CN116751162A - Quinoline compound, preparation method thereof, pharmaceutical composition and medical application - Google Patents

Quinoline compound, preparation method thereof, pharmaceutical composition and medical application Download PDF

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CN116751162A
CN116751162A CN202310774718.5A CN202310774718A CN116751162A CN 116751162 A CN116751162 A CN 116751162A CN 202310774718 A CN202310774718 A CN 202310774718A CN 116751162 A CN116751162 A CN 116751162A
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group
cancer
unsubstituted
compound
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郑志兵
李鹏运
李松
杨婷婷
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
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    • 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
    • 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
    • C07D215/20—Oxygen atoms
    • C07D215/22—Oxygen atoms attached in position 2 or 4

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Abstract

The inventionThe compound is shown in a formula (I), and pharmaceutically acceptable salts, prodrugs, stable isotope derivatives, isomers, solvates or polymorphs thereof; also disclosed are processes for the preparation of the compounds, pharmaceutically acceptable salts, prodrugs, stable isotope derivatives, isomers, solvates or polymorphs thereof, pharmaceutical compositions containing the compounds, pharmaceutically acceptable salts, prodrugs, stable isotope derivatives, isomers, solvates or polymorphs thereof, and their pharmaceutical uses. The compounds of the invention can block VEGF/VEGFR pathway and can prevent or treat diseases related to VEGF/VEGFR pathway, especially tumor diseases.

Description

Quinoline compound, preparation method thereof, pharmaceutical composition and medical application
Technical Field
The invention belongs to the field of medicines, and particularly relates to quinoline compounds, pharmaceutically acceptable salts, prodrugs, stable isotope derivatives, isomers, solvates or polymorphs thereof, as well as a preparation method, a pharmaceutical composition and medical application of the compounds.
Background
The neovascularization components are angiogenesis and revascularization. The former refers to the process of dividing the angioblast into blood cells and mature endothelial cells to form new blood vessels in the embryo development stage, and the latter refers to the process of sprouting original capillary vessels to form new blood vessels. The formation of new blood vessels mainly occurs in the physiological and pathological processes of embryo development, wound healing, ovarian luteal formation, tumor and the like. In 1971, judah Folkman first proposed that angiogenesis is an important process for growth and proliferation of solid tumors, and hypoxia was observed when tumor diameters reached about 0.2-2.0mm, and tumor volume was limited in the absence of angiogenesis. Thus, targeting tumor angiogenesis is an effective therapeutic approach for a variety of cancers.
Angiogenesis is controlled and regulated by endogenous active factors and by a variety of proteins. There are about 30 known endogenous pro-angiogenic factors, and about 30 known endogenous anti-angiogenic factors. Among them, endothelial vascular growth factor and its receptor (VEGF/VEGFR) family is the most studied pro-angiogenic regulator at present, and has the function of inducing endothelial cell differentiation and angiogenesis. Vascular Endothelial Growth Factor (VEGF) belongs to the family of homodimeric glycoproteins and is critical for angiogenesis, lymphoangiogenesis and pathologic angiogenesis in embryonic development. VEGF is involved in regulating the occurrence and progression of a variety of diseases, such as: tumor growth and metastasis, macular degeneration, diabetic retinopathy, rheumatoid arthritis, myocardial ischemia, preeclampsia, and the like. The study found that there are mainly five receptors to which VEGF ligand binds: VEGFR-1, VEGFR-2, VEGFR-3, and neuropilin-1 (NP-1) and neuropilin-2 (NP-2). Three vascular endothelial growth factor receptors (VEGFR-1, VEGFR-2, VEGFR-3) belong to receptor tyrosine kinases and are mainly expressed in vascular and lymphatic endothelial cells and are highly expressed in most tumor cells. After VEGF binds to VEGFR, tyrosine kinase in the intracellular domain of VEGFR is activated, and intracellular tyrosine residues are phosphorylated, thereby activating intracellular signaling pathways and exerting regulatory effects. Therefore, the VEGFR activity is inhibited, and the signal transduction is blocked, so that the angiogenesis in the tumor can be effectively inhibited, and the effects of inhibiting the growth and the metastasis of the tumor and controlling the growth of the tumor are achieved. As an important antitumor target, the FDA currently approved 12 VEGFR small molecule inhibitors, and NMPA approved 3 VEGFR small molecule inhibitors developed independently in china.
VEGFR inhibitors have poor efficacy in treating tumors due to the development of drug resistance, for example, renal cell carcinoma patients often develop primary or acquired drug resistance within one year of treatment. Secondly, the marketed VEGFR inhibitors still have certain adverse reactions. Therefore, there remains a need to develop next generation drugs to overcome drug resistance and reduce adverse reactions.
Disclosure of Invention
The invention aims to provide novel small molecule compounds acting on VEGFR, which can block VEGF/VEGFR channels, can prevent or treat diseases related to the VEGF/VEGFR channels, for example, have strong angiogenesis inhibiting effect and anti-tumor activity, and have improving, preventing and treating effects on other various diseases accompanied with abnormal proliferation of neovascularization.
The present inventors have found through research that a compound having the following general formula (I) can act on the VEGF/VEGFR pathway, significantly inhibit the protein kinase activity such as VEGF, and have a significant anti-tumor effect.
The first aspect of the present invention relates to a compound of formula (I), a pharmaceutically acceptable salt, prodrug, stable isotope derivative, isomer, solvate or polymorph thereof;
wherein,,
R 1 and R is 2 Each independently selected from the group consisting of hydroxy, aminoalkyl, alkoxy, alkylaminocarbonyl;
R 3 selected from- (NR) 5 ) n1 -C(O)-(NR 6 ) n2 -,R 5 And R is 6 Each independently selected from H, alkyl; n1 and n2 are each independently selected from 0,1;
R 4 selected from H, substituted or unsubstituted alkyl, substituted or unsubstituted aryl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heterocyclyl, cycloalkenyl, alkenyl, alkynyl, alkylaminocarbonyl, aminocarbonyl, cyano; the substitution is one ofOr a plurality of substituents: halogen, alkyl, alkoxy, haloalkyl, nitro, cycloalkyl, aryl. In any embodiment of the first aspect of the invention, R 1 And R is 2 Each independently selected from hydroxy, amino C 1 -C 6 Alkanoyl, C 1 -C 6 Alkoxy, C 1 -C 6 An alkylaminocarbonyl group.
In any embodiment of the first aspect of the invention, R 1 And R is 2 Each independently selected from amino C 1 -C 6 Alkanoyl, C 1 -C 6 An alkoxy group.
In any embodiment of the first aspect of the invention, R 1 And R is 2 Each independently selected from carbamoyl, methoxy.
In any embodiment of the first aspect of the invention, R 3 Selected from- (NR) 5 ) n1 -C(O)-(NR 6 ) n2 -,R 5 And R is 6 Each independently selected from H, C 1 -C 6 An alkyl group; n1 and n2 are each independently selected from 0,1.
In any embodiment of the first aspect of the invention, R 3 Selected from-C (O) NH-, -NH-C (O) -NH-,-C(O)-，-C(O)N(CH 3 )-，-N(CH 3 )-C(O)-N(CH 3 )-。
in any embodiment of the first aspect of the invention, R 3 Selected from- (NR) 5 ) n1 -C(O)-(NR 6 ) n2 -,R 5 And R is 6 Is H; n1 and n2 are each independently selected from 0,1.
In any embodiment of the first aspect of the invention, R 3 Selected from-C (O) NH-, -NH-C (O) -NH-,
in any embodiment of the first aspect of the invention, R 4 Selected from substituted or unsubstituted C 1 -C 6 Alkyl, substituted or unsubstituted 5-10 membered aryl, substituted or unsubstituted 3-8 membered cycloalkyl, substituted or unsubstituted 5-10 membered heteroaryl, substituted or unsubstituted 5-10 membered heterocyclyl; the substitution is substituted with one or more substituents selected from the group consisting of: halogen, C 1 -C 6 Alkyl, C 1 -C 6 Alkoxy, halo C 1 -C 6 Alkyl, nitro, 3-8 membered cycloalkyl, 5-10 membered aryl.
In any embodiment of the first aspect of the invention, R 4 Selected from substituted or unsubstituted 5-10 membered aryl, substituted or unsubstituted 3-8 membered cycloalkyl; the substitution is substituted with one or more substituents selected from the group consisting of: halogen, C 1 -C 6 Alkyl, C 1 -C 6 An alkoxy group.
In any embodiment of the first aspect of the invention, R 4 Selected from substituted or unsubstituted phenyl, substituted or unsubstituted cyclopropyl; the substitution is substituted with one or more substituents selected from the group consisting of: fluorine, methyl, methoxy.
In any embodiment of the first aspect of the invention, R 4 Selected from the group consisting ofCyclopropyl,/->
In any embodiment of the first aspect of the present invention, the compound includes (but is not limited to):
the second aspect of the present invention provides a process for the preparation of a compound of the first aspect of the present invention, a pharmaceutically acceptable salt, prodrug, stable isotope derivative, isomer, solvate or polymorph thereof, which is process a or process B as follows;
the method A comprises the following steps:
4-nitronaphthylamine is subjected to diazotization reaction and substitution reaction to obtain an intermediate A2;
carrying out substitution reaction on the intermediate A2 and 4-hydroxyquinoline to obtain an intermediate A3;
reducing the nitro group of the intermediate A3 to obtain an intermediate A4;
the intermediate A4 is subjected to different condensation reactions to respectively obtain target products A5-A7;
the method B comprises the following steps:
4-nitronaphthol and 4-chloroquinoline are subjected to substitution reaction to obtain an intermediate B2;
reducing the nitro group of the intermediate B2 to obtain an intermediate B3;
the intermediate B3 is subjected to different condensation reactions to respectively obtain target products B4-B6;
r as described above 1 、R 2 And R is 4 Is as defined in the first aspect of the invention.
Methods for preparing the compounds of the present invention include, but are not limited to, the methods described above. During specific operations, steps in the method may be expanded or combined as desired.
A third aspect of the present invention relates to a pharmaceutical composition comprising a compound of the first aspect of the present invention, a pharmaceutically acceptable salt, prodrug, stable isotope derivative, isomer, solvate or polymorph thereof;
optionally, the pharmaceutical composition further comprises a pharmaceutically acceptable carrier or excipient.
In any embodiment of the third aspect of the invention, the pharmaceutical composition further comprises a further medicament and/or immunomodulator (such as an immune checkpoint inhibitor, an antibiotic, an alkylating agent, an antimetabolite, a hormonal agent, an immunologically active agent, an interferon-based active agent and a mixed active agent) for the treatment of tumors.
In any embodiment of the third aspect of the invention, the other agent for treating a tumor is an agent for treating a tumor other than the compound of the first aspect of the invention, a pharmaceutically acceptable salt, prodrug, stable isotope derivative, isomer, solvate and polymorph thereof.
A fourth aspect of the invention relates to the use of a compound of the first aspect of the invention, a pharmaceutically acceptable salt, prodrug, stable isotope derivative, isomer, solvate or polymorph thereof or a pharmaceutical composition of the third aspect of the invention in the manufacture of a medicament for the prevention and/or treatment of a disease associated with the VEGF/VEGFR pathway.
A fifth aspect of the invention relates to a method for preventing and/or treating a disease associated with the VEGF/VEGFR pathway comprising administering to a subject in need thereof an effective amount of a compound of the first aspect of the invention, a pharmaceutically acceptable salt, prodrug, stable isotope derivative, isomer, solvate or polymorph thereof or an effective amount of a pharmaceutical composition of the third aspect of the invention.
A compound of the first aspect of the invention, a pharmaceutically acceptable salt, prodrug, stable isotope derivative, isomer, solvate or polymorph thereof or a pharmaceutical composition of the third aspect of the invention for use in the prevention and/or treatment of diseases associated with the VEGF/VEGFR pathway.
In any embodiment, the disease associated with the VEGF/VEGFR pathway is selected from one or more of atherosclerosis, pulmonary fibrosis, retinopathy, endometriosis, arthritis and cancer.
In any embodiment, the cancer is selected from one or more of lung cancer, kidney cancer, gastric cancer, hepatocellular carcinoma, thyroid cancer, melanoma, breast cancer, pancreatic cancer, colon cancer, rectal cancer, prostate cancer, bladder cancer, ovarian cancer, cervical cancer, and glioma.
The list of the aforementioned compounds is as follows:
while the products, methods and applications of this invention have been described in terms of preferred embodiments, it will be apparent to those skilled in the relevant art that the invention can be practiced and practiced with modification and alteration and combination of the methods and applications described herein without departing from the spirit and scope of the invention, and the resulting technology is intended to be covered by the claims herein.
The term "pharmaceutically acceptable salt" in the present invention includes acid salts of the compounds of the present invention with pharmaceutically acceptable inorganic or organic acids or base salts with pharmaceutically acceptable bases. Wherein the acid salts include, but are 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; base salts include, but are not limited to, ammonium salts, alkali metal salts such as sodium and potassium salts, alkaline earth metal salts such as calcium and magnesium salts, organic base salts such as dicyclohexylamine and N-methyl-D-glucamine salts, and amino acid salts such as arginine and lysine salts.
The term "base" in the present invention is not particularly limited as long as it is generally known as a base in organic synthesis, and examples thereof include sodium carbonate, sodium hydrogencarbonate, potassium carbonate, potassium hydrogencarbonate, sodium hydride, potassium hydrogencarbonate, sodium tert-butoxide, potassium tert-butoxide, cesium carbonate, triethylamine, trimethylamine, N-methylmorpholine, N, N-dimethylaniline, pyridine, isoquinoline, potassium hydroxide, sodium methoxide, potassium methoxide and the like.
The term "alkyl" in the present invention refers to a hydrocarbon group in which one hydrogen atom is less in the alkane molecule. For example C 1-6 Alkyl, C 1-4 Alkyl, C 1-2 An alkyl group; specific examples include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, and the like.
The term "alkoxy" in the present invention refers to a group provided in the form of an alkyl-O-, wherein "alkyl" is as defined above. For example C 1-6 Alkoxy, C 1-4 Alkoxy, C 1-2 An alkoxy group; specific examples include, but are not limited to, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy, tert-butoxy and the like.
The term "alkoxycarbonyl" in the present invention refers to a group provided in the form of an alkoxy-C (O) -group, wherein "alkoxy" is as defined above. For example C 1-6 Alkoxycarbonyl group, C 1-4 Alkoxycarbonyl group, C 1-2 An alkoxycarbonyl group; specific examples include, but are not limited to, methoxycarbonyl, ethoxycarbonyl, n-propoxycarbonyl, isopropoxycarbonyl, n-butoxycarbonyl, and the like.
The term "alkanoyl" in the present invention means a radical formed by the dehydroxylation of a saturated fatty acid containing a monocarboxylic group. For example C 1-6 Alkanoyl, C 1-4 Alkanoyl, C 1-2 An alkanoyl group; specific examples include, but are not limited to, formyl, acetyl, n-propionyl, isopropanoyl, and the like.
The term "aminoalkyl" in the present invention is an amino group as NH 2 Alkanoyl-(s) amino-substituted amino-carboxylic acidsThe groups provided in the form in which "alkanoyl" is as defined above. For example amino C 1-6 Alkanoyl, amino C 1-4 Alkanoyl, amino C 1-2 An alkanoyl group; specific examples include, but are not limited to, carbamoyl, aminoacetyl, amino-n-propionyl, amino-isopropyl, amino-n-butyryl, and the like.
The term "alkylaminoacyl" in the context of the present invention is a group provided in the form of an alkyl-NH-C (O) -wherein "alkyl" is as defined above. For example C 1-6 Alkanoyl, C 1-4 Alkanoyl, C 2-6 Alkanoyl, C 1-2 An alkylaminoacyl group; specific examples include, but are not limited to, methylaminoacyl, ethylaminoacyl, n-propylaminoacyl, isopropylaminoacyl, n-butylaminoacyl, and the like.
The term "aryl" in the present invention refers to a monocyclic or fused ring group having aromaticity. For example, a 5-10 membered aryl group, a 5-8 membered aryl group, a 5-6 membered aryl group; specific examples include, but are not limited to, phenyl, naphthyl, anthryl, phenanthryl, and the like.
The term "heteroaryl" in the present invention refers to an aromatic monocyclic or fused ring group 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, porphyrin, pyrazole, pyrrole, thiazole, pyridine, imidazole, quinoline, and the like.
The term "heterocyclyl" as used herein refers to a monocyclic or polycyclic saturated hydrocarbon group containing at least one N, O or S heteroatom. For example, 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, and the like.
The term "cycloalkyl" in the present invention means a group formed by dropping one hydrogen atom from a monocyclic saturated alkane ring. For example 3-6 membered cycloalkyl, 5-6 membered cycloalkyl; specific examples include, but are not limited to, cyclobutyl, cyclopentyl, cyclohexyl, and the like.
The term "halogen" in the present invention refers to fluorine, chlorine, bromine, iodine, astatine, and the like.
The term "haloalkyl" in the present invention refers to a group formed by substitution of at least one hydrogen atom in an alkyl group with a halogen. Wherein "alkyl" is as defined above.
The "pharmaceutically acceptable carrier" in the present invention includes, but is not limited to: ion exchangers, aluminum oxide, 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, polyvinylpyrrolidone, cellulose substances, polyethylene glycol, sodium carboxymethylcellulose, polyacrylates, beeswax, polyethylene-polyoxypropylene-block polymers and lanolin.
The compounds of the invention, their pharmaceutically acceptable salts, prodrugs, stable isotope derivatives, isomers, solvates or polymorphs, or the pharmaceutical compositions of the invention have systemic and/or local action and therefore may be administered by any suitable route, such as oral, parenteral, pulmonary, nasal, sublingual, lingual, buccal, rectal, transdermal, conjunctival, topical or in the form of implants. Administration may be carried out in a form suitable for these routes of administration.
Suitable for oral administration are the well-known forms of administration which allow rapid and/or altered delivery of the active ingredient, such as tablets (uncoated or coated tablets, e.g. with enteric or film coatings), capsules, dragees, granules, pellets, powders, emulsions, suspensions and aerosols.
The use of parenteral administration may possibly avoid the step of absorption (intravenous, intra-arterial, intracardiac, intraspinal or intramedullary administration) or involve absorption (intramuscular, subcutaneous, intradermal, transdermal or intraperitoneal administration). Administration forms suitable for parenteral administration are in particular solutions, suspensions, emulsions, lyophilized and sterile powder-form preparations for injection and infusion.
Suitable other routes of administration are: for example inhaled (in particular powder inhalation, nebulization) medicaments, nasal drops/solutions, nebulization; tablets or capsules for lingual, sublingual or buccal administration, suppositories, formulations for the ear and eye, vaginal capsules, aqueous suspensions (lotions, shake mixtures), lipophilic suspensions, ointments, creams, emulsions, pastes, powders or implants, such as stents.
The active ingredient may be converted into the administration form by methods known per se. Which can be achieved with inert non-toxic suitable pharmaceutical excipients. It includes, inter alia, carriers (e.g., microcrystalline cellulose), solvents (e.g., liquid polyethylene glycol), emulsifiers (e.g., sodium lauryl sulfate), dispersants (e.g., polyvinylpyrrolidone), 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 and/or taste masking agents. In suitable cases, the active ingredient may be present in microencapsulated form in one or more of the above-mentioned carriers.
The above pharmaceutical formulations may contain other pharmaceutically active ingredients in addition to the compounds of the present invention, pharmaceutically acceptable salts, prodrugs, stable isotope derivatives, isomers, solvates or polymorphs thereof.
The invention has the following beneficial effects:
the compound, the pharmaceutically acceptable salt, the prodrug, the stable isotope derivative, the isomer, the solvate or the polymorph thereof can block the VEGF/VEGFR pathway, thereby preventing or treating diseases related to the VEGF/VEGFR pathway, for example, improving, preventing and treating tumor diseases and other various diseases accompanied with abnormal proliferation of neovascularization.
Description of the drawings:
fig. 1 is a plot of tumor volume versus time for model control, test, and positive control mice.
Fig. 2 is a photograph showing tumor appearance of mice in the model control group, the test group and the positive control group with time.
Fig. 3 is the tumor weights of the model control, test and positive control mice after the end of the experiment.
Detailed Description
The following examples are presented to provide those skilled in the art with a complete disclosure of how to make and evaluate the methods and compounds claimed herein. The present embodiments merely exemplify the present invention and do not limit the scope of the present invention.
The process for preparing the compounds of the formula (I) according to the invention is described in more detail below, but these particular processes do not constitute any limitation on the invention. The compounds of the present invention may also be conveniently prepared by combining, optionally, the various synthetic methods described in this specification or known in the art, such combinations being readily apparent to those skilled in the art to which the present invention pertains. The following examples are illustrative of the preferred embodiments of the invention and are not intended to limit the invention in any way.
For all of the following examples, standard procedures and purification methods known to those skilled in the art may be used. Unless otherwise indicated, all temperatures are expressed in degrees Celsius. The structure of the compounds was confirmed by Nuclear Magnetic Resonance (NMR) or Mass Spectrometry (MS). The melting point of the compound was determined by a RY-1 type of melting point apparatus, the thermometer not being calibrated and is given in degrees Celsius. 1 HNMR is measured by Japanese electron JNM-ECA-400 nuclear magnetic resonance. Mass spectra were determined by API3000 (ESI) type mass spectrometer. All solvents used for the reaction were not pretreated with standardization unless otherwise noted. In the following examples,% refers to mass percent unless otherwise specified. The silica gel for column chromatography is produced by Qingdao ocean chemical plant (200-300 mesh); the silica gel plate for thin layer chromatography is a thin layer chromatography silica gel prefabricated plate produced by the research institute of smoke desk chemistry industry. The compounds of the present invention may be prepared by methods conventional in the art and using suitable reagents, starting materials and purification methods known to those skilled in the art.
Example 17 Synthesis of 4- ((4- (3-methoxybenzamide) naphthalen-1-yl) oxy) quinoline-6-carboxamide (1)
Step (a) preparation of 7-methoxy-4- ((4-nitronaphthalen-1-yl) oxy) quinoline-6-carboxamide
4-hydroxy-7-methoxyquinoline-6-carboxamide (3.00 g,13.75 mmol) was dissolved in dimethyl sulfoxide (DMSO, 30 mL) and sodium bicarbonate (3.46 g,41.25 mmol) was added. After stirring at room temperature for 30min, 1-chloro-4-nitronaphthalene (3.13 g,15.12 mmol) was added. After reaction for 24 hours at 90 ℃, cooling to room temperature, adding 80mL of water, precipitating a large amount of solid, and filtering to obtain yellow solid. The yellow solid was purified by silica gel column chromatography (dichloromethane/methanol=80/1) to give the objective product 2.41g, yellow solid, yield 45.0%.
Preparation of step (b) 4- ((4-aminonaphthalen-1-yl) oxy) -7-methoxyquinoline-6-carboxamide
Ammonium chloride (1.43 g,26.71 mmol) was dissolved in water (15 mL) to prepare an ammonium chloride solution. 7-methoxy-4- ((4-nitronaphthalen-1-yl) oxy) quinoline-6-carboxamide (2.60 g,6.68 mmol) was dissolved in 95% ethanol (100 mL) and the prepared ammonium chloride solution was added. After warming to 85℃and a significant reflux was observed, iron powder (2.24 g,40.07 mmol) was added. After further refluxing for 2h, filtration through celite was performed. The solvent was removed from the filtrate under reduced pressure, and the residue was purified by silica gel column chromatography (dichloromethane/methanol=40/1) to give 1.86g of the objective compound as an orange solid in 77.5% yield.
Step (c) Synthesis of 7-methoxy-4- ((4- (3-methoxybenzamide) naphthalen-1-yl) oxy) quinoline-6-carboxamide
3-Methoxybenzoic acid (0.09 g,0.61 mmol) was dissolved in N, N-dimethylformamide (5 mL) and 2- (7-azobenzotriazole) -N, N, N ', N' -tetramethyluronium hexafluorophosphate (HATU, 0.42g,1.11 mmol), N, N-diisopropylethylamine (DIPEA, 0.18g,1.39 mmol) was added. After stirring at room temperature for 30min, 4- ((4-aminonaphthalen-1-yl) oxy) -7-methoxyquinoline-6-carboxamide (0.2 g,0.57 mmol) was added. After heating to 90 ℃ for reaction for 6 hours, cooling to room temperature, adding 50mL of water, precipitating a large amount of solid, and filtering to obtain reddish brown solid. The reddish brown solid was purified by silica gel column chromatography (dichloromethane/methanol=20/1) to give 0.06g of the objective compound as a white solid in 22.2% yield. Mp.157-158 ℃. ESI-MS M/Z: [ M+H ]] + 494.16。 1 H NMR(400MHz,DMSO-d 6 )δ(ppm)：10.54(s,1H),8.91(s,1H),8.66(s,1H),8.13(d,J＝8.3Hz,1H),7.93(d,J＝8.3Hz,2H),7.85–7.45(m,9H),7.23(d,J＝7.2Hz,1H),6.41(s,1H),4.09(s,3H),3.90(s,3H)。 13 C NMR(151MHz,DMSO-d 6 )δ(ppm)：166.54,166.38,162.37,159.79,158.71,153.90,152.23,147.69,136.21,132.51,131.16,130.15,127.70,127.53,127.02,125.86,125.14,124.76,124.65,121.67,120.57,118.14,117.74,114.80,113.44,108.53,103.47,56.72,55.86。
Example 2 4- ((4- (cyclopropanecarboxamide) naphthalen-1-yl) oxy) -7-methoxyquinoline-6-carboxamide (2)
Prepared according to the method of example 1 to give 0.07g of a white solid in 29.6% yield, mp.244-245 ℃. ESI-MS m/z: [ M+H ]] + 428.15。 1 H NMR(600MHz,DMSO-d 6 )δ(ppm)：10.28(s,1H),8.87(s,1H),8.61(d,J＝5.3Hz,1H),8.24(d,J＝8.6Hz,1H),7.92–7.89(m,1H),7.84(d,J＝8.3Hz,2H),7.79–7.76(m,1H),7.67(ddd,J＝8.4,6.8,1.3Hz,1H),7.56(d,J＝6.9Hz,2H),7.46(d,J＝8.2Hz,1H),6.35(d,J＝5.3Hz,1H),4.06(s,3H),0.88(dd,J＝6.7,3.8Hz,4H)。 13 C NMR(151MHz,DMSO-d 6 )δ(ppm)：173.09,166.16,163.92,159.42,152.43,149.90,146.02,132.81,129.36,127.69,127.36,126.78,126.60,125.28,124.10,121.80,121.56,117.97,114.70,106.61,103.47,56.88,14.64,7.83。
Example 37 Synthesis of 4- ((4- (3- (3-methoxyphenyl) ureido) naphthalen-1-yl) oxy) quinoline-6-carboxamide (3)
4- ((4-Aminonaphthalen-1-yl) oxy) -7-methoxyquinoline-6-carboxamide (0.20 g,0.57 mmol) was dissolved in tetrahydrofuran/N, N-dimethylformamide (3/2 mL) and 3-methoxyphenyl isocyanate (0.1 g,0.67 mmol) was added. The reaction was carried out at room temperature for 24 hours, and a solid was formed. Suction filtering to obtain white solid, washing twice with water, oven drying, and adding dichloromethaneWashing twice and drying gave the title compound as a white solid, 0.12g, 42.5% yield. Mp.240-241 ℃. ESI-MS m/z: [ M+H ]] + 509.17。 1 H NMR(400MHz,DMSO-d 6 )δ(ppm)：10.00(s,1H),9.53(s,1H),8.95(s,1H),8.81(d,J＝6.3Hz,1H),8.58(d,J＝8.6Hz,1H),8.24(d,J＝8.4Hz,1H),8.02(s,1H),7.91(s,1H),7.84(d,J＝8.4Hz,1H),7.73(d,J＝9.4Hz,2H),7.59(t,J＝8.3Hz,2H),7.32(s,1H),7.23(t,J＝8.1Hz,1H),7.05(d,J＝8.1Hz,1H),6.65(d,J＝6.2Hz,1H),6.59(dd,J＝8.4,2.5Hz,1H),4.12(s,3H),3.77(s,3H)。 13 C NMR(151MHz,DMSO-d 6 )δ(ppm)：166.39,162.70,160.25,158.67,153.86,153.40,152.15,144.85,141.44,133.19,130.15,127.97,127.54,127.24,127.00,125.74,125.16,122.78,121.88,118.35,118.14,114.73,110.97,108.48,107.87,104.41,103.20,56.70,55.41。
The following compounds were prepared in a similar manner to the procedure described in example 1
Example 44- ((4- (3- (3-fluorophenyl) ureido) naphthalen-1-yl) oxy) -7-methoxyquinoline-6-carboxamide (4)
The procedure is as described in example 3, giving 0.08g of a white solid in 28.9% yield, mp.266-267 ℃. ESI-MS m/z: [ M+H ]] + 497.15。 1 H NMR(600MHz,DMSO-d 6 )δ(ppm)：9.31(s,1H),8.95(s,1H),8.89(s,1H),8.60(d,J＝5.3Hz,1H),8.24(d,J＝8.6Hz,1H),8.08(d,J＝8.3Hz,1H),7.91(s,1H),7.84(d,J＝8.5Hz,1H),7.77(s,1H),7.71(t,J＝7.7Hz,1H),7.58(d,J＝8.9Hz,3H),7.49(d,J＝8.3Hz,1H),7.35(q,J＝7.8Hz,1H),7.19(dd,J＝8.2,2.0Hz,1H),6.82(td,J＝8.5,2.6Hz,1H),6.34(d,J＝5.3Hz,1H),4.07(s,3H)。 13 C NMR(151MHz,DMSO-d 6 )δ(ppm)：166.39,162.96(d,J＝239.9Hz),162.62,158.65,153.89,153.38,152.21,145.13,142.10(d,J＝11.0Hz),132.93,130.91(d,J＝9.7Hz),128.17,127.58,127.32,127.01,125.73,125.15,122.85,121.90,118.56,118.29,114.74,114.41,108.74(d,J＝21.6Hz),108.53,105.36(d,J＝26.6Hz),103.23,56.70。
Example 5 7-methoxy-4- ((4- (3- (4-methoxyphenyl) ureido) naphthalen-1-yl) oxy) quinoline-6-carboxamide (5)
The procedure is as described in example 3, giving 0.09g of a white solid in 31.3% yield, mp.248-249 ℃. ESI-MS m/z: [ M+H ]] + 509.17。 1 H NMR(400MHz,DMSO-d 6 )δ(ppm)：8.93(s,1H),8.91(s,1H),8.84(s,1H),8.60(d,J＝5.2Hz,1H),8.27(d,J＝8.6Hz,1H),8.13(d,J＝8.4Hz,1H),7.93(s,1H),7.84(dd,J＝8.5,1.2Hz,1H),7.79(s,1H),7.71(ddd,J＝8.4,6.8,1.3Hz,1H),7.61–7.53(m,2H),7.52–7.42(m,3H),6.96–6.89(m,2H),6.35(d,J＝5.3Hz,1H),4.08(s,3H),3.75(s,3H)。 13 C NMR(151MHz,DMSO-d 6 )δ(ppm)：166.39,162.82,158.71,155.03,153.78,153.61,152.01,144.56,133.52,133.24,127.79,127.51,127.16,126.99,125.77,125.17,122.79,121.85,120.44(2C),118.39,117.68,114.72,114.58(2C),108.36,103.18,56.71,55.66。
Example 6 4- ((4- (3-Cyclopropylureido) naphthalen-1-yl) oxy) -7-methoxyquinoline-6-carboxamide (6)
The procedure is as described in example 3, giving 0.06g of a white solid in 25.2% yield, mp.237-238 ℃. ESI-MS m/z: [ M+H ]] + 443.16。 1 H NMR(400MHz,DMSO-d 6 )δ(ppm)：8.90(s,1H),8.69(s,1H),8.65(d,J＝5.5Hz,1H),8.26(d,J＝8.6Hz,1H),8.11(d,J＝8.4Hz,1H),7.95(s,1H),7.84–7.76(m,2H),7.66(ddd,J＝8.4,6.8,1.3Hz,1H),7.60(s,1H),7.54(ddd,J＝8.1,6.8,1.0Hz,1H),7.47(d,J＝8.4Hz,1H),7.01(d,J＝3.0Hz,1H),6.39(d,J＝5.5Hz,1H),4.09(s,3H),2.66(tp,J＝6.9,3.5Hz,1H),0.71(td,J＝6.9,4.7Hz,2H),0.54–0.46(m,2H)。 13 C NMR(151MHz,DMSO-d 6 )δ(ppm)：166.39,162.84,158.69,156.87,153.77,152.01,144.18,134.01,127.38,126.93(2C),125.73,125.17,122.85,121.74,118.39,114.70,108.36(2C),103.11(2C),56.70,23.01,6.92(2C)。
Example 7 7-methoxy-4- ((4- (3- (p-tolyl) ureido) naphthalen-1-yl) oxy) quinoline-6-carboxamide (7)
The procedure is as described in example 3, giving 0.11g of a white solid in 39.0% yield, mp 251-252 ℃. ESI-MS m/z: [ M+H ]] + 493.17。 1 H NMR(400MHz,DMSO-d 6 )δ(ppm)：9.01(s,1H),8.89(d,J＝12.2Hz,2H),8.61(d,J＝5.3Hz,1H),8.27(d,J＝8.3Hz,1H),8.14(d,J＝8.0Hz,1H),7.93(s,1H),7.87–7.78(m,2H),7.72(t,J＝7.6Hz,1H),7.59(s,2H),7.49(d,J＝8.3Hz,1H),7.44(d,J＝8.0Hz,2H),7.15(d,J＝6.8Hz,2H),6.35(d,J＝5.3Hz,1H),4.08(s,3H),2.29(s,3H)。 13 C NMR(151MHz,DMSO-d 6 )δ(ppm)：166.40,162.70,158.65,153.88,153.46,152.19,144.67,137.62,133.37,131.26,129.76(2C),127.83,127.51,127.18,127.00,125.70,125.17,122.76,121.87,118.77(2C),118.37,117.80,114.73,108.50,103.18,56.70,20.83。
Example 8 Synthesis of N- (4- ((6-carbamoyl-7-methoxyquinolin-4-yl) oxy) naphthalen-1-yl) -N- (4-fluorophenyl) cyclopropane-1, 1-dicarboxamide (8)
1- (4-Fluorophenylcarbamoyl) cyclopropanecarboxylic acid (0.11 g,0.50 mmol) was dissolved in N, N-dimethylformamide (5 mL), 2- (7-azobenzotriazole) -N, N, N ', N' -tetramethylurea hexafluorophosphate (HATU, 0.42g,1.11 mmol) was added, and N, N-diisopropylethylamine (DIPEA, 0.18g,1.39 mmol) was added while ice-cooling. After 30min of ice bath reaction, 4- ((4-aminonaphthalen-1-yl) oxy) -7-methoxyquinoline-6-carboxamide (0.20 g,0.57 mmol) was added. After the reaction was carried out at 60℃for 24 hours, the reaction mixture was diluted with ethyl acetate, extracted in water, and the organic layer was dried over anhydrous sodium sulfate, followed by removal of the solvent under reduced pressure. The residue was chromatographed on a silica gel column (dichloromethane/methyl ether)Alcohol=40/1) to give the desired product as a white solid 0.11g, 33.6% yield, mp.239-240 ℃. ESI-MS m/z: [ M+H ]] + 565.17。 1 H NMR(400MHz,DMSO-d 6 )δ(ppm)：10.69(s,1H),10.23(s,1H),8.87(s,1H),8.61(d,J＝5.2Hz,1H),8.13(d,J＝8.5Hz,1H),7.87(dd,J＝16.5,9.2Hz,3H),7.77(s,1H),7.66(ddd,J＝10.1,7.3,3.1Hz,3H),7.56(d,J＝6.4Hz,2H),7.49(d,J＝8.2Hz,1H),7.18(t,J＝8.6Hz,2H),6.32(d,J＝5.2Hz,1H),4.07(s,3H),1.66(t,J＝4.4Hz,4H)。 13 C NMR(151MHz,DMSO-d 6 )δ(ppm)：168.73,168.57,165.28,161.34,157.84(d,J＝240.7Hz),157.61,152.77,151.12,145.89,134.32,131.04,128.90,126.58,126.50,125.84,124.72,124.05,122.77,122.14,122.08,121.64,120.63,116.72,114.62,114.47,113.68,107.43,102.28,55.62,29.69,15.88(2C)。
EXAMPLE 9 Synthesis of N- (4- ((6, 7-dimethoxyquinolin-4-yl) oxy) naphthalen-1-yl) -3-methoxybenzamide (9)
Preparation of 6, 7-dimethoxy-4- ((4-nitronaphthalen-1-yl) oxy) quinoline of step (a)
6, 7-Dimethoxyquinolin-4-ol (2.00 g,9.75 mmol) was dissolved in N, N-dimethylformamide (15 mL), and cesium carbonate (3.18 g,9.75 mmol) was added. After 30min at room temperature, 1-chloro-4-nitronaphthalene (2.02 g,9.75 mmol) was added. After reaction for 24 hours at 90 ℃, the mixture is cooled to room temperature, 100mL of water is added, and a large amount of solid is separated out. Filtering to obtain yellow solid, and drying. The yellow solid was purified by silica gel column chromatography (petroleum ether/ethyl acetate=40/1) to give the objective product as a yellow solid, 2.50g, yield 68.3%.
Preparation of step (b) 4- ((6, 7-dimethoxyquinolin-4-yl) oxy) naphthalen-1-amine
Ammonium chloride (1.05 g,19.68 mmol) was dissolved in water (10 mL) to prepare an ammonium chloride solution. 6, 7-dimethoxy-4- ((4-nitronaphthalen-1-yl) oxy) quinoline (1.85 g,4.92 mmol) was dissolved in 95% ethanol (70 mL) and the prepared ammonium chloride solution was added. After heating to 85℃and a significant reflux is observed, iron powder (1.65 g,29.52 mmol) is added. After further refluxing for 2h, filtration through celite was performed. The solvent was removed from the filtrate under reduced pressure, and the residue was purified by silica gel column chromatography (dichloromethane/methanol=80/1) to give 1.40g of the objective compound as an orange solid in 82.4% yield.
Step (c) Synthesis of N- (4- ((6, 7-dimethoxyquinolin-4-yl) oxy) naphthalen-1-yl) -3-methoxybenzamide
3-Methoxybenzoic acid (0.09 g,0.58 mmol) was dissolved in N, N dimethylformamide (5 mL) and 2- (7-azobenzotriazole) -N, N, N ', N' -tetramethylurea hexafluorophosphate (HATU, 0.44g,1.16 mmol), N, N-diisopropylethylamine (DIPEA, 0.19g,1.45 mmol) was added. After stirring at room temperature for 30min, 4- ((6, 7-dimethoxyquinolin-4-yl) oxy) naphthalen-1-amine (0.20 g,0.58 mmol) was added. After heating to 60 ℃ for reaction for 10 hours, cooling to room temperature, adding 50mL of water, precipitating a large amount of solid, and filtering to obtain reddish brown solid. The reddish brown solid was purified by column chromatography on silica gel (dichloromethane/methanol=80/1) to give the title compound 0.05g, as a pink solid, yield 18.1%, mp.247-248 ℃. ESI-MS m/z: [ M+H ]] + 481.17。 1 H NMR(600MHz,DMSO-d 6 )δ(ppm)：10.60(s,1H),8.77(d,J＝6.6Hz,1H),8.17(d,J＝8.6Hz,1H),7.99(s,1H),7.89(d,J＝8.4Hz,1H),7.83(d,J＝8.1Hz,1H),7.71(t,J＝8.2Hz,3H),7.67(t,J＝2.1Hz,1H),7.62(ddd,J＝8.2,6.7,1.1Hz,1H),7.59(s,1H),7.52(t,J＝7.9Hz,1H),7.23(dd,J＝8.6,2.6Hz,1H),6.74(d,J＝6.7Hz,1H),4.11(s,3H),4.09(s,3H),3.88(s,3H)。 13 CNMR(151MHz,DMSO-d 6 )δ(ppm)：166.02,165.51,159.22,156.14,151.21,145.89,143.44,137.42,135.59,133.08,130.47,129.62,127.55,127.24,125.96,124.36,123.80,120.95,120.04,117.80,117.58,115.22,112.96,103.17,100.40,100.10,56.57,56.46,55.31。
Example 10 Synthesis of 1- (4- ((6, 7-dimethoxyquinolin-4-yl) oxy) naphthalen-1-yl) -3- (3-methoxyphenyl) urea (10)
4- ((6, 7-Dimethoxyquinolin-4-yl) oxy) naphthalen-1-amine (0.2)0g,0.58 mmol) in tetrahydrofuran/N, N-dimethylformamide (3/2 mL) was added followed by 3-methoxyphenyl isocyanate (0.10 g,0.69 mmol). The temperature is raised to 80 ℃ for reaction for 24 hours, the mixture is cooled to room temperature, 50mL of water is added, and solid is generated. And (5) carrying out suction filtration to obtain a tan solid, and drying. The off-brown solid was purified by column chromatography on silica gel (dichloromethane/methanol=40/1) to give the title compound as a white solid 0.065g, 22.7% yield, mp.180-181 ℃. ESI-MS m/z: [ M+H ]] + 496.17。 1 H NMR(600MHz,DMSO-d 6 )δ(ppm)：9.14(s,1H),8.89(s,1H),8.40(d,J＝5.3Hz,1H),8.25(dt,J＝8.7,0.9Hz,1H),8.11(d,J＝8.3Hz,1H),7.88–7.83(m,1H),7.73(s,1H),7.70(ddd,J＝8.4,6.8,1.3Hz,1H),7.56(ddd,J＝8.1,6.8,1.1Hz,1H),7.46(d,J＝8.6Hz,2H),7.28(t,J＝2.2Hz,1H),7.22(t,J＝8.1Hz,1H),7.01(ddd,J＝8.1,2.0,0.9Hz,1H),6.59(ddd,J＝8.3,2.5,0.9Hz,1H),6.30(d,J＝5.3Hz,1H),3.99(s,3H),3.98(s,3H),3.76(s,3H)。 13 C NMR(151MHz,DMSO-d 6 )δ(ppm)：160.37,159.67,152.84,152.62,149.42,148.75,146.30,144.64,140.87,132.36,129.57,127.38,126.82,126.60(2C),122.14,121.52,117.79,117.56,114.74,110.39,107.78,107.29,103.83,102.65,99.02,55.69,54.84,54.82。
Example 11 1- (4- ((6, 7-Dimethoxyquinolin-4-yl) oxy) naphthalen-1-yl) -3- (3-fluorophenyl) urea (11) was prepared in a similar manner to the procedure described in example 10
The procedure is as described in example 10, giving 0.11g of a white solid in 39.4% yield, mp.234-235 ℃. ESI-MS m/z: [ M+H ]] + 484.16。 1 H NMR(600MHz,DMSO-d 6 )δ(ppm)：9.25(s,1H),8.96(s,1H),8.43(d,J＝5.4Hz,1H),8.29(d,J＝8.6Hz,1H),8.10(d,J＝8.2Hz,1H),7.89–7.81(m,1H),7.75(s,1H),7.69(ddd,J＝8.4,6.7,1.3Hz,1H),7.59–7.53(m,3H),7.46(d,J＝8.9Hz,2H),7.17(t,J＝8.8Hz,2H),6.34(d,J＝5.3Hz,1H),4.00(s,3H),3.99(s,3H)。 13 C NMR(151MHz,DMSO-d 6 )δ(ppm)：160.81,157.31(d,J＝238.6Hz),153.03,152.90,149.57,148.33,145.59,144.51,136.03,132.55,127.39,126.87,126.62,126.55,122.27,121.47,119.81,119.76,117.82,117.47,115.38,115.23,114.78,107.17,102.71,99.13,55.75(2C)。
Example 12 Synthesis of N- (4- ((6, 7-dimethoxyquinolin-4-yl) oxy) naphthalen-1-yl) -N- (4-fluorophenyl) cyclopropane-1, 1-dicarboxamide (12)
1- (4-Fluorophenylcarbamoyl) cyclopropanecarboxylic acid (0.13 g,0.58 mmol) was dissolved in N, N-dimethylformamide (5 mL), 2- (7-azobenzotriazole) -N, N, N ', N' -tetramethylurea hexafluorophosphate (HATU, 0.44g,1.16 mmol) was added, and N, N-diisopropylethylamine (DIPEA, 0.19g,1.45 mmol) was added while ice-cooling. After 30min of ice bath reaction at 0deg.C, 4- ((6, 7-dimethoxyquinolin-4-yl) oxy) naphthalen-1-amine (0.20 g,0.58 mmol) was added. After 4h reaction at room temperature, 50mL of water was added to give a large amount of solid. Filtering to obtain reddish brown solid, and oven drying. The solid was purified by column chromatography on silica gel (dichloromethane/methanol=70/1) to give the desired product as a yellow solid, 0.057g, 17.9% yield, mp 233-234 ℃. ESI-MS m/z: [ M+H ]] + ：552.19。 1 H NMR(400MHz,DMSO-d 6 )δ(ppm)：10.93(s,1H),10.12(s,1H),8.74(d,J＝6.6Hz,1H),8.19(d,J＝8.5Hz,1H),7.99(d,J＝8.2Hz,1H),7.96(s,1H),7.85(d,J＝8.4Hz,1H),7.65(tt,J＝19.1,7.5Hz,5H),7.56(s,1H),7.19(t,J＝8.7Hz,2H),6.68(d,J＝6.6Hz,1H),4.09(s,3H),4.08(s,3H),1.67(s,3H)。 13 C NMR(151MHz,DMSO-d 6 )δ(ppm)：169.66,169.45,164.27,158.74(d,J＝240.7Hz),155.42,151.01,145.93,145.33,140.39,135.06,132.59,129.49,127.67,127.56,126.39,123.54,123.14,123.09,121.96,121.46,117.99,115.47,115.39,115.33,103.36,102.71,100.28,56.63,56.54,30.50,16.83(2C)。
Example 13 test of Compounds for inhibitory Activity of VEGFR-2 kinase
The inhibition activity of the 12 compounds of the invention on VEGFR-2 kinase was evaluated using an in vitro kinase assay, outlined below:
1. experimental materials and apparatus
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2. The experimental steps are as follows:
2.1 preparation of stock solutions of compounds:
all compounds were dissolved in DMSO and prepared into 10mM stock solutions. The compounds used within three months were stored in a desiccator at room temperature, and others could be stored for extended periods at-20 ℃.
2.2 preparation of working solution:
both stock compound and positive reference compound Lenvantinib were diluted with DMSO at an initial concentration of 1000nM, and subjected to 3-fold gradient dilution 10 times to obtain 10 concentration points.
1000x positive controls (1 mM, lenretinib) and 1000x blank (100% DMSO) were prepared.
Shake on shaker for 5min.
Preparation of kinase buffer (1X): 1 volume of 5 Xenzyme buffer (reagent in HTRF KinEASE-TK kit) and 4 volumes of distilled water; the kinase buffer (1X) after preparation contained: 5mM MgCl 2 ；1mM DTT；1mM MnCl 2 。
2.3 titration of the kinase VEGFR-2 (100. Mu.M ATP, 1. Mu.M TK-substrate-biotin, all reagents in HTRFKinEASE-TK kit):
a) Dilutions of each compound were transferred separately to individual wells of assay plates (784075, greiner) using Echo 550.
b) The assay plate was sealed and the composite plate was centrifuged at 1000g for 1min.
c) 2 XVEGFR-2 was prepared using 1 Xkinase buffer.
d) mu.L of 2 XVEGFR-2 was added to each well of the 384-well assay plate (784075, greiner) described above.
e) The assay plate was centrifuged at 1000g for 30s and left at room temperature for 10min.
f) mu.M 5 XTK-substrate-biotin and 500. Mu.M 5 XATP were prepared using 1 Xkinase buffer and then mixed in a volume ratio of 1:1 to give a mixture.
g) To each well of the 384-well assay plate, 5. Mu.L of TK-substrate-biotin and ATP mixture were added to start the reaction.
h) Centrifuge 1000g for 30s. Sealing the detection plate, and standing at room temperature for 40min.
i) 250nM 4 XSa-XL 665 was prepared using HTRF detection buffer (for the reagent in HTRF KinEASE-TK kit).
j) mu.L of Sa-XL665 and 5. Mu.L of TK-anti-Cryptate (as reagents in HTRF KinEASE-TK kit) were prepared per well of 384 assay plates as described above.
k) Centrifuge 1000g for 30s and leave at room temperature for 1h.
l) fluorescence values at 620nm (Cryptate) and 665nm (XL 665) were read on an Envision 2104 plate reader.
3. Data analysis:
a) Calculating a ratio of 665/620 per hole;
b) Percent inhibition was calculated:
percentage of inhibition = 1-100% × (Signal cmpd -Signal Ave_PC )/(Signal Ave_VC -Signal Ave_PC ).
Wherein Signal cmpd Representing the 665/620 ratio of the experimental well; signal (S) Ave_PC The 665/620 ratio (without cells and compounds) for blank wells; signal (S) Ave_VC The 665/620 ratio (without compound) for the control wells;
c) IC for plotting curves and calculating compounds 50 ；
The relationship between percent inhibition and logarithm of compound concentration was fitted by nonlinear regression (dose response-variable slope) with Graphpad 5.0.
Y＝Bottom+(Top-Bottom)/(1+10^((LogIC 50 -X)*Hill Slope))
Y is the percentage of inhibition, X is the logarithmic value of the compound concentration, bottom is the maximum percentage of inhibition, top is the minimum percentage of inhibition, hillSlope is the coefficient of withdrawal slope.
4. Experimental results
As shown in Table 1, the experimental results show that the compound of the invention has a remarkable inhibition effect on the enzyme activity of VEGFR-2, and the inhibition of the compounds 3,6 and 7 on VEGFR-2 kinase is superior to that of the positive drug Lenretinib.
TABLE 1 IC of test compounds for VEGFR-2 kinase inhibition 50 Value (nM)
Note that: compound No. is example no.
Test of inhibitory Activity of Compounds of example 14 against relevant tumor cells
The inhibitory activity of the 12 compounds of the invention on a549, hepG2, HUVEC cells was evaluated using an in vitro cell proliferation inhibition assay, outlined below:
1. experimental materials and instruments
Materials and reagents Manufacturer(s) Cat#
A549 ATCC CCL-185
HepG2 ATCC HB-8065
HUVEC ATCC PCS-100-010
CCK-8 Dojindo CK04
DMEM GIBCO C11995500BT
RPMI-1640 GIBCO C11875500BT
Fetal Bovine Serum(FBS) Hyclone SH30406.05
DMSO Sigma D8418
Consumable and instrument Manufacturer(s) Cat#
96-well polypropylene plate Corning 3599
Plate shaker Thermo 4625-1CECN/THZ Q
Centrifuge Eppendorf 5810R
Envision 2104multi-label Reader PerkinElmer 74785
Echo Labcyte 550
2. Experimental procedure
2.1 preparation of stock solutions of compounds
The compounds were selected and dissolved in DMSO to prepare a 10mM stock solution. The compounds used within three months were stored in a desiccator at room temperature, and others could be stored for extended periods at-20 ℃.
Preparation of working solution:
the stock solution of the above compound and the positive reference compound Lenvantinib were diluted with DMSO at an initial concentration of 1000nM and subjected to 2-fold gradient dilutions at 8 concentration points in A549, hepG2, HUVEC cell experiments. Oscillating on the oscillator for 5min.
2.2 cell dosing
2.2.1A 549, hepG2, HUVEC cells in logarithmic growth phase were seeded in 96-well plates at 3000-4000 cells per well and plates were pre-incubated in incubator for 24 hours (5% CO at 37 ℃ C.) 2 Is under the condition of (2).
2.2.2 exchange of the medium in the well plate, 100. Mu.L of the compound in the corresponding concentration and positive reference compound were added to the plate.
2.2.3 plates were incubated in the incubator for a period of 72 hours, 10. Mu.L of CCK-8 solution was added to each well, and plates were incubated in the incubator for 1-4 hours.
2.2.4 absorbance at 450nm was measured with a microplate reader.
3. Data analysis
Percent inhibition was calculated:
percentage of inhibition = 1-100% × (Signal cmpd -Signal Ave_PC )/(Signal Ave_VC -Signal Ave_PC ).
Wherein Signal cmpd The absorbance of the experimental well is shown; signal (S) Ave_PC Represents blank well absorbance (without cells and compounds); signal (S) Ave_VC Control well absorbance (no compound);
calculation of IC for Compounds 50 And Plot effect dose curves:
IC was calculated using GraphPad 6.0 by fitting the log of the percent inhibition and compound concentration to a nonlinear regression (dose response-variable slope) 50 Values.
Y＝Bottom+(Top-Bottom)/(1+10^((LogIC 50 -X)*HillSlope))
Y is the percentage of inhibition, X is the logarithmic value of the compound concentration, bottom is the maximum percentage of inhibition, top is the minimum percentage of inhibition, hillSlope is the coefficient of withdrawal slope.
4. Experimental results
As shown in Table 2, the experimental results show that the compounds of the present invention have excellent proliferation inhibitory activity on compounds 1 to 12 on A549, hepG2, HUVEC.
TABLE 2 IC of test compounds for inhibition of A549, hepG2, HUVEC cell proliferation 50 Value (mu M)
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Example 15: evaluation of proliferation Activity of Compounds against various tumor cells
With reference to the method of example 14, a 2-fold gradient dilution was performed at an initial concentration of 27. Mu.M for a total of 8 concentration points. The inhibitory activity of the compounds against various tumor cells was determined, including human lung cancer (EBC-1, NCI-H1975), human liver cancer (SMMC-7721, PLCPRF 5), human breast cancer (MCF 7, ZR75-1, hs578T, MDA-MB-231, HCC-38), human ovarian cancer (A2780, SKOV 3), human renal cancer 786-O, human colorectal cancer (HT-29, NCI-H23, HCT-116), human gastric cancer Hs746T and human cervical cancer Hela cells.
1. Experimental materials and instruments
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2. The test results are shown in table 3: the 4 compounds have better antiproliferative activity on the tested 8 tumor cells, wherein the antiproliferative activity of the compounds 1, 8 and 11 on 17 cells is better than that of Lenretinib.
Antiproliferative activity of the compounds of table 3 on various tumor cells (IC 50 Value of
ND: not detected. No IC was fitted with an inhibition of < 50% at a maximum concentration of 27. Mu.M 50 Values.
EXAMPLE 16 Compound 8 in vivo anti-liver cancer HepG2 nude mice engrafting tumor Activity
1. Experimental materials and instruments
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2. Establishment of tumor model
Human hepatoma cell HepG2 (from ATCC) was treated with 10% fetal bovine serum in high-sugar DMEM at 37deg.C and 5% CO 2 After conventional culture in an incubator and three generations of in vitro transfer, after the cells grow to more than 80% and the fusion rate reaches the required amount, the cells are digested and collected, counted after being washed by PBS, and the cell concentration is adjusted to about 5x10 7 The individual/mL was placed in a 4mL centrifuge tube on ice for further use.
Female Balb/C nude mice with the age of 4-5 weeks are selected, and the human liver cancer cell line HepG2 tumor cells are inoculated subcutaneously in an ectopic mode. The mice were grasped to the sides, the forelimb axilla was sterilized with 75% alcohol, and 100. Mu.L of the cell suspension was aspirated with a 1mL syringe and injected under the axilla, i.e., 5X10 6 Individual cells/individual 100. Mu.L.
3. Grouping and administration of laboratory animals
When the tumor grows to 90-150 mm 3 Animals were then randomly grouped, 6 animals per group, fed in different dosing forms, respectively:
model control group: the same volume of blank vehicle (DMSO: 0.5% sodium carboxymethylcellulose: distilled water = 1:1:8) was infused daily;
test group: the stomach was filled with 50mg/kg (mouse body weight) of compound 8 solution per day.
Positive control group: a50 mg/kg (mouse body weight) solution of Lenretinib was infused daily.
The administration route was oral gavage, the administration frequency was once daily, the administration was continued for 13 days, the day of the first administration was defined as day 1 of the test, and tumor volume changes of the mice were measured and recorded once every two days. The tumor volume is measured by using a vernier caliper to measure the long diameter (a) and the short diameter (b) of the tumor, the tumor volume is calculated, and the tumor volume V (mm) 3 )＝a×b 2 /2. After the end of the experiment, the mice were dissected and the tumor weights were weighed. Data were entered and statistically analyzed by GraphPad Prism 6 software. Data are all expressed by mean+ -SEM (Standard Error of Mean, standard error) and P.ltoreq.0.05 is considered statistically significant by one-way ANOVA.
4. Experimental results
FIG. 1 is a plot of tumor volume versus time for model control, test, and positive control mice; FIG. 2 is a photograph showing tumor appearance of mice in a model control group, a test group and a positive control group as a function of time; fig. 3 is the tumor weights of the model control, test and positive control mice after the end of the experiment.
As shown in fig. 1-3 and table 4, the experimental result shows that the compound 8 significantly inhibits the growth of human liver cancer HepG2 cell transplantation tumor, and the effect is equivalent to that of the positive drug Lenvatinib at the same dosage.
TABLE 4 inhibition of liver cancer HepG2 nude mice xenograft tumor by Compound 8
Compounds of formula (I) Average volume (mm) 3 )(Day13) Tumor inhibition rate TGI (%)
Control 1908.55 —
Lenvatinib 654.10 80.78％
8 605.00 78.50％
The above description is only of the preferred embodiments of the present invention and is not intended to limit the present invention, and it should be noted that it is possible for those skilled in the art to make several improvements and modifications without departing from the technical principle of the present invention, and these improvements and modifications should also be regarded as the protection scope of the present invention.

Claims (10)

1. A compound of formula (I), a pharmaceutically acceptable salt, prodrug, stable isotope derivative, isomer, solvate or polymorph thereof;
wherein,,
R 1 and R is 2 Each independently selected from the group consisting of hydroxy, aminoalkyl, alkoxy, alkylaminocarbonyl;
R 3 selected from- (NR) 5 ) n1 -C(O)-(NR 6 ) n2 -,R 5 And R is 6 Each independently selected from H, alkyl; n1 and n2 are each independently selected from 0,1;
R 4 selected from H, substituted or unsubstituted alkyl, substituted or unsubstituted aryl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heterocyclyl, cycloalkenyl, alkenyl, alkynyl, alkylaminocarbonyl, aminocarbonyl, cyano; the substitution is substituted with one or more substituents selected from the group consisting of: halogen, alkyl, alkoxy, haloalkyl, nitro, cycloalkyl, aryl.
2. The compound, pharmaceutically acceptable salt, prodrug, stable isotope derivative, isomer, solvate or polymorph thereof according to claim 1, wherein,
R 1 and R is 2 Each independently selected from hydroxy, amino C 1 -C 6 Alkanoyl, C 1 -C 6 Alkoxy, C 1 -C 6 An alkylaminocarbonyl group;
preferably, R 1 And R is 2 Each independently selected from amino C 1 -C 6 Alkanoyl, C 1 -C 6 An alkoxy group;
more preferably, R 1 And R is 2 Each independently selected from carbamoyl, methoxy.
3. The compound, pharmaceutically acceptable salt, prodrug, stable isotope derivative, isomer, solvate or polymorph thereof according to claim 1 or 2, wherein,
R 3 selected from- (NR) 5 ) n1 -C(O)-(NR 6 ) n2 -,R 5 And R is 6 Each independently selected from H, C 1 -C 6 An alkyl group; n1 and n2 are each independently selected from 0,1;
preferably, R 3 Selected from-C (O) NH-, -NH-C (O) -NH-,-C(O)-，-C(O)N(CH 3 )-，-N(CH 3 )-C(O)-N(CH 3 )-；
preferably, R 3 Selected from- (NR) 5 ) n1 -C(O)-(NR 6 ) n2 -,R 5 And R is 6 Is H; n1 and n2 are each independently selected from 0,1;
more preferably, R 3 Selected from-C (O) NH-, -NH-C (O) -NH-,
4. a compound, pharmaceutically acceptable salt, prodrug, stable isotope derivative, isomer, solvate or polymorph thereof according to any one of claim 1 to 3, wherein,
R 4 selected from substituted or unsubstituted C 1 -C 6 Alkyl, substituted or unsubstituted 5-10 membered aryl, substituted or unsubstituted 3-8 membered cycloalkyl, substituted or unsubstituted 5-10 membered heteroaryl, substituted or unsubstituted 5-10 membered heterocyclyl; the substitution is substituted with one or more substituents selected from the group consisting of: halogen, C 1 -C 6 Alkyl, C 1 -C 6 Alkoxy, halo C 1 -C 6 Alkyl, nitro, 3-8 membered cycloalkyl, 5-10 membered aryl;
preferably, R 4 Selected from substituted or unsubstituted 5-10 membered aryl, substituted or unsubstituted 3-8 membered cycloalkyl; the substitution is substituted with one or more substituents selected from the group consisting of: halogen, C 1 -C 6 Alkyl, C 1 -C 6 An alkoxy group;
more preferably, R 4 Selected from substituted or unsubstituted phenyl, substituted or unsubstituted cyclopropyl; the substitution is substituted with one or more substituents selected from the group consisting of: fluorine, methyl, methoxy;
further preferably, R 4 Selected from the group consisting ofCyclopropyl,/->
5. A compound according to any one of claims 1 to 4, a pharmaceutically acceptable salt, prodrug, stable isotope derivative, isomer, solvate or polymorph thereof, wherein the compound is selected from the group consisting of:
6. a process for preparing a compound of any one of claims 1 to 5, a pharmaceutically acceptable salt, prodrug, stable isotope derivative, isomer, solvate or polymorph thereof, which is process a or process B as follows;
the method A comprises the following steps:
4-nitronaphthylamine is subjected to diazotization reaction and substitution reaction to obtain an intermediate A2;
carrying out substitution reaction on the intermediate A2 and 4-hydroxyquinoline to obtain an intermediate A3;
reducing the nitro group of the intermediate A3 to obtain an intermediate A4;
the intermediate A4 is subjected to different condensation reactions to respectively obtain target products A5-A7;
the method B comprises the following steps:
4-nitronaphthol and 4-chloroquinoline are subjected to substitution reaction to obtain an intermediate B2;
reducing the nitro group of the intermediate B2 to obtain an intermediate B3;
the intermediate B3 is subjected to different condensation reactions to respectively obtain target products B4-B6;
r as described above 1 、R 2 And R is 4 Is as defined in any one of claims 1 to 5.
7. A pharmaceutical composition comprising a compound of any one of claims 1 to 5, a pharmaceutically acceptable salt, prodrug, stable isotope derivative, isomer, solvate or polymorph thereof;
optionally, the pharmaceutical composition further comprises a pharmaceutically acceptable carrier or excipient.
8. The pharmaceutical composition according to claim 7, further comprising other drugs and/or immunomodulators (such as one or more selected from immune checkpoint inhibitors, antibiotics, alkylating agents, antimetabolites, hormonal agents, immune-active agents, interferon-active agents and mixed-active agents) for the treatment of tumors.
9. Use of a compound according to any one of claims 1 to 5, a pharmaceutically acceptable salt, prodrug, stable isotope derivative, isomer, solvate or polymorph thereof or a pharmaceutical composition according to claim 7 or 8 in the manufacture of a medicament for the prevention and/or treatment of a disease associated with the VEGF/VEGFR pathway.
10. The use according to claim 9, wherein the VEGF/VEGFR pathway related disease is selected from one or more of atherosclerosis, pulmonary fibrosis, retinopathy, endometriosis, arthritis and cancer;
optionally, the cancer is selected from one or more of lung cancer, kidney cancer, stomach cancer, hepatocellular carcinoma, thyroid cancer, melanoma, breast cancer, pancreatic cancer, colon cancer, rectal cancer, prostate cancer, bladder cancer, ovarian cancer, cervical cancer, and glioma.
CN202310774718.5A 2023-06-28 2023-06-28 Quinoline compound, preparation method thereof, pharmaceutical composition and medical application Pending CN116751162A (en)

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