WO2021031071A1 - Dérivé d'amide et son utilisation dans la médecine - Google Patents

Dérivé d'amide et son utilisation dans la médecine Download PDF

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Publication number
WO2021031071A1
WO2021031071A1 PCT/CN2019/101388 CN2019101388W WO2021031071A1 WO 2021031071 A1 WO2021031071 A1 WO 2021031071A1 CN 2019101388 W CN2019101388 W CN 2019101388W WO 2021031071 A1 WO2021031071 A1 WO 2021031071A1
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WO
WIPO (PCT)
Prior art keywords
group
alkyl
haloalkyl
alkoxy
methyl
Prior art date
Application number
PCT/CN2019/101388
Other languages
English (en)
Chinese (zh)
Inventor
习宁
张涛
李敏雄
陈鹏
白长林
陈武宏
陈疏影
王元泽
王茜
彭菊
Original Assignee
广东东阳光药业有限公司
加拓科学公司
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 广东东阳光药业有限公司, 加拓科学公司 filed Critical 广东东阳光药业有限公司
Priority to PCT/CN2019/101388 priority Critical patent/WO2021031071A1/fr
Priority to CN201980099402.2A priority patent/CN114585616B/zh
Publication of WO2021031071A1 publication Critical patent/WO2021031071A1/fr

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Classifications

    • 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
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/4353—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems
    • 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
    • A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/16—Drugs for disorders of the alimentary tract or the digestive system for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P13/00—Drugs for disorders of the urinary system
    • A61P13/12—Drugs for disorders of the urinary system of the kidneys
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing three or more hetero rings

Definitions

  • the present invention belongs to the field of medicine, and specifically relates to an amide derivative with enzyme inhibitory activity and a pharmaceutical composition thereof.
  • the compound and composition can be used to prepare a medicine for treating ASK1 regulated diseases.
  • ASK1 not only regulates cell death, but also plays an important role in cell activities such as cytokine response, cell differentiation, and innate immune response.
  • Regulating the activity of ASK1 can treat or prevent a variety of diseases, including neurodegenerative diseases, cardiovascular diseases, inflammation, autoimmune diseases, and metabolic disorders.
  • diseases including neurodegenerative diseases, cardiovascular diseases, inflammation, autoimmune diseases, and metabolic disorders.
  • fibrotic diseases including pulmonary fibrosis and renal fibrosis
  • respiratory diseases including chronic embolic pulmonary obstruction and acute lung injury
  • liver diseases including chronic embolic pulmonary obstruction and acute lung injury
  • R a, R b, R c, R d, R e and R f are each independently hydrogen, deuterium, a halogen atom, hydroxyl, amino, cyano, methyl, ethyl, n Propyl, isopropyl, trifluoromethyl, difluoromethyl, methoxy, ethoxy, isopropyloxy, trifluoromethoxy, difluoromethoxy, methylamino, ethylamino, two Methylamino, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, propylene oxide, tetrahydrofuranyl, tetrahydropyranyl Or morpholinyl, wherein the methyl, ethyl, n-propyl, isopropyl,
  • the present invention relates to methods for the preparation, separation and purification of the compounds contained in formula (I).
  • C 1 - 6 alkyl refers particularly to the disclosure independently methyl, ethyl, C 3 alkyl, C 4 alkyl, C 5 alkyl, and C 6 alkyl.
  • carbocyclic groups further include, cyclopropyl, cyclobutyl, cyclopentyl, 1-cyclopentyl-1-enyl, 1-cyclopentyl-2-enyl, 1-cyclopentyl- 3-alkenyl, cyclohexyl, 1-cyclohexyl-1-alkenyl, 1-cyclohexyl-2-enyl, 1-cyclohexyl-3-enyl, cyclohexadienyl, cycloheptyl, cyclooctyl Group, cyclononyl, cyclodecyl, cycloundecyl, cyclododecyl, etc.
  • Y is -CR c R d - or - (CR e R f) 2 -; R c, R d, R e and R f are have the meanings according to the present invention.
  • the reagents are purchased from commodity suppliers such as Aldrich Chemical Company, Arco Chemical Company and Alfa Chemical Company, and they are used without further purification. Unless otherwise indicated, the general reagents are from Shantou Xilong Chemical Factory, Guangdong Guanghua Chemical Reagent Factory, Guangzhou Chemical Reagent Factory, Tianjin Haoyuyu Chemical Co., Ltd., Tianjin Fuchen Chemical Reagent Factory, Wuhan Xinhuayuan Technology Development Co., Ltd. The company, Qingdao Tenglong Chemical Reagent Co., Ltd., and Qingdao Ocean Chemical Factory purchased
  • Anhydrous tetrahydrofuran, dioxane, toluene and ether are obtained by refluxing and drying with sodium metal.
  • Anhydrous dichloromethane and chloroform are obtained by refluxing and drying with calcium hydride.
  • Ethyl acetate, petroleum ether, n-hexane, N,N-dimethylacetamide and N,N-dimethylformamide are dried in advance with anhydrous sodium sulfate.
  • reaction flask is plugged with a suitable rubber stopper, and the substrate is injected through a syringe. The glassware is dried.
  • the first step is the synthesis of 2,4-difluoro-5-nitrobenzamide
  • the fifth step is the synthesis of methyl 5-fluoro-1,3,3-trimethyl-2-oxoindole-6-carboxylate
  • the third step is the synthesis of methyl 4-((1-ethoxy-2-methyl-1-oxopropan-2-yl)oxy)-2-fluoro-5-nitrobenzoate
  • the first step 1- (2,4-difluoro-5-((3-(4-isopropyl-4H-1,2,4-triazol-3-yl)phenyl)carbamoyl)phenyl ) Synthesis of -1H-imidazole-5-carboxylic acid methyl ester
  • the kinase test is done by detecting myelin base protein (MBP) incorporated into ⁇ -33 P-ATP.
  • MBP myelin base protein
  • TBS Tris Buffered Salt Solution
  • 50mM Tris pH 8.0, 138mM NaCl, 2.7mM KCl Tris Buffered Salt Solution
  • Greiner high binding white 384-well plate

Landscapes

  • Chemical & Material Sciences (AREA)
  • Health & Medical Sciences (AREA)
  • Organic Chemistry (AREA)
  • Veterinary Medicine (AREA)
  • Animal Behavior & Ethology (AREA)
  • Public Health (AREA)
  • General Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • General Chemical & Material Sciences (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Engineering & Computer Science (AREA)
  • Epidemiology (AREA)
  • Pulmonology (AREA)
  • Gastroenterology & Hepatology (AREA)
  • Cardiology (AREA)
  • Heart & Thoracic Surgery (AREA)
  • Urology & Nephrology (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

L'invention concerne un dérivé d'amide et son utilisation. L'invention concerne en particulier un dérivé d'amide et une composition pharmaceutique contenant le composé. L'invention concerne également un procédé de préparation du composé et de la composition pharmaceutique, et leur utilisation dans la préparation de médicaments pour le traitement de maladies et/ou de pathologies régulées par ASK1, en particulier, leur utilisation dans la préparation de médicaments pour le traitement de la stéatohépatite non alcoolique.
PCT/CN2019/101388 2019-08-19 2019-08-19 Dérivé d'amide et son utilisation dans la médecine WO2021031071A1 (fr)

Priority Applications (2)

Application Number Priority Date Filing Date Title
PCT/CN2019/101388 WO2021031071A1 (fr) 2019-08-19 2019-08-19 Dérivé d'amide et son utilisation dans la médecine
CN201980099402.2A CN114585616B (zh) 2019-08-19 2019-08-19 酰胺衍生物及其在药物中的应用

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
PCT/CN2019/101388 WO2021031071A1 (fr) 2019-08-19 2019-08-19 Dérivé d'amide et son utilisation dans la médecine

Publications (1)

Publication Number Publication Date
WO2021031071A1 true WO2021031071A1 (fr) 2021-02-25

Family

ID=74659583

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/CN2019/101388 WO2021031071A1 (fr) 2019-08-19 2019-08-19 Dérivé d'amide et son utilisation dans la médecine

Country Status (2)

Country Link
CN (1) CN114585616B (fr)
WO (1) WO2021031071A1 (fr)

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2023246876A1 (fr) * 2022-06-24 2023-12-28 上海科技大学 Utilisation médicale de dérivés de formamide, dérivés de formamide et composition pharmaceutique les comprenant

Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2018157857A1 (fr) * 2017-03-03 2018-09-07 江苏豪森药业集团有限公司 Inhibiteur de kinase de régulation du signal apoptotique, son procédé de préparation et son application
WO2018233553A1 (fr) * 2017-06-19 2018-12-27 广东东阳光药业有限公司 Composé bicyclique fusionné et son utilisation en médecine
WO2019134680A1 (fr) * 2018-01-05 2019-07-11 广州市恒诺康医药科技有限公司 Inhibiteur de kinase-1 régulateur du signal apoptotique et utilisation associée
WO2020063727A1 (fr) * 2018-09-30 2020-04-02 山东轩竹医药科技有限公司 Inhibiteurs de l'ask1 à noyau tricyclique et leur utilisation

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2018157857A1 (fr) * 2017-03-03 2018-09-07 江苏豪森药业集团有限公司 Inhibiteur de kinase de régulation du signal apoptotique, son procédé de préparation et son application
WO2018233553A1 (fr) * 2017-06-19 2018-12-27 广东东阳光药业有限公司 Composé bicyclique fusionné et son utilisation en médecine
WO2019134680A1 (fr) * 2018-01-05 2019-07-11 广州市恒诺康医药科技有限公司 Inhibiteur de kinase-1 régulateur du signal apoptotique et utilisation associée
WO2020063727A1 (fr) * 2018-09-30 2020-04-02 山东轩竹医药科技有限公司 Inhibiteurs de l'ask1 à noyau tricyclique et leur utilisation

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2023246876A1 (fr) * 2022-06-24 2023-12-28 上海科技大学 Utilisation médicale de dérivés de formamide, dérivés de formamide et composition pharmaceutique les comprenant

Also Published As

Publication number Publication date
CN114585616B (zh) 2024-01-16
CN114585616A (zh) 2022-06-03

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