Macrolides and methods of their preparation and use

Patent metadata

Field	Value
Publication number	US-10913764-B2
Application number	US-201815946658-A
Country	US
Kind code	B2
Filing date	Apr 5, 2018
Priority date	Apr 4, 2013
Publication date	Feb 9, 2021
Grant date	Feb 9, 2021

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:
Z is a group of formula:

wherein:
L 1 and L 2 are each a bond;
z1 and z2 are each independently 0 or 1;
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 heterocyclyl, optionally substituted aryl, or optionally substituted heteroaryl, or wherein R 1 a 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 heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, —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 heterocyclyl, optionally substituted aryl, or optionally substituted heteroaryl;
L 3 is a group of formula:

represents a single or double bond;
R 3 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 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, or 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, or 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 or optionally substituted alkyl;
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 optionally substituted alkyl;
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, or halogen;
G 3 is —O—;
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;
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),

A is

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, or two R W2 groups are joined to form an optionally substituted cyclic moiety;
R 23 is optionally substituted alkyl optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl optionally substituted heterocyclyl, 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 heterocyclyl, optionally substituted aryl, or optionally substituted heteroaryl, or two R Z8 groups are joined to form an optionally substituted heterocyclyl or optionally substituted heteroaryl ring.

2. The compound of claim 1 , wherein the compound is of formula:

or a salt thereof.

3. The compound of claim 1 , wherein the compound is of formula:

or a salt thereof.

4. The compound of claim 1 or 2 , or a salt thereof, wherein
L 1 and L 2 are each a bond;
z1 and z2 are each 1;
each instance of R 1a , R 1b , R 2a , and R 2b is independently hydrogen, optionally substituted alkyl, optionally substituted alkenyl, or optionally substituted carbocyclyl;
R Z2 is hydrogen, optionally substituted alkyl, or —C(═O)R Z8 ; and
R Z3 is hydrogen or optionally substituted alkyl.

5. The compound of claim 1 , or a salt thereof, wherein L 3 is a group of formula:

6. The compound of claim 5 , or a salt thereof, wherein R 3 is optionally substituted alkyl.

7. The compound of claim 1 , or a salt thereof, wherein R 3 is a group of formula:

8. The compound of claim 7 , or a salt thereof, wherein R 23 is of formula:

Assignees

• Harvard College

Inventors

• Myers Andrew G
• Seiple Ian Bass
• Zhang Ziyang

Classifications

• C07H17/00 Primary

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

• C07D498/08

  Bridged systems · CPC title

• A61P31/04

  Antibacterial agents · CPC title

• A61K31/706

  containing six-membered rings with nitrogen as a ring hetero atom · CPC title

• A61K31/7056

  containing five-membered rings with nitrogen as a ring hetero atom · CPC title