WO2020098516A1 - 4-(苯并噻唑-2-基)芳胺类化合物治疗胃癌的用途 - Google Patents

4-(苯并噻唑-2-基)芳胺类化合物治疗胃癌的用途 Download PDF

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WO2020098516A1
WO2020098516A1 PCT/CN2019/115183 CN2019115183W WO2020098516A1 WO 2020098516 A1 WO2020098516 A1 WO 2020098516A1 CN 2019115183 W CN2019115183 W CN 2019115183W WO 2020098516 A1 WO2020098516 A1 WO 2020098516A1
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fluorobenzothiazol
alkyl
gastric cancer
fluoro
aniline
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PCT/CN2019/115183
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English (en)
French (fr)
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布拉德肖特蕾西·D
史蒂文斯马尔科姆·F·G
张继虹
王玉玲
史东方
承曦
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诺丁汉大学
昆明理工大学
江苏新元素医药科技有限公司
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/425—Thiazoles
    • A61K31/428—Thiazoles condensed with carbocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents

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  • the invention belongs to the field of medicinal chemistry, and specifically relates to the use of a class of 4- (benzothiazol-2-yl) aromatic amine compounds in the treatment of gastric cancer.
  • gastric cancer is the fifth most common cancer and the third most likely cancer.
  • gastric cancer accounted for 7% of the global cancer incidence rate (IARC. All Cancers (excluding non-melanoma skin cancer) Estimated Incidence, Mortality and Prevalence Worldwide in 2012).
  • IARC. All Cancers excluding non-melanoma skin cancer
  • IARC. All Cancers excluding non-melanoma skin cancer
  • the incidence of gastric cancer in China is the highest in the world, and more than 40% of new cases of gastric cancer come from China.
  • Gastric cancer is China's second leading cause of death (Torre, LA, Siegel, RL, Ward, EM, et al.
  • Most chemotherapy regimens for gastric cancer are based on the combined use of at least two drugs, such as 5-fluorouracil and cisplatin, or related derivative compounds such as capecitabine and oxaliplatin.
  • drugs such as 5-fluorouracil and cisplatin, or related derivative compounds such as capecitabine and oxaliplatin.
  • Other commonly used drugs are paclitaxel, docetaxel, epirubicin, and irinotecan.
  • these are cytotoxic chemotherapeutic drugs which can cause systemic toxic reactions related to the system, including bone marrow suppression, increased risk of infection, fatigue, nausea and vomiting, hair loss, loss of appetite, diarrhea, and often dose-limiting.
  • Recent targeted therapies have been used clinically, such as trastuzumab (anti-HER2 antibody) and ramucirumab (anti-VEGFR2 antibody) (Li Kaichun, Li Ping. The choice of drugs for the treatment of advanced gastric cancer. Pharmaceutical services And Research, 2018, 18 (1): 1-5).
  • gastric cancer is a highly heterogeneous disease driven by multiple genetic mutations and epigenetic abnormalities. Therefore, the development of targeted drugs has lagged, and existing drugs have poor targeting and low sensitivity.
  • the development of a new treatment plan for gastric cancer is crucial to ultimately improve the prognosis and quality of life of patients with gastric cancer.
  • CN201610299350.1 announced the benzoselenazole-2-benzene compounds and their anti-mammary glands Cancer pharmacological activity. These two compounds were human breast cancer cells nanomolar inhibitory effect, wherein the benzothiazole compound of ER + (MCF-7 cell lines, and BO) and ER - (MT-1 and MT-3 cell line)
  • ER + MCF-7 cell lines
  • BO ER -
  • MT-1 and MT-3 cell line The breast cancer xenografts of nude mice all show very significant tumor suppressive effects, but these two types of compounds have no inhibitory activity against other tumor cell lines such as prostate cancer, bladder cancer, melanoma, lung cancer, liver cancer, and esophageal cancer.
  • the object of the present invention is to provide a class of 4- (benzothiazol-2-yl) aromatic amine compounds for the treatment of gastric cancer based on the prior art.
  • the object of the present invention can be achieved by the following measures:
  • R 1 and R 2 are independently selected from H, D, halogen, -CN, C 1-3 alkyl, substituted C 1-3 alkyl, C 1-3 alkoxy or substituted C 1-3 alkyl Oxy;
  • R 4 is selected from H, D, halogen, -OH, -CN, -NH 2 , substituted -NH 2 , C 1-3 alkyl, substituted C 1-3 alkyl, C 1-3 alkoxy or One or two of substituted C 1-3 alkoxy;
  • R 5 is selected from H, -CN, -OH, C 1-3 alkyl, C 1-3 alkoxy or amino acid residues;
  • n 1 or 2;
  • R 1 , R 2 , R 3 or R 4 are selected from D, halogen, -OH, C 1-3 alkyl or C 1-3 alkoxy.
  • R 1 and R 2 in the present invention are independently selected from H, D, halogen, -CN, C 1-3 alkyl, substituted C 1-3 alkyl, C 1-3 Alkoxy or substituted C 1-3 alkoxy, the substituent is selected from D, F or C 1-3 alkoxy;
  • R 1 and R 2 in the present invention are independently selected from H, D, F, Cl, —CN, —CH 3 , —CF 3 , —OCF 3 or —OCHF 2 .
  • R 1 in the present invention is selected from D, F, Cl, —CN, —CH 3 or —CF 3
  • R 2 is selected from H.
  • R 3 in the present invention is selected from halogen, —CN, —C ( ⁇ O) NH 2 , C 1-2 alkyl, C 2-3 alkenyl, C 2-3 alkynyl, C 1-3 alkoxy or substituted C 1-3 alkoxy.
  • R 4 in the present invention is selected from H, D, halogen, -CN, C 1-3 alkyl, substituted C 1-3 alkyl, C 1-3 alkoxy or substituted One or two of C 1-3 alkoxy groups.
  • R 4 in the present invention is selected from D, F, Cl, Br, I, -CN, -CH 3 , -CF 3 , -OCH 3 , -OCH 2 CH 3 , -OCHF 2 Or -OCF 3 .
  • R 5 in the present invention is selected from H or amino acid residues.
  • R 5 in the present invention is selected from H or 2,6-diamino-hexanoyl.
  • the compound of general formula (I) in the present invention is selected from:
  • H or hydrogen, refers to protium (1H), which is the main stable isotope of hydrogen.
  • D deuterium, refers to a stable form of hydrogen isotope, also known as heavy hydrogen, and its element symbol is D.
  • Halogen means fluorine atom, chlorine atom, bromine atom or iodine atom.
  • Alkyl refers to a saturated aliphatic hydrocarbon group of 1-10 carbon atoms, including straight-chain and branched-chain groups (the numerical range mentioned in this application, for example “1-10", refers to this group In this case, it is an alkyl group, which may contain 1 carbon atom, 2 carbon atoms, 3 carbon atoms, etc., up to 10 carbon atoms).
  • An alkyl group containing 1-4 carbon atoms is called a lower alkyl group. When the lower alkyl group has no substituent, it is called an unsubstituted lower alkyl group.
  • the alkyl can be selected from C 1-6 alkyl, C 1-5 alkyl, C 1-4 alkyl, C 1-3 alkyl, C 1-2 alkyl, C 2-3 alkyl, C 2-4 Alkyl and so on.
  • Specific alkyl groups include, but are not limited to, methyl, ethyl, propyl, 2-propyl, n-butyl, isobutyl or tert-butyl, and the like.
  • the alkyl group may be substituted or unsubstituted.
  • Alkenyl means an unsaturated hydrocarbon group having at least one carbon-carbon double bond, including straight-chain and branched-chain groups (the numerical range mentioned in this application, such as “2-5", refers to this group At this time, it is an alkenyl group, which may contain 2 carbon atoms, 3 carbon atoms, 4 carbon atoms, etc., up to 5 carbon atoms).
  • the alkenyl in the present invention may be C 2-8 alkenyl, C 2-6 alkenyl, C 2-5 alkenyl, C 2-4 alkenyl, C 2-3 alkenyl, etc.
  • Specific alkenyl groups include but It is not limited to vinyl, propenyl, and butenyl.
  • Alkynyl means an unsaturated hydrocarbon group having at least one carbon-carbon triple bond, including straight-chain and branched-chain groups (the numerical range mentioned in this application, such as "2-5", refers to this group In this case, it is an alkynyl group, which may contain 2 carbon atoms, 3 carbon atoms, 4 carbon atoms, etc., up to 5 carbon atoms).
  • the alkynyl group in the present invention may be C 2-8 alkynyl, C 2-6 alkynyl, C 2-5 alkynyl, C 2-4 alkynyl, C 2-3 alkynyl, etc.
  • Specific alkenyl groups include but It is not limited to ethynyl, propynyl and butynyl.
  • Alkoxy means -O- (unsubstituted alkyl) and -O- (unsubstituted cycloalkyl) groups, which further means -O- (unsubstituted alkyl).
  • Representative embodiments include but are not limited to methoxy, ethoxy, propoxy, cyclopropoxy, and the like.
  • amino acid residue refers to a group formed by an amino acid lacking a certain group (such as -OH, -COOH, or -NH 2 ), where amino acids include, but are not limited to, 20 naturally occurring species usually designated by three-letter symbols Amino acids, and also includes ⁇ -alanine, citrulline, demosine, ⁇ -aminobutyric acid, homocysteine, homoserine, 4-hydroxyproline, hydroxylysine, iso Isodemosine, 3-methylhistidine, norvaline, methioninesulfone and ornithine.
  • An example of an amino acid residue includes, but is not limited to: 2,6-diamino-hexanoyl.
  • “Pharmaceutically acceptable salt” is a salt comprising a compound of general formula (I) formed with an organic acid or an inorganic acid, and means those salts that retain the biological effectiveness and properties of the parent compound. Such salts include:
  • a salt with an acid obtained by the reaction of the free base of the parent compound with an inorganic acid or an organic acid, such as (but not limited to) hydrochloric acid, hydrobromic acid, nitric acid, phosphoric acid, metaphosphoric acid, sulfuric acid, sulfurous acid And perchloric acid, organic acids such as (but not limited to) acetic acid, propionic acid, acrylic acid, oxalic acid, (D) or (L) malic acid, fumaric acid, maleic acid, hydroxybenzoic acid, ⁇ -hydroxybutyric acid , Methoxybenzoic acid, phthalic acid, methanesulfonic acid, ethanesulfonic acid, naphthalene-1-sulfonic acid, naphthalene-2-sulfonic acid, p-toluenesulfonic acid, salicylic acid, tartaric acid, citric acid, lactic acid, Mandelic acid, succinic acid or malonic acid etc.
  • the salts of acid protons present in the parent compound are replaced by metal ions or coordinated with organic bases, metal ions such as alkali metal ions, alkaline earth metal ions or aluminum ions, organic bases such as ethanolamine, diethanolamine, trivalent Ethanolamine, tromethamine, N-methylglucamine, etc.
  • “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 the organism.
  • a pharmaceutically acceptable salt or a solvate thereof can be used as an active ingredient or a main active ingredient, supplemented with a pharmaceutically acceptable auxiliary material to make a pharmaceutical composition, and then The patient is administered.
  • the present invention also provides a method for treating human gastric cancer, that is, administering a compound, a pharmaceutically acceptable salt, or a solvate thereof to a patient suffering from gastric cancer, in particular, to a patient suffering from gastric cancer
  • the patient administers 0.1-1000 mg of the compound of the present invention, a pharmaceutically acceptable salt or a solvate thereof per dose, or 0.1-1000 mg of the pharmaceutical composition of the present invention per dose.
  • the present invention finds a new use of 4- (benzothiazol-2-yl) arylamine compounds in the treatment of diseases, and provides a potential drug for the treatment of gastric cancer.
  • Figure 1 is the inhibitory effect of compound 2 on the tumor volume of human gastric cancer cell line AGS xenograft in nude mice;
  • Figure 2 is the inhibitory effect of compound 2 on the tumor volume of human gastric cancer cell line MKN-45 xenograft in nude mice;
  • Figure 3 is the inhibitory effect of compound 13 on the tumor volume of human gastric cancer cell line AGS xenograft in nude mice;
  • Fig. 4 shows the inhibitory effect of compound 13 on the tumor volume of human gastric cancer cell line MKN-45 xenograft in nude mice.
  • Step A Place a mixture containing 5-fluoro-2-methylbenzothiazole (2.0g, 12.0mmol), sodium hydroxide (1.60g, 40.0mmol), water (4mL) and ethylene glycol (16mL) under nitrogen Stir at 130 ° C for 4 hours. Cool to room temperature, add water (60 mL), and adjust the pH to 5-6 with 2M hydrochloric acid. It was extracted with ethyl acetate (40 mL ⁇ 3), and the combined organic phase was washed with saturated brine (20 mL ⁇ 2) and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure to obtain 2-amino-4-fluorothiophenol (1) (1.50 g). The yield was 87.3%.
  • Step B A mixture containing Compound 1 (180 mg, 1.26 mmol), 4-amino-3-fluoro-5-methylbenzoic acid (213 mg, 1.26 mmol) and polyphosphoric acid (5.0 g) was stirred at 150 ° C for 1.5 hours . Cool to room temperature and adjust the pH to 7-8 with 2M sodium hydroxide solution. It was extracted with ethyl acetate (40 mL ⁇ 3), and the combined organic phases were washed successively with water (30 mL) and saturated brine (20 mL), and dried over anhydrous sodium sulfate.
  • NBS (44.8 mg, 0.252 mmol) was added to a solution of compound 3 (60 mg, 0.229 mmol) in DMF (5 mL). After the addition was complete, the resulting mixture was stirred at room temperature for 0.5 hour. Water (20 mL) was added and extracted with ethyl acetate (20 mL ⁇ 3). The combined organic phases were washed with saturated sodium bicarbonate solution (15 mL) and saturated brine (15 mL) in this order, and dried over anhydrous sodium sulfate.
  • NCS (62 mg, 0.464 mmol) was added to a solution of compound 3 (80 mg, 0.305 mmol) in DMF (5 mL). After the addition was complete, the resulting mixture was stirred at room temperature overnight. Water (20 mL) was added and extracted with ethyl acetate (20 mL ⁇ 3). The combined organic phases were washed with saturated sodium bicarbonate solution (15 mL) and saturated brine (15 mL) in this order, and dried over anhydrous sodium sulfate.
  • Step A A mixture containing 3,5-difluoro-4-nitrobenzyl alcohol (1.0 g, 5.29 mmol), Oxone (16.3 g, 26.5 mmol), acetonitrile (22 mL) and water (22 mL) was stirred under reflux overnight. Cool to room temperature, add water (80 mL) and extract with ethyl acetate (30 mL ⁇ 3). The product is in the organic phase. Water (20 mL) was added to the combined organic phase, and then the pH was adjusted to 9-10 with 2M sodium hydroxide solution, the layers were separated, and the product was in the aqueous phase.
  • the aqueous phase was adjusted to pH 2 to 3 with 2M hydrochloric acid, extracted with ethyl acetate (20 mL ⁇ 3), and dried over anhydrous sodium sulfate.
  • the solvent was distilled off under reduced pressure to obtain 3,5-difluoro-4-nitrobenzoic acid (7) (410 mg). The yield was 38.2%.
  • Step B A mixture containing compound 7 (410 mg, 2.02 mmol), 10% palladium on carbon (40 mg) and methanol (10 mL) was stirred at room temperature under hydrogen overnight. Filter through silica bath soil and rinse the filter cake with ethyl acetate (10 mL). Then, water (30 mL) was added to the filtrate and extracted with ethyl acetate (20 mL ⁇ 3). The combined organic phase was washed with saturated brine (10 mL) and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure to obtain 4-amino-3,5-difluorobenzoic acid (8) (306 mg). The yield was 87.5%.
  • Step C Using compound 1 and compound 8 as raw materials to synthesize 2,6-difluoro-4- (5-fluorobenzothiazol-2-yl) aniline (9), the experimental operation was prepared according to the method of Example 1, step B .
  • Step A A mixture containing compound 1 (1.30 g, 9.08 mmol), 4-aminobenzoic acid (1.24 g, 9.04 mmol) and polyphosphoric acid (15.0 g) was stirred at 130 ° C for 1 hour. Cool to room temperature and adjust the pH to 7-8 with 2M sodium hydroxide solution. It was extracted with ethyl acetate (40 mL ⁇ 3), and the combined organic phases were washed successively with water (30 mL) and saturated brine (20 mL), and dried over anhydrous sodium sulfate.
  • Step B At -10 ⁇ -15 ° C, add NBS (55 mg, 0.309 mmol) to a solution of compound 11 (100 mg, 0.409 mmol) in methylene chloride (10 mL). After the addition, the resulting mixture is at this temperature Continue stirring for 0.5 hour. Water (20 mL) was added and extracted with dichloromethane (20 mL ⁇ 3). The combined organic phases were washed with saturated sodium bicarbonate solution (15 mL) and saturated brine (15 mL) in this order, and dried over anhydrous sodium sulfate.
  • NCS (66 mg, 0.494 mmol) was added to a solution of compound 11 (100 mg, 0.409 mmol) in DMF (10 mL). After the addition was complete, the resulting mixture was stirred at room temperature overnight. Water (40 mL) was added and extracted with ethyl acetate (20 mL ⁇ 3). The combined organic phase was washed with saturated sodium bicarbonate solution (15 mL) and saturated brine (15 mL) in this order, and dried over anhydrous sodium sulfate.
  • Example 12 2-amino-5- (5-fluorobenzothiazol-2-yl) benzonitrile and 2,6-diamino-N- [4- (5-fluorobenzothiazol-2-yl) See the patent US6858633B1 for the synthesis of -2-methylphenyl] hexanamide.
  • Example 13 Compounds inhibit growth of human gastric cancer cell lines AGS, MKN-45 and NCI-N87
  • Human gastric cancer cell lines AGS, MKN-45 and NCI-N87 were purchased from the Cell Resource Center, Shanghai Academy of Life Sciences, Chinese Academy of Sciences.
  • Paclitaxel, Resazurin and methylene blue were purchased from Sigma-Aldrich Co., LLC; potassium ferricyanide and potassium ferrocyanide were purchased from Aladdin Reagent Co., Ltd; DMEM medium, 1640 medium, phenol red-free DMEM and fetal bovine serum Purchased from Thermo Fisher Inc .; Penicillin and Streptomycin were purchased from Biyuntian Biotechnology Co., Ltd.
  • DMEM medium for AGS containing 10% fetal bovine serum, 100U / mL penicillin, 0.1mg / mL streptomycin
  • MKN-45 1640 medium containing 10% fetal bovine serum, 100U / mL penicillin, 0.1mg / mL streptomycin
  • NCI-N87 with DMEM medium containing 20% fetal bovine serum, 100U / mL penicillin, 0.1mg / mL streptomycin
  • three cells were cultured at 37 °C, 5% CO 2 incubator To the cell density of about 90%.
  • the cells were seeded in 96-well plates at 3 ⁇ 10 3 / well, and incubated at 37 ° C in a 5% CO 2 incubator for 24 hours.
  • test compound or control drug paclitaxel Prepare different concentrations of test compound or control drug paclitaxel with medium, and add 100 ⁇ L / well to 96-well plate as test compound well or control drug well; add 100 ⁇ L / well medium without test compound or control drug , As a negative control well. Incubate at 37 ° C, 5% CO 2 , AGS and MKN-45 cells were cultured for 72 hours, and NCI-N87 cells were cultured for 120 hours.
  • the fluorescence value of the cells was detected at 530nm at Ex 530 / Em with Victor X4 (Perkin Elmer).
  • the fluorescence value of the test compound well is represented by F (test compound) ;
  • the fluorescence value of the blank control well is represented by F (blank control) ;
  • the fluorescence value of the negative control well is represented by F (negative control) .
  • Prism Graph software was used to calculate the half-inhibitory concentration (IC 50 ) of the test compound or control drug on the cells according to the cell survival rate.
  • Example 14 Compound 2 and 13 on human gastric cancer AGS or MKN-45 xenograft growth inhibitory activity in nude mice
  • SPF grade BALB / c nude mice, female are 6-8 weeks old at the start of administration and weigh 18-20 g. Provided by Changzhou Cavens Experimental Animal Co., Ltd. (Experimental Animal Production License: SCXK (Su) 2016-0010; Experimental Animal Use License: SYXK (Su) 2017-0007). Purchased animal batch number: 201820473.
  • Polyethylene glycol 400 (PEG400), batch number 20180412, purchased from Chengdu Kelong Chemical Reagent Factory; sodium chloride injection (physiological saline), batch number A17111105, purchased from Hebei Tiancheng Pharmaceutical Co., Ltd .; DMSO, batch number Q6949, purchased from MP Biomedicals.
  • Human gastric cancer AGS and MKN-45 cells were purchased from the Cell Resource Center of Shanghai Academy of Life Sciences, Chinese Academy of Sciences; AGS was cultured in 1640 medium containing 10% fetal bovine serum, and MKN-45 was cultured in DMEM medium containing 10% fetal bovine serum Medium cultivation.
  • Low-dose group (administration dose: 2.5 mg / kg): accurately weigh 2.0 mg of the test compound before administration and dissolve it into 8 mL of clear solution with a solvent for intravenous injection (PEG400 25%, DMSO 2.5%, physiological saline 72.5%) Solution, the final concentration of the intravenous solution of the test compound in the low-dose group was 0.25 mg / mL, and the intravenous administration volume was 0.2 mL / 20 g body weight.
  • a solvent for intravenous injection PEG400 25%, DMSO 2.5%, physiological saline 72.5%
  • High-dose group (administration dose: 5.0 mg / kg): accurately weigh 4.0 mg of the test compound before administration and dissolve it to 8 mL of clear solution with a vehicle for intravenous injection (PEG400 50%, DMSO 5%, saline 45%) Solution, the final concentration of the intravenous injection solution of the test compound in the high-dose group was 0.50 mg / mL, and the intravenous administration volume was 0.2 mL / 20 g body weight.
  • a vehicle for intravenous injection PEG400 50%, DMSO 5%, saline 45%
  • AGS tumor-bearing mice When the tumor grows to about 100mm 3 , select the tumor-bearing nude mice with good growth status and good tumor size uniformity (40 AGS tumor-bearing mice, MKN-45 tumor-bearing mice 24) Mice), AGS tumor-bearing mice were randomly divided into 5 groups, 8 in each group, namely model group, compound 2 and 13 low-dose group and high-dose group; MKN-45 tumor-bearing mice were randomly divided into 3 groups, 8 in each , Namely the model group, compound 2 low-dose group and high-dose group. Each group was administered via tail vein injection, which was administered once a day on days 0, 1, 2, 3, and 4 for a total of 5 days. The model group was given an equal volume of vehicle control.
  • the formula for calculating the tumor volume (TV) is:
  • the formula for calculating the% of tumor suppression is:
  • Test results are shown in Table 2, Table 3, and Figures 1 to 3.
  • Compounds 2 and 13 may be It significantly inhibited the tumor growth of gastric cancer cell AGS xenograft tumor in nude mice.
  • Compound 2 also significantly inhibited the tumor growth of MKN-45 xenograft tumor in nude mice.
  • Example 15 Study on the growth inhibitory activity of compound 13 on human gastric cancer MKN-45 xenograft tumor in nude mice
  • Tween 80 (S24644 Aladdin Pharmaceutical Grade), batch number C10094183, purchased from Yunnan Chien Technology Co., Ltd .; Matrigel (354234BD), batch number 4069011, purchased from Kunming Chipu Biotechnology Company; Sino-American Serum (04-001 -1B1A Biological Industries), batch number 11F267, purchased from Yunnan Chien Technology Co., Ltd .; 1mL sterile syringe, batch number 1801001, purchased from Hunan Oasis Wellcome Development Co., Ltd .; sodium chloride injection (normal saline), batch number A15102005- 2. Purchased from Kelun Pharmaceutical Co., Ltd.
  • Human gastric cancer MKN-45 cells were purchased from Beijing Union Cell Bank; MKN-45 was cultured in 1640 medium containing 10% fetal bovine serum.
  • Low-dose group (administration dose: 5.0 mg / kg): accurately weigh 2.0 mg of the test compound before administration, first dissolve it into suspension with 0.4 mL of Tween 80, and then dissolve into 4 mL of resuspended solution with physiological saline The amount of Tween 80 does not exceed 10%. It is now used.
  • the final concentration of the test compound in the low-dose group is 0.5 mg / mL, and the intraperitoneal injection volume is 0.2 mL / 20 g body weight.
  • High-dose group (administration dose: 10.0 mg / kg): accurately weigh 4.0 mg of the test compound before administration, first dissolve it into suspension with 0.4 mL of Tween 80, and then dissolve into 4 mL of resuspended solution with physiological saline The amount of Tween 80 does not exceed 10%, and it is currently used.
  • the final concentration of the test compound in the high-dose group is 1 mg / mL, and the intraperitoneal injection volume is 0.2 mL / 20 g body weight.
  • MKN-45 cells in the logarithmic growth phase were taken and inoculated under the sterile conditions in 20 nude mice under the skin of the right armpit, the cell inoculation amount was 2 ⁇ 10 6 cells / cell.
  • 18 tumor-bearing nude mice with good growth status and good tumor size uniformity are selected and randomly divided into 3 groups, 6 in each group.
  • Compound 13 low-dose group 5.0 mg / kg
  • Compound 13 high-dose group (10.0 mg / kg).
  • Each group was administered by intraperitoneal injection, which was continuously administered once a day on days 0, 1, 2, 3, 4, 5, and 6 for a total of 7 days.
  • the model group was given an equal volume of vehicle control. Using the method of measuring tumor diameter, the anti-tumor effect of the test compound was dynamically observed. The tumor diameter was measured every two days and weighed at the same time.
  • the formula for calculating the tumor volume (TV) is:
  • test results are shown in FIG. 4.
  • Compound 13 was administered intraperitoneally for 7 days at 5.0 mg / kg and 10.0 mg / kg, respectively, which could significantly inhibit the tumor growth of gastric cancer cell MKN-45 xenograft tumor in nude mice.

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Abstract

本发明公开了一类4-(苯并噻唑-2-基)芳胺类化合物治疗胃癌的用途，其为通式(I)所示的化合物或其药学上可接受的盐。

Description

4-(苯并噻唑-2-基)芳胺类化合物治疗胃癌的用途 技术领域
本发明属于药物化学领域，具体涉及一类4-(苯并噻唑-2-基)芳胺类化合物在治疗胃癌方面的用途。
背景技术
在世界范围内，胃癌是第五大常见的癌症，也是第三大致死性癌症。2012年新增胃癌患者大于950,000人，新增因胃癌死亡病例约有720,000人，胃癌占全球癌症发病率的7％(IARC.All Cancers(excluding non-melanoma skin cancer)Estimated Incidence,Mortality and Prevalence Worldwide in 2012)。虽然胃癌的全球发病率呈现下降趋势，但相较于西方，亚洲地区的发病率仍居高不下。中国的胃癌发病率居全球最高，有大于40％的胃癌新增病例都来自于中国。胃癌是中国的第二大致死性癌症(Torre LA,Siegel RL,Ward EM,et al.Global Cancer Incidence and Mortality Rates and Trends-an Update.Cancer Epidemiology and Prevention Biomarkers,2016,25(1):16-27)。全球的胃癌患者达到5年生存期的约有30％；而70％的胃癌患者在确诊时，已发生癌症转移，这类患者的预后非常差，中位生存期在4个月(支持治疗)至12个月(联合细胞毒化疗)，且5年生存率极低(约5％)。
胃癌的发病机制至今尚未完全阐明，主要认为胃癌发病与饮食习惯、幽门螺杆菌(Helicobacter pylori,Hp)感染、遗传因素、血清胃蛋白酶原(PG)、代谢综合征、和心理压力等因素都有一定关联。而幽门螺旋杆菌可能是胃癌最大的诱发因素，大约有90％的新增非贲门胃癌病例与此相关(Chang M,Zhang JC,Zhou Q,et al.Research Progress of Clinical Epidemiology of Gastric Cancer.Chinese Journal of Gastroenterology&Hepatology,2017,26(9):966-969)。
目前治疗胃癌的手段有限，手术切除仍是根治胃癌的唯一临床方法。对于早期胃癌，虽然术后原则上是无需接受化疗，但患者若出现以下情况，仍需进行化疗：(1)年龄小于40岁；(2)存在多个病灶；(3)病灶面积大于5cm 2；(4)病理类型的恶性程度偏高(贺阿青，张成武.探讨胃癌的诊断及治疗.世界最新医学信息文摘,2018,18(14):55)。我国由于胃癌筛查体系尚不完善，胃癌早期诊断率低，所以多数患者确诊时已是处于进展期胃癌或晚期胃癌(Advanced Gastric Cancer)，此时单纯手术治疗往往无法取得较好的疗效，且 术后复发转移率较高，且有部分患者的肿瘤体积大，无法进行手术，须予以新辅助化疗，待肿瘤体积缩小，才可以进行手术。且有研究表明，对于进展期胃癌，联合手术不仅不能带来生存优势，对于部分患者的总生存期甚至低于单纯化疗(Gastrectomy plus Chemotherapy versus Chemotherapy Alone for Advanced Gastric Cancer with Single Non-curable Factor(REGATTA):a Phase 3,Randomized Controlled Trial.Lancet Oncology,2016,17(3):309-318)。因此，以化疗为主的综合疗法是晚期胃癌患者的主要治疗手段，可改善患者预后，提高患者生活质量。
大多数胃癌的化疗方案是基于至少有2种药物的联合使用，例如5-氟尿嘧啶和顺铂，或相关衍生化合物如卡培他滨和奥沙利铂。其他常用药物有紫杉醇、多西他赛、表柔比星和伊立替康。但这类均是细胞毒性化疗药物，其会导致相关全身系统性的毒性反应，包括骨髓抑制、感染风险加剧、疲劳、恶心和呕吐、脱发、食欲不振、腹泻，且常是剂量限制性的。近期靶向治疗方案已在临床上使用，如曲妥珠单抗(抗HER2抗体)和雷莫芦单抗(抗VEGFR2抗体)(李开春，李平.进展期胃癌治疗药物的选择.药学服务与研究,2018,18(1):1-5)。但是胃癌是一种由多个基因突变和表观遗传异常所驱动的高度异质性疾病，因此靶向药物开发滞后，且已有药物的靶向性差、灵敏度低。目前尚无国际公认的标准治疗方案可用于胃癌这种难治性疾病。胃癌已严重危害居民的健康，给家庭和社会造成沉重的负担，临床需求未得到满足。开发新的胃癌治疗方案，对于最终改善胃癌患者的预后和生活品质是至关重要的。
本专利发明人Malcolm F.G.Stevens和Tracey D.Bradshaw所申请的美国专利(Malcolm F.G.Stevens，Andrew D.Westwell,Mei-Sze Chua,et al.Substituted 2-arylbenzazole compounds and their use as antitumour agents.US6858633B1)公布了下式(II)化合物，并指出了这类化合物在癌症方面的用途，但其说明书内容主要针对的是乳腺癌，由于不同癌症之间发病机理和治疗途径基本上并不相同，而且大部分抗癌化合物仅对某些敏感癌症具有治疗作用。因此，该类化合物在其他癌症方面是否能起作用实际上仍然是未知的。
Figure PCTCN2019115183-appb-000001
本专利发明人史东方，Tracey D.Bradshaw和Malcolm F.G.Stevens已发表了关于苯并噻唑类化合物的合成及其体内外抗乳腺癌作用的文章(Dong-Fang Shi,Tracey D.Bradshaw,Samantha Wrigley,et al.Antitumor Benzothiazoles.3.Synthesis of 2-(4-Aminophenyl)benzothiazoles and Evaluation of Their Activities against Breast Cancer Cell Lines in vitro and in vivo.Journal of Medicinal Chemistry,1996，39:3375-3384)；同时，本专利发明人史东方所申请的中国专利(史东方，傅长金，承曦等.用于治疗或预防乳腺癌的化合物.CN201610299350.1)公布了苯并硒唑-2-苯类化合物及其抗乳腺癌的药理活性。这两类化合物均对人乳腺癌细胞具有纳摩尔级别的抑制效果，其中苯并噻唑类化合物对ER +(MCF-7和BO细胞株)和ER -(MT-1和MT-3细胞株)的乳腺癌裸鼠移植瘤均表现出十分显著的抑瘤效果，但是这两类化合物对其他如前列腺癌、膀胱癌、黑色素瘤、肺癌、肝癌、食管癌等肿瘤细胞株并无抑制活性。
苯并噻唑的药效基团是十分重要的药物化学结构，构建在这种母核基础上的药物具有包括癌症在内的多种医学和临床领域的活性。但是至今未见有任何关于抗癌苯并噻唑类化合物对胃癌模型有作用的报道。
发明内容
本发明的目的是在现有技术的基础上，提供一类4-(苯并噻唑-2-基)芳胺类化合物在治疗胃癌方面的用途。
本发明的目的可以通过以下措施达到：
通式(I)所示的化合物或其药学上可接受的盐在制备治疗或预防胃癌药物方面的应用，
Figure PCTCN2019115183-appb-000002
其中，
R 1和R 2分别独立地选自H、D、卤素、-CN、C 1-3烷基、取代的C 1-3烷基、C 1-3烷氧基或取代的C 1-3烷氧基；
R 3选自H、卤素、-OH、-CN、-C(＝O)NH 2、取代的-C(＝O)NH 2、C 1-3烷基、取代的C 1-3烷基、C 2-3烯基、C 2-3炔基、C 1-3烷氧基或取代的C 1-3烷氧基；
R 4选自H、D、卤素、-OH、-CN、-NH 2、取代的-NH 2、C 1-3烷基、取代的C 1-3烷基、C 1-3烷氧基或取代的C 1-3烷氧基中的一种或两种；
R 5选自H、-CN、-OH、C 1-3烷基、C 1-3烷氧基或氨基酸残基；
n＝1或2；
R 1、R 2、R 3或R 4中的取代基选自D、卤素、-OH、C 1-3烷基或C 1-3烷氧基。
在一种优选方案中，本发明中的R 1和R 2分别独立地选自H、D、卤素、-CN、C 1-3烷基、取代的C 1-3烷基、C 1-3烷氧基或取代的C 1-3烷氧基，所述取代基选自D、F或C 1-3烷氧基；
在另一种优选方案中，本发明中的R 1和R 2分别独立地选自H、D、F、Cl、-CN、-CH 3、-CF 3、-OCF 3或-OCHF 2。
在另一种优选方案中，本发明中的R 1选自D、F、Cl、-CN、-CH 3或-CF 3，R 2选自H。
在一种优选方案中，本发明中的R 3选自卤素、-CN、-C(＝O)NH 2、C 1-2烷基、C 2-3烯基、C 2-3炔基、C 1-3烷氧基或取代的C 1-3烷氧基。
在另一种优选方案中，本发明中的R 3选自F、Cl、Br、-CN、-C(＝O)NH 2、-CH 3、-CF 3、-CH＝CH 2、-C≡CH、-OCH 3、-OCH 2CH 3、-OCHF 2或-OCF 3。
在一种优选方案中，本发明中的R 4选自H、D、卤素、-CN、C 1-3烷基、取代的C 1-3烷基、C 1-3烷氧基或取代的C 1-3烷氧基中的一种或两种。
在另一种优选方案中，本发明中的R 4选自D、F、Cl、Br、I、-CN、-CH 3、-CF 3、-OCH 3、-OCH 2CH 3、-OCHF 2或-OCF 3。
在一种优选方案中，本发明中的R 5选自H或氨基酸残基。
在另一种优选方案中，本发明中的R 5选自H或2,6-二氨基-己酰基。
在一种优选方案中，本发明中的通式(I)化合物选自：
2-氟-4-(5-氟苯并噻唑-2-基)-6-甲基苯胺，
2-溴-6-氟-4-(5-氟苯并噻唑-2-基)苯胺，
2-氟-4-(5-氟苯并噻唑-2-基)-6-碘苯胺，
2-氯-6-氟-4-(5-氟苯并噻唑-2-基)苯胺，
2,6-二氟-4-(5-氟苯并噻唑-2-基)苯胺，
2-氨基-3-氟-5-(5-氟苯并噻唑-2-基)苯甲腈，
2-氨基-3-氯-5-(5-氟苯并噻唑-2-基)苯甲腈，
2-氟-4-(5-氟苯并噻唑-2-基)-6-三氟甲基苯胺，
2-氟-4-(5-氟苯并噻唑-2-基)-6-乙烯基苯胺，
2-乙炔基-6-氟-4-(5-氟苯并噻唑-2-基)苯胺，
4-(5-氟苯并噻唑-2-基)-2-甲基苯胺，
2-二氟甲基-4-(5-氟苯并噻唑-2-基)苯胺，
2-氨基-5-(5-氟苯并噻唑-2-基)苯甲腈，
2-乙炔基-4-(5-氟苯并噻唑-2-基)苯胺，
2-氟-4-(5-氟苯并噻唑-2-基)苯胺，
2-氯-4-(5-氟苯并噻唑-2-基)苯胺，
2-溴-4-(5-氟苯并噻唑-2-基)苯胺，
4-(5-氟苯并噻唑-2-基)-2-碘基苯胺，
2,6-二氨基-N-[4-(5-氟苯并噻唑-2-基)-2-甲基苯基]己酰胺。
如无特别说明，本发明中所涉及的各基团分别具有如下含义。
“H”，即氢，是指氕(1H)，它是氢元素的主要稳定同位素。
“D”，即氘，是指氢的一种稳定形态同位素，也被称为重氢，其元素符号为D。
“卤素”，是指氟原子，氯原子，溴原子或碘原子。
“-OH”，是指羟基基团。
“-NH 2”，是指氨基基团。
“-CONH 2”，即C(＝O)-NH 2，是指酰胺基团。
“-CN”，是指氰基基团。
“-NO 2”，是指硝基基团。
“烷基”，是指1-10个碳原子的饱和的脂烃基，包括直链和支链基团(本申请书中提到的数字范围，例如“1-10”，是指该基团，此时为烷基，可以含1个碳原子、2个碳原子、3个碳原子等，直至包括10个碳原子)。含1-4个碳原子的烷基称为低级烷基。当低级烷基没有取代基时，称其为未取代的低级烷基。烷基可以选用C 1-6烷基、C 1-5烷基、C 1-4烷基、C 1-3烷基、C 1-2烷基、C 2-3烷基、C 2-4烷基等。具体的烷基包括但不限于甲基、乙基、丙基、2-丙基、正丁基、异丁基或叔丁基等。烷基可以是取代的或未取代的。
“烯基”表示具有至少一个碳碳双键的不饱和烃基基团，包括直链和支链基团(本申请书中提到的数字范围，例如“2-5”，是指该基团，此时为烯基，可以含2个碳原子、3个碳 原子、4个碳原子等，直至包括5个碳原子)。本发明中的烯基可以为C 2-8烯基、C 2-6烯基、C 2-5烯基、C 2-4烯基、C 2-3烯基等，具体的烯基包括但不限于乙烯基、丙烯基和丁烯基。
“炔基”表示具有至少一个碳碳三键的不饱和烃基基团，包括直链和支链基团(本申请书中提到的数字范围，例如“2-5”，是指该基团，此时为炔基，可以含2个碳原子、3个碳原子、4个碳原子等，直至包括5个碳原子)。本发明中的炔基可以为C 2-8炔基、C 2-6炔基、C 2-5炔基、C 2-4炔基、C 2-3炔基等，具体的烯基包括但不限于乙炔基、丙炔基和丁炔基。
“烷氧基”表示-O-(未取代的烷基)和-O-(未取代的环烷基)基团，其进一步表示-O-(未取代的烷基)。代表性实施例包括但不限于甲氧基、乙氧基、丙氧基、环丙氧基等。
“氨基酸残基”是指氨基酸缺少了某一基团(如-OH、-COOH或-NH 2)所形成的基团，其中氨基酸包括但不限于通常由三个字母符号指定的20种天然存在的氨基酸，并且还包括β-丙氨酸、瓜氨酸、锁链素(demosine)、γ-氨基丁酸、同型半胱氨酸、同型丝氨酸、4-羟基脯氨酸、羟基赖氨酸、异锁链素(isodemosine)、3-甲基组氨酸、正缬氨酸、甲硫氨酸砜(methioninesulfone)和鸟氨酸等。一种氨基酸残基的例子包括但不限于：2,6-二氨基-己酰基。
“药学上可接受的盐”是包含通式(I)的化合物与有机酸或无机酸形成的盐，表示保留母体化合物的生物有效性和性质的那些盐。这类盐包括：
(1)与酸成盐，通过母体化合物的游离碱与无机酸或有机酸的反应而得，无机酸例如(但不限于)盐酸、氢溴酸、硝酸、磷酸、偏磷酸、硫酸、亚硫酸和高氯酸等，有机酸例如(但不限于)乙酸、丙酸、丙烯酸、草酸、(D)或(L)苹果酸、富马酸、马来酸、羟基苯甲酸、γ-羟基丁酸、甲氧基苯甲酸、邻苯二甲酸、甲磺酸、乙磺酸、萘-1-磺酸、萘-2-磺酸、对甲苯磺酸、水杨酸、酒石酸、柠檬酸、乳酸、扁桃酸、琥珀酸或丙二酸等。
(2)存在于母体化合物中的酸性质子被金属离子代替或者与有机碱配位化合所生成的盐，金属离子例如碱金属离子、碱土金属离子或铝离子，有机碱例如乙醇胺、二乙醇胺、三乙醇胺、氨丁三醇、N-甲基葡糖胺等。
“药用组合物”指的是在此描述的一种或多种化合物或者它们的药学上可接受的盐和前药与其它的化学成分，例如药学上可接受的载体和赋形剂的混合物。药用组合物的目的是促进化合物对生物体的给药。
在本发明化合物的应用中，可以将本发明的化合物、药学上可接受的盐或其溶剂合物作为活性成分或主要活性成分，辅以药学上可接受的辅料制成药物组合物，再对病人进行 施用。
本发明还提供了一种治疗人类胃癌的方法，即对患有胃癌的患者施以权利要求1所述的化合物、药学上可接受的盐或其溶剂合物，特别的，对患有胃癌的患者施每次剂量0.1-1000mg的本发明的化合物、药学上可接受的盐或其溶剂合物，或者施以每次剂量0.1-1000mg的本发明的药物组合物。
本专利涉及到的这类化合物尽管有抗乳腺癌方面的药理活性，但体外试验表明，它们对于前列腺癌、膀胱癌、黑色素瘤、肺癌、肝癌、食管癌等肿瘤细胞株均无明显的抑制作用。然而我们发现，该类化合物对于胃癌的治疗效果十分优异：对人胃癌细胞株MKN-45、AGS以及NCI-N87具有显著地抑制生长的作用，效果基本接近于阳性对照药物紫杉醇；该类化合物对人胃癌MKN-45和AGS裸鼠异种移植瘤也表现出极佳的抑制肿瘤生长的效果，抑瘤率均大于40％。因此这些化合物可以应用在人类胃癌治疗领域。
本发明发现了4-(苯并噻唑-2-基)芳胺类化合物在疾病治疗方面的一种新的用途，为胃癌的治疗提供了一种潜在的药物。
附图说明
图1是化合物2对人胃癌细胞株AGS裸鼠异种移植肿瘤体积的抑制作用；
图2是化合物2对人胃癌细胞株MKN-45裸鼠异种移植肿瘤体积的抑制作用；
图3是化合物13对人胃癌细胞株AGS裸鼠异种移植肿瘤体积的抑制作用；
图4是化合物13对人胃癌细胞株MKN-45裸鼠异种移植肿瘤体积的抑制作用。
具体实施方式
以下结合实施例对本发明的内容做进一步说明，但本专利的保护范围并不局限于以下各实施例。
实施例1：2-氟-4-(5-氟苯并噻唑-2-基)-6-甲基苯胺(2)的合成
Figure PCTCN2019115183-appb-000003
步骤A：将含有5-氟-2-甲基苯并噻唑(2.0g，12.0mmol)、氢氧化钠(1.60g，40.0mmol)、水(4mL)和乙二醇(16mL)的混合物在氮气下130℃搅拌4小时。冷却到室温，加入 水(60mL)，用2M盐酸调节pH值至5～6。用乙酸乙酯(40mL×3)萃取，合并的有机相用饱和食盐水(20mL×2)洗涤，无水硫酸钠干燥。减压蒸除溶剂，得2-氨基-4-氟苯硫酚(1)(1.50g)。收率为87.3％。
步骤B：将含有化合物1(180mg，1.26mmol)、4-氨基-3-氟-5-甲基苯甲酸(213mg，1.26mmol)和多聚磷酸(5.0g)的混合物在150℃搅拌1.5小时。冷却到室温，用2M氢氧化钠溶液调节pH值至7～8。用乙酸乙酯(40mL×3)萃取，合并的有机相依次用水(30mL)和饱和食盐水(20mL)洗涤，无水硫酸钠干燥。减压蒸除溶剂，产物经柱层析纯化(200～300目硅胶，乙酸乙酯:石油醚＝1:50～1:40洗脱)，得2-氟-4-(5-氟苯并噻唑-2-基)-6-甲基苯胺(2)。 1H NMR(DMSO-d6，400MHz)δ8.17-8.13(m，1H)，7.84-7.80(m，1H)，7.66-7.61(m，2H)，7.36-7.31(m，1H)，5.80(s，2H)，2.28(s，3H)。MS(EI，m/z)：275.1[M-H] -。
实施例2：2-氟-4-(5-氟苯并噻唑-2-基)苯胺(3)的合成
Figure PCTCN2019115183-appb-000004
将含有化合物1(800mg，5.59mmol)、4-氨基-3-氟苯甲酸(864mg，5.57mmol)和多聚磷酸(10.0g)的混合物在110℃搅搅拌1小时，然后升温到140℃搅拌1小时。冷却到室温，用2M氢氧化钠溶液调节pH值至7～8。用乙酸乙酯(40mL×3)萃取，合并的有机相依次用水(30mL)和饱和食盐水(20mL)洗涤，无水硫酸钠干燥。减压蒸除溶剂，产物经柱层析纯化(200～300目硅胶，乙酸乙酯:石油醚＝1:50～1:40洗脱)，得2-氟-4-(5-氟苯并噻唑-2-基)苯胺(3)(140mg)。收率为9.58％。 1H NMR(DMSO-d6，400MHz)δ8.11-8.07(m，1H)，7.78-7.75(m，1H)，7.71-7.67(m，1H)，7.64-7.61(m，1H)，7.30-7.25(m，1H)，6.90-6.85(m，1H)，6.02(s，2H)。MS(EI，m/z)：261.0[M-H] -。
实施例3：2-溴-6-氟-4-(5-氟苯并噻唑-2-基)苯胺(4)的合成
Figure PCTCN2019115183-appb-000005
将NBS(44.8mg，0.252mmol)加入到化合物3(60mg，0.229mmol)的DMF(5mL)溶液中，加完后，所得混合物在室温下搅拌0.5小时。加入水(20mL)，用乙酸乙酯(20mL×3)萃取，合并的有机相依次用饱和碳酸氢钠溶液(15mL)和饱和食盐水(15mL)洗涤，无水硫酸钠干燥。减压蒸除溶剂，产物经柱层析纯化(200～300目硅胶，乙酸乙酯:石油醚＝1:60～1:50洗脱)，得2-溴-6-氟-4-(5-氟苯并噻唑-2-基)苯胺(4)。 1H NMR(DMSO-d6，400MHz)δ8.13-8.11(m，1H)，7.93(s，1H)，7.82-7.74(m，2H)，7.34-7.29(m，1H)，6.18(s，2H)。MS(EI，m/z)：341.0[M-H] -。
实施例4：2-氟-4-(5-氟苯并噻唑-2-基)-6-碘苯胺(5)的合成
Figure PCTCN2019115183-appb-000006
将含有化合物3(60mg，0.229mmol)、碘(70mg，0.276mmol)、硝酸银(47mg，0.277mmol)和甲醇(5mL)的混合物在室温下搅拌5小时。加入水(20mL)，用乙酸乙酯(20mL×3)萃取，合并的有机相用饱和食盐水(15mL)洗涤，无水硫酸钠干燥。减压蒸除溶剂，产物经柱层析纯化(200～300目硅胶，乙酸乙酯:石油醚＝1:70～1:60洗脱)，得2-氟-4-(5-氟苯并噻唑-2-基)-6-碘苯胺(5)。 1H NMR(DMSO-d6，400MHz)δ8.15-8.10(m，2H)，7.82-7.79(m，1H)，7.76-7.73(m，1H)，7.34-7.29(m，1H)，6.00(s，2H)。MS(EI，m/z)：387.0[M-H] -。
实施例5：2-氯-6-氟-4-(5-氟苯并噻唑-2-基)苯胺(6)的合成
Figure PCTCN2019115183-appb-000007
将NCS(62mg，0.464mmol)加入到化合物3(80mg，0.305mmol)的DMF(5mL)溶液中，加完后，所得混合物在室温下搅拌过夜。加入水(20mL)，用乙酸乙酯(20mL×3)萃取，合并的有机相依次用饱和碳酸氢钠溶液(15mL)和饱和食盐水(15mL)洗涤，无水硫酸钠干燥。减压蒸除溶剂，产物经柱层析纯化(200～300目硅胶，乙酸乙酯:石油醚＝1:80洗脱)，得2-氯-6-氟-4-(5-氟苯并噻唑-2-基)苯胺(6)。 1H NMR(DMSO-d6，400 MHz)δ8.14-8.11(m，1H)，7.82-7.78(m，2H)，7.74-7.71(m，1H)，7.34-7.29(m，1H)，6.25(s，2H)。MS(EI，m/z)：295.0[M-H] -。
实施例6：2,6-二氟-4-(5-氟苯并噻唑-2-基)苯胺(9)的合成
Figure PCTCN2019115183-appb-000008
步骤A：将含有3,5-二氟-4-硝基苯甲醇(1.0g，5.29mmol)，Oxone(16.3g，26.5mmol)、乙腈(22mL)和水(22mL)的混合物在回流下搅拌过夜。冷却到室温，加入水(80mL)，用乙酸乙酯(30mL×3)萃取，产品在有机相中。向合并的有机相中加入水(20mL)，然后用2M氢氧化钠溶液调节pH值至9～10，分层，产品在水相中。水相用2M盐酸调节pH值至2～3，用乙酸乙酯(20mL×3)萃取，无水硫酸钠干燥。减压蒸除溶剂，得3,5-二氟-4-硝基苯甲酸(7)(410mg)。收率为38.2％。
步骤B：将含有化合物7(410mg，2.02mmol)、10％钯碳(40mg)和甲醇(10mL)的混合物在氢气下室温搅拌过夜。通过硅澡土过滤，滤饼用乙酸乙酯(10mL)淋洗。然后向滤液中加入水(30mL)，用乙酸乙酯(20mL×3)萃取，合并的有机相用饱和食盐水(10mL)洗涤，无水硫酸钠干燥。减压蒸除溶剂，得4-氨基-3,5-二氟苯甲酸(8)(306mg)。收率为87.5％。
步骤C：以化合物1和化合物8为原料，合成2,6-二氟-4-(5-氟苯并噻唑-2-基)苯胺(9)的实验操作按照实施例1步骤B的方法制备。 1H NMR(DMSO-d6，400MHz)δ8.17-8.11(m，1H)，7.84-7.78(m，1H)，7.67-7.61(m，2H)，7.36-7.29(m，1H)，6.10(s，2H)。MS(EI，m/z)：279.1[M-H] -。
实施例7：2-氨基-3-氟-5-(5-氟苯并噻唑-2-基)苯甲腈(10)的合成
Figure PCTCN2019115183-appb-000009
将含有化合物4(700mg，2.05mmol)、氰化亚铜(280mg，3.13mmol)和DMF(15mL)的混合物在150℃搅拌过夜。冷却到室温，加入水(45mL)，用2M碳酸钠溶液调节pH值至8～9。用乙酸乙酯(30mL×3)萃取，合并的有机相用饱和食盐水(20mL×2)洗涤，无水硫酸钠干燥。减压蒸除溶剂，产物经柱层析纯化(200～300目硅胶，乙酸乙酯:石油醚＝1:100～1:20洗脱)，得2-氨基-3-氟-5-(5-氟苯并噻唑-2-基)苯甲腈(10)。 1H NMR(DMSO-d6，400MHz)δ8.18-8.15(m，1H)，8.00-7.96(m，2H)，7.83-7.81(m，1H)，7.36-7.32(m，1H)，7.01(s，2H)。MS(EI，m/z)：288.1[M+H] +。
实施例8：2-溴-4-(5-氟苯并噻唑-2-基)苯胺(12)的合成
Figure PCTCN2019115183-appb-000010
步骤A：将含有化合物1(1.30g，9.08mmol)、4-氨基苯甲酸(1.24g，9.04mmol)和多聚磷酸(15.0g)的混合物在130℃搅拌1小时。冷却到室温，用2M氢氧化钠溶液调节pH值至7～8。用乙酸乙酯(40mL×3)萃取，合并的有机相依次用水(30mL)和饱和食盐水(20mL)洗涤，无水硫酸钠干燥。减压蒸除溶剂，产物经柱层析纯化(200～300目硅胶，乙酸乙酯:石油醚＝1:40～1:20洗脱)，得4-(5-氟苯并噻唑-2-基)苯胺(11)(324mg)。收率为14.7％。
步骤B：在-10～-15℃下，将NBS(55mg，0.309mmol)加入到化合物11(100mg，0.409mmol)的二氯甲烷(10mL)溶液中，加完后，所得混合物在该温度下继续搅拌0.5小时。加入水(20mL)，用二氯甲烷(20mL×3)萃取，合并的有机相依次用饱和碳酸氢钠溶液(15mL)和饱和食盐水(15mL)洗涤，无水硫酸钠干燥。减压蒸除溶剂，产物经柱层析纯化(200～300目硅胶，乙酸乙酯:石油醚＝1:30～1:20洗脱)，得2-溴-4-(5-氟苯并噻唑-2-基)苯胺(12)。 1H NMR(DMSO-d6，400MHz)δ8.11-8.06(m，2H)，7.79-7.76(m，2H)，7.31-7.26(m，1H)，6.91(d，J＝8.4Hz，1H)，6.15(s，2H)。MS(EI，m/z)： 323.0[M-H] -。
实施例9：4-(5-氟苯并噻唑-2-基)-2-甲基苯胺(13)的合成
Figure PCTCN2019115183-appb-000011
以化合物1和4-氨基-3-甲基苯甲酸为原料，合成化合物13的实验操作按照实施例2方法制备。 1H NMR(DMSO-d6，400MHz)δ8.06-8.02(m，1H)，7.70-7.68(m，3H)，7.26-7.23(m，1H)，6.71(d，J＝8.4Hz，1H)，5.71(s，2H)，2.14(s，2H)。MS(EI，m/z)：257.1[M-H] -。
实施例10：2-氯-4-(5-氟苯并噻唑-2-基)苯胺(14)的合成
Figure PCTCN2019115183-appb-000012
将NCS(66mg，0.494mmol)加入到化合物11(100mg，0.409mmol)的DMF(10mL)溶液中，加完后，所得混合物在室温下搅拌过夜。加入水(40mL)，用乙酸乙酯(20mL×3)萃取，合并的有机相依次用饱和碳酸氢钠溶液(15mL)和饱和食盐水(15mL)洗涤，无水硫酸钠干燥。减压蒸除溶剂，产物经柱层析纯化(200～300目硅胶，乙酸乙酯:石油醚＝1:70～1:30洗脱)，得2-氯-4-(5-氟苯并噻唑-2-基)苯胺(14)。 1H NMR(DMSO-d6，400MHz)δ8.11-8.07(m，1H)，7.90(d，J＝2.0Hz，1H)，7.79-7.73(m，2H)，7.31-7.26(m，1H)，6.91(d，J＝8.8Hz，1H)，6.20(s，2H)。MS(EI，m/z)：277.0[M-H] -。
实施例11：4-(5-氟苯并噻唑-2-基)-2-碘苯胺(15)的合成
Figure PCTCN2019115183-appb-000013
将含有化合物11(60mg，0.246mmol)、碘(62mg，0.244mmol)、硝酸银(42mg，0.247mmol)和甲醇(5mL)的混合物在室温下搅拌过夜。加入水(20mL)，用乙酸乙酯(20mL×3)萃取，合并的有机相用饱和食盐水(15mL)洗涤，无水硫酸钠干燥。减 压蒸除溶剂，产物经柱层析纯化(200～300目硅胶，乙酸乙酯:石油醚＝1:60～1:20洗脱)，得4-(5-氟苯并噻唑-2-基)-2-碘苯胺(15)。 1H NMR(DMSO-d6，400MHz)δ8.27(d，J＝2.4Hz，1H)，8.11-8.07(m，1H)，7.79-7.76(m，2H)，7.28-7.26(m，1H)，6.85(d，J＝8.4Hz，1H)，6.03(s，2H)。MS(EI，m/z)：370.1[M+H] +。
实施例12：2-氨基-5-(5-氟苯并噻唑-2-基)苯甲腈和2,6-二氨基-N-[4-(5-氟苯并噻唑-2-基)-2-甲基苯基]己酰胺的合成参见专利US6858633B1。
实施例13：化合物对人胃癌细胞株AGS、MKN-45和NCI-N87的生长抑制作用
一、实验材料名称及来源
人胃癌细胞株AGS、MKN-45和NCI-N87购于中国科学院上海生命科学研究院细胞资源中心。紫杉醇、Resazurin和亚甲基蓝购自Sigma-Aldrich Co.,LLC；铁氰化钾和亚铁氰化钾购自阿拉丁试剂股份有限公司；DMEM培养基、1640培养基、无酚红DMEM和胎牛血清购自Thermo Fisher Scientific Inc；青霉素和链霉素购自碧云天生物技术有限公司。
二、实验方法
AGS用DMEM培养基(含10％胎牛血清，100U/mL青霉素，0.1mg/mL链霉素)，MKN-45用1640培养基(含10％胎牛血清，100U/mL青霉素，0.1mg/mL链霉素)，NCI-N87用DMEM培养基(含20％胎牛血清，100U/mL青霉素，0.1mg/mL链霉素)，三株细胞分别在37℃，5％CO 2孵箱培养至细胞密度达90％左右。
按3×10 3/孔细胞数接种于96孔板中，置37℃，5％CO 2孵箱中培养24h。
用培养基配制不同浓度梯度的试验化合物或对照药物紫杉醇，并按100μL/孔加入96孔板中，作为试验化合物孔或对照药物孔；按100μL/孔加入不含试验化合物或对照药物的培养基，做为阴性对照孔。置37℃，5％CO 2孵箱中，AGS和MKN-45细胞培养72h，NCI-N87细胞培养120h。
将Resazurin(15mg/50mL，200×)、亚甲基蓝(25mg/10mL，1000×)、铁氰化钾(0.329g/100mL，100×)和亚铁氰化钾(0.422g/100mL，100×)溶于PBS(0.1M，pH＝7.4)中，配制出10×Alamar Blue溶液，再用无酚红DMEM培养基稀释成1×Alamar Blue溶液，临用前配制。
96孔板中的细胞用PBS(0.1M，pH＝7.4)小心清洗2次，并吸尽PBS，再按100μL/孔加入1×Alamar Blue溶液；在无细胞的孔中加入100μL 1×Alamar Blue溶液，做为空白对照孔。将96孔板置37℃，5％CO 2孵箱中培养3h。
用酶标仪Victor X4(Perkin Elmer)在Ex 530/Em 590nm处检测细胞荧光值。试验化合物孔的荧光值以F (试验化合物)表示；空白对照孔的荧光值以F (空白对照)表示；阴性对照孔的荧光值以F (阴性对照)表示。按以下公式计算不同药物浓度下的细胞存活率，每个浓度设置3个重复孔，得出平均值和标准偏差。
Figure PCTCN2019115183-appb-000014
利用Prism Graph软件根据细胞存活率分别计算出试验化合物或对照药物对细胞的半数抑制浓度(IC 50)。
三、实验结果
试验结果如表1所示，化合物对人胃癌细胞株AGS、MKN-45和NCI-N87的生长均有明显地抑制作用。其中化合物2、10、13和15的抑制效果较优。
表1.试验化合物对人胃癌细胞株AGS、MKN-45和NCI-N87的半数抑制浓度(IC 50，nM)
Figure PCTCN2019115183-appb-000015
实施例14：化合物2和13对人胃癌AGS或MKN-45裸鼠异种移植瘤的生长抑制活性研究
一、试验材料
1.试验动物
SPF级BALB/c裸小鼠，雌性，开始给药时为6-8周龄，体重为18-20g。由常州卡文斯实验动物有限公司提供(实验动物生产许可证：SCXK(苏)2016-0010；实验动物使用许可证：SYXK(苏)2017-0007)。所购动物批号：201820473。
2.试验试剂
聚乙二醇400(PEG400)，批号为20180412，购自成都市科龙化工试剂厂；氯化钠注射液(生理盐水)，批号为A17111105，购自河北天成药业股份有限公司；DMSO，批号为Q6949，购自MP Biomedicals。
3.细胞株
人胃癌AGS和MKN-45细胞购自中国科学院上海生命科学研究院细胞资源中心；AGS于含10％胎牛血清的1640培养基中培养，MKN-45于含10％胎牛血清的DMEM培养基中培养。
二、试验方法
1.受试化合物的制剂配制
低剂量组(给药剂量：2.5mg/kg)：给药前精确称取2.0mg受试化合物，用静脉注射用溶剂(PEG400 25％，DMSO 2.5％，生理盐水72.5％)溶解成8mL的澄清溶液，低剂量组受试化合物的静脉注射溶液终浓度为0.25mg/mL，静脉注射给药体积为0.2mL/20g体重。
高剂量组(给药剂量：5.0mg/kg)：给药前精确称取4.0mg受试化合物，用静脉注射用溶媒(PEG400 50％，DMSO 5％，生理盐水45％)溶解至8mL的澄清溶液，高剂量组受试化合物的静脉注射溶液终浓度为0.50mg/mL，静脉注射给药体积为0.2mL/20g体重。
2.试验分组与给药方式
取对数生长期的AGS和MKN-45细胞，在无菌条件下，接种AGS于45只裸小鼠，接种MKN-45于30只裸小鼠，接种位置为右侧腋窝皮下，细胞接种量均为5×10 6个/只。用游标卡尺测量移植瘤直径，待肿瘤生长至100mm 3左右时，分别挑选生长状态良好且肿瘤大小均一性较好的荷瘤裸鼠(AGS荷瘤小鼠40只，MKN-45荷瘤小鼠24只)，AGS荷瘤小鼠随机分成5组，每组8只，即模型组、化合物2和13低剂量组及高剂量组；MKN-45荷瘤小鼠随机分成3组，每组8只，即模型组、化合物2低剂量组及高剂量组。各组均尾 静脉注射给药，分别于0、1、2、3、4天连续每天给药一次，共给药5天，模型组给予等容量的溶媒对照。用测量瘤径的方法，动态观察受试化合物的抗肿瘤效应。每两天测量一次肿瘤直径，同时称重。第20天时各组脱颈处死裸鼠，手术剥取并准确称重瘤块。肿瘤体积(TV)的计算公式为：
Figure PCTCN2019115183-appb-000016
其中a、b分别表示长、宽。
抑瘤率％的计算公式为：
Figure PCTCN2019115183-appb-000017
三、试验结果
试验结果如表2、表3、图1至图3所示，上述受试化合物在分别连续5天以2.5mg/kg和5.0mg/kg的给药剂量尾静脉注射后，化合物2和13可显著地抑制胃癌细胞AGS裸鼠移植瘤的肿瘤生长，同时，化合物2也可显著地抑制MKN-45裸鼠移植瘤的肿瘤生长。
表2.受试化合物对人胃癌细胞株AGS裸鼠异种移植肿瘤生长的抑制作用(Mean±SD，n＝8)
Figure PCTCN2019115183-appb-000018
表3.受试化合物对人胃癌细胞株MKN-45裸鼠异种移植肿瘤生长的抑制作用(Mean±SD，n＝8)
组别或化合物 剂量(mg/kg) 瘤重(g) 抑瘤率(％)
模型组 / 1.761±0.082 -
2 2.5 0.900±0.070 48.9
  5 0.817±0.058 53.6
实施例15：化合物13对人胃癌MKN-45裸鼠异种移植瘤的生长抑制活性研究
一、试验材料
1.试验动物
SPF级BALB/c-nu裸小鼠，雄性，开始给药时为6-8周龄，体重为20-25g。由湖南斯莱克景达实验动物有限公司提供(实验动物生产许可证：SCXK(湘)2016-0002；实验动物使用许可证：SYXK(滇)K2013-0003)。所购动物批号：20180309。
2.试验试剂
吐温80(S24644阿拉丁药用级)，批号C10094183，购于云南驰恩科技有限公司；基质胶(354234 BD)，批号4069011，购于昆明驰普生物技术公司；中美血清(04-001-1B1A Biological Industries)，批号11F267，购于云南驰恩科技有限公司；1mL无菌注射器，批号1801001，购于湖南省绿洲惠康发展有限公司；氯化钠注射液(生理盐水)，批号A15102005-2，购于科伦药业股份有限公司。
3.细胞株
人胃癌MKN-45细胞购自北京协和细胞库；MKN-45于含10％胎牛血清的1640培养基中培养。
二、试验方法
1.试验结果受试化合物的配剂配制
低剂量组(给药剂量：5.0mg/kg)：给药前精准称取2.0mg受试化合物，先用0.4mL吐温80溶解成悬浮液，然后再用生理盐水溶解成4mL的重悬浮液，吐温80的量不超过10％，现配现用，低剂量组受试化合物的腹腔注射溶液终浓度为0.5mg/mL，腹腔注射给药体积为0.2mL/20g体重。
高剂量组(给药剂量：10.0mg/kg)：给药前精确称取4.0mg受试化合物，先用0.4mL吐温80溶解成悬浮液，然后再用生理盐水溶解成4mL的重悬浮液，吐温80的量不超过10％，现配现用，高剂量组受试化合物的腹腔注射溶液终浓度为1mg/mL，腹腔注射给药体积为0.2mL/20g体重。
2.试验分组与给药方式
取对数生长期的MKN-45细胞，在无菌条件下，分别接种于20只裸小鼠右侧腋窝皮 下，细胞接种量为2×10 6个/只。用游标卡尺测量移植瘤直径，待肿瘤生长至100mm 3左右时，分别挑选生长状态良好且肿瘤大小均一性较好的荷瘤裸鼠18只，随机分成3组，每组6只，即模型组，化合物13低剂量组(5.0mg/kg)及化合物13高剂量组(10.0mg/kg)。各组均腹腔注射给药，分别于0、1、2、3、4、5、6天每天连续给药一次，共给药7天，模型组给予等容量的溶媒对照。用测量瘤径的方法，动态观察受试化合物的抗肿瘤效应。每两天测量一次肿瘤直径，同时称重。肿瘤体积(TV)的计算公式为：
Figure PCTCN2019115183-appb-000019
其中a、b分别表示长、宽。
三、试验结果
试验结果如图4所示，化合物13分别在5.0mg/kg和10.0mg/kg剂量下连续腹腔给药7天，可显著地抑制胃癌细胞MKN-45裸鼠移植瘤的肿瘤生长。

Claims (10)

  1. 通式(I)所示的化合物或其药学上可接受的盐在制备治疗或预防胃癌药物方面的应用，
    Figure PCTCN2019115183-appb-100001
    其中，
    R 1和R 2分别独立地选自H、D、卤素、-CN、C 1-3烷基、取代的C 1-3烷基、C 1-3烷氧基或取代的C 1-3烷氧基；
    R 3选自H、卤素、-OH、-CN、-C(＝O)NH 2、取代的-C(＝O)NH 2、C 1-3烷基、取代的C 1-3烷基、C 2-3烯基、C 2-3炔基、C 1-3烷氧基或取代的C 1-3烷氧基；
    R 4选自H、D、卤素、-OH、-CN、-NH 2、取代的-NH 2、C 1-3烷基、取代的C 1-3烷基、C 1-3烷氧基或取代的C 1-3烷氧基中的一种或两种；
    R 5选自H、-CN、-OH、C 1-3烷基、C 1-3烷氧基或氨基酸残基；
    n＝1或2；
    R 1、R 2、R 3或R 4中的取代基选自D、卤素、-OH、C 1-3烷基或C 1-3烷氧基。
  2. 根据权利要求1所述的应用，其中，R 1和R 2分别独立地选自H、D、F、Cl、-CN、-CH 3、-CF 3、-OCF 3或-OCHF 2。
  3. 根据权利要求1所述的应用，其中，R 1选自D、F、Cl、-CN、-CH 3或-CF 3，R 2选自H。
  4. 根据权利要求1所述的应用，其中，R 3选自F、Cl、Br、-CN、-C(＝O)NH 2、-CH 3、-CF 3、-CH＝CH 2、-C≡CH、-OCH 3、-OCH 2CH 3、-OCHF 2或-OCF 3。
  5. 根据权利要求1所述的应用，其中，R 4选自H、D、卤素、-CN、C 1-3烷基、取代的C 1-3烷基、C 1-3烷氧基或取代的C 1-3烷氧基中的一种或两种；R 5选自H或氨基酸残基。
  6. 根据权利要求5所述的应用，其中，R 4选自D、F、Cl、Br、I、-CN、-CH 3、-CF 3、-OCHF 2或-OCF 3；R 5选自H或2,6-二氨基-己酰基。
  7. 根据权利要求1所述的应用，其中，所述化合物选自：
    2-氟-4-(5-氟苯并噻唑-2-基)-6-甲基苯胺，
    2-溴-6-氟-4-(5-氟苯并噻唑-2-基)苯胺，
    2-氟-4-(5-氟苯并噻唑-2-基)-6-碘苯胺，
    2-氯-6-氟-4-(5-氟苯并噻唑-2-基)苯胺，
    2,6-二氟-4-(5-氟苯并噻唑-2-基)苯胺，
    2-氨基-3-氟-5-(5-氟苯并噻唑-2-基)苯甲腈，
    2-氨基-3-氯-5-(5-氟苯并噻唑-2-基)苯甲腈，
    2-氟-4-(5-氟苯并噻唑-2-基)-6-三氟甲基苯胺，
    2-氟-4-(5-氟苯并噻唑-2-基)-6-乙烯基苯胺，
    2-乙炔基-6-氟-4-(5-氟苯并噻唑-2-基)苯胺，
    4-(5-氟苯并噻唑-2-基)-2-甲基苯胺，
    2-二氟甲基-4-(5-氟苯并噻唑-2-基)苯胺，
    2-氨基-5-(5-氟苯并噻唑-2-基)苯甲腈，
    2-乙炔基-4-(5-氟苯并噻唑-2-基)苯胺，
    2-氟-4-(5-氟苯并噻唑-2-基)苯胺，
    2-氯-4-(5-氟苯并噻唑-2-基)苯胺，
    2-溴-4-(5-氟苯并噻唑-2-基)苯胺，
    4-(5-氟苯并噻唑-2-基)-2-碘基苯胺，
    2,6-二氨基-N-[4-(5-氟苯并噻唑-2-基)-2-甲基苯基]己酰胺。
  8. 根据权利要求1所述的应用，其中以权利要求1所述的化合物、药学上可接受的盐或其溶剂合物作为活性成分或主要活性成分，辅以药学上可接受的辅料制成药物组合物。
  9. 一种治疗人类胃癌的方法，其特征在于对患有胃癌的患者施以权利要求1所述的化合物、药学上可接受的盐或其溶剂合物。
  10. 一种治疗人类胃癌的方法，其特征在于对患有胃癌的患者施以每次剂量0.1-1000mg的权利要求1所述的化合物、药学上可接受的盐或其溶剂合物，或者施以每次剂量0.1-1000mg的权利要求8所述的药物组合物。
PCT/CN2019/115183 2018-11-12 2019-11-02 4-(苯并噻唑-2-基)芳胺类化合物治疗胃癌的用途 WO2020098516A1 (zh)

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Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2001014354A1 (en) * 1999-08-20 2001-03-01 Cancer Research Ventures Limited Substituted 2-arylbenzazole compounds and their use as antitumour agents

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2001014354A1 (en) * 1999-08-20 2001-03-01 Cancer Research Ventures Limited Substituted 2-arylbenzazole compounds and their use as antitumour agents

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Title
KRISTEN M GARNER ET AL.: "Variations in Mrell/Rad50/Nbsl status and DNA damage-induced S-phase arrest in the cell lines of the NCI60 panel", BMC CANCER, 31 December 2011 (2011-12-31), XP021103364 *

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