Preparation method of lung-targeting tertiary amine modified honokiol derivative

Abstract

The invention relates to the technical field of medicinal chemistry, in particular to a preparation method of a lung-targeting tertiary amine modified honokiol derivative, which is characterized in that a series of novel derivatives are synthesized by introducing a tertiary amine ligand into honokiol molecules and adopting an ester bond, carbamate bond or ether bond covalent linkage mode. The water solubility and metabolic stability of honokiol are effectively improved, the in-vivo half-life period of honokiol is remarkably prolonged, the lung tissue targeting characteristic of the tertiary amine ligand is utilized, selective enrichment of the derivative in the lung is achieved, and the selectivity of the derivative in the lung is improved. Therefore, the technical problem that honokiol is difficult to reach and maintain an effective treatment concentration at a target site due to poor pharmacokinetic properties is solved. Wherein the ether bond connected derivative HM-16 shows excellent anti-tumor activity, good tolerance and prolonged in-lung residence time, and a potential candidate drug is provided for targeted therapy of lung cancer.

Description

Technical Field

[0001] This invention relates to the field of medicinal chemistry, and in particular to a method for preparing lung-targeting tertiary amine-modified magnolol derivatives. Background Technology

[0002] Honokiol (HK) is a natural small-molecule compound derived from the traditional Chinese medicinal herb Magnolia officinalis, possessing various pharmacological activities including anti-inflammatory, antibacterial, and antitumor effects. In recent years, its antiproliferative effects against various tumor cells, such as lung cancer, pancreatic cancer, and melanoma, have attracted widespread attention. Its mechanism of action involves inhibition of EGFR receptors, the STAT3 signaling pathway, and mitochondrial function. Therefore, honokiol is considered a promising antitumor drug candidate.

[0003] However, the in vivo application of magnolol is severely limited by its poor pharmacokinetic properties. The phenolic hydroxyl group in its chemical structure results in poor water solubility, and it readily binds to glucuronic acid or sulfuric acid in vivo, leading to rapid metabolism and an extremely short half-life. More critically, magnolol is difficult to effectively accumulate in target tissues (such as lung tumor tissue), failing to reach and maintain sufficient therapeutic concentrations, which greatly hinders its further clinical translation and application.

[0004] Therefore, there is an urgent need in this field to develop a strategy that can improve the pharmacokinetic properties of magnolol, especially to enhance its ability to target and accumulate in the lungs. Summary of the Invention

[0005] The purpose of this invention is to provide a method for preparing lung-targeting tertiary amine-modified magnolol derivatives, which solves the problem that magnolol is difficult to effectively accumulate in lung target tissues and exert therapeutic effects due to its poor pharmacokinetic properties (such as poor water solubility, rapid metabolism, and short half-life).

[0006] To achieve the above objectives, the present invention provides a method for preparing tertiary amine-modified magnolol derivatives with lung-targeting properties, wherein magnolol is covalently linked to a tertiary amine ligand via an ester bond, a carbamate bond, or an ether bond to obtain tertiary amine-modified magnolol derivatives.

[0007] Among them, the preparation of magnolol derivatives via ester bond linkage specifically includes: Add the compound succinic anhydride to the reaction vessel, add dichloromethane, and slowly add the ligand N-methylpiperazine dissolved in dichloromethane to the reaction vessel while stirring. Stir the reaction at room temperature for 5 to 6 hours. After the reaction was completed, the solvent was removed by rotary evaporation under reduced pressure. The residue was purified by silica gel column chromatography with a mixed solvent of dichloromethane and methanol as the eluent to obtain intermediate L-1. The obtained intermediate L-1 was added to a reaction vessel, followed by dichloromethane, and then EDCI, HOBT, DIPEA and magnolol were added in sequence. The mixture was stirred at room temperature for 5-6 hours. After the reaction was completed, the reaction solution was diluted in dichloromethane, water was added for extraction, and the organic phase was retained. The organic phase was washed three times with water, dried over anhydrous sodium sulfate, and the solvent was removed by rotary evaporation under reduced pressure. The residue was purified by silica gel column chromatography with a mixed solvent of dichloromethane and methanol as the eluent to obtain compound HP-1.

[0008] Among them, the preparation of magnolol derivatives via ester bond linkage specifically includes: Add ligand T-3 to the reaction vessel, add dichloromethane, and then add EDCI, HOBT, DIPEA and magnolol in sequence. Stir the reaction at room temperature for 5-6 hours. After the reaction was completed, the reaction solution was diluted in dichloromethane, water was added for extraction, and the organic phase was retained. The organic phase was washed three times with water, dried over anhydrous sodium sulfate, and the solvent was removed by rotary evaporation under reduced pressure. The residue was purified by silica gel column chromatography with a mixed solvent of dichloromethane and methanol as the eluent to obtain compound HP-3.

[0009] Among them, the preparation of magnolol derivatives via carbamate linkages specifically includes: First, an active carbonate intermediate of magnolol is prepared, and then the active carbonate intermediate is reacted with a tertiary amine ligand in dichloromethane. After the reaction was completed, the reaction solution was diluted with water, extracted with dichloromethane, and the organic phase was washed successively with water and saturated sodium chloride solution. After drying with anhydrous sodium sulfate, the solution was concentrated under reduced pressure. The residue was purified by silica gel column chromatography to obtain the magnolol derivative.

[0010] The activated carbonate intermediate is intermediate HK-3, and its preparation method is as follows: Honokiol was added to a reaction vessel, followed by dichloromethane and then triethylamine. The mixture was stirred at room temperature for 15 minutes under nitrogen protection. The reaction system was then transferred to an ice bath and 1-chloroethyl chloroformate was slowly added dropwise. After the addition was complete, the mixture was brought back to room temperature and stirred for 3-4 hours. The reaction process was monitored by thin-layer chromatography. After the reaction was completed, the solvent was removed by rotary evaporation under reduced pressure. The residue was purified by silica gel column chromatography using a mixed solvent of petroleum ether and dichloromethane as the eluent to obtain intermediate HK-3.

[0011] The intermediate HK-3 was reacted with ligand T-4 and piperazine or piperidine tertiary amine ligands in dichloromethane at room temperature. The reaction solution was post-treated and purified by silica gel column chromatography to obtain the 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.

[0012] Among them, the preparation of magnolol derivatives via ether linkage specifically includes: First, a terminal halogen-containing intermediate and magnolol are prepared, and then the terminal halogen-containing intermediate and a tertiary amine ligand are reacted by heating and reflux in acetonitrile. After the reaction was completed, the solvent was removed by vacuum distillation, the residue was dissolved in dichloromethane, diluted with water and extracted with dichloromethane, the organic phase was washed successively with water and saturated sodium chloride solution, dried with anhydrous sodium sulfate and concentrated under vacuum, and the obtained residue was purified by silica gel column chromatography to obtain the magnolol derivative.

[0013] The terminal halogen-containing honokiol intermediate is intermediate HK-7 or HK-8, and its preparation method is as follows: Magnolol, potassium carbonate, and a catalytic amount of potassium iodide were added to acetone, stirred at room temperature, and then compound 5 was added. The mixture was heated under reflux until the reaction was complete, cooled, filtered, and the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to obtain intermediates HK-7 or HK-8, respectively.

[0014] The intermediate HK-7 or HK-8 is reacted with an excess of ligands selected from N-methylpiperazine, T-4, and tertiary amine ligands of piperazine or piperidine in acetonitrile under reflux. The reaction solution is then post-treated and purified by silica gel column chromatography to obtain the corresponding derivatives HM-12, HM-13, HM-14, HM-15, HM-16, HM-17, HM-18, and HM-19.

[0015] This invention discloses a method for preparing lung-targeting tertiary amine-modified magnolol derivatives. By introducing tertiary amine ligands into the magnolol molecule and covalently linking them via ester, carbamate, or ether bonds, a series of novel derivatives were synthesized. This effectively improved the water solubility and metabolic stability of magnolol, significantly prolonged its in vivo half-life, and utilized the lung tissue-targeting properties of the tertiary amine ligands to achieve selective enrichment of the derivatives in the lungs. This solves the technical problem of magnolol's poor pharmacokinetic properties, making it difficult to achieve and maintain effective therapeutic concentrations at the target site. Among them, the ether-linked derivative HM-16 exhibited excellent antitumor activity, good tolerability, and prolonged intrapulmonary retention time, providing a potential candidate drug for targeted therapy of lung cancer. Attached Figure Description

[0016] To more clearly illustrate the technical solutions in the embodiments of this application or the prior art, the accompanying drawings used in the description of the embodiments or the prior art will be briefly introduced below.

[0017] Figure 1 This is a synthetic route diagram for intermediates L-1 and L-2 of the present invention.

[0018] Figure 2 This is a synthetic route diagram of compounds HP-1 and HP-2 of the present invention.

[0019] Figure 3 This is a synthetic route diagram for the compound HP-3 of this invention.

[0020] Figure 4 This is a synthetic route diagram for the intermediate HK-3 of this invention.

[0021] Figure 5 This is a synthetic route diagram of compounds HM-1 to HM-11 of the present invention.

[0022] Figure 6 This is a synthetic route diagram of the intermediates HK-1-a and HK-1-b of the present invention.

[0023] Figure 7 This is a synthetic route diagram for compound HD-1 of the present invention.

[0024] Figure 8 This is a synthetic route diagram for compound HD-2 of the present invention.

[0025] Figure 9 This is a synthetic route diagram for the intermediates HK-7 and HK-8 of this invention.

[0026] Figure 10 This is a synthetic route diagram of compounds HM-12 to HM-19 of the present invention. Detailed Implementation

[0027] The embodiments of the present invention are described in detail below. Examples of the embodiments are shown in the accompanying drawings. The embodiments described below with reference to the accompanying drawings are exemplary and intended to explain the present invention, but should not be construed as limiting the present invention.

[0028] Please see Figures 1 to 10 This invention provides a method for preparing lung-targeting tertiary amine modified magnolol derivatives, wherein magnolol is covalently linked to a tertiary amine ligand via an ester bond, a carbamate bond, or an ether bond to obtain tertiary amine modified magnolol derivatives.

[0029] Specifically, the synthesis of compounds HP-1 to HP-3: ①The synthetic routes for compounds L-1 and L-2 are shown in the figure. Figure 1 .

[0030] Synthesis of compound L-1: T-1 (N-methylpiperazine) and 1 (succinic anhydride) were both commercially available. 1 (800 mg, 8.0 mmol, 2.0 equiv) was added to a 50 mL round-bottom flask, followed by 20 mL of DCM. The flask was placed on a stirrer for reaction. Then, T-1 (400 mg, 4.0 mmol, 1.0 equiv) dissolved in 10 mL of DCM was slowly added dropwise to the round-bottom flask for reaction. The mixture was stirred at room temperature for 5–6 h. The reaction was monitored by TLC. After the reaction was complete, the solvent was removed by rotary evaporation under reduced pressure, and then purified by silica gel column chromatography (DCM / MeOH = 20 / 1–2 / 1) to obtain the compound and L-1 (400 mg, 50%). L-2 (300 mg, 45%) was prepared using the same method as L-1.

[0031] ②The synthetic routes for compounds HP-1 and HP-2 are shown in the figure. Figure 2 .

[0032] Synthesis of compound HP-1: L-1 (400 mg, 2.0 mmol, 4.0 equiv) was added to a 25 mL round-bottom flask, followed by 10 mL of DCM. Then, EDCI (230 mg, 1.2 mmol, 2.4 equiv), HOBT (162 mg, 1.2 mmol, 2.4 equiv), DIPEA (516 mg, 4.0 mmol, 8.0 equiv), and HK (133 mg, 0.5 mmol, 1.0 equiv) were added, and the mixture was stirred at room temperature for 5–6 h. The reaction was then monitored by TLC. After the reaction was complete, the reaction solution was diluted in 20 mL of DCM, and 30 mL of water was added. The organic phase was retained during extraction and washed with water (3 × 30 mL). The organic phase was collected, dried over anhydrous sodium sulfate, and the solvent was removed by rotary evaporation under reduced pressure. The resulting product was then purified by silica gel column chromatography (DCM / MeOH = 15 / 1-6 / 1) to obtain the oily liquid compound HP-1 (94 mg, 33%). The synthesis of compound HP-2 (104 mg, 29%) followed the same steps as compound HP-1.

[0033] ③The synthetic route diagram for compound HP-3 is shown below. Figure 3 .

[0034] Synthesis of compound HP-3: T-3 (286 mg, 2.0 mmol, 4.0 equiv) was added to a 25 mL round-bottom flask, followed by 10 mL of DCM. Then, EDCI (230 mg, 1.2 mmol, 2.4 equiv), HOBT (162 mg, 1.2 mmol, 2.4 equiv), DIPEA (516 mg, 4.0 mmol, 8.0 equiv), and HK (133 mg, 0.5 mmol, 1.0 equiv) were added, and the mixture was stirred at room temperature for 5–6 h. The reaction was then monitored by TLC. After the reaction was complete, the reaction solution was diluted in 20 mL of DCM, and 30 mL of water was added. The organic phase was retained during extraction and washed with water (3 × 30 mL). The organic phase was collected, dried over anhydrous sodium sulfate, and the solvent was removed by rotary evaporation under reduced pressure. Then, it was purified by silica gel column chromatography (DCM / MeOH=30 / 1-10 / 1) to obtain the oily liquid compound HP-3 (119 mg, 45%).

[0035] Synthesis of compounds HM-1 ~ HM-11: ①The synthetic route diagram for intermediate HK-3 is shown below. Figure 4 .

[0036] Synthesis of intermediate HK-3: HK (2.0 g, 7.5 mmol, 1.0 equiv) was added to a 50 mL round-bottom flask, followed by 15 mL of DCM. Then, TEA (2.27 g, 22.5 mmol, 3.0 equiv) was added, and the mixture was stirred at room temperature for 15 min under nitrogen protection. The flask was then transferred to an ice bath, and 4-(1-chloroethyl chloroformate) (4.29 g, 21.6 mmol, 4.0 equiv) was slowly added dropwise. After the addition was complete, the reaction mixture was stirred at room temperature for 3–4 h. The reaction was monitored by TLC. After the reaction was complete, the solvent was removed by rotary evaporation under reduced pressure, followed by purification by silica gel column chromatography (PE / DCM = 5 / 1–2 / 1) to obtain the oily liquid compound HK-3 (3.59 g, 98%).

[0037] ②The synthetic route diagrams for compounds HM-1 ~ HM-11 are shown below. Figure 5 .

[0038] Synthesis of compound HM-1: HK-3 (200 mg, 0.417 mmol, 1.0 equiv) was added to a 10 mL round-bottom flask, followed by 5 mL of DCM, and then T-4 (162 mg, 1.0 mmol, 3.0 equiv). The mixture was stirred at room temperature for 2–3 h. The reaction was monitored by TLC. After the reaction was complete, the reaction solution was diluted in 5 mL of DCM, and then 10 mL of water was added. The organic phase was retained during extraction. The organic phase was washed with water (3 × 10 mL), then with saturated sodium chloride solution (3 × 10 mL). The organic phase was dried over anhydrous sodium sulfate, and the solvent was removed by rotary evaporation under reduced pressure. The solution was then purified by silica gel column chromatography (DCM / MeOH = 30 / 1–6 / 1) to obtain the oily liquid compound HM-1 (60 mg, 33%). The synthesis steps of compounds HM-2 (58 mg, 30%), HM-3 (81 mg, 34%), HM-4 (91 mg, 35%), HM-5 (65 mg, 24%), HM-6 (65 mg, 33.5%), HM-7 (58 mg, 28.5%), HM-8 (95 mg, 35%), HM-9 (75 mg, 32%), HM-10 (76 mg, 37%), and HM-11 (55 mg, 32%) are the same as those of compound HM-1.

[0039] Synthesis of compounds HD-1 ~ HD-2: ①The synthetic route diagrams for intermediates HK-1-a and HK-1-b are shown below. Figure 6 .

[0040] Synthesis of compounds HK-1-a and HK-1-b: HK and 2 were both commercially available. HK (3.2 g, 12.0 mmol, 1.0 equiv) was added to a 50 mL round-bottom flask, followed by 20 mL of DCM. Then, TEA (2.92 g, 28.86 mmol, 2.4 equiv) and 2 (7.3 g, 24.0 mmol, 2.0 equiv) were added, and the mixture was stirred at room temperature for 5–6 h. The reaction was monitored by TLC. After the reaction was complete, the reaction solution was diluted in 30 mL of DCM, and 50 mL of water was added. The organic phase was retained for extraction and washed several times with water. The organic phase was dried over anhydrous sodium sulfate, and the solvent was removed by rotary evaporation under reduced pressure. The residues were then purified by silica gel column chromatography (PE / EA = 10 / 1–2 / 1) to obtain the oily liquid compounds HK-1-a (5.1 g, 71%) and HK-1-b (200 mg).

[0041] ②The synthetic route of compound HD-1 is shown in the figure. Figure 7 .

[0042] Synthesis of compound HD-1: HK-1-b (200 mg, 0.463 mmol, 1.0 equiv) was added to a 10 mL round-bottom flask, followed by 5 mL of DCM, and then T-1 (139 mg, 1.389 mmol, 3.0 equiv). The mixture was stirred at room temperature for 2–3 h. The reaction was monitored by TLC. After the reaction was complete, the reaction solution was diluted in 5 mL of DCM, and then 10 mL of water was added. The organic phase was retained during extraction and washed repeatedly with water until the aqueous layer no longer showed a distinct yellow color. The organic phase was dried over anhydrous sodium sulfate, and the solvent was removed by rotary evaporation under reduced pressure. The solution was then purified by silica gel column chromatography (DCM / MeOH = 40 / 1–10 / 1) to obtain the oily liquid compound HD-1 (80 mg, 44%).

[0043] ③The synthetic route diagram for compound HD-2 is shown below. Figure 8 .

[0044] Synthesis of compound HK-4: HK (1.065 mg, 4.0 mmol, 4.0 equiv) was added to a 50 mL round-bottom flask, evacuated, and then purged with nitrogen for protection. Next, 25 mL of dry DCM was added to the sealed flask, followed by TEA (101 mg, 1.0 mmol, 1.0 equiv). The mixture was stirred at room temperature for 15 min. The flask was then transferred to an ice bath, and TESCl (150 mg, 1.0 mmol, 1.0 equiv) was dissolved in 5 mL of dry DCM and slowly added dropwise over 10 min. The reaction flask was then transferred to room temperature and stirred for 2–3 h. The reaction was monitored by TLC. After the reaction was complete, the solvent was removed by rotary evaporation under reduced pressure, followed by purification by silica gel column chromatography (PE / DCM = 15 / 1–3 / 1) to obtain the oily liquid compound HK-4 (800 mg, 52.5%).

[0045] Synthesis of compound HK-5: HK-4 (800 mg, 2.1 mmol, 1.0 equiv) was added to a 25 mL round-bottom flask, followed by 10 mL of DCM, and then TEA (255 mg, 2.52 mmol, 1.2 equiv). The mixture was stirred at room temperature for 15 min. The flask was then transferred to an ice bath, and HK-4 (450 mg, 3.15 mmol, 1.5 equiv) was slowly added dropwise until the mixture was completely dissolved. The reaction flask was then stirred at room temperature for 1–2 h. The reaction was monitored by TLC. After the reaction was complete, the solvent was removed by rotary evaporation under reduced pressure, and the mixture was then purified by silica gel column chromatography (PE / DCM = 18 / 1–5 / 1) to obtain the oily liquid compound HK-5 (620 mg, 60%).

[0046] Synthesis of compound HK-6: HK-5 (400 mg, 0.821 mmol, 1.0 equiv) was added to a 25 mL round-bottom flask, followed by 8 mL of DCM, and then T-5 (276 mg, 1.64 mmol, 2.0 equiv). The mixture was stirred at room temperature for 2–3 h. The reaction was monitored by TLC. After the reaction was complete, the solvent was removed by rotary evaporation under reduced pressure, and then purified by silica gel column chromatography (PE / EA = 20 / 1–4 / 1) to obtain the oily liquid compound HK-6 (220 mg, 46%).

[0047] Synthesis of compound HD-2: HK-6 (220 mg, 0.383 mmol, 1.0 equiv) was added to a 10 mL round-bottom flask, followed by 5 mL of DCM, and then 0.1 mL of TBAF. The mixture was stirred at room temperature for 3–6 h. The reaction was monitored by TLC. After the reaction was complete, the solvent was removed by rotary evaporation under reduced pressure, and then purified by silica gel column chromatography (DCM / MeOH = 60 / 1–20 / 1) to obtain the oily liquid compound HD-2 (60 mg, 34%).

[0048] Synthesis of compounds HM-12 ~ HM-19: ①The synthesis route diagram for intermediates HK-7 and HK-8 is shown below. Figure 9 .

[0049] Synthesis of compound HK-7 (n=1): HK (1.0 g, 3.75 mmol, 1.0 equiv), potassium carbonate (829 mg, 22.5 mmol, 6.0 equiv), and potassium iodide (24 mg, 0.15 mmol, 0.04 equiv) were added to a 50 mL round-bottom flask, followed by 25 mL of acetone. The mixture was stirred at room temperature for 30 min. Then, 3 mL of compound 5 was added at room temperature, and the reaction flask was transferred to a 66 °C oil bath and refluxed for 24 h. The reaction was monitored by TLC. After the reaction was completed, the reaction flask was cooled to room temperature. The potassium carbonate was then removed by filtration through a sand funnel, the solvent was removed by rotary evaporation under reduced pressure, and the mixture was purified by silica gel column chromatography (PE / DCM = 12 / 1 - 6 / 1) to obtain the oily liquid compound HK-7 (1.5 g, 79%). The synthesis steps for compound HK-8 (n=3) (1.64 g, 77%) were the same as those for compound HK-7.

[0050] ②The synthetic route diagrams for compounds HM-12 ~ HM-19 are shown below. Figure 10 .

[0051] Synthesis of compound HM-12: HK-7 (200 mg, 0.395 mmol, 1.0 equiv) was added to a 10 mL round-bottom flask, followed by 8 mL of MeCN. T-1 (249 mg, 3.16 mmol, 8.0 equiv) was then added at room temperature. The reaction flask was then placed in a 90 °C oil bath and refluxed for 24 h. The reaction was monitored by TLC. After the reaction was completed, the reaction flask was cooled to room temperature. The solvent was removed by rotary evaporation under reduced pressure, and the solid residue was dissolved in 10 mL of DCM. 10 mL of water was added, and the organic phase was retained during extraction. The organic phase was washed with water (3 × 10 mL) and then with saturated sodium chloride solution (3 × 10 mL). The organic phase was dried over anhydrous sodium sulfate, and the solvent was removed by rotary evaporation under reduced pressure. The solution was then purified by silica gel column chromatography (DCM / MeOH = 40 / 1 - 8 / 1) to obtain the oily liquid compound HM-12 (66 mg, 30.5%). The synthesis steps of compounds HM-13 (80 mg, 28%), HM-14 (65 mg, 32%), HM-15 (60 mg, 23%), HM-16 (68 mg, 32%), HM-17 (88 mg, 32%), HM-18 (70 mg, 34.5%), and HM-19 (63 mg, 24%) were the same as those of compound HM-12.

[0052] Compound structure characterization: 1) Characterization data of compound HP-1: 1H NMR (400 MHz, CDCl3) δ 7.26 – 7.25 (m, 2H), 7.17 (d, J = 8.8 Hz,2H), 7.10 – 7.07 (m, 2H), 6.02 – 5.86 (m, 2H), 5.13 – 5.05 (m, 4H), 3.69 (s,4H), 3.57 (s, 2H), 3.49 (s, 2H), 3.41 (d, J = 6.4 Hz, 2H), 3.33 (d, J = 6.4Hz, 2H), 2.93 (t, J = 13.2 Hz, 2H), 2.77 – 2.69 (m, 4H), 2.56 – 2.40 (m,10H), 2.36 (s, 6H). 13C NMR (100 MHz, CDCl3) δ 122.25, 77.32, 77.21, 77.01,76.69, 59.50, 38.13, 31.92, 31.23, 29.69, 29.36, 22.69, 14.13. 2) Characterization data of compound HP-2: 1H NMR (400 MHz, CDCl3) δ 7.24 (d, J = 8.0 Hz, 2H), 7.14 (d, J = 10.4Hz, 2H), 7.07 – 7.04 (m, 2H), 5.98 – 5.83 (m, 2H), 5.10 – 5.02 (m, 4H), 3.67– 3.57 (m, 4H), 3.52 – 3.46 (m, 6H), 3.43 – 3.36 (m, 4H), 3.31 (t, J = 9.6Hz, 8H), 2.90 (t, J = 12.8 Hz, 2H), 2.72 – 2.65 (m, 4H), 2.58 – 2.53 (m, 4H),2.52 – 2.35 (m, 10H). 13C NMR (100 MHz, CDCl3) δ 171.72, 171.53, 169.14,169.11, 148.27, 145.96, 138.00, 136.94, 135.94, 135.42, 133.65, 131.75,130.80, 130.72, 128.61, 127.86, 122.84, 122.24, 116.23, 116.19, 77.46, 77.34,77.14, 76.82, 69.85, 60.35, 58.91, 57.77, 53.52, 53.03, 45.07, 45.02, 41.60, 41.52, 39.58, 34.54, 29.58, 29.40, 27.93, 27.76, 14.18. 3) Characterization data of compound HP-3: 1H NMR (400 MHz, CDCl3) δ 7.21 (d, J = 6.0 Hz, 2H), 7.16 (d, J = 4.4Hz, 2H), 7.03 – 6.89 (m, 2H), 6.00 – 5.83 (m, 2H), 5.11 – 4.00 (m, 4H), 3.37(d, J = 6.4 Hz, 2H), 3.22 (d, J = 6.4 Hz, 2H), 2.88 (d, J = 10.8 Hz, 2H), 2.70 (d, J = 9.2 Hz, 2H), 2.29 (s, 3H), 2.23 (s, 3H), 2.13 – 2.01 (m, 4H),1.97 – 1.89 (m, 4H), 1.84 – 1.76 (m, 2H), 1.72 – 1.62 (m, 2H). 13C NMR (100MHz, CDCl3) δ 173.43, 173.26, 148.26, 145.94, 138.03, 136.92, 135.55, 135.40,134.07, 131.45, 131.00, 130.92, 128.65, 128.10, 122.60, 122.08, 116.47,116.25, 77.39, 77.27, 77.07, 76.75, 54.88, 54.61, 46.36, 46.22, 40.65, 40.22, 39.57, 34.48, 28.25, 27.83. 4) Characterization data of compound HM-1: 1H NMR (400 MHz, CDCl3) δ 7.24 (s, 2H), 7.16 (d, J = 6.8 Hz, 2H), 7.10 (d, J = 8.4 Hz, 2H), 6.02 – 5.87 (m, 2H), 5.12 – 5.04 (m, 4H), 3.72 (s,2H), 3.60 (s, 2H), 3.47 – 3.33 (m, 8H), 2.58 – 2.22 (m, 12H), 1.14 – 1.06 (m,6H). 13C NMR (100 MHz, CDCl3) δ 156.22, 152.10, 144.77, 125.04, 122.26, 52.44, 52.27, 52.18, 44.61, 44.05, 11.89. 5) Characterization data of compound HM-2: 1H NMR (400 MHz, CDCl3) δ 7.25 – 7.23 (m, 2H), 7.15 (d, J = 7.2 Hz, 2H), 7.09 (d, J = 8.4 Hz, 2H), 6.01 – 5.86 (m, 2H), 5.11 – 5.03 (m, 4H), 3.69(s, 2H), 3.57 (s, 2H), 3.44 – 3.32 (m, 8H), 2.77 – 2.66 (m, 2H), 2.56 (s,4H), 2.40 (d, J = 19.2 Hz, 4H), 1.08 – 1.01(m, 12H). 13C NMR (100 MHz, CDCl3)δ 153.45, 153.25, 148.78, 146.56, 137.45, 137.09, 135.96, 135.20, 134.16, 131.67, 130.82, 130.69, 128.43, 128.00, 123.14, 122.31, 116.18, 116.08, 54.63, 48.51, 48.28, 44.80, 44.51, 44.27, 44.01, 39.60, 34.83, 18.34, 18.25. 6) Characterization data of compound HM-3: 1H NMR (400 MHz, CDCl3) δ 7.26 (d, J = 7.2 Hz, 2H), 7.16 (d, J = 7.6Hz, 2H), 7.12 – 7.09 (m, 2H), 6.02 – 5.86 (m, 2H), 5.12 – 5.05 (m, 4H), 3.65(s, 2H), 3.54 (s, 2H), 3.41 – 3.34 (m, 8H), 2.66 (s, 4H), 2.51 (d, J = 16.0Hz, 4H), 1.69 – 1.59 (m, 2H), 0.52 – 0.40 (m, 8H). 13C NMR (100 MHz, CDCl3) δ153.55, 153.28, 148.80, 146.53, 137.45, 137.11, 135.99, 135.19, 134.08,131.63, 130.83, 130.78, 128.43, 128.01, 123.16, 122.33, 116.21, 116.09,53.17, 52.87, 44.51, 44.34, 44.02, 43.85, 39.61, 38.46, 38.34, 34.88, 5.96,5.88. 7) Characterization data of compound HM-4: 1H NMR (400 MHz, CDCl3) δ 7.26 – 7.23 (m, 2H), 7.14 (d, J = 7.6 Hz,2H), 7.10 – 7.08 (m, 2H), 6.00 – 5.85 (m, 2H), 5.11 – 5.03 (m, 4H), 3.70 (s, 2H), 3.58 (s, 2H), 3.44 – 3.32 (m, 8H), 2.54 (s, 4H), 2.50 – 2.42 (m, 2H), 2.40 (s, 2H), 2.33 (s, 2H), 1.86 – 1.82 (m, 4H), 1.70 – 1.67 (m, 4H), 1.56 –1.51 (m, 4H), 1.44 – 1.36 (m, 4H). 13C NMR (100 MHz, CDCl3) δ 153.50, 153.21,151.13, 151.06, 148.80, 146.49, 137.60, 137.08, 135.91, 135.37, 134.12,131.70, 130.88, 130.76, 129.26, 129.14, 128.52, 128.09, 123.14, 122.38,120.63, 120.36, 116.80, 116.74, 116.28, 116.13, 49.48, 49.30, 44.46, 43.94, 39.61, 34.89. 8) Characterization data of compound HM-5: 1H NMR (400 MHz, CDCl3) δ 7.26 – 7.23 (m, 2H), 7.13 (d, J = 4.0 Hz, 2H), 7.07 (d, J = 8.0 Hz, 2H), 6.00 – 5.85 (m, 2H), 5.11 – 5.02 (m, 4H), 4.37– 4.26 (m, 2H), 4.13 (d, J = 12.0 Hz, 2H), 3.39 – 3.31 (m, 4H), 3.00 – 2.94(m, 1H), 2.81 – 2.66 (m, 4H), 2.53 – 2.44 (m, 9H), 1.89 (d, J = 12.0 Hz, 2H), 1.76 (s, 2H), 1.60 (s, 10H), 1.41 (d, J = 24.0 Hz, 6H). 13C NMR (100 MHz, CDCl3) δ 153.41, 153.15, 148.81, 146.53, 137.38, 137.10, 135.96, 135.20,134.11, 131.66, 130.82, 130.71, 128.38, 127.98, 123.22, 122.26, 116.17,116.06, 62.49, 62.41, 50.21, 49.98, 44.00, 39.59, 34.78, 28.35, 27.73, 26.23, 26.04, 24.64, 24.52. 9) Characterization data of compound HM-6: 1H NMR (400 MHz, CDCl3) δ 7.23 (s, 2H), 7.16 (d, J = 7.6 Hz, 2H), 7.11 – 7.08 (m, 2H), 6.02 – 5.85 (m, 2H), 5.12 – 5.03 (m, 4H), 3.72 – 3.59(m, 8H), 3.45 (d, J = 4.4 Hz, 4H), 3.41 – 3.32 (m, 4H), 2.63 – 2.55 (m, 8H),2.42 (d, J = 26.0 Hz, 4H). 13C NMR (100 MHz, CDCl3) δ 153.52, 153.25, 148.75, 146.50, 137.56, 137.07, 135.90, 135.34, 134.11, 131.66, 130.88, 130.72, 128.53, 128.06, 123.12, 122.31, 116.27, 116.13, 59.39, 59.32, 57.77, 52.78, 52.58, 52.40, 44.56, 44.03, 43.79, 39.60, 34.86. 10) Characterization data of compound HM-7: 1H NMR (400 MHz, CDCl3) δ 7.22 (d, J = 7.2 Hz, 2H), 7.12 (d, J = 6.8Hz, 2H), 7.07 (d, J = 7.6 Hz, 2H), 5.89 – 5.83 (m, 2H), 5.09 – 5.01 (m, 4H),3.71 (s, 2H), 3.58 (s, 2H), 3.53 – 3.45 (m, 8H), 3.38 – 3.31 (m, 10H), 2.61(t, J = 10.8 Hz, 2H), 2.54 (s, 6H), 2.39 (s, 2H), 2.34 (s, 2H). 13C NMR (100MHz, CDCl3) δ 153.44, 153.21, 148.76, 146.51, 137.45, 137.07, 135.92, 135.18,134.10, 131.64, 130.79, 130.69, 128.42, 127.96, 123.13, 122.32, 116.21,116.08, 69.92, 69.83, 58.92, 58.86, 57.89, 57.72, 53.38, 53.06, 44.34, 44.13,43.81, 43.61, 39.57, 34.83. 11) Characterization data of compound HM-8: 1H NMR (400 MHz, CDCl3) δ 7.33 – 7.26 (m, 6H), 7.20 – 7.13 (m, 4H), 6.99 – 6.88 (m, 6H), 6.04 – 5.88 (m, 2H), 5.14 – 5.04 (m, 4H), 3.82 (s, 2H),3.73 (s, 2H), 3.62 – 3.60 (m, 4H), 3.43 (d, J = 6.8 Hz, 2H), 3.35 (d, J = 6.4Hz, 2H), 3.25 – 3.22 (m, 4H), 3.11 (s, 2H), 3.04 (s, 2H). 13C NMR (100 MHz, CDCl3) δ 153.50, 153.21, 151.13, 151.06, 148.80, 146.49, 137.60, 137.08,135.91, 135.37, 134.12, 131.70, 130.88, 130.76, 129.26, 129.14, 128.52,128.09, 123.14, 122.38, 120.63, 120.36, 116.80, 116.74, 116.28, 116.13,49.48, 49.30, 44.46, 43.94, 39.61, 34.89. 12) Characterization data of compound HM-9: 1H NMR (400 MHz, CDCl3) δ 7.25 (s, 2H), 7.17 (d, J = 4.8 Hz, 2H), 7.10 (d, J = 8.4 Hz, 2H), 6.02 – 5.86 (m, 2H), 5.13 – 5.03 (m, 4H), 3.67 (s,2H), 3.51 (s, 6H), 3.41 – 3.32 (m, 12H), 1.47 (d, J = 11.2 Hz, 18H). 13C NMR (100 MHz, CDCl3) δ 154.55, 153.49, 153.25, 148.70, 147.40, 146.33, 141.38, 137.69, 137.03, 135.82, 135.34, 133.97, 131.63, 130.87, 130.81, 128.55, 128.05, 123.07, 122.31, 116.30, 116.17, 109.99, 86.09, 80.35, 80.18, 44.24, 43.82, 39.60, 34.85, 28.38. 13) Characterization data of compound HM-10: 1H NMR (400 MHz, CDCl3) δ 7.28 (d, J = 4.0 Hz, 2H), 7.16 – 7.10 (m,4H), 6.02 – 5.89 (m, 2H), 5.13 – 5.05 (m, 4H), 3.58 (d, J = 44.0 Hz, 4H),3.39 – 3.35 (m, 8H), 1.68 – 1.45 (m, 12H). 13C NMR (100 MHz, CDCl3) δ 153.65,153.36, 148.92, 146.67, 137.20, 136.10, 135.15, 134.08, 131.60, 130.79, 128.30, 128.00, 123.28, 122.31, 116.04, 116.01, 45.18, 39.62, 34.84, 26.04, 25.62, 24.34, 24.24. 14) Characterization data of compound HM-11: 1H NMR (400 MHz, CD3OD) δ 7.23 – 7.07 (m, 6H), 5.59 – 5.84 (m, 2H), 5.11 – 4.99 (m, 4H), 4.31 (s, 1H), 4.18 (s, 1H), 4.11 (s, 1H), 13C NMR (100 MHz, CD3OD) δ 152.94, 148.48, 146.31, 138.15, 136.90, 135.69, 134.18, 132.03, 130.92, 130.82, 128.80, 127.90, 122.95, 122.62, 122.39, 116.36, 116.25, 49.74, 49.52, 49.31, 49.09, 47.93, 47.58, 41.27, 40.68, 39.55, 34.76. 15) Characterization data of compound HD-1: 1H NMR (400 MHz, CDCl3) δ 7.15 (s, 2H), 7.12 – 7.08 (m, 3H), 6.66 (d,J = 8.4 Hz, 1H), 6.06 – 5.92 (m, 2H), 5.13 – 5.06 (m, 4H), 3.51 (s, 4H),3.40 (d, J = 6.4 Hz, 4H), 2.38 – 2.31 (m, 7H). 13C NMR (100 MHz, CDCl3) δ153.93, 153.73, 146.38, 137.59, 137.18, 136.59, 134.64, 130.86, 130.80, 129.60, 128.09, 127.94, 125.75, 123.02, 116.04, 115.13, 54.43, 45.90, 43.92, 43.41, 39.65, 34.82. 16) Characterization data of compound HD-2: 1H NMR (400 MHz, CDCl3) δ 7.14 – 7.08 (m, 5H), 6.65 (d, J = 8.0 Hz,1H), 6.06 – 5.91 (m, 2H), 5.09 (d, J = 8.0 Hz, 4H), 4.17 (d, J = 12.0 13C NMR (100 MHz, CDCl3) δ153.94, 153.67, 146.56, 137.41, 137.23, 136.75, 134.77, 130.81, 130.72, 129.50, 128.04, 127.84, 125.99, 123.08, 115.98, 115.80, 115.24, 62.46, 50.09, 44.12, 43.87, 39.65, 34.76, 27.93, 27.13, 25.86, 24.51. 17) Characterization data of compound HK-7: 1H NMR (400 MHz, CDCl3) δ 7.36 – 7.32 (m, 2H), 7.14 – 7.09 (m, 2H), 6.93 – 6.90 (m, 2H), 6.07 – 5.94 (m, 2H), 5.09 (t, J = 26.4 Hz, 4H), 4.16 (t,J = 10.8 Hz, 2H), 4.07 (t, J = 10.8 Hz, 2H), 3.66 (t, J = 12.4 Hz, 2H), 3.50(t, J = 12.4 Hz, 2H), 3.44 – 3.37 (m, 4H), 2.40 – 2.34 (m, 2H), 2.25 – 2.20(m, 2H). 13C NMR (100 MHz, CDCl3) δ 155.32, 153.89, 137.72, 136.94, 132.69,131.21, 131.00, 130.68, 128.21, 128.00, 127.92, 115.61, 115.50, 112.67,110.77, 65.75, 65.28, 39.44, 34.59, 32.55, 32.31, 30.57, 30.27. 18) Characterization data of compound HM-12: 1H NMR (400 MHz, CDCl3) δ 7.31 (d, J = 6.0 Hz, 2H), 7.10 – 7.03 (m,2H), 6.88 – 6.83 (m, 2H), 6.03 – 5.90 (m, 2H), 5.08 – 4.99(m, 4H), 4.03 (t, J= 10.8 Hz, 2H), 3.95 (t, J = 10.8 Hz, 2H), 3.40 – 3.33 (m, 4H), 2.60 – 2.29(m, 26H), 2.02 – 1.97 (m, 2H), 1.91 – 1.84 (m, 2H). 13C NMR (100 MHz, CDCl3)δ 155.59, 154.20, 137.77, 137.12, 132.35, 131.08, 130.87, 130.65, 128.26, 127.84, 127.81, 115.48, 115.31, 112.80, 110.58, 66.92, 66.15, 55.29, 55.17, 54.98, 54.91, 53.00, 52.87, 45.88, 45.85, 39.42, 34.61, 26.83, 26.65. 19) Characterization data of compound HM-13: 1H NMR (400 MHz, CDCl3) δ 7.32 (d, J = 6.4 Hz, 2H), 7.10 – 7.04 (m,2H), 6.89 – 6.84 (m, 2H), 6.04 – 5.91 (m, 2H), 5.10 – 5.00 (m, 4H), 4.05 (t,J = 10.8 Hz, 2H), 3.96 (t, J = 10.8 Hz, 2H), 3.45 – 3.34 (m, 12H), 2.57 (t, J= 14.4 Hz, 2H), 2.43 (d, J = 6.0 Hz, 6H), 2.32 (s, 4H), 2.04 – 1.97 (m, 2H),1.90 – 1.84 (m, 3H), 1.46 (d, J = 3.2 Hz, 18H). 13C NMR (100 MHz, CDCl3) δ155.58, 154.74, 154.19, 137.77, 137.12, 132.39, 131.12, 130.90, 130.71,130.63, 128.25, 127.83, 115.50, 115.33, 112.81, 110.59, 109.99, 79.60, 66.81,66.05, 55.37, 55.21, 53.07, 52.94, 39.43, 34.62, 28.42, 26.80, 26.60. 20) Characterization data of compound HM-14: 1H NMR (400 MHz, CDCl3) δ 7.32 (d, J = 6.8 Hz, 2H), 7.10 – 7.04 (m,2H), 6.86 (t, J = 18.0 Hz, 2H), 6.09 – 5.89 (m, 2H), 5.10 – 5.01(m, 4H), 4.04 (t, J = 10.8 Hz, 2H), 3.95 (t, J = 10.8 Hz, 2H), 3.42 – 3.34 (m, 4H), 2.59 – 2.40 (m, 12H), 2.08 – 2.02 (m, 2H), 1.96 – 1.90 (m, 2H), 1.66 – 1.60(m, 8H), 1.46 – 1.41 (m, 8H). 13C NMR (100 MHz, CDCl3) δ 155.59, 154.20,137.77, 137.18, 132.41, 131.09, 130.85, 130.71, 128.33, 127.86, 127.81,115.50, 115.31, 112.95, 110.62, 67.16, 66.38, 56.20, 55.99, 54.58, 54.39,39.43, 34.65, 26.72, 26.40, 25.68, 25.47, 24.24, 24.10. 21) Characterization data of compound HM-15: 1H NMR (400 MHz, CDCl3) δ 7.30 (d, J = 5.2 Hz, 2H), 7.09 – 7.02 (m,2H), 6.87 – 6.82 (m, 2H), 6.03 – 5.90 (m, 2H), 5.08 – 4.98 (m, 4H), 4.01 (t,J = 12.0 Hz, 2H), 3.93 (t,J = 12.0 Hz, 2H), 3.39 – 3.32 (m, 4H), 3.04 – 2.90(m, 4H), 2.59 – 2.36 (m, 14H), 2.00 – 1.80 (m, 12H), 1.66 – 1.57 (m, 12H),1.45 (s, 4H). 13C NMR (100 MHz, CDCl3) δ 155.58, 154.21, 137.78, 137.15,132.30, 131.08, 130.85, 130.66, 130.61, 128.26, 127.80, 115.48, 115.29,112.79, 110.59, 67.01, 66.27, 63.02, 55.32, 55.16, 53.41, 53.27, 50.04,39.42, 34.62, 27.34, 27.29, 27.16, 26.94, 25.74, 24.40. 22) Characterization data of compound HK-8: 1H NMR (400 MHz, CDCl3) δ 7.35 (d, J = 7.6 Hz, 2H), 7.14 (s, 1H), 7.09 – 7.07 (m, 1H), 6.90 – 6.86 (m, 2H), 6.09 – 5.94 (m, 2H), 5.12 – 5.04(m, 2H), 4.03 (t, J = 12.4 Hz, 2H), 3.94 (t, J = 12.4 Hz, 2H), 3.48 – 3.43 (m,4H), 3.36 (t, J = 13.6 Hz, 4H), 2.01 – 1.94 (m, 2H), 1.90 – 1.81 (m, 4H),1.77 – 1.65 (m, 4H), 1.58 – 1.50 (m, 2H). 13C NMR (101 MHz, CDCl3) δ 155.61,154.26, 137.81, 137.17, 132.37, 131.17, 130.92, 130.74, 130.68, 128.29,127.87, 127.84, 115.52, 115.31, 112.76, 110.59, 109.99, 68.28, 67.54, 39.46,34.62, 33.70, 32.48, 32.41, 28.57, 28.44, 24.98, 24.93. 23) Characterization data of compound HM-16: 1H NMR (400 MHz, CDCl3) δ 7.34 – 7.30 (m, 2H), 7.10 – 7.02 (m, 2H), 6.85 – 6.81 (m, 2H), 6.04 – 5.90 (m, 2H), 5.08 – 4.99 (m, 4H), 3.97 (t, J =12.4 Hz, 2H), 3.89 (t, J = 12.4 Hz, 2H), 3.39 (d, J = 6.4 Hz, 2H), 3.34 (d, J= 6.8 Hz, 2H), 2.63 – 2.29 (m, 18H), 1.86 – 1.77 (m, 2H), 1.75 – 1.66 (m,2H), 1.60 – 1.50 (m, 6H), 1.40 -1.36 (m, 2H). 13C NMR (101 MHz, CDCl3) δ155.64, 154.29, 137.81, 137.15, 132.19, 131.10, 130.85, 130.59, 130.56,128.16, 127.78, 127.74, 115.43, 115.27, 112.65, 110.58, 68.37, 67.73, 58.50,58.48, 54.92, 54.87, 53.00, 52.95, 50.37, 45.88, 39.41, 34.56, 29.31, 29.13, 26.55, 26.39, 24.20, 24.14. 24) Characterization data of compound HM-17: 1H NMR (400 MHz, CDCl3) δ 7.35 – 7.31 (m, 2H), 7.11 (s, 1H), 7.04 (d,J = 8.4 Hz, 1H), 6.84 (t, J = 18.4 Hz, 2H), 6.05 – 5.91 (m, 2H), 5.09 – 5.00(m, 4H), 3.99 (t, J = 12.0 Hz, 2H), 3.91 (t, J = 12.8 Hz, 2H), 3.44 – 3.34(m, 12H), 2.38 – 2.27 (m, 12H), 1.86 – 1.80 (m, 2H), 1.75 – 1.68 (m, 2H),1.58 – 1.31 (m, 26H). 13C NMR (101 MHz, CDCl3) δ 155.64, 154.71, 154.30,137.81, 137.16, 132.22, 131.14, 130.87, 130.62, 130.58, 128.16, 127.77,115.45, 115.26, 112.67, 110.57, 79.52, 68.38, 67.73, 58.60, 53.03, 39.42,34.58, 29.32, 29.13, 28.42, 26.59, 26.45, 24.17, 24.11. 25) Characterization data of compound HM-18: 1H NMR (400 MHz, CDCl3) δ 7.38 – 7.30 (m, 2H), 7.14 (s, 1H), 7.06 –7.03 (m, 1H), 6.89 – 6.81 (m, 2H), 6.07 – 5.92 (m, 2H), 5.10 – 5.01 (m, 4H), 3.99 (t, J = 12.4 Hz, 2H), 3.90 (t, J = 12.4 Hz, 2H), 3.41 (d, J = 6.4 Hz, 2H), 3.35 (d, J = 6.4 Hz, 2H), 2.54 – 2.22 (m, 12H), 1.88 – 1.79 (m, 2H),1.76 – 1.68 (m, 2H), 1.65 – 1.33 (m, 20H). 13C NMR (101 MHz, CDCl3) δ 155.66,154.32, 137.82, 137.17, 132.19, 131.10, 130.86, 130.60, 128.19, 127.80,127.75, 115.43, 115.27, 112.70, 110.60, 68.44, 67.76, 59.34, 59.29, 54.55,54.48, 39.43, 34.58, 29.34, 29.13, 26.45, 26.24, 25.69, 25.63, 24.34, 24.29, 24.25. 26) Characterization data of compound HM-19: 1H NMR (400 MHz, CDCl3) δ 7.33 – 7.29 (m, 2H), 7.09 (s, 1H), 7.02 (d,J = 8.4 Hz, 1H), 6.82 (t, J = 17.2 Hz, 2H), 6.03 – 5.89 (m, 2H), 5.07 – 4.98(m, 4H), 3.96 (t, J = 12.0 Hz, 2H), 3.88 (t, J = 12.0 Hz, 2H), 3.38 (d, J =6.4 Hz, 2H), 3.33 (d, J = 6.4 Hz, 2H), 3.01 – 2.93 (m, 4H), 2.64 – 2.52 (m,10H), 2.34 – 2.23 (m, 6H), 1.93 – 1.34 (m, 34H). 13C NMR (101 MHz, CDCl3) δ155.63, 154.28, 137.80, 137.15, 132.14, 131.08, 130.84, 130.54, 128.16,127.74, 115.44, 115.27, 112.61, 110.55, 68.36, 67.72, 62.93, 58.57, 53.49,53.46, 50.03, 46.10, 39.42, 34.57, 29.32, 29.14, 27.37, 26.91, 26.76, 26.02, 24.58, 24.29, 24.22, 10.94. This invention addresses the issue of poor pharmacokinetic properties of magnolol by introducing a series of tertiary amine ligands into the lungs, based on the lungs being a concentrated site for weakly basic molecules. Ester-bonded derivatives HP-1 ~ HP-3, carbamate-bonded derivatives HM-1 ~ HM-11 and HD-1 ~ HD-2, and ether-bonded derivatives HM-12 ~ HM-19 were designed and synthesized.

[0053] Pharmacokinetic studies showed that the ester-bonded derivatives had poor in vivo stability and failed to increase the half-life of honokiol, but did increase the exposure of honokiol in the lungs. Subsequently, in vitro cytotoxicity studies of the HM series derivatives indicated that steric hindrance was the main factor affecting the antitumor activity of the carbamate-bonded derivatives, with HM-5 and HD-2 showing the best activity under its influence. The ether-bonded derivatives exhibited significantly enhanced antitumor activity, superior to the former, with HM-15 and HM-16 showing the best activity. Preliminary in vivo toxicity studies of derivatives HM-5 and HM-16 revealed that they possessed some tolerability. Simultaneously, in vivo pharmacokinetic studies of the candidate compound HM-16 showed that the average concentration of HM-16 in the lungs was significantly higher than that of HK, and the concentration-time decay rate in the lungs was significantly reduced, indicating that HM-16 improved the pharmacokinetics of HK and prolonged its half-life. However, tissue distribution studies revealed high concentrations of HM-16 in the liver and heart of mice, indicating that compound HM-16 still exhibits some off-target effects in vivo. Furthermore, the antibacterial activity of ether-linked derivatives HM-12 to HM-19 against Gram-positive and Gram-negative bacteria was further investigated. Experimental results showed that, except for HM-13 and HM-17, this series of derivatives had broad-spectrum antibacterial activity against Gram-positive bacteria such as Staphylococcus aureus (S. aureus ATCC25923) and MRSA (USA300, 3390, ATCC330041). Finally, molecular docking experiments showed that HM-5 has a strong affinity for α-glucosidase, indicating potential for research in inhibiting α-glucosidase-mediated pathways.

[0054] The experimental results of this invention show that using magnolol as the basic backbone and modifying its molecular structure with tertiary amine ligands that have lung-targeting functions not only improves the pharmacokinetic properties of HK and prolongs its half-life, but also significantly enhances its antitumor and antibacterial activities.

[0055] The above-disclosed embodiments are merely one or more preferred embodiments of this application and should not be construed as limiting the scope of this application. Those skilled in the art can understand that all or part of the processes for implementing the above embodiments and equivalent changes made in accordance with the claims of this application still fall within the scope of this application.

Claims

1. A method for preparing lung-targeting tertiary amine-modified magnolol derivatives, characterized in that, Honokiol was covalently linked to a tertiary amine ligand via ester, carbamate, or ether bonds to obtain tertiary amine-modified honokiol derivatives.

2. The method for preparing lung-targeting tertiary amine modification and magnolol derivatives as described in claim 1, characterized in that, The preparation of magnolol derivatives via ester bond linkage specifically includes: Add the compound succinic anhydride to the reaction vessel, add dichloromethane, and slowly add the ligand N-methylpiperazine dissolved in dichloromethane to the reaction vessel while stirring. Stir the reaction at room temperature for 5 to 6 hours. After the reaction was completed, the solvent was removed by rotary evaporation under reduced pressure. The residue was purified by silica gel column chromatography with a mixed solvent of dichloromethane and methanol as the eluent to obtain intermediate L-1. The obtained intermediate L-1 was added to a reaction vessel, followed by dichloromethane, and then EDCI, HOBT, DIPEA and magnolol were added in sequence. The mixture was stirred at room temperature for 5-6 hours. After the reaction was completed, the reaction solution was diluted in dichloromethane, water was added for extraction, and the organic phase was retained. The organic phase was washed three times with water, dried over anhydrous sodium sulfate, and the solvent was removed by rotary evaporation under reduced pressure. The residue was purified by silica gel column chromatography with a mixed solvent of dichloromethane and methanol as the eluent to obtain compound HP-1.

3. The method for preparing lung-targeting tertiary amine modification and magnolol derivatives as described in claim 1, characterized in that, The preparation of magnolol derivatives via ester bond linkage specifically includes: Add ligand T-3 to the reaction vessel, add dichloromethane, and then add EDCI, HOBT, DIPEA and magnolol in sequence. Stir the reaction at room temperature for 5-6 hours. After the reaction was completed, the reaction solution was diluted in dichloromethane, water was added for extraction, and the organic phase was retained. The organic phase was washed three times with water, dried over anhydrous sodium sulfate, and the solvent was removed by rotary evaporation under reduced pressure. The residue was purified by silica gel column chromatography with a mixed solvent of dichloromethane and methanol as the eluent to obtain compound HP-3.

4. The method for preparing lung-targeting tertiary amine modification and magnolol derivatives as described in claim 1, characterized in that, The preparation of magnolol derivatives via carbamate linkages includes: First, an active carbonate intermediate of magnolol is prepared, and then the active carbonate intermediate is reacted with a tertiary amine ligand in dichloromethane. After the reaction was completed, the reaction solution was diluted with water, extracted with dichloromethane, and the organic phase was washed successively with water and saturated sodium chloride solution. After drying with anhydrous sodium sulfate, the solution was concentrated under reduced pressure. The residue was purified by silica gel column chromatography to obtain the magnolol derivative.

5. The method for preparing lung-targeting tertiary amine modification and magnolol derivatives as described in claim 4, characterized in that, The activated carbonate intermediate is intermediate HK-3, and its preparation method is as follows: Honokiol was added to a reaction vessel, followed by dichloromethane and then triethylamine. The mixture was stirred at room temperature for 15 minutes under nitrogen protection. The reaction system was then transferred to an ice bath and 1-chloroethyl chloroformate was slowly added dropwise. After the addition was complete, the mixture was brought back to room temperature and stirred for 3-4 hours. The reaction process was monitored by thin-layer chromatography. After the reaction was completed, the solvent was removed by rotary evaporation under reduced pressure. The residue was purified by silica gel column chromatography using a mixed solvent of petroleum ether and dichloromethane as the eluent to obtain intermediate HK-3.

6. The method for preparing lung-targeting tertiary amine-modified magnolol derivatives as described in claim 5, characterized in that, The intermediate HK-3 was reacted with ligands selected from T-4 and piperazine or piperidine tertiary amine ligands in dichloromethane at room temperature. The reaction solution was post-treated and purified by silica gel column chromatography to obtain the 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.

7. The method for preparing lung-targeting tertiary amine modification and magnolol derivatives as described in claim 1, characterized in that, The preparation of magnolol derivatives via ether linkage specifically includes: First, a terminal halogen-containing intermediate and magnolol are prepared, and then the terminal halogen-containing intermediate and a tertiary amine ligand are reacted by heating and reflux in acetonitrile. After the reaction was completed, the solvent was removed by vacuum distillation, the residue was dissolved in dichloromethane, diluted with water and extracted with dichloromethane, the organic phase was washed successively with water and saturated sodium chloride solution, dried with anhydrous sodium sulfate and concentrated under vacuum, and the obtained residue was purified by silica gel column chromatography to obtain the magnolol derivative.

8. The method for preparing lung-targeting tertiary amine modification and magnolol derivatives as described in claim 7, characterized in that, The terminal halogen-containing honokiol intermediate is intermediate HK-7 or HK-8, and its preparation method is as follows: Magnolol, potassium carbonate, and a catalytic amount of potassium iodide were added to acetone, stirred at room temperature, and then compound 5 was added. The mixture was heated under reflux until the reaction was complete, cooled, filtered, and the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to obtain intermediates HK-7 or HK-8, respectively.

9. The method for preparing lung-targeting tertiary amine modification and magnolol derivatives as described in claim 8, characterized in that, The intermediate HK-7 or HK-8 was reacted with an excess of ligands selected from N-methylpiperazine, T-4, and tertiary amine ligands of piperazine or piperidine in acetonitrile under reflux. The reaction solution was post-treated and purified by silica gel column chromatography to obtain the corresponding derivatives HM-12, HM-13, HM-14, HM-15, HM-16, HM-17, HM-18 and HM-19, respectively.

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