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CN-121991041-A - Benzofuranone compound, and pharmaceutical composition and application thereof

CN121991041ACN 121991041 ACN121991041 ACN 121991041ACN-121991041-A

Abstract

The invention provides a benzofuranone compound, a pharmaceutical composition and application thereof, and relates to the technical field of medicines. The benzofuranone compound is a compound shown in a formula I, a stereoisomer, a tautomer, a crystalline hydrate, a solvate, a prodrug or a pharmaceutically acceptable salt thereof. The benzofuranone compound and the pharmaceutical composition and pharmaceutical preparation prepared by the benzofuranone compound can prevent or treat organ injury diseases, and have good treatment effects on kidney injury, liver injury, lung injury, brain injury and heart injury.

Inventors

  • HE QIAOJUN
  • WENG QINJIE
  • CHEN BINHUI

Assignees

  • 杭州禹泓医药科技有限公司

Dates

Publication Date
20260508
Application Date
20251015
Priority Date
20241106

Claims (16)

  1. 1. A benzofuranone compound is characterized in that the compound is a compound shown in a formula I, a stereoisomer, a tautomer, a crystal hydrate, a solvate, a prodrug or a pharmaceutically acceptable salt thereof, ; Ring A is selected from 5-6 membered aromatic heterocycle, 8-12 membered aromatic ring and aliphatic heterocycle or 8-12 membered aromatic ring and aliphatic heterocycle, and ring A can be C 1-5 alkyl, halogen, cyano or A substitution, the C 1-5 alkyl group may be substituted with halogen, C 1-3 alkoxy, 4-7 membered aliphatic heterocyclic ring, or amine; L 1 is selected from 、 、 、 Or (b) ; R 1 and R 2 are each independently selected from H, C 1-5 alkyl, Or halogen, or R 1 and R 2 are adjacent and together with the attached atoms form a 5-7 membered aliphatic heterocyclic ring, the heteroatom of said 5-7 membered aliphatic heterocyclic ring being selected from O or S, said 5-7 membered aliphatic heterocyclic ring being optionally substituted by C 1-3 alkyl or halogen; Each R 3 、R 4 is independently selected from H or C 1-5 alkyl, which C 1-5 alkyl may be substituted with hydroxy, halogen or C 1-3 alkoxy; R 5 、R 6 、R 8 、R 9 and R 11 are each independently selected from H, C 1-9 alkyl, 4-7 membered aliphatic heterocyclic ring and 7-12 membered parallel, bridged or spiro ring, said C 1-9 alkyl group being optionally substituted by hydroxy, amino or C 1-3 alkoxy, Or (b) R 5 and R 6 together with the linking atoms form one of a 4-7 membered aliphatic heterocyclic ring and a 7-12 membered fused ring, bridged ring, spiro ring, R 8 and R 9 together with the linking atoms form one of a 4-7 membered aliphatic heterocyclic ring and a 7-12 membered fused ring, bridged ring, spiro ring, said 4-7 membered aliphatic heterocyclic ring and 7-12 membered fused ring, bridged ring, spiro ring being C 1-5 alkyl, hydroxy or amino, spiro ring, Substituted, C 1-5 alkyl may be substituted with halogen, hydroxy, amino, or C 1-3 alkoxy; R 7 、R 10 is independently selected from one of C 1-5 alkyl, 4-7 membered aliphatic heterocyclic ring, 7-12 membered parallel ring, bridged ring and spiro ring, wherein the 4-7 membered aliphatic heterocyclic ring, 7-12 membered parallel ring, bridged ring and spiro ring can be substituted by C 1-3 alkyl, halogen, hydroxyl or amino; R 12 is selected from H, C 1-3 alkyl, 4-7 membered aliphatic heterocyclic ring or The C 1-3 alkyl group may be substituted by halogen, and the 4-7 membered aliphatic heterocyclic ring may be substituted by hydroxy or Substitution; m is selected from 0 or 1; The ring A is selected from 、 、 、 Or (b) When m is selected from 1; The ring A is selected from 、 、 、 、 、 Or (b) And m is 0, the ring A substituents are not all selected from H and methyl; the compounds of formula I being not selected from 。
  2. 2. Benzofuranone compound according to claim 1, characterized in that: Wherein m is selected from 0 and ring A is selected from Ring A may be C 1-5 alkyl, halogen, cyano or A substitution, the C 1-5 alkyl group may be substituted with halogen, C 1-3 alkoxy, 4-7 membered aliphatic heterocyclic ring, or amine; The m is selected from 1, the ring A is selected from 5-6 membered aromatic heterocycle, 8-12 membered aromatic heterocycle and aliphatic heterocycle or 8-12 membered aromatic heterocycle and aliphatic heterocycle, and the ring A can be C 1-5 alkyl, halogen, cyano or The C 1-5 alkyl group may be substituted with halogen, C 1-3 alkoxy, 4-7 membered aliphatic heterocyclic ring or amino.
  3. 3. Benzofuranone compound according to claim 2, characterized in that it is a compound of formula II or III, a stereoisomer thereof, a tautomer thereof, a crystalline hydrate thereof, a solvate thereof, a prodrug thereof or a pharmaceutically acceptable salt thereof, X is selected from S, O, N-Y 3 ; Y 1 and Y 2 are each independently selected from H, C 1-5 alkyl, halogen, cyano or The C 1-5 alkyl group may be substituted with halogen, C 1-3 alkoxy, 4-7 membered aliphatic heterocyclic ring, or amine group; y 3 is selected from H, C 1-5 alkyl, which C 1-5 alkyl may be substituted with halogen, C 1-3 alkoxy, 4-7 membered aliphatic heterocyclic ring or amine.
  4. 4. The benzofuranone compound of claim 3, wherein the compound of formula IV, a stereoisomer thereof, a tautomer thereof, a crystalline hydrate thereof, a solvate thereof, a prodrug thereof, or a pharmaceutically acceptable salt thereof, 。
  5. 5. The benzofuranone compound of claim 4, wherein the compound of formula V or VI, a stereoisomer thereof, a tautomer thereof, a crystalline hydrate thereof, a solvate thereof, a prodrug thereof, or a pharmaceutically acceptable salt thereof, 。
  6. 6. Benzofuranone compound according to any one of claims 1 to 5, wherein L 1 is selected from 。
  7. 7. Benzofuranone compounds, including compounds of the structure, stereoisomers thereof, tautomers thereof, crystalline hydrates thereof, solvates thereof, prodrugs thereof, or pharmaceutically acceptable salts thereof, 。
  8. 8. A pharmaceutical composition comprising a benzofuranone compound according to any one of claims 1 to 6 or a benzofuranone compound according to claim 7.
  9. 9. A pharmaceutical formulation comprising an active ingredient selected from the group consisting of benzofuranones according to any one of claims 1 to 6, benzofuranones according to claim 7, and pharmaceutical compositions according to claim 8, and one or more pharmaceutically acceptable carriers or excipients.
  10. 10. The pharmaceutical formulation according to claim 9, wherein it is provided in the form of a tablet, pill, drop, capsule, granule, powder, suppository, powder, ointment, patch, injection, solution, suspension, spray, lotion, drops, liniment, emulsion.
  11. 11. The pharmaceutical formulation of claim 10, wherein the carrier or excipient comprises saline, saccharides, gelatin, starch, ringer's solution, and cellulose.
  12. 12. Use of a benzofuranone compound according to any one of claims 1 to 6, a benzofuranone compound according to claim 7 or a pharmaceutical composition according to claim 8 for the preparation of a medicament for the prevention or treatment of an organ injury disease, said organ injury disease being one or more of kidney injury, liver injury, lung injury, brain injury, heart injury.
  13. 13. The use according to claim 12, wherein the kidney injury is acute kidney injury or chronic nephritis and the acute kidney injury is one or more of prerenal acute kidney injury, acute kidney injury of renal origin and acute kidney injury of postrenal origin.
  14. 14. The use according to claim 13, wherein the acute kidney injury is one or more of ischemic acute kidney injury, acute kidney injury resulting from systemic infection, acute kidney injury from pharmaceutical use, acute kidney injury from surgery, acute kidney injury from compression syndrome, acute kidney injury from heart-kidney syndrome, and acute kidney injury from liver-kidney syndrome.
  15. 15. The use according to claim 14, wherein the drug in the acute kidney injury is one or more of aminoglycosides, cephalosporins, penicillins, quinolones, glycopeptides, sulfonamides, antiviral agents, antifungal agents, diuretics or dehydrating agents, non-steroidal anti-inflammatory agents, traditional Chinese medicines, contrast agents, antitumor agents, immunosuppressants and antitubercular agents.
  16. 16. Use of a benzofuranone compound of any one of claims 1 to 6, a benzofuranone compound of claim 7 or a pharmaceutical composition of claim 8 in the manufacture of a medicament for the prevention or treatment of autoimmune and inflammatory diseases selected from one or more of alopecia areata, lupus, multiple sclerosis, amyotrophic lateral sclerosis, rheumatoid arthritis, type I diabetes, autoimmune hemolytic anemia, rheumatoid arthritis, psoriasis, complications from organ transplantation, atopic dermatitis, autoimmune thyroiditis, ulcerative colitis, crohn's disease, sjogren's syndrome, systemic scleroderma, mixed connective tissue disease, vitiligo and chronic obstructive pulmonary disease.

Description

Benzofuranone compound, and pharmaceutical composition and application thereof Priority of claim the present invention priority of chinese patent application 2024115820331 filed on 11/06 of 2024 is hereby incorporated by reference in its entirety. Technical Field The invention belongs to the technical field of medicines, and relates to benzofuranone compounds, a pharmaceutical composition and application thereof. Background Acute kidney injury (Acute Kidney Injury, AKI), also known as acute renal failure, refers to the absolute rise in blood creatinine of greater than or equal to 26.5 μmol/L over 48 hours or known or predicted to be greater than or equal to 50% over 7 days or urine volume <0.5 mL/(kg.h) over a basal value and lasting over 6 hours. Blood creatinine (Cre) and urea nitrogen (Bun) levels are the main indicators for judging whether or not kidney injury and injury severity occur, and the degree of vividness of the appearance of the kidneys is also an important indicator in the animal experiment stage. The acute kidney injury has the characteristics of various etiologies, complex mechanism, high morbidity, high mortality and great harm. Acute kidney injury is usually caused by effects on kidney perfusion (mainly causing kidney hypoxia) and harmful substances, typically including surgery, malignant tumors, cardiopulmonary dysfunction, hepatorenal syndrome, sepsis and nephrotoxic drugs. According to the different causes, acute kidney injury includes ischemic AKI, AKI caused by systemic infection, pharmaceutical AKI, operation related AKI, AKI caused by compression syndrome, AKI caused by heart and kidney syndrome, and AKI caused by liver and kidney syndrome, and according to the different causes, acute kidney injury can be divided into three categories, namely prerenal, renal and postrenal. (Wang Jingdong, li Changjiang Main code, medical diagnosis and treatment of critical and critical conditions, 2014,64-69.) Because acute kidney injury is diagnosed later, the pathophysiology is complex and incompletely elucidated, and no specific therapeutic drug exists at present. At present, clinically commonly used acute kidney injury symptomatic medicaments such as vasodilators or diuretics are commonly applied to prerenal acute kidney injury with renal insufficiency, can help to recover a part of kidney functions, but does not improve the etiology of the acute kidney injury, and can cause renal toxicity when used at high dosage, thus being easy to cause renal acute kidney injury. In view of the above, there is a need for the development of safe and effective drugs for preventing and treating acute kidney injury. Priyanka et al in Fisetin attenuates renal ischemia/reperfusion injury by improving mitochondrial quality, reducing apoptosis and oxidative stress disclose that acetylcysteine (NAC) is a highly potent glutathione precursor substance with the effects of modulating cellular metabolic activity, antioxidant stress, and resistance to toxic damage, has been used clinically for the intervention of acute kidney injury such as that caused by contrast agents, and shows a therapeutic effect. Flavonoid compounds such as fisetin have antiinflammatory, antioxidant, free radical release reducing, and mitochondrial function enhancing effects, and can be used for preventing and treating acute renal injury. However, NAC and fisetin have limited improving effects on kidney injury. Disclosure of Invention In order to solve the defects in the prior art, the invention provides a benzofuranone compound and a pharmaceutical composition thereof, which have good treatment effects on kidney injury, liver injury, lung injury, brain injury and heart injury, and can also treat and prevent autoimmune and inflammatory diseases. In order to achieve the above purpose, the technical scheme adopted by the invention is as follows: In one aspect, the present invention provides a benzofuranone compound, which is a compound of formula I, a stereoisomer thereof, a tautomer thereof, a crystalline hydrate thereof, a solvate thereof, a prodrug thereof, or a pharmaceutically acceptable salt thereof, 。 Ring A is selected from 5-6 membered aromatic heterocycle, 8-12 membered aromatic ring and aliphatic heterocycle or 8-12 membered aromatic ring and aliphatic heterocycle, and ring A can be C 1-5 alkyl, halogen, cyano orThe C 1-5 alkyl group may be substituted with halogen, C 1-3 alkoxy, 4-7 membered aliphatic heterocyclic ring or amino. L 1 is selected from 。 R 1 and R 2 are each independently selected from H, C 1-5 alkyl,Or halogen, or R 1 and R 2 are adjacent and together with the attached atoms form a 5-7 membered aliphatic heterocyclic ring, the heteroatom of said 5-7 membered aliphatic heterocyclic ring being selected from O, S, said 5-7 membered aliphatic heterocyclic ring being optionally substituted by C 1-3 alkyl, halogen. R 3、R4 is each independently selected from H, C 1-5 alkyl, C 1-5 alkyl can be substituted with hydroxy, halogen or C