WO2025001997A1 - Composé quinoléine, son procédé de préparation, composition pharmaceutique et utilisation médicale associées - Google Patents

Composé quinoléine, son procédé de préparation, composition pharmaceutique et utilisation médicale associées Download PDF

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Publication number
WO2025001997A1
WO2025001997A1 PCT/CN2024/100648 CN2024100648W WO2025001997A1 WO 2025001997 A1 WO2025001997 A1 WO 2025001997A1 CN 2024100648 W CN2024100648 W CN 2024100648W WO 2025001997 A1 WO2025001997 A1 WO 2025001997A1
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cancer
compound
substituted
unsubstituted
pharmaceutically acceptable
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Chinese (zh)
Inventor
郑志兵
李鹏运
李松
刘彦东
肖军海
钟武
李行舟
周辛波
樊士勇
肖典
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Academy of Military Medical Sciences AMMS of PLA
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
    • C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
    • C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D215/48—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P15/00—Drugs for genital or sexual disorders; Contraceptives
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A61P19/02—Drugs for skeletal disorders for joint disorders, e.g. arthritis, arthrosis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a chain containing hetero atoms as chain links

Definitions

  • the present invention belongs to the field of medicine, and specifically relates to quinoline compounds, pharmaceutically acceptable salts, prodrugs, stable isotope derivatives, isomers, solvates or polymorphs thereof, and also relates to preparation methods, pharmaceutical compositions and medical uses of the above compounds.
  • Protein tyrosine kinase is an important factor in the cell signaling process. It participates in a series of cell functions and is closely related to cell growth, differentiation, and proliferation. It catalyzes the transfer of the ⁇ -phosphate group of ATP to the tyrosine residues of many important proteins, phosphorylating the phenolic hydroxyl group, thereby transmitting signals.
  • Tyrosine kinase belongs to the protein kinase family and can be divided into two major categories according to its structure: receptor tyrosine protein kinases (Receptor PTKs) and non-receptor tyrosine protein kinases (Non-receptor PTKs).
  • tyrosine protein kinases can be further divided into multiple enzyme genera according to structural homology. There are 518 kinase genes in the human body, of which 90 PTKs have been discovered, including 58 receptor-type tyrosine kinases and 32 non-receptor-type tyrosine kinases.
  • Receptor-type tyrosine kinases include platelet-derived growth factor receptor (PDGFR), epidermal growth factor receptor (EGFR), fibroblast growth factor receptor (FGFR) and other members. They usually have an extracellular domain, a transmembrane region and an intracellular kinase domain. Clinical studies on cancer have shown that these receptors and their ligands are closely related to many tumors.
  • Non-receptor tyrosine kinases generally have no extracellular structure. They are usually coupled to the cell membrane or exist in the cytoplasm, including Abl kinase, Src kinase, C-terminal Src kinase and other members. In tumor tissues, nrPTKs are often activated, which in turn activates downstream signal transduction pathways, promotes cell proliferation, resists cell apoptosis, and promotes tumor occurrence and development.
  • TPK is divided into receptor-dependent tyrosine protein kinase (RTK) and non-receptor-dependent tyrosine protein kinase.
  • RTK receptor-dependent tyrosine protein kinase
  • Receptor-dependent or catalytic receptors connect the inside and outside of cells through transmembrane enzyme protein receptors, and activate signal transduction after binding to growth factor ligands.
  • Receptor-type tyrosine protein kinases include EGFR, PDGFR, M-CSF, FGFR, VEGFR, and HGFR.
  • Etc. RTKs all contain active intracellular domains. The occurrence of tumors is closely related to the binding of receptors to corresponding ligands.
  • Angiogenesis is the process by which new blood vessels are formed or split from pre-existing blood vessels. Under normal physiological conditions, angiogenesis is a complex process in which pro-angiogenic factors and anti-angiogenic factors work in coordination. When angiogenesis is abnormal, it can cause a series of diseases, including retinopathy, arthritis, endometriosis, atherosclerosis and cancer. Folkman confirmed in the early 1970s that the growth and metastasis of primary tumors must rely on the formation of new blood vessels. In fact, in order to grow, tumors need new capillaries to provide nutrients and take away metabolic waste. New blood vessels also provide help in the metastasis of tumor cells in the later stage.
  • VEGF vascular permeability factor
  • VEGF family members include A, B, C, D, E and placental growth factor.
  • Most malignant tumor cells have the function of autocrine VEGF, and metastatic tumor cells release VEGF to stimulate local angiogenesis.
  • VEGFR As a specific receptor for VEGF, VEGFR is highly expressed in tumor neovascularization. vascular endothelial cells have genetic stability, so VEGFR inhibitors are not easy to develop drug resistance, are easy to reach the target, and accumulate in high concentrations in tumor tissues.
  • VEGFR-1 FLT-1
  • VEGFR-2 KDR
  • VEGFR-3 FLT-4
  • VEGFR is a highly specific transmembrane receptor, and its protein structure consists of three parts: the extracellular region, the transmembrane region, and the intracellular region.
  • the extracellular region is its binding site with VEGF, containing 7 immunoglobulin-like functional regions; the intracellular region has a tyrosine protein kinase (PTK) with an inserted fragment;
  • PTK tyrosine protein kinase
  • the biological function of VEGFR is to conduct and amplify the signal step by step through a cascade of phosphorylation reactions after binding to its ligand, causing the corresponding biological effects of the cells, thereby inducing the division, proliferation and migration of vascular endothelial cells, enhancing capillary permeability, causing plasma extravasation, and promoting the formation of a large number of peripheral blood vessels.
  • VEGF/VEGFR pathway is closely related to tumor angiogenesis and lymphangiogenesis. This signaling pathway creates a favorable microenvironment for its own survival and development. It can promote the formation of microvessels and obtain rich nutrient supply. The formation of lymphatic vessels plays a more important role in the process of tumor spread. Therefore, blocking the VEGF/VEGFR signaling pathway can effectively inhibit tumor angiogenesis and lymphangiogenesis, and inhibit tumor growth and metastasis.
  • the purpose of the present invention is to provide a small molecule compound that acts on VEGFR and can block VEGF/VEGFR pathway, can prevent or treat diseases related to VEGF/VEGFR pathway.
  • a small molecule compound that acts on VEGFR and can block VEGF/VEGFR pathway, can prevent or treat diseases related to VEGF/VEGFR pathway.
  • it has a strong angiogenesis inhibitory effect and anti-tumor activity, and has an improvement, prevention and treatment effect on various other diseases accompanied by abnormal proliferation of new blood vessels.
  • the present inventors have found through research that the compound having the following general formula (I) can act on the VEGF/VEGFR pathway, significantly inhibit the activity of protein kinases such as VEGF, and has a significant anti-tumor effect.
  • the first aspect of the present invention relates to a compound represented by formula (I), a pharmaceutically acceptable salt, prodrug, stable isotope derivative, isomer, solvate or polymorph thereof;
  • R1 and R2 are each independently selected from hydrogen, alkyl, alkoxy, alkoxycarbonyl, aminoalkanoyl, alkylaminocarbonyl;
  • R 3 is selected from Wherein, R 4 is selected from -(NR 6 ) n1 -C(O)-(NR 7 ) n2 -, R6 and R7 are each independently selected from H, alkyl; n1 and n2 are each independently selected from 0, 1; R5 is selected from substituted or unsubstituted alkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heterocyclyl, cycloalkyl, cycloalkenyl, H, alkenyl, alkynyl, alkylaminocarbonyl, aminocarbonyl, cyano; the substitution is substituted by one or more of the following substituents: halogen, alkyl, alkoxy, haloalkyl, nitro, cycloalkyl, aryl.
  • R1 and R2 are each independently selected from hydrogen, C1-C6 straight or branched alkyl, C1-C6 alkoxy, C1-C6 alkoxycarbonyl , aminoC1 - C6 alkanoyl , C1 - C6 alkylaminocarbonyl.
  • R 1 and R 2 are each independently selected from amino C 1 -C 6 alkanoyl, C 1 -C 6 alkoxy, C 1 -C 6 alkylaminocarbonyl.
  • R 1 and R 2 are each independently selected from carbamoyl and methoxy.
  • R3 is selected from Wherein, R 4 is selected from -(NR 6 ) n1 -C(O)-(NR 7 ) n2 -, R6 and R7 are each independently selected from H, C1 - C6 alkyl; n1 and n2 are each independently selected from 0, 1; R5 is selected from substituted or unsubstituted C1 - C6 alkyl, substituted or unsubstituted 5-10 membered aryl, substituted or unsubstituted 5-10 membered heteroaryl, substituted or unsubstituted 5-10 membered heterocyclyl; the substitution is substituted by one or more of the following substituents: halogen, C1 - C6 alkyl, C1 - C6 alkoxy, halogenated C1 - C6 alkyl, nitro, 3-6 membered cycloalkyl, 5-10 membered aryl.
  • R3 is selected from wherein R 4 is selected from -C(O)NH-, -C(O)-, -C(O)N(CH 3 )-, -NH(CO)NH-, R 5 is selected from substituted or unsubstituted phenyl, substituted or unsubstituted pyridyl, ethyl, substituted or unsubstituted thiazolyl, substituted or unsubstituted methyl, substituted or unsubstituted piperazinyl, substituted or unsubstituted morpholinyl, substituted or unsubstituted naphthyl, substituted or unsubstituted oxazolyl, substituted or unsubstituted isoxazolyl; the substitution is substituted by one or more of the following substituents: fluorine, methyl, chlorine, methoxy, trifluoromethyl, ethoxy, nitro, bromine,
  • R3 is selected from wherein R 4 is selected from -C(O)NH-, -C(O)-, -C(O)N(CH 3 )-, -NH(CO)NH-, R 5 is selected from Phenyl, Ethyl, methyl, Benzyl,
  • R3 is selected from
  • the compound is selected from:
  • R3 is selected from wherein R 4 is selected from -C(O)NH-, -C(O)-, -C(O)N(CH 3 )-, -NH(CO)NH-, R 5 is selected from substituted or unsubstituted phenyl, substituted or unsubstituted pyridyl, ethyl, substituted thiazolyl, substituted or unsubstituted methyl, substituted or unsubstituted piperazinyl, substituted or unsubstituted naphthyl, substituted or unsubstituted oxazolyl, substituted isoxazolyl; the substitution is substituted by one or more of the following substituents: fluorine, methyl, chlorine, methoxy, trifluoromethyl, ethoxy, nitro, bromine, cyclopropyl, phenyl.
  • R3 is selected from wherein R 4 is selected from -C(O)NH-, -C(O)-, -C(O)N(CH 3 )-, -NH(CO)NH-, R 5 is selected from Phenyl, Ethyl, methyl, Benzyl,
  • R3 is selected from
  • the second aspect of the present invention provides a method for preparing the compound of the first aspect of the present invention, which is any one of the following methods A to E;
  • the method A comprises:
  • Intermediate 4 is reacted with intermediate 5 to obtain intermediate 6, and then intermediate 6 is reacted with amine using Hobt and EDCI as condensing agents to obtain target compound 8; or, intermediate 4 is reacted with amine using Hobt and EDCI as condensing agents to obtain intermediate 7, and then intermediate 7 is reacted with intermediate 5 to obtain target compound 8;
  • the method B comprises:
  • the intermediate 10 is subjected to amide condensation with an amino compound to obtain the target compound 11;
  • the method C comprises:
  • the intermediate 13 is reacted with the intermediate 14 to obtain the target compound 15;
  • the method D comprises:
  • the raw intermediate 16 was reacted with Hobt and EDCI to obtain intermediate 17;
  • the intermediate 20 is reacted with the intermediate 5 to obtain the target compound 21;
  • the method E comprises:
  • the starting compound 22 is condensed and acylated to obtain the intermediate 23;
  • R 1 , R 2 and R 5 are as defined in the first aspect of the present invention.
  • the preparation method of the compound of the present invention may include (but is not limited to) the above method.
  • the steps in the method can be expanded or combined as needed.
  • the third aspect of the present invention relates to a pharmaceutical composition
  • a pharmaceutical composition comprising the compound of the first aspect of the present invention, its pharmaceutically acceptable salt, prodrug, stable isotope derivative, isomer, solvate or polymorph; optionally, the pharmaceutical composition further comprises a pharmaceutically acceptable carrier or excipient.
  • the pharmaceutical composition further comprises other drugs and/or immunomodulators for treating tumors (for example, one or more selected from immune checkpoint inhibitors, antibiotics, alkylating agents, antimetabolites, hormone drugs, immunoactive agents, and interferon-type active agents).
  • other drugs and/or immunomodulators for treating tumors for example, one or more selected from immune checkpoint inhibitors, antibiotics, alkylating agents, antimetabolites, hormone drugs, immunoactive agents, and interferon-type active agents.
  • the other drugs for treating tumors are drugs for treating tumors other than the compounds of the first aspect of the present invention, their pharmaceutically acceptable salts, prodrugs, stable isotope derivatives, isomers, solvates and polymorphs.
  • the fourth aspect of the present invention relates to the compound of the first aspect of the present invention, its pharmaceutically acceptable salt, prodrug, stable isotope derivative, isomer, solvate or polymorph thereof, or the pharmaceutical composition of the third aspect of the present invention.
  • the fifth aspect of the present invention relates to a method for preventing and/or treating diseases related to the VEGF/VEGFR pathway, comprising administering an effective amount of the compound of the first aspect of the present invention, its pharmaceutically acceptable salt, prodrug, stable isotope derivative, isomer, solvate or polymorph, or an effective amount of the pharmaceutical composition of the third aspect of the present invention to a subject in need.
  • the compound of the first aspect of the present invention its pharmaceutically acceptable salt, prodrug, stable isotope derivative, isomer, solvate or polymorph, or an effective amount of the pharmaceutical composition of the third aspect of the present invention is used to prevent and/or treat diseases related to the VEGF/VEGFR pathway.
  • the disease associated with the VEGF/VEGFR pathway is selected from one or more of atherosclerosis, pulmonary fibrosis, retinopathy, endometriosis, arthritis and cancer.
  • the cancer is selected from one or more of skin cancer, bladder cancer, ovarian cancer, breast cancer, stomach cancer, prostate cancer, colon cancer, lung cancer (e.g., small cell lung cancer, non-small cell lung cancer), bone cancer, brain cancer, rectal cancer, esophageal cancer, kidney cancer (e.g., renal parenchymal cancer), tongue cancer, cervical cancer, uterine body cancer, endometrial cancer, testicular cancer, melanoma, lymphoma, thyroid tumor, glioma, astrocytoma, and hepatocellular carcinoma.
  • lung cancer e.g., small cell lung cancer, non-small cell lung cancer
  • bone cancer e.g., brain cancer
  • rectal cancer esophageal cancer
  • kidney cancer e.g., renal parenchymal cancer
  • tongue cancer e.g., cervical cancer, uterine body cancer
  • endometrial cancer e.g., testicular cancer, melanoma, lymphoma, thyroid tumor,
  • the term "pharmaceutically acceptable salt” in the present invention includes a salt formed by a compound of the present invention with a pharmaceutically acceptable inorganic or organic acid or a basic salt formed with a pharmaceutically acceptable base.
  • the acid salt includes, but is not limited to, hydrochloride, hydrobromide, hydroiodide, nitrate, sulfate, bisulfate, phosphate, hydrogen phosphate, acetate, propionate, butyrate, oxalate, trimethylacetate, adipate, alginate, lactate, citrate, tartrate, succinate, maleate, fumarate, picrate, aspartate, gluconate, benzoate, methanesulfonate, ethanesulfonate, benzenesulfonate, p-toluenesulfonate and pamoate;
  • the basic salt includes, but is not limited to, ammonium salt, alkali metal salts such as sodium and potassium salts,
  • base in the present invention is generally any substance known as a base in organic synthesis without particular limitation, for example, sodium carbonate, sodium bicarbonate, potassium carbonate, potassium bicarbonate, sodium hydride, potassium hydride, sodium tert-butoxide, potassium tert-butoxide, cesium carbonate, triethylamine, trimethylamine, N-methylmorpholine, N,N-dimethylaniline, pyridine, isoquinoline, potassium hydroxide, sodium hydroxide, sodium methoxide, potassium methoxide, etc.
  • pharmaceutically acceptable carrier in the present invention includes, but is not limited to, ion exchangers, alumina, aluminum stearate, lecithin, serum proteins such as human serum proteins, buffer substances such as phosphates, glycerol, sorbic acid, potassium sorbate, partial glyceride mixtures of saturated vegetable fatty acids, water, salts or electrolytes, such as protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts, colloidal silica, magnesium trisilicate, polyvinyl pyrrolidone, cellulosic substances, polyethylene glycol, sodium carboxymethyl cellulose, polyacrylates, beeswax, polyethylene-polyoxypropylene block polymers and lanolin.
  • ion exchangers alumina, aluminum stearate, lecithin
  • serum proteins such as human serum proteins
  • buffer substances such as phosphates, glycerol, sorbic acid, potassium sorb
  • alkyl in the present invention refers to a hydrocarbon group formed by removing a hydrogen atom from an alkane molecule, such as C 1-6 alkyl, C 1-4 alkyl, C 1-2 alkyl; specific examples include but are not limited to methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, etc.
  • alkoxy in the present invention refers to a group provided in the form of alkyl-O-, wherein “alkyl” is as defined above.
  • alkyl for example, C 1-6 alkoxy, C 1-4 alkoxy, C 1-2 alkoxy; specific examples include but are not limited to methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy, tert-butoxy, etc.
  • alkoxycarbonyl in the present invention refers to a group provided in the form of alkoxy-C(O)-, wherein “alkoxy The definition of "alkyl” is as mentioned above.
  • alkoxycarbonyl C 1-6 alkoxycarbonyl, C 1-4 alkoxycarbonyl, C 1-2 alkoxycarbonyl; specific examples include but are not limited to methoxycarbonyl, ethoxycarbonyl, n-propoxycarbonyl, isopropoxycarbonyl, n-butoxycarbonyl and the like.
  • alkanoyl in the present invention refers to a group formed by removing the hydroxyl group from a saturated fatty acid containing a monocarboxyl group, such as C 1-6 alkanoyl, C 1-4 alkanoyl, C 1-2 alkanoyl; specific examples include but are not limited to formyl, acetyl, n-propionyl, isopropionyl, etc.
  • aminoalkanoyl in the present invention is a group provided in the form of NH2 -alkanoyl, wherein “alkanoyl” is as defined above, such as aminoC1-6alkanoyl , aminoC1-4alkanoyl , aminoC1-2alkanoyl ; specific examples include but are not limited to carbamoyl, aminoacetyl, amino-n-propionyl, amino-isopropionyl, amino-n-butyryl, etc.
  • alkylaminoacyl in the present invention is a group provided in the form of alkyl-NH-C(O)-, wherein “alkyl” is as defined above.
  • alkyl is as defined above.
  • aryl in the present invention refers to a monocyclic or condensed ring group having aromaticity, such as a 5-10-membered aryl, a 5-8-membered aryl, a 5-6-membered aryl; specific examples include but are not limited to phenyl, naphthyl, anthracenyl, phenanthrenyl, etc.
  • heteroaryl in the present invention refers to a monocyclic or condensed ring group with aromaticity containing at least one N, O or S heteroatom, such as 5-10 membered heteroaryl, 5-8 membered heteroaryl, 5-7 membered heteroaryl, 5-6 membered heteroaryl; specific examples include but are not limited to porphyrinyl, pyrazolyl, pyrrolyl, thiazolyl, pyridyl, imidazolyl, quinolyl, etc.
  • heterocyclic group in the present invention refers to a monocyclic or polycyclic saturated hydrocarbon group containing at least one heteroatom of N, O or S, such as a 5-10-membered heterocyclic group, a 5-8-membered heterocyclic group, a 5-7-membered heterocyclic group, a 5-6-membered heterocyclic group; specific examples include but are not limited to piperazinyl, morpholinyl, etc.
  • cycloalkyl in the present invention refers to a group formed by removing a hydrogen atom from a monocyclic saturated alkane ring, such as a 3-6-membered cycloalkyl group, a 5-6-membered cycloalkyl group; specific examples include but are not limited to cyclobutane, cyclopentane, cyclohexane, etc.
  • the compound of the present invention has systemic and/or local effects, and therefore can be administered by suitable routes, such as oral, parenteral, pulmonary, nasal, sublingual, lingual, buccal, rectal, transdermal, conjunctival, topical administration or administration in the form of an implant. Administration can be carried out in an administration form suitable for these administration routes.
  • Suitable for oral administration are known administration forms which deliver the active ingredient rapidly and/or in a modified manner, such as tablets (uncoated or coated, such as tablets with enteric coating or film coating), capsules, dragees, granules, pellets, powders, emulsions, suspensions and aerosols.
  • parenteral administration it is possible to avoid the absorption step (intravenous, intraarterial, intracardiac, intraspinal or intralumbar administration) or to include the absorption (intramuscular, subcutaneous, intradermal, transdermal or intraperitoneal administration).
  • Suitable administration forms for parenteral administration are, in particular, preparations in the form of solutions, suspensions, emulsions, lyophilizates and sterile powders for injection and infusion.
  • Suitable other routes of administration include, for example, drugs for inhalation (particularly powder inhalation, spray), nasal drops/solutions, sprays; tablets or capsules for tongue, sublingual or buccal administration, suppositories, preparations for ears and eyes, vaginal capsules, aqueous suspensions (lotions, shaken mixtures), lipophilic suspensions, ointments, creams, emulsions, pastes, dusting powders or implants, such as stents.
  • drugs for inhalation particularly powder inhalation, spray
  • nasal drops/solutions, sprays tablets or capsules for tongue, sublingual or buccal administration
  • suppositories preparations for ears and eyes
  • vaginal capsules aqueous suspensions (lotions, shaken mixtures)
  • lipophilic suspensions ointments
  • creams emulsions
  • pastes pastes
  • dusting powders or implants such as stents.
  • the active ingredient can be converted into the administration form by methods known per se. It can be achieved with inert, non-toxic, suitable pharmaceutical excipients. It particularly includes carriers (e.g. microcrystalline cellulose), solvents (e.g. liquid polyethylene glycol), emulsifiers (e.g. sodium lauryl sulfate), dispersants (e.g. polyvinyl pyrrolidone), synthetic and natural biopolymers (e.g. proteins), stabilizers (e.g. antioxidants and ascorbic acid), colorants (e.g. inorganic pigments such as iron oxide) or flavoring agents and/or taste masking agents.
  • the active ingredient can be present in one or more of the above-mentioned carriers in the form of microencapsulation.
  • the above-mentioned pharmaceutical preparation may further contain other pharmaceutically active ingredients.
  • FIG1 is a graph showing the inhibitory effects of compounds 12 and 28 on HUVECs cell angiogenesis in vitro.
  • FIG2 is a graph showing the inhibitory effects of compounds 12 and 28 on HepG2 liver cancer xenograft tumors in nude mice.
  • FIG3 is a graph showing the inhibitory effects of compounds 12 and 28 on human thyroid cancer 8305C xenograft tumors in nude mice.
  • FIG4 is a graph showing the immunohistochemical effects of compounds 12 and 28 on angiogenesis and proliferation inhibition of human thyroid cancer 8305C xenograft tumors in nude mice.
  • the preparation method of the compound of formula (I) of the present invention is described in more detail below, but these specific methods do not constitute any limitation to the present invention.
  • the compounds of the present invention can also be prepared more conveniently by combining the various synthetic methods described in the specification or known in the art, and such combination can be more easily performed by a technician in the field to which the present invention belongs.
  • Silica gel for column chromatography is produced by Qingdao Ocean Chemical Plant (200-300 mesh); silica gel plates for thin layer chromatography are thin layer chromatography silica gel prefabricated plates produced by Yantai Institute of Chemical Industry.
  • the compounds of the present invention can be prepared by referring to conventional methods in the art and using suitable reagents, raw materials and purification methods known to those skilled in the art.
  • 6-Hydroxy-1-naphthoic acid (9, 1.08 g, 5.74 mmol), cesium carbonate (5.2 g, 16.0 mmol), and DMF (11.0 mL) were added to an eggplant-shaped bottle (nitrogen protection) in sequence, and stirred at room temperature for 10 min. Then 4-chloro-7-methoxyquinoline-6-carboxamide (5, 0.8 g, 3.39 mmol) was added to the eggplant-shaped bottle, stirred at room temperature for 10 min, and then slowly heated to 75 ° C. The reaction was kept at this temperature for 5 h.
  • reaction solution was cooled to room temperature, 20.0 mL of distilled water was added, and the pH was adjusted to 4-5 with saturated NaHCO 3. A large amount of solid precipitated. Filter by suction, wash the filter cake with a small amount of water, and vacuum dry to obtain a white solid. 1.7 g was obtained, and the yield was 68.9%.
  • Example 2 The method was similar to that of Example 1. The product was separated by column chromatography (dichloromethane-methanol, volume ratio 20:1) to obtain 0.08 g.
  • Example 2 The method was similar to that in Example 1. The product was separated by column chromatography (dichloromethane-methanol, volume ratio 20:1) to obtain 0.16 g.
  • Example 8 4-(5-[(2,3-dimethylphenyl)carbamoyl)]naphthalene-2-yl)-7-methoxy-6-quinolinecarboxamide (Compound 8)
  • Example 2 The method was as described in Example 1. The product was separated by column chromatography (dichloromethane-methanol, volume ratio 20:1) to obtain 0.09 g.
  • Example 2 The method was similar to that of Example 1. The product was separated by column chromatography (dichloromethane-methanol, volume ratio 20:1), and obtained as a yellow solid, 0.06 g.
  • Example 1 The method was as in Example 1. The product was separated by column chromatography (dichloromethane-methanol, volume ratio 20:1), yellow solid, 0.06 g.
  • 6-Hydroxy-2-naphthoic acid (1.91 g, 10.17 mmol) was dissolved in dimethyl sulfoxide (35 mL), cesium carbonate (8.26 g, 25.42 mmol) was added, and after stirring at room temperature for 10 min, compound 5 (2.00 g, 8.5 mmol) was added, and the mixture was heated to 95°C for 10 h.
  • the reaction of compound 5 was complete as monitored by TLC. After the reaction solution was cooled to room temperature naturally, the reaction mixture was diluted with water and extracted with ethyl acetate. The aqueous layer was collected and the pH was adjusted to 6.5 with 1N HCl.
  • Example 31 The method was the same as that of Example 31.
  • Example 31 The method was as in Example 31.
  • the product was separated by column chromatography (MeOH/CH 2 Cl 2 , 1/80 to 1/40), and the product was a yellow solid, 0.11 g.
  • Example 31 The method was the same as that of Example 31.
  • the product was separated by column chromatography (MeOH/CH 2 Cl 2 , 1/80 to 1/40), yielding a yellow solid, 0.11 g.
  • N-benzyl-N'-(4-hydroxyphenyl)cyclopropane-1,1-dicarboxamide (20) (0.55 g, 1.78 mmol), DMF (5.0 mL), and cesium carbonate (0.62 g, 1.90 mmol) were added to an eggplant-shaped bottle (nitrogen protection) and stirred at room temperature for 10 min. Then 4-chloro-7-methoxyquinoline-6-carboxamide (5) (0.3 g, 1.27 mmol) was added to the eggplant-shaped bottle and the temperature was slowly raised to 75 ° C. After isothermal reaction for 24 h, TLC monitored the complete reaction.
  • Example 38 The method was as in Example 38.
  • the product was separated by column chromatography (dichloromethane-methanol, volume ratio 40:1) to obtain 0.09 g of a white solid.
  • Example 44 The method was similar to that of Example 44.
  • the product was separated by column chromatography (dichloromethane-methanol, volume ratio 40:1) to obtain 0.09 g of a white solid.
  • Example 50 Inhibitory effect of compounds on VEGFR-2 kinase activity
  • the compound stock solution was diluted with DMSO, and a 3-fold gradient dilution was performed, and 12 dilutions were performed 12 times to obtain 12 concentration points.
  • the starting concentration was determined based on the initial screening activity of the compound, starting from 0.05mM or 1mM.
  • the prepared 1X kinase buffer contains: 5mM MgCl 2 ; 1mM DTT; 1mM MnCl 2 ;
  • the starting concentration of kinase VEGFR-2 was 1 ng/ ⁇ L
  • the concentrations of TK-substrate-biotin and ATP were 1 ⁇ M and 100 ⁇ M, respectively.
  • the plates were centrifuged at 1000 g for 30 s, sealed, and placed at room temperature for 40 min.
  • Envision 2104 plate reader reads fluorescence values. Excitation light: 320nm; emission light: 620nm (Cryptate) and 665nm (XL665).
  • Envision 2104 plate reader reads fluorescence values. Excitation light: 320nm; emission light: 620nm (Cryptate) and 665nm (XL665).
  • Prepare 0.156ng/ ⁇ L of 5XVEGFR-2 with 1X kinase buffer add 5X VEGFR-2 to the above 384-well assay plate, 2 ⁇ L/well, centrifuge at 1000g for 30s, and let stand at room temperature for 10min.
  • Envision 2104 plate reader reads fluorescence values. Excitation light: 320nm; emission light: 620nm (Cryptate) and 665nm (XL665).
  • Suppression percentage 1-100% ⁇ (Signal cmpd - Signal Ave_PC )/(Signal Ave_VC - Signal Ave_PC ).
  • Signal cmpd represents the 665/620 ratio of the experimental well
  • Signal Ave_PC represents the 665/620 ratio of the blank well (without cells and compounds)
  • Signal Ave_VC represents the 665/620 ratio of the control well (without compounds);
  • Y is the inhibition percentage
  • X is the logarithm of the compound concentration
  • Bottom is the maximum inhibition percentage
  • Top is the minimum inhibition percentage
  • HillSlope is the current slope coefficient.
  • Example 51 Inhibition of other tyrosine kinases by compounds
  • the inhibitory activity of the compound on other tyrosine kinases including Kit, FGFR1, FGFR2, FGFR3, Flt1, PDGF ⁇ , Met, EGFR, Flt4, PDGF ⁇ , and Ret, was determined.
  • the compounds were tested for their inhibitory activity against a variety of tyrosine kinases. The results showed that compounds 4, 9, 11, and 8 had good inhibitory activity against Kit, FGFR1, FGFR2, FGFR3, Flt1, PDGF ⁇ , Flt4, PDGF ⁇ , Ret and other kinases, but had lower inhibitory activity against Met and EGFR.
  • the cell models in this example were human lung cancer A549, human liver cancer HepG2 and human umbilical vein endothelial cells HUVECs. Based on the evaluation results of VEGFR2 enzyme inhibition activity, the proliferation inhibition activity of some compounds of the present invention on A549, HepG2 and HUVECs cells was determined.
  • A549, HepG2, and HUVECs cells in the logarithmic growth phase were seeded in a 96-well plate, with 3000-4000 cells per well, and the culture plate was pre-cultured in an incubator for 24 hours (under the conditions of 37° C. and 5% CO 2 ).
  • Suppression percentage 1-100% ⁇ (Signal cmpd - Signal Ave_PC )/(Signal Ave_VC - Signal Ave_PC ).
  • Signal cmpd represents the absorbance of the experimental well
  • Signal Ave_PC represents the absorbance of the blank well (without cells and compounds).
  • Signal Ave_VC represents the absorbance of the control well (without compound);
  • IC50 values were calculated by fitting the logarithm of percent inhibition and compound concentration to a nonlinear regression (dose response - variable slope) using GraphPad 6.0.
  • Y is the inhibition percentage
  • X is the logarithm of the compound concentration
  • Bottom is the maximum inhibition percentage
  • Top is the minimum inhibition percentage
  • HillSlope is the current slope coefficient.
  • the test results of the above compounds and the positive reference compound Lenvatinib on A549, HepG2, and HUVECs cells are shown in Table 3:
  • the compounds In the A549 cell line, the compounds generally have good anti-proliferation activity, and the anti-A549 cell proliferation activity of 30 compounds is better than that of the positive control drug Lenvatinib, among which the activity of compounds 1, 10, 13, 27, and 44 is more than 5 times that of Lenvatinib.
  • the anti-A549 cell proliferation activity of 27 compounds is better than that of the positive control drug Lenvatinib, among which the activity of compounds 1, 2, 3, 5, 8, 10, 12, 14, 23, 39, 45, 46, and 49 is more than 10 times that of Lenvatinib.
  • the anti-HUVECs proliferation activity of 7 compounds is better than that of Lenvatinib.
  • Example 53 Evaluation of the anti-proliferation activity of compounds against various tumor cells
  • the inhibitory activity of the compound on various tumor cells was determined, including human lung cancer (EBC-1, NCI-H1975), human liver cancer (SMMC-7721, PLCPRF5), human breast cancer (MCF7, ZR75-1, Hs578T, MDA-MB-231, HCC-38), human ovarian cancer (A2780, SKOV3), human renal cancer 786-O, human colorectal cancer (HT-29, NCI-H23, HCT-116), human gastric cancer Hs746T and human cervical cancer Hela cells.
  • human lung cancer EBC-1, NCI-H1975
  • human liver cancer SMMC-7721, PLCPRF5
  • human breast cancer MCF7, ZR75-1, Hs578T, MDA-MB-231, HCC-38
  • human ovarian cancer A2780, SKOV3
  • human renal cancer 786-O human colorectal cancer
  • HT-29, NCI-H23, HCT-116 human gastric cancer H
  • HUVECs were selected as the cell model, and the inhibitory activity of some compounds of the present invention on HUVECs cell angiogenesis was determined.
  • HUVEC cells When HUVEC cells are 70-80% full, digest them and resuspend them in DMEM containing 10% FBS. Count them and add 50 ⁇ L of the resuspension solution to each well, with a concentration of 30,000 cells/well. Repeat three times.
  • the dose-effect curve was plotted with the logarithm of the test compound concentration as the horizontal axis and the number of angiogenesis as the vertical axis, as shown in Figure 1: the above compounds and the positive reference compound Lenvatinib can significantly inhibit the in vitro angiogenesis of HUVECs cells, among which, at the same dose, the inhibitory activity of compounds 12 and 28 is significantly better than that of Lenvatinib.
  • Example 55 In vivo activity of the compound against human liver cancer HepG2 nude mouse transplanted tumors
  • the cell model selected was the liver cancer HepG2 cell line, and the inhibitory effect of the compound on the growth of tumor cell transplanted tumors in nude mice was determined. The evaluation method and results are described below.
  • Human hepatoma cell HepG2 (from ATCC) was routinely cultured in a 37°C, 5% CO2 incubator with high-glucose DMEM containing 10% fetal bovine serum. After three generations in vitro, when the cells grew to more than 80% and the fusion rate reached the required amount, The cells were digested and collected, washed with PBS and counted, and the cell concentration was adjusted to about 5x107 /mL and placed in a 4mL centrifuge tube on ice for later use.
  • mice Female 4-5 week old Balb/C nude mice were selected and inoculated subcutaneously with human liver cancer cell line HepG2 tumor cells. The mice were grasped and placed on their side. The axilla of the forelimbs was disinfected with 75% alcohol. 100 ⁇ L of cell suspension was drawn with a 1 mL syringe and injected into the axilla subcutaneously, i.e. 5X 10 6 cells/mouse/100 ⁇ L.
  • Test group 30 mg/kg (mouse body weight) of compound 12, 28 solution was intragastrically administered every day.
  • Positive control group 30 mg/kg (mouse body weight) of Lenvatinib solution was intragastrically administered daily.
  • the administration route was oral gavage, and the administration frequency was once a day for 25 consecutive days.
  • the first day of administration was defined as the first day of the experiment.
  • the changes in the tumor volume of the mice were measured and recorded every two days.
  • the tumor volume was measured using a vernier caliper to measure the long diameter (a) and short diameter (b) of the tumor, and the tumor volume was calculated.
  • the tumor volume V (mm 3 ) a x b ⁇ 2 /2.
  • the mice were dissected and the tumor weight was weighed.
  • the data were entered and statistically analyzed using GraphPad Prism 6 software.
  • the data were expressed as mean ⁇ SEM (Standard Error of Mean, standard error), and one-way ANOVA was used. P ⁇ 0.05 was considered to be statistically significant.
  • Example 56 In vivo activity of the compound against human thyroid cancer 8305C transplanted tumors
  • the cell model was selected from the human thyroid cancer 8305C cell line to determine the effect of the compound on tumor cell nude mouse transplanted tumor. The evaluation methods and results are described below.
  • Human hepatoma cell HepG2 (from ATCC) was routinely cultured in a 37°C, 5% CO2 incubator with high-glucose DMEM containing 10% fetal bovine serum. After three generations in vitro, when the cells grew to more than 80% and the fusion rate reached the required amount, the cells were digested and collected, washed with PBS and counted, and the cell concentration was adjusted to about 5x107 /mL and placed in a 4mL centrifuge tube on ice for later use.
  • mice Female 4-5 week old Balb/C nude mice were selected and inoculated subcutaneously with human liver cancer cell line HepG2 tumor cells. The mice were grasped and placed on their side. The axilla of the forelimbs was disinfected with 75% alcohol. 100 ⁇ L of cell suspension was drawn with a 1 mL syringe and injected into the axilla subcutaneously, i.e. 5X 10 6 cells/mouse/100 ⁇ L.
  • Test group 60 mg/kg (mouse body weight) of compound 12, 28 solution was intragastrically administered once every two days.
  • Positive control group gavage of 60 mg/kg (mouse body weight) of Lenvatinib solution once every two days.
  • the administration route was oral gavage, and the administration frequency was once every two days for 20 consecutive days.
  • the first day of administration was defined as the first day of the experiment.
  • the mice were dissected, the tumor weight was weighed, and representative tumors were selected for endothelial differentiation marker CD31 and proliferation marker CD31.
  • the data were entered and statistically analyzed using GraphPad Prism 6 software. The data were expressed as mean ⁇ SEM (Standard Error of Mean, standard error), and one-way ANOVA was used. P ⁇ 0.05 was considered statistically significant.

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Abstract

La présente invention relève du domaine des médicaments, et concerne en particulier un composé représenté par la formule (I), et un sel, un promédicament, un dérivé isotopique stable, un isomère, un solvate ou un polymorphe pharmaceutiquement acceptable de celui-ci. La présente invention concerne en outre un procédé de préparation du composé, une composition pharmaceutique comprenant le composé, et une utilisation médicale et un procédé pour le composé et la composition pharmaceutique. Le composé selon la présente invention peut bloquer la voie VEGF/VEGFR, peut prévenir ou traiter des maladies associées à la voie VEGF/VEGFR, par exemple, inhibe significativement l'activité d'une protéine kinase telle que VEGF, et a une activité antitumorale.
PCT/CN2024/100648 2023-06-28 2024-06-21 Composé quinoléine, son procédé de préparation, composition pharmaceutique et utilisation médicale associées Ceased WO2025001997A1 (fr)

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