WO2022127751A1 - 医药组合物治疗肺癌的用途 - Google Patents

医药组合物治疗肺癌的用途 Download PDF

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WO2022127751A1
WO2022127751A1 PCT/CN2021/137647 CN2021137647W WO2022127751A1 WO 2022127751 A1 WO2022127751 A1 WO 2022127751A1 CN 2021137647 W CN2021137647 W CN 2021137647W WO 2022127751 A1 WO2022127751 A1 WO 2022127751A1
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compound
pharmaceutical composition
och
lung cancer
cells
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PCT/CN2021/137647
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French (fr)
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蔡长海
洪明奇
郭盛助
李培志
谢闵凔
庄声宏
林慧怡
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洪明奇
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Priority to US18/267,691 priority Critical patent/US20240000742A1/en
Priority to AU2021402788A priority patent/AU2021402788A1/en
Priority to CN202180085228.3A priority patent/CN117120438A/zh
Priority to JP2023538038A priority patent/JP2023554532A/ja
Priority to CA3205490A priority patent/CA3205490A1/en
Priority to EP21905680.1A priority patent/EP4265256A1/en
Priority to KR1020237024434A priority patent/KR20230131861A/ko
Publication of WO2022127751A1 publication Critical patent/WO2022127751A1/zh

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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
    • A61K31/21—Esters, e.g. nitroglycerine, selenocyanates
    • A61K31/215—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids
    • A61K31/216—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids of acids having aromatic rings, e.g. benactizyne, clofibrate
    • 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
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/506—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim not condensed and containing further heterocyclic rings
    • 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
    • A61K31/21—Esters, e.g. nitroglycerine, selenocyanates
    • A61K31/215—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids
    • A61K31/235—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids having an aromatic ring attached to a carboxyl group
    • 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
    • A61K31/12—Ketones
    • A61K31/121—Ketones acyclic
    • 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
    • A61K31/21—Esters, e.g. nitroglycerine, selenocyanates
    • A61K31/215—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids
    • A61K31/22—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids of acyclic acids, e.g. pravastatin
    • 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
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/517—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with carbocyclic ring systems, e.g. quinazoline, perimidine
    • 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
    • A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
    • A61K31/5375—1,4-Oxazines, e.g. morpholine
    • A61K31/5377—1,4-Oxazines, e.g. morpholine not condensed and containing further heterocyclic rings, e.g. timolol
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents

Definitions

  • the present invention relates to the use of a pharmaceutical composition, especially the use of a pharmaceutical composition comprising a diarylheptane compound or a pharmaceutically acceptable salt thereof for treating lung cancer.
  • Cancer also known as malignant tumor, is the abnormal growth of cells, and these proliferating cells may invade other parts of the body.
  • the number of people suffering from cancer in the world is increasing. About 20% of the world's cancer population is lung cancer patients, and the 5-year survival rate of lung cancer patients after treatment is still only about 15%, which has been the global fatality rate for many years. highest cancer.
  • lung cancer can be divided into small cell lung cancer and non-small cell lung cancer (non-small cell lung cancer; NSCLC), and about 85-90% of lung cancer belongs to non-small cell lung cancer.
  • Cancer is the most common and most common type of lung cancer among women and non-smokers. Treatment of lung cancer often depends on the patient's age, past medical history, current health status, the type of cancer cells, and the stage of the disease.
  • small cell lung cancer has the characteristics of rapid division and proliferation, so metastasis and spread may occur in a short time, so the treatment is mainly systemic chemotherapy or radiation therapy.
  • non-small cell lung cancer is slower, so the occurrence of metastasis is also slower, and its treatment principle is determined according to the clinical stage of the disease.
  • the radical treatment of early stage (I and II) NSCLC is still based on complete tumor resection by surgery.
  • the locally extended stage (stage III) includes patients with malignant pericardial or pleural effusions and patients with distant metastases (stage IV) or medical conditions that preclude surgical resection.
  • the main treatment principle is chemotherapy or chemotherapy combined with radiation therapy.
  • epidermal growth factor receptor-tyrosine kinase inhibitors epidermal growth factor-tyrosine kinase inhibitors, EGFR-TKIs
  • EGFR-TKIs epidermal growth factor receptor-tyrosine kinase inhibitors
  • an object of the present invention is to provide the use of a pharmaceutical composition, which can be used to prepare a medicine for treating lung cancer.
  • the pharmaceutical composition comprises a diarylheptane compound or a pharmaceutically acceptable salt thereof, which can inhibit epidermal growth factor receptor-tyrosine kinase inhibitor-resistant non-small cell lung cancer cells It is used alone or in combination with epidermal growth factor receptor-tyrosine kinase inhibitors for the treatment of EGFR gene mutations and epidermal growth factor receptor-tyrosine kinase inhibitors Drug-resistant lung cancer.
  • One aspect of the present invention is to provide the use of a pharmaceutical composition, which is used for preparing a medicament for treating lung cancer, wherein the pharmaceutical composition comprises a diarylheptane compound or a pharmaceutically acceptable salt thereof, the The diarylheptane compounds have a structure shown in formula (I):
  • R d is C1-C3 alkyl or C1- C3 alkanol.
  • diarylheptane compound can be selected from compound 1, compound 21a, compound 21b, compound 22a, compound 22b, compound 23a, compound having the structure represented by formula (II) The group consisting of 23b, compound 24a, compound 24b, compound 25, compound 26, compound 27, compound 31 and compound 33:
  • R 1 , R 1 ' of compound 1 are OCH 3 , R 2 , R 2 ' are H, R 3 , R 3 ' are H, respectively;
  • R 1 , R 1 ' of compound 21a are OCH 3 , R , respectively 2 , R 2 ' are OR 4 respectively, R 3 , R 3 ' are H respectively;
  • R 1 , R 1 ' of compound 21b are respectively OCH 3 , R 2 OH, R 2 ' are OR 4 , R 3 , R 3 ' is H respectively;
  • R 1 , R 1 ' of compound 22a are OCH 3 , R 2 , R 2 ' are respectively OR 5 , R 3 , R 3 ' are H respectively;
  • R 1 , R 1 ' of compound 22b are respectively OCH 3 respectively, R 2 is OH, R 2 ' is OR 5 , R 3 , R 3 ' are H respectively;
  • R 1 , R 1 ' of compound 23a are H respectively, R 2 , R 2
  • diarylheptane compound can be selected from the group consisting of compound 35a, compound 35c, compound 35d, compound 35e, compound 36 and compound 37 having the structure represented by formula (III) 's group:
  • R 6 , R 6 ' of compound 35a are OCH 3 , R 7 , R 7 ' are OR 4 , R 8 are CH 3 , respectively;
  • R 6 , R 6 ' of compound 35c are OCH 3 , R 7 , R respectively 7 ' is OR 4 , R 8 is benzyl, respectively;
  • R 6 , R 6 ' of compound 35d are OCH 3 , R 7 , R 7 ' are OR 4 , and R 8 are propargyl;
  • R 6 of compound 35e , R 6 ' is OCH 3 , R 7 , R 7 ' are OR 4 , R 8 is allyl respectively;
  • R 6 , R 6 ' of compound 36 are H, R 7 , R 7 ' are OR 4 , respectively, R 8 is CH 3 ;
  • R 6 , R 6 ' of compound 37 are OR 4 , R 7 , R 7 ' are respectively OCH 3 , and R 8 is CH 3 .
  • R 4 is a structure
  • diarylheptane compounds can be selected from:
  • the pharmaceutical composition may further comprise an epidermal cell growth factor receptor-tyrosine kinase inhibitor.
  • the epidermal growth factor receptor-tyrosine kinase inhibitor may be osimertinib, gefitinib, erlotinib or afatinib.
  • the lung cancer may be non-small cell lung cancer.
  • the lung cancer may be resistant to epidermal growth factor receptor-tyrosine kinase inhibitor.
  • Fig. 1A is a graph showing the analysis results of the inhibition of the growth of H1650 cells by the diarylheptane compounds of the present invention
  • Fig. 1B, Fig. 1C and Fig. 1D are diagrams showing the analysis results of the inhibition of the growth of non-small cell lung cancer cells resistant to epidermal growth factor receptor-tyrosine kinase inhibitors by the diarylheptane compounds of the present invention
  • Fig. 2A is a graph showing the analysis results of single treatment of compound 35d inhibiting tumor growth in GR6 tumor mice;
  • Figure 2B is a graph showing the analysis results of single treatment of compound 35d inhibiting tumor growth in GR8 tumor mice;
  • FIG. 2C is a graph showing the analysis results that single treatment of compound 35d inhibits tumor growth in HCC827 tumor mice;
  • Figure 2D is a statistical graph of the body weight change of tumor mice treated with compound 35d alone;
  • Figure 3A is a graph showing the results of analysis of combined treatment of compound 35d and osimertinib to inhibit tumor re-progression in mice with GR6 tumors;
  • Figure 3B is a statistical graph of body weight changes in GR6 tumor mice treated with compound 35d and osimertinib in combination.
  • the present invention proposes a novel use of a pharmaceutical composition comprising a diarylheptane compound or a pharmaceutically acceptable salt thereof, which is used for preparing a medicine for treating lung cancer.
  • the base heptane compounds have a structure shown in formula (I):
  • the pharmaceutical composition of the present invention may further comprise epidermal growth factor receptor-tyrosine kinase inhibitors (epidermal growth factor-tyrosine kinase inhibitors, EGFR-TKIs) and diarylheptane compounds or pharmaceutically acceptable compounds thereof Salts are used in combination, and EGFR-TKIs can be osimertinib, gefitinib, erlotinib, or afatinib.
  • the lung cancer that the pharmaceutical composition of the present invention is used to treat can be non-small cell lung cancer, and in addition, the lung cancer can be resistant to EGFR-TKIs.
  • references herein and in this specification to "a” and “an” mean that the grammatical objects in the text are one or more (ie, at least one) unless otherwise stated.
  • a class is an abbreviation for all members included in the class, for example, C1-C3 alkyl is an abbreviation for all C1-C3 alkyl, for example, C1-C3 alkyl includes methyl, ethyl , propyl and its isomers.
  • diarylheptane compounds disclosed in the present invention and their pharmaceutically acceptable salts can be verified by in vitro (in vitro) tests, and they can inhibit the growth of non-small cell lung cancer cells that are resistant to EGFR-TKIs . And further can be verified by in vivo test, the compound disclosed in this specification and/or at least one of its pharmaceutically acceptable salts can be administered to animals suffering from lung cancer that is resistant to EGFR-TKIs (such as mouse models), and therapeutic effects can be obtained. A positive result in one or more of the tests is sufficient to demonstrate the actual utility of the tested compound and/or salt. And an appropriate dosage range and route of administration for animals (eg, humans) can be determined based on the results of the experiments.
  • Useful pharmaceutical dosage forms for administering the diarylheptanes of the present invention and their pharmaceutically acceptable salts include, but are not limited to, hard and soft gelatin capsules, tablets, parenteral injections and oral suspensions.
  • the dose administered will depend upon factors including the age of the subject, the health and weight of the subject, the extent of the disease, the type of concomitant treatment (if any), the frequency of treatment and the nature of the effect desired.
  • the daily dose of active ingredient may be non-quantitative, eg 0.1 to 2000 mg per day. For example, 10-500 mg one or more times per day is effective to achieve the desired results.
  • the same dosage forms can generally be used when the diarylheptanes and pharmaceutically acceptable salts thereof of the present invention are administered stepwise or in combination with at least one other therapeutic agent.
  • the dosage form and route of administration should be selected according to the compatibility of the combined drugs.
  • co-administration in the context of this specification should be understood to encompass the concomitant or sequential administration of at least two agents, or as a fixed-dose combination of at least two active ingredients.
  • diarylheptane compounds of this specification and their pharmaceutically acceptable salts may be administered as the sole active ingredient, or in combination with at least one second active ingredient selected from, for example, known to be useful for Other active ingredients in the treatment of patients with non-small cell lung cancer, especially EGFR-TKIs.
  • test examples are hereby used to further demonstrate the present invention, for the benefit of those with ordinary knowledge in the technical field to which the present invention pertains, and can fully utilize and practice the present invention without excessive interpretation, and these test examples should not be regarded as It is intended to limit the scope of the invention, but to illustrate how the materials and methods of the invention may be practiced.
  • diarylheptane compounds of the present invention are based on curcumin (curcumin, CCM) as a guide compound, and the diarylheptane compounds of the design curcuminoid have a structure as shown in formula (I):
  • compound 21a possesses a heptadiene-3,5-dione moiety, which is easily interconvertible between the keto form and the enol form.
  • two methyl functionalities are incorporated into the 4-position of compound 21a and provide ((1E,6E)-4,4-dimethyl-3,5-dioxyheptane-1,6- Diene-1,7-diyl)bis(2-methoxy-4,1-phenylene)bis(3-hydroxy-2-hydroxymethyl)-2-methylpropionate (35a), It is a keto form found to be stable and not stable to tautomerization.
  • compound 35a was used as a new targeting compound and was derived into a series of its 4,4-dialkyl derivatives (compound 35a, compound 35d, compound 36 and compound 37) having the diazepine form.
  • the EGFR gene mutant non-small cell lung cancer cells were first treated with the diarylheptane compounds of the present invention, and then the cell survival assay was stained with crystal violet to measure the diarylheptane compounds of the present invention.
  • the IC50 value of EGFR gene mutant non-small cell lung cancer cells is used to determine the growth inhibitory effect of the diarylheptane compounds of the present invention on EGFR gene mutant non-small cell lung cancer cells.
  • EGFR gene mutations in lung cancer are more common in exons 18-21, that is, the coding region of intracellular tyrosine kinase.
  • the most common mutation forms include E746-A750del in exon 19 and L858R point mutation in exon 21. Mutations account for about 85%-90% of EGFR gene mutations, and tumor cells with these two mutations are sensitive to EGFR-TKIs, called activating mutations. Secondary mutations can occur in some tumor cells, and the most common secondary mutation is the T790M mutation in exon 20, which is a drug-resistant mutation.
  • FIG. 1A is the analysis result of the inhibition of the growth of H1650 cells by the diarylheptane compounds of the present invention.
  • Figure 1A shows the IC50 values of 22 diarylheptanes (including BDMC) and curcumin in H1650 cells after 3 days of treatment, wherein compound 1, compound 24b, compound 23b, compound 33, compound 25, compound 35b, Compound 22a, compound 21a, compound 22b, compound 26, compound 36, compound 35a, compound 35c, compound 27, compound 31, compound 37, compound 35e and compound 35d and other 18 diarylheptane compounds, for H1650 cell growth Has significantly better inhibitory activity than the parent compound-curcumin, wherein ** means p ⁇ 0.05, *** means p ⁇ 0.01, and **** means p ⁇ 0.001.
  • the EGFR-TKIs-resistant non-small cell lung cancer cells used in the test include H1975 cells, GR2 cells, GR5 cells, GR6 cells, GR8 cells, GR9 cells and GR10 cells, of which H1975 cells are L858R of exon 21. Point mutation, but accompanied by T790M secondary mutation in exon 20; GR2 cells, GR5 cells, GR6 cells, GR8 cells, GR9 cells and GR10 cells were treated with gefitinib with HCC827 cells as parent cells The resulting gefitinib-resistant cell line, while both HCC827 cells and H1650 cells were non-small cell lung cancer cells with E746-A750del mutation in EGFR exon 19.
  • FIG. 1B is an analysis result of the inhibition of the growth of H1975 cells by the diarylheptane compounds of the present invention
  • FIG. 1C is the inhibition of GR2 cells by the diarylheptane compounds of the present invention
  • Figure 1D shows GR2 cells, GR5 cells, GR6 cells, GR8 cells, GR9 cells and GR10 cells after treatment with compound 35d and gefitinib, respectively. Result plot of percent change in IC50 value.
  • Figure 1B shows the IC50 values measured after H1975 cells were treated with compound 21a, compound 35a, compound 35d, compound 36, compound 37 and curcumin for 3 days, respectively. The results showed that the compound 21a, compound 35a, compound 35d, compound 36 and compound 37 of the present invention had significantly better inhibitory activity than curcumin on the growth of H1975 cells.
  • Figure 1C shows the measured IC50 values of GR2 cells, GR5 cells, GR6 cells, GR8 cells, GR9 cells and GR10 cells treated with compound 21a, compound 35a, compound 35d, compound 36, compound 37 and curcumin for 3 days, respectively.
  • the results show that Compound 21a, Compound 35a, Compound 35d, Compound 36 and Compound 37 of the present invention all have significantly better inhibitory activity than curcumin on the growth of GR2 cells, GR5 cells, GR6 cells, GR8 cells, GR9 cells and GR10 cells.
  • Figure 1D shows the IC50 values measured after HCC827 cells, GR2 cells, GR5 cells, GR6 cells, GR8 cells, GR9 cells and GR10 cells were treated with compound 35d and gefitinib for 3 days, respectively. Plot of analysis results obtained by comparing IC50 values measured for cells, GR8 cells, GR9 cells and GR10 cells with IC50 values measured for HCC827 cells. The results in Figure 1D show that all gefitinib-resistant cell lines are indirectly sensitive to compound 35d, and all gefitinib-resistant cell lines are sensitive to gefitinib ( Gef) >200-fold resistance.
  • the xenografted GR6 tumor mouse model, GR8 tumor mouse model and HCC827 tumor mouse model were first established in the experiment, and the GR6 tumor mouse models were respectively sized. Mice, GR8 tumor mice and HCC827 tumor mice were treated with 100 mg/kg of compound 35d daily for 35 days, and tumor size and body weight were recorded in GR6 tumor mice, GR8 tumor mice and HCC827 tumor mice.
  • FIG. 2A shows the results of the analysis of the inhibition of tumor growth in mice with GR6 tumor by single treatment with compound 35d.
  • Fig. 2B shows the results of the analysis of the inhibition of tumor growth in mice with GR8 tumor by treatment with compound 35d alone.
  • EGFR-TKIs are currently the standard treatment for non-small cell lung cancer patients with EGFR mutations.
  • the GR6 tumor mice were divided into 4 groups, 1 group received 100 mg/kg of compound 35d every day (denoted as 35d), and 1 group received 1 mg/kg of osimertinib every day (denoted as Osi), One group received the combined treatment of compound 35d at 100 mg/kg and osimertinib at 1 mg/kg per day (denoted as 35d+Osi), and the other was a drug-free control group.
  • FIG. 3A is the analysis result of the combined treatment of compound 35d and osimertinib to inhibit the tumor re-progression of GR6 tumor mice
  • FIG. 3B is the combined treatment of compound 35d and osimertinib.
  • the present invention proposes a new use of a pharmaceutical composition, which can be used to prepare a drug for treating lung cancer.
  • the pharmaceutical composition comprises a diarylheptane compound or a pharmaceutically acceptable salt thereof, which can inhibit EGFR gene mutant non-small cell lung cancer cells and non-small cell lung cancer cells that are resistant to EGFR-TKIs
  • the growth of cells is to prepare a drug for the treatment of lung cancer, and it can have a synergistic effect when used in combination with EGFR-TKIs, which can increase the effectiveness of the treatment of lung cancer, especially for the treatment of lung cancer with EGFR gene mutation and EGFR-TKIs , has the potential to be used in the biomedical health care market.

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Abstract

提供一种医药组合物的用途，所述医药组合物包含二芳基庚烷类化合物或其医药上可接受的盐类，所述二芳基庚烷类化合物具有式(I)所示的一结构。式(I)中各符号如说明书中所定义者，其可抑制肺癌细胞的生长。藉此，所述医药组合物可用于制备治疗肺癌的药物。

Description

医药组合物治疗肺癌的用途 技术领域
本发明是有关于一种医药组合物的用途，特别是一种包含二芳基庚烷类化合物或其医药上可接受的盐类的医药组合物治疗肺癌的用途。
背景技术
癌症又名为恶性肿瘤，为细胞不正常增生，且这些增生的细胞可能侵犯身体的其他部分，为由控制细胞分裂增殖机制失常而引起的疾病。全世界罹患癌症的人口有不断增加的趋势，其中全世界癌症人口约有20％是肺癌患者，且肺癌病人经治疗后其5年存活率仍低只有约15％，多年来一直是全球致死率最高的癌症。
依生物特性、治疗和预后的不同，肺癌可分为小细胞肺癌和非小细胞肺癌(non-small cell lung cancer；NSCLC)，而约85-90％的肺癌属于非小细胞肺癌，其中肺腺癌是最常见也是女性及不抽烟患者中最常见的肺癌类型。肺癌的治疗常取决于病人的年龄、过去病史、目前健康状况、癌细胞型态及疾病的分期。一般而言，小细胞肺癌具快速分裂、增殖的特性，所以在短时间内就可能产生转移扩散，因此治疗是以全身性化学治疗或放射线治疗为主。非小细胞肺癌的生长则较缓，故转移的发生也较慢，其治疗原则是依疾病的临床分期而定。早期(第I、II期)的NSCLC根治方法仍以手术将肿瘤完全切除为主。局部扩展期(第III期)包括恶性心包膜或肋膜积水及发生远端转移(第IV期)或身体状况无法手术切除的患者。治疗原则以化学药物治疗或化学药物合并放射线治疗为主。
然而对于转移性或已经历化疗又复发的晚期非小细胞肺癌，在治疗上是个棘手的问题。目前临床研究证实表皮细胞生长因子受体-酪胺酸激酶抑制剂(epidermal growth factor-tyrosine kinase inhibitors,EGFR-TKIs)可作为第一线化疗失败后的第二线治疗药，但约有40-80％的非小细胞肺癌病人带有EGFR基因突变，其会过度表现表皮细胞生长因子受体，导致癌症的快速生长、转移与抗药性。此类病人临床上使用EGFR-TKIs治疗，几乎所有治疗后的病人都在 两年内复发，目前为止，复发后则无有效药物可使用。
发明内容
有鉴于此，本发明的一目的是在提供一种医药组合物的用途，其可用于制备治疗肺癌的药物。所述医药组合物包含二芳基庚烷类化合物或其医药上可接受的盐类，其可抑制对表皮细胞生长因子受体-酪胺酸激酶抑制剂具有耐药性的非小细胞肺癌细胞的生长，是以可单独使用或合并临床使用的表皮细胞生长因子受体-酪胺酸激酶抑制剂共同使用，用以治疗EGFR基因突变且具表皮细胞生长因子受体-酪胺酸激酶抑制剂耐药性的肺癌。
本发明的一态样是在提供一种医药组合物的用途，其是用于制备治疗肺癌的药物，其中医药组合物包含二芳基庚烷类化合物或其医药上可接受的盐类，所述二芳基庚烷类化合物具有式(I)所示的一结构：
Figure PCTCN2021137647-appb-000001
其中R a、R b、R a'及R b'独立地为H、C1-C2烷基、C1-C3烷氧基、OH、或-OC(＝O)R d，其中R d为C1-C3烷基或C1-C3烷醇；R c为H、C1-C2烷基、具有双或三键的C3-C6不饱和烷基或C7-C12芳基烷基；以及R e及R e'独立地为H、C1-C6烷基或C1-C6烷氧基。
依据前述的医药组合物的用途，其中R a、R b、R a'及R b'中至少一者可为-OC(＝O)R d，且R d为C1-C3烷基或C1-C3烷醇。
依据前述的医药组合物的用途，其中当R c为H时，所述二芳基庚烷类化合物于酮型式及烯醇型式之间为可互相转换。
依据前述的医药组合物的用途，其中所述二芳基庚烷类化合物可选自具有式(II)所示结构的化合物1、化合物21a、化合物21b、化合物22a、化合物22b、化合物23a、化合物23b、化合物24a、化合物24b、化合物25、化合物26、化合物27、化合物31及化合物33所组成的群组：
Figure PCTCN2021137647-appb-000002
其中化合物1的R 1,R 1'分别为OCH 3，R 2,R 2'分别为H，R 3,R 3'分别为H；化合物21a的R 1,R 1'分别为OCH 3，R 2,R 2'分别为OR 4，R 3,R 3'分别为H；化合物21b的R 1,R 1'分别为OCH 3，R 2为OH，R 2'为OR 4，R 3,R 3'分别为H；化合物22a的R 1,R 1'分别为OCH 3，R 2,R 2'分别为OR 5，R 3,R 3'分别为H；化合物22b的R 1,R 1'分别为OCH 3，R 2为OH，R 2'为OR 5，R 3,R 3'分别为H；化合物23a的R 1,R 1'分别为H，R 2,R 2'分别为OR 5，R 3,R 3'分别为H；化合物23b的R 1,R 1'分别为H，R 2为OR 5，R 2'为OH，R 3,R 3'分别为H；化合物24a的R 1,R 1'分别为OR 4，R 2,R 2'分别为OCH 3，R 3,R 3'分别为H；化合物24b的R 1为OR 4，R 1'为OH，R 2,R 2'分别为OCH 3，R 3,R 3'分别为H；化合物25的R 1为OR 5，R 1'为OH，R 2,R 2'分别为OCH 3，R 3,R 3'分别为H；化合物26的R 1,R 1'分别为OC 2H 5，R 2,R 2'分别为OR 4，R 3,R 3'分别为H；化合物27的R 1,R 1'分别为OC 2H 5，R 2,R 2'分别为OR 5，R 3,R 3'分别为H；化合物31的R 1,R 1'分别为C 2H 5，R 2,R 2'分别为OR 5，R 3,R 3'分别为C 2H 5；化合物33的R 1,R 1'分别为OCH 3，R 2为OCH 3，R 2'为OR 4，R 3,R 3'分别为H。其中R 4为如式(i)所示的一结构，R 5为如式(ii)所示的一结构：
Figure PCTCN2021137647-appb-000003
依据前述的医药组合物的用途，其中所述二芳基庚烷类化合物可选自具有式(III)所示结构的化合物35a、化合物35c、化合物35d、化合物35e、化合物36及化合物37所组成的群组：
Figure PCTCN2021137647-appb-000004
其中化合物35a的R 6,R 6'分别为OCH 3，R 7,R 7'分别为OR 4，R 8为CH 3；化合物35c的R 6,R 6'分别为OCH 3，R 7,R 7'分别为OR 4，R 8为苄基；化合物35d的R 6,R 6'分别为OCH 3，R 7,R 7'分别为OR 4，R 8为炔丙基；化合物35e的R 6,R 6'分别为OCH 3，R 7,R 7'分别为OR 4，R 8为烯丙基；化合物36的R 6,R 6'分别为H，R 7,R 7'为OR 4，R 8为CH 3；化合物37的R 6,R 6'分别为OR 4，R 7,R 7'分别为OCH 3，R 8为CH 3。其中R 4为如式(i)所示的一结构：
Figure PCTCN2021137647-appb-000005
依据前述的医药组合物的用途，其中所述二芳基庚烷类化合物可选自：
Figure PCTCN2021137647-appb-000006
依据前述的医药组合物的用途，其中所述医药组合物可更包含一表皮细胞生长因子受体-酪胺酸激酶抑制剂。较佳地，所述表皮细胞生长因子受体-酪胺酸激酶抑制剂可为奥希替尼(osimertinib)、吉非替尼(gefitinib)、得舒缓(erlotinib)或妥复克(afatinib)。
依据前述的医药组合物的用途，其中所述肺癌可为非小细胞肺癌。
依据前述的医药组合物的用途，其中所述肺癌可对表皮细胞生长因子受体-酪胺酸激酶抑制剂具有耐药性。
上述发明内容旨在提供本揭示内容的简化摘要，以使阅读者对本揭示内容具备基本的理解。此发明内容并非本揭示内容的完整概述，且其用意并非在指出本发明实施例的重要/关键元件或界定本发明的范围。
附图说明
为让本发明的上述和其他目的、特征、优点与实施例能更明显易懂，所附附图的说明如下：
图1A为本发明的二芳基庚烷类化合物抑制H1650细胞生长的分析结果图；
图1B、图1C和图1D为本发明的二芳基庚烷类化合物抑制对表皮细胞生长因子受体-酪胺酸激酶抑制剂具有耐药性的非小细胞肺癌细胞生长的分析结果图；
图2A为单独处理化合物35d抑制GR6肿瘤小鼠的肿瘤生长的分析结果图；
图2B为单独处理化合物35d抑制GR8肿瘤小鼠的肿瘤生长的分析结果图；
图2C为单独处理化合物35d抑制HCC827肿瘤小鼠的肿瘤生长的分析结果图；
图2D为单独处理化合物35d的肿瘤小鼠体重变化的统计图；
图3A为合并处理化合物35d和奥希替尼抑制GR6肿瘤小鼠的肿瘤再进展的分析结果图；以及
图3B为合并处理化合物35d和奥希替尼的GR6肿瘤小鼠体重变化的统计图。
具体实施方式
本发明提出一种医药组合物的新颖用途，所述医药组合物包含二芳基庚烷类化合物或其医药上可接受的盐类，其是用于制备治疗肺癌的药物，本发明的二芳基庚烷类化合物具有式(I)所示的一结构：
Figure PCTCN2021137647-appb-000007
其中R a、R b、R a'及R b'独立地为H、C1-C2烷基、C1-C3烷氧基、OH、或-OC(＝O)R d，其中R d为C1-C3烷基或C1-C3烷醇；R c为H、C1-C2烷基、具有双或三键的C3-C6不饱和烷基或C7-C12芳基烷基；以及R e及R e'独立地为H、C1-C6烷基或C1-C6烷氧基。
本发明的二芳基庚烷类化合物的R a、R b、R a'及R b'中至少一者可为-OC(＝O)R d，且R d为C1-C3烷基或C1-C3烷醇。此外，当R c为H时，所述二芳基庚烷类化合物于酮型式及烯醇型式之间为可互相转换。
本发明的医药组合物可更包含表皮细胞生长因子受体-酪胺酸激酶抑制剂(epidermal growth factor-tyrosine kinase inhibitors,EGFR-TKIs)与二芳基庚烷类化合物或其医药上可接受的盐类合并使用，而EGFR-TKIs可为奥希替尼(osimertinib)、吉非替尼(gefitinib)、得舒缓(erlotinib)或妥复克(afatinib)。本发明的医药组合物用以治疗的肺癌可为非小细胞肺癌，此外，所述的肺癌可对EGFR-TKIs具有耐药性。
除非另有说明，本说明书中所使用的所有专门术语、符号或其他科学名词或术语具有本发明所属领域中熟谙此技艺者习知的含意，除非使用它们的上下文另有说明。在某些情况下，具有习知含意的术语是在本文中界定以达到明确及/或即时参考的目的，且本说明书中所纳入的这些定义应被解释为不一定与该领域中习知的意义有实质差异。本文中所叙述或引用的许多技术与程序均为大众所习知且时常为该领域中的技术人员以常规方法使用。在适当情况下，除非另有说明，市售套组和试剂的使用程序一般均根据制造商界定的使用说明及/或参数来进行。
除非另有说明，本文中及本说明书所述的「一」及「一个」意指文章中的文法对象为一或多个(即至少一个)。此外，类别为包含于该类别的所有成员的缩写，例如，C1-C3的烷基为对所有C1-C3的烷基的缩写，举例而言，C1-C3的烷基包含甲基、乙基、丙基及其异构体。
本发明揭示的二芳基庚烷类化合物及其医药上可接受的盐类可以藉由体外(in vitro)试验验证，其可抑制对EGFR-TKIs具有耐药性的非小细胞肺癌细胞的生长。并进一步可藉由体内(in vivo)试验验证，本说明书揭示的化合物和/或其至少一种其医药上可接受的盐类可以施用于患有对EGFR-TKIs具耐药性肺癌的动物(例如小鼠模型)，并且可以获得治疗效果。在一个或多个测试中的阳 性结果足以证明所测试的化合物和/或盐的实际效用。并且可基于试验结果确定动物(例如人)的合适剂量范围和给药途径。
用于施用本发明的二芳基庚烷类化合物及其医药上可接受的盐类的有用药物剂型，包含但不限于硬和软明胶胶囊、片剂、肠胃外注射剂和口服混悬剂。而施用的剂量的取决因素包含受试者的年龄、受试者的健康和体重、疾病的程度、同时治疗的类型(如果有的话)、治疗频率和所需效果的性质。通常活性成分的每日剂量可以为非定量，例如每天0.1至2000毫克。例如，每天一次或多次10-500毫克可有效获得所需结果。
当本发明的二芳基庚烷类化合物及其医药上可接受的盐类逐步给药或与至少一种其它治疗剂联合给药时，通常可以使用相同的剂型。当药物以物理组合给药时，应根据组合药物的相容性选择剂型和给药途径。因此，本说明书所述的「共同给药」应理解为包含伴随或顺序给予至少两种药剂，或者作为至少两种活性组分的固定剂量组合。
本说明书二芳基庚烷类化合物及其医药上可接受的盐类可以作为唯一的活性成分，或与至少一种第二活性成分组合施用，所述第二活性成分选自例如已知可用于治疗非小细胞肺癌患者的其他活性成分，特别是EGFR-TKIs。
兹以下列具体试验例进一步示范说明本发明，用以有利于本发明所属技术领域通常知识者，可在不需过度解读的情形下完整利用并实践本发明，而不应将这些试验例视为对本发明范围的限制，但用于说明如何实施本发明的材料及方法。
1.本发明的二芳基庚烷类化合物的结构
本发明的二芳基庚烷类化合物是以姜黄素(curcumin,CCM)作为导向化合物，设计类姜黄素的二芳基庚烷类化合物，其具有如式(I)所示的一结构：
Figure PCTCN2021137647-appb-000008
请参照下表一，为本发明的二芳基庚烷类化合物的实施例-化合物1、化合物 21a、化合物21b、化合物22a、化合物22b、化合物23a、化合物23b、化合物24a、化合物24b、化合物25、化合物26、化合物27、化合物31、化合物33、化合物35a、化合物35c、化合物35d、化合物35e、化合物36及化合物37的R a、R b、R a'、R b'、R c、R e及R e'所代表的取代基。
表一
Figure PCTCN2021137647-appb-000009
Figure PCTCN2021137647-appb-000010
其中化合物21a-((1E,3Z,6E)-3-羟基-5-侧氧基庚-1,3,6-三烯-1,7-二基)双(2-甲氧基-4,1-伸苯基)双(3-羟基-2-羟基甲基)-2-甲基丙酸酯、化合物35a-((1E,6E)-4,4-二甲基-3,5-二侧氧基庚-1,6-二烯-1,7-二基)双(2-甲氧基-4,1-伸苯基)双(3-羟基-2-羟基甲基)-2-甲基丙酸酯、化合物35d-((1E,6E)-3,5-二侧氧基-4,4-二(丙-2-炔-1-基)庚-1,6-二烯-1,7-二基)双(2-甲氧基-4,1-伸苯基)双(3-羟基-2-(羟基甲基)-2-甲基丙酸酯)、化合物36-((1E,6E)-4,4-二甲基-3,5-二侧氧基庚-1,6-二烯-1,7-二基)双(4,1-伸苯基)双(3-羟基-2-(羟基甲基)-2-甲基丙酸酯)和化合物37-((1E,6E)-4,4-二甲基-3,5-二侧氧基庚-1,6-二烯-1,7-二基)双(2-甲氧基-5,1-伸苯基)双(3-羟基-2-(羟基甲基)-2-甲基丙酸酯)的化学结构如表二所示。
表二
Figure PCTCN2021137647-appb-000011
Figure PCTCN2021137647-appb-000012
而化合物21a拥有庚二烯-3,5-二酮部分，其容易地于酮型式及烯醇型式之间可互相转换。烯醇型的3-或5-OH基经由氢键分别与相邻的5-或3-C＝O结合，以安定化其结构。本发明中，二个甲基官能性是并入化合物21a的4-位且提供((1E,6E)-4,4-二甲基-3,5-二侧氧基庚-1,6-二烯-1,7-二基)双(2-甲氧基-4,1-伸苯基)双(3-羟基-2-羟基甲基)-2-甲基丙酸酯(35a)，其是经发现具有安定的酮型，且不安定于互变异构化。此外于本发明中，使用化合物35a作为新导向化合物且衍生为一系列的具有安定地酮型式的其4,4-二烷基衍生物(化合物35a、化合物35d、化合物36及化合物37)。
2.本发明的二芳基庚烷类化合物对EGFR基因突变型的非小细胞肺癌细胞及对EGFR-TKIs具有耐药性的非小细胞肺癌细胞的抑制生长作用
试验上先将EGFR基因突变型的非小细胞肺癌细胞以本发明的二芳基庚烷类化合物进行处理，再以结晶紫染色的细胞存活测定，以测量本发明的二芳基庚烷类化合物在EGFR基因突变型的非小细胞肺癌细胞的IC 50值，以确定本发明的二芳基庚烷类化合物对EGFR基因突变型的非小细胞肺癌细胞的抑制生长作用功效。
肺癌中EGFR基因突变多见于外显子18-21，即胞内酪胺酸激酶编码区，最常见突变形式包括外显子19的E746-A750del和外显子21的L858R点突变，这两种突变约占EGFR基因突变的85％-90％，发生这两种突变的肿瘤细胞对EGFR-TKIs敏感，称为活化突变。部分肿瘤细胞可发生二次突变，最常见二次突变为外显子20的T790M突变，为耐药突变。请参照图1A，为本发明的二芳基庚烷类化合物抑制H1650细胞生长的分析结果图，H1650细胞为EGFR 基因外显子19的E746-A750del突变，其中CCM为姜黄素，BDMC为去二甲氧姜黄素(bisdemethoxycurcumin)，而化合物的IC 50值>16μM显示用浓度高达16μM的化合物处理后，H1650细胞仍未达到50％的细胞生长抑制，图1A中的数据以平均值±SD(n＝3)表示。
图1A为处理22种二芳基庚烷类化合物(包含BDMC)和姜黄素3天后在H1650细胞中的IC 50值，其中化合物1、化合物24b、化合物23b、化合物33、化合物25、化合物35b、化合物22a、化合物21a、化合物22b、化合物26、化合物36、化合物35a、化合物35c、化合物27、化合物31、化合物37、化合物35e和化合物35d等18个二芳基庚烷类化合物，对于H1650细胞生长具有显著优于母体化合物-姜黄素的抑制活性，其中**表示p<0.05，***表示p<0.01，****表示p<0.001。
试验上以另外7个对EGFR-TKIs具有耐药性的非小细胞肺癌细胞处理化合物21a、化合物35a、化合物35d、化合物36或化合物37后，再进行细胞存活测定，以测量本发明的二芳基庚烷类化合物在对EGFR-TKIs具有耐药性的非小细胞肺癌细胞中的IC 50值，以确定本发明的二芳基庚烷类化合物对EGFR-TKIs具有耐药性的非小细胞肺癌细胞的抑制生长作用功效。试验所使用的对EGFR-TKIs具有耐药性的非小细胞肺癌细胞包含H1975细胞、GR2细胞、GR5细胞、GR6细胞、GR8细胞、GR9细胞以及GR10细胞，其中H1975细胞为外显子21的L858R点突变，但同时伴有外显子20的T790M二次突变；GR2细胞、GR5细胞、GR6细胞、GR8细胞、GR9细胞和GR10细胞为以HCC827细胞为亲代细胞处理吉非替尼(gefitinib)后得到的吉非替尼抗性细胞株，而HCC827细胞和H1650细胞均为EGFR外显子19的E746-A750del突变的非小细胞肺癌细胞。
请参照图1B、图1C和图1D，图1B为本发明的二芳基庚烷类化合物抑制H1975细胞生长的分析结果图，图1C为本发明的二芳基庚烷类化合物抑制GR2细胞、GR5细胞、GR6细胞、GR8细胞、GR9细胞和GR10细胞生长的分析结果图，图1D为GR2细胞、GR5细胞、GR6细胞、GR8细胞、GR9细胞和GR10细胞分别处理化合物35d和吉非替尼后IC 50值的百分比变化结果图。其中图1B和图1C中的数据以平均值±SD(n＝3)表示，而IC 50值>16μM显示用浓度高达16μM的化合物处理后，试验细胞仍未达到50％的细胞生长抑 制，图1D中的Gef表示吉非替尼。
图1B为H1975细胞分别处理化合物21a、化合物35a、化合物35d、化合物36、化合物37和姜黄素3天后所测量的IC 50值。结果显示，本发明的化合物21a、化合物35a、化合物35d、化合物36和化合物37对于H1975细胞生长具有显著优于姜黄素的抑制活性。
图1C为GR2细胞、GR5细胞、GR6细胞、GR8细胞、GR9细胞和GR10细胞分别处理化合物21a、化合物35a、化合物35d、化合物36、化合物37和姜黄素3天后所测量的IC 50值。结果显示，本发明的化合物21a、化合物35a、化合物35d、化合物36和化合物37对于GR2细胞、GR5细胞、GR6细胞、GR8细胞、GR9细胞和GR10细胞生长皆具有显著优于姜黄素的抑制活性。
由图1B和图1C的结果显示，所有对EGFR-TKIs具有耐药性的非小细胞肺癌细胞，对化合物21a、化合物35a、化合物35d、化合物36和化合物37比姜黄素更敏感，能以显著较低的浓度达到50％的细胞生长抑制的效果。
图1D为将HCC827细胞、GR2细胞、GR5细胞、GR6细胞、GR8细胞、GR9细胞和GR10细胞分别以化合物35d和吉非替尼处理3天后测量IC 50值，再将GR2细胞、GR5细胞、GR6细胞、GR8细胞、GR9细胞和GR10细胞所测得的IC 50值与HCC827细胞所测得的IC 50值进行比较所得到的分析结果图。图1D的结果显示，所有的吉非替尼抗性细胞株对于化合物35d皆具间接敏感性，与其亲代细胞-HCC827细胞相比，所有的吉非替尼抗性细胞株对于吉非替尼(Gef)的抗性>200倍。
3.化合物35d对GR6肿瘤、GR8肿瘤和HCC827肿瘤的抗癌活性
为验证本发明的二芳基庚烷类化合物于体内的抗癌功效，试验上先建立异种移植的GR6肿瘤小鼠模型、GR8肿瘤小鼠模型和HCC827肿瘤小鼠模型，并分别将GR6肿瘤小鼠、GR8肿瘤小鼠和HCC827肿瘤小鼠每天以100mg/kg的化合物35d治疗35天，并记录GR6肿瘤小鼠、GR8肿瘤小鼠和HCC827肿瘤小鼠的肿瘤大小和体重。
请参照图2A至图2D，图2A为单独处理化合物35d抑制GR6肿瘤小鼠的肿瘤生长的分析结果图，图2B为单独处理化合物35d抑制GR8肿瘤小鼠的肿瘤生长的分析结果图，图2C为单独处理化合物35d抑制HCC827肿瘤小鼠的 肿瘤生长的分析结果图，图2D为单独处理化合物35d的肿瘤小鼠体重变化的统计图，其中图2A至图2C的数据以平均值±SEM(n＝10)表示。
图2A至图2C的结果显示，化合物35d显著抑制GR6肿瘤小鼠和GR8肿瘤小鼠的肿瘤生长，但在抑制HCC827肿瘤小鼠的肿瘤生长状况效果较不显著。而图2D的结果显示，肿瘤小鼠在处理化合物35d超过1个月后其体重未显著下降。
4.化合物35d与奥希替尼合并使用抑制GR6肿瘤再进展
EGFR-TKIs是目前临床上针对EGFR基因突变的非小细胞肺癌患者的标准治疗方法。试验上进一步测试本发明的二芳基庚烷类化合物与已知的合并使用是否可提升非小细胞肺癌的治疗效果。试验上将GR6肿瘤小鼠分为4个组别，1组每天接受100mg/kg的化合物35d治疗(表示为35d)，1组每天接受1mg/kg的奥希替尼治疗(表示为Osi)，1组每天接受100mg/kg的化合物35d和1mg/kg的奥希替尼的合并治疗(表示为35d+Osi)，另1组为未经药物治疗的对照组。
请参照图3A和图3B，图3A为合并处理化合物35d和奥希替尼抑制GR6肿瘤小鼠的肿瘤再进展的分析结果图，图3B为合并处理化合物35d和奥希替尼的GR6肿瘤小鼠体重变化的统计图，其中图3A和图3B的数据以平均值±SEM(n＝10)表示。
图3A的结果显示，Osi组别的GR6肿瘤小鼠的肿瘤大小虽在一开始经奥希替尼治疗而降低，但治疗肿瘤随后重新生长，显示GR6肿瘤小鼠的肿瘤具有EGFR-TKIs抗性。然而不论是在单独处理化合物35d的组别或化合物35d与奥希替尼合并治疗的组别，皆显著抑制了GR6肿瘤小鼠的肿瘤再进展。且由图3B的结果显示，单独处理化合物35d或化合物35d与奥希替尼合并治疗皆不会显著减轻小鼠体重。
综上所述，本发明提出了一种医药组合物的新用途，其可用于制备治疗肺癌的药物。所述医药组合物包含二芳基庚烷类化合物或其医药上可接受的盐类，其可抑制EGFR基因突变型的非小细胞肺癌细胞和对EGFR-TKIs具有耐药性的非小细胞肺癌细胞的生长，是以制备治疗肺癌的药物，且其可与EGFR-TKIs合并使用时具有协同作用，更能增加治疗肺癌的有效性，特别是用以治疗 EGFR基因突变且具EGFR-TKIs的肺癌，具有运用于生医保健市场的潜能。
然本发明已以实施方式揭露如上，然其并非用以限定本发明，任何熟习此技艺者，在不脱离本发明的精神和范围内，当可作各种的更动与润饰，因此本发明的保护范围当视后附的申请专利范围所界定者为准。

Claims (10)

  1. 一种医药组合物的用途，其特征在于，该医药组合物是用于制备治疗肺癌的药物，其中该医药组合物包含二芳基庚烷类化合物或其医药上可接受的盐类，该二芳基庚烷类化合物具有式(I)所示的一结构：
    Figure PCTCN2021137647-appb-100001
    其中R a、R b、R a'及R b'独立地为H、C1-C2烷基、C1-C3烷氧基、OH、或-OC(＝O)R d，其中R d为C1-C3烷基或C1-C3烷醇；R c为H、C1-C2烷基、具有双或三键的C3-C6不饱和烷基或C7-C12芳基烷基；以及R e及R e'独立地为H、C1-C6烷基或C1-C6烷氧基。
  2. 如权利要求1所述的医药组合物的用途，其中R a、R b、R a'及R b'中至少一者为-OC(＝O)R d，且R d为C1-C3烷基或C1-C3烷醇。
  3. 如权利要求1所述的医药组合物的用途，其中当R c为H时，该二芳基庚烷类化合物于酮型式及烯醇型式之间为可互相转换。
  4. 如权利要求1所述的医药组合物的用途，其中该二芳基庚烷类化合物是选自具有式(II)所示结构的化合物1、化合物21a、化合物21b、化合物22a、化合物22b、化合物23a、化合物23b、化合物24a、化合物24b、化合物25、化合物26、化合物27、化合物31及化合物33所组成的群组：
    Figure PCTCN2021137647-appb-100002
    其中化合物1的R 1,R 1'分别为OCH 3，R 2,R 2'分别为H，R 3,R 3'分别为H；化合物21a的R 1,R 1'分别为OCH 3，R 2,R 2'分别为OR 4，R 3,R 3'分别为H；化合物21b的R 1,R 1'分别为OCH 3，R 2为OH，R 2'为OR 4，R 3,R 3'分别为H；化合物22a的R 1,R 1'分别为OCH 3，R 2,R 2'分别为OR 5，R 3,R 3'分别为H；化合物22b的R 1,R 1'分别为OCH 3，R 2为OH，R 2'为OR 5，R 3,R 3'分别为H；化合物23a的R 1,R 1'分别为H，R 2,R 2'分别为OR 5，R 3,R 3'分别为H；化合物23b的R 1,R 1'分别为H，R 2为OR 5，R 2'为OH，R 3,R 3'分别为H；化合物24a的R 1,R 1'分别为OR 4，R 2,R 2'分别为OCH 3，R 3,R 3'分别为H；化合物24b的R 1为OR 4，R 1'为OH，R 2,R 2'分别为OCH 3，R 3,R 3'分别为H；化合物25的R 1为OR 5，R 1'为OH，R 2,R 2'分别为OCH 3，R 3,R 3'分别为H；化合物26的R 1,R 1'分别为OC 2H 5，R 2,R 2'分别为OR 4，R 3,R 3'分别为H；化合物27的R 1,R 1'分别为OC 2H 5，R 2,R 2'分别为OR 5，R 3,R 3'分别为H；化合物31的R 1,R 1'分别为C 2H 5，R 2,R 2'分别为OR 5，R 3,R 3'分别为C 2H 5；化合物33的R 1,R 1'分别为OCH 3，R 2为OCH 3，R 2'为OR 4，R 3,R 3'分别为H；
    其中R 4为如式(i)所示的一结构，R 5为如式(ii)所示的一结构：
    Figure PCTCN2021137647-appb-100003
  5. 如权利要求1所述的医药组合物的用途，其中该二芳基庚烷类化合物是选自具有式(III)所示结构的化合物35a、化合物35c、化合物35d、化合物35e、化合物36及化合物37所组成的群组：
    Figure PCTCN2021137647-appb-100004
    其中化合物35a的R 6,R 6'分别为OCH 3，R 7,R 7'分别为OR 4，R 8为CH 3；化合物35c的R 6,R 6'分别为OCH 3，R 7,R 7'分别为OR 4，R 8为苄基；化合物35d的R 6,R 6'分别为OCH 3，R 7,R 7'分别为OR 4，R 8为炔丙基；化合物35e的R 6,R 6'分 别为OCH 3，R 7,R 7'分别为OR 4，R 8为烯丙基；化合物36的R 6,R 6'分别为H，R 7,R 7'为OR 4，R 8为CH 3；化合物37的R 6,R 6'分别为OR 4，R 7,R 7'分别为OCH 3，R 8为CH 3；
    其中R 4为如式(i)所示的一结构：
    Figure PCTCN2021137647-appb-100005
  6. 如权利要求1所述的医药组合物的用途，其中该二芳基庚烷类化合物是选自：
    Figure PCTCN2021137647-appb-100006
    Figure PCTCN2021137647-appb-100007
    及
    Figure PCTCN2021137647-appb-100008
  7. 如权利要求1所述的医药组合物的用途，其中该医药组合物更包含一表皮细胞生长因子受体-酪胺酸激酶抑制剂(epidermal growth factor-tyrosine kinase inhibitors,EGFR-TKIs)。
  8. 如权利要求7所述的医药组合物的用途，其中该表皮细胞生长因子受体-酪胺酸激酶抑制剂为奥希替尼(osimertinib)、吉非替尼(gefitinib)、得舒缓(erlotinib)或妥复克(afatinib)。
  9. 如权利要求1所述的医药组合物的用途，其中该肺癌为非小细胞肺癌。
  10. 如权利要求1所述的医药组合物的用途，其中该肺癌对表皮细胞生长 因子受体-酪胺酸激酶抑制剂具有耐药性。
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