CN107021960B - A kind of drug for treating malignant tumour - Google Patents
A kind of drug for treating malignant tumour Download PDFInfo
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- CN107021960B CN107021960B CN201710434901.5A CN201710434901A CN107021960B CN 107021960 B CN107021960 B CN 107021960B CN 201710434901 A CN201710434901 A CN 201710434901A CN 107021960 B CN107021960 B CN 107021960B
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- 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
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- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/04—Antibacterial agents
Abstract
The invention discloses a kind of drug for treating malignant tumour, chemical constitution is formula（Ⅰ）.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
Technical field
The present invention relates to a kind of drugs for treating malignant tumour.
Background technology
Cancer is a kind of malignant disease that the death rate is high, and treatment difficulty is high, and the death rate is brought heavy to patient and family
Burden.In recent years, China's cancer incidence obviously 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 is arranged as second 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, especially methicillin-resistant
(MRSA) it is the main pathogenic bacteria of bloodstream infection and 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%) caused by MRSA is much high
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.
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 a kind of drug for treating the microbial infection of Gram-positive, chemistry knots
Structure is above-mentioned formula（Ⅰ）Or formula（Ⅱ）.
Further, a kind of drug treated and infected caused by 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.
It is formula another object of the present invention is to provide chemical constitution（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 for treating 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.Solid dosage forms for oral medication includes capsule, tablet, pill, powder and granule.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 are poly-
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
Use gastric infusion into line in bright specific implementation mode（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, in conjunction with the actual needs of Modern preparations technology and sufferer, is prepared into injection, scalp absorbable preparation, implantation system
The several formulations such as agent 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 compounds, 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 especially 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 compounds, suspension may include suspending agent, such as ethoxylation isooctadecane alcohol, polyoxyethylene mountain
The mixture etc. of pears alcohol and Isosorbide Dinitrate, microcrystalline cellulose, aluminium methoxide and agar or these substances.
Composition for parenteral injection may include physiologically acceptable sterile, aqueous or anhydrous solution, dispersion liquid,
Suspension or lotion, and the aseptic powdery for re-dissolving into 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.
The dosage form of the compounds of this invention for local administration includes ointment, powder, patch, propellant and inhalant.
Active constituent aseptically with physiologically acceptable carrier and any preservative, buffer, or when necessary may need
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, positive effect is played to the treatment of the microbial infection of Gram-positive.
Specific implementation mode
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, and 1 gram of sodium borohydride is added thereto, keeps temperature
Then stirring two hours is warmed to room temperature and continues stirring 4 hours, 40 milliliters of water are added 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 it is solid to obtain 1.8 grams of yellow for 50 DEG C of vacuum drying
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 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, 1.2 grams of sodium borohydrides are then added, low temperature 2 hours is warmed to room temperature continuation
Half an hour is stirred, 100 ml water are then added 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 is added tetra-triphenylphosphine palladium, is warming up to 60 DEG C, after
Continuous stirring half an hour, phenyl boric acid (12 mmol) is added thereto, adds 10 milliliters of sodium carbonate (1 gram) aqueous solution, 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 rouses argon gas 20 minutes, then the air in emptying system adds
Enter tetra-triphenylphosphine palladium, be warming up to 60 DEG C, continues to stir half an hour, 2- naphthalene boronic acids (12 mmol) are added 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 rouses argon gas 20 minutes, then the air in emptying system adds
Enter tetra-triphenylphosphine palladium, be warming up to 60 DEG C, continues to stir half an hour, be added 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, stirs 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 rouses argon gas 20 minutes, then the air in emptying system adds
Enter tetra-triphenylphosphine palladium, be warming up to 60 DEG C, continue to stir half an hour, p-isopropyl phenyl boric acid (12 mmol) is added thereto, then
10 milliliters of sodium carbonate (1 gram) aqueous solutions are added, are warming up to 90 DEG C, stir 5 hours, whole process holding is passed through argon gas, then drops
Temperature, removes solvent under reduced pressure, and solid obtains 3.5 grams of light yellow 2- thiazole methyls -4- p-isopropyls phenyl-quickly through chromatographic column
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 rouses argon gas 20 minutes, then the air in emptying system adds
Enter tetra-triphenylphosphine palladium, be warming up to 60 DEG C, continues to stir half an hour, 3,5 difluoro phenyl boric acids (12 mmol) are added thereto, then
10 milliliters of sodium carbonate (1 gram) aqueous solutions are added, are warming up to 90 DEG C, stir 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-
The first two steps 1-1 and 1-2 of synthesis step first two steps 6-1 and 6-2 difference 1 synthesis step of corresponding embodiment.
The synthesis of the fluoro- quinoxalinyl -6- imines of 6-3 2- thiazole methene -4- phenyl -7-
Synthetic method is with the reaction 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 rouses argon gas 20 minutes, in emptying system
Air, tetra-triphenylphosphine palladium is then added, is warming up to 60 DEG C, continue stir half an hour, thereto be added 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-
Synthetic method is with the reaction 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 rouses argon gas 20 minutes, in emptying system
Air, tetra-triphenylphosphine palladium is then added, is warming up to 60 DEG C, continues to stir half an hour, 2- naphthalene boronic acids (12 is added 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-
Synthetic method is with the reaction 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 rouses argon gas 20 minutes, in emptying system
Air, tetra-triphenylphosphine palladium is then added, is warming up to 60 DEG C, continue stir half an hour, be added 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-
Synthetic method is with the reaction 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 rouses argon gas 20 minutes, in emptying system
Air, tetra-triphenylphosphine palladium is then added, is warming up to 60 DEG C, continue stir half an hour, thereto be added 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-
Synthetic method is with the reaction 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 rouses argon gas 20 minutes, in emptying system
Air, tetra-triphenylphosphine palladium is then added, is warming up to 60 DEG C, continue stir half an hour, 3,5 difluoro phenyl boric acids are added 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
One, 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.
Two, 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, adjusts 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.,：
64,32,16,8,4,2,1,0.5 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.
Three, 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 that concentration gradient is added is changed to that concentration ladder is added
The cis-platinum of degree）
Control group（Compared with medicine group to be measured, the drug to be measured that concentration gradient is added is changed to that the RPMI of not drug containing is added
1640 cell culture fluids）
Blank group（Compared with the control group, it is not added with cell）
Four, experimental procedure：
1. the cell of logarithmic growth phase, 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, sets 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
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 microscopically 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 per hole, sets low-speed oscillation 10min on shaking table, formazan is made to tie
Brilliant fully dissolving.
5. measuring the optical density in each hole at enzyme-linked immunosorbent assay instrument 490nm（OD values）.
6. parallel hole OD values are indicated 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）.
Five, 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）6 kinds of human tumor cell lines of a drug pair all have inhibitory activity.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, more deep research and development are done.
In addition, measuring inhibition of the mass mixings such as the I d and II d object to above-mentioned 6 kinds of human tumor cell lines using above-mentioned mtt assay
Activity finds IC50<1μg/ml.Illustrate that I d and II d inhibit 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：Inhibiting effect of the resazurin determination of color to different gram-positive bacterias
One, 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 100 μ L mixed bacteria liquids are respectively added 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, takes out the solution of 100 μ L after evenly mixing
It is transferred in the 2nd corresponding plate hole of row, same method multiplication is used in combination to be diluted to the 8th row.Finally, the orifice plate of sample will have been added to put
Enter to constant incubator, 37 DEG C of culture 10-12h.Bacterium solution becomes red as no bacteriostatic activity, and blue is to have 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.
Two, 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 all has 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, medicine dynamic
The structure adapted to is learned, more deep research and development are done.
In addition, it is necessary to it is important to note that formula（Ⅰ）Or formula（Ⅱ）Inhibitory activity substantially phase of each structure to 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 treating MRSA
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 is not departing from this hair according to the ordinary technical knowledge and means of this field
Under the premise of bright above-mentioned basic fundamental thought, the modification, replacement or change of other diversified forms can also be made.
Claims (5)
1. a kind of drug for treating malignant tumour, chemical constitution is formula（Ⅰ）
Wherein, R is、、、OrIn one kind.
2. a kind of drug for treating malignant tumour as described in claim 1, characterized in that the malignant tumour is lung cancer, liver
Cancer, neurogliocytoma, adenocarcinoma ovaries, breast cancer or chronic myelogenous leukemia.
3. a kind of pharmaceutical composition for treating malignant tumour, which is characterized in that described pharmaceutical composition includes a effective amount of formula（Ⅰ）
And pharmaceutically acceptable carrier,
Wherein, R is、、、OrIn one kind.
4. a kind of pharmaceutical composition for treating malignant tumour as claimed in claim 3, which is characterized in that described pharmaceutical composition
For capsule, tablet, pill, powder, granule or injection.
5. a kind of pharmaceutical composition for treating malignant tumour as claimed in claim 3, which is characterized in that described pharmaceutically to connect
The carrier received be filler or bulking agent, adhesive, moisturizer, disintegrant, retarding solvent, absorbsion accelerator, wetting agent, adsorbent,
Lubricant, PH conditioning agents.
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Denomination of invention: A drug for treating malignant tumors Effective date of registration: 20230627 Granted publication date: 20180731 Pledgee: Bank of Hangzhou Limited by Share Ltd. Shanghai branch Pledgor: Shanghai Pukang Pharmaceutical Co.,Ltd. Registration number: Y2023310000315 |