Ferrocene derivatives, processes for their preparation and uses thereof

Abstract

The application discloses a ferrocene derivative, a preparation method and application thereof. The ferrocene derivative is shown in formula (I), wherein Z is selected from O, NH or S; R1 is selected from hydrogen, methyl or halogen; R2 is selected from hydrogen, halogen, C1-C6 alkyl, C1-C6 alkoxy, halogenated C1-C6 alkyl, halogenated C1-C6 alkoxy or nitro; n is an integer of 0-5, and R2 can be the same or different. The compound has antitumor activity and can be used as a candidate drug or a leading compound for treating tumors, cancers and the like.

Description

[0001] This application is a divisional application of the invention patent application with the application number 202110206235.6 and the application name "Ferrocene Derivatives and Preparation Methods and Uses Thereof" filed on February 24, 2021. TECHNICAL FIELD

[0002] The present application belongs to the field of compounds, and particularly relates to a ferrocene derivative and a preparation method and uses thereof. BACKGROUND

[0003] Cancer has become the most important lethal disease worldwide. Cancer can occur in various organs and tissues at any age, and the main cancer types leading to death include lung cancer, gastric cancer, liver cancer, colon cancer, breast cancer, etc. Although some small molecule anticancer drugs have been used in clinical, some compounds are in preclinical research. Most cancer patients are in the middle to late stage when they find the disease, and the overall effect of clinical treatment is poor, especially the continuous emergence of multi-drug resistance, which makes the treatment of cancer very difficult. Therefore, it is urgent to develop new anticancer drugs with high activity and low side effects to meet the clinical needs.

[0004] Ferrocene is a compound with unique sandwich structure, in which divalent iron ion is sandwiched between two planar rings in a staggered conformation. Ferrocene and its derivatives have their own characteristics: (1) aromaticity, substitution reaction can occur, easy to modify; (2) lipophilicity, can interact with various enzymes in cells through cell membranes; (3) low toxicity, can be metabolized in vivo. Ferrocene derivatives show a wide range of pharmacological activity in the field of medicine, especially in the field of anti-tumor pharmacological activity is particularly prominent: A. Rosenefeld et al. study showed that ferrocene modified cisplatin derivatives have strong inhibitory activity on leukemia, and its renal toxicity is much lower than that of cis-DDP (A. Rosenfeld, et al. Inorg. Chim. Acta. 1992, 201:219); E. W. Neuse et al. study showed that ferrocene derivatives have unique anti-tumor, anticancer activity (E. W. Neuse. J. Inorga. Organomet. Polymers and Materials. 2005, 15(1):3-32); X. F. Huang et al. synthesized a series of ferrocene derivatives containing pyrazole ring, activity research showed that some compounds have stronger anticancer activity than 5-fluorouracil (X. F. Huang, et al. J. Organomet. Chem. 2012, 706-707:113-123); W. Liu et al. synthesized a series of ferrocene urea derivatives, activity research showed that some compounds have strong inhibitory activity on HIV-1 protease (W. Liu, et al. Appl. Organomet. Chem. 2012, 26:189-193); U.S. patent document 8426462B2 discloses that ferrocene derivatives containing aromatic ring have strong inhibitory activity on human breast cancer cell line MDA-MB-231 and prostate cancer cell line PC-3.

[0005] Ferrocene is a leading compound designed and synthesized as an anti-tumor drug (E.W. Neuse. J. Inorg. Organoment. P. 2005, 15(1): 3-32; S.S. Braga, et al. Organometallics, 2013, 32: 5626-5639). Isoxazole heterocycle is a potential bioactive pharmacophore, which is usually introduced into drug molecules to improve activity. In the applicant's previous research, isoxazole heterocycle was introduced into the ferrocene mother nucleus, and a series of novel isoxazole heterocycle-containing ferrocene derivatives were synthesized, and the preliminary in vitro inhibitory activities of lung cancer cell line A549, colon cancer cell line HCT-116 and breast cancer cell line MCF-7 were studied. The results showed that most of the compounds had strong inhibitory activity on A549, HCT116 and MCF-7 cell lines (Yong Jianping, et al. Application Publication No. CN103601762A). Based on the good research foundation in the previous stage, in order to enrich the types of such compounds, the applicant continues to design and synthesize such isoxazole heterocycle-containing ferrocene derivatives, in order to discover new anticancer lead compounds or candidate compounds. SUMMARY

[0006] The present application provides a ferrocene derivative represented by formula (I), or a pharmaceutically acceptable salt thereof, or a solvate thereof:

[0007]

[0008] wherein: Z is selected from NH, O or S;

[0009] R1 is selected from hydrogen, C1-C6 alkyl, halogen;

[0010] R2 is independently selected from hydrogen, halogen, C1-C6 alkyl, C1-C6 alkoxy, halogenated C1-C6 alkoxy, halogenated C1-C6 alkyl or nitro;

[0011] n is an integer from 0 to 5, and when n is greater than 1, R2 can be the same or different groups.

[0012] According to an embodiment of the present application, R1 is selected from hydrogen, methyl, chlorine, fluorine.

[0013] According to an embodiment of the present application, R2 is independently selected from at least one of the following groups: hydrogen, fluorine, chlorine, bromine, methyl, ethyl, methoxy, trifluoromethyl, tert-butyl, cyano and nitro,

[0014] According to an embodiment of the present application, n is 1, 2 or 3.

[0015] According to an embodiment of the present application, the term "C1-C6 alkyl" can be selected from alkyl groups having a carbon number of 1, 2, 3, 4, 5, or 6, and the C1-C6 alkyl moieties in the remaining terms (e.g., C1-C6 alkoxy) are defined the same.

[0016] According to an embodiment of the present application, the ferrocene derivative of formula (I) is any one of the following compounds:

[0017]

[0018]

[0019]

[0020]

[0021]

[0022]

[0023]

[0024]

[0025]

[0026]

[0027] According to an embodiment of the present application, the pharmaceutically acceptable salt of the ferrocene derivative of formula (I) can be a pharmaceutically acceptable salt formed by the compound of formula (I) with a pharmaceutically acceptable acid or a pharmaceutically acceptable cation. The pharmaceutically acceptable salt includes, but is not limited to, a salt formed with an inorganic acid, such as a hydrochloride, a phosphate, a diphosphate, a hydrobromide, a sulfate, a sulfinate, a nitrate, and the like; a salt formed with an organic acid, such as a lactate, an oxalate, a malate, a maleate, a fumarate, a tartrate, a succinate, a citrate, a lactate, a sulfonate, a p-toluenesulfonate, a 2-hydroxyethylsulfonate, a benzoate, a salicylate, a stearate, a trifluoroacetic acid, or an amino acid and an alkanoic acid salt (such as an acetate, HOOC-(CH2)n-COOH (where n is an integer of 1-4)), and the like; and a salt formed with a pharmaceutically acceptable cation, including but not limited to sodium, potassium, calcium, aluminum, lithium, and ammonium.

[0028] According to an embodiment of the present application, the solvate includes a hydrate and an alcoholate.

[0029] The present application also provides a method for preparing the ferrocene derivative of formula (I) as described above, which comprises the following steps:

[0030] (1) the reaction of ferrocene acetylene with a compound of formula A to obtain an intermediate B containing ferrocene;

[0031] The compound of formula A is 3-(R1)-4-bromobenzoic acid, and its structural formula is:

[0032] The structural formula of the compound of formula B is:

[0033] wherein R1 has the selection as described above;

[0034] (2) the reaction of the intermediate B with a compound of formula C to obtain a ferrocene derivative of formula (I);

[0035] The structural formula of the compound C is: wherein R2 and n have the selection as described above, and Z' represents NH2, OH or SH;

[0036] Preferably, the compound of formula C is 3-substituted phenyl-5-hydroxymethyl- isoxazole (II), 3-substituted phenyl-5-mercaptomethyl-isoxazole or 3-substituted phenyl-5- aminomethyl-isoxazole (III).

[0037] According to an embodiment of the present application, the reaction of step (1) is carried out in the presence of a palladium (II) compound, an organic phosphorus and a copper (I) compound. For example, the palladium (II) compound can be selected from the palladium (II) compounds known in the art, such as dichlorobis(triphenylphosphine)palladium, tetrakis(triphenylphosphine)palladium and / or diphenylphosphinoferrocene dichloropalladium; for example, the organic phosphorus can be selected from the organic phosphorus known in the art, such as triphenylphosphine; for example, the copper (I) compound can be selected from the copper (I) compounds known in the art, such as cuprous iodide.

[0038] According to an embodiment of the present application, the reactions of step (1) and step (2) are both carried out in a dry organic solvent. For example, the dry organic solvent can be selected from aromatic hydrocarbons, halogenated hydrocarbons, tetrahydrofuran (THF), dimethylsulfoxide (DMSO), dioxane, acetonitrile, pyridine, DMF or ionic liquids; preferably from tetrahydrofuran, chloroform, 1,2-dichloromethane, benzene, toluene, xylene, acetonitrile, pyridine, DMF or ionic liquids; more preferably tetrahydrofuran.

[0039] According to an embodiment of the present application, the reaction system of step (1) further comprises a basic acid-binding agent. Preferably, the basic acid-binding agent is selected from one, two or more of an organic base and / or an inorganic base. For example, the organic base is selected from one, two or more of triethylamine, tripropylamine, DMAP, DMF, N-methylmorpholine, and the like; for example, the inorganic base is selected from one, two or more of potassium carbonate, sodium hydride, sodium carbonate, and the like. More preferably, the basic acid-binding agent is triethylamine.

[0040] According to an embodiment of the present application, the molar volume ratio of the mixture of ferrocene acetylene, dry organic solvent and basic acid-binding agent in step (1) is (0.5-5) mmol: 6 mL, for example, 0.952 mmol: 6 mL.

[0041] According to an embodiment of the present application, step (1) comprises the following process: ferrocene acetylene and a compound of formula A are dispersed in a mixture of dry organic solvent and basic acid-binding agent, a palladium (II) compound, an organic phosphorus and a copper (I) compound are added to the mixture under stirring, the stirring is continued, then the reaction is refluxed, the reaction solution is filtered, and the filtrate is concentrated to obtain the intermediate B.

[0042] According to an embodiment of the present application, the reactions in steps (1) and (2) are both carried out under the protection of an inert atmosphere, for example, the inert atmosphere is nitrogen.

[0043] According to an embodiment of the present application, the reaction in step (2) is carried out in a dry organic solvent. The organic solvent has the selection as shown above.

[0044] According to an embodiment of the present application, the reaction in step (2) is carried out in the presence of a condensing agent. For example, the condensing agent can be selected from one, two or more of DCC, DMAP, NMM, HOBt, HATU; for example, the condensing agent can be selected from a combination of DCC and DMAP, a combination of DCC, HOBt and DMAP, a combination of DCC, HOBt and NMM, a combination of DCC and NMM, or a combination of DCC and HATU.

[0045] According to an embodiment of the present application, the 3-substituted phenyl-5- hydroxymethyl-isoxazole (II) or 3-substituted phenyl-5-aminomethyl-isoxazole (III) in step (2) is a known compound, which can be prepared according to the process optimized in the Chinese patent document CN103360382A. Specifically, the preparation route is as shown below:

[0046]

[0047] When Z' is SH, compound C is a 3-substituted phenyl-5-mercaptomethyl-isoxazole, which is prepared by using propargyl mercaptan as a starting material, and following the procedure for the synthesis of compound (II) to obtain a 3-substituted phenyl-5-mercaptomethyl-isoxazole.

[0048] According to an embodiment of the present application, the reaction in step (1) or step (2) is carried out at any temperature point in the range of -20 °C to refluxing condition, preferably any temperature point in the range of 0 °C to refluxing condition, and more preferably any temperature point in the range of room temperature to refluxing temperature.

[0049] According to an embodiment of the present application, step (2) comprises the following procedure: adding the intermediate B into a dry organic solvent, then adding a condensing agent into the solution, and then adding the compound of formula C into the solution to obtain the ferrocene derivative of formula (I). Preferably, the time for adding the condensing agent is 20-40 min, for example 30 min.

[0050] Preferably, the time for adding the compound of formula C is 20-40 min, for example 30 min.

[0051] Preferably, the synthetic route of the compound of formula (I) is as follows:

[0052]

[0053] If desired, any functional group in the compound of formula C can be protected;

[0054] and thereafter, if necessary (in any order):

[0055] (a) removing any protecting groups, and

[0056] (b) forming a pharmaceutical composition of the compound of formula (I).

[0057] The present application also provides a pharmaceutical composition comprising the ferrocene derivative of formula (I), or a pharmaceutically acceptable salt thereof, or a solvate thereof.

[0058] According to an embodiment of the present application, the pharmaceutical composition further comprises at least one pharmaceutically acceptable pharmaceutical adjuvant; for example, the at least one pharmaceutically acceptable, inert, non-toxic pharmaceutical adjuvant can be selected from excipients, carriers and / or diluents. The pharmaceutically acceptable pharmaceutical adjuvant refers to an inert, non-toxic pharmaceutical adjuvant.

[0059] According to an embodiment of the present application, the pharmaceutical adjuvant can be further selected from one or more of the following: a filler, a disintegrant, a lubricant, a glidant, an effervescent agent, a flavoring agent, a preservative, and a pharmaceutically acceptable coating material.

[0060] The present application also provides a pharmaceutical preparation comprising the ferrocene derivative as shown in formula (I), or a pharmaceutically acceptable salt thereof, or a solvate thereof.

[0061] According to an embodiment of the present application, the pharmaceutical preparation contains the above pharmaceutical composition.

[0062] According to an embodiment of the present application, the pharmaceutical preparation is a solid oral preparation, a liquid oral preparation, or an injection.

[0063] Preferably, the preparation is selected from a tablet, a dispersible tablet, an enteric-coated tablet, a chewable tablet, an oral disintegrating tablet, a capsule, a granule, an oral solution, an aqueous injection, a freeze-dried powder injection, a large volume infusion, or a small volume infusion.

[0064] The present application also provides the ferrocene derivative as shown in formula (I) or a pharmaceutically acceptable salt thereof of claims 1-3 for use as a medicament, in particular, a medicament or a lead compound effective for treating a tumor / cancer.

[0065] The present application also provides the use of the ferrocene derivative as shown in formula (I), a pharmaceutically acceptable salt thereof, a solvate thereof, or the pharmaceutical composition in the preparation of an anti-tumor or anti-cancer medicament.

[0066] The present application also provides the use of the ferrocene derivative as shown in formula (I), a pharmaceutically acceptable salt thereof, or a solvate thereof as a lead compound for treating a tumor / cancer.

[0067] Preferably, the tumor or cancer is selected from at least one of bladder cancer, ovarian cancer, breast cancer, gastric cancer, esophageal cancer, lung cancer, head and neck cancer, colon cancer, pharyngeal cancer, and pancreatic cancer; preferably, the lung cancer is non-small cell lung cancer; more preferably, the tumor or cancer is non-small cell lung cancer, gastric cancer, breast cancer, and / or cervical cancer.

[0068] The present application also provides a method for preventing and / or treating a disease related to the above tumor / cancer, comprising administering an effective amount of the ferrocene derivative as shown in formula (I), a pharmaceutically acceptable salt thereof, a solvate thereof, the pharmaceutical composition, or the pharmaceutical preparation to a patient in need, such as a human.

[0069] The term "effective amount" means an amount of the at least one compound and / or at least one pharmaceutically acceptable salt effective to "treat" a disease or condition in an individual. In the case of cancer, the effective amount is the amount that reduces the number of cancer or tumor cells; reduces tumor size; inhibits or arrests the invasion of organ(s) by tumor cells, e.g., tumor metastasis into soft tissue or bone; inhibits or arrests tumor growth; relieves to some extent one or more of the symptoms associated with the cancer; reduces morbidity and mortality; improves quality of life; or a combination of such effects. The effective amount can be the amount that reduces the symptoms of the disease by inhibiting EGFR activity. For cancer treatment, the effects of the in vivo experiment can be measured by assessing, e.g., survival, time to disease progression (TTP), response rates (RR), duration of response, and / or quality of life. Those skilled in the art will appreciate that the effective amount can vary depending on the route of administration, dosage form, and co-administration with other drugs.

[0070] The term "effective amount" also means an amount of the at least one compound and / or at least one pharmaceutically acceptable salt effective to inhibit overexpression and / or overactivity of EGFR.

[0071] Advantages of the present application:

[0072] The present application provides novel ferrocene derivatives as shown in formula (I). The ferrocene derivatives have good inhibitory effect on tumors or cancers. According to the results of in vitro studies on human lung cancer cell line (A549), breast cancer cell line (MCF-7) and cervical cancer cell line (Hela), the compounds have strong inhibitory activity on human lung cancer cell line (A549), breast cancer cell line (MCF-7) and cervical cancer cell line (Hela). The compounds can be used as candidate compounds or lead compounds for anticancer drugs. DETAILED DESCRIPTION

[0073] The present application is further illustrated by the following examples. It should be understood that these examples do not limit the scope of the present application, and any improvement made on the basis of the present application does not deviate from the spirit of the present application.

[0074] The synthesis processes of the intermediates and target compounds are illustrated by representative compounds in the examples, and the synthesis processes of the remaining intermediates and target compounds are the same as those of the representative compounds.

[0075] Instruments and reagents:

[0076] AVANCE III NMR spectrometer (400 MHz, DMSO-d6, TMS as internal standard), ion trap liquid chromatography-mass spectrometer (DECA X-30000 LCQ Deca XP), Shimadzu FTIR-8400S (manufactured by Shimadzu Corporation, Japan), XT5 digital display micro melting point tester (manufacted by Beijing Keyi Optoelectronic Instrument Factory), and tunable wavelength microplate reader (Molecular Devices SPECTRAMAX 190).

[0077] Synthesis of intermediates 3-substituted phenyl-5-hydroxymethyl-isoxazole (II) and 3-substituted phenyl-5-aminomethyl-isoxazole (III)

[0078] The substituted benzaldehyde is used as raw material to prepare (R2 is selected from hydrogen, halogen, C1-C6 alkyl, C1-C6 alkoxy, halogenated C1-C6 alkyl, or nitro; and n is an integer from 0 to 5) through synthesis of oxime, 1,3-dipolar cycloaddition reaction, mesyl esterification reaction, azidation, and reduction reaction, as shown in the following route:

[0079]

[0080] The specific synthesis process of intermediates 3-substituted phenyl-5-hydroxymethyl-isoxazole (II) and 3-substituted phenyl-5-aminomethyl-isoxazole (III) is shown in the previous application of the applicant with publication numbers CN103360382A, CN103664991A, and CN103601762A.

[0081] Synthesis process of intermediate B containing ferrocene ring (taking the synthesis of ferrocene acetylene and 4-bromobenzoic acid as an example):

[0082]

[0083] 2.00 g (9.52 mmol) of ferrocene acetylene and 1.91 g (9.52 mmol) of 4-bromobenzoic acid were added into a 250 mL two-necked round-bottom flask, followed by adding 60 mL of dry tetrahydrofuran and triethylamine. The reaction was stirred at room temperature for 10 minutes under nitrogen protection, followed by adding 0.2 g (0.76 mmol) of triphenylphosphine, 0.28 g (0.38 mmol) of dichlorobis(triphenylphosphine)palladium, and 0.07 g (0.38 mmol) of cuprous iodide into the reaction system. The reaction system was stirred at room temperature for 20 minutes, and then refluxed. The whole reaction was carried out under nitrogen protection. After the reaction was completed as detected by TLC, the reaction mixture was filtered, and the filtrate was concentrated to obtain a crude product. The crude product was column separated (V 石油醚 :V 乙酸乙酯= 5:1~1:1) to obtain pure 4-ferrocenylethynyl-benzoic acid, 2.53 g, yield: 81%, dark yellow solid. The purity of 4-ferrocenylethynyl-benzoic acid was 99.5% (HPLC). 1 H NMR (400 MHz, DMSO-d6): 4.29 (s, 5H, η 5 -C5H5), 4.38 (2H, t, J = 2.0 Hz), 4.61 (2H, t, J = 2.0 Hz), 7.58 (2H, d, J = 9.2 Hz), 7.90 (2H, d, J = 9.2 Hz), 12.83 (1H, brs, -COOH).

[0084] Changing R1, 3-(R1)-4-bromobenzoic acid is prepared by the reaction process of ferrocene acetylene and 4-bromobenzoic acid.

[0085] Example 3 Synthesis process of ester target compound (YJP-1) shown in formula (I)

[0086]

[0087] 0.165 g (0.5 mmol) of 4-ferrocenylethynyl-benzoic acid prepared in Example 2 and 8 mL of dry THF were added to a 50 mL single-necked round-bottom flask, and 0.103 g (0.5 mmol) of DCC and 0.061 g (0.5 mmol) of DMAP were added to the reaction system under stirring. After reaction at 0°C for 30 min, 0.088 g (0.5 mmol) of 3-phenyl-5-hydroxymethyl-isoxazole was added to the reaction system, and the reaction was allowed to proceed at 0°C for 30 min and then at room temperature. The entire reaction process was carried out under nitrogen protection. After the completion of the reaction was detected by TLC, the reaction solution was concentrated under reduced pressure, and the residue was column separated with V (石油醚) :V (乙酸乙酯) = 5:1~2:1) to obtain the target compound (YJP-1).

[0088] The remaining compounds YJP-2 to YJP-76 were synthesized according to the synthesis process of the target compound YJP-1.

[0089] Example 4 Synthesis process of amide target compound (YJP-77) shown in formula (I)

[0090]

[0091] Into a 50 mL single-necked round-bottomed flask, 0.165 g (0.5 mmol) of 4-ferrocenyl-benzoic acid prepared in Example 2 and 8 mL of dry THF were added, and 0.103 g (0.5 mmol) of DCC, 0.068 g (0.5 mmol) of HOBT and 0.061 g (0.5 mmol) of DMAP were added to the reaction system under stirring. After reaction at 0°C for 30 min, 0.087 g (0.5 mmol) of 3-phenyl-5-aminomethyl-isoxazole was added to the reaction system, and the reaction was allowed to proceed at 0°C for 30 min and then at room temperature. The entire reaction was carried out under nitrogen protection. After completion of the reaction as detected by TLC, the reaction solution was concentrated under reduced pressure, and the residue was column separated (V (石油醚) :V (乙酸乙酯) = 5:1~2:1) to obtain the target compound (YJP-77).

[0092] The remaining YJP-78 to YJP-152 compounds were synthesized according to the synthesis procedure of the target compound YJP-77.

[0093]

[0094]

[0095]

[0096]

[0097]

[0098]

[0099]

[0100]

[0101]

[0102]

[0103]

[0104] The structures of the compounds YJP-1 to YJP-152 were characterized by 1 H NMR analysis method. The numbers of the compounds YJP-1 to YJP-152 and the NMR characterization results are shown in Table 1:

[0105]

[0106] Table 1. The numbers of the compounds represented by Formula I 1 H NMR

[0107]

[0108]

[0109]

[0110]

[0111]

[0112]

[0113]

[0114]

[0115]

[0116]

[0117]

[0118]

[0119]

[0120]

[0121]

[0122]

[0123]

[0124]

[0125]

[0126] Example 5 Test of in vitro anti-tumor activity

[0127] The compounds in the above examples were tested for in vitro anti-tumor activity using the CCK-8 method. The in vitro inhibitory activity of the compounds on breast cancer cell lines (MCF-7), lung adenocarcinoma cell lines (A549) and cervical cancer cell lines (Hela) was mainly studied. Breast cancer cell lines (MCF-7), lung adenocarcinoma cell lines (A549) and cervical cancer cell lines (Hela) were obtained from the cell lines preserved by Ningxia Medical University. The specific testing process is described taking the testing process of breast cancer MCF-7 cell lines as an example:

[0128] (1) The culture of breast cancer cell line (MCF-7) and the process of testing the inhibitory activity

[0129] The breast cancer cell line MCF-7 was cultured in a 37℃, saturated humidity, 5% CO2 incubator for 24 hours. When the cells were in the logarithmic growth phase, the upper culture solution was aspirated and digested with 0.25% trypsin-EDTA solution, and then the digestion was terminated with high-glucose culture medium. The cells were inoculated in a 96-well plate to make the cell density 5000 cells per well. The 96-well plate was placed in the incubator for 24 hours. Then the cell culture solution in the 96-well plate was aspirated. 100 μL of high-glucose culture medium was added to the 96-well plate, and then 1 μL of the test sample of different concentrations was added to each well (5 replicate wells for each concentration). Then the 96-well plate was placed in a 37℃, saturated humidity, 5% CO2 incubator for continuous culture for 48 hours. Then 10 μL of CCK8 was added to each well, and the plate was incubated in a 37℃ incubator for 1-4 hours. The absorbance value of each well at 450 nm wavelength was measured on a multifunctional enzyme label instrument. The inhibition rate % = [(OD 对照细胞 -OD 加药细胞 ) / (OD 对照细胞 -OD 空白 )] x 100. The negative control was a mixture solution of V 高糖培养基 / V DMSO : 10:1.

[0130] (2) The culture of lung cancer cell line (A549) and cervical cancer cell line (Hela) and the process of testing the inhibitory activity

[0131] The process of inhibiting lung cancer cell line A549 and cervical cancer cell line (Hela) was the same as the screening process of breast cancer cell line (MCF-7).

[0132] The activity results of preferred compounds on breast cancer cell line MCF-7, human lung cancer cell line A549, and cervical cancer cell line Hela are shown in Tables 2, 3, and 4, respectively.

[0133] Table 2. The activity test results of some example compounds of formula (I) on inhibiting breast cancer cell line MCF-7

[0134]

[0135]

[0136] Table 3. The activity test results of some example compounds of formula (I) on inhibiting human lung cancer cell line A549

[0137] Compound No. Concentration (μM) Inhibition rate (%) YJP-14 16.22 57.00 YJP-17 12.43 60.42 YJP-18 11.35 79.29

[0138] Table 4. Test results of inhibiting Hela activity of some example compounds of formula (I)

[0139] Compound No. Concentration (μM) Inhibition rate (%) YJP-4 10.68 60.10 YJP-13 9.91 74.80 YJP-14 16.22 68.26 YJP-17 12.43 57.62 YJP-18 11.35 63.99 YJP-19 10.53 88.94

[0140] The above describes the embodiments of the present application. However, the present application is not limited to the above-described embodiments. Any modification, equivalent replacement, improvement, etc. made within the spirit and principle of the present application should be included in the protection scope of the present application.

Claims

1. A ferrocene derivative of formula (I) or a pharmaceutically acceptable salt thereof: (I) wherein: Z is selected from O, S, or NH. R1 is selected from hydrogen. R2 is independently selected from halogens, C1-C6 alkyl groups, and halogenated C1-C6 alkyl groups. n is 1.

2. The ferrocene derivative represented by Formula (I) or a pharmaceutically acceptable salt thereof according to claim 1, characterized by R2 is selected from fluorinated C1~C6 alkyl groups.

3. A ferrocene derivative or a pharmaceutically acceptable salt thereof, characterized by, The ferrocene derivative is any one of the following compounds: 。 4. The ferrocene derivative represented by Formula (I) or a pharmaceutically acceptable salt thereof according to claim 1, characterized by The pharmaceutically acceptable salt of the ferrocene derivative shown in formula (I) is formed by the combination of the compound of formula (I) and a pharmaceutically acceptable acid.

5. The method for preparing the ferrocene derivative shown in formula (I) according to claim 1, characterized in that, The method includes the following steps: (1) Ferrocene acetylene reacts with compound A to give intermediate B containing ferrocene; The compound of Formula A is 3-(R1)-4-bromobenzoic acid, which has the structural formula: ; The structural formula of the compound of formula B is: ; Wherein, R1 is hydrogen; (2) The intermediate B reacts with compound C to obtain the ferrocene derivative shown in formula (I); The structural formula of the compound C is: ; R2 is independently selected from halogens, C1-C6 alkyl groups, and halogenated C1-C6 alkyl groups, n is 1, and Z' represents NH2, OH, or SH.

6. The preparation method according to claim 5, characterized in that, The compound of formula C is 3-substituted phenyl-5-hydroxymethyl isoxazole (II), 3-substituted phenyl-5-mercaptomethyl isoxazole or 3-substituted phenyl-5-aminomethyl isoxazole (III); The reaction described in step (1) is carried out in the presence of a palladium(II) compound, an organophosphorus compound, and a copper(I) compound; The reactions described in steps (1) and (2) are both carried out in a dry organic solvent.

7. The preparation method according to claim 5, characterized in that, The reaction system in step (1) also contains an alkaline acid-binding agent, wherein the alkaline acid-binding agent is selected from organic bases and / or inorganic bases, wherein the organic base is selected from one, two or more of triethylamine, tripropylamine, DMAP, and N-methylmorpholine; and the inorganic base is selected from one, two or more of potassium carbonate, sodium hydride, and sodium carbonate.

8. The preparation method according to claim 5, characterized in that, Step (1) includes the following process: ferrocene acetylene and compound A are dispersed in a mixture of dry organic solvent and alkaline acid-binding agent. Palladium (II) compound, organophosphorus compound and copper (I) compound are added to the mixture under stirring. Stirring is continued, and then the reaction is refluxed. The reaction solution is filtered and the filtrate is concentrated to obtain intermediate B.

9. The preparation method according to claim 5, characterized in that, The reactions described in steps (1) and (2) are carried out under an inert atmosphere.

10. The method of claim 5, wherein, The reaction described in step (2) is carried out in the presence of a condensing agent selected from one, two or more of DCC, DMAP, NMM, HOBt, and HATU.

11. The method of claim 5, wherein, Step (2) includes the following process: adding the intermediate B to a dry organic solvent, then adding a condensing agent to react, and then adding the compound of formula C to react, to obtain the ferrocene derivative shown in formula (I); Optionally, any functional group in the compound of formula C is protected; optionally, the preparation method includes removing any protecting agent.

12. A pharmaceutical composition comprising a ferrocene derivative of formula (I) as described in any one of claims 1-4, or a pharmaceutically acceptable salt thereof.

13. A pharmaceutical preparation comprising a ferrocene derivative of formula (I) as described in any one of claims 1-4, or a pharmaceutically acceptable salt thereof.

14. The pharmaceutical preparation according to claim 13, characterized in that The pharmaceutical preparation is a solid oral preparation, a liquid oral preparation, or an injection.

15. Use of the ferrocene derivative of formula (I) as claimed in claim 1, a pharmaceutically acceptable salt thereof or the pharmaceutical composition as claimed in claim 12 for the manufacture of an anti-tumour or anticancer medicament. The tumour or cancer is selected from at least one of breast cancer, lung cancer and cervical cancer.

16. Use according to claim 15, characterized in that, The ferrocene derivative of formula (I) is selected from 、 、 、 ； The tumour or cancer is breast cancer.

17. The use according to claim 15, characterized in that, The ferrocene derivative of formula (I) is selected from 、 ； The tumour or cancer is cervical cancer.

18. Use of the ferrocene derivative of formula (I) as claimed in claim 1, a pharmaceutically acceptable salt thereof or the pharmaceutical composition as claimed in claim 12 for the manufacture of a lead compound for the treatment of tumour or cancer. The tumour or cancer is selected from at least one of breast cancer, lung cancer and cervical cancer.

19. Use according to claim 18, characterized in that, The ferrocene derivative of formula (I) is selected from 、 、 、 ； The tumour or cancer is breast cancer.

20. The use according to claim 18, characterized in that, The ferrocene derivative of formula (I) is selected from 、 ； The tumour or cancer is cervical cancer.

Images