CN103524396B - Two amidine analog derivatives containing indole ring and its preparation method and application - Google Patents
Two amidine analog derivatives containing indole ring and its preparation method and application Download PDFInfo
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- C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
- C07D209/04—Indoles; Hydrogenated indoles
- C07D209/10—Indoles; Hydrogenated indoles with substituted hydrocarbon radicals attached to carbon atoms of the hetero ring
- C07D209/12—Radicals substituted by oxygen atoms
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- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
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Abstract
The present invention provides a kind of two amidine analog derivatives containing indole ring and its preparation method and application, and the two amidine analog derivatives containing indole ring have the structure of formula I, wherein, R1, R2, R ＇ are independently selected from hydrogen, C1-12Straight chained alkyl, C3-12Branched alkyl, C3-12Cycloalkyl；Or R1, R2, R ＇ have heteroatomic C in carbochain3-12Straight chained alkyl, C3-12Branched alkyl, C3-12Cycloalkyl；Or two in R1, R2, R ＇ form 36 yuan of rings or 36 yuan of rings with substituent group with being connected their N；X, Y, V, W and X ＇, Y ＇, V ＇, W ＇ are independently selected from for C or N, and meet the six-membered ring structure where them；A, being selected from for A ＇ independences is connected to hexa-atomic ring hydrogen, halogen, lower alkoxy or low-grade halogenated alkyl,
Description
Technical field
The invention belongs to pharmaceutical technology fields, are related to a kind of two amidine analog derivatives containing indole ring and preparation method thereof and answer
With.
Background technology
The appearance of multi-drug resistant bacteria has become the problem that the 21 century whole world faces jointly[1].Infection is died of in the whole world every year
The number of property disease, is about 7,000,000 in five sixties, and 1999 have had increased to 20,000,000.In recent years, drug-fast bacteria
Development shows following trend：The speed that drug resistance is formed is more and more rapider, and the speed that drug resistance spreads through sex intercourse is getting faster, drug resistance
Intensity it is higher and higher, Antibiotic Resistance is more and more wider.
There is definite result of study to show, methicillin-resistant staphylococcus aureus MRSA（Methicillin—
resistant Straphylococcus aureus）Multidrug resistant it is very serious, to including aminoglycoside, fluorine quinoline promise
A variety of antibacterials such as ketone, Tetracyclines, macrolides while drug resistance.Currently for the multi-purpose vancomycin of caused infection
Treatment, which is considered as the last line of defense for effectively tackling gram positive bacteria, but has been occurred in world wide by resistance to
Vancomycin enterococcus VRE（Vancomycin-resistant Enterococci）It is caused and bacteremia blood sense can be triggered
Complexity urinary tract infections in the even dead institute of dye[2].Due to the propagation of Vancomycin resistant gene, so as to generate it is resistance to through the ages
Mycin S. aureus L-forms, this has become the fact.It can be seen that research and development are new to have new construction type or novel mechanism
Anti- multi-drug resistant bacteria drug is very urgent, significant, and can obtain significant economic benefit and social benefit.
[1]Arias,Cesar A.;Murray,Barbara E.N.Engl.J.Med.2009,360(5),439-443。
[2]Gu Juefen, Dai Jun, the clinical progress of the anti-MRSA antibiotic of a new generation, anti-infectious agent 2009December;6
(4)223-228。
The content of the invention
Technical problem underlying solved by the invention is to propose a kind of two amidine analog derivatives containing indole ring and its can
Drug salts, and confirm its remarkable result with resisting gram-positive bacteria, it is expected to become a kind of new antibacterials.
The present invention also provides the two amidine analog derivatives containing indole ring as the purposes of antibacterials and accordingly
Pharmaceutical composition.
One aspect of the present invention provides a kind of two amidine analog derivatives or its officinal salt containing indole ring, described to contain
Two amidine analog derivatives of indole ring have the structure of formula I：
Wherein,
R1, R2, R ＇ are independently selected from hydrogen, C1-12Straight chained alkyl, C3-12Branched alkyl, C3-12Cycloalkyl；Or R1, R2,
R ＇ have heteroatomic C in carbochain3-12Straight chained alkyl, C3-12Branched alkyl, C3-12Cycloalkyl；Or R1, R2,
Two in R ＇ form 3-6 yuan of rings or 3-6 yuan of rings with substituent group with being connected their N；X, Y, V, W and X ＇, Y ＇, V ＇, W ＇ are only
It is C or N to be on the spot selected from, and meets the six-membered ring structure where them；
A, being selected from for A ＇ independences is connected to hexa-atomic ring hydrogen, halogen, lower alkoxy or low-grade halogenated alkyl.
According to specific embodiment, the present invention provides a kind of two amidine analog derivatives or its officinal salt containing indole ring, institute
Stating the two amidine analog derivatives containing indole ring has the structure of formula II：
Wherein, n is 1 or 2.
The two amidine analog derivatives provided by the invention containing indole ring have the structure of formula I or formula II, wherein, X, Y, V, W,
X ＇, Y ＇, V ＇, W ＇ are C；Or one of X, Y, V, W, X ＇, Y ＇, V ＇, W ＇ are N, remaining is C.
The two amidine analog derivatives or its officinal salt containing indole ring of the present invention, A and A ＇ are the hexatomic rings for connecting indole ring
On one or more substituent groups, can be identical or differ, can be lower alkoxy, is i.e. the alkoxy with 1-6 carbon,
Such as methoxyl group, ethyoxyl or propoxyl group etc.；Can also be the low-grade halogenated alkyl with 1-6 carbon, such as trifluoromethyl, three
Fluoro ethyl, trifluoro propyl or isopropyl, trichloromethyl, trichloroethyl, three chloropropyls or isopropyl, trisbromomethyl, three bromomethyl,
Three bromopropyls or isopropyl etc..
The two amidine analog derivatives or its officinal salt containing indole ring of the present invention, in general structure I：
One of R1, R2 are hydrogen, another is selected from C1-6Straight chained alkyl, C3-6Branched alkyl, C3-6Cycloalkyl, for example, can be with
It is methyl, ethyl or isopropyl；
Alternatively, one of R1, R2 are hydrogen, another has the C of oxygen or sulphur atom in carbochain3-12Straight chained alkyl, C3-12
Branched alkyl, for example, it may be methyl, ethyl or isopropyl；
Alternatively, R1, R2 are independently selected from C1-6Straight chained alkyl, for example, it may be methyl, ethyl or n-propyl.
The two amidine analog derivatives or its officinal salt containing indole ring of the present invention, can synthesize to obtain by any method,
For example, it is hydrogen with one of R1 and R2, R ＇ are also hydrogen, and exemplified by the scheme that diphenyl ether is connected between two indole rings, building-up process can
To be described as follows：
In said synthesis route,
Process a：4- methyl-3-nitro benzene acetonitriles（Compound 2）With 4- (4- aldehyde radicals phenoxy group) benzaldehyde（Compound 3）
Reaction is heated in the presence of piperidines, obtain 4,4'- it is double-[2- nitro -4- cyanostyrenes base)] diphenyl ether（Compound 4）；
Process b：Obtained compound 4 is cyclized, for example, being heated to reflux in triethyl phosphite, the reaction was complete for raw material
After solid is precipitated（Such as with methanol or ethanol precipitation）, obtain compound 5, i.e. 4,4 '-bis--[2- (6- itrile groups indyl)] two
Phenylate；
Process c and d：The first acidified processing of compound 5, further with corresponding amine（R-NH2）Or alkane diamine reactant, two
Two amidines or two amidine derivatives are generated on a indole ring simultaneously.
Listed in table 1 present invention the two amidine analog derivatives containing indole ring part particular compound, wherein X, Y, V,
W, X ＇, Y ＇, V ＇, W ＇ are carbon atom, and A, A ＇ are H atom；Compound 6a-6q is for NR1R2 on amidino groups in lower structure shown in formula I
Selection, R ＇ are H atom, and compound 6t and 6u are then to be connected as 5 yuan of rings for indole ring in formula（n=1）With 6 yuan of rings
The selection of (n=2).
Table 1
Listed in table 2 present invention the two amidine analog derivatives containing indole ring part particular compound, wherein X, Y, W,
X ＇, Y ＇, V ＇, W ＇ are carbon atom, and R ＇ are H atom；Compound 7a-i is the choosing for NR1R2 on amidino groups in Formula Il I structures
It selects.
Table 2
Following compound is entitled according to above-mentioned Tables 1 and 2：
Compound 6a：4,4 '-bis--[2- (6-N- methyl-bis- amidino groups) indoles] diphenyl ether
Compound 6q：4,4 '-bis--[2- (6-N- dimethyl-bis- amidino groups) indoles] diphenyl ether
Compound 7d：3- methoxyl groups -4,4 '-bis--[2- (6-N- methylaminos-bis- amidino groups) indoles] diphenyl ether
Compound 7e：3- methoxyl groups -4,4 '-bis--[2- (6-N- isopropylamine bases-bis- amidino groups) indoles] diphenyl ether
Compound 7f：3- methoxyl groups -4,4 '-bis--[2- (6-N- dimethylamino-bis- amidino groups) indoles] diphenyl ether
Compound 7h：4,4 '-bis--[2- (6-N- isopropylamine bases-bis- amidino groups) indoles] -3- pyridine phenylates
Compound 7i：4,4 '-bis--[2- (6-N- dimethylamino-bis- amidino groups) indoles] -3- pyridine phenylates
Inventor has synthesized a series of two amidine classes containing indole ring by in-depth study and substantial amounts of experiment, design
Derivative, and it has surprisingly been found that these compounds have gram-positive bacteria good effect, especially for MRSA, MRSS
There is the activity better than comparison medicine lavo-ofloxacin with VRE.
Specific embodiment
Embodiment 1：4,4 '-bis--[2- (6-N- methyl-bis- amidino groups) indoles] diphenyl ether（Compound 6a）
1）The preparation of 4,4 '-bis--[2- (6- itrile groups indyl)] diphenyl ether
4- methyl-3-nitros benzene acetonitrile (5.10g, 31.5mmol), 4- (4- through pulverizing are added in into 25mL three-neck flasks
Formvlphenoxv) benzaldehyde (3.39g, 15mmol) and 0.6mL piperidines, it is protected by nitrogen, under 100 DEG C of constant temperature, stirring
2h is reacted, adds after 10mL ethyl acetate that be kept stirring rate constant, until there are a large amount of yellow insoluble matters.Filtered, title
7.2g yellow wet cakes are obtained after weight.
To above-mentioned 7.2g yellow wet cake and 90mL triethyl phosphites is added in 250mL there-necked flasks, under nitrogen protection
It is heated to reflux, until the reaction was complete for TCL displays raw material.Stop heating, add in methanol, 2.8g4,4 '-bis--[2- (6- is precipitated
Itrile group indyl)] diphenyl ether, its yield is calculated as 39.03%.
2）4,4 '-bis--[2- (6-N- methyl-bis- amidino groups) indoles] diphenyl ether（Compound a）Preparation
Added in into 500mL three-neck flasks obtained above 4,4 '-bis--[2- (6- itrile groups indyl)] diphenyl ether (1.3g,
2.88mmol), after then adding in 40mL tetrahydrofurans and 80mL absolute ethanols, being stirred is completely dissolved solid, reaction solution
It is transparent.After reaction solution reacted for two nights under HCl atmosphere, there is substantial amounts of insoluble matter to be precipitated in three-neck flask, until TCL is shown
Until showing raw material the reaction was complete.It is filtered, weigh after obtain 1.2g yellow wet cakes.
Above-mentioned yellow wet cake is added in into 100mL three-neck flasks（0.32g,0.72mmol）, 20mL ethyl alcohol, then add
0.42g methylamines, heating reflux reaction 2h, until the reaction was complete for TCL displays raw material.Insoluble matter is filtered to remove, filtrate is through subtracting
Pressure distillation adds in the hot acetone of about 10-15mL, yellow crystals is precipitated to 2-3mL（It crystallizes for the first time）, after ether washs, analysis
Go out yellow crystals（Second of crystallization）, evaporate and remove ether solvent, add acetone stirring, yellow crystals are precipitated（Third time is tied
It is brilliant）.Drying weighs to obtain about 210mg4, and 4 '-bis--[2- (6-N- methyl-bis- amidino groups) indoles] diphenyl ether, calculating its yield is
46.6%。
Embodiment 2：4,4 '-bis--[2- (6-N- ethyls-bis- amidino groups) indoles] diphenyl ether（Compound 6b）
In embodiment 1, methylamine is substituted for ethamine, with the method for similar embodiment 1, obtains 4,4 '-bis--[2- (6-N-
Ethyl-bis- amidino groups) indoles] diphenyl ether.
Embodiment 3：4,4 '-bis--[2- (6-N- propyl-bis- amidino groups) indoles] diphenyl ether（Compound 6c）
In embodiment 1, methylamine is substituted for propylamine, with the method for similar embodiment 1, obtains 4,4 '-bis--[2- (6-N-
Propyl-bis- amidino groups) indoles] diphenyl ether.
Embodiment 4：4,4 '-bis--[2- (6-N- isobutyl groups-bis- amidino groups) indoles] diphenyl ether（Compound 6d）
In embodiment 1, methylamine is substituted for 2- butylamine, with the method for similar embodiment 1, obtains 4,4 '-bis--[2- (6-
N- isobutyl groups-bis- amidino groups) indoles] diphenyl ether.
Embodiment 5：4,4 '-bis--[2- (6-N-（3- amyls）- bis- amidino groups) indoles] diphenyl ether（Compound 6e）
In embodiment 1, methylamine is substituted for 3- amylamines, with the method for similar embodiment 1, obtains 4,4 '-bis--[2- (6-
N-（3- amyls）- bis- amidino groups) indoles] diphenyl ether.
Embodiment 6：4,4 '-bis--[2- (6-N- cyclopropyl-bis- amidino groups) indoles] diphenyl ether（Compound 6f）
In embodiment 1, methylamine is substituted for cyclopropylamine, with the method for similar embodiment 1, obtains 4,4 '-bis--[2- (6-
N- cyclopropyl-bis- amidino groups) indoles] diphenyl ether.
Embodiment 7- embodiments 9：（Compound 6g-6i）
In embodiment 1, methylamine is replaced to cyclic butylamine, cyclopentamine and cyclohexylamine respectively, with the side of similar embodiment 1
Method obtains 4,4 '-bis--[2- (6-N- cyclobutyl-bis- amidino groups) indoles] diphenyl ether, 4,4 '-bis--[2- (6-N- cyclopenta-bis- amidines
Base) indoles] diphenyl ether and 4,4 '-bis--[2- (6-N- cyclohexyl-bis- amidino groups) indoles] diphenyl ether.
Embodiment 10：4,4 '-bis--[2- (6-N-（N- cyclopropyl）- bis- amidino groups) indoles] diphenyl ether（Compound 6j）
In embodiment 1, methylamine is substituted for N- ring butylamine, with the method for similar embodiment 1, obtains 4,4 '-bis--[2-
(6-N-（N- cyclobutyl）- bis- amidino groups) indoles] diphenyl ether.
Embodiment 11- embodiments 12：（Compound 6k-6l）
In embodiment 1, methylamine is substituted for N- rings butylamine and N- cyclopentamines respectively, with the method for similar embodiment 1, is obtained
To 4,4 '-bis--[2- (6-N-（N- cyclobutyl）- bis- amidino groups) indoles] diphenyl ether and 4,4 '-bis--[2- (6-N-（N- cyclopenta）-
Double amidino groups) indoles] diphenyl ether.
Embodiment 13：4,4 '-bis--[2- (6-N-（4- methyl-N- cyclopenta）- bis- amidino groups) indoles] diphenyl ether（Compound
6m）
In embodiment 1, methylamine is substituted for 4- methyl-N- cyclopentamines respectively, with the method for similar embodiment 1, is obtained
4,4 '-bis--[2- (6-N-（4- methyl-N- cyclopenta）- bis- amidino groups) indoles] diphenyl ether.
Embodiment 14：4,4 '-bis--[2- (6-N-（3,5- methyl-N- cyclopenta）- bis- amidino groups) indoles] diphenyl ether（Chemical combination
Object 6n）
In embodiment 1, methylamine is substituted for 3,5- methyl-N- cyclopentamines respectively, with the method for similar embodiment 1, obtained
To 4,4 '-bis--[2- (6-N-（3,5- methyl-N- cyclopenta）- bis- amidino groups) indoles] diphenyl ether.
Embodiment 15：4,4 '-bis--[2- (6-N-（Penta imido grpup-N- cyclopenta of 4- rings）- bis- amidino groups) indoles] diphenyl ether
（Compound 6o）
In embodiment 1, methylamine is substituted for penta imido grpup-N- cyclopenta of 4- rings, with the method for similar embodiment 1, obtained
To 4,4 '-bis--[2- (6-N-（Penta imido grpup-N- of 4- ringsCyclopenta）- bis- amidino groups) indoles] diphenyl ether.
Embodiment 16：4,4 '-bis--[2- (6- morpholinyls-bis- amidino groups) indoles] diphenyl ether（Compound 6p）
In embodiment 1, methylamine is substituted for morpholine, with the method for similar embodiment 1, obtains 4,4 '-bis--[2- (6-
Quinoline base-bis- amidino groups) indoles] diphenyl ether.
Embodiment 17：4,4 '-bis--[2- (6-N- dimethyl-bis- amidino groups) indoles] diphenyl ether（Compound 6q）
In embodiment 1, methylamine is substituted for dimethylamine, with the method for similar embodiment 1, obtains 4,4 '-bis--[2- (6-
N- dimethyl-bis- amidino groups) indoles] diphenyl ether.
Embodiment 18：4,4 '-bis--[2- (6-N- second diyl-bis- amidino groups) indoles] diphenyl ether（Compound 6t）
In embodiment 1, methylamine is substituted for ethylenediamine respectively, with the method for similar embodiment 1, obtain 4,4 '-bis--
[2- (6-N- second diyl-bis- amidino groups) indoles] diphenyl ether.
Embodiment 19：4,4 '-bis--[2- (6-N- glyceryl-bis- amidino groups) indoles] diphenyl ether（Compound 6u）
In embodiment 1, methylamine is substituted for propane diamine respectively, with the method for similar embodiment 1, obtain 4,4 '-bis--
[2- (6-N- glyceryl-bis- amidino groups) indoles] diphenyl ether.
Embodiment 20:3- trifluoromethyls -4,4 '-bis--[2- (6-N- methylaminos-bis- amidino groups) indoles] diphenyl ether（Compound
7a）
1）The preparation of 3- trifluoromethyls -4,4 '-bis--[2- (6- itrile groups indyl)] diphenyl ether
4- methyl-3-nitros benzene acetonitrile (5.10g, 31.5mmol), 3- tri- through pulverizing are added in into 25mL three-neck flasks
Methyl fluoride -4- (4- formvlphenoxvs) benzaldehyde (15mmol) and 0.6mL piperidines, are protected by nitrogen, in 130 DEG C of constant temperature
Under, 6h is stirred to react, adds after 10mL ethyl acetate that be kept stirring rate constant, until there are a large amount of yellow insoluble matters.Through
Filter, weigh after obtain 4.1g yellow solids.
To above-mentioned yellow solid and 80mL triethyl phosphites is added in 250mL there-necked flasks, heat under nitrogen protection
Reflux, until the reaction was complete for TCL displays raw material.Stop heating, cross column chromatography.Obtain yellow solid for 3- trifluoromethyls-
4,4 '-bis--[2- (6- itrile groups indyl)] diphenyl ether.
2）3- trifluoromethyls -4,4 '-bis--[2- (6-N- isopropylamine bases-bis- amidino groups) indoles] diphenyl ether（Compound 7a）'s
It prepares
3- trifluoromethyls -4,4 ' obtained above-bis--[2- (6- itrile groups indyl)] two is added in into 100mL three-necked bottles
Phenylate (0.8g), after then adding in 40mL tetrahydrofurans and 80mL absolute ethanols, stirring.Reaction solution reacted under HCl atmosphere
After two nights, there is substantial amounts of insoluble matter to be precipitated in three-neck flask, until the reaction was complete for TCL displays raw material.It is filtered, weigh
After obtain 0.8g yellow solids.
Above-mentioned yellow solid is added in into 100mL three-necked bottles（0.72mmol）, 20mL ethyl alcohol, it is different then to add 0.42g
Propylamine, heating reflux reaction 2h, until the reaction was complete for TCL displays raw material.Insoluble matter is filtered to remove, filtrate is through vacuum distillation
To 2-3mL, the hot acetone of about 10-15mL is added in, yellow crystals are precipitated（It crystallizes for the first time）, after ether washs, yellow is precipitated
Crystal（Second of crystallization）, evaporate and remove ether solvent, add acetone stirring, yellow crystals are precipitated（Third time crystallizes）.It is dry
It is dry to obtain product, column color gel column chromatography is crossed, obtains final product.
Embodiment 21：3- trifluoromethyls -4,4 '-bis--[2- (6-N- isopropylamine bases-bis- amidino groups) indoles] diphenyl ether（Chemical combination
Object 7b）
In embodiment 20, methylamine is substituted for isopropylamine respectively, with the method for similar embodiment 20, obtains 3- fluoroforms
Base -4,4 '-bis--[2- (6-N- isopropylamine bases-bis- amidino groups) indoles] diphenyl ether.
Embodiment 22：3- trifluoromethyls -4,4 '-bis--[2- (6-N- dimethylamino-bis- amidino groups) indoles] diphenyl ether（Chemical combination
Object 7c）
In embodiment 20, methylamine is substituted for dimethylamine respectively, with the method for similar embodiment 20, obtains 3- fluoroforms
Base -4,4 '-bis--[2- (6-N- dimethylamino-bis- amidino groups) indoles] diphenyl ether.
Embodiment 23：3- methoxyl groups -4,4 '-bis--[2- (6-N- methylaminos-bis- amidino groups) indoles] diphenyl ether（Compound 7d）
1）The preparation of 3- methoxyl groups -4,4 '-bis--[2- (6- itrile groups indyl)] diphenyl ether
In embodiment 20,3- methoxyl groups -4- (4- formvlphenoxvs) benzaldehyde is replaced into 3- trifluoromethyl -4- (4-
Formvlphenoxv) benzaldehyde, with the method for similar embodiment 20, obtain 3- methoxyl group -4,4 '-bis--[2- (6- itrile group indoles
Base)] diphenyl ether.
2）3- methoxyl groups -4,4 '-bis--[2- (6-N- methylaminos-bis- amidino groups) indoles] diphenyl ether（Compound 7d）Preparation
In embodiment 20, by 3- methoxyl group -4,4 '-bis--[2- (6- itrile groups indyl)] diphenyl ether replaces 3- fluoroforms
Base -4,4 '-bis--[2- (6- itrile groups indyl)] diphenyl ether with the method for similar embodiment 20, obtain 3- methoxyl group -4,4 ' -
Double-[2- (6-N- methylaminos-bis- amidino groups) indoles] diphenyl ether.
Embodiment 24：3- methoxyl groups -4,4 '-bis--[2- (6-N- isopropylamine bases-bis- amidino groups) indoles] diphenyl ether（Compound
7e）
In embodiment 20, by 3- methoxyl group -4,4 '-bis--[2- (6- itrile groups indyl)] diphenyl ether replaces 3- fluoroforms
Base -4,4 '-bis--[2- (6- itrile groups indyl)] diphenyl ether react with isopropylamine, with the method for similar embodiment 20, obtain 3-
Methoxyl group -4,4 '-bis--[2- (6-N- isopropylamine bases-bis- amidino groups) indoles] diphenyl ether.
Embodiment 25：3- methoxyl groups -4,4 '-bis--[2- (6-N- dimethylamino-bis- amidino groups) indoles] diphenyl ether（Compound
7f）
In embodiment 20, by 3- methoxyl group -4,4 '-bis--[2- (6- itrile groups indyl)] diphenyl ether replaces 3- fluoroforms
Base -4,4 '-bis--[2- (6- itrile groups indyl)] diphenyl ether react with dimethylamine, with the method for similar embodiment 20, obtain 3-
Methoxyl group -4,4 '-bis--[2- (6-N- dimethylamino-bis- amidino groups) indoles] diphenyl ether.
Embodiment 26：4,4 '-bis--[2- (6-N- methylaminos-bis- amidino groups) indoles] -3- pyridine phenylates（Compound 7g）
In embodiment 20,4,4 '-bis--[2- (6- itrile groups indyl)] -3- pyridines phenylate is replaced into 3- trifluoromethyl -4,
4 '-bis--[2- (6- itrile groups indyl)] diphenyl ether is reacted with methylamine, with the method for similar embodiment 20, obtain 4,4 '-bis--
[2- (6-N- methylaminos-bis- amidino groups) indoles] -3- pyridine phenylates.
Embodiment 27：4,4 '-bis--[2- (6-N- isopropylamine bases-bis- amidino groups) indoles] -3- pyridine phenylates（Compound 7h）
In embodiment 20,4,4 '-bis--[2- (6- itrile groups indyl)] -3- pyridines phenylate is replaced into 3- trifluoromethyl -4,
4 '-bis--[2- (6- itrile groups indyl)] diphenyl ether is reacted with isopropylamine, with the method for similar embodiment 20, obtain 4,4 '-bis--
[2- (6-N- isopropylamine bases-bis- amidino groups) indoles] -3- pyridine phenylates.
Embodiment 28：4,4 '-bis--[2- (6-N- dimethylamino-bis- amidino groups) indoles] -3- pyridine phenylates（Compound 7i）
In embodiment 20,4,4 '-bis--[2- (6- itrile groups indyl)] -3- pyridines phenylate is replaced into 3- trifluoromethyl -4,
4 '-bis--[2- (6- itrile groups indyl)] diphenyl ether is reacted with dimethylamine, with the method for similar embodiment 20, obtain 4,4 '-bis--
[2- (6-N- dimethylamino-bis- amidino groups) indoles] -3- pyridine phenylates.
Compound in above example 1-28 can pass through MS and HNMR test verification structures, test result such as following table
Shown in 3：
Table 3
Antibacterial tests（MIC）
1st, reagent and material
Test specimen：Compound shown in Tables 1 and 2
Culture medium:
1）MH agar mediums (Mueller Hinton Agar), purchased from Nat'l Pharmaceutical ＆ Biological Products Control Institute；
2）MH meat soups (Mueller Hinton Broth) culture medium；Purchased from Nat'l Pharmaceutical ＆ Biological Products Control Institute；
3）Brain heart infusion (Brain Heart Infusion) culture medium, U.S. company BD product.
Positive control：Lavo-ofloxacin (Levofloxacin), purchased from Nat'l Pharmaceutical ＆ Biological Products Control Institute.
Test organisms:The standard bacteria and be clinically separated bacterium that 36 plants of laboratories preserve.
Quality Control bacterium:Select staphylococcus aureus ATCC29213, enterococcus faecalis ATCC29212, escherichia coli
ATCC25922, pseudomonas aeruginosa ATCC27853.
2nd, experimental method：With reference to CLSI standards, susceptibility is carried out using plate doubling dilution and Denlay multi-point inoculators
Experiment.
1）Test organisms is subjected to Zengjing Granule with MH meat soups or brain heart infusion, drug is dissolved with DMSO, then with MH meat soups
After concentration needed for being diluted to, suitable above-mentioned experimental bacteria after Zengjing Granule and dissolved drug DMSO are added to respectively
In plate；
2）After MH agar mediums are melted, mixing in above-mentioned drug containing DMSO and the plate of experimental bacteria is quantitatively injected into,
The final concentration of sample is respectively 128,64 ... 0.06,0.03 μ g/mL in plate；
3）Test organisms is inoculated with after culture medium solidification（Inoculum concentration is 104cfu/ points）, seen after cultivating 18h under 35 DEG C of constant temperature
It examines as a result, the concentration of contained drug minimum is minimum inhibitory concentration (Minimal Inhibitory in the plate of asepsis growth
Concentration,MIC)。
3rd, experimental result
Antibacterial tests（MIC）, the results are shown in Table 4.
Table 4：The antibacterial activity of compound
Compound 6a-q, 6t-u, 7a-7i resisting gram-positive bacteria, the antibacterial activity test data of anti-Gram-negative bacteria
It is as follows：(MIC：μg/mL)
A Lflox, lavo-ofloxacin
The strain of b staphylococcus aureuses:ATCC2921,15,09-6.
C methicillin-resistant staphylococcus aureus strains:09-13.
D staphylococcus epidermis strains:ATCC12228,09-9.
E Methicillin-resistant Staphylococcus epidermidis strains:09-3.
F enterococcus faecalis strains:ATCC29212and09-8.
G enterococcus faecium strains:09-10.
H vancomycin-resistant enterococcus:faecalis09-9,faecium ATCC70022and05-8.
I escherichia coli:ATCC25922,1515,09-1,09-20;Klebsiella pneumoniae:ATCC700603,7.
BAA-2146,09-8,09-25；Pseudomonas aeruginosa：ATCC27853,PAO1,09-14；Acinetobacter bauamnnii：
ATCC19606；Enterobacter cloacae：45301；Clostridium perfringen：45102；Serratia marcescens：41002；Mo Genmo
Root Salmonella：
ATCC25830；Thunder pole Pu Lufeideng bacillus：ATCC31052；Proteus vulgaris：ATCC29905；Unusual deformation
Bacillus：
09-1；Salmonella typhi：H901；Not labor ground citric acid bacteria：ATCC43864.
Although the specific embodiment of the present invention has obtained detailed description, it will be understood to those of skill in the art that.Root
According to all introductions having disclosed, those details can be carry out various modifications and replaced, these change in the guarantor of the present invention
Within the scope of shield.The four corner of the present invention is provided by appended claims and its any equivalent.
Claims (4)
1. a kind of two amidine analog derivatives containing indole ring, the two amidine analog derivatives containing indole ring are selected from：
7a：3- trifluoromethyls -4,4 '-bis--[2- (6-N- methylaminos-bis- amidino groups) indoles] diphenyl ether；
7b：3- trifluoromethyls -4,4 '-bis--[2- (6-N- isopropylamine bases-bis- amidino groups) indoles] diphenyl ether；
7c：3- trifluoromethyls -4,4 '-bis--[2- (6-N- dimethylamino-bis- amidino groups) indoles] diphenyl ether；
7d：3- methoxyl groups -4,4 '-bis--[2- (6-N- methylaminos-bis- amidino groups) indoles] diphenyl ether；
7e：3- methoxyl groups -4,4 '-bis--[2- (6-N- isopropylamine bases-bis- amidino groups) indoles] diphenyl ether；
7f：3- methoxyl groups -4,4 '-bis--[2- (6-N- dimethylamino-bis- amidino groups) indoles] diphenyl ether.
2. a kind of pharmaceutically useful salt of compound described in claim 1.
3. the two amidine analog derivatives containing indole ring of claim 1 or 2 or its officinal salt answering in antibacterials are prepared
With.
4. a kind of antibacterial combination, described containing indole ring including the claim 1 or 2 as antibiotic effective ingredient
Two amidine analog derivatives or its officinal salt further include acceptable excipient substance in pharmacy.
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