CN103554038A - Polyhalogenated benzonitrile quinazolone compounds, preparation method and use thereof - Google Patents

Polyhalogenated benzonitrile quinazolone compounds, preparation method and use thereof Download PDF

Info

Publication number
CN103554038A
CN103554038A CN201310242148.1A CN201310242148A CN103554038A CN 103554038 A CN103554038 A CN 103554038A CN 201310242148 A CN201310242148 A CN 201310242148A CN 103554038 A CN103554038 A CN 103554038A
Authority
CN
China
Prior art keywords
compound
nitrile
compounds
phenyl
quinazolinones
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Granted
Application number
CN201310242148.1A
Other languages
Chinese (zh)
Other versions
CN103554038B (en
Inventor
金毅
林军
施丽萍
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.)
Yunnan University YNU
Original Assignee
Yunnan University YNU
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 Yunnan University YNU filed Critical Yunnan University YNU
Priority to CN201310242148.1A priority Critical patent/CN103554038B/en
Publication of CN103554038A publication Critical patent/CN103554038A/en
Application granted granted Critical
Publication of CN103554038B publication Critical patent/CN103554038B/en
Expired - Fee Related legal-status Critical Current
Anticipated expiration legal-status Critical

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
    • C07D239/70—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings condensed with carbocyclic rings or ring systems
    • C07D239/72—Quinazolines; Hydrogenated quinazolines
    • C07D239/86—Quinazolines; Hydrogenated quinazolines with hetero atoms directly attached in position 4
    • C07D239/88—Oxygen atoms
    • C07D239/90—Oxygen atoms with acyclic radicals attached in position 2 or 3

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Plural Heterocyclic Compounds (AREA)

Abstract

The present invention provides polyhalogenated benzonitrile quinazolone compounds with a structure represented by a formula (I), wherein R1 represents H atom or alkyl hydrocarbon, R2 represents alkane or aromatic hydrocarbon, and X1-X3 represent halogens. The present invention further provides a preparation method for the compounds. Results of activity determination on a variety of strains show that the compounds provide activity for the strains, and can be used for preparing drugs for diseases caused by gram-negative bacteria infections and gram-positive bacterial infections.

Description

Phenyl polyhalide nitrile quinazolinones and its production and use
Technical field
The present invention relates to pharmaceutical chemistry, chemotherapy field, be specifically related to phenyl polyhalide nitrile quinazolinones as treatment infectious diseases, the particularly medicine of the microbial infectious diseases of multidrug resistance.
Background technology
Find sulfonamide the thirties, use penicillin the beginning of the forties, find immediately aminoglycoside, paraxin, tsiklomitsin, macrolide, continuous and have large quantities of antimicrobial drug widespread uses such as semisynthetic penicillin, cynnematin, novel beta-lactan, complete synthesis quinolone, make the mankind almost can easily treat various bacterial infection diseases, even 20th century 70-80 age people, generally believe that the mankind have thoroughly defeated bacterium.Yet, along with antibiotic, be widely used and abuse, the Multidrug resistant bacteria of resistance to Multiple Classes of Antibiotics has formed new document to human health.(Swartz, M.N.Proc. Natl. Acad. Sci. U.S.A. 1994,91,2420) especially recent two decades comes gram-positive microorganism resistance to increase fast, and golden yellow staphylococcus (MRSA), staphylococcus epidermidis (MRSE), penicillin-fast streptococcus pneumoniae (PRSP), the particularly vancomycin-resistant enterococcus (VRE) of the methicillin-resistant occurring in world wide have become very stubborn problem of current clinical anti-infective therapy.Especially the appearance of vancomycin-resistant enterococcus (VRE), has broken through " last resort " of severe infections patient treatment.Development of new antimicrobial drug is extremely urgent, and the newtype drug that can do with Multidrug resistant bacteria is all actively being found by the many drugmakers in the world at present.
Quinazoline compounds is the nitrogen-containing heterocycle compound that a class has good biological activity, and it has a wide range of applications at agricultural chemicals and medicine and other fields, as sterilization, desinsection, antiviral, anti-inflammatory etc.Part quinazoline compounds is successfully developed as commercial medicine at present, as sterilant fluquinconazole, miticide fenazaquin and cancer therapy drug Iressa etc. (Liu, F etc. j. Med. Chem.2010,53,5844; Lockman, J.W etc. j. Med. Chem.2010,53,8734; Beria, I etc. j. Meal Chem. 2010,53,3532.).Meanwhile, halogen-containing compound thing has application widely on physiology and pharmacology, as m-tetrachlorophthalodinitrile; chemical name is 2,4,5; 6-tetrachloro-1,3-benzene dicarbonitrile, is that a kind of protectiveness cauline leaf sprays substituted beneze-group fungicides; belong to low toxicity sterilant; have multiple formulation can be widely used in the various crop diseases such as control vegetables, fruit tree, beans, paddy rice, wheat, in agriculture production, also can effectively control fungal disease (Deng Huan etc. chemical industry and material, 2012; (4), 26-27.).We are legal by compound pharmacophore slice groups, and the quianzolinones that phenyl polyhalide nitrile replaces has been synthesized in design, by anti-microbial activity, tests, and finds that they are the small-molecule drug molecules with good anti-microbial activity.
Summary of the invention
Technical scheme of the present invention is to provide the phenyl polyhalide nitrile quianzolinones that a class has anti-microbial activity.Technical scheme of the present invention is to provide the Preparation method and use of a class phenyl polyhalide nitrile quinazolinones.
A class phenyl polyhalide nitrile quinazolinones provided by the invention, has following structure (I)
Figure 2013102421481100002DEST_PATH_IMAGE001
X wherein 1~ X 3represent halogen F, Cl, Br, I atom;
R 1represent H atom or methyl, methylene radical, ethyl, propyl group alkane;
R 2for methyl, methylene radical, ethyl, propyl group or substituted-phenyl, wherein substituted-phenyl is methyl substituted, and halogen replaces, and alkoxyl group replaces, and nitro replaces, and itrile group replaces one or more substituted-phenyls wherein.
1. compound of the present invention is preferably certainly:
Figure 2013102421481100002DEST_PATH_IMAGE002
Figure 2013102421481100002DEST_PATH_IMAGE003
Figure 2013102421481100002DEST_PATH_IMAGE004
Compound 1 compound 2 compounds 3
Figure 2013102421481100002DEST_PATH_IMAGE006
Compound 4 compound 5 compounds 6
Figure 2013102421481100002DEST_PATH_IMAGE008
Figure 2013102421481100002DEST_PATH_IMAGE009
Compound 7 compound 8 compounds 9
Figure 2013102421481100002DEST_PATH_IMAGE012
Figure 2013102421481100002DEST_PATH_IMAGE013
Compound 10 compound 11 compounds 12
Figure 2013102421481100002DEST_PATH_IMAGE014
Figure 2013102421481100002DEST_PATH_IMAGE015
Figure 2013102421481100002DEST_PATH_IMAGE016
Compound 13 compound 14 compounds 15
Figure 2013102421481100002DEST_PATH_IMAGE017
Compound 16
Shown in the synthetic following reaction formula of formula of the present invention (I) compound:
Figure 2013102421481100002DEST_PATH_IMAGE018
Specifically, take phenyl polyhalide nitrile (II) and aminoquinazolinone (III) is raw material, and under alkali effect, in solvent, Hybrid Heating is directly carried out nucleophilic substitution and obtained phenyl polyhalide nitrile quinazolinones.Wherein, solvent is selected from: methyl alcohol, ethanol, ethyl acetate, acetonitrile, ether, tetrahydrofuran (THF), acetone, benzene, toluene, methylene dichloride, chloroform, 1, the mixing of 4-dioxane, DMF or dimethyl sulfoxide (DMSO) and above two or more solvents thereof.Alkali is selected from: salt of wormwood, sodium carbonate, sodium hydroxide, potassium hydroxide, potassium tert.-butoxide, sodium tert-butoxide, sodium ethylate, sodium methylate.Temperature of reaction is 20-150 ℃.
The Determination of Antibacterial Activity of phenyl polyhalide nitrile quianzolinones of the present invention is as follows:
Antibacterial activity in vitro is measured:
1. test method: adopt agar doubling dilution to measure compound to the minimum inhibitory concentration of strain subject (MIC).Draw respectively test-compound 1 mL and add in sterilizing plate, then in plate, add 19 mL M-H nutrient agars (being melted up to 50 ℃), making the final concentration of contained compound in each plate is 128,64,32,16,8,4,2,1,0.5,0.25 μ g/mL, then with multiple spot, inoculate instrument (Denley A400) in individual plate surface seeding bacterium respectively, bacterium liquid final concentration is 10 5cFU/mL.Insert in 37 ℃ and cultivate 20 hours, observations, the minimum inhibitory concentration (MIC) that the minimum concentration of take without medicine in bacterial growth plate is this bacterium.
2. test strain: test strain used has been bought 4 kinds of bacterial classifications from Yunnan Province Disease Control and Prevention Center, is respectively e. coli strains (EC), Pseudomonas aeruginosa strain (PA), bacillus cereus strain (BC), streptococcus aureus strain (SA).Fungi is Candida albicans (MA), derives from teacher Wang Xinghong of Institute of Micro-biology of Yunnan University laboratory; Test-compound CH 3after OH or DMSO dissolve, the mother liquor that is mixed with 2560 mg/mL with sterile purified water is standby.The MIC value of each compound is in Table 1, and positive control drug is m-tetrachlorophthalodinitrile and norfloxicin.
Table 1 compound 1-26 is to the inhibition of each bacterial strain (MIC)
Note: " N " in table represents this kind of bacterium without anti-microbial activity
As shown in Table 1, compound 6, 7, 10, 11anti-microbial activity best, suitable with the activity of control sample norfloxicin.Compound wherein 1, 2, 6, 10(0.5 μ g/mL), compound 4,7 (0.7 μ g/mL), compound 11, 8(0.8 μ g/mL), 5 (1.0 μ g/mL) are better to the activity of bacillus cereus strain, compound 6, 10(0.7 μ g/mL), compound 7(0.8 μ g/mL) has obvious activity, compound to streptococcus aureus strain 10(0.8 μ g/mL), compound 11(1.3 μ g/mL) is better than other compounds, compound to the anti-microbial activity of e. coli strains 7(1.7 μ g/mL), compound 10(1.3 μ g/mL), compound 11(2.0 μ g/mL) is best in surveyed compound to the activity of Pseudomonas aeruginosa strain.Most compounds is better than Gram-negative bacteria (EC, PA) to the anti-microbial activity of gram-positive microorganism (BC, SA).
Embodiment
Below in conjunction with embodiment, the invention will be further described, but be not construed as limiting the invention.
Embodiment 1 the chloro-6-of 2,4,5-tri-(4-oxo-5-(phenyl amino)-3,4-dihydroquinazoline-8-is amino) m-dicyanobenzene (compound 1)
In 100 mL round-bottomed flasks, add many halos isophthalic diformazan eyeball 0.26 g (1 mmol) and a small amount of K 2cO 3as catalyzer, get 7 mL tetrahydrofuran (THF)s (THF) and 1 mL N, N dimethyl formamide (DMF) mixed solvent dissolves, stirring at room, treat to add 8-amino-quinazoline compound 0.252 g (1 mmol) after material dissolution, reaction at 75 ℃, in reaction process, solution colour is deepened gradually, and TLC monitors reaction.React approximately 1 h, react completely, use NH 4cI saturated solution washing reaction, acetic acid second extremely extracts, extraction liquid anhydrous Na 2sO 4dry, suction filtration, solvent evaporated, through column chromatography, (acetic acid second purport at tenth of the twelve Earthly Branches sherwood oil is eluent: Petro/AcOEt=5/1) after separation, obtain red powder compound; Mp 260-263 oc; IR (KBr): 3464,3368,3054,2240,1663,1488,1320,1250,758,540 cm -1; 1h NMR (500 MHz, DMSO- d6): δ=5.29 (s, 2H, NH), 6.67 (d, j=8.0 Hz, 2H, ArH), 6.83 (t, j=7.2 Hz, 1H, ArH), 7.20 (t, j=7.8 Hz, 2H, ArH), 7.45 (d, j=8.7Hz, 1H, ArH), 7.50 (d, j=8.6 Hz, 1H, ArH), 8.11 (s, 1H, NCH=N), 8.35 (br, 1H, OH); 13c NMR (125 MHz, DMSO- d6): δ=112.0,112.6,114.8,115.9,116.3,117.8,119.8,123.4,124.6,126.0,129.0,133.8,139.2,139.3,139.6,142.3,143.2,143.3,143.7,160.1; HRMS (TOF ES +): m/z calcd for C 22h 11cl 3n 6o [(M+Na) +], 502.9958; Found, 502.9950.
Target compound 2-16 obtains by similar approach.
embodiment 22, the chloro-6-of 4,5-tri-(4-oxo-5-(o-tolyl is amino)-3,4-dihydroquinazoline-8-is amino) m-dicyanobenzene (compound 2)
Red solid; Mp 269-272 oc; IR (KBr): 3457,3364,2351,2229,1664,1486,1318,1253,752,541 cm -1; 1h NMR (500 MHz, DMSO- d6): δ=2.29 (s, 3H, ArCH 3), 6.23 (d, j=7.9 Hz, 1H, ArH), 6.78 (t, j=7.3 Hz, 1H, ArH), 7.00 (t, j=7.4 Hz, 1H, ArH), 7.14 (d, j=7.1 Hz, 1H, ArH), 7.40 (d, j=8.6 Hz, 1H, ArH), 7.44 (d, j=8.6Hz, 1H, ArH), 8.06 (s, 1H, NCH=N), 8.28 (br, 1H, OH); 13c NMR (125 MHz, DMSO- d6): δ=17.9,112.0,112.6,113.9,115.0,115.8,118.0,120.5,123.4,123.9,126.3,126.5,127.1,130.4,133.8,139.5,140.9,142.3,143.0,160.8; HRMS (TOF ES +): m/z calcd for C 23h 13cl 3n 6o [(M+Na) +], 517.0114; Found, 517.0108.
embodiment 32, the chloro-6-of 4,5-tri-(4-oxo-5-(m-tolyl is amino)-3,4-dihydroquinazoline-8-is amino) m-dicyanobenzene (compound 3)
Red solid; Mp 287-288 oc; IR (KBr): 3477,3375,2351,1664,1487,1324,1250,790,543 cm -1; 1h NMR (500 MHz, DMSO- d6): δ=2.23 (s, 3H, CH 3), 6.45 (d, j=7.7 Hz, 1H, ArH), 6.49-6.53 (m, 1H, ArH), 6.65 (d, j=7.3 Hz, 1H, ArH), 7.07 (t, j=7.9Hz, 1H, ArH), 7.45 (d, j=8.7 Hz, 1H, ArH), 7.49 (d, j=8.6 Hz, 1H, ArH), 8.11 (s, 1H, NCH=N), 8.32 (br, 1H, OH); 13c NMR (125 MHz, DMSO- d6): δ=21.6,112.0,112.6,113.5,114.7,115.9,117.0,117.8; 120.8,123.4,124.4,126.1,128.6,128.9,133.8; 138.2,139.3,139.6,142.3,143.2,143.5,160.2; HRMS (TOF ES +): m/z calcd for C 23h 13cl 3n 6o [(M+Na) +], 517.0114; Found, 517.010.
embodiment 42, the chloro-6-of 4,5-tri-(4-oxo-5-(p-tolyl is amino)-3,4-dihydroquinazoline-8-is amino) m-dicyanobenzene (compound 4)
Red solid; Mp 249-252 oc; IR (KBr): 3468,3372,2350,1663,1488,1320,1248,812,542 cm -1; 1h NMR (500 MHz, DMSO- d6): δ=2.19 (s, 3H, CH 3), 5.16 (br, 2H, NH), 6.55 (d, j=7.6 Hz, 2H, ArH), 6.97 (d, j=7.6 Hz, 2H, ArH), 7.40 (d, j=8.8 Hz, 2H, ArH), 8.06 (s, 1H, NCH=N), 8.37 (br, 1H, OH); 13c NMR (125 MHz, DMSO- d6): δ=20.6,112.0,112.6,114.1,115.9,116.8,117.9,123.4,124.0,126.9,129.0,129.5,133.8,139.3,139.5,140.8,142.3,142.7,143.1,147.5,160.5; HRMS (TOF ES +): m/z calcd for C 23h 13cl 3n 6o [(M+Na) +], 517.0114; Found, 517.0104.
embodiment 52, the chloro-6-of 4,5-tri-(5-(4-chloro-phenyl-is amino)-4-oxo-3,4-dihydroquinazoline-8-is amino) m-dicyanobenzene (compound 5)
Red solid; Mp 248-249 oc; IR (KBr): 3477,3377,2360,2230,1666,1488,1253,756,539 cm -1; 1h NMR (500 MHz, DMSO- d6): δ=2.13 (br, 2H, NH), 6.60-6.65 (m, 2H, ArH); 7.17-7.21 (m, 2H, ArH), 7.45-7.51 (m, 2H, ArH); 8.10 (s, 1H, NCH=N), 8.35 (br, 1H, OH); 13c NMR (125 MHz, DMSO- d6): δ=31.03,112.0,112.6,115.6,115.9,117.3,117.9,122.8,123.6,124.8,125.3,128.7,133.8,139.4,139.7,142.3,143.3,144.0,159.6; HRMS (TOF ES +): m/z calcd for C 22h 10cl 4n 6o [(M+H) +], 516.9719; Found, 516.9702.
embodiment 62, the chloro-6-of 4,5-tri-(5-(3-chloro-phenyl-is amino)-4-oxo-3,4-dihydroquinazoline-8-is amino) m-dicyanobenzene (compound 6)
Red solid; Mp 280-281 oc; IR (KBr): 3469,3371,2350,1665,1478,1252,777,541 cm -1; 1h NMR (500 MHz, DMSO- d6): δ=6.60-6.53 (m, 1H, ArH), 6.55-6.58 (m, 1H, ArH), 6.71-6.76 (m, 1H, ArH), 7.10-7.15 (m, 1H, ArH), 7.45 (d, j=8.8Hz, 2H, ArH), 8.07 (s, 1H, NCH=N), 8.18 (br, 1H, OH); 13c NMR (125 MHz, DMSO- d6): δ=112.0,112.6,114.0,114.9,115.9,117.9,118.5,123.6,123.8,125.8,130.5,133.6,133.8,139.2,139.4,139.8,142.3,143.3,146.5,159.3; HRMS (TOF ES +): m/z calcd for C 22h 10cl 4n 6o [(M+H) +], 516.9719; Found, 516.9756.
embodiment 72, the chloro-6-of 4,5-tri-(5-(4-fluorophenyl is amino)-4-oxo-3,4-dihydroquinazoline-8-is amino) m-dicyanobenzene (compound 7)
Red solid; Mp 273-275 oc; IR (KBr): 3482,3386,2921,2240,1665,1497,1220,752,532 cm -1; 1h NMR (500 MHz, DMSO- d6): δ=2.10 (s, 2H, NH), 6.60-6.64 (m, 2H, ArH); 6.96-7.01 (m, 2H, ArH), 7.40-7.47 (m, 2H, ArH); 8.07 (s, 1H, NCH=N), 8.30 (br, 1H, OH); 13c NMR (125 MHz, DMSO- d6): δ=112.0,112.6,114.7,115.4,115.5,115.9,117.6,117.9,123.5,124.5,126.2,133.8,139.3,139.6,140.1,142.3,143.2,155.8,157.7,160.1; HRMS (TOF ES +): m/z calcd for C 22h 10cl 3fN 6[(M+H) +], 499.0044; Found, 499.0013.
embodiment 82, the chloro-6-of 4,5-tri-(5-(3,4-3,5-dimethylphenyl is amino)-4-oxo-3,4-dihydroquinazoline-8-is amino) m-dicyanobenzene (compound 8)
Red solid; Mp 284-285 oc; IR (KBr): 3468,3367,2920,2238,1663,1490,1255,750,542 cm -1; 1h NMR (500 MHz, DMSO- d6): δ=2.11 (s, 6H, ArCH 3), 5.16 (s, 2H, NH); 6.33-6.34 (m, 1H, ArH), 6.35-6.37 (m; 1H, ArH), 6.90-6.93 (m, 1H; ArH), 7.37-7.43 (m, 2H; ArH) 8.07 (s, 1H, NCH=N); (8.36 br, 1H, OH); 13c NMR (125 MHz, DMSO- d6): δ=18.9,20.0,112.0,112.6,114.1,115.9,117.8,118.4,123.3,127.0,127.9,130.0,133.8,136.6,139.2,139.5,141.0,142.3,142.6,143.2,160.5; HRMS (TOF ES +): m/z calcd for C 24h 15cl 3n 6o [(M+H) +], 509.0451; Found, 509.0446.
embodiment 92, the chloro-6-of 4,5-tri-(5-(3,5-3,5-dimethylphenyl is amino)-4-oxo-3,4-dihydroquinazoline-8-is amino) m-dicyanobenzene (compound 9)
Red solid; Mp 284-286 oc; IR (KBr): 3466,3370,2918,2234,1632,1484,1243,758,540 cm -1; 1h NMR (500 MHz, DMSO- d6): δ=2.15 (s, 6H, ArCH 3), 5.17 (s, 2H, NH), 6.25-6.30 (m, 2H, ArH); 6.44-6.49 (m, 1H, ArH), 7.40-7.46 (m, 2H, ArH); 8.06 (s, 1H, NCH=N), 8.25 (br, 1H, OH); 13c NMR (125 MHz, DMSO- d6): δ=21.5,112.0,112.6,114.2,114.6,115.9,117.8,121.8,123.4,124.3,126.3,133.9,138.0,139.3,139.5,142.3,143.2,143.5,160.2; HRMS (TOF ES +): m/z calcd for C 24h 15cl 3n 6o [(M+H) +], 509.0451; Found, 509.0443.
embodiment 10 2, the chloro-6-of 4,5-tri-(4-oxo-5-(piperidin-1-yl)-3,4-dihydroquinazoline-8-is amino) m-dicyanobenzene (compound 10)
Red solid; Mp 263-264 oc; IR (KBr): 3470,3362,2924,2351,1681,1420,1222,842,753,534 cm -1; 1h NMR (500 MHz, DMSO- d6): δ=5.67 (br, 1H, NH), 1.60 (s, 4H ,-CH 2-), 2.10 (s, 4H ,-CH 2-), 2.62 (s, 2H ,-CH 2-), 7.37-7.42 (m, 2H, ArH), 8.00 (s, 1H, NCH=N), 13c NMR (125 MHz, DMSO- d6): δ=24.2,27.3,112.1,112.7,115.9,117.7,119.8,122.9,126.1,133.8,134.0,139.2,139.9,142.3,143.9,147.4,158.2; HRMS (TOF ES +): m/z calcd for C 21h 15cl 3n 6o [(M+H) +], 473.0451; Found, 473.0440.

Claims (7)

1. a class formation formula is as the phenyl polyhalide nitrile quinazolinones of (I) formula:
Figure DEST_PATH_IMAGE001
In formula:
X 1~ X 3represent halogen F, Cl, Br, I atom;
R 1represent H atom or methyl, methylene radical, ethyl, propyl group alkane;
R 2for methyl, methylene radical, ethyl, propyl group or substituted-phenyl, wherein substituted-phenyl is methyl substituted, and halogen replaces, and alkoxyl group replaces, and nitro replaces, and itrile group replaces one or more substituted-phenyls wherein.
2. phenyl polyhalide nitrile quinazolinones claimed in claim 1, is characterized in that: described compound is:
Figure DEST_PATH_IMAGE002
Figure DEST_PATH_IMAGE003
Figure DEST_PATH_IMAGE004
Compound 1 compound 2 compounds 3
Figure DEST_PATH_IMAGE005
Figure DEST_PATH_IMAGE006
Figure DEST_PATH_IMAGE007
Compound 4 compound 5 compounds 6
Figure DEST_PATH_IMAGE008
Figure DEST_PATH_IMAGE010
Compound 7 compound 8 compounds 9
Figure DEST_PATH_IMAGE011
Figure DEST_PATH_IMAGE012
Figure DEST_PATH_IMAGE013
Compound 10 compound 11 compounds 12
Figure DEST_PATH_IMAGE014
Figure DEST_PATH_IMAGE016
Compound 13 compound 14 compounds 15
Figure DEST_PATH_IMAGE017
Compound 16.
3. the preparation method of the phenyl polyhalide nitrile quinazolinones described in claim 1 or 2, is characterized in that: formula (II) compound and formula (III) compound, in solvent, are added to alkali generation nucleophilic substitution reaction and prepare formula (I) compound:
Figure DEST_PATH_IMAGE018
。
4. the preparation method of phenyl polyhalide nitrile quinazolinones according to claim 3, it is characterized in that: the solvent using is: methyl alcohol, ethanol, ethyl acetate, acetonitrile, ether, tetrahydrofuran (THF), acetone, benzene, toluene, methylene dichloride, chloroform, 1, the mixing of 4-dioxane, DMF or dimethyl sulfoxide (DMSO) and above two or more solvents thereof.
5. the preparation method of phenyl polyhalide nitrile quinazolinones according to claim 3, is characterized in that: the alkali using is: salt of wormwood, sodium carbonate, sodium hydroxide, potassium hydroxide, potassium tert.-butoxide, sodium tert-butoxide, sodium ethylate, sodium methylate.
6. the preparation method of phenyl polyhalide nitrile quinazolinones according to claim 3, is characterized in that: temperature of reaction is 20-150 ℃.
7. the phenyl polyhalide nitrile quinazolinones described in claim 1 or 2 causes the medicinal application of disease preparing prevention, treatment to be infected by gram-negative, positive bacteria.
CN201310242148.1A 2013-06-19 2013-06-19 Phenyl polyhalide nitrile quinazolinones and its production and use Expired - Fee Related CN103554038B (en)

Priority Applications (1)

Application Number Priority Date Filing Date Title
CN201310242148.1A CN103554038B (en) 2013-06-19 2013-06-19 Phenyl polyhalide nitrile quinazolinones and its production and use

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
CN201310242148.1A CN103554038B (en) 2013-06-19 2013-06-19 Phenyl polyhalide nitrile quinazolinones and its production and use

Publications (2)

Publication Number Publication Date
CN103554038A true CN103554038A (en) 2014-02-05
CN103554038B CN103554038B (en) 2015-10-14

Family

ID=50008443

Family Applications (1)

Application Number Title Priority Date Filing Date
CN201310242148.1A Expired - Fee Related CN103554038B (en) 2013-06-19 2013-06-19 Phenyl polyhalide nitrile quinazolinones and its production and use

Country Status (1)

Country Link
CN (1) CN103554038B (en)

Cited By (11)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2019526550A (en) * 2016-08-15 2019-09-19 ニューファーマ， インコーポレイテッド Specific chemical entities, compositions and methods
JP2020506178A (en) * 2017-01-23 2020-02-27 レヴォリューション・メディスンズ，インコーポレイテッド Bicyclic compounds as allosteric SHP2 inhibitors
CN112661750A (en) * 2020-12-29 2021-04-16 西南大学 Ketene-bridged quinazolinone thiazole compound and preparation method and application thereof
US11376105B2 (en) 2017-06-30 2022-07-05 Fresh Health Inc. Systems and methods for personalized oral irrigation
USD962422S1 (en) 2019-04-15 2022-08-30 Fresh Health Inc. Oral care device
US11661401B2 (en) 2016-07-12 2023-05-30 Revolution Medicines, Inc. 2,5-disubstituted 3-methyl pyrazines and 2,5,6-trisubstituted 3-methyl pyrazines as allosteric SHP2 inhibitors
US11673896B2 (en) 2017-01-23 2023-06-13 Revolution Medicines, Inc. Pyridine compounds as allosteric SHP2 inhibitors
US11673901B2 (en) 2017-12-15 2023-06-13 Revolution Medicines, Inc. Polycyclic compounds as allosteric SHP2 inhibitors
US11702411B2 (en) 2017-10-12 2023-07-18 Revolution Medicines, Inc. Pyridine, pyrazine, and triazine compounds as allosteric SHP2 inhibitors
US11865120B2 (en) 2013-08-23 2024-01-09 Neupharma, Inc. Substituted quinazolines for inhibiting kinase activity
US12018002B2 (en) 2021-10-20 2024-06-25 Neupharma, Inc Certain chemical entities, compositions, and methods

Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3155650A (en) * 1961-03-03 1964-11-03 Mead Johnson & Co 2-substituted-4-sulfanilamidoquinazolines and process
US3755581A (en) * 1968-02-27 1973-08-28 Ciba Geigy Ag Combatting phytopathogenic bacteria and fungi with n phenylquinazolones
CN1123028A (en) * 1993-05-12 1996-05-22 纳幕尔杜邦公司 Fungicidal fused bicyclic pyrimidinones
CN101431900A (en) * 2006-04-26 2009-05-13 巴斯夫欧洲公司 Composition comprising a glucan or a glucan derivative and a pesticide and methods for improving plant health
CN101463013A (en) * 2007-12-21 2009-06-24 上海百灵医药科技有限公司 Preparation of erlotinid hydrochloride

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3155650A (en) * 1961-03-03 1964-11-03 Mead Johnson & Co 2-substituted-4-sulfanilamidoquinazolines and process
US3755581A (en) * 1968-02-27 1973-08-28 Ciba Geigy Ag Combatting phytopathogenic bacteria and fungi with n phenylquinazolones
CN1123028A (en) * 1993-05-12 1996-05-22 纳幕尔杜邦公司 Fungicidal fused bicyclic pyrimidinones
CN101431900A (en) * 2006-04-26 2009-05-13 巴斯夫欧洲公司 Composition comprising a glucan or a glucan derivative and a pesticide and methods for improving plant health
CN101463013A (en) * 2007-12-21 2009-06-24 上海百灵医药科技有限公司 Preparation of erlotinid hydrochloride

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
贺能琴: "多卤代间苯二甲腈衍生物的合成及抗菌活性研究", 《中国优秀硕士学位论文全文数据库工程科技Ⅰ辑》, no. 4, 15 April 2012 (2012-04-15) *

Cited By (16)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US11865120B2 (en) 2013-08-23 2024-01-09 Neupharma, Inc. Substituted quinazolines for inhibiting kinase activity
US11661401B2 (en) 2016-07-12 2023-05-30 Revolution Medicines, Inc. 2,5-disubstituted 3-methyl pyrazines and 2,5,6-trisubstituted 3-methyl pyrazines as allosteric SHP2 inhibitors
JP2022058912A (en) * 2016-08-15 2022-04-12 ニューファーマ， インコーポレイテッド Particular chemical substance, composition, and method
JP2019526550A (en) * 2016-08-15 2019-09-19 ニューファーマ， インコーポレイテッド Specific chemical entities, compositions and methods
JP7101165B2 (en) 2016-08-15 2022-07-14 ニューファーマ， インコーポレイテッド Specific chemical entities, compositions, and methods
JP2020506178A (en) * 2017-01-23 2020-02-27 レヴォリューション・メディスンズ，インコーポレイテッド Bicyclic compounds as allosteric SHP2 inhibitors
US11739093B2 (en) 2017-01-23 2023-08-29 Revolution Medicines, Inc. Substituted pyrazolopyrazines, imidazopyrazines and [1,2,4]triazolopyrazines as allosteric SHP2 inhibitors
US11673896B2 (en) 2017-01-23 2023-06-13 Revolution Medicines, Inc. Pyridine compounds as allosteric SHP2 inhibitors
JP7240319B2 (en) 2017-01-23 2023-03-15 レヴォリューション・メディスンズ，インコーポレイテッド Bicyclic compounds as allosteric SHP2 inhibitors
US11376105B2 (en) 2017-06-30 2022-07-05 Fresh Health Inc. Systems and methods for personalized oral irrigation
US11702411B2 (en) 2017-10-12 2023-07-18 Revolution Medicines, Inc. Pyridine, pyrazine, and triazine compounds as allosteric SHP2 inhibitors
US11673901B2 (en) 2017-12-15 2023-06-13 Revolution Medicines, Inc. Polycyclic compounds as allosteric SHP2 inhibitors
USD962422S1 (en) 2019-04-15 2022-08-30 Fresh Health Inc. Oral care device
CN112661750B (en) * 2020-12-29 2022-10-21 西南大学 Ketene-bridged quinazolinone thiazole compound and preparation method and application thereof
CN112661750A (en) * 2020-12-29 2021-04-16 西南大学 Ketene-bridged quinazolinone thiazole compound and preparation method and application thereof
US12018002B2 (en) 2021-10-20 2024-06-25 Neupharma, Inc Certain chemical entities, compositions, and methods

Also Published As

Publication number Publication date
CN103554038B (en) 2015-10-14

Similar Documents

Publication Publication Date Title
CN103554038B (en) Phenyl polyhalide nitrile quinazolinones and its production and use
US20060258693A1 (en) Halogenated quinazolinyl nitrofurans as antibacterial agents
Chawla et al. Microwave assisted synthesis of some novel 2-pyrazoline derivatives as possible antimicrobial agents
WO2013052263A2 (en) Antifungal compounds
EP3484481B1 (en) Methods for use in the treatment of clostridium difficile
Yousif et al. Synthesis and antimicrobial screening of tetra Schiff bases of 1, 2, 4, 5-tetra (5-amino-1, 3, 4-thiadiazole-2-yl) benzene
CN108309977A (en) Application of the indoles ethylene substituted chinoline derivative in preparing drug-resistance bacteria medicine
Gondru et al. 3-(1-Phenyl-4-((2-(4-arylthiazol-2-yl) hydrazono) methyl)-1 H-pyrazol-3-yl)-2 H-chromen-2-ones: one-pot three component condensation, in vitro antimicrobial, antioxidant and molecular docking studies
CN107325093B (en) Synthesis and application of thiourea compound with antibacterial activity
Asadipour et al. N-substituted piperazinyl sarafloxacin derivatives: synthesis and in vitro antibacterial evaluation
Cagri Karaburun et al. Synthesis, antibacterial and antifungal activities of some carbazole dithiocarbamate derivatives
Sheikhi-Mohammareh et al. Robust approach leading to novel densely functionalized four-cyclic benzo [e] pyrazolo [5′, 1′: 2, 3] pyrimido [4, 5-b][1, 4] diazepines with antibacterial activity toward resistant strains
Alam et al. Synthesis, antibacterial, antioxidant activity and QSAR studies of novel 2-arylidenehydrazinyl-4-arylthiazole analogues
CN102675226A (en) 3-substituted-1-methyl-quinazoline-2,4-dione compounds, preparation method and application thereof
CN108586434A (en) A kind of purposes of indole-2-ketone compound in antibiosis
CN108017664A (en) A kind of p-aminobenzene sulfonic acid metal complex antiseptic and its preparation method and application
CN110437177A (en) A kind of pleuromutilin derivative and its preparation method and application
CN104356123A (en) 1,2,4-triazole Mannich base derivatives containing substituted piperazidine, and preparation method and application thereof
Ibrahim One-pot Synthesis, Characterization and Antimicrobial Activity of New 3-Cyano-4-alkyl-6-(2, 5-dichlorothiophen-3-yl)-2 (1H)-pyridones
EP3679037B1 (en) New 5-aminotetrazole derivatives with antibacterial and antifungal activity
Farhhod Review the Antibacterial Activity of Sulfonamides Derivatives
Joshi et al. Synthesis, antitubercular and antibacterial activities of novel N’-(substituted)-2-(2, 5-dimethyl-1h-pyrrol-1-yl) phenyl) benzamide derivatives
RU2602804C1 (en) Salts of benzofuroxane with lomefloxacin, having antibacterial activity
RU2148580C1 (en) 1-ARYL-7-METHYL-2-[β-(5'-NITRO-2'-FURYL)VINYL]-PYRIDO[2,3-D]- PYRIMIDINE-4-ONES SHOWING ANTIBACTERIAL ACTIVITY
Mohan et al. Synthesis, Characterization And In-Vitro Antimicrobial Study Of Series Of 1-((Substituted Aryl/Alkyl) Sulfonyl)-4-Tosylpiperazines

Legal Events

Date Code Title Description
C06 Publication
PB01 Publication
SE01 Entry into force of request for substantive examination
SE01 Entry into force of request for substantive examination
C14 Grant of patent or utility model
GR01 Patent grant
CF01 Termination of patent right due to non-payment of annual fee
CF01 Termination of patent right due to non-payment of annual fee

Granted publication date: 20151014

Termination date: 20180619