Alvocidib prodrugs having increased bioavailability

Inventors

Siddiqui-Jain, Adam • Bearss, David J.

Assignees

Sumitomo Pharma Oncology Inc

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 is directed to phosphate prodrug compounds of the alvocidib scaffold in which one of R1/R2/R3 is a phosphate group (—P(O)(OH)2) and the others are H. The disclosure includes stereoisomers, tautomers, pharmaceutically acceptable salts, and multiple illustrated phosphate regioisomers (I, I′, IA, IA′, IB, IB′, IC, IC′).

The invention addresses improved oral bioavailability relative to alvocidib and diphosphate prodrugs by using phosphate monoprodrugs rather than diphosphates. The disclosure provides reported mouse oral bioavailability findings, including a monophosphate improvement of about 1.3× versus the parent and a reported >8× versus diphosphate prodrugs. Additional support includes in vivo pharmacokinetic and aqueous kinetic solubility findings, as well as plasma stability findings.

The disclosure further relates to cancer treatment for diseases associated with cyclin-dependent kinases (CDK) overexpression, including hematologic cancers such as AML, CLL, and MDS. The document reports cancer-related outcomes for compound IB′, including MV4-11 xenograft efficacy and reduction of MCL-1 protein expression. Improved tolerability is also described through maximum tolerated dose (MTD) comparisons.

Claims Coverage

The partial content provides three independent claims, each directed to a pharmaceutical composition including a compound defined by the alvocidib scaffold phosphate prodrug structure (including a tautomer or pharmaceutically acceptable salt), with independent claim differences centered on additional formulation components such as glidant and lubricant and on specific excipient components.

Across the independent claims provided, coverage is directed to pharmaceutical compositions containing the specified structured phosphate prodrug compound (including tautomers and pharmaceutically acceptable salts), with additional independent-claim scope defined by the presence of a glidant and lubricant, and by specific excipient materials including lactose, colloidal silicon dioxide, and magnesium stearate.

Stated Advantages

Documented Applications