Substituted pyrrolidines as factor xia inhibitors for the treatment thromboembolic diseases

Abstract

COMPOUNDS The present invention provides compounds of the general formula (I), their salts and N-oxides, and solvates and prodrugs thereof (wherein the substituents are as defined in the description). The compounds of the general formula (I) are inhibitors of factor XIa, and are useful in the prevention of and/or therapy for thromboembolic diseases.

1 - 22 . (canceled) 
     
     
         23 . A method for treating a patient suffering from or susceptible to an arterial cardiovascular thromboembolic disorder, which method comprises administering to said patient a therapeutically effective amount of 4-[({(2S,4S)-1-(4-carbamimidoylbenzoyl)-4-[4-(methylsulfonyl)-1-piperazinyl]-2-pyrrolidinyl}carbonyl)amino]benzoic acid or a pharmaceutically acceptable salt thereof. 
     
     
         24 . The method of  claim 23 , wherein the 4-[({(2S,4S)-1-(4-carbamimidoylbenzoyl)-4-[4-(methylsulfonyl)-1-piperazinyl]-2-pyrrolidinyl}carbonyl)amino]benzoic acid or a pharmaceutically acceptable salt thereof is in a pharmaceutical composition. 
     
     
         25 . The method of  claim 23 , wherein the arterial cardiovascular thromboembolic disorder is selected from the group consisting of ischemic cardiomyopathy, ischemic complications of unstable angina and non-Q-wave myocardial infarction, acute non ST-segment elevation and/or ST-segment elevation myocardial infarction managed medically or with subsequent percutaneous coronary intervention, angina pectoris, variant angina pectoris, unstable angina pectoris, reocclusion and restenosis after coronary artery bypass surgery, and reocclusion and restenosis after percutaneous transluminal cardiac angioplasty/transluminal coronary artery stent placement surgery or after thrombolytic therapy for coronary artery. 
     
     
         26 . A method for treating a patient suffering from or susceptible to a venous cardiovascular thromboembolic disorder, which method comprises administering to said patient a therapeutically effective amount of 4-[({(2S,4S)-1-(4-carbamimidoylbenzoyl)-4-[4-(methylsulfonyl)-1-piperazinyl]-2-pyrrolidinyl}carbonyl)amino]benzoic acid or a pharmaceutically acceptable salt thereof. 
     
     
         27 . The method of  claim 26 , wherein the 4-[({(2S,4S)-1-(4-carbamimidoylbenzoyl)-4-[4-(methylsulfonyl)-1-piperazinyl]-2-pyrrolidinyl}carbonyl)amino]benzoic acid or a pharmaceutically acceptable salt thereof is in a pharmaceutical composition. 
     
     
         28 . The method of  claim 26 , wherein the venous cardiovascular thromboembolic disorder is selected from the group consisting of deep vein thrombosis (DVT) and/or pulmonary embolism (PE) in major general surgery, abdominal surgery, hip replacement surgery, knee replacement surgery, hip fracture surgery, multiple fracture, multiple injury, trauma, spinal cord injury, burns, critical care unit, DVT and/or PE in medical patients with severely restricted mobility during acute illness, DVT and/or PE in patients with cancer chemotherapy, DVT and/or PE in patients with stroke, and symptomatic or asymptomatic DVT with or without PE (pulmonary embolism). 
     
     
         29 . A method for treating a patient suffering from or susceptible to an arterial cerebrovascular thromboembolic disorder, which method comprises administering to said patient a therapeutically effective amount of 4-[({(2S,4S)-1-(4-carbamimidoylbenzoyl)-4-[4-(methylsulfonyl)-1-piperazinyl]-2-pyrrolidinyl}carbonyl)amino]benzoic acid or a pharmaceutically acceptable salt thereof. 
     
     
         30 . The method of  claim 29 , wherein the 4-[({(2S,4S)-1-(4-carbamimidoylbenzoyl)-4-[4-(methylsulfonyl)-1-piperazinyl]-2-pyrrolidinyl}carbonyl)amino]benzoic acid or a pharmaceutically acceptable salt thereof is in a pharmaceutical composition. 
     
     
         31 . The method of  claim 29 , wherein the arterial cerebrovascular thromboembolic disorder is selected from the group consisting of ischemic stroke, stroke in patients with non-valuvelar or valuvelar atrial fibrillation, cerebral arterial thrombosis, cerebral infarction, cerebral artery embolism, cerebrovascular disorder, and asymptomatic cerebral infarction. 
     
     
         32 . A method for treating a patient suffering from or susceptible to a venous cerebrovascular thromboembolic disorder, which method comprises administering to said patient a therapeutically effective amount of 4-[({(2S,4S)-1-(4-carbamimidoylbenzoyl)-4-[4-(methylsulfonyl)-1-piperazinyl]-2-pyrrolidinyl}carbonyl)amino]benzoic acid or a pharmaceutically acceptable salt thereof. 
     
     
         33 . The method of  claim 32 , wherein the 4-[({(2S,4S)-1-(4-carbamimidoylbenzoyl)-4-[4-(methylsulfonyl)-1-piperazinyl]-2-pyrrolidinyl}carbonyl)amino]benzoic acid or a pharmaceutically acceptable salt thereof is in a pharmaceutical composition. 
     
     
         34 . The method of  claim 32 , wherein the venous cerebrovascular thromboembolic disorder is selected from the group consisting of intracranial venous thrombosis, cerebral thrombosis, sinus thrombosis, intracranial venous sinus thrombosis, and cavernous sinus thrombosis. 
     
     
         35 . A method for treating a patient suffering from or susceptible to a thromboembolic disorders in the chambers of the heart or in the peripheral circulation, which method comprises administering to said patient a therapeutically effective amount of 4-[({(2S,4S)-1-(4-carbamimidoylbenzoyl)-4-[4-(methylsulfonyl)-1-piperazinyl]-2-pyrrolidinyl}carbonyl)amino]benzoic acid or a pharmaceutically acceptable salt thereof. 
     
     
         36 . The method of  claim 35 , wherein the 4-[({(2S,4S)-1-(4-carbamimidoylbenzoyl)-4-[4-(methylsulfonyl)-1-piperazinyl]-2-pyrrolidinyl}carbonyl)amino]benzoic acid or a pharmaceutically acceptable salt thereof is in a pharmaceutical composition. 
     
     
         37 . The method of  claim 35 , wherein the thromboembolic disorders in the chambers of the heart or in the peripheral circulation selected from the group consisting of systemic venous thromboembolism, thrombophlebitis, non-valuvelar or valuvelar atrial fibrillation, and peripheral arterial disease.