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CN-121974872-A - Preparation method of tertiary amine modified honokiol derivative with lung targeting

CN121974872ACN 121974872 ACN121974872 ACN 121974872ACN-121974872-A

Abstract

The invention relates to the technical field of pharmaceutical chemistry, in particular to a preparation method of a tertiary amine modified honokiol derivative with lung targeting, which synthesizes a series of novel derivatives by introducing tertiary amine ligands into honokiol molecules and adopting an ester bond, a carbamate bond or an ether bond covalent connection mode. The method effectively improves the water solubility and metabolic stability of honokiol, remarkably prolongs the in vivo half-life period of honokiol, and realizes the selective enrichment of derivatives in the lung by utilizing the lung tissue targeting characteristic of tertiary amine ligands, thereby solving the technical problems that honokiol has poor pharmacokinetic properties and is difficult to reach and maintain effective treatment concentration at a target position. Among them, ether bond-linked derivative HM-16 shows excellent anti-tumor activity, good tolerance and prolonged residence time in lung, and provides potential candidate drugs for lung cancer targeted therapy.

Inventors

  • PENG HAIBO
  • ZHANG LIJUN
  • HE LIANG

Assignees

  • 重庆市科学技术研究院

Dates

Publication Date
20260505
Application Date
20260120

Claims (9)

  1. 1. The preparation method of the tertiary amine modified honokiol derivative with lung targeting is characterized in that honokiol and a tertiary amine ligand are subjected to covalent connection through an ester bond, a carbamate bond or an ether bond to obtain the tertiary amine modified honokiol derivative.
  2. 2. The method for preparing a tertiary amine modified honokiol derivative with lung targeting as claimed in claim 1, wherein the preparation of honokiol derivative by ester bond connection specifically comprises: Adding a compound succinic anhydride into a reaction container, adding dichloromethane, slowly dropwise adding ligand N-methylpiperazine dissolved in the dichloromethane into the reaction container under stirring, and stirring at normal temperature for reaction for 5-6 hours; After the reaction is finished, removing the solvent by rotary evaporation under reduced pressure, purifying the obtained residue by using silica gel column chromatography, wherein an eluent is a mixed solvent of dichloromethane and methanol, and obtaining an intermediate L-1; adding the obtained intermediate L-1 into a reaction vessel, adding dichloromethane, then sequentially adding EDCI, HOBT, DIPEA and honokiol, and stirring at normal temperature for reaction for 5-6 hours; After the reaction, the reaction solution is diluted in dichloromethane, water is added for extraction, an organic phase is reserved, the organic phase is washed with water for three times, the organic phase is dried by anhydrous sodium sulfate, the solvent is removed by rotary evaporation under reduced pressure, the obtained residue is purified by using a silica gel column chromatography, and the eluent is a mixed solvent of dichloromethane and methanol, so that the compound HP-1 is obtained.
  3. 3. The method for preparing a tertiary amine modified honokiol derivative with lung targeting as claimed in claim 1, wherein the preparation of honokiol derivative by ester bond connection specifically comprises: Adding a ligand T-3 into a reaction container, adding dichloromethane, sequentially adding EDCI, HOBT, DIPEA and honokiol, and stirring at normal temperature for reaction for 5-6 hours; After the reaction, the reaction solution is diluted in dichloromethane, water is added for extraction, an organic phase is reserved, the organic phase is washed with water for three times, the organic phase is dried by anhydrous sodium sulfate, the solvent is removed by rotary evaporation under reduced pressure, the obtained residue is purified by using a silica gel column chromatography, and the eluent is a mixed solvent of dichloromethane and methanol, so that the compound HP-3 is obtained.
  4. 4. The method for preparing a tertiary amine modified honokiol derivative with lung targeting as claimed in claim 1, wherein the preparation of honokiol derivative by urethane linkage specifically comprises: Firstly preparing an active carbonate intermediate of honokiol, and then reacting the active carbonate intermediate with a tertiary amine ligand in dichloromethane; After the reaction, the reaction solution is diluted by adding water, extracted by dichloromethane, the organic phase is washed by water and saturated sodium chloride solution sequentially, dried by anhydrous sodium sulfate and concentrated under reduced pressure, and the obtained residue is purified by silica gel column chromatography to obtain the honokiol derivative.
  5. 5. The method for preparing a tertiary amine modified magnolol derivative with lung targeting as claimed in claim 4, wherein said activated carbonate intermediate is intermediate HK-3, which is prepared by the following steps: Adding honokiol into a reaction container, adding dichloromethane, adding triethylamine, stirring at normal temperature under the protection of nitrogen for reaction for 15 minutes, transferring the reaction system into an ice bath, slowly dripping 1-chloroethyl chloroformate, recovering to room temperature after dripping, stirring for reaction for 3-4 hours, monitoring the reaction process through thin layer chromatography, removing the solvent through reduced pressure rotary evaporation after the reaction is finished, purifying the obtained residue through silica gel column chromatography, and obtaining an intermediate HK-3 by using a mixed solvent of petroleum ether and dichloromethane as an eluent.
  6. 6. The method for preparing a tertiary amine modified magnolol derivative with lung targeting as claimed in claim 5, The intermediate HK-3 reacts with a tertiary amine ligand selected from a ligand T-4 and piperazine or piperidine in methylene chloride at room temperature, and the reaction liquid is subjected to post-treatment and silica gel column chromatography purification to obtain corresponding derivatives HM-1, HM-2, HM-3, HM-4, HM-5, HM-6, HM-7, HM-8, HM-9, HM-10 and HM-11 respectively.
  7. 7. The method for preparing a tertiary amine modified honokiol derivative with lung targeting as claimed in claim 1, wherein the preparation of honokiol derivative by ether linkage specifically comprises: firstly preparing a honokiol intermediate containing terminal halogen, and then carrying out heating reflux reaction on the intermediate containing terminal halogen and a tertiary amine ligand in acetonitrile; after the reaction, the solvent was distilled off under reduced pressure, the residue was dissolved in methylene chloride, diluted with water and extracted with methylene chloride, the organic phase was washed with water and saturated sodium chloride solution sequentially, dried over anhydrous sodium sulfate and concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography to give the honokiol derivative.
  8. 8. The method for preparing a tertiary amine modified honokiol derivative with lung targeting as claimed in claim 7, wherein the honokiol intermediate containing terminal halogen is an intermediate HK-7 or HK-8, and the method for preparing the same is as follows: Adding honokiol, potassium carbonate and catalytic amount of potassium iodide into acetone, stirring at room temperature, adding a compound 5, heating and refluxing for reaction, cooling after the reaction is completed, filtering, concentrating the filtrate under reduced pressure, and purifying the obtained residue by silica gel column chromatography to obtain an intermediate HK-7 or HK-8 respectively.
  9. 9. The method for preparing tertiary amine modified magnolol derivative with lung targeting according to claim 8, The intermediate HK-7 or HK-8 and excessive tertiary amine ligand selected from ligand N-methylpiperazine, T-4 and piperazine or piperidine are heated and reflux reacted in acetonitrile, and the reaction liquid is treated and purified by silica gel column chromatography to obtain corresponding derivatives HM-12, HM-13, HM-14, HM-15, HM-16, HM-17, HM-18 and HM-19 respectively.

Description

Preparation method of tertiary amine modified honokiol derivative with lung targeting Technical Field The invention relates to the technical field of pharmaceutical chemistry, in particular to a preparation method of tertiary amine modified honokiol derivatives with lung targeting. Background Honokiol (Honokiol, HK) is a natural small molecular compound derived from traditional Chinese medicinal material magnolia officinalis, and has various pharmacological activities such as anti-inflammatory, antibacterial and antitumor. In recent years, the antiproliferative effect on various tumor cells such as lung cancer, pancreatic cancer and melanoma has been attracting attention, and the mechanism of action thereof involves inhibition of EGFR receptor, STAT3 signaling pathway, mitochondrial function and the like. Thus, honokiol is considered as a potential antitumor drug candidate. However, the in vivo use of honokiol is severely limited by its poor pharmacokinetic properties. The phenolic hydroxyl group in the chemical structure of the modified starch has poor water solubility and is extremely easy to combine with glucuronic acid or sulfuric acid in vivo, so that the modified starch has rapid metabolism and extremely short half-life. More importantly, honokiol is difficult to effectively enrich in target tissues (such as lung tumor tissues), and a sufficient therapeutic concentration cannot be achieved and maintained, which greatly hinders further clinical transformation and application thereof. Thus, there is a great need in the art to develop a strategy that can improve the pharmacokinetic properties of honokiol, particularly its pulmonary targeting enrichment capacity. Disclosure of Invention The invention aims to provide a preparation method of a tertiary amine modified honokiol derivative with lung targeting, which solves the problem that honokiol is difficult to effectively enrich in lung target tissues and exert a therapeutic effect due to poor pharmacokinetic properties (such as poor water solubility, fast metabolism and short half-life). In order to achieve the above purpose, the invention provides a preparation method of a tertiary amine modified honokiol derivative with lung targeting, which is characterized in that honokiol and a tertiary amine ligand are covalently connected through an ester bond, a carbamate bond or an ether bond to obtain the tertiary amine modified honokiol derivative. Wherein, the honokiol derivative is prepared by ester bond connection and specifically comprises: Adding a compound succinic anhydride into a reaction container, adding dichloromethane, slowly dropwise adding ligand N-methylpiperazine dissolved in the dichloromethane into the reaction container under stirring, and stirring at normal temperature for reaction for 5-6 hours; After the reaction is finished, removing the solvent by rotary evaporation under reduced pressure, purifying the obtained residue by using silica gel column chromatography, wherein an eluent is a mixed solvent of dichloromethane and methanol, and obtaining an intermediate L-1; adding the obtained intermediate L-1 into a reaction vessel, adding dichloromethane, then sequentially adding EDCI, HOBT, DIPEA and honokiol, and stirring at normal temperature for reaction for 5-6 hours; After the reaction, the reaction solution is diluted in dichloromethane, water is added for extraction, an organic phase is reserved, the organic phase is washed with water for three times, the organic phase is dried by anhydrous sodium sulfate, the solvent is removed by rotary evaporation under reduced pressure, the obtained residue is purified by using a silica gel column chromatography, and the eluent is a mixed solvent of dichloromethane and methanol, so that the compound HP-1 is obtained. Wherein, the honokiol derivative is prepared by ester bond connection and specifically comprises: Adding a ligand T-3 into a reaction container, adding dichloromethane, sequentially adding EDCI, HOBT, DIPEA and honokiol, and stirring at normal temperature for reaction for 5-6 hours; After the reaction, the reaction solution is diluted in dichloromethane, water is added for extraction, an organic phase is reserved, the organic phase is washed with water for three times, the organic phase is dried by anhydrous sodium sulfate, the solvent is removed by rotary evaporation under reduced pressure, the obtained residue is purified by using a silica gel column chromatography, and the eluent is a mixed solvent of dichloromethane and methanol, so that the compound HP-3 is obtained. Wherein, the honokiol derivative is prepared by urethane bond connection and specifically comprises the following steps: Firstly preparing an active carbonate intermediate of honokiol, and then reacting the active carbonate intermediate with a tertiary amine ligand in dichloromethane; After the reaction, the reaction solution is diluted by adding water, extracted by dichloromethane, the organic phase is washed by water