Pharmaceutically active compounds and methods of use thereof

Abstract

The invention includes pharmaceutically active compounds and methods of treatment and pharmaceutical compositions that utilize or comprise one or more such compounds. Compounds of the invention are particularly useful for treatment or prophylaxis of undesired thrombosis.

1 . A method for treating a mammal susceptible to, suffering from, suspected of having or recovering from a disease impacted by tissue factor (TF), the method comprising administering to the mammal a therapeutically effective amount of at least one TF blocking compound to treat the disease.  
   
   
       2 . The method of  claim 1 , wherein the disease is selected from the group consisting of a cardiovascular disease, a blood coagulation disorder, a cell proliferation disorder, post-operative complication, an immune disorder, atherosclerosis, inflammation or cancer.  
   
   
       3 . A method of blocking or inhibiting tissue factor-dependent activation of factor X and/or factor IX, comprising contacting tissue factor with a TF blocking compound to thereby inhibit formation of a functional complex of factor X or factor IX with tissue factor or TF VIIA.  
   
   
       4 . The method of  claim 3  wherein the TF blocking compound binds to tissue factor to thereby inhibit formation of the functional complex.  
   
   
       5 . The method of any one of claims  1 - 4  wherein the tissue factor blocking compound exhibits an IC 50  of less than about 100 μM in a standard assay for measuring TF/VIIa-dependent factor X activation.  
   
   
       6 . The method of any one of claims  1 - 4  wherein the tissue factor blacking compound exhibits an IC 50  of about 200 μM or less in a standard assay for measuring TF/VIIa-dependent factor IX activation.  
   
   
       7 . The method of any one of claims  1 - 4  wherein the tissue factor compound comprises at least one phosphonate group.  
   
   
       8 . The method of any one of claims  1 - 4  wherein the tissue factor compound comprises at least one bis-phosphonate group.  
   
   
       9 . The method of  claim 7  or  8  wherein the tissue factor compound further comprises an optionally substituted carbocyclic aryl group, or an optionally substituted heteroaryl group.  
   
   
       10 . The method of  claim 7  or  8  wherein the tissue factor compound further comprises an optionally substituted phenyl group.  
   
   
       11 . The method of any one of claims  1 - 4  wherein the TF blocking compound is of the following Formula I:  
       Ar-(CXY) m -(Het) 0 or 1 -(CX 1 Y 1 ) n —C(Z) p -(PO 3 ) 3-p    I  wherein Ar is optionally substituted carbocyclic aryl or optionally substituted heteroaryl;    Het is optionally substituted N, O, S, S(O) or S(O 2 );    each X, each Y, each X′, each Y′ and each Z are each independently hydrogen; halogen; hydroxyl; sulfhydryl; amino; optionally substituted alkyl preferably; optionally substituted alkenyl; optionally substituted alkynyl; optionally substituted alkoxy; optionally substituted alkylthio; optionally substituted alkylsulfinyl; optionally substituted alkylsulfonyl; or optionally substituted alkylamino;    m and n each is independently an integer of from 0 to 4; p is 1 or 2; and pharmaceutically acceptable salts thereof.    
   
   
       12 . The method of any one of claims  1 - 4  wherein the TF blocking compound is of the following Formula II:  
     
       
         
         
             
             
         
       
       wherein Ar is optionally substituted carbocyclic aryl or optionally substituted heteroaryl;  
       Het is optionally substituted N, O, S, S(O) or S(O 2 );  
       each X, each Y, each X′, each Y′ and each Z are each independently hydrogen; halogen; hydroxyl; sulfhydryl; amino; optionally substituted alkyl preferably; optionally substituted alkenyl; optionally substituted alkynyl; optionally substituted alkoxy; optionally substituted alkylthio; optionally substituted alkylsulfinyl; optionally substituted alkylsulfonyl; or optionally substituted alkylamino;  
       each R 1  is independently halogen; amino; hydroxy; nitro; carboxy; sulfhydryl; optionally substituted alkyl; optionally substituted alkenyl; optionally substituted alkynyl; optionally substituted alkoxy; optionally substituted alkylthio; optionally substituted alkylsulfinyl; optionally substituted alkylsulfonyl; optionally substituted alkylamino; optionally substituted alkanoyl; optionally substituted carbocyclic aryl; or optionally substituted aralkyl;  
       m and n each is independently an integer of from 0 to 4; p is 1 or 2; q is an integer of from 0 to 5; and pharmaceutically acceptable salts thereof.  
     
   
   
       13 . A method for identifying a candidate TF blocking compound, the method comprising screening the compound in at least one primary screening assay using purified tissue factor; and selecting the TF blocking compound.  
   
   
       14 . The method of  claim 13  further comprising screening the candidate TF blocking compound in at least one secondary screening assay.  
   
   
       15 . The method of  claim 13  or  14  comprising screening the candidate TF blocking compound in a standard in vitro assay for measuring TF/VIIa-dependent factor X activation.  
   
   
       16 . The method of  claim 13  or  14  comprising screening the candidate TF blocking compound in a standard in vitro assay for measuring TF/VIIa dependent factor IX activation.  
   
   
       17 . The method of  claim 13  wherein the screening assay is a standard prothrombin time (PT) assay.  
   
   
       18 . The method of any of claims  13 - 17  wherein the purified tissue factor is lipidated recombinant human tissue factor.  
   
   
       19 . A tissue factor (TF) blocking compound exhibiting an IC 50  of less than about 100 μM in a standard assay for measuring TF/VIIa-dependent factor X activation.  
   
   
       20 . The compound of  claim 19  further exhibiting equivalent or greater than about 70% inhibition in the assay.  
   
   
       21 . The compound of  claim 19  further exhibiting an IC 50  of about 200 μM or less in a standard assay for measuring TF/VIIa-dependent factor IX activation.  
   
   
       22 . The compound of  claim 19  further exhibiting at least about a 5% to 20% increase in plasma clotting time relative to a control in a standard prothrombin time (PT) assay.  
   
   
       23 . The compound of  claim 19  further exhibiting at least 70% inhibition in the assay for measuring TF/VIIa-dependent factor X activation and at least of the following activities: 1) an IC 50  of less than about 100 μM in a standard assay for measuring TF/VIIa-dependent factor IX activation, and 2) at least about a 5% to 20% increase in plasma clotting time relative to a control in a standard prothrombin time (PT) assay.  
   
   
       24 . The compound of  claim 19  wherein the compound is represented by the following Formula I:  
       Ar-(CXY) m -(Het) 0 or 1 -(CX 1 Y 1 ) n —C(Z) p -(PO 3 ) 3-p    I  wherein Ar is optionally substituted carbocyclic aryl or optionally substituted heteroaryl;    Het is optionally substituted N, O or S;    each X, each Y, each X′, each Y′ and each Z are each independently hydrogen; halogen; hydroxyl; sulfhydryl; amino; optionally substituted alkyl preferably; optionally substituted alkenyl; optionally substituted alkynyl; optionally substituted alkoxy; optionally substituted alkylthio; optionally substituted alkylsulfinyl; optionally substituted alkylsulfonyl; or optionally substituted alkylamino;    m and n each is independently an integer of from 0 to 4; p is 1 or 2; and pharmaceutically acceptable salts thereof.    
   
   
       25 . The compound of  claim 19  wherein the compound is represented by the following Formula II:  
     
       
         
         
             
             
         
       
       wherein Ar is optionally substituted carbocyclic aryl or optionally substituted heteroaryl;  
       Het is optionally substituted N, O, S, S(O) or S(O 2 );  
       each X, each Y, each X′, each Y′ and each Z are each independently hydrogen; halogen; hydroxyl; sulfhydryl; amino; optionally substituted alkyl preferably; optionally substituted alkenyl; optionally substituted alkynyl; optionally substituted alkoxy; optionally substituted alkylthio; optionally substituted alkylsulfinyl; optionally substituted alkylsulfonyl; or optionally substituted alkylamino;  
       each R 1  is independently halogen; amino; hydroxy; nitro; carboxy; sulfhydryl; optionally substituted alkyl; optionally substituted alkenyl; optionally substituted alkynyl; optionally substituted alkoxy; optionally substituted alkylthio; optionally substituted alkylsulfinyl; optionally substituted alkylsulfonyl; optionally substituted alkylamino; optionally substituted alkanoyl; optionally substituted carbocyclic aryl; or optionally substituted aralkyl;  
       m and n each is independently an integer of from 0 to 4; p is 1 or 2; q is an integer of from 0 to 5; and pharmaceutically acceptable salts thereof.  
     
   
   
       26 . The compound of  claim 19  wherein the compound is represented by the following Formula III:  
     
       
         
         
             
             
         
       
       wherein each X, each Y, each X′, each Y′ and each Z are each independently hydrogen; halogen; hydroxyl; sulfhydryl; amino;.optionally substituted alkyl preferably; optionally substituted alkenyl; optionally substituted alkynyl; optionally substituted alkoxy; optionally substituted alkylthio; optionally substituted alkylsulfinyl; optionally substituted alkylsulfonyl; or optionally substituted alkylamino;  
       m and n each is independently an integer of from 0 to 4; p is 1 or 2; q is an integer of from 0 to 5;  
       W is hydrogen, optionally substituted alkyl; optionally substituted alkenyl; optionally substituted alkynyl; optionally substituted alkoxy; optionally substituted alkylthio; optionally substituted alkylsulfinyl; optionally substituted alkylsulfonyl; optionally substituted alkylamino; optionally substituted alkanoyl; optionally substituted carbocyclic aryl; or optionally substituted aralkyl;  
       R 1  is independently halogen; amino; hydroxy; nitro; carboxy; sulfhydryl; optionally substituted alkyl; optionally substituted alkenyl; optionally substituted alkynyl; optionally substituted alkoxy; optionally substituted alkylthio; optionally substituted alkylsulfinyl; optionally substituted alkylsulfonyl; optionally substituted alkylamino; optionally substituted alkanoyl; optionally substituted carbocyclic aryl; or optionally substituted aralkyl;  
       q is an integer of from 0 to 5; and pharmaceutically acceptable salts thereof.  
     
   
   
       27 . The compound of  claim 19  wherein the compound is represented by the following Formula IIIa:  
     
       
         
         
             
             
         
       
       wherein R 1  is independently halogen; amino; hydroxy; nitro; carboxy; sulfhydryl; optionally substituted alkyl; optionally substituted alkenyl; optionally substituted alkynyl; optionally substituted alkoxy; optionally substituted alkylthio; optionally substituted alkylsulfinyl; optionally substituted alkylsulfonyl; optionally substituted alkylamino; optionally substituted alkanoyl; optionally substituted carbocyclic aryl; or optionally substituted aralkyl; and  
       q is an integer of from 0 to 5; and pharmaceutically acceptable salts thereof.  
     
   
   
       28 . The compound of  claim 19  wherein the compound is represented by the following Formula IV:  
     
       
         
         
             
             
         
       
       wherein each X, each Y, each X′, each Y′ and each Z are each independently hydrogen; halogen; hydroxyl; sulfhydryl; amino; optionally substituted alkyl preferably; optionally substituted alkenyl; optionally substituted alkynyl; optionally substituted alkoxy; optionally substituted alkylthio; optionally substituted alkylsulfinyl; optionally substituted alkylsulfonyl; or optionally substituted alkylamino;  
       m and n each is independently an integer of from 0 to 4; p is 1 or 2; q is an integer of from 0 to 5;  
       R 1  is independently halogen; amino; hydroxy; nitro; carboxy; sulfhydryl; optionally substituted alkyl; optionally substituted alkenyl; optionally substituted alkynyl; optionally substituted alkoxy; optionally substituted alkylthio; optionally substituted alkylsulfinyl; optionally substituted alkylsulfonyl; optionally substituted alkylamino; optionally substituted alkanoyl; optionally substituted carbocyclic aryl; or optionally substituted aralkyl;  
       q is an integer of from 0 to 5; and pharmaceutically acceptable salts thereof.  
     
   
   
       29 . The compound of  claim 19  wherein the compound is represented by the following Formula IVA:  
     
       
         
         
             
             
         
       
       wherein each X′ and each Y′ is independently hydrogen; halogen; hydroxyl; sulfhydryl; amino; optionally substituted alkyl preferably; optionally substituted alkenyl; optionally substituted alkynyl; optionally substituted alkoxy; optionally substituted alkylthio; optionally substituted alkylsulfinyl; optionally substituted alkylsulfonyl; or optionally substituted alkylamino;  
       R 1  is independently halogen; amino; hydroxy; nitro; carboxy; sulfhydryl; optionally substituted alkyl; optionally substituted alkenyl; optionally substituted alkynyl; optionally substituted alkoxy; optionally substituted alkylthio; optionally substituted alkylsulfinyl; optionally substituted alkylsulfonyl; optionally substituted alkylamino; optionally substituted alkanoyl; optionally substituted carbocyclic aryl; or optionally substituted aralkyl;  
       n is an integer of from 0 to 4; q is an integer of from 0 to 5; and pharmaceutically acceptable salts thereof.  
     
   
   
       30 . A compound of any one of claims  24  through  27  wherein at least one R 1  is hydroxy and m is 1 or 2.  
   
   
       31 . A pharmaceutical composition comprising a compound of any one of  claims 19  to  30  and a pharmaceutically acceptable carrier.  
   
   
       32 . A method for treating a mammal suffering from or susceptible to a disease impacted by tissue factor, comprising administering to the mammal an effective amount of a compound or composition of any one of claims  19 - 31 .  
   
   
       33 . A method for treating a mammal suffering from or susceptible to a cardiovascular disease, a blood coagulation disorder, a cell proliferation disorder, post-operative complication, an immune disorder, atherosclerosis, inflammation, or cancer, comprising administering to the mammal an effective amount of a compound or composition of any one of claims  19 - 31 .  
   
   
       34 . A method of inhibiting blood coagulation in a mammal, comprising administering to the mammal an effective amount of a compound or composition of any one of  claims 19  to  31 .  
   
   
       35 . The method of  claim 34  wherein the mammal is suffering from, suspected of having, or recovering from a thrombosis.  
   
   
       36 . The method of  claim 34  wherein the mammal is suffering from, susceptible to, or recovering from restenosis associated with an invasive medical procedure.  
   
   
       37 . The method of  claim 34  wherein the invasive medical procedure is angioplasty, endarterectomy, deployment of a stent, use of catheter, graft implantation or use of an arteriovenous shunt.  
   
   
       38 . The method of  claim 34  wherein the mammal is suffering from, at risk of developing, or recovering from a thromboembolic condition associated with cardiovascular disease, an infectious disease, a neoplastic disease or use of a thrombolytic agent.  
   
   
       39 . The method of any one of claims  34 - 38  wherein at least one of an anti-platelet composition, thrombolytic composition or an anti-coagulant composition is administered in combination with a tissue factor blocking compound exhibiting an IC 50  of less than about 100 μM in a standard assay for measuring TF/VIIa-dependent factor X activation.  
   
   
       40 . A method of treating or preventing a thromboembolic disorder in a mammal, comprising administering to the mammal an effective amount of the TF blocking compound of any one of claims  19 - 31 .  
   
   
       41 . The method of  claim 40  wherein the mammal is suffering from, at risk developing, or is recovering from a thromboembolic condition associated with cardiovascular disease, an infectious disease, a neoplastic disease or use of a thrombolytic agent or an anti-platelet agent.  
   
   
       42 . The method of  claim 40  wherein at least one of an anti-platelet, thrombolytic, or an anti-coagulant composition is administered in combination with a tissue factor blocking compound exhibiting an IC 50  of less than about 100 μM in a standard assay for measuring TF/VIIa-dependent factor X activation.  
   
   
       43 . The method of any one of claims  32 - 42  wherein the mammal is a human.  
   
   
       44 . A compound of the following Formula I:  
       Ar-(CXY) m -(Het) 0 or 1 -(CX 1 Y 1 ) n —C(Z) p -(PO 3 ) 3-p    I  wherein Ar is optionally substituted carbocyclic aryl or optionally substituted heteroaryl;    Het is optionally substituted N, O, S, S(O) or S(O) 2 ;    each X, each Y, each X′, each Y′ and each Z are each independently hydrogen; halogen; hydroxyl; sulfhydryl; amino; optionally substituted alkyl preferably; optionally substituted alkenyl; optionally substituted alkynyl; optionally substituted alkoxy; optionally substituted alkylthio; optionally substituted alkylsulfinyl; optionally substituted alkylsulfonyl; or optionally substituted alkylamino;    m and n each is independently an integer of from 0 to 4; p is 1 or 2; and pharmaceutically acceptable salts thereof.    
   
   
       45 . A compound of  claim 44  having the following Formula II:  
     
       
         
         
             
             
         
       
       wherein Ar is optionally substituted carbocyclic aryl or optionally substituted heteroaryl;  
       Het is optionally substituted N, O, S, S(O) or S(O 2 );  
       each X, each Y, each X′, each Y′ and each Z are each independently hydrogen; halogen; hydroxyl; sulfhydryl; amino; optionally substituted alkyl preferably; optionally substituted alkenyl; optionally substituted alkynyl; optionally substituted alkoxy; optionally substituted alkylthio; optionally substituted alkylsulfinyl; optionally substituted alkylsulfonyl; or optionally substituted alkylamino;  
       each R 1  is independently halogen; amino; hydroxy; nitro; carboxy; sulfhydryl; optionally substituted alkyl; optionally substituted alkenyl; optionally substituted alkynyl; optionally substituted alkoxy; optionally substituted alkylthio; optionally substituted alkylsulfinyl, optionally substituted alkylsulfonyl; optionally substituted alkylamino; optionally substituted alkanoyl; optionally substituted carbocyclic aryl; or optionally substituted aralkyl;  
       m and n each is independently an integer of from 0 to 4; p is 1 or 2; q is an integer of from 0 to 5; and pharmaceutically acceptable salts thereof.  
     
   
   
       46 . A compound of  claim 44  having the following Formula III:  
     
       
         
         
             
             
         
       
       wherein each X, each Y, each X′, each Y′ and each Z are each independently hydrogen; halogen; hydroxyl; sulfhydryl; amino; optionally substituted alkyl preferably; optionally substituted alkenyl; optionally substituted alkynyl; optionally substituted alkoxy; optionally substituted alkylthio; optionally substituted alkylsulfinyl; optionally substituted alkylsulfonyl; or optionally substituted alkylamino;  
       m and n each is independently an integer of from 0 to 4; p is 1 or 2; q is an integer of from 0 to 5;  
       W is hydrogen, optionally substituted alkyl; optionally substituted alkenyl; optionally substituted alkynyl; optionally substituted alkoxy; optionally substituted alkylthio; optionally substituted alkylsulfinyl; optionally substituted alkylsulfonyl; optionally substituted alkylamino; optionally substituted alkanoyl; optionally substituted carbocyclic aryl; or optionally substituted aralkyl;  
       R 1  is independently halogen; amino; hydroxy; nitro; carboxy; sulfhydryl; optionally substituted alkyl; optionally substituted alkenyl; optionally substituted alkynyl; optionally substituted alkoxy; optionally substituted alkylthio; optionally substituted alkylsulfinyl; optionally substituted alkylsulfonyl; optionally substituted alkylamino; optionally substituted alkanoyl; optionally substituted carbocyclic aryl; or optionally substituted aralkyl;  
       q is an integer of from 0 to 5; and pharmaceutically acceptable salts thereof.  
     
   
   
       47 . A compound of  claim 44  having the following Formula IIIa:  
     
       
         
         
             
             
         
       
       wherein R 1  is independently halogen; amino; hydroxy; nitro; carboxy; sulfhydryl; optionally substituted alkyl; optionally substituted alkenyl; optionally substituted alkynyl; optionally substituted alkoxy; optionally substituted alkylthio; optionally substituted alkylsulfinyl; optionally substituted alkylsulfonyl; optionally substituted alkylamino; optionally substituted alkanoyl; optionally substituted carbocyclic aryl; or optionally substituted aralkyl; and  
       q is an integer of from 0 to 5; and pharmaceutically acceptable salts thereof.  
     
   
   
       48 . A compound of  claim 44  having the following Formula IV:  
     
       
         
         
             
             
         
       
       wherein wherein each X, each Y, each X′, each Y′ and each Z are each independently hydrogen; halogen; hydroxyl; sulfhydryl; amino; optionally substituted alkyl preferably; optionally substituted alkenyl; optionally substituted alkynyl; optionally substituted alkoxy; optionally substituted alkylthio; optionally substituted alkylsulfinyl; optionally substituted alkylsulfonyl; or optionally substituted alkylamino;  
       m and n each is independently an integer of from 0 to 4; p is 1 or 2; q is an integer of from 0 to 5;  
       R 1  is independently halogen; amino; hydroxy; nitro; carboxy; sulfhydryl; optionally substituted alkyl; optionally substituted alkenyl; optionally substituted alkynyl; optionally substituted alkoxy; optionally substituted alkylthio; optionally substituted alkylsulfinyl; optionally substituted alkylsulfonyl; optionally substituted alkylamino; optionally substituted alkanoyl; optionally substituted carbocyclic aryl; or optionally substituted aralkyl;  
       q is an integer of from 0 to 5; and pharmaceutically acceptable salts thereof.  
     
   
   
       49 . A compound of  claim 44  having the following Formula IVa:  
     
       
         
         
             
             
         
       
       wherein each X′ and each Y′ is independently hydrogen; halogen; hydroxyl; sulfhydryl; amino; optionally substituted alkyl preferably; optionally substituted alkenyl; optionally substituted alkynyl; optionally substituted alkoxy; optionally substituted alkylthio; optionally substituted alkylsulfinyl; optionally substituted alkylsulfonyl; or optionally substituted alkylamino;  
       R 1  is independently halogen; amino; hydroxy; nitro; carboxy; sulfhydryl; optionally substituted alkyl; optionally substituted alkenyl; optionally substituted alkynyl; optionally substituted alkoxy; optionally substituted alkylthio; optionally substituted alkylsulfinyl; optionally substituted alkylsulfonyl; optionally substituted alkylamino; optionally substituted alkanoyl; optionally substituted carbocyclic aryl;,or optionally substituted aralkyl; and  
       q is an integer of from 0 to 5; and pharmaceutically acceptable salts thereof.  
     
   
   
       50 . A compound of any one of claims  44  through  46  wherein at least one R 1  is hydroxy and m is 1 or 2.  
   
   
       51 . A compound of  claim 44 , that is:  
     
       
         
         
             
             
         
       
       or a pharmaceutically acceptable salt thereof.  
     
   
   
       52 . A method of inhibiting blood coagulation in a mammal, comprising administering to the mammal an effective amount of a compound of any one of  claims 44  to  51 .  
   
   
       53 . The method of  claim 52  wherein the mammal is suffering from or suspected of having a thrombosis.  
   
   
       54 . The method of  claim 52  wherein the mammal is suffering from or susceptible to restenosis associated with an invasive medical procedure.  
   
   
       55 . The method of  claim 54  wherein the invasive medical procedure is angioplasty, endarterectomy, deployment of a stent, use of catheter, graft implantation or use of an arteriovenous shunt.  
   
   
       56 . The method of  claim 52  wherein the mammal is suffering from or at risk of developing a thromboembolic condition associated with cardiovascular disease, an infectious disease, a neoplastic disease or use of a thrombolytic agent.  
   
   
       57 . The method of any one of  claims 52  to  56  wherein an anti-platelet composition, a thrombolytic composition or an anti-coagulant composition is administered in combination with a compound of Formula I.  
   
   
       58 . A method of treating or preventing a thromboembolic disorder in a mammal, comprising administering to the mammal an effective amount of a compound of any one of  claims 44  to  51 .  
   
   
       59 . The method of  claim 58  wherein the mammal is suffering from or at risk developing a thromboembolic condition associated with cardiovascular disease, an infectious disease, a neoplastic disease or use of a thrombolytic agent or an anti-platelet agent.  
   
   
       60 . The method of  claim 58  or  59  wherein an anti-platelet composition, a thrombolytic composition or an anti-coagulant composition is administered in combination with a compound of Formula I.  
   
   
       61 . A method of treating a mammal suffering from or susceptible to atherosclerosis, comprising administering to the mammal an effective amount of a compound of any one of  claims 44  to  51 .  
   
   
       62 . The method of any one of  claims 52  to  61  wherein the mammal is a human.  
   
   
       63 . A pharmaceutical composition comprising a compound of any one of claims  44  through  51  and a pharmaceutically acceptable carrier.