Harvard College

Other

President and Fellows of Havard College

Ziyang Zhang

Andrew G Myers

Ian Bass Seiple

Roger B Clark

Xiben Li

Takehiro Fukuzaki

Jonathan F Lawrence

Senkara Rao Allu

Wenying Wang

Wesley Francis Austin

Sushmita D Lahiri

Yoshitaka Ichikawa

Udara Anulal Premachandra Ilandari Dewage

Provided are macrolide compounds for the treatment of infectious diseases. The macrolides disclosed herein include 14-membered ketolides and 14-15-membered azaketolides, and may comprise modified sugars which are desosamine analogues. The disclosed macrolides may have a bicyclic structure. Also provided are pharmaceutical compositions and methods of treating infectious diseases, and in particular, disease which results from Gram negative bacteria using the disclosed macrolides. This disclosure additionally provides methods of preparing the macrolides by a strategy that enables late-stage modification of the 6'-position of the sugar moiety, thereby allowing facile access to previously difficult-to-make macrolide compounds.

Macrolides with modified desosamine sugars and uses thereof

Provided herein are methods of preparing macrolides by the coupling of an eastern and western half, followed by macrocyclization, to provide macrolides, including both known and novel macrolides. Intermediates in the synthesis of macrolides including the eastern and western halves are also provided. Pharmaceutical compositions and methods of treating infectious diseases and inflammatory conditions using the inventive macrolides are also provided. A general diastereoselective aldol methodology used in the synthesis of the western half is further provided.

Macrolides and methods of their preparation and use

Provided herein are macrolide compounds of Formula (I) and (I-N) for the treatment of infectious diseases and inflammatory conditions. The 14-membered ketolides and 14-, 15-, and 16-membered azaketolides described herein comprise modified sugars which are desosamine or mycaminose analogs. Pharmaceutical compositions and methods of treating infection diseases and inflammatory conditions using the inventive macrolides are also provided. This disclosure additionally provides methods of preparing the macrolides by the coupling of an eastern and western half. 

Provided herein are methods of preparing new 14-membered ketolides via coupling of an eastern and western half moiety, followed by macrocyclization, and optional functionalization. Intermediates in the synthesis of these ketolides including the eastern and western halves are also provided. Pharmaceutical compositions and methods of treating infectious diseases and inflammatory conditions using these ketolides are also provided.

14-membered ketolides and methods of their preparation and use

The present invention provides desosamine and mycaminose analogs and nitro sugars and methods for their preparation. The invention also provides methods of cyclizing a compound of Formula (A') with glyoxal to give a nitro sugar of Formula (B). Methods for the preparation of compound of Formula (D&#x2032;) are provided comprising cyclization of a nitro alcohol to give a nitro sugar and reduction and alkylation of the nitro sugar to give a desosamine, mycaminose, or an analog thereof. 

Synthesis of desosamines

Provided herein are methods of preparing new 14-membered ketolides via coupling of an eastern and western half moiety, followed by macro-cyclization, and optional functionalization. Intermediates in the synthesis of these ketolides including the eastern and western halves are also provided. Pharmaceutical compositions and methods of treating infectious diseases and inflammatory conditions using these ketolides are also provided.

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San Francisco, CA, United States of America

Ziyang Zhang