Novel regimes of fxr agonists

Abstract

The invention provides novel regimens of farnesoid X receptor (FXR) agonist and methods for modulating the activity of farnesoid X receptors (FXRs) using novel regimes of specific FXR agonists, in particular for treating or preventing fibrotic or cirrhotic diseases or disorders, such as liver diseases.

We claim: 
     
         1 . A method for treating a fibrotic or cirrhotic liver disease or disorder in a patient in need thereof, comprising administering to said patient a dose of about 15 mg to about 250 mg of 4-((N-benzyl-8-chloro-1-methyl-1,4-dihydrochromeno[4,3-c]pyrazole-3 carboxamido)methyl)benzoic acid, or a pharmaceutically acceptable salt thereof; and optionally with an additional therapeutic agent. 
     
     
         2 . The method of  claim 1 , wherein said dose is about 25 mg to about 250 mg of said 4-((N-benzyl-8-chloro-1-methyl-1,4-dihydrochromeno[4,3-c]pyrazole-3 carboxamido)methyl)benzoic acid, or a pharmaceutically acceptable salt thereof. 
     
     
         3 . The method of  claim 1 , wherein said dose is about 50 mg to about 200 mg of said 4-((N-benzyl-8-chloro-1-methyl-1,4-dihydrochromeno[4,3-c]pyrazole-3 carboxamido)methyl)benzoic acid, or a pharmaceutically acceptable salt thereof. 
     
     
         4 . The method of  claim 1 , wherein said dose is about 50 mg of 4-((N-benzyl-8-chloro-1-methyl-1,4-dihydrochromeno[4,3-c]pyrazole-3-carboxamido)methyl)benzoic acid meglumine salt. 
     
     
         5 . The method of  claim 1 , wherein said dose is about 100 mg of 4-((N-benzyl-8-chloro-1-methyl-1,4-dihydrochromeno[4,3-c]pyrazole-3-carboxamido)methyl)benzoic acid meglumine salt. 
     
     
         6 . The method of  claim 1 , wherein said dose is about 50 mg of 4-((N-benzyl-8-chloro-1-methyl-1,4-dihydrochromeno[4,3-c]pyrazole-3 carboxamido)methyl)benzoic acid meglumine mono-hydrate. 
     
     
         7 . The method of  claim 1 , wherein said dose is about 100 mg of 4-((N-benzyl-8-chloro-1-methyl-1,4-dihydrochromeno[4,3-c]pyrazole-3 carboxamido)methyl)benzoic acid meglumine mono-hydrate. 
     
     
         8 . The method of  claim 1 , wherein said dose is a daily dose. 
     
     
         9 . The method of  claim 1 , wherein said dose is twice daily dose. 
     
     
         10 . The method of  claim 1 , wherein said dose is every two days. 
     
     
         11 . The method of  claim 1 , comprising administering 4-((N-benzyl-8-chloro-1-methyl-1,4-dihydrochromeno[4,3-c]pyrazole-3 carboxamido)methyl)benzoic acid or a pharmaceutically acceptable salt to said patient, simultaneously, sequentially or separately with one or more additional therapeutic agent. 
     
     
         12 . The method of  claim 1 , wherein said additional therapeutic agent is selected from the group consisting of a therapeutic agent for the treatment of obesity, metabolic syndrome, cholesterol disorder or cardiometabolic disease. 
     
     
         13 . The method of  claim 1 , wherein said additional therapeutic agent is a therapeutic agent for the treatment of cardiometabolic disease selected from diabetes, insulin resistance, dyslipidemia and liver disease. 
     
     
         14 . The method of  claim 1 , wherein said additional therapeutic agent is an anti-fibrotic agent. 
     
     
         15 . The method of  claim 1 , wherein said liver disease or disorder is selected from the group consisting of cholestasis, intrahepatic cholestasis, estrogen-induced cholestasis, drug-induced cholestasis, cholestasis of pregnancy, parenteral nutrition-associated cholestasis, primary biliary cirrhosis (PBC), primary sclerosing cholangitis (PSC), progressive familiar cholestasis (PFIC), non-alcoholic fatty liver disease (NAFLD), non-alcoholic steatohepatitis (NASH), drug-induced bile duct injury, gallstones, liver cirrhosis, alcohol-induced cirrhosis, cystic fibrosis-associated liver disease (CFLD), bile duct obstruction, cholelithiasis, liver fibrosis, renal fibrosis, dyslipidemia, atherosclerosis, diabetes, diabetic nephropathy, colitis, newborn jaundice, prevention of kernicterus, veno-occlusive disease, portal hypertension, metabolic syndrome, hypercholesterolemia, intestinal bacterial overgrowth, erectile dysfunction, progressive fibrosis of the liver caused by any of the diseases above or by infectious hepatitis. 
     
     
         16 . The method of  claim 15 , wherein said liver disease is primary biliary cirrhosis (PBC). 
     
     
         17 . The method of  claim 15 , wherein said liver disease is non-alcoholic fatty liver disease (NAFLD) or non-alcoholic steatohepatitis (NASH). 
     
     
         18 . The method of  claim 15 , wherein said liver disease is liver fibrosis. 
     
     
         19 . The method of  claim 15 , wherein said liver disease is diabetic nephropathy. 
     
     
         20 . The method of  claim 1 , wherein said patient is diabetic.