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CN-118026958-B - 3, 4-Dihydro-1 (2H) -naphthalenone derivative, preparation method and application thereof

CN118026958BCN 118026958 BCN118026958 BCN 118026958BCN-118026958-B

Abstract

The invention discloses a 3, 4-dihydro-1 (2H) -naphthalenone derivative, a preparation method and application thereof. The 3, 4-dihydro-1 (2H) -naphthalenone derivative of the invention shows good anti-inflammatory activity and can be used for treating inflammatory diseases such as rheumatoid arthritis and the like.

Inventors

  • HOU GUIGE
  • LI WENXUAN
  • YU LU

Assignees

  • 滨州医学院

Dates

Publication Date
20260512
Application Date
20240111

Claims (6)

  1. 1. A3, 4-dihydro-1 (2H) -naphthalenone derivative having the structural formula: 。
  2. 2. A process for the preparation of 3, 4-dihydro-1 (2H) -naphthalenone derivatives according to claim 1, comprising the steps of Adding into solvent And In the presence of a catalyst, the reaction is carried out to obtain a product, wherein the reaction formula is as follows: wherein, when R 2 is R 1 is bromo; When R 2 is R 1 is bromo or hydroxy.
  3. 3. The preparation method according to claim 2, wherein the product is purified by silica gel column chromatography, and the solvent of the column chromatography is dichloromethane and methanol with a volume ratio of (5-15): 1 or dichloromethane and petroleum ether with a volume ratio of (1-10): 1, so as to obtain the purified product.
  4. 4. The method according to claim 2, wherein the solvent is methanol and the catalyst is sodium hydroxide.
  5. 5. A pharmaceutical formulation comprising a 3, 4-dihydro-1 (2H) -naphthalenone derivative according to claim 1 or a 3, 4-dihydro-1 (2H) -naphthalenone derivative prepared by a method of preparation according to any one of claims 2 to 4.
  6. 6. Use of a3, 4-dihydro-1 (2H) -naphthalenone derivative according to claim 1 or a3, 4-dihydro-1 (2H) -naphthalenone derivative prepared by the preparation method according to any one of claims 2 to 4 in the preparation of an anti-inflammatory drug.

Description

3, 4-Dihydro-1 (2H) -naphthalenone derivative, preparation method and application thereof Technical Field The invention relates to the technical field of pharmaceutical chemistry, in particular to a3, 4-dihydro-1 (2H) -naphthalenone derivative, a preparation method and application thereof. Background Inflammation is a nonspecific reaction of an organism to external stimulus, is also a protective reaction of an immune system, and plays an important role in removing harmful stimulus, activating immune cells and the like. However, excessive inflammatory reaction may cause the occurrence of inflammatory diseases such as gouty arthritis, type 2 diabetes, alzheimer's disease, etc. NLRP3 inflammatory corpuscles are important regulatory centers of inflammatory response, and under the stimulation of various inducers such as Adenosine Triphosphate (ATP), lipopolysaccharide (LPS) and pathogens, N-terminal pryin domain of NOD-like receptor protein 3 (NLRP 3) protein interacts with pyrin domain of apoptosis-related speckle-like protein (ASC) protein to form ASC nucleated protein scaffold, and pro-caspase-1 is subsequently recruited to form protein complex NLRP3 inflammatory corpuscles in cytoplasm through the interaction of CARD-CARD. Studies have shown that activation of the nuclear factor- κB (NF- κB) signaling pathway releases the NF- κB complex into the nucleus, which, in combination with DNA, promotes transcription of NLRP3 protein and assembly of inflammatory corpuscles. Activated inflammatory bodies promote inflammatory responses by mediating pro-caspase-1 to active caspase-1 stimulating macrophage migration to the contact site to produce TNF- α, IL-6, IL-18 and IL-1β, and thus studies using macrophage activation may reflect the inflammatory process. In recent years, ferns have been widely concerned for their medicinal value. Wherein pteridophyte metabolites including lachrysin Z, inosine 1 and inosine 2 have strong smooth muscle relaxing effect. But its structure is unstable, bioavailability is low, and false positive, etc. limit its clinical application. Therefore, based on the pharmacodynamic structure and literature reports, imidazole rings are modified by ring expansion structures, wherein 3, 4-dihydro-1 (2H) -naphthalenone (DHN) is typified, and the imidazole rings have good anti-inflammatory activity by inhibiting the assembly and activation of NLRP3 inflammatory corpuscles. Methoxy substituted 2- (4-methoxy-3- (trifluoromethyl) benzylidene) -3, 4-dihydronaphthalen-1 (2H) -one (6 m, FIG. 1) exhibits potent anti-inflammatory activity by inhibiting phosphorylation of NF- κB signaling pathways IκBa and NF- κ B p65, and down-regulating secretion of inflammatory mediators IL-6, IL-1 β, ROS. The amino-substituted L1 has anti-edema and anti-inflammatory effects, can inhibit the generation of degranulation of mast cells, and has therapeutic effect on mouse ear inflammatory edema caused by arachidonic acid. Disclosure of Invention The invention aims to provide a 3, 4-dihydro-1 (2H) -naphthalenone derivative, a preparation method and application thereof, which are used for solving the problems in the prior art. The invention provides a 3, 4-dihydro-1 (2H) -naphthalenone derivative, which has the following structural formula: wherein R 1 is halogen, methoxy or hydroxy, R 2 is phenyl or pyridinyl, said phenyl or pyridinyl being substituted with one or more R a groups, said R a being selected from nitrogen-containing heterocycles. Preferably, the R a is selected from one or more of N-methylpiperazine, morphinan, and imidazole. Preferably, the R 2 is selected from one or more of the following groups: the invention further provides a preparation method of the 3, 4-dihydro-1 (2H) -naphthalenone derivative, which comprises the following steps: Addition of reactant 1R 2 -CHO and reactant 2 in solvent Strips in the presence of catalyst Under the reaction conditions, the product is obtained, and the reaction formula is: In some embodiments, the synthetic route for the 3, 4-dihydro-1 (2H) -naphthalenone derivatives of the invention is shown in FIG. 6. The substituents for compounds 6a-u, compounds 7a-e, and compounds 8a-n are shown below: Preferably, the product is purified by silica gel column chromatography, wherein the solvent of the column chromatography is dichloromethane with the volume ratio of 5-15:1, methanol or 1-10:1, and petroleum ether, so as to obtain the purified product. Preferably, the solvent comprises methanol. Preferably, the catalyst is sodium hydroxide. Preferably, the reaction temperature is room temperature. In the present application, the room temperature may be 20±5 ℃. Preferably, the mol ratio of the reactant 1 to the reactant 2 is (0.8-1.2): 0.8-1.2. The invention further provides a pharmaceutical composition comprising the 3, 4-dihydro-1 (2H) -naphthalenone derivative or the 3, 4-dihydro-1 (2H) -naphthalenone derivative prepared by the preparation method. The pharmaceutical composition comprises on