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Publication Number
US-7601852-B2
Publication Date
2009-10-13
Expiration Date
Abstract
A compound having a structure according to formula I wherein R1, R2, R3, R4, and R5 are as defined herein, are useful as kinase inhibitors.
Core Innovation
The invention relates to macrocyclic resorcylic acid lactone (RAL) analog kinase inhibitors, including compounds having a structure represented by formula I and pharmaceutically acceptable salts. The compounds are defined with substituent options for R1–R5, including H or C1–C4 alkyl for R1, R3, and R5; H for R4; and H, hydroxyl, or protected hydroxyl for R2. The disclosure also includes pharmaceutically acceptable esters, solvates, and hydrates.
The disclosure expands the chemical definition through related structure representations (formula II, formula III, and formula IV) and through preferred embodiments with refined substituent limitations. Prodrugs are mentioned as being convertible in vivo to the formula I compounds. The chemical scope is supported by detailed substituent definitions and examples, including specific compound examples 29 and 30 with characterization described.
The background problem is that disease is driven by abnormal kinase activity, and there is a need for kinase inhibitors effective against relevant kinase targets. The mechanism is described as targeting kinases that have an ATP-binding-site cysteine residue adjacent to two aspartates, consistent with a Michael-addition/covalent inhibition model. An extensive list of example cysteine-motif kinases is provided, and biological activity data are reported comparing compounds (including compounds III and IV) to hypothemycin, including potency and ERK2 binding/inactivation parameters.
Claims Coverage
The partial claims provided include one independent claim (a compound defined by formula I) and multiple dependent claims that refine the allowable structural features through specific formula representations and substituent limitations. Overall, the claim coverage is centered on the formula I scaffold with defined options for R1–R5 and narrowing dependent refinements specifying alternative structural representations (formula II/III/IV) and specific substituent restrictions (notably for R1 and R2).
Formula I compound scaffold with defined R1–R5 substituents
A compound having a structure represented by formula I and pharmaceutically acceptable salts thereof, wherein R1 is H or C1–C4 alkyl, R2 is H, hydroxyl or protected hydroxyl, R3 is H or C1–C4 alkyl, R4 is H, and R5 is H or C1–C4 alkyl.
Alternative structure representation by formula II
A compound having a structure represented by formula I, further defined as having the structure corresponding to formula (II).
Alternative structure representation by formula III
A compound having a structure represented by formula I, further defined as having the structure corresponding to formula III.
Alternative structure representation by formula IV
A compound having a structure represented by formula I, further defined as having the structure shown by formula IV, explicitly including HO/O/OH entities.
Specific R1 restriction to H or CH3
A compound having the structure of claim 3 in which the substituent R1 is either H or CH3.
Refined R1 and R2 substituent sets
A compound of claim 2 in which the substituent R1 is either H or a C1–C4 alkyl group, and substituent R2 is either a hydroxyl group or a protected hydroxyl group.
The provided claim set defines a formula I macrocyclic resorcylic acid lactone analog scaffold with specified permissible substituents at R1–R5, and then narrows scope via dependent refinements that introduce alternative structural representations (formula II, formula III, and formula IV) and specific substituent-set restrictions, including an R1 limitation to H or CH3 and refinement of R2 to hydroxyl/protected hydroxyl.
Stated Advantages
Not explicitly described in patent.
Documented Applications
Not explicitly described in patent.
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