Rational design and synthesis of novel, potent bis-phenylamidine carboxylate factor Xa inhibitors

Article abstract of DOI:10.1021/jm970485a

The molecular modeling studies, rational design, and synthesis of a novel series of bis-phenylamidine carboxylate compounds which are inhibitors of factor Xa in the blood coagulation cascade are described. Inhibition of blood coagulation has been proposed

Full text of DOI:10.1021/jm970485a

J . Med. Chem. 1998, 41, 53-62
53
Ra tion a l Design a n d Syn th esis of Novel, P oten t Bis-p h en yla m id in e Ca r boxyla te
F a ctor Xa In h ibitor s
Thomas P. Maduskuie, J r.,* Kevin J . McNamara,† Yu Ru,‡ Robert M. Knabb, and Pieter F. W. Stouten*
The DuPont Merck Pharmaceutical Company, DuPont Experimental Station E500/ 2401, P.O. Box 80500,
Wilmington, Delaware 19880-0500
Received J uly 28, 1997X
The molecular modeling studies, rational design, and synthesis of a novel series of bis-
phenylamidine carboxylate compounds which are inhibitors of factor Xa in the blood coagulation
cascade are described. Inhibition of blood coagulation has been proposed to have several
potential therapeutic utilities (Kaiser and Hauptmann, Cardiovasc. Drug Rev. 1994, 12, 225-
236). Factor Xa (fXa) holds a central position in the coagulation cascade (Coleman et al. in
Hemostasis and Thrombosis: Basic Principles and Clinical Practice, 1994, pp 3-18). Its major
role is the generation of thrombin by the proteolytic cleavage of prothrombin. Inhibition of
fXa would serve to reduce the formation of platelet clots. The fXa dimer crystal structure
(Tulinsky et al., J . Mol. Biol. 1993, 232, 947-966) was used in our molecular modeling studies
to design a novel series of fXa inhibitors. We initially docked and minimized isolated small
molecule fragments in the S1 and S4 aryl-binding subsites. Subsequently, these fragments
were connected with a tether, so as not to disturb the orientation of the fragments in their
respective pockets. These modeling studies led to the initial compound (1) which was found to
have significant inhibitory potency for fXa (Ki ) 34 nM). The synthesis of the core structure,
structure-activity relationships (SAR), and proposed binding orientation based on molecular
modeling for this novel bis-phenylamidine series of fXa inhibitors are described.
In tr od u ction
in the aryl-binding pocket (Figure 1). This binding motif
has been confirmed by Bode’s group.7 The fXa-DX-
9065a crystal structure complex shows the pyrrolidine
in the aryl-binding pocket with the acetimidoyl func-
tionality hydrogen bonding in a cation hole created by
the carbonyl groups of Lys96 and Glu97 together with
the Glu97 side chain. The Daiichi scientists found that
the carboxylic acid was important for fXa selectivity:
specificity for fXa versus thrombin is >28000-fold with
the carboxylic acid compared to 280-fold with the
corresponding methyl ester. The specificity for fXa over
thrombin is proposed to stem from the interaction
between the carboxylate of DX-9065a and Gln192 in fXa.
The corresponding residue in thrombin (Glu192) is
expected to be deprotonated which would cause a strong
repulsive interaction between the DX-9065a carboxylate
and this residue.
Since there were no inhibitor-bound fXa crystal
structures reported at the time this work was done, the
X-ray coordinates of fXa structural dimer3 served as the
starting point for our molecular modeling studies. The
fXa dimer crystal structure has the C-terminal arginine
of the light chain of one monomer bound in the S1
pocket of the other. We envisioned a phenylamidine
group binding in the S1 site, hydrogen bonding to the
Asp189 residue analogous to the trypsin-phenylami-
dine complex.8 The lowest energy orientation9 for the
phenylamidine residue in the S1 pocket is shown in
Figure 2. Subsequently, we attempted to find a frag-
ment which would be compatible to the S4 aryl-binding
pocket.7 The aryl-binding pocket is outlined with three
aromatic residues: Phe174, Tyr99, and Trp215. Ini-
tially we modeled a phenyl ring into the S4 aryl-binding
pocket to find an optimal binding orientation. This
Factor Xa (fXa) holds a central position in the
coagulation cascade that links the intrinsic and extrinsic
activation mechanisms. The major biological role of fXa
is the generation of thrombin by the proteolysis of
prothrombin. The generation of thrombin, the final
serine protease in the pathway to generate a fibrin clot,
is amplified by formation of a prothrombinase complex
(factor Xa, factor V, Ca2+, and phospholipid). Since it
is calculated that one molecule of fXa can generate 138
molecules of thrombin,4 inhibition of fXa may be more
efficient than inactivation of thrombin in interrupting
the blood coagulation system. Therefore, we have
targeted this enzyme in our efforts to develop novel
antithrombotic agents.
There are several examples of dibasic fXa inhibitors
disclosed in the literature.5 Of these the bis-amidine
DX-9065a is the most selective fXa inhibitor with an
IC50 of 41 nM.6 DX-9065a was proposed to bind to the
receptor site with the naphthyl amidine hydrogen
bonding to Asp189 in the S1 site, the carboxylic acid
functionality hydrogen bonding to Gln192 in fXa, and
the acetimidoyl pyrrolidine group presumably binding
† Current address: Houston, TX.
‡ Current address: Smith, Kline & Beecham, Philadelphia, PA.
X Abstract published in Advance ACS Abstracts, December 15, 1997.
S0022-2623(97)00485-8 CCC: $15.00 © 1998 American Chemical Society
Published on Web 01/01/1998

54 J ournal of Medicinal Chemistry, 1998, Vol. 41, No. 1
Maduskuie et al.
F igu r e 1. Binding model of DX-9065a to the fXa active site.
For clarity, only the residues closest to the ligand are dis-
played. The ligand’s 3-point pharmacophore comprises (1) the
naphthyl amidino moiety forming hydrogen bonds with Asp189
and Gly218 in the S1 pocket (long white dashed lines); (2) the
carboxylate in the region of positive electrostatic potential
defined by Arg143, Gln192, and Gly218-NH (short white
dashed lines); and (3) the acetimidoyl pyrrolidine which fills
the S4 pocket (Phe174, Trp215, Tyr99) and puts a positive
charge in the region of negative electrostatic potential defined
by the backbone carbonyls of Lys96, Glu97, and Thr98 and
the side chain of Glu97.
F igu r e 2. Optimum binding modes of phenylamidino moieties
in the fXa S1 and S4 pockets, accounting for two of the three
points of the pharmacophore model defined in Figure 1. The
phenylamidine in the S4 pocket does not go as deep as the
equivalent acetimidoyl pyrrolidine of DX-9065a and may
interact directly with the Thr98 carbonyl rather than with
Glu97.
to the para position of the P4 phenylamidine satisfied
these requirements as shown in Figure 3. Finally we
needed to tether a carboxylate group off this framework
toward the Gln192 interaction, similar to the Daiichi
pharmacophore. This was best achieved by function-
alizing the benzylic methylene of the P1 phenylamidine.
The initial bis-phenylamidine carboxylate compound
(1) was found to have good binding affinity in the fXa
assay11 (Ki ) 34 nM). A subsequent set of compounds
was prepared to confirm the 3-point pharmacophore,
confirm the regio position of the amidines, and optimize
the distal phenylamidine.
phenyl ring fragment was then substituted with an
amidine group to try and take advantage of the binding
into the cation hole that the Daiichi group had found
with their acetimidoyl group. We found that a phenyl-
amidine residue placed into various positions in this
pocket consistently minimized to the same position
(Figure 2) with the amidine stacked over residue Trp215
and protons pointing toward the phenyl rings.10 This
orientation of the phenylamidine in the S4 pocket is
different from the position of the acetimidoyl group for
the Daiichi compound. Assuming the orientation of the
phenylamidine in S1 and the phenylamidine in aryl-
binding pocket to be preferred, the next step was to
connect these fragments so as not to disrupt their
respective orientations. We found that a 3-atom spacer
connecting the meta position of the P1 phenylamidine

Bis-phenylamidine Carboxylate fXa Inhibitors
J ournal of Medicinal Chemistry, 1998, Vol. 41, No. 1 55
Sch em e 1a
a
Reagents: (a) NaOMe, methanol, room temperature; (b)
toluene, reflux; (c) 10% Pd/carbon, 50 psi H2, THF; (d) HCl gas,
methanol, room temperature; (e) (NH4)2CO3, methanol; (f) 6 N HCl.
Ch a r t 1
F igu r e 3. Binding model of 1 to the fXa active site. All three
aspects of the pharmacophore defined in Figure 1 are present.
Both phenylamidines are in almost identical positions as their
optimum binding mode shown in Figure 2. The methyl ester
is shown to interact with Arg143 and Gln192 simultaneously.
Most likely only one of these interactions actually occurs
because simultaneous hydrogen bonding would bring the
terminal side chain nitrogens of those residues too close
together.
Discu ssion
Ch em istr y
To confirm the critical functional groups in the
pharmacophore of compound 1, it was necessary to
prepare a series of deletion analogues (Chart 1). The
elimination of the P1 m-amidine group (10) was found
to have the most critical effect on activity. The resulting
compound (10) was totally devoid of fXa activity, while
compounds with elimination of the distal P4 p-amidine
group (12) or the ester group (11) still retained some
micromolar activity. These analogues thus confirmed
that all functional groups were important to achieve
nanomolar activity.
The other regio isomers of the amidine groups were
also prepared to confirm the optimum substitution
pattern for the basic centers (Chart 2). Moving the P1
m-amidine group to the para position (13) completely
eliminated activity in the fXa assay. However, moving
the P4 p-amidine to the meta position reduced inhibitory
activity for fXa by 90-fold. The double-reposition isomer
(15) was found to have micromolar activity (Ki ) 1642
The bis-phenylamidine carboxylate compounds such
as 1 were prepared as described in Scheme 1. The aldol
condensation product 4 was prepared from m-cyano-
acetophenone (2) and p-cyanobenzaldehyde (3) with
sodium methoxide in methanol to give a mixture of E
and Z isomers. The dienone ester 6 was prepared by
reaction of methyl (triphenylphosphoranyldiene)acetate
(5) in toluene at reflux with the enone 4. The diene was
reduced to the saturated ester 7 by hydrogenation over
palladium on carbon under Parr shaker conditions. The
bis-phenylamidine carboxylate 1 was prepared from the
bis-nitrile 7 using modified Pinner12 conditions to
prepare the imidate and reaction with ammonium
carbonate to give the bis-amidine 1. The bis-phenyl-
amidine carboxylates were purified by preparative
HPLC using an acetonitrile/water/TFA gradient on a
Vydac C-18 semipreparative column. The free acid 9
was prepared by treating the ester 1 with 6 N HCl.

56 J ournal of Medicinal Chemistry, 1998, Vol. 41, No. 1
Maduskuie et al.
Ch a r t 2
Ta ble 1. Effect on in Vitro Activity by Substitution of the P4
p-Amidine
Ki, nM
compd
n
R
fXaa
thromb
Trpc
1
16
17
18
19
20
21
23
1
1
1
1
1
1
1
3
p-amidine
34
2800
654
1100
550
5000
9
1200
3600
3100
1750
6500
7700
3100
3300
99
330
110
610
870
1200
96
p-CO2CH3
p-NHSO2CH3
p-NHSO2Ph
p-C(dO)NH2
p-NH2
F igu r e 4. Binding model of 21 to the fXa active site. The
phenylguanidine moiety sits deeper in the S4 pocket than the
equivalent phenylamidine of 1 (see Figure 3) and potentially
interacts with the same residues as DX-9065a (see Figure 1).
The methyl ester is shown to interact with Gly218-NH rather
than Arg143 or Gln192. The ester can, in principle, form any
of those three hydrogen bonds.
p-guanidine
p-guanidine
57
760
In vitro inhibition of factor Xa Ki.11 In vitro inhibition of
a
b
thrombin Ki.11 c In vitro inhibition of trypsin Ki.11
nM), better than either compound 13 or 14. These data
may suggest that analogue 15 is binding in the reverse
direction compared to 1, with the m-amidine in the S1
pocket and the p-amidine in the S4 pocket. This reverse
orientation for 15 was confirmed by modeling experi-
ments, but it puts the ester side chain in a nonoptimal
position, resulting in the reduced affinity but more
activity than the ester deletion analogue 11. The
amidine regio isomer arrangement in 1 was confirmed
to be the most active analogue.
The distal P4 p-amidine was replaced with a variety
of modifications to explore the important polar and
lipophilic binding interactions in the S4 pocket (Table
1). When the P4 p-amidine was replaced with a methyl
ester (16), fXa activity was the same as having no
substitution in the para position (12). The methyl
sulfonamide 17 was 20-fold less active than compound
1, and the larger phenyl sulfonamide 18 was less active
then the methyl sulfonamide. The primary amide 19
was almost 20-fold less active than compound 1 but was
more active than the methyl ester 10. The aniline
compound 20 was more than 100-fold less active than
the amidine. Introducing the guanidine compound 21
significantly improved inhibitory potency for fXa (Ki )
9 nM) while decreasing the inhibition of thrombin (Ki
) 3100 nM).
These combinations suggest that the S4 pocket prefers
a basic charged group. We believe the protonated
p-amidinophenyl residue is located in the S4 aryl-
binding pocket where it engages in cation-π10 and
lipophilic interactions with the surrounding Phe174,
Tyr99, and Trp215 and also possibly hydrogen bonds
with the carbonyl of Thr98 (Figure 3). The anilino
group (20) on the other hand is not very basic and is
too small to fill this binding pocket. The guanidine
analogue 21 would fill the aryl-binding pocket more
completely than the amidino group and would also
extend deeper into the S4 pocket to interact with the
putative “cation hole”, the Glu97 backbone carbonyl
(Figure 4).
Subsequently, we attempted to extend even deeper
into the S4 pocket by extending the 3-atom spacer of

Bis-phenylamidine Carboxylate fXa Inhibitors
J ournal of Medicinal Chemistry, 1998, Vol. 41, No. 1 57
Ta ble 2. Effect on in Vitro Activity by Substitution of the
Methyl Ester
selectivity versus thrombin (Ki ) 3100 nM) and 10-fold
selectivity versus trypsin (Ki ) 96 nM).
Exp er im en ta l Section
All reactions detailed below were performed using reagent-
grade materials and solvents under a dry atmosphere. All
solvents were distilled prior to use or stored over 4-Å molecular
sieves. The phrase “flash chromatography” and related phrases
refer to the separation methods reported by Still et al.13
Melting points were determined in an open capillary on a
Thomas Scientific melting point apparatus and are uncor-
rected. 1H NMR spectra were obtained on a Varian VXR-300A
spectrometer, and chemical shifts are reported in ppm (δ) using
tetramethylsilane as reference. Mass spectra were obtained
on a Hewlett-Packard 5988A MS spectrometer. Microanalyses
were determined by Quantitative Technologies, Inc., Bound
Brook, NJ .
P r ep a r a t ion of (()-Met h yl 4-(Am in oim in om et h yl)-â-
[3-(a m in oim in om eth yl)p h en yl]ben zen ep en ta n oa te Bis-
(tr iflu or oa ceta te) (1). P a r t A: P r ep a r a tion of 3-[3-(4-
Cya n op h en yl)-1-oxo-2-p r op en yl]ben zon itr ile (4). Sodium
methoxide (25% in MeOH, 1.5 mL, 6.8 mmol) was added
dropwise to a solution of 3-acetylbenzonitrile (0.987 g, 6.8
mmol) and 4-cyanobenzaldehyde (0.891 g, 6.8 mmol) in dry
methanol. Within 5 min, a precipitate began to form. The
mixture was stirred at room temperature for 4 h and was
diluted with methanol. The solids were filtered off, washed
with cold methanol, and dried to give 3-[3-(4-cyanophenyl)-1-
oxo-2-propenyl]benzonitrile as a white solid (1.7 g, 97%): MS
(M + H)+ 259; 1H NMR (CDCl3) 7.55 (d, 1H), 7.65 (t, 1H), 7.75
(s, 4H), 7.85 (m, 2H), 8.25 (d, 1H), 8.30 (s, 1H).
P a r t B: P r ep a r a tion of Meth yl 3-(3-Cya n op h en yl)-5-
(4-cya n op h en yl)-2,4-p en ta d ien oa te (6). The 3-[3-(4-cyano-
phenyl)-1-oxo-2-propenyl]benzonitrile (4) (2 g, 7.75 mmol) was
suspended in dry toluene and methyl (triphenylphosphor-
anylidene)acetate (2.59 g, 7.75 mmol) added. The mixture was
then heated at 100 °C for 24 h and cooled and the solvent
removed under vacuum. The residue was chromatographed
on silica gel eluting ethyl acetate/hexanes (25:75, v:v) to give
methyl 3-(3-cyanophenyl)-5-(4-cyanophenyl)-2,4-pentadienoate
(6) as an oil (2.1 g, 87%): MS (M + H)+ 315; 1H NMR (CDCl3)
3.60 (s, 3H), 3.80 (s, 3H), 5.90 (s, 1H), 6.23 (m, 2H), 6.45 (d,
1H), 7.15 (d, 1H), 7.55 (m, 16H), 8.60 (d, 1H).
Ki, nM
compd
R
fXaa
thromb
Trpc
99
>1200
110
140
820
440
nt
1
24
25
26
27
28
29
30
OCH3
OH
34
1400
42
192
940
1150
2400
2400
1200
>4200
1100
1535
8000
2800
12600
19600
OCH2CH3
O-isopropyl
NHCH3
pyrrole
NHCH2CO2CH3
NHOCH3
nt
In vitro inhibition of factor Xa Ki.11 In vitro inhibition of
a
b
thrombin Ki.11 c In vitro inhibition of trypsin Ki.11
21 to a 5-atom spacer (23). The fXa activity for this
analogue was 5-fold less active than the shorter guani-
dine modification (21). It appears that the preferred
distance is close to the 3-atom spacer with guanidine,
and no advantage is gained with the longer 5-atom
spacer.
The ester group was shown earlier (Chart 1, com-
pound 11) to be vital for fXa binding. Surprisingly the
free acid compound 24 is 50-fold less active than the
corresponding ester 1, although its thrombin activity is
also significantly reduced by at least 30-fold (Table 2).
This is contrary to what was found in the Daiichi work
and what we had predicted from our modeling experi-
ments. We further explored functional group changes
for the ester to determine where this group may be
interacting in fXa. As the ester alkyl is substituted with
increasing size, the fXa activity tends to decrease.
Replacing the methyl ester with a methyl amide,
compound 27, reduces the fXa activity significantly.
Extending the chain length to the ester compound 29
or using an O-methyl hydroxamate greatly reduced
activity for fXa. It is unclear where the ester binds, but
an alternative binding mode in which the ester is
hydrogen bonding to the N-H of Gly218 and less
solvent-exposed might help to explain these observa-
tions (Figure 4).
P a r t C: P r ep a r a t ion of Met h yl 4-Cya n o-â-(3-cya n o-
p h en yl)b en zen ep en t a n oa t e (7). The methyl 3-(3-cyano-
phenyl)-5-(4-cyanophenyl)-2,4-pentadienoate (6) (0.328 g, 1.04
mmol) was dissolved in ethyl acetate/THF (1:1) and degassed
with N2. A catalytic amount of 10% Pd on carbon was added,
and the flask was placed on a Parr shaker for 1 h at 45 psi.
The contents of the flask were filtered through Celite, and the
filtrate was concentrated under vacuum. The residue was
chromatographed on silica gel eluting with ethyl acetate/
hexanes (25:75, v:v) to give methyl 4-cyano-â-(3-cyanophenyl)-
benzenepentanoate (7) as an oil (0.190 g, 57%): MS (M +
1
NH4)+ 336; H NMR (CDCl3) 1.95 (m, 1H), 2.05 (m, 1H), 2.55
(m, 2H), 2.65 (dd, 2H), 3.15 (m, 1H), 3.60 (s, 3H), 7.20 (d, 2H),
7.45 (d, 2H), 7.50 (s, 1H), 7.55 (m, 3H).
Con clu sion
P a r t D: Hydrogen chloride gas was bubbled through a
solution of methyl 4-cyano-â-(3-cyanophenyl)benzenepen-
tanoate (7) (0.058 g, 0.185 mmol) dissolved in 10 mL of ethanol
under a nitrogen atmosphere and cooled to 0 °C in an ice bath
for 15 min. The reaction flask was stoppered and allowed to
warm to ambient temperature. The reaction mixture was
stirred for 24 h and was concentrated in vacuo to give a
semisolid residue. The crude imidate was taken up in 10 mL
of ethanol, and the ammonium carbonate (0.142 g, 1.48 mmol)
was added. The reaction flask was stoppered and stirred at
ambient temperature for 28 h, and then the mixture was
concentrated in vacuo to give the crude product as a solid
residue. The title compound 1 was isolated after HPLC
purification on a Vydac C-18 column, solvent A (acetonitrile/
water/TFA, 80:20:0.2) and solvent B (water/TFA, 99.8:0.2),
using a gradient (Rf ) 21 min), as a white solid (0.051 g,
Molecular modeling experiments using the active site
coordinates of the fXa dimer enabled us to rationally
design a series of novel bis-phenylamidine carboxylate
compounds which are very potent fXa inhibitors. The
proposed 3-point pharmacophore was confirmed by a
series of deletion analogues and regio isomer analogues.
It still remains to cocrystallize these inhibitors with fXa
to confirm the binding orientation of the bis-phenyl-
amidines and to determine the critical interaction for
the ester group. The initially designed targets with a
carboxylic acid did not have the activity or selectivity
we had predicted from our modeling studies. However,
these studies have led to a very active fXa inhibitor
compound (21) (Ki ) 9 nM) which has shown 400-fold
1
78%): mp >200 °C; MS (M + H)+ 353; H NMR (DMSO-d6)

58 J ournal of Medicinal Chemistry, 1998, Vol. 41, No. 1
Maduskuie et al.
2.0 (m, 2H), 2.5 (m, 2H), 2.7 (dd, 1H), 2.85 (dd, 1H), 3.15 (m,
1H), 3.50 (s, 3H), 7.40 (d, 2H), 7.55 (m, 2H), 7.75 (m, 4H), 9.1
(d, 4H), 9.25 (d, 4H). Anal. (C20H24N4O2(CF3CO2H)2.0) C, H,
N.
cyanophenyl)-1-oxo-2-propenyl]benzonitrile was isolated as a
1
pale yellow powder (0.4 g, 20%): MS 259 (M + H)+; H NMR
(CDCl3) 7.78 (d, 2H), 7.6 (t, 1H), 7.5-7.0 (m, 7H).
P a r t B: Employing methods similar to example 1, part B,
but using 4-[3-(4-cyanophenyl)-1-oxo-2-propenyl]benzonitrile
(0.3 g, 1.16 mmol), methyl 3-(4-cyanophenyl)-5-(4-cyanophen-
yl)-2,4-pentadienoate was obtained as a mixture of E and Z
isomers. This was purified by flash chromatography on silica
gel eluting with methylene chloride to a give mixture of
isomers (0.31 g, 85%): MS 332 (M + NH4)+; 1H NMR (CDCl3)
8.5 (d, 1H), 7.75 (d, 2H), 7.65 (d, 2H), 7.56 (d, 2H), 7.45 (d,
2H), 6.47 (d, 2H), 3.82 (s, 3H).
P r ep a r a t ion of (()-Met h yl 4-(Am in oim in om et h yl)-â-
p h en ylben zen ep en ta n oa te Mon o(tr iflu or oa ceta te) (10).
Employing methods similar to example 1, above, the title
compound 10 was prepared and isolated after HPLC purifica-
tion on a Vydac C-18 column, solvent A (acetonitrile/water/
TFA, 80:20:0.2) and solvent B (water/TFA, 99.8:0.2), using a
gradient (Rf ) 25 min), as a white powder (0.07 g, 56%): mp
202 °C; MS (M + H)+ 311; HRMS calcd 311.1759, found
1
311.1740; H NMR (DMSO-d6) 9.2 (s, 2H), 9.0 (2,2H), 7.7 (d,
P a r t C: Employing methods similar to example 1, part C,
but using methyl 3-(4-cyanophenyl)-5-(4-cyanophenyl)-2,4-
pentadienoate (0.5 g, 1.59 mmol), methyl 3-(4-cyanophenyl)-
5-(4-cyanophenyl)pentanoate was isolated as an oil (0.3 g,
2H), 7.2-7.4 (m, 7H), 3.5 (s, 3H), 3.4 (s, 2H), 3.0 (m, 1H), 2.8
(m, 1H), 2.6 (m, 1H), 2.0 (m, 2H). Anal. (C19H22N2O2(CF3-
CO2H)1.0) C, H, N.
1
99%): MS 319 (M + H)+; H NMR (CDCl3) 7.65 (d, 2H), 7.55
P r ep a r a t ion of 3-[3-[4-(Am in oim in om et h yl)p h en yl]-
1-oxop r op yl]b en zen eca r b oxim id a m id e Bis(t r iflu or o-
a cet a t e) (11). P a r t A: 3-[3-(4-Cyanophenyl)-1-oxo-2-pro-
penyl]benzonitrile was dissolved in THF and degassed with
N2. A catalytic amount of 10% Pd/C was added and the
solution placed on a Parr shaker for 45 min at 10 psi. The
solution was filtered through Celite and the filtrate concen-
trated. The residue was chromatographed on silica gel (20%
ethyl acetate/toluene) to give 3-(4-cyanophenyl)propio(3-cyano)-
phenone as a white solid (0.200 g, 66%): MS (M + NH4)+ 278;
1H NMR (CDCl3) 3.15 (t, 2H), 3.35 (t, 2H), 7.40 (d, 2H), 7.6 (d,
3H), 7.85 (d, 1H), 8.15 (d, 1H), 8.20 (s, 1H).
(d, 2H), 7.45 (d, 2H), 7.17 (d, 2H), 3.7 (s, 3H), 3.2 (m, 1H), 2.65
(m, 2H), 2.50 (t, 2H), 2.1-1.90 (m, 2H).
P a r t D: Employing methods similar to example 1, part D,
but using methyl 3-(4-cyanophenyl)-5-(4-cyanophenyl)pen-
tanoate (0.30 g, 0.94 mmol), the title compound 13 was isolated
after HPLC purification on a Vydac C-18 column, solvent A
(acetonitrile/water/TFA, 80:20:0.2) and solvent B (water/TFA,
99.8:0.2), using a gradient (Rf ) 14.3 min), as a white powder
1
(0.12 g, 35%): mp 248-249 °C; MS 367 (M + H)+; H NMR
(DMSO-d6) 9.27 (s, 2H), 9.25 (s, 2H), 9.17 (s, 2H), 9.15 (s, 2H),
7.78 (d, 2H), 7.75 (d, 2H), 7.55 (d, 2H), 7.37 (d, 2H), 3.90 (m,
2H), 3.15 (m, 1H), 2.85 (dd, 1H), 2.7 (dd, 1H), 2.6-2.4 (m, 2H),
1.95 (m, 2H), 1.1 (t, 3H). Anal. (C21H26N4O2(CF3CO2H)2.2) C,
H, N.
P a r t B: Employing methods similar to example 1, part D,
but using 3-(4-cyanophenyl)propio(3-cyano)phenone (0.150 g,
0.576 mmol), the title compound 11 was isolated after HPLC
purification on a Vydac C-18 column, solvent A (acetonitrile/
water/TFA, 80:20:0.2) and solvent B (water/TFA, 99.8:0.2),
using a gradient (Rf ) 18 min), as a semisolid (0.018 g, 10%):
P r ep a r a t ion of (()-Met h yl 3-(Am in oim in om et h yl)-â-
[3-(a m in oim in om eth yl)p h en yl]ben zen ep en ta n oa te Bis-
(tr iflu or oa ceta te) (14). P a r t A: Employing methods similar
to example 1, part A, but using 3-acetylbenzonitrile (1 g, 6.8
mmol) and 3-cyanobenzaldehyde (2.76 g, 17 mmol), 3-[3-(3-
cyanophenyl)-1-oxo-2-propenyl]benzonitrile was isolated as a
1
MS (M + H)+ 295; H NMR (DMSO-d6) 3.10 (t, 2H), 3.50 (t,
2H), 7.55 (d, 2H), 7.80 (m, 3H), 8.05 (d, 1H), 8.30 (d, 1H), 8.40
(s, 1H), 8.90 (s (broad), 2H), 9.20 (d (broad), 4H), 9.40 (s (broad),
2H). Anal. (C17H18N4O(CF3CO2H)2.1) C, H, N.
1
solid (0.285 g, 15%): MS (M + H)+ 259; H NMR (CDCl3) 7.6
P r ep a r a tion of (()-Meth yl â-[3-(Am in oim in om eth yl)-
p h en yl]ben zen ep en ta n oa te Mon o(tr iflu or oa ceta te) (12).
P a r t A: Employing methods similar to example 1, part A, but
using benzaldehyde, methyl 3-(3-phenyl-1-oxo-2-propenyl)-
benzonitrile was isolated as an oil: MS 234 (M + H)+.
P a r t B: Employing methods similar to example 1, part B,
but using methyl 3-(3-phenyl-1-oxo-2-propenyl)benzonitrile
(1.1 g, 4.7 mmol), methyl 3-(3-cyanophenyl)-5-phenyl-2,4-
pentadienoate was obtained as a mixture of E and Z isomers.
This was purified by flash chromatography on silica gel eluting
with methylene chloride to give a mixture of isomers (0.59 g,
44%): MS 290 (M + H)+; 1H NMR (CDCl3) 3.8 (s, 3H), 6.45 (d,
2H), 7.2-7.8 (m, 9H).
P a r t C: Employing methods similar to example 1, part C,
but using methyl 3-(3-cyanophenyl)-5-phenyl-2,4-pentadi-
enoate (0.55 g, 1.90 mmol), methyl 3-(3-cyanophenyl)benzene-
pentanoate was isolated as an oil (0.52 g, 93%): MS 311 (M +
NH4)+; 1H NMR (CDCl3) 1.90-2.10 (m, 2H), 2.45 (t, 2H), 2.55-
2.75 (m, 2H), 3.1-3.2 (m, 1H), 3.58 (s, 3H), 7.08 (d, 2H), 7.15-
7.60 (m, 7H).
(t, 2H), 7.7 (m, 2H), 7.85 (m, 3H), 7.95 (s, 1H), 8.25 (d, 1H),
8.35 (s, 1H).
P a r t B: Employing methods similar to example 1, part B,
but using 3-[3-(3-cyanophenyl)-1-oxo-2-propenyl]benzonitrile
(0.280 g, 1.08 mmol), methyl 3-(3-cyanophenyl)-5-(3-cyanophen-
yl)-2,4-pentadienoate as a mixture of the E/Z isomers was
prepared as an oil (0.297 g, 87%): MS (M + NH4)+ 332; 1H
NMR (CDCl3) 3.60 (s, 3H), 3.80 (s, 3H), 5.85 (s, 1H), 6.23 (t,
2H), 6.45 (d, 1H), 7.15 (d, 1H), 7.55 (m, 16H), 8.60 (d, 1H).
P a r t C: Employing methods similar to example 1, part C,
but using methyl 3-(3-cyanophenyl)-5-(3-cyanophenyl)-2,4-
pentadienoate (0.297 g, 0.945 mmol) methyl 3-(3-cyanophenyl)-
5-(3-cyanophenyl)pentanoate was prepared as an oil (0.250 g,
83%): MS (M + NH4)+ 336; 1H NMR (CDCl3) 1.9 (m, 2H), 2.45
(m, 2H), 2.65 (m, 2H), 3.15 (m, 1H), 3.6 (s, 3H), 7.5 (m, 8H).
P a r t D: Employing methods similar to example 1, part D,
but using methyl 3-(3-cyanophenyl)-5-(3-cyanophenyl)pen-
tanoate (0.250 g, 0.786 mmol), the title compound 14 was
isolated after HPLC purification on a Vydac C-18 column,
solvent A (acetonitrile/water/TFA, 80:20:0.2) and solvent B
(water/TFA, 99.8:0.2), using a gradient (Rf ) 22 min), as a solid
(0.030 g, 11%): MS (M + H)+ 353; 1H NMR (DMSO-d6) 2.0
(m, 2H), 2.5 (m, 2H), 2.7 (dd, 1H), 2.85 (dd, 1H), 3.15 (m, 1H),
3.50 (s, 3H), 7.5 (s, 2H), 7.55 (m, 2H), 7.6 (t, 2H), 7.7 (d, 1H),
7.75 (s, 1H), 9.2 (s (v broad), 6H). Anal. (C20H24N4O2(CF3-
CO2H)2.1) C, H, N.
P r ep a r a tion of (()-Eth yl 3-(Am in oim in om eth yl)-â-[4-
(a m in oim in om eth yl)p h en yl]ben zen ep en ta n oa te Bis(tr i-
flu or oa ceta te) (15). P a r t A: Employing methods similar to
example 1, part A, but using m-cyanobenzaldehyde (0.91 g,
6.89 mmol) and 4-acetylbenzonitrile (1.0 g, 6.89 mmol), 4-[3-
(3-cyanophenyl)-1-oxo-2-propenyl]benzonitrile was isolated as
a pale yellow powder (1.4 g, 79%): 1H NMR (CDCl3) 8.53 (s,
1H), 8.35 (d, 2H), 8.15-8.20 (m, 3H), 7.92 (d, 1H), 7.82 (d, 1H),
7.67 (t, 1H).
P a r t D: Employing methods similar to example 1, part D,
but using methyl 3-(3-cyanophenyl)benzenepentanoate (0.30
g, 1.02 mmol), the title compound 13 was isolated after HPLC
purification on a Vydac C-18 column, solvent A (acetonitrile/
water/TFA, 80:20:0.2) and solvent B (water/TFA, 99.8:0.2),
using a gradient (Rf ) 14.3 min), as a white powder (0.12 g):
1
mp 248-249 °C; MS 311 (M + H)+; H NMR (DMSO-d6) 9.3
(s, 2H), 9.0 (s, 2H), 7.85 (s, 1H), 7.8 (m, 2H), 7.4 (t, 1H), 7.2-
7.4 (m, 5H), 3.50 (s, 3H), 3.15 (m, 1H), 2.85 (dd, 1H), 2.7 (dd,
1H), 2.5 (m, 2H), 2.0 (m, 2H). Anal. (C19H22N2O2(CF3CO2H)1.0
C, H, N.
)
P r ep a r a tion of (()-Eth yl 4-(Am in oim in om eth yl)-â-[4-
(a m in oim in om eth yl)p h en yl]ben zen ep en ta n oa te Bis(tr i-
flu or oa ceta te) (13). P a r t A: Employing methods similar to
example 1, part A, but using 4-cyanobenzaldehyde (1.80 g, 13.8
mmol) and 4-acetylbenzonitrile (1.0 g, 6.89 mmol), 4-[3-(4-

Bis-phenylamidine Carboxylate fXa Inhibitors
J ournal of Medicinal Chemistry, 1998, Vol. 41, No. 1 59
P a r t B: Employing methods similar to example 1, part B,
but using 4-[3-(3-cyanophenyl)-1-oxo-2-propenyl]benzonitrile
(0.5 g, 1.95 mmol), methyl 3-(4-cyanophenyl)-5-(3-cyanophen-
yl)-2,4-pentadienoate was prepared as mixture of isomers as
a semisolid (0.52 g, 85%): MS 332 (M + NH4)+; 1H NMR
(CDCl3) 8.55-7.0 (m, 10H), 6.45-6.15 (m, 1H), 3.8 (s, 3H).
P a r t C: Employing methods similar to example 1, part C,
but using methyl 3-(4-cyanophenyl)-5-(3-cyanophenyl)-2,4-
pentadienoate (0.5 g, 1.59 mmol), methyl 3-(3-cyanophenyl)-
5-(4-cyanophenyl)pentanoate was isolated after flash chroma-
tography on silica gel (100 mL) eluting with toluene/ethyl
acetate (95:5) to give a viscous oil (0.43 g, 85%): MS 319 (M +
H)+; 1H NMR (CDCl3) 7.65 (d, 2H), 7.48 (d, 1H), 7.4-7.15 (m,
5H), 3.7 (s, 3H), 3.2 (m, 1H), 2.67 (m, 2H), 2.42 (t, 2H), 2.1-
1.9 (m, 2H).
P a r t D: Employing methods similar to example 1, part D,
but using methyl 3-(3-cyanophenyl)-5-(4-cyanophenyl)pen-
tanoate (0.31 g, 0.97 mmol) and ethanol, the title compound
15 was isolated after HPLC purification on a Vydac C-18
column, eluting with solvent A (acetonitrile/water/TFA, 80:
20:0.2) and solvent B (water/TFA, 99.8:0.2), using a gradient
(Rf ) 15 min), as a white powder (0.146 g, 41%): mp 180-185
°C; MS 367 (M + H)+; HRMS calcd 367.2134, found 367.2136;
1H NMR (DMSO-d6) 9.27 (s, 4H), 9.22 (s, 2H), 9.21 (s, 2H), 7.8
(d, 2H), 7.65-7.47 (m, 6H), 3.92 (m, 2H), 3.18 (m, 1H), 2.8 (dd,
1H), 2.67 (dd, 1H), 2.6-2.33 (m, 2H), 2.0 (m, 2H). Anal.
(C21H26N4O2(CF3CO2H)2.1) C, H, N.
(()-Meth yl â-[3-(Am in oim in om eth yl)p h en yl]-4-(m eth -
oxycar bon yl)ben zen epen tan oate Mon o(tr iflu or oacetate)
(16). P a r t A: Employing methods similar to example 1, part
A, but using 3-acetylbenzonitrile (1.0 g, 6.8 mmol) and methyl
4-formylbenzoate (3.12 g, 17 mmol), the residue was chro-
matographed on silica gel eluting with methylene chloride to
give 3-[3-(methyl 4-benzoate)-1-oxo-2-propenyl]benzonitrile
(0.340 g, 20%): 1H NMR (CDCl3) 3.95 (s, 3H), 7.55 (d, 1H),
7.7 (m, 3H), 7.85 (t, 2H), 8.1 (d, 2H), 8.25 (d, 1H), 8.3 (s, 1H).
P a r t B: Employing methods similar to example 1, part B,
but using 3-[3-(methyl 4-benzoate)-1-oxo-2-propenyl]benzo-
nitrile (0.192 g, 0.655 mmol), methyl 3-(3-cyanophenyl)-5-
(methyl 4-benzoate)-2,4-pentadienoate was prepared as a
mixture of E and Z isomers as an oil (0.215 g, 95%): MS (M +
H)+ 348; 1H NMR (CDCl3) 3.6-3.9 (m, 6H), 7.1-8.0 (m, 11H).
P a r t C: Employing methods similar to example 1, part C,
but using methyl 3-(3-cyanophenyl)-5-(methyl 4-benzoate)-2,4-
pentadienoate (0.200 g, 0.574 mmol), methyl 3-(3-cyanophen-
yl)-5-(methyl 4-benzoate)pentanoate was prepared as an oil
(0.150 g, 75%): MS (M + NH4)+ 369; 1H NMR (CDCl3) 2.0 (m,
2H), 2.5 (t, 2H), 2.7 (m, 2H), 3.15 (m, 1H), 3.6 (s, 3H), 3.9 (s,
3H), 7.15 (d, 2H), 7.5 (m, 4H), 7.95 (d, 2H).
P a r t D: Employing methods similar to example 1, part D,
but using methyl 3-(3-cyanophenyl)-5-(methyl 4-benzoate)-
pentanoate (0.151 g, 0.43 mmol), the title compound 16 was
isolated after HPLC purification on a Vydac C-18 column,
solvent A (acetonitrile/water/TFA, 80:20:0.2) and solvent B
(water/TFA, 99.8:0.2), using a gradient (Rf ) 24 min), as a solid
(0.017 g, 10%): mp >200 °C; MS (M + H)+ 369; 1H NMR
(DMSO-d6) 1.95 (m, 2H), 2.5 (m, 2H), 2.65 (dd, 1H), 2.85 (dd,
1H), 3.15 (m, 1H), 3.55 (s, 3H), 3.8 (s, 3H). Anal.
(C21H24N2O4(CF3CO2H)1.1) C, H, N.
benzenepentanoate (0.038 g, 0.098 mmol), the title compound
17 was isolated after HPLC purification on a Vydac C-18
column, solvent A (acetonitrile/water/TFA, 80:20:0.2) and
solvent B (water/TFA, 99.8:0.2), using a gradient (Rf ) 21 min),
as a white solid (0.030 g, 76%): mp >200 °C; MS (M + H)+
1
404; H NMR (DMSO-d6) 1.95 (m, 2H), 2.4 (m, 2H), 2.7 (dd,
1H), 2.85 (dd, 1H), 2.95 (s, 3H), 3.55 (s, 3H), 7.05 (q, 4H), 7.65
(m, 4H), 8.9 (s (broad), 2H), 9.25 (s (broad), 2H), 9.55 (s, 1H).
Anal. (C20H25N3O4S(CF3CO2H)1.2) C, H, N.
P r ep a r a tion of (()-Meth yl â-[3-(Am in oim in om eth yl)-
p h en yl]-4-[(p h en ylsu lfon yl)a m in o]b en zen ep en t a n oa t e
Mon o(tr iflu or oa ceta te) (18). P a r t A: methyl 3-(3-cyano-
phenyl)-5-(4-aminophenyl)pentanoate (0.100 g, 0.325 mmol)
was dissolved in dioxane, and 0.5 mL of 1 N NaOH was added
followed by benzenesulfonyl chloride. The solution was stirred
for 1 h, quenched in 1 N HCl, and extracted with ethyl acetate.
The organic layer was washed with water and brine and dried
over MgSO4. The solvent was removed under vacuum, and
the residue was chromatographed on silica gel eluting with
ethyl acetate/toluene (20:80, v:v) to give methyl â-(3-cyano-
phenyl)-4-[(phenylsulfonyl)amino]benzenepentanoate as an oil
(0.060 g, 41%): MS (M + NH4)+ 466; 1H NMR (CDCl3) 1.9 (m,
2H), 2.35 (m, 2H), 2.6 (m, 2H), 3.15 (m, 1H), 3.55 (s, 3H), 6.95
(s, 4H), 7.45 (m, 5H), 7.55 (m, 2H), 7.75 (d, 2H).
P a r t B: Employing methods similar to example 1, part D,
but using methyl â-(3-cyanophenyl)-4-[(phenylsulfonyl)amino]-
benzenepentanoate (0.060 g, 0.135 mmol), the title compound
18 was isolated after HPLC purification on a Vydac C-18
column, solvent A (acetonitrile/water/TFA, 80:20:0.2) and
solvent B (water/TFA, 99.8:0.2), using a gradient (Rf ) 25 min),
as a white powder (0.015 g, 24%): mp >200 °C; MS (M + H)+
1
366; H NMR (DMSO-d6) 1.85 (m, 2H), 2.3 (m, 2H), 2.65 (dd,
1H), 2.9 (dd, 1H), 3.05 (m, 1H), 3.5 (s, 3H), 6.95 (s, 4H), 7.6
(m, 9H), 8.9 (s (broad), 2H), 9.25 (s (broad), 2H), 10.1 (s, 1H).
Anal. (C25H27N3O4S(CF3CO2H)1.1) C, H, N.
P r ep a r a tion of (()-Meth yl 4-(Am in oca r bon yl)-â-[3-
(a m in oim in om eth yl)p h en yl]ben zen ep en ta n oa te Mon o-
(tr iflu or oa ceta te) (19). P a r t A: 2,4-Dimethoxybenzylamine
hydrochloride (6.78 g, 33.3 mmol) was dissolved in dry DMF
under N2. 4-Carboxybenzaldehyde (5 g, 33.3 mmol) was added
followed by 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide
hydrochloride (7 g, 36.6 mmol) and 4-(dimethylamino)pyridine
(4 g, 33.3 mmol). The resulting solution was stirred at room
temperature for 24 h and quenched in 1 N HCl. After
extraction with ethyl acetate, the organic layer was washed
with water (3×) and brine, dried over MgSO4, and concen-
trated. The residue was chromatographed on silica gel eluting
with ethyl acetate/toluene (20:80, v:v) to give 4-(N-2,4-
dimethoxybenzenecarboxamido)benzaldehyde as an oil (4.3 g,
1
43%): MS (M + H)+ 300; H NMR (CDCl3) 3.80 (s, 3H), 3.85
(s, 3H), 4.6 (d, 2H), 6.45 (m, 2H), 7.2 (m, 1H), 7.90 (s, 4H),
10.0 (s, 1H).
P a r t B: Employing methods similar to example 1, part A,
but using 3-acetylbenzonitrile (0.200 g, 1.52 mmol) and 4-(N-
2,4-dimethoxybenzenecarboxamido)benzaldehyde (0.908 g, 3.04
mmol), 3-[3-[4-[N-(2,4-dimethoxybenzyl)benzamido]]-1-oxo-2-
propenyl]benzonitrile was isolated as a white solid (0.338 g,
1
52%): MS (M + H)+ 427; H NMR (CDCl3) 3.80 (s, 3H), 3.85
(s, 3H), 4.60 (d, 2H), 6.45 (m, 2H), 6.65 (t, 1H), 7.25 (d, 1H),
7.7 (m, 6H), 8.25 (d, 1H), 8.30 (s, 1H).
P r ep a r a tion of (()-Meth yl â-[3-(Am in oim in om eth yl)-
p h en yl]-4-[(m et h ylsu lfon yl)a m in o]b en zen ep en t a n oa t e
Mon o(tr iflu or oa ceta te) (17). P a r t A: Methyl 3-(3-cyano-
phenyl)-5-(4-aminophenyl)pentanoate (0.100 g, 0.325 mmol)
was dissolved in 3 mL of benzene and treated with methane-
sulfonic anhydride (0.062 g, 0.357 mmol). The solution was
stirred for 0.5 h, and the solvent was removed under vacuum.
The residue was chromatographed on silica gel eluting (ethyl
acetate/methylene chloride/toluene, v:v:v, 20:40:40) to give
methyl â-(3-cyanophenyl)-4-[(methylsulfonyl)amino]benzene-
pentanoate as an oil (0.038 g, 30%): 1H NMR (CDCl3) 1.9 (m,
2H), 2.4 (t, 2H), 2.6 (m, 2H), 3.0 (s, 3H), 3.15 (m, 1H), 3.6 (s,
3H), 6.25 (s (broad), 1H), 7.1 (q, 4H), 7.5 (m, 4H).
P a r t C: Employing methods similar to example 1, part B,
but using 3-[3-[4-[N-(2,4-dimethoxybenzyl)benzamido]]-1-oxo-
2-propenyl]benzonitrile (0.318 g, 0.746 mmol), the residue was
chromatographed on silica gel eluting with ethyl acetate/
toluene (v:v, 20:80) to afford a mixture of E and Z isomers of
methyl 3-(3-cyanophenyl)-5-[4-[N-(2,4-dimethoxybenzyl)benz-
amido]]-2,4-pentadienoate as an oil (0.210 g, 58%): MS (M +
H)+ 483; 1H NMR (CDCl3) 375-3.9 (m, 9H), 4.58 (m, 2H), 6.2-
6.6 (m, 3H), 7.05-7.8 (m, 12H).
P a r t D: Employing methods similar to example 1, part C,
but using methyl 3-(3-cyanophenyl)-5-[4-[N-(2,4-dimethoxy-
benzyl)benzamido]]-2,4-pentadienoate (0.165 g, 0.342 mmol),
methyl 3-(3-cyanophenyl)-5-[4-[N-(2,4-dimethoxybenzyl)benz-
amido]]pentanoate was isolated as an oil (0.140 g, 84%): MS
P a r t B: Employing methods similar to example 1, part D,
but using methyl â-(3-cyanophenyl)-4-[(methylsulfonyl)amino]-

60 J ournal of Medicinal Chemistry, 1998, Vol. 41, No. 1
Maduskuie et al.
(M + H)+ 487; 1H NMR (CDCl3) 1.95 (m, 2H), 2.45 (t, 2H), 2.6
(m, 2H), 3.15 (m, 1H), 3.59 (s, 3H), 3.80 (s, 3H), 3.85 (s, 3H),
4.55 (d, 2H), 6.45 (d, 2H), 6.55 (t, 1H), 7.10 (d, 2H), 7.25 (d,
1H), 7.55 (m, 6H).
After removing the solvent, the residue (0.150 g, 0.428 mmol)
was converted to the amidine employing methods similar to
example 1, part D. The title compound was isolated after
HPLC purification on a Vydac C-18 column, solvent A (aceto-
nitrile/water/TFA, 80:20:0.2) and solvent B (water/TFA, 99.8:
0.2), using a gradient (Rf ) 16 min), as a solid (0.080 g, 51%):
P a r t E: A solution of methyl 3-(3-cyanophenyl)-5-[4-[N-(2,4-
dimethoxybenzyl)benzamido]]pentanoate (0.140 g, 0.288 mmol)
in acetonitrile was added to a solution of ceric ammonium
sulfate (0.686 g, 1.152 mmol) in water. The resulting solution
was heated at 60 °C for 4 h, cooled to room temperature, and
poured into water. The water was extracted with ethyl acetate
(2×) and the organic layer washed with water and brine and
dried over magnesium sulfate. After the solvent was removed,
the residue was chromatographed on silica gel, ethyl acetate/
toluene (90:10, v:v), to give methyl 3-(3-cyanophenyl)-5-(4-
benzamido)pentanoate as an oil (0.053 g, 55%): MS (M +
NH4)+ 354; 1H NMR (DMSO-d6) 1.95 (m, 2H), 2.4 (m, 2H), 2.65
(dd, 1H), 2.8 (dd, 1H), 3.05 (m, 1H), 3.45 (s, 3H), 7.19 (d, 2H),
7.25 (s (broad), 1H), 7.56 (m, 6H), 7.90 (s (broad), 1H).
P a r t F : Employing the method of example 1, part D but
using methyl 3-(3-cyanophenyl)-5-(4-benzamido)pentanoate
(0.050 g, 0.148 mmol), the title compound 19 was isolated after
HPLC purification on a Vydac C-18 column, solvent A (aceto-
nitrile/water/TFA, 80:20:0.2) and solvent B (water/TFA, 99.8:
0.2), using a gradient (Rf ) 16 min), as a solid (0.030 g, 57%):
mp >200 °C; MS (M + H)+ 354; 1H NMR (DMSO-d6) 1.95 (m,
2H), 2.45 (m, 2H), 2.7 (dd, 1H), 2.85 (dd, 1H), 3.15 (m, 1H),
3.50 (s, 3H), 7.20 (d, 2H), 7.25 (s, 1H), 7.6 (m, 8H), 7.85 (s,
1H), 8.95 (s (broad), 2H), 9.30 (s (broad), 2H). Anal.
(C20H23N3O3(CF3CO2H)1.0) C, H, N.
1
MS (M + H)+ 368; H NMR (DMSO-d6) 2.0 (m, 2H), 2.5 (m,
2H), 2.7 (dd, 1H), 2.85 (dd, 1H), 3.15 (m, 1H), 3.50 (s, 3H),
7.15 (q, 4H), 7.35 (s (broad), 4H), 7.65 (m, 4H), 9.05 (s (broad),
2H), 9.25 (s (broad), 2H), 9.65 (s, 1H). Anal. (C20H25N5O2(CF3-
CO2H)2.1) C, H, N.
P r ep a r a tion of (()-Meth yl 4-[(Am in oim in om eth yl)-
a m i n o ]-â-[3-(a m i n o i m i n o m e t h y l)p h e n y l]b e n z e n e -
h ep ta n oa te Bis(tr iflu or oa ceta te) (23). P a r t A: Employing
a method similar to example 1, part A, but using 3-acetyl-
benzonitrile (3.7 g, 28.2 mmol) and 4-nitrocinnamaldehyde (5
g, 28.2 mmol), 3-[5-(4-nitrophenyl)-1-oxo-2,4-pentadienyl]-
benzonitrile was prepared as a solid (6.5 g, 73%): MS (M +
H)+ 319; 1H NMR (CDCl3) 7.15 (m, 3H), 7.65 (m, 4H), 7.85 (d,
1H), 8.25 (m, 4H).
P a r t B: Employing methods similar to example 1, part B,
but using 3-[5-(4-nitrophenyl)-1-oxo-2,4-pentadienyl]benzo-
nitrile (2 g, 6.28 mmol), the methyl 3-(3-cyanophenyl)-7-(4-
nitrophenyl)-2,4,6-heptatrienoate was prepared as an oil (0.550
1
g, 25%): MS (M + NH4)+ 378; H NMR (CDCl3) 3.8 (s, 3H),
5.8 (s, 1H), 6.3 (dd, 1H), 6.65 (d, 1H), 7.15 (dd, 1H), 7.6 (m,
6H), 8.1 (d, 1H), 8.2 (d, 2H).
P a r t C: Employing methods similar to example 1, part C,
but using methyl 3-(3-cyanophenyl)-7-(4-nitrophenyl)-2,4,6-
heptatrienoate (0.363 g, 1 mmol), methyl 3-(3-cyanophenyl)-
7-(4-aminophenyl)heptanoate was prepared as an oil (0.296
g, 87%): MS (M + H)+ 337; 1H NMR (CDCl3) 1.15 (m, 1H),
1.65 (m, 4H), 2.55 (m, 4H), 3.1 (m, 1H), 3.6 (s, 3H), 6.6 (d, 2H),
6.9 (d, 2H), 7.45 (m, 4H).
P a r t D: Employing methods similar to example 1, part D,
but using methyl 3-(3-cyanophenyl)-7-(4-aminophenyl)hep-
tanoate (0.200 g, 0.595 mmol), the title compound 23 was
isolated after HPLC purification on a Vydac C-18 column,
solvent A (acetonitrile/water/TFA, 80:20:0.2) and solvent B
(water/TFA, 99.8:0.2), using a gradient (Rf ) 20 min), as a
white solid (0.110 g, 46%): MS (M + H)+ 396; 1H NMR (DMSO-
d6) 1.2 (m, 1H), 2.55 (m, 2H), 2.65 (m, 2H), 2.5 (m, 2H), 2.65
(dd, 1H), 2.75 (dd, 1H), 3.1 (m, 1H), 3.5 (s, 3H), 7.1 (d, 2H),
7.2 (d, 2H), 7.4 (s (broad), 4H), 7.55 (t, 1H), 7.6 (d, 1H), 7.65
(m, 2H), 9.05 (s (broad), 2H), 9.25 (s (broad), 2H), 9.65 (s, 1H).
Anal. (C22H29N5O2(CF3CO2H)2.1) C, H, N.
P r ep a r a tion of (()-Meth yl 4-Am in o-â-[3-(a m in oim in o-
m et h yl)p h en yl]b en zen ep en t a n oa t e
Mon o(t r iflu or o-
a cet a t e) (20). P a r t A: Employing methods similar to
example 1, part A, but using 3-acetylbenzonitrile (987 g, 6.8
mmol) and 4-nitrobenzaldehyde (1.0 g, 6.8 mmol), 3-[3-(4-
nitrophenyl)-1-oxo-2-propenyl]benzonitrile was isolated as a
1
white solid (1.7 g, 97%): MS 279 (M + H)+; H NMR (CDCl3)
7.60 (d, 1H), 7.70 (t, 1H), 7.85 (m, 4H), 8.25 (m, 4H).
P a r t B: Employing methods similar to example 1, part B,
but using 3-[3-(4-nitrophenyl)-1-oxo-2-propenyl]benzonitrile
(0.500 g, 1.79 mmol), the residue was chromatographed on
silica gel, ethyl acetate/toluene (20:80, v:v), to afford methyl
3-(3-cyanophenyl)-5-(4-nitrophenyl)-2,4-pentadienoate (0.441
g, 74%) as a mixture of the E/Z isomers: MS 335 (M + H)+;
1H NMR (CDCl3) 3.6 (s, 3H), 3.8 (s, 3H), 5.9 (s, 1H), 6.25 (m,
2H), 6.6 (d, 1H), 7.15 (m, 2H), 7.6 (m, 11H), 8.2 (d, 4H), 8.65
(d, 1H).
P a r t C: Employing methods similar to example 1, part C,
but using methyl 3-(3-cyanophenyl)-5-(4-nitrophenyl)-2,4-pen-
tadienoate (0.441 g, 1.32 mmol), the residue was chromato-
graphed on silica gel eluting with ethyl acetate/methylene
chloride (10:90, v:v) to yield methyl 3-(3-cyanophenyl)-5-(4-
aminophenyl)pentanoate (0.220 g, 54%): MS 309 (M + H)+;
1H NMR (CDCl3) 1.9 (m, 2H), 2.35 (t, 2H), 2.6 (m, 2H), 3.15
(m, 1H), 3.55 (s, 3H), 6.60 (d, 2H), 6.85 (d, 2H), 7.5 (m, 4H).
P a r t D: Employing methods similar to example 1, part D,
but using methyl 3-(3-cyanophenyl)-5-(4-aminophenyl)pen-
tanoate (0.220 g, 0.71 mmol), the title compound 20 was
isolated after HPLC purification on a Vydac C-18 column,
solvent A (acetonitrile/water/TFA, 80:20:0.2) and solvent B
(water/TFA, 99.8:0.2), using a gradient (Rf ) 13 min), as a
white solid (0.105 g, 45%): mp >200 °C; MS 326 (M + H)+; 1H
NMR (DMSO-d6) 2.0 (m, 2H), 2.5 (m, 2H), 2.7 (dd, 1H), 2.85
(dd, 1H), 3.15 (m, 1H), 3.50 (s, 3H), 7.1 (q, 4H), 7.55 (m, 2H),
7.7 (m, 2H), 9.3 (d (broad), 4H). Anal. (C19H23N3O2(CF3-
CO2H)1.2) C, H, N.
P r ep a r a tion of (()-Meth yl 4-[(Am in oim in om eth yl)-
a m i n o ]-â-[3-(a m i n o i m i n o m e t h y l)p h e n y l]b e n z e n e -
p en ta n oa te Bis(tr iflu or oa ceta te) (21). Methyl 3-(3-cyano-
phenyl)-5-(4-aminophenyl)pentanoate (0.10 g, 0.325 mmol) was
dissolved in 5 mL of pyridine, and 3,5-dimethylpyrazole-1-
carboxamidine nitrate (0.098 g, 0.048 mmol) was added. The
solution was heated at 80 °C overnight, cooled, and partitioned
between ethyl acetate and water. The organic layer was
washed with a small amount of water and dried over MgSO4.
P r ep a r a t ion of 4-(Am in oim in om et h yl)-â-[3-(a m in o-
im in om eth yl)p h en yl]ben zen ep en ta n oic Acid Dih yd r o-
ch lor id e (24). Methyl 4-(aminoiminomethyl)-â-[3-(amino-
iminomethyl)phenyl]benzenepentanoate bis(trifluoroacetate)
(1) (0.030 g, 0.08 mmol) was dissolved in 0.5 mL of 6 N HCl
under N2 and stirred at room temperature for 48 h. The
solution was concentrated to give the title compound 24 as a
white solid (0.018 g, 66%): mp >200 °C dec; MS (M + H)+
339; 1H NMR (DMSO-d6) 2.0 (m, 2H), 2.5 (m, 2H), 2.7 (dd, 1H),
2.85 (dd, 1H), 3.15 (m, 1H), 7.40 (d, 2H), 7.55 (m, 2H), 7.75
(m, 4H), 9.1 (d, 4H), 9.25 (d, 4H). Anal. (C19H22N4O2(HCl)2.1
C, H, N.
)
P r ep a r a tion of (()-Eth yl 4-(Am in oim in om eth yl)-â-[3-
(a m in oim in om eth yl)p h en yl]ben zen ep en ta n oa te Bis(tr i-
flu or oa ceta te) (25). Employing a method similar to example
26, part B, using ethanol instead of 2-propanol, the title
compound 25 was prepared as a white solid (0.015 g, 7%) after
HPLC purification on a Vydac C-18 column, solvent A (aceto-
nitrile/water/TFA, 80:20:0.2) and solvent B (water/TFA, 99.8:
0.2), using a gradient (Rf ) 17 min): mp >200 °C; MS (M +
H)+ 367; 1H NMR (DMSO-d6) 1.05 (t, 3H), 2.0 (m, 2H), 2.5 (m,
2H), 2.7 (dd, 1H), 2.85 (dd, 1H), 3.15 (m, 1H), 3.50 (s, 3H),
3.95 (m, 2H), 7.40 (d, 2H), 7.55 (m, 2H), 7.75 (m, 4H), 9.1 (d,
4H), 9.25 (d, 4H). Anal. (C21H26N4O2(CF3CO2H)2.2) C, H, N.
P r ep a r a t ion of (()-1-Met h ylet h yl 4-(Am in oim in o-
m e t h y l)-â-[3-(a m in o im in o m e t h y l)p h e n y l]b e n ze n e -
p en ta n oa te Bis(tr iflu or oa ceta te) (26). P a r t A: Methyl
4-cyano-â-(3-cyanophenyl)benzenepentanoate (7) (0.250 g, 0.786

Bis-phenylamidine Carboxylate fXa Inhibitors
J ournal of Medicinal Chemistry, 1998, Vol. 41, No. 1 61
min) as a white powder (0.085 g, 60%): MS 392 (M + H)+,
mmol) was dissolved in methanol, and LiOH (0.056 g, 2.3
mmol) in 1 mL of water was added. The solution was stirred
at room temperature for 2 h and extracted with ethyl acetate.
The resultant aqueous layer was made acidic with 1 N HCl
and extracted with ethyl acetate. The organic phase was dried
over MgSO4 and concentrated to give 4-cyano-â-(3-cyano-
phenyl)benzenepentanoic acid as an oil (0.138 g, 58%): 1H
NMR (DMSO-d6) 1.95 (m, 2H), 2.3 (m, 3H), 2.70 (dd, 1H), 3.05
(m, 1H), 7.3 (d, 2H), 7.5 (t, 1H), 7.60 (d, 1H), 7.7 (m, 3H), 12.10
(s, 1H).
P a r t B: 4-Cyano-â-(3-cyanophenyl)benzenepentanoic acid
(0.111 g, 0.37 mmol) was dissolved in 2-propanol and treated
with anhydrous HCl for 2 min. The resulting solution was
stirred at room temperature overnight and then concentrated.
The residue was dissolved in fresh 2-propanol, and ammonium
carbonate (0.284 g, 2.9 mmol) was added. The solution was
stirred at room temperature for 24 h and concentrated, and
the title compound 26 was isolated after HPLC purification
on a Vydac C-18 column, solvent A (acetonitrile/water/TFA,
80:20:0.2) and solvent B (water/TFA, 99.8:0.2), using a gradient
(Rf ) 18 min), as a white powder (0.015 g, 11%): mp >200 °C
dec; MS (M + H)+ 381; 1H NMR (DMSO-d6) 1.15 (dd, 6H), 2.0
(m, 2H), 2.5 (m, 2H), 2.7 (dd, 1H), 2.85 (dd, 1H), 3.15 (m, 1H),
4.80 (m, 1H), 7.40 (d, 2H), 7.55 (m, 2H), 7.75 (m, 4H), 9.1 (d,
4H), 9.25 (d, 4H). Anal. (C22H28N4O2(CF3CO2H)1.0) C, H, N.
1
196.7 (M + 2H)2+; H NMR (DMSO-d6) 9.31 (s, 2H), 9.23 (s,
2H), 9.20 (s, 2H), 9.12 (s, 2H), 7.75-7.5 (m, 6H), 7.37 (d, 2H),
3.4-3.1 (m, 7H), 2.75-2.45 (m, 2H), 2.0 (m, 2H), 1.85-1.65
(m, 4H). Anal. (C23H29N5O2(CF3CO2H)2.0) C, H, N.
P r ep a r a tion of (()-Meth yl N-[3-[3-(Am in oim in om eth -
yl)ph en yl]-5-[4-(am in oim in om eth yl)ph en yl]-1-oxopen tyl]-
glycin e Bis(tr iflu or oa ceta te) (29). P a r t A: Employing
methods similar to example 27, part A, but using 3-(3-
cyanophenyl)-5-(4-cyanophenyl)pentanoic acid (0.15 g, 0.49
mmol) and methyl glycine ester (0.068 g, 0.54 mmol), methyl
N-[3-(3-cyanophenyl)-5-(4-cyanophenyl)-1-oxopentyl]glycine was
isolated after flash chromatography purification on silica gel
(75 mL) eluting with methylene chloride/ethyl acetate (v:v, 75:
25) as a colorless viscous oil (0.13 g, 71%): MS 393 (M + NH4);
1H NMR (CDCl3) 7.57-7.42 (m, 6H), 7.17 (d, 2H), 5.85 (m, 1H),
4.0 (dd, 1H), 3.92 (dd, 1H), 3.25 (m, 1H), 2.65-2.45 (m, 4H),
2.1 (m, 1H), 1.93 (m, 1H).
P a r t B: Employing methods similar to example 1, part D,
but using methyl N-[3-(3-cyanophenyl)-5-(4-cyanophenyl)-1-
oxopentyl]glycine (0.11 g, 0.29 mmol), the title compound 29
was isolated after HPLC purification on a Vydac C-18 column
eluting with solvent A (acetonitrile/water/TFA, 80:20:0.2) and
solvent B (water/TFA, 99.8:0.2) using a gradient (Rf ) 13 min)
as a semisolid residue (0.012 g, 10%): MS 205.8 (M + 2H)2+
;
1H NMR (DMSO-d6) 9.25 (s, 2H), 9.20 (s, 2H), 9.0 (s, 2H), 8.9
(s, 2H), 8.27 (t, 1H), 7.73-7.52 (m, 6H), 7.37 (d, 2H), 3.8 (dd,
1H), 3.72 (dd, 1H), 3.17 (m, 3H), 2.57-2.42 (m, 2H), 2.0 (m,
2H). Anal. (C22H27N5O3(CF3CO2H)3.0) C, H, N.
P r ep a r a tion of (()-4-(Am in oim in om eth yl)-â-[3-(a m in o-
im in om eth yl)ph en yl]-N-m eth ylben zen epen tan am ide Bis-
(tr iflu or oa ceta te) (27). P a r t A: Oxalyl chloride was added
to a solution of 3-(3-cyanophenyl)-5-(4-cyanophenyl)pentanoic
acid (0.25 g, 0.82 mmol) in 10 mL of methylene chloride under
a nitrogen atmosphere at ambient temperature. The reaction
mixture was stirred for 2 h and concentrated in vacuo to give
a semisolid residue. The residue was taken up in 5 mL of
methylene chloride, and 40% methylamine in water (5 mL)
was added. The reaction mixture was stirred vigorously for 2
h and then was partioned between 1 N HCl and ethyl acetate.
The organic layer was washed with water and brine, dried over
magnesium sulfate, and concentrated to give the crude product
as a semisolid. The residue was purified by flash chromatog-
raphy on silica gel (100 mL) eluting with methylene chloride/
ethyl acetate (v:v, 80:20) to give 4-cyano-â-(3-cyanophenyl)-
N-methylbenzenepentanamide as a semisolid (0.120 g, 46%):
P r ep a r a tion of (()-4-(Am in oim in om eth yl)-â-[3-(a m in o-
im in om et h yl)p h en yl]-N-m et h oxyb en zen ep en t a n a m id e
Bis(tr iflu or oa ceta te) (30). P a r t A: A solution of 3-(3-
cyanophenyl)-5-(4-cyanophenyl)pentanoic acid (0.15 g, 0.49
mmol), methoxylamine hydrochloride (0.041 g, 0.54 mmol),
1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochlo-
ride (0.14 g, 0.73 mmol), and 4-(dimethylamino)pyridine (0.15
g, 1.22 mmol) in 5 mL of DMF under a nitrogen atmosphere
was stirred for 18 h. The reaction solution was poured into
water and extracted with ethyl acetate. The combined organic
layer was washed with 1 N HCl (2×), water, brine, and dried
over magnesium sulfate, and concentrated to give the crude
product as a colorless viscous oil. The product was purified
by flash chromatography on silica gel (50 mL) eluting with
methylene chloride/ethyl acetate (v:v, 60:40) to give 4-cyano-
â-(3-cyanophenyl)-N-methoxybenzenepentanamide as a color-
less viscous oil (0.15 g, 91%): 1H NMR (CDCl3) 8.03 (bs, 1H),
7.56-7.42 (m, 6H), 7.15 (d, 2H), 3.58 (s, 3H), 3.28 (m, 1H),
2.8-1.85 (m, 6H).
1
MS 335 (M + NH4)+; H NMR (CDCl3) 7.6-7.4 (m, 6H), 7.17
(d, 2H), 5.3 (m, 1H), 3.27 (m, 1H), 2.67 (d, 2H), 2.55-2.35 (m,
4H), 2.07 (m, 1H), 1.95 (m, 1H).
P a r t B: Employing methods similar to example 1, part D,
but using 4-cyano-â-(3-cyanophenyl)-N-methylbenzenepentan-
amide (0.1 g, 0.32 mmol), the title compound 27 was isolated
after HPLC purification on a Vydac column eluting with
solvent A (acetonitrile/water/TFA, 80:20:0.2) and solvent B
(water/TFA, 99.8:0.2) using a gradient (Rf ) 15.3 min) as a
white solid (0.045 g, 40%): MS 176.7 (M + 2H)2+; HRMS calcd
P a r t B: Employing methods similar to example 1, part D,
but using 4-cyano-â-(3-cyanophenyl)-N-methoxybenzene-
pentanamide (0.12 g, 0.36 mmol), the title compound 30 was
isolated after HPLC purification on a Vydac C-18 column
eluting with solvent A (acetonitrile/water/TFA, 80:20:0.2) and
solvent B (water/TFA, 99.8:0.2) using a gradient (Rf ) 14 min)
1
352.2137, found 352.2138; H NMR (DMSO-d6) 9.31 (s, 2H),
9.23 (s, 2H), 9.21 (s, 2H), 9.11 (s, 2H), 7.75-7.65 (m, 5H), 7.55
(d, 2H), 7.37 (d, 2H), 3.15 (m, 1H), 2.55-2.35 (m, 4H), 1.95
(m, 2H). Anal. (C20H25N5O(CF3CO2H)2.4) C, H, N.
as a white powder (0.058 g, 44%): MS 184.7 (M + 2H)2+
;
1
HRMS calcd 368.2086, found 368.2083; H NMR (DMSO-d6)
10.9 (s, 1H), 9.28 (s, 2H), 9.21 (s, 2H), 9.08 (s, 2H), 8.98 (s,
2H), 7.73 (d, 2H), 7.67 (m, 2H), 7.56 (m, 2H), 7.38 (d, 2H), 3.35
(s, 3H), 3.12 (m, 1H), 2.55-1.95 (m, 6H). Anal.
(C20H25N5O2(CF3CO2H)2.1) C, H, N.
P r ep a r a tion of (()-1-[3-[3-(Am in oim in om eth yl)p h en -
yl]-5-[4-(a m in oim in om et h yl)p h en yl]-1-oxop en t yl]p yr -
r olid in e Bis(tr iflu or oa ceta te) (28). Employing methods
similar to example 27, part A, but using 3-(3-cyanophenyl)-5-
(4-cyanophenyl)pentanoic acid (0.2 g, 0.66 mmol) and pyyro-
lidine (0.047 g, 0.66 mmol), 1-[3-(3-cyanophenyl)-5-(4-cyano-
phenyl)-1-oxopentyl]pyrrolidine was isolated after flash chro-
matography on silica gel eluting with methylene chloride/ethyl
acetate (v:v, 60:40) as a viscous oil (0.14 g, 45%): MS 358 (M
+ H)+, 375 (M + NH4)+; 1H NMR (CDCl3) 7.55-7.39 (m, 6H),
7.2 (d, 2H), 3.45-3.3 (m, 4H), 3.2 (m, 1H), 2.6-2.4 (m, 4H),
2.17 (m, 1H), 1.95-1.75 (m, 5H).
P a r t B: Employing methods similar to example 1, part D,
but using 1-[3-(3-cyanophenyl)-5-(4-cyanophenyl)-1-oxopentyl]-
pyrrolidine (0.13 g, 0.36 mmol), the title compound 28 was
isolated after HPLC purification using a Vydac C-18 column
eluting with solvent A (acetonitrile/water/TFA, 80:20:0.2) and
solvent B (water/TFA, 99.8:0.2) using a gradient (Rf ) 14.2
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