Macrolides and methods of their preparation and use

Patent metadata

Field	Value
Publication number	US-9982005-B2
Application number	US-201414781719-A
Country	US
Kind code	B2
Filing date	Apr 4, 2014
Priority date	Apr 4, 2013
Publication date	May 29, 2018
Grant date	May 29, 2018

Abstract

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.

First claim

What is claimed is:

1. A compound of formula:

or a salt thereof;
wherein:
each instance of R 1a , R 1b , R 2a , and R 2b is independently hydrogen, halogen, carbonyl, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocylyl, optionally substituted aryl, optionally substituted heteroaryl, or wherein R 1a and R 1b or R 2a and R 2b can be taken together to form

R Z2 is hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocylyl, optionally substituted aryl, optionally substituted heteroaryl, hydroxyl, substituted hydroxyl, amino, substituted amino, —C(═O)R Z8 , —C(═O)OR Z8 , —C(═O)N(R Z8 ) 2 , or a nitrogen protecting group;
R Z3 is hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocylyl, optionally substituted aryl, or optionally substituted heteroaryl;
L 3 is a group of formula:

R 3 is hydrogen, optionally substituted alkyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, —C(═O)R Z8 , —C(═O)OR Z8 , —C(═O)N(R Z8 ) 2 , an oxygen protecting group, or a group of formula:

R 4 is hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl;
each instance of R 18 and R 19 independently hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, or optionally substituted heteroaryl;
each instance of R 20 and R 21 is independently hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, hydroxyl, substituted hydroxyl, thiol, substituted thiol, amino, substituted amino, halogen, carbonyl, or R 20 and R 21 are joined to form an optionally substituted cyclopropyl or an oxiranyl ring;
each instance of R 5a and R 5b is independently hydrogen, halogen, silyl, optionally substituted alkyl, optionally substituted carbocyclyl, or optionally substituted heterocyclyl;
R 6 is hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted heteroaryl, optionally substituted heteroaralkyl, hydroxyl, substituted hydroxyl, thiol, substituted thiol, amino, substituted amino, carbonyl, silyl, or halogen;
R 7 and R 8 are each independently hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, or optionally substituted heteroaryl;
R 9 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)R Z8 , —C(═O)OR Z8 , —C(═O)N(R Z8 ) 2 , an oxygen protecting group, or a carbohydrate;
R 10 is hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, hydroxyl, substituted hydroxyl, thiol, substituted thiol, amino, substituted amino, carbonyl, silyl, and halogen;
G 3 is —O—, —S—, or —N(R G1 )—, wherein R G1 is hydrogen, optionally substituted alkyl, or a nitrogen protecting group;
G 1 is —NR 13 R 14 ;

R 11 and R 13 are joined as a group of formula —C(═O)— to provide a cyclic carbamate;
R 14 is hydrogen, or a group of formula:

each instance of L C1 and L C2 is independently 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, optionally substituted heteroalkynylene, and combinations thereof;
each instance of A 1 is independently a leaving group (LG), —SH, —OH, —NH 2 , —NH—NH 2 , —N 3 , —O—NH 2 ,
C(═O)R X1 ,

A is

W is O, S, or NR W1 ;

R W1 is hydrogen, substituted or unsubstituted alkyl; substituted or unsubstituted alkenyl; substituted or unsubstituted alkynyl; substituted or unsubstituted carbocyclyl; substituted or unsubstituted heterocyclyl; substituted or unsubstituted aryl; substituted or unsubstituted heteroaryl; or a nitrogen protecting group;
R W2 is hydrogen, optionally substituted alkyl; optionally substituted alkenyl; optionally substituted alkynyl; optionally substituted carbocyclyl; optionally substituted heterocyclyl;

optionally substituted aryl; or optionally substituted heteroaryl;
R X1 is hydrogen, halogen, or —OR X2 , wherein R X2 is hydrogen; optionally substituted alkenyl; optionally substituted alkynyl; optionally substituted carbocyclyl; optionally substituted heterocyclyl; optionally substituted aryl; optionally substituted heteroaryl; or an oxygen protecting group;
R 23 is optionally substituted aryl; or optionally substituted heteroaryl; and
each instance of R Z8 is independently hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocylyl, optionally substituted aryl, or optionally substituted heteroaryl, or two R z8 groups are joined to form an optionally substituted heterocylyl or optionally substituted heteroaryl ring;
or A is optionally substituted carbocyclyl.

2. The compound of claim 1 , or a salt thereof, wherein each instance of R 5a and R 5b is independently hydrogen, optionally substituted alkyl, or halogen.

3. The compound of claim 1 , or a salt thereof, wherein R 6 is optionally substituted alkyl, optionally substituted alkenyl, optionally substituted aralkyl, or optionally

Assignees

• Harvard College

Inventors

• Myers Andrew G
• Seiple Ian Bass
• Zhang Ziyang

Classifications

• A61P33/00

  Antiparasitic agents · CPC title

• A61P29/00

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

• A61P31/04

  Antibacterial agents · CPC title

• A61P31/00

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

• C07H17/00 Primary

  Compounds containing heterocyclic radicals directly attached to hetero atoms of saccharide radicals · CPC title