WO2017107993A1 - 聚醚类化合物用途 - Google Patents

聚醚类化合物用途 Download PDF

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WO2017107993A1
WO2017107993A1 PCT/CN2016/111820 CN2016111820W WO2017107993A1 WO 2017107993 A1 WO2017107993 A1 WO 2017107993A1 CN 2016111820 W CN2016111820 W CN 2016111820W WO 2017107993 A1 WO2017107993 A1 WO 2017107993A1
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group
halogen
phenyl
benzyl
hydrogen
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PCT/CN2016/111820
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French (fr)
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刘然
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武汉臻智生物科技有限公司
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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
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/35—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D519/00—Heterocyclic compounds containing more than one system of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring system not provided for in groups C07D453/00 or C07D455/00

Definitions

  • the present invention relates to the field of medicinal chemistry and pharmacotherapeutics, and in particular to polyether compounds, processes for their preparation, pharmaceutical compositions containing such compounds, and uses.
  • Cancer has become one of the most important diseases that endanger human health. At present, it usually includes surgical treatment, natural therapy, radiation therapy, chemotherapy, and Chinese medicine treatment.
  • Chemotherapy refers to the purpose of killing or inhibiting the growth of tumor cells by using chemotherapeutic drugs.
  • the chemotherapeutic drugs can be divided into alkylating agents, antimetabolites, anticancer antibiotics, plants, hormones and impurities, among which existing Although anticancer antibiotics can achieve certain effects, long-term use can easily lead to drug resistance of tumor cells, and often cause toxic side effects. Therefore, it is necessary to expand the diversity of such anticancer drugs.
  • the present inventors have found that ether antibiotics have a good effect of inhibiting tumor growth.
  • the present invention aims to solve at least one of the technical problems existing in the prior art.
  • the present invention aims to solve at least one of the technical problems in the related art to some extent. To this end, it is an object of the present invention to provide a means for effectively treating or preventing cancer.
  • a polyether compound of the formula I a chelated form thereof, a hydrated form or a pharmaceutically acceptable salt thereof for the preparation of a medicament for the treatment Cancer and prevent cancer from recurring
  • R1, R2, R3, R4, R5, R6, R7 and R8 are each independently hydrogen, -OH, -NH2, halogen, optionally substituted a C1-10 linear or branched saturated or unsaturated hydrocarbon group, an optionally substituted C1-10 linear or branched alkoxy group, an optionally substituted C1-10 acyl group, an optionally substituted C6-20 aryl group , optionally substituted heteroaryl, or
  • R 9 and R 10 are each independently hydrogen, -OH, -NH 2 , halogen, C 1-5 linear or branched saturated or unsaturated hydrocarbon group, carboxyl group, azide group, sulfhydryl group, amine group, a mercapto group, an amide group, sulfate group, rhamnose group, phenyl or benzyl, and optionally substituted with one or more substituents selected from halo, -OCH 3, -OH, -OCF 3 , -NH 2, phenyl Substituted by a group of a benzyl group, a heteroaryl group, and -NHR X and -NR X 2 , wherein each R X is independently a saturated aliphatic C 1-4 alkyl group, a phenyl group or a benzyl group,
  • the heteroaryl group is a 3- to 6-membered monocyclic or bicyclic heteroaryl group, optionally containing 1
  • n is an integer of 2-7;
  • the halogen is -F, -Cl, -Br or -I.
  • the drug of the present invention not only inhibits the growth of tumor cells, but also inhibits the growth of cancer stem cells, thereby completely eliminating cancer cells, preventing cancer recurrence, and particularly preventing breast cancer recurrence.
  • the R 1 , the R 2 , the R 3 , the R 4 , the R 5 , the R 6 , the R 7 and the R 8 are each independently hydrogen, —OH, —NH 2 , halogen, optionally substituted C 1-5 linear or branched saturated or unsaturated hydrocarbon group, optionally substituted C 1-5 linear or branched alkoxy group, optionally substituted C 1-5 acyl group , optionally substituted phenyl, or
  • R 9 and R 10 are each independently hydrogen, -OH, -NH 2 , halogen, C 1-5 linear or branched saturated or unsaturated hydrocarbon group, carboxyl group, azide group, sulfhydryl group, amine group a base, a mercapto group, an amide group, a sulfate group, a rhamnose group, a phenyl group or a benzyl group, and optionally one or more selected from the group consisting of halogen, -OCH 3 , -OH, -OCF 3 , -NH 2 , Substituted by a group of phenyl, benzyl, heteroaryl, -NHR X and -NR X 2 wherein R X is each independently saturated aliphatic C 1-4 alkyl, phenyl or benzyl
  • the heteroaryl group is a 5- to 6-membered monocyclic heteroaryl group, and optionally contains 1 to 3 hetero atoms
  • n is an integer of 2-7;
  • the halogen is -F, -Cl, -Br or -I.
  • the R 1 , the R 2 , the R 3 , the R 4 , the R 5 , the R 6 , the R 7 , the R 8 and the R 9 are each independently hydrogen, -OH, -NH 2 , halogen, optionally substituted C 1-3 straight or branched saturated or unsaturated hydrocarbon group, optionally substituted C 1-3 straight or branched alkoxy group, optionally substituted C 1-3 acyl group, optionally substituted phenyl group, or
  • R 9 and R 10 are each independently hydrogen, -OH, -NH 2 , halogen, C 1-3 linear or branched saturated or unsaturated hydrocarbon group, carboxyl group, azide group, sulfhydryl group, amine group a base, a mercapto group, an amide group, a sulfate group, a rhamnose group, a phenyl group or a benzyl group, and optionally one or more selected from the group consisting of halogen, -OCH 3 , -OH, -OCF 3 , -NH 2 , Substituted by a group of phenyl, benzyl, heteroaryl, -NHR X and -NR X 2 wherein R X is each independently saturated aliphatic C 1-4 alkyl, phenyl or benzyl a heteroaryl 5- to 6-membered monocyclic heteroaryl group, and optionally containing 1 hetero atom selected from N, O or
  • n is an integer of 2-7;
  • the halogen is -F, -Cl, -Br or -I.
  • the R 1 , the R 2 , the R 3 , the R 4 , the R 5 , the R 6 , the R 7 , and the R 8 are each independently hydrogen, —OH, —NH 2 , halogen, -OCH 3 , -OCF 3 , C 2-10 saturated aliphatic chain hydrocarbon, propenyl, propynyl, 2-(trifluoromethyl)ethyl, 2-bromoethyl, 2-azide Ethyl, acetyl, 2-halo(chloro, bromo)acetyl, 2-azidoacetyl, benzoyl, phenylacetyl, optionally substituted phenyl, or
  • R 9 and R 10 are each independently hydrogen, -OH, -NH 2 , halogen, methyl, ethyl, isopropyl, vinyl, propenyl, carboxyl, azide, decyl, amine a base, a mercapto group, an amide group, a sulfate group, a rhamnose group, a phenyl group or a benzyl group, and the phenyl group and the benzyl group are optionally selected from one or more selected from the group consisting of halogen, -OCH 3 , -OH, - Substituted by a group of OCF 3 , —NH 2 , —NHR X and —NR X 2 , wherein each R X is independently a saturated aliphatic C 1-4 alkyl group, a phenyl group or a benzyl group;
  • n is an integer of 2-7;
  • the halogen is -F, -Cl, -Br or -I.
  • the R 1 is The R 2 , the R 3 and the R 4 are all hydrogen, the R 5 is a methyl group, and the R 7 and the R 8 are both -OH, and the structural formula of the compound is as follows:
  • R 6 is hydrogen, -OH, -NH 2 , halogen, -OCH 3 , -OCF 3 , methyl, ethyl, isopropyl, vinyl, propenyl, propynyl, 2-(trifluoromethyl) Ethyl, 2-bromoethyl, 2-azidoethyl, acetyl, 2-halo(chloro, bromo)acetyl, 2-azidoacetyl, benzoyl, phenylacetyl or
  • R 10 is hydrogen, -OH, -NH 2 , halogen, methyl, ethyl, isopropyl, vinyl, propenyl, carboxyl, azide, decyl, amine, sulfhydryl, amide a sulfate group, a rhamnosyl group, a phenyl group or a benzyl group, and the phenyl group and the benzyl group are optionally one or more selected from the group consisting of halogen, -OCH 3 , -OH, -OCF 3 , -NH 2 Substituting a group of -NHR X and -NR X 2 wherein R X is each independently a saturated aliphatic C 1-4 alkyl group, a phenyl group or a benzyl group;
  • n is an integer of 2-7;
  • the halogen is -F, -Cl, -Br or -I.
  • the R 1 is R 2 , R 3 and R 4 are all hydrogen, R 5 is a methyl group, and R 6 is -OH, and the structural formula of the compound is as follows:
  • R 7 and R 8 are each independently hydrogen, -OH, -NH 2 , halogen, -OCH 3 , -OCF 3 , methyl, ethyl, isopropyl, vinyl, propenyl, propynyl, 2-(Trifluoromethyl)ethyl, 2-bromoethyl, 2-azidoethyl, acetyl, 2-halo(chloro, bromo)acetyl, 2-azidoacetyl, benzoyl, Phenylacetyl or
  • R 9 is hydrogen, -OH, -NH 2 , halogen, methyl, ethyl, isopropyl, vinyl, propenyl, carboxyl, azide, sulfhydryl, amine, fluorenyl, amide a sulfate group, a rhamnosyl group, a phenyl group or a benzyl group, and the phenyl group and the benzyl group are optionally one or more selected from the group consisting of halogen, -OCH 3 , -OH, -OCF 3 , -NH 2 Substituting a group of -NHR X and -NR X 2 wherein R X is each independently a saturated aliphatic C 1-4 alkyl group, a phenyl group or a benzyl group;
  • n is an integer of 2-7;
  • the halogen is -F, -Cl, -Br or -I.
  • the R 2 is R 1 , R 7 and R 8 are both -OH, R 3 and R 5 are both hydrogen, and R 4 is a methyl group.
  • the structural formula of the compound is as follows, and the structural formula of the compound is as follows:
  • R 6 is hydrogen, -OH, -NH 2 , halogen, -OCH 3 , -OCF 3 , methyl, ethyl, isopropyl, vinyl, propenyl, propynyl, 2-(trifluoromethyl) Ethyl, 2-bromoethyl, 2-azidoethyl, acetyl, 2-halo(chloro, bromo)acetyl, 2-azidoacetyl, benzoyl, phenylacetyl or
  • R 10 is hydrogen, -OH, -NH 2 , halogen, methyl, ethyl, isopropyl, vinyl, propenyl, carboxyl, azide, decyl, amine, sulfhydryl, amide a sulfate group, a rhamnosyl group, a phenyl group or a benzyl group, and the phenyl group and the benzyl group are optionally one or more selected from the group consisting of halogen, -OCH 3 , -OH, -OCF 3 , -NH 2 Substituting a group of -NHR X and -NR X 2 wherein R X is each independently a saturated aliphatic C 1-4 alkyl group, a phenyl group or a benzyl group;
  • n is an integer of 2-7;
  • the halogen is -F, -Cl, -Br or -I.
  • the R 2 is R 6 is -OH, R 3 and R 5 are all hydrogen, and R 4 is a methyl group.
  • the structural formula of the compound is as follows:
  • R 1 , R 7 , and R 8 are each independently hydrogen, —OH, —NH 2 , halogen, —OCH 3 , —OCF 3 , methyl, ethyl, isopropyl, vinyl, propenyl, and propyl.
  • R 9 is hydrogen, -OH, -NH 2 , halogen, methyl, ethyl, isopropyl, vinyl, propenyl, carboxyl, azide, sulfhydryl, amine, fluorenyl, amide a sulfate group, a rhamnosyl group, a phenyl group or a benzyl group, and the phenyl group and the benzyl group are optionally one or more selected from the group consisting of halogen, -OCH 3 , -OH, -OCF 3 , -NH 2 , -NHR X and -NR X 2 substituted groups, wherein, R X is independently saturated aliphatic C 1-4 alkyl, phenyl or benzyl;
  • n is an integer of 2-7;
  • the halogen is -F, -Cl, -Br or -I.
  • the R 3 is R 1 , R 7 and R 8 are all -OH, R 2 and R 5 are all hydrogen, and R 4 is a methyl group, and the structural formula of the compound is as follows:
  • R 6 is hydrogen, -OH, -NH 2 , halogen, -OCH 3 , -OCF 3 , methyl, ethyl, isopropyl, vinyl, propenyl, propynyl, 2-(trifluoromethyl) Ethyl, 2-bromoethyl, 2-azidoethyl, acetyl, 2-halo(chloro, bromo)acetyl, 2-azidoacetyl, benzoyl, phenylacetyl or
  • R 10 is hydrogen, -OH, -NH 2 , halogen, methyl, ethyl, isopropyl, vinyl, propenyl, carboxyl, azide, decyl, amine, sulfhydryl, amide a sulfate group, a rhamnosyl group, a phenyl group or a benzyl group, and the phenyl group and the benzyl group are optionally one or more selected from the group consisting of halogen, -OCH 3 , -OH, -OCF 3 , -NH 2 Substituting a group of -NHR X and -NR X 2 wherein R X is each independently a saturated aliphatic C 1-4 alkyl group, a phenyl group or a benzyl group;
  • n is an integer of 2-7;
  • the halogen is -F, -Cl, -Br or -I.
  • the R 3 is R 1 , R 7 and R 6 are both -OH, R 2 and R 5 are all hydrogen, and R 4 is a methyl group.
  • the structural formula of the compound is as follows:
  • R1, R7 and R 8 are each independently hydrogen, -OH, -NH 2, halo, -OCH 3, -OCF 3, methyl, ethyl, isopropyl, ethenyl, propenyl, propynyl , 2-(Trifluoromethyl)ethyl, 2-bromoethyl, 2-azidoethyl, acetyl, 2-halo(chloro,bromo)acetyl, 2-azidoacetyl, benzoyl Phenylacetyl or
  • R 9 is hydrogen, -OH, -NH 2 , halogen, methyl, ethyl, isopropyl, vinyl, propenyl, carboxyl, azide, sulfhydryl, amine, fluorenyl, amide a sulfate group, a rhamnosyl group, a phenyl group or a benzyl group, and the phenyl group and the benzyl group are optionally one or more selected from the group consisting of halogen, -OCH 3 , -OH, -OCF 3 , -NH 2 Substituting a group of -NHR X and -NR X 2 wherein R X is each independently a saturated aliphatic C 1-4 alkyl group, a phenyl group or a benzyl group;
  • n is an integer of 2-7;
  • the halogen is -F, -Cl, -Br or -I.
  • the polyether compound is one of the following compounds: R1 is Or -OH, R2, R3 are each independently Or hydrogen, R4 and R5 are each independently methyl or hydrogen, and R6, R7 and R8 are all -OH.
  • the polyether compound is one of the following compounds:
  • the cancer is brain cancer, skin cancer, kidney cancer, bone cancer, sarcoma, prostate cancer, uterine cancer, melanoma, colon cancer, lymphoma, leukemia, pancreatic cancer, epithelial cancer, breast Cancer, liver cancer, lung cancer, stomach cancer, ovarian cancer and corresponding tumor cell stem cells.
  • the medicament prevents cancer recurrence by inhibiting tumor cell stem cell proliferation.
  • the compound with polyether as the mother core is mainly used as an antibiotic, and the inventors have accidentally found that the compound has good antitumor activity through a large number of experiments. By mixing the three compounds with malignant tumor cells, they all have different degrees of antitumor activity.
  • a compound having a polyether as a mother core can be used for treating malignant tumor cells in a pharmaceutically acceptable administration form (free form, sodium salt or potassium salt form, chelated form, hydrated form), enriching the treatment of such a compound The diversity of disease drugs.
  • the inventors have found that the polyether compound represented by the general formula I can inhibit the proliferation of malignant tumor cells, and has studied three compounds of the compound 1, the compound 2 and the compound 3, and found that it has an inhibitory effect on various cancer cells. Specifically, the inventors have proved the inventor's point of view by the following experimental procedure:
  • the inventors mixed and cultured various cancer cells with the three compounds of Compound 1, Compound 2 and Compound 3, especially the sodium salt thereof, in vitro.
  • the inhibition rate and IC 50 (half inhibition rate) of tumor cell proliferation by compound 1, compound 2 and compound 3 were calculated by MTT staining by measuring the OD value.
  • the inventors have found that the three compounds of Compound 1, Compound 2 and Compound 3 have different degrees of inhibition on various tumor cells.
  • Figure 1 shows a schematic diagram of a compound 1 according to an embodiment of the present invention
  • Figure 2 shows a schematic representation of a compound 2 in accordance with one embodiment of the present invention
  • Figure 3 shows a schematic diagram of a compound 3 according to one embodiment of the present invention
  • FIG. 4 shows a schematic diagram of a flow pattern detection of stem cells in accordance with one embodiment of the present invention.
  • Compound 1 Compound 2 and Compound 3 were obtained by Streptomyces hygroscopicus Streptomyces and Streptomyces endus subtype Streptomyces, as follows:
  • Two Streptomyces hygroscopicus subtypes and Streptomyces endus subtype Streptomyces were inoculated on SFM plates and cultured for three to four days.
  • the single colony is cultured in the seed medium for about three days to four days, and the bacteria are inoculated to the fermentation medium in an amount of 1% (the composition of the fermentation medium is soluble starch 30 g/L, yellow).
  • the fermentation broth is collected, and the supernatant is separated from the mycelium by high-speed centrifugation.
  • the mycelium is added with the same amount of acetone, and the mixture is sonicated for 20 minutes, and the acetone and the mycelium are used.
  • the amount of ethyl acetate was extracted and repeated once.
  • the mixture was concentrated to dryness by rotary distillation, and then separated on a silica gel column to obtain crude product.
  • the product was determined by HPLC. The HPLC results showed that the yield of the three strains was relatively high.
  • MTT assay was used to detect the inhibitory effect of compound 1 sodium salt and paclitaxel on MCF-7 tumor cells.
  • the specific methods are as follows:
  • MCF-7 breast cancer cells, Wuhan University Basic Medical Research Institute Collection
  • 0.25%-EDTA trypsin digestion 3min-5min
  • the cells are suspended.
  • the cell suspension was inoculated into a 96-well cell culture plate (the number of cells per well was about 5000), 200 ⁇ L per well; the control group was a group of 200 ⁇ L of drug-free cells per well; the blank group was 200 ⁇ L per well.
  • a group of cell-free media The above-mentioned cells-inoculated 96-well cell culture plates were placed in a cell containing 5% CO 2 incubator and incubated at 37 ° C overnight to allow the cells to adhere.
  • Sample compound 1 sodium salt, salinomycin (salinomycin) and the existing anticancer drug paclitaxel were dissolved in DMSO, prepared as a 100 mg/mL stock solution, and then diluted to different concentrations with the corresponding medium before use (final concentration of DMSO was less than 0.1 %) sample solution. Add 200 ⁇ L of different concentrations of sample solution (Compound 1 sodium salt, salinomycin) (100 ⁇ g/mL, 10 ⁇ g/mL, 1 ⁇ g/mL, 0.1 ⁇ g/mL, 0.01 ⁇ g/mL) or paclitaxel solution to different experimental groups.
  • the control group was a group in which 200 ⁇ L of the medium was added to the adherent cells; the blank group was cell-free and only 200 ⁇ L of the medium was added. group. Then, the 96-well cell culture plate supplemented with different concentrations of the drug solution (100, 10, 1, 0.1, 0.01 ⁇ g / L sample solution or salinomycin or paclitaxel solution) was cultured in a cell culture incubator (37 ° C) for 48 hours.
  • the drug solution 100, 10, 1, 0.1, 0.01 ⁇ g / L sample solution or salinomycin or paclitaxel solution
  • the 96-well cell culture plate with DMSO was shaken on a plate shaker for 10 minutes, and the OD value (reference wavelength was 490 nm) was measured at 570 nm using an enzyme-linked immunosorbent assay to calculate the inhibition rate and IC 50 (half number). Inhibition rate).
  • Inhibition rate% (AA 0 )/(AA 1 ) ⁇ 100%
  • A represents the OD value of the control group
  • a 0 represents the OD value of the sample group
  • a 1 represents the OD value of the blank group.
  • Test substance IC 50 ( ⁇ mol/L) for MCF-7 Compound 1 sodium salt 1.63 ⁇ 0.04 Paclitaxel 8.49 ⁇ 1.43 Salinomyicn 3.86 ⁇ 0.08
  • the sodium salt of Compound 1 has a more significant inhibitory effect on the proliferation of MCF-7 cells in vitro, and the IC 50 value of MCF-7 cells is 5.21 times lower than that of paclitaxel. Compared with salinomycin, it was 2.34 times lower. It indicated that the sodium salt of compound 1 had a strong inhibitory effect on the proliferation of MCF-7 tumor cells, and its inhibitory effect was significantly stronger than that of paclitaxel.
  • the inhibitory effect of Compound 2 and paclitaxel on MCF-7 tumor cells was examined by MTT assay.
  • the experimental method and detection method were the same as those in Example 2, except that the compound used was Compound 2.
  • the sodium salt of Compound 2 and the IC 50 value of paclitaxel to MCF-7 cells are shown in the following table.
  • Test substance IC 50 ( ⁇ mol/L) for MCF-7 Compound 2 sodium salt 2.25 ⁇ 0.19 Paclitaxel 8.49 ⁇ 1.43 Salinomyicn 3.86 ⁇ 0.08
  • the sodium salt of compound 2 has a more significant inhibitory effect on the proliferation of MCF-7 cells in vitro, and the IC 50 value of MCF-7 cells is lower than that of paclitaxel. It was reduced by 3.77 times, which is equivalent to salinomycin. It indicated that the sodium salt of compound 2 had a strong inhibitory effect on the proliferation of MCF-7 tumor cells, and its inhibitory effect was significantly stronger than that of paclitaxel.
  • the inhibitory effect of Compound 3 and paclitaxel on MCF-7 tumor cells was examined by MTT assay.
  • the experimental method and detection method were the same as those in Example 2, except that the compound used was Compound 3.
  • the sodium salt of Compound 3 and the IC 50 value of paclitaxel to MCF-7 cells are shown in the following table.
  • Test substance IC 50 ( ⁇ mol/L) for MCF-7 Compound 3 sodium salt 5.19 ⁇ 1.4 Paclitaxel 8.49 ⁇ 1.43 Salinomyicn 3.86 ⁇ 0.08
  • the compound 3 sodium salt has a more significant inhibitory effect on the proliferation of MCF-7 cells in vitro than the paclitaxel, and the IC 50 value of the MCF-7 cell line is 1.61 times lower than that of paclitaxel. It indicated that the sodium salt of compound 4 had a strong inhibitory effect on the proliferation of MCF-7 tumor cells, and its inhibitory effect was stronger than that of paclitaxel, but its anticancer activity was inferior to that of salinomycin.
  • the preparation method of the compound sodium salt derivative compound of the general formula of the present invention is specifically as follows:
  • the preparation method of the compound sodium salt derivative compound of the general formula of the present invention is specifically as follows:
  • Cell Growth inhibition% 100% ⁇ [1-RLU sample/RLU negative], wherein the RLU sample is the sample well or the positive control well RLU value, and the RLU negative is the DMSO-only RLU value.
  • Data analysis was performed using GraphPad Prism 6.0 software, and the results are shown in the following table, indicating that the compound has a significant inhibitory effect on various tumors.
  • Cell culture subject human breast cancer cell line MDA-MB-231 cells.
  • Culture method cultured in suspension cell culture, cultured in a 37-degree incubator.
  • Suspension cell culture medium (200 ml): B27 4 ml; insulin 80 ⁇ l; DMEM-F12 194 ml; hEGF: 40 ⁇ l; double antibody: 2 ml
  • Inoculation density 1000 / ml
  • Test kit Aldefluor TM kit
  • Cultivation time 10 days to 15 days or so (shake more than 2 times a day).
  • the cells were detected by flow cytometry.
  • the results of the experiment are shown in Fig. 4.
  • the content of stem cells in adherent cells was 2.36%, and the proportion of stem cells obtained after suspension cell culture was 25.95%, which was nearly 11 times higher. There are significant differences between the data. It can be seen that we have achieved the goal of enriching stem cells.
  • step (1) enriched stem cells
  • Cell seeding The amount of cells per well per well of 96-well cells was about 12,000 per 120 ⁇ L.
  • Dilution concentration of drug diluted with PBS: setting concentration: 100 ⁇ g/ML, 20 ⁇ g/ML, 4 ⁇ g/ML, 0.8 ⁇ g/ML, 0.16 ⁇ g/ML, 0.032 ⁇ g/ML, 0.0064 ⁇ g/ML, 0.00128 ⁇ g/ML, 0.000256 Gg/ML.
  • the cell plate was incubated overnight at 37 ° C / 5% CO 2 incubator, and 10 ⁇ L of a compound sample of 5 times the concentration to be tested was added the next day.
  • Detection time and detection method After 72 hours of administration, the MTT method was used for detection, and then the triple solution (10% SDS, 5% isobutanol, 0.1% concentrated hydrochloric acid) was used for dissolution, and the OD value was detected at 570 nm by a microplate reader.
  • Test drug IC 50 (g/ml) Compound 1 1.176E-06 ⁇ 0.041 Compound 2 2.35E-06 ⁇ 0.152 Compound 3 4.251E-06 ⁇ 0.129

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Abstract

一种通式1所示的聚醚类化合物、其鳌合形式、水合形式或其药学上可接受的盐在制备药物中的用途，所述药物在制备治疗癌症和预防癌症复发的药物中的用途。通式1所示的聚醚类化合物能够抑制恶性肿瘤细胞和恶性肿瘤细胞干细胞的增殖。

Description

聚醚类化合物用途
优先权信息
本申请请求2015年12月24日向中国国家知识产权局提交的、专利申请号为.201511000381.4的专利申请的优先权和权益，并且通过参照将其全文并入此处。
技术领域
本发明涉及药物化学和药物治疗学领域，具体涉及聚醚类化合物、其制备方法、含此类化合物的药物组合物及用途。
背景技术
癌症已经成为危害人类健康的最主要的疾病之一。目前临床上通常包括手术治疗、自然疗法、放射治疗、化学治疗、中医治疗等手段。其中化学治疗是指利用化疗药物达到杀死或抑制肿瘤细胞生长的目的，化疗药物可分为烷化剂、抗代谢药、抗癌抗生素、植物类、激素类和杂类等，其中现有的抗癌抗生素虽然可以达到一定的效果，但长期使用易导致肿瘤细胞具有耐药性，且常常引起毒副作用。因此，有必要扩充该类抗癌药物多样性。本发明发现醚类抗生素具有很好的抑制肿瘤生长的效果。
发明内容
本发明旨在至少解决现有技术中存在的技术问题之一。
本发明旨在至少在一定程度上解决相关技术中的技术问题之一。为此，本发明的一个目的在于提出一种能够有效治疗或预防癌症的手段。
根据本发明的一个方面，本发明提供了通式I所示的聚醚类化合物、其螯合形式、水合形式或其药学上可接受的盐在制备药物中的用途，所述药物用于治疗癌症和预防癌症复发，
Figure PCTCN2016111820-appb-000001
其中，所述R1、所述R2、所述R3、所述R4、所述R5、所述R6、所述R7和所述R8各自独立地为氢、-OH、-NH2、卤素、任选取代的C1～10直链或支链的饱和或不饱和烃基、任选取代的C1～10直链或支链烃氧基、任选取代的C1～10酰基、任选取代的C6～20芳基、任选取代的杂芳基、
Figure PCTCN2016111820-appb-000002
或者
Figure PCTCN2016111820-appb-000003
其中，R9、R10各自独立地为氢、-OH、-NH2、卤素、C1-5直链或支链的饱和或不饱和烃基、羧基、叠氮基、肟基、胺基、巯基、酰胺基、硫酸酯基、鼠李糖基、苯基或苄基，且任选地被一个或多个选自卤素、-OCH3、-OH、-OCF3、-NH2、苯基、苄基、杂芳基和、-NHRX和-NRX 2中的基团所取代，其中，RX各自独立地是饱和的脂肪族的C1-4烷基、苯基或苄基，所述杂芳基为3元～6元的单环或二环的杂芳基，任选地含有1～3个选自N、O或S的杂原子；
n为2～7的整数；
所述卤素为-F、-Cl、-Br或-I。
其中，需要说明的是，本发明的药物不仅可以抑制肿瘤细胞的生长，还可以抑制肿瘤干细胞的生长，从而彻底清除癌细胞、预防癌症复发，尤其是预防乳腺癌的复发。
根据本发明的实施例，通式I中：
所述R1、所述R2、所述R3、所述R4、所述R5、所述R6、所述R7和所述R8各自独立地为氢、-OH、-NH2、卤素、任选取代的C1～5直链或支链的饱和或不饱和烃基、任选取代的C1～5直链或支链烃氧基、任选取代的C1～5酰基、任选取代的苯基、
Figure PCTCN2016111820-appb-000004
Figure PCTCN2016111820-appb-000005
或者
Figure PCTCN2016111820-appb-000006
其中，所述R9、R10各自独立地为氢、-OH、-NH2、卤素、C1～5直链或支链的饱和或不饱和烃基、羧基、叠氮基、肟基、胺基、巯基、酰胺基、硫酸酯基、鼠李糖基、苯基或苄基，且任选地被一个或多个选自卤素、-OCH3、-OH、-OCF3、-NH2、苯基、苄基、杂芳基、-NHRX和-NRX 2中的基团所取代，其中，RX各自独立地是饱和的脂肪族的C1-4烷基、苯基或苄基，所述杂芳基为5元～6元的单环杂芳基，且任选地含有1～3个选自N、O或S的杂原子；
n为2～7的整数；
所述卤素为-F、-Cl、-Br或-I。
根据本发明的实施例，通式I中：
所述R1、所述R2、所述R3、所述R4、所述R5、所述R6、所述R7、所述R8和所述R9各自独立地为氢、-OH、-NH2、卤素、任选取代的C1～3直链或支链的饱和或不饱和烃基、 任选取代的C1～3直链或支链烃氧基、任选取代的C1～3酰基、任选取代的苯基、
Figure PCTCN2016111820-appb-000007
或者
Figure PCTCN2016111820-appb-000008
其中，所述R9、R10各自独立地为氢、-OH、-NH2、卤素、C1～3直链或支链的饱和或不饱和烃基、羧基、叠氮基、肟基、胺基、巯基、酰胺基、硫酸酯基、鼠李糖基、苯基或苄基，且任选地被一个或多个选自卤素、-OCH3、-OH、-OCF3、-NH2、苯基、苄基、杂芳基、-NHRX和-NRX 2中的基团所取代，其中，RX各自独立地是饱和的脂肪族的C1-4烷基、苯基或苄基，所述杂芳基5元～6元的单环杂芳基，且任选地含有1个选自N、O或S的杂原子；
n为2～7的整数；
所述卤素为-F、-Cl、-Br或-I。
根据本发明的实施例，通式I中：
所述R1、所述R2、所述R3、所述R4、所述R5、所述R6、所述R7、所述R8各自独立地为氢、-OH、-NH2、卤素、-OCH3、-OCF3、C2-10饱和脂肪族链烃、丙烯基、丙炔基、2-(三氟甲基)乙基、2-溴乙基、2-叠氮乙基、乙酰基、2-卤(氯、溴)乙酰基、2-叠氮基乙酰基、苯甲酰基、苯乙酰基、任选取代的苯基、
Figure PCTCN2016111820-appb-000009
或者
Figure PCTCN2016111820-appb-000010
其中，所述R9、R10各自独立地为氢、-OH、-NH2、卤素、甲基、乙基、异丙基，乙烯基，丙烯基、羧基、叠氮基、肟基、胺基、巯基、酰胺基、硫酸酯基、鼠李糖基、苯基或苄基，且所述苯基和苄基任选地被一个或多个选自卤素、-OCH3、-OH、-OCF3、-NH2、-NHRX和-NRX 2中的基团所取代，其中，RX各自独立地是饱和的脂肪族的C1-4烷基、苯基或苄基；
n为2～7的整数；
所述卤素为-F、-Cl、-Br或-I。
根据本发明的实施例，所述R1为
Figure PCTCN2016111820-appb-000011
所述R2、所述R3、所述R4均为氢，所述R5为甲基，所述R7和所述R8均为-OH，所述化合物的结构式如下：
Figure PCTCN2016111820-appb-000012
其中，R6为氢、-OH、-NH2、卤素、-OCH3、-OCF3、甲基、乙基、异丙基，乙烯基，丙烯基、丙炔基、2-(三氟甲基)乙基、2-溴乙基、2-叠氮乙基、乙酰基、2-卤(氯、溴)乙酰基、2-叠氮基乙酰基、苯甲酰基、苯乙酰基或
Figure PCTCN2016111820-appb-000013
其中，所述R10为氢、-OH、-NH2、卤素、甲基、乙基、异丙基，乙烯基，丙烯基、羧基、叠氮基、肟基、胺基、巯基、酰胺基、硫酸酯基、鼠李糖基、苯基或苄基，且所述苯基和苄基任选地被一个或多个选自卤素、-OCH3、-OH、-OCF3、-NH2、-NHRX和-NRX 2中的基团所取代，其中，RX各自独立地是饱和的脂肪族的C1-4烷基、苯基或苄基；
n为2～7的整数；
所述卤素为-F、-Cl、-Br或-I。
根据本发明的实施例，所述R1为
Figure PCTCN2016111820-appb-000014
R2、R3、R4均为氢，所述R5为甲基,所述R6为-OH，所述化合物的结构式如下：
Figure PCTCN2016111820-appb-000015
其中，R7和R8各自独立地为氢、-OH、-NH2、卤素、-OCH3、-OCF3、甲基、乙基、异丙基，乙烯基，丙烯基、丙炔基、2-(三氟甲基)乙基、2-溴乙基、2-叠氮乙基、乙酰基、2-卤(氯、溴)乙酰基、2-叠氮基乙酰基、苯甲酰基、苯乙酰基或、
Figure PCTCN2016111820-appb-000016
其中，所述R9为氢、-OH、-NH2、卤素、甲基、乙基、异丙基，乙烯基，丙烯基、羧基、叠氮基、肟基、胺基、巯基、酰胺基、硫酸酯基、鼠李糖基、苯基或苄基，且所述苯基和苄基任选地被一个或多个选自卤素、-OCH3、-OH、-OCF3、-NH2、-NHRX和-NRX 2中的基团所取代，其中，RX各自独立地是饱和的脂肪族的C1-4烷基、苯基或苄基；
n为2～7的整数；
所述卤素为-F、-Cl、-Br或-I。
根据本发明的实施例，所述R2为
Figure PCTCN2016111820-appb-000017
R1、R7和R8均为-OH，R3和R5均为氢，R4为甲基，所述化合物的结构式如下，所述化合物的结构式如下：
Figure PCTCN2016111820-appb-000018
其中，R6为氢、-OH、-NH2、卤素、-OCH3、-OCF3、甲基、乙基、异丙基，乙烯基，丙烯基、丙炔基、2-(三氟甲基)乙基、2-溴乙基、2-叠氮乙基、乙酰基、2-卤(氯、溴)乙酰基、2-叠氮基乙酰基、苯甲酰基、苯乙酰基或
Figure PCTCN2016111820-appb-000019
其中，所述R10为氢、-OH、-NH2、卤素、甲基、乙基、异丙基，乙烯基，丙烯基、羧基、叠氮基、肟基、胺基、巯基、酰胺基、硫酸酯基、鼠李糖基、苯基或苄基，且所述苯基和苄基任选地被一个或多个选自卤素、-OCH3、-OH、-OCF3、-NH2、-NHRX和-NRX 2中的基团所取代，其中，RX各自独立地是饱和的脂肪族的C1-4烷基、苯基或苄基；
n为2～7的整数；
所述卤素为-F、-Cl、-Br或-I。
根据本发明的实施例，所述R2为
Figure PCTCN2016111820-appb-000020
R6为-OH，R3、R5均为氢，R4为甲基，所述化合物的结构式如下：
Figure PCTCN2016111820-appb-000021
其中，R1,R7,R8各自独立地为氢、-OH、-NH2、卤素、-OCH3、-OCF3、甲基、乙基、异丙基，乙烯基，丙烯基、丙炔基、2-(三氟甲基)乙基、2-溴乙基、2-叠氮乙基、乙酰基、2-卤(氯、溴)乙酰基、2-叠氮基乙酰基、苯甲酰基、苯乙酰基或、
Figure PCTCN2016111820-appb-000022
其中，所述R9为氢、-OH、-NH2、卤素、甲基、乙基、异丙基，乙烯基，丙烯基、羧基、叠氮基、肟基、胺基、巯基、酰胺基、硫酸酯基、鼠李糖基、苯基或苄基，且所述苯基和苄基任选地被一个或多个选自卤素、-OCH3、-OH、-OCF3、-NH2、-NHRX和-NRX 2中的基团所取代，其中，RX各自独立地是饱和的脂肪族的C1-4烷基、苯基或苄基；
n为2～7的整数；
所述卤素为-F、-Cl、-Br或-I。
根据本发明的实施例，所述R3为
Figure PCTCN2016111820-appb-000023
R1、R7和R8均为-OH，R2、R5均为氢，R4为甲基，所述化合物的结构式如下：
Figure PCTCN2016111820-appb-000024
其中，R6为氢、-OH、-NH2、卤素、-OCH3、-OCF3、甲基、乙基、异丙基，乙烯基，丙烯基、丙炔基、2-(三氟甲基)乙基、2-溴乙基、2-叠氮乙基、乙酰基、2-卤(氯、溴)乙酰基、2-叠氮基乙酰基、苯甲酰基、苯乙酰基或
Figure PCTCN2016111820-appb-000025
其中，所述R10为氢、-OH、-NH2、卤素、甲基、乙基、异丙基，乙烯基，丙烯基、羧 基、叠氮基、肟基、胺基、巯基、酰胺基、硫酸酯基、鼠李糖基、苯基或苄基，且所述苯基和苄基任选地被一个或多个选自卤素、-OCH3、-OH、-OCF3、-NH2、-NHRX和-NRX 2中的基团所取代，其中，RX各自独立地是饱和的脂肪族的C1-4烷基、苯基或苄基；
n为2～7的整数；
所述卤素为-F、-Cl、-Br或-I。
根据本发明的实施例，所述R3为
Figure PCTCN2016111820-appb-000026
R1、R7和R6均为-OH，R2、R5均为氢，R4为甲基，所述化合物的结构式如下：
Figure PCTCN2016111820-appb-000027
其中，R1、R7和R8各自独立地为氢、-OH、-NH2、卤素、-OCH3、-OCF3、甲基、乙基、异丙基，乙烯基，丙烯基、丙炔基、2-(三氟甲基)乙基、2-溴乙基、2-叠氮乙基、乙酰基、2-卤(氯、溴)乙酰基、2-叠氮基乙酰基、苯甲酰基、苯乙酰基或
Figure PCTCN2016111820-appb-000028
其中，所述R9为氢、-OH、-NH2、卤素、甲基、乙基、异丙基，乙烯基，丙烯基、羧基、叠氮基、肟基、胺基、巯基、酰胺基、硫酸酯基、鼠李糖基、苯基或苄基，且所述苯基和苄基任选地被一个或多个选自卤素、-OCH3、-OH、-OCF3、-NH2、-NHRX和-NRX 2中的基团所取代，其中，RX各自独立地是饱和的脂肪族的C1-4烷基、苯基或苄基；
n为2～7的整数；
所述卤素为-F、-Cl、-Br或-I。
根据本发明的实施例，所述聚醚类化合物为下列化合物之一：R1为
Figure PCTCN2016111820-appb-000029
或-OH，R2、R3各自独立地为
Figure PCTCN2016111820-appb-000030
或氢，R4、R5各自独立地为甲基或氢， R6、R7、R8均为-OH。
根据本发明的实施例，所述聚醚类化合物为下列化合物之一：
Figure PCTCN2016111820-appb-000031
根据本发明的实施例，所述癌症为脑癌、皮肤癌、肾癌、骨癌、肉瘤、***癌、子宫癌、黑色素癌、结肠癌、淋巴癌、白血病、胰腺癌、上皮细胞癌、乳腺癌、肝癌、肺癌、胃癌、卵巢癌及相应的肿瘤细胞干细胞。
根据本发明的实施例，所述药物通过抑制肿瘤细胞干细胞增殖预防癌症复发。
目前以聚醚为母核的化合物先主要作为抗生素使用，发明人经大量实验偶然发现该类化合物具有良好的抗肿瘤活性。通过将该三个化合物分别与恶性肿瘤细胞混合培养，其都可以有不同程度的抗肿瘤活性。由此，以聚醚为母核的化合物在其药学上可接受给药形式(游离形式、钠盐或钾盐形式、螯合形式、水合形式)可用于治疗恶性肿瘤细胞，丰富了治疗这类疾病药物的多样性。发明人发现通式I所示的聚醚类化合物能够抑制恶性肿瘤细胞的增殖，并对化合物1、化合物2和化合物3这三个化合物进行了研究，发现其对多种癌细胞具有抑制作用。具体地，发明人通过下面的实验过程证明了发明人的观点：
(1)发明人将多种癌细胞与化合物1、化合物2和化合物3这三个化合物尤其是其钠盐在体外分别混合培养。利用MTT染色法，通过测其OD值，计算化合物1、化合物2和化合物3这三个化合物对肿瘤细胞增殖的抑制率及IC50(半数抑制率)。发明人发现，化合物1、化合物2和化合物3这三个化合物对多种肿瘤细胞均有不同程度的抑制作用。
(2)发明人通过与抗癌药紫杉醇以及与同类被发现具有抗癌作用的盐霉素(salinomycin)对比发现，这三个化合物都对多种癌细胞增殖的抑制作用明显强于紫杉醇的抑制作用，部分强于盐霉素。
本发明的附加方面和优点将在下面的描述中部分给出，部分将从下面的描述中变得明显，或通过本发明的实践了解到。
附图说明
本发明的上述和/或附加的方面和优点从结合下面附图对实施例的描述中将变得明显和容易理解，其中：
图1显示了根据本发明一个实施例的化合物1的图谱示意图；
图2显示了根据本发明一个实施例的化合物2的图谱示意图；
图3显示了根据本发明一个实施例的化合物3的图谱示意图；
图4显示了根据本发明一个实施例的干细胞流式检测的图谱示意图。
发明详细描述
下面通过参考附图描述的实施例是示例性的，旨在用于解释本发明，而不能理解为对本发明的限制。
实施例1
化合物1、化合物2和化合物3是通过Streptomyces hygroscopicus亚型链霉菌和Streptomyces endus亚型链霉菌发酵获得的，具体方法如下：
将两株Streptomyces hygroscopicus亚型和Streptomyces endus亚型链霉菌分别接种于SFM平板，培养三天到四天左右。待SFM培养基中形成菌落时，挑单菌落至种子培养基中培养三天到四天左右，按照1％的量接菌至发酵培养基(发酵培养基的成份为可溶性淀粉30g/L，黄豆饼粉10g/L，酵母抽提物2.5g/L，CaCO3 3g/L，pH7.2)中。培养条件：30度，220转速，培养7到8天时间。
待培养到第7或8天时，收取发酵液，高速离心使上清与菌丝体分离，菌丝体加入等量的丙酮破菌，超声20min，旋蒸丙酮，上清与菌丝体采用等量的乙酸乙酯萃取，重复一次。旋蒸浓缩至干，后用硅胶柱粗分离，得到粗品用HPLC检测产物，鉴于HPLC结果显示该三株菌的产量比较高，因此，我们也对浓缩完的样品进行了TLC点板，并在碘缸里显色，将很明显的点抠下，用甲醇溶解，高速离心取上清做质谱确定目标点的位置，化合物检测的结果如图1-3所示，图1表明该化合物为化合物1，图2表明该化合物为化合物2，图3表明该化合物为化合物3。
实施例2
利用MTT实验检测化合物1钠盐与紫杉醇对MCF-7肿瘤细胞的抑制作用，具体方法如下：
分别取对数生长期的MCF-7(乳腺癌细胞,武汉大学基础医学院菌种保藏中心)，待细胞长满瓶壁80％时，采用0.25％-EDTA胰蛋白酶消化(3min-5min)使细胞悬浮。将该细胞悬液接种于96孔细胞培养板中(每孔细胞数在5000个左右)，每孔200μL；对照组为每孔加入200μL不加药物的细胞的组；空白组为每孔加入200μL不含细胞的培养基的组。将上述接种了细胞的96孔细胞培养板放入细胞含5％的CO2培养箱中孵育37℃过夜，使细胞贴壁。样品化合物1钠盐，盐霉素(salinomycin)和现有抗癌药物紫杉醇分别用DMSO溶解，配制为100mg/mL的储存液，然后使用前用相应培养基稀释成不同浓度(DMSO终浓度小于0.1％)的样品溶液。在不同的实验组中分别加入200μL不同浓度的样品溶液(化合物1钠盐，盐霉素)(100μg/mL，10μg/mL，1μg/mL，0.1μg/mL，0.01μg/mL)或紫杉醇溶液(100μg/mL，10μg/mL，1μg/mL，0.1μg/mL，0.01μg/mL)；对照组为往贴壁细胞中加入200μL培养基的组；空白组为无细胞只加200μL培养基的组。然后将此加过不同浓度药物溶液(100、10、1、0.1、0.01μg/L样品溶液或盐霉素或紫杉醇溶液)的96孔细胞培养板在细胞培养箱(37℃)中培养48小时后，在取出的上述96孔细胞培养板的每个孔中加入20μL 0.5mg/mL的噻唑蓝(MTT)，然后继续放入细胞培养箱(37℃)中培养。2-4个小时后，将与MTT共同孵育的96孔细胞培养板在高速离心机中以2000rpm离心10分钟。离心后，去除96孔细胞培养板中上清液，然后通过向每孔加100μL二甲基亚砜(DMSO)溶解在96孔板底部生成的甲臢蓝色结晶。该加过DMSO的96孔细胞培养板在平板振荡器上振荡10分钟后，利用酶联免疫检测仪，在570nm波长下检测OD值(参比波长为490nm)，计算抑制率及IC50(半数抑制率)。
抑制率％＝(A-A0)/(A-A1)×100％
式中：A代表对照组的OD值；A0代表样品组的OD值；A1代表空白组的OD值。
化合物1钠盐及紫杉醇对MCF-7细胞的IC50值
受试物 对MCF-7的IC50(μmol/L)
化合物1钠盐 1.63±0.04
紫杉醇 8.49±1.43
Salinomyicn 3.86±0.08
由上表所示的结果可知，与紫杉醇相比，化合物1钠盐对MCF-7细胞体外增殖均有更显著的抑制作用，其对MCF-7细胞株的IC50值较紫杉醇降低了5.21倍，较salinomycin降低了2.34倍。说明化合物1钠盐对MCF-7肿瘤细胞增殖有较强的抑制作用，其抑制作用明显强于紫杉醇的抑制作用。
实施例3：
利用MTT实验检测化合物2与紫杉醇对MCF-7肿瘤细胞的抑制作用，实验方法以及检测方法同实施例2，区别在于所采用的化合物为化合物2。化合物2的钠盐及紫杉醇对MCF-7细胞的IC50值如下表所示。
化合物2钠盐及紫杉醇对MCF-7细胞的IC50值
受试物 对MCF-7的IC50(μmol/L)
化合物2钠盐 2.25±0.19
紫杉醇 8.49±1.43
Salinomyicn 3.86±0.08
由上表所示的结果可知，与盐霉素、紫杉醇相比，化合物2钠盐对MCF-7细胞体外增殖均有更显著的抑制作用，其对MCF-7细胞株的IC50值较紫杉醇降低了3.77倍，与盐霉素相当。说明化合物2钠盐对MCF-7肿瘤细胞增殖有较强的抑制作用，其抑制作用明显强于紫杉醇的抑制作用。
实施例4：
利用MTT实验检测化合物3与紫杉醇对MCF-7肿瘤细胞的抑制作用，实验方法以及检测方法同实施例2，区别在于所采用的化合物为化合物3。化合物3的钠盐及紫杉醇对MCF-7细胞的IC50值如下表所示。
受试物 对MCF-7的IC50(μmol/L)
化合物3钠盐 5.19±1.4
紫杉醇 8.49±1.43
Salinomyicn 3.86±0.08
由表中所示的结果可知，与紫杉醇相比化合物3钠盐对MCF-7细胞体外增殖均有更显著的抑制作用，其对MCF-7细胞株的IC50值较紫杉醇降低了1.61倍。说明化合物4钠盐对MCF-7肿瘤细胞增殖有较强的抑制作用，其抑制作用强于紫杉醇的抑制作用，但抗癌活性不及salinomycin。
实施例5：
本发明通式的化合物钠盐衍生物化合物的制备方法，具体如下：
在0℃，无水无氧条件下，分别将化合物1、2、3(1.7g，200毫摩尔)、二环己基碳二亚胺(240毫摩尔)和4-二甲氨基吡啶(10毫摩尔)溶解于二氯甲烷(8ml)中，后在搅拌下缓慢滴加相应的试剂，滴加结束后放置室温过夜反应。向反应体系中加入0.1mol/L的HCl溶液淬灭，饱和食盐水洗涤反应液，用乙酸乙酯萃取，合并有机相，有机相中加入无水硫酸钠干燥，旋蒸除去溶剂得到浓缩液，浓缩液经过快速过柱得到如式II、IV、VI所式的结构衍生物。
实施例6：
本发明通式的化合物钠盐衍生物化合物的制备方法，具体如下：
在0℃，无水无氧条件下，任意将化合物1，2，3(1.7g，200毫摩尔)、和4-二甲氨基吡啶(10毫摩尔)溶解于二氯甲烷(8ml)，后在搅拌下缓慢滴加三乙胺(600毫摩尔)，搅拌10min后，再滴加相应的酰氯，溴代化合物。滴加结束后放置室温反应数小时。向反应体系中加入0.1mol/L的HCl溶液淬灭，饱和食盐水洗涤反应液，用乙酸乙酯萃取，合并有机相，有机相中加入无水硫酸钠干燥，旋蒸除去溶剂得到浓缩液，浓缩液经过快速过柱得到如式III、V、VII所示的结构的衍生物。
实施例7
检测化合物1、2、和3对多种肿瘤细胞的抑制作用，具体方法如下：
(1)细胞复苏：实验前，超净工作台台面用紫外线照射30min。将水浴锅预热至37℃，将新鲜配制的培养基置于水浴锅预热。取出冻存的细胞，迅速将冻存管投入到已经预热的水浴锅中迅速解冻，并不断的摇动，使管中的液体迅速融化。约1-2min后冻存管内液体完全溶解，取出用含70％酒精棉球擦拭冻存管的外壁。吸取冻存管内细胞，转移至15ml离心管中，同时加入5ml预热完全培养基。500g低转速离心3-5min，吸弃上清液。向离心管内加入10ml培养液，轻柔吹打制成细胞悬液。通过台盼蓝染色细胞记数并进行活力测定后，将细胞悬液加入10cm培养皿中，于含37℃/5％CO2培养箱中培养过夜。
(2)细胞培养：细胞培养时所需的培养基及传代的比例参考ATCC，细胞实验前的一代传代培养过程中，将该细胞的培养基换成无酚红培养基+10％FBS。
(3)细胞抑制实验：化合物样品均用DMSO进行8浓度5倍梯度稀释，检测时用无酚红的完全培养基进行稀释，配置成实验用浓度(5倍最终浓度)的溶液。
细胞活力检测方法:
a)接种细胞：收集对数期细胞，调整细胞悬液浓度，在384孔板中接种40μl细胞悬液，边缘孔用无菌PBS填充。
b)将细胞板放在37℃/5％CO2培养箱孵育过夜，第二天加入10μL 5倍待测浓度的化合物样品。
c)细胞在37℃/5％CO2培养箱孵育，72小时用倒置显微镜进行观察。
d)读板：72小时后室温孵育10min，每孔加入30μL每孔CellTiter-Glo反应混合物，将检测板振荡2-3分钟，室温孵育10min。在Pherastar(BMG labtech)读RLU值并保存数据。
Cell Growth inhibition％＝100％×[1-RLU样品/RLU阴性]，其中RLU样品为加样品孔或阳性对照孔RLU值，RLU阴性为仅含DMSO的RLU值。运用GraphPad Prism 6.0软件进行数据分析，结果如下表所示，表明化合物对多种肿瘤均具有显著的抑制作用。
化合物1、化合物2和化合物3对多种肿瘤细胞的IC50值
Figure PCTCN2016111820-appb-000032
Figure PCTCN2016111820-appb-000033
实施例8：
检测化合物1、化合物2和化合物3对肿瘤干细胞增殖的抑制作用，具体方法如下：
(1)悬浮培养的富集干细胞的含量测定：
细胞培养对象：人乳腺癌细胞株MDA-MB-231细胞。
培养方式：采用悬浮细胞培养方式培养，37度培养箱培养。
悬浮细胞培养培养基(200ml)：B27 4ml；insulin 80μl；DMEM-F12 194ml；hEGF:40μl；双抗：2ml
培养瓶：T25(15ml)；T75(75ml)；
接种密度：1000个/ml；
检测试剂盒：AldefluorTM kit；
培养时间：10天到15天左右(每天摇晃2次以上)。
实验过程：
(1)将细胞培养后分装15ml离心管中，并清洗一次T25瓶，配平离心250g,10min；
(2)移去上清，各加入1ml(0.05％)胰酶，并用PBS清洗一次，转移到T25培养瓶中，缓慢轻轻对打至单个细胞过程5min到10min；
(3)转移至15ml离心管中，配平离心250g 10min；
(4)用1ml PBS分两次加入，转移至1.5ml EP管中，对打均匀，取少量计数；
(5)计算数量在10万到20万个细胞与EP管中，离心去掉PBS,加入试剂盒缓冲液1ml重悬；
(6)去另外一个EP管中加入DEAB 10μl，后向细胞EP管中加入已经激活的Aldfluor试剂10μl，快速混合充分，吸取0.5ml于DEAB的EP管中，混合均匀，放入37度培养箱中培养45min；
(7)45min后，离心(250g，10min)去掉上清，加入试剂缓冲液0.5ml重悬，放在冰上避光保存。
采用流式细胞仪对细胞进行检测，实验结果如图4所示，贴壁细胞中干细胞的含量为2.36％，经过悬浮细胞培养后得到的干细胞比例为25.95％，从而提高了近11倍。数据间存在显著性差异。从而可以看到达到了我们富集干细胞的目的。
(2)药物抑制试验：
药物：化合物1、化合物2和化合物3
细胞种类：步骤(1)富集的干细胞
细胞接种：96孔细胞每孔接种细胞量12000左右每120μL。
药物的稀释浓度：采用PBS稀释：设置浓度：100μg/ML、20μg/ML、4μg/ML、0.8μg/ML、0.16μg/ML、0.032μg/ML、0.0064μg/ML、0.00128μg/ML、0.000256μg/ML。
加化合物：将细胞板放在37℃/5％CO2培养箱孵育过夜，第二天加入10μL 5倍待测浓度的化合物样品。
检测时间以及检测方式：给药72h后采用MTT法进行检测，后用三联溶液(10％SDS、5％异丁醇、0.1％浓盐酸)溶解采用酶标仪在570nm处检测OD值。
每个化合物独立重复一次。结果如下表
受试药物 IC50(g/ml)
化合物1 1.176E-06±0.041
化合物2 2.35E-06±0.152
化合物3 4.251E-06±0.129
结果表明，化合物1、化合物2和化合物3均对肿瘤干细胞有显著的抑制作用，从而可以抑制肿瘤的复发。
在本说明书的描述中，参考术语“一个实施例”、“一些实施例”、“示例”、“具体示例”、或“一些示例”等的描述意指结合该实施例或示例描述的具体特征、结构、材料或者特点包含于本发明的至少一个实施例或示例中。在本说明书中，对上述术语的示意性表述不必须针对的是相同的实施例或示例。而且，描述的具体特征、结构、材料或者特点可以在任一个或多个实施例或示例中以合适的方式结合。此外，在不相互矛盾的情况下，本领域的技术人员可以将本说明书中描述的不同实施例或示例以及不同实施例或示例的特征进行结合和组合。
尽管上面已经示出和描述了本发明的实施例，可以理解的是，上述实施例是示例性的，不能理解为对本发明的限制，本领域的普通技术人员在本发明的范围内可以对上述实施例进行变化、修改、替换和变型。

Claims (14)

  1. 一种通式I所示的聚醚类化合物、其螯合形式、水合形式或其药学上可接受的盐在制备药物中的用途，所述药物用于治疗癌症和预防癌症复发，
    Figure PCTCN2016111820-appb-100001
    其中，
    所述R1、所述R2、所述R3、所述R4、所述R5、所述R6、所述R7和所述R8各自独立地为氢、-OH、-NH2、卤素、任选取代的C1～10直链或支链的饱和或不饱和烃基、任选取代的C1～10直链或支链烃氧基、任选取代的C1～10酰基、任选取代的C6～20芳基、任选取代的杂芳基、
    Figure PCTCN2016111820-appb-100002
    其中，所述R9和所述R10各自独立地为氢、-OH、-NH2、卤素、C1-5直链或支链的饱和或不饱和烃基、羧基、叠氮基、肟基、胺基、巯基、酰胺基、硫酸酯基、鼠李糖基、苯基或苄基，且任选地被一个或多个选自卤素、-OCH3、-OH、-OCF3、-NH2、苯基、苄基、杂芳基、-NHRX和-NRX 2中的基团所取代，其中，RX各自独立地是饱和的脂肪族的C1-4烷基、苯基或苄基，所述杂芳基为3元～6元的单环或二环的杂芳基，且任选地含有1～3个选自N、O或S的杂原子；
    n为2～7的整数；
    所述卤素为-F、-Cl、-Br或-I。
  2. 根据权利要求1所述的用途，其特征在于，通式I中：
    所述R1、所述R2、所述R3、所述R4、所述R5、所述R6、所述R7和所述R8各自独立地为氢、-OH、-NH2、卤素、任选取代的C1～5直链或支链的饱和或不饱和烃基、任选取代的C1～5直链或支链烃氧基、任选取代的C1～5酰基、任选取代的苯基、
    Figure PCTCN2016111820-appb-100003
    Figure PCTCN2016111820-appb-100004
    其中，所述R9和所述R10各自独立地为氢、-OH、-NH2、卤素、C1～5直链或支链的饱和或不饱和烃基、羧基、叠氮基、肟基、胺基、巯基、酰胺基、硫酸酯基、鼠李糖基、苯 基或苄基，且任选地被一个或多个选自卤素、-OCH3、-OH、-OCF3、-NH2、苯基、苄基、杂芳基、-NHRX和-NRX 2中的基团所取代，其中，RX各自独立地是饱和的脂肪族的C1-4烷基、苯基或苄基，所述杂芳基为5元～6元的单环杂芳基，且任选地含有1～3个选自N、O或S的杂原子；
    n为2～7的整数；
    所述卤素为-F、-Cl、-Br或-I。
  3. 根据权利要求2所述的用途，其特征在于，通式I中：
    所述R1、所述R2、所述R3、所述R4、所述R5、所述R6、所述R7和所述R8各自独立地为氢、-OH、-NH2、卤素、任选取代的C1～3直链或支链的饱和或不饱和烃基、任选取代的C1～3直链或支链烃氧基、任选取代的C1～3酰基、任选取代的苯基、
    Figure PCTCN2016111820-appb-100005
    Figure PCTCN2016111820-appb-100006
    其中，所述R9和所述R10各自独立地为氢、-OH、-NH2、卤素、C1～3直链或支链的饱和或不饱和烃基、羧基、叠氮基、肟基、胺基、巯基、酰胺基、硫酸酯基、鼠李糖基、苯基或苄基，且任选地地被一个或多个选自卤素、-OCH3、-OH、-OCF3、-NH2、苯基、苄基、杂芳基、-NHRX和-NRX 2中的基团所取代，其中，RX各自独立地是饱和的脂肪族的C1-4烷基、苯基或苄基，所述杂芳基为5元～6元的单环杂芳基，且任选地含有1个选自N、O或S的杂原子；
    n为2～7的整数；
    所述卤素为-F、-Cl、-Br或-I。
  4. 根据权利要求3所述的用途，其特征在于，所述通式I中：
    所述R1、所述R2、所述R3、所述R4、所述R5、所述R6、所述R7、所述R8各自独立地为氢、-OH、-NH2、卤素、-OCH3、-OCF3、C2-10饱和脂肪族链烃、丙烯基、丙炔基、2-(三氟甲基)乙基、2-溴乙基、2-叠氮乙基、乙酰基、2-卤(氯、溴)乙酰基、2-叠氮基乙酰基、苯甲酰基、苯乙酰基、任选取代的苯基、
    Figure PCTCN2016111820-appb-100007
    Figure PCTCN2016111820-appb-100008
    其中，所述R9和所述R10各自独立地为氢、-OH、-NH2、卤素、甲基、乙基、异丙基，乙烯基，丙烯基、羧基、叠氮基、肟基、胺基、巯基、酰胺基、硫酸酯基、鼠李糖基、苯 基或苄基，且所述苯基和苄基任选地被一个或多个选自卤素、-OCH3、-OH、-OCF3、-NH2、-NHRX和-NRX 2中的基团所取代，其中，RX各自独立地是饱和的脂肪族的C1-4烷基、苯基或苄基；
    n为2～7的整数；
    所述卤素为-F、-Cl、-Br或-I。
  5. 根据权利要求4所述的用途，其特征在于，所述R1为
    Figure PCTCN2016111820-appb-100009
    所述R2、所述R3、所述R4均为氢，所述R5为甲基，所述R7和所述R8均为-OH，所述化合物的结构式如下：
    Figure PCTCN2016111820-appb-100010
    其中，R6为氢、-OH、-NH2、卤素、-OCH3、-OCF3、甲基、乙基、异丙基、乙烯基、丙烯基、丙炔基、2-(三氟甲基)乙基、2-溴乙基、2-叠氮乙基、乙酰基、2-卤(氯、溴)乙酰基、2-叠氮基乙酰基、苯甲酰基、苯乙酰基或
    Figure PCTCN2016111820-appb-100011
    其中，所述R10为氢、-OH、-NH2、卤素、甲基、乙基、异丙基，乙烯基，丙烯基、羧基、叠氮基、肟基、胺基、巯基、酰胺基、硫酸酯基、鼠李糖基、苯基或苄基，且所述苯基和所述苄基任选地被一个或多个选自卤素、-OCH3、-OH、-OCF3、-NH2、-NHRX和-NRX 2中的基团所取代，其中，RX各自独立地是饱和的脂肪族的C1-4烷基、苯基或苄基；
    n为2～7的整数；
    所述卤素为-F、-Cl、-Br或-I。
  6. 根据权利要求4所述的用途，其特征在于，所述R1为
    Figure PCTCN2016111820-appb-100012
    R2、R3和R4均为氢，所述R5为甲基，所述R6为-OH，所述化合物的结构式如下：
    Figure PCTCN2016111820-appb-100013
    其中，所述R7和所述R8各自独立地为氢、-OH、-NH2、卤素、-OCH3、-OCF3、甲基、乙基、异丙基，乙烯基，丙烯基、丙炔基、2-(三氟甲基)乙基、2-溴乙基、2-叠氮乙基、乙酰基、2-卤(氯、溴)乙酰基、2-叠氮基乙酰基、苯甲酰基、苯乙酰基或
    Figure PCTCN2016111820-appb-100014
    其中，所述R9为氢、-OH、-NH2、卤素、甲基、乙基、异丙基、乙烯基、丙烯基、羧基、叠氮基、肟基、胺基、巯基、酰胺基、硫酸酯基、鼠李糖基、苯基或苄基，且所述苯基和苄基任选地被一个或多个选自卤素、-OCH3、-OH、-OCF3、-NH2、-NHRX和-NRX 2中的基团所取代，其中，RX各自独立地是饱和的脂肪族的C1-4烷基、苯基或苄基；
    n为2～7的整数；
    所述卤素为-F、-Cl、-Br或-I。
  7. 根据权利要求4所述的用途，其特征在于，所述R2为
    Figure PCTCN2016111820-appb-100015
    所述R1、所述R7和所述R8均为-OH，所述R3和所述R5均为氢，所述R4为甲基，所述化合物的结构式如下，所述化合物的结构式如下：
    Figure PCTCN2016111820-appb-100016
    其中，所述R6为氢、-OH、-NH2、卤素、-OCH3、-OCF3、甲基、乙基、异丙基，乙烯基，丙烯基、丙炔基、2-(三氟甲基)乙基、2-溴乙基、2-叠氮乙基、乙酰基、2-卤(氯、溴)乙酰基、2-叠氮基乙酰基、苯甲酰基、苯乙酰基或
    Figure PCTCN2016111820-appb-100017
    其中，所述R10为氢、-OH、-NH2、卤素、甲基、乙基、异丙基，乙烯基，丙烯基、羧基、叠氮基、肟基、胺基、巯基、酰胺基、硫酸酯基、鼠李糖基、苯基或苄基，且所述苯基和苄基任选地被一个或多个选自卤素、-OCH3、-OH、-OCF3、-NH2、-NHRX和-NRX 2中的基团所取代，其中，RX各自独立地是饱和的脂肪族的C1-4烷基、苯基或苄基；
    n为2～7的整数；
    所述卤素为-F、-Cl、-Br或-I。
  8. 根据权利要求4所述的用途，其特征在于，所述R2为
    Figure PCTCN2016111820-appb-100018
    所述R6为-OH，R3和所述R5均为氢，R4为甲基，所述化合物的结构式如下：
    Figure PCTCN2016111820-appb-100019
    其中，所述R1、所述R7和所述R8各自独立地为氢、-OH、-NH2、卤素、-OCH3、-OCF3、甲基、乙基、异丙基，乙烯基，丙烯基、丙炔基、2-(三氟甲基)乙基、2-溴乙基、2-叠氮乙基、乙酰基、2-卤(氯、溴)乙酰基、2-叠氮基乙酰基、苯甲酰基、苯乙酰基或
    Figure PCTCN2016111820-appb-100020
    其中，所述R9为氢、-OH、-NH2、卤素、甲基、乙基、异丙基，乙烯基，丙烯基、羧基、叠氮基、肟基、胺基、巯基、酰胺基、硫酸酯基、鼠李糖基、苯基或苄基，且所述苯基和苄基任选地被一个或多个选自卤素、-OCH3、-OH、-OCF3、-NH2、-NHRX和-NRX 2中的基团所取代，其中，RX各自独立地是饱和的脂肪族的C1-4烷基、苯基或苄基；
    n为2～7的整数；
    所述卤素为-F、-Cl、-Br或-I。
  9. 根据权利要求4所述的用途，其特征在于，所述R3为
    Figure PCTCN2016111820-appb-100021
    所述R1、所述R7和所述R8均为-OH，所述R2和所述R5为氢，所述R4为甲基，所述化合物的结构式如下：
    Figure PCTCN2016111820-appb-100022
    其中，所述R6为氢、-OH、-NH2、卤素、-OCH3、-OCF3、甲基、乙基、异丙基，乙烯基，丙烯基、丙炔基、2-(三氟甲基)乙基、2-溴乙基、2-叠氮乙基、乙酰基、2-卤(氯、溴)乙酰基、2-叠氮基乙酰基、苯甲酰基、苯乙酰基或
    Figure PCTCN2016111820-appb-100023
    其中，所述R10为氢、-OH、-NH2、卤素、甲基、乙基、异丙基，乙烯基，丙烯基、羧基、叠氮基、肟基、胺基、巯基、酰胺基、硫酸酯基、鼠李糖基、苯基或苄基，且所述苯基和苄基任选地被一个或多个选自卤素、-OCH3、-OH、-OCF3、-NH2、-NHRX和-NRX 2中的基团所取代，其中，RX各自独立地是饱和的脂肪族的C1-4烷基、苯基或苄基；
    n为2～7的整数；
    所述卤素为-F、-Cl、-Br或-I。
  10. 根据权利要求4所述的用途，其特征在于，所述R3为
    Figure PCTCN2016111820-appb-100024
    所述R1、所述R7和所述R6均为-OH，所述R2和所述R5均为氢，所述R4为甲基，所述化合物的结构式如下：
    Figure PCTCN2016111820-appb-100025
    其中，所述R1、所述R7和所述R8各自独立地为氢、-OH、-NH2、卤素、-OCH3、-OCF3、甲基、乙基、异丙基，乙烯基，丙烯基、丙炔基、2-(三氟甲基)乙基、2-溴乙基、2-叠氮乙基、乙酰基、2-卤(氯、溴)乙酰基、2-叠氮基乙酰基、苯甲酰基、苯乙酰基或
    Figure PCTCN2016111820-appb-100026
    其中，所述R9为氢、-OH、-NH2、卤素、甲基、乙基、异丙基，乙烯基，丙烯基、羧 基、叠氮基、肟基、胺基、巯基、酰胺基、硫酸酯基、鼠李糖基、苯基或苄基，且所述苯基和苄基任选地被一个或多个选自卤素、-OCH3、-OH、-OCF3、-NH2、-NHRX和-NRX 2中的基团所取代，其中，RX各自独立地是饱和的脂肪族的C1-4烷基、苯基或苄基；
    n为2～7的整数；
    所述卤素为-F、-Cl、-Br或-I。
  11. 根据权利要求4所述的用途，其特征在于，所述聚醚类化合物为下列化合物之一：所述R1为
    Figure PCTCN2016111820-appb-100027
    或-OH，所述R2和所述R3各自独立地为
    Figure PCTCN2016111820-appb-100028
    或氢，所述R4和所述R5各自独立地为甲基或氢，所述R6、所述R7和所述R8均为-OH。
  12. 根据权利要求1～11任一项所述的用途，其特征在于，所述聚醚类化合物为下列化合物之一：
    Figure PCTCN2016111820-appb-100029
  13. 根据权利要求1所述的用途，其特征在于，所述癌症为脑癌、皮肤癌、肾癌、骨癌、肉瘤、***癌、子宫癌、黑色素癌、结肠癌、淋巴癌、白血病、胰腺癌、上皮细胞癌、乳腺癌、肝癌、肺癌、胃癌和卵巢癌。
  14. 根据权利要求1所述的用途，其特征在于，所述药物通过抑制肿瘤细胞干细胞增殖预防癌症复发。
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