N,N-Dialkylated 4-(4-arylsulfonylpiperazine-1-carbonyl)-benzamidines and 4-((4-arylsulfonyl)-2-oxo-piperazin-1-ylmethyl)-benzamidines as potent factor Xa inhibitors

Article abstract of DOI:10.1016/j.bmcl.2004.02.049

A class of N,N-dialkylated 4-(4-arylsulfonylpiperazine-1-carbonyl)- benzamidines and 4-((4-arylsulfonyl)-2-oxo-piperazin-1-ylmethyl)-benzamidines has been discovered as potent factor Xa inhibitors with desirable in vitro and in vivo anticoagulant activity

Full text of DOI:10.1016/j.bmcl.2004.02.049

Bioorganic & Medicinal Chemistry Letters 14 (2004) 2073–2078
N,N-Dialkylated 4-(4-arylsulfonylpiperazine-1-carbonyl)-
benzamidines and 4-((4-arylsulfonyl)-2-oxo-piperazin-1-ylmethyl)-
benzamidines as potent factor Xa inhibitors
Zhaozhong J. Jia,*, Ting Su, Jingmei F. Zuckett, Yanhong Wu, Erick A. Goldman,
Wenhao Li, Penglie Zhang, Lane A. Clizbe, Yonghong Song, Shawn M. Bauer,
Wenrong Huang, John Woolfrey, Uma Sinha, Ann E. Arfsten,
Athiwat Hutchaleelaha, Stanley J. Hollenbach, Joseph L. Lambing,
Robert M. Scarborough and Bing-Yan Zhu*,à
Millennium Pharmaceuticals, Inc., 256 East Grand Ave., South San Francisco, CA 94080, USA
Received 12 December 2003; revised 10 February 2004; accepted 12 February 2004
Abstract—A class of N,N-dialkylated 4-(4-arylsulfonylpiperazine-1-carbonyl)-benzamidines and 4-((4-arylsulfonyl)-2-oxo-pipera-
zin-1-ylmethyl)-benzamidines has been discovered as potent factor Xa inhibitors with desirable in vitro and in vivo anticoagulant
activity, but with low oral bioavailability. The 5-chloroindole and 6-chlorobenzo[b]thiophene groups are optimal as the factor Xa S1
binding elements. The strategy of incorporating a side chain on the piperazine nucleus to enhance binding affinity has been
examined.
ꢀ 2004 Elsevier Ltd. All rights reserved.
Factor Xa (fXa) is a pivotal serine protease in the blood
coagulation cascade, responsible for the conversion of
prothrombin to thrombin. The design and discovery of
orally active small molecule human fXa inhibitors as a
novel therapy for thromboembolic disorders has been a
major focus of the pharmaceutical industry.1 Since 1998,
a variety of substituted (4-(6-halonaphthalene-2-sulfon-
yl)-piperazine-1-carbonyl)-benzene derivatives (1) have
been reported in patent publications as fXa inhibitors.2
Using a biphenylsulfonamide3 as the S4 binding ele-
ment, we prepared the 6-bromo-2-naphthyl containing
analog 2 based on molecular modeling of this template,
which indicated that the 6-bromo-2-naphthyl moiety fits
in the S1 pocket of the fXa active site and points into the
aromatic ring of Tyr228 at the bottom of the pocket. In
vitro, 2 displays a modest fXa IC50 of 240 nM with
marginal water solubility.
O
O
O
O
N
N S O
N
N S O
H2NO 2S
Sub
X
Br
1 (X=Cl, Br)
2
In order to improve the binding affinity and hydrophi-
licity of our inhibitor, we designed a series of com-
pounds, 3a–k, employing N,N-dialkylated benz-
amidines which, according to our docking studies,
should be tolerated as an S4 binding motif.4 At physi-
ological pH, these benzamidines would be positively
charged and thus would not only increase the inhibitorÕs
hydrophilicity, but could also increase the binding
affinity through ionic interactions with the S4 pocket.
Unsubstituted benzamidines have long been used in fXa
inhibitors as binding elements in both the S1 and S4
pockets. However, most of these benzamidine com-
pounds suffer low oral bioavailability and a short half
life. The N,N-dialkylated benzamidines have better
oral absorption than the corresponding unsubstituted
Keywords: Factor Xa inhibitors; Benzamidines.
* Corresponding authors. Tel.: +1-650-246-7073; fax: +1-650-246-7776
(Z.J.J.), tel.: +1-510-402-4032 (B.-Y.Z.); e-mail addresses: zjia@
portola.com; bzhu@qbius.com
Present address: Portola Pharmaceuticals, Inc., 270 East Grand Ave.,
Suite 22, South San Francisco, CA 94080, USA.
Present address: Quark Biotech, Inc., 6536 Kaiser Dr., Fremont, CA
à
94555, USA.
0960-894X/$ - see front matter ꢀ 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmcl.2004.02.049

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Z. J. Jia et al. / Bioorg. Med. Chem. Lett. 14 (2004) 2073–2078
Table 2. S1 SAR of the 1-(4-arylsulfonylpiperazine-1-carbonyl)-4-(N-
methylimidazolin-2-yl)-benzenes
benzamidine, as known in the platelet glycoprotein IIb–
IIIa antagonist literature.5;6 Moreover, researchers at
Berlex have reported a compound, ZK-807834,7 which
contains a N-methylimidazoline––a cyclized alkyl ami-
dine––group as the S4 binding moiety.
O
S1
N
N
N
The N,N-dialkylated benzamidine S4 SAR results are
given in Table 1. The N-methylimidazoline analog 3h
(IC50 31 nM) is the most potent in this group. Any
modification from 3h leads to loss in fXa potency,
including de-methylation (3g), methyl homologation
(3i), ring cleavage (3c) and ring expansion (3k).
N
4a-8
Compound
S1
fXa IC50 (nM)
31
O
O
O
S
S
3h
Br
O
To explore the S1 binding region of our inhibitor, we
synthesized compounds 4a–8 (Table 2). From this series
of inhibitors, we found that the 6-chlorobenzo[b]thio-
4a
5
9
S
Cl
Cl
O
O
O
S
S
270
S
O
Table 1. S4 SAR of the N,N-dialkylated 4-(4-(6-bromonaphthalene-2-
sulfonyl)-piperazine-1-carbonyl)-benzamidines
6
590
5
HN
O
Cl
Cl
O
O
N S O
O
S
7a
N
HN
O
RN
8
>11,000
NR1R2
RN
Br
Cl
3
HN
Compound
fXa IC50 (nM)
R2R1N
phene-2-sulfonyl (4a: IC50 9 nM) and 5-chloroindole-2-
sulfonyl (7a: IC50 5 nM) moieties significantly increase
fXa activity as the S1 binding ligands. Interestingly, the
isomeric 5-chlorobenzo[b]thiophene-2-sulfonyl (5) and
6-chloroindole-2-sulfonyl (6) groups show a significant
decrease in potency. It is also clear that the sulfonyl
linkage is required as replacement with a carbonyl group
(8) completely destroys the fXa activity.
HN
H2N
HN
3a
3b
64
230
NH
HN
N
3c
3d
230
390
After the 6-chlorobenzo[b]thiophene-2-sulfonyl and
5-chloroindole-2-sulfonyl were identified as the optimal
S1 motifs, we revisited the N,N-dialkylated benzamidine
SAR. As shown in Table 3, we discovered the
N-methylimidazoline (4a and 7a) is still the most potent
S4 binding element for this class of inhibitors. We found
that less bulky amidines, such as the N,N-dimethylam-
idine (4c: IC50 27 nM; 7c: IC50 20 nM) and the azetidine-
containing analog (4e: IC50 25 nM; 7e: IC50 24 nM),
possess relatively higher fXa activity than larger ami-
dines. Enlargement of the azetidine ring by even one
methylene to pyrrolidine resulted in an approximately
3-fold drop in potency (4f and 7f).
HN
N
HN
3e
3f
160
640
N
HN
N
O
N
3g
3h
530
31
N
H
The in vitro anticoagulant activity, enzyme selectivity
and rat PK profiles of lead inhibitor 7a are summarized
in Table 4. Its fXa Ki is 1.9 nM. In our human plasma
based thrombin generation (TG) assay,8 a concentration
of 1.3 lM was needed to double the time of maximum
thrombin formation (2 · TG). In a rabbit clotting assay,
a concentration of 1.6 lM was required to prolong the
prothrombin time (PT) by twofold (2 · PT). Compound
7a displays excellent fXa selectivity (>1000-fold by IC50)
against thrombin, trypsin, tissue plasminogen activator
(t-PA), activated protein C(aPC), plasmin, and kallik-
rein. To evaluate this fXa inhibitor in vivo, we studied it
N
N
N
N
3i
67
1300
430
N
3j
NH
N
N
3k

Z. J. Jia et al. / Bioorg. Med. Chem. Lett. 14 (2004) 2073–2078
2075
Table 3. In vitro activity of N,N-dialkylated benzamidines
Table 4. The in vitro anticoagulant activity, enzyme selectivity and PK
profiles of fXa inhibitor 7a
O
N S O
O
N S O
O
O
N
N
O
O
N
N S O
S
HN
HN
RN
RN
Cl
NR1R2
NR1R2
4
Cl
RN
7
N
Cl
N
7a
Compound
fXa IC50 (nM)
fXa IC50 (nM)
fXa Ki (nM)
5
R2R1N
1.9
1.3
1.6
2 · TG (lM)
2 · PT (lM) (rabbit)
N
N
4a
9
Thrombin IC50 (lM)
Trypsin IC50 (lM)
t-PA IC50 (lM)
>10
>10
>10
>10
>10
5.8
N
N
4b
36
aPCIC (lM)
50
HN
N
Plasmin IC50 (lM)
Kallikrein IC50 (lM)
4c
4d
4e
27
90
25
F (%)
1.4
7.8
HN
N
T1=2 (IV) (h)
Vd (L/kg)
CL (mL/min/kg)
28.9
42.9
HN
N
volume of distribution and clearance are 7.8 h, 28.9 L/
kg, and 42.9 mL/min/kg, respectively.
HN
N
4f
70
71
In an attempt to pick up additional binding interactions
in the fXa active site, we installed a side chain on the
central piperazine nucleus (see Table 5). However, we
found that this modification has little effect on fXa
activity. Furthermore, we discovered in some cases that
this compromises the fXa/thrombin selectivity. For
example, the fXa and thrombin IC50 values of com-
pound 10h are 15 nM and 3.2 lM. Its fXa/thrombin
selectivity is only about 200-fold, significantly reduced
from that of compound 4a (fXa IC50 9 nM; thrombin
IC50 > 10 lM; >1000-fold selectivity).
HN
N
4g
N
N
7a
7b
7c
7d
7e
5
12
20
27
24
N
N
HN
N
Several series of 4-arylsulfonylpiperazin-2-one-based
fXa inhibitors with a variety of S4 motifs have been
reported in patent applications11 and publications.12 We
investigated the possibility of using N,N-dialkylated
benzamidines as S4 motifs in the 4-arylsulfonylpipera-
zin-2-one series by preparing the corresponding analogs
11 and 12. As shown in Table 6, the resulting amidine
series has good potency. Interestingly, N-methylim-
idazoline (11a and 12a) is no longer the optimal S4
motif. The N,N-dimethylamidine (11b and 12b) and
azetidine-containing analog (11c and 12c) show in-
creased potency, with the azetidine substituted amidine
being optimum for both the benzothiophene and indole
series. Unfortunately, this class of 4-arylsulfonylpi-
perazin-2-one fXa inhibitors also suffers poor oral bio-
availability. For example, the bioavailability for analogs
11b and 12b are <1% and 4.1%, respectively.9
HN
N
HN
N
HN
N
7f
84
HN
N
7g
120
in a rabbit deep vein thrombosis model.10 Infusion of
compound 7a produced a 37% inhibition of thrombus
accretion at a plasma level of 1.1 lM and an ex vivo PT
change of 1.26-fold. At a plasma concentration of
2.6 lM, 57% inhibition and 2.09-fold ex vivo PT change
were observed. Disappointingly, the oral bioavailability
of this fXa inhibitor is only 1.4% in rat.9 Its half life,
Scheme 1 details the syntheses of both the 4-(4-aryl-
sulfonylpiperazine-1-carbonyl)-benzamidine and 4-((4-
arylsulfonyl)-2-oxo-piperazin-1-ylmethyl)-benzamidine
classes of fXa inhibitors. All of the corresponding
arylsulfonyl chlorides were synthesized following liter-
ature procedures.11d;e For preparation of 10h, racemic

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Z. J. Jia et al. / Bioorg. Med. Chem. Lett. 14 (2004) 2073–2078
Table 6. In vitro activity of N,N-dialkylated benzamidines
Table 5. Effects of side chains on fXa potency (all compounds racemic)
Z
Z
O
O
O
N S O
O
O
O
O
N S O
O
N S O
N
N
N S O
N
N
HN
S
S
HN
N
N
RN
RN
Cl
Cl
NR1R2
NR1R2
N
N
9
10
Cl
11
Cl
RN
12
Compounds
Z
fXa IC50 (nM)
Compounds
fXa IC50 (nM)
45
9a
9b
9c
9d
9e
–CO2Me
–CO2H
27
12
3
R2R1N
N
N
–CH2CO2Me
–CH2CO2H
–CH2CONH2
11a
41
18
HN
N
11b
11c
30
11
O
9f
9g
9h
9i
11
10
14
5
-CH2 NHMe
HN
N
O
-CH2 NMe2
HN
N
O
11d
11e
140
100
-CH2 NMe
O
-CH2
-CH2
-CH2
N
N
N
N
HN
N
O
O
O
9j
7
N
N
9k
9l
7
12a
12b
12c
57
37
8
11
HN
N
-CH2
O
N
O
9m
8
HN
N
-CH2
N
N
10a
10b
–CH2CO2Me
–CH2CO2H
13
29
HN
N
12d
12e
240
150
O
10c
10d
10e
10f
10g
10h
10i
7
19
10
6
-CH2 NMe2
HN
N
O
-CH2 NMe
O
-CH2
-CH2
-CH2
N
N
N
N
N
N
N
O
O
O
ester 16 was then converted to amide 10h by saponifi-
cation and BOP-assisted coupling with morpholine to
furnish the fully elaborated inhibitor.
6
Preparation of inhibitor 12c started from the nucleo-
philic displacement of 4-cyanobenzylbromide with Cbz-
protected piperazinone in DMF. Deprotection of the
benzyl carbamate afforded amine 17, which was coupled
to N-Boc-5-chloroindole-2-sulfonyl chloride in pyridine
at room temperature. Then the benzonitrile was con-
verted to the benzamidine (12c) via methyl imidate 19.
15
8
-CH2
-CH2
O
N
O
N
O
10j
8
-CH2
CO2Me
CO2H
O
10k
8
-CH2
In conclusion, using N,N-dialkylated benzamidines as
S4 motifs and piperazine or piperazinone as the central
linker, we have discovered two related series of fXa
inhibitors. We found that 6-chlorobenzo[b]thiophene
and 5-chloroindole groups are the optimal S1 binding
elements and that the use of a substituted amidine as the
S4 group improved both the potency and physico-
chemical properties of the inhibitors as compared to the
biphenylsulfonamide lead. These compounds have good
sulfonylpiperazine 14 was assembled from acylated
piperazine 13 and 6-chlorobenzo[b]thiophene-2-sulfonyl
chloride in pyridine. Treatment of resulting sulfonamide
14 with HCl-saturated methanol produced methyl imi-
date 15, which reacted with N-methylethylenediamine to
furnish the N-methylimidazoline functionality. Methyl

Z. J. Jia et al. / Bioorg. Med. Chem. Lett. 14 (2004) 2073–2078
2077
CO2Me
CO2Me
O
O
O
N
N S O
CO2Me
N
NH2+Cl-
c
S
O
O
d
a,b
HN
N
NC
NC
13
14
Cl
O
CO2Me
CO2Me
O
N
O
O
O
O
O
O
N
N S O
N
N S O
N
N S O
f,g
e
S
S
S
MeO
N
N
NH2+Cl-
N
N
15
16
Cl
Cl
10h
Cl
O
O
N
O
N
N S O
NH
O
O
N
c
h,i
d
N
O
HN
O
O
18
NC
Cl
NC
17
O
O
O
O
N
N S O
-Cl+H2N
N
N S O
j
HN
MeO
HN
Cl
Cl
NH2+Cl-
N
19
12c
Scheme 1. (a) 4-Cyanobenzoyl chloride (1.2 equiv), pyridine, THF, rt; (b) 4 N HCl in dioxane, rt; (c) ArSO2Cl, pyr, rt; (d) MeOH, saturated with HCl
(g), 0 ꢁCto rt, overnight; (e) MeNHCH 2CH2NH2 (3 equiv), MeOH, reflux, 1 h; (f) LiOH, MeOH, water, rt; (g) morpholine (1 equiv), BOP (1 equiv),
DIEA (3 equiv), DMF, rt, overnight; (h) 4-cyanobenzyl bromide (1 equiv), Cs2CO3 (1 equiv), DMF, rt; (i) H2 (g), 10% Pd/C, MeOH, rt; (j) azetidine
(3 equiv), MeOH, rt.
2. (a) Preston, J.; Stocker, A.; Turner, P.; Smithers, M. J.;
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in vitro and in vivo activity as well as excellent speci-
ficity. However, the low oral bioavailability of this class
of compounds has made them less attractive for further
development.
Acknowledgements
We would like to thank Jaya Kothule, Paul Wong,
Brian Huang, Bridget May, and Shannon Poole for
performing the biological assays. We would like to
thank Keith Abe and Gail Siu for performing the rabbit
DVT experiment.
References and notes
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