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Publication Number
US-10844049-B2
Publication Date
2020-11-24
Expiration Date
Abstract
The invention described herein provides compounds of Formula (I) and pharmaceutical compositions thereof, for use in, e.g. treating type 2 diabetes mellitus, pre-diabetes, obesity, non-alcoholic fatty liver disease, non-alcoholic steatohepatitis, and cardiovascular disease.
Core Innovation
The invention is directed to a compound represented by structural formula (I′), and includes pharmaceutically acceptable salt, stereoisomer, solvate, or hydrate forms, and optionally a pharmaceutical composition comprising the compound and a pharmaceutically acceptable excipient. The compound class is defined by selections for X1, X2, X3, X4, and X5 from N, C, and CH, together with constraints on the number and contiguity of nitrogen ring atoms in ring A and ring B.
The structural definition further specifies W as O, NH, or CH2; Y1, Y3, Y4, and Y5 as independently selected from N, NH, C, CH, and CH2; Y2 and Y6 as independently selected from N, C, or CH; and T6, T7, and T8 as independently selected from N and CR4, with no more than 2 of T6, T7, and T8 selected from N. EE is defined as —COOH, and the scaffold includes detailed substituent definitions for Ra, Rb, Rc, R1, R2, R3, R4, R5, and R6, with indices m, n, and o restricted to defined integer ranges.
The disclosed compound family is described as a benzimidazole-based carboxylic acid scaffold with defined ring substituent choices and ring-atom pattern constraints for rings A and B. The document also provides structures and analytical characterization for multiple related compounds, including LCMS [M+H]+, retention time, and 1H NMR data, and identifies stereochemically defined analogs within the family.
Claims Coverage
The consolidated claim coverage centers on a compound class defined by structural formula (I′), with optional pharmaceutically acceptable salt, stereoisomer, solvate, hydrate, and pharmaceutical composition forms. The independent inventive coverage includes the constrained scaffold definition, the atom-selection variables, the ring nitrogen limitations, the defined EE group, and the allowed substituent systems.
Compound of structural formula (I′) with ring-atom constraints
A compound represented by structural formula (I′), or a pharmaceutically acceptable salt, stereoisomer, solvate, or hydrate thereof, with X1, X2, X3, X4, and X5 independently selected from N, C, and CH, and with limits on the number and contiguous placement of nitrogen atoms in ring A and ring B.
Defined scaffold variables W, Y1–Y6, and T6–T8
W is selected from O, NH, and CH2; Y1, Y3, Y4, and Y5 are independently selected from N, NH, C, CH, and CH2; Y2 and Y6 are independently selected from N, C, or CH; and T6, T7, and T8 are independently selected from N and CR4, with no more than 2 of T6, T7, and T8 selected from N.
EE fixed to —COOH and defined substituent framework
EE is —COOH, with Ra as hydrogen, Rb as a 5-6 membered heteroaryl or 4-7 membered saturated or partially saturated heterocyclyl optionally substituted with defined groups, Rc as hydrogen, C1–C6 alkyl, or C1–C6 haloalkyl, and R1, R2, R3, R4, R5, and R6 defined by listed substituent sets and index ranges m, n, and o.
Pharmaceutical composition with excipient
A pharmaceutical composition comprising the compound represented by structural formula (I′) or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.
The consolidated claim coverage is directed to a structurally defined compound class with explicit ring nitrogen pattern limits, defined atom-selection variables, a fixed EE group of —COOH, and constrained substituent sets and index ranges, together with optional pharmaceutical compositions containing a pharmaceutically acceptable excipient.
Stated Advantages
Not explicitly described in patent.
Documented Applications
Combination therapy for obesity and NASH by co-administering the claimed compounds with anti-obesity agents and NASH-targeting agents.
GLP-1R-related biological characterization, including β-arrestin recruitment, GLP-1R internalization, GLP-1R/β-arrestin interaction, and GLP-1R cAMP signaling assays.
Non-human primate oral pharmacokinetics demonstrating sustained plasma concentrations over 24 h for certain tested compounds compared with a comparator.
Treatment of cardiometabolic and associated diseases, including type 1 diabetes, type 2 diabetes, pre-diabetes, hyperglycemia, insulin resistance, diabetic complications, NAFLD/NASH, fibrosis and cirrhosis, cardiovascular diseases and atherosclerosis, hypertension, heart failure, stroke, Polycystic Ovary Syndrome, and addiction.
Therapeutic use for cardiometabolic diseases including type 2 diabetes mellitus, pre-diabetes, obesity, non-alcoholic fatty liver disease, non-alcoholic steatohepatitis, and cardiovascular disease.
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