Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Nitrogen containing other than solely as a nitrogen in an...
Reexamination Certificate
1999-03-30
2002-02-19
Shah, Mukund J. (Department: 1624)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Nitrogen containing other than solely as a nitrogen in an...
Reexamination Certificate
active
06348504
ABSTRACT:
FIELD OF THE INVENTION
The present invention relates generally to oxime ethers which are useful as antagonists of the platelet glycoprotein IIb/IIIa fibrinogen receptor complex, to pharmaceutical compositions containing such compounds, processes for preparing such compounds, and to methods of using these compounds for the inhibition of platelet aggregation, as thrombolytics, and/or for the treatment of thromboembolic disorders.
BACKGROUND OF THE INVENTION
Hemostasis is the normal physiological process in which bleeding from an injured blood vessel is arrested. It is a dynamic and complex process in which platelets play a key role. Within seconds of vessel injury, resting platelets become activated and are bound to the exposed matrix of the injured area by a phenomenon called platelet adhesion. Activated platelets also bind to each other in a process called platelet aggregation to form a platelet plug. The platelet plug can stop bleeding quickly, but it must be reinforced by fibrin for long-term effectiveness, until the vessel injury can be permanently repaired.
Thrombosis may be regarded as the pathological condition wherein improper activity of the hemostatic mechanism results in intravascular thrombus formation. Activation of platelets and the resulting platelet aggregation and platelet factor secretion has been associated with a variety of pathophysiological conditions including cardiovascular and cerebrovascular thromboembolic disorders, for example, the thromboembolic disorders associated with unstable angina, myocardial infarction, transient ischemic attack, stroke, atherosclerosis and diabetes. The contribution of platelets to these disease processes stems from their ability to form aggregates, or platelet thrombi, especially in the arterial wall following injury.
Platelets are activated by a wide variety of agonists resulting in platelet shape change, secretion of granular contents and aggregation. Aggregation of platelets serves to further focus clot formation by concentrating activated clotting factors at the site of injury. Several endogenous agonists including adenosine diphosphate (ADP), serotonin, arachidonic acid, thrombin, and collagen, have been identified. Because of the involvement of several endogenous agonists in activating platelet function and aggregation, an inhibitor which acts against all agonists would represent a more efficacious antiplatelet agent than currently available antiplatelet drugs, which are agonist-specific.
Current antiplatelet drugs are effective against only one type of agonist; these include aspirin, which acts against arachidonic acid; ticlopidine, which acts against ADP; thromboxane A
2
synthetase inhibitors or receptor antagonists, which act against thromboxane A
2
; and hirudin, which acts against thrombin.
Recently, a common pathway for all known agonists has been identified, namely platelet glycoprotein IIb/IIIa complex (GPIIb/IIIa), which is the membrane protein mediating platelet aggregation. A recent review of GPIIb/IIIa is provided by Phillips et al.
Cell
(1991) 65: 359-362. The development of a GPIIb/IIIa antagonist represents a promising new approach for antiplatelet therapy.
GPIIb/IIIa on unstimulated platelets does not bind soluble proteins, but GPIIb/IIIa on activated platelets is known to bind four soluble adhesive proteins, namely fibrinogen, von Willebrand factor, fibronectin, and vitronectin. The binding of fibrinogen and von Willebrand factor to GPIIb/IIIa causes platelets to aggregate. The binding of fibrinogen is mediated in part by the Arg-Gly-Asp (RGD) recognition sequence which is common to the adhesive proteins that bind GPIIb/IIIa.
Several RGD-peptidomimetic compounds have been reported which block fibrinogen binding and prevent the formation of platelet thrombi.
European Patent Application Publication Number 478363 relates to compounds having the general formula:
European Patent Application Publication Number 478328 relates to compounds having the general formula:
European Patent Application Publication Number 525629 (corresponds to Canadian Patent Application Publication Number 2,074,685) discloses compounds having the general formula:
PCT Patent Application 9307867 relates to compounds having the general formula:
European Patent Application Publication Number 512831 relates to compounds having the general formula:
Copending commonly assigned U.S. patent application (U.S. Ser. No. 08/337,920, filed Nov. 10, 1994, Wityak et al.; published as WO95/13155, Jun. 1, 1995) discloses compounds having the general formula:
which are useful as IIB/IIIA antagonists.
Copending commonly assigned U.S. patent application (U.S. Ser. No. 08/455,768, filed May 31, 1995, Voss et al.) discloses compounds having the general formula:
which are useful as a
v
b
3
antagonists.
None of the above references teaches or suggests the compounds of the present invention which are described in detail below.
SUMMARY OF THE INVENTION
One aspect of this invention provides novel compounds of Formula I (described below) which are useful as antagonists of the platelet glycoprotein IIb/IIIa complex. The compounds of the present invention inhibit the binding of fibrinogen to platelet glycoprotein IIb/IIIa complex and inhibit the aggregation of platelets. The present invention also includes pharmaceutical compositions containing such compounds of Formula I, and methods of using such compounds of Formula I, and methods of using such compounds for the inhibition of platelet aggregation, as thrombolytics, and/or for the treatment of thromboembolic disorders.
The present invention also includes methods of treating cardiovascular disease, thrombosis or harmful platelet aggregation, reocclusion following thrombolysis, reperfusion injury, or restenosis by administering a compound of Formula I alone or in combination with one or more additional therapeutic agents selected from: anti-coagulants such as warfarin or heparin; anti-platelet agents such as aspirin, piroxicam or ticlopidine; thrombin inhibitors such as boroarginine derivatives, hirudin or argatroban; or thrombolytic agents such as tissue plasminogen activator, anistreplase, urokinase or streptokinase; or combinations thereof.
Also included in the present invention are pharmaceutical kits comprising one or more containers containing pharmaceutical dosage units comprising a compound of Formula I, for the treatment of cell adhesion related disorders, including but not limited to thromboembolic disorders.
DETAILED DESCRIPTION OF THE INVENTION
This invention relates to novel compounds of Formula I
and pharmaceutically acceptable salt or prodrug forms thereof, wherein:
B is selected from
R
2
(R
2a
)N—,
R
2
HN(R
2a
N═)C—
R
2
HN(R
2a
N═)CNH—
Z
1
and Z
2
are independently selected from
a single bond,
C
1
-C
6
alkylene, optionally substituted by R
2b
,
C
2
-C
6
alkenylene, optionally substituted by R
2b
,
C
2
-C
6
alkynylene, optionally substituted by R
2b
;
wherein any carbon atom in each alkylene, alkenylene or alkynylene chain may optionally be replaced with O, S(O)
0-2
or NR
7
, with the proviso that O, S(O)
0-2
or NR
7
when present are adjacent to saturated or aromatic carbon atoms;
V is selected from
a single bond,
1,4-phenylene;
wherein 1-2 carbon atoms in the phenylene may be optionally replaced with N and wherein said phenylene or azaphenylene group is optionally substituted with 1-2 R
5
substituents; provided that
B, Z
1
, Z
2
and V are chosen such that the oxime carbon in Formula I is not directly connected to an
oxygen, sulfur or nitrogen atom of B, Z
1
or Z
2
;
L is a C
1
-C
4
alkylene chain, C
3
-C
4
alkenylene chain or
C
3
-C
4
alkynylene chain optionally substituted with
C
1
-C
4
alkyl,
C
3
-C
7
cycloalkyl,
C
4
-C
8
cycloalkylalkyl,
aryl,
arylmethyl,
heteroaryl,
heteroarylmethyl,
R
1
is selected from
H,
C
1
-C
6
alkyl, substituted with 0-2 R
6
,
C
3
-C
7
cycloalkyl, substituted with 0-2 R
6
,
aryl, wherein aryl is as defined above;
R
2
is selected from
H,
C
1
-C
6
alkyl,
C
3
-C
7
cycloalkyl,
C
4
-C
8
cycloalkylalkyl,
arylmethyl;
R
2a
is selec
Frietze William E.
Olson Richard E.
Dolan Peter L.
Patel Sudhaker B.
Reinert Norbert F.
Shah Mukund J.
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