US 12,134,606 B2
Benzothia(di)azepine compounds and their use as bile acid modulators
Per-Göran Gillberg, Åsbro (SE); Ingemar Starke, Gothenburg (SE); and Santosh S. Kulkarni, Bangalore (IN)
Assigned to Albireo AB, Gothenburg (SE)
Filed by Albireo AB, Gothenburg (SE)
Filed on Jan. 12, 2023, as Appl. No. 18/153,947.
Application 18/153,947 is a division of application No. 17/672,086, filed on Feb. 15, 2022, granted, now 11,572,350.
Application 17/672,086 is a continuation of application No. PCT/EP2021/084081, filed on Dec. 3, 2021.
Claims priority of application No. PCT/EP2020/084567 (WO), filed on Dec. 4, 2020.
Prior Publication US 2023/0250073 A1, Aug. 10, 2023
This patent is subject to a terminal disclaimer.
Int. Cl. C07D 285/36 (2006.01); A61P 1/16 (2006.01); C07D 281/10 (2006.01)
CPC C07D 285/36 (2013.01) [A61P 1/16 (2018.01); C07D 281/10 (2013.01)] 19 Claims
 
1. A method for treating a disease or disorder in a subject, the method comprising administering to the subject a therapeutically effective amount of a compound of formula (I)

OG Complex Work Unit Chemistry
wherein M and R1 to R4 are as indicated in Table 1 below, or a pharmaceutically acceptable salt thereof:
TABLE 1
 
M R1 R2 R3 R4
 
CH2 CH2CH2CH2CH3 F SCH3 F
NH CH2CH2CH2CH3 F SCH3 H
NH CH2CH2CH2CH3 F SCH3 F
NCH3 CH2CH2CH2CH3 F SCH3 F
CH2 CH2CH2CH2CH3 H SCH2CH3 H
CH2 CH2CH2CH2CH3 H SCH2CH3 F
CH2 CH2CH2CH2CH3 F SCH2CH3 H
CH2 CH2CH2CH2CH3 F SCH2CH3 F
NH CH2CH2CH2CH3 F SCH2CH3 H
NCH3 CH2CH2CH2CH3 H SCH2CH3 F
NCH3 CH2CH2CH2CH3 F SCH2CH3 F
 
wherein the disease or disorder is selected from the group consisting of: a liver disease or disorder; a cardiovascular disease; a disorder of fatty acid metabolism; a glucose utilization disorder; a gastrointestinal disease or disorder; a hyperabsorption syndrome; hypertension; glomerular hyperfiltration; polycystic kidney disease (PKD); and pruritus of renal failure;
wherein the cardiovascular disease, disorder of fatty acid metabolism, or glucose utilization disorder is selected from the group consisting of: hypercholesterolemia, type 1 or type 2 diabetes mellitus, insulin resistance, hyperglycemia, hyperinsulinemia, elevated blood levels of fatty acids or glycerol, obesity, dyslipidemia, and hyperlipidemia;
wherein the gastrointestinal disease or disorder is selected from the group consisting of: constipation, Crohn's disease, and primary bile acid malabsorption;
wherein the hyperabsorption syndrome is selected from the group consisting of: abetalipoproteinemia, familial hypobetalipoproteinemia (FHBL), chylomicron retention disease (CRD), and sitosterolemia; and
wherein the liver disease or disorder is selected from the group consisting of: an inborn error of bile acid synthesis, a congenital bile duct anomaly, biliary atresia, post-Kasai biliary atresia, post-liver transplantation biliary atresia, neonatal hepatitis, neonatal cholestasis, hereditary forms of cholestasis, cerebrotendinous xanthomatosis, a secondary defect of BA synthesis, Zellweger's syndrome, cystic fibrosis-associated liver disease, alpha1-antitrypsin deficiency, Alagille syndrome (ALGS), Byler syndrome, a primary defect of bile acid (BA) synthesis, progressive familial intrahepatic cholestasis (PFIC), benign recurrent intrahepatic cholestasis (BRIC), autoimmune hepatitis, primary biliary cirrhosis (PBC), liver fibrosis, non-alcoholic fatty liver disease (NAFLD), non-alcoholic steatohepatitis (NASH), portal hypertension, cholestasis, Down syndrome cholestasis, drug-induced cholestasis, intrahepatic cholestasis of pregnancy, jaundice during pregnancy, intrahepatic cholestasis, extrahepatic cholestasis, parenteral nutrition associated cholestasis (PNAC), low phospholipid-associated cholestasis, lymphedema cholestasis syndrome 1 (LCS1), primary sclerosing cholangitis (PSC), immunoglobulin G4 associated cholangitis, primary biliary cholangitis, cholelithiasis, gallstones, biliary lithiasis, choledocholithiasis, gallstone pancreatitis, Caroli disease, malignancy of bile ducts, malignancy causing obstruction of the biliary tree, biliary strictures, AIDS cholangiopathy, ischemic cholangiopathy, pruritus due to cholestasis or jaundice, pancreatitis, chronic autoimmune liver disease leading to progressive cholestasis, hepatic steatosis, alcoholic hepatitis, acute fatty liver, fatty liver of pregnancy, drug-induced hepatitis, iron overload disorders, congenital bile acid synthesis defect type 1 (BAS defect type 1), drug-induced liver injury DILI), hepatic fibrosis, congenital hepatic fibrosis, hepatic cirrhosis, Langerhans cell histiocytosis (LCH), neonatal ichthyosis sclerosing cholangitis (NISCH), erythropoietic protoporphyria (EPP), idiopathic adulthood ductopenia (IAD), idiopathic neonatal hepatitis (INH), non syndromic paucity of interlobular bile ducts (NS PILBD), North American Indian childhood cirrhosis (NAIC), hepatic sarcoidosis, necrotizing enterocolitis, serum bile acid-caused toxicities, polycystic liver disease, viral hepatitis, hepatocellular carcinoma, cholangiocarcinoma, a bile acid-related gastrointestinal cancer, and cholestasis caused by tumors and neoplasms of the liver, of the biliary tract and of the pancreas.