WO2020042996A1

WO2020042996A1 - Oxaliplatin coupled prodrug, and preparation method and use thereof

Info

Publication number: WO2020042996A1
Application number: PCT/CN2019/101933
Authority: WO
Inventors: 于海军; 李亚平; 牛自飞; 冯兵; 侯博
Original assignee: 中国科学院上海药物研究所
Priority date: 2018-08-29
Filing date: 2019-08-22
Publication date: 2020-03-05
Also published as: CN110872324B; CN110872324A

Abstract

Disclosed is an oxaliplatin coupled prodrug. The oxaliplatin coupled prodrug has structures as shown in formula 1 and formula 2, wherein R is –NHR1 or –CH2CH2COR2; R1 is selected from C2-C16 alkyl group; and R2 is a group having a small molecule inhibitor NLG919 containing disulfide ethanol active group. Further disclosed are a preparation method and use thereof. According to the present invention, purposes of improving the efficacy of oxaliplatin and combined medication are expected to be implemented by means of a coupled drug of oxaliplatin and small molecules constructed by chemical bonds. (1), (2)

Description

Oxaliplatin coupling prodrug, preparation method and application thereof

Technical field

The invention belongs to the technical field of medicine and chemical engineering, and particularly relates to an oxaliplatin coupling prodrug, and a preparation method and application thereof.

Background technique

Chemotherapy is one of the main methods of current cancer treatment. Among them, (divalent) platinum drugs have good anti-cancer effects and wide indications. At present, Cisplatin and Oxaliplatin are mainly used in clinical treatment. Malignant tumor. However, oxaliplatin is likely to cause severe gastrointestinal reactions, renal toxicity and bone marrow toxicity. At the same time, oxaliplatin is likely to lead to acquired resistance, which severely reduces the efficacy and limits the clinical use of oxaliplatin. The use of covalent coupling strategy to construct a coupling prodrug of oxaliplatin and active molecules is expected to reduce the dosage of oxaliplatin and reduce toxic and side effects. At the same time avoid the development of drug resistance and improve the efficacy.

According to the literature, oxaliplatin can induce immune cell death and activate the body's immune response. However, stimulation with chemotherapeutic drugs such as oxaliplatin can lead to excessive activation of indoleamine 2,3-dioxygenase 1 (IDO-1) in tumor cells. Indoleamine 2,3-dioxygenase 1 (IDO-1) degrades tryptophan (Trp) to generate kynurenine (Kyn). Tryptophan is a nutrient for cytotoxic T lymphocytes, and kynurenine can induce T cell apoptosis. Therefore, high expression of IDO-1 can inhibit differentiation and increase value, leading to an immunosuppressive microenvironment. The high expression of IDO-1 is related to the poor clinical prognosis of patients with multiple malignancies. IDO-1 has become one of the important targets for tumor immunotherapy. NLG919 inhibits tumor cell immune escape by inhibiting IDO-1 activity. In the present invention, covalently modified tetravalent oxaliplatin of NLG919 is synthesized, and the compound can be reduced to release oxaliplatin and NLG919 in the cell to realize the combined treatment of chemotherapy and immunotherapy, which is very innovative.

Summary of the Invention

Based on the above background, the object of the present invention is to provide an oxaliplatin coupling prodrug, which has the structure shown in Formulas 1 and 2:

among them,

R is -NHR ₁ , -CH ₂ CH ₂ COR ₂ ;

R _{1 is} selected from C2 to C16 alkyl;

R ₂ is a group containing a small molecule inhibitor NLG919 containing a dithioethanol active group, and its structure is as follows:

Preferably, the oxaliplatin coupling prodrug is selected from the following compounds:

The invention also provides a method for preparing the oxaliplatin coupling prodrug, which is selected from the following methods:

Method 1: When R is -NHR ₁ , the preparation method of the oxaliplatin coupling prodrug includes the following steps:

Step a: Preparation of Oxaliplatin Oxide

Oxaliplatin was suspended in water to obtain an oxaliplatin solution, and oxaliplatin was added to the oxaliplatin solution in a molar ratio of hydrogen peroxide and oxaliplatin contained in the hydrogen peroxide solution of 20: 1 to 100: 1. Oxyplatin oxide with a mass fraction of 30% is placed at any constant temperature between 0-40 ° C and protected from light for 6-48h, and then rotary evaporation removes water, ether precipitation, and vacuum drying to obtain oxaliplatin oxide;

Step b: Preparation of monocarboxylated oxaliplatin

Take the oxaliplatin oxide obtained in step a and dissolve it in dimethyl sulfoxide, and add succinic anhydride. The molar ratio of oxaliplatin oxide to succinic anhydride is 1: 1-1: 5, at 0-40 ° C. After reacting at any constant temperature between 1-24h, add ether to precipitate and dry in vacuo to obtain monocarboxylated oxaliplatin;

Step c: Preparation of R ₂ and monocarboxylated oxaliplatin

Take the product prepared in step b and dissolve it in dimethyl sulfoxide. Add DMAP (4-dimethylaminopyridine) and EDCI (carbodiimide) to activate the carboxyl group. The moles of DMAP and monocarboxylated oxaliplatin are added. The ratio is 1: 1-1: 10, the molar ratio of EDCI and monocarboxylated oxaliplatin is 1: 1-1: 10, and 1-4 times the molar amount of R _{2 is added} H. After reacting at room temperature for 1-24 hours, dimethyl sulfoxide (DMSO) is removed by precipitation with ether, and R ₂ is obtained by vacuum drying, and oxaliplatin is monocarboxylated; wherein, the definition of R ₂ is as described above;

Step d: Preparation of oxaliplatin coupling prodrug

The product obtained in step c is dissolved in DMF, 1-5 times equivalent of alkylating reagent is added, and the reaction is performed at a constant temperature between 0-40 ° C for 1-24h; rotary evaporation and concentration, ether precipitation, and vacuum drying, that is, The oxaliplatin coupling prodrug is obtained; wherein R ₁ and R ₂ are defined as described above; the alkylating agent is O = C = NR ₁ .

Method 2: When R is -CH ₂ CH ₂ COR ₂ , the preparation method of the oxaliplatin coupling prodrug includes the following steps:

Step a: Preparation of Oxaliplatin Oxide

Oxaliplatin was suspended in water to obtain an oxaliplatin solution, and oxaliplatin was added to the oxaliplatin solution in a molar ratio of hydrogen peroxide and oxaliplatin contained in the hydrogen peroxide solution of 20: 1 to 100: 1. Oxyplatin oxide with a mass fraction of 30% is placed at any constant temperature between 0-40 ° C and protected from light for 6-48h, and dried under vacuum to obtain oxaliplatin oxide;

Step b: Preparation of biscarboxylated oxaliplatin

Take the product obtained in step a and dissolve it in dimethyl sulfoxide, add 1-5 times molar amount of oxaliplatin oxide to succinic anhydride, and react at any constant temperature between 0-60 ° C for 1-24h. The resulting material was precipitated with ether and dried under vacuum to obtain dicarboxylated oxaliplatin;

Step c: Preparation of oxaliplatin coupling prodrug

Take the product obtained in step b and dissolve it in an organic solvent. Add DMAP (4-dimethylaminopyridine) and EDCI (carbodiimide) to activate the carboxyl group. The molar ratio of DMAP and biscarboxylated oxaliplatin is 1 : 1-1: 10. The molar ratio of EDCI and bis-carboxylated oxaliplatin is 1: 1-1: 10. Add 1-4 times molar amount of R ₂ H to bis-carboxylated oxaliplatin, at room temperature. After 1-24 hours of reaction, diethyl ether is added for precipitation, and vacuum drying is performed to obtain oxaliplatin coupling prodrug; wherein R ₂ is as defined above.

Preferably, the organic reagent in step c of method two is selected from N, N-dimethylformamide, N, N-dimethylacetamide or dimethylsulfoxide.

Another aspect of the present invention is to provide the use of the oxaliplatin coupling prodrug in the preparation of a cancer treatment medicament.

In the application, after the oxaliplatin-coupled prodrug enters the inside of tumor cells, after reduction of glutathione, the tetravalent oxaliplatin-coupled prodrug is reduced to divalent oxaliplatin and R2H The drug concentration in the tumor cells can be increased rapidly and kill the tumor cells, thereby effectively improving the effect of tumor chemotherapy.

The cancer is selected from lung cancer, gastric cancer, ovarian cancer, prostate cancer, pancreatic cancer, breast cancer, liver cancer, head and neck cancer, and the like.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 is a mass spectrum of a monocarboxylated oxaliplatin prepared in Example 2 of the present invention. The molecular weight of the synthesized product shown in the mass spectrum is 530, which is consistent with the theoretical molecular weight, which proves that the monocarboxylated oxaliplatin was successfully prepared.

2 is (A) a nuclear magnetic resonance hydrogen spectrum and (B) a mass spectrum of a disulfide of NLG919 prepared in Example 3 of the present invention. As shown in the nuclear magnetic resonance spectrum of (A), the peaks b and c are characteristic peaks of methylene on both sides of the disulfide bond of bis (2-hydroxyethyl) disulfide, and the peak a is the hex ring in NLG919. The characteristic peaks proved that the disulfide of NLG919 was successfully prepared. The molecular weight of the synthesized product shown in (B) in the figure is 462, which is consistent with the theoretical molecular weight, which proves that the disulfide of NLG919 was successfully prepared.

3 is a (A) nuclear magnetic resonance hydrogen spectrum and a (B) mass spectrum of NLG919 and monocarboxylated oxaliplatin prepared in Example 4 of the present invention. As shown in the nuclear magnetic resonance spectrum of (A), the peak a is the characteristic peak of the hexane of oxaliplatin and NLG919, and the peak b is the bis (2-hydroxyethyl) disulfide adjacent to the disulfide bond methylene. The characteristic peaks proved that NLG919 was successfully prepared and oxaliplatin was monocarboxylated. (B) The molecular weight of the synthesized product shown in the mass spectrum is 976, which further proves that NLG919 was successfully prepared and oxaliplatin was monocarboxylated.

FIG. 4 is (A) a nuclear magnetic resonance spectrum and a (B) mass spectrum of an NLG919 and alkylated oxaliplatin coupling prodrug prepared in Example 5 of the present invention. (A) In the nuclear magnetic resonance spectrum shown in the figure, the i peak is the terminal methyl peak of hexadecyl isocyanate, which proves that NLG919 and alkylated oxaliplatin coupling prodrug were successfully prepared. (B) The molecular weight of the synthetic product shown in the mass spectrum in the figure is 1244, which is consistent with the predicted results, which further proves that NLG919 and alkylated oxaliplatin coupling prodrugs were successfully prepared.

5 is a (A) nuclear magnetic resonance hydrogen spectrum and a (B) mass spectrum of the dicarboxylated oxaliplatin prepared in Example 6 of the present invention. As shown in the nuclear magnetic resonance spectrum of (A), the f3 peak is a methylene characteristic peak of succinic anhydride, which proves that the monocarboxylated oxaliplatin was successfully prepared; (B) the molecular weight of the synthesized product shown in the mass spectrum It is 630, which is consistent with the theoretical molecular weight, which proves that dicarboxylated oxaliplatin was successfully prepared.

6 is a (A) nuclear magnetic resonance spectrum and a (B) mass spectrum of a NLG919 and dicarboxylated oxaliplatin coupling prodrug prepared in Example 7 of the present invention. As shown in the nuclear magnetic resonance spectrum of (A), the peak a is the characteristic peak of the hexane of oxaliplatin and NLG919, and the peak b is the bis (2-hydroxyethyl) disulfide adjacent to the disulfide bond methylene. The characteristic peaks of NLG919 and dicarboxylated oxaliplatin coupling prodrug were proved to be successfully prepared; (B) The molecular weight of the synthetic product shown in the mass spectrum is 1521, which proved that NLG919 and dicarboxylated oxaliplatin couple were successfully prepared. Prodrugs.

FIG. 7 is the MTT toxicity test data of NLG919 and monocarboxylated oxaliplatin micelles prepared in Example 4 of the present invention on CT26 mouse colon cancer cells. The results showed that when the drug concentration was 100 μM, the cell survival rate of the oxaliplatin original drug group was 29%, the cell survival rate of the NLG919 original drug group was 40%, and the cells of the NLG919 and monocarboxylated oxaliplatin micelle group were The survival rate is 30%, indicating that amphiphilic oxaliplatin precursor nanoparticles can significantly inhibit tumor cell growth, and the cytotoxicity is better than that of oxaliplatin original drug. Among them, OXA is oxaliplatin; NSP is NLG919 and monocarboxylated oxaliplatin micelles.

FIG. 8 is experimental data of MTT toxicity of NLG919 and dicarboxylated oxaliplatin coupled prodrug micelles prepared in Example 7 of the present invention on CT26 mouse colon cancer cells. The results showed that when the drug concentration was 100 μM, the cell survival rate of the oxaliplatin group was 24%, the cell survival rate of the NLG919 group was 40%, and NLG919 was dicarboxylated with oxaliplatin coupled prodrug gel. The cell survival rate of the bundle group was 24%, suggesting that amphiphilic oxaliplatin precursor nanoparticles can significantly inhibit tumor cell growth. Among them, OXA is oxaliplatin; NSSP is NLG919 and biscarboxylated oxaliplatin coupled prodrug.

detailed description

The invention is illustrated by the following specific examples, but the invention is not limited by these specific examples.

The hexadecyl isocyanate used in the examples was purchased from Sigma-Aldrich (China) Company. Oxaliplatin was purchased from Shandong Platinum Source Company. Succinic anhydride, 1-ethyl- (3-dimethylaminopropyl) carbodiimide hydrochloride, and 1-hydroxybenzotriazole were purchased from Thiex (Shanghai) Chemical Industry Development Co., Ltd. The solvents N, N-dimethylformamide and dimethyl sulfoxide were purchased from Shanghai Bellingway Technology Co., Ltd. NLG919 comes from Shanghai Ruozhi Chemical Technology Co., Ltd.

In this application, unless otherwise specified, the remaining reagents and solvents used were purchased from Sinopharm (Shanghai) Chemical Reagent Co., Ltd.

In this application, unless otherwise specified, the equipment and test methods used are conventional equipment and methods in the art.

Example 1. Preparation of Oxaliplatin Oxide

Weigh 500mg of oxaliplatin, suspend it in 30ml of water, add 8ml of 30% hydrogen peroxide, place it in a 50ml round bottom flask, stir the reaction at 40 ° C in the dark for 10 hours, remove the solvent by rotary evaporation, and dry in vacuo Lipin.

Example 2. Preparation of monocarboxylated oxaliplatin

413 mg of oxaliplatin oxide prepared in Example 1 was dissolved in 5 ml of anhydrous dimethyl sulfoxide, 100 mg of succinic anhydride was added, and the mixture was reacted at room temperature for 12 hours. The ether was precipitated and dried under vacuum to obtain monocarboxylated oxoxanes. Lipin. The obtained material was characterized by nuclear magnetic resonance proton spectroscopy and mass spectrometry, and the results are shown in FIG. 1.

Example 3. Preparation of Disulfide of NLG919

Weigh 300 mg of NLG919 and 450 mg of DMAP in 15 ml of DCM in a 200 ml round bottom flask. 140 mg of triphosgene was weighed and dissolved in 5 ml of DCM, and slowly added to the round bottom flask with stirring. After 30 minutes of reaction, 500 ml of bis (2-hydroxyethyl) disulfide was slowly added dropwise to the reaction system. The reaction was carried out at room temperature for 20 hours. The product was spin-dried and dried under vacuum to obtain the disulfide of NLG919. The obtained material was characterized by nuclear magnetic resonance proton spectroscopy and mass spectrometry, and the results are shown in FIG. 2.

Example 4. Preparation of NLG919 and monocarboxylated oxaliplatin and its micelles

100 mg of monocarboxylated oxaliplatin prepared in Example 2 was dissolved in 3 ml of anhydrous DMSO, and 150 mg of the disulfide of NLG919 prepared in Example 3 was added, and 114 mg of EDCI (carbodiimide) was added. And 75 mg of DMAP (4-dimethylaminopyridine). The reaction was stirred at 25 ° C overnight, concentrated by rotary evaporation, DMSO was removed by diethyl ether precipitation, the obtained precipitate was washed with dichloromethane to remove the activator, and dried under vacuum to obtain NLG919 and oxaliplatin monocarboxylated. Weigh out 10 mg of HSA (human serum albumin) and dissolve it in 10 ml of PBS to prepare an HSA stock solution with a concentration of 1 mg / ml. Weigh 4 mg of NLG919 and monocarboxylate oxaliplatin, dissolve it in 100 μl of DMSO, and prepare 40 μg / μl of NLG919 and monocarboxylate oxaliplatin stock solution. 25 μl of NLG919 and monocarboxylated oxaliplatin mother liquor was added dropwise to 1 ml of HSA mother liquor while sonicating to form a uniform and stable NLG919 and monocarboxylated oxaliplatin micelle. The prepared material was characterized by nuclear magnetic resonance hydrogen spectroscopy and mass spectrometry, and the results are shown in FIG. 3.

Example 5. Alkylation of NLG919 and Monocarboxylated Oxaliplatin

Take NLG919 prepared in Example 4 and monocarboxylate 100 mg of oxaliplatin, dissolve it in 5 ml of N, N-dimethylformamide, add 300 ul of hexadecyl isocyanate, and stir to activate at 25 ° C for 2 h. The reaction was carried out overnight, concentrated by rotary evaporation, precipitated with ether, and dried under vacuum to obtain NLG919 and alkylated oxaliplatin coupling prodrug (that is, the oxaliplatin coupling prodrug according to the present invention). The obtained material was characterized by nuclear magnetic resonance hydrogen spectrum and mass spectrum, and the results are shown in FIG. 4.

Example 6. Preparation of biscarboxylated oxaliplatin

413 mg of oxaliplatin oxide prepared in Example 1 was dissolved in 5 ml of anhydrous dimethyl sulfoxide, 1 g of succinic anhydride was added, and the mixture was reacted at 40 ° C for 24 hours. The ether was precipitated. The obtained material was dissolved in methanol and washed with ether. Dicarboxylated oxaliplatin was obtained by vacuum drying. The obtained material was characterized by nuclear magnetic resonance proton spectroscopy and mass spectrometry, and the results are shown in FIG. 5.

Example 7. Preparation of NLG919 and biscarboxylated oxaliplatin and its micelles

Take 300 mg of the dicarboxylated oxaliplatin prepared in Example 6 and dissolve it in 5 ml of anhydrous dimethyl sulfoxide, then add 95 mg of the disulfide of NLG919 prepared in Example 3, and add 114 mg of EDCI Imine) and 75 mg of DMAP (4-dimethylaminopyridine). The reaction was stirred at 25 ° C overnight, concentrated by rotary evaporation, and the obtained material was washed with ether and dried under vacuum to obtain NLG919 and dicarboxylated oxaliplatin coupling prodrug (that is, the oxaliplatin coupling prodrug according to the present invention). ). Weigh out 10 mg of HSA and dissolve it in 10 ml of PBS to prepare a mother liquor of HSA at a concentration of 1 mg / ml. Weigh 4 mg of NLG919 and dicarboxylated oxaliplatin-coupled prodrug and dissolve it in 100 μl of DMSO to prepare 40 μg / μl of NLG919 and dicarboxylated oxaliplatin-coupled prodrug (NSSP) stock solution. 25 μl of NSSP mother liquor was added dropwise to 1 ml of HSA mother liquor while sonicating to form a uniform and stable NLG919 and dicarboxylated oxaliplatin coupled prodrug micelles. The prepared substance was characterized by nuclear magnetic resonance proton spectroscopy and mass spectrometry, and the results are shown in FIG. 6.

Example 8.NLG919 and Monocarboxylated Oxaliplatin (NSP) Toxicity Test

The micelles prepared in Example 4 were prepared at an equimolar concentration of 100 μmol / ml, and then nine gradient concentrations were prepared in sequence using a two-fold dilution method, namely 50, 25, 12.5, 6.25, 3.125, 1.56, and 0.78 and 0.39 μmol. / ml. 4T1 breast cancer cells were seeded in a 96-well cell culture plate (5000 cells / well), and 100 μl of 1640 medium (containing 10% serum) was added to each well. After 24 hours of incubation, the fresh complete culture medium was replaced, and drugs with different concentration gradients were respectively added, and PBS was used as a blank control group. Continue to culture for 48 hours, and the cell survival rate was measured by MTT method. The results are shown in Fig. 7.

Example 9.NLG919 and Dicarboxylated Oxaliplatin (NSSP) Toxicity Test

The micelles prepared in Example 7 were prepared at an equimolar concentration of 100 μmol / ml, and then nine gradient concentrations were sequentially prepared by a double dilution method, namely 50, 25, 12.5, 6.25, 3.125, 1.56, and 0.78, 0.39 μmol. / ml. 4T1 breast cancer cells were seeded in a 96-well cell culture plate (5000 cells / well), and 100 μl of 1640 medium (containing 10% serum) was added to each well. After 24 hours of incubation, the fresh complete culture medium was replaced, and drugs with different concentration gradients were respectively added, and PBS was used as a blank control group. The culture was continued for 48 h, and the cell survival rate was measured by the MTT method. The results are shown in FIG. 8.

Claims

An oxaliplatin coupling prodrug is characterized in that it has the structure shown in Formulas 1 and 2:

among them,

R is -NHR 1 or -CH 2 CH 2 COR 2 ;

R 1 is selected from C2 to C16 alkyl;

R 2 is a group containing a small molecule inhibitor NLG919 containing a dithioethanol active group, and its structure is as follows:
The oxaliplatin-coupled prodrug according to claim 1, characterized in that it is selected from the following compounds:
The method for preparing oxaliplatin coupling prodrug according to claim 1, characterized in that it is selected from the following methods:

Method 1: When R is -NHR 1 , the preparation method of the oxaliplatin coupling prodrug includes the following steps:

Step a: Preparation of Oxaliplatin Oxide

Take oxaliplatin and suspend it in water to obtain oxaliplatin solution, and add mass to the oxaliplatin solution in a molar ratio of hydrogen peroxide contained in hydrogen peroxide and oxaliplatin of 20: 1 to 100: 1. Fraction of 30% hydrogen peroxide, placed at any constant temperature between 0-40 ° C, protected from light for 6-48h, then rotary evaporation to remove water, ether precipitation, and vacuum drying to obtain oxaliplatin oxide;

Step b: Preparation of monocarboxylated oxaliplatin

Take the oxaliplatin oxide obtained in step a and dissolve it in dimethyl sulfoxide, and add succinic anhydride. The molar ratio of oxaliplatin oxide to succinic anhydride is 1: 1-1: 5, at 0-40 ° C. After reacting at any constant temperature between 1-24h, add ether to precipitate and dry in vacuo to obtain monocarboxylated oxaliplatin;

Step c: Preparation of R 2 and monocarboxylated oxaliplatin

Take the product obtained in step b and dissolve it in dimethyl sulfoxide, add 4-dimethylaminopyridine and carbodiimide to activate the carboxyl group, and the molar ratio of 4-dimethylaminopyridine to oxaliplatin monocarboxylated oxide The ratio is 1: 1-1: 10, and the molar ratio of carbodiimide and monocarboxylated oxaliplatin is 1: 1-1: 10. R 2 H. After reacting at room temperature for 1-24 h, dimethyl sulfoxide is removed by ether precipitation, and R 2 is obtained by vacuum drying, and oxaliplatin is monocarboxylated; wherein R 2 is defined in claim 1;

Step d: Preparation of oxaliplatin coupling prodrug

The product obtained in step c is dissolved in DMF, 1-5 times equivalent of alkylating reagent is added, and the reaction is performed at a constant temperature between 0-40 ° C for 1-24h; rotary evaporation and concentration, ether precipitation, and vacuum drying, that is, Get oxaliplatin coupling prodrug; wherein R 1 and R 2 are defined as described in claim 1; the alkylating agent is O = C = NR 1 ;

Method 2: When R is -CH 2 CH 2 COR 2 , the preparation method of the oxaliplatin coupling prodrug includes the following steps:

Step a: Preparation of Oxaliplatin Oxide

Take oxaliplatin and suspend it in water to obtain oxaliplatin solution, and add mass to the oxaliplatin solution in a molar ratio of hydrogen peroxide contained in hydrogen peroxide and oxaliplatin of 20: 1 to 100: 1. Fraction of 30% hydrogen peroxide, placed at any constant temperature between 0-40 ° C, protected from light for 6-48h, and dried under vacuum to obtain oxaliplatin oxide;

Step b: Preparation of biscarboxylated oxaliplatin

Take the product obtained in step a and dissolve it in dimethyl sulfoxide, add 1-5 times molar amount of oxaliplatin oxide to succinic anhydride, and react at any constant temperature between 0-60 ° C for 1-24h. The resulting material was precipitated with ether and dried under vacuum to obtain dicarboxylated oxaliplatin;

Step c: Preparation of oxaliplatin coupling prodrug

The product obtained in step b was dissolved in an organic solvent, and 4-dimethylaminopyridine and carbodiimide were added to activate the carboxyl group. The molar ratio of 4-dimethylaminopyridine and biscarboxylated oxaliplatin was 1: 1-1: 10, the molar ratio of carbodiimide and biscarboxylated oxaliplatin is 1: 1-1: 10, adding 1-4 times molar amount of R 2 H After 1-24 hours of reaction at normal temperature, diethyl ether is added to precipitate and vacuum dried to obtain oxaliplatin coupling prodrug; wherein R 2 is defined as described in claim 1.
The preparation method according to claim 3, wherein the organic reagent in step c of method two is selected from N, N-dimethylformamide, N, N-dimethylacetamide, or dimethylsulfoxide .
Use of the oxaliplatin coupling prodrug according to claim 1 or 2 in the manufacture of a medicament for treating cancer.
The use according to claim 5, wherein the cancer is selected from the group consisting of lung cancer, gastric cancer, ovarian cancer, prostate cancer, pancreatic cancer, breast cancer, liver cancer, and head and neck cancer.