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WO2020186504A1 - Nouveau type de composés anti-tumoraux : dérivés du benzoxaborole substitué par le 7-propanamide - Google Patents

Nouveau type de composés anti-tumoraux : dérivés du benzoxaborole substitué par le 7-propanamide Download PDF

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Publication number
WO2020186504A1
WO2020186504A1 PCT/CN2019/079004 CN2019079004W WO2020186504A1 WO 2020186504 A1 WO2020186504 A1 WO 2020186504A1 CN 2019079004 W CN2019079004 W CN 2019079004W WO 2020186504 A1 WO2020186504 A1 WO 2020186504A1
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WIPO (PCT)
Prior art keywords
propanamide
derivatives
substituted
derivative
preparation
Prior art date
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Ceased
Application number
PCT/CN2019/079004
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English (en)
Inventor
Huchen Zhou
Zezhong LI
Jinyi ZHANG
Mingyan Zhu
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Shanghai Jiao Tong University
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Shanghai Jiao Tong University
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Filing date
Publication date
Application filed by Shanghai Jiao Tong University filed Critical Shanghai Jiao Tong University
Priority to PCT/CN2019/079004 priority Critical patent/WO2020186504A1/fr
Publication of WO2020186504A1 publication Critical patent/WO2020186504A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F5/00—Compounds containing elements of Groups 3 or 13 of the Periodic Table
    • C07F5/02—Boron compounds
    • C07F5/025—Boronic and borinic acid compounds
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents

Definitions

  • the present disclosure relates to the research in the field of drug for inhibition of tumor cells, especially relates to the derivatives of 7-propanamide substituted benzoxaborole and their preparation and pharmaceutical use.
  • benzoxaboroles are widely used in the antifungal, anti-bacterial, anti-parasitic, anti-viral and anti-inflammatory field (Chem. Rev. 2015, 115, 5224-5247; Sci. China Chem. 2013, 56, 1372-1381) , few studies have been reported about their antitumor activity. It has been reported that benzoxaborole-chalcone hybrids have anti-tumor activity, but their half maximal inhibitor concentration (IC 50 ) for inhibiting the proliferation of tumor cells is micromolar (Bioorg. Med. Chem. 2016, 26, 5797-5801. ) . Recent research found that some derivatives of 7-propanamide substituted benzoxaborole showed better inhibition activity towards the tumor cells, among which the lowest IC 50 value is around 20 nanomolar (CN107090000) .
  • the purpose of the present disclosure is to overcome the existing shortcomings of the prior art and to provide derivatives of 7-propanamide substituted benzoxaborole, which can inhibit the proliferation of tumor cells effectively with IC 50 value around 2 nM.
  • linker is at the meta position of phenyl group and linker is one selected from carbonyl, carbinol, alkyoxy, amide or atom N and O, R is selected from phenyl or substituted phenyl, or a salt thereof.
  • the substituted phenyl is selected from one of hydrogen, halogen, C1-C10 alkyl, alkoxy, alkynyl, ethoxycarbonyl, nitro, amino, aminomethyl, methlmercapto, trifluoromethoxy, trifluoromethyl, cyano or acetyl.
  • the linker is amide and R is phenyl.
  • the above derivatives also include their isotopic compounds, racemates, optically active isomers, polymorphs or mixtures thereof, and pharmaceutically acceptable salts thereof, such as salts formed with metallic elements such as sodium, potassium, lithium, calcium, etc., or salts formed with organic bases such as organic amines, pyridines, alkaloids and the like; or salts formed with inorganic acids such as hydrochloric acid, hydrobromic acid, hydrofluoric acid, nitric acid, sulfuric acid and phosphoric acid and the like, or salts formed with organic acids such as formic acid, acetic acid, sulfonic acid, tartaric acid and the like.
  • pharmaceutically acceptable salts thereof such as salts formed with metallic elements such as sodium, potassium, lithium, calcium, etc., or salts formed with organic bases such as organic amines, pyridines, alkaloids and the like; or salts formed with inorganic acids such as hydrochloric acid, hydrobromic acid, hydrofluoric acid, nitric acid, sulfur
  • linker is at the meta position of phenyl group and linker is one selected from carbonyl, carbinol, alkyoxy, amide or atom N and O, R is selected from phenyl or substituted phenyl.
  • the molar ratio of and EDCI is 1: (0.5-3) : (1-3) , stirring is performed at room temperature for a duration of 1-24h, and purification is performed by silica gel column chromatography.
  • the derivative is used for the preparation of a medicament for the prevention and treatment of tumors. Since the present derivatives inhibit the proliferation of tumor cells at the nanomolar level, therefore they can prevent and treat tumors, especially tumor cell lines such as ovarian cancer SKOV3, breast cancer MDA-MB231, and colon cancer HCT116, but are not limited to the aforesaid tumor cell lines.
  • the compounds have good inhibition to proliferation of tumor cells with IC 50 around 2 nM, and can effectively inhibit the proliferation of cells of common tumors exemplified by ovarian cancer, breast cancer, colon cancer.
  • reaction fluid was subjected to rotary evaporation at vacuum to remove the tetrahydrofuran and methanol.
  • the remaining reaction fluid was extracted with ethyl acetate, dried over anhydrous sodium sulfate and spinned in vacuum to obtain crude product 6 (11.9 g) as gray solid.
  • the crude product was used directly in the next step without further purification.
  • step (10) was prepared by using the synthesis method similar to Embodiment 1, in which steps (1) to step (9) are the same, except that in step (10) , the molar ratio of and EDCI is 1: 3: 2, stirring is performed at temperature of 20 °C for a duration of 24 h, and purification is performed by silica gel column chromatography.
  • step (10) was prepared by using the synthesis method similar to Embodiment 1, in which steps (1) to step (9) are the same, except that in step (10) , the molar ratio of and EDCI is 1: 3: 2, stirring is performed at temperature of 20 °C for a duration of 24 h, and purification is performed by silica gel column chromatography.
  • step (10) was prepared by using the synthesis method similar to Embodiment 1, in which steps (1) to step (9) are the same, except that in step (10) , the molar ratio of and EDCI is 1: 3: 2, stirring is performed at temperature of 20 °C for a duration of 24 h, and purification is performed by silica gel column chromatography.
  • step (10) was prepared by using the synthesis method similar to Embodiment 1, in which steps (1) to step (9) are the same, except that in step (10) , the molar ratio of and EDCI is 1: 3: 2, stirring is performed at temperature of 20 °C for a duration of 24 h, and purification is performed by silica gel column chromatography.
  • inhibition rate of proliferation (OD negative control -OD test ) / (OD negative control -OD blank ) ⁇ 100%.
  • Dose response curves were plotted with inhibition rate of cell proliferation by different concentrations of the same sample, and analyzed by GraphPad Prism 5 software, to determine the half maximal inhibitory concentration IC 50 of the sample.
  • a linker within the defined scope might not achieve similar desirable inhibition effect.
  • compound II a potent antiprotozoal agent (US 2011/0207701 A1) , which has a substituent at para position of phenyl group, has s relatively weak anticancer activity, thus serves as another negative control.
  • the superior inhibition effect of Compound 11-15 draws our attention to the specific meta position of linker on the phenyl group, instead of para position.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

La présente invention concerne des dérivés du benzoxaborole substitué par le 7-propanamide, ainsi que leur préparation et leur utilisation. La formule générale structurelle des dérivés est (formule). Les dérivés sont utilisés pour la préparation d'un médicament destiné à la prévention et au traitement de tumeurs. Par comparaison avec l'état de la technique, les présents dérivés inhibent la prolifération de cellules tumorales au niveau nanomolaire, les composés ayant une inhibition évidente pour la prolifération de cellules tumorales, en particulier des lignées de cellules tumorales telles que le cancer de l'ovaire SKAL3, le cancer du sein MDA-MB231 et le cancer du côlon HCT116, mais ne sont pas limités aux lignées de cellules tumorales susmentionnées.
PCT/CN2019/079004 2019-03-21 2019-03-21 Nouveau type de composés anti-tumoraux : dérivés du benzoxaborole substitué par le 7-propanamide Ceased WO2020186504A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
PCT/CN2019/079004 WO2020186504A1 (fr) 2019-03-21 2019-03-21 Nouveau type de composés anti-tumoraux : dérivés du benzoxaborole substitué par le 7-propanamide

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
PCT/CN2019/079004 WO2020186504A1 (fr) 2019-03-21 2019-03-21 Nouveau type de composés anti-tumoraux : dérivés du benzoxaborole substitué par le 7-propanamide

Publications (1)

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WO2020186504A1 true WO2020186504A1 (fr) 2020-09-24

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Application Number Title Priority Date Filing Date
PCT/CN2019/079004 Ceased WO2020186504A1 (fr) 2019-03-21 2019-03-21 Nouveau type de composés anti-tumoraux : dérivés du benzoxaborole substitué par le 7-propanamide

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Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2011022337A1 (fr) * 2009-08-19 2011-02-24 Anacor Pharmaceuticals, Inc. Petites molécules contenant du bore en tant qu'agents anti-protozoaires
CN107090000A (zh) * 2017-04-27 2017-08-25 上海交通大学 一种苯并硼唑7位脂肪酸的衍生物及其制备与药物用途

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2011022337A1 (fr) * 2009-08-19 2011-02-24 Anacor Pharmaceuticals, Inc. Petites molécules contenant du bore en tant qu'agents anti-protozoaires
CN107090000A (zh) * 2017-04-27 2017-08-25 上海交通大学 一种苯并硼唑7位脂肪酸的衍生物及其制备与药物用途

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