RU2021125969A - Benzothiadiazepine Compounds and Their Use as Bile Acid Modulators - Google Patents

Claims (44)

1. Compound of formula (I)

where each of R ¹ and R ² independently represents C _1-4 alkyl; R ³ is independently selected from the group consisting of hydrogen, halogen, hydroxy, C _1-4 alkyl, C _1-4 haloalkyl, C _1-4 alkoxy, C _1-4 haloalkoxy, cyano, nitro, amino, N-(C _{1 -4} alkyl) amino, N,N-di(C _1-4 alkyl) amino and N-(aryl-C _1-4 alkyl) amino; n is an integer 1, 2 or 3; R ⁴ is selected from the group consisting of hydrogen, halogen, hydroxy, cyano, C _1-4 alkyl, C _3-6 cycloalkyl, C _1-4 alkoxy, C _3-6 cycloalkyloxy, C _1-4 alkylthio, C _3-6 cycloalkylthio, amino, N-(C _1-4 alkyl) amino and N,N-di(C _1-4 alkyl) amino; each of R ^5A , R ^5B , R ^5C and R ^5D is independently selected from the group consisting of hydrogen, halogen, hydroxy, amino and C _1-4 alkyl; And R ⁶ is selected from the group consisting of hydrogen and C _1-4 alkyl; or a pharmaceutically acceptable salt thereof. 2. A compound according to claim 1, wherein R ¹ is n-butyl. 3. A compound according to claim 1 or 2, wherein R ² is n-butyl. 4. A compound according to claim 1 or 2, wherein R ² is ethyl. 5. Connection according to any one of paragraphs. 1-4, where R ³ is independently selected from the group consisting of hydrogen, halogen, hydroxy, amino, cyano, C _1-4 haloalkyl, C _1-4 alkoxy, and C _1-4 haloalkoxy. 6. The connection according to any one of paragraphs. 1-5, where R ⁴ is selected from the group consisting of halogen, hydroxy, cyano, C _1-4 alkyl, C _1-4 alkoxy, C _1-4 alkylthio, amino, N-(C _1-4 alkyl) amino and N,N-di(C _1-4 alkyl) amino. 7. Connection according to any one of paragraphs. 1-6, where each of R ^5A and R ^5B is independently selected from the group consisting of hydrogen, halogen, hydroxy, amino and methyl. 8. Connection according to any one of paragraphs. 1-7, where R ⁶ represents hydrogen or methyl. 9. The compound according to claim 1, selected from the group consisting of: 3-((3,3-dibutyl-7-(methylthio)-1,1-dioxydo-5-phenyl-2,3,4,5-tetrahydrobenzo-1,2,5-thiadiazepin-8-yl)oxy) propanoic acid; 3-((3-butyl-3-ethyl-7-(methylthio)-1,1-dioxydo-5-phenyl-2,3,4,5-tetrahydro-1,2,5-benzothiadiazepin-8-yl) hydroxy) propanoic acid; (S)-3-((3-butyl-3-ethyl-7-(methylthio)-1,1-dioxydo-5-phenyl-2,3,4,5-tetrahydro-1,2,5-benzothiadiazepine- 8-yl)oxy) propanoic acid; (R)-3-((3-butyl-3-ethyl-7-(methylthio)-1,1-dioxido-5-phenyl-2,3,4,5-tetrahydro-1,2,5-benzothiadiazepine- 8-yl)oxy) propanoic acid; 3-((3,3-dibutyl-7-(methylthio)-1,1-dioxydo-5-phenyl-2,3,4,5-tetrahydro-1,2,5-benzothiadiazepin-8-yl)oxy) -2-hydroxypropanoic acid; (S)-3-((3,3-dibutyl-7-(methylthio)-1,1-dioxido-5-phenyl-2,3,4,5-tetrahydro-1,2,5-benzothiadiazepine-8- yl)oxy)-2-hydroxypropanoic acid; (R)-3-((3,3-dibutyl-7-(methylthio)-1,1-dioxydo-5-phenyl-2,3,4,5-tetrahydro-1,2,5-benzothiadiazepine-8- yl)oxy)-2-hydroxypropanoic acid; 3-((3,3-dibutyl-7-(methylthio)-1,1-dioxydo-5-phenyl-2,3,4,5-tetrahydro-1,2,5-benzothiadiazepin-8-yl)oxy) butanoic acid; (S)-3-((3,3-dibutyl-7-(methylthio)-1,1-dioxido-5-phenyl-2,3,4,5-tetrahydro-1,2,5-benzothiadiazepine-8- yl)hydroxy) butanoic acid; (R)-3-((3,3-dibutyl-7-(methylthio)-1,1-dioxydo-5-phenyl-2,3,4,5-tetrahydro-1,2,5-benzothiadiazepine-8- yl)hydroxy) butanoic acid; 3-((3,3-dibutyl-7-chloro-1,1-dioxido-5-phenyl-2,3,4,5-tetrahydro-1,2,5-benzothiadiazepin-8-yl)oxy) propanoic acid ; 3-((3,3-dibutyl-5-(4-hydroxyphenyl)-7-(methylthio)-1,1-dioxido-2,3,4,5-tetrahydro-1,2,5-benzothiadiazepine-8- yl) hydroxy) propanoic acid; 3-((3-Butyl-7-(dimethylamino)-3-ethyl-1,1-dioxydo-5-phenyl-2,3,4,5-tetrahydro-1,2,5-benzothiadiazepin-8-yl) hydroxy) propanoic acid; (S)-3-((3-butyl-7-(dimethylamino)-3-ethyl-1,1-dioxido-5-phenyl-2,3,4,5-tetrahydro-1,2,5-benzothiadiazepine- 8-yl)oxy) propanoic acid; (R)-3-((3-butyl-7-(dimethylamino)-3-ethyl-1,1-dioxido-5-phenyl-2,3,4,5-tetrahydro-1,2,5-benzothiadiazepine- 8-yl)oxy) propanoic acid; O-(3-butyl-3-ethyl-7-(methylthio)-1,1-dioxido-5-phenyl-2,3,4,5-tetrahydro-1,2,5-benzothiadiazepin-8-yl)serine ; (S)-O-((R)-3-butyl-3-ethyl-7-(methylthio)-1,1-dioxido-5-phenyl-2,3,4,5-tetrahydro-1,2,5 -benzothiadiazepin-8-yl)serine; (R)-O-((R)-3-butyl-3-ethyl-7-(methylthio)-1,1-dioxido-5-phenyl-2,3,4,5-tetrahydro-1,2,5 -benzothiadiazepin-8-yl)serine; (S)-O-((S)-3-butyl-3-ethyl-7-(methylthio)-1,1-dioxido-5-phenyl-2,3,4,5-tetrahydro-1,2,5 -benzothiadiazepin-8-yl)serine; And (R)-O-((S)-3-butyl-3-ethyl-7-(methylthio)-1,1-dioxido-5-phenyl-2,3,4,5-tetrahydro-1,2,5 -benzothiadiazepin-8-yl)serine; or a pharmaceutically acceptable salt thereof. 10. A pharmaceutical composition containing a therapeutically effective amount of a compound according to any one of paragraphs. 1-9 and one or more pharmaceutically acceptable excipients. 11. The connection according to any one of paragraphs. 1-9 for use as a medicine. 12. Connection according to any one of paragraphs. 1-9 for use in the treatment or prevention of cardiovascular disease or a disorder of fatty acid metabolism or a disorder of glucose utilization such as hypercholesterolemia; metabolic disorders of fatty acids; diabetes mellitus type 1 and 2; complications of diabetes, including cataracts, micro- and macrovascular diseases, retinopathy, neuropathy, nephropathy and delayed wound healing, tissue ischemia, diabetic foot, arteriosclerosis, myocardial infarction, acute coronary syndrome, unstable angina, stable angina, stroke, peripheral occlusive disease arteries, cardiomyopathy, heart failure, cardiac arrhythmias and vascular restenosis; diseases associated with diabetes such as insulin resistance (impaired glucose homeostasis), hyperglycemia, hyperinsulinemia, elevated levels of fatty acids or glycerol in the blood, obesity, dyslipidemia, hyperlipidemia, including hypertriglyceridemia, metabolic syndrome (syndrome X), atherosclerosis and hypertension; and to increase high-density lipoprotein levels. 13. Connection according to any one of paragraphs. 1-9 for use in the treatment or prevention of a gastrointestinal disease or disorder such as constipation (including chronic constipation, functional constipation, chronic idiopathic constipation (CIC), intermittent/sporadic constipation, constipation due to diabetes mellitus, constipation due to stroke, constipation due to chronic kidney disease, constipation due to multiple sclerosis, constipation due to Parkinson's disease, constipation due to systemic sclerosis, constipation due to drugs, irritable bowel syndrome with constipation (IBS-C), irritable bowel syndrome mixed (IBS-M) , children's functional constipation and constipation caused by opioids); Crohn's disease; primary malabsorption of bile acids; irritable bowel syndrome (IBS); inflammatory bowel disease (IBD); inflammation of the ileum; and reflux disease and its complications such as Barrett's esophagus, biliary reflux esophagitis and biliary reflux gastritis. 14. Connection according to any one of paragraphs. 1-9 for use in the treatment or prevention of a disease or disorder of the liver, such as: an inherited disorder of liver metabolism; congenital disorders of bile acid synthesis; congenital anomalies of the bile ducts; atresia of the biliary tract; post-kasai biliary atresia; post-transplant atresia of the biliary tract; neonatal hepatitis; neonatal cholestasis; hereditary forms of cholestasis; cerebrotechnical xanthomatosis; secondary defect in FA synthesis; Zellweger's syndrome; liver disease associated with cystic fibrosis; alpha1 antitrypsin deficiency; Alagille syndrome (ALGS); Byler's syndrome; primary defect in bile acid (BA) synthesis; progressive familial intrahepatic cholestasis (PFIC), including PFIC-1, PFIC-2, PFIC-3 and non-specific PFIC, post-biliary diversion PFIC and post-transplant PFIC; benign recurrent intrahepatic cholestasis (BRIC), including BRIC1, BRIC2 and non-specific BRIC, BRIC after biliary tract transplantation and BRIC after liver transplantation; 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 cholestasis; intrahepatic cholestasis of pregnancy (jaundice during pregnancy); intrahepatic cholestasis; extrahepatic cholestasis; cholestasis associated with parenteral nutrition (PNAC); cholestasis associated with low phospholipids; lymphedema cholestasis syndrome 1 (LSC1); primary sclerosing cholangitis (PSC); cholangitis associated with immunoglobulin G4; primary biliary cholangitis; cholelithiasis (gallstones); bile lithiasis; choledocholithiasis; gallstone pancreatitis; Caroli disease; malignancy of the bile ducts; a malignant tumor that causes obstruction of the biliary tree; biliary strictures; cholangiopathy in AIDS; ischemic cholangiopathy; skin itching due to cholestasis or jaundice; pancreatitis; chronic autoimmune liver disease leading to progressive cholestasis; liver steatosis; alcoholic hepatitis; acute fatty hepatosis; fatty liver during pregnancy; medicinal hepatitis; iron overload disorders; congenital defect in the synthesis of bile acids type 1 (BAS type 1); drug-induced liver injury (DILI); liver fibrosis; congenital fibrosis of the liver; cirrhosis of the liver; Langerhans cell histiocytosis (LCH); neonatal ichthyosis, sclerosing cholangitis (NISCH); erythropoietic protoporphyria (EPP); idiopathic ductopenia in adulthood (IAD); idiopathic neonatal hepatitis (INH); non-syndromic interlobular bile duct insufficiency (NS PILBD); cirrhosis in North American Indian children (NAIC); sarcoidosis of the liver; amyloidosis; necrotizing enterocolitis; serum bile acid toxicity, including cardiac arrhythmias (eg, atrial fibrillation) with an abnormal serum bile acid profile, cardiomyopathy associated with liver cirrhosis ("cholecardia"), and skeletal muscle wasting associated with cholestatic liver disease; viral hepatitis (including hepatitis A, hepatitis B, hepatitis C, hepatitis D and hepatitis E); hepatocellular carcinoma (hepatoma); cholangiocarcinoma; gastrointestinal cancer associated with bile acids; and cholestasis caused by tumors and neoplasms of the liver, biliary tract and pancreas; or for use in enhancing corticosteroid therapy for liver disease. 15. Connection according to any one of paragraphs. 1-9 for use in the treatment or prevention of hyperabsorption syndromes (including abetalipoproteinemia, familial hypobetalipoproteinemia (FHBL), chylomicron retention disease (CRD), and sitosterolemia); hypervitaminosis and osteopetrosis; hypertension; glomerular hyperfiltration; and pruritus in renal failure; or for use in protecting against kidney damage associated with liver disease or metabolic disease.