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CN-122010968-A - Furanoquinoline dictamnine derivative and preparation method and application thereof

CN122010968ACN 122010968 ACN122010968 ACN 122010968ACN-122010968-A

Abstract

The invention belongs to the technical field of biological medicines, and particularly relates to a furoquinoline dictamnine derivative, a preparation method and application thereof. The compound has novel and stable structure, obvious anticancer effect, particularly higher inhibition rate on NCI-H460 and 786-O tumor cells, lower IC 50 , obvious antitumor effect and better application prospect in anticancer treatment. In addition, the preparation method of the furoquinoline dictamnine derivative has the advantages of wide substrate application range, good functional group compatibility, mild reaction conditions, simplicity and convenience in operation and the like, can be used for large-scale industrial production, and has wide application value in the aspect of developing anticancer drugs.

Inventors

  • ZHU DAQIAN
  • LIU SONG
  • WEN SHIJUN
  • HUANG KAITAO
  • GUO XIAOYING
  • DAI YUTING

Assignees

  • 广东药科大学

Dates

Publication Date
20260512
Application Date
20251223

Claims (10)

  1. 1. The furoquinoline dictamnine derivative or a pharmaceutically acceptable salt thereof is characterized in that the furoquinoline dictamnine derivative has the following structure: Wherein R 1 is selected from hydrogen, C 1~6 alkyl, halogenated C 1~6 alkyl, C 1~6 alkoxy, halogenated C 1~6 alkoxy, halogen, amino, nitro, ester, carbonyl, or carbamoyl; R 2 is selected from hydrogen, C 1~6 alkyl, halogenated C 1~6 alkyl, C 1~6 alkoxy, halogenated C 1~6 alkoxy, halogen, ester group or nitro; R 3 is selected from hydrogen, halogen, amino, nitro, ester, C 2~6 alkenyl, C 2~6 alkynyl, silicon, C 1~6 alkyl, halogenated C 1~6 alkyl, C 1~6 alkoxy, halogenated C 1~6 alkoxy, phenyl, naphthyl, phenanthryl, a metal-containing organic group, a substituted benzoheterocyclyl, a substituted aryl, a heteroaryl, or a substituted heteroaryl; the heterocyclic group of the substituted benzo heterocyclic group is a 5-6 membered saturated ring, 1-2 hetero atoms of the heterocyclic group are selected from N or S; one or more substituents of the substituted benzoheterocyclyl, each independently selected from the group consisting of C 1~6 alkyl; the heteroaryl is a 5-6 membered aromatic monocyclic ring or an 8-10 membered aromatic bicyclic ring, the hetero atoms of the heteroaryl are 1-4, and the hetero atoms are selected from N, S or O; The substituents of the substituted heteroaryl are one or more, and each substituent is independently selected from C 1~6 alkyl; The substituted aryl is one or more, the substituents are each independently selected from halogen, amino, nitro, ester, C 1~6 alkyl, halogenated C 1~6 alkyl, C 1~6 alkoxy, halogenated C 1~6 alkoxy, phenyl, or-NR 4 R 5 ; Each R 4 、R 5 is independently selected from C 1~6 alkyl or phenyl.
  2. 2. The furoquinoline dictamnine derivative or a pharmaceutically acceptable salt thereof according to claim 1 wherein R 1 is selected from the group consisting of hydrogen, C 1~4 alkyl, halogenated C 1~3 alkoxy, halogen or ; R 2 is selected from hydrogen, C 1~4 alkyl, halogenated C 1~3 alkyl, halogen, ester group or nitro; R 3 is selected from hydrogen, naphthyl, phenanthryl, a metal-containing organic group, a substituted benzoheterocyclyl, a substituted aryl, heteroaryl, or a substituted heteroaryl; The metal-containing organic group is selected from ferrocenyl; the heterocyclic group of the substituted benzo heterocyclic group is a 5-6 membered saturated ring, 1-2 hetero atoms of the heterocyclic group are selected from S; The substituent of the substituted benzoheterocyclyl is on the heterocyclyl, which is one or more, each independently selected from the group consisting of C 1~3 alkyl; The heteroaryl is a 5-6 membered aromatic monocyclic ring, the number of heteroatoms of the heteroaryl is 1-2, and the heteroatoms are selected from N or S; the substituents of the substituted heteroaryl are one or more, and each substituent is independently selected from C 1~3 alkyl; The substituent of the substituted aryl is selected from halogen, amino, ester, C 1~4 alkyl, halogenated C 1~3 alkyl, C 1~3 alkoxy, halogenated C 1~3 alkoxy, phenyl or-NR 4 R 5 ; Each R 4 、R 5 is independently selected from C 1~3 alkyl or phenyl; The substituent of the substituted heteroaryl is selected from C 1~3 alkyl.
  3. 3. The furoquinoline dictamnine derivative or a pharmaceutically acceptable salt thereof according to claim 1, wherein R 1 is selected from hydrogen, isopropyl, tert-butyl, fluoro, chloro, bromo, trifluoromethoxy or ; R 2 is selected from hydrogen, tert-butyl, trifluoromethyl, fluoro, chloro, bromo, methyl or nitro; r 3 is selected from hydrogen, naphthyl, phenanthryl, ferrocenyl, substituted benzoheterocyclyl, substituted aryl or heteroaryl; The heterocyclic group of the substituted benzo heterocyclic group is a 6-membered saturated ring, the number of hetero atoms of the heterocyclic group is 1, and the hetero atoms are selected from S; The substituent of the substituted benzoheterocyclyl is on the heterocyclyl, which is one or more, each independently selected from methyl; The heteroaryl is a 5-6 membered aromatic monocyclic ring, the number of heteroatoms of the heteroaryl is 1, and the heteroatoms are selected from N; the substituent of the substituted aryl is selected from fluorine, chlorine, bromine, amino, methyl ester group, methyl, tertiary butyl, trifluoromethyl, methoxy, trifluoromethoxy, phenyl or-NR 4 R 5 ; Each R 4 、R 5 is independently selected from methyl or phenyl.
  4. 4. The furoquinoline dictamnine derivative or a pharmaceutically acceptable salt thereof according to claim 1, wherein R 1 is selected from hydrogen, 10-isopropyl, 8-tert-butyl, 10-fluoro, 10-chloro, 10-bromo, 10-trifluoromethoxy or 10-benzoyl; R 2 is selected from hydrogen, 3-tert-butyl, 3-trifluoromethyl, 3-fluoro, 3-chloro, 3-bromo, 2-bromo, 3-methyl or 2-nitro; r 3 is selected from hydrogen, 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 Or (b) 。
  5. 5. The method for preparing the furoquinoline dictamnine derivative or the pharmaceutically acceptable salt thereof according to any one of claims 1 to 4, wherein the furoquinoline dictamnine derivative is prepared by the following steps: In an inert atmosphere, using quinolinone condensed cyclic diaryl iodonium salt shown in a formula 1 and alkyne shown in a formula 2 as raw materials, reacting in an organic solvent in the presence of a palladium catalyst, a copper salt, an organic ligand and alkali at room temperature, and then heating to react to obtain the furoquinoline dictamnine derivative shown in a formula 3: ; Wherein R 1 、R 2 、R 3 is as defined in any one of claims 1 to 4.
  6. 6. The preparation method according to claim 5, wherein the preparation method comprises one or more of the following (1) to (9): (1) The organic ligand is selected from halogen-containing aryl phosphine ligands; (2) The organic solvent comprises one or more of N, N-dimethylformamide, dimethyl sulfoxide and N-butanol; (3) The palladium catalyst is at least one selected from palladium acetate, tetra (triphenylphosphine) palladium and dichloro bis (triphenylphosphine) palladium; (4) The copper salt is selected from cuprous iodide; (5) The alkali is at least one of sodium carbonate, potassium carbonate and sodium hydroxide; (6) The molar ratio of the quinolinone condensed cyclic diaryl iodonium salt, alkyne, palladium catalyst, copper salt, organic ligand and alkali is 1 (1-2): 0.05-0.15): 0.1-0.3): 0.2-0.4): 2-4; (7) The room temperature reaction time is 1-3 hours; (8) The reaction temperature for the reaction at the temperature rising is 80-120 ℃; (9) The reaction time for the reaction after heating is 2-12 h.
  7. 7. The method of claim 5, wherein when R 2 is selected from the group consisting of hydrogen, the quinolinone fused cyclic diaryliodonium salt is prepared by: s1, uniformly mixing (diacetoxyiodide) benzene, sodium carbonate, water and a compound shown in a formula 1-1, reacting at room temperature, performing aftertreatment to obtain a solid, dissolving the obtained solid in N, N-dimethylformamide, and reacting under an oil bath condition to obtain the compound shown in the formula 1-2; S2, dissolving the compound shown in the formula 1-2 obtained in the step S1 in dichloromethane, adding m-chloroperoxybenzoic acid and trifluoromethanesulfonic acid, and reacting at room temperature to obtain quinolinone condensed cyclic diaryl iodonium salt shown in the formula 1: ; When R 2 is other than hydrogen, the quinolinone fused cyclic diaryliodonium salt is prepared by the steps of: sI. dissolving a compound shown in the formula 1-3 and 2, 4-dichloroquinoline in N, N-dimethylformamide, and reacting in the presence of cesium carbonate to obtain a compound shown in the formula 1-4; sII. mixing the compound shown in the formula 1-4 obtained in the step sI with acetic acid aqueous solution, and carrying out reflux reaction to obtain the compound shown in the formula 1-5; dissolving the compound shown in the formulas 1-5 obtained in the step sII in methylene dichloride, adding m-chloroperoxybenzoic acid and trifluoromethanesulfonic acid, and reacting at room temperature to obtain quinolinone condensed cyclic diaryl iodonium salt shown in the formula 1: ; Wherein R 1 、R 2 is as defined in any one of claims 1 to 4.
  8. 8. The use of the furoquinoline dictamnine derivative or a pharmaceutically acceptable salt thereof in the preparation of an anticancer drug according to any one of claims 1 to 4.
  9. 9. The use according to claim 8, wherein the cancer in the anticancer drug comprises lung cancer and/or renal cell carcinoma.
  10. 10. A pharmaceutical composition comprising one or more of the furoquinoline dictamnine derivatives or pharmaceutically acceptable salts thereof as claimed in any one of claims 1 to 4.

Description

Furanoquinoline dictamnine derivative and preparation method and application thereof Technical Field The invention belongs to the technical field of biological medicine. More particularly relates to a furoquinoline dictamnine derivative, a preparation method and application thereof. Background Cancer is one of the major public health problems worldwide, and its treatment has always been a central challenge for medical research. Among them, lung cancer and renal cell carcinoma are common malignant tumors with high mortality, and the current treatment methods have been significantly advanced, but still face a plurality of limitations. The treatment scheme of lung cancer comprises surgical excision, radiotherapy, chemotherapy, targeted therapy, immunotherapy and the like, wherein the application of targeted drugs aiming at specific driving gene mutations (such as EGFR and ALK) and immunotherapy such as PD-1/PD-L1 inhibitors and the like obviously improves the prognosis of a part of patients, renal cell carcinoma is insensitive to traditional chemotherapy, and the treatment mainly comprises surgery, targeted drugs (such as VEGFR inhibitors) and immunotherapy. However, both types of cancers have problems of easy recurrence and easy drug resistance, and especially for advanced or metastatic patients, the efficacy of the existing therapies is still limited. Therefore, the development of novel and efficient anticancer drugs to enrich clinical treatment options and improve patient quality of life has become an urgent need in the current oncology field. Under the background, natural products become an important source for the development of anticancer drugs due to their structural diversity and good biological activity. Modern pharmacological studies have shown that dictamnine and its analogues, as a class of furoquinoline alkaloids, exhibit a broad range of anticancer potential. For example, the prior art shows that dictamnine can inhibit proliferation of non-small cell lung cancer cells (e.g., A549, H1299) and c-Met dependent cells (e.g., EBC-1) by directly inhibiting the c-Met receptor and thereby down-regulating the PI3K/AKT/mTOR and MAPK signaling pathways. However, although dictamnine shows activity against lung adenocarcinoma cells such as a549, its activity against more aggressive and less therapeutically selected lung cancer subtypes, such as large cell lung cancer, is not known. Large cell lung cancer (as represented by NCI-H460 cell line) accounts for about 10% of non-small cell lung cancer, and is characterized by rapid progression, susceptibility to metastasis, and poor response to conventional treatment regimens, with clear unmet clinical need. Therefore, the development of novel compounds effective for the refractory lung cancer subtypes has important significance. In addition, the clinical chemotherapeutic drugs which can be successfully applied at present are relatively limited, and more anticancer drugs still need to be provided, so that more diversified and more effective drug selections are provided for the treatment of malignant tumors such as lung cancer, renal cell carcinoma and the like. Disclosure of Invention The invention aims to overcome the defect and the defect that the existing anti-cancer drugs are still limited, and provides a furoquinoline dictamnine derivative or pharmaceutically acceptable salt thereof. The invention aims to provide a preparation method of the furoquinoline dictamnine derivative. The invention also aims to provide application of the furoquinoline dictamnine derivative or pharmaceutically acceptable salt thereof. It is a further object of the present invention to protect a pharmaceutical composition. The above object of the present invention is achieved by the following technical scheme: The invention provides a furoquinoline dictamnine derivative or a pharmaceutically acceptable salt thereof, wherein the furoquinoline dictamnine derivative has the following structure: Wherein R 1 is selected from hydrogen, C 1~6 alkyl, halogenated C 1~6 alkyl, C 1~6 alkoxy, halogenated C 1~6 alkoxy, halogen, amino, nitro, ester, carbonyl, or carbamoyl; R 2 is selected from hydrogen, C 1~6 alkyl, halogenated C 1~6 alkyl, C 1~6 alkoxy, halogenated C 1~6 alkoxy, halogen, ester group or nitro; R 3 is selected from hydrogen, halogen, amino, nitro, ester, C 2~6 alkenyl, C 2~6 alkynyl, silicon, C 1~6 alkyl, halogenated C 1~6 alkyl, C 1~6 alkoxy, halogenated C 1~6 alkoxy, phenyl, naphthyl, phenanthryl, a metal-containing organic group, a substituted benzoheterocyclyl, a substituted aryl, a heteroaryl, or a substituted heteroaryl; the heterocyclic group of the substituted benzo heterocyclic group is a 5-6 membered saturated ring, 1-2 hetero atoms of the heterocyclic group are selected from N or S; one or more substituents of the substituted benzoheterocyclyl, each independently selected from the group consisting of C 1~6 alkyl; the heteroaryl is a 5-6 membered aromatic monocyclic ring or an