[4-(6-HALO-7-Substituted-2,4-DIOXO-1,4-DIHYDRO-2H-QUINAZOLIN-3-YL)-PHENYL]-5-CHLORO-THIOPHEN-2-YL-SULFONYLUREAS and Forms and Methods Related Thereto

Abstract

The present invention provides novel sulfonylurea compounds of formula (I) and pharmaceutically acceptable derivatives and polymorph and amorphous forms thereof. The compounds in their various forms are effective platelet ADP receptor inhibitors and may be used in various pharmaceutical compositions, and are particularly effective for the prevention and/or treatment of cardiovascular diseases, particularly those diseases related to thrombosis. The invention also provides a method for preparing such compounds and forms and for preventing or treating thrombosis and thrombosis related conditions in a mammal comprising the step of administering a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt or forms thereof.

1 . A method for preventing or treating thrombosis and thrombosis related conditions in a mammal comprising the step of administering to a mammal a therapeutically effective amount of [4-(6-fluoro-7-methylamino-2,4-dioxo-1,4-dihydro-2H-quinazolin-3-yl)-phenyl]-5-chloro-thiophen-2-yl-sulfonylurea having the following formula: 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt or hydrate thereof. 
       
     
     
         2 . A method for preventing or treating a condition or disorder mediated at least in part by ADP-induced platelet aggregation in a mammal comprising the step of administering to a mammal in need of such treatment in a therapeutically effective amount of [4-(6-fluoro-7-methylamino-2,4-dioxo-1,4-dihydro-2H-quinazolin-3-yl)-phenyl]-5-chloro-thiophen-2-yl-sulfonylurea having the following formula: 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt or hydrate thereof. 
       
     
     
         3 . The method of  claim 2 , wherein said mammal is prone to or suffers from a cardiovascular disease. 
     
     
         4 . The method of  claim 3 , wherein said cardiovascular disease is at least one 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 retenotic complications following invasive procedures resulting from angioplasty, carotid endarterectorny, post CABG (coronary artery bypass graft) surgery, vascular gram surgery, stent, in-stent thrombosis, and insertion of endovascular devices and prostheses, and hypercoagulable states related to genetic predisposition or cancers. 
     
     
         5 . The method of  claim 1 , wherein the compound is administered orally, parenterally or topically. 
     
     
         6 . The method of  claim 1 , wherein the compound is administered in combination with a second therapeutic agent. 
     
     
         7 . The method of  claim 6 , wherein the patient is a human. 
     
     
         8 . The method of  claim 6 , wherein the second therapeutic agent is useful for treating a condition or disorder 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 endarterectorny, post CABG (coronary artery bypass graft) surgery, vascular gram surgery, stent placements and insertion of endovascular devices, prostheses, and hypercoagulable states related to genetic predisposition and cancer. 
     
     
         9 . The method in accordance with  claim 6 , wherein said compound is administered in combination with a second therapeutic agent selected from the group consisting of antiplatelet compounds, anticoagulants, fibrinolytics, anti-inflammatory compounds, cholesterol-lowering agents, proton pump inhibitors, blood pressure-lowering agents, serotonin blockers, and nitrates. 
     
     
         10 . The method in accordance with  claim 9 , wherein said second therapeutic agent is an antiplatelet compound selected from the group consisting of GPIIB-IIIa antagonists, aspirin, phosphodiesterase III inhibitors and thromboxane A2 receptor antagonists. 
     
     
         11 . The method in accordance with  claim 9 , wherein said second therapeutic agent is an anticoagulant selected from the group consisting of thrombin inhibitors, coumadin, heparin, and fXa inhibitors. 
     
     
         12 . The method in accordance with  claim 9 , wherein said second therapeutic agent is an anti-inflammatory compound selected from the group consisting of non-steroidal anti-inflammatory agents, cyclooxygenase-2 inhibitors and rheumatoid arthritis agents. 
     
     
         13 . A method for preventing the occurrence of a secondary ischemic event comprising administering to a patient who has suffered a primary ischemic event a therapeutically effective amount of [4-(6-fluoro-7-methylamino-2,4-dioxo-1,4-dihydro-2H-quinazolin-3-yl)-phenyl]-5-chloro-thiophen-2-yl-sulfonylurea having the following formula: 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt or hydrate thereof, together with a pharmaceutically acceptable carrier. 
       
     
     
         14 . The method in accordance with  claim 13 , wherein said primary and/or secondary ischemic event is selected from the group consisting of myocardial infarction, stable or unstable angina, acute reocclusion after percutaneous coronary intervention, and/or stenting, restenosis, peripheral vessel balloon angioplasty and/or stenting, thrombotic stroke, transient ischemic attack, reversible ischemic neurological deficit and intermittent claudication. 
     
     
         15 . The method in accordance with  claim 13 , wherein said primary and/or secondary ischemic event is selected from the group consisting of percutaneous coronary intervention (PCI) including angioplasty and/or stent, acute myocardial infarction (AMI), unstable angina (USA), coronary artery disease (CAD), transient ischemic attacks (TIA), stroke, peripheral vascular disease (PVD), Surgeries-coronary bypass, carotid endarectomy.