[go: up one dir, main page]
More Web Proxy on the site http://driver.im/

WO2018035884A1 - 一种具有抗肿瘤药物功效的联合用药物 - Google Patents

一种具有抗肿瘤药物功效的联合用药物 Download PDF

Info

Publication number
WO2018035884A1
WO2018035884A1 PCT/CN2016/097789 CN2016097789W WO2018035884A1 WO 2018035884 A1 WO2018035884 A1 WO 2018035884A1 CN 2016097789 W CN2016097789 W CN 2016097789W WO 2018035884 A1 WO2018035884 A1 WO 2018035884A1
Authority
WO
WIPO (PCT)
Prior art keywords
antitumor drug
drug
acid derivative
weight ratio
antitumor
Prior art date
Application number
PCT/CN2016/097789
Other languages
English (en)
French (fr)
Inventor
雍智全
Original Assignee
东莞安好医药科技有限公司
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by 东莞安好医药科技有限公司 filed Critical 东莞安好医药科技有限公司
Priority to EP16913905.2A priority Critical patent/EP3378473A4/en
Priority to US15/781,987 priority patent/US10675259B2/en
Priority to JP2018544938A priority patent/JP6656397B2/ja
Publication of WO2018035884A1 publication Critical patent/WO2018035884A1/zh
Priority to US16/858,259 priority patent/US11033519B2/en

Links

Classifications

    • 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
    • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
    • A61K31/19—Carboxylic acids, e.g. valproic acid
    • A61K31/192—Carboxylic acids, e.g. valproic acid having aromatic groups, e.g. sulindac, 2-aryl-propionic acids, ethacrynic acid 
    • 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
    • A61K31/28—Compounds containing heavy metals
    • A61K31/282—Platinum compounds
    • 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
    • A61K31/337—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having four-membered rings, e.g. taxol
    • 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
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • 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
    • A61K31/66—Phosphorus compounds
    • A61K31/675—Phosphorus compounds having nitrogen as a ring hetero atom, e.g. pyridoxal phosphate
    • 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
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/04—Peptides having up to 20 amino acids in a fully defined sequence; Derivatives thereof
    • A61K38/14—Peptides containing saccharide radicals; Derivatives thereof, e.g. bleomycin, phleomycin, muramylpeptides or vancomycin
    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A61P35/04—Antineoplastic agents specific for metastasis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K2300/00—Mixtures or combinations of active ingredients, wherein at least one active ingredient is fully defined in groups A61K31/00 - A61K41/00
    • 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
    • A61K31/351—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 not condensed with another ring

Definitions

  • the present invention relates to a combination drug having the efficacy of an antitumor drug.
  • Trans-styryl derivatives have anti-tumor effects, and the effects of their use alone are not satisfactory.
  • a combination drug for antitumor drug efficacy of the present invention which comprises a styrene acid derivative and an antitumor drug for simultaneous or separate administration of the same or different unit preparations, and a pharmaceutically acceptable carrier;
  • R1, R2, R3, R4 and R5 are preferably hydrogen, a hydroxyl group or a methoxy group. More preferably, R1 is hydrogen, R2 is hydroxy, R3 is methoxy, R4 is hydrogen, and R5 is hydrogen.
  • the above styrene acid derivative has a cis-trans structure, and a trans structure is preferred.
  • the trans-styryl derivative is (E)-3-(2',3'-dihydroxy-4'-methoxyphenyl)-2-(3", 4", 5" -Trimethoxyphenyl)-2-acrylic acid.
  • trans-styryl derivative is (E)-3-(2',3'-dihydroxy-4'-methoxyphenyl)-2-(3",4",5"-trimethoxyphenyl -2-Acene is described in the patent document No. 101074189B, which can be prepared according to the method in the document.
  • the anti-tumor drug is selected from the group consisting of an alkylating agent, a platinum complex, an antitumor antibiotic, paclitaxel and its derivatives, sorafenib.
  • the alkylating agent is cyclophosphamide; the platinum complex is carboplatin; the antitumor antibiotic is in the range of doxorubicin or bleomycin hydrochloride; and the paclitaxel derivative is docetaxel.
  • the weight ratio of the styric acid derivative to the antitumor drug is from 1:1 to 640:1.
  • the weight ratio of the styric acid derivative and the antitumor drug is 112:1;
  • the weight ratio of the styrene acid derivative and the antitumor drug is 1:1 to 840:11;
  • the weight ratio of the styric acid derivative and the antitumor drug is 5:1;
  • the antitumor drug is cyclophosphamide, the weight ratio of the styric acid derivative and the antitumor drug is 65:60;
  • the weight ratio of the styric acid derivative and the antitumor drug is 4400:9;
  • the antitumor drug is docetaxel, the weight ratio of the styric acid derivative and the antitumor drug is 640:1;
  • the weight ratio of the styrene acid derivative to the antitumor drug is 400:1.
  • the present invention also provides the use of the aforementioned combination drug for the preparation of a medicament for treating lung cancer, liver cancer, ovarian cancer, melanoma, colon cancer, kidney cancer, bladder cancer.
  • the drug for treating lung cancer is a drug for treating small cell lung cancer.
  • the present invention also provides the use of a trans-styryl derivative and an antitumor drug in the preparation of a combination antitumor drug;
  • R1, R2, R3, R4 and R5 are preferably hydrogen, a hydroxyl group or a methoxy group. More preferably, R1 is hydrogen, R2 is hydroxy, R3 is methoxy, R4 is hydrogen, R5 is hydrogen, and the above-mentioned styrene acid derivative has a cis-trans structure, of which a trans structure is preferred.
  • the trans-styryl derivative is (E)-3-(2',3'-dihydroxy-4'-methoxyphenyl)-2-(3", 4", 5" -Trimethoxyphenyl)-2-acrylic acid.
  • the anti-tumor drug is selected from the group consisting of an alkylating agent, a platinum complex, an antitumor antibiotic, paclitaxel and its derivatives, sorafenib.
  • the alkylating agent is cyclophosphamide; the platinum complex is carboplatin; the antitumor antibiotic is in the range of doxorubicin or bleomycin hydrochloride; and the paclitaxel derivative is docetaxel.
  • the weight ratio of the styric acid derivative to the antitumor drug is from 1:1 to 640:1.
  • the weight ratio of the styric acid derivative and the antitumor drug is 112:1;
  • the weight ratio of the styrene acid derivative and the antitumor drug is 1:1 to 840:11;
  • the weight ratio of the styric acid derivative and the antitumor drug is 5:1;
  • the antitumor drug is cyclophosphamide, the weight ratio of the styric acid derivative and the antitumor drug is 65:60;
  • the weight ratio of the styric acid derivative and the antitumor drug is 4400:9;
  • the antitumor drug is docetaxel, the weight ratio of the styric acid derivative and the antitumor drug is 640:1;
  • the weight ratio of the styrene acid derivative to the antitumor drug is 400:1.
  • the combined drug is for treating lung cancer, liver cancer, ovarian cancer, melanoma, colon cancer, Kidney cancer, bladder cancer drugs.
  • the drug for treating lung cancer is a drug for treating small cell lung cancer.
  • a method for treating a tumor is as follows: simultaneously or separately administering a styrene acid derivative and an antitumor drug in the same or different unit dosage formulations;
  • R1, R2, R3, R4 and R5 are preferably hydrogen, a hydroxyl group or a methoxy group. More preferably, R1 is hydrogen, R2 is hydroxy, R3 is methoxy, R4 is hydrogen, and R5 is hydrogen.
  • the above styrene acid derivative has a cis-trans structure, and a trans structure is preferred.
  • the trans-styryl derivative is (E)-3-(2',3'-dihydroxy-4'-methoxyphenyl)-2-(3", 4", 5" -Trimethoxyphenyl)-2-acrylic acid.
  • the anti-tumor drug is selected from the group consisting of an alkylating agent, a platinum complex, an antitumor antibiotic, paclitaxel and its derivatives, sorafenib.
  • the alkylating agent is cyclophosphamide; the platinum complex is carboplatin; the antitumor antibiotic is in the range of doxorubicin or bleomycin hydrochloride; and the paclitaxel derivative is docetaxel.
  • the weight ratio of the styric acid derivative to the antitumor drug is from 1:1 to 640:1.
  • the weight ratio of the styric acid derivative and the antitumor drug is 112:1;
  • the weight ratio of the styrene acid derivative and the antitumor drug is 1:1 to 840:11;
  • the weight ratio of the styric acid derivative and the antitumor drug is 5:1;
  • the antitumor drug is cyclophosphamide, the weight ratio of the styric acid derivative and the antitumor drug is 65:60;
  • the weight ratio of the styric acid derivative and the antitumor drug is 4400:9;
  • the antitumor drug is docetaxel, the weight ratio of the styric acid derivative and the antitumor drug is 640:1;
  • the weight ratio of the styrene acid derivative to the antitumor drug is 400:1.
  • the administration method can be administered parenterally by intravenous, subcutaneous or intramuscular route, and is preferably administered by intravenous and subcutaneous routes for the purpose of improving the effectiveness.
  • the invention also provides the use of the aforementioned method for the treatment of lung cancer, liver cancer, ovarian cancer, melanoma, colon cancer, kidney cancer, bladder cancer.
  • the drug for treating lung cancer is a drug for treating small cell lung cancer.
  • trans-styryl acid derivative of the present invention can exert a synergistic effect, and can also exert a detoxifying effect in combination with a part of the anti-tumor drug, and the trans-styryl acid derivative and the anti-tumor
  • the combination of oncology drugs and drugs has excellent curative effect, low toxicity and good clinical application prospects.
  • the tumor long diameter a (mm) and the vertical tumor short diameter b (mm) were measured twice a week with a digital electronic caliper.
  • Ea+b is the tumor inhibition rate of the combined drug
  • Ea and Eb are the tumor inhibition rates of drug A and drug B, respectively.
  • the Q value of 0.85 to 1.15 is additive (+), and >1.15 is enhanced (++).
  • Example 1 Therapeutic effect of DX1002 combined with CBP on human lung cancer 95D xenografts in nude mice
  • DX1002 (E)-3-(2',3'-dihydroxy-4'-methoxyphenyl)-2-(3",4",5"-trimethoxyphenyl)-2-propenoic acid.
  • Preparation Method 140 g (610 mmol) of 3,4,5-trimethoxyphenylacetic acid, 724 mmol of 2,3-dihydroxy-4-methoxybenzaldehyde, 200 ml of acetic anhydride and 100 ml of NEt3 (717 mmol) were added to a 1000 ml round bottom. The flask was stirred and refluxed at an external temperature of 150 ° C for 2.5 hours. The solvent was evaporated under reduced pressure to give an oily material. EtOAc EtOAc EtOAc EtOAcjjjjjjjjjjj 98%).
  • mice BALB/C nude mice (SPF grade, body weight: 19-21 g, male).
  • Tumor strain Human lung cancer 95D cell line was provided by West China Medical Center of Sichuan University.
  • Each group of the drug-administered group is 8 Groups greater than 8 are:
  • Group 1 DX1002 400mg/kg/day (ig ⁇ 14 days)
  • Group 2 CBP 10 mg/kg/day (ip ⁇ 10 days, once every other day)
  • the tumor mass was about 100mm 3 , and the tumors were regrouped according to the tumor size.
  • the tumors were oversized and undersized.
  • the average volume of each tumor was basically the same.
  • the drug was administered according to the above protocol and continued oral gavage for 14 days.
  • the administration volume was 0.5 ml/20 g body weight, and CBP was administered intraperitoneally (ip) once every other day for 10 days.
  • Test drug paclitaxel injection (PAC, batch number: 15120024, specification: 30mg/5ml), produced by Sichuan Taiji Pharmaceutical Co., Ltd., prepared with sterile physiological saline before use.
  • PAC paclitaxel injection
  • mice BALB/C nude mice (SPF grade, body weight: 19-21 g, male).
  • Tumor strain Human lung cancer A549 cell line, provided by West China Medical Center of Sichuan University.
  • a well-developed lung cancer A549 tumor mass was cut into 3 mm uniform pieces under sterile conditions, and each mouse was inoculated subcutaneously with a trocar. The following 4 groups were set, and 8 groups in each group were administered. Groups greater than 8 are:
  • Group 2 PAC 5mg/kg/day (ip ⁇ 21d, once every other day)
  • the tumor mass was about 100mm 3 , and the tumors were regrouped according to the tumor size. The animals with too large and too small tumors were eliminated.
  • the average volume of each tumor was basically the same.
  • the drug was administered according to the above protocol and continued oral gavage for 21 days. The dose is 0.5 ml / 20 g body weight.
  • the paclitaxel injection was intraperitoneally injected, and the administration volume was 0.2 ml/20 g once every other day for 21 days.
  • the combination of DX1002 and paclitaxel in the treatment of human lung cancer A549 has a tumor inhibition rate of 94.83%, while the inhibition rate of DX1002 and paclitaxel alone is only 61.08% and 51.96%, calculated by the Q value of the Jin's equation.
  • the Q value of the combination of DX1002 and paclitaxel (weight ratio of the two is 840:11) of the present invention is 1.17, which is greater than the synergistic limit value of 1.15; in addition, the animal body weight is not significantly reduced, and no obvious toxicity addition reaction is observed.
  • Example 3 Effect of DX1002 combined with paclitaxel on human A2780 nude mice transplanted with tumor
  • Test drug paclitaxel injection (PAC, batch number: 15120024, specification: 30mg/5ml), produced by Sichuan Taiji Pharmaceutical Co., Ltd., prepared with sterile physiological saline before use.
  • PAC paclitaxel injection
  • mice BALB/C nude mice (SPF grade, body weight: 19-21 g, male).
  • Tumor strain human ovarian cancer A2780 cell line, provided by West China Medical Center, Sichuan University.
  • Human ovarian cancer A2780 nude mice xenografts were established by inoculating human ovarian cancer A2780 cell line in the axilla of nude mice.
  • the amount of cells inoculated was 1 ⁇ 10 6 , and the cells were inoculated to form transplanted tumors and then used in nude mice for 3 generations.
  • the tumor tissue in the vigorous growth period was cut into 1.5 mm 3 and homogenized under aseptic conditions to prepare a cell suspension, which was inoculated into the right axilla of the nude mice with 0.1 ml.
  • the nude mice xenografts were measured with a vernier caliper to measure the diameter of the transplanted tumors. After the tumors were grown to 100 mm 3 , the animals were randomly divided into groups of 6 animals. The effect of the anti-tumor effect of the test substance was dynamically observed using a method of measuring the tumor diameter.
  • DX1002 was dissolved in water at 10 mg/kg, it was orally administered orally, once every other day for three weeks; paclitaxel was administered intravenously at 10 mg/kg, once every other day for three weeks. The number of measurements of tumor diameter was measured every three days. The administration volume was 0.1 ml / 20 g. The negative control group was intravenously injected with an equal amount of physiological saline solution.
  • the combination of DX1002 and paclitaxel in the treatment of human ovarian cancer A2780 was 92.20%, while the inhibition rate of DX1002 and paclitaxel alone was only 55.51% and 54.53%, the Q value of the Jin's equation Calculated, the present invention DX1002 and paclitaxel (the weight ratio of the two is 1:1)
  • the Q value used in combination was 1.16, which was greater than the synergistic limit of 1.15; in addition, the toxicity was also significantly reduced compared to the two alone.
  • Example 4 Effect of DX1002 combined with sorafenib on tumor growth of human liver cancer huh-7 nude mice
  • mice BALB/C nude mice (SPF grade, body weight: 19-21 g, male).
  • Tumor strain human ovarian cancer A2780 cell line, provided by West China Medical Center, Sichuan University.
  • Human liver cancer huh-7 nude mice xenografts were established by inoculating human liver cancer huh-7 cell strain into the axilla of nude mice.
  • the inoculation amount of the cells was 1 cell line, and 6 cells were inoculated to form a transplanted tumor, and then used in nude mice for 3 generations.
  • the tumor tissue in the vigorous growth period was cut into 1.5 mm 3 and homogenized under aseptic conditions to prepare a cell suspension, which was inoculated into the right axilla of the nude mice with 0.1 ml.
  • the nude mice xenografts were measured with a vernier caliper to measure the diameter of the transplanted tumors.
  • the animals were randomly divided into groups of 6 animals.
  • the effect of the anti-tumor effect of the test substance was dynamically observed using a method of measuring the tumor diameter.
  • DX1002 was orally administered at 100 mg/kg, administered once every other day for three weeks; sorafenib 20 mg/kg was orally administered once every other day for three weeks.
  • the number of measurements of tumor diameter was measured every three days.
  • the negative control group was orally administered an equal amount of physiological saline solution.
  • the tumor inhibition rate was 92.03%, while the tumor inhibition rate of DX1002 and sorafenib alone was only 50.63% and 58.81%.
  • the Q value of the combination of DX1002 and sorafenib (the weight ratio of the two is 5:1) is 1.16, which is greater than the cooperative limit value of 1.15; in addition, the two are used separately In comparison, toxicity is also significantly reduced.
  • Test reagent cyclophosphamide (CTX, batch number: 15122125, specification: 0.2g), produced by Jiangsu Shengdi Pharmaceutical Co., Ltd., prepared with sterile physiological saline before use.
  • mice BALB/C nude mice (SPF grade, body weight: 19-21 g, male).
  • Tumor strain Melanoma B16 cell line, provided by West China Medical Center, Sichuan University.
  • Mouse melanoma B16 model C57BL/6 mice, male, 18-22 g.
  • the tumor tissues with good growth were taken, cut, ground, filtered, and diluted with a 1:3 ratio of sterile physiological saline to prepare a tumor cell suspension, and 0.2 ml of tumor solution was inoculated into the back of each mouse.
  • Animals were randomized the next day after inoculation, weighed, and dosing.
  • the volume of cyclophosphamide injection administered was intraperitoneal injection per 10 g of mice. Cyclophosphamide alone and in combination were injected with cyclophosphamide (CTX) once a day on the next day of inoculation.
  • CTX cyclophosphamide
  • DX1002 was orally administered once a day for 13 consecutive days.
  • the combination of DX1002 and cyclophosphamide was injected intraperitoneally with DX1002 in the left side and cyclophosphamide was injected into the right side.
  • the experimental animals were divided into 4 groups, the negative control group, cyclophosphamide 60 mg/kg single administration group, DX10025 mg/kg group, cyclophosphamide 60 mg/kg and DX1002 5 mg/kg combination group. 10 animals per group. After the DX1002 was discontinued, the animals were sacrificed the next day, weighing, weighing and weighing. The tumor inhibition rate (%) was calculated from the tumor weight. Body weight and tumor weight mean ⁇ standard deviation The t-test between the combination group and the negative control group, the combination group and the cyclophosphamide single-use group was performed.
  • the combination of DX1002 and cyclophosphamide in the treatment of melanoma B16 has a tumor inhibition rate of 92.03%, while the inhibition rate of DX1002 and cyclophosphamide alone is only 57.8% and 44.04%, according to the Jin's equation.
  • Q value calculation the combined use of the DX1002 of the present invention and cyclophosphamide (the weight ratio of the two is 65:60) is 1.16, which is greater than the synergistic limit value of 1.15; in addition, the toxicity is also obvious compared with the two alone. decline.
  • Test drug Doxorubicin (batch number: 2160102, specification: 10mg), produced by Shanxi Pude Pharmaceutical Co., Ltd., prepared with sterile physiological saline before use.
  • mice BALB/C nude mice (SPF grade, body weight: 19-21 g, male).
  • Tumor strain liver cancer H22 cell line, provided by West China Medical Center, Sichuan University.
  • the mouse liver cancer H22 model was selected from Kunming mice, male, 18-22 g. During the experiment, the mouse ascites was aspirated and diluted with a 1:3 ratio of sterile physiological saline to prepare a tumor cell suspension, and 0.2 ml of tumor fluid was inoculated into the back of each mouse. Animals were randomized the next day after inoculation, weighed, and dosing.
  • the experimental animals were divided into 4 groups, negative control group, doxorubicin 3 mg/kg single injection group, DX1002 800 mg/kg oral group, doxorubicin injection 3 mg/kg and DX1002 800 mg/kg oral combination group, last time.
  • the animals were sacrificed the day after the administration, weighing, weighing and weighing.
  • the tumor inhibition rate (%) was calculated from the tumor weight.
  • Body weight and tumor weight mean ⁇ standard deviation The t-test between each of the administration groups and the negative control group was performed.
  • TXT Docetaxel injection
  • batch number: 16022115, specification: 20mg Docetaxel injection
  • Jiangsu Hengrui Pharmaceutical Co., Ltd. prepared with sterile physiological saline before use.
  • mice BALB/C nude mice (SPF grade, body weight: 19-21 g, male).
  • Tumor strain Lewis lung cancer cell line, provided by West China Medical Center of Sichuan University.
  • Mouse Lewis lung cancer model C57BL/6 mice, male, 18-20 g were used. During the experiment, the tumor tissues with good growth were taken, cut, ground, filtered, and diluted with a 1:3 ratio of sterile physiological saline to prepare a tumor cell suspension, and 0.2 ml of tumor solution was inoculated into the back of each mouse. Animals were randomized the next day after inoculation, weighed, and dosing. The solvent control group was intraperitoneally injected with 0.2 ml of physiological saline per 10 g of mice, once a day.
  • Docetaxel injection was administered in a volume of 0.2 ml per 10 g of mice, once a day, and docetaxel alone or in combination was given to docetaxel for 5 days. The administration was stopped on the sixth day. DX1002 was orally administered once a day for 10 consecutive days.
  • the experimental animals were divided into 4 groups, negative control group, docetaxel 5 mg/kg single administration group, DX10021600 mg/kg group, docetaxel 5 mg/kg and DX1002 1600 mg/kg combination group, 10 animals in each group. . After the DX1002 was discontinued, the animals were sacrificed the next day, weighing, weighing and weighing. The tumor inhibition rate (%) was calculated from the tumor weight. Body weight and tumor weight mean ⁇ standard deviation The t-test between the combination group and the negative control group, the combination group and the docetaxel single-use group was performed.
  • the combination of DX1002 and docetaxel in the treatment of Lewis lung cancer has a tumor inhibition rate of 89.61%, while the inhibition rate of DX1002 and docetaxel alone is only 50.28% and 53.65%.
  • the Q value is calculated.
  • the Q value of the combination of DX1002 and docetaxel (the weight ratio of the two is 640:1) is 1.16, which is greater than the synergistic limit value of 1.15.
  • the animal body weight is not significantly reduced, nor is it seen. Significant toxicity additive reaction.
  • Example 8 Effect of DX1002 combined with BON on human colon cancer HT-29
  • Test bleomycin hydrochloride (BON, batch number: 151102, specification: 15,000 units), produced by the company, prepared with sterile physiological saline before use.
  • mice BALB/C nude mice (SPF grade, body weight: 19-21 g, male).
  • Tumor strain Human colon cancer HT-29, provided by West China Medical Center of Sichuan University.
  • the well-developed colon cancer HT-29 tumor mass was cut into 3 mm uniform pieces under sterile conditions, and each mouse was inoculated subcutaneously with a trocar.
  • the following 4 groups were set, and each group of the drug group was 8 Only the Control group is greater than 8 and are:
  • the tumor mass was about 100mm 3 , and the tumors were regrouped according to the tumor size.
  • the tumors were oversized and undersized.
  • the average volume of each tumor was basically the same.
  • the drug was administered according to the above protocol.
  • the oral administration was continued for 14 days.
  • the dose is 0.5 ml / 20 g body weight.
  • BON was intraperitoneally injected, 0.2 ml/20 g body weight, once every other day for 14 consecutive days.
  • the tumor long diameter and the vertical tumor short diameter were measured twice a week from the 14th day of the inoculation using a digital display caliper. Animals were sacrificed 29 days after inoculation.
  • the combination of the trans-styryl acid derivative of the present invention and an anti-tumor drug can exert a synergistic effect, and can also exert a detoxifying effect in combination with a part of the anti-tumor drug, and the trans-styryl acid can be derived.
  • the combination of anti-tumor drugs and anti-tumor drugs has excellent curative effect, low toxicity and good clinical application prospects.

Landscapes

  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • General Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Veterinary Medicine (AREA)
  • Medicinal Chemistry (AREA)
  • Public Health (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Animal Behavior & Ethology (AREA)
  • Epidemiology (AREA)
  • Organic Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • General Chemical & Material Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Gastroenterology & Hepatology (AREA)
  • Engineering & Computer Science (AREA)
  • Molecular Biology (AREA)
  • Immunology (AREA)
  • Proteomics, Peptides & Aminoacids (AREA)
  • Oncology (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)

Abstract

本发明提供了一种具有抗肿瘤药物功效的联合用药物，它含有相同或不同规格单位制剂的用于同时或者分别给药的苯乙烯酸类衍生物和抗肿瘤药物，以及药学上可接受的载体。本发明反式苯乙烯酸类衍生物与抗肿瘤药物的联合使用可以发挥协同增效作用，与部分抗肿瘤药物联合使用还可以发挥降毒的作用，临床应用前景良好。

Description

一种具有抗肿瘤药物功效的联合用药物 技术领域
本发明涉及一种具有抗肿瘤药物功效的联合用药物。
背景技术
恶性肿瘤是当前人类健康的主要杀手，是严重威胁人类生命的最主要的疾病之一。肿瘤综合治疗主要是外科手术、放射治疗和肿瘤化疗。药物在恶性肿瘤化疗中发挥着重要作用。近年来，抗肿瘤药物的研究与开发工作使肿瘤化疗取得很大进步，上世纪卡铂、紫杉醇等药物的应用，使某些特定肿瘤有了很高的治愈率。但由于抗肿瘤药物存在选择性差，毒副作用大，耐药性等缺陷，目前仍有半数以上肿瘤患者对治疗无反应或耐药而最终导致治疗失败，特别是实体肿瘤的治疗。
反式苯乙烯酸类衍生物具有抗肿瘤作用，其单独使用的效果也不尽如人意。
发明内容
本发明的目的在于提供一种具有抗肿瘤药物功效的联合用药物，以克服单独使用反式苯乙烯酸类衍生物和现有其他抗肿瘤药物分别单独使用抗肿瘤效果不佳的问题。
本发明抗肿瘤药物功效的联合用药物，它含有相同或不同规格单位制剂的用于同时或者分别给药的苯乙烯酸类衍生物和抗肿瘤药物，以及药学上可接受的载体；
所述苯乙烯酸类衍生物结构如式(I)所示：
Figure PCTCN2016097789-appb-000001
其中R1、R2、R3、R4、R5优选氢、羟基、甲氧基。其中R1更优选的为氢，R2为羟基，R3为甲氧基，R4为氢，R5为氢。上述苯乙烯酸衍生物具有顺反结构，其中优选反式结构。
优选地，所述反式苯乙烯酸类衍生物为(E)-3-(2′，3′-二羟基-4′-甲氧苯基)-2-(3″，4″，5″-三甲氧苯基)-2-丙烯酸。
反式苯乙烯酸类衍生物为(E)-3-(2′，3′-二羟基-4′-甲氧苯基)-2-(3″，4″，5″-三甲氧苯基)-2-丙烯酸记载于公告号为101074189B的专利文件中，可以按照该文件中的方法制备。
优选地，所述抗肿瘤药物选自烷化剂、铂类配合物、抗肿瘤抗生素、紫杉醇及其衍生物、索拉非尼。
优选地，所述烷化剂为环磷酰胺；所述铂类配合物为卡铂；所述抗肿瘤抗生素范围阿霉素或盐酸博来霉素；所述紫杉醇衍生物为多西他赛。
优选地，苯乙烯酸类衍生物和抗肿瘤药物的重量比为1:1～640:1。
优选地，所述抗肿瘤药物为卡铂时，苯乙烯酸类衍生物和抗肿瘤药物的重量比为112:1；
所述抗肿瘤药物为紫杉醇时，苯乙烯酸类衍生物和抗肿瘤药物的重量比为1:1～840:11；
所述抗肿瘤药物为索拉非尼时，苯乙烯酸类衍生物和抗肿瘤药物的重量比为5:1；
所述抗肿瘤药物为环磷酰胺时，苯乙烯酸类衍生物和抗肿瘤药物的重量比为65:60；
所述抗肿瘤药物为阿霉素时，苯乙烯酸类衍生物和抗肿瘤药物的重量比为4400:9；
所述抗肿瘤药物为多西他赛时，苯乙烯酸类衍生物和抗肿瘤药物的重量比为640:1；
所述抗肿瘤药物为盐酸博来霉素时，苯乙烯酸类衍生物和抗肿瘤药物的重量比为400：1。
本发明还提供了前述联合用药物在制备治疗肺癌、肝癌、卵巢癌、黑色素瘤、结肠癌、肾癌、膀胱癌的药物中的用途。其中，所述治疗肺癌的药物是治疗小细胞肺癌的药物。
本发明还提供了反式苯乙烯酸类衍生物和抗肿瘤药物在制备抗肿瘤的联合用药物中的用途；
所述反式苯乙烯酸类衍生物结构如式(I)所示：
Figure PCTCN2016097789-appb-000002
其中R1、R2、R3、R4、R5优选氢、羟基、甲氧基。其中R1更优选的为氢，R2为羟基，R3为甲氧基，R4为氢，R5为氢，上述苯乙烯酸衍生物具有顺反结构，其中优选反式结构。
优选地，所述反式苯乙烯酸类衍生物为(E)-3-(2′，3′-二羟基-4′-甲氧苯基)-2-(3″，4″，5″-三甲氧苯基)-2-丙烯酸。
优选地，所述抗肿瘤药物选自烷化剂、铂类配合物、抗肿瘤抗生素、紫杉醇及其衍生物、索拉非尼。
优选地，所述烷化剂为环磷酰胺；所述铂类配合物为卡铂；所述抗肿瘤抗生素范围阿霉素或盐酸博来霉素；所述紫杉醇衍生物为多西他赛。
优选地，苯乙烯酸类衍生物和抗肿瘤药物的重量比为1:1～640:1。
进一步优选地，所述抗肿瘤药物为卡铂时，苯乙烯酸类衍生物和抗肿瘤药物的重量比为112:1；
所述抗肿瘤药物为紫杉醇时，苯乙烯酸类衍生物和抗肿瘤药物的重量比为1:1～840:11；
所述抗肿瘤药物为索拉非尼时，苯乙烯酸类衍生物和抗肿瘤药物的重量比为5:1；
所述抗肿瘤药物为环磷酰胺时，苯乙烯酸类衍生物和抗肿瘤药物的重量比为65:60；
所述抗肿瘤药物为阿霉素时，苯乙烯酸类衍生物和抗肿瘤药物的重量比为4400:9；
所述抗肿瘤药物为多西他赛时，苯乙烯酸类衍生物和抗肿瘤药物的重量比为640:1；
所述抗肿瘤药物为盐酸博来霉素时，苯乙烯酸类衍生物和抗肿瘤药物的重量比为400：1。
其中，所述联合用药物是治疗肺癌、肝癌、卵巢癌、黑色素瘤、结肠癌、 肾癌、膀胱癌的药物。
其中，所述治疗肺癌的药物是治疗小细胞肺癌的药物。
一种治疗肿瘤的方法，步骤如下：同时或者分别给于相同或不同规格单位制剂的苯乙烯酸类衍生物和抗肿瘤药物；
所述苯乙烯酸类衍生物结构如式(I)所示：
Figure PCTCN2016097789-appb-000003
其中R1、R2、R3、R4、R5优选氢、羟基、甲氧基。其中R1更优选的为氢，R2为羟基，R3为甲氧基，R4为氢，R5为氢。上述苯乙烯酸衍生物具有顺反结构，其中优选反式结构。
优选地，所述反式苯乙烯酸类衍生物为(E)-3-(2′，3′-二羟基-4′-甲氧苯基)-2-(3″，4″，5″-三甲氧苯基)-2-丙烯酸。
优选地，所述抗肿瘤药物选自烷化剂、铂类配合物、抗肿瘤抗生素、紫杉醇及其衍生物、索拉非尼。
优选地，所述烷化剂为环磷酰胺；所述铂类配合物为卡铂；所述抗肿瘤抗生素范围阿霉素或盐酸博来霉素；所述紫杉醇衍生物为多西他赛。
优选地，苯乙烯酸类衍生物和抗肿瘤药物的重量比为1:1～640:1。
进一步优选地，所述抗肿瘤药物为卡铂时，苯乙烯酸类衍生物和抗肿瘤药物的重量比为112:1；
所述抗肿瘤药物为紫杉醇时，苯乙烯酸类衍生物和抗肿瘤药物的重量比为1:1～840:11；
所述抗肿瘤药物为索拉非尼时，苯乙烯酸类衍生物和抗肿瘤药物的重量比为5:1；
所述抗肿瘤药物为环磷酰胺时，苯乙烯酸类衍生物和抗肿瘤药物的重量比为65:60；
所述抗肿瘤药物为阿霉素时，苯乙烯酸类衍生物和抗肿瘤药物的重量比为4400:9；
所述抗肿瘤药物为多西他赛时，苯乙烯酸类衍生物和抗肿瘤药物的重量比为640:1；
所述抗肿瘤药物为盐酸博来霉素时，苯乙烯酸类衍生物和抗肿瘤药物的重量比为400：1。
所述的给药方法可以通过静脉、皮下、肌内途径经胃肠外给药，为了提高有效性，优选通过静脉内和皮下给药途径给药。
本发明还提供了前述方法用于治疗肺癌、肝癌、卵巢癌、黑色素瘤、结肠癌、肾癌、膀胱癌的用途。其中，所述治疗肺癌的药物是治疗小细胞肺癌的药物。
本发明反式苯乙烯酸类衍生物与抗肿瘤药物的联合使用可以发挥协同增效作用，与部分抗肿瘤药物联合使用还可以发挥降毒的作用，将反式苯乙烯酸类衍生物与抗肿瘤药物制成联合用药物的疗效优良，毒性小，临床应用前景良好。
下面通过具体实施方式对本发明做进一步详细说明，但是并不是对本发明的限制，根据本发明的上述内容，按照本领域的普通技术知识和惯用手段，在不脱离本发明上述基本技术思想前提下，还可以做出其它多种形式的修改、替换或变更。
具体实施方式
计算公式：
每周2次用数显电子卡尺测量肿瘤长径a(mm)，及相垂直的肿瘤短径b(mm)，肿瘤体积计算公式为：TV＝ab2/2，相对肿瘤体积计算公式为：RTV＝Vt/Vo，Vo为分笼时(即d1)测量所得肿瘤体积，Vt为每一次测量时的肿瘤体积。
结果判定根据以下公式：
Figure PCTCN2016097789-appb-000004
判断标准(金氏公式计算Q值)：
Figure PCTCN2016097789-appb-000005
Ea+b为合并用药的抑瘤率，Ea和Eb分别为A药和B药的抑瘤率。如Q值0.85～1.15为相加(+)，>1.15为增强(++)。
实施例1DX1002联合CBP对人体肺癌95D裸鼠移植瘤的疗效
1、实验材料
试药：卡铂注射液(波贝，CBP，批号：WB1J1411012，规格：10ml:50mg)，齐鲁制药有限公司生产，临用前用灭菌生理盐水稀释至所需浓度。
DX1002：(E)-3-(2′，3′-二羟基-4′-甲氧苯基)-2-(3″，4″，5″-三甲氧苯基)-2-丙烯酸。制备方法：将3，4，5-三甲氧基苯乙酸140g(610mmol)，2，3-二羟基-4-甲氧基苯甲醛724mmol，醋酸酐200ml和NEt3 100ml(717mmol)加入到1000ml的圆底烧瓶中，在外温150℃下搅拌回流2.5小时，减压蒸尽溶剂，得油状物，加入1N盐酸约300ml，室温搅拌过夜，得黄色固体，用乙醇400ml重结晶得淡黄色固体(DX1002纯度大于98％)。
动物：BALB/C裸鼠(SPF级，体重：19-21g，雄性)。
动物数：8只/组。
瘤株：人体肺癌95D细胞株由四川大学华西医学中心提供。
2、试验方法
取生长良好的肺癌95D瘤块，无菌条件下切割成3mm大小的均匀小块，用套管针每只小鼠右腋皮下接种一块，设以下4组，给药组每组8只，Control组大于8只，分别为：
组1：DX1002 400mg/kg/天(ig×14天)
组2：CBP 10mg/kg/天(ip×10天，隔天注射一次)
组3：DX1002+CBP
组4：Control
接种后13天见瘤块体积平均约100mm3，根据肿瘤大小重新分组，淘汰肿瘤过大和过小的动物，每组肿瘤平均体积基本一致，开始按以上方案给药，连续经口灌胃14天，给药体积为0.5ml/20g体重，CBP腹腔给药(ip)，隔天注射一次，共10天。自接种第14天起每周2次用数显电子卡尺测量肿瘤长径a(mm)，及相垂直的肿瘤短径b(mm)，肿瘤体积计算公式为：TV＝ab2/2，相对肿瘤体积计算公式为：RTV＝Vt/Vo，Vo为分笼时(即d1)测量所得肿瘤体积，Vt为每一次测量时的肿瘤体积。接种后29天(d17)处死动物，称体重。
3、实验结果
试验结果如表1：
表1 DX1002合并CBP对移植于裸鼠的人体肺癌95D的抑瘤作用
Figure PCTCN2016097789-appb-000006
Figure PCTCN2016097789-appb-000007
与Control组比较：*P<0.05，**P<0.01。
由表1可以看出，DX1002与CBP联合用药治疗人体肺癌95D时，抑瘤率为86.85％，而DX1002与CBP单独使用的抑瘤率仅41.85％和56.65％，经金氏方程的Q值计算，本发明DX1002与CBP(二者的重量比为112:1)联合使用的Q值为1.16，大于1.15的协同限量值；另外，动物体重无明显降低，也未见明显毒性相加反应。
结果说明，治疗小细胞肺癌，特别是高转移性的小细胞肺癌(95D)时，本发明DX1002与CBP联合使用可以发挥协同增效的作用。
实施例2DX1002联合PAC对人体肺癌A549裸鼠移植瘤的疗效
1、实验材料
试药：紫杉醇注射液(PAC，批号：15120024，规格：30mg/5ml)，四川太极制药有限公司生产，临用前用灭菌生理盐水配制需浓度。
DX1002的制备方法同实施例1。
动物：BALB/C裸鼠(SPF级，体重：19-21g，雄性)。
动物数：8只/组。
瘤株：人体肺癌A549细胞株，由四川大学华西医学中心提供。
2、试验方法
取生长良好的肺癌A549瘤块，无菌条件下切割成3mm大小的均匀小块，用套管针每只小鼠右腋皮下接种一块，设以下4组，给药组每组8只，Control组大于8只，分别为：
组1：DX1002 200mg/kg/天(ig×21d)
组2：PAC 5mg/kg/天(ip×21d，隔天一次)
组3：DX1002 200mg/kg(ig×21d)+PAC 5mg/kg(ip×21d，qod)
组4：Control
接种后14天见瘤块体积平均约100mm3，根据肿瘤大小重新分组，淘汰肿瘤过大和过小的动物，每组肿瘤平均体积基本一致，开始按以上方案给药，连续经口灌胃21天，给药体积为0.5ml/20g体重。紫杉醇注射液腹腔注射，给药容积0.2ml/20g，隔天一次，共21天。自接种第21天起每周2次用数显电子卡尺测量肿瘤长径a(mm)，及相垂直的肿瘤短径b(mm)，肿瘤体积计算公式为：TV＝ab2/2，相对肿瘤体积计算公式为：RTV＝Vt/Vo，Vo为分笼时(即d1)测量所得肿瘤体积，Vt为每一次测量时的肿瘤体积。接种后29天处死动物。
3、实验结果
结果见表2。由表2可以看出，DX1002与紫杉醇联合用药治疗人肺癌A549时，抑瘤率为94.83％，而DX1002与紫杉醇单独使用的抑瘤率仅41.85％和56.65％，经金氏方程的Q值计算，本发明DX1002与紫杉醇联合使用的Q值为1.17，大于1.15的协同限量值；另外，动物体重无明显降低，也未见明显毒性相加反应。
表2 DX1002联合紫杉醇对A549人肺癌裸鼠异种移植肿瘤生长的抑制作用(X异种移植
Figure PCTCN2016097789-appb-000008
与Control组比较：*P<0.05，**P<0.01。
由表2可以看出，DX1002与紫杉醇联合用药治疗人肺癌A549时，抑瘤率为94.83％，而DX1002与紫杉醇单独使用的抑瘤率仅61.08％和51.96％，经金氏方程的Q值计算，本发明DX1002与紫杉醇(二者的重量比为840:11)联合使用的Q值为1.17，大于1.15的协同限量值；另外，动物体重无明显降低，也未见明显毒性相加反应。
实验结果说明，治疗肺癌时，本发明DX1002与紫杉醇联合使用可以发挥协同增效的作用。
实施例3DX1002联合紫杉醇对人A2780裸鼠移植肿瘤的疗效
1、实验材料
试药：紫杉醇注射液(PAC，批号：15120024，规格：30mg/5ml)，四川太极制药有限公司生产，临用前用灭菌生理盐水配制需浓度。
DX1002的制备方法同实施例1。
动物：BALB/C裸鼠(SPF级，体重：19-21g，雄性)。
动物数：8只/组。
瘤株：人卵巢癌A2780细胞株，由四川大学华西医学中心提供。
2、试验方法
人卵巢癌A2780裸小鼠移植瘤，由人卵巢癌A2780细胞株接种于裸小鼠腋窝皮下而建立。细胞接种量为1×106，接种形成移植瘤后再在裸小鼠体内传3代后使用。取生长旺盛期的瘤组织剪切成1.5mm3左右，在无菌条件下匀浆后制备成细胞悬液，以0.1ml接种于裸小鼠右侧腋窝皮下。裸小鼠移植瘤用游标卡尺测量移植瘤直径，待肿瘤生长至100mm3后将动物随机分组，每组6只。使用测量瘤径的方法，动态观察被试物抗肿瘤的效应。
DX1002以10mg/kg，用水溶解后，连续经口灌胃，每隔一天给药一次，给药三周；紫杉醇以10mg/kg静脉注射给药，每隔一天给药一次，给药三周。肿瘤直径的测量次数为每三天测一次。给药体积为0.1ml/20g。阴性对照组静脉注射等量生理盐水溶液。
3、实验结果
结果见表3。
表3 DX1002联合紫杉醇对人卵巢癌A2780裸鼠异种移植肿瘤生长抑制作用(X异种移植
Figure PCTCN2016097789-appb-000009
与Control组比较：*P<0.05，**P<0.01。
由表3可以看出，DX1002与紫杉醇联合用药治疗人卵巢癌A2780时，抑瘤率为92.20％，而DX1002与紫杉醇单独使用的抑瘤率仅55.51％和54.53％，经金氏方程的Q值计算，本发明DX1002与紫杉醇(二者的重量比为1:1) 联合使用的Q值为1.16，大于1.15的协同限量值；另外，与二者单独使用相比，毒性也明显下降。
实验结果说明，治疗卵巢癌时，本发明DX1002与紫杉醇联合使用可以发挥协同增效的作用，同时还有降低毒性的作用。
实施例4DX1002联合索拉非尼对人肝癌huh-7裸鼠肿瘤生长的疗效
1、实验材料
试药：索拉非尼(批号：BXGECL1，规格：200mg/片)，德国拜耳医药保健
有限公司生产，临用前用灭菌生理盐水配制需浓度。
DX1002的制备方法同实施例1。
动物：BALB/C裸鼠(SPF级，体重：19-21g，雄性)。
动物数：8只/组。
瘤株：人卵巢癌A2780细胞株，由四川大学华西医学中心提供。
2、试验方法
人肝癌huh-7裸小鼠移植瘤，由人肝癌huh-7细胞株接种于裸小鼠腋窝皮下而建立。细胞接种量为1胞株接6，接种形成移植瘤后再在裸小鼠体内传3代后使用。取生长旺盛期的瘤组织剪切成1.5mm3左右，在无菌条件下匀浆后制备成细胞悬液，以0.1ml接种于裸小鼠右侧腋窝皮下。裸小鼠移植瘤用游标卡尺测量移植瘤直径，待肿瘤生长至100mm3后将动物随机分组，每组6只。使用测量瘤径的方法，动态观察被试物抗肿瘤的效应。DX1002以100mg/kg，口服给药，每隔一天给药一次，给药三周；索拉非尼20mg/kg口服给药，每隔一天给药一次，给药三周。肿瘤直径的测量次数为每三天测一次。阴性对照组口服等量生理盐水溶液。
3、实验结果
结果见表4：
表4 DX1002联合索拉非尼对人肝癌huh-7裸鼠异种移植肿瘤生长抑制作用(X异种移植
Figure PCTCN2016097789-appb-000010
与Control组比较：*P<0.05，**P<0.01。
由表4可以看出，DX1002与索拉非尼联合用药治疗人肝癌huh-7时，抑瘤率为92.03％，而DX1002与索拉非尼单独使用的抑瘤率仅50.63％和58.81％，经金氏方程的Q值计算，本发明DX1002与索拉非尼(二者的重量比为5:1)联合使用的Q值为1.16，大于1.15的协同限量值；另外，与二者单独使用相比，毒性也明显下降。
实验结果说明，治疗肝癌时，本发明DX1002与索拉非尼联合使用可以发挥协同增效的作用，同时还有降低毒性的作用。
实施例5DX1002单用及与CTX联合应用对小鼠B16生长的疗效
1、实验材料
试药：环磷酰胺(CTX，批号：15122125，规格：0.2g)，江苏盛迪医药有限公司生产，临用前用灭菌生理盐水配制需浓度。
DX1002的制备方法同实施例1。
动物：BALB/C裸鼠(SPF级，体重：19-21g，雄性)。
动物数：8只/组。
瘤株：黑色素瘤B16细胞株，由四川大学华西医学中心提供。
2、试验方法
小鼠黑色素瘤B16模型，选用C57BL/6小鼠，雄性，18-22g。实验时，取生长良好的肿瘤组织，剪碎，研磨，过滤，用无菌生理盐水按1：3比例稀释后制成肿瘤细胞悬液，每只小鼠腋背部接种0.2ml瘤液。接种后次日动物随机分组，称重，并开始给药。环磷酰胺注射液给药体积为每10g小鼠腹腔注射。环磷酰胺单用及联合用药均于接种次日注射环磷酰胺(CTX)1次。DX1002口服给药每日1次，连续给药13天。DX1002及环磷酰胺联合用药组先于左侧腹腔注射DX1002，再于右侧腹腔注射环磷酰胺。
实验动物共分4组，阴性对照组、环磷酰胺60mg/kg单用给药组、DX10025mg/kg组，环磷酰胺60mg/kg与DX1002 5mg/kg联合用药组。每组10只动物。DX1002停药后次日处死动物，称体重，剥瘤并称瘤重。根据肿瘤重量计算肿瘤抑制率(％)。体重及瘤重用均值±标准差
Figure PCTCN2016097789-appb-000011
表示，并进行各给药组与阴性对照组之间，联合用药组与环磷酰胺单用组之间的t检验。
3、实验结果
结果如表5：
表5.DX1002单用及与CTX联合用药对小鼠黑色素瘤B16的疗效
Figure PCTCN2016097789-appb-000012
与Control组比较：*P<0.05，**P<0.01。
由表5可以看出，DX1002与环磷酰胺联合用药治疗黑色素瘤B16，抑瘤率为92.03％，而DX1002与环磷酰胺单独使用的抑瘤率仅57.8％和44.04％，经金氏方程的Q值计算，本发明DX1002与环磷酰胺(二者的重量比为65:60)联合使用的Q值为1.16，大于1.15的协同限量值；另外，与二者单独使用相比，毒性也明显下降。
实验结果说明，治疗黑色素瘤时，本发明DX1002与环磷酰胺联合使用可以发挥协同增效的作用，同时还有降低毒性的作用。
实施例6DX1002联合阿霉素对小鼠肝癌H22生长的影响
1、实验材料
试药：阿霉素(批号：2160102，规格：10mg)，山西普德药业股份有限公司生产，临用前用灭菌生理盐水配制需浓度。
DX1002的制备方法同实施例1。
动物：BALB/C裸鼠(SPF级，体重：19-21g，雄性)。
动物数：8只/组。
瘤株：肝癌H22细胞株，由四川大学华西医学中心提供。
2、试验方法
小鼠肝癌H22模型，选用昆明种小鼠，雄性，18-22g。实验时，吸取小鼠腹水，用无菌生理盐水按1:3比例稀释后制成肿瘤细胞悬液，每只小鼠腋背部接种0.2ml瘤液。接种后次日动物随机分组，称重，并开始给药。
实验动物共分4组，阴性对照组、阿霉素3mg/kg单用注射给药组、DX1002 800mg/kg口服组、阿霉素注射3mg/kg与DX1002 800mg/kg口服联合用药组、最后一次给药后次日处死动物，称体重，剥瘤并称瘤重。根据肿瘤重量计算肿瘤抑制率(％)。体重及瘤重用均值±标准差
Figure PCTCN2016097789-appb-000013
表示，并进行各给药组与阴性对照组之间的t检验。
3、实验结果
实验结果见表6。
表6 DX1002单用及与阿霉素联合用药对小鼠肝癌H22的生长抑制作用
Figure PCTCN2016097789-appb-000014
与Control组比较：*P<0.05，**P<0.01。
由表6可以看出，DX1002与阿霉素联合用药治疗肝癌H22，抑瘤率为94.82％，而DX1002与阿霉素单独使用的抑瘤率仅57.67％和57.02％，经金氏方程的Q值计算，本发明DX1002与阿霉素(二者的重量比为4400:9)联合使用的Q值为1.16，大于1.15的协同限量值；另外，动物体重无明显降低，也未见明显毒性相加反应。
实验结果说明，治疗肝癌时，本发明DX1002与阿霉素联合使用可以发挥协同增效的作用。
实施例7DX1002与TXT联合用药对小鼠Lewis肺癌的生长的疗效
1、实验材料
试药：多西他赛注射液(TXT，批号：16022115，规格：20mg)，江苏恒瑞医药股份有限公司公司生产，临用前用灭菌生理盐水配制需浓度。
DX1002的制备方法同实施例1。
动物：BALB/C裸鼠(SPF级，体重：19-21g，雄性)。
动物数：8只/组。
瘤株：Lewis肺癌细胞株，由四川大学华西医学中心提供。
2、试验方法
小鼠Lewis肺癌模型，选用C57BL/6小鼠，雄性，18-20g。实验时，取生长良好的肿瘤组织，剪碎，研磨，过滤，用无菌生理盐水按1：3比例稀释后制成肿瘤细胞悬液，每只小鼠腋背部接种0.2ml瘤液。接种后次日动物随机分组，称重，并开始给药。溶剂对照组按每10g小鼠腹腔注射0.2ml生理盐水给药，每日1次。多西他赛注射液(TXT)给药体积为每10g小鼠腹腔注射0.2ml，每日1次，多西他赛单用及联合用药组均连续给多西他赛5天， 第6天起停止给药。DX1002口服给药，每日1次，连续给药10天。
实验动物共分4组，阴性对照组、多西他赛5mg/kg单用给药组、DX10021600mg/kg组，多西他赛5mg/kg与DX1002 1600mg/kg联合用药组，每组10只动物。DX1002停药后次日处死动物，称体重，剥瘤并称瘤重。根据肿瘤重量计算肿瘤抑制率(％)。体重及瘤重用均值±标准差
Figure PCTCN2016097789-appb-000015
表示，并进行各给药组与阴性对照组之间，联合用药组与多西他赛单用组之间的t检验。
3、实验结果
试验结果见表7：由表7可以看出，DX1002与多西他赛联合用药治疗Lewis肺癌，抑瘤率为89.61％，而DX1002与多西他赛单独使用的抑瘤率仅50.28％和53.65％，经金氏方程的Q值计算，本发明DX1002与多西他赛(二者的重量比为640:1)联合使用的Q值为1.16，大于1.15的协同限量值；另外，动物体重无明显降低，也未见明显毒性相加反应。
表7 DX1002单用及联合多西他赛对小鼠Lewis肺癌的生长的抑制作用
Figure PCTCN2016097789-appb-000016
与Control组比较：*P<0.05，**P<0.01。
由表7可以看出，DX1002与多西他赛联合用药治疗Lewis肺癌，抑瘤率为89.61％，而DX1002与多西他赛单独使用的抑瘤率仅50.28％和53.65％，经金氏方程的Q值计算，本发明DX1002与多西他赛(二者的重量比为640:1)联合使用的Q值为1.16，大于1.15的协同限量值；另外，动物体重无明显降低，也未见明显毒性相加反应。
实验结果说明，治疗肺癌时，本发明DX1002与多西他赛联合使用可以发挥协同增效的作用。
实施例8DX1002联合BON对人体结肠癌HT-29的疗效
1、实验材料
试药：盐酸博来霉素(BON，批号：151102，规格：1.5万单位)，公司生产，临用前用灭菌生理盐水配制需浓度。
DX1002的制备方法同实施例1。
动物：BALB/C裸鼠(SPF级，体重：19-21g，雄性)。
动物数：8只/组。
瘤株：人体结肠癌HT-29，由四川大学华西医学中心提供。
2、试验方法
取生长良好的结肠癌HT-29瘤块，无菌条件下切割成3mm大小的均匀小块，用套管针每只小鼠右腋皮下接种一块，设以下4组，给药组每组8只，Control组大于8只，分别为：
1)DX1002 200mg/kg(ig，qd×14)
2)BON 1mg/kg(ip，qod×14)
3)DX1002 200mg/kg(ig，qd×14)+CBP 1mg/kg(ip，qod×14)
4)Control
接种后14天见瘤块体积平均约100mm3，根据肿瘤大小重新分组，淘汰肿瘤过大和过小的动物，每组肿瘤平均体积基本一致，开始按以上方案给药，连续经口灌胃14天，给药体积为0.5ml/20g体重。BON腹腔注射，0.2ml/20g体重，隔日一次，连续14天。自接种第14天起每周2次用数显电子卡尺测量肿瘤长径和相垂直的肿瘤短径。接种后29天处死动物。
3、实验结果
试验结果见表8：
表8 DX1002合并BON对移植于裸鼠的人体结肠癌HT-29的抑瘤作用
Figure PCTCN2016097789-appb-000017
Figure PCTCN2016097789-appb-000018
与Control组比较：*P<0.05，**P<0.01。
由表8可以看出，DX1002与盐酸博来霉素联合用药治疗结肠癌HT-29，抑瘤率为86.29％，而DX1002与盐酸博来霉素单独使用的抑瘤率仅48.87％和5.31％，经金氏方程的Q值计算，本发明DX1002与盐酸博来霉素(二者的重量比为400：1)联合使用的Q值为1.16，大于1.15的协同限量值；另外，动物体重无明显降低，也未见明显毒性相加反应。
实验结果说明，治疗结肠癌时，本发明DX1002与盐酸博来霉素联合使用可以发挥协同增效的作用。
综上，本发明反式苯乙烯酸类衍生物与抗肿瘤药物的联合使用可以发挥协同增效作用，与部分抗肿瘤药物联合使用还可以发挥降毒的作用，将反式苯乙烯酸类衍生物与抗肿瘤药物制成联合用药物的疗效优良，毒性小，临床应用前景良好。

Claims (24)

  1. 一种具有抗肿瘤药物功效的联合用药物，其特征在于：它含有相同或不同规格单位制剂的用于同时或者分别给药的苯乙烯酸类衍生物和抗肿瘤药物，以及药学上可接受的载体；
    所述苯乙烯酸类衍生物结构如式(I)所示：
    Figure PCTCN2016097789-appb-100001
    其中R1、R2、R3、R4、R5优选氢、羟基、甲氧基，其中R1更优选的为氢，R2为羟基，R3为甲氧基，R4为氢，R5为氢，上述苯乙烯酸衍生物具有顺反结构，其中优选反式结构。
  2. 根据权利要求1所述的联合用药物，其特征在于：所述反式苯乙烯酸类衍生物为(E)-3-(2′，3′-二羟基-4′-甲氧苯基)-2-(3″，4″，5″-三甲氧苯基)-2-丙烯酸。
  3. 根据权利要求1或2所述的联合用药物，其特征在于：所述抗肿瘤药物选自烷化剂、铂类配合物、抗肿瘤抗生素、紫杉醇及其衍生物、索拉非尼。
  4. 根据权利要求3所述的联合用药物，其特征在于：所述烷化剂为环磷酰胺；所述铂类配合物为卡铂；所述抗肿瘤抗生素范围阿霉素或盐酸博来霉素；所述紫杉醇衍生物为多西他赛。
  5. 根据权利要求1～4任意一项所述的联合用药物，其特征在于：苯乙烯酸类衍生物和抗肿瘤药物的重量比为1:1～640:1。
  6. 根据权利要求5所述的联合用药物，其特征在于：
    所述抗肿瘤药物为卡铂时，苯乙烯酸类衍生物和抗肿瘤药物的重量比为112:1；
    所述抗肿瘤药物为紫杉醇时，苯乙烯酸类衍生物和抗肿瘤药物的重量比为1:1～840:11；
    所述抗肿瘤药物为索拉非尼时，苯乙烯酸类衍生物和抗肿瘤药物的重量 比为5:1；
    所述抗肿瘤药物为环磷酰胺时，苯乙烯酸类衍生物和抗肿瘤药物的重量比为65:60；
    所述抗肿瘤药物为阿霉素时，苯乙烯酸类衍生物和抗肿瘤药物的重量比为4400:9；
    所述抗肿瘤药物为多西他赛时，苯乙烯酸类衍生物和抗肿瘤药物的重量比为640:1；
    所述抗肿瘤药物为盐酸博来霉素时，苯乙烯酸类衍生物和抗肿瘤药物的重量比为400：1。
  7. 权利要求1～6任意一项所述的联合用药物在制备治疗肺癌、肝癌、卵巢癌、黑色素瘤、结肠癌、肾癌、膀胱癌的药物中的用途。
  8. 根据权利要求6所述的用途，其特征在于：所述治疗肺癌的药物是治疗小细胞肺癌的药物。
  9. 反式苯乙烯酸类衍生物和抗肿瘤药物在制备抗肿瘤的联合用药物中的用途；
    所述反式苯乙烯酸类衍生物结构如式(I)所示：
    Figure PCTCN2016097789-appb-100002
    其中R1、R2、R3、R4、R5优选氢、羟基、甲氧基，其中R1更优选的为氢，R2为羟基，R3为甲氧基，R4为氢，R5为氢，上述苯乙烯酸衍生物具有顺反结构，其中优选反式结构。
  10. 根据权利要求9所述的用途，其特征在于：所述反式苯乙烯酸类衍生物为(E)-3-(2′，3′-二羟基-4′-甲氧苯基)-2-(3″，4″，5″-三甲氧苯基)-2-丙烯酸。
  11. 根据权利要求9或10所述的用途，其特征在于：所述抗肿瘤药物选自烷化剂、铂类配合物、抗肿瘤抗生素、紫杉醇及其衍生物、索拉非尼。
  12. 根据权利要求11所述的用途，其特征在于：所述烷化剂为环磷酰胺；所述铂类配合物为卡铂；所述抗肿瘤抗生素范围阿霉素或盐酸博来霉素；所述紫杉醇衍生物为多西他赛。
  13. 根据权利要求9～12任意一项所述的用途，其特征在于：苯乙烯酸类衍生物和抗肿瘤药物的重量比为1:1～640:1。
  14. 根据权利要求13所述的用途，其特征在于：
    所述抗肿瘤药物为卡铂时，苯乙烯酸类衍生物和抗肿瘤药物的重量比为112:1；
    所述抗肿瘤药物为紫杉醇时，苯乙烯酸类衍生物和抗肿瘤药物的重量比为1:1～840:11；
    所述抗肿瘤药物为索拉非尼时，苯乙烯酸类衍生物和抗肿瘤药物的重量比为5:1；
    所述抗肿瘤药物为环磷酰胺时，苯乙烯酸类衍生物和抗肿瘤药物的重量比为65:60；
    所述抗肿瘤药物为阿霉素时，苯乙烯酸类衍生物和抗肿瘤药物的重量比为4400:9；
    所述抗肿瘤药物为多西他赛时，苯乙烯酸类衍生物和抗肿瘤药物的重量比为640:1；
    所述抗肿瘤药物为盐酸博来霉素时，苯乙烯酸类衍生物和抗肿瘤药物的重量比为400：1。
  15. 权利要求9～14任意一项所述的用途，其特征在于：所述联合用药物是治疗肺癌、肝癌、卵巢癌、黑色素瘤、结肠癌、肾癌、膀胱癌的药物。
  16. 根据权利要求15所述的用途，其特征在于：所述治疗肺癌的药物是治疗小细胞肺癌的药物。
  17. 一种治疗肿瘤的方法，其特征在于：步骤如下：同时或者分别给于相同或不同规格单位制剂的苯乙烯酸类衍生物和抗肿瘤药物；
    所述苯乙烯酸类衍生物结构如式(I)所示：
    Figure PCTCN2016097789-appb-100003
    其中R1、R2、R3、R4、R5优选氢、羟基、甲氧基，其中R1更优选的为氢，R2为羟基，R3为甲氧基，R4为氢，R5为氢，上述苯乙烯酸衍生物具有顺反结构，其中优选反式结构。
  18. 根据权利要求17所述的方法，其特征在于：所述反式苯乙烯酸类衍生物为(E)-3-(2′，3′-二羟基-4′-甲氧苯基)-2-(3″，4″，5″-三甲氧苯基)-2-丙烯酸。
  19. 根据权利要求17或18所述的方法，其特征在于：所述抗肿瘤药物选自烷化剂、铂类配合物、抗肿瘤抗生素、紫杉醇及其衍生物、索拉非尼。
  20. 根据权利要求19所述的方法，其特征在于：所述烷化剂为环磷酰胺；所述铂类配合物为卡铂；所述抗肿瘤抗生素范围阿霉素或盐酸博来霉素；所述紫杉醇衍生物为多西他赛。
  21. 根据权利要求17～21任意一项所述的方法，其特征在于：苯乙烯酸类衍生物和抗肿瘤药物的重量比为1:1～640:1。
  22. 根据权利要求21所述的方法，其特征在于：
    所述抗肿瘤药物为卡铂时，苯乙烯酸类衍生物和抗肿瘤药物的重量比为112:1；
    所述抗肿瘤药物为紫杉醇时，苯乙烯酸类衍生物和抗肿瘤药物的重量比为1:1～840:11；
    所述抗肿瘤药物为索拉非尼时，苯乙烯酸类衍生物和抗肿瘤药物的重量比为5:1；
    所述抗肿瘤药物为环磷酰胺时，苯乙烯酸类衍生物和抗肿瘤药物的重量比为65:60；
    所述抗肿瘤药物为阿霉素时，苯乙烯酸类衍生物和抗肿瘤药物的重量比为4400:9；
    所述抗肿瘤药物为多西他赛时，苯乙烯酸类衍生物和抗肿瘤药物的重量 比为640:1；
    所述抗肿瘤药物为盐酸博来霉素时，苯乙烯酸类衍生物和抗肿瘤药物的重量比为400：1。
  23. 权利要求17～22任意一项所述的方法用于治疗肺癌、肝癌、卵巢癌、黑色素瘤、结肠癌、肾癌、膀胱癌的用途。
  24. 根据权利要求23所述的用途，其特征在于：所述治疗肺癌的药物是治疗小细胞肺癌的药物。
PCT/CN2016/097789 2016-08-26 2016-09-01 一种具有抗肿瘤药物功效的联合用药物 WO2018035884A1 (zh)

Priority Applications (4)

Application Number Priority Date Filing Date Title
EP16913905.2A EP3378473A4 (en) 2016-08-26 2016-09-01 MEDICINE COMBINATION WITH ANTITUMOR EFFECT
US15/781,987 US10675259B2 (en) 2016-08-26 2016-09-01 Drug combination with antitumor effects
JP2018544938A JP6656397B2 (ja) 2016-08-26 2016-09-01 抗腫瘍薬物の効果を有する併用薬物
US16/858,259 US11033519B2 (en) 2016-08-26 2020-04-24 Drug combination with antitumor effects

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
CN201610739597.0 2016-08-26
CN201610739597.0A CN107773556B (zh) 2016-08-26 2016-08-26 一种具有抗肿瘤药物功效的联合用药物

Related Child Applications (2)

Application Number Title Priority Date Filing Date
US15/781,987 A-371-Of-International US10675259B2 (en) 2016-08-26 2016-09-01 Drug combination with antitumor effects
US16/858,259 Division US11033519B2 (en) 2016-08-26 2020-04-24 Drug combination with antitumor effects

Publications (1)

Publication Number Publication Date
WO2018035884A1 true WO2018035884A1 (zh) 2018-03-01

Family

ID=61245348

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/CN2016/097789 WO2018035884A1 (zh) 2016-08-26 2016-09-01 一种具有抗肿瘤药物功效的联合用药物

Country Status (5)

Country Link
US (2) US10675259B2 (zh)
EP (1) EP3378473A4 (zh)
JP (1) JP6656397B2 (zh)
CN (1) CN107773556B (zh)
WO (1) WO2018035884A1 (zh)

Families Citing this family (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN110613704B (zh) * 2018-10-17 2023-06-13 广东华清园生物科技有限公司 右旋龙脑作为阿霉素或其衍生物增敏剂在制备抗肺癌药物中的应用
CN113230242A (zh) * 2021-06-18 2021-08-10 广西壮族自治区中医药研究院 肉桂酸在制备治疗环磷酰胺致骨髓抑制的药物中的应用
CN113520995B (zh) * 2021-08-16 2023-03-10 海南鑫开源医药科技有限公司 一种离子敏感型眼用原位凝胶、其制备方法及应用
CN116492323B (zh) * 2022-01-19 2024-02-02 广州安好医药科技有限公司 一种苯乙烯酸类化合物的新用途
CN115444841B (zh) * 2022-09-21 2023-05-12 广州安好医药科技有限公司 二苯乙烯类化合物在制备抗肿瘤药物中的用途
US11977085B1 (en) 2023-09-05 2024-05-07 Elan Ehrlich Date rape drug detection device and method of using same

Family Cites Families (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
YU33730B (en) * 1967-04-18 1978-02-28 Farmaceutici Italia Process for preparing a novel antibiotic substance and salts thereof
CH588505A5 (zh) * 1972-06-08 1977-06-15 Research Corp
WO2002056692A1 (en) * 2000-12-22 2002-07-25 Bristol-Myers Squibb Company Methods for modulating tumor growth and metastasis
CN101074189B (zh) * 2006-05-15 2011-04-13 雍智全 苯乙烯酸衍生物及其在制备血管靶向剂药物中的应用
WO2009059448A1 (fr) * 2007-11-05 2009-05-14 Zhiquan Yong Dérivé styrène-acide et utilisation dans la fabrication de médicaments de type agent ciblé sur les vaisseaux sanguins

Non-Patent Citations (3)

* Cited by examiner, † Cited by third party
Title
BORREL C. ET AL.: "New anti tubulin derivatives in the combretastatin A4 series: synthesis and biological evaluation", BIOORGANIC & MEDICINAL CHEMISTRY, vol. 13, no. 11, 9 April 2005 (2005-04-09), pages 3853 - 3864, XP029246533, ISSN: 0968-0896 *
SANGHEE KIM, ET AL.: "Comparative Molecular Field Analysis Study of Stilbene Derivatives Active against A549 Lung Carcinoma", CHEM. PHARM. BULL., vol. 51, no. 5, 31 December 2003 (2003-12-31), pages 516 - 521, XP002268021, ISSN: 0009-2363 *
See also references of EP3378473A4 *

Also Published As

Publication number Publication date
US11033519B2 (en) 2021-06-15
US10675259B2 (en) 2020-06-09
EP3378473A1 (en) 2018-09-26
US20180353449A1 (en) 2018-12-13
EP3378473A4 (en) 2019-07-31
US20200246290A1 (en) 2020-08-06
CN107773556A (zh) 2018-03-09
CN107773556B (zh) 2020-08-18
JP6656397B2 (ja) 2020-03-04
JP2019524637A (ja) 2019-09-05

Similar Documents

Publication Publication Date Title
WO2018035884A1 (zh) 一种具有抗肿瘤药物功效的联合用药物
Chen et al. Expanding the use of arsenic trioxide: leukemias and beyond
KR101848131B1 (ko) 저용량 이리노테칸염산염 수화물을 함유하는 항종양제
CN118059108B (zh) 一种药物组合物及其在制备抗肿瘤药物中的应用
EP2808016B1 (en) Use of icaritin for the preparation of a composition for treating cancer
WO2022028615A1 (zh) 治疗肿瘤的方法
CN113082210B (zh) 一种肿瘤化疗药物组合物
JP7311177B2 (ja) Ａ－ＮＯＲ－５αアンドロスタン薬物と抗がん薬物との併用
EP2902028A1 (en) Drug composition for treating tumors and application thereof
CN111821303B (zh) 沃替西汀及其盐在制备抗肿瘤药物中的应用
CN113786491A (zh) 一种含汉防己甲素、二氢槲皮素或槲皮素的抗肿瘤联用制剂
CN108853114B (zh) 硝呋莫司在制备治疗癌症衍生的脑转移瘤的药物中的应用
CN114288303B (zh) 包含哌乙酰嗪的抗肿瘤药物组合物及其应用
CN115089576B (zh) 木犀草素和菊苣酸联合在制备乳腺癌治疗药物中的应用
CN110448555B (zh) 多环化合物在制备抗肿瘤药物中的应用及抗肿瘤药物
RU2784809C2 (ru) Комбинированный продукт, содержащий дициклоплатин, и способ его получения и применения
CN113993515B (zh) 使用藏红花酸治疗实体肿瘤的方法
BR112020009596A2 (pt) combinações de moduladores duplos de irs/stat3 e anticorpos anti pd-1/pd-l1 para tratar câncer
JP2007535521A (ja) 抗腫瘍剤耐性を処置するのに有用なインドール誘導体
WO2021196335A1 (zh) Pyr3的用途
CN118615268A (zh) 芬戈莫得在制备癌症治疗药物中的应用
CN117860747A (zh) 新白叶藤碱衍生物及其联合黄芩素在制备治疗卵巢癌药物中的应用
CN113599370A (zh) 8-oh-dpat及其衍生物在制备抗肿瘤药物中的应用
CN111728960A (zh) 富马酸比索洛尔联合多西他赛在制备抗肿瘤药物中的应用
CN116421596A (zh) 白花前胡乙素在制备逆转肿瘤多药耐药性的药物中的应用

Legal Events

Date Code Title Description
WWE Wipo information: entry into national phase

Ref document number: 2016913905

Country of ref document: EP

ENP Entry into the national phase

Ref document number: 2016913905

Country of ref document: EP

Effective date: 20180621

ENP Entry into the national phase

Ref document number: 2018544938

Country of ref document: JP

Kind code of ref document: A

NENP Non-entry into the national phase

Ref country code: DE