WO2021114313A1 - Ion channel antagonists/blockers and uses thereof - Google Patents

Ion channel antagonists/blockers and uses thereof Download PDF

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Publication number
WO2021114313A1
WO2021114313A1 PCT/CN2019/125453 CN2019125453W WO2021114313A1 WO 2021114313 A1 WO2021114313 A1 WO 2021114313A1 CN 2019125453 W CN2019125453 W CN 2019125453W WO 2021114313 A1 WO2021114313 A1 WO 2021114313A1
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Prior art keywords
mmol
substituted
unsubstituted
group
naphthalen
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PCT/CN2019/125453
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English (en)
French (fr)
Inventor
Yihan CHEN
Dandan LIANG
Yi Liu
Subas Man Sakya
Jinhua Yang
Li Li
Duanyang XIE
Dan SHI
Ke XIONG
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Shanghai East Hospital
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Shanghai East Hospital
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Priority to US17/755,398 priority Critical patent/US12187681B2/en
Priority to PCT/CN2019/125453 priority patent/WO2021114313A1/en
Priority to JP2022561215A priority patent/JP7478251B2/ja
Priority to CN201980099282.6A priority patent/CN114401935B/zh
Publication of WO2021114313A1 publication Critical patent/WO2021114313A1/en
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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    • C07D217/22—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to carbon atoms of the nitrogen-containing ring
    • C07D217/24—Oxygen atoms
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
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Definitions

  • the object of the present invention is to provide an effective and safe ion channel antagonist which is useful for treatment in heart disease and other ion channel related diseases.
  • R b is selected from the group consisted of - (CH 2 ) -, -CH (OH) -, -NH-, -N (CH 3 ) -, -O-, and -S-.
  • R 1 , R 2 , R 3 , R 7 , R c , R d , L 1 , and R' are as define above;
  • R 1 is O, NH, CH 2 , S, S (O) and S (O) 2 .
  • C6-C10 aryl refers to aromatic hydrocarbon group having 6 to 10 carbon atoms, for example phenyl, naphthyl and the like.
  • Alkylidene is replaced refers to the methylidene in the divalent straight or branched C 1-3 hydrocarbyl may be replaced with the groups as defined herein, for example, it is -CH 2 -S (O) -CH 2 -, -CH 2 -O-CH 2 -, -CH 2 -C (O) NR y -CH 2 -, -C (O) -CH 2 -CH 2 -, -CH 2 -C (R y R x ) -CH 2 -, -N (R y ) -CH 2 -CH 2 -, -C (R y R x ) -C (R y R x ) -CH 2 -and the like after replacement.
  • term “monocyclic ring” saturated or partially unsaturated, refers to a saturated all-carbon monocyclic ring or partially unsaturated all-carbon monocyclic ring.
  • the “monocyclic ring” having 3 to 7 ring atoms, i.e. 3 to 7 membered monocyclic ring.
  • the examples of 3 to 7 membered monocyclic ring including (but not limited to) : cyclopropane, cyclobutane, cyclopentane, cyclohexane, cyclohexadiene ring, cycloheptane, cycloheptanetriene ring and the like.
  • the known starting materials of the invention are synthesized by the methods known in the art, or are purchased from Bide Chemical ltd., Bridge, Combi Blocks, Wuxi Lab Networks, Acros Organics, Aldrich Chemical Company, Accela ChemBio Inc and Darui Chemical Company etc.
  • DMF refers to dimethylformamide
  • DMSO dimethylsulfoxide
  • THF tetrahydrofuran
  • DIEA N, N-diisopropylethylamine
  • EA ethyl acetate
  • PE petroleum ether.
  • compound No. "TJU-AXXX" and “AXXX” means same compounds.
  • compound TJU-A001 and compound A001 are same.
  • Step A To a solution of 2-bromo-4, 5-dimethylphenol (200 mg, 1 mmol) and 1, 3, 5-trioxane (15 mg, 0.167 mmol) in dichloromethane (5 mL) was added TfOH (375 mg, 2.5 mmol) . The reaction mixture was stirred for 2 h at room temperature. The reaction mixture was washed with water (5 mL) and brine (10 mL ⁇ 3) , dried over anhydrous sodium sulfate, and concentrated to afford crude 6, 6'-methylenebis (2-bromo-4, 5-dimethylphenol) (150 mg) which was used for the next step without purification.
  • Example 56 2- (2- (diethylamino) ethoxy) -N- (2-methoxynaphthalen-1-yl) naphthalen-1-amine (A111-I-1)

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