Acid derivatives useful as serine protease inhibitors

Details Acid derivatives useful as serine protease inhibitors Acid derivatives useful as serine protease inhibitors

2001-11-07

2003-11-04

Davis, Zinna Northington (Department: 1625)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Having -c-, wherein x is chalcogen, bonded directly to...

C514S338000, C514S354000, C546S143000, C546S273400, C546S323000

Reexamination Certificate

active

06642252

ABSTRACT:

FIELD OF THE INVENTION
The present invention relates to acid derivatives that are inhibitors of serine proteases such as Factor VIIa, Factor IXa, Factor Xa, Factor FXIa, tryptase, and urokinase. These acid derivatives are useful as anticoagulants in treating and preventing cardiovascular diseases, as anti-inflammatory agents, and as metastasis inhibitors in treating cancer.
BACKGROUND OF THE INVENTION
Under normal conditions, the coagulation system is naturally balanced in favor of anticoagulation by a number of proteins circulating in the blood. These proteins include antithrombin III, a serine-protease inhibitor, and protein C, a vitamin-K dependent protein formed in the liver. When injury or trauma occurs, thrombin is produced at precise levels through an ordered series of reactions. Thrombin is a proteolytic enzyme that occupies a central position in the coagulation process. Thrombin catalyzes the conversion of fibrinogen to fibrin, is a key effector enzyme for blood clotting, and also is pivotal for other functions, such as activation of helper proteins (including Factors V and VIII and thrombomodulin), and its own activation. Disturbances in the natural balance between pro- and anti-coagulant forces may result in bleeding or thrombotic diseases.
The series of reactions leading to thrombin production involve a number of coagulation factors present in the blood as precursors (e.g., Factors VII-XII). When the coagulation system is triggered (e.g., when trauma occurs), the coagulation factors are transformed into activated factors (e.g., Factors VIIa, IXa, Xa, XIa, etc.). Factor VII forms a complex with a membrane protein called tissue factor, to which Factor VIIa tightly binds. Thus, Factor VIIa is present as a complex bound to tissue factor. When triggered, the coagulation factors and tissue factor complexes undergo an ordered chain of reactions that ultimately lead to conversion of Factor X to Factor Xa, and Factor Xa catalyzes the conversion of prothrombin to thrombin.
An elevated plasma level of coagulation factors, particularly Factor VIIa, is a risk factor for fatal myocardial infarction and associated with coronary artery disease and other abnormalities of the coagulation system, e.g., thrombosis, ischemic vascular disease, intravascular clotting, stroke, embolisms, and so forth. Accordingly, antithrombotic agents have been researched and developed for use in treating cardiovascular and other diseases. Presently established antithrombotic agents include heparin, coumarin, and aspirin, among others. There are, however, limitations with these agents. For example, both heparin and coumarin have a highly-variable dose-related response, and their anticoagulant effects must be closely monitored to avoid a risk of serious bleeding. The erratic anticoagulant response of heparin is likely due to its propensity to bind non-specifically to plasma proteins. Aspirin has a limited efficacy and at high doses presents a risk of gastrointestinal bleeding. Thrombin inhibitors and their drawbacks are further discussed in WO 96/20689 to duPont Merck Pharmaceutical Co.
As may be appreciated, those in the field of pharmaceutical research continue to seek to develop new compounds and compositions having increased effectiveness and bioavailability and/or having fewer side effects. See, e.g., Jakobsen et al., “
Inhibitors of the Tissue Factor/Factor VIIa
-
induced Coagulation: Synthesis and In vitro Evaluation of Novel Specific
2-
aryl Substituted
4
H
-3,1-
benzoxazin
-4-
ones,” Bioorganic
&
Medicinal Chemistry
, Vol. 8 (August 2000), at pp. 2095-2103; and J. Hirsh et al., “
Thrombosis, New Antithrombotic Agents,” Lancet,
Vol. 353 (Apr. 24, 1999), at pp. 1431-36. There is particularly an interest in developing agents that can selectively and directly inhibit key factors in the complicated coagulation process. Compounds effective in inhibiting Factor Xa are described in U.S. Pat. application Ser. No. 09/478,632, filed Jan. 6, 2000, Ser. No. 09/633,751, filed Aug. 7, 2000, and Ser. No. 09/496,571, filed Feb. 2, 2000. Compounds effective in inhibiting Factors VIIa, Xa, as well as tryptase and urokinase are described in U.S. patent application Ser. No. 09/458,847, filed Dec. 13, 1999. The above referenced '632, '751, '571, and '847 applications show lactam compounds and are each assigned to the present assignee with common inventors herewith. Factor Xa inhibitors are also disclosed in PCT applic. WO 98/57937 to the duPont Merck Pharmaceutical Co.
PCT patent application WO 99/41231 to Ono Pharmaceuticals Inc., (“Ono”) discloses a series of amidino derivatives such as 2-(3-(4-amidinophenylcarbamoyl)-naphthalen-2-yl)-5-((2,2-methylpropyl)carbamoyl benzoic acid, which are claimed to be Factor VIIa inhibitors. The Ono application is discussed in Kohrt et al., “
An Efficient Synthesis of
2-(3-(4-
Amidinophenylcarbamoyl
)
naphthalen
-2-
yl
)-5-((2,2-
methylpropyl
)
carbamoyl benzoic acid: a Factor VIIa Inhibitor Discovered by the Ono Pharmaceutical Company,” Tetrahedron Letters,
Vol. 41 (June 2000), at pp. 6041-44, which reports that Ono fails to fully describe an effective method for making the titled compound. Inhibitors of Factor VIIa are also reported in WO 01/44172 to Axys Pharm. Inc. PCT patent application WO 98/47876 to Akzo Novel N. V., published Oct. 29, 1998, discloses certain bicyclic groups such as isoquinoline groups which reportedly are advantageous for promoting pharmacological properties, and isoquinoline-containing compounds are disclosed in WO 94/29273 to SmithKline Beecham Corp. Biphenyl compounds and/or acid substituted bicyclic compounds are also disclosed in U.S. Pat. Nos. 5,612,341, 6,248,767 B1, 3,995,045, EP patent application 0 206 567 A2 to Warner Lambert Co., and WO 01/70678 to Merck Patent GmbH.
The patents, patent applications, and articles cited above are incorporated herein by reference.
The present invention provides acid-based compounds useful as inhibitors of Factor VIIa, Factor IXa, Factor Xa, Factor FXIa, tryptase, and urokinase.
SUMMARY OF THE INVENTION
Acid derivatives are provided that are inhibitors of serine proteases having the Formula I:
or pharmaceutically-acceptable salts, hydrates or prodrugs thereof, wherein:
W is selected from C
2-10
alkyl, C
2-10
alkenyl, substituted C
2-10
alkyl, substituted C
2-10
alkenyl, —C(═O)NR
4
R
5
, —OR
6
, —CO
2
R
4
, —C(═O)R
4
, —SR
4
, —S(O)
p
R
4
, —NR
4
R
5,
—NR
4
SO
2
R
5
, —NR
4a
SO
2
NR
4
R
5,
—NR
4
CO
2
R
5
, —NR
4
C(═O)R
5
, —NR
4a
C(═O)NR
4
R
5,
—SO
2
NR
4
R
5
, heterocyclo, heteroaryl, aryl, and cycloalkyl;
ring B is phenyl or pyridyl;
X
2
is N, CH, or C, provided that X
2
is C when R
1
and R
2
join to form a fully unsaturated ring;
L is —(CR
18
R
19
)
s
—Y—(CR
18a
R
19a
)
t
;
Y is selected from —C(═O), —C(═O)NR
13
—, —NR
13
C(═O)—, —NR
13
CR
14
R
15
—, —CR
14
R
15
—NR
13
—, and —CR
13
R
14
—CR
15
R
16
—;
Z is a 5 to 7-membered monocyclic or 8 to 11-membered bicyclic aryl, heteroaryl, heterocyclo, or cycloalkyl, wherein each Z group is optionally substituted with up to two R
20
and/or up to one R
21
, except Z is not phenyl substituted with phenyloxy when W is methoxy, s is 0 and Y is —CH
2
—CH
2
—;
R
1
and R
2
(i) are independently selected from hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, heteroaryl, aryl, heterocyclo, and cycloalkyl; or (ii) are taken together to form an aryl, heteroaryl, cycloalkyl, or heterocyclo, provided that R
1
and R
2
do not together form pyrazole when W is methoxy and Z is biphenyl; and when R
1
and R
2
individually or together form a heteroaryl, aryl, heterocyclo, or cycloalkyl, said cyclic group is optionally substituted with up to three R
26
;
R
3
is hydrogen, alkyl, substituted alkyl, heteroaryl, aryl, heterocyclo, cycloalkyl, or alkyl substituted with —OC(═O)R
24
or —OC(═O)OR
24
, wherein R
24
is alkyl, substituted alkyl, or cycloalkyl, provided that R
3
is not phenyl when W is methoxy;
R
4,
R
4a,
R
5
and R
6
are (i) independently selected from hydrogen, alkyl, substit

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