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CN-121990980-A - Compound and application thereof in preparation of anti-inflammatory drugs

CN121990980ACN 121990980 ACN121990980 ACN 121990980ACN-121990980-A

Abstract

The present application provides a compound of formula (I) or a pharmaceutically acceptable salt thereof, and the use thereof in the treatment or prevention of inflammation, in the reduction of inflammatory factor (particularly inflammatory factor release by immune cells), in the treatment or prevention of a disease associated with excessive inflammatory factor release, in the inhibition of the cGAS-STING pathway, or in the treatment of a disease associated with the cGAS-STING pathway. (I)

Inventors

  • ZHENG PENGFEI
  • WANG NA
  • WANG HUAN
  • HU ZITIAN
  • NI ZHENHONG
  • XIANG WEI
  • ZHOU JIE
  • Liu Yangwuyue
  • OU JUANJUAN

Assignees

  • 中国人民解放军陆军军医大学

Dates

Publication Date
20260508
Application Date
20251105
Priority Date
20241105

Claims (10)

  1. 1. The use of a compound of formula (I) or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for the treatment or prophylaxis of inflammation, (I) Wherein, the R 1 is selected from the group consisting of hydrogen, halogen, alkoxy, alkanoyl, alkoxycarbonyl, and heteroaryl; r 2 is selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, azidoalkyl, arylalkyl, and heteroarylalkyl; R 3 is aryl or heteroaryl which is unsubstituted or substituted by halogen, alkyl, aryl or haloalkyl, and R 4 is cyano, or a fatty acyl, fatty oxycarbonyl, arylformyl, aryloxycarbonyl, heteroarylformyl, heteroaryloxycarbonyl, which is unsubstituted or substituted with halogen, alkyl or haloalkyl, and R 5 is cyano, or R 4 and R 5 together form indene-1, 3 (2H) -dione-2-ylidene.
  2. 2. The use according to claim 1, wherein, The inflammation is gastritis, appendicitis, bursitis, duodenitis, enteritis, ileitis, colitis, cystitis, dermatitis, epididymitis, encephalitis, gingivitis, meningitis, myelitis, myocarditis, nephritis, neuritis, pancreatitis, periodontitis, pharyngitis, phlebitis, prostatitis, rhinitis, sinusitis, tendinitis, tonsillitis, urethritis, vasculitis, vaginitis, keratitis, conjunctivitis, otitis media, pneumonia, hepatitis, endometritis, cervicitis, pelvic inflammation, paronychia, osteoarthritis, inflammation caused by acute kidney injury, or autoinflammation or autoimmune disease.
  3. 3. The use according to claim 1 or 2, wherein, The agent for treating or preventing inflammation is an agent for reducing the release of inflammatory factors, particularly IL-6, TNF- α, or type I interferon, more particularly IL-6.
  4. 4. The use according to claim 1 to 3, R 1 is selected from the group consisting of hydrogen, fluorine, chlorine, bromine, iodine, methoxy, ethoxy, propoxy, formyl, acetyl, propionyl, methoxycarbonyl, ethoxycarbonyl, and propoxycarbonyl, particularly selected from the group consisting of hydrogen, fluorine, chlorine, bromine, iodine, methoxy, and formyl, more particularly selected from the group consisting of hydrogen, fluorine, chlorine, and methoxy; alternatively, formula (I) includes R 1 on carbon number 4 of its indoline ring; alternatively, formula (I) includes R 1 on carbon number 5 of its indoline ring; alternatively, formula (I) includes R 1 on carbon number 6 of its indoline ring; alternatively, formula (I) includes R 1 located on carbon No. 7 of its indoline ring.
  5. 5. The use according to any one of claims 1 and 4, wherein, R 2 is selected from the group consisting of hydrogen, methyl, ethyl, propyl, isopropyl, allyl, propargyl, azidomethyl, azidoethyl, azidopropyl, phenyl, and benzyl; Alternatively, R 2 is selected from the group consisting of hydrogen, methyl, ethyl, allyl, propargyl, phenyl, and benzyl.
  6. 6. The use according to claim 1 to 5, wherein, R 3 is aryl which is unsubstituted or substituted by halogen, alkyl, aryl or haloalkyl; Optionally, R 3 is phenyl or naphthyl, unsubstituted or substituted with halogen, alkyl, aryl, or haloalkyl; optionally, R 3 is naphthyl, optionally substituted by halogen, alkyl, aryl, or haloalkyl, especially R 3 is naphthyl; optionally, R 3 is phenyl unsubstituted or substituted by halogen, alkyl, aryl, or haloalkyl, in particular R 3 is phenyl.
  7. 7. The use according to claim 1 to 6, wherein, R 3 is phenyl substituted with halogen or haloalkyl, more particularly phenyl substituted with fluoro or fluoroalkyl; Alternatively, R 3 is phenyl substituted with halo; Alternatively, R 3 is phenyl substituted with haloalkyl; optionally, the halogen is fluorine, chlorine, bromine, or iodine, particularly fluorine; alternatively, the haloalkyl is trihalomethyl, in particular trifluoromethyl; Optionally, the substitution includes or consists in particular of meta substitution; Alternatively, R 3 is 3-fluorophenyl or 3- (trifluoromethyl) phenyl.
  8. 8. The use according to any one of claims 1 to 7, wherein, R 4 is cyano, or fatty acyl, fatty oxycarbonyl, arylformyl, aryloxycarbonyl, heteroarylformyl, heteroaryloxycarbonyl, unsubstituted or substituted with halogen, alkyl, or haloalkyl, and R 5 is cyano; alternatively, R 4 is cyano, or fatty acyl, unsubstituted or substituted with halo, alkyl, or haloalkyl; Alternatively, the fatty acyl group is selected from the group consisting of formyl, acetyl, propionyl, n-butyryl, isobutyryl, n-pentanoyl, isopentanoyl, and pivaloyl; Optionally, R 4 is fatty oxycarbonyl, unsubstituted or substituted with halogen, alkyl, or haloalkyl; Alternatively, the fatty oxycarbonyl group is selected from the group consisting of carboxyl, methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, n-butoxycarbonyl, isobutoxycarbonyl, and tert-butoxycarbonyl; Alternatively, R 4 is cyano, or aryl formyl, aryl oxycarbonyl, heteroaryl formyl, or heteroaryl oxycarbonyl, unsubstituted or substituted with halogen, alkyl, or haloalkyl; Alternatively, R 4 is cyano, or aryl formyl, aryl oxycarbonyl, heteroaryl formyl, or heteroaryl oxycarbonyl, unsubstituted or substituted with halogen or haloalkyl; optionally, R 4 is an aryl or heteroaryl formyl group unsubstituted or substituted with halogen or haloalkyl; Optionally, R 4 is heteroarylformyl, particularly pyrroloyl, furanoyl, or thiophenoyl, more particularly thiophenoyl, unsubstituted or substituted with halogen or haloalkyl; optionally, R 4 is cyano, or aryl formyl unsubstituted or substituted with halogen, alkyl, or haloalkyl; optionally, R 4 is cyano, or aryl formyl unsubstituted or substituted with halogen or haloalkyl; Optionally, R 4 is cyano, or benzoyl, unsubstituted or substituted with halogen or haloalkyl.
  9. 9. The use according to any one of claims 1 to 8, wherein, R 4 is benzoyl substituted with halogen or haloalkyl, more particularly benzoyl substituted with fluoro or fluoroalkyl; Alternatively, R 4 is benzoyl substituted with halogen; alternatively, R 4 is benzoyl substituted with haloalkyl; optionally, the halogen is fluorine, chlorine, bromine, or iodine, particularly fluorine; alternatively, the haloalkyl is trihalomethyl, in particular trifluoromethyl; Optionally, the substitution includes or consists in particular of meta substitution; Alternatively, R 4 is 3-fluorobenzoyl or 3- (trifluoromethyl) benzoyl.
  10. 10. The use according to any one of claims 1 to 9, wherein, R 3 is Wherein X 1 、X 2 、X 3 、X 4 , and X 5 are each independently hydrogen, halogen, or haloalkyl, particularly hydrogen, halogen, or trihalomethyl, wherein halogen is fluorine, chlorine, bromine, or iodine, particularly fluorine, and particularly X 1 、X 2 、X 3 、X 4 , and X 5 , more particularly X 2 、X 3 , and X 4 , more particularly X 2 , and X 4 , at least one of which is not hydrogen, and/or R 4 is Wherein X 1 、X 2 、X 3 、X 4 and X 5 are each independently hydrogen, halogen, or haloalkyl, particularly hydrogen, halogen, or trihalomethyl, wherein halogen is fluorine, chlorine, bromine, or iodine, particularly fluorine, and particularly at least one of X 1 、X 2 、X 3 、X 4 and X 5 , more particularly X 2 、X 3 , and X 4 , more particularly X 2 and X 4 , is not hydrogen.

Description

Compound and application thereof in preparation of anti-inflammatory drugs Technical Field The application relates to the field of biological medicine, in particular to a compound and application thereof in preparing anti-inflammatory medicines. Background Inflammation is an adaptive response of the body under the stimulation of deleterious conditions (e.g., infection, tissue damage, etc.). Under normal conditions, the body can accurately regulate and control the start and stop of inflammatory response. After the removal of the deleterious conditions is completed, the inflammatory response is terminated and the repair process of the tissue injury is initiated. However, when the injury stimulus is long-term or the immune regulation is defective, the body's regulation of the inflammatory response is unbalanced, and thus excessive cytokines, particularly Interleukin 6 (IL-6), are produced, and these excessive cytokines may cause multiple organ injury in the human body. However, current drug therapies for excessive inflammatory response remain lacking. The cyclic guanosine-adenosine-phosphate synthase-interferon gene stimulatory protein (CYCLIC GMP-AMP SYNTHASE-Stimulator of Interferon Genes, cGAS-STING) signaling pathway is an important member of the human natural immune system. In this pathway, cGAS acts as a unique pathogen recognition receptor, recognizing a variety of exogenous and self-derived double-stranded DNA. After cGAS binds to abnormal DNA, a second messenger cyclic dinucleotide is generated (Cyclic dinucleotide, CDN). After CDN and STING are combined, NF- κB and interferon regulatory factor 3 (Interferon Regulatory Factor, IRF 3) downstream signal channels are activated, so that the expression of inflammatory cytokines such as I-type interferon is induced, and finally the immune response is started. The cGAS-STING pathway in equilibrium is an important tool of the body against exogenous pathogens. However, when cGAS-STING pathway is in abnormal activation state, it causes excessive synthesis and release of inflammatory factors, and may promote occurrence of autoimmune diseases, neurodegenerative diseases, etc., such as STING-related infant onset vascular diseases (STING-associated Vasculopathy of Infancy, SAVI) caused by the acquired mutation of STING gene function, and the TREX1 gene mutation encoding nuclease causes alcafrican-gultim syndrome (AGS) caused by the accumulation of self DNA, systemic lupus erythematosus (Systemic Lupus Erythematosus, SLE), amyotrophic lateral sclerosis (Amyotrophic Lateral Sclerosis, ALS), etc. The STING proteins are key signaling molecules in the cGAS-STING pathway, and small molecule inhibitors directed against STING targets can be classified into two classes according to the mechanism, the first class being inhibitors occupying CDN binding sites and the second class being inhibitors binding to STING palmitoylation sites, however, there is still a lack of small molecule inhibitors targeting the cGAS-STING pathway in disease in the prior art. Disclosure of Invention There is provided a compound of formula (I) or a pharmaceutically acceptable salt thereof, or the use thereof in the manufacture of a medicament for the treatment or prophylaxis of inflammation, (I) Wherein, the R 1 is selected from the group consisting of hydrogen, halogen, alkoxy, alkanoyl, alkoxycarbonyl, and heteroaryl; R 2 is selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, azidoalkyl, arylalkyl, and heteroarylalkyl; R 3 may be aryl or heteroaryl which is unsubstituted or substituted by halogen, alkyl, aryl or haloalkyl, and R 4 can be cyano, or fatty acyl, fatty oxycarbonyl, arylformyl, aryloxycarbonyl, heteroarylformyl, heteroaryloxycarbonyl, and R 5 can be cyano, or R 4 and R 5 can together form indene-1, 3 (2H) -dione-2-ylidene, optionally substituted with halogen, alkyl, or haloalkyl. The compounds of some embodiments of the present application are novel small molecule inhibitors with therapeutic or prophylactic activity against inflammation, which are effective in reducing inflammatory factor release and in treating inflammation. Drawings FIG. 1 (a) is a mass spectrum of a compound D1, and (b) is a 1 H NMR spectrum of the compound D1 and an enlarged view of several characteristic peaks thereof. FIG. 2 (a) shows the results of sodium dodecyl sulfate polyacrylamide gel electrophoresis (SDS-PAGE) using compound C0 to label Bovine Serum Albumin (BSA), and (b) shows a secondary mass spectrum obtained by liquid chromatography-mass spectrometry/mass spectrometry (LC-MS/MS) using compound C0 to label BSA. (a) Fluorescent groups TAMRA in the upper row and Coomassie brilliant blue in the lower row, DMSO and 0.5. Mu.M, 1. Mu.M, 2. Mu.M, 5. Mu.M, and 10. Mu.M of Compound C0 in this order from left to right. (b) The vertical axis is intensity (count, 10 3). FIG. 3 (a) flow cytometry showing inflammatory factor release from treatment of primary bone marrow neutrophils in mice with L