Combinations comprising benzodioxol as GLP-1R agonists for use in the treatment of NASH/NAFLD and related diseases

Inventors

Aspnes, Gary E. • Bagley, Scott W. • Curto, John M. • Dowling, Matthew • Edmonds, David James • Fernando, Dilinie • Flanagan, Mark E. • Futatsugi, Kentaro • Griffith, David Andrew • HUARD, KIM • Ingle, Gajendra • Jiao, Wenhua • LACASSE, SHAWN M. • Lian, Yajing • Limberakis, Chris • Londregan, Allyn T. • Mathiowetz, Alan M. • Piotrowski, David Walter • Ruggeri, Roger B. • WIGLESWORTH, KRISTIN

Assignees

Pfizer Inc

Abstract

In part, the invention provides a new combination comprising (1) a GLP-1R agonist and (2) an ACC inhibitor or a DGAT2 inhibitor, or a KHK inhibitor or FXR agonist. The invention further provides new methods for treating diseases and disorders, for example, fatty liver, nonalcoholic fatty liver disease, nonalcoholic steatohepatitis, nonalcoholic steatohepatitis with liver fibrosis, nonalcoholic steatohepatitis with cirrhosis, and nonalcoholic steatohepatitis with cirrhosis and with hepatocellular carcinoma or with a metabolic-related disease, obesity, and type 2 diabetes, for example, using the new combination described herein.

Core Innovation

The invention relates to a method for treating a disease or condition in a patient in need thereof by administering a therapeutically effective amount of a combination comprising a GLP-1R agonist and 4-(4-(1-isopropyl-7-oxo-1,4,6,7-tetrahydrospiro[indazole-5,4′-piperidine]-1′-carbonyl)-6-methoxypyridin-2-yl)benzoic acid or a pharmaceutically acceptable salt thereof. The disease or condition is selected from fatty liver, nonalcoholic fatty liver disease, nonalcoholic steatohepatitis, nonalcoholic steatohepatitis with liver fibrosis, nonalcoholic steatohepatitis with cirrhosis, and nonalcoholic steatohepatitis with cirrhosis and with hepatocellular carcinoma or with a metabolic-related disease, obesity, and type 2 diabetes.

The GLP-1R agonist is selected from a set of named benzimidazole-6-carboxylic acid derivatives, including DIAST-X2, or a pharmaceutically acceptable salt thereof. The disclosure also describes specific chiral GLP-1R agonist scaffold intermediates and final compounds, including enantiomeric intermediates, stereochemical separation, and conversion to carboxylic acid or salt forms.

The disclosure further describes salt forms and crystalline solid forms associated with the compounds, including the 2-amino-2-(hydroxymethyl)propane-1,3-diol salt form of the specified benzoic acid component and the tris salt of DIAST-X2. It also references formate, trifluoroacetate, ammonium, citric acid, hemicitrate, hemisulfate, and other salt forms, together with crystal form and characterization context.

Claims Coverage

The provided claim coverage centers on one independent treatment claim. It requires administering a therapeutically effective amount of a combination comprising a GLP-1R agonist and the specified 4-(4-(1-isopropyl-7-oxo-1,4,6,7-tetrahydrospiro[indazole-5,4′-piperidine]-1′-carbonyl)-6-methoxypyridin-2-yl)benzoic acid or a pharmaceutically acceptable salt thereof for selected liver and metabolic diseases, with dependent claims narrowing the GLP-1R agonist and salt/crystal forms and adding at least one other pharmaceutical agent from a defined list.

The claim coverage is directed to combination therapy using a GLP-1R agonist chosen from the enumerated benzimidazole-6-carboxylic acid derivatives, including DIAST-X2, together with the specified 4-(4-(1-isopropyl-7-oxo-1,4,6,7-tetrahydrospiro[indazole-5,4′-piperidine]-1′-carbonyl)-6-methoxypyridin-2-yl)benzoic acid or a pharmaceutically acceptable salt thereof, for treating the stated fatty liver and metabolic disease conditions. Dependent claims further narrow the salt and crystal forms and allow inclusion of at least one additional pharmaceutical agent from the defined therapeutic classes.

Stated Advantages

Documented Applications