Glycosylated hydroxypyridinone ligands, methods of making and using the same

Abstract

The application discloses a glycosylated hydroxypyridinone ligand and a preparation method and application thereof. The glycosylated hydroxypyridinone ligand has excellent coordination capacity with uranium ions, thorium ions and the like, and can realize optimization of the decontamination effect under single administration through intraperitoneal or tail vein administration, and has extremely application prospects in preparation of actinide decontamination agents. Meanwhile, the preparation method is simple, the synthesis condition is mild, and the yield is high, and is suitable for large-scale production.

Description

Technical Field

[0001] This invention relates to the field of biomedical technology, specifically to a glycosylated hydroxypyridinone ligand, its preparation method, and its application. Background Technology

[0002] Some long-lived and highly radioactive nuclides, such as uranium and thorium (actinide elements), can enter the human body through the skin, respiration, and food. These radioactive nuclides are not only radiotoxic but also highly chemically toxic. Once inside the body, they can cause internal radiation, potentially leading to cancer or even death. Therefore, researching low-toxicity, high-efficiency nuclide excretion promoters to accelerate the excretion of actinide elements from the body and reduce the accumulation and duration of metallic nuclides is a primary measure for addressing heavy metal detoxification and internal radionuclide contamination.

[0003] Currently, DTPA-CaNa3 is the clinically used actinide excretion promoter. Studies have found that DTPA-CaNa3 has a good excretion-promoting effect on the actinide elements plutonium and americium, but almost no effect on the excretion of uranium, and its effect on thorium is also limited. Moreover, DTPA-CaNa3 is only effective when administered intraperitoneally, and is almost ineffective when administered orally, making it unsuitable for nuclear accident emergency scenarios. In addition, DTPA-CaNa3 is difficult to remove nuclides deposited in bones; and in scenarios involving the removal of large amounts of nuclides, multiple injections of DTPA-CaNa3 are required, resulting in significant side effects. Maltol, as a novel siderophore chelating unit, has a strong binding capacity to various actinide elements. There are reports demonstrating that maltol-containing ligands can effectively remove uranium from the body, but the effect is limited.

[0004] Therefore, there is an urgent need for excretion promoters that can effectively remove actinide elements from the body. Summary of the Invention

[0005] To address the shortcomings of existing technologies, this invention provides a glycosylated hydroxypyridinone ligand, its preparation method, and its application. This ligand exhibits excellent coordination ability with uranyl ions, thorium ions, etc., and can efficiently remove actinide elements such as uranium and thorium deposited in the body through various administration methods such as intraperitoneal or tail vein.

[0006] To address the aforementioned technical problems, the first aspect of the present invention provides a glycosylated hydroxypyridinone ligand having one of the structures shown in formula AC:

[0007] ;

[0008] Among them, R1, R3, and R5 are independently selected. , or ;

[0009] R6 is selected from , , or ;

[0010] R2, R4, R7, R8, and R9 are independently selected from hydrogen, hydroxyl, carboxyl, chlorine, bromine, methyl, ethyl, isopropyl, tert-butyl, methoxy, ethoxy, isopropoxy, or allyloxy.

[0011] Preferably, compound A is:

[0012] .

[0013] Preferably, compound B has one of the following structures:

[0014] .

[0015] Preferably, the compound of formula C is:

[0016] .

[0017] Furthermore, the preparation method of the compound of formula A includes the following steps:

[0018] A1. The reaction of compound I with a glycosamine compound in the presence of a base yields intermediate 1;

[0019] A2. Intermediate 1 reacts with acid to remove the hydroxyl protecting group, yielding compound A;

[0020] The structural formula of compound I is:

[0021] ;

[0022] R2 is selected from hydrogen, hydroxyl, carboxyl, chlorine, bromine, methyl, ethyl, isopropyl, tert-butyl, methoxy, ethoxy, isopropoxy, or allyloxy.

[0023] R 10 The hydroxyl protecting group is selected from methyl, acetyl, benzyl, or tert-butyldimethylsilyl.

[0024] The glycosamine compound is selected from , or .

[0025] Furthermore, in steps A1 and A2, the reaction temperature is independently selected from 75-85°C.

[0026] Furthermore, the preparation method of the compound of formula B includes the following steps:

[0027] B1. Compound of formula II reacts with glycosamine compound in the presence of an amidation activator and an organic base to give intermediate 2;

[0028] B2, intermediate 2 reacts with acid to remove the hydroxyl protecting group, yielding compound B;

[0029] The structural formula of compound II is:

[0030] ;

[0031] R4 is selected from hydrogen, hydroxyl, carboxyl, chlorine, bromine, methyl, ethyl, isopropyl, tert-butyl, methoxy, ethoxy, isopropoxy, or allyloxy.

[0032] R 10 The hydroxyl protecting group is selected from methyl, acetyl, benzyl, or tert-butyldimethylsilyl.

[0033] The glycosamine compound is selected from , or .

[0034] Furthermore, in step B1, the amidation activator is 2-(7-azabenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate, the organic base is N,N-diisopropylethylamine, and the reaction temperature is 20-30°C.

[0035] In step B2, the reaction temperature is 75-85℃.

[0036] Furthermore, the preparation method of the compound of formula C includes the following steps:

[0037] Compound C1 and Formula III react with an amino linker with a protecting group on one side in the presence of an amidation activator to give intermediate 3;

[0038] C2. The intermediate 3 reacts with a glycosamine compound in the presence of a base to obtain intermediate 4;

[0039] C3. The intermediate 4 reacts with acid to obtain intermediate 5;

[0040] C4. The intermediate 5 reacts with a catechol unit whose side chain has an active group to obtain intermediate 6;

[0041] C5. The intermediate 6 is reacted with an acid to remove the hydroxyl protecting group, yielding the compound of formula C;

[0042] The structural formula of compound III is:

[0043] ;

[0044] Among them, R 10 The hydroxyl protecting group is selected from methyl, acetyl, benzyl, or tert-butyldimethylsilyl.

[0045] The amino linker with a protecting group on one side is selected from... , , or ;

[0046] The glycosamine compound is selected from , or ;

[0047] The catechol unit, whose side chain is an active group, is... ;

[0048] R7, R8, and R9 are independently selected from hydrogen, hydroxyl, carboxyl, chlorine, bromine, methyl, ethyl, isopropyl, tert-butyl, methoxy, ethoxy, isopropoxy, or allyloxy.

[0049] Furthermore, in step C1, the amidation activator is selected from N-hydroxysuccinimide and / or dicyclohexylcarbodiimide.

[0050] Furthermore, the reaction temperatures for steps C1, C3, and C4 are independently selected from 20-30°C; the reaction temperatures for steps C2 and C5 are independently selected from 75-85°C.

[0051] The present invention provides the use of the glycosylated hydroxypyridinone ligand described in the first aspect in the preparation of radioactive element excretion promoters.

[0052] Furthermore, the radioactive element is selected from one or more of U, Th, Np, Pu, and Am.

[0053] The beneficial effects of this invention are:

[0054] The glycosylated hydroxypyridinone ligand of this invention has excellent coordination ability with uranyl ions, thorium ions, etc., and can optimize the ovulation-inducing effect with a single dose through intraperitoneal or tail vein administration, which is of great application potential in the preparation of actinide ovulation-inducing agents.

[0055] The method for preparing glycosylated hydroxypyridinone ligands of the present invention is simple, has mild synthesis conditions and high yield, and is suitable for large-scale mass production. Attached Figure Description

[0056] To more clearly illustrate the technical solution of the present invention, the drawings used in the embodiments will be briefly introduced below. Obviously, the drawings described below are only embodiments of the present invention. For those skilled in the art, other drawings can be obtained based on these drawings without creative effort.

[0057] Figure 1 This refers to the complexation ratios of TAM-2LI-GluMAM2 with uranyl ions at different ratios in DMSO : H2O = 4 : 1, as shown in Example 1.

[0058] Figure 2 It refers to the different ratios of TAM-2LI-GluMAM2 complexed with uranyl ions in 10 mM HEPES buffer solution in Application Example 1;

[0059] Figure 3 This is the UV titration spectrum of TAM-2LI-GluMAM2 with uranyl ions at DMSO : H2O = 4 : 1 in Example 2;

[0060] Figure 4 The UV titration spectrum of TAM-2LI-GluMAM2 with uranyl ions in a 10 mM HEPES solution containing 10% DMSO is shown in Example 2. Figure 5 This is the NMR spectrum of the product obtained in Example 1 of the present invention; Figure 6 This is the NMR spectrum of the product obtained in Example 2 of the present invention; Figure 7 This is the NMR spectrum of the product obtained in Example 3 of the present invention; Figure 8 This is the NMR spectrum of the product obtained in Example 4 of the present invention; Figure 9 This is the NMR spectrum of the product obtained in Example 5 of the present invention. Detailed Implementation

[0061] The technical solution of the present invention will be clearly and completely described below with reference to specific embodiments. Obviously, the described embodiments are only some embodiments of the present invention, and not all embodiments. Based on the embodiments of the present invention, all other embodiments obtained by those skilled in the art without creative effort are within the scope of protection of the present invention.

[0062] Example 1

[0063] This embodiment relates to a method for preparing a glycosylated hydroxypyridinone ligand (1-Glu-Maltol), and the synthetic route is as follows:

[0064]

[0065] Specifically, the following steps are included:

[0066] (1) 3-Benzyloxy-4-oxo-4H-pyran-2-carboxylic acid (123.1 mg, 0.5 mmol) and 2-(7-azabenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate (HATU, 247.2 mg, 0.65 mmol) were added to a 50 mL double-necked reaction flask under nitrogen protection. Then, 5 mL of ultra-dry N,N-dimethylformamide diluted with N,N-diisopropylethylamine (DIPEA, 96.9 mg, 0.75 mmol) was added to the reaction apparatus and stirred at room temperature for 1 h. Then, 5 mL of ultra-dry N,N-dimethylformamide dissolved with D-glucosamine (108.7 mg, 0.6 mmol) was added to the reaction apparatus and stirred at room temperature for 24 h. After the reaction was complete, the solvent was removed by rotary evaporation to obtain the crude product, which was purified by column chromatography using a reversed-phase column to obtain 99.5 mg of a white solid, with a yield of 48.6%. The NMR of the product is as follows:

[0067] 1 H NMR (400 MHz, DMSO-d6) δ 8.46 (t, J = 5.6 Hz, 1H), 8.19 (d, J = 5.6Hz, 1H), 7.48 – 7.41 (m, 2H), 7.41 – 7.29 (m, 3H), 6.52 (d, J = 5.6 Hz, 1H),5.21 (s, 2H), 4.90 (d, J = 4.8 Hz, 1H), 4.50 (d, J = 5.5 Hz, 1H), 4.42 (dd, J= 6.4, 1.6 Hz, 2H), 4.35 (d, J = 5.6 Hz, 1H), 3.75 – 3.54 (m, 3H), 3.53 –3.35 (m, 2H), 3.30 (intersecting with the water peak in DMSO-d6), 3.17 (m, 1H).

[0068] (2) The above product (203.5 mg, 0.5 mmol) was added to a 50 mL double-necked reaction flask under nitrogen protection. 18 mL of 2 M hydrochloric acid solution prepared with ultrapure water was transferred to the reaction apparatus via syringe and stirred to dissolve. The mixture was heated to 80 °C and refluxed for 2.5 h. After the reaction was complete, the solvent was removed by rotary evaporation to obtain the crude product. Column chromatography purification using a reversed-phase column yielded 148.3 mg of a pale yellow solid, with a yield of 93.4%. The product NMR (reference) was used. Figure 5 )as follows:

[0069] 1H NMR (400 MHz, D2O) δ 8.09 (d, J = 5.5, 1H), 6.60 (d, J = 5.5 Hz, 1H), 4.45 – 4.31 (m, 1H), 4.27 (m, 1H), 4.18 – 3.47 (m, 6H).

[0070] Example 2

[0071] This embodiment relates to a method for preparing a glycosylated hydroxypyridinone ligand (2-Glu-Maltol), and the synthetic route is as follows:

[0072]

[0073] Specifically, the following steps are included:

[0074] (1) 3-benzyloxy-4-oxo-4H-pyran-2-carboxylic acid (246.2 mg, 1.0 mmol) and 2-(7-azabenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate (HATU, 494.3 mg, 1.3 mmol) were added to a 100 ml double-necked reaction flask under nitrogen protection. Then, 10 ml of ultra-dry N,N-dimethylformamide diluted with N,N-diisopropylethylamine (DIPEA, 193.9 mg, 1.5 mmol) was added to the reaction apparatus and stirred at room temperature for 1 h. Then, 1,3,4,6-tetra-O-acetyl-2-amino-2-deoxy-β-D-glucose hydrochloride (498.9 mg, 1.3 mmol) and N,N-diisopropylethylamine (168.0 mg, 1.3 mmol) were dissolved in 10 ml of ultra-dry N,N-dimethylformamide and added to the reaction apparatus. The mixture was stirred at room temperature for 24 h. After the reaction was completed, the solvent was removed by rotary evaporation to obtain the crude product. The crude product was purified by column chromatography using a normal-phase silica gel column to obtain 297.7 mg of a white solid, with a yield of 51.7%. The NMR spectra of the product are as follows:

[0075] 1H NMR (400 MHz, DMSO-d6) δ 8.83 (d, J = 9.3 Hz, 1H), 8.20 (d, J = 5.6Hz, 1H), 7.46 – 7.24 (m, 5H), 6.52 (d, J = 5.6 Hz, 1H), 5.87 (d, J = 8.8 Hz,1H), 5.36 (dd, J = 10.5, 9.3 Hz, 1H), 5.11 (s, 2H), 4.96 (t, J = 9.8 Hz, 1H),4.27 – 4.15 (m, 2H), 4.01 (m, 2H), 2.02 (s, 3H), 1.98 (s, 3H), 1.94 (s, 3H), 1.84 (s, 3H).

[0076] (2) The above product (0.35 mmol, 199.2 mg) was added to a 50 mL double-necked reaction flask under nitrogen protection. A 2 M hydrochloric acid solution prepared with 24 mL of ultrapure water was transferred to the reaction apparatus via syringe and stirred to dissolve the product. The mixture was heated to 80 °C and refluxed for 3 h. After the reaction was complete, the solvent was removed by rotary evaporation to obtain the crude product. Column chromatography purification using a reversed-phase column yielded 40.3 mg of a pale yellow solid, with a yield of 36.7%. The product NMR (reference) was used. Figure 6 )as follows:

[0077] 1 H NMR (400 MHz, D2O) δ 8.10 (d, J = 5.6, 1H), 6.62 (d, J = 5.7, 1H), 4.62 (d, J = 8.6 Hz, 1H), 4.00 – 3.91 (m, 1H), 3.86 – 3.67 (m, 1H), 3.52 (m,4H).

[0078] Example 3

[0079] This embodiment relates to a method for preparing a glycosylated hydroxypyridinone ligand (2-Gla-Maltol), and the synthetic route is as follows:

[0080]

[0081]

[0082] Specifically, the following steps are included:

[0083] (1) 3-benzyloxy-4-oxo-4H-pyran-2-carboxylic acid (123.1 mg, 0.5 mmol) and 2-(7-azabenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate (HATU, 247.2 mg, 0.65 mmol) were added to a 100 ml double-necked reaction flask under nitrogen protection. Then, 5 ml of ultra-dry N,N-dimethylformamide diluted with N,N-diisopropylethylamine (DIPEA, 96.9 mg, 0.75 mmol) was added to the reaction apparatus and stirred at room temperature for 1 h. Then, 1,3,4,6-tetra-O-acetyl-2-amino-2-deoxy-β-D-galactose hydrochloride (230.3 mg, 0.6 mmol) and N,N-diisopropylethylamine (77.6 mg, 0.6 mmol) were dissolved in 10 ml of ultra-dry N,N-dimethylformamide and added to the reaction apparatus. The mixture was stirred at room temperature for 24 h. After the reaction was completed, the solvent was removed by rotary evaporation to obtain the crude product. The crude product was purified by column chromatography using a normal-phase silica gel column to obtain 192.9 mg of a white solid, with a yield of 67.7%. The NMR spectra of the product are as follows:

[0084] 1 H NMR (400 MHz, DMSO-d6) δ 8.78 (d, J = 9.3 Hz, 1H), 8.20 (d, J = 5.6Hz, 1H), 7.46 – 7.30 (m, 5H), 6.51 (d, J = 5.6 Hz, 1H), 5.83 – 5.73 (m, 1H),5.32 (m, 1H), 5.25 (m, 1H), 5.11 (s, 2H), 4.38 – 4.28 (m, 1H), 4.27 – 4.20(m, 1H), 4.05 (m, 2H), 2.15 (s, 3H), 2.00 (s, 3H), 1.94 (s, 3H), 1.81 (s,3H).

[0085] (2) The above product (0.18 mmol, 101.6 mg) was added to a 50 mL double-necked reaction flask under nitrogen protection. A 2 M hydrochloric acid solution prepared with 12 mL of ultrapure water was transferred to the reaction apparatus via syringe and stirred to dissolve the product. The mixture was heated to 80 °C and refluxed for 2.5 h. After the reaction was complete, the solvent was removed by rotary evaporation to obtain the crude product. Column chromatography purification using a C18 reversed-phase AQ column yielded 23.6 mg of a pale yellow solid, with a yield of 42.1%. The product NMR (reference) was analyzed. Figure 7 )as follows:

[0086] 1H NMR (400 MHz, D2O) δ 8.07 (d, J = 5.4 Hz, 1H), 6.58 (d, J = 5.5 Hz,1H), 4.90 (d, J = 3.7 Hz, 1H), 4.43 – 4.36 (m, 1H), 4.05 – 3.89 (m, 3H), 3.85– 3.75 (m, 2H).

[0087] Example 4

[0088] This embodiment relates to a method for preparing a glycosylated hydroxypyridinone ligand (Glu-3,4-HOPO), and the synthetic route is as follows:

[0089]

[0090] Specifically, the following steps are included:

[0091] (1) 3-(benzyloxy)-4H-pyran-4-one (1.0 mmol, 203.2 mg) was added to a 50 mL double-necked reaction flask under nitrogen protection. Then, 6 mL of methanol was added to the reaction apparatus to dissolve and stir until homogeneous. D-glucosamine (0.9 mmol, 161.0 mg) and sodium hydroxide (0.9 mmol, 36.6 mg) were dissolved in 3 mL of ultrapure water and then added dropwise to the reaction apparatus. The mixture was heated to 80 °C and refluxed with stirring for 48 h. After the reaction, the pH of the reaction solution was adjusted to approximately 7 with 1 M dilute hydrochloric acid solution. The solvent was removed by rotary evaporation to obtain the crude product. Column chromatography purification using a C18 reversed-phase AQ column yielded 316.8 mg of a pale yellow solid, with a yield of 97.6%. The NMR of the product is as follows:

[0092] 1 H NMR (400 MHz, D2O) δ 7.72 (dd, J = 7.1, 2.1 Hz, 1H), 7.60 (d, J =2.1 Hz, 1H), 7.51 - 7.39 (m, 5H), 6.60 (d, J = 7.1 Hz, 1H), 5.16 (s, 2H), 4.24 (m, 1H), 4.04 - 3.91 (m, 2H), 3.86 - 3.62 (m, 5H).

[0093] (2) The above product (0.547 mmol, 200.3 mg) was added to a 50 mL double-necked reaction flask under nitrogen protection. 24 mL of a 6 M hydrochloric acid solution prepared with anhydrous methanol was transferred to the reaction apparatus via syringe and stirred to dissolve. The mixture was heated to 80 °C and refluxed with stirring for 2.5 h. After the reaction was complete, the solvent was removed by rotary evaporation to obtain the crude product. Column chromatography purification using a reversed-phase column yielded 139.4 mg of a pale yellow solid, with a yield of 92.6%. The product NMR (reference) was analyzed. Figure 8 )as follows:

[0094] 1 H NMR (400 MHz, DMSO-d6) δ 8.04 (d, J = 1.8 Hz, 1H), 7.99 (dd, J =6.8, 1.8 Hz, 1H), 7.10 (d, J = 6.7 Hz, 1H), 4.46 (m, 1H), 4.20 (m, 1H), 4.14- 4.03 (m, 1H), 3.84 - 3.54 (m, 5H).

[0095] Example 5

[0096] This embodiment relates to a method for preparing a glycosylated hydroxypyridinone ligand (TAM-2LI-GluMAM2), and the synthetic route is as follows:

[0097]

[0098] Specifically, the following steps are included:

[0099] (1) 3-(benzyloxy)-4-oxoylide-4H-pyran-2-carboxylic acid (15.0 mmol, 3693.5 mg) and N-hydroxysuccinimide (NHS, 15.0 mmol, 1724.5 mg) were added sequentially to a 250 mL double-necked reaction flask under nitrogen protection. 30 mL of ultra-dry tetrahydrofuran was added to dissolve the precipitate, and the mixture was stirred at room temperature for 30 min. Dicyclohexylcarbodiimide (DCC, 15.0 mmol, 3099.3 mg) was dissolved in 10 mL of ultra-dry tetrahydrofuran solution and slowly added dropwise to the reaction system. The mixture was stirred at room temperature for 3 h. Finally, N-tert-butoxycarbonyl-1,2-ethylenediamine (15.0 mmol, 2405.6 mg) was dissolved in 10 mL of ultra-dry tetrahydrofuran solution and slowly added dropwise to the reaction apparatus. The mixture was stirred overnight at room temperature. After the reaction was complete, the precipitate was removed by vacuum filtration, and the solvent was removed by rotary evaporation of the filtrate to obtain the crude product. The crude product was thoroughly dissolved in an appropriate amount of dichloromethane and transferred to a separatory funnel. The organic phase was washed three times with saturated NaHCO3 aqueous solution and once with saturated NaCl. After standing and separating the layers, the organic phase was collected, and the solvent was removed by rotary evaporation to obtain a pale yellow solid. The crude product was purified by recrystallization using 50 ml of ice-cold anhydrous ethanol to obtain 3675.4 mg of a light gray solid, with a yield of 63.1%. The NMR spectra of the product are as follows:

[0100] 1 H NMR (400 MHz, CDCl3) δ 7.94 (s, 1H), 7.82 (d, J = 5.6 Hz, 1H), 7.40(m, 5H), 6.48 (d, J = 5.6 Hz, 1H), 5.46 (s, 2H), 4.64 (s, 1H), 3.35 (q, J =5.9 Hz, 2H), 3.17 (m, 2H), 1.43 (s, 9H).

[0101] (2) The above product (1.0 mmol, 384.5 mg) was added to a 100 mL double-necked reaction flask under nitrogen protection. 12 mL of methanol was added to the reaction apparatus to dissolve and stir until homogeneous. D-glucosamine (0.9 mmol, 163.1 mg) and sodium hydroxide (0.9 mmol, 35.9 mg) were dissolved in 6 mL of ultrapure water and added dropwise to the reaction apparatus. The mixture was heated to 80 °C and refluxed with stirring for 48 h. After the reaction, the pH of the reaction solution was adjusted to approximately 7 with 1 M dilute hydrochloric acid solution. The solvent was removed by rotary evaporation to obtain the crude product. Column chromatography using a C18 reversed-phase column purified the crude product to obtain 67.4 mg of a pale yellow solid, with a yield of 13.6%. The NMR spectra of the product are as follows:

[0102] 1H NMR (400 MHz, DMSO-d6) δ 8.85 (t, J = 5.7 Hz, 1H), 7.58 (d, J = 7.5Hz, 1H), 7.44 - 7.26 (m, 5H), 6.78 (t, J = 5.8 Hz, 1H), 6.23 (d, J = 7.5 Hz,1H), 5.12 - 5.02 (m, 3H), 4.58 (d, 2H), 4.38 (br, 2H), 4.09 - 3.99 (m, 1H), 3.74 - 3.91 (m, 2H), 3.66 - 3.56 (m, 2H), 3.48 (d, J = 3.0 Hz, 2H), 3.44 -3.13 (Intersecting with water peak in DMSO-d6), 3.06 (m, 2H), 1.38 (s, 9H).

[0103] (3) The above product (0.18 mmol, 100.2 mg) was added to a 50 mL double-necked reaction flask. Under nitrogen protection, 10 mL of anhydrous methanol and 3 mL of 1 M dilute hydrochloric acid solution prepared with anhydrous methanol were added to the reaction apparatus using a syringe under an ice bath at 0 °C. After stirring and dissolving evenly, the ice bath was removed, and the mixture was stirred at room temperature for 2 h. After the reaction was completed, the solvent was removed by rotary evaporation, and the mixture was washed three times with a small amount of methanol to obtain 85.5 mg of a light yellow oily substance, with a yield of 96.3%. The NMR of the product is as follows:

[0104] 1 H NMR (400 MHz, DMSO-d6) δ 9.56 (t, J = 5.7 Hz, 1H), 8.19 (d, J = 7.2Hz, 1H), 8.06 (t, J = 5.7 Hz, 3H), 7.45 - 7.31 (m, 5H), 7.17 (d, J = 7.2 Hz,1H), 5.20 - 5.09 (m, 2H), 4.39 (m, 1H), 4.17 (m, 1H), 3.99 - 3.90 (m, 1H),3.73 (dd, J = 4.6, 1H), 3.64 - 3.39 (m, 6H), 2.95 (q, J = 6.4 Hz, 2H).

[0105] (4) Add the above product (0.1 mmol, 48.8 mg) to a 50 mL double-necked reaction flask, and add 3 mL of ultra-dry N,N-dimethylformamide solution (1.0 mmol, 101.2 mg, 139.0 μL) of triethylamine to the reaction apparatus and stir to dissolve. Then, slowly add 1,4-bis[(thiazolidin-2-thion-3-yl)carbonyl]-2,3-bis(benzyloxy)benzene dissolved in 3 mL of ultra-dry N,N-dimethylformamide solution to the reaction apparatus through a dropping funnel, and react overnight at room temperature. After the reaction is complete, remove the solvent by rotary evaporation to obtain the crude product, and purify it by column chromatography using a C18 reversed-phase AQ column to obtain 20.0 mg of pale yellow solid, with a yield of 49.1%. The NMR of the product is as follows:

[0106] 1 ¹H NMR (400 MHz, DMSO-d6) δ 8.95 (d, 1H), 8.33 (d, 1H), 7.58 (d, J = 7.6 Hz, 1H), 7.45 - 7.22 (m, 11H), 6.24 (d, J = 7.5 Hz, 1H), 5.07 (dd, J = 13.2, 6.8 Hz, 5H), 4.62 (d, J = 6.5 Hz, 1H), 4.55 (d, J = 4.5 Hz, 1H), 4.40 (d, J = 5.8 Hz, 2H), 4.06 (d, 1H), 3.92 - 3.76 (m, 2H), 3.67 - 3.34 (intersecting with water peaks in DMSO-d6).

[0107] (5) Add the above product (0.024 mmol, 30.3 mg) to a 50 mL double-necked reaction flask, under nitrogen protection, and transfer 24 mL of 6 M hydrochloric acid solution prepared with anhydrous methanol into the reaction apparatus using a syringe and stir to dissolve. Heat to 80 °C and reflux with stirring for 2.5 h. After the reaction is complete, remove the solvent by rotary evaporation to obtain the crude product, which is then purified by column chromatography using a C18 reversed-phase AQ column to obtain 14.0 mg of a pale yellow solid, with a yield of 59.5%. The product NMR (reference) was used. Figure 9 )as follows:

[0108] 1H NMR (400 MHz, D2O) δ 12.50 (br, 1H), 9.27 (t, J = 5.2 Hz, 1H), 8.97 (d, J = 5.7 Hz, 1H), 8.07 (d, J = 7.0 Hz, 1H), 7.37 (s, 1H), 7.17 (d, J = 6.9Hz, 1H), 4.49 (m, 1H), 4.20 (m, 1H), 3.99 - 3.90 (m, 1H), 3.73 (m, 1H), 3.64- 3.36 (m, 8H).

[0109] Application Example 1

[0110] Taking TAM-2LI-GluMAM2 prepared in Example 5 as an example, the binding ratio of TAM-2LI-GluMAM2 with uranium under different solvent conditions was studied. The specific operation is as follows:

[0111] A series of solutions containing 50 μM total concentration of TAM-2LI-GluMAM2 and uranyl nitrate were prepared using DMSO (dimethyl sulfoxide):H2O = 4:1 (V / V) or 10 mM HEPES (4-hydroxyethylpiperazine ethanesulfonic acid) buffer as solvents (uranyl to TAM-2LI-GluMAM2 concentration ratios were 0:10, 1:9, 2:8, 3:7, 4:6, 5:5, 6:4, 7:3, 8:2, 9:1, and 10:0). The absorption spectra of the solutions in the 200-800 nm range were measured using a UV spectrophotometer, and the binding ratio of TAM-2LI-GluMAM2 to uranyl was determined by Job's Plot method.

[0112] Figure 1-2 The figures show the binding ratios of TAM-2LI-GluMAM2 and uranyl ions in DMSO:H2O=4:1 (V / V) and 10 mM HEPES buffer solutions, respectively. It can be seen that TAM-2LI-GluMAM2 can form a 1:1 complex with uranyl ions.

[0113] Application Example 2

[0114] Taking TAM-2LI-GluMAM2 prepared in Example 5 as an example, the conditional complexation constant of TAM-2LI-GluMAM2 with uranyl ions was studied. The specific operation is as follows:

[0115] A 50 μM TAM-2LI-GluMAM2 solution was prepared using DMSO:H2O = 4:1 (V / V) and a 10 mM HEPES solution containing 10% DMSO as solvents. 2 mL of the 50 μM TAM-2LI-GluMAM2 solution was placed in a cuvette. First, the absorption spectrum of the ligand in the 260-600 nm range was measured. Then, 10 μL of 1 mM uranyl ion solution (0.1 equivalent) was added sequentially, and the solution was stirred and equilibrated for 5 min before measuring the absorption spectrum. After adding 1 equivalent of uranyl ions, 20 μL of 1 mM uranyl ion solution (0.2 equivalent) was added sequentially, and the solution was stirred and equilibrated for 5 min before measuring the absorption spectrum. This process was repeated until 2 equivalents were reached. The spectral data were fitted using HypSpec2014 software to obtain the conditional complexation constant between TAM-2LI-GluMAM2 and uranyl ions. The titration curve of TAM-2LI-GluMAM2 with uranyl ions is shown below. Figure 3-4 As shown in Table 1, the conditional complexation constants of TAM-2LI-GluMAM2 with uranyl ions are as follows:

[0116] Table 1

[0117]

[0118] It can be seen that the conditional complexation constants of TAM-2LI-GluMAM2 with uranyl ions in the organic system and the aqueous system are 4.77 and 4.89, respectively, indicating that TAM-2LI-GluMAM2 has better coordination ability with uranyl ions under different solvent conditions.

[0119] Application Example 3

[0120] Taking Glu-3,4-HOPO prepared in Example 4 as an example, the effects of immediate and delayed intraperitoneal administration of Glu-3,4-HOPO on the excretion of uranyl ions in the kidneys and bones of mice were studied. The specific operation is as follows:

[0121] Twenty-five BALB / c mice were randomly divided into five groups: one control group and four treatment groups, with five mice in each group. Mice in the control and treatment groups were injected intravenously with uranyl nitrate (VI) at a dose of 0.50 mg U / kg, either immediately after injection or 1 hour later. The uranium-treated control group received an equivalent volume of physiological saline intraperitoneally. The treatment groups were administered 184 molar amounts of uranyl nitrate (Glu-3,4-HOPO:U) of Glu-3,4-HOPO ligand and 184 molar amounts of uranyl nitrate (Me-3,4-HOPO:U) of unmodified glycosyl Me-3,4-HOPO ligand, respectively. Twenty-four hours later, the mice were euthanized, and their liver, spleen, kidney, and femur were harvested. A mixture of concentrated nitric acid and hydrogen peroxide was added, and the samples were digested using a microwave digester. The uranium content in each sample was determined using inductively coupled plasma mass spectrometry (ICP-MS). The uranium accumulation in the tissues was calculated, and the results are shown in Tables 2 and 3.

[0122] Table 2

[0123]

[0124] Table 3

[0125]

[0126] As shown in Tables 2 and 3, when administered intraperitoneally immediately or 1 hour later, Glu-3,4-HOPO can promote the excretion of 61.4% and 33.1% of uranium in the kidneys, respectively, when administered immediately and 1 hour later. Compared with the 49.7% and 18.2% of the unmodified hydroxypyridinone ligand Me-3,4-HOPO, the renal excretion-promoting effect of the glycosylated ligand is significantly improved.

[0127] Application Example 4

[0128] Taking TAM-2LI-GluMAM2 prepared in Example 5 as an example, the effects of immediate intraperitoneal administration and delayed administration of TAM-2LI-GluMAM2 on the excretion of uranyl ions in the kidneys and bones of mice were studied. The specific operation is as follows:

[0129] Twenty-five BALB / c mice were randomly divided into five groups: one control group and four treatment groups, with five mice in each group. Mice in the control and treatment groups were injected intravenously with uranyl nitrate (VI) at a dose of 0.50 mg U / kg, either immediately after injection or 1 hour later. The uranium-treated control group received an equivalent volume of physiological saline intraperitoneally. The treatment groups were administered 92 molar amounts (TAM-2LI-GluMAM2:U) of TAM-2LI-GluMAM2 ligand and 92 molar amounts (TAM-2LI-MAM2:U) of unmodified glycosyl TAM-2LI-MAM2 ligand, respectively. After 24 hours, the mice were euthanized, and their liver, spleen, kidney, and femur were harvested. A mixture of concentrated nitric acid and hydrogen peroxide was added, and the samples were digested using a microwave digester. The uranium content in each sample was determined by inductively coupled plasma mass spectrometry (ICP-MS). The uranium accumulation in the tissues was calculated, and the results are shown in Tables 4 and 5.

[0130] Table 4

[0131]

[0132] Table 5

[0133]

[0134] As shown in Tables 4 and 5, when administered immediately via intraperitoneal single-dose, TAM-2LI-GluMAM2 can promote the excretion of 98.1% of uranium in the kidneys and 96.7% of uranium in the bones, respectively. This surpasses the excretion-promoting effect of unmodified TAM-2LI-MAM2 (95.2% kidney excretion rate and 85.8% bone excretion rate). When administered 1 hour later, TAM-2LI-GluMAM2 still has a good excretion-promoting effect of 73.5% on uranium in the bones, which is significantly higher than that of TAM-2LI-MAM2 (44.3%). This indicates that the glycosylated ligand significantly improves the delayed excretion-promoting effect of the original ligand on uranyl in the bones.

[0135] Application Example 5

[0136] Taking TAM-2LI-GluMAM2 prepared in Example 5 as an example, the effect of intraperitoneal low-dose administration of TAM-2LI-GluMAM2 on promoting the excretion of uranyl ions in the kidneys and bones of mice was studied. The specific operation is as follows:

[0137] Fifteen BALB / c mice were randomly divided into three groups: one control group and two treatment groups, with five mice in each group. Mice in the control and treatment groups were injected intravenously with uranyl nitrate (VI) at a dose of 0.50 mg U / kg, followed immediately by intraperitoneal injection. The uranium-treated control group received an equivalent volume of physiological saline intraperitoneally. The treatment groups received 23 molar amounts (TAM-2LI-GluMAM2:U) of TAM-2LI-GluMAM2 ligand and 23 molar amounts (TAM-2LI-MAM2:U) of unmodified glycosyl TAM-2LI-MAM2 ligand. After 24 hours, the mice were euthanized, and their liver, spleen, kidney, and femur were harvested. A mixture of concentrated nitric acid and hydrogen peroxide was added, and the samples were digested using a microwave digester. The uranium content in each sample was determined using inductively coupled plasma mass spectrometry (ICP-MS). The uranium accumulation in the tissues was calculated, and the results are shown in Table 6.

[0138] Table 6

[0139]

[0140] As shown in Table 6, even at a lower dosage, i.e., TAM-2LI-GluMAM2:U=23:1, there is still an excretion-promoting effect on the kidneys (89.3%) and bones (94.9%). The effect remains good at low doses, reducing unnecessary drug toxicity burden.

[0141] Application Example 6

[0142] Taking TAM-2LI-GluMAM2 prepared in Example 5 as an example, the effect of delayed administration of TAM-2LI-GluMAM2 via tail vein for 1 h on the excretion of uranyl ions in the kidneys and bones of mice was studied. The specific operation is as follows:

[0143] Fifteen BALB / c mice were randomly divided into three groups: one control group and two treatment groups, with five mice in each group. Mice in the control and treatment groups were injected intravenously with uranyl nitrate (VI) at a dose of 0.50 mg U / kg, with the injection occurring 1 hour later. The control group received an equivalent volume of physiological saline via the tail vein. The treatment groups were administered 92 molar amounts (TAM-2LI-GluMAM2:U) of TAM-2LI-GluMAM2 ligand and 92 molar amounts (TAM-2LI-MAM2:U) of unmodified glycosyl TAM-2LI-MAM2 ligand, respectively. After 24 hours, the mice were euthanized, and their liver, spleen, kidney, and femur were harvested. A mixture of concentrated nitric acid and hydrogen peroxide was added, and the samples were digested using a microwave digester. The uranium content in each sample was determined by inductively coupled plasma mass spectrometry (ICP-MS). The uranium accumulation in the tissues was calculated, and the results are shown in Table 7.

[0144] Table 7

[0145]

[0146] As shown in Table 7, TAM-2LI-GluMAM2 can still promote the excretion of 86.9% of uranium in the kidneys and 77.8% of uranium in the bones by a single dose administered via the tail vein with a delay of 1 hour. The renal effect is slightly higher than that of TAM-2LI-MAM2, but the bone effect is significantly improved by about 22.1%. Therefore, glycosylated ligands have a high excretion-promoting effect when administered via intravenous delay.

[0147] Application Example 7

[0148] Taking Glu-3,4-HOPO prepared in Example 4 as an example, the effect of immediate intraperitoneal administration of Glu-3,4-HOPO on promoting thorium excretion in the liver and bones of mice was studied. The specific operation is as follows:

[0149] Fifteen BALB / c mice were randomly divided into three groups: one control group and two treatment groups, with five mice in each group. Mice in the control and treatment groups were injected intravenously with thorium nitrate (IV) at a dose of 0.50 mg Th / kg, immediately followed by intraperitoneal injection. The thorium-treated control group received an equivalent volume of physiological saline intraperitoneally. The treatment groups were administered 92 molar amounts of DTPA ligand (DTPA: Th) and 184 molar amounts of Glu-3,4-HOPO ligand (Glu-3,4-HOPO: Th), respectively. After 24 hours, the mice were euthanized, and the liver, femur, spleen, and kidneys were harvested. A mixture of concentrated nitric acid and hydrogen peroxide was added, and the samples were digested using a microwave digester. The uranium content in each sample was determined by inductively coupled plasma mass spectrometry (ICP-MS). The thorium accumulation in the tissues was calculated, and the results are shown in Table 8.

[0150] Table 8

[0151]

[0152] As shown in Table 8, Glu-3,4-HOPO can promote the excretion of up to 37.3% of thorium in the liver by immediate single intraperitoneal administration, achieving an excretion-promoting effect close to that of the clinical drug DTPA as a bidentate ligand.

[0153] Application Example 8

[0154] Taking 2-Gla-Maltol prepared in Example 3 as an example, the effect of immediate or delayed intraperitoneal administration of 2-Gla-Maltol on the excretion of thorium in the liver and bones of mice was studied. The specific operation is as follows:

[0155] Twenty-five BALB / c mice were randomly divided into five groups: one control group and four treatment groups, with five mice in each group. Mice in the control and treatment groups were injected intravenously with thorium nitrate (IV) at a dose of 0.50 mg Th / kg, either immediately or 1 hour after injection. The thorium-treated control group received an equivalent volume of physiological saline intraperitoneally. The treatment groups were administered 184 molar amounts (Me-Maltol:Th) of Me-Maltol ligand and 184 molar amounts (2-Gla-Maltol:Th) of 2-Gla-Maltol ligand, respectively. Twenty-four hours later, the mice were euthanized, and their liver, femur, spleen, and kidneys were harvested. A mixture of concentrated nitric acid and hydrogen peroxide was added, and the samples were digested using a microwave digester. The uranium content in each sample was determined by inductively coupled plasma mass spectrometry (ICP-MS). The thorium accumulation in the tissues was calculated, and the results are shown in Tables 9 and 10.

[0156] Table 9

[0157]

[0158] Table 10

[0159]

[0160] As shown in Tables 9 and 10, when administered intraperitoneally immediately or 1 hour later, the galactosyl-modified ligand 2-Gla-Maltol promoted the excretion of thorium from the liver by 33.9% and 11.8%, respectively. Compared with the unmodified glycosylated control ligand Me-Maltol (4.6% and -8.6%), the glycosylated ligand significantly improved the excretion of thorium from the liver.

[0161] The present invention has been described in detail above with reference to specific embodiments and exemplary examples; however, these descriptions should not be construed as limiting the present invention. Those skilled in the art will understand that various equivalent substitutions, modifications, or improvements can be made to the technical solutions and embodiments of the present invention without departing from the spirit and scope of the invention, and all such modifications and improvements fall within the scope of the present invention. The scope of protection of the present invention is defined by the appended claims.

Claims

1. A glycosylated hydroxypyridinone ligand, characterized in that, It has one of the following structures: 。 2. The use of the glycosylated hydroxypyridinone ligand according to claim 1 in the preparation of a radioactive element excretion promoter.

3. The application as described in claim 2, characterized in that, The radioactive element is selected from one or more of U, Th, Np, Pu, and Am.

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