CN102659687A - Benzimidazolamines compounds as well as preparation method and application thereof - Google Patents
Benzimidazolamines compounds as well as preparation method and application thereof Download PDFInfo
- Publication number
- CN102659687A CN102659687A CN2012101519967A CN201210151996A CN102659687A CN 102659687 A CN102659687 A CN 102659687A CN 2012101519967 A CN2012101519967 A CN 2012101519967A CN 201210151996 A CN201210151996 A CN 201210151996A CN 102659687 A CN102659687 A CN 102659687A
- Authority
- CN
- China
- Prior art keywords
- compound
- methyl
- benzimidazolyl
- radicals
- benzoglyoxaline
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Granted
Links
- 0 *c1cccc(NCc2nc3ccccc3[n]2)c1 Chemical compound *c1cccc(NCc2nc3ccccc3[n]2)c1 0.000 description 2
Classifications
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
- Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
- Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change
Landscapes
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
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
Technical field
The invention belongs to chemical field, relate to one type of new organic cpds, also relate to the preparation method and the medicinal use thereof of this compound.
Background technology
Fluconazole has 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 specified treatment systemic fungal infection of the World Health Organization, in clinical application, have irreplaceable effect so far.Yet because widely-used its multidrug resistance that causes of fluconazole takes place frequently; And it is to not obvious, the narrow antimicrobial spectrum of result of treatment of non-Candida albicans such as aspergillus fumigatus etc.; Also have the water-soluble relatively poor problems such as administering mode is limited that cause, lot of domestic and foreign investigator all is devoted to fluconazole is done further exploitation.At present, more fluconazole analogue with good resistance fungi activity is developed, like ravuconazole (Ravuconazole), A Bakang azoles, Ai Shakang azoles (Isavuconazole) etc.Exploitation to fluconazole at present mainly concentrates on following three aspects: the one, and the fluconazole prodrug is studied, and is devoted to increase the chemicalstability of medicine, prolongs action time, improves the intermiscibility of medicine, strengthens to absorb, and improves bioavailability; The 2nd, on the basis of the triazole ring, 2,4 difluorobenzene base and the alcoholic extract hydroxyl group that keep fluconazole, another side chain is transformed, expectation obtain can with the efficient bonded verivate of fungi lanosterol 14 α-demethylation enzyme active sites; The 3rd, design synthetic molecules basic framework and fluconazole similar compounds expect to obtain the new texture antifungal drug that more has superiority than fluconazole.
Contain a plurality of heteroatomss in the nitrogen azole compounds structure, be prone to produce in vivo multiple non-covalent interaction (interact like hydrogen bond, π-π etc.) or with metals ion (like Zn
2+, Fe
2+Deng) coordination, and then the activity of inhibition organism endoenzyme, be widely used in fields such as medicine, agricultural chemicals.In recent years discover, some nitrogen heterocyclics such as imidazoles, benzoglyoxaline 、 oxazole, benzoxazole, thiazole etc. are introduced in the drug molecule, can obtain to have the bioactive molecule of novel texture.
Summary of the invention
In view of this, the object of the present invention is to provide a class formation novel benzoglyoxaline tertiary amine fluconazole analogue, its preparation method and the application of these compounds in pharmacy field.
Through big quantity research, the present invention provides following technical scheme:
1. benzoglyoxaline aminated compounds and the pharmacologically acceptable salt thereof shown in general formula I-V:
In the 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-two (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
3Be hydrogen, fluorine, chlorine, iodine, nitro, trifluoromethyl, methyl or methoxy; R
4Be methyl or ethanoyl; R is an 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-two (trifluoromethyl) or 4-methyl; R
3Be hydrogen; R
4Be methyl or ethanoyl; R is the alkyl or phenyl of 1～4 carbon; N is 1 to 16 positive integer.
Further, R
1Be 2-fluorine, 4-fluorine, 2,4-difluoro, 4-chlorine, 2,4-dichloro, 4-iodine, 3-trifluoromethyl, 3,5-two (trifluoromethyl) or 4-methyl; R
2Be 4-fluorine, 2,4-difluoro, 2-chlorine, 3-chlorine, 4-chlorine, 2,3-dichloro, 2,4-dichloro, 3,4-dichloro or 4-nitro; R
3Be hydrogen; R
4Be 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 the 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-two (trifluoromethyl) aniline;
Compound I I-1:N-((1H-benzimidazolyl-2 radicals-yl) methyl)-N-(3, the 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, the 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-two (trifluoromethyl) aniline;
Compound I I-14:N-((1H-benzimidazolyl-2 radicals-yl) methyl)-N-(2,4 difluorobenzene base)-3,5-two (trifluoromethyl) aniline;
Compound I I-15:N-((1H-benzimidazolyl-2 radicals-yl) methyl)-N-(2,4 dichloro benzene base)-3,5-two (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, said pharmacologically acceptable salt is hydrochloride, nitrate salt 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 the general formula I: with 75～90 ℃ of stirring reactions of temperature control in organic solvent of compound shown in 2-chloromethyl-1H-benzoglyoxaline and the general formula VII; Under agitation condition, add alkali reagent again; 10～60 ℃ of stirring reactions of temperature control promptly make the aminated compounds of benzoglyoxaline shown in the general formula I; Said organic solvent is any one or more mixing in ethanol, toluene and the benzene; Said alkali reagent is any one or more mixing in salt of wormwood, yellow soda ash, Pottasium Hydroxide, sodium hydroxide, sodium tert-butoxide, sodium hydride and the sodium Metal 99.5;
B. the preparation of benzoglyoxaline aminated compounds shown in general formula I I～V: with 50～70 ℃ of stirring reactions of temperature control in organic solvent of compound shown in the aminated compounds of benzoglyoxaline shown in the general formula I and general formula VIII, IX, X or the XI; After the system of treating is acidity; Add alkali reagent; 50～70 ℃ of stirring reactions of temperature control promptly make benzoglyoxaline aminated compounds shown in general formula I I, III, IV or the V; Said organic solvent is acetonitrile, methyl alcohol, ethanol, toluene, THF and N, any one or more mixing in the dinethylformamide; Said alkali reagent is any one or more mixing in saleratus, sodium hydrogencarbonate, salt of wormwood, yellow soda ash, Pottasium Hydroxide, sodium hydroxide, potassium hydride KH, sodium hydride, POTASSIUM BOROHYDRIDE 97MIN, Peng Qinghuana and the 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, THF and the trichloromethane; Under agitation condition, add aqueous hydrochloric acid, aqueous nitric acid or aqueous acetic acid; Stirring reaction does not generate to there being deposition, promptly makes hydrochloride, nitrate salt or the acetate of benzoglyoxaline aminated compounds shown in general formula I I～V; Perhaps; Benzoglyoxaline aminated compounds shown in general formula I I～V is dissolved in any one or more mixing in chloroform, acetone, methyl alcohol and the acetonitrile; Stirring at room; Add excessive aqueous hydrochloric acid, aqueous nitric acid or aqueous acetic acid again, 0～50 ℃ of stirring reaction of temperature control promptly makes hydrochloride, nitrate salt or the acetate of benzoglyoxaline aminated compounds shown in general formula I I～V;
R in the compound shown in the general formula VII-XI
1, R
2, R
3, R
4, R and n definition and general formula I-V shown in R in the benzoglyoxaline aminated compounds
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 the general formula I: said organic solvent is an ethanol; Said alkali reagent is salt of wormwood or yellow soda ash; Said 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: said organic solvent is an acetonitrile; Said alkali reagent is salt of wormwood or yellow soda ash; Benzoglyoxaline aminated compounds shown in the said general formula I: compound shown in general formula VIII, IX, X or the XI: the mol ratio of alkali reagent is 1: 1.0～1.5: 1.2～1.4.
3. benzoglyoxaline aminated compounds shown in general formula I-V and pharmacologically acceptable salt thereof the application in preparation antibacterium and/or antifungal drug.
Further, said bacterium is any one or more in streptococcus aureus, methicillin-resistant staphylococcus aureus (MRSA), micrococcus luteus, Bacillus subtilus, intestinal bacteria, Pseudomonas aeruginosa and the Bacillus proteus; Said 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 the general formula I is a benzoglyoxaline aryl secondary-amine compound; Compound shown in general formula I I, IV and the V is a benzoglyoxaline aryl tertiary amine fluconazole analogue; Compound shown in the general formula III is a benzoglyoxaline alkyl tertiary amine fluconazole analogue; These compounds detect through in vitro anti-microbial activity and find all have certain inhibition active to gram-positive microorganism (streptococcus aureus, MRSA, micrococcus luteus, Bacillus subtilus), Gram-negative bacteria (intestinal bacteria, Pseudomonas aeruginosa, Bacillus proteus) and fungi (Candida albicans, candidiasis); Can be used to prepare antibacterium and/or antifungal drug; Thereby for clinical antimicrobial therapy more how efficient, safe drug candidate is provided, helps to solve clinical treatment problems such as the resistance that is on the rise, obstinate invasive organism and emerging harmful microorganism.In addition, the synthetic route of these compounds is short, the preparation method is simple, and raw material is easy to get, and cost is lower.
Embodiment
In order to make the object of the invention, technical scheme and advantage clearer, carry out detailed description in the face of exemplary embodiment of the present invention down.
The preparation of embodiment 1,2-chloromethyl-1H-benzoglyoxaline (compound VI)
In the 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 the ammoniacal liquor neutralization, constantly be stirred to yellow solid and separate out suction filtration; Dry; Use the absolute ethyl alcohol recrystallization, promptly get 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 the 100mL round-bottomed flask, add compound VI 1.669g (0.010mol), 2-fluoroaniline 1.110g (0.010mol) and ethanol in right amount (dissolve be as the criterion fully with raw material); 75～90 ℃ of stirring reactions of temperature control 24～72 hours; Add soda ash light 1.272g (0.012mol) down in agitation condition again; 10～60 ℃ of reactions of temperature control 2～4 hours, thin-layer chromatography tracks to reaction to be finished, again through aftertreatments such as concentrated, extraction, column chromatography for separation, recrystallization, dryings; Promptly get compound I-1 1.764g, 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)
With compound VI 1.665g (0.010mol), 3-5-trifluoromethylaniline 1.607g (0.010mol) and soda ash light 1.272g (0.012mol) is starting raw material, makes compound I-2 2.074g, productive rate 71.2% according to embodiment 2 said methods; 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)
With compound VI 1.665g (0.010mol), 4-fluoroaniline 1.116g (0.011mol) and soda ash light 1.272g (0.012mol) is starting raw material, makes compound I-3 1.788g, productive rate 74.1% according to embodiment 2 said methods; 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)
With compound VI 1.670g (0.010mol), 4-chloroaniline 1.312g (0.010mol) and soda ash light 1.272g (0.012mol) is starting raw material, makes compound I-4 1.948g, productive rate 75.6% according to embodiment 2 said methods; 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)
With compound VI 1.614g (0.010mol), 4-Iodoaniline 2.079g (0.009mol) and soda ash light 1.274g (0.012mol) is starting raw material, makes compound I-5 2.458g, productive rate 70.4% according to embodiment 2 said methods; The 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)
With compound VI 1.659g (0.010mol), 4-monomethylaniline 1.282g (0.012mol) and soda ash light 1.276g (0.012mol) is starting raw material, makes compound I-6 1.987g, productive rate 83.7% according to embodiment 2 said methods; 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 difluorobenzene amine 1.290g (0.010mol) and soda ash light 1.273g (0.012mol) is starting raw material, makes compound I-7 2.070g, productive rate 79.8% according to embodiment 2 said methods; 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 dichloro aniline 1.615g (0.010mol) and soda ash light 1.275g (0.012mol) is starting raw material, makes compound I-8 2.102g, productive rate 71.9% according to embodiment 2 said methods; 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-two 5-trifluoromethylanilines (compound I-9)
With compound VI 1.662g (0.010mol), 3,5-two (trifluoromethyl) aniline 2.234g (0.010mol) and soda ash light 1.276g (0.012mol) are starting raw material, make compound I-9 2.964g, productive rate 2.5% according to embodiment 2 said methods; 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, the 4-dichlorophenyl)-2-fluoroaniline (compound I I-1)
In the 100mL round-bottomed flask, add compound I-1 0.486g (0.002mol), 3,4-benzyl dichloride chlorine 0.390g (0.002mol) and acetonitrile in right amount (dissolve be as the criterion fully with raw material); 50～70 ℃ of stirrings of temperature control; After the system of treating 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; Through aftertreatments such as concentrated, extraction, column chromatography for separation, recrystallization, dryings, promptly get compound I I-1 0.252g, productive rate 31.4% again; 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-2 0.586g (0.002mol), 2,4-benzyl dichloride chlorine 0.416g (0.002mol) and Anhydrous potassium carbonate 0.345g (0.003mol) are starting raw material, make compound I I-2 0.260g, productive rate 28.9% according to embodiment 11 said methods; 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-3 0.483g (0.002mol), 2,4-benzyl dichloride chlorine 0.401g (0.002mol) and Anhydrous potassium carbonate 0.336g (0.003mol) are starting raw material, make compound I I-3 0.257g, productive rate 32.1% according to embodiment 11 said methods; 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)
With compound I-6 0.231g (0.001mol), o-chloro benzyl chloride 0.174g (0.001mol) and Anhydrous potassium carbonate 0.169g (0.0012mol) is starting raw material, makes compound I I-4 0.182g, productive rate 50.4% according to embodiment 11 said methods; 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)
With compound I-6 0.234g (0.001mol), a benzyl chloride chlorine 0.161g (0.001mol) and Anhydrous potassium carbonate 0.172g (0.001mol) is starting raw material, makes compound I I-5 0.176g, productive rate 48.7% according to embodiment 11 said methods; White is equipped with
With compound I-6 0.240g (0.001mol), 2,4-two fluorobenzyl bromide 0.211g (0.001mol) and Anhydrous potassium carbonate 0.251g (0.002mol) are starting raw material, make compound I I-8 0.186g, productive rate 51.2% according to embodiment 11 said methods; 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-6 0.956g (0.004mol), 2,4-benzyl dichloride chlorine 0.902g (0.004mol) and Anhydrous potassium carbonate 0.660g (0.005mol) are starting raw material, make compound I I-9 0.755g, productive rate 47.6% according to embodiment 11 said methods; 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, the 4-dichlorophenyl)-4-monomethylaniline (compound I I-10)
With compound I-6 0.475g (0.002mol), 3,4-benzyl dichloride chlorine 0.393g (0.002mol) and Anhydrous potassium carbonate 0.420g (0.003mol) are starting raw material, make compound I I-10 0.345g, productive rate 43.5% according to embodiment 11 said methods; 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-7 0.522g (0.002mol), 2,4-benzyl dichloride chlorine 0.401g (0.002mol) and Anhydrous potassium carbonate 0.659g (0.0048mol) are starting raw material, make compound I I-11 0.172g, productive rate 20.6% according to embodiment 11 said methods; 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-8 0.237g (0.002mol), 2,4-two fluorobenzyl bromide 0.313g (0.002mol) and Anhydrous potassium carbonate 0.414g (0.003mol) are starting raw material, make compound I I-12 0.276g, productive rate 33.1% according to embodiment 11 said methods; 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-two (trifluoromethyl) aniline (compound I I-13)
With compound I-9 1.069g (0.003mol), 4-fluorine benzyl chlorine 0.456g (0.003mol) and Anhydrous potassium carbonate 0.495g (0.004mol) is starting raw material, makes compound I I-13 0.063g, productive rate 4.3% according to embodiment 11 said methods; 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-two (trifluoromethyl) aniline (compound I I-14)
With compound I-9 1.079g (0.003mol), 2,4-two fluorobenzyl bromide 0.635g (0.003mol) and Anhydrous potassium carbonate 0.497g (0.004mol) are starting raw material, make compound I I-14 0.130g, productive rate 8.9% according to embodiment 11 said methods; 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-two (trifluoromethyl) aniline (compound I I-15)
With compound I-9 1.049g (0.003mol), 2,4-benzyl dichloride chlorine 0.603g (0.003mol) and Anhydrous potassium carbonate 0.492g (0.004mol) are starting raw material, make compound I I-15 0.092g, productive rate 5.9% according to embodiment 11 said methods; 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)
With compound I-6 0.475g (0.002mol), N-PROPYLE BROMIDE 0.247g (0.002mol) and Anhydrous potassium carbonate 0.410g (0.003mol) is starting raw material, makes compound III-1 0.345g, productive rate 43.5% according to embodiment 11 said methods; 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)
With compound I-6 0.243g (0.001mol), n-hexyl bromine 0.168g (0.001mol) and Anhydrous potassium carbonate 0.275g (0.002mol) is starting raw material, makes compound III-2 0.132g, productive rate 40.6% according to embodiment 11 said methods; 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)
With compound I-6 0.478g (0.002mol), bromooctane 0.405g (0.002mol) and Anhydrous potassium carbonate 0.413g (0.003mol) is starting raw material, makes compound III-3 0.270g, productive rate 42.1% according to embodiment 11 said methods; 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)
With compound I-6 0.477g (0.002mol), bromo-decane 0.426g (0.002mol) and Anhydrous potassium carbonate 0.417g (0.003mol) is starting raw material, makes compound III-4 0.341g, productive rate 45.1% according to embodiment 11 said methods; 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～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)
With compound I-6 0.232g (0.001mol), to benzyl chloride chlorine 0.160g (0.001mol) and Anhydrous potassium carbonate 0.164g (0.001mol) is starting raw material, makes compound I I-6 0.162g, productive rate 44.8% according to embodiment 11 said methods; 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)
With compound I-6 0.474g (0.002mol), to nitrobenzyl bromine 0.442g (0.002mol) and Anhydrous potassium carbonate 0.403g (0.003mol) is starting raw material, makes compound I I-7 0.445g, productive rate 59.5% according to embodiment 11 said methods; 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), 7.86～7.85 (s, 2H, nitrophenyl-3,5-H) ppm; MS (m/z): 394 [M+Na]
+, 372 [M+H]
+.
The system 6.99 of embodiment 18, N-((1H-benzimidazolyl-2 radicals-yl) methyl)-N-(2,4 difluorobenzene base)-4-monomethylaniline (compound I I-8) (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)
With compound I-6 0.235g (0.001mol), bromo-dodecane 0.255g (0.001mol) and Anhydrous potassium carbonate 0.169g (0.001mol) is starting raw material, makes compound III-5 0.175g, productive rate 43.2% according to embodiment 11 said methods; 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)
With compound I-6 0.233g (0.001mol), bromo-octadecane 0.389g (0.001mol) and Anhydrous potassium carbonate 0.172g (0.001mol) is starting raw material, makes compound III-6 0.199g, productive rate 40.7% according to embodiment 11 said methods; 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
28C
H3), 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)
With compound I-1 0.242g (0.001mol), brombutyl carbazole 0.305g (0.001mol) and Anhydrous potassium carbonate 0.175g (0.001mol) is starting raw material, makes compound IV-1 0.179g, productive rate 39.1% according to embodiment 11 said methods; 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)
With compound I-6 0.230g (0.001mol), 9-(4-(brooethyl) benzyl)-9H-carbazole 0.349g (0.001mol) and Anhydrous potassium carbonate 0.179g (0.001mol) is starting raw material; Make compound IV-2 0.209g, productive rate 41.2% according to embodiment 11 said methods; 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)
With compound I-3 0.239g (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; Make compound V-10.185g, productive rate 39.6% according to embodiment 11 said methods; Pale brown look 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)
With compound I-6 0.229g (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; Make compound V-2 0.207g, productive rate 40.1% according to embodiment 11 said methods; The 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, the 4-dichlorophenyl)-4-methylaniline hydrochloride (compound I I-16)
Compound I I-10 0.051g (0.129mmol) is dissolved in the E-C mixed solvent, slow dripping hydrochloric acid solution under the stirring at room, stirring reaction does not generate to there being deposition, and underpressure distillation promptly gets compound I I-16 0.058g, productive rate 96.1% except that desolvating; 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-two (trifluoromethyl) anilinechloride (compound I I-17)
Compound I I-14 0.049g (0.101mmol) is dissolved in the E-C mixed solvent, slow dripping hydrochloric acid solution under the stirring at room, stirring reaction does not generate to there being deposition, and underpressure distillation promptly gets compound I I-17 0.055g, productive rate 97.2% except that desolvating; 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-3 0.026g (0.074mmol) is dissolved in the E-C mixed solvent, slow dripping hydrochloric acid solution under the stirring at room, stirring reaction does not generate to there being deposition, and underpressure distillation promptly gets compound III-7 0.028g, productive rate 90.4% except that desolvating; Yellow solid, 112～114 ℃ of fusing points.
The above-mentioned exemplary embodiment 2～38 of reference also combines ordinary skill in the art means, and those skilled in the art can make the benzoglyoxaline aminated compounds and the pharmacologically acceptable salt thereof of other structure shown in general formula I-V, here do not give unnecessary details one by one.
The antimicrobial acivity of embodiment 39, benzoglyoxaline aminated compounds
Employing meets clinical experiment standard (the National Committee for Clinical Laboratory Standards of United States National Committee's formulation in 1993; NCCLS) 96 hole micro-dilution methods; Benzoglyoxaline aminated compounds that detection embodiment 2～38 makes and hydrochloride thereof are to the minimum inhibitory concentration (MIC) of streptococcus aureus, MASR, micrococcus luteus, Bacillus subtilus, intestinal bacteria, Pseudomonas aeruginosa, Bacillus proteus, Candida albicans and candidiasis; Testing compound is dissolved with a small amount of methyl-sulphoxide; Thin up is processed the solution that concentration is 1.28mg/mL again, is diluted to 128 μ g/mL with nutrient solution again, cultivates 24～72 hours for 35 ℃; With culture plate put fully stir on the vibrator after, measure MIC at wavelength 490nm place
50The result sees 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 generally is superior 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 the better inhibited 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 the mutual-through type I-V of the present invention and the antibacterium and the anti-mycotic activity of pharmacologically acceptable salt thereof also detect.The result finds; These compounds are the same with the compound that embodiment 2～38 makes, and are active to 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) all demonstrate more or less.
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 antibacterium, anti-mycotic activity preferably, can process antibacterium, antifungal drug supplies clinical use.These medicines both can be single preparationss of ephedrine, were for example processed by a kind of benzoglyoxaline aminated compounds of structure or its pharmacologically acceptable salt and acceptable accessories; It also can be compound preparation; For example process, perhaps process by several kinds of benzoglyoxaline aminated compoundss of different structure or its pharmacologically acceptable salt and acceptable accessories by a kind of benzoglyoxaline aminated compounds of structure or its pharmacologically acceptable salt and existing antibacterium, anti-mycotic activity composition (like norfloxicin, CIPROFLOXACIN USP 24, SULPHAMETHOXAZOLE USP, fluconazole, phosphorus fluconazole, itraconazole etc.) and acceptable accessories.Said preparation type includes but not limited to 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-2 100g, starch 40g, Microcrystalline Cellulose 80g, Magnesium Stearate 3.0g, Vltra tears E-30 (massfraction is 40% solution) is an amount of, processes 4000 altogether.
Method for making: the preparation massfraction is 4% Vltra tears E-30 solution, and is subsequent use; Take by weighing starch 20g, 105 ℃ of dryings 5 hours, dry starch, subsequent use; Take by weighing compound I-2, the Microcrystalline Cellulose of starch 20g and recipe quantity, mixing was pulverized 80 mesh sieves; The use massfraction is 4% Vltra tears E-30 solution system softwood, and 20 mesh sieves are granulated, and 50～60 ℃ are dried to moisture content about 3%; Cross the whole grain of 20 mesh sieves, in dried particle, add the Magnesium Stearate of dry starch 20g and recipe quantity, mixing; Compressing tablet promptly gets.
Usage and consumption: according to patient's the state of an illness and difference between individuals, 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, drink cupful water when taking; Or follow the doctor's advice.
2, the preparation of compound I-9 capsule
Prescription: compound I-9 100g, 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 an amount of, and water is an amount of, processes 4000.
Method for making: after compound I-9 micronization of recipe quantity is ground into superfine powder; With treated starch, Microcrystalline Cellulose, low-substituted hydroxypropyl cellulose, talcum powder, sweeting agent, orange essence and the pigment mixing of recipe quantity, water system softwood, 12～14 mesh sieves are granulated; 40～50 ℃ of dryings; Sieve whole, the capsulae vacuus of packing into promptly gets.
Usage and consumption: according to patient's the state of an illness and difference between individuals, 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, drink cupful water when taking; Or follow the doctor's advice.
3, the preparation of compound I I-2 aerosol
Prescription: compound I I-2 2.5g, Span20 3g, talcum powder (100 order) 4g, Trichloromonofluoromethane adds in right amount.
Method for making: compound I I-2, Span20 and talcum powder are put vacuum drying oven inner drying number hour respectively; Put the moisture eliminator internal cooling to room temperature, be ground into micro mist, press the recipe quantity mixing again with micronizer mill; Pour in the encloses container, add Trichloromonofluoromethane to specified amount.
Usage and consumption: according to patient's the state of an illness and difference between individuals, suggestion is used 3～4 times every day.
4, the preparation of compound I I-3 suppository
Prescription: compound I I-3 4g, gelatin 14g, glycerine 70g, zero(ppm) water adds to 100mL, processes 100 pieces altogether.
Method for making: get the gelatin and the glycerine of recipe quantity, adding distil water is to 100mL, and 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, during approaching solidifying, pour in the suitable vaginal suppository mould, wipe off after the cooled and solidified; Take out, packing promptly gets.
Usage and consumption: suppository places the vagina depths, and 1 time every night, each 1 piece.
5, the preparation of compound I I-5 injection liquid
Prescription: compound I I-5 10g, Ucar 35 500mL, water for injection 500mL processes 1000mL altogether.
Method for making: take by weighing the compound I I-5 of recipe quantity, add the Ucar 35 and the water for injection of recipe quantity, stir and make dissolving; Adding gac to final quality mark again is 0.1%, stirs, and leaves standstill 15 minutes; The use aperture is that the titanium rod of 5 μ m takes off charcoal, and using the aperture more successively is the smart filter of millipore filtration of 0.45 μ m and 0.22 μ m, and the filtrating embedding is in the 10mL ampoule; 100 ℃ of flowing steams were sterilized 45 minutes, promptly got.
Usage and consumption: intravenous drip, every 200mg adds among 5% glucose injection or the 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-7 2g, Triple Pressed Stearic Acid 12g, Vaseline 3g, direactive glyceride 3g, ethyl p-hydroxybenzoate 0.05g, zero(ppm) water 60mL, borax 1g, Pottasium Hydroxide 0.5g, POTASSIUM SORBATE GRANULAR WHITE 0.3g, glycerine 0.5g, whiteruss 0.5g processes 85g altogether.
Method for making: get Triple Pressed Stearic Acid, Vaseline, Tegin 55G and the ethyl p-hydroxybenzoate of recipe quantity, heating and melting is crossed 100 mesh sieves, is incubated 80 ℃, and is as oil phase, subsequent use; Get zero(ppm) water, borax, Pottasium Hydroxide, POTASSIUM SORBATE GRANULAR WHITE, glycerine and the whiteruss of recipe quantity, heated and boiled is as water; Water is cooled to 85 ℃, under constantly stirring, adds oil phase, after the emulsification, add the compound I I-7 of recipe quantity again, cooling and stirring promptly gets.
Usage and consumption: be applied to the affected part, repeated friction to skin generates heat, every day 2 times.
7, the preparation of compound I I-14 liniment
Prescription: compound I I-14 4g, SOFT SOAP 7.5g, camphor 5g, zero(ppm) water adds to 100mL.
Method for making:, subsequent use with SOFT SOAP heating liquefaction; Camphor is used 95% dissolve with ethanol, subsequent use; Get the compound I I-14 of recipe quantity, under constantly stirring, add the potash fertilizer soap lye, the ethanolic soln that camphorates again progressively adds entry, treats to add zero(ppm) water again to full dose after the emulsification fully.
Usage and consumption: 1～2 drips in no damaged affected part, or dips in cotton swab and to get an amount of soup and smear the affected part, every day 2 times.
8, the preparation of compound I I-10 and fluconazole compound powder injection
Prescription: compound I I-10 50g, fluconazole 50g, Sodium Benzoate 1g processes 100 bottles altogether.
Method for making: get compound I I-10, fluconazole and the Sodium Benzoate of recipe quantity, under sterile state, mix, 100 bottles of packing promptly get.
9, the preparation of compound III-6 and CIPROFLOXACIN USP 24 compound powder injection
Prescription: compound III-6 50g, CIPROFLOXACIN USP 24 50g, SS 1g processes 100 bottles altogether.
Method for making: get compound III-6, CIPROFLOXACIN USP 24 and the SS of recipe quantity, under sterile state, mix, 100 bottles of packing promptly get.
10, the preparation of compound I I-16 tablet
Prescription: compound I I-16 25g, starch 10g, Microcrystalline Cellulose 20g, Magnesium Stearate 0.75g, Vltra tears E-30 (massfraction is 40% solution) is an amount of, processes 1000 altogether.
Method for making: the preparation massfraction is 4% Vltra tears E-30 solution, and is subsequent use; Take by weighing starch 5g, 105 ℃ of dryings 5 hours, dry starch, subsequent use; Take by weighing compound I I-16, the Microcrystalline Cellulose of starch 5g and recipe quantity, mixing was pulverized 80 mesh sieves; The use massfraction is 4% Vltra tears E-30 solution system softwood, and 20 mesh sieves are granulated, and 50～60 ℃ are dried to moisture content about 3%; Cross the whole grain of 20 mesh sieves, in dried particle, add the Magnesium Stearate of dry starch 5g and recipe quantity, mixing; Compressing tablet promptly gets.
Usage and consumption: according to patient's the state of an illness and difference between individuals, 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, drink cupful water when taking; Or follow the doctor's advice.
11, the preparation of compound I I-17 capsule
Prescription: compound I I-17 25g, 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 an amount of, and water is an amount of, processes 1000.
Method for making: after the compound I I-17 micronization of recipe quantity is ground into superfine powder; With treated starch, Microcrystalline Cellulose, low-substituted hydroxypropyl cellulose, talcum powder, sweeting agent, orange essence and the pigment mixing of recipe quantity, water system softwood, 12～14 mesh sieves are granulated; 40～50 ℃ of dryings; Sieve whole, the capsulae vacuus of packing into promptly gets.
Usage and consumption: according to patient's the state of an illness and difference between individuals, 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, drink cupful water when taking; Or follow the doctor's advice.
12, the preparation of compound III-7 aerosol
Prescription: compound III-7 2.5g, Span20 3g, talcum powder (100 order) 4g, Trichloromonofluoromethane adds in right amount.
Method for making: compound III-7, Span20 and talcum powder are put vacuum drying oven inner drying number hour respectively; Put the moisture eliminator internal cooling to room temperature, be ground into micro mist, press the recipe quantity mixing again with micronizer mill; Pour in the encloses container, add Trichloromonofluoromethane to specified amount.
Usage and consumption: according to patient's the state of an illness and difference between individuals, suggestion is used 3～4 times every day.
Explanation is that above embodiment only is used to explain technical scheme of the present invention, does not constitute the restriction to content of the present invention at last.Although the present invention has been done comparatively detailed giving an example through the foregoing description; 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 form with on the details it is made various changes, and the spirit and scope of the present invention that do not depart from appended claims and limited.
Claims (9)
1. benzoglyoxaline aminated compounds and the pharmacologically acceptable salt thereof shown in general formula I-V:
In the 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-two (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
3Be hydrogen, fluorine, chlorine, iodine, nitro, trifluoromethyl, methyl or methoxy; R
4Be methyl or ethanoyl; R is an 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-two (trifluoromethyl) or 4-methyl; R
3Be hydrogen; R
4Be 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
1Be 2-fluorine, 4-fluorine, 2,4-difluoro, 4-chlorine, 2,4-dichloro, 4-iodine, 3-trifluoromethyl, 3,5-two (trifluoromethyl) or 4-methyl; R
2Be 4-fluorine, 2,4-difluoro, 2-chlorine, 3-chlorine, 4-chlorine, 2,3-dichloro, 2,4-dichloro, 3,4-dichloro or 4-nitro; R
3Be hydrogen; R
4Be 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, are any and the pharmacologically acceptable salt thereof in the 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-two (trifluoromethyl) aniline;
Compound I I-1:N-((1H-benzimidazolyl-2 radicals-yl) methyl)-N-(3, the 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, the 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-two (trifluoromethyl) aniline;
Compound I I-14:N-((1H-benzimidazolyl-2 radicals-yl) methyl)-N-(2,4 difluorobenzene base)-3,5-two (trifluoromethyl) aniline;
Compound I I-15:N-((1H-benzimidazolyl-2 radicals-yl) methyl)-N-(2,4 dichloro benzene base)-3,5-two (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 claim 1 to 4 each described benzoglyoxaline aminated compounds and pharmacologically acceptable salt thereof, it is characterized in that said pharmacologically acceptable salt is hydrochloride, nitrate salt or acetate.
6. the preparation method of each described benzoglyoxaline aminated compounds of claim 1 to 5 and pharmacologically acceptable salt thereof is characterized in that,
A. the preparation of the aminated compounds of benzoglyoxaline shown in the general formula I: with 75～90 ℃ of stirring reactions of temperature control in organic solvent of compound shown in 2-chloromethyl-1H-benzoglyoxaline and the general formula VII; Under agitation condition, add alkali reagent again; 10～60 ℃ of stirring reactions of temperature control promptly make the aminated compounds of benzoglyoxaline shown in the general formula I; Said organic solvent is any one or more mixing in ethanol, toluene and the benzene; Said alkali reagent is any one or more mixing in salt of wormwood, yellow soda ash, Pottasium Hydroxide, sodium hydroxide, sodium tert-butoxide, sodium hydride and the sodium Metal 99.5;
B. the preparation of benzoglyoxaline aminated compounds shown in general formula I I～V: with 50～70 ℃ of stirring reactions of temperature control in organic solvent of compound shown in the aminated compounds of benzoglyoxaline shown in the general formula I and general formula VIII, IX, X or the XI; After the system of treating is acidity; Add alkali reagent; 50～70 ℃ of stirring reactions of temperature control promptly make benzoglyoxaline aminated compounds shown in general formula I I, III, IV or the V; Said organic solvent is acetonitrile, methyl alcohol, ethanol, toluene, THF and N, any one or more mixing in the dinethylformamide; Said alkali reagent is any one or more mixing in saleratus, sodium hydrogencarbonate, salt of wormwood, yellow soda ash, Pottasium Hydroxide, sodium hydroxide, potassium hydride KH, sodium hydride, POTASSIUM BOROHYDRIDE 97MIN, Peng Qinghuana and the 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, THF and the trichloromethane; Under agitation condition, add aqueous hydrochloric acid, aqueous nitric acid or aqueous acetic acid; Stirring reaction does not generate to there being deposition, promptly makes hydrochloride, nitrate salt or the acetate of benzoglyoxaline aminated compounds shown in general formula I I～V; Perhaps; Benzoglyoxaline aminated compounds shown in general formula I I～V is dissolved in any one or more mixing in chloroform, acetone, methyl alcohol and the acetonitrile; Stirring at room; Add excessive aqueous hydrochloric acid, aqueous nitric acid or aqueous acetic acid again, 0～50 ℃ of stirring reaction of temperature control promptly makes hydrochloride, nitrate salt or the acetate of benzoglyoxaline aminated compounds shown in general formula I I～V;
R in the compound shown in the general formula VII-XI
1, R
2, R
3, R
4, R and n definition and general formula I-V shown in R in the benzoglyoxaline aminated compounds
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 the general formula I: said organic solvent is an ethanol; Said alkali reagent is salt of wormwood or yellow soda ash; Said 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: said organic solvent is an acetonitrile; Said alkali reagent is salt of wormwood or yellow soda ash; Benzoglyoxaline aminated compounds shown in the said general formula I: compound shown in general formula VIII, IX, X or the XI: the mol ratio of alkali reagent is 1: 1.0～1.5: 1.2～1.4.
8. each described benzoglyoxaline aminated compounds of claim 1 to 5 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 said bacterium is any one or more in streptococcus aureus, methicillin-resistant staphylococcus aureus, micrococcus luteus, Bacillus subtilus, intestinal bacteria, Pseudomonas aeruginosa and the Bacillus proteus; Said fungi is Candida albicans and/or candidiasis.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201210151996.7A CN102659687B (en) | 2012-03-16 | 2012-05-16 | Benzimidazolamines compounds as well as preparation method and application thereof |
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201210070960.6 | 2012-03-16 | ||
| CN201210070960 | 2012-03-16 | ||
| CN201210151996.7A CN102659687B (en) | 2012-03-16 | 2012-05-16 | Benzimidazolamines compounds as well as preparation method and application thereof |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN102659687A true CN102659687A (en) | 2012-09-12 |
| CN102659687B CN102659687B (en) | 2014-10-08 |
Family
ID=46769298
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201210151996.7A Active CN102659687B (en) | 2012-03-16 | 2012-05-16 | Benzimidazolamines compounds as well as preparation method and application thereof |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN102659687B (en) |
Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN106588955A (en) * | 2015-10-14 | 2017-04-26 | 西南大学 | Imidazobenzothiazole-derived fluconazole analogues and preparation method and application thereof |
| CN109758457A (en) * | 2019-01-30 | 2019-05-17 | 临沂大学 | Sulfanilamide (SN) double-benzimidazoles compound and its officinal salt are preparing the application in antimicrobial agents |
| CN110862374A (en) * | 2019-12-03 | 2020-03-06 | 临沂大学 | Naphthalimide benzimidazole compound and preparation method and application thereof |
| CN111018840A (en) * | 2017-10-25 | 2020-04-17 | 西南大学 | 3-imidazole substituted isatin alcohol compound and preparation method and medical application thereof |
Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0598962A1 (en) * | 1991-05-23 | 1994-06-01 | Neurosearch A/S | Imidazole derivatives as calcium channel blockers |
| EP1517687B1 (en) * | 2002-06-20 | 2007-06-20 | BOEHRINGER INGELHEIM PHARMA GMBH & CO. KG | Medicament for the treatment of the systemic inflammatory response syndrome |
| CN102040592A (en) * | 2009-10-10 | 2011-05-04 | 西南大学 | Coumarin azole compound with antimicrobial activity, and preparation method and medicinal application thereof |
-
2012
- 2012-05-16 CN CN201210151996.7A patent/CN102659687B/en active Active
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0598962A1 (en) * | 1991-05-23 | 1994-06-01 | Neurosearch A/S | Imidazole derivatives as calcium channel blockers |
| EP1517687B1 (en) * | 2002-06-20 | 2007-06-20 | BOEHRINGER INGELHEIM PHARMA GMBH & CO. KG | Medicament for the treatment of the systemic inflammatory response syndrome |
| CN102040592A (en) * | 2009-10-10 | 2011-05-04 | 西南大学 | Coumarin azole compound with antimicrobial activity, and preparation method and medicinal application thereof |
Non-Patent Citations (1)
| Title |
|---|
| 《广州化工》 20111231 杨鹏辉等 2－(4－氯苯胺) 甲基苯并咪唑的合成 55-56页，特别是55页左栏第1-2段，55页1.2.2，56页左栏第3段 1-9 第39卷, 第12期 * |
Cited By (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN106588955A (en) * | 2015-10-14 | 2017-04-26 | 西南大学 | Imidazobenzothiazole-derived fluconazole analogues and preparation method and application thereof |
| CN106588955B (en) * | 2015-10-14 | 2020-08-18 | 西南大学 | Fluconazole analogue derived from imidazobenzothiazole, and preparation method and application thereof |
| CN111018840A (en) * | 2017-10-25 | 2020-04-17 | 西南大学 | 3-imidazole substituted isatin alcohol compound and preparation method and medical application thereof |
| CN111018840B (en) * | 2017-10-25 | 2022-09-09 | 西南大学 | 3-imidazole substituted isatin alcohol compound and preparation method and medical application thereof |
| CN109758457A (en) * | 2019-01-30 | 2019-05-17 | 临沂大学 | Sulfanilamide (SN) double-benzimidazoles compound and its officinal salt are preparing the application in antimicrobial agents |
| CN110862374A (en) * | 2019-12-03 | 2020-03-06 | 临沂大学 | Naphthalimide benzimidazole compound and preparation method and application thereof |
| CN110862374B (en) * | 2019-12-03 | 2022-11-08 | 临沂大学 | Naphthalimide benzimidazole compound and preparation method and application thereof |
Also Published As
| Publication number | Publication date |
|---|---|
| CN102659687B (en) | 2014-10-08 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN102659687B (en) | Benzimidazolamines compounds as well as preparation method and application thereof | |
| CN109942546B (en) | Quinolone pyrimidine compound and preparation method and application thereof | |
| CN109553579A (en) | The preparation method and applications of aloe-emodin azole compounds | |
| CN107698567A (en) | Isatin azoles alcohol compound and preparation method thereof and medical applications | |
| CN110330489A (en) | Quinolone thiazole oxime compound and its preparation method and application | |
| CN109734723A (en) | Ofloxacin thiazole analog and its preparation method and application | |
| CN101323600A (en) | Triadimefon and triadimenol compounds having antimicrobial activity, salts, synthetic methods and uses thereof | |
| CN107709335A (en) | Kakeromycin and its derivative manufacture method | |
| CN102180835A (en) | Synthesis of imidazole aromatic alcohol derivatives and preparations of imidazole aromatic alcohol derivatives | |
| CN105294661B (en) | 5 fluorouracil benzimidazoles compounds and its preparation method and application | |
| CN102060792B (en) | 2 '-amido chalcone azole compounds and pyrazoline thereof and cyclopropyl azole derivative, preparation method and purposes | |
| CN105287522B (en) | Purposes of the bisbenzimidazole aminated compounds in antimicrobial agents are prepared | |
| CN101323594B (en) | Benzyl chloride tertiary amine double azole antimicrobial compounds, preparation and medical use thereof | |
| CN109575007A (en) | Aminothiazole isatin class compound and its preparation method and application | |
| CN101921225B (en) | Pirfenidone compound, preparation method and application thereof | |
| CN101397276B (en) | Dibenzimidazole and onium compound thereof, preparation method and medical use thereof | |
| CN110452224A (en) | Pyrimidine azoles alcohol compound and its preparation method and application | |
| CN105130981A (en) | Berberine benzimidazole compounds, and preparation method and application thereof | |
| CN102060793B (en) | Dual aryl tertiary amine azole compounds with biological activity as well as preparation method and medical application thereof | |
| CN110396090A (en) | Imidazoles alcohols tetrahydro coptis oxime conjugate and its preparation method and application | |
| CN101817792B (en) | Bistriazolone, bistriadimenol compounds with antimicrobial activity, and salts, synthesis method and uses thereof | |
| CN108658971A (en) | Tetrahydroberberine thiophene cyclohexadione compounds and its preparation method and application | |
| CN1349540A (en) | Antifungal ethers | |
| CN103483315A (en) | 7-(3-aminomethyl-4-alkoxyimino-1-piperidyl)-1-[(1R,2S)-2-fluorocyclopropyl] quinolone carboxylic acid compounds and preparation method thereof | |
| JPH0372468A (en) | Triazole compound and antifungal agent containing the same |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| C06 | Publication | ||
| PB01 | Publication | ||
| C10 | Entry into substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| C14 | Grant of patent or utility model | ||
| GR01 | Patent grant |