Benzothia(di)azepine compounds and their use as bile acid modulators

Abstract

The present invention relates to certain 1,5-benzothiazepine and 1,2,5-benzothiadiazepine derivatives as defined herein.These compounds are bile acid modulators with apical sodium-dependent bile acid transporter (ASBT) and / or hepatic bile acid transport (LBAT) inhibitory activity.The present invention also relates to pharmaceutical compositions comprising these compounds, and the use of these compounds in the treatment of cardiovascular disease, disorders of fatty acid metabolism and glucose utilization, gastrointestinal disease, and liver disease.

Claims

1. (S)-(Z)-3-((3-butyl-5-(4-fluorophenyl)-7-(methylthio)-1,1-dioxide-2,3,4,5-tetrahydro-1,5-benzothiazepine-8-yl)oxy)-2-fluoroacrylic acid; (R)-(Z)-3-((3-butyl-5-(4-fluorophenyl)-7-(methylthio)-1,1-dioxide-2,3,4,5-tetrahydro-1,5-benzothiazepine-8-yl)oxy)-2-fluoroacrylic acid; (S)-(Z)-3-((3-butyl-7-(ethylthio)-1,1-dioxide-5-phenyl-2,3,4,5-tetrahydro-1,5-benzothiazepine-8-yl)oxy)-2-fluoroacrylic acid; (R)-(Z)-3-((3-butyl-7-(ethylthio)-1,1-dioxide-5-phenyl-2,3,4,5-tetrahydro-1,5-benzothiazepine-8-yl)oxy)-2-fluoroacrylic acid; (S)-(Z)-3-((3-butyl-7-(ethylthio)-5-(4-fluorophenyl)-1,1-dioxide-2,3,4,5-tetrahydro-1,5-benzothiazepine-8-yl)oxy)-2-fluoroacrylic acid; (R)-(Z)-3-((3-butyl-7-(ethylthio)-5-(4-fluorophenyl)-1,1-dioxide-2,3,4,5-tetrahydro-1,5-benzothiazepine-8-yl)oxy)-2-fluoroacrylic acid; (S)-(Z)-3-((3-butyl-5-(4-fluorophenyl)-2-methyl-7-(methylthio)-1,1-dioxide-2,3,4,5-tetrahydro-1,2,5-benzothiadiazepine-8-yl)oxy)-2-fluoroacrylic acid; (R)-(Z)-3-((3-butyl-5-(4-fluorophenyl)-2-methyl-7-(methylthio)-1,1-dioxide-2,3,4,5-tetrahydro-1,2,5-benzothiadiazepine-8-yl)oxy)-2-fluoroacrylic acid; (S)-(Z)-3-((3-butyl-7-(ethylthio)-5-(4-fluorophenyl)-2-methyl-1,1-dioxide-2,3,4,5-tetrahydro-1,2,5-benzothiadiazepine-8-yl)oxy)-2-fluoroacrylic acid; (R)-(Z)-3-((3-butyl-7-(ethylthio)-5-(4-fluorophenyl)-2-methyl-1,1-dioxide-2,3,4,5-tetrahydro-1,2,5-benzothiadiazepine-8-yl)oxy)-2-fluoroacrylic acid; (S)-(Z)-3-((3-butyl-7-(ethylthio)-2-methyl-1,1-dioxide-5-phenyl-2,3,4,5-tetrahydro-1,2,5-benzothiadiazepine-8-yl)oxy)-2-fluoroacrylic acid; (R)-(Z)-3-((3-butyl-7-(ethylthio)-2-methyl-1,1-dioxide-5-phenyl-2,3,4,5-tetrahydro-1,2,5-benzothiadiazepine-8-yl)oxy)-2-fluoroacrylic acid; (S)-(Z)-3-((3-butyl-5-(4-fluorophenyl)-7-(methylthio)-1,1-dioxide-2,3,4,5-tetrahydro-1,2,5-benzothiadiazepine-8-yl)oxy)-2-fluoroacrylic acid; (R)-(Z)-3-((3-butyl-5-(4-fluorophenyl)-7-(methylthio)-1,1-dioxide-2,3,4,5-tetrahydro-1,2,5-benzothiadiazepine-8-yl)oxy)-2-fluoroacrylic acid; (S)-(E)-3-((3-butyl-7-(ethylthio)-5-(4-fluorophenyl)-1,1-dioxide-2,3,4,5-tetrahydro-1,2,5-benzothiadiazepine-8-yl)oxy)acrylic acid; (R)-(E)-3-((3-butyl-7-(ethylthio)-5-(4-fluorophenyl)-1,1-dioxide-2,3,4,5-tetrahydro-1,2,5-benzothiadiazepine-8-yl)oxy)acrylic acid; or their pharmaceutically acceptable salts, A compound selected from the group consisting of the following.

2. A pharmaceutical composition comprising a therapeutically effective amount of the compound described in claim 1 and one or more pharmaceutically acceptable excipients.

3. A pharmaceutical product comprising the compound described in claim 1.

4. The pharmaceutically acceptable agent according to claim 3, for use in the treatment or prevention of cardiovascular diseases or disorders of fatty acid metabolism or glucose utilization, such as hypercholesterolemia; impaired fatty acid metabolism; type 1 and type 2 diabetes; complications of diabetes, including cataracts, microvascular and macrovascular diseases, retinopathy, neuropathy, nephropathy and delayed wound healing, tissue ischemia, diabetic foot lesions, arteriosclerosis, myocardial infarction, acute coronary syndrome, unstable angina, stable angina, stroke, peripheral artery occlusive disease, cardiomyopathy, heart failure, heart rhythm disorders and restenosis; and diabetes-related diseases such as insulin resistance (impaired glucose homeostasis), hyperglycemia, hyperinsulinemia, high levels of blood fatty acids or glycerol, obesity, dyslipidemia, hyperlipidemia including antitriglyceridemia, metabolic syndrome (syndrome X), atherosclerosis and hypertension, or for increasing high-density lipoprotein levels.

5. The pharmaceutically acceptable agent according to claim 3, for use in the treatment or prevention of gastrointestinal diseases or disorders, including constipation (including chronic constipation, functional constipation, chronic idiopathic constipation (CIC), intermittent / sporadic constipation, constipation secondary to diabetes, constipation secondary to stroke, constipation secondary to chronic kidney disease, constipation secondary to multiple sclerosis, constipation secondary to Parkinson's disease, constipation secondary to systemic sclerosis, drug-induced constipation, constipation-predominant irritable bowel syndrome (IBS-C), mixed irritable bowel syndrome (IBS-M), pediatric functional constipation and opioid-induced constipation); Crohn's disease; primary bile acid malabsorption; irritable bowel syndrome (IBS); inflammatory bowel disease (IBD); ileitis; and reflux diseases and their complications, such as Barrett's esophagus, bile reflux esophagitis and bile reflux gastritis.

6. Hereditary metabolic disorders of the liver; congenital disorders of bile acid synthesis; congenital biliary tract anomalies; biliary atresia; post-Kasai procedure biliary atresia; post-liver transplant biliary atresia; neonatal hepatitis; neonatal cholestasis; genetic forms of cholestasis; cerebral tendon xanthomatous disease; secondary deficiency of BA synthesis; Zellweger syndrome; cystic fibrosis-associated liver disease; alpha-1 antitrypsin deficiency; Alagille syndrome (ALGS); Weiler syndrome; biliary tract Primary deficiency of juic acid (BA) synthesis; PFIC including progressive familial intrahepatic cholestasis (PFIC)-1, PFIC-2, PFIC-3, and unspecified PFIC, post-biliary diversion PFIC, and post-liver transplant PFIC; BRIC including benign recurrent intrahepatic cholestasis (BRIC)-1, BRIC-2, and unspecified BRIC, post-biliary diversion BRIC, and post-liver transplant BRIC; autoimmune liver Inflammation; Primary biliary cirrhosis (PBC); Hepatic fibrosis; Non-alcoholic fatty liver disease (NAFLD); Non-alcoholic steatohepatitis (NASH); Portal hypertension; Cholestasis; Down syndrome cholestasis; Drug-induced cholestasis; Intrahepatic cholestasis due to pregnancy (jaundice during pregnancy); Intrahepatic cholestasis; Extrahepatic cholestasis; Parenteral nutrition-related cholestasis (PNAC); Low phospholipid-related cholestasis Stasis; Lymphedema-associated cholestatic syndrome 1 (LSC1); Primary sclerosing cholangitis (PSC); Immunoglobulin G4-associated cholangitis; Primary biliary cholangitis; Gallstones; Biliary tract stones; Common bile duct stones; Gallstone pancreatitis; Caroline's disease; Malignant disease of the bile duct; Malignant disease causing obstruction of the biliary system; Biliary stricture; AIDS biliary disorder; Ischemic biliary disorder; Pruritus due to cholestasis or jaundice; Pancreatitis; Chronic autoimmune liver disease leading to progressive cholestasis; fatty liver; Alcoholic hepatitis; acute fatty liver; fatty liver due to pregnancy; drug-induced hepatitis; iron overload injury; congenital bile acid synthesis deficiency type 1 (BAS1); drug-induced liver injury (DILI); hepatic fibrosis; congenital hepatic fibrosis; cirrhosis; Langerhans cell histiocytosis (LCH); neonatal ichthyosis cholangitis (NISCH); pure red protoporphyria (EPP); idiopathic adult bile duct deficiency (IAD); idiopathic neonatal hepatitis (INH); asymptomatic intrahepatic bile duct deficiency (NS-PILBD); cirrhosis in North American Indian children (NAIC); hepatic sarcoidosis; amyloidosis; necrotizing enterocolitis; irregular heartbeat in the context of abnormal serum bile acid profiles The pharmaceutically acceptable agent according to claim 3, for use in the treatment or prevention of liver diseases or disorders, including, for example, atrial fibrillation, cardiomyopathy associated with cirrhosis ("gallstone disease"), and skeletal muscle fatigue associated with cholestatic liver disease; polycystic liver disease; viral hepatitis (including hepatitis A, B, C, D, and E); hepatocellular carcinoma; cholangiocarcinoma; bile acid-associated gastrointestinal cancer; and cholestasis caused by tumors and neoplasms of the liver, bile ducts, and pancreas, or for use in improving corticosteroid therapy in liver diseases.

7. The pharmacopoeci of claim 3, for use in the treatment or prevention of hyperabsorption syndromes (including abetalipoproteinemia, familial hypobetalipoproteinemia (FHBL), chylomicron retention disease (CRD), and sitosterolemia); hypervitaminemia or osteopetrosis; hypertension; glomerular hyperfiltration; polycystic kidney disease (PKD), including autosomal dominant polycystic kidney disease (ADPKD) and autosomal recessive polycystic kidney disease (ARPKD); or pruritus in renal failure; or for use in protection against renal impairment related to liver disease or metabolic disease.

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