Heterobifunctional inhibitors of E-selectin and galectin-3
Inventors
Magnani, John L. • Peterson, John M. • Sarkar, Arun K. • VOHRA, Yusufbhai U. • Yang, Hong-Woon
Assignees
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Publication Number
US-11548908-B2
Publication Date
2023-01-10
Expiration Date
Abstract
Compounds, compositions, and methods for treatment and/or prevention of at least one disease, disorder, and/or condition by inhibiting binding of an E-selectin, galectin-3, or E-selectin and galectin-3 to ligands a disclosed. For example, heterobifunctional inhibitors of E-selectin and galectin-3 are described and pharmaceutical compositions comprising at least one such agent is described.
Core Innovation
The invention relates to at least one compound chosen from compounds of Formula (I), prodrugs of Formula (I), and pharmaceutically acceptable salts of any of the foregoing. Formula (I) includes substituents R1, R2, R3, R4, R5, a group M, and a linker L, each defined using selected options and ranges. The prodrugs incorporate variable substituent choices, including alkyl, alkenyl, alkynyl, haloalkyl, haloalkenyl, haloalkynyl, cycloalkylalkyl, aryl, and heteroaryl groups.
In Formula (I), R1 is chosen from defined alkyl, alkenyl, alkynyl, and haloalkyl, haloalkenyl, and haloalkynyl group options, and R6 is chosen from H, C1-8 alkyl, C2-8 alkenyl, C2-8 alkynyl, C4-16 cycloalkylalkyl, and C(=O)R7 groups. Each R7 is independently chosen from H, C1-8 alkyl, C2-8 alkenyl, C2-8 alkynyl, C4-16 cycloalkylalkyl, C6-18 aryl, and C1-13 heteroaryl groups.
The structure further specifies R2 as OH, OY1, halo, NH2, NY1Y2, OC(=O)Y1, NHC(=O)Y1, and NHC(=O)NHY1 groups, where Y1 and Y2 are independently selected from defined carbon-based and ring-based group classes. R3 is chosen from CN, CH2CN, and C(=O)Y3 groups, with Y3 selected from defined options including OZ1 and NHOH, NHOCH3, NHCN, and NZ1Z2 patterns, and R4 and R5 are selected from their respective defined sets, while M is chosen from groups defined by X and aryl, heteroaryl, arylalkyl, arylalkoxy, heteroarylalkyl, heteroarylalkoxy, and NHC(=O)Y4 options and L is chosen from linker groups.
The disclosed subject matter also includes heterobifunctional inhibitors of E-selectin and galectin-3 and ties these targets to suppression of E-selectin and/or galectin-3 mediated binding to ligands. The document states that the compounds are associated with treatment and/or prevention of diseases associated with these targets, including inflammatory diseases, fibrosis, and cancers, and references pharmaceutical compositions and administration of an effective amount to a subject in need.
Claims Coverage
The consolidated claim coverage centers on a broad Formula (I) prodrug/salt genus defined by substituent selections across R1 to R5, M, and L, together with a therapeutic feature directed to inhibiting E-selectin and/or galectin-3 mediated functions. Across the inputs, the claim material repeatedly narrows the same structural variables, including ring-forming Y1/Y2 and Y3 options, the macro-group M, and linker L.
Formula (I) prodrugs and pharmaceutically acceptable salts
At least one compound chosen from compounds of Formula (I), prodrugs of Formula (I), and pharmaceutically acceptable salts of any of the foregoing, with R1, R2, R3, R4, R5, M, and linker L defined by the stated option sets.
Variable substituent set for R1 and R6/R7
R1 is chosen from H and specified C1-8 alkyl, C2-8 alkenyl, C2-8 alkynyl, C1-8 haloalkyl, C2-8 haloalkenyl, and C2-8 haloalkynyl groups; R6 is chosen from H, C1-8 alkyl, C2-8 alkenyl, C2-8 alkynyl, C4-16 cycloalkylalkyl, and C(=O)R7, where each R7 is independently chosen from H, C1-8 alkyl, C2-8 alkenyl, C2-8 alkynyl, C4-16 cycloalkylalkyl, C6-18 aryl, and C1-13 heteroaryl groups.
Variable substituent set for R2 and ring-forming Y1/Y2
R2 is chosen from OH, OY1, halo, NH2, NY1Y2, OC(=O)Y1, NHC(=O)Y1, and NHC(=O)NHY1, where Y1 and Y2 are independently chosen from carbon-based, cycloalkylalkyl, heterocyclyl, aryl, and heteroaryl groups, with Y1 and Y2 optionally joining to form a ring with the nitrogen atom.
Variable substituent set for R3 and carbonyl-linked Y3
R3 is chosen from CN, CH2CN, and C(=O)Y3, where Y3 is chosen from OZ1 and NHOH, NHOCH3, NHCN, and NZ1Z2 groups, with Z1 and Z2 independently chosen from H, C1-8 alkyl, C2-8 alkenyl, C2-8 alkynyl, C1-8 haloalkyl, C2-8 haloalkenyl, C2-8 haloalkynyl, and C7-12 arylalkyl groups, and Z1 and Z2 optionally forming a ring with the nitrogen atom.
Variable substituent set for R4 and R5
R4 is chosen from H, C1-8 alkyl, C2-8 alkenyl, C2-8 alkynyl, C1-8 haloalkyl, C2-8 haloalkenyl, C2-8 haloalkynyl, C4-16 cycloalkylalkyl, and C6-18 aryl groups; R5 is chosen from CN, C1-8 alkyl, and C1-4 haloalkyl groups.
Macrostructural group M with X=0 or S and R9 options
M is chosen from groups wherein X is 0 or S, and R9 and R9 are independently chosen from C6-18 aryl, C1-13 heteroaryl, C7-19 arylalkyl, C7-19 arylalkoxy, C2-14 heteroarylalkyl, C2-14 heteroarylalkoxy, and NHC(=O)Y4 groups, where Y4 is chosen from C1-8, C2-12 heterocyclyl, C6-18 aryl, and C1-13 heteroaryl groups.
Linker L selected from linker groups
L is chosen from linker groups.
Inhibiting E-selectin and galectin-3 mediated functions
E-selectin, galectin-3, or both their mediated functions are inhibited by administering to a subject an effective amount of at least one compound of the Formula (I) compound class.
The consolidated inventive coverage is centered on Formula (I) prodrugs and pharmaceutically acceptable salts defined by broad, combinable substituent sets across R1 to R5, M, and L, together with therapeutic use directed to inhibition of E-selectin and/or galectin-3 mediated functions in a subject.
Stated Advantages
Suppresses E-selectin and/or galectin-3 mediated binding to ligands.
Associated with the treatment and/or prevention of diseases associated with E-selectin and/or galectin-3, including inflammatory diseases, fibrosis, and cancers.
Documented Applications
Treatment and/or prevention of diseases by inhibiting E-selectin and/or galectin-3 mediated functions, including inflammatory diseases, fibrosis, cancer adhesion/extravasation/metastasis and bone marrow infiltration, thrombosis, mucositis, cardiovascular conditions such as atherosclerosis and myocardial infarction, epileptic syndromes, neurodegenerative diseases/α-synucleinopathies, pathological angiogenesis, and sinusoidal obstruction syndrome.
Use of the disclosed compounds for manufacture of a medicament.
Therapeutic and prophylactic use, including combination therapy described as chemotherapy/radiotherapy adjunct therapy.
Treatment and/or prevention of diseases associated with E-selectin and/or galectin-3, including inflammatory diseases, fibrosis, and cancers.
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