CN101759637A - N-aryl-3,4-dihydro-isoquinoline salt and application thereof in preparing acaricidal and antibiotic medicament - Google Patents
N-aryl-3,4-dihydro-isoquinoline salt and application thereof in preparing acaricidal and antibiotic medicament Download PDFInfo
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Abstract
The invention relates to N-aryl-3,4-dihydro-isoquinoline salt and application thereof in preparing an acaricidal and antibiotic medicament. The N-aryl-3,4-dihydro-isoquinoline salt has favorable bacteriostatic activity with unequal degrees to various pathogenic bacteria of animals and plants and also has favorable killing activity to various animal acarids and plant acarids. The invention relates to the N-aryl-3,4-dihydro-isoquinoline salt with the following molecular structure characteristic, wherein R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, R11 and R12 are identical or different hydrogen, alkyl, naphthenic groups, alkenyl, alkynyl, unsaturated monocyclic hydrocarbon groups, alkoxyl groups, halogen, hydroxy groups, nitryl, nitrile groups, trifluoromethyl, heterocyclic substituent groups, carboxylic groups, ester groups, amido groups, acyl or aldehyde groups; and X- is a sulfate radical, a halogen negative ion, carbonate, a bicarbonate radical, a phosphate radical, a phosphate radical, a fatty acid radical, a sulfonic acid radical or a tetraphenylboron radical.
Description
One, technical field:
The present invention relates to a class formation brand-new 3,4-dihydroisoquinoline derivative synthetic especially relates to a kind of N-aryl-3,4-dihydro-isoquinoline salt and kill the application of mite and antibacterials as preparation.
Two, background technology:
In a lot of plants, exist a class and have the active natural alkaloid of valuable pharmacological, promptly quaternary ammonium type benzo phenanthridines compounds (quaternary benzo[c] phenanthridine alkaloids, QBAs).For example, chelerythrine, sanguilutine, chelirubine, chelilutine, sangrirubine, sanguinarine, nitidine, fagaronine etc.The most significant constructional feature of QBAs is to have positively charged carbon-to-nitrogen double bon (C=N in the molecule
+-).Pharmacology activity research proves that the pyridine of quaternary ammonium type benzo coffee has notable antitumor activity, carbon-to-nitrogen double bon (C=N wherein
+-) be active function groups.Our research work finds that also chelerythrine and sanguinarine have significant bacteriostatic activity to various bacteria, and the carbon-to-nitrogen double bon (C=N in the molecule
+-) also be the functional group of its bacteriostatic activity.Based on above-mentioned result of study, the applicant is according to the constructional feature of natural quaternary ammonium type benzo coffee pyridine compounds, designed and synthesized serial N-aryl-3 first, 4-dihydro-isoquinoline salt derivative, wherein most target compounds are new compound, and its acaricidal activity and anti-microbial activity are compared research.The result proves, related serial N-aryl-3 among the present invention, and 4-dihydro-isoquinoline salt derivative all has the good bacteriostatic activity of varying degree to multiple animal and plant pathogenic bacteria.Simultaneously, find that also these compounds also have the good activity of killing to multiple animal acarid and plant acarid.
Before this research, most of N-aryl-3 involved in the present invention, the structure of 4-dihydro-isoquinoline salt derivative and the synthetic report that there is no.Known compound related among the present invention mainly contains: bromination N-phenyl-3,4-dihydro-isoquinoline salt (I, R
1～R
12=H, X=Br
-) (Z.Li, et al.Tetrahedron:Asymmetry, 2006,17:590-597)), bromination N-(2-p-methoxy-phenyl)-3,4-dihydro-isoquinoline salt (I, R
2～R
12=H, R
1=OCH
3, X=Br
-) (Gross, H.Journal fuer Praktische Chemie (Leipzig), 1983,325 (3), 437-45), bromination N-(4-p-methoxy-phenyl)-3,4-dihydro-isoquinoline salt (I, R
1=R
2=R
4～R
12=H, R
3=OCH
3, X=Br
-), bromination N-(4-aminomethyl phenyl)-3,4-dihydro-isoquinoline salt (I, R
1=R
2=R
4～R
12=H, R
3=CH
3, X=Br
-), bromination N-(2-chloro-phenyl-)-3,4-dihydro-isoquinoline salt (I, R
2～R
12=H, R
1=Cl, X=Br
-), bromination N-(3-chloro-phenyl-)-3,4-dihydro-isoquinoline salt (I, R
1=R
3～R
12=H, R
2=Cl, X=Br
-), bromination N-(3-nitrophenyl)-3,4-dihydro-isoquinoline salt (I, R
1=R
3～R
12=H, R
2=NO
2, X=Br
-), bromination N-(4-nitrophenyl)-3,4-dihydro-isoquinoline salt (I, R
1=R
2=R
4～R
12=H, R
3=NO
2, X=Br
-).Tetraphenyl borate N-(1,3,5-tribromo phenyl)-3,4-dihydro-isoquinoline salt I, R
2=R
4～R
12=H, R
1=R
3=R
5=Br, X=Br
-), tetraphenyl borate N-(1, the 5-3,5-dimethylphenyl)-3,4-dihydro-isoquinoline salt I, R
2=R
3=R
4～R
12=H, R
1=R
5=CH
3, X=Br
-), tetraphenyl borate N-(1, the 5-diisopropyl phenyl)-3,4-dihydro-isoquinoline salt I, R
2=R
4～R
12=H, R
1=R
5=CH (CH
3)
2, X=Br
-), tetraphenyl borate N-(2, the 4-Dimethoxyphenyl)-3,4-dihydro-isoquinoline salt I, R
1=R
3=R
5～R
12=H, R
2=R
4=OCH
3, X=Br
-) (P.C.B.Page.Synthesis, 2005,19,3405-3411).
About all related in this research N-aryl-3,4-dihydro-isoquinoline salt derivative kill mite and anti-microbial activity research with and be used for extremely that the purposes of mite and antibacterials there is no any bibliographical information.
Three, summary of the invention
The object of the present invention is to provide a kind of N-aryl-3, the application of mite and antibacterials is killed in 4-dihydro-isoquinoline salt and conduct preparation thereof, the good bacteriostatic activity that it all has varying degree to multiple animal and plant pathogenic bacteria also has the good activity of killing to multiple animal acarid and plant acarid simultaneously.
For achieving the above object, the technical solution used in the present invention is:
A kind of N-aryl-3,4-dihydro-isoquinoline salt is characterized in that having following molecular characterization:
Wherein, R
1, R
2, R
3, R
4, R
5, R
6, R
7, R
8, R
9, R
10, R
11, R
12Be identical or different hydrogen, alkyl, cycloalkyl, alkenyl, alkynyl group, undersaturated monocycle alkyl, alkoxyl group, halogen, hydroxyl, nitro, cyano group, trifluoromethyl, heterocyclic substituent, carboxyl, ester group, amide group, acyl group or aldehyde radical;
X
-Be sulfate radical, halogen anion, carbonate, bicarbonate radical, phosphate radical, hydrogen phosphate, lipid acid acid group, sulfonate radical or tetraphenylboron acid group.
N-aryl-3,4-dihydro-isoquinoline salt kill the application of mite and antibacterials as preparation.
Compared with prior art, the present invention has following advantage and effect:
The objective of the invention is to design bromination N-aryl-3, the molecular structure of 4-dihydro-isoquinoline salt, set up the synthetic route and the method for synthetic this compounds, finish its structural analysis, pass through biological activity determination, prove that this compounds has strong acarid and the sterilizing ability of killing, be a class at the medicine that has potential using value aspect people's medicine, veterinary drug and the agricultural chemicals, synthetic and other more extensive pharmacology activity researchs of compounds provide basic data for this reason.
Four, embodiment
In the present invention, the N-aryl-3 that the applicant designs and synthesizes, the general structure of 4-dihydro-isoquinoline salt compounds is as follows:
Wherein, R
1, R
2, R
3, R
4, R
5, R
6, R
7, R
8, R
9, R
10, R
11, R
12Be identical or different and represent hydrogen, alkyl, cycloalkyl, alkenyl, alkynyl group, undersaturated monocycle alkyl, alkoxyl group, halogen, hydroxyl, nitro, trifluoromethyl, heterocyclic substituent, carboxyl, ester group, amide group, acyl group, aldehyde radical.
X
-Be sulfate radical, halogen anion, carbonate, bicarbonate radical, phosphate radical, hydrogen phosphate, lipid acid acid group, sulfonate radical.
The present invention sets up is used to prepare N-aryl-3, and the typical synthetic route of 4-dihydro-isoquinoline salt compounds is as follows:
The applicant adopts external bacteriostatic activity test and acaricidal activity test respectively, and above-claimed cpd has been carried out pharmacology activity research.In external bacteriostatic activity test, adopt nephelometry to measure the minimal inhibitory concentration (MIC) of each test compound, and compare with antibiotic Western medicine ceftriaxone sodium of broad spectrum and the positive medicine of Ciprofloxacin commonly used clinically, analyze the bacteriostatic activity of each test compound, prove that all test compounds (I) are the medicines that a class can be used in the animal and plant antibacterial application.In the acaricidal activity test, the mortality ratio of acarid is an index during with different concns, and with practice in commonly used high efficiency miticide thing Avrmectin compare, analyze the acaricidal activity of each test compound, prove that all test compounds (I) are that a class can be used in the medicine that animal and plant kills the mite purposes.
Subordinate list 1 is a bromination N-aryl-3, four kinds of MIC values for examination bacterium bacteriostatic activity of 4-dihydro-isoquinoline salt pair.Subordinate list 2 is bromination N-aryl-3, and 4-dihydro-isoquinoline salt is at the lethality rate of different concns to the rabbit mite.
Below in conjunction with subordinate list and synthetic method and determination of activity thereof the present invention is described in further detail:
4.1N-aryl-3, the preparation of 4-dihydro-isoquinoline salt
4.1.1 compound (II) is synthetic
With heterochromatic full (R
6～R
12=H) be prepared as example, its concrete synthetic method is:
With Paraformaldehyde 96 (12.0g, 4.0mol) and the 110ml concentrated hydrochloric acid be added at the bottom of the 500ml garden in the flask, 60 ℃ of heating in water bath 30 minutes, Paraformaldehyde 96 all dissolves.Reaction solution is cooled to 30 ℃, adds about 100mL protective material, adding in three batches is dissolved in 50mL protectant 2-phenylethyl alcohol (12.2g, 0.1mol) solution in advance in 30 minutes then.Reaction mixture is 50 ℃ of heating 30～50 minutes, complete until the TLC detection reaction.To room temperature, add about 150g trash ice to the cooling reaction solution.After icing molten finishing, tell upper organic phase with separating funnel.Water with ether (4 * 60mL) extractions merge ether extraction liquid and the organic phase told in advance, and anhydrous sodium sulfate drying filters, and collects filtrate, steam remove solution after, 105-106.5 ℃/20 cuts that hold in the palm are collected in underpressure distillation, be heterochromatic full, productive rate 94%.
4.1.2 compound (III) is synthetic
With 2-(2-bromotrifluoromethane) phenyl aldehyde (R
6～R
12=H) be example, its concrete synthetic method is:
In the 250mL flask, add 34g heterochromatic full (0.25mol) and 100mL tetracol phenixin.Under the ice bath cooling and stirring, in 10 minutes, drip 40g bromine (0.25mol) by dropping funnel.After exothermic heat of reaction stops, removing cryostat, use heating in water bath instead and reflux, become light yellowly to solution by dark-brown, hydrogen bromide stops to discharge.Reaction solution is chilled to room temperature, removes solvent under reduced pressure, get yellow oily liquid.In debris, add 50mL Hydrogen bromide (48%), reflux 10-15 minute, be cooled to room temperature, with ether (4 * 50mL) extractions.Water (2 * 30mL) and saturated sodium bicarbonate solution washing ether extraction liquid, anhydrous sodium sulfate drying.The filtering ether solution removes solvent under reduced pressure, gets gained light red oily liquids, promptly thick 2-(2-bromotrifluoromethane) phenyl aldehyde, productive rate 95%.Analytically pure 2-(2-bromotrifluoromethane) phenyl aldehyde can obtain by top product is carried out underpressure distillation.Thick all can be used for the synthetic of back compound (I) with analytically pure 2-(2-bromotrifluoromethane) phenyl aldehyde.：v
max/cm
-1(neat)2742，1697，1600，1575，1260，1193，755；δ
H(CDCl
3，400MHz)3.54-3.63(4H，m)，7.33(1H，d，J)8.0Hz)，7.48(1H，t，J＝7.5Hz)，7.54(1H，t，J＝7.9Hz)，7.80(1H，d，J＝7.6Hz)，10.14(1H，s)；δ
C(62.50MHz)33.17(CH
2)，36.70(CH
2)，128.10(CH)，132.51(CH)，134.14(CH)134.33(quat)，134.88(CH)，140.95(quat)，193.33(CH)；m/z?211；calcd?for?C
9H
9BrO?211.98373；found?211.98370。
4.1.2 compound (I) is synthetic
The synthetic of all compounds (I) all carries out according to following schedule of operation:
In the 100mL Erlenmeyer flask, add thick 2-(2-bromotrifluoromethane) phenyl aldehyde of 16mmol or analytical pure sample and the 50mL dioxane of 12mmol, ice bath is cooled to 0 ℃, under agitation drips the solution (30mL) of the dioxane of 10mmol aromatic amine.After adding, stirred overnight at room temperature.Suction filtration is collected solid, with a small amount of ether repetitive scrubbing for several times, dries or 40 ℃ of oven dry, gets compound (I).
Below be the states of matter and the productive rate of several representation compounds
Bromination N-phenyl-3,4-dihydro-isoquinoline salt, white crystal, productive rate 92%.
Bromination N-(4-aminomethyl phenyl)-3,4-dihydro-isoquinoline salt, yellow crystals, 93%.
Bromination N-(4-aminomethyl phenyl)-3,4-dihydro-isoquinoline salt, yellow crystals, 93%.
Bromination N-(2-aminomethyl phenyl)-3,4-dihydro-isoquinoline salt, safran crystal, 90%.
Bromination N-(3-aminomethyl phenyl)-3,4-dihydro-isoquinoline salt, yellow crystals, 86%.
Bromination N-(4-chloro-phenyl-)-3,4-dihydro-isoquinoline salt, pale yellow crystals, 93%.
Bromination N-(2-chloro-phenyl-)-3,4-dihydro-isoquinoline salt, oyster white crystal, 85%.
Bromination N-(3-chloro-phenyl-)-3,4-dihydro-isoquinoline salt, pale yellow crystals, 82%.
Bromination N-(4-nitrophenyl)-3,4-dihydro-isoquinoline salt, yellow crystals, 97%.
Bromination N-(2-nitrophenyl)-3,4-dihydro-isoquinoline salt, yellow-green colour crystal, 94%.
Bromination N-(3-nitrophenyl)-3,4-dihydro-isoquinoline salt, yellow crystals, 90%.
Bromination N-(4-hydroxy phenyl)-3,4-dihydro-isoquinoline salt, yellow-green colour crystal, 95%.
Bromination N-(4-aminophenyl)-3,4-dihydro-isoquinoline salt, red powder, 85%.
Bromination N-(4-p-methoxy-phenyl)-3,4-dihydro-isoquinoline salt, yellow-green colour crystal, 95%.
Bromination N-(4-carboxyl phenyl)-3,4-dihydro-isoquinoline salt, yellow-green colour crystal, 94%.
4.2N-aryl-3, the structural analysis of 4-dihydro-isoquinoline salt
The applicant adopts fusing point test and Spectrum Analysis (UV spectrum, infrared spectra, 1H nuclear magnetic resonance spectrum, 13C nuclear magnetic resonance spectrum and electrospray ionization mass spectrum) that the structure of compound (I) is identified.It below is the structure qualification result of representation compound among the 4.1.2 (I).
Bromination N-phenyl-3,4-dihydro-isoquinoline salt: m.p.106～108 ℃; UV (MeOH) λ
Max(log ε) 312 (4.02) nm;
1H NMR (CDCl
3, TMS) δ: 9.50 (1H, s, H-1), 8.21 (1H, d, J7.6Hz, H-8), 7.89 (1H, t, J7.6Hz, H-6), 7.81-7.83 (2H, m), 7.45-7.41 (4H, m), 7.38 (1H, d, J7.6Hz, H-5), 4.65 (2H, t, J 8.0Hz, H-4), 3.51 (2H, t, J 8.0Hz, H-3); ESI MS m/z:209.1[M]
+
Bromination N-(4-hydroxy phenyl)-3,4-dihydro-isoquinoline salt: m.p.222～224 ℃; UV (MeOH) λ
Max(log ε) 229 (3.88) nm, 280 (3.70) nm, 283 (3.74) nm;
1H NMR (CD
3OD, TMS) δ: 9.34 (1H, s, H-1), 7.96 (1H, d, J7.6Hz, H-8), 7.85 (1H, t, J7.6Hz, H-6), 7.64 (2H, d, J 8.8Hz, H-2 ', H-6 '), 7.00 (2H, d, J 8.8Hz, H-3 ', 5 '), 7.60 (1H, t, J 7.6Hz, H-7), 7.56 (1H, d, J 7.6Hz, H-5), 4.58 (2H, t, J 8.0Hz, H-4), 3.46 (2H, t, J 8.0Hz, H-3) .ESIMSm/z:224.1[M]
+
Bromination N-(4-p-methoxy-phenyl)-3,4-dihydro-isoquinoline salt: m.p.164～165 ℃; UV (MeOH) λ
Max(log ε) 227 (4.17) nm, 282 (3.95) nm, 356 (4.07) nm; .
1H NMR (CD
3OD, TMS) δ: 10.27 (1H, s, H-1), 8.43 (1H, d, J 7.6Hz, H-8), 7.70 (1H, t, J 7.6Hz, H-6), 8.01 (2H, d, J8.8Hz, H-2 ', H-6 '), 6.99 (2H, d, J 8.8Hz, H-3 ', 5 '), 7.44 (1H, t, J 7.6Hz, H-7), 7.37 (1H, d, J 7.6Hz, H-5), 4.57 (2H, t, J 8.0Hz, H-4), 3.79 (3H, s, OCH
3), 3.48 (2H, t, J 8.0Hz, H-3); ESI MSm/z:239.2[M]
+
Bromination N-(4-aminophenyl)-3,4-dihydro-isoquinoline salt: m.p.200～202 ℃; UV (MeOH) λ
Max(log ε) 249 (3.96) nm, 287 (3.91) nm, 425 (3.80) nm; .
1H NMR (CD
3OD, TMS) δ: 9.26 (1H, s, H-1), 7.93 (1H, d, J7.6Hz, H-8), 7.81 (1H, t, J7.6Hz, H-6), (7.54 3H, d, J8.8Hz, H-5, H-2 ', H-6 '), (6.88 2H, d, J 8.8Hz, H-3 ', 5 '), 7.57 (1H, t, J7.6Hz, H-7), 4.55 (2H, t, J 8.0Hz, H-4), 3.43 (2H, t, J 8.0Hz, H-3) .ESI MS m/z:223.1[M]
+
Bromination N-(4-carboxyl phenyl)-3,4-dihydro-isoquinoline salt: m.p.208 ℃ (decomposition); UV (MeOH) λ
Max(log ε) 301 (4.45) nm; ...
1H NMR (CD
3OD, TMS) δ: 9.59 (1H, s, H-1), 8.27 (2H, d, J 8.8Hz, H-3 ', H-5 '), 8.03 (1H, d, J 7.2Hz, H-8), 7.91 (J 8.0 for 3H, t-like, 7.6Hz, H-6, H-2 ', H-6 '), 7.64 (1H, d, J 7.6Hz, H-7), 7.61 (1H, d, J 7.2Hz, H-5), 4.67 (2H, t, J 8.0Hz, H-4), 3.51 (2H, t, J 8.0Hz, H-3) .ESI MS m/z:252.2[M]
+
Bromination N-(2-aminomethyl phenyl)-3,4-dihydro-isoquinoline salt: m.p.94～96 ℃; UV (MeOH) λ
Max(log ε) 213 (4.25) nm, 296 (3.97) nm; ....
1H NMR (d
6-DMSO, TMS) δ: 9.57 (1H, d-like, H-1), 8.03,8.02 (1H, dd, J 8.0,7.6Hz, H-8), 7.93,7.92 (1H, dt, J 7.6,7.6Hz, H-6), 7.74 (1H, d, J 7.6Hz, H-2 '), 7.66-7.62 (2H, m), 7.47-7.58 (3H, m), 4.43 (2H, t, J 7.6Hz, H-4), 3.46 (2H, t, J 7.6Hz, H-3), 2.45 (3H, s, CH
3) .ESI MS m/z:222.1[M]
+
Bromination N-(3-aminomethyl phenyl)-3,4-dihydro-isoquinoline salt: Yellow crystral, m.p.61～63 ℃; UV (MeOH) λ
Max(log ε) 213 (4.31) nm, 255 (3.97) nm; ....
1H NMR (d
6-DMSO, TMS) δ: 9.68,9.67 (1H, d-like, H-1), 8.05,8.05 (1H, dd, J 7.6,7.6Hz, and H-8), 7.89,7.89 (J 7.6,7.6Hz for 1H, dt, H-6), 7.74 (1H, s, H-2 '), 7.69 (1H, d, J 8.0Hz, H-6 '), 7.47 (1H, d, J 7.6Hz, H-5), 7.64-7.55 (3H, m, H-7, H-4 ', H-5 '), 4.59 (2H, t, J 8.0Hz, H-4), 3.42 (2H, t, J8.0Hz, H-3), 2.44 (3H, s, CH
3) .ESI MS m/z:222.1[M]
+
Bromination N-(4-aminomethyl phenyl)-3,4-dihydro-isoquinoline salt: m.p.163～164 ℃; UV (MeOH) λ
Max(log ε) 250 (3.88) nm; .
1H NMR (CD
3OD, TMS) δ: 9.44 (1H, s, H-1), 8.00 (1H, d, J7.6Hz, H-8), 7.87 (1H, t, J 7.6Hz, H-6), 7.79 (2H, d, J 8.8Hz, H-2 ', H-6 '), 7.58 (1H, d, J 7.6Hz, H-5), (7.48 2H, d, J 8.8Hz, H-3 ', 5 '), 7.60 (1H, t, J 7.6Hz, H-7), 4.61 (2H, t, J 8.0Hz, H-4), 3.48 (2H, t, J 8.0Hz, H-3), 2.45 (3H, s, CH
3) .ESI MS m/z:222.1[M]
+
Bromination N-(2-chloro-phenyl-)-3,4-dihydro-isoquinoline salt: m.p.199～200 ℃; UV (MeOH) λ
Max(log ε) 216 (4.35) nm, 253 (3.88) nm, 300 (4.07) nm; ..
1H NMR (CD
3OD, TMS) δ: 9.50 (1H, s, H-1), 8.02 (1H, d, J 7.6Hz, H-8), 7.96 (1H, t, J 7.6Hz, H-6), 7.87 (J 8.0,1.6Hz for 1H, dd, H-6 '), 7.79 (1H, d, J 8.0Hz, H-3 '), 7.71-7.62 (4H, m), 4.51 (2H, t, J 8.0Hz, H-4), 3.55 (2H, t, J 8.0Hz, H-3).
Bromination N-(3-chloro-phenyl-)-3,4-dihydro-isoquinoline salt: m.p.206～208 ℃; UV (MeOH) λ
Max(log ε) 212 (3.98) nm, 258 (3.98) nm; ..
1H NMR (d
6-DMSO, TMS) δ: 9.74 (1H, s, H-1), 8.10 (1H, d, J 1.2Hz, H-2 '), 8.05 (1H, d, J 7.6Hz, H-8), 7.92 (1H, dd, J 7.6,1.2Hz, H-6 '), and 7.70-7.87 (1H, m, H-6), 7.70-7.76 (2H, m, H-7, H-5 '), 7.64 (1H, t, J 7.6Hz, H-4 '), 7.61 (1H, d, J 7.6Hz, H-5), 4.59 (2H, t, J 8.0Hz, H-4), 3.42 (2H, t, J 8.0Hz, H-3).
Bromination N-(4-chloro-phenyl-)-3,4-dihydro-isoquinoline salt: m.p.198～200 ℃ (decomposition) .UV (MeOH) λ
Max(log ε) 261 (4.20) nm; .
1H NMR (CD
3OD, TMS) δ: 9.50 (1H, s, H-1), 8.00 (1H, d, J 7.6Hz, H-8), 7.89 (1H, t, J 7.6Hz, H-6), 7.82 (2H, d, J 8.8Hz, H-2 ', H-6 '), 7.74 (2H, d, J 8.8Hz, H-3 ', 5 '), 7.62 (1H, t, J 7.6Hz, H-7), 7.59 (1H, d, J 7.6Hz, H-5), 4.61 (2H, t, J 8.0Hz, H-4), 3.49 (2H, t, J 8.0Hz, H-3).
Bromination N-(2-nitrophenyl)-3,4-dihydro-isoquinoline salt: m.p.188～189 ℃; UV (MeOH) λ
Max(log) 228 (4.26) nm, 295 (4.08) nm; .
1H NMR (CD
3OD, TMS) δ: 9.49 (1H, s, H-1), 8.51 (1H, d, J 8.4Hz, H-8), 8.06 (1H, t, J 8.0Hz, H-6), 7.94-8.00 (4H, q-like), 7.64 (2H, t, J 8.0Hz), 4.56 (2H, t, J 8.0Hz, H-4), 3.59 (2H, t, J 8.0Hz, H-3) .ESI MSm/z:253.2[M]
+
Bromination N-(3-nitrophenyl)-3,4-dihydro-isoquinoline salt: m.p.218～220 ℃; UV (MeOH) λ
Max(log ε) 255 (4.32) nm, 313 (3.87) nm; ...
1H NMR (CD
3OD, TMS) δ: 9.65 (1H, s, H-1), 8.75 (1H, s, H-2 '), (8.50 1H, d, J 8.0Hz, H-6 '), 8.24 (1H, d, J 7.6Hz, H-4 '), 8.03 (1H, d, J 7.6Hz, H-8), 7.90-7.96 (2H, m, H-7, H-5 '), 7.65 (1H, d, J 7.6Hz, H-6), 7.61 (1H, d, J 7.6Hz, H-5), 4.68 (2H, t, J 8.0Hz, H-4), 3.53 (2H, t, J 8.0Hz, H-3) .ESIMS m/z:253.2[M]
+
Bromination N-(4-nitrophenyl)-3,4-dihydro-isoquinoline salt: m.p.192～194 ℃; UV (MeOH) λ
Max(log ε) 371 (4.28) nm; .
1H NMR (CD
3OD, TMS) δ: 9.60 (1H, s br, H-1), 8.49 (2H, d, J 8.8Hz, H-2 ', H-6 '), 7.90-8.03 (4H, m, H-3 ', H-4 ', H-6, H-8), 7.59-7.64 (2H, q-like, H-5, H-7), 4.64 (2H, s br, H-4), 3.50 (2H, t-like, H-3) .ESI MS m/z:253.2[M]
+.
By the CA retrieval, except the synthetic of following 10 compounds has the bibliographical information, structure of other compounds (I) involved in the present invention and the synthetic report that there is no.
Bromination N-phenyl-3,4-dihydro-isoquinoline salt; Bromination N-(2-p-methoxy-phenyl)-3,4-dihydro-isoquinoline salt; Bromination N-(4-p-methoxy-phenyl)-3,4-dihydro-isoquinoline salt; Bromination N-(4-aminomethyl phenyl)-3,4-dihydro-isoquinoline salt; Bromination N-(2-chloro-phenyl-)-3,4-dihydro-isoquinoline salt; Bromination N-(3-chloro-phenyl-)-3,4-dihydro-isoquinoline salt; Bromination N-(3-nitrophenyl)-3,4-dihydro-isoquinoline salt; Bromination N-(4-nitrophenyl)-3,4-dihydro-isoquinoline salt; Tetraphenyl borate N-(1,3,5-tribromo phenyl)-3,4-dihydro-isoquinoline salt; Tetraphenyl borate N-(1, the 5-3,5-dimethylphenyl)-3,4-dihydro-isoquinoline salt; Tetraphenyl borate N-(1, the 5-diisopropyl phenyl)-3,4-dihydro-isoquinoline salt; Tetraphenyl borate N-(2, the 4-Dimethoxyphenyl)-3,4-dihydro-isoquinoline salt.
4.3N-aryl-3, the mite and the anti-microbial activity extremely of 4-dihydro-isoquinoline salt
4.3.1N-aryl-3, the anti-microbial activity of 4-dihydro-isoquinoline salt
A. for the examination bacterium
(i) intestinal bacteria (Escherichia coli); (ii) streptococcus aureus (Staphylococcus aureus); (iii) Aeromonas hydrophila (Aeromonas hydrophila) (iv) breathes out arc maintenance bacterium (Vibrio harvey)
B. substratum configuration
Bacteriostatic test adopts the BPA substratum.Its compound method is as follows:
With extractum carnis 3.0g, peptone 10.0g and sodium-chlor 5.0g join in the 1000mL water, and after the stirring and dissolving, the sterilization back is stand-by in the Autoclave.
C. test liquid preparation
Will be in right amount be dissolved in the dimethyl sulfoxide (DMSO) for test agent, adjacent to be diluted to volumetric concentration with the BPA substratum be 5% dimethyl sulphoxide solution with preceding, and as the concentration of confession test agent in this solution as initial trial concentration.Employing is accompanied than dilution method initial trial solution is carried out serial dilution, obtains the test liquid with series concentration gradient.
D. test method
Supplying after the activation in advance tried bacterium (intestinal bacteria and streptococcus aureus, 37 ℃, 20h; Aeromonas hydrophila and Kazakhstan arc maintenance bacterium breathe out 28 ℃ of arc maintenance bacterium, and 24h) bacterium liquid is diluted to following concentration respectively with identical substratum: streptococcus aureus, 2.2 * 10 then by colony counting method mensuration concentration separately
7CFU; ForS.aureus, intestinal bacteria, 3.6 * 10
7CFU; Aeromonas hydrophila, 2.3 * 10
8CFU; Breathe out the arc maintenance bacterium, 1.8 * 10
8CFU.With the bacterium liquid after the dilution as inoculation bacterium liquid.On the aseptic technique platform, get 5 of sterile test tube, the 1st pipe adds 1ml BPA nutrient broth, and 2～5 pipes add the sample liquid of 1mL different concns, and every test tube adds the good bacterium liquid 1ml of dilution, and absorbent cotton seals.Contrast as positive antibacterials with ceftriaxone sodium and Ciprofloxacin, with the substratum of 5%DMSO as negative control.Place 37 ℃ to cultivate 24h intestinal bacteria and streptococcus aureus developmental tube, place 28 ℃ to cultivate 24h Aeromonas hydrophila and Kazakhstan arc maintenance bacterium developmental tube.Then, by the muddy level determinations minimal inhibitory concentration (MIC) of each developmental tube of visual inspection, be minimal inhibitory concentration with the minimum drug level of bacteria growing inhibiting fully.By relatively reaching MIC value between each sample, each bacteriostatic activity size of assay for sample for sample and positive drug.The results are shown in Table 1.
Each MIC value of table 1 for sample and positive drug bacteriostatic activity.
The result shows, N-aryl-3, and 4-dihydro-isoquinoline salt all has good bacteriostatic action and antimicrobial spectrum for gram-positive microorganism and Gram-negative bacteria.The N-aryl-3 that wherein has, 4-dihydro-isoquinoline salt is better than the clinical microbiotic ceftriaxone sodium ring commonly used and the third husky star for the bacteriostatic activity of some bacterium, the N-aryl-3 that the present invention relates to is described, 4-dihydro-isoquinoline salt compounds has the potential use that is used for antibacterials.
4.3.2N-aryl-3, the acaricidal activity of 4-dihydro-isoquinoline salt
With the acaricidal activity sample to the rabbit mite is example, and concrete operations are as follows:
1. liquor strength is determined
Accurately take by weighing medicine 60mg, be made into mother liquor with distilled water diluting to 5mL with 0.5mL DMSO dissolving back, concentration is 10mg/mL (1%).According to the test desired concn, the DMSO aqueous solution with 10% dilutes: 2mg/mL, 1mg/mL, 0.4mg/mL, 0.2mg/mL, 0.08mg/mL etc. then.
2. reagent
Avrmectin (Shaanxi Petroleum Chemical Engineering Institute,＞90%)
Pyrethrin (40%)
3 test methods:
Psoroptes cuniculi (P.cuniculi) separates the rabbit from natural infection.Collect incrustation and earwax in the infected rabbits duct, under stereomicroscope, separate all active mites, comprise female, male larva (larvae), nymph (nymphs) and adult mite.With the pin picking and place in the culture dish of 6cm (about 20 the adult mites of every ware), each culture dish adds above-mentioned soup 2mL with mite, and each concentration is done 3 repetitions.Simultaneously, blank group (respectively adding 2mL 10%DMSO solution in 3 culture dish) and positive controls: the paraffin oil solution (25% of the pyrethrin of respective concentration, 1%, 0.2%, 0.04%, 0.008% for handling control group) and DMSO (10% aqueous solution) solution (5mg/mL of the Avrmectin of respective concentration, 2.5mg/mL, 0.8mg/mL, 0.5mg/mL, 0.1mg/mL).
Above culture dish is placed in 22 ℃ the incubator of saturated humidity, behind the 24h, all motionless mites are used needle stimulus, and the reaction expression is not dead, and adds up.
Subordinate list 2 bromination N-aryl-3,4-dihydro-isoquinoline salt is at the lethality rate of different concns to the rabbit mite.
The result shows, N-aryl-3, and 4-dihydro-isoquinoline salt has good killing action for the rabbit mite.The N-aryl-3 that wherein has, 4-dihydro-isoquinoline salt acaricidal activity significantly is better than miticide pyrethrin and Avrmectin commonly used clinically, the N-aryl-3 that the present invention relates to is described, 4-dihydro-isoquinoline salt compounds has the potential use that is used for miticide.
Claims (2)
1. N-aryl-3,4-dihydro-isoquinoline salt is characterized in that having following molecular characterization:
Wherein, R
1, R
2, R
3, R
4, R
5, R
6, R
7, R
8, R
9, R
10, R
11, R
12Be identical or different hydrogen, alkyl, cycloalkyl, alkenyl, alkynyl group, undersaturated monocycle alkyl, alkoxyl group, halogen, hydroxyl, nitro, cyano group, trifluoromethyl, heterocyclic substituent, carboxyl, ester group, amide group, acyl group or aldehyde radical;
X-is sulfate radical, halogen anion, carbonate, bicarbonate radical, phosphate radical, hydrogen phosphate, lipid acid acid group, sulfonate radical or tetraphenylboron acid group.
2. N-aryl-3 according to claim 1,4-dihydro-isoquinoline salt kill the application of mite and antibacterials as preparation.
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| CN102603629A (en) * | 2012-04-06 | 2012-07-25 | 西北农林科技大学 | Dihydroisoquinoline compounds and application of dihydroisoquinoline compounds for preparing antibacterial agents for plants |
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