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CN-122011078-A - Pentacyclic triterpene derivative, preparation method and application thereof

CN122011078ACN 122011078 ACN122011078 ACN 122011078ACN-122011078-A

Abstract

The invention relates to the fields of pharmaceutical chemistry and medicine, and discloses pentacyclic triterpene derivatives and application thereof in preventing and/or treating immune diseases. The pentacyclic triterpene derivative has the structure shown in the formula (I), has excellent immunoregulation effect on Tc1, tc17 and Th17 cells, and also provides application of the compound in preparation of medicines for preventing and/or treating immune diseases.

Inventors

  • WANG HONGLIN
  • LI QUN
  • ZHAO XINGE
  • CUI LINLIN
  • FANG ZILONG
  • MA MIN

Assignees

  • 上海博创源生物技术有限公司

Dates

Publication Date
20260512
Application Date
20241114
Priority Date
20241111

Claims (10)

  1. 1. A compound of formula (I) or an isomer, solvate or precursor thereof, or a pharmaceutically acceptable salt thereof, Wherein R1 comprises a group selected from the group consisting of: L is a linking group which is a bond, or a linear or branched C1-C6 alkylene chain, wherein the linear or branched C1-C6 alkylene is optionally substituted with hydroxymethyl or methyl; r2 is free or comprises a group selected from OH, NH2 or a substituted amino group comprising a linear or cyclic amino group comprising a group selected from the group consisting of:
  2. 2. A compound of formula (I) or an isomer, solvate or precursor thereof, or a pharmaceutically acceptable salt thereof, as claimed in claim 1, wherein the compound comprises a compound selected from:
  3. 3. Use of a compound of formula (I) or an isomer, solvate or precursor thereof, or a pharmaceutically acceptable salt thereof, as claimed in claim 1 or 2, for the manufacture of a pharmaceutical composition or kit for the prevention, alleviation or treatment of an immune disorder.
  4. 4. The use of a compound of formula (I) or an isomer, solvate or precursor thereof, or a pharmaceutically acceptable salt thereof, as claimed in claim 3, wherein the immune disease includes autoimmune disease, tumor; preferably, the autoimmune disease comprises: multiple sclerosis; depigmentation skin disease, preferably comprising vitiligo, albinism, pityriasis albus, leprosy, hypopigmentation after inflammation, progressive porphyria pigmentosa or tinea versicolor; Inflammatory skin diseases, preferably psoriasis, atopic dermatitis, alopecia areata; inflammatory enteritis.
  5. 5. The use of a compound of formula (I) or an isomer, solvate or precursor thereof, or a pharmaceutically acceptable salt thereof as claimed in claim 3, wherein the immune disorder includes a Tc1 cell over-elevation disorder, a Tc17 cell over-elevation disorder, a Th17 cell over-elevation disorder.
  6. 6. Use of a compound of formula (I) or an isomer, solvate or precursor thereof, or a pharmaceutically acceptable salt thereof, as claimed in claim 1 or 2, for the preparation of a reagent or kit for inhibiting differentiation of immune cells, including CD8 + T cells or CD4 + T cells; Preferably, the inhibition of immune cell differentiation comprises inhibition of differentiation of CD8 + T cells to Tc1 cells, inhibition of differentiation of CD8 + T cells to Tc17 cells, and inhibition of differentiation of CD4 + T cells to Th17 cells.
  7. 7. A method for inhibiting differentiation of immune cells, which comprises treating immune cells comprising CD8 + T cells or CD4 + T cells with a compound of formula (I) as defined in claim 1 or 2 or an isomer, solvate or precursor thereof, or a pharmaceutically acceptable salt thereof.
  8. 8. The method of claim 7, wherein inhibiting immune cell differentiation comprises inhibiting differentiation of CD8 + T cells to Tc1 cells, inhibiting differentiation of CD8 + T cells to Tc17 cells, and inhibiting differentiation of CD4 + T cells to Th17 cells.
  9. 9. A composition comprising a compound of formula (I) as defined in claim 1 or 2 or an isomer, solvate or precursor thereof, or a pharmaceutically acceptable salt thereof, and a pharmaceutically or biologically acceptable carrier; preferably, the composition is a pharmaceutical composition; Preferably, the composition is a reagent composition, preferably an immune cell culture medium.
  10. 10. A kit or kit comprising a compound of formula (I) as defined in claim 1 or 2 or an isomer, solvate or precursor thereof, or a pharmaceutically acceptable salt thereof, or a composition as defined in claim 9.

Description

Pentacyclic triterpene derivative, preparation method and application thereof Technical Field The invention relates to the fields of pharmaceutical chemistry and medicine, in particular to application of pentacyclic triterpene derivatives or pharmaceutically acceptable salts thereof in preventing and/or treating immune diseases. Background T lymphocytes can be divided into several sub-populations, including helper T cells (cd4+), cytotoxic T cells (cd8+) and regulatory T cells (tregs). These different subpopulations play different roles in the immune response. For example, helper T cells may stimulate B cells to produce antibodies, whereas cytotoxic T cells may kill virus-infected cells directly. Helper T cells 17 (Th 17) are effector subpopulations of CD4 + T cells that are capable of secreting the pro-inflammatory factor IL-17 and play an important role in the development of a variety of inflammatory diseases. Plays an important role in the occurrence and development of certain inflammatory diseases including autoimmune diseases. There is increasing evidence that the number of Th17 cells and their associated cytokines are significantly elevated in the blood of patients with various autoimmune diseases, and targeting Th17 cell differentiation may become a new clinical treatment regimen for autoimmune diseases. Biological agents directed against the IL-17/Th17 pathway have shown positive effects, questor Qiyuzumab, IQizumab, specific and Jilizumab, and the like have been marketed in batches. Depending on the cytokine secreted by CD8 + T cells and their function, they can be classified into different cytotoxic T lymphocyte (cytotoxic T lymphocytes, tc cell) subtypes, including Tc1, tc2, tc17, tc22 cells, and the like. Tc1 cells can secrete IFN-gamma, granzyme and perforin to kill melanocytes, so that vitiligo develops. Tc17 cells exert biological effects mainly by secreting inflammatory factors, and many studies report that they play an important role in the pathogenesis of autoimmune diseases such as psoriatic arthritis, type I diabetes, and the like. Pentacyclic triterpene compounds extracted from medicinal plants, fruits and vegetables, such as ursolic acid, oleanolic acid, glycyrrhetinic acid and boswellic acid compounds, have various biological activities, such as anti-tumor, anti-inflammatory, liver-protecting, antiviral, antidiabetic, antibacterial and the like, but have the defects of low activity, poor water solubility, low bioavailability and the like, so that the compound structure is modified to find excellent candidate medicaments, and the pentacyclic triterpene compounds have great scientific research value and social benefit. Boswellia extract has been used as an anti-inflammatory agent in traditional medicine, and 3-O-acetyl-11-carbonyl-beta-boswellic acid (AKBA) is one of the anti-inflammatory ingredients reported in the literature for boswellic acids. Extraction of AKBA from natural mastic resins has been described in U.S. patent No. 2003/0199581, et al. It was found that AKBA inhibited T cell activity to a lesser extent. The patent US2017/002039 reports that CKBA compounds are being developed in China for the treatment of autoimmune diseases (such as psoriasis, vitiligo and the like), CKBA is a candidate compound obtained by modifying AKBA as a lead, but the bioavailability of the compound is low, however, the bioavailability of the compound is low, and the prospect of oral drug development is influenced. . In view of the above, there is a need in the art to further optimize substances that are more effective in the inhibition of immune diseases. Disclosure of Invention The invention aims to provide pentacyclic triterpene derivatives and application of pharmaceutically acceptable salts thereof in preventing and/or treating autoimmune diseases, wherein the application of diseases improved by Tc1, tc17 and Th17 cells with good immunoregulatory effect is selected from autoimmune diseases such as multiple sclerosis, psoriasis, vitiligo, atopic dermatitis, inflammatory enteritis, alopecia areata and the like. The invention also relates to a preparation method of the compound. In a first aspect of the present invention there is provided a compound of formula (I) or an isomer, solvate or precursor thereof, or a pharmaceutically acceptable salt thereof, Wherein R1 comprises a group selected from the group consisting of: L is a linking group which is a bond, or a linear or branched C1-C6 alkylene chain, wherein the linear or branched C1-C6 alkylene is optionally substituted with hydroxymethyl or methyl; r2 is free or comprises a group selected from OH, NH2 or a substituted amino group comprising a linear or cyclic amino group comprising a group selected from the group consisting of: in one or more embodiments, the compound comprises a compound selected from the group consisting of: In another aspect of the present invention, there is provided the use of a compound of formula (I) or an isomer, solva