阅读说明：本技术 洛铂中有关物质的检测方法 (Method for detecting related substances in lobaplatin ) 是由 窦啟玲 汪立冬 常新亮 于 2019-03-19 设计创作，主要内容包括：本发明还提供一种洛铂中有关物质的检测方法,所述有关物质包括6个化合物,其中所述检测方法为HPLC法或HPLC-MS法。HPLC法的色谱柱为：硅胶表面涂敷有纤维素-三(3-氯-4-甲基苯基氨基甲酸酯)为填充剂。所述的HPLC法的流动相为正已烷-乙醇(60～70:30～40),HPLC法的流速为每分钟0.8-1.5ml,检测波长为208-212nm,柱温为30-40℃,等度洗脱30-50min；优选地,流速为每分钟1.0ml,检测波长为210nm,柱温为35℃,等度洗脱时间为40min。所述相关物质的应用是在肺癌、肝癌、小细胞肺癌、乳腺癌、血液肿瘤、白血病、胃癌、卵巢癌、前列腺癌和/或肾癌细胞中的应用。(The invention also provides a method for detecting related substances in lobaplatin, wherein the related substances comprise 6 compounds, and the detection method is an HPLC method or an HPLC-MS method. The chromatographic column of the HPLC method is as follows: the surface of the silica gel is coated with cellulose-tri (3-chloro-4-methyl phenyl carbamate) as a filler. The mobile phase of the HPLC method is n-hexane-ethanol (60-70: 30-40), the flow rate of the HPLC method is 0.8-1.5ml per minute, the detection wavelength is 208-212nm, the column temperature is 30-40 ℃, and isocratic elution is carried out for 30-50 min; preferably, the flow rate is 1.0ml per minute, the detection wavelength is 210nm, the column temperature is 35 ℃ and the isocratic elution time is 40 min. The related substances are applied to cells of lung cancer, liver cancer, small cell lung cancer, breast cancer, blood tumor, leukemia, gastric cancer, ovarian cancer, prostatic cancer and/or renal cancer.)

1. A method for detecting related substances in lobaplatin is characterized in that the related substances are any one of or a mixture of any two or more of the following compounds H1, H2, G1, G2, L1 and L2:

compound H1:

compound G1:compound G2:

compound L1:

2. the detection method according to claim 1, wherein the substance of interest is any one of compound H1, compound H2, a mixture of compounds G1 and G2, compound L1, or compound L2.

3. The detection method according to claim 1 or 2, wherein the substance of interest simultaneously comprises compound H1, compound H2, a mixture of compounds G1 and G2, compound L1 and compound L2.

4. The detection method according to any one of claims 1 to 3, wherein the lobaplatin comprises either one or both of lobaplatin diastereomer I and lobaplatin diastereomer II.

5. The assay of any one of claims 1-4 wherein said compounds H1 and H2 are via intermediatesPreparing to obtain; the compounds G1 and G2, L1 and L2 are via intermediatesAnd (4) preparing.

6. The detecting method according to any one of claims 1 to 5, wherein the compounds H1 and H2 are separated to obtain H1 and H2 by obtaining a mixture H by the following reaction equation (1):

alternatively, the compounds G1 and G2 are obtained by the following reaction scheme (2):

alternatively, the compounds L1 and L2 were obtained by the following reaction equation (3):

7. the detection method according to any one of claims 1 to 6, wherein the detection method is an HPLC method or an HPLC-MS method.

8. The assay of any one of claims 1 to 7 wherein the HPLC column is: the surface of the silica gel is coated with cellulose-tri (3-chloro-4-methyl phenyl carbamate) as a filler.

9. The detection method according to any one of claims 1 to 4, wherein the mobile phase of the HPLC method is n-hexane-ethanol in a volume ratio of 60-70: 30-40, preferably 63-67: 37-33; preferably, more preferably, the mobile phase is n-hexane-ethanol in a volume ratio of 65: 35.

10. The detection method according to any one of claims 1 to 9, wherein the elution pattern of the HPLC method is isocratic elution.

11. The detection method according to any one of claims 1 to 10, wherein the flow rate of the HPLC method is 0.8 to 1.5ml per minute, the detection wavelength is 208-212nm, the column temperature is 30 to 40 ℃, and isocratic elution is 30 to 50 min; preferably, the flow rate is 1.0ml per minute, the detection wavelength is 210nm, the column temperature is 35 ℃ and the isocratic elution time is 40 min.

12. The detecting method according to any one of claims 1 to 11, wherein the peak area of each of the substance of interest H1, the substance of interest L1 and the substance of interest L2 is not more than 0.5 times the peak area of the main component in the control solution and the total of the substance of interest G1, the substance of interest G2 and the substance of interest H2 is not more than the peak area of the main component in the control solution, as calculated by the main component self-control method without addition of a correction factor.

13. The detection method according to any one of claims 1 to 12, wherein, if a peak of a substance of interest is present in the test solution, the peak is located by identifying a chromatographic peak in a typical chromatogram with the substance of interest: the relative retention time of related substances G1, G2 and H2 is 2.40-2.70, preferably 2.58, and the relative retention time of related substance H1 is 2.00-2.30, preferably 2.16; the relative retention time of compound L1 is 1.2 to 1.5, preferably 1.35; the relative retention time of compound L2 was 3.4-3.7, preferably 3.58.

Technical Field

The invention relates to the field of medicines, in particular to a method for detecting related substances in lobaplatin, and belongs to the technical field of medicine analysis quality control.

Background

Lobaplatin (Lobaplatin, D19466), also known as Lobaplatin, is a third-generation platinum-based antitumor drug following cisplatin and carboplatin, and its chemical name is: cis- [ trans-1, 2-cyclobutanebis (methylamine) -N, N']- [ (2S) -lactic acid-O1, O2]-platinum (II), formula C₉H₁₈N₂O₃Pt has a molecular weight of 397.34 and a chemical structural formula shown in the following formula (1):

lobaplatin has alkylating action and belongs to an alkylating agent (in a broad sense). Has good antitumor effect, such as inhibiting in vitro AH 135-tumor, B16-melanoma, colon cancer 115, and in vivo mouse P338 leukemia. Lobaplatin is characterized by strong anticancer activity, low toxicity, no accumulative toxicity and renal toxicity and less toxicity to bone marrow, and currently marketed lobaplatin for injection is mainly used for treating breast cancer, small cell lung cancer and chronic myelogenous 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 drug, due to the existence of three chiral carbons and related substances generated in the preparation process, confirming the structure of the related substances and finding a suitable detection method for controlling the product quality of the drug become technical problems to be solved urgently in the field.

The invention aims to provide a novel detection method which can simultaneously detect a plurality of related substances in lobaplatin.

One skilled in the art will recognize that any substance that affects the purity of a drug is collectively referred to as a related substance (or related substances). Research on related substances is an important part of drug development, and comprises selecting a proper analysis method, accurately distinguishing and determining the content of the related substances, and determining the reasonable limit of the related substances by combining the results of pharmaceutical, toxicological and clinical researches. This study is throughout the entire process of drug development.

Specifically, the present invention is realized by the following technical means.

A method for detecting related substances in lobaplatin, wherein the related substances are selected from the following compounds H1, H2, G1, G2, L1 or L2:

compound H1:compound H2:

compound G1:

compound G2:compound L1:and compound L2:

preferably, in the detection method, the substance concerned is any one of compound H1, compound H2, a mixture of compounds G1 and G2, compound L1 or compound L2.

Preferably, for the detection method, the related substances simultaneously include compound H1, compound H2, a mixture of compounds G1 and G2, compound L1 and compound L2.

Preferably, for the detection method of any one of the preceding claims, wherein said lobaplatin comprises either or both of lobaplatin diastereomer I and lobaplatin diastereomer II.

Preferably, the detection method of any one of the preceding claims, wherein the preparation of compounds H1 and H2 is via intermediates

And/orPreparing to obtain; the preparation method of the compounds G1 and G2, L1 and L2 is to pass through intermediates

And (4) preparing.

Preferably, the detection method described in any one of the above, wherein the compounds H1 and H2 are obtained by the following reaction equation (1):

alternatively, the compounds G1 and G2 are obtained by the following reaction scheme (2):

alternatively, the compounds L1 and L2 were obtained by the following reaction equation (3):

among them, still more preferably, in the above reaction equation (1), the trans-diiodide, compound 1, is prepared by the following equation (1-a):

in the above reaction equation (2), the compound 1 (cis oxalate) can be obtained by reacting cis dicyanocyclobutane to obtain diaminomethylcyclobutane and then reacting with oxalic acid as in the reaction equation (3); that is, the compounds G1 and G2 can be prepared by the following reaction formula (1-b):

preferably, the detection method of any one of the preceding claims, wherein the detection method is an HPLC method or an HPLC-MS method.

Preferably, the detection method according to any one of the preceding claims, wherein the HPLC method comprises a column: the surface of the silica gel is coated with cellulose-tri (3-chloro-4-methyl phenyl carbamate) as a filler.

Preferably, the detection method is any one of the detection methods, wherein the mobile phase of the HPLC method is n-hexane-ethanol with a volume ratio of 60-70: 30-40, preferably 63-67: 37-33; more preferably, the mobile phase is n-hexane-ethanol in a volume ratio of 65: 35.

Preferably, the detection method according to any one of the preceding claims, wherein the elution profile of the HPLC method is isocratic elution.

Preferably, for the detection method of any one of the preceding claims, wherein the flow rate of the HPLC method is 0.8-1.5ml per minute, the detection wavelength is 208-212nm, the column temperature is 30-40 ℃, and isocratic elution is 30-50 min; preferably, the flow rate is 1.0ml per minute, the detection wavelength is 210nm, the column temperature is 35 ℃ and the isocratic elution time is 40 min.

Preferably, in the detection method according to any one of the above, the detection method is such that the related substance H1, the related substance L1, and the related substance L2 each do not exceed 0.5 times the peak area of the main component in the control solution, and the total of the related substance G1, the related substance G2, and the related substance H2 does not exceed the peak area of the main component in the control solution, as calculated in terms of the peak area by the main component self-control method without addition of a correction factor.

Preferably, in the detection method according to any one of the preceding claims, if there is a peak of the relevant substance in the test solution, the peak is located by identifying a chromatographic peak in a typical chromatogram with the relevant substance: the relative retention time of the substances G1, G2 and/or H2 is 2.40-2.70, preferably 2.58, and the relative retention time of the substance H1 is 2.00-2.30, preferably 2.16; the relative retention time of compound L1 is from 1.2 to 1.5, preferably 1.35, and the relative retention time of compound L2 is from 3.4 to 3.7, preferably 3.58.

The invention has the following beneficial effects:

the invention carries out structure confirmation on the compound H1, the compound H2, the compound G1, the compound G2, the compound L1 or the compound L2, confirms related substances of the lobaplatin, and can simultaneously detect a plurality of related substances (impurities) in the lobaplatin in order to establish a complete lobaplatin quality detection system. The method has the advantages of high sensitivity, strong specificity, good repeatability and high accuracy.

Drawings

FIG. 1A: the HPLC-MS of the substance H of the present invention;

FIG. 1B: the present invention relates to the MS spectrum in HPLC-MS of substance H;

FIG. 2: of the invention with respect to substance H¹An H-NMR spectrum;

FIG. 3: of the invention with respect to substance H¹³A C-NMR spectrum;

FIG. 4: the invention relates to the Q-NMR spectrum of substance H;

FIG. 5: the invention relates to the UV spectrum of substance H;

FIG. 6: the invention relates to the IR spectrum of substance H;

FIG. 7: the invention relates to the DSC pattern of substance H;

FIG. 8A-1: HPLC chromatogram (wavelength 220nm) for HPLC-MS structure confirmation detection of the substance H1 of the present invention;

FIG. 8A-2: HPLC chromatogram (wavelength 254nm) for HPLC-MS structure confirmation detection of the substance H1 of the present invention;

FIG. 8B: the invention relates to the MS map of substance H1;

FIG. 9A: the invention relates to the SFC profile of substance H1;

FIG. 9B: the molecular three-dimensional structure diagram of the substance H1 of the invention;

FIG. 10A-1: HPLC chromatogram (wavelength 220nm) for HPLC-MS structure confirmation detection of the substance H2 of the present invention;

FIG. 10A-2: HPLC chromatogram (wavelength 254nm) for HPLC-MS structure confirmation detection of the substance H2 of the present invention;

FIG. 10B: the HPLC-MS structure of the related substance H2 confirms the detected MS map;

FIG. 11: the invention relates to the SFC profile of substance H2;

FIG. 12A-1: the HPLC-MS combined structure of the compound G1 of the invention confirms the HPLC spectrum (the wavelength is 215nm) in the detection;

FIG. 12A-2: the HPLC-MS combined structure of the compound G1 of the present invention confirms the HPLC profile (wavelength 210nm) in the detection;

FIG. 12B: the HPLC-MS combined structure of the related substance G1 confirms the MS map in the detection;

FIG. 13: of the invention with respect to substance G1¹An H-NMR spectrum;

FIG. 14: of the invention with respect to substance G1¹³A C-NMR spectrum;

FIG. 15: the invention relates to the Q-NMR spectrum of substance G1;

FIG. 16: the present invention relates to the UV spectrum of substance G1;

FIG. 17: the invention relates to the IR spectrum of substance G1;

FIG. 18A: the present invention relates to the DSC profile of substance G1;

FIG. 18B: the invention relates to an HPLC spectrogram confirmed by the structure of a substance G1;

FIG. 19A-1: the HPLC-MS combined structure of the compound G2 of the invention confirms the HPLC spectrum (the wavelength is 215nm) in the detection;

FIG. 19A-2: the HPLC-MS combined structure of the compound G2 of the present invention confirms the HPLC profile (wavelength 210nm) in the detection;

FIG. 19B: the HPLC-MS combined structure of the related substance G2 confirms the MS map in the detection;

FIG. 20: of the invention with respect to substance G2¹An H-NMR spectrum;

FIG. 21: of the invention with respect to substance G2¹³A C-NMR spectrum;

FIG. 22: the invention relates to the Q-NMR spectrum of substance G2;

FIG. 23: the present invention relates to the UV spectrum of substance G2;

FIG. 24: the invention relates to the IR spectrum of substance G2;

FIG. 25A: the present invention relates to the DSC profile of substance G2;

FIG. 25B: the invention relates to an HPLC spectrogram confirmed by the structure of a substance G2;

FIG. 26: intermediate of the invention for preparing Compounds L1 and L2 Compound 3¹An H-NMR spectrum;

FIG. 27A-1: the HPLC-MS combined structure of the compound L1 confirms the HPLC spectrum (the wavelength is 215nm) in the detection;

FIG. 27A-2: the HPLC-MS combined structure of the compound L1 confirms the HPLC spectrum (the wavelength is 210nm) in the detection;

FIG. 27B: the HPLC-MS combined structure of the related substance L1 confirms the MS map in the detection;

FIG. 28: of the invention with respect to the substance L1¹An H-NMR spectrum;

FIG. 29: of the invention with respect to the substance L1¹³A C-NMR spectrum;

FIG. 30: the present invention relates to a Q-NMR spectrum of substance L1;

FIG. 31: the present invention relates to the UV spectrum of substance L1;

FIG. 32: the present invention relates to the IR spectrum of substance L1;

fig. 33A: the present invention relates to the DSC pattern of substance L1;

FIG. 33B: the HPLC spectrogram confirmed by the structure of the related substance L1 of the invention;

FIG. 34A-1: the HPLC-MS combined structure of the compound L2 confirms the HPLC spectrum (the wavelength is 215nm) in the detection;

fig. 34A-2: the HPLC-MS combined structure of the compound L2 confirms the HPLC spectrum (the wavelength is 210nm) in the detection;

FIG. 34B: the present invention relates to the MS spectrum of substance L2;

FIG. 35: of the invention with respect to the substance L2¹An H-NMR spectrum;

FIG. 36: of the invention with respect to the substance L2¹³A C-NMR spectrum;

FIG. 37: the present invention relates to a Q-NMR spectrum of substance L2;

FIG. 38: the present invention relates to the UV spectrum of substance L2;

FIG. 39: the present invention relates to the IR spectrum of substance L2;

FIG. 40A: DSC chart of substance L2 according to the present invention;

FIG. 40B: the HPLC spectrogram confirmed by the structure of the related substance L2 of the invention;

FIG. 41: the related substance of the invention is taken as a typical HPLC (high performance liquid chromatography) spectrum in a detection example of the related substance of the lobaplatin;

FIG. 42A-1: dose response profile of substance H to HCCC-9810;

FIG. 42A-2: dose response profile of STSP to HCCC-9810;

FIG. 42B-1: dose response profile of substance H to NCI-H460;

FIG. 42B-2: dose response profile of substance L2 to NCI-H460;

FIG. 42B-3: dose response profiles of STSP to NCI-H460;

FIG. 42C-1: dose response profile of substance H to MDA-MB-453;

FIG. 42C-2: dose response profile of STSP to MDA-MB-453;

FIG. 42D-1: dose response plot of substance H against DU 145;

FIG. 42D-2: dose response plots of STSP versus DU 145;

FIG. 42D-3: dose response plot of substance L1 against SK-OV-3;

FIGS. 42D-4: dose response profiles of STSP to SK-OV-3;

FIGS. 42D-5: dose response plot of substance G1 against K562;

FIGS. 42D-6: dose response plot of substance G2 against K562;

FIGS. 42D-7: dose response plot of substance L1 against K562;

FIGS. 42D-8: dose response plots of STSP versus K562;

FIGS. 42D-9: dose response plot of substance L2 against K562;

FIGS. 42D-10: dose response plots of STSP versus K562;

FIG. 42E-1: dose response profile of substance G1 to Jurkat Clone E6-1;

FIG. 42E-2: dose response profile of substance L1 to Jurkat Clone E6-1;

FIG. 42E-3: dose response profile of substance L2 to Jurkat Clone E6-1;

FIG. 42E-4: dose response profile of substance G2 to Jurkat Clone E6-1;

FIGS. 42E-5: dose response plot of substance H against Jurkat Clone E6-1;

FIGS. 42E-6: dose response profiles of STSP to Jurkat Clone E6-1;

FIG. 42F-1: dose response profile of substance G2 to AGS;

FIG. 42F-2: dose response profile of substance L1 to AGS;

FIG. 42F-3: dose response profile of substance L2 to AGS;

FIG. 42F-4: dose response profile of substance G1 to AGS;

FIG. 42F-5: dose response profile of substance H to AGS;

FIGS. 42F-6: dose response plots of STSP versus AGS;

FIG. 42G-1: dose response profile of substance H to HL-60;

FIG. 42G-2: dose response plots of STSP versus HL-60;

FIG. 42G-3: dose response profile of substance G2 to HL-60;

FIGS. 42G-4: dose response plot of L1 against HL-60;

FIGS. 42G-5: dose response plot of substance L2 against HL-60;

FIGS. 42G-6: dose response profile of substance G1 to HL-60;

FIG. 42H-1: dose response profile of substance H to SK-NEP-1;

FIG. 42H-2: dose response profiles of STSP to SK-NEP-1;

FIG. 42H-3: the dose response plot of substance G2 for SK-NEP-1;

FIGS. 42H-4: the dose response plot of substance L1 against SK-NEP-1;

FIGS. 42H-5: the dose response plot of substance L2 against SK-NEP-1;

FIGS. 42H-6: the dose response plot of substance G1 for SK-NEP-1;

FIG. 42I-1: dose response profile of substance H versus 95-D;

FIG. 42I-2: dose response profiles of STSP versus 95-D;

FIG. 42I-3: dose response profile of substance G1 versus 95-D;

FIG. 42I-4: dose response profile of substance G2 versus 95-D;

FIGS. 42I-5: a dose response plot of substance L2 versus 95-D;

FIG. 42J-1: dose response profile of substance H to THP-1;

FIG. 42J-2: dose response profiles of STSP versus THP-1;

FIG. 42J-3: dose response profile of substance G2 to THP-1;

FIGS. 42J-4: a dose response plot of substance L1 against THP-1;

FIGS. 42J-5: a dose response plot of substance L2 against THP-1;

FIGS. 42J-6: dose response profile of substance G1 to THP-1;

FIG. 42K-1: dose response profile of substance H to OVCAR-3;

FIG. 42K-2: dose response profiles of STSP to OVCAR-3;

FIG. 42K-3: dose response profile of substance G1 to OVCAR-3;

FIG. 42K-4: dose response profile of substance G2 to OVCAR-3;

FIG. 42K-5: dose response profile of substance L2 to OVCAR-3;

FIG. 43: the detection methodology of the invention verifies the chromatogram of the hollow white solution;

FIG. 44: the chromatogram of the RS solution in the detection methodology verification is adopted;

FIG. 45: the linear plot of diastereomer II in the validation of the detection methodology of the invention;

FIG. 46: the linear graph of diastereomer I in the detection methodology validation of the invention;

FIG. 47: the linear plot of diastereomer H2 in the validation of the detection methodology of the present invention;

FIG. 48: the invention detects the linear graph of related substance H1 in the methodological verification;

FIG. 49: the invention detects the linear graph of the related substance G1 in the methodology validation;

FIG. 50: the invention detects the linear graph of the related substance G2 in the methodology validation;

FIG. 51: the invention detects the linear graph of related substance L1 in the methodological verification;

FIG. 52: the detection methodology of the present invention validates the linear plot of the related substance L2.

Detailed Description

The invention finds and prepares the preparation of new substances related to the quality of lobaplatin and a detection method for controlling the quality of lobaplatin, and particularly provides a detection method for a plurality of related substances of lobaplatin related to the quality of lobaplatin.

In the present invention, any substance affecting the purity of the lobaplatin medicament is collectively referred to as "related substance affecting the lobaplatin mass" or "related substance affecting the mass", abbreviated as "related substance" (also referred to as "related substance" in some cases herein), for example, a peak of related substance affecting the lobaplatin mass, which appears in an XRD diffraction peak for detecting the lobaplatin mass, abbreviated as "related substance peak"; the "related substance" in the present invention is sometimes an "impurity" known to those skilled in the art to affect the purity of the drug, however, the "related substance" in the present invention is not limited to the category of "impurity" but also includes substances having a certain anticancer activity even higher than that of lobaplatin, which belong to the category of materials related to lobaplatin with respect to the active molecule "lobaplatin", and the principles of their anticancer activity or other positive effects and functions in developing new drugs have not been fully studied. The research of the related substances in the invention is an important content of drug development, and comprises the steps of selecting a proper analysis method, accurately distinguishing and measuring the content of impurities and determining the reasonable limit of the impurities by integrating the results of pharmaceutical, toxicological and clinical researches, wherein the research is carried out in the whole process of drug development.

In a preferred embodiment of the present invention, the present invention provides a method for detecting the quality of a lobaplatin bulk drug or preparation, which comprises the step of measuring a related substance affecting the quality of lobaplatin therein, wherein the related substance is any one of the following compounds H1, H2, G1, G2, L1 or L2, or a mixture of any two or more of them:

compound H1:

compound H2:compound G1:compound G2:compound L1:

compound L2:

wherein the detection method is an HPLC method or an HPLC-MS method; the chromatographic column of the HPLC method comprises the following steps: the surface of the silica gel is coated with cellulose-tri (3-chloro-4-methyl phenyl carbamate) as a filling agent; the mobile phase of the HPLC method is n-hexane-ethanol with the volume ratio of 60-70: 30-40, preferably 63-67: 37-33; preferably, the mobile phase is n-hexane-ethanol with a volume ratio of 65:35, and the elution mode is isocratic elution.

Preferably, the flow rate of the HPLC method is 0.8-1.5ml per minute, the detection wavelength is 208-212nm, the column temperature is 30-40 ℃, and isocratic elution is performed for 30-50 min; preferably, the flow rate is 1.0ml per minute, the detection wavelength is 210nm, the column temperature is 35 ℃ and the isocratic elution time is 40 min.

Preferably, wherein the related substance H1, the related substance L1, and the related substance L2 are each not more than 0.5 times the peak area of the main component in the control solution, as calculated by the peak area of the main component self-control method without addition of a correction factor, the total of the related substance G1, the related substance G2, and the related substance H2 should not exceed the peak area of the main component in the control solution.

Preferably, the detection method is characterized in that if a peak of a relevant substance exists in the test sample-lobaplatin solution, the peak is located by identifying a chromatographic peak in a typical chromatogram with the relevant substance: the relative retention time of related substances G1, G2 and H2 is 2.40-2.70, preferably 2.58, and the relative retention time of related substance H1 is 2.00-2.30, preferably 2.16; the relative retention time of compound L1 was 1.2-1.5, preferably 1.35, and the relative retention time of compound L2 was 3.4-3.7, preferably 3.58.

The relative retention time of the material refers to the retention time relative to lobaplatin, specifically relative to lobaplatin diastereomer II. Specifically, as the lobaplatin compound, 2 isomers, lobaplatin diastereomer I and lobaplatin diastereomer II, which are represented by the following structural formulae, are known:

lobaplatin diastereomer I (RRS for short):

lobaplatin diastereomer II (SSS for short):

the preparation of compounds of the present invention, such as the lobaplatin-related substances H1, H2, G1 or G2, L1 or L2, the confirmation of the structure of these novel substances and the antitumor activity of the compounds of these novel substances will be described below by way of examples; the method for detecting related substances in lobaplatin of the present invention will be further described in detail by examples.