CN107021960A - A kind of medicine for treating malignant tumour - Google Patents
A kind of medicine for treating malignant tumour Download PDFInfo
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- CN107021960A CN107021960A CN201710434901.5A CN201710434901A CN107021960A CN 107021960 A CN107021960 A CN 107021960A CN 201710434901 A CN201710434901 A CN 201710434901A CN 107021960 A CN107021960 A CN 107021960A
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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 medicine for treating malignant tumour, its 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, and the treatment of cancer is played and energetically acted on.
Description
Technical field
The present invention relates to a kind of medicine 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 brings heavy to patient and family
Burden.In recent years, China's cancer incidence substantially increases, and prevention and control of cancer is faced with the situation of sternness.In the last few years, China
Cancer incidence is in trend is gradually increasing, by the extensive concern of personages of various circles of society.Show according to research reports, in 20 generation
Record the seventies, China's Cancer in China increases to 22.32% by 10.13%, and dead increment rate is 82.11%.Cancer is that to come city dead
First died, second is arranged as in rural area.Especially aging is increasingly aggravated now, smoking, dietary structure change, micro- life
Thing infection, fat, activity reduction, the factor such as bad of working and resting are to cause the generation main cause of cancer.The especially overweight rate of China
And obesity rates are significantly more than 50%.At present come China's cancer top ten be：Lung cancer, stomach 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；Stomach 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 long
It has been always the focus of research and development since phase, chemical classes medicine and biological species medicine fall over each other to contend, but new effective malignant tumour
Still demand is urgent for medicine.
Gram-positive bacteria is the staphylococcus aureus of important 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
In 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.The new anti-gram sun of exploitation
Property bacterium medicine be antibiotic exploitation vital task.
The content of the invention
It is an object of the invention to provide a kind of medicine for treating malignant tumour, its 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 medicine for treating the microbial infection of Gram-positive, its chemistry knot
Structure is above-mentioned formula（Ⅰ）Or formula（Ⅱ）.
Further there is provided a kind of medicine treated and infected caused by MRSA, its 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 for 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 the formula of effective dose
（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 be filler or bulking agent, it is adhesive, NMF, disintegrant, slow
One or more in 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
Do not limit, representational method of application includes（But it is not limited to）：Orally, parenteral（Intravenous, intramuscular is subcutaneous）, drawn game
Portion is administered.Solid dosage forms for oral administration 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
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, PVP, sucrose and Arabic gum；（c）NMF, example
Such as glycerine；（d）Disintegrant, such as agar, calcium carbonate, farina or tapioca, alginic acid, some 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, formulation can also include buffer.
Wherein, gastrointestinal administration preparation is presently the most common administration form, and convenient experimental operation, therefore, this hair
Line is entered using gastric infusion in bright embodiment（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 being actually needed for Modern preparations technology and sufferer, injection, scalp absorbable preparation, implantation system is prepared into
The several formulations such as agent, so as to expand its method of administration, and improve target-oriented drug or are prevented effectively from unnecessary toxic side effect.
Liquid formulation for oral administration includes pharmaceutically acceptable emulsion, solution, suspension, syrup or tincture.
Except active ingredient beyond the region of objective existence, liquid dosage form can include the inert diluent routinely used in this area, and such as water or other solvents increase
Solvent and emulsifying agent, example know ethanol, isopropanol, ethyl carbonate, ethyl acetate, propane diols, 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 materials
Deng.
In addition to these inert diluents, composition can also include auxiliary agent, such as wetting agent, emulsifying agent and suspending agent, sweet taste
Agent, flavouring and spices.
Except active ingredient beyond the region of objective existence, suspension can include suspending agent, such as ethoxylation isooctadecane alcohol, polyoxyethylene mountain
Mixture of pears alcohol and Isosorbide Dinitrate, microcrystalline cellulose, aluminium methoxide and agar or these materials etc..
For parenteral injection composition can comprising physiologically acceptable sterile, aqueous or anhydrous solution, dispersion liquid,
Suspension or emulsion, and for being dissolved into the aseptic powdery of sterile Injectable solution or dispersion liquid again.It is suitable aqueous and
Nonaqueous carrier, diluent, solvent or excipient include water, ethanol, polyalcohol and its suitable mixture.
Formulation for the local the compounds of this invention being administered includes ointment, powder, patch, propellant and inhalant.
Active component aseptically with physiologically acceptable carrier and any preservative, buffer, or if 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 invention provides a kind of medicine for treating malignant tumour, treating malignant tumor compound library is enriched, to cancer
Treatment play and energetically act on.
The invention provides a kind of medicine for treating the microbial infection of Gram-positive, feel caused by especially MRSA
Positive role is played in dye, the treatment to the microbial infection of Gram-positive.
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）It is mixed
In bonding solvent, stir 20 minutes, then Quan Rong is cooled to 0-5 DEG C, 1 gram of sodium borohydride, keeping temperature stirring are added thereto
Two hours, then it is warmed to room temperature continuation and stirs 4 hours, 40 milliliters of water are added into reaction, extracted, had with 50 milliliters of ethyl acetate
Machine mutually uses anhydrous sodium sulfate drying 2 hours, filtering, is evaporated organic solvent, and 50 DEG C of vacuum drying obtain 1.8 grams of yellow solids, i.e.,
For the fluoro- quinazolyl -6- amine of the chloro- 7- of 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, returns
Stream 2 hours, is then down to room temperature, water is added into system（50 ml）, extracted with 50 ml dichloromethane, anhydrous sodium sulfate drying
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- thiazole methylenes
Fluoro- quinoxalinyl -6- imines the solids of the chloro- 7- of base -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, adds 5
Milliliter glacial acetic acid, is cooled to 0-5 DEG C, then adds 1.2 grams of sodium borohydrides, and low temperature 2 hours is warmed to room temperature continuation and stirred
Half an hour, 100 ml water are then added into system, stirred 1 hour, filtering, 50 DEG C of vacuum drying obtain 2.1 grams of off-white colors and consolidated
Body, 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 N,N-Dimethylformamides
In, system rouses argon gas 20 minutes, and then the air in emptying system adds tetra-triphenylphosphine palladium, be warming up to 60 DEG C, continue to stir
Mix half an hour, phenyl boric acid (12 mmol) added thereto, 10 milliliters of sodium carbonate (1 gram) aqueous solution is added, is warming up to 90 DEG C,
Stirring 5 hours, whole process keeps being passed through argon gas, then cools, removes solvent under reduced pressure, solid is obtained quickly through chromatographic column
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- naphthalenes 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 molten
In 30 milliliters of N,N-Dimethylformamides, system rouses argon gas 20 minutes, and then the air in emptying system adds four triphens
Base phosphine palladium, is warming up to 60 DEG C, continues to stir half an hour, 2- naphthalene boronic acids (12 mmol) are added thereto, 10 milliliters of carbonic acid are added
Sodium (1 gram) aqueous solution, is warming up to 90 DEG C, stirs 5 hours, and whole process keeps being passed through argon gas, then cools, removes under reduced pressure molten
Agent, solid quickly through chromatographic column,
Obtain 3.4 grams of off-white color 2- thiazole methyls -4- (2- naphthalenes 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 molten
In 30 milliliters of N,N-Dimethylformamides, system rouses argon gas 20 minutes, and then the air in emptying system adds four triphens
Base phosphine palladium, is warming up to 60 DEG C, continues to stir half an hour, adds thereto to itrile group phenyl boric acid (12 mmol), add 10 milliliters
Sodium carbonate (1 gram) aqueous solution, is warming up to 90 DEG C, stirs 5 hours, and whole process keeps being passed through argon gas, then cools, removes under reduced pressure
Solvent, solid obtains 3.3 grams of light yellow 4- [the fluoro- 6- of 7- (2- thiazole methylamines base)] quinoxalinyls-benzene first quickly through chromatographic column
Nitrile 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 molten
In 30 milliliters of N,N-Dimethylformamides, system rouses argon gas 20 minutes, and then the air in emptying system adds four triphens
Base phosphine palladium, is warming up to 60 DEG C, continues to stir half an hour, p-isopropyl phenyl boric acid (12 mmol) is added thereto, adds 10 millis
Sodium carbonate (1 gram) aqueous solution is risen, 90 DEG C are warming up to, stirred 5 hours, whole process is kept being passed through argon gas, then cools, and decompression is steamed
Except solvent, solid obtains 3.5 grams of fluoro- quinolines of light yellow 2- thiazole methyls -4- p-isopropyl phenyl -7- quickly through chromatographic column
Quinoline base -6- secondary amine solids, 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 molten
In 30 milliliters of N,N-Dimethylformamides, system rouses argon gas 20 minutes, and then the air in emptying system adds four triphens
Base phosphine palladium, is warming up to 60 DEG C, continues to stir half an hour, 3,5 difluoro phenyl boric acids (12 mmol) are added thereto, adds 10 millis
Sodium carbonate (1 gram) aqueous solution is risen, 90 DEG C are warming up to, stirred 5 hours, whole process is kept being passed through argon gas, then cools, and decompression is steamed
Except solvent, solid obtains 3.1 grams of fluoro- quinoxalines of yellow 2- thiazole methyls -4- (3,5 difluorophenyl) -7- quickly through chromatographic column
Base -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 correspond to the first two steps 1-1 and 1-2 of the synthesis step of embodiment 1 respectively.
The synthesis of the fluoro- quinoxalinyl -6- imines of 6-3 2- thiazole methene -4- phenyl -7-
Reaction method in synthetic method be the same as Example 1 described in 1-4, by the fluoro- quinoxalinyl -6- of the 2- chloro- 7- of thiazole methene -4-
Imines（10 mmol）It is dissolved in 30 milliliters of N,N-Dimethylformamides, system drum argon gas 20 minutes, the sky in emptying system
Gas, then adds tetra-triphenylphosphine palladium, is warming up to 60 DEG C, continues to stir half an hour, phenyl boric acid (12 mmol) is added thereto,
10 milliliters of sodium carbonate (1 gram) aqueous solution is added, 90 DEG C are warming up to, stirred 5 hours, whole process keeps being passed through argon gas, then
Cooling, removes solvent under reduced pressure, solid obtains 3.1 grams of off-white color 2- thiazole methene -4- phenyl -7- fluoro- quickly through chromatographic column
Quinoxalinyl -6- imines solids, 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- naphthalenes sweet smell base) fluoro- quinoxalinyl -6- imines of -7-
Reaction method in synthetic method be the same as Example 6 described in 6-3, by the fluoro- quinoxalinyl -6- of the 2- chloro- 7- of thiazole methene -4-
Imines（10 mmol）It is dissolved in 30 milliliters of N,N-Dimethylformamides, system drum argon gas 20 minutes, the sky in emptying system
Gas, then adds tetra-triphenylphosphine palladium, is warming up to 60 DEG C, continues to stir half an hour, 2- naphthalene boronic acids (12 are added thereto
Mmol), 10 milliliters of sodium carbonate (1 gram) aqueous solution is added, 90 DEG C are warming up to, stirred 5 hours, whole process keeps being passed through argon
Gas, then cools, and removes 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 in synthetic method be the same as Example 6 described in 6-3, by the fluoro- quinoxalinyl -6- of the 2- chloro- 7- of thiazole methene -4-
Imines（10 mmol）It is dissolved in 30 milliliters of N,N-Dimethylformamides, system drum argon gas 20 minutes, the sky in emptying system
Gas, then adds tetra-triphenylphosphine palladium, is warming up to 60 DEG C, continues to stir half an hour, adds thereto to cyanophenylboronic acid (12
Mmol), 10 milliliters of sodium carbonate (1 gram) aqueous solution is added, 90 DEG C are warming up to, stirred 5 hours, whole process keeps being passed through argon
Gas, then cools, and removes solvent under reduced pressure, and solid obtains 3.0 grams of yellow 2- thiazoles methene -4- to cyanogen quickly through chromatographic column
Fluoro- quinoxalinyl -6- imines the solids of base 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 in synthetic method be the same as Example 6 described in 6-3, by the fluoro- quinoxalinyl -6- of the 2- chloro- 7- of thiazole methene -4-
Imines（10 mmol）It is dissolved in 30 milliliters of N,N-Dimethylformamides, system drum argon gas 20 minutes, the sky in emptying system
Gas, then adds tetra-triphenylphosphine palladium, is warming up to 60 DEG C, continues to stir half an hour, p-isopropyl phenyl boric acid (12 is added thereto
Mmol), 10 milliliters of sodium carbonate (1 gram) aqueous solution is added, 90 DEG C are warming up to, stirred 5 hours, whole process keeps being passed through argon
Gas, then cools, and removes solvent under reduced pressure, and solid obtains 3.1 grams of yellow 2- thiazoles methene -4- to different quickly through chromatographic column
Fluoro- quinoxalinyl -6- imines the solids of propyl group 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 in synthetic method be the same as Example 6 described in 6-3, by the fluoro- quinoxalinyl -6- of the 2- chloro- 7- of thiazole methene -4-
Imines（10 mmol）It is dissolved in 30 milliliters of N,N-Dimethylformamides, system drum argon gas 20 minutes, the sky in emptying system
Gas, then adds tetra-triphenylphosphine palladium, is warming up to 60 DEG C, continues to stir half an hour, 3,5 difluoro phenyl boric acids (12 are added thereto
Mmol), 10 milliliters of sodium carbonate (1 gram) aqueous solution is added, 90 DEG C are warming up to, stirred 5 hours, whole process keeps being passed through argon
Gas, then cools, and removes solvent under reduced pressure, solid quickly through chromatographic column, obtain 3.3 grams of glassy yellow 2- thiazole methenes -4- (3,
5 difluorophenyls) the fluoro- quinoxalinyl -6- imines solids of -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 determines the inhibitory action to different tumour cells
First, cell line
Human lung cancer cell A549, Human hepatoma cell line Bel-7402, neuroglia cell of human oncocyte U251, people's ovary adenocarcinoma cells
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, and 0.22 μm of membrane filtration is degerming, and 4 DEG C standby.
The cell culture fluids of 3.RPMI 1640：
（1）The culture powder of 10.4g/ bags RPMI 1640 is molten into tri-distilled water, magnetic agitation 20min；
（2）Plus 2g NaHCO3, continue to stir 10min；
（3）Plus penicillin solution（2×105U/mL）0.5mL, Streptomycin Solution（2× 105U/mL）0.5mL；
（4）Plus 100ml inactivated fetal bovine serums；
（5）Plus 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 are 0.1%
Within）, 128 μ g/ml are configured to the cell culture fluids of RPMI 1640, half-and-half dilution is configured to 8 concentration gradients, i.e.,：64、32、
16th, 8,4,2,1,0.5 μ g/ml, are prepared with preceding.
（2）Cis-platinum gradient solution：Cisplatin injections are configured to 128 μ g/ml with the cell culture fluids of RPMI 1640, half-and-half dilute
Release and be configured to 8 concentration gradients, i.e., 128,64,32,16,8,4,2,1 μ g/ml are prepared with preceding.
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 medicine to be measured for adding concentration gradient is changed to add concentration gradient
Cis-platinum）
Control group（Compared with medicine group to be measured, the medicine to be measured for adding concentration gradient is changed to add the RPMI 1640 of not drug containing
Cell culture fluid）
Blank group（Compared with control group, cell is not added with）
4th, experimental procedure：
1. the cell in growth period of taking the logarithm, Trypsin Induced, the cell culture fluids of RPMI 1640 adjust concentration of cell suspension be 6 ×
104Individual/mL.Add the μ L of cell suspension 100 per hole in 96 well culture plates, put 37 DEG C, 5% CO224h, cell patch are cultivated in incubator
Wall.
2. removing the cell culture fluids of RPMI 1640, the cell culture fluids of RPMI 1640 of the medicine to be measured of concentration gradient are added
100 μ L, each concentration sets 6 parallel holes.96 orifice plates after dosing are placed in 37 DEG C, 5% CO248h is cultivated in incubator, is inverted
The action effect of micro- Microscopic observation medicine.
Nutrient solution is discarded after the centrifugation of 3.96 orifice plates, after carefully being rushed 2 ~ 3 times with PBS, the RPMI containing 0.5% MTT is added
The μ L of 1640 cell culture fluid 100, continue to cultivate 4h.
4. removing supernatant, 150 μ L dimethyl sulfoxide (DMSO)s are added 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 the data processing softwares of GraphPad Prism 5, 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.As a result
It has been shown that, formula（Ⅰ）Or formula（Ⅱ）Individual medicine is respectively provided with inhibitory activity to 6 kinds of human tumor cell lines.Compared with positive drug cis-platinum, no
Larger with inhibitory activity difference between R bases, R isOrWhen activity be higher than, but formula
（Ⅰ）Or formula（Ⅱ）Active rule is not obvious between identical R bases, and explanation further on R bases can be researched and developed, and selects side effect
Small, the structure that pharmacokinetics is adapted to does more deep research and development.
In addition, measuring suppression of the mass mixing such as the I d and II d thing 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 suppress tumour cell and have synergy jointly.
The formula of table 1（Ⅰ）Or formula（Ⅱ）To 6 kinds of human tumor cells inhibitory action
Experimental result explanation, formula（Ⅰ）Or formula（Ⅱ）The medicine for treating malignant tumour can be used as.Malignant tumour can for lung cancer,
Liver cancer, neurogliocytoma, adenocarcinoma ovaries, breast cancer or chronic myelogenous leukemia.
Test example 2：Inhibitory action of the resazurin determination of color to different gram-positive bacterias
First, experimental method
First by 7.5mL indicator solution（The 100 μ g/mL resazurin aqueous solution）With 5mL bacterium solution to be measured（108 CFU/
mL）Mix, and the 100 μ L mixed bacteria liquids of each addition into all instrument connections of the 1st ~ 8 row.Then by 100 μ L testing samples
DMSO solution（16-500μg/mL）In each plate hole for being added sequentially to the 1st row, the solution that 100 μ L are taken out after uniform mixing turns
Move on in the 2nd corresponding plate hole of row, and the 8th row are diluted to same method multiplication.Finally, the orifice plate for having added sample is put into
To constant incubator, 37 DEG C of culture 10-12h.Bacterium solution becomes red into without bacteriostatic activity, blueness is has bacteriostatic activity, and bacterium solution is maintained
The minimum diluted concentration of blueness is considered as the minimum inhibitory concentration of testing compound（MIC）, each sample does 2 groups of repetition measurements of laying equal stress on
It is fixed 3 times.Positive control is vancomycin.
2nd, experimental result
Formula（Ⅰ）Or formula（Ⅱ）To the inhibitory action of different gram-positive bacterias, MIC value is shown in Table 2.As a result show, formula（Ⅰ）Or formula
（Ⅱ）Individual medicine is respectively provided with inhibitory activity to different gram-positive bacterias.Compared with positive drug vancomycin, between different R bases
Inhibitory activity difference is larger, and R isOrWhen activity be higher than, but formula（Ⅰ）Or formula
（Ⅱ）Active rule is not obvious between identical R bases, and explanation further on R bases can be researched and developed, and selects Small side effects, and medicine is moved
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 medicine, and MRSA does not have tolerance to each structure, in being infected caused by treatment MRSA
Show especially prominent meaning.
The formula of table 2（Ⅰ）Or formula（Ⅱ）To the inhibitory action of different gram-positive bacterias
Experimental result explanation, formula（Ⅰ）Or formula（Ⅱ）The medicine for treating the microbial infection of Gram-positive can be used as.Formula（Ⅰ）
Or formula（Ⅱ）The medicine infected caused by treatment MRSA can be used as.
Obviously, according to the above of the present invention, according to the ordinary technical knowledge and means of this area, this hair is not being departed from
Under the premise of bright above-mentioned basic fundamental thought, the modification of other diversified forms can also be made, replaces or changes.
Claims (5)
1. a kind of medicine for treating malignant tumour, its chemical constitution is formula（Ⅰ）
Wherein, R is、、、OrIn one kind.
2. a kind of medicine for treating malignant tumour as claimed in claim 1, it is 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, it is characterised in that described pharmaceutical composition includes the formula of effective dose（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, it is characterised in that described pharmaceutical composition
For capsule, tablet, pill, powder, granule or injection；It is preferred that：Tablet, capsule or injection.
5. a kind of pharmaceutical composition for treating malignant tumour as claimed in claim 3, it is characterised in that described pharmaceutically to connect
The carrier received be filler or bulking agent, adhesive, NMF, disintegrant, retarding solvent, absorbsion accelerator, wetting agent, adsorbent,
Lubricant, PH conditioning agents.
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