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WO2018161476A1 - Composé amide, procédé de préparation et utilisation associés - Google Patents

Composé amide, procédé de préparation et utilisation associés Download PDF

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WO2018161476A1
WO2018161476A1 PCT/CN2017/091212 CN2017091212W WO2018161476A1 WO 2018161476 A1 WO2018161476 A1 WO 2018161476A1 CN 2017091212 W CN2017091212 W CN 2017091212W WO 2018161476 A1 WO2018161476 A1 WO 2018161476A1
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aryl
alkyl
cycloalkyl
heteroaryl
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Chinese (zh)
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袁其朋
谢瑞
邓炳华
李岩
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Beijing University of Chemical Technology
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Beijing University of Chemical Technology
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
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    • C07D217/00—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems
    • C07D217/02—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems with only hydrogen atoms or radicals containing only carbon and hydrogen atoms, directly attached to carbon atoms of the nitrogen-containing ring; Alkylene-bis-isoquinolines
    • C07D217/06—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems with only hydrogen atoms or radicals containing only carbon and hydrogen atoms, directly attached to carbon atoms of the nitrogen-containing ring; Alkylene-bis-isoquinolines with the ring nitrogen atom acylated by carboxylic or carbonic acids, or with sulfur or nitrogen analogues thereof, e.g. carbamates
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    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C333/00—Derivatives of thiocarbamic acids, i.e. compounds containing any of the groups, the nitrogen atom not being part of nitro or nitroso groups
    • C07C333/14—Dithiocarbamic acids; Derivatives thereof
    • C07C333/18—Esters of dithiocarbamic acids
    • C07C333/20—Esters of dithiocarbamic acids having nitrogen atoms of dithiocarbamate groups bound to hydrogen atoms or to acyclic carbon atoms
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    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
    • C07D209/04—Indoles; Hydrogenated indoles
    • C07D209/08—Indoles; Hydrogenated indoles with only hydrogen atoms or radicals containing only hydrogen and carbon atoms, directly attached to carbon atoms of the hetero ring
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    • C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
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    • C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D211/08—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms
    • C07D211/10—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with radicals containing only carbon and hydrogen atoms attached to ring carbon atoms
    • C07D211/16—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with radicals containing only carbon and hydrogen atoms attached to ring carbon atoms with acylated ring nitrogen atom
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    • C07—ORGANIC CHEMISTRY
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    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/24—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with substituted hydrocarbon radicals attached to ring carbon atoms
    • C07D213/36—Radicals substituted by singly-bound nitrogen atoms
    • C07D213/38—Radicals substituted by singly-bound nitrogen atoms having only hydrogen or hydrocarbon radicals attached to the substituent nitrogen atom
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    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/24—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with substituted hydrocarbon radicals attached to ring carbon atoms
    • C07D213/36—Radicals substituted by singly-bound nitrogen atoms
    • C07D213/40—Acylated substituent nitrogen atom
    • C—CHEMISTRY; METALLURGY
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    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom 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 ring carbon atoms
    • C07D213/72—Nitrogen atoms
    • C07D213/74—Amino or imino radicals substituted by hydrocarbon or substituted hydrocarbon radicals
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    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom 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 ring carbon atoms
    • C07D213/72—Nitrogen atoms
    • C07D213/75—Amino or imino radicals, acylated by carboxylic or carbonic acids, or by sulfur or nitrogen analogues thereof, e.g. carbamates
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
    • C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
    • C07D215/04—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with only hydrogen atoms or radicals containing only hydrogen and carbon atoms, directly attached to the ring carbon atoms
    • C07D215/08—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with only hydrogen atoms or radicals containing only hydrogen and carbon atoms, directly attached to the ring carbon atoms with acylated ring nitrogen atom
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
    • C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
    • C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
    • C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
    • C07D239/32—One oxygen, sulfur or nitrogen atom
    • C07D239/42—One nitrogen atom
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D241/00—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings
    • C07D241/02—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings
    • C07D241/10—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members
    • C07D241/14—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members 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 ring carbon atoms
    • C07D241/20—Nitrogen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
    • C07D295/16—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms acylated on ring nitrogen atoms
    • C07D295/20—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms acylated on ring nitrogen atoms by radicals derived from carbonic acid, or sulfur or nitrogen analogues thereof
    • C07D295/21—Radicals derived from sulfur analogues of carbonic acid

Definitions

  • HDAC zinc ion-dependent metalloproteinase family-histone deacetylase
  • amide HDAC inhibitors are in clinical research. Among them, Tacedinaline (1, CI-994) shows certain inhibitory activity against HDAC and has a broad spectrum of antitumor activity, making it the first amide HDAC inhibition to enter clinical trials.
  • Agent, CI-994 is currently used in combination with gemcitabine in phase II clinical trials for patients with solid tumors such as non-small cell lung cancer and colon cancer.
  • Sedabamide (2, Chidamide, CS055) is an approved oral anti-acetylase inhibitor developed by Shenzhen Microcore Biotechnology Co., Ltd., and the approved indication is recurrent and refractory peripheral T-cell lymphoma.
  • Sidabenamine is in the clinical stage for the treatment of lung cancer, stomach cancer, liver cancer and breast cancer.
  • benzamide compounds such as MS-275 (3), and MGCD-0103 (4) is in the clinical stage.
  • Aminodithioformate is a class of compounds with a wide range of biological activities such as antioxidant, antibacterial, antiviral, and antitumor activities.
  • Brassinin (Compound 5 in the structure shown in the following figure) is a natural compound having an aminodithioformate structure extracted from Brassica juncea, and this compound was found to have excellent antitumor activity.
  • a series of derivatives of Brassinin (compounds 6, 7, 8 in the structure shown in the following figure) have been synthesized, and these derivatives also have excellent antitumor and antioxidant activities.
  • the above structural formula is a compound containing an aminodithioformate structure
  • the inventors of the present invention have creatively introduced a broadly biologically active aminodithioformate structure into the development of novel HDAC inhibitors, synthesized a series of novel skeletal structure amide compounds, and have HDAC inhibitory activity,
  • the anti-tumor activity in vitro the effect on the formation of monoclonal cells in tumor cells, the influence on tumor cell cycle and the effect on tumor cell apoptosis, the compounds in this patent showed more than the reference drugs CI994 and Chidamide (CS055).
  • MS275 has stronger antitumor activity and selectivity for HDAC enzymes.
  • the present invention relates to the design and synthesis of a class of compounds.
  • the present invention provides an amide compound which is more excellent in pharmacodynamic activity, a preparation method and use thereof. The reason why the present invention can solve the above problems is achieved by the following technical solutions:
  • A is selected from the group consisting of alkyl, cycloalkyl, aryl, heteroaryl, heterocyclic, alkenyl, alkynyl, alkyl, cycloalkyl, aryl, heteroaryl, heterocyclyl, alkenyl, alkyne
  • the group is optionally unsubstituted or substituted by one or more substituents each independently selected from the group consisting of alkyl, cycloalkyl, aryl, heteroaryl, heterocyclyl, alkenyl, alkynyl, amino , hydroxy, mercapto, carboxy, alkoxy, cycloalkoxy, halogen, cyano, nitro, nitroso, sulfo;
  • Z is selected from the group consisting of alkyl, cycloalkyl, aryl, heteroaryl, heterocyclyl, alkenyl, alkynyl, alkyl, cycloalkyl, aryl, heteroaryl, heterocyclyl, alkenyl, alkyne
  • the group is optionally unsubstituted or substituted by one or more substituents each independently selected from the group consisting of alkyl, cycloalkyl, aryl, heteroaryl, heterocyclyl, alkenyl, alkynyl, amino , hydroxy, mercapto, carboxy, alkoxy, cycloalkoxy, halogen, cyano, nitro, nitroso, sulfo;
  • R 1 and R 2 satisfy one of the following two conditions: (1) R 1 and R 2 are each independently selected from hydrogen, alkyl, cycloalkyl, cycloalkylalkyl, alkylcycloalkyl, aryl , arylalkyl, alkylaryl, heteroaryl, heteroarylalkyl, alkylheteroaryl, heterocyclyl, heterocyclylalkyl, alkylheterocyclyl, alkenyl, alkynyl, above Alkyl, cycloalkyl, cycloalkylalkyl, alkylcycloalkyl, aryl, arylalkyl, alkylaryl, heteroaryl, heteroarylalkyl, alkylheteroaryl, heterocycle And optionally substituted or substituted by one or more substituents each independently selected from alkyl, cycloalkyl , aryl, heteroaryl, heterocyclic, alkenyl, alkynyl, amino, hydroxy
  • R 3 and R 4 each independently are selected from hydrogen, hydroxy, amino, thiol, alkyl, cycloalkyl, cycloalkylalkyl, alkylcycloalkyl, aryl, arylalkyl, alkylaryl, hetero Aryl, heteroarylalkyl, alkylheteroaryl, heterocyclyl, heterocyclylalkyl, alkylheterocyclyl, alkenyl, alkynyl, alkyl, cycloalkyl, cycloalkylalkyl , alkylcycloalkyl, aryl, arylalkyl, alkylaryl, heteroaryl, heteroarylalkyl, alkylheteroaryl, heterocyclyl, heterocyclylalkyl, alkylheterocycle
  • the base, alkenyl, alkynyl group is optionally unsubstituted or substituted by one or more substituents, each independently selected from alkyl,
  • A is selected from the group consisting of alkyl, cycloalkyl, aryl, heteroaryl, heterocyclic, alkenyl, alkynyl, alkyl, cycloalkyl, aryl, heteroaryl, heterocyclyl, alkenyl, alkyne
  • the group is optionally unsubstituted or substituted by one or more substituents each independently selected from the group consisting of alkyl, cycloalkyl, aryl, heteroaryl, heterocyclyl, alkenyl, alkynyl, amino , hydroxy, mercapto, carboxy, alkoxy, cycloalkoxy, halogen, cyano, nitro, nitroso, sulfo;
  • R 1 and R 2 satisfy one of the following two conditions: (1) R 1 and R 2 are each independently selected from hydrogen, alkyl, cycloalkyl, cycloalkylalkyl, alkylcycloalkyl, aryl , arylalkyl, alkylaryl, heteroaryl, heteroarylalkyl, alkylheteroaryl, heterocyclyl, heterocyclylalkyl, alkylheterocyclyl, alkenyl, alkynyl, above Alkyl, cycloalkyl, cycloalkylalkyl, alkylcycloalkyl, aryl, arylalkyl, alkylaryl, heteroaryl, heteroarylalkyl, alkylheteroaryl, heterocycle And optionally substituted or substituted by one or more substituents each independently selected from alkyl, cycloalkyl , aryl, heteroaryl, heterocyclic, alkenyl, alkynyl, amino, hydroxy
  • R 1 and R 2 satisfy one of the following two conditions: (1) R 1 and R 2 are each independently selected from hydrogen, alkyl, cycloalkyl, cycloalkylalkyl, alkylcycloalkyl, aryl , arylalkyl, alkylaryl, heteroaryl, heteroarylalkyl, alkylheteroaryl, heterocyclyl, heterocyclylalkyl, alkylheterocyclyl, alkenyl, alkynyl, above Alkyl, cycloalkyl, cycloalkylalkyl, alkylcycloalkyl, aryl, arylalkyl, alkylaryl, heteroaryl, heteroarylalkyl, alkylheteroaryl, heterocycle And optionally substituted or substituted by one or more substituents each independently selected from alkyl, cycloalkyl , aryl, heteroaryl, heterocyclic, alkenyl, alkynyl, amino, hydroxy
  • X 1 , X 2 , X 3 , X 4 are each independently selected from the group consisting of hydrogen, alkyl, cycloalkyl, aryl, heteroaryl, heterocyclyl, alkenyl, alkynyl, amino, hydroxy, decyl, carboxy, Alkoxy, cycloalkoxy, haloaryl, alkoxycarbonyl, halogen, cyano, nitro, nitroso, amido, thiocyano, isothiocyano, ureido, sulfo;
  • the compound is selected from the group consisting of compounds of formula IV:
  • R 1 and R 2 satisfy one of the following two conditions: (1) R 1 and R 2 are each independently selected from hydrogen, alkyl, cycloalkyl, cycloalkylalkyl, alkylcycloalkyl, aryl , arylalkyl, alkylaryl, heteroaryl, heteroarylalkyl, alkylheteroaryl, heterocyclyl, heterocyclylalkyl, alkylheterocyclyl, alkenyl, alkynyl, above Alkyl, cycloalkyl, cycloalkylalkyl, alkylcycloalkyl, aryl, arylalkyl, alkylaryl, heteroaryl, heteroarylalkyl, alkylheteroaryl, heterocycle And optionally substituted or substituted by one or more substituents each independently selected from alkyl, cycloalkyl , aryl, heteroaryl, heterocyclic, alkenyl, alkynyl, amino, hydroxy
  • a pharmaceutical composition comprising: the compound of the first aspect of the invention, or a pharmaceutically acceptable salt thereof, or a solvate thereof, or a prodrug molecule thereof, is provided.
  • a compound of the above formula I and a pharmaceutically acceptable salt thereof, or a solvate thereof, or a prodrug thereof, for use in the treatment or prevention of antitumor, anticancer, anti-inflammatory, antibacterial
  • a pharmaceutically acceptable salt thereof, or a solvate thereof, or a prodrug thereof for use in the treatment or prevention of antitumor, anticancer, anti-inflammatory, antibacterial
  • antiviral and anti-oxidant drugs for use in the treatment or prevention of antitumor, anticancer, anti-inflammatory, antibacterial.
  • the tumor or cancer is selected from the group consisting of melanoma, gastric cancer, cervical cancer, ovarian cancer, liver cancer, lung cancer, nasopharyngeal cancer, colon cancer, rectal cancer, lymphoma, and blood cancer.
  • A, Z, R 1 , R 2 , R 3 , R 4 are the compounds of the first aspect of the invention as defined in formula I.
  • the base used in the reaction step (a) is selected from the group consisting of potassium phosphate, potassium carbonate, sodium phosphate, sodium carbonate, cesium carbonate, aluminum oxide, dipotassium hydrogen phosphate, and hydrogen phosphate.
  • the peptide condensing agent used is selected from the group consisting of: benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate, benzotriazol-1-yl-oxytripyrolidine hexafluorophosphate Phosphorus, N,N'-dicyclohexylcarbodiimide, O-benzotriazole-N,N,N',N'-tetramethyluronium tetrafluoroborate.
  • alkyl group the following linear or branched groups may be mentioned: methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl , n-pentyl and its other seven isomers, n-hexyl and its other sixteen isomers, n-heptyl and their respective isomers, n-octyl and its various isomers, n-decyl and Its various isomers.
  • cycloalkyl group the following groups may be mentioned: cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclodecyl; and by two or more
  • the above-mentioned single ring is a fused ring, a bridged ring, or a spiro ring group formed by a common side and a common carbon atom.
  • alkenyl refers to a group formed in the case where one or more double bonds are present in the above alkyl group (except for a methyl group).
  • alkynyl refers to a group formed in the case where one or more triple bonds are present in the above alkyl group (except for a methyl group).
  • alkoxy refers to a group in which an oxygen atom is bonded to the above alkyl group and is bonded to the remainder of the molecule by a single bond of the oxygen atom, which encompasses various possible geometric isomers. With stereoisomeric groups.
  • alkoxy groups the following straight or branched groups may be mentioned: methoxy, ethoxy, n-propoxy, isopropoxy, n-Butoxy, isobutoxy, sec-butoxy, tert-butoxy, n-pentyloxy and seven other isomers, n-hexyloxy and sixteen other isomers, n-heptyloxy and each Isomers, n-octyloxy groups, and various isomers, n-decyloxy groups, and various isomers.
  • aryl refers to an aromatic ring system consisting of at least 6 carbon atoms, which ring system may be monocyclic, bicyclic or polycyclic, wherein the bicyclic and polycyclic rings may be bonded by a single ring through a single bond. Formed in a fused manner.
  • aryl group the following groups may be mentioned: phenyl, naphthyl, anthryl, phenanthryl, anthracenyl, fluorenyl, fluorenyl, pentenyl, heptyl, triphenylene, And tetraphenyl, penfenolyl, pentacene, tetra-p-phenylene, hephenenyl, hexaphenyl, decyl, trimethylene, heptendyl, heptaphenyl, egg phenyl, biphenyl Base, binaphthyl.
  • heteroaryl refers to a 5-14 membered aromatic heterocyclic ring system having one or more heteroatoms independently selected from N, O or S, which ring system may be monocyclic, Bicyclic and polycyclic, wherein the bicyclic ring and the polycyclic ring may be formed by a single ring by a single bond connection or a condensed manner.
  • heteroaryl groups the following groups may be mentioned: oxazolyl, isoxazolyl, imidazolyl, furyl, fluorenyl, isodecyl, pyrrolyl, triazolyl, triazinyl , tetrazolyl, thienyl, thiazolyl, isothiazolyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, benzofuranyl, benzothiazolyl, benzoxazolyl, benzimidazolyl, Benzothiophenyl, benzofuranyl, oxazolyl, isoquinolyl, quinazolinyl, naphthyridinyl, fluorenyl, thiadiazolyl, pyridazinyl, phenazinyl, coumarinyl, Pyridopyridyl, pyridopyrida
  • heterocyclyl refers to a non-aromatic 3-18 membered ring system composed of a carbon atom and a hetero atom independently selected from N, O or S, which ring system may be monocyclic, bicyclic, Or a polycyclic ring, which may also be a fused ring, a bridged ring, a spiro ring, and may optionally contain one or more double bonds.
  • the heterocyclic group the following groups may be mentioned: acridinyl group, benzodioxanyl group, benzopyranyl group, benzohydropyranyl group, dioxolane group, decahydrogen Isoquinolyl, indanyl, porphyrin, isoindolyl, isochroman, morpholinyl, piperazinyl, 2-oxopiperrazinyl, octahydrofluorenyl , octahydroisodecyl, 4-piperidinone, dihydroquinolyl, dihydroisoquinolinyl, tetrahydroquinolyl, tetrahydroisoquinolinyl, 1-(diphenylmethyl) Piperazinyl, tetrahydrofuranyl, tetrahydropyranyl, tetrahydropyrrolyl, piperidinyl.
  • alkylcycloalkyl as used in the present invention means a cycloalkyl group in which one or more hydrogen atoms are independently substituted by an alkyl group, wherein the cycloalkyl group and the alkyl group are as defined above.
  • arylalkyl refers to an alkyl group in which one or more hydrogen atoms are independently substituted by an aryl group, wherein the aryl group and the alkyl group are as defined above.
  • alkylaryl as used in the present invention means an aryl group in which one or more hydrogen atoms are independently substituted by an alkyl group, wherein the aryl group and the alkyl group are as defined above.
  • heteroarylalkyl refers to an alkyl group wherein one or more hydrogen atoms are independently substituted by a heteroaryl group, wherein said heteroaryl group and alkyl group are as defined above.
  • alkylheteroaryl refers to a heteroaryl group in which one or more hydrogen atoms are independently substituted by an alkyl group, wherein said heteroaryl group and alkyl group are as defined above.
  • alkylheterocyclyl as used in the present invention means a heterocyclic group wherein one or more hydrogen atoms are independently substituted by an alkyl group, wherein the heterocyclic group and the alkyl group are as defined above.
  • heterocyclylalkyl refers to an alkyl group in which one or more hydrogen atoms are independently substituted by a heterocyclic group, wherein the heterocyclic group and the alkyl group are as defined above.
  • Substituent means that the above substituent may be substituted by a single substituent, or the substituents may be freely combined to form a new substituent to participate in the substitution.
  • substituents the following groups may be mentioned: alkyl, cycloalkyl, aryl, alkylcycloalkyl, cycloalkylalkyl, heteroaryl, heteroarylalkyl, alkane Heteroaryl, heterocyclic, heterocyclylalkyl, alkylheterocyclyl, heterocyclylalkenyl, alkenylheterocyclyl, heterocyclylalkynyl, alkynylheterocyclyl, alkoxycarbonyl , haloaryl, cyanoaryl, alkoxycarbonylheteroaryl, haloheteroaryl, cyanoheteroaryl, haloarylalkyl, alkoxyarylalkyl, halo Aryl
  • Example 1 Synthesis of a part of the compounds in the present invention
  • Step (1) Weigh 1,3,3,4-tetrahydroisoquinoline 0.3 g (2.25 mmol), 4-bromomethylbenzoic acid 0.484 g (2.25 mmol), potassium phosphate 0.478 g (2.25 mmol), 30 ml of acetone was placed in a single-mouth round bottom flask with a volume of 100 ml, and magnetic stirring at room temperature After 30 minutes, 0.857 g (11.25 mmol) of carbon disulfide was added, and magnetic stirring was continued at room temperature, and the progress of the reaction was followed by a thin layer chromatography plate, and the final reaction completion time was 1 h. After the reaction was completed, the reaction system was spin-dried using a vacuum rotary evaporator.
  • Step (2) adding 15 ml of DMF (N,N-dimethylformamide) to the system after spin-drying in the step (1), and adding BOP (benzotriazol-1-yloxytri(dimethyl) Base amino)phosphonium hexafluorophosphate) 1.195g (2.70mmol), triethylamine 0.912g (9.00mmol), stirred at room temperature for 10min, then added o-phenylenediamine 0.292g (2.7mmol), continue magnetic stirring at room temperature, with thin The layer chromatography plate was used to track the progress of the reaction, and the final reaction time was 2 h.
  • DMF N,N-dimethylformamide
  • the compounds M102 to M134 were prepared in a similar manner to the compound M101 except that the starting material 1,2,3,4-tetrahydroisoquinoline in the step (1) was replaced with 1,2,3,4-tetrahydroquinoline ( 0.3 g, 2.25 mmol) (Compound M102); tetrahydropyrrole (0.16 g, 2.25 mmol) (Compound M103); 2-methylpiperidine (0.22 g, 2.25 mmol) (Compound M104); 4-methylpiperidine (0.22 g, 2.25 mmol) (Compound M105); 1-(Diphenylmethyl)piperazine (0.57 g, 2.25 mmol) (Compound M106); indoline (0.27 g, 2.25 mmol) (Compound M107) ; porphyrin-5-carboxylic acid methyl ester (0.40 g, 2.25 mmol) (compound M108); 5-chloroindoline (0.35 g, 2.25 mmol

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Abstract

La présente invention se rapporte au domaine de la chimie pharmaceutique. L'invention concerne un composé amide, son procédé de préparation et son utilisation. Le composé de l'invention peut inhiber la prolifération de cellules cancéreuses, ce qui permet de traiter un cancer. En particulier, le composé de l'invention possède une excellente activité d'inhibition de la prolifération des cellules cancéreuses pour le mélanome de la peau humaine A375, la cellule cancéreuse de l'estomac humain MGC80-3, la cellule cancéreuse Hela du col de l'utérus humain, la cellule cancéreuse du foie humain SMMC7721, la cellule cancéreuse du poumon humain H1299, et la cellule cancéreuse du côlon humain HCT116. Le composé de l'invention possède la structure représentée par la formule générale I suivante, dans laquelle A, Z, R1, R2, R3 et R4 sont tels que définis dans la description.
PCT/CN2017/091212 2017-03-05 2017-06-30 Composé amide, procédé de préparation et utilisation associés Ceased WO2018161476A1 (fr)

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CN103319402A (zh) * 2012-03-22 2013-09-25 齐鲁制药有限公司 二苯基硫脲类衍生物及其制备方法和应用
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CN103319402A (zh) * 2012-03-22 2013-09-25 齐鲁制药有限公司 二苯基硫脲类衍生物及其制备方法和应用
CN106146487A (zh) * 2015-04-27 2016-11-23 北京大学 吡啶甲氨基二硫代甲酸杂芳环烷基酯类化合物及其制备方法和用途
CN106432208A (zh) * 2015-08-10 2017-02-22 北京大学 氨基二硫代甲酸(氨磺酰基)乙酯类化合物及其制备方法和用途

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