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CN-122005549-A - Application of indole alkali compound in preparation of medicine or skin care product for treating or preventing skin diseases

CN122005549ACN 122005549 ACN122005549 ACN 122005549ACN-122005549-A

Abstract

The invention relates to application of an indole alkali compound or pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier in preparation of medicines or skin care products for treating or preventing high HMGB1 type and skin diseases, wherein the indole alkali compound comprises at least one functional group of quaternary ammonium cations, amino groups or amino groups containing substituent groups, and the HMGB1 type skin diseases are marked by the increase of the level of high mobility group protein B1 (HMGB 1) or abnormal signal paths of the high HMGB1 type skin diseases. The invention can specifically bind with the N37 residue of HMGB1, accurately block pathological release from cell nucleus to cytoplasm, and not affect physiological functions such as DNA protection in the nucleus, and the like, and overcomes potential side effects of the existing broad-spectrum HMGB1 inhibitor.

Inventors

  • MA HONGYUE
  • ZHU YUYU
  • ZHOU JING
  • LV XIANG

Assignees

  • 南京效真生物科技有限公司

Dates

Publication Date
20260512
Application Date
20260303

Claims (10)

  1. 1. The application of an indole alkali compound or pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier in preparing a medicament or skin care product for treating or preventing HMGB1 type skin diseases, wherein the indole alkali compound comprises at least one functional group of quaternary ammonium cations, amino groups or amino groups containing substituent groups.
  2. 2. The use according to claim 1, wherein the skin disorder of HMGB type 1 is marked by an elevated level of high mobility group box B1 (HMGB 1), or by an abnormal signal pathway thereof.
  3. 3. The use according to claim 2, wherein the skin condition comprises at least one of psoriasis, atopic dermatitis, vitiligo, eczema, contact dermatitis, seborrheic dermatitis, rosacea, systemic lupus erythematosus skin manifestations, scleroderma skin manifestations, dermatomyositis, human papillomavirus infection related skin lesions, herpes virus infection related skin lesions, chronic urticaria, neurodermatitis, prurigo nodularis, lichen planus, skin aging, skin lesions.
  4. 4. The use according to claim 1, characterized in that it reduces the level of high mobility group box B1 (HMGB 1) in blood or skin tissues by means of said indole base compound, in order to achieve the treatment or care of skin diseases of HMGB1 type.
  5. 5. The use according to claim 4, wherein the indole base compound comprises at least one of the following compounds: Preferably, the indole base compound comprises 、 One of them.
  6. 6. The use according to any one of claims 1 to 5, wherein the indole base compound exerts a therapeutic or prophylactic effect by at least one of the following mechanisms: (a) Site-specific binding to the N37 residue of high mobility group box B1 (HMGB 1), blocking the high mobility group box B1 (HMGB 1) -CRM1 interaction, thereby inhibiting the transport of HMGB1 from the nucleus to the cytoplasm and its extracellular release; (b) Inhibiting the expression and/or release of a pro-inflammatory cytokine selected from at least one of IL-1 beta, TNF-alpha, IL-6, IL-17, IL-23, IL-22, IL-4, IL-13, IL-31, IL-18 or TSLP; (c) Inhibiting activation of NF- κb signaling pathway and/or MAPK signaling pathway; (d) Inhibit Th 17-type and/or Th 2-type immune responses; (e) Blocking the nervous-immune malignant cycle with increased anxiety-itching-skin lesions.
  7. 7. A pharmaceutical composition comprising a therapeutically effective amount of an indole base compound according to any one of claims 1 to 6 or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier, and a therapeutically effective amount of one or more other therapeutic agents, the weight ratio of the indole base compound or a pharmaceutically acceptable salt thereof and the pharmaceutically acceptable carrier to the other therapeutic agents being 1 (0.1 to 10); Wherein the other therapeutic agent is selected from at least one of a Bufonis venenum total steroid site, a glucocorticoid, a JAK inhibitor, a PDE4 inhibitor, an IL-31 antibody, an IL-12/23 antibody, and an IL-4Rα antibody.
  8. 8. The pharmaceutical composition of claim 7, wherein, the components of the total bufonin steroid parts comprise ester bufogenin, resibufaginol, deacetylated cinobufagin, daily bufogenin, deacetylated bufogenin, 1 beta-hydroxy-bufogenin, and cinobufagin, bufotalin, cinobufagin, bufotalin, 19-oxocinobufagin cinobufagin, 19-oxo-bufagin, desacetylcinobufagin; Preferably, the weight ratio of the indole alkali compound to the total bufonin steroid alkene part is 1 (0.2-5), and more preferably 1 (0.5-2).
  9. 9. A pharmaceutical formulation comprising a therapeutically effective amount of an indole base compound according to any one of claims 1 to 6 or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier, wherein the indole base compound is present in the pharmaceutical formulation in an amount of 0.01% to 99% by total weight; Preferably, the administration route comprises skin external application, oral administration, rectal administration, nasal cavity, intravenous injection or intramuscular injection, and the administration dosage is 0.1-100mg/kg body weight/day; preferably, the dosage form is selected from an external preparation, an oral preparation, a sustained release preparation, an injection preparation or an inhalant; preferably, the oral preparation comprises tablets, capsules, granules, oral liquid and buccal tablets; The external preparation comprises spray, film coating agent, ointment, cream, powder and skin lotion; the slow release preparation comprises a slow release tablet, a slow release capsule and a slow release suppository; the injection preparation comprises injection and freeze-dried powder injection; The inhalants include spray and powder inhalation.
  10. 10. A method of diagnosing or aiding in the treatment of a skin condition, comprising the steps of: Detecting high mobility group box B1 (HMGB 1) levels in blood, skin tissue, and/or cortisol levels in urine of an individual; When the detected high mobility group protein B1 (HMGB 1) level and/or cortisol level is above the normal reference range, administering to the individual an indole base compound according to any one of claims 1-6 or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.

Description

Application of indole alkali compound in preparation of medicine or skin care product for treating or preventing skin diseases Technical Field The invention relates to the technical field of medicines, in particular to application of an indole alkali compound or pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier in preparation of a medicine or skin care product for treating or preventing skin diseases characterized by pathological increase of HMGB1, and also relates to a pharmaceutical composition containing the indole alkali compound, a preparation thereof and related diagnosis and treatment methods. Background High mobility group box B1 (HMGB 1) is a structural protein of chromatin, packaging DNA into chromosomes. HMGB1 consists of three domains, two positively charged DNA binding domains (A-box and B-box) and one negatively charged C-terminal (acidic tail). Under physiological conditions, HMGB1 exists mainly in the nucleus, and by combining with DNA and histone, the HMGB1 helps to maintain the structure of nucleosomes and limit mutagens and photons to enter the DNA, so that DNA damage is prevented, and the effect of protecting the DNA is achieved. HMGB1 also regulates the strength of histone interactions with DNA, affecting DNA packaging in chromatin and nucleosome sliding to regulate gene expression. However, under stress or inflammatory conditions, high cortisol levels can induce the release of HMGB1 outside the cell, functioning as a siren as a damage-associated molecular pattern (DAMP). Extracellular HMGB1 mediates inflammatory responses through interactions with a variety of pattern recognition receptors, including but not limited to Toll-like receptor 4 (TLR 4), toll-like receptor 2 (TLR 2), and late glycosylation end product specific receptor (RAGE/AGER). Activation of the HMGB 1-receptor axis can trigger downstream signaling cascades, including activation of the NF- κ B, MAPK pathway, resulting in massive release of pro-inflammatory cytokines, forming an inflammatory amplification loop. Numerous clinical and fundamental research evidence suggest that HMGB1 plays a key role in the mechanism of a variety of skin diseases, being an important pathological target and disease biomarker, skin disorders of this subtype in which HMGB1 is pathologically elevated include the following: (1) The serum tests of the HMGB1 type atopic dermatitis (atopic dermatitis, AD) Cuppari and the like on 104 AD infants and 93 healthy control groups show that the HMGB1 expression level of the AD group is obviously increased and positively correlated with the clinical severity. Karuppagounder et al found that the levels of HMGB1 expression at serum and skin lesions were increased in the NC/Nga mouse-induced AD model compared to the control group and correlated positively with dermatitis severity, and further demonstrated that HMGB1/RAGE activated the MAPK/NF- κB pathway to promote secretion of Th2 cytokines, exacerbating the inflammatory response of AD. Nygaard et al found through keratinocyte model experiments that HMGB1 can down regulate the expression of epidermis-related proteins such as silk fibroin and the like, finally influence the growth, differentiation and maturation of epidermal cells, damage the skin barrier function and promote the occurrence of AD. (2) HMGB1 psoriasis (psoriasis vulgaris, PV) has been studied to show that HMGB1 expression levels in serum and skin lesions of PV patients are significantly elevated compared to control and that serum HMGB1 expression levels are positively correlated with PV severity. Chen et al found that HMGB1 expression levels were significantly elevated in the mouse PV model, and that after administration of HMGB1 inhibitors, psoriasis lesions were ameliorated and HMGB1 and other inflammatory factors tended to be normal. Zhang et al found that HMGB1 stimulated significant elevation of IL-18 in keratinocytes by activating NF- κB pathway, inducing the occurrence of PV, and further demonstrated that blocking HMGB1 or IL-18 in a mouse model of PV could suppress Th 17-type immune responses, thereby ameliorating psoriasis-like dermatitis. (3) HMGB1 vitiligo (vitelligo) Kim et al found that the expression level of HMGB1 was significantly increased in both serum and skin lesions of vitiligo patients and correlated positively with the severity of vitiligo. Further research shows that after melanocytes of vitiligo patients are treated by exogenous HMGB1, expression of apoptosis-related protein caspase 3 is increased, which indicates that HMGB1 can promote occurrence of vitiligo by increasing apoptosis of melanocytes. (4) HMGB1 type skin aging (SKIN AGING) HMGB1 is closely related to many common skin aging causes. The prior literature shows that after the ultraviolet UVB irradiates keratinocytes, iron death of skin glial cells is caused, the iron death is further triggered to release high mobility group protein (HMGB 1), inflammatory cascade reaction is indu