Platelet ADP receptor inhibitors

Details Platelet ADP receptor inhibitors Platelet ADP receptor inhibitors

1999-01-07

2003-12-23

Ford, John M. (Department: 1624)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Heterocyclic carbon compounds containing a hetero ring...

C544S009000, C544S006000

Reexamination Certificate

active

06667306

ABSTRACT:

FIELD OF THE INVENTION
The invention relates to novel heterocycles containing aminobenzothiazole and aminobenzoxazole derivatives which are effective platelet ADP receptor inhibitors. These derivatives may be used in various pharmaceutical compositions. In particular, the derivatives may be used in pharmaceutical compositions effective for the prevention and/or treatment of cardiovascular diseases, particularly those diseases related to thrombosis.
DESCRIPTION OF THE RELATED ART
Thrombotic complications are a major cause of death in the industrialized world. Examples of these complications include acute myocardial infarction, unstable angina, chronic stable angina, transient ischemic attacks, strokes, peripheral vascular disease, preeclampsia/eclampsia, deep venous thrombosis, embolism, disseminated intravascular coagulation and thrombotic cytopenic purpura. Thrombotic and restenotic complications also occur following invasive procedures, e.g., angioplasty, carotid endarterectomy, post CABG (coronary artery bypass graft) surgery, vascular graft surgery, stent placements and insertion of endovascular devices and protheses. It is generally thought that platelet aggregates play a critical role in these events. Blood platelets, which normally circulate freely in the vasculature, become activated and aggregate to form a thrombus with disturbed blood flow caused by ruptured atherosclerotic lesions or by invasive treatments such as angioplasty, resulting in vascular occlusion. Platelet activation can be initiated by a variety of agents, e.g., exposed subendothelial matrix molecules such as collagen, or by thrombin which is formed in the coagulation cascade.
An important mediator of platelet activation and aggregation is ADP (adenosine 5′-diphosphate) which is released from blood platelets in the vasculature upon activation by various agents, such as collagen and thrombin, and from damaged blood cells, endothelium or tissues. ADP activates platelets through specific platelet ADP receptors, sometimes referred to as P
2T
receptors (Hourani et al.,
Trends Pharmacol. Sci.
15, 103 (1994); Savi et al.,
Med Res. Rev.
16, 159 (1996); Mills,
Thromb. Hemost.
76, 835 (1996); Gachet et al.,
Thromb. Hemost.
78, 271 (1997)). This results in the recruitment of more platelets and stabilization of existing platelet aggregates. Platelet ADP receptors mediating aggregation are activated by ADP and some of its derivatives and antagonized by ATP (adenosine 5′-triphosphate) and some of its derivatives. Therefore, platelet ADP receptors are members of the family of P2 receptors activated by purine and/or pyrimidine nucleotides (Harden et al.,
Annu. Rev. Pharmacol. Toxicol.
35, 541 (1995); North et al.,
Curr. Opin. Neurobiol.
7, 346 (1997)). Studies of inherited disorders in humans and rats which result in a reduction of ADP release from platelets or reduced ADP receptor number and signaling confirm the critical role in platelet aggregation of ADP and the ADP receptor itself. Potent inhibitors of ADP-induced platelet aggregation therefore might be useful as antithrombotic drugs.
Various directly or indirectly acting synthetic inhibitors of ADP-dependent platelet aggregation with antithrombotic activity have been reported. The orally active antithrombotic thienopyridines ticlopidine and clopidogrel inhibit ADP-induced platelet aggregation, binding of radiolabeled ADP receptor agonist 2-methylthioadenosine 5′-diphosphate to platelets, and other ADP-dependent events indirectly, probably via formation of an unknown metabolite, in humans or animals (Savi et al.,
Med. Res. Rev.
16, 159 (1996)). Some derivatives of the endogenous antagonist ATP, e.g., ARL (formerly FPL) 67085, are selective platelet ADP receptor antagonists which inhibit ADP-dependent platelet aggregation and are effective in animal thrombosis models (Mills,
Thromb. Hemost.
76, 835 (1996); Humphries et al.,
Trends Pharmacol. Sci.
16, 179 (1995); WO 92/17488)). Derivatives of P
1
,P
4
-diadenosine 5′, 5′″-P
1
,P
4
-tetraphosphate have also been reported to both inhibit ADP-dependent platelet aggregation in vitro and thrombosis in animal models (Kim et al.,
Proc. Natl. Acad. Sci. USA
89, 11056 (1992); Chan et al.,
Proc. Natl. Acad Sci. USA
94, 4034 (1997); U.S. Pat. No. 5,681,823; WO 89/04321).
Despite these compounds, there exists a need for more effective platelet ADP receptor inhibitors. In particular, there is a need for platelet ADP receptor inhibitors having antithrombotic activity that are useful in the prevention and/or treatment of cardiovascular diseases, particularly those related to thrombosis.
SUMMARY OF THE INVENTION
The invention provides compounds of formula (I):
In another aspect, the invention provides pharmaceutical compositions for preventing or treating thrombosis in a mammal containing a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier. The invention further provides a method for preventing or treating thrombosis in a mammal by administering a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof.
DETAILED DESCRIPTION OF THE INVENTION
1. Definitions
In accordance with the invention and as used herein, the following terms are defined with the following meanings, unless explicitly stated otherwise.
The term “C
1
-C
6
alkyl” as used herein refers to a straight or branched hydrocarbon containing one to six carbon atoms.
The term “C
3
-C
8
cycloalkyl” as used herein refers to a cyclic aliphatic hydrocarbon containing three to eight carbon atoms.
The term “phenyl” as used herein refers to a six carbon containing aromatic ring which can be variously mono- or poly-substituted with H, C
1
-C
6
alkyl, hydroxyl, C
1
-C
6
alkoxy, amino, mono-C
1
-C
6
alkylamino, di-C
1
-C
6
alkylamino, nitro, fluoro, chloro, bromo, iodo, hydroxycarbonyl, or C
1
-C
6
alkoxycarbonyl.
The term “C
1
-C
6
alkoxy” as used herein refers to an ether moiety whereby the oxygen is connected to a straight or branched chain of carbon atoms of the number indicated.
The term “phenoxy” as used herein refers to an ether moiety whereby the oxygen is connected to a phenyl substituent, the latter being defined as above.
The term “mono-C
1
-C
6
alkylamino” as used herein refers to an amino moiety whereby the nitrogen is substituted with one H and one C
1
-C
6
alkyl substituent, the latter being defined as above.
The term “di-C
1
-C
6
alkylamino” as used herein refers to an amino moiety whereby the nitrogen is substituted with two C
1
-C
6
alkyl substituents as defined above.
The term “monoarylamino” as used herein refers to an amino moiety whereby the nitrogen is substituted with one H and one aryl substituent, such as a phenyl, the latter being defined as above.
The term “diarylamino” as used herein refers to an amino moiety whereby the nitrogen is substituted with two aryl substituents, such as phenyl, the latter being defined as above.
The term “C
1
-C
6
alkylsulfonyl” as used herein refers to a dioxosulfur moiety with the sulfur atom also connected to one C
1
-C
6
alkyl substituent, the latter being defined as above.
The term “C
1
-C
6
alkoxycarbonyl” as used herein refers to a hydroxycarbonyl moiety whereby the hydrogen is replaced by a C
1
-C
6
alkyl substituent, the latter being defined as above.
The term “heterocyclic group” as used herein refers to any saturated or unsaturated mono- or bicyclic ring system, containing from one to five heteroatoms. Each heteroatom may independently be nitrogen, oxygen or sulfur. Examples of suitable heterocyclic groups include, but are not limited to, piperidyl, pyrrolidinyl, pyridyl, piperazinyl, piperidonyl, thiazolyl, benzimidazolyl, benzothiazolyl, benzoxazolyl, pyridoxazolyl, pyridothiazolyl, pyridazinoxazolyl, pyridazinothiazolyl, pyrimidothiazolyl, pyrimidoxazolyl, pyrazinothiazolyl, pyrazinoxazolyl, triazinothiazolyl, and triazinoxazolyl.
A “pharmaceutically acceptable acid addition salt” refers to th

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