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-10689419-B2
Publication Date
2020-06-23
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 disclosed subject matter centers on substituted cyclic depsipeptides and thioester compounds of Formula (XXV), including pharmaceutically acceptable salts thereof. The chemical scope is defined by multiple substituent variables, including R1-R6, R8-R11, and R13-R14, with allowed options such as H, C1-C10 alkyl, C3-C7 cycloalkyl, C3-C7 heterocycloalkyl, aryl, heteroaryl, halo, hydroxyl, CN, COOH, CF3, OCH2F, OCHF2, OC1-C10 alkyl, O-aryl, O-heteroaryl, and various amino-carbonyl or carboxyl-related groups.
The description also presents synthetic sequence logic for preparing the compounds, including conversion of an alcohol to a carbamate, coupling with a heterocycle, selective deprotection, formation of amine intermediates, ring closure intermediates, and coupling with a thiol to yield Formula (1) and Formula (2) products. It further identifies key early fragment formation using ruthenium carbene-catalyzed cross olefin metathesis and oxidation, and it references conversion data in Table 1.
The disclosed compound framework is tied to treatment of disorders associated with inhibited histone deacetylase and to diseases mediated by HDAC dysregulation. The narrative also states environmental or synthetic advantages versus organophosphorus or phosphorus-based Horner-Wadsworth-Emmons approaches, including reduced waste and recyclable catalysts/solvents.
Claims Coverage
The provided independent claim coverage is directed to a thioester compound of Formula (XXV) or a pharmaceutically acceptable salt thereof. The claim scope includes extensive substituent definition elements for R1-R6, R8-R11, and R13-R14, with allowed ring/alkyl options, optional substitution sets, and specific constraints on how paired substituents relate to ring formation. In total, the merged claim coverage reflects four inventive features.
Thioester compound of formula (XXV)
A thioester compound of Formula (XXV) or a pharmaceutically acceptable salt thereof, with R1 and R2 independently selected from H, C1-C10 alkyl, and C3-C7 cycloalkyl, or taken together forming a C3-C7 cycloalkyl or C3-C7 heterocycloalkyl with optional substituents; and with R3, R4, R5, and R6 similarly defined.
Substituent options for R8-R11 and optional functional substituents
R8 and R9 are independently selected from H, C1-C10 alkyl, and C3-C7 cycloalkyl, with optional substitution by C1-C10 alkyl, C3-C7 cycloalkyl, C3-C7 heterocycloalkyl, aryl, heteroaryl, halo, hydroxyl, CN, COOH, CF3, OCH2F, OCHF2, OC1-C10 alkyl, O-aryl, O-heteroaryl, NR8R9, NR8C(O)R9, NR8C(O)OR9, NR8CO2R9, and C(O)NR8R9; and R10 and R11 are independently selected from H, C1-C10 alkyl, and C3-C7 cycloalkyl.
Substituent options for R13-R14
R13 and R14 are independently selected from H, C1-C10 alkyl, C3-C7 cycloalkyl, C3-C7 heterocycloalkyl, aryl, and heteroaryl.
Pharmaceutically acceptable salt form
The thioester compound of Formula (XXV) is provided as a pharmaceutically acceptable salt thereof.
Across the provided claim set, the coverage focuses on a Formula (XXV) thioester compound defined by extensive position-by-position substituent constraints and optional functional groups, together with pharmaceutically acceptable salt forms.
Stated Advantages
Environmental or synthetic advantages versus organophosphorus reagent routes, including reduced waste and recyclable catalysts/solvents.
Compounds are described as histone deacetylase (HDAC) inhibitors for diseases mediated by HDAC dysregulation, including cancer, inflammatory, autoimmune, allergic, and CNS indications.
Documented Applications
Treating disorders linked to inhibited histone deacetylase by administering a compound as specified in claim 1.
Treating diseases mediated by HDAC dysregulation, including cancer, inflammatory, autoimmune, allergic, and CNS indications.
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