CN-122010834-A - Piroctone derivative, and preparation method and application thereof

Abstract

The invention provides piroctone derivatives, and a preparation method and application thereof, and belongs to the technical field of medicines. The piroctone derivative has novel structure, good solubility and simple preparation method. Compared with a positive control drug DFO, the piroctone ketone derivative provided by the invention has extremely strong iron ion chelating capacity, has better anti-inflammatory and antibacterial activities, promotes fibroblast migration and promotes healing of diabetes refractory wounds, and can stabilize HIF-alpha. The piroctone derivative provided by the invention has good application prospects in the aspects of developing a novel iron chelator and a HIF-alpha stabilizer drug with the effects of resisting inflammation, inhibiting bacteria, promoting wound healing, relieving iron overload and the like.

Inventors

• QIU PEIJU
• ZHOU LIYING
• WU LIJUAN
• BAI GUANGTAO
• WAN SHENGBIAO
• HAN LU
• YU RILEI
• FU PENG
• YANG JINBO
• QI KANGKANG

Assignees

• 中国海洋大学
• 青岛海洋生物医药研究院

Dates

Publication Date

20260512

Application Date

20251223

Claims (10)

1. 1. The piroctone derivatives are characterized in that the structural formula is shown as the formula (I): , the compound of formula (I), Wherein R 1 is selected from at least one of the following substituents: 。
2. 2. piroctone derivative according to claim 1, characterized in that it is in particular the following compound: 。
3. 3. the method for preparing piroctone derivative according to claim 2, wherein the method for preparing carboxylic acid compound 1c to 5c comprises the steps of: oxidizing 6-bromo-2-pyridine carboxylic acid serving as a raw material by using oxygen trifluoroacetic acid to obtain a compound S2, then hydrolyzing the compound S2 in a potassium hydroxide aqueous solution to obtain 6-hydroxypyridine-2-carboxylic acid, namely S3, further protecting nitrogen hydroxyl by using benzyl bromide to obtain benzyl-protected hydroxypyralid, namely a compound S4, and reacting the benzyl-protected compound S4 with different substituted glycine derivatives and beta-alanine to obtain compounds 1a-5a; Then respectively removing benzyl for protecting carboxyl and hydroxyl by alkali hydrolysis and acid hydrolysis to obtain carboxylic acid compounds 1c-5c; 。
4. 4. The preparation method of piroctone derivative according to claim 2, wherein the synthetic route of aryl compound, namely 6b-25b, is shown as follows, benzyl-protected hydroxy pyridone acid, namely compound S4, reacts with aryl amine derivative, intermediate 6a-25a series compound is obtained through condensation reaction, and final product 6b-25b is obtained through further hydrolysis and debenzylation; 。
5. 5. Use of piroctone derivatives according to claim 1 or 2 for the preparation of anti-inflammatory drugs.
6. 6. Use of piroctone derivatives according to claim 1 or 2 for the preparation of antibacterial agents.
7. 7. Use of a piroctone derivative according to claim 1 or 2 for the manufacture of a medicament for the treatment of a disease associated with wound healing.
8. 8. The use according to claim 7, wherein the diseases related to wound healing include wounds caused by hyperglycemia, wounds caused by atherosclerosis and anemia, oral mucosa diseases, inflammatory wounds caused by bacterial infection, chronic wounds caused by foreign matter residues, rheumatoid arthritis, systemic lupus erythematosus, pressure sores, burns, frostbite, wound surfaces caused by surgical incision infection and wounds caused by malignant tumors.
9. 9. Use of piroctone derivatives according to claim 1 or 2 for the preparation of iron ion chelators for ameliorating iron overload disorders.
10. 10. Use of piroctone derivative according to claim 1 or 2 for the preparation of a HIF-a stabilizer.

Description

Piroctone derivative, and preparation method and application thereof Technical Field The invention belongs to the technical field of pharmaceutical chemistry, and particularly relates to a piroctone derivative, a preparation method and application thereof. Background The iron chelator forms a stable complex by binding with iron ions, preventing its catalytic action in redox reactions, and displacing fe2+ out of the body. Iron supply and control is critical to a variety of physiological processes, iron chelators have powerful iron scavenging capacity and serve a variety of functions by affecting iron homeostasis. Under normoxic conditions, prolyl Hydroxylase (PHD) catalyzes HIF-1. Alpha. Hydroxylation in dependence on iron (Fe 2+), promoting its degradation by the proteasome. Iron ion chelators such as deferoxamine mesylate (DFO, trade name Desferal) significantly up-regulate its protein level ‌ by chelating free iron ions, inhibiting PHD activity, blocking the degradation pathway of HIF-1 a. This iron chelation mimics the hypoxic environment, activates HIF-1 alpha mediated adaptive signaling pathways, promotes expression of various downstream genes, performs physiological functions such as promoting neovascularization ‌ in diabetic wound healing by regulating angiogenesis-related factors ‌ (vascular endothelial growth factor, VEGF and erythropoietin, EPO) expression, enhances cell viability ‌ in the hypoxic or iron-deficient state by regulating expression of metabolic adaptation gene ‌ (glycolytic related enzyme), reduces oxidative stress-induced cell damage ‌ by regulating expression of anti-apoptotic proteins (BCL-2 family members), and the like. DFO is a natural iron chelator containing hydroxamic acid groups that specifically bind ferric iron (Fe 3+) to form a stable water-soluble complex (iron amine) that is excreted in vitro ‌ through urine (60%) and bile (40%). DFO has high selectivity and strong affinity for Fe 3+, preferentially scavenges free iron (NTBI) and iron in ferritin, but does not affect bound iron ‌ in hemoglobin, transferrin, or cytochrome. DFO ‌ is produced by fermentation processes of streptomyces bacteria. The half-life period is 5-10 minutes, and three active hydroxamic acid groups are contained in the molecule, so that stable chelate can be formed with ferric iron (Fe 3 +) through six coordination sites. The limited absorption through the gastrointestinal tract when DFO is orally administered, requires administration via intramuscular, subcutaneous or intravenous routes, greatly limiting the versatility of use. DFO treatment requires dynamic monitoring of serum ferritin, liver function and hearing (due to potential ototoxicity), and dose adjustment to avoid hypoferric ‌, and DFO has the disadvantages of poor water solubility, large cytotoxicity, etc., and it is significant to find safer and more effective alternative iron chelators. Piroctone is a compound with a chemical name of 1-hydroxy-4-methyl-6- (2, 4-trimethyl amyl) -2-pyridone, and an ethanolamine salt form (piroctone olamine salt, OCT) thereof is widely applied in the cosmetic field, and is used for reducing the generation of flaking dandruff by inhibiting excessive reproduction of scalp fungi, regulating and controlling abnormal metabolism of keratinocytes. Its action targets include fungal cell membrane structure and metabolic enzyme activity. The invention takes piroctone as a lead, and obtains a series of carboxylic acid (c) and aryl (b) derivatives through structural transformation and optimization design synthesis, and the invention has the characteristics of novel structure and low cytotoxicity. As a HIF-alpha stabilizer, the preparation method has good application prospect in preparing novel iron chelator medicines with the effects of resisting inflammation, inhibiting bacteria, promoting diabetic wound healing and the like. Disclosure of Invention The invention aims to provide piroctone derivatives, and a preparation method and application thereof. The invention obtains a series of carboxylic acid (c) and aryl (b) compounds by structurally modifying piroctone, and the iron ion chelating agent provided by the invention has the advantages of novel structure, high solubility and low cytotoxicity. The HIF-alpha stabilizer has good application prospect in preparing novel iron chelators with the effects of resisting inflammation, inhibiting bacteria, promoting wound healing, relieving iron deposition, iron overload and the like and HIF-alpha stabilizer drugs for treating renal anemia and the like. In order to achieve the aim of the invention, the invention is realized by adopting the following technical scheme: The invention provides piroctone derivatives, the structural formula of which is shown as formula (I): , Formula (I) Wherein R 1 is selected from at least one of the following substituents: 。 Further, the piroctone derivatives specifically comprise compounds 1c, 2c, 3c, 4c, 5c, 6b, 7b, 8b, 9b, 10b, 11b, 12b, 13b,