Combination therapy with a compound acting as a platelet adp receptor inhibitor

Abstract

The present invention is directed to pharmaceutical compositions and methods of using combination therapies containing [4-(6-fluoro-7-methylamino-2,4-dioxo-1,4-dihydro-2H-quinazolin-3-yl)-phenyl]-5-chloro-thiophen-2-yl-sulfonylurea, or a pharmaceutically acceptable salt thereof, for the treatment of thrombosis diseases.

1 . A method for a condition in a mammal characterized by undesired thrombosis comprising administering to said mammal a therapeutically effective amount of the following therapeutic agents:
 (1) [4-(6-fluoro-7-methylamino-2,4-dioxo-1,4-dihydro-2H-quinazolin-3-yl)-phenyl]-5-chloro-thiophen-2-yl-sulfonylurea, or a pharmaceutically acceptable salt thereof; and   (2) a therapeutic agent selected from the group consisting of an anticoagulant agent, an antiplatelet agent, and combinations thereof.   
     
     
         2 . The method of  claim 1  comprising administering to said mammal a therapeutically effective amount of the following two therapeutic agents:
 (1) [4-(6-fluoro-7-methylamino-2,4-dioxo-1,4-dihydro-2H-quinazolin-3-yl)-phenyl]-5-chloro-thiophen-2-yl-sulfonylurea, or a pharmaceutically acceptable salt thereof; and   (2) an anticoagulant agent.   
     
     
         3 . The method according to  claim 2 , wherein the anticoagulant agent is a factor Xa inhibitor. 
     
     
         4 . The method according to  claim 3 , wherein the factor Xa inhibitor is selected from the group consisting of YM-150, Daiichi DU-176b, N-{(1R)-2-[4-(1-methyl-4-piperidinyl)-1-piperazinyl]-2-oxo-1-phenylethyl}-1H-indole-6-carboxamide, apixaban, rivaroxaban, otamixaban, and razaxaban. 
     
     
         5 . The method according to  claim 3 , wherein the factor Xa inhibitor is selected from the group consisting of: 
       
         
           
           
               
               
           
         
       
     
     
         6 . The method according to  claim 3 , wherein the factor Xa inhibitor is betrixaban, or a pharmaceutically acceptable salt thereof. 
     
     
         7 . The method according to  claim 6 , wherein the pharmaceutically acceptable salt of betrixaban is the maleate salt. 
     
     
         8 . The method according to  claim 2 , wherein the anticoagulant agent is selected from the group consisting of specific inhibitors of thrombin, factor IXa, factor XI, factor XIa or factor VIIa. 
     
     
         9 . The method according to  claim 2 , wherein the anticoagulant agent is selected from the group consisting of AZD0837, RB2006, ximelagatran, dabigatran, bivalirudin, argatroban, lepirudin, warfarin, and phenocoumarol. 
     
     
         10 . The method according to  claim 2 , wherein the anticoagulant agent is an injectable anticoagulant agent. 
     
     
         11 . The method according to  claim 2 , wherein the anticoagulant agent is selected from the group consisting of synthetic pentasaccharides and low molecular weight heparin. 
     
     
         12 . The method according to  claim 2 , wherein the anticoagulant agent is selected from the group consisting of fondaparinux, idraparinux, biotinylated idraparinux, danaparoid, enoxaparin, dalteparin and unfractionated heparin. 
     
     
         13 . The method according to  claim 2 , wherein the anticoagulant agent is an anti-factor XI antibody. 
     
     
         14 . The method according to  claim 2 , wherein the anticoagulant agent is bivalirudin. 
     
     
         15 . The method of  claim 1  comprising administering to said mammal a therapeutically effective amount of the following two therapeutic agents:
 (1) [4-(6-fluoro-7-methylamino-2,4-dioxo-1,4-dihydro-2H-quinazolin-3-yl)-phenyl]-5-chloro-thiophen-2-yl-sulfonylurea, or a pharmaceutically acceptable salt thereof; and   (2) another antiplatelet agent.   
     
     
         16 . The method according to  claim 15 , wherein the antiplatelet agent is an antagonist of TP receptor or a cyclooxygenase inhibitor. 
     
     
         17 . The method according to  claim 16 , wherein the cyclooxygenase inhibitor is a reversible cyclooxygenase-1 inhibitor. 
     
     
         18 . The method according to  claim 15 , wherein the antiplatelet agent is selected from the group consisting of acetylsalicylic acid, abciximab, eptifibatide, tirofiban, dipyridamole, aggrenox, cilostazol, ifetroban, isbogrel, furegrelate, resveratrol and ozagrel. 
     
     
         19 . The method according to  claim 1 , wherein at least one of the therapeutic agents is administered in a sub-therapeutic dosage. 
     
     
         20 . The method according to  claim 1 , wherein both of the therapeutic agents are administered in sub-therapeutic dosages. 
     
     
         21 . The method according to  claim 1 , wherein the two therapeutic agents are administered simultaneously. 
     
     
         22 . The method according to  claim 1 , wherein the two therapeutic agents are administered sequentially. 
     
     
         23 . The method of  claim 1 , comprising administering to said mammal a therapeutically effective amount of the following three therapeutic agents:
 (1) [4-(6-fluoro-7-methylamino-2,4-dioxo-1,4-dihydro-2H-quinazolin-3-yl)-phenyl]-5-chloro-thiophen-2-yl-sulfonylurea, or a pharmaceutically acceptable salt thereof;   (2) an antiplatelet agent; and   (3) an anticoagulant agent.   
     
     
         24 . The method according to  claim 23 , wherein the antiplatelet agent is a cyclooxygenase inhibitor. 
     
     
         25 . The method according to  claim 23 , wherein the antiplatelet agent is acetylsalicylic acid. 
     
     
         26 . The method according to  claim 23 , wherein the anticoagulant agent is a factor Xa inhibitor. 
     
     
         27 . The method according to  claim 26 , wherein the factor Xa inhibitor is betrixaban, or a pharmaceutically acceptable salt thereof. 
     
     
         28 . The method according to  claim 27 , wherein the pharmaceutically acceptable salt of betrixaban is the maleate salt. 
     
     
         29 . The method according to  claim 23 , wherein at least one of the therapeutic agents is administered in a sub-therapeutic dosage. 
     
     
         30 . The method according to  claim 23 , wherein all of the therapeutic agents are administered in sub-therapeutic dosages. 
     
     
         31 . The method according to  claim 23 , wherein the three therapeutic agents are administered simultaneously. 
     
     
         32 . The method according to  claim 23 , wherein the three therapeutic agents are administered sequentially. 
     
     
         33 . The method according to  claim 1 , wherein the pharmaceutically acceptable salt of [4-(6-fluoro-7-methylamino-2,4-dioxo-1,4-dihydro-2H-quinazolin-3-yl)-phenyl]-5-chloro-thiophen-2-yl-sulfonylurea is the potassium salt or sodium salt. 
     
     
         34 . The method according to  claim 1 , wherein said thrombosis-related condition is selected from the group consisting of acute myocardial infarction, unstable angina, chronic stable angina, transient ischemic attacks, strokes, peripheral vascular disease, preeclampsia/eclampsia, deep venous thrombosis, embolism, disseminated intravascular coagulation and thrombotic cytopenic purpura, thrombotic and restenotic complications following invasive procedures resulting from angioplasty, carotid endarterectomy, post CABG (Coronary arteryl bypass graft) surgery, vascular graft surgery, stent placements and insertion of endovascular devices and prosthesis. 
     
     
         35 . A pharmaceutical composition, comprising a pharmaceutically acceptable carrier and the following therapeutic agents:
 (1) [4-(6-fluoro-7-methylamino-2,4-dioxo-1,4-dihydro-2H-quinazolin-3-yl)-phenyl]-5-chloro-thiophen-2-yl-sulfonylurea, or a pharmaceutically acceptable salt thereof; and   (2) a therapeutic agent selected from the group consisting of an anticoagulant agent, an antiplatelet agent and combinations thereof.   
     
     
         36 . The pharmaceutical composition of  claim 35 , comprising a pharmaceutically acceptable carrier and the following two therapeutic agents:
 (1) [4-(6-fluoro-7-methylamino-2,4-dioxo-1,4-dihydro-2H-quinazolin-3-yl)-phenyl]-5-chloro-thiophen-2-yl-sulfonylurea, or a pharmaceutically acceptable salt thereof; and   (2) an anticoagulant agent.   
     
     
         37 . The pharmaceutical composition according to  claim 36 , wherein the anticoagulant agent is a factor Xa inhibitor. 
     
     
         38 . The pharmaceutical composition according to  claim 37 , wherein the factor Xa inhibitor is selected from the group consisting of YM-150, Daiichi DU-176b, N-{(1R)-2-[4-(1-methyl-4-piperidinyl)-1-piperazinyl]-2-oxo-1-phenylethyl}-1H-indole-6-carboxamide, apixaban, rivaroxaban, otamixaban, and razaxaban or is selected from the group consisting of: 
       
         
           
           
               
               
           
         
       
     
     
         39 . The pharmaceutical composition according to  claim 37 , wherein the factor Xa inhibitor is betrixaban, or a pharmaceutically acceptable salt thereof. 
     
     
         40 . The pharmaceutical composition according to  claim 39 , wherein the pharmaceutically acceptable salt of betrixaban is the maleate salt. 
     
     
         41 . The pharmaceutical composition according to  claim 37 , wherein the anticoagulant is selected from the group consisting of specific inhibitors of thrombin, factor IXa, factor XI, factor XIa or factor VIIa. 
     
     
         42 . The pharmaceutical composition according to  claim 37 , wherein the anticoagulant agent is selected from the group consisting of AZD0837, RB2006, ximelagatran, dabigatran, bivalirudin, argatroban, lepirudin, warfarin, and phenocoumarol. 
     
     
         43 . The pharmaceutical composition according to  claim 37 , wherein the anticoagulant agent is an injectable anticoagulant agent. 
     
     
         44 . The pharmaceutical composition according to  claim 37 , wherein the anticoagulant is selected from the group consisting of synthetic pentasaccharides and low molecular weight heparin. 
     
     
         45 . The pharmaceutical composition according to  claim 37 , wherein the anticoagulant is selected from the group consisting of fondaparinux, idraparinux, biotinylated idraparinux, danaparoid, enoxaparin, dalteparin and unfractionated heparin. 
     
     
         46 . The pharmaceutical composition according to  claim 37 , wherein the anticoagulant agent is an anti-factor XI antibody. 
     
     
         47 . The pharmaceutical composition of  claim 35  comprising a pharmaceutically acceptable carrier and the following two therapeutic agents:
 (1) [4-(6-fluoro-7-methylamino-2,4-dioxo-1,4-dihydro-2H-quinazolin-3-yl)-phenyl]-5-chloro-thiophen-2-yl-sulfonylurea, or a pharmaceutically acceptable salt thereof; and   (2) another antiplatelet agent.   
     
     
         48 . The pharmaceutical composition according to  claim 47 , wherein the antiplatelet agent is an antagonist of TP receptor or a cyclooxygenase inhibitor. 
     
     
         49 . The pharmaceutical composition according to  claim 48 , wherein the cyclooxygenase inhibitor is a reversible cyclooxygenase-1 inhibitor. 
     
     
         50 . The pharmaceutical composition according to  claim 47 , wherein the antiplatelet agent is selected from the group consisting of abciximab, acetylsalicylic acid, eptifibatide, tirofiban, dipyridamole, aggrenox, cilostazol, isbogrel, ifetroban, resveratrol, furegrelate and ozagrel. 
     
     
         51 . The pharmaceutical composition according to  claim 35 , wherein at least one of the two therapeutic agents is present in a sub-therapeutic dosage. 
     
     
         52 . The pharmaceutical composition according to  claim 35 , wherein both of the two therapeutic agents are present in sub-therapeutic dosages. 
     
     
         53 . The pharmaceutical composition of  claim 35  comprising a pharmaceutically acceptable carrier and the following three therapeutic agents:
 (1) [4-(6-fluoro-7-methylamino-2,4-dioxo-1,4-dihydro-2H-quinazolin-3-yl)-phenyl]-5-chloro-thiophen-2-yl-sulfonylurea, or a pharmaceutically acceptable salt thereof;   (2) another antiplatelet agent; and   (3) an anticoagulant agent.   
     
     
         54 . The pharmaceutical composition according to  claim 53 , wherein the antiplatelet agent is a cyclooxygenase inhibitor. 
     
     
         55 . The pharmaceutical composition according to  claim 53 , wherein the antiplatelet agent is acetylsalicylic acid. 
     
     
         56 . The pharmaceutical composition according to  claim 53 , wherein the anticoagulant agent is a factor Xa inhibitor. 
     
     
         57 . The pharmaceutical composition according to  claim 56 , wherein the factor Xa inhibitor is betrixaban, or a pharmaceutically acceptable salt thereof. 
     
     
         58 . The pharmaceutical composition according to  claim 57 , wherein the pharmaceutically acceptable salt of betrixaban is the maleate salt. 
     
     
         59 . The pharmaceutical composition according to  claim 53 , wherein at least one of the therapeutic agents is administered in a sub-therapeutic dosage. 
     
     
         60 . The pharmaceutical composition according to  claim 53 , wherein all of the therapeutic agents are administered in sub-therapeutic dosages. 
     
     
         61 . The pharmaceutical composition according to  claim 35 , wherein the pharmaceutically acceptable salt of [4-(6-fluoro-7-methylamino-2,4-dioxo-1,4-dihydro-2H-quinazolin-3-yl)-phenyl]-5-chloro-thiophen-2-yl-sulfonylurea is the potassium salt or the sodium salt. 
     
     
         62 . A kit comprising:
 (1) a first container, wherein said first container contains [4-(6-fluoro-7-methylamino-2,4-dioxo-1,4-dihydro-2H-quinazolin-3-yl)-phenyl]-5-chloro-thiophen-2-yl-sulfonylurea, or a pharmaceutically acceptable salt thereof; and   (2) a second container, wherein said second container contains an anticoagulant agent or another antiplatelet agent.   
     
     
         63 . The kit according to  claim 62 , further comprising a package insert stating that the two therapeutic agents can be used together.