WO2007117621A1 - Use of combination preparations containing thrombin receptor antagonists for treating cardiovascular disorders - Google Patents
Use of combination preparations containing thrombin receptor antagonists for treating cardiovascular disorders Download PDFInfo
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- 0 C[C@]([C@]1(*)[C@@]2(CO)C[C@](C)[C@](C)[C@@]1CCc(nc1)ccc1-c1ccccc1C#N)OC2=O Chemical compound C[C@]([C@]1(*)[C@@]2(CO)C[C@](C)[C@](C)[C@@]1CCc(nc1)ccc1-c1ccccc1C#N)OC2=O 0.000 description 2
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- A61P7/02—Antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors
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- A—HUMAN NECESSITIES
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- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
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- A61P9/06—Antiarrhythmics
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- A—HUMAN NECESSITIES
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- 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
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- A—HUMAN NECESSITIES
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- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/12—Antihypertensives
Definitions
- thrombin receptors are known to be present in such cell types as human platelets, vascular smooth muscle cells, endothelial cells and fibroblasts.
- thrombin receptor antagonists ("TRAs") have been identified based on structure-activity studies involving substitutions of amino acids on thrombin receptors. In Bernatowicz et al, J. Med. Chem., vol. 39, pp.
- tetra- and pentapeptides are disclosed as being potent thrombin receptor antagonists, for example N-trans-cinnamoyl-p-fluoroPhe-p-guanidinoPhe-Leu- Arg-NH2 and N-trans-cinnamoyl-p-fluoroPhe-p-guanidinoPhe-Leu-Arg-Arg- NH2- Peptide thrombin receptor antagonists are also disclosed in WO 94/03479, published February 17, 1994.
- Thrombin receptor antagonists have been suggested in the literature as being potentially useful in treating a variety of cardiovascular diseases or conditions including, for example, thrombosis, vascular restenosis, deep venous thrombosis, lung embolism, cerebral infarction, heart disease, disseminated intravascular coagulation syndrome, hypertension (Suzuki, Shuichi, PCT Int. Appls. WO 0288092 (2002), WO 0285850 (2002) and WO 0285855 (2002)), arrhythmia, inflammation, angina, stroke, atherosclerosis, ischemic conditions (Zhang, Han-cheng, PCT Int. Appl. WO 0100659 (2001), WO 0100657(2001 ) and WO 0100656 (2001 )).
- Substituted thrombin receptor antagonists are disclosed in US patent nos. 6,063,847; 6,326,380; and 6,645,987 and U.S. publication nos. 03/0203927; 04/0216437A1 ; 04/0152736; and 03/0216437.
- the use of a small subset of thrombin receptor antagonists to treat a variety of conditions and diseases is disclosed in U.S. publication no. 04/0192753.
- the prevention of complications associated with cardiopulmonary bypass surgery by administration of a thrombin receptor antagonist is taught in U.S. application no. 11/613,450.
- a crystalline form of the bisulfate salt of a particular thrombin receptor antagonist (identified as "Compound A" below) is disclosed in 04/0176418A1.
- the two or more active agents may act by very different biochemical pathways to provide particularly beneficial therapeutic results.
- the two or more active agents may be delivered as either co-administered individual formulations, or as a single co-formulation. Co-formulations have the patient- compliance advantages of reducing the number of distinct doses and fixing the ratio of the two active agents being administered.
- Vytorin® is a single dosage form comprising simvastatin (marketed in the U.S. as a monotherapy as Zocor®) and ezetimibe (marketed in the U.S. as a monotherapy as Zetia®).
- the present invention is directed to pharmaceutical compositions comprising an effective amount of at least one thrombin receptor antagonist, an effective amount of at least one cardiovascular agent selected from the group consisting of calcium channel blockers, statins, cholesterol absorption inhibitors, low molecular weight heparins, antiarrhythmic agents, alpha adrenergic agonists, beta adrenergic blocking agents, aldosterone antagonists, angiotensin-converting-enzyme (“ACE”) inhibitors, ACE/NEP inhibitors, angiotensin Il receptor blockers (“ARBs”), endothelin antagonists, neutral endopeptidase inhibitors, phosphodiesterase inhibitors, fibrinolytics, GP llb/llla antagonists, direct thrombin inhibitors, indirect thrombin inhibitors, lipoprotein- associated phospholipase A2 (“LpPLA 2 ”) modulators, direct factor X a inhibitors, indirect factor X 3 inhibitors, indirect factor Xa/ll a inhibitors
- the thrombin receptor antagonist is selected from the group consisting of
- the thrombin receptor antagonist is N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N
- the salt is a bisulfate salt.
- the thrombin receptor antagonist is N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N
- the thrombin receptor antagonist is N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N
- the thrombin receptor antagonist is E-5555.
- the cardiovascular agent is a calcium channel blocker selected from the group consisting of amlodipine, felodipine, diltiazem, verapamil, nifedipine, nicardipine, nisoldipine, bepridil, and verapamil.
- the cardiovascular agent is a statin selected from the group consisting of atorvastatin, fluvastatin, lovastatin, pravastatin, pravastatin, rosuvastatin, and simvastatin.
- the cardiovascular agent is a cholesterol absorption inhibitor selected from the group consisting of ezetimibe and AZD 4121.
- the cardiovascular agent is a low molecular weight heparin selected from the group consisting of dalteparin, ardeparin, certoparin, enoxaparin, pamaparin, tinzaparin, reviparin, nadroparin, warfarin, ximelagatran, fondaparin, and enoxaparin.
- the cardiovascular agent is an antiarrhythmic agent selected from the group consisting of dofetilide, ibutilide, metoprolol, propranolol, atenolol, ajmaline, disopyramide, prajmaline, procainamide, quinidine, sparteine, aprindine, lidocaine, mexiletine, tocainide, encainide, flecainide, lorcainide, moricizine, propafenone, acebutolol, pindolol, amiodarone, bretylium, bunaftine, dofetilide, sotalol, adenosine, atropine and digoxin.
- an antiarrhythmic agent selected from the group consisting of dofetilide, ibutilide, metoprolol, propranolol, atenolol, ajmaline, disopyramide, prajmaline, procainamide,
- the cardiovascular agent is an alpha adrenergic agonist selected from the group consisting of doxazosin, terazoson and prazosin.
- the cardiovascular agent is a beta adrenergic blocking agent selected from the group consisting of carvedilol, propranolol, timolol, nadolol, atenolol, metoprolol, bisoprolol, nebivolol, betaxolol, acebutolol, and bisoprolol.
- the cardiovascular agent is an ACE inhibitor selected from the group consisting of moexipril, quinapril ramipril, lisinopril, benazapril, enalapril, captopril, spirapril, perindopril, fosinopril and trandolapril.
- the cardiovascular agent is an ARB selected from the group consisting of olmesartan, candesartan, valsartan, telmisartan, irbesartan, losartan and eprosartan.
- the cardiovascular agent is an endothelin antagonist selected from the group consisting of tezosentan, bosentan, and sitaxsentan.
- the cardiovascular agent is a direct thrombin inhibitor selected from the group consisting of ximelagatran and AZD0837.
- the cardiovascular agent is a direct factor X a inhibitor selected from the group consisting of fondaparinux, apixaban, razaxaban, rivaroxaban, KFA-1982, DX-9065a, AVE3247, otamixaban, AVE6324 and SAR377142.
- the cardiovascular agent is an inhibitor of adenosine diphosphate ("ADP") -induced platelet aggregation selected from the group consisting of clopidogrel, ticlopidine, prasugrel, and AZD6140.
- ADP adenosine diphosphate
- the invention comprises a method of treating or preventing a cardiovascular condition in a mammal in need thereof comprising administering to said mammal any of the above pharmaceutical compositions, wherein said cardiovascular condition is acute coronary syndrome, secondary prevention, peripheral arterial disease, thrombosis, atherosclerosis, restenosis, hypertension, angina pectoris, arrhythmia, heart failure, myocardial infarction, glomerulonephritis, thrombotic stroke, thromboembolic stroke, deep vein thrombosis, venous thromboembolism, a cardiovascular disease associated with hormone replacement therapy, disseminated intravascular coagulation syndrome, renal ischemia, cerebral stroke, cerebral ischemia, cerebral infarction, migraine, renal vascular homeostasis or erectile dysfunction.
- said cardiovascular condition is acute coronary syndrome, secondary prevention, peripheral arterial disease, thrombosis, atherosclerosis, restenosis, hypertension, angina pectoris, arrhythmia, heart failure, myocardial infarction
- the invention comprises a method of treating or preventing a cardiovascular condition in a mammal in need of said treating comprising administering to said mammal a first pharmaceutical composition comprising a thrombin receptor antagonist and a second pharmaceutical composition comprising a cardiovascular agent.
- the thrombin receptor antagonist is N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N
- the cardiovascular agent is selected from the group consisting of calcium channel blockers, statins, cholesterol absorption inhibitors, low molecular weight heparins, antiarrhythmic agents, alpha adrenergic agonists, beta adrenergic blocking agents, aldosterone antagonists, angiotensin-converting-enzyme ("ACE") inhibitors, ACE/NEP inhibitors, angiotensin Il receptor blockers ("ARBs”), endothelin antagonists, neutral endopeptidase inhibitors, phosphodiesterase inhibitors, fibrinolytics, GP llb/llla antagonists, direct thrombin inhibitors, indirect thrombin inhibitors, lipoprotein-associated phospholipase A2 (“LpPLA 2 ”) modulators, direct factor X a inhibitors, indirect factor X a inhibitors, indirect factor Xa/ll a inhibitors, diuretics, nitrates, thromboxane antagonists, platelet
- Subject includes both mammals and non-mammalian animals.
- “Mammal” includes humans and other mammalian animals.
- an effective amount or “therapeutically effective amount” is meant to describe an amount of compound or a composition of the present invention effective in producing the desired therapeutic, ameliorative, inhibitory or preventative effect.
- an effective amount of a thrombin receptor antagonist is an amount sufficient to achieve a desired threshold of PAR-1 antagonism.
- Acute coronary syndrome includes any group of clinical symptoms compatible with acute myocardial ischemia.
- Acute myocardial ischemia is chest pain due to insufficient blood supply to the heart muscle that results from coronary artery disease (also called coronary heart disease).
- Acute coronary syndrome thus covers the spectrum of clinical conditions ranging from unstable angina to non-Q-wave myocardial infarction and Q-wave myocardial infarction.
- Symptoms may include chest pain, shortness of breath, nausea, vomiting, diaphoresis (sweating), palpitations, anxiety or a sense of impending doom and a feeling of being acutely ill.
- “Secondary prevention” means treating patients who have already suffered a significant cardiovascular event, such as a heart attack or stroke, to prevent another future, potentially more serious, perhaps lethal, cardiovascular or cerebrovascular event. "Ml” mean myocardial infarction.
- CABG coronary bypass graft
- PCI percutaneous coronary intervention
- coronary angioplasty is an invasive cardiologic therapeutic procedure to treat the stenotic (narrowed) coronary arteries of the heart. These stenotic segments are due to the build up of cholesterol-laden plaques that form due to coronary heart disease.
- PCI as used herein, will be understood to include balloon angioplasty, implantation of stents, rotational or laser atherectomy, and brachytherapy.
- the bisulfate salt of Compound A is currentty in development as a thrombin receptor antagonist by Schering Corp. Its synthesis is disclosed in U.S. publication no. 03/0216437, published Nov. 20, 2003, which publication also discloses Compound C.
- Compound B is disclosed in U.S. Patent no. 6,645,987.
- the therapeutic combinations of the present invention encompass at least one thrombin receptor antagonist along with at least one additional therapeutically effective agent.
- the thrombin receptor antagonist can be chosen from any of those disclosed herein, or from other compounds which display activity as thrombin receptor antagonists.
- the therapeutically effective agents may be cardiovascular agents.
- cardiovascular agents that can be used in combination with the thrombin receptor antagonist include drugs that have anti-thrombotic, anti- platelet aggregation, antiatherosclerotic, antirestenotic and/or anti-coagulant activity.
- drugs are useful in treating thrombosis-related diseases including thrombosis, atherosclerosis, restenosis, hypertension, angina pectoris, arrhythmia, heart failure, myocardial infarction, glomerulonephritis, thrombotic and thromboembolic stroke, peripheral vascular diseases, other cardiovascular diseases, cerebral ischemia, inflammatory disorders and cancer, as well as other disorders in which thrombin and its receptor play a pathological role.
- Suitable cardiovascular agents are selected from one or more of the group consisting of: calcium channel blockers, such as amlodipine besilate, marketed as
- NORV ASC® and LOTREL® felodipine, marketed as PLENDIL®, diltiazem, marketed as CARDIZEM®, verapamil, marketed as CALAN®, nifedipine, marketed as ADALAT®, nicardipine, marketed as CARDENE®, nisoldipine, marketed as SULAR®, bepridil, marketed as VASCOR®, and verapamil, marketed as CALAN®; lomerizine, used as an anti-hypertensive and in the treatment of angina; statins, such as atorvastatin, marketed as LIPITOR®, fluvastatin, marketed as LESCOL®, lovastatin, marketed as MEVACOR®, pravastatin, marketed as LIVALO®, pravastatin, marketed as PRAVACHOL®, rosuvastatin, marketed as CRESTOR®, and simvastatin, marketed as Z
- FRAGMIN® ardeparin, marketed as NORMIFLO®, certoparin, marketed as SANDOPARIN®, enoxaparin, marketed as LOVENOX® and CLEXANE®, parnaparin, marketed as FLUXUM®, tinzaparin, marketed as INNOHEP® and LOGIPARIN®, reviparin, marketed as CLIVARIN®, nadroparin, marketed as FRAXIPARIN®, warfarin, ximelagatran, fondaparin, and enoxaparin, used for prophylaxis or treatment of deep vein thrombosis and pulmonary embolism; antiarrhythmic agents, such as dofetilide and ibutilide fumarate, marketed as TIKOSYN®, metoprolol, marketed as TOPROL-XL®, metoprolol tartrate, marketed as LOPRESSOR®, propranolol, marketed as IN
- COREG® propranolol, marketed as BETACHRON E-R®, timolol, marketed as BLOCADREN®, nadolol, marketed as CORGARD®, atenolol, marketed as TENORMIN®, metoprolol, marketed as TOPROL XL®, bisoprolol, marketed as ZEBET A®, nebivolol, betaxolol, marketed as KERLONE®; acebutolol, marketed as SECTRAL, and bisoprolol, marketed as ZEBETA; aldosterone antagonists, such as eplerenone, marketed as INSPRA®, and spironolactone, marketed as Aldactone®, used for reducing cardiovascular risk in patients following myocardial infarction; angiotensin-converting-enzyme (“ACE”) inhibitors, such as moexipril, marketed as UNIVASC®, quinapri
- GP llb/llla antagonists such as integrillin, abciximab, and tirofiban
- direct thrombin inhibitors such as ximelagatran, which has been marketed as EXANTA®, and AZD0837, which is in development for thrombosis:
- indirect thrombin inhibitors such as odiparcil, currently in development by GlaxoSmithKline for prevention of thrombotic complications of cardiovascular disease; lipoprotein-associated phospholipase A2 (“LpPLA 2 ”) modulators; direct factor X a inhibitors, such as fondaparinux sodium, marketed as
- ARIXTRA® apixaban, razaxaban, INDUPRUX®, rivaroxaban (BAY 59-7939), KFA-1982, DX-9065a, AVE3247, otamixaban (XRP0673), AVE6324 and SAR377142; indirect X a inhibitors, such as idraparinux (long-acting pentasaccharide), fondaparinux sodium (pentasaccharide) and SSR126517; indirect X a /N a inhibitors, such as enoxaparin sodium, marketed as SR123781 (short-acting hexadecasaccharide), AVE5026, SSR128428 (long- acting hexadecasaccharide), and SSR128429; diuretics, such as chlorthalidone, a component in the combination marketed as TENORETIC®, ethacrynic acid, furosemide, amiloride
- CPU inhibiters such as AZD9684, which is in development for thrombosis; renin inhibitors such as aliskirin, marketed as RASILEZ, and VNP489; inhibitors of adenosine diphosphate ("ADP") -induced platelet aggregation, such as clopidogret, marketed as PLAVIX®, ticlopidine, marketed as TICLID®, prasugrel, and AZD6140, which is in development for arterial thrombosis:
- renin inhibitors such as aliskirin, marketed as RASILEZ, and VNP489
- ADP adenosine diphosphate
- PLAVIX® clopidogret
- ticlopidine marketed as TICLID®
- prasugrel prasugrel
- AZD6140 which is in development for arterial thrombosis
- AZD6140 AZD6140
- NHE-1 inhibitors such as AVE4454 and AVE4890. All of the pharmaceutically acceptable free base and salt forms of the above-listed cardiovascular agents are within the scope of the present invention.
- the two or more active components may each be formulated individually and coadministered simultaneously or sequentially.
- the components of the combination can be administered individually or together in any conventional dosage form such as capsule, tablet, powder, cachet, suspension, solution, suppository, nasal spray, etc.
- the active agents may be formulated in a single fixed-dose pharmaceutical composition comprising a thrombin receptor antagonist and the other therapeutically effective agent(s) along with a pharmaceutically acceptable carrier.
- the term "at least one thrombin receptor antagonist” means that one more different compounds that are active as thrombin receptor antagonists may be used in a pharmaceutical combination or method of treatment. Preferably, one to three thrombin receptor antagonists are used.
- the term “one or more additional cardiovascular agents” means that one to three additional drugs may be administered in combination with a thrombin receptor antagonist; preferably, one cardiovascular agent is administered in combination with one thrombin receptor antagonist.
- an inert, pharmaceutically acceptable carrier can be either solid or liquid.
- Solid form preparations include powders, tablets, dispersible granules, capsules, cachets and suppositories.
- the powders and tablets may be comprised of from about 5 to about 95 percent active ingredient.
- Suitable solid carriers are known in the art, e.g., magnesium carbonate, magnesium stearate, talc, sugar or lactose. Tablets, powders, cachets and capsules can be used as solid dosage forms suitable for oral administration. Examples of pharmaceutically acceptable carriers and methods of manufacture for various compositions may be found in A. Gennaro (ed.), The Science and Practice of Pharmacy, 20 th Edition, Lippincott Williams & Wilkins, Baltimore, MD, (2000).
- Liquid form preparations include solutions, suspensions and emulsions. As an example may be mentioned water or water-propylene glycol solutions for parenteral injection or addition of sweeteners and opacifiers for oral solutions, suspensions and emulsions. Liquid form preparations may also include solutions for intranasal administration.
- Aerosol preparations suitable for inhalation may include solutions and solids in powder form, which may be in combination with a pharmaceutically acceptable carrier, such as an inert compressed gas, e.g., nitrogen.
- a pharmaceutically acceptable carrier such as an inert compressed gas, e.g., nitrogen.
- solid form preparations which are intended to be converted, shortly before use, to liquid form preparations for either oral or parenteral administration.
- liquid forms include solutions, suspensions and emulsions.
- the combinations of the invention may also be deliverable transdermally.
- the transdermal compositions can take the form of creams, lotions, aerosols and/or emulsions and can be included in a transdermal patch of the matrix or reservoir type as are conventional in the art for this purpose.
- the administration of the above-described combinations is carried out by specifying not only the formulations, but also the modes of administration and the dosing regimen.
- the formulations are solid and designed for oral administration.
- Orally dissolving formulations of thrombin receptor antagonists are disclosed in U.S. provisional application no. 60/689,207, which is herein incorporated in its entirety by reference.
- the pharmaceutical preparation is in a unit dosage form.
- the preparation is subdivided into suitably sized unit doses containing appropriate quantities of the active component, e.g., an effective amount to achieve the desired purpose.
- the dosing regimen for the above-described thrombin receptor antagonists may comprise a loading dose followed by a series of maintenance doses.
- loading doses of 20 and 40 mgs. and maintenance doses of 1 and 2.5 mg. of compound A are preferred. More preferably, monotherapy includes doses of 40 mg. and 2.5 mg. for the loading and maintenance doses, respectively. In combination therapy, it is possible that lower doses may be favored.
- the loading dose of the thrombin receptor antagonist is about 5 to about 50 mg., preferably about 10 to about 40 mg.
- the daily maintenance dose of the thrombin receptor antagonist is about 0.5 to about 10 mg., preferably about 1 to about 5 mg.
- the dosage of the other therapeutically active agent(s) may range from 1 to 1000 mg per dose.
- the amount and frequency of administration of the compounds of the invention and/or the pharmaceutically acceptable salts thereof will be regulated according to the judgment of the attending clinician considering such factors as age, condition and size of the patient as well as severity of the symptoms being treated.
- the present invention also encompasses methods of treating conditions by administration of the above-described combinations.
- cardiovascular or circulatory diseases or conditions such as acute coronary syndrome, secondary prevention, peripheral arterial disease, thrombosis, atherosclerosis, restenosis, hypertension, angina pectoris, arrhythmia, heart failure, myocardial infarction, glomerulonephritis, thrombotic stroke, thromboembolic stroke, deep vein thrombosis, venous thromboembolism, a cardiovascular disease associated with hormone replacement therapy, disseminated intravascular coagulation syndrome, renal ischemia, cerebral stroke, cerebral ischemia, cerebral infarction, migraine, renal vascular homeostasis or erectile dysfunction.
- the treatment of acute coronary syndrome is the reduction of thrombotic vascular events in at-risk patients identified by acute coronary syndrome, including unstable angina/non-ST segment elevation myocardial infarction (Ml). It includes acute protection followed by maintenance. Secondary prevention is the reduction of thrombotic vascular events in at-risk patients identified by one or more of such factors as: acute coronary syndrome (including unstable angina/non-ST segment elevation and/or Ml); a history of coronary artery disease (prior Ml, CABG, PCI); a history of stroke; and established peripheral arterial disease.
- Peripheral arterial disease (“PAD”) is a chronic condition that results from narrowing of the vessels that supply oxygen-rich blood to the legs, abdomen, pelvis, arms, or neck. Peripheral arterial disease is also called peripheral vascular disease.
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Application Number | Priority Date | Filing Date | Title |
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MX2008012933A MX2008012933A (en) | 2006-04-06 | 2007-04-05 | Use of combination preparations containing thrombin receptor antagonists for treating cardiovascular disorders. |
AU2007235353A AU2007235353A1 (en) | 2006-04-06 | 2007-04-05 | Use of combination preparations containing thrombin receptor antagonists for treating cardiovascular disorders |
EP07755024A EP2001471A1 (en) | 2006-04-06 | 2007-04-05 | Use of combination preparations containing thrombin receptor antagonists for treating cardiovascular disorders |
BRPI0710840-0A BRPI0710840A2 (en) | 2006-04-06 | 2007-04-05 | tra combination therapies |
JP2009504321A JP2009532487A (en) | 2006-04-06 | 2007-04-05 | Combination preparations containing thrombin receptor antagonists for treating cardiovascular disorders |
CA002648613A CA2648613A1 (en) | 2006-04-06 | 2007-04-05 | Use of combination preparations containing thrombin receptor antagonists for treating cardiovascular disorders |
NO20084677A NO20084677L (en) | 2006-04-06 | 2008-11-05 | Use of combination preparations containing thrombin receptor antagonists for the treatment of cardiovascular disorders |
Applications Claiming Priority (10)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US79046906P | 2006-04-06 | 2006-04-06 | |
US60/790,469 | 2006-04-06 | ||
US80861106P | 2006-05-26 | 2006-05-26 | |
US60/808,611 | 2006-05-26 | ||
US80978506P | 2006-05-31 | 2006-05-31 | |
US60/809,785 | 2006-05-31 | ||
US83947406P | 2006-08-23 | 2006-08-23 | |
US83948406P | 2006-08-23 | 2006-08-23 | |
US60/839,474 | 2006-08-23 | ||
US60/839,484 | 2006-08-23 |
Publications (1)
Publication Number | Publication Date |
---|---|
WO2007117621A1 true WO2007117621A1 (en) | 2007-10-18 |
Family
ID=38458156
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
PCT/US2007/008612 WO2007117621A1 (en) | 2006-04-06 | 2007-04-05 | Use of combination preparations containing thrombin receptor antagonists for treating cardiovascular disorders |
Country Status (11)
Country | Link |
---|---|
EP (1) | EP2001471A1 (en) |
JP (1) | JP2009532487A (en) |
AR (1) | AR060354A1 (en) |
AU (1) | AU2007235353A1 (en) |
BR (1) | BRPI0710840A2 (en) |
CA (1) | CA2648613A1 (en) |
MX (1) | MX2008012933A (en) |
NO (1) | NO20084677L (en) |
PE (1) | PE20080183A1 (en) |
TW (1) | TW200812619A (en) |
WO (1) | WO2007117621A1 (en) |
Cited By (6)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2008005353A2 (en) * | 2006-06-30 | 2008-01-10 | Schering Corporation | Immediate-release tablet formulations of a thrombin receptor antagonist |
WO2009074249A1 (en) * | 2007-12-11 | 2009-06-18 | Bayer Schering Pharma Aktiengesellschaft | Oxazolidinones for the treatment and/or prophylaxis of heart failure |
WO2009124103A2 (en) * | 2008-04-02 | 2009-10-08 | Schering Corporation | Combination therapies comprising par1 antagonists with par4 antagonists |
EP2241315A1 (en) * | 2008-01-11 | 2010-10-20 | Eisai R&D Management Co., Ltd. | Pharmaceutical composition, use of 2-iminopyrrolidine derivative for production of pharmaceutical composition, and kit for treatment or amelioration of heart diseases |
WO2010144339A3 (en) * | 2009-06-08 | 2011-05-12 | Schering Corporation | A thrombin receptor antagonist and clopidogrel fixed dose tablet |
US20130183392A1 (en) * | 2011-07-15 | 2013-07-18 | Steven Moore | Insect repellant and system |
Families Citing this family (2)
Publication number | Priority date | Publication date | Assignee | Title |
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KR20140028971A (en) * | 2012-08-31 | 2014-03-10 | 한미약품 주식회사 | Bilayered tablet composite formulation of atorvastatin, irbesartan and magnesium carbonate |
CN105125504A (en) * | 2015-09-17 | 2015-12-09 | 青岛华之草医药科技有限公司 | Composition granules of blood lipid-lowering drug pitavastatin calcium |
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2007
- 2007-04-04 AR ARP070101439A patent/AR060354A1/en not_active Application Discontinuation
- 2007-04-04 PE PE2007000416A patent/PE20080183A1/en not_active Application Discontinuation
- 2007-04-04 TW TW096112178A patent/TW200812619A/en unknown
- 2007-04-05 CA CA002648613A patent/CA2648613A1/en not_active Abandoned
- 2007-04-05 BR BRPI0710840-0A patent/BRPI0710840A2/en not_active IP Right Cessation
- 2007-04-05 AU AU2007235353A patent/AU2007235353A1/en not_active Abandoned
- 2007-04-05 WO PCT/US2007/008612 patent/WO2007117621A1/en active Application Filing
- 2007-04-05 EP EP07755024A patent/EP2001471A1/en not_active Withdrawn
- 2007-04-05 MX MX2008012933A patent/MX2008012933A/en unknown
- 2007-04-05 JP JP2009504321A patent/JP2009532487A/en not_active Withdrawn
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2008
- 2008-11-05 NO NO20084677A patent/NO20084677L/en not_active Application Discontinuation
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US20040152736A1 (en) * | 2000-06-15 | 2004-08-05 | Samuel Chackalamannil | Thrombin receptor antagonists |
US20040176418A1 (en) * | 2000-06-15 | 2004-09-09 | Schering Corporation | Crystalline polymorph of a bisulfate salt of a thrombin receptor antagonist |
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WO2008005353A3 (en) * | 2006-06-30 | 2008-06-26 | Schering Corp | Immediate-release tablet formulations of a thrombin receptor antagonist |
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JP2011506363A (en) * | 2007-12-11 | 2011-03-03 | バイエル・シェーリング・ファルマ・アクチェンゲゼルシャフト | Oxazolidinones for the treatment and / or prevention of heart failure |
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WO2009124103A3 (en) * | 2008-04-02 | 2010-01-14 | Schering Corporation | Combination therapies comprising par1 antagonists with par4 antagonists |
WO2009124103A2 (en) * | 2008-04-02 | 2009-10-08 | Schering Corporation | Combination therapies comprising par1 antagonists with par4 antagonists |
WO2010144339A3 (en) * | 2009-06-08 | 2011-05-12 | Schering Corporation | A thrombin receptor antagonist and clopidogrel fixed dose tablet |
US20130183392A1 (en) * | 2011-07-15 | 2013-07-18 | Steven Moore | Insect repellant and system |
Also Published As
Publication number | Publication date |
---|---|
NO20084677L (en) | 2008-11-05 |
AR060354A1 (en) | 2008-06-11 |
BRPI0710840A2 (en) | 2011-08-23 |
PE20080183A1 (en) | 2008-03-10 |
AU2007235353A1 (en) | 2007-10-18 |
EP2001471A1 (en) | 2008-12-17 |
JP2009532487A (en) | 2009-09-10 |
CA2648613A1 (en) | 2007-10-18 |
MX2008012933A (en) | 2008-10-15 |
TW200812619A (en) | 2008-03-16 |
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