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C4-modified oleanolic acid derivatives for inhibition of IL-17 and other uses

A chemical compound, atomic technology, applied in biology and medicine, which can solve the problems of patients who cannot relieve symptoms, significant side effects, and life-threatening problems

Active Publication Date: 2018-07-17
REATA PHARMA INC
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, a large number of patients are not adequately relieved by these therapies or cannot tolerate them
Even in patients who do respond, side effects can be significant and potentially life-threatening due to immunosuppression or other complications

Method used

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  • C4-modified oleanolic acid derivatives for inhibition of IL-17 and other uses
  • C4-modified oleanolic acid derivatives for inhibition of IL-17 and other uses
  • C4-modified oleanolic acid derivatives for inhibition of IL-17 and other uses

Examples

Experimental program
Comparison scheme
Effect test

example 1

[1033] Example 1: Synthesis and Characterization

[1034] Process 1

[1035]

[1036] Reagents and conditions: a) NH 2 OH·HCl, NaOAc, CH 2 Cl 2 , MeOH, 60°C; b) AcOH, Ac 2 O; PhI(OAc) 2 , Pd(OAc) 2 , ClCH 2 CH 2 Cl, 60-80°C, 43% from 1; c) K 2 CO 3 , MeOH, room temperature; d) sodium bisulfite, EtOH aqueous solution, 80 ° C, 73% from 3; e) Jones reagent, acetone, 0 ° C; 80-120 ° C, vacuum, 81%; f) HCO 2 Et, NaOMe, MeOH, THF, 0°C-room temperature; NH 2 OH·HCl, aqueous EtOH, 55°C, 44%; g) NaOMe, MeOH, THF, 55°C, 51%; h) DBDMH, DMF, 0°C; Py, 55°C, 80%.

[1037] Process 2

[1038]

[1039] Reagents and conditions: a) HCO 2 Et, NaOMe, MeOH, 0°C; NH 2 OH·HCl, EtOH aqueous solution, 55°C, 57%; b) Jones reagent, acetone, 0°C-room temperature, 88%; c) TMSCHN 2 、Et 2 O, toluene, MeOH, 0°C, 84%; d) NaOMe, MeOH, 55°C, quantitative yield; e) DBDMH, DMF, 0°C; Py, 55°C, 77%.

[1040] Process 3

[1041]

[1042] Reagents and conditions: a) i) Jones reagent, acetone,...

example 2

[1335] Example 2: Bioactive Methods and Materials

[1336] A. Analysis of Nitric Oxide Production and Cell Viability

[1337] RAW 264.7 mouse macrophages were seeded in triplicate at a density of 30,000 cells per well in 96-well culture dishes in RPMI 1640+0.5% FBS and incubated at 37°C and 5% CO 2 Grow in a moist atmosphere. The next day, cells were pretreated with DMSO (vehicle) or test compounds (concentration range 0.4-200 nM or 2-1000 nM) for 2 hours, followed by recombinant mouse IFNγ (R&D Systems) for 24 hours . The nitric oxide concentration in the medium was determined using the Griess reagent system (Promega). Cell viability was determined using WST-1 reagent (Roche). Values ​​of test compound samples were normalized to values ​​of DMSO / IFNγ-treated samples. IC was determined based on inhibition of IFNγ-induced nitric oxide production normalized to cell viability 50 value.

[1338] B. AREc32 luciferase reporter assay

[1339] The AREc32 luciferase reporter as...

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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.

Description

[0001] This application claims priority to US Provisional Patent Application No. 62 / 222,632, filed September 23, 2015, which is hereby incorporated by reference in its entirety. technical field [0002] The present invention relates generally to the fields of biology and medicine. More specifically, the invention relates to compounds, compositions and methods for the treatment and prevention of diseases or conditions, such as those associated with the overproduction of IL-17. Background technique [0003] Inflammatory diseases, especially autoimmune diseases such as rheumatoid arthritis, osteoarthritis, psoriasis and multiple sclerosis, often have serious and long-term adverse effects on physical health and quality of life. In many patients, these diseases lead to severe disability and, in some cases (such as lupus and multiple sclerosis), can be life-threatening. Recent advances in treatment options, such as the development of therapeutic antibodies against tumor necrosis ...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07J63/00C07J71/00A61P29/00A61K31/58A61K31/585A61K31/56
CPCC07J71/0005C07J63/008A61P29/00Y02A50/30
Inventor 麦琳·维斯尼克江昕M·R·奥特玛芝塔斯·李B·W·卡普拉瑟威廉·H·洛克加里·波尔顿
Owner REATA PHARMA INC