CN105311020A - Bis-benzimidazole amine compound and preparing method thereof - Google Patents
Bis-benzimidazole amine compound and preparing method thereof Download PDFInfo
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- CN105311020A CN105311020A CN201510835518.1A CN201510835518A CN105311020A CN 105311020 A CN105311020 A CN 105311020A CN 201510835518 A CN201510835518 A CN 201510835518A CN 105311020 A CN105311020 A CN 105311020A
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Abstract
The invention provides a bis-benzimidazole amine compound with the structure shown in the formula (I) and a preparing method thereof. The compound is simple in structure, has high in-vitro anti-microbial activity, shows high inhibitory activity to gram-positive bacteria such as staphylococcus aureus, methicillin-resistant staphylococcus aureus, bacillus subtilis and micrococcus luteus, gram-negative bacteria such as escherichia coli, proteusbacillus vulgaris, pseudomonas aeruginosa and salmonella typhi as well as fungi such as candida utilis bacteria, aspergillus flavus, saccharomyces cerevisiae, candida albicans and candida mycoderma bacteria, and can be used for preparing antibacterial and/or antifungal drugs. In addition, the preparing method of the bis-benzimidazole amine compound has the advantages of being short in synthesis path, simple in process and low in cost and allowing industrial production, and raw materials are easy to obtain.
Description
Technical field
The invention belongs to field of pharmaceutical chemistry technology, particularly relate to a kind of newtype drug micromolecular compound and preparation method thereof.
Background technology
Benzimidazole is as the condensed ring of imidazoles and phenyl ring, there is large conjugated structure and strong cyclic voltammetry method ability, its special structure makes it can form hydrogen bond with the enzyme in organism and receptor etc., with metallic ion coordination and hydrophobic interaction, pi-pi accumulation, electrostatic interaction etc. occur.Therefore, can there is multiple non-covalent interaction in benzimidazoles compound, shows the performance that some is special, demonstrates broad application prospect and huge Development volue in various fields such as medicine, pesticide, chemistry, physics.
In recent years, the drug molecule constructed with benzimidazole ring presents biological activity widely, as antibacterial, antifungal, antiviral, anticancer, anti-inflammatory analgesic, as histamine receptor antagonists, proton pump inhibitor, resisting hypertension, parasiticide etc.At present, existing numerous medicinal application containing benzimidazole structure fragment in clinical, as being used for the treatment of the medicine omeprazole of gastric ulcer and rabeprazole etc.; The astemizole of the allergic inflammations such as treatment of allergic rhinitis and mizolastine etc.; Antihypertensive Candesartan and telmisartan etc.; Antiparasitic albendazole, oxibendazole and mebendazole etc.Because benzimidazoles compound has potential broadness application, attract and encourage countless researcher to be engaged in the research and development of benzimidazoles compound, making the research of the medicine containing benzimidazole structure fragment become current medicine and research and develop one of very active field.Particularly because benzimidazole has and structure like purines, can the effectively synthesis of nucleic acid or protein in anti-bacteria, thus kill or bacteria growing inhibiting, therefore, how to carry out structure optimization to benzimidazoles compound and have to obtaining the novel benzimidazoles derivant being different from the conventional medicament mechanism of action, this is still a still unsolved technical barrier to those skilled in the art.
Summary of the invention
The technical problem to be solved in the present invention is to overcome antibacterial, defect that antifungal activity is lower existing for benzimidazoles compound of the prior art, and then provides a kind of and have novel bisbenzimidazole aminated compounds of higher antibacterial, antifungal activity and preparation method thereof.
The technical scheme that the present invention realizes above-mentioned purpose is:
A kind of bisbenzimidazole aminated compounds such as formula structure (I) Suo Shi and officinal salt thereof:
Wherein, described R
1for C
1~ C
6alkyl or R
3the phenyl replaced, described R
3be selected from hydrogen, 2-fluorine, 3-fluorine, 4-fluorine, 2, 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, 2-methyl, 3-methyl, 4-methyl, 2, 3-dimethyl, 2, 4-dimethyl, 2, 5-dimethyl, 3, 4-dimethyl, 3, 5-dimethyl, 2-methoxyl group, 3-methoxyl group, 4-methoxyl group, 2, 3-dimethoxy, 2, 4-dimethoxy, 2, 5-dimethoxy, 3, 4-dimethoxy, 3, 5-dimethoxy, 4-iodine, 4-nitro, 3-trifluoromethyl or 3, 5-bis-(trifluoromethyl),
Described R
2for-(CH
2)
n-or R
4mono-substituted to dibenzyl, described R
4be selected from hydrogen, fluorine, chlorine, methyl, methoxyl group, trifluoromethyl or nitro, described n is the positive integer of 2 ~ 9.
Preferably, in formula (I), described R
1for C
1~ C
4alkyl or R
3the phenyl replaced, described R
3be selected from hydrogen, 4-fluorine, 2,4-difluoros, 3,5-difluoros, 4-chlorine, 2,4-dichloros, 3,5-dichloros, 4-methyl, 2,4-dimethyl, 3,5-dimethyl, 4-methoxyl group, 2,4-dimethoxys, 3,5-dimethoxys or 3-trifluoromethyl.
Preferably, in formula (I), described R
2for-(CH
2)
2-,-(CH
2)
5-,-(CH
2)
9-or R
4mono-substituted to dibenzyl, described R
4be selected from hydrogen, fluorine, methyl, trifluoromethyl, nitro.
Preferably, described bisbenzimidazole aminated compounds has any one in structure shown in formula (II) ~ (V):
The preparation method of above-mentioned bisbenzimidazole aminated compounds, comprise, in the polar organic solvent of 50 ~ 70 DEG C, under the catalytic action of inorganic base, mol ratio is (2.0 ~ 2.5): secondary amine compound VI and the dibromo compound VII of 1 react, obtained described bisbenzimidazole aminated compounds I;
Reaction equation is as follows:
Preferably, described polar organic solvent is one or more in methanol, ethanol or acetonitrile; Described inorganic base is one or more in potassium carbonate, sodium carbonate, sodium bicarbonate or sodium hydroxide.
Preferably, the mol ratio of described dibromo compound VII and described inorganic base is 1: (2.2 ~ 2.4).
Preferably, in described polar organic solvent, add secondary amine compound VI and inorganic base, react under stirring forming reactions liquid, then in described reactant liquor, add described dibromo compound VII react.
Technique scheme tool of the present invention has the following advantages:
Bisbenzimidazole aminated compounds provided by the invention, its structure is simple, there is stronger in vitro anti-microbial activity, especially to staphylococcus aureus, methicillin-resistant staphylococcus aureus, bacillus subtilis, the gram positive bacterias such as micrococcus luteus, escherichia coli, Bacillus proteus, Pseudomonas aeruginosa, the gram-negative bacterias such as Salmonella typhi, and Candida utilis, Aspergillus flavus, cereuisiae fermentum, Candida albicans, the funguses such as candidiasis all show very high inhibit activities, can be used in preparation antibacterium and/or antifungal drug, thus for clinical antimicrobial treatment provide more how efficient, the drug candidate of safety, contribute to solving the drug resistance be on the rise, the clinical treatment problems such as obstinate invasive organism and emerging harmful microorganism.
In addition, the preparation method of bisbenzimidazole aminated compounds provided by the invention, its raw material is easy to get, synthetic thread is short out, simple process, have with low cost, can the advantage of suitability for industrialized production.
Detailed description of the invention
To be clearly and completely described technical scheme of the present invention below, obviously, described embodiment is the present invention's part embodiment, instead of whole embodiments.Based on the embodiment in the present invention, those of ordinary skill in the art, not making the every other embodiment obtained under creative work prerequisite, belong to the scope of protection of the invention.In addition, if below in the described different embodiment of the present invention involved technical characteristic do not form conflict each other and just can be combined with each other.
Embodiment 1
Bisbenzimidazole amines described in the present embodiment, have the structure shown in formula II, its preparation method comprises the steps:
N-((1H-benzimidazolyl-2 radicals-Ji) methyl)-4-monomethylaniline. VI-1, potassium carbonate 3.312g and the acetonitrile 60mL of 5.701g is added in 100mL round-bottomed flask, temperature control 50 DEG C stirs after 0.5 hour, add 1 of 2.621g again, two (bromomethyl) benzene VII-1 of 4-, be warming up to 70 DEG C to react, thin layer chromatography tracks to reaction to be terminated, and is cooled to room temperature, distilling under reduced pressure removing acetonitrile, residue volume ratio is 5
:the petroleum ether of 1 and the mixed liquor of ethyl acetate carry out purification by silica gel column chromatography as eluant, dry, obtain the bisbenzimidazole amines II-1 of 3.118g white solid, yield 54%; Fusing point 167-168 DEG C;
1hNMR (300MHz, CDCl
3) δ ppm:2.23 (s, 6H, 4,4 '-CH
3ph), 4.59 (s, 4H, benzimidazole-CH
2), 4.99 (s, 4H, Ph-CH
2), 6.62 (d, 4H, J=6.0Hz, 4-CH
3ph-2,2 ', 6,6 '-H), 6.96 (d, 4H, J=6.0Hz, 4-CH
3ph-3,3 ', 5,5 '-H), 7.18-7.22 (m, 4H, benzimidazole-6,6 ', 7,7 '-H), 7.26 (s, 4H, benzene-2,3,5,6-H), 7.49-7.55 (m, 4H, benzimidazole-5,5 ', 8,8 '-H).
Wherein, raw material N-((1H-benzimidazolyl-2 radicals-Ji) methyl)-4-monomethylaniline. VI-1 is reference literature method (ZhangH.Z.; DamuG.L.V.; CaiG.X.; ZhouC.H.Design, synthesisandantimicrobialevaluationofnovelbenzimidazolet ypeoffluconazoleanaloguesandtheirsynergisticeffectswithc hloromycin, norfloxacinandfluconazole.EuropeanJournalofMedicinalChem istry, 2013,64:329-344), there is N-alkylated reaction by 4-monomethylaniline. and chloromethyl benzimidazole to obtain.
Embodiment 2
Bisbenzimidazole amines described in the present embodiment, have the structure shown in formula III, its preparation method comprises the steps:
The secondary amine compound VI-2 of 4.068g, sodium bicarbonate 1.935g and ethanol 50mL is added in 100mL round-bottomed flask, temperature control 60 DEG C stirs after 0.5 hour, add the dibromo compound VII-2 of 3.312g again, reaction is proceeded under stirring, thin layer chromatography tracks to reaction to be terminated, be cooled to room temperature, distilling under reduced pressure removing ethanol, residue volume ratio is that the petroleum ether of 6: 1 and the mixed liquor of ethyl acetate carry out purification by silica gel column chromatography as eluant, dry, obtain 2.591g melicera bisbenzimidazole amines III, yield 47%;
1hNMR (300MHz, CDCl
3) δ ppm:0.88-0.93 (t, 6H, J=7.5Hz, ((CH
2)
3cH
3)
2), 1.22-1.48 (m, 8H, (CH
2c
2h
4cH
3)
2), 2.41-2.47 (t, 4H, J=9.0Hz, (CH
2c
2h
4cH
3)
2), 3.60 (s, 2H, Ph-CH
2), 3.66 (s, 2H, Ph-CH
2), 4.43 (s, 4H, benzimidazole-CH
2), 7.13-7.19 (m, 4H, benzimidazole-6,6 ', 7,7 '-H), 7.27-7.30 (m, 3H, benzene-3,5,6-H), 7.50-7.56 (m, 4H, benzimidazole-5,5 ', 8,8 '-H).
Embodiment 3
Bisbenzimidazole amines described in the present embodiment, have the structure shown in formula V, its preparation method comprises the steps:
The secondary amine compound VI-3 of 6.335g, sodium hydroxide 2.010g and methanol 60mL is added in 100mL round-bottomed flask, temperature control 50 DEG C stirs after 0.5 hour, add the dibromo compound VII-3 of 2.351g again, temperature control 60 DEG C proceeds reaction, thin layer chromatography tracks to reaction to be terminated, be cooled to room temperature, distilling under reduced pressure removing methanol, residue volume ratio is that the petroleum ether of 5: 1 and the mixed liquor of ethyl acetate carry out purification by silica gel column chromatography as eluant, dry, obtain the bisbenzimidazole amines V of 3.213g white solid, yield 49%; Fusing point 167-168 DEG C;
1hNMR (300MHz, CDCl
3) δ ppm:3.67-3.69 (m, 4H, CH
2cH
2), 3.72 (s, 6H, 3,3 '-OCH
3ph), 4.58 (s, 4H, benzimidazole-CH
2), 6.12-6.16 (m, 2H, benzene-4,4 '-H), 6.34-6.36 (m, 2H, benzene-2,2 '-H), 6.57-6.61 (m, 2H, benzene-6,6 '-H), 7.06-7.16 (m, 6H, benzene-5,5 '-H, benzimidazole-6,6 ', 7,7 '-H), 7.46-7.53 (m, 4H, benzimidazole-5,5 ', 8,8 '-H).
Experimental example
Adopt the clinical experiment standard (NationalCommitteeforClinicalLaboratoryStandards meeting United States National Committee's formulations in 1993, NCCLS) 96 hole micro-dilution methods, the bisbenzimidazole amines obtained to embodiment 1-3 carries out in vitro anti-microbial activity test, detect these compounds to staphylococcus aureus, MASR, micrococcus luteus, bacillus subtilis, escherichia coli, Pseudomonas aeruginosa, Bacillus proteus, Candida utilis, Aspergillus flavus, cereuisiae fermentum, the minimum inhibitory concentration (MIC) of Candida albicans and candidiasis.
Concrete method of testing is: dissolved by a small amount of dimethyl sulfoxine of testing compound, thin up makes the solution that concentration is 1.28mg/mL again, 1024 μ g/mL are diluted to again with culture fluid, cultivate 24-72 hour for 35 DEG C, culture plate is placed in after agitator fully stirs evenly, measure MIC value at wavelength 490nm place, the results are shown in Table 1 and table 2.
The antibacterial activity (MIC, μ g/mL) of table 1 bisbenzimidazole amines II, III, V
| Compound | Staphylococcus aureus | MASR | Micrococcus luteus | Bacillus subtilis | Escherichia coli | Pseudomonas aeruginosa | Bacillus proteus |
| II | 16 | 32 | 16 | 16 | 8 | 16 | 16 |
| III | 16 | 32 | 32 | 8 | 16 | 16 | 8 |
| V | 32 | 32 | 16 | 32 | 8 | 8 | 16 |
| Chloromycetin | 16 | 32 | 8 | 32 | 32 | 32 | 32 |
| Norfloxacin | 1 | 8 | 2 | 4 | 2 | 2 | 4 |
The antifungal activity (MIC, μ g/mL) of table 2 bisbenzimidazole amines II, III, V
| Compound | Candida utilis | Aspergillus flavus | Beer yeast | Candida albicans | Candidiasis |
| II | 16 | 64 | 8 | 16 | 8 |
| III | 8 | 32 | 16 | 8 | 16 |
| V | 16 | 32 | 8 | 16 | 8 |
| Fluconazol | 8 | 256 | 16 | 4 | 8 |
As can be seen from Table 1, bisbenzimidazole amines shows the fungistatic effect suitable with reference medicine chloromycetin to gram positive bacterias such as Staphylococcus aureus, MASR, bacillus subtilis, and surveyed gram-negative bacteria is all showed to the inhibitory action being better than chloromycetin, and to the rejection ability of micrococcus luteus a little less than chloromycetin, but with compared with medicine norfloxacin, the inhibit activities of bisbenzimidazole amines to surveyed antibacterial needs to improve.It is basic and suitable with reference to medicine fluconazol to the inhibitory action of fungus to be measured that table 2 shows bisbenzimidazole amines, illustrate that bisbenzimidazole amines of the present invention has very strong antimicrobial acivity thus, can be used in preparation antibacterium and/or antifungal drug.
Obviously, above-described embodiment is only for clearly example being described, and the restriction not to embodiment.For those of ordinary skill in the field, can also make other changes in different forms on the basis of the above description.Here exhaustive without the need to also giving all embodiments.And thus the apparent change of extending out or variation be still among the protection domain of the invention.
Claims (8)
1. the bisbenzimidazole aminated compounds such as formula structure (I) Suo Shi and officinal salt thereof:
Wherein, described R
1for C
1~ C
6alkyl or R
3the phenyl replaced, described R
3be selected from hydrogen, 2-fluorine, 3-fluorine, 4-fluorine, 2, 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, 2-methyl, 3-methyl, 4-methyl, 2, 3-dimethyl, 2, 4-dimethyl, 2, 5-dimethyl, 3, 4-dimethyl, 3, 5-dimethyl, 2-methoxyl group, 3-methoxyl group, 4-methoxyl group, 2, 3-dimethoxy, 2, 4-dimethoxy, 2, 5-dimethoxy, 3, 4-dimethoxy, 3, 5-dimethoxy, 4-iodine, 4-nitro, 3-trifluoromethyl or 3, 5-bis-(trifluoromethyl),
Described R
2for-(CH
2)
n-or R
4mono-substituted to dibenzyl, described R
4be selected from hydrogen, fluorine, chlorine, methyl, methoxyl group, trifluoromethyl or nitro, described n is the positive integer of 2 ~ 9.
2. bisbenzimidazole aminated compounds according to claim 1, is characterized in that, in formula (I), and described R
1for C
1~ C
4alkyl or R
3the phenyl replaced, described R
3be selected from hydrogen, 4-fluorine, 2,4-difluoros, 3,5-difluoros, 4-chlorine, 2,4-dichloros, 3,5-dichloros, 4-methyl, 2,4-dimethyl, 3,5-dimethyl, 4-methoxyl group, 2,4-dimethoxys, 3,5-dimethoxys or 3-trifluoromethyl.
3. bisbenzimidazole aminated compounds according to claim 1 and 2, is characterized in that, in formula (I), and described R
2for-(CH
2)
2-,-(CH
2)
5-,-(CH
2)
9-or R
4mono-substituted to dibenzyl, described R
4be selected from hydrogen, fluorine, methyl, trifluoromethyl, nitro.
4. the bisbenzimidazole aminated compounds according to any one of claim 1-3, is characterized in that, described bisbenzimidazole aminated compounds have in structure shown in formula (II) ~ (V) any one:
5. the preparation method of the bisbenzimidazole aminated compounds according to any one of claim 1-4, comprise, in the polar organic solvent of 50 ~ 70 DEG C, under the catalytic action of inorganic base, mol ratio is (2.0 ~ 2.5): secondary amine compound VI and the dibromo compound VII of 1 react, obtained described bisbenzimidazole aminated compounds I;
Reaction equation is as follows:
6. the preparation method of bisbenzimidazole aminated compounds according to claim 5, is characterized in that, described polar organic solvent is one or more in methanol, ethanol or acetonitrile; Described inorganic base is one or more in potassium carbonate, sodium carbonate, sodium bicarbonate or sodium hydroxide.
7. the preparation method of the bisbenzimidazole aminated compounds according to claim 5 or 6, is characterized in that, the mol ratio of described dibromo compound VII and described inorganic base is 1: (2.2 ~ 2.4).
8. the preparation method of the bisbenzimidazole aminated compounds according to any one of claim 5-7, it is characterized in that, secondary amine compound VI and inorganic base is added in described polar organic solvent, react under stirring forming reactions liquid, then in described reactant liquor, add described dibromo compound VII react.
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|---|---|---|---|---|
| CN107141310A (en) * | 2016-08-08 | 2017-09-08 | 重庆文理学院 | A kind of preparation method and applications of novel antibacterial Zn complex |
| CN109761907A (en) * | 2019-01-30 | 2019-05-17 | 临沂大学 | Sulfanilamide (SN) double-benzimidazoles compound and its officinal salt and preparation method |
Citations (2)
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|---|---|---|---|---|
| US20070112048A1 (en) * | 2005-08-12 | 2007-05-17 | Sina Bavari | Broad Spectrum Antibacterial Compounds |
| CN101333225A (en) * | 2008-07-03 | 2008-12-31 | 天津师范大学 | Method for preparing biimidazole, bisbenzimidaze salts and metal complexes thereof and applications |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20070112048A1 (en) * | 2005-08-12 | 2007-05-17 | Sina Bavari | Broad Spectrum Antibacterial Compounds |
| CN101333225A (en) * | 2008-07-03 | 2008-12-31 | 天津师范大学 | Method for preparing biimidazole, bisbenzimidaze salts and metal complexes thereof and applications |
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN107141310A (en) * | 2016-08-08 | 2017-09-08 | 重庆文理学院 | A kind of preparation method and applications of novel antibacterial Zn complex |
| CN109761907A (en) * | 2019-01-30 | 2019-05-17 | 临沂大学 | Sulfanilamide (SN) double-benzimidazoles compound and its officinal salt and preparation method |
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