JPWO2021110887A5

JPWO2021110887A5 -

Info

Publication number: JPWO2021110887A5
Application number: JP2022532833A
Authority: JP
Publication date: 2023-12-05

Claims

Compound of formula (I)
(In the formula,
R ¹ and R ² are each independently C _1-4 alkyl;
R ³ is independently 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 selected from the group consisting of N,N-di(C _1-4 alkyl)amino, and N-(aryl-C _1-4 alkyl)amino;
n is an integer of 1, 2, or 3;
R ⁴ is 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 cyclo (selected from the group consisting of alkylthio, amino, N-(C _1-4 alkyl)amino, and N,N-di(C _1-4 alkyl)amino)
or a pharmaceutically acceptable salt thereof,
However, if the compound is
2-((3,3-dipropyl-7-(methylthio)-5-phenyl-1,1-dioxide-2,3,4,5-tetrahydro-1,5-benzothiazepin-8-yl)oxy) acetic acid;
2-((3,3-dibutyl-7-(methylthio)-5-phenyl-1,1-dioxide-2,3,4,5-tetrahydro-1,5-benzothiazepin-8-yl)oxy) acetic acid;
2-((3,3-dibutyl-5-(4-chlorophenyl)-7-(methylthio)-1,1-dioxide-2,3,4,5-tetrahydro-1,5-benzothiazepine-8- yl)oxy)acetic acid;
2-((3-butyl-3-ethyl-7-(methylthio)-5-phenyl-1,1-dioxide-2,3,4,5-tetrahydro-1,5-benzothiazepin-8-yl) oxy)acetic acid;
2-((3-butyl-3-ethyl-5-phenyl-1,1-dioxide-2,3,4,5-tetrahydro-1,5-benzothiazepin-8-yl)oxy)acetic acid;
2-((3-butyl-3-ethyl-7-methoxy-5-phenyl-1,1-dioxide-2,3,4,5-tetrahydro-1,5-benzothiazepin-8-yl)oxy) acetic acid;
2-((3-butyl-3-ethyl-7-isopropoxy-5-phenyl-1,1-dioxide-2,3,4,5-tetrahydro-1,5-benzothiazepin-8-yl)oxy ) acetic acid;
2-((3,3-dibutyl-7-methoxy-5-phenyl-1,1-dioxide-2,3,4,5-tetrahydro-1,5-benzothiazepin-8-yl)oxy)acetic acid;
2-((7-bromo-3,3-dibutyl-5-phenyl-1,1-dioxide-2,3,4,5-tetrahydro-1,5-benzothiazepin-8-yl)oxy)acetic acid; as well as
2-((7-bromo-3-butyl-3-ethyl-5-phenyl-1,1-dioxide-2,3,4,5-tetrahydro-1,5-benzothiazepin-8-yl)oxy) A compound of formula (I) or a pharmaceutically acceptable salt thereof, provided that it is not a compound from the group consisting of acetic acid.

2. A compound according to claim 1, wherein R ¹ is n-butyl.

3. A compound according to claim 1 or 2, wherein ^R2 is n-butyl.

3. A compound according to claim 1 or 2, wherein ^R2 is ethyl.

Any one of claims 1 to 4, wherein R ³ is independently selected from the group consisting of hydrogen, halogen, hydroxy, cyano, C _1-4 haloalkyl, C _1-4 alkoxy, and C _1-4 haloalkoxy. Compounds described in Section.

6. A compound according to any one of claims 1 to 5, wherein ^R3 is independently selected from the group consisting of hydrogen, fluoro, chloro, bromo, hydroxy, cyano, trifluoromethyl, methoxy, and trifluoromethoxy. .

R ⁴ is 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 7. A compound according to any one of claims 1 to 6, selected from the group consisting of -4} alkyl)amino.

Any one of claims 1 to 7, wherein R ⁴ is selected from the group consisting of fluoro, chloro, bromo, hydroxy, cyano, methyl, methoxy, ethoxy, methylthio, ethylthio, amino, methylamino, and dimethylamino. Compounds described in.

2-((3,3-dibutyl-7-(dimethylamino)-1,1-dioxide-5-phenyl-2,3,4,5-tetrahydro-1,5-benzothiazepin-8-yl)oxy ) acetic acid;
2-((3,3-dibutyl-5-(4-methoxyphenyl)-7-(methylthio)-1,1-dioxide-2,3,4,5-tetrahydro-1,5-benzothiazepine-8 -yl)oxy)acetic acid;
2-((5-(4-bromophenyl)-3,3-dibutyl-7-(methylthio)-1,1-dioxide-2,3,4,5-tetrahydro-1,5-benzothiazepine-8 -yl)oxy)acetic acid;
2-((3,3-dibutyl-5-(4-hydroxyphenyl)-7-(methylthio)-1,1-dioxide-2,3,4,5-tetrahydro-1,5-benzothiazepine-8 -yl)oxy)acetic acid;
2-((3,3-dibutyl-5-(4-cyanophenyl)-7-(methylthio)-1,1-dioxide-2,3,4,5-tetrahydro-1,5-benzothiazepine-8 -yl)oxy)acetic acid;
2-((3,3-dibutyl-7-(methylthio)-1,1-dioxide-5-(4-(trifluoromethyl)phenyl)-2,3,4,5-tetrahydro-1,5-benzo Thiazepin-8-yl)oxy)acetic acid;
2-((3-butyl-7-(dimethylamino)-3-ethyl-1,1-dioxide-5-phenyl-2,3,4,5-tetrahydro-1,5-benzothiazepin-8-yl )oxy)acetic acid;
(S)-2-((3-butyl-7-(dimethylamino)-3-ethyl-1,1-dioxide-5-phenyl-2,3,4,5-tetrahydro-1,5-benzothiazepine -8-yl)oxy)acetic acid;
(R)-2-((3-Butyl-7-(dimethylamino)-3-ethyl-1,1-dioxide-5-phenyl-2,3,4,5-tetrahydro-1,5-benzothiazepine -8-yl)oxy)acetic acid;
2-((3,3-dibutyl-7-fluoro-1,1-dioxide-5-phenyl-2,3,4,5-tetrahydro-1,5-benzothiazepin-8-yl)oxy)acetic acid;
2-((3,3-dibutyl-7-cyano-1,1-dioxide-5-phenyl-2,3,4,5-tetrahydro-1,5-benzothiazepin-8-yl)oxy)acetic acid;
2-((3-butyl-3-ethyl-7-fluoro-1,1-dioxide-5-phenyl-2,3,4,5-tetrahydro-1,5-benzothiazepin-8-yl)oxy) acetic acid;
2-((3,3-dibutyl-7-chloro-1,1-dioxide-5-phenyl-2,3,4,5-tetrahydro-1,5-benzothiazepin-8-yl)oxy)acetic acid;
2-((3-butyl-3-ethyl-5-(4-fluorophenyl)-7-(methylthio)-1,1-dioxide-2,3,4,5-tetrahydro-1,5-benzothiazepine -8-yl)oxy)acetic acid;
(S)-2-((3-butyl-3-ethyl-5-(4-fluorophenyl)-7-(methylthio)-1,1-dioxide-2,3,4,5-tetrahydro-1,5 -benzothiazepin-8-yl)oxy)acetic acid;
(R)-2-((3-Butyl-3-ethyl-5-(4-fluorophenyl)-7-(methylthio)-1,1-dioxide-2,3,4,5-tetrahydro-1,5 -benzothiazepin-8-yl)oxy)acetic acid;
2-((3-butyl-3-ethyl-5-(4-methoxyphenyl)-7-(methylthio)-1,1-dioxide-2,3,4,5-tetrahydro-1,5-benzothiazepine -8-yl)oxy)acetic acid;
2-((3-butyl-3-ethyl-5-(4-hydroxyphenyl)-7-(methylthio)-1,1-dioxide-2,3,4,5-tetrahydro-1,5-benzothiazepine -8-yl)oxy)acetic acid;
(S)-2-((3-butyl-3-ethyl-5-(4-hydroxyphenyl)-7-(methylthio)-1,1-dioxide-2,3,4,5-tetrahydro-1,5 -benzothiazepin-8-yl)oxy)acetic acid; and
(R)-2-((3-butyl-3-ethyl-5-(4-hydroxyphenyl)-7-(methylthio)-1,1-dioxide-2,3,4,5-tetrahydro-1,5 -benzothiazepin-8-yl)oxy)acetic acid;
2. A compound according to claim 1, or a pharmaceutically acceptable salt thereof, selected from the group consisting of.

10. A pharmaceutical composition comprising a therapeutically effective amount of a compound according to any one of claims 1 to 9 and one or more pharmaceutically acceptable excipients.

Compound of formula (I)
(In the formula,
R ¹ and R ² are each independently C _1-4 alkyl;
R ³ is independently 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 selected from the group consisting of N,N-di(C _1-4 alkyl)amino, and N-(aryl-C _1-4 alkyl)amino;
n is an integer of 1, 2, or 3;
R ⁴ is 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 cyclo or a pharmaceutically _acceptable salt _thereof .

Cardiovascular diseases or disorders of fatty acid metabolism or glucose utilization, e.g. hypercholesterolemia; disorders of fatty acid metabolism; type 1 and type 2 diabetes mellitus; complications of diabetes, e.g. cataracts, small and macrovascular disease, 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. diseases, cardiomyopathy, heart failure, heart rate disorders, and vascular restenosis; diabetes-related diseases, such as insulin resistance (disturbance of glucose homeostasis), hyperglycemia, hyperinsulinemia, increased blood levels of fatty acids or glycerol; For use in the treatment or prevention of obesity, dyslipidemia, hyperlipidemia, such as hypertriglyceridemia, metabolic syndrome (Syndrome X), atherosclerosis, and hypertension; and increased levels of high-density lipoproteins. 12. The medicament according to claim 11.

Gastrointestinal diseases or disorders, such as constipation (chronic constipation, functional constipation, chronic idiopathic constipation (CIC), intermittent/sporadic constipation, constipation secondary to diabetes mellitus, constipation secondary to stroke, secondary to chronic kidney disease) Constipation, constipation secondary to multiple sclerosis, constipation secondary to Parkinson's disease, constipation secondary to systemic sclerosis, drug-induced constipation, constipation-type irritable bowel syndrome (IBS-C), mixed type irritable bowel syndrome ( Crohn's disease; primary bile acid malabsorption; irritable bowel syndrome (IBS); inflammatory bowel disease (IBD); ileal inflammation; and 12. The medicament according to claim 11 , for use in the treatment or prevention of reflux disease and its complications, such as Barrett's esophagus, bile reflux esophagitis, and bile reflux gastritis.

Liver diseases or disorders, such as inherited metabolic disorders of the liver; congenital abnormalities of bile acid synthesis; congenital bile duct abnormalities; biliary atresia; biliary atresia after Kasai surgery; biliary atresia after liver transplantation; neonatal hepatitis; neonatal bile Stasis; inherited forms of cholestasis; cerebrotendinous xanthomatosis; secondary defects in BA synthesis; Zellweger syndrome; liver disease associated with cystic fibrosis; α1-antitrypsin deficiency; Alagille syndrome (ALGS); Beiler Syndrome; primary defect in bile acid (BA) synthesis; progressive familial intrahepatic cholestasis (PFIC), e.g. PFIC-1, PFIC-2, PFIC-3, and unspecified PFIC, PFIC after biliary diversion , and PFIC after liver transplantation; benign recurrent intrahepatic cholestasis (BRIC), such as BRIC1, BRIC2, and unspecified BRIC, BRIC after bile diversion, and BRIC after liver transplantation; autoimmune hepatitis; primary biliary cirrhosis (PBC); liver fibrosis; nonalcoholic fatty liver disease (NAFLD); nonalcoholic steatohepatitis (NASH); portal hypertension; cholestasis; cholestasis of Down syndrome; Drug-induced cholestasis; Intrahepatic cholestasis of pregnancy (jaundice in pregnancy); Intrahepatic cholestasis; Extrahepatic cholestasis; Parenteral nutrition-associated cholestasis (PNAC); Associated with hypophospholipids cholestasis; lymphedema cholestasis syndrome 1 (LSC1); primary sclerosing cholangitis (PSC); cholangitis associated with immunoglobulin G4; primary biliary cholangitis; cholelithiasis (gallstones); biliary stones biliary lithiasis; choledocholithiasis; gallstone pancreatitis; Calori disease; malignant tumor of the bile duct; malignant tumor causing obstruction of the bile tree; bile duct stricture; AIDS cholangiopathy; ischemic cholangiopathy; due to cholestasis or jaundice Pruritus; 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; congenital bile acid metabolism Abnormal disease type 1 (BAS type 1); drug-induced liver injury (DILI); liver fibrosis; congenital liver fibrosis; cirrhosis; Langerhans cell histiocytosis (LCH); neonatal ichthyosis sclerosing cholangitis (NISCH); bone marrow sexual protoporphyria (EPP); idiopathic adult bile duct deficiency (IAD); idiopathic neonatal hepatitis (INH); nonsyndromic intrahepatic bile duct deficiency (NS PILBD); autosomal recessive intrahepatic cholestasis (North American Indian childhood cirrhosis (NAIC); hepatic sarcoidosis; amyloidosis; necrotizing enterocolitis; serum bile acid-induced toxicity, e.g., cardiac rhythm disorders (e.g., atrial fibrillation) in the setting of abnormal serum bile acid profiles; Cardiomyopathy associated with cirrhosis (“cholecardia”) and skeletal muscle wasting associated with cholestatic liver disease; polycystic liver disease; viral hepatitis (hepatitis A, B, C hepatocellular carcinoma (hepatoma); bile duct cancer; gastrointestinal cancers related to bile acids; and tumors and neoplasms of the liver, biliary tract, and pancreas. 12. A medicament according to claim 11, for use in the treatment or prevention of cholestasis; or for use in augmenting corticosteroid therapy in liver disease.

Hyperabsorption syndromes (including abetalipoproteinemia, familial hypobetalipoproteinemia (FHBL), chylomicron retention disease (CRD), and sitosterolemia); hypervitaminosis and osteopetrosis; hypertension; Glomerular hyperfiltration; used in the treatment or prevention of polycystic kidney disease (PKD), such as autosomal dominant polycystic kidney disease (ADPKD) and autosomal recessive polycystic kidney disease (ARPKD); and pruritus in renal failure. or for use in protection against kidney damage associated with liver or metabolic diseases .