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WO1999045913A1 - Therapie associee destinee au syndrome ischemique coronarien aigu ainsi qu'a des troubles connexes - Google Patents

Therapie associee destinee au syndrome ischemique coronarien aigu ainsi qu'a des troubles connexes Download PDF

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Publication number
WO1999045913A1
WO1999045913A1 PCT/US1999/005063 US9905063W WO9945913A1 WO 1999045913 A1 WO1999045913 A1 WO 1999045913A1 US 9905063 W US9905063 W US 9905063W WO 9945913 A1 WO9945913 A1 WO 9945913A1
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Prior art keywords
phenyl
methylsulfonyl
cox
inhibitor
amino
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PCT/US1999/005063
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English (en)
Inventor
Steven A. Nichtberger
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Merck & Co., Inc.
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Priority claimed from GBGB9815857.9A external-priority patent/GB9815857D0/en
Application filed by Merck & Co., Inc. filed Critical Merck & Co., Inc.
Priority to CA002322824A priority Critical patent/CA2322824A1/fr
Priority to JP2000535328A priority patent/JP2002506024A/ja
Priority to EP99911208A priority patent/EP1061908A4/fr
Publication of WO1999045913A1 publication Critical patent/WO1999045913A1/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/04—Peptides having up to 20 amino acids in a fully defined sequence; Derivatives thereof
    • A61K38/08—Peptides having 5 to 11 amino acids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/04—Peptides having up to 20 amino acids in a fully defined sequence; Derivatives thereof
    • A61K38/05—Dipeptides
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P7/00—Drugs for disorders of the blood or the extracellular fluid
    • A61P7/02—Antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis

Definitions

  • Platelet activation and aggregation are involved in unstable angina and acute myocardial infarction, in reocclusion following thrombolytic therapy and angioplasty, in transient ischemic attacks and 0 in a variety of other vaso-occlusive disorders.
  • thrombolytic therapy and angioplasty in transient ischemic attacks and 0 in a variety of other vaso-occlusive disorders.
  • platelets When a blood vessel is damaged either by acute intervention such as angioplasty, or more chronically by the pathophysiological processes of atherosclerosis, platelets are activated to adhere to the disrupted surface and to each other. This activation, adherence and aggregation may lead to occlusive 5 thrombus formation in the lumen of the blood vessel.
  • Antiplatelet therapy has been used in a wide variety of cardiovascular disease states and in conjunction with interventional therapy such as coronary artery or peripheral bypass grafting, cardiac valve replacement, and percutaneous transluminal coronary 0 angioplasty (PTCA).
  • interventional therapy such as coronary artery or peripheral bypass grafting, cardiac valve replacement, and percutaneous transluminal coronary 0 angioplasty (PTCA).
  • Available drugs such as aspirin and ticlopidine (TICLID®)
  • aspirin and ticlopidine have shown efficacy in syndromes involving vascular occlusion, presumably due to sustained inhibition of platelet function.
  • the inhibitory effects of aspirin and ticlopidine are dependent upon the agonist which activates the platelet.
  • aspirin is 5 effective in blocking platelet aggregation induced by agonists such as collagen that are dependent upon the cyclooxygenase pathway.
  • CAMs which serve as receptors recognizing an array of adhesive proteins in the extracellular matrix. These proteins include von Willebrand factor (vWf), fibronectin, vitronectin, thrombospondin, laminins, collagen fibrils, elastin, microfibrils of elastin, and glycosaminoglycans. Most of the matrix adhesive molecules are the ligands for integrin receptors expressed in endothelial cells. Integrins constitute an extended family (“superfamily") of membrane receptors interacting with adhesive proteins in plasma and extracellular matrix and with other membrane receptors (counter- receptors).
  • Integrin implies that they integrate the ligands on the outside of the cell with the cytoskeletal apparatus in the inside of the cell. Integrin receptors consist of a noncovalently linked Ca ⁇ +- dependent, heterodimeric glycoprotein complex composed of ⁇ and ⁇ subunits. The eight known integrin ⁇ subunits give rise to eight families in which one "founder" ⁇ subunit forms heterodimers with different ⁇ subunits. There are at least 14 known ⁇ subunits. Receptors belonging to the ⁇ i and ⁇ 3 families are expressed in endothelial cells.
  • the ⁇ i family also named Very Late Antigens (VLA), is represented by the fibronectin receptor ( ⁇ l, or VLA-5), the collagen receptor ( ⁇ 2 ⁇ l, or VLA-2) and the laminin receptor ( ⁇ l).
  • the ⁇ 3 family is represented by the vitronectin receptor ( ⁇ v ⁇ 3), which is structurally similar (the same ⁇ 3 subunit) to the platelet integrin receptor for fibrinogen, glycoprotein (GP) Hb/IIIa complex (also referred to as ⁇ b ⁇ 3).
  • the functional difference between these two receptors is that the platelet receptor recognizes the g chain domain (HHLGGAKQAGDV) of human fibrinogen and the endothelial vitronectin receptor does not.
  • the final obligatory step in platelet aggregation is the binding of fibrinogen to an activated membrane-bound glycoprotein complex, GP Ilb/IIIa.
  • Platelet activators such as thrombin, collagen, epinephrine or ADP, are generated as an outgrowth of tissue damage.
  • GP Ilb/IIIa undergoes changes in conformation that results in exposure of occult binding sites for fibrinogen.
  • fibrinogen can potentially act as a hexavalent ligand to crossing GP Ilb/IIIa molecules on adjacent platelets.
  • a deficiency in either fibrinogen or GP Ilb/IIIa prevents normal platelet aggregation regardless of the agonist used to activate the platelets. Since the binding of fibrinogen to its platelet receptor is an obligatory component of normal aggregation, GP Ilb/IIIa is an attractive target for an antithrombotic agent.
  • the monoclonal antibody 7E3 which blocks the GP Ilb/IIIa receptor, has been shown to be an effective therapy for the high risk angioplasty population. It is used as an adjunct to percutaneous transluminal coronary angioplasty or atherectomy for the prevention of acute cardiac ischemic complications in patients at high risk for abrupt closure of the treated coronary vessel. Although 7E3 blocks both the Ilb/IIIa receptor and the ⁇ y ⁇ 3 receptor, its ability to inhibit platelet aggregation has been attributed to its function as a Ilb/IIIa receptor binding inhibitor.
  • Integrelin also known as INTEGRILINTM is a cyclic peptide that is based on the KGD sequence in the snake venom protein barbourin (Cook et al., ibid.; and Cox et al., ibid.). It inhibits ligand binding to GP Ilb/IIIa but has very little effect on ligand binding to ⁇ v ⁇ 3-
  • non-peptide compounds are Ro 44-9883 and MK-383, which are administered intravenously, and are also selective for GPIIb/IIIa (Cook et al., ibid.; and Cox et al., ibid.).
  • Orally active agents include SC54684, which is a prodrug (i.e., it requires biotransformation in vivo to its active form) with high oral bioavailability and Ro 43-8857, GR144053, and DMP728, which are themselves the active inhibitors (Cook et al., ibid.; and Cox et al., ibid.).
  • SC54684 which is a prodrug (i.e., it requires biotransformation in vivo to its active form) with high oral bioavailability
  • Inhibitors of cyclooxygenase-2 are a sub-class of the class of drugs known as non-steroidal antiinflammatory drugs (NSAIDs).
  • NSAIDs non-steroidal antiinflammatory drugs
  • the NSAIDs are active in reducing the prostaglandin-induced pain and swelling associated with the inflammation process but are also active in affecting other prostaglandin-regulated processes not associated with the inflammation process.
  • use of high doses of most common NSAIDs can produce severe side effects, including life threatening ulcers, that limit their therapeutic potential.
  • An alternative to NSAIDs is the use of corticosteroids, which have even more drastic side effects, especially when long term therapy is involved.
  • Previous NSAIDs have been found to prevent the production of prostaglandin by inhibiting enzymes in the human arachidonic acid/prostaglandin pathway including the enzyme cyclooxygenase (COX).
  • COX cyclooxygenase
  • the instant invention addresses this problem by providing a combination therapy comprised of an antiplatelet agent, and more particularly, a GP Ila/IIIb receptor antagonist, with a COX-2 inhibitor.
  • a combination therapy comprised of an antiplatelet agent, and more particularly, a GP Ila/IIIb receptor antagonist, with a COX-2 inhibitor.
  • the COX-2 inhibitor together with the antiplatelet agent provide enhanced treatment options as compared to administration of either the antiplatelet agent or the COX-2 inhibitor alone.
  • the instant invention provides a novel drug combination comprised of an antiplatelet agent in combination with a COX-2 inhibitor, which is useful for inhibiting platelet aggregation in mammals.
  • the instant invention further provides novel methods for treating, preventing and reducing the risk of occurrence of acute coronary ischemic syndrome, including first or subsequent Q-wave myocardial infarction or angina pectoris, thrombosis, thromboembolism, thrombotic occlusion and reocclusion, restenosis, transient ischemic attack, and first or subsequent thrombotic stroke.
  • Another object of this invention is to provide pharmaceutical compositions which can be used with the above-described methods.
  • a further object is to provide a kit comprised of a COX-2 inhibitor
  • the instant invention involves a novel combination therapy comprising the administration of a therapeutically effective amount of a COX-2 inhibitor in combination with a therapeutically effective amount of an antiplatelet agent to a mammal, and more particularly, to a human.
  • the combination therapy is used to inhibit platelet aggregation in mammals who are in need of such inhibition, to inhibit inflammation in the vessels of mammals who are in need of such inhibition, and to prevent or treat disorders related to platelet aggregation.
  • the instant invention also provides pharmaceutical compositions comprised of a therapeutically effective amount of a COX-2 inhibitor, or a pharmaceutically acceptable salt thereof, in combination with a therapeutically effective amount of an antiplatelet agent, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.
  • One embodiment of the instant compositions is a single composition adapted for oral administration comprised of a therapeutically effective amount of a COX-2 inhibitor in combination with a therapeutically effective amount of an antiplatelet agent and a pharmaceutically acceptable carrier.
  • the combination can also be administered in separate dosage forms, each having one of the active agents. If administered in separate dosage forms, the separate dosage forms are administered such that the beneficial effect of each active agent is realized by the patient at substantially the same time.
  • “Pharmaceutically acceptable salts” means non- toxic salts of the compounds employed in this invention which are generally prepared by reacting the free acid with a suitable organic or inorganic base.
  • salt forms of antiplatelet agents may include, but are not limited to, acetate, benzenesulfonate, benzoate, bicarbonate, bisulfate, bitartrate, borate, bromide, calcium, calcium edetate, camsylate, carbonate, chloride, clavulanate, citrate, dihydrochloride, edetate, edisylate, estolate, esylate, fumarate, gluceptate, gluconate, glutamate, glycollylarsanilate, hexylresorcinate, hydrabamine,
  • salt forms of COX-2 inhibitors include but are not limited to salts derived from inorganic bases including aluminum, ammonium, calcium, copper, ferric, ferrous, lithium, magnesium, manganic salts, manganous, potassium, sodium, zinc, and the like. Particularly preferred are the ammonium, calcium, magnesium, potassium, and sodium salts.
  • Salts derived from pharmaceutically acceptable organic non-toxic bases include salts of primary, secondary, and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines, and basic ion exchange resins, such as arginine, betaine, caffeine, choline, N,N- dibenzylethylenediamine, diethylamine, 2-diethylaminoethanol, 2- dimethylaminoethanol, ethanolamine, ethylenediamine, N- ethylmorpholine, N-ethylpiperidine, glucamine, glucosamine, histidine, hydrabamine, isopropylamine, lysine, methylglucamine, morpholine, piperazine, piperidine, polyamine resins, procaine, purines, theobromine, triethylamine, trimethylamine, tripropylamine, tromethamine, and the like.
  • basic ion exchange resins such as argin
  • Acute coronary ischemia refers to local anemia due to mechanical obstruction, e.g. arterial narrowing, of the blood supply.
  • the condition is also referred to as myocardial ischemia and is characterized by inadequate circulation of blood to the myocardium, usually as a result of coronary artery disease.
  • Ischemia of the heart muscle is evidenced by a pain in the chest often radiating from the precordium to the left shoulder and down the arm (angina pectoris) and is caused by coronary disease.
  • Ischemia also includes myocardial infarction, which results from occlusion of a coronary artery.
  • myocardial infarction is intended to include both Q- wave and non-Q-wave myocardial infarction, unless otherwise noted.
  • “Therapeutically effective amount” means that amount of a drug or pharmaceutical agent that will elicit the biological or medical response of a tissue, a system, animal or human that is being sought by a researcher, veterinarian, medical doctor or other clinician.
  • “Prophylactically effective amount” means that amount of a pharmaceutical drug that will prevent or reduce the risk of occurrence of the biological or medical event that is sought to be prevented in a tissue, a system, animal or human by a researcher, veterinarian, medical doctor or other clinician.
  • Reducing the risk” or “reduction of risk” of occurrence of conditions selected from acute coronary ischemic syndrome including first or subsequent Q-wave myocardial infarction or angina pectoris, thrombosis, thromboembolism, thrombotic occlusion and reocclusion, restenosis, transient ischemic attack, and first or subsequent thrombotic stroke refers to lowering the risk occurrence of any of the above conditions in a patient at risk to developing the conditions.
  • Patients at risk to developing the conditions include those having a history of heart disease, a family history of heart disease, a genetic predisposition to developing the conditions, diabetes, hypercholesteremia, hypertension, and smokers.
  • patient includes mammals, especially humans, who take an antiplatelet agent in combination with a COX-2 inhibitor for any of the uses described herein.
  • “Cerebrovascular ischemic events” are those relating to reduced blood supply to the brain, and include but are not limited to first or subsequent thrombotic strokes, or transient ischemic attacks. Ester derivatives of the described compounds may act as prodrugs which, when absorbed into the bloodstream of a warm-blooded animal, may cleave in such a manner as to release the drug form and permit the drug to afford improved therapeutic efficacy.
  • the compounds have a cyclooxygenase-2 IC50 of less than about 2 ⁇ M in the human whole blood COX-2 assay, yet have a cyclooxygenase- 1 IC50 of greater than about 5 ⁇ M in the human whole blood COX-1 assay.
  • the compounds have a selectivity ratio of cyclooxygenase-2 inhibition over cyclooxygenase- 1 inhibition of at least 10, and more preferably of at least 40. The resulting selectivity may indicate an ability to reduce the incidence of common NSAID-induced side effects.
  • the inhibitor of cyclooxygenase-2 may be administered at a dosage level up to conventional dosage levels for NSAIDs. Suitable dosage levels will depend upon the antiinflammatory effect of the chosen inhibitor of cyclooxygenase-2, but typically suitable levels will be about 0.001 to 50 mg/kg per day, preferably 0.005 to 30mg/kg per day, and especially 0.05 to lOmg/kg per day.
  • the compound may be administered on a regimen of up to 6 times per day, preferably 1 to 4 times per day, and especially once per day.
  • NHSOoCH .
  • NHSOoCH .
  • NHSOoCH .
  • a second class is the tricyclic inhibitor class, which can be further divided into the sub-classes of tricyclic inhibitors with a central carbocyclic ring (examples include SC-57666, 1 . and 2); those with a central monocyclic heterocyclic ring (examples include DuP 697, SC- 58125, SC-58635, and 3, 4 and 5J; and those with a central bicyclic heterocyclic ring (examples include 6, 7, 8_ 9 and 10).
  • Compounds 3, 4 and 5 are described in U.S. Patent No. 5,474,995 .
  • the third identified class can be referred to as those which are structurally modified NSAIDS, and includes 11a and structure H as example members.
  • COX-2 inhibitor compounds which are included in the scope of this invention include:
  • Patent No. 5,474,995. See Examples herein for compounds 13 and 25 .
  • Particularly preferred compounds of formula (I) include:
  • Antiplatelet agents suitable for use in the present invention include glycoprotein Ilb/IIIa receptor antagonists, clopidogrel, ticlopidine, dipyridamole and aspirin.
  • Glycoprotein Ilb/IIIa receptor antagonists inhibit the binding of fibrinogen to the Ilb/IIIa platelet receptor site, thereby inhibiting platelet aggregation.
  • -22- receptor antagonists are described in United States Patent No.'s 5,470,849, 5,463,011, 5,455,243, 5,451,578, 5,446,056, 5,441,952, 5,422,249, 5,416,099, 5,405,854, 5,397,791, 5,393,760, 5,389,631, 5,380,713, 5,374,622, 5,358,956, 5,344,783, 5,340,798, 5,338,723, 5,334,596, 5,321,034, 5,318,899 (e.g.
  • cyclic heptapeptides such as Mpr-(Acetimidyl-Lys)-Gly-Asp-Trp- Phe-Cys-NH2, Mpr-(Acetimidyl-Lys)-Gly-Asp-Trp-Phe-Pen-NH2, Mpr- (Phenylimidyl-Lys)-Gly-Asp-Trp-Phe-Pen-NH2, and Mpr-(Phenylimidyl- Lys)-Gly-Asp-Trp-Phe-Cys-NH2, wherein Mpr is mercapto propionyl), 5,312,923, 5,294,616, 5,292,756 (which includes tirofiban), 5,281,585, 5,272,158, 5,264,420, 5,260,307, 5,239,113 (e.g. ethyl 3-[[4-[[4-[[4-[4-[4
  • the GP Ilb/IIIa receptor antagonist is selected from the following compounds and the pharmaceutically acceptable salts, esters, and solvates (including hydrates) thereof: [3(R)- [2-piperidin-4-yl)ethyl]-2-piperidone-l]acetyl-3(R)-methyl- ⁇ -alanine described in United States Patent No. 5,281,585, (see compound 57 in column 67) and referred to herein as Compound A:
  • MK-383 (2-S-(n-Butylsulfonylamino)-3[4-piperidin-4- yl)butyloxyphenyl]propionic acid hydrochloride, and also known as tirofiban) described in United States Patent 5,292,756; DMP 728; DMP 754 ((R)-methyl-3-[[[3-[4-(aminoiminomethyl)phenyl]-4,5-dihydro-5- isoxazolyl]acetyl]amino]-N-(butoxycarbonyl)-L-alanine monoacetate) from DuPont-Merck, described in WO 95/14683 and in Tetrahedron Letters, 1996, 37 :4455-4458:
  • Ro44-9883, Ro43-8857 and Ro48-3657 (acetic acid, [[l-[2-[[4- [amino(hydroxyimino)methyl]benzoyl]amino]-l-oxopropyl]-4- piperidinyl]oxy]-, ethyl ester, and also known as sibrafiban) from Hoffman-LaRoche; sibrafiban and related compounds are described in EP 656348:
  • xemlofiban ethyl 3-[[4-[[4-(aminoiminomethyl)phenyl]amino]-l,4- dioxobutyl]amino]-4-pentynoate, also known as xemilofiban and SC- 54684
  • xemilofiban ethyl 3-[[4-[[4-(aminoiminomethyl)phenyl]amino]-l,4- dioxobutyl]amino]-4-pentynoate, also known as xemilofiban and SC- 54684
  • HCl salt thereof described in U.S. Patent No.'s 5,344,957 and 5,239,113:
  • orbofiban N-[[(3S)-l-(p-Amidinophenyl)-2-oxo-3-pyrrolidinyl-carbamoyl]- ⁇ -alanine, ethyl ester
  • orbofiban N-[[(3S)-l-(p-Amidinophenyl)-2-oxo-3-pyrrolidinyl-carbamoyl]- ⁇ -alanine, ethyl ester
  • SB 214857 ((-)-(S)-2-[7-(4,4'-Bipiperidin-l-ylcarbonyl)-4-methyl-3-oxo- 2,3,4,5-tetrahydro-lH-l,4-benzodiazepin-2-yl]acetic acid) from SmithKline Beecham, as described in WO 95/18619; ZD-2486 ((R)-3- Methyl-4-[4-[4-(4-pyridyl)piperazin-l-yl]phenoxy]butyric acid) from Zeneca, as described in U.S.
  • DMP 728 is also described in Circulation, 1996, 93 :537-543; and GR144053 is also described in Thrombosis and Hematosis, 1993, 69 :1071.
  • TAK 029 is described in J. Pharmacology and Experimental Therapeutics, 1996, 277 :502-510.
  • Xemlofiban is described in Circulation, 1995, 92 :2331.
  • the GP Ilb/IIIa receptor antagonist is selected from Compound A, Compound B, and DMP 754, which are all orally available compounds. Most particularly, the GP Ilb/IIIa receptor antagonist is DMP 754.
  • One test which is used to evaluate Ilb/IIIa receptor antagonist activity is based on evaluation of inhibition of ADP-stimulated platelets. Aggregation requires that fibrinogen bind to and occupy the platelet fibrinogen receptor site. Inhibitors of fibrinogen binding inhibit aggregation.
  • human platelets are isolated from fresh blood, collected into acid citrate/dextrose by differential centrifugation followed by gel filtration on Sepharose 2B in divalent ion-free Tyrode's buffer (pH 7.4) containing 2% bovine serum albumin.
  • Platelet aggregation is measured at 37°C in a Chronolog aggregometer.
  • the reaction mixture contains gel-filtered human platelets (2 x 108 per ml), fibrinogen (100 micrograms per ml (ug/ml)), Ca2+ (1 mM), and the compound to be tested.
  • the aggregation is initiated by adding 10 mM ADP 1 minute after the other components are added.
  • the reaction is then allowed to proceed for at least 2 minutes.
  • the extent of inhibition of aggregation is expressed as the percentage of the rate of aggregation observed in the absence of inhibitor.
  • the IC50 is the dose of a particular compound inhibiting aggregation by 50% relative to a control lacking the compound.
  • Oral dosages of GP Ilb/IIIa receptor antagonists when used for the indicated effects will range between about 0.001 mg per kg of body weight per day (mg/kg/day) to about 50 mg/kg/day and preferably 0.005-20 mg/kg/day and most preferably 0.005-10 mg/kg/day.
  • Suitable oral tablets and capsules contain between 0.1 mg and 5 g, preferably between 0.5 mg and 2 g, most preferably between 0.5 mg and lg, for example, 0.5 mg, 1 mg, 5 mg, 10 mg, 50 mg, 150 mg, 250 mg, or 500 mg of GP Ilb/IIIa
  • Oral administration may be in one or divided doses of two, three, or four times daily. A single daily dose is preferred.
  • the most preferred doses for GP Ilb/IIIa receptor antagonists will range from about 0.5 ⁇ g to about 5 mg/kg/minute during a constant rate infusion, to achieve a plasma level concentration during the period of time of administration of between 0.1 ng/ml and 1 ⁇ g/ml.
  • antiplatelet agent (or inhibitor of platelet aggregation) is intended to include all pharmaceutically acceptable salt, ester and solvate forms, including hydrates, of compounds which have platelet aggregation inhibitory activity as well as pro-drug forms.
  • pro-drugs are compounds which do not have platelet aggregation inhibitory activity outside the body but become active as inhibitors after they are administered to the patient. Therefore the use of such salts, esters solvate forms and pro-drugs of antiplatelet agents is included within the scope of this invention.
  • GP Ilb/IIIa receptor antagonist is intended to include all pharmaceutically acceptable salt, ester and solvate forms, including hydrates, of compounds which have GP Ilb/IIIa receptor antagonist activity as well as pro-drug forms.
  • pro-drugs are compounds which do not have GP Ilb/IIIa receptor antagonist activity outside the body but become active as antagonists after they are administered to the patient. Therefore the use of such salts, esters, solvate forms and pro-drugs of GP Ilb/IIIa receptor antagonists is also included within the scope of this invention.
  • Pro-drug forms of Ilb/IIIa receptor antagonists generally are not active antagonists until after they are metabolized in the body to the active drug form; such prodrugs may be, but are not limited to, ester derivatives. Ester derivatives of the described compounds may act as prodrugs which, when absorbed into the bloodstream of a warm-blooded animal, may cleave in such a manner as to release the drug form and permit the drug to afford improved therapeutic efficacy.
  • An example of such a prodrug is Ro 48-3657.
  • the compounds may have one or more chiral centers and the present compounds may occur as racemates, racemic mixtures and
  • crystalline forms for compounds may exist as polymorphs and as such are intended to be included in the present invention.
  • some of the compounds may form solvates with water or common organic solvents. Such solvates and hydrates, as well as anhydrous compositions, are encompassed within the scope of this invention.
  • Some of the compounds described herein may contain olefinic double bonds, and unless specified otherwise, are meant to include both E and Z geometric isomers.
  • antiplatelet agents suitable for use in the present invention include clopidogrel (PLAVIX®, Bristol Myers Squibb) and ticlopidine (TICLID®, Roche Laboratories), both of which block ADP- induced platelet aggregation, as well as dipyridamole (PERSANTINE®, Boehringer Ingelheim), a platelet adhesion inhibitor, and aspirin.
  • Suitable oral formulations of clopidogrel may contain from 25 mg to 500 mg, preferably from 75 mg to 375 mg, and most preferably from 75 mg to 150 mg of clopidogrel.
  • the formulation may contain 25 mg, 50 mg, 75 mg, 150 mg, 250 mg, or 500 mg of clopidogrel.
  • Oral administration may be in one or divided doses of two, three, or four times daily. A single daily dose is preferred.
  • Dosage amounts for ticlopidine and for dipyridamole are described in the Physicians' Desk Reference .
  • Dosage amounts of aspirin for the indicated effects are known to those skilled in medical arts, and generally range from about 75 mg to about 325 mg per day.
  • a formulation may contain 75 mg, 80 mg, 160 mg, 250 mg, or 325 mg of aspirin.
  • the instant pharmaceutical combinations comprising an antiplatelet agent in combination with a COX-2 inhibitor includes administration of a single pharmaceutical dosage formulation which contains both the antiplatelet agent and the COX-2 inhibitor, as well as administration of each active agent in its own separate pharmaceutical dosage formulation.
  • the antiplatelet agent and the COX-2 inhibitor can be administered at essentially the same time, i.e., concurrently, or at separately staggered times, i.e, sequentially.
  • the "instant pharmaceutical combination” is understood to include all these regimens. Administration in these various ways are suitable for the present invention as long as the beneficial pharmaceutical effect of the antiplatelet agent and the COX-2 inhibitor are realized by the patient at substantially the same time.
  • Such beneficial effect is preferably achieved when the target blood level concentrations of each active drug are maintained at substantially the same time. It is preferred that the antiplatelet agent and the COX-2 inhibitor be co-administered concurrently on a once-a-day dosing schedule; however, varying dosing schedules, such as the antiplatelet agent once per day and the COX-2 inhibitor once, twice or more times per day, is also encompassed herein.
  • a single oral dosage formulation comprised of both an antiplatelet agent and the COX-2 inhibitor is preferred.
  • a single dosage formulation will provide convenience for the patient, which is an important consideration especially for patients who already have coronary heart disease and may be in need of multiple medications.
  • a combination therapy of intravenously administered GP Ilb/IIIa receptor antagonist with orally administered COX-2 inhibitor could be used in response to an acute medical event where inhibition of platelet aggregation is needed, and may generally be administered for a period of time of one or two weeks or up to a month or longer if deemed necessary.
  • the combination therapy involves for example oral administration of both the GP Ilb/IIIa receptor antagonist and the COX-2 inhibitor, the therapy may be administered on a longer-
  • the therapeutically effective amount is that amount of a drug or pharmaceutical agent that will elicit the biological or medical response of a tissue, a system, animal or human that is being sought by a researcher, veterinarian, medical doctor or other clinician.
  • the prophylactically effective amount that amount of a pharmaceutical drug that will prevent or reduce the risk of occurrence of the biological or medical event that is sought to be prevented in a tissue, a system, animal or human by a researcher, veterinarian, medical doctor or other clinician.
  • the dosage regimen utilizing an antiplatelet agent in combination with COX-2 inhibitor is selected in accordance with a variety of factors including type, species, age, weight, sex and medical condition of the patient; the severity of the condition to be treated; the route of administration; the renal and hepatic function of the patient; and the particular compound or salt or ester thereof employed. Since two different active agents are being used together in a combination therapy, the potency of each of the agents and the interactive effects achieved by combining them together must also be taken into account. A consideration of these factors is well within the purview of the ordinarily skilled clinician for the purpose of determining the therapeutically effective or prophylactically effective dosage amounts needed to prevent, counter, or arrest the progress of the condition.
  • Administration of the drug combination to the patient includes both self-administration and administration to the patient by another person.
  • Additional active agents may be used in combination with the COX-2 inhibitor and antiplatelet agent in a single dosage formulation, or may be administered to the patient in a separate dosage formulation, which allows for concurrent or sequential administration.
  • additional active agents include HMG-CoA synthase inhibitors; squalene epoxidase inhibitors; squalene synthetase inhibitors (also known as squalene synthase inhibitors), acyl- coenzyme A: cholesterol acyltransferase (ACAT) inhibitors; probucol; niacin; fibrates such as clofibrate, fenofibrate, and gemfibrizol;
  • vitamin B ⁇ also known as pyridoxine
  • ⁇ -adrenergic receptor blockers folic acid or a pharmaceutically acceptable salt or ester thereof such as the sodium salt and the methylglucamine salt
  • anti-oxidant vitamins such as vitamin C and E and beta carotene.
  • the active drugs can also be administered in the form of liposome delivery systems, such as small unilamellar vesicles, large unilamellar vesicles and multilamellar vesicles.
  • Liposomes can be formed from a variety of phospholipids, such as cholesterol, stearylamine or phosphatidylcholines.
  • the active drugs may also be delivered by the use of monoclonal antibodies as individual carriers to which the compound molecules are coupled. They may also be coupled with soluble polymers as targetable drug carriers.
  • soluble polymers can include polyvinyl - pyrrolidone, pyran copolymer, polyhydroxy-propyl-methacrylamide- phenol, polyhydroxy-ethyl-aspartamide-phenol, or polyethyleneoxide- polylysine substituted with palmitoyl residues.
  • the active drugs may be coupled to a class of biodegradable polymers useful in achieving controlled release of a drug, for example, polylactic acid, polyglycolic acid, copolymers of polylactic and polyglycolic acid, polyepsilon caprolactone, polyhydroxy butyric acid, polyorthoesters, polyacetals, polydihydropyrans, polycyanoacrylates and cross linked or amphipathic block copolymers of hydrogels.
  • a drug for example, polylactic acid, polyglycolic acid, copolymers of polylactic and polyglycolic acid, polyepsilon caprolactone, polyhydroxy butyric acid, polyorthoesters, polyacetals, polydihydropyrans, polycyanoacrylates and cross linked or amphipathic block copolymers of hydrogels.
  • the active agents may be administered in divided doses, for example two or three times daily, a single daily dose of each of the antiplatelet agent and the COX-2 inhibitor is preferred, with a single daily dose of both agents in a single pharmaceutical composition being most preferred.
  • the instant invention also encompasses a process for preparing a pharmaceutical composition comprising combining the antiplatelet agent and the COX-2 inhibitor with a pharmaceutically acceptable carrier, as well as the pharmaceutical composition which is
  • compositions of this invention, and methods for administering the combination therapy of an antiplatelet agent with a COX-2 inhibitor are useful for treating, preventing or reducing the risk of occurrence of acute coronary ischemic syndrome in mammals, and more particularly in humans, who are at risk of developing acute coronary ischemic syndrome.
  • Acute coronary ischemic syndrome includes the conditions of unstable angina and non-Q-wave myocardial infarction.
  • compositions and methods of the invention may be used to treat, prevent or reduce the risk of formation of thrombi and thromboemboli and therefore to prevent or reduce the risk of thrombotic occlusions and reocclusions. They are useful in surgery on peripheral arteries (arterial grafts, carotid endaterectomy) and in cardiovascular surgery where manipulation of arteries and organs, and/or the interaction of platelets with artificial surfaces, leads to platelet aggregation and potential formation of thrombi and thromboemboli.
  • the combination therapy can be used for preventing or reducing the risk of occurrence of platelet thrombosis, thromboembolism and reocclusion after acute intervention such as atherectomy, angioplasty, coronary artery bypass procedures or cardiac valve replacement.
  • the combination therapy can also be used for preventing or reducing the risk of occurrence of platelet thrombosis, thromboembolism and reocclusion during and after thrombolytic therapy.
  • blood vessels can also sustain chronic damage by the pathophysiological processes of atherosclerosis, patients with atherosclerosis can also be treated with the instant combination therapy to prevent or reduce the risk of occlusive thrombus formation.
  • the instant combination therapy can be used to treat, prevent or reduce the risk of intermittent claudication, which is a clinical manifestation of peripheral vessel disease.
  • Combination therapy of a COX-2 inhibitor with an antiplatelet agent may reduce the risk of thrombocytopenia.
  • the instant combination therapy can also be used to treat, prevent or reduce the risk of a first or subsequent Q-wave myocardial
  • the instant combination therapy can be used for treating, preventing or reducing the risk of occurrence of acute cerebrovascular ischemic events (e.g. a first or subsequent thrombotic stroke, or transient ischemic attack).
  • the instant combination therapy can be used whenever antiplatelet therapy, or inhibition of platelet aggregation, is needed.
  • compositions and methods of the present invention are also useful in combination with procedures for treating patients with other anticoagulants (e.g. thrombin inhibitors such as heparin and Factor Xa inhibitors such as warfarin), and thrombolytic agents (e.g. streptokinase and tissue plasminogen activator).
  • anticoagulants e.g. thrombin inhibitors such as heparin and Factor Xa inhibitors such as warfarin
  • thrombolytic agents e.g. streptokinase and tissue plasminogen activator.
  • a therapeutically effective amount of a COX-2 inhibitor and a therapeutically effective amount of an antiplatelet agent can be used for the preparation of a medicament useful for inhibiting platelet aggregation, and for treating, preventing or reducing the risk of developing acute coronary ischemic syndrome in mammals, particularly in humans.
  • a therapeutically effective amount of a COX-2 inhibitor and a therapeutically effective amount of an antiplatelet agent can be used for the preparation of a medicament useful for preventing or reducing the risk of formation of thrombi and thromboemboli, for preventing or reducing the risk of thrombotic occlusions and reocclusions, for treating, preventing or reducing the risk of a first or subsequent myocardial infarction, for preventing or reducing the risk of restenosis, for treating, preventing or reducing the risk of acute cerebrovascular ischemic events such as a first or subsequent thrombotic stroke or transient ischemic attack, and for halting or slowing the progression of atherosclerotic disease.
  • a therapeutically effective amount of a COX-2 inhibitor and a therapeutically effective amount of an antiplatelet agent can be used together for the preparation of a medicament suitable for oral administration which is useful for the above-described treatments.
  • a therapeutically effective amount of a COX-2 inhibitor can be used for the preparation of a
  • a therapeutically effective amount of an antiplatelet agent can be used for the preparation of a medicament for use in combination with a therapeutically effective amount of a COX-2 inhibitor, which is useful for the above-described treatments.
  • kits comprised of a COX-2 inhibitor in an oral dosage formulation and an antiplatelet agent in a separate oral dosage formulation.
  • the kit is comprised of a COX-2 inhibitor selected from the group consisting of 5-chloro-3-(4- (methylsulfonyl)phenyl)-2-(2-methyl-5-pyridinyl)pyridine; 2-(3,5- difluorophenyl)-3-(4-(methylsulfonyl)phenyl)-2-cyclopenten-l-one; 3- phenyl-4-(4-(methylsulfonyl)phenyl)-2-(5H)-furanone; 3-(3,4- difluorophenyl)-4-(4-(methylsulfonyl)phenyl)-2-(5H)-furanone; 5,5- dimethyl-4-(4-(methylsulfonyl)phenyl)-3-(3-fluorophenyl)-5H-fur
  • the COX-2 inhibitor is selected from 5-chloro-3-(4-(methylsulfonyl)phenyl)-2-(2- methyl-5-pyridinyl)pyridine; 2-(3,5-difluorophenyl)-3-(4- (methylsulfonyl)phenyl)-2-cyclopenten- 1-one; 3-phenyl-4-(4- (methylsulfonyl)phenyl)-2-(5H)-furanone; 3-(3,4-difluorophenyl)-4-(4- (methylsulfonyl)phenyl)-2-(5H)-furanone; 5,5-dimethyl-4-(4- (methylsulfonyl)phenyl)-3-(3-fluorophenyl)-5H-furan-2-one, and more particularly the GP Ilb/IIIa receptor antagonist is selected from Mpr-(Acetimidyl-Lys)-Gly-Asp-
  • the antiplatelet agent is a GP Ilb/IIIa receptor antagonist selected from the group consisting of Compound A, Compound B, and DMP 754.
  • kits comprised of an oral dosage formulation of a COX-2 inhibitor and an oral dosage formulation of a GP Ilb/IIIa receptor antagonist.
  • the packaging for the kit could be designed and manufactured in a variety of ways.
  • a preferred example is a blister package containing rows of a COX-2 inhibitor tablet and a GP Ilb/IIIa receptor antagonist tablet placed side by side on the same blister card, each of the two tablets in its own blister bubble, with calendar or similar type markings on the card that convey to the user that one "pair" of tablets (i.e., one COX-2 inhibitor tablet and one GP Ilb/IIIa receptor antagonist tablet) is to be ingested per day.
  • the COX-2 inhibitor is 3-phenyl-4-(4-(methylsulfonyl)phenyl)-2-(5H)-furanone and the GP Ilb/IIIa receptor antagonist is any one of [3(R)-[2-piperidin-4- yl)ethyl]-2-piperidone-l]acetyl-3(R)-methyl- ⁇ -alanine, 2(S)-[(p- Toluenesulfonyl)amino]-3-[[[5,6,7,8-tetrahydro-4-oxo-5-[2-(piperidin-4- yl)ethyl]-4H-pyrazolo-[l,5-a][l,4]diazepin-2-yl]carbonyl]-amino]propionic acid, or ((R)-methyl-3-[[[3-[4-(aminoiminomethyl)phenyl
  • Tablets containing 25.0, 50.0, and 100.0 mg, respectively, of a GP Ilb/IIIa receptor antagonist are prepared as illustrated below:
  • All of the active compound, cellulose, and a portion of the corn starch are mixed and granulated to 10% corn starch paste.
  • the resulting granulation is sieved, dried and blended with the remainder of the corn starch and the magnesium stearate.
  • the resulting granulation is then compressed into tablets containing 25.0, 50.0, and 100.0 mg, respectively, of active ingredient per tablet.
  • An intravenous dosage form of the GP Ilb/IIIa receptor antagonist is prepared as follows:
  • the active compound is dissolved at room temperature in a previously prepared solution of sodium chloride, citric acid, and sodium citrate in Water for Injection (USP, see page 1636 of United States Pharmacopeia/National Formulary for 1995, published by United States Pharmacopeial Convention, Inc., Rockville, Maryland, copyright 1994.
  • Tablet dose strengths of between 5 and 125 mg can be accommodated by varying total tablet weight, and the ratio of the first
  • Tablet dose strengths of between 5 and 125 mg can be accommodated by varying total tablet weight, and the ratio of the first three ingredients. Generally it is preferable to maintain a 1:1 ratio for microcrystalline cellulose : lactose monohydrate.
  • Capsule dose strengths of between 1 and 50 mg can be accommodated by varying total fill weight, and the ratio of the first three ingredients. Generally it is preferable to maintain a 1:1 ratio for microcrystalline cellulose : lactose monohydrate.
  • Solution dose strengths of between 1 and 50 mg/5mL can be accommodated by varying the ratio of the two ingredients.
  • Suspension dose strengths of between 1 and 50 mg/5ml can be accommodated by varying the ratio of the first two ingredients.
  • Tablets containing 25.0, 50.0, and 100.0 mg, respectively, of a GP Ilb/IIIa receptor antagonist and 25 mg COX-2 Inhibitor are prepared as illustrated below:
  • Both active compounds, cellulose, and a portion of the corn starch are mixed and granulated to 10% corn starch paste.
  • the resulting granulation is sieved, dried and blended with the remainder of the corn starch and the magnesium stearate.
  • the resulting granulation is then compressed into tablets containing 25.0, 50.0, and 100.0 mg,

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Abstract

Cette invention a trait à une méthode visant à traiter, prévenir ou réduire le risque chez un patient de développer un trouble faisant partie du groupe constitué par les états pathologiques suivants: le syndrome ischémique coronarien aigu, la thrombose, la thrombo-embolie, l'occlusion ou la ré-occlusion thrombotique, la resténose, l'accident ischémique transitoire, le premier ictus thrombotique ou l'ictus subséquent. Cette méthode consiste à administrer au patient une dose efficace du point de vue thérapeutique d'un anti-agrégant plaquettaire associé à une dose efficace du point de vue thérapeutique d'un inhibiteur de COX-2. L'invention concerne porte également sur une composition pharmaceutique renfermant une dose efficace du point de vue thérapeutique d'un inhibiteur de COX-2 ou un sel acceptable du point de vue pharmaceutique de celui-ci et un anti-agrégant plaquettaire ou un sel acceptable du point de vue pharmaceutique de celui-ci.
PCT/US1999/005063 1998-03-13 1999-03-09 Therapie associee destinee au syndrome ischemique coronarien aigu ainsi qu'a des troubles connexes WO1999045913A1 (fr)

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CA002322824A CA2322824A1 (fr) 1998-03-13 1999-03-09 Therapie associee destinee au syndrome ischemique coronarien aigu ainsi qu'a des troubles connexes
JP2000535328A JP2002506024A (ja) 1998-03-13 1999-03-09 急性冠動脈虚血症候群および関連状態に対する併用療法および組成物
EP99911208A EP1061908A4 (fr) 1998-03-13 1999-03-09 Therapie associee destinee au syndrome ischemique coronarien aigu ainsi qu'a des troubles connexes

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GBGB9815857.9A GB9815857D0 (en) 1998-07-21 1998-07-21 Combination therapy for treating preventing or reducing the risks associated with acute coronary ischemic syndrome and related conditions

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WO2000053264A1 (fr) * 1999-03-11 2000-09-14 Du Pont Pharmaceuticals Company Traitement de la thrombose au moyen d'une combinaison d'un inhibiteur du facteur xa et d'aspirine, d'un activateur tissulaire du plasminogene (tpa), d'un antagoniste de gpiib/iiia, d'heparine a faible masse moleculaire ou d'heparine
WO2001034138A1 (fr) * 1999-11-08 2001-05-17 Massachusetts Institute Of Technology, Inc. Compositions et methodes de traitement de troubles neurologiques et de maladies neurodegeneratives
US6794412B1 (en) 1999-03-11 2004-09-21 Bristol-Myers Squibb Pharma Company Treatment of thrombosis by combined use of a factor Xa inhibitor and aspirin
US6825185B2 (en) 2000-12-21 2004-11-30 Nitromed, Inc. Substituted aryl compounds as novel cyclooxygenase-2 selective inhibitors, compositions and methods of use
WO2004049095A3 (fr) * 2002-11-25 2004-12-23 Jallal Messadek Compositions de betaine
EP1680121A2 (fr) * 2003-10-15 2006-07-19 CombinatoRx, Incorporated Procedes et reactifs pour le traitement de troubles inflammatoires
US7371759B2 (en) 2003-09-25 2008-05-13 Bristol-Myers Squibb Company HMG-CoA reductase inhibitors and method
US7420059B2 (en) 2003-11-20 2008-09-02 Bristol-Myers Squibb Company HMG-CoA reductase inhibitors and method
US7608640B2 (en) 1999-03-02 2009-10-27 Jallal Messadek Glycine betaine and its use
US7780990B2 (en) 2005-02-15 2010-08-24 Jallal Messadek Combination therapeutic compositions and method of use
US7786077B2 (en) 2005-04-27 2010-08-31 Jallal Messadek Insulins combinations
US8318805B2 (en) 2004-11-10 2012-11-27 Jallal Messadek Modulation of nitric oxide synthases by betaines
US8343947B2 (en) 2003-07-15 2013-01-01 Jallal Messadek Therapeutic treatment

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JP2004189711A (ja) * 2002-12-11 2004-07-08 Raul Altman 急性冠動脈症候群および関連病態の治療のための抗血小板薬と組合せたメロキシカムの使用

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Publication number Priority date Publication date Assignee Title
US7608640B2 (en) 1999-03-02 2009-10-27 Jallal Messadek Glycine betaine and its use
US6794412B1 (en) 1999-03-11 2004-09-21 Bristol-Myers Squibb Pharma Company Treatment of thrombosis by combined use of a factor Xa inhibitor and aspirin
WO2000053264A1 (fr) * 1999-03-11 2000-09-14 Du Pont Pharmaceuticals Company Traitement de la thrombose au moyen d'une combinaison d'un inhibiteur du facteur xa et d'aspirine, d'un activateur tissulaire du plasminogene (tpa), d'un antagoniste de gpiib/iiia, d'heparine a faible masse moleculaire ou d'heparine
WO2001034138A1 (fr) * 1999-11-08 2001-05-17 Massachusetts Institute Of Technology, Inc. Compositions et methodes de traitement de troubles neurologiques et de maladies neurodegeneratives
US6825185B2 (en) 2000-12-21 2004-11-30 Nitromed, Inc. Substituted aryl compounds as novel cyclooxygenase-2 selective inhibitors, compositions and methods of use
WO2004049095A3 (fr) * 2002-11-25 2004-12-23 Jallal Messadek Compositions de betaine
US8343947B2 (en) 2003-07-15 2013-01-01 Jallal Messadek Therapeutic treatment
US7371759B2 (en) 2003-09-25 2008-05-13 Bristol-Myers Squibb Company HMG-CoA reductase inhibitors and method
EP1680121A2 (fr) * 2003-10-15 2006-07-19 CombinatoRx, Incorporated Procedes et reactifs pour le traitement de troubles inflammatoires
EP1680121A4 (fr) * 2003-10-15 2007-12-26 Combinatorx Inc Procedes et reactifs pour le traitement de troubles inflammatoires
US7420059B2 (en) 2003-11-20 2008-09-02 Bristol-Myers Squibb Company HMG-CoA reductase inhibitors and method
US8318805B2 (en) 2004-11-10 2012-11-27 Jallal Messadek Modulation of nitric oxide synthases by betaines
US7780990B2 (en) 2005-02-15 2010-08-24 Jallal Messadek Combination therapeutic compositions and method of use
US7786077B2 (en) 2005-04-27 2010-08-31 Jallal Messadek Insulins combinations

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