CN102659687B - Benzimidazolamines compounds as well as preparation method and application thereof - Google Patents

Benzimidazolamines compounds as well as preparation method and application thereof Download PDF

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CN102659687B
CN102659687B CN201210151996.7A CN201210151996A CN102659687B CN 102659687 B CN102659687 B CN 102659687B CN 201210151996 A CN201210151996 A CN 201210151996A CN 102659687 B CN102659687 B CN 102659687B
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methyl
benzimidazolyl
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benzoglyoxaline
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CN102659687A (en
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周成合
张慧珍
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Southwest University
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Abstract

The invention discloses benzimidazolamines compounds shown by general formulas I-V, medical salt of the benzimidazolamines compounds, and a preparation method of the benzimidazolamines compounds; the preparation method comprises the following steps of: stirring 2-chloromethyl-1H-benzimidazole and a compound shown by a general formula VII in an organic solvent for reaction, and controlling the temperature to be within the range of 75-90 DEG C; then, adding an alkali reagent under the stirring condition, controlling the temperature to be within the range of 10-60 DEG C, and stirring for reaction, thus obtaining the benzimidazolamines compound shown in the general formula I; stirring the benzimidazolamines compound shown in the general formula I and compound shown in the general formula VIII, IX, X or XI in an organic solvent for reaction, and controlling the temperature to be within the range of 50-70 DEG C; and after the system is acidic, adding the alkali reagent, controlling the temperature to be within the range of 50-70 DEG C, and stirring for reaction, thus obtaining the compound shown in the general formula II, III, IV or V. The benzimidazolamines compounds and the medical salt of the benzimidazolamines compounds have certain inhibitory activity for gram-positive bacteria, gram-negative bacteria and fungi, thus being used for preparing medicines for resisting bacteria and/ or fungi.

Description

Benzoglyoxaline aminated compounds and its preparation method and application
Technical field
The invention belongs to chemical field, relate to the organic compound that a class is new, also relate to preparation method and the medicinal use thereof of this compound.
Background technology
Fluconazole has the advantages such as antibacterial ability is strong, liver toxicity is little, oral absorption is good, bioavailability is high, tissue distribution is wide, be first by the choice drug of the treatment systemic fungal infection of World Health Organization's appointment, in clinical application, there is so far irreplaceable effect.Yet because causing its multidrug resistance, being widely used of fluconazole take place frequently, and its, narrow antimicrobial spectrum as not obvious in the result for the treatment of of aspergillus fumigatus etc. to non-Candida albicans, also have the water-soluble poor problems such as administering mode is limited that cause, lot of domestic and foreign investigator is all devoted to fluconazole to do further exploitation.At present, the more fluconazole analogue with good anti-mycotic activity is developed, as ravuconazole (Ravuconazole), albaconazole, Ai Shakang azoles (Isavuconazole) etc.At present the exploitation of fluconazole is mainly concentrated on to following three aspects: the one, fluconazole prodrug is studied, and is devoted to increase the chemical stability of medicine, extends action time, improves the intermiscibility of medicine, strengthens and absorbs, and improves bioavailability; The 2nd, on the basis of a triazole ring, 2,4 difluorobenzene base and alcoholic extract hydroxyl group that retains fluconazole, another side chain is transformed, expectation obtain can with the derivative of the efficient combination of lanosterol 14α-demethylase of fungi avtive spot; The 3rd, design synthetic molecules basic framework and the similar compound of fluconazole, the new texture antifungal drug that expectation obtains more having superiority than fluconazole.
In nitrogen azole compounds structure, contain a plurality of heteroatomss, easily produce in vivo multiple non-covalent interaction (as hydrogen bond, π-π interacts etc.) or with metal ion (as Zn 2+, Fe 2+deng) coordination, and then the activity of inhibition organism endoenzyme, be widely used in the fields such as medicine, agricultural chemicals.Research in recent years is found, some nitrogen heterocyclics are introduced in drug molecule as imidazoles, benzoglyoxaline, oxazole, benzoxazole, thiazole etc., can obtain the bioactive molecule with novel texture.
Summary of the invention
In view of this, the object of the present invention is to provide benzoglyoxaline tertiary amine fluconazole analogue, its preparation method and the application of these compounds in pharmacy field of a class formation novelty.
Through large quantity research, the invention provides following technical scheme:
1. benzoglyoxaline aminated compounds and the pharmacologically acceptable salt thereof shown in general formula I-V:
In formula, R 1and R 2be hydrogen, 2-fluorine, 3-fluorine, 4-fluorine, 2 independently, 3-difluoro, 2,4-difluoro, 2,5-difluoro, 2,6-difluoro, 3,4-difluoro, 3,5-difluoro, 2-chlorine, 3-chlorine, 4-chlorine, 2,3-dichloro, 2,4-dichloro, 2,5-dichloro, 2,6-dichloro, 3,4-dichloro, 3,5-dichloro, 4-iodine, 4-nitro, 3-trifluoromethyl, 3,5-bis-(trifluoromethyl), 2-methyl, 3-methyl, 4-methyl, 2,3-dimethyl, 2,4-dimethyl, 2,5-dimethyl, 2,6-dimethyl, 3,4-dimethyl, 3,5-dimethyl or 3-methoxyl group; R 3for hydrogen, fluorine, chlorine, iodine, nitro, trifluoromethyl, methyl or methoxy; R 4for methyl or ethanoyl; R is alkyl or aryl; N is 1 to 16 positive integer.
Further, R 1and R 2be 2-fluorine, 3-fluorine, 4-fluorine, 2 independently, 3-difluoro, 2,4-difluoro, 3,4-difluoro, 3,5-difluoro, 2-chlorine, 3-chlorine, 4-chlorine, 2,3-dichloro, 2,4-dichloro, 3,4-dichloro, 3,5-dichloro, 4-iodine, 4-nitro, 3-trifluoromethyl, 3,5-bis-(trifluoromethyl) or 4-methyl; R 3for hydrogen; R 4for methyl or ethanoyl; R is the alkyl or phenyl of 1～4 carbon; N is 1 to 16 positive integer.
Further, R 1for 2-fluorine, 4-fluorine, 2,4-difluoro, 4-chlorine, 2,4-dichloro, 4-iodine, 3-trifluoromethyl, 3,5-bis-(trifluoromethyl) or 4-methyl; R 2for 4-fluorine, 2,4-difluoro, 2-chlorine, 3-chlorine, 4-chlorine, 2,3-dichloro, 2,4-dichloro, 3,4-dichloro or 4-nitro; R 3for hydrogen; R 4for 4-methyl or 3-ethanoyl; R is the alkyl or phenyl of 2～4 carbon; N is 1 to 16 positive integer.
Further, be any and pharmacologically acceptable salt thereof in following compound:
Compound I-1:N-((1H-benzimidazolyl-2 radicals-yl) methyl)-2-fluoroaniline;
Compound I-2:N-((1H-benzimidazolyl-2 radicals-yl) methyl)-3-5-trifluoromethylaniline;
Compound I-3:N-((1H-benzimidazolyl-2 radicals-yl) methyl)-4-fluoroaniline;
Compound I-4:N-((1H-benzimidazolyl-2 radicals-yl) methyl)-4-chloroaniline;
Compound I-5:N-((1H-benzimidazolyl-2 radicals-yl) methyl)-4-Iodoaniline;
Compound I-6:N-((1H-benzimidazolyl-2 radicals-yl) methyl)-4-monomethylaniline;
Compound I-7:N-((1H-benzimidazolyl-2 radicals-yl) methyl)-2,4 difluorobenzene amine;
Compound I-8:N-((1H-benzimidazolyl-2 radicals-yl) methyl)-2,4 dichloro aniline;
Compound I-9:N-((1H-benzimidazolyl-2 radicals-yl) methyl)-3,5-bis-(trifluoromethyl) aniline;
Compound I I-1:N-((1H-benzimidazolyl-2 radicals-yl) methyl)-N-(3,4-dichlorophenyl)-2-fluoroaniline;
Compound I I-2:N-((1H-benzimidazolyl-2 radicals-yl) methyl)-N-(2,4 dichloro benzene base)-3-5-trifluoromethylaniline;
Compound I I-3:N-((1H-benzimidazolyl-2 radicals-yl) methyl)-N-(2,4 dichloro benzene base)-4-fluoroaniline;
Compound I I-4:N-((1H-benzimidazolyl-2 radicals-yl) methyl)-N-(2-chloro-phenyl-)-4-monomethylaniline;
Compound I I-5:N-((1H-benzimidazolyl-2 radicals-yl) methyl)-N-(3-chloro-phenyl-)-4-monomethylaniline;
Compound I I-6:N-((1H-benzimidazolyl-2 radicals-yl) methyl)-N-(4-chloro-phenyl-)-4-monomethylaniline;
Compound I I-7:N-((1H-benzimidazolyl-2 radicals-yl) methyl)-N-(4-nitrophenyl)-4-monomethylaniline;
Compound I I-8:N-((1H-benzimidazolyl-2 radicals-yl) methyl)-N-(2,4 difluorobenzene base)-4-monomethylaniline;
Compound I I-9:N-((1H-benzimidazolyl-2 radicals-yl) methyl)-N-(2,4 dichloro benzene base)-4-monomethylaniline;
Compound I I-10:N-((1H-benzimidazolyl-2 radicals-yl) methyl)-N-(3,4-dichlorophenyl)-4-monomethylaniline;
Compound I I-11:N-((1H-benzimidazolyl-2 radicals-yl) methyl)-N-(2,4 dichloro benzene base)-2,4 difluorobenzene amine;
Compound I I-12:N-((1H-benzimidazolyl-2 radicals-yl) methyl)-N-(2,4 difluorobenzene base)-2,4 dichloro aniline;
Compound I I-13:N-((1H-benzimidazolyl-2 radicals-yl) methyl)-N-(4-fluorophenyl)-3,5-bis-(trifluoromethyl) aniline;
Compound I I-14:N-((1H-benzimidazolyl-2 radicals-yl) methyl)-N-(2,4 difluorobenzene base)-3,5-bis-(trifluoromethyl) aniline;
Compound I I-15:N-((1H-benzimidazolyl-2 radicals-yl) methyl)-N-(2,4 dichloro benzene base)-3,5-bis-(trifluoromethyl) aniline;
Compound III-1:N-((1H-benzimidazolyl-2 radicals-yl) methyl)-N-propyl group-4-monomethylaniline;
Compound III-2:N-((1H-benzimidazolyl-2 radicals-yl) methyl)-N-hexyl-4-monomethylaniline;
Compound III-3:N-((1H-benzimidazolyl-2 radicals-yl) methyl)-N-octyl group-4-monomethylaniline;
Compound III-4:N-((1H-benzimidazolyl-2 radicals-yl) methyl)-N-decyl-4-monomethylaniline;
Compound III-5:N-((1H-benzimidazolyl-2 radicals-yl) methyl)-N-dodecyl-4-monomethylaniline;
Compound III-6:N-((1H-benzimidazolyl-2 radicals-yl) methyl)-N-octadecyl-4-monomethylaniline;
Compound IV-1:N-((1H-benzimidazolyl-2 radicals-yl) methyl)-N-(4-(9H-carbazole-9-yl) butyl)-2-fluoroaniline;
Compound IV-2:N-((1H-benzimidazolyl-2 radicals-yl) methyl)-N-(4-((9H-carbazole-9-yl) methyl) benzyl-4-monomethylaniline;
Compound V-1:7-(4-(((1H-benzimidazolyl-2 radicals-yl) methyl) (4-fluorophenyl) amido) hexyloxy)-4-methyl-2H-chromen-2-one;
Compound V-2:7-(4-(((1H-benzimidazolyl-2 radicals-yl) methyl) (4-tolyl) amido) methyl)-3-ethanoyl-2H-chromen-2-one.
Further, described pharmacologically acceptable salt is hydrochloride, nitrate or acetate.
2. the benzoglyoxaline aminated compounds shown in general formula I-V and the preparation method of pharmacologically acceptable salt thereof:
A. the preparation of the aminated compounds of benzoglyoxaline shown in general formula I: by 75～90 ℃ of stirring reactions of temperature control in organic solvent of compound shown in 2-chloromethyl-1H-benzoglyoxaline and general formula VII, under agitation condition, add alkali reagent again, 10～60 ℃ of stirring reactions of temperature control, make the aminated compounds of benzoglyoxaline shown in general formula I; Described organic solvent is any one or more mixing in ethanol, toluene and benzene; Described alkali reagent is any one or more mixing in salt of wormwood, sodium carbonate, potassium hydroxide, sodium hydroxide, sodium tert-butoxide, sodium hydride and sodium Metal 99.5;
B. the preparation of benzoglyoxaline aminated compounds shown in general formula I I～V: by 50～70 ℃ of stirring reactions of temperature control in organic solvent of compound shown in the aminated compounds of benzoglyoxaline shown in general formula I and general formula VIII, IX, X or XI, after system is acidity, add alkali reagent, 50～70 ℃ of stirring reactions of temperature control, make benzoglyoxaline aminated compounds shown in general formula I I, III, IV or V; Described organic solvent is any one or more mixing in acetonitrile, methyl alcohol, ethanol, toluene, tetrahydrofuran (THF) and DMF; Described alkali reagent is any one or more mixing in saleratus, sodium bicarbonate, salt of wormwood, sodium carbonate, potassium hydroxide, sodium hydroxide, potassium hydride KH, sodium hydride, POTASSIUM BOROHYDRIDE, sodium borohydride and lithium aluminum hydride;
C. the preparation of the pharmacologically acceptable salt of benzoglyoxaline aminated compounds shown in general formula I I～V: benzoglyoxaline aminated compounds shown in general formula I I～V is dissolved in any one or more mixing in ethanol, ether, tetrahydrofuran (THF) and trichloromethane, under agitation condition, add aqueous hydrochloric acid, aqueous nitric acid or aqueous acetic acid, stirring reaction, to generating without precipitation, makes hydrochloride, nitrate or the acetate of benzoglyoxaline aminated compounds shown in general formula I I～V; Or, benzoglyoxaline aminated compounds shown in general formula I I～V is dissolved in any one or more mixing in chloroform, acetone, methyl alcohol and acetonitrile, stirring at room, add again excessive aqueous hydrochloric acid, aqueous nitric acid or aqueous acetic acid, 0～50 ℃ of stirring reaction of temperature control, makes hydrochloride, nitrate or the acetate of benzoglyoxaline aminated compounds shown in general formula I I～V;
R in compound shown in general formula VII-XI 1, R 2, R 3, R 4, R in benzoglyoxaline aminated compounds shown in the definition of R and n and general formula I-V 1, R 2, R 3, R 4, R and n definition identical.
Further, the benzoglyoxaline aminated compounds shown in general formula I-V and the preparation method of pharmacologically acceptable salt thereof:
A. the preparation of the aminated compounds of benzoglyoxaline shown in general formula I: described organic solvent is ethanol; Described alkali reagent is salt of wormwood or sodium carbonate; Described 2-chloromethyl-1H-benzoglyoxaline: aniline or substituted aniline: the mol ratio of alkali reagent is 1: 1.0～1.5: 1.2～1.4;
B. the preparation of benzoglyoxaline aminated compounds shown in general formula I I～V: described organic solvent is acetonitrile; Described alkali reagent is salt of wormwood or sodium carbonate; Benzoglyoxaline aminated compounds shown in described general formula I: compound shown in general formula VIII, IX, X or XI: the mol ratio of alkali reagent is 1: 1.0～1.5: 1.2～1.4.
3. the benzoglyoxaline aminated compounds shown in general formula I-V and pharmacologically acceptable salt thereof the application in preparation antibacterium and/or antifungal drug.
Further, described bacterium is any one or more in streptococcus aureus, methicillin-resistant staphylococcus aureus (MRSA), micrococcus luteus, Bacillus subtilus, intestinal bacteria, Pseudomonas aeruginosa and Bacillus proteus; Described fungi is Candida albicans and/or candidiasis.
Beneficial effect of the present invention is: the present invention designs the benzoglyoxaline aminated compounds that has synthesized a series of novel structures, wherein compound shown in general formula I is benzoglyoxaline aryl secondary-amine compound, general formula I I, compound shown in IV and V is benzoglyoxaline aryl tertiary amine fluconazole analogue, compound shown in general formula III is benzoglyoxaline alkyl tertiary amine fluconazole analogue, these compounds detect and find gram-positive microorganism (streptococcus aureus through in vitro anti-microbial activity, MRSA, micrococcus luteus, Bacillus subtilus), Gram-negative bacteria (intestinal bacteria, Pseudomonas aeruginosa, Bacillus proteus) and fungi (Candida albicans, candidiasis) there is certain inhibition active, can be for the preparation of antibacterium and/or antifungal drug, thereby for clinical antimicrobial therapy provides more how efficient, the drug candidate of safety, contribute to solve the resistance being on the rise, the clinical treatment problems such as obstinate invasive organism and emerging harmful microorganism.In addition, the synthetic route of these compounds is short, preparation method is simple, and raw material is easy to get, and cost is lower.
Embodiment
In order to make the object, technical solutions and advantages of the present invention clearer, below exemplary embodiment of the present invention is described in detail.
The preparation of embodiment 1,2-chloromethyl-1H-benzoglyoxaline (compound VI)
In 100mL round-bottomed flask, add O-Phenylene Diamine 5.412g (0.050mol), Mono Chloro Acetic Acid 7.114g (0.075mol) and 5mol/L hydrochloric acid 60mL, heating reflux reaction 4 hours, cooling, with ammonia neutralization, be constantly stirred to yellow solid and separate out, suction filtration, dry, use dehydrated alcohol recrystallization, obtain compound VI 7.803g, productive rate 91.2%; Yellow solid, 143～144 ℃ of fusing points.
The preparation of embodiment 2, N-((1H-benzimidazolyl-2 radicals-yl) methyl)-2-fluoroaniline (Compound I-1)
In 100mL round-bottomed flask, add compound VI 1.669g (0.010mol), 2-fluoroaniline 1.110g (0.010mol) and appropriate ethanol (completely dissolve and be as the criterion with raw material), 75～90 ℃ of stirring reactions of temperature control 24～72 hours, under agitation condition, add again anhydrous sodium carbonate 1.272g (0.012mol), 10～60 ℃ of reactions of temperature control 2～4 hours, thin-layer chromatography tracks to reaction to be finished, again through concentrated, extraction, column chromatography for separation, recrystallization, the aftertreatment such as dry, obtain Compound I-11.764g, productive rate 73.1%; Yellow solid, 164～165 ℃ of fusing points; 1h NMR (300MHz, CDCl 3) δ: 4.60 (s, 2H, benzimidazolyl-CH 2), 6.46～6.44 (m, H, benzene-6-H), 6.50 (m, H, benzene-4-H), 6.94～6.91 (m, H, benzene-5-H), 7.17～7.14 (m, H, benzene-3-H), 7.27～7.23 (m, 2H, benzimidazole-5,6-H), 7.57～7.55 (m, 2H, benzimidazole-4,7-H) ppm.
The preparation of embodiment 3, N-((1H-benzimidazolyl-2 radicals-yl) methyl)-3-5-trifluoromethylaniline (Compound I-2)
Take compound VI 1.665g (0.010mol), 3-5-trifluoromethylaniline 1.607g (0.010mol) and anhydrous sodium carbonate 1.272g (0.012mol) is starting raw material, according to method described in embodiment 2, make Compound I-22.074g, productive rate 71.2%; Yellow solid, 155～156 ℃ of fusing points; 1h NMR (300MHz, CDCl 3) δ: 4.61 (s, 2H, benzimidazolyl-CH 2), 6.74～6.71 (d, H, benzene-6-H), (6.82 s, H, benzene-2-H), 7.00～6.97 (d, H, benzene-4-H), 7.21～7.19 (d, H, benzene-5-H), 7.27～7.24 (m, 2H, benzimidazole-5,6-H), 7.58～7.55 (m, 2H, benzimidazole-4,7-H) ppm.
The preparation of embodiment 4, N-((1H-benzimidazolyl-2 radicals-yl) methyl)-4-fluoroaniline (Compound I-3)
Take compound VI 1.665g (0.010mol), 4-fluoroaniline 1.116g (0.011mol) and anhydrous sodium carbonate 1.272g (0.012mol) is starting raw material, makes Compound I-31.788g, productive rate 74.1% according to method described in embodiment 2; White solid, 168～169 ℃ of fusing points; 1h NMR (300MHz, CDCl 3) δ: 4.63 (s, 2H, benzimidazolyl-CH 2), 7.05～7.03 (m, 2H, benzene-3,5-H), 7.11～7.08 (m, 2H, benzene-2,6-H), 7.27～7.24 (m, 2H, benzimidazole-5,6-H), 7.56～7.54 (m, 2H, benzimidazole-4,7-H) ppm.
The preparation of embodiment 5, N-((1H-benzimidazolyl-2 radicals-yl) methyl)-4-chloroaniline (Compound I-4)
Take compound VI 1.670g (0.010mol), 4-chloroaniline 1.312g (0.010mol) and anhydrous sodium carbonate 1.272g (0.012mol) is starting raw material, makes Compound I-41.948g, productive rate 75.6% according to method described in embodiment 2; White solid, 208～210 ℃ of fusing points; 1h NMR (300MHz, CDCl 3) δ: 4.64 (s, 2H, benzimidazolyl-CH 2), 6.64～6.62 (d, 2H, chlorobenzene-2,6-H), 7.25～7.23 (m, 2H, benzimidazole-5,6-H), 7.28～7.26 (d, 2H, chlorobenzene-3,5-H), 7.55 (s, 2H, benzimidazole-4,7-H) ppm.
The preparation of embodiment 6, N-((1H-benzimidazolyl-2 radicals-yl) methyl)-4-Iodoaniline (Compound I-5)
Take compound VI 1.614g (0.010mol), 4-Iodoaniline 2.079g (0.009mol) and anhydrous sodium carbonate 1.274g (0.012mol) is starting raw material, makes Compound I-52.458g, productive rate 70.4% according to method described in embodiment 2; Brown thick liquid, 1h NMR (300MHz, CDCl 3) δ: 4.63 (s, 2H, benzimidazolyl-CH 2), 6.61～6.60 (d, 2H, iodobenzene-2,6-H), 7.24～7.23 (m, 2H, benzimidazole-5,6-H), 7.48～7.47 (d, 2H, iodobenzene-3,5-H), 7.55 (s, 2H, benzimidazole-4,7-H) ppm.
The preparation of embodiment 7, N-((1H-benzimidazolyl-2 radicals-yl) methyl)-4-monomethylaniline (Compound I-6)
Take compound VI 1.659g (0.010mol), 4-monomethylaniline 1.282g (0.012mol) and anhydrous sodium carbonate 1.276g (0.012mol) is starting raw material, makes Compound I-61.987g, productive rate 83.7% according to method described in embodiment 2; Yellow solid, 198～200 ℃ of fusing points; 1h NMR (300MHz, CDCl 3) δ: 2.23 (s, 3H ,-CH 3), 4.63 (s, 2H, benzimidazolyl-CH 2), 6.57～6.54 (d, 2H, toluene-2,6-H), 6.98～6.96 (d, 2H, toluene-3,5-H), 7.26～7.23 (m, 2H, benzimidazole-5,6-H), 7.56～7.53 (m, 2H, benzimidazole-4,7-H) ppm.
The preparation of embodiment 8, N-((1H-benzimidazolyl-2 radicals-yl) methyl)-2,4 difluorobenzene amine (Compound I-7)
With compound VI 1.665g (0.010mol), 2,4-difluoroaniline 1.290g (0.010mol) and anhydrous sodium carbonate 1.273g (0.012mol) are starting raw material, according to method described in embodiment 2, make Compound I-72.070g, productive rate 79.8%; Yellow solid, 166～167 ℃ of fusing points; 1h NMR (300MHz, CDCl 3) δ: 4.64 (s, 2H, benzimidazolyl-CH 2), 6.56～6.48 (m, 1H, fluorobenzene-3-H), 6.66～6.60 (m, 1H, fluorobenzene-5-H), 6.81～6.74 (m, 1H, fluorobenzene-6-H), 7.27～7.24 (m, 2H, benzimidazole-5,6-H), 7.58～7.54 (m, 2H, benzimidazole-4,7-H) ppm.
The preparation of embodiment 9, N-((1H-benzimidazolyl-2 radicals-yl) methyl)-2,4 dichloro aniline (Compound I-8)
With compound VI 1.669g (0.010mol), 2,4-dichlorphenamide bulk powder 1.615g (0.010mol) and anhydrous sodium carbonate 1.275g (0.012mol) are starting raw material, according to method described in embodiment 2, make Compound I-82.102g, productive rate 71.9%; Yellow solid, 163～164 ℃ of fusing points; 1h NMR (300MHz, CDCl 3) δ: 4.63 (s, 2H, benzimidazolyl-CH 2), 6.54～6.51 (d, 1H, benzene-6-H), 7.18～7.15 (d, 1H, benzene-5-H), 7.27～7.25 (m, 2H, benzimidazole-5,6-H), 7.59～7.54 (m, 2H, benzimidazole-4,7-H), 7.85～7.82 (d, 1H, benzene-3-H) ppm.
Embodiment 10, N-((1H-benzimidazolyl-2 radicals-yl) methyl)-3, the preparation of 5-bis-5-trifluoromethylanilines (Compound I-9)
With compound VI 1.662g (0.010mol), 3,5-bis-(trifluoromethyl) aniline 2.234g (0.010mol) and anhydrous sodium carbonate 1.276g (0.012mol) are starting raw material, according to method described in embodiment 2, make Compound I-92.964g, productive rate 2.5%; White solid, 212～214 ℃ of fusing points; 1h NMR (300MHz, CDCl 3) δ: 4.63～4.62 (d, 2H, benzimidazolyl-CH 2), 6.95 (s, 2H, bis (trifluoromethyl) benzene-2,6-H), 7.18 (s, H, bis (trifluoromethyl) benzene-4-H), 7.26 (s, 2H, benzimidazole-5,6-H), 7.57 (s, 2H, benzimidazole-4,7-H) ppm.
The preparation of embodiment 11, N-((1H-benzimidazolyl-2 radicals-yl) methyl)-N-(3,4-dichlorophenyl)-2-fluoroaniline (Compound I I-1)
In 100mL round-bottomed flask, add Compound I-10.486g (0.002mol), 3,4-benzyl dichloride chlorine 0.390g (0.002mol) and appropriate acetonitrile (completely dissolve and be as the criterion with raw material), 50～70 ℃ of stirrings of temperature control, after system is acidity, add Anhydrous potassium carbonate 0.336g (0.003mol), 50～70 ℃ of stirring reactions of temperature control 12～48 hours, thin-layer chromatography tracks to reaction to be finished, again through concentrated, extraction, column chromatography for separation, recrystallization, the aftertreatment such as dry, obtain Compound I I-10.252g, productive rate 31.4%; White solid, 128～129 ℃ of fusing points; 1h NMR (300MHz, CDCl 3) δ: 4.54 (s, 2H, benzimidazolyl-CH 2), 4.70 (s, 2H, dichlorobenzyl-CH 2), 6.68～6.64 (m, H, fluorobenzene-4-H), 6.93 (d, H, fluorobenzene-6-H), 7.02～7.01 (d, 2H, fluorobenzene-3,5-H), 7.23 (s, 1H, chlorobenzyl-6-H), 7.26～7.25 (d, 2H, benzimidazole-5,6-H), 7.28 (s, 1H, chlorobenzyl-2-H), 7.52～7.50 (d, 2H, benzimidazole-4,7-H), 7.80～7.77 (d, 1H, chlorobenzyl-5-H) ppm; MS (m/z): 422[M+Na] +, 400[M+H] +.
The preparation of embodiment 12, N-((1H-benzimidazolyl-2 radicals-yl) methyl)-N-(2,4 dichloro benzene base)-3-5-trifluoromethylaniline (Compound I I-2)
With Compound I-20.586g (0.002mol), 2,4-benzyl dichloride chlorine 0.416g (0.002mol) and Anhydrous potassium carbonate 0.345g (0.003mol) are starting raw material, according to method described in embodiment 11, make Compound I I-20.260g, productive rate 28.9%; Yellow solid, 134～135 ℃ of fusing points; 1h NMR (300MHz, CDCl 3) δ: 4.52 (s, 2H, benzimidazolyl-CH 2), 4.71 (s, 2H, chlorobenzyl-CH 2), 6.73～6.69 (d, H, (trifluoromethyl) benzene-6-H), 6.83 (s, H, (trifluoromethyl) benzene-2-H), 6.91 (d, 1H, chlorobenzyl-6-H), 7.21 (m, 2H, (trifluoromethyl) benzene-2,5-H), 7.26～7.23 (m, 2H, benzimidazole-5,6-H), 7.29 (d, H, chlorobenzyl-5-H), 7.51 (s, 2H, benzimidazole-4,7-H), 7.62 (s, 1H, chlorobenzyl-3-H) ppm; MS (m/z): 472[M+Na] +, 450[M+H] +.
The preparation of embodiment 13, N-((1H-benzimidazolyl-2 radicals-yl) methyl)-N-(2,4 dichloro benzene base)-4-fluoroaniline (Compound I I-3)
With Compound I-30.483g (0.002mol), 2,4-benzyl dichloride chlorine 0.401g (0.002mol) and Anhydrous potassium carbonate 0.336g (0.003mol) are starting raw material, according to method described in embodiment 11, make Compound I I-30.257g, productive rate 32.1%; Yellow solid, 127～128 ℃ of fusing points; 1h NMR (300MHz, CDCl 3) δ: 4.55 (s, 2H, benzimidazolyl-CH 2), 4.72 (s, 2H, dichlorobenzyl-CH 2), 6.72～6.68 (m, 2H, fluorobenzene-2,6-H), 7.05～7.01 (m, 2H, fluorobenzene-3,5-2H), 7.14 (s, 1H, chlorobenzyl-6-H), 7.27～7.24 (d, 2H, benzimidazole-5,6-H), 7.30 (s, 1H, chlorobenzyl-5-H), 7.54～7.51 (d, 2H, benzimidazole-4,7-H), 7.82～7.79 (s, 1H, chlorobenzyl-3-H) ppm; MS (m/z): 422[M+Na] +, 400[M+H] +.
The preparation of embodiment 14, N-((1H-benzimidazolyl-2 radicals-yl) methyl)-N-(2-chloro-phenyl-)-4-monomethylaniline (Compound I I-4)
Take Compound I-60.231g (0.001mol), o-chloro benzyl chloride 0.174g (0.001mol) and Anhydrous potassium carbonate 0.169g (0.0012mol) is starting raw material, according to method described in embodiment 11, make Compound I I-40.182g, productive rate 50.4%; White solid, 158～160 ℃ of fusing points; 1h NMR (300MHz, CDCl 3) δ: 2.23 (s, 3H ,-CH 3), 4.51 (s, 2H, benzimdazole-CH 2), 4.69 (s, 2H, chlorobenzyl-CH 2), 6.70～6.69 (d, 2H, toluene-2,6-H), 7.05～7.02 (d, 3H, toluene-3,5-H, chlorobenzyl-6-H), 7.25～7.23 (m, 4H, benzimdazole-5,6-H, chlorobenzyl-4,5-H), 7.36～7.34 (d, 1H, chlorobenzyl-5-H), 7.52 (s, 2H, benzimdazole-4,7-H) ppm; MS (m/z): 384[M+Na] +, 362[M+H] +.
The preparation of embodiment 15, N-((1H-benzimidazolyl-2 radicals-yl) methyl)-N-(3-chloro-phenyl-)-4-monomethylaniline (Compound I I-5)
Take Compound I-60.234g (0.001mol), a benzyl chloride chlorine 0.161g (0.001mol) and Anhydrous potassium carbonate 0.172g (0.001mol) is starting raw material, according to method described in embodiment 11, make Compound I I-50.176g, productive rate 48.7%; White solid, 115～117 ℃ of fusing points; 1h NMR (300MHz, CDCl 3) δ: 2.23 (s, 3H ,-CH 3), 4.52 (s, 2H, benzimdazole-CH 2), 4.71 (s, 2H, chlorobenzyl-CH 2), 6.70～6.69 (d, 2H, toluene-2,6-H), 7.05～7.02 (d, 3H, toluene-3,5-H, chlorobenzyl-6-H), 7.25～7.24 (m, 2H, benzimdazole-5,6-H), 7.33～7.32 (d, 2H, chlorobenzyl-4,5-H), 7.42 (s, 1H, chlorobenzyl-2-H), 7.52 (s, 2H, benzimdazole-4,7-H) ppm; MS (m/z): 384[M+Na] +, 362[M+H] +.
The preparation of embodiment 16, N-((1H-benzimidazolyl-2 radicals-yl) methyl)-N-(4-chloro-phenyl-)-4-monomethylaniline (Compound I I-6)
Take Compound I-60.232g (0.001mol), to benzyl chloride chlorine 0.160g (0.001mol) and Anhydrous potassium carbonate 0.164g (0.001mol), be starting raw material, according to method described in embodiment 11, make Compound I I-60.162g, productive rate 44.8%; White solid, 118～119 ℃ of fusing points; 1h NMR (300MHz, CDCl 3) δ: 2.23 (s, 3H ,-CH 3), 4.51 (s, 2H, benzimdazole-CH 2), 4.70 (s, 2H, chlorobenzyl-CH 2), 6.71～6.69 (d, 2H, toluene-2,6-H), 7.07 (d, 2H, toluene-3,5-H), 7.25～7.24 (m, 2H, benzimdazole-5,6-H), 7.34～7.32 (d, 2H, chlorobenzyl-2,6-H), 7.41 (s, 2H, chlorobenzyl-3,5-H), 7.50 (s, 2H, benzimdazole-4,7-H) ppm; MS (m/z): 384[M+Na] +, 362[M+H] +.
The preparation of embodiment 17, N-((1H-benzimidazolyl-2 radicals-yl) methyl)-N-(4-nitrophenyl)-4-monomethylaniline (Compound I I-7)
Take Compound I-60.474g (0.002mol), to nitrobenzyl bromine 0.442g (0.002mol) and Anhydrous potassium carbonate 0.403g (0.003mol), be starting raw material, according to method described in embodiment 11, make Compound I I-70.445g, productive rate 59.5%; White solid, 123～125 ℃ of fusing points; 1h NMR (300MHz, CDCl 3) δ: 2.38 (s, 3H ,-CH 3), 4.52 (s, 2H, benzimdazole-CH 2), 4.84 (s, 2H, nitrophenyl-CH 2), 6.71～6.69 (d, 2H, toluene-2,6-H), 7.07 (d, 2H, toluene-3,5-H), 7.25～7.24 (m, 2H, benzimdazole-5,6-H), 7.50 (s, 2H, benzimdazole-4,7-H), 7.58～7.56 (d, 2H, nitrophenyl-2,6-H),～7.85 7.86 (s, 2H, nitrophenyl-3,5-H) ppm; MS (m/z): 394[M+Na] +, 372[M+H] +.
The preparation of embodiment 18, N-((1H-benzimidazolyl-2 radicals-yl) methyl)-N-(2,4 difluorobenzene base)-4-monomethylaniline (Compound I I-8)
With Compound I-60.240g (0.001mol), 2,4-bis-fluorobenzyl bromide 0.211g (0.001mol) and Anhydrous potassium carbonate 0.251g (0.002mol) are starting raw material, according to method described in embodiment 11, make Compound I I-80.186g, productive rate 51.2%; White solid, 155～156 ℃ of fusing points; 1h NMR (300MHz, CDCl 3) δ: 2.23 (s, 3H ,-CH 3), 4.53 (s, 2H, benzimdazole-CH 2), 4.66 (s, 2H, difluorobenzyl-CH 2), 6.65～6.62 (d, 2H, toluene-2,6-H), 6.74～6.71 (d, 2H, toluene-3,5-H), 6.91～6.84 (m, 1H, difluorobenzyl-3-H), 7.01～6.98 (d, 2H, benzimdazole-5,6-H), 7.25 (s, 3H, benzimdazole-4,7-H, difluorobenzyl-5-H), 7.81～7.78 (d, 1H, difluorobenzyl-6-H) ppm; MS (m/z): 385[M+Na] +, 363[M+H] +.
The preparation of embodiment 19, N-((1H-benzimidazolyl-2 radicals-yl) methyl)-N-(2,4 dichloro benzene base)-4-monomethylaniline (Compound I I-9)
With Compound I-60.956g (0.004mol), 2,4-benzyl dichloride chlorine 0.902g (0.004mol) and Anhydrous potassium carbonate 0.660g (0.005mol) are starting raw material, according to method described in embodiment 11, make Compound I I-90.755g, productive rate 47.6%; White solid, 125～127 ℃ of fusing points; 1h NMR (300MHz, CDCl 3) δ: 2.24 (s, 3H ,-CH 3), 4.51 (s, 2H, benzimdazole-CH 2), 4.68 (s, 2H, dichlorobenzyl-CH 2), 6.65～6.63 (d, 2H, toluene-2,6-H), 6.75～6.72 (d, 2H, toluene-3,5-H), 6.89～6.87 (m, 1H, dichlorobenzyl-6-H), 7.10～7.06 (d, 3H, benzimdazole-5,6-H, dichlorobenzyl-5-H), 7.26 (s, 2H, benzimdazole-4,7-H), 7.56～7.52 (s, 1H, dichlorobenzyl-3-H) ppm; MS (m/z): 418[M+Na] +, 396[M+H] +.
The preparation of embodiment 20, N-((1H-benzimidazolyl-2 radicals-yl) methyl)-N-(3,4-dichlorophenyl)-4-monomethylaniline (Compound I I-10)
With Compound I-60.475g (0.002mol), 3,4-benzyl dichloride chlorine 0.393g (0.002mol) and Anhydrous potassium carbonate 0.420g (0.003mol) are starting raw material, according to method described in embodiment 11, make Compound I I-100.345g, productive rate 43.5%; White solid, 161～163 ℃ of fusing points; 1h NMR (300MHz, CDCl 3) δ: 2.22 (s, 3H ,-CH 3), 4.50 (s, 2H, benzimdazole-CH 2), 4.70 (s, 2H, chlorobenzyl-CH 2), 6.71～6.68 (d, 2H, toluene-2,6-H), 7.02～6.99 (d, 3H, toluene-3,5-H chlorobenzyl-6-H), 7.24～7.23 (m, 2H, benzimdazole-5,6-H), 7.28 (s, 1H, chlorobenzyl-2-H), 7.35～7.32 (d, 1H, chlorobenzyl-5-H), 7.52 (s, 2H, benzimdazole-4,7-H) ppm; MS (m/z): 418[M+Na] +, 396[M+H] +.
The preparation of embodiment 21, N-((1H-benzimidazolyl-2 radicals-yl) methyl)-N-(2,4 dichloro benzene base)-2,4 difluorobenzene amine (Compound I I-11)
With Compound I-70.522g (0.002mol), 2,4-benzyl dichloride chlorine 0.401g (0.002mol) and Anhydrous potassium carbonate 0.659g (0.0048mol) are starting raw material, according to method described in embodiment 11, make Compound I I-110.172g, productive rate 20.6%; Yellow liquid; 1h NMR (300MHz, CDCl 3) δ: 4.54 (s, 2H, benzimdazole-CH 2), 4.74 (s, 2H, chlorobenzyl-CH 2), 6.55～6.48 (m, 1H, fluorobenzene-3-H), 6.67～6.60 (m, 1H, fluorobenzene-6-H), 6.82～6.74 (m, 1H, fluorobenzene-5-H), 7.27～7.25 (m, 2H, benzimdazole-5,6-H), 7.28 (s, H, chlorobenzyl-5-H), 7.52 (s, 2H, benzimdazole-4,7-H), 7.71 (s, 1H, chlorobenzene-3-H) ppm; MS (m/z): 440[M+Na] +, 418[M+H] +.
The preparation of embodiment 22, N-((1H-benzimidazolyl-2 radicals-yl) methyl)-N-(2,4 difluorobenzene base)-2,4 dichloro aniline (Compound I I-12)
With Compound I-80.237g (0.002mol), 2,4-bis-fluorobenzyl bromide 0.313g (0.002mol) and Anhydrous potassium carbonate 0.414g (0.003mol) are starting raw material, according to method described in embodiment 11, make Compound I I-120.276g, productive rate 33.1%; White solid, 128～129 ℃ of fusing points; 1h NMR (300MHz, CDCl 3) δ: 4.55 (s, 2H, benzimdazole-CH 2), 4.69 (s, 2H, fluorobenzyl-CH 2), 6.65 (m, H, fluorobenzyl-4-H), 6.68～6.67 (d, H, chlorobenzene-6-H), 7.10～7.06 (m, H, fluorobenzyl-5-H), 7.18 (m, 1H, fluorobenzyl-6-H), 7.22～7.20 (d, H, chlorobenzene-5-H), 7.27～7.24 (m, 2H, benzimdazole-5,6-H), 7.53 (s, 2H, benzimdazole-4,7-H), 7.84 (d, 1H, chlorobenzene-3-H) ppm; MS (m/z): 440[M+Na] +, 418[M+H] +.
Embodiment 23, N-((1H-benzimidazolyl-2 radicals-yl) methyl)-N-(4-fluorophenyl)-3, the preparation of 5-bis-(trifluoromethyl) aniline (Compound I I-13)
Take Compound I-91.069g (0.003mol), 4-fluorine benzyl chlorine 0.456g (0.003mol) and Anhydrous potassium carbonate 0.495g (0.004mol) is starting raw material, according to method described in embodiment 11, make Compound I I-130.063g, productive rate 4.3%; White solid, 177～179 ℃ of fusing points; 1h NMR (300MHz, CDCl 3) δ: 4.55 (s, 2H, chlorobenzyl-CH 2), 4.71 (s, 2H, fluorobenzyl-CH 2), 6.47～6.42 (d, 2H, fluorobenzyl-3,5-H), 7.03 (s, 2H, bis (trifluoromethyl) benzene-2,6-H), 7.26～7.23 (s, 2H, benzimdazole-5,6-H), 7.31 (s, 1H, bis (trifluoromethyl) benzene-4-H), 7.35～7.33 (d, 2H, fluorobenzyl-2,6-H), 7.57 (s, 2H, benzimdazole-4,7-H) ppm; MS (m/z): 489[M+Na] +, 467[M+H] +.
Embodiment 24, N-((1H-benzimidazolyl-2 radicals-yl) methyl)-N-(2,4 difluorobenzene base)-3, the preparation of 5-bis-(trifluoromethyl) aniline (Compound I I-14)
With Compound I-91.079g (0.003mol), 2,4-bis-fluorobenzyl bromide 0.635g (0.003mol) and Anhydrous potassium carbonate 0.497g (0.004mol) are starting raw material, according to method described in embodiment 11, make Compound I I-140.130g, productive rate 8.9%; White solid, 128～130 ℃ of fusing points; 1h NMR (300MHz, CDCl 3) δ: 4.63 (s, 2H, chlorobenzyl-CH 2), 4.81 (s, 2H, difluorobenzyl-CH 2), 6.58～6.50 (q, 1H, difluorobenzyl-3-H), 6.72～6.67 (t, 1H, difluorobenzyl-5-H), 6.80～6.77 (s, 2H, bis (trifluoromethyl) benzene-2,6-H), 6.86 (s, 1H, difluorobenzyl-6-H), 7.26～7.23 (s, 2H, benzimdazole-5,6-H), 7.29 (s, 1H, bis (trifluoromethyl) benzene-4-H), 7.57 (s, 2H, benzimdazole-4,7-H) ppm; MS (m/z): 507[M+Na] +, 485[M+H] +.
Embodiment 25, N-((1H-benzimidazolyl-2 radicals-yl) methyl)-N-(2,4 dichloro benzene base)-3, the preparation of 5-bis-(trifluoromethyl) aniline (Compound I I-15)
With Compound I-91.049g (0.003mol), 2,4-benzyl dichloride chlorine 0.603g (0.003mol) and Anhydrous potassium carbonate 0.492g (0.004mol) are starting raw material, according to method described in embodiment 11, make Compound I I-150.092g, productive rate 5.9%; White solid, 132～133 ℃ of fusing points; 1h NMR (300MHz, CDCl 3) δ: 4.52～4.50 (d, 2H, chlorobenzyl-CH 2), 4.78 (s, 2H, dichlorobenzyl-CH 2), 6.40～6.38 (q, 1H, dichlorobenzyl-3-H), 7.00 (s, 2H, bis (trifluoromethyl) benzene-2,6-H), 7.06～7.04 (t, 1H, dichlorobenzyl-5-H), 7.36～7.19 (s, 4H, benzimdazole-H), 7.49 (s, 1H, bis (trifluoromethyl) benzene-4-H), 7.81～7.79 (d, 1H, dichlorobenzyl-6-H) ppm; MS (m/z): 540[M+Na] +, 518[M+H] +.
The preparation of embodiment 26, N-((1H-benzimidazolyl-2 radicals-yl) methyl)-N-propyl group-4-monomethylaniline (compound III-1)
Take Compound I-60.475g (0.002mol), N-PROPYLE BROMIDE 0.247g (0.002mol) and Anhydrous potassium carbonate 0.410g (0.003mol) is starting raw material, makes compound III-10.345g, productive rate 43.5% according to method described in embodiment 11; White solid, 161～163 ℃ of fusing points; 1h NMR (300MHz, CDCl 3) δ: 1.08 (t, 3H ,-CH 2cH 2cH 3), 1.34 (q, 2H ,-CH 2cH 2cH 3), 2.23 (s, 3H, Ph-CH 3), 3.40～3.35 (t, 2H ,-CH 2cH 2cH 3), 4.69 (s, 2H, chlorobenzyl-CH 2), 6.71～6.68 (d, 2H, toluene-2,6-H), 7.03～7.01 (d, 2H, toluene-3,5-H), 7.22 (s, 2H, benzimdazole-5,6-H), 7.52 (s, 2H, benzimdazole-4,7-H) ppm; MS (m/z): 301[M+Na] +, 279[M+H] +.
The preparation of embodiment 27, N-((1H-benzimidazolyl-2 radicals-yl) methyl)-N-hexyl-4-monomethylaniline (compound III-2)
Take Compound I-60.243g (0.001mol), n-hexyl bromine 0.168g (0.001mol) and Anhydrous potassium carbonate 0.275g (0.002mol) is starting raw material, according to method described in embodiment 11, make compound III-20.132g, productive rate 40.6%; Yellow liquid; 1h NMR (300MHz, CDCl 3) δ: 0.87～0.86 (t, 3H ,-CH 2c 4h 8cH 3), 1.32～1.30 (br, 8H ,-CH 2c 4h 8cH 3), 2.23 (s, 3H, Ph-CH 3), 3.39～3.35 (t, 2H ,-CH 2c 4h 8cH 3), 4.70 (s, 2H, chlorobenzyl-CH 2), 6.70～6.68 (d, 2H, toluene-2,6-H), 7.02～7.01 (d, 2H, toluene-3,5-H), 7.24 (s, 2H, benzimdazole-5,6-H), 7.52 (s, 2H, benzimdazole-4,7-H) ppm; MS (m/z): 343[M+Na] +, 321[M+H] +.
The preparation of embodiment 28, N-((1H-benzimidazolyl-2 radicals-yl) methyl)-N-octyl group-4-monomethylaniline (compound III-3)
Take Compound I-60.478g (0.002mol), bromooctane 0.405g (0.002mol) and Anhydrous potassium carbonate 0.413g (0.003mol) is starting raw material, makes compound III-30.270g, productive rate 42.1% according to method described in embodiment 11; Yellow liquid; 1h NMR (300MHz, CDCl 3) δ: 0.88～0.86 (t, 3H ,-CH 2c 6h 12cH 3), 1.30～1.28 (br, 12H ,-CH 2c 6h 12cH 3), 2.23 (s, 3H, Ph-CH 3), 3.41～3.38 (t, 2H ,-CH 2c 6h 12cH 3), 4.72 (s, 2H, chlorobenzyl-CH 2), 6.71～6.68 (d, 2H, toluene-2,6-H), 7.04～7.01 (d, 2H, toluene-3,5-H), 7.25 (s, 2H, benzimdazole-5,6-H), 7.56 (s, 2H, benzimdazole-4,7-H) ppm; MS (m/z): 372[M+Na] +, 350[M+H] +.
The preparation of embodiment 29, N-((1H-benzimidazolyl-2 radicals-yl) methyl)-N-decyl-4-monomethylaniline (compound III-4)
Take Compound I-60.477g (0.002mol), bromo-decane 0.426g (0.002mol) and Anhydrous potassium carbonate 0.417g (0.003mol) is starting raw material, makes compound III-40.341g, productive rate 45.1% according to method described in embodiment 11; Yellow liquid; 1h NMR (300MHz, CDCl 3) δ: 0.84～0.81 (t, 3H ,-CH 2cH 2c 7h 14cH 3), 1.30～1.28 (br, 14H ,-CH 2cH 2c 7h 14cH 3), 1.76～1.74 (m, 2H ,-CH 2cH 2c 7h 14cH 3), 2.23 (s, 3H, Ph-CH 3), 3.40～3.38 (t, 2H ,-CH 2cH 2c 7h 14cH 3), 4.69 (s, 2H, chlorobenzyl-CH 2), 6.68～6.65 (d, 2H, toluene-2,6-H), 7.02～6.99 (d, 2H, toluene-3,5-H), 7.28 (s, 2H, benzimdazole-5,6-H), 7.55 (s, 2H, benzimdazole-4,7-H) ppm; MS (m/z): 400[M+Na] +, 378[M+H] +.
The preparation of embodiment 30, N-((1H-benzimidazolyl-2 radicals-yl) methyl)-N-dodecyl-4-monomethylaniline (compound III-5)
Take Compound I-60.235g (0.001mol), bromo-dodecane 0.255g (0.001mol) and Anhydrous potassium carbonate 0.169g (0.001mol) is starting raw material, according to method described in embodiment 11, make compound III-50.175g, productive rate 43.2%; Yellow liquid; 1h NMR (300MHz, CDCl 3) δ: 0.87～0.84 (t, 3H ,-CH 2c 2h 4c 8h 16cH 3), 1.36～1.30 (br, 16H ,-CH 2c 2h 4c 8h 16cH 3), 1.79～1.75 (m, 4H ,-CH 2c 2h 4c 8h 16cH 3), 2.23 (s, 3H, Ph-CH 3), 3.43～3.41 (t, 2H ,-CH 2c 2h 4c 8h 16cH 3), 4.65 (s, 2H, chlorobenzyl-CH 2), 6.67～6.64 (d, 2H, toluene-2,6-H), 7.04～7.01 (d, 2H, toluene-3,5-H), 7.30 (s, 2H, benzimdazole-5,6-H), 7.57 (s, 2H, benzimdazole-4,7-H) ppm; MS (m/z): 428[M+Na] +, 406[M+H] +.
The preparation of embodiment 31, N-((1H-benzimidazolyl-2 radicals-yl) methyl)-N-octadecyl-4-monomethylaniline (compound III-6)
Take Compound I-60.233g (0.001mol), bromo-octadecane 0.389g (0.001mol) and Anhydrous potassium carbonate 0.172g (0.001mol) is starting raw material, according to method described in embodiment 11, make compound III-60.199g, productive rate 40.7%; Yellow liquid; 1h NMR (300MHz, CDCl 3) δ: 0.87～0.86 (t, 3H ,-CH 2c 2h 4c 14h 28cH 3), 1.38～1.35 (br, 28H ,-CH 2c 2h 4c 14h 28cH 3), 1.75～1.72 (m, 4H ,-CH 2c 2h 4c 14h 28cH 3), 2.23 (s, 3H, Ph-CH 3), 3.40～3.35 (t, 2H ,-CH 2c 2h 4c 14h 28cH 3), 4.69 (s, 2H, chlorobenzyl-CH 2), 6.70～6.67 (d, 2H, toluene-2,6-H), 7.04～7.01 (d, 2H, toluene-3,5-H), 7.22 (s, 2H, benzimdazole-5,6-H), 7.52 (s, 2H, benzimdazole-4,7-H) ppm; MS (m/z): 512[M+Na] +, 490[M+H] +.
The preparation of embodiment 32, N-((1H-benzimidazolyl-2 radicals-yl) methyl)-N-(4-(9H-carbazole-9-yl) butyl)-2-fluoroaniline (compound IV-1)
Take Compound I-10.242g (0.001mol), brombutyl carbazole 0.305g (0.001mol) and Anhydrous potassium carbonate 0.175g (0.001mol) is starting raw material, according to method described in embodiment 11, make compound IV-10.179g, productive rate 39.1%; Yellow solid, 143～145 ℃ of fusing points; 1h NMR (300MHz, CDCl 3) δ: 1.95～1.86 (m, 2H, carbazole-CH 2cH 2cH 2cH 2), 2.11～2.01 (m, 2H, carbazole-CH 2cH 2cH 2cH 2), 3.56～3.53 (t, 2H, carbazole-CH 2cH 2cH 2cH 2), 4.26～4.24 (t, 2H, carbazole-CH 2cH 2cH 2cH 2), 4.61 (s, 2H, benzimidazolyl-CH 2), 6.72～6.66 (m, H, benzene-4-H), 6.83～6.78 (m, H, benzene-6-H), 6.99～6.96 (m, H, benzene-3-H), 7.03～7.00 (m, H, benzene-5-H), 7.16～7.13 (m, 1H, carbazole-6-H), 7.26～7.24 (m, 2H, benzimidazole-5,6-H), 7.32～7.29 (d, 2H, carbazole-3,6-H), 7.59～7.52 (m, 4H, carbazole-2,7-H, benzimidazole-4,7-H), 7.76～7.73 (m, 2H, carbazole-1,8-H), 8.11～8.09 (d, 2H, carbazole-4,5-H) ppm; MS (m/z): 463[M+H] +.
Embodiment 33, N-((1H-benzimidazolyl-2 radicals-yl) methyl)-N-(preparation of 4-((9H-carbazole-9-yl) methyl) benzyl-4-monomethylaniline (compound IV-2)
Take Compound I-60.230g (0.001mol), 9-(4-(brooethyl) benzyl)-9H-carbazole 0.349g (0.001mol) and Anhydrous potassium carbonate 0.179g (0.001mol) is starting raw material, according to method described in embodiment 11, make compound IV-20.209g, productive rate 41.2%; Yellow solid, 133～134 ℃ of fusing points; 1h NMR (300MHz, CDCl 3) δ: 2.22 (s, 3H ,-CH 3), 4.64 (s, 2H, benzimidazolyl-CH 2), 4.96 (s, 2H, Ph-CH 2), 5.21 (s, 2H, carbazole-CH 2), 6.61～6.58 (d, 2H, toluene-2,6-H), 7.11～7.09 (d, 2H, toluene-3,5-H), 7.13～7.10 (m, 4H, Ph-H), 7.27～7.24 (m, 2H, benzimidazole-5,6-H), 7.31～7.28 (m, 4H, carbazole-2,3,6,7-H), 7.57～7.53 (m, 2H, benzimidazole-4,7-H), 7.82～7.78 (m, 2H, carbazole-1,8-H), 8.12～8.09 (d, 2H, carbazole-4,5-H) ppm; MS (m/z): 507[M+H] +.
The preparation of embodiment 34,7-(4-(((1H-benzimidazolyl-2 radicals-yl) methyl) (4-fluorophenyl) amido) hexyloxy)-4-methyl-2H-chromene-2 ketone (compound V-1)
Take Compound I-30.239g (0.001mol), 7-(4-bromine hexyloxy)-4-methyl-2H-chromen-2-one 0.342g (0.001mol) and Anhydrous potassium carbonate 0.221g (0.002mol) is starting raw material, according to method described in embodiment 11, make compound V-10.185g, productive rate 39.6%; Brown color solid, 123～124 ℃ of fusing points; 1h NMR (300MHz, CDCl 3) δ: 1.52～1.42 (m, 4H, coumarin-OCH 2cH 2cH 2cH 2cH 2cH 2), 1.80～1.78 (m, 4H, coumarin-OCH 2cH 2cH 2cH 2cH 2cH 2), 2.39 (s, 3H, coumarin-CH 3), 3.52～3.49 (m, 2H, coumarin-OCH 2cH 2cH 2cH 2cH 2cH 2), 4.39～4.36 (t, 2H, coumarin-OCH 2), 4.65 (s, 2H, benzimidazolyl-CH 2), 6.13 (s, 1H, coumarin-3-H), 6.80～6.74 (m, 2H, benzene-2,6-H), 6.99～6.94 (m, 2H, coumarin-6,8-H), 7.13～7.07 (m, 2H, benzene-2,6-H), 7.28～7.27 (m, 2H, benzimidazole-5,6-H), 7.50～7.45 (m, 2H, benzimidazole-4,7-H), 7.77～7.74 (d, 1H, coumarin-5-H) ppm; MS (m/z): 499[M+H] +.
The preparation of embodiment 35,7-(4-(((1H-benzimidazolyl-2 radicals-yl) methyl) (4-tolyl) amido) methyl)-3-ethanoyl-2H-chromene-2 ketone (compound V-2)
Take Compound I-60.229g (0.001mol), 7-(4-(brooethyl) benzyloxy)-3-ethanoyl-2H-chromen-2-one 0.383g (0.001mol) and Anhydrous potassium carbonate 0.217g (0.002mol) is starting raw material, according to method described in embodiment 11, make compound V-20.207g, productive rate 40.1%; Brown thick liquid; 1h NMR (300MHz, CDCl 3) δ: 2.17 (s, 3H, coumarin-CH 3), 2.23 (s, 3H, Ph-CH 3), 4.64 (s, 2H, benzimidazolyl-CH 2), 4.96 (s, 2H, Ph-CH 2), 5.19 (s, 2H, coumarin-OCH 2), 6.65～6.62 (d, 2H, toluene-2,6-H), 7.06～7.01 (m, 2H, coumarin-6,8-H), 7.13～7.10 (d, 2H, toluene-3,5-H), 7.18～7.13 (m, 4H, Ph-H), 7.26～7.24 (m, 2H, benzimidazole-5,6-H), 7.58～7.54 (m, 2H, benzimidazole-4,7-H), 7.82～7.79 (d, 1H, coumarin-5-H), 8.91 (s, 1H, coumarin-4-H) ppm; MS (m/z): 544[M+H] +.
The preparation of embodiment 36, N-((1H-benzimidazolyl-2 radicals-yl) methyl)-N-(3,4-dichlorophenyl)-4-methylaniline hydrochloride (Compound I I-16)
Compound I I-100.051g (0.129mmol) is dissolved in E-C mixed solvent, slowly drips hydrochloric acid soln under stirring at room, stirring reaction is to generating without precipitation, and underpressure distillation, except desolventizing, obtains Compound I I-160.058g, productive rate 96.1%; Yellow solid, 134～135 ℃ of fusing points.
Embodiment 37, N-((1H-benzimidazolyl-2 radicals-yl) methyl)-N-(2,4 difluorobenzene base)-3, the preparation of 5-bis-(trifluoromethyl) anilinechloride (Compound I I-17)
Compound I I-140.049g (0.101mmol) is dissolved in E-C mixed solvent, slowly drips hydrochloric acid soln under stirring at room, stirring reaction is to generating without precipitation, and underpressure distillation, except desolventizing, obtains Compound I I-170.055g, productive rate 97.2%; Yellow solid, 137～138 ℃ of fusing points.
The preparation of embodiment 38, N-((1H-benzimidazolyl-2 radicals-yl) methyl)-N-eight alkyl-4-methylaniline hydrochloride (compound III-7)
Compound III-30.026g (0.074mmol) is dissolved in E-C mixed solvent, slowly drips hydrochloric acid soln under stirring at room, stirring reaction is to generating without precipitation, and underpressure distillation, except desolventizing, obtains compound III-70.028g, productive rate 90.4%; Yellow solid, 112～114 ℃ of fusing points.
With reference to above-mentioned exemplary embodiment 2～38 and in conjunction with ordinary skill in the art means, those skilled in the art can make benzoglyoxaline aminated compounds and the pharmacologically acceptable salt thereof of other structure shown in general formula I-V, here do not repeat one by one.
The antimicrobial acivity of embodiment 39, benzoglyoxaline aminated compounds
Employing meets clinical experiment standard (the National Committee for ClinicalLaboratory Standards of United States National Committee's formulation in 1993, NCCLS) 96 hole micro-dilution methods, the benzoglyoxaline aminated compounds that detection embodiment 2～38 makes and hydrochloride thereof are to streptococcus aureus, MASR, micrococcus luteus, Bacillus subtilus, intestinal bacteria, Pseudomonas aeruginosa, Bacillus proteus, the minimum inhibitory concentration of Candida albicans and candidiasis (MIC), testing compound is dissolved with a small amount of methyl-sulphoxide, thin up is made the solution that concentration is 1.28mg/mL again, with nutrient solution, be diluted to 128 μ g/mL again, cultivate 24～72 hours for 35 ℃, after culture plate is put and is fully stirred evenly on vibrator, at wavelength 490nm place, measure MIC 50.The results are shown in Table 1.Aspect antibacterium, all testing compounds all show certain restraining effect to institute's bacteria tested, and the inhibition ability of gram-negative bacteria is generally better than to gram positive organism.Wherein, Compound I-2, I-9, II-2, II-14 have stronger restraining effect to intestinal bacteria; Compound I-2, I-9, II-2, II-3, II-7, II-14, II-17, III-5, V-1 can effectively suppress the propagation of Pseudomonas aeruginosa; Compound I-2, I-9, II-2, II-17 demonstrate significant inhibition ability to Bacillus subtilus; Compound I-2, I-9, II-2, II-14, II-17 show the stronger ability of killing streptococcus aureus, and MRSA is also had to good inhibition ability.Aspect antimycotic, Compound I-2, I-8, I-9, II-7, II-11, II-14, II-17, III-6, V-1 all can effectively suppress the propagation of Candida albicans and candidiasis, and wherein the restraining effect of Compound I-2 is the strongest.
Antimicrobial acivity (the MIC of table 1 benzoglyoxaline aminated compounds 50, μ g/mL)
According to above-mentioned detection method, the benzoglyoxaline aminated compounds of other structure shown in mutual-through type I-V of the present invention and antibacterium and the anti-mycotic activity of pharmacologically acceptable salt thereof also detect.Found that, these compounds are the same with the compound that embodiment 2～38 makes, and the inhibition that gram-positive microorganism (streptococcus aureus, MRSA, micrococcus luteus, Bacillus subtilus), Gram-negative bacteria (intestinal bacteria, Pseudomonas aeruginosa, Bacillus proteus) and fungi (Candida albicans, candidiasis) are all demonstrated is more or less active.
The pharmaceutical applications of embodiment 40, benzoglyoxaline aminated compounds
According to above-mentioned antimicrobial acivity detected result, benzoglyoxaline aminated compounds of the present invention and pharmacologically acceptable salt thereof have good antibacterium, anti-mycotic activity, can make antibacterium, antifungal drug for clinical.These medicines can be both single preparationss of ephedrine, for example, by a kind of benzoglyoxaline aminated compounds of structure or its pharmacologically acceptable salt and pharmaceutically acceptable auxiliary material, made; Also can be compound preparation, such as the benzoglyoxaline aminated compounds by a kind of structure or its pharmacologically acceptable salt and existing antibacterium, Active antifungal compound (as norfloxicin, Ciprofloxacin, Sulfamethoxazole, fluconazole, phosphorus fluconazole, itraconazole etc.) and pharmaceutically acceptable auxiliary material, make, or made by several benzoglyoxaline aminated compoundss of different structure or its pharmacologically acceptable salt and pharmaceutically acceptable auxiliary material.Described preparation type includes but not limited to the formulations such as tablet, capsule, powder, granule, pill, injection, powder injection, solution, suspensoid, emulsion, suppository, ointment, gelifying agent, film, aerosol, percutaneous absorption patch, and various slowly-releasing, controlled release preparation and nanometer formulation.
1, the preparation of Compound I-2 tablet
Prescription: Compound I-2100g, starch 40g, Microcrystalline Cellulose 80g, Magnesium Stearate 3.0g, Vltra tears E-30 (solution that massfraction is 40%) is appropriate, makes altogether 4000.
Method for making: the Vltra tears E-30 solution that preparation massfraction is 4%, standby; Take starch 20g, 105 ℃ are dried 5 hours, obtain dry starch, standby; Take Compound I-2, the Microcrystalline Cellulose of starch 20g and recipe quantity, mix, pulverized 80 mesh sieves, the Vltra tears E-30 solution softwood processed that is 4% with massfraction, 20 mesh sieves are granulated, 50～60 ℃ are dried to moisture content approximately 3%, cross the whole grain of 20 mesh sieves, in dry particle, add the Magnesium Stearate of dry starch 20g and recipe quantity, mix, compressing tablet, obtains.
Usage and consumption: according to patient's the state of an illness and individual difference, suggestion dose every day is 3～6, is equivalent to 0.075～0.15g Compound I-2/60kg body weight/day, divides 3 inferior to one after each meal, drinks cupful water while taking; Or follow the doctor's advice.
2, the preparation of Compound I-9 capsule
Prescription: Compound I-9100g, treated starch (120 order) 50g, Microcrystalline Cellulose (100 order) 30g, low-substituted hydroxypropyl cellulose (100 order) 10g, talcum powder (100 order) 10g, sweeting agent 5g, orange essence 1g, pigment is appropriate, and water is appropriate, makes 4000.
Method for making: Compound I-9 micronization of recipe quantity is ground into after superfine powder, mix with treated starch, Microcrystalline Cellulose, low-substituted hydroxypropyl cellulose, talcum powder, sweeting agent, orange essence and the pigment of recipe quantity, water softwood processed, 12～14 mesh sieves are granulated, 40～50 ℃ dry, sieve whole, pack capsulae vacuus into, obtain.
Usage and consumption: according to patient's the state of an illness and individual difference, suggestion dose every day is 3～6, is equivalent to 0.075～0.15g Compound I-9/60kg body weight/day, divides 3 inferior to one after each meal, drinks cupful water while taking; Or follow the doctor's advice.
3, the preparation of Compound I I-2 aerosol
Prescription: Compound I I-22.5g, Span203g, talcum powder (100 order) 4g, Trichloromonofluoromethane adds in right amount.
Method for making: Compound I I-2, Span20 and talcum powder are put respectively to vacuum drying oven inner drying a few hours, put in moisture eliminator and be cooled to room temperature, with micronizer mill, be ground into micro mist, then mix by recipe quantity, pour in encloses container, add Trichloromonofluoromethane to specified amount.
Usage and consumption: according to patient's the state of an illness and individual difference, suggestion is used 3～4 times every day.
4, the preparation of Compound I I-3 suppository
Prescription: Compound I I-34g, gelatin 14g, glycerine 70g, distilled water adds to 100mL, makes altogether 100 pieces.
Method for making: get gelatin and the glycerine of recipe quantity, adding distil water is to 100mL, 60 ℃ of heat fused of water-bath, add the Compound I I-3 of recipe quantity in the time of in the pasty state, stir, approach while solidifying, pour in suitable vaginal suppository mould, after cooled and solidified, strike off, take out, packing, obtains.
Usage and consumption: suppository is placed in vagina depths, 1 time every night, each 1 piece.
5, the preparation of Compound I I-5 injection liquid
Prescription: Compound I I-510g, propylene glycol 500mL, water for injection 500mL, makes 1000mL altogether.
Method for making: the Compound I I-5 that takes recipe quantity, the propylene glycol and the water for injection that add recipe quantity, be stirred to dissolve, then to add gac to final quality mark be 0.1%, stir, standing 15 minutes, with aperture, be the de-charcoal of titanium rod of 5 μ m, then with aperture, be the millipore filtration essence filter of 0.45 μ m and 0.22 μ m successively, filtrate embedding is in 10mL ampoule, 100 ℃ of flowing steam sterilizings 45 minutes, obtain.
Usage and consumption: intravenous drip, every 200mg adds in 5% glucose injection or 0.9% sodium chloride injection 250mL, and the instillation time is 30～60 minutes.
6, the preparation of Compound I I-7 ointment
Prescription: Compound I I-72g, stearic acid 12g, Vaseline 3g, direactive glyceride 3g, ethyl p-hydroxybenzoate 0.05g, distilled water 60mL, borax 1g, potassium hydroxide 0.5g, potassium sorbate 0.3g, glycerine 0.5g, whiteruss 0.5g, makes 85g altogether.
Method for making: get stearic acid, Vaseline, Tegin 55G and the ethyl p-hydroxybenzoate of recipe quantity, heating and melting, crosses 100 mesh sieves, is incubated 80 ℃, as oil phase, standby; Distilled water, borax, potassium hydroxide, potassium sorbate, glycerine and the whiteruss of getting recipe quantity, heated and boiled, as water; Water is cooled to 85 ℃, under constantly stirring, is adding oil phase, after emulsification, then add the Compound I I-7 of recipe quantity, cooling and stirring, obtains.
Usage and consumption: be applied to affected part, repeatedly rub to skin heating, every day 2 times.
7, the preparation of Compound I I-14 liniment
Prescription: Compound I I-144g, SOFT SOAP 7.5g, camphor 5g, distilled water adds to 100mL.
Method for making: by SOFT SOAP heating liquefaction, standby; By camphor 95% dissolve with ethanol, standby; Get the Compound I I-14 of recipe quantity, under constantly stirring, add potash fertilizer soap lye, then the ethanolic soln that camphorates, progressively add water, after emulsification completely, add again distilled water to full dose.
Usage and consumption: 1～2 drips in without damaged affected part, or with cotton swab, dips appropriate liquid medicine painting affected part, every day 2 times.
8, the preparation of Compound I I-10 and fluconazole compound powder injection
Prescription: Compound I I-1050g, fluconazole 50g, Sodium Benzoate 1g, makes 100 bottles altogether.
Method for making: get Compound I I-10, fluconazole and the Sodium Benzoate of recipe quantity, mix under sterile state, 100 bottles of packing, obtain.
9, the preparation of compound III-6 and Ciprofloxacin compound powder injection
Prescription: compound III-650g, Ciprofloxacin 50g, sodium salicylate 1g, makes 100 bottles altogether.
Method for making: get compound III-6, Ciprofloxacin and the sodium salicylate of recipe quantity, mix under sterile state, 100 bottles of packing, obtain.
10, the preparation of Compound I I-16 tablet
Prescription: Compound I I-1625g, starch 10g, Microcrystalline Cellulose 20g, Magnesium Stearate 0.75g, Vltra tears E-30 (solution that massfraction is 40%) is appropriate, makes altogether 1000.
Method for making: the Vltra tears E-30 solution that preparation massfraction is 4%, standby; Take starch 5g, 105 ℃ are dried 5 hours, obtain dry starch, standby; Take Compound I I-16, the Microcrystalline Cellulose of starch 5g and recipe quantity, mix, pulverized 80 mesh sieves, the Vltra tears E-30 solution softwood processed that is 4% with massfraction, 20 mesh sieves are granulated, 50～60 ℃ are dried to moisture content approximately 3%, cross the whole grain of 20 mesh sieves, in dry particle, add the Magnesium Stearate of dry starch 5g and recipe quantity, mix, compressing tablet, obtains.
Usage and consumption: according to patient's the state of an illness and individual difference, suggestion dose every day is 3～6, is equivalent to 0.075～0.15g Compound I I-16/60kg body weight/day, divides 3 inferior to one after each meal, drinks cupful water while taking; Or follow the doctor's advice.
11, the preparation of Compound I I-17 capsule
Prescription: Compound I I-1725g, treated starch (120 order) 12.5g, Microcrystalline Cellulose (100 order) 7.5g, low-substituted hydroxypropyl cellulose (100 order) 2.5g, talcum powder (100 order) 2g, sweeting agent 1.25g, orange essence 0.25g, pigment is appropriate, and water is appropriate, makes 1000.
Method for making: the Compound I I-17 micronization of recipe quantity is ground into after superfine powder, mix with treated starch, Microcrystalline Cellulose, low-substituted hydroxypropyl cellulose, talcum powder, sweeting agent, orange essence and the pigment of recipe quantity, water softwood processed, 12～14 mesh sieves are granulated, 40～50 ℃ dry, sieve whole, pack capsulae vacuus into, obtain.
Usage and consumption: according to patient's the state of an illness and individual difference, suggestion dose every day is 3～6, is equivalent to 0.075～0.15g Compound I I-17/60kg body weight/day, divides 3 inferior to one after each meal, drinks cupful water while taking; Or follow the doctor's advice.
12, the preparation of compound III-7 aerosol
Prescription: compound III-72.5g, Span203g, talcum powder (100 order) 4g, Trichloromonofluoromethane adds in right amount.
Method for making: compound III-7, Span20 and talcum powder are put respectively to vacuum drying oven inner drying a few hours, put in moisture eliminator and be cooled to room temperature, with micronizer mill, be ground into micro mist, then mix by recipe quantity, pour in encloses container, add Trichloromonofluoromethane to specified amount.
Usage and consumption: according to patient's the state of an illness and individual difference, suggestion is used 3～4 times every day.
Finally explanation, above embodiment only, for technical scheme of the present invention is described, does not form the restriction to content of the present invention.Although the present invention has been done to comparatively detailed exemplifying by above-described embodiment, but those skilled in the art still can be according to summary of the invention part and the described technology contents of embodiment part, in the form and details it is made to various changes, and do not depart from the spirit and scope of the present invention that appended claims limits.

Claims (9)

1. benzoglyoxaline aminated compounds and the pharmacologically acceptable salt thereof shown in general formula I I-V:
In formula, R 1and R 2be 2-fluorine, 3-fluorine, 4-fluorine, 2 independently, 3-difluoro, 2,4-difluoro, 2,5-difluoro, 2,6-difluoro, 3,4-difluoro, 3,5-difluoro, 2-chlorine, 3-chlorine, 4-chlorine, 2,3-dichloro, 2,4-dichloro, 2,5-dichloro, 2,6-dichloro, 3,4-dichloro, 3,5-dichloro, 4-iodine, 4-nitro, 3-trifluoromethyl, 3,5-bis-(trifluoromethyl), 2-methyl, 3-methyl, 4-methyl, 2,3-dimethyl, 2,4-dimethyl, 2,5-dimethyl, 2,6-dimethyl, 3,4-dimethyl, 3,5-dimethyl or 3-methoxyl group; R 3for hydrogen, fluorine, chlorine, iodine, nitro, trifluoromethyl, methyl or methoxy; R 4for methyl or ethanoyl; R is alkyl or aryl; N is 1 to 16 positive integer.
2. benzoglyoxaline aminated compounds according to claim 1 and pharmacologically acceptable salt thereof, is characterized in that R 1and R 2be 2-fluorine, 3-fluorine, 4-fluorine, 2 independently, 3-difluoro, 2,4-difluoro, 3,4-difluoro, 3,5-difluoro, 2-chlorine, 3-chlorine, 4-chlorine, 2,3-dichloro, 2,4-dichloro, 3,4-dichloro, 3,5-dichloro, 4-iodine, 4-nitro, 3-trifluoromethyl, 3,5-bis-(trifluoromethyl) or 4-methyl; R 3for hydrogen; R 4for methyl or ethanoyl; R is the alkyl or phenyl of 1～4 carbon; N is 1 to 16 positive integer.
3. benzoglyoxaline aminated compounds according to claim 2 and pharmacologically acceptable salt thereof, is characterized in that R 1for 2-fluorine, 4-fluorine, 2,4-difluoro, 4-chlorine, 2,4-dichloro, 4-iodine, 3-trifluoromethyl, 3,5-bis-(trifluoromethyl) or 4-methyl; R 2for 4-fluorine, 2,4-difluoro, 2-chlorine, 3-chlorine, 4-chlorine, 2,3-dichloro, 2,4-dichloro, 3,4-dichloro or 4-nitro; R 3for hydrogen; R 4for 4-methyl or 3-ethanoyl; R is the alkyl or phenyl of 2～4 carbon; N is 1 to 16 positive integer.
4. benzoglyoxaline aminated compounds according to claim 3 and pharmacologically acceptable salt thereof, is characterized in that, is any and the pharmacologically acceptable salt thereof in following compound:
Compound I I-1:N-((1H-benzimidazolyl-2 radicals-yl) methyl)-N-(3,4-dichlorophenyl)-2-fluoroaniline;
Compound I I-2:N-((1H-benzimidazolyl-2 radicals-yl) methyl)-N-(2,4 dichloro benzene base)-3-5-trifluoromethylaniline;
Compound I I-3:N-((1H-benzimidazolyl-2 radicals-yl) methyl)-N-(2,4 dichloro benzene base)-4-fluoroaniline;
Compound I I-4:N-((1H-benzimidazolyl-2 radicals-yl) methyl)-N-(2-chloro-phenyl-)-4-monomethylaniline;
Compound I I-5:N-((1H-benzimidazolyl-2 radicals-yl) methyl)-N-(3-chloro-phenyl-)-4-monomethylaniline;
Compound I I-6:N-((1H-benzimidazolyl-2 radicals-yl) methyl)-N-(4-chloro-phenyl-)-4-monomethylaniline;
Compound I I-7:N-((1H-benzimidazolyl-2 radicals-yl) methyl)-N-(4-nitrophenyl)-4-monomethylaniline;
Compound I I-8:N-((1H-benzimidazolyl-2 radicals-yl) methyl)-N-(2,4 difluorobenzene base)-4-monomethylaniline;
Compound I I-9:N-((1H-benzimidazolyl-2 radicals-yl) methyl)-N-(2,4 dichloro benzene base)-4-monomethylaniline;
Compound I I-10:N-((1H-benzimidazolyl-2 radicals-yl) methyl)-N-(3,4-dichlorophenyl)-4-monomethylaniline;
Compound I I-11:N-((1H-benzimidazolyl-2 radicals-yl) methyl)-N-(2,4 dichloro benzene base)-2,4 difluorobenzene amine;
Compound I I-12:N-((1H-benzimidazolyl-2 radicals-yl) methyl)-N-(2,4 difluorobenzene base)-2,4 dichloro aniline;
Compound I I-13:N-((1H-benzimidazolyl-2 radicals-yl) methyl)-N-(4-fluorophenyl)-3,5-bis-(trifluoromethyl) aniline;
Compound I I-14:N-((1H-benzimidazolyl-2 radicals-yl) methyl)-N-(2,4 difluorobenzene base)-3,5-bis-(trifluoromethyl) aniline;
Compound I I-15:N-((1H-benzimidazolyl-2 radicals-yl) methyl)-N-(2,4 dichloro benzene base)-3,5-bis-(trifluoromethyl) aniline;
Compound III-1:N-((1H-benzimidazolyl-2 radicals-yl) methyl)-N-propyl group-4-monomethylaniline;
Compound III-2:N-((1H-benzimidazolyl-2 radicals-yl) methyl)-N-hexyl-4-monomethylaniline;
Compound III-3:N-((1H-benzimidazolyl-2 radicals-yl) methyl)-N-octyl group-4-monomethylaniline;
Compound III-4:N-((1H-benzimidazolyl-2 radicals-yl) methyl)-N-decyl-4-monomethylaniline;
Compound III-5:N-((1H-benzimidazolyl-2 radicals-yl) methyl)-N-dodecyl-4-monomethylaniline;
Compound III-6:N-((1H-benzimidazolyl-2 radicals-yl) methyl)-N-octadecyl-4-monomethylaniline;
Compound IV-1:N-((1H-benzimidazolyl-2 radicals-yl) methyl)-N-(4-(9H-carbazole-9-yl) butyl)-2-fluoroaniline;
Compound IV-2:N-((1H-benzimidazolyl-2 radicals-yl) methyl)-N-(4-((9H-carbazole-9-yl) methyl) benzyl-4-monomethylaniline;
Compound V-1:7-(4-(((1H-benzimidazolyl-2 radicals-yl) methyl) (4-fluorophenyl) amido) hexyloxy)-4-methyl-2H-chromen-2-one;
Compound V-2:7-(4-(((1H-benzimidazolyl-2 radicals-yl) methyl) (4-tolyl) amido) methyl)-3-ethanoyl-2H-chromen-2-one.
5. according to benzoglyoxaline aminated compounds and pharmacologically acceptable salt thereof described in claim 1 to 4 any one, it is characterized in that, described pharmacologically acceptable salt is hydrochloride, nitrate or acetate.
6. the benzoglyoxaline aminated compounds described in claim 1 to 5 any one and the preparation method of pharmacologically acceptable salt thereof, is characterized in that,
A. the preparation of the aminated compounds of benzoglyoxaline shown in general formula I: by 75～90 ℃ of stirring reactions of temperature control in organic solvent of compound shown in 2-chloromethyl-1H-benzoglyoxaline and general formula VII, under agitation condition, add alkali reagent again, 10～60 ℃ of stirring reactions of temperature control, make the aminated compounds of benzoglyoxaline shown in general formula I; Described organic solvent is any one or more mixing in ethanol, toluene and benzene; Described alkali reagent is any one or more mixing in salt of wormwood, sodium carbonate, potassium hydroxide, sodium hydroxide, sodium tert-butoxide, sodium hydride and sodium Metal 99.5;
B. the preparation of benzoglyoxaline aminated compounds shown in general formula I I～V: by 50～70 ℃ of stirring reactions of temperature control in organic solvent of compound shown in the aminated compounds of benzoglyoxaline shown in general formula I and general formula VIII, IX, X or XI, after system is acidity, add alkali reagent, 50～70 ℃ of stirring reactions of temperature control, make benzoglyoxaline aminated compounds shown in general formula I I, III, IV or V; Described organic solvent is any one or more mixing in acetonitrile, methyl alcohol, ethanol, toluene, tetrahydrofuran (THF) and DMF; Described alkali reagent is any one or more mixing in saleratus, sodium bicarbonate, salt of wormwood, sodium carbonate, potassium hydroxide, sodium hydroxide, potassium hydride KH, sodium hydride, POTASSIUM BOROHYDRIDE, sodium borohydride and lithium aluminum hydride;
C. the preparation of the pharmacologically acceptable salt of benzoglyoxaline aminated compounds shown in general formula I I～V: benzoglyoxaline aminated compounds shown in general formula I I～V is dissolved in any one or more mixing in ethanol, ether, tetrahydrofuran (THF) and trichloromethane, under agitation condition, add aqueous hydrochloric acid, aqueous nitric acid or aqueous acetic acid, stirring reaction, to generating without precipitation, makes hydrochloride, nitrate or the acetate of benzoglyoxaline aminated compounds shown in general formula I I～V; Or, benzoglyoxaline aminated compounds shown in general formula I I～V is dissolved in any one or more mixing in chloroform, acetone, methyl alcohol and acetonitrile, stirring at room, add again excessive aqueous hydrochloric acid, aqueous nitric acid or aqueous acetic acid, 0～50 ℃ of stirring reaction of temperature control, makes hydrochloride, nitrate or the acetate of benzoglyoxaline aminated compounds shown in general formula I I～V;
R in compound shown in general formula I, VII-XI 1, R 2, R 3, R 4, R in benzoglyoxaline aminated compounds shown in the definition of R and n and general formula I I-V 1, R 2, R 3, R 4, R and n definition identical.
7. the preparation method of benzoglyoxaline aminated compounds according to claim 6 and pharmacologically acceptable salt thereof, is characterized in that,
A. the preparation of the aminated compounds of benzoglyoxaline shown in general formula I: described organic solvent is ethanol; Described alkali reagent is salt of wormwood or sodium carbonate; Described 2-chloromethyl-1H-benzoglyoxaline: aniline or substituted aniline: the mol ratio of alkali reagent is 1: 1.0～1.5: 1.2～1.4;
B. the preparation of benzoglyoxaline aminated compounds shown in general formula I I～V: described organic solvent is acetonitrile; Described alkali reagent is salt of wormwood or sodium carbonate; Benzoglyoxaline aminated compounds shown in described general formula I: compound shown in general formula VIII, IX, X or XI: the mol ratio of alkali reagent is 1: 1.0～1.5: 1.2～1.4.
8. the benzoglyoxaline aminated compounds described in claim 1 to 5 any one and pharmacologically acceptable salt thereof the application in preparation antibacterium and/or antifungal drug.
9. application according to claim 8, it is characterized in that, described bacterium is any one or more in streptococcus aureus, methicillin-resistant staphylococcus aureus, micrococcus luteus, Bacillus subtilus, intestinal bacteria, Pseudomonas aeruginosa and Bacillus proteus; Described fungi is Candida albicans and/or candidiasis.
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