CN110862410A

CN110862410A - Trifluoromethyl selenium compound and application thereof

Info

Publication number: CN110862410A
Application number: CN201811502004.4A
Authority: CN
Inventors: 贺贤然; 李少磊
Original assignee: SHENZHEN FUSHAN BIOTECHNOLOGY CO Ltd
Current assignee: SHENZHEN FUSHAN BIOTECHNOLOGY CO Ltd
Priority date: 2018-08-27
Filing date: 2018-12-10
Publication date: 2020-03-06

Abstract

The invention provides a trifluoromethyl selenium compound and application thereof in preventing or treating cancers, wherein the trifluoromethyl selenium compound has a structure shown in a formula I. The invention also provides a preparation method of the compound shown in the formula I and a pharmaceutical composition containing the compound shown in the formula I.

Description

Trifluoromethyl selenium compound and application thereof

Technical Field

The invention belongs to the field of biomedicine, and particularly relates to a trifluoromethyl selenium compound, and a preparation method and pharmaceutical application thereof.

Background

Cancer is the leading cause of illness and death worldwide, and is expected to increase as modern technology extends life expectancy. During the life of a cell, small changes in DNA called "mutations" occasionally occur. Among these mutations, some mutations (referred to as "silent mutations") do not result in any substantial change in cell function, while others may alter the mode of action of the cell. Various mechanisms can prevent cells that have mutated from continuing the cell cycle and if genetic errors are not corrected, these cells will "suicide" through a process called "apoptosis". However, if mutations occur in proteins involved in cell cycle regulation, this can lead to uncontrolled cell proliferation (known as tumor formation), which can further progress to cancer.

Cancer cells often have adverse effects on the body. Cancer can spread by invasion of adjacent tissues by malignant tumor cells, and can also spread by a process known as "metastasis" in which malignant cells detach from the tumor mass and spread to distant sites. Cancer appears in many different types of tissues in multiple forms and can be characterized by its degree of invasion and invasiveness.

Cancer occurs as a mass of abnormal tissue in a living host organism, which receives nutrients from the host without relying on host hyperproliferation and destroys the host organism. The human organ is composed of a large number of cells. Cancer occurs when normal cells of the human body become abnormal cells and the abnormal cells divide and proliferate without examination. Although genetic factors are closely related to the onset of cancer, environmental factors also have a significant impact on whether an individual develops cancer. Cancer is particularly prevalent in developed countries. It has been reported that the causes of cancer are increased use of pesticides, insecticides, etc. (and thus the amount of such substances remaining in foods) and consumption of processed foods containing additives such as food preservatives and colorants, increased pollution of water, soil and air, stress of modern life, reduction of activities, obesity caused by greasy dietary habits, and the like. In recent years, it has also been pointed out that cancer is caused when the cell signaling system of normal cells fails, when cancer genes are activated, or when cancer suppressor genes fail.

Various cancer treatment methods exist, such as surgical treatment, chemotherapy and radiotherapy. The surgical treatment method effectively removes cancer at an early stage, but has disadvantages in that organs have to be removed from time to time, which causes side effects, and there is uncertainty in spreading cancer to other organs. Radiation therapy is advantageous for effectively treating cancer occurring in a particular organ, but has the following disadvantages: exposure of the patient to other cancer risks due to radiation, failure to prevent the spread of cancer cells to other organs, and significant pain to the patient during treatment. Chemotherapy is generally performed using anticancer drugs, but it is known that toxicity of anticancer drugs acts not only on cancer cells but also on normal cells of patients, causing side effects. Therefore, development of new anticancer drugs having higher cancer cell selectivity and as little toxicity as possible is desired.

Selenium is a trace element essential for life activities of the body. In recent years, studies have been made on selenium compounds, particularly organic selenium compounds, in an attempt to find compounds having anticancer or antitumor activities therefrom. For example, EI-Baulomy et al [ K El-Baulomy, Drugs Future,1997, 22(5): 539-545 ] found that benzyl selenium cyanide exhibited anti-tumor effects in a mouse model of DMBA-induced breast cancer. Benzyl selencyanide has a higher anticancer activity than sodium selenite, but has a strong off-taste itself and has side effects that cause significant weight loss in patients.

The research shows that the action mechanism of ebselen is mainly to inhibit the activity of target enzyme thioredoxin reductase and regulate the downstream signal conduction path and the anti-tumor apoptosis path thereof to realize the anti-tumor action of the drug, and the bioactivity and low toxicity of ebselen may be related to the cyclic selenamide structure or the benzisoselenone-containing heterocyclic ring (H J Reich, et al J.Am.chem.Soc., 1987, 109(18):5549-, has synergistic effect and activity superior to that of ebselen.

Despite the discovery of the above organic selenium compounds, the existing organic selenium compounds still have the problems of further improved antitumor efficacy, limited anticancer spectrum, and limited structural types of the compounds, and are far from meeting the increasing demands of human beings for tumor prevention and treatment. Therefore, the development of pharmaceutical compounds, particularly organic selenium compounds, having better tumor prevention and/or treatment effects has been urgently needed.

Therefore, there is still an urgent need in the art for new compounds for preventing and/or treating tumors with good effects.

Disclosure of Invention

Through a large number of experimental researches, the inventor unexpectedly discovers that the trifluoromethyl selenium organic compound has unexpected biological activity of preventing and treating tumors. The compounds are useful for the prevention and/or treatment of various cancers.

The trifluoromethyl selenium organic compound is a compound with a structure shown in the formula I

Or a pharmaceutically acceptable salt thereof, wherein L is a direct bond or OCOCHR, wherein R is a hydrogen atom or a linear or branched alkyl group. Preferably, the alkyl group is C₁-C₆Alkyl, more preferably C₁-C₄An alkyl group.

In another aspect, the present invention also provides a process for the preparation of a compound of formula I as described above, comprising the steps of:

(i) reacting a compound of formula IV

With a haloacyl halide represented by X' -CO-CHR-X in an organic solvent to obtain a compound of formula III

And

(ii) reacting a compound of formula III with silver trifluoromethyl seleno [ Ag (bpy) (SeCF)₃)]₂The reaction is carried out in the presence of a catalyst,to give the compound of the formula I

Wherein L is as defined above; x and X', which may be the same or different, are independently a halogen selected from the group consisting of fluorine, chlorine, bromine and iodine atoms.

Particularly preferred compounds in the present invention are selected from the following compounds:

or a pharmaceutically acceptable salt thereof.

In another aspect of the present invention, there is also provided a process for the preparation of compounds of formulae I-a, I-b and I-c as described above, said process comprising the steps of:

(i) reacting a compound of formula VI

Reacting with a halogenated acyl halide represented by X-CO-CHR-X in an organic solvent to obtain a compound

And

(ii) reacting a compound of formula III with silver trifluoromethyl seleno [ Ag (bpy) (SeCF)₃)]₂The reaction to obtain the compound of formula I-a, I-b or I-c.

In the production method of the present invention, it is preferable to use potassium hydrogencarbonate as a catalyst in step (i).

The present invention also provides a process for the preparation of a compound of formula (I-d) as defined above, said process comprising the steps of:

(i) reacting a compound of formula VI

Reacting with triphenyl phosphine in organic solvent to obtain compound

And

(ii) reacting a compound of formula II with silver trifluoromethyl selenide [ Ag (bpy) (SeCF)₃)]₂Reaction to give the compound of formula (I-d)

The invention also provides a trifluoromethyl seleno silver salt [ Ag (bpy) (SeCF)₃)]₂A process for the preparation of a compound of the formula:

the preparation method of the invention is simple, has high yield, and can easily prepare the compound of the formula I.

In another aspect of the present invention, there is also provided a pharmaceutical composition comprising a compound of formula I as described herein, or a pharmaceutically acceptable salt thereof, and optionally a pharmaceutically acceptable excipient and/or carrier.

In a further aspect of the invention there is also provided the use of a compound of formula I according to the invention, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for the prevention and/or treatment of tumours. Preferably, the tumor is selected from colon cancer, breast cancer, prostate cancer, cervical cancer, liver cancer and lung cancer; particularly preferably, the tumor is selected from the group consisting of gastric cancer, lung cancer, liver cancer and leukemia.

Detailed Description

The present invention provides compounds of formula I

Or a pharmaceutically acceptable salt thereof,

wherein L is a direct bond or OCOCHR, wherein R is a hydrogen atom or a linear or branched alkyl group. Preferably, the first and second electrodes are formed of a metal,the alkyl group is C₁-C₆Alkyl, more preferably C₁-C₄An alkyl group. Particularly preferably, the alkyl group is selected from the group consisting of methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl and tert-butyl.

The pharmaceutical compositions of the present invention comprise a compound of formula I of the present invention, or a pharmaceutically acceptable salt thereof, and optionally a pharmaceutically acceptable excipient and/or carrier. In the pharmaceutical composition of the present invention, other pharmaceutically active ingredients may be further included in addition to the compound of formula I of the present invention or a pharmaceutically acceptable salt thereof. The pharmaceutical compositions of the invention may be prepared by conventional techniques, for example as described in Remington: the method described in The Science and Practice of Pharmacy, 19 th edition, 1995, which is incorporated herein by reference. The compositions may be presented in conventional forms, such as capsules, tablets, aerosols, solutions, suspensions or topical application forms.

Typical compositions comprise a compound of formula I of the present invention or a salt thereof and a pharmaceutically acceptable excipient or carrier. For example, the active compound is typically mixed with a carrier, or diluted by a carrier, or enclosed within a carrier which may be in the form of an ampoule, capsule, sachet (sachet), paper or other container. When the active compound is mixed with a carrier, or when the carrier serves as a diluent, the carrier can be a solid, semi-solid, or liquid material that serves as a carrier, excipient, or medium for the active compound. The active compound may be adsorbed on a particulate solid carrier (e.g. contained in a sachet). Some examples of suitable carriers are water, salt solutions, alcohols, polyethylene glycols, polyhydroxyethoxylated castor oil, peanut oil, olive oil, gelatin, lactose, terra alba, sucrose, dextrin, magnesium carbonate, sugars, cyclodextrins, amylose, magnesium stearate, talc, gelatin, agar, pectin, acacia, stearic acid or lower alkyl ethers of cellulose, silicic acid, fatty acids, fatty acid amines, fatty acid mono-and diglycerides, pentaerythritol fatty acid esters, polyoxyethylene, hydroxymethylcellulose and polyvinylpyrrolidone. Similarly, the carrier or diluent may include any sustained release material known in the art, such as glyceryl monostearate or glyceryl distearate alone or with a wax.

The formulations may be mixed with adjuvants which do not deleteriously react with the active compound. These additives may include wetting agents, emulsifying and suspending agents, salts for influencing osmotic pressure, buffering and/or coloring substances, preservatives, sweeteners or flavorings. The composition may also be sterilized, if desired.

The route of administration may be any route which is effective for the transport of a compound of formula I of the present invention to the appropriate or desired site of action, for example the oral, nasal, pulmonary, buccal, subcutaneous, intradermal, transdermal or parenteral routes, for example the rectal, depot (depot), subcutaneous, intravenous, intraurethral, intramuscular, intranasal, ophthalmic solutions or ointments route, the oral route being preferred.

If a solid carrier is used for oral administration, the formulation may be tableted, placed in a hard gelatin capsule as a powder or pellet, or it may be in the form of a troche (troche) or lozenge. If a liquid carrier is used, the formulation may be in the form of a syrup, emulsion, soft gelatin capsule, or sterile injectable liquid, such as an aqueous or non-aqueous liquid suspension or solution.

Injectable dosage forms typically comprise an aqueous or oily suspension, which may be formulated using suitable dispersing or wetting agents and suspending agents. Injectable forms may be in the form of a solution phase or a suspension prepared with a solvent or diluent. Acceptable solvents or carriers include sterile water, ringer's solution, or isotonic saline solution. Alternatively, sterile oils may be employed as a solvent or suspending agent. Preferably, the oil or fatty acid is non-volatile and comprises a natural or synthetic oil, a fatty acid, a monoglyceride, diglyceride, or triglyceride.

For injection, the formulation may also be a powder suitable for reconstitution with a suitable solution as described above. Examples of these include, but are not limited to, freeze-dried, spin-dried or spray-dried powders, amorphous powders, granules, precipitates or microparticles. For injections, the formulation may optionally include stabilizers, pH modifiers, surfactants, bioavailability modifiers, and combinations of these agents. The compounds may be formulated for parenteral administration by injection, for example by bolus injection or continuous infusion. Unit dosage forms for injection may be in ampoules or in multi-dose containers.

The formulations of the present invention may be designed to provide rapid, sustained or delayed release of the active ingredient after administration to a patient by methods well known in the art. Thus, the formulation may also be formulated for controlled release or slow release.

The compounds of formula I of the present invention are effective over a wide dosage range. For example, in the treatment of adults, a dose of about 0.05 to about 5000mg, preferably about 1 to about 2000mg, more preferably about 2 to about 2000mg per day may be used. Typical dosages are from about 10mg to about 1000mg per day. When selecting a patient treatment regimen, it may often be necessary to start with a higher dose and reduce the dose when the condition is controlled. The precise dosage will depend upon the mode of administration, the desired treatment, the form of administration, the subject to be treated and the weight of the subject to be treated, as well as the preferences and experience of the attending physician.

Typically, the compounds of formula I of the present invention are dispensed in unit dosage forms containing from about 0.05mg to about 1000mg of the active ingredient per unit dose and a pharmaceutically acceptable carrier.

In general, a dosage form suitable for oral, nasal, pulmonary or transdermal administration comprises from about 125 μ g to about 1250mg, preferably from about 250 μ g to about 500mg, more preferably from about 2.5mg to about 250mg of said compound of formula I in admixture with a pharmaceutically acceptable carrier or diluent.

The dosage form may be administered once daily, or more than once daily, e.g., twice daily or three times daily. Alternatively, the dosage form may be administered less frequently than once daily, for example every other day or weekly, if deemed appropriate by the prescribing physician.

The pharmaceutical compositions of the present invention may be in the form of tablets, capsules, powders, granules, lozenges, liquids or gels. Tablets and capsules for oral administration may be in a form suitable for unit dose administration and may contain conventional excipients, such as: binders such as syrup, gum arabic, gelatin, sorbitol, tragacanth, polyvinylpyrrolidone (PVP); fillers such as lactose, sugars, corn flour, calcium phosphate, sorbitol or glycine; tablet lubricants such as magnesium stearate, silicon dioxide, talc, polyethylene glycol or silicon dioxide; disintegrants such as potato starch; acceptable lubricants such as sodium lauryl sulfate. The tablets may be coated according to known methods of conventional pharmaceutical practice. Oral liquid preparations may be in the form of aqueous or oily suspensions, solutions, emulsions, syrups or tinctures, or may be presented as a dry substance for reconstitution with water or other suitable vehicle before use. These liquid preparations may contain conventional additives such as suspending agents (e.g., sorbitol, syrup, methyl cellulose, glucose syrup, gelatin, hydrogenated edible fats and oils). Emulsifying agents (e.g. lecithin, sorbitol monooleate or acacia), non-aqueous vehicles (including edible oils such as almond oil, fractionated coconut oil, fats and oils such as glycerol, propylene glycol or ethanol), preservatives (e.g. methyl or propyl p-hydroxybenzoic acid or sorbic acid), and if desired conventional flavouring or colouring agents.

The dosage may vary with the method and dosage form of administration, as well as the age, weight, condition and sensitivity of the patient. In the case of oral administration, an effective daily dosage range, for example, may be from 0.1mg to 1 g. Single dose units containing a compound of formula I or a pharmaceutically acceptable salt thereof in an amount of from 0.1mg to 100mg may conveniently be employed to meet the daily dosage requirements. The dosages and dosage units employed may be outside the ranges set forth above.

The invention also provides the application of the compound shown in the formula I or the pharmaceutically acceptable salt thereof in preparing a medicament for preventing and/or treating tumors. Preferably, the tumor is selected from the group consisting of gastric cancer, lung cancer, liver cancer and leukemia.

In another aspect, the present invention provides a method for the prevention or treatment of a tumor or cancer, said method comprising administering to a subject in need thereof an effective amount of a compound of formula I of the present invention or a pharmaceutically acceptable salt thereof.

The percentage of active substance in the pharmaceutical composition of the present invention is variable because the pharmaceutical formulation must be formulated in a suitable proportion of the dosage to achieve the desired therapeutic effect. In general, the pharmaceutical preparations of the invention can be administered orally or by injection in an amount of 0.1 to 100mg of the compound of formula I per day per 70kg of body weight. The following examples are for the purpose of illustrating certain aspects of the invention and should not be construed as limiting the scope of the invention in any way.

Examples

Examples of synthetic preparations

Trifluoromethyl seleno silver salt [ Ag (bpy) (SeCF)₃)]₂Synthesis of (2)

The reaction formula is as follows:

in a three-necked flask, silver iodide (665mg, 0.23mmol), selenium powder (560mg, 7mmol), and sodium iodide (610mg, 10.5mmol) were dissolved in acetonitrile, and trifluoromethyl trimethylsilane (1.6ml, 10.5mmol) was slowly added dropwise, and stirred at room temperature for 24 hours under nitrogen. The reaction was complete by TLC. The reaction solution was filtered through celite, the solvent evaporated to dryness to give a brown solid, which was washed with n-hexane (3X 1.5mL), the solid was redissolved in 2.5mL acetonitrile, a solution of 2, 2' -bipyridine (545mg, 3.5mmol) in diethyl ether (10mL) was added dropwise at room temperature, and 0.9g of the filtered brown solid was obtained as trifluoromethyl seleno-silver [ Ag (bpy) (SeCF)₃)]₂

Nuclear magnetic resonance:¹H NMR(400MHz,CD₃CN)δ(ppm):7.51-7.66(m,4H),8.06(t,J＝4.2Hz,4H),8.40(d,J＝7.2Hz,4H),8.70(s,4H).

¹⁹F NMR(376MHz,CD₃CN)δ-23.4.

preparation example 1: synthesis of Compounds of formula I-a

The reaction formula is as follows:

a compound of formula IV, paclitaxel (200mg, 0.23mmol) was dissolved in a mixed solvent of dichloromethane and water (CH) in a three-necked flask₂Cl₂(V)：H₂O(V)＝1:1) To this solution, potassium hydrogencarbonate (42mg, 0.2mmol) was added, bromoacetyl bromide (56mg, 0.28mmol) was added at room temperature, and the mixture was stirred for 1 hour to complete the reaction by TLC. The reaction was washed twice with 1N HCl (35ml), 1% NaHCO₃(35ml) washed twice with Na₂SO₃And (5) drying. After evaporation of the solvent, the solid was dissolved in EtOAc under heating and crystallized on standing. Filtration gave compound III-a as a light brown solid (191mg, 71% yield). Directly dissolving the compound III-a in anhydrous acetonitrile, and adding trifluoromethyl selenium silver salt (Ag (bpy) (SeCF) in batches₃)₂)²(33mg, 0.23mmol) and stirred at room temperature for 24 hours. The reaction solution was concentrated and dropped into 150ml of water, and the obtained solid was filtered with 5% CH₃OH/CH₂Cl₂Plate chromatography separation was performed for the developing solvent to obtain compound I-a as a white solid (125mg, 54% yield).

Nuclear magnetic resonance:¹H NMR(400MHz,CDCl₃)δ(ppm):1.14(s,3H),1.24(s,3H),1.68(s,3H),1.82(s,3H),2.16(s,3H),2.35-2.56(m,6H),3.72-3.82(m,2H,),4.16-4.17(m,1H),4.19-4.21(m,1H),4.31(s,1H),4.98(d,1H,J＝12.0Hz),5.51(d,1H,J＝4.0Hz),5.69(d,1H,J＝4.0Hz),6.0(d,1H,J＝8.0Hz),6.25-6.29(m,2H),6.85(d,1H,J＝12.0Hz),7.34-7.41(m,7H),7.50-7.51(m,3H),7.52-7.54(m,1H),7.63-7.74(m,2H),8.13(d,J＝8.0Hz,2H).

¹³C NMR(100MHz,CDCl₃)δ(ppm):9.6,14.8,20.8,22.7,26.8,35.5,43.2,45.6,52.8,58.5,72.2,75.1,79.2,84.5,126.6,127.1,128.8,129.2,130.3,132.1,132.9,133.7,136.6,142.6,167.1,169.8,171.3,203.8.

¹⁹F NMR(376MHz,CDCl₃)δ-34.9.

MS[ESI]:C₅₀H₅₂F₃NO₁₅Se[M+H]⁺＝1043.9

preparation example 2: synthesis of Compounds of formula I-b

The reaction formula is as follows:

in a three-necked flask, the compound of formula IV, paclitaxel (200mg,0.23mmol) in a mixed solvent of dichloromethane and water (CH)₂Cl₂(V)：H₂To o (v) ═ 1:1, potassium hydrogencarbonate (42mg, 0.2mmol) was added, and 2-bromopropionyl bromide (60mg, 0.28mmol) was added at room temperature, followed by stirring for 1 hour to complete the reaction by TLC. The reaction was washed twice with 1N HCl (35ml), 1% NaHCO₃(35ml) washed twice with Na₂SO₃And (5) drying. After evaporation of the solvent, the solid was dissolved in EtOAc under heating and crystallized on standing. Filtration afforded compound III-b as a light brown solid (191mg, 71% yield). Directly dissolving the compound III-b in anhydrous acetonitrile, and adding trifluoromethyl selenium silver salt (Ag (bpy) (SeCF) in batches₃)₂)²(52mg, 0.23mmol), and stirred at room temperature for 24 hours. The reaction solution was concentrated and dropped into 150ml of water, and the obtained solid was filtered with 5% CH₃OH/CH₂Cl₂Plate chromatography separation was performed for the developing solvent to obtain compound I-b as a white solid (140mg, yield 60%).

Nuclear magnetic resonance:¹H NMR(400MHz,CDCl₃)δ(ppm):1.13(s,3H),1.23(s,3H),1.72(s,3H),1.80-1.95(m,9H),2.16(s,3H),2.35-2.55(m,6H),3.80-3.81(m,2H),4.19-4.21(m,1H),4.32(s,1H),4.98(d,1H,J＝12.0Hz,-CH),5.49(d,1H,J＝4.0Hz),5.69(d,1H,J＝4.0Hz),5.95(d,1H,J＝8.0Hz),6.23-6.29(m,2H),6.88(d,1H,J＝12.0Hz),7.35-7.42(m,7H),7.49-7.51(m,3H),7.53-7.57(m,1H),7.66-7.76(m,2H),8.12(d,J＝8.0Hz,2H).

¹³C NMR(100MHz,CDCl₃)δ(ppm):9.6,10.5,10.7,14.8,20.8,22.1,26.8,29.7,35.6,43.2,45.6,52.9,58.5,72.0,75.0,79.1,81.3,84.5,126.6,127.3,129.0,129.5,130.4,132.5,132.9,133.2,136.7,142.4,167.5,169.4,171.2,203.8.

¹⁹F NMR(376MHz,CDCl₃)δ-33.3.

MS[ESI]:C₅₁H₅₄F₃NO₁₅Se[M+H]⁺＝1057.9

preparation example 3: synthesis of Compounds of formula I-c

The reaction formula is as follows:

a compound of formula IV, paclitaxel (200mg, 0.23mmol) was dissolved in a mixed solvent of dichloromethane and water (CH) in a three-necked flask₂Cl₂(V)：H₂To o (v) ═ 1:1, potassium hydrogencarbonate (42mg, 0.2mmol) was added, and 2-bromobutyryl bromide (60mg, 0.28mmol) was added at room temperature, followed by stirring for 1 hour to complete the reaction by TLC. The reaction was washed twice with 1N HCl (35ml), 1% NaHCO₃(35ml) washed twice with Na₂SO₃And (5) drying. After evaporation of the solvent, the solid was dissolved in EtOAc under heating and crystallized on standing. Filtration afforded compound III-c as a light brown solid (191mg, 71% yield). Directly dissolving the compound III-c in anhydrous acetonitrile, and adding trifluoromethyl selenium silver salt (Ag (bpy) (SeCF) in batches₃)₂)²(52mg, 0.23mmol), and stirred at room temperature for 24 hours. The reaction solution was concentrated and dropped into 150ml of water, and the obtained solid was filtered with 5% CH₃OH/CH₂Cl₂Plate chromatography separation was performed for the developing solvent to obtain compound I-c as a white solid (140mg, yield 60%).

Nuclear magnetic resonance:¹H NMR(400MHz,CDCl₃)δ(ppm):0.88-0.98(m,3H),1.17(d,6H,J＝4.0Hz),1.82(s,3H),1.82-1.93(m,9H),2.13(s,3H),2.35-2.56(m,6H),3.39-3.73(m,2H),3.94(d,1H,J＝8.0Hz),4.20-4.35(m,1H),4.32(s,1H),4.70(d,1H,J＝12.0Hz,-CH),5.49(d,1H,J＝4.0Hz),5.75(d,1H,J＝4.0Hz),5.99(d,1H,J＝8.0Hz),6.22-6.26(m,2H),6.91(d,1H,J＝12.0Hz),7.34-7.44(m,7H),7.51-7.54(m,3H),7.57-7.59(m,1H),7.62-7.72(m,2H),8.17(d,J＝8.0Hz,2H).

¹³C NMR(100MHz,CDCl₃)δ(ppm):9.6,13.8,14.8,16.3,20.5,25.9,29.5,35.3,40.4,42.7,52.7,53.4,57.6,71.9,74.9,79.1,82.1,82.7,126.6,127.2,129.4,129.1,130.6,132.4,132.7,133.5,136.3,142.8,167.2,169.1,171.5,203.4.

¹⁹F NMR(376MHz,CDCl₃)δ-34.5.

MS[ESI]:C₅₂H₅₆F₃NO₁₅Se[M+H]⁺＝1072.0

preparation example 4: synthesis of Compounds I-d

The reaction formula is as follows:

in a three-necked flask, paclitaxel (200mg, 0.23mmol), which is a compound of formula IV, was dissolved in dichloromethane, triphenylphosphine (42mg, 0.2mmol) was added, and the mixture was stirred at room temperature for 1 hour to complete the reaction by TLC. The reaction solution is mixed with 1% NaHCO₃(35ml) washed twice with Na₂SO₄And (5) drying. After the solvent is evaporated to dryness, the solid is heated and dissolved by acetonitrile, and is placed for crystallization. Filtration gave compound II as a light brown solid (191mg, 71% yield). Directly dissolving compound II in anhydrous acetonitrile, and adding trifluoromethyl selenium silver salt (Ag (bpy) (SeCF) in batches₃)₂)²(52mg, 0.23mmol), and stirred at room temperature for 24 hours. The reaction solution was concentrated and dropped into 150ml of water, and the obtained solid was filtered with 5% CH₃OH/CH₂Cl₂Plate chromatography separation was performed for the developing solvent to obtain compound I-d as a white solid (120mg, 52% yield).

Nuclear magnetic resonance:¹H NMR(400MHz,CDCl₃)δ(ppm):0.54-0.62(m,6H),0.91-0.95(m,9H),1.05(s,3H),1.22(s,3H),1.69(s,4H),1.85-1.92(t,1H,J＝8.4Hz),2.19-2.20(m,6H),2.28-2.30(m,5H),2.25-2.58(m,1H),3.88-3.90(d.1H,J＝6.8Hz),4.14-4.16(d,1H,J＝8.4Hz),4.31-4.33(d,1H,J＝8.0Hz),4.48-4.52(m,1H),4.83-4.87(t,1H,J＝8.0Hz),4.96-4.98(d,1H,J＝8.8Hz),5.63-5.65(d,1H,J＝6.8Hz),6.47(s,1H),7.47-7.51(t,2H,J＝7.6Hz),7.60-7.63(t,1H,J＝7.6Hz),8.11-8.13(d,2H,J＝7.6Hz).

¹³C NMR(100MHz,CDCl₃)δ(ppm):5.3,6.8,10.0,15.0,20.1,22.7,26.8,37.2,38.7,42.8,48.3,58.6,67.9,72.4,74.7,75.8,78.9,80.8,84.2,128.4,129.8,130.3,132.6,133.6,144.0,169.3,170.7,202.8.

¹⁹F NMR(376MHz,CDCl₃)δ-33.4.

MS[ESI]:C₄₈H₅₀F₃NO₁₃Se[M+H]⁺＝986.2

pharmacological Activity

EXAMPLE 1 screening of antitumor Activity in vitro (preliminary inhibition experiment)

Positive control drug: paclitaxel injection (TAXOL), 5ml:30 mg/count, Jiangsu Osekang pharmaceutical Co., Ltd., lot number: 171211. The tested cell strain is selected from four cell strains of human poorly differentiated gastric adenocarcinoma cell BGC-823, human hepatoma cell SMMC-7721, human lung carcinoma cell A549 and human promyelocytic leukemia cell HL-60.

The test method comprises the following steps: taking a bottle of cells in an exponential growth phase, adding 0.25% trypsin digestion solution, digesting to make adherent cells fall off, and counting by 2-4 multiplied by 10⁴And (4) preparing cell suspension per ml. Inoculating the cell suspension on a 96-well plate at a concentration of 180 μ l/well, and placing in a constant temperature CO₂The culture was carried out in an incubator for 24 hours. The solution was changed, the test drug was added at 20. mu.l/well, and the culture was carried out for 48 hours. MTT was added to a 96-well plate at 20. mu.l/well and reacted in an incubator for 4 hours. The supernatant was aspirated, DMSO was added at 150. mu.l/well, and shaken on a shaker for 5 minutes. Test substance three concentrations (1X 10)^-7，1×10^-6,1×10^-5(ii) a mol/L), measuring the light absorption value of each hole at the position with the wavelength of 570nm by using a microplate reader, and respectively calculating the cell inhibition rate at each concentration.

Percent cell inhibition (negative control group OD value-drug sensitive group OD value)/negative control group OD value x 100%

TABLE 1

Test results show that the compounds I-a, I-b, I-c and I-d have in-vitro inhibition effect on four tumor cell lines, the effect strength on BGC-823, SMMC-7721, A549 and HL-60 cell lines is superior to that of TAXOL (TAXOL) which is a reference medicament, and particularly the IC of the compounds I-d on BGC-823₅₀The value was only 0.05. mu.M.

Experimental example 2 in vivo antitumor Activity

The experimental animal selects SPF male Kunming mouse with the body mass of 19-22g, which is provided by animal experiment center of Wuhan university, tumor mouse S180 sarcoma is introduced by pharmaceutical research institute of Chinese medical academy of sciences, the seed is frozen and preserved in laboratory at low temperature, the S180 cell for experiment is cell suspension for 4 th generation after recovery, and the positive control drug selects paclitaxel.

The S180 tumor-bearing mouse model is established by aseptically extracting ascites from S180 mice, counting the cell suspension under a microscope, and adjusting the cell concentration to 2.0 × 10⁷and/mL, 0.2mL of the S180 ascites tumor fluid was inoculated subcutaneously in the right armpit of the mouse aseptically, and 20 healthy mice were divided into groups at random according to body weight.

The administration method and the tumor inhibition rate are calculated as follows: the administration is started 2 days after the tumor cells are inoculated to the mice, the mice are randomly divided into 3 dose groups of high, medium and low compounds I, positive control groups (paclitaxel 5mg/kg) and negative control groups according to body weight, the intraperitoneal administration is carried out 1 time every day, the administration volume is 0.5 mL/animal, the experimental administration time is 9 days, the animals are sacrificed 24 hours after the last administration, the body mass is weighed, tumor masses are dissected, the mass is weighed, and the tumor growth inhibition rate is calculated according to the following formula.

TABLE 2 inhibitory Effect of Compound I on mouse S180

Animal experiment results show that the compounds I-a, I-b, I-c and I-d have the effect of inhibiting tumor growth on S180-bearing mice, the tumor inhibition effect is obvious, and the anti-tumor effect (5mg/kg) under the same dose is obviously superior to that of a control compound taxol. Thus, compounds I-a, I-b, I-c and I-d showed significantly greater tumor growth inhibition efficiency than paclitaxel.

Claims

1. A compound of formula I:

or a pharmaceutically acceptable salt thereof,

wherein L is a direct bond or OCOCHR, wherein R is a hydrogen atom or a linear or branched alkyl group.

2. The compound according to claim 1, wherein the compound of formula I is a compound selected from the group consisting of:

or a pharmaceutically acceptable salt thereof.

3. A process for the preparation of a compound of formula I according to claim 1, comprising the steps of:

(i) reacting a compound of formula IV

And

(ii) reacting a compound of formula III with silver trifluoromethyl seleno [ Ag (bpy) (SeCF)₃)]₂Reaction to give the compound of formula I

Wherein L is as defined in claim 1; x and X', which may be the same or different, are independently a halogen selected from the group consisting of fluorine, chlorine, bromine and iodine atoms.

4. A process for preparing compounds I-d comprising the steps of:

(i) reacting a compound of formula IV

Reacting with triphenyl phosphine in organic solvent to obtain the compound of formula II

And

(ii) reacting a compound of formula II with silver trifluoromethyl selenide [ Ag (bpy) (SeCF)₃)]₂Reaction to give the compound of formula I-d

5. A process according to claim 3 wherein in step (i) the compound of formula IV is reacted with a halo acyl halide represented by X' -CO-CHR-X in an organic solvent, the reaction being carried out under catalysis of potassium bicarbonate.

6. A pharmaceutical composition comprising a compound of formula I as claimed in claim 1 or 2, or a pharmaceutically acceptable salt thereof, and optionally a pharmaceutically acceptable excipient or carrier.

7. Use of a compound of formula I according to claim 1 or 2 or a pharmaceutically acceptable salt thereof for the preparation of a medicament for the prevention and/or treatment of tumors.

8. The use of claim 7, wherein the tumor is selected from the group consisting of colon cancer, breast cancer, prostate cancer, cervical cancer, liver cancer, and lung cancer.