Ferritin ligand, ferritin degradation agent, pharmaceutical preparation and application

Abstract

The invention discloses a ferritin ligand, a ferritin degradation agent, a pharmaceutical preparation and application. The ferritin degradation agent is prepared by reacting a ferritin ligand with any one of a pomalidomide fragment compound, a coumarin analogue fragment compound, a VHL fragment compound, a hydrophobic tag fragment compound and an MDM2 fragment compound. The ferritin ligand has a structure shown as a formula (B): # imgabs0 #, R is selected from H or # imgabs1 #, and the ferritin degradation agent not only has good anti-tumor activity, but also is high in stability, small in toxic and side effects and good in drug resistance, and can be widely used for preparing pharmaceutical preparations and treating or preventing malignant tumors.

Description

Technical Field

[0001] The present invention belongs to the field of medical technology, and in particular relates to a ferritin ligand, a ferritin degradation agent, a pharmaceutical preparation and an application thereof. Background Art

[0002] Iron plays a key role in various metabolic processes and is an essential metal element for maintaining life. However, excessive iron, especially ferrous ions, can lead to cellular iron overload. Reactive oxygen species produced by the Fenton reaction of ferrous ions can cause organ damage. Therefore, iron ions must be properly regulated to maintain iron homeostasis. Ferritin is a 24-mer composed of H subunits and L subunits in different proportions. It is one of the key factors in the iron homeostasis regulation network. When the cell is iron-rich and needs to lower the iron level, the H subunit converts Fe 2+ Oxidized to Fe 3+ Ferritin is transferred to the nucleation site of the L subunit for storage; when the intracellular iron deficiency requires the increase of iron levels, ferritin will be degraded by lysosomal autophagy or ubiquitin-proteasome pathway, releasing the iron ions stored in it. Ferritin is highly expressed in malignant tumor cells and plays an important role in the growth and proliferation of tumor cells. Therefore, the development of a degrader targeting ferritin is expected to become a new strategy for tumor treatment. Summary of the invention

[0003] In order to solve the above technical problems, the purpose of the present invention is to provide a ferritin ligand, a ferritin degrading agent, a pharmaceutical preparation and application. The ferritin degrading agent not only has good anti-tumor activity, but also has high stability, low toxic and side effects, and good drug resistance. It can be widely used in the preparation of pharmaceutical preparations and in the treatment or prevention of malignant tumors.

[0004] In order to achieve the above technical objectives and the above technical effects, the present invention is implemented through the following technical solutions:

[0005] In one aspect, the present invention provides a ferritin degradation agent, which is a compound represented by the general formula (A), or a pharmaceutically acceptable salt thereof:

[0006]

[0007] Wherein, Ⅰ is one of the following structures:

[0008]

[0009] n is an integer from 1 to 3;

[0010] Ⅱ is one of the following structures:

[0011]

[0012]

[0013] Preferably, the ferritin degrading agent is selected from:

[0014] (2S)-N-(8-((3-aminopropyl)amino)octyl)-2-(2-(2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)ethoxy)ethoxy)acetamido)-3-(4-hydroxyphenyl)propanamide;

[0015] (2S)-N-(8-((3-aminopropyl)amino)octyl)-2-(2-(2-(2-((2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)ethoxy)ethoxy)acetamido)-3-(4-hydroxyphenyl)propanamide;

[0016] N-((S)-1-((8-((3-aminopropyl)amino)octyl)amino)-3-(4-hydroxyphenyl)-1-oxopropan-2-yl)-14-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)-3,6,9,12-tetraoxatetradecanoic acid amide;

[0017] (S)-N-(8-((3-aminopropyl)amino)octyl)-2-(2-((7-hydroxy-4-methyl-2-oxo-2H-benzopyran-5-yl)oxy)ethoxy)acetamido)-3-(4-hydroxyphenyl)propanamide;

[0018] (S)-N-(8-((3-aminopropyl)amino)octyl)-2-(2-(2-((7-hydroxy-4-methyl-2-oxo-2H-benzopyran-5-yl)oxy)ethoxy)ethoxy)acetamido)-3-(4-hydroxyphenyl)propanamide;

[0019] (S)-N-(8-((3-aminopropyl)amino)octyl)-2-(2-(2-(2-((7-hydroxy-4-methyl-2-oxo-2H-benzopyran-5-yl)oxy)ethoxy)ethoxy)acetamido)-3-(4-hydroxyphenyl)propanamide;

[0020] (S)-N-(1-((8-((3-aminopropyl)amino)octyl)amino)-3-(4-hydroxyphenyl)-1-oxopropan-2-yl)-14-((7-hydroxy-4-methyl-2-oxo-2H-benzopyran-5-yl)oxy)-3,6,9,12-tetraoxatetradecanoic acid amide.

[0021] Furthermore, the ferritin degrader is prepared by reacting a ferritin ligand with any one of a pomalidomide fragment compound, a coumarin analog fragment compound, a VHL fragment compound, a hydrophobic tag fragment compound, and an MDM2 fragment compound.

[0022] Another aspect of the present invention provides a ferritin ligand having a structure as shown in formula (B):

[0023]

[0024] Wherein, R is selected from H or

[0025] The present invention also provides a method for preparing a ferritin ligand, comprising the following steps:

[0026] (1) dissolving the compound represented by Formula 1 in an organic solvent, adding o-nitrobenzenesulfonyl chloride at low temperature to react to obtain the compound represented by Formula 2;

[0027] (2) dissolving the compound represented by Formula 2 in an organic solvent, adding triethylamine and triphenylmethane at low temperature to react to obtain the compound represented by Formula 3;

[0028] (3) dissolving the compound of formula 3 in an organic solvent, adding Teoc-protected aminoethanol, tributylphosphine and azodicarbonyl dipyridine at low temperature to react to obtain the compound of formula 4;

[0029] (4) dissolving the compound represented by Formula 4 in an organic solvent, adding tetrabutylammonium fluoride, and reacting to obtain the compound represented by Formula 5;

[0030] (5) dissolving the compound of formula 5 in an organic solvent, adding protected tyrosine, HATU and collidine to react to obtain the compound of formula 6;

[0031] (6) dissolving the compound represented by Formula 6 in an organic solvent, adding piperidine, and reacting to obtain the compound represented by Formula 7;

[0032] (7) dissolving the compound of formula 7 in an organic solvent, adding 2,2-dimethylpropionic acid, HAT U and trimethylpyridine, and reacting to obtain the compound of formula 8;

[0033] (8) dissolving the compound represented by Formula 8 in an organic solvent, adding DBU and mercaptoethanol, and reacting to obtain the compound represented by Formula 9;

[0034] (9) adding CH2Cl2 / TFA / triisopropylsilane / H2O solution to the compound of formula 9 to react to obtain the compound of formula 10;

[0035] The synthetic route is as follows:

[0036]

[0037] The present invention also provides another method for preparing a ferritin ligand, comprising the following steps:

[0038] (1) dissolving the compound represented by Formula 1 in an organic solvent, adding o-nitrobenzenesulfonyl chloride at low temperature to react to obtain the compound represented by Formula 2;

[0039] (2) dissolving the compound represented by Formula 2 in an organic solvent, adding triethylamine and triphenylmethane at low temperature to react to obtain the compound represented by Formula 3;

[0040] (3) dissolving the compound of formula 3 in an organic solvent, adding Teoc-protected aminoethanol, tributylphosphine and azodicarbonyl dipyridine at low temperature to react to obtain the compound of formula 4;

[0041] (4) dissolving the compound represented by Formula 4 in an organic solvent, adding tetrabutylammonium fluoride, and reacting to obtain the compound represented by Formula 5;

[0042] (5) dissolving the compound of formula 5 in an organic solvent, adding protected tyrosine, HATU and collidine to react to obtain the compound of formula 6;

[0043] (6) dissolving the compound represented by Formula 6 in an organic solvent, adding piperidine, and reacting to obtain the compound represented by Formula 7;

[0044] (7) dissolving the compound represented by Formula 7 in an organic solvent, adding DBU and mercaptoethanol, and reacting to obtain the compound represented by Formula 9′;

[0045] (8) adding CH2Cl2 / TFA / triisopropylsilane / H2O solution to the compound represented by formula 9' to react and obtain the compound represented by formula 10';

[0046] The synthetic route is as follows:

[0047]

[0048] The present invention further provides a method for preparing a ferritin degradation agent, comprising the following steps:

[0049] The ferritin ligand represented by formula (B) is reacted with any one of pomalidomide fragment compounds, coumarin analog fragment compounds, VHL fragment compounds, hydrophobic tag fragment compounds, and MDM2 fragment compounds to obtain a compound represented by general formula (A).

[0050] Wherein, the structural formula of the pomalidomide fragment compound is:

[0051]

[0052] Among them, n1=1, 2, 3.

[0053] Wherein, the structural formula of the coumarin analog fragment compound is:

[0054]

[0055] Among them, n2=1, 2, 3.

[0056] Wherein, the structural formula of the VHL fragment compound is:

[0057]

[0058] Among them, n3=1, 2, 3.

[0059] Wherein, the structural formula of the hydrophobic tag fragment compound is:

[0060]

[0061] Among them, n4=1, 2, 3.

[0062] Wherein, the structural formula of the MDM2 fragment compound is:

[0063]

[0064] Among them, n5=1, 2, 3.

[0065] The present invention further provides a pharmaceutical preparation comprising a compound represented by general formula (A), or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carriers.

[0066] The present invention further provides use of the ferritin degrading agent in preparing a drug for treating and / or preventing malignant tumors.

[0067] The beneficial effects of the present invention are:

[0068] The present invention synthesizes a novel ferritin ligand, and uses the ferritin ligand as an intermediate and a pomalidomide fragment compound, a coumarin analog fragment compound, a VHL fragment compound, a hydrophobic tag fragment compound, or an MDM2 fragment compound to undergo amidation reaction and then deprotect to obtain a compound represented by general formula (A); the compound or a pharmaceutically acceptable salt thereof not only has good anti-tumor activity, but also has high stability, low toxic and side effects, and good drug resistance, and can be widely used in the preparation of pharmaceutical preparations and in the treatment or prevention of malignant tumors. BRIEF DESCRIPTION OF THE DRAWINGS

[0069] Figure 1This is a concentration gradient binding curve of the ligand protein Ferritin H chain and the target compound of Example 2.

[0070] Figure 2 This is a graph evaluating the degradation ability of the target compounds of Examples 1-7 on FTH1 in MCF-7 cells. DETAILED DESCRIPTION

[0071] The technical solutions in the present invention will be described clearly and completely below in conjunction with specific embodiments. Obviously, the described embodiments are only part of the embodiments of the present invention, not all of them. Based on the embodiments of the present invention, all other embodiments obtained by ordinary technicians in this field without creative work are within the scope of protection of the present invention.

[0072] The present invention provides a ferritin degradation agent, which is a compound represented by general formula (A), or a pharmaceutically acceptable salt thereof:

[0073]

[0074] Wherein, Ⅰ is one of the following structures:

[0075]

[0076] n is an integer from 1 to 3;

[0077] Ⅱ is one of the following structures:

[0078]

[0079] Table 1 below shows the chemical names and structural formulas of seven examples of ferritin degrading agents.

[0080] Table 1

[0081]

[0082]

[0083]

[0084] The ferritin degradation agent is prepared by deprotection after amidation reaction between a ferritin ligand and any one of a pomalidomide fragment compound, a coumarin analog fragment compound, a VHL fragment compound, a hydrophobic tag fragment compound and an MDM2 fragment compound.

[0085] A ferritin ligand having a structure as shown in formula (B):

[0086]

[0087] Wherein, R is selected from H or

[0088] A method for preparing a ferritin ligand with a structure comprising the following steps:

[0089] (1) dissolving the compound represented by Formula 1 in an organic solvent, adding o-nitrobenzenesulfonyl chloride at low temperature to react to obtain the compound represented by Formula 2;

[0090] (2) dissolving the compound represented by Formula 2 in an organic solvent, adding triethylamine and triphenylmethane at low temperature to react to obtain the compound represented by Formula 3;

[0091] (3) dissolving the compound of formula 3 in an organic solvent, adding Teoc-protected aminoethanol, tributylphosphine and azodicarbonyl dipyridine at low temperature to react to obtain the compound of formula 4;

[0092] (4) dissolving the compound represented by Formula 4 in an organic solvent, adding tetrabutylammonium fluoride, and reacting to obtain the compound represented by Formula 5;

[0093] (5) dissolving the compound of formula 5 in an organic solvent, adding protected tyrosine, HATU and collidine to react to obtain the compound of formula 6;

[0094] (6) dissolving the compound represented by Formula 6 in an organic solvent, adding piperidine, and reacting to obtain the compound represented by Formula 7;

[0095] (7) dissolving the compound of formula 7 in an organic solvent, adding 2,2-dimethylpropionic acid, HAT U and trimethylpyridine, and reacting to obtain the compound of formula 8;

[0096] (8) dissolving the compound represented by Formula 8 in an organic solvent, adding DBU and mercaptoethanol, and reacting to obtain the compound represented by Formula 9;

[0097] (9) adding CH2Cl2 / TFA / triisopropylsilane / H2O solution to the compound of formula 9 to react to obtain the compound of formula 10;

[0098] The synthetic route is as follows:

[0099]

[0100] A method for preparing a ferritin ligand of another structure comprises the following steps:

[0101] (1) dissolving the compound represented by Formula 1 in an organic solvent, adding o-nitrobenzenesulfonyl chloride at low temperature to react to obtain the compound represented by Formula 2;

[0102] (2) dissolving the compound represented by Formula 2 in an organic solvent, adding triethylamine and triphenylmethane at low temperature to react to obtain the compound represented by Formula 3;

[0103] (3) dissolving the compound of formula 3 in an organic solvent, adding Teoc-protected aminoethanol, tributylphosphine and azodicarbonyl dipyridine at low temperature to react to obtain the compound of formula 4;

[0104] (4) dissolving the compound represented by Formula 4 in an organic solvent, adding tetrabutylammonium fluoride, and reacting to obtain the compound represented by Formula 5;

[0105] (5) dissolving the compound of formula 5 in an organic solvent, adding protected tyrosine, HATU and collidine to react to obtain the compound of formula 6;

[0106] (6) dissolving the compound represented by Formula 6 in an organic solvent, adding piperidine, and reacting to obtain the compound represented by Formula 7;

[0107] (7) dissolving the compound represented by Formula 7 in an organic solvent, adding DBU and mercaptoethanol, and reacting to obtain the compound represented by Formula 9′;

[0108] (8) adding CH2Cl2 / TFA / triisopropylsilane / H2O solution to the compound represented by formula 9' to react and obtain the compound represented by formula 10';

[0109] The synthetic route is as follows:

[0110]

[0111] The preparation method of the ferritin degradation agent comprises the following steps:

[0112] The ferritin ligand represented by formula (B) is subjected to amidation reaction with any one of pomalidomide fragment compounds, coumarin analog fragment compounds, VHL fragment compounds, hydrophobic tag fragment compounds, and MDM2 fragment compounds under the protection of hydroxyl and amino groups, followed by deprotection to obtain the compound represented by general formula (A).

[0113] Wherein, the structural formula of the pomalidomide fragment compound is:

[0114]

[0115] Among them, n1=1, 2, 3.

[0116] The main reaction equation of the preparation method of the pomalidomide fragment compound is as follows:

[0117]

[0118] Wherein, the structural formula of the coumarin analog fragment compound is:

[0119]

[0120] Among them, n2=1, 2, 3.

[0121] The main reaction equations of the preparation method of the coumarin analog fragment compound are as follows:

[0122]

[0123] Wherein, the structural formula of the VHL fragment compound is:

[0124]

[0125] Among them, n3=1, 2, 3.

[0126] Wherein, the structural formula of the hydrophobic tag fragment compound is:

[0127]

[0128] Among them, n4=1, 2, 3.

[0129] Wherein, the structural formula of the MDM2 fragment compound is:

[0130]

[0131] Among them, n5=1, 2, 3.

[0132] Examples of the main reaction equations for the preparation of the ferritin ligand-linked pomalidomide fragment compound:

[0133] Examples of the main reaction equations for the preparation of ferritin ligand-linked coumarin analog compounds:

[0134] Examples of the main reaction equations for the preparation of the ferritin ligand-linked VHL fragment compound:

[0135] An example of the main reaction equations for the preparation of the ferritin ligand-linked hydrophobic tag fragment compound:

[0136] Examples of the main reaction equations for the preparation of the ferritin ligand-linked MDM2 fragment compound:

[0137]

[0138] The present invention further provides a pharmaceutical preparation comprising a compound represented by general formula (A), or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carriers.

[0139] The ferritin degradation agent can be used to prepare drugs for treating and / or preventing malignant tumors.

[0140] The present invention will be further described below by means of specific examples.

[0141] Ferritin ligand preparation

[0142] (1) Preparation of Compound 2

[0143] Take 1,3-propylenediamine (3.01 g, 41 mmol) and add it to a 250 mL dry flask, add dichloromethane (22.5 mL) to dissolve. Stir the solution at -5 ° C, dissolve o-nitrobenzenesulfonyl chloride (13.5 mmol, 3 g) in dichloromethane solution (90 mL) and add it to the mixture dropwise using a constant pressure dropping funnel within 45 minutes. Stir the reaction mixture for 1 h. After the reaction is completed, filter to remove the precipitate, wash the resulting solution with saturated sodium bicarbonate and sodium chloride solutions, add anhydrous sodium sulfate to dry, and vacuum concentrate to obtain compound 2, which can be put into the next step of reaction without further purification, with a yield of 87%.

[0144] (2) Preparation of Compound 3

[0145] The mono-Ns protected 1,3-propylenediamine (3.5 g, 13.5 mmol) and triethylamine (2.73 g, 27 mmol, 2 eq) were added to a 250 mL dry flask, 20 mL of dichloromethane was added for dissolution, and stirred at room temperature for 30 min; triphenylmethane (3.76 g, 13.5 mmol, 1 eq) was dissolved in dichloromethane (90 mL), and it was slowly added to the reaction bottle at 0 ° C using a constant pressure dropping funnel. After the addition was completed, the mixture was warmed to room temperature and stirred for 5 h. After the reaction was completed, it was washed with saturated sodium chloride solution, dried with anhydrous sodium sulfate, vacuum concentrated to remove dichloromethane, and purified by column chromatography (PE: EA = 5: 1) to obtain a white solid compound 3 with a yield of 91%.

[0146] (3) Preparation of Compound 4

[0147] Under nitrogen protection, Teoc-protected aminoethanol (100 mg, 0.345 mmol, 1 eq), Trt-propylenediamine-Ns (190 mg, 0.379 mmol, 1.1 eq), and tributylphosphine (349 mg, 1.73 mmol, 5 eq) were added to a 25 mL dry flask, 3 mL of dry THF was added for stirring, and azodicarbonyl dipyridine (ADDP) (435 mg, 1.73 mmol, 5 eq) dissolved in tetrahydrofuran was added under ice bath conditions, and the reaction mixture was continued to be stirred at room temperature overnight. The reaction was terminated after TLC monitoring, and the next step of reaction was directly performed.

[0148] (4) Preparation of Compound 5

[0149] The mitsunobu reaction solution from the previous step was added with tetrabutylammonium fluoride (TBAF) solution (1M in THF) (3 mL, 3 mmol), and the mixture was stirred at 50°C for 30 min. After the reaction, the mixture was extracted with ethyl acetate, washed twice with saturated brine, dried over anhydrous sodium sulfate, and concentrated in vacuo to remove ethyl acetate. The product 5 was purified by column chromatography (DCM:MeOH=10:1) to give a total yield of 65% for the two steps.

[0150] (5) Preparation of Compound 6

[0151] The product obtained in the previous step (0.345 mmol, 1 eq) was placed in a 25 mL flask, and Fmoc-O-tert-butyl-tyrosine (fluorenylmethoxycarbonyl-O-tert-butyl-L-tyrosine 190 mg, 0.414 mmol, 1.2 eq), a peptide condensation reagent (HATU) (196.8 mg, 0.517.6 mmol, 1.5 eq) and trimethylpyridine (83.6 mg, 0.690 mmol, 2 eq) were added. 3 mL of N,N-dimethylformamide was added, and the mixture was stirred at room temperature for 2 h. The reaction was terminated after TLC monitoring, and the next step was directly performed.

[0152] (6) Preparation of Compound 7

[0153] Take the reaction solution from the previous step, add 0.75 mL of piperidine to make it a 20% piperidine DMF solution, stir at room temperature for 0.5 h and monitor the reaction using TLC. After the reaction is completed, add EA for extraction, wash three times with saturated brine, dry the organic phase with anhydrous sodium sulfate, concentrate under vacuum and purify by column chromatography to obtain a light yellow oily liquid as compound 7, with a total yield of 53% for the two steps.

[0154] (7) Preparation of Compound 8

[0155] The product of the previous step was added with 2,2-dimethylpropionic acid (1.08 mmol), HATU (1.08 mmol), 2 mL of N,N-dimethylformamide and collidine (1.62 mmol). The mixture was stirred at room temperature for 2 hours. After the reaction was completed, the next step was performed after monitoring by TLC.

[0156] (8) Preparation of Compound 9

[0157] The reaction solution from the previous step was taken, and DBU (1.35 mmol) and mercaptoethanol (1.35 mmol) were added to treat at room temperature for 30 minutes. After the reaction was completed by TLC monitoring, ethyl acetate was added for extraction. After saturated laboratory washing, the organic phase was dried over anhydrous sodium sulfate. The solvent was removed in vacuo and purified by column chromatography to obtain compound 9. The total yield of the two steps was 44%.

[0158] (9) Preparation of Compound 10

[0159] Compound 9 was treated with CH2Cl2 / TFA / triisopropylsilane / H2O (47.5 / 47.5 / 2.5 / 2.5, 5 mL) solution for 2 h, and the solvent was removed in vacuo. Compound 10 was obtained as a colorless oily liquid with a yield of 76% after separation and purification by reverse column chromatography; 1 H NMR(400MHz,Methanol-d4)δ7.07-7.00(m,2H),6.77-6.69(m,2H),4.58-4.48( m,1H),3.62(q,J=7.0Hz,1H),3.26-3.12(m,2H),3.10(s,1H),3.09-2.95(m,5H ),2.92-2.81(m,1H),2.11(tt,J=9.4,6.8Hz,2H),1.69(dq,J=15.5,7.7,6.8Hz ,2H),1.49-1.33(m,5H),1.33-1.28(m,3H),1.27-1.14(m,3H),1.11(s,8H).13C NMR (101MHz, Methanol-d4) δ179.47 (d, J = 7.4Hz), 172.45 (d, J = 8.8Hz), 155.96, 130.08, 127.60, 114.92, 57.04, 55.65-54.92 (m), 47.56, 47.3 5,47.14,44.43,39.09(d,J=12.9Hz),38.31(d,J=2.2Hz),37.07(d,J=3 .3Hz),36.53,29.11-28.43(m),27.05-25.92(m),25.73,23.95,17.16.

[0160] HRMS(ES+):calcd For C 25 H 44 N4O3[M+H]+449.6520found 449.3498.

[0161] Preparation of Pomalidomide Fragments

[0162] (1) Preparation of Compound 12

[0163] Under nitrogen atmosphere, polyethylene glycol (80 mmol, 8 eq) was dissolved in 30 mL of anhydrous tetrahydrofuran, potassium tert-butoxide (11.2 g, 10 mmol, 1 eq) was added at room temperature, and the mixture was stirred at 60 ° C for 30 min, and then cooled to room temperature; tert-butyl bromoacetate (19.5 g, 10 mmol, 1 eq) was dissolved in 20 mL of anhydrous tetrahydrofuran, added to the reaction bottle using a syringe, and stirred at room temperature for 24 h. After the reaction was completed under TLC monitoring, it was extracted with ethyl acetate, washed with saturated brine, and the organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography to obtain product 12 in a yield of 32%-35%.

[0164] (2) Preparation of Compound 13

[0165] The product of the previous step (10 mmol, 1 eq) was dissolved in 50 mL of dichloromethane, and Dess-Martin reagent (12 mmol, 1.2 eq) was slowly added at 0°C. After the addition was completed, the reaction was stirred at room temperature for 2 h. After the reaction was completed by TLC monitoring, dichloromethane was added to the reaction solution for extraction, and the solution was washed with sodium thiosulfate solution and sodium bicarbonate solution, respectively. The organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography to obtain product 13 with a yield of 79%-88%.

[0166] (3) Preparation of Compound 14

[0167] Take a dry 50mL Schlenk bottle, add the reaction product of the previous step (33mmol, 1.1eq) and pomalidomide (30mmol, 1eq) into the bottle and dissolve them in 20mL of anhydrous DMF, add TMSCl (75mmol, 2.5eq) under nitrogen protection, cool the mixture to 0°C, slowly inject borane (BH3·THF, 1M in THF) solution (30mmol, 1eq) into the bottle using a syringe, continue stirring the reaction at 0°C until the reaction is completed as monitored by TLC, add 3mL of water to quench the reaction, extract with ethyl acetate, wash with saturated sodium carbonate solution several times, dry the organic phase over anhydrous sodium sulfate and concentrate under reduced pressure, and purify the residue by column chromatography to obtain product 14 with a yield of 25%-31%.

[0168] (4) Preparation of Compound 15

[0169] The product of the previous step (10 mmol) was dissolved in 20 mL of dichloromethane, 10 mL of trifluoroacetic acid was added, and the mixture was stirred at room temperature for 2 h, then concentrated under reduced pressure. The residue was purified by reverse phase chromatography to obtain product 15.

[0170] Preparation of coumarin analog fragments

[0171] (1) Preparation of Compound 17

[0172] Take a dry 250mL flask, place phloroglucinol (5 g, 39.6 mmol) and 50 mL of trifluoroacetic acid in the flask, stir and dissolve in an ice bath, slowly add 50 mL of trifluoroacetic acid solution of ethyl acetoacetate (7.1 mL, 40.8 mmol) through a dropping funnel, after the addition is complete, warm the reaction flask to room temperature and stir overnight, after the reaction is completed, remove the trifluoroacetic acid by distillation under reduced pressure, add 100 mL of dichloromethane and stir to dissolve, and filter to obtain compound 17 as a white solid (4.1 g, yield: 54%).

[0173] (2) Preparation of Compound 18

[0174] Take a dry 100mL flask, under nitrogen atmosphere, weigh compound 17 (1.5g, 6mmoL), compound ethylene glycol monoacetate tert-butyl ester (1.3g, 6mmoL), PPh3 (3.1g, 12mmoL) and 30mL anhydrous tetrahydrofuran and add them into the flask, add DIAD (2mL, 12mmoL) dropwise into the flask through a syringe at 0°C with stirring, after the addition is complete, heat to 40°C, stir for 8 hours, after the reaction is complete, remove tetrahydrofuran by concentrating under reduced pressure, and purify the concentrate by column chromatography to obtain compound 18 as a white solid (1.1g, yield: 46%)

[0175] (3) Preparation of Compound 19

[0176] Take a dry 100 mL flask, weigh compound 18 (1.1 g, 2.7 mmol) and place it in the flask, add 30 mL of trifluoroacetic acid, and stir at room temperature for 2 hours. After the reaction is completed, distill the trifluoroacetic acid under reduced pressure to remove the trifluoroacetic acid. The concentrate is purified by column chromatography to obtain compound 19, which is an oily liquid (701 mg, yield: 76%).

[0177] Preparation of ferritin degrader

[0178] Preparation of compound 21

[0179] Compound 20 (1mmol) was added with pomalidomide-polyethylene glycol-acid (1.1mmol), HATU (1.5mmol) and 2mL of N,N-dimethylformamide, and trimethylpyridine (1.5mmol). The mixture was stirred at room temperature for 2 hours. After the reaction was completed by TLC monitoring, the next step was performed. The reaction solution of the previous step was taken, DBU (1.35mmoL) and mercaptoethanol (1.35mmoL) were added and treated at room temperature for 30 minutes. After the reaction of the raw materials was completed by TLC monitoring, ethyl acetate was added for extraction. After washing with saturated brine, the organic phase was dried with anhydrous sodium sulfate, and the solvent was removed in vacuo and concentrated before the next step of reaction was performed. The concentrated product of the previous step was treated with CH2Cl2 / TFA / triisopropylsilane / H2O (47.5 / 47.5 / 2.5 / 2.5, 5mL) solution for 2h. After the solvent was removed in vacuo, compound 21 was obtained after separation and purification by reverse column chromatography.

[0180] Example 1

[0181]

[0182] Yellow oily liquid; 1 H NMR (400MHz, Methanol-d4) δ7.54(dd,J=8.6,7.1Hz,2H),7.13–6.95(m,7H),6.72–6.60(m,4H),5.03(dt,J=12.8,5. 3Hz,2H),4.50(td,J=7.3,2.8Hz,2H),4.01(dd,J=15.6,3.4Hz,2H),3.92(dd,J=15.6,1.8Hz,2H),3.81–3.58(m,11H ),3.53(dt,J=5.4,2.7Hz,4H),3.35(s,10H),3.25-2.97(m,15H),2.97-2.82(m,5H),2.82-2.76(m,2H),2.76-2.69( m,2H),2.69-2.58(m,2H),2.12-1.99(m,5H),1.73-1.61(m,4H),1.43-1.27(m,15H),1.19(tt,J=8.1,3.6Hz,4H).13C NMR (101MHz, Methanol-d4) δ130.06,114.84,47.61,47.39,47.18,46.97.

[0183] HR-MS(ES+):calcd.For C 39 H 55 N7O9[M+H]+766.4061,found 766.4146.

[0184] Example 2

[0185]

[0186] Yellow oily liquid; 1 H NMR (400MHz, Methanol-d4) δ7.51(dd,J=8.5,7.1Hz,1H),7.07–6.98(m,4H),6.67(d,J=8.2Hz,2H),5.03(dd,J=12.7,5.5Hz,2H),4.52(t,J= 7.3Hz,1H),3.97(d,J=15.7Hz,1H),3.88(d,J=16.0Hz,2H),3.74–3.66(m,7H),3.66-3.58(m,5H),3.58-3.51(m,2H),3.47(t,J=5.2Hz,2H),3 .35(s,25H),3.20-3.03(m,6H),3.00(d,J=13.8Hz,3H),2.95(dt,J=6.9,2.7Hz,3H),2.87(dd,J=10.8,4.9Hz,2H),2.85-2.78(m,1H),2.74(t d,J=7.2,5.8,3.3Hz,1H),2.72-2.61(m,3H),2.14-1.99(m,4H),1.66(t,J=7.8Hz,3H),1.44-1.25(m,10H),1.18(dd,J=12.9,7.4Hz,3H).13C NMR (101MHz, Methanol-d4) δ173.51,135.93,130.12,117.00,114.93,70.17,69.64,54.48,48.82,48.33,48. 12,47.90,47.69,47.48,47.26,47.05,44.43,41.82,36.52,30.85,28.76,28.60,26.01,25.76,23.99,22.41.

[0187] HR-MS(ES+):calcd.For C 41 H 59 N7O 10 [M+H]+810.4323,found 810.4408.

[0188] Example 3

[0189]

[0190] Yellow oily liquid; 1H NMR (400MHz, Methanol-d4) δ7.53(dd,J=8.6,7.1Hz,1H),7.12–6.98(m,4H),6.68(d,J=8.5Hz,3H),5.05(dd,J=12.4,5.4Hz,2H),4.5 3(t,J=7.3Hz,1H),3.99(d,J=15.5Hz,1H),3.90(d,J=15.5Hz,1H),3.69(dt,J=8.7,4.9Hz,5H),3.66-3.56(m,10H),3.53(d,J=6.9Hz ,1H),3.47(t,J=5.2Hz,2H),3.35(s,14H),3.21-3.13(m,2H),3.13-3.03(m,6H),3.03-2.95(m,4H),2.92-2.79(m,3H),2.79-2.62(m ,2H),2.16-2.08(m,2H),2.08-1.99(m,2H),1.67(t,J=7.7Hz,3H),1.37(ddq,J=24.2,13.5,6.6,4.5Hz,11H),1.27-1.19(m,3H).13C NMR (101MHz, Methanol-d4) δ130.08,114.89,70.21,69.62,47.64,47.43,47.22,47.00,44.40,36.47,28.77,28.57,25.97,25.72,23.98.

[0191] HR-MS(ES+):calcd.For C 39 H 59 N7O 10 [M+H]+854.4586,found 854.4669.

[0192] Example 4

[0193]

[0194] Colorless oily liquid; 1H NMR (400MHz, Methanol-d4) δ7.04–6.96(m,2H),6.72–6.62(m,2H),6.38–6.26(m,2H),5.85(dd,J=14. 8,1.4Hz,1H),4.57(td,J=7.2,4.0Hz,1H),4.13(t,J=4.5Hz,2H),4.12–3.90(m,2H),3.90–3.75(m,2H ),3.36(s,13H),3.18-2.91(m,9H),2.91-2.78(m,2H),2.56(d,J=1.2Hz,1H),2.47(d,J=1.2Hz,2H),2 .15-2.03(m,2H),1.74-1.61(m,2H),1.48-1.36(m,3H),1.36-1.24(m,5H),1.20(t,J=5.3Hz,2H).13C NMR (101MHz, Methanol-d4) δ130.02,129.99,114.92,109.30,96.37,95.62,69.74,69.43,67.67,54.25,47.77,47.6 7,47.45,47.24,47.03,44.40,39.04,37.25,36.48,28.79,28.66,28.64,28.62,26.34,26.04,25.75,23.98,23.46.

[0195] HR-MS(ES+):calcd.For C34H48N4O8[M+H]+641.3472, found 641.3552.

[0196] Example 5

[0197]

[0198] Colorless oily liquid; 1H NMR(400MHz, Methanol-d4)δ7.08–7.01(m,1H),6.99–6.88(m,1H),6.74–6.61(m,2H), 6.53–6.39(m,1H),4.61–4.45(m,1H),4.31–4.07(m,2H),4.07–3.81(m,4H),3.81–3.5 3(m,9H),3.35(s,4H),3.24–2.89(m,10H),2.88–2.73(m,2H),2.64-2.52(m,1H),2.13 -2.01(m,2H),1.75-1.61(m,2H),1.47-1.30(m,7H),1.25(dt,J=10.6,5.3Hz,10H).13C NMR(101MHz,Methanol-d4)δ130.07,114.87,70.67,70.03,69.62,69.24,67.52,54.46,47.63,47.42 ,47.21,46.99,44.38,38.98,37.35,36.45,28.76,28.64,28.60,26.31,26.02,25.75,23.98,20.95.

[0199] HR-MS(ES+):calcd.For C 36 H 52 N4O9[M+H]+685.3734,found 685.3818.

[0200] Example 6

[0201]

[0202] Colorless oily liquid; 1H NMR(400MHz, Methanol-d4)δ7.08–6.96(m,2H),6.74–6.63(m,2H),6.48–6.20(m,2H),4.59–4.47(m,1H),4.22–4.06(m,2H),4.06–3.68( m,9H),3.68–3.52(m,7H),3.35(s,4H),3.19–2.96(m,8H),2.96–2.78(m,3H),2.59–2.51(m,2H),2.14-2.02(m,2H),1.68(t,J=7.2Hz,2H ),1.46-1.32(m,5H),1.24(t,J=6.3Hz,6H).13CNMR(101MHz,Methanol-d4)δ130.06,114.90,114.86,70.59,70.32,70.11,70.00,69.67 ,54.43,47.76,47.65,47.44,47.23,47.01,44.40,39.00,37.18,36.48,28.79,28.64,28.60,26.31,26.02,25.75,23.98,23.40,20.95.

[0203] HR-MS(ES+):calcd.For C 38 H 56 N4O 10 [M+H]+729,3996,found 729.4067.

[0204] Example 7

[0205]

[0206] Colorless oily liquid; 1H NMR (400MHz, Methanol-d4) δ7.08–6.98 (m, 2H), 6.68 (dt, J = 8.6, 2.0Hz, 2H) ,6.47–6.26(m,2H),4.21–3.74(m,8H),3.74–3.51(m,14H),3.35(s,11H),3. 25–2.94(m,10H),2.94–2.79(m,3H),2.59–2.51(m,3H),2.14–2.02(m,2H), 1.68(dq,J=15.4,7.7,7.0Hz,2H),1.49-1.32(m,7H),1.32-1.17(m,6H).13C NMR(101MHz,Methanol-d4)δ130.07,114.88,70.24,70.16,70.14,69.66,54.48,47.76,47.65,47 .43,47.22,47.01,44.40,38.99,37.14,36.48,28.79,28.61,28.59,26.29,26.00,25.74,23.98.

[0207] HR-MS(ES+):calcd.For C40H60N4O11[M+H]+773.4259,found773.4339.

[0208] The affinity of the compound of Example 2 to ferritin was tested by surface plasmon resonance. The results are shown in Figure 1 .

[0209] The compounds of the above examples were screened for ferritin degradation levels; the results of ferritin degradation of breast cancer cells MCF-7 by the compounds of each example at a concentration of 50 μmol / L are shown in Figure 2 Among them, Example 2 and Example 4 can obviously degrade FTH1, and other examples can degrade FTH1 to a certain extent.

[0210] The anti-proliferation activity of Examples 2 and 4 was tested on MCF-7 cells. The experimental results are shown in Tables 1 and 2. Example 2 and Example 4 alone did not show obvious anti-proliferation activity; but after being used in combination with artesunate, they could exert a certain synergistic anti-proliferation effect.

[0211] Table 1

[0212]

[0213] Table 2

[0214]

[0215] The above descriptions are merely embodiments of the present invention and are not intended to limit the patent scope of the present invention. Any modifications or equivalent transformations made using the contents of the present invention specification, or directly or indirectly applied in other related technical fields, are also included in the patent protection scope of the present invention.

Claims

1. A ferritin degradation agent, characterized in that The ferritin degradation agent is a compound represented by general formula (A), or a pharmaceutically acceptable salt thereof: Wherein, Ⅰ is one of the following structures: n is an integer from 1 to 3; Ⅱ is one of the following structures:

2. A ferritin degradation agent according to claim 1, characterized in that The ferritin degrading agent is selected from: (2S)-N-(8-((3-aminopropyl)amino)octyl)-2-(2-(2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)ethoxy)ethoxy)acetamido)-3-(4-hydroxyphenyl)propanamide; (2S)-N-(8-((3-aminopropyl)amino)octyl)-2-(2-(2-(2-((2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)ethoxy)ethoxy)acetamido)-3-(4-hydroxyphenyl)propanamide; N-((S)-1-((8-((3-aminopropyl)amino)octyl)amino)-3-(4-hydroxyphenyl)-1-oxopropan-2-yl)-14-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)-3,6,9,12-tetraoxatetradecanoic acid amide; (S)-N-(8-((3-aminopropyl)amino)octyl)-2-(2-((7-hydroxy-4-methyl-2-oxo-2H-benzopyran-5-yl)oxy)ethoxy)acetamido)-3-(4-hydroxyphenyl)propanamide; (S)-N-(8-((3-aminopropyl)amino)octyl)-2-(2-(2-((7-hydroxy-4-methyl-2-oxo-2H-benzopyran-5-yl)oxy)ethoxy)ethoxy)acetamido)-3-(4-hydroxyphenyl)propanamide; (S)-N-(8-((3-aminopropyl)amino)octyl)-2-(2-(2-(2-((7-hydroxy-4-methyl-2-oxo-2H-benzopyran-5-yl)oxy)ethoxy)ethoxy)acetamido)-3-(4-hydroxyphenyl)propanamide; (S)-N-(1-((8-((3-aminopropyl)amino)octyl)amino)-3-(4-hydroxyphenyl)-1-oxopropan-2-yl)-14-((7-hydroxy-4-methyl-2-oxo-2H-benzopyran-5-yl)oxy)-3,6,9,12-tetraoxatetradecanoic acid amide.

3. The ferritin degradation agent according to claim 1, characterized in that The ferritin degradation agent is prepared by reacting a ferritin ligand with any one of a pomalidomide fragment compound, a coumarin analog fragment compound, a VHL fragment compound, a hydrophobic tag fragment compound, and an MDM2 fragment compound.

4. A ferritin ligand, characterized in that It has a structure as shown in formula (B): Wherein, R is selected from H or 5. A method for preparing a ferritin ligand according to claim 4, characterized in that: The steps include: (1) dissolving the compound represented by Formula 1 in an organic solvent, adding o-nitrobenzenesulfonyl chloride at low temperature, and reacting to obtain the compound represented by Formula 2; (2) dissolving the compound represented by Formula 2 in an organic solvent, adding triethylamine and triphenylmethane at low temperature to react to obtain the compound represented by Formula 3; (3) dissolving the compound of formula 3 in an organic solvent, adding Teoc-protected aminoethanol, tributylphosphine and azodicarbonyl dipyridine at low temperature to react to obtain the compound of formula 4; (4) dissolving the compound represented by Formula 4 in an organic solvent, adding tetrabutylammonium fluoride, and reacting to obtain the compound represented by Formula 5; (5) dissolving the compound of formula 5 in an organic solvent, adding protected tyrosine, HATU and collidine to react to obtain the compound of formula 6; (6) dissolving the compound represented by Formula 6 in an organic solvent, adding piperidine, and reacting to obtain the compound represented by Formula 7; (7) dissolving the compound of formula 7 in an organic solvent, adding 2,2-dimethylpropionic acid, HAT U and trimethylpyridine, and reacting to obtain the compound of formula 8; (8) dissolving the compound represented by Formula 8 in an organic solvent, adding DBU and mercaptoethanol, and reacting to obtain the compound represented by Formula 9; (9) adding CH2Cl2 / TFA / triisopropylsilane / H2O solution to the compound of formula 9 to react to obtain the compound of formula 10; The synthetic route is as follows:

6. A method for preparing a ferritin ligand according to claim 4, characterized in that: The steps include: (1) dissolving the compound represented by Formula 1 in an organic solvent, adding o-nitrobenzenesulfonyl chloride at low temperature, and reacting to obtain the compound represented by Formula 2; (2) dissolving the compound represented by Formula 2 in an organic solvent, adding triethylamine and triphenylmethane at low temperature to react to obtain the compound represented by Formula 3; (3) dissolving the compound of formula 3 in an organic solvent, adding Teoc-protected aminoethanol, tributylphosphine and azodicarbonyl dipyridine at low temperature to react to obtain the compound of formula 4; (4) dissolving the compound represented by Formula 4 in an organic solvent, adding tetrabutylammonium fluoride, and reacting to obtain the compound represented by Formula 5; (5) dissolving the compound of formula 5 in an organic solvent, adding protected tyrosine, HATU and collidine to react to obtain the compound of formula 6; (6) dissolving the compound represented by Formula 6 in an organic solvent, adding piperidine, and reacting to obtain the compound represented by Formula 7; (7) dissolving the compound represented by Formula 7 in an organic solvent, adding DBU and mercaptoethanol, and reacting to obtain the compound represented by Formula 9′; (8) adding CH2Cl2 / TFA / triisopropylsilane / H2O solution to the compound represented by formula 9' to react and obtain the compound represented by formula 10'; The synthetic route is as follows:

7. A method for preparing a ferritin degradation agent, characterized in that: The steps include: The compound represented by the general formula (A) is prepared by reacting the ferritin ligand with any one of the pomalidomide fragment compound, the coumarin analog fragment compound, the VHL fragment compound, the hydrophobic tag fragment compound and the MDM2 fragment compound.

8. The method for preparing a ferritin degradation agent according to claim 7, characterized in that: The structural formula of the pomalidomide fragment compound is: Among them, n1=1, 2, 3.

9. The method for preparing a ferritin degradation agent according to claim 7, characterized in that: The structural formula of the coumarin analog fragment compound is: Among them, n2=1, 2, 3.

10. The method for preparing a ferritin degradation agent according to claim 7, characterized in that: The structural formula of the VHL fragment compound is: Among them, n3=1, 2, 3.

11. The method for preparing a ferritin degradation agent according to claim 7, characterized in that: The structural formula of the hydrophobic tag fragment compound is: Among them, n4=1, 2, 3.

12. The method for preparing a ferritin degradation agent according to claim 7, characterized in that: The structural formula of the MDM2 fragment compound is: Among them, n5=1, 2, 3.

13. A pharmaceutical preparation comprising a compound represented by general formula (A), or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carriers.

14. Use of the ferritin degrading agent according to any one of claims 1 to 3 in the preparation of a drug for treating and / or preventing malignant tumors.

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