CN102260190A - N-benzyl-N'-(terminal carboxylic acid substituted acyloxy)octanediamide compounds with anti-tumor effect and pharmaceutical salts thereof - Google Patents

Abstract

The invention relates to a histone deacetylase (HDAC) inhibitor-based predrug of dicarboxylic acid monoester derivatives of N-hydroxy-N'-benzyl octanediamide (vorinostat), namely N-benzyl-N'-(terminal carboxylic acid substituted acyloxy)octanediamide compounds and pharmaceutical salts thereof. Compared with free hydroximic acid vorinostat, the terminal carboxylic acid substituted acyloxy acylated derivative predrug has higher water solubility and cell permeability, can effectively inhibit the HDAC in vivo, and selectively induces terminal differentiation, growth arrest and/or apoptosis of tumor cells so as to inhibit the multiplication of the tumor cells. Therefore, the predrug can be used for treating tumor patients suffering tumor cell amplification.

Description

N-phenyl-N'-(terminal carboxylic acid substituted acyloxy) suberamide compounds with antitumor effect and pharmaceutically acceptable salts thereof

technical field

The present invention relates to dibasic carboxylic acid monoester derivatives based on the prodrug N-hydroxy-N'-phenylsuberamide (vorinostat) of hydroxamic acid histone deacetylase (HDAC) inhibitors - - N-phenyl-N'-(terminal carboxylic acid substituted acyloxy) suberamide compounds and pharmaceutically acceptable salts thereof with antitumor effect. the

Background technique

Vorinostat (SAHA), chemical name: N-hydroxy-N'-phenylsuberamide, is a hydroxamic acid histone deacetylase inhibitor developed by Merck. In vivo studies, SAHA can show anti-tumor activity in various cancer models. Phase II clinical studies have shown that SAHA can exhibit anti-tumor activity in patients with solid tumors and hematological malignancies. SAHA was approved by the US FDA in October 2006 under the trade name Zolinza for the treatment of cutaneous T-cell lymphoma (CTCL). This product is clinically developed for the treatment of leukemia, breast cancer and colorectal cancer. It is also being studied for the treatment of diffuse large cell lymphoma, a type of non-Hodgkin's lymphoma (NHL). SAHA combined with chemotherapeutic drugs can improve the effective rate of thyroid cancer treatment (Clin Cancer Res, 2006, 12(18): 5570-5577). The in vitro test of SAHA on three kinds of pancreatic cancer cells showed that SAHA expressed in the cytoplasm by up-regulating P21 increase, prevent pancreatic cancer cells in the G1 phase, enhance the anticancer effect of gemcitabine, and have the potential to treat pancreatic cancer (Clin Cancer Res, 2007, 13(1): 18-26). the

Contents of the invention

The object of the present invention is to overcome the deficiency of hydroxamic acid histone deacetylase (HDAC) inhibitor N-hydroxyl-N'-phenylsuberamide (vorinostat), and provide vorinostat with antitumor effect Nuota's prodrug--dibasic carboxylic acid monoester derivatives of N-hydroxy-N'-phenylsuberamide N-phenyl-N'-terminal carboxylic acid substituted acyloxy-suberamide compounds and its medicinal salt. Compared with N-hydroxy-N'-phenylsuberamide, these derivatives have improved water solubility and cell permeability, and can be used to inhibit HDAC and selectively induce terminal differentiation of neoplastic cells, resulting in cell growth arrest And, apoptosis, so as to achieve the purpose of inhibiting the proliferation of such cells. (intestinal cancer), Skov3 (ovarian cancer), BGC-823 (gastric cancer), KB (oral epithelial cancer), MCF-7 (breast cancer), k562 (leukemia), DU145 (prostate cancer) and human umbilical vein endothelial cells The inhibitory activity of HUVEC is not as good as that of vorinostat; however, in the in vivo activity test, it has a good inhibitory effect on tumor colon cancer C26, liver cancer H22, Lewis lung cancer and B16 melanoma, and its strength is comparable to that of vorinostat. the

The N-phenyl-N'-terminal carboxylic acid substituted acyloxy-suberamide compound to be prepared in the present invention has a structure as shown in formula Ia:

In formula I a, Y is:

(CH ₂ ) _n (n is equal to 2, 3, 4, 5, 6);

Or ethylenic bond (CHCH) _n (n=1,2,3;

Or C3-C8 aliphatic carbocycle, aliphatic heterocycle;

Or aromatic ring and aromatic heterocyclic ring Ar;

or Ar(CHCH)n ₁ (n ₁ is 1, 2, 3);

Or (CHCH)n ₁ Ar(CHCH)n ₁ (n ₁ is 1, 2, 3);

Ar is phenyl, naphthyl, 5-6 membered aromatic heterocyclic group, benzo 5-6 membered aromatic heterocyclic group, 6-membered aromatic heterocyclic group and 5-6 membered aromatic heterocyclic group, substituted phenyl , Substituted naphthyl, substituted 5-6 membered aromatic heterocyclic group, substituted benzo 5-6 membered aromatic heterocyclic group, substituted 6-membered aromatic heterocyclic group and 5-6 membered aromatic heterocyclic group;

Wherein, the heteroatoms of the aromatic heterocyclic group are selected from one or more than two (including two) of N, O or S, and the number of heteroatoms is an integer of 1 to 3;

The substituted phenyl, substituted naphthyl, substituted 5-6 membered aromatic heterocyclic group, substituted benzo 5-6 membered aromatic heterocyclic group, substituted 6-membered aromatic heterocyclic and 5-6 membered aromatic The substituent of the heterocyclic group is selected from one or two of halogen (F, Cl, Br or I), nitro (-NO ₂ ), hydroxyl (-OH), cyano (-CN) or alkoxy above (including two).

The pharmaceutically acceptable salt of N-phenyl-N'-terminal carboxylic acid substituted acyloxy-suberamide compound is N-phenyl-N'-terminal carboxylic acid substituted acyloxy-suberamide compound Ia Metal salt (I b):

Among them, the metal ion M represents: sodium ion, potassium ion, calcium ion, magnesium ion, zinc ion, iron ion, aluminum ion;

Or N-phenyl-N'-terminal carboxylic acid substituted acyloxy-suberamide compound (I a) and the compound salt (I c) formed by base B:

I c

Among them, the base B represents: triethanolamine, vitamin B6 free base, imidazole, pyridine, pyrimidine, various natural amino acid esters, such as: glycine ester, alanine ester, phenylalanine ester, lysine ester, arginine Ester, proline ester, etc.; wherein, the ester group is a 1-6 carbon alcohol, such as: methanol, ethanol, propanol; phenol and benzyl alcohol; wherein, Y is as defined above. the

The method for the compound shown in the preparation formula provided by the present invention, its main steps are: by N-hydroxyl-N'-phenylsuberamide (vorinostat) (its structure is shown in formula II) and dibasic carboxylic acid The acid anhydride (III) of the acid HOCOYCOOH is reacted at 20-200° C. to obtain the target compound (compound represented by formula I). the

In formula III, the definition of Y is the same as described above. the

Detailed ways

In a preferred technical scheme of the present invention, N-phenyl-N'-terminal carboxylic acid substituted acyloxy-suberamide compound (I a) represents the following structure:

Y is: (CH ₂ ) _n (n is equal to 2, 3, 4, 5, 6) or ethylenic bond (CHCH) _n (n = 1, 2, 3) or C3-C8 aliphatic carbocyclic, aliphatic heterocyclic or aromatic Ring and aromatic heterocycle Ar or Ar(CHCH)n ₁ (n ₁ is 1, 2, 3); or (CHCH)n ₁ Ar(CHCH)n ₁ (n ₁ is 1, 2, 3);

Ar is phenyl, naphthyl, 5-6 membered aromatic heterocyclic group, benzo 5-6 membered aromatic heterocyclic group, 6-membered aromatic heterocyclic group and 5-6 membered aromatic heterocyclic group, substituted phenyl , Substituted naphthyl, substituted 5-6 membered aromatic heterocyclic group, substituted benzo 5-6 membered aromatic heterocyclic group, substituted 6-membered aromatic heterocyclic group and 5-6 membered aromatic heterocyclic group;

Wherein, the heteroatoms of the aromatic heterocyclic group are selected from one or more than two (including two) of N, O or S, and the number of heteroatoms is an integer of 1 to 3;

The substituted phenyl, substituted naphthyl, substituted 5-6 membered aromatic heterocyclic group, substituted benzo 5-6 membered aromatic heterocyclic group, substituted 6-membered aromatic heterocyclic and 5-6 membered aromatic The substituent of the heterocyclic group is selected from one or two of halogen (F, Cl, Br or I), nitro (-NO ₂ ), hydroxyl (-OH), cyano (-CN) or alkoxy above (including two).

In another preferred technical solution of the present invention, the pharmaceutically acceptable salt of said N-phenyl-N'-terminal carboxylic acid substituted acyloxy-suberamide compound is N-phenyl-N'-terminal carboxylic acid Metal salts (I b) of substituted acyloxy-suberamide compounds (I a), such as: sodium salts, potassium salts, magnesium salts, zinc salts, calcium salts, iron salts, aluminum salts;

In yet another preferred technical scheme of the present invention, the pharmaceutically acceptable salt of said N-phenyl-N'-(terminal carboxylic acid substituted acyloxy group) suberamide compound Ia is N-phenyl-N' -Compound salt (I c) formed by terminal carboxylic acid substituted acyloxy group-suberamide compound (I a) and base B:

Among them, the base B represents: triethanolamine, vitamin B6 free base, imidazole, pyridine, pyrimidine, various natural amino acid esters, such as: glycine ester, alanine ester, phenylalanine ester, lysine ester, arginine Ester, proline ester, etc.;

Among them, the ester group is 1-6 carbon alcohols, such as: methanol, ethanol, propanol; phenol and benzyl alcohol. the

The method for the compound shown in the preparation formula provided by the present invention, its main steps are: by N-hydroxyl-N'-phenylsuberamide (vorinostat) (its structure is shown in formula II) and dibasic carboxylic acid The acid anhydride (Ⅲ) of the acid HOCOYCOOH is reacted in a reaction medium at room temperature - 200°C under the action of a catalyst such as DMAP to obtain the target compound (compound shown in formula Ia). the

In formula III, the definition of Y is the same as described above. the

In yet another preferred technical solution of the present invention, the molar ratio of the compound shown in formula II to the compound shown in formula III is 1:0.8-5, and the more preferred technical solution is: the compound shown in formula II and the compound shown in formula III The molar ratio is 1:1.1～2.5. the

In yet another preferred technical solution of the present invention, said reaction medium is an organic solvent or an ionic liquid, such as (but not limited to): pyridine, toluene, xylene, acetic acid, 1,4-dioxane, N, N-dimethylformamide (DMF), N,N-dimethylacetamide, dimethyl sulfoxide (DMSO), sulfolane, 1-butyl-3-methylimidazolium bromide ([bmIm]Br) , 1-butyl-3-methylimidazolium tetrafluoroborate ([bmIm]BF ₄ ) or 1-butyl-3-methylimidazolium hexafluorophosphate ([bmIm]PF ₆ ), etc.;

The organic solvent recommended by the present invention is: pyridine, N, N-dimethylformamide (DMF), N, N-dimethylacetamide, and dimethylsulfoxide (DMSO);

The recommended dosage of the organic solvent is 10mL-20mL/g N-hydroxy-N'-phenylsuberamide, that is: per gram of N-hydroxy-N'-phenylsuberamide (compound shown in formula II) Need to use 10mL ~ 20mL of the organic solvent. the

In the preparation method of the present invention, thin layer chromatography (TLC) can be used to judge the end point of the preparation reaction; and the crude product of the compound shown in the prepared formula Ia can be obtained by alkali-dissolving acid analysis or recrystallization or Purification by conventional purification methods such as column chromatography. the

The N-phenyl-N'-terminal carboxylic acid substituted acyloxy-suberamide compound Ia prepared in the present invention can be made into a hydrate or a solvate. the

In another preferred technical scheme of the present invention, the pharmaceutical alkali metal salt (I b) of said N-phenyl-N'-terminal carboxylic acid substituted acyloxy-suberamide compound is composed of N-phenyl The -N'-terminal carboxylic acid substituted acyloxy-suberamide compound (Ia) is obtained by neutralizing an equimolar alkali metal hydroxide salt solution or bicarbonate solution at low temperature. the

In another preferred technical scheme of the present invention, the medicinal alkaline earth metal salt (I b) of said N-phenyl-N'-(terminal carboxylic acid substituted acyloxy group) suberamide compound is composed of N- Phenyl-N'-(terminal carboxylic acid substituted acyloxy) suberamide compound (I a), obtained by neutralizing with 0.5 mole alkaline earth metal hydroxide salt solution or bicarbonate solution at low temperature. the

In yet another specific embodiment of the present invention, HDACs subtype HDAC1 is taken as an entry point, and substances with good enzyme/cell inhibitory activity are screened out through in vitro enzyme inhibition and tumor cell proliferation inhibition experiments. the

In yet another specific embodiment of the present invention, the antitumor activity research at the enzyme level of the cell-free system is based on the enzyme-fluorescent substrate interaction theory, using BIOMOL Fluor-de-Lys The HDAC&HDAC1 fluorometric activity assay kit screens the activity of the synthesized drugs, reacts the synthesized compounds with different concentrations for a period of time, and uses a multifunctional fluorescent microplate reader to measure the fluorescence intensity after the action, and compares it with the blank and negative, and compares the fluorescence intensity value Non-linear fitting, calculation of growth inhibition IC50 value, used to evaluate the inhibitory effect of different structural compounds on HDACs and HDAC1.

In yet another specific embodiment of the present invention, the research steps of anti-tumor activity at the cell level in vitro are as follows: culturing human glial tumor cells U251, adding experimental drugs to the cells, and setting different drug action times and action concentrations, To study the time-effect relationship and dose-effect relationship of experimental drugs; use the MTT method to calculate the IC50 value of growth inhibition, evaluate the inhibitory effect of the experimental drug on tumor cell growth, and use the clone formation method to calculate the EC50 value of the clone formation rate, and evaluate the effect of the drug on the tumor For the influence of cell clone formation, the safety factor value was calculated by safety factor TI=EC50/IC50, and compounds with higher activity were evaluated. the

In yet another specific embodiment of the present invention, HDAC inhibition in cell lines was tested for the ability of the novel compounds of the present invention to inhibit the proliferation of the murine erythroleukemia cell line SC9 using the MTS assay, MTS assay, also known as 96-well cell titer plate Cell Titer 96 Aqueous One Solution Cell Proliferation Assay (Cell Titer 96 Aqueous One Solution Cell Proliferation Assay), is a colorimetric method for the determination of the number of viable cells in proliferation, cytotoxicity or chemosensitivity analysis. MTS reagent contains a new tetrazolium compound [3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H- tetrazolium, inner salt] and electron coupling reagent (phenazine ethyl sulfate, PES). the

In yet another embodiment of the invention, the MTS assay comprises the following steps: murine erythroleukemia cells (SC-9) are incubated with vehicle or increasing concentrations of compounds for 48 hours, and cell proliferation is quantified by: Add a small amount of MTS reagent directly to the culture well, incubate for 1-4 hours, and then record the absorbance at 490nm with a 96-well plate reader. The amount of formazan product is directly proportional to the number of viable cells in the medium, as measured by measuring absorbance at 490 nm. the

N-phenyl-N'-terminal carboxylic acid substituted acyloxy-suberamide compounds (I a) and their pharmaceutically acceptable salts (I b and I c) are less active than vorinostat in in vitro screening experiments, while The activity in vivo experiment is equivalent to vorinostat, or slightly better than vorinostat. the

In yet another specific embodiment of the present invention, N-phenyl-N'-terminal carboxylic acid substituted acyloxy-suberamide compounds (I a) and pharmaceutically acceptable salts thereof (I b and I c) are effective for acute Acute myeloid leukemia (AML); chronic leukemias such as chronic lymphocytic leukemia (CLL) and chronic myelogenous leukemia (CML), hairy cell leukemia, cutaneous T-lymphocytoma (CTCL), non-pericutaneous T-cell lymphoma Lymphomas associated with human T-lymphotropic virus (HTLV) such as adult T-cell leukemia/lymphoma (ATLL), Hodgkin's disease, non-Hodgkin's lymphoma, large cell lymphoma, diffuse large B Burkitt's lymphoma; basic central nervous system (CNS) lymphoma; multiple myeloma; early solid tumors such as brain tumors, neuroblastoma, retinoblastoma, Wilm's tumor, soft tissue Sarcoma, oral cavity, larynx, esophagus, prostate, bladder, kidney, uterus, ovary, testicle, rectum, colon, lung, breast, pancreas, melanoma, and other skin cancers , gastric cancer, brain tumor, liver cancer and thyroid cancer have therapeutic effect. the

The present invention is further elaborated below by embodiment, and purpose is only for better understanding content of the present invention. Therefore, listed embodiment does not limit protection scope of the present invention:

Example 1 Synthesis of N-hydroxyl-N'-phenylsuberamide (vorinostat) prodrug (I a)

Preparation of N-hydroxy-N'-phenylsuberamide succinate (I a ₁ , HLY-0019):

Suspend 0.4g (1.5mmol) N-hydroxy-N'-phenylsuberamide in 4ml toluene, add 5ml pyridine, 0.29g DMAP (0.01eq). Under the condition of ice bath, 0.17 g (1.66 mmol) toluene solution (3 ml) of succinic anhydride was added dropwise for about 15 min. After the dropwise addition was completed, the mixture was heated to reflux and stirred overnight, and the reaction was traced by TLC to complete. The solvent was recovered under reduced pressure, the residue was poured into 10ml of water, extracted three times with ethyl acetate, 10ml each time, the ethyl acetate extract was washed with water until neutral, the sodium bicarbonate solution extract was neutralized with hydrochloric acid, and then extracted with ethyl acetate 3 times, 10ml each time, dried with anhydrous sodium sulfate, and the filtrate was evaporated to dryness under reduced pressure to obtain 0.37g light yellow solid, yield: 67%;

¹ H NMR (400MHz, CDCl ₃ ) ppm11.51 (1H, s, OH), 9.83 (1H, s, NH), 7.58 (2H, d, J=7.81 Hz, 2o-ArCH), 7.26 (2H, d, J=7.81Hz, 2 m-ArCH), 7.05 (1H, m, p-ArCH), 2.63-1.97 (8H, m, COCH ₂ CH ₂ CO, COCH ₂ , COCH ₂ ), 1.59-1.27 (8H _, m, _{CH2CH2CH2CH2 ) .}

ESI-MS(m/z): 365.2[M+H] ⁺

Preparation of N-hydroxy-N'-phenylsuberamide glutaric acid monoester (I a ₂ ):

Except for 0.19g (1.66mmol) of glutaric anhydride instead of 0.17g (1.66mmol) of succinic anhydride, the preparation of N-hydroxy-N'-phenylsuberamide succinic acid monoester was the same as above to obtain a light yellow solid 0.35, yield: 62%;

¹ H NMR (400MHz, CDCl ₃ ) ppm11.50 (1H, s, OH), 9.78 (1H, s, NH), 7.57 (2H, d, J=7.80Hz, 2 o-ArCH), 7.25 (2H, d, J = 7.81Hz, 2m-ArCH), 7.07 (1H, m, p-ArCH), 2.59-2.01 (8H, m, COCH ₂ , COCH ₂ , COCH ₂ , COCH ₂ ), 1.61-1.23 (10H, _{m , CH2CH2CH2CH2CH2 ) .}

ESI-MS (m/z): 379.2[M+H] ⁺

N-Hydroxy-N'-phenylsuberamide adipate monoester (I a ₃ , HLY-0119):

¹ H NMR (400MHz, CDCl ₃ ) ppm11.50 (1H, s, OH), 9.81 (1H, s, NH), 7.58 (2H, d, J=7.81Hz, 2 o-ArCH), 7.27 (2H, d, J=7.81Hz, 2 m-ArCH), 7.06 (1H, m, p-ArCH), 2.63-1.97 (8H, m, COCH ₂ , COCH ₂ , COCH ₂ , COCH ₂ ), 1.58-1.25 (12H _{, m , CH2CH2CH2CH2CH2CH2 ) .}

ESI-MS (m/z): 393.2[M+H] ⁺

N-Hydroxy-N'-phenylsuberamide suberate monoester (I a ₄ ):

¹ H NMR (400MHz, CDCl ₃ ) ppm11.50 (1H, s, OH), 9.81 (1H, s, NH), 7.58 (2H, d, J=7.81Hz, 2 o-ArCH), 7.27 (2H, d, J=7.81Hz, 2m-ArCH), 7.06 (1H, m, p-ArCH), 2.32-1.94 (8H, m, COCH ₂ , COCH ₂ , COCH ₂ , COCH ₂ ), 1.58-1.25 (16H, _{m , -CH2CH2CH2CH2- , -CH2CH2CH2CH2- ) . _}

ESI-MS(m/z): 421.2[M+H] ⁺

Example 2 Antitumor activity research at the enzyme level in a cell-free system

Based on the enzyme-fluorosubstrate interaction theory, using BIOMOL Fluor-de-Lys The HDAC&HDAC1 fluorometric activity assay kit screens the activity of the synthesized drugs, reacts the synthesized compounds with different concentrations for a period of time, and uses a multifunctional fluorescent microplate reader to measure the fluorescence intensity after the action, and compares it with the blank and negative, and compares the fluorescence intensity value Non-linear fitting, calculation of growth inhibition IC50 value, used to evaluate the inhibitory effect of different structural compounds on HDACs and HDAC1.

Results: HDAC enzyme test results are as follows:

N-Hydroxy-N'-phenylsuberamide (vorinostat) HDAC 1 IC50Ave＝45 ⁺ _- 17.6(N＝68)nM

I a ₁ : HDAC1 IC50Ave = 558 ⁺ _- 301.2 (N = 2) nM; 10 uM, 94% INH, 100 uM, 95% INH;

I a ₂ : HDAC1 IC50Ave = 586 ⁺ _- 306.7 (N = 2) nM; 10 uM, 45% INH, 100 uM, 90% INH;

I a ₃ : HDAC1 IC50Ave = 576 ⁺ _- 311.4 (N = 2) nM; 10 uM, 89% INH, 100 uM, 99% INH;

I a ₄ : HDAC1 IC50Ave = 581 ⁺ _- 309.8 (N = 2) nM, 10 uM, 59% INH, 100 uM, 87% INH.

Example 3 HDAC Inhibition in Cell Lines

MTS test

Murine erythroleukemia cells (SC-9) were incubated with vehicle or increasing concentrations of compounds for 48 hours, and cell proliferation was quantified by adding a small amount of MTS reagent directly to the wells, incubating for 1-4 hours, and then Absorbance at 490 nm was recorded using a 96-well plate reader. The amount of formazan product measured by absorbance at 490 nm is directly proportional to the number of viable cells in the medium. the

The SC-9 cell-based MTS test results (MTS assay) for a selected group of novel compounds are as follows:

Vorinostat: 515 ⁺ _- 171nM (N=59)

I a ₁ : 446 nM (N=1)

I a ₂ : 443 nM (N=1)

I a ₃ : 746 nM (N=1)

I a ₄ : 784 ⁺ _- 5.5 nM (N=2).

Claims (6)

1. The dibasic carboxylic acid monoester derivation of the prodrug N-hydroxyl-N'-phenylsuberamide (vorinostat) of the histone deacetylase inhibitor represented by the structure of a class such as formula I a-c Object--N-phenyl-N'-(terminal carboxylic acid substituted acyloxy) suberamide compound (I a) and its pharmaceutically acceptable salts (I b and I c) with anti-tumor effect:

Among them, Y represents the linking group; M represents the metal ion; B represents the base; and Y represents the following structure: (CH ₂ ) _n , where n is equal to 2, 3, 4, 5, 6); Or ethylenic bond (CHCH) _n , wherein, n=1, 2, 3; Or C3-C8 aliphatic carbocycle, aliphatic heterocycle; Or aromatic ring and aromatic heterocycle Ar; or Ar(CHCH)n ₁ , wherein n ₁ is 1, 2, 3; Or (CHCH)n ₁ Ar(CHCH)n ₁ , wherein n ₁ is 1, 2, 3. 2. The prodrug of claim 1, wherein, Ar is phenyl, naphthyl, 5-6 membered aromatic heterocyclic group, benzo 5-6 membered aromatic heterocyclic group, 6-membered aromatic heterocyclic ring and 5-6 membered aromatic group. Heterocyclic group, substituted phenyl, substituted naphthyl, substituted 5-6 membered aromatic heterocyclic group, substituted benzo 5-6 membered aromatic heterocyclic group, substituted 6-membered aromatic heterocyclic group and 5-6 membered Aromatic heterocyclic group; Wherein, the heteroatoms of the aromatic heterocyclic group are selected from one or more than two (including two) of N, O or S, and the number of heteroatoms is an integer of 1 to 3; The substituted phenyl, substituted naphthyl, substituted 5-6 membered aromatic heterocyclic group, substituted benzo 5-6 membered aromatic heterocyclic group, substituted 6-membered aromatic heterocyclic and 5-6 membered aromatic The substituent of the heterocyclic group is selected from one or two of halogen (F, Cl, Br or I), nitro (-NO ₂ ), hydroxyl (-OH), cyano (-CN) or alkoxy above (including two). 3. The prodrug according to claim 1, wherein the metal ion M represents: sodium ion, potassium ion, calcium ion, magnesium ion, zinc ion, iron ion, aluminum ion. 4. The prodrug of claim 1, wherein base B represents: triethanolamine, vitamin B6 free base, imidazole, pyridine, pyrimidine, amino acid ester. 5. The prodrug of claim 1, wherein the amino acid ester represented by base B is various natural amino acid esters, such as: glycine ester, alanine ester, phenylalanine ester, lysine ester, arginine Esters, proline esters, etc. 6. The prodrug of claim 1, wherein the ester group of the amino acid ester represented by base B is a 1-6 carbon alcohol, such as: methanol, ethanol, propanol; phenol and benzyl alcohol.