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WO2000053264A1 - Treatment of thrombosis by combined use of a factor xa inhibitor and aspirin, tissue plasminogen activator (tpa), a gpiib/iiia antagonist, low molecular weight heparin or heparin - Google Patents

Treatment of thrombosis by combined use of a factor xa inhibitor and aspirin, tissue plasminogen activator (tpa), a gpiib/iiia antagonist, low molecular weight heparin or heparin Download PDF

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Publication number
WO2000053264A1
WO2000053264A1 PCT/US2000/006451 US0006451W WO0053264A1 WO 2000053264 A1 WO2000053264 A1 WO 2000053264A1 US 0006451 W US0006451 W US 0006451W WO 0053264 A1 WO0053264 A1 WO 0053264A1
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Prior art keywords
heparin
factor
inhibitor
combination
tpa
Prior art date
Application number
PCT/US2000/006451
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French (fr)
Inventor
Pancras C. Wong
Original Assignee
Du Pont Pharmaceuticals Company
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Publication date
Application filed by Du Pont Pharmaceuticals Company filed Critical Du Pont Pharmaceuticals Company
Priority to NZ513217A priority Critical patent/NZ513217A/en
Priority to CA002361650A priority patent/CA2361650A1/en
Priority to EA200100966A priority patent/EA200100966A1/en
Priority to BR0010381-0A priority patent/BR0010381A/en
Priority to AU35254/00A priority patent/AU766089B2/en
Priority to IL14479800A priority patent/IL144798A0/en
Priority to JP2000603752A priority patent/JP2002538226A/en
Priority to EP00913894A priority patent/EP1161279A1/en
Priority to KR1020017011454A priority patent/KR20020005614A/en
Publication of WO2000053264A1 publication Critical patent/WO2000053264A1/en

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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
    • A61K38/02—Peptides of undefined number of amino acids; Derivatives thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/715—Polysaccharides, i.e. having more than five saccharide radicals attached to each other by glycosidic linkages; Derivatives thereof, e.g. ethers, esters
    • A61K31/726—Glycosaminoglycans, i.e. mucopolysaccharides
    • A61K31/727—Heparin; Heparan
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
    • A61K31/19—Carboxylic acids, e.g. valproic acid
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/42—Oxazoles
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/47—Quinolines; Isoquinolines
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/60—Salicylic acid; Derivatives thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/715—Polysaccharides, i.e. having more than five saccharide radicals attached to each other by glycosidic linkages; Derivatives thereof, e.g. ethers, esters
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • A61K38/43—Enzymes; Proenzymes; Derivatives thereof
    • A61K38/46—Hydrolases (3)
    • A61K38/48—Hydrolases (3) acting on peptide bonds (3.4)
    • A61K38/49—Urokinase; Tissue plasminogen activator
    • 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
    • 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
    • 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
    • A61P9/04—Inotropic agents, i.e. stimulants of cardiac contraction; Drugs for heart failure
    • 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
    • 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
    • A61P9/12—Antihypertensives

Definitions

  • This invention relates to the treatment of thrombosis in mammals and more particularly to such treatment by the administration of a combination of (i) a Factor Xa inhibitor, and (II) a compound selected from the group consisting of aspirin, TPA, GPIIb/IIIa antagonist, low molecular weight heparin and heparin, wherein the dose administered for at least one of (i) and (ii) is a subtherapeutic dose.
  • the selected class of Factor Xa inhibitors and the selected class of aspirin, GPIIb/IIIa antagonist, tissue plasminogen activator (TPA) , low-molecular-weight-heparin and heparin are essential as component parts of the novel compositions of this invention.
  • Aspirin and GPIIb/IIIa antagonists are known in the art as antiplatelet agents.
  • Tissue plasminogen activator (TPA) is known as a thrombolytic agent.
  • Low-molecular-weight heparin and heparin are known as anticoagulants .
  • Factor Xa is a blood coagulation protein.
  • peptide Factor Xa inhibitors are antistasin and tick anticoagulant peptide, and nonpeptide Factor Xa inhibitors are described in W098/2326, Thro b Haemost 1994; 71: 314-9, Thromb Haemost 1994; 72:393-6, and Thromb
  • One object of the present invention is to provide a method of treating thrombosis in a mammal comprising: administering to said mammal a therapeutically effective amount of a combination of (i) a Factor Xa inhibitor, and (ii) a compound selected from the group consisting of aspirin, TPA a GPIIb/IIIa antagonist, low molecular weight heparin and heparin, wherein the dose administered for at least one of (i) and (ii) is a subtherapeutic dose.
  • Another object of the present invention is to provide a method of treating thrombosis in a mammal wherein the combination of (i) and (ii) above are administered in amounts to provide a synergistic effect.
  • Fig. 1 is a graph showing carotid blood flow versus time for saline vehicle, aspirin alone, a Factor Xa inhibitor alone, and a combination of aspirin and the same Factor Xa inhibitor;
  • Fig. 2 is a graph showing carotid blood flow versus time for saline vehicle, a GPIIb/IIIa antagonist alone, a Factor Xa inhibitor alone, and a combination of the same Ilb/IIIa antagonist and Factor X inhibitor;
  • Fig. 3 is a graph showing carotid blood flow versus time for saline vehicle, fragmin, a Factor Xa inhibitor, and a combination of fragmin and the same Factor Xa inhibitor;
  • Fig. 4 is a bar chart showing the duration of patency for saline vehicle, a Factor Xa inhibitor alone, TPA alone, and a combination of the same TPA and Factor Xa inhibitor;
  • Fig. 5 is a bar chart showing the antithrombotic effect of a saline vehicle and heparin alone, and a combination of heparin with 3 different doses of a Factor Xa inhibitor.
  • the combinations of active compounds (i) and (ii) of this invention are useful in the treatment of thrombotic disorders including atherosclerotic arterial disease, valvular heart disease, heart failure, cerebrovascular disease such as stroke, atrial fibrillation, coronary artery disease such as myocardial infarction and unstable angina, coronary artery bypass grafts, peripheral vascular disease, thromboembolic complications of prosthetic cardiovascular devices such heart valves and vascular grafts and deep vein thrombosis following major orthopaedic surgery, major fractures and/or abdominal surgery.
  • thromboembolic complications of prosthetic cardiovascular devices such heart valves and vascular grafts and deep vein thrombosis following major orthopaedic surgery, major fractures and/or abdominal surgery.
  • endovascular stenting procedures such as percutaneous transluminal coronary angioplasty to prevent subsequent arterial thrombus formation and reocclusion.
  • Factor Xa inhibitor compounds (i) useful in the present invention are well-known in the prior art. Preferred Factor Xa inhibitors are described in PCT Pat. Appln. No. US97/22895, filed December 15, 1997; published July 2, 1998, as W098/28269, the disclosure of which is hereby incorporated by reference. Specifically preferred compounds within W098/28269 are: Compound (1) :
  • DX-9065a Another Factor Xa inhibitor compound is DX-9065a described in Thromb Haemost 1994; 71:314-9; and Thromb Haemost 1994; 72:393-6.
  • DX-9065a is (+) -2S-2 [4- [ [ (3S) -1- acetimidoyl-3-pyrrolidinyl] oxy] phenyl] -3- [7-amidino-2- naphthyl] propanoic acid hydrochloride pentahydrate .
  • a still further Factor Xa inhibitor compound is YM-60828 described in Thromb Haemost 1998; 79:859-64.
  • YM-60828 is [N- [4- [ ( 1-acetimidoyl-4-piperidyl) oxy] phenyl] -N- [ (7- amidino-2-naphthyl) methyl] sulfamoyl] acetic acid dihydrochloride .
  • Other Factor Xa inhibitor compounds will be readily known by those skilled in the art.
  • the compounds (ii) useful in the combination of the present invention are either commercially available and/or well-known in the prior art. Aspirin, fragmin (Pharmacia AB, Sweden) , heparin (Upjohn, Kalamazoo,
  • Fragmin is a low molecular weight heparin. It is isolated from standard heparin with a mean molecular weight of 4.5 kDa whereas standard heparin has a molecular weight of 750 to 1000 kDa. Low-molecular- weight heparin such as fragmin differs from heparin in both their pharmacokinetic properties and mechanism of action.
  • the potency for fragmin is expressed in unit of anti-Factor Xa activity. Each mg of fragmin has about 150 U of anti- Factor Xa activity.
  • Preferred GPIIb/IIIa antagonist compounds useful as component (ii) of the combination are described in published PCT Application W095/14683, published 1 June 1995, as the second embodiment. Preferred compounds described therein have the formula:
  • Z is selected from a bond, 0, or S
  • R2 and R3 are independently selected from: H; C1-C6 alkyl; C7-C11 arylalkyl optionally substituted with 0-3 groups selected from hydroxy, halogen, C1-C6 alkoxy, C1-C6 alkyl, CF3, S(0)mCH3, -N(CH3)2, C1-C4 haloalkyl, methylenedioxydiyl, ethylenedioxydiyl; (C1-C10 alkoxy) carbonyl; aryl(Cl-C10 alkoxy) carbonyl where the aryl group is optionally substituted with 0-3 groups selected from hydroxy, halogen, C1-C6 alkoxy, C1-C6 alkyl, CF3, S(0)mCH3, -N(CH3)2, C1-C4 haloalkyl, methylenedioxydiyl, ethylenedioxydiyl; or heteroaryl (C1-C5) alkyl where the heteroaryl group
  • V is selected from:
  • X is -C(R 4 ) (R 8 )-CHR 4a -;
  • R 4 is selected from H, C1-C10 alkyl, C1-C10 alkylcarbonyl, aryl, arylalkyl, cycloalkyl, or cycloalkylalkyl;
  • R 4a is selected from hydroxy, C1-C10 alkoxy, nitro, - N(R 5 )R 5a , -N(R 12 )R 13 , or -N(R 16 )R 17 , aryl substituted with 0-3 R ⁇ , or (C1-C10 alkyl) carbonyl;
  • R 4b is selected from H, Ci-C ⁇ alkyl, C2-C6 alkenyl, C2-C6 alkynyl, hydroxy, Ci-C ⁇ alkoxy, C ⁇ -C6 alkylthio, Ci-C-s alkylsulfinyl, C1-C-5 alkylsulfonyl, nitro, (C ⁇ -C6 alkyl) carbonyl, C6-C10 aryl, -N(R 12 )R 13 , halo, CF3, CN, (C1-C6 alkoxy) carbonyl, carboxy, piperidinyl, morpholinyl or pyridyl; R5 is selected from H or Ci-Cio alkyl substituted with 0-6 R b ;
  • R ⁇ a is selected from hydrogen, hydroxy, Ci to C ⁇ alkyl, C2 to C6 alkenyl, C3 to Cn cycloalkyl, C4 to Cn cycloalkylmethyl, C ⁇ -C-5 alkoxy, benzyloxy, C Q to C10 aryl, heteroaryl, heteroarylalkyl, C7 to Cn arylalkyl, or adamantylmethyl, C1-C10 alkyl substituted with 0-2 R b ;
  • R- 1 and R ⁇ a can be taken together to be 3- azabicyclononyl, 1,2,3, 4-tetrahydro-l-quinolinyl, 1, 2 , 3, 4-tetrahydro-2-isoquinolinyl, 1-piperidinyl, 1- morpholinyl, 1-pyrrolidinyl, thiamorpholinyl, thiazolidinyl or 1-piperazinyl, each being optionally substituted with C1-C6 alkyl, C-5-C ⁇ o aryl, heteroaryl, C7-C11 arylalkyl, (C ⁇ -C-5 alkyl) carbonyl, JC3-C7 cycloalkyl) carbonyl, (C ⁇ -C6 alkoxy) carbonyl or (C7-C11 arylalkoxy) carbonyl;
  • R ⁇ b is selected from C ⁇ -C-3 alkyl, C2-C-5 alkenyl, C3-C11 cycloalkyl, C4-C11 cycloalkylmethyl, C ⁇ -Cio aryl, C7- C ⁇ arylalkyl, or C1-C10 alkyl substituted with 0-2 R 4b
  • Y is selected from hydroxy, Ci to C ⁇ o alkyloxy, C3 to C11 cycloalkyloxy, C ⁇ to C ⁇ o aryloxy, C7 to O ⁇ aralkyloxy, C3 to C ⁇ o alkylcarbonyloxyalkyloxy, C3 to C ⁇ o alkoxycarbonyloxyalkyloxy, C2 to C ⁇ o alkoxycarbonylalkyloxy, C5 to C ⁇ o cycloalkylcarbonyloxyalkyloxy, C5 to C ⁇ o cycloalkoxycarbonyloxyalkyloxy, C5 to C ⁇ o cycloalkoxycarbonylalkyloxy, C7 to C ⁇ aryloxycarbonylalkyloxy, C8 to C ⁇ 2 aryloxycarbonyloxyalkyloxy, C8 to C ⁇ 2 arylcarbonyloxyalkyloxy, C5 to C ⁇ o alkoxyalkylcarbonyloxyalkyloxy, C5 to C ⁇ o (5-alky
  • R6 and R 7 are each independently selected from H, C ⁇ -C ⁇ o alkyl, hydroxy, C ⁇ -C ⁇ o alkoxy, nitro, (C ⁇ -C ⁇ o alkyl) carbonyl , -N(R1 2 )R 13 , cyano, or halo;
  • R 12 and R 13 are each independently selected from H, C ⁇ -C ⁇ o alkyl, (C ⁇ -C ⁇ o alkoxy) carbonyl, (C ⁇ -C ⁇ o alkyl) carbonyl, C ⁇ -C ⁇ o alkylsulfonyl, aryl(C ⁇ -C ⁇ o alkyl) sulfonyl, arylsulfonyl, heteroarylsulfonyl, heteroarylcarbonyl, heteroarylalkylcarbonyl or aryl, wherein said aryl groups being optionally substituted with 0-3 substituents selected from the group consisting of: C1-C4 alkyl, C1-C4 alkoxy, halo, CF3, and O2 ;
  • R1 ⁇ is selected from: H or C1-C5 alkyl _
  • Rl8a ⁇ s selected from: C ⁇ -C8 alkyl substituted with 0-2 R 19 ,
  • heterocyclic ring system selected from pyridinyl, furanyl, thiazolyl, thienyl, pyrrolyl, pyrazolyl, triazolyl, imidazolyl, benzofuranyl, indolyl, indolinyl, quinolinyl, isoquinolinyl, isoxazolyl, isoxazolinyl, benzimidazolyl, piperidinyl, tetrahydrofuranyl, pyranyl, pyrimidinyl, 3H-indolyl, pyrrolidinyl, piperidinyl, indolinyl, or morpholinyl, said heterocyclic ring being substituted with 0-4 R ⁇ - 9 ;
  • R 18b is selected from R 18a or H
  • R 19 is selected from H, halogen, CF3, CN, NO2, NR 12 R 13 , C ⁇ C8 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C ⁇ -C-5 alkoxy, C3-C11 cycloalkyl, C4-C11 cycloalkylalkyl, aryl, heteroaryl, aryl(C ⁇ -C6 alkyl)-, (C ⁇ -C4 alkyl) sulfonyl, aryl-sulfonyl, or C1-C4 alkoxycarbonyl;
  • n 0-4
  • n 0-1 ;
  • Z is selected from a bond or 0;
  • V is a single bond, -(phenyl)- or -(pyridyl)-;
  • W is selected from:
  • X is selected from: -CH2-CH(N(R 16 )R 17 )-, or
  • Y is selected from: hydroxy
  • R 17 is selected from H or C1-C5 alkyl
  • Rl8a i s selected from:
  • heterocyclic ring system selected from pyridinyl, furanyl, thiazolyl, thienyl, pyrrolyl, pyrazolyl, triazolyl, imidazolyl, benzofuranyl, indolyl, indolinyl, quinolinyl, isoquinolinyl, isoxazolyl, isoxazolinyl, benzimidazolyl, piperidinyl, tetrahydrofuranyl, pyranyl, py ⁇ midinyl, 3-ff-mdolyl, pyrrolidinyl, piperidinyl, indolinyl, or morpholinyl, said heterocyclic ring being substituted with 0-4 R ⁇ -9;
  • a specifically preferred compound has the formula :
  • GPIIb/IIIa antagonist compounds are abciximab, eptifibatide, tirofiban, lamifiban, lefradafiban, sibrafiban (Ro-48-3657 ) , orbofiban and xemilofiban described in the paper of Graul et al . and Scarborough (Graul A, Martel AM and Castaner J. Xemilifiban; Drugs of the Future 22: 508-517, 1997;
  • “Therapeutically effective amount” is intended to include an amount of a combination of compounds claimed effective to treat thrombosis in a mammal.
  • the combination of compounds is preferably a synergistic combination.
  • Synergy as described for example by Chou and Talalay, Adv. Enzyme Regul . 22:27-55 (1984), occurs when the effect (in this case, an antithrombotic effect) of the compounds when administered in combination is greater than the additive effect of the compounds when administered alone as a single agent.
  • a synergistic effect is most clearly demonstrated at suboptimal concentrations of the compounds.
  • Synergy can be in terms of antihypertensive effect, antithrombotic effect, or some other non-additive beneficial effect of the combination compared with the individual components.
  • component (i) and component (ii) of the present invention it is meant that the components are administered concurrently to the mammal being treated.
  • each component may be administered at the same time or sequentially in any order or at different points in time.
  • component (i) and component (ii) may be administered separately but sufficiently closely in time so as to provide the desired therapeutic effect.
  • component (i) and component (ii) of the present invention it is meant that each component when administered to a mammal alone does not give the desired therapeutic effect for the disease being treated.
  • Rabbits were anesthetized with ketamine (50 mg/kg i.m.) and xylazine (10 mg/kg i.m.) and then surgically prepared with arterial and venous catheters.
  • An electromagnetic flow probe was placed on a segment of an isolated carotid artery to monitor blood flow. Thrombus formation was induced by electrical stimulation of the carotid artery for 3 min at 4 A using an external stainless-steel bipolar electrode. Carotid blood flow was measured continuously over a 90-min period to monitor thrombus occlusion. Test agents were infused intravenously 1 hour prior to the electrical stimulation of the carotid artery and continuously during the 90-min period.
  • thrombus formation was induced and carotid blood flow was gradually declined in saline vehicle-treated animals.
  • the artery was totally occluded and blood flow was zero.
  • Aspirin at 1 mg/kg/hr i.v. concentration in saline was 0.167 mg/ml
  • Compound (1) a Factor Xa inhibitor
  • Compound (1) 0.1 mg/kg/hr i.v. in combination with aspirin at 1 mg/kg/hr i.v. prevented the artery from occlusion and maintained the blood flow for at least 90 min.
  • TPA tissue-type plasminogen activator
  • heparin at 4 U/kg/hr i.v. did not cause antithrombotic effect.
  • heparin at 4 U/kg/hr i.v. potentiated the antithrombotic effects of Compound (3) (a Factor Xa inhibitor) at 0.3, 1 or 3 mg/kg/hr i.v. (concentration in saline for 0.3 dose was 0.05 mg/ml) .
  • Compound (3) a Factor Xa inhibitor
  • the results presented indicate that a combination therapy comprising a Factor Xa inhibitor and one of aspirin, TPA, a GPIIb/IIIa antagonist, low molecular weight heparin or heparin will be effective in treating thrombosis in patients.
  • the method of the present invention provides important advantages over currently available treatments for thrombosis.
  • the Factor Xa inhibitor (i) and a compound (ii) of this invention can be administered as treatment for thrombosis by any means that produces contact of the active agent with the agents site of action, i.e., Factor Xa, in the body of a mammal. They can be administered by any conventional means available for use in conjunction with pharmaceuticals, either as individual therapeutic agents or in a combination of therapeutic agents. They can be administered alone, but preferably are administered with a pharmaceutical carrier selected on the basis of the chosen route of administration and standard pharmaceutical practice .
  • the dosage administered will, of course, vary depending upon known factors, such as the pharmacodynamic characteristics of the particular agent and its mode and route of administration; the age, health and weight of the recipient; the nature and extent of the symptoms; the kind of concurrent treatment; the frequency of treatment; and the effect desired.
  • a daily dosage of active ingredient can be expected to be about 0.001 to about 1000 milligrams per kilogram of body weight, with the preferred dose being about 0.01 to about 30 mg/kg.
  • compositions suitable for administration contain from about 1 mg to about 100 mg of active ingredient per unit.
  • the active ingredient will ordinarily be present in an amount of about 0.5-95% by weight based on the total weight of the composition.
  • the active ingredient can be administered orally in solid dosage forms, such as capsules, tablets and powders, or in liquid dosage forms, such as elixirs, syrups and suspensions. It can also be administered parenterally, in sterile liquid dosage forms.
  • Gelatin capsules contain the active ingredient and powdered carriers, such as lactose, starch, cellulose derivatives, magnesium stearate, stearic acid, and the like. Similar diluents can be used to make compressed tablets . Both tablets and capsules can be manufactured as sustained release products to provide for continuous release of medication over a period of hours. Compressed tablets can be sugar coated or film coated to mask any unpleasant taste and protect the tablet from the atmosphere, or enteric coated for selective disintegration in the gastrointestinal tract. Liquid dosage forms for oral administration can contain coloring and flavoring to increase patient acceptance.
  • water, a suitable oil, saline, aqueous dextrose (glucose), and related sugar solutions and glycols such as propylene glycol or polyethylene glycols are suitable carriers for parenteral solutions.
  • Solutions for parenteral administration preferably contain a water soluble salt of the active ingredient, suitable stabilizing agents, and if necessary, buffer substances.
  • Antioxidizing agents such as sodium bisulfite, sodium sulfite, or ascorbic acid, either alone or combined, are suitable stabilizing agents.
  • citric acid and its salts, and sodium EDTA are also used.
  • parenteral solutions can contain preservatives, such as benzalkonium chloride, methyl- or propyl-paraben and chlorobutanol .
  • Suitable pharmaceutical carriers are described in Remington's Pharmaceutical Sciences, 17th ed., Mack Publishing Company, Easton, PA, 1985, a standard reference text in this field, the disclosure of which is hereby incorporated by reference.
  • a large number of unit capsules can be prepared by filling standard two-piece hard gelatin capsules each with 0.1 to 100 mg of powdered active ingredient, 150 mg of lactose, 50 mg of cellulose, and 6 mg magnesium stearic.
  • Soft Gelatin Capsules A mixture of active ingredient in a digestible oil such as soybean oil, cottonseed oil or olive oil can be prepared and injected by means of a positive displacement pump into gelatin to form soft gelatin capsules containing 0.1 to 100 mg of the active ingredient. The capsules should then be washed and dried.
  • a digestible oil such as soybean oil, cottonseed oil or olive oil
  • a large number of tablets can be prepared by conventional procedures so that the dosage unit is 0.1 to 100 mg of active ingredient, 0.2 mg of colloidal silicon dioxide, 5 milligrams of magnesium stearate, 275 mg of microcrystalline cellulose, 11 mg of starch and 98.8 mg of lactose.
  • Appropriate coatings may be applied to increase palatability or delay absorption.
  • An aqueous suspension can be prepared for oral administration so that each 5 mL contain 0.1 to 100 mg of finely divided active ingredient, 200 mg of sodium carboxymethyl cellulose, 5 mg of sodium benzoate, 1.0 g of sorbitol solution, U.S. P., and 0.025 mg of vanillin.
  • a parenteral composition suitable for administration by injection can be prepared by stirring 0.1 to 100 mg by weight of active ingredient in 10% by volume propylene glycol and water. The solution is sterilized by commonly used techniques .
  • Each therapeutic agent component of this invention can independently be in any dosage form, such as those described above, and can also be administered in various ways, as described above.
  • component (ii) is to be understood to represent one or more agents as described previously.
  • each agent of component (ii) may also be treated the same or independently .
  • Components (i) and (ii) of the present invention may be formulated together, in a single dosage unit (that is, combined together in one capsule, tablet, powder, or liquid, etc.) as a combination product.
  • the component (i) may be administered at the same time as component (ii) or in any order; for example component (i) of this invention may be administered first, followed by administration of component (ii) , or they may be administered in the reverse order. If component (ii) contains more that one agent, e.g., aspirin and heparin, these agents may be administered together or in any order.
  • the administration of component (i) and (ii) occurs less than about one hour apart.
  • the route of administration of component (i) and (ii) is intravenously (i.v.) .
  • the terms oral agent, oral inhibitor, oral compound, or the like, as used herein, denote compounds which may be orally administered.
  • component (i) and component (ii) both be administered by the same route (that is, for example, both orally) or dosage form, if desired, they may each be administered by different routes (that is, for example, one component of the combination product may be administered orally, and another component may be administered intravenously) or dosage forms.
  • the dosage of the combination therapy of the invention may vary depending upon various factors such as the pharmacodynamic characteristics of the particular agent and its mode and route of administration, the age, health and weight of the recipient, the nature and extent of the symptoms, the kind of concurrent treatment, the frequency of treatment, and the effect desired, as described above.
  • the proper dosage of components (i) and (ii) of the present invention will be readily ascertainable by a medical practitioner skilled in the art, based upon the present disclosure.
  • typically a daily dosage may be about 0.01 milligram to about 1 gram of each component.
  • component (ii) represents more than one compound
  • typically a daily dosage may be about 0.01 milligram to about 0.1 gram of each agent of component (ii) .
  • the dosage amount of each component may be reduced by about 70-80% relative to the usual dosage of the component when it is administered alone as a single agent for the treatment of thrombosis, in view of the synergistic effect of the combination.
  • the combination products of this invention may be formulated such that, although the active ingredients are combined in a single dosage unit, the physical contact between the active ingredients is minimized.
  • one active ingredient may be enteric coated.
  • enteric coating one of the active ingredients it is possible not only to minimize the contact between the combined active ingredients, but also, it is possible to control the release of one of these components in the gastrointestinal tract such that one of these components is not released in the stomach but rather is released in the intestines.
  • Another embodiment of this invention where oral administration is desired provides for a combination product wherein one of the active ingredients is coated with a sustained-release material which effects a sustained-release throughout the gastrointestinal tract and also serves to minimize physical contact between the combined active ingredients.
  • the sustained- released component can be additionally enteric coated such that the release of this component occurs only in the intestine.
  • Still another approach would involve the formulation of a combination product in which the one component is coated with a sustained and/or enteric release polymer, and the other component is also coated with a polymer such as a low viscosity grade of hydroxypropyl methylcellulose or other appropriate materials as known in the art, in order to further separate the active components.
  • the polymer coating serves to form an additional barrier to interaction with the other component.
  • contact may also be prevented between the individual agents of component (ii) .
  • Dosage forms of the combination products of the present invention wherein one active ingredient is enteric coated can be in the form of tablets such that the enteric coated component and the other active ingredient are blended together and then compressed into a tablet or such that the enteric coated component is compressed into one tablet layer and the other active ingredient is compressed into an additional layer.
  • one or more placebo layers may be present such that the placebo layer is between the layers of active ingredients.
  • dosage forms of the present invention can be in the form of capsules wherein one active ingredient is compressed into a tablet or in the form of a plurality of microtablets, particles, granules or non-perils, which are then enteric coated.
  • enteric coated microtablets, particles, granules or non-perils are then placed into a capsule or compressed into a capsule along with a granulation of the other active ingredient.

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Abstract

Provided is a method of treating thrombosis in mammals by administering therapeutically effective amounts of a combination of (i) a Factor Xa inhibitor, and (ii) a compound selected from the group consisting of aspirin, TPA, a GPIIb/IIIa antagonist, low molecular weight heparin and heparin, wherein the dose administered for at least one of (i) and (ii) is a subtherapeutic dose. Preferably, the combination of (i) and (ii) provides a synergistic effect.

Description

Title
Treatment of Thrombosis by Combined Use of a Factor Xa Inhibitor and Aspirin, Tissue Plasminogen Activator (TPA) , a GPIIb/IIIa Antagonist, Low Molecular Weight Heparin or Heparin .
Field of the Invention
This invention relates to the treatment of thrombosis in mammals and more particularly to such treatment by the administration of a combination of (i) a Factor Xa inhibitor, and (II) a compound selected from the group consisting of aspirin, TPA, GPIIb/IIIa antagonist, low molecular weight heparin and heparin, wherein the dose administered for at least one of (i) and (ii) is a subtherapeutic dose.
Background of the Invention
The selected class of Factor Xa inhibitors and the selected class of aspirin, GPIIb/IIIa antagonist, tissue plasminogen activator (TPA) , low-molecular-weight-heparin and heparin are essential as component parts of the novel compositions of this invention. Aspirin and GPIIb/IIIa antagonists are known in the art as antiplatelet agents. Tissue plasminogen activator (TPA) is known as a thrombolytic agent. Low-molecular-weight heparin and heparin are known as anticoagulants . Factor Xa is a blood coagulation protein. It plays a major role in blood coagulation because of its central position at the convergent point of the intrinsic and extrinsic pathways of coagulation. It is believed that inhibition of Factor Xa may eliminate the production of thrombin by either the extrinsic or intrinsic pathways without interfering with a basal level of thrombin activity necessary for normal hemostasis (Harke LA, Hanson SR and Kelly AB . Antithrombotic strategies targeting thrombin activities, thrombin receptors and thrombin generation. Thrombosis and Haemostasis 78: 736-741, 1997). Both peptide and nonpeptide Factor Xa inhibitors are currently available (Kaiser B. Thrombin and factor Xa inhibitors. Drugs of the Future 23: 423-436, 1998). Examples of peptide Factor Xa inhibitors are antistasin and tick anticoagulant peptide, and nonpeptide Factor Xa inhibitors are described in W098/2326, Thro b Haemost 1994; 71: 314-9, Thromb Haemost 1994; 72:393-6, and Thromb
Haemost 1998; 79: 859-64. The antithrombotic effects of these peptide and nonpeptide Factor Xa inhibitors have been well demonstrated in various experimental models of arterial and venous thrombosis (Kaiser B. Thrombin and factor Xa inhibitors. Drugs of the Future 23: 423-436, 1998) .
Summary of the Invention
One object of the present invention is to provide a method of treating thrombosis in a mammal comprising: administering to said mammal a therapeutically effective amount of a combination of (i) a Factor Xa inhibitor, and (ii) a compound selected from the group consisting of aspirin, TPA a GPIIb/IIIa antagonist, low molecular weight heparin and heparin, wherein the dose administered for at least one of (i) and (ii) is a subtherapeutic dose. Another object of the present invention is to provide a method of treating thrombosis in a mammal wherein the combination of (i) and (ii) above are administered in amounts to provide a synergistic effect.
These and other objects, which will become apparent during the following detailed description, have been achieved by the discovery that the administration of a Factor Xa inhibitor (i) in combination with one of (ii) aspirin, tissue plasminogen activator (TPA) , a GPIIb/IIIa antagonist, low molecular weight heparin or heparin, with at least one of (i) and (ii), preferably both, being administered at a dose which would be a subtherapeutic dose when administered alone.
Brief Description of Drawings
Fig. 1 is a graph showing carotid blood flow versus time for saline vehicle, aspirin alone, a Factor Xa inhibitor alone, and a combination of aspirin and the same Factor Xa inhibitor;
Fig. 2 is a graph showing carotid blood flow versus time for saline vehicle, a GPIIb/IIIa antagonist alone, a Factor Xa inhibitor alone, and a combination of the same Ilb/IIIa antagonist and Factor X inhibitor;
Fig. 3 is a graph showing carotid blood flow versus time for saline vehicle, fragmin, a Factor Xa inhibitor, and a combination of fragmin and the same Factor Xa inhibitor;
Fig. 4 is a bar chart showing the duration of patency for saline vehicle, a Factor Xa inhibitor alone, TPA alone, and a combination of the same TPA and Factor Xa inhibitor; and
Fig. 5 is a bar chart showing the antithrombotic effect of a saline vehicle and heparin alone, and a combination of heparin with 3 different doses of a Factor Xa inhibitor.
Detailed Description of the Invention
The combinations of active compounds (i) and (ii) of this invention are useful in the treatment of thrombotic disorders including atherosclerotic arterial disease, valvular heart disease, heart failure, cerebrovascular disease such as stroke, atrial fibrillation, coronary artery disease such as myocardial infarction and unstable angina, coronary artery bypass grafts, peripheral vascular disease, thromboembolic complications of prosthetic cardiovascular devices such heart valves and vascular grafts and deep vein thrombosis following major orthopaedic surgery, major fractures and/or abdominal surgery. These combinations are also expected to be useful in combining with endovascular stenting procedures such as percutaneous transluminal coronary angioplasty to prevent subsequent arterial thrombus formation and reocclusion.
Factor Xa inhibitor compounds (i) useful in the present invention are well-known in the prior art. Preferred Factor Xa inhibitors are described in PCT Pat. Appln. No. US97/22895, filed December 15, 1997; published July 2, 1998, as W098/28269, the disclosure of which is hereby incorporated by reference. Specifically preferred compounds within W098/28269 are: Compound (1) :
Figure imgf000007_0001
Compound (2)
Figure imgf000007_0002
HCl Salt
Compound (3)
Figure imgf000007_0003
Another Factor Xa inhibitor compound is DX-9065a described in Thromb Haemost 1994; 71:314-9; and Thromb Haemost 1994; 72:393-6. DX-9065a is (+) -2S-2 [4- [ [ (3S) -1- acetimidoyl-3-pyrrolidinyl] oxy] phenyl] -3- [7-amidino-2- naphthyl] propanoic acid hydrochloride pentahydrate . A still further Factor Xa inhibitor compound is YM-60828 described in Thromb Haemost 1998; 79:859-64. YM-60828 is [N- [4- [ ( 1-acetimidoyl-4-piperidyl) oxy] phenyl] -N- [ (7- amidino-2-naphthyl) methyl] sulfamoyl] acetic acid dihydrochloride . Other Factor Xa inhibitor compounds will be readily known by those skilled in the art.
The compounds (ii) useful in the combination of the present invention are either commercially available and/or well-known in the prior art. Aspirin, fragmin (Pharmacia AB, Stockholm, Sweden) , heparin (Upjohn, Kalamazoo,
Michigan) , and TPA (Genentech, San Francisco, California) are available commercially. Fragmin is a low molecular weight heparin. It is isolated from standard heparin with a mean molecular weight of 4.5 kDa whereas standard heparin has a molecular weight of 750 to 1000 kDa. Low-molecular- weight heparin such as fragmin differs from heparin in both their pharmacokinetic properties and mechanism of action. The potency for fragmin is expressed in unit of anti-Factor Xa activity. Each mg of fragmin has about 150 U of anti- Factor Xa activity.
Preferred GPIIb/IIIa antagonist compounds useful as component (ii) of the combination are described in published PCT Application W095/14683, published 1 June 1995, as the second embodiment. Preferred compounds described therein have the formula:
Figure imgf000009_0001
( l a )
or a pharmaceutically acceptable salt thereof, wherein:
Rl is selected from R2a(R3)N-, R2 (R3) N (R2N=) C-, R2a (R3)N(CH2)p'Z-, R2 (R3 ) N (R2N=) C (CH2 ) p"Z-, R2 (R3)N(R2N=)CN(R2)-, R2 (R3) NC (0) -, R2 (R50) N (R2N=) C-, R2 (R3)N(R50N=)C-;
Figure imgf000009_0002
Figure imgf000009_0003
Z is selected from a bond, 0, or S;
R2 and R3 are independently selected from: H; C1-C6 alkyl; C7-C11 arylalkyl optionally substituted with 0-3 groups selected from hydroxy, halogen, C1-C6 alkoxy, C1-C6 alkyl, CF3, S(0)mCH3, -N(CH3)2, C1-C4 haloalkyl, methylenedioxydiyl, ethylenedioxydiyl; (C1-C10 alkoxy) carbonyl; aryl(Cl-C10 alkoxy) carbonyl where the aryl group is optionally substituted with 0-3 groups selected from hydroxy, halogen, C1-C6 alkoxy, C1-C6 alkyl, CF3, S(0)mCH3, -N(CH3)2, C1-C4 haloalkyl, methylenedioxydiyl, ethylenedioxydiyl; or heteroaryl (C1-C5) alkyl where the heteroaryl group is optionally substituted with 0-2 groups selected from hydroxy, halogen, C1-C6 alkoxy, C1-C6 alkyl, CF3, S(0)mCH3, -N(CH3)2, C1-C4 haloalkyl, methylenedioxydiyl , ethylenedioxydiyl ;
R2a is R2 or R2 (R3) N (R2N=) C;
U is a single bond,
V is selected from:
a single bond; - (C1-C7 alkyl)-, substituted with 0-3 groups independently selected from R^ or R^ ; -(C2-C7 alkenyl)-, substituted with 0-3 groups independently selected from R^ or R^ ; - (C2-C7 alkynyl)-, substituted with 0-3 groups independently selected from R^ or R^ ;
- (phenyl) -Q-, said phenyl substituted with 0-2 groups independently selected from R^ or R^ ; - (pyridyl) -Q-, said pyridyl substituted with 0-2 groups independently selected from R^ or R^ ; or - (pyridazinyl) -Q-, said pyridazinyl substituted with 0-2 groups independently selected from R6 or R7 '
Q is selected from a single bond, -0-, -S(0)m-, -N(R12)-, -(CH2)m-, -C(=0)-, -
N(R5a)C(=0)-, -C(=0)N(R5a)-, -CH2O-, -OCH2-, - CH2N(R12)-, -N(R12)CH2~, -CH2C(=0)-, -C(=0)CH2", - CH2S(0)m-, or -S(0)mCH2--
provided that when b is a single bond, and R^-U-V- is a substituent on C5 of the central 5-membered ring of
Formula Ic, then Q is not -0-, -S(0)m-, -N(R12)-, - C(=0)N(R5a)-, -CH20-, CH2N(R12)- or -CH2S(0)m-;
W is selected from: -(C(R )2)"C(=0)-N(R5a)-, or
-C(=0)-N(R5a)-(C(R4)2)-;
X is -C(R4) (R8)-CHR4a-;
R4 is selected from H, C1-C10 alkyl, C1-C10 alkylcarbonyl, aryl, arylalkyl, cycloalkyl, or cycloalkylalkyl;
R4a is selected from hydroxy, C1-C10 alkoxy, nitro, - N(R5)R5a, -N(R12)R13, or -N(R16)R17, aryl substituted with 0-3 R^, or (C1-C10 alkyl) carbonyl;
R4b is selected from H, Ci-Cβ alkyl, C2-C6 alkenyl, C2-C6 alkynyl, hydroxy, Ci-Cβ alkoxy, Cχ-C6 alkylthio, Ci-C-s alkylsulfinyl, C1-C-5 alkylsulfonyl, nitro, (Cχ-C6 alkyl) carbonyl, C6-C10 aryl, -N(R12)R13, halo, CF3, CN, (C1-C6 alkoxy) carbonyl, carboxy, piperidinyl, morpholinyl or pyridyl; R5 is selected from H or Ci-Cio alkyl substituted with 0-6 R b ;
R^a is selected from hydrogen, hydroxy, Ci to Cβ alkyl, C2 to C6 alkenyl, C3 to Cn cycloalkyl, C4 to Cn cycloalkylmethyl, Cχ-C-5 alkoxy, benzyloxy, C Q to C10 aryl, heteroaryl, heteroarylalkyl, C7 to Cn arylalkyl, or adamantylmethyl, C1-C10 alkyl substituted with 0-2 R b;
alternately, R-1 and R^a can be taken together to be 3- azabicyclononyl, 1,2,3, 4-tetrahydro-l-quinolinyl, 1, 2 , 3, 4-tetrahydro-2-isoquinolinyl, 1-piperidinyl, 1- morpholinyl, 1-pyrrolidinyl, thiamorpholinyl, thiazolidinyl or 1-piperazinyl, each being optionally substituted with C1-C6 alkyl, C-5-Cχo aryl, heteroaryl, C7-C11 arylalkyl, (Cχ-C-5 alkyl) carbonyl, JC3-C7 cycloalkyl) carbonyl, (Cχ-C6 alkoxy) carbonyl or (C7-C11 arylalkoxy) carbonyl;
R^b is selected from Cχ-C-3 alkyl, C2-C-5 alkenyl, C3-C11 cycloalkyl, C4-C11 cycloalkylmethyl, Cβ-Cio aryl, C7- Cχι arylalkyl, or C1-C10 alkyl substituted with 0-2 R4b
Y is selected from hydroxy, Ci to Cχo alkyloxy, C3 to C11 cycloalkyloxy, Cβ to Cχo aryloxy, C7 to Oχχ aralkyloxy, C3 to Cχo alkylcarbonyloxyalkyloxy, C3 to Cχo alkoxycarbonyloxyalkyloxy, C2 to Cχo alkoxycarbonylalkyloxy, C5 to Cχo cycloalkylcarbonyloxyalkyloxy, C5 to Cχo cycloalkoxycarbonyloxyalkyloxy, C5 to Cχo cycloalkoxycarbonylalkyloxy, C7 to Cχι aryloxycarbonylalkyloxy, C8 to Cχ2 aryloxycarbonyloxyalkyloxy, C8 to Cχ2 arylcarbonyloxyalkyloxy, C5 to Cχo alkoxyalkylcarbonyloxyalkyloxy, C5 to Cχo (5-alkyl- 1, 3-dioxa-cyclopenten-2-one-yl)methyloxy, or Cχo to Cχ (5-aryl-l, 3-dioxa-cyclopenten-2-one-yl) methyloxy;
R6 and R7 are each independently selected from H, Cχ-Cχo alkyl, hydroxy, Cχ-Cχo alkoxy, nitro, (Cχ-Cχo alkyl) carbonyl , -N(R12)R13, cyano, or halo;
R12 and R13 are each independently selected from H, Cχ-Cχo alkyl, (Cχ-Cχo alkoxy) carbonyl, (Cχ-Cχo alkyl) carbonyl, Cχ-Cχo alkylsulfonyl, aryl(Cχ-Cχo alkyl) sulfonyl, arylsulfonyl, heteroarylsulfonyl, heteroarylcarbonyl, heteroarylalkylcarbonyl or aryl, wherein said aryl groups being optionally substituted with 0-3 substituents selected from the group consisting of: C1-C4 alkyl, C1-C4 alkoxy, halo, CF3, and O2 ;
R1^ is selected from H, Cχ-Cχo alkyl, C2~Cχo alkenyl, C2~Cχo alkynyl, Cχ-Cχo alkoxy, aryl, heteroaryl or (Cχ-Cχo alkoxy) carbonyl, CO2R5 or -C (=0) N (R5) R5a ;
Rlβ is selected from: -C(=0)-0-R18a,
-C(=0)-R18b,
-C(=0)N(Rl8b) 2/
-S02-R18a, or -S02-N(R18b)2;
R1^ is selected from: H or C1-C5 alkyl _
Rl8a χs selected from: Cχ-C8 alkyl substituted with 0-2 R19,
C2-C8 alkenyl substituted with 0-2 R19, C2-C8 alkynyl substituted with 0-2 R19, C3-C8 cycloalkyl substituted with 0-2 R^-9, aryl substituted with 0-4 R19, aryl(Cχ-C6 alkyl)- substituted with 0-4 R19,
a heterocyclic ring system selected from pyridinyl, furanyl, thiazolyl, thienyl, pyrrolyl, pyrazolyl, triazolyl, imidazolyl, benzofuranyl, indolyl, indolinyl, quinolinyl, isoquinolinyl, isoxazolyl, isoxazolinyl, benzimidazolyl, piperidinyl, tetrahydrofuranyl, pyranyl, pyrimidinyl, 3H-indolyl, pyrrolidinyl, piperidinyl, indolinyl, or morpholinyl, said heterocyclic ring being substituted with 0-4 R^-9;
Cχ-C6 alkyl substituted with a heterocyclic ring system selected from pyridinyl, furanyl, thiazolyl, thienyl, pyrrolyl, pyrazolyl, imidazolyl, isoxazolyl, isoxazolinyl, benzofuranyl, indolyl, indolenyl, quinolinyl, isoquinolinyl, benzimidazolyl, piperidinyl, tetrahydrofuranyl, pyranyl, pyridinyl, 3-H-indolyl, indolyl, pyrrolidinyl, piperidinyl, indolinyl, or morpholinyl, said heterocyclic ring being substituted with 0-4 R19;
R18b is selected from R18a or H;
R19 is selected from H, halogen, CF3, CN, NO2, NR12R13, Cχ~ C8 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, Cχ-C-5 alkoxy, C3-C11 cycloalkyl, C4-C11 cycloalkylalkyl, aryl, heteroaryl, aryl(Cχ-C6 alkyl)-, (Cχ-C4 alkyl) sulfonyl, aryl-sulfonyl, or C1-C4 alkoxycarbonyl;
n is 0-4
P ' i s 1-7
P" is 1-7 r is 0-3
More preferred compounds have the formula
R1-\ «^W_XJ
(lb
or a pharmaceutically acceptable salt thereof, wherein:
R1 is selected from: R2a(R3)N-, R2NH (R2N=) C-, R2NH (R2N=) CNH-, R2a (R3) N (CH ) p ' Z-,
R2NH(R2N=)C(CH2)p"Z-, R2 (R3 ) NC (0) -, R2 (R^O) N (R2N=) C-, R2 (R3)N(R5ON=)C-; nZ-
Figure imgf000016_0001
„Z-
Figure imgf000016_0002
n is 0-1 ;
is 4-6;
is 2-4;
Z is selected from a bond or 0;
V is a single bond, -(phenyl)- or -(pyridyl)-;
W is selected from:
-(C(R4)2)-C(=0)-N(R5a)-,
-C(=0)-N(R5a)-CH2-;
X is selected from: -CH2-CH(N(R16)R17)-, or
-CH2-CH(NR5R5a)-;
Y is selected from: hydroxy;
Cx to Cχo alkoxy; methylcarbonyloxymethoxy-; ethylcarbonyloxymethoxy- ; t-butylcarbonyloxymethoxy-; cyclohexylcarbonyloxymethoxy- ;
1- (methylcarbonyloxy) ethoxy-; 1- (ethylcarbonyloxy) ethoxy-;
1- (t-butylcarbonyloxy) ethoxy-;
1- (cyclohexylcarbonyloxy) ethoxy-; i-propyloxycarbonyloxymethoxy- ; t-butyloxycarbonyloxymethoxy- ; 1- (i-propyloxycarbonyloxy) ethoxy-;
X- (cyclohexyloxycarbonyloxy) ethoxy-;
X- ( -butyloxycarbonyloxy) ethoxy-; dimethylaminoethoxy- ; diethylaminoethoxy- ; (5-methyl-l, 3-dioxacyclopenten-2-on-4-yl) methoxy-;
(5- ( t-butyl) -1, 3-dioxacyclopenten-2-on-4-yl) methoxy-;
(1, 3-dioxa-5-phenyl-cyclopenten-2-on-4-yl) methoxy-;
1- (2- (2-methoxypropyl) carbonyloxy) ethoxy-;
R!6 is selected from: -C(=0) -0-R18a, -C(=0)-R18b, -S (=0)2"R18a or -S02-N(R18 )2;
R 17 is selected from H or C1-C5 alkyl;
Rl8a is selected from:
Cχ-C8 alkyl substituted with 0-2 R19, C2-C8 alkenyl substituted with 0-2 R19, C2-C8 alkynyl substituted with 0-2 R19, C3-C8 cycloalkyl substituted with 0-2 R19, aryl substituted witn 0-4 R19, aryl(Cχ-C6 alkyl)- suostituted with 0-4 R19,
a heterocyclic ring system selected from pyridinyl, furanyl, thiazolyl, thienyl, pyrrolyl, pyrazolyl, triazolyl, imidazolyl, benzofuranyl, indolyl, indolinyl, quinolinyl, isoquinolinyl, isoxazolyl, isoxazolinyl, benzimidazolyl, piperidinyl, tetrahydrofuranyl, pyranyl, pyπmidinyl, 3-ff-mdolyl, pyrrolidinyl, piperidinyl, indolinyl, or morpholinyl, said heterocyclic ring being substituted with 0-4 R^-9;
Cχ-C6 alkyl substituted with a heterocyclic ring system selected from pyridinyl, furanyl, thiazolyl, thienyl, pyrrolyl, pyrazolyl, imidazolyl, isoxazolyl, isoxazolinyl, benzofuranyl, indolyl, mdolenyl, quinolinyl, isoquinolinyl, benzimidazolyl, piperidinyl, tetrahydrofuranyl, pyranyl, pyridinyl, 3-H-ιndolyl, indolyl, pyrrolidinyl, piperidinyl, indolinyl, or morpholinyl, said heterocyclic ring being substituted witn 0-4 Rl9.
A specifically preferred compound has the formula :
Compound (4 '
Figure imgf000018_0001
Other salts of this compound are also specifically preferred.
Specific examples of other GPIIb/IIIa antagonist compounds are abciximab, eptifibatide, tirofiban, lamifiban, lefradafiban, sibrafiban (Ro-48-3657 ) , orbofiban and xemilofiban described in the paper of Graul et al . and Scarborough (Graul A, Martel AM and Castaner J. Xemilifiban; Drugs of the Future 22: 508-517, 1997;
Scarborough RM; Eptifibatide . Drugs of the Future 23: 585- 590, 1998). Others will be readily apparent to those skilled in the art.
"Therapeutically effective amount" is intended to include an amount of a combination of compounds claimed effective to treat thrombosis in a mammal. The combination of compounds is preferably a synergistic combination. Synergy, as described for example by Chou and Talalay, Adv. Enzyme Regul . 22:27-55 (1984), occurs when the effect (in this case, an antithrombotic effect) of the compounds when administered in combination is greater than the additive effect of the compounds when administered alone as a single agent. In general, a synergistic effect is most clearly demonstrated at suboptimal concentrations of the compounds. Synergy can be in terms of antihypertensive effect, antithrombotic effect, or some other non-additive beneficial effect of the combination compared with the individual components.
By "administered in combination", "combination", or "combined" when referring to component (i) and component (ii) of the present invention, it is meant that the components are administered concurrently to the mammal being treated. When administered in combination each component may be administered at the same time or sequentially in any order or at different points in time. Thus, component (i) and component (ii) may be administered separately but sufficiently closely in time so as to provide the desired therapeutic effect.
By "subtherapeutic dose" when referring to component (i) and component (ii) of the present invention, it is meant that each component when administered to a mammal alone does not give the desired therapeutic effect for the disease being treated.
The invention can be understood further by the following examples wherein Compounds (1) - (4) are as shown above. Saline (0.9 weight % NaCl) is the vehicle in all examples .
Example 1
The combination of aspirin and a Factor Xa inhibitor
Rabbits were anesthetized with ketamine (50 mg/kg i.m.) and xylazine (10 mg/kg i.m.) and then surgically prepared with arterial and venous catheters. An electromagnetic flow probe was placed on a segment of an isolated carotid artery to monitor blood flow. Thrombus formation was induced by electrical stimulation of the carotid artery for 3 min at 4 A using an external stainless-steel bipolar electrode. Carotid blood flow was measured continuously over a 90-min period to monitor thrombus occlusion. Test agents were infused intravenously 1 hour prior to the electrical stimulation of the carotid artery and continuously during the 90-min period.
As shown in Fig. 1 following the electrical stimulation, thrombus formation was induced and carotid blood flow was gradually declined in saline vehicle-treated animals. At about 40 min after stimulation, the artery was totally occluded and blood flow was zero. Aspirin at 1 mg/kg/hr i.v. (concentration in saline was 0.167 mg/ml) or Compound (1) (a Factor Xa inhibitor) at 0.1 mg/kg/hr i.v. (concentration in saline was 0.017 mg/ml) did not prevent the occlusion of the artery; and blood flow in these animals was decreased to zero at about the same time as those in vehicle-treated animals. Surprisingly, Compound (1) 0.1 mg/kg/hr i.v. in combination with aspirin at 1 mg/kg/hr i.v. prevented the artery from occlusion and maintained the blood flow for at least 90 min. These results indicate that a combination of Compound (1) and aspirin at their subtherapeutic doses unexpectedly produced a significant antithrombotic effect in a rabbit model of arterial thrombosis.
Example 2
The combination of Compound (4) (a GP-IIb/IIIa antagonist) and a Factor Xa inhibitor
Experimental protocol was described as above for Example 1. As shown in Figure 2, Compound (4) (a GPIIb/IIIa antagonist) at 0.03 mg/kg/hr i.v. and Compound (3) (a Factor Xa inhibitor) at 0.1 mg/kg/hr i.v. did not prevent the occlusion of the artery; and blood flow in these animals was decreased to zero at about the same time as those in vehicle-treated animals. Surprisingly, Compound (3) at 0.1 mg/kg/hr i.v. (concentration in saline was 0.017 mg/ml) in combination with Compound (4) at 0.03 mg/kg/hr i.v. (concentration in saline was 0.005 mg/ml) prevented the artery from occlusion and maintained the blood flow for at least 90 min. These results indicate that a combination of Compound (3) and Compound (4) at their subtherapeutic doses unexpectedly produced a significant antithrombotic effect in a rabbit model of arterial thrombosis.
Example 3
The combination of fragmin (low-molecular-weight-heparin) and a Factor Xa inhibitor
Experimental protocol was described as above for Example 1. As shown in Figure 3, fragmin (a low-molecular- weight-heparin) at 60 U/kg/hr i.v. was moderately active. Compound (3) (a Factor Xa inhibitor) at 0.1 mg/kg/hr i.v. did not prevent the occlusion of the artery; and blood flow in these animals was decreased to zero similar to those in vehicle-treated animals. Surprisingly, Compound (3) at 0.1 mg/kg/hr i.v. (concentration in saline was 0.017 mg/ml) in combination with fragmin at 60 U/kg/hr i.v. (concentration in saline was 0.067 mg/ml or 10 U/mX) prevented the artery from occlusion and maintained the blood flow for at least 90 min. These results indicate that a combination of Compound (3) at its subtherapeutic dose and fragmin at a medium dose unexpectedly produced a significant antithrombotic effect in a rabbit model of arterial thrombosis .
Example 4
The combination of recombinant tissue-type plasminogen activator (TPA) and a Factor Xa inhibitor
Experiments were conducted in rats. It is similar to that of the rabbit protocol as described above in Example 1 except that Compound (2) and/or TPA were given 5 min after a preformed clot was formed. The measured parameter is its duration of patency. As shown in Figure 4, five minutes after the induction of occlusive thrombosis, neither Compound (2) at 5.6 mg/kg (concentration in saline was 0.23 mg/ml) and 1.4 mg/kg/hr i.v. nor TPA at 1 mg/kg i.v. (concentration in saline was 1 mg/ml) produced a therapeutic effect on the duration of patency. However, a combination of Compound (2) at 5.6 mg/kg and 1.4 mg/kg/hr i.v., and TPA at 1 mg/kg i.v. increased the duration of patency to 70%. This result suggests that a Factor Xa inhibitor such as Compound (2) is a promising useful adjunctive agent, which accelerates thrombolysis induced by TPA or other thrombolytic agents. Compound (2) enhanced the thrombolysis induced by a subtherapeutic dose of TPA.
Example 5
The combination of heparin and a Factor Xa inhibitor
Experiments were conducted in male guinea pigs anesthetized with a mixture of ketamine (90 mg/kg i.m.) and xylazine (12 mg/kg i.m.) . The arterio-venous shunt was connected between the carotid artery and jugular vein. The exposure of flowing blood to a silk thread induced the formation of a significant thrombus. Thirty minutes later, the shunt was disconnected and the silk thread covered with thrombus was weighed. The compounds or saline vehicle were given as continuous i.v. infusion starting 1 hr before blood was circulated in the shunt and continuing throughout the experiment (i.e., 90 min) . As shown in figure 5, heparin at 4 U/kg/hr i.v. (concentration in saline was 0.667 U/ml) did not cause antithrombotic effect. However, heparin at 4 U/kg/hr i.v. potentiated the antithrombotic effects of Compound (3) (a Factor Xa inhibitor) at 0.3, 1 or 3 mg/kg/hr i.v. (concentration in saline for 0.3 dose was 0.05 mg/ml) . This result suggests that heparin at a subtherapeutic dose enhances the antithrombotic effect of Compound (3) in a guinea model of venous thrombosis.
The results presented indicate that a combination therapy comprising a Factor Xa inhibitor and one of aspirin, TPA, a GPIIb/IIIa antagonist, low molecular weight heparin or heparin will be effective in treating thrombosis in patients. The method of the present invention provides important advantages over currently available treatments for thrombosis.
DOSAGE AND FORMULATION
The Factor Xa inhibitor (i) and a compound (ii) of this invention can be administered as treatment for thrombosis by any means that produces contact of the active agent with the agents site of action, i.e., Factor Xa, in the body of a mammal. They can be administered by any conventional means available for use in conjunction with pharmaceuticals, either as individual therapeutic agents or in a combination of therapeutic agents. They can be administered alone, but preferably are administered with a pharmaceutical carrier selected on the basis of the chosen route of administration and standard pharmaceutical practice .
The dosage administered will, of course, vary depending upon known factors, such as the pharmacodynamic characteristics of the particular agent and its mode and route of administration; the age, health and weight of the recipient; the nature and extent of the symptoms; the kind of concurrent treatment; the frequency of treatment; and the effect desired. A daily dosage of active ingredient can be expected to be about 0.001 to about 1000 milligrams per kilogram of body weight, with the preferred dose being about 0.01 to about 30 mg/kg.
Dosage forms of compositions suitable for administration contain from about 1 mg to about 100 mg of active ingredient per unit. In these pharmaceutical compositions the active ingredient will ordinarily be present in an amount of about 0.5-95% by weight based on the total weight of the composition. The active ingredient can be administered orally in solid dosage forms, such as capsules, tablets and powders, or in liquid dosage forms, such as elixirs, syrups and suspensions. It can also be administered parenterally, in sterile liquid dosage forms.
Gelatin capsules contain the active ingredient and powdered carriers, such as lactose, starch, cellulose derivatives, magnesium stearate, stearic acid, and the like. Similar diluents can be used to make compressed tablets . Both tablets and capsules can be manufactured as sustained release products to provide for continuous release of medication over a period of hours. Compressed tablets can be sugar coated or film coated to mask any unpleasant taste and protect the tablet from the atmosphere, or enteric coated for selective disintegration in the gastrointestinal tract. Liquid dosage forms for oral administration can contain coloring and flavoring to increase patient acceptance.
In general, water, a suitable oil, saline, aqueous dextrose (glucose), and related sugar solutions and glycols such as propylene glycol or polyethylene glycols are suitable carriers for parenteral solutions. Solutions for parenteral administration preferably contain a water soluble salt of the active ingredient, suitable stabilizing agents, and if necessary, buffer substances. Antioxidizing agents such as sodium bisulfite, sodium sulfite, or ascorbic acid, either alone or combined, are suitable stabilizing agents. Also used are citric acid and its salts, and sodium EDTA. In addition, parenteral solutions can contain preservatives, such as benzalkonium chloride, methyl- or propyl-paraben and chlorobutanol . Suitable pharmaceutical carriers are described in Remington's Pharmaceutical Sciences, 17th ed., Mack Publishing Company, Easton, PA, 1985, a standard reference text in this field, the disclosure of which is hereby incorporated by reference.
Useful pharmaceutical dosage-forms for administration of the compounds of this invention can be illustrated as follows :
Capsules
A large number of unit capsules can be prepared by filling standard two-piece hard gelatin capsules each with 0.1 to 100 mg of powdered active ingredient, 150 mg of lactose, 50 mg of cellulose, and 6 mg magnesium stearic.
Soft Gelatin Capsules A mixture of active ingredient in a digestible oil such as soybean oil, cottonseed oil or olive oil can be prepared and injected by means of a positive displacement pump into gelatin to form soft gelatin capsules containing 0.1 to 100 mg of the active ingredient. The capsules should then be washed and dried.
Tablets
A large number of tablets can be prepared by conventional procedures so that the dosage unit is 0.1 to 100 mg of active ingredient, 0.2 mg of colloidal silicon dioxide, 5 milligrams of magnesium stearate, 275 mg of microcrystalline cellulose, 11 mg of starch and 98.8 mg of lactose. Appropriate coatings may be applied to increase palatability or delay absorption.
Suspension
An aqueous suspension can be prepared for oral administration so that each 5 mL contain 0.1 to 100 mg of finely divided active ingredient, 200 mg of sodium carboxymethyl cellulose, 5 mg of sodium benzoate, 1.0 g of sorbitol solution, U.S. P., and 0.025 mg of vanillin.
Injectable A parenteral composition suitable for administration by injection can be prepared by stirring 0.1 to 100 mg by weight of active ingredient in 10% by volume propylene glycol and water. The solution is sterilized by commonly used techniques .
Combination of components (i) and (ii)
Each therapeutic agent component of this invention can independently be in any dosage form, such as those described above, and can also be administered in various ways, as described above. In the following description component (ii) is to be understood to represent one or more agents as described previously. Thus, if components (i) and (ii) are to be treated the same or independently, each agent of component (ii) may also be treated the same or independently .
Components (i) and (ii) of the present invention may be formulated together, in a single dosage unit (that is, combined together in one capsule, tablet, powder, or liquid, etc.) as a combination product. When component (i) and (ii) are not formulated together in a single dosage unit, the component (i) may be administered at the same time as component (ii) or in any order; for example component (i) of this invention may be administered first, followed by administration of component (ii) , or they may be administered in the reverse order. If component (ii) contains more that one agent, e.g., aspirin and heparin, these agents may be administered together or in any order. When not administered at the same time, preferably the administration of component (i) and (ii) occurs less than about one hour apart. Preferably, the route of administration of component (i) and (ii) is intravenously (i.v.) . The terms oral agent, oral inhibitor, oral compound, or the like, as used herein, denote compounds which may be orally administered. Although it is preferable that component (i) and component (ii) both be administered by the same route (that is, for example, both orally) or dosage form, if desired, they may each be administered by different routes (that is, for example, one component of the combination product may be administered orally, and another component may be administered intravenously) or dosage forms. As is appreciated by a medical practitioner skilled in the art, the dosage of the combination therapy of the invention may vary depending upon various factors such as the pharmacodynamic characteristics of the particular agent and its mode and route of administration, the age, health and weight of the recipient, the nature and extent of the symptoms, the kind of concurrent treatment, the frequency of treatment, and the effect desired, as described above. The proper dosage of components (i) and (ii) of the present invention will be readily ascertainable by a medical practitioner skilled in the art, based upon the present disclosure. By way of general guidance, typically a daily dosage may be about 0.01 milligram to about 1 gram of each component. If component (ii) represents more than one compound, then typically a daily dosage may be about 0.01 milligram to about 0.1 gram of each agent of component (ii) . By way of general guidance, when the compounds of component (i) and component (ii) are administered in combination, the dosage amount of each component may be reduced by about 70-80% relative to the usual dosage of the component when it is administered alone as a single agent for the treatment of thrombosis, in view of the synergistic effect of the combination.
The combination products of this invention may be formulated such that, although the active ingredients are combined in a single dosage unit, the physical contact between the active ingredients is minimized. In order to minimize contact, for example, where the product is orally administered, one active ingredient may be enteric coated. By enteric coating one of the active ingredients, it is possible not only to minimize the contact between the combined active ingredients, but also, it is possible to control the release of one of these components in the gastrointestinal tract such that one of these components is not released in the stomach but rather is released in the intestines. Another embodiment of this invention where oral administration is desired provides for a combination product wherein one of the active ingredients is coated with a sustained-release material which effects a sustained-release throughout the gastrointestinal tract and also serves to minimize physical contact between the combined active ingredients. Furthermore, the sustained- released component can be additionally enteric coated such that the release of this component occurs only in the intestine. Still another approach would involve the formulation of a combination product in which the one component is coated with a sustained and/or enteric release polymer, and the other component is also coated with a polymer such as a low viscosity grade of hydroxypropyl methylcellulose or other appropriate materials as known in the art, in order to further separate the active components. The polymer coating serves to form an additional barrier to interaction with the other component. In each formulation wherein contact is prevented between components (i) and (ii) via a coating or some other material, contact may also be prevented between the individual agents of component (ii) . Dosage forms of the combination products of the present invention wherein one active ingredient is enteric coated can be in the form of tablets such that the enteric coated component and the other active ingredient are blended together and then compressed into a tablet or such that the enteric coated component is compressed into one tablet layer and the other active ingredient is compressed into an additional layer. Optionally, in order to further separate the two layers, one or more placebo layers may be present such that the placebo layer is between the layers of active ingredients. In addition, dosage forms of the present invention can be in the form of capsules wherein one active ingredient is compressed into a tablet or in the form of a plurality of microtablets, particles, granules or non-perils, which are then enteric coated. These enteric coated microtablets, particles, granules or non-perils are then placed into a capsule or compressed into a capsule along with a granulation of the other active ingredient. These as well as other ways of minimizing contact between the components of combination products of the present invention, whether administered in a single dosage form or administered in separate forms but at the same time or concurrently by the same manner, will be readily apparent to those skilled in the art, based on the present disclosure.
Obviously, numerous modifications and variations of the present invention are possible in light of the above teachings. It is therefore to be understood that within the scope of the appended claims, the invention may be practiced otherwise than as specifically described herein.

Claims

What is claimed is:
1. A method of treating thrombosis in a mammal comprising: administering to said mammal a therapeutically effective amount of a combination of (i) a Factor Xa inhibitor, and (ii) a compound selected from the group consisting of aspirin, TPA, a GPIIb/IIIa antagonist, low molecular weight heparin and heparin, wherein the dose administered for at least one of (i) and (ii) is a subtherapeutic dose.
2. A method of Claim 1 wherein the combination of (i) and (ii) provides a synergistic effect.
3. A method of Claim 2 wherein (ii) is aspirin.
4. A method of Claim 2 wherein (ii) is TPA.
5. A method of Claim 2 wherein (ii) is a GPIIb/IIIa antagonist.
6. A method of Claim 2 wherein (ii) is a low molecular weight heparin.
7. A method of Claim 2 wherein (ii) is heparin.
8. The use of a combination of (i) a Factor Xa inhibitor, and (ii) a compound selected from the group consisting of aspirin, TPA, a GPIIb/IIIa antagonist, low molecular weight heparin and heparin for the manufacture of a medicament for the treatment of thrombosis .
PCT/US2000/006451 1999-03-11 2000-03-10 Treatment of thrombosis by combined use of a factor xa inhibitor and aspirin, tissue plasminogen activator (tpa), a gpiib/iiia antagonist, low molecular weight heparin or heparin WO2000053264A1 (en)

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NZ513217A NZ513217A (en) 1999-03-11 2000-03-10 Treatment of thrombosis by combined use of a factor Xa inhibitor and aspirin, tissue plasminogen activator (TPA), a GPIIb/IIIa antagonist, low molecular weight heparin or heparin
CA002361650A CA2361650A1 (en) 1999-03-11 2000-03-10 Treatment of thrombosis by combined use of a factor xa inhibitor and aspirin, tissue plasminogen activator (tpa), a gpiib/iiia antagonist, low molecular weight heparin or heparin
EA200100966A EA200100966A1 (en) 1999-03-11 2000-03-10 TREATMENT OF THROMBOSIS BY THE COMBINED APPLICATION OF THE INHIBITOR OF THE FACTOR Xa AND ASPIRIN, THE ACTIVATOR OF A TISSUE PLASMINOGEN (TPA), ANTAGONIST GPIIB / IIIA, A LOW-MOLECULAR HEPARIN OR HEPARIN
BR0010381-0A BR0010381A (en) 1999-03-11 2000-03-10 Method of treating thrombosis in a mammal, and using a combination of (i) a factor xa inhibitor, and (ii) a compound selected from the group consisting of aspirin, tpa, a gpiib / iiia antagonist, low weight heparin molecular and heparin
AU35254/00A AU766089B2 (en) 1999-03-11 2000-03-10 Treatment of thrombosis by combined use of a factor Xa inhibitor and aspirin, tissue plasminogen activator (TPA), a GPIIb/IIIa antagonist, low molecular weight heparin or heparin
IL14479800A IL144798A0 (en) 1999-03-11 2000-03-10 Treatment of thrombosis by combined use of a factor xa inhibitor and aspirin, tissue plasminogen activator (tpa), a gpiib/iiia antagonist, low molecular weight heparin or heparin
JP2000603752A JP2002538226A (en) 1999-03-11 2000-03-10 Treatment of thrombosis by using a combination of factor Xa inhibitor and aspirin, tissue plasminogen activator (TPA), GPIIb / IIIa antagonist, low molecular weight heparin or heparin
EP00913894A EP1161279A1 (en) 1999-03-11 2000-03-10 Treatment of thrombosis by combined use of a factor xa inhibitor and aspirin, tissue plasminogen activator (tpa), a gpiib/iiia antagonist, low molecular weight heparin or heparin
KR1020017011454A KR20020005614A (en) 1999-03-11 2000-03-10 Treatment of Thrombosis by Combined Use of a Factor Xa Inhibitor and Aspirin, Tissue Plasminogen Activator (TPA), a GPIIb/IIIa Antagonist, Low Molecular Weight Heparin or Heparin

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Cited By (13)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6297233B1 (en) 1999-02-09 2001-10-02 Bristol-Myers Squibb Company Lactam inhibitors of FXa and method
WO2001074774A1 (en) * 2000-04-05 2001-10-11 Daiichi Pharmaceutical Co., Ltd. Ethylenediamine derivatives
WO2002000647A1 (en) * 2000-06-23 2002-01-03 Bristol-Myers Squibb Pharma Company Heteroaryl-phenyl substituted factor xa inhibitors
US6344450B1 (en) 1999-02-09 2002-02-05 Bristol-Myers Squibb Company Lactam compounds and their use as inhibitors of serine proteases and method
WO2002096428A1 (en) * 2001-05-31 2002-12-05 Astrazeneca Ab Pharmaceutical combinations
WO2002102325A2 (en) * 2001-02-28 2002-12-27 Griffin John H Plasma glucosylceramide deficiency as risk factor for thrombosis and modulator of anticoagulant protein c
US6511973B2 (en) 2000-08-02 2003-01-28 Bristol-Myers Squibb Co. Lactam inhibitors of FXa and method
EP1679067A1 (en) * 2003-09-19 2006-07-12 Kissei Pharmaceutical Co., Ltd. Concurrent drugs
US7829082B2 (en) 2001-11-26 2010-11-09 Genentech, Inc. Catheter composition and uses thereof
US8202999B2 (en) 2005-01-07 2012-06-19 Synta Pharmaceuticals Corp. Compounds for inflammation and immune-related uses
CZ303715B6 (en) * 2001-06-20 2013-04-03 Bayer Intellectual Property Gmbh Pharmaceutical combination of 5-chloro-N-({(5S)-2-oxo-3-[4-(3-oxo-4-morpholinyl)phenyl] -1,3-oxazolidin-5-yl}methyl-2-thiophenecarboxamide with clopidogrel or aspirin, medicament in which the combination is comprised and use thereof
US8916148B2 (en) 2006-11-07 2014-12-23 Genentech, Inc. Tissue plasminogen activator variant uses
EP2982668A2 (en) 2002-12-03 2016-02-10 Pharmacyclics LLC 2-(2-hydroxybiphenyl-3-yl)-1h-benzoimidazole-5-carboxamidine derivatives as factor viia inhibitors for the treatment of thromboembolic disorders

Citations (9)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1994012204A1 (en) * 1992-12-01 1994-06-09 Merck & Co., Inc. Anticoagulant proteins
WO1995014683A1 (en) * 1993-11-24 1995-06-01 The Du Pont Merck Pharmaceutical Company Novel isoxazoline and isoxazole fibrinogen receptor antagonists
EP0735050A2 (en) * 1995-03-31 1996-10-02 Hamilton Civic Hospitals Research Development, Inc. Compositions for inhibiting thrombogenesis
WO1996040744A1 (en) * 1995-06-07 1996-12-19 Cor Therapeutics, Inc. KETOHETEROCYCLIC INHIBITORS OF FACTOR Xa
EP0832879A1 (en) * 1995-05-18 1998-04-01 Bristol-Myers Squibb Company Process for preparing intermediates for thrombin inhibitors
WO1998028269A1 (en) * 1996-12-23 1998-07-02 Du Pont Pharmaceuticals Company NITROGEN CONTAINING HETEROAROMATICS AS FACTOR Xa INHIBITORS
WO1999038827A1 (en) * 1998-02-02 1999-08-05 Merck & Co., Inc. PLATELET AGGREGATION INHIBITION USING LOW MOLECULAR WEIGHT HEPARIN IN COMBINATION WITH A GP IIb/IIIa ANTAGONIST
WO1999045913A1 (en) * 1998-03-13 1999-09-16 Merck & Co., Inc. Combination therapy and composition for acute coronary ischemic syndrome and related conditions
DE19816983A1 (en) * 1998-04-17 1999-10-21 Boehringer Ingelheim Pharma New bicyclic heteroaromatic amidine or nitrile compounds, used as thrombin inhibitors, antithrombotic agents or intermediates

Patent Citations (9)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1994012204A1 (en) * 1992-12-01 1994-06-09 Merck & Co., Inc. Anticoagulant proteins
WO1995014683A1 (en) * 1993-11-24 1995-06-01 The Du Pont Merck Pharmaceutical Company Novel isoxazoline and isoxazole fibrinogen receptor antagonists
EP0735050A2 (en) * 1995-03-31 1996-10-02 Hamilton Civic Hospitals Research Development, Inc. Compositions for inhibiting thrombogenesis
EP0832879A1 (en) * 1995-05-18 1998-04-01 Bristol-Myers Squibb Company Process for preparing intermediates for thrombin inhibitors
WO1996040744A1 (en) * 1995-06-07 1996-12-19 Cor Therapeutics, Inc. KETOHETEROCYCLIC INHIBITORS OF FACTOR Xa
WO1998028269A1 (en) * 1996-12-23 1998-07-02 Du Pont Pharmaceuticals Company NITROGEN CONTAINING HETEROAROMATICS AS FACTOR Xa INHIBITORS
WO1999038827A1 (en) * 1998-02-02 1999-08-05 Merck & Co., Inc. PLATELET AGGREGATION INHIBITION USING LOW MOLECULAR WEIGHT HEPARIN IN COMBINATION WITH A GP IIb/IIIa ANTAGONIST
WO1999045913A1 (en) * 1998-03-13 1999-09-16 Merck & Co., Inc. Combination therapy and composition for acute coronary ischemic syndrome and related conditions
DE19816983A1 (en) * 1998-04-17 1999-10-21 Boehringer Ingelheim Pharma New bicyclic heteroaromatic amidine or nitrile compounds, used as thrombin inhibitors, antithrombotic agents or intermediates

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
LEFKOVITS, JEFFREY ET AL: "Selective inhibition of factor Xa is more efficient than factor VIIa-tissue factor complex blockade at facilitating coronary thrombolysis in the canine model", J. AM. COLL. CARDIOL. (1996), 28(7), 1858-1865, XP000933719 *

Cited By (22)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6297233B1 (en) 1999-02-09 2001-10-02 Bristol-Myers Squibb Company Lactam inhibitors of FXa and method
US6344450B1 (en) 1999-02-09 2002-02-05 Bristol-Myers Squibb Company Lactam compounds and their use as inhibitors of serine proteases and method
WO2001074774A1 (en) * 2000-04-05 2001-10-11 Daiichi Pharmaceutical Co., Ltd. Ethylenediamine derivatives
US7935824B2 (en) 2000-04-05 2011-05-03 Daiichi Pharmaceutical Co., Ltd. Ethylenediamine derivatives
US7192968B2 (en) 2000-04-05 2007-03-20 Daiichi Pharmaceutical Co., Ltd. Ethylenediamine derivatives
WO2002000647A1 (en) * 2000-06-23 2002-01-03 Bristol-Myers Squibb Pharma Company Heteroaryl-phenyl substituted factor xa inhibitors
US6511973B2 (en) 2000-08-02 2003-01-28 Bristol-Myers Squibb Co. Lactam inhibitors of FXa and method
WO2002102325A3 (en) * 2001-02-28 2003-09-12 John H Griffin Plasma glucosylceramide deficiency as risk factor for thrombosis and modulator of anticoagulant protein c
US6756208B2 (en) 2001-02-28 2004-06-29 John H. Griffin Plasma glucosylceramide deficiency as risk factor for thrombosis and modulator of anticoagulant protein C
WO2002102325A2 (en) * 2001-02-28 2002-12-27 Griffin John H Plasma glucosylceramide deficiency as risk factor for thrombosis and modulator of anticoagulant protein c
JP2004532869A (en) * 2001-05-31 2004-10-28 アストラゼネカ アクチボラグ Pharmaceutical composition
AU2002305952B2 (en) * 2001-05-31 2007-08-09 Astrazeneca Ab Pharmaceutical combinations
CN100352442C (en) * 2001-05-31 2007-12-05 阿斯特拉曾尼卡有限公司 Pharmaceutical combinations
WO2002096428A1 (en) * 2001-05-31 2002-12-05 Astrazeneca Ab Pharmaceutical combinations
CZ303715B6 (en) * 2001-06-20 2013-04-03 Bayer Intellectual Property Gmbh Pharmaceutical combination of 5-chloro-N-({(5S)-2-oxo-3-[4-(3-oxo-4-morpholinyl)phenyl] -1,3-oxazolidin-5-yl}methyl-2-thiophenecarboxamide with clopidogrel or aspirin, medicament in which the combination is comprised and use thereof
US7829082B2 (en) 2001-11-26 2010-11-09 Genentech, Inc. Catheter composition and uses thereof
EP2982668A2 (en) 2002-12-03 2016-02-10 Pharmacyclics LLC 2-(2-hydroxybiphenyl-3-yl)-1h-benzoimidazole-5-carboxamidine derivatives as factor viia inhibitors for the treatment of thromboembolic disorders
EP1679067A4 (en) * 2003-09-19 2010-04-07 Kissei Pharmaceutical Concurrent drugs
EP1679067A1 (en) * 2003-09-19 2006-07-12 Kissei Pharmaceutical Co., Ltd. Concurrent drugs
US8202999B2 (en) 2005-01-07 2012-06-19 Synta Pharmaceuticals Corp. Compounds for inflammation and immune-related uses
US8592486B2 (en) 2005-01-07 2013-11-26 Synta Pharmaceuticals Corp. Compounds for inflammation and immune-related uses
US8916148B2 (en) 2006-11-07 2014-12-23 Genentech, Inc. Tissue plasminogen activator variant uses

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