala n in e An a logu es: 3-(N-Boc)a m in o-2,2-d im eth yl-
h ep ta n oic a cid (12f). 3-Amino-2,2-dimethylheptanoic acid
hydrochloride 4f (3.65 g, 17.4 mmol) was dissolved in 10% Na2-
CO3 (18.4 mL), and di-tert-butyl dicarbonate (4.6 g, 20.87
mmol) in dioxane (50 mL) was added to the above ice-chilled
solution. After being stirred at room temperature overnight,
the solution was washed with ether (100 mL) and the aqueous
phase was acidified to pH 3 with citric acid. The resulting
powder was dissolved in EtOAc (70 mL), and the organic phase
was washed with saturated NaCl, dried over Na2SO4, and
concentrated in vacuo. The residue was recrystallized from
EtOAc with ether-hexane (1:1): yield 3.16 g (66%); mp 125-
126 °C; 1H NMR (270 MHz, CD3OD) δ 0.84-0.93 (m, 3H), 1.06
(s, 3H), 1.14 (s, 3H), 1.22-1.46 (m, 6H), 1.44 (s, 9H), 3.17-
3.82 (m, 1H); MS (ESI) m/ z 296 (M + Na)+.
N-[3-(N-4-Am id in oben zoyl)a m in o-2,2-d im eth yl-3-(4-h y-
dr oxyph en yl)pr opion yl]piper idin e-4-acetic acid (29): 33%
1
yield from 10l; H NMR (400 MHz, CD3OD) δ 1.08 (dq, J )
1.6, 10.4 Hz, 1H), 1.22 (dq, J ) 1.4, 10.4 Hz, 1H), 1.29 (s, 3H),
1.33 (s, 3H), 1.79 (br d, J ) 13.2 Hz, 2H), 1.94-2.07 (m, 1H),
2.13-2.24 (m, 2H), 2.55-3.00 (m, 2H), 4.44-4.53 (m, 2H), 5.48
Compounds 12a ,b,q were prepared according to the general
procedure E described for 12f starting from the appropriate
â-alanine analogues (4a ,b,q).

GPIIb/ IIIa Integrin Antagonists
J ournal of Medicinal Chemistry, 1998, Vol. 41, No. 13 2357
3-(N-Boc)a m in o-2,2-d im eth ylbu ta n oic a cid (12a ): 31%
yield from 4a ; mp 123-124 °C; H NMR (270 MHz, CDCl3) δ
(3 × 30 mL), and saturated NaCl (3 × 30 mL), dried over Na2-
SO4, and concentrated in vacuo. The residue was purified by
column chromatography on silica (1.8 × 20 cm) using hexane-
EtOAc (3:1) as an eluent to give a powder of 13f (0.37 g, 43%):
1
1.15 (d, J ) 6.8 Hz, 3H), 1.33 (s, 3H), 1.37 (s, 3H), 1.46 (s,
9H), 3.15 (q, J ) 6.8 Hz, 1H); MS (ESI) m/ z 232 (M + H)+.
3-(N-Boc)a m in o-2,2-d im eth ylp en ta n oic a cid (12b): 98%
1
mp 128-132 °C; H NMR (270 MHz, CDCl3) δ 0.87 (m, 3H),
1
1.08-1.42 (m, 6H), 1.34 (s, 3H), 1.40 (s, 3H), 1.59-1.75 (m,
2H), 1.73-1.86 (m, 2H), 1.96-2.15 (m, 1H), 2.27 (d, J ) 6.8
Hz, 2H), 2.81 (m, 2H), 3.68 (s, 3H), 4.12 (m, 1H), 4.40 (br d, J
) 13.2 Hz, 2H), 7.44 (dd, J ) 1.5, 10.7 Hz, 1H), 7.55 (dd, J )
1.5, 8.3 Hz, 1H), 7.81 (br t, J ) 9.3 Hz, 1H), 8.12 (t, J ) 7.8
Hz, 1H); 13C NMR (67.5 MHz, CDCl3) δ 14.0, 22.5, 24.2, 24.4,
29.4, 30.8, 32.0, 32.2, 33.1, 40.6, 46.4, 51.5, 59.9, 115.8, 115.9,
116.8, 116.9, 119.8, 120.3, 126.6, 126.8, 128.3, 128.4, 132.89,
132.94, 157.8, 161.5, 161.7, 161.8, 172.6, 174.9; MS (ESI) m/ z
482 (M + Na)+.
yield from 4b; mp 146-149 °C; H NMR (270 MHz, CDCl3) δ
0.94 (t, J ) 7.3 Hz, 3H), 1.23 (s, 6H), 1.17-1.32 (m, 1H), 1.45
(s, 9H), 1.68 (ddq, J ) 14.2, 7.8, 2.9 Hz, 1H), 3.55 (dt, J )
10.7, 2.4 Hz, 1H), 4.93 (d, J ) 10.7 Hz, 1H); 13C NMR (67.5
MHz, CDCl3) δ 11.2, 22.9, 23.3, 24.3, 28.3, 46.3, 58.6, 79.1,
156.5, 182.7; MS (ESI) m/ z 246 (M + H)+.
3-(N-Boc)a m in o-2,2-d im eth yl-3-p h en ylp r op ion ic a cid
(12q): 95% yield from 3-amino-2,2-dimethyl-3-phenylpropionic
acid hydrochloride;16 mp 144-146 °C; 1H NMR (270 MHz,
CDCl3) δ 1.15 (s, 3H), 1.26 (br s, 3H), 1.40 (br s, 9H), 4.74 (d,
J ) 9.2 Hz, 1H), 6.05 (d, J ) 9.2 Hz, 1H), 7.22-7.34 (m, 5H);
MS (ESI) m/z 294 (M + H)+.
Compounds 14a ,b,q were prepared according to the general
procedure G described for 14f starting from the appropriate
intermediates (13a ,b,q).
Gen er a l P r oced u r e F for P r ep a r a tion of 13: Meth yl
N-[3-(N-Boc)a m in o-2,2-d im eth ylh ep ta n oyl]p ip er id in e-4-
a ceta te (13f). To a solution of 12f (1.68 g, 6.13 mmol) and
methyl piperidine-4-acetate (1.45 g, 9.12 mmol) in CH2Cl2 (20
mL) were added O-(7-azabenzotriazol-1-yl)-1,1,3,3-tetramethy-
luronium hexafluorophosphate (HATU, 2.8 g, 7.37 mmol) and
DIEA (6.58 mL, 36.8 mmol), and the mixture was stirred at
room temperature for 18 h. After the solvent was removed
by evaporation, the residue was dissolved in EtOAc (50 mL).
The organic layer was washed with 5% citric acid (3 × 30 mL),
5% NaHCO3 (3 × 30 mL), and saturated NaCl (3 × 30 mL),
dried over Na2SO4, and concentrated in vacuo. The residue
was purified by column chromatography on silica (2.2 × 20
cm) using hexane-EtOAc (2:1) as an eluent to give 1.70 g
(67%) of 13f as a white powder: mp 106-108 °C; 1H NMR
(270 MHz, CD3OD) δ 0.84-0.93 (m, 3H), 1.10 (s, 3H), 1.21 (s,
3H), 1.06-1.42 (m, 8H), 1.44 (s, 9H), 1.73-1.86 (m, 2H), 1.95-
2.12 (m, 1H), 2.28 (d, J ) 6.8 Hz, 2H), 2.74-3.02 (m, 2H), 3.65
(s, 3H), 3.88-4.01 (m, 1H), 4.42-4.57 (m, 2H), 6.55 (d, J )
9.8 Hz, 1H); MS (ESI) m/ z 435 (M + Na)+.
Meth yl N-[3-(N-4-cya n o-2-flu or oben zoyl)a m in o-2,2-d i-
m et h ylb u t a n oyl]p ip er id in e-4-a cet a t e (14a ): 21% yield
from all of the crude product of 13a obtained in previous step;
1H NMR (270 MHz, CD3OD) δ 1.23 (d, J ) 6.8 Hz, 3H), 1.29
(s, 3H), 1.35 (s, 3H), 1.83 (br d, J ) 12.7 Hz, 2H), 1.93-2.14
(m, 1H), 2.25 (d, J ) 6.8 Hz, 2H), 2.80-3.05 (m, 2H), 3.30 (s,
3H), 4.49 (br d, J ) 13.2 Hz, 2H), 4.55-4.71 (m, 1H), 7.69 (d,
J ) 9.3 Hz, 2H), 7.86 (t, J ) 7.8 Hz, 1H); MS (ESI) m/ z 440
(M + Na)+.
E t h yl N-[3-(N-4-cya n o-2-flu or ob en zoyl)a m in o-2,2-d i-
m eth ylp en ta n oyl]p ip er id in e-4-a ceta te (14b): 77% yield
1
from 13b; H NMR (270 MHz, CDCl3) δ 1.00 (t, J ) 7.3 Hz,
3H), 1.13-1.40 (m, 2H), 1.31 (t, J ) 7.3 Hz, 3H), 1.39 (s, 3H),
1.46 (s, 3H), 1.68-1.93 (m, 4H), 2.02-2.23 (br m, 1H), 2.31 (d,
J ) 6.8 Hz, 2H), 2.90 (br t, J ) 11.2 Hz, 2H), 4.10-4.25 (m,
1H), 4.18 (q, J ) 6.8 Hz, 2H), 4.48 (br d, J ) 12.7 Hz, 2H),
7.50-7.68 (m, 2H), 7.89 (br t, J ) 7.8 Hz, 1H), 8.11 (t, J ) 7.8
Hz, 1H); 13C NMR (67.5 MHz, CDCl3) 11.2, 13.6, 23.4, 23.5,
23.7, 31.5, 31.7, 32.6, 40.3, 44.5, 44.8, 45.9, 59.8, 60.5, 115.2,
115.3, 116.3, 119.4, 119.8, 126.5, 126.7, 127.8, 127.9, 132.1,
157.2, 160.9, 161.7, 161.8, 171.6, 174.2; MS (ESI) m/ z 469 (M
+ Na)+.
Compounds 13a ,b,q were prepared according to the general
procedure F described for 13f starting from the appropriate
intermediates (12a ,b,q).
Ben zyl N-[3-(N-4-cya n o-2-ch lor ob en zoyl)a m in o-2,2-
d im eth yl-3-p h en ylp r op ion yl]p ip er id in e-4-a ceta te (14q):
63% yield from 13q; mp 155-157 °C; 1H NMR (270 MHz,
CDCl3) δ 0.93-1.25 (m, 2H), 1.31 (s, 3H), 1.52 (s, 3H), 1.63-
1.79 (m, 2H), 1.93-2.10 (m, 1H), 2.26 (d, J ) 7.3 Hz, 2H),
2.59-2.84 (m, 2H), 4.30 (br t, J ) 14.0 Hz, 2H), 5.11 (s, 2H),
5.12 (d, J ) 8.8 Hz, 1H), 7.23-7.45 (m, 10H), 7.51-7.68 (m,
3H), 8.52 (d, J ) 8.8 Hz, 1H); MS (ESI) m/ z 594 (M + Na)+.
N-[3-(N-4-am idin o-2-ch lor oben zoyl)am in o-2,2-dim eth yl-
3-p h en ylp r op ion yl]p ip er id in e-4-a cetic Acid (34). 34 was
prepared via the general procedure D: 24% yield from 14q;
1H NMR (400 MHz, CD3OD) δ 1.18-1.41 (m, 4H), 1.27 (s, 3H),
1.30 (s, 3H), 1.86 (br d, J ) 11.2 Hz, 2H), 1.99-2.14 (m, 1H),
2.25 (d, J ) 7.2 Hz, 2H), 2.87-3.14 (m, 2H), 4.57 (br d, J )
12.4 Hz, 2H), 5.78 (s, 1H), 7.28-7.37 (m, 3H), 7.39-7.45 (m,
2H), 7.58 (d, J ) 8.0 Hz, 1H), 7.78 (dd, J ) 1.2, 7.8 Hz, 1H),
7.93 (d, J ) 2.0 Hz, 1H); MS (ESI) m/ z 499 (M + H)+; HRMS
(FAB) calcd for C26H32ClN4O4 (M + H)+ 499.2111, found
499.2083; HPLCa K′ 12.28. Anal. (C26H31ClN4O4‚1.5CF3-
COOH‚0.5H2O) C, H, N.
Eth yl N-[3-(N-Boc)a m in o-2,2-d im eth ylp en ta n oyl]p ip -
er id in e-4-a ceta te (13b): 91% yield from 12b; H NMR (270
1
MHz, CDCl3) δ 0.93 (t, J ) 7.3 Hz, 3H), 1.12-1.30 (m, 2H),
1.22 (s, 3H), 1.26 (t, J ) 7.3 Hz, 3H), 1.27 (s, 3H), 1.32-1.58
(m, 2H), 1.43 (s, 9H), 1.79 (br d, J ) 11.2 Hz, 2H), 1.93-2.14
(br m, 1H), 2.24 (d, J ) 6.8 Hz, 2H), 2.81 (br q, J ) 12.7 Hz,
2H), 3.66 (dt, J ) 10.3, 2.9 Hz, 1H), 4.14 (q, J ) 6.8 Hz, 2H),
4.37-4.54 (br m, 2H), 4.96 (d, J ) 10.3 Hz, 1H); 13C NMR (67.5
MHz, CDCl3) δ 11.5, 14.2, 23.0, 23.5, 24.3, 28.3, 32.1, 33.1,
40.9, 45.0, 45.3, 47.0, 59.3, 60.3, 77.2, 78.7, 156.6, 172.2, 174.5;
MS (ESI) m/ z 399 (M + H)+.
Ben zyl N-[3-(N-Boc)a m in o-2,2-d im eth yl-3-p h en ylp r o-
p ion yl]p ip er id in e-4-a ceta te (13q): 98% yield from 12q; mp
1
128-131 °C; H NMR (270 MHz, CDCl3) δ 1.19 (s, 3H), 1.32
(s, 3H), 1.37 (s, 9H), 1.02-1.28 (m, 2H), 1.68-1.79 (m, 2H),
1.94-2.11 (m, 1H), 2.27 (d, J ) 6.8 Hz, 2H), 2.68-2.82 (m,
2H), 4.28-4.44 (m, 2H), 4.83 (br d, J ) 8.8 Hz, 2H), 5.11 (s,
2H), 5.98 (br s, 1H), 7.18-7.36 (m, 10H); MS (ESI) m/ z 509
(M + H)+.
Gen er a l P r oced u r e G for P r ep a r a tion of 14: Meth yl
N-[3-(N-4-Cyan o-2-flu or oben zoyl)am in o-2,2-dim eth ylh ep-
ta n oyl]p ip er id in e-4-a ceta te (14f). To 13f (0.77 g, 1.86
mmol) were added anisole (0.7 mL) and TFA (20 mL). The
reaction mixture was stirred for 1 h under cooling with ice.
After TFA was removed in vacuo at room temperature, the
resulting residue was washed with hexane three times and
dissolved in DMF (20 mL) under cooling with ice. After being
neutralized by triethylamine, 2-fluoro-4-cyanobenzoic acid
(0.40 g, 2.42 mmol), 1-hydroxybenzotriazole (HOBt, 0.33 g, 2.42
mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydro-
chloride (WSCD‚HCl, 0.56 g, 2.91 mmol) were added, and the
mixture was stirred overnight. After the solvent was removed
by evaporation, the resulting residue was dissolved in EtOAc
(50 mL), washed with 5% citric acid (3 × 30 mL), 5% NaHCO3
N-[3-(N-4-Am idin o-2-flu or oben zoyl)am in o-2,2-dim eth yl-
bu ta n oyl]p ip er id in e-4-a cetic Acid (35). 35 was prepared
from 14a via the general procedure D with the modification
for the deprotection of methyl ester described for 18: 17% yield
1
from 14a ; H NMR (400 MHz, CD3OD) δ 1.05 (d, J ) 7.5 Hz,
3H), 1.05-1.28 (m, 2H), 1.27 (s, 3H), 1.30 (s, 3H), 1.81 (m, 2H),
1.91-2.07 (m, 1H), 2.26 (d, J ) 7.4 Hz, 2H), 2.81-3.12 (m,
2H), 4.41 (m, 1H), 4.57 (br d, J ) 13.3 Hz, 2H), 7.62 (s, 1H),
7.69 (d, J ) 7.2 Hz, 1H), 7.79 (t, J ) 7.3 Hz, 1H); MS (ESI)
m/ z 421 (M + H)+; HRMS (FAB) calcd for C21H30FN4O4 (M +
H)+ 421.2250, found 421.2231; HPLCa K′ 6.83. Anal. (C21H29
FN4O4‚1.25CF3COOH) C, H, N.
-
N-[3-(N-4-Am idin o-2-flu or oben zoyl)am in o-2,2-dim eth yl-
p en ta n oyl]p ip er id in e-4-a cetic Acid (36). 36 was prepared

2358 J ournal of Medicinal Chemistry, 1998, Vol. 41, No. 13
Hayashi et al.
from 14b via the general procedure D with the modification
for the deprotection of ethyl ester described for 18: 51% yield
from 14b; H NMR (400 MHz, CD3OD) δ 0.97 (t, J ) 7.3 Hz,
N-[3-(2-F lu or o-4-(p yr r olid in yl(im in o)m eth yl)ben zoyl)-
a m in o-2,2-d im et h ylp en t a n oyl]p ip er id in e-4-a cet ic Acid
(Biologica lly Active F or m of 39). This compound was
prepared according to the procedure described for 18: 39%
1
3H), 1.10-1.28 (m, 2H), 1.25 (s, 3H), 1.34 (s, 3H), 1.56 (m, 2H),
1.84 (br t, J ) 8.9 Hz, 2H), 1.95-2.15 (m, 1H), 2.26 (d, J ) 7.3
Hz, 2H), 2.75-3.08 (m, 2H), 4.44 (m, 1H), 4.53 (br d, J ) 13.7
Hz, 2H), 7.68 (s, 1H), 7.70 (d, J ) 7.3 Hz, 1H), 7.82 (t, J ) 7.3
Hz, 1H); MS (ESI) m/ z 435 (M + H)+; HRMS (FAB) calcd for
C22H32FN4O4 (M + H)+ 435.2407, found 435.2408; HPLCa K′
8.36. Anal. (C22H31FN4O4‚1.5CF3COOH‚H2O) C, H, N.
N-[3-(N-4-Am idin o-2-flu or oben zoyl)am in o-2,2-dim eth yl-
h ep ta n oyl]p ip er id in e-4-a cetic Acid (37). 37 was prepared
from 14f via the general procedure D with the modification
for the deprotection of methyl ester described for 18: 10% yield
from 14f; 1H NMR (400 MHz, CD3OD) δ 0.91 (br t, J ) 6.4
Hz, 3H), 1.15-1.65 (m, 8H), 1.25 (s, 3H), 1.34 (s, 3H), 1.80-
1.88 (m, 2H), 2.00-2.13 (m, 1H), 2.25 (d, J ) 7.2 Hz, 2H),
2.75-3.14 (m, 2H), 4.47-4.58 (m, 3H), 7.70 (d, J ) 7.2 Hz,
2H), 7.81 (t, J ) 7.2 Hz, 1H); MS (ESI) m/ z 464 (M + H)+;
HRMS (FAB) calcd for C24H36FN4O4 (M + H)+ 463.2720, found
463.2738; HPLCa K′ 11.63. Anal. (C24H35FN4O4‚1.25CF3-
COOH‚0.25H2O) C, H, N.
1
yield from 39; H NMR (400 MHz, CD3OD) δ 0.97 (t, J ) 7.2
Hz, 3H), 1.14-1.28 (m, 2H), 1.26 (s, 3H), 1.34 (s, 3H), 1.50-
1.62 (m, 2H), 1.78-1.91 (m, 2H), 1.94-2.13 (m, 3H), 2.13-
2.23 (m, 2H), 2.26 (d, J ) 7.2 Hz, 2H), 3.48 (t, J ) 6.8 Hz,
2H), 3.63 (t, J ) 7.2 Hz, 2H), 4.38-4.46 (m, 1H), 4.53 (br d, J
) 12.8 Hz, 2H), 7.53 (d, J ) 8.0 Hz, 1H), 7.57 (d, J ) 10.4 Hz,
1H), 7.83 (t, J ) 6.8 Hz, 1H); 13C NMR (100 MHz, CD3OD) δ
12.7, 24.1, 24.7, 25.2, 26.7, 27.3, 34.1, 34.2, 35.2, 42.3, 47.4,
47.8, 50.9, 54.0, 59.8, 117.8, 118.1, 125.9, 129.5, 129.7, 133.3,
135.7, 135.8, 160.2, 163.3, 167.17, 167.21, 176.8, 177.0; MS
(ESI) m/ z 489 (M + H)+; HRMS (FAB) calcd for C26H38FN4O4
(M + H)+ 489.2876, found 489.2862; HPLCb K′ 6.45. Anal.
(C26H37FN4O4‚1.5CF3COOH‚0.5H2O) C, H, N.
Eth yl N-[3-(2-Flu or o-4-(th ia zolid in -3-yl(im in o)m eth yl)-
ben zoyl)a m in o-2,2-d im eth ylp en ta n oyl]p ip er id in e-4-a c-
eta te (40). 40 was prepared via the general procedure D.
However, thiazolidine was used instead of ammonium ac-
etate: 23% yield from 14b; 1H NMR (400 MHz, CDCl3) δ 0.92
(t, J ) 7.2 Hz, 3H), 1.16 (br q, J ) 12.0 Hz, 2H), 1.24 (t, J )
7.2 Hz, 3H), 1.30 (s, 3H), 1.35 (s, 3H), 1.59-1.73 (m, 2H), 1.78
(br d, J ) 12.0 Hz, 2H), 1.97-2.09 (m, 1H), 2.23 (d, J ) 6.8
Hz, 2H), 2.70-2.93 (m, 2H), 3.05 (t, J ) 6.4 Hz, 1H), 3.31 (t,
J ) 6.0 Hz, 1H), 3.72 (t, J ) 5.6 Hz, 1H), 4.02-4.08 (m, 2H),
4.12 (q, J ) 6.8 Hz, 2H), 4.37 (br d, J ) 13.2 Hz, 2H), 4.41 (s,
1H), 4.79 (s, 1H), 7.34 (t, J ) 8.4 Hz, 1H), 7.38 (t, J ) 8.0 Hz,
1H), 7.98 (q, J ) 8.0 Hz, 1H); 13C NMR (100 MHz, CDCl3) δ
11.7, 14.3, 24.0, 24.1, 24.2, 30.2, 30.5, 32.1, 32.3, 33.3, 41.0,
45.2, 45.6, 46.7, 51.1, 51.8, 54.4, 55.2, 60.5, 61.06, 61.14, 114.6,
115.9, 116.0, 116.1, 116.3, 117.4, 123.6, 123.70, 123.73, 126.8,
127.0, 132.8, 132.9, 133.0, 158.6, 160.7, 161.1, 161.3, 161.6,
162.7, 162.8, 172.3, 175.1; MS (ESI) m/ z 535 (M + H)+; HRMS
(FAB) calcd for C27H40FN4O4S (M + H)+ 535.2754, found
535.2750. Anal. (C27H39FN4O4S‚1.3CF3COOH) C, H, N.
Eth yl N-[3-(2-F lu or o-4-(m or p h olin -4-yl(im in o)m eth yl)-
ben zoyl)a m in o-2,2-d im eth ylp en ta n oyl]p ip er id in e-4-a c-
eta te (38). 38 was prepared via the general procedure D.
However, morpholine was used instead of ammonium ac-
etate: 28% yield from 14b; 1H NMR (270 MHz, CDCl3) δ 0.93
(m, 3H), 1.12-1.41 (m, 8H), 1.26 (t, J ) 7.0 Hz, 3H), 1.57-
1.89 (m, 4H), 1.92-2.16 (m, 1H), 2.24 (d, J ) 6.8 Hz, 2H), 2.82
(m, 2H), 3.41 (br s, 2H), 3.70 (br s, 2H), 3.85-3.97 (m, 4H),
4.03-4.19 (m, 1H), 4.13 (q, J ) 7.3 Hz, 2H), 4.27-4.47 (m,
2H), 7.32-7.43 (m, 2H), 7.68-7.82 (m, 1H), 8.00 (t, J ) 7.6
Hz, 1H); 13C NMR (67.5 MHz, CDCl3) δ 11.6, 14.2, 23.8, 23.9,
24.1, 32.0, 32.2, 33.0, 33.1, 40.6, 40.8, 45.1 (br), 46.5, 47.2, 50.1,
60.4, 60.7, 65.6, 66.2, 77.2, 116.4, 116.8, 124.2, 126.4, 126.6,
132.1, 132.2, 132.7, 157.9, 161.6, 162.7, 163.1, 172.3, 174.8;
MS (ESI) m/ z 533 (M + H)+; HRMS (FAB) calcd for C28H42
FN4O5 (M + H)+ 533.3139, found 533.3136. Anal. (C28H41
FN4O5‚CF3COOH‚H2O) C, H, N.
-
-
N-[3-(2-F lu or o-4-(t h ia zolid in -3-yl(im in o)m et h yl)b en -
zoyl)a m in o-2,2-d im et h ylp en t a n oyl]p ip er id in e-4-a cet ic
Acid (Biologica lly Active F or m of 40). This compound was
prepared according to the procedure described for 18: 71%
N-[3-(2-F lu or o-4-(m or p h olin -4-yl(im in o)m et h yl)b en -
zoyl)a m in o-2,2-d im et h ylp en t a n oyl]p ip er id in e-4-a cet ic
Acid (Biologica lly Active F or m of 38). This compound was
prepared according to the procedure described for 18: 77%
1
yield from 40; H NMR (400 MHz, CD3OD) δ 0.97 (t, J ) 7.6
Hz, 3H), 1.12-1.28 (m, 2H), 1.26 (s, 3H), 1.34 (s, 3H), 1.49-
1.62 (m, 2H), 1.84 (br t, J ) 11.2 Hz, 2H), 1.98-2.12 (m, 1H),
2.26 (d, J ) 7.6 Hz, 2H), 2.69-3.08 (m, 2H), 3.13 (t, J ) 6.4
Hz, 1H), 3.38 (t, J ) 6.4 Hz, 1H), 3.79 (t, J ) 6.0 Hz, 1H), 3.92
(t, J ) 6.0 Hz, 1H), 4.42 (dd, J ) 8.8, 4.8 Hz, 1H), 4.52 (br d,
J ) 14.8 Hz, 2H), 4.56 (s, 1H), 4.71 (s, 1H), 7.57 (ddd, J ) 7.6,
4.0, 1.6 Hz, 1H), 7.61 (ddd, J ) 9.6, 4.0, 1.6 Hz, 1H), 7.85 (t,
J ) 7.6 Hz, 1H); 13C NMR (100 MHz, CD3OD) δ 12.7, 24.1,
24.7, 25.2, 31.8, 34.0, 35.2, 47.3, 47.8, 52.3, 53.7, 56.0, 57.2,
59.7, 117.1, 117.3, 117.9, 118.0, 118.1, 118.2, 125.8, 126.0,
129.9, 130.1, 133.4, 135.1, 135.2, 135.7, 160.2, 162.7, 163.0,
163.4, 163.7, 167.1, 176.8, 177.0; MS (ESI) m/ z 507 (M + H)+;
HRMS (FAB) calcd for C25H36FN4O4S (M + H)+ 507.2441,
found 507.2426; HPLCb K′ 6.54. Anal. (C25H35FN4O4S‚1.5CF3-
COOH) C, H, N.
1
yield from 38; H NMR (400 MHz, CD3OD) δ 0.97 (t, J ) 7.6
Hz, 3H), 1.12-1.25 (m, 2H), 1.26 (s, 3H), 1.34 (s, 3H), 1.50-
1.63 (m, 2H), 1.78-1.91 (m, 2H), 2.06 (br s, 1H), 2.26 (d, J )
7.2 Hz, 2H), 2.78-3.08 (m, 2H), 3.39-3.50 (m, 2H), 3.65-3.76
(m, 2H), 3.76-3.84 (m, 2H), 3.86-3.95 (m, 2H), 4.37-4.45 (m,
1H), 4.52 (br d, J ) 12.4 Hz, 2H), 7.53 (d, J ) 7.6 Hz, 1H),
7.58 (d, J ) 10.4 Hz, 1H), 7.85 (t, J ) 7.6 Hz, 1H); 13C NMR
(100 MHz, CD3OD) δ 12.7, 24.1, 24.7, 25.3, 34.0, 34.1, 35.2,
42.3, 47.3, 47.8, 48.9, 49.3, 52.2, 59.9, 67.1, 68.0, 118.5, 118.7,
126.5, 129.8, 129.9, 133.5, 134.5, 134.6, 160.4, 162.9, 165.6,
167.0, 176.8, 177.1; MS (ESI) m/ z 506 (M + H)+; HRMS (FAB)
calcd for C26H38FN4O5 (M + H)+ 505.2826, found 505.2827;
HPLCb K′ 6.00. Anal. (C26H37FN4O5‚1.5CF3COOH‚0.5H2O) C,
H, N.
E t h yl N-[3-(2-F lu or o-4-(p yr r olid in yl(im in o)m et h yl)-
ben zoyl)a m in o-2,2-d im eth ylp en ta n oyl]p ip er id in e-4-a c-
eta te (39). 39 was prepared via the general procedure D.
However, pyrrolidine was used instead of ammonium ac-
etate: 25% yield from 14b; 1H NMR (270 MHz, CDCl3) δ 1.16-
1.42 (m, 2H), 1.26 (t, J ) 7.29 Hz, 6H), 1.31 (s, 3H), 1.37 (s,
3H), 1.59-1.89 (m, 4H), 1.91-2.30 (m, 5H), 2.25 (d, J ) 7.3
Hz, 2H), 2.71-2.91 (m, 2H), 3.43 (br t, J ) 6.3 Hz, 2H), 3.76
(br s, 2H), 4.06-4.48 (m, 1H), 4.13 (q, J ) 6.9 Hz, 2H), 4.41
(br d, J ) 12.7 Hz, 2H), 7.28-7.43 (m, 2H), 7.66 (br d, J ) 8.2
Hz, 1H), 8.00 (m, 1H); 13C NMR (67.5 MHz, CDCl3) δ 11.5,
14.2, 23.8, 23.9, 24.1, 24.9, 25.0, 25.5, 29.7, 32.0, 32.2, 32.3,
33.1, 40.8, 45.1, 45.4, 46.5, 49.1, 52.1, 60.4, 60.7, 77.2, 115.7,
116.1, 123.6, 125.9, 126.1, 132.6, 133.2, 133.4, 157.8, 160.9,
161.0, 161.5, 162.7, 172.2, 174.8; MS (ESI) m/ z 517 (M + H)+;
HRMS (FAB) calcd for C28H42FN4O4 (M + H)+ 517.3189, found
517.3207. Anal. (C28H41FN4O4‚CF3COOH‚1.5H2O) C, H, N.
Eth yl N-[3-(2-F lu or o-4-(4-h yd r oxyp ip er id in yl(im in o)-
m eth yl)ben zoyl)am in o-2,2-dim eth ylpen tan oyl]piper idin e-
4-a ceta te (41). 41 was prepared via the general procedure
D. However, 4-hydroxypiperidine was used instead of am-
monium acetate: 30% yield from 14b; 1H NMR (270 MHz,
CDCl3) δ 0.92 (t, J ) 7.3 Hz, 3H), 1.09-1.39 (m, 2H), 1.25 (t,
J ) 7.0 Hz, 6H), 1.29 (s, 3H), 1.35 (s, 3H), 1.55-1.92 (m, 7H),
1.92-2.13 (m, 2H), 2.24 (d, J ) 6.75 Hz, 2H), 2.74-2.93 (m,
2H), 3.22-3.36 (m, 1H), 3.53-3.68 (m, 1H), 3.68-3.83 (m, 1H),
3.94-4.19 (m, 3H), 4.12 (q, J ) 7.2 Hz, 2H), 4.37 (br d, J )
11.6 Hz, 2H), 7.29-7.39 (m, 2H), 7.72 (br t, J ) 8.1 Hz, 1H),
7.94 (t, J ) 7.6 Hz, 1H); 13C NMR (67.5 MHz, CDCl3) δ 11.5,
14.2, 23.8, 24.0, 31.9, 32.1, 32.5, 33.1, 33.4, 40.8, 43.8, 45.0,
45.5, 46.5, 47.3, 60.4, 60.6, 63.9, 77.2, 113.8, 116.1, 116.5, 118.1,
124.0, 126.1, 126.3, 132.4, 132.7, 132.9, 157.8, 160.3, 160.8,
161.5, 162.3, 163.0, 172.3, 174.9; MS (ESI) m/ z 547 (M + H)+;

GPIIb/ IIIa Integrin Antagonists
J ournal of Medicinal Chemistry, 1998, Vol. 41, No. 13 2359
HRMS (FAB) calcd for C29H44FN4O5 (M + H)+ 547.3295, found
547.3309. Anal. (C29H43FN4O5‚CF3COOH‚H2O) C, H, N.
N-[3-(2-Flu or o-4-(4-(4-flu or oph en yl)piper azin yl(im in o)-
m eth yl)ben zoyl)am in o-2,2-dim eth ylpen tan oyl]piper idin e-
4-a cetic Acid (Biologica lly Active F or m of 43). This
compound was prepared according to the procedure described
for 18: 72% yield from 43; 1H NMR (400 MHz, CD3OD) δ 0.98
(t, J ) 7.6 Hz, 3H), 1.15-1.28 (m, 2H), 1.26 (s, 3H), 1.35 (s,
3H), 1.51-1.62 (m, 2H), 1.84 (br t, J ) 11.2 Hz, 2H), 1.98-
2.15 (m, 1H), 2.25 (d, J ) 7.2 Hz, 2H), 2.75-3.07 (m, 2H), 3.20
(t, J ) 4.8 Hz, 2H), 3.40 (t, J ) 4.8 Hz, 2H), 3.61 (t, J ) 4.4
Hz, 2H), 3.95 (t, J ) 4.8 Hz, 2H), 4.41 (dd, J ) 5.2, 9.6 Hz,
1H), 4.52 (br d, J ) 13.2 Hz, 2H), 7.01 (d, J ) 6.8 Hz, 4H),
7.56 (dd, J ) 1.2, 7.6 Hz, 1H), 7.61 (d, J ) 10.4 Hz, 1H), 7.87
(t, J ) 6.8 Hz, 1H); 13C NMR (100 MHz, CD3OD) δ 12.7, 24.1,
24.7, 25.2, 34.0, 34.1, 35.2, 42.3, 47.3, 47.7, 50.9, 51.9, 52.0,
59.8, 117.3, 117.5, 118.5, 118.8, 120.7, 120.8, 126.5, 129.8,
129.9, 133.4, 134.7, 134.8, 149.1, 165.4, 167.1, 176.8, 177.0;
MS (ESI) m/ z 598 (M + H)+; HPLCb K′ 8.83. Anal.
(C32H41F2N5O4‚2CF3COOH) C, H, N.
N-[3-(2-Flu or o-4-(4-h ydr oxypiper idin yl(im in o)m eth yl)-
ben zoyl)a m in o-2,2-d im eth ylp en ta n oyl]p ip er id in e-4-a ce-
tic Acid (Biologica lly Active F or m of 41). This compound
was prepared according to the procedure described for 18: 84%
1
yield from 41; H NMR (400 MHz, CD3OD) δ 0.91-1.04 (m,
3H), 1.12-1.28 (m, 2H), 1.26 (s, 3H), 1.34 (s, 3H), 1.50-1.67
(m, 3H), 1.74-1.95 (m, 4H), 2.09 (br s, 2H), 2.26 (br d, J ) 6.4
Hz, 2H), 2.70-3.10 (m, 2H), 3.30-3.38 (br s, 1H), 3.55-3.74
(m, 2H), 3.90-4.08 (m, 2H), 4.42 (br s, 1H), 4.53 (br d, J )
12.0 Hz, 2H), 7.51 (br d, J ) 7.6 Hz, 1H), 7.57 (br d, J ) 10.0
Hz, 1H), 7.84 (m, 1H); 13C NMR (100 MHz, CD3OD) δ 12.7,
24.0, 24.7, 25.2, 34.0, 34.2, 34.3, 35.2, 35.4, 42.3, 45.7, 47.4,
47.7, 59.7, 66.1, 118.1, 118.4, 126.1, 129.7, 129.8, 133.3, 135.1,
135.2, 160.3, 162.8, 164.8, 167.2, 176.8, 177.0; MS (ESI) m/ z
519 (M + H)+; HRMS (FAB) calcd for C27H40FN4O5 (M + H)+
519.2982, found 519.2981; HPLCb K′ 5.70. Anal. (C27H39
FN4O5‚1.5CF3COOH‚H2O) C, H, N.
-
N-[(R)-3-(N-Boc)a m in o-2,2-d im et h ylp en t a n oyl]-(R)-1-
(1-n a p h th yl)eth yla m in e (15-R). To a solution of 3-(N-Boc)-
amino-2,2-dimethylpentanoic acid 12b (4 g, 16.4 mmol) and
(R)-1-(1-naphthyl)ethylamine (5 g, 33 mmol) in CH2Cl2 (200
mL) were added HATU (8 g, 21 mmol) and Et3N (10 mL, 72
mmol) at 0 °C. After being stirred at room temperature for 5
h, the solvent was removed in vacuo and the residue was
purified by the column chromatography on silica using hex-
ane-EtOAc (1:1) as an eluent to give N-(3-(N-Boc)amino-2,2-
dimethylpentanoyl)-(R)-1-(1-naphthyl)ethylamine 15 (4.2 g,
64%). The diastereomers of 15 were separated into two
fractions by the silica gel column chromatography (LiChrosorb
Si60-7, 250 × 25 mm) using hexane-EtOAc (1:4) as an eluent.
Evaporation of each solvent yielded a product as a colorless
powder. Recrystallization from hexane yielded the product as
colorless needles. The absolute configuration of the needles
from the front fraction (15-R, 1.64 g, 39%) was determined as
R by the X-ray crystallographic analysis: mp 127-128 °C; 1H
NMR (270 MHz, CDCl3) δ 0.85 (t, J ) 6.8 Hz, 3H), 1.13 (s,
3H), 1.85 (s, 3H), 1.06-1.24 (m, 1H), 1.44 (s, 9H), 1.39-1.58
(m, 1H), 1.63 (d, J ) 6.8 Hz, 3H), 3.41 (dt, J ) 10.7, 2.4 Hz,
1H), 5.31 (d, J ) 10.3 Hz, 1H), 5.88 (dq, J ) 6.8, 6.8 Hz, 1H),
6.06 (d, J ) 7.3 Hz, 1H), 7.40-7.58 (m, 4H), 7.72-7.92 (m,
2H), 7.97-8.08 (m, 1H); 13C NMR (67.5 MHz, CDCl3) δ 11.1,
14.1, 20.4, 22.7, 23.9, 24.3, 28.4, 44.5, 45.9, 59.4, 78.8, 122.4,
123.3, 125.1, 125.8, 126.3, 128.3, 128.7, 131.0, 133.9, 138.2,
156.7, 175.8; [R]25D ) -35.6° (c 1.0, EtOH); MS (ESI) m/ z 399
(M + H)+.
Eth yl N-[3-(2-F lu or o-4-(4-m eth ylp ip er a zin yl(im in o)m -
eth yl)ben zoyl)a m in o-2,2-d im eth ylp en ta n oyl]p ip er id in e-
4-a ceta te (42). 42 was prepared via the general procedure
D. However, 4-methylpiperazine was used instead of am-
monium acetate: 28% yield from 14b; 1H NMR (270 MHz,
CDCl3) δ 0.90 (t, J ) 7.3 Hz, 3H), 1.03-1.40 (m, 2H), 1.25 (t,
J ) 7.3 Hz, 3H), 1.28 (s, 3H), 1.32 (s, 3H), 1.48-1.92 (m, 4H),
2.03 (br s, 1H), 2.23 (d, J ) 6.5 Hz, 2H), 2.65-3.00 (m, 2H),
2.88 (s, 3H), 3.42 (br s, 2H), 3.61 (br s, 2H), 3.78 (br s, 2H),
3.95-4.17 (m, 1H), 4.11 (q, J ) 6.8 Hz, 2H), 4.19-4.50 (m,
4H), 7.44 (m, 2H), 7.86 (m, 1H); 13C NMR (67.5 MHz, CDCl3)
δ 11.4, 14.2, 23.8, 23.9, 31.9, 32.0, 33.0, 40.8, 42.9, 43.8, 45.0,
45.5, 46.4, 46.8, 51.3, 51.9, 60.4, 60.7, 77.2, 113.9, 116.7, 117.0,
118.2, 124.4, 126.8, 127.0, 131.4, 131.5, 132.2, 157.7, 160.4,
161.0, 161.4, 161.5, 162.1, 163.0, 164.1, 172.3, 174.9; MS (ESI)
m/ z 546 (M + H)+; HRMS (FAB) calcd for C29H45FN5O4 (M +
H)+ 546.3455, found 546.3443. Anal. (C29H44FN5O4‚2CF3-
COOH‚1.5H2O) C, H, N.
N-[3-(2-F lu or o-4-(4-m eth ylp ip er a zin yl(im in o)m eth yl)-
ben zoyl)a m in o-2,2-d im eth ylp en ta n oyl]p ip er id in e-4-a ce-
tic Acid (Biologica lly Active F or m of 42). This compound
was prepared according to the procedure described for 18: 76%
1
yield from 42; H NMR (400 MHz, CD3OD) δ 0.97 (t, J ) 7.6
Hz, 3H), 1.14-1.27 (m, 2H), 1.26 (s, 3H), 1.34 (s, 3H), 1.50-
1.63 (m, 2H), 1.84 (br t, J ) 10.0 Hz, 2H), 2.01-2.13 (m, 1H),
2.25 (d, J ) 6.8 Hz, 2H), 2.78-3.02 (m, 2H), 2.93 (s, 3H), 3.36
(br s, 2H), 3.54 (br s, 2H), 3.74 (br s, 2H), 4.09 (br s, 2H), 4.40
(dd, J ) 4.4, 10.0 Hz, 1H), 4.51 (br d, J ) 13.6 Hz, 2H), 7.56
(dd, J ) 1.2, 7.6 Hz, 1H), 7.61 (dd, J ) 1.2, 10.0 Hz, 1H), 7.88
(t, J ) 7.2 Hz, 1H); 13C NMR (100 MHz, CD3OD) δ 12.7, 24.1,
24.7, 25.2, 34.0, 34.1, 35.1, 42.3, 44.6, 45.9, 47.7, 53.5, 54.4,
59.9, 118.6, 118.9, 126.6, 130.3, 133.6, 133.9, 162.8, 163.8,
166.6, 166.9, 176.8, 177.0, 186.9; MS (ESI) m/ z 518 (M + H)+;
HRMS (FAB) calcd for C27H41FN5O4 (M + H)+ 518.3142, found
518.3125; HPLCb K′ 5.00. Anal. (C27H40FN5O4‚2.5CF3-
COOH‚1.5H2O) C, H, N.
(R)-3-(N-Boc)Am in o-2,2-d im eth ylp en ta n oic Acid (12b-
R). 12b-R was prepared according to the general procedure
E described for 12f: 81% yield from 15-R; [R]25 ) 15.7° (c
D
1.0, EtOH); MS (ESI) m/ z 244 (M - H)-.
Biologica lly Active F or m of 40-R. This compound was
prepared according to the same procedure described for
biologically active form of 40: 14% yield (TFA salt) from 12b-
R; [R]20 ) -39.1° (c 0.1, H2O); MS (ESI) m/ z 507 (M + H)+.
D
Ack n ow led gm en t. The authors thank Dr. Subrata
Chakravarty, Department of Chemistry, State Univer-
sity of New York at Stony Brook, for his valuable advice.
Eth yl N-[3-(2-F lu or o-4-(4-(4-flu or op h en yl)p ip er a zin yl-
(im in o)m et h yl)b en zoyl)a m in o-2,2-d im et h ylp en t a n oyl]-
p ip er id in e-4-a ceta te (43). 43 was prepared via the general
procedure D. However, 4-(4-fluorophenyl)piperazine was used
Su p p or tin g In for m a tion Ava ila ble: X-ray crystallo-
graphic data of 15-R (35 pages). Ordering information is given
on any current masthead page.
1
instead of ammonium acetate: 19% yield from 14b; H NMR
(400 MHz, CDCl3) δ 0.92 (t, J ) 7.2 Hz, 3H), 1.16 (br q, J )
12 Hz, 2H), 1.24 (t, J ) 7.0 Hz, 3H), 1.30 (s, 3H), 1.35 (s, 3H),
1.60-1.72 (m, 2H), 1.78 (br d, J ) 11.6 Hz, 2H), 1.97-2.08
(m, 1H), 2.23 (d, J ) 6.8 Hz, 2H), 2.82 (br s, 2H), 3.15 (m, 2H),
3.37 (m, 2H), 3.59 (m, 2H), 4.02-4.14 (m, 3H), 4.11 (q, J ) 7.2
Hz, 2H), 4.35 (br d, J ) 12.4 Hz, 2H), 6.92 (dd, J ) 4.4, 9.6
Hz, 2H), 6.99 (t, J ) 8.4 Hz, 2H), 7.33 (dd, J ) 10.8, 14.0 Hz,
2H), 7.96 (t, J ) 7.2 Hz, 1H); 13C NMR (67.5 MHz, CDCl3) δ
11.6, 14.3, 23.8, 24.0, 24.1, 32.0, 32.2, 33.1, 40.9, 45.2, 45.6,
46.5, 47.0, 49.8, 50.0, 50.8, 60.6, 61.2, 116.0, 116.3, 116.4, 116.8,
119.4, 119.5, 124.3, 126.6, 126.8, 132.1, 132.3, 132.8, 145.7,
145.8, 156.8, 158.0, 160.4, 161.0, 161.7, 162.9, 163.1, 172.4,
175.1; MS (ESI) m/ z 626 (M + H)+. Anal. (C34H45F2N5-
O4‚1.5CF3COOH) C, H, N.
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(2) Coller, B. S. Platelets and Thrombolytic Therapy. N. Engl. J .
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(3) Scharf, R. E.; Harker, L. A. Thrombosis and Atherosclerosis:
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(4) Phillips, D. R.; Charo, I. F.; Parise, L. V.; Fitzgerald, L. A. The
Platelet Membrane Glycoprotein IIb-IIIa Complex. Blood 1988,
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2360 J ournal of Medicinal Chemistry, 1998, Vol. 41, No. 13
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(5) Ruoslahti, E.; Pierschbacher, M. D. New Perspectives in Cell
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