Alvocidib prodrugs having increased bioavailability
Inventors
Siddiqui-Jain, Adam • Bearss, David J.
Assignees
Interested in licensing this patent?
MTEC can help explore whether this patent might be available for licensing for your application.
Publication Number
US-12338261-B2
Publication Date
2025-06-24
Expiration Date
Abstract
Compounds having the following structure (I):or a stereoisomer, tautomer or pharmaceutically acceptable salt thereof, wherein one of R1, R2 or R3 is —P(═O)(OH)2, and the other two of R1, R2 and R3 are each H, are provided. Pharmaceutical compositions comprising the compounds, and methods for use of the compounds for treating diseases associated with overexpression of a cyclin-dependent kinase (CDK) are also provided.
Core Innovation
The invention relates to a method for preparing a compound of structure (I), or a stereoisomer, tautomer or pharmaceutically acceptable salt thereof, wherein one of R1, R2 or R3 is —P(⊙O)(OH)2 and the other two are each H. The method comprises adding a phosphate group to one of three free hydroxyls of alvocidib, or a salt or solvate thereof, to obtain the specified monophosphate prodrug motif.
The disclosed approach emphasizes preparing labeled phosphate regio-/stereoisomers of structure (I), including I′, IA, IA′, IB, IB′, IC and IC′. It further encompasses related forms of the resulting compound, including stereoisomers, tautomers and pharmaceutically acceptable salts.
The document describes that conversion and metabolism of the monophosphate prodrug to alvocidib is expected, and it states corresponding advantages relative to the parent alvocidib and diphosphate prodrugs. The expected advantages include improved oral bioavailability and solubility, together with reduced GI toxicity.
Claims Coverage
The independent claim covers a method of preparing monophosphate prodrugs of alvocidib with a defined substituent constraint on R1/R2/R3, based on addition of a phosphate group to one of three free hydroxyls. The dependent claims mainly cover specific labeled regio-/stereoisomers and additional salt/free-base interconversions.
Phosphate addition to one of three alvocidib hydroxyls to form defined structure (I)
A method for preparing a compound of structure (I) (or a stereoisomer, tautomer or pharmaceutically acceptable salt thereof), wherein one of R1, R2 or R3 is —P(⊙O)(OH)2 and the other two are each H, the method comprising adding a phosphate group to one of three free hydroxyls of alvocidib, or a salt or solvate thereof.
Preparation of labeled stereoisomer structure (I′)
The method of claim 1 wherein the compound has structure (I′) as shown in the provided chemical structures/images.
Preparation of labeled structure (IA)
The method of claim 1 is wherein the compound has structure (IA) shown in the claim.
Preparation of labeled structure (IB)
The method of claim 1 is characterized in that the compound has the chemical structure (IB) shown in the provided structure images.
Salt formation using inorganic or organic base or acid
The method further includes treating the compound of structure (I) with an inorganic or organic base or acid to form a pharmaceutically acceptable salt of the compound of structure (I).
Conversion of a structure (I) salt to free base or acid
The method further converts a salt of the compound having structure (I) into its free base or acid form.
Overall, claim coverage is centered on preparing structure (I) monophosphate prodrugs of alvocidib by adding a phosphate group to one of three free hydroxyls under the defined R1/R2/R3 pattern, with additional dependent coverage for specific labeled regio-/stereoisomers and pharmaceutically acceptable salt/free-base interconversions.
Stated Advantages
Higher oral bioavailability versus the parent alvocidib and diphosphate prodrugs.
Improved solubility.
Reduced GI toxicity.
Documented Applications
Phosphate monophosphate prodrug evaluation includes IV/PO pharmacokinetics and pharmacodynamic effects in a MV4-11 AML xenograft model, including tumor growth inhibition and MCL-1 protein reduction.
Kinetic solubility assessment across pH and plasma stability assessment across species are described in the document.
In vivo efficacy/pharmacodynamics are described for MV4-11 acute myeloid leukemia (AML) xenograft studies.
Interested in licensing this patent?