CN111718376B - Platinum compound with structure of formula (J), preparation and application thereof - Google Patents

Platinum compound with structure of formula (J), preparation and application thereof Download PDF

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CN111718376B
CN111718376B CN201910208959.7A CN201910208959A CN111718376B CN 111718376 B CN111718376 B CN 111718376B CN 201910208959 A CN201910208959 A CN 201910208959A CN 111718376 B CN111718376 B CN 111718376B
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resin
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CN111718376A (en
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窦啟玲
汪立冬
常新亮
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Hainan Changan International Pharmaceutical Co ltd
Guizhou Yibai Pharmaceutical Co Ltd
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Guizhou Yibai Pharmaceutical Co Ltd
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    • C07—ORGANIC CHEMISTRY
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    • C07F15/00—Compounds containing elements of Groups 8, 9, 10 or 18 of the Periodic Table
    • C07F15/0006—Compounds containing elements of Groups 8, 9, 10 or 18 of the Periodic Table compounds of the platinum group
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    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
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    • A61P35/02—Antineoplastic agents specific for leukemia
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Abstract

The invention relates to a platinum compound with a structure shown in a formula (J), and a preparation method and application thereof. The invention provides a platinum compound, the structure of which is shown as a formula (J):

Description

Platinum compound with structure of formula (J), preparation and application thereof
Technical Field
The invention relates to the field of medicines, in particular to a platinum compound with a structure shown in a formula (J), a preparation method thereof and application thereof in medicines.
Background
Lobaplatin (D19466), also known as Lobaplatin, is a third generation of platinum-based antitumor drug following cisplatin, carboplatin, and has the chemical name: cis- [ trans-1, 2-cyclobutanebis (methylamine) -N, N ]']- [ (2S) -lactic acid-O1, O2]Platinum (II) of formula C 9 H 18 N 2 O 3 Pt has a molecular weight of 397.34, and has a chemical structural formula shown in the following formula (a):
lobaplatin has alkylation effect, belongs to alkylating agents (in a broad sense), has good anti-tumor effect, such as good inhibition effect on in-vitro AH 135-tumor, B16-melanoma, colon cancer 115, in-vivo mouse P338 leukemia and the like. The lobaplatin has the characteristics of strong anticancer activity, low toxicity, no accumulated toxicity and renal toxicity, and small toxicity to bone marrow, and the lobaplatin for injection which is currently marketed is mainly used for treating breast cancer, small cell lung cancer and chronic granulocytic leukemia.
Disclosure of Invention
In order to ensure the safety, effectiveness and controllable quality of the medicine, the research on related substances and detection methods of the related substances is very important. For the medicine, due to the existence of three chiral carbons and related substances generated in the preparation process, confirming the structures of the related substances and finding a proper detection method for controlling the product quality of the medicine are technical problems which are urgently needed to be solved in the field.
The invention aims to provide a platinum compound with a structure shown in a formula (J), a preparation method thereof and application of the compound in resisting tumors.
Those skilled in the art will appreciate that any substance that affects the purity of a drug will be collectively referred to as a relevant substance. Research on substances is an important item in drug development, which involves selecting an appropriate analytical method to accurately distinguish and determine the content of the substances of interest and to integrate the results of pharmaceutical, toxicological and clinical studies to determine the reasonable limits of the substances of interest. This study extends throughout the process of drug development.
Specifically, the invention is realized by the following technical scheme.
The invention provides a platinum compound, which has the structure shown in the following formula (J):
the invention provides a preparation method of a platinum compound, wherein the compound shown in the formula (J) is prepared by a compound 4 shown in the following structural formula
Preferably, in the reaction for preparing the product by the compound 4, the resulting solution of the compound 3 is adjusted to be slightly alkaline with an acidic regulator, and then lyophilized to obtain the final product; preferably, the acidity regulator is selected from one of p-toluenesulfonic acid or methanesulfonic acid, preferably p-toluenesulfonic acid; preferably the concentration of the aqueous solution of p-toluene sulphonic acid is 5-15wt%, preferably 10wt%; the alkalescence is ph=7-8; preferably, after adjustment to the slightly alkaline state, the reaction is carried out at a temperature of 20-30℃for 15-25 hours; preferably, the reaction is carried out at 25℃for 20 hours.
Preferably, for the preparation method, the compound 4 is prepared by a compound 3 of the following structural formula
Preferably, the solution of the compound 3 and the resin are mixed and stirred, and then filtered to obtain a solution of the compound 4; preferably, the temperature of mixing and stirring the solution of the compound 3 and the resin is 25-35 ℃; preferably, the stirring time is 0.5-2 hours; preferably, the stirring time is 1 hour, and more preferably, the stirring temperature is 30 ℃; more preferably, the resin is a resin that has been treated; preferably, the resin which has been treated is a resin treated with an aqueous sodium hydroxide solution, preferably at a concentration of 1 to 2mol/L, preferably 1.5mol/L.
Preferably, in the above preparation method, the compound 3 is prepared by a compound 2 of the following structural formula
Preferably, adding the compound 2 into water and ketone solvent to obtain a material A, adding silver nitrate solution into the material A for reaction, and filtering to obtain a solution of the compound 3; preferably, the molar ratio of compound 2 to silver nitrate is 1 (1-2), preferably 1:1.7; preferably, the reaction temperature is 25-35 ℃; more preferably, the reaction temperature is 30 ℃; preferably, the light-shielding reaction time is 15-20 hours; more preferably, the light-shielding reaction time is 18 hours; preferably, the ketone solvent is selected from one of acetone, methyl butanone, methyl ethyl ketone or methyl isobutyl ketone, and more preferably acetone.
Preferably, for the preparation method, the compound 2 is prepared by using a compound 1 with the following structural formula:
preferably, in the reaction for producing compound 2 from compound 1, chloroplatinite or chloroplatinite and alkali metal iodide are reacted with hydroxide to produce compound 2; preferably, the molar ratio of compound 1 to chloroplatinic acid salt is 1:0.5-2, preferably 1:0.85;
preferably, the chloroplatinic acid salt is selected from potassium or sodium chloroplatinate, preferably potassium chloroplatinate;
preferably, the alkali metal iodide is selected from potassium iodide or sodium iodide, preferably potassium iodide;
preferably, the hydroxide is selected from potassium hydroxide or sodium hydroxide, preferably potassium hydroxide.
For the preparation method, the steps of the preparation method are as follows:
wherein, in the reaction of preparing the compound 2 from the compound 1, chloroplatinite or chloroplatinite and alkali metal iodide are reacted with hydroxide to prepare the compound 2; preferably, the chloroplatinic acid salt is selected from potassium or sodium chloroplatinates, preferably potassium chloroplatinate; preferably, the alkali metal iodide is selected from potassium iodide or sodium iodide, preferably potassium iodide; preferably, the hydroxide is selected from potassium hydroxide or sodium hydroxide, preferably potassium hydroxide;
and/or, in the reaction for preparing the compound 3 by the compound 2, adding the compound 2 into water and a ketone solvent to obtain a material A, adding a silver nitrate solution into the material A for reaction, and filtering to obtain a solution of the compound 3;
and/or, in the reaction for preparing the compound 4 by the compound 3, mixing and stirring the solution of the compound 3 and the resin, and then filtering to obtain a compound 4 solution;
and/or, in the reaction of preparing the product by the compound 4, the obtained solution of the compound 4 is regulated to be slightly alkaline by an acid regulator, and then the final product is obtained by freeze-drying.
Preferably, in the preparation method, in the reaction step of preparing the compound 2 from the compound 1, mixing an aqueous solution of the compound 1 and potassium hydroxide to obtain a solution F, mixing an aqueous solution of potassium chloroplatinite and potassium iodide to obtain a solution E, and mixing the solution F and the solution E to react to obtain the compound 2; preferably, the reaction temperature is 25-35 ℃, preferably 30 ℃; preferably, the reaction time is 1 to 3 hours, preferably 2 hours; preferably, the molar ratio of compound 1 to chloroplatinic acid salt is 1:0.5-2, preferably 1:0.85;
preferably, in the reaction step of compound 2 to prepare compound 3, the molar ratio of compound 2 to silver nitrate is 1 (1-2), preferably 1:1.7; preferably, the reaction temperature is 25-35 ℃; more preferably, the reaction temperature is 30 ℃; preferably, the light-shielding reaction time is 15-20 hours; more preferably, the light-shielding reaction time is 18 hours; preferably, the ketone solvent is selected from one of acetone, methyl butanone, methyl ethyl ketone or methyl isobutyl ketone, and more preferably acetone;
preferably, in the reaction for preparing the compound 4 from the compound 3, the temperature at which the compound 3 solution and the resin are mixed and stirred is 25-35 ℃; preferably, the stirring time is 0.5-2 hours, preferably the stirring time is 1 hour, more preferably the stirring temperature is 30 ℃; preferably, the resin is a resin that has been treated; preferably, the resin that has been treated is a resin treated with an aqueous sodium hydroxide solution, preferably at a concentration of 1 to 2mol/L, more preferably 1.5mol/L;
preferably, in the reaction for preparing the product by the compound 4, the acidity regulator is selected from one of p-toluenesulfonic acid or methanesulfonic acid, preferably p-toluenesulfonic acid; preferably, the concentration of the aqueous solution of p-toluenesulfonic acid is 5-15wt%, preferably 10wt%; the alkalescence is ph=7-8; preferably, after adjustment to the slightly alkaline state, the reaction is carried out at a temperature of 20-30℃for 15-25 hours; preferably, the reaction is carried out at 25℃for 20 hours.
The invention provides a method for detecting platinum compounds, which is an HPLC-MS method or an HPLC method; preferably, the HPLC detection conditions of the HPLC-MS method are as follows: octadecylsilane chemically bonded silica is used as a filler, 18-22mmol/L ammonium formate is used as a mobile phase A, and methanol: acetonitrile volume ratio=1, (0.8-1.2) is mobile phase B, gradient elution is carried out; preferably, mobile phase A is a 20mmol/L ammonium formate solution and mobile phase B is methanol: volume ratio of acetonitrile = 1:1; more preferably, the gradient elution is performed in the following order:
0 to 3 minutes: 97% by volume of mobile phase A: 3% by volume of mobile phase B;
3-10 minutes: mobile phase a decreased from 97 to 92% by volume and mobile phase B increased from 3 to 8% by volume;
10-18 minutes: mobile phase a decreased from 92 to 87% by volume and mobile phase B increased from 8 to 13% by volume;
18-25 minutes: mobile phase a decreased from 87 to 10% by volume and mobile phase B increased from 13 to 90% by volume;
25-26 minutes: mobile phase a increased from 10 to 97% by volume and mobile phase B decreased from 90 to 3% by volume;
26-34 minutes: 97% by volume of mobile phase A: 3% by volume of mobile phase B;
wherein, each time range of the gradient elution can be increased by 1-2 minutes or the gradient elution time range from 3-10 minutes can be reduced by 1-2 minutes;
for example, the time range for gradient elution may be 0 to 4 minutes (or 0 to 5 minutes), 4 to 11 minutes (or 5 to 12 minutes), 11 to 19 minutes (or 12 to 20 minutes), 19 to 26 minutes (or 20 to 27 minutes), 26 to 27 minutes (or 27 to 28 minutes), 27 to 35 minutes (or 28 to 36 minutes); it may be 0 to 3 minutes, 3 to 9 minutes (or 3 to 8 minutes), 9 to 17 minutes (or 8 to 16 minutes), 17 to 24 minutes (or 16 to 23 minutes), 24 to 25 minutes (or 23 to 24 minutes), 25 to 33 minutes (or 24 to 32 minutes).
Preferably, the MS condition in the HPLC-MS is that an electrospray ion source is adopted, and the m/z of the compound detected by a positive ion detection method is 326; further preferably, the flow rate is 0.8-1.2ml per minute, preferably 1.0ml; the column temperature is 39-41℃and preferably 40 ℃.
The invention provides a pharmaceutical composition containing the platinum compound, which is a pharmaceutical preparation; preferably, the pharmaceutical composition is a pharmaceutical preparation for injection.
Preferably, for the pharmaceutical composition described above, wherein the pharmaceutical preparation includes an auxiliary material, preferably, the auxiliary material is selected from one or more of a filler, a disintegrant, a lubricant, a suspending agent, an adhesive, a sweetener, a flavoring agent, a preservative, an antioxidant, and a matrix; more preferably, the auxiliary materials are fillers and/or antioxidants.
The invention provides application of the platinum compound or the pharmaceutical composition in preparation of antitumor drugs.
Preferably, for the above-mentioned use, wherein the tumor is a lung cancer, ovarian cancer, leukemia and/or renal cancer cell; further preferred, the tumor is a leukemia cell.
Preferably, for the above application, the platinum compound or the pharmaceutical composition is applied to preparation of anti-THP-1 tumor drugs.
To enable formulation in the compositions of the invention, pharmaceutically acceptable excipients may be added in the preparation of these formulations, for example: fillers, disintegrants, lubricants, suspending agents, binders, sweeteners, flavoring agents, preservatives, antioxidants, matrices, and the like. The filler comprises: starch, pregelatinized starch, lactose, mannitol, chitin, microcrystalline cellulose, sucrose, and the like; the disintegrating agent comprises: starch, pregelatinized starch, microcrystalline cellulose, sodium carboxymethyl starch, crosslinked polyvinylpyrrolidone, low-substituted hydroxypropyl cellulose, crosslinked sodium carboxymethyl cellulose, and the like; the lubricant comprises: magnesium stearate, sodium lauryl sulfate, talc, silica, and the like; the suspending agent comprises: polyvinylpyrrolidone, microcrystalline cellulose, sucrose, agar, hydroxypropyl methylcellulose, and the like; the adhesive comprises: starch slurry, polyvinylpyrrolidone, hydroxypropyl methylcellulose, and the like; the sweetener comprises: saccharin sodium, aspartame, sucrose, sodium cyclamate, glycyrrhetinic acid, etc.; the flavoring agent comprises: sweetener and various flavors; the preservative comprises: nipagin, benzoic acid, sodium benzoate, sorbic acid and salts thereof, benzalkonium bromide, chlorhexidine acetate, eucalyptus oil and the like; the antioxidant comprises: sodium sulfite, sodium metabisulfite, dibutyl phenol, sodium bisulfite, sodium thiosulfate, tert-butyl p-hydroxy anisole, thiourea, vitamin c, propyl gallate, alpha-tocopherol, ascorbyl palmitate; the matrix comprises: PEG6000, PEG4000, insect wax, and the like. It is therefore within the scope of the present invention to add any other substance to the compounds of the present invention that will help to form a stable pharmaceutical effect.
The beneficial effects of the invention are as follows:
the platinum compound prepared by the invention has better inhibitory activity on lung cancer, ovarian cancer, leukemia and renal cancer cells and has anti-tumor effect.
Drawings
FIG. 1-1A is an HPLC chromatogram (215 nm) of the compound prepared in example 1-1 in an HPLC-MS structure confirmation assay;
FIG. 1-1B is an HPLC chromatogram (210 nm) of the compound prepared in example 1-1 in an HPLC-MS structure confirmation assay;
FIGS. 1-2A are MS spectra of the compound prepared in example 1-1 at a time of 0.13min in HPLC-MS structure confirmation detection;
FIGS. 1-2B are MS spectra of the compound prepared in example 1-1 at a time of 0.249min in HPLC-MS structure confirmation detection;
FIG. 2 is a diagram of the compound prepared in example 1-1 1 H-NMR spectrum;
FIG. 3 is a diagram of the compound prepared in example 1-1 13 C-NMR spectrum;
FIG. 4 is a QNMR spectrum of the compound obtained in example 1-1;
FIG. 5 is a UV spectrum of the compound produced in example 1-1, in which the wavelength of peak 1 is 256.5nm, the absorbance is 0.7763, the wavelength of peak 2 is 226.5nm, the absorbance is 0.3026, the wavelength of peak 3 is 218.5nm, the absorbance is 0.2872, the wavelength of peak 4 is 382.0nm, the absorbance is 0.0038, the wavelength of peak 5 is 229.0nm, the absorbance is 0.2932, and the wavelength of peak 6 is 220.5nm, the absorbance is 0.2746;
FIG. 6 is an IR spectrum of a compound prepared in example 1-1;
FIG. 7 is a DSC chart of the compound produced in example 1-1;
FIG. 8 is a typical spectrum of the compound prepared in example 1-1 of example 2;
FIG. 9-1 is a graph showing the inhibitory activity of the compound prepared in example 1-1 of example 3 on NCI-H460, which is a lung cancer cell;
FIG. 9-2 is a graph showing the inhibitory activity of the positive control drug of example 3 on NCI-H460, a lung cancer cell;
FIG. 10-1 is a graph showing the inhibitory activity of the compound prepared in example 1-1 of example 3 on SK-OV-3, which is an ovarian cancer cell;
FIG. 10-2 is a graph showing the inhibitory activity of the positive control drug of example 3 on SK-OV-3 cells of ovarian cancer;
FIG. 11-1 is a graph showing the inhibitory activity of the compound prepared in example 1-1 of example 3 on leukemia cell Jurkat Clone E6-1;
FIG. 11-2 is a graph showing the inhibitory activity of the positive control drug against leukemia cell Jurkat Clone E6-1 in example 3;
FIG. 12-1 is a graph showing the inhibitory activity of the compound obtained in example 1-1 of example 3 on THP-1 of leukemia cells;
FIG. 12-2 is a graph showing the inhibitory activity of the positive control drug against leukemia cell THP-1 in example 3;
FIG. 13-1 is a graph showing the inhibitory activity of the compound obtained in example 1-1 of example 3 on SK-NEP-1, a renal cancer cell;
FIG. 13-2 is a graph showing the inhibitory activity of the positive control drug of example 3 on kidney cancer cells SK-NEP-1.
Detailed Description
The invention provides a platinum compound with a structure shown in a formula (J), a preparation method thereof and application thereof in resisting tumors.
Wherein, in the present invention, any substance affecting the purity of the drug is collectively called "substance of interest affecting the quality of lobaplatin" or "substance of interest affecting the quality", simply referred to as "substance of interest", such as peak of interest affecting the quality of lobaplatin appearing in HPLC chromatographic peaks for detecting the quality of lobaplatin, simply referred to as "substance of interest peak"; the "related substances" in the present invention are sometimes "impurities" known to those skilled in the art to affect the purity of the drug, however, the "related substances" in the present invention are not limited to the category of "impurities" but include substances having a certain anticancer activity even higher than lobaplatin, which belong to the category of substances related to lobaplatin with respect to the active molecule "lobaplatin", their anticancer activity or other principles of positive effects and functions in developing new drugs have not been fully studied.
The chemicals described in the examples are not identified as chemically pure grades of conventional reagents, wherein compound 1 was prepared according to the method described in example 1 of patent number CN102093226B and confirmed by structural identification;
potassium chloroplatinite was purchased from Shanghai Jiuyue chemical Co., ltd;
potassium iodide was purchased from guangzhou chemical reagent plant as analytically pure.
Preparation of the Compounds of example 1-1
The preparation method comprises the following steps:
1) Preparation of Compound 2
Compound 1 (30.0 g,101.9 mmol), potassium chloroplatinite (36.0 g,86.7 mmol), potassium iodide (86.0 g,518.1 mmol) and potassium hydroxide (24.0 g,427.7 mmol) were dissolved in 170mL,180mL,87mL and 120mL of purified water, respectively, to give solutions A, B, C and D.
Ii, heating the solution B to 30 ℃. Stirring and scattering the material A.
And iii, adding the solution C into the solution B, and stirring for 0.5h to obtain the solution E.
And iv, adding the solution D into the solution A, stirring, clarifying the system, and filtering by using a 0.45-micrometer filter membrane to obtain the solution F.
V. adding F to E, precipitating yellow solid, and stirring at 30deg.C for 2 hr.
Vi. Filtering, washing the filter cake with purified water (100 ml. Times.6) until no halogen ion remains. The filter cake was dried by rotary evaporator to give compound 2 (35 g) as yellow powder.
2) Preparation of Compound 3
Compound 2 (8.0 g,14.2 mmol) was dispersed in purified water (33.6 mL) and acetone (4.8 mL) to give a material a, silver nitrate (4.13 g,24.3 mmol) was dissolved in purified water (12.8 mL), added to the material a, stirred at 30 ℃ in the dark for 18 hours, filtered, the filter cake washed 6 times with water (20 mL x 3), and the filtrate was combined to give 110mL of a solution of compound 3 directly for the next step;
3) Preparation of Compound 4
Resin (80 g, manufacturer: mitsubishi chemical Co., ltd., model DIAION SA10 AX) was treated with 1.5mol/L aqueous sodium hydroxide (120 mL) three times; 110mL of the solution of Compound 3 and the treated resin (32 g) were placed in a three-necked flask and stirred at 30℃for 1 hour; filtration, washing the resin with purified water (25 mL x 3), combining the washing and filtrate to give a solution of compound 4 (185 mL) which is used directly in the next step;
4) Preparation of the product
The solution of compound 4 was adjusted to ph=7-8 with 10wt% aqueous p-toluenesulfonic acid, stirred at 25 ℃ for 20 hours, then lyophilized to give the product, which was sampled for LCMS, 13 CNMR, 1 HNMR and Q NMR.
Structural confirmation of the product obtained
1)HPLC-MS:
The instrument model is Agilent 1200LC&Agilent 6110MSD
HPLC conditions: gradient elution was performed using octadecylsilane chemically bonded silica as filler (Agilent ZORBAX SB-Aq,2.1 x 50mm,5 μm), 0.0375% by volume trifluoroacetic acid as mobile phase a, acetonitrile (+0.01875% by volume trifluoroacetic acid) as mobile phase B, following the procedure in the table; the detection wavelengths were 210nm and 215nm (DAD detector) and the column temperature was 50 ℃.
TABLE 1 gradient elution conditions
Time (minutes) Mobile phase a (vol%) Mobile phase B (vol%) Flow rate (ml/min)
0.00 10 90 1.2
1.50 10 90 1.2
MS conditions: the method is characterized by detecting by a single four-stage rod tandem mass spectrometer, wherein an ion source is an Electrospray (ESI) ion source, a positive ion scanning mode is used, a monitoring mode is full scanning, and the scanning range is 100-1000.
The result is that:
table 2 measurement results
m/e Peak of fragment ion Remarks
651.2 [M’+H] + Excimer ion peak of sample
M' is the molecular weight of Compound J
The detection results are shown in figures 1-1A, 1-1B, 1-2A and 1-2B, and can be seen that the compound is a platinum-containing organic matter, and due to the high-abundance isotope of platinum element 194 Pt、 195 Pt、 196 Pt, therefore, appears in the LCMS of the sample at about 651.2 [ M' +H ]] + The peak is the sample excimer ion peak corresponding to compound J (C 12 H 28 N 4 O 2 Pt 2 ) Molecular weight of 650.54, mass spectrum information and compound J (C 12 H 28 N 4 O 2 Pt 2 ) The molecular structure is consistent.
2) 1 H-NMR:
Instrument name: BRUKERBV-400 nuclear magnetic resonance apparatus
Its hydrogen spectrum% 1 H NMR DMSO 400 MHz) chemical shift and assignment are as follows:
TABLE 3 chemical shifts in hydrogen spectra
Chemical shift (ppm) Multiple of Proton number Hydrogen attribution
1.60 s 4 8,8’
1.91 s 4 1,1’
2.15-2.50 m 8 2,2’,7,7’,13
2.63-2.78 m 8 3,3’,6,6’
4.95-5.34 m 8 4,4', 5' (active hydrogen)
7.15-7.17 m 3 11,11’
7.53-7.55 m 3 10,10’
The spectrogram is shown in figure 2, and it can be seen that the compound contains 4 active hydrogen and 24 inactive hydrogen, and the hydrogen spectrum data of the sample is consistent with the molecular structure of the compound J.
3) 13 C-NMR:
Instrument name: BRUKERBV-400 nuclear magnetic resonance apparatus
Carbon spectrum @ 13 NMR DMSO 400 MHz) chemical shift and assignment are as follows:
TABLE 4 carbon spectrum chemical shifts
Chemical shift (ppm) Type of carbon atom Number of carbon atoms Of carbon (C)Attribution to
20.08-20.78 Primary carbon 1 13
22.27 Secondary carbon 4 1,1’,8,8’
49.35-50.26 Secondary carbon 4 3,3’,6,6’
125.46 Tertiary carbon 2 10,10’
130.71 Tertiary carbon 2 11,11’
138.02 Quaternary carbon 1 12
145.09 Quaternary carbon 1 9
The spectrogram is shown in fig. 3, and as can be seen, 13 the C-NMR resonance spectrum showed 1 saturated primary carbon peak, 8 saturated Zhong Tanfeng peaks, 4 unsaturated tertiary carbon peaks and 2 unsaturated quaternary carbon peaks, which substantially match the molecular structure of the shown compound J (wherein 4 saturated tertiary carbon peaks overlap with the solvent peak).
4)QNMR：
The method adopts Bruker AVANCE NEO 400 to carry out measurement, uses DMSO as a solvent, adopts an internal standard method to carry out measurement, adopts benzyl benzoate as an internal standard (99.8 percent), and has the following measurement results:
TABLE 5 measurement results
The calculation formula of W% is as follows:
in which W is ISTD The mass (mg) of the internal standard;
W Sam is the mass (mg) of the sample;
A Sam /A ISTD is the area ratio of the sample to the internal standard;
MW SAM molecular weight of the sample;
MW ISTD is the molecular weight of the internal standard;
n ISTD and n Sam The number of protons for each functional group;
W ISTD % is the mass percentage of the internal standard,
the spectrogram is shown in fig. 4, and the calibration content is 68.2% as can be seen from the table.
5) Ultraviolet absorption spectrum (UV):
UV-2600Series; measuring the temperature to room temperature; the measurement range is 190-400nm; measuring solvent, namely water; the map is shown in figure 5.
As can be seen from fig. 5, compound J has a maximum ultraviolet absorption at a wavelength of 265.5 nm.
6) Infrared spectrum (IR)
Infrared spectrometer: ALPHA-BRUKER; measurement conditions: solid KBr pellets. Measurement range: 4000cm -1 ～400cm -1 The measurement results and analyses were as follows:
TABLE 6 measurement results
The map is shown in figure 6.
7) Optical Rotation (OR)
Polarimeter: anton Paar MCP 500; measurement conditions were c=0.5 mol/L (water), 25 ℃, and the results were as follows:
TABLE 7 measurement results
8) Differential Scanning Calorimetry (DSC)
METTELER DSC1 instrument model; the temperature rising rate is 10.0 ℃/min; the temperature is 40-350 DEG C
The map is shown in figure 7.
As can be seen from FIG. 7, the p-toluenesulfonate salt of compound J was decomposed from 153.28 ℃.
The p-toluenesulfonate structure of the compound J of the present invention was confirmed by the above-mentioned pattern to be
Preparation of Compounds of examples 1-2
1) Preparation of Compound 2
Compound 1 (30.0 g,101.9 mmol), potassium chloroplatinite (36.0 g,86.7 mmol), potassium iodide (86.0 g,518.1 mmol) and potassium hydroxide (24.0 g,427.7 mmol) were dissolved in 170mL,180mL,87mL and 120mL of purified water, respectively, to give solutions A, B, C and D.
Ii, heating the solution B to 30 ℃. Stirring and scattering the material A.
And iii, adding the solution C into the solution B, and stirring for 0.5h to obtain the solution E.
And iv, adding the solution D into the solution A, stirring, clarifying the system, and filtering by using a 0.45-micrometer filter membrane to obtain the solution F.
V. adding F to E, precipitating yellow solid, and stirring at 25deg.C for 3 hr.
Vi. Filtering, washing the filter cake with purified water (100 ml. Times.6) until no halogen ion remains. The filter cake was dried by rotary evaporator to give compound 2 (34.1 g) as a yellow powder.
2) Preparation of Compound 3
Compound 2 (8.0 g,14.2 mmol) was dispersed in purified water (33.6 mL) and acetone (4.8 mL) to give a material a, silver nitrate (4.13 g,24.3 mmol) was dissolved in purified water (12.8 mL), added to the material a, stirred at 25 ℃ in the dark for 20 hours, filtered, the filter cake washed 6 times with water (20 mL x 3), and the filtrate was combined to give 110mL of a solution of compound 3 directly for the next step;
3) Preparation of Compound 4
Resin (80 g, manufacturer and model identical to example 1-1) was treated with 1mol/L aqueous sodium hydroxide (120 mL) three times; 110mL of the solution of Compound 3 and the treated resin (32 g) were placed in a three-necked flask and stirred at 25℃for 2 hours; the resin was washed with purified water (25 mL x 3), and the washings and filtrates were combined to give a solution of compound 4 (185 mL) which was used directly in the next step.
4) Preparation of the product
The solution of compound 4 was stirred for 25 hours at 20 ℃ after ph=7-8 with 5wt% aqueous p-toluenesulfonic acid; then freeze-drying to obtain the product, sampling and detecting LCMS, 13 CNMR, 1 HNMR and Q NMR.
The structure of the product obtained by the preparation is confirmed to be the compound of the invention.
Preparation of Compounds of examples 1-3
1) Preparation of Compound 2
Compound 1 (30.0 g,101.9 mmol), potassium chloroplatinite (36.0 g,86.7 mmol), potassium iodide (86.0 g,518.1 mmol) and potassium hydroxide (24.0 g,427.7 mmol) were dissolved in 170mL,180mL,87mL and 120mL of purified water, respectively, to give solutions A, B, C and D.
Ii, heating the solution B to 30 ℃. Stirring and scattering the material A.
And iii, adding the solution C into the solution B, and stirring for 0.5h to obtain the solution E.
And iv, adding the solution D into the solution A, stirring, clarifying the system, and filtering by using a 0.45-micrometer filter membrane to obtain the solution F.
V. adding F to E, precipitating yellow solid, and stirring at 35 deg.C for 1 hr.
Vi. Filtering, washing the filter cake with purified water (100 ml. Times.6) until no halogen ion remains. The filter cake was dried by rotary evaporator to give compound 2 (33.8 g) as a yellow powder.
2) Preparation of Compound 3
Compound 2 (8.0 g,14.2 mmol) was dispersed in purified water (33.6 mL) and acetone (4.8 mL) to give a material a, silver nitrate (4.13 g,24.3 mmol) was dissolved in purified water (12.8 mL), added to the material a, stirred for 15 hours at 35 ℃ protected from light, filtered, the filter cake washed 6 times with water (20 mL x 3), and the filtrates were combined to give 110mL of a solution of compound 2 directly for the next step;
3) Preparation of Compound 4
Resin (80 g, manufacturer and model identical to example 1-1) was treated with 2mol/L aqueous sodium hydroxide (120 mL) three times; 110mL of the solution of Compound 3 and the treated resin (32 g) were placed in a three-necked flask and stirred at 35℃for 0.5 hour; the resin was washed with purified water (25 mL x 3), and the washings and filtrates were combined to give a solution of compound 4 (185 mL) which was used directly in the next step.
4) Preparation of the product
The solution of compound 4 was adjusted to ph=7-8 with 15wt% aqueous p-toluenesulfonic acid, stirred at 30 ℃ for 15 hours, then lyophilized to give the product, which was sampled for LCMS, 13 CNMR, 1 HNMR and Q NMR.
The structure of the product obtained by the preparation is confirmed to be the compound of the invention.
Example 2 detection method
According to mass spectrometry (Chinese pharmacopoeia 2015 edition four general rules 0431)
Chromatographic condition and System applicability test
Instrument model: agilent 1260+6130ms with octadecylsilane chemically bonded silica as filler (Waters Xselect CSH 4.6.6 x 150mm,3.5 μm), 20mmol/L ammonium formate as mobile phase a, methanol: acetonitrile volume ratio = 1:1 as mobile phase B, gradient elution was performed according to the following table procedure; the flow rate was 1.0ml per minute and the column temperature was 40 ℃. Detecting by a single-four-stage rod tandem mass spectrometer, wherein the ion source is an Electrospray (ESI) ion source, a positive ion scanning mode is used, the monitoring mode is selected ion monitoring, the monitoring ion is 326, the acquisition time is 13-20 min, and the capillary outlet voltage is 70V. In the chromatogram of the system applicability test solution, the separation degree of the peak of the compound J from the peak of the adjacent lobaplatin-related substance should be not less than 1.5; the system applicability test solution is continuously injected for 6 times, and the relative standard deviation of the peak area of the compound J is not more than 10.0%.
TABLE 8 gradient elution conditions
Preparation of System suitability test solution/control solution
Taking about 10mg of a lobaplatin related substance J reference substance (the compound prepared in the example 1-1), precisely weighing, placing into a 20mL volumetric flask, adding a proper amount of water for ultrasonic dissolution, adding water for dilution to a scale, and shaking uniformly to serve as a reference substance stock solution (1); precisely measuring 1ml of reference stock solution (1), placing in a10 ml volumetric flask, diluting with water to scale, shaking, and taking as reference stock solution (2); precisely measuring 1ml of reference stock solution (2), placing into a10 ml volumetric flask, adding water to dilute to scale, shaking uniformly to obtain system applicability solution, and simultaneously obtaining reference solution.
Preparation of test solutions
The lobaplatin to be measured (lobaplatin samples which are prepared by adopting the method disclosed in the embodiment 2 in the specification of the patent CN 102020679B and are confirmed by structural identification, namely lobaplatin trihydrate is added to be taken as lobaplatin to be measured in the embodiment, the lobaplatin content is calculated by lobaplatin anhydrate in each embodiment), the lobaplatin is precisely weighed, placed in a10 ml volumetric flask, ultrasonically dissolved by adding water and diluted to scale, and uniformly shaken to be taken as a sample solution.
Assay
Taking 20 mu l of each of the system applicability test solution and the test sample solution, injecting into a liquid chromatograph-mass spectrometer, and recording a mass spectrogram for 25 minutes.
A typical spectrum of compound J is shown in FIG. 8.
The chromatogram of the test solution contains compound J, and the peak area of the chromatogram is not larger than that of compound J of the reference solution.
Example 3: in vitro antitumor Activity assay (Activity test experiment of Compound J of the invention)
1. Reagent and consumable
1. Cell lines from cell banks of the Chinese sciences
TABLE 9 cell lines
Species of genus Cell name
Lung cancer cell NCI-H460
Ovarian cancer cells SK-OV-3
Leukemia cells Jurkat Clone E6-1
Leukemia cells THP-1
Renal cancer cells SK-NEP-1
Rpmi medium, chinese procall, cat: PM150110
Mccoy's5a medium, chinese procall, cat: PM150710
4.Luminescent Cell Viability Assay Promega, USA, cat: g7572
5.96 well cell culture plate, corning, usa, cat: 3610
Envision, U.S. PerkinElmer
Fbs, lonsera, cat: S711-001S
8. Sodium pyruvate, chinese procall, cat: PB180422
9. Beta-mercaptoethanol, gibco, cat: 21985
Dmso, sigma, cat: d8418
Penicillin & Streptomycin (P/S), china Procell, cat: PB180120
12.0.25% pancreatin-EDTA, chinese procall, cat: PB180228
2. Solution and buffer
1. Cell growth medium
After the preparation, the mixture is stored at 4 ℃ for standby.
Table 10 cells and culture Medium therefor
Cell name Culture medium
NCI-H460 RPMI-1640+10 vol% FBS+1 vol% P/S
SK-OV-3 McCoy' S5A+10 vol% FBS+1 vol% P/S
Jurkat Clone E6-1 RPMI-1640+10 vol% FBS+1 vol% P/S
THP-1 RPMI-1640+10 vol% FBS+0.05mM beta-mercaptoethanol+1 vol% P/S
SK-NEP-1 McCoy' S5A+15% FBS+1% P/S
Heat-inactivated serum of heat-inactivated FBS
The serum is put in a water bath at 56 ℃ for 30 minutes.
3. Compound treatment:
compound J (3.37 g) prepared in example 1-1 was dissolved in DMSO to prepare a 30mM solution, which was stored at-20℃until use. The positive control was Staurosporine (STSP) (available from MedChemExpress (MCE) under the trade designation HY-15141), a natural product originally isolated in 1977 from the bacterial mould Staurosporeus.
3. The experimental method comprises the following steps:
(1) Resuscitating cells
And quickly taking out the cells to be recovered from the liquid nitrogen tank, melting the cells in a water bath at 37 ℃, and quickly adding the cells into the preheated culture medium. 1000 rpm, centrifuging for 5 min, taking out the centrifuge tube, discarding supernatant, adding fresh preheated culture medium into the centrifuge tube, re-suspending cells, adding cell suspension into culture dish, and adding 5 vol% CO at 37deg.C 2 Culturing.
(2) Cell passage
Cell passage: adherent cells, when the cells grow over the dish 80-90%, the cells are digested with 0.25% pancreatin (prepared by adding 0.25g pancreatin to 100ml abs solution), then resuspended in fresh medium, and passaged at appropriate ratio for about 2-3 d for 1 passage. The cells were suspended, the cell suspension was collected, centrifuged at 800rpm for 5 minutes, the supernatant was removed, resuspended in fresh medium, and passaged at an appropriate ratio for about 2-3 d for 1 passage.
(3) Preparation of working solution concentration of compound
A. Single concentration test of compounds
According to the assay requirements, compound J prepared in example 1-1 was diluted to 1mM stock solution using DMSO and further diluted to 50uM (5 Xfinal concentration) working solution using culture medium on the day of the experiment, the test concentration of the compound was 10. Mu. Moles, and the incubation time of the compound was 72 hours.
B. Compound IC 50 Testing
According to the assay requirements, the compounds were diluted to 1mM stock solution as the highest concentration using DMSO and subjected to 2-fold, 3-fold or 5-fold gradient dilution, followed by further dilution of each concentration point to 5 Xfinal concentration of working solution using medium.
(4) Cell seeding and drug treatment
1. 1 day before detection according toCell growth Rate cells were seeded at different densities in 96 well cell plates with 80. Mu.L of cell suspension per well, 37℃and 5% CO by volume 2 Incubator, incubate overnight.
Specific plating densities of cells are shown in the following table:
TABLE 11 cell plating Density
Cell name Density (cells/well)
NCI-H460 4000
SK-OV-3 2000
Jurkat Clone E6-1 10000
THP-1 15000
SK-NEP-1 3000
2. According to the experimental requirements, 20 mu L of compound working solution is added into each hole, the temperature is 37 ℃, and the CO content is 5 vol% 2 Incubator, incubate for 72 hours.
3. After the incubation, the cell activity was calculated by performing detection according to the CTG kit (from Promega under the designation G7572, titled celliter-glo) protocol to obtain the corresponding chemiluminescent value.
4. Calculation of
Cell viability = dosing/control (solvent) RLU value x 100%
(5) Experimental results:
the inhibitory activity of a single concentration of 10 μm compound was as follows:
TABLE 12 inhibitory Activity of Compound J
From the table, the compound J has better inhibition activity on THP-1, and the inhibition rate reaches more than 90%.
The dose-response curves are shown in FIGS. 9-1 to 13-2, wherein the abscissa represents concentration in micromolar and the ordinate represents cell viability.
IC of compound 50 The values are as follows:
TABLE 13 IC50 of Compound J
Cell name Compound IC 50 Control (STSP)
NCI-H460 ＞10μM 40.35nM/40.41nM
SK-OV-3 4.44μM 8.46nM
Jurkat Clone E6-1 3.23μM 14.67/11.63/12.12/12.84nM
THP-1 4.54μM 73.02/74.45/42.58nM
SK-NEP-1 2.95μM 12.09/12.38/11.81/10.72nM
As can be seen from the activity data, the compound has the maximum inhibitory activity on the human lung cancer cell strain THP-1, has certain inhibitory activity on other tumor cells, and has smaller inhibitory activity on NCI-H460 of lung cancer cells.
In conclusion, the compound has good inhibition activity on the cancer cells at the concentration of 10 mu M, particularly has remarkable tumor inhibition activity aiming at THP-1 with the inhibition rate of more than 90%, and can be further developed into anticancer drugs for clinical application.
The above description is not intended to limit the invention in any way, but is intended to cover all modifications, equivalents, and alternatives falling within the spirit and principles of the invention.

Claims (70)

1. A platinum compound has a structure shown in the following formula (J):
2. the process for producing a platinum compound according to claim 1, wherein the compound of formula (J) is produced by the process of formula (I) compound 4
In the reaction of preparing the formula (J) through the compound 4, the obtained solution of the compound 4 is regulated to be slightly alkaline by an acid regulator, and then the final product is obtained by freeze-drying; the acidity regulator is selected from one of p-toluenesulfonic acid or methanesulfonic acid;
the compound 4 is prepared by a compound 3 with the following structural formula
The solution of the compound 3 and the resin are mixed and stirred, and then the mixture is filtered to obtain a solution of the compound 4.
3. The production method according to claim 2, wherein the acidity regulator is p-toluenesulfonic acid; the alkalescence is ph=7-8.
4. The process according to claim 3, wherein the concentration of the aqueous solution of p-toluenesulfonic acid is 5 to 15wt%.
5. The process according to claim 3, wherein the concentration of the aqueous solution of p-toluenesulfonic acid is 10wt%.
6. The production process according to claim 2, wherein the reaction is carried out at a temperature of 20 to 30 ℃ for 15 to 25 hours after the adjustment to the slightly alkaline state.
7. The production process according to claim 2, wherein the reaction is carried out at a temperature of 25℃for 20 hours after the adjustment to the slightly basic state.
8. The preparation method according to claim 2, wherein the temperature at which the compound 3 solution and the resin are mixed and stirred is 25 to 35 ℃.
9. The production method according to claim 2, wherein the compound 3 solution and the resin are mixed and stirred for a period of 0.5 to 2 hours.
10. The production method according to claim 8, wherein the temperature at which the compound 3 solution and the resin are mixed and stirred is 30 ℃.
11. The production method according to claim 9, wherein the time for mixing and stirring the compound 3 solution and the resin is 1 hour.
12. The production method according to claim 2, wherein the resin is a resin which has been treated.
13. The production method according to claim 12, wherein the resin which has been treated is a resin treated with an aqueous sodium hydroxide solution.
14. The production process according to claim 13, wherein the concentration of the aqueous sodium hydroxide solution is 1 to 2mol/L.
15. The production process according to claim 13, wherein the concentration of the aqueous sodium hydroxide solution is 1.5mol/L.
16. The preparation method according to claim 2, wherein the compound 3 is prepared by the following compound 2 of the formula
17. The process according to claim 8, wherein the compound 3 is prepared from the compound 2 having the structural formula
18. The preparation method according to claim 16, wherein the compound 2 is added to water and a ketone solvent to obtain a material a, then a silver nitrate solution is added to the material a for reaction, and the solution of the compound 3 is obtained by filtration.
19. The preparation method of claim 18, wherein the ketone solvent is selected from one of acetone, methyl butanone, methyl ethyl ketone, and methyl isobutyl ketone.
20. The method of claim 18, wherein the ketone solvent is selected from acetone.
21. The preparation method of claim 16, wherein the compound 2 is prepared from a compound 1 of the following structural formula:
22. the production process according to claim 21, wherein in the production of compound 2 by compound 1, chloroplatinic acid salt or chloroplatinic acid salt and alkali metal iodide are reacted with hydroxide to produce compound 2.
23. The process according to claim 22, wherein the molar ratio of the compound 1 to chloroplatinic acid salt is 1:0.5-2.
24. The preparation method according to claim 22, wherein the molar ratio of the compound 1 to the chloroplatinic acid salt is 1:0.85.
25. the method of claim 22, wherein the chloroplatinic acid salt is selected from potassium chloroplatinic acid or sodium chloroplatinic acid.
26. The method according to claim 22, wherein the chloroplatinic acid salt is potassium chloroplatinic acid.
27. The method according to claim 22, wherein the alkali iodide is selected from potassium iodide or sodium iodide.
28. The method according to claim 22, wherein the alkali iodide is potassium iodide.
29. The method of claim 22, wherein the hydroxide is selected from potassium hydroxide or sodium hydroxide.
30. The method of claim 22, wherein the hydroxide is potassium hydroxide.
31. The preparation method according to any one of claims 2 to 30, wherein the preparation method comprises the steps of:
wherein, in the reaction of preparing the compound 2 from the compound 1, chloroplatinite or chloroplatinite and alkali metal iodide are reacted with hydroxide to prepare the compound 2; in the reaction of preparing the compound 3 from the compound 2, adding the compound 2 into water and ketone solvents to obtain a material A, adding a silver nitrate solution into the material A for reaction, and filtering to obtain a solution of the compound 3;
in the reaction for preparing the compound 4 by the compound 3, mixing and stirring the solution of the compound 3 and the resin, and then filtering to obtain a compound 4 solution;
in the reaction for preparing the product by the compound 4, the obtained solution of the compound 4 is adjusted to be slightly alkaline by an acidic regulator, and then the final product is obtained by freeze-drying.
32. The process according to claim 31, wherein in the step of preparing the compound 2 from the compound 1, the compound 1 and the aqueous solution of potassium hydroxide are mixed to obtain a solution F, the potassium chloroplatinic acid and the aqueous solution of potassium iodide are mixed to obtain a solution E, and the solution F and the solution E are mixed to react to obtain the compound 2.
33. The process according to claim 32, wherein the reaction temperature is 25-35 ℃.
34. The process of claim 32, wherein the reaction temperature is 30 ℃.
35. The process of claim 32, wherein the reaction time is 1-3 hours.
36. The method of claim 32, wherein the reaction time is 2 hours.
37. The process according to claim 32, wherein the molar ratio of the compound 1 to chloroplatinic acid salt is 1:0.5-2.
38. The process according to claim 32, wherein the molar ratio of compound 1 to chloroplatinic acid salt is 1:0.85.
39. the process according to claim 31, wherein in the step of preparing compound 3 from compound 2, the molar ratio of compound 2 to silver nitrate is 1 (1-2).
40. The production method according to claim 31, wherein in the reaction step of producing the compound 3 from the compound 2, a molar ratio of the compound 2 to silver nitrate is 1:1.7.
41. the production process according to claim 31, wherein, in the reaction step of producing compound 3 from compound 2, the reaction temperature is 25 to 35 ℃.
42. The production process according to claim 31, wherein, in the reaction step of producing compound 3 from compound 2, the reaction temperature is 30 ℃.
43. The production process according to claim 31, wherein, in the reaction step of producing compound 3 from compound 2, the light-shielding reaction time is 15 to 20 hours.
44. The production process according to claim 31, wherein, in the reaction step of producing compound 3 from compound 2, the light-shielding reaction time is 18 hours.
45. The preparation method of claim 31, wherein the ketone solvent is selected from one of acetone, methyl butanone, methyl ethyl ketone, or methyl isobutyl ketone.
46. The process of claim 31, wherein the ketone solvent is acetone.
47. The production method according to claim 31, wherein, in the reaction for producing the compound 4 from the compound 3, the temperature at which the compound 3 solution and the resin are mixed and stirred is 25 to 35 ℃.
48. The production process according to claim 31, wherein, in the reaction for producing the compound 4 from the compound 3, the stirring time is 0.5 to 2 hours.
49. The production process according to claim 31, wherein, in the reaction for producing the compound 4 from the compound 3, the stirring time is 1 hour.
50. The production process according to claim 31, wherein the temperature of stirring in the reaction for producing the compound 4 from the compound 3 is 30 ℃.
51. The production method according to claim 31, wherein the resin is a resin which has been treated.
52. The process according to claim 51, wherein the resin which has been treated is a resin treated with an aqueous sodium hydroxide solution.
53. The process according to claim 52, wherein the concentration of the aqueous sodium hydroxide solution is 1 to 2mol/L.
54. The process according to claim 52, wherein the concentration of the aqueous sodium hydroxide solution is 1.5mol/L.
55. The production method according to claim 31, wherein the acidity regulator is selected from one of p-toluenesulfonic acid and methanesulfonic acid in the reaction for producing a product by the compound 4.
56. The production process according to claim 31, wherein in the reaction for producing a product by the compound 4, the acidity regulator is p-toluenesulfonic acid.
57. The process according to claim 55, wherein the concentration of the aqueous solution of p-toluenesulfonic acid is 5-15wt%.
58. The process according to claim 55, wherein the concentration of the aqueous solution of p-toluenesulfonic acid is 10wt%.
59. The method of claim 31, wherein the alkalescence is ph=7-8.
60. The production process according to claim 31, wherein the reaction is carried out at a temperature of 20 to 30 ℃ for 15 to 25 hours after the adjustment to the alkalescence.
61. The production process according to claim 31, wherein the reaction is carried out at a temperature of 25 ℃ for 20 hours after the adjustment to the slightly alkaline state.
62. A pharmaceutical composition comprising the platinum-group compound according to claim 1, wherein said pharmaceutical composition is a pharmaceutical formulation.
63. The pharmaceutical composition of claim 62, wherein the pharmaceutical composition is a pharmaceutical formulation for injection.
64. The pharmaceutical composition of claim 62 or 63, wherein the pharmaceutical formulation comprises an adjuvant.
65. The pharmaceutical composition of claim 64, wherein the adjuvant is selected from one or more of a filler, a disintegrant, a lubricant, a suspending agent, a binder, a sweetener, a flavoring agent, a preservative, an antioxidant, and a matrix.
66. The pharmaceutical composition according to claim 64, wherein the adjuvant is a filler and/or an antioxidant.
67. Use of a platinum compound as claimed in claim 1 or a pharmaceutical composition as claimed in any one of claims 62 to 66 in the manufacture of an anti-tumour medicament.
68. The use according to claim 67, wherein the tumour is a lung cancer, ovarian cancer, leukemia and/or renal cancer cell.
69. The use of claim 67, wherein the tumor is a leukemia cell.
70. The use of claim 67, wherein the platinum-based compound or the pharmaceutical composition is for the manufacture of an anti-THP-1 tumor medicament.
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CN101918379A (en) * 2008-01-16 2010-12-15 天真堂制药株式会社 Platinum complex compound and utilization of the same
CN102020679A (en) * 2010-11-24 2011-04-20 贵州益佰制药股份有限公司 Method for preparing lobaplatin trihydrate by usingoxalate

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CN101918379A (en) * 2008-01-16 2010-12-15 天真堂制药株式会社 Platinum complex compound and utilization of the same
CN102020679A (en) * 2010-11-24 2011-04-20 贵州益佰制药股份有限公司 Method for preparing lobaplatin trihydrate by usingoxalate

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