Compositions and methods for modulating farnesoid x receptors

Abstract

The present invention relates to compounds of Formula I,a stereoisomer, enantiomer, a pharmaceutically acceptable salt or an amino acid conjugate thereof; wherein variables are as defined herein; and their pharmaceutical compositions, which are useful as modulators of the activity of Farnesoid X receptors (FXR).

We claim: 
     
         1 . A crystalline form of 4-((N-benzyl-8-chloro-1-methyl-1,4-dihydrochromeno[4,3-c]pyrazole-3-carboxamido)methyl)benzoic acid, produced by contacting 4-((N-benzyl-8-chloro-1-methyl-1,4-dihydrochromeno[4,3-c]pyrazole-3-carboxamido)methyl)benzoic acid in a solvent with meglumine in water solution under suitable conditions. 
     
     
         2 . The crystalline form of  claim 1 , produced by adding said meglumine in water solution to a suspension of said 4-((N-benzyl-8-chloro-1-methyl-1,4-dihydrochromeno[4,3-c]pyrazole-3-carboxamido)methyl)benzoic acid in acetone. 
     
     
         3 . The crystalline form of  claim 1 , having a dehydration point at about 71° C. as determined by differential scanning calorimetry. 
     
     
         4 . The crystalline form of  claim 1 , wherein said crystalline form is 4-((N-benzyl-8-chloro-1-methyl-1,4-dihydrochromeno[4,3-c]pyrazole-3-carboxamido)methyl)benzoic acid meglumine monohydrate. 
     
     
         5 . The crystalline form of  claim 4 , produced by further heating said 4-((N-benzyl-8-chloro-1-methyl-1,4-dihydrochromeno[4,3-c]pyrazole-3-carboxamido)methyl)benzoic acid meglumine monohydrate at a temperature ranging from 60-90° C. under suitable conditions. 
     
     
         6 . The crystalline form of  claim 5 , having a melting point of about 167.5° C. as determined by differential scanning calorimetry. 
     
     
         7 . The crystalline form of  claim 4 , produced by adding said 4-((N-benzyl-8-chloro-1-methyl-1,4-dihydrochromeno[4,3-c]pyrazole-3-carboxamido)methyl)benzoic acid meglumine monohydrate to acetone in water solution; and heating reaction mixture at a temperature of about 50° C. under suitable conditions. 
     
     
         8 . The crystalline form of  claim 7 , having a dehydration point at about 61° C. by differential scanning calorimetry. 
     
     
         9 . A crystalline form of 4-((N-benzyl-8-chloro-1-methyl-1,4-dihydrochromeno[4,3-c]pyrazole-3-carboxamido)methyl)benzoic acid, produced by contacting 4-((N-benzyl-8-chloro-1-methyl-1,4-dihydrochromeno[4,3-c]pyrazole-3-carboxamido)methyl)benzoic acid with meglumine under suitable conditions. 
     
     
         10 . The crystalline form of  claim 9 , produced by adding 4-((N-benzyl-8-chloro-1-methyl-1,4-dihydrochromeno[4,3-c]pyrazole-3-carboxamido)methyl)benzoic acid and meglumine to methanol thereby providing a suspension; and heating said suspension under suitable conditions. 
     
     
         11 . The crystalline form of  claim 9 , having a melting point of about 180.6° C. by differential scanning calorimetry. 
     
     
         12 . A method for treating diabetic nephropathy in a subject suffering therefrom, comprising administering to the subject a therapeutically effective amount of a crystalline form of 4-((N-benzyl-8-chloro-1-methyl-1,4-dihydrochromeno[4,3-c]pyrazole-3-carboxamido)methyl)benzoic acid according to  claim 1  or a pharmaceutically acceptable salt thereof, and optionally in combination with a second agent. 
     
     
         13 . The method of  claim 12 , wherein said crystalline form has a dehydration point at about 71° C. as determined by differential scanning calorimetry. 
     
     
         14 . The method of  claim 12 , wherein said crystalline form is 4-((N-benzyl-8-chloro-1-methyl-1,4-dihydrochromeno[4,3-c]pyrazole-3-carboxamido)methyl)benzoic acid meglumine monohydrate. 
     
     
         15 . The method of  claim 14 , wherein said 4-((N-benzyl-8-chloro-1-methyl-1,4-dihydrochromeno[4,3-c]pyrazole-3-carboxamido)methyl)benzoic acid meglumine monohydrate is heated at a temperature ranging from 60-90° C. under suitable conditions to produce a second crystalline form. 
     
     
         16 . The method of  claim 15 , wherein said second crystalline form has a melting point of about 167.5° C. as determined by differential scanning calorimetry. 
     
     
         17 . The method of  claim 14 , wherein said 4-((N-benzyl-8-chloro-1-methyl-1,4-dihydrochromeno[4,3-c]pyrazole-3-carboxamido)methyl)benzoic acid meglumine monohydrate is added to acetone in water solution; and heated at a temperature of about 50° C. under suitable conditions to produce a third crystalline form. 
     
     
         18 . The method of  claim 17 , wherein said third crystalline form has a dehydration point at about 61° C. by differential scanning calorimetry. 
     
     
         19 . A method for treating diabetic nephropathy in a subject suffering therefrom, comprising administering to the subject a therapeutically effective amount of a crystalline form of 4-((N-benzyl-8-chloro-1-methyl-1,4-dihydrochromeno[4,3-c]pyrazole-3-carboxamido)methyl)benzoic acid according to  claim 9  or a pharmaceutically acceptable salt thereof, and optionally in combination with a second agent. 
     
     
         20 . The method of  claim 19 , wherein said crystalline form has a melting point of about 180.6° C. by differential scanning calorimetry.