Sugar derivatives and uses thereof to prepare novel senolytic agents
Inventors
Keitz, Paul • Bergnes, Gus • Gallop, Mark A. • Quarta, Marco
Assignees
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Publication Number
US-11897915-B2
Publication Date
2024-02-13
Expiration Date
Abstract
Provided herein are novel sugar derivatives which are intermediates for preparing senolytic agents that selectively kill senescent cells associated with numerous pathologies and diseases, including age-related pathologies and diseases.
Core Innovation
The patent describes carbohydrate-derived compounds of Formula (I)/(II) and Formula (III)/(IV) as intermediates to make senolytic agents designed as non-toxic prodrugs activated by hydrolase enzymes preferentially accumulating in senescent cells. The document defines compounds with detailed structural definitions of substituents R1-R19 and multiple allowed functional group options, including alternative structural motifs formed from R3 and R4.
The core concept includes a compound of Formula (II), including pharmaceutically available salts, hydrates, and solvates, and a family of structurally defined compound variants via substituent selection rules. The definitions include alternative 5 membered cyclic acetal substituted by R19 at the acetal carbon or alternative 5 membered cyclic carbonate constructions formed from R3 and R4.
Exemplary sugar structures, tables, and labeled synthetic intermediates are presented, and the document includes illustrative exemplary synthesis routes and example preparation steps for obtaining the defined compounds. The described content centers on carbohydrate-derived intermediates and fluorinated and aminooxy derivatives corresponding to the broader defined compound space of Formula (II).
Claims Coverage
The consolidated claim coverage includes two independent claims. One independent claim is directed to a compound of Formula (II) with extensive substituent scope across R1-R19, including alternative cyclic acetal/cyclic carbonate constructions and pharmaceutically acceptable salt, hydrate and solvate forms; the other independent claim recites a compound having a structure, but the structural details are not present in the provided excerpt.
Compound of Formula (II) with pharmaceutically available salt, hydrate and solvate forms
A compound having Formula (II) or pharmaceutically available salts, hydrate and solvates thereof, with R1 -NH2; R2 -H or -F; R3 and R4 selected from H, F, OH, OC(O)R11 or OC(O)OR12, together with the specified substituent definitions for R5, R6, R7, R8, R9-R18 and R19.
Alternative 5 membered cyclic acetal or cyclic carbonate formed from R3 and R4
Where both R3 and R4 together with the atoms to which they are bonded form a 5 membered cyclic acetal substituted by R19 at the acetal carbon, or where both R3 and R4 together with the atoms to which they are bonded form a 5 membered cyclic carbonate.
Substituent scope for R9-R18 and R19
R9-R18 are independently selected from alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, substituted aryl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, cycloheteroalkyl, substituted cycloheteroalkyl, cycloheteroalkenyl, substituted cycloheteroalkenyl, heteroaryl or substituted heteroaryl, and R19 is alkyl, substituted alkyl, aryl, substituted aryl, cycloalkyl, substituted cycloalkyl, cycloheteroalkyl, substituted cycloheteroalkyl, heteroaryl or substituted heteroaryl.
Compound having the structure
A compound having the structure, with structural details not included in the provided excerpt.
The claim coverage is dominated by Formula (II) defining specific substituent selections for R1-R19, allowing alternative constructions where R3 and R4 form either a 5 membered cyclic acetal substituted by R19 or a 5 membered cyclic carbonate, together with broad substituent scope for R9-R18 and R19 and inclusion of pharmaceutically acceptable salt, hydrate and solvate forms. A second independent claim recites a compound having a structure, but the actual structural content is not present in the excerpt.
Stated Advantages
Non-toxic prodrugs that are activated by hydrolase enzymes preferentially accumulating in senescent cells.
Compounds act preferentially on senescent cells while being non-toxic in an unactivated prodrug form.
Documented Applications
Senolytic agents.
Intermediates to make senolytic agents.
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