U.S. patent application number 11/672140 was filed with the patent office on 2007-06-21 for aryl sulfonic pyridoxines as antiplatelet agents.
Invention is credited to James Diakur, Wasimul Haque.
Application Number | 20070142270 11/672140 |
Document ID | / |
Family ID | 36226998 |
Filed Date | 2007-06-21 |
United States Patent
Application |
20070142270 |
Kind Code |
A1 |
Haque; Wasimul ; et
al. |
June 21, 2007 |
Aryl Sulfonic Pyridoxines as Antiplatelet Agents
Abstract
Aryl sulfonic pyridoxine compounds with inhibition of serine
protease activity and antiplatelet aggregation characteristics for
the treatment of cardiovascular and cardiovascular related diseases
are described. The methods are directed to administering
pharmaceutical compositions comprising aryl sulfonic
pyridoxines.
Inventors: |
Haque; Wasimul; (Edmonton,
CA) ; Diakur; James; (Winnipeg, CA) |
Correspondence
Address: |
MERCHANT & GOULD PC
P.O. BOX 2903
MINNEAPOLIS
MN
55402-0903
US
|
Family ID: |
36226998 |
Appl. No.: |
11/672140 |
Filed: |
February 7, 2007 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
|
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10974707 |
Oct 28, 2004 |
|
|
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11672140 |
Feb 7, 2007 |
|
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Current U.S.
Class: |
514/65 ;
514/13.9; 514/14.4; 514/14.8; 514/165; 514/20.3; 514/262.1;
514/301; 514/302; 514/350; 514/56 |
Current CPC
Class: |
A61P 7/10 20180101; C07D
491/04 20130101; A61P 9/10 20180101; A61P 43/00 20180101; A61P 9/00
20180101; A61P 9/12 20180101; A61P 7/02 20180101; A61P 31/04
20180101; A61P 11/00 20180101; A61P 9/06 20180101; C07D 213/66
20130101 |
Class at
Publication: |
514/009 ;
514/302; 514/350; 514/165; 514/262.1; 514/301; 514/056 |
International
Class: |
A61K 38/12 20060101
A61K038/12; A61K 31/519 20060101 A61K031/519; A61K 31/60 20060101
A61K031/60; A61K 31/4743 20060101 A61K031/4743; A61K 31/4741
20060101 A61K031/4741; A61K 31/4415 20060101 A61K031/4415; A61K
31/727 20060101 A61K031/727 |
Claims
1. A method of inhibiting serine protease activity comprising:
administering a compound of the formula: ##STR49## wherein R.sup.1
is --OH, --O-alkyl, --(CH.sub.2).sub.n'OH where n' is an integer
from 1 to 8, alkyl, cycloalkyl, or O-alkyl-aryl-R.sup.4, where
R.sup.4 is --CN or amidine; R.sup.2 is alkyl; --(CH.sub.2).sub.n'OH
where n' is as defined above; --(CH.sub.2).sub.nCOOH where n is an
integer from 0 to 8; --(CH.sub.2).sub.nCOO(CH.sub.2).sub.nCH.sub.3
where n is as defined above; or R.sup.5 where R.sup.5 is
(CH.sub.2).sub.n-aryl-R.sup.6 where n is as defined above and
R.sup.6 is SO.sub.2NH.sub.2 or SO.sub.2NHC(CH.sub.3).sub.3;
(CH.sub.2).sub.n-aryl-aryl-R.sup.6, where n and R.sup.6 are as
defined above; (CH.sub.2).sub.n--NH-aryl-aryl-R.sup.6, where n and
R.sup.6 are as defined above;
(CH.sub.2).sub.n--NH--CO-aryl-aryl-R.sup.6, where n and R.sup.6 are
as defined above; or --(CH.sub.2).sub.n--NH-aryl-R.sup.6, where n
and R.sup.6 are as defined above; R.sup.3 is alkyl;
--(CH.sub.2).sub.n'OH where n' is as defined above; or R.sup.5
where R.sup.5 is (CH.sub.2).sub.n--NH-aryl-R.sup.6, where n and
R.sup.6 are as defined above; (CH.sub.2).sub.n--NH--CO-aryl-R where
n and R.sup.6 are as defined above;
(CH.sub.2).sub.n--NH-aryl-aryl-R.sup.6 where n and R.sup.6 are as
defined above; or (CH.sub.2).sub.n--NH--CO-aryl-aryl-R.sup.6 where
n and R.sup.6 are as defined above; further wherein R.sup.2 is
alkyl or --(CH.sub.2).sub.n'OH where n' is as defined above, and
R.sup.3 is R.sup.5; or R.sup.2 is R.sup.5 and R.sup.3 is alkyl or
--(CH.sub.2).sub.n'OH where n' is as defined above; and R.sup.1 and
R.sup.2 when taken together form compounds of formula II, ##STR50##
wherein R.sup.7 and R.sup.8 are independently H or CH.sub.3, and
R.sup.5 is as defined above; or a pharmaceutically acceptable salt
thereof.
2. The method of claim 1, wherein said serine protease is Factor
Xa.
3. The method of claim 1, wherein said serine protease is Factor
IIa.
4. The method of claim 1, wherein said serine protease is
trypsin.
5. The method of claim 1, wherein at least one alkyl is substituted
with one or more of fluorine, chlorine, alkoxy groups having 1 to 8
carbon atoms, or amido groups having from 1 to 8 carbon atoms.
6. The method of claim 5, wherein the alkoxy group is methoxy or
ethoxy.
7. The method of claim 5, wherein the amido group is acetamido.
8. The method of claim 1, wherein the aryl group is a phenyl group
or a naphthyl group.
9. The method of claim 1, wherein the aryl group is substituted
with one or more of fluorine, chlorine, bromine, alkyl groups
having 1 to 8 carbon atoms, alkoxy groups having 1 to 8 carbon
atoms, alkoxyalkyl groups having 1 to 8 carbon atoms, or amido
groups having 1 to 8 carbon atoms.
10. The method of claim 9, wherein the alkyl group is methyl or
ethyl.
11. The method of claim 9, wherein the alkoxy group is methoxy or
ethoxy.
12. The method of claim 9, wherein the amido group is
acetamido.
13. The method of claim 1, wherein the aryl group is substituted
with one or more functional groups.
14. The method of claim 13, wherein the functional group is a
hydroxy group, carboxy group, or acetoxy group.
15. A method of inhibiting serine protease activity comprising:
administering a compound of the formula ##STR51## wherein R.sub.1
is OH; OCH.sub.3; OCH.sub.2-(4-tert-Butyl-phenyl); or ##STR52##
where R.sup.4 is --CN or amidine; R.sup.2 is (CH.sub.2).sub.mOH,
where m=0 to 8; or R.sup.5, where R.sup.5 is ##STR53## where W is
(CH.sub.2).sub.n where n=1, 2, or 3; where X is C=0 or
(CH.sub.2).sub.n', where n'=0, 1, 2, or 3; Y is CH, CF, or N; and
R.sup.6 is ##STR54## R.sup.3 is (CH.sub.2).sub.mOH, where m is as
defined above; or R.sup.5, where R.sup.5 is as defined above;
further wherein R.sup.2 is (CH.sub.2).sub.mOH, where m is as
defined above, and R.sup.3 is R.sup.5; or R.sup.2 is R.sup.5 and
R.sup.3 is (CH.sub.2).sub.mOH, where m is as defined above; and
R.sup.1 and R.sup.2 when taken together form a compound of formula
IV ##STR55## wherein R.sup.7 and R.sup.8 are independently H or
CH.sub.3; and R.sup.5 is as defined above; or a pharmaceutically
acceptable salt thereof.
16. The method of claim 15, wherein said serine protease is Factor
Xa.
17. The method of claim 15, wherein said serine protease is Factor
Ia.
18. The method of claim 15, wherein said serine protease is
trypsin.
19. The method of claim 15, wherein said compound is administered
enterally, parenterally, or by inhalation.
20. The method of claim 15, wherein the compound is administered
concurrently with another therapeutic agent.
21. The method of claim 20, wherein said other therapeutic agent is
an anti-platelet agent, glycoprotein IIb/IIIa inhibitor, or
anticoagulant.
22. The method of claim 21, wherein said anti-platelet agent is
clopidogrel, aspirin, or dipyridamole.
23. The method of claim 21, wherein said glycoprotein IIb/IIIa
inhibitor is eptifibatide.
24. The method of claim 21, wherein said anticoagulant is
unfractionated heparin, low molecular weight heparin, hirudin, or
argatroban.
25. A method of inhibiting in vitro serine protease activity
comprising: contacting an isolated cell with a compound of the
formula: ##STR56## wherein R.sup.1 is --OH, --O-alkyl,
--(CH.sub.2).sub.n'OH where n' is an integer from 1 to 8, alkyl,
cycloalkyl, or O-alkyl-aryl-R.sup.4, where R.sup.4 is --CN or
amidine; R.sup.2 is alkyl; --(CH.sub.2).sub.n'OH where n' is as
defined above; --(CH.sub.2).sub.nCOOH where n is an integer from 0
to 8; --(CH.sub.2).sub.nCOO(CH.sub.2).sub.nCH.sub.3 where n is as
defined above; or R.sup.5 where R.sup.5 is
(CH.sub.2).sub.n-aryl-R.sup.6 where n is as defined above and
R.sup.6 is SO.sub.2NH.sub.2 or SO.sub.2NHC(CH.sub.3).sub.3;
(CH.sub.2).sub.n-aryl-aryl-R.sup.6, where n and R.sup.6 are as
defined above; (CH.sub.2).sub.n--NH-aryl-aryl-R.sup.6, where n and
R.sup.6 are as defined above;
(CH.sub.2).sub.n--NH--CO-aryl-aryl-R.sup.6, where n and R.sup.6 are
as defined above; or --(CH.sub.2).sub.n--NH-aryl-R.sup.6, where n
and R.sup.6 are as defined above; R.sup.3 is alkyl;
--(CH.sub.2).sub.n'OH where n' is as defined above; or R.sup.5
where R.sup.5 is (CH.sub.2).sub.n--NH-aryl-R.sup.6, where n and
R.sup.6 are as defined above; (CH.sub.2).sub.n--NH--CO-aryl-R.sup.6
where n and R.sup.6 are as defined above;
(CH.sub.2).sub.n--NH-aryl-aryl-R.sup.6 where n and R.sup.6 are as
defined above; or (CH.sub.2).sub.n--NH--CO-aryl-aryl-R.sup.6 where
n and R.sup.6 are as defined above; further wherein R.sup.2 is
alkyl or --(CH.sub.2).sub.n'OH where n' is as defined above, and
R.sup.3 is R.sup.5; or R.sup.2 is R.sup.5 and R.sup.3 is alkyl or
--(CH.sub.2).sub.n'OH where n' is as defined above; and R.sup.1 and
R.sup.2 when taken together form compounds of formula II, ##STR57##
wherein R.sup.7 and R.sup.8 are independently H or CH.sub.3, and
R.sup.5 is as defined above; or a pharmaceutically acceptable salt
thereof.
26. A method of inhibiting serine protease activity comprising:
contacting an organism with a compound of the formula: ##STR58##
wherein R.sup.1 is --OH, --O-alkyl, --(CH.sub.2).sub.n'OH where n'
is an integer from 1 to 8, alkyl, cycloalkyl, or
O-alkyl-aryl-R.sup.4, where R.sup.4 is --CN or amidine; R.sup.2 is
alkyl; --(CH.sub.2).sub.n'OH where n' is as defined above;
--(CH.sub.2).sub.nCOOH where n is an integer from 0 to 8;
--(CH.sub.2).sub.nCOO(CH.sub.2).sub.nCH.sub.3 where n is as defined
above; or R.sup.5 where R.sup.5 is (CH.sub.2).sub.n-aryl-R.sup.6
where n is as defined above and R.sup.6 is SO.sub.2NH.sub.2 or
SO.sub.2NHC(CH.sub.3).sub.3; (CH.sub.2).sub.n-aryl-aryl-R.sup.6,
where n and R.sup.6 are as defined above;
(CH.sub.2).sub.n--NH-aryl-aryl-R.sup.6, where n and R.sup.6 are as
defined above; (CH.sub.2).sub.n--NH--CO-aryl-aryl-R.sup.6, where n
and R.sup.6 are as defined above; or
--(CH.sub.2).sub.n--NH-aryl-R.sup.6, where n and R.sup.6 are as
defined above; R.sup.3 is alkyl; --(CH.sub.2).sub.nOH where n' is
as defined above; or R.sup.5 where R.sup.5 is
(CH.sub.2).sub.n--NH-aryl-R.sup.6, where n and R.sup.6 are as
defined above; (CH.sub.2).sub.n--NH--CO-aryl-R.sup.6 where n and
R.sup.6 are as defined above;
(CH.sub.2).sub.n--NH-aryl-aryl-R.sup.6 where n and R.sup.6 are as
defined above; or (CH.sub.2).sub.n--NH--CO-aryl-aryl-R.sup.6 where
n and R.sup.6 are as defined above; further wherein R.sup.2 is
alkyl or --(CH.sub.2).sub.n'OH where n' is as defined above, and
R.sup.3 is R.sup.5; or R.sup.2 is R.sup.5 and R.sup.3 is alkyl or
--(CH.sub.2).sub.n'OH where n' is as defined above; and R.sup.1 and
R.sup.2 when taken together form compounds of formula II, ##STR59##
wherein R.sup.7 and R.sup.8 are independently H or CH.sub.3, and
R.sup.5 is as defined above; or a pharmaceutically acceptable salt
thereof.
27. A compound of the formula ##STR60## wherein R.sup.1 is OH;
OCH.sub.3; OCH.sub.2-(4-tert-Butyl-phenyl); or ##STR61## where
R.sup.4 is --CN or amidine; R.sup.2 is (CH.sub.2).sub.mOH, where
m=0 to 8; or R.sup.5, where R.sup.5 is ##STR62## where W is
(CH.sub.2).sub.n where n=1, 2, or 3; where X is C=0 or
(CH.sub.2).sub.n', where n'=0, 1, 2, or 3; Y is CH, CF, or N; and
R.sup.6 is ##STR63## R.sup.3 is (CH.sub.2).sub.mOH, where m is as
defined above; or R.sup.5, where R.sup.5 is as defined above;
further wherein R.sup.2 is (CH.sub.2).sub.mOH, where m is as
defined above, and R.sup.3 is R.sup.5; or R.sup.2 is R.sup.5 and
R.sup.3 is (CH.sub.2).sub.mOH, where m is as defined above; and
R.sup.1 and R.sup.2 when taken together form a compound of formula
IV ##STR64## wherein R.sup.7 and R.sup.8 are independently H or
CH.sub.3; and R.sup.5 is as defined above; or a pharmaceutically
acceptable salt thereof.
28. A method of treating cardiovascular or related diseases in a
mammal comprising administering a therapeutically effective amount
of a compound of claim 27.
29. The method of claim 29, wherein the compound is administered
concurrently with another therapeutic agent.
30. The method of claim 29, wherein said other therapeutic agent is
an anti-platelet agent, glycoprotein IIb/IIIa inhibitor, or
anticoagulant.
31. The method of claim 30, wherein said anti-platelet agent is
clopidogrel, aspirin, or dipyridamole.
32. The method of claim 30, wherein said glycoprotein IIb/IIIa
inhibitor is eptifibatide.
33. The method of claim 30, wherein said anticoagulant is
unfractionated heparin, low molecular weigh heparins, hirudin, or
argatroban.
Description
CROSS REFERENCE TO RELATED APPLICATIONS
[0001] This application is a continuation-in-part of U.S.
application Ser. No. 10/974,707, filed Oct. 28, 2004, the entire
disclosure of which is hereby incorporated by reference.
FIELD OF THE INVENTION
[0002] This invention relates to aryl sulfonic pyridoxines and
methods of treating cardiovascular, cerebrovascular, and
cardiovascular related diseases or symptoms by administering
pharmaceutical compositions comprising an aryl sulfonic
pyridoxine.
BACKGROUND
[0003] Thrombosis, the development of blood clots within arterial
vessels, is due to a complex mechanism involving the activation of
both platelet aggregation and the coagulation protease cascade
(Ann. Intern Med. (2001) 134: 224-38; N. Engl. J. Med. (2002) 347:
5-12; Thromb. Haemost. (2002) 86: 51-6). The pathways involved
normally inhibit blood loss after vessel injury, but in thrombosis
and related conditions, these reactions are inappropriately
initiated and propagated.
[0004] On the molecular level, thrombosis is initiated by the
release of mediators such as tissue factor (TF), von Willebrand
Factor (vWF) (J. Thromb. Haemost. (2003) 1: 1602-1612), and
collagen from ruptured atherosclerotic plaques or from damaged
blood vessels. Collagen and vWF bind to receptors on platelets and
initiate their activation. Once activated, platelets release
secretory granules containing ADP, ATP, and calcium (Curr. Opin.
Hematol. (2001) .delta.: 270-276). Activated platelets also
synthesize and release thromboxane. The released ADP and
thromboxane bind to receptors on the platelets to further propagate
platelet activation. Once platelets are activated they start
aggregating to initiate clot formation.
[0005] The trypsin-like family of serine proteases play an
important role in thrombogenesis (Abbenante & Fairlie (2005)
Med. Chem. 1: 71-104; Walenga et al., "Factor Xa Inhibitors" in
Anticoagulants, Antiplatelets, and Thrombolytics (Mousa ed.), 93:
95-117 (2004), Humana Press Inc.). Tissue factor (TF), transiently
exposed at a vascular site damaged either mechanically or by
inflammatory processes, is responsible for initiating the
coagulation cascade leading to thrombus formation (Giesen et al.
(1999) Proc. Natl. Acad. Sci. USA 96: 2311-2315). Association of TF
with activated factor VII (fvIIa) on the membrane surface triggers
a complex enzyme amplification network of events that leads to the
generation of thrombin and subsequently, conversion of fibrinogen
to fibrin. In addition to its role in clot formation, thrombin
amplifies its own production and activates platelets via its
enzymatic action on platelet protease-activated receptors PAR-1 and
PAR-4 (Lane (2005) Blood 106: 2605-2612).
[0006] Since the middle of the last century, anticoagulant therapy
has consisted primarily of heparin treatment in acute situations,
while vitamin k antagonists have been utilized for chronic therapy.
Though these two regimens have proved indispensable in
anticoagulant therapy, both approaches have shortcomings which have
prompted the development of improved drugs in an attempt to address
the limitations of these traditional agents. New approaches involve
targeting specific pathways in the coagulation system in order to
streamline anticoagulation (Weitz & Bates (2005) J. Thromb.
Haemost. 3: 1843-1853). For example, factor Xa (fxa) in the
prothrombinase complex generates thrombin (fIIa), and inhibiting
either of these enzymes (Yavin et al. (2005) Eur. J. Intern. Med.
16: 257-266), or both Deng, et al. (2005) Bioorg. Med. Chem. Lett.
15: 4411-4416), has been the subject of recent drug design efforts.
The notion of dual inhibition in the area of antithrombotics is not
new, and in fact unfractionated heparin has several activities
including the inhibition of the coagulation pathway serine
proteases fIIa and fXa when complexed to antithrombin III.
[0007] Therefore, there is a need for compounds that inhibit the
proteases of the blood and thus block platelet aggregation.
SUMMARY OF THE INVENTION
[0008] One embodiment of the invention includes aryl sulfonic
pyridoxines, compositions containing the aryl sulfonic pyridoxines,
and methods of treatment using therapeutically effective amounts of
aryl sulfonic pyridoxines. Compounds and compositions of the
invention can be used to treat cardiovascular, cerebovascular or
related diseases and symptoms thereof.
[0009] The invention also provides an embodiment of the formula I:
##STR1##
[0010] wherein
[0011] R.sup.1 is --OH, --O-alkyl, --(CH.sub.2).sub.n' OH where n'
is an integer from 1 to 8, alkyl, cycloalkyl, or
O-alkyl-aryl-R.sup.4, where R.sup.4 is --CN or amidine;
[0012] R.sup.2 is alkyl; --(CH.sub.2).sub.n'OH where n' is as
defined above; --(CH.sub.2).sub.nCOOH where n is an integer from 0
to 8; --(CH.sub.2).sub.nCOO(CH.sub.2).sub.nCH.sub.3 where n is as
defined above; or R.sup.5 where R.sup.5 is
(CH.sub.2).sub.n-aryl-R.sup.6 where n is as defined above and
R.sup.6 is SO.sub.2NH.sub.2 or SO.sub.2NHC(CH.sub.3).sub.3;
(CH.sub.2).sub.n-aryl-aryl-R.sup.6, where n and R.sup.6 are as
defined above; (CH.sub.2).sub.n--NH-aryl-aryl-R.sup.6, where n and
R.sup.6 are as defined above;
(CH.sub.2).sub.n--NH--CO-aryl-aryl-R.sup.6, where n and R.sup.6 are
as defined above; or --(CH.sub.2).sub.n--NH-aryl-R.sup.6, where n
and R.sup.6 are as defined above;
[0013] R.sup.3 is alkyl; --(CH.sub.2).sub.n'OH where n' is as
defined above; or R.sup.5 where R.sup.5 is
(CH.sub.2).sub.n--NH-aryl-R.sup.6, where n and R.sup.6 are as
defined above; (CH.sub.2).sub.n--NH--CO-aryl-R.sup.6 where n and
R.sup.6 are as defined above;
(CH.sub.2).sub.n--NH-aryl-aryl-R.sup.6 where n and R.sup.6 are as
defined above; or (CH.sub.2).sub.n--NH--CO-aryl-aryl-R.sup.6 where
n and R.sup.6 are as defined above;
[0014] further wherein [0015] R.sup.2 is alkyl or
--(CH.sub.2).sub.n'OH where n' is as defined above, and R.sup.3 is
R.sup.5; or [0016] R.sup.2 is R.sup.5 and R.sup.3 is alkyl or
--(CH.sub.2).sub.n'OH where n' is as defined above; and
[0017] R.sup.1 and R.sup.2 when taken together form compounds of
formula II, ##STR2## wherein R.sup.7 and R.sup.8 are independently
H or CH.sub.3, and R.sup.5 is as defined above; or a
pharmaceutically acceptable salt thereof.
DETAILED DESCRIPTION OF THE INVENTION
[0018] The invention provides compounds of the formula I:
##STR3##
[0019] wherein
[0020] R.sup.1 is --OH, --O-alkyl, --(CH.sub.2).sub.n' OH where n'
is an integer from 1 to 8, alkyl, cycloalkyl, or
O-alkyl-aryl-R.sup.4, where R.sup.4 is --CN or amidine;
[0021] R.sup.2 is alkyl; --(CH.sub.2).sub.n'OH where n' is as
defined above; --(CH.sub.2).sub.n' COOH where n is an integer from
0 to 8; --(CH.sub.2).sub.nCOO(CH.sub.2).sub.nCH.sub.3 where n is as
defined above; or R.sup.5 where R.sup.5 is
(CH.sub.2).sub.n-aryl-R.sup.6 where n is as defined above and
R.sup.6 is SO.sub.2NH.sub.2 or SO.sub.2NHC(CH.sub.3).sub.3;
(CH.sub.2).sub.n-aryl-aryl-R.sup.6, where n and R.sup.6 are as
defined above; (CH.sub.2).sub.n--NH-aryl-aryl-R.sup.6, where n and
R.sup.6 are as defined above;
(CH.sub.2).sub.n--NH--CO-aryl-aryl-R.sup.6, where n and R.sup.6 are
as defined above; or --(CH.sub.2).sub.n--NH-aryl-aryl-R.sup.6 where
n and R.sup.6 are as defined above;
[0022] R.sup.3 is alkyl; --(CH.sub.2).sub.n'OH where n' is as
defined above; or R.sup.5 where R.sup.5 is
(CH.sub.2).sub.n--NH-aryl-R.sup.6, where n and R.sup.6 are as
defined above; (CH.sub.2).sub.n--NH--CO-aryl-R.sup.6 where n and
R.sup.6 are as defined above;
(CH.sub.2).sub.n--NH-aryl-aryl-R.sup.6 where n and R.sup.6 are as
defined above; or (CH.sub.2).sub.n--NH--CO-aryl-aryl-R.sup.6 where
n and R.sup.6 are as defined above;
[0023] further wherein [0024] R.sup.2 is alkyl or
--(CH.sub.2).sub.n' OH where n' is as defined above, and R.sup.3 is
R.sup.5; or [0025] R.sup.2 is R.sup.5 and R.sup.3 is alkyl or
--(CH.sub.2).sub.n' OH where n' is as defined above; and
[0026] R.sup.1 and R.sup.2 when taken together form compounds of
formula II, ##STR4##
[0027] wherein R.sup.7 and R.sup.8 are independently H or CH.sub.3,
and R.sup.5 is as defined above;
[0028] or a pharmaceutically acceptable salt thereof.
[0029] The invention also provides an embodiment of the formula
III: ##STR5##
[0030] wherein
[0031] R.sup.1 is OH; OCH.sub.3; OCH.sub.2-(4-tert-Butyl-phenyl);
or ##STR6## where R.sup.4 is --CN or amidine;
[0032] R.sup.2 is (CH.sub.2).sub.mOH, where m=0 to 8; or R.sup.5,
where R.sup.5 is ##STR7## [0033] where W is (CH.sub.2).sub.n where
n=1, 2, or 3; where X is C=0 or (CH.sub.2).sub.n', where n'=0, 1,
2, or [0034] 3; Y is CH, CF, or N; and R.sup.6 is ##STR8##
[0035] R.sup.3 is (CH.sub.2).sub.mOH, where m is as defined above;
or R.sup.5, where R.sup.5 is as defined above;
[0036] further wherein [0037] R.sup.2 is (CH.sub.2).sub.mOH, where
m is as defined above, and R.sup.3 is R.sup.5; or [0038] R.sup.2 is
R.sup.5 and R.sup.3 is (CH.sub.2).sub.mOH, where m is as defined
above; and
[0039] R.sup.1 and R.sup.2 when taken together form a compound of
formula IV ##STR9##
[0040] wherein R.sup.7 and R.sup.8 are independently H or CH.sub.3;
and R.sup.5 is as defined above;
[0041] or a pharmaceutically acceptable salt thereof.
[0042] As used herein "alkyl" includes a saturated linear or
branched hydrocarbon radical. In one embodiment, alkyl has from 1
to 8 carbon atoms. In another embodiment, alkyl has from 1 to 6
carbon atoms. In another embodiment, alkyl has from 1 to 4 carbon
atoms. In one embodiment, alkyl has 1 carbon. The alkyl group may
optionally be substituted with one or more substituents such as
fluorine, chlorine, alkoxy groups having from 1 to 8 carbon atoms
(e.g., methoxy or ethoxy), or amido groups having from 1 to 8
carbon atoms, such as acetamido. These substituents may themselves
be substituted with one or more functional groups such as hydroxy
groups, carboxy groups, acetoxy groups, or halogens.
[0043] As used herein "cycloalkyl" refers to a cyclic hydrocarbon
having from 3 to 8 carbon atoms, preferably 3 to 6 carbon atoms,
such as, for example, cyclopropyl, cyclopentyl, cyclohexyl, and the
like.
[0044] As used herein "aryl" means a mono- or poly-nuclear aromatic
hydrocarbon radical. Examples of "aryl" groups include, but are not
limited to aromatic hydrocarbons such as a phenyl group or a
naphthyl group. The aromatic group may optionally be substituted
with one or more substituents such as fluorine, chlorine, alkyl
groups having from 1 to 10 carbon atoms (e.g., methyl or ethyl),
alkoxy groups having from 1 to 8 carbon atoms (e.g., methoxy or
ethoxy), alkoxyalkyl groups having from 1 to 8 carbon atoms and one
or more oxygen atoms, or amido groups having from 1 to 8 carbon
atoms, such as acetamido. These substituents may themselves be
substituted with one or more functional groups such as hydroxy
groups, carboxy groups, acetoxy groups, or halogens.
[0045] In one embodiment, aryl is a phenyl group or a naphthyl
group that is either unsubstituted or substituted.
[0046] In another embodiment, aryl is a heteroaryl in which one or
more of the carbon atoms of an aromatic hydrocarbon is substituted
with a nitrogen, sulfur, or oxygen. Examples of a "heteroaryl"
include, but are not limited to pyridine, pyrimidine, pyran,
dioxin, oxazine, and oxathiazine. Likewise, the heteroaryl may
optionally be substituted with functional groups such as hydroxy
groups, carboxy groups, halogens, and amino groups.
[0047] As used herein, "amidine" means a group having the formula
##STR10##
[0048] The invention also includes pharmaceutically acceptable
salts of the compounds of the invention. The compounds of the
invention are capable of forming both pharmaceutically acceptable
acid addition and/or base salts. Pharmaceutically acceptable acid
addition salts of the compounds of the invention include salts
derived from nontoxic inorganic acids such as hydrochloric, nitric,
phosphoric, sulfuric, hydrobromic, hydriodic, hydrofluoric,
phosphorous, and the like, as well as the salts derived from
nontoxic organic acids, such as aliphatic mono- and di-carboxylic
acids, phenyl-substituted alkanoic acids, hydroxy alkanoic acids,
alkanedioic acids, aromatic acids, aliphatic and aromatic sulfonic
acids, etc. Such salts thus include sulfate, pyrosulfate,
bisulfate, sulfite, bisulfite, nitrate, phosphate,
monohydrogenphosphate, dihydrogenphosphate, metaphosphate,
pyrophosphate, chloride, bromide, iodide, acetate,
trifluoroacetate, propionate, caprylate, isobutyrate, oxalate,
malonate, succinate, suberate, sebacate, fumarate, maleate,
mandelate, benzoate, chlorobenzoate, methylbenzoate,
dinitrobenzoate, phthalate, benzenesulfonate, toluenesulfonate,
phenylacetate, citrate, lactate, maleate, tartrate,
methanesulfonate, and the like. Also contemplated are salts of
amino acids such as arginate and the like and gluconate,
galacturonate, n-methyl glucamine, etc. (see Berge et al., J.
Pharmaceutical Science, 66: 1-19 (1977). The term "pharmaceutically
acceptable salts" also includes any pharmaceutically acceptable
base salt including, but not limited to, amine salts, trialkyl
amine salts and the like. Such salts can be formed quite readily by
those skilled in the art using standard techniques.
[0049] The acid addition salts of the basic compounds are prepared
by contacting the free base form with a sufficient amount of the
desired acid to produce the salt in the conventional manner. The
free base form may be regenerated by contacting the salt form with
a base and isolating the free base in the conventional manner. The
free base forms differ from their respective salt forms somewhat in
certain physical properties such as solubility in polar solvents,
but otherwise the salts are equivalent to their respective free
base for purposes of the present invention. Base salts are formed
with metals or amines, such as alkali and alkaline earth metals or
organic amines. Examples of metals used as cations include, but are
not limited to, sodium, potassium, magnesium, and calcium. Examples
of suitable amines are N,N'-dibenzylethylenediamine,
chloroprocaine, choline, diethanolamine, ethylenediamine,
N-methylglucamine, and procaine.
[0050] Some of the compounds described herein contain one or more
asymmetric centers and may thus give rise to enantiomers,
diastereomers, and other stereoisomeric forms which may be defined
in terms of absolute stereochemistry as (R)- or (S)- . The present
invention is meant to include all such possible diastereomers and
enantiomers as well as their racemic and optically pure forms.
Optically active (R)- and (S)-isomers may be prepared using chiral
synthons or chiral reagents, or resolved using conventional
techniques. When the compounds described herein contain centers of
geometric asymmetry, and unless specified otherwise, it is intended
that the compounds include both E and Z geometric isomers. Likewise
all tautomeric forms are intended to be included.
General Methods of Preparing Compounds of Formulae I, II, III, and
IV
[0051] The compounds are generally prepared by combining an
aldehyde or a carboxylate with an amine group to produce an
elaborated pyridine structure. The general scheme of preparing the
compounds of the formulae comprise protecting the hydroxyl groups
at R.sub.1 and R.sub.2 of pyridoxine with known blocking groups
such as esters, ethers, cyclic acetals, cyclic ketals, etc. and
elaborating R.sup.3 through generating an aldehyde, acid, halide,
or amine functionality as shown in Schemes 1-4. R.sup.3 may be an
aryl or biaryl containing a nitro, amino, or cyano group that can
be converted to an amidine by known chemical procedures.
Additionally, protecting R.sup.1 and R.sup.3 with known blocking
groups such as esters, ethers, cyclic acetals, cyclic ketals, etc.
and elaborating R.sup.2 through generating an aldehyde, acid,
halide, or amine functionality can be achieved through the same
general scheme as shown in Scheme 5. ##STR11## where the dashed
lines are (CH.sub.2).sub.n where n=0-8. ##STR12## where the dashed
lines are (CH.sub.2).sub.n and n=0-8. ##STR13## where the dashed
lines are (CH.sub.2).sub.n and n=0-8. ##STR14## where the dashed
lines are (CH.sub.2).sub.n and n=0-8. ##STR15## where R.sup.3 is
(CH.sub.2).sub.n--Ar--X, where n=0-8 and Ar--X is any aromatic
terminating in --SO.sub.2NH.sub.2 or
--SO.sub.2NH.sub.2C(CH.sub.3).sub.3.
[0052] Other positions on the pyridoxine ring can also be
substituted according to the aforementioned general scheme.
Substitutions are not specific to the positions described
above.
Conditions to Be Treated
[0053] In one embodiment of the invention, compounds of the
invention can be used to treat cardiovascular or related diseases.
Cardiovascular or related diseases include, for example, cerebral
ischemia, cerebral hemorrhage, ischemic stroke, hemorrhagic stroke,
hypertension, myocardial infarction, ischemia reperfusion injury,
myocardial ischemia, congestive heart failure, blood coagulation
disorders, cardiac hypertrophy, and platelet aggregation.
Cardiovascular or related diseases also include diseases that arise
from thrombotic and prothrombotic states in which the coagulation
cascade is activated such as, for example, deep vein thrombosis,
disseminated intravascular coagulopathy, and pulmonary
embolism.
[0054] Heart failure is a pathophysiological condition in which the
heart is unable to pump blood at a rate commensurate with the
requirement of the metabolizing tissues or can do so only from an
elevated filling pressure (increased load). Thus, the heart has a
diminished ability to keep up with its workload. Over time, this
condition leads to excess fluid accumulation, such as peripheral
edema, and is referred to as congestive heart failure.
[0055] When an excessive pressure or volume load is imposed on a
ventricle, myocardial hypertrophy (i.e., enlargement of the heart
muscle) develops as a compensatory mechanism. Hypertrophy permits
the ventricle to sustain an increased load because the heart muscle
can contract with greater force. However, a ventricle subjected to
an abnormally elevated load for a prolonged period eventually fails
to sustain an increased load despite the presence of ventricular
hypertrophy, and pump failure can ultimately occur.
[0056] Heart failure can arise from any disease that affects the
heart and interferes with circulation. For example, a disease that
increases the heart muscle's workload, such as hypertension, will
eventually weaken the force of the heart's contraction.
Hypertension is a condition in which there is an increase in
resistance to blood flow through the vascular system. This
resistance leads to increases in systolic pressure, diastolic blood
pressure, or both. Hypertension places increased tension on the
left ventricular myocardium, causing it to stiffen and hypertrophy,
and accelerates the development of atherosclerosis in the coronary
arteries. The combination of increased demand and lessened supply
increases the likelihood of myocardial ischemia leading to
myocardial infarction, sudden death, arrhythmias, and congestive
heart failure.
[0057] Ischemia is a condition in which an organ or a part of the
body fails to receive a sufficient blood supply. When an organ is
deprived of a blood supply, it is said to be hypoxic. An organ will
become hypoxic even when the blood supply temporarily ceases, such
as during a surgical procedure or during temporary artery blockage.
Ischemia initially leads to a decrease in or loss of contractile
activity. When the organ effected is the heart, this condition is
known as myocardial ischemia, and myocardial ischemia initially
leads to abnormal electrical activity. This can generate an
arrhythmia. When myocardial ischemia is of sufficient severity and
duration, cell injury can progress to cell death--i.e., myocardial
infarction--and subsequently to heart failure, hypertrophy, or
congestive heart failure.
[0058] Ischemic reperfusion of the organ occurs when blood flow
resumes to an organ after temporary cessation. For example,
reperfusion of an ischemic myocardium can counter the effects of
coronary occlusion, a condition that leads to myocardial ischemia.
Ischemic reperfusion to the myocardium can lead to reperfusion
arrhythmia or reperfusion injury. The severity of reperfusion
injury is affected by numerous factors, such as, for example,
duration of ischemia, severity of ischemia, and speed of
reperfusion. Conditions observed with ischemia reperfusion injury
include neutrophil infiltration, necrosis, and apoptosis.
Pharmaceutical Compositions
[0059] Although it is possible for compounds of the invention to be
administered alone in a unit dosage form, the compounds are
typically administered in admixture with a carrier as a
pharmaceutical composition to provide a unit dosage form. The
invention provides pharmaceutical compositions containing at least
one compound of the invention. A pharmaceutical composition
comprises a pharmaceutically acceptable carrier in combination with
a compound of the invention or a pharmaceutically acceptable salt
of a compound of the invention.
[0060] A pharmaceutically acceptable carrier includes, but is not
limited to, physiological saline, ringers, phosphate-buffered
saline, and other carriers known in the art. Pharmaceutical
compositions can also include additives such as, for example,
stabilizers, antioxidants, colorants, excipients, binders,
thickeners, dispersing agents, readsorpotion enhancers, buffers,
surfactants, preservatives, emulsifiers, isotonizing agents, and
diluents. Pharmaceutically acceptable carriers and additives are
chosen such that side effects from the pharmaceutical compound are
minimized and the performance of the compound is not canceled or
inhibited to such an extent that treatment is ineffective.
[0061] Methods of preparing pharmaceutical compositions containing
a pharmaceutically acceptable carrier in combination with a
therapeutic compound of the invention or a pharmaceutically
acceptable acid addition salt of a compound of the invention are
known to those of skill in the art. All methods can include the
step of bringing the compound of the invention in association with
the carrier and additives. The formulations generally are prepared
by uniformly and intimately bringing the compound of the invention
into association with a liquid carrier or a finely divided solid
carrier or both, and then, if necessary, shaping the product into
the desired unit dosage forms.
[0062] For oral administration as a tablet or capsule, the
compositions can be prepared according to techniques well known in
the art of pharmaceutical formulation. The compositions can contain
microcrystalline cellulose for imparting bulk, alginic acid or
sodium alginate as a suspending agent, methylcellulose as a
viscosity enhancer, and sweeteners or flavoring agents. As
immediate release tablets, the compositions can contain
microcrystalline cellulose, starch, magnesium stearate and lactose
or other excipients, binders, extenders, disintegrants, diluents
and lubricants known in the art.
[0063] For administration by inhalation or aerosol, the
compositions can be prepared according to techniques well known in
the art of pharmaceutical formulation. The compositions can be
prepared as solutions in saline, using benzyl alcohol or other
suitable preservatives, absorption promoters to enhance
bioavailability, fluorocarbons or other solubilizing or dispersing
agents known in the art.
[0064] For administration as injectable solutions or suspensions,
the compositions can be formulated according to techniques
well-known in the art, using suitable dispersing or wetting and
suspending agents, such as sterile oils, including synthetic mono-
or di-glycerides, and fatty acids, including oleic acid.
[0065] For rectal administration as suppositories, the compositions
can be prepared by mixing with a suitable non-irritating excipient,
such as cocoa butter, synthetic glyceride esters or polyethylene
glycols, which are solid at ambient temperatures, but liquefy or
dissolve in the rectal cavity to release the drug.
Method of Treatment Using Compounds of the Invention
[0066] In another aspect of the invention, methods are provided for
the treatment of cardiovascular or related diseases and symptoms
thereof.
[0067] As used herein, the terms "treatment" and "treating" include
inhibiting, alleviating, and healing cardiovascular or related
diseases or symptoms thereof. Treatment can be carried out by
administering a therapeutically effective amount of at least one
compound of the invention. A "therapeutically effective amount" as
used herein includes a prophylactic amount, for example an amount
effective for alleviating or healing the above mentioned diseases
or symptoms thereof.
[0068] A physician or veterinarian of ordinary skill readily
determines a mammalian subject who is exhibiting symptoms of any
one or more of the diseases described above. Regardless of the
route of administration selected, a compound of the invention or a
pharmaceutically acceptable acid addition salt of a compound of the
invention can be formulated into pharmaceutically acceptable unit
dosage forms by conventional methods known in the pharmaceutical
art. An effective but nontoxic quantity of the compound is employed
in treatment. The compounds can be administered in enteral unit
dosage forms, such as, for example, tablets, sustained-release
tablets, enteric coated tablets, capsules, sustained-release
capsules, enteric coated capsules, pills, powders, granules,
solutions, and the like. They can also be administered
parenterally, such as, for example, subcutaneously,
intramuscularly, intradermally, intramammarally, intravenously, and
by other administrative methods known in the art.
[0069] The ordinarily skilled physician or veterinarian will
readily determine and prescribe the therapeutically effective
amount of the compound to treat the disease for which treatment is
administered. In so proceeding, the physician or veterinarian could
employ relatively low dosages at first, subsequently increasing the
dose until a maximum response is obtained. Typically, the
particular disease, the severity of the disease, the compound to be
administered, the route of administration, and the characteristics
of the mammal to be treated, for example, age, sex, and weight, are
considered in determining the effective amount to administer.
Administering a therapeutic amount of a compound of the invention
for treating cardiovascular or related diseases or symptoms
thereof, is in a range of about 0.1-100 mg/kg of a patient's body
weight, more preferably in the range of about 0.5-50 mg/kg of a
patient's body weight, per daily dose. The compound can be
administered for periods of short and long duration. Although some
individual situations can warrant to the contrary, short-term
administration, for example, 30 days or less, of doses larger than
25 mg/kg of a patient's body weight is preferred to long-term
administration. When long-term administration, for example, months
or years, is required, the suggested dose usually does not exceed
25 mg/kg of a patient's body weight.
[0070] A therapeutically effective amount of a compound of the
invention or a pharmaceutically acceptable addition salt of a
compound of the invention for treating the above-identified
diseases or symptoms thereof can be administered prior to,
concurrently with, or after the onset of the disease or symptom. A
compound of the invention can be administered concurrently.
"Concurrent administration" and "concurrently administering" as
used herein includes administering a compound of the invention and
another therapeutic agent in admixture, such as, for example, in a
pharmaceutical composition or in solution, or separately, such as,
for example, separate pharmaceutical compositions or solutions
administered consecutively, simultaneously, or at different times
but not so distant in time such that the compound of the invention
and the other therapeutic agent cannot interact and a lower dosage
amount of the active ingredient cannot be administered.
[0071] In one embodiment of the invention, a method is provided for
treating cardiovascular or related diseases comprising
administering to a mammal a therapeutically effective amount of a
compound of the invention or a pharmaceutically acceptable addition
salt of a compound of the invention in a unit dosage form. The
cardiovascular or related diseases that can be treated include
hypertrophy, hypertension, congestive heart failure, heart failure
subsequent to myocardial infarction, myocardial ischemia, cerebral
ischemia, ischemia reperfusion injury, arrhythmia, myocardial
infarction, blood coagulation, platelet aggregation,
atherosclerosis, atrial fibrillation, or acute coronary syndrome.
Preferably, the cardiovascular disease treated is hypertrophy,
congestive heart failure, arrhythmia, or ischemia reperfusion
injury. Compounds of the invention may also be administered as
anticoagulants to patients with heparin induced thrombocyotpenia
(HIT).
[0072] Serine protease activity can be inhibited by the
administration of a compound of the invention or a pharmaceutically
acceptable acid addition salt of a compound of the invention.
Compounds of the invention can be administered to inhibit serine
protease activity in a mammal, thereby affecting varying disease
states, including platelet aggregation. Compounds of the invention
can inhibit serine proteases such as, but not limited to, trypsin,
chymotrypsin, kallikrein, elastase, thrombin (Factor IIa), plasmin,
Factors VIIa, IXa, Xa, XIa, XIIa, and protein C. Preferably, the
mammal is a human. Compounds of the invention can also be used to
inhibit serine protease activity in vitro. Serine protease
inhibitors can be useful for research and diagnostic purposes. For
instance, compounds of the invention can inhibit serine protease
activity in a monolayer of a cell culture following contact with
the cells of said cell culture.
[0073] In another embodiment, compounds of the invention can be
administered to inhibit non-mammalian serine proteases. The
non-mammalian serine protease can be from microorganisms, including
bacteria and viruses. Bacterial serine proteases include, but is
not limited to, subtilisin (from Bacillus subtilis). Viral serine
proteases can be inhibitied by compounds disclosed herein,
including, but not limited to, hepatitis C virus (HCV) serine
proteases, for example the HCV serine protease NS3. Additionally,
compounds disclosed herein can be used to treat viral infections.
Treating viral infections can include administering compounds
disclosed herein in order to inhibit viral serine proteases (e.g.,
HCV) or to inhibit mammalian serine proteases necessary for viral
infection (e.g., human immunodeficiency virus (HIV); see, e.g.,
U.S. Pat. No. 6,849,605).
[0074] The compound of the invention can also be administered to
treat cardiovascular diseases and other diseases that arise from
thrombotic and prothrombotic states in which the coagulation
cascade is activated, such as, for example, deep vein thrombosis,
disseminated intravascular coagulopathy, Kasabach-Merritt syndrome,
pulmonary embolism, myocardial infarction, stroke, thromboembolic
complications of surgery, and peripheral arterial occlusion. A
compound of the invention may also be useful in the treatment of
adult respiratory distress syndrome, septic shock, septicemia, or
inflammatory responses, such as edema and acute or chronic
atherosclerosis, because thrombin has been shown to activate a
large number of cells outside of the coagulation process, such as,
for example, neutrophils, fibroblasts, endothelial cells, and
smooth muscle cells.
[0075] The method for treating cardiovascular or related diseases
can further comprise concurrent administration of other therapeutic
agents already known to be suitable for treating the
above-identified diseases. For example, methods of the invention
include concurrently administering a compound of the invention or a
pharmaceutically acceptable acid addition salt of a compound of the
invention in combination with a therapeutic cardiovascular compound
to treat hypertrophy, hypertension, congestive heart failure, heart
failure subsequent to myocardial infarction, myocardial ischemia,
ischemia reperfusion injury, arrhythmia, or myocardial infarction.
Preferably, the cardiovascular disease treated is hypertrophy,
congestive heart failure, arrhythmia, or ischemia reperfusion
injury.
[0076] The compounds of the invention can also be used in
combination with other therapeutic cardiovascular compounds that
are generally used to treat cardiovascular or related diseases as
well as symptoms thereof. A skilled physician or veterinarian
readily determines a subject who is exhibiting symptoms of any one
or more of the diseases described above and makes the determination
about which compound is generally suitable for treating specific
cardiovascular conditions and symptoms.
[0077] For example, myocardial ischemia can be treated by the
administration of a compound of the invention or a pharmaceutically
acceptable acid addition salt of a compound of the invention
concurrently with another therapeutic agent. Other suitable
therapeutic agents include, for example, a angiotensin converting
enzyme inhibitor, an angiotensin II receptor antagonist, a calcium
channel blocker, an antithrombolytic agent, a .beta.-adrenergic
receptor antagonist, a diuretic, an .alpha.-adrenergic receptor
antagonist, or a mixture thereof.
[0078] As another example, congestive heart failure can be treated
by the administration of a compound of the invention or a
pharmaceutically acceptable acid addition salt of a compound of the
invention concurrently with another therapeutic agent. Other
suitable therapeutic agents include, for example, an angiotensin
converting enzyme inhibitor, an angiotensin II receptor antagonist,
a calcium channel blocker, a vasodilator, a diuretic, or a mixture
thereof.
[0079] Myocardial infarction can be treated by the administration
of a compound of the invention or a pharmaceutically acceptable
acid addition salt of a compound of the invention concurrently with
another therapeutic agent. Other suitable therapeutic agents
include, for example, an angiotensin converting enzyme inhibitor, a
calcium channel blocker, an antithrombolytic agent, a
.beta.-adrenergic receptor antagonist, a diuretic, an
.alpha.-adrenergic receptor antagonist, or a mixture thereof.
[0080] Hypertension can be treated by the administration of a
compound of the invention or a pharmaceutically acceptable acid
addition salt of a compound of the invention concurrently with
another therapeutic agent. Other suitable therapeutic agents
include, for example, an angiotensin converting enzyme inhibitor, a
calcium channel blocker, a .beta.-adrenergic receptor antagonist, a
vasodilator, a diuretic, an .alpha.-adrenergic receptor antagonist,
or a mixture thereof.
[0081] Arrhythmia can be treated by the administration of a
compound of the invention or a pharmaceutically acceptable acid
addition salt of a compound of the invention concurrently with
another therapeutic agent. Other suitable therapeutic agents
include, for example, a calcium channel blocker, a
.beta.-adrenergic receptor antagonist, or a mixture thereof.
[0082] Blood clots in the arteries (arterial thrombosis) or veins
(venous thrombosis) can be reduced or removed by the administration
of a compound of the invention or a pharmaceutically acceptable
acid addition salt of a compound of the invention concurrently with
an anti-platelet agent such as clopidogrel (aspirin, dipyridamole,
etc.), glycoprotein IIb/IIIa inhibitor such as eptifibatide
(INTEGRILIN.RTM.), or by an anticoagulant such as UFH
(unfractionated heparins), LMWH (low molecular weight heparins),
hirudin, or argatroban.
[0083] Hypertrophy can be treated by the administration of a
compound of the invention or a pharmaceutically acceptable acid
addition salt of a compound of the invention concurrently with
another therapeutic agent. Other suitable therapeutic agents
include, for example, an angiotensin converting enzyme inhibitor,
an angiotensin II receptor antagonist, a calcium channel blocker,
or a mixture thereof.
[0084] Ischemia reperfusion injury can be treated by the
administration of a compound of the invention or a pharmaceutically
acceptable acid addition salt of a compound of the invention
concurrently with another therapeutic agent. Other suitable
therapeutic agents include, for example, an angiotensin converting
enzyme inhibitor, an angiotensin II receptor antagonist, a calcium
channel blocker, or a mixture thereof.
[0085] Compounds of the invention or pharmaceutically acceptable
salts thereof can be administered post-surgically, alone or
concurrently with other suitable therapeutic agents. For instance,
the method would include, but is not limited to, administration to
patients following hip replacement surgery, or invasive
cardiovascular surgery, including coronary artery bypass graft
(CABG), endarectomy, and heart valve replacement. Compounds of the
invention or pharmaceutically acceptable salts thereof can be
administered, alone or concurrently with other suitable therapeutic
agents, following any angioplasty procedure. For instance,
administration of said compounds may follow percutaneous
transluminal angioplasty (PTA). PTA is used in coronary, pulmonary,
peripheral, intracranial, extracranial carotid, renal, and aortic
stenoses.
[0086] Additionally, medical devices can be coated with the
compounds of the invention or pharmaceutically acceptable acid
salts of the compound alone or in mixture with other suitable
therapeutic agents (e.g., an angiotensin converting enzyme
inhibitor). Medical devices that can be coated with the compounds
of the invention or pharmaceutically acceptable salts thereof alone
or in mixture with other suitable therapeutic agents include, but
are not limited to, intravascular stents and catheters.
Intravascular stents are used to prevent blood vessel wall
collapse. Drug-eluting stents are coated with a mixture of polymers
and drug to prevent restenosis. Examples of drug-eluting stents are
the CYPHER.TM. sirolimus-eluting stent (Cordis Corp., Miami, Fla.)
and TAXUS.TM. paclitaxel-eluting stent (Boston Scientific Corp.,
Natick, Mass.).
[0087] This invention is further characterized by the following
examples. These examples are not meant to limit the scope of the
invention but are provided for exemplary purposes to more fully
describe the invention. Variation within the scope of the invention
will be apparent to those skilled in the art.
EXAMPLES
[0088] All reagents used were purchased from standard commercial
sources, or synthesized by known literature methods. HPLC analysis
was performed using a Waters 996 PDA high performance liquid
chromatograph equipped with a Waters 600 controller. Signals were
detected with a photodiode array detector (set at max plot 254-400
nm). NMR spectra were recorded on a Bruker AM-300 instrument
(.sup.13C, .sup.19F and .sup.31P at 75.5, 282 and 121 MHz
respectively) and were calibrated using residual nondeuterated
solvent as the internal reference. All .sup.19F spectra are
reported using hexafluorobenzene (.delta. -162.9 ppm) as the
external standard while .sup.31p spectra were collected using 85%
H.sub.3PO.sub.4 (.delta.0.0 ppm) as the external reference.
Example 1
Synthesis of
4-[(2,2,8-Trimethyl-4H-[1,3]dioxino[4,5-c]pyridin-5-ylmethyl)-amino]-biph-
enyl-2-sulfonic acid tert-butylamide (1)
[0089] ##STR16##
[0090] To a 250 mL three neck flask fitted with a condenser and
Dean-Stark apparatus was added 4'-amino-biphenyl-2-sulfonic acid
tert-butylamide (1.22 g, 4.0 mmol), p-toluenesulfonic acid
monohydrate (152 mg, 0.8 mmol),
2,2,8-trimethyl-4H-[1,3]dioxino[4,5-c]pyridine-5-carbaldehyde (995
mg, 4.8 mmol, see Korytnyk et al., Methods Enzymol. 1970; 18A:
524-566) and toluene (120 ml). The reaction mixture was stirred at
120.degree. C. under nitrogen atmosphere for 7 h before
concentrating to dryness. The resulting solid was then dissolved in
acetic acid (20 mL), cooled to 0.degree. C., and sodium borohydride
(529 mg, 14 mmol) was added slowly. After the addition of sodium
borohydride was complete, dichloromethane (30 mL) was added to the
reaction mixture and stirring was continued at room temperature for
an additional 3 h. Sodium hydroxide (5 N) was added to neutralize
the solution, and the reaction mixture was extracted with ethyl
acetate, dried over MgSO.sub.4, filtered and evaporated. The crude
mixture was purified by column chromatography on silica gel using a
mixture of ethyl acetate and hexane (1:1) as eluant, to give
4'-[(2,2,8-trimethyl-4H-[1,3]dioxino[4,5-c]pyridin-5-ylmethyl)-amino]-bip-
henyl-2-sulfonic acid tert-butylamide (1) (0.457 g, 24% yield) as a
colorless solid.
[0091] .sup.1H-NMR (CDCl.sub.3): .delta. 8.13 (d, 1H), 8.04 (s,
1H), 7.52 (t, 1H), 7.41 (t, 1H), 7.35 (d, 2H), 7.28 (d, 1H), 6.70
(d, 2H), 4.90 (s, 2H), 4.20 (d, 2H), 3.99 (t, 1H), 3.69 (s, 1H),
2.41(s, 3H), 1.56 (s, 6H), 0.98 (s, 9H).
Example 2
Synthesis of
4'-[(5-Hydroxy-4-hydroxymethyl-6-methyl-pyridin-3-ylmethyl)
-amino]-biphenyl-2-sulfonic acid tert-butylamide (2)
[0092] ##STR17##
[0093] To a solution of 10% formic acid in water (50 mL) was added
3-[(2,2,8-trimethyl-4H-[1,3]dioxino[4,5-c]pyridin-5-ylmethyl)-amino]-benz-
onitrile (1) (336 mg, 0.7 mmol) and the reaction mixture was heated
at 100.degree. C. under nitrogen atmosphere. The reaction mixture
was then concentrated to dryness. The resulting pale yellow solid
was dissolved in small amount of dichloromethane and diethyl ether
was added to induce precipitation of a yellow solid. The pale
yellow
4'-[(5-hydroxy-4-hydroxymethyl-6-methyl-pyridin-3-ylmethyl)-amino]-biphen-
yl-2-sulfonic acid tert-butylamide (2) (215 mg, 70% yield) was
collected by filtration.
[0094] .sup.1H-NMR (DMSO-d6): .delta. 8.70 (s, 1H), 8.07 (d, 1H),
7.77 (s, 1H), 7.60 (m, 2H), 7.43 (s, 4H), 7.33 (d, 1H), 5.14 (s,
2H), 4.77 (s, 2H), 2.33 (s, 3H), 0.98 (s, 9H).
Example 3
Synthesis of
4'-[(5-Hydroxy-4-hydroxymethyl-6-methyl-pyridin-3-ylmethyl)-amino]-biphen-
yl-2-sulfonic acid amide (3)
[0095] ##STR18##
[0096] Hydrogen chloride gas was bubbled into a suspension of
4'-[(5-hydroxy-4-hydroxymethyl-6-methyl-pyridin-3-ylmethyl)-amino]-biphen-
yl-2-sulfonic acid tert-butylamide (2) (160 mg, 0.36 mmol) in
methyl alcohol (20 mL) at 0.degree. C. for 10 min. The solvent was
evaporated and the products were purified on a silica gel column
using a mixture of methyl alcohol:dichloromethane (1:9) as eluant
to give
4'-[(5-hydroxy-4-hydroxymethyl-6-methyl-pyridin-3-ylmethyl)-amino]-biphen-
yl-2-sulfonic acid amide (3) (139 mg, 25% yield).
[0097] .sup.1H-NMR (CD.sub.3OD): .delta. 8.08 (d, 1H), 7.92 (s,
1H), 7.59 (t, 1H), 7.47 (t, 1H), 7.33 (d, 1H), 7.24 (d, 2H), 6.74
(d, 2H), 4.99 (s, 2H), 4.36 (s, 2H), 2.43 (s, 3H). MS m/z
(ES.sup.+): 400.22 (M+H.sup.+).
Example 4
Synthesis of 2'-tert-Butylsulfamoyl-biphenyl-4-carboxylic acid
(2,2,8-trimethyl-4H-[1,3]dioxino[4,5-c]pyridin-5-ylmethyl)-amide
(4)
[0098] ##STR19##
[0099] A mixture of 2'-tert-butylsulfamoyl-biphenyl-4-carboxylic
acid mono-sodium salt (200 mg, 0.56 mmol),
2,2,8-trimethyl-4H-[1,3]dioxino[4,5-c]pyridin-5-yl)-methylamine
(123 mg, 0.59 mmol), 1-[3-(dimethylamino)propyl]-3-ethyl
carbodiimide hydrochloride (EDC) (226 mg, 1.18 mmol), and
4-(dimethylamino)pyridine (DMAP) (144 mg, 1.18 mmol) in anhydrous
dichloromethane (25 mL) was stirred at room temperature under
nitrogen atmosphere overnight. The reaction mixture was
concentrated and the crude mixture was purified by column
chromatography on silica gel using a mixture of methyl
alcohol:dichloromethane (1:9) as eluant to give
2'-tert-butylsulfamoyl-biphenyl-4-carboxylic acid
(2,2,8-trimethyl-4H-[1,3]dioxino[4,5-c]pyridin-5-ylmethyl)-amide
(4) (196 mg, 67% yield) as a colorless solid.
[0100] .sup.1H-NMR (CDCl.sub.3): .delta. 8.16 (s, 1H), 8.04 (d,
1H), 7.94 (d, 2H), 7.57-7.46 (m, 5H), 5.01(s, 2H), 4.58 (d, 2H),
4.03 (s, 1H), 2.50 (s, 3H), 1.56 (s, 6H), 1.01 (s, 9H).
Example 5
Synthesis of 2'-tert-Butylsulfamoyl-biphenyl-4-carboxylic acid
(5-hydroxy-4-hydroxymethyl-6-methyl-pyridin-3-ylmethyl)-amide
(5)
[0101] ##STR20##
[0102] The hydrolysis of
2'-tert-butylsulfamoyl-biphenyl-4-carboxylic acid
(2,2,8-trimethyl-4H-[1,3]dioxino[4,5-c]pyridin-5-ylmethyl)-amide
(4) (300 mg, 0.57 mmol), following the procedure described in
Example 2, gave 2'-tert-butylsulfamoyl-biphenyl-4-carboxylic acid
(5-hydroxy-4-hydroxymethyl-6-methyl-pyridin-3-ylmethyl)-amide (5)
(219 mg, 79% yield) as a colorless solid.
[0103] .sup.1H-NMR (CD.sub.3OD): .delta. 8.32 (m, 4H), 8.16 (s,
1H), 8.09 (d, 2H), 7.84 (t, 1H), 7.75 (d, 3H), 7.54 (d, 1H), 5.23
(s, 2H), 4.84 (s, 2H), 2.66 (s, 3H), 1.25 (s, 9H). MS m/z
(ES.sup.+): 484.41 (M+H.sup.+).
Example 6
Synthesis of 2'-Sulfamoyl-biphenyl-4-carboxylic acid
(5-hydroxy-4-hydroxymethyl-6-methyl-pyridin-3-ylmethyl)-amide
(6)
[0104] ##STR21##
[0105] The hydrolysis of
2'-tert-butylsulfamoyl-biphenyl-4-carboxylic acid
(5-hydroxy-4-hydroxymethyl-6-methyl-pyridin-3-ylmethyl)-amide (5)
(101 mg, 0.21 mmol), following the procedure described in Example
3, gave 2'-sulfamoyl-biphenyl-4-carboxylic acid
(5-hydroxy-4-hydroxymethyl-6-methyl-pyridin-3-ylmethyl)-amide (6)
(219 mg, 79% yield) as a colorless solid.
[0106] .sup.1H-NMR (CD.sub.3OD): .delta. 8.27 (m, 2H), 8.05 (d,
2H), 7.81-7.72 (m, 2H), 7.68 (d, 2H), 7.48 (d, 1H), 5.35 (s, 2H),
4.85 (s, 2H), 2.78 (s, 3H). MS m/z (ES.sup.+): 428.29
(M+H.sup.+).
Example 7
Synthesis of
4'-[(3-Hydroxy-5-hydroxymethyl-2-methyl-pyridin-4-ylmethyl)-amino]-biphen-
yl-2-sulfonic acid tert-butylamide (7)
[0107] ##STR22##
[0108] A mixture of pyridoxal hydrochloride (330 mg, 1.62 mmol),
4'-amino-biphenyl-2-sulfonic acid tert-butylamide (494 mg, 1.62
mmol), p-toluenesulfonic acid monohydrate (68 mg, 0.36 mmol) and
toluene (150 mL) was added to a 250 mL three-necked round bottom
flask fitted with a condenser and a Dean-Stark trap, and heated at
100.degree. C. under nitrogen atmosphere for 3 h. The solvent was
then evaporated and the crude product was dissolved in
dichloromethane (70 mL), cooled down to 0.degree. C. and then
sodium borohydride (163 mg, 4.32 mmol) and methyl alcohol (15 mL)
were added. The reaction mixture was stirred at room temperature
overnight, after which time the solvent was removed. The residue
was diluted with saturated aqueous sodium bicarbonate and extracted
with ethyl acetate. The organic layer was dried over anhydrous
magnesium sulfate, filtered and evaporated. The crude product was
purified by column chromatography on silica gel using a mixture of
dichloromethane:methyl alcohol (9:1) as eluant to give
4'-[(3-hydroxy-5-hydroxymethyl-2-methyl-pyridin-4-ylmethyl)-amino]-biphen-
yl-2-sulfonic acid tert-butylamide (7) (178 mg, 24% overall yield
for two steps) as a colorless solid.
[0109] .sup.1H-NMR (CDCl.sub.3): .delta. 8.13 (dd, 1H), 7.84 (s,
1H), 7.53 (td, 1H), 7.44 (td, 1H), 7.37 (d, 2H), 7.27 (dd, 1H),
6.89 (d, 2H), 4.68 (s, 2H), 4.61 (s, 2H), 3.71 (s, 1H), 2.44 (s,
3H), 0.98 (s, 9H). MS m/z (ES.sup.+): 456.29 (M+H.sup.+).
Example 8
Synthesis of
4'-[(3-Hydroxy-5-hydroxymethyl-pyridin-4-ylmethyl)-amino]-biphenyl-2-sulf-
onic acid amide (8)
[0110] ##STR23##
[0111] The hydrolysis of
4'-[(3-hydroxy-5-hydroxymethyl-2-methyl-pyridin-4-ylmethyl)-amino]-biphen-
yl-2-sulfonic acid tert-butylamide (7) (75 mg, 0.16 mmol),
following the procedure described in Example 3, gave
4'-[(3-hydroxy-5-hydroxymethyl-pyridin-4-ylmethyl)-amino]-biphenyl-2-sulf-
onic acid amide (8) (49 mg, 76% yield) as a colorless solid.
[0112] .sup.1H-NMR (CD.sub.3OD): .delta. 8.09 (s, 1H), 7.92 (dd,
1H), 7.45-7.38 (m, 2H), 7.28 (dt, 2H), 7.16-7.10 (m, 3H), 4.70 (s,
2H), 4.66 (s, 2H), 2.53 (s, 3H). MS m/z (ES.sup.+): 400.28
(M+H.sup.+).
Example 9
Synthesis of
3'-Fluoro-4'-[(3-hydroxy-5-hydroxymethyl-2-methyl-pyridin-4-ylmethyl)-ami-
no]-biphenyl-2-sulfonic acid tert-butylamide (9)
[0113] ##STR24##
[0114] The reductive amination of pyridoxal hydrochloride (436.4
mg, 2.143 mmol) and 4'-amino-3'-fluoro-biphenyl-2-sulfonic acid
tert-butylamide (760 mg, 2.357 mmol), following the procedure
described in Example 7, gave
3'-fluoro-4'-[(3-hydroxy-5-hydroxymethyl-2-methyl-pyridin-4-ylmethyl)-ami-
no]-biphenyl-2-sulfonic acid tert-butylamide (9).
[0115] .sup.1H-NMR (CD.sub.3OD): .delta. 8.06 (d, 1H), 7.9 (br s,
1H), 7.57 (t, 1H), 7.47 (t, 1H), 7.3 (d, 1H), 7.1 (dd, 1H), 7.07
(d, 1H), 7.01 (t, 1H), 4.75 (s, 2H), 4.61 (s, 2H), 0.98 (s, 9H).
.sup.9F-NMR (CD.sub.3OD; .sup.1H-decoupled): .delta. -135.5.
Example 10
Synthesis of
(5-Bromo-pyridin-2-yl)-(2,2,8-trimethyl-4H-[1,3]dioxino[4,5-c]pyridine-5--
ylmethyl)-amine (10)
[0116] ##STR25##
[0117] Compound (10) was prepared according to the procedure
described in Example 1 from 2-amino-5-bromopyridine (4.33 g, 25
mmol) and
2,2,8-trimethyl-4H-[1,3]dioxino[4,5-c]pyridine-5-carbaldehyde (5.18
g, 25 mmol). The crude mixture was purified by column
chromatography over silica gel using a hexane/ethyl acetate (1:1)
mixture as eluant to furnish 1.8 g (20%) of (10).
[0118] .sup.1H-NMR CD.sub.3OD): .delta. 7.99 (d, 1H), 7.89 (s, 1H),
7.5 (dd, 1H), 6.5 (d, 1H), 4.95 (s, 2H), 4.37 (s, 2H), 2.33 (s,
3H), 1.56 (s, 6H).
Example 11
Synthesis of
N-tert-Butyl-2-[6-(2,2,8-trimethyl-4H-[1,3]dioxino[4,5-c]pyridin-5-ylamin-
o)-pyridin-3-yl]-benzenesulfonamide (11)
[0119] ##STR26##
[0120] A mixture of
(5-bromo-pyridin-2-yl)-(2,2,8-trimethyl-4H-[1,3]dioxino[4,5-c]pyridin-5-y-
l)-amine (10) (564 mg, 1.55 mmol), tetrakis(triphenylphosphine)
palladium(0) (174 mg, 0.15 mmol), cesium carbonate (1.56 g, 4.8
mmol), 2-tert-butylsulfamoyl-phenylboronic acid (438 mg, 1.7 mmol)
in a solution of toluene (20 mL), iso-butyl alcohol (15 mL) and
water (5 mL) was stirred at 80.degree. C. under nitrogen for 5 h.
The reaction was diluted with water and extracted with ethyl ether.
The organic layer was dried over anhydrous magnesium sulfate,
filtered and evaporated. The crude product was purified by column
chromatography on silica gel to give
N-tert-butyl-2-[6-(2,2,8-trimethyl-4H-[1,3]dioxino[4,5-c]pyridin-5-ylamin-
o)-pyridin-3-yl]-benzenesulfonamide (11) as a colorless solid (554
mg, 74% yield).
[0121] .sup.1H-NMR (CDCl.sub.3): .delta. 8.15 (d, 1H), 8.10 (s,
1H), 8.03 (s, 1H), 7.68 (d, 1H), 7.55 (t, 1H), 7.46 (t, 1H), 7.27
(d, 1H), 6.47 (d, 1H), 4.91 (s, 2H), 4.84 (t, 1H), 4.44 (d, 2H),
3.76 (s, 1H), 2.40 (s, 3H), 1.55 (s, 6H), 1.03 (s, 9H).
Example 12
Synthesis of
N-tert-Butyl-2-[6-(5-hydroxy-4-hydroxymethyl-6-methyl-pyridin-3-ylamino)--
pyridin-3-yl]-benzenesulfonamide (12)
[0122] ##STR27##
[0123] The hydrolysis of
N-tert-butyl-2-[6-(2,2,8-trimethyl-4H-[1,3]dioxino[4,5-c]pyrdin-5-ylamino-
)-pyridin-3-yl]-benzenesulfonamide (12) (305 mg, 0.63 mmol),
following the procedure described in Example 2, gave
N-tert-butyl-2-[6-(5-hydroxy-4-hydroxymethyl-6-methyl-pyridin-3-ylamino)--
pyridin-3-yl]-benzenesulfonamide (12) (244 mg, 84% yield) as a
colorless solid.
[0124] .sup.1H-NMR (CD.sub.3OD): .delta. 8.13-8.10 (m, 3H), 7.97
(d, 2H), 7.64-7.60 (m, 2H), 7.52 (t, 1H), 7.34 (d, 1H), 6.69 (d,
1H), 5.02 (s, 2H), 4.59 (s, 2H), 2.46 (s, 3H), 1.06 (s, 9H).
Example 13
Synthesis of
4'-{[5-(3-Cyano-benzyloxy)-4-hydroxymethyl-6-methyl-pyridin-3-ylmethyl]-a-
mino}-biphenyl-2-sulfonic acid tert-butylamide (13)
[0125] ##STR28##
[0126] A mixture of
4'-[(5-hydroxy-4-hydroxymethyl-6-methyl-pyridin-3-ylmethyl)-amino]-biphen-
yl-2-sulfonic acid tert-butylamide (2) (190 mg, 0.42 mmol),
.alpha.-bromo-m-tolunitrile (90 mg, 0.46 mmol) and potassium
carbonate (177 mg, 1.28 mmol) in DMF (10 mL) were stirred at room
temperature under nitrogen atmosphere overnight. The reaction
mixture was evaporated to dryness, and the crude product was
purified by column chromatography on silica gel using a gradient of
dichloromethane:methyl alcohol (1:0 to 9:1) as eluant to give
4'-{[5-(3-cyano-benzyloxy)-4-hydroxymethyl-6-methyl-pyridin-3-ylmethyl]-a-
mino}-biphenyl-2-sulfonic acid tert-butylamide (13) (149 mg, 62%
yield) as a colorless solid.
[0127] .sup.1H-NMR (CDCl.sub.3): .delta. 8.39 (s, 1H), 8.16 (d,
1H), 7.83 (s, 1H), 7.75-7.68 (m, 2H), 7.59-7.53 (m, 2H), 7.49-7.41
(m, 3H), 7.31 (d, 2H), 6.87 (d, 2H), 5.03 (s, 2H), 4.81 (s, 2H),
4.46 (s, 2H), 3.70 (s, 1H), 2.58 (s, 3H), 1.02 (s, 9H).
Example 14
Synthesis of
3-{4-Hydroxymethyl-5-[(2'-sulfamoyl-biphenyl-4-ylamino)-methyl]-pyridin-3-
-yloxymethyl}-benzamidine (14)
[0128] ##STR29##
[0129] Hydrogen chloride gas was bubbled into a suspension of
4'-{[5-(3-cyano-benzyloxy)-4-hydroxymethyl-6-methyl-pyridin-3-ylmethyl]-a-
mino}-biphenyl-2-sulfonic acid tert-butylamide (13) (100 mg, 0.17
mmol) in absolute ethyl alcohol (30 mL) at 0.degree. C. for 30 min.
The septum was replaced and the reaction mixture was stirred at
room temperature overnight. Hydrogen chloride gas was purged with
nitrogen gas for 2 h and the solvent evaporated to give the crude
amide ester as a solid. Ammonia in methyl alcohol (30 mL, 7 M, 350
mmol) was added to the crude amide ester and the reaction mixture
was stirred overnight at room temperature. The solvent was
evaporated and the product purified on a silica gel column using a
mixture of dichloromethane:methyl alcohol (4:1) as eluant to give
the corresponding
3-{4-hydroxymethyl-5-[(2'-sulfamoyl-biphenyl-4-ylamino)-methyl]-pyridin-3-
-yloxymethyl}-benzamidine (14) (90 mg, 97% yield) as a colorless
powder.
[0130] .sup.1H-NMR (CD.sub.3OD): .delta. 8.30 (s, 1H), 8.07 (d,
1H), 8.01 (s, 1H), 7.92 (d, 1H), 7.84 (d, 1H), 7.70 (t, 1H) 7.58
(t, 1H), 7.46 (t, 1H), 7.32 (d, 1H), 7.24 (d, 2H), 6.77 (d, 2H),
5.11 (s, 2H), 4.58 (s, 2H), 3.36 (s, 2H), 2.52 (s, 3H). MS m/z
(ES.sup.+): 532.37 (M+H.sup.+).
Example 15
Synthesis of
N-tert-Butyl-2-{6-[3-(3-cyano-benzyloxy)-2-hydroxymethyl-4-methyl-benzyla-
mino]-pyridin-3-yl}-benzenesulfonamide (15)
[0131] ##STR30##
[0132] The coupling of
N-tert-butyl-2-[6-(5-hydroxy-4-hydroxymethyl-6-methyl-pyridin-3-ylamino)--
pyridin-3-yl]-benzenesulfonamide (12) (205 mg, 0.45 mmol) and
.alpha.-bromo-m-tolunitrile (88 mg, 0.45 mmol), following the
procedure described in Example 13, gave
N-tert-butyl-2-{6-[3-(3-cyano-benzyloxy)-2-hydroxymethyl-4-methyl-benzyla-
mino]-pyridin-3-yl}3-benzenesulfonamide (15) (23 mg, 9% yield).
[0133] .sup.1H-NMR (CDCl.sub.3): .delta. 8.38 (s, 1H), 8.14 (dd,
1H), 7.98 (d, 1H), 7.81 (s, 1H), 7.74-7.64 (m, 3H), 7.55-7.46 (m,
3H), 7.24 (dd, 1H), 6.56 (d, 1H), 5.35 (t, 1H), 4.99 (s, 2H), 4.85
(s, 2H), 4.71 (d, 2H), 3.63 (s, 1H), 2.51 (s, 3H), 1.00 (s,
9H).
Example 16
Synthesis of
3-(2-Hydroxymethyl-6-methyl-3-{[5-(2-sulfamoyl-phenyl)-pyridin-2-ylamino]-
-methyl}-phenoxymethyl)-benzamidine (16)
[0134] ##STR31##
[0135] The conversion of nitrile (15) to amidine (16) was carried
out as described in Example 14.
[0136] .sup.1H-NMR (CD.sub.3OD): .delta. 8.32 (s, 1H), 8.11 (dd,
1H), 8.01 (t, 1H), 7.96 (d, 1H), 7.92 (d, 1H), 7.83 (d, 1H), 7.69
(t, 1H), 7.64-7.50 (m, 3H), 7.32 (dd, 1H), 6.67 (d, 1H), 5.12 (s,
2H), 4.88 (s, 2H), 4.73 (s, 2H), 2.52 (s, 3H). MS m/z (ES.sup.+):
533.42 (M+H.sup.+).
Example 17
Synthesis of
4'-{[5-(3-Cyano-benzyloxy)-4-hydroxymethyl-6-methyl-pyridin-3-ylmethyl]-a-
mino}-biphenyl-2-sulfonic acid tert-butylamide (17)
[0137] ##STR32##
[0138] The coupling of
4'-[(5-hydroxy-4-hydroxymethyl-6-methyl-pyridin-3-ylmethyl)-amino]-biphen-
yl-2-sulfonic acid tert-butylamide (2) (190 mg, 0.42 mmol) and
.alpha.-bromo-p-tolunitrile (90 mg, 0.46 mmol), following the
procedure described in Example 13, gave
4'-{[5-(3-cyano-benzyloxy)-4-hydroxymethyl-6-methyl-pyridin-3-ylmethyl]-a-
mino}-biphenyl-2-sulfonic acid tert-butylamide (58) (149 mg, 62%
yield) as a colorless solid.
[0139] .sup.1H-NMR (CDCl.sub.3): .delta. 8.39 (s, 1H), 8.16 (d,
1H), 7.83 (s, 1H), 7.75-7.68 (m, 2H), 7.59-7.53 (m, 2H), 7.49-7.41
(m, 3H), 7.31 (d, 2H), 6.87 (d, 2H), 5.03 (s, 2H), 4.81 (s, 2H),
4.46 (s, 2H), 3.70 (s, 1H), 2.58 (s, 3H), 1.02 (s, 9H).
Example 18
Synthesis of
3-{4-Hydroxymethyl-5-[(2'-sulfamoyl-biphenyl-4-ylamino)-methyl]-pyridin-3-
-yloxymethyl}-benzamidine (18)
[0140] ##STR33##
[0141] The conversion of nitrile (17) to amidine (18) was carried
out as described in Example 14.
[0142] .sup.1H-NMR (CD.sub.3OD): .delta. 8.30 (s, 1H), 8.07 (d,
1H), 8.01 (s, 1H), 7.92 (d, 1H), 7.84 (d, 1H), 7.70 (t, 1H) 7.58
(t, 1H), 7.46 (t, 1H), 7.32 (d, 1H), 7.24 (d, 2H), 6.77 (d, 2H),
5.11 (s, 2H), 4.58 (s, 2H), 3.36 (s, 2H), 2.52 (s, 3H). MS m/z
(ES.sup.+): 532.37 (M+H.sup.+).
Example 19
Synthesis of 3'-Amino-biphenyl-2-sulfonic acid tert-butylamide
(19)
[0143] ##STR34## Compound (19) was prepared according to the
procedure described in Example 11 from 3-bromoanaline (2.08 g, 12.1
mmol) and 2-tert-butylsulfamoyl-phenylboronic acid (2.83 g, 11
mmol). The crude mixture was purified by column chromatography over
silica gel using a hexane ethyl acetate (1:1) mixture as eluant to
give 2.6 g (84%) of (19).
[0144] .sup.1H-NMR (CDCl.sub.3): .delta. 8.15 (dd, 1H), 7.54 (dt,
1H), 7.45 (dt, 1H), 7.33 (dd, 1H), 7.23 (t, 1H), 6.88 (s, 1H), 6.85
(d, 1H), 6.74 (dd, 1H), 3.76 (s, 1H), 3.40 (br s, 2H), 1.0 (s,
9H).
Example 20
Synthesis of
3'-[(2,2,8-Trimethyl-4H-[1,3]dioxino[4,5-c]pyridin-5-ylmethyl)-amino]-bip-
henyl-2-sulfonic acid tert-butylamide (20)
[0145] ##STR35## Compound (20) was prepared according to the
procedure described in Example 1 from biphenyl amine (19) (913 mg,
3 mmol) and
2,2,8-trimethyl-4H-[1,3]dioxino[4,5-c]pyridine-5-carbaldehyde (622
mg, 3 mmol). The crude mixture was purified by column
chromatography over silica gel using a hexane/ethyl acetate (1:1)
mixture as eluant to give 167 mg (11%) of (20).
[0146] .sup.1H-NMR (CDCl.sub.3): .delta. 8.13 (dd, 1H), 8.02 (s,
1H), 7.55 (dt, 1H), 7.42 (dt, 1H), 7.33 (dd, 1H), 7.26 (t, 1H),
6.90 (s, 1H), 6.82 (dd, 1H), 6.68 (dd, 1H), 4.88 (s, 2H), 4.20 (s,
2H), 3.96 (br s, 1H), 3.66 (s, 1H), 2.40 (s, 3H), 1.54 (s, 6H),
0.97 (s, 9H).
Example 21
Synthesis of
3'-[(5-Hydroxy-4-hydroxymethyl-6-methyl-pyridin-3-ylmethyl)-amino]-biphen-
yl-2-sulfonic acid amide (21)
[0147] ##STR36## Compound (20) (105 mg, 0.21 mmol) was dissolved in
anhydrous methanol (30 ml), and the solution was cooled to
5.degree. C. then saturated with HCl gas. The solution was allowed
to slowly warm to room temperature and stirred overnight. The
remaining HCl was removed with a steady stream of nitrogen, and the
trace amounts of remaining acid neutralized with 7 N methanolic
ammonia. The solvents were removed and the residue purified by
column chromatography over silica gel using a
dichloromethane/methanol (9:1) mixture as eluant to furnish (21)
(52 mg, 62%) as a white powder.
[0148] .sup.1H-NMR (CD.sub.3OD): .delta. 8.08 (dd, 1H), 7.89 (s,
1H), 7.60 (dt, 1H), 7.50 (dt, 1H), 7.34 (dd, 1H), 7.21 (dt, 1H),
6.76-6.70 (m, 3H), 4.96 (s, 2H), 4.33 (s, 2H), 2.41 (s, 3H). MS m/z
(ES.sup.+): 400.26 (M+H.sup.+).
Example 22
Synthesis of 2'-tert-Butylsulfamoyl-biphenyl-4-carboxylic acid
[5-(3-cyano-benzyloxy)-4-hydroxymethyl-6-methyl-pyridin-3-ylmethyl]-amide
(22)
[0149] ##STR37##
[0150] Compound (22) was prepared according to the procedure
described in Example 13 from (5) (156 mg, 0.32 mmol) and
.alpha.-bromo-m-tolunitrile (69 mg, 0.35 mmol). The crude mixture
was purified by column chromatography over silica gel using a
mixture of dichloromethane/methyl alcohol (gradient from 1:0 to
9:1) as eluant gave 100 mg (52%) of (22).
[0151] .sup.1H-NMR (CD.sub.3OD): .delta. 8.49 (br s, 1H), 8.12 (dd,
1H), 7.94-7.91 (m, 3H), 7.85 (d, 1H), 7.78 (dd, 1H), 7.63-7.61 (m,
2H), 7.6-7.53 (m, 3H), 7.32 (dd, 1H), 5.18 (s, 2H), 4.96 (s, 2H),
4.90 (s, 2H), 2.7 (s, 3H), 1.06 (s, 9H).
Example 23
Synthesis of 2'-tert-Butylsulfamoyl-biphenyl-4-carboxilic
acid[5-(carbamimidoyl-benzyloxy)-4-hydroxymethyl-6-methyl-pyridin-3-ylmet-
hyl]-amide (23)
[0152] ##STR38## Compound (23) was prepared according to the
procedure described in Example 14 from (22) (100 mg, 0.17 mmol).
The crude mixture was purified by reverse phase preparatory HPLC
(Waters XTerra.RTM. Prep RP.sub.18 OBD.TM. (10 .mu.M), 19.times.250
mm)) using 10% to 100% acetonitrile versus 0.1% aqueous
trifluoroacetic acid to provide 30 mg, (32%) of (23).
[0153] .sup.1H-NMR (CD.sub.3OD): .delta. 8.44 (s, 1H), 8.12 (dd,
1H), 7.99 (br s, 1H), 7.93-7.89 (m, 3H), 7.84 (dd, 1H), 7.70 (t,
1H), 7.63 (dd, 1H), 7.58 (dd, 1H), 7.55-7.52 (m, 2H), 7.34 (dd,
1H), 5.20 (s, 2H), 4.95 (s, 2H), 4.83 (s, 2H), 2.52 (s, 3H). MS m/z
(ES.sup.+): 560.57 (M+H.sup.+).
Example 24
Synthesis of
4'-{[3-(3-Cyano-benzyloxy)-5-hydroxymethyl-2-methyl-pyridin-4-ylmethyl]-a-
mino}-biphenyl-2-sulfonic acid tert-butylamide (24)
[0154] ##STR39## Compound (24) was prepared according to the
procedure described in Example 13 from (7) (85 mg, 0.19 mmol) and
.alpha.-bromo-m-tolunitrile (40 mg, 0.2 mmol). The crude mixture
was purified by column chromatography over silica gel using a
dichloromethane/methyl alcohol (9:1) mixture as eluant to give 62
mg (58%) of (24).
[0155] .sup.1H-NMR (CDCl.sub.3): .delta. 8.33 (br s, 1H), 8.13 (dd,
1H), 7.72 (br s, 1H), 7.64 (m, 2H), 7.52 (m, 2H), 7.45 (dd, 1H),
7.38-7.35 (m, 2H), 7.32 (dd, 1H), 6.76 (m, 2H), 4.96 (s, 2H), 4.79
(s, 2H), 4.42 (s, 2H), 3.7 (s, 1H), 2.60 (s, 3H), 1.02 (s, 9H).
Example 25
Synthesis of
3-{5-Hydroxymethyl-2-methyl-4-[(2'-sulfamoyl-biphenyl-4-ylamino)-methyl]--
pyridin-3-yloxymethyl}-benzamidine (25)
[0156] ##STR40## Compound (25) was prepared according to the
procedure described in Example 14 from (24) (62 mg, 0.11 mmol). The
crude mixture was purified by column chromatography over silica gel
using a dichloromethane/methanol (gradient from 19:1 to 4:1)
mixture as eluant to give 5 mg, (9%) of (25). The major product (33
mg, 56%) was the corresponding benzimidic acid methyl ester (MS m/z
(ES.sup.+): 547.42 (M+H.sup.+)) as determined by MS.
[0157] .sup.1H-NMR (CD.sub.3OD): .delta. 8.12 (s, 1H), 7.88 (dd,
1H), 7.75 (br s, 1H), 7.58 (dd, 1H), 7.55 (dd, 1H), 7.44-7.37 (m,
2H), 7.29 (dt, 1H), 7.12 (dd, 1H), 7.04 (d, 2H), 6.55 (d, 2H), 4.92
(s, 2H), 4.58 (s, 2H), 4.21 (s, 2H), 2.4 (s, 3H). MS m/z
(ES.sup.+): 532.43 (M+H.sup.+).
Example 26
Synthesis of
3'-[(3-Hydroxy-5-hydroxymethyl-2-methyl-pyridin-4-ylmethyl)-amino]-biphen-
yl-2-sulfonic acid tert-butylamide (26)
[0158] ##STR41## Compound (26) was prepared according to the
procedure described in Example 17 from (19) (1 g, 3.3 mmol) and
pyridoxal hydrochloride (802 mg, 3.9 mmol). The crude product was
purified by column chromatography over silica gel using a
dichloromethane/methanol (9:1) mixture as eluant to give 389 mg
(26%) of (26).
[0159] .sup.1H-NMR (CDCl.sub.3): .delta. 8.15 (dd, 1H), 7.88 (s,
1H), 7.53 (t, 1H), 7.49 (t, 1H), 7.35-7.27 (m, 2H), 7.1 (s, 1H),
6.98 (d, 1H), 6.88 (d, 1H), 4.65 (s, 2H), 4.61 (s, 2H), 2.42 (s,
3H), 1.01 (s, 9H).
Example 27
Synthesis of
3'-{[3-(4-Cyano-benzyloxy)-5-hydroxymethyl-2-methyl-pyridin-4-ylmethyl]-a-
mino}-biphenyl-2-sulfonic acid tert-butylamide (27)
[0160] ##STR42## Compound (27) was prepared according to the
procedure described in Example 13 from (7) (184 mg, 0.4 mmol) and
.alpha.-bromo-p-tolunitrile (87 mg, 0.44 mmol). The crude mixture
was purified by column chromatography over silica gel using a
dichloromethane/methyl alcohol (9:1) mixture to furnish 118 mg
(51%) of (27).
[0161] .sup.1H-NMR (CDCl.sub.3): .delta. 8.27 (s, 1H), 8.14 (dd,
1H), 7.63 (d, 2H), 7.59-7.47 (m, 2H), 7.53 (d, 2H), 7.3 (dd, 1H),
7.23 (d, 1H), 7.0 (m, 1H), 6.79 (d, 1H), 6.7 (dd, 1H), 4.96 (s,
2H), 4.73 (s, 2H), 4.43 (s, 2H), 3.74 (s, 1H), 2.54 (s, 3H), 0.95
(s, 9H).
Example 28
Synthesis of
4-{5-Hydroxymethyl-2-methyl-4-[(2'-sulfamoyl-biphenyl-3-ylamino)-methyl]--
pyridin-3-yloxymethyl}-benzamidine (28)
[0162] ##STR43## Compound (28) was prepared according to the
procedure described in Example 14 from (27) (103 mg, 0.18 mmol).
The crude mixture was purified by column chromatography over silica
gel using a dichloromethane/methanol (gradient from 9:1 to 1:1)
mixture as eluant to provide 54 mg (56%) of (28).
[0163] .sup.1H-NMR (CD.sub.3OD): .delta. 8.28 (s, 1H), 8.08 (dd,
1H), 7.77 (d, 2H), 7.66 (d, 2H), 7.56 (dt, 1H), 7.5 (dt, 1H), 7.29
(dd, 1H), 7.15 (t, 1H), 6.79 (t, 1H), 6.72-6.69 (m, 2H), 5.08 (s,
2H), 4.76 (s, 2H), 4.37 (s, 2H), 2.53 (s, 3H). MS m/z (ES.sup.+):
532.37 (M+H.sup.+).
Example 29
Synthesis of
4'-{[3-(4-Cyano-benzyloxy)-5-hydroxymethyl-2-methyl-pyridin-4-ylmethyl]-a-
mino}-3'-fluoro-biphenyl-2-sulfonic acid tert-butylamide (29)
[0164] ##STR44## Compound (29) was prepared according to the
procedure described in Example 13 from (9) (137 mg, 0.29 mmol) and
.alpha.-bromo-p-tolunitrile (62 mg, 0.45 mmol). The crude mixture
was purified by column chromatography over silica gel using a
dichloromethane/methyl alcohol (19:1) mixture as eluant to give 94
mg (55%) of (29).
[0165] .sup.1H-NMR (CD.sub.3OD): .delta. 8.28 (s, 1H), 8.07 (dd,
1H), 7.97 (br s, 1H), 7.71 (d, 2H), 7.63 (d, 2H), 7.58 (dt, 1H),
7.47 (dt, 1H), 7.32 (dd, 1H), 7.12 (dd, 1H), 7.04 (dd, 1H), 6.87
(t, 1H), 5.07 (s, 2H), 4.77 (s, 2H), 4,47 (s, 2H), 2.54 (s, 3H),
0.98 (s, 9H).
[0166] .sup.19F-NMR (CD.sub.3OD; .sup.1H-decoupled): .delta.
-137.9.
Example 30
Synthesis of
4-{4-[(3-Fluoro-2'-sulfamoyl-biphenyl-4-ylamino)-methyl]-5-hydroxymethyl--
2-methyl-pyridin-3-yloxymethyl}-benzamidine (30)
[0167] ##STR45## Compound (30) was prepared according to the
procedure described in Example 14 from (29) (65 mg, 0.11 mmol). The
crude mixture was purified by column chromatography over silica gel
using a dichloromethane/methanol (9:1) mixture as eluant to give 41
mg (84%) of (30).
[0168] .sup.1H-NMR (MeOH-d.sub.4): .delta. 8.29 (s, 1H), 8.07 (dd,
1H), 7.81 (d, 2H), 7.69 (d, 1H), 7.58 (dt, 1H), 7.49 (dt, 1H), 7.3
(dd, 1H), 7.08 (dd, 1H), 7.04 (dd, 1H), 6.85 (t, 1H), 5.12 (s, 2H),
4.78 (s, 2H), 4.47 (s, 2H), 2.57 (s, 3H).
[0169] .sup.19F-NMR (CD.sub.3OD; .sup.1H-decoupled): 6-137.8. MS
m/z (ES.sup.+): 550.56 (M+H.sup.+).
Example 31
Synthesis of
2-{6-[(5-Hydroxy-4-hydroxymethyl-6-methyl-pyridin-3-ylmethyl)-amino]-pyri-
din-3-yl}-benzenesulfonamide (31)
[0170] ##STR46## Compound (31) was prepared from (12) (90 mg, 0.2
mmol) following the procedure described in Example 3. The crude
mixture was purified by column chromatography over silica gel using
a dichloromethane/methanol (9:1) mixture as eluant to furnish 19 mg
(24%) of (31).
[0171] .sup.1H-NMR (CD.sub.3OD): .delta. 7.94 (d, 1H), 7.89 (s,
1H), 7.81 (s, 1H), 7.45 (m, 4H), 7.22 (dd, 1H), 6.51 (d, 1H), 4.87
(s, 2H), 4.44 (s, 2H), 2.31 (s, 3H).
Example 32
Synthesis of
3'-[(3-Hydroxy-5-hydroxymethyl-2-methyl-pyridin-4-ylmethyl)-amino]-biphen-
yl-2-sulfoniamide (32)
[0172] ##STR47## This compound was prepared from compound (26) (100
mg, 0.22 mmol) according to the procedure described for Example 3.
The crude mixture was purified by column chromatography over silica
gel using a dichloromethane/methanol (9:1) mixture as eluant. to
provide 80 mg, (91%) of (32).
[0173] .sup.1H-NMR (CD.sub.3OD): .delta. 8.08 (dd, 1H), 7.86 (s,
1H), 7.59 (dt, 1H), 7.5 (dt, 1H), 7.32 (dd), 7.24 (dt, 1H),
6.88-6.83 (m, 3H), 4.70 (s, 2H), 4.53 (s, 2H), 2.4 (s, 2H).
Example 33
Inhibition of Platelet Aggregation
[0174] Platelet rich plasma (PRP) was obtained by drawing whole
blood from normal human donors (not on any medication) into sodium
citrate tubes (3.2%), and centrifuging at 160.times.g for about 10
minutes. Platelet poor plasma (PPP) was obtained by centrifuging
the remainder of the sample after the platelets were removed at
800.times.g for about 10 minutes. The PRP was adjusted to a count
of 280.times.10.sup.9/L using a mixture of PRP and PPP. The
platelets (200 .mu.L) were incubated with the test compounds (25
.mu.L) adjusted to various concentrations (from a 250 .mu.M stock
solution) for about 30 minutes at room temperature (approximate
final platelet count in the incubation mixture of
250.times.10.sup.9/L). The samples were incubated for about 3
minutes at about 37.degree. C., and then transferred to the mixing
wells of a Chrono-log 4 channel aggregometer (Chrono-log Corp.,
Havertown, Pa.). After baselines were established, the agonist (25
.mu.L of 40 .mu.M ADP (Sigma, St. Louis, Mo.) or 25 .mu.L of 50
.mu.g/mL and 10 .mu.g/mL collagen (Helena Laboratories, Beaumont,
Tex.) or 25 .mu.L of 120 .mu.M thrombin receptor activating peptide
(TRAP) (Sigma)) was then added. Aggregation was monitored for 5
minutes at 37.degree. C. with stirring (1000 rpm). The amplitude
and slope of each tracing were calculated to determine the amount
of aggregation. Control samples were performed using only solvent.
The % reduction in aggregation was calculated for each sample
compared to the proper solvent control. See Table 1. TABLE-US-00001
TABLE 1 Platelet inhibition % Reduction in Aggregation
Concentration Collagen Collagen ADP TRAP Compound (.mu.M) (5
.mu.g/mL) (1 .mu.g/mL) (4 .mu.M) (12 .mu.M) 3 250 5 0 0 6 6 250 0 5
0 1 14 250 5 15 10 9 16 250 0 14 3 1.3 18 250 9 23 50 74 21 250 0 4
14 0 28 250 15 10 26 11 30 100 19 57 23 57 33 500 15 5 4 1 34 250 1
41 63 93
Compound 33 is Compound XXXV in U.S. Pat. No. 6,417,204 B1, which
is hereby incorporated by reference, and compound 34 is Compound XL
in U.S. Pat. No. 6,417,204 B1 ##STR48##
Example 34
Inhibition of Serine Proteases
[0175] Compounds were evaluated for inhibition of serine protease
activity.
Methods
[0176] The enzymes factor Xa (fXa), thrombin (factor IIa or fIIa),
and trypsin were purchased from Haematologic Technologies Inc.
(Essex Junction, Vt.). The substrates Pefachromes Xa, Th, and Try
were purchased from Centerchem Inc. (Stamford, Conn.). Varying
concentrations of the sulfonamide compounds were incubated for 30
min at room temperature with purified activated human enzyme in the
appropriate buffer. Various concentrations of the corresponding
synthetic substrate were added, and activity was measured at
37.degree. C. by monitoring absorbance at 405 nm for 15 min with a
Flurostar Optima plate reader. Each assay had a final volume of 200
.mu.L, and assays were performed in 96-well plates. For IC.sub.50
determinations, 300 .mu.M of substrate was tested against five
concentrations (50, 100, 200, 300, and 500 .mu.M) of test compound
plus control (run in duplicate). For controls, the appropriate
percentage of solvent was used instead of test compound. The
specific activity (.DELTA.A.sub.405/min/nM protein), and the
percent activity was calculated for each data point. The IC.sub.50
was calculated by linear regression of log[test compound] vs. %
activity. The enzyme activity of the sulfonamide compound was
determined using the Enzyme Kinetics Module of Sigmaplot 8.0 (SPSS
Inc.)
[0177] The final concentration of human Factor Xa was 2 nM in a
Tris/NaCl buffer (pH 7.5) containing 0.25% (w/v) polyethylene
glycol (MW 8000). The substrate employed was Pefachrome Xa.
[0178] The final concentration of human thrombin was 2 nM in a
Tris/NaCl buffer (pH 8.3) containing 0.125% (w/v) bovine serum
albumin. The substrate used was Pefachrome Th.
[0179] The final concentration of human trypsin was 2 nM in a
Tris/NaCl buffer (pH 7.5) containing 0.25% (w/v) bovine serum
albumin and 20 .mu.M CaCl.sub.2. The substrate used was Pefachrome
Try.
[0180] The serine protease activity (fXa, fIIa and trypsin) of the
pyridoxine sulfonamides (Table 2) showed that some of these
compounds may serve as compounds with improved anticoagulant
(possibly anti-fxa) properties. Compounds 3, 8, 31, and 32 were
virtually inactive against all three serine proteases (>1000
.mu.M). Unexpectedly, the N-blocked sulfonamides 2, 7, and 12
displayed some enhanced, albeit low, inhibition of fXa activity
over their deprotected counterparts 3, 8, and 31, respectively. An
exception to this was noted in the case where the linker contained
an amide as exemplified by compounds 5 and 6, where both the
N-protected and free sulfonamide showed similar fXa activity. As
could be expected, significant improvement in inhibition of flia
and especially fXa activity was observed upon incorporation of the
basic benzamidine moiety that is anticipated to interact with Asp
189 in the S1 pocket. For the pyridoxine scaffold described herein,
the 4-position biaryl isomer (compound 25) displayed similar
overall inhibitory properties when compared to the corresponding
5-position biaryl isomers (e.g., compound 14), with a slight
improvement in inhibition of fXa activity observed with the former.
However, neither of these arrangements showed significant
improvements in terms of selectivity over trypsin. Also, insertion
of a carbonyl improved inhibition of fIIa activity (see 23 versus
14). TABLE-US-00002 TABLE 2 Inhibition of serine protease (fXa,
fIIa and Trypsin) activity by sulfonamides Compound IC.sub.50 (fXa)
(.mu.M) IC.sub.50 (fIIa) (.mu.M) IC.sub.50 (Trypsin) (.mu.M) 2 329
>1000 >1000 3 >1000 >1000 >1000 5 362 >1000
>1000 6 306 >1000 >1000 7 197 >1000 >1000 8 >1000
>1000 >1000 12 317 >1000 >1000 14 15 862 12 16 11
>1000 11 18 32 370 43 21 326 >1000 >1000 23 5 97 24 25 4
>1000 15 28 17 476 3 30 18 171 4 31 >1000 >1000 >1000
32 >1000 >1000 >1000 33 105 300 18 34 29 >1000 4
* * * * *