USE OF BILIARY ACID RECYCLING INHIBITORS FOR THE TREATMENT OF HYPERCOLEMIA AND CHOLESTATIC HEPATIC D

专利摘要:
use of bile acid recycling inhibitors for the treatment of hypercholemia and cholestatic liver disease methods of treating or better hypercholemia or cholestatic liver disease are provided herein by administration to an individual in need of a therapeutically effective amount of a carrier inhibitor of apical sodium-dependent bile acid (asbti) or a pharmaceutically acceptable salt thereof. methods are also provided for the treatment or amelioration of liver disease, decreased levels of serum bile acids or hepatic bile acids, treatment or amelioration of itching, reduction of liver enzymes, or reduction of bilirubin comprising administration to an individual in need that of a therapeutically effective amount of asbti or a pharmaceutically acceptable salt thereof.
公开号:BR112014010228B1
申请号:R112014010228-7
申请日:2012-10-26
公开日:2020-09-29
发明作者:Bronislava Gedulin；Michael Grey；Niall O'Donnell
申请人:Lumena Pharmaceuticals Llc；
IPC主号:

专利说明:

Cross-referencing related orders
This request claims the benefit of US Provisional Application No.: 61 / 553,094, filed on October 28, 2011, US Provisional Application No.: 61 / 607,487, filed on March 6, 2012, which are incorporated herein in full by reference. Background of the invention
Hypercholemia and cholestatic liver diseases are liver diseases associated with impaired bile secretion (ie cholestasis), associated and often secondary to the intracellular accumulation of bile acids / salts in the hepatocyte. Hypercholemia is characterized by increased serum concentration of bile acid or bile salt. Cholestasis can be categorized clinicopathologically into two main categories of obstructive cholestasis, often extrahepatic, and non-obstructive, or intrahepatic cholestasis. Non-obstructive intrahepatic cholestasis can also be classified into two main subgroups of primary intrahepatic cholestasis resulting from constitutively defective bile secretion, and secondary intrahepatic cholestasis resulting from hepatocellular injury. Primary intrahepatic cholestasis includes diseases such as benign recurrent intrahepatic cholestasis, which is predominantly an adult form with similar clinical symptoms, and progressive familial intrahepatic cholestasis types 1, 2, and 3, which are diseases that affect children. Neonatal respiratory stress syndrome and pulmonary pneumonia is often associated with intrahepatic cholestasis of pregnancy. The treatment of pneumonia and prevention is limited. Currently, effective treatments for hypercholemia and cholestatic liver diseases include surgery, liver transplantation, and rarely administration of ursodiol. Effective and safe medication for hypercholemia and cholestatic liver disease is needed. Summary of the invention
Therapeutic compositions and methods for the treatment or amelioration of hypercholemia and / or cholestatic liver disease are provided herein. In certain embodiments, methods are provided here for the treatment or amelioration of hypercholemia and / or cholestatic liver disease comprising the non-systemic administration to an individual in need of a therapeutically effective amount of an apical sodium-dependent bile transporter inhibitor ( ASBTI) or a pharmaceutically acceptable salt thereof. In certain embodiments, methods are provided herein for the treatment or amelioration of hypercholemia and / or cholestatic liver disease which comprises administering to a subject in need thereof a therapeutically effective amount of a non-systemically absorbed ASBTI or a pharmaceutically acceptable salt thereof.
In certain embodiments, compositions are provided herein which comprise a non-systemically absorbed apical sodium-dependent bile acid transporter inhibitor (ASBTI) or a pharmaceutically acceptable salt thereof. In some embodiments, compositions are provided herein which comprise any non-systemically absorbed ASBTI or a pharmaceutically acceptable salt described herein. In some embodiments, compositions are provided herein which comprise any non-systemically absorbed ASBTI or a pharmaceutically acceptable salt thereof and a second agent described herein.
Therapeutic compositions and methods for treating or ameliorating itching are provided herein. In certain embodiments, methods are provided herein for the treatment or amelioration of pruritus comprising the non-systemic administration to an individual in need thereof of a therapeutically effective amount of an ASBTI or a pharmaceutically acceptable salt thereof. In certain embodiments, methods are provided herein for the treatment or improvement of pruritus which comprises administering to a subject in need thereof a therapeutically effective amount of a non-systemically absorbed ASBTI or a pharmaceutically acceptable salt thereof.
Therapeutic compositions and methods for decreasing serum bile acid concentrations or levels or hepatic bile acid concentrations or levels are provided herein. In certain embodiments, methods are provided herein for decreasing serum bile acid concentrations or levels or hepatic bile acid concentrations or levels comprising non-systemic administration to an individual in need of a therapeutically effective amount of an ASBTI or a salt. pharmaceutically acceptable thereto. In certain embodiments, methods are provided herein for decreasing serum bile acid concentrations or levels or hepatic bile acid concentrations or levels comprising administering to a subject in need of a therapeutically effective amount of a non-systemically absorbed ASBTI or a pharmaceutically acceptable salt thereof.
In some embodiments, the compositions and methods provided herein decrease serum or hepatic levels of bile acid by at least 50%, 45%, 40%, 35%, 30%, 25%, 20%, 15%, or 10%, when compared to levels prior to administration of the compositions provided herein or when compared to control subjects. In some embodiments, the methods provided here decrease serum or hepatic levels of bile acid by at least 30%. In some embodiments, the methods provided here decrease serum or hepatic levels of bile acid by at least 25%. In some embodiments, the methods provided here decrease serum or hepatic levels of bile acid by at least 20%. In some embodiments, the methods provided here decrease serum or hepatic levels of bile acid by at least 15%.
Therapeutic compositions and methods for the treatment or improvement of xanthoma are provided herein. In certain embodiments, methods are provided herein for treating or improving xanthoma that comprise non-systemic administration to an individual in need thereof of a therapeutically effective amount of an ASBTI or a pharmaceutically acceptable salt thereof. In certain embodiments, methods are provided herein for treating or improving xanthoma that comprise administering to a subject in need thereof a therapeutically effective amount of a non-systemically absorbed ASBTI or a pharmaceutically acceptable salt thereof.
Therapeutic compositions and methods for decreasing serum lipoprotein X levels or concentrations are provided herein. In certain embodiments, methods are provided herein for decreasing levels or concentrations of serum lipoprotein X which comprise non-systemic administration to an individual in need thereof of a therapeutically effective amount of an ASBTI or a pharmaceutically acceptable salt thereof. In certain embodiments, methods are provided herein for decreasing levels or concentrations of serum lipoprotein X which comprise administering to a subject in need thereof a therapeutically effective amount of a non-systemically absorbed ASBTI or a pharmaceutically acceptable salt thereof.
In certain embodiments, methods and compositions for reducing serum levels of bilirubin, gamma-glutamyl transpeptidase or gamma-glutamyl transferase (GGT), or liver enzymes, such as alkaline phosphatase, ALT and AST, are described herein in an individual in need of these which comprise the non-systemic administration of a therapeutically effective amount of an ASBTI or a pharmaceutically acceptable salt thereof. In some embodiments, the methods comprise administering a therapeutically effective amount of a non-systemically absorbed ASBTI or a pharmaceutically acceptable salt thereof.
In certain embodiments, the methods provided herein comprise administration of compounds that inhibit ASBT or any recovering bile salt transporter. In certain embodiments, the use of the compounds provided herein reduces or inhibits the recycling of bile acid salts in the gastrointestinal tract. In some embodiments, the methods provided here reduce intraenterocyte bile acids / salts or reduce necrosis and / or damage to the intestinal or hepatocellular architecture. In certain embodiments, the bile transport inhibitors described herein increase the secretion of enteroendocrine peptides by intestinal L cells.
In certain embodiments, the methods described here treat or ameliorate hypercholemia and / or cholestatic liver disease by increasing the intraluminal concentrations of bile acids / salts, which are then excreted in the faeces, thereby reducing the overall load of bile acid and serum bile acid or hepatic bile acid in an individual in need of these. In certain embodiments, the increase in intraluminal bile acid concentrations according to the methods described herein provides protection and / or control of the integrity of the liver and / or intestine of an individual who has been injured by hypercholemia and / or cholestatic liver disease.
In certain embodiments, the methods described herein treat or ameliorate itching by increasing intraluminal concentrations and / or reducing serum concentrations, or hepatic concentrations of bile acids / salts in an individual in need of these. In certain embodiments, the increase in intraluminal bile acid concentrations according to the methods described herein provides protection and / or control of the integrity of the liver and / or intestine of an individual who has been injured by a cholestatic liver disease.
In certain embodiments, the methods described herein decrease serum bile acid concentrations or hepatic bile acid concentrations by increasing intraluminal concentrations of bile acids / salts in an individual in need of these. In certain embodiments, the increase in intraluminal bile acid concentrations according to the methods described herein provides protection and / or control of the integrity of the liver and / or intestine of an individual who has been injured by a cholestatic liver disease.
In certain embodiments, methods are provided herein for the treatment or amelioration of a liver disease comprising non-systemic administration to the distal ileum of an individual in need of a therapeutically effective amount of an apical sodium-dependent bile transporter inhibitor (ASBTI ) or a pharmaceutically acceptable salt thereof. In some embodiments, methods are provided here for the treatment or amelioration of a liver disease comprising non-systemic administration to the distal ileum of an individual in need of a therapeutically effective amount of an ASBTI or a pharmaceutically acceptable salt thereof, where the liver disease is hepatitis A, hepatitis B, hepatitis C, non-alcoholic steatohepatitis (NASH), non-alcoholic fatty liver disease (NAFLD), hemochromatosis, Wilson's disease, ischemic hepatitis, liver inflammation, liver fibrosis, or a chronic liver disease.
In certain embodiments, an ASBTI or a pharmaceutically acceptable salt thereof is provided herein for use in the treatment of hypercholemia and / or cholestatic liver disease, wherein the ASBTI is non-systemically absorbed or is formulated to be non-systemically absorbed. In some embodiments, a pharmaceutical composition is provided herein for use in the treatment of hypercholemia and / or cholestatic liver disease, wherein the composition comprises an ASBTI and a pharmaceutically acceptable excipient, where the ASBTI is not systemically absorbed or is pelleted to be non-systemic. systemically absorbed. In some embodiments, a composition provided herein is suitable for non-systemic administration to the distal ileum, colon, and / or rectum.
In certain embodiments, an ASBTI or a pharmaceutically acceptable salt thereof is provided herein for use in the treatment of pruritus, wherein the ASBTI is not systemically absorbed or is formulated to be non-systemically absorbed. In some embodiments, a pharmaceutical composition for use in the treatment of pruritus is provided herein, wherein the compositions comprise an ASBTI and a pharmaceutically acceptable excipient, where the ASBTI is non-systemically absorbed or is formulated to be non-systemically absorbed. In some embodiments, a composition provided herein is suitable for non-systemic administration to the distal ileum, colon, and / or rectum.
In certain embodiments, an ASBTI or a pharmaceutically acceptable salt thereof is provided herein for use in decreasing serum bile acid concentrations or hepatic bile acid concentrations, wherein ASBTI is not systemically absorbed or is formulated to be non-systemically absorbed. In some embodiments, a pharmaceutical composition is provided herein for use in decreasing serum bile acid concentrations or hepatic bile acid concentrations, wherein the compositions comprise an ASBTI and a pharmaceutically acceptable excipient, where the ASBTI is not systemically absorbed or is formulated to be not systemically absorbed. In some embodiments, a composition provided herein is suitable for non-systemic administration to the distal ileum, colon, and / or rectum.
In some embodiments, an ASBTI provided here is minimally absorbed or formulated to be minimally absorbed. In some embodiments, an ASBTI is administered systemically to the distal ileum, colon, and / or rectum of an individual in need of it. In some modalities, an ASBTI is administered systemically to the ileum, colon or rectum of an individual in need. In some modalities, less than 50%, less than 40%, less than 30%, less than 20%, less than 10%, less than 9%, less than 8%, less than 7%, less than 6%, less than 5%, less than 4%, less than 3%, less than 2%, or less than 1% of the ASBTI is systemically absorbed. In a preferred embodiment, less than 10% of the ASBTI is systemically absorbed. In other preferred embodiments, less than 5% of the ASBTI is systemically absorbed. In other preferred embodiments, less than 1% of the ASBTI is systemically absorbed.
In one aspect, a method is provided here for the prevention or treatment of hypercholemia and / or cholestatic liver disease in an individual in need of that comprising non-systemic administration to the individual's distal gastrointestinal tract in need of a therapeutically effective amount of one. ASBTI or a pharmaceutically acceptable salt thereof. In one aspect, a method is provided herein for the prevention or treatment of itching in an individual in need thereof which comprises non-systemic administration to the distal gastrointestinal tract of the individual in need thereof of a therapeutically effective amount of an ASBTI or a pharmaceutically acceptable salt this. In one aspect, a method for decreasing serum bile acid concentrations in an individual in need is provided herein which comprises non-systemic administration to the individual's distal gastrointestinal tract in need of a therapeutically effective amount of an ASBTI or a salt. pharmaceutically acceptable thereto. In some embodiments, the distal gastrointestinal tract is jejunum, ileum, colon, or rectum. In some embodiments, the distal gastrointestinal tract is the ileum, colon, or rectum. In some modalities, the distal gastrointestinal tract is jejunum. In some embodiments, the distal gastrointestinal tract is ileum.
In certain modalities, cholestasis and / or cholestatic liver disease is obstructive cholestasis, non-obstructive cholestasis, extrahepatic cholestasis, intrahepatic cholestasis, primary intrahepatic cholestasis, secondary intrahepatic cholestasis, progressive family intrahepatic cholestasis (PFIC ), PFIC type 1, PFIC type 2, PFIC type 3, benign recurrent intrahepatic cholestasis (BRIC), BRIC type 1, BRIC type 2, BRIC type 3, cholestasis associated with total parenteral nutrition, paraneoplastic cholestasis, Stauffer syndrome, intrahepatic cholestasis of pregnancy, cholestasis associated with contraceptive, cholestasis associated with drug, cholestasis associated with infection, Dubin-Johnson syndrome, primary biliary cirrhosis (PBC), primary sclerosing cholangitis (PSC), cholelithiasis, Alagille syndrome, biliary atresia , post-Kasai biliary atresia, post-liver transplant biliary atresia, post-liver transplant cholestasis, associated liver disease post-liver transplantation, liver disease it is associated with intestinal failure, bile acid-mediated liver damage, MRP2 deficiency syndrome, or neonatal sclerosing cholangitis. In some embodiments, pediatric cholestatic liver disease is a pediatric form of liver disease described here.
In certain modalities, hypercholemia and / or cholestatic liver disease is characterized by one or more selected symptoms of jaundice, pruritus, cirrhosis, neonatal respiratory stress syndrome, pulmonary pneumonia, increased serum concentration of bile acids, increased liver concentration of bile acids, concentration increased serum bilirubin, hepatocellular injury, hepatocellular scarring, hepatocellular insufficiency, hepatomegaly, xanthomas, malabsorption, splenomegaly, diarrhea, pancreatitis, hepatocellular necrosis, giant cell formation, hepatocellular carcinoma, gastrointestinal bleeding, portal hypertension, hearing loss, fatigue, hearing loss loss of appetite, anorexia, peculiar smell, dark urine, light stools, steatorrhea, developmental failure.
In some cases, any of the methods or compositions described above reduces or improves the symptoms of hypercholemia and / or cholestatic liver disease and / or reduces the severity of symptoms and / or reduces the recurrence of hypercholemia and / or cholestatic liver disease in an individual pediatric patients in need of this. In some cases, any of the methods or compositions described above reduces or improves itching in a pediatric individual in need of it. In some cases, any of the methods or compositions described above decreases serum bile acid concentrations or hepatic bile acid concentrations in a pediatric individual in need of it. In some cases, for any of the methods and / or compositions described here, the individual is a baby less than 2 years old. In some cases, for any of the methods and / or compositions described herein, the individual is a baby between 0 to 18 months of age. In some cases, for any of the methods and / or compositions described here, the individual is a baby between 1 to 18 months of age. In some cases, for any of the methods and / or compositions described here, the individual is a baby between 2 to 18 months of age. In some cases, for any of the methods and / or compositions described here, the individual is a baby between 3 to 18 months of age. In some cases, for any of the methods and / or compositions described here, the individual is a baby between 4 to 18 months of age. In some cases, for any of the methods and / or compositions described here, the individual is a baby between 6 to 18 months of age. In some cases, for any of the methods and / or compositions described herein, the individual is a baby between 18 to 24 months of age. In some cases, for any of the methods and / or compositions described herein, the individual is a baby between 6 to 12 months of age. In some cases, for any of the methods and / or compositions described herein, the individual is a child between about 2 to about 10 years old. In some cases, the individual is less than 10 years old. In some cases, the individual is over 10 years old. In some cases, the individual is an adulti.
Therapeutic compositions and methods using compounds that inhibit the apical sodium-dependent bile transporter (ASBT) or a pharmaceutically acceptable salt thereof, or any recovering bile salt transporter for the treatment of hypercholemia and / or cholestatic liver disease. In certain cases, the use of the compounds provided herein reduces or inhibits the recycling of bile acid salts in the gastrointestinal tract. In some modalities, the methods provided here reduce intraenterocyte bile acids / salts and / or damage to the ileal or hepatocellular architecture caused by hypercholemia and / or cholestatic liver disease and / or provide regeneration of the intestinal lining or liver. In some embodiments, bile transport inhibitors are non-systemic compounds. In other embodiments, bile acid transporter inhibitors are systemic compounds released non-systemically. In other embodiments, bile acid transporter inhibitors are systemic compounds. In certain embodiments, the bile transport inhibitors described herein increase the secretion of enteroendocrine peptide by intestinal L cells.
Therapeutic compositions and methods using compounds that inhibit the apical sodium-dependent bile transporter (ASBT) or a pharmaceutically acceptable salt thereof, or any recovering bile salt transporter for the treatment of pruritus are provided here in certain embodiments. In certain cases, the use of the compounds provided herein reduces or inhibits the recycling of bile acid salts in the gastrointestinal tract. In some embodiments, the methods provided here reduce intraenterocyte bile acids / salts and / or damage to the ileal or hepatocellular architecture caused by a cholestatic liver disease and / or provide regeneration of the intestinal lining or liver. In some embodiments, bile transport inhibitors are non-systemic compounds. In other embodiments, bile acid transporter inhibitors are systemic compounds released non-systemically. In other embodiments, bile acid transporter inhibitors are systemic compounds. In certain embodiments, the bile transport inhibitors described herein increase the secretion of enteroendocrine peptide by intestinal L cells.
Therapeutic compositions and methods using compounds that inhibit the apical sodium-dependent bile transporter (ASBT) or a pharmaceutically acceptable salt thereof, or any recovering bile salt transporter to decrease serum bile acid concentrations are provided here in certain modalities . In certain cases, the use of the compounds provided herein reduces or inhibits the recycling of bile acid salts in the gastrointestinal tract. In some embodiments, the methods provided here reduce intraenterocyte bile acids / salts and / or damage to the ileal or hepatocellular architecture caused by a cholestatic liver disease and / or provide regeneration of the intestinal lining or liver. In some embodiments, bile transport inhibitors are non-systemic compounds. In other embodiments, bile acid transporter inhibitors are systemic compounds released non-systemically. In other embodiments, bile acid transporter inhibitors are systemic compounds. In certain embodiments, the bile transport inhibitors described herein increase the secretion of enteroendocrine peptide by intestinal L cells.
In some embodiments of the methods described above, ASBTI is a compound of Formula I or a pharmaceutically acceptable salt thereof, as described herein. In some embodiments of the methods described above, ASBTI is a compound of Formula II or a pharmaceutically acceptable salt thereof, as described herein. In some embodiments of the methods described above, ASBTI is a compound of Formula III or a pharmaceutically acceptable salt thereof, as described herein. In some embodiments of the methods described above, ASBTI is a compound of Formula IV or a pharmaceutically acceptable salt thereof, as described herein. In some embodiments of the methods described above, ASBTI is a compound of Formula V or a pharmaceutically acceptable salt thereof, as described herein. In some embodiments of the methods described above, ASBTI is a compound of Formula VI or Formula VID or a pharmaceutically acceptable salt thereof, as described herein.
In some embodiments, a method for treating or ameliorating hypercholemia and / or cholestatic liver disease is provided herein which comprises the non-systemic administration to an individual in need of a therapeutically effective amount of an ASBTI of Formula I or a pharmaceutically acceptable salt. this. In some embodiments, a method for the treatment or amelioration of a liver disease is provided herein comprising non-systemic administration to an individual in need of a therapeutically effective amount of a Formula I ASBTI or a pharmaceutically acceptable salt thereof, wherein liver disease is hepatitis A, hepatitis B, hepatitis C, non-alcoholic steatohepatitis (NASH), non-alcoholic fatty liver disease (NAFLD), hemochromatosis, Wilson's disease, ischemic hepatitis, liver inflammation, liver fibrosis, or a chronic liver disease. In some embodiments, a method for treating or ameliorating itching is provided herein which comprises the non-systemic administration to an individual in need thereof of a therapeutically effective amount of a Formula I ASBTI or a pharmaceutically acceptable salt thereof. In some embodiments, a method is provided here for increasing the levels of an enteroendocrine peptide or hormone in an individual suffering from hypercholemia and / or a cholestatic liver disease that comprises the non-systemic administration to the individual in need of a therapeutically effective amount of an ASBTI of Formula I or a pharmaceutically acceptable salt thereof. In some embodiments, a method for decreasing serum bile acid concentrations or hepatic bile acid concentration is provided herein which comprises non-systemic administration to an individual in need of a therapeutically effective amount of a Formula I ASBTI or a salt. pharmaceutically acceptable thereto.
In some embodiments, a method for the treatment or amelioration of hypercholemia and / or a cholestatic liver disease is provided herein which comprises the non-systemic administration to an individual in need thereof of a therapeutically effective amount of a Formula II ASBTI or a pharmaceutically salt. acceptable of this. In some embodiments, a method for the treatment or amelioration of a liver disease is provided herein comprising non-systemic administration to an individual in need thereof of a therapeutically effective amount of a Formula II ASBTI or a pharmaceutically acceptable salt thereof, wherein liver disease is hepatitis A, hepatitis B, hepatitis C, non-alcoholic steatohepatitis (NASH), non-alcoholic fatty liver disease (NAFLD), hemochromatosis, Wilson's disease, ischemic hepatitis, liver inflammation, liver fibrosis, or a chronic liver disease. In some embodiments, a method for the treatment or amelioration of itching is provided herein which comprises the non-systemic administration to an individual in need thereof of a therapeutically effective amount of a Formula II ASBTI or a pharmaceutically acceptable salt thereof. In some embodiments, a method is provided here for increasing the levels of an enteroendocrine peptide or hormone in an individual suffering from hypercholemia and / or a cholestatic liver disease that comprises the non-systemic administration to the individual in need of a therapeutically effective amount of a Formula II ASBTI or a pharmaceutically acceptable salt thereof. In some embodiments, a method is provided here for decreasing serum bile acid concentrations in an individual suffering from cholestatic liver disease which comprises the non-systemic administration to the individual in need of a therapeutically effective amount of a Formula II ASBTI or a pharmaceutically acceptable salt thereof.
In some embodiments, a method for the treatment or amelioration of hypercholemia and / or a cholestatic liver disease is provided herein which comprises the non-systemic administration to an individual in need thereof of a therapeutically effective amount of a Formula III ASBTI or a pharmaceutically salt. acceptable of this. In some embodiments, a method for the treatment or amelioration of a liver disease is provided herein which comprises non-systemic administration to an individual in need thereof of a therapeutically effective amount of a Formula III ASBTI or a pharmaceutically acceptable salt thereof, wherein liver disease is hepatitis A, hepatitis B, hepatitis C, non-alcoholic steatohepatitis (NASH), non-alcoholic fatty liver disease (NAFLD), hemochromatosis, Wilson's disease, ischemic hepatitis, liver inflammation, liver fibrosis, or a chronic liver disease. In some embodiments, a method for treating or ameliorating itching is provided herein which comprises non-systemic administration to an individual in need thereof of a therapeutically effective amount of a Formula III ASBTI or a pharmaceutically acceptable salt thereof. In some embodiments, a method is provided here for increasing the levels of an enteroendocrine peptide or hormone in an individual suffering from hypercholemia and / or a cholestatic liver disease that comprises the non-systemic administration to the individual in need of a therapeutically effective amount of a Formula III ASBTI or a pharmaceutically acceptable salt thereof. In some embodiments, a method is provided here for decreasing serum bile acid concentrations in an individual suffering from cholestatic liver disease which comprises the non-systemic administration to the individual in need of a therapeutically effective amount of a Formula III ASBTI or a pharmaceutically acceptable salt thereof.
In some embodiments, a method for the treatment or amelioration of hypercholemia and / or a cholestatic liver disease is provided herein which comprises the non-systemic administration to an individual in need thereof of a therapeutically effective amount of a Formula IV ASBTI or a pharmaceutically salt acceptable of this. In some embodiments, a method for the treatment or amelioration of liver disease is provided herein which comprises the non-systemic administration to an individual in need thereof of a therapeutically effective amount of a Formula IV ASBTI or a pharmaceutically acceptable salt thereof, wherein liver disease is hepatitis A, hepatitis B, hepatitis C, non-alcoholic steatohepatitis (NASH), non-alcoholic fatty liver disease (NAFLD), hemochromatosis, Wilson's disease, ischemic hepatitis, liver inflammation, liver fibrosis, or a chronic liver disease. In some embodiments, a method for treating or ameliorating itching is provided herein which comprises the non-systemic administration to an individual in need thereof of a therapeutically effective amount of a Formula IV ASBTI or a pharmaceutically acceptable salt thereof. In some embodiments, a method is provided here for increasing the levels of an enteroendocrine peptide or hormone in an individual suffering from hypercholemia and / or a cholestatic liver disease that comprises the non-systemic administration to the individual in need of a therapeutically effective amount of a Formula IV ASBTI or a pharmaceutically acceptable salt thereof. In some embodiments, a method is provided here for decreasing serum bile acid concentrations in an individual suffering from cholestatic liver disease that comprises non-systemic administration to the individual in need of a therapeutically effective amount of a Formula IV ASBTI or a pharmaceutically acceptable salt thereof.
In some embodiments, a method for the treatment or amelioration of hypercholemia and / or a cholestatic liver disease is provided herein comprising the non-systemic administration to an individual in need thereof of a therapeutically effective amount of a Formula V ASBTI or a pharmaceutically salt. acceptable of this. In some embodiments, a method for the treatment or amelioration of a liver disease is provided herein comprising non-systemic administration to an individual in need thereof of a therapeutically effective amount of a Formula V ASBTI or a pharmaceutically acceptable salt thereof, wherein liver disease is hepatitis A, hepatitis B, hepatitis C, non-alcoholic steatohepatitis (NASH), non-alcoholic fatty liver disease (NAFLD), hemochromatosis, Wilson's disease, ischemic hepatitis, liver inflammation, liver fibrosis, or a chronic liver disease. In some embodiments, a method for the treatment or amelioration of itching is provided herein which comprises non-systemic administration to an individual in need thereof of a therapeutically effective amount of a Formula V ASBTI or a pharmaceutically acceptable salt thereof. In some embodiments, a method is provided here for increasing the levels of an enteroendocrine peptide or hormone in an individual suffering from hypercholemia and / or a cholestatic liver disease that comprises the non-systemic administration to the individual in need of a therapeutically effective amount of a Formula V ASBTI or a pharmaceutically acceptable salt thereof. In some embodiments, a method is provided here for decreasing serum bile acid concentrations in an individual suffering from cholestatic liver disease which comprises the non-systemic administration to the individual in need of such a therapeutically effective amount of a Formula V ASBTI or a pharmaceutically acceptable salt thereof.
In some embodiments, a method for the treatment or amelioration of hypercholemia and / or a cholestatic liver disease is provided herein which comprises the non-systemic administration to an individual in need thereof of a therapeutically effective amount of a Formula VI ASBTI or a pharmaceutically salt. acceptable of this. In some embodiments, a method for the treatment or amelioration of liver disease is provided herein which comprises the non-systemic administration to an individual in need thereof of a therapeutically effective amount of a Formula VI ASBTI or a pharmaceutically acceptable salt thereof, wherein liver disease is hepatitis A, hepatitis B, hepatitis C, non-alcoholic steatohepatitis (NASH), non-alcoholic fatty liver disease (NAFLD), hemochromatosis, Wilson's disease, ischemic hepatitis, liver inflammation, liver fibrosis, or a chronic liver disease. In some embodiments, a method for the treatment or amelioration of itching is provided herein which comprises the non-systemic administration to an individual in need thereof of a therapeutically effective amount of a Formula VI ASBTI or a pharmaceutically acceptable salt thereof. In some embodiments, a method is provided here for increasing the levels of an enteroendocrine peptide or hormone in an individual suffering from hypercholemia and / or a cholestatic liver disease that comprises the non-systemic administration to the individual in need of a therapeutically effective amount of a Formula VI ASBTI or a pharmaceutically acceptable salt thereof. In some embodiments, a method for decreasing concentrations of serum bile acid concentrations in an individual suffering from a cholestatic liver disease is provided here which comprises the non-systemic administration to the individual in need of such a therapeutically effective amount of a Formula VI ASBTI. or a pharmaceutically acceptable salt thereof.
In certain embodiments, an ASBTI is any compound described herein that inhibits the recycling of bile acids / salts in an individual's gastrointestinal tract. In certain embodiments, an ASBTI is (-) - (3R, 5R) -trans-3-butyl-3-ethyl-2,3,4,5-tetrahydro-7,8-dimethoxy-5-phenyl-1,4 - benzothiazepinal, 1-dioxide; ("Compound 100A") or any other salt or the like. In any of the aforementioned embodiments, an ASBTI is a salt of 1- [4- [4- [(4R, 5R) -3,3-dibutyl-7- (dimethylamino) -2,3,4,5-tetrahydro- 4-hydroxy-1, 1-dioxide-1-benzothiepin-5-yl] phenoxy] butyl] 4-aza-1-azoniabicyclo [2.2.2] octane methane sulfonate ("Compound 100B") or any other salt or analog thereof . In certain embodiments, an ASBTI is N, N-dimethylimido-dicarbonimide diamide ("Compound 100C") or any salt or analog thereof. In certain embodiments, an ASBTI is any commercially available ASBTI that includes, without limitation, SD-5613, A-3309, 264W94, S-8921, SAR-548304, BARI-1741, HMR-1453, TA-7552, R-146224 , or SC-435. In some embodiments, an ASBTI is 1,1-dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8- (N- {(R) -a- [N - ((R) -l-carboxy -2-methylthio-ethyl) carbamoyl] -4-hydroxybenzyl} carbamoylmethoxy) -2,3,4,5-tetrahydro-1,2,5-benzothiadiazepine; 1,1-dioxo-3,3-dibutyl-5-phenyl-7 - methylthio-8- (N - {(R) -a- [N - ((S) -l-carboxy-2- (R) - hydroxypropyl) carbamoyl] -4-hydroxybenzyl} carbamoylmethoxy) - 2,3,4,5-tetrahydro-1,2,5-benzothiadiazepine; 1,1-dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8- (N - {(R) -a- [N - ((S) -1-carboxy-2-methylpropyl) carbamoyl] -4-hydroxybenzyl} carbamoylmethoxy) - 2,3,4,5-tetrahydro-1,2,5-benzothiadiazepine; 1,1-dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8- (N - {(R) -a- [N - ((S) -1- carboxybutyl) carbamoyl] -4-hydroxybenzyl } carbamoylmethoxy) - 2,3,4,5-tetrahydro-1,2,5-benzothiadiazepine; 1,1-dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8 - (N - {(R) -a- [N - ((S) -1- carboxypropyl) carbamoyl] benzyl} carbamoylmethoxy) -2,3,4,5-tetrahydro-1,2,5-benzothiadiazepine; 1,1-dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8 - (N - {(R) -a- [N - ((S) -1- carboxyethyl) carbamoyl] benzyl} carbamoylmethoxy) -2,3,4,5-tetrahydro-1,2,5-benzothiadiazepine; 1,1-dioxo-3,3-di butyl-5-phenyl-7-methylthio-8- (N - {(R) -a- [N - ((S) -1-carboxy-2- (R) -hydroxypropyl) carbamoyl] benzyl) carbamoylmethoxy) -2,3,4,5-tetrahydro-1,2,5-benzothiadiazepine; 1,1-dioxo-3,3-dibutyl-5-phenyl-7 - methylthio-8- (N - {(R) -a- [N- (2-sulfoethyl) carbamoyl] -4-hydroxybenzyl) carbamoylmethoxy) - 2,3,4,5-tetrahydro-1,2,5-benzothiadiazepine; 1,1-dioxo-3,3-dibutyl-5-phenyl-7 - methylthio-8- (N - {(R) -a- [N - ((S) -1-carboxyethyl) carbamoyl] -4-hydroxybenzyl ) carbamoylmethoxy) -2,3,4,5-tetrahydro-1,2,5-benzothiadiazepine; 1,1-dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8- (N - {(R) -a- [N - ((R) -1-carboxy-2-methylthioethyl) carbamoyl] benzyl) carbamoylmethoxy) -2,3,4,5-tetrahydro-1,2,5-benzothiadiazepine; 1,1-dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8 - (N - {(R) -a- [N - {(S) -1- [N - ((S) - 2-hydroxy-1-carboxyethyl) carbamoyl] propyl) carbamoyl] benzyl) carbamoylmet xi) -2,3,4,5-tetrahydro-1,2,5-benzothiadiazepine; 1,1-dioxo- 3,3-dibutyl-5-phenyl-7-methylthio-8- (N - {(R) -a- [N - ((S) -1- carboxy-2-methylpropyl) carbamoyl] benzyl) carbamoylmethoxy) - 2,3,4,5 -tetrahydro-1,2,5-benzothiadiazepine; 1,1-dioxo-3,3 - dibutyl-5-phenyl-7-methylthio-8 - (N - {(R) -α- [N - ((S) -1- carboxypropyl) carbamoyl] -4-hydroxybenzyl ) carbamoylmethoxy) - 2,3,4,5-tetrahydro-1,2,5-benzothiadiazepine; 1,1-dioxo-3,3 - dibutyl-5-phenyl-7-methylthio-8- [N - {(R) -α-carboxy-4-hydroxybenzyl) carbamoylmethoxy] -2,3,4,5-tetrahydro -1,5,5-benzothiadiazepine; or 1,1-dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8- (N - {(R) -a- [N- (carboxy) carbamoyl] benzyl) carbamoylmethoxy) -2,3, 4,5-tetrahydro-1,2,5-benzothiadiazepine; 1,1-dioxo-3,3-dibutyl-5-phenyl-7 - methylthio-8- (N - {(R) -1'-phenyl-1 '- [N' - (carboxy) carbamoyl] methyl) carbamoylmethoxy ) -2,3,4,5-tetrahydro-1,5-benzothiazepine; 1,1-dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8- (N - {(R) -α- [N '- ((S) -1-carboxypropyl) carbamoyl] -4- hydroxybenzyl) carbamoylmethoxy) -2,3,4,5-tetrahydro-1,5-benzothiazepine; 1,1-dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8- (N - {(R) -1'-phenyl-1 '- [N' - (carboxy) carbamoyl] methyl) carbamoylmethoxy ) -2,3,4,5-tetrahydro-1,5-benzothiazepine; 1,1-dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8- (N - {(R) -α- [N'- ((S) -1-carboxyethyl) carbamoyl] benzyl) carbamoylmethoxy ) - 2,3,4,5-tetrahydro-1,5-benzothiazepine; or a pharmaceutically acceptable salt thereof; l - [[5 - [[3- [(3S, 4R, 5R) - 3-butyl-7- (dimethylamino) -3-ethyl-2,3,4,5-tetrahydro-4-hydroxy-1,1 -dioxido-1-benzothiepin-5-yl] phenyl] amino] -5-oxopentyl] amino] -1-deoxy-D-glucitol; or Potassium ((2R, 3R, 4S, 5R, 6R) -4-benzyloxy-6- {3- [3- ((3S, 4R, 5R) - 3-butyl-7-dimethylamino-3-ethyl-4- hydroxy-1,1-dioxo-2,3,4,5-tetrahydro-1H-benzo [b] tiepin-5-yl) -phenyl] -ureido) -3,5-dihydroxy-tetrahydro-pyran-2- ylmethyl) sulfate ethanolate, hydrate. In certain embodiments, an ASBTI is 264W94 (Glaxo), SC-435 (Pfizer), SD-5613 (Pfizer), or A3309 (Astra-Zeneca).
In some embodiments, an ASBTI is not 1,1-dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8- (N - {(R) -a- [N - ((R) -l- carboxy-2-methylthio-ethyl) carbamoyl] -4-hydroxybenzyl) carbamoylmethoxy) - 2,3,4,5-tetrahydro-1,2,5-benzothiadiazepine; 1,1-dioxo-3,3 - dibutyl-5-phenyl-7-methylthio-8 - (N - {(R) -a- [N - ((S) -1- carboxi- 2- (R) - hydroxypropyl) carbamoyl] -4-hydroxybenzyl) carbamoylmethoxy) -2,3,4,5-tetrahydro-1,2,5-benzothiadiazepine; 1,1-dioxo-3,3-dibutyl-5-phenyl-7 - methylthio-8- (N - {(R) -a- [N - ((S) -1-carboxy-2-methylpropyl) carbamoyl] -4-hydroxybenzyl) carbamoylmethoxy) - 2,3,4,5-tetrahydro-1,2,5-benzothiadiazepine; 1,1-dioxo-3,3 - dibutyl-5-phenyl-7-methylthio-8 - (N - {(R) -a- [N - ((S) -1- carboxybutyl) carbamoyl] -4-hydroxybenzyl ) carbamoylmethoxy) - 2,3,4,5-tetrahydro-1,2,5-benzothiadiazepine; 1,1-dioxo-3,3 - dibutyl-5-phenyl-7-methylthio-8- (N - {(R) -a- [N - ((S) -1- carboxypropyl) carbamoyl] benzyl} carbamoylmethoxy) -2,3,4,5-tetrahydro-1,2,5-benzothiadiazepine; 1,1-dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8- (N - {(R) -α- [N - ((S) -1-carboxyethyl) carbamoyl] benzyl} carbamoylmethoxy) -2,3,4,5-tetrahydro-1,2,5-benzothiadiazepine; 1,1-dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8- (N - {(R) -a- [N - ((S) -1-carboxy-2- (R) - hydroxypropyl) carbamoyl] benzyl} carbamoylmethoxy) -2,3,4,5-tetrahydro-1,2,5-benzothiadiazepine; 1,1-dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8- (N - {(R) -α- [N- (2-sulfoethyl) carbamoyl] -4-hydroxybenzyl} carbamoylmethoxy) - 2,3,4,5-tetrahydro-1,2,5-benzothiadiazepine, -1,1-dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8- (N - {(R) -α - [N - (((S) -1-carboxyethyl) carbamoyl] -4-hydroxybenzyl} carbamoylmethoxy) -2,3,4,5-tetrahydro-1,2,5-benzothiadiazepine; 1,1-dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8- (N- {(R) -ex- [N- ((R) -1-carboxy-2-methylthioethyl) carbamoyl] benzyl} carbamoylmethoxy) -2,3,4,5-tetrahydro-1,2,5-benzothiadiazepine; 1,1-dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8- (N - {(R) -α- [N - {(S) -1- [N - ((S) - 2-hydroxy-1-carboxyethyl) carbamoyl] propyl} carbamoyl] benzyl} carbamoylmethoxy) -2,3,4,5-tetrahydro-1,2,5-benzothiadiazepine; 1,1-dioxo-3,3-dibutyl-5-phenyl-7 - methylthio-8- (N - {(R) -α- [N - ((S) -1-carboxy-2-methylpropyl) carbamoyl] benzyl} carbamoylmethoxy) -2,3,4,5-tetrahydro-1,2,5-benzothiadiazepine; 1,1-dioxo-3,3-dibutyl-5-phenyl-7 - methylthio-8- (N - {(R) -α- [N - ((S) -1-carboxypropyl) carbamoyl] -4-hydroxybenzyl } carbamoylmethoxy) -2,3,4,5-tetrahydro-1,2,5-benzothiadiazepine; 1,1-dioxo-3,3-dibutyl-5-phenyl-7 - methylthio-8- [N - {(R) -a-carboxy4-hydroxybenzyl} carbamoylmethoxy] -2,3,4,5-tetrahydro-l , 2,5-benzothiadiazepine; or 1,1-dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8- (N- {((R) -α- [N- (carboxy) carbamoyl] benzyl} carbamoylmethoxy) -2,3, 4,5-tetrahydro-1,2,5-benzothiadiazepine; 1,1-dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8- (N - {(R) -1'-phenyl-1 '- [N' - (carboxy) carbamoyl] methyl} carbamoylmethoxy ) -2,3,4,5-tetrahydro-1,5-benzothiazepine; 1,1-dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8- (N - {(R) -α- [N '- ((S) -1-carboxypropyl) carbamoyl] -4- hydroxybenzyl} carbamoylmethoxy) -2,3,4,5-tetrahydro-1,5-benzothiazepine; 1,1-dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8- (N - {(R) -1'-phenyl-1 '- [N' - (carboxy) carbamoyl] methyl} carbamoylmethoxy ) -2,3,4,5-tetrahydro-1,5-benzothiazepine; 1,1-dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8- (N - {(R) -α- [N'- ((S) -1-carboxyethyl) carbamoyl] benzyl} carbamoylmethoxy ) - 2,3,4,5-tetrahydro-1,5-benzothiazepine; or a pharmaceutically acceptable salt thereof.
In certain embodiments, the methods provided here also comprise the administration of a second selected ursodiol agent, UDCA, cholestyramine / resins, antihistamines (e.g., hydroxyzine, diphenidamine), rifampin, nalaxone, Phenobarbital, dronabinol (CB1 agonist) ), methotrexate, corticosteroids, cyclosporine, colchicines, TPGS - vitamin A, D, E, or K optionally with polyethylene glycol, zinc, and a resin or scavenger for absorption of bile acids or an analog of these. In certain embodiments, the methods provided herein also include administering a second agent selected from a bile acid or salt with reduced toxicity or a hydrophilic bile acid such as ursodiol, norursodiol, ursodeoxycholic acid, chenodeoxycholic acid, cholic acid, taurocholic acid, ursocholic acid , glycocholic acid, glycodoxycholic acid, taurodeoxycholic acid, taurocholate, glycoquenodeoxycholic acid, or tauroursodeoxycholic acid.
In some embodiments, the dosage of an ASBTI is between about 1 gg / kg / day and about 10 mg / kg / day. In some embodiments, the dosage of an ASBTI is between about 5 pg / kg / day and about 1 mg / kg / day. In some embodiments, the dosage of an ASBTI is between about 10 pg / kg / day and about 300 pg / kg / day. In some embodiments, the dosage of an ASBTI is any dosage of about 14 pg / kg / day and about 280 pg / kg / day. In some embodiments, the dosage of an ASBTI is any dosage of about 14 pg / kg / day and about 140 pg / kg / day. In some embodiments, the dosage of an ASBTI is between about 5 pg / kg / day and about 200 pg / kg / day. In some embodiments, the dosage of an ASBTI is between about 10 pg / kg / day and about 200 pg / kg / day. In some embodiments, the dosage of an ASBTI is between about 10 pg / kg / day and about 175 pg / kg / day. In some embodiments, the dosage of an ASBTI is between about 10 Pg / kg / day and about 150 pg / kg / day. In some embodiments, the dosage of an ASBTI is between about 10 pg / kg / day and about 140 pg / kg / day. In some embodiments, the dosage of an ASBTI is between about 25 pg / kg / day and about 140 pg / kg / day. In some embodiments, the dosage of an ASBTI is between about 50 pg / kg / day and about 140 pg / kg / day. In some embodiments, the dosage of an ASBTI is between about 70 pg / kg / day and about 140 pg / kg / day. In some embodiments, the dosage of an ASBTI is between about 10 pg / kg / day and about 100 pg / kg / day. In some embodiments, the dosage of an ASBTI is 10 pg / kg / day. In some embodiments, the dosage of an ASBTI is 20 pg / kg / day. In some embodiments, the dosage of an ASBTI is 30 pg / kg / day. In some embodiments, the dosage of an ASBTI is 35 pg / kg / day. In some embodiments, the dosage of an ASBTI is 40 pg / kg / day. In some embodiments, the dosage of an ASBTI is 50 pg / kg / day. In some embodiments, the dosage of an ASBTI is 60 pg / kg / day. In some embodiments, the dosage of an ASBTI is 70 pg / kg / day. In some embodiments, the dosage of an ASBTI is 80 pg / kg / day. In some embodiments, the dosage of an ASBTI is 90 pg / kg / day. In some embodiments, the dosage of an ASBTI is 100 pg / kg / day. In some embodiments, the dosage of an ASBTI is 110 pg / kg / day. In some embodiments, the dosage of an ASBTI is 120 pg / kg / day. In some embodiments, the dosage of an ASBTI is 130 pg / kg / day. In some embodiments, the dosage of an ASBTI is 140 pg / kg / day. In some embodiments, the dosage of an ASBTI is 150 pg / kg / day. In some embodiments, the dosage of an ASBTI is 175 pg / kg / day.
In some embodiments, dosages of an ASBTI between 14 pg / kg / day and 140 pg / kg / day, or between 14 pg / kg / day and 280 pg / kg / day are provided here.
In some embodiments, the dosage of an ASBTI is between about 0.5 mg / day and about 40 mg / day. In some embodiments, the dosage of an ASBTI is between about 0.5 mg / day and about 30 mg / day. In some embodiments, the dosage of an ASBTI is between about 1 mg / day and about 20 mg / day. In some embodiments, the dosage of an ASBTI is between about 1 mg / day and about 10 mg / day. In some embodiments, the dosage of an ASBTI is between about 1 mg / day and about 5 mg / day. In some modalities, the dosage of an ASBTI is 1 mg / day. In some modalities, the dosage of an ASBTI is 5 mg / day. In some modalities, the dosage of an ASBTI is 10 mg / day. In some modalities, the dosage of an ASBTI is 20 mg / day. In some embodiments, the dosage of an ASBTI is between 0.5 mg / day and 5 mg / day. In some embodiments, the dosage of an ASBTI is between 0.5 mg / day and 4.5 mg / day. In some embodiments, the dosage of an ASBTI is between 0.5 mg / day and 4 mg / day. In some modalities, the dosage of an ASBTI is between 0.5 mg / day and 3.5 mg / day. In some embodiments, the dosage of an ASBTI is between 0.5 mg / day and 3 mg / day. In some embodiments, the dosage of an ASBTI is between 0.5 mg / day and 2.5 mg / day. In some embodiments, the dosage of an ASBTI is between 0.5 mg / day and 2 mg / day. In some embodiments, the dosage of an ASBTI is between 0.5 mg / day and 1.5 mg / day. In some embodiments, the dosage of an ASBTI is between 0.5 mg / day and 1 mg / day. In some modalities, the dosage of an ASBTI is between 1 mg / day and 4.5 mg / day. In some modalities, the dosage of an ASBTI is between 1 mg / day and 4 mg / day. In some modalities, the dosage of an ASBTI is between 1 mg / day and 3.5 mg / day. In some modalities, the dosage of an ASBTI is between 1 mg / day and 3 mg / day. In some embodiments, the dosage of an ASBTI is between 1 mg / day and 2.5 mg / day. In some modalities, the dosage of an ASBTI is between 1 mg / day and 2 mg / day. In some embodiments, the dosage of an ASBTI is 0.5 mg / day. In some modalities, the dosage of an ASBTI is 1 mg / day. In some modalities, the dosage of an ASBTI is 1.5 mg / day. In some modalities, the dosage of an ASBTI is 2 mg / day. In some embodiments, the dosage of an ASBTI is 2.5 mg / day. In some embodiments, the dosage of an ASBTI is 3 mg / day. In some embodiments, the dosage of an ASBTI is 3.5 mg / day. In some embodiments, the dosage of an ASBTI is 4 mg / day. In some embodiments, the dosage of an ASBTI is 4.5 mg / day. In some embodiments, the dosage of an ASBTI is 5 mg / day. In some embodiments, the pediatric dosage described herein is the dosage of the total composition administered.
In some embodiments, the dosage form comprises 0.5 mg of ASBTI. In some embodiments, the dosage form comprises 1 mg of ASBTI. In some embodiments, the dosage form comprises 2.5 mg of ASBTI. In some embodiments, the dosage form comprises 5 mg of ASBTI. In some embodiments, the dosage form comprises 10 mg of ASBTI. In some embodiments, the dosage form comprises 20 mg of ASBTI.
In certain modalities, the dosage of an ASBTI is given once a day. In some embodiments, the dosage of an ASBTI is given q.d. In some modalities, the dosage of an ASBTI is given once a day in the morning. In some modalities, the dosage of an ASBTI is given once a day in the afternoon. In some modalities, the dosage of an ASBTI is given once a day at night. In some modalities, the dosage of an ASBTI is given twice a day. In some embodiments, the dosage of an ASBTI is given b.i.d. In some modalities, the dosage of an ASBTI is given twice a day, in the morning and in the afternoon. In some modalities, the dosage of an ASBTI is given twice a day, in the morning and at night. In some modalities, the dosage of an ASBTI is given twice a day, in the morning and at night. In some modalities, the dosage of an ASBTI is given twice a day, in the afternoon and in the evening. In some modalities, the dosage of an ASBTI is given twice a day, in the afternoon and in the evening. In some modalities, the dosage of an ASBTI is given three times a day. In some embodiments, the dosage of an ASBTI is given t.i.d. In some modalities, the dosage of an ASBTI is given four times a day. In some embodiments, the dosage of an ASBTI is given q.i.d. In some modalities, the dosage of an ASBTI is given every four hours. In some embodiments, the dosage of an ASBTI is given q.q.h. In some modalities, the dosage of an ASBTI is given on alternate days. In some embodiments, the dosage of an ASBTI is given q.o.d. In some modalities, the dosage of an ASBTI is given three times a week. In some embodiments, the dosage of an ASBTI is given t.i.w. Dosage forms and forms (for example, oral or rectal dosage form) are provided in certain modalities for use in the treatment of hypercholemia and / or a cholestatic liver disease and / or itching, or for use in decreasing serum bile acid levels or hepatic levels of bile acid comprising a therapeutically effective amount of an ASBTI, or a pharmaceutically acceptable salt thereof, and a carrier. In some embodiments, the methods comprise the oral administration of a therapeutically effective amount of a minimally absorbed ASBTI, or a pharmaceutically acceptable salt thereof, to an individual in need thereof. In some embodiments, the methods comprise rectally administering a therapeutically effective amount of a minimally absorbed ASBTI, or a pharmaceutically acceptable salt thereof, to an individual in need thereof. In specific embodiments, the dosage form is an enteric formulation, a pH-sensitive release formulation of the ileum, or a suppository or other suitable form.
In some embodiments, the composition for use in the treatment of hypercholemia and / or a cholestatic liver disease or itching or decreased serum bile acid concentrations comprises at least one of a spreading agent or a wetting agent. In some embodiments, the composition comprises an absorption inhibitor. In some cases an absorption inhibitor is a mucoadhesive agent (for example, a mucoadhesive polymer). In certain embodiments, the mucoadhesive agent is selected from methyl cellulose, polycarbophil, polyvinylpyrrolidone, sodium carbonoxyl cellulose, and combinations thereof. In some embodiments, the enteroendocrine peptide-secreting-enhancing agent is covalently linked to the absorption inhibitor. In certain embodiments, the pharmaceutical composition comprises an enteric coating. In some embodiments, the composition for use in treating cholestasis, a cholestatic liver disease or itching described above comprises a carrier. In certain embodiments, the carrier is a carrier suitable for the rectum. In certain embodiments, any pharmaceutical composition described herein is formulated as a suppository, enema solution, rectal foam, or rectal gel. In some embodiments, any pharmaceutical composition described herein comprises an orally acceptable carrier.
In some embodiments, a pharmaceutical composition formulated for non-systemic ileal rectal or colonic release from the ASBTI is provided here.
In some cases, for any of the methods described above, administration of an ASBTI reduces intraenterocyte bile acids / salts to an individual in need. In some embodiments, the methods described herein reduce the accumulation of bile acids / salts in ileal enterocytes of an individual in need. In some cases, for any of the methods described above, administration of an ASBTI inhibits the transport of bile acids / salts from the ileum lumen to enterocytes of an individual in need thereof. In some cases, for any of the methods described above, administration of an ASBTI increases the ileal luminal bile acids / salts in an individual in need of it. In some cases, for any of the methods described above, administration of an ASBTI reduces damage to the intestinal (eg, ileal cells) or hepatocellular (eg, liver cells) architecture associated with hypercholemia and / or a cholestatic liver disease or acid elevated serum or liver bile in an individual in need of it. In some cases, for any of the methods described above, administration of an ASBTI regenerates the intestinal lining or liver cells that have been damaged by hypercholemia and / or cholestatic liver disease in an individual suffering from cholestatic liver disease.
In some embodiments, the methods described above also include the administration of a second selected agent of ursodiol, norursodiol, UDCA, ursodeoxycholic acid, chenodeoxycholic acid, cholic acid, cholic tauroacid, ursocholic acid, glycocholic acid, taurodeoxycholic acid, taurocholate, glycoquenodeoxycholic acid, tauroursodeoxycholic, cholestyramine / resins, antihistamine agents (eg, hydroxyzine, diphenidamine), rifampin, nalaxone, Phenobarbital, dronabinol (CB1 agonist), methotrexate, corticosteroids, cyclosporine, colchicines, TPGS-vitamin A, D, E, or K optionally with polyethylene glycol, zinc, a resin or scavenger for absorption of bile acids.
In some embodiments, methods are provided herein for the treatment of hypercholemia and / or cholestatic liver disease which comprises administering a therapeutically effective amount of a combination of an ASBTI and ursodiol to an individual in need thereof. In some embodiments, methods are provided herein for the treatment of hypercholemia and / or a cholestatic liver disease which comprises administering a therapeutically effective amount of a combination of an ASBTI and a resin or sequester to absorb bile acids to an individual in need of that. In some embodiments, an ASBTI is administered in combination with one or more agents selected from the group consisting of ursodiol, ursodeoxycholic acid, chenodeoxycholic acid, cholic acid, cholic tauro acid, ursocholic acid, glycocholic acid, glycodoxycholic acid, taurodeoxycholic acid, taurocolate, glycoquenodeoxycholic, tauroursodeoxycholic acid, UDCA, cholestyramine / resins, antihistamines (eg hydroxyzine, diphenidamine), rifampin, nalaxone, Phenobarbital, dronabinol (CB1 agonist), methotrexate, corticosteroids, cyclosporine, cyclosporine, mattresses D, E, or K optionally with polyethylene glycol, zinc, a resin or scavenger for absorption of bile acids.
In some modalities, ASBTI is administered orally. In some embodiments, ASBTI is administered as a pH-sensitive release formulation of the ileum that releases ASBTI to an individual's distal ileum, colon and / or rectum. In some embodiments, ASBTI is administered as an enterically coated formulation. In some embodiments, oral delivery of an ASBTI provided herein may include formulations, as are well known in the art, to provide sustained or sustained release of the drug to the gastrointestinal tract by any number of mechanisms. These include, without limitation, pH sensitive release of the dosage form based on the pH change of the small intestine, slow erosion of a tablet or capsule, retention in the stomach based on the physical properties of the formulation, bioadhesion of the dosage form to the lining of the mucosa intestinal tract, or enzymatic release of the active drug from the dosage form. The desired effect is the extension of the period of time for which the active drug molecule is released to the site of action (the ileum) by manipulation of the dosage form. Therefore, enteric-coated formulations and enteric-coated controlled release formulations are within the scope of the present invention. Suitable enteric coatings include cellulose acetate phthalate, polyvinylacetate phthalate, hydroxypropylmethylcellulose phthalate and anionic polymers of methacrylic acid and methyl ester of methacrylic acid.
In some modalities of the methods described above, ASBTI is administered before eating food. In some modalities of the methods described above, ASBTI is administered with or after food intake.
In some embodiments, the methods provided here also include administering vitamin supplements to compensate for reduced digestion of vitamins, in particular fat-soluble vitamins, in an individual with hypercholemia and / or cholestatic liver disease. In some embodiments, vitamin supplements comprise fat-soluble vitamins. In some embodiments, the fat-soluble vitamins are vitamin A, D, E, or K.
In some embodiments, the methods provided here also include administering vitamin supplements to compensate for reduced digestion of vitamins, in particular fat-soluble vitamins, in an individual suffering from itching. In some embodiments, vitamin supplements comprise fat-soluble vitamins. In some embodiments, the fat-soluble vitamins are vitamin A, D, E, or K.
In some embodiments, the methods provided here also include administering vitamin supplements to compensate for reduced digestion of vitamins, in particular fat-soluble vitamins, in an individual with high serum bile acid concentrations. In some embodiments, vitamin supplements comprise fat-soluble vitamins. In some embodiments, the fat-soluble vitamins are vitamin A, D, E, or K.
In some embodiments, the methods and compositions provided here also comprise the administration of a bile acid scavenger or ligand to reduce gastrointestinal side effects. In some embodiments, the methods include administering an unstable bile acid scavenger, where the unstable bile acid scavenger has a low affinity in the individual's colon or rectum for at least one bile acid. In some embodiments, an unstable bile acid scavenger provided here releases bile acid into a human's colon or rectum. In some embodiments, an unstable bile acid scavenger provided here does not sequester bile acid for secretion or elimination in the stool. In some embodiments, an unstable bile acid scavenger provided here is a non-systemic unstable bile acid scavenger. In some embodiments, the non-systemic unstable bile acid scavenger is less than 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 15%, 20% , 25%, 30%, 35%, 40%, 45% systemically absorbed. In some embodiments, the unstable bile acid scavenger is a modified lining or lining. In some embodiments, the unstable bile acid scavenger is a polycationic polymer or copolymer. In certain embodiments, the unstable bile acid scavenger is a polymer or copolymer that comprises one or more N-alkenyl-N-alkylamine residues; one or more residues of N, N, N-trialkyl-N- (N'-alkenylamino) alkyl-azanium; one or more residues of N, N, N-trialkyl-N-alkenyl-azanium; one or more alkenyl amine residues; cholestyramine, colestipol, or colesevelam or a combination of these.
In some embodiments, the methods provided here also comprise partial external biliary bypass (LDPE).
A kit comprising any composition described herein (for example, a pharmaceutical composition formulated for rectal administration) and a device for localized delivery to the rectum or colon is provided in some embodiments. In certain embodiments, the device is a syringe, bag, or pressurized container. Brief description of the drawings
FIGURE 1. Oral administration of 264W94 dose-dependently increased bile acids in the stool. Fecal bile acid concentrations were increased up to 6.5 times with an ED50 of 0.17 mg / kg, when compared to vehicle-treated rats. Fecal NEFA also increased slightly in rats treated with 264W94. Plasma bile acid concentrations were decreased dose-dependent in rats treated with 264W94.
FIGURE 2. Plasma bile acid levels of ZDF rats after administration of ascending doses of SC-435 and LUM002. Male ZDF rats (n = 4) were administered with vehicle, SC-435 (1, 10 or 30 mg / kg) or LUM002 (0.3, 1, 3, 10 or 30 mg / kg) by oral ingestion twice daily for 2 weeks. Plasma bile acid levels were determined at the end of the second week. The data are expressed as mean values ± SEM.
FIGURE 3. Analysis of serum bile acid (SBA) in healthy subjects after administration of multiple ascending oral doses of LUM001 a randomized, double-blind, placebo-controlled study. Data on the dosage groups of 0.5 (n = 16), 1.0 (n = 8), 2.5 (n = 8), 5.0 (n = 8) and 10 (n = 8) mg. At Iodia, blood was drawn for base SBA approximately 30 minutes before and after breakfast and 30 minutes after lunch and dinner. The samples were obtained on day 14.
FIGURE 4. Analysis of fecal bile acid in healthy subjects after administration of multiple ascending oral doses of LUM001 with a randomized, double-blind, placebo-controlled study. Fecal samples were collected for all panels except for the dose titration panel, 2.5 (2) and 5 mg (2), on Days 9 to 14 and 23 to 28.
FIGURE 5. Serum fasting bile acid levels and morning postprandial peak in children below 12 years of age. LUM001 was administered once daily (QD) in the morning for fourteen days. Placebo patients had an average fasting serum bile acid level of 8.6 p mol / 1 and a peak postprandial serum bile acid level of 11.9 pmol / 1. For patients treated with LUM001 the values were 6.5 pmol / 1 and 9.2, respectively, representing a decrease of 24% and 23%. Detailed description of the invention
Bile acids / salts play a critical role in the activation of digestive enzymes and solubilization of fat and fat-soluble vitamins and are involved in liver, biliary, and intestinal disease. Bile acids are synthesized in the liver via a multistep, multiorgan pathway. The hydroxyl groups are added to specific sites in the steroid structure, the double bond of the cholesterol B ring is reduced and the hydrocarbon chain is shortened by three carbon atoms resulting in a carboxyl group at the end of the chain. The most common bile acids are cholic acid and chenodeoxycholic acid (the "primary bile acids"). Before leaving hepatocytes and forming bile, bile acids are conjugated to glycine (to produce glycocholic acid or glycoquenodeoxycholic acid) or taurine (to produce taurocholic acid or taurochenodeoxycholic acid). Conjugated bile acids are called bile salts and their amphiphatic nature makes them more efficient detergents than bile acids. Bile salts, not bile acids, are found in bile.
Bile salts are excreted by hepatocytes in the canaliculi to form bile. The canaliculi drain into the right and left hepatic ducts and the bile flows into the gallbladder. Bile is released from the gallbladder and travels to the duodenum, where it contributes to fat metabolism and breakdown. The bile salts are reabsorbed in the terminal ileum and transported back to the liver through the portal vein. Bile salts often undergo multiple enterohepatic circulations before being excreted via faeces. A small percentage of bile salts can be reabsorbed in the proximal intestine by passive or carrier-mediated transport processes. Most of the bile salts are recovered in the distal ileum by an apically located sodium-dependent bile acid transporter referred to as the apical sodium-dependent bile acid transporter (ASBT). On the basolateral surface of the enterocyte, a truncated version of ASBT is involved in vector transfer of bile acids / salts in the portal circulation. The completion of enterohepatic circulation occurs on the basolateral surface of the hepatocyte through a transport process that is primarily mediated by a sodium-dependent bile acid transporter. Transport of intestinal bile acid plays a key role in the enterohepatic circulation of bile salts. The molecular analysis of this process has recently led to important advances in our understanding of the biology, physiology and pathophysiology of intestinal bile acid transport.
In the intestinal lumen, bile acid concentrations vary, with most reuptake occurring in the distal intestine. Bile acids / salts alter the growth of bacterial flora in the intestine. Certain compositions and methods that control bile acid concentrations in the intestinal lumen are described herein, thereby controlling hepatocellular damage caused by accumulation of bile acid in the liver.
In another aspect, the compositions and methods provided herein increase bile acid concentrations in the intestine. Increased concentrations of bile acids / salts stimulate the subsequent secretion of factors that protect and control the integrity of the intestine when it is damaged by hypercholemia and / or cholestatic liver disease (eg, cholestatic liver disease associated with pruritus, or a disease cholestatic liver disease associated with high serum bile acid concentrations or high liver bile acid concentrations).
In yet another aspect, the compositions and methods described herein have an advantage over systemically absorbed agents. The compositions and methods described herein use ASBT inhibitors that are not systemically absorbed. Thus, the compositions are effective without leaving the lumen of the intestine, thereby reducing any toxicity and / or side effects associated with systemic absorption.
In an additional aspect, the compositions and methods described herein stimulate the release of enteroendocrine hormones GLP-2 and PYY. Increased secretion of GLP-2 or PYY allows the prevention or treatment of hypercholemia and / or cholestatic liver disease (eg, cholestatic liver disease associated with pruritus, or cholestatic liver disease associated with elevated serum bile acid concentrations or concentrations hepatic bile acid levels) by controlling the adaptive process, attenuating intestinal damage, reducing bacterial translocation, inhibiting the release of free radical oxygen, inhibiting the production of pro-inflammatory cytokines, or any combination thereof.
The use of ASBT inhibitors or any recovering bile salt transporter that is active in the gastrointestinal (GI) tract for the treatment or amelioration of hypercholemia and / or a cholestatic liver disease (for example, a cholestatic liver disease associated with pruritus) is described herein. , or a cholestatic liver disease associated with high serum bile acid concentrations or high liver bile acid concentrations) in an individual in need of these. In certain embodiments, the use of ASBT inhibitors or any recovering bile salt transporter that is active in the gastrointestinal tract (GI) for the treatment or improvement of itching in an individual in need is described herein. In certain embodiments, the use of ASBT inhibitors or any bile salt recovery carrier that is active in the gastrointestinal tract (GI) to decrease serum bile acid concentrations or hepatic bile acid concentrations in an individual in need is described here. In certain embodiments, the methods provided herein comprise administering a therapeutically effective amount of an ASBT inhibitor (ASBTI) to an individual in need thereof. In some embodiments, such ASBT inhibitors are not systemically absorbed. In some of these modalities, such bile salt transport inhibitors include a portion or group that prevents, reduces or inhibits the systemic absorption of the compound in vivo. In some embodiments, a charged portion or group in the compounds prevents, reduces or inhibits the compounds from leaving the gastrointestinal tract and reduces the risk of side effects due to systemic absorption. In other embodiments, such ASBT inhibitors are systemically absorbed. In some modalities, the ASBTIs provided here are formulated for non-systemic release to the distal ileum. In some embodiments, an ASBTI is minimally absorbed. In some modalities, an ASBTI is administered systemically to the colon or rectum of an individual in need.
In certain embodiments, methods are provided herein for the treatment or prevention of a liver disease comprising non-systemic administration to the distal ileum of an individual in need thereof of a therapeutically effective amount of an ASBTI or a pharmaceutically acceptable salt thereof, wherein the liver disease is hepatitis A, hepatitis B, hepatitis C, non-alcoholic steatohepatitis (NASH), non-alcoholic fatty liver disease (NAFLD), hemochromatosis, Wilson's disease, ischemic hepatitis, liver inflammation, fibrosis, or a chronic liver disease. In some embodiments, such ASBT inhibitors are not systemically absorbed. In some of such embodiments, such bile salt transport inhibitors include a portion or group that prevents, reduces or inhibits the systemic absorption of the compound in vivo. In some embodiments, a charged portion or group in the compounds prevents, reduces or inhibits the compounds from leaving the gastrointestinal tract and reduces the risk of side effects due to systemic absorption. In other embodiments, such ASBT inhibitors are systemically absorbed. In some modalities, ASBTIs are formulated for non-systemic release to the distal ileum. In some embodiments, an ASBTI is minimally absorbed. In some modalities, an ASBTI is administered systemically to the colon or rectum of an individual in need.
In some modalities, less than 50%, less than 40%, less than 30%, less than 20%, less than 10%, less than 9%, less than 8%, less than 7%, less than 6%, less than 5%, less than 4%, less than 3%, less than 2%, or less than 1% of the ASBTI is systemically absorbed. In certain embodiments, ASBTIs described herein inhibit the recovery of bile salts by recovering bile acid salt carriers in the distal gastrointestinal tract (for example, the distal ileum, colon and / or rectum).
In some cases, inhibition of bile salt recycling results in higher concentrations of bile salts in the lumen of the distal gastrointestinal tract or portions thereof (for example, the distal small intestine and / or colon and / or rectum). As used herein, the distal gastrointestinal tract includes the region of the distal ileum to the anus. In some embodiments, the compounds described herein reduce intraenterocyte bile acids / salts or accumulate these. In some embodiments, the compounds described herein reduce the damage to the hepatocellular or intestinal architecture associated with cholestasis and / or a cholestatic liver disease. Mammalian microbiome, bile acid clusters and metabolic interactions
The integrated metabolism of bile acid clusters in the intestinal lumen leads to complex biochemical interactions between host and microbiome symbionts.
Bile acids / salts are synthesized from cholesterol in the liver by a coordinated multi-enzyme process and are crucial for the absorption of dietary fats and fat-soluble vitamins in the intestine. Bile acids / salts play a role in maintaining the function of the intestinal barrier to prevent intestinal bacterial overgrowth and translocation, as well as invasion of underlying tissues by enteric bacteria.
Under normal conditions (that is, when an individual does not suffer from hypercholemia and / or cholestatic liver disease), symbiotic intestinal microorganisms (microbiome) interact closely with the host's metabolism and are important health determinants. Several bacterial species in the intestine are able to modify and metabolize bile acids / salts and the intestinal flora affects systemic processes such as metabolism and inflammation.
Bile acids / salts have strong antimicrobial and antiviral effects - deficiency leads to bacterial overgrowth and increased disjugation, leading to less ileal resorption. In animals, the supply of conjugated bile acid abolishes bacterial overgrowth, decreases bacterial translocation to lymph nodes and reduces endotoxemia.
Therefore, the methods and compositions described herein allow the replacement, displacement, and / or redirection of acids / bile salts to different areas of the gastrointestinal tract thereby affecting (for example, inhibiting or delaying) the growth of microorganisms that may cause cholestasis associated with infection and / or cholestatic liver disease. Classes of cholestasis and cholestatic liver disease
As used herein, "cholestasis" means the disease or symptoms that comprise deficiency of bile formation and / or flow of bile. As used herein, "cholestatic liver disease" means a liver disease associated with cholestasis. Cholestatic liver diseases are often associated with jaundice, fatigue, and itching. Biomarkers of cholestatic liver disease include high serum bile acid concentrations, high serum alkaline phosphatase (AP), high gamma-glutamyltranspeptidase, high conjugated hyperbilirubinemia, and high serum cholesterol.
Cholestatic liver disease can be divided clinicopathologically into two main categories of obstructive cholestasis, often extrahepatic, and non-obstructive, or intrahepatic cholestasis. In the first, cholestasis results when the flow of bile is mechanically blocked, as by gallstones or tumor, or as in extrahepatic biliary atresia.
The posterior group that has non-obstructive intrahepatic cholestasis in turn in two main subgroups. In the first subgroup, cholestasis results when processes of bile secretion and modification, or synthesis of bile constituents, are secondarily suspended in hepatocellular lesions so severe that a non-specific deficiency of several functions, including those related to the formation of bile. In the second subgroup, no presumed cause of hepatocellular damage can be identified. Cholestasis in such patients appears to result when one of the steps in the secretion of bile or modification, or synthesis of constituents of bile, is constitutively damaged. Such cholestasis is considered primary.
Therefore, methods and compositions for stimulating epithelial proliferation and / or regenerating the intestinal lining and / or improving adaptive processes in the intestine in individuals with hypercholemia and / or cholestatic liver disease are provided herein. In some of such modalities, the methods comprise increasing concentrations of bile acid and / or concentrations of GLP-2 in the intestinal lumen.
Increased levels of bile acids, and elevated levels of AP (alkaline phosphatase), LAP (leukocyte alkaline phosphatase), gamma GT (gamma-glutamyl transpeptidase), and 5'-nucleotidase are biochemical hallmarks of cholestasis and cholestatic liver disease. Therefore, methods and compositions are provided here to stimulate epithelial proliferation and / or regeneration of the intestinal lining and / or improvement of adaptive processes in the intestine in individuals with hypercholemia, and elevated levels of AP (alkaline phosphatase), LAP (leukocyte alkaline phosphatase) , gamma GT (gamma-glutamyl transpeptidase or GGT), and / or 5'-nucleotidase. In some of these modalities, the methods comprise increasing concentrations of bile acid in the intestinal lumen. Also provided here are methods and compositions for the reduction of hypercholemia, and elevated levels of AP (alkaline phosphatase), LAP (leukocyte alkaline phosphatase), gamma GT (gamma-glutamyl transpeptidase), and 5'-nucleotidase that comprise load reduction of total bile acid by excretion of bile acid in the stool.
Itching is often associated with hypercholemia and cholestatic liver disease. Itching has been suggested to result from bile salts that act on peripheral afferent pain nerves. The degree of itching varies with the individual (that is, some individuals are more sensitive to high levels of bile acids / salts). The administration of agents that reduce serum bile acid concentrations has been shown to reduce itching in certain individuals. Therefore, methods and compositions for stimulating epithelial proliferation and / or regenerating the intestinal lining and / or improving adaptive processes in the intestine in individuals with pruritus are provided herein. In some of these modalities, the methods comprise increasing concentrations of bile acid in the intestinal lumen. Also provided herein are methods and compositions for the treatment of pruritus which comprises reducing the total bile acid load by excreting bile acid in the faeces.
Another symptom of hypercholemia and cholestatic liver disease is an increase in the serum concentration of conjugated bilirubin. Elevated serum concentrations of conjugated bilirubin result in jaundice and dark urine. The magnitude of the elevation is not diagnostically important since no relationship has been established between serum levels of conjugated bilirubin and the severity of hypercholemia and cholestatic liver disease. The conjugated bilirubin concentration rarely exceeds 30 mg / dl. Therefore, methods and compositions for stimulation of epithelial proliferation and / or regeneration of the intestinal lining and / or improvement of adaptive processes in the intestine in individuals with elevated serum concentrations of conjugated bilirubin are provided herein. In some of these modalities, the methods comprise increasing concentrations of bile acid in the intestinal lumen. Also provided herein are methods and compositions for the treatment of elevated serum concentrations of conjugated bilirubin which comprise the reduction of the total bile acid load by excretion of bile acid in the faeces.
Increased serum concentration of unconjugated bilirubin is also considered a diagnosis of hypercholemia and cholestatic liver disease. Portions of serum bilirubin and covalently bound to albumin (delta bilirubin or biliprotein). This fraction may account for a large proportion of total bilirubin in patients with cholestatic jaundice. The presence of large amounts of delta bilirubin indicates long-term cholestasis. Delta bilirubin in umbilical cord blood or blood of a newborn is indicative of cholestasis / cholestatic liver disease that precedes birth. Therefore, methods and compositions for stimulating epithelial proliferation and / or regenerating the intestinal lining and / or improving adaptive processes in the intestine in individuals with elevated serum concentrations of unconjugated bilirubin or delta bilirubin are provided herein. In some of these modalities, the methods comprise increasing concentrations of bile acid in the intestinal lumen. Also provided herein are methods and compositions for the treatment of elevated serum concentrations of unconjugated bilirubin and delta bilirubin which comprise the reduction of the total bile acid load by excretion of bile acid in the faeces.
Cholestasis and cholestatic liver disease result in hypercholemia. During metabolic cholestasis, hepatocytes retain bile salts. Bile salts are regurgitated from the hepatocyte into the serum, which results in an increase in the concentration of bile salts in the peripheral circulation. In addition, the uptake of bile salts that enter the liver in the blood of the portal vein is inefficient, which results in spillage of bile salts into the peripheral circulation. Therefore, methods and compositions for stimulating epithelial proliferation and / or regenerating the intestinal lining and / or improving adaptive processes in the intestine in individuals with hypercholemia are provided here. In some of these modalities, the methods comprise increasing concentrations of bile acid in the intestinal lumen. Also provided herein are methods and compositions for the treatment of hypercholemia which comprise reducing the total bile acid load by excreting bile acid in the stool.
Hyperlipidemia is characteristic of some, but not all cholestatic diseases. Serum cholesterol is elevated in cholestasis due to the decrease in circulating bile salts that contribute to cholesterol metabolism and degradation. Cholesterol retention is associated with an increase in the cholesterol content in the membrane and a reduction in membrane fluidity and membrane function. In addition, since bile salts are the metabolic products of cholesterol, the reduction in cholesterol metabolism results in a decrease in bile acid / salt synthesis. The serum cholesterol observed in children with cholestasis ranges from about 1,000 mg / dl to about 4,000 mg / dl. Therefore, methods and compositions for stimulating epithelial proliferation and / or regenerating the intestinal lining and / or improving adaptive processes in the intestine in individuals with hyperlipidemia are provided here. In some of these modalities, the methods comprise increasing concentrations of bile acid in the intestinal lumen. Also provided herein are methods and compositions for the treatment of hyperlipidemia that comprise reducing the total bile acid load by excreting bile acid in the stool.
In individuals with hypercholemia and cholestatic liver diseases, xanthomas develops from the deposit of excess circulating cholesterol in the dermis. The development of xanthomas is more characteristic of obstructive cholestasis than hepatocellular cholestasis. Flat xanthomas occur first around the eyes and then in the folds of the palms and plants, followed by the neck. Tuberous xanthomas are associated with chronic and long-lasting cholestasis. Therefore, methods and compositions for stimulating epithelial proliferation and / or regenerating the intestinal lining and / or improving adaptive processes in the intestine in individuals with xanthomas are provided herein. In some of these modalities, the methods comprise increasing concentrations of bile acid in the intestinal lumen. Also provided herein are methods and compositions for the treatment of xanthomas that comprise reducing the total bile acid load by excreting bile acid in the faeces.
In children with chronic cholestasis, one of the main consequences of hypercholemia and cholestatic liver disease is developmental failure. Developmental failure is a consequence of reduced release of bile salts into the intestine, which contributes to inefficient digestion and fat absorption, and reduced uptake of vitamins (vitamins E, D, K, and A are all malabsorpted in cholestasis). In addition, the release of fat into the colon can result in colonic secretion and diarrhea. The treatment of developmental failure involves dietary substitution and supplementation with long chain triglycerides, medium chain triglycerides, and vitamins. Ursodeoxycholic acid, which is used to treat some cholestatic conditions, does not form mixed micelles and has no effect on fat absorption. Therefore, methods and compositions for stimulating epithelial proliferation and / or regenerating the intestinal lining and / or improving adaptive processes in the intestine in individuals (e.g., children) with developmental failure are provided here. In some of these modalities, the methods comprise increasing concentrations of bile acid in the intestinal lumen. Also provided herein are methods and compositions for treating developmental failure that comprise reducing the total bile acid load by excreting bile acid in the stool.
Symptoms of hypercholemia and cholestatic liver disease have been treated with choleretic agents (eg, ursodiol), phenobarbitols, corticosteroids (eg, prednisone and budesonide), immunosuppressive agents (eg, azathioprine, cyclosporine A, methotrexate, chlorambucil and mycophenolate) , sulindac, bezafibrate, tamoxifen, and lamivudine. Therefore, in some embodiments, any of the methods disclosed herein also comprise the administration of an additional active agent selected from: choleretic agents (eg, ursodiol), phenobarbitols, corticosteroids (eg, prednisone and budesonide), immunosuppressive agents (eg , azathioprine, cyclosporine A, methotrexate, chlorambucil and mycophenolate), sulindac, bezafibrate, tamoxifen, lamivudine, and combinations thereof. In some embodiments, the methods are used to treat individuals who are not responsive to treatment with choleretic agents (eg, ursodiol), phenobarbitols, corticosteroids (eg, prednisone and budesonide), immunosuppressive agents (eg, azathioprine, cyclosporine A, methotrexate, chlorambucil and mycophenolate), sulindac, bezafibrate, tamoxifen, lamivudine, and combinations thereof. In some modalities, the methods are used to treat individuals who are not responsive to treatment with choleretic agents. In some modalities, the methods are used to treat individuals who are unresponsive to ursodiol treatment. Primary biliary cirrhosis (PBC)
Primary biliary cirrhosis is an autoimmune disease of the liver characterized by the destruction of bile ducts. Damage to the bile ducts results in the accumulation of bile in the liver (ie cholestasis). Retention of bile in the liver damages liver tissue and can lead to scarring, fibrosis, and cirrhosis. PBC commonly presents in adults (for example, ages 40 and over). Individuals with PBC often present with fatigue, itching, and / or jaundice. PBC is diagnosed if the individual has high concentrations of AP for at least 6 months, high levels of gammaGT, antimitochondrial antibodies (AMA) in the serum (> 1:40), and red bile duct lesions. Serum ALT and AST and conjugated bilirubin may also be elevated, but these are not considered to be diagnostic. Cholestasis associated with PBC has been treated or improved by administration of ursodeoxycholic acid (UDCA or Ursodiol). Corticosteroids (eg, prednisone and budesonide) and immunosuppressive agents (eg, azathioprine, cyclosporine A, methotrexate, chlorambucil and mycophenolate) have been used to treat cholestasis associated with PBC. Sulindac, bezafibrate, tamoxifen, and lamivudine are also used to treat or ameliorate the cholestasis associated with PBC.
Methods of treating primary biliary cirrhosis in an individual in need thereof are disclosed herein in certain embodiments, comprising the non-systemic administration of a therapeutically effective amount of an apical sodium-dependent bile acid transporter inhibitor (ASBTI) or a salt pharmaceutically acceptable thereto. In some embodiments, such ASBT inhibitors are not systemically absorbed. In some of such embodiments, such bile salt transport inhibitors include a portion or group that prevents, reduces or inhibits the systemic absorption of the compound in vivo. In some embodiments, a charged portion or group in the compounds prevents, reduces or inhibits the compounds from leaving the gastrointestinal tract and reduces the risk of side effects due to systemic absorption. In other embodiments, such ASBT inhibitors are systemically absorbed. In some modalities, ASBTIs are formulated for non-systemic release to the distal ileum. In some embodiments, an ASBTI is minimally absorbed. In some modalities, an ASBTI is administered systemically to the colon or rectum of an individual in need. In some embodiments, the methods also include administering a therapeutically effective amount of a secondary bile acid (eg, ursodiol), a corticosteroid (eg, prednisone and budesonide), an immunosuppressive agent (eg, azathioprine, cyclosporine A, methotrexate, chlorambucil and mycophenolate), sulindac, bezafibrate, tamoxifen, lamivudine or any combination of these. Progressive familial intrahepatic cholestasis (PFIC) PFIC 1
PFIC 1 (also known as, Biler's disease or FIC1 deficiency) is associated with mutations in the ATP8B1 gene (also known as FIC1). This gene, which encodes a type P ATPase, is located on human chromosome 18 and is also mutated in the milder phenotype, benign recurrent type 1 intra-hepatic cholestasis (BRIC1) and in familial Greenland cholestasis. The FIC1 protein is located on the hepatocyte canalicular membrane but in the liver it is mainly expressed in cholangiocytes. Type P ATPase appears to be an aminophospholipid transporter responsible for maintaining the enrichment of phosphatidylserine and phosphatidylethanolamine in the inner leaflet of the plasma membrane compared to the outer leaflet. The asymmetric distribution of lipids in the membrane bilayer has a protective role against high concentrations of bile salt in the lumen of the canaliculi. The abnormal function of the protein can indirectly disrupt bile acid secretion. Anomalous secretion of bile acids / salts leads to hepatocyte bile acid overload.
PFIC-1 typically presents in babies (for example, ages 6-18 months). Babies may show signs of itching, jaundice, bloating, diarrhea, malnutrition, and short stature. Biochemically, individuals with PFIC-1 have elevated serum transaminases, elevated bilirubin, elevated serum bile acid levels, and low gammaGT levels. The individual may also have liver fibrosis. Individuals with PFIC-1 typically do not have bile duct proliferation. Most individuals with PFIC-1 will develop end-stage liver disease by the age of 10. No medical treatments have been shown to be beneficial for the long-term treatment of PFIC-1. To reduce extrahepatic symptoms (for example, malnutrition and failure to develop), children are often given medium-chain triglycerides and fat-soluble vitamins. Ursodiol has not been shown to be effective in individuals with PFIC-1.
Methods of treating PFIC-1 in an individual in need thereof are disclosed herein in certain embodiments comprising the non-systemic administration of a therapeutically effective amount of an ASBTI or a pharmaceutically acceptable salt thereof. In some embodiments, such ASBT inhibitors are not systemically absorbed. In some of such embodiments, such bile salt transport inhibitors include a portion or group that prevents, reduces or inhibits the systemic absorption of the compound in vivo. In some embodiments, a charged portion or group in the compounds prevents, reduces or inhibits the compounds from leaving the gastrointestinal tract and reduces the risk of side effects due to systemic absorption. In other embodiments, such ASBT inhibitors are systemically absorbed. In some modalities, ASBTIs are formulated for non-systemic release to the distal ileum. In some embodiments, an ASBTI is minimally absorbed. In some modalities, an ASBTI is administered systemically to the colon or rectum of an individual in need. In some embodiments, the methods also include administering a therapeutically effective amount of a secondary bile acid (eg, ursodiol), a corticosteroid (eg, prednisone and budesonide), an immunosuppressive agent (eg, azathioprine, cyclosporine A, methotrexate, chlorambucil and mycophenolate), sulindac, bezafibrate, tamoxifen, lamivudine or any combination of these. PFIC 2
PFIC 2 (also known as Biler syndrome or BSEP deficiency) is associated with mutations in the ABCB11 gene (also called BSEP). The ABCB11 gene encodes the ATP-dependent canalicular bile salt export pump (BSEP) of the human liver and is located on human chromosome 2. The BSEP protein, expressed on the hepatocyte canalicular membrane, is the main acid / salt exporter primary bile ducts against extreme concentration gradients. Mutations in this protein are responsible for the decreased secretion of bile bile salt described in affected patients, which leads to decreased bile flow and accumulation of bile salts inside the hepatocyte with severe progressive hepatocellular damage.
PFIC-2 typically occurs in infants (for example, 6-18 months). Babies may show signs of itching. Biochemically, individuals with PFIC-2 have elevated serum transaminases, elevated bilirubin, elevated serum bile acid levels, and low gammaGT levels. The individual may also have portal inflammation and giant cell hepatitis. In addition, individuals often develop hepatocellular carcinoma. No medical treatment has been shown to be beneficial for the long-term treatment of PFIC-1. To reduce extrahepatic symptoms (eg, malnutrition and developmental failure), children are often given medium-chain triglycerides and fat-soluble vitamins. Ursodiol has not been shown to be effective in individuals with PFIC-2,
Methods of treating PFIC-2 in an individual in need thereof are disclosed herein in certain embodiments comprising the non-systemic administration of a therapeutically effective amount of an ASBTI or a pharmaceutically acceptable salt thereof. In some embodiments, such ASBT inhibitors are not systemically absorbed. In some of such embodiments, such bile salt transport inhibitors include a portion or group that prevents, reduces or inhibits the systemic absorption of the compound in vivo. In some embodiments, a charged portion or group in the compounds prevents, reduces or inhibits the compounds from leaving the gastrointestinal tract and reduces the risk of side effects due to systemic absorption. In other embodiments, such ASBT inhibitors are systemically absorbed. In some modalities, ASBTIs are formulated for non-systemic release to the distal ileum. In some embodiments, an ASBTI is minimally absorbed. In some modalities, an ASBTI is administered systemically to the colon or rectum of an individual in need. In some embodiments, the methods also comprise administering a therapeutically effective amount of a secondary bile acid (eg, ursodiol), a corticosteroid (eg, prednisone and budesonide), an immunosuppressive agent (eg, azathioprine, cyclosporine A, methotrexate, chlorambucil and mycophenolate), sulindac, bezafibrate, tamoxifen, lamivudine or any combination of these. PFIC 3
PFIC3 (also known as MDR3 deficiency) is caused by a genetic defect in the ABCB4 gene (also referred to as MDR3) located on chromosome 7. P-glycoprotein (P-gp) class III multidrug resistance (MDR3), is a translocator phospholipid involved in the secretion of bile phospholipid (phosphatidylcholine) in the hepatocyte canalicular membrane. PFIC3 results from bile toxicity in which detergent bile salts are not inactivated by phospholipids, leading to damage to the bile ducts and bile epithelium.
PFIC-3 also appears in childhood. In contrast to PFIC-1 and PFIC-2, individuals have high levels of gammaGT. Individuals also have portal inflammation, fibrosis, cirrhosis, and massive bile duct proliferation. Individuals can also develop intrahepatic cholelithiasis. Ursodiol has been effective in treating or improving PFIC-3.
Methods of treating PFIC-3 in an individual in need thereof are disclosed herein in certain embodiments comprising the non-systemic administration of a therapeutically effective amount of an ASBTI or a pharmaceutically acceptable salt thereof. In some embodiments, such ASBT inhibitors are not systemically absorbed. In some of such embodiments, such bile salt transport inhibitors include a portion or group that prevents, reduces or inhibits the systemic absorption of the compound in vivo. In some embodiments, a charged portion or group in the compounds prevents, reduces or inhibits the compounds from leaving the gastrointestinal tract and reduces the risk of side effects due to systemic absorption. In other embodiments, such ASBT inhibitors are systemically absorbed. In some modalities, ASBTIs are formulated for non-systemic release to the distal ileum. In some embodiments, an ASBTI is minimally absorbed. In some modalities, an ASBTI is administered systemically to the colon or rectum of an individual in need. In some embodiments, the methods also comprise administering a therapeutically effective amount of a secondary bile acid (eg, ursodiol), a corticosteroid (eg, prednisone and budesonide), an immunosuppressive agent (eg, azathioprine, cyclosporine A, methotrexate, chlorambucil and mycophenolate), sulindac, bezafibrate, tamoxifen, lamivudine or any combination of these. Benign recurrent intrahepatic cholestasis (BRIC) BRIC 1
BRIC1 is caused by a genetic defect of the FIC1 protein in the hepatocyte canalicular membrane. BRIC1 is typically associated with normal serum cholesterol and Y_glutamyltranspeptidase levels, but elevated serum bile salts. The expression and function of residual FIC1 is associated with BRIC1. Despite recurrent attacks of cholestasis or cholestatic liver disease, there is no progression to chronic liver disease in most patients. During attacks, patients are severely jaundiced and have itching, steatorrhea, and weight loss. Some patients also have kidney stones, pancreatitis, and diabetes. BRIC 2
BRIC2 is caused by mutations in ABCB11, which lead to defective BSEP expression and / or function in the hepatocyte canalicular membrane. BRIC 3
BRIC3 is related to the expression and / or defective function of MDR3 in the hepatocyte canalicular membrane. Patients with MDR3 deficiency commonly have elevated serum levels of y-glutamyltranspeptidase in the presence of normal or slightly elevated levels of bile acid. Dubin-Johnson syndrome (DJS)
DJS is characterized by conjugated hyperbilirubinaemia due to dysfunction inherited from MRP2. Liver function is preserved in affected patients. Several different mutations have been associated with this condition, resulting in the complete absence of immunohistochemically detectable MRP2 in affected patients or impaired protein maturation and classification. Acquired cholestatic disease Primary biliary cirrhosis (PBC)
PBC is a chronic inflammatory liver disorder that progresses slowly to end-stage hepatocellular failure in most affected patients. In PBC, the inflammatory process predominantly affects small bile ducts. Primary sclerosing cholangitis (PSC)
PSC is a chronic inflammatory liver disorder that progresses slowly to end-stage hepatocellular failure in most affected patients. In PSC, inflammation, fibrosis and obstruction of large and medium-sized intra- and extra-hepatic ducts are predominant. Intrahepatic cholestasis of pregnancy (PCI)
PCI is characterized by the occurrence of transient cholestasis or cholestatic liver disease in pregnant women that typically occurs in the third trimester of pregnancy, when circulating estrogen levels are high. PCI is associated with biochemical itching and cholestasis or cholestatic liver disease of varying severity and constitutes a risk factor for intrauterine prematurity and fetal death. A genetic predisposition has been suspected based on strong regional grouping, the highest prevalence in female family members of patients with PCI and the susceptibility of patients with PCI to develop intrahepatic cholestasis or cholestatic liver disease under other hormonal loads such as oral contraception . In a heterogeneous state, an MDR3 gene defect may represent a genetic predisposition. Gallstones disease
Gallstone disease is one of the most common and costly of all digestive diseases with a prevalence of up to 17% in Caucasian women. Gallstones that contain cholesterol are the main form of gallstones and supersaturation of bile with cholesterol is therefore a prerequisite for the formation of gallstones. ABCB4 mutations may be involved in the pathogenesis of cholesterol cholelithiasis. Drug-induced cholestasis
Inhibition of BSEP function by drugs is an important mechanism of drug-induced cholestasis, which leads to hepatic accumulation of bile salts and subsequent damage to the liver cell. Several drugs have been involved in BSEP inhibition. Most of these drugs, such as rifampicin, cyclosporine, glibenclamide, or cis-troglitazone directly inhibit the transport of ATP-dependent taurocholate in a competitive manner, while estrogen and progesterone metabolites indirectly trans-inhibit Bsep after secretion into bile ducts by Mrp2. Alternatively, drug-mediated stimulation of MRP2 can promote cholestasis or cholestatic liver disease by altering the composition of bile. Cholestasis associated with total parenteral nutrition
TPNAC is one of the most serious clinical scenarios in which cholestasis or cholestatic liver disease occurs quickly and is highly linked with early death. Babies, who are commonly premature and have undergone intestinal resection, are dependent on TPN for growth and often develop cholestasis or cholestatic liver disease that progresses rapidly to fibrosis, cirrhosis, and portal hypertension, commonly before 6 months of life. The degree of cholestasis or cholestatic liver disease and chance of survival in these babies has been linked to the number of septic episodes, probably started by recurrent bacterial translocation through their intestinal mucosa. Although there are also cholestatic effects of the intravenous formulation in these babies, septic mediators are likely to contribute the most to the impaired liver function. Alagille syndrome
Alagille syndrome is a genetic disorder that affects the liver and other organs. It presents frequently during childhood (for example, 6-18 months) throughout childhood (for example, 3-5 years of age) and can stabilize after 10 years of age. Symptoms may include chronic progressive cholestasis, ductopenia, jaundice, pruritus, xanthomas, congenital heart problems, shortage of intrahepatic bile ducts, poor linear growth, hormonal resistance, posterior embryotoxon, Axenfeld anomaly, pigmented retinitis, pupil abnormalities, cardiac murmur , atrial septal defect, ventricular septal defect, patent ductus arteriosus, and Tetralogy of Fallot. Individuals diagnosed with Alagille syndrome have been treated with ursodiol, hydroxyzine, cholestyramine, rifampicin, and phenobarbitol. Due to the reduced ability to absorb fat-soluble vitamins, individuals with Alagille syndrome are also given high doses of multivitamins.
Methods of treating Alagille syndrome in an individual in need thereof are disclosed herein in certain embodiments comprising the non-systemic administration of a therapeutically effective amount of an ASBTI or a pharmaceutically acceptable salt thereof. In some embodiments, such ASBT inhibitors are not systemically absorbed. In some of such embodiments, such bile salt transport inhibitors include a portion or group that prevents, reduces or inhibits the systemic absorption of the compound in vivo. In some embodiments, a charged portion or group in the compounds prevents, reduces or inhibits the compounds from leaving the gastrointestinal tract and reduces the risk of side effects due to systemic absorption. In other embodiments, such ASBT inhibitors are systemically absorbed. In some modalities, ASBTIs are formulated for non-systemic release to the distal ileum. In some embodiments, an ASBTI is minimally absorbed. In some modalities, an ASBTI is administered systemically to the colon or rectum of an individual in need. In some embodiments, the methods also include administering a therapeutically effective amount of a secondary bile acid (eg, ursodiol), a corticosteroid (eg, prednisone and budesonide), an immunosuppressive agent (eg, azathioprine, cyclosporine A, methotrexate, chlorambucil and mycophenolate), sulindac, bezafibrate, tamoxifen, lamivudine or any combination of these. Biliary atresia
Biliary atresia is a life-threatening condition in babies in which the bile ducts inside or outside the liver do not have normal openings. With biliary atresia, bile becomes trapped, accumulates, and damages the liver. The damage leads to scarring, loss of liver tissue, and cirrhosis. Without treatment, the liver ultimately fails, and the baby needs a liver transplant to stay alive. The two types of biliary atresia are fetal and perinatal. Fetal biliary atresia arises while the baby is in the womb. Perinatal biliary atresia is much more common and does not become evident until 2 to 4 weeks after birth. Post-Kasai biliary atresia
Biliary atresia is treated with surgery called a Kasai procedure or a liver transplant. The Kasai procedure is commonly the first treatment for biliary atresia. During a Kasai procedure, the pediatric surgeon removes the baby's damaged bile ducts and pulls an intestinal loop to replace it. Although the Kasai procedure can restore the flow of bile and correct various problems caused by biliary atresia, surgery does not cure biliary atresia. If the Kasai procedure is unsuccessful, babies commonly need a liver transplant in 1 to 2 years. Even after successful surgery, most babies with biliary atresia slowly develop cirrhosis over the years and require a liver transplant in adulthood. Possible complications after the Kasai procedure include ascites, bacterial cholangitis, portal hypertension, and itching. Biliary atresia after liver transplantation
If atresia is complete, liver transplantation is the [only option. Although liver transplantation is generally successful in treating biliary atresia, liver transplantation can have complications such as organ rejection. In addition, a donated liver may not be available. Also, in some patients, liver transplantation may not be successful in curing biliary atresia. Xanthoma
Xanthoma is a skin condition associated with cholestatic liver disease, in which certain fats accumulate under the surface of the skin. Cholestasis results in various disorders of lipid metabolism resulting in the formation of an abnormal lipid particle in the blood called lipoprotein X. Lipoprotein X is formed by regurgitation of bile lipids in the liver's blood and does not bind to the LDL receptor to release cholesterol at cells through the body as normal LDL does. Lipoprotein X increases liver cholesterol production fivefold and blocks the normal removal of lipoprotein particles from the blood by the liver. Compounds
In some embodiments, ASBT inhibitors are provided here that reduce or inhibit the recycling of bile acid in the distal gastrointestinal (GI) tract, including the distal ileum, colon and / or rectum. In certain embodiments, ASBTIs are systemically absorbed. In certain embodiments, ASBTIs are not systemically absorbed. In some embodiments, the SBTIs described here are modified or replaced (for example, with an L-K-group) to be non-systemic. In certain embodiments, any ASBT inhibitor is modified or replaced with one or more charged groups (for example, K) and optionally, one or more ligands (for example, L), where L and K are as defined herein.
In some embodiments, an ASBTI suitable for the methods described here is a compound of Formula I:
wherein: R1 is a straight-chain C1-6 alkyl group; R2 is a straight-chain C1-6 alkyl group; R3 is hydrogen or an OR11 group in which R11 is hydrogen, optionally substituted C1-6 alkyl or or a C1-6 alkylcarbonyl group; R4 is pyridyl or optionally substituted phenyl or - Lz-Kz; where z is 1, 2 or 3; each L is independently substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted alkoxy, substituted or unsubstituted aminolaalkyl group, substituted or unsubstituted aryl group, substituted or unsubstituted heteroaryl group, one substituted or unsubstituted cycloalkyl, or substituted or unsubstituted heterocycloalkyl; each K is a portion that prevents systemic absorption; R5, R6, R7 and R8 are the same or different and each is selected from hydrogen, halogen, cyano, R5-acetylide, OR15, optionally substituted C1-6 alkyl, COR15, CH (OH) R15, S (O) nR15 , P (O) (OR15) 2, OCOR15, OCRs, OCN, SCN, NHCN, CH2OR15, CHO, (CH2) PCN, CONR12R13, (CH2) pCO2R15, (CH2) pNR12R13, CO2R15, NHCOCF3, NHSO2R15, OCH2OR15, OCH2OR15, OCH = CHR15, O (CH2CH2O) nR15, O (CH2) PSO3R15, O (CH2) PNR12R13, O (CH2) pN + R12R13R14 and -W-R31, where W is O or NH and R31 is selected from
where p is an integer from 1-4, n is an integer from 0-3 and, R12, R13, R14 and R15 are independently selected from hydrogen and optionally substituted C1-6 alkyl; or R6 and R7 are linked to form a group
where R12 and R13 are as previously defined in is 1 or 2; and R9 and R10 are the same or different and each is selected from hydrogen or C1-6 alkyl; and salts, solvates and physiologically functional derivatives thereof. In some embodiments of the methods described herein, the compound of Formula I is a compound wherein R1 is a straight-chain C1-6 alkyl group; R2 is a straight-chain C1-6 alkyl group; R3 is hydrogen or an OR11 group where R11 is hydrogen, optionally substituted C1-6 alkyl or a C1-6 alkylcarbonyl group; R4 is optionally substituted phenyl; O, 0HR5, R6 and R8 are independently selected from hydrogen, C1-4 alkyl optionally substituted by fluorine, C1-4 alkoxy, halogen, or hydroxy; R7 is selected from halogen, cyano, R15-acetylide, OR15, C1-6 alkyl optionally substituted, COR15, CH (OH) R15, S (O) nR15, P (0) (OR15) 2, OCOR15, OCF3, OCN, SCN, HNCN, CH2OR15, CHO, (CH2) PCN, CONR12R13, (CH2) pCO2R15, (CH2) PNR12R13, CO2R15, NHCOCF3, NHSO2R15, OCH2OR15, OCH = CHR15, O (CH2CH2O) pR15, 0 (CH2) PSO3R15 (CH2) PNR12R13 and 0 (CH2) PN + R12R13R14; where n, p and R to R are as previously defined; with the proviso that at least two of R5 to R8 are not hydrogen; and solvate salts and physiologically functional derivatives thereof.
In some embodiments of the methods described herein, the compound of Formula I is a compound wherein R1 is a straight-chain C1-6 alkyl group; R is a straight chain C1-6 alkyl group; R3 is hydrogen or an OR11 group where R11 is hydrogen, optionally substituted C1-6 alkyl or a C1-6 alkylcarbonyl group; R4 is unsubstituted phenyl; R5 is hydrogen or halogen; R6 and R8 are independently selected from hydrogen, C1-4 alkyl optionally substituted by fluorine, C1-4 alkoxy, halogen, or hydroxy; R7 is selected from OR15, S (O) nR15, OCOR15, OCF3, OCN, SCN, CHO, OCH2OR15, OCH = CHR15, 0 (CH2CH2O) nR15, 0 (CH2) PSO3R15, 0 (CH2) pNR12R13 and O (CH2) PN + R12R13R14 where p is an integer from 1-4, n is an integer from 0-3, and R12, R13, R14, and R15 are independently selected from hydrogen and optionally substituted C1-6 alkyl; R9 and R10 are the same or different and each is selected from hydrogen or C1-6 alkyl; and salts, solvates and physiologically functional derivatives thereof. In some embodiments of the methods, wherein the compound of Formula I is a compound in which R1 is methyl, ethyl or n-propyl; R2 is methyl, ethyl, n-propyl, n-butyl or n-pentyl; R3 is hydrogen or an OR11 group where R11 is hydrogen, optionally substituted C1-6 alkyl or a C1-6 alkylcarbonyl group; R4 is unsubstituted phenyl; R5 is hydrogen; R and R are independently selected from hydrogen, C1-4 alkyl optionally substituted by fluorine, C1-4 alkoxy, halogen, or hydroxy; R7 is selected from OR15, S (O) nR15, OCOR15, OCF3, OCN, SCN, CHO, OCH2OR15, OCH = CHR15, 0 (CH2CH2O) nR15, 0 (CH2) PSO3R15, O (CH2) PN R12R13 and 0 (CH2 ) PN + R12R13R14 where p is an integer from 1-4, n is an integer from 0-3, and R12, R13, R14, and R15 are independently selected from hydrogen and optionally substituted C1-6 alkyl; R9 and R10 are the same or different and each is selected from hydrogen or C1-6 alkyl; and salts, solvates and physiologically functional derivatives thereof. In some method embodiments, the compound of Formula I is a compound in which R1 is methyl, ethyl or n-propyl; R2 is methyl, ethyl, n-propyl, n-butyl or n-pentyl; R3 is hydrogen or an OR11 group where R11 is hydrogen, optionally substituted C1-6 alkyl or a C1-6 alkylcarbonyl group; R4 is unsubstituted phenyl; R5 is hydrogen; R6 is C1-4 alkoxy, halogen, or hydroxy; R7 is OR15, where R15 is hydrogen or optionally substituted C1-6 alkyl; R8 is hydrogen or halogen; R9 and R10 are the same or different and each is selected from hydrogen or C1-6 alkyl; and salts, solvates and physiologically functional derivatives thereof.
In some method embodiments, the compound of Formula I is (3R, 5R) -3-Butyl-3-ethyl-2,3,4,5-tetrahydro-7,8-dimethoxy-5-phenyl-1,4- benzothiazepine 1,1-dioxide; (3R, 5R) -3-Butyl-3-ethyl-2,3,4,5-tetrahydro-7,8-dimethoxy-5-phenyl-1,4-benzothiazepin-4-ol 1,1-dioxide; (±) -Trans-3-butyl-3-ethyl-2,3,4,5-tetrahydro-7,8-dimethoxy-5-phenyl-1,4-benzothiazepine 1,1-dioxide; (±) -Trans-3-butyl-3-ethyl-2,3,4,5-tetrahydro-7,8-dimethoxy-5-phenyl-1,4, -benzothiazepin-4-ol 1,1-dioxide; (3R, 5R) -7-Bromo-3-butyl-3-ethyl-2,3,4,5-tetrahydro-8-methoxy-5-phenyl-1,4-benzothiazepine 1,1-dioxide; (3R, 5R) -7-Bromo-3-butyl-3-ethyl-2,3,4,5-tetrahydro-8-methoxy-5-phenyl-1,4-benxothiaxepin-4-ol 1,1-dioxide ; (3R, 5R) -3-Butyl-3-ethyl-2,3,4,5-tetrahydro-5-phenyl-1,4-benzothiazepine-7,8-diol 1,1-dioxide; (3R, 5R) -3-Butyl-3-ethyl-2,3,4,5-tetrahydro-8-methoxy-5-phenyl-1,4-benzothiazepin-7-ol 1,1-dioxide; (3R, 5R) -3-Butyl-3-ethyl-2,3,4,5-tetrahydro-7-methoxy-5-phenyl-1,4-benzothiazepin-8-ol 1,1-dioxide; (±) -Trans-3-butyl-3-ethyl-2,3,4,5-tetrahydro-8-methoxy5-phenyl-1,4-benzothiazepine 1,1-dioxide; (±) -Trans-3-butyl-3-ethyl-2,3,4,5-tetrahydro-5-phenyl1,4-benzothiazepin-8-ol 1,1-dioxide; (±) -Trans-3-butyl-3-ethyl-2,3,4,5-tetrahydro-5-phenyl1,4-benzothiazepine-4,8-diol; (±) -Trans-3-butyl-3-ethyl-2,3,4,5-tetrahydro-5-phenyl1,4-benzothiazepin-8-thiol 1,1-dioxide; 1,1-dioxide (±) -Trans-3-butyl-3-ethyl-2,3,4,5-tetrahydro-5-phenyl-1,4-benzothiazepin-8-sulfonic acid; (±) -Trans-3-butyl-3-ethyl-2,3,4,5-tetrahydro-8,9-dimethoxy-5-phenyl-1,4-benzothiazepine 1,1-dioxide; (3R, 5R) -3-butyl-7,8-diethoxy-2,3,4,5-tetrahydro-5-phenyl-1,4-benzothiazepine 1,1-dioxide; (±) -Trans-3-butyl-8-ethoxy-3-ethyl-2,3,4,5-tetrahydro-5-phenyl-1,4-benzothiazepine 1,1-dioxide; (±) -Trans-3-butyl-3-ethyl-2,3,4,5-tetrahydro-8-isopropoxy-5-phenyl-1,4-benzothiazepine 1,1-dioxide hydrochloride; (±) -Trans-3-butyl-3-ethyl-2,3,4,5-tetrahydro-5-phenyl1,4-benzothiazepin-8-carbaldehyde-1,1-dioxide; 3,3-Diethyl-2,3,4,5-tetrahydro-7,8-dimethoxy-5-phenyl1,4-benzothiazepine 1,1-dioxide; 3,3-Diethyl-2,3,4,5-tetrahydro-8-methoxy-5-phenyl-1,4-benzothiazepine 1,1-dioxide; 3,3-Diethyl-2,3,4,5-tetrahydro-5-phenyl-1,4-benzothiazpin-4,8-diol 1,1-dioxide; (RS) -3,3-Diethyl-2,3,4,5-tetrahydro-4-hydroxy-7,8-dimethoxy-5-phenyl-1,4-benzothiazepine 1,1-dioxide; (±) -Trans-3-butyl-8-ethoxy-3-ethyl-2,3,4,5-tetrahydro-5-phenyl-1,4-benzothiazepin-4-ol-1-dioxide; (±) -Trans-3-butyl-3-ethyl-2,3,4,5-tetrahydro-8-isopropoxy-5-phenyl-1,4-benzothiazepin-4-ol 1,1-dioxide; (±) -Trans-3-butyl-3-ethyl-2,3,4,5-tetrahydro-7,8,9-trimethoxy-5-phenyl-1,4-benzothiazepin-4-ol 1,1-dioxide ; (3R, 5R) -3-butyl-3-ethyl-2,3,4,5-tetrahydro-5-phenyl-1,4-benzothiazepin-4,7,8-triol 1,1-dioxide; (±) -Trans-3-butyl-3-ethyl-2,3,4,5-tetrahydro-4,7,8-trimethoxy-5-phenyl-1,4-benzothiazepine 1,1-dioxide; 3,3-Diethyl-2,3,4,5-tetrahydro-5-phenyl-1,4-benzothiazepin-8-ol 1,1-dioxide; 3,3-Diethyl-2,3,4,5-tetrahydro-7-methoxy-5-phenyl-1,4-benzothiazepin-8-ol 1,1-dioxide; 3,3Dibutyl-2,3,4,5-tetrahydro-5-phenyl-1,4-benzothiazepin-8-ol 1,1-dioxide; (±) -Trans-3-Butyl-3-ethyl-2,3,4,5-tetrahydro-1,1-dioxo5-phenyl-1,4-benzothiazepin-8-yl hydrogen sulfate; or 3,3-Diethyl-2,3,4,5-tetrahydro-1,1-dioxo-5-phenyl-1,4-benzothiazepin-8-yl hydrogen sulfate. In some embodiments, the Formula I compound is


In some modalities of the methods, the compound of Formula I is

In some embodiments, the Formula I compound is not a structure shown as:
where m represents an integer of 1 or 2, and R3 and R4, which can be mutually different, each represents an alkyl group having 1 to 5 carbon atoms.
In some embodiments, an ASBTI suitable for the methods described here is a compound of Formula II
where: q is an integer from 1 to 4; n is an integer from 0 to 2; R1 and R2 are independently selected from the group consisting of H, alkyl, alkenyl, alkynyl, haloalkyl, alkylaryl, arylalkyl, alkoxy, alkoxyalkyl, dialkylamino, alkylthio, (polyalkyl) aryl, and cycloalkyl, wherein alkyl, alkenyl, alkyl, haloalkyl, alkylaryl, arylalkyl, alkoxy, alkoxyalkyl, dialkylamino, alkylthio, (polyalkyl) aryl, and cycloalkyl are optionally substituted with one or more substituents selected from the group consisting of OR9, NR9R10, N + R9R10RwA ", SR9, S + R9R10A", P + R9R1OR11A-, S (O) R9, SO2R9, SO3R9, CO2R9, CN, halogen, oxo, and CONR9R10, where alkyl, alkenyl, alkynyl, alkylaryl, alkoxy, alkoxyalkyl, (polyalkyl) aryl, and cycloalkyl optionally have one or plus carbons replaced by 0, NR9, N + R9R10A ', S, SO, S02, S + R9A', P + R9R1OA ", OR phenylene, where R9, R10, and Rw are independently selected from the group consisting of H, alkyl, alkenyl, alkynyl, cycloalkyl, aryl, acyl, heterocycle, ammonioalkyl, arylalkyl, and alkylammonioalkyl useful; or R1 and R2 together with the carbon to which they are attached form C3-C10 cycloalkyl; R3 and R4 are independently selected from the group consisting of H, alkyl, alkenyl, alkynyl, acyloxy, aryl, heterocycle, OR9, NR9R10, SR9, S (O) R9, SO2R9, and SO3R9, where R9 and R10 are as above defined; or R3 and R4 next to = 0, = N0R11, = S, = NNR41R12, = NR9, or = CR41 R12, where R11 and R12 are independently selected from the group consisting of H, alkyl, alkenyl, alkynyl, aryl, arylalkyl , alkenylalkyl, alkynylalkyl, heterocycle, carboxyalkyl, carboalkoxyalkyl, cycloalkyl, cyanoalkyl, OR9, N R9R10, SR9, S (O) R9, SO2R9, SO3R9, CO2R9, CN, halogen, oxo, and CON R9R10, where R9 and R9 are R9 and R9 as defined above, provided that both R3 and R4 cannot be OH, NH2, and SH, or R11 and R12 together with the nitrogen or carbon atom to which they are attached form a cyclic ring; R5 and R6 are independently selected from the group consisting of H, alkyl, alkenyl, alkynyl, aryl, cycloalkyl, heterocycle, quaternary heterocycle, quaternary heteroaryl, OR9, SR9, S (O) R9, SO2R9, SO3R9, and -Lz-Kz ; where z is 1, 2 or 3; each L is independently substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted alkoxy, substituted or unsubstituted aminolaalkyl group, substituted or unsubstituted aryl group, substituted or unsubstituted heteroaryl group, one substituted or unsubstituted cycloalkyl, or substituted or unsubstituted heterocycloalkyl; each K is a portion that prevents systemic absorption; wherein alkyl, alkenyl, alkynyl, aryl, cycloalkyl, heterocycle, quaternary heterocycle, and quaternary heteroaryl can be substituted with one or more substituent groups independently selected from the group consisting of alkyl, alkenyl, alkynyl, polyalkyl, polyether, aryl, haloalkyl, cycloalkyl, heterocycle, arylalkyl, quaternary heterocycle, quaternary heteroaryl, halogen, oxo, R15, OR13, OR13R14, NR 13R14, SR13, S (O) R13, SO2R13, SO3R13, NR13OR14, NR13NR14R15, N02, CO2R13, CN, OM2 , SO2NR13R14, C (O) NR13R14, C (O) OM, CR13, P (O) R13R14, P + R13R14R15A ", P (OR13) OR14, S + R13R14A", and N + R9R11R12A ", where: A" is a pharmaceutically acceptable anion and M is a pharmaceutically acceptable cation, said alkyl, alkenyl, alkynyl, polyalkyl, polyether, aryl, haloalkyl, cycloalkyl, and heterocycle can also be substituted with one or more substituent groups selected from the group consisting of OR7 , N R7R8, S (0) R7, SO2R7, SO3R7, CO2R7, CN, oxo, CON R7R8, N + R7R8R9A ", alkyl, alkenyl, alkynyl, aryl, cycloalkyl, heterocycle, arylalkyl, quaternary heterocycle, quaternary heteroaryl, P (O) R7R8, P + R7R8R9A", and P (0) (OR7) OR8 and in which said alkyl, alkenyl , alkynyl, polyalkyl, polyether, aryl, haloalkyl, cycloalkyl, and heterocycle can optionally have one or more carbons substituted by 0, NR7, N + R7R8A ", S, SO, S02, S + R7A", PR7, P (0) R7, P + R7R8A ", OR phenylene, and R13, R14, and R15 are independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, polyalkyl, aryl, arylalkyl, cycloalkyl, heterocycle, heteroaryl, quaternary heteroaryl, quaternary heteroaryl, quaternary heteroarylalkyl, and -GTVW, where alkyl, alkenyl, alkynyl, arylalkyl, heterocycle, and polyalkyl optionally have one or more carbons substituted by 0, NR9, N + R9R10A-, S, SO, S02, S + R9A-, PR , P + R9R10A ", P (0) R9, phenylene, carbohydrate, C2-C7 polyol, amino acid, peptide, or polypeptide, and G, T and V are independently an alloy -0-, -S-, -N (H) -, substituted or unsubstituted alkyl, -0-alkyl, - N (H) -alkyl, -C (0) N (H) -, -N ( H) C (0) -, -N (H) C (0) N (H) -, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted aryl, substituted or unsubstituted arylalkyl, substituted alkenylalkyl or unsubstituted, alkynylalkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted heterocycle, substituted or unsubstituted carboxyalkyl, substituted or unsubstituted carboalkoxyalkyl, or substituted or unsubstituted cycloalkyl, and W is quaternary heteroaryl, quaternary heteroaryl, quaternary heteroarylalkyl, N + R9R11R12A ", P + R9R10R11A", OS (O) 2OM, OR S + R9R1OA ", and R13, R14 and R15 are optionally substituted with one or more groups selected from the group consisting of sulfoalkyl, quaternary heteroaryl, quaternary heteroaryl, OR9, NR9R10 , N + R9R11R12A ", SR9, S (O) R9, SO2R9, SO3R9, OXO, CO2R9, CN, halogen, CONR9R10, SO2OM, SO2N R9R10, PO (OR16) OR17, P + R9R1OR11A ", S + R9R1OA", and C (O) OM, where R16 and R17 are independently selected from the substituents that constitute R9 and M; or R14 and R15, together with the nitrogen to which they are attached, form a cyclic ring; and is selected from the group consisting of alkyl, alkenyl, alkynyl, cycloalkyl, aryl, acyl, heterocycle, ammonioalkyl, alkylammonioalkyl, and arylalkyl; and R7 and R8 are independently selected from the group consisting of hydrogen and alkyl; and one or more Rx are independently selected from the group consisting of H, alkyl, alkenyl, alkynyl, polyalkyl, acyloxy, aryl, arylalkyl, halogen, haloalkyl, cycloalkyl, heterocycle, heteroaryl, polyether, quaternary heterocycle, quaternary heteroaryl, OR13, NR13R14 , SR13, S (O) R13, S (O) 2R13, SO3R13, S + R13R14A ", NR13OR14, NR13NR14R15, N02, CO2R13, CN, OM, SO2OM, SO2NR13R14, NR14C (O) R13, C (O) NR13R14, NR14C (O) R13, C (O) OM, COR13, OR18, S (O) n NR18, NR13R18, NR18R14, N + R9R1: LR12A ", P + R9R1: LR12A", amino acid, peptide, polypeptide, and carbohydrate, where alkyl, alkenyl, alkynyl, cycloalkyl, aryl, polyalkyl, heterocycle, acyloxy, arylalkyl, haloalkyl, polyether, quaternary heterocycle, and quaternary heteroaryl can also be replaced with OR9, NR9R10, N + R9R1: LR12A, SR9, O) R9, SO2R9, SO3R9, oxo, CO2R9, CN, halogen, CONR9R10, S020M, SO2NR9R10, PO (0Rlδ) OR17, P + R9R11R12A ", S + R9R10A", or C (O) M, and where R18 is selected from the group consisting of acyl, arylalkoxy bonyl, arylalkyl, heterocycle, heteroaryl, alkyl, wherein acyl, arylalkoxycarbonyl, arylalkyl, heterocycle, heteroaryl, alkyl, quaternary heterocycle, and quaternary heteroaryl are optionally substituted with one or more substituents selected from the group consisting of OR9, NR9R10, N + R9R11R12A ', SR9, S (O) R9, SO2R9, SO3R9, oxo, CO3R9, CN, halogen, CONR9R10, SO3R9, SO2OM, SO2NR9R10, PO (OR16) OR17, and C (O) OM, where in Rx, one or more carbons are optionally substituted by 0, NR13, N + R13R14A ", S, SO, S02, S + R13A ', PR13, P (0) R13, P + R13R14A", phenylene, amino acid, peptide, polypeptide, carbohydrate, polyether, or polyalkyl, wherein in said polyalkyl, phenylene, amino acid, peptide, polypeptide, and carbohydrate, one or more carbons are optionally substituted by 0, NR9, R9R10A ", S, S0, S02, S + R9A", PR9, P + R9R10A ", OR P (0) R9; wherein quaternary heterocycle and quaternary heteroaryl are optionally substituted with one or more groups selected from the group consisting of alkyl, alkenyl, alkynyl, polyalkyl, polyether, aryl, haloalkyl, cycloalkyl, heterocycle, arylalkyl, halogen, oxo, 0R13, NR13R14, SR13 , S (O) R13, SO2R13, SO3R13, NR13OR14, NR13NR14R15, N02, CO2R13, CN, 0M, S020M, SO2NR13R14, C (O) NR13R14, C (0) 0M, COR13, P (O) R13R14, P + R13R14R15A ", P (OR13) OR 14, S + R13R14A", and N + R9R1: LR12A ', provided that both R5 and Rδ cannot be hydrogen or SH; provided that when R5 or R6 is phenyl, only one of R1 or R2 is H; since when q = 1 and Rx is styryl, anilide, or anilinocarbonyl, only one of R5 or R6 is alkyl; or a pharmaceutically acceptable salt, solvate, or prodrug thereof.
In some method embodiments, the compound of Formula II is a compound in which q is an integer from 1 to 4; n is 2; R1 and R2 are independently selected from the group consisting of H, alkyl, alkoxy, dialkylamino, and alkylthio, where alkyl, alkoxy, dialkylamino, and alkylthio are optionally substituted with one or more substituents selected from the group consisting of OR9, N R9R10 , SR9, SO2R9, CO2R9, CN, halogen, oxo, and CONR9R10; each R9 and R10 is independently selected from the group consisting of H, alkyl, cycloalkyl, aryl, acyl, heterocycle, and arylalkyl; R3 and R4 are independently selected from the group consisting of H, alkyl, acyloxy, OR9, NR9R10, SR9, and SO2R9, where R9 and R10 are as defined above; R11 and R12 are independently selected from the group consisting of H, alkyl, alkenyl, alkynyl, aryl, arylalkyl, alkenylalkyl, alkynylalkyl, heterocycle, carboxyalkyl, carboalkoxyalkyl, cycloalkyl, cyanoalkyl, OR9, NR9R10, SR9, S (O) R9, S9 , SO3R9, CO2R9, CN, halogen, oxo, and CONR9R10, where R9 and R10 are as defined above, provided that both R3 and R4 cannot be OH, NH2, and SH, or R11 and R12 together with the nitrogen atom or carbon to which they are attached form a cyclic ring; R5 and R6 are independently selected from the group consisting of H, alkyl, aryl, cycloalkyl, heterocycle, and -Lz-Kz; where z is 1 or 2; each L is independently substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted aryl group, substituted or unsubstituted heteroaryl group, substituted or unsubstituted cycloalkyl, or substituted or unsubstituted heterocycloalkyl; each K is a portion that prevents systemic absorption; wherein alkyl, aryl, cycloalkyl, and heterocycle can be substituted with one or more substituent groups independently selected from the group consisting of alkyl, aryl, haloalkyl, cycloalkyl, heterocycle, arylalkyl, quaternary heterocycle, quaternary heteroaryl, halogen, oxo, OR13, OR13R14, NR13R14, SR13, SO2R13, NR13NR14R15, N02, CO2R13, CN, OM, and CR13, where: A "is a pharmaceutically acceptable anion and M is a pharmaceutically acceptable cation; R13, R14, and R15 are independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, polyalkyl, aryl, arylalkyl, cycloalkyl, heterocycle, heteroaryl, quaternary heterocycle, quaternary heteroaryl, and quaternary alkyl heteroaryl, where R13, R14 and R15 are optionally substituted with one or more groups selected from group consisting of quaternary heterocycle, quaternary heteroaryl, OR9, NR9R10, N + R9R11R12A ", SR9, S (O) R9, SO2R9, SO3R9, oxo, CO2R9, CN, halogen, and CONR9R10; or R14 and R15, together with the nitrogen to which they are attached, form a cyclic ring; and is selected from the group consisting of alkyl, alkenyl, alkynyl, cycloalkyl, aryl, acyl, heterocycle, ammonioalkyl, alkylammonioalkyl, and arylalkyl; and R7 and R8 are independently selected from the group consisting of hydrogen and alkyl; and one or more Rx are independently selected from the group consisting of H, alkyl, acyloxy, aryl, arylalkyl, halogen, haloalkyl, cycloalkyl, heterocycle, heteroaryl, OR13, NR13R14, SR13, S (O) 2R13, NR13NR14R15, N02, CO2R13 , CN, SO2NR13R14, NR14C (O) R13, C (O) NR13 R 14, NR14C (O) R13, and COR13; provided that both R5 and R6 cannot be hydrogen; provided that when R5 or R6 is phenyl, only one of R1 or R2 is H; since when q = 1 and Rx is styryl, anilide, or anilinocarbonyl, only one of R5 or R6 is alkyl; or a pharmaceutically acceptable salt, solvate, or prodrug thereof. In some embodiments, the compound of Formula II is a compound in which q is 1; n is 2; Rx is N (CH3) 2; R7 and R8 are independently H; R1 and R2 is alkyl; R3 is H, and R4 is OH; R5 is H, and Rδ is selected from the group consisting of alkyl, alkenyl, alkynyl, aryl, cycloalkyl, heterocycle, quaternary heterocycle, quaternary heteroaryl, OR9, SR9, S (O) R9, SO2R9, SO3R9, and -Lz-Kz; where z is 1, 2 or 3; each L is independently substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted alkoxy, substituted or unsubstituted aminolaalkyl group, substituted or unsubstituted aryl group, substituted or unsubstituted heteroaryl group, one substituted or unsubstituted cycloalkyl, or substituted or unsubstituted heterocycloalkyl; each K is a portion that prevents systemic absorption; wherein alkyl, alkenyl, alkynyl, aryl, cycloalkyl, heterocycle, quaternary heterocycle, and quaternary heteroaryl can be substituted with one or more substituent groups independently selected from the group consisting of alkyl, alkenyl, alkynyl, polyalkyl, polyether, aryl, haloalkyl, cycloalkyl, heterocycle, arylalkyl, quaternary heterocycle, quaternary heteroaryl, halogen, oxo, R15, OR13, OR13R14, NR13R14, SR13, S (O) R13, SO2R13, SO3R13, NR13OR14, NR13NR14R15, N02, CO2R13, CN, OM2 SO2NR13R14, C (O) NR13R14, C (O) OM, CR13, P (O) R13R14, P + R13R14R15A ", P (OR13) OR14, S + R13R14A", and N + R9R41R12A ", where A" is a pharmaceutically acceptable anion and M is a pharmaceutically acceptable cation, said alkyl, alkenyl, alkynyl, polyalkyl, polyether, aryl, haloalkyl, cycloalkyl, and heterocycle can also be substituted with one or more substituent groups selected from the group consisting of OR7, NR7R8 , S (O) R7, SO2R7, SO3R7, CO2R7, CN, oxo, C0NR7R8, N + R7R8R9A ", al quil, alkenyl, alkynyl, aryl, cycloalkyl, heterocycle, arylalkyl, quaternary heterocycle, quaternary heteroaryl, P (O) R7R8, P + R7R8R9A ", and P (0) (OR7) OR8 and wherein said alkyl, alkenyl, alkynyl , polyalkyl, polyether, aryl, haloalkyl, cycloalkyl, and heterocycle can optionally have one or more carbons substituted by 0, NR7, N + R7R8A ", S, SO, S02, S + R7A", PR7, P (O) R7, P + R7R8A ', OR phenylene, and R13, R14, and R15 are independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, polyalkyl, aryl, arylalkyl, cycloalkyl, heterocycle, heteroaryl, quaternary heterocycle, quaternary heteroaryl, heteroarylaryl , and -GTVW, where alkyl, alkenyl, alkynyl, arylalkyl, heterocycle, and polyalkyl optionally have one or more carbons substituted by 0, NR9, N + R9R10A ", S, SO, S02, S + R9A", PR, P + RSR1OA, P (O) R9, phenylene, carbohydrate, C2-C7 polyol, amino acid, peptide, or polypeptide, and G, T and V are independently a bond o, -0-, -S-, -N (H) -, substituted or unsubstituted alkyl, -0-alkyl, - N (H) -alkyl, -C (O) N (H) -, -N ( H) C (O) -, -N (H) C (0) N (H) -, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted aryl, substituted or unsubstituted arylalkyl, substituted alkenylalkyl or unsubstituted, alkynylalkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted heterocycle, substituted or unsubstituted carboxyalkyl, substituted or unsubstituted carboalkoxyalkyl, or substituted or unsubstituted cycloalkyl, and W is quaternary heteroaryl, quaternary heteroaryl, heteroarylalkyl, quaternary R9R11R12A ", P + R9R10R11A", OS (O) 2OM, OR S + R9R1OA ", and R9 and R10 are independently selected from the group consisting of H, alkyl, alkenyl, alkynyl, cycloalkyl, aryl, acyl, heterocycle, ammonioalkyl, arylalkyl, and alkylammonioalkyl; R and R are independently selected from the group consisting of H, alkyl, alkenyl, alkynyl, aryl, arylalkyl, alkenylalkyl, alkynylalkyl, heterocycle, carboxyalkyl, carboalkoxyalkyl, cycloalkyl, cyanoalkyl, OR9, NR9R10, SR9, S (O) R9, SO2R , SO3R9, CO2R9, CN, halogen, oxo, and CONR9R10, where R9 and R10 are as defined above, provided that both R3 and R4 cannot be OH, NH2, and SH, or R and R together with the nitrogen atom or carbon to which they are attached form a cyclic ring; R13, R14 and R15 are optionally substituted with one or more groups selected from the group consisting of sulfoalkyl, quaternary heterocycle, quaternary heteroaryl, OR9, NR9R10, N + R9R41R12A ", SR9, S (O) R9, SO2R9, SO3R9, 0X0, CO2R9, CN, halogen, CONR9R10, S020M, SO2NR9R10, PO (OR16) OR17, P + R9R1OR11A ", S + R9R1OA", and C (O) OM, where R16 and R17 are independently selected from the substituents that constitute R9 and M ; or R14 and R15, together with the nitrogen to which they are attached, form a cyclic ring; and is selected from the group consisting of alkyl, alkenyl, alkynyl, cycloalkyl, aryl, acyl, heterocycle, ammonioalkyl, alkylammonioalkyl, and arylalkyl; or a pharmaceutically acceptable salt, solvate, or prodrug thereof.
In some embodiments, the compound of Formula II is a compound in which q is 1; n is 2; Rx is N (CH3) 2; R7 and R8 are independently H; R and R and independently C 1 -C 4 alkyl; R3 is H, and R4 is OH; R5 is H, and R6 is aryl substituted with one or more substituent groups independently selected from the group consisting of alkyl, alkenyl, alkynyl, polyalkyl, polyether, aryl, haloalkyl, cycloalkyl, heterocycle, arylalkyl, quaternary heterocycle, quaternary heteroaryl, halogen, oxo, R15, OR13, OR13R14, NR13R14, SR13, S (O) R13, SO2R13, SO3R13, NR13OR14, NR13NR14R15, N02, CO2R13, CN, OM, SO2OM, SO2NR13R14, C (O) NR13R14, C (O) OM, CR13, P (O) R13R14, P + R13R14R15A ', P (OR13) OR14, S + R13R14A', and N + R9R11R12A_, where A "is a pharmaceutically acceptable anion and M is a pharmaceutically acceptable cation, said alkyl, alkenyl, alkynyl, polyalkyl, polyether, aryl, haloalkyl, cycloalkyl, and heterocycle can also be substituted with one or more substituent groups selected from the group consisting of OR7, NR7R8, S (O) R7, SO2R7, SO3R7, CO2R7, CN, oxo, CONR7R8, N + R7R8R9A ", alkyl, alkenyl, alkynyl, aryl, cycloalkyl, heterocycle, arylalkyl, quaternary heterocycle, heteroaryl quat ernary, P (O) R7R8, P + R7R8R9A ", and P (0) (OR7) OR8e wherein said alkyl, alkenyl, alkynyl, polyalkyl, polyether, aryl, haloalkyl, cycloalkyl, and heterocycle may optionally have one or more carbons substituted by 0, NR7, N + R7R8A ", S, SO, S02, S + R7A", PR7, P (0) R7, P + R7R8A ", OR phenylene, and R13, R14, and R15are independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, polyalkyl, aryl, arylalkyl, cycloalkyl, heterocycle, heteroaryl, quaternary heterocycle, quaternary heteroaryl, quaternary heteroarylalkyl, and -GTVW, in which alkyl, alkenyl, alkyl, aryl, alkyl, aryl, alkyl, aryl, alkyl, alkyl, aryl, alkyl, alkyl optionally have one or more carbons substituted by 0, NR9, N + R9R10A ", S, SO, S02, S + R9A", PR, P + R9R10A ", P (0) R9, phenylene, carbohydrate, C2-C7 polyol, amino acid, peptide, or polypeptide, and G, T and V are independently a bond, -0-, -S-, -N (H) -, substituted or unsubstituted alkyl, -0-alkyl, - N (H) - alkyl, -C (0) N (H) -, -N (H) C (0) -, - N (H) C (0) N (H) -, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted aryl, substituted or unsubstituted arylalkyl, substituted or unsubstituted alkenylalkyl, substituted or unsubstituted heteroalkyl substituted, substituted or unsubstituted heterocycle, substituted or unsubstituted carboxyalkyl, substituted or unsubstituted carboalkoxyalkyl, or substituted or unsubstituted cycloalkyl, and W is quaternary heterocycle, quaternary heteroaryl, quaternary heteroarylalkyl, N + R9R11R12A ', P + R9R10R11A ", 0S (0) 20M, OU S + R9R1OA ', and R9 and R10 are independently selected from the group consisting of H, alkyl, alkenyl, alkynyl, cycloalkyl, aryl, acyl, heterocycle, ammonioalkyl, arylalkyl, and alkylammonioalkyl; R11 and R12 are independently selected from the group consisting of H, alkyl, alkenyl, alkynyl, aryl, arylalkyl, alkenylalkyl, alkynylalkyl, heterocycle, carboxyalkyl, carboalkoxyalkyl, cycloalkyl, cyanoalkyl, OR9, NR9R10, SR9, S (O) R9, S9 , SO3R9, CO2R9, CN, halogen, oxo, and CONR9R10, where R9 and R10 are as defined above, provided that both R3 and R4 cannot be OH, NH2, and SH, or R and R together with the nitrogen atom or carbon to which they are attached form a cyclic ring; R13, R14 and R15 are optionally substituted with one or more groups selected from the group consisting of sulfoalkyl, quaternary heterocycle, quaternary heteroaryl, OR9, NR9R10, N + R9R41R12A ", SR9, S (O) R9, SO2R9, SO3R9, OXO, CO2R9, CN, halogen, CONR9R10, S020M, SO2NR9R10, PO (OR16) OR17, P + R9R10R11A ", S + R9R1OA ', and C (O) OM, where R16 and R17 are independently selected from the substituents that constitute R9 and M ; or R14 and R15, together with the nitrogen to which they are attached, form a cyclic ring; and is selected from the group consisting of alkyl, alkenyl, alkynyl, cycloalkyl, aryl, acyl, heterocycle, ammonioalkyl, alkylammonioalkyl, and arylalkyl; or a pharmaceutically acceptable salt, solvate, or prodrug thereof. In some method embodiments, the compound of Formula II is a compound in which R5 and Rδ are independently selected from the group consisting of H, aryl, heterocycle, quaternary heterocycle, and quaternary heteroaryl in which aryl, heteroaryl, quaternary heterocycle and quaternary heteroaryl are optionally substituted with one or more groups selected from the group consisting of alkyl, alkenyl, alkynyl, polyalkyl, polyether, aryl, haloalkyl, cycloalkyl, heterocycle, arylalkyl, halogen, oxo, OR13, OR13R14, NR13R14, SR13, S (O) R13, SO2R13, SO3R13, NR13OR14, NR13NR14R15, N02, CO2R13, CN, OM, SO2OM, SO2NR13R14, C (O) NR13R14, C (O) OM, COR13, P (O) R13R14, P + R13R14R15A ", P (OR13 ) OR14, S + R13R14A “, N + R9R1: LR12A" and -Lz-Kz. In some method embodiments, the compound of Formula II is a compound in which R5 or R6 is -Ar- (Ry) t t is an integer from 0 to 5; Ar is selected from the group consisting of phenyl, thiophenyl, pyridyl, piperazinyl, piperonyl, pyrrolyl, naphthyl, furanyl, anthracenyl, quinolinyl, isoquinolinyl, quinoxalinyl, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, pyrimidinyl, trifol, benzoimidazolyl, benzoxazolyl, benzothiazolyl, and benzoisothiazolyl; and one or more RY are independently selected from the group consisting of alkyl, alkenyl, alkynyl, polyalkyl, polyether, aryl, halo alkyl, cycloalkyl, heterocycle, arylalkyl, halogen, oxo, OR13, OR13R14, NR13R14, SR13, S (O) R13, SO2R13, SO3R13, NR13OR14, NR13NR14R15, N02, CO2R13, CN, OM, SO2OM, SO2NR13R14, C (0) NR13R14, C (O) OM, COR13, P (O) R13R14, P + R13R14R15A-, P (OR13 ) OR14, S + R13R14A ", N + R9R4 1 R12A 'e-Lz-Kz; wherein said alkyl, alkenyl, alkynyl, polyalkyl, polyether, aryl, haloalkyl, cycloalkyl, and heterocycle can also be replaced with one or more substituent groups selected from the group consisting of OR13, NR13R14, SR13, S (O) R13, SO2R13, SO3R13, NR13OR14, NR13NR14R15, N02, CO2R13, CN, oxo, CONR7R8, N + R7R8R9A ", alkyl, alkenyl, alkynyl, aryl , cycloalkyl, heterocycle, arylalkyl, quaternary heterocycle, quaternary heteroaryl, P (O) R7R8, P + R7R8A ", and P (O) (OR7) OR8, and or phenylene; wherein said alkyl, alkenyl, alkynyl, polyalkyl, polyether, air useful, haloalkyl, cycloalkyl, and heterocycle may optionally have one or more carbons substituted by 0, NR7, N + R7R8A ', S, SO, S02, S + R7A', PR7, P (0) R7, P + R7R8A ", or phenylene.
In some method embodiments, the compound of Formula II is a compound in which R5 or R6 is

In some method embodiments, the Formula II compound is a compound in which n is 1 or 2. In some method embodiments, the Formula II compound is a compound in which R1 and R2 are independently H or Cl-7 alkyl. In some embodiments of the methods, the compound of Formula II is a compound in which each Cl-7 alkyl is independently ethyl, n-propyl, n-butyl, or isobutyl. In some method embodiments, the compound of Formula II is a compound in which R3 and R4 are independently H or OR9. In some method modalities, a compound of Formula II and a compound in which R and H.
In some method embodiments, the Formula II compound is a compound in which one or more Rx are at the 7-, 8- or 9- position of the Formula II benzo ring. In some method embodiments, the Formula II compound is a compound in which Rx is at the 7- position of the Formula II benzo ring. In some method embodiments, the compound of Formula II is a compound in which one or more Rx are independently selected from OR13 and NR13R14.
In some method embodiments, the compound of Formula II is a compound in which: q is 1 or 2; n is 2; R and R are each alkyl; R3 is hydroxy; R4 and R6 are hydrogen; R5 has the formula
where t is an integer from 0 to 5; one or more Ry are OR13or OR13R14; R13 and R14 are independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, polyalkyl, aryl, arylalkyl, cycloalkyl, heterocycle, heteroaryl, quaternary heterocycle, quaternary heteroaryl, and quaternaryalkyl heteroaryl; wherein said alkyl, alkenyl, alkynyl, arylalkyl, heterocycle, and polyalkyl groups optionally have one or more carbons substituted by 0, NR9, N + R9R10A ', S, SO, S02, S + R9A ", PR9, P + R9R10A ", P (0) R9, phenylene, carbohydrate, amino acid, peptide, or polypeptide; R13 and R14 are optionally substituted with one or more groups independently selected from the group consisting of sulfoalkyl, quaternary heterocycle, quaternary heteroaryl, OR9, NR9R10, N + R9R41R12A ", SR9, S (O) R9, SO2R9, SO3R9, OXO, CO2R9 , CN, halogen, CONR9R10, S020M, SO2NR9R10, PO (OR16) 0R17, P + R9R1OR11A ', S + R9R1OA ", and C (0) 0M, where A is a pharmaceutically acceptable anion, and M is a pharmaceutically acceptable cation , R9 and R10 are independently selected from the group consisting of H, alkyl, alkenyl, alkynyl, cycloalkyl, aryl, acyl, heterocycle, ammonioalkyl, arylalkyl, and alkylammonioalkyl; R11 and R 12 are independently selected from the group consisting of H, alkyl, alkenyl, alkynyl, aryl, arylalkyl, alkenylalkyl, alkynylalkyl, heterocycle, carboxyalkyl, carboalkoxyalkyl, cycloalkyl, cyanoalkyl, 0R9, NR9R10, SR9, S (O) R9, S (O) R9 SO2R9, SO3R9, CO2R9, CN, halogen, oxo, and CONR9R10, where R9 and R10 are as defined above, provided that both R3 and R4 cannot be OH, N H2, and SH; or R11 and R12 together with the nitrogen or carbon atom to which they are attached form a cyclic ring; and R16 and R17 are independently selected from the substituents that constitute R and M; R7 and R8 are hydrogen; and one or more Rx are independently selected from the group consisting of alkoxy, alkylamino and dialkylamino and –W-R31, where W is O or NH and R31 is selected from
or a pharmaceutically acceptable salt, solvate or prodrug thereof.
In some embodiments, a Formula II compound is

or others.
In some method modalities, the compound of Formula II is

In certain embodiments, ASBTIs suitable for the methods described herein are non-systemic analogues of Compound 100C. Certain compounds provided herein are analogs modified or substituted for Compound 100C to comprise a charged group. In specific embodiments, the analogues of Compound 100C are modified or replaced with a charged group that is an ammonium group (for example, a cyclic or acyclic ammonium group). In certain embodiments, the ammonium group is a non-protic ammonium group that contains quarternary nitrogen.
In some embodiments, a Formula II compound is

In some embodiments, a compound of Formula II is 1- [[5 - [[3 - [(3S, 4R, 5R) -3-butyl-7- (dimethylamino) -3-ethyl- 2,3,4,5 -tetrahydro-4-hydroxy-1,1-dioxido-1-benzothiepin-5yl] phenyl] amino] -5-oxopentyl] amino] -1-deoxy-D-glucitol or SA HMR1741 (known as BARI-1741).
In some embodiments, a Formula II compound is

In some embodiments, a compound of Formula II is potassium ((2R, 3R, 4S, 5R, 6R) -4-benzyloxy-6- {3- [3 - ((3S, 4R, 5R) - 3-butyl-7 -dimethylamino-3-ethyl-4-hydroxy-1,1-dioxo-2,3,4,5-tetrahydro-1H-benzo [b] tiepin-5-yl) -phenyl] -ureido} -3,5- dihydroxy-tetrahydro-pyran-2-ylmethyl) sulfate ethanolate, hydrate or SAR548304B (known as SAR-548304).
In some embodiments, an ASBTI suitable for the methods described here is a compound of Formula III:
where: each R1, R2 is independently H, hydroxy, alkyl, alkoxy, -C (= X) YR8, -YC (= X) R8, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted aryl , substituted or unsubstituted alkylaryl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted alkylcycloalkyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted alkyl heteroaryl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted alkyleterocycloalkyl, or —LK; or R1 and R2 together with the nitrogen to which they are attached form a 3-8 membered ring that is optionally substituted with R8; each R3, R4 is independently H, hydroxy, alkyl, alkoxy, -C (= X) YR8, -YC (= X) R8, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted aryl, substituted alkylaryl or unsubstituted, substituted or unsubstituted cycloalkyl, substituted or unsubstituted alkylcycloalkyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted alkyl heteroaryl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted alkyletherocycloalkyl, or -LK; R5 is H, hydroxy, alkyl, alkoxy, -C (= X) YR8, -YC (= X) R8, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted aryl, substituted or unsubstituted alkylaryl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted alkylcycloalkyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted alkylheteroaryl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted alkyletherocycloalkyl, each R6, R7 is independently H, hydroxy, alkyl, alkoxy, -C (= X) YR8, -YC (= X) R8, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted aryl, substituted or unsubstituted alkylaryl, substituted or unsubstituted cycloalkyl, substituted alkylcycloalkyl or unsubstituted, substituted or unsubstituted heteroaryl, substituted or unsubstituted alkylheteroaryl, substituted or unsubstituted heterocycloalkyl, alkyl substituted or unsubstituted heterocycloalkyl, or -LK; or R6 and R7 together form a bond; each X is independently NH, S, or 0; each Y is independently NH, S, or 0; R8 is substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted aryl, substituted or unsubstituted alkylaryl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted alkylcycloalkyl substituted or unsubstituted heteroaryl, substituted or unsubstituted alkyl heteroaryl substituted, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted alkyletherocycloalkyl, or -LK; L is An, where each A is independently NR1, S (0) m, 0, C (= X) Y, Y (C = X), substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted aryl substituted, substituted or unsubstituted heteroaryl, substituted or unsubstituted cycloalkyl, or substituted or unsubstituted heterocycloalkyl; where each m is independently 0-2; n is 0 - 7; K is a portion that prevents systemic absorption; provided that at least one of R1, R2, R3 or R4 is -LK; or such a pharmaceutically acceptable prodrug.
In some embodiments of a compound of Formula III, R1 and R3 are -L-K. In some modalities, R1, R2 and R3 are - L-K.
In some embodiments, at least one of R1, R2, R3, R4, R5, R6 and R7 is H. In certain embodiments, R5, R6, R7 are H and R1, R2, R3 and R4 are alkyl, aryl, alkyl- aryl, or heteroalkyl. In some embodiments, R1 and R2 are H. In some embodiments, R1, R2, R5, R6 and R7 are H. In some embodiments, R6 and R7 together form a bond. In certain embodiments, R5, R6 and R7 are H, alkyl or 0-alkyl.
In some embodiments, R1 and R3 are -L-K. In some embodiments, R1, R2 and R3 are -L-K. In some modalities, R3 and R4 are -L-K. In some embodiments, R1 and R2 together with the nitrogen to which they are attached form a 3-8 membered ring and the ring is replaced with -L-K. In some embodiments, R1 or R2 or R3 or R4 are aryl optionally substituted with -L-K. In some embodiments, R1 or R2 or R3 or R4 are alkyl optionally substituted with -L-K. In some embodiments, R1 or R2 or R3 or R4 are alkyl-aryl optionally substituted with -L-K. In some embodiments, R1 or R2 or R3 or R4 are heteroalkyl optionally substituted with -L-K.
In some embodiments, L is a Cl-C7alkyl. In some embodiments, L is heteroalkyl. In certain embodiments, L is Cl-C7alkyl-aryl. In some embodiments, L is Cl-C7alkyl-aryl-Cl-C7alkyl.
In certain embodiments, K is a charged non-protic group. In some specific embodiments, each K is an ammonium group. In some embodiments, each K is a non-protic cyclic ammonium group. In some embodiments, each K is a non-protic acyclic ammonium group.
In certain embodiments, each K is a non-protic cyclic ammonium group with a structure:
In certain embodiments, K is a non-protic acyclic ammonium group with a structure:
where p, q, R9, R10 and Z are as defined above. In certain modalities, p is 1. In other modalities, p is 2. In additional modalities, p is 3. In some modalities, q is 0. In other modalities, q is 1. In other modalities, q is 2. The compounds also comprise 1, 2, 3 or 4 anionic contrions selected from Cl ', Br', I ', RI: LSO3', (SO3'-R11-SO3 '), RI: LCO2', (CO2'-R11- CO2 '), (R11) 2 (P = O) O' and (R11) (P = O) O22 "where R11 is as defined above. In some embodiments, the contrion is Cl ', Br", I ", CH2CO2 ", CH3SO3", or C6H5SO3 "OR CO2 '- (CH2) 2-CO2". In some embodiments, the Formula III compound has a K group and a contrion. In other embodiments, the Formula III compound has a group K, and two molecules of the Formula III compound have a contrion. In still other embodiments, the Formula III compound has two K groups and two contractions. In other embodiments, the Formula III compound has a K group that comprises two ammonium groups. and two contraions. Also described here are compounds that have Formula IIIA:
wherein: each R1, R2 is independently H, substituted or unsubstituted alkyl, or -L-K; or R1 and R2 together with the nitrogen to which they are attached form a 3-8 membered ring that is optionally substituted with R8; and R3, R4, R8, L and K are as defined above.
In some embodiments of the Formula IIIA compounds, L is An, where each A is substituted or unsubstituted alkyl, or substituted or unsubstituted heteroalkyl, and n is 0- 7. In certain specific embodiments of the Formula IIIA compound, R1 is H. In some Formula IIIA modalities, R1 and R2 together with the nitrogen to which they are attached form a 3-8 membered ring that is optionally replaced with —LK. Also described here are compounds that have Formula IIIB:
where: each R3, R4 is independently H, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted aryl, substituted or unsubstituted alkylaryl, or —LK; and R1, R2, L and K are as defined above.
In certain modalities of Formula II IB, R3 is H. In certain modalities, R3 and R4 are -L-K. In some embodiments, R3 is H and R4 is substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted aryl, substituted or unsubstituted alkyl aryl containing one or two groups - L-K.
In some embodiments, an ASBTI suitable for the methods described here is a compound of Formula IIIC
where: each R1, R2 is independently H, hydroxy, alkyl, alkoxy, -C (= X) YR8, -YC (= X) R8, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted aryl, substituted or unsubstituted alkylaryl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted alkylcycloalkyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted alkylheteroaryl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted alkyleterocycloalkyl, or -LK; or R1 and R2 together with the nitrogen to which they are attached form a 3-8 membered ring that is optionally substituted with R8; each R3, R4 is independently H, hydroxy, alkyl, alkoxy, -C (= X) YR8, -YC (= X) R8, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted aryl, substituted alkylaryl or unsubstituted, substituted or unsubstituted cycloalkyl, substituted or unsubstituted alkylcycloalkyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted alkyl heteroaryl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted alkyletherocycloalkyl, or -LK; R5 is H, hydroxy, alkyl, alkoxy, -C (= X) YR8, -YC (= X) R8, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted aryl, substituted or unsubstituted alkylaryl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted alkylcycloalkyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted alkylheteroaryl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted alkyletherocycloalkyl, each R6, R7 is independently H, hydroxy, alkyl, alkoxy, -C (= X) YR8, -YC (= X) R8, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted aryl, substituted or unsubstituted alkyl-aryl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted alkylcycloalkyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted alkylheteroaryl, substituted or unsubstituted heterocycloalkyl, alkyl substituted or unsubstituted uilheterocycloalkyl, or -LK; or Rê and R7 together form a bond; each X is independently NH, S, or 0; each Y is independently NH, S, or 0; R8 is substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted aryl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted alkylcycloalkyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted alkylethyl , substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted alkyletherocycloalkyl, or -LK; L is An, where each A is independently NR1, S (O) m, O, C (= X) Y, Y (C = X), substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted aryl substituted, substituted or unsubstituted heteroaryl, substituted or unsubstituted cycloalkyl, or substituted or unsubstituted heterocycloalkyl; where each m is independently 0-2; n is 0 - 7; K is a portion that prevents systemic absorption; or a pharmaceutically acceptable salt thereof.
In some specific Formula I, II or III modalities, K is selected from
In some embodiments, an ASBTI suitable for the methods described here is a compound of Formula IV:
wherein R1 is a straight chain C1-6 alkyl group; R is a straight chain C 1-6 alkyl group; R3 is hydrogen or an OR11 group where R11 is hydrogen, optionally substituted C1-6 alkyl or a C1-6 alkylcarbonyl group; R4 is pyridyl or an optionally substituted phenyl; R5, R6 and R8 are the same or different and each is selected from: hydrogen, halogen, cyano, R15 -acetylide, OR15, optionally substituted C1-6 alkyl, COR15, CH (OH) R15, S (O) nR15, P (O) (OR15) 2, OCOR15, OCF3, OCN, SON, NHCN, CH2OR15, CHO, (CH2) PCN, CONR12R13, (CH2) PCO2R15, (CH2) pNR12R13, CO2R15, NHCOCF3, NHSO2R15, OCH2OR15, OCH = CHR15, O (CH2CH2O) nR15, O (CH2) PSO3R15, O (CH2) PNR12R13 and O (CH2) PN + R12R13R14 where p is an integer 1-4, n is an integer 0-3 and R12 , R13, R14 and R15 are independently selected from hydrogen and optionally substituted C1-6 alkyl; R7 is a group of formula
wherein the hydroxyl groups can be substituted with acetyl, benzyl, or - (C1-C6) -alkyl-R17, where the alkyl group can be substituted with one or more hydroxyl groups; R16 is -COOH, -CH2-OH, -CH2-O-Acetyl, -COOMe or -COOEt; R17 is H, -OH, -NH2, -COOH or COOR18; R18 is (C1-C4) -alkyl or -NH- (C1-C4) -alkyl; X is -NH- or -O-; and R9 and R10 are the same or different and each is hydrogen or C1-C6 alkyl; and salts like that. In some embodiments, a Formula IV compound has the Formula IVA or Formula IVB structure:
In some embodiments, a Formula IV compound has the Formula IVC structure:
In some Formula IV modalities, X is O and R7 is selected from
In some embodiments, a Formula IV compound is:
In some embodiments, an ASBTI suitable for the methods described here is a compound of Formula V:
where: Rv is selected from hydrogen or Ci-6alkyl; One from R1 and R2 is selected from hydrogen or C1-6alkyl and the other is selected from C1-6alkyl; Rx and Ry are independently selected from hydrogen, hydroxy, amino, mercapto, Ci-6alkyl, Cl- δalkoxy, N— (Ci-6alkyl) amino, N, N— (Ci_5alkyl) 2amino, Ci- 6alkylS (O) to which a is 0 to 2; Rz is selected from halo, nitr, cyano, hydroxy, amino, carboxy, carbamoyl, mercapto, sulfamoyl, Ci-6alkyl, C2-6al kenyl, C2-6alkynyl, Ci-6alcoxy, Ci-6Alcanoyl, Ci- 6Alcanoyloxy, N— ( C1-6alkyl) amino, N, N— (C1-6alkyl) 2amino, C1-3alkanoylamino, N— (C1-6alkyl) carbamoyl, N, N— (C1-6alkyl) 2carbamoyl, Ci_6alkylS (O) to which a is 0 to 2, C1-6 alkoxycarbonyl, N— (C1-6 alkyl) sulfamoyl and N, N— (Cl- δalkyl) 2 sulfamoyl; n is 0 - 5; one of R4 and R5 is a Formula (VA) group:
R3 and Rδ and the other from R4 and R5 are independently selected from hydrogen, halo, nitro, cyano, hydroxy, amino, carboxy, carbamoyl, mercapto, sulfamoyl, Ci-6alkyl, C2-βalkenyl, C2-βalkynyl, Ci-6alkoxy, Ci_6alkaneyl , C1-6alkanoyloxy, N— (C1-6alkyl) amino, N, N— (C1-6alkyl) 2amino, C1-6alkanoylamino, N— (C1-6alkyl) carbamoyl, N, N— (C1-6alkyl) 2carbamoyl, Ci_6alkylS (0) a where a is 0 to 2, C1-6 alkoxycarbonyl, N- (C1-6alkyl) sulfamoyl and N, N (C1-6alkyl) 2sulfamoyl; wherein R3 and Rδ and the other of R4 and R5 can be optionally substituted on carbon by one or more R17; X is -0-, -N (Ra) -, -S (0) b— or -CH (Ra) -; where Ra is hydrogen or Ci-6alkyl and b is 0-2; ring A is aryl or heteroaryl; wherein ring A is optionally substituted on the carbon by one or more substituents selected from R18; R7 is hydrogen, C1-6 alkyl, carbocyclyl or heterocyclyl; wherein R7 is optionally substituted on carbon by one or more substituents selected from R19; and wherein if said heterocyclyl contains an -NH- group, that nitrogen can be optionally substituted by a group selected from R20; R is hydrogen or C1-6 alkyl; R9 is hydrogen or C1-6 alkyl; R10 is hydrogen, halo, nitro, cyano, hydroxy, amino, carbamoyl, mercapto, sulfamoyl, hydroxyminocarbonyl, Ci_loalkyl, C2_i0alquinyl, C2_i0alquinyl, Ci_i0alcoxi, Ci_ loalcanoil, Ci-i0alcanoyloxi, N- (Ci-i, N- (Ci-i, N) - (Cycloalkyl) 2amino, N, N, N- (Ci-iOalkyl) 3ammonium, Cycloalkanoylamino, N- (Ci-iOalkyl) carbamoyl, N, N- (Cx-iOalkyl) 2carbamoyl, Ci-iOalkylS (O ) a where a is 0 to 2, N- (C1-10alkyl) sulfamoyl, N, N- (C1-10alkyl) 2sulfamoyl, N- (C1-10alkyl) sulfamoylamino, N, N- (C1-10alkyl) 2sulfamoylamino , Cycloalkoxycarbonylamino, carbocyclyl, carbocyclylCi-10alkyl, heterocyclyl, heterocyclylCi-10alkyl, carbocyclyl- (Cycloalkylene) p-R21- (Cy-ioalkylene) q- or heterocyclyl- (Cx-10alkylene) r-R22- (Ci- 10 alkylene) s-; wherein R10 is optionally substituted on carbon by one or more substituents selected from R23; and wherein if said heterocyclyl contains an NH group, that nitrogen can be optionally substituted by a group selected from R24; or R10 is a Formula group (VB):
where: R11 is hydrogen or C1-6-alkyl; R12 and R13 are independently selected from hydrogen, halo, carbamoyl, sulphamoil, Ci-10alkyl, C2-10alkynyl, C2-10alkynyl, C1-10alkanoyl, N- (C1-10alkyl) carbamoyl, N, N- (Ci-iOalkyl) 2carbamoyl, CycloalkylS (O) a where a is 0 to 2, N- (Ci-iOalkyl) sulfamoyl, N, N- (Ci-ioalkyl) 2sulfamoyl, N- (Ci-iOalkyl) sulfamoylamino, N , N- (Ci-ioalkyl) 2 south phamoylamino, carbocyclyl or heterocyclyl; wherein R12 and R13 can independently be optionally substituted on carbon by one or more substituents selected from R25; and wherein if said heterocyclyl contains an -NH- group, that nitrogen can be optionally substituted by a group selected from R26; R14is selected from hydrogen, halo, carbamoyl, sulfamoyl, hydroxyminocarbonyl, C1-10 alkyl, C2-10 alkenyl, C2_10 alquinyl, C1-10 alkanoyl, N- (Ci_ loalkyl) carbamoyl, N, N- (Ci_10alkyl) 2carbamoil, Ci_O (O) where a is 0 to 2, N- (C1-10alkyl) sulfamoyl, N, N- (Cicalylalkyl) 2sulfameyl, N- (C1-10alkyl) sulfamoylamino, N, N- (C1-10alkyl) 2sulfamoylamino, carbocyclyl, carbocyclylC1-10alkyl, heterocyclyl, heterocyclylC1-10alkyl, carbocyclyl- (C1-10alkylene) P-R27- (C1-10alkylene) q- or heterocyclyl- (C1-10alkylene) r-R28- (C1-10alkylene) s-; wherein R14 can be optionally substituted on carbon by one or more substituents selected from R29; and wherein if said heterocyclyl contains an -NH- group, that nitrogen can be optionally substituted by a selected group of R30; or R14 is a Formula group (VC):
R15 is hydrogen or C1-6 alkyl; and R16 is hydrogen or C1-6 alkyl; wherein R1 6 may be optionally substituted on carbon by one or more selected groups of R31; or R15 and R16 together with the nitrogen to which they are attached form a heterocyclyl; wherein said heterocyclyl can be optionally substituted on carbon by one or more R37; and wherein if said heterocyclyl contains an -NH- group, that nitrogen can be optionally substituted by a group selected from R38; m is 1-3; wherein the values of R7 can be the same or different; R17, R18, R19, R23, R25, R29, R31 and R37 are independently selected from halo, nitro, cyano, hydroxy, amino, carbamoyl, mercapto, sulfamoyl, hydroxyminocarbonyl, Ci_10alkyl, C2-ioalkenyl, C2_loalquinyl, Ci-ioalcoxy, C1-10alkanoyl, C1-10alkanoyloxy, N- (Cyloalkyl) amino, N, N- (C1-10alkyl) 2amino, N, N, N- (C1-10alkyl) 3ammonio, Ci-i0alkanoylamino, N- (Ci- iOalkyl) carbamoyl, N, N- (Ci-iOalkyl) 2carbamoyl, Ci_loalkylS (0) a where a is 0 to 2, N- (Ci-iOalkyl) sulfamoyl, N, N- (Ci-ioalkyl) 2sulfameyl, N- (C1-10alkyl) sulfamoylamino, N, N- (C1-10alkyl) 2sulfameylamino, C1-10 alkoxycarbonylamino, carbocyclyl, carbocyclylC1-10alkyl, heterocyclyl, heterocyclylCi-ioalkyl, carbocyclyl (C1-10-alkylene) P-R32 C1-10alkylene) q- or heterocyclyl- (C1-10alkylene) r-R33- (C1-10alkylene) s-; wherein R17, R18, R19, R23, R25, R29, R31 and R37 can independently be optionally substituted on carbon by one or more R34; and wherein if said heterocyclyl contains an -NH- group, that nitrogen can be optionally substituted by a group selected from R35; R21, R22, R27, R28, R32OU R33 are independently selected from -0-, -NR36-, -S (0) x-, -NR36C (0) NR36-, - NR36C (S) NR36-, -OC (O ) N = C-, -NR36C (O) - OR -C (O) NR36-; where R36 is selected from hydrogen or C1-6alkyl, ex is 0-2; p, q, res are independently selected from 0-2; R34 is selected from halo, hydroxy, cyano, carbamoyl, ureido, amino, nitro, carbamoyl, mercapto, sulfamoyl, trifluormethyl, trifl uoromethoxy, methyl, ethyl, methoxy, ethoxy, vinyl, alii, ethinyl, formyl, acetyl, formed, acetylamino , acetoxy, methylamino, dimethylamino, N-methylcarbamoyl, N, N-dimethylcarbamoyl, methylthio, methylsulfinyl, mesyl, N-methylsulfamoyl, N, N-dimethylsulfamoyl, N-methylsulfamoylamino and N, N-dimethylsulfamoylamino; R20, R24, R26, R30, R35 and R38 are independently selected from Ci_6alkyl, Ci_6alkanoyl, Ci-6alkylsulfonyl, Ci_6alkoxycarbonyl, carbamoyl, N- (Ci_6alkyl) carbamoyl, N, N- (Ci-6alkyl) carbamoyl, benzyl, benzyloxy and phenylsulfonyl; and where a "heteroaryl" is a totally unsaturated mono- or bicyclic ring containing 3-12 atoms of which at least one atom is chosen from nitrogen, sulfur and oxygen, whose heteroaryl may, unless otherwise specified, be carbon or bound nitrogen; wherein a "heterocyclyl" is a saturated, partially saturated or unsaturated mono or bicyclic ring containing 3-12 atoms of which at least one atom is chosen from nitrogen, sulfur and oxygen, which heterocyclyl can, unless otherwise specified , be carbon or nitrogen bonded, where a -CH2- group can be optionally substituted by a -C (0) - group, and a ring sulfur atom can be optionally oxidized to form an S-oxide; and wherein a "carbocyclyl" is a saturated, partially saturated or unsaturated mono or bicyclic carbon ring containing 3-12 atoms; wherein a -CH2- group can be optionally substituted by a -C (0) group; or a pharmaceutically acceptable salt or ester or amide hydrolyzable in vivo formed in a carboxy or hydroxy group available therefrom.
In some modalities, R4 and R5 is not S-CH3 and / or
wherein R1 is H or hydroxy 1; and R2 is H, CH3, -CH2CH3, -CH2CH2CH3, -CH2CH2CH2CH3, -OUCHES, -CH2CH (CH3) 2, CH (CH3) CH2CH3, -CH2OH, -CH2OCH3, -CH (OH) CH3, -CH2SCH3, OR - CH2CH2SCH3.
In some embodiments, the Formula V compound is not 1,1-dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8 - (N- {((R) -a- [N- ((R) -1-carboxy-2-methylthio-ethyl) carbamoyl] -4-hydroxybenzyl) carbamoylmethoxy) -2,3,4,5-tetrahydro-1,2,5-benzothiadiazepine; 1,1-dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8- (N - {(R) -a- [N - ((S) -1-carboxy-2- (R) - hydroxypropyl) carbamoyl] -4-hydroxybenzyl) carbamoylmethoxy) - 2,3,4,5-tetrahydro-1,2,5-benzothiadiazepine; 1,1-dioxo-3,3 - dibutyl-5-phenyl-7-methylthio-8 - (N- {(R) -a- [N - ((S) -1-carboxy-2-methylpropyl) carbamoyl] -4-hydroxybenzyl) carbamoylmethoxy) - 2,3,4,5-tetrahydro-1,2,5-benzothiadiazepine; 1,1-dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8 - (N- {(R) -a- [N - ((S) -1- carboxybutyl) carbamoyl] -4-hydroxybenzyl ) carbamoylmethoxy) - 2,3,4,5-tetrahydro-1,2,5-benzothiadiazepine; 1,1-dioxo-3,3 - dibutyl-5-phenyl-7-methylthio-8 - (N- {(R) -a- [N - ((S) -1- carboxypropyl) carbamoyl] benzyl) carbamoylmethoxy) -2,3,4,5-tetrahydro-1,2,5-benzothiadiazepine; 1,1-dioxo-3,3-dibutyl - 5-phenyl-7-methylthio-8- (N - {(R) -a- [N - ((S) -1-carboxyethyl) carbamoyl] benzyl) carbamoylmethoxy) -2,3,4,5-tetrahydro-1,2,5-benzothiadiazepine; 1,1-dioxo-3,3-dibutyl-5-phenyl-7 - methylthio-8- (N - {(R) -α- [N - ((S) -l-carboxy-2- (R) - hydroxypropyl) carbamoyl] benzyl) carbamoylmethoxy) -2,3,4,5-tetrahydro-1,2,5-benzothiadiazepine; 1,1-dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8- (N - {(R) -a- [N- (2-sulfoethyl) carbamoyl] - 4-hydroxybenzyl) carbamoylmethoxy) - 2,3,4,5-tetrahydro-1,2,5-benzothiadiazepine; 1,1-dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8- (N - {(R) -α- [N - ((S) -1-carboxyethyl) carbamoyl] -4-hydroxybenzyl ) carbamoylmethoxy) -2,3,4,5-tetrahydro-1,2,5-benzothiadiazepine; 1,1-dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8- (N - {(R) -α- [N - ((R) -1-carboxy-2-methylthioethyl) carbamoyl] benzyl) carbamoylmethoxy) -2,3,4,5-tetrahydro-1,2,5-benzothiadiazepine; 1,1-dioxo-3,3-dibutyl-5-phenyl-7 - methylthio-8- (N - {(R) -α- [N - {(S) -1- [N - ((S) - 2-hydroxy-1-carboxyethyl) carbamoyl] propyl) carbamoyl] benzyl) carbamoylmeth xi) -2,3,4,5-tetrahydro-1,2,5-benzothiadiazepine; 1,1-dioxo- 3,3-dibutyl-5-phenyl-7-methylthio-8- (N - {(R) -α- [N - ((S) -1- carboxy-2-methylpropyl) carbamoyl] benzyl) carbamoylmethoxy) - 2,3,4,5-tetrahydro-1,2,5-benzothiadiazepine; 1,1-dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8- (N - {(R) -α- [N - ((S) -1- carboxypropyl) carbamoyl] -4-hydroxybenzyl ) carbamoylmethoxy) - 2,3,4,5-tetrahydro-1,2,5-benzothiadiazepine; 1,1-dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8- [N - {(R) -α-carboxy-4-hydroxybenzyl) carbamoylmethoxy] -2,3,4,5-tetrahydro -1,5,5-benzothiadiazepine; or 1,1-dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8- (N - {(R) -a- [N- (carboxy) carbamoyl] benzyl) carbamoylmethoxy) -2,3, 4,5-tetrahydro-1,2,5-benzothiadiazepine
In some embodiments, the Formula V compound is not

In some embodiments, an ASBTI suitable for those is a compound of Formula VI:
where: Rv and Rw are independently selected from hydrogen or Ch-galquil; one from R1 and R2 is selected from hydrogen or Ci-6alkyl and the other is selected from Ci-Salquil; Rx and RY are independently selected from hydrogen or Ci-6alkyl, or one from Rx and Ryé hydrogen or Ci-6alkyl and the other is hydroxy or Ci-Salcoxi; Rzé selected from halo, nitro, cyano, hydroxy, amino, carboxy, carbamoyl, mercapto, sulfamoyl, Ci-6alkyl, C2-6al kenyl, C2-βalkynyl, Ci-6alcoxy, Ci-5alkanoyl, Ci- 6 alkanoyloxy, N- (Ci -6alkyl) amino, N, N (C1-6alkyl) 2amino, C1-6alkanoylamino, N- (C1-6alkyl) carbamoyl, N, N- (C1-6alkyl) 2carbamoyl, Ci-SalquylS (0) where a is 0 a 2, C1-6 alkoxycarbonyl, N (C1-6 alkyl) sulfamoyl and N, N (C1-6 alkyl) 2 sulfamoyl; n is 0 - 5; one of R4 and R5 is a Formula group (VIA):
R3 and R6 and the other from R4 and R5 are independently selected from hydrogen, halo, nitro, cyano, hydroxy, amino, carboxy, carbamoyl, mercapto, sulfamoyl, Ci-6alkyl, C2-βalkenyl, C2-βalkynyl, Ci-6alkoxy, C1-6alkanoyl, C1-6alkanoyloxy, N- (C1-6alkyl) amino, N, N- (C1-6alkyl) 2amino, Ci-6alkanoylamino, N- (C1-6alkyl) carbamoyl, N, N- (Cx- 6alkyl) 2carbamoyl, C1-6 alkylS (0) a where a is 0 to 2, C1-6 alkoxycarbonyl, N- (C1-6 alkyl) sulfamoyl and N, N- (Ca.- 6 alkyl) 2 sulfamoyl; wherein R3 and R6 and the other of R4 and R5 can be optionally substituted on carbon by one or more R17; X is -0-, -N (Ra) -, -S (O) b- or -CH (Ra) -; where Ra is hydrogen or Ci-6alkyl and b is 0-2; Ring A is aryl or heteroaryl; wherein ring A is optionally substituted on the carbon by one or more substituents selected from R18; R7 is hydrogen, C1-6 alkyl, carbocyclyl or heterocyclyl; wherein R7 is optionally substituted on carbon by one or more substituents selected from R19; and wherein if said heterocyclyl contains an -NH- group, that nitrogen can be optionally substituted by a group selected from R20; R8 is hydrogen or C1-6 alkyl; R9 is hydrogen or C1-6 alkyl; R10 is hydrogen, halo, nitro, cyano, hydroxy, amino, carbamoyl, mercapto, sulfamoyl, hydroxyminocarbonyl, C1-10 alkyl, C2-1 Oalkenyl, C2-ioalkynyl, Ci_10alcoxy, Ci_loalcanoyl, Ci-i0alkanoyloxy, N- (Ci-iOal ) amino, N, N- (C1- loalkyl) 2amino, N, N, N- (C1-10alkyl) 3ammonium, C2_loalkanoylamino, N- (Ci-iOalkyl) carbamoyl, N, N- (Ci_ loalkyl) 2carbamoyl, Ci- iOalkylS (0) a where a is 0 to 2, N- (Cycloalkyl) sulfamoyl, N, N- (Ci-iOalkyl) 2sulfamoyl, N- (Ci_ loalkyl) sulfamoylamino, N, N- (Cy- iOalkyl) 2sulfamoylamino, C2-loalkoxycarbonylamino, carbocyclyl, carbocyclylC1-10 alkyl, heterocyclyl, heterocyclylCi-i0alkyl, carbocyclyl- (C2_ loalkyl) p-R21- (Cy-ioalkylene) q- or heterocyclyl- (Cy- ) s- ; wherein R10 is optionally substituted on carbon by one or more substituents selected from R23; and wherein if said heterocyclyl contains an -NH- group, that nitrogen can be optionally substituted by a group selected from R24; or R10 is a Formula group (VIB):
where: R11is hydrogen or Ci-6alkyl; R12 and R13 are independently selected from hydrogen, halo, nitro, cyano, hydroxy, amino, carbamoyl, mercapto, sulfamoyl, Cx-xoalkyl, C2-i0alkenyl, C2-i0alkynyl, Ci-i0alkoxy, Ci-ioalkanoyl, Ci-i0alkanoyloxy, N- (Ci- iOalkyl) amino, N, N- (Cx-xoalkyl) 2amino, C1-10 alkanoylamino, N- (C1-10 alkyl) carbamoyl, N, N- (C1-10 alkyl) 2carbamoyl, C1-10alkylS (O) a in that a is 0 to 2, N- (C1-10 alkyl) sulfamoyl, N, N- (C1-10 alkyl) 2 sulfamoyl, N- (C1-10 alkyl) sulfamoylamino, N, N- (Ci-ioalkyl) 2 sulfamoylamino, carbocyclyl or heterocyclyl; wherein R12 and R13 may independently be optionally substituted on carbon by one or more substituents selected from R25; and wherein if said heterocyclyl contains an -NH- group, that nitrogen can be optionally substituted by a group selected from R26; R14 is selected from hydrogen, halo, nitro, cyano, hydroxy, amino, carbamoyl, mercapto, sulfamoyl, hydroxyminocarbonyl, Ci-iOalkyl, C2-i0alkenyl, C2_ iOalquinyl, Ci-i0alcoxy, Ci-i0alcanoil, Cl - lOalcanoiloxi, N- ( C1-10 alkyl) amino, N, N- (C1-10 alkyl) 2amino, N, N, N- (C1-10 alkyl) 3ammonium, C1-10 alkanoylamino, N- (C1-10 alkyl) carbamoyl, N, N- (C1-10) iOalkyl) 2carbamoyl, Ci- iOalkylS (O) a where a is 0 to 2, N- (Ci-iOalkyl) sulfamoyl, N, N- (Ci-ioalkyl) 2sulfamoyl, N- (Ci-iOalkyl) sulfamoylamino , N, N- (C1-10alkyl) 2sulfamoylamino, C1-10 alkoxycarbonylamino, carbocyclyl, carbocyclylC1-10 alkyl, heterocyclyl, heterocyclylC1-10alkyl, carbocyclyl- (C1-10- alkylene) P-R27- (C1-10 alkylene) q- or hetero- C1-10 alkylene) r-R28- (C1-10 alkylene) s-; wherein R14 may be optionally substituted on carbon by one or more substituents selected from R29; and wherein if said heterocyclyl contains an -NH- group, that nitrogen can be optionally substituted by a group selected from R30; or R14 is a Formula group (VIC):
R15 is hydrogen or C1-6 alkyl; R16 is hydrogen or C1-6 alkyl; wherein R16 can be optionally substituted on carbon by one or more groups selected from R31; n is 1-3; wherein the values of R7 can be the same or different; R17, R18, R19, R23, R25, R29 or R31 are independently selected from halo, nitro, cyano, hydroxy, amino, carbamoyl, mercapto, sulfamoyl, hydroxyminocarbonyl, amidino, Ci-ioalkyl, C2_10alkenyl, C2-i0alquinyl, Ci-ioalkoxy , Ci-ioalkanoyl, Ci-i0alkanoyloxy, (Ci-iOalkyl) 3silyl, N- (Cycloalkyl) amino, N, N- (Ci-iOalkyl) 2amino, N, N, N- (Cyloalkyl) 3ammonio, Ci -i0alkanoylamino, N- (C1-10 alkyl) carbamoyl, N, N- (C1-10 alkyl) 2carbamoyl, C1-00 alkylS (O) a where a is 0 to 2, N- (C1-10 alkyl) sulfamoyl, N, N- (C1-10alkyl) 2sulfamoyl, N- (Cj-ioalkyl) sulfamoylamino, N, N- (C1-10alkyl) 2sulfamoylamino, C1-10alkoxycarbonylamino, carbocyclyl, carbocyclylCi-10alkyl, heterocyclyl, heterocyclyl-carbocyclyl 10alkylene) P-R32- (C1-10alkylene) q- or heterocyclyl- (C1-10alkylene) r-R33- (C1-10alkylene) s-; wherein R17, R18, R19, R23, R25, R29 or R31 may independently be optionally substituted on carbon by one or more R34; and wherein if said heterocyclyl contains an -NH- group, that nitrogen can be optionally substituted by a group selected from R35; R21, R22, R27, R28, R32 OR R33 are independently selected from -0-, -NR36-, -S (0) x-, -NR36C (0) NR36-, NR36C (S) NR36-, -OC (O ) N = C-, -NR36C (O) - OR -C (O) NR36-; where R36 is selected from hydrogen or C1-6alkyl, ex is 0-2; p, q, res are independently selected from 0-2; R34 is selected from halo, hydroxy, cyano, carbamoyl, ureido, amino, nitro, carbamoyl, mercapto, sulfamoyl, trifluormethyl, trifl uoromethoxy, methyl, ethyl, methoxy, ethoxy, vinyl, alii, ethinyl, formyl, acetyl, formed, acetylamino , acetoxy, methylamino, di methylamino, N-methylcarbamoyl, N, N-dimethylcarbamoyl, methylthio, methylsulfinyl, mesyl, N-methylsulfamoyl, N, N-dimethylsulfamoyl, N-methylsulfamoylamino and N, N-dimethylsulfamoylamino; R20, R24, R26, R30 or R35 are independently selected from C1-6alkyl, C1-6alkanoyl, C1-6alkylsulfonyl, C1-6alkoxycarbonyl, carbamoyl, N- (C1-6alkyl) carbamoyl, N, N- (Ci-6alkyl) carbamoyl, benzyl, benzyloxycarbonyl, benzoyl and phenylsulfonyl; or a pharmaceutically acceptable salt, solvate or solvate of such a salt, or a hydrolyzable ester in vivo formed in a carboxy or hydroxy available therefrom, or either a hydrolyzable amide in vivo formed in a carboxy available therefrom. In some embodiments, a Formula VI compound has the Formula VID structure:
where: R1 and R2 are independently selected from C1-6 alkyl; one of R4 and R5 is a group of Formula (VIE):
R3 and R6 and the other from R4 and R5 are independently selected from hydrogen, halo, nitro, cyano, hydroxy, amino, carboxy, carbamoyl, mercapto, sulfamoyl, C1-4alkyl, C2.4alkenyl, C2-4alkynyl, C4 alkoxy, C1-4alkanoyl, C1-4alkanoyloxy, N- (C4alkyl) amino, N, N- (C1-4alkyl) 2amino, C1-4alkanoylamino, N- (C1-4alkyl) carbamoyl, N, N- (C1-4alkyl) 2carbamoyl, C1-4 alkylS (O) a where a is 0 to 2, C1-4 alkoxycarbonyl, N- (C1-4alkyl) sulfamoyl and N, N- (C1-4alkyl) 2sulfamoyl; wherein R3 and R6 and the other of R4 and R5 can be optionally substituted on carbon by one or more R14; R7 is carboxy, sulpho, sulfine, phosphono, -P (0) (0Ra) (0Rb), P (O) (OH) (0Ra), -P (0) (OH) (Ra) or P (0) ( 0Ra) (Rb), where Ra and Rb are independently selected from C1-6alkyl; or R7is a Formula group (VIF):
R8 and R9 are independently hydrogen, C1-4 alkyl or a saturated cyclic group, or R8 and R9 together form C2-Salkylene; wherein R8 and R9 or R8 and R9 together can be optionally independently substituted on carbon by one or more substituents selected from R15; and wherein if said saturated cyclic group contains an -NH- moiety, that nitrogen can be optionally substituted by one or more R20; R10 is hydrogen or C1-4 alkyl; wherein R10 is optionally substituted on carbon by one or more substituents selected from R24; R11 is hydrogen, C1-4 alkyl, carbocyclyl or heterocyclyl; wherein R11 is optionally substituted on carbon by one or more substituents selected from R16; and wherein if said heterocyclyl contains an -NH- moiety, that nitrogen can be optionally substituted by one or more R; R12 is hydrogen or C1-4 alkyl, carbocyclyl or heterocyclyl; wherein R12 optionally substituted on carbon by one or more substituents selected from R17; and wherein if said heterocyclyl contains an -NH- moiety, that nitrogen can be optionally substituted by one or more R; R13 is carboxy, sulfo, sulfine, phosphono, -P (0) (ORc) (ORd), -P (0) (OH) (ORc), - P (0) (OH) (Rc) or -P (0 ) (ORc) (Rd) where Rc and Rd are independently selected from C1-6 alkyl; m is 1-3; wherein the values of R8 and R9 may be the same or different; n is 1-3; wherein the values of R11 may be the same or different; p is 1-3; wherein the values of R12 may be the same or different; R14 and Rlδ are independently selected from halo, nitro, cyano, hydroxy, amino, carboxy, carbamoyl, mercapto, sulfamoyl, Ci-4alkyl, C2_4alkenyl, C2_4alkynyl, Ci-4alkoxy, Ci_4alkanoyl, Ci-4alkanoyloxy, N- (Ci-4alkyl) , N, N- (C1-4alkyl) 2amino, C1-4alkanoylamino, N- (C1-4alkyl) carbamoyl, N, N- (C1-4alkyl) 2carbamoyl, Ci_4alkylS (0) a where a is 0 to 2, Ci-4alkoxycarbonyl , N- (C1-4alkyl) sulfamoyl and N, N- (C1-4alkyl) 2 sulfamoyl; wherein R14 and Rlδ can independently be optionally substituted on carbon by one or more R; R15 and R17 are independently selected from halo, nitro, cyano, hydroxy, amino, carboxy, carbamoyl, mercapto, sulfamoyl, C1-4alkyl, C2_4alkenyl, C2_4alkynyl, Ci-4alkoxy, Ci_4alkanoyl, Ci_4alkanoyloxy, N- (Ci-4alkyl) amino N, N- (C1-4alkyl) 2amino, C1-4alkanoylamino, N- (C1-4alkyl) carbamoyl, N, N- (C1-4alkyl) 2carbamoyl, Ci_4alkylS (0) a where a is 0 to 2, Ci-4alkoxycarbonyl, N- (C1-4alkyl) sulfamoyl and N, N- (C1-4alkyl) 2sulfamoyl, carbocyclyl, heterocyclyl, sulfo, sulfine, amidino, phosphono, - P (0) (0Re) (0Rf), -P (0) ( OH) (0Re), -P (0) (OH) (Re) or -P (0) (0Re) (Rf), where Re and Rf are independently selected from C1-6 alkyl; wherein R15 and R17 can independently be optionally substituted on carbon by one or more R19; and wherein if said heterocyclyl contains an -NH- moiety, that nitrogen can be optionally substituted by one or more R23; R18, R19 and R25 are independently selected from halo, hydroxy, cyano, carbamoyl, amino nitro ureido, carboxy, carbamoyl, mercapto, sulfamoyl, trifluoromethyl, trifluormethoxy, methyl, ethyl, methoxy, ethoxy, vinyl, alii, ethyl, methoxycarbonyl, formyl , acetyl, formamide, acetylamino, acetoxy, methylamino, dimethylamino, N-methylcarbamoyl, N, N-dimethylcarbamoyl, methylthio, methylsulfinyl, mesyl, N-methylsulfamoyl and N, N-dimethylsulfamoyl; R20, R21, R22, R23 and R26 are independently C1-4alkyl, C1-4alkanoyl, C1-4alkylsulfonyl, sulfamoyl, N- (C1-4alkyl) sulfamoyl, N, N- (C1-4alkyl) 2sulfamoyl, C1-4alkoxycarbonyl, carbamoyl, N- (C1-4alkyl) carbamoyl, N, N- (C1-4alkyl) 2carbamoyl, benzyl, phenethyl, benzoyl, phenylsulfonyl and phenyl; R24is selected from halo, nitro, cyano, hydroxy, amino, carboxy, carbamoyl, mercapto, sulfamoyl, C1-4alkyl, C2_4alkenyl, C2_4alkynyl, Ci-4alkoxy, Ci-4alkanoyl, C4_ 4alkanoyloxy, N- (Ci_4alkyl) amino, N, N - (C ^ alkyl) 2amino, C4_4alkanoylamino, N- (C1-4alkyl) carbamoyl, N, N- (C1-4alkyl) 2carbamoyl, C1-4alkylS (0) a where a is 0 to 2, C4_4alkoxycarbonyl, N- (Ci- 4alkyl) sulfamoyl and N, N- (C1-4alkyl) 2sulfamoyl, carbocyclyl, heterocyclyl; wherein R24 can independently be optionally substituted on carbon by one or more R25; and wherein if said heterocyclyl contains an -NH- moiety, that nitrogen can be optionally substituted by one or more R26; wherein any saturated cyclic group is a mono- or bicyclic ring, fully or partially saturated, contains 3-12 atoms of which 0-4 atoms are chosen from nitrogen, sulfur or oxygen, which can be carbon or nitrogen bonded; where any heterocyclyl is a saturated, partially saturated or unsaturated mono or bicyclic ring containing 3-12 atoms of which at least one atom is chosen from nitrogen, sulfur or oxygen, which may be carbon or nitrogen bond, in which a group -CH2- can be optionally substituted by a -C (0) - or a sulfur ring atom can be optionally oxidized to form the S-oxides; and wherein any carbocyclyl is a saturated, partially saturated or unsaturated mono or bicyclic carbon ring containing 3-12 atoms, where a -CH2- group can be optionally substituted by a -C (0) -; or a pharmaceutically acceptable salt thereof. In some embodiments, a compound of Formula IV is 1,1-dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8- (N - {(R) -1'- phenyl-1 '- [N '- (carboxyl) carbamoyl] methyl} carbamoylmethoxy) -2,3,4,5-tetrahydro-1,5-benzothiazepine; 1,1-dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8- (N - {(R) -α- [N'- ((S) -1-carboxypropyl) carbamoyl] -4- hydroxybenzyl} carbamoylmethoxy) -2,3,4,5-tetrahydro-1,5-benzothiazepine; 1,1-dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8 - (N - {(R) -1'-phenyl-1 '- [N' - (carboxy) carbamoyl] methyl} carbamoylmethoxy ) -2,3,4,5-tetrahydro-1,5-benzothiazepine; 1,1-dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8- (N - {(R) -α- [N'- ((S) -1-carboxyethyl) carbamoyl] benzyl} carbamoylmethoxy ) - 2,3,4,5-tetrahydro-1,5-benzothiazepine; or a salt like that. In some embodiments, any compound described herein is covalently conjugated to a bile acid using any suitable method. In some embodiments, the compounds described herein are covalently linked to a cyclodextrin or a biodegradable polymer (for example, a polysaccharide). In certain embodiments, the compounds described herein are not systemically absorbed. In addition, compounds are provided herein that inhibit the recycling of bile salt in an individual's gastrointestinal tract. In some embodiments, the compounds described herein may not be transported from the intestinal lumen and / or do not interact with ASBT. In some embodiments, the compounds described here do not affect, or minimally affect, fat digestion and / or absorption. In certain embodiments, administration of a therapeutically effective amount of any compound described herein does not result in gastrointestinal disturbance or lactic acidosis in an individual. In certain embodiments, the compounds described herein are administered orally. In some embodiments, an ASBTI is released into the distal ileum. An ASBTI compatible with the methods described herein can be a direct inhibitor, an allosteric inhibitor, or a partial inhibitor of the apical sodium-dependent bile acid transporter. In certain embodiments, compounds that inhibit ASBT or any bile acid recovery transport are compounds that are described in EP1810689, US Patent Nos. 6,458,851, 7,413,536, 7,514,421, US Order Publication Nos. 2002/0147184, 2003/0119809, 2003/0149010, 2004/0014806, 2004/0092500, 2004/0180861, 2004/0180860, 2005/0031651, 2006/0069080, 2006/0199797, 2006/0241121, 2007/0065428, 2007 /0065428, 2007 / 0066644, 2007/0161578, 2007/0197628, 2007/0203183, 2007/0254952, 2008/0070888, 2008/0070892, 2008/0070889, 2008/0070984, 2008/0070984, 2008/0089858, 2008/0096921, 2008/0161400, 2008/0167356, 2008/0194598, 2008/0255202, 2008/0261990, WO 2002/50027, W02005 / 046797, W02006 / 017257, W02006 / 105913, W02006 / 105912, WO2006 / 116499, W02006 / 117076, W02006 / 121861, WO2006 / 122186, WO2006 / 122186, WO2006 / 122186 / 124713, W02007 / 050628, W02007 / 101531, WO2007 / 134862, W02007 / 140934, W02007 / 140894, W02008 / 028590, W02008 / 033431, W02008 / 033464, W02008 / 031501, W02008 / 0334, W02008 / 0315, 0 , W02008 / 039829, W02008 / 064788, W02008 / 064789, W02008 / 088836, W02008 / 104306, W02008 / 124505, and WO2008 / 130616; the compounds therein which inhibit bile acid recovery transport are incorporated herein by reference. In certain embodiments, compounds that inhibit ASBT or any bile acid recovery transport are compounds described in WO93 / 16055, WO94 / 18183, WO94 / 18184, WO96 / 05188, WO96 / 08484, WO96 / 16051, WO97 / 33882, WO98 / 38182, WO99 / 35135, WO98 / 40375, WO99 / 64409, WO99 / 64410, WO00 / 01687, WOOO / 47568, WOOO / 61568, DE19825804, WOOO / 38725, WOOO / 38726, WOOO / 38727 (including those compounds with a structure 2,3,4,5-tetrahydro-1-benzothiepine 1,1-dioxide), WOOO / 38728, WOOl / 66533, W002 / 50051, EP0864582 (eg (3R, 5R) -3-butyl-3 acid -ethyl-1,1-dioxide-5-Phenyl-2,3,4,5-tetrahydro-1,4-benzo-thiazepin-8-yl (β-D-glucopyranosidurδnic, WO94 / 24087, WO98 / 07749, WO98 / 56757, WO99 / 32478, WO99 / 35135, WO00 / 20392, WO00 / 20393, WO00 / 20410, WO00 / 20437, W001 / 34570, WOOO / 35889, WOOl / 68637, W001 / 68096, W002 / 08211, W003 / 020710 , WO03 / 022825, W003 / 022830, WO03 / 0222861, JP10072371, US Patent Nos. 5,910,494; 5,723,458; 5,817,652; 5,663,165; 5,998,400; 6,458,451; 6,465,451; 5,994,391; 6,107,494; 6,107,494; ; 6,387,924; 6,784.20 1; 6,875,877; 6,740,663; 6,852,753; 5,070,103, 6,114,322, 6,020,330, 7,179,792, EP251315, EP417725, EP489-423, EP549967, EP573848, EP624593, EP624594, EP624595, EP869121, EP1070703, W004 / 005247, compounds disclosed to have IBAT activity in "Drugs of the Future", 24, 425 -430 (1999), Journal of Medicinal Chemistry, 48, 5,837-5,852, (2005) and Current Medicinal Chemistry, 13, 997-1,016, (2006); the compounds described therein which inhibit bile acid recovery transport are incorporated herein by reference. In some embodiments, compounds that inhibit ASBT or any bile acid recovery transport are benzothiepines, benzothiazepines (including 1,2-benzothiazepines; 1,4-benzothiazepines; 1,5-benzothiazepines; and / or 1,2,5-benzothiadiazepines ). In some embodiments, compounds that inhibit ASBT or any bile acid recovery transport include, without limitation, S-8921 (disclosed in EP597107, WO 93/08155), 264W94 (GSK) disclosed in WO 96/05188; SC-435 (1- [4 - [4 - [(4R, 5R) - 3,3-dibutyl-7- (dimethylamino) -2,3,4,5-tetrahydro-4-hydroxy-1,1-dioxide -l-benzothiepin-5-yl] phenoxy] butyl] 4-aza-1-azoniabicyclo [2.2.2] octane methanesulfonate), SC-635 (Searle); 2164U90 (3-butyl-3-ethyl-2,3,4,5-tetrahydro-5-phenyl-1,4-benzothiazepine 1,1-dioxide); BARI-1741 (Aventis SA), AZD 7508 (Astra Zeneca); barixibat (11- (D-gluconamido) -N- {2 - [(1S, 2R, 3S) -3-hydroxy-3-phenyl-2- (2-pyridyl) -1- (2-pyridylamino) Propyl] phenyl } undecanamide) or others, or combinations thereof. In some modalities, an ASBTI is:
In certain embodiments, the compounds described herein have one or more chiral centers. As such, all stereoisomers are provided for here. In various embodiments, the compounds described herein are present in optically active or racemic forms. It is to be understood that the compounds of the present invention encompass racemic, optically active, regioisomeric and stereoisomeric forms, or combinations thereof which have the therapeutically useful properties described herein. The preparation of optically active forms is carried out in any suitable manner, including, as a non-limiting example, by resolving the racemic form by recrystallization techniques, by synthesis from optically active starting materials, by chiral synthesis, or by chromatographic separation using a chiral stationary phase. In some embodiments, mixtures of one or more isomers are used as the therapeutic compound described herein. In certain embodiments, the compounds described herein contain one or more chiral centers. These compounds are prepared by any means, including enantioselective synthesis and / or separation of a mixture of enantiomers and / or diastereomers. The resolution of compounds and isomers of these is accomplished by any means including, as a non-limiting example, chemical processes, enzymatic processes, fractional crystallization, distillation, chromatography, and others. The compounds described herein, and other related compounds that have different substituents are synthesized using the techniques and materials described herein and as described, for example, in Fieser and Fieser's "Reagents for Organic Synthesis", Volumes 1-17 (John Wiley and Sons, 1991); Rodd's Chemistry of Carbon Compounds, Volumes 1-5 and Supplements (Elsevier Science Publishers, 1989); "Organic Reactions", Volumes 1-40 (John Wiley and Sons, 1991), Larock's Comprehensive Organic Transformations (VCH Publishers Inc., 1989), March, "ADVANCED ORGANIC CHEMISTRY" 4aEd., (Wiley 1992); Carey and Sundberg, "ADVANCED ORGANIC CHEMISTRY" 4th Ed., Vols. A and B (Plenum 2000, 2001), and Green and Wuts, "PROTECTIVE GROUPS IN ORGANIC SYNTHESIS" 3aEd., (Wiley 1999) (all are incorporated herein by reference for such disclosure). General methods for preparing the compound as described herein are modified by the use of suitable reagents and conditions, for the introduction of the various portions found in the formulas as provided herein. As a guide the following synthetic methods are used. Formation of covalent bonds by reaction of an electrophile with a nucleophile The compounds described herein are modified with the use of various electrophiles and / or nucleophiles to form new functional or substituent groups. Table A entitled "Examples of covalent bonds and precursors thereof" lists selected non-limiting examples of covalent bonds and functional precursor groups that produce covalent bonds. Table A is used as a guide to the variety of combinations of electrophiles and / or nucleophiles available that provide covalent bonds. Precursor functional groups are shown as electrophilic groups and nucleophilic groups. Table A: Examples of covalent bonds and precursors to these

Use of protection groups In the reactions described, it is necessary to protect reactive functional groups, for example, hydroxy, amino, imino, uncle or carboxy groups, in which these are desired in the final product, 'to avoid their unwanted participation in reactions. Protective groups are used to block some or all of the reactive moieties and prevent such groups from participating in chemical reactions until the protective group is removed. In some modalities it is contemplated that each protective group can be removed by a different means. Protection groups that are cleaved under completely different reaction conditions meet the requirements for differential removal. In some embodiments, the protecting groups are removed by acidic, basic reducing conditions (such as, for example, hydrogenolysis), and / or oxidative conditions. Groups such as trityl, dimethoxytrityl, acetal and t-butyldimethylsilyl are unstable in acid and are used to protect reactive moieties carboxy and hydroxy in the presence of amino groups protected with Cbz groups, which are removable by hydrogenolysis, and Fmoc groups, which are unstable on a base . Carboxylic acid and reactive hydroxy moieties are blocked with unstable groups on the basis of, without limitation, methyl, ethyl, and acetyl in the presence of amines blocked with acid unstable groups such as t-butyl carbamate or with carbamates that are both unstable in acid and in base but hydrolytically removable. In some embodiments, the carboxylic acid and reactive hydroxy moieties are blocked with hydrolytically removable protecting groups such as the benzyl group, while amine groups capable of hydrogen bonding with acids are blocked with unstable groups on the basis of Fmoc. The reactive portions of carboxylic acid are protected by conversion to simple ester compounds as exemplified herein, which include conversion to alkyl esters, or are blocked with oxidatively removable protecting groups like 2,4-dimethoxybenzyl, while coexisting amino groups are blocked with fluoride unstable silyl carbamates. Allyl blocking groups are useful in the presence of acid and base protecting groups since the former are stable and are subsequently removed by metal or pi-acid catalyst. For example, an ally blocked carboxylic acid is deprotected with a catalyzed reaction with Pd ° in the presence of acid-unstable t-butyl carbamate protecting groups or base-unstable amine acetate. Yet another form of protection group is a resin to which a compound or intermediate is attached. As long as the residue is attached to the resin, the functional group of which is blocked and does not react. Once released from the resin, the functional group is available to react. Typically blocking groups / protection groups are selected from:
Other protection groups, plus a detailed description of techniques applicable to the creation of protection groups and their removal are described in Greene and Wuts, "Protective Groups in Organic Synthesis", 3aEd., John Wiley & Sons, New York, NY, 1999, and Kocienski, "Protective Groups", Tieme Verlag, New York, NY, 1994, which are hereby incorporated by reference for such disclosure.
In some embodiments, the ASBTIs described herein are synthesized as described, for example, in WO 96/05188, US Patent Nos. 5,994,391; 7,238,684; 6,906,058; 6,020,330; and 6,114,322. In some embodiments, ASBTIs described here are synthesized from compounds that are available from commercial sources or that are prepared using the procedures shown here. In some embodiments, the compounds described here are prepared according to the process shown in Scheme 1: Scheme 1:

In certain embodiments, the synthesis begins with a reaction of 1,4-diazabicyclo [2.2.2] octane with 4-iodo-1-chloro butane to provide a compound of structure 1-1. Such compounds are prepared in any suitable manner, for example, as presented in Tremont, S. J. et al. , J. Med. Chem. 2005, 48, 5.837-5.852. The compound of structure 1-1 is then subjected to a reaction with phenethylamine to provide a compound of structure 1-II. The compound of structure l-II then reacts with dicyandiamide to provide a compound of Formula I.
In some embodiments, a first compound of Formula III is subjected to an additional reaction to provide a second compound in Scheme 2 below. Scheme 2:

A first Formula III compound, 1-IA, is alkylated with iodomethane to provide a second Formula III compound, 1-IB. Alkylation of 1-IB with a compound of structure 2-II provides an additional compound of Formula III, IC. In an alternative embodiment, a first compound of Formula III, 1-IA, is alkylated with a compound of structure 2-1 to provide a second compound of Formula III, 1-IC.
In some embodiments, the compounds described here are prepared according to the process shown in Scheme 3:

General settings
The term "bile acid", as used herein, includes steroid acids (and / or their carboxylate anion), and salts thereof, found in the bile of an animal (for example, a human), including, as a non-limiting example , cholic acid, cholate, deoxycholic acid, deoxycholate, hiodesoxicolic acid, hiodesoxycholate, glycocholic acid, glycocholate, taurocholic acid, taurocholate, chenodeoxycholic acid, ursodeoxycholic acid, ursodiol, a tauroursodeoxycholic acid, a glycodesodeoxycholic acid, a 7-B-methyl , a methyl lithocholic acid, kenodeoxycholate, lithocholic acid, litocolate, and others. Taurocholic acid and / or taurocholate are referred to herein as TCA. Any reference to a bile acid used herein includes reference to a bile acid, one and only one bile acid, one or more bile acids, or at least one bile acid. Therefore, the terms "bile acid", "bile salt", "bile acid / salt", "bile acids", "bile salts", and "bile acids / salts" are, unless otherwise indicated, used interchangeably in that. Any reference to a bile acid used herein includes reference to a bile acid or a salt thereof. In addition, pharmaceutically acceptable bile acid esters are optionally used as the "bile acids" described herein, for example, bile acids / salts conjugated to an amino acid (for example, glycine or taurine). Other bile acid esters include, for example, substituted or unsubstituted alkyl ester, substituted or unsubstituted heteroalkyl esters, substituted or unsubstituted aryl esters, substituted or unsubstituted heteroaryl esters, or the like. For example, the term "bile acid" includes cholic acid conjugated to glycine or taurine: glycocholate and taurocholate, respectively (and salts thereof). Any reference to a bile acid used herein includes reference to an identical compound naturally or synthetically prepared. In addition, it should be understood that any singular reference to a component (bile acid or others) used herein includes reference to one and only one, one or more, or at least one of such components. Similarly, any plural reference to a component used herein includes reference to one and only one, one or more, or at least one of such components, unless otherwise noted.
The term "individual", "patient" or "individual" are used interchangeably therein and refer to mammals and non-mammals, for example, who suffer from a disorder described herein. Examples of mammals include, without limitation, any member of the mammalian class: humans, non-human primates such as chimpanzees, and other species of apes and monkeys; farm animals such as gdo, horses, sheep, goats, pigs; domestic animals such as rabbits, dogs, and cats; laboratory animals that include rodents, such as rats, mice and guinea pigs, and others.
Examples of non-mammals include, without limitation, birds, fish and others. In one embodiment of the methods and compositions provided herein, the mammal is a human being.
The term "about", as used herein, includes any value that is 10% of the value described.
The term "between", as used here, is inclusive of the lower and upper number of the range.
The term "colon", as used herein, includes the cecum, ascending colon, hepatic flexure, splenic flexure, descending colon and sigmoid.
The term "composition" as used herein includes the disclosure of both a composition and a composition administered in a method as described herein. In addition, in some embodiments, the composition of the present invention is or comprises a "formulation", an oral dosage form or a rectal dosage form as described herein.
The terms "treats", "treat" or "treatment", and other grammatical equivalents as used herein, include relief, inhibition or reduction of symptoms, inhibition or reduction of severity, reduction of incidence, inhibition or reduction of recurrence, delay of onset , delayed recurrence, preventing or improving a disease or symptoms of a condition, improving the underlying causes of symptoms, inhibiting the disease or condition, for example, preventing the development of the disease or condition, relieving the disease or condition, which cause the regression of the disease or condition, relief of the condition caused by the disease or condition, or interruption of the symptoms of the disease or condition. The terms also include obtaining a therapeutic benefit. Therapeutic benefit means the eradication or improvement of the underlying disorder being treated, and / or the eradication or improvement of one or more of the physiological symptoms associated with the underlying disorder so that an improvement is seen in the patient.
The terms "avoid", "prevent" or "prevention", and other grammatical equivalents as used herein, include the prevention of additional symptoms, the prevention of the underlying causes of symptoms, the inhibition of the disease or condition, for example, impediment of development disease or condition and are intended to include prophylaxis. The terms also include obtaining a prophylactic benefit. For prophylactic benefit, the compositions are optionally administered to a patient at risk of developing a particular disease, to a patient who reports one or more of the physiological symptoms of the disease, or to a patient at risk for the disease to reoccur.
When combined treatments or methods of prevention are contemplated, it is not desired that the agents described herein are limited by the particular nature of the combination. For example, the agents described herein are optionally administered in combination as simple mixtures as well as chemical hybrids. An example of the latter is when the agent is covalently linked to a targeting carrier or to an active drug. Covalent bonding can be accomplished in a number of ways, such as, although not limited to, the use of a commercially available cross-linking agent. In addition, the combined treatments are optionally administered separately or concurrently.
As used herein, the terms "pharmaceutical combination", "administration of an additional therapy", "administering an additional therapeutic agent" and others refer to a pharmaceutical therapy that results from mixing or combining more than one active ingredient and includes combinations and unfixed active ingredients. The term "fixed combination" means that at least one of the agents described herein, and at least one co-agent, are administered to a patient simultaneously in the form of a single entity or dosage. The term "combination not fixed" means that at least one of the agents described herein, and at least one co-agent, are administered to a patient as separate entities simultaneously, concomitantly or sequentially with varying intervening time limits, where such administration provides effective levels of the two or more agents in the patient's body. In some cases, the co-agent is administered once or for a period of time, after which the agent is administered once or for a period of time. In other cases, the co-agent is administered for a period of time, after which, therapy involving the administration of both the co-agent and the agent is administered. In still other embodiments, the agent is administered once or for a period of time, after which the co-agent is administered once or for a period of time. These also apply to cocktail therapies, for example, the administration of three or more active ingredients.
As used herein, the terms "co-administration", "administered in combination with" and their grammatical equivalents must encompass the administration of the selected therapeutic agents to a single patient, and must include treatment regimens in which the agents are administered by the same route or different routes of administration or at the same time or at different times. In some embodiments, the agents described herein will be co-administered with other agents. These terms encompass the administration of two or more agents to an animal so that both agents and / or their metabolites are present in the animal at the same time. They include simultaneous administration in separate compositions, administration at different times in separate compositions, and / or administration in a composition in which both agents are present. Therefore, in some embodiments, the agents described herein and the other agents are administered in a single composition. In some embodiments, the agents described herein and other agents are administered in the composition.
The terms "effective amount" or "therapeutically effective amount" as used herein, refer to a sufficient amount of at least one agent being administered that achieves a desired result, for example, to relieve to some extent one or more symptoms of a disease or condition being treated. In certain cases, the result is a reduction and / or relief of the signs, symptoms, or causes of an illness, or any other desired change to a biological system. In certain cases, an "effective amount" for therapeutic uses is the amount of the composition comprising an agent as presented herein necessary to provide a clinically significant decrease in a disease. An adequate "effective" amount in any individual case is determined using any suitable technique, such as a dose escalation study.
The terms "administer", "administering", "administration", and others, as used herein, refer to methods that can be used to allow the release of agents or compositions to the desired site of biological action. These methods include, without limitation, oral, intraduodenal, parenteral injection (including intravenous, subcutaneous, intraperitoneal, intramuscular, intravascular or infusion), topical and rectal administration. Administration techniques that are optionally employed with the agents and methods described herein are found in sources, for example, Goodman and Gilman, "The Pharmacological Basis of Therapeutics", ed. current; Pergamon; and "Remington's, Pharmaceutical Sciences" (current addition), Mack Publishing Co., Easton, Pa. In certain embodiments, the agents and compositions described herein are administered orally.
The term "pharmaceutically acceptable" as used herein, refers to a material that does not negate the biological activity or properties of the agents described herein, and is relatively non-toxic (that is, the toxicity of the material does not outweigh the benefit of the material). In some cases, a pharmaceutically acceptable material can be administered to an individual without causing significant unwanted biological effects or interacting significantly in a harmful manner with any of the components of the composition in which it is contained.
The term "carrier" as used herein, refers to relatively non-toxic chemical agents that, in certain cases, facilitate the incorporation of an agent into cells or tissues.
The term "non-systemic" or "minimally absorbed" as used herein refers to low systemic bioavailability and / or absorption of an administered compound. In some cases a non-systemic compound is a compound that is substantially not absorbed systemically. In some embodiments, the ASBTI compositions described herein release the ASBTI to the distal ileum, colon, and / or rectum and not systemically (for example, a substantial portion of the ASBTI is not systemically absorbed). In some embodiments, the systemic absorption of a non-systemic compound is <0.1%, <0.3%, <0.5%, <0.6%, <0.7%, <0.8%, < 0.9%, <1%, <1.5%, <2%, <3%, or <5% of the administered dose (wt.% Or mol%). In some embodiments, the systemic absorption of a non-systemic compound is <10% of the administered dose. In some embodiments, the systemic absorption of a non-systemic compound is <15% of the administered dose. In some embodiments, the systemic absorption of a non-systemic compound is <25% of the administered dose. In an alternative approach, a non-systemic ASBTI is a compound that has less systemic bioavailability than the systemic bioavailability of a systemic ASBTI (eg, compound 100A, 100C). In some embodiments, the bioavailability of a non-systemic ASBTI described herein is <30%, <40%, <50%, <60%, or <70% of the bioavailability of a systemic ASBTI (for example, compound 100A, 100C).
In another alternative approach, the compositions described herein are formulated to deliver <10% of the administered dose of ASBTI systemically. In some embodiments, the compositions described herein are formulated to deliver <20% of the administered dose of ASBTI systemically. In some embodiments, the compositions described herein are formulated to deliver <30% of the administered dose of ASBTI systemically. In some embodiments, the compositions described herein are formulated to deliver <40% of the administered dose of ASBTI systemically. In some embodiments, the compositions described herein are formulated to deliver <50% of the administered dose of ASBTI systemically. In some embodiments, the compositions described herein are formulated to deliver <60% of the administered dose of ASBTI systemically. In some embodiments, the compositions described herein are formulated to deliver <70% of the administered dose of ASBTI systemically. In some embodiments, systemic absorption is determined in any appropriate manner, including the total circulating amount, the amount absorbed after administration, or others.
The term "ASBT inhibitor" refers to a compound that inhibits apical sodium-dependent bile transport or any recovery bile salt transport. The term apical sodium-dependent bile transporter (ASBT) is used interchangeably with the term Ileal bile acid transport (IBAT).
The term "increased enteroendocrine peptide secretion" refers to a sufficient increase in the level of the enteroendocrine peptide agent, for example, to treat any disease or disorder described herein. In some embodiments, increased secretion of enteroendocrine peptide reverses or relieves symptoms of cholestasis or cholestatic liver disease.
In various embodiments, pharmaceutically acceptable salts described herein include, as a non-limiting example, nitrate, chloride, bromide, phosphate, sulfate, acetate, hexafluorphosphate, citrate, gluconate, benzoate, propionate, butyrate, sulfosal icylate, maleate, laurate, malate , fumarate, succinate, tartrate, amsonate, pamoate, p-toluenesulfonate, mesylate and others. In addition, pharmaceutically acceptable salts include, as a non-limiting example, alkaline earth metal salts (for example, calcium or magnesium), alkali metal salts (for example, sodium-dependent or potassium), ammonium salts and the like.
The term "optionally substituted" or "substituted" means that the said group is replaced with one or more additional groups. In certain embodiments, one or more additional groups are individually and independently selected from amide, ester, alkyl, cycloalkyl, heteroalkyl, aryl, heteroaryl, heteroalicylic, hydroxy, alkoxy, aryloxy, alkylthio, arylthio, alkylsulfoxide, arylsulfoxide, ester, alkylsulfone, arylsulfone , cyano, halo, alcohol, alkoxy, isocyanate, thiocyanate, isothiocyanate, nitro, haloalkyl, haloalkoxy, fluoroalkyl, amino, alkyl-amino, dialkyl-amino, starch.
An "alkyl" group refers to an aliphatic hydrocarbon group. Reference to an alkyl group includes "saturated alkyl" and / or "unsaturated alkyl". The alkyl group, whether saturated or unsaturated, includes branched, straight-chain, or cyclic groups. As an example only, alkyl includes methyl, ethyl, propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl, t-butyl, pentyl, iso-pentyl, neo-pentyl, and hexyl. In some embodiments, alkyl groups include, but are not limited to, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tertiary butyl, pentyl, hexyl, ethenyl, propenyl, butenyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and others. A "lower alkyl" is a C1-C6 alkyl. A "heteroalkyl" group replaces any of the carbons in the alkyl group with a heteroatom that has the appropriate number of attached hydrogen atoms (for example, a CH2 group to an NH group or a group 0).
The term "alkylene" refers to a divalent alkyl radical. Any of the monovalent alkyl groups mentioned above may be an alkylene by abstraction of a second hydrogen atom of the alkyl. In one aspect, an alkylene is a Cl-ClOalkylene. In another aspect, an alkylene is a Cl-Cβalkylene. Typical alkylene groups include, without limitation, -CH2-, -CH (CH3) -, -C (CH3) 2-, -CH2CH2-, -CH2CH (CH3) -, -CH2C (CH3) 2-, - CH2CH2CH2-, -CH2CH2CH2CH2-, - CH2CH2CH2CH2CH2 -, -CH2CH2CH2CH2CH2CH2-, and others.
An "alkoxy" group refers to a 0- (alkyl) group, where alkyl is as defined herein.
The term "alkylamine" refers to the group -N (alkyl) xHy group, where alkyl is as defined herein and x and y are selected from the group x = 1, y = 1 and x = 2, y = 0. When x = 2, the alkyl groups, together with the nitrogen to which they are attached, optionally form a cyclic ring system.
An "amide" is a chemical moiety with the formula -C (0) NHR or -NHC (0) R, where R is selected from alkyl, cycloalkyl, aryl, heteroaryl (bonded through a ring carbon) and heteroalicyclic (bonded through a ring carbon).
The term "ester" refers to a chemical moiety with the formula -C (= O) OR, where R is selected from the group consisting of alkyl, cycloalkyl, aryl, heteroaryl and heteroalicylic.
As used herein, the term "aryl" refers to an aromatic ring in which each of the atoms forming the ring is a carbon atom. Aryl rings described herein include rings that have five, six, seven, eight, nine, or more than nine carbon atoms. Aryl groups are optionally substituted. Examples of aryl groups include, without limitation, phenyl, and naphthalenyl.
The term "aromatic" refers to a flat ring that has a relocated K-electron system that contains 4n + 2 π- electrons, where n is an integer. Aromatic rings can be formed of five, six, seven, eight, nine, ten, or more than ten atoms. Aromas are optionally substituted. The term "aromatic" includes carbocyclic aryl ("aryl", for example, phenyl) and heterocyclic (or "heteroaryl" or "heteroaromatic") groups (for example, pyridine). The term includes fused ring monocyclic or polycyclic groups (i.e. rings that share adjacent pairs of carbon atoms).
The term "cycloalkyl" refers to a monocyclic or polycyclic non-aromatic radical, in which each of the atoms that form the ring (ie skeleton atoms) is a carbon atom. In several embodiments, cycloalkyls are saturated, or partially unsaturated. In some embodiments, cycloalkyls are fused with an aromatic ring. Cycloalkyl groups include groups that have 3 to 10 ring atoms. Illustrative examples of cycloalkyl groups include, without limitation, the following portions:
and others. Monocyclic cycloalkyl include, without limitation, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl.
The term "heterocycle" refers to heteroaromatic and heteroalicyclic groups that contain four ring heteroatoms each selected from 0, S and N. In certain cases, each heterocyclic group has 4 to 10 atoms in its ring system, and with the condition that the ring of that group does not contain two adjacent atoms of 0 or S. Non-aromatic heterocyclic groups include groups that have 3 atoms in their ring system, but aromatic heterocyclic groups must have at least 5 atoms in their ring system . Heterocyclic groups include benzo-fused ring systems. An example of a 3-membered heterocyclic group is aziridinyl (derived from aziridine). An example of a 4-membered heterocyclic group is azetidinyl (derived from azetidine). An example of a 5-membered heterocyclic group is thiazolyl. An example of a 6-membered heterocyclic group is pyridyl, and an example of a 10-membered heterocyclic group is quinolinyl. Examples of non-aromatic heterocyclic groups are pyrrolidinyl, tetrahydrofuranyl, dihydrofuranyl, tetrahydrothienyl, tetrahydropyranyl, dihydropyranyl, tetrahydrothiopyranyl, piperidine, morphino, tiomorphino, tylanil, tylanil, tylanil, tylanilil, tiperanil, tiperanil, tilanilil, piperazilil, tiperanil, tiperanilil, piperazilil, piperazilil thiazepinil, 1,2,3,6-tetrahydropyridinyl, 2-pyrrolinyl, 3-pyrrolinyl, indolinyl, 2H-pyranyl, 4H-pyranyl, dioxanil, 1,3-dioxolanil, pyrazolinyl, dithianyl, dithiolanil, dihydropyranyl, dihydrofuranil, dihydrofuran pyrazolidinyl, imidazolinyl, imidazolidinyl, 3-azabicyclo [3.1 .0] hexanil, 3-azabicyclo [4. 1.0] heptanil, 3H-indolyl and quinolizinyl. Examples of aromatic heterocyclic groups are pyridinyl, imidazolyl, pyrimidinyl, pyrazolyl, triazolyl, pyrazinyl, tetrazolyl, furyl, thienyl, isoxazolyl, thiazolyl, oxazolyl, isothiazolyl, pyrrolyl, quinolinyl, benzyl, benzyl, benzyl, benzyl, benzyl, benzyl, benzyl phthalazinyl, pyridazinyl, triazinyl, isoindolyl, pteridinyl, purinyl, oxadiazolyl, thiadiazolyl, furazanil, benzofurazanyl, benzothiophenyl, benzothiazolyl, benzoxazolil, quinazolinyl, quinoxalinyl, eftiridinin.
The terms "heteroaryl" or, alternatively, "heteroaromatic" refer to an aryl group that includes one or more ring heteroatoms selected from nitrogen, oxygen and sulfur. A "heteroaromatic" or "heteroaryl" moiety that contains N refers to an aromatic group in which at least one of the atoms in the ring skeleton is a nitrogen atom. In certain embodiments, heteroaryl groups are monocyclic or polycyclic. Illustrative examples of heteroaryl groups include the following portions:
and others.
A "heteroalicyclic" group or "heterocycle" group refers to a cycloalkyl group, in which at least one ring atom of the skeleton is a heteroatom selected from nitrogen, oxygen and sulfur. In various modalities, the radicals are an aryl or heteroaryl. Illustrative examples of heterocycle groups, also referred to as non-aromatic heterocycles, include:
and others. The term heteroalicyclic also includes all carbohydrate ring forms, including, without limitation, monosaccharides, disaccharides and oligosaccharides.
The term "halo" or, alternatively, "halogen" means fluorine, chlorine, bromine and iodine.
The terms "haloalkyl", and "haloalkoxy" include alkyl and alkoxy structures that are replaced with one or more halogens. In modalities, in which more than one halogen is included in the group, the halogens are the same or they are different. The terms "fluoralkyl" and "fluoralkoxy" include haloalkyl and haloalkoxy groups, respectively, where the halo is fluorine.
The term "heteroalkyl" includes optionally substituted alkyl, alkenyl and alkynyl radicals having one or more backbone atoms selected from an atom other than carbon, for example, oxygen, nitrogen, sulfur, phosphorus, silicon, or combinations thereof. In certain embodiments, the heteroatom (s) is placed in any interior position of the heteroalkyl group. Examples include, without limitation, -CH2-O-CH3, -CH2-CH2-0-CH3, -CH2-NH-CH3, -CH2-CH2-NH-CH3, -CH2-N (CH3) -CH3, -CH2 -CH2- NH-CH3, -CH2-CH2-N (CH3) - CH3, -CH2-S-CH2-CH3, -CH2-CH2, -S (0) - CH3, -CH2-CH2-S (0) 2-CH3, -CH = CH-O-CH3, -SÍ (CH3) 3, -CH2-CH = N-0CH3, and -CH = CH-N (CH3) -CH3. In some embodiments, up to two heteroatoms are consecutive, such as -CH2-NH-0CH3 and -CH2-O-Si (CH3) 3. A "cyan" group refers to a -CN group. An "isocyanate" group refers to an -NCO group. A "thiocyanate" group refers to a -CNS group. An "isothiocyanate" group refers to an -NCS group. "Alcohiloxy" refers to an RC group (= 0) 0-, "Alcohil" refers to an RC group (= 0) -.
The term "modular" as used herein refers to having an effect on (for example, increasing, intensifying or maintaining a certain level).
The term "optionally substituted" or "substituted" means that the said group can be substituted with one or more additional group (s) individually and independently selected from Cl-C6alkyl, C3-Cδcycloalkyl, aryl, heteroaryl, C2-Cβheteroalicyclic, hydroxy, Cl -Cβalkoxy, aryloxy, arylalkoxy, aralkyloxy, arylalkyloxy, Cl-C6alkylthio, arylthio, Cl- C6alkylsulfoxide, arylsulfoxide, Cl-C6alkylsulfone, arylsulfone, cyano, halo, C2-C8acyl, Cl2-C8-alkyl, Cl2-C8-alkyl, Cl2-C8 C6fluoroalkyl, and amino, including Cl-Cβalkylamino, and the protected derivatives thereof. As an example, an optional substituent can be LSRS, where each Ls is independently selected from a bond, -0-, -C (= 0) -, -S-, -S (= 0) -, -S (= 0) 2-, -NH-, -NHC (= 0) -, C (= 0) NH-, S (= 0) 2NH-, -NHS (= 0) 2-, -0C (= 0) NH- , -NHC (= 0) 0-, - (Cl- Cβalkyl) -, or - (C2-Cβalkenyl) -; and each Rs is independently selected from H, (Cl-C4alkyl), (C3-C8cycloalkyl), heteroaryl, aryl, and Cl-C6 heteroalkyl. Non-aromatic groups Optionally substituted can be substituted with one or more oxo (= 0). The protecting groups that can form the protected derivatives of the above substituents are known to those skilled in the art and can be found in references such as Greene and Wuts, above. In some embodiments, the alkyl groups described herein are optionally substituted with a 0 that is connected to two adjacent carbon atoms (that is, forming an epoxide).
The term "therapeutically effective amount" or an "effective amount" as used herein, refers to a sufficient amount of a therapeutically active agent to provide a desired effect on an individual. In some embodiments, a "therapeutically effective amount" or an "effective amount" of an ASBTI refers to a sufficient amount of an ASBTI to treat cholestasis or cholestatic liver disease in an individual. L cells
The inventors found that enteroendocrine L cells play a role in repair. The epithelial barrier is also a key component in the defense of the host. A pre-proclucagon junction product, GLP-2, is secreted by enteroendocrine L cells in the distal small intestine and has improved the healing of intestinal injuries in a process mediated by TGF-B (anti-inflammatory cytokine TGF-B), the small intestine responding better than the large intestine. GLP-2 has also been shown to improve barrier dysfunction induced by experimental stress and food allergy. Again, L cells are activated by luminous nutrients, and the impairment of the barrier observed in TPN may partially reflect its hyposecretion in the absence of enteral stimulus. In addition, GLP-2 is also responsible, at least in part for growth and adaptation seen in small bowel models. Therefore, the function of abnormal enteroendocrine cells (EEC) may predispose to inflammatory GI disorders, and the underlying nutrient-EEC-vagal pathways are targets in the injured intestine as contemplated in the present modalities.
L cells are spread throughout the epithelial layer of the intestine from the duodenum to the rectum, with the largest numbers occurring in the ileum, colon, and rectum. They are characterized by an open cell morphology, with apical microvilli directed to the intestinal lumen and secretory vesicles located adjacent to the basolateral membrane, and are in direct contact with nutrients in the intestinal lumen. In addition, L cells are located close to neurons and the microvasculature of the intestine, thereby allowing the L cell to be affected by neural and hormonal signals. Like Glucagon-Like Peptide 1 (GLP-1) and Glucagon-Like Peptide 2 (GLP-2), L cells also secrete YY peptide (PYY), and glutamate. The cells are just one member of a much larger family of enteroendocrine cells that secrete a variety of hormones, including ghrelin, GIP, cholecystokinin, somatostatin, and secretin, which are involved in the local coordination of intestinal physiology, as well as having greater roles in controlling cytokine release and / or control of the adaptive process, attenuation of intestinal damage, reduction of bacterial translocation, inhibition of free radical oxygen release, or any combination of these. L cells are distributed non-uniformly in the gastrointestinal tract, in higher concentrations in the distal portion of the gastrointestinal tract (for example, in the distal ileum, colon and rectum). Bile acid
Bile contains water, electrolytes and numerous organic molecules that include bile acids, cholesterol, phospholipids and bilirubin. Bile is secreted from the liver and stored in the gallbladder, and after contraction of the gallbladder, due to the ingestion of a fatty meal, the bile passes through the bile duct into the intestine. Bile acids / salts are critical for the digestion and absorption of fat and fat-soluble vitamins in the small intestine. Human adults produce 400 to 800 ml of bile daily. Bile secretion can be considered to occur in two stages. Initially, hepatocytes secrete bile into the canaliculi, from which it flows into the bile ducts and this liver bile contains large amounts of bile acids, cholesterol and other organic molecules. Then, as bile flows through the bile ducts, it is modified by adding a watery, bicarbonate-rich secretion from the ductal epithelial cells. Bile is concentrated, typically five times, during storage in the gallbladder.
The flow of bile is most slow during fasting, and a majority of it is diverted to the gallbladder for concentration. When the chyme of an ingested meal enters the small intestine, acid and partially digested fats and proteins stimulate the secretion of cholecystokinin and secretin, both are important for the secretion and flow of bile. Cholecystokinin (cholecystis = gallbladder and quinine = movement) is a hormone that stimulates contractions of the gallbladder and bile duct, resulting in the release of bile into the intestine. The most potent stimulus for cholecystokinin release is the presence of fat in the duodenum. Secretin is a hormone secreted in response to acid in the duodenum, and it stimulates bile duct cells to secrete bicarbonate and water, which expand the volume of bile and increase its flow to the intestine.
Bile acids / salts are derived from cholesterol. Cholesterol, taken as part of the diet or derived from liver synthesis, is converted to bile acids / salts in the hepatocyte. Examples of such bile acids / salts include cholic acid and chenodeoxycholic acid, which are then conjugated to an amino acid (such as glycine or taurine) to produce the conjugated form that is actively secreted in the canaliculi. The most abundant of bile salts in humans are cholate and deoxycholate, and they are normally conjugated with glycine or taurine to generate glycocholate or taurocholate respectively.
Free cholesterol is virtually insoluble in aqueous solutions, however, in bile it becomes soluble by the presence of bile acids / salts and lipids. Liver synthesis of bile acids / salts accounts for the majority of the breakdown of cholesterol in the body. In humans, approximately 500 mg of cholesterol is converted to bile acids / salts and eliminated in bile daily. Therefore, bile secretion is a major pathway for the elimination of cholesterol. Large amounts of bile acids / salts are secreted from the intestine each day, but only relatively small amounts are lost from the body. This is because approximately 95% of the bile acids / salts released into the duodenum are absorbed back into the blood in the ileum, by a process known as "Enterohepatic Recirculation".
The venous blood from the ileum goes straight to the portal vein, and therefore through the sinusoid in the liver. Hepatocytes extract bile acids / salts very efficiently from sinusoidal blood, and little escapes from the healthy liver into the systemic circulation. Bile acids / salts are then transported through the hepatocytes to be secreted into the canaliculi. The effect of this enterohepatic recirculation is that each molecule of bile salt is reused about 20 times, often two or three times during a single digestive phase. Bile biosynthesis represents the main metabolic destination of cholesterol, accounting for more than half of the approximate 800 mg / day of cholesterol that an average adult uses in metabolic processes. In comparison, steroid hormone biosynthesis consumes only about 50 mg of cholesterol per day. More than 400 mg of bile salts are needed and secreted in the intestine daily, and this is accomplished by recycling bile salts. Most of the salts of bile secreted in the upper region of the small intestine are absorbed together with the dietary lipids that they emulsify at the lower end of the small intestine. They are separated from the dietary lipid and returned to the liver for reuse. Recycling thus allows 20-30g of bile salts to be secreted in the small intestine each day.
Bile acids / salts are amphiphatic, with the cholesterol-derived portion containing hydrophobic (lipid-soluble) and polar (hydrophilic) portions while the conjugated amino acid is generally polar and hydrophilic. This amphiphatic nature allows bile acids / salts to carry out two important functions: emulsification of lipid aggregates and solubilization and transport of lipids in an aqueous environment. Bile acids / salts have a detergent action on fat particles in the diet that cause the breakdown of fat globules or their emulsification. Emulsification is important since it greatly increases the fat surface area available for digestion by lipases that cannot access the interior of the lipid droplets. In addition, bile acids / salts are lipid carriers and are capable of solubilizing various lipids by forming micelles and are critical for the transport and absorption of fat-soluble vitamins. Pharmaceutical compositions and methods of use
In some embodiments, the compositions described herein are administered to deliver enteroendocrine peptide secretion-enhancing agents to an individual. In certain embodiments, any compositions described herein are formulated for ileal, rectal and / or colonic release. In more specific modalities, the composition is formulated for non-systemic or local release to the rectum and / or colon. It should be understood that as used herein, colon release includes release to the sigmoid colon, transverse colon, and / or ascending colon. In more specific modalities, the composition is formulated for non-systemic or local delivery to the rectum and / or colon is administered rectally. In other specific modalities, the composition is formulated for non-systemic or local delivery to the rectum and / or colon and is administered orally.
In some embodiments, a composition comprising an enteroendocrine peptide secretion-enhancing agent and, optionally, a pharmaceutically acceptable carrier for relief of symptoms of cholestasis or cholestatic liver disease in an individual is provided herein.
In certain embodiments, the composition comprises an enteroendocrine peptide secretion-enhancing agent and an absorption inhibitor. In specific embodiments, the absorption inhibitor is an inhibitor that inhibits the absorption of (or at least one of) specific enteroendocrine peptide-enhancing agents with which it is combined. In some embodiments, the composition comprises an enteroendocrine peptide secretion-enhancing agent, an absorption inhibitor and a carrier (e.g., a suitable oral carrier or a suitable rectal carrier, depending on the intended mode of administration). In certain embodiments, the composition comprises an enteroendocrine peptide secretion-enhancing agent, an absorption inhibitor, a carrier, and one or more of a cholesterol absorption inhibitor, an enteroendocrine peptide, a peptidase inhibitor, a spreading agent , and a wetting agent.
In other embodiments, the compositions described herein are administered orally for non-systemic release of the active component of the bile salt to the rectum and / or colon, including the sigmoid colon, transverse colon, and / or ascending colon. In specific embodiments, compositions formulated for oral administration, as a non-limiting example, enterically coated or formulated oral dosage forms, such as, tablets and / or capsules. It should be understood that the terms "individual" and "individual" are used interchangeably in this and include, for example, humans and human patients in need of treatment. Absorption inhibitors
In certain embodiments, the composition described herein as being formulated for the non-systemic release of ASBTI also includes an absorption inhibitor. As used herein, an absorption inhibitor includes an agent or group of agents that inhibit the absorption of a bile acid / salt.
Suitable bile acid absorption inhibitors (also described herein as absorption inhibiting agents) include, as a non-limiting example, anion exchange matrices, polyamines, polymers containing quaternary amine, quaternary ammonium salts, polyalylamine polymers and copolymers, colesevelam, colesevelam hydrochloride, ColestaGel polymer of (N, N, N-trimethyl-6- (2-propenylamino) -1-hexanamino chloride with (chloromethyl) oxirane, 2-propen-1-amine and N-2-propenyl-1 - decanamine hydrochloride), cyclodextrins, chitosan, chitosan derivatives, carbohydrates that bind bile acids, lipids that bind bile acids, proteins and proteinaceous materials that bind bile acids, and antibodies and albumins that bind bile acids . Suitable cyclodextrins include those that bind bile acids / salts, as a non-limiting example, R-cyclodextrin and hydroxypropyl-R-cyclodextrin. Suitable proteins include those that bind acid / bile salts such as, a non-limiting example, bovine serum albumin, new albumin, casein, a-glycoprotein acid, gelatin, soy proteins, peanut proteins, almond proteins, and proteins wheat vegetables.
In certain embodiments, the absorption inhibitor is cholestyramine. In specific embodiments, cholestyramine is combined with a bile acid. Cholestyramine, an ion exchange resin, is a polymer of styrene that contains quaternary ammonium groups intertwined with divinylbenzene. In other embodiments, the absorption inhibitor is colestipol. In specific embodiments, colestipol is combined with a bile acid. Colestipol, an ion exchange resin, is a copolymer of diethylenetriamine and l-chloro-2,3-epoxypropane.
In certain embodiments of the compositions and methods described herein, the ASBTI is linked to an absorption inhibitor, while in other embodiments the ASBTI and the absorption inhibitor are separate molecular entities. Cholesterol absorption inhibitors
In certain embodiments, a composition described herein optionally includes at least one cholesterol absorption inhibitor. Suitable cholesterol absorption inhibitors include, as a non-limiting example, ezetimibe (SCH 58235), ezetimibe analogs, ACT inhibitors, stigmastanil phosphorylcholine, stigmastanyl phosphorylcholine analogs, β-lactam cholesterol absorption inhibitors, polysaccharide sulfate, neomycin , plant sponins, plant sterols, phytostanol preparation FM-VP4, Sitostanol, β-sitosterol, acyl-CoA inhibitors: cholesterol-O-acyltransferase (ACAT), Avasimibe, Implitapide, steroidal glycosides and others. Suitable analysts of enzetimib include, as a non-limiting example, SCH 48461, SCH 58053 and others. Suitable ACT inhibitors include, as a non-limiting example, trimethoxy fatty acid anilides such as Cl-976, 3- [decyldimethylsilyl] -N- [2- (4-methylphenyl) -1-phenylethyl] - propanamide, melinamide and others. Cholesterol absorption inhibitors of β-lactam include, as a non-limiting example, (3R-4S) -1,4-bis- (4-methoxyphenyl) -3- (3-phenylpropyl) -2-azetidinone and others. Peptidase Inhibitors
In some embodiments, the compositions described herein optionally include at least one peptidase inhibitor. Such peptidase inhibitors include, without limitation, dipeptidyl peptidase-4 (DPP-4) inhibitors, neutral endopeptidase inhibitors, and conversion enzyme inhibitors. Suitable dipeptidyl peptidase-4 (DPP-4) inhibitors include, as a non-limiting example, Vildaglipti, 2S) -1- {2 - [(3-hydroxy-1-adamantyl) amino] acetyl} pyrrolidine-2-carbonitrile, Sitagliptin, (3R) -3-amino-1- [9- (trifluoromethyl) -1,4,7,8-tetrazabicyclo [4.3.0] nonA "6,8-dien- 4-yl] -4- (2 , 4,5-trifluorfenyl) butan-l-one, Saxagliptin, and (IS, 3S, 5S) -2 - [(2S) -2-amino-2- (3-hydroxy-1-damantyl) acetyl] - 2 -azabicyclo [3.1.0] hexane-3-carbonitrile Such neutral endopeptidase inhibitors include, without limitation, Candoxatrilat and Ecadotril. Dissemination agents / Wetting agents
In certain embodiments, the composition described herein optionally comprises a spreading agent. In some embodiments, a spreading agent is used to improve the spread of the composition in the colon and / or rectum. Suitable spreading agents include, as a non-limiting example, hydroxyethylcellulose, hydroxypropylmethyl cellulose, polyethylene glycol, colloidal silicon dioxide, propylene glycol, cyclodextrins, microcrystalline cellulose, polyvinylpyrrolidone, polyoxyethylated glycerides, polycarbophil, di-n-octyl ethanol; polyalkylene glycol fatty ethers, AetoxalTMB), 2-ethylhexyl palmitate, CegesoftTMC 24), and isopropyl fatty acid esters.
In some embodiments, the compositions described herein optionally comprise a wetting agent. In some embodiments, a wetting agent is used to improve the wetting of the composition in the colon and rectum. Suitable wetting agents include, as a non-limiting example, surfactants. In some embodiments, the surfactants are selected from, as a non-limiting example, polysorbate (eg 20 or 80), stearyl hethoate, caprylic / capric fatty acid esters of C12-C18 chain length saturated fatty alcohols, isostearic acid isostearyl diglycerol, sodium dodecyl sulfate, isopropyl myristate, isopropyl palmitate, and isopropyl myristate / isopropyl stearate / isopropyl palmitate mixture. Vitamins
In some embodiments, the methods provided herein also comprise the administration of one or more vitamins.
In some embodiments, the vitamin is vitamin A, Bl, B2, B3, B5, B6, B7, B9, B12, C, D, E, K, folic acid, pantothenic acid, niacin, riboflavin, thiamine, retinol, beta carotene , pyridoxine, ascorbic acid, cholecalciferol, cyanocobalamin, tocopherols, phylloquinone, menaquinone.
In some embodiments, the vitamin is a fat-soluble vitamin such as vitamin A, D, E, K, retinol, beta carotene, cholecalciferol, tocopherols, phylloquinone. In a preferred embodiment, the fat-soluble vitamin is tocopherol polyethylene glycol succinate (TPGS). Bile acid / ligand sequestrant
In some embodiments, an unstable bile acid scavenger is an enzyme-dependent bile acid scavenger. In certain embodiments, the enzyme is a bacterial enzyme. In some embodiments, the enzyme is a bacterial enzyme found in high concentration in the human colon or rectum in relation to the concentration found in the small intestine. Examples of microflora-activated systems include dosage forms comprising pectin, galactomannan, and / or Azo hydrogels and / or glycosidic conjugates (e.g., D-galactoside conjugates, β-D-xylopyranoside or others) of the active agent. Examples of enzymes in the gastrointestinal microflora include bacterial glycosidases such as, for example, D-galactosidase, β-D-glucosidase, α-L-arabinofuranosidase, β-D-xylopyranidasidase or others.
In certain embodiments, an unstable bile acid scavenger is a time-dependent bile acid scavenger. In some embodiments, an unstable bile acid scavenger releases bile acid or is degraded after 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 seconds of kidnapping. In some embodiments, an unstable bile acid scavenger releases bile acid or is degraded after 15, 20, 25, 30, 35, 40, 45, 50, or 55 seconds of kidnapping. In some embodiments, an unstable bile acid scavenger releases bile acid or is degraded after 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 minutes of kidnapping. In some embodiments, an unstable bile acid scavenger releases a bile acid or is degraded after about 15, 20, 25, 30, 35, 45, 50, or 55 unstable bile acid scavenger releases a bile acid or is degraded afterwards about dei, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, or 24 hours of kidnapping. In some embodiments, an unstable bile acid scavenger releases bile acid or is degraded after 1, 2, or 3 days of scavenging.
In some embodiments, the unstable bile acid scavenger has a low affinity for bile acid. In certain embodiments, the unstable bile acid scavenger has a high affinity for a primary bile acid and a low affinity for a secondary bile acid.
In some embodiments, the unstable bile acid scavenger is a pH-dependent bile acid scavenger. In certain embodiments, the pH-dependent bile acid scavenger has a high bile acid affinity at a pH of 6 or below and a low bile acid affinity at a pH above 6. In certain embodiments, the pH-dependent bile acid scavenger pH has a high affinity for bile acid at a pH of 6.5 or below and a low affinity for bile acid at a pH above 6.5. In certain embodiments, the pH-dependent bile acid scavenger has a high bile acid affinity at a pH of 7 or below and a low bile acid affinity at a pH above 7. In certain embodiments, the pH-dependent bile acid scavenger pH has a high affinity for bile acid at a pH of 7.1 or below and a low affinity for bile acid at a pH above 7.1. In certain embodiments, the pH-dependent bile acid scavenger has a high bile acid affinity at a pH of 7.2 or below and a low bile acid affinity at a pH above 7.2. In certain embodiments, the pH-dependent bile acid scavenger has a high affinity for bile acid at a pH of 7.3 or below and a low affinity for bile acid at a pH above 7.3. In certain embodiments, the pH-dependent bile acid scavenger has a high affinity for bile acid at a pH of 7.4 or below and a low affinity for bile acid at a pH above 7.4. In certain embodiments, the pH-dependent bile acid scavenger has a high affinity for bile acid at a pH of 7.5 or below and a low affinity for bile acid at a pH above 7.5. In certain embodiments, the pH-dependent bile acid scavenger has a high affinity for bile acid at a pH of 7.6 or below and a low affinity for bile acid at a pH above 7.6. In certain embodiments, the pH-dependent bile acid scavenger has a high affinity for bile acid at a pH of 7.7 or below and a low affinity for bile acid at a pH above 7.7. In certain embodiments, the pH-dependent bile acid scavenger has a high affinity for bile acid at a pH of 7.8 or below and a low affinity for bile acid at a pH above 7.8. In some embodiments, the pH-dependent bile acid scavenger degrades at a pH above 6. In some embodiments, the pH-dependent bile acid scavenger degrades at a pH above 6.5. In some embodiments, the pH-dependent bile acid scavenger degrades at a pH above 7. In some embodiments, the pH-dependent bile acid scavenger degrades at a pH above 7.1. In some embodiments, the pH-dependent bile acid scavenger degrades at a pH above 7.2. In some embodiments, the pH-dependent bile acid scavenger degrades at a pH above 7.3. In some embodiments, the pH-dependent bile acid scavenger degrades at a pH above 7.4. In some embodiments, the pH-dependent bile acid scavenger degrades at a pH above 7.5. In some embodiments, the pH-dependent bile acid scavenger degrades at a pH above 7.6. In some embodiments, the pH-dependent bile acid scavenger degrades at a pH above 7.7. In some embodiments, the pH-dependent bile acid scavenger degrades at a pH above 7.8. In some embodiments, the pH-dependent bile acid scavenger degrades at a pH above 7.9.
In certain embodiments, the unstable bile acid scavenger is lignin or a modified lignin. In some embodiments, the unstable bile acid scavenger is a polycationic polymer or copolymer. In certain embodiments, the unstable bile acid scavenger is a polycationic polymer or copolymer that comprises one or more residues of N-alkenyl-N-alkylamine; one or more N, N, N-trialkyl-N- (N'-alkenylamino) alkyl azanium residues; one or more residues of N, N, N-trialkyl-N-alkenyl azanium; one or more alkenyl amine residues; or a combination of these.
In some embodiments, the bile acid ligand is cholestyramine, and various compositions that include cholestyramine, which are described, for example, in U. S. Nos. 3,383,281; 3,308,020; 3,769,399; 3,846,541; 3,974,272; 4,172,120; 4,252,790; 4,340,585; 4,814,354; 4,874,744; 4,895,723; 5,695,749; and 6,066,336. In some embodiments, the bile acid ligand is colestipol or colesevelam. Methods
Here, in certain embodiments, methods are provided for the treatment of cholestasis or a cholestatic liver disease comprising the non-systemic administration of a therapeutically effective amount of an ASBTI. Here, in certain modalities, methods are provided for the treatment of cholestasis or a cholestatic liver disease that comprises contact of the gastrointestinal tract, including the distal ileum and / or the colon and / or rectum, of an individual in need of it with a ASBTI. Also provided herein are methods for reducing intraenterocyte bile acids, reducing damage to the hepatocellular or intestinal architecture caused by cholestasis or a cholestatic liver disease, from an individual comprising administering a therapeutically effective amount of an ASBTI to an individual in need of it. .
In some embodiments, a method of treating cholestasis or cholestatic liver disease in an individual is provided here comprising the release to the individual's ileum or colon of a therapeutically effective amount of any ASBTI described herein. In certain embodiments, the therapeutically effective amount of a bile salt, a bile acid mimetic, or a bile salt mimetic solubilizes cholesterol, promotes the dispersion of cholesterol in aqueous fluid, reduces viscosity, and / or improves the flow of bile.
Methods are provided herein for reducing damage to the hepatocellular or intestinal architecture or cholestasis cells or a cholestatic liver disease which comprises administering a therapeutically effective amount of an ASBTI. In certain embodiments, methods for reducing intraenterocyte bile acids / salts are provided herein comprising administering a therapeutically effective amount of an ASBTI to an individual in need thereof.
In some embodiments, the methods provide for the inhibition of bile salt recycling after administration of any of the compounds described herein to an individual. In some embodiments, an ASBTI described herein is systemically absorbed after administration. In some embodiments, an ASBTI described here is not absorbed systemically. In some modalities, an ASBTI is administered to the individual orally. In some embodiments, an ASBTI described herein is released and / or distributed in the individual's distal ileum.
In certain cases, contact of an individual's distal ileum with an ASBTI (for example, any ASBTI described here) inhibits bile acid reuptake and increases the concentration of bile acids / salts in the vicinity of L cells in the distal ileum and / or colon and / or rectum, thereby reducing intraenterocyte bile acids, reducing serum and / or hepatic levels of bile acid, a reduction in the total bile acid load, and / or reducing damage to the ileal architecture caused by cholestasis or a disease cholestatic liver disease. Without being limited by any particular theory, the reduction of serum and / or hepatic levels of bile acid improves hypercholemia and / or cholestatic disease.
Administration of a compound described herein is performed in any suitable manner including, as a non-limiting example, oral, enteral, parenteral (e.g., intravenous, subcutaneous, intramuscular), intranasal, buccal, topical, rectal, or transdermal. Any compound or composition described herein is administered in a method or formulation suitable for treating a newborn or baby. Any compound or composition described herein is administered in an oral formulation (for example, solid or liquid) to treat a newborn or baby. Any compound or composition described herein is administered before eating food, without food or after eating food.
In certain embodiments, a compound or composition comprising a compound described herein is administered for prophylactic and / or therapeutic treatments. In therapeutic applications, the compositions are administered to an individual who is already suffering from a disease or condition, in an amount sufficient to cure or at least partially prevent the symptoms of the disease or condition. In several cases, the effective amount for this use depends on the severity and duration of the disease or condition, prior therapy, the individual's health status, weight, and response to drugs, and the judgment of the physician.
In prophylactic applications, the compounds or compositions containing compounds described herein are administered to an individual susceptible to or at risk for a particular disease, disorder or condition. In certain embodiments of this use, the precise amounts of compound administered depend on the individual's state of health, weight and others. In addition, in some cases, when a compound or composition described herein is administered to an individual, the effective amounts for that use depend on the severity and duration of the disease, disorder or condition, prior therapy, the individual's health status and response to drugs, and the doctor's judgment.
In certain cases, when after administration of a selected dose of a compound or composition described here, a condition of the individual does not improve, after the judgment of the doctor, the administration of a compound or composition described here is optionally administered chronically, that is, for an extended period of time, including throughout the individual's life to improve or control or limit the symptoms of the individual's disorder, disease or condition.
In certain embodiments, an effective amount of a given agent varies depending on one or more of a number of factors such as the particular compound, disease or condition and its severity, the identity (eg weight) of the individual or host in need of treatment, and it is determined according to the particular circumstances surrounding the case, including, for example, the specific agent being administered, the route of administration, the condition being treated, and the individual or host being treated. In some embodiments, the doses administered include those up to the maximum tolerable dose. In some embodiments, the doses administered include those up to the maximum tolerable dose for a newborn or baby.
In certain embodiments, about 0.001 - .5000 mg per day, about 0.001-1.500 mg per day, about 0.001 to about 100 mg / day, about 0.001 to about 50 mg / day, or about 0.001 at about 30 mg / day, or about 0.001 to about 10 mg / day of a compound described herein is administered to an individual in need. In various embodiments, the desired dose is conveniently presented in a single dose or in divided doses administered simultaneously (or for a short period of time) or at appropriate intervals, for example, as two, three, four or more sub-doses per day. In several embodiments, a single dose is about 0.001 mg / kg to about 500 mg / kg. In various embodiments, a single dose is about 0.001, 0.01, 0.1, 1, or 10 mg / kg to about 10, 50, 100, or 250 mg / kg. In various embodiments, a single dose of an ASBTI is from about 0.001 mg / kg to about 100 mg / kg. In various embodiments, a single dose of an ASBT I is about 0.001 mg / kg to about 50 mg / kg. In various embodiments, a single dose of an ASBTI is about 0.001 mg / kg to about 10 mg / kg. In several modalities, a single dose of an ASBTI is administered every 6 hours, every 12 hours, every 24 hours, every 48 hours, every 72 hours, every 96 hours, every 5 days, every 6 days, or once a week . In some embodiments, the total single dose of an ASBTI is in the range described above.
In the event that the patient's condition improves, after the doctor's judgment an ASBTI is optionally given continuously; alternatively, the dose of drug being administered is temporarily reduced or temporarily suspended for a certain length of time (i.e., a "drug vacation"). The duration of the drug's vacation optionally varies between 2 days and 1 years, including, as an example only, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 10 days, 12 days, 15 days, 20 days, 28 days, 35 days, 50 days, 70 days, 100 days, 120 days, 150 days, 180 days, 200 days, 250 days, 280 days, 300 days, 320 days, 350 days, or 365 days. Dose reduction during long drug holidays includes 10% -100%, including, as an example only, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50% , 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 100%. In some embodiments, the total single dose of an ASBTI is in the range described above.
Once the patient's condition has improved, a maintenance dose is administered if necessary. Subsequently, the dosage or frequency of administration, or both, are reduced, as a function of the symptoms, to a level where the improved disease, disorder or condition is retained. In some modalities, patients require intermittent treatment on a long-term basis after any recurrence of symptoms.
In certain cases, there are a large number of variables in relation to an individual treatment regimen, and considerable variations from these recommended values are considered within the scope described here. The dosages described here are optionally changed depending on numerous variables such as a non-limiting example, the activity of the compound used, the disease or condition to be treated, the mode of administration, the individual's requirements, the severity of the disease or condition being treated, and the doctor's judgment.
The toxicity and therapeutic efficacy of such therapeutic regimes are optionally determined by pharmaceutical procedures in cell cultures or experimental animals, including, without limitation, the determination of LD50 (the lethal dose for 50% of the population) and ED50 (the therapeutically effective dose 50% of the population). The dose ratio between toxic and therapeutic effects is the therapeutic index and it can be expressed as the ratio between LD50 and ED50. Compounds that exhibit high therapeutic indexes are preferred. In certain embodiments, data obtained from cell culture assays and animal studies are used in formulating a dosage range for use in humans. In specific embodiments, the dosage of compounds described here is based on a range of circulating concentrations that include ED50 with minimal toxicity. The dosage optionally varies in this range depending on the dosage form used and the route of administration used.
In some embodiments, the systemic exposure of a therapeutically effective amount of any non-systemic ASBTIs described herein (for example, an ASBTI comprising a non-systemic portion such as LK or other groups described herein) is reduced when compared to systemic exposure of a therapeutically amount efficacy of any systemically absorbed ASBTI (eg Compounds 100A, 100C). In some embodiments, the AUC of a therapeutically effective amount of any non-systemic ASBTI described herein (for example, an ASBTI comprising a non-systemic portion such as LK or other groups described herein) is at least 10%, at least 20%, at least at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 80% or at least 90% reduced when compared to the AUC of any systemically absorbed ASBTI (eg Compounds 100A, 100C) .
In some embodiments, the systemic exposure of a therapeutically effective amount of a Formula I compound that is not systemically absorbed (for example, a Formula I compound that comprises a non-systemic portion such as LK or other groups described herein) is reduced when compared systemic exposure of a therapeutically effective amount of Compound 100A. In some embodiments, the AUC of a therapeutically effective amount of a Formula I compound that is not systemically absorbed (for example, a Formula I compound that comprises a non-systemic portion such as LK or other groups described herein) is about 10% , about 20%, about 30%, about 40%, about 50%, about 60%, about 70%, about 80% or about 90% reduced when compared to the AUC of a therapeutically effective amount of Compound 100A. In some embodiments, the AUC of a therapeutically effective amount of a Formula I compound that is not systemically absorbed (for example, a Formula I compound that comprises a non-systemic portion such as LK or other groups described herein) is about 50% reduced when compared to the AUC of a therapeutically effective amount of Compound 100A. In other embodiments, the AUC of a therapeutically effective amount of a Formula I compound that is not systemically absorbed (for example, a Formula I compound that comprises a non-systemic portion such as LK or other groups described herein) is about 75% reduced when compared to the AUC of a therapeutically effective amount of Compound 100A.
In some embodiments, the systemic exposure of a therapeutically effective amount of a Formula II compound that is not systemically absorbed (for example, a Formula II compound that comprises a non-systemic portion such as LK or other groups described herein) is reduced when compared systemic exposure of a therapeutically effective amount of Compound 100A. In some embodiments, the AUC of a therapeutically effective amount of a Formula II compound that is not systemically absorbed (for example, a Formula II compound that comprises a non-systemic portion such as LK or other groups described herein) is about 10% , about 20%, about 30%, about 40%, about 50%, about 60%, about 70%, about 80% or about 90% reduced when compared to the AUC of a therapeutically effective amount of Compound 100A. In some embodiments, the AUC of a therapeutically effective amount of a Formula II compound that is not systemically absorbed (for example, a Formula II compound that comprises a non-systemic portion such as LK or other groups described herein) is about 50% reduced when compared to the AUC of a therapeutically effective amount of Compound 100A. In other embodiments, the AUC of a therapeutically effective amount of a Formula II compound that is not systemically absorbed (for example, a Formula II compound that comprises a non-systemic portion such as LK or other groups described herein) is about 75% reduced when compared to the AUC of a therapeutically effective amount of Compound 100A.
In some embodiments, the systemic exposure of a therapeutically effective amount of a Formula III, IIIA, IIIB or IIIC compound is reduced when compared to the systemic exposure of a therapeutically effective amount of Compound 100C. In some embodiments, the AUC of a therapeutically effective amount of a Formula III, IIIA, IIIB or IIIC compound is about 10%, about 20%, about 30%, about 40%, about 50%, about 60%, about 70%, about 80% or about 90% reduced when compared to the AUC of a therapeutically effective amount of Compound 100C. In some embodiments, the AUC of a therapeutically effective amount of a Formula III, IIIA, IIIB or IIIC compound is about 50% reduced when compared to the AUC of a therapeutically effective amount of Compound 100C. In other embodiments, the AUC of a therapeutically effective amount of a compound of Formula III, IIIA, IIIB or IIIC is about 75% reduced when compared to the AUC of a therapeutically effective amount of Compound 100C.
In some embodiments, the systemic exposure of a therapeutically effective amount of a Formula IV compound that is not systemically absorbed (for example, a Formula IV compound comprising a non-systemic portion such as LK or other groups described herein) is reduced when compared systemic exposure of a therapeutically effective amount of Compound 100A. In some embodiments, the AUC of a therapeutically effective amount of a Formula IV compound that is not systemically absorbed (for example, a Formula I compound comprising a non-systemic portion such as LK or other groups described herein) is about 10% , about 20%, about 30%, about 40%, about 50%, about 60%, about 70%, about 80% or about 90% reduced when compared to the AUC of a therapeutically effective amount of Compound 100A. In some embodiments, the AUC of a therapeutically effective amount of a Formula IV compound that is not systemically absorbed (for example, a Formula IV compound that comprises a non-systemic portion such as LK or other groups described herein) is about 50% reduced when compared to the AUC of a therapeutically effective amount of Compound 100A. In other embodiments, the AUC of a therapeutically effective amount of a Formula IV compound that is not systemically absorbed (for example, a Formula IV compound that comprises a non-systemic portion such as LK or other groups described herein) is about 75% reduced when compared to the AUC of a therapeutically effective amount of Compound 100A.
In some embodiments, the systemic exposure of a therapeutically effective amount of a Formula V compound that is not systemically absorbed (for example, a Formula V compound that comprises a non-systemic portion such as LK or other groups described herein) is reduced when compared systemic exposure of a therapeutically effective amount of Compound 100A. In some embodiments, the AUC of a therapeutically effective amount of a Formula V compound that is not systemically absorbed (for example, a Formula V compound comprising a non-systemic portion such as LK or other groups described herein) is about 10% , about 20%, about 30%, about 40%, about 50%, about 60%, about 70%, about 80% or about 90% reduced when compared to the AUC of a therapeutically effective amount of Compound 100A. In some embodiments, the AUC of a therapeutically effective amount of a Formula I compound that is not systemically absorbed (for example, a Formula V compound that comprises a non-systemic portion such as LK or other groups described herein) is about 50% reduced when compared to the AUC of a therapeutically effective amount of Compound 100A. In other embodiments, the AUC of a therapeutically effective amount of a Formula I compound that is not systemically absorbed (for example, a Formula V compound that comprises a non-systemic portion such as LK or other groups described herein) is about 75% reduced when compared to the AUC of a therapeutically effective amount of Compound 100A.
In some embodiments, systemic exposure of a therapeutically effective amount of a Formula VI or VID compound that is not systemically absorbed (for example, a Formula VI or VID compound that comprises a non-systemic portion such as LK or other groups described herein) is reduced when compared to the systemic exposure of a therapeutically effective amount of Compound 100A. In some embodiments, the AUC of a therapeutically effective amount of a Formula VI or VID compound that is not systemically absorbed (for example, a Formula VI or VID compound that comprises a non-systemic portion such as LK or other groups described herein) about 10%, about 20%, about 30%, about 40%, about 50%, about 60%, about 70%, about 80% or about 90% reduced when compared to the AUC of a therapeutically effective amount of Compound 100A. In some embodiments, the AUC of a therapeutically effective amount of a Formula VI or VID compound that is not systemically absorbed (for example, a Formula VI or VID compound that comprises a non-systemic portion such as LK or other groups described herein) about 50% reduced when compared to the AUC of a therapeutically effective amount of Compound 100A. In other embodiments, the AUC of a therapeutically effective amount of a Formula I compound that is not systemically absorbed (for example, a Formula VI or VID compound that comprises a non-systemic portion such as LK or other groups described herein) is about 75% reduced when compared to the AUC of a therapeutically effective amount of Compound 100A.
In certain embodiments, the Cmax of a therapeutically effective amount of any non-systemic ASBTI described herein (for example, an ASBTI comprising a non-systemic portion such as LK or other groups described herein) is at least 10%, at least 20%, at least at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 80% or at least 90% reduced when compared to the Cmax of any systemically absorbed ASBTI (for example, Compound 100A ).
As an example, the Cmax of a therapeutically effective amount of a compound of Formula III, IIIA, IIIB or IIIC is about 10%, about 20%, about 30%, about 40%, about 50%, about 60%, about 70%, about 80%, or about 90% reduced when compared to a Cmax of a therapeutically effective amount of Compound 100C. In some embodiments, the Cmax of a therapeutically effective amount of a Formula III, IIIA, IIIB or IIIC compound is about 25% reduced when compared to a Cmax of a therapeutically effective amount of Compound 100C. In certain embodiments, the Cmax of a therapeutically effective amount of a compound of III, IIIA or IIIB is about 50% reduced when compared to a Cmax of a therapeutically effective amount of Compound 100C. In other embodiments, the Cmax of a therapeutically effective amount of a Formula III, IIIA, IIIB or IIIC compound is about 75% reduced when compared to a Cmax of a therapeutically effective amount of Compound 100C.
In certain embodiments, the pharmaceutical composition administered includes a therapeutically effective amount of a bile salt, a bile acid mimetic, or a bile salt mimetic, an absorption inhibitor and a carrier (for example, a suitable oral carrier) or a suitable rectal carrier, depending on the mode of administration desired). In certain embodiments, the pharmaceutical composition used or administered comprises a bile salt, a bile acid mimetic, or a bile salt mimetic, an absorption inhibitor, a carrier, and one or more of a cholesterol absorption inhibitor, an enteroendocrine peptide, a peptidase inhibitor, a spreading agent, and a wetting agent.
In another specific embodiment, the pharmaceutical composition used to prepare an oral or oral dosage form comprises a bile salt, a bile acid mimetic, or a bile salt mimetic, an absorption inhibitor, a suitable carrier for orally, an optional cholesterol absorption inhibitor, an optional enteroendocrine peptide, an optional peptidase inhibitor, an optional spreading agent, and an optional wetting agent. In certain embodiments, compositions administered orally elicit an anorectal response. In specific modalities, the anorectal response is an increase in the secretion of one or more enteroendocrines by cells in the colon and / or rectum (for example, in L cells of the epithelial layer of the colon and / or rectum). In some modalities, the anorectal response persists for at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 , 20, 21, 22, 23 or 24 hours. In other modalities the ano-rectal response persists for a period between 24 hours and 48 hours, while in other modalities the ano-rectal response persists for a period longer than 48 hours. Routes of administration and dosage
In some embodiments, the compositions described herein and the compositions administered in the methods described herein are formulated to inhibit reuptake of bile acid, or to reduce serum or hepatic levels of bile acid. In certain embodiments, the compositions described herein are formulated for rectal or oral administration. In some embodiments, such formulations are administered rectally or orally, respectively. In some embodiments, the compositions described herein are combined with a device for local delivery of the compositions to the rectum and / or colon (sigmoid colon, transverse colon, or ascending colon). In certain embodiments, for rectal administration of the composition described herein, they are formulated as enemas, rectal gels, rectal foams, rectal aerosols, suppositories, gelatinous suppositories or retention enemas. In some embodiments, for oral administration the compositions described here are formulated for oral administration and enteric release to the colon.
In certain embodiments, the compositions or methods described herein are non-systemic. In some embodiments, the compositions described herein deliver ASBTI to the distal ileum, colon, and / or rectum and non-systemically (for example, a substantial portion of the enteroendocrine peptide secretion-enhancing agent is not systemically absorbed). In some embodiments, the oral compositions described herein release ASBTI to the distal ileum, colon, and / or rectum and non-systemically (for example, a substantial portion of the enteroendocrine peptide secretion-enhancing agent is not systemically absorbed). In some embodiments, the rectal compositions described herein release ASBTI to the distal ileum, colon, and / or rectum and non-systemically (e.g., a substantial portion of the enteroendocrine peptide secretion-enhancing agent is not systemically absorbed). In certain embodiments, the non-systemic compositions described herein release less than 90% v / v of the ASBTI systemically. In certain embodiments, the non-systemic compositions described herein release less than 80% v / v of the ASBTI systemically. In certain embodiments, the non-systemic compositions described herein release less than 70% v / v of the ASBTI systemically. In certain embodiments, the non-systemic compositions described herein release less than 60% v / v of the ASBTI systemically. In certain embodiments, the non-systemic compositions described herein release less than 50% v / v of the ASBTI systemically. In certain embodiments, the non-systemic compositions described herein release less than 40% v / v of the ASBTI systemically. In certain embodiments, the non-systemic compositions described herein release less than 30% v / v of the ASBTI systemically. In certain embodiments, the non-systemic compositions described herein release less than 25% v / v of the ASBTI systemically. In certain embodiments, the non-systemic compositions described herein release less than 20% v / v of the ASBTI systemically. In certain embodiments, the non-systemic compositions described herein release less than 15% v / v of the ASBTI systemically. In certain embodiments, the non-systemic compositions described herein release less than 10% v / v of the ASBTI systemically. In certain embodiments, the non-systemic compositions described herein release less than 5% v / v of the ASBTI systemically. In some embodiments, systemic absorption is determined in any appropriate manner, including the total circulating amount, the amount absorbed after administration, or others.
In certain embodiments, the compositions and / or formulations described herein are administered at least once a day. In certain embodiments, formulations containing ASBTI are administered at least twice a day, while in other embodiments, formulations containing ASBTI are administered at least three times a day. In certain embodiments, formulations containing ASBTI are administered up to five times a day. It should be understood that in certain modalities, the dosage regimen of the composition containing the ASBTI described here is determined by considering several factors such as the patient's age, sex, and diet.
The concentration of ASBTI administered in the formulations described herein varies from about 1 mM to about 1 M. In certain embodiments, the concentration of ASBTI administered in the formulations described here ranges from about 1 mM to about 750 mM. In certain embodiments, the concentration of ASBTI administered in the formulations described herein ranges from about 1 mM to about 500 mM. In certain embodiments, the concentration of ASBTI administered in the formulations described herein ranges from about 5 mM to about 500 mM. In certain embodiments, the concentration of ASBTI administered in the formulations described herein ranges from about 10 mM to about 500 mM. In certain embodiments, the concentration of ASBTI administered in the formulations described herein ranges from about 25 mM to about 500 mM. In certain embodiments, the concentration of ASBTI administered in the formulations described herein ranges from about 50 mM to about 500 mM. In certain embodiments, the concentration of ASBTI administered in the formulations described herein ranges from about 100 mM to about 500 mM. In certain embodiments, the concentration of ASBTI administered in the formulations described herein ranges from about 200 mM to about 500 mM.
In certain embodiments, any composition described herein comprises a therapeutically effective amount (for example, to treat cholestasis or a cholestatic liver disease) of ursodiol. In some embodiments, ursodiol can be replaced by any other therapeutic acid or bile salt. In some embodiments, the compositions described herein comprise the methods described herein which comprise administering from about 0.01 mg to about 10 g of ursodiol. In certain embodiments, the composition described herein comprises a method described herein which comprises administering from about 0.1 mg to about 500 mg of ursodiol. In certain embodiments, the composition described herein comprises a method described herein which comprises administering from about 0.1 mg to about 100 mg of ursodiol. In certain embodiments, the composition described herein comprises a method described herein which comprises administering from about 0.1 mg to about 50 mg of ursodiol. In certain embodiments, the composition described herein comprises a method described herein which comprises administering from about 0.1 mg to about 10 mg of ursodiol. In certain embodiments, the composition described herein comprises a method described herein which comprises administering from about 0.5 mg to about 10 mg of ursodiol. In some embodiments, the compositions described herein comprise the methods described herein which comprise administration from about 0.1 mmol to about 1 mol of ursodiol. In certain embodiments, the composition described herein comprises a method described herein which comprises administering from about 0.01 mmol to about 500 mmol of ursodiol. In certain embodiments, the composition described herein comprises a method described herein which comprises administering from about 0.1 mmol to about 100 mmol of ursodiol. In certain embodiments, the composition described herein comprises a method described herein which comprises administering from about 0.5 mmol to about 30 mmol of ursodiol. In certain embodiments, the composition described herein comprises a method described herein which comprises administering from about 0.5 mmol to about 20 mmol of ursodiol. In certain embodiments, the composition described herein comprises a method described herein which comprises administering from about 1 mmol to about 10 mmol of ursodiol. In certain embodiments, the composition described herein comprises a method described herein which comprises administering from about 0.01 mmol to about 5 mmol of ursodiol. In certain embodiments, the composition described herein comprises a method described herein which comprises administering from about 0.1 mmol to about 1 mmol of ursodiol. In various modalities, certain bile acids / salts have different potencies and the dosage is optionally adjusted accordingly.
In certain embodiments, when targeting the distal gastrointestinal tract (for example, distal ileum, colon, and / or rectum), the compositions and methods described herein provide efficacy (for example, in reducing microbial growth and / or alleviating cholestasis symptoms or from cholestatic liver disease) with a reduced dose of enteroendocrine peptide-secreting agent (for example, when compared to an oral dose that does not target the distal gastrointestinal tract). Rectal administration formulations
The pharmaceutical compositions described herein for the non-systemic delivery of a compound described herein to the rectum and / or colon are formulated for rectal administration as rectal enemas, rectal foams, rectal gels, and rectal suppositories. The components of such formulations are described herein. It is to be understood that as used herein, pharmaceutical compositions and compositions comprise formulations as described herein. In some embodiments, rectal formulations comprise rectal enemas, foams, gels, or suppositories.
In certain embodiments, liquid or co-solvent carriers in the compositions and / or formulations described herein include, as a non-limiting example, purified water, propylene glycol, PEG200, PEG300, PEG400, PEG600, polyethylene glycol, ethanol, 1-propanol, 2-propanol, 1-propen-3-ol (allyl alcohol), propylene glycol, glycerol, 2-methyl-2-propanol, formamide, methyl formamide, dimethyl formamide, ethyl formamide, diethyl formamide, acetamide, methyl acetamide, dimethyl acetamide , ethyl acetamide, diethyl acetamide, 2-pyrrolidone, N-methyl-2-pyrrolidone, N-ethyl-2-pyrrolidone, tetramethyl urea, 1,3-di-methyl-2-imidazolidinone, propylene carbonate, 1,2-butylene carbonate , 2,3-butylene carbonate, dimethyl sulfoxide, diethyl sulfoxide, hexamethyl phosphoramide, pyruvic aldehyde dimethylacetal, dimethylisosorbide and combinations thereof.
In some embodiments, the stabilizers used in the compositions and / or formulations described herein include, without limitation, partial glycerides of saturated polyoxyethylene fatty acids.
In certain embodiments, surfactants / emulsifiers used in the compositions and / or formulations described herein include, as a non-limiting example, mixtures of cetostearyl alcohol with sorbitan esterified with polyoxyethylene fatty acids, polyoxyethylene fatty ethers, polyoxyethylene fatty esters, fatty acids, fatty acids , sulfosuccinate acids, amphoteric surfactants, non-ionic polaxamers, non-meroxapols, petroleum derivatives, aliphatic amines, polysiloxane derivatives, sorbitan fatty acid esters, laureth-4, PEG-2 dilaurate, stearic acid, sodium lauryl sulfate, dioctyl sodium sulfosuccinate, cocoanphopropionate, poloxamer 188, meroxapol 258, triethanolamine, dimethicone, polysorbate 60, sorbitan monostearate, pharmaceutically acceptable salts thereof, and combinations thereof.
In some embodiments, non-ionic surfactants used in the compositions and / or formulations described herein include, as a non-limiting example, phospholipids, poly (ethylene oxide) alkyl, poloxamers (eg poloxamer 188), polysorbates, sodium dioctyl sulfosuccinate, Brij ™ -30 (Laureth-4), Brij ™ -58 (Ceteth-20) and BrijTM-78 (Steareth-20), Brij ™ -721 (Steareth-21), Crillet-1 (Polysorbate 20), Crillet-2 ( Polysorbate 40), Crillet-3 (Polysorbate 60), Crillet 45 (Polysorbate 80), Myrj-52 (PEG-40 Stearate), Myrj-53 (PEG-50 Stearate), Pluronic ™ F77 (Poloxamer 217), Pluronic ™ F87 (Poloxamer 237), Pluronic ™ F98 (Poloxamer 288), Pluronic ™ L62 (Poloxamer 182), Pluronic ™ L64 (Poloxamer 184), Pluronic ™ F68 (Poloxamer 188), Pluronic ™ L81 (Poloxamer 231), Pluronic ™ L92 (Poloxamer 282), Pluronic ™ L101 (Poloxamer 331), Pluronic ™ P103 (Poloxamer 333), Pluracare ™ F 108 NF (Poloxamer 338), and Pluracare ™ F 127 NF (Poloxamer 407) and combinations thereof. Pluronic ™ polymers are commercially available from BASF, USA and Germany. in the compositions and / or formulations described herein include, as a non-limiting example, sodium lauryl sulfate, sodium dodecyl sulfate (SDS), ammonium lauryl sulfate, alkyl sulfate salts, alkyl benzene sulfonate, and combinations thereof.
In some embodiments, the cationic surfactants used in the compositions and / or formulations described herein include, as a non-limiting example, benzalkonium chloride, benzethonium chloride, cetyl trimethylammonium bromide, hexadecyl trimethyl ammonium bromide, other alkyltrimethylammonium salts, chloride chloride cetylpyridinium, tallow polyethoxylate and combinations of these.
In certain embodiments, the thickeners used in the compositions and / or formulations described herein include, as a non-limiting example, natural polysaccharides, semi-synthetic polymers, synthetic polymers and combinations thereof. Natural polysaccharides include, as a non-limiting example, acacia gum, agar, alginates, carrageenan, guar, arabica, tragacanth, pectins, dextran, gellana and xanthan. Semi-synthetic polymers include, as a non-limiting example, cellulose esters, modified starches, modified celluloses, carboxyl cellulose, methyl cellulose, ethyl cellulose, hydroxyethyl cellulose, hydroxypropyl cellulose and hydroxypropyl methyl cellulose. Synthetic polymers include, as a non-limiting example, polyoxyalkylenes, polyvinyl alcohol, polyacrylamide, polyacrylates, carboxypolymethylene (carbomer), polyvinylpyrrolidone (povidones), polyvinylacetate, polyethylene glycols and poloxamer. Other thickeners include, as a non-limiting example, polyoxyethylene glycol isostearate, cetyl alcohol, Polyglycol 300 isostearate, propylene glycol, collagen, gelatin, and fatty acids (e.g. lauric acid, myristic acid, palmitic acid, stearic acid, palmitole acid, linoleic acid , linolenic acid, oleic acid and others).
In some embodiments, chelating agents used in the compositions and / or formulations described herein include, as a non-limiting example, ethylene diaminetetraacetic acid (EDTA) or salts thereof, phosphates and combinations thereof.
In some embodiments, the concentration of the chelating agent or agents used in the rectal formulations described herein is an appropriate concentration, for example, about 0.1%, 0.15%, 0.2%, 0.25%, 0.3 %, 0.4%, or 0.5% (w / v).
In some embodiments, the preservatives used in the compositions and / or formulations described herein include, as a non-limiting example, parabens, ascorbyl palmitate, benzoic acid, butylated hydroxyanisol, butylated hydroxytoluene, chlorobutanol, ethylenediamine, ethylparaben, methylparaben, butyl paraben, propylparaben monothioglycerol, phenol, phenylethyl alcohol, propylparaben, sodium benzoate, sodium propionate, sodium formaldehyde sulfoxylate, sodium metabisulfite, sorbic acid, sulfur dioxide, maleic acid, propyl gaiate, benzalkonium chloride, benzethonium chloride, benzyl alcohol, chlorhexidine acetate, chlorhexidine gluconate, sorbic acid, potassium sorbitol, chlorobutanol, phenoxyethanol, cetylpyridinium chloride, phenylmercuric nitrate, thimerosol, and combinations thereof.
In certain embodiments, antioxidants used in the compositions and / or formulations described herein include, as a non-limiting example, ascorbic acid, ascorbyl palmitate, butylated hydroxyanisol, butylated hydroxytoluene, hypophosphorous acid, monothioglycerol, propylate, sodium ascorbate, sodium sulfite, bisulfite sodium, sodium formaldehyde sulfoxylate, potassium metabisulfite, sodium metabisulfite, oxygen, quinones, t-butyl hydroquinone, erythorbic acid, olive oil (olea eurpaea), pentassodium penetetate, pentetic acid, tocopheryl, tocopheryl acetate and combinations thereof.
In some embodiments, the concentration of the antioxidant or antioxidants used in the rectal formulations described here is sufficient to achieve a desired result, for example, about 0.1%, 0.15%, 0.2%, 0.25%, 0 , 3%, 0.4%, or 0.5% (w / v).
Lubricating agents used in the compositions and / or formulations described herein include, as a non-limiting example, natural or synthetic fat or oil (for example, a tris-glycerate fatty acid and others). In some embodiments, lubricating agents include, as a non-limiting example, glycerin (also called glycerin, glycerol, 1,2,3-propanotriol, and trihydroxypropane), polyethylene glycols (PEGs), polypropylene glycol, polyisobutene, polyethylene oxide, behenic acid, behenyl alcohol, sorbitol, mannitol, lactose, polydimethylsiloxane and combinations of these.
In certain embodiments, mucoadhesive and / or bioadhesive polymers are used in the compositions and / or formulations described herein as agents for inhibiting the absorption of the enteroendocrine peptide secretion-enhancing agent throughout the rectal or colonic mucosa. Mucoadhesive and / or bioadhesive polymers include, as a non-limiting example, hydroxypropyl cellulose, ethylene polyoxide homopolymers, polyvinyl ether-maleic acid copolymers, methyl cellulose, ethyl cellulose, propyl cellulose, hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxypropyl cellulose, hydroxypropyl cellulose, hydroxypropylmethyl cellulose, hydroxypropyl cellulose, hydroxypropylmethyl cellulose, hydroxypropylmethyl cellulose, hydroxypropylmethyl cellulose, hydroxypropylmethyl cellulose, hydroxypropylmethyl cellulose, hydroxypropylmethyl cellulose, hydroxypropylmethyl cellulose, hydroxypropylmethyl cellulose, hydroxypropylmethyl cellulose, hydroxypropylmethyl cellulose, hydroxypropylmethyl cellulose, hydroxypropylmethyl cellulose, hydroxypropylmethyl cellulose, hydroxypropylmethyl cellulose, hydroxypropylmethyl cellulose, hydroxypropylmethyl cellulose. , polycarbophil, polyvinylpyrrolidone, carbopol, polyurethanes, ethylene polyoxide-polypropylene oxide, sodium carboxyl cellulose, polyethylene, polypropylene, lectins, xanthan gum, alginates, sodium alginate, polyacrylic acid, chitosan, hyaluronic acid and ester derivatives, vinyl acetate homopolymer, polycarbophil calcium, gelatin, natural gums, karaya, tragacanth, algin, chitosan, starches, pectins, and combinations thereof.
In some embodiments, pH buffering / adjusting agents used in the compositions and / or formulations described herein include, as a non-limiting example, phosphoric acid, monobasic sodium or potassium phosphate, triethanolamine (TRIS), BICINE, HEPES, Trizma, glycine , histidine, arginine, lysine, asparagine, aspartic acid, glutamine, glutamic acid, carbonate, bicarbonate, potassium metaphosphate, potassium phosphate, monobasic sodium acetate, acetic acid, acetate, citric acid, anhydrous sodium citrate, sodium citrate dihydrate and combinations of these. In certain embodiments, an acid or base is added to adjust the pH. Suitable acids or bases include, as a non-limiting example, HCL, NaOH and KOH.
In certain embodiments, the concentration of the buffering agent or agents used in the rectal formulations described herein is sufficient to achieve or maintain a physiologically desirable pH, for example, about 0.1%, 0.2%, 0.3%, 0.4%, 0.5%, 0.6%, 0.8%, 0.9%, or 1.0% (v / v).
Tonicity modifiers used in the compositions and / or formulations described herein include, as a non-limiting example, sodium chloride, potassium chloride, sodium phosphate, mannitol, sorbitol or glucose. Oral administration for colonic release
In certain respects, the composition or formulation containing one or more compounds described herein is administered orally for local delivery of an ASBTI, or a compound described here to the colon and / or rectum. Unit dosage forms of such compositions include a pill, tablet or capsule formulated for enteric delivery to the colon. In certain embodiments, such pills, tablets or capsule contain the compositions described herein imprisoned or embedded in microspheres. In some embodiments, the microspheres include, as a non-limiting example, HPMC capsules of chitosan micronuclei and microspheres of cellulose acetate butyrate (CAB). In certain embodiments, oral dosage forms are prepared using conventional methods known to those in the field of pharmaceutical formulation. For example, in certain embodiments, tablets are manufactured using standard tablet-forming procedures and equipment. An example method for forming tablets is by directly compressing a powdered, crystalline or granular composition containing the active agent, alone or in combination with one or more carriers, additives, or the like. In alternative embodiments, the tablets are prepared using wet granulation or dry granulation processes. In some embodiments, the tablets are molded instead of compresses, starting with a moist or manageable material.
In certain embodiments, tablets prepared for oral administration contain various excipients, including, as a non-limiting example, binders, diluents, lubricants, disintegrants, fillers, stabilizers, surfactants, preservatives, coloring agents, flavoring agents and others. In some embodiments, binders are used to impart cohesive qualities to a tablet, ensuring that the tablet remains intact after compression. Suitable binder materials include, as a non-limiting example, starch (including corn starch and pregelatinized starch), gelatin, sugars (including sucrose, glucose, dextrose and lactose), polyethylene glycol, propylene glycol, waxes, and natural gums and synthetic, for example, acacia sodium alginate, polyvinylpyrrolidone, cellulosic polymers (including hydroxypropyl cellulose, hydroxypropyl methyl cellulose, methyl cellulose, ethyl cellulose, hydroxyethyl cellulose, and others), Veegum, and combinations thereof. In certain embodiments, diluents are used to increase the volume of the tablet so that a practical-sized tablet is provided. Suitable diluents include, as a non-limiting example, dicalcium phosphate, calcium sulfate, lactose, cellulose, kaolin, mannitol, sodium chloride, dry starch, powdered sugar and combinations thereof. In certain embodiments, lubricants are used to facilitate the manufacture of compressed te; Examples of suitable lubricants include, as a non-limiting example, vegetable oils such as peanut oil, cottonseed oil, sesame oil, olive oil, corn oil, and theobroma oil, glycerin, magnesium stearate, calcium, stearic acid and combinations of these. In some embodiments, disintegrants are used to facilitate the disintegration of the tablet, and include, as a non-limiting example, starches, clays, celluloses, algins, gums, interlocking polymers and combinations thereof, 'fillers include, as a non-limiting example, materials such as silicon dioxide, titanium dioxide, alumina, talc, kaolin, cellulose powder and microcrystalline cellulose as well as soluble materials such as mannitol, urea, sucrose, lactose, dextrose, sodium chloride and sorbitol. In certain embodiments, stabilizers are used to inhibit or delay drug decomposition reactions which include, as an example, oxidative reactions. In certain modalities, surfactants are anionic, cationic, amphoteric or non-ionic surface active agents.
In some embodiments, ASBTIs, or other compounds described herein, are administered orally in association with a suitable carrier to release the distal gastrointestinal tract (for example, distal ileum, colon, and / or rectum).
In certain embodiments, the composition described herein comprises an ASBTI, or other compounds described herein in association with a matrix (for example, a matrix comprising hypermelose) that allows for the controlled release of an active agent in the distal part of the ileum and / or colon. In some embodiments, the composition comprises a polymer that is sensitive to pH (for example, an MMXTM matrix from Cosmo Pharmaceuticals) and allows for the controlled release of an active agent in the distal part of the ileum. Examples of such pH sensitive polymers suitable for controlled release include, without limitation, polyacrylic polymers (for example, anionic polymers of methacrylic acid and / or esters of methacrylic acid, for example, Carbopol® polymers) that comprise acid groups (by methacrylic and / or methacrylic acid esters, for example, Carbopol® polymers) that comprise acid groups (for example, COOH, -SO3H) and swell at the basic pH of the intestine (for example, pH about 7 to about 8). In some embodiments, the composition suitable for controlled release into the distal ileum comprises microparticulate active agent (e.g., micronized active agent). In some embodiments, a nucleus that does not enzymatically break down poly (dl-lactide-co-glycolide) (PLGA) is suitable for releasing an enteroendocrine peptide-secreting agent (eg, bile acid) to the distal ileum. In some embodiments, a dosage form comprising an enteroendocrine peptide-enhancing agent (eg, bile acid) is coated with an enteric polymer (eg, Eudragit® S-100, cellulose acetate phthalate, polyvinylacetate phthalate, hydroxypropylmethylcellulose phthalate, anionic polymers of methacrylic acid, methacrylic acid esters or others) for local-specific release to the distal ileum and / or colon. In some embodiments, bacteria-activated systems are suitable for targeted delivery to the distal part of the ileum. Examples of microflora-activated systems include dosage forms that comprise pectin, galactomannans and / or Azo hydrogels and / or glycoside conjugates (e.g., D-galactoside, β-D-xylopyranosphide or other conjugates) of the active agent. Examples of enzymes in the gastrointestinal microflora include bacterial glycosidases such as, for example, D-galactosidase, β-D-glucosidase, α-L-arabinofuranosidase, β-D-xylopyranidasidase or others.
The pharmaceutical composition described herein optionally includes an additional therapeutic compound described herein and one or more pharmaceutically acceptable additives such as, for example, a compatible carrier, binder, filler, suspending agent, flavoring agent, sweetening agent, disintegrating agent, dispersing agent , surfactant, lubricant, dye, diluent, solubilizer, wetting agent, plasticizer, stabilizer, penetration enhancer, wetting agent, antifoaming agent, antioxidant, preservative, or one or more combinations thereof. In some respects, using standard coating procedures, such as those described in "Remington's Pharmaceutical Sciences", 20th Edition (2000), a film coating is provided around the formulation of the Formula I compound. In one embodiment, a compound described herein it is in the form of a particle and some or all particles of the compound are coated. In certain embodiments, some or all of the particles of a compound described herein are microencapsulated. In some embodiments, the particles of the compound described herein are not microencapsulated and are not coated.
In other embodiments, a tablet or capsule comprising an ASBTI or other compounds described herein is coated with film to deliver to the desired sites in the gastrointestinal tract. Examples of enteric film coatings include, without limitation, hydroxypropyl methylcellulose, polyvinyl pyrrolidone, hydroxypropyl cellulose, polyethylene glycol 3350, 4500, 8000, methyl cellulose, pseudo ethyl cellulose, amylopectin and others. Bile acid sequestrant
In certain embodiments, an oral formulation for use in any method described herein is, for example, an ASBTI in association with an unstable bile acid scavenger. An unstable bile acid scavenger is a bile acid scavenger with an unstable affinity for bile acids. In certain embodiments, a bile acid scavenger described herein is an agent that scavenges (for example, absorbs or is loaded with) bile acid, and / or the salts thereof.
In specific embodiments, the unstable bile acid scavenger is an agent that sequesters (for example, absorbs or is loaded with) bile acid, and / or the salts thereof, and releases at least a portion of the absorbed or charged bile acid, and / or salts thereof in the distal gastrointestinal tract (for example, the colon, ascending colon, sigmoid colon, distal colon, rectum, or any combination thereof).
In certain embodiments, the unstable bile acid scavenger is an enzyme-dependent bile acid scavenger. In specific embodiments, the enzyme is a bacterial enzyme. In some embodiments, the enzyme is a bacterial enzyme found in high concentration in the human colon or rectum in relation to the concentration found in the small intestine. Examples of microflora-activated systems include dosage forms comprising pectin, galactomannan, and / or Azo hydrogels and / or glycosidic conjugates (e.g., D-galactoside conjugates, β-D-xylopyranoside or others) of the active agent. Examples of enzymes in the gastrointestinal microflora include bacterial glycosidases such as, for example, D-galactosidase, β-D-glucosidase, α-L-arabinofuranosidase, β-D-xylopyranidasidase or others. In certain embodiments, the unstable bile acid scavenger is a time-dependent bile acid scavenger ie bile acid scavenges bile acid and / or salts and after a while releases at least a portion of bile acid and / or salts thereof). In some embodiments, a time-dependent bile acid scavenger is an agent that degrades in an aqueous environment over time. In certain embodiments, an unstable bile acid scavenger described here is a bile acid scavenger that has a low affinity for bile acid and / or its salts, thereby allowing the bile acid scavenger to continue to sequester bile acid and / or salts of this in an environment where the bile acids / salts and / or salts of these are present in high concentration and release them in an environment in which the bile acids / salts and / or salts of these are present in a lower relative concentration. In some embodiments, the unstable bile acid scavenger has a high affinity for a primary bile acid and a low affinity for a secondary bile acid, allowing the bile acid scavenger to sequester a primary bile acid or salt from it and subsequently release a bile acid secondary or salt thereof as the primary bile acid or salt thereof is converted (for example, metabolized) to the secondary bile acid or salt thereof. In some embodiments, the unstable bile acid scavenger is a pH-dependent bile acid scavenger. In some embodiments, the pH-dependent bile acid scavenger has a high bile acid affinity at a pH of 6 or below and a low bile acid affinity at a pH of 6. In certain embodiments, the pH-dependent bile acid scavenger pH degrades at a pH above 6.
In some embodiments, the unstable bile acid scavengers described herein include any compound, for example, a macrostructured compound, which can sequester bile acids / salts and / or salts thereof by any suitable mechanism. For example, in certain modalities, the bile acid scavenger sequesters bile acids / salts and / or their salts through ionic interactions, polar interactions, static interactions, hydrophobic interactions, lipophilic interactions, hydrophilic interactions, spherical interactions, or others. In certain embodiments, macrostructured compounds sequester bile acids / salts and / or sequestrants by trapping bile acids / salts and / or their salts in interactions pockets, such as those described above. In some embodiments, bile acid scavengers (eg, unstable bile acid scavengers) include, as a non-limiting example, lignin, modified lignin, polymers, polycationic polymers and copolymers, polymers and / or copolymers that comprise any one or more of N-alkenyl-N-alkylamine residues; one or more N, N, N-trialkyl-N- (N'-alkenylamino) alkyl azanium residues; one or more N, N, N-trialkyl-N-alkenyl-azanium residues; one or more alkenyl amine residues; or a combination of these, or any combination of these. Covalent binding of the drug with a carrier
In some embodiments, the strategies used for colon-directed delivery include, as a non-limiting example, covalent attachment of ASBTI or other compounds described herein to a carrier, coating a dosage form with a pH-sensitive polymer for release after reaching the environment of colon pH, using redox-sensitive polymers, using a formulation released over time, using coatings that are specifically degraded by colonic bacteria, using bioadhesive system and using osmotically controlled drug delivery systems.
In certain embodiments, such oral administration of the composition containing an ASBTI or other compounds described herein involves covalent attachment to a carrier where, after oral administration, the bound portion remains intact in the stomach and small intestine. After entering the colon, the covalent bond is broken by changing pH, enzymes and / or degradation by the intestinal microflora. In certain embodiments, the covalent bond between the ASBTI and the carrier includes, as a non-limiting example, azo bond, glycoside conjugates, glucuronide conjugates, cyclodextrin conjugates, dextran conjugates and amino acid conjugates (high hydrophilicity and long chain length of the carrier amino acid). Polymer coating: pH sensitive polymers
In some embodiments, the oral dosage forms described herein are coated with an enteric coating to facilitate the release of an ASBTI or other compounds described herein to the colon and / or rectum. In certain embodiments, an enteric coating is one that remains intact in the low pH environment of the stomach, but is easily dissolved when the optimal pH dissolving pH of the particular coating is reached, which depends on the chemical composition of the enteric coating. The thickness of the coating will depend on the solubility characteristics of the coating material. In certain embodiments, the coating thicknesses used in the formulations described herein vary from about 25 pm to about 200 pm.
In certain embodiments, the compositions or formulations described herein are coated in such a way that an ASBTI or other compounds described herein from the composition or formulation is released into the colon and / or rectum without absorption in the upper part of the intestine. In a specific embodiment, the specific release to the colon and / or rectum is obtained by coating the dosage form with polymers that only degrade in the colon's pH environment. In alternative embodiments, the composition is coated with an enteric coating that dissolves at the pH of the intestines and a matrix of the outer layer that slowly erodes in the intestine.
In some of these embodiments, the matrix slowly erodes until only a central composition comprising an enteroendocrine peptide-secreting enhancing agent (and, in some embodiments, an agent absorption inhibitor) is over and the nucleus is released to the colon and / or straight.
In certain embodiments, pH-dependent systems exploit the progressively increasing pH throughout the human gastrointestinal (GIT) tract from the stomach (pH 1-2, which increases to 4 during digestion), small intestine (pH 6-7) at the site digestion and goes up to 7-8 in the distal ileum. In certain embodiments, the dosage forms for oral administration of the compositions described herein are coated with a pH sensitive polymer (or polymers) to provide delayed release and protect the enteroendocrine peptide secretion-enhancing agents from the gastric fluid. In certain embodiments, these polymers are able to withstand the lower pH values of the stomach and the proximal part of the small intestine, but disintegrate at the neutral or slightly alkaline pH of the terminal ileum and / or the ileocecal junction. Thus, in certain embodiments, an oral dosage form comprising a coating, the coating comprising a pH sensitive polymer, is provided herein. In some embodiments, polymers used to target the colon and / or rectum include, as a non-limiting example, methacrylic acid copolymers, methacrylate and methacrylate copolymers, Eudragit L100, Eudragit S100, Eudragit L-30D, Eudragit FS-30D , Eudragit L100-55, polyvinylacetate phthalate, hydroxypropyl ethyl cellulose phthalate, hydroxypropyl methyl cellulose phthalate 50, hydroxypropyl methyl cellulose phthalate 55, cellulose trimellate acetate, cellulose acetate phthalate and combinations thereof.
In certain embodiments, oral dosage forms suitable for delivery to the colon and / or rectum comprise a coating that has a biodegradable and / or degradable polymer by bacteria or polymers that are degraded by the microflora (bacteria) in the colon. In such biodegradable systems, suitable polymers include, as a non-limiting example, azo polymers, segmented polyurethanes of the type containing azo groups, polygalactomannans, pectin, glutaraldehyde, crosslinked dextran, polysaccharides, amylose, guar gum, pectin, chitosan, inulin, cyclodextrins, cyclodextrins chondroitin, dextrans, locust bean gum, chondroitin sulfate, chitosan, poly (- caprolactone), polylactic acid and poly (lactic-co-glycolic acid).
In certain embodiments of such oral administration of compositions containing one or more ASBTIs or other compounds described herein, the compositions are released to the colon without absorption in the upper part of the intestine by coating the dosage forms with redox-sensitive polymers that are degraded by the microflora ( bacteria) in the colon. In such biodegradable systems, these polymers include, as a non-limiting example, redox-sensitive polymers that contain an azo and / or disulfide bond in the framework.
In some embodiments, compositions formulated for release to the colon and / or rectum are formulated to release over time. In some embodiments, time-release formulations resist the acidic environment of the stomach, thereby delaying the release of enteroendocrine peptide-secreting agents until the dosage form enters the colon and / or rectum.
In certain embodiments, the time-release formulations described herein comprise a capsule (comprising an enteroendocrine peptide secretion-enhancing agent and an optional absorption inhibitor) with a hydrogel plug. In certain embodiments, the capsule and the hydrogel plug are covered by a water-soluble cap and the entire unit is coated with an enteric polymer. When the capsule enters the small intestine, the enteric coating dissolves and the hydrogel plug swells and displaces from the capsule after a period of time, and the composition is released from the capsule. The amount of hydrogel is used to adjust the amount of time until its content is released.
In some embodiments, an oral dosage form is provided which comprises a multilayer coating, wherein the coating comprises different layers of polymers having different pH sensitivities. As the coated dosage form moves along the GIT, the different layers dissolve depending on the pH found. The polymers used in these formulations include, as a non-limiting example, polymethacrylates with appropriate pH dissolving characteristics, Eudragit® RL and Eudragit® RS (inner layer) and Eudragit® FS (outer layer). In other embodiments, the dosage form is an enteric-coated tablet that has an external hydroxypropyl cellulose shell or hydroxypropyl methyl cellulose acetate succinate (HPMCAS).
In some embodiments, an oral dosage form is provided which comprises coating with cellulose butyrate phthalate, cellulose hydrogen phthalate, cellulose phthalate, polyvinyl acetate phthalate, cellulose acetate phthalate, cellulose trimellitate acetate, hydroxypropyl methyl cellulose phthalate, hydroxypropyl methylcellulose acetate, dioxypropyl methylcellulose succinate, carboxymethyl ethylcellulose, hydroxypropyl methylcellulose succinate, polymers and copolymers formed by acrylic acid, methacrylic acid, and combinations thereof. Combined therapy with fat-soluble vitamins
In some embodiments, the methods provided herein also comprise the administration of one or more vitamins. In some embodiments, the vitamin is vitamin A, Bl, B2, B3, B5, B6, B7, B9, B12, C, D, E, K, folic acid, pantothenic acid, niacin, riboflavin, thiamine, retinol, beta carotene , pyridoxine, ascorbic acid, cholecalciferol, cyanocobalamin, tocopherols, phylloquinone, menaquinone.
In some embodiments, the vitamin is a fat-soluble vitamin such as vitamin A, D, E, K, retinol, beta carotene, cholecalciferol, tocopherols, phylloquinone. In a preferred embodiment, the fat-soluble vitamin is tocopherol polyethylene glycol succinate (TPGS). Combination therapy with partial external biliary bypass (LDPE)
In some embodiments, the methods provided here also include the use of partial external biliary bypass as a treatment for patients who have not yet developed cirrhosis. This treatment helps to reduce the circulation of bile acids / salts in the liver in order to reduce complications and avoid the need for early transplantation in many patients.
This surgical technique involves isolating a 10 cm long segment of the intestine for use as a bile duct (a channel for the passage of bile) from the rest of the intestine. One end of the conduit is attached to the gallbladder and the other end is brought up to the skin to form a mouth (an opening surgically constructed to allow the passage of waste). The partial external biliary bypass can be used for patients who do not respond to all medical therapies, especially older, older patients. This procedure may not be useful for young patients, such as babies. The partial external biliary bypass can decrease the intensity of the itch and abnormally low blood cholesterol levels. Combination therapy with ASBTI and ursodiol
In some modalities, an ASBTI is administered in combination with ursodiol or ursodeoxycholic acid, chenodeoxycholic acid, cholic acid, taurocholic acid, ursocholic acid, glycocholic acid, glycodesoxycholic acid, taurodeoxycholic acid, taurocholate, glycoquenodeoxycholic acid, tauroursodeoxycholic acid. In some cases, an increase in the concentration of bile acids / salts in the distal intestine induces intestinal regeneration, attenuation of intestinal damage, reduction of bacterial translocation, inhibition of free radical oxygen release, inhibition of pro-inflammatory cytokine production, or any combination of these
An ASBTI and a second active ingredient are used in such a way that the combination is present in a therapeutically effective amount. That therapeutically effective amount arises from the use of a combination of an ASBTI and the other active ingredient (for example, ursodiol), each of which is used in a therapeutically effective amount, or because of the additive or synergistic effects of combined use, and each can also be used in a subclinical therapeutically effective amount, that is, an amount that, if used alone, allows reduced efficacy for the therapeutic purposes observed here, provided that the combined use is therapeutically effective. In some embodiments, the use of a combination of an ASBTI and any other active ingredient as described herein encompasses combinations in which ASBTI or the other active ingredient is present in a therapeutically effective amount, and the other is present in a therapeutically effective subclinical amount , provided that the combined use is therapeutically effective due to its additive or synergistic effects. As used herein, the term "additive effect" describes the combined effect of two (or more) pharmaceutically active agents that is equal to the sum of the effect of each agent given alone. A synergistic effect is one in which the combined effect of two (or more) pharmaceutically active agents is greater than the sum of the effect of each agent given in isolation. Any suitable combination of an ASBTI with one or more of the other active ingredients mentioned above and, optionally, with one or more other pharmacologically active substances is contemplated to be within the scope of the methods described herein.
In some modalities, the particular choice of compounds depends on the diagnosis of the attending physicians and their assessment of the individual's condition and the appropriate treatment protocol. The compounds are optionally administered concomitantly (for example, simultaneously, basically simultaneously or within the same treatment protocol) or sequentially, depending on the nature of the disease, disorder or condition, the condition of the individual, and the actual choice of compounds used. In certain cases, determining the order of administration and the number of repetitions of administration for each therapeutic agent during a treatment protocol is based on an assessment of the disease being treated and the condition of the individual.
In some embodiments, therapeutically effective dosages vary when drugs are used in combinations of treatments. Methods for experimentally determining therapeutically effective dosages of drugs and other agents for use in combined treatment regimens are described in the literature.
In some modalities of the combined therapies described herein, the dosages of the co-administered compounds vary depending on the type of co-drug employed, the specific drug employed, the disease or condition being treated, and so on. In addition, when co-administered with one or more biologically active agents, the compound provided herein is optionally administered simultaneously with the biologically active agent (s), or sequentially. In certain cases, if administered sequentially, the attending physician will decide the appropriate sequence of the therapeutic compound described herein in combination with the additional therapeutic agent.
The multiple therapeutic agents (at least one of which is a therapeutic compound described herein) are optionally administered in any order or even simultaneously. If administered simultaneously, the multiple therapeutic agents are optionally supplied in a single unified form or in multiple forms (just as an example, as a single pill or as two separate pills). In certain cases, one of the therapeutic agents is optionally given in multiple doses. In other cases, both are optionally given as multiple doses. If administration is not simultaneous, the time between multiple doses is any suitable interval, for example, from more than zero weeks to less than four weeks. In addition, the methods, compositions and formulations of the combination are not limited to the use of just two agents; the use of multiple therapeutic combinations is also envisaged (including two or more compounds described herein).
In certain modalities, a dosage regimen to treat, prevent or improve the condition (or conditions) for which relief is sought, is modified according to several factors. These factors include the disorder from which the individual suffers, as well as the age, weight, sex, diet and medical condition of the individual. Thus, in various modalities, the dosage regimen actually employed varies from the dosage regimens established here.
In some embodiments, the pharmaceutical agents that make up the combination therapy described herein are provided in a combined dosage form or in separate dosage forms intended for substantially simultaneous administration. In certain embodiments, the pharmaceutical agents that make up the combined therapy are administered sequentially, with one of the therapeutic compounds being administered by a regimen that requires administration in two stages. In some modalities, the two-stage administration regime requires sequential administration of active agents or interval administration of separate active agents. In certain embodiments, the time between multiple administration steps varies, as a non-limiting example, from a few minutes to several hours, depending on the properties of each pharmaceutical agent, such as potency, solubility, bioavailability, plasma half-life and kinetic profile. of the pharmaceutical agent.
In certain embodiments, combination therapies are provided here. In certain embodiments, the compositions described herein comprise an additional therapeutic agent. In some embodiments, the methods described herein comprise the administration of a second dosage form which comprises an additional therapeutic agent. In certain embodiments of the combination therapies, the compositions described herein are administered as part of a regimen. Therefore, additional therapeutic agents and / or additional pharmaceutical dosage forms can be applied to a patient directly or indirectly, and concomitantly or sequentially, with the compositions and formulations described herein. Kits
In another aspect, kits are provided herein that contain a device for pre-filled rectal administration and a pharmaceutical composition described herein. In certain embodiments, the kits contain a device for oral administration and a pharmaceutical composition as described herein. In certain modalities, the kits include pre-filled sachets or bottles for oral administration, while in other modalities, the kits include pre-filled bags for administration of rectal gels. In certain embodiments, the kits include pre-filled syringes for administration of oral enemas, while in other modalities, the kits include pre-filled syringes for administration of rectal gels. In certain embodiments, the kits include pre-filled pressurized cans for administration of rectal foams. Pharmaceutical compositions
Here, in certain embodiments, a pharmaceutical composition is provided which comprises a therapeutically effective amount of any compound described herein. In certain cases, the pharmaceutical composition comprises an ASBT inhibitor (for example, any ASBTI described herein).
In certain embodiments, pharmaceutical compositions are formulated in a conventional manner using one or more physiologically acceptable carriers, including, for example, excipients and auxiliaries that facilitate the processing of active compounds in preparations that are suitable for pharmaceutical use. In certain embodiments, the appropriate formulation depends on the chosen route of administration. A summary of pharmaceutical compositions described herein is found, for example, in "Remington: The Science and Practice of Pharmacy", 19th Edition (Easton, Pa .: Mack Publishing Company, 1995); Hoover, John E., "Remington's Pharmaceutical Sciences", Mack Publishing Co., Easton, Pennsylvania 1975; Liberman, H.A. and Lachman, L., Eds., "Pharmaceutical Dosage Forms", Marcel Decker, New York, N.Y., 1980; and "Pharmaceutical Dosage Forms ans Drug Delivery Systems", 7th Edition (Lippincott Williams & Wilkins 1999).
The term "pharmaceutical composition", as used herein, refers to a mixture of a compound described herein, for example, a compound of Formula I-VI, with other chemical components, such as carriers, stabilizers, diluents, dispersing agents, agents suspension agents, thickening agents and / or excipients. In certain cases, the pharmaceutical composition facilitates the administration of the compound to an individual or cell. In certain embodiments of the practice of the methods of treatment or use provided herein, therapeutically effective amounts of compounds described herein are administered in a pharmaceutical composition to an individual who has a disease, disorder or condition to be treated. In specific modalities, the individual is a human being. As discussed herein, the compounds described herein are used alone or in combination with one or more additional therapeutic agents.
In certain embodiments, the pharmaceutical formulations described herein are administered to an individual in any form, including one or more of several routes of administration such as, as a non-limiting example, the oral, parenteral (for example, intravenous, subcutaneous, intramuscular) route of administration ), intranasal, buccal, topical, rectal or transdermal.
In certain embodiments, the pharmaceutical compositions described herein include one or more compounds described herein as an active ingredient in the form of a free acid or free base, or in a pharmaceutically acceptable salt form. In some embodiments, the compounds described herein are used as a W-oxide or in a crystalline or amorphous form (i.e., a polymorph). In some situations, a compound described here exists as tautomers. All tautomers are included within the scope of the compounds presented here. In certain embodiments, a compound described herein exists in an unsolvated or solvated form, wherein the solvated forms comprise any pharmaceutically acceptable solvent, for example, water, ethanol, and the like. The solvated forms of the compounds presented herein are also considered to be described herein.
A "carrier" includes, in some embodiments, a pharmaceutically acceptable excipient and is selected based on compatibility with compounds described herein, such as, compounds of any of Formulas I-VI, and the properties of the release profile of the desired dosage form . Exemplary carrier materials include, for example, binders, suspending agents, disintegrating agents, fillers, surfactants, solubilizers, stabilizers, lubricants, wetting agents, diluents, and the like. See, for example, "Remington: The Science and Practice of Pharmacy", 19th Edition (Easton, Pa .: Mack Publishing Company, 1995); Hoover, John E., "Remington's Pharmaceutical Sciences", Mack Publishing Co., Easton, Pennsylvania 1975; Liberman, H.A. and Lachman, L., Eds., "Pharmaceutical Dosage Forms", Marcel Decker, New York, N.Y., 1980; and "Pharmaceutical Dosage Forms and Drug Delivery Systems", 7th Edition (Lippincott Williams & Wilkins, 1999).
In addition, in certain embodiments, the pharmaceutical compositions described herein are formulated as a dosage form. Thus, in some embodiments, a dosage form comprising a compound described herein, suitable for administration to an individual, is provided herein. In certain embodiments, suitable dosage forms include, as a non-limiting example, aqueous oral dispersions, liquids, gels, syrups, elixirs, broths, suspensions, solid oral dosage forms, aerosols, controlled release formulations, rapid melt formulations, formulations effervescent, lyophilized formulations, tablets, powders, pills, pills, capsules, delayed release formulations, extended release formulations, pulsatile release formulations, multiparticulate formulations and mixed immediate and controlled release formulations. Release in the distal ileum and / or colon
In certain embodiments, a dosage form comprises a matrix (for example, a matrix comprising hypromellosis) that allows for the controlled release of an active agent in the distal jejunum, proximal ileum, distal ileum and / or the colon. In some embodiments, a dosage form comprises a polymer that is sensitive to pH (for example, an MMX ™ matrix from Cosmo Pharmaceuticals) and allows for the controlled release of an active agent into the ileum and / or colon. Examples of such pH sensitive polymers suitable for controlled release include, without limitation, polyacrylic polymers (for example, anionic polymers of methacrylic acid and / or esters of methacrylic acid, for example, Carbopol® polymers) that comprise acid groups (for example, - COOH, -SO3H) and swell at the basic pH of the intestine (for example, pH about 7 to about 8). In some embodiments, a dosage form suitable for controlled release into the distal ileum comprises microparticulate active agent (for example, micronized active agent). In some embodiments, a core that does not enzymatically degrade poly (dl-lactide-co-glycolide) (PLGA) core is suitable for releasing an ASBTI to the distal ileum. In some embodiments, a dosage form comprising an ASBTI is coated with an enteric polymer (for example, Eudragit® S-100, cellulose acetate phthalate, polyvinylacetate phthalate, hydroxypropyl methylcellulose phthalate, anionic polymers of methacrylic acid, esters of methacrylic acid or others) for local-specific release to the ileum and / or colon. In some embodiments, bacteria-activated systems are suitable for targeted delivery to the ileum. Examples of microflora-activated systems include dosage forms comprising pectins, galactomannans and / or Azo hydrogels and / or glycoside conjugates (e.g., D-galactoside, β-D-xylopyranoside conjugates or others) of the active agent. Examples of enzymes in the gastrointestinal microflora include bacterial glycosidases such as, for example, D-galactosidase, β-D-glucosidase, α-L-arabinofuranosidase, β-D-xylopyranidasidase or others.
The solid dosage forms described herein optionally include an additional therapeutic compound described herein and one or more pharmaceutically acceptable additives such as, for example, a compatible carrier, binder, filler, suspending agent, flavoring agent, sweetening agent, disintegrating agent , dispersing agent, surfactant, lubricant, dye, diluent, solubilizer, wetting agent, plasticizer, stabilizer, penetration enhancer, wetting agent, antifoaming agent, antioxidant, preservative, or one or more combinations thereof. In some respects, using standard coating procedures, such as those described in "Remington's Pharmaceutical Sciences", 20th Edition (2000), a film coating is provided around the formulation of the Formula I-VI compound. In one embodiment, a compound described herein is in the form of a particle and some or all of the particles of the compound are coated. In certain embodiments, some or all of the particles of a compound described herein are microencapsulated. In some embodiments, the particles of the compound described herein are not microencapsulated and are not coated.
An ASBT inhibitor (for example, a Formula I-VI compound) is used in the preparation of drugs for the prophylactic and / or therapeutic treatment of cholestasis or cholestatic liver disease. One method for treating any of the diseases or conditions described herein in an individual in need of such treatment, involves the administration of pharmaceutical compositions containing at least one ASBT inhibitor described herein, or a pharmaceutically acceptable salt, pharmaceutically acceptable N-oxide, pharmaceutically active metabolite, pharmaceutically acceptable prodrug or pharmaceutically acceptable solvate thereof, in amounts therapeutically effective for said individual. Evaluation process
In certain modalities, processes and kits are provided to identify compounds suitable for the treatment of cholestasis or cholestatic liver disease. In certain embodiments, assays are provided here for identifying compounds that selectively inhibit ASBT by: a. providing cells that are a model of intestinal cells; B. contacting the cells with a compound (for example, a compound as described herein); ç. detection or measurement of the compound on inhibiting ASBT activity. In certain embodiments, assays are provided for identifying compounds that are non-systemic compounds by: a. supply of cells that are a model of intestinal permeability (for example, Caco-2 cells); B. culturing the cells as a monolayer on semipermeable plastic supports that are adapted in the wells of multi-well culture plates; ç. contacting the apical or basolateral surface of cells with a compound (for example, a compound as described herein) and incubation for an appropriate period of time; d. detecting or measuring the concentration of the compound on both sides of the monolayer by liquid chromatography / mass spectrometry (LC-MS) and computing the intestinal permeability of the compound.
In certain embodiments, non-systemic compounds are identified by appropriate parallel artificial membrane (PAMPA) permeability assays.
In certain embodiments, non-systemic compounds are identified using isolated intestinal preparations with vascular perfusion.
In certain embodiments, assays for identifying compounds that inhibit recycling of bile acid salts are provided here by: a. supply of cells that are a model of intestinal cells with apical transport of bile acids (for example, BHK cells, CHO cells); B. incubating the cells with a compound (for example, a compound as described herein) and / or radiolabelled bile acid (for example, 14C-taurocholate) for an appropriate period of time; ç. washing the cells with a suitable buffer (for example, phosphate buffered saline); d. detection or measurement of residual concentration of radiolabeled bile acid in cells. EXAMPLES
Example 1: Synthesis of 1-phenethyl-l - ((1,4-diazabicyclo [2.2.2] octanyl) pentyl) imidodicarbonimide diamide, iodide salt

Step 1: Synthesis of 5- (1,4-diazabicyclo [2.2.2] octanyl) -1-pentane iodine, iodide salt
1,4-diazabicyclo [2.2.2] octane is suspended in THF. Diiodopentane is added in drops and the mixture is refluxed overnight. The reaction mixture is filtered.
Step 2: Synthesis of N-phenethyl-5- (1,4 - diazabicyclo [2.2.2] octanyl) -1-iodine pentane, iodide salt.
5- (1,4-diazabicyclo [2.2.2] octanyl) -1-iodine pentane, iodide salt is suspended in acetonitrile. Phenethylamine is added in drops and the mixture is refluxed overnight. The reaction mixture is filtered.
Step 3: Synthesis of 1-phenethyl-1 - ((1,4-diazabicyclo [2.2.2] octanyl) pentyl) imidodicarbonimide diamide, iodide salt.
N-phenethyl- 5- (1,4-diazabicyclo [2.2.2] octanyl) -1- pentane iodine, iodide salt is heated with dicyandiamide in n-butanol for 4 h. The reaction mixture is concentrated under reduced pressure.
The compounds in Table 1 are prepared using methods as described herein, and using suitable starting materials. Table 1

Example 2: In-vitro assay for inhibition of ASBT-mediated bile acid uptake
Hamster cub kidney (BHK) cells are transfected with human ASBT cDNA. The cells are seeded in 96-well tissue culture plates at 60,000 cells / well. The tests are carried out 24 hours after sowing.
On the day of the test the cell monolayer is washed with 100 ml of assay buffer. The test compound is added to each well together with 6 mM [14C] taurocholate in assay buffer (final concentration of 3 mM [14C] taurocholate in each well). Cell cultures are incubated for 2 h at 37 ° C. The wells are washed with PBS. Scintillation counting fluid is added to each well, the cells are shaken for 30 minutes before measuring the amount of radioactivity in each well. A test compound that has significant ASBT inhibitor activity provides an assay in which low levels of radioactivity are observed in cells. Example 3: In-glass assay for GLP-2 secretion
Human NCI-716 cells are used as a model for L cells. Two days before each test experiment, cells are seeded in 12-well culture plates coated with Matrigel® to induce cell adhesion. On the day of the test, the cells are washed with buffer. The cells are incubated for 2 hours with medium only, or with test compound. The extracellular medium is analyzed for the presence of GLP-2. Peptides in the medium are collected by reversed phase adsorption and the extracts are stored until testing. The presence of GLP-2 is analyzed using ELISA. The detection of increased levels of GLP-2 in a well containing a test compound identifies the test compound as a compound that can increase the secretion of GLP-2 from L cells. Example 4: In vivo bioavailability test
The test compounds are solubilized in saline solutions. Sprague Dawley rats are dosed at 2-10 mg / kg of body weight by iv and oral dosing. Peripheral blood samples are taken from the femoral artery for selected periods of time up to 8 hours. The plasma concentrations of the compounds are determined by quantitative HPLC and / or mass spectrometry. The clearance and AUC values are determined for the compounds.
For oral dosing, bioavailability is calculated by taking plasma samples from the portal vein. Cannulas are inserted into the femoral artery and the hepatic portal vein to obtain estimates of total drug absorption without clearing the first passage through the liver. The absorbed fraction (F) is calculated by F = AUCpo / AUCiv Example 5: Assay to determine levels of ileal intraenterocyte and luminal bile acid
Levels of ileal luminal bile acid in SD rats are determined by immersing a 3 cm section of distal ileum with cold sterile PBS. After immersion with more PBS, the same section of the ileum is weighed and then homogenized in fresh PBS to determine the levels of bile acid interenterocyte. An LC / MS / MS system is used to assess levels of cholic acid, DCA, ACL, chenodeoxycholic acid, and ursodeoxycholic acid. Example 6: Animal to determine the effect of therapy on cholestasis or a cholestatic liver disease
Mouse model MdR2knock out of cholestasis or cholestatic liver disease induced in rats (by carbon tetrachloride / phenobarbital) is used to test the compositions described here. The animals are administered orally with a composition comprising an ASBTI such as 100B, 264W94; SD5613; SA R548304B; SA HMR1741; 1,1- Dioxo-3,3-dibutyl-5-phenyl- 7-methylthio-8 - (N - [(R) -a- [N- (2-sulfoethyl) carbamoyl] -4-hydroxybenzyl] carbamoylmethoxy) - 2,3,4,5-tetrahydro-1,2,5-benzothiadiazepine; 1,1-Dioxo-3,3 - dibutyl-5-phenyl-7-methylthio-8- (N- [(R) -a- [N - ((S) -1-carboxi- 2- (R) - hydroxypropyl) carbamoyl] -4-hydroxybenzyl] carbamoylmethoxy) -2,3,4,5-tetrahydro-1,2,5-benzothiadiazepine; 1,1-Dioxo-3,3-dibutyl-5-phenyl-7 - methylthio-8- (N - [(R) -a- [N - ((S) -1-carboxy-2-methylpropyl) carbamoyl] -4-hydroxybenzyl] carbamoylmethoxy) -2,3,4,5 - tetrahydro-1,2,5-benzothiadiazepine; 1,1-dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8- (N- {(R) -a- [N - ((S) -1-carboxypropyl) carbamoyl] -4-hydroxybenzyl } carbamoylmethoxy) -2,3,4,5 - tetrahydro-1,2,5-benzothiadiazepine; or 1,1-dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8- [N - ((R) -a-carboxy-4-hydroxybenzyl) carbamoylmethoxy] -2,3,4,5- tetrahydro-1,2,5-benzothiadiazepine.
Cholestasis or cholestatic liver disease is quantified by bile acid and total bilirubin in the serum versus that in placebo-controlled mice / rats. Serum bile acids / salts are determined by ELISA with specific antibodies for colic and CCDCA. Serum bilirubin levels are determined by routine automated assays. Alternatively, the livers of the mice can be collected and pathology of hepatocellular damage can be measured. Example 7 Investigation of LU M001 released orally and 1- [4- [4 - [(4R, 5R) -3,3-dibutyl-7 - (dimethylamino) -2,3,4,5- tetrahydro-4- hydroxy-1,1-dioxido-1-benzothiepin-5-yl] phenoxy] butyl] 4-aza-1-azoniabicyclo [2.2.2] octane methane sulfonate (Compound 100B) at plasma levels of GLP-2 in normal rats
Males of 12-week-old HSD rats are fasted for 16 hours and receive an oral dose of 0, 3, 30, 100 mg / kg from ASBTIs LUM001 or 1- [4- [4 - [(4R, 5R) - 3,3- dibutyl-7- (dimethylamino) -2,3,4,5-tetrahydro-4-hydroxy-1,1-dioxido-1-benzothiepin-5-yl] phenoxy] butyl] 4-aza-l- azoniabicycle [2. 2 . 2] octane methane sulfonate (synthesized by Nanosyn I nc., CA, USA) in a mixture of valine-pyrrolidine in water (n = 5 per group). Blood samples in 0.6 ml volume for each time point are taken from the caudal vein with a heparinized capillary tube 0, 1, 3 and 5 h after the administration of compounds and plasma. The level of GLP-2 is determined. Aprotinin and 10 µl of DPP-IV inhibitor per ml of blood are used to preserve the blood sample for 10 minutes of centrifugation and for storage at -70 ° C or below. GLP-2 (pM Active) is tested by any commercially available ELISA kit. Example 8: Tablet formulation
10 kg of a compound of Formula I-VI is first sieved through a suitable sieve (for example, 500 microns). 25 kg of Lactose monohydrate, 8 kg of hydroxypropylmethyl cellulose, the sieved Formula I-VI compound and 5 kg of calcium hydrogen phosphate (anhydrous) are then added to a suitable mixer and mixed. The mixed portion is sieved through a suitable sieve (for example, 500 microns) and mixed again. About 50% of the lubricant (2.5 kg, magnesium stearate) is sieved, added to the mixer and mixed quickly. The remaining lubricant (2 kg, magnesium stearate) is sieved, added to the mixer and mixed quickly. The granules are screened (for example, 200 microns) to obtain granulation particles of the desired size. In some embodiments, the granules are optionally coated with a drug release control polymer such as polyvinylpyrrolidine, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, methyl cellulose, or a methacrylic acid copolymer, to provide an extended release formulation. The granules are filled in gelatin capsules. Example 9: Pediatric formulation
Disintegration of tablet formulation- The following example describes a large scale preparation (100 kg) of an ASBTI compound of Formula I-VI (e.g., LUM-001 or LUM-002).

Pass ASBTI (2.5 kg), lactose monohydrate NF (47.5 kg), pregelatinized starch NF (18 kg), microcrystalline cellulose NF (17 kg), croscarmellose sodium NF (6.5 kg) and povidone K2 9/32 USP (8.5 kg) through a # 10 weft sieve. Add the sieve material to a 600 Collette mixer. Mix for 6 minutes at low speed, without grinder. Add direct mixing from the previous step to a "20-cubic foot V-shell PK blender" mixer (Model C266200). Pass NF magnesium stearate (0.5 to 1 kg) through a # 10 screen sieve in a suitably prepared container. Add approximately half of the magnesium stearate to each side of the PK mixer and beat for 5 minutes. Add the mixture from the previous step to the Kikusui tablet press for tablet compression. The compression equipment can be fitted to make 50 mg tablets, 75 mg tablets and 100 mg tablets. Example 10: Chewable tablet
A 40% (v / v) solution of Eudragit E 100 in ethanol was added with mixing to the active ingredient and mixed until granules were formed. The resulting granules were dried and then sieved through a 16 mesh screen.


The active ingredient granules and extragranular excipients were placed in a conical mixer and mixed thoroughly. The resulting mixture was discharged from the mixer and compressed in a suitable rotary tablet press fitted with suitable orifices. Example 11: animal study
Preparation of the animal. Males from Zucker diabetic fatty rats (ZDF / GmiCrl-fa / fa) were purchased from Charles River (Raleigh, NC) and housed under controlled conditions (12:12 light-dark cycle, at 24 ° C and 50% relative humidity) ) with free access to feed (Purina 5008, Harlan Teklad, Indianapolis, IN). All rats arrived at seven weeks of age (± 3 days). After a week of acclimatization, the rats were anesthetized with isoflurane (Abbott Laboratories, IL) and blood samples from the tail vein were collected at 9 am without fasting. Blood glucose was measured using a glucometer (Bayer, Leverkusen, Germany). To ensure balanced treatment groups, ZDF rats were assigned to six treatment groups based on base glucose: vehicle (0.5% HPMC, 0.1% Tween80) and five doses of 264W94 (0.001, 0.01, 0.1, 1, 10mg / kg). All treatments were given orally twice a day and the animals were followed for two weeks with blood samples collected from the tail vein at the end of each week at 9 am without fasting. Fecal samples were collected for 24 hours during the second week of treatment.
Measurement of clinical chemical parameters. Non-esterified fatty acids (NEFA), bile acids, and bile acids in fecal extract were measured using the "Olympus AU640" chemical analyzer (Beckman Coulter, Irving, TX).
Changes in fecal bile acid secretion and plasma bile acid concentrations Oral administration of 264W94 dose-dependent increased bile acids in the stool. Fecal bile acid concentrations were increased up to 6.5 times with an ED50 of 0.17 mg / kg, when compared to vehicle-treated rats. Fecal NEFA also increased slightly in rats treated with 264W94. In contrast, plasma bile acid concentrations were decreased dose-dependent in rats treated with 264W94. See FIGURE 1.
Plasma bile acid levels of ZDF rats after administration of ascending doses of SC-435 and LUM002. vehicle, SC-435 (1, 10 or 30 mg / kg) or LUM002 (0.3, 1, 3, 10 or 30 mg / kg) by forced oral intake twice daily for 2 weeks. Plasma bile acid levels were determined at the end of the second week. Plasma bile acid levels were decreased for all doses of SC-435 and LUM002. The data are expressed as mean values ± SEM. See FIGURE 2. Example 12
Animal study on the duration of action and time for the appearance of ASBTI activity of a single oral dose of LUM001 on total postprandial serum bile acids in beagle dogs Test compound: LU M001 - Form I
Preparation of dosage and administration: LUM001 was dissolved in water in concentrations that required the administration of 0.2 ml / kg of solution. The solutions were placed in gelatin capsules, Torpac Inc., size 13 Batch 594, East Hanover NJ, and administered orally.
Dogs: males of beagle dogs were obtained from Covance Research Products, Cumberland VA or Marshall Farms USA, Inc., North Rose NY. A total of 20 dogs, from 1 to 5 years old, 6.8 to 15.6 kg of body weight, were used in these experiments. The dogs were conditioned to a cycle of 12 hours of light / dark and kept in a food restriction of access for 1 hour a day to the feed (Richman Standard Certified Canine Diet # 5007, PMI Nutrition, Inc., St Louis MO) of 7 at 8 in the morning. They were trained to eat a special meal immediately in 20 minutes when presented (1 397g can, "Evanger's 100% Beef for Dogs", Evanger's Dog and Cat Food Co., Inc., Wheeling IL, mixed with 50g of Cheddar cheese) .
Measurement of total serum bile acid (SBA): SBA was measured by an enzymatic assay. SBA values are expressed as gg of total bile acids / ml of serum.
Control experiments to estimate the elevation and duration of elevation in systemic serum bile acid: previous work has shown that SBA in dogs rises to an epic level one hour after feeding with the above meal, and remains up to a plateau for 4 hours and then it declines. To estimate the details of this plateau, 6 dogs received a test meal and blood samples for SBA measurement were collected at -30, 0, 30, 60, 65, 70, 80, 90, 120, 180, 240, 360, 480 , 720, 1,410 and 1,440 minutes of feeding time. Any remaining food was removed 20 minutes after it was first introduced to the dogs. To establish a method for extending the elevated SBA plateau, 6 dogs received a meal at 0 hr and a further 1/2 the meal size again 4 hr after the first meal. Blood samples taken at 0, 1, 2, 3, 4, 4.5, 6, 7 and 8 hr. The curves for SBA level vs time obtained in these experiments were used as references for the determination of blood sample times in experiments with LUM001. When possible, the experimental design allowing, in experiments with a test compound, each dog served as its simultaneous control, and the mean SBA value of 1 hr served as the reference to which all other mean values were compared. Experiments to measure the time for the appearance of
LUMOOl activity: LUMOOl was administered at 0, 0.01, 0.05, 0.2 and 1 mg / kg, po to dogs, n = 6, 1 hr after feeding with the standard experimental food. Blood samples for SBA measurement were taken at -30, 0, 30, 60, 65, 70, 80, 90, 120 and 180 minutes from the moment of feeding. Each dog served as its own control, and the average SBA levels were compared to the average SBA level in 60 minutes. Table 1. Emergence of LUMOOl activity on dog's serum bile acids
All animals were fed in 0 minutes and dosed in 60 minutes. * = p <0.05 compared to the value of 60 minutes on the same curve by two-tailed paired t-test
Experiments to measure the duration of action of LUMOOl: In dogs, a single experimental meal produces a postprandial elevation in SBA that is raised to a peak in 1 hour after feeding and constant for another 3 hours. Previous experiments (2) indicate that LUMOOl remains active for more than 4.5 hours. To measure the duration of action of an ASBT inhibitor with the use of postprandial levels of SBA it is necessary that in the control situation the SBA levels remain high and constant for the entire period of action of the compound, or that the compound is administered well before postprandial elevation occurs, and remains active in the empty digestive system for long periods before feeding. Therefore, two alternative methods were used to provide a constant SBA elevation window that can be used to measure the duration of action of ASBT inhibitors.
Method 1: two meals for extended elevation of SBA: LUM001 was administered at 0.05 and 0.2 mg / kg, p.o. to 6 dogs 1 hr after feeding. Within 4 hours of the meal being offered, a second meal half the size of the first meal was offered. It was also consumed as readily and totally as the first meal, and provided an extended, constant plateau of SBA. Blood samples for SBA measurement were taken at 0, 1, 1.5, 2, 4, 4.5, 5, 5.5, 6, 6.5, 7, 7.5 and 8 hours from the moment of offering the first meal. The average levels of SBA were compared to the average level of SBA in 1 hour, each dog serving as its own control. The end of the activity is considered to have occurred at a point in time when the average value of SBA is not significantly less than the average value of 1 hr.
Table 2. Duration of action of LUM001 on dog 1 serum bile acids

All animals received a complete meal in 0 hours, dosed orally with the compound in 1 hour and then fed with another half meal in 4 hours. * = p <0.05 compared to the mean value on the same curve in 1 hour by two-tailed paired t-test
Method 2: one meal and extended interval between dosage and meal: Alternatively, 6 dogs were dosed with water or LUM001, at 0.05 mg / kg, p.o. in 1.5 hours before being fed, or 0.05, or 0.2 mg / kg, in 2 hours before being fed. This moved the high plateau of SBA in time from the dose point. Blood samples for SBA measurement were taken immediately before dosing (0 or 0.5 hr), with 2 hr feeding), 2.5, 3, 4 and 5 hours after feeding. This allowed the detection of activity at 5.5 and 6 hours after dosing without feeding the dogs a second time. The average levels of SBA were compared to the corresponding average levels of SBA in controls treated with water. The end of the activity is considered to occur at the first point of time when the average value of SBA is not significantly lower than the corresponding control value.
Table 3. Duration of action of LUM001 on dog II serum bile acids
* = p <0.05 vs water treatment by t-test of two samples paired two-tailed without assuming equal variances
Conclusion: in the dog's SBA model, the ED50 dose (0.2 mg / kg) of LUM001 administered orally 1 hour after feeding significantly decreased serum bile acid levels in 30 minutes of dosing and these levels remained significantly decreased for at least 6 hours. In comparison, a threshold dose of 0.05 mg / kg significantly decreased SBA levels approximately 1 to 2 hours after dosing but the significant decrease was not sustained beyond 3 hours after dosing. Increasing the dose above the ED50 level to 1 mg / kg did not shorten the onset time for a significant decrease in SBA and still sustained maximal suppression for 2 hours after dosing. When LUMOOl was administered 2 hours before feeding, a dose of 0.2 mg / kg was required to produce a significant effect that was sustained for at least 2-3 hours after feeding. The results of these studies indicate that the presence of food in the GI tract has a significant impact on the pharmacodynamic activity of the ASBT inhibitor, most likely by altering the residence time of the drug in the small intestine. Example 13
A randomized, double-blind, placebo-controlled, safety, tolerability, pharmacokinetic, and pharmacodynamic study of multiple ascending oral doses of LUMOOl in healthy adult subjects
This phase 1 study was a randomized, double-blind, placebo-controlled study of multiple ascending oral doses of LUMOOl in healthy adults. This study was conducted at a single center. There were 13 LUMOOl dosage panels: 10, 20, 60, 100, and 20 mg each morning (qAM) (2) (ie, the regimen was tested a second time in the study), 5 mg each afternoon (qPM ), 0.5, 1, 2.5, 5, 2.5 (2), 5 (2), and 0.5 to 5 mg qAM dose titration. Most dosing panels included subjects treated with placebo. Data are shown in the graphs of 0.5 (n = 16), 1.0 (n = 8), 2.5 (n = 8), 5.0 (n = 8) and 10 (n = 8) mg of dosing groups.
For qAM, LUMOOl or placebo dosing panels, it was administered each day of the treatment period (28 days) immediately before the morning meal at approximately 8:00 am and after any necessary blood draw.
Analysis of serum bile acid (SBA): on day -1, blood was taken for base SBA in approximately 30 minutes before and after breakfast and 30 minutes after lunch and dinner. During the treatment period, samples were obtained on days 2, 14 and 28 (results from day 14 are shown in FIGURE 3) at -30, 30, 60 120, and 240 minutes after each of the 3 daily meals for analysis. For each sample, approximately 3 ml of venous blood were collected by venipuncture.
SBA were analyzed as part of the routine clinical analysis of serum samples collected at each time point.
Analysis of fecal bile acid: Fecal samples were collected for all panels except for the dose titration panel, 2.5 (2) and 5 mg (2), on Days 9 through 14 and 23 through 28 (data shown in FIGURE 4). Twenty-four hour FBA secretions were quantified by "Pharmacia" for Days 9 to 14 and 23 to 28. Faeces were collected in a 24-hour collection container starting at 8:00 am and ending 24 hours later. This procedure was followed on Days 9 to 14 and 23 to 28, with new collection containers for each period of 24 hours. The weight of each 24-hour fecal collection was recorded on the CRFs. Specimens were stored in 24-hour containers, frozen at approximately -80 ° C before analysis.
An aliquot for each 24-hour fecal sample collected on Days 23 to 28 was combined, homogenized, and analyzed for concentrations of bile acid species by ANAPHARM. The species of fecal bile acid evaluated include chenodeoxycholic acid, cholic acid, deoxycholic acid, and lithocholic acid.
Conclusion: The results showed a significant reduction in serum bile acids and a significant increase in fecal bile acids. Example 14 Human study to test the effectiveness of ASBTI in decreasing serum bile acids
LUMOOl was administered to forty patients aged 18 years of age. The Table below shows the sample characteristics of five patients who received LUMOOl. The drug was administered once daily (QD) in the morning for fourteen days. Systemic exposure levels of LUMOOl were measured on day eight and the drug was confirmed to be minimally absorbed by any patient. These doses are similar to those used to treat patients with cholestatic diseases.
Table 4. Pharmacokinetics of LUMOOl in individuals (study NB-00-02-014)

The effectiveness of LUMOOl was determined by measuring total serum bile acids after eight days of dosing in children and adolescents under eighteen years. Thirty minutes before the next drug administration, at approximately 8 am in the morning, serum bile acid levels were measured. The child had restricted food for 12 hours before this sample thus providing a fasting level of serum bile acid. After breakfast, serum bile acids were measured for up to the next 4 hours (8 am until noon) and the serum epic bile acid concentration noted. LUM001 has been shown to generally decrease fasting and postprandial levels of serum bile acids (see table). In the table below, placebo patients had an average fasting serum bile acid level of 8.6 pmol / 1 and a peak mean postprandial serum bile acid level of 11.9 pmol / 1. For patients treated with LUM001 the values were 6.5 pmol / 1 and 9.2, respectively, representing a decrease of 24% and 23% (see FIGURE 5).
Table 5. SBA fasting and postprandial peak of morning in individuals
Example 15 Clinical experiment to test the effectiveness of ASBTI in the treatment and / or relief of symptoms of cholestasis or a cholestatic liver disease
This study will determine the effectiveness of treatment with ASBTI in patients with cholestasis or cholestatic liver disease.
Individuals 18 years of age or older, clinically diagnosed with cholestasis or cholestatic liver disease will be studied. Individuals can be diagnosed by symptoms such as jaundice, chronic itching, elevated total serum bile acid / bilirubin.
Individuals with life-threatening kidney disease, cardiovascular disease, or congenital anomalies will be excluded.
Individuals will be administered a daily oral dose of compound 100B formulated for delivery to the distal ileum. Alternatively, any of the following compounds may be the subject of the clinical trial: 264W94; SD5613; SAR548304B; SA HMR1741; 1,1-DIOXO-3,3-dibutyl-5-phenyl-7-methylthio-8 - (N - [(R) -a- [N- (2-sulfoethyl) carbamoyl] -4-hydroxybenzyl] carbamoylmethoxy) - 2,3,4,5 - tetrahydro-1,2,5-benzothiadiazepine; 1,1-Dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8- (N- [(R) -a- [N - ((S) -l-carboxy-2- (R) - hydroxypropyl) carbamoyl] -4-hydroxybenzyl] carbamoylmethoxy) - 2,3,4,5-tetrahydro-1,2,5-benzothiadiazepine; 1,1-Dioxo-3,3 - dibutyl-5-phenyl-7-methylthio-8- (N - [(R) -a- [N - ((S) -1-carboxy-2-methylpropyl) carbamoyl] -4-hydroxybenzyl] carbamoylmethoxy) - 2,3,4,5-tetrahydro-1,2,5-benzothiadiazepine; 1,1-dioxo-3,3 - dibutyl-5-phenyl-7-methylthio-8 - (N - {(R) -a- [N - ((S) -1- carboxypropyl) carbamoyl] -4-hydroxybenzyl } carbamoylmethoxy) - 2,3,4,5-tetrahydro-1,2,5-benzothiadiazepine; or 1,1-dioxo- 3,3-dibutyl-5-phenyl-7-methylthio-8- [N- ((R) -A "carboxy-4-hydroxybenzyl) carbamoylmethoxy] -2,3,4,5- tetrahydro-1,2,5-benzothiadiazepine.
The primary end point is the proportion of individuals who show resolution or improvement of underlying signs and symptoms, for example, jaundice, serum levels of bile acids / salts and / or bilirubin, itching. Example 16 Clinical experiment to test the effectiveness of ASBTI in the treatment and / or relief of symptoms of progressive familial intrahepatic 1 (PFIC-1)
This study will determine the effectiveness of an ASBTI for the treatment of patients with PFIC.
Patients genetically diagnosed with abnormalities in the ATP8B1, ABCB11, or ABCB4 gene and presenting with PFIC-1 are eligible for the study.
Inclusion criteria include severe itching (greater than grade II); native liver unresponsive to ursodiol; native liver; genetic or immunohistochemical findings consistent with PFIC1 or Alagille syndrome; informed consent; age of 12 months or more.
Exclusion criteria include chronic diarrhea that requires IV fluid or nutritional interventions; surgical interruption of enterohepatic circulation; or decompensated cirrhosis (PT> 16s, alb <3.0 gr / dl, ascites, diuretic therapy, varicose hemorrhage, encephalopathy).
Individuals will be administered a daily oral dose of LUM001 formulated for delivery to the distal ileum.
Alternatively, any of the following compounds can be administered to the individual in the clinical trial: 264W94; SAR548304B; SA HMR1741; 1,1-DIOXO-3,3-dibutyl-5-phenyl-7-methylthio-8- (N - [(R) -α- [N- (2-sulfoethyl) carbamoyl] -4-hydroxybenzyl] carbamoylmethoxy) - 2,3,4,5-tetrahydro-1,2,5-benzothiadiazepine; 1,1-Dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8- (N - [(R) -ot- [N - ((S) -1-carboxy-2- (R) - hydroxypropyl) carbamoyl] -4-hydroxybenzyl] carbamoylmethoxy) - 2,3,4,5-tetrahydro-1,2,5-benzothiadiazepine; 1,1-Dioxo-3,3 - dibutyl-5-phenyl-7-methylthio-8- (N - [(R) -a- [N - ((S) -1-carboxy-2-methylpropyl) carbamoyl] -4-hydroxybenzyl] carbamoylmethoxy) - 2,3,4,5-tetrahydro-1,2,5-benzothiadiazepine; 1,1-dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8- (N - {(R) -a- [N - ((S) -1- carboxypropyl) carbamoyl] -4-hydroxybenzyl } carbamoylmethoxy) - 2,3,4,5-tetrahydro-1,2,5-benzothiadiazepine; or 1,1-dioxo- 3,3-dibutyl-5-phenyl-7-methylthio-8- [N - ((R) -a-carboxy-4-hydroxybenzyl) carbamoylmethoxy] -2,3,4,5- tetrahydro-1,2,5-benzothiadiazepine.
Stage 1 will be a 4-week dose escalation study to determine the patient's minimum tolerated dose. Dose 1: 14 ug / kg / day for 7 days; dose 2: 35 ug / kg / day for 7 days; dose 3; 70 ug / kg / day for 7 days; dose 4: 140 ug / kg / day for 7 days.
Stage 2 will be a double-blind placebo-controlled cross-over study. Subjects will be randomized to the maximum tolerated dose or placebo for 8 weeks, followed by a 2-week drug vacation, and cross-over to receive the alternative regimen for 8 weeks. week.
The primary end point is the proportion of individuals who show resolution or improvement of underlying signs and symptoms, for example, jaundice, serum levels of bile acids / salts and / or bilirubin, itching. Example 17 Clinical experiment to test the effectiveness of ASBTI in the treatment and / or relief of symptoms of benign recurrent intrahepatic cholestasis or a cholestatic liver disease (BRIC)
The aim of this study is to determine the effect of a non-systemic ASBTI suspension on the treatment of BRIC. An enteric suspension of release at the ileal pH of an ASBTI can also be administered to an individual once a day.
Patients genetically diagnosed with abnormalities in the ATP8B1, ABCB11, or ABCB4 genes and who present with symptoms of non-chronic but recurrent cholestasis or cholestatic liver disease will be studied.
Individuals will be administered a daily oral dose of compound LUM001 formulated for release into the distal ileum. Alternatively, any of the following compounds can be administered to the individual in the clinical trial: 264W94; SD5613; SAR548304B; SA HMR1741; 1,1-Dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8- (N- [(R) -a- [N- (2-sulfoethyl) carbamoyl] -4-hydroxybenzyl] carbamoylmethoxy) - 2,3,4,5-tetrahydro-1,2,5-benzothiadiazepine; 1,1-Dioxo-3,3-dibutyl-5-phenyl-7 - methylthio-8- (N - [(R) -a- [N - ((S) -l-carboxy-2- (R) - hydroxypropyl) carbamoyl] -4-hydroxybenzyl] carbamoylmethoxy) - 2,3,4,5-tetrahydro-1,2,5-benzothiadiazepine; 1,1-Dioxo-3,3 - dibutyl-5-phenyl-7-methylthio-8- (N - [(R) -a- [N - ((S) -1-carboxy-2-methylpropyl) carbamoyl] -4-hydroxybenzyl] carbamoylmethoxy) - 2,3,4,5-tetrahydro-1,2,5-benzothiadiazepine; 1,1-dioxo-3,3 - dibutyl-5-phenyl-7-methylthio-8 - (N - {(R) -a- [N - ((S) -1- carboxypropyl) carbamoyl] -4-hydroxybenzyl } carbamoylmethoxy) - 2,3,4,5-tetrahydro-1,2,5-benzothiadiazepine; or 1,1-dioxo- 3,3-dibutyl-5-phenyl-7-methylthio-8- [N - ((R) -α-carboxy-4-hydroxybenzyl) carbamoylmethoxy] -2,3,4,5- tetrahydro-1,2,5-benzothiadiazepine. The primary end point is the proportion of individuals showing resolution or improvement of underlying signs and symptoms, for example, jaundice, serum levels of bile acid / salts and / or bilirubin, itching. Example 18 Clinical experiment to test the effectiveness of ASBTI in the treatment and / or relief of symptoms of hypercholemia
The aim of this study is to determine the effect of a non-systemic ASBTI suspension on the treatment of hypercholemia. An enteric suspension of release at the ileal pH of an ASBTI can also be administered to an individual once a day.
Patients clinically diagnosed with hypercholemia and associated symptoms will be studied.
Individuals will be administered a daily oral dose of compound LUM001 formulated for release into the distal ileum. Alternatively, any of the following compounds can be administered to the individual in the clinical trial: 264W94; SD5613; SAR548304B; SA HMR1741; 1,1-Dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8- (N - [(R) -a- [N- (2-sulfoethyl) carbamoyl] -4-hydroxybenzyl] carbamoylmethoxy) - 2,3,4,5-tetrahydro-1,2,5-benzothiadiazepine; 1,1-Dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8- (N - [(R) -a- [N - ((S) -1-carboxy-2- (R) - hydroxypropyl) carbamoyl] -4-hydroxybenzyl] carbamoylmethoxy) -2,3,4,5-tetrahydro-1,2,5-benzothiadiazepine; 1,1-Dioxo-3,3-dibutyl-5-phenyl-7 - methylthio-8- (N - [(R) -α- [N - ((S) -1-carboxy-2-methylpropyl) carbamoyl] -4-hydroxybenzyl] carbamoylmethoxy) - 2,3,4,5-tetrahydro-1,2,5-benzothiadiazepine; 1,1-dioxo-3,3 - dibutyl-5-phenyl-7-methylthio-8- (N - {(R) -α- [N - ((S) -1- carboxypropyl) carbamoyl] -4-hydroxybenzyl } carbamoylmethoxy) - 2,3,4,5-tetrahydro-1,2,5-benzothiadiazepine; or 1,1-dioxo- 3,3-dibutyl-5-phenyl-7-methylthio-8- [N - ((R) -α-carboxy-4-hydroxybenzyl) carbamoylmethoxy] -2,3,4,5- tetrahydro-1,2,5-benzothiadiazepine. The primary end point is the proportion of individuals showing resolution or improvement of underlying signs and symptoms, for example, jaundice, serum levels of bile acid / salts and / or bilirubin, itching. Example 19 Clinical experiment to test the effectiveness of LUM-001 in the treatment and / or relief of symptoms of FIC1 disease and Alagille syndrome
Pediatric patients suffering from FIC1 disease (n = 15) and Alagille syndrome (n = 20) 12 months of age and older will be tested.
Inclusion criteria include (1) severe itching (greater than grade II) that does not respond to routine pharmacological therapy; (2) native liver; (3) genetic or clinical findings consistent with PFIC1 or Alagille syndrome; and (4) informed consent ;.
Exclusion criteria include (1) chronic diarrhea that requires specific IV fluid or nutritional interventions for diarrhea and / or its sequelae; (2) surgical interruption of the enterohepatic circulation; (3) decompensated cirrhosis (PT> 16s, alb <3.0 gr / dl, ascites, diuretic therapy, varicose hemorrhage, encephalopathy).
Stage 1: 4-week dose escalation of LUM-001 (doses based on adolescent / adult doses) to determine the patient's maximum tolerated dose. Dose 1: 14 pg / kg / day for 7 days; dose 2: 35 pg / kg / day for 7 days; dose 3; 70 pg / kg / day for 7 days; dose 4: 140 pg / kg / day for 7 days.
Stage 2: double-blind placebo-controlled cross-over study. Subjects are randomized to the maximum tolerated dose or placebo for 8 weeks, followed by a 2-week drug vacation, and cross-over to receive the alternative regimen for 8 weeks.
Possible stage 3 with open label therapy.
Primary end point: safety and tolerability of LUM-001.
Secondary end points: changes in pruritus scores, clinical laboratory, fecal bile acid secretion, serum bile acids and serum 7a-hydroxy-4-cholesten-3-one (7aC4).
The baseline evaluation will include: FIC1 or Jagged 1 genotyping, complete history and physical examination, clinical laboratory profile, 72-hour collection of fecal bile acid, serum bile acid levels, bile acid synthesis marker (7αC4).
Stage 1- Baseline assessments (except for genotyping, history and physical examination) will be repeated at the end of each 7-day treatment period. The pruritus score will be assessed by parents, child (if possible) and doctors at the beginning and end of each dose.
Stage 2- Baseline assessments (except for genotyping, history and physical examination) will be repeated at the end of each 8-week treatment period.
LUM-001 was shown to be well tolerated in a pediatric multiple dose study: 2 weeks daily up to 5 mg q.d. (39 treated individuals aged 10-17 years).
Although preferred embodiments of the present invention have been shown and described here, it will be obvious to those skilled in the art that such modalities are provided as an example only. Numerous variations, changes, and substitutions will now occur for those skilled in the art without evading the invention. It should be understood that several alternatives to the modalities of the invention described herein can be used in the practice of the invention. It is to be understood that the following claims define the scope of the invention and that the methods and structures within the scope of that claim and its equivalents are covered herein.

权利要求:
Claims (11)
[0001]
l.Use of a composition characterized by the fact that it is for the manufacture of a medicament for the treatment of cholestatic liver disease or itching comprising the non-systemic administration to an individual in need of such a therapeutically effective amount of the composition comprising a transporter inhibitor. apical sodium-dependent bile acid (ASBTI) or a pharmaceutically acceptable salt or solvate thereof, where ASBTI is:
[0002]
2. Use, according to claim 1, characterized by the fact that the ASBTI compound is
[0003]
3. Use according to claim 1, characterized by the fact that the compound of Formula II is
[0004]
4. Use, according to claim 1, characterized by the fact that ASBTI decreases the levels of serum bile acids or hepatic bile acid, reduces bilirubin, reduces liver enzymes, reduces intraenterocyte bile acids / salts, or reduces necrosis and / or damage to hepatocellular architecture.
[0005]
5. Use according to claim 1, characterized by the fact that liver disease is a cholestatic liver disease selected from the group consisting of obstructive cholestasis, non-obstructive cholestasis, extrA-hepatic cholestasis, intrA-hepatic cholestasis, intrA ~ cholestasis primary liver disease, secondary intrA ~ hepatic cholestasis, family progressive hepatic cholestasis (PFIC), type 1 PFIC, type 2 PFIC, type 3, benign recurrent liver cholera (BRIC), type 1, BRIC type 2, BRIC type 3, cholestasis associated with total parenteral nutrition, paraneoplastic cholestasis, Stauffer syndrome, intra-hepatic cholestasis of pregnancy, cholestasis associated with contraceptive, cholestasis associated with drug, cholestasis associated with infection, Dubin-Johnson syndrome, primary biliary cirrhosis (PBC ), primary sclerosing cholangitis (PSC), cholelithiasis, Alagille syndrome, Dubin-Johnson syndrome, biliary atresia, post-Kasai biliary atresia, post-liver biliary atresia liver disease, post-liver transplant cholestasis, liver disease associated with post-liver transplantation, liver disease associated with intestinal insufficiency, bile acid-mediated liver injury, MRP2 deficiency syndrome, and neonatal sclerosing cholangitis.
[0006]
6. Use according to claim 1, characterized by the fact that cholestatic liver disease presents one or more selected symptoms of jaundice, pruritus, cirrhosis, hypercholemia, neonatal respiratory stress syndrome, pulmonary pneumonia, increased serum bile acid concentration, increased serum bilirubin concentration, hepatocellular injury, hepatocellular scarring, hepatocellular failure, hepatomegaly, xanthomas, malabsorption, splenomegaly, diarrhea, pancreatitis, hepatocellular necrosis, giant cell formation, hepatocellular carcinoma, gastrointestinal bleeding, portal hypertension, hearing loss , loss of appetite, anorexia, peculiar smell, dark urine, light stools, steatorrhea, developmental failure, and kidney failure.
[0007]
7. Use, according to claim 1, characterized by the fact that less than 10% of the ASBTI is systemically absorbed.
[0008]
8. Use according to claim 1, characterized by the fact that ASBTI is administered before eating food, optionally in which ASBTI is administered less than about 60 minutes or less than about 30 minutes before eating food.
[0009]
9. Use according to claim 1, characterized by the fact that ASBTI is administered orally as a pH-sensitive ileal release formulation or an enterically coated formulation.
[0010]
10. Use according to claim 1, characterized in that it also comprises a bile acid scavenger or binder.
[0011]
11. Use, according to claim 1, characterized by the fact that the liver disease is progressive familial intrahepatic cholestasis (PFIC), primary biliary cirrhosis (PBC), primary sclerosing cholangitis (PSC), intrahepatic cholestasis of pregnancy or Alagille syndrome.

类似技术:

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法律状态:
2018-01-23| B07D| Technical examination (opinion) related to article 229 of industrial property law [chapter 7.4 patent gazette]|

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2018-03-20| B25D| Requested change of name of applicant approved|Owner name: LUMENA PHARMACEUTICALS LLC (US) |

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2018-03-27| B06F| Objections, documents and/or translations needed after an examination request according [chapter 6.6 patent gazette]|

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2018-12-18| B07E| Notification of approval relating to section 229 industrial property law [chapter 7.5 patent gazette]|Free format text: NOTIFICACAO DE ANUENCIA RELACIONADA COM O ART 229 DA LPI |

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2019-07-09| B06T| Formal requirements before examination [chapter 6.20 patent gazette]|

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2020-08-11| B09A| Decision: intention to grant [chapter 9.1 patent gazette]|

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2020-09-29| B16A| Patent or certificate of addition of invention granted [chapter 16.1 patent gazette]|Free format text: PRAZO DE VALIDADE: 20 (VINTE) ANOS CONTADOS A PARTIR DE 26/10/2012, OBSERVADAS AS CONDICOES LEGAIS. |

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2021-08-17| B25A| Requested transfer of rights approved|Owner name: SHIRE HUMAN GENETIC THERAPIES, INC. (US) |

优先权:

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申请号 | 申请日 | 专利标题

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US201161553094P| true| 2011-10-28|2011-10-28|

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US61/553.094|2011-10-28|

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US201261607487P| true| 2012-03-06|2012-03-06|

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US61/607.487|2012-03-06|

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PCT/US2012/062303|WO2013063526A1|2011-10-28|2012-10-26|Bile acid recycling inhibitors for treatment of hypercholemia and cholestatic liver disease|

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