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WO2018058863A1 - 聚醚类化合物用途 - Google Patents

聚醚类化合物用途 Download PDF

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WO2018058863A1
WO2018058863A1 PCT/CN2017/071450 CN2017071450W WO2018058863A1 WO 2018058863 A1 WO2018058863 A1 WO 2018058863A1 CN 2017071450 W CN2017071450 W CN 2017071450W WO 2018058863 A1 WO2018058863 A1 WO 2018058863A1
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group
halogen
cancer
phenyl
benzyl
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French (fr)
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刘天罡
黄敏坚
刘然
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WUHAN J1 BIOTECH CO Ltd
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WUHAN J1 BIOTECH CO Ltd
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    • 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
    • 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
    • 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
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/7028—Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages
    • A61K31/7034—Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages attached to a carbocyclic compound, e.g. phloridzin
    • A61K31/704—Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages attached to a carbocyclic compound, e.g. phloridzin attached to a condensed carbocyclic ring system, e.g. sennosides, thiocolchicosides, escin, daunorubicin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A61P35/02—Antineoplastic agents specific for leukemia

Definitions

  • the invention relates to the field of medicinal chemistry and pharmacotherapeutics.
  • the invention relates to the use of polyether compounds.
  • 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 invention aims to solve at least one of the technical problems existing in the related art at least to some extent. To this end, it is an object of the present invention to provide a means for effectively preventing or treating cancer.
  • the present invention proposes the use of a polyether compound, a chelated form thereof, a hydrated form or a pharmaceutically acceptable salt thereof for the preparation of a medicament.
  • the medicament is for treating brain cancer, skin cancer, kidney cancer, bone cancer, sarcoma, prostate cancer, uterine cancer, melanoma, colon cancer, lymphoma, leukemia, pancreatic cancer, breast
  • the structural formula of the polyether compound is as follows:
  • the R 1 , the R 2 , the R 3 , the R 4 and the R 5 are each independently hydrogen, —OH, —NH 2 , halogen, optionally substituted C 1-10 linear or branched, saturated or unsaturated hydrocarbon group, an optionally substituted C 1 ⁇ 10 linear or branched hydrocarbon group, an optionally substituted C 1 ⁇ 10 acyl group, an optionally substituted C 6 ⁇ 20 aryl group, optionally substituted Heteroaryl, or
  • R 6 and R 7 are each independently hydrogen, -OH, -NH 2 , halogen, C 1-5 linear or branched saturated or unsaturated hydrocarbon group, carboxyl group, azide group, fluorenyl group , an amine group, a mercapto group, an amide group, a sulfate group, a rhamnose group, a phenyl group or a benzyl group, said -NH 2 , a halogen, a C 1-5 linear or branched saturated or unsaturated hydrocarbon group, a carboxyl group, azido, oxime group, amino group, a mercapto group, an amide group, sulfate group, rhamnose group, phenyl or benzyl group is optionally substituted by one or more substituents selected from halo, -OCH 3, -OH, -OCF 3, -NH 2, phenyl, benzyl, heteroaryl, -NHR X and
  • n is an integer of 2-7;
  • the halogen is -F, -Cl, -Br, -I.
  • polyether compounds have good anti-tumor activity and can effectively treat brain cancer, skin cancer, kidney cancer, bone cancer, sarcoma, prostate cancer, uterine cancer, melanoma, colon cancer, lymphoma. At least one of leukemia, pancreatic cancer, breast cancer, liver cancer, lung cancer, stomach cancer, and ovarian cancer.
  • the polyether compound, its chelated form, the hydrated form or a pharmaceutically acceptable salt thereof can be mixed and cultured with malignant tumor cells, respectively, which can 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
  • a pharmaceutically acceptable administration form free form, sodium salt or potassium salt form, chelated form, hydrated form
  • the inventors separately cultured various cancer cells and polyether compound sodium salts in vitro.
  • the MTT staining method was used to calculate the inhibition rate of tumor cell proliferation and IC50 (half inhibition rate) by measuring its OD value.
  • the inventors have found that the polyether compound sodium salt has various degrees of inhibition on various tumor cells.
  • the use of the above polyether compound, its chelated form, hydrated form or a pharmaceutically acceptable salt thereof for the preparation of a medicament may further have the following additional technical features:
  • the R 1 , the R 2 , the R 3 , the R 4 and the R 5 are each independently hydrogen, —OH, —NH 2 , halogen, optionally substituted a C 1 to 5 linear or branched saturated or unsaturated hydrocarbon group, an optionally substituted C 1-5 linear or branched alkoxy group, an optionally substituted C 1-5 acyl group, an optionally substituted phenyl group, or
  • R 6 and R 7 are each independently hydrogen, -OH, -NH 2 , halogen, C 1-5 linear or branched saturated or unsaturated hydrocarbon group, carboxyl group, azide group, fluorenyl group , an amine group, a mercapto group, an amide group, a sulfate group, a rhamnose group, a phenyl group or a benzyl group, said -NH 2 , a halogen, a C 1-5 linear or branched saturated or unsaturated hydrocarbon group, a carboxyl group, azido, oxime group, amino group, a mercapto group, an amide group, sulfate group, rhamnose group, phenyl or benzyl optionally substituted with one or more substituents selected from halo, -OCH 3, -OH, -OCF 3, -NH 2, phenyl, benzyl, heteroaryl, -NHR X and -
  • n is an integer of 2-7;
  • the halogen is -F, -Cl, -Br, -I.
  • the R 1 , the R 2 , the R 3 , the R 4 and the R 5 are each independently hydrogen, —OH, —NH 2 , halogen, optionally substituted a C 1 to 3 linear or branched saturated or unsaturated hydrocarbon group, an optionally substituted C 1-3 straight or branched alkoxy group, an optionally substituted C 1-3 acyl group, an optionally substituted phenyl group, or
  • R 6 and R 7 are each independently hydrogen, -OH, -NH 2 , halogen, C 1-3 linear or branched saturated or unsaturated hydrocarbon group, carboxyl group, azide group, fluorenyl group , an amine group, a mercapto group, an amide group, a sulfate group, a rhamnose group, a phenyl group or a benzyl group, said -NH 2 , a halogen, a C 1-3 linear or branched saturated or unsaturated hydrocarbon group, a carboxyl group, azido, oxime group, amino group, a mercapto group, an amide group, sulfate group, rhamnose group, phenyl or benzyl optionally substituted with one or more substituents selected from halo, -OCH 3, -OH, -OCF 3, -NH 2, phenyl, benzyl, heteroaryl, -NHR X and -
  • n is an integer of 2-7;
  • the halogen is -F, -Cl, -Br, -I.
  • the R 1 , the R 2 , the R 3 , the R 4 and the R 5 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-azidoethyl, acetyl, 2- Halogen (chloro, bromo)acetyl, 2-azidoacetyl, benzoyl, phenylacetyl, optionally substituted phenyl, or
  • R 6 and R 7 are each independently hydrogen, -OH, -NH 2 , halogen, methyl, ethyl, isopropyl, vinyl, propenyl, carboxyl, azide, fluorenyl
  • n is an integer of 2-7;
  • the halogen is -F, -Cl, -Br, -I.
  • the structural formula of the polyether compound is as follows:
  • R 5 is hydrogen, -OH, -NH 2 , halogen, -OCH 3 , -OCF 3 , methyl, ethyl, isopropyl, vinyl, propenyl, propynyl, 2-(three Fluoromethyl)ethyl, 2-bromoethyl, 2-azidoethyl, acetyl, 2-chloroacetyl, 2-bromoacetyl, 2-azidoacetyl, benzoyl, phenylacetyl , or
  • R 6 and R 7 are hydrogen, -OH, -NH 2 , halogen, methyl, ethyl, isopropyl, vinyl, propenyl, carboxyl, azide, sulfhydryl, amine , mercapto, amide, sulfate, rhamnose, phenyl or benzyl, and the phenyl and benzyl are optionally selected from one or more selected from the group consisting of halogen, -OCH 3 , -OH, -OCF 3, -NH 2, -NHR X 2 and -NR X group substituted with the 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, -I.
  • the structural formula of the polyether compound is as follows:
  • R 3 and R 4 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-chloroacetyl, 2-bromoacetyl, 2-azidoacetyl Benzoyl, phenylacetyl, or
  • R 6 and R 7 are hydrogen, -OH, -NH 2 , halogen, methyl, ethyl, isopropyl, vinyl, propenyl, carboxyl, azide, sulfhydryl, amine , thiol, amide, sulfate, rhamnose, phenyl or benzyl, optionally substituted by one or more selected from the group consisting of halogen, -OCH 3 , -OH, -OCF 3 Substituting a group of -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, -I.
  • the structural formula of the polyether compound is as follows:
  • R 1 , R 3 and R 4 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-chloroacetyl, 2-bromoacetyl, 2-azidoacetyl Base, benzoyl, phenylacetyl, or
  • R 6 and R 7 are hydrogen, -OH, -NH 2 , halogen, methyl, ethyl, isopropyl, vinyl, propenyl, carboxyl, azide, fluorenyl, amine , thiol, amide, sulfate, rhamnose, phenyl or benzyl, optionally substituted by one or more selected from the group consisting of halogen, -OCH 3 , -OH, -OCF 3 Substituting a group of -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, -I.
  • the structural formula of the polyether compound is as follows, abbreviated as J1-001 compound:
  • the J1-001 compound is an acidic ester-soluble polyether antibiotic, which has an inhibitory effect on Gram-positive and negative bacteria; has strong anti-coccidial activity, and is currently used for prevention and treatment. Coccidiosis in laying hens and broilers; at the same time, the toxicity and triad test results show that the antibiotic is safe and has no side effects.
  • the manner of obtaining the J1-001 compound is not particularly limited.
  • the J1-001 compound may be produced by fermentation with a microorganism containing a gene cluster encoding the compound, or may be Produced by chemical synthesis or chemical semi-synthesis.
  • the preparation of a malignant tumor cell and a drug-resistant malignant tumor cell by using the J1-001 compound has good industrial applicability.
  • the J1-001 compound has long been used as an antibiotic for the control of chicken coccidia.
  • the antibiotic toxicity and triad test results show that it is safe and has no side effects. Therefore, the J1-001 compound has operability and applicability in preparation for pharmaceutical use. From the above, the J1-001 compound has great market prospects for the preparation of a medicament for treating malignant tumors.
  • the drug inhibits tumor stem cell proliferation, and better treats brain cancer, skin cancer, kidney cancer, bone cancer, sarcoma, prostate cancer, uterine cancer, melanoma, colon cancer, lymphoma,
  • the medicament is for inhibiting proliferation of tumor cells and drug-resistant tumor cells, so as to To better treat brain cancer, skin cancer, kidney cancer, bone cancer, sarcoma, prostate cancer, uterine cancer, melanoma, colon cancer, lymphoma, leukemia, pancreatic cancer, breast cancer, liver cancer, lung cancer, stomach cancer and ovarian cancer
  • brain cancer skin cancer, kidney cancer, bone cancer, sarcoma, prostate cancer, uterine cancer, melanoma, colon cancer, lymphoma, leukemia, pancreatic cancer, breast cancer, liver cancer, lung cancer, stomach cancer and ovarian cancer
  • existing anticancer drugs have a good effect on the treatment of cancer in a certain period of time, but because of the long cycle of treatment of cancer, long-term use of a certain anticancer drug is prone to drug resistance.
  • polyether compounds are effective in inhibiting a variety of human malignant tumor cells, particularly drug-resistant tumor cells, and their effects are superior to various existing chemotherapy drugs. Thereby, the superiority of the polyether compound as a drug for treating malignant tumors is further improved.
  • treatment as used in the present invention is used to mean obtaining a desired pharmacological and/or physiological effect.
  • the effect may be prophylactic in terms of completely or partially preventing the disease or its symptoms, and/or may be therapeutic in terms of partially or completely curing the disease and/or the adverse effects caused by the disease.
  • treatment encompasses diseases of a mammal, particularly a human, including: (a) preventing the occurrence of a disease or condition in an individual who is susceptible to the disease but has not yet been diagnosed; (b) inhibiting the disease, such as arresting the progression of the disease; Or (c) alleviating the disease, for example, alleviating the symptoms associated with the disease.
  • treatment encompasses any administration of a medicament or compound to an individual to treat, cure, ameliorate, ameliorate, ameliorate or inhibit the disease of the individual, including but not limited to the inclusion of a polyether compound described herein, a chelated form thereof.
  • a drug, a hydrated form or a pharmaceutically acceptable salt thereof, is administered to an individual in need thereof.
  • the frequency and dose of the drug of the present invention can be determined by a number of related factors including the type of disease to be treated, the route of administration, the age, sex, weight and severity of the disease, and the drug as an active ingredient. Types of. According to some embodiments of the invention, the daily dose may be divided into 1 dose, 2 doses or multiple doses in a suitable form for administration once, twice or more times throughout the time period, as long as a therapeutically effective amount is achieved. .
  • administering means introducing a predetermined amount of a substance into a patient in a suitable manner.
  • the medicament of the present invention can be administered by any conventional route as long as it can reach the intended tissue.
  • Various modes of administration are contemplated, including peritoneal, venous, muscular, subcutaneous, cortical, oral, topical, nasal, pulmonary, and rectal, but the invention is not limited to these exemplary modes of administration.
  • the term "therapeutically effective amount” refers to an amount of a compound that is sufficient to significantly ameliorate certain symptoms associated with a disease or condition, that is, an amount that provides a therapeutic effect for a given condition and dosage regimen.
  • a drug or compound that reduces, prevents, delays, inhibits, or blocks any symptoms of a disease or condition should be therapeutically effective.
  • a therapeutically effective amount of a drug or compound does not require a cure for the disease or condition, but will provide a treatment for the disease or condition such that the onset of the disease or condition of the individual is delayed, prevented or prevented, or the symptoms of the disease or condition are alleviated, or the disease or The duration of the condition is altered, or for example the disease or condition becomes less severe, or the recovery is accelerated.
  • Figure 1 shows a chromatogram in accordance with one embodiment of the present invention
  • Figure 2 shows a micrograph of adherent cells (magnification 100 times) according to one embodiment of the present invention
  • Figure 3 shows a micrograph of a stem cell in suspension culture (magnification 20 times) 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
  • Figure 5 is a schematic diagram showing the flow pattern detection of stem cells according to another embodiment of the present invention.
  • Figure 6 shows a histogram in accordance with one embodiment of the present invention
  • Figure 7 shows a micrograph of a tumor stem cell (magnification of 100 times) according to one embodiment of the present invention
  • Figure 8 shows a histogram in accordance with another embodiment of the present invention.
  • Figure 9 shows a histogram in accordance with yet another embodiment of the present invention.
  • J1-001 sodium salt of a polyether compound having the following structure:
  • Streptomyces nanchangensis subtype Streptomyces is 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. Therefore, the concentrated sample was subjected to TLC dot plate and in the iodine cylinder.
  • 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 Table 1, indicating that the compound has a significant inhibitory effect on various tumors.
  • Test cell Compound IC 50 (mol) T98G (Brain Cancer brain cancer) 2.82E-07 MeWo (Skin Cancer Skin Cancer) 1.70E-06 A-498 (Kidney Cancer) 7.11E-07 SK-MEL-2 (Skin Cancer Skin Cancer) 1.69E-07 SK-HEP-1 (Liver Cancer) 3.66E-07 MG-63 (Bone Cancer Bone Cancer) 6.21E-08 ACHN (Kidney Cancer) 1.73E-06 SW 982 (Synovial Sarcoma Synovial Sarcoma) 7.86E-07 SK-OV-3 (Ovary Cancer Ovarian Cancer) 1.39E-06 PC-3 (Prostate Cancer Prostate Cancer) 6.68E-07 A-673 (Rhabdomyo Sarcoma rhabdomyosarcoma) 1.72E-07 DU 145 (Prostate Cancer prostate cancer) 9.38E-07 SK-UT-1 (Uterine Sarcoma uterine sarcoma) 3.59E-07 MES-SA
  • the three-negative cell line MDA-MB-231 was used as the experimental object, and the breast cancer stem cells were enriched by the suspension medium, and the inoculation density of the breast cancer stem cells was 1000/mL.
  • Suspension culture solution 200ml
  • the experimental results of adherent cells and suspension cells are shown in Figures 2 and 3.
  • J1-001 inhibits breast cancer stem cells better than paclitaxel.
  • the average tumor weight of the model group was 0.2299 g; the average tumor weight of the paclitaxel group was 0.1739 g, and the tumor inhibition rate was 24.34%, which was not significantly different from the model group; the average tumor weight of the J1-001H group (1 mg/kg nanchangmycin high dose group) The tumor inhibition rate was 0.0496%, which was significantly lower than that of the model group (P ⁇ 0.01).
  • the average tumor weight of the J1-001M (nanchangmycin medium dose group 0.5 mg/kg) group was 0.07741g, and the tumor inhibition rate was 66.32.
  • % was significantly less than the tumor weight of the model group (P ⁇ 0.01); the average tumor weight of the J1-001L (0.25mg/kg nanchangmycin group) group was 0.1381 g, and the tumor inhibition rate was 39.92%, which was significantly smaller than that of the model group ( P ⁇ 0.05).
  • J1-001 compound has a good tumor suppressing effect, can significantly inhibit the growth of MCF7-resistant paclitaxel cells in vivo, and provide support for the drug-forming properties of J1-001.
  • the J1-001 compound (1.7 g, 200 mmol) and 4-dimethylaminopyridine (10 mmol) were dissolved in dichloromethane (8 ml) at 0 ° C under anhydrous anaerobic conditions and then slowly stirred. Triethylamine (600 mmol) was added dropwise, and after stirring for 10 min, the corresponding acid chloride, bromo compound (R 5 in the following formula) was further added dropwise. After the completion of the dropwise addition, the reaction was allowed to stand at room temperature for several hours. The reaction system was quenched by the addition of a 0.1 mol/L HCl solution, and the reaction mixture was washed with brine, and extracted with ethyl acetate. The organic phase was combined and dried over anhydrous sodium sulfate. The concentrate is rapidly passed through a column to obtain a derivative of the J1-001 compound, and the specific structural formula is as follows:

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Abstract

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。所述药物用于治疗脑癌、皮肤癌、肾癌、骨癌、肉瘤、前列腺癌、子宫癌、黑色素癌、结肠癌、淋巴癌、白血病、胰腺癌、乳腺癌、肝癌、肺癌、胃癌、卵巢癌的至少之一。

Description

聚醚类化合物用途 技术领域
本发明涉及药物化学和药物治疗学领域。具体地，本发明涉及聚醚类化合物用途。
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。
发明内容
本发明旨在至少在一定程度上解决相关技术中存在的技术问题之一。为此，本发明的一个目的在于提出一种能够有效预防或治疗癌症的手段。
为此，本发明提出了一种聚醚类化合物、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。根据本发明的实施例，所述所述药物用于治疗脑癌、皮肤癌、肾癌、骨癌、肉瘤、前列腺癌、子宫癌、黑色素癌、结肠癌、淋巴癌、白血病、胰腺癌、乳腺癌、肝癌、肺癌、胃癌和卵巢癌的至少之一，所述聚醚类化合物的结构式如下：
Figure PCTCN2017071450-appb-000001
其中，
所述R1、所述R2、所述R3、所述R4和所述R5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 PCTCN2017071450-appb-000002
Figure PCTCN2017071450-appb-000003
或者
Figure PCTCN2017071450-appb-000004
其中，所述R6和所述R7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，所述-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，所述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，所述杂芳基任选地含有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、-I。
发明人经大量实验偶然发现聚醚类化合物具有良好的抗肿瘤活性，能够有效地治疗脑癌、皮肤癌、肾癌、骨癌、肉瘤、前列腺癌、子宫癌、黑色素癌、结肠癌、淋巴癌、白血病、胰腺癌、乳腺癌、肝癌、肺癌、胃癌、卵巢癌的至少之一。通过将聚醚类化合物、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。具体地，发明人通过下面的实验过程证明了发明人的观点：
发明人将多种癌细胞与聚醚类化合物钠盐在体外分别混合培养。利用MTT染色法，通过测其OD值，计算其对肿瘤细胞增殖的抑制率及IC50(半数抑制率)。发明人发现，聚醚类化合物钠盐对多种肿瘤细胞均有不同程度的抑制作用。
根据本发明的实施例，上述聚醚类化合物、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还可以具有下列附加技术特征：
根据本发明的实施例，所述R1、所述R2、所述R3、所述R4和所述R5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 PCTCN2017071450-appb-000005
Figure PCTCN2017071450-appb-000006
或者
Figure PCTCN2017071450-appb-000007
其中，所述R6和所述R7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，所述-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，所述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，所述杂芳基任选地含有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、-I。
根据本发明的实施例，所述R1、所述R2、所述R3、所述R4和所述R5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 PCTCN2017071450-appb-000008
Figure PCTCN2017071450-appb-000009
或者
Figure PCTCN2017071450-appb-000010
其中，所述R6和所述R7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，所述-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，所述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，所述杂芳基任选地含有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、-I。
根据本发明的实施例，所述R1、所述R2、所述R3、所述R4和所述R5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 PCTCN2017071450-appb-000011
或者
Figure PCTCN2017071450-appb-000012
其中，所述R6和所述R7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，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，所述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、-I。
根据本发明的实施例，所述聚醚类化合物的结构式如下：
Figure PCTCN2017071450-appb-000013
其中，所述R5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-氯乙酰基、2-溴乙酰基、2-叠氮基乙酰基、苯甲酰基、苯乙酰基、
Figure PCTCN2017071450-appb-000014
Figure PCTCN2017071450-appb-000015
或者
Figure PCTCN2017071450-appb-000016
其中，所述R6和所述R7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，所述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、-I。
根据本发明的实施例，所述聚醚类化合物的结构式如下：
Figure PCTCN2017071450-appb-000017
其中，所述R3和所述R4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-氯乙酰基、2-溴乙酰基、2-叠氮基乙酰基、苯甲酰基、苯乙酰基、
Figure PCTCN2017071450-appb-000018
Figure PCTCN2017071450-appb-000019
或者
Figure PCTCN2017071450-appb-000020
其中，所述R6和所述R7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，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，所述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、-I。
根据本发明的实施例，所述聚醚类化合物的结构式如下：
Figure PCTCN2017071450-appb-000021
其中，所述R1、R3和R4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-氯乙酰基、2-溴乙酰基、2-叠氮基乙酰基、苯甲酰基、苯乙酰基、
Figure PCTCN2017071450-appb-000022
Figure PCTCN2017071450-appb-000023
或者
Figure PCTCN2017071450-appb-000024
其中，所述R6和所述R7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，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，所述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、-I。
根据本发明的实施例，所述聚醚类化合物的结构式如下，简称J1-001化合物：
Figure PCTCN2017071450-appb-000025
根据本发明的实施例，所述J1-001化合物是一种酸性酯溶性聚醚类抗生素，对革兰氏阳性、阴性细菌均有抑制作用；具有很强的抗球虫活性，现多用于防治蛋鸡和肉鸡的球虫病；同时，经毒性和三致试验结果表明该抗生素安全、无副作用。根据本发明的实施例，获得J1-001化合物的方式并不受特别限制，根据本发明的具体实施例，J1-001化合物可以由含有编码合成该化合物的基因簇的微生物发酵生产，也可以由化学合成或化学半合成的方式生产得到。因此，利用J1-001化合物制备治疗恶性肿瘤细胞及耐药性恶性肿瘤细胞具有很好工业实用性。另一方面，J1-001化合物作为抗生素长期应用于鸡球虫防治，同时，该抗生素毒性和三致试验结果表明其安全、无副作用。因此，J1-001化合物在制备药物用途上具有可操作性、适用性。由上所述，J1-001化合物用于制备治疗恶性肿瘤药物具有很大市场发展前景。
根据本发明的实施例，所述药物抑制肿瘤干细胞增殖，起到较好地治疗脑癌、皮肤癌、肾癌、骨癌、肉瘤、前列腺癌、子宫癌、黑色素癌、结肠癌、淋巴癌、白血病、胰腺癌、乳腺癌、肝癌、肺癌、胃癌和卵巢癌的至少之一的目的。
根据本发明的实施例，所述药物用于抑制肿瘤细胞和耐药性肿瘤细胞的增殖，以便起 到较好地治疗脑癌、皮肤癌、肾癌、骨癌、肉瘤、前列腺癌、子宫癌、黑色素癌、结肠癌、淋巴癌、白血病、胰腺癌、乳腺癌、肝癌、肺癌、胃癌和卵巢癌的至少之一的目的。在现代医疗技术领域中，已有的抗癌药物在一定时期内对癌症的治疗具有较好疗效，但由于治疗癌症周期往往较长，所以长期使用某一种抗癌药物容易产生耐药性。由此，需要研发出更多治疗癌症的药物，尤其是对已经产生耐药性的肿瘤细胞具有明显抑制作用的药物。发明人惊奇地发现，聚醚类化合物能有效抑制多种人类恶性肿瘤细胞，特别是耐药性肿瘤细胞，且其效果优于现有多种化疗药物。由此，进一步提高了聚醚类化合物作为治疗恶性肿瘤药物的优越性。
本发明所使用的术语“治疗”用于指获得期望的药理学和/或生理学效果。所述效果就完全或部分预防疾病或其症状而言可以是预防性的，和/或就部分或完全治愈疾病和/或疾病导致的不良作用而言可以是治疗性的。本文使用的“治疗”涵盖哺乳动物、特别是人的疾病，包括：(a)在容易患病但是尚未确诊得病的个体中预防疾病或病症发生；(b)抑制疾病，例如阻滞疾病发展；或(c)缓解疾病，例如减轻与疾病相关的症状。本文使用的“治疗”涵盖将药物或化合物给予个体以治疗、治愈、缓解、改善、减轻或抑制个体的疾病的任何用药，包括但不限于将含本文所述聚醚类化合物、其螯合形式、水合形式或其药学上可接受的盐的药物给予有需要的个体。
本发明的药物的给药频率和剂量可以通过多个相关因素被确定，该因素包括要被治疗的疾病类型，给药途径，病人年龄，性别，体重和疾病的严重程度以及作为活性成分的药物类型。根据本发明的一些实施例，日剂量可分为适宜形式的1剂、2剂或多剂，以在整个时间段内以1次、2次或多次给药，只要达到治疗有效量即可。
本发明所使用的术语“给药”指将预定量的物质通过某种适合的方式引入病人。本发明的药物可以通过任何常见的途径被给药，只要它可以到达预期的组织。给药的各种方式是可以预期的，包括腹膜，静脉，肌肉，皮下，皮层，口服，局部，鼻腔，肺部和直肠，但是本发明不限于这些已举例的给药方式。
本发明所使用的术语“治疗有效量”是指化合物足以显著改善某些与疾病或病症相关的症状的量，也即为给定病症和给药方案提供治疗效果的量。例如，在淋巴癌治疗中，减少、预防、延缓、抑制或阻滞疾病或病症的任何症状的药物或化合物应当是治疗有效的。治疗有效量的药物或化合物不需要治愈疾病或病症，但将为疾病或病症提供治疗，使得个体的疾病或病症的发作被延缓、阻止或预防，或者疾病或病症的症状得以缓解，或者疾病或病症的期限被改变，或者例如疾病或病症变得不严重，或者加速康复。
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色谱图；
图2显示了根据本发明一个实施例的贴壁细胞显微镜照片(放大倍数为100倍)；
图3显示了根据本发明一个实施例的悬浮培养的干细胞显微镜照片(放大倍数为20倍)；
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；
图5显示了根据本发明另一个实施例的干细胞流式检测的图谱示意图；
图6显示了根据本发明一个实施例的柱状图；
图7显示了根据本发明一个实施例的肿瘤干细胞显微镜照片(放大倍数为100倍)；
图8显示了根据本发明另一个实施例的柱状图；以及
图9显示了根据本发明又一个实施例的柱状图。
具体实施方式
下面将结合实施例对本发明的方案进行解释。本领域技术人员将会理解，下面的实施例仅用于说明本发明，而不应视为限定本发明的范围。实施例中未注明具体技术或条件的，按照本领域内的文献所描述的技术或条件或者按照产品说明书进行。所用试剂或仪器未注明生产厂商者，均为可以通过市购获得的常规产品。
下述实施例均以如下结构的聚醚类化合物(下列简称J1-001)的钠盐作为研究对象：
Figure PCTCN2017071450-appb-000026
实施例1
生物法获得J1-001钠盐
将Streptomyces nanchangensis亚型链霉菌接种于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，对浓缩后的样品进行了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所示。
可以看出，质谱确认了经过纯化J1-001主要以钠盐的形式存在。
实施例2
检测J1-001钠盐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℃及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(含10％FBS)。
(3)细胞抑制实验：化合物样品均用DMSO进行8个药物浓度按照5倍浓度梯度稀释，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 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，结果如表1所示，表明化合物对多种肿瘤均具有显著的抑制作用。
表1对多种肿瘤细胞的IC50值
受试细胞 化合物IC50(mol)
T98G(Brain Cancer脑癌) 2.82E-07
MeWo(Skin Cancer皮肤癌) 1.70E-06
A-498(Kidney Cancer肾癌) 7.11E-07
SK-MEL-2(Skin Cancer皮肤癌) 1.69E-07
SK-HEP-1(Liver Cancer肝癌) 3.66E-07
MG-63(Bone Cancer骨癌) 6.21E-08
ACHN(Kidney Cancer肾癌) 1.73E-06
SW 982(Synovial Sarcoma滑液肉瘤) 7.86E-07
SK-OV-3(Ovary Cancer卵巢癌) 1.39E-06
PC-3(Prostate Cancer前列腺癌) 6.68E-07
A-673(RhabdomyoSarcoma横纹肌肉瘤) 1.72E-07
DU 145(Prostate Cancer前列腺癌) 9.38E-07
SK-UT-1(Uterine Sarcoma子宫肉瘤) 3.59E-07
MES-SA/Dx-5(Uterine Sarcoma子宫肉瘤) 1.38E-07
A-204(RhabdomyoSarcoma横纹肌肉瘤) 6.58E-08
G-361(Melanoman.黑素瘤) 2.74E-07
HCT 116(Colon Cancer结肠癌) 2.90E-07
SJSA-1(Bone Cancer骨癌) 2.45E-07
COLO 205(Colon Cancer结肠癌) 2.90E-07
MKN-45(Gastric Cancer胃癌) 4.85E-07
A549(Lung Cancer肺癌) 3.21E-07
OVCAR-4(Ovary Cancer卵巢癌) 2.20E-06
Calu-3(Lung Cancer肺癌) 3.48E-07
U-87MG(Brain Cancer脑癌) 2.25E-07
Hep 3B2.1-7[Hep3B](Liver Cancer肝癌) 6.49E-08
A375(Melanoman.黑素瘤) 5.36E-07
MD(Spleen Macrophage脾巨噬细胞) 8.45E-09
AHH-1(Lymphoid淋巴癌) 1.44E-06
MV-4-11(Leukemia白血病俗称血癌) 1.56E-08
Jurkat(Lymphoma淋巴瘤) 2.88E-07
DOHH2(Lymphoma淋巴瘤) 2.61E-09
K562(Leukemia白血病俗称血癌) 2.81E-08
HPAC(Pancreas Cancer胰腺癌) 6.81E-07
NUGC-4(Gastric Cancer胃癌) 1.49E-07
MIA PaCa-2(Pancreas Cancer胰腺癌) 3.10E-08
实施例3
J1-001钠盐抑制乳腺癌干细胞的研究
以三阴细胞株MDA-MB-231为实验对象，通过悬浮培养基富集乳腺癌干细胞，乳腺癌干细胞接种密度：1000个/mL。悬浮培养液(200ml)成分：B27营养添加因子4mL；胰岛素80μL；DMEM-F12培养液194mL；人表皮生长因子40μL；双抗：2mL，培养12天左右(每天摇晃2次以上)。采用检测试剂盒AldefluorTM kit检测。贴壁细胞与悬浮细胞的实验结果如图2和3所示。
可以看出，经过12天左右的悬浮细胞培养，用流式细胞仪检测悬浮培养的干细胞比例提高至25.12％(参见图4)，相比于贴壁细胞中的干细胞比例3.97％(参见图4)，可以达到后续实验要求。
为了增加药物之间的可比性，测定J1-001钠盐抑制能力的同时，选择以干细胞抑制剂盐霉素和紫杉醇作为阴性对照，在悬浮培养12天后获得悬浮细胞铺6孔板，隔天统一给药剂量5μM，实验结果如图5～7所示。
可以看到，J1-001对乳腺癌干细胞的抑制能力要好于紫杉醇。
实施例4
J1-001钠盐对小鼠MCF7耐紫杉醇细胞株构建的体内实验
本实验以60只体重为20-22g的雄性BALB/c裸鼠作为研究对象，经组织插块法接种MCF-7/TAX细胞肿瘤块，2周后筛选瘤质均一的裸鼠随机分为6组，每组8只，另设空白组；21d疗程，每3d给药一次，测量一次瘤体积并记录体重。第20天后处理动物，测量并计算各种裸鼠肿瘤的相对肿瘤体积、抑瘤率和相对肿瘤增值率，结果如图8和9。
模型组平均瘤重为0.2299g；紫杉醇组的平均瘤重为0.1739g，肿瘤抑制率为24.34％，与模型组无显著性差异；J1-001H(nanchangmycin高剂量组1mg/kg)组平均瘤重为0.04962g，肿瘤抑制率为78.41％，极显著小于模型组肿瘤重量(P＜0.01)；J1-001M(nanchangmycin中等剂量组0.5mg/kg)组平均瘤重为0.07741g，肿瘤抑制率为66.32％，极显著小于模型组肿瘤重量(P＜0.01)；J1-001L(nanchangmycin低剂量组0.25mg/kg)组平均瘤重为0.1381g，肿瘤抑制率为39.92％，显著小于模型组肿瘤重量(P＜0.05)。
可以看出J1-001化合物高剂量拥有较好的肿瘤抑制效果，能够明显抑制对MCF7耐紫杉醇细胞在体内的生长，为J1-001的成药性提供支持。
实施例5
化学合成法制备J1-001化合物的衍生物
在0℃，无水无氧条件下，将J1-001化合物(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)，然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(如下式中的R5)。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J1-001化合物的衍生物，具体结构式如下：
Figure PCTCN2017071450-appb-000027
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 (10)

  1. 一种聚醚类化合物、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，其特征在于，所述药物用于治疗脑癌、皮肤癌、肾癌、骨癌、肉瘤、前列腺癌、子宫癌、黑色素癌、结肠癌、淋巴癌、白血病、胰腺癌、乳腺癌、肝癌、肺癌、胃癌和卵巢癌的至少之一，所述聚醚类化合物的结构式如下：
    Figure PCTCN2017071450-appb-100001
    其中，
    所述R1、所述R2、所述R3、所述R4和所述R5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 PCTCN2017071450-appb-100002
    Figure PCTCN2017071450-appb-100003
    其中，所述R6和所述R7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，所述-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，所述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，所述杂芳基任选地含有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、-I。
  2. 根据权利要求1所述的用途，其特征在于，所述R1、所述R2、所述R3、所述R4和所述R5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 PCTCN2017071450-appb-100004
    其中，所述R6和所述R7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，所述-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，所述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，所述杂芳基任选地含有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、-I。
  3. 根据权利要求1所述的用途，其特征在于，所述R1、所述R2、所述R3、所述R4和所述R5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 PCTCN2017071450-appb-100005
    其中，所述R6和所述R7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，所述-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，所述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，所述杂芳基任选地含有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、-I。
  4. 根据权利要求1所述的用途，其特征在于，所述R1、所述R2、所述R3、所述R4和所述R5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 PCTCN2017071450-appb-100006
    Figure PCTCN2017071450-appb-100007
    其中，所述R6和所述R7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，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，所述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、-I。
  5. 根据权利要求1所述的用途，其特征在于，所述聚醚类化合物的结构式如下：
    Figure PCTCN2017071450-appb-100008
    其中，所述R5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-氯乙酰基、2-溴乙酰基、2-叠氮基乙酰基、苯甲酰基、苯乙酰基、
    Figure PCTCN2017071450-appb-100009
    Figure PCTCN2017071450-appb-100010
    其中，所述R6和所述R7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，所述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、-I。
  6. 根据权利要求1所述的用途，其特征在于，所述聚醚类化合物的结构式如下：
    Figure PCTCN2017071450-appb-100011
    其中，所述R3和所述R4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-氯乙酰基、2-溴乙酰基、2-叠氮基乙酰基、苯甲酰基、苯乙酰基、
    Figure PCTCN2017071450-appb-100012
    Figure PCTCN2017071450-appb-100013
    其中，所述R6和所述R7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，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，所述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、-I。
  7. 根据权利要求1所述的用途，其特征在于，所述聚醚类化合物的结构式如下：
    Figure PCTCN2017071450-appb-100014
    其中，所述R1、所述R3和所述R4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-氯乙酰基、2-溴乙酰基、2-叠氮基乙酰基、苯甲酰基、苯乙酰基、
    Figure PCTCN2017071450-appb-100015
    其中，所述R6和所述R7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，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，所述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、-I。
  8. 根据权利要求1所述的用途，其特征在于，所述聚醚类化合物的结构式如下：
    Figure PCTCN2017071450-appb-100016
  9. 根据权利要求1所述的用途，其特征在于，所述药物抑制肿瘤干细胞增殖。
  10. 根据权利要求1所述的用途，其特征在于，所述药物用于抑制耐药性肿瘤细胞的增殖。
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CN117024447A (zh) * 2023-07-12 2023-11-10 武汉合生科技有限公司 聚醚化合物及其制备方法

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JP2011213612A (ja) * 2010-03-31 2011-10-27 Kyowa Hakko Kirin Co Ltd 癌幹細胞及び／または癌前駆細胞の減少剤
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