C4-modified oleanolic acid derivatives for inhibition of IL-17 and other uses
Inventors
Visnick, Melean • Jiang, Xin • HOTEMA, Martha R. • Lee, Chitase • Caprathe, Bradley William • Roark, William H. • Bolton, Gary L.
Assignees
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Publication Number
US-11584775-B2
Publication Date
2023-02-21
Expiration Date
Abstract
Disclosed herein are C4 modified oleanolic acid derivatives of the formula: Formula (X) or Formula (XII), as well as analogs thereof, wherein the variables are defined herein. In addition, disclosed herein are pharmaceutical compositions of these derivatives or analogs, methods for their manufacture, and methods for their use, including for the prevention and treatment of diseases or disorders associated with overproduction of IL-17.
Core Innovation
The disclosure provides compounds defined by a specified chemical formula in which substituents are controlled by variables R1, R2, R3, and Y. The variable Y is heteroaryl (C8 or less) or substituted heteroaryl, including oxadiazolyl examples, and the embodiments include permitted structural space for R2, such as amino, acyloxy, and alkylsilyloxy groups, together with R3 substituents such as hydrogen, hydroxy, alkoxy, and acyloxy.
The disclosed compounds include pharmaceutically acceptable salts, acetals, hemiacetals, and carbonitrile or nitrile-containing scaffold variants with carbonyl functionalities. The examples further describe ester-like or carbonyl-containing groups and fluorinated substituents such as difluoromethyl, F, CF3, and CF2.
The embodiments further describe stereochemical constraints for at least some members, including an orientation or configuration related to carbon atom 4. Multiple structure drawings illustrate member examples that conform to the stated variable definitions for R1, R2, R3, and Y, including cases with epoxidized and non-epoxidized double bond at atoms 1-2.
Claims Coverage
The consolidated claim coverage includes multiple independent formula-based compound claims and related composition claims. Across the claims, the inventive features center on a defined chemical formula with substituent variables, the Y taken together with R3 linkage, optional fluorine replacement in substituted modifiers, and pharmaceutically acceptable salts; one composition claim adds excipient or pharmaceutically acceptable carrier. The coverage spans four recurring inventive features.
Compound of defined formula with substituent variables
A compound of the formula wherein R1 is alkyl (C8 or less), R3 is hydrogen or hydroxy, or R3 is taken together with Y as described below, and Y is heteroaryl (C8 or less) or substituted heteroaryl (C8 or less).
Y taken together with R3 as a C(O)O linkage
Y is taken together with R3 and is C(O)O.
Permitted C(O)Rc and NRdC(O)Re substituent patterns
The compound includes substituent patterns including C(O)Rc, wherein Rc is hydroxy, alkoxy (C8 or less), alkylamino (C8 or less), dialkylamino (C8 or less), or a substituted version of any of these groups; or NRdC(O)Re, wherein Rd is hydrogen and Re is alkyl (C8 or less), alkoxy (C8 or less), or a substituted version of any of these groups.
Optional fluorination and pharmaceutically acceptable salts
When the terms alkyl, alkoxy, alkylamino, dialkylamino, and heteroaryl are used with the substituted modifier, one or more hydrogen atom has been independently replaced by F; or a pharmaceutically acceptable salt thereof.
Pharmaceutical composition including the claimed compound
A pharmaceutical composition that includes a compound of the claim family together with an excipient or a pharmaceutically acceptable carrier.
Overall, the claim set is directed to compounds defined by a specific formula with variable substituents R1, R3, and Y, explicit functional-group patterns C(O)Rc and NRdC(O)Re, a defined linkage when Y is taken together with R3 as C(O)O, optional F substitution on substituted modifiers, and pharmaceutically acceptable salts, with composition coverage for formulations containing excipient or carrier.
Stated Advantages
Retained hIL-17 inhibition with reduced NRF2 activation.
Reduced suppression of IFNγ-induced nitric oxide production.
Pharmacological advantages are discussed in the context of potency/functional thresholds (IC50 and EC2x).
Documented Applications
Methods of treating disease associated with dysregulated IL-17 by IL-17 inhibition and IL-17 activity inhibition sufficient to treat disease associated with dysregulated IL-17 and nitric oxide production.
Prevention and treatment of diseases associated with overproduction of IL-17.
Treatment/prevention contexts associated with IL-17/Th17 roles, including rheumatoid arthritis, osteoarthritis, psoriasis, multiple sclerosis, inflammatory bowel disease, vasculitis, atherosclerosis, cystic fibrosis, COPD, epilepsy, Alzheimer’s disease, Parkinson’s disease, ALS, and infectious disease contexts including Toxoplasma gondii and Leishmania.
Pharmaceutical compositions corresponding to the described compounds.
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