1,4,5-substituted 1,2,3-triazole analogues as antagonists of the pregnane X receptor

Patent metadata

Field	Value
Publication number	US-10550091-B2
Application number	US-201716085972-A
Country	US
Kind code	B2
Filing date	Mar 10, 2017
Priority date	Mar 25, 2016
Publication date	Feb 4, 2020
Grant date	Feb 4, 2020

Abstract

In an aspect, the invention relates to 1,4,5-substituted 1,2,3-triazole and 1,2,4,5-substituted imidazoles, which are modulators the pregnane X receptor (“PXR”); synthesis methods for making the compounds; pharmaceutical compositions comprising the compounds; and methods of modulating an adverse drug reaction in a mammal using the compounds and pharmaceutical compositions; methods of treatment of a disorder of uncontrolled cellular proliferation, such as a cancer, using the compounds and pharmaceutical compositions; methods of modulating pregnane X receptor activity in a mammal using the compounds and pharmaceutical compositions. This abstract is intended as a scanning tool for purposes of searching in the particular art and is not intended to be limiting of the present invention.

First claim

What is claimed is:

1. A method for modulating pregnane X receptor activity in a mammal comprising the step of administering to the mammal a therapeutically effective amount of at least one compound having a structure represented by a formula:

wherein R 1 is hydroxy, halogen, C1-C6 alkyl, C1-C6 alkoxy, and —(C1-C6)-OH; wherein R 2 is hydrogen, halogen, cyano, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 monohaloalkyl, C1-C6 polyhaloalkyl, —CO 2 H, —(C═O)H, —(C═O)-(C1-C6 alkyl), —(C═O)—O(C1-C6 alkyl); wherein R 3 is hydrogen, hydroxy, halogen, C1-C6 alkyl, C1-C6 alkoxy, and —(C1-C6)-OH; and wherein R 4 is methyl; or
wherein R 1 is hydroxy, halogen, C1-C6 alkyl, C1-C6 alkoxy, and —(C1-C6)-OH; wherein R 2 is halogen, cyano, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 monohaloalkyl, C1-C6 polyhaloalkyl, —CO 2 H, —(C═O)H, —(C═O)-(C1-C6 alkyl), —(C═O)—O(C1-C6 alkyl); wherein R 3 is hydroxy, halogen, C1-C6 alkyl, C1-C6 alkoxy, and —(C1-C6)-OH; and wherein R 4 is hydrogen, cyano, halogen, C1-C6 alkyl, C1-C6 monohaloalkyl, C1-C6 polyhaloalkyl, —(C═O)-(C1-C6 alkyl), —(C═O)—O(C1-C6 alkyl), —(C1-C6 alkyl)-(C═O)-(C1-C6 alkyl), —(C1-C6 alkyl)-(C═O)—O(C1-C6 alkyl), Ar 1 , or Cy 1 ;
wherein Ar 1 is monocyclic aryl or monocyclic heteroaryl substituted with 0, 1, 2, or 3 groups selected from halogen, hydroxy, cyano, amino, C1-C3 alkyl, C1-C3 hydroxyalkyl, C1-C3 monohaloalkyl, or C1-C3 polyhaloalkyl;
wherein Cy 1 is C3-C8 cycloalkyl or C2-C7 heterocycloalkyl substituted with 0, 1, 2, or 3 groups selected from halogen, hydroxy, cyano, amino, C1-C3 alkyl, C1-C3 hydroxyalkyl, C1-C3 monohaloalkyl, or C1-C3 polyhaloalkyl; and

wherein R 5 is hydrogen, halogen, hydroxy, or C1-C3 alkyl;
wherein R 6 is hydrogen, halogen, hydroxy, or C1-C3 alkyl; and
wherein R 7 is C1-C6 alkyl;
or a pharmaceutically acceptable salt thereof.

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

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

4. The method of claim 1 , wherein the mammal is a human.

5. The method of claim 1 , wherein R 1 is alkoxy and R 3 is alkoxy.

6. The method of claim 1 , wherein R 3 is methoxy.

7. The method of claim 1 , wherein R 4 is methyl.

8. The method of claim 1 , wherein R 7 is tert-butyl.

9. The method of claim 1 , wherein R 1 is hydroxy, halogen, methyl, ethyl, methoxy, or ethoxy; wherein R 2 is fluoro or methyl; wherein R 3 is hydroxy, halogen, methyl, ethyl, methoxy, or ethoxy; wherein R 4 is fluoro, chloro, bromo, cyano, methyl, ethyl, propyl, isopropyl, —CH 2 F, —CH 2 Cl, —(C═O)CH 3 , or —CH 2 (C═O)OCH 3 , wherein R 5 is hydrogen, hydroxy, or methyl; wherein R 6 is hydrogen, hydroxy, or methyl; and wherein R 7 is propyl, isopropyl, n-butyl, tert-butyl, or sec-butyl.

10. The method of claim 1 , wherein the compound has a structure represented by formula:

11. The method of claim 1 , wherein the compound has a structure represented by formula:

12. The method of claim 1 , wherein the compound is selected from:

13. The method of claim 1 , wherein the compound is selected from:

14. The method of claim 1 , wherein the compound is:

15. The method of claim 1 , wherein the compound is:

Assignees

• St Jude Childrens Res Hospital

Inventors

• Chen Taosheng
• Lin Wenwei
• Wang Yueming

Classifications

• A61P35/00

  Antineoplastic agents · CPC title

• A61K9/205

  Polysaccharides, e.g. alginate, gums; Cyclodextrin · CPC title

• A61K9/2054

  Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose · CPC title

• A61K9/0095

  Drinks; Beverages; Syrups; Compositions for reconstitution thereof, e.g. powders or tablets to be dispersed in a glass of water; Veterinary drenches (A61K9/0007 takes precedence; eatable gels or foams A61K9/0056; oral mucosa adhesive forms A61K9/006) · CPC title

• A61K9/2018

  Sugars, or sugar alcohols, e.g. lactose, mannitol; Derivatives thereof, e.g. polysorbates · CPC title