Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Phosphorus containing other than solely as part of an...
Reexamination Certificate
1999-06-09
2001-06-19
Henley, III, Raymond (Department: 1614)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Phosphorus containing other than solely as part of an...
C514S214020, C514S301000, C514S381000, C514S397000, C514S423000
Reexamination Certificate
active
06248729
ABSTRACT:
FIELD OF THE INVENTION
The present invention relates to a novel combination of an ADP-receptor blocking antiplatelet drug, such as clopidogrel, and an antihypertensive drug, for example, an angiotensin II antagonist such as irbesartan, or an ACE inhibitor such as fosinopril, or a NEP/ACE inhibitor such as omapatrilat, and to a method for preventing or inhibiting onset of a cerebral infarction employing such combination.
BACKGROUND OF THE INVENTION
Ticlopidine hydrochloride is disclosed in U.S. Pat. No. 4,591,592 as a platelet aggregation inhibitor, is marketed in the U.S. under the name Ticlid® by Roche Laboratories, and has the chemical name 5-[(2-chlorophenyl)methyl]-4,5,6,7-tetrahydrothieno[3,2-c]pyridine hydrochloride and the structure
Clopidogrel is a thieno-[3,2-c]pyridine derivative which has the chemical name methyl (4)-(S)-&agr;-(o-chloro-phenyl)-6,7-dihydrothieno[3,2-c]pyridine-5-acetate and the formula
including pharmaceutically acceptable acid addition salts thereof, preferably the hydrogen sulfate salt, and is disclosed in U.S. Pat. Nos. 4,529,596 to Aubert et al and U.S. Pat. No. 4,847,265 to Badorc et al as having blood platelet aggregation inhibiting activity and anti-thrombotic activity and thus useful in inhibiting or preventing arterial and venous thrombosis.
U.S. Pat. No. 5,576,328 to Herbert et al discloses that clopidogrel may be employed in secondary prevention of ischemic events such as myocardial infarction, unstable or stable angina, acute reocclusion after percutaneous transluminal coronary angioplasty (PTCA), restenosis after PTCA, thrombotic stroke, transient ischemic attack, reversible ischemic neurological deficit, and intermittent claudication.
The above Aubert et al, Badorc et al and Herbert et al patents are incorporated herein by reference.
WO 97/29753 published Aug. 21, 1997, discloses a pharmaceutical composition containing clopidogrel and aspirin.
Bernhart et al in U.S. Pat. No. 5,270,317 disclose a series of N-substituted heterocyclic derivatives which possess angiotensin II antagonist activity. Bernhart et al disclose that such compounds can be used in the treatment of various cardiovascular complaints, especially hypertension, heart failure, and venous insufficiency, as well as in the treatment of glaucoma, diabetic retinopathy and various complaints of the central nervous system. It is also disclosed that such compound can be used in combination with other active agents such as tranquilizers, beta-blocking compounds, a calcium antagonist, or a diuretic.
Selective neutral endopeptidase inhibitors are taught by Delaney et al in U.S. Pat. Nos. 4,722,810 and 5,223,516 and the use of selective neutral endopeptidase inhibitors alone or in combination with angiotensin converting enzyme inhibitors to treat hypertension are disclosed by Delaney et al U.K. Patent Application 2,207,351 and by Haslanger et al in U.S. Pat. No. 4,749,688. The treatment of congestive heart failure by administration of a combination of a selective neutral endopeptidase inhibitor and an angiotensin converting enzyme inhibitor is disclosed by Seymour in U.S. Pat. No. 5,225,401.
Compounds possessing both neutral endopeptidase and angiotensin converting enzyme inhibition activity are disclosed by Flynn et al in U.S. Pat. No. 5,366,973, European Patent Application 481,522 and PCT Patent Applications WO 93/16103, and WO 94/10193, Warshawsky et al European Patent Applications 534,363, 534,396 and 534,492, Fournie-Zaluski European Patent Application 524,553, Barrish et al European Patent Application 599,444, Karanewsky European Patent Application 595,610, Robl et al, European Patent Application 629,627, Robl U.S. Pat. No. 5,362,727 and U.S. patent application Ser. No. 153,854 filed Nov. 18, 1993, now U.S. Pat. No. 5,525,723.
DESCRIPTION OF THE INVENTION
In accordance with the present invention, a method for preventing or inhibiting onset of a cerebral infarction in mammals is provided wherein an ADP-receptor blocking antiplatelet drug, such as clopidogrel, in combination with an antihypertensive drug is administered in therapeutically effective amounts to inhibit onset of a cerebral infarction (also known as a thrombotic stroke).
In addition, in accordance with the present invention, a novel combination is provided which includes an ADP-receptor blocking antiplatelet drug, such as clopidogrel, and an antihypertensive drug.
ADP-receptor blocking drugs which may be used in the combination and method of the invention include clopidogrel, ticlopidine and the like.
Antihypertensive drugs, which may be used in the combination and method of the invention in combination with the ADP-receptor blocking antiplatelet drug include angiotensin II antagonists, angiotensin converting enzyme (ACE) inhibitors or NEP/ACE inhibitors.
It is believed that the combination of an ADP-receptor blocking antiplatelet drug and the antihypertensive drug, which works by a mechanism other than inhibition of ADP-induced platelet aggregation, is a surprising and unique concept in treating diseases involved with platelet aggregation, thrombus formation and ischemic events, in that the combination may provide additional antiplatelet aggregation, antiischemic and anti-thrombus effects over that which may be obtained using each of the components of the combination alone. It may be expected that reduced levels of each of the ADP-receptor blocking antiplatelet drug and antihypertensive drug may be employed to achieve desired results, albeit with reduced side effects and at reduced cost of goods.
DETAILED DESCRIPTION OF THE INVENTION
The following definitions apply to the terms as used throughout this specification, unless otherwise limited in specific instances.
The term “ADP-receptor blocking antiplatelet drug” refers to drugs which inhibit ADP-induced platelet aggregation via platelet ADP-receptor blocking including clopidogrel and/or ticlopidine and do not include drugs such as aspirin which inhibit platelet aggregation by other mechanisms.
The term “clopidogrel” as employed herein includes clopidogrel in its free acid form, esters thereof including the acetate and/or all pharmaceutically acceptable salts thereof, including the hydrogen sulfate salt.
The term “ticlopidine” as employed herein includes all pharmaceutically acceptable salts of ticlopidine, including the hydrochloride salt thereof.
The term “cerebral infarction” as employed herein refers to primary or secondary thrombotic stroke.
It is to be understood that the term “antihypertensive drug” refers to various classes of antihypertensive agents including angiotensin II antagonists, ACE inhibitors and NEP/ACE inhibitors which contribute, with the antiplatelet drug, to inhibit onset of primary or secondary cerebral infarction.
The combination of the ADP-receptor blocking antiplatelet drug, such as clopidogrel or ticlopidine, and the antihypertensive drug will be employed in a weight ratio to each other of within the range of from about 1000:1 to about 0.001:1, and preferably from about 0.05:1 to about 100:1.
The angiotensin II receptor antagonist (also referred to herein as angiotensin II antagonist or AII antagonist) suitable for use herein includes, but is not limited to, irbesartan, including salts thereof such as the K and Na salts thereof (disclosed in U.S. Pat. No. 5,270,317 to Bernhart et al), losartan, valsartan, telmisartan, candesartan, tasosartan or eprosartan, with irbesartan or losartan being preferred.
The angiotensin converting enzyme inhibitor which may be employed herein includes those containing a mercapto (-S-) moiety such as substituted proline derivatives, such as any of those disclosed in U.S. Pat. No. 4,046,889 to Ondetti et al mentioned above, with captopril, that is, 1-[(2S)-3-mercapto-2-methylpropionyl]-L-proline, being preferred, and mercaptoacyl derivatives of substituted prolines such as any of those disclosed in U.S. Pat. No. 4,316,906 with zofenopril being preferred.
Other examples of mercapto containing ACE inhibitors that may be employed herein include rentiapril (fenti
Blumenthal Melvin S.
Coniglio Anthony A.
Plat Francis R.
Bristol-Myers Squibb Co.
Davis Stephen B.
Henley III Raymond
Rodney Burton
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