Process for the preparation of cyclic depsipeptides
Inventors
Piscopio, Anthony D. • Fu, Xiaoyong • Shi, Feng • Liu, Huayan • Li, Zhifeng
Assignees
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Publication Number
US-11053284-B2
Publication Date
2021-07-06
Expiration Date
Abstract
Processes for preparing compounds of Formula (1) and Formula (2) are described, wherein X, Y, Z, R1-R7, L and n are defined herein. Intermediates useful in the preparation of the compounds of Formula (1) and Formula (2) are also described.
Core Innovation
The disclosure describes thioester-containing compounds defined by structural Formula (XXV), including pharmaceutically acceptable salts, with substituent definitions for R1, R2, R3, R4, R5, R6, R13, and R14. The thioester functionality is presented as part of a broader set of cyclic depsipeptide or HDAC inhibitor-related chemical frameworks described through multiple intermediates and structural variants.
The document further characterizes synthesis of substituted cyclic depsipeptides as histone deacetylase (HDAC) inhibitors via multi-step synthetic schemes that lead to compounds corresponding to Formula (1) and Formula (2). It includes ring closure to core scaffolds and subsequent reaction with R12—SH to install thioester/thioamide functionality, and it describes key aldehyde intermediate (E)-5-chloropent-2-enal formation through ruthenium carbene-catalyzed cross olefin metathesis followed by oxidation.
The disclosure also describes multi-step conversion of macrocyclic intermediates to thioester/thioate products, including carbamate/ester hydrolysis to reach a macrocyclic intermediate, followed by macrolactamization to form a subsequent macrocyclic intermediate. A key part of the described sequence uses a thioate nucleophile to generate thioester/thioate intermediate products from a macrocyclic intermediate, and subsequent deprotection yields amino acid/thiol-bearing intermediates and Largazole analog precursors.
Claims Coverage
Two independent claims are present: one directed to a thioester compound of Formula (XXV) or a pharmaceutically acceptable salt thereof, and one directed to a method of treating disorders associated with inhibition of histone deacetylase by administering that thioester compound or its pharmaceutically acceptable salt. Across the independent claims, the coverage includes compound-level structural definition and treatment-level administration context, with 2 inventive features at the core and additional dependent narrowing to specific salt forms and a preparation sequence.
Thioester compound of formula (xxv)
A thioester compound of Formula (XXV), or a pharmaceutically acceptable salt thereof, wherein R1 and R2 are H; R3 and R4 are CH3; R5 is H and R6 is isopropyl, or R5 is isopropyl and R6 is H; and R13 is H and R14 is C1-C10 alkyl, or R13 is C1-C10 alkyl and R14 is H.
Treatment of disorders associated with histone deacetylase inhibition
A method of treating disorders associated with inhibition of histone deacetylase, comprising administration of a thioester compound having the specified formula or a pharmaceutically acceptable salt thereof.
Preparation of the formula (xxv) thioester via intermediate formula (xxiv) and deprotection
A method for preparing the thioester of Formula (XXV) by treating Compound (XX) with a compound of Formula (XXIII) to provide a compound of Formula (XXIV), followed by deprotecting the Formula (XXIV) compound to obtain Formula (XXV) or a pharmaceutically acceptable salt thereof.
Chloride pharmaceutically acceptable salt form
A method as recited in the earlier method claim, wherein the pharmaceutically acceptable salt is a chloride salt.
Sulfonate pharmaceutically acceptable salt form
A method as recited in the earlier method claim, wherein the pharmaceutically acceptable salt is a sulfonate salt.
Overall, claim coverage spans a specifically defined Formula (XXV) thioester compound, or pharmaceutically acceptable salt, with constrained substituent patterns, therapeutic administration for disorders associated with inhibition of histone deacetylase, and a preparation sequence from Compound (XX) through Formula (XXIV) with deprotection to reach Formula (XXV).
Stated Advantages
Reduced waste streams or waste reduction versus routes using organophosphorous Horner-Wadsworth-Emmons reagents.
Recyclability of components or use of recoverable catalysts/reagents is emphasized versus Horner-Wadsworth-Emmons-type routes.
Documented Applications
Treatment of disorders associated with inhibition of histone deacetylase by administering the defined thioester compound or a pharmaceutically acceptable salt thereof.
The treated disorder is selected from cancer, inflammatory diseases, autoimmune diseases, allergic diseases, or diseases of the central nervous system.
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