CN111170963A - Application of 4- (benzoselenazole-2-yl) arylamine compound in treating gastric cancer - Google Patents

Application of 4- (benzoselenazole-2-yl) arylamine compound in treating gastric cancer Download PDF

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CN111170963A
CN111170963A CN201811342015.0A CN201811342015A CN111170963A CN 111170963 A CN111170963 A CN 111170963A CN 201811342015 A CN201811342015 A CN 201811342015A CN 111170963 A CN111170963 A CN 111170963A
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史东方
承曦
杨艳
傅长金
顾杰
龚维伟
李鹏飞
张敏
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Jiangsu Atom Bioscience and Pharmaceutical Co Ltd
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Abstract

The invention discloses application of 4- (benzoselenazole-2-yl) arylamine compounds in treating gastric cancer, which are compounds shown in a general formula (I) or pharmaceutically acceptable salts thereof. The invention finds a new application of the 4- (benzoselenazole-2-yl) arylamine compound in disease treatment, and provides a potential medicine for treating gastric cancer.

Description

Application of 4- (benzoselenazole-2-yl) arylamine compound in treating gastric cancer
Technical Field
The invention belongs to the field of pharmaceutical chemistry, and particularly relates to application of 4- (benzoselenazole-2-yl) arylamine compounds in treatment of gastric cancer.
Background
Gastric cancer is one of the most common malignancies of the digestive system. Worldwide, the incidence of gastric cancer ranks 5 th in malignant tumors, and the mortality rate is 3 rd in malignant tumors. Data published by the international research center for cancer (IARC) indicate that there are 951,600 new cases of gastric cancer (with approximately 2 times as many cases in men as women) and 723,100 cases of death worldwide in 2012. The incidence of Gastric Cancer is statistically highest in east Asia (notably Korea, Mongolia, Japan and China) and second in Europe, east and south America, while in North America and most Africa regions it is lowest (Torre LA, Bray F, Siegel RL, ethyl. Global Cancer standards, 2012.Ca A Cancer Journal for clinics, 2015,65(2): 87-108; IARC. Al Cancers (explicit non-medial in Cancer) estimated and updated company, motion and previous company in 2012; Worreal R, Park, JY FormanD. the Fit Cancer-the IARC workshop creating Group, Bestrest Research in Clinical Research, Clinical Research study, scientific, 28, 2014-19; truck LP 19. 16: 13. Journal of Cancer).
According to statistics, the incidence of gastric cancer in China is 2 nd in malignant tumors, and the number of newly added cases and death population exceeds 40% of the whole world each year (Torre LA, Siegel RL, Ward EM, et al. Global cancer inclusion and Mortality Rates and Trends-an update. cancer epidemic and prevention biometers, 2016,25(1): 16-27); and about 352,300 patients die from gastric cancer each year (Layke JC, Lopez PP. gastric cancer: choice of diagnosis and treatment protocol. Chinese general medicine 2015,18(3): 248-249).
The pathogenesis of gastric cancer is not completely elucidated so far, and the incidence of gastric cancer is mainly considered to be related to dietary habits, helicobacter pylori (Hp) infection, serum Pepsinogen (PG), genetic factors, metabolic syndrome, psychological stress and other factors. Helicobacter pylori is probably the largest causative factor of Gastric cancer, and about 90% of the newly added cases of noncardial Gastric cancer are associated therewith (Chang M, Zhang JC, Zhou Q, et al. research Progress of clinical Epidemiology of Gastric cancer, Chinese medicine Journal of Gastric cancer & Hepatology,2017,26(9): 966-969).
At present, the means for treating the gastric cancer is limited, and surgical resection is still the only clinical method for radically treating the gastric cancer. For early stage gastric cancer, chemotherapy is not required in principle after surgery, but is required if: (1) the age is less than 40 years; (2) there are multiple lesions; (3) the area of the focus is more than 5cm2(ii) a (4) The malignancy of the pathological type is high (Haqing, Zhang Wu. discussing the diagnosis and treatment of gastric cancer. world latest medical information abstracts, 2018,18(14): 55).
In China, the screening system of the Gastric Cancer is not complete, and the early diagnosis rate of the Gastric Cancer is low, so most patients are diagnosed with Advanced Gastric Cancer or Advanced Gastric Cancer (Advanced Gastric Cancer). At the moment, better curative effect cannot be obtained by simple operation treatment, and the recurrence and metastasis rate after operation is higher; some patients have large tumor volume and can not be operated, and the operation can be performed only after the tumor volume is reduced by newly-assisted chemotherapy. It has been shown that for Advanced Gastric Cancer, combined surgery does not only provide survival advantage, but the overall survival for some patients is even lower than that of Chemotherapy Alone (Chemotherapy plus Chemotherapy top Chemotherapy Alone for Advanced Cancer with single Non-viable Factor (REGATTA): a Phase 3, random controlled Cancer. Lancet Oncology,2016,17(3): 309-318). Therefore, chemotherapy-based comprehensive therapy is a main treatment means for patients with advanced gastric cancer, and can improve the prognosis and the life quality of the patients.
Currently, the cytotoxic drugs used clinically for chemotherapy for advanced gastric cancer mainly include four major classes: (1) oral fluorouracils, such as capecitabine, tegafur; (2) taxoids, such as paclitaxel, docetaxel; (3) third-generation platins, such as oxaliplatin; (4) topoisomerase I inhibitors, such as irinotecan. In addition, the marketed molecular targeted drugs mainly include human epidermal growth factor receptor 2(HER2) antibodies, such as trastuzumab, vascular endothelial growth factor receptor (VEGFR-2) antibodies, such as ramucirumab, and small molecule tyrosinase inhibitor apatinib targeting VEGFR-2, etc. (Lekaichun, Leping. selection of advanced gastric cancer treatment drugs, pharmaceutical services and research, 2018,18(1): 1-5).
Although the combination of chemotherapy for Gastric Cancer is the standard treatment method (NCCN clinical practice patient in Oncology: Gastric Cancer (2015Version)) suggested by NCCN guidelines, the effect has reached a bottleneck, the survival benefit of patients cannot be increased more, and patients can further worsen their physical conditions due to toxic and side effects such as myelosuppression of leucopenia and thrombocytopenia caused by the cytotoxicity of chemotherapeutic drugs. In addition, Gastric Cancer is a highly heterogeneous disease driven by multiple genetic mutations and epigenetic abnormalities, and therefore drug development is delayed in targeting, and existing drugs have poor targeting and low sensitivity, such as trastuzumab, which is effective only in about 20% of patients with Gastric Cancer who are HER2 positive (Bang YJ, Van Cutsem E, Feyereislova A, et al Trastuzumab in combining with Chemotherapy Treatment Chemotherapy Alone for Treatment of HER2-positiveAdvanced Gastric Cancer-associated tissue Cancer (ToGA): a Phase 3, Open-label, Randomized Controlled Cancer. Lancet,2010,376(6): 687-697). Thus, neither current chemotherapy nor targeted therapy is effective against gastric cancer, increasing the patient's survival benefit.
The incidence and mortality of gastric cancer in China are at a high level in the world, and the incidence and mortality of gastric cancer are seriously harmful to the health of residents, causing heavy burden to families and society, and due to the high heterogeneity of gastric cancer and the lack of current clinical treatment means, the development of novel treatment methods or drugs is urgently needed to cope with the current situation that the incidence and mortality of gastric cancer are increasing.
Selenium is one of the essential trace elements in human body, and the decrease of selenium content in blood can induce many diseases including tumor and cardiovascular (Reeves MA, Hoffmann PR. the human seleninoptome: Recentred instruments inter Functions and regulations. cellular and Molecular Life Sciences,2009,66(15): 2457-78). Selenium-containing drugs have become hot spots for researchers at home and abroad due to their application in anti-tumor, anti-virus and treatment of diseases related to nervous system, and research on drugs mainly focuses on anti-tumor, anti-inflammatory and anti-hypertension (Romuldo C, Stefania C, Marina DG, et al, Novel Selenium-relating Non-natural Diamino acids, tetrahedron Letters,2007,48(7): 1425-1427).
The compounds of formula (II) and their use in cancer are disclosed in the united states patents (Malcolm f.g.stevens, andrewd.westwell, Mei-Sze Chua, et al, substitated 2-arylbenzozazole compounds and the use of such compounds as anticancer agents, us6858633b1) by Malcolm f.g.stevens et al, but the description is primarily directed to breast cancer, and since the pathogenesis and therapeutic pathways differ substantially between different cancers and most anticancer compounds are therapeutic for only certain sensitive cancers, it remains virtually unknown whether such compounds would be effective in other cancers.
Figure BDA0001862811860000031
The inventor of the present invention has published an article on the synthesis of benzothiazole compounds and Their in Vitro and in vivo anti-Breast Cancer effects (Dong-Fan Shi, Tracey D. Bradshaw, Samantha Wrigley, et al.Antitumor Benzothiazoles.3.Synthesis of 2- (4-Aminophenyl) benzothiazoles and evaluation of the action against the Cancer vaccine Breast Cancer cells in Vitro and vivo Vivo. journal of medical Chemistry,1996,39:3375-3384), and Chinese patents (history, Fourdrin, ray et al. Compound for treating or preventing Breast Cancer. CN201610299350.1) filed in the Oriental of the inventor's history, published the benzo-selenazole-2-benzene compounds of formula (III) and Their pharmacological Activities against Breast Cancer. Both compounds have nanomolar inhibitory effects on human breast cancer cells, wherein the benzothiazole compounds have an ER inhibitory effect+(MCF-7 and BO cell lines) and ER-The breast cancer nude mouse transplantation tumor of (MT-1 and MT-3 cell strains) shows very obvious tumor inhibition effect,however, the two compounds have no inhibitory activity on other tumor cell lines such as prostate cancer, bladder cancer, melanoma, lung cancer, liver cancer, esophageal cancer and the like.
Figure BDA0001862811860000041
To date, no report is available on the effect of 4- (benzoselenazole-2-yl) arylamine compounds on gastric cancer models.
Disclosure of Invention
The invention aims to provide application of 4- (benzoselenazole-2-yl) arylamine compounds in treating gastric cancer on the basis of the prior art.
The object of the invention can be achieved by the following measures:
the application of the compound shown in the general formula (I) or the pharmaceutically acceptable salt thereof in preparing the medicine for treating or preventing gastric cancer,
Figure BDA0001862811860000042
wherein,
R1and R2Each independently selected from H, D, halogen, -CN, C1-3Alkyl, substituted C1-3Alkyl radical, C1-3Alkoxy or substituted C1-3An alkoxy group;
R3selected from H, halogen, -OH, -CN, -C (═ O) NH2substituted-C (═ O) NH2、C1-3Alkyl, substituted C1-3Alkyl radical, C2-3Alkenyl radical, C2-3Alkynyl, C1-3Alkoxy or substituted C1-3An alkoxy group;
R4selected from H, D, halogen, -OH, -CN, -NH2substituted-NH2、-C(＝O)NH2substituted-C (═ O) NH2、C1-3Alkyl, substituted C1-3Alkyl radical, C2-3Alkenyl radical, C2-3Alkynyl, C1-3Alkoxy or substituted C1-3One or two of alkoxy groups;
n is 1 or 2;
R5selected from H, -CN, -OH, C1-3Alkyl radical, C1-3Alkoxy or amino acid residues;
z is selected from CH or N;
R1、R2、R3or R4Wherein the substituents are selected from D, halogen, OH, C1-3Alkyl or C1-3An alkoxy group.
In a preferred embodiment, R in the present invention1And R2Each independently selected from H, D, halogen, -CN, C1-3Alkyl, substituted C1-3Alkyl radical, C1-3Alkoxy or substituted C1-3Alkoxy, the substituent is selected from D, F or C1-3An alkoxy group;
in another preferred embodiment, R in the present invention1And R2Each independently selected from H, D, F, Cl, -CN, -CH3、-CF3、-OCF3or-OCHF2。
In another preferred embodiment, R in the present invention1Selected from D, F, Cl, -CN, -CH3or-CF3。
In another preferred embodiment, R in the present invention2Is selected from H.
In a preferred embodiment, R in the present invention3Selected from H, halogen, -CN, -C (═ O) NH2、C1-2Alkyl radical, C2-3Alkenyl radical, C2-3Alkynyl, C1-3Alkoxy or substituted C1-3An alkoxy group.
In another preferred embodiment, R in the present invention3Selected from H, F, Cl, Br, -CN, -C (═ O) NH2、-CH3、-CH2CH3、-CF3、-CH＝CH2、-C≡CH、-OCHF2or-OCF3。
In a preferred embodiment, R in the present invention4Selected from H, D, halogen, -CN, C1-3Alkyl, substituted C1-3Alkyl radical, C1-3Alkoxy or substituted C1-3One or two of alkoxyAnd (4) seed preparation.
In another preferred embodiment, R in the present invention4Selected from H, D, F, Cl, Br, I, -CN, -CH3、-CF3、-OCH3、-OCH2CH3、-OCHF2or-OCF3。
In a preferred embodiment, R in the present invention5Selected from H, C1-3Alkyl radical, C1-3Alkoxy groups or amino acid residues.
In another preferred embodiment, R in the present invention5Selected from H, -CH3、-CF3、-OCH3Or 2, 6-diamino-hexanoyl.
In a preferred embodiment, the compounds referred to in the present invention are selected from:
2-amino-5- (5-fluorobenzoselenol-2-yl) benzonitrile,
2-amino-3-fluoro-5- (5-fluorobenzeneselenazol-2-yl) benzonitrile,
2-ethynyl-4- (5-fluorobenzoselenol-2-yl) aniline,
5-fluoro-4- (5-fluorobenzoselenol-2-yl) -2-methylaniline,
2-bromo-6- (5-fluoro-benzoselenazol-2-yl) pyridine-3-ammonia,
3-amino-6- (5-fluorobenzeneselenazol-2-yl) -2-formamido pyridine,
4- (5-fluorobenzeneselenazol-2-yl) -2-methylaniline,
2-bromo-4- (5-fluoro-benzoselenazol-2-yl) -6-methylaniline,
2-bromo-6-fluoro-4- (5-fluoro benzoselenazol-2-yl) aniline,
2, 6-difluoro-4- (5-fluoro-benzoselenazol-2-yl) aniline,
2-fluoro-4- (5-fluoro-benzoselenazol-2-yl) -6-methylaniline.
Unless otherwise specified, each group referred to in the present invention has the following meaning.
"H", i.e., hydrogen, refers to protium (1H), which is the predominant stable isotope of hydrogen.
"D", deuterium, refers to a stable form isotope of hydrogen, also known as deuterium, and the element symbol is D.
"halogen" means a fluorine atom, chlorine atom, bromine atom or iodine atom.
"-OH" means a hydroxyl group.
“-NH2", refers to an amino group.
“-CONH2", i.e., C (═ O) -NH2And refers to an amide group.
"-CN" means a cyano group.
“-NO2", refers to a nitro group.
"alkyl" means a saturated aliphatic radical of 1 to 10 carbon atoms, including straight and branched chain radicals (a numerical range referred to herein, e.g., "1 to 10", means that the radical, in this case alkyl, may contain 1 carbon atom, 2 carbon atoms, 3 carbon atoms, etc., up to and including 10 carbon atoms). Alkyl groups having 1 to 4 carbon atoms are referred to as lower alkyl groups. When a lower alkyl group has no substituent, it is referred to as unsubstituted lower alkyl. The alkyl group may be C1-6Alkyl radical, C1-5Alkyl radical, C1-4Alkyl radical, C1-3Alkyl radical, C1-2Alkyl radical, C2-3Alkyl radical, C2-4Alkyl groups, and the like. Specific alkyl groups include, but are not limited to, methyl, ethyl, propyl, 2-propyl, n-butyl, isobutyl, tert-butyl, and the like. Alkyl groups may be substituted or unsubstituted.
"alkenyl" means an unsaturated hydrocarbon group having at least one carbon-carbon double bond, including straight and branched chain groups (a numerical range referred to herein, e.g., "2-5", means that the group, in this case alkenyl, may contain 2 carbon atoms, 3 carbon atoms, 4 carbon atoms, etc., up to and including 5 carbon atoms). The alkenyl group in the present invention may be C2-8Alkenyl radical, C2-6Alkenyl radical, C2-5Alkenyl radical, C2-4Alkenyl radical, C2-3Alkenyl groups and the like, specific alkenyl groups include, but are not limited to, ethenyl, propenyl, and butenyl.
"alkynyl" means an unsaturated hydrocarbon group having at least one carbon-carbon triple bond, including straight and branched chain groups (a numerical range referred to in this application, e.g., "2-5", refers to the group, in this case an alkyneGroups, which may contain 2 carbon atoms, 3 carbon atoms, 4 carbon atoms, and the like, up to and including 5 carbon atoms). The alkynyl group in the present invention may be C2-8Alkynyl, C2-6Alkynyl, C2-5Alkynyl, C2-4Alkynyl, C2-3Alkynyl and the like, with specific alkenyl groups including, but not limited to, ethynyl, propynyl, and butynyl.
"alkoxy" represents the groups-O- (unsubstituted alkyl) and-O- (unsubstituted cycloalkyl), which further represents-O- (unsubstituted alkyl). Representative examples include, but are not limited to, methoxy, ethoxy, propoxy, cyclopropoxy, and the like.
"amino acid residue" means that the amino acid lacks a group (e.g., -OH, -COOH, or-NH)2) groups formed wherein amino acids include, but are not limited to, the 20 naturally occurring amino acids commonly designated by three letter symbols and also include β -alanine, citrulline, desmosine (desmosine), gamma-aminobutyric acid, homocysteine, homoserine, 4-hydroxyproline, hydroxylysine, isodesmosine (isodesmosine), 3-methylhistidine, norvaline, methionine sulfone (methioninesulfone), ornithine, and the like.
"pharmaceutically acceptable salts" are salts comprising a compound of formula (I) with an organic or inorganic acid, and refer to those salts that retain the biological effectiveness and properties of the parent compound. Such salts include:
(1) salts with acids are formed by reaction of the free base of the parent compound with inorganic acids such as, but not limited to, hydrochloric, hydrobromic, nitric, phosphoric, metaphosphoric, sulfuric, sulfurous, and perchloric acids or organic acids such as, but not limited to, acetic, propionic, acrylic, oxalic, (D) or (L) malic, fumaric, maleic, hydroxybenzoic, γ -hydroxybutyric, methoxybenzoic, phthalic, methanesulfonic, ethanesulfonic, naphthalene-1-sulfonic, naphthalene-2-sulfonic, p-toluenesulfonic, salicylic, tartaric, citric, lactic, mandelic, succinic, or malonic acids, and the like.
(2) The acidic proton present in the parent compound is replaced by a metal ion such as an alkali metal ion, an alkaline earth metal ion or an aluminum ion, or is complexed with an organic base such as ethanolamine, diethanolamine, triethanolamine, tromethamine, N-methylglucamine, or the like.
"pharmaceutical composition" refers to a mixture of one or more compounds described herein or their pharmaceutically acceptable salts and prodrugs with other chemical ingredients, such as pharmaceutically acceptable carriers and excipients. The purpose of the pharmaceutical composition is to facilitate the administration of the compound to an organism.
In the application of the compound, the pharmaceutically acceptable salt or the solvate thereof can be used as an active ingredient or a main active ingredient, and can be prepared into a pharmaceutical composition by being assisted with pharmaceutically acceptable auxiliary materials, and then the pharmaceutical composition is applied to a patient.
The compounds of the present invention may be formulated into any clinically or pharmaceutically acceptable dosage form in a manner known in the art. For oral administration, it can be made into conventional solid preparations such as tablet, capsule, pill, granule, etc.; it can also be made into oral liquid, such as oral solution, oral suspension, syrup, etc. When the composition is formulated into oral preparations, appropriate filler, binder, disintegrating agent, lubricant, etc. can be added. For parenteral administration, it can be made into injection, including injection solution, sterile powder for injection and concentrated solution for injection. The injection can be prepared by conventional method in the existing pharmaceutical field, and can be prepared without adding additives or adding appropriate additives according to the properties of the medicine.
The present invention also provides a method of treating gastric cancer in a human by administering to the human having gastric cancer 0.1 to 1000mg per dose of a compound, a pharmaceutically acceptable salt or solvate thereof of the present invention, or 0.1 to 1000mg per dose of a pharmaceutical composition of the present invention.
The 4- (benzoselenazole-2-yl) arylamine compound has pharmacological activity in resisting breast cancer, but in vitro tests show that the compound has no obvious inhibition effect on tumor cell strains such as prostate cancer, bladder cancer, melanoma, lung cancer, liver cancer, esophageal cancer and the like. However, the present patent found that such compounds are excellent in the therapeutic effect on gastric cancer: has obvious growth inhibition effect on human gastric cancer cell strains MKN-45, AGS and NCI-N87, and the effect is basically close to that of a positive control medicament taxol; the compound also shows excellent effect of inhibiting tumor growth on gastric cancer MKN-45 and AGS nude mouse xenograft tumor, and the tumor inhibition rate is more than 35 percent. Therefore, the compounds can be applied to the field of human gastric cancer treatment.
The invention finds a new application of the 4- (benzoselenazole-2-yl) arylamine compound in disease treatment, and provides a potential medicament for treating gastric cancer.
Drawings
FIG. 1 shows the effect of compound 6 on the inhibition of human gastric cancer cell line AGS in xenografted tumor volume in nude mice;
FIG. 2 shows the effect of compound 6 on the inhibition of xenograft tumor volume of human gastric cancer cell line MKN-45 nude mice;
FIG. 3 shows the inhibitory effect of Compound 22 on the tumor volume of human gastric cancer cell line AGS xenografted in nude mice;
FIG. 4 shows the inhibitory effect of Compound 22 on the xenograft tumor volume of human gastric cancer cell line MKN-45 in nude mice;
FIG. 5 shows the inhibitory effect of Compound 23 on the tumor volume of human gastric cancer cell line AGS xenografted in nude mice;
FIG. 6 shows the effect of compound 23 on the inhibition of xenograft tumor volume of human gastric cancer cell line MKN-45 nude mice;
Detailed Description
The present invention is further illustrated by the following examples, but the scope of the present patent is not limited to the following examples.
Example 1: synthesis of 2-amino-5- (5-fluorobenzoselenazol-2-yl) benzonitrile (6)
Figure BDA0001862811860000081
Step A: a solution of 2-nitro-4-fluoroaniline (5.0g, 32.0mmol) in dichloromethane (80mL) was added dropwise to boron trifluoride ether (6.82g, 48.1mmol) at-20 to-25 ℃. After stirring for 15 minutes, a solution of isoamyl nitrite (4.50g, 38.4mmol) in methylene chloride (20mL) was added dropwise at this temperature. After the addition is finished, stirring is continued for 30 minutes, and then stirring is carried out for 30 minutes at the temperature of minus 10-0 ℃. Cooled petroleum ether (60mL) was added dropwise to the reaction system, and the mixture was filtered, and the filter cake was washed with cooled methyl t-butyl ether (10mL) to give a crude product (8.10g) of 2-nitro-4-fluorophenyl-fluoroborate diazonium salt (1). This compound was used in the next reaction without purification.
And B: to a mixture of crude compound 1 (8.10g) and water (150mL) was added dropwise a solution of potassium selenocyanate (4.35g, 30.2mmol) in water (20mL) in an ice-water bath, and stirring was continued for 1 hour after the addition. Filtration and dissolution of the filter cake with dichloromethane (150 mL). Insoluble matter was removed by filtration, and the filtrate was dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure to obtain a crude product (6.10g) of 4-fluoro-2-nitro-1-selenenylcyanate (2). This compound was used in the next reaction without purification.
And C: metallic sodium (3.23g, 140mmol) was added to a mixture of crude compound 2 (6.10g) and absolute ethanol (90mL) at room temperature and the resulting mixture was stirred for 1 hour under a water bath. Cooling to 0-5 ℃, filtering, washing a filter cake with a small amount of cooled ethanol to obtain a crude product (3.90g) of the 1, 2-bis (4-fluoro-2-nitrophenyl) -diselenide (3). This compound was used in the next reaction without purification.
Step D: the crude compound 3 (3.90g) was dissolved in ethanol (60mL), stannous chloride (7.90g, 41.7mmol) was added and the resulting mixture was stirred under reflux under nitrogen for 4 hours. Most of the solvent was evaporated under reduced pressure, water (120mL) and ethyl acetate (200mL) were added, and the pH was adjusted to 8-9 with 2M sodium hydroxide solution. The insoluble matter was removed by filtration through Celite, the layers were separated, the aqueous layer was extracted with ethyl acetate (60 mL. times.2), and the combined organic layers were dried over anhydrous sodium sulfate. Then, the mixture was purified by column chromatography under reduced pressure (200 to 300 mesh silica gel, eluted with ethyl acetate), and the obtained product was recrystallized from petroleum ether to give 6, 6' -diseleno-bis (3-fluoroaniline) (4) (3.0 g). The overall yield of steps A, B, C and D was 49.6%.
Step E: to a solution of compound 4(3.0g, 7.93mmol) and 4-amino-3-bromobenzoic acid (1.70g, 7.87mmol) in toluene (50mL) was added tributylphosphine (8.0g, 39.5mmol) and the resulting mixture was stirred at reflux under nitrogen for 48 h. Cooling to room temperature, adding water (50mL), and adjusting the pH value to 9-10 by using 2M sodium hydroxide solution. The mixture was extracted with ethyl acetate (40 mL. times.3), and the combined organic phases were washed with saturated brine (25mL) and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure and the product was purified by column chromatography (200-300 mesh silica gel, ethyl acetate: petroleum ether: 1: 50-1: 5 elution) to give 2-bromo-4- (5-fluoro-benzoselenazol-2-yl) aniline (5) (1.60 g). The yield thereof was found to be 54.9%.
Step F: a mixture containing Compound 5(400mg, 1.08mmol), cuprous cyanide (145mg, 1.62mmol) and NMP (10mL) was stirred at 150 deg.C overnight. Cooling to room temperature, adding water (40mL), and adjusting the pH value to 8-9 by using 2M sodium carbonate solution. The mixture was extracted with ethyl acetate (30 mL. times.3), and the combined organic phases were washed with saturated brine (20 mL. times.2) and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the product was purified by column chromatography (200-300 mesh silica gel, ethyl acetate: dichloromethane: petroleum ether ═ 1:1:20 to 1:1:8 elution) to give 2-amino-5- (5-fluoroselenazol-2-yl) benzonitrile (6) (84 mg). The yield thereof was found to be 54.9%.1H NMR(DMSO-d6，400MHz)δ8.15-8.12(m，1H)，8.06(d，J＝2.4Hz，1H)，7.98-7.96(m，1H)，7.79-7.76(m，1H)，7.24-7.19(m，1H)，6.90(d，J＝8.8Hz，1H)，6.83(s，2H)。MS(EI，m/z)：316.0[M-H]-。
Example 2: synthesis of 2-amino-3-fluoro-5- (5-fluorobenzoselenol-2-yl) benzonitrile (9)
Figure BDA0001862811860000101
Step A: to a solution of compound 4(4.30g, 11.4mmol) and 4-amino-3-fluorobenzoic acid (1.76g, 11.3mmol) in toluene (50mL) was added tributylphosphine (11.5g, 39.5mmol), and the resulting mixture was stirred at reflux under nitrogen for 48 h. Cooling to room temperature, adding water (50mL), and adjusting the pH value to 9-10 by using 2M sodium hydroxide solution. The mixture was extracted with ethyl acetate (40 mL. times.3), and the combined organic phases were washed with saturated brine (25mL) and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure and the product was purified by column chromatography (200-300 mesh silica gel, ethyl acetate: petroleum ether: 1:100 to 1:20 elution) to give 2-fluoro-4- (5-fluoro-benzoselenazol-2-yl) aniline (7) (780 mg). The yield thereof was found to be 22.3%.
And B: NBS (585mg, 3.29mmol) was added to a solution of Compound 7(780mg, 2.52mmol) in DMF (10mL) and after addition the mixture was stirred at room temperature for 30 min. Water (40mL) was added, extraction was performed with ethyl acetate (30 mL. times.2), and the combined organic phases were washed successively with water (15mL), saturated aqueous sodium bicarbonate (15mL), and saturated brine (15mL), and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure and the product was recrystallized from petroleum ether/ethyl acetate to give 2-bromo-6-fluoro-4- (5-fluoro-benzoselenazol-2-yl) aniline (8) (720 mg). The yield thereof was found to be 73.6%.1H NMR(DMSO-d6，500MHz)δ8.16-8.13(m，1H)，7.90(s，1H)，7.79(dd，J＝2.0，10.0Hz，1H)，7.73(dd，J＝2.0，10.0Hz，1H)，7.24-7.20(m，1H)，6.12(s，2H)。MS(EI，m/z)：388.9[M+H]+。
And C: a mixture containing compound 8(520mg, 1.34mmol), cuprous cyanide (180mg, 2.01mmol) and NMP (10mL) was stirred at 150 deg.C overnight. Cooling to room temperature, adding water (40mL), and adjusting the pH value to 8-9 by using 2M sodium carbonate solution. The mixture was extracted with ethyl acetate (30 mL. times.3), and the combined organic phases were washed with saturated brine (20 mL. times.2) and dried over anhydrous sodium sulfate. The solvent is evaporated under reduced pressure, and the product is purified by column chromatography (200-300 mesh silica gel, ethyl acetate: petroleum ether ═ 1: 50-1: 20 elution) to obtain 2-amino-3-fluoro-5- (5-fluoro benzoselenazol-2-yl) benzonitrile (9) (150 mg). The yield thereof was found to be 33.5%.1HNMR(DMSO-d6，400MHz)δ8.19-8.16(m，1H)，7.99-7.94(m，2H)，7.80(dd，J＝2.4，10.0Hz，1H)，7.27-7.23(m，1H)，6.99(s，2H)。MS(EI，m/z)：336.0[M+H]+。
Example 3: synthesis of 2-ethynyl-4- (5-fluorophenylselenazol-2-yl) aniline (12)
Figure BDA0001862811860000111
Step A: a mixture containing compound 5(500mg, 1.35mmol), acetic anhydride (0.5mL), pyridine (10mL) and 4-dimethylaminopyridine (10mg, 0.0819mmol) was stirred at 90 ℃ overnight. After cooling to room temperature, water (50mL) was added, extraction was performed with ethyl acetate (30 mL. times.3), and the combined organic phases were washed with saturated brine (15 mL. times.2) and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the product was purified by column chromatography (200-300 mesh silica gel, ethyl acetate: dichloromethane: petroleum ether ═ 1:1:25 to 1:1:10 elution) to give N- [ 2-bromo-4- (5-fluoro-phenylselenazol-2-yl) phenyl ] acetamide (10) (500 mg). The yield thereof was found to be 89.8%.
And B: trimethylsilylacetylene (131mg, 1.33mmol) was added by syringe to a mixture containing compound 10(500mg, 1.21mmol), bis triphenylphosphine palladium dichloride (40mg, 0.0570mmol), triethylamine (40mL) and DMF (4mL) and after addition the resulting mixture was stirred at 50 ℃ overnight. Most of the solvent was distilled off under reduced pressure, water (30mL) was added, extraction was performed with ethyl acetate (30 mL. times.3), and the combined organic phases were washed with saturated brine (15 mL. times.2) and dried over anhydrous sodium sulfate. The solvent is evaporated under reduced pressure, and the product is purified by column chromatography (200-300 mesh silica gel, ethyl acetate: petroleum ether ═ 1: 50-1: 20 elution) to obtain N- {4- (5-fluoro-benzoselenazol-2-yl) -2- [ (trimethylsilyl) ethynyl ] phenyl } acetamide (11) (211 mg). The yield thereof was found to be 40.6%.
And C: a mixture containing Compound 11(100mg, 0.233mmol), 2M sodium hydroxide solution (10mL), THF (5mL) and methanol (10mL) was stirred at 80 ℃ for 1 hour. After cooling to room temperature, water (30mL) was added, extraction was performed with ethyl acetate (30 mL. times.3), and the combined organic phases were washed with saturated brine (15 mL. times.2) and dried over anhydrous sodium sulfate. The solvent is removed by evaporation under reduced pressure, and the obtained product is recrystallized by petroleum ether/ethyl acetate to obtain 2-ethynyl-4- (5-fluorobenzeneselenazol-2-yl) aniline (12).1H NMR(DMSO-d6，400MHz)δ8.13-8.09(m，1H)，7.82(d，J＝2.0Hz，1H)，7.77-7.73(m，2H)，7.22-7.19(m，1H)，6.81(d，J＝8.4Hz，1H)，6.20(s，2H)，4.48(s，1H)。MS(EI，m/z)：315.0[M-H]-。
Example 4: synthesis of 5-fluoro-4- (5-fluoro-benzoselenazol-2-yl) -2-methylaniline (16)
Figure BDA0001862811860000121
Step A: NBS (3.55g, 19.9mmol) was added portionwise to a solution of 5-fluoro-2-methylaniline (2.50g, 20.0mmol) in DMF (20mL) in an ice-water bath and after addition the resulting mixture was stirred at this temperature for a further 1 h. Water (80mL) was added, the mixture was extracted with ethyl acetate (60 mL. times.3), and the combined organic phases were washed successively with a saturated sodium bicarbonate solution (30 mL. times.2) and a saturated brine (30 mL. times.2), and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure to give a crude product (4.87g) of 4-bromo-3-fluoro-6-methylaniline (13). This compound was used in the next reaction without purification.
And B: a mixture containing crude compound 13 (4.87g), cuprous cyanide (2.63g, 29.4mmol) and NMP (15mL) was stirred at 180 ℃ for 7 hours under nitrogen. Water (75mL) was added, extraction was performed with ethyl acetate (50 mL. times.3), and the combined organic phases were washed successively with water (30 mL. times.2) and saturated brine (30mL), and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure and the product was purified by column chromatography (200-300 mesh silica gel, ethyl acetate: petroleum ether: 1:30 to 1:5 elution) to give 4-amino-2-fluoro-5-methylbenzonitrile (14) (1.74 g). The total yield of the two reactions of the step A and the step B is 58.2 percent.
And C: a mixture containing compound 14(1.74g, 11.6mmol), 1M sodium hydroxide solution (50mL) and ethanol (5mL) was stirred at reflux overnight. Cooled to room temperature, water (50mL) was added, extracted with methyl tert-butyl ether (20 mL. times.2) and the product was in the aqueous phase. And (4) adjusting the pH value of the water phase to 3-4 by using 2M hydrochloric acid, and separating out solids. Filtration and drying of the filter cake gave 4-amino-2-fluoro-5-methylbenzoic acid (15) (1.75 g). The yield thereof was found to be 89.2%.
Step D: to a solution of compound 4(1.0g, 2.64mmol) and compound 15(447mg, 2.64mmol) in toluene (30mL) was added tributylphosphine (2.68g, 13.2mmol), and the resulting mixture was stirred at reflux under nitrogen for 36 h. Cooling to room temperature, adding water (40mL), and adjusting the pH value to 9-10 by using 2M sodium hydroxide solution. The mixture was extracted with ethyl acetate (40 mL. times.3), and the combined organic phases were washed with saturated brine (25mL) and dried over anhydrous sodium sulfate. Evaporating under reduced pressure to remove the solvent, and purifying the product by column chromatography (200-300 mesh silica gel, ethyl acetate and petroleum ether: 1: 50-1: 10 elution) to obtain 5-fluoro-4- (5-fluorobenzeneselenazole-2-yl) -2-methylaniline (16)) (655 mg). The yield thereof was found to be 72.9%.1H NMR(DMSO-d6，400MHz)δ8.14-8.10(m，1H)，7.90(d，J＝8.8Hz，1H)，7.78(dd，J＝2.4，10.0Hz，1H)，7.22-7.17(m，1H)，6.54-6.51(m，1H)，6.08(s，2H)，2.13(s，3H)。MS(EI，m/z)：323.0[M-H]-。
Example 5: synthesis of 2-bromo-6- (5-fluoro-benzoselenazol-2-yl) pyridin-3-amino (18)
Figure BDA0001862811860000131
Step A: to a solution of compound 4(1.80g, 4.76mmol) and 5-aminopyridine-2-carboxylic acid (657mg, 4.76mmol) in toluene (50mL) was added tributylphosphine (4.82g, 23.8mmol) and the resulting mixture was stirred at reflux under nitrogen for 36 h. Cooling to room temperature, adding water (40mL), and adjusting the pH value to 9-10 by using 2M sodium hydroxide solution. The mixture was extracted with ethyl acetate (40 mL. times.3), and the combined organic phases were washed with saturated brine (25mL) and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure and the product was purified by column chromatography (200-300 mesh silica gel, ethyl acetate: dichloromethane: petroleum ether ═ 1:1:20 to 1:1:5 elution) to give 6- (5-fluoro-benzoselenazol-2-yl) pyridin-3-amino (17) (712 mg). The yield thereof was found to be 51.2%.
And B: NBS (61mg, 0.343mmol) was added portionwise to a solution of compound 17(100mg, 0.342mmol) in dichloromethane (6mL) under an ice-water bath, and after the addition was complete, the resulting mixture was stirred at this temperature for a further 0.5 h. Water (15mL) was added, the mixture was extracted with methylene chloride (60 mL. times.3), and the combined organic phases were washed successively with a saturated sodium hydrogencarbonate solution (20mL) and a saturated brine (20mL), and dried over anhydrous sodium sulfate. The solvent is evaporated under reduced pressure, and the product is purified by column chromatography (200-300 mesh silica gel, THF: dichloromethane: petroleum ether ═ 1:1:20 to 1:1:10 elution) to obtain 2-bromo-6- (5-fluoro-benzoselenazol-2-yl) pyridine-3-amino (18).1H NMR(DMSO-d6，400MHz)δ8.15-8.11(m，1H)，7.98(d，J＝8.4Hz，1H)，7.80(dd，J＝2.4，10.0Hz，1H)，7.26-7.19(m，2H)，6.37(s，2H)。MS(EI，m/z)：369.9[M-H]-。
Example 6: synthesis of 3-amino-6- (5-fluorobenzoselenol-2-yl) -2-formamidopyridine (19)
Figure BDA0001862811860000132
Experimental procedure for the synthesis of compound 19 starting from compound 18 was carried out as in step F of example 1 (since this batch of compound 18 was not purified by column chromatography, little sodium bicarbonate was present in the workup and water was not removed, so that compound 19 was formed in this reaction).1H NMR(DMSO-d6，400MHz)δ8.16-8.12(m，1H)，8.08(d，J＝8.8Hz，1H)，7.82(dd，J＝2.4，10.0Hz，1H)，7.76(s，1H)，7.65(s，1H)，7.54(s，2H)，7.30(d，J＝8.8Hz，1H)，7.26-7.21(m，1H)。MS(EI，m/z)：335.0[M-H]-。
Example 7:
the synthesis of the compounds 4- (5-fluoro-selenazol-2-yl) -2-methylaniline (20), 2-bromo-4- (5-fluoro-selenazol-2-yl) -6-methylaniline (21), 2-bromo-6-fluoro-4- (5-fluoro-selenazol-2-yl) aniline (22), 2, 6-difluoro-4- (5-fluoro-selenazol-2-yl) aniline (23) and 2-fluoro-4- (5-fluoro-selenazol-2-yl) -6-methylaniline (24) is described in patent CN201610299350.1 or US10005744B 2.
Example 8: growth inhibition effect of compound on human gastric cancer cell strains AGS, MKN-45 and NCI-N87
First, name and source of experimental material
Human gastric cancer cell strains AGS, MKN-45 and NCI-N87 were purchased from cell resource center of Shanghai Life sciences research institute of Chinese academy of sciences. Paclitaxel, Resazurin, and methylene blue were purchased from Sigma-Aldrich co., LLC; potassium ferricyanide and potassium ferrocyanide were purchased from alatin reagent, inc; DMEM medium, 1640 medium, phenol red free DMEM and fetal bovine serum were purchased from Thermo Fisher Scientific Inc; penicillin and streptomycin were purchased from bi yun biotechnology limited.
Second, Experimental methods
DMEM medium for AGS (containing 10% fetal calf serum, 100U/mL penicillin, 0.1mg/mL streptomycin), 1640 medium for MKN-45 (containing 10% fetal calf serum, 100U/mL penicillin, 0.1mg/mL streptomycin), DMEM medium for NCI-N87 (containing 20%Fetal bovine serum, 100U/mL penicillin, 0.1mg/mL streptomycin), at 37 deg.C and 5% CO, respectively2Culturing in incubator until the cell density reaches about 90%.
According to 3X 103The cell count per well was inoculated into a 96-well plate at 37 ℃ with 5% CO2Culturing in an incubator for 24 h.
Preparing test compounds or paclitaxel as control drugs with different concentration gradients by using a culture medium, and adding the test compounds or paclitaxel into a 96-well plate according to 100 mu L/well to serve as test compound wells or control drug wells; medium containing no test compound or control drug was added at 100. mu.L/well as a negative control well. Standing at 37 deg.C for 5% CO2In the incubator, AGS and MKN-45 cells are cultured for 72h, and NCI-N87 cells are cultured for 120 h.
Resazurin (15mg/50mL, 200X), methylene Blue (25mg/10mL, 1000X), potassium ferricyanide (0.329g/100mL, 100X) and potassium ferrocyanide (0.422g/100mL, 100X) were dissolved in PBS (0.1M, pH 7.4) to prepare a 10 × Alamar Blue solution, which was diluted with phenol-free red DMEM medium to prepare a1 × Alamar Blue solution just before use.
The cells in the 96-well plate were carefully washed 2 times with PBS (0.1M, pH 7.4) and the PBS was aspirated off, and 1 × Alamar Blue solution was added at 100 μ L/well; to the cell-free wells, 100. mu.L of 1 × Alamar Blue solution was added as blank wells. Placing 96-well plate at 37 deg.C and 5% CO2Culturing in incubator for 3 h.
The fluorescence of the cells was measured at Ex 530/Em 590nm using a microplate reader Victor X4(Perkin Elmer). Fluorescence values of the test compound wells are given as F(test Compound)Represents; fluorescence values of blank control wells are given as F(blank control)Represents; fluorescence values of negative control wells are given as F(negative control)And (4) showing. The cell viability was calculated at different drug concentrations according to the following formula, with 3 replicate wells per concentration, giving the mean and standard deviation.
Figure BDA0001862811860000151
Calculating the cell viability of the test compound or control drug using Prism Graph softwareMedian Inhibitory Concentration (IC)50)。
Third, experimental results
The test results are shown in Table 1, and the compound has obvious inhibition effect on the growth of human gastric cancer cell strains AGS, MKN-45 and NCI-N87. Among them, compounds 6, 9, 12, 19, 22 and 23 had superior inhibitory effects.
TABLE 1 half Inhibitory Concentration (IC) of test compounds against human gastric cancer cell lines AGS, MKN-45 and NCI-N8750，nM)
Figure BDA0001862811860000152
Example 9: study of growth inhibitory Activity of Compounds 6, 22 and 23 against human gastric cancer AGS and MKN-45 nude mouse xenograft tumors
First, test materials
1. Test animal
SPF-grade BALB/c nude mice, female, were 6-8 weeks old at the start of dosing and had a body weight of 18-20 g. Provided by the Changzhou Kavens laboratory animals Co., Ltd. (laboratory animal production license: SCXK (su) 2016-0010; laboratory animal use license: SYXK (su) 2017-0007). The purchased animal batch number: 201820473.
2. test reagent
Polyethylene glycol 400(PEG400) with lot number 20180412, purchased from a metropolis chemical reagent plant; sodium chloride injection (normal saline), lot number A17111105, purchased from Hebei Tian Chengyao GmbH; DMSO, Lot Q6949 from MP Biomedicals.
3. Cell line
Human gastric cancer AGS and MKN-45 cells are purchased from cell resource center of Shanghai Life sciences research institute of Chinese academy of sciences; AGS is cultured in 1640 culture medium of 10% fetal bovine serum, and MKN-45 is cultured in DMEM culture medium containing 10% fetal bovine serum.
Second, test method
1. Test compounds
Low dose group (administration dose: 2.5 mg/kg): 2.0mg of test compound was accurately weighed before administration, dissolved in 8mL of a clear solution with intravenous solvent (PEG 40025%, DMSO 2.5%, physiological saline 72.5%), and the final concentration of test compound in the low dose group was 0.25mg/mL in intravenous solution, and the volume of intravenous administration was 0.2mL/20g body weight.
High dose group (administration dose: 5.0 mg/kg): 4.0mg of test compound was accurately weighed before administration, dissolved in 8mL of a clear solution in an intravenous vehicle (PEG 40050%, DMSO 5%, physiological saline 45%), and the final concentration of the intravenous solution of the test compound in the high dose group was 0.50mg/mL, and the volume of intravenous administration was 0.2mL/20g body weight.
2. Test grouping and administration mode
Taking AGS and MKN-45 cells in logarithmic growth phase, respectively inoculating the AGS and MKN-45 cells to the right axillary subcutaneous part of each 60 nude mice under the aseptic condition, wherein the inoculation amount of the cells is 5 multiplied by 106One/only. Measuring the diameter of the transplanted tumor by using a vernier caliper until the tumor grows to 100mm3On the left and right, 56 mice bearing tumors, namely AGS and MKN-45, which have good growth state and good tumor size uniformity, are respectively selected and randomly divided into 7 groups, wherein each group comprises 8 mice, namely a model group, and compounds 6, 22 and 23, namely a low-dose group and a high-dose group. Each group was administered by intravenous injection once daily for 5 days on days 0, 1,2, 3, and 4, respectively, and vehicle control of equal volume was administered to the model group. The antitumor effect of the tested compound is dynamically observed by using a method for measuring the tumor size. Tumor diameters were measured every two days and weighed simultaneously. On day 20, each group was decapped and sacrificed, and tumor mass was surgically removed and accurately weighed.
The formula for Tumor Volume (TV) is:
Figure BDA0001862811860000171
wherein a and b represent length and width, respectively.
The calculation formula of the tumor inhibition rate% is as follows:
Figure BDA0001862811860000172
third, test results
As shown in tables 2 and 3 and fig. 1 to 6, test compounds 6, 22 and 23 significantly inhibited the tumor growth of gastric cancer cell AGS and MKN-45 nude mouse transplantable tumor after tail vein injection at the administration doses of 2.5mg/kg and 5.0mg/kg for 5 consecutive days, respectively.
TABLE 2 inhibition of growth of xenograft tumors in nude mice by human gastric carcinoma cell line AGS (Mean + -SD, n ═ 8)
Figure BDA0001862811860000173
TABLE 3 inhibition of human gastric cancer cell line MNK-45 xenograft tumor growth in nude mice by compounds (Mean + -SD, n ═ 8)
Figure BDA0001862811860000174
Figure BDA0001862811860000181

Claims (10)

1. The application of the compound shown in the general formula (I) or the pharmaceutically acceptable salt thereof in preparing the medicine for treating or preventing gastric cancer,
Figure FDA0001862811850000011
wherein,
R1and R2Each independently selected from H, D, halogen, -CN, C1-3Alkyl, substituted C1-3Alkyl radical, C1-3Alkoxy or substituted C1-3An alkoxy group;
R3selected from H, halogen, -OH, -CN, -C (═ O) NH2substituted-C (═ O) NH2、C1-3Alkyl, substituted C1-3Alkyl radical, C2-3Alkenyl radical, C2-3Alkynyl, C1-3Alkoxy or substituted C1-3An alkoxy group;
R4selected from H, D, halogen, -OH,-CN、-NH2substituted-NH2、-C(＝O)NH2substituted-C (═ O) NH2、C1-3Alkyl, substituted C1-3Alkyl radical, C2-3Alkenyl radical, C2-3Alkynyl, C1-3Alkoxy or substituted C1-3One or two of alkoxy groups;
n is 1 or 2;
R5selected from H, -CN, -OH, C1-3Alkyl radical, C1-3Alkoxy or amino acid residues;
z is selected from CH or N;
R1、R2、R3or R4Wherein the substituents are selected from D, halogen, OH, C1-3Alkyl or C1-3An alkoxy group.
2. Use according to claim 1, wherein R1And R2Each independently selected from H, D, F, Cl, -CN, -CH3、-CF3、-OCF3or-OCHF2。
3. Use according to claim 2, wherein R1Selected from D, F, Cl, -CN, -CH3or-CF3，R2Is selected from H.
4. Use according to claim 1, wherein R3Selected from H, F, Cl, Br, -CN, -C (═ O) NH2、-CH3、-CH2CH3、-CF3、-CH＝CH2、-C≡CH、-OCHF2or-OCF3。
5. Use according to claim 1, wherein R4Selected from H, D, halogen, -CN, C1-3Alkyl, substituted C1-3Alkyl radical, C1-3Alkoxy or substituted C1-3One or two of the alkoxy groups.
6. Use according to claim 1, wherein R4Selected from H, D、F、Cl、Br、I、-CN、-CH3、-CF3、-OCHF2or-OCF3；R5Selected from H or an amino acid residue.
7. Use according to claim 1, wherein R5Selected from H or 2, 6-diamino-hexanoyl.
8. Use according to claim 1, wherein the compound is selected from:
2-amino-5- (5-fluorobenzoselenol-2-yl) benzonitrile,
2-amino-3-fluoro-5- (5-fluorobenzeneselenazol-2-yl) benzonitrile,
2-ethynyl-4- (5-fluorobenzoselenol-2-yl) aniline,
5-fluoro-4- (5-fluorobenzoselenol-2-yl) -2-methylaniline,
2-bromo-6- (5-fluoro-benzoselenazol-2-yl) pyridine-3-ammonia,
3-amino-6- (5-fluorobenzeneselenazol-2-yl) -2-formamido pyridine,
4- (5-fluorobenzeneselenazol-2-yl) -2-methylaniline,
2-bromo-4- (5-fluoro-benzoselenazol-2-yl) -6-methylaniline,
2-bromo-6-fluoro-4- (5-fluoro benzoselenazol-2-yl) aniline,
2, 6-difluoro-4- (5-fluoro-benzoselenazol-2-yl) aniline,
2-fluoro-4- (5-fluoro-benzoselenazol-2-yl) -6-methylaniline.
9. The use according to claim 1, wherein the compound, pharmaceutically acceptable salt or solvate thereof according to claim 1 is used as an active ingredient or a main active ingredient, and is supplemented with pharmaceutically acceptable auxiliary materials to prepare a pharmaceutical composition.
10. A method for treating gastric cancer in a human, comprising administering to a human suffering from gastric cancer 0.1-1000mg per dose of a compound, pharmaceutically acceptable salt or solvate thereof of claim 1, or 0.1-1000mg per dose of a pharmaceutical composition of claim 9.
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