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WO2019240701A1 - Nouveaux composés inhibant l'enzyme ef2-kinase - Google Patents

Nouveaux composés inhibant l'enzyme ef2-kinase Download PDF

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Publication number
WO2019240701A1
WO2019240701A1 PCT/TR2018/050935 TR2018050935W WO2019240701A1 WO 2019240701 A1 WO2019240701 A1 WO 2019240701A1 TR 2018050935 W TR2018050935 W TR 2018050935W WO 2019240701 A1 WO2019240701 A1 WO 2019240701A1
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WIPO (PCT)
Prior art keywords
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Legal status (The legal status 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 status listed.)
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Application number
PCT/TR2018/050935
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English (en)
Inventor
Mehmet AY
Bulent Ozpolat
Ferah COMERT ONDER
Tugba TASKIN TOK
Esen Bellur Atici
Bekir Karliga
Hakan KANDEMIR
Ali Cagir
Nurettin Sahiner
Gizem TATAR
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Canakkale Onsekiz Mart Universitesi Rektorlugu
Original Assignee
Canakkale Onsekiz Mart Universitesi Rektorlugu
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.)
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Publication date
Application filed by Canakkale Onsekiz Mart Universitesi Rektorlugu filed Critical Canakkale Onsekiz Mart Universitesi Rektorlugu
Publication of WO2019240701A1 publication Critical patent/WO2019240701A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom

Definitions

  • the invention is related to synthesis of novel compounds that inhibit the EF2- Kinase enzyme which is an emerging therapeutic target that has been shown to be an important driver of tumor growth and progression in most commonly diagnosed human cancers including breast, lung, prostate, and other highly aggressive cancers such as pancreas, brain and ovarian cancers.
  • EF2-Kinase inhibitors Prior Art Suitable, specific and potent inhibitors of EF2-Kinase enzyme are not available commercially. Although a few molecules have been published as EF2 -Kinase inhibitors these are not specific for EF2-kinase and inhibit other kinases and not potent enough to inhibit EF2-Kinase enzyme in low concentrations.
  • A-484954 which is a pyrido pyrimidine carboxamide derivative has been published as an eEF2K inhibitor [5] however these have shown to be not effective in inhibiting cancer cell proliferation at clinically relevant lowers concentrations.
  • A484954 inhibits cell proliferation and EF2kinase activity at very high doses (i.e,
  • the aim of this invention is to carry out the synthesis of novel compounds that inhibit EF2-Kinase enzyme.
  • Another aim of this invention is to carry out the synthesis of potent inhibitors compounds that can achieve EF2K inhibition at submicromolar concentrations (less than 1 micro molar) or idealy around 0.1 micro molar concentrations at 90% or higher rates in cancer cells.
  • pre-testing compounds 1-5 and 2A-2Z have been designed and synthesized which may be effective in treating breast and pancreas cancers and it has been observed that they inhibit cell growth in breast cancer and pancreas cancer cells. Synthesis of the pre-testing compounds:
  • Methyl 2-(4-mctil-2-okso-2/7-kromcn-7-iloksi (acetate (3) compound has been synthesized with a yield of 71% as a result of mixing at room temperature all night in the presence of K 2 CO 3 and acetone.
  • the primarily pre-testing compounds that are expressed as the formula (A) compound are synthesized.
  • Diagram 1 The general reaction diagram of the 2A-2K derived compounds.
  • Piperidine has been added (5-10 drops) into the mixture of 3-Acetylcoumarin (1 equivalent) and substituted benzaldehyde (1.96 equivalent) in ethanol.
  • the mixture is boiled under a condenser.
  • the sediment solids have been collected after they are filtered. It is then washed with ethanol [11, 12] and purified by using column chromatography.
  • Formula (A) compound has been used in order to synthesize the 2-2Z compounds of the invention.
  • R 3 -OCH 3 ;
  • R 3 -OCH 3 ;
  • Aliphatic and aromatic amine derivatives that comprise various functional groups have been used in synthesizing compounds derived from position 3 of the coumarin ring.
  • the purification has been carried out by silica column chromatography and/or crystallization from ethanol.
  • R 3 -OCH 3 ;
  • R 3 -OCH 3 ;
  • Compound 2 and its derivatives (2A-2Z) that have been subjected to clinical trials and that have been approved and that are anticipated to be used in medicines that are planned to be taken to the clinic inhibited EF2 -kinase over 90% in invasive breast cancer cells (MDA-MB-231) and pancreas cancer (PANC1) cells at sub micro molar (1 micromolar and lower) concentrations (for example at doses of 0 1 micromolar or 100 nanomolar doses).
  • Compound 2 has been subjected to pre-clinical trials and it has been discovered that it inhibited EF2-kinase when injected through the tail veins of rats intravenously.
  • EF2K enzyme Having compounds that are candidates for clinical trials that can be used in cancer treatment by developing small molecules that can inhibit EF2K enzyme which is efficient in human cancers shall provide novel molecules for cancer medicines that are very expensive.
  • the inhibition of the EF2K enzyme in cancer cells besides breast and pancreas cancers, is effective in some cancer types as it inhibits tumor grown in cancers such as ovarian cancer, brain tumors, melanoma, lung and prostate cancers and some blood cancers that may all be malign and which may not have a precise cure.
  • EF2K enzyme resembles (homology) the ones in humans in other species genetically it probably plays a significant role in animal tumors and it may be used in the field of veterinary medicine for treating pets (cats, dogs).
  • EF2K inhibitors in brain degenerative diseases such as atherosclerosis, depression and Alzheimer’s that are accompanied with the increased activity of EF2K.
  • the efficiencies of these discovered compounds can be investigated against other cancer types and/or other diseases and their treatment field can be expanded.

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

Abstract

L'invention concerne la synthèse de nouveaux composés qui inhibent l'enzyme EF2-kinase ayant un effet dans le cancer du sein, du pancréas, du cerveau, des ovaires, des poumons, de la peau (mélanome) et du sang.
PCT/TR2018/050935 2018-06-12 2018-12-28 Nouveaux composés inhibant l'enzyme ef2-kinase Ceased WO2019240701A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
TR2018/08406 2018-06-12
TR2018/08406A TR201808406A2 (tr) 2018-06-12 2018-06-12 Ef2-ki̇naz enzi̇mi̇ni̇ i̇nhi̇be eden yeni̇ bi̇leşi̇kler

Publications (1)

Publication Number Publication Date
WO2019240701A1 true WO2019240701A1 (fr) 2019-12-19

Family

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Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/TR2018/050935 Ceased WO2019240701A1 (fr) 2018-06-12 2018-12-28 Nouveaux composés inhibant l'enzyme ef2-kinase

Country Status (2)

Country Link
TR (1) TR201808406A2 (fr)
WO (1) WO2019240701A1 (fr)

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN111588718A (zh) * 2020-05-20 2020-08-28 五邑大学 一种α-葡萄糖苷酶抑制剂及其应用
WO2021167554A1 (fr) * 2020-02-18 2021-08-26 Canakkale Onsekiz Mart Universitesi Rektorlugu Utilisation de composés synthétisés en tant qu'inhibiteur de l'enzyme ef2-kinase
CN119775207A (zh) * 2024-12-09 2025-04-08 山东农业大学 一种含吗啉的酰胺类化合物及其制备方法和应用

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2014023081A1 (fr) * 2012-08-07 2014-02-13 中国科学院上海生命科学研究院 Dérivés d'artémisinine, leur processus de préparation et leur utilisation
US20180042864A1 (en) * 2016-08-11 2018-02-15 National Taiwan Normal University Method for Treating Abnormal B-Amyloid Aggregation Mediated Diseases

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2014023081A1 (fr) * 2012-08-07 2014-02-13 中国科学院上海生命科学研究院 Dérivés d'artémisinine, leur processus de préparation et leur utilisation
US20180042864A1 (en) * 2016-08-11 2018-02-15 National Taiwan Normal University Method for Treating Abnormal B-Amyloid Aggregation Mediated Diseases

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2021167554A1 (fr) * 2020-02-18 2021-08-26 Canakkale Onsekiz Mart Universitesi Rektorlugu Utilisation de composés synthétisés en tant qu'inhibiteur de l'enzyme ef2-kinase
CN111588718A (zh) * 2020-05-20 2020-08-28 五邑大学 一种α-葡萄糖苷酶抑制剂及其应用
CN119775207A (zh) * 2024-12-09 2025-04-08 山东农业大学 一种含吗啉的酰胺类化合物及其制备方法和应用

Also Published As

Publication number Publication date
TR201808406A2 (tr) 2018-07-23

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