Substituted 4-phenyl pyridine compounds as non-systemic TGR5 agonists
Inventors
Lewis, Jason Gustaf • Leadbetter, Michael Robert • Caldwell, Jeremy • Dragoli, Dean • Bell, Noah • Jacobs, Jeffrey W. • Finn, Patricia • Jain, Rakesh • Chen, Tao • Siegel, Matthew
Assignees
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Publication Number
US-10392413-B2
Publication Date
2019-08-27
Expiration Date
Abstract
The invention relates to non-systemic TGR5 agonist useful in the treatment of chemotherapy-induced diarrhea, diabetes, Type II diabetes, gestational diabetes, impaired fasting glucose, impaired glucose tolerance, insulin resistance, hyperglycemia, obesity, metabolic syndrome, ulcerative colitis, Crohn's disease, disorders associated with parenteral nutrition especially during short bowel syndrome, and irritable bowel syndrome (IBS), and other TGR5 associated diseases and disorders, having the Formula: where R1, R2, R2′, R3, R4, X1, X2, X3, X4, Q, and n are described herein.
Core Innovation
The invention relates to compounds of Formula (I²) and pharmaceutically acceptable forms thereof, including salts, hydrates, solvates, prodrugs, stereoisomers, and tautomers. The compounds are defined by constrained structural variables including Q, Q1, X1–X4, and Y, together with extensive substituent definitions for R groups and the indices m, n, o, p, q, and r. The scope includes conditional relationships between Q and Q1, allowed heteroatom positions, and permitted optional substitution patterns within the Formula (I²) framework.
A further aspect concerns prodrugs of compounds of Formula (f) having Formula (IF) or Formula (II), where the prodrug includes a cleavable group P selected from —O, —CH2OC(O)(C1–C6)alkyl, or —CH2OC(O)NRs(C1–C6)alkyl. The same general heterocyclic framework variables are retained, including Q, Q1, X1–X4, Y, and broad R-group definitions, with additional constraints on optional substitution and ring formation. The partial content also describes specific enumerated prodrug structures and example compound families within this framework.
The disclosure further includes broad TGR5 modulator subject matter, including TGR5 agonists and substituted 4-phenyl pyridine compounds represented by Formula (I²). It states that the compounds include pharmaceutically acceptable forms and cover broad stereochemical and isomeric scope, and it links the chemistry to compositions and methods that prolong a TGR5-mediated GLP-1 signal. The provided material also references compound embodiments and examples that are used to support the claimed chemical space.
Claims Coverage
The provided claim set covers one Formula (I²) compound claim and one prodrug claim, with dependent claim content also addressing pharmaceutical composition and medical-use limitations. In total, the inventive coverage centers on the Formula (I²) scaffold, the prodrug cleavable-group P framework, and composition/use claims tied to TGR5-mediated GLP-1 signaling and delaying renal replacement therapy. The core inventive features are structural, with extensive variable definitions and explicit non-contiguity rules for substituted methylene replacements.
Formula (I²) compound framework with constrained heteroatom positions
A compound of Formula (I²) (or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof) wherein Q is C(O), —CH2—, —NR5—, or —O—; Q1 is defined according to the selected Q; X1–X4 are each CR or N as specified; and Y is CRb or N, with broad substituent definitions for R, R1–R18 and related variables. The claim includes rules for allowed ring formation and explicit non-contiguity constraints when substituted methylene units are replaced by specified heteroatom-containing moieties.
Prodrug of a Formula (f) compound with cleavable group P
A prodrug of a compound of Formula (f) having Formula (IF) or Formula (II), wherein P is a cleavable group selected from —O, —CH2OC(O)(C1–C6)alkyl, or —CH2OC(O)NRs(C1–C6)alkyl, with Rs being H or (C1–C6) alkyl. The prodrug retains the same general Q/Q1, X1–X4, Y, and R-group framework and is further defined by the same broad substituent classes and structural constraints.
Pharmaceutical composition prolonging a TGR5-mediated GLP-1 signal
A pharmaceutical composition comprising the claimed compound and one or more additional biologically active agents that prolong the TGR5-mediated GLP-1 signal.
Pharmaceutical composition including a DPP-4 inhibitor
A pharmaceutical composition further including at least one additional biologically active agent that is a DPP-4 inhibitor selected from sitagliptin, vildagliptin, saxagliptin, linagliptin, alogliptin, gemigliptin, omarigliptin, or dutogliptin.
Method delaying renal replacement therapy
A method for delaying renal replacement therapy (RRT) by administering an effective amount of a compound of claim 1 (or a pharmaceutically acceptable salt) to a patient in need of RRT.
Overall, the claim coverage is anchored by the Formula (I²) compound definition with tightly specified heteroatom placement, extensive substituent variability, and explicit non-contiguity rules, and by a parallel prodrug claim that adds a cleavable group P while retaining the same framework. The provided dependent claim content also covers pharmaceutical compositions that prolong a TGR5-mediated GLP-1 signal, compositions including DPP-4 inhibitors, and a method for delaying renal replacement therapy.
Stated Advantages
Delays renal replacement therapy (RRT).
Prolongs the TGR5-mediated GLP-1 signal.
Improved efficacy/safety versus known TGR5 agonists.
Documented Applications
A method for delaying renal replacement therapy (RRT) by administering an effective amount of a compound of claim 1 (or a pharmaceutically acceptable salt) to a patient in need of RRT.
A pharmaceutical composition that includes one or more additional biologically active agents that prolong the TGR5-mediated GLP-1 signal.
A pharmaceutical composition further including at least one additional biologically active agent that is a DPP-4 inhibitor selected from sitagliptin, vildagliptin, saxagliptin, linagliptin, alogliptin, gemigliptin, omarigliptin, or dutogliptin.
Therapeutic use of TGR5 modulation/activation across metabolic, gastrointestinal, renal/phosphate disorders, and inflammatory or neuropsychiatric indications.
Chemotherapy-induced diarrhea.
Type II diabetes and related metabolic disorders, including gestational diabetes, impaired fasting glucose, impaired glucose tolerance, insulin resistance, hyperglycemia, obesity, and metabolic syndrome.
Inflammatory bowel disease, including ulcerative colitis and Crohn's disease.
Short bowel syndrome and disorders linked to parenteral nutrition.
Irritable bowel syndrome (IBS).
Hyperphosphatemia and postprandial hyperphosphatemia.
Endothelial dysfunction and vascular calcification.
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