CN112778217A - Quinazoline compound and application thereof - Google Patents

Quinazoline compound and application thereof Download PDF

Info

Publication number
CN112778217A
CN112778217A CN201911084758.7A CN201911084758A CN112778217A CN 112778217 A CN112778217 A CN 112778217A CN 201911084758 A CN201911084758 A CN 201911084758A CN 112778217 A CN112778217 A CN 112778217A
Authority
CN
China
Prior art keywords
cancer
hydrogen
halogen
cyano
compound
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Granted
Application number
CN201911084758.7A
Other languages
Chinese (zh)
Other versions
CN112778217B (en
Inventor
毕弋
冉兆晋
柴宝山
王婉秋
王云华
焦佳媛
吴依蒙
赵宪成
石凯强
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Shenyang Research Institute of Chemical Industry Co Ltd
Original Assignee
Shenyang Research Institute of Chemical Industry Co Ltd
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Shenyang Research Institute of Chemical Industry Co Ltd filed Critical Shenyang Research Institute of Chemical Industry Co Ltd
Priority to CN201911084758.7A priority Critical patent/CN112778217B/en
Publication of CN112778217A publication Critical patent/CN112778217A/en
Application granted granted Critical
Publication of CN112778217B publication Critical patent/CN112778217B/en
Active legal-status Critical Current
Anticipated expiration legal-status Critical

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
    • C07D239/70—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings condensed with carbocyclic rings or ring systems
    • C07D239/72—Quinazolines; Hydrogenated quinazolines
    • C07D239/86—Quinazolines; Hydrogenated quinazolines with hetero atoms directly attached in position 4
    • C07D239/88—Oxygen atoms
    • 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
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • 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
    • A61P35/00—Antineoplastic agents
    • A61P35/02—Antineoplastic agents specific for leukemia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/02—Immunomodulators

Landscapes

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

Abstract

The invention relates to quinazoline-containing compounds shown as a general formula (I), and pharmaceutically acceptable salts, solvates and prodrugs thereof, wherein a substituent R1、R2、R3、R4、R5、R6P, m, n have the meanings given in the description. The invention also relates to the application of the compound shown in the general formula (I) in preparing antitumor drugsAnd also relates to the application of the compounds and the pharmaceutically acceptable salts, solvates and prodrugs thereof in preparing and/or preventing and relieving cancers caused by tumor cells of human tissues or organs. The cancer is preferably colon cancer, hepatocarcinoma, lymphoma, lung cancer, esophageal cancer, breast cancer, central nervous system tumor, melanoma, skin cancer, ovarian cancer, cervical cancer, renal cancer, leukemia, prostatic cancer, pancreatic cancer, bladder cancer, rectal cancer, osteosarcoma, nasopharyngeal carcinoma or gastric cancer.

Description

Quinazoline compound and application thereof
Technical Field
The invention belongs to the field of medicines, and particularly relates to a quinazoline compound and application thereof in preventing and/or treating cancers.
Background
Although studies on the mechanism of quinazoline compounds inhibiting the proliferation of HepG2, MGC-803 and A549 tumor cells have been described in European Journal of Medicinal Chemistry 107(2016)12-25, no studies have been made on the inhibition of other cancers such as lung cancer, bladder cancer, colon cancer and leukemia.
Figure BDA0002265055540000011
The patent CN 102977014B relates to the research on the in vitro anti-tumor inhibitory activity of the compound A with the general formula, but the structure of the compound is obviously different from that of the compound of the invention.
Figure BDA0002265055540000012
Patent CN106632287A relates to quinazoline compounds with certain anticancer activity on human skin squamous cell carcinoma cell line A431 and human lung cancer cell line A549.
Despite the numerous patents mentioned in connection with the introduction, there is a continuing need to develop new anti-cancer compounds to control the harm of cancer to humans. All of the compounds disclosed in the above patents are structurally distinct from the compounds of the present invention.
Disclosure of Invention
The invention aims to provide a quinazoline compound with a novel structure and application of the compound in preventing and/or treating cancer.
In order to achieve the purpose, the invention adopts the following technical scheme:
a quinazoline compound, which is shown in a general formula (I),
Figure BDA0002265055540000013
in the formula (I), the compound is shown in the specification,
R1selected from hydrogen, halogen, hydroxy, cyano, nitro, amino, C unsubstituted or substituted by at least one1-C12Alkyl radical, C1-C12Alkoxy radical, C3-C12Cycloalkyl, heterocyclyl, aryl, heteroaryl, C1-C12Alkylthio radical, C1-C12Alkylsulfonyl radical, C1-C12Alkylcarbonyl or C1-C12Alkoxycarbonyl, such as halogen, hydroxy, amino, cyano or nitro;
R2selected from hydrogen, C1-C12Alkyl radical, C1-C12Alkoxy radical, C3-C12Cycloalkyl, heterocyclyl, aryl or heteroaryl;
R3selected from hydrogen, C1-C12Alkyl radical, C1-C12Alkoxy radical, C3-C12Cycloalkyl, heterocyclyl, aryl or heteroaryl;
R4selected from hydrogen, halogen, hydroxy, amino, cyano, nitro, C unsubstituted or substituted by at least one1-C12Alkyl radical, C1-C12Alkoxy radical, C3-C12Cycloalkyl, heterocyclyl, aryl or heteroaryl, wherein the following are halogen, hydroxy, amino, cyano or nitro;
m is selected from 1 to 4;
R5selected from hydrogen, halogen, hydroxy, amino, cyano, nitro, C unsubstituted or substituted by at least one1-C12Alkyl radical, C1-C12Alkoxy radical, C3-C12Cycloalkyl, heterocyclyl, aryl or heteroaryl, wherein the following are halogen, hydroxy, amino, cyano or nitro;
p is selected from 1-4;
R6selected from hydrogen, halogen, hydroxy, amino, cyano, nitro, C unsubstituted or substituted by at least one1-C12Alkyl radical, C1-C12Alkoxy radical, C3-C12Cycloalkyl, heterocyclyl, aryl, heteroaryl, C1-C12Alkylthio radical, C1-C12Alkylsulfonyl radical, C1-C12Alkylcarbonyl or C1-C12Alkoxycarbonyl, such as halogen, hydroxyl, amino, cyano, nitro;
n is selected from 1-5;
or isomers of the compound shown in the general formula (I), and pharmaceutically acceptable salts, solvates or prodrugs thereof.
In the preferred general formula (i),
R1selected from hydrogen, halogen, hydroxy, amino, cyano, nitro, C unsubstituted or substituted by at least one1-C4Alkyl radical, C1-C4Alkoxy radical, C3-C6Cycloalkyl, heterocyclyl, aryl, heteroaryl, C1-C4Alkylthio radical, C1-C4Alkylsulfonyl radical, C1-C4Alkylcarbonyl or C1-C4Alkoxycarbonyl wherein the following are halogen, hydroxy, cyano, nitro or amino;
R2selected from hydrogen, C1-C4Alkyl or C3-C12A cycloalkyl group;
R3selected from hydrogen, C1-C4Alkyl or C3-C12A cycloalkyl group;
R4selected from hydrogen, halogen, hydroxy, amino, cyano, nitro, C1-C4Alkyl radical, C1-C4Alkoxy or C3-C6A cycloalkyl group;
m is selected from 1 to 4;
R5selected from hydrogen, halogen, hydroxy, amino, cyano, nitro, C1-C4Alkyl radical, C1-C4Alkoxy or C3-C6A cycloalkyl group;
p is selected from 1-4;
R6selected from hydrogen, halogen, hydroxy, amino, cyano, nitro, C unsubstituted or substituted by at least one halogen1-C4Alkyl radical, C1-C4Alkoxy radical, C3-C6Cycloalkyl, heterocyclyl, aryl or heteroaryl;
n is selected from 1-5;
or isomers of the compound shown in the general formula (I), and pharmaceutically acceptable salts, solvates or prodrugs thereof.
In a further preferred general formula (i),
R1selected from hydrogen, halogen, hydroxy, amino, cyano, nitro, C1-C4Alkyl radical, C1-C4Alkoxy, C substituted by one or more halogens1-C4Alkyl radical, C1-C4An alkoxy group;
R2selected from hydrogen, methyl, ethyl or cyclopropyl;
R3selected from hydrogen, methyl, ethyl or cyclopropyl;
R4、selected from hydrogen, fluoro, chloro, methyl, ethyl or cyclopropyl;
m is selected from 1 to 4;
R5、selected from hydrogen, fluorine, chlorine, methyl, ethyl, cyclopropyl, methoxy,Ethoxy and propoxy groups;
p is selected from 1-4;
R6selected from hydrogen, halogen, hydroxy, amino, cyano, nitro, C unsubstituted or substituted by at least one halogen1-C4Alkyl radical, C1-C4An alkoxy group;
n is selected from 1-5;
or isomers of the compound shown in the general formula (I), and pharmaceutically acceptable salts, solvates or prodrugs thereof.
Still further preferably, in the general formula (i),
R1selected from hydrogen, trifluoromethyl or methyl;
R2selected from hydrogen or methyl;
R3selected from hydrogen or methyl;
R4selected from hydrogen;
R5selected from hydrogen or methoxy;
R6selected from hydrogen, halogen, hydroxy, cyano, methoxy, ethoxy, methyl, ethyl, isopropyl;
n is selected from 1-5;
or isomers of the compound shown in the general formula (I), and pharmaceutically acceptable salts, solvates or prodrugs thereof.
The salt corresponding to the compound of the general formula I or the isomer thereof is hydrochloride, sulfate, nitrate, bicarbonate, carbonate, phosphate, formate, acetate, trifluoroacetate, benzenesulfonate, p-toluenesulfonate, methanesulfonate, benzoate, citrate, malate, tartrate, maleate, succinate, ascorbate or oxalate.
According to the invention, prodrugs of compounds of formula (I) are derivatives of compounds of formula (I) which may themselves have a weaker activity or even no activity, but which, after administration, are converted under physiological conditions (e.g. by metabolism, solvolysis or otherwise) into the corresponding biologically active form.
The compound solvate of the general formula (I) is prepared by reacting the compound of the general formula (I) or an isomer thereof with methanol, ethanol, isopropanol, n-butanol, ethyl acetate, dichloromethane, petroleum ether and acetonitrile.
The application of the compound shown in the general formula (I), the isomer thereof, and the pharmaceutically acceptable salt, solvate or prodrug thereof in preparing a medicament for treating cell proliferation diseases.
The cell proliferation diseases are selected from cancer, infection, inflammation or autoimmune diseases.
The cancer is selected from colon cancer, liver cancer, lymphoma, lung cancer, esophageal cancer, breast cancer, central nervous system tumor, melanoma, skin cancer, ovarian cancer, cervical cancer, renal cancer, leukemia, prostate cancer, pancreatic cancer, bladder cancer, rectal cancer, osteosarcoma, nasopharyngeal cancer or gastric cancer.
A pharmaceutical composition comprising a therapeutically effective amount of a compound of formula (I) or its isomer, and pharmaceutically acceptable salts, solvates or prodrugs thereof, and one or more pharmaceutically acceptable carriers or excipients.
The application of the pharmaceutical composition in preparing medicines for treating cell proliferation diseases.
In the definitions of the compounds of the general formula (I) given above, the terms used in the collection generally represent the following substituents:
halogen: refers to fluorine, chlorine, bromine or iodine. Alkyl groups: straight-chain or branched alkyl groups, such as methyl, ethyl, propyl, isopropyl or tert-butyl. Halogenated alkyl groups: straight-chain or branched alkyl groups in which the hydrogen atoms may be partially or completely substituted by halogen atoms, such as chloromethyl, dichloromethyl, trichloromethyl, fluoromethyl, difluoromethyl, trifluoromethyl and the like. Alkoxy groups: straight or branched chain alkyl groups attached to the structure via oxygen atom linkages. Cycloalkyl groups: substituted or unsubstituted heteroatom-containing cyclic alkyl groups, such as cyclopropyl, cyclopentyl, or cyclohexyl. Substituents such as methyl, halogen, and the like. Attached to the structure via an oxygen atom bond. Alkoxy groups: straight or branched chain alkyl groups attached to the structure via oxygen atom linkages. Alkylthio group: straight or branched chain alkyl groups attached to the structure via a sulfur atom. An alkylcarbonyl group: straight or branched chainThe alkanyl group is linked to the structure via a carbonyl (-CO-) group, such as acetyl. Alkoxycarbonyl group: the alkoxy group is attached to the structure via a carbonyl group. Such as-COOCH3，-COOCH2CH3. An alkylsulfonyl group: straight-chain or branched alkyl group via sulfone group (-SO)2-) is attached to a structure, such as a methylsulfonyl group. Aryl includes phenyl or naphthyl and the like. Heteroaryl is a five or six membered ring containing 1 or more heteroatoms N, O, S. Such as furyl, pyrrolyl, pyrazolyl, thiazolyl, pyridyl, pyrimidinyl and the like.
In the compounds of the invention of the partial general formula I (R)6)nThe substituents are listed in Table 1, but do not limit the present invention.
Figure BDA0002265055540000031
Figure BDA0002265055540000041
TABLE 1
Figure BDA0002265055540000042
Figure BDA0002265055540000051
Further, some of the compounds of formula (I) may be represented by Table 2,
Figure BDA0002265055540000061
TABLE 2
Figure BDA0002265055540000062
Figure BDA0002265055540000071
Figure BDA0002265055540000081
Figure BDA0002265055540000091
Figure BDA0002265055540000101
Figure BDA0002265055540000111
Figure BDA0002265055540000121
Figure BDA0002265055540000131
Figure BDA0002265055540000141
The compounds of the general formula (I) according to the invention can be prepared as follows. The reaction is as follows, wherein the groups are as defined above unless otherwise indicated:
synthetic routes of general formula (I):
Figure BDA0002265055540000142
the preparation process comprises the following steps:
the method comprises the following steps: cpd.1 and cpd.2 were added to formic acid and heated to 135 ℃ with stirring for 5 hours. The reaction solution was poured into a water bath to precipitate the product, which was then filtered to obtain cpd.3.
Step two: the cpd.3 is dissolved in a solvent, a chlorinating agent is added, and the reaction is heated under reflux for 3 hours. And after the reaction is finished, desolventizing to obtain the product cpd.4.
Step three: dissolving cpd.4 and cpd.5 in a solvent, adding alkali, water and TBAB at 100 ℃ for reacting for 4h, and after the reaction is finished, performing column chromatography purification to obtain a product cpd.6.
Step four: cpd.6 and cpd.7 were dissolved in solvent, added base and HBTU, stirred at rt for 6h, and column chromatographed to give cpd.8.
The chlorinating agent may be selected from thionyl chloride, phosphorus trichloride, phosphorus pentachloride, phosphorus oxychloride, Vilesmeier-Haack reagent, sulfuryl chloride, and the like.
The base is selected from sodium hydroxide, lithium hydroxide, sodium carbonate, sodium bicarbonate, potassium hydroxide, potassium carbonate, and potassium bicarbonate.
The solvent used in each step can be selected from ethanol, acetonitrile, tetrahydrofuran, toluene, xylene, benzene, N-dimethylformamide, N-methylpyrrolidone, dimethyl sulfoxide, acetone or butanone, etc.
The reaction temperature in the above steps may be between room temperature and the boiling temperature of the solvent, preferably in the range of 20-150 ℃.
Intermediates cpd.1, cpd.2, cpd.5 and cpd.7 in the above reactions are commercially available.
The salts of the compounds of the formula (I) can be prepared from the compounds of the formula (I) and the corresponding acids in a conventional manner. Suitable acids are selected from hydrochloric, sulfuric, nitric, carbonic, phosphoric, formic, acetic, trifluoroacetic, benzenesulfonic, p-toluenesulfonic, methanesulfonic, benzoic, citric, malic, tartaric, maleic, succinic, ascorbic or oxalic acids and the like; further preferred are hydrochloric acid, sulfuric acid, phosphoric acid, trifluoroacetic acid, methanesulfonic acid, p-toluenesulfonic acid and the like.
The invention comprises a preparation prepared by taking the compound contained in the general formula (I) as an active ingredient and a preparation consisting of the preparation. The preparation method comprises the following steps: dissolving the compound covered by the present invention in a water-soluble organic solvent, a nonionic surfactant, a water-soluble lipid, various cyclodextrins, fatty acids, fatty acid esters, phospholipids or a combination thereof to prepare a preparation solution; adding physiological saline to obtain 1-20% carbohydrate. The organic solvent includes polyethylene glycol (PEG), ethanol, propylene glycol or a combination of these solvents.
The compounds covered in the general formula (I) and the salts and prodrugs thereof are used for preparing anti-tumor medicaments or medicinal preparations for treating, preventing or relieving tumor, and the active ingredients of the medicaments are one or more quinazoline compounds shown in the general formula (I). Is especially suitable for treating or relieving cancer caused by tumor cells of human tissues or organs. The cancer is preferably colon cancer, hepatocarcinoma, lymphoma, lung cancer, esophageal cancer, breast cancer, central nervous system tumor, melanoma, ovarian cancer, cervical cancer, renal cancer, leukemia, prostatic cancer, pancreatic cancer, bladder cancer, rectal cancer, osteosarcoma, nasopharyngeal carcinoma or gastric cancer.
The compound synthesized by the invention can be used as an active component of an anti-tumor medicament, can be used independently, and can also be used together with other anti-tumor and anti-virus medicaments. The combination therapy of the present invention includes the use of at least one compound of the present invention and its active derivatives in combination with one or more other anti-tumor and anti-viral agents to increase the overall therapeutic effect. The dosage and administration time of the combination should be determined according to the most reasonable therapeutic effect obtained under different conditions.
The pharmaceutical formulation contemplated includes an effective dose of the compound of formula (I). An "effective amount" as used herein refers to the amount of the compound required to produce a therapeutic effect in the subject being treated. The effective dose or dosages may be varied by the experiential person according to the recommendations of the individual case. For example, the types of tumors to be treated are different, and the use of drugs is different; whether the composition is used together with other treatment methods such as other antitumor drugs or antiviral drugs, etc., the dosage can be changed. Can be made into any available dosage form. If certain compounds have basic or acidic properties and can form non-toxic acids or salts, the salt forms of the compounds can be used. Pharmaceutically acceptable organic acid salts include physiologically acceptable negative ion salts such as p-toluenesulfonate, methanesulfonate, acetate, benzoate, citrate, malate, tartrate, maleate, succinate, ascorbate or glycerophosphate, and the like; inorganic salts that may be used include chlorides, bromides, fluorides, iodides, sulfates, nitrates, bicarbonates, carbonates, or phosphates, and the like; basic compounds such as amines with suitable acids can be prepared in the form of the salts; the carboxylic acid compounds may form usable salts with alkali metals or alkaline earth metals.
The compounds encompassed in the general formula (I) in the present invention are generally easily soluble in organic solvents, water-soluble solvents, and mixed solvents of organic solvents and water-soluble solvents with water. The water-soluble solvent is preferably alcohol, polyethylene glycol, N-methyl-2-pyrrolinone, N-dimethylacetamide, N-dimethylformamide, dimethylsulfoxide, acetonitrile, or a combination thereof. The alcohol is preferably methanol, ethanol, isopropanol, glycerol or ethylene glycol. The compounds of the present invention can be formulated by mixing with conventional formulation carriers. Dissolving the compound in water-soluble organic solvent, aprotic solvent, water-soluble lipid, cyclodextrin, fatty acid, phospholipid or their mixture to obtain medicinal solution; adding physiological saline to obtain 1-20% carbohydrate, such as glucose water solution. The thus-prepared preparation is stable and useful for animals and clinics.
The product medicine prepared by using the compound in the general formula (I) as an active ingredient can be administrated by oral or parenteral routes, and also can be administrated by a medicine pump transplanted in vivo and other methods, wherein the parenteral route administration refers to perfusion, subcutaneous intracutaneous, intramuscular, intravenous, intra-arterial, intra-atrial, intra-synovial, intrasternal, intrathecal, intra-traumatic, intracranial injection or instillation technology and the like. The technical personnel mix the components by a conventional method to finally obtain the required medicament form. Can be made into tablet, pill, capsule, granule, syrup, injection, lyophilized powder for injection, emulsion, powder, lyophilized powder, dripping pill, emulsion suspension, aqueous suspension, water solution, colloid solution, sustained release preparation, nanometer preparation, or other dosage forms for animal or clinical use.
The compound in the general formula (I) is used for preparing a medicine for treating or relieving cancer of a certain tissue or organ. The cancer includes but is not limited to colon cancer, liver cancer, lymphoma, lung cancer, esophageal cancer, breast cancer, central nervous system tumor, melanoma, ovarian cancer, cervical cancer, renal cancer, leukemia, prostate cancer, pancreatic cancer, bladder cancer, rectal cancer, osteosarcoma, nasopharyngeal cancer or gastric cancer.
Detailed Description
The following specific examples are provided to further illustrate the present invention, but the present invention is not limited to these examples. (all materials are commercially available unless otherwise noted)
Synthetic examples
Example 1: preparation of Compound 1
Figure BDA0002265055540000161
The method comprises the following steps: intermediate a (20g,101mmol), amine formate (80mL) and formic acid (8mL) were added to a 250mL single-neck flask and heated to 135 deg.C with stirring for 5 hours. The reaction solution was poured into a water bath to precipitate the product, which was then filtered to obtain 23g of the product.
Step two: intermediate b (5g,24.3mmol) was added to SOCl2(50mL), the reaction was heated under reflux for 3 h. After the reaction, the product 5.3g was obtained by desolventizing.
Step three: intermediate c (5.3g,23.7mmol) and intermediate d (2.8g,25.69mmol) were dissolved in butanone (100mL), NaOH (3g,75mmol), H were added2O (20mL,1.1mol), and TBAB (4g,12mmol), heating to 100 deg.C, reacting for 4h, and purifying by column chromatography to obtain 2.6 g.
Step four: intermediate e (100mg, 0.337mmol) and intermediate f (50mg,0.325mmol) were dissolved in THF (10mL), DIPEA (200mg, 1.55mmol) and HBTU (130mg,0.343mmol) were added and stirred at room temperature for 6 hours, and column chromatography gave 100mg of Compound 1.
1H NMR(600MHz,DMSO-d6)δ10.34(s,1H),8.54(s,1H),7.73–7.67(m,2H),7.56(s,1H),7.43(td,J＝7.6,1.7Hz,1H),7.39(s,1H),7.33(ddd,J＝7.4,5.6,1.9Hz,1H),7.28–7.24(m,2H),7.23–7.17(m,2H),3.99(d,J＝8.9Hz,6H),3.77(s,2H).MS:433.44.
Example 2: preparation of Compound 2
Figure BDA0002265055540000171
Intermediate e was prepared as in example 1. The preparation method of the compound 2 comprises the following steps:
the method comprises the following steps: intermediate e (100mg, 0.337mmol) and intermediate f (54mg,0.325mmol) were dissolved in THF (10mL), DIPEA (200mg, 1.55mmol) and HBTU (130mg,0.343mmol) were added and stirred at room temperature for 6 hours, and column chromatography gave 100mg of Compound 2.
1H NMR(600MHz,DMSO-d6)δ10.23(s,1H),8.53(s,1H),7.71–7.66(m,2H),7.55(s,1H),7.37(s,1H),7.30–7.26(m,2H),7.25–7.22(m,2H),6.92–6.88(m,2H),3.99(s,3H),3.97(s,3H),3.74(s,3H),3.59(s,2H).MS:445.16.
Example 3: preparation of Compound 3
Figure BDA0002265055540000172
Intermediate e was prepared as in example 1. The preparation method of the compound 3 comprises the following steps:
the method comprises the following steps: intermediate e (100mg, 0.337mmol) and intermediate f (54mg,0.325mmol) were dissolved in THF (10mL), DIPEA (200mg, 1.55mmol) and HBTU (130mg,0.343mmol) were added and stirred at room temperature for 6 hours, and column chromatography gave 100mg of Compound 3.
1H NMR(600MHz,DMSO-d6)δ10.17(s,1H),8.53(s,1H),7.74–7.66(m,2H),7.55(s,1H),7.38(s,1H),7.28–7.22(m,4H),6.99(dd,J＝8.1,1.1Hz,1H),6.92(td,J＝7.4,1.1Hz,1H),3.99(s,3H),3.97(s,3H),3.79(s,3H),3.66(s,2H).MS:445.16.
Example 4: preparation of Compound 4
Figure BDA0002265055540000173
Intermediate e was prepared as in example 1. The preparation method of the compound 4 comprises the following steps:
the method comprises the following steps: intermediate e (100mg, 0.337mmol) and intermediate f (55mg,0.325mmol) were dissolved in THF (10mL), DIPEA (200mg, 1.55mmol) and HBTU (130mg,0.343mmol) were added and stirred at room temperature for 6 hours, and column chromatography gave 100mg of compound 4.
1H NMR(600MHz,DMSO-d6)δ10.30(s,1H),8.53(s,1H),7.72–7.66(m,2H),7.55(s,1H),7.43–7.35(m,5H),7.28–7.22(m,2H),3.99(s,3H),3.97(s,3H),3.68(s,2H).MS:499.84.
Example 5: preparation of Compound 5
Figure BDA0002265055540000181
Intermediate e was prepared as in example 1. The preparation method of the compound 5 comprises the following steps:
the method comprises the following steps: intermediate e (100mg, 0.337mmol) and intermediate f (67mg,0.325mmol) were dissolved in THF (10mL), DIPEA (200mg, 1.55mmol) and HBTU (130mg,0.343mmol) were added and stirred at room temperature for 6 hours, and column chromatography gave 100mg of compound 5.
1H NMR(600MHz,DMSO-d6)δ10.54(d,J＝7.2Hz,1H),8.80(d,J＝4.9Hz,1H),7.76–7.71(m,2H),7.65(dd,J＝4.8,2.0Hz,2H),7.61(d,J＝8.3Hz,1H),7.47(d,J＝1.6Hz,1H),7.37(dd,J＝8.3,2.0Hz,1H),7.31–7.26(m,2H),4.04–3.99(m,6H),3.75(s,2H).MS:484.33.
Other example compound data are as follows:
compound 6:1H NMR (600MHz, DMSO-d6) δ 10.29(s,1H),8.63(s,1H),7.71(d, J ═ 8.6Hz,2H),7.59(s,1H),7.40(s,1H),7.26(dd, J ═ 8.3,5.9Hz,3H), 6.97-6.93 (m,2H),6.83(d, J ═ 2.7Hz,1H),4.00(d, J ═ 10.9Hz,6H),3.76(s,3H),3.64(s,2H). MS:445.16.
Compound 7:1H NMR (600MHz, DMSO-d6) δ 10.37(s,1H),8.54(s,1H), 7.74-7.67 (m,2H),7.54(s,1H),7.46(dt, J ═ 7.1,2.3Hz,2H),7.37(s,1H), 7.35-7.30 (m,2H), 7.27-7.24 (m,2H),3.99(s,3H),3.98(s,3H),3.88(s,2H). MS:449.11.
Compound 8:1H NMR (600MHz, DMSO-d6) δ 10.34(s,1H),8.65(s,1H), 7.72-7.68 (m,2H),7.59(s,1H),7.44(t, J ═ 1.9Hz,1H),7.39(s,1H), 7.35-7.32 (m,3H), 7.28-7.25 (m,2H),4.01(s,3H),3.99(s,3H),3.71(s,2H). MS:449.11.
Compound 9:1H NMR (600MHz, DMSO-d6) δ 10.32(s,1H),8.57(s,1H),7.69(d, J ═ 8.5Hz,2H),7.57(s,1H),7.39(d, J ═ 5.0Hz,2H),7.25(d, J ═ 8.6Hz,2H),7.20(d, J ═ 8.0Hz,2H),7.10(d, J ═ 2.4Hz,1H),3.99(d, J ═ 10.2Hz,6H),3.71(s,2H). MS:433.14.
Compound 10:1H NMR (600MHz, DMSO-d6) δ 8.65(s,1H), 7.72-7.68 (m,2H),7.59(s,1H),7.54(d, J ═ 8.1Hz,2H), 7.52-7.48 (m,2H),7.33(d, J ═ 8.0Hz,2H), 7.28-7.25 (m,2H),4.00(d, J ═ 11.5Hz,6H),3.67(s,2H). MS:493.06.
Compound 11:1H NMR (600MHz, DMSO-d6) δ 10.35(s,1H),8.54(s,1H),7.88(dd, J ═ 7.8,1.1Hz,1H), 7.72-7.69 (m,2H),7.56(s,1H), 7.42-7.38 (m,3H), 7.28-7.24 (m,2H),7.04(ddd, J ═ 7.8,6.7,2.3Hz,1H),3.99(d, J ═ 8.2Hz,6H),3.88(s,2H). MS:541.05.
Compound 12:1H NMR (600MHz, DMSO-d6) δ 10.31(s,1H),8.54(s,1H),7.76(t, J ═ 1.7Hz,1H), 7.72-7.67 (m,2H),7.64(dt, J ═ 7.9,1.4Hz,1H),7.55(s,1H),7.39(d, J ═ 9.7Hz,2H), 7.28-7.24 (m,2H),7.16(t, J ═ 7.8Hz,1H),3.98(d, J ═ 9.5Hz,6H),3.67(s,2H). MS:541.05.
Compound 13:1H NMR (600MHz, DMSO-d6) δ 10.30(s,1H),8.54(s,1H), 7.73-7.66 (m,4H),7.55(s,1H),7.38(s,1H), 7.27-7.23 (m,2H), 7.20-7.15 (m,2H),3.98(d, J ═ 9.9Hz,6H),3.65(s,2H). MS:541.05.
Compound 14:1H NMR (600MHz, DMSO-d6) δ 10.28(s,1H),8.54(s,1H), 7.73-7.67 (m,2H),7.55(s,1H),7.38(s,1H), 7.30-7.23 (m,3H), 7.21-7.14 (m,3H),3.99(d, J ═ 9.1Hz,6H),3.72(s,2H),2.33(s,3H). MS:429.17.
Compound 15:1H NMR (600MHz, DMSO-d6) δ 10.26(s,1H),8.54(s,1H), 7.71-7.67 (m,2H),7.56(s,1H),7.38(s,1H), 7.27-7.22 (m,4H),7.15(d, J ═ 7.8Hz,2H),3.99(d, J ═ 9.8Hz,6H),3.62(s,2H),2.29(s,3H). MS:429.17.
Compound 16:1H NMR (600MHz, DMSO-d6) δ 10.36(s,1H),8.53(s,1H),7.81(d, J ═ 1.8Hz,1H),7.75(dt, J ═ 7.7,1.4Hz,1H),7.70(td, J ═ 7.4,6.8,1.7Hz,3H),7.57(t, J ═ 7.8Hz,1H),7.54(s,1H),7.37(s,1H), 7.28-7.23 (m,2H),3.99(s,3H),3.97(s,3H),3.79(s,2H), MS:440.15.
Compound 17:1H NMR (600MHz, DMSO-d6) δ 10.36(s,1H),8.53(s,1H), 7.86-7.78 (m,2H), 7.72-7.64 (m,2H), 7.60-7.50 (m,3H),7.38(s,1H), 7.29-7.21 (m,2H),3.98(d, J ═ 9.8Hz,6H),3.81(s,2H). MS:440.15.
Compound 18:1H NMR (600MHz, DMSO-d6) δ 10.36(s,1H),8.54(s,1H), 7.72-7.67 (m,2H),7.56(s,1H),7.53(dd, J ═ 6.5,2.8Hz,1H),7.40(ddd, J ═ 9.0,4.6,2.9Hz,1H),7.38(s,1H), 7.29-7.26 (m,2H),7.26(d, J ═ 2.9Hz,1H),3.99(d, J ═ 8.9Hz,6H),3.80(s,2H). MS:467.10.
Compound 19: 1H NMR (600MHz, DMSO-d6) δ 10.33(s,1H),8.54(s,1H), 7.73-7.66 (m,2H), 7.58-7.53 (m,2H),7.41(dd, J ═ 10.4,1.9Hz,1H),7.38(s,1H), 7.28-7.24 (m,2H),7.23(dd, J ═ 8.4,1.9Hz,1H),3.98(d, J ═ 9.7Hz,6H),3.74(s,2H). MS:467.10
Compound 20:1H NMR (600MHz, DMSO-d6) δ 10.31(s,1H),8.53(s,1H),7.75(t, J ═ 1.8Hz,1H), 7.70-7.66 (m,2H),7.60(d, J ═ 1.8Hz,2H),7.55(s,1H),7.38(s,1H), 7.27-7.24 (m,2H),3.98(d, J ═ 9.4Hz,6H),3.73(s,2H). MS:570.97.
Compound 21:1H NMR (600MHz, DMSO-d6) δ 10.36(s,1H),8.54(s,1H), 7.70-7.68 (m,2H),7.66(dd, J ═ 8.8,5.4Hz,1H),7.55(s,1H), 7.38-7.35 (m,1H), 7.28-7.24 (m,2H),7.13(td, J ═ 8.5,3.1Hz,1H),3.98(d, J ═ 8.5Hz,6H),3.90(s,2H). MS:511.05.
According to the descriptions of the above examples and the preparation process of the compound of formula (i) in the summary of the invention, other compounds represented by formula (i) can be further prepared;
and (3) obtaining the compound shown in the general formula (I) according to the preparation method, and reacting the obtained compound with a corresponding salt to obtain a pharmaceutically acceptable salt of the compound shown in the general formula (I).
Determination of antitumor Activity
Example 1: the in vitro assay for tumor cell inhibition (MTT assay) was as follows:
the human cancer tumor cell line: human colon cancer HT-29 and human cervical carcinoma cell Hela.
The inhibition rate of 5 concentration samples to the growth of each human cancer cell is determined by adopting an in vitro cell culture technology and using a conventional MTT method to measure the inhibition rate of the human colon cancer HT-29 and the human cervical cancer Hela.
MTT method: the cells were removed from the incubator, washed twice with PBS solution, digested with 0.25% trypsin solution, digested by addition of RPMI1640 complete medium (containing 10% FBS), centrifuged, and the supernatant was spun off, and the cell suspension was formed by addition of complete medium, and counted under an inverted microscope. Cells were formulated at a concentration of 5x104The method comprises the steps of adding 100 mu L of cells into each well of a 96-well plate, placing the 96-well plate in a humidified air at 37 ℃ for overnight culture, removing supernatant by placing the 96-well plate in a humidified air at 5% carbon dioxide, adding complete culture medium for dilution into five different concentration gradients of 40 mu g/mL, 8 mu g/mL, 1.6 mu g/mL, 0.32 mu g/mL and 0.064 mu g/mL to obtain a compound to be tested, removing the supernatant after the complete culture medium acts for 48 hours, adding 100 mu L of 0.5mg/mL MTT, reacting for 4 hours, reducing MTT tetrazolium (tetrazole) components by living cells to generate formazan (formazan) to remove the supernatant, adding 100 mu L of DMSO to dissolve the formazan, and finally measuring the absorbance value of 490nm and 630nm on a 96-well plate reader.
The cell inhibition rate (1-absorbance of experiment/absorbance of control) x 100%
According to the inhibition rate of 5 concentration test samples, IC is calculated by GraphPad Prism6 software by a nonlinear regression method50The value is obtained. Part of the test results (see table 3) are as follows:
TABLE 3 cytotoxic Activity of Compounds on human tumor cells
Figure BDA0002265055540000201
The data in the table show that the quinazoline compounds 1, 15 and 21 have very obvious inhibition effects on high-expression cell strains of Tubulin and C-Met targets, have certain antitumor activity and can effectively inhibit the growth of tumor cells; the quinazoline and phenylacetamide derivative structures exist in the structure of the compound shown in the general formula (I); the compound has obvious difference with the reported compounds, and the compound with the general formula (I) and the pharmaceutically acceptable salts, solvates and prodrugs thereof can be used for preparing and/or preventing and relieving cancers caused by tumor cells of human tissues or organs.
The above-described embodiments of the present invention should not be construed as limiting the scope of the present invention. Any other corresponding changes and modifications made according to the technical idea of the present invention should be included in the protection scope of the claims of the present invention.

Claims (10)

1. A quinazoline compound characterized in that: the compound is shown in a general formula (I),
Figure FDA0002265055530000011
in the formula (I), the compound is shown in the specification,
R1selected from hydrogen, halogen, hydroxy, cyano, nitro, amino, C unsubstituted or substituted by at least one1-C12Alkyl radical, C1-C12Alkoxy radical, C3-C12Cycloalkyl, heterocyclyl, aryl, heteroaryl, C1-C12Alkylthio radical, C1-C12Alkylsulfonyl radical, C1-C12Alkylcarbonyl or C1-C12Alkoxycarbonyl, such as halogen, hydroxy, amino, cyano or nitro;
R2selected from hydrogen, C1-C12Alkyl radical, C1-C12Alkoxy radical, C3-C12Cycloalkyl, heterocyclyl, aryl or heteroaryl;
R3selected from hydrogen, C1-C12Alkyl radical, C1-C12Alkoxy radical, C3-C12Cycloalkyl, heterocyclyl, aryl or heteroaryl;
R4selected from hydrogen, halogen, hydroxy, amino, cyano, nitro, C unsubstituted or substituted by at least one1-C12Alkyl radical, C1-C12Alkoxy radical, C3-C12Cycloalkyl, heterocyclyl, aryl or heteroaryl, wherein the following are halogen, hydroxy, amino, cyano or nitro;
m is selected from 1 to 4;
R5selected from hydrogen, halogen, hydroxy, amino, cyano, nitro, C unsubstituted or substituted by at least one1-C12Alkyl radical, C1-C12Alkoxy radical, C3-C12Cycloalkyl, heterocyclyl, aryl or heteroaryl, wherein the following are halogen, hydroxy, amino, cyano or nitro;
p is selected from 1-4;
R6selected from hydrogen, halogen, hydroxy, amino, cyano, nitro, C unsubstituted or substituted by at least one1-C12Alkyl radical, C1-C12Alkoxy radical, C3-C12Cycloalkyl, heterocyclyl, aryl, heteroaryl, C1-C12Alkylthio radical, C1-C12Alkylsulfonyl radical, C1-C12Alkylcarbonyl or C1-C12Alkoxycarbonyl, such as halogen, hydroxyl, amino, cyano, nitro;
n is selected from 1-5;
or isomers of the compound shown in the general formula (I), and pharmaceutically acceptable salts, solvates or prodrugs thereof.
2. The quinazoline compound according to claim 1, wherein: in the general formula (I), the first step is,
R1selected from hydrogen, halogen, hydroxy, amino, cyano, nitro, C unsubstituted or substituted by at least one1-C4Alkyl radical, C1-C4Alkoxy radical, C3-C6Cycloalkyl, heterocyclyl, aryl, heteroaryl, C1-C4Alkylthio radical, C1-C4Alkylsulfonyl radical, C1-C4Alkylcarbonyl or C1-C4Alkoxycarbonyl, wherein the following radicals are halogen, hydroxy,Cyano, nitro or amino;
R2selected from hydrogen, C1-C4Alkyl or C3-C12A cycloalkyl group;
R3selected from hydrogen, C1-C4Alkyl or C3-C12A cycloalkyl group;
R4selected from hydrogen, halogen, hydroxy, amino, cyano, nitro, C1-C4Alkyl radical, C1-C4Alkoxy or C3-C6A cycloalkyl group;
m is selected from 1 to 4;
R5selected from hydrogen, halogen, hydroxy, amino, cyano, nitro, C1-C4Alkyl radical, C1-C4Alkoxy or C3-C6A cycloalkyl group;
p is selected from 1-4;
R6selected from hydrogen, halogen, hydroxy, amino, cyano, nitro, C unsubstituted or substituted by at least one halogen1-C4Alkyl radical, C1-C4Alkoxy radical, C3-C6Cycloalkyl, heterocyclyl, aryl or heteroaryl;
n is selected from 1-5;
or isomers of the compound shown in the general formula (I), and pharmaceutically acceptable salts, solvates or prodrugs thereof.
3. The quinazoline compound according to claim 2, wherein: in the general formula (I), the first step is,
R1selected from hydrogen, halogen, hydroxy, amino, cyano, nitro, C1-C4Alkyl radical, C1-C4Alkoxy, C substituted by one or more halogens1-C4Alkyl radical, C1-C4An alkoxy group;
R2selected from hydrogen, methyl, ethyl or cyclopropyl;
R3selected from hydrogen, methyl, ethyl or cyclopropyl;
R4selected from hydrogen, fluorine, chlorine, methyl, ethyl or cyclopropylA group;
m is selected from 1 to 4;
R5selected from hydrogen, fluoro, chloro, methyl, ethyl, cyclopropyl, methoxy, ethoxy and propoxy;
p is selected from 1-4;
R6selected from hydrogen, halogen, hydroxy, amino, cyano, nitro, C unsubstituted or substituted by at least one halogen1-C4Alkyl radical, C1-C4An alkoxy group;
n is selected from 1-5;
or isomers of the compound shown in the general formula (I), and pharmaceutically acceptable salts, solvates or prodrugs thereof.
4. The quinazoline compound according to claim 3, wherein: in the general formula (I), the first step is,
R1selected from hydrogen, trifluoromethyl or methyl;
R2selected from hydrogen or methyl;
R3selected from hydrogen or methyl;
R4selected from hydrogen;
R5selected from hydrogen or methoxy;
R6selected from hydrogen, halogen, hydroxy, cyano, methoxy, ethoxy, methyl, ethyl, isopropyl;
n is selected from 1-5;
or isomers of the compound shown in the general formula (I), and pharmaceutically acceptable salts, solvates or prodrugs thereof.
5. The compound of any one of claims 1-4, wherein: the salt corresponding to the compound of the general formula I or the isomer thereof is hydrochloride, sulfate, nitrate, bicarbonate, carbonate, phosphate, formate, acetate, trifluoroacetate, benzenesulfonate, p-toluenesulfonate, methanesulfonate, benzoate, citrate, malate, tartrate, maleate, succinate, ascorbate or oxalate.
6. Use of a compound according to claim 1, wherein: the compound shown in the general formula (I), isomers thereof, pharmaceutically acceptable salts thereof, solvates thereof or prodrugs thereof are applied to preparation of medicines for treating cell proliferation diseases.
7. Use of a compound according to claim 6, characterized in that: the cell proliferation diseases are selected from cancer, infection, inflammation or autoimmune diseases.
8. Use of a compound according to claim 7, characterized in that: the cancer is selected from colon cancer, liver cancer, lymphoma, lung cancer, esophageal cancer, breast cancer, central nervous system tumor, melanoma, skin cancer, ovarian cancer, cervical cancer, renal cancer, leukemia, prostate cancer, pancreatic cancer, bladder cancer, rectal cancer, osteosarcoma, nasopharyngeal cancer or gastric cancer.
9. A pharmaceutical composition characterized by: containing a therapeutically effective amount of a compound of any one of claims 1 to 6, or an isomer thereof, or a pharmaceutically acceptable salt, solvate or prodrug thereof, in combination with one or more pharmaceutically acceptable carriers or excipients.
10. Use of the pharmaceutical composition according to claim 9 for the preparation of a medicament for the treatment of a cell proliferative disorder.
CN201911084758.7A 2019-11-08 2019-11-08 Quinazoline compound and application thereof Active CN112778217B (en)

Priority Applications (1)

Application Number Priority Date Filing Date Title
CN201911084758.7A CN112778217B (en) 2019-11-08 2019-11-08 Quinazoline compound and application thereof

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
CN201911084758.7A CN112778217B (en) 2019-11-08 2019-11-08 Quinazoline compound and application thereof

Publications (2)

Publication Number Publication Date
CN112778217A true CN112778217A (en) 2021-05-11
CN112778217B CN112778217B (en) 2024-01-26

Family

ID=75748065

Family Applications (1)

Application Number Title Priority Date Filing Date
CN201911084758.7A Active CN112778217B (en) 2019-11-08 2019-11-08 Quinazoline compound and application thereof

Country Status (1)

Country Link
CN (1) CN112778217B (en)

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN114031563A (en) * 2021-12-01 2022-02-11 武汉科技大学 Cyclobutylquinoxaline compound and application thereof

Citations (13)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1996009294A1 (en) * 1994-09-19 1996-03-28 The Wellcome Foundation Limited Substituted heteroaromatic compounds and their use in medicine
US6143764A (en) * 1995-11-07 2000-11-07 Kirin Beer Kabushiki Kaisha Quinoline and quinazoline derivatives inhibiting platelet-derived growth factor receptor autophosphorylation and pharmaceutical compositions containing the same
US20020147214A1 (en) * 1996-07-13 2002-10-10 Cockerill George Stuart Heterocyclic compounds
CN1391562A (en) * 1999-09-21 2003-01-15 阿斯特拉曾尼卡有限公司 Quinazoline derivatives as pharmaceuticals
WO2005070929A1 (en) * 2004-01-23 2005-08-04 Amgen Inc. Vanilloid receptor ligands and their use in treatments
WO2006117570A1 (en) * 2005-05-05 2006-11-09 Chroma Therapeutics Ltd Quinoline derivatives as kinase enzyme inhibitors
CN101166726A (en) * 2005-05-05 2008-04-23 色品疗法有限公司 Quinoline and quinoxaline derivatives as inhibitors of kinase enzymatic activity
CN101558055A (en) * 2007-03-14 2009-10-14 美国爱德程实验室有限公司 Spiro substituted compounds as angiogenesis inhibitors
WO2009140549A1 (en) * 2008-05-14 2009-11-19 Amgen Inc. Combinations vegf(r) inhibitors and hepatocyte growth factor (c-met) inhibitors for the treatment of cancer
CN102317269A (en) * 2009-02-11 2012-01-11 默克专利有限公司 Novel amino azaheterocyclic carboxamides
WO2016022626A1 (en) * 2014-08-06 2016-02-11 Merck Sharp & Dohme Corp. Heterocyclic cgrp receptor antagonists
US20170355678A1 (en) * 2003-09-26 2017-12-14 Exelixis, Inc. C-Met Modulators and Methods of Use
CN110372666A (en) * 2018-04-13 2019-10-25 华东理工大学 Quinazoline compounds are as tri- inhibition from mutation agent of EGFR and its application

Patent Citations (13)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1996009294A1 (en) * 1994-09-19 1996-03-28 The Wellcome Foundation Limited Substituted heteroaromatic compounds and their use in medicine
US6143764A (en) * 1995-11-07 2000-11-07 Kirin Beer Kabushiki Kaisha Quinoline and quinazoline derivatives inhibiting platelet-derived growth factor receptor autophosphorylation and pharmaceutical compositions containing the same
US20020147214A1 (en) * 1996-07-13 2002-10-10 Cockerill George Stuart Heterocyclic compounds
CN1391562A (en) * 1999-09-21 2003-01-15 阿斯特拉曾尼卡有限公司 Quinazoline derivatives as pharmaceuticals
US20170355678A1 (en) * 2003-09-26 2017-12-14 Exelixis, Inc. C-Met Modulators and Methods of Use
WO2005070929A1 (en) * 2004-01-23 2005-08-04 Amgen Inc. Vanilloid receptor ligands and their use in treatments
CN101166726A (en) * 2005-05-05 2008-04-23 色品疗法有限公司 Quinoline and quinoxaline derivatives as inhibitors of kinase enzymatic activity
WO2006117570A1 (en) * 2005-05-05 2006-11-09 Chroma Therapeutics Ltd Quinoline derivatives as kinase enzyme inhibitors
CN101558055A (en) * 2007-03-14 2009-10-14 美国爱德程实验室有限公司 Spiro substituted compounds as angiogenesis inhibitors
WO2009140549A1 (en) * 2008-05-14 2009-11-19 Amgen Inc. Combinations vegf(r) inhibitors and hepatocyte growth factor (c-met) inhibitors for the treatment of cancer
CN102317269A (en) * 2009-02-11 2012-01-11 默克专利有限公司 Novel amino azaheterocyclic carboxamides
WO2016022626A1 (en) * 2014-08-06 2016-02-11 Merck Sharp & Dohme Corp. Heterocyclic cgrp receptor antagonists
CN110372666A (en) * 2018-04-13 2019-10-25 华东理工大学 Quinazoline compounds are as tri- inhibition from mutation agent of EGFR and its application

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
PATRICK A. PLÉ，等: "Discovery of AZD2932, a new Quinazoline Ether Inhibitor with high affinity for VEGFR-2 and PDGFR tyrosine kinases", BIOORGANIC & MEDICINAL CHEMISTRY LETTERS *
SERAFIN, BARBARA等: "Synthesis and fungistatic activity of aryloxyquinazoline derivatives", EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY *

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN114031563A (en) * 2021-12-01 2022-02-11 武汉科技大学 Cyclobutylquinoxaline compound and application thereof

Also Published As

Publication number Publication date
CN112778217B (en) 2024-01-26

Similar Documents

Publication Publication Date Title
RU2537319C2 (en) Method for making and prescribing sphaelactone derivate and its composites
US10011614B2 (en) Bis-β-carboline compound and preparation method, pharmaceutical composition and use thereof
JP2010540471A (en) Gambogic acid glycoside derivatives and analogs, and their production and application
CN102796124A (en) Di-beta-carboline alkali compound and preparation method, medicinal composition and application thereof
CN104163823B (en) camptothecin and artesunate conjugate as well as preparation method and application thereof
ES2831021T3 (en) Quinazoline derivative
EP2826474B1 (en) Use of substituted diphenylamine compounds in preparing anti-tumour drugs
CN112778217B (en) Quinazoline compound and application thereof
CN111171018B (en) Chalcone compound and application thereof
CN102688234B (en) Indolone derivatives is as the Synthesis and application of RSK2 inhibitor
CN103965175A (en) 4-(substituted phenylamino)quinazoline compounds, and preparation method and application thereof
CN101691384B (en) Phosphate-containing toluylene compound, preparation method thereof and use thereof
JP2015506990A (en) Method for preparing aqueous nanoparticle suspensions of derivatives of 4,9-dihydroxy-naphtho [2,3-b] furan aliphatic acid ester
ES2898026T3 (en) N-{3-[3-cyclopropyl-5-(2-fluoro-4-iodophenylamino)-6,8-dimethyl-2,4,7-trioxo-3,4,6,7-tetrahydro-dimethylsulfoxide solvate 2H-pyrido[4,3-d]pyrimidin-1-yl]-phenyl}-cyclopropanecarboxamide as MEK1/2 inhibitor
CN103755695B (en) A kind of amides and application thereof with anti-tumor activity
CN108164476B (en) Isophthalonitrile compound, application thereof and medicine containing compound
CN111171044B (en) Thienopyrimidine compound and medical application thereof
CN109928935B (en) Anilino pyrimidine compound and medical application thereof
CN104672213A (en) Amide compound with antitumor activity, and application thereof
CN110981865B (en) Medicine for treating brain glioma and preparation method thereof
CN105503865A (en) Novel pyrazolopyridine antineoplastic compound
CN111732597A (en) Preparation and application of 2-aminopyrimidine heterocyclic compound containing 4-amidophenoxy
CN103772374B (en) A kind of heterocyclic compound and application thereof
CN103301103B (en) Application of cyano-containing diphenylamine compound to preparation of antitumor drugs
CN111285900B (en) Coupling molecule DCZ0847 compound based on pterostilbene and apocynin, preparation method and application thereof

Legal Events

Date Code Title Description
PB01 Publication
PB01 Publication
SE01 Entry into force of request for substantive examination
SE01 Entry into force of request for substantive examination
GR01 Patent grant
GR01 Patent grant