WO2019047824A1 - Nouveau composé d'imidazoquinoline, son procédé de préparation et son utilisation - Google Patents

Nouveau composé d'imidazoquinoline, son procédé de préparation et son utilisation Download PDF

Info

Publication number
WO2019047824A1
WO2019047824A1 PCT/CN2018/103963 CN2018103963W WO2019047824A1 WO 2019047824 A1 WO2019047824 A1 WO 2019047824A1 CN 2018103963 W CN2018103963 W CN 2018103963W WO 2019047824 A1 WO2019047824 A1 WO 2019047824A1
Authority
WO
WIPO (PCT)
Prior art keywords
amino
cancer
ethyl
butyl
quinolin
Prior art date
Application number
PCT/CN2018/103963
Other languages
English (en)
Chinese (zh)
Inventor
赵旭阳
白骅
徐肖杰
刘礼飞
冯仁田
王海彬
林赟
汪建洁
董文献
张文彪
程英雀
李译
王二文
Original Assignee
浙江海正药业股份有限公司
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by 浙江海正药业股份有限公司 filed Critical 浙江海正药业股份有限公司
Priority to CN201880053123.8A priority Critical patent/CN111094285B/zh
Publication of WO2019047824A1 publication Critical patent/WO2019047824A1/fr

Links

Images

Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
    • Y02P20/00—Technologies relating to chemical industry
    • Y02P20/50—Improvements relating to the production of bulk chemicals
    • Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups

Definitions

  • the present invention relates to a novel class of imidazoquinoline compounds which have TLR7 and TLR8 agonistic activities and are useful in the treatment of cancer and in the prevention and treatment of viral infections.
  • the invention also relates to a process for the preparation of such compounds.
  • Innate immunity is the first line of defense against infectious diseases.
  • the main functions of innate immunity are opsonization, activation of the complement pathway, enhancement of phagocytosis, activation of inflammatory signals, and induction of apoptosis (Janeway et al. Annu. Rev. Immunol. 2002, 20, 197.).
  • Pathogen recognition receptors PRRs
  • PRRs are important components of the innate immune system. These receptors recognize the highly conserved structure of pathogens, the Pathogen-associated molecular pattern (PAMP).
  • Toll like receptors (TLRs) were first discovered in Drosophila, which are involved in the innate immunity of Drosophila and are the most important family of pattern recognition receptors.
  • TLRs were later discovered in humans, with TLRs 1, 2, 4, 5, 6, and 10 located on the cell surface, while TLRs 3, 7, 8, and 9 were located in endosomes or lysosomes (Akira Curr Top Microbiol Immunol). .2006, 311, 1.).
  • TLRs are mainly expressed in spleen, macrophages, mast cells and dendritic cells, and each TLR can recognize and bind to its unique ligand to exert immune activation.
  • TLR7 is mainly expressed in plasmacytoid dendritic cells and has a certain degree of expression in B cells and monocytes/macrophages.
  • Viral or non-viral single-stranded RNA is capable of inducing the production of TLR7-dependent interferon to exert an antiviral effect (Hemmi et al. Nat Immunol. 2002, 3, 196.).
  • the TLR7 agonist imiquimod has been approved for the treatment of basal cell carcinoma and genital warts caused by HPV infection.
  • TLR8 is mainly expressed in monocytes/macrophages and bone marrow dendritic cells.
  • the high degree of homology between TLR7 and TLR8 in the sequence makes them recognize the same ligands, all of which are single-stranded RNA viruses.
  • TLR8 recognizes RNA released by bacteria. Activation of the TLR8 signal is capable of upregulating the expression of inflammatory factors (Cervantes et al. Cell Mol. Immunol. 2012, 9, 434.).
  • TLR8 agonists have the potential to be used in the treatment of cancer and as a vaccine adjuvant.
  • 3M-052 is a TLR7 and TLR8 dual agonist developed by 3M Company (Wightman US7799800). Compared with imiquimod and resiquimod, 3M-052 contains a very long fatty chain, which makes this The compound is deposited in the oil-water mixture solvent and in the liposome to act as a sustained release, and stays at the site of administration of the injection to prevent the drug from entering the blood circulation, thereby avoiding a drastic systemic inflammatory response. In experiments with Balb/c mice, subcutaneous injection of 3M-052 and H1N1 A/Perto Rico/8/34 virus hemagglutinin as adjuvants can induce a strong Th1 response, and the antibodies produced can be effective.
  • 3M-052 combined with TLR9 agonist CpG ODN intratumoral injection can significantly enhance intratumoral CTL activity and promote the production of Th1 factor, while down-regulating the immunosuppressive MDSC cell activity.
  • This compound has now entered the anti-cancer clinical trial.
  • 3M-052 is promising as a new anti-cancer and anti-viral drug, there is still a need to develop other drugs for treating or preventing diseases associated with stimulating TLR7 and/or TLR8, such as viral infections or cancer.
  • One of the objects of the present invention is to disclose a novel class of imidazoquinoline compounds or pharmaceutically acceptable salts thereof.
  • the compounds of the invention may be represented by formula (I):
  • R is -(CH 2 ) m NR 1 R 2 , -(CH 2 ) n OR 3 or -(CH 2 ) q SR 4 ;
  • R 1 and R 2 are independently selected from hydrogen and (C 1 -C 17 )alkyl, but R 1 and R 2 are not simultaneously hydrogen;
  • R 3 is (C 1 -C 17 )alkyl
  • R 4 is (C 1 -C 17 )alkyl
  • n 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10;
  • n 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10;
  • q is 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10.
  • R is -(CH 2 ) m NR 1 R 2 , wherein R 1 and R 2 are independently selected from hydrogen and (C 1 -C 17 )alkyl, but R 1 and R 2 are not At the same time, it is hydrogen; m is 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10.
  • R is -(CH 2 ) m NR 1 R 2 , wherein R 1 and R 2 are independently selected from hydrogen and (C 1 -C 15 )alkyl, but R 1 and R 2 are not At the same time it is hydrogen; m is 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10, preferably 1 or 3.
  • R is -(CH 2 ) m NR 1 R 2 , wherein R 1 and R 2 are independently selected from (C 1 -C 15 )alkyl; m is 1, 2, 3, 4 , 5, 6, 7, 8, 9 or 10, preferably 1 or 3.
  • R is -(CH 2 ) n OR 3 or -(CH 2 ) q SR 4 ; wherein R 3 and R 4 are (C 1 -C 17 )alkyl, n and q are 1 , 2, 3, 4, 5, 6, 7, 8, 9, or 10.
  • R is -(CH 2 ) n OR 3 ; wherein R 3 is (C 1 -C 17 )alkyl; n is 1, 2, 3, 4, 5, 6, 7, 8 , 9 or 10.
  • R is -(CH 2 ) n OR 3 ; wherein R 3 is (C 1 -C 15 )alkyl, preferably (C 3 -C 15 )alkyl, more preferably (C 7 - C 15 )alkyl, most preferably (C 10 -C 15 )alkyl; n is 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10, preferably 1 or 3.
  • R is -(CH 2 ) q SR 4 ; wherein R 4 is selected from (C 1 -C 17 )alkyl; q is 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10
  • R is -(CH 2 ) q SR 4 , wherein R 4 is selected from (C 1 -C 15 )alkyl, preferably (C 3 -C 15 )alkyl, more preferably (C 7 -C 15 )alkyl, most preferably (C 10 -C 15 )alkyl; q is 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10, preferably 1 or 3.
  • the compound of formula (I) is selected from the group consisting of:
  • a pharmaceutical composition comprising an effective amount of a compound of formula (I) of the invention or a pharmaceutically acceptable salt thereof.
  • Pharmaceutically acceptable carriers compatible with the compounds of formula (I) may also be included in the pharmaceutical compositions of the invention.
  • the dosage form of the compound of formula (I) is generally an injection, and the pharmaceutical compositions and dosage forms of the present invention can be prepared by conventional formulation techniques using conventional pharmaceutically suitable solvents and additional agents, including pharmaceutically acceptable solvents and additional agents.
  • a compound of formula (I) and a pharmaceutical composition thereof for the manufacture of a medicament for the treatment or prevention of a disease associated with agonizing TLR7 and/or TLR8.
  • the disease described therein is a viral infection or cancer.
  • a compound of formula (I) and a pharmaceutical composition thereof for the manufacture of a medicament for the treatment or prevention of a viral infection.
  • the virus therein is preferably selected from the group consisting of hepatitis B virus (HBV), HIV (HIV), respiratory syncytial virus (RSV), human papillomavirus (HPV), influenza virus, hepatitis C virus (HCV), and B.
  • Encephalitis virus dengue virus, forest encephalitis virus, yellow fever virus, West Nile virus, Zika virus, bovine viral diarrhea virus, Omsk hemorrhagic fever virus, Junin virus, Murray Valley encephalitis virus And St. Louis encephalitis virus.
  • the cancer is preferably selected from the group consisting of bone cancers, including: Ewing sarcoma, osteosarcoma, chondrosarcoma; brain and CNS tumors, including: acoustic neuroma, neuroblastoma, glioma; spinal cord tumor; breast cancer; endocrine cancer , including: adrenal cortical cancer, pancreatic cancer, pituitary cancer, thyroid cancer, thyroid-rich cancer, thymic cancer, multiple endocrine cancer; lung cancer: small cell lung cancer and non-small cell lung cancer; gastrointestinal and liver cancer, including: gastric cancer , esophageal cancer, small intestine cancer, colorectal cancer, liver cancer, extrahepatic cholangiocarcinoma, gastrointestinal carcinoid tumor, gallbladder cancer; genitourinary cancer, including: testicular cancer, pen
  • a process for producing a compound (I) by reacting a compound represented by the formula (II) with a compound represented by the formula (III) or a salt thereof (as shown in the reaction formula 1).
  • the method is applicable to the preparation of a compound of formula (I) when R is -(CH 2 ) m NR 1 R 2 , -(CH 2 ) n OR 3 or -(CH 2 ) q SR 4 , wherein R 1 , R 2 , R 3 and R 4 are independently selected from (C 1 -C 17 )alkyl; m, n and q are 1 , 2 , 3 , 4 , 5, 6, 7, 8, 9, or 10.
  • the method is applicable to the preparation of a compound of formula (I) when R is -(CH 2 ) m NR 1 R 2 wherein R 1 is selected from (C 1 -C 17 )alkyl and R 2 is hydrogen; R 5 is an amino protecting group, preferably a benzyl group; m is 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10.
  • intermediate compounds of formula (II) are provided.
  • Step 1 reacting a compound represented by the formula (VII) with a compound represented by the formula (VIII) to obtain a compound represented by the formula (VI),
  • R 6 is an amino protecting group, preferably benzyloxycarbonyl (Cbz).
  • Step 2 introducing an amino group onto the quinoline ring of the compound represented by the formula (VI), and then removing the branched amino protecting group,
  • R 6 is a protecting group for an amino group, preferably benzyloxycarbonyl (Cbz).
  • R 1 is selected from (C 1 -C 17 )alkyl;
  • R 5 is an amino protecting group, preferably benzyl;
  • n 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10.
  • R 1 is selected from (C 1 -C 17 )alkyl;
  • R 5 is an amino protecting group, preferably benzyl;
  • n 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10.
  • Halogen means fluoro, chloro, bromo and iodo.
  • alkyl group as a group means a linear or branched saturated aliphatic hydrocarbon group, and in the present invention, it is preferably a (C 1 -C 17 )alkyl group, further preferably (C 3 -C) 15 ) an alkyl group, more preferably a (C 7 -C 15 )alkyl group, most preferably a (C 10 -C 15 )alkyl group.
  • (C 1 -C 17 )alkyl includes methyl, ethyl, n-propyl, 2-propyl, n-butyl and all of its isomers, n-pentyl and all its isomers, And all its isomers, n-heptyl and all its isomers, n-octyl and all its isomers, n-decyl and all its isomers, n-decyl and All of its isomers, n-undecyl and all its isomers, n-dodecyl and all its isomers, n-tridecyl and all its isomers, N-tetradecyl and all its isomers, n-pentadecyl and all its isomers, n-hexadecyl and all its isomers, n-heptadecyl and all of them Isomer; (C 1 -C 15 )alkyl includes
  • the pharmaceutically acceptable salt of the compound represented by the formula (I) may be a salt formed with a suitable acid, and the suitable acid includes an inorganic acid and an organic acid such as acetic acid, benzenesulfonic acid, benzoic acid, camphorsulfonic acid, citric acid.
  • ethanesulfonic acid fumaric acid, gluconic acid, glutamic acid, hydrobromic acid, hydrochloric acid, isethionic acid, lactic acid, malic acid, maleic acid, mandelic acid, methanesulfonic acid, nitric acid, phosphoric acid, succinic acid , sulfuric acid, tartaric acid, p-toluenesulfonic acid, and the like.
  • Particularly preferred are hydrochloric acid, phosphoric acid and sulfuric acid.
  • TLR7 and TLR8 agonists which are effective in activating the immune system and are useful in the treatment of cancer as well as in the prevention and treatment of viral infections.
  • the glassware is dried in an oven and/or dried by heating.
  • the reaction was followed by glass silica gel-60F254 plate (0.25 mm) (TLC).
  • Analytical thin layer chromatography was carried out and developed in a suitable solvent ratio (v/v). The end point of the reaction was taken when the starting material was depleted on TLC.
  • Mass spectrometry was measured by LC/MS, and the ionization method was ESI or APCI.
  • Root temperature in the present application means 20-30 °C.
  • Figure 1 is a graph showing the tumor growth inhibition curves of Compounds I-17 and I-21 on a B16F10 tumor-bearing model (*, p ⁇ 0.05; **, p ⁇ 0.01; ***, p ⁇ 0.001) compared with the control group. .
  • Figure 2 is a graph showing the tumor growth inhibition curve of Compound I-21 on a CT26.WT tumor-bearing model (**, p ⁇ 0.01; ***, p ⁇ 0.001 compared to the control group).
  • Figure 3 is a graph showing the tumor growth inhibition curve of Compound I-21 on the RM-1 tumor-bearing model (*, p ⁇ 0.05; **, p ⁇ 0.01) compared with the control group.
  • Figure 4 is the total tumor growth inhibition curve of compound I-17 and I-21 on the CT26.WT bilateral tumor-bearing model (administered side + unadministered side) (*, p ⁇ 0.05 compared with the control group; **, p ⁇ 0.01).
  • Figure 5 is a graph showing the tumor growth inhibition curves of the compounds I-17 and I-21 on the CT26.WT bilateral tumor-bearing model (*, p ⁇ 0.05; **, p ⁇ 0.01; * compared with the control group) **, p ⁇ 0.001).
  • Figure 6 is a graph showing the tumor growth inhibition curves of compounds I-17 and I-21 on the distal (non-administered side) CT26.WT bilateral tumor-bearing model (*, p ⁇ 0.05; **, compared with the control group). p ⁇ 0.01).
  • Figure 7 is the inhibition of Compound I-21 on 4T1 lung metastasis (*, p ⁇ 0.05; **, p ⁇ 0.01) compared to the control group.
  • Figure 8 is the inhibition of B16F10 lung metastasis by Compounds I-2 and I-21 (**, p ⁇ 0.01; ***, p ⁇ 0.001 compared to the control group).
  • Step 1 Preparation of benzyl N-[2-(2-hydroxyethoxy)ethyl]carbamate:
  • Step 4 Preparation of 1-[2-(2-aminoethoxy)ethoxy]-2-butyl-1H-imidazo[4,5-c]quinolin-4-amine (Compound II):
  • Example 21 Preparing compound I-20 according to the method of Example 21 using suitable 1-bromoundecane and thiourea as raw materials; or using commercially available 1-alkyl mercaptan as raw material, according to step 2 and step 3 of Example 21.
  • the compounds were prepared to give compounds I-21, I-22 and I-23.
  • Step 1 Preparation of 4-[benzyl(dodecyl)amino]butyric acid methyl ester
  • murine melanoma cell B16F10 murine colon cancer cell line CT26.WT, human colon cancer cell HCT-116, human lung cancer cell A549, human ovarian cancer cell OVCAR-5, human prostate cancer cell PC -3, human lung cancer cell NCI-H460, human breast cancer cell MCF-7, human renal clear cell carcinoma cell Caki-2, human liver cancer cell HepG2, human neuroblastoma cell SH-Y5Y, human oral epidermoid carcinoma cell KB
  • Human esophageal cancer cell line EC109, human osteosarcoma cell MG-63 was purchased from ATCC, and cultured in DMEM medium or RPMI1640 medium containing 10% fetal bovine serum.
  • Table 1 Compound inhibits tumor cell proliferation activity in vitro
  • Experimental method Compounds were serially diluted with pH 7.2 PBS, and each group was added to a 96-well plate according to the experimental design by adding 20 ⁇ l of the compound or PBS.
  • the HEK-TLR7 or HEK-TLR8 cells in the logarithmic growth phase were mechanically blown off, and the SEAP reaction solution was added to prepare a cell solution of 220,000 cells/ml, and 180 ⁇ l of the cell solution was added to each well.
  • the cells were cultured for 16 h in a CO 2 incubator, and the absorbance at 620 nm was measured on a MD 5 plate reader.
  • the experimental data was statistically analyzed by Graphpad prism 5.0 software, and the EC 50 was calculated. The experimental results are shown in Table 2.
  • Compound (I-17 and I-21) inhibits proliferation of murine melanin B16F10 tumor
  • mice B16F10 cells in the exponential growth phase were collected, and the RPMI1640 medium was resuspended to the appropriate concentration for subcutaneous inoculation of C57BL/6 mice.
  • the tumors were grown to about 100 mm 3 and grouped on day 0, day 4, and eighth. 25 ⁇ l (50 ⁇ g) was administered intratumorally, and the control group was intratumorally injected with an equal volume of solvent.
  • Tumor inhibition rate (%) (1-T (drug group tumor volume) / C (solvent group tumor volume)) * 100.
  • Compounds I-17 and I-21 had excellent tumor growth inhibition on the B16F10 tumor-bearing model (Table 3), which significantly inhibited the growth of B16F10 tumors over 3M-052 (Fig. 1).
  • Compound I-21 inhibits the proliferation of murine colon cancer CT26.WT tumor
  • the tumor inhibition rate of compound I-21 in the CT26.WT tumor-bearing model of 6.25 ⁇ g, 12.5 ⁇ g, 25 ⁇ g, 50 ⁇ g was 61.4%, 96.2%, 91.5%, 86.6%; 3M-052 in CT26.WT
  • the tumor inhibition rates of the 6.25 ⁇ g, 12.5 ⁇ g, 25 ⁇ g, and 50 ⁇ g dose groups were 23.1%, 86.7%, 94.7%, and 80.1%, respectively.
  • Fig. 2 at the same time, all the 3M-052 and I-21 dose groups had tumor-bearing mice, the tumor disappeared completely and cured.
  • the cure rate of I-21 low dose 6.25 ⁇ g group was 40%, which was much better than
  • the cure rate of 3M-052 at a dose of 6.25 ⁇ g was 10% (Table 4).
  • RM-1 cells in the exponential growth phase were collected, and RPMI1640 medium was resuspended to the appropriate concentration for subcutaneous inoculation of C57BL/6 mice.
  • the tumors were grown to about 100 mm 3 and grouped on day 0 and day 4, respectively.
  • 25 ⁇ l (50 ⁇ g) was intratumorally administered, and the control group was intratumorally injected with an equal volume of solvent.
  • the tumor volume of the mice was measured three times per week, and the tumor inhibition rate was calculated after the end of the experiment.
  • Tumor volume calculation formula: tumor volume (mm 3 ) 0.5 ⁇ (tumor long diameter ⁇ tumor short diameter 2 ).
  • Tumor inhibition rate (%) (1-T (drug group tumor volume) / C (solvent group tumor volume)) * 100.
  • the total tumor inhibition rates of compounds 3M-052, I-17 and I-21 on the CT26.WT bilateral tumor-bearing model in mice were 20.4%, 52.8% and 64.3%, respectively (Fig. 4), I-17 and I-21.
  • the drug-effect side of the murine colon cancer tumor-bearing model was significantly better than that of 3M-052 (Fig. 5), and the growth inhibitory effects of I-17 and I-21 on the distal (non-administered side) tumor were also significant. Better than 3M-052 ( Figure 6).
  • mice Female BabL/C mice were inoculated with 20 ⁇ l of 1 ⁇ 10 6 4T1 cells in situ in the mammary fat pad, and grouped when the average tumor volume reached 80-120 mm 3 , respectively on day 0, day 4, 25 ⁇ l of intratumoral administration was given for 8 days (50 ⁇ g and 12.5 ⁇ g dose groups were set for each test drug), and the control group was intratumorally injected with an equal volume of solvent.
  • the animals were anesthetized on the 14th day, the lungs of the animals were removed, and the number of lung nodules was calculated under a dissecting microscope and statistical analysis was performed.
  • the inhibitory rates of 4T1 lung metastases in the 12.5 ⁇ g and 50 ⁇ g groups of the compound I-21 were 39% and 57%, respectively, while the 3M-052 12.5 ⁇ g and 50 ⁇ g dose groups could not reduce the formation of 4T1 lung metastases.
  • mice C57BL/6 mice were injected with tumor cells (anhydrous ethanol inactivated) and a mixture of drugs (1.5 ⁇ 10 5 B16F10 cells + 50 ⁇ g drug) on the right hind leg muscle on day 0, and the tail vein was injected on the third day. 3x10 5 B16F10 cells. After inoculation of the tail vein tumor cells, the animals were anesthetized on the 21st day, the lungs of the animals were taken out, the number of lung nodules was counted under a dissecting microscope, and statistical analysis was performed.
  • tumor cells anhydrous ethanol inactivated
  • a mixture of drugs 1.5 ⁇ 10 5 B16F10 cells + 50 ⁇ g drug
  • the present invention provides a new class of imidazoquinoline compounds which are potent TLR7 and TLR8 agonists and which can reside at the site of injection to avoid influx into the bloodstream and produce a fierce systemic inflammatory response.
  • the heteroatoms (oxygen, nitrogen, sulfur) contained in the long chain of fats of such compounds produce unexpected biological activity, making such new imidazoquinoline compounds have far greater anticancer activity than 3M-052 in vitro. And anti-cancer effects in the body.
  • 3M-052 in the 4T1 spontaneous metastasis model, 3M-052 not only failed to inhibit tumor metastasis to the lungs, but promoted its transfer; in contrast, the imidazoquinoline compounds provided by the present invention were large. To a certain extent, it can inhibit the metastasis of tumors to the lungs.
  • the prospect of this new imidazoquinoline compound as an anticancer and antiviral drug is very bright.

Landscapes

  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Public Health (AREA)
  • General Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Veterinary Medicine (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Health & Medical Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Immunology (AREA)
  • Virology (AREA)
  • Communicable Diseases (AREA)
  • Oncology (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

L'invention concerne un nouveau composé d'imidazoquinoline et un procédé de préparation de celui-ci. L'invention concerne également un composé représenté par la formule (I) ou un sel pharmaceutiquement acceptable de celui-ci qui présente des activités agonistes de TLR7 et TLR8 et peut être utilisé dans le traitement du cancer ainsi que dans la prévention ou le traitement d'une infection virale.
PCT/CN2018/103963 2017-09-05 2018-09-04 Nouveau composé d'imidazoquinoline, son procédé de préparation et son utilisation WO2019047824A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
CN201880053123.8A CN111094285B (zh) 2017-09-05 2018-09-04 新型咪唑喹啉化合物及其制备方法和用途

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
CN201710792102 2017-09-05
CN201710792102.5 2017-09-05

Publications (1)

Publication Number Publication Date
WO2019047824A1 true WO2019047824A1 (fr) 2019-03-14

Family

ID=65634595

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/CN2018/103963 WO2019047824A1 (fr) 2017-09-05 2018-09-04 Nouveau composé d'imidazoquinoline, son procédé de préparation et son utilisation

Country Status (3)

Country Link
CN (1) CN111094285B (fr)
TW (1) TWI693223B (fr)
WO (1) WO2019047824A1 (fr)

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2020160054A1 (fr) * 2019-02-01 2020-08-06 Canwell Biotech Limited Dérivés d'imidazoquinoline amine, composition pharmaceutique, utilisation de ceux-ci
WO2022037631A1 (fr) * 2020-08-21 2022-02-24 浙江海正药业股份有限公司 Dérivé hétérocyclique, son procédé de préparation et son utilisation

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2007100634A2 (fr) * 2006-02-22 2007-09-07 3M Innovative Properties Company Conjugués du modificateur de réponse immune
CN103582640A (zh) * 2011-06-03 2014-02-12 3M创新有限公司 肼基1h-咪唑并喹啉-4-胺以及由其制成的缀合物
CN106535938A (zh) * 2014-07-09 2017-03-22 上海博笛生物科技有限公司 用于治疗癌症的联合治疗组合物和联合治疗方法

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2007100634A2 (fr) * 2006-02-22 2007-09-07 3M Innovative Properties Company Conjugués du modificateur de réponse immune
CN103582640A (zh) * 2011-06-03 2014-02-12 3M创新有限公司 肼基1h-咪唑并喹啉-4-胺以及由其制成的缀合物
CN106535938A (zh) * 2014-07-09 2017-03-22 上海博笛生物科技有限公司 用于治疗癌症的联合治疗组合物和联合治疗方法

Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2020160054A1 (fr) * 2019-02-01 2020-08-06 Canwell Biotech Limited Dérivés d'imidazoquinoline amine, composition pharmaceutique, utilisation de ceux-ci
US10954239B2 (en) 2019-02-01 2021-03-23 Canwell Biotech Limited Imidazoquinoline amine derivatives, pharmaceutical compositions and therapeutic methods thereof
CN114585621A (zh) * 2019-02-01 2022-06-03 康威(广州)生物科技有限公司 咪唑并喹啉胺衍生物、及其药物组合物和应用
CN114585621B (zh) * 2019-02-01 2023-11-14 康威(广州)生物科技有限公司 咪唑并喹啉胺衍生物、及其药物组合物和应用
WO2022037631A1 (fr) * 2020-08-21 2022-02-24 浙江海正药业股份有限公司 Dérivé hétérocyclique, son procédé de préparation et son utilisation

Also Published As

Publication number Publication date
TW201912644A (zh) 2019-04-01
TWI693223B (zh) 2020-05-11
CN111094285A (zh) 2020-05-01
CN111094285B (zh) 2022-05-10

Similar Documents

Publication Publication Date Title
TWI659957B (zh) 新穎吡唑并［3,4-d］嘧啶化合物或其鹽
ES2589801T3 (es) Derivados de dihidroquinolina como inhibidores de bromodominio
CN116348477A (zh) 作为抗病毒剂的功能化肽
CA2632653C (fr) Derives chimiques de jasmonate, compositions pharmaceutiques et procedes d'utilisation correspondants dans le traitement du cancer
CA2901022A1 (fr) Composes pyridiniques substitues en tant qu'inhibiteurs d'histone demethylases
WO2021027724A1 (fr) Immunomodulateur
CN112543755A (zh) 一类细胞坏死抑制剂及其制备方法和用途
RU2600928C2 (ru) Цианохинолиновые производные
WO2021000770A1 (fr) Composé hétérocyclique capable d'améliorer l'activité immunitaire, son procédé de préparation et son application en médecine
WO2016074532A1 (fr) Procédé de préparation d'alectinib
WO2019047824A1 (fr) Nouveau composé d'imidazoquinoline, son procédé de préparation et son utilisation
CN110577526B (zh) 溴域结构蛋白抑制剂的盐及其制备方法和应用
US20140100225A1 (en) Novel compounds, their preparation and their uses
TWI704139B (zh) 羥基三化合物及其醫藥用途
WO2013107428A1 (fr) Dérivé d'hanfangichin b substitué en position 7, et procédé de préparation et utilisation de celui-ci
CN114585621B (zh) 咪唑并喹啉胺衍生物、及其药物组合物和应用
JP2019521193A (ja) 抗癌剤としての４−アニリノ−キノリン化合物
KR101572929B1 (ko) 퀴놀린 유도체 및 티로신 키나제 저해제로서의 이의 용도
US9284274B2 (en) Chemical derivatives of jasmonate, pharmaceutical compositions and methods of use thereof
TWI404709B (zh) 4- (3-benzamidophenyl) -6,7-dimethoxy-2-methylamine quinazoline derivatives
ES2345377B1 (es) Compuestos aminociclitoles, procedimiento de obtencion y usos.
JP2023501163A (ja) ４－アミノ－イミダゾキノリン化合物及びその使用
TW201031402A (en) New retinoid derivatives endowed with cytotoxic and/or antiangiogenic properties
CN115160222B (zh) 含喹啉或异喹啉的异羟肟酸类化合物及其制备与应用
JP7394790B2 (ja) Ｎ－１分枝状シクロアルキル置換イミダゾ［４，５－ｃ］キノリン化合物、組成物、及び方法

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 18855011

Country of ref document: EP

Kind code of ref document: A1

NENP Non-entry into the national phase

Ref country code: DE

122 Ep: pct application non-entry in european phase

Ref document number: 18855011

Country of ref document: EP

Kind code of ref document: A1