WO2020186812A1 - 一种多靶点激酶抑制剂、药物组合物及多靶点激酶抑制剂的制备方法和应用 - Google Patents

一种多靶点激酶抑制剂、药物组合物及多靶点激酶抑制剂的制备方法和应用 Download PDF

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WO2020186812A1
WO2020186812A1 PCT/CN2019/121231 CN2019121231W WO2020186812A1 WO 2020186812 A1 WO2020186812 A1 WO 2020186812A1 CN 2019121231 W CN2019121231 W CN 2019121231W WO 2020186812 A1 WO2020186812 A1 WO 2020186812A1
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formula
acid
target kinase
kinase inhibitor
pharmaceutical composition
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PCT/CN2019/121231
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English (en)
French (fr)
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刘兵
戴静思
王嫣
钱学启
董俊军
刘希红
邓联武
谢爽
李大萍
陈能安
马进
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广州六顺生物科技股份有限公司
北京北科华夏生物医药科技有限公司
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Priority to US17/441,618 priority Critical patent/US20220125790A1/en
Priority to KR1020217031782A priority patent/KR20220004020A/ko
Priority to JP2021556917A priority patent/JP7319383B2/ja
Priority to EP19920117.9A priority patent/EP3929182A4/en
Publication of WO2020186812A1 publication Critical patent/WO2020186812A1/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
    • A61K31/33—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
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/20—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing sulfur, e.g. dimethyl sulfoxide [DMSO], docusate, sodium lauryl sulfate or aminosulfonic acids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0087—Galenical forms not covered by A61K9/02 - A61K9/7023
    • A61K9/009—Sachets, pouches characterised by the material or function of the envelope
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/08—Solutions
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2022—Organic macromolecular compounds
    • A61K9/205—Polysaccharides, e.g. alginate, gums; Cyclodextrin
    • A61K9/2054—Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/4841—Filling excipients; Inactive ingredients
    • A61K9/4866—Organic macromolecular compounds
    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
    • C07D239/70—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings condensed with carbocyclic rings or ring systems
    • C07D239/72—Quinazolines; Hydrogenated quinazolines
    • C07D239/86—Quinazolines; Hydrogenated quinazolines with hetero atoms directly attached in position 4
    • C07D239/88—Oxygen atoms

Definitions

  • the invention belongs to the technical field of biomedicine, and specifically relates to a multi-target kinase inhibitor and a pharmaceutical composition containing the multi-target kinase inhibitor, and also relates to a preparation method and application of the multi-target kinase inhibitor.
  • tyrosine protein kinases which involve changes in the structure and function of numerous proteins in the human body.
  • Abnormal signal transduction in cells is one of the key factors for tumor occurrence and development.
  • the target of tyrosine protein kinase has been the hot spot of anti-tumor drug research in recent decades. With the deepening of research and the clinical application of drugs, it has been discovered that single-target drugs are used to block the specific signal transduction pathways of tumor cells. The curative effect may not be objective enough, and there is resistance to the activation of bypass compensatory signal pathways.
  • the drug phenomenon also has certain toxic and side effects. The development of new, non-toxic side effects and multi-target drugs that can act on multiple signal pathways has great social significance and broad market prospects.
  • RET protein belongs to one of the receptor type kinases of the cadherin superfamily, and is a typical TK structure.
  • RET protein is the receptor of GDNF. Its function is to activate the kinase domain through the formation of GDNF-GFRas-Ret, which leads to autophosphorylation of the intracellular domain, thereby initiating multiple signal pathways to regulate the proliferation and differentiation of neural crest cells.
  • the kinase of RET protein can activate multiple downstream signaling pathways, including RAS/RAF/ERK pathway, PI3K/Akt pathway, and JNK pathway.
  • RET gene pathogenic mutations in the RET gene, such as gene mutations or rearrangements, will encode RET proteins with abnormal activities, which will transmit abnormal signals and cause various effects: including cell growth, survival, invasion, and metastasis. Continuous signal transmission will cause excessive cell proliferation, thus leading to the occurrence and progression of tumors.
  • VEGF and VEGFR are closely related to tumor growth, invasion and metastasis.
  • the receptors of the VEGFR family include VEGFR-1, VEGFR-2, and VEGFR-3.
  • VEGF-C and VEGFR 3 in a variety of tumors can induce the proliferation and migration of endothelial cells, regulate the production of blood vessels and lymph vessels, and at the same time It plays an important role in regulating tumor growth and metastasis. Inhibition of lymphangiogenesis and its regulatory mechanism, and promotion of tumor metastasis due to lymphangiogenesis have become an important direction in the field of malignant tumor treatment.
  • VEGFR-3 fusion protein can inhibit the regeneration of lymphatic vessels, suggesting that blocking the VEGFR-3 signaling pathway may be one of the ways to inhibit tumor lymphatic metastasis.
  • the overexpressed VEGFR-3 fusion protein was applied to the human lung cancer cell line LNM35, and it was found that it can inhibit tumor lymphangiogenesis and tumor lymph node metastasis, and the existing lymphatic vessels were not affected by the VEGFR-3 fusion protein treatment .
  • PDGFRA is one of the platelet-derived growth factor receptors and a member of the tyrosine protein kinase family. It can promote the chemotactic division and proliferation of cells. It plays a very important role in the growth and development of the body, wound repair and other processes. Its excessive activation and Abnormal expression can induce tumor angiogenesis, directly or indirectly promote tumor cell proliferation and migration.
  • the purpose of the present invention is to overcome the shortcomings of the prior art and provide a multi-target kinase inhibitor that can effectively inhibit the enzyme activities of RET, VEGFR3 and PDGFRA, and can also effectively treat cancer.
  • Another object of the present invention is to provide a method for preparing the multi-target kinase inhibitor.
  • Another object of the present invention is to provide the use of the multi-target kinase inhibitor.
  • Another object of the present invention is to provide a pharmaceutical composition in which the active ingredient includes the multi-target kinase inhibitor.
  • the present invention provides a multi-target kinase inhibitor, the general structural formula of which is shown in formula (I):
  • R is selected from the following formula (a), formula (b), formula (c), formula (d), formula (e), and formula (f):
  • the multi-target kinase inhibitor of the present invention has very good inhibitory activity on RET, VEGFR and PDGFRA, and has a better anti-tumor effect on multiple tumors in mice than the positive drugs Sorafenib and Cabozantinib, and It has the characteristics of no cardiac side effects and good tolerance.
  • the multi-target inhibitors of the present invention can effectively treat diseases related to abnormal signal transduction pathways of RET, VEGFR and PDGFRA.
  • the present invention provides a preparation method of the above-mentioned multi-target kinase inhibitor, which comprises the following steps:
  • the compound represented by formula (IV) is prepared by reacting the compound represented by formula (II) with the compound represented by formula (III);
  • the multi-target kinase inhibitor is prepared by reacting the compound represented by formula (VI) and the compound represented by formula (VII);
  • R is selected from formula (a), formula (b), formula (c), formula (d), formula (e), and formula (f).
  • the present invention provides the use of the multi-target kinase inhibitor or its pharmaceutically acceptable salt or hydrate in the preparation of drugs for treating diseases with abnormal transduction of the multi-target kinase signal pathway.
  • the multi-target kinase signaling pathway is mediated by RET or VEGFR3 or PDGFRA, and the multi-target kinase inhibitor can effectively inhibit the enzymatic activity of RET, VEGFR3 and PDGFRA, thereby treating diseases with abnormal transduction of the multi-target kinase signaling pathway
  • the multi-target kinase inhibitor has a good effect in treating tumor occurrence, development and metastasis.
  • the disease with abnormal transduction of the multi-target kinase signal pathway is cancer.
  • the cancer is liver cancer, breast cancer, respiratory tract cancer, digestive system tumor, brain cancer, reproductive organ cancer, urinary tract tumor, skin cancer, head and neck cancer, eye tumor and their Distal metastatic cancer, and at least one of sarcoma, lymphoma, and leukemia.
  • the liver cancer includes, but is not limited to, hepatoblastoma, liver lymphoma, liver mesenchymal tumor, liver secondary tumor, gallbladder and extrahepatic cholangiocarcinoma, cholangiocarcinoma, hepatoblastoma, mixed liver Cell carcinoma;
  • the breast cancer includes but is not limited to non-invasive cancer, early invasive cancer, invasive special cancer, invasive non-special cancer;
  • the respiratory tract cancer includes but not limited to small cell lung cancer, non-small cell lung cancer, lymph Cancer, head and neck cancer, pleural mesothelioma;
  • the digestive system tumors include, but are not limited to, esophageal tumors, stomach tumors, small bowel tumors, appendix tumors, colon and rectal tumors, anal tumors, liver and internal bile duct tumors, gallbladder and extrahepatic tumors Bile duct tumors, pancreatic exocrine tumors;
  • the brain cancers include but
  • the pharmaceutically acceptable salt is a salt formed by a multi-target kinase inhibitor and an acid; preferably, the acid is methanesulfonic acid, hydrochloric acid, acetic acid, trifluoroacetic acid , Tartaric acid, malic acid, citric acid, hydrobromic acid, phosphoric acid, sulfuric acid, trifluoromethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, 1-naphthalenesulfonic acid, 2-naphthalenesulfonic acid, lactic acid, oxalic acid, succinic acid , Fumaric acid, maleic acid, salicylic acid, benzoic acid, phenylacetic acid or mandelic acid; more preferably, the acid is methanesulfonic acid, hydrochloric acid or benzenesulfonic acid.
  • the present invention provides a pharmaceutical composition in which the active ingredient includes the multi-target kinase inhibitor.
  • the pharmaceutical composition further includes at least one well-known pharmaceutical excipient in the pharmaceutical field, and the pharmaceutical excipient includes a filler, a binder, and a disintegrating agent.
  • the multi-target kinase inhibitor accounts for 1%-50% by weight of the pharmaceutical composition.
  • the weight percentage of the pharmaceutical excipient in the pharmaceutical composition is: 10% to 80% of filler, 1% to 45% of binder, and disintegration Agent 5%-20%, lubricating glidant 0.1%-10%.
  • the filler is an excipient with good stability, fluidity and compressibility, selected from lactose, microcrystalline cellulose, mannitol, sorbitol, calcium hydrogen phosphate, starch, pregelatinized starch, chitosan At least one of sucrose, starch hydrolyzed oligosaccharides, and silicified microcrystalline cellulose; more preferably one or more of lactose, microcrystalline cellulose, mannitol, and sucrose.
  • lactose lactose
  • microcrystalline cellulose mannitol
  • sorbitol calcium hydrogen phosphate
  • starch pregelatinized starch
  • chitosan At least one of sucrose, starch hydrolyzed oligosaccharides, and silicified microcrystalline cellulose; more preferably one or more of lactose, microcrystalline cellulose, mannitol, and sucrose.
  • the binder is a polymer with high viscosity, selected from hydroxypropyl methylcellulose, dextrin, carbomer, xanthan gum, acacia, sodium alginate, tragacanth, malt At least one of fine paste, polyvinylpyrrolidone, and hydroxypropyl cellulose; more preferably one or more of polyvinylpyrrolidone, hydroxypropyl methylcellulose, and tragacanth.
  • the disintegrant is an auxiliary material with good fluidity and compressibility, selected from low-substituted hydroxypropyl cellulose, crospovidone, croscarmellose sodium, and croscarmellose starch At least one of sodium and sodium carboxymethyl starch; more preferably one or more of low-substituted hydroxypropyl cellulose, crospovidone, and croscarmellose sodium.
  • the lubricating glidant is selected from magnesium stearate, calcium stearate, stearic acid, sodium fumarate, sodium lauryl sulfate, glyceryl behenate, talc, silicon dioxide, At least one of polyethylene glycol and sodium stearyl fumarate; more preferably one or more of magnesium stearate, silicon dioxide, sodium lauryl sulfate, and polyethylene glycol.
  • the pharmaceutical composition provided by the present invention can be prepared into any pharmaceutically acceptable dosage form.
  • the dosage form is an oral solid preparation.
  • the oral solid preparation includes tablets, capsules, and granules.
  • the pharmaceutical composition of the present invention is used for the treatment of patients with intermediate and advanced esophageal cancer and gastric cancer; a pharmaceutical combination preparation of 5 mg to 250 mg is administered once a day for the treatment of patients with intermediate and advanced esophageal cancer and gastric cancer; preferably, A drug combination preparation of 10 mg-50 mg is administered once a day for the treatment of patients with middle and advanced esophageal cancer and gastric cancer.
  • the multi-target kinase inhibitor provided by the present invention can effectively inhibit the enzymatic activities of RET, VEGFR3 and PDGFRA, and can effectively treat diseases that are regulated by multi-target kinases and are abnormal in signal transduction pathways of said multi-target kinases.
  • diseases that are regulated by multi-target kinases and are abnormal in signal transduction pathways of said multi-target kinases Including cancers of the breast, respiratory tract, brain, reproductive organs, digestive tract, urinary tract, eyes, liver, skin, head and/or neck and their distant metastatic cancers, as well as lymphoma, sarcoma and leukemia;
  • the raw materials are pretreated by ultra-fine pulverization, and the conventional dosage form is adopted to obtain a drug with a finer particle size, so that the drug can be better dissolved in the body. Improved drug dissolution and absorption in the body;
  • the drug dissolves quickly, and can basically release the drug to a plateau within 15 minutes, which is more conducive to the absorption of the drug by the upper half of the small intestine.
  • the active ingredient multi-target kinase The content of the inhibitor in the pharmaceutical composition, the pharmaceutical composition only needs to be taken by the patient once a day, which greatly improves the patient's compliance;
  • the amount of organic solvent used in the auxiliary materials is small, which is beneficial to environmental protection.
  • Figure 1 is a graph showing the results of inhibition of the tumor volume of SMMC-7721 liver cancer mice by the multi-target kinase inhibitor [compound (I-1)] of the present invention, wherein formula (I-1) represents the multi-target kinase inhibitor of the present invention Compound (I-1);
  • Figure 2 is a graph showing the inhibition results of the multi-target kinase inhibitor of the present invention [Compound (I-1)] on the tumor volume of KYSE 410 esophageal cancer mice, where formula (I-1) represents the multi-target kinase inhibitor of the present invention Compound (I-1);
  • Figure 3 is a graph showing the dissolution rate results of a sample of the pharmaceutical composition of Example 4 of the present invention in solvents with different pH values;
  • Figure 4 is a graph showing the dissolution rate results of a sample of the pharmaceutical composition of Example 5 of the present invention in solvents with different pH values.
  • This embodiment is the multi-target kinase inhibitor (I-1), (I-2), (I-3), (I-4), (I-5), (I-6) and
  • the general structural formula of the multi-target kinase inhibitor is shown in formula (I):
  • R is selected from the following formula (a), formula (b), formula (c), formula (d), formula (e), and formula (f):
  • reaction 2 After the addition was completed, the temperature was increased to 120°C, and reaction 2 After hours, the reaction stops, cool to 15-20°C, pour the reaction mixture into 100ml ice water, control the temperature at 15-30°C, add 20ml ethyl acetate, separate the solids, stir and filter with suction, and wash the solids with 20ml ethanol once , Vacuum drying at 40°C for 12 hours to obtain 4.12 g (62.14%) of off-white solid, which is compound (IV);
  • This example further uses nuclear magnetic resonance spectroscopy and mass spectrometry to characterize the multi-target kinase inhibitor of this example.
  • ESI-MS (m/z): 381 [M+H]+.
  • This example further uses nuclear magnetic resonance spectroscopy and mass spectrometry to characterize the multi-target kinase inhibitor of this example.
  • ESI-MS (m/z): 395 [M+H]+.
  • the prepared (VI) (2.01g, 5mmol) was dissolved in dimethylformamide (20ml), and cyclopentylamine [Compound (VII-3)] (0.64g, 7.5mmol) was added and stirred at 80°C for 2 hours. Stop, cool to 15-20°C, pour the reaction mixture into 50ml ice water, control the temperature at 15-30°C, perform suction filtration to separate the solid, wash with water (20ml) once, wash once with acetonitrile (20ml), and dry in vacuo
  • the multi-target kinase inhibitor [Compound (I)] of the present invention is 1.19 g, and the powdery solid yield is 60.6%.
  • This example further uses nuclear magnetic resonance spectroscopy and mass spectrometry to characterize the multi-target kinase inhibitor of this example.
  • ESI-MS (m/z): 409 [M+H]+.
  • the prepared (VI) (2.01g, 5mmol) was dissolved in dimethylformamide (20ml), and vinylamine [Compound (VII-4)] (0.32g, 7.5mmol) was added and stirred at 80°C for 2 hours. The reaction was stopped. After cooling to 15 ⁇ 20°C, the reaction mixture was poured into 50ml ice water. When the temperature was controlled at 15 ⁇ 30°C, the solid was separated by suction filtration, washed once with water (20ml), washed once with acetonitrile (20ml), and dried under vacuum.
  • the multi-target kinase inhibitor [Compound (I)] of the invention is 1.01 g, and the powdery solid yield is 58.8%.
  • This example further uses nuclear magnetic resonance spectroscopy and mass spectrometry to characterize the multi-target kinase inhibitor of this example.
  • ESI-MS (m/z): 367 [M+H]+.
  • the prepared (VI) (2.01g, 5mmol) was dissolved in dimethylformamide (20ml), and 4-hydropyrrole [Compound (VII-5)] (0.53g, 7.5mmol) was added and stirred at 80°C for 2 hours. Stop, cool to 15-20°C, pour the reaction mixture into 50ml ice water, control the temperature at 15-30°C, perform suction filtration to separate the solid, wash with water (20ml) once, wash once with acetonitrile (20ml), and dry in vacuo
  • the multi-target kinase inhibitor [Compound (I)] of the present invention is 1.26 g, and the powdery solid yield is 66.4%.
  • This example further uses nuclear magnetic resonance spectroscopy and mass spectrometry to characterize the multi-target kinase inhibitor of this example.
  • ESI-MS (m/z): 395[M+H]+.
  • the prepared (VI) (2.01g, 5mmol) was dissolved in dimethylformamide (20ml), piperidine [Compound (VII-6)] (0.64g, 7.5mmol) was added and stirred at 80°C for 2 hours, the reaction was stopped After cooling to 15 ⁇ 20°C, the reaction mixture was poured into 50ml ice water. When the temperature was controlled at 15 ⁇ 30°C, the solid was separated by suction filtration, washed once with water (20ml), washed once with acetonitrile (20ml), and dried under vacuum.
  • the multi-target kinase inhibitor of the invention [Compound (I)] 1.27g, and the powdery solid yield is 65.1%.
  • This example further uses nuclear magnetic resonance spectroscopy and mass spectrometry to characterize the multi-target kinase inhibitor of this example.
  • ESI-MS (m/z): 409 [M+H]+.
  • This example studies the inhibitory activity of the multi-target kinase inhibitor of the present invention on RET, VEGFR3 and PDGFRA.
  • the multi-target kinase inhibitor provided by the present invention has a half-inhibitory concentration of the target at the nanomolar level, and multi-target The half-inhibitory concentration of kinase inhibitors (I-1), (I-3), and (I-4) on kinases RET, VEGFR3, and PDGFRA are all below 100 nM.
  • Multi-target kinase inhibitors (I-2) on kinase RET The half-inhibitory concentration of VEGFR3 is below 100nM.
  • the multi-target kinase inhibitors (I-1), (I-3), (I-4) provided by the present invention can effectively inhibit RET, VEGFR3 and PDGFRA Multi-target kinase inhibitor (I-2) can effectively inhibit the enzymatic activity of RET and VEGFR3. It can be seen that most of the multi-target kinase inhibitors synthesized by the present invention have IC 50 values within 100 nM, and in vitro experiments have verified that they have good druggability.
  • the anti-tumor activity of the multi-target kinase inhibitor [compound (I-1)] provided by the present invention in vivo was studied according to the requirements of "Guiding Principles of Pharmacodynamics of Antitumor Drugs".
  • the experimental method results are as follows:
  • mice were used to establish tumor models, and the modeled mice were divided into 5 groups: model group, compound (I-1) 5mg/kg group, Compound (I-1) 10mg/kg group, compound (I-1) 20mg/kg group, positive control group (positive control is: sorafenib or cabozantinib), the day of grouping is marked as day1, For 21 consecutive days, the 21st day was recorded as day21, and the tumor volume was measured twice a week during the administration period for statistical testing. The test results are shown in Figure (1) and Figure (2).
  • the multi-target kinase inhibitor [compound (I-1)] of the present invention has two sets of experimental test results of anti-tumor effect on SMMC-7721 liver cancer mice and KYSE 410 esophageal cancer mice. The results are similar. The analysis of the results shows that it is similar to the model group.
  • the tumor volume of mice in the experimental group and the positive control group with doses of 5 mg/kg, 10 mg/kg, and 20 mg/kg was lower than that of the model group, and the tumor volume was significantly different at day 21 by analysis of variance (P ⁇ 0.0001), indicating that the compound (I-1) provided by the present invention has a significant inhibitory effect on liver cancer like the positive control group; compared with the positive control group, the tumors of mice in the experimental group at doses of 10 mg/kg and 20 mg/kg, respectively
  • the low volume indicates that the compound (I-1) provided by the present invention has stronger anti-tumor activity in vivo than the positive drugs Sorafenib and Cabotinib at a lower dose.
  • the preparation process of the above tablet includes the following steps:
  • This example shows the formula and preparation process of a dispersible tablet containing 50 mg of multi-target kinase inhibitor (I-1) per tablet:
  • the preparation process of the dispersible tablet includes the following steps:
  • I-1 is passed through a 300 mesh sieve, and the particle size D 90 of the multi-target kinase inhibitor (I-1) is controlled to be less than 50 ⁇ m to obtain an ultrafine powder raw material.
  • Other excipients in the prescription are passed through a 60 mesh sieve Pretreatment; 50 grams of sieved multi-target kinase inhibitor raw materials, 87.5 grams of microcrystalline cellulose, 262.5 grams of lactose, 15 grams of polyvinylpyrrolidone, 50 grams of low-substituted hydroxypropyl cellulose, cross-linked carboxymethyl fiber 25 grams of plain sodium is placed in a three-dimensional mixer and mixed evenly to prepare a premixed material;
  • This example shows the formula and preparation process of a dispersible tablet containing 25 mg of multi-target kinase inhibitor (I-1) per tablet:
  • This example shows the formula and preparation process of a dispersible tablet containing 10 mg of multi-target kinase inhibitor (I-1) per tablet:
  • This example shows the formula and preparation process of dispersible tablets containing 5 mg of multi-target kinase inhibitor (I-1) per tablet:
  • This example shows the formula and preparation process of a sustained-release tablet containing 250 mg of multi-target kinase inhibitor (I-1) per tablet:
  • the preparation process of the dispersible tablet includes the following steps:
  • I-1 is passed through a 300 mesh sieve, and the particle size D 90 of the multi-target kinase inhibitor (I-1) is controlled to be less than 50 ⁇ m to obtain an ultrafine powder raw material.
  • Other excipients in the prescription are passed through a 60 mesh sieve Pretreatment; 250 grams of screened multi-target kinase inhibitor (I-1), 87.5 grams of hydroxypropyl methylcellulose, 112.5 grams of sodium alginate, and 15 grams of polyvinylpyrrolidone are placed in a highly efficient mixing granulator Mix well, add 30% ethanol aqueous solution to prepare soft material, dry the above soft material and sizing, add 25 grams of croscarmellose sodium and place it in a three-dimensional mixer and mix well to prepare premixed material ;
  • the preparation process of the above-mentioned capsule includes the following steps:
  • the multi-target kinase inhibitor (I-1) is superfinely pulverized and passed through a 300-mesh sieve to control the particle size D 90 of the multi-target kinase inhibitor (I-1) to be less than 50 ⁇ m to obtain superfine powder raw materials.
  • the other excipients are pretreated through a 60-mesh sieve; 50 grams of the sieved multi-target kinase inhibitor raw materials, 167.5 grams of microcrystalline cellulose, and 26 grams of lactose are placed in a three-dimensional mixer and mixed thoroughly to obtain a premixed material .
  • This example shows the formula and preparation process of granules containing 50 mg of multi-target kinase inhibitor (I-1) per tablet:
  • the preparation process of the above granules includes the following steps:
  • I-1 is superfinely pulverized and passed through a 300-mesh sieve to control the multi-target kinase inhibitor (I-1) with a particle size D90 of less than 50 ⁇ m, and other excipients in the formulation are pretreated through a 60-mesh sieve;
  • the dissolution test is determined by the 2015 edition of "Chinese Pharmacopoeia" fourth part 0931 dissolution and release test requirements for the test, using the second method, the volume of the dissolution medium is 900mL, the speed is 50rpm, and the dissolution medium is purified water, pH1.2 hydrochloric acid Solution, pH 4.5 acetate buffer, pH 6.8 phosphate buffer, in which, except for pH 1.2 hydrochloric acid solution, 0.5% sodium dodecyl sulfate (abbreviated as "SDS”) is added to the above three dissolution media ”)Surfactant.
  • SDS sodium dodecyl sulfate
  • Example 4 dissolves in different dissolution media in vitro.
  • the dissolution rate of the sample of Example 5 reached more than 94 in different dissolution media in vitro, and its dissolution rate reached 88 or more in 15 minutes.

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Abstract

本发明属于生物医药技术领域，具体个公开了一种多靶点激酶抑制剂和含多靶点激酶抑制剂的药物组合物，还公开了多靶点激酶抑制剂的制备方法和应用。本发明提供的多靶点激酶抑制剂的结构通式如式(Ⅰ)所示，其中，R的结构选自式(a)、式(b)、式(c)、式(d)、式(f)、式(d)，多靶点激酶抑制剂能有效抑制RET、VEGFR3和PDGFRA的酶活性，可有效治疗受多靶点激酶调控并与所述多靶点激酶信号转导途径异常相关的疾病，包括乳房、呼吸道、脑、生殖器官、消化道、泌尿道、眼、肝、皮肤、头和/或颈的癌症和它们的远端转移癌，以及淋巴瘤、肉瘤和白血病等。本发明的药物组合物的活性成分包括多靶点激酶抑制剂，其在组合物中的重量百分含量为1％～50％。

Description

一种多靶点激酶抑制剂、药物组合物及多靶点激酶抑制剂的制备方法和应用 技术领域
本发明属于生物医药技术领域，具体涉及一种多靶点激酶抑制剂和含多靶点激酶抑制剂的药物组合物，还涉及多靶点激酶抑制剂的制备方法和应用。
背景技术
细胞含有复杂的信号转导通路，这种由酪氨酸蛋白激酶介导信号通路，涉及人类机体众多蛋白结构和功能变化，而细胞的信号转导异常是肿瘤发生和发展的关键因素之一，酪氨酸蛋白激酶靶点是近几十年抗肿瘤药物研究的热点。随着研究的深入和药物的临床应用，发现通过单靶点药物来阻断肿瘤细胞具有特异性的信号转导通路的治疗方式，疗效可能不够客观，存在有旁路代偿信号通路激活的耐药现象，同时还有一定的毒副作用，而开发新型、无毒副作用且能作用于多条信号通路的多靶点药物，具有重大的社会意义和广阔的市场前景。
RET蛋白属于钙粘蛋白超家族的受体型激酶之一，为典型的TK结构。RET蛋白是GDNF的受体，其功能是通过形成GDNF-GFRas-Ret激活激酶结构域，导致胞内结构域自身磷酸化，从而启动多种信号通路调节神经嵴细胞的增殖、分化。RET蛋白的激酶可激活多个下游信号通路，包括RAS/RAF/ERK通路、PI3K/Akt通路、JNK通路。据报道RET基因发生致病性突变，如基因突变或重排，会编码出具有异常活动的RET蛋白，其将传递异常信号并造成多方面的影响：包括细胞生长、生存、侵袭、转移等。持续的信号传递会造成细胞的过度增殖，因此导致肿瘤的发生与进展。
肿瘤的远处转移是其重要的生物学特性之一，也是其难以彻底根治的主要原因。VEGF及VEGFR的表达与肿瘤的生长、浸润、转移有密切联系。VEGFR家族的受体包括VEGFR-1、VEGFR-2、VEGFR-3，研究结果表明多种肿瘤中VEGF-C及VEGFR 3能够诱导内皮细胞的增殖和迁移，调控血管和淋巴管的生成，还同时对肿瘤的生长转移起着重要的调节作用。抑制淋巴管生成及其调控机制、因淋巴管生成而促进肿瘤转移等已成为恶性肿瘤治疗领域中的一个重要方向。有研究结果显示VEGF-C可以促进肿瘤相关淋巴管的生成，而使用VEGFR-3融合蛋白可以抑制淋巴管的新生，提示阻断VEGFR-3信号通路可能是抑制肿瘤淋巴转移的途径之一。此外，将过量表达的VEGFR-3融合蛋白应用于人肺癌细胞系LNM35，发现其能够抑制肿瘤的淋巴管生成和肿瘤淋巴结转移，且原来存在的淋巴管并没有受到VEGFR-3融合蛋白治疗的影响。
PDGFRA是血小板衍化生长因子受体之一，是酪氨酸蛋白激酶家族成员，能促进细胞的趋化分裂与增殖，在机体生长发育、创伤修复等过程中起极重要的作用，其过度激活和异常表达可诱导肿瘤新生血管的形成，直接或间接地促进肿瘤细胞增殖与迁移。
发明内容
本发明的目的在于克服现有技术的不足，提供一种既能有效抑制RET、VEGFR3和PDGFRA的酶活性，还能有效治疗癌症的多靶点激酶抑制剂。
本发明的另一目的是提供所述多靶点激酶抑制剂的制备方法。
本发明的另一目的是提供所述多靶点激酶抑制剂的用途。
本发明的再一目的是提供一种活性成分包括所述多靶点激酶抑制剂的药物组合物。
为了实现上述目的，本发明是提供以下技术方案：
第一方面，本发明提供了一种多靶点激酶抑制剂，其结构通式如式(I)所示：
Figure PCTCN2019121231-appb-000001
其中，R的结构选自如下式(a)、式(b)、式(c)、式(d)、式(e)、式(f)：
Figure PCTCN2019121231-appb-000002
本发明所述多靶点激酶抑制剂对RET、VEGFR和PDGFRA具有非常好的抑制活性，对小鼠多种肿瘤具有比阳性药索拉非尼和卡博替尼更好的抑瘤作用，且具有无心脏毒副作用和耐受性较好的特点。
本发明所述的多靶点抑制剂可有效治疗RET、VEGFR和PDGFRA信号转导途径异常的相关疾病。
第二方面，本发明提供了上述多靶点激酶抑制剂的制备方法，其包括以下步骤：
(1)由式(Ⅱ)所示化合物和式(Ⅲ)所示化合物反应制备如式(Ⅳ)所示化合物；
(2)由式(Ⅳ)所示化合物和式(Ⅴ)所示化合物反应制备如式(Ⅵ)所示化合物；
(3)由式(Ⅵ)所示化合物和式(Ⅶ)所示化合物反应制得所述多靶点激酶抑制剂；
所述式(Ⅱ)、式(Ⅲ)、式(Ⅳ)、式(Ⅴ)、式(Ⅵ)和式(Ⅶ)的结构式如下所示：
Figure PCTCN2019121231-appb-000003
Figure PCTCN2019121231-appb-000004
其中，R的结构选自式(a)、式(b)、式(c)、式(d)、式(e)、式(f)。
第三方面，本发明提供了所述多靶点激酶抑制剂或其药学上可接受的盐或水合物在制备治疗多靶点激酶信号通路转导异常的疾病药物中的应用。
所述多靶点激酶信号通路由RET或VEGFR3或PDGFRA介导，所述多靶点激酶抑制剂能有效抑制RET、VEGFR3和PDGFRA的酶活性，从而治疗多靶点激酶信号通路转导异常的疾病，所述多靶点激酶抑制剂在治疗肿瘤发生发展及转移方面具有良好的效果。
作为本发明所述应用的优选实施方式，所述多靶点激酶信号通路转导异常的疾病为癌症。
作为本发明所述应用的优选实施方式，所述癌症为肝癌、乳房癌、呼吸道癌、消化系统肿瘤、脑癌、生殖器官癌、泌尿道肿瘤、皮肤癌、头颈癌、眼部肿瘤和它们的远端转移癌，以及肉瘤、淋巴瘤和白血病中的至少一种。
优选地，所述肝癌包括但不限于肝母细胞瘤、肝淋巴瘤、肝间叶性肿瘤、肝继发性肿瘤、胆囊和肝外胆管癌、胆管上皮癌、肝胚细胞瘤、混合型肝细胞癌；所述乳房癌包括但不限于非浸润性癌、早期浸润性癌、浸润性特殊癌、浸润性非特殊癌；所述呼吸道癌包括但不限于小细胞肺癌、非小细胞肺癌、淋巴癌、头颈癌、胸膜间皮瘤；所述消化系统肿瘤包括但不限于食管肿瘤、胃肿瘤、小肠肿瘤、阑尾肿瘤、结肠和直肠肿瘤、肛管肿瘤、肝和内胆管肿瘤、胆囊和肝外胆管肿瘤、胰腺外分泌肿瘤；所述脑癌包括但不限于中枢神经肿瘤、外周神经肿瘤、脑膜肿瘤、松果体瘤；所述生殖器官癌包括雄性生殖器官肿瘤或雌性生殖器官肿瘤，所述雄性生殖器官肿瘤包括但不限于前列腺肿瘤、睾丸和周围组织肿瘤、阴茎肿瘤，所述雌性生殖器官肿瘤包括但不限于卵巢和腹膜肿瘤、输卵管和子宫韧带肿瘤、子宫肿瘤、子宫颈肿瘤、外阴肿瘤；所述泌尿道肿瘤包括但不限于肾脏肿瘤、浸润性尿路上皮癌、膀胱癌、绒毛状腺癌、颗粒细胞瘤、脐尿管癌；所述皮肤癌包括但不限于上皮细胞肿瘤、黑色素细胞肿瘤、淋巴造血系统肿瘤、皮肤软组织肿瘤；所述头颈癌包括但不限于鼻腔/鼻窦肿瘤、喉咽和颈段食管肿瘤、甲状腺肿瘤、口咽/鼻咽肿瘤；所述眼部肿瘤包括但不限于视网膜母细胞瘤、眼睑皮脂腺癌、眼眶淋巴管肿瘤、眼眶骨肉瘤、虹膜黑色素瘤、视神经胶质瘤、虹膜平滑肌瘤；所述肉瘤包括但不限于传统型骨肉瘤、毛细血管扩张型骨肉瘤、未分化多形性肉瘤、胃肠间质瘤、脂肪肉瘤、平滑肌肉瘤；所述淋巴瘤包括但不限于霍奇金淋巴瘤、B细胞淋巴瘤、T细胞淋巴瘤、NK细胞淋巴瘤；所述白血病包括但不限于髓系的粒-单核细胞白血病、单核细胞白血病、红白血病、原始巨核细胞白血病、淋巴系的T和B细胞白血病。
作为本发明所述应用的优选实施方式，所述药学上可接受的盐为多靶点激酶抑制剂与酸形成的盐；优选地，所述酸为甲磺酸、盐酸、醋酸、三氟乙酸、酒石酸、苹果酸、柠檬酸、氢溴酸、磷酸、硫酸、三氟甲磺酸、苯 磺酸、对甲苯磺酸、1-萘磺酸、2-萘磺酸、乳酸、草酸、琥珀酸、富马酸、马来酸、水杨酸、苯甲酸、苯乙酸或扁桃酸；更优选地，所述酸为甲磺酸、盐酸或苯磺酸。
第四方面，本发明提供一种活性成分包括所述多靶点激酶抑制剂的药物组合物。
作为本发明所述药物组合物的优选实施方式，所述药物组合物还包括至少一种药学领域公知的药用赋形剂，所述药用赋形剂包括填充剂、粘合剂、崩解剂、润滑助流剂。
作为本发明所述药物组合物的优选实施方式，所述多靶点激酶抑制剂占药物组合物的重量百分含量为1％～50％。
作为本发明所述药物组合物的优选实施方式，所述药用赋形剂占药物组合物的重量百分含量为：填充剂10％～80％、粘合剂1％～45％、崩解剂5％～20％、润滑助流剂0.1％～10％。
优选地，所述填充剂为稳定性、流动性和可压性良好的辅料，选自乳糖、微晶纤维素、甘露醇、山梨醇、磷酸氢钙、淀粉、预胶化淀粉、壳聚糖、蔗糖、淀粉水解寡糖、硅化微晶纤维素中的至少一种；更优选为乳糖、微晶纤维素、甘露醇、蔗糖中的一种或多种。
优选地，所述粘合剂为具有高粘度的聚合物，选自羟丙基甲基纤维素、糊精、卡波姆、黄原胶、阿拉伯胶、海藻酸钠、西黄蓍胶、麦芽精糊、聚乙烯吡咯烷酮、羟丙基纤维素中的至少一种；更优选为聚乙烯吡咯烷酮、羟丙基甲基纤维素、西黄蓍胶中的一种或多种。
优选地，所述崩解剂为流动性、可压性良好的辅料，选自低取代羟丙基纤维素、交联聚维酮、交联羧甲基纤维素钠、交联羧甲基淀粉钠、羧甲基淀粉钠中的至少一种；更优选为低取代羟丙基纤维素、交联聚维酮、交联羧甲基纤维素钠中的一种或多种。
优选地，所述润滑助流剂选自硬脂酸镁、硬脂酸钙、硬脂酸、富马酸钠、十二烷基硫酸钠、山嵛酸甘油酯、滑石粉、二氧化硅、聚乙二醇、硬脂富马酸钠中的至少一种；更优选为硬脂酸镁、二氧化硅、十二烷基硫酸钠、聚乙二醇中的一种或多种。
本发明提供的药物组合物可制备成药学上允许的任意一种剂型。
作为本发明所述药物组合物的优选实施方式，所述剂型为口服固体制剂。
优选地，所述口服固体制剂包括片剂、胶囊、颗粒剂。
本发明所述的药物组合物用于中、晚期食管癌和胃癌患者的治疗；以5mg～250mg的药物组合制剂每日给药1次用于中、晚期食管癌、胃癌患者治疗；优选地，以10mg～50mg的药物组合制剂每日给药1次用于中、晚期食管癌和胃癌患者治疗。
与现有技术相比，本发明的有益效果：
(1)本发明提供的多靶点激酶抑制剂能有效抑制RET、VEGFR3和PDGFRA的酶活性，可有效治疗受多靶点激酶调控并与所述多靶点激酶信号转导途径异常的相关疾病，包括乳房、呼吸道、脑、生殖器官、消化道、泌尿道、眼、肝、皮肤、头和/或颈的癌症和它们的远端转移癌，以及淋巴瘤、肉瘤和白血病；
(2)本发明在制备含多靶点激酶抑制剂药物组合物时，对原料采用超微粉碎预处理，采用常规剂型，获 得粒径更细的药物，使药物在体内得到更好的溶解，提高了药物溶出和体内吸收；
(3)本发明药物组合物经制备制成片剂后，其药物溶出快，能在15min内基本释药达到平台，更有利于药物被小肠上半部的吸收，根据活性成分多靶点激酶抑制剂在药物组合物中的含量，所述药物组合物只需患者每日一次口服，大大提高了患者的依从性；
(4)本发明药物组合物制备工艺，所用的辅料中有机溶剂用量少，有利于环境保护。
附图说明
图1为本发明多靶点激酶抑制剂[化合物(I-1)]对SMMC-7721肝癌小鼠肿瘤体积的抑制结果图，其中，式(I-1)代表本发明多靶点激酶抑制剂的化合物(I-1)；
图2为本发明多靶点激酶抑制剂[化合物(I-1)]对KYSE 410食管癌小鼠肿瘤体积的抑制结果图，其中，式(I-1)代表本发明多靶点激酶抑制剂的化合物(I-1)；
图3为本发明实施例4的药物组合物样品在不同pH值溶媒中的溶出速率结果图；
图4为本发明实施例5的药物组合物样品在不同pH值溶媒中的溶出速率结果图。
具体实施方式
为了使本发明的目的、技术方案及优点更加清楚明白，下面结合具体实施方式对本发明作进一步的详细描述。
实施例1
本实施例为本发明的多靶点激酶抑制剂(I-1)、(I-2)、(I-3)、(I-4)、(I-5)、(I-6)及其制备方法，所述多靶点激酶抑制剂的结构通式如式(I)所示：
Figure PCTCN2019121231-appb-000005
其中，R的结构选自如下式(a)、式(b)、式(c)、式(d)、式(e)、式(f)：
Figure PCTCN2019121231-appb-000006
本实施例多靶点激酶抑制剂的制备方法为：
(1)化合物4-((6，7-二甲氧基喹啉咪唑-4-基)氧基)苯胺[化合物(Ⅳ)]的制备：
向250ml三口烧瓶中加入4-氨基苯酚[化合物(Ⅲ)](3.46g，31.2mmol)，NaOH(1.26g，31.2mmol)和二甲基亚砜50ml混合搅拌，将二甲基亚砜50ml与4-氯-6，7-二甲氧基喹唑啉[化合物(Ⅱ)](5g，22.3mmol)混合，加入到上述反应溶液中，滴加完毕后，将温度升至120℃，反应2小时，反应停止，冷却至15～20℃，将反应混合物倒入100ml冰水中，控制温度在15～30℃时，加入20ml乙酸乙酯，进行固体分离搅拌抽滤，固体用乙醇20ml洗涤1次，在40℃下真空干燥12小时，得到类白色固体4.12g(62.14％)，即为化合物(Ⅳ)；
(2)苯基(4-((6，7-二甲氧基喹唑啉-4-基)氧基)苯基)氨基甲酸酯[化合物(Ⅵ)]的制备：
将氯甲酸苯基酯[化合物(Ⅴ)](1.64g；0.0105mol)缓慢地加入冰冷却4-((6，7-二甲氧基喹啉咪唑-4-基)氧基)苯胺[化合物(Ⅳ)](2.97g；0.01mol)和碳酸钾(1g，0.012mol)的丙酮(30ml)溶液中；加完后，除去水-水浴，将反应混合物在室温下搅拌30分钟，将甲醇(20ml)加入上述反应混合物中，并从反应液中分离出无机盐固体，再对有机层滤液浓缩，最后用乙酸乙酯(10ml)洗涤得(Ⅵ)白色粉末3.58g，收率85.85％；
(3)多靶点激酶抑制剂[化合物(I-1)]的制备：
Figure PCTCN2019121231-appb-000007
将制备得到的(Ⅵ)(2.01g，5mmol)溶于二甲基甲酰胺(20ml)，加入环丙胺[化合物(Ⅶ-1)](0.43g，7.5mmol)80℃搅拌2小时，反应停止，冷却至15～20℃，将反应混合物倒入50ml冰水中，控制温度在15～30℃时，进行抽滤分离固体，水(20ml)洗涤一次，乙腈(20ml)洗涤一次，真空干燥得到本发明所述多靶点激酶抑制剂[化合物(I-1)]1.25g，粉末状固体收率为62.8％。
上述制备方法中，化合物的结构式如下：
Figure PCTCN2019121231-appb-000008
Figure PCTCN2019121231-appb-000009
本实施例进一步采用核磁共振光谱和质谱对本实施例的多靶点激酶抑制剂进行表征，实验结果如下：1H NMR(400MHz，DMSO-d6):δ8.52(s，1H)，8.39(brs，1H)，7.53(s，1H)，7.50(m，1H)，7.47(m，1H)，7.36(s，1H)，7.17(m，1H)，7.14(m，1H)，6.42(d，J＝2.6Hz，1H)，3.98(s，3H)，3.96(s，3H)，2.55(m，1H)，0.64(m，2H)，0.42(m，2H)。ESI-MS(m/z):381[M+H]+。
(4)多靶点激酶抑制剂[化合物(I-2)]的制备：
Figure PCTCN2019121231-appb-000010
将制备得到的(Ⅵ)(2.01g，5mmol)溶于二甲基甲酰胺(20ml)，加入环丁胺[化合物(Ⅶ-2)](0.53g，7.5mmol)80℃搅拌2小时，反应停止，冷却至15～20℃，将反应混合物倒入50ml冰水中，控制温度在15～30℃时，进行抽滤分离固体，水(20ml)洗涤一次，乙腈(20ml)洗涤一次，真空干燥得到本发明所述多靶点激酶抑制剂[化合物(I-2)]1.38g，粉末状固体收率为64.8％。
上述制备方法中，化合物的结构式如下：
Figure PCTCN2019121231-appb-000011
本实施例进一步采用核磁共振光谱和质谱对本实施例的多靶点激酶抑制剂进行表征，实验结果如下：1H NMR(400MHz，DMSO-d6):δ8.50(s，1H)，8.37(brs，1H)，7.51(s，1H)，7.48(m，1H)，7.45(m，1H)，7.34(s，1H)，7.15(m，1H)，7.13(m，1H)，6.40(d，J＝2.6Hz，1H)，4.25(m，1H)3.96(s，3H)，3.94(s，3H)，2.35(m，2H)，1.92(m，2H)，δ1.73(m，2H)。ESI-MS(m/z):395[M+H]+。
(5)多靶点激酶抑制剂[化合物(I-3)]的制备：
Figure PCTCN2019121231-appb-000012
将制备得到的(Ⅵ)(2.01g，5mmol)溶于二甲基甲酰胺(20ml)，加入环戊胺[化合物(Ⅶ-3)](0.64g，7.5mmol)80℃搅拌2小时，反应停止，冷却至15～20℃，将反应混合物倒入50ml冰水中，控制温度在15～30℃时，进行抽滤分离固体，水(20ml)洗涤一次，乙腈(20ml)洗涤一次，真空干燥得到本发明所述多靶点激酶抑制剂[化合物(I)]1.19g，粉末状固体收率为60.6％。
上述制备方法中，化合物的结构式如下：
Figure PCTCN2019121231-appb-000013
本实施例进一步采用核磁共振光谱和质谱对本实施例的多靶点激酶抑制剂进行表征，实验结果如下：1H NMR(400MHz，DMSO-d6):δ8.59(s，1H)，8.44(brs，1H)，7.53(s，1H)，7.50(m，1H)，7.47(m，1H)，7.36(s，1H)，7.17(m，1H)，7.14(m，1H)，6.42(d，J＝2.6Hz，1H)，3.98(s，3H)，3.96(s，3H)，3.78(m，1H)，1.68(m，2H)，1.49(m，2H，)，1.40(m，2H)1.20(m，2H)。ESI-MS(m/z):409[M+H]+。
(6)多靶点激酶抑制剂[化合物(I-4)]的制备：
Figure PCTCN2019121231-appb-000014
将制备得到的(Ⅵ)(2.01g，5mmol)溶于二甲基甲酰胺(20ml)，加入乙烯胺[化合物(Ⅶ-4)](0.32g，7.5mmol)80℃搅拌2小时，反应停止，冷却至15～20℃，将反应混合物倒入50ml冰水中，控制温度在15～30℃时，进行抽滤分离固体，水(20ml)洗涤一次，乙腈(20ml)洗涤一次，真空干燥得到本发明所述多靶点激酶抑制剂[化合物(I)]1.01g，粉末状固体收率为58.8％。
上述制备方法中，化合物的结构式如下：
Figure PCTCN2019121231-appb-000015
本实施例进一步采用核磁共振光谱和质谱对本实施例的多靶点激酶抑制剂进行表征，实验结果如下：1H NMR(400MHz，DMSO-d6):δ8.78(s，1H)，8.61(brs，1H)，7.41(s，1H)，7.50(m，1H)，7.47(m，1H)，7.31(s，1H)，7.18(m，1H)，7.15(m，1H)，6.42(d，J＝2.6Hz，1H)，6.05(m，1H)，5.61(d，1H)，4.04(d，1H)，3.98(s，3H)，3.96(s，3H)。ESI-MS(m/z):367[M+H]+。
(7)多靶点激酶抑制剂[化合物(I-5)]的制备：
Figure PCTCN2019121231-appb-000016
将制备得到的(Ⅵ)(2.01g，5mmol)溶于二甲基甲酰胺(20ml)，加入4氢吡咯[化合物(Ⅶ-5)](0.53g，7.5mmol)80℃搅拌2小时，反应停止，冷却至15～20℃，将反应混合物倒入50ml冰水中，控制温度在15～30℃时，进行抽滤分离固体，水(20ml)洗涤一次，乙腈(20ml)洗涤一次，真空干燥得到本发明所述多靶点激酶抑制剂[化合物(I)]1.26g，粉末状固体收率为66.4％。
上述制备方法中，化合物的结构式如下：
Figure PCTCN2019121231-appb-000017
本实施例进一步采用核磁共振光谱和质谱对本实施例的多靶点激酶抑制剂进行表征，实验结果如下：1H NMR(400MHz，DMSO-d6):δ8.52(s，1H)，8.39(brs，1H)，7.53(s，1H)，7.50(m，1H)，7.47(m，1H)，7.36(s，1H)，7.17(m，1H)，6.42(d，J＝2.6Hz，1H)，3.98(s，3H)，3.96(s，3H)，3.25(m，4H)，1.70(m，4H)。ESI-MS (m/z):395[M+H]+。
(8)多靶点激酶抑制剂[化合物(I-6)]的制备：
Figure PCTCN2019121231-appb-000018
将制备得到的(Ⅵ)(2.01g，5mmol)溶于二甲基甲酰胺(20ml)，加入哌啶[化合物(Ⅶ-6)](0.64g，7.5mmol)80℃搅拌2小时，反应停止，冷却至15～20℃，将反应混合物倒入50ml冰水中，控制温度在15～30℃时，进行抽滤分离固体，水(20ml)洗涤一次，乙腈(20ml)洗涤一次，真空干燥得到本发明所述多靶点激酶抑制剂[化合物(I)]1.27g，粉末状固体收率为65.1％。
上述制备方法中，化合物的结构式如下：
Figure PCTCN2019121231-appb-000019
本实施例进一步采用核磁共振光谱和质谱对本实施例的多靶点激酶抑制剂进行表征，实验结果如下：1H NMR(400MHz，DMSO-d6):δ8.53(s，1H)，8.40(brs，1H)，7.55(s，1H)，7.51(m，1H)，7.48(m，1H)，7.38(s，1H)，7.18(m，1H)，6.42(d，J＝2.6Hz，1H)，3.99(s，3H)，3.97(s，3H)，3.77(m，4H)，1.59(m，2H)，1.53(m，4H)。ESI-MS(m/z):409[M+H]+。
实施例2
本实施例研究本发明所述多靶点激酶抑制剂对RET、VEGFR3和PDGFRA的抑制活性。
(一)实验步骤：
1、待测化合物精确称量，加入DMSO溶剂成母液，然后使用缓冲液配制待测化合物溶液至所需浓度；
2、在384反应容器中加入RET或VEGFR3或PDGFRA激酶溶液，Z’-LYTE各对应底物溶液，缓冲液或待测化合物，ATP，室温反应1小时；
3、每孔加入荧光增强剂，室温孵育1小时；
4、利用荧光分析仪分别读取数据。
(二)数据处理
1、根据公式计算各孔的相对抑制率；
2、活性样品进行浓度稀释后检测的相对抑制率，使用Xlfit软件作图求算抑制率IC 50值。
(三)实验结果
实验结果如表1所示：
表1多靶点激酶抑制剂对激酶RET、VEGFR3、PDGFRA的抑制活性
Figure PCTCN2019121231-appb-000020
IC 50在100nM以下确认为能有效抑制靶点蛋白的活性，由表1的实验结果可知，本发明提供的多靶点激酶抑制剂，对靶点的半抑制浓度在纳摩尔级别，多靶点激酶抑制剂(I-1)、(I-3)、(I-4)对激酶RET、VEGFR3、PDGFRA的半抑制浓度均在100nM以下，多靶点激酶抑制剂(I-2)对激酶RET、VEGFR3的半抑制浓度均在100nM以下，由此可知，本发明提供的多靶点激酶抑制剂(I-1)、(I-3)、(I-4)能有效抑制RET、VEGFR3和PDGFRA的酶活性，多靶点激酶抑制剂(I-2)能有效抑制RET、VEGFR3的酶活性。可见本发明所合成的多靶点激酶抑制剂多数IC 50值在100nM以内，体外实验验证其具有较好的成药性。
实施例3
本实施例按《抗肿瘤药物药效学指导原则》的要求研究本发明提供的多靶点激酶抑制剂[化合物(I-1)]在体内的抗肿瘤活性(肝癌\食管癌)。其实验方法结果如下：
(一)实验方法
用符合建模条件的SMMC-7721肝癌细胞和KYSE 410食管癌细胞将裸小鼠建立肿瘤模型，对建模完成的小鼠分5组：模型组、化合物(I-1)5mg/kg组、化合物(I-1)10mg/kg组、化合物(I-1)20mg/kg组、阳性对照组(阳性对照为：索拉非尼或卡博替尼)，分组当天开始给药记为day1，连续21天，第21天记为day21，给药期间每周测量2次肿瘤体积，做统计学检测。检测结果如图(1)和图(2)所示。
(二)实验结果
本发明多靶点激酶抑制剂[化合物(I-1)]对SMMC-7721肝癌小鼠和KYSE 410食管癌小鼠抑瘤作用的两组实验检测结果比较相似，结果分析显示：与模型组相比，剂量分别为5mg/kg、10mg/kg、20mg/kg的实验组和阳性对照组小鼠的肿瘤体积低于模型组，且肿瘤体积经方差分析在day21时，出现极显著差异(P<0.0001)，说明本发明提供的化合物(I-1)和阳性对照组一样对肝癌具有明显抑制作用；与阳性对照组相比，剂量分别为10mg/kg、20mg/kg的实验组小鼠的肿瘤体积要低，说明本发明提供的化合物(I-1)在较低剂量时就比阳性药索拉非尼和卡博替尼具有更强的体内抗肿瘤活性。
实施例4
本实施例为每片含有50mg多靶点激酶抑制剂(I-1)的片剂的配方和制备工艺：
表2 1000片含多靶点激酶抑制剂(I-1)的片剂的配方
Figure PCTCN2019121231-appb-000021
上述片剂的制备工艺，包括以下步骤：
1、将多I-1经超微粉碎，过300以上目筛，控制多靶点激酶抑制剂(I-1)粒径D 90小于50μm，得到超微粉原料，处方中的其他辅料过60目筛预处理；将过筛的多靶点激酶抑制剂原料50克、乳糖375克、聚乙烯吡咯烷酮25克、低取代羟丙基纤维素25克、交联羧甲基纤维素钠15克置于三维混合机中充分混合均匀，制得预混物料；
2、将上述所得的预混物料加入硬脂酸镁5克、二氧化硅5克，得到混合粉，混合粉置于三维混合机进行充分混合，根据中间体检测的含量结果，确定压片的片重范围，使用旋转式压片机压片，获得所述片剂。
实施例5
本实施例为每片含有50mg多靶点激酶抑制剂(I-1)的分散片的配方和制备工艺：
表3 1000片含多靶点激酶抑制剂(I-1)的分散片的配方
Figure PCTCN2019121231-appb-000022
Figure PCTCN2019121231-appb-000023
上述分散片的制备工艺，包括以下步骤：
1、将I-1经超微粉碎，过300以上目筛，控制多靶点激酶抑制剂(I-1)粒径D 90小于50μm，得到超微粉原料，处方中的其他辅料过60目筛预处理；将过筛的多靶点激酶抑制剂原料50克、微晶纤维素87.5克、乳糖262.5克、聚乙烯吡咯烷酮15克、低取代羟丙基纤维素50克、交联羧甲基纤维素钠25克置于三维混合机中充分混合均匀，制得预混物料；
2、将上述所得的预混物料加入硬脂酸镁5克、二氧化硅5克，得到混合粉，混合粉置于三维混合机进行充分混合，根据中间体检测的含量结果，确定压片的片重范围，使用旋转式压片机压片，获得所述分散片。
实施例6
本实施例为每片含有25mg多靶点激酶抑制剂(I-1)的分散片的配方和制备工艺：
表4 1000片多靶点激酶抑制剂(I-1)的分散片的配方
Figure PCTCN2019121231-appb-000024
上述分散片的制备工艺，其步骤同实施例5。
实施例7
本实施例为每片含有10mg多靶点激酶抑制剂(I-1)的分散片的配方和制备工艺：
表5 1000片含多靶点激酶抑制剂(I-1)的分散片的配方
Figure PCTCN2019121231-appb-000025
上述分散片的制备工艺，其步骤同实施例5。
实施例8
本实施例为每片含有5mg多靶点激酶抑制剂(I-1)分散片的配方和制备工艺：
表6 1000片含多靶点激酶抑制剂(I-1)的分散片的配方
Figure PCTCN2019121231-appb-000026
上述分散片的制备工艺，其步骤同实施例5。
实施例9
本实施例为每片含有250mg多靶点激酶抑制剂(I-1)的缓释片的配方和制备工艺：
表7 1000片含多靶点激酶抑制剂(I-1)的缓释片的配方
Figure PCTCN2019121231-appb-000027
上述分散片的制备工艺，包括以下步骤：
1、将I-1经超微粉碎，过300以上目筛，控制多靶点激酶抑制剂(I-1)粒径D 90小于50μm，得到超微粉原料，处方中的其他辅料过60目筛预处理；将过筛的多靶点激酶抑制剂(I-1)250克、羟丙基甲基纤维素87.5克、海藻酸钠112.5克、聚乙烯吡咯烷酮15克置于高效混合制粒机中充分混合，加入30％乙醇水溶液制得软材，将上述的软材干燥后进行整粒，加交联羧甲基纤维素钠25克置于三维混合机中充分混合均匀，制得预混物料；
2、将上述所得的预混物料加入硬脂酸镁5克、二氧化硅5克，得到混合粉，混合粉置于三维混合机进行充分混合，根据中间体检测的含量结果，确定压片片重范围，使用旋转式压片机压片，获得所述多靶点激酶抑制剂缓释片。
实施例10
本实施例为每片含有50mg多靶点激酶抑制剂(I-1)的胶囊的配方和制备工艺：
表8 1000粒含多靶点激酶抑制剂(I-1)的胶囊的配方
Figure PCTCN2019121231-appb-000028
Figure PCTCN2019121231-appb-000029
上述胶囊的制备工艺，包括以下步骤：
1、将多靶点激酶抑制剂(I-1)经超微粉碎，过300以上目筛，控制多靶点激酶抑制剂(I-1)粒径D 90小于50μm，得到超微粉原料，处方中的其它辅料过60目筛预处理；将过筛的多靶点激酶抑制剂原料50克、微晶纤维素167.5克、乳糖26克置于三维混合机中充分混合均匀，制得预混物料。
2、将上述所得的预混物料加入硬脂酸镁2.5克、二氧化硅3.75克，得到混合粉，混合粉置于三维混合机进行充分混合，根据中间体检测的含量结果确定填充量重量范围，使用自动胶囊填充机填充胶囊，获得所述多靶点激酶抑制剂胶囊。
实施例11
本实施例为每片含有50mg多靶点激酶抑制剂(I-1)的颗粒剂的配方和制备工艺：
表9 1000袋含多靶点激酶抑制剂(I-1)的颗粒剂的配方
Figure PCTCN2019121231-appb-000030
上述颗粒剂的制备工艺，包括以下步骤：
1、将I-1经超微粉碎，过300以上目筛，控制多靶点激酶抑制剂(I-1)粒径D90小于50μm，处方中其他辅料过60目筛预处理；
2、将过筛后的多靶点激酶抑制剂(I-1)、蔗糖、阿拉伯胶、西黄蓍胶于高效混合制粒机中充分混合均匀，加入30％乙醇溶液适量充分混匀，制得软材，经过30目筛制粒，放置50℃～60℃的流化床中干制，干物料经过30目筛制得干颗粒；
3、在上述的干颗粒中加入润滑助流剂、矫味剂，得到混合粉，再将混合粉全部加入多向运动混合机中，进行充分混合均匀，使用颗粒分装机进行分装填充包装，制得所述多靶点激酶抑制剂颗粒剂。
效果例1
分别取上述实施例4、5所制得的样品各100片，进行体外多种溶出介质的溶出度试验研究。
溶出度试验测定采用2015年版《中国药典》第四部0931项溶出度与释放度测定法要求进行试验，采用第二法、溶出介质体积900mL、转速50rpm，溶出介质采用纯化水、pH1.2盐酸溶液、pH4.5醋酸盐缓冲液、pH6.8磷酸盐缓冲液，其中除pH1.2盐酸溶液外，在上述其他三个溶出介质中均加入0.5％十二烷基硫酸钠(简称“SDS”)表面活性剂。研究实施例4和5样品在4种溶出介质中的溶出度实验，经HPLC测定溶出数据记录如表10、表11和图3、图4所示：
表10实施例4样品在不同pH值溶媒中溶出度结果
Figure PCTCN2019121231-appb-000031
表11实施例5样品在不同pH值溶媒中溶出度结果
Figure PCTCN2019121231-appb-000032
通过对实施例4和实施例5两组多靶点激酶抑制剂样品进行体外多种溶出介质的溶出度试验研究，结果显示，实施例4的样品在体外不同溶出介质中，15min时，其溶出度达到94以上，实施例5的样品在体外不同溶出介质中，15min时，其溶出度达到88以上，由此说明，本发明药物组合物经制备制成片剂后，其药物溶出快，能在15min时达到释药平台；上述结果还显示，药物组合物的样品随pH值的升高其溶出度呈降低趋势，而所述样品为口服固体制剂中的普通片和分散片，经患者口服后，预期在患者胃部溶出和在小肠上半部吸收，由此说明，本发明的药物组合物通过一定生产工艺制备成片剂，提高了药物溶出度和体内吸收，而且，根据活性成分多靶点激酶抑制剂在药物组合物中的含量，所述药物组合物只需患者每日一次口服，大大提高了患者的依从性。
最后所应当说明的是，以上实施例仅用以说明本发明的技术方案而非对本发明保护范围的限制，尽管参照较佳实施例对本发明作了详细说明，本领域的普通技术人员应当理解，可以对本发明的技术方案进行修改或者等同替换，而不脱离本发明技术方案的实质和范围。

Claims (12)

  1. 一种多靶点激酶抑制剂，其特征在于，所述多靶点激酶抑制剂的结构通式如式(Ⅰ)所示：
    Figure PCTCN2019121231-appb-100001
    其中，R的结构选自如下式(a)、式(b)、式(c)、式(d)、式(e)、式(f)：
    Figure PCTCN2019121231-appb-100002
  2. 根据权利要求1所述的多靶点激酶抑制剂的制备方法，其特征在于：包括以下步骤：
    (1)由式(Ⅱ)所示化合物和式(Ⅲ)所示化合物反应制备如式(Ⅳ)所示化合物；
    (2)由式(Ⅳ)所示化合物和式(Ⅴ)所示化合物反应制备如式(Ⅵ)所示化合物；
    (3)由式(Ⅵ)所示化合物和式(Ⅶ)所示化合物反应制得所述多靶点激酶抑制剂；
    所述式(Ⅱ)、式(Ⅲ)、式(Ⅳ)、式(Ⅴ)、式(Ⅵ)和式(Ⅶ)的结构式如下所示：
    Figure PCTCN2019121231-appb-100003
    其中，R的结构选自式(a)、式(b)、式(c)、式(d)、式(e)、式(f)。
  3. 根据权利要求1所述的多靶点激酶抑制剂的应用，其特征在于，所述多靶点激酶抑制剂或其药学上可接受的盐或水合物在制备治疗多靶点激酶信号通路转导异常的疾病药物中的应用。
  4. 根据权利要求3所述的应用，其特征在于，所述多靶点激酶信号通路转导异常的疾病为癌症；所述癌症为肝癌、乳房癌、呼吸道癌、消化系统肿瘤、脑癌、生殖器官癌、泌尿道肿瘤、皮肤癌、头颈癌、眼部肿瘤和它们的远端转移癌，以及肉瘤、淋巴瘤和白血病中的至少一种。
  5. 根据权利要求3所述的应用，其特征在于，所述药学上可接受的盐为多靶点激酶抑制剂与酸形成的盐，所述酸为甲磺酸、盐酸、醋酸、三氟乙酸、酒石酸、苹果酸、柠檬酸、氢溴酸、磷酸、硫酸、三氟甲磺酸、苯磺酸、对甲苯磺酸、1-萘磺酸、2-萘磺酸、乳酸、草酸、琥珀酸、富马酸、马来酸、水杨酸、苯甲酸、苯乙酸或扁桃酸。
  6. 一种药物组合物，其特征在于，所述药物组合物的活性成分包括权利要求1所述的多靶点激酶抑制剂。
  7. 根据权利要求6所述的药物组合物，其特征在于，所述药物组合物还包括至少一种药学领域公知的药用赋形剂，所述药用赋形剂包括填充剂、粘合剂、崩解剂、润滑助流剂。
  8. 根据权利要求6所述的药物组合物，其特征在于，所述多靶点激酶抑制剂占药物组合物的重量百分含量为1％～50％。
  9. 根据权利要求7所述的药物组合物，其特征在于，所述药用赋形剂占药物组合物的重量百分含量为：填充剂10％～80％、粘合剂1％～45％、崩解剂5％～20％、润滑助流剂0.1％～10％。
  10. 根据权利要求7所述的药物组合物，其特征在于，所述填充剂选自乳糖、微晶纤维素、甘露醇、山梨醇、磷酸氢钙、淀粉、预胶化淀粉、壳聚糖、蔗糖、淀粉水解寡糖、硅化微晶纤维素中的至少一种；所述粘合剂选自羟丙基甲基纤维素、糊精、卡波姆、黄原胶、阿拉伯胶、海藻酸钠、西黄蓍胶、麦芽精糊、聚乙烯吡咯烷酮、羟丙基纤维素中的至少一种；所述崩解剂选自低取代羟丙基纤维素、交联聚维酮、交联羧甲基纤维素钠、交联羧甲基淀粉钠、羧甲基淀粉钠中的至少一种；所述润滑助流剂选自硬脂酸镁、硬脂酸钙、硬脂酸、富马酸钠、十二烷基硫酸钠、山嵛酸甘油酯、滑石粉、二氧化硅、聚乙二醇、硬脂富马酸钠中的至少一种。
  11. 根据权利要求6-10任一所述的药物组合物，其特征在于，所述药物组合物可制备成药学上允许的任意一种剂型。
  12. 根据权利要求11所述的药物组合物，其特征在于，所述剂型为口服固体制剂，所述口服固体制剂包括片剂、胶囊、颗粒剂。
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