Polyhydroxylated bile acids for treatment of biliary disorders

Abstract

The invention provides, in part, polyhydroxylated bile adds for treating biliary disorders, for example, biliary disorders arising out of cholestasis of portal hypertension. The invention also provides, in part, polyhydroxylated bile acids for stimulating bile flow. New compounds 2α,3α,7α,12α-tetrahydroxy-5β-cholanoic acid and 3α,4α,7α,12α-tetrahydroxy-5β-cholanoic acid are disclosed, uses thereof and synthesis thereof.

1 . A method of treating a biliary disorder or stimulating bile flow in a subject in need thereof, the method comprising administering a therapeutically effective amount of a compound according to Formula I: 
       
         
           
           
               
               
           
         
         or a derivative thereof, wherein 
         any one of R 1  to R 9  may be —H or —OH, provided that at least four of R 1  to R 9  are —OH; and 
         R 10  may be —COOH or —CH 2 OH. 
       
     
     
         2 . The method of  claim 1  wherein said compound is selected from the group consisting of a tetrahydroxylated bile acid and a pentahydroxylated bile acid, or a derivative thereof. 
     
     
         3 . The method of  claim 2  wherein said tetrahydroxylated bile acid is selected from the group consisting of:
 a 3,6,7,12-tetrahydroxycholanoic acid, 
 a 3,4,7,12-tetrahydroxycholanoic acid, 
 a 1,3,7,12-tetrahydroxycholanoic acid, 
 a 2,3,7,12-tetrahydroxycholanoic acid, 
 a 3,7,16,24-tetrahydroxycholanoic acid, and 
 a 3,7,15,24-tetrahydroxycholanoic acid, 
 or a derivative thereof. 
 
     
     
         4 . The method of  claim 3  wherein said 3,6,7,12-tetrahydroxycholanoic acid is selected from the group consisting of:
 a 3α,6α,7α,12α-tetrahydroxy-5β-cholan-24-oic acid, 
 a 3α,6β,7α,12α-tetrahydroxy-5β-cholan-24-oic acid, 
 a 3α,6α,7β,12α-tetrahydroxy-5β-cholan-24-oic acid, 
 a 3α,6β,7β,12α-tetrahydroxy-5β-cholan-24-oic acid, 
 a 3α,6α,7α,12β-tetrahydroxy-5β-cholan-24-oic acid, 
 a 3α,6β,7α,12β-tetrahydroxy-5β-cholan-24-oic acid, and 
 a 3α,6β,7β,12β-tetrahydroxy-5β-cholan-24-oic acid, 
 or wherein said 2,3,7,12-tetrahydroxycholanic acid is a 2α,3α,7α,12α-tetrahydroxy-5β-cholanic acid, 
 or wherein said a 3,4,7,12-tetrahydroxycholanic acid is a 3α,4α,7α,12α-tetrahydroxy-5β-cholanic acid, 
 or a derivative thereof. 
 
     
     
         5 . The method of  claim 1  wherein said compound has a hydrophilicity greater than that of cholate, or has a preferential affinity for MDRI when compared to BSEP, or wherein said compound has a high affinity for MDR1, or wherein said compound is selected from the group consisting of a tauryl or glycyl conjugate of a 3α,6β,7α,12β-tetrahydroxy-5β-cholan-24-oic acid, a tauryl or glycyl conjugate of a 3α,6β,7β,12β-tetrahydroxy-5β-cholan-24-oic acid, a tauryl conjugate of a 3α,6β,7α,12α-tetrahydroxy-5β-cholan-24-oic acid, and a tauryl conjugate of 3α,6β,7β,12α tetrahydroxy-5β-cholan-24-oic acid. 
     
     
         6 . The method of  claim 1  wherein said compound is a conjugated compound. 
     
     
         7 . The method of  claim 6  wherein said conjugated compound is a taurine or a glycine conjugate. 
     
     
         8 . The method of  claim 1  further comprising administering at least one other therapeutic agent. 
     
     
         9 . The method of  claim 1  wherein said biliary disorder is selected from the group consisting of benign biliary strictures, benign pancreatic disease cysts, diverticulitis, liver fibrosis, liver damage, common bile duct stones, pancreatitis, pancreatic cancer or pseudocyst, periampullary cancer, bile duct carcinoma, primary sclerosing cholangitis, autoimmune cholangitis, extrinsic duct compression (e.g., compression due to a mass or tumor on a nearby organ), viral hepatitis, sepsis, bacterial abscess, use of drugs e.g., drug-induced idiosyncratic hepatotoxicity, lymphoma, tuberculosis, metastatic carcinoma, sarcoidosis, amyloidosis, intravenous feeding, primary biliary cirrhosis, primary sclerosing cholangitis, alcoholic hepatitis with or without cirrhosis, intrahepatic cholestasis of pregnancy, biliary calculosis, biliary dyscinesia, Sjogren syndrome, Wilson's disease, ischemia, toxins, alcohol, acute liver failure, α1-antitrypsin deficiency, PFIC2, Benign Recurrent Intrahepatic Cholestasis, hepatocellular carcinoma, portal hypertension, veno-occlusive disease, and hepatic vein thrombosis, or wherein said biliary disorder arises from cholestasis. 
     
     
         10 . The method of  claim 1  wherein said subject is a human. 
     
     
         11 . A pharmaceutical or nutritional composition comprising a compound according to Formula I: 
       
         
           
           
               
               
           
         
         or a derivative thereof, together with a pharmaceutically acceptable carrier, wherein
 any one of R 1  to R 9  may be —H or —OH, provided that at least four of R 1  to R 9  are —OH; and 
 R 10  may be —COON or —CH 2 OH. 
 
       
     
     
         12 . The composition of  claim 11 , wherein said compound is selected from the group consisting of a tetrahydroxylated bile acid, a pentahydroxylated bile acid, or a derivative thereof. 
     
     
         13 . The composition of  claim 12 , wherein said tetrahydroxylated bile acid is selected from the group consisting of:
 a 3,6,7,12-tetrahydroxycholanoic acid,   a 3,4,7,12-tetrahydroxycholanoic acid,   a 1,3,7,12-tetrahydroxycholanoic acid,   a 2,3,7,12-tetrahydroxycholanoic acid,   a 3,7,16,24-tetrahydroxycholanoic acid, and   a 3,7,15,24-tetrahydroxycholanoic acid,   or a derivative thereof.   
     
     
         14 . The composition of  claim 13 , wherein said 3,6,7,12-tetrahydroxycholanoic acid is selected from the group consisting of:
 a 3α,6α,7α,12α-tetrahydroxy-5β-cholan-24-oic acid,   a 3α,6β,7α,12α-tetrahydroxy-5β-cholan-24-oic acid,   a 3α,6α,7β,12α-tetrahydroxy-5β-cholan-24-oic acid,   a 3α,6β,7β,12α-tetrahydroxy-5β-cholan-24-oic acid,   a 3α,6α,7α,12β-tetrahydroxy-5β-cholan-24-oic acid,   a 3α,6β,7α,12β-tetrahydroxy-5β-cholan-24-oic acid, and   a 3α,6β,7β,12β-tetrahydroxy-5β-cholan-24-oic acid,   or wherein said 2,3,7,12-tetrahydroxycholanoic acid is 2α,3α,7α,12α-tetrahydroxy-5β-cholanoic acid,   or wherein said 3,4,7,12-tetrahydroxycholanoic acid is 3α,4α,7α,12α-tetrahydroxy-5β-cholanoic acid,   or a derivative thereof.   
     
     
         15 . The composition of  claim 11 , wherein said compound has a hydrophilicity greater than that of cholate, or has a preferential affinity for MDRI when compared to BSEP, or wherein said compound has a high affinity for MDR1, or wherein said compound has a high affinity for MDR1, or wherein said compound is selected from the group consisting of a tauryl or glycyl conjugate of a 3α,6β,7α,12β-tetrahydroxy-5β-cholan-24-oic acid, a tauryl or glycyl conjugate of a 3α,6β,7β,12β-tetrahydroxy-5β-cholan-24-oic acid, a tauryl conjugate of a 3α,6β,7α,12α-tetrahydroxy-5β-cholan-24-oic acid, and a tauryl conjugate of 3α,6β,7β,12α tetrahydroxy-5β-cholan-24-oic acid. 
     
     
         16 . The composition of  claim 11 , wherein said compound is a conjugated compound. 
     
     
         17 . The composition of  claim 16 , wherein said conjugated compound is a taurine or a glycine conjugate. 
     
     
         18 . The composition of  claim 11 , further comprising at least one other therapeutic agent. 
     
     
         19 . An article of manufacture comprising: 
       
         
           
           
               
               
           
         
         composition of  claim 11 , together with instructions for treating a biliary disorder or stimulating bile flow. 
       
     
     
         20 . A 2α,3α,7α,12α-tetrahydroxy-5β-cholanoic acid or a 3α,4α,7α,12α-tetrahydroxy-5β-cholanoic acid.