Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
2001-06-18
2002-09-10
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...
C514S456000, C546S205000, C549S398000
Reexamination Certificate
active
06448269
ABSTRACT:
FIELD OF THE INVENTION
This invention relates to bicyclic compounds useful as glycoprotein IIb/IIIa antagonists for the prevention of thrombosis.
BACKGROUND OF THE INVENTION
The most prevalent vascular disease states are related to platelet dependent narrowing of the blood supply such as atherosclerosis and arteriosclerosis, acute myocardial infarction, chronic stable angina, unstable angina, transient ischemic attacks and strokes, peripheral vascular disease, arterial thrombosis, preeclampsia, embolism, restenosis or abrupt closure following angioplasty, carotid endarterectomy, anastomosis of vascular grafts, and etc. These conditions represent a variety of disorders thought to be initiated by platelet activation on vessel walls. Platelet adhesion and aggregation is believed to be an important part of thrombus formation. This activity is mediated by a number of platelet adhesive glycoproteins. The binding sites for fibrinogen, fibronectin and other clotting factors have been located on the platelet membrane glycoprotein complex IIb/IIIa. When a platelet is activated by an agonist such as thrombin the GPIIb/IIIa binding site becomes available to fibrinogen, eventually resulting in platelet aggregation and clot formation.
Heretofore it has been proposed to block these thrombus formation sites by the use of various therapeutic agents.
U.S. Pat. No. 5,064,814 teaches N-amidino-piperidine carboxyl cyclic amino acid derivatives as anti-thrombotic agents.
U.S. Pat. 5,039,805 teaches various benzoic acid and phenylacetic acid derivatives for the inhibition of the binding of fibrinogen to the fibrinogen receptor, glycoprotein IIb/IIIa.
Seven membered ring containing bicyclic compounds are taught to be fibrinogen antagonists in PCT International patent application WO 93/00095.
EP 456835 describes bicyclic compounds having fused six membered rings (quinazoline-3-alkanoic acid derivates) which are reported to have an inhibitory effect on platelet aggregation.
PCT International patent application WO 93/08174 describes nonpeptidyl integrin inhibitors which are bicyclic 6 and 7 membered fused ring systems which have therapeutic applications in diseases for which blocking platelet aggregation is indicated.
Patent Application WO94/12478 describes the preparation of 6,5-bicyclic compounds stated to be effective for inhibiting platelet aggregation.
Patent Application WO94/08962 describes the preparation of 6,5-bicyclic compounds stated to be effective for inhibiting platelet aggregation.
British Patent application GB 2276384 describes novel oxoquinazolin derivatives stated to have fibrinogen receptor antagonistic activity.
The article, “From Peptide to Non-Peptide. 1. The Elucidation of a Bioactive Conformation of the arginine-glycine-aspartic Acid Recognition Sequence”, by Robert S. McDowell, et. al., J. Am. Chem. Soc. 1994, 116, pp. 5069-5076, describes design of non-peptidal inhibitors of fibrinogen-glycoprotein IIb/IIIa binding.
The publication, “Chapter 9. Glycoprotein IIbIIIa Antagonists” by Brent K. Blackburn and Thomas R. Gadek, Annual Reports in Medicinal Chemistry—28, Section II—Cardiovascular and Pulmonary Agents, pp 79-88, 1993, publ. by Academic Pres, Inc., describes non-peptides as antagonists of GPIIbIIIa/fibrinogen interaction.
The article, “From Peptide to Non-Peptide. 2. The de Novo Design of Potent, Non-Peptidal Inhibitors of Platelet Aggregation Based on a Benzodiazepinedione Scaffold”, by Robert S. McDowell, et. al., J. Am. Chem. Soc. 1994, 116, pp 5077-5083, describes benzodiazepinedione which are inhibitors of platelet aggregation.
Quinoline compounds have been recited in the patent literature for a variety of medicinal uses. For example, European Patent Application 0 315 399; U.S. Pat. No. 5,041,453; PCT Patent Application WO 89/04303, and PCT Patent Application WO 89/04304 describe quinoline derivatives useful as lipoxygenase inhibitors and/or leukotriene antagonists possessing anti-inflammatory and anti-allergic. properties. These compounds must contain three aromatic rings, each interrupted with oxygen, or sulfur, and possibly other groups.
There is a need in the area of cardiovascular and cerebrovascular therapeutics for alternative agents which can be used in the prevention and treatment of thrombi.
It is a discovery of this invention that certain novel bicyclic compounds block the GPIIb/IIIa fibrinogen receptor, thereby inhibiting platelet aggregation and subsequent thrombus formation. Pharmaceutical formulations containing the bicyclic compounds of this invention inhibit aggregation and are useful for the prophylaxis and treatment of thrombogenic diseases, such as myocardial infarction, angina, stroke, peripheral arterial disease, disseminated intravascular coagulation and venous thrombosis.
SUMMARY OF THE INVENTION
The present invention is a novel bicyclic compound having a nucleus formed from two fused six membered rings, A and B, represented by the formula (I), as hereinafter defined, and all pharmaceutically acceptable salts, solvates and prodrug derivatives thereof:
Another aspect of the invention is a pharmaceutical formulation containing the novel bicyclic compounds of the invention.
Another aspect of the invention is a method of inhibiting platelet aggregation, inhibiting fibrinogen binding, or preventing thrombosis by administering to a mammal the bicyclic compounds of the invention.
Another aspect of this invention is a method of treating a human to alleviate the pathological effects of atherosclerosis and arteriosclerosis, acute myocardial infarction, chronic stable angina, unstable angina, transient ischemic attacks and strokes, peripheral vascular disease, arterial thrombosis, preeclampsia, embolism, restenosis following angioplasty, carotid endarterectomy, and anastomosis of vascular grafts; wherein the method comprises administering to said human the novel bicyclic compound of this invention.
DETAILED DESCRIPTION OF THE INVENTION
The term “alkyl” used herein refers to a monovalent straight or branched chain radical of from one to ten carbon atoms, including, but not limited to methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, n-hexyl, and the like.
The term, “halosubstituted alkyl” as used herein refers to an alkyl group as just defined, substituted by one, two or three halogen atoms selected from fluorine, chlorine, bromine, and iodine. Examples of such groups include chloromethyl, bromoethyl, trifluoromethyl, and the like.
The term, “aryl”, when used alone means a homocyclic aromatic radical whether or not fused. Preferred aryl groups include phenyl, napthyl, biphenyl, phenanthrenyl, naphthacenyl, and the like.
The term, “substituted aryl”, denotes an aryl group substituted with one, two, or three substituents chosen from halogen, hydroxy, protected hydroxy, cyano, nitro, C
1
-C
10
alkyl, C
1
-C
10
alkoxy, trifluoromethyl, amino, aminomethyl, and the like. Examples of such groups are 4-chlorophenyl, 2-methylphenyl, 3-methyl-4-hydroxyphenyl, and 3-ethoxyphenyl.
The term, “arylalkyl”, means one, two or three aryl groups having the number of carbon atoms designated, appended to an alkyl radical having the number of carbon atoms designated. A typical arylalkyl group is the benzyl group.
The term “alkenyl” as used herein refers to a monovalent straight or branched chain radical of from two to six carbon atoms containing a carbon double bond including, but not limited to, 1-propenyl, 2-propenyl, 2-methyl-l-propenyl, 1-butenyl, 2-butenyl and the like.
The term, “alkylene” as used herein refers to a divalent straight or branched chain group of from one to ten carbon atoms, including but not limited to, —CH
2
—, —(CH
2
)
2
—, —(CH
2
)
3
—, —CH(CH
3
)—, —CH(C
2
H
5
)—, —CH(CH
3
)CH
2
—, and the like.
The term “alkenylene” as used herein refers to a divalent straight or branched chain group of from two to ten carbon atoms containing a carbon-carbon double bond, including but not limited to, —CH═CH—, —C(CH
3
)═CH—, CH═CH—CH
2
—, —CH═C(CH
3
)—CH
2
—, —CH
2
CH(CH═CH
2
)CH
2
, and the like.
The term, “alkynylene” as
Fisher Matthew J.
Happ Anne Marie
Jakubowski Joseph A.
Kinnick Michael Dean
Kline Allen D.
Davis Zinna Northington
Eli Lilly and Company
Knobbe Martens Olson & Bear LLP
LandOfFree
Glycoprotein IIb/IIIa antagonists does not yet have a rating. At this time, there are no reviews or comments for this patent.
If you have personal experience with Glycoprotein IIb/IIIa antagonists, we encourage you to share that experience with our LandOfFree.com community. Your opinion is very important and Glycoprotein IIb/IIIa antagonists will most certainly appreciate the feedback.
Profile ID: LFUS-PAI-O-2829157