WO2018201939A1 - Promédicament de dérivé de benzoindazole, son procédé de préparation et son application - Google Patents

Promédicament de dérivé de benzoindazole, son procédé de préparation et son application Download PDF

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Publication number
WO2018201939A1
WO2018201939A1 PCT/CN2018/084340 CN2018084340W WO2018201939A1 WO 2018201939 A1 WO2018201939 A1 WO 2018201939A1 CN 2018084340 W CN2018084340 W CN 2018084340W WO 2018201939 A1 WO2018201939 A1 WO 2018201939A1
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WO
WIPO (PCT)
Prior art keywords
cancer
benzoindazole
prodrug
salt
derivative
Prior art date
Application number
PCT/CN2018/084340
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English (en)
Chinese (zh)
Inventor
周有骏
郑灿辉
蒋俊航
Original Assignee
中国人民解放军第二军医大学
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 中国人民解放军第二军医大学 filed Critical 中国人民解放军第二军医大学
Publication of WO2018201939A1 publication Critical patent/WO2018201939A1/fr

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D231/00—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings
    • C07D231/54—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings condensed with carbocyclic rings or ring systems
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
    • Y02P20/00—Technologies relating to chemical industry
    • Y02P20/50—Improvements relating to the production of bulk chemicals
    • Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups

Definitions

  • the invention relates to the technical field of medicinal chemistry, in particular to a prodrug of a benzoxazole derivative (TCd-1), a preparation method thereof and an application thereof.
  • TCd-1 benzoxazole derivative
  • Microtubules are composed of tubulin and microtubule-binding proteins and are the main components of the cytoskeleton. Microtubules have the kinetic properties of polymerization and depolymerization, and play an important role in maintaining cell morphology, cell division and proliferation, organelle composition and transport, and signal material conduction.
  • the anti-tumor drug targeting microtubules utilizes its kinetic properties, or promotes its depolymerization or inhibits its polymerization, thereby directly affecting the mitosis of cells, affecting many normal physiological functions of cells, and stopping cell division in M phase. . Studies have shown that there are three different drug binding sites in the microtubule: the paclitaxel site, the vincristine site, and the colchicine site. Since the cavity volume of the colchicine site is small and the structure of the corresponding inhibitor is relatively simple, research on its inhibitor has also received much attention in recent years.
  • CA-4 Combretastatin A-4
  • CA-4P granted its status as an orphan drug for ovarian cancer in July 2013.
  • CA-4P has carried out clinical research on undifferentiated thyroid cancer, neuroendocrine tumor and ovarian cancer.
  • the object of the present invention is to provide a prodrug of a benzoxazole derivative (TCd-1) against the deficiencies in the prior art.
  • Still another object of the present invention is to provide a process for preparing a prodrug of a benzoxazole derivative (TCd-1).
  • Another object of the present invention is to provide a prodrug of a benzoxazole derivative (TCd-1).
  • R is selected from the group consisting of amino acids, saccharides, and other groups having a basic group.
  • the basic group is an amino group.
  • the salt is the hydrochloride salt.
  • the synthetic route is:
  • the technical solution adopted by the present invention is: application in the preparation of a tubulin polymerization inhibitor.
  • the tumor disease is leukemia, non-small cell lung cancer, colon cancer, central nervous system tumor, melanoma, ovarian cancer, kidney cancer, prostate cancer or breast cancer.
  • the benzoxazole derivative prodrug of the present invention and its salt structure solve the problem of poor water solubility of the compound in the prior patent, and can be used for intravenous injection.
  • the prodrug of the benzoxazole derivative of the present invention inhibits tubulin polymerization, for leukemia, non-small cell lung cancer, colon cancer, central nervous system tumor, melanoma, ovarian cancer, renal cancer, prostate cancer, and breast. Cancer and the like have antitumor activity.
  • Reagents and conditions (a) BOC-L-serine, propylphosphoric anhydride (T3P), triethylamine, anhydrous dichloromethane, reflux; (b) methanolic hydrochloric acid solution, methanol.
  • Example 3 Determination of Solubility of Original Drug TCd-1 and Prodrug Hydrochloride TCd-1-PH
  • the HPLC method was used to test the solubility of the sample.
  • the standard curve was obtained by accurately weighing the appropriate amount of the sample, gradually adding physiological saline, shaking it to a sufficient concentration in the shaker, and detecting by HPLC.
  • a sample saturated solution was then configured in a similar manner and tested by HPLC.
  • the results showed that the solubility of the compound TCd-1 in physiological saline was much less than 0.001 g/mL, while the solubility of the prodrug hydrochloride TCd-1-PH was more than 0.945 g/mL, which was more than 945 times higher than that of the original drug.
  • Example 4 Prodrug hydrochloride TCd-1-PH in vivo activity test
  • the anti-tumor effect of the sample was evaluated using a human colon cancer colo205 model transplanted into nude mice.
  • the sample was injected intravenously 4 times at a dose of 20 mg/kg once every 4 days.
  • the sample has a tumor inhibition rate of >50% on human colon cancer colo205 xenografts in nude mice, and has obvious anti-tumor activity.
  • the body weight of the nude mice in the experimental group was not significantly different from that of the control group, and the sample showed no obvious toxicity.
  • T-dk-a was prepared by reacting 5,6,7-trimethoxy-3,4-dihydronaphthalen-2-one (2) with 4-methoxybenzoyl chloride. It is a yellow solid.
  • human colon cancer cell Colo205 was used as a screening target, and the cancer cell lines were all provided by the pharmacology research laboratory of Shanghai Pharmaceutical Industry Research Institute.
  • the culture medium is DMEM+10% FBS+ double antibody, and the model of the automatic microplate reader used is: Varioskan Flash, manufacturer: Thermo scientific. Import 96-well culture plates, etc.
  • the in vitro antitumor activity was determined by the MTT method.
  • MTT method 100 ⁇ l of a cell suspension having a concentration of 5 ⁇ 10 4 /ml was added to each well of a 96-well plate, and placed in a 37 ° C, 5% CO 2 incubator. After 24 h, the sample solution was added, 10 ⁇ l/well, and three replicate wells were set at 37 ° C, 5% CO 2 for 72 h. 20 ⁇ l of 5 mg/ml MTT solution was added to each well. After 4 hours, the solution was added, 100 ⁇ l/well, placed in an incubator, and dissolved, and the OD value of 570 nm was measured by a full-wavelength multi-plate reader.
  • bovine tubulin was used as a screening target, and the manufacturer: Cytoskeleton.
  • Tubulin Glycerol Buffer 60% glycerol, manufacturer: Cytoskeleton.
  • the fully automatic microplate reader model used is: Synergy 4, manufacturer: BioTek. Imported 96-well half-area culture plates, etc.
  • Sample preparation After dissolving in DMSO (Merck), buffer was added to prepare a corresponding concentration of the solution or a homogeneous suspension, and then diluted with a buffer.

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Plural Heterocyclic Compounds (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

La présente invention concerne un promédicament d'un dérivé de benzoindazole et un sel pharmaceutiquement acceptable de celui-ci, un procédé de préparation associé, et une application correspondante. Le promédicament de dérivé de benzoindazole est représenté par la formule structurale générale, formule I, dans laquelle R est choisi parmi divers acides aminés, sucres et autres groupes basiques. Le promédicament de dérivé de benzoindazole de la présente invention et sa structure de sel apportent une solution au problème de faible solubilité dans l'eau des composés rencontré dans les brevets existants, et peuvent ainsi être utilisés pour des injections intraveineuses. Le promédicament de dérivé de benzoindazole et le sel de celui-ci peuvent inhiber la polymérisation de la tubuline et ont une activité antitumorale pour la leucémie, le cancer du poumon non à petites cellules, le cancer du côlon, la tumeur du système nerveux central, le mélanome, le cancer de l'ovaire, le cancer rénal, le cancer de la prostate, le cancer du sein, etc.
PCT/CN2018/084340 2017-05-02 2018-04-25 Promédicament de dérivé de benzoindazole, son procédé de préparation et son application WO2018201939A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
CN201710301409.0 2017-05-02
CN201710301409.0A CN107011266B (zh) 2017-05-02 2017-05-02 苯并吲唑类衍生物的前药及其制备方法、应用

Publications (1)

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WO2018201939A1 true WO2018201939A1 (fr) 2018-11-08

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WO (1) WO2018201939A1 (fr)

Families Citing this family (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN107011266B (zh) * 2017-05-02 2023-04-14 中国人民解放军第二军医大学 苯并吲唑类衍生物的前药及其制备方法、应用

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN101687822A (zh) * 2007-07-06 2010-03-31 安斯泰来制药株式会社 二(芳基氨基)芳基化合物
CN106632050A (zh) * 2015-11-04 2017-05-10 中国人民解放军第二军医大学 苯并吲唑类衍生物及其制备方法、应用
CN107011266A (zh) * 2017-05-02 2017-08-04 中国人民解放军第二军医大学 苯并吲唑类衍生物的前药及其制备方法、应用

Family Cites Families (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
KR100824233B1 (ko) * 2001-10-10 2008-04-24 씨제이제일제당 (주) 사이클로옥시게나제-2의 저해제로서 선택성이 뛰어난3,4-디하이드로-1ｈ-나프탈렌 유도체
CN103130631A (zh) * 2011-11-29 2013-06-05 中国人民解放军第二军医大学 1-取代苯亚甲基-2-萘酮类衍生物及制备方法和用途

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN101687822A (zh) * 2007-07-06 2010-03-31 安斯泰来制药株式会社 二(芳基氨基)芳基化合物
CN106632050A (zh) * 2015-11-04 2017-05-10 中国人民解放军第二军医大学 苯并吲唑类衍生物及其制备方法、应用
CN107011266A (zh) * 2017-05-02 2017-08-04 中国人民解放军第二军医大学 苯并吲唑类衍生物的前药及其制备方法、应用

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CN107011266A (zh) 2017-08-04
CN107011266B (zh) 2023-04-14

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