Methods of prevention or treatment for pathologic thrombosis or inflammation

Abstract

The present disclosure relates to methods of affecting platelet activation by the use of a PC-TP inhibitor. The PC-TP inhibitor can be administered to a subject in need thereof in order to prevent or treat pathologic thrombosis, or to treat a disorder treatable by a PAR4 inhibitor.

What is claimed is: 
     
         1 . A method of preventing pathologic thrombosis, treating pathologic thrombosis, or treating a disorder treatable by a protease-activated receptor-4 (PAR4) inhibitor in a subject in need thereof, comprising administering a phosphatidylcholine transfer protein (PC-TP) inhibitor to said subject. 
     
     
         2 . The method of  claim 1 , wherein the PC-TP inhibitor inhibits PAR4 activation. 
     
     
         3 . The method of  claim 1  or  2 , wherein the PC-TP inhibitor is selected from compounds of Formula I: 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof; wherein: 
         X is N or CR 8 ; 
         Y is N or CR 9 ; 
         Z is N or CR 10 ; 
         W is O; 
         R′, R″, and R′″ are each independently selected from H and C 1-4  alkyl; wherein said C 1-4  alkyl is optionally substituted by di-C 1-6 -alkylamino; 
         R 1 , R 2 , R 3 , R 4 , and R 5  are each independently selected from H, halogen, cyano, hydroxyl, carboxyl, carbamyl, amino, C 1-6  alkyl, C 1-6  haloalkyl, C 2-6  alkenyl, C 2-6  alkynyl, C 1-6  alkoxy, C 1-6  haloalkoxy, C 1-6  alkylamino, di-C 1-6 -alkylamino, C 1-6  alkylcarbamyl, di-C 1-6  alkylcarbamyl, C 1-6  alkoxycarbonyl, C 1-6  alkylcarbonyl, C 1-6  alkylcarbonyl amino, di-C 1-6  alkylcarbonyl amino, C 1-6  alkylthio, C 1-6  alkylsulfinyl, C 1-6  alkylsulfonyl, C 3-7  cycloalkyl, C 3-7  cycloalkyl-C 1-4 -alkyl, C 2-14  heterocycloalkyl, C 2-7  heterocycloalkyl-C 1-4 -alkyl, phenyl, phenyl-C 1-4 -alkyl, C 1-6  heteroaryl, and C 1-6  heteroaryl-C 1-4 -alkyl; wherein C 1-6  alkyl, C 1-6  haloalkyl, C 2-6  alkenyl, C 2-6  alkynyl, C 1-6  alkoxy, C 1-6  haloalkoxy, C 1-6  alkylamino, di-C 1-6 -alkylamino, C 1-6  alkylcarbamyl, alkylcarbamyl, C 1-6  alkoxycarbonyl, C 1-6  alkylcarbonyl, C 1-6  alkylcarbonylamino, alkylcarbonylamino, C 1-6  alkylthio, C 1-6  alkylsulfinyl, and C 1-6  alkylsulfonyl are each optionally substituted by 1, 2, 3, or 4 independently selected R a′  groups; and wherein C 3-7  cycloalkyl, C 3-7  cycloalkyl-C 1-4 -alkyl, C 2-14  heterocycloalkyl, C 2-7  heterocycloalkyl-C 1-4 -alkyl, phenyl, phenyl-C 1-4 -alkyl, C 1-6  heteroaryl, and C 1-6  heteroaryl-C 1-4 -alkyl are each optionally substituted by 1, 2, 3, or 4 independently selected R a″  groups; 
         or R 1  and R 2 , together with the carbon atoms to which they are attached, form a phenyl or C 1-6  heteroaryl ring, which is optionally substituted with 1, 2, 3, or 4 independently selected R a″  groups; 
         or R 2  and R 3 , together with the carbon atoms to which they are attached, form a phenyl or C 1-6  heteroaryl ring, which is optionally substituted with 1, 2, 3, or 4 independently selected R a″  groups; 
         or R 3  and R 4 , together with the carbon atoms to which they are attached, form a phenyl or C 1-6  heteroaryl ring, which is optionally substituted with 1, 2, 3, or 4 independently selected R a″  groups; 
         R 6 , R 7 , R 8 , R 9 , and R 10  are each independently selected from H, halogen, cyano, nitro, hydroxyl, carboxyl, carbamyl, amino, C 1-6  alkyl, C 1-6  haloalkyl, C 2-6  alkenyl, C 2-6  alkynyl, C 1-6  alkoxy, C 1-6  haloalkoxy, C 1-6  alkylamino, C 1-6  alkylcarbamyl, di-C 1-6  alkylcarbamyl, C 1-6  alkoxycarbonyl, C 1-6  alkylcarbonyl, C 1-6  alkylcarbonylamino, alkylcarbonylamino, C 1-6  alkylthio, C 1-6  alkylsulfinyl, C 1-6  alkylsulfonyl, C 3-7  cycloalkyl, C 3-7  cycloalkyl-C 1-4 -alkyl, C 2-14  heterocycloalkyl, C 2-7  heterocycloalkyl-C 1-4 -alkyl, phenyl, phenyl-C 1-4 -alkyl, C 1-6  heteroaryl, and C 1-6  heteroaryl-C 1-4 -alkyl; wherein C 1-6  alkyl, C 1-6  haloalkyl, C 2-6  alkenyl, C 2-6  alkynyl, C 1-6  alkoxy, C 1-6  haloalkoxy, C 1-6  alkylamino, C 1-6  alkylcarbamyl, alkylcarbamyl, C 1-6  alkoxycarbonyl, C 1-6  alkylcarbonyl, C 1-6  alkylcarbonylamino, alkylcarbonylamino, C 1-6  alkylthio, C 1-6  alkylsulfinyl, and C 1-6  alkylsulfonyl are each optionally substituted by 1, 2, 3, or 4 independently selected R b′  groups; 
         and wherein C 3-7  cycloalkyl, C 3-7  cycloalkyl-C 1-4 -alkyl, C 2-14  heterocycloalkyl, C 2-7  heterocycloalkyl-C 1-4 -alkyl, phenyl, phenyl-C 1-4 -alkyl, C 1-6  heteroaryl, and C 1-6  heteroaryl-C 1-4 -alkyl are each optionally substituted by 1, 2, 3, or 4 independently selected R b″  groups; 
         or R 6  and R 8 , together with the carbon atoms to which they are attached, form a phenyl or C 1-6  heteroaryl ring, which is optionally substituted with 1, 2, 3, or 4 independently selected R b″  groups; 
         or R 6  and R 10 , together with the carbon atoms to which they are attached, form a phenyl or C 1-6  heteroaryl ring, which is optionally substituted with 1, 2, 3, or 4 independently selected R b″  groups; 
         or R 7  and R 9 , together with the carbon atoms to which they are attached, form a phenyl or C 1-6  heteroaryl ring, which is optionally substituted with 1, 2, 3, or 4 independently selected R b″  groups; 
         or R 7  and R 10 , together with the carbon atoms to which they are attached, form a phenyl or C 1-6  heteroaryl ring, which is optionally substituted with 1, 2, 3, or 4 independently selected R b″  groups; 
         each R 11  is independently selected from halogen, cyano, nitro, hydroxyl, carboxyl, carbamyl, amino, C 1-6  alkyl, C 1-6  haloalkyl, C 2-6  alkenyl, C 2-6  alkynyl, C 1-6  alkoxy, C 1-6  haloalkoxy, C 1-6  alkylamino, di-C 1-6 -alkylamino, C 1-6  alkylcarbamyl, di-C 1-6  alkylcarbamyl, C 1-6  alkoxycarbonyl, C 1-6  alkylcarbonyl, C 1-6  alkylcarbonylamino, di-C 1-6  alkylcarbonylamino, C 1-6  alkylthio, C 1-6  alkylsulfinyl, and C 1-6  alkylsulfonyl; 
         each R a′  and R b′  is independently selected from halogen, cyano, nitro, hydroxyl, carboxyl, amino, C 1-4  alkoxy, C 1-4  haloalkoxy, C 1-4  alkylamino, and di-C 1-4 -alkylamino; 
         each R a′  and R b″  is independently selected from halogen, cyano, nitro, hydroxyl, carboxyl, amino, C 1-4  alkyl, C 1-4  haloalkyl, C 1-4  alkoxy, C 1-4  haloalkoxy, C 1-4  alkylamino, and di-C 1-4 -alkylamino; and 
         n is an integer selected from 0, 1, 2, 3, and 4; 
         provided that: 
         (1) when the compound has Formula I, W is O, Z is CH, n is 0, R 1 , R 2 , R 4 , R 5 , R 6  and R 7  are each H, and either X is N and Y is CH, or X is CH and Y is N, then R 3  is other than chloro; and 
         (2) when the compound has Formula I, W is O, X is N, Y is N, and Z is CR 10 , then the following provisos apply: (a) when R 6  and IC are each methyl or each H, R 10  is H, 
         and R 1 , R 2 , R 4 , and R 5  are H, then R 3  is not methoxy or chloro; and (b) when R 6  and R 7  are each methyl or each H and R 10  is H, then at least one of R 10 , R 2 , R 3 , R 4 , and R 5  is other than H. 
       
     
     
         4 . The method of  claim 3 , wherein the PC-TP inhibitor is selected from:
 2,4-dichloro-N-(4-(N-(4,6-dimethylpyrimidin-2-yl)sulfamoyl)phenylcarbamoyl)-benzamide (LDN-193,188);   2-chloro-N-(4-(N-(4,6-dimethylpyrimidin-2-yl)sulfamoyl)phenylcarbamoyl)benzamide;   2,4-dichloro-N-(4-(N-(4,6-dimethylpyridin-2-yl)sulfamoyl)phenylcarbamoyl)benzamide;   2,3-dichloro-N-(4-(N-(4,6-dimethylpyrimidin-2-yl)sulfamoyl)phenylcarbamoyl)-benzamide;   3,4-dichloro-N-(4-(N-(4,6-dimethylpyrimidin-2-yl)sulfamoyl)phenylcarbamoyl)-benzamide;   2,4-dichloro-N-((4-(N-(4,6-dimethylpyrimidin-2-yl)sulfamoyl)phenyl)(methyl)carba-moyl)benzamide;   2,4-dichloro-N-(4-(N-(4,6-dimethylpyrimidin-2-yl)-N-methylsulfamoyl)phenyl-carbamoyl)benzamide;   2,4-dichloro-N-(4-(N-(2,6-dimethylpyrimidin-4-yl)sulfa-moyl)phenylcarbamoyl)-benzamide;   2,4-dichloro-N-(4-(N-(3,5-dimethylphenyl)sulfamoyl)phenylcarbamoyl)benzamide;   and 2,4-dichloro-N-(4-(N-(4,6-dimethylpyrimidin-2-yl)sulfa-moyl)phenylcarbamoyl)-N-methylbenzamide;   or a pharmaceutically acceptable salt thereof.   
     
     
         5 . The method of  claim 4 , wherein the PC-TP inhibitor is 2,4-dichloro-N-(4-(N-(4,6-dimethylpyrimidin-2-yl)sulfamoyl)phenylcarbamoyl)-benzamide (LDN-193,188), or a pharmaceutically acceptable salt thereof. 
     
     
         6 . The method of  claim 1 , wherein the disorder treatable by a PAR4 inhibitor is selected from hepatitis, primary sclerosing cholangitis, sarcoidosis, inflammatory bowel disease, pancreatitis, thyroiditis, and fetal development disorders caused by placental dysfunction. 
     
     
         7 . The method of  claim 1 , wherein said subject is a mammal. 
     
     
         8 . The method of  claim 7 , wherein said mammal is a human. 
     
     
         9 . The method of  claim 1 , further comprising administering a PAR1 inhibitor. 
     
     
         10 . (canceled) 
     
     
         11 . (canceled) 
     
     
         12 . (canceled) 
     
     
         13 . (canceled) 
     
     
         14 . The method of  claim 1 , wherein the PC-TP inhibitor is 2,4-dichloro-N-(4-(N-(4,6-dimethylpyrimidin-2-yl)sulfamoyl)phenylcarbamoyl)-benzamide (LDN-193,188), or a pharmaceutically acceptable salt thereof, and wherein the PC-TP inhibitor inhibits PAR4 activation. 
     
     
         15 . (canceled) 
     
     
         16 . (canceled) 
     
     
         17 . (canceled) 
     
     
         18 . (canceled) 
     
     
         19 . (canceled) 
     
     
         20 . (canceled)