Synthetic triterpenoids with nitrogen-based substituents at c-17 and methods of use thereof

Patent metadata

Field	Value
Publication number	US-2023111914-A1
Application number	US-202017757701-A
Country	US
Kind code	A1
Filing date	Dec 18, 2020
Priority date	Dec 19, 2019
Publication date	Apr 13, 2023
Grant date	—

Abstract

In some aspects, the present disclosure provides compounds of the formula: (I) and (II), wherein the variables are defined herein. Also provided are pharmaceutical compositions thereof. In some aspects, the compounds and compositions provided herein may be used as antioxidant inflammation modulators. In some aspects, the present disclosure provides methods wherein the compounds and composition described herein are used for the treatment of diseases and disorders associated with inflammation and cancer.

First claim

What is claimed is:

1 . A compound of the formula:

wherein:
R 1 is hydrogen; or
alkyl (C≤8) , substituted alkyl (C≤8) , a monovalent amino protecting group, or —C(O)R 4 , wherein:
R 4 is hydrogen; or
alkyl (C≤8) , alkenyl (C≤8) , alkynyl (C≤8) , alkoxy (C≤8) , alkylamino (C≤8) , dialkylamino (C≤8) , cycloalkyl (C≤8) , cycloalkoxy (C≤8) , cycloalkylamino (C≤8) , heterocyclo-alkyl (C≤8) , or a substituted version of any one of these groups; or

R 1 and R 2 are taken together as defined below;

R 2 is alkyl (C≤8) or substituted alkyl (C≤8) ; or
—NR c R d , wherein:
R c and R d are each independently hydrogen, alkyl (C≤8) , substituted alkyl (C≤8) , acyl (C≤8) , substituted acyl (C≤8) , or a monovalent amino protecting group; or

—C(O)R 5 , wherein:
R 5 is hydrogen; or
alkyl (C≤8) , alkenyl (C≤8) , alkynyl (C≤8) , alkylamino (C≤8) , dialkylamino (C≤8) , cycloalkyl (C≤8) , cycloalkoxy (C≤8) , cycloalkylamino (C≤8) , heterocycloalkyl (C≤8) , or a substituted version of any one of these groups; or

R 2 and R 1 are taken together as defined below;

R 1 and R 2 , when taken together with the nitrogen atom of the —NR 1 R 2 group, is N-heteroaryl (C≤8) , substituted N-heteroaryl (C≤8) , N-heterocycloalkyl (C≤8) , substituted N-heterocycloalkyl (C≤8) , or 3-oxo-1-(t-butoxycarbonyl)pyrazolidin-2-yl;
R 3 and R 3 ′ are each independently hydrogen, alkyl (C≤8) , or substituted alkyl (C≤8) ; and
R 6 is hydrogen, hydroxy, or amino; or
acyloxy (C≤8) , alkoxy (C≤8) , alkylamino (C≤8) , dialkylamino (C≤8) , amido (C≤8) , or a substituted version of any of these groups; or

a compound of the formula:

wherein:
R 1 is hydrogen; or
alkyl (C≤8) or substituted alkyl (C≤8) , or a monovalent amino protecting group; or
R 1 and R 2 are taken together as defined below;

R 2 is —NR c R d , wherein:
R c and R d are each independently hydrogen, alkyl (C≤8) , substituted alkyl (C≤8) , acyl (C≤8) , substituted acyl (C≤8) , or a monovalent amino protecting group; or
R 1 and R 2 are taken together as defined below;

R 1 and R 2 , when taken together with the nitrogen atom of the —NR 1 R 2 group, is N-heteroaryl (C≤8) , substituted N-heteroaryl (C≤8) , N-heterocycloalkyl (C≤8) , substituted N-heterocycloalkyl (C≤8) , or 3-oxo-1-(t-butoxycarbonyl)pyrazolidin-2-yl;
R 3 and R 3 ′ are each independently hydrogen, alkyl (C≤8) , or substituted alkyl (C≤8) ; and
R 6 is hydrogen, hydroxy, or amino; or
acyloxy (C≤8) , alkoxy (C≤8) , alkylamino (C≤8) , dialkylamino (C≤8) , amido (C≤8) , or a substituted version of any of these groups;

or a pharmaceutically acceptable salt of either of these formulae.

2 . The compound of claim 1 , wherein the compound is further defined as:

wherein:
R 1 is hydrogen; or
alkyl (C≤8) , substituted alkyl (C≤8) , a monovalent amino protecting group, or —C(O)R 4 , wherein:
R 4 is hydrogen; or
alkyl (C≤8) , alkenyl (C≤8) , alkynyl (C≤8) , alkoxy (C≤8) , alkylamino (C≤8) , dialkylamino (C≤8) , cycloalkyl (C≤8) , cycloalkoxy (C≤8) , cycloalkylamino (C≤8) , heterocyclo-alkyl (C≤8) , or a substituted version of any one of these groups; or

R 1 and R 2 are taken together as defined below;

R 2 is alkyl (C≤8) or substituted alkyl (C≤8) ; or
—NR c R d , wherein:
R c and R d are each independently hydrogen, alkyl (C≤8) , substituted alkyl (C≤8) , acyl (C≤8) , substituted acyl (C≤8) , or a monovalent amino protecting group; or

—C(O)R 5 , wherein:
R 5 is hydrogen; or
alkyl (C≤8) , alkenyl (C≤8) , alkynyl (C≤8) , alkylamino (C≤8) , dialkylamino (C≤8) , cycloalkyl (C≤8) , cycloalkoxy (C≤8) , cycloalkylamino (C≤8) , heterocycloalkyl (C≤8) , or a substituted version of any one of these groups; or

R 2 and R 1 are taken together as defined below;

R 1 and R 2 , when taken together with the nitrogen atom of the —NR 1 R 2 group, is N-heteroaryl (C≤8) , substituted N-heteroaryl (C≤8) , N-heterocycloalkyl (C≤8) , substituted N-heterocycloalkyl (C≤8) , or 3-oxo-1-(t-butoxycarbonyl)pyrazolidin-2-yl;
R 3 and R 3 ′ are each independently hydrogen, alkyl (C≤8) , or substituted alkyl (C≤8) ; and
R 6 is hydrogen, hydroxy, or amino; or
acyloxy (C≤8) , alkoxy (C≤8) , alkylamino (C≤8) , dialkylamino (C≤8) , amido (C≤8) , or a substituted version of any of these groups;

or a pharmaceutically acceptable salt thereof.

3 . The compound of either claim 1 or claim 2 , wherein the compound is further defined as:

wherein:
R 1 is hydrogen; or
alkyl (C≤8) , substituted alkyl (C≤8) , a monovalent amino protecting group, or —C(O)R 4 , wherein:
R 4 is hydrogen; or
alkyl (C≤8) , alkenyl (C≤8) , alkynyl (C≤8) , alkoxy (C≤8) , alkylamino (C≤8) , dialkylamino (C≤8) , cycloalkyl (C≤8) , cycloalkoxy (C≤8) , cycloalkylamino (C≤8) , heterocyclo-alkyl (C≤8) , or a substituted version of any one of these groups; or

R 1 and R 2 are taken together as defined below;

R 2 is alkyl (C≤8) or substituted alkyl (C≤8) ; or
—NR c R d , wherein:
R c and R d are each independently hydrogen, alkyl (C≤8) , substituted alkyl (C≤8) , acyl (C≤8) , substituted acyl (C≤8) , or a monovalent amino protecting group; or

—C(O)R 5 , wherein:
R 5 is hydrogen; or
alkyl (C≤8) , alkenyl (C≤8) , alkynyl (C≤8) , alkylamino (C≤8) , dialkylamino (C≤8) , cycloalkyl (C≤8) , cycloalkoxy (C≤8) , cycloalkylamino (C≤8) , heterocycloalkyl (C≤8) , or a substituted version of any one of these groups; or

R 2 and R 1 are taken together as defined below;

R 1 and R 2 , when taken together with the nitrogen atom of the —NR 1 R 2 group, is N-heteroaryl (C≤8) , substituted N-heteroaryl (C≤8) , N-heterocycloalkyl (C≤8) , substituted N-heterocycloalkyl (C≤8) , or 3-oxo-1-(t-butoxycarbonyl)pyrazolidin-2-yl; and
R 6 is hydrogen, hydroxy, or amino; or
acyloxy (C≤8) , alkoxy (C≤8) , alkylamino (C≤8) , dialkylamino (C≤8) , amido (C≤8) , or a substituted version of any of these groups;

or a pharmaceutically acceptable salt thereof.

4 . The compound according to any one of claims 1 - 3 , wherein the compound is further defined as:

wherein:
R 1 is hydrogen; or
alkyl (C≤8) , substituted alkyl (C≤8) , a monovalent amino protecting group, or —C(O)R 4 , wherein:
R 4 is hydrogen; or
alkyl (C≤8) , alkenyl (C≤8) , alkynyl (C≤8) , alkoxy (C≤8) , alkylamino (C≤8) , dialkylamino (C≤8) , cycloalkyl (C≤8) , cycloalkoxy (C≤8) , cycloalkylamino (C≤8) , heterocyclo-alkyl (C≤8) , or a substituted version of any one of these groups; or

R 1 and R 2 are taken together as defined below;

R 2 is alkyl (C≤8) or substituted alkyl (C≤8) ; or
—NR c R d , wherein:
R c and R d are each independently hydrogen, alkyl (C≤8) , substituted alkyl (C≤8) , acyl (C≤8) , substituted acyl (C≤8) , or a monovalent amino protecting group; or

—C(O)R 5 , wherein:
R 5 is hydrogen; or
alkyl (C≤8) , alkenyl (C≤8) , alkynyl (C≤8) , alkylamino (C≤8) , dialkylamino (C≤8) , cycloalkyl (C≤8) , cycloalkoxy (C≤8) , cycloalkylamino (C≤8) , heterocycloalkyl (C≤8) , or a substituted version of any one of these groups; or

R 2 and R 1 are taken together as defined below; and

R 1 and R 2 , when taken together with the nitrogen atom of the —NR 1 R 2 group, is N-heteroaryl (C≤8) , substituted N-heteroaryl (C≤8) , N-heterocycloalkyl (C≤8) , substi

Assignees

• Reata Pharmaceuticals Inc

Inventors

• Bender Christopher F
• Do Ha
• Jiang Xin
• Sun Haizhou
• Visnick Melean
• Janser Ingo
• Simons Lloyd J
• Schostarez Heinrich J

Classifications

• A61P35/00

  Antineoplastic agents · CPC title

• A61P25/08

  Antiepileptics; Anticonvulsants · CPC title

• A61P25/28

  for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia · CPC title

• A61P19/02

  for joint disorders, e.g. arthritis, arthrosis · CPC title

• C07J63/008 Primary

  Expansion of ring D by one atom, e.g. D homo steroids · CPC title