CN107033138B - A kind of drug for treating malignant tumour - Google Patents

A kind of drug for treating malignant tumour Download PDF

Info

Publication number
CN107033138B
CN107033138B CN201710434900.0A CN201710434900A CN107033138B CN 107033138 B CN107033138 B CN 107033138B CN 201710434900 A CN201710434900 A CN 201710434900A CN 107033138 B CN107033138 B CN 107033138B
Authority
CN
China
Prior art keywords
formula
fluoro
drug
cancer
thiazole
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.)
Expired - Fee Related
Application number
CN201710434900.0A
Other languages
Chinese (zh)
Other versions
CN107033138A (en
Inventor
徐晓东
高丽华
徐美玲
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.)
Xu Xiaodong
Original Assignee
Individual
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 Individual filed Critical Individual
Priority to CN201810313203.4A priority Critical patent/CN108690012A/en
Priority to CN201710434900.0A priority patent/CN107033138B/en
Publication of CN107033138A publication Critical patent/CN107033138A/en
Application granted granted Critical
Publication of CN107033138B publication Critical patent/CN107033138B/en
Expired - Fee Related legal-status Critical Current
Anticipated expiration legal-status Critical

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/04—Antibacterial agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Communicable Diseases (AREA)
  • Oncology (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Nitrogen And Oxygen Or Sulfur-Condensed Heterocyclic Ring Systems (AREA)

Abstract

The invention discloses a kind of drug for treating malignant tumour, chemical constitution is formula（Ⅱ）.Malignant tumour can be lung cancer, liver cancer, neurogliocytoma, adenocarcinoma ovaries, breast cancer or chronic myelogenous leukemia.The present invention enriches treating malignant tumor compound library, plays the role of energetically to the treatment of cancer.

Description

A kind of drug for treating malignant tumour
Technical field
The present invention relates to a kind of drugs for treating malignant tumour.
Background technology
Cancer is a kind of high malignant disease of death rate, and treatment difficulty is high, and the death rate is brought heavy to patient and family Burden.In recent years, China's cancer incidence significantly increases, and prevention and control of cancer is made to be faced with severe situation.In recent years, China Cancer incidence is in trend is gradually increasing, by the extensive concern of personages of various circles of society.It shows according to research reports, in 20 generation It records the seventies, China's Cancer in China increases to 22.32% by 10.13%, and dead increment rate is 82.11%.Cancer is that come city dead First died, second is arranged as in rural area.Especially aging increasingly aggravates now, smoking, dietary structure variation, micro- life Object infection, fat, activity is reduced, the factors such as bad of working and resting are to lead to the generation main cause of cancer.The especially overweight rate in China And obesity rates are significantly more than 50%.At present come China's cancer top ten be：Lung cancer, gastric cancer, colorectal cancer, liver cancer, oesophagus Cancer, women with breast cancer, cancer of pancreas, lymph cancer, carcinoma of urinary bladder and thyroid cancer.Lung cancer is city male's common disease, and breast cancer is Urban Women common cancer；Gastric cancer is that rural area men and women morbidity is the first, and lung cancer mortality occupies highest order.The exploitation of cancer drug is grown It has been always the hot spot of research and development since phase, chemical classes drug and biological species drug fall over each other to contend, but new effective malignant tumour Medicine is still in urgent need.
Gram-positive bacteria is important the staphylococcus aureus of clinical infection pathogen, particularly methicillin-resistant (MRSA) it is bloodstream infection and the Main Pathogenic Bacteria of other severe nosocomial infections.Methicillin-resistant staphylococcus aureus（MRSA） With multi-drug resistant, to penicillins, cephalosporins, chloramphenicol, lincomycin, aminoglycoside, Tetracyclines, big ring Lactone and quinolione class are insensitive.Retrospective study shows that the bacteremic death rate (35.3%) is much high caused by MRSA The bacteremic death rate (8.8%) caused by Methicillin Sensitive Staphylococcus aureus (MSSA).Vancomycin is treatment The choice drug of MRSA infection, but its adverse drug reaction limits it in clinical application.Develop novel anti-gram sun Property bacterium drug be antibiotic exploitation vital task.
Invention content
The purpose of the present invention is to provide a kind of drug for treating malignant tumour, chemical constitution is formula（Ⅰ）Or formula（Ⅱ）
Wherein, R is、、、OrIn one kind.
Wherein, * C atom adjacents are bonding atom.
Another object of the present invention is to provide a kind of drug for treating the microbial infection of Gram-positive, chemistry knot Structure is above-mentioned formula（Ⅰ）Or formula（Ⅱ）.
Further, a kind of drug for treating the caused infection of MRSA is provided, chemical constitution is above-mentioned formula（Ⅰ）Or formula （Ⅱ）.
Further, formula（Ⅰ）Or formula（Ⅱ）The compound of expression, its salt or its solvated compounds.
Another object of the present invention is to provide chemical constitution as formula（Ⅰ）Or formula（Ⅱ）Synthetic route：
Wherein, R is、、、OrIn one kind.
Another object of the present invention is to provide a kind of pharmaceutical composition, described pharmaceutical composition includes a effective amount of formula （Ⅰ）Or formula（Ⅱ）And pharmaceutically acceptable carrier,
Wherein, R is、、、OrIn one kind.
Further, described pharmaceutical composition is used to treat the microbial infection of malignant tumour, Gram-positive.
Further, described pharmaceutical composition is capsule, tablet, pill, powder, granule or injection.It is preferred that：Piece Agent, capsule or injection.
Further, the pharmaceutically acceptable carrier is filler or bulking agent, adhesive, moisturizer, disintegrant, delays One or more of solvent, absorbsion accelerator, wetting agent, adsorbent, lubricant, PH conditioning agents.
The present invention is not to formula（Ⅰ）Or formula（Ⅱ）Or include formula（Ⅰ）Or formula（Ⅱ）Composition method of application carry out it is special It does not limit, representative method of application includes（But it is not limited to）：Oral, parenteral（Intravenously, intramuscular or subcutaneous）, drawn game Portion is administered.Include capsule, tablet, pill, powder and granule for the solid dosage forms of oral medication.In these solid dosage forms In, formula（Ⅰ）Or formula（Ⅱ）With at least one conventional inert excipients（Or carrier）Mixing, such as sodium citrate or Dicalcium Phosphate or It is mixed with following compositions：（a）Filler or bulking agent, such as starch, lactose, sucrose, glucose, mannitol and silicic acid；（b）Bonding Agent, such as hydroxymethyl cellulose, alginates, gelatin, polyvinylpyrrolidone, sucrose and Arabic gum；（c）Moisturizer, example Such as glycerine；（d）Disintegrant, such as agar, calcium carbonate, potato starch or tapioca, alginic acid, certain composition silicates, carbon Sour sodium；（e）Retarding solvent, such as paraffin；（f）Absorbsion accelerator, such as quaternary ammonium compound；（g）Wetting agent, such as cetanol and list Tristerin；（h）Adsorbent, such as kaolin；（i）Lubricant, such as talcum, calcium stearate, magnesium stearate, solid gather Ethylene glycol, lauryl sodium sulfate.In capsule, tablet and pill, dosage form also may include buffer.
Wherein, gastrointestinal administration preparation is presently the most common administration form, and convenient experimental operation, therefore, this hair Gastric infusion is used in bright specific embodiment into line（Ⅰ）Or formula（Ⅱ）The test of pesticide effectiveness, it is not intended that, formula（Ⅰ）Or Formula（Ⅱ）Administration form be only limitted to gastrointestinal administration, those skilled in the art can be according to formula（Ⅰ）Or formula（Ⅱ）It is physico Property is learned, with reference to Modern preparations technology and the actual needs of sufferer, is prepared into injection, scalp absorbable preparation, implantation system The several formulations such as agent so as to expand its administration route, and improve target-oriented drug or effectively avoid unnecessary toxic side effect.
Liquid formulation for oral administration includes pharmaceutically acceptable lotion, solution, suspension, syrup or tincture. In addition to active ingredient beyond the region of objective existence, liquid dosage form may include the inert diluent routinely used in this field, such as water or other solvents, increase Solvent and emulsifier, example know ethyl alcohol, isopropanol, ethyl carbonate, ethyl acetate, propylene glycol, 1,3-BDO, dimethylformamide And oil, the particularly mixture of cottonseed oil, peanut oil, maize germ, olive oil, castor oil and sesame oil or these substances Deng.
Other than these inert diluents, composition also may include auxiliary agent, such as wetting agent, emulsifier and suspending agent, sweet taste Agent, corrigent and fragrance.
In addition to active ingredient beyond the region of objective existence, suspension may include suspending agent, such as ethoxylation isooctadecane alcohol, polyoxyethylene mountain Pears alcohol and the mixture of Isosorbide Dinitrate, microcrystalline cellulose, aluminium methoxide and agar or these substances etc..
For parenteral injection composition may include physiologically acceptable sterile, aqueous or anhydrous solution, dispersion liquid, Suspension or lotion with for re-dissolving into the aseptic powdery of sterile Injectable solution or dispersion liquid.It is suitable aqueous and Nonaqueous carrier, diluent, solvent or excipient include water, ethyl alcohol, polyalcohol and its suitable mixture.
Dosage form for the compounds of this invention of local administration includes ointment, powder, patch, propellant and inhalant. Active constituent aseptically with that physiologically acceptable carrier and any preservative, buffer or may need when necessary Propellant be mixed together.
The compounds of this invention can be administered alone or with other pharmaceutically acceptable other drugs administering drug combinations.
The present invention provides a kind of drugs for treating malignant tumour, treating malignant tumor compound library are enriched, to cancer Treatment play the role of energetically.
The present invention provides a kind of drug for treating the microbial infection of Gram-positive, feel caused by especially MRSA Dye, to Gram-positive, positive effect is played in the treatment of microbial infection.
Specific embodiment
Embodiment 1：The synthesis of the fluoro- quinoxalinyl -6- secondary amine of 2- thiazole methyl -4- phenyl -7-
Synthetic route is：
Synthesis step：
The synthesis of the fluoro- quinazolyl -6- amine of the chloro- 7- of 1-1 4-
40 ml methanols and tetrahydrofuran will be added in the fluoro- 6- nitro-quinazolins of the chloro- 7- of 4- (10 mmol)（Volume ratio 3: 1）In the mixed solvent stirs 20 minutes, then Quan Rong is cooled to 0-5 DEG C, adds in 1 gram of sodium borohydride thereto, keeps temperature Then stirring two hours is warmed to room temperature and continues stirring 4 hours, 40 milliliters of water are added in into reaction, is extracted with 50 milliliters of ethyl acetate It takes, organic phase is dried 2 hours with anhydrous sodium sulfate, filtering, is evaporated organic solvent, and 50 DEG C of vacuum drying obtain 1.8 grams of yellow and consolidate Fluoro- quinazolyl -6- the amine of the chloro- 7- of body, as 4-, yield 91%.1H-NMR (400 MHz, CDCl3) δ: 6.94(m,2H), 7.04(s,2H), 9.56(s,1H). 13C-NMR (75 MHz, CDCl3) δ: 110.66, 111.08, 126.39, 140.34, 149.10, 150.45, 151.31, 155.42.
The synthesis of the fluoro- quinoxalinyl -6- imines of the 1-2 chloro- 7- of 2- thiazole methene -4-
By the fluoro- quinazolyl -6- amine of the chloro- 7- of 4-（10 mmol）With 2- thiazole carboxaldehydes（11 mmol）It is dissolved in 40 ml methanol In, it flows back 2 hours, is then down to room temperature, water is added in into system（50 ml）, extracted with 50 ml dichloromethane, anhydrous slufuric acid Sodium dries organic phase, removes solvent under reduced pressure, and residue is beaten with water, filtering, 50 DEG C of vacuum drying.Obtain 2.7 grams of yellow 2- thiophenes Fluoro- quinoxalinyl -6- imines the solids of the chloro- 7- of azoles methene -4-, yield 92%.13C-NMR (75 MHz, CDCl3) δ: 108.4, 115.35, 122.83, 126.81, 135.49, 139.68, 142.87, 151.12, 151.48, 153.89, 155.11, 155.88.
The synthesis of the fluoro- quinoxalinyl -6- secondary amine of the chloro- 7- of 1-3 2- thiazole methyls -4-
By the fluoro- quinoxalinyl -6- imines of the chloro- 7- of 2- thiazole methene -4-（10 mmol）It is dissolved in 40 ml methanol, then adds Enter 5 milliliters of glacial acetic acids, be cooled to 0-5 DEG C, then add in 1.2 grams of sodium borohydrides, low temperature 2 hours is warmed to room temperature continuation Half an hour is stirred, 100 ml water are then added in into system, is stirred 1 hour, it is white to obtain 2.1 grams of classes for filtering, 50 DEG C of vacuum drying Color solid, the as fluoro- quinoxalinyl -6- secondary amine of the chloro- 7- of 2- thiazole methyls -4-, two step yields totally 71%.1H-NMR (400 MHz, CDCl3) δ: 4.37(s,2H), 6.96(t,2H), 7.17(d,1H), 7.62(d,1H), 8.05(s,1H), 9.52(s,1H). 13C-NMR (75 MHz, CDCl3) δ: 39.76, 109.58, 109.84, 117.16, 126.62, 137.87, 139.57, 147.09, 150.76, 151.37, 155.64, 164.92.
The synthesis of the fluoro- quinoxalinyl -6- secondary amine of 1-4 2- thiazole methyl -4- phenyl -7-
By the fluoro- quinoxalinyl -6- secondary amine of the chloro- 7- of 2- thiazole methyls -4-（10 mmol）It is dissolved in 30 milliliters of nitrogen nitrogen dimethyl methyls In amide, system rouses argon gas 20 minutes, then the air in emptying system adds in tetra-triphenylphosphine palladium, is warming up to 60 DEG C, after Continuous stirring half an hour, phenyl boric acid (12 mmol) is added in thereto, 10 milliliters of sodium carbonate (1 gram) aqueous solution is added, is warming up to 90 DEG C, it stirs 5 hours, whole process holding is passed through argon gas, then cools down, removes solvent under reduced pressure, solid is obtained quickly through chromatographic column To 3.2 grams of off-white powders, the as fluoro- quinoxalinyl -6- secondary amine of 2- thiazole methyls -4- phenyl -7-, yield 95%.1H-NMR (400 MHz, CDCl3) δ:3.93(s,1H), 4.40(d,2H), 7.14(d,1H), 7.20(d,1H), 7.49(m, 1H), 7.65(m,4H), 7.79(m,2H), 9.33(s,1H). 13C-NMR (75 MHz, CDCl3) δ: 39.76, 107.95, 109.44, 117.16, 124.54, 128.34, 128.99, 130.56, 133.03, 136.58, 139.57, 149.34, 149.79, 155.81, 162.97, 164.92.m/z: 336.08 (100.0%), 337.09 (19.6%), 338.08 (4.8%).
Embodiment 2：The synthesis of 2- thiazole methyls -4- (2- naphthalene sweet smell base) fluoro- quinoxalinyl -6- secondary amine of -7-
1-4 in synthetic method such as embodiment 1, by the fluoro- quinoxalinyl -6- secondary amine of the chloro- 7- of 2- thiazole methyls -4-（10 mmol）It is dissolved in 30 milliliters of N,N-Dimethylformamides, system drum argon gas 20 minutes, the air in emptying system, Ran Houjia Enter tetra-triphenylphosphine palladium, be warming up to 60 DEG C, continue to stir half an hour, add in 2- naphthalene boronic acids (12 mmol) thereto, add 10 Milliliter sodium carbonate (1 gram) aqueous solution, is warming up to 90 DEG C, stirs 5 hours, and whole process holding is passed through argon gas, then cools down, and depressurizes Be evaporated off solvent, solid quickly through chromatographic column,
Obtain 3.4 grams of off-white color 2- thiazole methyls -4- (2- naphthalene sweet smell base) fluoro- quinoxalinyl -6- secondary amine solids of -7-, yield 88%。1H-NMR (400 MHz, CDCl3) δ: 3.92(s,1H), 4.40(d,2H), 7.18(d,1H), 7.20(d,1H), 7.57-7.66(m,4H), 7.98-8.06(m,4H), 8.46(t,1H), 9.33(t,1H). 13C-NMR (75 MHz, CDCl3) δ: 39.76, 107.95, 109.44, 117.16, 124.32, 125.91, 126.64, 127.55, 127.59, 129.46, 131.75, 133.03, 134.11, 134.44, 136.86, 139.57, 149.26, 149.38, 155.81, 163.46, 164.92.m/z: 386.10 (100.0%), 387.10 (26.1%), 388.10 (5.1%)。
Embodiment 3：The synthesis of 4- [the fluoro- 6- of 7- (2- thiazole methylamines base)] quinoxalinyl-benzonitrile
1-4 in synthetic method such as embodiment 1, by the fluoro- quinoxalinyl -6- secondary amine of the chloro- 7- of 2- thiazole methyls -4-（10 mmol）It is dissolved in 30 milliliters of N,N-Dimethylformamides, system drum argon gas 20 minutes, the air in emptying system, Ran Houjia Enter tetra-triphenylphosphine palladium, be warming up to 60 DEG C, continue to stir half an hour, be added in thereto to itrile group phenyl boric acid (12 mmol), then add Entering 10 milliliters of sodium carbonate (1 gram) aqueous solution, be warming up to 90 DEG C, stir 5 hours, whole process holding is passed through argon gas, then cools down, Remove solvent under reduced pressure, solid obtains 3.3 grams of light yellow 4- [the fluoro- 6- of 7- (2- thiazole methylamines base)] quinolines quickly through chromatographic column Quinoline base-benzonitrile solid, yield 91%.1H-NMR (400 MHz, CDCl3) δ: 3.93(s,1H), 4.41(s,2H), 7.12(d,1H), 7.20(d,1H), 7.65(d,1H), 7.66(d,1H), 7.91-7.95(m,4H), 9.41(s,1H).13C-NMR (75 MHz, CDCl3) δ:39.76, 107.95, 109.44, 117.15, 117.16, 118.94, 124.54, 131.1, 133.02, 133.03, 139.57, 141.53, 149.34, 149.79, 155.81, 162.97, 164.92.m/z: 361.08 (100.0%), 362.08 (23.2%).
Embodiment 4：The synthesis of the fluoro- quinoxalinyl -6- secondary amine of 2- thiazole methyl -4- p-isopropyl phenyl -7-
1-4 in synthetic method such as embodiment 1, by the fluoro- quinoxalinyl -6- secondary amine of the chloro- 7- of 2- thiazole methyls -4-（10 mmol）It is dissolved in 30 milliliters of N,N-Dimethylformamides, system drum argon gas 20 minutes, the air in emptying system, Ran Houjia Enter tetra-triphenylphosphine palladium, be warming up to 60 DEG C, continue to stir half an hour, add in p-isopropyl phenyl boric acid (12 mmol) thereto, then 10 milliliters of sodium carbonate (1 gram) aqueous solutions are added in, are warming up to 90 DEG C, are stirred 5 hours, whole process holding is passed through argon gas, then drops Temperature, removes solvent under reduced pressure, solid quickly through chromatographic column, obtain 3.5 grams of light yellow 2- thiazole methyls -4- p-isopropyls phenyl - Fluoro- quinoxalinyl -6- secondary amine the solids of 7-, yield 93%.1H-NMR (400 MHz, CDCl3) δ: 1.20(d,6H), 2.87 (m,1H), 3.91(s,1H), 4.40(s,2H), 7.13(d,1H), 7.20(d,1H), 7.57-7.65(m,6H), 9.29 (s,1H). 13C-NMR (75 MHz, CDCl3) δ: 23.38, 33.96, 39.76, 107.95, 109.44, 117.16, 124.4, 124.54, 131.31, 131.65, 133.03, 139.57, 149.34, 149.79, 151.02, 155.81, 162.97, 164.92.m/z: 378.13 (100.0%), 379.13 (25.0%), 380.13 (5.1%).
Embodiment 5：The synthesis of the fluoro- quinoxalinyl -6- secondary amine of 2- thiazole methyls -4- (3,5 difluorophenyl) -7-
1-4 in synthetic method such as embodiment 1, by the fluoro- quinoxalinyl -6- secondary amine of the chloro- 7- of 2- thiazole methyls -4-（10 mmol）It is dissolved in 30 milliliters of N,N-Dimethylformamides, system drum argon gas 20 minutes, the air in emptying system, Ran Houjia Enter tetra-triphenylphosphine palladium, be warming up to 60 DEG C, continue to stir half an hour, add in 3,5 difluoro phenyl boric acids (12 mmol) thereto, then 10 milliliters of sodium carbonate (1 gram) aqueous solutions are added in, are warming up to 90 DEG C, are stirred 5 hours, whole process holding is passed through argon gas, then drops Temperature, removes solvent under reduced pressure, and solid obtains 3.1 grams of yellow 2- thiazole methyls -4- (3,5 difluorophenyl) -7- quickly through chromatographic column Fluoro- quinoxalinyl -6- secondary amine solids, yield 83%.1H-NMR (400 MHz, CDCl3) δ: 3.94(s,1H), 4.40(d, 2H), 6.99(tt,1H), 7.11(d,1H), 7.20(d,1H), 7.29(m,2H), 7.65(d,2H), 9.35(s,1H).13C-NMR (75 MHz, CDCl3) δ: 39.76, 105.25, 107.95, 109.44, 111.47, 117.16, 124.49, 133.03, 133.12, 139.57, 149.43, 149.96, 155.81, 162.29, 164.92, 166.36. m/z: 372.07 (100.0%), 373.07 (20.4%), 374.07 (2.2%).
Embodiment 6：The synthesis of the fluoro- quinoxalinyl -6- imines of 2- thiazole methene -4- phenyl -7-
Synthesis step first two steps 6-1 and 6-2 distinguish the first two steps 1-1 and 1-2 of 1 synthesis step of corresponding embodiment.
The synthesis of the fluoro- quinoxalinyl -6- imines of 6-3 2- thiazole methene -4- phenyl -7-
Reaction method of the synthetic method described in 1-4 in embodiment 1, by the fluoro- quinoxalines of the 2- chloro- 7- of thiazole methene -4- Base -6- imines（10 mmol）It is dissolved in 30 milliliters of N,N-Dimethylformamides, system drum argon gas 20 minutes, in emptying system Air, then add in tetra-triphenylphosphine palladium, be warming up to 60 DEG C, continue stir half an hour, thereto add in phenyl boric acid (12 Mmol), 10 milliliters of sodium carbonate (1 gram) aqueous solution is added, is warming up to 90 DEG C, is stirred 5 hours, whole process holding is passed through argon Then gas cools down, remove solvent under reduced pressure, and solid obtains 3.1 grams of off-white color 2- thiazole methene -4- benzene quickly through chromatographic column Fluoro- quinoxalinyl -6- imines the solids of base -7-, yield 93%.1H-NMR (400 MHz, CDCl3) δ: 7.39-7.52(m, 2H), 7.62-7.68(m,2H), 7.75-7.86(m,4H), 8.03(d,1H), 9.33(s,1H). 13C-NMR (75 MHz, CDCl3) δ: 106.72, 116.24, 122.83, 124.57, 128.34, 128.99, 130.56, 132.15, 136.58, 139.68, 142.87, 149.38, 150.16, 155.11, 159.68, 163.31. m/z: 334.07 (100.0%), 335.07 (21.7%), 336.06 (4.5%).
Embodiment 7：The synthesis of 2- thiazole methenes -4- (2- naphthalene sweet smell base) fluoro- quinoxalinyl -6- imines of -7-
Reaction method of the synthetic method described in 6-3 in embodiment 6, by the fluoro- quinoxalines of the 2- chloro- 7- of thiazole methene -4- Base -6- imines（10 mmol）It is dissolved in 30 milliliters of N,N-Dimethylformamides, system drum argon gas 20 minutes, in emptying system Air, then add in tetra-triphenylphosphine palladium, be warming up to 60 DEG C, continue to stir half an hour, add in 2- naphthalene boronic acids (12 thereto Mmol), 10 milliliters of sodium carbonate (1 gram) aqueous solution is added, is warming up to 90 DEG C, is stirred 5 hours, whole process holding is passed through argon Then gas cools down, remove solvent under reduced pressure, and solid obtains 3.3 grams of faint yellow 2- thiazoles methene -4- (2- quickly through chromatographic column Naphthalene sweet smell base) the fluoro- quinoxalinyl -6- imines solids of -7-, yield 86%.1H-NMR (400 MHz, CDCl3) δ: 7.41(d, 1H), 7.53-7.65(m,2H), 7.77-7.86(m,2H), 7.96-8.11(m,5H), 8.30(s,1H), 8.46(t, 1H), 9.31(s,1H). 13C-NMR (75 MHz, CDCl3) δ: 106.72, 116.24, 122.83, 124.26, 125.91, 125.91, 126.64, 127.55, 127.59, 129.46, 131.75, 132.15, 134.11, 134.44, 136.86, 139.68, 142.87, 149.3, 149.76, 155.11, 159.68, 163.85. m/z: 384.08 (100.0%), 385.09 (23.9%).
Embodiment 8：The synthesis of 2- thiazoles methene -4- quinoxalinyl -6- imines fluoro- to cyano-phenyl -7-
Reaction method of the synthetic method described in 6-3 in embodiment 6, by the fluoro- quinoxalines of the 2- chloro- 7- of thiazole methene -4- Base -6- imines（10 mmol）It is dissolved in 30 milliliters of N,N-Dimethylformamides, system drum argon gas 20 minutes, in emptying system Air, then add in tetra-triphenylphosphine palladium, be warming up to 60 DEG C, continue stir half an hour, added in thereto to cyanophenylboronic acid (12 mmol) adds 10 milliliters of sodium carbonate (1 gram) aqueous solution, is warming up to 90 DEG C, stirs 5 hours, and whole process holding is passed through Then argon gas cools down, remove solvent under reduced pressure, and solid obtains 3.0 grams of -4- pairs of yellow 2- thiazoles methenes quickly through chromatographic column Fluoro- quinoxalinyl -6- imines the solids of cyano-phenyl -7-, yield 84%.1H-NMR (400 MHz, CDCl3) δ: 7.33(d, 1H), 7.69-7.94(m,7H), 8.24(s,1H). 13C-NMR (75 MHz, CDCl3) δ: 106.72, 116.24, 117.15, 118.94, 122.83, 124.57, 131.1, 132.15, 133.02, 139.68, 141.53, 142.87, 149.38, 150.16, 155.11, 159.68, 163.31. m/z: 359.06 (100.0%), 360.07 (20.7%), 361.06 (4.9%).
Embodiment 9：The synthesis of the fluoro- quinoxalinyl -6- imines of 2- thiazole methene -4- p-isopropyl phenyl -7-
Reaction method of the synthetic method described in 6-3 in embodiment 6, by the fluoro- quinoxalines of the 2- chloro- 7- of thiazole methene -4- Base -6- imines（10 mmol）It is dissolved in 30 milliliters of N,N-Dimethylformamides, system drum argon gas 20 minutes, in emptying system Air, then add in tetra-triphenylphosphine palladium, be warming up to 60 DEG C, continue stir half an hour, thereto add in cumic aldehyde boron Sour (12 mmol), adds 10 milliliters of sodium carbonate (1 gram) aqueous solution, is warming up to 90 DEG C, stirs 5 hours, and whole process keeps logical Enter argon gas, then cool down, remove solvent under reduced pressure, solid obtains 3.1 grams of yellow 2- thiazole methenes -4- quickly through chromatographic column Fluoro- quinoxalinyl -6- imines the solids of p-isopropyl phenyl -7-, yield 82%.1H-NMR (400 MHz, CDCl3) δ: 1.20 (d,6H), 2.87(m,1H), 7.41(d,1H), 7.55-7.66(m,4H), 7.77(d,1H), 7.84(d,1H), 8.01 (d,1H), 8.34(s,1H), 9.34(s,1H). 13C-NMR (75 MHz, CDCl3) δ: 23.38, 33.96, 106.72, 116.24, 122.83, 124.4, 124.57, 131.31, 131.65, 132.15, 139.68, 142.87, 149.38, 150.16, 151.02, 155.11, 159.68, 163.31. m/z: 376.12 (100.0%), 377.12 (23.7%).
Embodiment 10：The synthesis of the fluoro- quinoxalinyl -6- imines of 2- thiazole methenes -4- (3,5 difluorophenyl) -7-
Reaction method of the synthetic method described in 6-3 in embodiment 6, by the fluoro- quinoxalines of the 2- chloro- 7- of thiazole methene -4- Base -6- imines（10 mmol）It is dissolved in 30 milliliters of N,N-Dimethylformamides, system drum argon gas 20 minutes, in emptying system Air, then add in tetra-triphenylphosphine palladium, be warming up to 60 DEG C, continue stir half an hour, add in 3,5 difluoro phenyl boric acids thereto (12 mmol) adds 10 milliliters of sodium carbonate (1 gram) aqueous solution, is warming up to 90 DEG C, stirs 5 hours, and whole process holding is passed through Then argon gas cools down, remove solvent under reduced pressure, and solid obtains 3.3 grams of glassy yellow 2- thiazole methenes -4- quickly through chromatographic column Fluoro- quinoxalinyl -6- imines the solids of (3,5 difluorophenyl) -7-, yield 89%.1H-NMR (400MHz, CDCl3) δ: 6.99 (m,1H), 7.29(m,1H), 7.41(d,1H), 7.78-7.84(m,2H), 8.00(d,1H), 8.34(s,1H), 9.28 (s,1H). 13C-NMR (75 MHz, CDCl3) δ: 105.25, 106.72, 111.47, 116.24, 122.83, 124.43, 132.15, 133.12, 139.68, 142.87, 149.49, 150.33, 155.11, 159.68, 162.63, 166.36. m/z: 370.05 (100.0%), 371.05 (21.7%), 372.05 (5.0%).
Test example 1：Mtt assay measures the inhibiting effect to different tumour cells
First, cell strain
Human lung cancer cell A549, Human hepatoma cell line Bel-7402, neuroglia cell of human oncocyte U251, people's adenocarcinoma ovaries Cell SK-OV-3, human breast cancer cell line Bcap-37, people's chronic myelogenous leukemia cell K562.
2nd, main solution is prepared：
1.PBS buffer solutions：
NaCl 8g、KCl 0.2g、Na2HPO4 1.44g、KH2PO40.24g adjusts ph 7.4, constant volume 1L.
2. trypsin solution：
0.25% trypsase+0.02%EDTA, is prepared with PBS buffer solution, and 0.22 μm of membrane filtration degerming, 4 DEG C spare.
1640 cell culture fluids of 3.RPMI：
（1）It is molten in tri-distilled water that 10.4g/ packets RPMI 1640 cultivates powder, magnetic agitation 20min；
（2）Add 2g NaHCO3, continue to stir 10min；
（3）Add penicillin solution（2×105U/mL）0.5mL, Streptomycin Solution（2× 105U/mL）0.5mL；
（4）Add 100ml inactivated fetal bovine serums；
（5）Add 1mol/L HCl, adjust PH to 7.2, constant volume 1L；
（6）Filtration sterilization.
4. test medicine gradient solution：
（1）Formula（Ⅰ）Or formula（Ⅱ）Gradient solution：Formula（Ⅰ）Or formula（Ⅱ）After being dissolved with a small amount of DMSO（Final DMSO contents exist Within 0.1%）, 128 μ g/ml are configured to 1640 cell culture fluids of RPMI, half-and-half dilution is configured to 8 concentration gradients, i.e.,： 64th, 32,16,8,4,2,1,0.5 μ g/ml, with preceding preparation.
（2）Cis-platinum gradient solution：Cisplatin injections are configured to 128 μ g/ml with 1640 cell culture fluids of RPMI, half-and-half dilute It releases and is configured to 8 concentration gradients, i.e., 128,64,32,16,8,4,2,1 μ g/ml, with preceding preparation.
3rd, experiment packet：
Medicine group to be measured（Referring to experimental procedure part）
Positive control medicine group（Compared with medicine group to be measured, the drug to be measured for adding in concentration gradient is changed to add in concentration ladder The cis-platinum of degree）
Control group（Compared with medicine group to be measured, the drug to be measured for adding in concentration gradient is changed to add in the RPMI of not drug containing 1640 cell culture fluids）
Blank group（Compared with the control group, it is not added with cell）
4th, experimental procedure：
1. the cell in growth period of taking the logarithm, trypsin digestion, 1640 cell culture fluid tune concentration of cell suspension of RPMI are 6×104A/mL.Add 100 μ L of cell suspension per hole in 96 well culture plates, put 37 DEG C, 5% CO2It is cultivated in incubator for 24 hours, carefully Born of the same parents are adherent.
2. removing 1640 cell culture fluids of RPMI, 1640 cell culture fluids of RPMI of the drug to be measured of concentration gradient are added in 100 μ L, each concentration set 6 parallel holes.96 orifice plates after dosing are placed in 37 DEG C, 5% CO248h is cultivated in incubator, is inverted The function and effect of micro- Microscopic observation drug.
Culture solution is discarded after the centrifugation of 3.96 orifice plates, after carefully being rushed 2 ~ 3 times with PBS, adds the RPMI containing 0.5% MTT 1640 cell culture fluid, 100 μ L continue to cultivate 4h.
4. removing supernatant, 150 μ L dimethyl sulfoxide (DMSO)s are added in per hole, low-speed oscillation 10min on shaking table is put, ties formazan Brilliant fully dissolving.
5. the optical density in each hole is measured at enzyme-linked immunosorbent assay instrument 490nm（OD values）.
6. parallel hole OD values are represented with mean ± SD, inhibiting rate formula is calculated：[(ODControl group-ODBlank group)-(ODDrug study group- ODBlank group)]/(ODControl group-ODBlank group)*100%。
7. using 5 data processing softwares of GraphPad Prism, by drawing amount effect curve calculation of half inhibitory concentration （IC50）.
5th, experimental result
Formula（Ⅰ）Or formula（Ⅱ）There are different degrees of In-vitro Inhibitory Effect, IC with to 6 kinds of human tumor cell lines50It is shown in Table 1. The results show that formula（Ⅰ）Or formula（Ⅱ）A drug is respectively provided with inhibitory activity to 6 kinds of human tumor cell lines.Compared with positive drug cis-platinum Compared with inhibitory activity difference is larger between different R bases, and R isOrWhen activity be higher than, so And formula（Ⅰ）Or formula（Ⅱ）Active rule unobvious, explanation further on R bases can be researched and developed between identical R bases, and selection is secondary The structure small, pharmacokinetics adapts to is acted on, does more deep research and development.
In addition, inhibition of the mass mixings such as the I d and II d object to above-mentioned 6 kinds of human tumor cell lines is measured using above-mentioned mtt assay Activity finds IC50<1μg/ml.Illustrate that I d and II d inhibits tumour cell to have synergistic effect jointly.
1 formula of table（Ⅰ）Or formula（Ⅱ）To 6 kinds of human tumor cells inhibiting effect
The experiment results show that formula（Ⅰ）Or formula（Ⅱ）It can be as the drug for the treatment of malignant tumour.Malignant tumour can be lung Cancer, liver cancer, neurogliocytoma, adenocarcinoma ovaries, breast cancer or chronic myelogenous leukemia.
Test example 2：Resazurin determination of color is to the inhibiting effect of different gram-positive bacterias
First, experimental method
First by the indicator solution of 7.5mL（The resazurin aqueous solution of 100 μ g/mL）With the bacterium solution to be measured of 5mL（108 CFU/mL）Mixing, and respectively add in 100 μ L mixed bacteria liquids into all instrument connections of the 1st ~ 8 row.Then by 100 μ L samples to be tested DMSO solution（16-500μg/mL）It is added sequentially in each plate hole of the 1st row, the solution of 100 μ L is uniformly taken out after mixing It is transferred in the 2nd corresponding plate hole of row, and the 8th row are diluted to the multiplication of same method.Finally, the orifice plate for having added sample is put Enter to constant incubator, 37 DEG C of culture 10-12h.Bacterium solution becomes red as no bacteriostatic activity, and blue is has bacteriostatic activity, bacterium solution dimension The minimum diluted concentration for holding blue is considered as the minimum inhibitory concentration of untested compound（MIC）, each sample does 2 groups and repetition It measures 3 times.Positive control is vancomycin.
2nd, experimental result
Formula（Ⅰ）Or formula（Ⅱ）To the inhibiting effect of different gram-positive bacterias, MIC value is shown in Table 2.The results show that formula（Ⅰ）Or Formula（Ⅱ）A drug is respectively provided with inhibitory activity to different gram-positive bacterias.Compared with positive drug vancomycin, different R bases it Between inhibitory activity difference it is larger, R isOrWhen activity be higher than, however formula（Ⅰ）Or formula （Ⅱ）Active rule unobvious, explanation further on R bases can be researched and developed between identical R bases, select Small side effects, and medicine moves The structure adapted to is learned, does more deep research and development.
In addition, it is necessary to it is important to note that formula（Ⅰ）Or formula（Ⅱ）Each structure is to the inhibitory activity substantially phase of MSSA and MRSA Together, illustration mechanism is different from existing drug, and MRSA does not have tolerance to each structure, in being infected caused by MRSA is treated Show especially prominent meaning.
2 formula of table（Ⅰ）Or formula（Ⅱ）To the inhibiting effect of different gram-positive bacterias
The experiment results show that formula（Ⅰ）Or formula（Ⅱ）It can be as the drug of the treatment microbial infection of Gram-positive.Formula （Ⅰ）Or formula（Ⅱ）It can be as the drug infected caused by treatment MRSA.
Obviously, the above according to the present invention according to the ordinary technical knowledge and means of this field, is not departing from this hair Under the premise of bright above-mentioned basic fundamental thought, the modification, replacement or change of other diversified forms can also be made.

Claims (4)

1. a kind of compound for treating malignant tumour, chemical constitution is formula（Ⅱ）
Wherein, R isIn one kind.
2. a kind of pharmaceutical composition for treating malignant tumour, which is characterized in that described pharmaceutical composition includes a effective amount of formula （Ⅱ）And pharmaceutically acceptable carrier,
Wherein, R isIn one kind.
A kind of 3. pharmaceutical composition for treating malignant tumour as claimed in claim 2, which is characterized in that described pharmaceutical composition For capsule, tablet, pill, powder, granule or injection.
4. a kind of pharmaceutical composition for treating malignant tumour as claimed in claim 2, which is characterized in that described pharmaceutically to connect The carrier received is filler or bulking agent, adhesive, moisturizer, disintegrant, retarding solvent, absorbsion accelerator, wetting agent, adsorbent, Lubricant, PH conditioning agents.
CN201710434900.0A 2017-06-10 2017-06-10 A kind of drug for treating malignant tumour Expired - Fee Related CN107033138B (en)

Priority Applications (2)

Application Number Priority Date Filing Date Title
CN201810313203.4A CN108690012A (en) 2017-06-10 2017-06-10 A kind of drug and its synthetic method for treating the microbial infection of Gram-positive
CN201710434900.0A CN107033138B (en) 2017-06-10 2017-06-10 A kind of drug for treating malignant tumour

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
CN201710434900.0A CN107033138B (en) 2017-06-10 2017-06-10 A kind of drug for treating malignant tumour

Related Child Applications (1)

Application Number Title Priority Date Filing Date
CN201810313203.4A Division CN108690012A (en) 2017-06-10 2017-06-10 A kind of drug and its synthetic method for treating the microbial infection of Gram-positive

Publications (2)

Publication Number Publication Date
CN107033138A CN107033138A (en) 2017-08-11
CN107033138B true CN107033138B (en) 2018-06-08

Family

ID=59542310

Family Applications (2)

Application Number Title Priority Date Filing Date
CN201710434900.0A Expired - Fee Related CN107033138B (en) 2017-06-10 2017-06-10 A kind of drug for treating malignant tumour
CN201810313203.4A Pending CN108690012A (en) 2017-06-10 2017-06-10 A kind of drug and its synthetic method for treating the microbial infection of Gram-positive

Family Applications After (1)

Application Number Title Priority Date Filing Date
CN201810313203.4A Pending CN108690012A (en) 2017-06-10 2017-06-10 A kind of drug and its synthetic method for treating the microbial infection of Gram-positive

Country Status (1)

Country Link
CN (2) CN107033138B (en)

Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2001004111A1 (en) * 1999-07-09 2001-01-18 Glaxo Group Limited Anilinoquinazolines as protein tyrosine kinase inhibitors
CN1882570A (en) * 2003-09-19 2006-12-20 阿斯利康(瑞典)有限公司 Quinazoline derivatives
CN102250075A (en) * 2010-05-21 2011-11-23 中国医学科学院药物研究所 2,4-disubstituted quinazoline compounds and preparation method, medicinal composition and application thereof
CN105358549A (en) * 2013-12-06 2016-02-24 卡尔那生物科学株式会社 Novel quinazoline derivative

Family Cites Families (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CA2534405A1 (en) * 2003-08-08 2005-02-17 Ulysses Pharmaceutical Products Inc. Halogenated quinazolinyl nitrofurans as antibacterial agents

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2001004111A1 (en) * 1999-07-09 2001-01-18 Glaxo Group Limited Anilinoquinazolines as protein tyrosine kinase inhibitors
CN1882570A (en) * 2003-09-19 2006-12-20 阿斯利康(瑞典)有限公司 Quinazoline derivatives
CN102250075A (en) * 2010-05-21 2011-11-23 中国医学科学院药物研究所 2,4-disubstituted quinazoline compounds and preparation method, medicinal composition and application thereof
CN105358549A (en) * 2013-12-06 2016-02-24 卡尔那生物科学株式会社 Novel quinazoline derivative

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
喹唑啉类化合物抗癌活性研究进展;李鹏程，等;《中国药学杂志》;20160630;第51卷(第11期);第867-874页 *

Also Published As

Publication number Publication date
CN107033138A (en) 2017-08-11
CN108690012A (en) 2018-10-23

Similar Documents

Publication Publication Date Title
CN105246887B (en) Coumarin derivative and the method for treating hyperproliferative disease
CN105461720B (en) Morpholine class tyrosine kinase inhibitor
CN103044395A (en) Desloratadine-containing amino acid derivative as well as preparation method and application thereof
CN105026388B (en) It can be used as the substituted pyridine derivate of C-fms kinase inhibitors
CN107033138B (en) A kind of drug for treating malignant tumour
CN107021960B (en) A kind of drug for treating malignant tumour
WO2017107993A1 (en) Use of polyether compound
CN111393368B (en) Indenopyrazole hydrochloride derivative and preparation method and application thereof
CN102786458B (en) Pyrrole formamide derivative, and preparation method and application thereof
CN107226815B (en) Quinazoline compounds and its application in antitumor drug
CN107880060A (en) Polyether compound purposes
CN104926804A (en) Compounds with anti-tumor effect, and preparation method and application of compounds
CN104292242A (en) Pyrantel compound and preparation, as well as preparation method and application of pyrantel compound and preparation
CN113072503B (en) Linolenic acid-metronidazole compound and preparation method and application thereof
CN102276625B (en) Thiadiazole derivative
CN103880793B (en) Containing furan imine compound and its production and use
CN110845473B (en) Inhibitor Lo-ethyl acetate for resisting staphylococcus aureus virulence and biofilm formation and application thereof
CN103304556B (en) Schiff bases compounds containing chromene, Preparation Method And The Use
CN110698457B (en) Inhibitor Lo-tert-butyl ester for resisting staphylococcus aureus virulence and biofilm formation and application thereof
CN102329327B (en) Furan derivatives and preparation method and application thereof
CN111087389B (en) Medicine for treating glioblastoma
CN106946888B (en) A kind of sulfoamido derivative and its purposes in antitumor drug is prepared
CN102358742B (en) Thiazole compound with antitumor activity
CN116407540A (en) Application of medicine in preventing and treating HER2 expression positive solid tumor
CN102276626A (en) Isoxazole-containing compound

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
CB03 Change of inventor or designer information

Inventor after: Xu Xiaodong

Inventor after: Gao Lihua

Inventor after: Xu Meiling

Inventor before: Cao Yan

CB03 Change of inventor or designer information
TA01 Transfer of patent application right

Effective date of registration: 20180503

Address after: 266700 oncology department, Pingdu Municipal People's Hospital, 112 Yangzhou Road, Pingdu City, Qingdao, Shandong

Applicant after: Xu Xiaodong

Address before: 261053 northward 160 meters Road East of Xuanwu Street and Yuhe Road intersection in Kuiwei District, Weifang, Shandong

Applicant before: Cao Yan

TA01 Transfer of patent application right
GR01 Patent grant
GR01 Patent grant
CF01 Termination of patent right due to non-payment of annual fee

Granted publication date: 20180608

Termination date: 20190610

CF01 Termination of patent right due to non-payment of annual fee