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Publication Number
US-11026905-B2
Publication Date
2021-06-08
Expiration Date
Abstract
Compounds as STAT3 inhibitors are described. A pharmaceutical composition comprising the same, methods of making the same, and a method for treating or preventing conditions such as cancer, chronic inflammation, and fibrosis using the same, are described.
Core Innovation
STAT3 inhibitor compounds are described, including compounds defined by Formula I, Formula II, Formula III, and Formula IIIx, with broad substituent definitions and representative structures in Tables 1a and 1b. The disclosure includes a compound of Formula III that is referenced in pharmaceutical compositions, together with pharmaceutically acceptable salt forms.
The invention describes pharmaceutical formulations for compositions containing a compound of Formula III and/or a pharmaceutically acceptable salt thereof, together with a pharmaceutically acceptable carrier or diluent. The formulations include rectal suppository and vaginal pessary dosage forms, including tampons, creams, and gels, as well as topical and transdermal powders, sprays, ointments, and patches, with controlled delivery and absorption enhancers.
The compositions are also described for ophthalmic use and for sterile parenteral administration, including sterile isotonic solutions and suspensions. Depot delivery using suspensions and formulations including polymer matrices, microencapsulation, and liposomes is also described, together with unit dosage forms, dosing ranges, buffering agents, preservatives, and salt forms.
A key inventive concept is that the described compounds inhibit STAT3 and modulate STAT3 activity, including STAT3 phosphorylation, nuclear-to-cytoplasmic translocation of STAT3, and surface plasmon resonance (SPR) binding assay endpoint results. These effects are linked to therapeutic outcomes for treating cancer and fibrosis-associated disorders.
Claims Coverage
The independent claim family coverage is directed to a pharmaceutical composition comprising a compound of Formula III or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier or diluent, with three inventive features directed to therapeutic methods and fibrosis-associated diseases or disorders.
Pharmaceutical composition with Formula III compound and pharmaceutically acceptable carrier
A pharmaceutical composition comprising a compound of Formula III or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier or diluent.
Treating cancer by administering Formula III composition inhibiting STAT3
A method for treating cancer in a subject by administering a therapeutically effective amount of the pharmaceutical composition comprising a Formula III compound that inhibits STAT3, for cancers selected from head and neck cancer, lung cancer, liver cancer, breast cancer, ovarian cancer, colon cancer, multiple myeloma, and pancreatic cancer.
Treating fibrosis by administering Formula III composition inhibiting STAT3
A method for treating fibrosis by administering a therapeutically effective amount of a pharmaceutical composition comprising a Formula III compound that inhibits STAT3 to treat the fibrosis.
Fibrosis associated with specified diseases or disorders
The method includes fibrosis associated with pulmonary fibrosis, intestine fibrosis, pancreatic fibrosis, joint fibrosis, liver fibrosis, retroperitoneal fibrosis, myelofibrosis, dermal fibrosis, non-alcoholic fatty liver disease, steatohepatitis, and systemic sclerosis.
Fibrosis associated with a narrowed set of specified diseases or disorders
The method further specifies fibrosis associated with pulmonary fibrosis, non-alcoholic fatty liver disease, steatohepatitis, or systemic sclerosis.
Across the claim set, the core composition feature is the combination of a Formula III compound or salt with a pharmaceutically acceptable carrier or diluent. The dependent claims refine use by specifying therapeutic methods for treating cancer and fibrosis where the Formula III compound inhibits STAT3, including narrowed selections of cancer types and fibrosis-associated diseases or disorders.
Stated Advantages
STAT3 inhibition is linked to apoptosis, angiogenesis, tumor activity, and anti-tumor immune-mediated cytotoxicity.
STAT3 inhibition is linked to STAT3 phosphorylation and nuclear-to-cytoplasmic translocation of STAT3.
Documented Applications
Therapeutic treatment of cancer, including head and neck cancer, lung cancer, liver cancer, breast cancer, ovarian cancer, colon cancer, multiple myeloma, and pancreatic cancer.
Therapeutic treatment of fibrosis, including pulmonary fibrosis, intestine fibrosis, pancreatic fibrosis, joint fibrosis, liver fibrosis, retroperitoneal fibrosis, myelofibrosis, dermal fibrosis, non-alcoholic fatty liver disease, steatohepatitis, and systemic sclerosis.
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