CN106866539A - The alkyl imidazole derivative of 1 substituted-phenyl 2 and its application - Google Patents
The alkyl imidazole derivative of 1 substituted-phenyl 2 and its application Download PDFInfo
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- CN106866539A CN106866539A CN201710126508.XA CN201710126508A CN106866539A CN 106866539 A CN106866539 A CN 106866539A CN 201710126508 A CN201710126508 A CN 201710126508A CN 106866539 A CN106866539 A CN 106866539A
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- C07D233/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
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Abstract
The present invention relates to the alkyl imidazole derivative of 1 substituted-phenyl 2 and its available salt that are represented by general formula (I)：Wherein：R represents straight or branched C1‑C12Alkyl, phenyl or halogenophenyl；R1Represent straight or branched C1‑C12Alkyl, halo benzyl or alkyl substituted benzene methyl.Present invention also offers the application of the pharmaceutical composition containing the derivative and its salt and the derivative and its salt in antibacterials are prepared.The derivative and its available salt are to staphylococcus aureus and Escherichia coli, and inhibitory action is respectively provided with to other Gram-negative bacterias (such as Pseudomonas aeruginosa, Friedlander's bacillus, proteus, salmonella, Pasteurella) and various gram positive bacterias, can be used to prepare antibacterials.
Description
Technical field
The invention belongs to noval chemical compound field, it is related to a kind of 1- substituted-phenyls -2- alkyl imidazoles derivative and its application.
Background technology
Courses of infection still threatens life and health, and natural or synthetic antibiotic constantly go out, new can be treatment
Courses of infection disease provides more choices.During courses of infection is treated, bacterium constantly by self structure or
The change of enzymatic structure, becomes more resistant to medicine.This causes the reduction of some antibiotic curative effects, or even loses activity, and more seriously, causes
Some non-pathogenic bacterias turn into conditioned pathogen, or the superbacteria to the universal resistance of existing antibiotic occur.Controlled to improve
Therapeutic effect is, it is necessary to new architectural feature and the newtype drug of the mechanism of new effect occurs.
Current antibacterials are classified mainly from structure beta-lactam, glycopeptide class, aminoglycoside, tetracycline
Class, quinolones, polypeptide, many alkenes, sulfamido, ketolide, oxazolone class, chloramphenicol, macrolides etc., with nitrogenous
Based on heterocycle compound.In nitrogen-containing heterocycle compound in addition to above-mentioned a few class medicines, imidazole alkaloid class material exhibits are good
Antibacterial or bactericidal activity, just there is many imidazole alkaloid class materials in disinfectant use in agriculture, show excellent bioactivity.Right
In the alkaloidal drug exploitation of pathogenic microorganism, the imidazo triazole derivative of the synthesis such as Ramprasad J, Harer SL etc.
Imidazo piperidine compounds of synthesis etc., bacterium and fungi to many cause people infection show good bacteriostatic activity.From with
Upper example understands, can suppress from imidazole alkaloid exploitation or kill malignant bacteria and the antibacterials of fungi are feasible comparings.
The content of the invention
It is an object of the invention to provide a kind of 1- substituted-phenyls -2- alkyl imidazole derivatives, answering for current antibiotic is solved
With being restricted, it is easily caused bacterium and produces drug resistance, causes the problem of the antibacterials for needing synthesis new.
The second object of the present invention is to provide the pharmaceutical composition containing 1- substituted-phenyl -2- alkyl imidazole derivatives.
The third object of the present invention is to provide 1- substituted-phenyls -2- alkyl imidazoles derivative answering in antibacterials are prepared
With.
The present invention is achieved through the following technical solutions：The invention provides the 1- substituted benzenes represented by general formula (I)
Base -2- alkyl imidazoles derivative and its available salt：
Wherein：R represents straight or branched C1-C12Alkyl, phenyl or halogenophenyl；
R1Represent straight or branched C1-C12Alkyl, halo benzyl or alkyl substituted benzene methyl.
Wherein, C1-C12Alkyl includes methyl, ethyl, propyl group, isopropyl, butyl, isobutyl group, penta of straight chain or side chain
Base, hexyl, heptyl, octyl group, nonyl, decyl, undecyl, dodecyl etc.；Halogenophenyl refer to the ortho position of phenyl ring,
There is the phenyl of the halogens such as single or multiple fluorine, chlorine, bromine, iodine substitution on position, contraposition；Halo benzyl refers to the neighbour in phenyl ring
Position, meta, the benzyl that there is the substitution of the halogens such as single or multiple fluorine, chlorine, bromine, iodine in contraposition；Alkyl substituted benzene methyl refers to
It is there is C in the ortho position of phenyl ring, meta, contraposition1-C12Alkyl-substituted benzyl.
The salt of 1- substituted-phenyls -2- alkyl imidazole derivatives of the invention refers to pharmaceutically acceptable salt, such as with salt
Acid, hydrobromic acid, sulfuric acid, phosphoric acid, acetic acid, trifluoroacetic acid, lactic acid, pyruvic acid, malonic acid, butanedioic acid, glutaric acid, fumaric acid, wine
Stone acid, maleic acid, citric acid, ascorbic acid, methanesulfonic acid, camphoric acid, oxalic acid.React the salt of generation.
Compound of the invention includes：
2- ethyls -1- [4- (4- fluorobenzyloxies)] phenyl -1H- imidazoles (1)
2- ethyls -1- [4- (4- Chlorobenzyloxies)] phenyl -1H- imidazoles (2)
2- ethyls -1- [4- (4- bromobenzenes methoxyl group)] phenyl -1H- imidazoles (3)
2- ethyls -1- [4- (4- methyl benzyloxy)] phenyl -1H- imidazoles (4)
2- ethyls -1- (4- butoxy) phenyl -1H- imidazoles (5)
2- ethyls -1- (4- amoxys) phenyl -1H- imidazoles (6)
2- ethyls -1- (4- hexyloxies) phenyl -1H- imidazoles (7)
2- ethyls -1- (4- epoxides in heptan) phenyl -1H- imidazoles (8)
2- ethyls -1- (4- octyloxies) phenyl -1H- imidazoles (9)
2- propyl group -1- [4- (4- fluorobenzyloxies)] phenyl -1H- imidazoles (10)
2- propyl group -1- [4- (4- Chlorobenzyloxies)] phenyl -1H- imidazoles (11)
2- propyl group -1- (4- butoxy) phenyl -1H- imidazoles (12)
2- propyl group -1- (4- amoxys) phenyl -1H- imidazoles (13)
2- propyl group -1- (4- hexyloxies) phenyl -1H- imidazoles (14)
2- phenyl -1- (4- butoxy) phenyl -1H- imidazoles (15)
2- phenyl -1- (4- amoxys) phenyl -1H- imidazoles (16)
2- phenyl -1- (4- hexyloxies) phenyl -1H- imidazoles (17)
2- phenyl -1- (4- epoxides in heptan) phenyl -1H- imidazoles (18)
2- (4- trifluoromethyls) phenyl -1- (4- butoxy) phenyl -1H- imidazoles (19).
Compound of the invention through the following steps that prepare：
1st, formula II is initial substance：
2nd, in DMF solution with carboxylic acid reaction, obtain compound III：
3rd, compound III in acetonitrile with phosphorus pentasulfide react, obtain compound IV：
4th, then in ethanol, compound IV and equimolar aminoacetaldehyde dimethanol, back flow reaction 5h；After reaction terminates
Solvent is evaporated off, formula column chromatography obtains compound V：
5th, in H2Under (60psi) environment, compound V is through palladium carbon (20%H2O) be catalyzed, 60 DEG C reaction 4h, filter catalyst,
Solvent evaporated obtains compound VI：
6th, compound VI respectively with halogenated straight or side chain C1-C12Alkane, iodobenzene and substitution iodobenzene, benzyl chloride and substituted benzyl
Chlorine obtains the compound represented by formula I：
Reaction scheme is as follows：
Route 1：(a)RCOOH,DCC/DMF,60℃；(b)P2S5/CH3CN,N(C2H5)3,refluxing；(c)NH2CH2CH
(OCH3)2/ethanol,refluxing；(d)H2,Pd/C,ethanol,60℃；(e)R1X,NaOH/DMF,100℃.
1- substituted-phenyls -2- alkyl imidazoles derivative of the invention and its available salt are medicinal as active ingredient, and routine
Carrier can be made into conventional formulation, be prepared into the tablet or sugar for being adapted to oral, non-bowel (vein is subcutaneous) and nasal administration
Garment piece agent, sublingual tablets, capsule, gelatine capsule, suppository, creme, ointment, skin gel, injectable formulation or can
Use the formulations such as suspending agent.The dosage of compound of the invention, for adult, daily 500-1000mg is proper.
1- substituted-phenyls -2- alkyl imidazoles derivative of the invention and its available salt can be used to prepare antibacterials, treatment
Bacterium infection.
Using the good effect of above-mentioned technical proposal：1- substituted-phenyls -2- alkyl imidazoles derivative of the invention and its can
With salt to staphylococcus aureus and Escherichia coli, and to other Gram-negative bacterias (such as Pseudomonas aeruginosa, e coil k 1 pneumonia
Bacterium, proteus, salmonella, Pasteurella etc.) and various gram positive bacterias be respectively provided with inhibitory action, resist in some respects
Bacterium effect is better than Ciprofloxacin and Amoxicillin, therefore, the compound can be used to prepare antibacterials, be the research and development of antibacterials
There is provided new thinking.
Specific embodiment
Strain source explanation used in the present invention：
Staphylococcus aureus (S.Aureus ATCC 29213), Escherichia coli (E.Coli ATCC 8739), green pus bar
Bacterium (P.Aeruginosa ATCC 27853), Friedlander's bacillus (K.Peneumoniae ATCC 10031), proteus
(Proteusbacillus vulgaris, ATCC 35659), salmonella (Salmonella ATCC14028), Pasteurella
(Pasteurella ATCC 6529), three kinds of gram positive bacteria (M.Mutans ATCC 25175, Micrococcus luteus
ATCC 21102, Pneumococcus ATCC 15519) and to penicillin resistant sodium Escherichia coli (Penicillin-
Resistance E.coli, PREC) it is purchased from Shanghai Kun Ken biochemical industries Co., Ltd.
Technical scheme is described further below by embodiment, test example and example of formulations, but not
It is interpreted as limitation of the present invention, wherein, embodiment is used to illustrate the preparation of compound and the preparation of antibacterials, tests
For illustrating the pharmacological action of compound of the invention and the superiority relative to other antibacterials, example of formulations is used for example
Illustrate the pharmaceutical preparation comprising compound provided by the present invention.
[embodiment 1] prepares N- (4- benzyloxies) propionamide
In round-bottomed flask, the DMF (DMF, 100mL) to benzyloxy-aniline (19.9g, 100mmol) is molten
Liquid, adds dicyclohexylcarbodiimide (DCC, 20.6g, 100mmol) and propionic acid (7.4g, 100mmol).Reaction solution is heated to 60
DEG C, reaction end is determined by thin-layered chromatography (TLC).After reaction terminates, reaction solution is poured into frozen water, filtered, dried, obtain white
Color powder 22.4g, yield 88.2%.
[embodiment 2] prepares N- (4- benzyloxies) thiopropionamide
Acetonitrile (120mL) and triethylamine (40mL) are added in round-bottomed flask.Under ice-water bath, five vulcanizations two are added in batches
Phosphorus (11.1g, 50mmol) is simultaneously stirred continuously, and after after phosphorus pentasulfide all dissolving, adds compound N-(4- benzyloxies) propionyl
Amine (12.8g, 50mmol).It is stirred at reflux reaction 12h.Remove solvent under reduced pressure, residue obtains yellow powder 9.1g through ethyl alcohol recrystallization,
Yield 67.3%.
[embodiment 3] prepares 2- ethyls -1- (4- benzyloxies) phenyl -1H- imidazoles
By N- (4- benzyloxies) thiopropionamide (5.4g, 20mmol), aminoacetaldehyde dimethyl acetal (2.1g, 20mmol)
In triethylamine (5mL) addition round-bottomed flask, ethanol (100mL) is added, reaction solution is heated to reflux 24h.Verified through TLC chromatograms
Reaction is complete.Solvent is evaporated off, to acetic acid (75mL) is added in residue, 4h is reacted in 100 DEG C, it is complete through TLC confirmatory reactions.It is evaporated off
Solvent, sterling 2.5g, yield 45.0% are obtained with column chromatography for separation.1H-NMR(300MHz,CDCl3)δ:1.22-1.27(t,3H,J
=6Hz, 9Hz ,-CH3), 1.97 (s, H ,-CH-), 2.59-2.66 (q, 2H, J=6Hz, 6Hz ,-CH2-),5.11(s,2H,-
CH2O-),6.93-7.47(m,9H,Ar-H)；13C-NMR(300MHz,CDCl3)δ:12.35,20.48,70.38,76.58,
77.01,77.43,115.44,120.92,127.14,127.39,127.46,128.20,128.69,136.43,149.87,
158.56.MS-EI m/z 279(M+1).
[embodiment 4] prepares 2- ethyls -1- (4- hydroxyls) phenyl -1H- imidazoles
Replace -3- (4- benzyloxies) phenylimidazole (5mmol) to be put into reaction bulb 2-, add palladium carbon (0.5g, 20%),
Add absolute ethyl alcohol (30mL).In H2(60 DEG C, 45psi) reaction 24h under environment.It is complete through TLC confirmatory reactions.Filter palladium
Carbon, is evaporated off solvent afforded crude material, is directly used in next step reaction.1H-NMR(300MHz,CDCl3)δ:1.22-1.27 (t, 3H, J=
6Hz,9Hz,-CH3), 2.67-2.74 (q, 2H, J=6Hz, 9Hz ,-CH2-),6.99-7.26(m,5H,Ar-H).13C-NMR
(300MHz,CDCl3)δ:12.35,20.48,127.14,127.39,127.46,128.20,136.43,149.87,
158.56.MS-EI m/z 189(M+1).
[embodiment 5] prepares 2- ethyls -1- [4- (4- fluorobenzyloxies)] phenyl -1H- imidazoles (1)
2- ethyls -1- (4- hydroxy phenyls) -1H- imidazoles (0.38g, 2mmol) and NaOH (0.08g, 2mmol) are put into burning
In bottle, DMF (20mL) is added.In solution upward, add to fluorobenzyl chloride (0.32g, 2.2mmol), reaction solution is heated to reflux
Reaction 4h, TLC show that reaction terminates.Solvent is evaporated off, residue is recrystallized with ethanol (85%), obtains 0.47g, yield 79%.1H-
NMR(CDCl3,300MHz)δ:1.23-1.28 (t, 3H, J=6Hz, 9Hz ,-CH3), 2.61-2.68 (q, 2H, J=6Hz, 6Hz ,-
CH2-),5.07(s,2H,-CH2O-),6.95-7.45(m,10H,Ar-H).MS-EI m/z 279(M+1).
[embodiment 6] prepares 2- ethyls -1- [4- (4- Chlorobenzyloxies)] phenyl -1H- imidazoles (2)
Mode described in similar preparation example 5, by 2- ethyls -1- (4- hydroxy phenyls) -1H- imidazoles (0.38g, 2mmol) with
NaOH (0.08g, 2mmol) is put into flask, adds DMF (20mL).In solution upward, addition p-chlorobenzylchloride (0.35g,
2.2mmol), reaction solution heating reflux reaction 4h, TLC show that reaction terminates.Solvent is evaporated off, residue ethanol (85%) is tied again
Crystalline substance, obtains 0.51g, yield 81%.1H-NMR(300MHz,CDCl3)δ:1.22-1.27 (t, 3H, J=6Hz, 9Hz ,-CH3),
2.59-2.67 (q, 2H, J=9Hz, 9Hz ,-CH2-),5.08(s,2H,-CH2O-),6.94-7.39(m,8H,Ar-H).MS-EI
m/z 313(M+1),315(M+3).
[embodiment 7] prepares 2- ethyls -1- [4- (4- bromobenzenes methoxyl group)] phenyl -1H- imidazoles (3)
Mode described in similar preparation example 5, by 2- ethyls -1- (4- hydroxy phenyls) -1H- imidazoles (0.38g, 2mmol) with
NaOH (0.08g, 2mmol) is put into flask, adds DMF (20mL).In solution upward, add to bromine benzyl chloride (0.35g,
2.2mmol), reaction solution heating reflux reaction 4h, TLC show that reaction terminates.Solvent is evaporated off, residue ethanol (85%) is tied again
Crystalline substance, obtains 0.51g, yield 76%.1H-NMR(300MHz,CDCl3)δ:1.23-1.28 (t, 3H, J=6.0Hz, 9.0Hz ,-CH3),
2.61-2.68 (q, 2H, J=6.0Hz, 9.0Hz ,-CH2-),5.08(s,2H,-CH2O-),6.95-7.57(m,10H,Ar-H)
；13C-NMR(300MHz,CDCl3)δ:12.34,20.46,69.60,115.44,120.91,122.14,127.19,127.31,
129.03,131.16,131.84,135.44,149.82,158.28.MS-EI m/z 357(M+1),359(M+3).
[embodiment 8] prepares 2- ethyls -1- [4- (4- methyl benzyloxy)] phenyl -1H- imidazoles (4)
Mode described in similar preparation example 5, by 2- ethyls -1- (4- hydroxy phenyls) -1H- imidazoles (0.38g, 2mmol) with
NaOH (0.08g, 2mmol) is put into flask, adds DMF (20mL).In solution upward, add to methyl benzyl chloride
(0.31g, 2.2mmol), reaction solution heating reflux reaction 4h, TLC show that reaction terminates.Solvent, residue ethanol is evaporated off
(85%) recrystallize, obtain 0.48g, yield 82%.1H-NMR(300MHz,CDCl3)δ:1.22-1.27 (t, 3H, J=6Hz,
9Hz,-CH3), 2.38 (s, 3H ,-CH-), 2.59-2.67 (q, 2H, J=9Hz, 9Hz ,-CH2-),5.07(s,2H,-CH2O-),
6.94-7.35(m,10H,Ar-H)；13C-NMR(300MHz,CDCl3)δ:12.36,20.43,21.21,70.32,76.59,
77.01,77.44,115.44,120.95,127.11,127.16,127.60,129.37,130.80,133.35,138.06,
149.86,158.67.MS-EI m/z 293(M+1).
[embodiment 9] prepares 2- ethyls -1- [4- (4- butoxy)] phenyl -1H- imidazoles (5)
Mode described in similar preparation example 5, by 2- ethyls -1- (4- hydroxy phenyls) -1H- imidazoles (0.38g, 2mmol) with
NaOH (0.08g, 2mmol) is put into flask, adds DMF (20mL).In solution upward, addition NBB (0.30g,
2.2mmol), 60 DEG C of reactions 4h, TLC show that reaction terminates.Solvent is evaporated off, residue is recrystallized with ethanol (85%), obtains 0.37g,
Yield 75%.1H-NMR(300MHz,CDCl3)δ:0.97-1.02 (t, 3H, J=6Hz, 9Hz ,-CH3),1.21-1.26(t,3H,
J=6Hz, 9Hz ,-CH3), 1.51-1.56 (t, 2H, J=6Hz, 9Hz ,-CH2-), 1.78-1.83 (q, 2H, J=6Hz, 6Hz ,-
CH2-), 2.60-2.67 (q, 2H, J=6Hz, 6Hz ,-CH2-), 3.98-4.03 (t, 2H, J=6Hz, 9Hz ,-CH2O-),6.94-
7.26(m,4H,Ar-H)；13C-NMR(600MHz,CDCl3)δ:12.35,13.79,19.21,20.41,31.22,68.09,
76.57,76.99,77.41,115.03,120.97,127.06,127.15,130.44,149.88,159.04.MS-EI m/z
245(M+1).
[embodiment 10] prepares 2- ethyls -1- [4- (4- amoxys)] phenyl -1H- imidazoles (6)
Mode described in similar preparation example 5, by 2- ethyls -1- (4- hydroxy phenyls) -1H- imidazoles (0.38g, 2mmol) with
NaOH (0.08g, 2mmol) is put into flask, adds DMF (20mL).In solution upward, addition bromo pentane silane (0.33g,
2.2mmol), 60 DEG C of reactions 4h, TLC show that reaction terminates.Solvent, residue column chromatography (ethyl acetate is evaporated off：Petroleum ether, 1:
1) purify, obtain slightly yellow grease 0.42g, yield 81%.1H-NMR(300MHz,CDCl3)δ:0.93-0.97 (t, 3H, J=
6Hz,6Hz,-CH3), 1.21-1.26 (t, 3H, J=6Hz, 9Hz ,-CH3),1.43-1.45(m,4H,-CH2-),1.80-1.85
(t, 3H, J=6Hz, 9Hz ,-CH3), 2.59-2.67 (q, 2H, J=9Hz, 9Hz ,-CH2-), 3.97-4.02 (t, 2H, J=6Hz,
9Hz,-CH2O-),6.93-7.26(m,4H,-CH2-)；13CNMR(300MHz,CDCl3)δ:12.35,13.98,20.42,
22.42,28.17,28.88,68.40,76.57,76.99,77.19,77.41,99.98,115.03,120.96,127.07,
127.14,130.48,149.88,159.03.MS-EI m/z 259(M+1).
[embodiment 11] prepares 2- ethyls -1- [4- (4- hexyloxies)] phenyl -1H- imidazoles (7)
Mode described in similar preparation example 5, by 2- ethyls -1- (4- hydroxy phenyls) -1H- imidazoles (0.38g, 2mmol) with
NaOH (0.08g, 2mmol) is put into flask, adds DMF (20mL).In solution upward, addition bromohexane (0.36g,
2.2mmol), 60 DEG C of reactions 4h, TLC show that reaction terminates.Solvent, residue column chromatography (ethyl acetate is evaporated off：Petroleum ether, 1:
1) purify, obtain slightly yellow grease 0.43g, yield 79%.1H-NMR(300MHz,CDCl3)δ:0.90-0.94 (t, 3H, J=
6Hz,6Hz,-CH3), 1.21-1.26 (t, 3H ,=6Hz, 9Hz ,-CH3),1.34-1.38(m,6H,-(CH2)3-),1.79-
1.84 (t, 2H, J=6Hz, 9Hz ,-CH2-), 2.59-2.67 (q, 2H, J=9Hz, 9Hz ,-CH2-),3.97-4.02(t,2H,J
=6Hz, 9Hz ,-CH2O-),6.93-7.26(m,4H,Ar-H)；13C-NMR(300MHz,CDCl3)δ:12.35,13.99,
20.42,22.57,25.68,29.15,31.54,68.42,115.03,120.95,127.06,127.15,130.47,
149.88,159.02.MS-EI m/z 273(M+1).
By the way of described in similar preparation example 5,2- ethyls -1- (4- hydroxy phenyls) -1H- imidazoles respectively with bromohexane or
Bromooctane reacts, and prepares 2- ethyls -1- (4- epoxides in heptan) phenyl -1H- imidazoles (8) and 2- ethyls -1- (4- octyloxies) benzene
Base -1H- imidazoles (9).
It is (real through thio reaction respectively after benzyloxy-aniline and butyric acid reaction (embodiment 1) using the method for embodiment 1-5
Apply example 2) and aminoacetaldehyde dimethyl acetal ring-closure reaction (embodiment 3) and debenzylation protection (embodiment 4) key intermediate
2- propyl group -1- (4- hydroxy phenyls) -1H- imidazoles, then through alkylation reaction (embodiment 5), respectively with to fluorobenzyl chloride, p-chlorobenzylchloride,
The reaction of NBB, bromo pentane silane or bromohexane obtains 2- propyl group -1- [4- (4- fluorobenzyloxies)] phenyl -1H- imidazoles (10), 2- third
Base -1- [4- (4- Chlorobenzyloxies)] phenyl -1H- imidazoles (11), 2- propyl group -1- (4- butoxy) phenyl -1H- imidazoles (12),
2- propyl group -1- (4- amoxys) phenyl -1H- imidazoles (13) or 2- propyl group -1- (4- hexyloxies) phenyl -1H- imidazoles (14).
Using the method for embodiment 1-5, after benzyloxy-aniline and benzoic acid (embodiment 1), respectively through thio reaction
(embodiment 2) and aminoacetaldehyde dimethyl acetal ring-closure reaction (embodiment 3) and debenzylation protection (embodiment 4) it is crucial in
Mesosome 2- phenyl -1- (4- hydroxy phenyls) -1H- imidazoles, then through alkylation reaction (embodiment 5), respectively with NBB, bromo pentane silane,
Bromohexane or the pungent reaction of bromine obtain 2- phenyl -1- (4- butoxy) phenyl -1H- imidazoles (15), 2- phenyl -1- (4- amoxys) benzene
Base -1H- imidazoles (16), 2- phenyl -1- (4- hexyloxies) phenyl -1H- imidazoles (17) or 2- phenyl -1- (4- epoxides in heptan) phenyl -
1H- imidazoles (18).
After being reacted using the method for embodiment 1-5, benzyloxy-aniline and to trifluoromethylbenzoic acid (embodiment 1), respectively
Through thio reaction (embodiment 2) and aminoacetaldehyde dimethyl acetal ring-closure reaction (embodiment 3) and debenzylation protection (embodiment
4) key intermediate 2- (4- trifluoromethyls) phenyl -1- (4- hydroxy phenyls) -1H- imidazoles is obtained, then through alkylation reaction (embodiment
5), 2- (4- trifluoromethyls) phenyl -1- (4- butoxy) phenyl -1H- imidazoles (19) is obtained with NBB reaction.
[test example 1] antibacterial pharmacological evaluation
Compound representated by formula I, positive control Amoxicillin and Ciprofloxacin are surveyed using sesquialter dilution method respectively
It is determined to staphylococcus aureus (S.aureus) and Escherichia coli (E.coli) minimal inhibitory concentration (MIC).Culture medium is selected
MH culture mediums, solid plate selects MH solid mediums (Shanghai epoch Bioisystech Co., Ltd).
By the compound representated by the formula I of various concentrations after doubling dilution, positive control Amoxicillin and Ciprofloxacin
(DMSO solution), is added separately in 96 hole polystyrene plates of sterilizing, and the 1st to the 11st hole adds liquid, and per the μ L of hole 10, the 1st hole is extremely
11st hole drug concentration is respectively 2560,1280,640,320,160,80,40,20,10,5,2.5nmol/mL, the 12nd hole is not added with
Medicine is used as growth control.Sealed after freezing dried, less than -20 DEG C save backup.
The bacterial population that will be prepared with growth method is 1 × 106-1×107Bacterium solution, upward added 96 holes of test sample
In, per Kong Zhongjia 90 μ l, the 1st hole to the 11st hole drug concentration is respectively 256,128,64,32,16,8,4,2,1,0.5,
0.25nmol/mL.Seal and be incubated 16-20h in rearmounted 35 DEG C of normal air incubators.When experiment hemophilus, during streptococcus,
Incubation time is 20-24h, incubation time 24h when experiment staphylococcus and enterococcus are tested.
The μ L of bacterium solution 50 in 96 hole polystyrene plate holes are taken, solid plate is spread evenly across, 35 DEG C of normal air incubators are put
In, it is incubated 16-20h judged results.Clump count on solid plate<5, be considered as medicine has bacteriostatic activity to the bacterial strain[3]。
The bacteriostatic test result such as table 1 of compound (1-19), Amoxicillin and Ciprofloxacin to S.aureus and E.coli
It is shown.
MIC (nmol/mL) of the compound of the table 1. (1-19) to S.aureus and E.coli
In listed compound 1-19, part of compounds is better than comparison medicine to the inhibitory activity of S.aureus and E.coli
Amoxicillin and Ciprofloxacin, wherein, the bacteriostatic activity of compound 6 is better than other compounds.
The antibacterial pharmacological evaluation of [test example 2] compound 6
Compound 6 pair five kinds of Gram-negative bacterias (Pseudomonas aeruginosa p.aeruginosa, Friedlander's bacillus
K.peneumoniae, proteus proteusbacillus vulgaris, salmonella Salmonella, Pasteurella
) and three kinds of gram positive bacterias (M.mutans, Micrococcus luteus, Pneumococcus) and to resistance to Pasteurella
The inhibitory activity experiment of Benzylpenicillin sodium salt Escherichia coli (Penicillin-resistance E.coli, PREC) uses test example 1
Method.
2. compound of table, 6 pairs of eight kinds of MIC of different strains (nmol/mL)
As seen from Table 2, compound 6 shows certain inhibitory activity to P.aeruginosa, with Ciprofloxacin quite, by force
In Amoxicillin.To the bacteriostatic activity of Pasteurella not as good as Amoxicillin and Ciprofloxacin.Suppression to K.peneumoniae
System activity is suitable with Amoxicillin.MIC to Proteus vulgaris is 64nmol/mL, hence it is evident that is better than Amoxicillin, is ring
4 times of third husky star.MIC to Salmonella is 128nmol/mL, is better than comparison medicine Amoxicillin and Ciprofloxacin.Compound
The activity of 6 couples of gram positive bacteria M.Mutans and Micrococcus luteus is suitable with Amoxicillin and Ciprofloxacin but right
The activity of Pneumococcus is better than Amoxicillin.Compound 6 has inhibitory activity to penicillin resistant sodium Escherichia coli (PREC),
It is better than Amoxicillin and Ciprofloxacin.
Therefore, compound of the invention has wide market prospects in the preparation of antibacterials.
[example of formulations 1]
Tablet is prepared according to methods known in the art, every contains following compositions：
[example of formulations 2]
Capsule is prepared according to methods known in the art, following compositions are contained in each capsule：
Claims (8)
1. the 1- substituted-phenyls -2- alkyl imidazoles derivative and its available salt for being represented by general formula (I)：
Wherein：R represents straight or branched C1-C12Alkyl, phenyl or halogenophenyl；
R1Represent straight or branched C1-C12Alkyl, halo benzyl or alkyl substituted benzene methyl.
2. compound according to claim 1 is：
2- ethyls -1- [4- (4- fluorobenzyloxies)] phenyl -1H- imidazoles (1)
2- ethyls -1- [4- (4- Chlorobenzyloxies)] phenyl -1H- imidazoles (2)
2- ethyls -1- [4- (4- bromobenzenes methoxyl group)] phenyl -1H- imidazoles (3)
2- ethyls -1- [4- (4- methyl benzyloxy)] phenyl -1H- imidazoles (4)
2- ethyls -1- (4- butoxy) phenyl -1H- imidazoles (5)
2- ethyls -1- (4- amoxys) phenyl -1H- imidazoles (6)
2- ethyls -1- (4- hexyloxies) phenyl -1H- imidazoles (7)
2- ethyls -1- (4- epoxides in heptan) phenyl -1H- imidazoles (8)
2- ethyls -1- (4- octyloxies) phenyl -1H- imidazoles (9)
2- propyl group -1- [4- (4- fluorobenzyloxies)] phenyl -1H- imidazoles (10)
2- propyl group -1- [4- (4- Chlorobenzyloxies)] phenyl -1H- imidazoles (11)
2- propyl group -1- (4- butoxy) phenyl -1H- imidazoles (12)
2- propyl group -1- (4- amoxys) phenyl -1H- imidazoles (13)
2- propyl group -1- (4- hexyloxies) phenyl -1H- imidazoles (14)
2- phenyl -1- (4- butoxy) phenyl -1H- imidazoles (15)
2- phenyl -1- (4- amoxys) phenyl -1H- imidazoles (16)
2- phenyl -1- (4- hexyloxies) phenyl -1H- imidazoles (17)
2- phenyl -1- (4- epoxides in heptan) phenyl -1H- imidazoles (18)
2- (4- trifluoromethyls) phenyl -1- (4- butoxy) phenyl -1H- imidazoles (19).
3. compound according to claim 1, wherein R represents ethyl.
4. compound according to claim 1, wherein R1 represents amyl group.
5. compound according to claim 1, wherein R represents ethyl, and R1 represents amyl group.
6. the compound described in claim 1 is 2- ethyls -1- (4- amoxys) phenyl -1H- imidazoles (6).
7. medical compounds, wherein containing 1- substituted-phenyls -2- alkyl imidazoles derivative and its available salt described in claim 1
As active ingredient, and contain conventional pharmaceutical carrier.
8. the 1- substituted-phenyls -2- alkyl imidazoles derivative and its available salt described in claim 1 are in antibacterials are prepared
Using.
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|---|---|---|---|---|
| CN110256357A (en) * | 2019-04-12 | 2019-09-20 | 河南科技大学第一附属医院 | A kind of imidazoles molecule and preparation method thereof with bactericidal activity |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2009041972A1 (en) * | 2007-09-27 | 2009-04-02 | University Of Notre Dame Du Lac | Antibacterial compounds and methods of using same |
| US20150175582A1 (en) * | 2012-04-24 | 2015-06-25 | Board of Trustees of Nothern Illinois University | Design and synthesis of novel inhibitors of isoprenoid biosynthesis |
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2017
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2009041972A1 (en) * | 2007-09-27 | 2009-04-02 | University Of Notre Dame Du Lac | Antibacterial compounds and methods of using same |
| US20150175582A1 (en) * | 2012-04-24 | 2015-06-25 | Board of Trustees of Nothern Illinois University | Design and synthesis of novel inhibitors of isoprenoid biosynthesis |
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| XIAN-YU SUN，等: "Synthesis and Antibacterial Evaluation of 2-Ethyl-1-(4-substituted)phenyl-1H-imidazole Derivatives as Open-Chain Analogues of 7-Alkoxyl-4,5-dihydro-imidazo[1,2-a]quinolines", 《J. BRAZ. CHEM. SOC.》 * |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN110256357A (en) * | 2019-04-12 | 2019-09-20 | 河南科技大学第一附属医院 | A kind of imidazoles molecule and preparation method thereof with bactericidal activity |
| CN110256357B (en) * | 2019-04-12 | 2020-05-01 | 河南科技大学第一附属医院 | Imidazole drug molecule with bactericidal activity and preparation method thereof |
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