Meglumine salts of thienopyrimidines

Abstract

Disclosed herein are thienopyrimidine meglumine salts according to Formula (I) used for treating or preventing heart failure:

What is claimed is: 
     
         1 . A salt according to Formula (I) having the structure: 
       
         
           
           
               
               
           
         
         or stereoisomers, tautomers or hydrates thereof, 
         wherein:
 R 1  is hydrogen, (C 1- C 6 )alkyl, (C 1- C 6 )alkoxy or (C 1- C 6 )haloalkyl containing 1-6 halogen atoms; 
 R 2  is hydrogen, (C 1- C 6 )alkyl, [(C 1- C 6 )alkylene]aryl or amino; 
 R 3  is hydrogen, (C 1- C 6 )alkyl, (C 2- C 6 )alkenyl, [(C 1- C 6 )alkylene]N(R 4 )(R 5 ), [(C 1- C 6 )alkylene]S(R 4 ) or —X—Y, or R 2  and R 3  together with the atoms to which they are attached form a heterocyclyl; 
 R 4  and R 5  are independently H or (C 1- C 6 )alkyl; 
 X is a chemical bond, —CH 2 —, —CH(OH)—, —CH(C 6 H 5 )—, —CO—, —CH 2 CH 2 —, CH 2 CO—, —COCH 2 —, S, O or NH; 
 Y is cycloalkyl, heterocyclyl, aryl or heteroaryl; 
 Z is S or O; 
 n is 0, 1, 2, 3 or 4; 
 M +  is 
 
       
       
         
           
           
               
               
           
         
       
       and
 wherein any alkyl, alkylene, cycloalkyl, heterocyclyl, heteroaryl or aryl is optionally substituted with 1, 2 or 3 groups selected from OH, CN, halogen, (C 1 -C 6 )alkyl, O(C 1 -C 6 )alkyl, (C 2 -C 6 )alkenyl, haloalkyl, amino, oxo and nitro. 
 
     
     
         2 . The salt, or stereoisomers, tautomers or hydrates thereof according to  claim 1 , wherein R 1  is (C 1 -C 6 )alkyl, R 2  is —H and R 3  is —X—Y. 
     
     
         3 . The salt, or stereoisomers, tautomers or hydrates thereof according to  claim 2 , wherein X is —CH 2 — and Y is an aryl group. 
     
     
         4 . The salt, or stereoisomers, tautomers or hydrates thereof according to  claim 3 , wherein X is —CH 2 — and Y is (C 1 -C 6 )aryl substituted by one more halogen atoms. 
     
     
         5 . The salt, or stereoisomers, tautomers or hydrates thereof according to  claim 2 , wherein Z is oxygen. 
     
     
         6 . The salt, or stereoisomers, tautomers or hydrates thereof according to  claim 1 , wherein n is 0. 
     
     
         7 . The salt, or stereoisomers, tautomers or hydrates thereof according to  claim 1 , having the structure: 
       
         
           
           
               
               
           
         
       
     
     
         8 . The salt, or stereoisomers, tautomers or hydrates thereof according to  claim 1 , wherein the meglumine salts of Formula (I) are crystalline solids. 
     
     
         9 . The salt, or stereoisomers, tautomers or hydrates thereof according to  claim 8 , wherein the crystalline solids of Formula (I) are a monohydrate. 
     
     
         10 . The salt according to  claim 8 , wherein the crystalline solids of Formula (I) are anhydrous. 
     
     
         11 . The salt according to  claim 9 , wherein the crystalline solid of Formula (I) is a monohydrate having an X-ray powder diffraction pattern with characteristic peaks expressed in values of degrees 2θ at about 5.24, about 7.53, about 11.40, about 11.62, about 15.04, about 16.77, about 17.58, about 19.54, about 22.18, about 23.33, about 24.38, about 25.90 and about 28.67±0.2. 
     
     
         12 . The salt according to  claim 9 , wherein the crystalline solid of Formula (I) is a monohydrate having an X-ray powder diffraction pattern with characteristic peaks expressed in values of degrees 2Θ at about 5.24, about 7.53, about 11.40, about 15.04, about 19.54, about 22.18, and about 25.90±0.2. 
     
     
         13 . The salt according to  claim 9 , wherein the crystalline solid of Formula (I) is a monohydrate having an X-ray powder diffraction pattern with characteristic peaks expressed in values of degrees 2Θ at about 7.53, about 11.40, about 19.54, and about 25.90±0.2. 
     
     
         14 . The salt according to  claim 9 , wherein the crystalline solid of Formula (I) is a monohydrate having an X-ray powder diffraction pattern according to  FIG. 1 . 
     
     
         15 . A method of treating or preventing a cardiovascular disease or condition in a mammal in need thereof comprising administering to the mammal a therapeutically effective amount of a salt of a compound according to Formula (I): 
       
         
           
           
               
               
           
         
         or stereoisomers, tautomers or hydrates thereof, 
         wherein:
 R 1  is hydrogen, (C 1- C 6 )alkyl, (C 1- C 6 )alkoxy or (C 1- C 6 )haloalkyl containing 1-6 halogen atoms; 
 R 2  is hydrogen, (C 1- C 6 )alkyl, [(C 1- C 6 )alkylene]aryl or amino; 
 R 3  is hydrogen, (C 1- C 6 )alkyl, (C 2- C 6 )alkenyl, [(C 1- C 6 )alkylene]N(R 4 )(R 5 ), [(C 1- C 6 )alkylene]S(R 4 ) or —X—Y, or R 2  and R 3  together with the atoms to which they are attached form a heterocyclyl; 
 R 4  and R 5  are independently H or (C 1- C 6 )alkyl; 
 X is a chemical bond, —CH 2 —, —CH(OH)—, —CH(C 6 H 5 )—, —CO—, —CH 2 CH 2 —, CH 2 CO—, —COCH 2 —, S, O or NH; 
 Y is cycloalkyl, heterocyclyl, aryl or heteroaryl; 
 Z is S or O; 
 n is 0, 1, 2, 3 or 4; 
 M +  is 
 
       
       
         
           
           
               
               
           
         
       
       and
 wherein any alkyl, alkylene, cycloalkyl, heterocyclyl, heteroaryl or aryl is optionally substituted with 1, 2 or 3 groups selected from OH, CN, halogen, (C 1 -C 6 )alkyl, O(C 1 -C 6 )alkyl, (C 2 -C 6 )alkenyl, haloalkyl, amino, oxo and nitro. 
 
     
     
         16 . The method of  claim 15 , wherein the meglumine salt, or stereoisomers, tautomers or hydrates thereof, according to Formula (I) is: 
       
         
           
           
               
               
           
         
       
     
     
         17 . The method of  claim 16 , wherein the meglumine salt, or stereoisomers, tautomers or hydrates thereof, according to Formula (I) is the crystalline monohydrate form of: 
       
         
           
           
               
               
           
         
       
     
     
         18 . The method of  claim 17 , wherein the meglumine salt, or stereoisomers, tautomers or hydrates thereof, has an X-ray powder diffraction pattern according to  FIG. 1 . 
     
     
         19 . The method of  claim 15 , wherein the cardiovascular disease or condition is cardiac hypertrophy, heart failure, heart failure with preserved ejection fraction (HfpEF), heart failure with reduced ejection fraction (HFrEF) (reduced systolic function), reduced diastolic function, maladaptive hypertrophy, heart failure with preserved systolic function, diastolic heart failure, hypertensive heart disease, aortic stenosis, hypertrophic cardiomyopathy, or post ischemic cardiac remodeling. 
     
     
         20 . The method of  claim 19 , wherein the cardiovascular disease or condition is heart failure.