A platinum compound for treating cancer and its preparation method

Abstract

The present invention discloses a novel platinum compound represented by formula (I), and their use as a medicament, especially a medicament for treating cancer alone or in combination, and preventing cancer. Experiments have shown that the novel platinum compound of the present invention has a superior in vivo anti-tumor effect, which is significantly better than the clinical drug carboplatin; and the water solubility of the platinum drug is significantly improved, and it can be made into a lyophilized powder or an injection, solving the defect of inconvenient clinical use. In summary, the platinum compound disclosed in the present invention has a good prospect for clinical application.

Description

Technical Field

[0001] The invention relates to a novel platinum anticancer compound and a preparation method thereof, and belongs to the field of chemical pharmacy. Background Art

[0002] Cancer is a disease that seriously threatens human health and life. In 2015, there were 4.3 million new cancer cases and 2.8 million cancer deaths in my country. my country ranks first in the world in terms of cancer incidence and mortality, with about 10,000 people diagnosed with cancer every day, an average of 7 people every minute. Cancer has become one of the medical problems that humans are eager to overcome.

[0003] There are three main methods for treating cancer at present: surgery, radiotherapy and chemotherapy. The basis of chemotherapy is chemotherapy drugs. Countries around the world invest a lot of manpower, material resources and financial resources every year to study anticancer drugs. The application of platinum drugs in clinical cancer treatment originated in 1969, when Rosenberg et al. discovered the promising anticancer activity of the platinum (II) complex cisplatin. Platinum drugs represented by cisplatin, carboplatin and oxaliplatin are widely used as the first choice for treating many tumors due to their strong anticancer activity and wide spectrum of action. According to the latest statistics, 85% of the combined chemotherapy regimens currently used in clinical practice use platinum anti-tumor drugs as the main drug, or platinum anti-tumor drugs are involved in the combination.

[0004] Studies have shown that platinum drugs have the defect of poor water solubility. The water solubility of cisplatin is 1.0 mg / ml, the water solubility of carboplatin is 17.0 mg / ml, and the water solubility of oxaliplatin is 6.0 mg / ml, which has brought many adverse effects on the stability of drug preparations and clinical applications. The low water solubility of platinum drugs also directly affects the accumulation and metabolism of drugs in the body, causing them to accumulate in kidney tissue and blood, and cannot be excreted by the body in time, which can easily lead to cumulative poisoning.

[0005] A large number of clinical trials have confirmed that anti-tumor angiogenesis is crucial in the treatment of cancer and is a key link in the process of inhibiting tumor growth. Tumor angiogenesis is regulated by various protein molecules in the integrin family, such as αvβ3, αvβ6, α5β1, etc. Integrin was first proposed by Richard in 1987. It is a class of heterodimeric transmembrane glycoproteins composed of two subunits, α and β. At present, at least 25 α subunits and 11 β subunits are known, and the two are connected to form more than 20 different integrin molecules. Integrin is an extracellular matrix receptor, among which integrin αvβ3 is highly expressed on the surface of neovascular endothelial cells and tumor cells such as neuroblastoma, osteosarcoma, glioblastoma, breast cancer, and prostate cancer, but not expressed or expressed very low in existing blood vessels and normal tissues; integrin αvβ6 is upregulated in pancreatic cancer, breast cancer, lung cancer, oral and skin squamous cell carcinoma, colon cancer, gastric cancer, and endometrial cancer, and downregulated in normal adults; integrin α5β1 is highly expressed in a variety of tumors such as colorectal cancer, breast cancer, ovarian cancer, lung cancer, gastric cancer, and glioma, but not expressed or expressed at a low level in mature normal cells and blood vessels. The highly restricted expression during tumor growth and metastasis makes integrin a very favorable target for tumor targeted therapy. Summary of the invention

[0006] The present invention discloses a novel platinum compound represented by formula (I), and the use of the platinum compound as a medicament, in particular, a medicament for treating cancer alone or in combination, or preventing cancer.

[0007]

[0008] The present invention discloses a novel platinum compound represented by formula (I). Compared with the anti-tumor platinum compounds in the prior art, the platinum compounds disclosed in the present invention have greatly improved solubility and in vivo tumor inhibition activity, producing unexpected technical effects.

[0009]

[0010] The present invention provides a compound of the following formula (I) or a pharmaceutically acceptable salt thereof:

[0011]

[0012] in:

[0013] R1 and R2 are connected together to form the following structure:

[0014]

[0015] R3 is a group with certain functionality, characterized in that it can effectively enhance the targeting or water solubility of the platinum compound.

[0016] In certain embodiments of the present invention, R1 and R2 are linked together to form moiety (A1), (A2), (A3) or (A4):

[0017]

[0018] In certain embodiments of the present invention, R1 and R2 are connected together to form part (A1), and the general formula of the series of platinum compounds is:

[0019] In certain embodiments of the present invention, R1 and R2 are linked together to form part (A2), and the general formula of the series of platinum compounds is:

[0020] In certain embodiments of the present invention, R1 and R2 are linked together to form part (A3), and the general formula of the series of platinum compounds is:

[0021] In certain embodiments of the present invention, R1 and R2 are linked together to form part (A4), and the general formula of the series of platinum compounds is:

[0022] In certain embodiments of the present invention, R3 is a group having certain functionality, characterized in that it can effectively enhance the targeting or water solubility of the platinum compound;

[0023] R3 is selected from the following structures:

[0024]

[0025] Wherein, X is selected from C or O; R4 is a connecting arm having the function of improving the water solubility of the compound; and R5 is a group having a targeting function.

[0026] In certain embodiments of the present invention, R4 is selected from: C1-12 alkyl, C1-12 alkoxy, C1-12 alkylcarbonyl, phenoxy or phenylamino optionally substituted by 1-2 halogens, C1-12 alkylamino, C1-12 alkoxy-C1-12 alkylamino, C1-12 alkylcarbonyloxy, C1-12 alkyl-C3-8 cycloalkylcarbonyloxy, (C1-4 alkyl-O)m-C1-12 alkylcarbonyloxy, C1-12 alkylcarbonylamino-(C1-4 alkyl-O)m-C1-12 alkylcarbonyloxy, C1-12 alkylcarbonylamino and phenyl-C1-12 alkylcarbonylamino.

[0027] In certain embodiments of the present invention, R4 is selected from the following structures:

[0028]

[0029]

[0030] In certain embodiments of the present invention, R5 is selected from: human serum albumin HAS; antibodies that bind to tumor-associated antigens, such as anti-folate receptor α antibodies, anti-mesothelin antibodies, anti-Her2 antibodies, anti-EGFR antibodies, anti-VEGFR antibodies, anti-CD20 antibodies, anti-CD22 antibodies, anti-CD28 antibodies, anti-CD33 antibodies, and anti-BR96 antibodies; molecules that can specifically bind to integrin receptors on the surface of tumor cells.

[0031] In certain embodiments of the present invention, R5 is selected from molecules that can specifically bind to integrin receptors on the surface of tumor cells, wherein the integrin receptors include but are not limited to αvβ3, αvβ6, and α5β1.

[0032] In certain embodiments of the present invention, R5 is selected from: molecules that can specifically bind to integrins, all of which contain an arginine-glycine-aspartic acid (RGD) tripeptide sequence in chemical structure, preferably but not limited to the following structures:

[0033]

[0034]

[0035] In certain embodiments of the present invention, the general structural formula is shown as any one of the following:

[0036]

[0037]

[0038] In certain embodiments of the present invention, the compound of formula (I) is:

[0039]

[0040]

[0041]

[0042]

[0043]

[0044]

[0045]

[0046]

[0047]

[0048]

[0049]

[0050]

[0051]

[0052] The present invention provides a pharmaceutical composition comprising a compound of formula (I) according to any one of claims 1 to 14 or a pharmaceutically acceptable salt thereof and an acceptable carrier.

[0053] The present invention provides a compound of formula (I) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition for use in the preparation of a drug for preventing and / or treating cancer. The cancer is preferably selected from gastrointestinal cancer, colorectal cancer, colon cancer, liver cancer, hepatocellular carcinoma, pancreatic cancer, biliary tract cancer, gastric cancer, urogenital cancer, bladder cancer, testicular cancer, cervical cancer, malignant mesothelioma, osteogenic sarcoma, esophageal cancer, laryngeal cancer, prostate cancer, hormone-resistant prostate cancer, lung cancer, small cell lung cancer, non-small cell lung cancer, breast cancer, triple-negative breast cancer, breast cancer with BRCA1 and / or BRCA2 gene mutations, blood cancer, leukemia, acute prostatic lymphocytic leukemia, acute myeloid leukemia, The present invention relates to a cancer of the present invention to a type of cancer of the present invention, wherein the present invention is selected from the group consisting of: adenocarcinoma, leukemia, chronic lymphocytic leukemia, chronic myeloid leukemia, lymphoma, Hodgkin's lymphoma, non-Hodgkin's lymphoma, follicular lymphoma, diffuse large B-cell lymphoma, ovarian cancer, brain cancer, neuroblastoma, Ewing's sarcoma, kidney cancer, epidermoid carcinoma, skin cancer, melanoma, head and / or neck cancer, head and neck squamous cell carcinoma and oral cancer, more preferably selected from the group consisting of colorectal cancer, colon cancer, pancreatic cancer, lung cancer, non-small cell lung cancer, ovarian cancer, cervical cancer, melanoma, head and / or neck cancer and head and neck squamous cell carcinoma.

[0054] The present invention provides a use of the above-mentioned compound of formula (I) or its pharmaceutically acceptable salt, or the above-mentioned pharmaceutical composition in the preparation of a drug for preventing and / or treating cancer, wherein the compound of formula (I) or its pharmaceutically acceptable salt, or the above-mentioned pharmaceutical composition is administered in combination with an anticancer drug and / or in combination with radiotherapy and / or immunotherapy.

[0055] Beneficial results

[0056] The present invention discloses a series of novel platinum derivatives of formula I and tests their in vitro water solubility and in vivo tumor inhibition activity. This has led to completely unexpected findings:

[0057] 1) In vitro water solubility experiments show that the water solubility of Examples S47, S72, S80, S95, and S97 disclosed in the present invention is significantly improved compared to listed drugs. In particular, the water solubility of Examples 72 and S80 is nearly 1 times higher than that of listed drug carboplatin; the water solubility of Examples S47, S95, and S97 is more than 3 times higher than that of listed drug oxaliplatin, and can be made into lyophilized powder or aqueous solution dosage forms, solving the adverse effects of low water solubility of platinum drugs in clinical applications.

[0058] 2) The tumor inhibition experiment in mice showed that Examples S47, S70, etc. of the present invention have a more significant ability to inhibit the growth of transplanted tumor S180 than the clinical drug carboplatin, and have a good dose-effect relationship, and have broad anti-tumor application prospects. DETAILED DESCRIPTION

[0059] The embodiments of the present invention will be described in detail below in conjunction with the examples, but those skilled in the art will appreciate that the following examples are only used to illustrate the present invention and should not be considered to limit the scope of the present invention. If no specific conditions are specified in the examples, they are carried out according to normal conditions or the conditions recommended by the manufacturer. If the manufacturer is not specified for the reagents or instruments used, they are all conventional products that can be obtained commercially.

[0060] The structure of the compound was determined by HPLC-MS. The mass spectrum was determined by a waters ZQ2000 mass spectrometer, manufacturer: Waters, model: ZQ2000.

[0061] When using LC-MS for determination, the liquid chromatography instrument model used is Water 2695HPLC Waters2998, detector: UV detector, chromatographic column: YMC pack ODS-AQ 100*4.6mm*5um. The detection conditions of the liquid chromatography are as follows:

[0062] Chromatographic column temperature: 35°C; flow rate: 1 ml / min; detection wavelength: 214 nm; elution gradient: (0 min: 90% (v / v) A, 10% (v / v) B; 10 min: 10% (v / v) A, 90% (v / v) B; 15 min: 10% (v / v) A, 90% (v / v) B; 15.1 min: 90% (v / v) A, 10% (v / v) B; 20 min: 90% (v / v) A, 10% (v / v) B); mobile phase A: 0.1% formic acid; mobile phase B: acetonitrile.

[0063] When using a liquid phase instrument for purification, the instrument used is Dalian Yilite preparative liquid chromatograph, model: P270, detector: UV detector, chromatographic column: C18 reverse phase silica gel 20*250mm. The preparation method of the preparative high performance liquid chromatograph is as follows:

[0064] Chromatographic column temperature: 25°C; detection wavelength: 214nm; elution gradient: (0min: 85% (v / v) A, 15% (v / v) B, flow rate: 25ml / min; 8min: 20% (v / v) A, 80% (v / v) B, flow rate: 25ml / min; 8.01min: 5% (v / v) A, 95% (v / v) B, flow rate: 40ml / min; 10min: 5% (v / v) A, 95% (v / v) B, flow rate: 40ml / min; 10.01min: 50% (v / v) A, 50% (v / v) B, flow rate: 40ml / min; 12min: 50% (v / v) A, 50% (v / v) B, flow rate: 40ml / min); mobile phase A: 0.01% formic acid / H2O; mobile phase B: acetonitrile.

[0065] The reaction was detected by thin layer chromatography (TLC), and the developing system used was dichloromethane:methanol=10:1 (volume ratio).

[0066] The stirrer used was a digital display magnetic stirrer, manufacturer: Dalong Xingchuang Experimental Instruments, model: MS-H280-Pro.

[0067] The general synthesis method of the embodiment is as follows:

[0068]

[0069] A1-A4 and Coupled to generate (i.e., Examples 1, 3, 5, 7, 9, 11, 13, 15, 17, 19, 21, 22, 23, 24, 25, 27, 29, 30, 31, 33, 35, 37, 39, 41, 43, 45, 47, 49, 51, 53, 55, 57, 59, 61, 63);

[0070] A1-A4 and Coupled to generate (i.e., Examples 2, 4, 6, 8, 10, 12, 14, 16, 18, 20, 26, 28, 32, 34, 36, 38, 40, 42, 44, 46, 48, 50, 52, 54, 56, 58, 60, 62, 64);

[0071] Add with R5 to generate (i.e., Examples 65, 67, 69, 70, 71, 72, 77, 78, 79, 80, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95);

[0072] Add with R5 to generate (i.e., Examples 66, 68, 73, 74, 75, 76, 81, 82, 83, 84, 96, 97).

[0073] Taking Example S1 and Example 65 as examples, the specific implementation process is as follows:

[0074]

[0075] 1) In a 50 ml single-necked flask, A1 (177.2 mg, 0.46 mmol) and 2-(aminooxy)-N-(2-(2,5-dioxo-2,5-dihydro-1H-pyrrol-1-yl)ethyl)acetamide (98 mg, 0.46 mmol) were weighed successively, 15 ml of N,N-dimethylformamide was added to dissolve, and then 4A molecular sieves (162 mg) were added. After nitrogen was replaced, the reaction was allowed to react at room temperature overnight, and the reaction solution was dried under reduced pressure. The crude product was purified by silica gel column chromatography to obtain a white solid (169.0 mg, yield 63.3%), i.e. Example S1.

[0076]

[0077] 2) In a 50 ml single-necked flask, Example S1 (151 mg, 0.26 mmol) and R5-1 (117.5 mg, 0.26 mmol) were weighed successively, 15 ml of methanol was added, the nitrogen was replaced, and the reaction was allowed to react at room temperature overnight. The reaction solution was then dried under reduced pressure, purified and separated by semi-preparative HPLC, and freeze-dried using a freeze dryer to obtain a white solid (181.2 mg, yield 65%), i.e., Example S65.

[0078] When A, R4 and R5 are different substituents, the compounds shown in Table 1 below can be obtained, namely Examples S1-S97.

[0079] Table 1 Structure of the embodiment

[0080]

[0081]

[0082]

[0083]

[0084]

[0085]

[0086]

[0087]

[0088]

[0089]

[0090]

[0091]

[0092]

[0093]

[0094]

[0095]

[0096]

[0097]

[0098]

[0099]

[0100]

[0101]

[0102]

[0103]

[0104]

[0105] The mass spectrometry (MS) detection results confirmed compounds S1-S97, and the molecular weights were shown in Table 2, which were consistent with the molecular weights predicted by structural calculations:

[0106] Table 2 Mass spectrometry results of the examples

[0107]

[0108]

[0109]

[0110]

[0111]

[0112] In vitro water solubility test of the examples

[0113] In order to compare the differences in water solubility between the platinum compounds of the present invention and the marketed drugs cisplatin, carboplatin, and oxaliplatin, the solubility in water at room temperature was determined. At room temperature of 25°C, the test sample ground into fine powder was accurately weighed and strongly shaken for 30 seconds every 5 minutes in a certain volume of distilled water; the dissolution of each test sample within 30 minutes was observed, and if there were no visible solute particles, it was considered to be completely dissolved. The experimental results are shown in Table 3 Solubility of the test sample in water.

[0114] Table 3 Solubility of the test samples in water

[0115]

[0116]

[0117] Conclusion: The water solubility of the listed drugs cisplatin and oxaliplatin is poor, both less than 6 mg / ml. Carboplatin has a slightly better solubility, which can reach 16.6 mg / ml in water. The water solubility of Examples S47, S72, S80, S95, and S97S disclosed in the present invention is significantly improved compared to the listed drugs. In particular, the water solubility of Example 72 and Example S80 is nearly 1 times higher than that of carboplatin; the water solubility of Example S47, Example S95, and Example S97 is more than 3 times higher than that of oxaliplatin, and it is easier to prepare lyophilized powder or aqueous solution dosage form, which solves the adverse effects of low water solubility of platinum drugs in clinical application.

[0118] In vivo tumor inhibition experiment of the embodiment

[0119] The experiment tested the inhibitory effects of Example S47 and Example S70 of the present invention on animal transplanted tumor S180.

[0120] Kunming mice, ♀, 22±1g, were purchased from Shanghai Slake Experimental Animal Co., Ltd. Certificate No.: SCXK(Shanghai)2013-0010-02. Rearing environment: SPF grade. Example S47, Example S70 and positive control drug carboplatin were prepared with 5% glucose to the required concentration. Mice were subcutaneously inoculated with S180 sarcoma cells, and medication was started the next day after inoculation. The dosage and regimen are shown in Table 4. The mice were killed on the eighth day, the tumors were weighed, and the tumor inhibition rate was calculated.

[0121] Tumor inhibition rate = (tumor weight of control group - tumor weight of treatment group) / tumor weight of control group × 100

[0122] Table 4. Efficacy of Example S47, Example S70 and Carboplatin on S180 sarcoma in mice

[0123]

[0124]

[0125] *P<0.01 compared with the control group

[0126] Conclusion: Example S47 and Example S70 have a significant inhibitory effect on the growth of mouse S180 sarcoma. The inhibitory effects at equimolar concentrations are significantly better than that of carboplatin, an anticancer drug widely used in the clinic, and have a good dose-effect relationship, and have good clinical application prospects.

Claims

1. A compound of the following formula (I-A1), (I-A2), (I-A3) or (I-A4) or a pharmaceutically acceptable salt thereof, in: R3 is selected from the following structures: Wherein, X is selected from CH2 or O; R4 is a C1-12 alkylene-carbonylamino group; wherein the amino group is connected to the N of "C=N" in formula (I-A1), (I-A2), (I-A3) or (I-A4); R5 is selected from the group consisting of: human serum albumin HAS, anti-folate receptor α antibody, anti-mesothelin antibody, anti-Her2 antibody, anti-EGFR antibody, anti-VEGFR antibody, anti-CD20 antibody, anti-CD22 antibody, anti-CD28 antibody, anti-CD33 antibody and anti-BR96 antibody.

2. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, characterized in that The general formula of platinum compounds is:

3. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, characterized in that: The general formula of platinum compounds is:

4. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, characterized in that: The general formula of platinum compounds is:

5. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, characterized in that: The general formula of platinum compounds is:

6. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, characterized in that: R4 is selected from the following structures:

7. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, characterized in that: R5 is selected from a molecule that specifically binds to an integrin receptor on the surface of a tumor cell, wherein the integrin receptor is αvβ3, αvβ6 or α5β1.

8. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein R5 is selected from: a molecule that specifically binds to integrin and contains an arginine-glycine-aspartic acid (RGD) tripeptide sequence in chemical structure.

9. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein The general structural formula is shown in any of the following: wherein R4 and R5 are as described in claim 1; 10. The following compound or a pharmaceutically acceptable salt thereof:

11. A pharmaceutical composition comprising the compound according to any one of claims 1 to 10 or a pharmaceutically acceptable salt thereof and an acceptable carrier.

12. Use of the compound according to any one of claims 1 to 10 or a pharmaceutically acceptable salt thereof or the pharmaceutical composition according to claim 11 in the preparation of a drug for treating cancer.

13. The use according to claim 12, characterized in that The cancer is selected from the group consisting of gastrointestinal cancer, liver cancer, pancreatic cancer, biliary tract cancer, genitourinary cancer, malignant mesothelioma, osteogenic sarcoma, esophageal cancer, laryngeal cancer, lung cancer, breast cancer, blood cancer, brain cancer, Ewing's sarcoma, kidney cancer, skin cancer, and head and / or neck cancer.

14. The use according to claim 12, characterized in that The cancer is selected from prostate cancer and ovarian cancer.

15. The use according to claim 12, characterized in that The cancer is selected from the group consisting of colorectal cancer, hepatocellular carcinoma, gastric cancer, bladder cancer, testicular cancer, cervical cancer, hormone-resistant prostate cancer, small cell lung cancer, non-small cell lung cancer, triple-negative breast cancer, breast cancer with BRCA1 and / or BRCA2 gene mutations, leukemia, lymphoma, neuroblastoma, epidermoid carcinoma, melanoma, head and neck squamous cell carcinoma, and oral cancer.

16. The use according to claim 12, characterized in that The cancer is selected from the group consisting of colon cancer, acute lymphoblastic leukemia, acute myeloid leukemia, chronic lymphocytic leukemia, chronic myeloid leukemia, Hodgkin's lymphoma and non-Hodgkin's lymphoma.

17. The use according to claim 12, characterized in that The cancer is selected from the group consisting of follicular lymphoma and diffuse large B-cell lymphoma.

18. The use according to claim 12, wherein the cancer is selected from colorectal cancer, pancreatic cancer, lung cancer, ovarian cancer, cervical cancer, melanoma and head and / or neck cancer.

19. The use according to claim 12, wherein the cancer is selected from colon cancer, non-small cell lung cancer and head and neck squamous cell carcinoma.

20. Use of a compound according to any one of claims 1 to 10 or a pharmaceutically acceptable salt thereof or a pharmaceutical composition according to claim 11 in the preparation of a medicament for treating cancer, wherein the compound according to any one of claims 1 to 10 or a pharmaceutically acceptable salt thereof or a pharmaceutical composition according to claim 11 is administered in combination with an anticancer drug and / or in combination with radiotherapy and / or immunotherapy.

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