Small molecule direct inhibitors of KEAP1-NRF2 protein-protein interaction
AssigneeRutgers, The State University of New Jersey
InventorsLongqin Hu, Dhulfiqar A. Abed
Life of this patent
Estimating the term…
Abstract
This patent document discloses novel compounds and methods of preventing or treating diseases or conditions related to Keap1-Nrf2 interaction activity by use of the novel compounds. As direct inhibitors of Keap1-Nrf2 interaction, the compounds disclosed herein are more specific and free of various undesirable effects than existing indirect inhibitors, and are potential dmg candidates of chemopreventive and therapeutic agents for treatment of various diseases or conditions involving oxidative stress and/or inflammation, including but not limited to cancers, diabetes, Alzheimer's, Parkinson's, and inflammatory bowel disease including ulcerative colitis.
Claims21
A compound or
- a pharmaceutically acceptable salt, an isomer, or a prodrug thereof, wherein the compound is Formula I or Formula II,
- wherein Formula I is defined as follows:
- R1 is
- (a) hydrogen;
- or
- (b) two R1 groups link up to each other together with the carbons they are attached to and ring C to form a ring;
- R2 is C1-C4 alkyl;
- R3 is carboxylic acid or carboxamide or tetrazole;
- R4 is selected from the group consisting of hydrogen, C1-C4 alkoxy, C1-C6 alkyl, halogen, CF3, sulfonamido, amido, carboxamide, amino, nitro, trifluoroacetamido, aryl, heteoaryl, and aryl-C1-C2 alkoxy;
- R5 is selected from the group consisting of hydrogen, C1-C6 alkyl, C1-C4 alkoxy, halogen, CF3, sulfonamido, amido, trifluoroacetamido, aryl, heteoaryl, or aryl-C1-C2 alkoxy;
- alternatively R4 and R5 link up together with the ring to which they are attached to form a bicylic or tricyclic ring;
- R6 is hydrogen, C1-C6 alkyl, halogen, or CF3;
- R7 is hydrogen, halogen, C1-C3 alkyl, or C1-C3 alkoxy;
- provided that when the two R1 groups link up to each other together with the carbons they are attached to and ring C to form a ring, the compound is one of (a), (b), (c), and (d):
- (a) the compound is represented as Formula I-a
- Wherein
- n is an integer of 0 to 5 inclusive;
- Ra is selected from the group consisting of —CONRcRd, aryl, heteroaryl, O-aryl, S-aryl, O-heteroaryl, S-heteroaryl, and phthalimide, wherein the aryl, heteroaryl, O-aryl, S-aryl, O-heteroaryl, S-heteroaryl, or phthalimide is optionally substituted with halogen or C1-C4 alkyl, and wherein Rc and Rd are independently H or alkyl, or Rc and Rd link up to form a ring 3 to 8 membered carbocycle or heterocycle;
- (b) the compound is represented as Formula I-b
- (c) the compound is represented as Formula I-c
- wherein R4 is selected from the group consisting of sulfonamido, trifluoroacetamido, aryl, heteoaryl, and aryl-C1-C2 alkoxy;
- and
- (d) R4 and R5 link up together with the ring to which they are attached to form a bicylic ring, wherein at least one of the ring atom in the bicyclic ring is a sp3 hybridized carbon, further wherein the bicyclic ring is optionally substituted with halogen or C1-C4 alkyl;
- and
- Formula II is defined as follows:
- wherein X is S or NRa;
- Ra is hydrogen or C1-C4 alkyl;
- R1 and R2 are independently carboxylic acid (COOH) or tetrazole;
- R3 and R4 are independently selected from the group consisting of C1-C4 alkoxy, C1-C6 alkyl, halogen, CF3, sulfonamido, amido, trifluoroacetamido, aryl, heteoaryl, and aryl-C1-C2 alkoxy;
- R5 is hydrogen, C1-C4 alkyl, or halogen;
- and
- n in each instance is independently an integer of 1 to 3, inclusive.
Dependencies are inferred from the claim text.