WO2018054304A1 - Composé de furoquinolinedione et son utilisation médicale - Google Patents

Composé de furoquinolinedione et son utilisation médicale Download PDF

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Publication number
WO2018054304A1
WO2018054304A1 PCT/CN2017/102476 CN2017102476W WO2018054304A1 WO 2018054304 A1 WO2018054304 A1 WO 2018054304A1 CN 2017102476 W CN2017102476 W CN 2017102476W WO 2018054304 A1 WO2018054304 A1 WO 2018054304A1
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compound
group
prodrug
stereoisomer
pharmaceutically acceptable
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PCT/CN2017/102476
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English (en)
Chinese (zh)
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蔡雄
钟宪斌
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东莞市真兴贝特医药技术有限公司
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Publication of WO2018054304A1 publication Critical patent/WO2018054304A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
    • C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
    • C07D491/04—Ortho-condensed systems
    • C07D491/044—Ortho-condensed systems with only one oxygen atom as ring hetero atom in the oxygen-containing ring
    • C07D491/048—Ortho-condensed systems with only one oxygen atom as ring hetero atom in the oxygen-containing ring the oxygen-containing ring being five-membered

Definitions

  • the invention belongs to the field of medicinal chemistry, and in particular relates to a furanoquinolinedione compound and a medical use thereof.
  • STAT3 is an important member of the Signal Transducer and Activator of Transcription (STAT) family.
  • STAT3 has a wide range of functions that regulate gene expression associated with cell cycle, survival, and immune response, and is closely associated with the progression and progression of multiple tumors.
  • Phosphorylation of two important sites of STAT3 is involved in STAT3 activation, namely tyrosine at position 705 and serine at position 727.
  • Various tyrosine kinase entities such as EGFR, VEGFR, and PDGF
  • non-tyrosine kinases such as Arc and Abl
  • cytokine receptors involved in JAK activation activate STAT3 705 tyrosine ( Tyr705) phosphorylation.
  • STAT3 727 locus serine (Ser727) (Kamran MZ et al. BioMed Res Intern 2013 Article ID 421821).
  • Phosphorylated STAT3 forms a dimer that is transferred into the nucleus to become an activated transcription factor that binds to the promoter region of its target gene, regulating downstream and anti-apoptotic, angiogenic, invasive, and migration-related gene expression.
  • STAT3 is an important target for antineoplastic agents.
  • Multiple STAT3 inhibitors including OPB-51602, AZD9150, OPB-31121, WP1066 and BBI608 have entered the clinical research phase.
  • BBI608 Japanese AZD9150, OPB-31121, WP1066 and BBI608 (Napabucasin) is a pluripotent inhibitor of cancer cells with STAT3 inhibitory activity. It can effectively inhibit the self-renewal of highly multifunctional cancer cells by down-regulating STAT3-driven stem cell gene expression and cancer stem cell performance. In tumor models, tumor metastasis and recurrence can be significantly inhibited (LiY., et al. PNAS 112: 1839-1844, 2015).
  • a compound represented by the formula (I) has STAT3 inhibitory activity; for example, it is capable of inhibiting the expression level of STAT3 in various tumor cells; for example, it can inhibit phosphorylation of STAT3.
  • Inhibition of STAT3 activation eg, phosphorylation of tyrosine at position 7053; for example, phosphorylation of serine at position 7273; thus, the compound acts as a STAT3 inhibitor.
  • the compounds can be used to prevent or treat diseases associated with STAT3 (eg, tumors).
  • the compound of the formula (I), a prodrug thereof, a stereoisomer or a pharmaceutically acceptable salt thereof inhibits proliferation of tumor cells, for example, inhibits proliferation of cancer cells of colon cancer, breast cancer, colon cancer and lung cancer.
  • the compound of the formula (I), a prodrug, a stereoisomer or a pharmaceutically acceptable salt thereof of the present invention can be used for the preparation of a medicament for preventing and/or treating a tumor such as colon cancer, breast cancer, colon cancer, lung cancer.
  • one aspect of the application relates to a compound of formula (I), a prodrug thereof, a stereoisomer or a pharmaceutically acceptable salt thereof,
  • the A, B, D and E atoms are each independently selected from the group consisting of a C atom and an N atom, and at least one (for example 1, 2, 3 or 4) is an N atom;
  • R 1 is selected from the group consisting of hydrogen, halogen, nitro, cyano, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, 6-14 a aryl group and a 5-14 membered heteroaryl group; wherein the C 1 -C 6 alkyl group, a C 1 -C 6 alkoxy group, a C 2 -C 6 alkenyl group, a C 2 -C 6 alkynyl group, The -14 membered aryl group and the 5-14 membered heteroaryl group are unsubstituted or substituted by one or more (e.g., 1, 2, 3 or 4) substituents selected from the group consisting of halogen, hydroxy, amino, cyano.
  • R 2 is selected from the group consisting of C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 6 cycloalkyl, 6-14 membered aryl and 5-14 membered heteroaryl a C 1 -C 6 alkyl group, a C 2 -C 6 alkenyl group, a C 2 -C 6 alkynyl group, a C 3 -C 6 cycloalkyl group, a C 3 -C 6 cycloalkylmethyl group,
  • the 6-14 membered aryl group and the 5-14 membered heteroaryl group are unsubstituted or substituted by one or more (e.g., 1, 2, 3 or 4) substituents selected from the group consisting of halogen, hydroxy, amino, cyanide , C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 6 cycloal
  • R 3 is selected from the group consisting of hydrogen, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl and C 3 -C 6 cycloalkyl; wherein said C 1 -C 6 alkyl , C 2 -C 6 alkenyl, C 2 -C 6 alkynyl and C 3 -C 6 cycloalkyl are unsubstituted or one or more (for example 1, 2, 3 or 4) are selected from the group consisting of Substituent substitution: halogen, hydroxy, amino, cyano, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 alkoxy, C 1 -C 6 alkylamino, C 1 -C 6 alkylthio and C 1 -C 6 alkylsulfonyl.
  • the A, B, D and E atoms are each independently selected from the group consisting of a C atom and an N atom, and one of A, B, D and E is an N atom; R 1 is selected from hydrogen.
  • R 1 is selected from the group consisting of hydrogen, halogen, nitro, cyano, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, 6-14 membered aryl, and 5 a -6 membered heteroaryl group; wherein the C 1 -C 6 alkyl group, the C 1 -C 6 alkoxy group, the 6-14 membered aryl group and the 5-6 membered heteroaryl group are unsubstituted or one or more (for example 1, 2, 3 or 4) substituted with a substituent selected from the group consisting of halogen, hydroxy, amino, cyano, C 2 -C 4 alkenyl, C 2 -C 4 alkynyl, C 1 -C 4 alkoxy, C 1 -C 4 alkylamino, C 1 -C 4 alkylthio and C 1 -C 4 alkylsulfonyl.
  • R 1 is selected from the group consisting of hydrogen, halogen, nitro, cyano, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, phenyl, and 5-6 membered An aryl group; wherein the C 1 -C 6 alkyl group, C 1 -C 6 alkoxy group, phenyl group and 5-6 membered heteroaryl group are unsubstituted or one or more (eg 1, 2, 3) Or 4) substituents selected from the group consisting of halogen, hydroxy, amino and cyano.
  • R 1 is selected from the group consisting of hydrogen, halogen, nitro, cyano, trifluoromethyl, C 1 -C 4 alkyl, C 1 -C 4 alkoxy, phenyl, and a 5-6 membered heteroaryl group; wherein the 5-6 membered heteroaryl group is selected from the group consisting of furan, thiophene, pyrrole, pyrimidine, pyrazine, pyridazine and pyrimidine.
  • R 1 is selected from the group consisting of hydrogen, halogen, nitro, cyano, trifluoromethyl, C 1 -C 4 alkyl, C 1 -C 4 alkoxy, phenyl, Furan, thiophene, pyrrole, pyrimidine, pyrazine, pyridazine and pyrimidine.
  • R 1 is C 1 -C 6 alkyl.
  • R 1 is C 1 -C 4 alkyl.
  • R 1 is methyl
  • R 1 is methyl or ethyl.
  • R 1 is methyl, ethyl or propyl.
  • R 1 is selected from the group consisting of hydrogen, fluorine, chlorine, nitro, cyano, trifluoromethyl, methyl, ethyl, propyl, isopropyl, butyl, isobutyl Base, methoxy, ethoxy, phenyl, furan and thiophene.
  • R 1 is selected from the group consisting of halogen, nitro, cyano, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, aryl, and heteroaryl;
  • the C 1 -C 6 alkyl group, the C 1 -C 6 alkoxy group, the aryl group and the heteroaryl group are unsubstituted.
  • R 1 is selected from the group consisting of halogen, nitro, cyano, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, phenyl, and 5-6 membered heteroaryl Wherein the C 1 -C 6 alkyl group, the C 1 -C 6 alkoxy group, the phenyl group and the 5-6 membered heteroaryl group are unsubstituted.
  • R 1 is selected from the group consisting of halogen, nitro, cyano, trifluoromethyl, C 1 -C 4 alkyl, C 1 -C 4 alkoxy, phenyl, furan, Thiophene, pyrrole, pyrimidine, pyrazine, pyridazine and pyrimidine.
  • R 1 is selected from the group consisting of fluorine, chlorine, nitro, cyano, trifluoromethyl, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, Methoxy, ethoxy, phenyl, furan and thiophene.
  • R 2 is C 1 -C 6 alkyl or aryl; wherein the C 1 -C 6 alkyl and aryl are unsubstituted or one or more (eg, 1, 2, 3 or 4) substituted with a substituent selected from the group consisting of halogen, hydroxy, amino, cyano, C 2 -C 4 alkenyl, C 2 -C 4 alkynyl, C 3 -C 6 naphthenic a group, a C 1 -C 4 alkoxy group, a C 1 -C 4 alkylamino group, a C 1 -C 4 alkylthio group, and a C 1 -C 4 alkylsulfonyl group.
  • a substituent selected from the group consisting of halogen, hydroxy, amino, cyano, C 2 -C 4 alkenyl, C 2 -C 4 alkynyl, C 3 -C 6 naphthenic a group, a C 1 -C 4 alk
  • R 2 is C 1 -C 4 alkyl or phenyl.
  • R 2 is selected from the group consisting of methyl, ethyl, propyl, isopropyl, butyl, isobutyl, and phenyl.
  • R 2 is C 1 -C 6 alkyl.
  • R 2 is C 1 -C 4 alkyl.
  • R 2 is methyl
  • R 2 is methyl or ethyl.
  • R 2 is methyl, ethyl or propyl.
  • R 3 is selected from hydrogen or C 1 -C 6 alkyl; wherein the C 1 -C 6 alkyl group is unsubstituted or one or more (eg 1, 2 , 3 or 4) substituents selected from the group consisting of halogen, hydroxy, amino, cyano, C 2 -C 4 alkenyl, C 2 -C 4 alkynyl, C 1 -C 4 alkoxy, C a 1- C 4 alkylamino group, a C 1 -C 4 alkylthio group and a C 1 -C 4 alkylsulfonyl group;
  • R 3 is selected from the group consisting of hydrogen and C 1 -C 4 alkyl.
  • R 3 is hydrogen or methyl
  • R 3 is hydrogen
  • R 3 is methyl
  • the compound has the structure shown in formula (II):
  • R 1 , R 2 , R 3 are as defined in the compounds of formula (I) herein.
  • R 1 in formula (II) is at the meta or para position of the N atom.
  • R 1 in formula (II) is in the meta position of the N atom.
  • R 1 in formula (II) is in the para position of the N atom.
  • R 1 in formula (II) is selected from the group consisting of hydrogen, methyl, ethyl, propyl, isopropyl, fluoro, chloro, bromo, nitro, cyano, methoxy. , furyl, thienyl and phenyl.
  • R 1 in formula (II) is selected from the group consisting of hydrogen, fluoro, chloro, nitro, cyano, methyl, ethyl, isopropyl, methoxy, phenyl, furan. And thiophene.
  • R 1 in formula (II) is selected from the group consisting of hydrogen, methyl, ethyl and furanyl.
  • R 1 in formula (II) is selected from the group consisting of methyl, ethyl, propyl, isopropyl, fluoro, chloro, bromo, nitro, cyano, methoxy, furan. , thiophene and phenyl.
  • R 1 in formula (II) is C 1 -C 6 alkyl.
  • R 1 in formula (II) is C 1 -C 4 alkyl.
  • R 1 in formula (II) is methyl
  • R 1 in formula (II) is methyl, ethyl or propyl.
  • R 1 in formula (II) is methyl or ethyl.
  • R 2 in formula (II) is a C 1 -C 6 alkyl group.
  • R 2 in formula (II) is a C 1 -C 4 alkyl group.
  • R 2 in formula (II) is selected from the group consisting of methyl, ethyl, isopropyl, and phenyl.
  • R 2 in formula (II) is methyl
  • R 2 in formula (II) is methyl or ethyl.
  • R 2 in formula (II) is methyl, ethyl or propyl.
  • R 3 in formula (II) is hydrogen or methyl.
  • R 3 in formula (II) is hydrogen
  • R 3 in formula (II) is methyl
  • the compound has the structure shown in formula (III):
  • R 1 , R 2 , R 3 are as defined in the compounds of formula (I) herein.
  • R 1 in formula (III) is at the meta or para position of the N atom.
  • R 1 in formula (III) is in the meta position of the N atom.
  • R 1 in formula (III) is in the para position of the N atom.
  • R 1 in formula (III) is selected from the group consisting of hydrogen, methyl, methoxy, fluoro, chloronitro and cyano.
  • R 1 in formula (III) is selected from the group consisting of hydrogen, fluoro, chloro, nitro, cyano, methyl, ethyl, isopropyl, methoxy, phenyl, furan. And thienyl.
  • R 1 in formula (III) is selected from the group consisting of fluorine, chlorine, nitro, cyano, methyl, ethyl, isopropyl, methoxy, phenyl, furanyl, and Thienyl.
  • R 1 in formula (III) is methyl or ethyl.
  • R 1 in formula (III) is hydrogen
  • R 2 in formula (III) is selected from the group consisting of methyl, ethyl, isopropyl, and phenyl.
  • R 2 in formula (III) is methyl
  • R 3 in formula (III) is hydrogen or methyl.
  • R 3 in formula (III) is hydrogen
  • the compound has the structure of formula (IV) or formula (V):
  • R 1 in formula (IV) or formula (V) is hydrogen.
  • R 2 in formula (IV) or formula (V) is methyl or phenyl.
  • R 2 in formula (IV) or formula (V) is phenyl.
  • R 2 in formula (IV) or formula (V) is methyl.
  • R 3 in formula (IV) or formula (V) is hydrogen.
  • the compound has the structure shown in formula (VI) or formula (VII):
  • R 1 is a C 1 -C 6 alkyl group
  • R 2 is a C 1 -C 6 alkyl group.
  • R 1 in formula (VI) or formula (VII) is C 1 -C 4 alkyl.
  • R 1 in formula (VI) is C 1 -C 4 alkyl.
  • R 1 in formula (VII) is C 1 -C 4 alkyl.
  • R 1 in formula (VI) is methyl, ethyl or propyl.
  • R 1 in formula (VII) is methyl, ethyl or propyl.
  • R 1 in formula (VI) is methyl or ethyl.
  • R 1 in formula (VII) is methyl or ethyl.
  • R 1 in formula (VI) is methyl
  • R 1 in formula (VII) is methyl
  • R 2 in formula (VI) or formula (VII) is C 1 -C 4 alkyl.
  • R 2 in formula (VI) is C 1 -C 4 alkyl.
  • R 2 in formula (VII) is C 1 -C 4 alkyl.
  • R 2 in formula (VI) is methyl, ethyl or propyl.
  • R 2 in formula (VII) is methyl, ethyl or propyl.
  • R 2 in formula (VI) is methyl or ethyl.
  • R 2 in formula (VII) is methyl or ethyl.
  • R 2 in formula (VI) is methyl
  • R 2 in formula (VII) is methyl
  • the compound is selected from the group consisting of
  • Another aspect of the present application relates to a pharmaceutical composition
  • a pharmaceutical composition comprising a compound, a prodrug, a stereoisomer or a pharmaceutically acceptable salt thereof, as described herein, and one or more pharmaceutical excipients.
  • the medicinal excipient refers to an excipient and an additive used in the production of a medicine and a prescription, and refers to a substance which has been evaluated for safety in addition to the active ingredient and which is included in the pharmaceutical preparation. .
  • pharmaceutical excipients also have important functions such as solubilization, solubilization, and controlled release, which are important components that may affect the quality, safety and effectiveness of drugs. According to its source, it can be divided into natural materials, semi-synthetic materials and total synthetic materials.
  • solvent propellant
  • solubilizer cosolvent
  • emulsifier colorant
  • binder disintegrant
  • filler filler
  • lubricant wetting agent
  • osmotic pressure regulator stabilizer
  • Glidants flavoring agents, preservatives, suspending agents, coating materials, fragrances, anti-adhesives, antioxidants, chelating agents, penetration enhancers, pH adjusters, buffers, plasticizers, surface active agents Agent, foaming agent, antifoaming agent, thickener, inclusion agent, moisturizer, absorbent, diluent, flocculant and deflocculant, filter aid, release retardant, etc.
  • solvent propellant
  • solubilizer cosolvent
  • emulsifier colorant
  • binder disintegrant
  • filler filler
  • lubricant wetting agent
  • osmotic pressure regulator stabilizer
  • Glidants osmotic pressure regulator
  • flavoring agents preservatives
  • suspending agents coating materials
  • fragrances anti
  • the pharmaceutical composition can be formulated into various suitable dosage forms depending on the route of administration.
  • the pharmaceutical composition or a suitable dosage form may contain 0.01 mg to 1000 mg of the compound of the present invention, a prodrug, a stereoisomer or a pharmaceutically acceptable salt thereof, suitably containing 0.1 mg to 800 mg, preferably 0.5- 500 mg, preferably from 1 to 350 mg, preferably from 5 to 250 mg, preferably from 5 to 150 mg, preferably from 5 to 100 mg.
  • the pharmaceutical composition can be formulated into any orally acceptable preparation including, but not limited to, tablets, capsules, granules, pills, syrups, oral solutions, oral suspensions, and oral emulsions. Wait.
  • the carrier used for the tablet generally includes lactose and corn starch, and a lubricant such as magnesium stearate may also be added.
  • the diluent used in the capsules generally includes lactose and dried corn starch.
  • Oral suspensions are usually prepared by admixing the active ingredient with suitable emulsifying and suspending agents.
  • suitable emulsifying and suspending agents may also be added to the above oral formulation forms.
  • the pharmaceutical compositions When administered transdermally or topically, the pharmaceutical compositions may be in the form of a suitable ointment, lotion or lozenge, wherein the active ingredient is suspended or dissolved in one or more carriers.
  • Carriers that can be used in ointment formulations include, but are not limited to, minerals Oil, liquid petrolatum, white petrolatum, propylene glycol, polyethylene oxide, polypropylene oxide, emulsifying wax and water; detergents or elixirs may be used, including but not limited to: mineral oil, sorbitan monostearate Tween 60, cetyl ester wax, hexadecene aromatic alcohol, 2-octyldodecanol, benzyl alcohol and water.
  • the pharmaceutical composition can also be administered in the form of an injection, including an injection, a sterile powder for injection, and a concentrated solution for injection.
  • carriers and solvents which can be used include water, Ringer's solution and isotonic sodium chloride solution.
  • sterile, fixed oils may also be employed as a solvent or suspension medium such as a monoglyceride or a diglyceride.
  • Another aspect of the present application relates to a compound, prodrug, stereoisomer or pharmaceutically acceptable salt thereof, or use of the pharmaceutical composition, in the preparation of a reagent for inhibiting STAT3 expression.
  • Another aspect of the present application relates to a compound, prodrug, stereoisomer or pharmaceutically acceptable salt thereof, or use of the pharmaceutical composition, in the preparation of an agent that inhibits STAT3 activation.
  • Another aspect of the present application relates to a compound, prodrug, stereoisomer or pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, for inhibiting STAT3 phosphorylation (e.g., inhibiting STAT3 705 tyrosine)
  • STAT3 phosphorylation e.g., inhibiting STAT3 705 tyrosine
  • Use of a reagent for phosphorylation or phosphorylation of STAT3 at position 727 Use of a reagent for phosphorylation or phosphorylation of STAT3 at position 727.
  • Another aspect of the present application relates to a compound, prodrug, stereoisomer or pharmaceutically acceptable salt thereof, or use of the pharmaceutical composition, in the manufacture of a STAT3 inhibitor.
  • Another aspect of the present application relates to a compound, prodrug, stereoisomer or pharmaceutically acceptable salt thereof, or use of the pharmaceutical composition, for the manufacture of a medicament for preventing or treating a disease associated with STAT3.
  • Another aspect of the present application relates to a compound, prodrug, stereoisomer or pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, for use in the prevention or treatment of a disease associated with STAT3.
  • Another aspect of the present application relates to a method of preventing or treating a disease associated with STAT3 comprising administering to a subject in need thereof an effective amount of a compound described herein, a prodrug thereof, a stereoisomer or a pharmaceutical An acceptable salt or a step of the pharmaceutical composition.
  • the disease associated with STAT3 is a tumor.
  • the tumor is a solid tumor or a hematological tumor.
  • the solid tumor is colorectal cancer, gastric cancer, breast cancer, pancreatic cancer, or lung cancer.
  • the hematological tumor is lymphoma, myeloma, lymphocytic leukemia or acute myeloid leukemia.
  • Another aspect of the present application relates to the use of a compound, prodrug, stereoisomer or pharmaceutically acceptable salt thereof, or a pharmaceutical composition of the present application, in the manufacture of a medicament for inhibiting tumor cell proliferation.
  • the tumor cell is selected from the group consisting of cancer cells of colon cancer, breast cancer, colon cancer, and lung cancer.
  • the tumor cells are selected from the group consisting of SW620, MCF7, MDA-MD-231, LOVO, H1975, and Colon 205.
  • Another aspect of the present application relates to a compound, a prodrug, a stereoisomer or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition as described herein, in the manufacture of a medicament for the prevention and/or treatment of a tumor use.
  • the tumor is selected from the group consisting of colon cancer, breast cancer, colorectal cancer, and lung cancer.
  • Another aspect of the present application relates to a method of inhibiting tumor cell proliferation in vivo or in vitro, comprising administering to a subject in need thereof an effective amount of a compound described herein, a prodrug thereof, a stereoisomer, or a pharmaceutically acceptable Salt or a pharmaceutical composition as described herein.
  • the tumor cell is selected from the group consisting of cancer cells of colon cancer, breast cancer, colon cancer, and lung cancer.
  • the tumor cells are selected from the group consisting of SW620, MCF7, MDA-MD-231, LOVO, H1975, and Colon 205.
  • Another aspect of the present application relates to a method of preventing and/or treating a tumor comprising administering to a subject in need thereof an effective amount of a compound, prodrug, stereoisomer or pharmaceutically acceptable salt thereof, or The medicine described in the present application Composition.
  • the tumor is selected from the group consisting of colon cancer, breast cancer, colorectal cancer, and lung cancer.
  • Another aspect of the invention relates to a compound, prodrug, stereoisomer or pharmaceutically acceptable salt thereof, or a pharmaceutical composition described herein for use in inhibiting STAT3.
  • Another aspect of the invention relates to a compound, prodrug, stereoisomer or pharmaceutically acceptable salt thereof, or a pharmaceutical composition as described herein for use in inhibiting tumor cell proliferation or for preventing and/or Treat tumors.
  • the tumor cell is selected from the group consisting of cancer cells of colon cancer, breast cancer, colon cancer, and lung cancer.
  • the tumor is selected from the group consisting of colon cancer, breast cancer, colorectal cancer, and lung cancer.
  • the tumor cells are selected from the group consisting of SW620, MCF7, MDA-MD-231, LOVO, H1975, and Colon 205.
  • stereoisomer includes conformational isomers and configurational isomers, wherein the configurational isomers primarily include cis and trans isomers and optical isomers.
  • the compounds of the invention may exist in stereoisomeric forms and thus encompass all possible stereoisomeric forms, as well as any combination or any mixture thereof. For example, a single enantiomer, a single diastereomer or a mixture of the above.
  • the compound of the present invention contains an olefinic double bond, it includes a cis isomer and a trans isomer, and any combination thereof, unless otherwise specified.
  • the term "pharmaceutically acceptable salts” refers to (1) a compound of the present invention, in the presence of acidic functional group (e.g. -COOH, -OH, -SO 3 H, etc.) with a suitable inorganic or organic a salt formed by a cation (base), for example, a salt of a compound of the invention with an alkali metal or alkaline earth metal, an ammonium salt of a compound of the invention, and a salt of a compound of the invention with a nitrogen-containing organic base; and (2) a compound of the invention A salt of a basic functional group (e.g., -NH 2 or the like) which is formed with a suitable inorganic or organic anion (acid), such as a salt of a compound of the present invention with an inorganic acid or an organic carboxylic acid.
  • acidic functional group e.g. -COOH, -OH, -SO 3 H, etc.
  • bases for example, a salt of a compound of the invention
  • salts of the compounds of the invention include, but are not limited to, alkali metal salts such as sodium, potassium, lithium, and the like; alkaline earth metal salts such as calcium, magnesium, and the like; other metal salts, Such as aluminum salt, iron salt, zinc salt, copper salt, nickel salt, cobalt salt, etc.; inorganic alkali salt, such as ammonium salt; organic alkali salt, such as t-octylamine salt, dibenzylamine salt, morpholine salt, Portuguese Glycosylamine salt, phenylglycine alkyl ester salt, ethylenediamine salt, N-methylglucamine salt, sulfonium salt, diethylamine salt, triethylamine salt, dicyclohexylamine salt, N, N'- Dibenzylethylenediamine salt, chloroprocaine salt, procaine salt, diethanolamine salt, N-benzyl-phenethylamine salt, piperaz
  • prodrug also referred to as prodrug, prodrug, prodrug, etc.
  • prodrug means that the compound of the present application is modified to be inactive or less active in vitro, in vivo.
  • An enzyme or non-enzymatic conversion that releases the active drug to exert a pharmacological effect.
  • the design principles and preparation methods of prodrugs are known to those skilled in the art.
  • halogen refers to fluoro, chloro, bromo and iodo.
  • C 1 -C 6 alkyl refers to a straight or branched alkyl group having from 1 to 6 carbon atoms, for example, C 1 -C 4 alkyl, C 1 -C 2 alkane.
  • Specific examples include, but are not limited to, methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, n-hexyl, and the like.
  • C 1 -C 6 alkoxy refers to a group formed in the C 1 -C 6 alkyl-O- form, wherein "C 1 -C 6 alkyl” is as defined As mentioned above. Specific examples include, but are not limited to, methoxy, ethoxy, propoxy, isopropoxy, butoxy, 2-butoxy, isobutoxy, sec-butoxy, tert-butoxy, pentane Oxyl, hexyloxy, and the like.
  • C 1 -C 6 alkylamino refers to a group formed in the C 1 -C 6 alkyl-NH- form, wherein "C 1 -C 6 alkyl” is as defined above Said. Specific examples include, but are not limited to, methylamino, ethylamino, propylamino, isopropylamino, butylamino, 2-butylamino, isobutylamino, sec-butylamino, tert-butylamino, pentylamino, hexylamino, and the like.
  • C 1 -C 6 alkylthio refers to a group formed in the C 1 -C 6 alkyl-S- mode, wherein "C 1 -C 6 alkyl” is as defined As mentioned above. Specific examples include, but are not limited to, methylthio, ethylthio, propylthio, isopropylthio, butylthio, 2-butylthio, isobutylthio, sec-butylthio, tert-butylthio, pentane Sulfur-based, hexylthio, and the like.
  • C 1 -C 6 alkylsulfonyl refers to a group formed in the manner of C 1 -C 6 alkyl-S(O) 2 -, wherein "C 1 -C 6 alkane
  • base is as described above. Specific examples include, but are not limited to, methylsulfonyl, ethylsulfonyl, and the like.
  • C 2 -C 6 alkenyl refers to a straight or branched chain hydrocarbon radical containing from 2 to 6 carbon atoms and one, two or three carbon-carbon double bonds, preferably containing one carbon Carbon double bond C 2 -C 6 alkenyl.
  • C 2 -C 4 alkenyl, C 2 alkenyl, C 3 alkenyl, C 4 alkenyl, C 5 alkenyl or C 6 alkenyl C 2 -C 6 alkenyl.
  • Specific examples include, but are not limited to, ethenyl, propenyl, 2-propenyl, butenyl, 2-butenyl, 2-methyl-propenyl, butadienyl, pentenyl, 2-methyl- Butenyl, 3-methyl-butenyl, 1,3-pentadienyl, 1,4-pentadienyl, hexenyl, 2-ethyl-butenyl, 3-methyl-pentyl Alkenyl, 4-methyl-pentenyl, 1,3-hexadienyl, 1,4-hexadienyl, 1,5-hexadienyl and the like.
  • C 2 -C 6 alkynyl refers to a straight or branched chain hydrocarbon radical containing from 2 to 6 carbon atoms and one, two or three carbon-carbon triple bonds, preferably containing one carbon a C 3 -C 6 alkynyl group having a carbon triple bond.
  • C 2 -C 4 alkynyl, C 2 alkynyl, C 3 alkynyl, C 4 alkynyl, C 5 alkynyl or C 6 alkynyl are straight or branched chain hydrocarbon radical containing from 2 to 6 carbon atoms and one, two or three carbon-carbon triple bonds, preferably containing one carbon a C 3 -C 6 alkynyl group having a carbon triple bond.
  • Specific examples include, but are not limited to, ethynyl, propynyl, 2-propynyl, butynyl, 2-butynyl, 2-methyl-propynyl, butadiynyl, pentynyl, 2- Methyl-butynyl, 3-methyl-butynyl, 1,3-pentadiynyl, 1,4-pentadiynyl, hexynyl, 2-ethyl-butynyl, 3-methyl A pentynynyl group, a 4-methyl-pentynyl group, a 1,3-hexadiynyl group, a 1,4-hexadiynyl group, a 1,5-hexadiynyl group, and the like.
  • aryl refers to a monocyclic or polycyclic hydrocarbon group having an aromatic character, such as a 6-10 membered aryl group and the like. Specific examples include, but are not limited to, phenyl, naphthyl, anthracenyl, phenanthryl, and the like.
  • heteroaryl refers to containing at least one heteroatom selected from N, as described above heteroatoms O and S aryl group, for example C 5 -C 6 heteroaryl.
  • heteroaryl refers to containing at least one heteroatom selected from N, as described above heteroatoms O and S aryl group, for example C 5 -C 6 heteroaryl.
  • Specific examples include, but are not limited to, furyl, thienyl, pyrrolyl, thiazolyl, isothiazolyl, thiadiazolyl, oxazolyl, isoxazolyl, imidazolyl, pyrazolyl, 1,2,3- Triazolyl, 1,2,4-triazolyl, 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,5-oxadiazolyl, 1,3 , 4-oxadiazolyl, pyridyl, 2-pyridinone, 4-pyridinone, pyrimidinyl, 2H-1,
  • C 3 -C 6 cycloalkyl refers to a monocyclic saturated alkyl group containing 3 to 6 ring members, such as a 3-5 membered cycloalkyl group, 3 members, 4 members, 5 Yuan, 6-membered cycloalkyl. Specific examples include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and the like.
  • C 3 -C 6 cycloalkylmethyl refers to a group formed as a C 3 -C 6 cycloalkyl-CH 2 - group, wherein C 3 -C 6 cycloalkyl
  • the definition is as described above. Specific examples include, but are not limited to, cyclopropylmethyl, cyclobutylmethyl, cyclopentylmethyl, cyclohexylmethyl, and the like.
  • the inventors have discovered a class of compounds of formula (I) which, in a variety of tumor cells, also significantly inhibits the expression level of STAT3; said compounds significantly inhibit the phosphorylation of STAT3, such as STAT3705 Phosphorylation of tyrosine, such as phosphorylation of serine at position 7273, inhibits STAT3 activation.
  • the compounds of the present application act as STAT3 inhibitors for the treatment of diseases associated with STAT3, such as tumors.
  • the compound of the present invention is active for inhibiting proliferation of tumor cells, particularly for inhibiting proliferation of cancer cells of colon cancer, breast cancer, colon cancer and lung cancer.
  • the compounds of the invention, prodrugs, stereoisomers or pharmaceutically acceptable salts thereof have good pharmacokinetic properties.
  • Figure 1 shows the results of immunoblot analysis of STAT3 and phosphorylated STAT3 in SW480 cells treated with different concentrations of Compound 1 and BBI608, respectively, under different time conditions.
  • Figure 2 shows the results of immunoblot analysis of STAT3 and phosphorylated STAT3 in K562 cells treated with different concentrations of Compound 1 and BBI608, respectively, under different time conditions.
  • Figure 3 shows the results of immunoblot analysis of total STAT3 and p-Stat3 (Tyr705) in SW480 cells and K562 cells treated with different concentrations of Compound 2, Compound 3 and BBI608, respectively, under different time conditions.
  • Figure 4 shows the treatment with different concentrations of Compound 2, Compound 3 and BBI608, respectively, at different times.
  • the results of immunoblot analysis of total STAT3 and p-Stat3 (Ser727) in SW480 cells and K562 cells were detected.
  • Figure 5 shows the pharmacokinetic results of Compound 2 administered orally in rats.
  • Figure 6 shows the pharmacokinetic results of Compound 3 administered orally in rats.
  • the compounds of the invention can be prepared by the following synthetic routes:
  • Step 1a 1-(4,6-Dibromo-7-hydroxybenzofuran-2-yl)ethyl-1-one (1-(4,6-dibromo-7-hydroxybenzofuran-2-yl)ethan- 1-one, Preparation of Compound 102-1): 2-Acetyl-7-hydroxybenzofuran (1.76 g, 10 mmol, 1.0 eq.) was dissolved in dichloromethane (100 mL). Aluminum (5.32 g, 40 mmol, 4.0 eq.), the mixture was stirred for 40 hrs in an oil bath for 1 hour, and then bromine (3.52 g, 22 mmol, 2.2 eq. The solution was kept for one hour and the reaction was continued for 16 hours.
  • Step 1b Preparation of 2-acetyl-6-bromobenzofuran-4,7-dione (2-acetyl-6-bromobenzofuran-4,7-dione, compound 103-1): 1-(4, 6-Dibromo-7-hydroxybenzofuran-2-yl)ethyl-1-one (Compound 102-1) (0.334 g, 1 mmol, 1.0 eq.) was dissolved in acetic acid (7.5 mL). Chromium trioxide (0.22 g, 2.2 mmol, 2.2 eq.) was stirred at room temperature for 1 hour.
  • Step 1c Preparation of (E)-N'-allyl-N,N-dimethylindole ((E)-N'-allylidene-N, N-dimethylhydrazine, compound 105-1): acrolein (Compound 104-1) (0.56 g, 10 mmol, 1.0 eq.) was dissolved in dichloromethane (10 mL), then dimethyl hydrazine (0.6 g, 10 mmol, 1.0 eq.) and acetic acid (1 ml) The reaction was stirred for 1 hour under ice water bath.
  • Step 1d Preparation of 2-acetylfuro[3,2-g]quinoline-4,9-dione (2-acetylfuro[3,2-g]quinoline-4,9-dione, compound 1): 2-Acetyl-6-bromobenzofuran-4,7-dione (Compound 103-1) (100 mg, 0.37 mmol, 1.0 eq.) was dissolved in dichloromethane (10 mL). E)-N'-Allyl-N,N-dimethylindole (Compound 105-1) (36 mg, 0.37 mmol, 1.0 eq.).
  • Step 2a (E)-N,N-Dimethyl-N'-(2-methylallyl-propyl)hydrazine ((E)-1,1-dimethyl-2-(2-methylallylidene)hydrazine, Compound 105 -2)
  • 2-Methylpropenal (Compound 104-2) (0.70 g, 10 mmol, 1.0 eq.) was dissolved in dichloromethane (10 mL). The reaction was stirred for 1 hour under ice-water bath with 10 mmol, 1.0 eq.
  • Step 2b 2-Acetyl-6-methylfuro[3,2-g]quinoline-4,9-dione (2-acetyl-6-methylfuro[3,2-g]quinoline-4,9 -dione, preparation of compound 2): 2-acetyl-6-bromobenzofuran-4,7-dione (compound 103-1) (40 mg, 0.15 mmol, 1.0 eq.) was dissolved in dichloromethane (10 ml) was further charged with (E)-N,N-dimethyl-N'-(2-methylallylpropene) oxime (Compound 105-2) (18.5 mg, 0.16 mmol, 1.0 eq.) The reaction was stirred at room temperature for 30 minutes.
  • Step 3a (E)-N,N-Dimethyl-N'-(2-methylenebutylene) hydrazine ((E)-1, 1-dimethyl-2-(2-methylenebutylidene) hydrazine, compound 105 Preparation of -3): 2-Ethyl acrolein (Compound 104-3) (0.186 g, 2 mmol, 1.0 eq.) was dissolved in dichloromethane (10 mL) and then dimethyl hydrazine (0.12 g) The reaction was stirred for 1 hour under ice-water bath with 2 mmol, 1.0 eq.
  • Step 3b 2-Acetyl-6-ethylfuro[3,2-g]quinoline-4,9-dione (2-acetyl-6-ethylfuro[3,2-g]quinoline-4,9 -dione, preparation of compound 3): 2-acetyl-6-bromobenzofuran-4,7-dione (compound 103-1) (114 mg, 0.42 mmol, 1.0 eq.) was dissolved in dichloromethane (10 ml) was further charged with (E)-N,N-dimethyl-N'-(2-methylenebutylene) hydrazine (Compound 105-3) (54 mg, 0.42 mmol, 1.0 eq.) The reaction was stirred at room temperature for 30 minutes.
  • Step 4a (E)-N'-((E)-2-butenylene)-N,N-dimethylhydrazine ((E)-N'-((E)-but-2-en-1
  • 2-butenal (0.14 g, 2 mmol, 1.0 eq.) was dissolved in dichloromethane (10 ml) The reaction was further stirred for 1 hour while further adding dimethylhydrazine (0.12 g, 2 mmol, 1.0 eq.) and acetic acid (0.5 ml) in ice water.
  • Step 4b 2-Acetyl-5-methylfuro[3,2-g]quinoline-4,9-dione (2-acetyl-5-methylfuro[3,2-g]quinoline-4,9 -dione, preparation of compound 5): 2-acetyl-6-bromobenzofuran-4,7-dione (103-1) (80 mg, 0.295 mmol, 1.0 eq.) was dissolved in toluene (10 ml) In addition, (E)-N'-((E)-2-butenylene)-N,N-dimethylhydrazine (Compound 202-5) (33 mg, 0.295 mmol, 1.0 eq.) oil The reaction was stirred at 100 ° C for 2 hours.
  • Step 5a (E)-N,N-Dimethyl-N'-((E)-2-pentopentyl)anthracene ((E)-N,N-dimethyl-N'-((E)- Preparation of pent-2-en-1-ylidene)hydrazine, compound 202-6): 2-pentenal (compound 201-6) (0.168 g, 2 mmol, 1.0 eq.) was dissolved in dichloromethane (10) In ML), dimethyl hydrazine (0.12 g, 2 mmol, 1.0 eq.) and acetic acid (0.5 ml) were further added and the mixture was stirred for 1 hour.
  • Step 5b 2-Acetyl-5-ethylfuro[3,2-g]quinoline-4,9-dione (2-acetyl-5-ethylfuro[3,2-g]quinoline-4,9
  • -dione compound 6
  • 2-acetyl-6-bromobenzofuran-4,7-dione compound 103-1 (100 mg, 0.37 mmol, 1.0 eq.) was dissolved in toluene (10) (ml) plus (E)-N,N-dimethyl-N'-((E)-2-pentopentyl)indole (Compound 202-6) (46.6 mg, 0.37 mmol, 1.0 eq.
  • Step 6a (E)-N'-((E)-3-furan-2-yl-p-propylidene)-N,N-dimethylindole ((E)-2-((E)-3- Preparation of (furan-2-yl)allylidene)-1,1-dimethylhydrazine, compound 202-13): 3-(2-furyl)propenal (compound 201-13) (0.224 g, 2 mmol, 1.0) Equivalent) was dissolved in dichloromethane (10 mL), and dimethyl hydrazine (0.12 g, 2 mmol, 1.0 eq.) and acetic acid (0.5 mL) After adding 10 ml of water to the reaction mixture, the methylene chloride layer was separated and dried to give (E)-N'-((E)-3-furan-2-yl-p-propylidene)-N,N-dimethyl ⁇ (0.2 g, yield 60.9%).
  • LCMS (ES
  • Step 6b 2-Acetyl-5-furan-2-yl-furo[3,2-g]quinoline-4,9-dione (2-acetyl-5-(furan-2-yl)furo [ Preparation of 3,2-g]quinoline-4,9-dione, compound 13): 2-acetyl-6-bromobenzofuran-4,7-dione (compound 103-1) (43 mg, 0.158) Millimol, 1.0 eq.) was dissolved in toluene (10 mL), followed by (E)-N'-((E)-3-furan-2-yl-isopropylidene)-N,N-dimethylhydrazine (Compound 202-13) (26 mg, 0.158 mmol, 1.0 eq.).
  • Step 7a Preparation of 2-(3-butyn-2-yloxy)tetrahydro-2H-pyran (2-(but-3-yn-2-yloxy)tetrahydro-2H-pyran, compound 302): Compound p-toluenesulfonic acid (0.1 g, 0.58 mmol), 3-butyn-2-ol (5.0 g, 71.4 mmol) and 3,4-dihydro-2H-pyran (6.0 g, 71.4 mmol) Dissolved in 50 ml of dichloromethane and stirred at room temperature overnight. The reaction solution was quenched with water and then ethyl acetate.
  • Step 7b 2-(1-(tetrahydro-2H-pyran-2-oxy)ethyl)-4-hydroxybenzofuran (2-(1-(Tetrahydro-2H-pyran-2-yloxy)ethyl) Preparation of benzofuran-4-ol, compound 304): Under the protection of nitrogen, the compound 2-(3-butyn-2-yloxy)tetrahydro-2H-pyran (compound 302) (1.7 g, 11.0 mmol) , 1,3-dihydroxy-2-iodobenzene (compound 303) (1.3 g, 5.5 mmol), di-triphenylphosphine palladium dichloride (135 mg, 0.2 mmol), cuprous iodide ( 56 mg, 0.3 mmol) and triethylamine (5 ml) were dissolved in 5 ml of N,N-dimethylformamide and stirred at 60 °C overnight.
  • Step 7c 2-(1-(tetrahydro-2H-pyran-2-oxy)ethyl)benzofuran-4,7-dione (2-(1-(tetrahydro-2H-pyran-2-) Preparation of yloxy)ethyl)benzofuran-4,7-dione, compound 305): the compound 2-(1-(tetrahydro-2H-pyran-2-oxy)ethyl)-4-hydroxybenzofuran Compound 304) (800 mg, 3.0 mmol) in ethanol (5 ml) was added dropwise at 0 ° C to KH 2 PO 4 (0.6M, 15 mL) and potassium nitrite (2.0 g, 7.62 mmol) Among the 10 ml aqueous solutions.
  • Step 7d Preparation of (E)-N'-allylacetyl hydrazide ((E)-N'-allylideneacetohydrazide, compound 308): Compound acrolein (Compound 306) (1.0 g, 17.8 mmol) and acetyl The hydrazine (Compound 307) (1.3 g, 17.8 mmol) was dissolved in ethanol (50 mL) The reaction solution was cooled to room temperature, quenched with water and then ethyl acetate. The obtained organic phase was washed with saturated brine and dried over anhydrous sodium sulfate. The object compound (E)-N'-allylacetyl hydrazide (1.8 g, yield: 90%).
  • Step 7e Mixture 2-(1-(tetrahydro-2H-pyran-2-oxy)ethyl)furo[3,2-g]quinoline-4,9-dione (2-(1- ((tetrahydro-2H-pyran-2-yl)oxy)ethyl)furo[3,2-g]quinoline-4,9-dione, compound 309) and 2-(1-(tetrahydro-2H-pyran)- 2-oxy)ethyl)furo[2,3-g]quinoline-4,9-dione (2-(1-((tetrahydro-2H-pyran-2-yl)oxy)ethyl)furo[ Preparation of 2,3-g]quinoline-4,9-dione, compound 309'): Compound 2 (1-(tetrahydro-2H-pyran-2-yloxy)ethyl)benzofuran-4, 7-Diketone (Compound 305) (260 mg, 0.94 mmol) and compound (E)-N
  • Step 7f Mixture 2-(1-hydroxyethyl)furo[3,2-g]quinoline-4,9-dione (2-(1-hydroxyethyl)furo[3,2-g]quinoline-4 , 9-dione, compound 310) and 2-(1-hydroxyethyl)furo[2,3-g]quinoline-4,9-dione (2-(1-hydroxyethyl)furo[2,3- g] quinoline-4,9-dione, compound 310') Preparation: compound mixture 2-(1-(tetrahydro-2H-pyran-2-yloxy)ethyl)furan[3,2-g Quinoline-4,9-dione (compound 309) and 2-(1-(tetrahydro-2H-pyran-2-oxy)ethyl)furo[2,3-g]quinoline-4 , 9-diketone (compound 309') (260 mg, 0.94 mmol) was dissolved in 10 ml of 2N hydrogen chloride
  • Step 7g Preparation of 2-acetylfuro[2,3-g]quinoline-4,9-dione (2-acetylfuro[2,3-g]quinoline-4,9-dione, compound 20):
  • the mixture obtained in the previous step was crude 2-(1-hydroxyethyl)furo[3,2-g]quinolin-4,9-dione (compound 310) and 2-(1-hydroxyethyl)furan.
  • [2,3-g]quinoline-4,9-dione (compound 310') manganese dioxide (5.0 eq.) was suspended in 10 ml of dichloromethane, stirred at room temperature for 3 hours, filtered over Celite.
  • Cell viability was assessed by measuring the amount of adenosine triphosphate (ATP) using the CellTiter-Glo Luminescent Cell Viability Assay Kit (Promega, #G7572, Madison, WI).
  • Tumor cell lines were purchased from the Shanghai Fudan IBS Cell Resource Center and the American Type Culture Collection (ATCC). Cells were digested with trypsin from cell culture dishes and resuspended in DPBS medium and assayed for cell density using a Scepter automated cell counter (Millipore, #PHCC00000). The cells were diluted to a solution containing 44,000 cells per ml. The cell solution after the density adjustment was added to the cell assay plate at 90 ⁇ l per liter per well.
  • ATP adenosine triphosphate
  • the plates were placed in a 37 ° C, 5% CO 2 incubator for 24 hours and then added with different concentrations of test compound.
  • the cells were incubated with the compound for 72 hours in the presence of 10% fetal bovine serum. use The Luminescent Cell Viability Assay kit (see manufacturer's instructions) was assayed for ATP content to assess cell growth inhibition. Briefly, add 30 ⁇ l to each well. The reagents were shaken for 10 minutes, cell lysis was induced, and fluorescence signals were recorded using a fluorescence/chemiluminescence analyzer Fluoroskan Ascent FL (Thermo Scientific Fluoroskan Ascent FL). The cells were treated with dimethyl sulfoxide (DMSO) for 72 hours to obtain the maximum signal value.
  • DMSO dimethyl sulfoxide
  • Inhibition rate % (maximum signal value - compound signal value) / (maximum signal value - minimum signal value) X 100%.
  • IC50 values were calculated by sigmoidal dose-response curve fitting.
  • Table 1 lists the representative compounds 2, 3, and 5 described in the present invention, which have anti-cell proliferation against tumor cells SW620, MCF7, MDA-MD-231, LOVO, H1975, and Colon 205 in cell-based assays. The activity was compared with BBI608 (Shanghai Haiyan Yan Chemical Co., Ltd., batch number: 1512224) and compounds 1, 20 in the examples.
  • the compound of the present invention has strong anti-tumor cell proliferation activity against various tumor cells.
  • the anti-tumor cell proliferation activity of the compounds of the invention is superior to the control BBI608.
  • the anti-tumor cell proliferation activity of the compounds of the present invention against various tumor cells is significantly superior to that of Compounds 1, 20.
  • test compound 1, compound 2, compound 3 or reference compound STAT3 inhibitor BBI608 (Shanghai Haiyan Chemical Co., Ltd., batch number: 1512224), Jak inhibitor INCB018424 (ChemExpress, Cat. No.
  • HY-50856 was cultured for 6, 12 or 24 hours, washed once with pre-cooled PBS, and collected in tubes, using cell extract (Invitrogen, Cat#FNN0011) The cells were lysed, the tubes were placed on ice for 30 minutes, centrifuged at 14,000 rpm for 30 min at 4 ° C, and the supernatant was taken and stored at -80 ° C.
  • the protein concentration was determined by Bradford method. 15 ug of protein was loaded from each sample. Protein was separated by SDS-PAGE electrophoresis (120 V) and transferred to PVDF membrane (40 min, 120 V) using Bio-Rad's Tran-Blot. The solution (25 g BSA per 100 ml TBST) was blocked for 120 min at room temperature, and the corresponding primary anti-Stat3 antibody (D3Z2G) (CST, #12640S), Phospho-Stat3 (Tyr705) antibody (CST, #9145S), Phospho-Stat2 (Ser727) were added.
  • D3Z2G primary anti-Stat3 antibody
  • Phospho-Stat3 Tyr705
  • CST, #9145S Phospho-Stat2
  • CST The antibody (CST, #9134S), GAPDH antibody (D16H11) (CST, #5174S) was incubated overnight at 4 ° C, and then the membrane was washed with TBST solution for 3 x 5 minutes.
  • HRP-linked Anti-Rabbit lgG (CST#7074) Incubate for 45 minutes at room temperature in the dark and then wash the membrane with TBST for 3 x 5 minutes.
  • Chemiluminescence scanning imaging was detected by placing the membrane on an imaging system (Cell Biosciences) using ECL Western Blotting Detection (Thermo, #34095).
  • the Jak inhibitor INCB018424 did not affect the phosphorylation level of STAT3 in SW480 and K562 cells.
  • Figure 3-4 (“Veh” is a vehicle abbreviation) shows total STAT3, p-Stat3 (Tyr705) and p-Stat3 in SW480 cells and K562 cells treated with different concentrations of Compound 2, Compound 3, and BBI608 at different times. (Ber727) results of immunoblot analysis.
  • the decrease in total STAT3 and ⁇ -actin levels after treatment of compounds 2 and 3 at high concentrations for 24 hours may be associated with partial tumor cell death.
  • compound 2 and compound 3 reduced phospho-STAT3Tyr705 levels after 6 hours and 24 hours of treatment, especially at high concentrations; under the same experimental conditions, the two compounds were treated at high concentrations.
  • the phospho-STAT3Ser727 level was significantly reduced in 24 hours.
  • Compounds 2 and 3 were more potent at the same concentration (2 ⁇ M) than the control compound BBI608, especially after 24 hours of treatment.
  • mice Male SD rats (Guangdong Provincial Medical Laboratory Animal Center) weighing 300-350 g were fasted overnight before the test.
  • the test compound was dissolved in 30% sulfobutyl- ⁇ -cyclodextrin (SBE- ⁇ -CD) and administered orally at 20 mg/kg.
  • Blood was taken at the end of the 15th, 30th, and 1st, 2nd, 3rd, 4th, 6th, 8th and 24th hours after administration. About 0.3ml was taken at each time point and placed in a centrifuge tube containing K2-EDTA. Plasma was taken by centrifugation (2,000 g, 10 minutes, 4 ° C) and stored in an ultra-low temperature freezer at -80 °C.
  • T max refers to the peak time
  • C max refers to the maximum blood concentration
  • T 1/2 is the half life
  • AUC last refers to the area under the time-concentration curve of 0-24 hours
  • AUC inf refers to 0-Inf Area under the time-concentration curve.
  • the compound 2-3 of the present invention has a fast absorption rate and good absorption after gavage, and Tmax is 0.58 hours and 0.42 hours, respectively; the half-lives are 12.02 hours and 8.58 hours, respectively.

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Abstract

L'invention porte sur un composé de furoquinolinedione représenté par la formule (I), sur un promédicament, un stéréoisomère ou un sel de qualité pharmaceutique de celui-ci, une composition pharmaceutique de celui-ci, un procédé de préparation associé et l'utilisation médicale de celui-ci.
PCT/CN2017/102476 2016-09-20 2017-09-20 Composé de furoquinolinedione et son utilisation médicale WO2018054304A1 (fr)

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