Truncated itraconazole analogues and methods of use thereof
Inventors
Assignees
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Publication Number
US-12435067-B2
Publication Date
2025-10-07
Expiration Date
Abstract
Disclosed herein are analogues of itraconazole that are potent hedgehog signaling pathway inhibitors. The compounds are expected to be useful in the treatment of cell proliferation disorders such as cancer, particularly cancers that are dependent upon the hedgehog signaling pathway such as basal cell carcinoma and medulloblastoma.
Core Innovation
The invention relates to a compound defined by Formula (Ia-1), (Ia-2), (Ia-3), or (Ia-4), including pharmaceutically acceptable salts, stereoisomeric forms thereof, or combinations thereof. The compound requires Q to be O, R1 to be methyl, R4 to be chloro, and n to be 2, with one of substitution patterns (a), (b), or (c) defining whether J1 and J2 are absent or present and how R3 is selected.
For substitution pattern a), J1 and J2 are absent and R3 is H. For substitution pattern b), J1 is —C(=O)— or —C(=O)NH—N=CH—, J2 is absent, C1-4 alkyl, or C2-4 alkenyl, and R3 is unsubstituted or substituted phenyl or pyridyl. For substitution pattern c), J1 is absent, J2 is C3-4 alkyl, and R3 is unsubstituted or substituted phenyl, with substituted phenyl or pyridyl individually substituted with 1, 2, or 3 substituents selected from the listed substituent classes.
The invention relates to truncated itraconazole (ITZ) analogues as inhibitors of Hedgehog (Hh) signaling and as potent inhibitors of the Hh pathway. The disclosed compounds include truncated analogues and metabolites, and the document presents structure-activity relationships, measured IC50 values, and comparisons of anti-Hh activity, microsomal stability, and solubility.
Claims Coverage
The provided claim family centers on one independent structural claim for Formula (Ia-1), (Ia-2), (Ia-3), or (Ia-4), with fixed scaffold variables and a three-way structural selection for J1, J2, and R3. Dependent coverage further narrows the substituent options for phenyl or pyridyl and includes pharmaceutically acceptable salt and stereoisomeric form coverage, together with therapeutic treatment language for cell proliferation disorders including Vismodegib-resistant cases.
Formula-defined chloro/methyl/O-n=2 scaffold
A compound having the structure of Formula (Ia-1), (Ia-2), (Ia-3), or (Ia-4), wherein Q is O, R1 is methyl, R4 is chloro, and n is 2.
Three-way selection for J1, J2, and R3
The compound satisfies one of (a) J1 and J2 are absent and R3 is H; (b) J1 is —C(=O)— or —C(=O)NH—N=CH—, J2 is absent, C1-4 alkyl, or C2-4 alkenyl, and R3 is unsubstituted or substituted phenyl or pyridyl; or (c) J1 is absent, J2 is C3-4 alkyl, and R3 is unsubstituted or substituted phenyl.
Defined substituent set for substituted phenyl or pyridyl
Each substituted phenyl or pyridyl is substituted with 1, 2, or 3 substituents, independently selected from C1-6 alkyl, halo, —OH, —COOH, cyano, nitro, amino, C1-6 monoalkylamine, C1-6 dialkylamine, C1-6 haloalkyl, or C1-6 haloalkoxy.
Pharmaceutically acceptable salt and stereoisomeric form
The compound is a pharmaceutically acceptable salt, a stereoisomeric form thereof, or a combination thereof.
Claim coverage is centered on a Formula (Ia) structural definition with fixed Q, R1, R4, and n values, a three-part selection for J1 and J2 and the form of R3, and explicit coverage of pharmaceutically acceptable salts and stereoisomers.
Stated Advantages
Potent inhibition of Hedgehog (Hh) signaling through Smoothened (Smo).
Improved potency for selected simplified analogues based on measured IC50 values.
Improved microsomal stability and better solubility.
Reduces severity of the cell proliferation disorder.
Slows progression of the cell proliferation disorder.
Documented Applications
Therapeutic use for Hh-dependent cancers and cell proliferation disorders, including basal cell carcinoma and medulloblastoma, including Vismodegib-resistant cases.
Treating basal cell carcinoma in a subject by administering a therapeutically effective amount of the compound.
Treating medulloblastoma in a subject by administering a therapeutically effective amount of the compound.
Treating a cell proliferation disorder resistant to Vismodegib by administering a therapeutically effective amount of the compound.
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