Macrolides with modified desosamine sugars and uses thereof

Patent metadata

Field	Value
Publication number	US-10640528-B2
Application number	US-201615558896-A
Country	US
Kind code	B2
Filing date	Mar 25, 2016
Priority date	Mar 25, 2015
Publication date	May 5, 2020
Grant date	May 5, 2020

Abstract

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.

First claim

What is claimed is:

1. A compound of Formula (I-c):

or pharmaceutically acceptable salt thereof, wherein:
X is —NR B — or —O—;
R Z2 is hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, acyl, or a nitrogen protecting group;
R A is hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, —C(═O)-L S2 -R S , —C(═NR SN2 )-L S2 -R S , —S(═O)-L S2 -R S , —S(═O) 2 -L S2 -R S , a nitrogen protecting group when attached to a nitrogen atom, or an oxygen protecting group when attached to an oxygen atom, and R SN2 is independently hydrogen, optionally substituted C 1 -C 6 alkyl, or a nitrogen protecting group;
R B is hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, or a nitrogen protecting group;
or R A and R B are taken together to form ═N 2 or an optionally substituted heterocyclyl or heteroaryl ring;
L S2 is a bond, —NR S —, —O—, or —S—, or a linking group selected from the group consisting of optionally substituted alkylene, optionally substituted alkenylene, optionally substituted alkynylene, optionally substituted heteroalkylene, optionally substituted heteroalkenylene, and optionally substituted heteroalkynylene, and combinations thereof;
each R S is independently hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, an oxygen protecting group when attached to an oxygen atom, a nitrogen protecting group when attached to a nitrogen atom, or a sulfur protecting group when attached to a sulfur atom, or two R S groups attached to the same nitrogen atom are joined to form an optionally substituted heterocyclyl or heteroaryl ring;
each of R S4a and R S4b is independently hydrogen, halogen, optionally substituted C 1 -C 6 alkyl, or —OR SO ;
each of R S6a and R S6b is independently hydrogen, halogen, or optionally substituted C 1 -C 6 alkyl;
each R SN is independently hydrogen, optionally substituted C 1 -C 6 alkyl, or a nitrogen protecting group, or two R SN groups attached to the same nitrogen atom are joined to form an optionally substituted heterocyclyl or heteroaryl ring;
each R SO is independently hydrogen, optionally substituted C 1 -C 6 alkyl, a carbohydrate, or an oxygen protecting group;
each of R 1a and R 1b is independently hydrogen, halogen, acyl, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, or optionally substituted heteroaryl;
each of R 2a and R 2b is independently hydrogen, halogen, optionally substituted alkyl, or optionally substituted alkenyl;
each of R 3 and R 4 is independently hydrogen, halogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, or —OR 3a ;
each R 3a is independently hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, an oxygen protecting group, or of formula:

each L C3 is independently a bond, or is a linking group selected from the group consisting of optionally substituted alkylene, optionally substituted alkenylene, optionally substituted alkynylene; optionally substituted heteroalkylene, optionally substituted heteroalkenylene, and optionally substituted heteroalkynylene, and combinations thereof;
each A 3 is independently optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, or optionally substituted heteroaryl;
each of R 5a and R 5b is independently hydrogen, halogen, optionally substituted alkyl, optionally substituted carbocyclyl, or optionally substituted heterocyclyl;
R 6 is hydrogen, halogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted heteroaryl, or optionally substituted heteroaralkyl;
R 10 is hydrogen, halogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted heteroaryl, or optionally substituted heteroaralkyl;
R 7 is hydrogen, halogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, or optionally substituted heteroaryl;
R 8 is hydrogen, halogen, or optionally substituted C 1 -C 6 alkyl;
R 14 is hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, a nitrogen protecting group, or of formula:

L C1 is a bond, or a linking group selected from the group consisting of optionally substituted alkylene, optionally substituted alkenylene, optionally substituted alkynylene; optionally substituted heteroalkylene, optionally substituted heteroalkenylene, and optionally substituted heteroalkynylene, and combinations thereof;
A 1 is a leaving group (LG), —SH, —OH, —NH 2 , —NH—NH 2 , —N 2 , —N 3 , —O—NH 2 , —CCH, —OC(═O)R Z8 , —C(═O)OR Z8 , or of formula:

A is —NH—, —NH—NH—, —NH—O—, —O—NH—, —S—, —SS—, —O—, or of formula:

Q is —NH—, —NH—NH—, —O—NH—, —NH—O—, —S—, or —O—;
L C2 is a bond, or a linking group selected from the group consisting of optionally substituted alkylene, optionally substituted alkenylene, optionally substituted alkynylene; optionally substituted heteroalkylene, optionally substituted heteroalkenylene, and optionally substituted heteroalkynylene, and combinations thereof;
R W1 is hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, or a nitrogen protecting group;
each R W2 is independently hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optional

Assignees

• Harvard College
• President And Fellows Of Havard College

Inventors

• Myers Andrew G
• Seiple Ian Bass
• Zhang Ziyang

Classifications

• A61P31/00

  Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics · CPC title

• C07H15/26

  Acyclic or carbocyclic radicals, substituted by hetero rings · CPC title

• A61P29/00

  Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID] · CPC title

• C07H1/00

  Processes for the preparation of sugar derivatives · CPC title

• A61P33/00

  Antiparasitic agents · CPC title