Hydrogen peroxide-responsive KEAP1-NRF2 ppi inhibitor prodrug, and preparation method therefor

Patent metadata

Field	Value
Publication number	US-12383535-B2
Application number	US-202017623882-A
Country	US
Kind code	B2
Filing date	Nov 16, 2020
Priority date	Nov 28, 2019
Publication date	Aug 12, 2025
Grant date	Aug 12, 2025

Abstract

The present application relates to a hydrogen peroxide-responsive Keap1-Nrf2 PPI inhibitor prodrug, and a preparation method therefor. The hydrogen peroxide-responsive Keap1-Nrf2 PPI inhibitor prodrug pro2 has a chemical structure as shown below. By modifying a key carboxyl pharmacophore in a Keap1-Nrf2 inhibitor with a H 2 O 2 -responsive thiazolidinone moiety, a novel ROS-responsive antioxidant prodrug pro2 is synthesized. The H 2 O 2 activated prodrug pro2 can simultaneously achieve targeted activation of Nrf2 and enhancement of therapeutic efficacy in the body. The prodrug is based on the concept of ROS activation-ROS clearance therapy, is the first example of a H 2 O 2 -responsive prodrug suitable for oral administration, and is expected to be used clinically by virtue of the characteristics of druggability and high targeting ability.

First claim

What is claimed is:

1. A prodrug pro2 of hydrogen peroxide-responsive Keap1-Nrf2 PPI inhibitor having the following structural formula:

2. A method for preparing a prodrug pro2, wherein a synthetic route is as follows:

wherein, the reagents and conditions in each step are as follows:
(b) Pd/C, H 2 , THF, rt, 4 h;
(c) 4-methoxybenzenesulfonyl chloride, Na 2 CO 3 , THF, 0° C., 2 h;
(d) 4-methoxybenzenesulfonyl chloride, toluene, pyridine, 100° C., 2 h;
(e) DMF, K 2 CO 3 , ethyl bromoacetate, rt, 3 h;
(f) LiOH, MeOH, H 2 O, 2 h; and
(g) thiazolidin-2-one, DMAP, DCC, DMF, rt, 6 h.

3. The method according to claim 2 , wherein compound 4 is synthesized by the following route:

wherein, the reagents and conditions in the step (a) are as follows: NH 2 OH·HCl, 95% ethanol, MeOH, 60° C., and 2 h.

4. A method for preparing a prodrug pro2 in preparing an anti-inflammatory drug, the prodrug pro2 having the following structural formula:

5. The method according to claim 4 , wherein the drug increases levels of Nrf2 and downstream antioxidant enzymes, and enhances the activation of the Nrf2-ARE system at a cellular level.

6. The method according to claim 4 , wherein the drug inhibits expression of pro-inflammatory factors IL-1β and IL-6 at a protein level.

7. The method according to claim 4 , wherein the drug is for oral administration.

Assignees

• Univ China Pharma

Inventors

• You Qidong
• Jiang Zhengyu
• Lu Mengchen
• Zhang Xian
• Zhao Jing
• Guo Xiaoke
• Xu Xiaoli
• Wang Lei

Classifications

• C07D277/14 Primary

  Oxygen atoms · CPC title

• A61P29/00

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

• A61K31/426 Primary

  1,3-Thiazoles · CPC title