Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
1999-10-27
2003-01-21
Fay, Zohreh (Department: 1614)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C514S374000, C514S212010, C514S365000
Reexamination Certificate
active
06509348
ABSTRACT:
FIELD OF THE INVENTION
The present invention relates to a novel combination of an ADP-receptor blocking antiplatelet drug, such as clopidogrel, and a thromboxane A
2
receptor antagonist such as ifetroban, and optionally a cholesterol lowering drug, such as pravastatin, and to a method for inhibiting platelet aggregation and thrombus formation employing such combination.
BACKGROUND OF THE INVENTION
Clopidogrel is a thieno-[3,2-c]pyridine derivative which has the chemical name methyl (4)-(S)-&agr;-(o-chlorophenyl)-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. No. 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 patents are incorporated herein by reference.
WO 97/29753 published Aug. 21, 1997, discloses a pharmaceutical composition containing clopidogrel and aspirin.
Ticlopidine hydrochloride is disclosed in U.S. Pat. No. 4,591,592 as a platelet aggregation inhibitor and 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
U.S. Pat. No. 5,288,726 (assigned to Sankyo) discloses a platelet aggregation inhibitor CS-747 which has the structure and name as follows:
2-acetoxy-5-(&agr;-cyclopropylcarbonyl-2-fluorobenzyl)-4,5,6,7-tetrahydrothieno[3,2-c]pyridine.
U.S. Pat. No. 5,100,889 to Misra et al discloses 7-oxabicycloheptyl substituted heterocyclic amide prostacyclin analogs which are potent thromboxane A
2
receptor antagonists and thus are useful in inhibiting platelet aggregation and thrombus formation. The Misra et al compounds have the structure
and including all stereoisomers thereof, wherein
m is 1, 2 or 3; n is 0, 1, 2, 3 or 4;
Z is —(CH
2
)
2
—, —CH═CH— or
wherein Y is O, a single bond or vinyl (—CH═CH—), with the provisos that when n is 0, if Z is
then Y cannot be 0; and when Z is —CH═CH—, n is 1,2,3, or 4; and when Y=vinyl, n=0;
R is CO
2
H, CO
2
lower alkyl, CO
2
alkali metal, CH
2
OH, CONHSO
2
R
3
, CONHR
3a
, or
(—CH
2
-5-tetrazolyl);
X is O, S or NH;
R
1
is hydrogen, lower alkyl, lower alkenyl, lower alkynyl, aralkyl, aryl, cycloalkyl, cycloalkylalkyl, cycloheteroalkyl, cycloheteroalkylalkyl, heteroaryl or heteroarylalkyl, or amide
wherein
t is 1 to 12 and R
a
is lower alkyl, aryl, cycloalkyl, or cycloalkylalkyl);
R
2
is hydrogen, lower alkyl, aryl, or aralkyl; or
R
1
and R
2
together with the nitrogen to which they are linked may form a 5- to 8-membered ring;
R
3
is lower alkyl, aryl or aralkyl; and
R
3a
is hydrogen, lower alkyl, aryl or aralkyl.
Ifetroban which is a particularly potent thromboxane A
2
antagonist is disclosed in the Misra et al patent and has the structure
and the name [1S-(1&agr;,2&agr;,3&agr;,4&agr;)]-2-[[3-[4-[(pentylamino)carbonyl]-2-oxazolyl]-7-oxabicyclo[2.2.1]hept-2-yl]methyl]benzenepropanoic acid or a pharmaceutically acceptable salt thereof such as its sodium salt.
U.S. Pat. No. 5,312,818 to Rubin et al discloses use of thromboxane A
2
receptor antagonists in combination with anti-inflammatory agents including aspirin to prevent or treat ulcerative conditions caused by anti-inflammatory agents.
DESCRIPTION OF THE INVENTION
In accordance with the present invention, a method for preventing or inhibiting platelet aggregation and thrombus formation in mammals is provided wherein an ADP-receptor blocking antiplatelet drug, such as clopidogrel, in combination with a thromboxane A
2
receptor antagonist, such as ifetroban, and optionally a cholesterol lowering drug, is administered in therapeutically effective amounts to inhibit platelet aggregation and thrombus formation.
Furthermore, in accordance with the present invention, a method is provided for preventing or inhibiting onset of ischemic events including cardiovascular, cerebrovascular and peripheral vascular events, such as myocardial infarction, unstable and 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 wherein a combination of an ADP-receptor blocking antiplatelet drug, such as clopidogrel, and a thromboxane A
2
receptor antagonist, such as ifetroban, and optionally a cholesterol lowering agent, is administered in therapeutic effective amounts.
In addition, in accordance with the present invention, a novel combination of antithrombotic agents is provided which includes an ADP receptor blocking antiplatelet drug, such as clopidogrel, and a thromboxane A
2
receptor antagonist, such as ifetroban, and optionally a cholesterol lowering drug, such as an HMG CoA reductase inhibitor such as pravastatin.
It is believed that the combination of ADP-receptor blocking antiplatelet drug and thromboxane A
2
receptor antagonist, 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, anti-ischemic, 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 thromboxane A
2
receptor antagonist may be employed to achieve desired results, albeit with reduced side effects.
In addition, in accordance with the present invention, a method is provided wherein a combination of an ADP-receptor blocking antiplatelet drug and a thromboxane A
2
receptor antagonist, and optionally aspirin, is employed to prevent or inhibit platelet aggregation and thrombus formation and to prevent or inhibit any of the disease states set out above, including thrombotic stroke.
The ADP-receptor blocking antiplatelet drug suitable for use herein includes antiplatelet drugs which inhibit ADP-induced platelet aggregation and include clopidogrel and/or ticlopidine and/or CS-747 (described herein), 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, ester thereof, including the acetate, and/or pharmaceutically acceptable acid addition salts thereof, including the hydrogen sulfate salt.
The term “ticlopidine” as employed herein includes all pharmaceutical acceptable salts thereof including the hydrochloride salt thereof.
The term “CS-747” as employed herein includes 2-acetoxy-5-(&agr;-cyclopropylcarbonyl-2-fluorobenzyl)-4,5,6,7-tetrahydrothieno[3,2-c]pyridine and pharmaceutically acceptable salts thereof.
Thromboxane A
2
receptor antagonists which may be employed herein include the interphenylene 7-oxabicycloheptyl substituted heterocyclic amide prostaglandin analogs as disclosed in U.S. Pat. No. 5,100,889, issued Mar. 31, 1992, including [1S-(1&agr;,2&agr;,3&agr;,4&agr;)]-2-[[3-[4-[[(4-cyclohexylbutyl)amino]carbonyl]-2-oxazolyl]-7-oxabicyclo[2.2.1]hept-2-yl]methyl]benzenepropanoic acid (SQ 33,961) which is preferred, or esters or salts thereo
Bristol--Myers Squibb Company
Fay Zohreh
Kwon Brian-Yong
Rodney Burton
LandOfFree
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