Anticoagulant reversal agents

Abstract

Novel anticoagulant reversal compounds are disclosed, as well as methods of making the compounds, pharmaceutical compositions including the compounds, methods of using the compounds to reverse the anticoagulant effects of coagulation inhibitors, and diagnostic assays comprising the compounds.

1 . A compound of formula I
   Y-M-X-L-A-L′-X′-M′-Y′  (I)
   or a pharmaceutically acceptable salt thereof, wherein:   A is a substituted or unsubstituted aromatic or non-aromatic, carbocyclic or heterocyclic ring or a linear moiety;   L and L′ are the same or different and are linkers;   X and X′ are the same or different and are absent or are a functional group that attaches the linker L to M and linker L′ to M′, respectively;   M and M′ are the same or different and are absent or is a linker that attaches X to Y and X′ to Y′, respectively; and   Y and Y′ are the same or different and are a moiety containing one or more cationic atoms or groups or one or more groups that become cationic under physiological conditions.   
     
     
         2 . The compound of  claim 1 , wherein A is a non-aromatic, heterocyclic ring or a linear moiety, and wherein the ring or the linear moiety contain reactive functional groups that can form a bond to X and/or X′, when present, or Y and/or Y′. 
     
     
         3 . The compound of  claim 2 , wherein A is a piperazine or diketopiperazine. 
     
     
         4 . The compound of  claim 1 , wherein X and X′, when present, is a functional group that attaches linker L to Y and linker L′ to Y′, respectively, and wherein the functional group is selected from the group consisting of esters, amides, and ketones. 
     
     
         5 . The compound of  claim 1 , wherein L and/or L′ is a substituted or unsubstituted alkylene chain that is C 1  to C 6 . 
     
     
         6 . The compound of  claim 1 , wherein the compound is represented by formula II: 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof. 
     
     
         7 . The compound of  claim 6 , wherein the compound is represented by formula III: 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof. 
       
     
     
         8 . The compound of  claim 7 , wherein the compound is represented by formula IV: 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof, 
       wherein n is 3 to 5, m is 3 to 6 and G is selected from —NH 2  and OH. 
     
     
         9 . The compound of  claim 8 , wherein G is amino. 
     
     
         10 . The compound of  claim 1 , wherein Y and Y′ are independently selected from 
       
         
           
           
               
               
           
         
       
     
     
         11 . The compound of  claim 10 , wherein Y and Y′ is 
       
         
           
           
               
               
           
         
       
     
     
         12 . A compound of formula V 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof. 
     
     
         13 . A compound of formula VI 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof. 
     
     
         14 . A compound of formula VII 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof. 
     
     
         15 . A compound of formula VIII 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof. 
     
     
         16 . A pharmaceutical composition comprising the compound of  claim 1  and a pharmaceutically acceptable carrier. 
     
     
         17 . The pharmaceutical composition of  claim 16 , wherein the composition is adapted for enteral administration. 
     
     
         18 . The pharmaceutical composition of  claim 17 , wherein the composition is adapted for oral administration. 
     
     
         19 . The pharmaceutical composition of  claim 16 , wherein the composition is adapted for parenteral administration. 
     
     
         20 . The pharmaceutical composition of  claim 19 , wherein the composition is adapted for intravenous or subcutaneous administration. 
     
     
         21 . A method of completely or partially reversing an anticoagulant effect of a coagulation inhibitor comprising administering to a subject in need thereof a therapeutically effective amount of a compound of  claim 1  or pharmaceutically acceptable salt thereof. 
     
     
         22 . The method of  claim 21 , wherein the coagulation inhibitor is selected from the group consisting of an unfractionated heparin, low molecular weight heparin (LMWH), Factor Ha inhibitor, and Factor Xa inhibitor. 
     
     
         23 . The method of  claim 22 , wherein the coagulation inhibitor is a factor Xa inhibitor. 
     
     
         24 . The method of  claim 23 , wherein the factor Xa inhibitor is selected from the group consisting of rivaroxaban, apixaban, edoxaban, and fondaparinux. 
     
     
         25 . The method of  claim 21 , wherein the subject is a mammal. 
     
     
         26 . The method of  claim 25 , wherein the subject is a human. 
     
     
         27 . The method of  claim 21 , wherein the complete or partial reversal of an anticoagulant effect of a coagulation inhibitor is measured by anti-factor Xa activity assay. 
     
     
         28 . The method of  claim 21 , wherein the subject in need thereof is a subject in whom acute or planned reversal of anticoagulation is indicated. 
     
     
         29 . The method of  claim 28 , wherein the subject in whom acute or planned reversal of anticoagulation is indicated is a subject suffering from anticoagulant overdose, a subject suffering from hemorrhage, a subject requiring planned surgical intervention, a subject undergoing an invasive or non-invasive procedure requiring a biopsy, a subject undergoing a procedure wherein a procedural error may result in hemorrhage if the subject remains anticoagulated, or a subject requiring spinal or epidural anesthesia. 
     
     
         30 . The method of  claim 28 , wherein the subject in need thereof is a subject receiving anticoagulation for stroke prevention, cardiac surgical and diagnostic procedures, cardiac arrhythmias, deep vein thrombosis (DVT) prevention, pulmonary embolism, or generally for the prevention of pathologic blood clots. 
     
     
         31 . The method of  claim 22 , wherein the coagulation inhibitor is a LMWH, and wherein the LMWH is selected from the group consisting of bemiparin, certoparin, dalteparin, enoxaparin, nadroparin, parnaparin, reviparin, and tinzaparin. 
     
     
         32 . The method of  claim 21 , wherein the compound or the pharmaceutically acceptable salt thereof is administered at a dose mass ratio of between about 0.01:1 to about 1000:1 of the compound or the pharmaceutically acceptable salt thereof to anticoagulant. 
     
     
         33 . The method of  claim 32 , wherein the compound or the pharmaceutically acceptable salt thereof is administered at a dose mass ratio of about 10:1 of the compound or the pharmaceutically acceptable salt thereof to anticoagulant. 
     
     
         34 . The method of  claim 21 , wherein the method comprises administering at least one additional therapeutic agent. 
     
     
         35 . The method of  claim 34 , wherein the at least one additional therapeutic agent is vitamin K. 
     
     
         36 . A diagnostic kit comprising the compound of  claim 1 . 
     
     
         37 . The kit of  claim 36 , wherein the kit is used for determining an anticoagulant concentration in blood.