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 PDF

Info

Publication number
CN103524396B
CN103524396B CN201310452864.2A CN201310452864A CN103524396B CN 103524396 B CN103524396 B CN 103524396B CN 201310452864 A CN201310452864 A CN 201310452864A CN 103524396 B CN103524396 B CN 103524396B
Authority
CN
China
Prior art keywords
bis
indole
diphenyl ether
diamidino
compound
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.)
Expired - Fee Related
Application number
CN201310452864.2A
Other languages
Chinese (zh)
Other versions
CN103524396A (en
Inventor
胡来兴
游雪甫
陈晓芳
胡辛欣
武燕彬
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Institute of Medicinal Biotechnology of CAMS
Original Assignee
Institute of Medicinal Biotechnology of CAMS
Priority date (The priority date 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 date listed.)
Filing date
Publication date
Application filed by Institute of Medicinal Biotechnology of CAMS filed Critical Institute of Medicinal Biotechnology of CAMS
Priority to CN201310452864.2A priority Critical patent/CN103524396B/en
Publication of CN103524396A publication Critical patent/CN103524396A/en
Application granted granted Critical
Publication of CN103524396B publication Critical patent/CN103524396B/en
Expired - Fee Related legal-status Critical Current
Anticipated expiration legal-status Critical

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • 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

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Indole Compounds (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

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

Diamidine derivative containing indole ring and preparation method and application thereof
Technical Field
The invention belongs to the technical field of medicines, and relates to diamidine derivatives containing indole rings, and a preparation method and application thereof.
Background
The emergence of multiple drug-resistant bacteria has become a common problem in the world of the 21 st century[1]. The number of deaths annually from infectious diseases worldwide is approximately 700 million in the fifty years, and has risen to 2000 million in 1999. In recent years, the development of drug-resistant bacteria has been trending as follows: the drug resistance is formed more and more rapidly, the drug resistance is spread more and more rapidly, the drug resistance strength is higher and higher, and the drug resistance spectrum is wider and wider.
The results of the exact research show that the product has the resistance to the methoxy groupThe multidrug resistance of staphylococcus aureus MRSA (Methicillin-resistant streptococcus aureus) is very serious, and it can resist various antibacterial drugs including aminoglycosides, fluoroquinolones, tetracyclines, macrolides, and the like. At present, the Vancomycin treatment is used for treating caused infection, the medicine is considered to be the last line of defense against gram-positive bacteria, but hospital complex urinary tract infection caused by Vancomycin-resistant enterococcus VRE (Vancomycin-resistant Enterococci) and capable of causing bacteremia blood infection and even death appears worldwide[2]. It has been the fact that vancomycin-resistant Staphylococcus aureus was produced due to the spread of vancomycin resistance genes. Therefore, the research and development of novel multiple drug-resistant bacteria resistant drugs with new structure types or new action mechanisms are not slow, the significance is great, and remarkable economic and social benefits can be obtained.
[1]Arias,Cesar A.;Murray,Barbara E.N.Engl.J.Med.2009,360(5),439-443。
[2]Considering the excitement, Dajun, the clinical research progress of a new generation of anti-MRSA antibiotics, an anti-infective drug 2009December, 6(4) 223-.
Disclosure of Invention
The invention provides a diamidine derivative containing indole ring and its medicinal salt, and proves its significant effect in resisting gram-positive bacteria, and is expected to become a novel antibacterial medicament.
The invention also provides application of the diamidine derivative containing the indole ring as an antibacterial drug and a corresponding drug combination.
In one aspect of the present invention, there is provided an indole ring-containing diamidine derivative or a pharmaceutically acceptable salt thereof, wherein the indole ring-containing diamidine derivative has a structure of formula i:
wherein,
r1, R2 and R' are independently selected from hydrogen and C1－12Straight chain alkyl, C3－12Branched alkyl radical, C3－12A cycloalkyl group; or R1, R2 and R' are independently selected from C with hetero atom in carbon chain3－12Straight chain alkyl, C3－12Branched alkyl radical, C3－12A cycloalkyl group; or two of R1, R2 and R' and N connecting the two form a 3-6 membered ring or a 3-6 membered ring with substituent groups; x, Y, V, W and X ', Y', V ', W' are independently selected from C or N and satisfy the six-membered ring structure in which they are located;
A. a' is independently selected from hydrogen, halogen, lower alkoxy or lower haloalkyl attached to a six-membered ring.
According to a specific embodiment, the present invention provides an indole ring-containing diamidine derivative having a structure of formula ii:
wherein n is 1 or 2.
The diamidine derivative containing the indole ring has a structure shown in a formula I or a formula II, wherein X, Y, V, W, X ', Y', V 'and W' are all C; or X, Y, V, W, X ', Y', V ', W', one of which is N, the others are C.
In the diamidine derivative containing indole ring or the pharmaceutically acceptable salt thereof, A and A' are one or more substituents which are connected with the six-membered ring of the indole ring, can be the same or different, and can be lower alkoxy, that is, alkoxy with 1-6 carbons, such as methoxy, ethoxy or propoxy, etc.; lower haloalkyl having 1 to 6 carbons may also be present, such as trifluoromethyl, trifluoroethyl, trifluoropropyl or isopropyl, trichloromethyl, trichloroethyl, trichloropropyl or isopropyl, tribromomethyl, tribromoethyl, tribromopropyl or isopropyl, and the like.
The diamidine derivative containing indole ring or the medicinal salt thereof has the following structural formula I:
one of R1 and R2 is hydrogen, and the other is selected from C1－6Straight chain alkyl, C3－6Branched alkyl radical, C3－6Cycloalkyl, for example, may be methyl, ethyl or isopropyl;
or one of R1 and R2 is hydrogen, and the other is selected from C with oxygen or sulfur atoms in the carbon chain3－12Straight chain alkyl, C3－12Branched alkyl, for example, may be methyl, ethyl or isopropyl;
or R1 and R2 are independently selected from C1－6The straight-chain alkyl group may be, for example, methyl, ethyl or n-propyl.
The diamidine derivative containing indole ring or its pharmaceutically acceptable salt of the present invention can be synthesized by any method, for example, taking one of R1 and R2 as hydrogen, R' as hydrogen, and the scheme of connecting diphenyl ether between two indole rings as an example, the synthetic process can be described as follows:
in the above-mentioned synthetic route, the amino acid sequence,
the process a: heating 4-methyl-3-nitrobenzonitrile (compound 2) and 4- (4-aldehyde phenoxy) benzaldehyde (compound 3) in the presence of piperidine to react to obtain 4,4' -bis- [ 2-nitro-4-nitrile styryl) ] diphenyl ether (compound 4);
and a process b: cyclizing the obtained compound 4, for example, heating and refluxing the compound in triethyl phosphite, and precipitating a solid (for example, precipitating with methanol or ethanol) after the raw material reaction is completed to obtain a compound 5, i.e., 4,4' -bis- [2- (6-cyanoindolyl) ] diphenyl ether;
processes c and d: compound 5 is first acidified and then further reacted with the corresponding amine (R-NH)2) Or alkyldiamine reaction to produce diamidine or diamidine derivative simultaneously on two indole rings.
Some specific compounds of diamidine derivatives containing indole ring of the present invention are listed in table 1, wherein X, Y, V, W, X ', Y ', V ', W ' are all carbon atoms, A, A ' is H atom; compounds 6a-6q are selected for NR1R2 at the amidino group in the structure of formula i below, R' is an H atom, and compounds 6t and 6u are selected for 5-membered (n = 1) and 6-membered (n =2) rings to which the indole ring is attached in the structure of formula i below.
TABLE 1
Some specific compounds of the diamidine derivatives containing indole ring of the present invention are listed in table 2, wherein X, Y, W, X ', Y ', V ', W ' are all carbon atoms, and R ' is H atom; compounds 7a-i are selected for NR1R2 on the amidino group in the structure of formula III below.
TABLE 2
From the above tables 1 and 2, the names of the following compounds can be found:
compound 6 a: 4,4' -bis- [2- (6-N-methyl-diamidino) indole ] diphenyl ether
Compound 6 q: 4,4' -bis- [2- (6-N-dimethyl-diamidino) indole ] diphenyl ether
Compound 7 d: 3-methoxy-4, 4' -bis- [2- (6-N-methylamino-diamidino) indole ] diphenyl ether
Compound 7 e: 3-methoxy-4, 4' -bis- [2- (6-N-isopropylamino-diamidino) indole ] diphenyl ether
Compound 7 f: 3-methoxy-4, 4' -bis- [2- (6-N-dimethylamino-diamidino) indole ] diphenyl ether
Compound 7 h: 4,4' -bis- [2- (6-N-isopropylamino-diamidino) indole ] -3-pyridinylphenyl ether
Compound 7 i: 4,4' -bis- [2- (6-N-dimethylamino-diamidino) indole ] -3-pyridinylphenyl ether
The inventor designs and synthesizes a series of diamidine derivatives containing indole rings through intensive research and a large number of experiments, and surprisingly finds that the compounds have good effects on gram-positive bacteria, particularly have better activity on MRSA, MRSS and VRE than the control drug levofloxacin.
Detailed Description
Example 1: 4,4' -bis- [2- (6-N-methyl-diamidino) indole ] diphenyl ether (Compound 6 a)
1) Preparation of 4,4' -bis- [2- (6-cyanoindolyl) ] diphenyl ether
A25 mL three-necked flask was charged with crushed 4-methyl-3-nitrophenylacetonitrile (5.10g, 31.5mmol), 4- (4-formylphenoxy) benzaldehyde (3.39g, 15mmol) and 0.6mL piperidine, and the reaction was stirred at 100 ℃ for 2h under nitrogen protection, followed by addition of 10mL ethyl acetate and maintaining the stirring rate until a large amount of yellow insoluble material appeared. After filtration and weighing, 7.2g of a yellow wet cake was obtained.
To a 250mL three-necked flask were added 7.2g of the yellow wet cake and 90mL of triethyl phosphite, and the mixture was heated under reflux under nitrogen until TCL indicated complete reaction of the starting materials. Heating was stopped, methanol was added to precipitate 2.8g of 4,4' -bis- [2- (6-cyanoindolyl) ] diphenyl ether, and the yield was calculated to be 39.03%.
2) Preparation of 4,4' -bis- [2- (6-N-methyl-diamidino) indole ] diphenyl ether (Compound a)
To a 500mL three-necked flask, the 4,4' -bis- [2- (6-cyanoindolyl) ] diphenyl ether (1.3g, 2.88mmol) obtained above was charged, 40mL of tetrahydrofuran and 80mL of absolute ethanol were added, and the mixture was stirred and mixed to completely dissolve the solid, whereby the reaction solution was transparent. After the reaction mixture was reacted overnight under HCl atmosphere, a large amount of insoluble matter was precipitated in a three-necked flask until TCL showed complete reaction of the starting materials. After filtration and weighing, 1.2g of a yellow wet cake was obtained.
A100 mL three-necked flask was charged with the yellow wet cake (0.32 g,0.72 mmol) and 20mL of ethanol followed by 0.42g of methylamine, and heated to reflux for 2h until TCL indicated complete reaction of the starting materials. Filtering to remove insoluble substances, distilling the filtrate under reduced pressure to 2-3mL, adding about 10-15mL hot acetone to precipitate yellow crystal (first crystallization), washing with diethyl ether to precipitate yellow crystal (second crystallization), evaporating to remove diethyl ether solvent, adding acetone, and stirring to precipitate yellow crystal (third crystallization). Dried and weighed to give about 210mg of 4,4' -bis- [2- (6-N-methyl-diamidino) indole ] diphenyl ether in a calculated yield of 46.6%.
Example 2: 4,4' -bis- [2- (6-N-ethyl-diamidino) indole ] diphenyl ether (Compound 6 b)
In example 1, 4' -bis- [2- (6-N-ethyl-diamidino) indole ] diphenyl ether was obtained in a similar manner to example 1, substituting methylamine for ethylamine.
Example 3: 4,4' -bis- [2- (6-N-propyl-diamidino) indole ] diphenyl ether (Compound 6 c)
In example 1, 4' -bis- [2- (6-N-propyl-diamidino) indole ] diphenyl ether was obtained in a similar manner to example 1, substituting methylamine for propylamine.
Example 4: 4,4' -bis- [2- (6-N-isobutyl-diamidino) indole ] diphenyl ether (Compound 6 d)
In example 1, methylamine was replaced with 2-butylamine and the procedure of example 1 was repeated to give 4,4' -bis- [2- (6-N-isobutyl-diamidino) indole ] diphenyl ether.
Example 5: 4,4' -bis- [2- (6-N- (3-pentyl) -diamidino) indole ] diphenyl ether (Compound 6 e)
In example 1, methylamine was replaced with 3-pentylamine, and in a similar manner to example 1, 4' -bis- [2- (6-N- (3-pentyl) -diamidino) indole ] diphenyl ether was obtained.
Example 6: 4,4' -bis- [2- (6-N-cyclopropyl-diamidino) indole ] diphenyl ether (Compound 6 f)
In example 1, methylamine was replaced with cyclopropylamine, and in a similar manner to example 1, 4' -bis- [2- (6-N-cyclopropyl-diamidino) indole ] diphenyl ether was obtained.
Example 7-example 9: (Compound 6g-6 i)
In example 1, 4' -bis- [2- (6-N-cyclobutyl-diamidino) indole ] diphenyl ether, 4' -bis- [2- (6-N-cyclopentyl-diamidino) indole ] diphenyl ether and 4,4' -bis- [2- (6-N-cyclohexyl-diamidino) indole ] diphenyl ether were obtained in a similar manner to example 1 by replacing methylamine with cyclobutylamine, cyclopentylamine and cyclohexylamine, respectively.
Example 10: 4,4' -bis- [2- (6-N- (N-cyclopropyl) -diamidino) indole ] diphenyl ether (Compound 6 j)
In example 1, methylamine was replaced with N-cyclobutylamine, and in a similar manner to example 1, 4' -bis- [2- (6-N- (N-cyclobutyl) -diamidino) indole ] diphenyl ether was obtained.
Example 11-example 12: (Compound 6k-6 l)
In example 1, 4 '-bis- [2- (6-N- (N-cyclobutyl) -diamidino) indole ] diphenyl ether and 4,4' -bis- [2- (6-N- (N-cyclopentyl) -diamidino) indole ] diphenyl ether were obtained in a similar manner to example 1 by replacing methylamine with N-cyclobutylamine and N-cyclopentylamine, respectively.
Example 13: 4,4' -bis- [2- (6-N- (4-methyl-N-cyclopentyl) -diamidino) indole ] diphenyl ether (Compound 6 m)
In example 1, methylamine was replaced with 4-methyl-N-cyclopentylamine, respectively, and in a similar manner to example 1, 4' -bis- [2- (6-N- (4-methyl-N-cyclopentyl) -diamidino) indole ] diphenyl ether was obtained.
Example 14: 4,4' -bis- [2- (6-N- (3, 5-methyl-N-cyclopentyl) -diamidino) indole ] diphenyl ether (Compound 6N)
In example 1, methylamine was replaced with 3, 5-methyl-N-cyclopentylamine, respectively, and in a similar manner to example 1, 4' -bis- [2- (6-N- (3, 5-methyl-N-cyclopentyl) -diamidino) indole ] diphenyl ether was obtained.
Example 15: 4,4' -bis- [2- (6-N- (4-cyclopentylimino-N-cyclopentyl) -diamidino) indole ] diphenyl ether (Compound 6 o)
In example 1, 4' -bis- [2- (6-N- (4-cyclopentylimino-N-Cyclopentyl group)-diamidino) indoles]Diphenyl ether.
Example 16: 4,4' -bis- [2- (6-morpholinyl-diamidino) indole ] diphenyl ether (Compound 6 p)
In example 1, 4' -bis- [2- (6-morpholinyl-diamidino) indole ] diphenyl ether was obtained in a similar manner to example 1, substituting methylamine for morpholine.
Example 17: 4,4' -bis- [2- (6-N-dimethyl-diamidino) indole ] diphenyl ether (Compound 6 q)
In example 1, 4' -bis- [2- (6-N-dimethyl-diamidino) indole ] diphenyl ether was obtained in a similar manner to example 1, except that methylamine was replaced with dimethylamine.
Example 18: 4,4' -bis- [2- (6-N-ethanediyl-diamidino) indole ] diphenyl ether (Compound 6 t)
In example 1, 4' -bis- [2- (6-N-ethanediyl-diamidino) indole ] diphenyl ether was obtained in a similar manner to example 1, substituting methylamine for ethylenediamine, respectively.
Example 19: 4,4' -bis- [2- (6-N-propanediyl-diamidino) indole ] diphenyl ether (Compound 6 u)
In example 1, 4' -bis- [2- (6-N-propanediyl-diamidino) indole ] diphenyl ether was obtained in a similar manner to example 1 except that methylamine was replaced with propylenediamine, respectively.
EXAMPLE 20 3-trifluoromethyl-4, 4' -bis- [2- (6-N-methylamino-diamidino) indole ] diphenyl ether (Compound 7 a)
1) Preparation of 3-trifluoromethyl-4, 4' -bis- [2- (6-cyanoindolyl) ] diphenyl ether
A25 mL three-necked flask was charged with crushed 4-methyl-3-nitrophenylacetonitrile (5.10g, 31.5mmol), 3-trifluoromethyl-4- (4-formylphenoxy) benzaldehyde (15mmol) and 0.6mL of piperidine, and the reaction was stirred at a constant temperature of 130 ℃ for 6 hours under nitrogen protection, and 10mL of ethyl acetate was added thereto while maintaining the stirring rate until a large amount of yellow insoluble matter appeared. After filtration and weighing, 4.1g of a yellow solid was obtained.
To a 250mL three-necked flask was added the yellow solid and 80mL triethyl phosphite and heated to reflux under nitrogen until TCL indicated complete reaction of the starting materials. Stopping heating, and performing column chromatography. The obtained yellow solid is 3-trifluoromethyl-4, 4' -bis- [2- (6-cyanoindolyl) ] diphenyl ether.
2) Preparation of 3-trifluoromethyl-4, 4' -bis- [2- (6-N-isopropylamino-diamidino) indole ] diphenyl ether (Compound 7 a)
To a 100mL three-necked flask was added 3-trifluoromethyl-4, 4' -bis- [2- (6-cyanoindolyl) ] diphenyl ether (0.8g) obtained above, followed by addition of 40mL of tetrahydrofuran and 80mL of absolute ethanol, and the mixture was stirred. After the reaction mixture was reacted overnight under HCl atmosphere, a large amount of insoluble matter was precipitated in a three-necked flask until TCL showed complete reaction of the starting materials. After filtration and weighing, 0.8g of a yellow solid is obtained.
A100 mL three-necked flask was charged with the yellow solid (0.72 mmol), 20mL ethanol, and then 0.42g isopropylamine, and heated to reflux for 2h until TCL indicated complete reaction of the starting materials. Filtering to remove insoluble substances, distilling the filtrate under reduced pressure to 2-3mL, adding about 10-15mL hot acetone to precipitate yellow crystal (first crystallization), washing with diethyl ether to precipitate yellow crystal (second crystallization), evaporating to remove diethyl ether solvent, adding acetone, and stirring to precipitate yellow crystal (third crystallization). Drying to obtain the final product, and performing column chromatography with column chromatography gel.
Example 21: 3-trifluoromethyl-4, 4' -bis- [2- (6-N-isopropylamino-diamidino) indole ] diphenyl ether (Compound 7 b)
In example 20, methylamine was replaced with isopropylamine, respectively, and in a similar manner to example 20, 3-trifluoromethyl-4, 4' -bis- [2- (6-N-isopropylamino-diamidino) indole ] diphenyl ether was obtained.
Example 22: 3-trifluoromethyl-4, 4' -bis- [2- (6-N-dimethylamino-diamidino) indole ] diphenyl ether (Compound 7 c)
In example 20, methylamine was replaced with dimethylamine, respectively, and in a similar manner to example 20, 3-trifluoromethyl-4, 4' -bis- [2- (6-N-dimethylamino-diamidino) indole ] diphenyl ether was obtained.
Example 23: 3-methoxy-4, 4' -bis- [2- (6-N-methylamino-diamidino) indole ] diphenyl ether (Compound 7 d)
1) Preparation of 3-methoxy-4, 4' -bis- [2- (6-cyanoindolyl) ] diphenyl ether
In example 20, 3-methoxy-4, 4' -bis- [2- (6-cyanoindolyl) ] diphenyl ether was obtained by substituting 3-methoxy-4- (4-formylphenoxy) benzaldehyde for 3-trifluoromethyl-4- (4-formylphenoxy) benzaldehyde and by a method similar to example 20.
2) Preparation of 3-methoxy-4, 4' -bis- [2- (6-N-methylamino-diamidino) indole ] diphenyl ether (Compound 7 d)
In example 20, 3-methoxy-4, 4' -bis- [2- (6-cyanoindolyl) ] diphenyl ether was used in place of 3-trifluoromethyl-4, 4' -bis- [2- (6-cyanoindolyl) ] diphenyl ether, and by a method similar to example 20, 3-methoxy-4, 4' -bis- [2- (6-N-methylamino-diamidino) indole ] diphenyl ether was obtained.
Example 24: 3-methoxy-4, 4' -bis- [2- (6-N-isopropylamino-diamidino) indole ] diphenyl ether (Compound 7 e)
In example 20, 3-methoxy-4, 4' -bis- [2- (6-cyanoindolyl) ] diphenyl ether was reacted with isopropylamine in place of 3-trifluoromethyl-4, 4' -bis- [2- (6-cyanoindolyl) ] diphenyl ether, and in a similar manner to example 20, 3-methoxy-4, 4' -bis- [2- (6-N-isopropylamino-diamidino) indole ] diphenyl ether was obtained.
Example 25: 3-methoxy-4, 4' -bis- [2- (6-N-dimethylamino-diamidino) indole ] diphenyl ether (Compound 7 f)
In example 20, 3-methoxy-4, 4' -bis- [2- (6-N-dimethylamino-diamidino) indole ] diphenyl ether was obtained by reacting 3-methoxy-4, 4' -bis- [2- (6-cyanoindolyl) ] diphenyl ether instead of 3-trifluoromethyl-4, 4' -bis- [2- (6-cyanoindolyl) ] diphenyl ether with dimethylamine in a similar manner to example 20.
Example 26: 4,4' -bis- [2- (6-N-methylamino-diamidino) indole ] -3-pyridinylphenyl ether (Compound 7 g)
In example 20, 4' -bis- [2- (6-nitriloindolyl) ] -3-pyridylphenyl ether was reacted with methylamine in place of 3-trifluoromethyl-4, 4' -bis- [2- (6-nitriloindolyl) ] diphenylether to give 4,4' -bis- [2- (6-N-methylamino-diamidino) indole ] -3-pyridylphenyl ether in a similar manner to example 20.
Example 27: 4,4' -bis- [2- (6-N-isopropylamino-diamidino) indole ] -3-pyridinylphenyl ether (Compound 7 h)
In example 20, 4' -bis- [2- (6-nitriloindolyl) ] -3-pyridylphenyl ether was reacted with isopropylamine in place of 3-trifluoromethyl-4, 4' -bis- [2- (6-nitriloindolyl) ] diphenylether to give 4,4' -bis- [2- (6-N-isopropylamino-diamidino) indol ] -3-pyridylphenyl ether in a similar manner to example 20.
Example 28: 4,4' -bis- [2- (6-N-dimethylamino-diamidino) indole ] -3-pyridinylphenyl ether (Compound 7 i)
In example 20, 4' -bis- [2- (6-N-dimethylamino-bisamidamino) indole ] -3-pyridylphenyl ether was obtained by reacting 4,4' -bis- [2- (6-cyanoindolyl) ] -3-pyridylphenyl ether with dimethylamine in place of 3-trifluoromethyl-4, 4' -bis- [2- (6-cyanoindolyl) ] diphenyl ether in a similar manner to example 20.
The compounds of examples 1-28 above were tested to verify structure by MS and HNMR testing, the results of which are shown in table 3 below:
TABLE 3
Antibacterial tests (MIC)
1. Reagents and materials
Test samples: compounds shown in Table 1 and Table 2
Culture medium:
1) MH Agar medium (Mueller Hinton Agar) purchased from china pharmaceutical biologicals institute;
2) MH Broth (Mueller Hinton Broth) medium; purchased from China pharmaceutical biologicals institute;
3) brain Heart Infusion (Brain Heart Infusion) medium, BD company, usa.
Positive control: levofloxacin (Levofloxacin) was purchased from the Chinese institute for drug and biological products.
The test bacteria comprise 36 standard bacteria and clinical isolate preserved in a laboratory.
Quality control bacteria selected from Staphylococcus aureus ATCC29213, enterococcus faecalis ATCC29212, Escherichia coli ATCC25922 and Pseudomonas aeruginosa ATCC 27853.
2. The experimental method comprises the following steps: with reference to CLSI standard, the drug sensitivity experiment was performed by using a two-fold plate dilution method and a Denlay multi-point inoculator.
1) Carrying out enrichment culture on test bacteria by using MH broth or brain-heart infusion, dissolving the medicine by using DMSO, then diluting the medicine by using MH broth to the required concentration, and respectively adding a proper amount of the test bacteria subjected to enrichment culture and the dissolved medicine DMSO into a plate;
2) melting MH agar culture medium, quantitatively injecting into the plate containing the drug DMSO and the experimental bacteria, and mixing uniformly, wherein the final concentration of the sample in the plate is 128, 64 … … 0.06.06 and 0.03 mu g/mL respectively;
3) after the culture medium is solidified, test bacteria (the inoculation amount is 104 cfu/point) are inoculated, the result is observed after the culture is carried out for 18h at the constant temperature of 35 ℃, and the minimum concentration of the drug contained in the plate which grows aseptically is the Minimum Inhibitory Concentration (MIC).
3. Results of the experiment
The results of the antibacterial test (MIC) are shown in Table 4.
Table 4: antibacterial activity of the compounds
The antibacterial activity test data of the compounds 6a-q,6t-u,7a-7i against gram-positive bacteria and gram-negative bacteria are as follows: (MIC: μ g/mL)
a Lflox, levofloxacin.
b Staphylococcus aureus strain ATCC2921,15,09-6.
c methicillin-resistant staphylococcus aureus strain 09-13.
d Staphylococcus epidermidis strain ATCC12228,09-9.
e methicillin-resistant staphylococcus epidermidis strain 09-3.
f enterococcus faecalis strain ATCC29212and09-8.
g enterococcus faecium strain 09-10.
Vancomycin-resistant enterococci, faecalis09-9, faecalis ATCC70022and05-8.
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 baumannii:
ATCC 19606; enterobacter cloacae: 45301, respectively; enterobacter aerogenes: 45102, and (b); serratia marcescens: 41002; morganella morganii:
ATCC 25830; radipidemi sp: ATCC 31052; proteus vulgaris: ATCC 29905; proteus mirabilis:
09-1; salmonella typhi: h901; citric acid bacteria of the species Frondosa: ATCC 43864.
Although specific embodiments of the invention have been described in detail, those skilled in the art will appreciate. Various modifications and substitutions of those details may be made in light of the overall teachings of the disclosure, and such changes are intended to be within the scope of the present invention. The full scope of the invention is given by the appended claims and any equivalents thereof.

Claims (4)

1. An indole ring-containing diamidine derivative is selected from the group consisting of:
7 a: 3-trifluoromethyl-4, 4' -bis- [2- (6-N-methylamino-diamidino) indole ] diphenyl ether;
7 b: 3-trifluoromethyl-4, 4' -bis- [2- (6-N-isopropylamino-diamidino) indole ] diphenyl ether;
7 c: 3-trifluoromethyl-4, 4' -bis- [2- (6-N-dimethylamino-diamidino) indole ] diphenyl ether;
7 d: 3-methoxy-4, 4' -bis- [2- (6-N-methylamino-diamidino) indole ] diphenyl ether;
7 e: 3-methoxy-4, 4' -bis- [2- (6-N-isopropylamino-diamidino) indole ] diphenyl ether;
7 f: 3-methoxy-4, 4' -bis- [2- (6-N-dimethylamino-diamidino) indole ] diphenyl ether.
2. A pharmaceutically acceptable salt of the compound of claim 1.
3. Use of the diamidine derivative containing an indole ring or a pharmaceutically acceptable salt thereof according to claim 1 or 2 for the production of an antibacterial agent.
4. An antibacterial pharmaceutical composition comprising the diamidine derivative containing an indole ring or a pharmaceutically acceptable salt thereof according to claim 1 or 2 as an antibacterial active ingredient, and further comprising pharmaceutically acceptable pharmaceutical excipients.
CN201310452864.2A 2012-09-29 2013-09-27 Two amidine analog derivatives containing indole ring and its preparation method and application Expired - Fee Related CN103524396B (en)

Priority Applications (1)

Application Number Priority Date Filing Date Title
CN201310452864.2A CN103524396B (en) 2012-09-29 2013-09-27 Two amidine analog derivatives containing indole ring and its preparation method and application

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
CN201210375690 2012-09-29
CN201210375690.X 2012-09-29
CN201210375690X 2012-09-29
CN201310452864.2A CN103524396B (en) 2012-09-29 2013-09-27 Two amidine analog derivatives containing indole ring and its preparation method and application

Publications (2)

Publication Number Publication Date
CN103524396A CN103524396A (en) 2014-01-22
CN103524396B true CN103524396B (en) 2018-05-25

Family

ID=49926802

Family Applications (1)

Application Number Title Priority Date Filing Date
CN201310452864.2A Expired - Fee Related CN103524396B (en) 2012-09-29 2013-09-27 Two amidine analog derivatives containing indole ring and its preparation method and application

Country Status (1)

Country Link
CN (1) CN103524396B (en)

Families Citing this family (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2015109496A1 (en) * 2014-01-23 2015-07-30 中国医学科学院医药生物技术研究所 Diamidine derivative containing indole ring and preparation method and use thereof
CN105218427B (en) * 2014-07-01 2018-05-25 中国医学科学院医药生物技术研究所 Two amidine analog derivatives containing double amidino groups indoles benzene and its preparation method and application
WO2017223260A1 (en) * 2016-06-23 2017-12-28 Albert Einstein College Of Medicine, Inc. Pu.1 inhibitors
CN110724087B (en) * 2019-09-29 2021-04-20 西安交通大学 Organic long-afterglow compound and preparation method and application thereof

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2011071849A2 (en) * 2009-12-07 2011-06-16 University Of Georgia Research Foundation, Inc. Pyridinone hydroxycyclopentyl carboxamides: hiv integrase inhibitors with therapeutic applications

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2011071849A2 (en) * 2009-12-07 2011-06-16 University Of Georgia Research Foundation, Inc. Pyridinone hydroxycyclopentyl carboxamides: hiv integrase inhibitors with therapeutic applications

Non-Patent Citations (4)

* Cited by examiner, † Cited by third party
Title
Inhibitory activity of diarylamidine derivatives on murine leukemia LI210 cell growth;Jan Balzarini，等;《[nvestigational New Drugs》;19831231;第1卷;第103-115页 *
Synthesen antimikrobieller biskationischer 2-(Phenoxypheny1)-indole und -1-benzofurane;Otto Dann，等;《LIEBIGS ANNALEN DER CHEMIE》;19841231;第3卷;第409-425页 *
Synthesis and structure–activity relationship of dicationic diaryl ethers as novel potent anti-MRSA and anti-VRE agents;Laixing Hua，等;《Bioorganic & Medicinal Chemistry Letters》;20090625;第19卷;第4626–4629页 *
新一代抗MRSA 抗生素的临床研究进展;顾觉奋，等;《抗感染药学》;20091231;第6卷(第4期);第223-228页 *

Also Published As

Publication number Publication date
CN103524396A (en) 2014-01-22

Similar Documents

Publication Publication Date Title
CN103524396B (en) Two amidine analog derivatives containing indole ring and its preparation method and application
KR101720885B1 (en) Prodrug derivatives of (e)-n-methyl-n-((3-methylbenzofuran-2-yl)methyl)-3-(7-oxo-5,6,7,8-tetrahydro-1,8-naphthyridin-3-yl)acrylamide
WO2008041966A2 (en) Broad spectrum antibacterial compounds
Pahlavani et al. A study on antitubercular and antimicrobial activity of isoniazid derivative
CN104211708B (en) Benzoxazinone derivatives and its application as antiseptic
CN113350336A (en) Application of heptamethine indocyanine or derivative thereof
CN112645897A (en) Thiazole derivative and preparation method and application thereof
Darehkordi et al. Synthesis of N-aryl-2, 2, 2-trifluoroacetimidoyl piperazinylquinolone derivatives and their antibacterial evaluations
CN104529915A (en) Quinoxalinone analog with DNA (deoxyribonucleic acid) topoismerase II inhibiting activity, and preparation method and application thereof
JP7339288B2 (en) A set of glycopeptide compounds with antidrug-resistant bacterial activity, their preparation methods and applications
JPS5951537B2 (en) Method for producing novel α-aminooxycarboxylic acid hydrazide derivative
CN105218427B (en) Two amidine analog derivatives containing double amidino groups indoles benzene and its preparation method and application
CN110049973B (en) 1, 4-diphenyl-1H-imidazole and 2, 4-diphenyl thiazole derivatives, and preparation method and application thereof
Khan et al. Synthesis, antibacterial, and antifungal evaluation of norfloxacin derivatives
AU2015287661A1 (en) Main chain polyamines
WO2009121304A1 (en) Preparation of ulifloxacin optical isomer
Pahlavani et al. Synthesis, Characterization, and Study of Anti-Tubercular and Anti-Microbial Activity of Isonicotinohydrazide Tridentate Schiff Base Ligands
Aiswarya et al. Synthesis and anti-microbial activity of novel mannich bases containing 2-phenoxy-1, 3, 2-dioxa phospholanes and Indole systems
Ajjah et al. Design, synthesis, docking study and preliminary pharmacological assessment of new norfloxacin analogues having thiazole nucleus
TWI680983B (en) The l-proline complex, monohydrate and crystal of a sodium-glucose contransporter 2 inhibitor
CN108947961B (en) Indazole derivative and preparation method and application thereof
CN107602465A (en) A kind of carbostyril derivative and its application
WO2015109496A1 (en) Diamidine derivative containing indole ring and preparation method and use thereof
CN113045494B (en) Pyridone derivative and application thereof in preparation of drugs for preventing and/or treating tuberculosis caused by mycobacterium tuberculosis
CN110981888A (en) N-aryl dithiopyrryl ketonuria and amino ester derivatives, preparation and application thereof

Legal Events

Date Code Title Description
C06 Publication
PB01 Publication
EXSB Decision made by sipo to initiate substantive examination
SE01 Entry into force of request for substantive examination
GR01 Patent grant
GR01 Patent grant
CF01 Termination of patent right due to non-payment of annual fee
CF01 Termination of patent right due to non-payment of annual fee

Granted publication date: 20180525

Termination date: 20210927