Modular synthesis of aminoglycosides
Inventors
Calabrese, Andrew Antony • Kane, Timothy Robert • Hildebrandt, Darin • Lopez, Michael • Evdokimov, Nikolai • Cohen, Frederick • Bayrakdarian, Malken • XU, Sanijia • DESJARDINS, SAMUEL • SOUEIDAN, Olivier
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Assignees
Intellisyn R&d • Revagenix Inc
Member
Revagenix, IncRevagenix is a precision-therapeutics company specializing in the discovery and development of targeted medicines for serious chronic diseases, with a primary focus on respiratory conditions such as non-cystic fibrosis bronchiectasis. Leveraging a biology-driven, first-principles approach, the company engineers therapies optimized for disease biology, patient need, and real-world delivery requirements. The team brings experience spanning the entire drug lifecycle from discovery through commercialization and collaborates closely with public and private partners to accelerate advancement from early-stage science to clinical development.
Revagenix is a precision-therapeutics company specializing in the discovery and development of targeted medicines for serious chronic diseases, with a primary focus on respiratory conditions such as non-cystic fibrosis bronchiectasis. Leveraging a biology-driven, first-principles approach, the company engineers therapies optimized for disease biology, patient need, and real-world delivery requirements. The team brings experience spanning the entire drug lifecycle from discovery through commercialization and collaborates closely with public and private partners to accelerate advancement from early-stage science to clinical development.
Publication Number
US-12129274-B2
Publication Date
2024-10-29
Expiration Date
Abstract
The present disclosure relates to novel methods for preparing antibacterial aminoglycoside compounds and the compounds used in such preparations.
Core Innovation
The patent discloses multistep processes for preparing compounds of formula ABC-1 and ABCD-1, or salts thereof, by contacting a compound of formula A-9 with a compound of formula B-12 to yield an intermediate of formula AB-1. The intermediate AB-1 contains Pg2e as a hydroxyl protecting group, and the process selectively deprotects AB-1 by removing the Pg2e moiety to yield AB-3 or a salt thereof.
After selective deprotection, AB-3 is contacted with a compound of formula C-1 or CD-1, where LVG4 or LVG5 is a leaving group, to yield the target compound of formula ABC-1 or ABCD-1, or a salt thereof. Dependent refinements include additional removal of amino protecting groups and hydroxyl protecting groups when present to yield further compound forms such as ABCD-2.
The disclosure also defines extensive substituent and ring-variable embodiments for the compound families, including stereochemical definitions for ring systems and possible final forms such as salts, solvates, enantiomers, and diastereomers. Related descriptions mention modular synthetic routes to antibacterial aminoglycosides using protected carbohydrate building blocks, and further functionalized polycyclic or heterocyclic scaffold embodiments with azide, amino, hydroxyl, acetate, benzyl, and Cbz-related forms.
Claims Coverage
The consolidated claim coverage includes two independent process claims directed to multistep preparation of ABC-1 or ABCD-1, with a total of 6 merged inventive features. The claims center on formation of AB-1 from A-9 and B-12, selective removal of Pg2e to form AB-3, and final coupling with C-1 or CD-1 using defined leaving groups.
Multistep synthesis to form AB-1
Contacting a compound of formula A-9 with a compound of formula B-12, wherein LVG3 is a leaving group and Pg2e is a hydroxyl protecting group, to yield a compound of formula AB-1.
Selective deprotection of Pg2e to form AB-3
Selectively deprotecting AB-1 by removing the Pg2e group or Pg2e moiety to yield AB-3, or a salt thereof.
Final coupling with C-1 to form ABC-1
Contacting AB-3 with a compound of formula C-1, wherein LVG4 is a leaving group, to yield ABC-1, or a salt thereof.
Multistep synthesis to form AB-1 for ABCD-1
Contacting a compound of formula A-9 with a compound of formula B-12, wherein LVG3 is a leaving group and Pg2e is a hydroxyl protecting group, to yield a compound of formula AB-1.
Selective deprotection of Pg2e to form AB-3 for ABCD-1
Selectively deprotecting AB-1 by removing the Pg2e moiety to yield AB-3, or a salt thereof.
Final coupling with CD-1 to form ABCD-1
Contacting AB-3 with a compound of formula CD-1, wherein LVG5 is a leaving group, to yield ABCD-1, or a salt thereof.
The claims are consolidated around a protected-intermediate sequence: A-9 and B-12 form AB-1, Pg2e is selectively removed to give AB-3, and AB-3 is coupled with C-1 or CD-1 to yield ABC-1 or ABCD-1, optionally as salts.
Stated Advantages
Provides detailed synthetic work-up and characterization for stereochemically defined azido/aminated sugar-like polyol/oligosaccharide intermediates.
Reports high yields for multiple illustrated intermediates and transformations.
Uses NMR (1H) and MS characterization for the described intermediate compounds and conversions.
Documented Applications
Preparation of compounds of formula ABC-1 or salts thereof via multistep contacting, selective deprotection of a hydroxyl protecting group, and further contacting to reach the target compound.
Preparation of compounds of formula ABCD-1 or salts thereof via multistep contacting, selective deprotection of Pg2e, and further contacting to yield ABCD-1.
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