SHIP1 modulators and methods related thereto
Inventors
Mackenzie, Lloyd F. • MACRURY, Thomas B. • Harwig, Curtis • Bogucki, David • Raymond, Jeffery R. • PETTIGREW, Jeremy D.
Assignees
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Publication Number
US-10174046-B2
Publication Date
2019-01-08
Expiration Date
Abstract
Compounds of formula (II): wherein R1, R2, R5 and R13 are described herein, or a stereoisomer, enantiomer or tautomer thereof or mixtures thereof, or a pharmaceutically acceptable salt or solvate thereof, are described herein, as well as other compounds. These compounds have activity as SHIP1 modulators, and thus may be useful in treating a variety of diseases, disorders or conditions that would benefit from SHIP1 modulation. Compositions comprising a compound of the invention are also disclosed, as are methods of SHIP1 modulation by administration of such compounds to an animal in need thereof.
Core Innovation
The disclosed subject matter provides compounds of formula (IV) having substituent-defined groups R1, R2, R5, R6, R8/R9, R10, R13, R14, R15, and R16, including stereoisomers, enantiomers, tautomers, mixtures, and pharmaceutically acceptable salts or solvates thereof. The structural scope includes OR9, N(R9)2, O–R10–OR9, O–R10–N(R9)2, C(O)OR9, and C(O)N(R9)2 patterns, as well as alkyl, alkenyl, alkynyl, aryl, and heteroaryl definitions for selected substituents.
The compounds are described as SHIP1 modulators, including SHIP1 agonists or SHIP1 antagonists, and the disclosure relates SHIP1 to immune and hematopoietic cells and PI3K pathway signaling through phosphoinositides such as PIP3, PI-4,5-P2, and PI-3,4-P2. The document presents the need for improved small-molecule SHIP1 modulators beyond prior natural and patent modulators, and includes stereochemically defined exemplars within the broader formula (IV) coverage.
The therapeutic context includes administering an effective amount of a formula (IV) compound, or its stereoisomeric and salt/solvate forms, to a mammal in need thereof for treatment of autoimmune, inflammatory, and neoplastic or cell proliferative diseases, disorders, or conditions. The disclosure also includes pharmaceutical compositions comprising the SHIP1 modulator compound and pharmaceutically acceptable carriers, excipients, salts, or solvates.
Claims Coverage
The claim coverage centers on one chemical class claim and multiple use and composition claim entries, with four main inventive feature areas: a formula (IV) compound class, SHIP1 modulation by administration, treatment of disease categories, and pharmaceutical compositions.
Compounds of formula (IV) with variable R-group substituents
A compound of formula (IV) wherein R1, R2, R5, R6, R8/R9, R10, R13, R14, R15, and R16 are defined by the listed substitution options, including OR9, N(R9)2, O–R10–OR9, O–R10–N(R9)2, C(O)OR9, and C(O)N(R9)2 patterns, and including stereoisomers, enantiomers, tautomers, mixtures, pharmaceutically acceptable salts, and solvates.
Modulating SHIP1 by administering an effective amount
A method of modulating SHIP1 by administering an effective amount of the compound of formula (IV), or a stereoisomer, enantiomer, tautomer, mixture, pharmaceutically acceptable salt, or solvate thereof, to a mammal in need thereof, including administration of a pharmaceutical composition comprising the compound.
Treating autoimmune, inflammatory, or neoplastic/cell proliferative disease
A method of treating a disease by administering an effective amount of the compound of formula (IV), or a stereoisomer, enantiomer, tautomer, mixture, pharmaceutically acceptable salt, or solvate thereof, to a mammal in need, where the disease is an autoimmune disease, an inflammatory disease, or a neoplastic or cell proliferative disease, disorder or condition.
Pharmaceutical composition comprising a compound and pharmaceutically acceptable excipient
A pharmaceutical composition comprising a compound of formula (IV), or one of its stereoisomers, enantiomers, tautomers, or mixtures, together with a pharmaceutically acceptable salt or solvate form and a pharmaceutically acceptable excipient.
Overall, the claim coverage is directed to a defined class of compounds of formula (IV) with extensive substitution variability and permitted stereochemical and salt/solvate forms, together with methods of modulating SHIP1, treating autoimmune, inflammatory, and neoplastic or cell proliferative diseases, and pharmaceutical compositions containing the compounds.
Stated Advantages
Improved small-molecule SHIP1 modulators are needed beyond prior natural and patent modulators.
Documented Applications
Modulating SHIP1 by administering an effective amount of a compound of formula (IV) or a pharmaceutical composition to a mammal in need thereof.
Treating autoimmune disease, inflammatory disease, and neoplastic or cell proliferative disease, disorder or condition by administering an effective amount of a compound of formula (IV) to a mammal in need.
Use of isotopically labeled, radiolabelled derivatives, including references to PET and Positron Emission Topography.
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