CN118063524A - Ferrocene carboxamide derivative, preparation method and application thereof - Google Patents

Ferrocene carboxamide derivative, preparation method and application thereof Download PDF

Info

Publication number
CN118063524A
CN118063524A CN202410216579.9A CN202410216579A CN118063524A CN 118063524 A CN118063524 A CN 118063524A CN 202410216579 A CN202410216579 A CN 202410216579A CN 118063524 A CN118063524 A CN 118063524A
Authority
CN
China
Prior art keywords
alkyl
cancer
substituted phenyl
substituted
ferrocenecarboxamide
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Pending
Application number
CN202410216579.9A
Other languages
Chinese (zh)
Inventor
雍建平
卢灿忠
卢绍基
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Xiamen Tasman Bio Tech Co ltd
Xiamen Institute of Rare Earth Materials
Original Assignee
Xiamen Tasman Bio Tech Co ltd
Xiamen Institute of Rare Earth Materials
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Xiamen Tasman Bio Tech Co ltd, Xiamen Institute of Rare Earth Materials filed Critical Xiamen Tasman Bio Tech Co ltd
Priority to CN202410216579.9A priority Critical patent/CN118063524A/en
Publication of CN118063524A publication Critical patent/CN118063524A/en
Pending legal-status Critical Current

Links

Landscapes

  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

The invention provides a ferrocenecarboxamide derivative containing 1,3, 4-thiadiazole or 1,3, 4-oxadiazole heterocycle, which is shown in a formula (I), and research results of an in vitro cervical cancer inhibition cell strain (Hela), a human ovarian cancer cell strain (A2780) and a breast cancer cell strain MCF-7 show that: the compound has strong inhibition activity on cervical cancer cell strain (Hela), human ovarian cancer cell strain (A2780) and breast cancer cell strain MCF-7.

Description

Ferrocene carboxamide derivative, preparation method and application thereof
Technical Field
The invention belongs to the technical field of medicines, and particularly relates to ferrocenecarboxamide derivatives containing 1,3, 4-thiadiazole or 1,3, 4-oxadiazole heterocycle, a pharmaceutical composition containing the derivatives and application thereof.
Background
Cancer has become the leading fatal disease worldwide. Cancers can occur in various organs and tissues at any age, with the major types of cancer leading to death: lung cancer, stomach cancer, liver cancer, colon cancer, breast cancer, etc. While some small molecule anticancer drugs have been used clinically, some compounds are being studied preclinically. However, most cancer patients find the disease to be in the middle to late stage of the cancer, and the overall clinical treatment effect is poor, especially the continuous occurrence of multi-drug resistance, so that the treatment difficulty of the cancer is serious. Therefore, development of a novel anticancer drug with high activity and low side effect is urgent to meet clinical demands.
Ferrocene (Ferrocene) is a compound with a unique sandwich structure, and ferrous ions are sandwiched between two five-membered ring planes in a staggered configuration. Ferrocene and its derivatives have the following characteristics: (1) aromatic, can take place substitution reaction, easy to modify; (2) Lipophilicity, the ability to interact with various enzymes within a cell via the cell membrane; (3) low toxicity, capable of metabolism in vivo. Ferrocene derivatives show wide pharmacological activity in the medical field, and particularly have outstanding pharmacological activity in the anti-tumor field: studies by Rosenfeld et al show that ferrocene modified cisplatin derivatives have quite potent leukemia inhibitory activity and have much lower nephrotoxicity than cis-DDP (A.Rosenfeld, et al, inorg.Chim. Acat.1992, 201:219); research by E.W.Neuse et al shows that ferrocene derivatives have unique anti-tumor and anti-cancer activity (E.W.Neuse.J.Inorga.organism.polymers and materials.2005,15 (1): 3-32); a series of ferrocene derivatives containing pyrazole rings are synthesized by X.F.Huang et al, and activity research shows that part of the compounds have stronger anticancer activity than 5-fluorouracil (X.F.Huang, et al J.organomet. Chem.2012, 706-707:113-123); a series of ferrocene urea derivatives are synthesized by Liu et al, and activity researches show that part of the compounds have strong HIV-1 protease inhibition activity (W.Liu, et al, appl. Organomet. Chem.2012, 26:189-193); U.S. patent application 8426462B2 discloses that ferrocene derivatives containing an aromatic ring have strong inhibitory activity on human breast cancer cell line MDA-MB-231 and prostate cancer cell line PC-3.
However, how to develop ferrocene anticancer derivatives with novel structures is a great challenge for organic developers.
Disclosure of Invention
The invention provides a ferrocenecarboxamide derivative containing 1,3, 4-thiadiazole or 1,3, 4-oxadiazole heterocycle, which is shown in the following formula (I), wherein research results of in vitro cervical cancer inhibition cell strain (Hela), human ovarian cancer cell strain (A2780) and breast cancer cell strain MCF-7 show that: the compound has strong inhibition activity on cervical cancer cell strain (Hela), human ovarian cancer cell strain (A2780) and breast cancer cell strain MCF-7, and can be used as candidate compound or lead compound of anticancer drugs.
The invention is realized by the following technical scheme:
ferrocenecarboxamide derivatives of formula (I), pharmaceutically acceptable salts or solvates thereof:
Wherein R is selected from the group consisting of hydrogen, C 1～C18 alkyl, halogenated C 1～C12 alkyl, C 1～C12 alkoxy, C 1～C12 alkylthio, halogenated C 1～C12 alkoxy, O hetero C 2～C18 alkyl, C 3-8 cycloalkyl, -COOC 1～C18 alkyl, 3-8 membered heterocyclyl, unsubstituted or optionally substituted with n R 2: a C 6-14 aryl or a 5-14 membered heteroaryl;
n is 1,2,3, 4 or 5;
R 2 is selected from halogen, nitro, C 1～C18 alkyl, halogenated C 1～C12 alkyl, C 1～C12 alkoxy, C 1～C12 alkylthio, halogenated C 1～C12 alkoxy or O hetero C 2～C18 alkyl;
X is selected from O or S.
According to an embodiment of the invention, R is selected from hydrogen, C 1～C18 alkyl, halo C 1～C6 alkyl, O heteroc 2～C6 alkyl, C 3-6 cycloalkyl, -COOC 1～C3 alkyl, C 1～C6 alkoxy, C 1～C6 alkylthio, 3-6 membered heterocyclyl, the following groups unsubstituted or optionally substituted with n R 2: phenyl or pyridyl; n is 1,2 or 3;
R 2 is selected from halogen, nitro, C 1～C6 alkyl, halogenated C 1～C6 alkyl, C 1～C6 alkoxy, C 1～C6 alkylthio, halogenated C 1～C12 alkoxy or O hetero C 2～C6 alkyl.
According to an embodiment of the invention, R is selected from H, methyl, trifluoromethyl, ethyl, propyl, isopropyl, N-butyl, isobutyl, tert-butyl, N-pentyl, N-undecyl, N-heptadecyl, -CH 2OCH3, 4-pyridyl, -COOCH 3、-COOCH2CH3、-SCH3, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, N-morpholinyl, methyl-substituted pyridyl (2-, 3-or 4-substituted), ethyl-substituted pyridyl (2-, 3-or 4-substituted), halogen-substituted (fluoro, chloro or bromo) pyridyl (2-, 3-or 4-substituted), phenyl, 2-methyl-substituted phenyl, 4-ethyl-substituted phenyl, 4-isopropyl-substituted phenyl, 4-tert-butyl-substituted phenyl, 4-methoxy-substituted phenyl, 2-methoxy-substituted phenyl, 3-methoxy-substituted phenyl, 4-fluoro-substituted phenyl, 2-fluoro-substituted phenyl, 4-chloro-substituted phenyl, 2-fluoro-4-bromo-substituted phenyl, 2-chloro-substituted phenyl, 3-chloro-substituted phenyl, 2, 3-dichloro-substituted phenyl, 2, 4-methoxy-substituted phenyl, 3-fluoro-substituted phenyl, 3-methyl-substituted phenyl, 3-fluoro-substituted phenyl;
X is selected from O or S.
According to an embodiment of the present invention, the ferrocenecarboxamide derivative represented by formula (I) is selected from the following compounds:
According to an embodiment of the present invention, ferrocenecarboxamide derivatives represented by the formula (I) as described above may be selected to form pharmaceutically acceptable salts with pharmaceutically acceptable acids, respectively. Wherein the term "pharmaceutically acceptable salt" includes, but is not limited to, salts with inorganic acids such as hydrochloride, phosphate, diphosphate, hydrobromide, sulfate, sulfinate, nitrate, and the like; salts with organic acids such as lactic acid, oxalic acid, malic acid, maleic acid, fumaric acid, tartaric acid, succinic acid, citric acid, lactic acid, sulphonic acid, p-toluene sulphonic acid, 2-isethionic acid, benzoic acid, salicylic acid, stearic acid, trifluoroacetic acid or salts of amino acids and alkanoic acid salts such as acetate, HOOC- (CH 2)m -COOH (where m is an integer from 1 to 4), and the like are also included.
The term "solvate" includes both hydrates and alkoxides.
The invention also provides a pharmaceutical composition comprising a ferrocenecarboxamide derivative of formula (I) as described above, a pharmaceutically acceptable salt or solvate thereof, and one or more of a pharmaceutically acceptable, inert, non-toxic excipient, carrier or diluent.
According to an embodiment of the present invention, the pharmaceutical composition further comprises one, two or more pharmaceutically acceptable auxiliary materials selected from the group consisting of fillers, disintegrants, lubricants, glidants, effervescent agents, flavoring agents, preservatives and coating materials.
The present invention also provides a pharmaceutical formulation comprising a ferrocenecarboxamide derivative of formula (I) as hereinbefore described, or a pharmaceutically acceptable salt or solvate thereof, together with at least one pharmaceutically acceptable, inert, non-toxic excipient, carrier or diluent.
According to an embodiment of the present invention, the pharmaceutical formulation is a solid oral formulation, a liquid oral formulation or an injection.
According to an embodiment of the present invention, the pharmaceutical formulation is selected from the group consisting of tablets, dispersible tablets, enteric-coated tablets, chewable tablets, orally disintegrating tablets, capsules, granules, oral solutions, injectable water needles, injectable lyophilized powder needles, infusion solutions or infusion solutions.
The invention also provides application of at least one of ferrocene carboxamide derivatives shown in the formula (I) and pharmaceutically acceptable salts or solvates thereof in preparing anti-tumor medicaments.
According to an embodiment of the invention, the tumor is a cancer.
The use according to the invention, wherein the cancer is selected from: cervical cancer, bladder cancer, non-small cell lung cancer, ovarian cancer, breast cancer, gastric cancer, esophageal cancer, lung cancer, head and neck cancer, colon cancer, pharyngeal cancer, pancreatic cancer, and the like, preferably cervical cancer, ovarian cancer, breast cancer, and non-small cell lung cancer.
The invention also provides a preparation method of the ferrocene carboxamide derivative shown in the formula (I), which comprises the following steps:
ferrocenecarboxylic acids and compounds Obtaining ferrocene carboxamide derivatives shown in formula (I) through reaction;
Compounds of formula (I) Wherein R and X have the meanings as defined above.
According to an embodiment of the invention, the temperature of the reaction is from-20 ℃ to reflux conditions, preferably from room temperature to reflux conditions.
According to the invention, the reaction is carried out in an organic solvent, which is an aromatic hydrocarbon, a halogenated hydrocarbon, tetrahydrofuran (THF), dimethylsulfoxide (DMSO), 1, 4-dioxane, acetonitrile, DMF and an ionic liquid. Preferably, the organic solvent is selected from benzene, toluene, xylene, methylene chloride, chloroform, tetrahydrofuran, acetonitrile or DMF, more preferably tetrahydrofuran.
According to an embodiment of the invention, the reaction is carried out in the presence of a condensing agent, which is DCC/DMAP, or DCC, HOBt/DMAP, or DCC/NMM, or DCC/HATU, etc.
According to an embodiment of the invention, the compoundsSelected from 2-amino-5-R-1, 3, 4-thiadiazole (i), 2-amino-5- (R 2)n substituted phenyl-1, 3, 4-thiadiazole (ii), 2-amino-5-R-1, 3, 4-oxadiazole (i) or 2-amino-5- (R 2)n substituted phenyl-1, 3, 4-oxadiazole (ii), prepared by the following method:
(1) Reacting fatty acid with thiosemicarbazide or semicarbazide under the action of concentrated sulfuric acid at a reaction temperature of 80-120 ℃ to synthesize a formula i:
(2) (R 2)n substituted benzoic acid and thiosemicarbazide or semicarbazide are reacted in a system of concentrated sulfuric acid or phosphorus oxychloride at 100 to 140 ℃ to prepare the compound shown in the formula ii;
the synthetic route is as follows:
wherein R, n, R 2 and X have the definitions given above.
The term "effective amount" refers to an amount of the at least one compound and/or at least one pharmaceutically acceptable salt effective to "treat" a disease or disorder in an individual. In the case of a tumor, an effective amount reduces the number of tumor cells; reducing the size of the tumor; inhibit or prevent invasion of tumor cells into peripheral organs, e.g., tumor spread into soft tissues or bones; inhibit or prevent metastasis of tumors; inhibit or prevent tumor growth; to some extent, one or more symptoms associated with the tumor are alleviated; reducing morbidity and mortality; improving the quality of life; or a combination of the above effects. For cancer treatment, the effect of in vivo experiments can be measured by assessing, for example, survival, time to disease progression (Time to Disease Progression, TDP), response rate (Response Rates, RR), duration of response, and/or quality of life. The skilled artisan has appreciated that the effective amount may vary with the route of administration, the dosage of the excipient, and the use with other drugs.
Advantageous effects
The compound shown in the formula (I) provided by the invention has stronger inhibitory activity on cervical cancer cell strains (Hela), human ovarian cancer cell strains (A2780), lung cancer cell strains (A549) and breast cancer cell strains (MCF-7). In addition, the preparation process of the compound is simple, the raw materials are easy to obtain, and the synthesis cost is low. Therefore, the method has a certain application prospect.
Terminology and definition
The term "halogen" in the present application means F, cl, br and I. In other words, F, cl, br, and I may be described as "halogen" in the present specification.
The term "C 1～C 18 alkyl" is understood to mean preferably a straight-chain or branched saturated monovalent hydrocarbon radical having from 1 to 18 carbon atoms, preferably a C 1～C10 alkyl radical. "C 1～C10 alkyl" is understood to mean preferably a straight-chain or branched saturated monovalent hydrocarbon radical having 1,2, 3, 4,5, 6,7,8,9 or 10 carbon atoms. The alkyl group is, for example, methyl, ethyl, propyl, butyl, pentyl, hexyl, isopropyl, isobutyl, sec-butyl, tert-butyl, isopentyl, 2-methylbutyl, 1-ethylpropyl, 1, 2-dimethylpropyl, neopentyl, 1-dimethylpropyl, 4-methylpentyl, 3-methylpentyl, 2-methylpentyl, 1-methylpentyl, 2-ethylbutyl, 1-ethylbutyl, 3-dimethylbutyl, 2-dimethylbutyl, 1-dimethylbutyl, 2, 3-dimethylbutyl, 1, 3-dimethylbutyl, or 1, 2-dimethylbutyl, or the like, or an isomer thereof. In particular, the groups have 1,2, 3, 4,5, 6, carbon atoms ("C 1-6 alkyl"), such as methyl, ethyl, propyl, butyl, isopropyl, isobutyl, sec-butyl, tert-butyl, more particularly the groups have 1,2 or 3 carbon atoms ("C 1-3 alkyl"), such as methyl, ethyl, n-propyl or isopropyl. Similarly, C 1～C12 alkyl represents a straight or branched saturated monovalent hydrocarbon radical having 1,2, 3, 4,5, 6,7,8,9 or 10 carbon atoms.
The term "C 3-8 cycloalkyl" is understood to mean a saturated monovalent monocyclic or bicyclic hydrocarbon ring having 3, 4,5, 6, 7 or 8 carbon atoms. The C 3-8 cycloalkyl group may be a monocyclic hydrocarbon group such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or cycloheptyl.
The term "3-8 membered heterocyclyl" means a saturated monovalent monocyclic or bicyclic hydrocarbon ring comprising 1 to 5, preferably 1 to 3 heteroatoms selected from N, O and S. The heterocyclic group may be attached to the remainder of the molecule through any of the carbon atoms or a nitrogen atom, if present. In particular, the heterocyclic groups may include, but are not limited to: 4-membered rings such as azetidinyl, oxetanyl; a 5-membered ring such as tetrahydrofuranyl, dioxolyl, pyrrolidinyl, imidazolidinyl, pyrazolidinyl, pyrrolinyl; or a 6 membered ring such as tetrahydropyranyl, piperidinyl, morpholinyl, dithianyl, thiomorpholinyl, piperazinyl or trithianyl; or a 7-membered ring such as diazepanyl.
The term "C 6-14 aryl" is understood to mean preferably a mono-, bi-or tricyclic hydrocarbon ring ("C 6-14 aryl") having a monovalent aromatic or partially aromatic nature of 6, 7, 8, 9, 10, 11, 12, 13 or 14 carbon atoms, in particular a ring having 6 carbon atoms ("C 6 aryl"), for example phenyl; or biphenyl, or a ring having 9 carbon atoms ("C 9 aryl"), such as indanyl or indenyl, or a ring having 10 carbon atoms ("C 10 aryl"), such as tetrahydronaphthyl, dihydronaphthyl or naphthyl, or a ring having 13 carbon atoms ("C 13 aryl"), such as fluorenyl, or a ring having 14 carbon atoms ("C 14 aryl"), such as anthracenyl.
The term "5-14 membered heteroaryl" is understood to include such monovalent monocyclic, bicyclic or tricyclic aromatic ring systems: it has 5,6, 7, 8, 9, 10, 11, 12, 13 or 14 ring atoms, in particular 5 or 6 or 9 or 10 carbon atoms, and it contains 1 to 5, preferably 1 to 3 heteroatoms independently selected from N, O and S and, in addition, can be benzo-fused in each case. In particular, the heteroaryl group is selected from thienyl, furyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, triazolyl, thiadiazolyl, thia-4H-pyrazolyl and the like and their benzo derivatives, such as benzofuryl, benzothienyl, benzoxazolyl, benzisoxazolyl, benzimidazolyl, benzotriazole, indazolyl, indolyl, isoindolyl and the like; or pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl, and the like, and their benzo derivatives, such as quinolinyl, quinazolinyl, isoquinolinyl, and the like; or an axcinyl group, an indolizinyl group, a purinyl group, etc., and their benzo derivatives; or cinnolinyl, phthalazinyl, quinazolinyl, quinoxalinyl, naphthyridinyl, pteridinyl, carbazolyl, acridinyl, phenazinyl, phenothiazinyl, phenoxazinyl, and the like.
The above definition of the term "C 1～C12 alkyl" applies equally to other terms containing "C 1～C12 alkyl", for example the terms "halogenated C 1～C12 alkyl" or "C 1～C12 alkoxy" or "halogenated C 1～C12 alkoxy" and the like.
The term "oxaC 2～C18 alkyl" means that 1,2,3,4, 5 or 6 carbon atoms in the "C 2～C18 alkyl" are replaced by O. Wherein C 2～C18 alkyl represents a straight or branched saturated monovalent hydrocarbon radical having 2 to 18 carbon atoms, preferably C 2～C6 alkyl or C 2～C3 alkyl.
Detailed Description
The invention is further illustrated below with reference to examples. It should be noted that the following examples should not be construed as limiting the scope of the invention, and any modifications made thereto do not depart from the spirit of the invention.
Wherein, the synthesis processes of the intermediate and the target compound are represented by the examples, and the synthesis processes of the rest intermediate and the target compound are represented by the compounds.
Instrument and reagent:
AVANCE III Nuclear magnetic resonance apparatus (400 MHz, DMSO-d 6 or CDCl 3, TMS as internal standard); ion trap liquid mass spectrometer (DECAX-30000 LCQ Deca XP), shimadzu FTIR-8400S (manufactured by Shimadzu corporation), XT5 digital display micro-melting point tester (manufactured by electro-optical instruments works of Beijing Corp., temperature is uncorrected), adjustable wavelength micro-pore plate enzyme-labeled tester (Molecular Devies SPECTRAMAX 190); tumor cells were derived from cell lines maintained at Ningxia university of medical science.
Example 1 Synthesis of the intermediate 2-amino-5-R-1, 3, 4-thiadiazole (i)/2-amino-5 [ (R 2)n -phenyl ] -1,3, 4-thiadiazole (ii) or 2-amino-5-R-1, 3, 4-oxadiazole (i)/2-amino-5 [ (2)n -phenyl ] -1,3, 4-oxadiazole (ii)
The fatty acid or substituted benzoic acid and thiosemicarbazide/semicarbazide are used as raw materials and are reacted and synthesized under the action of concentrated sulfuric acid at the reaction temperature of 80-120 ℃ (R, R 2, X and n are defined as above), and the specific preparation route is as follows:
Wherein R, n, R 2 and X have the definitions given above; the intermediates of formulae (i) and (ii) are illustrated by the preparation of 2-amino-5-methyl-1, 3, 4-thiadiazole.
0.3Mol of acetic acid and 0.25mol of thiosemicarbazide were added to a 250mL single-neck round-bottom flask, and 31.5mL of concentrated sulfuric acid (dropwise addition over 30 min) was slowly added dropwise with stirring in an ice bath. The reaction was then stirred to room temperature and then slowly heated to 80-90 ℃ for 7h. After the reaction solution was cooled to room temperature, it was slowly poured into 500mL of ice water, a large amount of colorless solid was formed, filtered, and the cake was washed with cold water to neutrality. And collecting a filter cake, drying the filter cake by using an infrared lamp, and recrystallizing the filter cake by using ethanol to obtain the 2-amino-5-methyl-1, 3, 4-thiadiazole. The preparation process of other compounds is the same as that of 2-amino-5-methyl-1, 3, 4-thiadiazole. The structure and nuclear magnetic data of this intermediate are shown in table 1 below:
TABLE 15 Structure of substituted-1, 3, 4-thiadiazoles and 1,3, 4-oxadiazole intermediates and 1 H NMR data
/>
/>
/>
/>
/>
Example 2 synthesis of ferrocenecarboxamide derivative (I):
the reaction of ferrocenecarboxylic acid with 2-amino-5-methyl-1, 3, 4-thiadiazole is illustrated as an example:
0.23g (1 mmol) of ferrocenecarboxylic acid and 8mL of dry THF are added into a 50mL single-neck round-bottom flask, 0.206g (1 mmol) of DCC and 0.122g (1 mmol) of DMAP are added into the reaction system under stirring, after 30min of reaction at 0 ℃, 0.115g (1 mmol) of 2-amino-5-methyl-1, 3, 4-thiadiazole is added into the reaction system, and after 30min of reaction at 0 ℃, the reaction is naturally carried out to room temperature, and the whole reaction process is carried out under the protection of nitrogen. After the TLC detection reaction is finished, the reaction solution is decompressed and concentrated, and the residue is separated by a column [ V ( Petroleum ether )：V( Acetic acid ethyl ester ) =5:1-2:1 ] to obtain the target compound N- [ (5-methyl-1, 3, 4-thiadiazole) -2-yl ] -ferrocenecarboxamide (YJP-2).
The remaining compounds were prepared according to the synthetic procedure of N- [ (5-methyl-1, 3, 4-thiadiazole) -2-yl ] -ferrocenecarboxamide (YJP-2).
The synthesized compound was characterized by 1 H NMR and other analytical methods. The structure and characterization data for these compounds are shown in table 2 below:
TABLE 2
/>
/>
/>
/>
/>
/>
/>
/>
/>
Example 3 anti-tumor Activity test
The inhibition effect of some of the compounds in example 2 on cervical cancer cell line (Hela), human ovarian cancer cell line (A2780), breast cancer cell line (MCF-7) and human lung cancer cell line (A549) was tested by CCK-8 method. Cervical cancer cell line (Hela), human ovarian cancer cell line (A2780), breast cancer cell line (MCF-7) and human lung cancer cell line (A549) are derived from cell lines stored in Ningxia university of medical science. The specific test procedure is described by taking the test procedure of the breast cancer MCF-7 cell strain as an example:
(1) Culture of breast cancer cell line (MCF-7) and inhibitory activity testing procedure
The breast cancer cell line MCF-7 was placed in an incubator containing 5% CO 2 at 37℃and saturated humidity for 24 hours, when the cells were in the logarithmic growth phase, the upper layer of the culture broth was aspirated, and after digestion with 0.25% trypsin-EDTA solution, the digestion was stopped using a high sugar medium. And cells were seeded in 96-well plates such that the cell density was 5000 cells/well. The 96-well plate was placed in an incubator for 24 hours. With consequent pipetting of the cell culture broth in the 96-well plate. And 100 mu L of high sugar culture medium is added into a 96-well plate, then 1 mu L of test samples with different concentrations are added into each well (5 compound wells are arranged at each concentration), then the mixture is placed into an incubator with 37 ℃ and saturated humidity and 5% CO 2 for continuous culture for 48 hours, 10 mu L of CCK8 is added into each well, and incubation is continued for 1-4 hours in the incubator with 37 ℃. The absorbance value per well at a wavelength of 450nm was measured on a multifunctional microplate reader. Inhibition = [ (OD Control cells -OD Medicated cell )/(OD Control cells -OD Blank space ) ] ×100. The negative control was a mixed solution with V High sugar culture medium /VDMSO = 10:1.
(2) Culturing and inhibitory activity testing procedures of human ovarian cancer cell strain (a 2780), lung cancer cell strain (a 549) and cervical cancer cell strain (Hela):
The experimental procedure for inhibiting the human ovarian cancer cell line (A2780), lung cancer cell line (A549) and cervical cancer cell line (Hela) was the same as the screening procedure for the breast cancer cell line (MCF-7). The results of inhibiting the activity of the breast cancer cell line MCF-7, the human lung cancer cell line A549 and the cervical cancer cell line Hela by the compounds of the present application are shown in tables 3, 4, 5 and 6, respectively.
TABLE 3 results of test of inhibition of cervical cancer cell line (Hela) Activity by some example Compounds
Numbering device Concentration (mg/mL) Inhibition ratio (%) Numbering device Concentration (mg/mL) Inhibition ratio (%)
YJP-3 8.925 72.02 YJP-6 6.725 67.09
YJP-9 2.975 71.33 YJP-16 5.1 79.61
YJP-28 4.15 84.12 YJP-20 6.1 67.02
YJP-22 5.05 54.28 YJP-31 3.8 68.08
YJP-34 3.0 65.27 YJP-35 7.55 82.94
TABLE 4 results of test for Activity of partial example Compounds against human ovarian cancer cell line (A2780)
Numbering device Concentration (mg/mL) Inhibition ratio (%) Numbering device Concentration (mg/mL) Inhibition ratio (%)
YJP-3 8.925 73.05 YJP-6 6.725 56.30
YJP-9 2.975 75.19 YJP-16 5.1 70.62
YJP-28 4.15 62.60 YJP-31 3.8 55.90
YJP-35 7.55 70.53 YJP-55 4.75 61.05
TABLE 5 results of test for inhibition of breast cancer cell line (MCF-7) Activity by some example compounds
Numbering device Concentration (mg/mL) Inhibition ratio (%) Numbering device Concentration (mg/mL) Inhibition ratio (%)
YJP-9 2.975 57.42 YJP-16 5.1 59.73
YJP-28 4.15 72.07 YJP-20 6.1 50.91
TABLE 6 results of test for inhibition of lung cancer cell line (A549) Activity by some example compounds
The embodiments of the present invention have been described above. However, the present invention is not limited to the above embodiments. Any modification, equivalent replacement, improvement, etc. made within the spirit and principle of the present invention should be included in the protection scope of the present invention.

Claims (10)

1. Ferrocenecarboxamide derivatives of formula (I), pharmaceutically acceptable salts or solvates thereof:
Wherein R is selected from the group consisting of hydrogen, C 1～C18 alkyl, halogenated C 1～C12 alkyl, C 1～C12 alkoxy, C 1～C12 alkylthio, halogenated C 1～C12 alkoxy, O hetero C 2～C18 alkyl, C 3-8 cycloalkyl, -COOC 1～C18 alkyl, 3-8 membered heterocyclyl, unsubstituted or optionally substituted with n R 2: a C 6-14 aryl or a 5-14 membered heteroaryl;
n is 1,2,3, 4 or 5;
R 2 is selected from halogen, nitro, C 1～C18 alkyl, halogenated C 1～C12 alkyl, C 1～C12 alkoxy, C 1～C12 alkylthio, halogenated C 1～C12 alkoxy or O hetero C 2～C18 alkyl;
X is selected from O or S.
2. A ferrocenecarboxamide derivative according to claim 1, wherein R is selected from hydrogen, C 1～C18 alkyl, halogenated C 1～C6 alkyl, O heteroc 2～C6 alkyl, C 3-6 cycloalkyl, -COOC 1～C3 alkyl, C 1～C6 alkoxy, C 1～C6 alkylthio, 3-6 membered heterocyclyl, unsubstituted or optionally substituted with n R 2: phenyl or pyridyl;
n is 1,2 or 3;
R 2 is selected from halogen, nitro, C 1～C6 alkyl, halogenated C 1～C6 alkyl, C 1～C6 alkoxy, C 1～C6 alkylthio, halogenated C 1～C12 alkoxy or O hetero C 2～C6 alkyl.
3. A ferrocenecarboxamide derivative according to claim 1 or 2, wherein R is selected from H, methyl, trifluoromethyl, ethyl, propyl, isopropyl, N-butyl, isobutyl, tert-butyl, N-pentyl, N-undecyl, N-heptadecyl, -CH 2OCH3, 4-pyridyl, -COOCH 3、-COOCH2CH3、-SCH3, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, N-morpholinyl, methyl-substituted pyridyl (2-, 3-or 4-substituted), ethyl-substituted pyridyl (2-, 3-or 4-substituted), halo-substituted (fluoro, chloro or bromo) pyridyl (2-, 3-or 4-substituted), phenyl, 2-methyl-substituted phenyl, 4-ethyl-substituted phenyl, 4-isopropyl-substituted phenyl, 4-tert-butyl-substituted phenyl, 4-methoxy-substituted phenyl, 2-methoxy-substituted phenyl, 3-methoxy-substituted phenyl, 4-fluoro-substituted phenyl, 2-fluoro-substituted phenyl, 4-chloro-substituted phenyl, 2-fluoro-4-bromo-substituted phenyl, 2-chloro-substituted phenyl, 3-chloro-substituted phenyl, 2-chloro-substituted phenyl, 3-chloro-substituted phenyl, 2-fluoro-substituted phenyl; x is selected from O or S.
4. A ferrocenecarboxamide derivative according to any one of claims 1 to 3, which is a pharmaceutically acceptable salt or solvate thereof, wherein the ferrocenecarboxamide derivative of formula (I) is selected from the group consisting of:
5. A pharmaceutical composition comprising a ferrocenecarboxamide derivative of formula (I) according to any one of claims 1 to 4, a pharmaceutically acceptable salt or solvate thereof, and one or more of a pharmaceutically acceptable, inert, non-toxic excipient, carrier or diluent;
Preferably, the pharmaceutical composition further comprises one, two or more pharmaceutically acceptable auxiliary materials selected from the group consisting of fillers, disintegrants, lubricants, glidants, effervescent agents, flavoring agents, preservatives and coating materials.
6. A pharmaceutical formulation comprising a ferrocenecarboxamide derivative of formula (I) according to any one of claims 1 to 4, or a pharmaceutically acceptable salt or solvate thereof, and at least one pharmaceutically acceptable, inert, non-toxic excipient, carrier or diluent;
preferably, the pharmaceutical preparation is a solid oral preparation, a liquid oral preparation or an injection;
Preferably, the pharmaceutical preparation is selected from tablets, dispersible tablets, enteric-coated tablets, chewable tablets, orally disintegrating tablets, capsules, granules, oral solutions, water injection needles, freeze-dried powder injection for injection, large infusion or small infusion.
7. Use of a ferrocenecarboxamide derivative of formula (I) according to any one of claims 1 to 4, in the manufacture of a medicament for use in the treatment of cancer, in the form of at least one of a pharmaceutically acceptable salt or solvate thereof.
8. The use according to claim 7, wherein the tumour is a cancer.
9. The use according to claim 8, wherein the cancer is selected from the group consisting of: cervical cancer, bladder cancer, non-small cell lung cancer, ovarian cancer, breast cancer, gastric cancer, esophageal cancer, lung cancer, head and neck cancer, colon cancer, pharyngeal cancer, pancreatic cancer, and the like, preferably cervical cancer, ovarian cancer, breast cancer, and non-small cell lung cancer.
10. A process for the preparation of a ferrocenecarboxamide derivative of formula (I) according to any one of claims 1 to 4, comprising the steps of:
ferrocenecarboxylic acids and compounds Obtaining ferrocene carboxamide derivatives shown in formula (I) through reaction;
Compounds of formula (I) Wherein R and X have the meanings given in any of claims 1 to 4.
CN202410216579.9A 2024-02-27 2024-02-27 Ferrocene carboxamide derivative, preparation method and application thereof Pending CN118063524A (en)

Priority Applications (1)

Application Number Priority Date Filing Date Title
CN202410216579.9A CN118063524A (en) 2024-02-27 2024-02-27 Ferrocene carboxamide derivative, preparation method and application thereof

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
CN202410216579.9A CN118063524A (en) 2024-02-27 2024-02-27 Ferrocene carboxamide derivative, preparation method and application thereof

Publications (1)

Publication Number Publication Date
CN118063524A true CN118063524A (en) 2024-05-24

Family

ID=91105322

Family Applications (1)

Application Number Title Priority Date Filing Date
CN202410216579.9A Pending CN118063524A (en) 2024-02-27 2024-02-27 Ferrocene carboxamide derivative, preparation method and application thereof

Country Status (1)

Country Link
CN (1) CN118063524A (en)

Similar Documents

Publication Publication Date Title
AU2005306458B2 (en) Kinase inhibitors
US8304579B2 (en) Boronic acid aryl analogs
KR102373577B1 (en) Multikinase inhibitor compounds, crystalline forms and uses thereof
CN112300153B (en) Heterocyclic compound, pharmaceutical composition and application
CN112851663B (en) Parallel heterocyclic compound and application thereof
CN114516832A (en) Tubulin inhibitor and preparation method and application thereof
US10894790B2 (en) Production method of thiazole derivative
CN112979719B (en) Ferrocene oxime formate derivative, preparation method and application thereof
CN113135909B (en) DPD inhibitor, preparation method thereof, pharmaceutical composition and application
CN112979718B (en) Ferrocenecarboxylic acid derivative, preparation method and application thereof
CN113527260A (en) Compound capable of degrading STAT3 enzyme, preparation method and pharmaceutical application thereof
CN118063524A (en) Ferrocene carboxamide derivative, preparation method and application thereof
CN110229171B (en) Oxazinoquinazoline and oxazinoquinoline compound and preparation method and application thereof
CN111646986B (en) Nicotinic acid derivative and preparation method and application thereof
CN110357905B (en) Macrocyclic derivatives as protein kinase inhibitors, and preparation method and application thereof
EP3805212A1 (en) 3-oxazolinone compound, preparation method therefor and pharmaceutical application thereof
CN111732597B (en) Preparation and application of 2-aminopyrimidine heterocyclic compound containing 4-amidophenoxy
CN115477608A (en) Tubulin inhibitor and preparation method and application thereof
CN112940050B (en) Ferrocene derivatives, preparation method and application thereof
AU2020100093A4 (en) Isonicotinic acid derivative and preparation method and application thereof technical field
AU2019101281A4 (en) Pyridine-2-carboxylic derivative, and preparation method and use thereof
CN104774188A (en) Benzohetercyclic or benzoheteraromatic-cyclic derivative and preparation method and application thereof in medicines
WO2019170086A1 (en) Acyl-substituted oxazino-quinazoline compound, preparation method therefor, and uses thereof
WO2022178701A1 (en) Ferrocene derivative, preparation method therefor, and use thereof
WO2024056091A1 (en) Pyridonopyrimidine derivative as rsk inhibitor and use thereof

Legal Events

Date Code Title Description
PB01 Publication
PB01 Publication
SE01 Entry into force of request for substantive examination