CN112940050B - Ferrocene derivatives, preparation method and application thereof - Google Patents
Ferrocene derivatives, preparation method and application thereof Download PDFInfo
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Abstract
The invention discloses a ferrocene derivative anda preparation method and application thereof. A ferrocene derivative represented by formula (I) and salts or solvates thereof and pharmaceutical compositions thereof: z is selected from O, NH or S; r is 1 Selected from hydrogen, methyl, halogen; r 2 Selected from hydrogen, halogen, C 1 ～C 6 Alkyl radical, C 1 ～C 6 Alkoxy, halo C 1 ～C 6 Alkyl, halo C 1 ～C 6 Alkoxy or nitro; n is an integer of 0 to 5, R 2 May be the same or different. The compounds have antitumor activity, and can be used as candidate drugs or lead compounds for treating diseases such as tumor and cancer.
Description
Technical Field
The invention belongs to the field of compounds, and particularly relates to a ferrocene derivative, and a preparation method and application thereof.
Background
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 that lead to death are: lung cancer, gastric cancer, liver cancer, colon cancer, breast cancer, and the like. Although a part of small molecule anticancer drugs have been used clinically, a part of compounds are undergoing preclinical studies. The disease is detected by most cancer patients from the middle stage to the late stage, the overall effect of clinical treatment is poor, and especially the continuous occurrence of multidrug resistance makes the treatment of cancer difficult. Therefore, the development of novel anticancer drugs with high activity and low side effects to meet clinical needs is urgent.
Ferrocene (Ferrocene) is a compound with a unique sandwich structure, and ferrous ions are clamped between two planar rings to form a staggered configuration. Ferrocene and its derivatives have the following characteristics: (1) The aromatic property can generate substitution reaction, and the modification is easy to carry out; (2) Lipophilic, capable of interacting with various enzymes in the cell via the cell membrane; and (3) low toxicity and capability of metabolizing in vivo. The ferrocene derivatives show wide pharmacological activity in the medical field, and particularly have outstanding pharmacological activity in the anti-tumor field: rosenefeld et al showed that ferrocene-modified cisplatin derivatives have considerable leukemia inhibitory activity and are much less nephrotoxic than cis-DDP (A. Rosenfeld, et al. Inorg. Chim. Acat.1992,201: 219); the study of E.W.Neuse et al shows that the ferrocene derivatives have unique antitumor and anticancer activities (E.W.Neuse.J.Inorga.organic.polymers and materials.2005,15 (1): 3-32); a series of ferrocene derivatives containing pyrazole rings are synthesized by X.F. Huang and the like, and activity studies show that part of compounds have stronger anticancer activity than 5-fluorouracil (X.F. Huang, et al. J. organomet. Chem.2012, 706-707; liu et al synthesized a series of ferrocenyl urea derivatives, and activity studies showed that some compounds have stronger inhibition activity on HIV-1 protease (W.Liu, et al. Appl. Organomet. Chem.2012, 26; U.S. Pat. No. 4,849,462B 2 discloses that ferrocene derivatives containing aromatic ring have strong inhibitory activity against human breast cancer cell line MDA-MB-231 and prostate cancer cell line PC-3.
Ferrocene is used as a lead compound for designing and synthesizing antitumor drugs (E.W.Neuse.J.Inorg.Organoment.P.2005, 15 (1): 3-32, S.S.Braga, et al.organometallics,2013, 32. Isoxazole heterocycles are a potentially biologically active pharmacophore that is often incorporated into drug molecules to enhance activity. In the previous research of the applicant, isoxazole heterocycle is introduced into ferrocene mother nucleus to synthesize a series of ferrocene derivatives containing isoxazole heterocycle with novel structure, and the activity of preliminary in vitro lung cancer cell strain A549, large intestine cancer cell strain HCT-116 and breast cancer cell strain MCF-7 is researched, and the result shows that most of the compounds have strong inhibitory activity to A549, HCT116 and MCF-7 cell strains (Yongjiaping, et al. Application publication No. CN 01762A). Based on good research foundation in the early period, in order to enrich the types of the compounds, the applicant continues to design and synthesize the isooxazole heterocycle-containing ferrocene derivatives so as to discover new anticancer lead compounds or candidate compounds.
Disclosure of Invention
The invention provides a ferrocene derivative shown in a formula (I), or pharmaceutically acceptable salt or solvate thereof:
wherein: z is selected from NH, O or S;
R 1 selected from hydrogen, C 1 ～C 6 Alkyl, halogen;
R 2 independently selected from hydrogen, halogen, C 1 ～C 6 Alkyl radical, C 1 ～C 6 Alkoxy, halo C 1 ～C 6 Alkoxy, halo C 1 ～C 6 Alkyl or nitro;
n is an integer of 0 to 5, and when n is greater than 1, R 2 May be the same or different groups.
According to an embodiment of the present invention, R 1 Selected from hydrogen, methyl, chlorine, fluorine.
According to an embodiment of the invention, R 2 Independently selected from at least one of the following groups: hydrogen, fluorine, chlorine, bromine, methyl, ethyl, methoxy, trifluoromethyl, tert-butyl, cyano and nitro,
according to an embodiment of the invention, n is 1,2 or 3.
According to an embodiment of the invention, the term "C 1 ～C 6 Alkyl groups "may be selected from alkyl groups having a carbon number of 1,2,3,4,5,6, the remaining terms (e.g., C) 1 ～C 6 Alkoxy group) having C 1 ～C 6 Alkyl moieties are as defined herein.
According to an embodiment of the present invention, the ferrocene derivative represented by formula (I) is any one of the following compounds:
according to an embodiment of the present invention, the pharmaceutically acceptable salt of the ferrocene derivative represented by formula (I) may be a pharmaceutically acceptable salt formed by the compound of formula (I) and a pharmaceutically acceptable acid or a pharmaceutically acceptable cation. Wherein the pharmaceutically acceptable salts include, but are not limited to, salts with inorganic acids such as hydrochlorides, phosphates, diphosphates, hydrobromides, sulfates, sulfinates, nitrates, and the like; also included are salts with organic acids, such as lactic acid, oxalic acid, malic acid, maleic acid, fumaric acid, tartaric acid, succinic acid, citric acid, lactic acid salts, sulfonic acid salts, p-toluenesulfonic acid salts, 2-isethionic acid salts, benzoic acid salts, salicylic acid salts, stearic acid salts, trifluoroacetic acid or amino acids and alkanoic acid salts (e.g., acetate, HOOC- (CH- (CH) s, stearate salts, and alkanoic acid salts) 2 ) Salts of n-COOH (where n is an integer of 1 to 4), and the like. Wherein, thePharmaceutically acceptable cations include, but are not limited to, sodium, potassium, calcium, aluminum, lithium, and ammonium.
According to an embodiment of the invention, the solvate includes hydrates and alcoholates.
The invention also provides a preparation method of the ferrocene derivative shown in the formula (I), which comprises the following steps:
(1) Reacting ferrocenyl acetylene with a compound shown in a formula A to obtain an intermediate B containing ferrocene;
the compound of formula A is 3- (R) 1 ) -4-bromobenzoic acid of the formula:
the structural formula of the compound of the formula B is as follows:
wherein R is 1 With the options as described above;
(2) Reacting the intermediate B with a compound shown in a formula C to obtain a ferrocene derivative shown in a formula (I);
the structural formula of the compound C is as follows:
wherein R is 2 And n has the choice as described above, Z' represents NH 2 OH or SH;
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).
According to an embodiment of the invention, the reaction described in 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 may be selected from palladium (II) compounds known in the art, such as palladium bis (triphenylphosphine) dichloride, palladium tetrakis (triphenylphosphine) chloride and/or palladium diphenylphosphinoferrocene dichloride; for example, the organophosphorus may be selected from organophosphorus known in the art, such as triphenylphosphine; for example, the copper (I) compound may be selected from copper (I) compounds known in the art, such as copper iodide.
According to an embodiment of the present invention, the reactions described in step (1) and step (2) are both carried out in a dry organic solvent. For example, the dry organic solvent may be selected from: an aromatic hydrocarbon, a halogenated hydrocarbon, tetrahydrofuran (THF), dimethylsulfoxide (DMSO), dioxane, acetonitrile, pyridine, DMF, or an ionic liquid; preferably selected from tetrahydrofuran, chloroform, 1, 2-dichloromethane, benzene, toluene, xylene, acetonitrile, pyridine or DMF or ionic liquids; more preferably tetrahydrofuran.
According to the embodiment of the present invention, the reaction system of step (1) further contains an alkaline acid-binding agent. Preferably, the basic acid scavenger is selected from organic bases and/or inorganic bases. 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 scavenger is triethylamine.
According to an embodiment of the invention, the molar volume ratio of ferroceneethynyl to the dry mixture of organic solvent and basic acid-scavenger in step (1) is (0.5-5) mmol:6mL, e.g. 0.952mmol.
According to an embodiment of the present invention, step (1) comprises the following processes: the method comprises the following steps of dispersing ferroceneacetylene and a compound shown in the formula A in a mixture of a dry organic solvent and an alkaline acid-binding agent, adding a palladium (II) compound, an organic phosphorus compound and a copper (I) compound into the mixture under the stirring condition, continuously stirring, carrying out reflux reaction, filtering a reaction solution, and concentrating the filtrate to obtain an intermediate B.
According to an embodiment of the present invention, the reactions of step (1) and step (2) are both performed under an inert atmosphere, for example, nitrogen.
According to an embodiment of the present invention, the reaction in step (2) is carried out in a dry organic solvent. Wherein the organic solvent has the choice as indicated above.
According to an embodiment of the invention, the reaction in step (2) is carried out in the presence of a condensing agent. For example, the condensing agent may be selected from one, two or more selected from DCC, DMAP, NMM, HOBt, HATU; for example, the condensing agent may be selected from the group consisting of a combination of DCC and DMAP, a combination of DCC, HOBt and NMM, a combination of DCC and NMM, or a combination of DCC and HATU.
According to an embodiment of the present invention, the 3-substituted phenyl-5-hydroxymethyl-isoxazole (II) or 3-substituted phenyl-5-aminomethyl-isoxazole (III) described in step (2) is a known compound, and can be prepared according to the procedure optimized in chinese patent document with publication No. CN 103360382A. Specifically, the preparation route is shown as the following formula:
when Z' is SH, compound C is a 3-substituted phenyl-5-mercaptomethyl-isoxazole prepared by the process comprising: the 3-substituted phenyl-5-mercaptomethyl-isoxazole is prepared by taking the propiolic thiol as a raw material according to the synthesis process of the compound (II).
According to an embodiment of the present invention, the temperature of the reaction of step (1) or step (2) is in the range of-20 ℃ to any temperature point within the range of reflux conditions, preferably 0 ℃ to any temperature point within the range of reflux conditions, and further preferably room temperature to any temperature point within the range of reflux temperatures.
According to an embodiment of the present invention, the step (2) includes the following processes: adding the intermediate B into a dry organic solvent, adding a condensing agent into the intermediate B for reaction, and adding the compound shown in the formula C into the intermediate B for reaction to obtain the ferrocene derivative shown in the formula (I). Preferably, the time for the addition of the condensing agent is 20-40min, for example 30min.
Preferably, the time for adding the compound of formula C for reaction is 20-40min, for example 30min.
Preferably, the compound of formula (I) is synthesized as follows:
any functional group in the compound of formula C may be protected if desired;
and thereafter, if necessary (in any order):
(a) Removing any protecting agent, and
(b) To form a pharmaceutical composition of the compound of formula (I).
The invention also provides a pharmaceutical composition which contains the ferrocene derivative shown as the formula (I) or pharmaceutically acceptable salt or solvate thereof.
According to an embodiment of the invention, the pharmaceutical composition further comprises at least one pharmaceutically acceptable pharmaceutical excipient; for example, at least one pharmaceutically acceptable, inert, non-toxic pharmaceutical excipient may be selected from excipients, carriers and/or diluents. Wherein the pharmaceutically acceptable pharmaceutic adjuvant refers to an inert and nontoxic pharmaceutic adjuvant.
According to an embodiment of the present invention, the pharmaceutical excipients may also be selected from one or more of the following excipients: fillers, disintegrants, lubricants, glidants, effervescent agents, flavoring agents, preservatives and pharmaceutically acceptable auxiliary materials for coating materials.
The invention also provides a pharmaceutical preparation which comprises the ferrocene derivative shown as the formula (I) or pharmaceutically acceptable salt or solvate thereof.
According to an embodiment of the present invention, the pharmaceutical preparation contains the above pharmaceutical composition.
According to an embodiment of the invention, the pharmaceutical formulation is a solid oral formulation, a liquid oral formulation or an injection.
Preferably, the preparation is selected from tablets, dispersible tablets, enteric-coated tablets, chewable tablets, orally disintegrating tablets, capsules, granules, oral solutions, water injection for injection, freeze-dried powder injection for injection, large infusion solutions or small infusion solutions.
The present invention also provides a ferrocene derivative represented by formula (I) of claims 1 to 3 or a pharmaceutically acceptable salt thereof for use as a medicament, in particular a medicament or lead compound effective for treating tumors/cancers.
The invention also provides application of the ferrocene derivative shown as the formula (I), pharmaceutically acceptable salt and solvate thereof, or the pharmaceutical composition in preparing anti-tumor or anti-cancer drugs.
The invention also provides application of the ferrocene derivative shown in the formula (I), the pharmaceutically acceptable salt thereof or the solvate thereof as a lead compound for resisting tumor/cancer.
Preferably, the tumor or cancer is selected from: at least one of bladder cancer, ovarian cancer, breast cancer, stomach cancer, esophageal cancer, lung cancer, head and neck cancer, colon cancer, pharyngeal cancer, pancreatic cancer, etc.; 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.
The present invention also provides a method for preventing and/or treating the above-mentioned tumor/cancer-related diseases, which comprises administering an effective amount of the ferrocene derivative represented by the formula (I), the pharmaceutically acceptable salt thereof, the solvate thereof, the pharmaceutical composition, or the pharmaceutical preparation to a patient, such as a human, in need thereof.
The term "effective amount" refers to an amount of the at least one compound and/or at least one pharmaceutically acceptable salt that is effective to "treat" a disease or disorder in a subject. In the case of cancer, the effective amount reduces the number of cancer or tumor cells; reducing the size of the tumor; inhibiting or preventing invasion of tumor cells into peripheral organs, e.g., tumor spread into soft tissue or bone; inhibiting or preventing metastasis of a tumor; inhibiting or preventing the growth of a tumor; alleviating to some extent one or more symptoms associated with cancer; reducing morbidity and mortality; the quality of life is improved; or a combination of the above effects. An effective amount may be an amount that reduces the symptoms of disease by inhibiting EGFR activity. For cancer treatment, the effect of in vivo experiments can be measured by assessing, for example, survival, time to disease progression (TTP), response Rate (RR), duration of Response, and/or quality of life. One skilled in the art will appreciate that the effective amount may vary with the route of administration, the dosage of the excipient, and the combination with other drugs.
The term "effective amount" may also refer to a dose of the at least one compound and/or at least one pharmaceutically acceptable salt thereof that is effective to inhibit overexpression and/or overactivity of EGFR.
The invention has the beneficial effects that:
the invention provides a ferrocene derivative with a novel structure as shown in a formula (I). The ferrocene derivative has good inhibition effect on tumors or cancers. According to the research results of in vitro human lung cancer inhibiting cell strain (A549), breast cancer cell strain (MCF-7) and cervical cancer cell strain (Hela), the following results show that: the compounds have strong inhibitory activity on human lung cancer cell strains (A549), breast cancer cell strains (MCF-7) and cervical cancer cell strains (Hela). Can be used as candidate compound or lead compound of anticancer drug.
Detailed Description
The present invention will be further described with reference to the following examples. It should be noted that the following examples are not intended to limit the scope of the present invention, and any modifications made on the basis of the present invention do not depart from the spirit of the present invention.
Wherein, the synthesis processes of the intermediate and the target compound are shown as representatives in the examples, and the synthesis processes of the rest intermediate and the target compound are the same as the representative compounds.
Instruments and reagents:
AVANCE III NMR spectrometer (400MHz, DMSO-d) 6 TMS as an internal standard), ion trap liquid chromatograph (DECAX-30000 LCQ Deca XP), shimadzu FTIR-8400S (manufactured by Shimadzu corporation, japan), XT5 digital display micro melting point apparatus (manufactured by electro-optic instruments, beijing, inc.), wavelength-tunable microplate reader (Molecular devices SPECTRAMAX 190).
EXAMPLE 1 Synthesis of intermediates 3-substituted phenyl-5-hydroxymethyl-isoxazole (II) and 3-substituted phenyl-5-aminomethyl-isoxazole (III)
Substituted benzaldehyde is used as a raw material,prepared by synthesis of oxime, 1, 3-dipolar cycloaddition reaction, mesyl esterification reaction, azidation and reduction reaction 2 Selected from hydrogen, halogen, C 1 ～C 6 Alkyl radical, C 1 ～C 6 Alkoxy, halo C 1 ～C 6 Alkyl or nitro; n is an integer of 0 to 5), see in particular the following scheme:
the specific synthetic process of the intermediate 3-substituted phenyl-5-hydroxymethyl-isoxazole (II) and 3-substituted phenyl-5-aminomethyl-isoxazole (III) is described in the applicant's earlier application publication nos. CN103360382A, CN103664991A and CN103601762A.
Example 2 synthesis of intermediate B containing a ferrocene ring (exemplified by the synthesis of ferroceneacetylene and p-bromobenzoic acid):
adding 2.00g (9.52 mmol) of ferroceneacetylene and 1.91g (9.52 mmol) of 4-bromobenzoic acid into a 250mL double-neck round-bottom flask, then adding 60mL of dried tetrahydrofuran and triethylamine, stirring the reactants at room temperature for 10 minutes under the protection of nitrogen, then adding 0.2g (0.76 mmol) of triphenylphosphine, 0.28g (0.38 mmol) of bis (triphenylphosphine) palladium dichloride and 0.07g (0.38 mmol) of cuprous iodide into the reaction system, stirring the reaction system at room temperature for 20 minutes, then carrying out reflux reaction, carrying out the whole reaction under the protection of nitrogen, filtering the reaction mixture after the TLC detection reaction is finished, concentrating the filtrate to obtain a crude product, and carrying out column separation (V) on the crude product Petroleum ether :V Ethyl acetate 1-1) to obtain a pure product of 4-ferrocenylethynyl-benzoic acid, 2.53 g, yield: 81% and light yellow solid. Process for preparation of 4-ferrocenylethynyl-benzoic acid 1 H NMR(400 MHz,DMSO-d 6 ):4.29(s,5H,η 5 -C 5 H 5 ),4.38(2H,t,J＝2.0Hz),4.61(2H,t,J＝2.0Hz),7.58(2H,d,J＝9.2 Hz),7.90(2H,d,J＝9.2Hz),12.83(1H,brs,-COOH)。
Changing R 1 ，3-(R 1 ) Preparation of additional intermediates from 4-bromobenzoic acid reference was made to the reaction of ferroceneethyne with 4-bromobenzoic acid.
Example 3 Synthesis Process of ester target Compound (YJP-1) represented by the formula (I)
0.165g (0.5 mmol) of 4-ferrocenylethynyl-benzoic acid prepared in example 2 and 8mL of dry THF are added into a 50mL single-neck round-bottom flask, 0.103g (0.5 mmol) of DCC and 0.061g (0.5 mmol) of DMAP are added into the reaction system under stirring, after reaction at 0 ℃ for 30min, 0.088g (0.5 mmol) of 3-phenyl-5-hydroxymethyl-isoxazole is added into the reaction system, after reaction at 0 ℃ for 30min, the temperature naturally rises to room temperature for reaction, and the whole reaction process is carried out under the protection of nitrogen. After the TLC detection reaction is finished, the reaction liquid is decompressed and concentrated, and residue column separation V (Petroleum Ether) :V (Ethyl acetate) 1 to 2) to obtain the target compound (YJP-1).
The remaining compounds YJP-2 to YJP-76 were synthesized by referring to the synthetic procedure of the target compound YJP-1.
Example 4 Synthesis Process of amide-based target Compound (YJP-77) represented by the formula (I)
0.165g (0.5 mmol) of 4-ferrocenyl-benzoic acid prepared in example 2 and 8mL of dry THF are added to a 50mL single-neck round-bottom flask, 0.103g (0.5 mmol) of DCC,0.068g (0.5 mmol) of HOBT and 0.061g (0.5 mmol) of DMAP are added to the reaction system with stirring, after reaction at 0 ℃ for 30min, 0.087g (0.5 mmol) of 3-phenyl-5-aminomethyl-isoxazole is added to the reaction system, after reaction at 0 ℃ for 30min, the temperature naturally rises to room temperature for reaction, and the whole reaction process is carried out under nitrogen protection. After TLC detection reaction is finished, the reaction solution is decompressed and concentrated, and residue column separation V (Petroleum Ether) :V (Ethyl acetate) 1 to 2) to obtain a target compound (YJP-77)。
The remaining YJP-78 to YJP-152 compounds were synthesized by reference to the synthetic procedure of the object compound YJP-77.
The structures of the compounds YJP-1 to YJP-152 are all as follows 1 H NMR analytical methods were characterized. The numbering and nuclear magnetic characterization results of the YJP-1 to YJP-152 compounds are shown in Table 1:
TABLE 1 preparation of compounds of formula I 1 H NMR
Example 5 in vitro antitumor Activity assay
The compounds in the above examples were tested for in vitro anti-tumor activity using the CCK-8 method. Mainly researches the in vitro inhibition activity of the compounds on breast cancer cell strains (MCF-7), lung adenocarcinoma cell strains (A549) and cervical cancer cell strains (Hela). The breast cancer cell strain (MCF-7), the lung adenocarcinoma cell strain (A549) and the cervical cancer cell strain (Hela) are from cell lines stored in Ningxia medical university. The specific test process is illustrated by taking the test process of the breast cancer MCF-7 cell line as an example:
(1) Culture and inhibitory activity test process of breast cancer cell strain (MCF-7)
Placing the breast cancer cell strain MCF-7 at 37 deg.C and saturated humidity, and containing 5% CO 2 After 24 hours in the incubator, when the cells were in logarithmic phase, the upper layer of the culture was aspirated and digested with 0.25% trypsin-EDTA solution, and then the digestion was terminated using a high-sugar medium. And the cells were seeded in a 96-well plate such that the cell density was 5000 cells/well. The 96-well plate was placed in an incubator for 24 hours. The cell culture medium in the 96-well plate was then aspirated. And 100. Mu.L of the high-sugar medium was supplemented to the 96-well plate, and then 1. Mu.L of the test sample (5 multiple wells per concentration) was added to each well, followed by setting at 37 ℃ for saturation humidity, 5% CO 2 After further incubation for 48h, 10. Mu.L of CCK8 was added to each well and further incubation was carried out for 1-4h at 37 ℃. The absorbance value of each well at a wavelength of 450nm was measured on a multifunctional microplate reader. According to the inhibition ratio% = [ (OD) Control cells -OD Medicated cell )/(OD Control cells -OD Blank space )]X 100. Negative control is V High-sugar culture medium /V DMSO 10.
(2) Culture and inhibition activity test process of lung cancer cell strain (A549) and cervical cancer cell strain (Hela)
The experiment process for inhibiting the lung cancer cell strain A549 and the cervical cancer cell strain (Hela) is the same as the screening process of the breast cancer cell strain (MCF-7).
The activity results of the preferred compound breast cancer cell strain MCF-7, human lung cancer cell strain A549 and cervical cancer cell strain Hela are shown in the following tables 2,3 and 4 respectively.
TABLE 2 results of the activity test of some compounds of the examples in the formula (I) against breast cancer cell line MCF-7
TABLE 3 test results of partial example compounds in the formula (I) for inhibiting the activity of human lung cancer cell strain A549
| Compound numbering | Concentration (μ M) | Inhibition ratio (%) |
| YJP-14 | 16.22 | 57.00 |
| YJP-17 | 12.43 | 60.42 |
| YJP-18 | 11.35 | 79.29 |
TABLE 4 test results of the inhibition of Hela activity of cervical cancer cell lines by some of the compounds of the examples in the formula (I)
| Compound number | Concentration (μ M) | Inhibition ratio (%) |
| 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 |
The embodiments of the present invention have been described above. However, the present invention is not limited to the above embodiment. Any modification, equivalent replacement, or improvement made without departing from the spirit and principle of the present invention shall fall within the protection scope of the present invention.
Claims (19)
1. A ferrocene derivative represented by formula (I), or a pharmaceutically acceptable salt thereof:
(I)
wherein: z is selected from O;
R 1 selected from hydrogen;
R 2 independently selected from ethyl, chloro, trifluoromethyl, tert-butyl or nitro;
n is an integer of 1-5, and when n is greater than 1, R 2 Are identical or different radicals.
2. The ferrocene derivative represented by the formula (I) or the pharmaceutically acceptable salt thereof according to claim 1, wherein the ferrocene derivative represented by the formula (I) is any one of the following compounds:
3. a ferrocene derivative represented by formula (I) or a pharmaceutically acceptable salt thereof according to claim 1 or 2, wherein the pharmaceutically acceptable salt of the ferrocene derivative represented by formula (I) is a pharmaceutically acceptable salt formed by a compound represented by formula (I) and a pharmaceutically acceptable acid or a pharmaceutically acceptable cation.
4. A process for the preparation of a ferrocene derivative represented by formula (I) as defined in any one of claims 1 to 3, which comprises the steps of:
(1) Reacting ferrocenyl acetylene with a compound shown in a formula A to obtain an intermediate B containing ferrocene;
the compound of the formula A is 4-bromobenzoic acid;
the structural formula of the intermediate B is as follows:
；
wherein R is 1 Selected from hydrogen;
(2) Reacting the intermediate B with a compound shown as a formula C in the presence of a condensing agent, wherein the condensing agent is one, two or more selected from DCC, DMAP, NMM, HOBt and HATU to obtain a ferrocene derivative shown as a formula (I);
the structural formula of the compound of formula C is:
(ii) a Wherein Z' represents OH, R 2 Independently selected from ethyl, chloro, trifluoromethyl, tert-butyl or nitro.
5. The process of claim 4, wherein the compound of formula C is 3-substituted phenyl-5-hydroxymethyl-isoxazole (II).
6. The production method according to claim 4, wherein the step (1) is carried out in the presence of a palladium (II) compound, an organic phosphorus and a copper (I) compound.
7. The method according to claim 4, wherein the reactions of step (1) and step (2) are carried out in a dry organic solvent.
8. The process according to any one of claims 4 to 7, wherein the reaction system of step (1) further contains an alkaline acid-binding agent selected from an organic base and/or an inorganic base.
9. The method according to claim 8, wherein the organic base is one, two or more selected from triethylamine, tripropylamine, DMAP, DMF, N-methylmorpholine; the inorganic base is one or two or more selected from potassium carbonate, sodium hydride and sodium carbonate.
10. The method according to claim 4, wherein the step (1) comprises the steps of: and (2) dispersing ferrocenyl acetylene and the compound of the formula A in a mixture of a dry organic solvent and an alkaline acid-binding agent, adding a palladium (II) compound, organic phosphorus and a copper (I) compound into the mixture under the stirring condition, continuously stirring, carrying out reflux reaction, filtering the reaction solution, and concentrating the filtrate to obtain an intermediate B.
11. The preparation method according to claim 4, wherein the reaction in step (1) and step (2) is carried out under an inert atmosphere.
12. The production method according to claim 4, wherein the step (2) comprises the following process: adding the intermediate B into a dry organic solvent, then adding a condensing agent into the intermediate B for reaction, and then adding the compound shown in the formula C into the intermediate B for reaction to obtain the ferrocene derivative shown in the formula (I).
13. The method according to claim 4 or 12, wherein any functional group in the compound of formula C is protected; the preparation method includes removing any protecting agent.
14. A pharmaceutical composition comprising a ferrocene derivative of formula (I) as defined in any one of claims 1 to 3, or a pharmaceutically acceptable salt thereof.
15. A pharmaceutical formulation comprising a ferrocene derivative represented by formula (I) as defined in any one of claims 1 to 3, or a pharmaceutically acceptable salt thereof.
16. The pharmaceutical formulation of claim 15, wherein the pharmaceutical formulation comprises the pharmaceutical composition of claim 14.
17. The pharmaceutical formulation according to claim 15 or 16, wherein the pharmaceutical formulation is a solid oral formulation, a liquid oral formulation or an injection.
18. Use of a ferrocene derivative represented by formula (I), a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 13 as claimed in any one of claims 1 to 3 in the preparation of an anti-tumor or anti-cancer medicament;
the tumor or cancer is selected from: at least one of breast cancer, lung cancer and cervical cancer.
19. Use of a ferrocene derivative represented by formula (I) or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 3, in the preparation of a lead compound for treating tumor or cancer;
the tumor or cancer is selected from: at least one of breast cancer, lung cancer and cervical cancer.
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