CN105272903A - Series of fluorine-containing carbazole compounds and preparation method and application thereof - Google Patents

Series of fluorine-containing carbazole compounds and preparation method and application thereof Download PDF

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CN105272903A
CN105272903A CN201510788567.4A CN201510788567A CN105272903A CN 105272903 A CN105272903 A CN 105272903A CN 201510788567 A CN201510788567 A CN 201510788567A CN 105272903 A CN105272903 A CN 105272903A
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fluorine
containing carbazole
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CN105272903B (en
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曹昌盛
周生亮
史延慧
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Jiangsu Normal University
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    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
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    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • A61K31/403—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil condensed with carbocyclic rings, e.g. carbazole
    • 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
    • C07D209/56—Ring systems containing three or more rings
    • C07D209/80—[b, c]- or [b, d]-condensed
    • C07D209/82—Carbazoles; Hydrogenated carbazoles
    • C07D209/86—Carbazoles; Hydrogenated carbazoles with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to carbon atoms of the ring system
    • 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
    • C07D209/56—Ring systems containing three or more rings
    • C07D209/80—[b, c]- or [b, d]-condensed
    • C07D209/82—Carbazoles; Hydrogenated carbazoles
    • C07D209/88—Carbazoles; Hydrogenated carbazoles with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to carbon atoms of the ring system
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Abstract

The invention discloses a series of fluorine-containing carbazole compounds and a preparation method and application thereof, and belongs to the field of organic chemistry, medicinal chemistry and drug intermediates. The series of fluorine-containing carbazole compounds are obtained through a catalytic C-C key coupling reaction, and the general structural formula of the series of fluorine-containing carbazole compounds is shown in the specification. As is shown in in-vitro experiments, part of the compounds have the activity of inhibiting escherichia coli and klebsiella pneumoniae carrying NDM-1 drug-resistant genes, methicillin-resistant staphylococcus aureus (MRSA) and other superbacteria strains. Lead compounds are provided for developing antibacterial drugs of a completely new structure, the synthesis method is simple, the production cost is low, and the series of fluorine-containing carbazole compounds have great development value and broad application prospects.

Description

Series fluorosurfactants carbazole compound and its preparation method and application
Technical field
The invention belongs to organic chemistry, pharmaceutical chemistry and pharmaceutical intermediate field, be specifically related to series fluorosurfactants carbazole compound and its preparation method and application.
Background technology
Bacterial drug resistance is worldwide on the rise and complexity, and " superbacteria " with Multiresistant genes continues to bring out, and brings huge challenge to the treatment of bacterial infection disease.Continue methicillin-resistant staphylococcus aureus (Methicillin-resistantStaphylococcusaureus, be abbreviated as MRSA), vancomycin-resistant enterococcus (Vancomycin-resistantEnterococcusspp., be abbreviated as VRE), after the multi-drug resistant bacterias such as multiple-drug resistance tuberculosis bacillus (Mycobacteriumtuberculosis) occur, in August, 2010 world-renowned medical journal " TheLancetInfectiousDiseases " (" lancet-transmissible disease ") reports one and carries " New Delhi metal-beta-lactamase-1 " (NewDelhimetallo-β-lactamase-1, be abbreviated as NDM-1) novel " superbacteria " of drug resistant gene, " superbacteria " should can tolerate microbiotic all except polymyxin (colistin) and Tigecycline (tigecycline), and polymyxin has larger toxic side effect, the indication of Tigecycline is very limited, under-18s patient is inapplicable.This drug resistant gene transmits between heterologous bactericidal by plasmid, thus makes its fast propagation and spread.Alive boundary is multinational is in succession found for this type of bacterium, and comprise India, Pakistan, Britain, the U.S., Canada and the country such as Australian, China also announces to detect the bacterial strain carrying NDM-1 drug resistant gene in October, 2010.Carry the appearance of " superbacteria " of NDM-1 drug resistant gene and report to cause people and shake greatly and pay close attention to, research and development new antibiotic is extremely urgent.
Current listing or the new antibiotic that is in clinical development be all that structural modification is carried out to existing microbiotic substantially, parent nucleus and original medicine of these new drugs are same or similar, corresponding resistant organism often occurs very soon, sometimes a medicine is still in development, and corresponding drug resistant gene and Resistant strain just produce.People also make great efforts the microbiotic of research and development brand new always from multiple approach, but over nearly 40 years, almost do not have the Broad spectrum antibiotics of brand new to go on the market in world wide.
At present, the compound of fluorine-containing carbazoles is not a lot, on the phenyl ring of carbazole structure side, wherein contain nearly 2000 kinds of the compound of a fluorine atom, containing nearly 100 kinds of the compound of two fluorine atoms on the phenyl ring of side, compound containing three fluorine atoms on the phenyl ring of side have not been reported, containing nearly 20 kinds of the compound of four fluorine atoms on the phenyl ring of side.Quite a few is had to be the carbazole of symmetrical configuration in these known fluorochemicalss, namely on the phenyl ring of carbazole structure both sides, contain fluorine atom identical on position with number, this is because the carbazole of this kind of symmetry is easier in synthesis relative to asymmetric carbazole.
Summary of the invention
The invention provides series fluorosurfactants carbazole compound and its preparation method and application, serial fluorine substituted carbazole compounds majority of the present invention is asymmetric carbazole, antibacterial experiment in vitro shows, part of compounds of the present invention has the activity of the bacterial strains such as suppression wild-type e. coli (Escherichiacoli), streptococcus aureus and subtilis (Bacillussubtilis).More importantly, part of compounds of the present invention have suppress carry the intestinal bacteria of NDM-1 drug resistant gene and the biological activity of Klebsiella Pneumoniae (Klebsiellapneumoniae) and MRSA etc. " superbacteria ".Preliminary toxicological experiment shows, the LD with the Compound II per d of better bacteriostatic activity that choosing is surveyed 50>1000mg/Kg, the LD of Compound II per l 50for 595mg/Kg.The present invention is the antibacterials of development brand new, and particularly suppress the medicine carrying " superbacteria " of NDM-1 drug resistant gene to provide lead compound, its synthetic method is simple, and production cost is low, has higher Development volue and application prospect.
The object of the invention is to be achieved through the following technical solutions:
A series of fluorine-containing carbazole compound and pharmaceutically acceptable salt, ester, acid amides or prodrug, its general structure for shown in formula 1,
R 0for any one in following listed group:
R 1~ R 8for any one in following listed group, R 1~ R 4substituting group has one at least for F atom: H, F, Cl, Br, I, OTf, OTs, OH, Y, OY, CH 2cH 3, CF 3, COOH, NO 2, NH 2, NHY, NY 2, CONH 2, CONHY, CONHNH 2,
Described a series of fluorine-containing carbazole compound and pharmaceutically acceptable salt, ester, acid amides or prodrug, preferably, on the right side of it on phenyl ring only containing a fluorine atom, their general structure for shown in formula 2,
General formula 2 is further divided into two kinds of situations:
Situation one, R ≠ CH in formula 2 3; R 0=H; M=1-4;
R 1-2be any one of following listed group with R:
H,Cl,Br,I,OTf,OTs,OH,Y,OY,CH 2CH 3,CF 3,COOH,NO 2,NH 2,NHY,NY 2,CONH 2,CONHY,
R mfor any one of following listed group:
Situation two, R=CH in formula 2 3and the C4 of right side phenyl ring is connected with F substituting group;
R 1-2＝R 1～R 8；m＝1-4；
R 0for any one of following listed group:
R mfor any one of following listed group:
F,Cl,Br,I,OTf,OTs,OH,Y,OY,CH 2CH 3,CF 3,COOH,NO 2,NH 2,NHY,NY 2,CONH 2,CONHY,CONHNH 2,
Described a series of fluorine-containing carbazole compound and pharmaceutically acceptable salt, ester, acid amides or prodrug, preferably, on the right side of it on phenyl ring only containing two fluorine atoms, their general structure for shown in formula 3,
General formula 3 is further divided into two kinds of situations:
Situation one, two F substituting groups in formula 3 on the phenyl ring of right side are not connected on C2 and C4 position simultaneously;
R 0＝H；R 1-2＝R 1～R 8；m＝1-4；
R mfor any one of following listed group:
Cl,Br,I,OTf,OTs,Y,OY,CH 2CH 3,CF 3,COOH,NO 2,NH 2,NHY,NY 2,CONH 2,CONHY,
Situation two, two F substituting groups in formula 3 on the phenyl ring of right side are connected on C2 and C4 position;
R 1-2＝R 1～R 8；m＝1-4；
R 0for any one of following listed group:
R mfor any one of following listed group:
H,Cl,Br,I,OTf,OTs,OH,Y,OY,CH 2CH 3,CF 3,COOH,NO 2,NH 2,NHY,NY 2,CONH 2,CONHY,CONHNH 2,
Described a series of fluorine-containing carbazole compound and pharmaceutically acceptable salt, ester, acid amides or prodrug, preferably, on the right side of it, phenyl ring only contains three their general structures of fluorine atom for shown in formula 4,
Wherein R=R 1~ R 8; R m=R 1~ R 8; M=1-4;
R 0for any one of following listed group:
Described a series of fluorine-containing carbazole compound and pharmaceutically acceptable salt, ester, acid amides or prodrug, preferably, on the right side of it on phenyl ring containing four fluorine atoms, their general structure for shown in formula 5,
Wherein R 0=H; R 1-2=R 1~ R 8; M=1-4;
R mfor any one of following listed group:
Cl,Br,I,OTf,OTs,OH,Y,OY,CH 2CH 3,CF 3,COOH,NO 2,NH 2,NHY,NY 2,CONH 2,CONHY,
As the compounds of general structure 2 only containing a fluorine atom, structural formula is as general formula 6, and in formula, 1 and 4 of right side phenyl ring is respectively methyl and fluoro substituents, 2 and 3 nothing replacements or have other substituting groups,
Wherein R 1-2=R 1~ R 8; M=1-4;
R 0for any one of following listed group:
R mfor any one of following listed group:
F,Cl,Br,I,OTf,OTs,OH,Y,OY,CH 2CH 3,CF 3,COOH,NO 2,NH 2,NHY,NY 2,CONH 2,CONHY,CONHNH 2,
The structure of four kinds of compounds of concrete synthesis is such as formula 10.
As a compounds of the general structure 3 only containing two fluorine atoms, structural formula is as general formula 7.In formula, 2 and 4 of right side phenyl ring are respectively two fluoro substituents,
Wherein R 1-2=R 1~ R 8; M=1-4;
R 0for any one of following listed group:
R mfor any one of following listed group:
H,Cl,Br,I,OTf,OTs,OH,Y,OY,CH 2CH 3,CF 3,COOH,NO 2,NH 2,NHY,NY 2,CONH 2,CONHY,CONHNH 2,
The structure of 15 kinds of compounds of concrete synthesis is such as formula 11.
As the compounds of general structure 4 only containing three fluorine atoms, structural formula is as general formula 8.In formula, 1,3 and 4 of right side phenyl ring is three fluoro substituents,
wherein m=1-4; R morR=R 1~ R 8.
Wherein R=R 1~ R 8; R m=R 1~ R 8; M=1-4;
R 0for any one of following listed group:
The structure of 7 kinds of compounds of concrete synthesis is such as formula 12.
The invention still further relates to a kind of method preparing above-mentioned fluorine-containing carbazole compound, step is as follows:
Take the diarylamine of 1mmol, the sodium tert-butoxide of 2.5mmol, the palladium of 0.5mol%, the cuprous iodide of 20mol% joins in the flat bottle of 4mL containing stirrer, screws the bottle cap with holes with tetrafluoroethylene pad.Add 0.8mL dioxane as solvent with syringe, bottle is placed in the hole of heating plate, be heated to 120 DEG C and keep 10h.After bottle is taken out from the hole of heating plate, be cooled to room temperature, go out reaction with shrend.Use dichloromethane extraction product, anhydrous sodium sulfate drying solution.Be spin-dried for solvent, be separated with column chromatography method, developping agent is the sherwood oil of 30-60 DEG C and the mixed solvent of ether, and volume ratio is 10:1.Obtain corresponding pure products, reaction equation is shown in formula 9.
The invention still further relates to the application of fluorine-containing carbazole compound in preparation suppression microbial medicine of a series of above-mentioned formula.The kind of the described microorganism suppressed by this compounds includes but not limited to carry intestinal bacteria and Klebsiella Pneumoniae and MRSA etc. " superbacteria " bacterial strain of NDM-1 drug resistant gene and the bacterial strain such as wild-type e. coli, streptococcus aureus and subtilis.
Work of the present invention obtains project of national nature science fund project (NSFC31300067,21071121,21172188 and 21571087), the subsidy of Jiangsu College physicism major project (15KJA150004,15KJA180002).
Beneficial effect
The invention provides fluorine-containing carbazoles new compound and synthetic method thereof and application.Part of compounds of the present invention has the activity suppressing the bacterial strains such as wild-type e. coli, streptococcus aureus, subtilis.More importantly, part of compounds of the present invention has suppression and carries the intestinal bacteria of NDM-1 gene and the activity of Klebsiella Pneumoniae and MRSA etc. " superbacteria ", its bacteriostatic activity is better, toxicity is lower, have and be developed further into the antibiotic potential quality of brand new, for the antibiotic synthesis of brand new provides lead compound, also can be applicable to the synthesis of pharmaceutical intermediate.Compou nd synthesis method of the present invention is simple, and production cost is low, has higher Development volue and application prospect.
Embodiment
Below in conjunction with specific embodiment, the present invention is described in further detail, but these embodiments are only exemplary, protection scope of the present invention is not limited to following embodiment.Those of ordinary skill in the art is easy to make various replacement, amendment or change according to illustrating to the present invention herein, and these replacements, amendment or change are all in protection scope of the present invention.
Embodiment 1: the synthesis of 6-ethyl-4-fluoro-1-methyl-9H-carbazole (Ic) in formula 2
Chemical equation:
Experimentation: the bromo-4-ethyl of 2--N-(the 5-fluoro-2-methylbenzene base) aniline taking 0.3082g (1mmol), the sodium tert-butoxide of 0.2403g (2.5mmol), the palladium of 1.123mg (0.5mol%), the cuprous iodide of 38.09mg (20mol%) joins in the flat bottle of 4mL containing stirrer, screws the bottle cap with holes with tetrafluoroethylene pad.Add 0.8mL dioxane as solvent with syringe, bottle is placed in the hole of heating plate, be heated to 120 DEG C and keep 10h.After bottle is taken out from the hole of heating plate, be cooled to room temperature, go out reaction with shrend.Use dichloromethane extraction product, anhydrous sodium sulfate drying solution.Be spin-dried for solvent, column chromatography (developping agent is mixed solvent, 30-60 DEG C of sherwood oil: ether=10:1), obtains corresponding pure product.Productive rate 88%.
The characterization data of product: MP127.1-130.1 DEG C. 1hNMR (400MHz, CDCl 3): δ=8.03 (s, 1H), 7.92 (br, 1H), 7.39-7.26 (m, 2H), 7.10 (dd, J 1=7.2Hz, J 2=5.2Hz, 1H), 6.82 (dd, J 1=10.4Hz, J 2=8.4Hz, 1H), 2.85 (q, J=7.6Hz, 2H), 2.50 (s, 3H), 1.36 (J=7.6Hz, 3H). 13cNMR (100MHz, CDCl 3): δ=157.2 (d, J=244.1Hz), 140.9 (d, J=10.5Hz), 137.4,136.4,126.5 (d, J=7.9Hz), 126.3,121.8 (d, J=3.3Hz), 121.6 (d, J=2.1Hz), 115.3 (d, J=3.7Hz), 111.2 (d, J=20.8Hz), 110.4,104.9 (d, J=18.9Hz), 29.1,16.7,16.4. 19fNMR (376MHz, CDCl 3): δ=-123.6.Anal.Calc.forC 15h 14fN (227.28g/mol): C, 79.27; H, 6.21; N, 6.16; Found:C, 79.01; H, 6.18; N, 6.19%.
Embodiment 2: the synthesis of the fluoro-1-methyl of 4--7-(trifluoromethyl)-9H-carbazole (Id) in formula 2
Chemical equation:
Experimentation: the bromo-N-of 2-(5-fluoro-2-methylbenzene base)-5-(trifluoromethyl) aniline taking 0.3481g (1mmol), the sodium tert-butoxide of 0.2403g (2.5mmol), the palladium of 1.123mg (0.5mol%), the cuprous iodide of 38.09mg (20mol%) joins in the flat bottle of 4mL containing stirrer, screws the bottle cap with holes with tetrafluoroethylene pad.Add 0.8mL dioxane as solvent with syringe, bottle is placed in the hole of heating plate, be heated to 120 DEG C and keep 10h.After bottle is taken out from the hole of heating plate, be cooled to room temperature, go out reaction with shrend.Use dichloromethane extraction product, anhydrous sodium sulfate drying solution.Be spin-dried for solvent, column chromatography (developping agent is mixed solvent, the sherwood oil of 30-60 DEG C: ether=10:1 (v:v)), obtains corresponding pure products 0.2325mg.Productive rate 87%.
The characterization data of product: MP161.5-163.0 DEG C. 1hNMR (400MHz, CDCl 3): δ=8.26 (d, J=8.0Hz, 1H), 8.19 (br, 1H), 7.72 (s, 1H), 7.51 (d, J=8.0Hz, 1H), 7.20 (m, 1H), 6.87 (dd, J=10.0Hz, J=8.0Hz, 1H), 2.54 (s, 3H). 13cNMR (100MHz, CDCl 3): δ=157.3 (d, J=246.1Hz), 141.3 (d, J=9.6Hz), 138.1,128.1 (d, J=8.0Hz), 127.8 (d, J=31.7Hz), 124.8 (q, J=270.3Hz), 124.0,123.3 (d, J=3.4Hz), 117.0 (q, J=3.6Hz), 115.8 (d, J=4.0Hz), 110.7 (d, J=20.8Hz), 107.9 (q, J=4.4Hz), 105.8 (d, J=18.6Hz), 16.3. 19fNMR (376MHz, CDCl 3): δ=-61.1 ,-122.5.
The carbazole that right side phenyl ring used by embodiment 8 bacteriostatic activity test is connected with a fluorine atom has 4 kinds, and their structure and code name are such as formula 10.Ia-Id is new compound.Embodiment 1-2 sets forth the synthetic method of carbazole Ic, Id, the available identical method of synthesis of Ia with Ib, does not just specifically provide their synthesis step and characterization data here.The preparation of the main raw material (the fluorine-containing pentanoic namely replaced) used in above-mentioned synthetic method can reference X.Kong, H.Zhang, Y.Xiao, C.Cao, Y.Shi, G.Pang, RSCAdv., 2015,5,7035 – 7048.
Embodiment 3: the synthesis of 2,4-bis-fluoro-7-methyl-9H-carbazole (IIa) in formula 3
Chemical equation:
Experimentation: the bromo-N-(3 of 2-taking 0.2981g (1mmol), 5-difluorophenyl)-5-monomethylaniline, the sodium tert-butoxide of 0.2403g (2.5mmol), the palladium of 1.123mg (0.5mol%), the cuprous iodide of 38.09mg (20mol%) joins in the flat bottle of 4mL containing stirrer, screws the bottle cap with holes with tetrafluoroethylene pad.Add 0.8mL dioxane as solvent with syringe, bottle is placed in the hole of heating plate, be heated to 120 DEG C and keep 10h.After bottle is taken out from the hole of heating plate, be cooled to room temperature, go out reaction with shrend.Use dichloromethane extraction product, anhydrous sodium sulfate drying solution.Be spin-dried for solvent, column chromatography (developping agent is mixed solvent, the sherwood oil of 30-60 DEG C: ether=10:1 (v:v)), obtains corresponding pure products 197.7mg.Productive rate 91%.
The characterization data of product: MP133.6-134.0 DEG C. 1hNMR (400MHz, CDCl 3): δ=8.01 (br, 1H), 7.98 (d, J=8.0Hz, 1H), 7.17 (s, 1H), 7.08 (d, J=8.0Hz, 1H), 6.86 (dd, J 1=9.2Hz, J 2=2.0Hz, 1H), 6.66 (td, J 1=10.0Hz, J 2=2.0Hz, 1H), 2.50 (s, 3H). 13cNMR (100MHz, CDCl 3): δ=161.5 (dd, J 1=241.0Hz, J 2=6.0Hz), 157.9 (dd, J 1=249.0Hz, J 2=7.5Hz), 141.2 (dd, J 1=15.0Hz, J 2=13.0Hz), 139.9 (d, J=2.0Hz), 136.2 (s), 122.2,122.1,118.6,110.7,108.6 (dd, J 1=21.0Hz, J 2=2.0Hz), 95.3 (dd, J 1=28.0Hz, J 2=23.0Hz), 93.6 (dd, J 1=27.0Hz, J 2=4.0Hz), 22.2. 19f{ 1h}NMR (376MHz, CDCl 3): δ=-113.8 (d, J=3.8Hz) ,-116.4 (d, J=7.5Hz) .HRMS (ESI): m/z [M+H] +calcforC 12h 6f 5n260.0499, found260.0501.Anal.Calc.forC 35h 38cl 4n 6pd 2(897.37g/mol): C, 46.85; H, 4.27; N, 9.37.Found:C, 46.27; H, 3.79; N, 9.89%.
Embodiment 4: the synthesis of 2,4-bis-fluoro-9H-carbazoles (IIb) in formula 3
Chemical equation:
Experimentation: the N-(2-bromophenyl)-3 taking 0.2841g (1mmol), 5-difluoroaniline, the sodium tert-butoxide of 0.2403g (2.5mmol), the palladium of 1.123mg (0.5mol%), the cuprous iodide of 38.09mg (20mol%) joins in the flat bottle of 4mL containing stirrer, screws the bottle cap with holes with tetrafluoroethylene pad.Add 0.8mL dioxane as solvent with syringe, bottle is placed in the hole of heating plate, be heated to 120 DEG C and keep 10h.After bottle is taken out from the hole of heating plate, be cooled to room temperature, go out reaction with shrend.Use dichloromethane extraction product, anhydrous sodium sulfate drying solution.Be spin-dried for solvent, column chromatography (developping agent is mixed solvent, the sherwood oil of 30-60 DEG C: ether=10:1 (v:v)), obtains corresponding pure products 195.1mg.Productive rate 96%.
The characterization data of product: MP110.1-111.2 DEG C. 1hNMR (400MHz, CDCl 3): δ=8.14 (br, 1H), 8.11 (d, J=8.0Hz, 1H), 7.43-7.37 (m, 2H), 7.29-7.24 (m, 1H), 6.89 (dd, J 1=8.8Hz, J 2=2.0Hz, 1H), 6.68 (td, J 1=10.0Hz, J 2=2.0Hz, 1H). 13cNMR (100MHz, CDCl 3): δ=161.8 (dd, J 1=241.0Hz, J 2=12.0Hz), 158.2 (dd, J 1=249.0Hz, J 2=16.0Hz), 141.2 (dd, J 1=14.0Hz, J 2=13.0Hzm), 139.4 (d, J=2.0Hz), 126.0 (s), 122.6 (d, J=3.0Hz), 120.8 (s), 120.7 (m), 110.6 (s), 108.7 (dd, J 1=20.0Hz, J 2=2.0Hz), 95.5 (dd, J 1=28.0Hz, J 2=23.0Hz), 93.7 (dd, J 1=27.0Hz, J 2=4.0Hz). 19f{ 1h}NMR (376MHz, CDCl 3): δ=-112.9 (d, J=3.8Hz) ,-115.9 (d, J=7.5Hz) .Anal.Calc.forC 12h 7f 2n (203.18g/mol): C, 70.93; H, 3.47; N, 6.89; Found:C, 71.34; H, 3.43; N, 6.82%.
Embodiment 5: the synthesis of 2,4,7-tri-fluoro-9H-carbazoles (IId) in formula 3
Chemical equation:
Experimentation: the bromo-N-(3 of 2-taking 0.3021g (1mmol), 5-difluorophenyl)-5-fluoroaniline, the sodium tert-butoxide of 0.2403g (2.5mmol), the palladium of 1.123mg (0.5mol%), the cuprous iodide of 38.09mg (20mol%) joins in the flat bottle of 4mL containing stirrer, screws the bottle cap with holes with tetrafluoroethylene pad.Add 0.8mL dioxane as solvent with syringe, bottle is placed in the hole of heating plate, be heated to 120 DEG C and keep 10h.After bottle is taken out from the hole of heating plate, be cooled to room temperature, go out reaction with shrend.Use dichloromethane extraction product, anhydrous sodium sulfate drying solution.Be spin-dried for solvent, column chromatography (developping agent is mixed solvent, the sherwood oil of 30-60 DEG C: ether=10:1 (v:v)), obtains corresponding pure products 192.4mg.Productive rate 87%.
The characterization data of product: MP111.5-112.8 DEG C. 1hNMR (400MHz, CDCl 3): δ=8.16 (br, 1H), 7.79 (dd, J 1=8.8Hz, J 2=2.4Hz, 1H), 7.34 (dd, J 1=8.8Hz, J 2=4.0Hz, 1H), 7.16 (td, J 1=9.2Hz, J 2=2.4Hz, 1H), 6.92 (dd, J 1=9.2Hz, J 2=2.0Hz, 1H), 6.70 (td, J 1=10.0Hz, J 2=2.0Hz, 1H). 13cNMR (100MHz, CDCl 3): δ=161.8 (d, J=241.0Hz), 161.5 (dd, J 1=213.9Hz, J 2=12.2Hz), 157.7 (dd, J=248.7Hz, J=15.0Hz), 141.6 (m), 140.0 (dd, J=125.0Hz, J=1.6Hz), 123.4 (dd, J 1=10.3Hz, J 2=3.0Hz), 117.0,108.8 (d, J=23.9Hz), 97.6 (d, J=26.7Hz), 95.8 (dd, J 1=28.0Hz, J 2=23.2Hz), 93.8 (dd, J 1=26.6Hz, J 2=4.2Hz). 19f{ 1h}NMR (376MHz, CDCl 3): δ=-113.2 (d, J=6.4Hz) ,-115.1 ,-116.6 (d, J=6.4Hz) .Anal.Calc.forC 12h 6f 3n (221.18g/mol): C, 65.16; H, 2.73; N, 6.33; Found:C, 64.87; H, 2.71; N, 6.42%.
Embodiment 6: in formula 3, the synthesis of N, N-dimethyl-3-(the fluoro-9H-carbazole of 2,4,7-tri--9-base)-1-propylamin hydrochloride (IIn)
Chemical equation:
Claim 2,4, the 7-tri-fluoro-9H-carbazoles of 0.2212g (1mmol) to be dissolved in 10mLDMF, then add the NaH (60%inoil) of 0.14g (3.47mmol), stir 10min.In this system, add the chloro-1-of 3-(N, N-dimethyl) propylamin hydrochloride (0.16g, 1.01mmol) again, be warmed up to 50 DEG C, then react 2.5h.Then pour in frozen water by reaction solution, with DCM extraction, anhydrous sodium sulfate drying, is spin-dried for and obtains liquid 0.306g, productive rate 100%.
By N, N-dimethyl-3-(2,4 obtained above, the fluoro-9H-carbazole of 7-tri--9-base)-1-propylamine (0.306g, 1mmol) is dissolved in the methanol hydrochloride solution of 6mL0.2M, is spin-dried for after stirring 1h, add washed with diethylether, obtain white solid 0.308g, productive rate is 90%.
The characterization data of product: MP217.8-219.6 DEG C, 1hNMR (400MHz, DMSO): δ=7.75 (dd, J 1=8.8Hz, J 2=2.4Hz, 1H), 7.68 (dd, J 1=8.8Hz, J 2=4.0Hz, 1H), 7.45-7.34 (m, 2H), 7.02 (m, 1H), 4.40 (t, J=6.8Hz, 2H), 2.17 (t, J=6.8Hz, 2H), 2.13 (s, 6H), 1.88 (m, 2H). 13cNMR (100MHz, DMSO): δ=162.6,162.5,158.4,158.3,158.1,156.0,155.8,142.8 (dd, J 1=15.0Hz, J 2=12.5Hz), 136.8,119.2 (d, J=10.7Hz), 113.5 (d, J=25.0Hz), 110.8 (d, J=9.3Hz), 107.1 (dd, J 1=23.8Hz, J 2=2.3Hz), 55.6,44.9,40.8,26.1. 19fNMR (376MHz, DMSO): δ=-111.4 (d, J=6.8Hz) ,-116.4 (d, J=6.8Hz) ,-123.4.Anal.Calc.forC 17h 18clF 3n 2(342.79g/mol): C, 59.57; H, 5.29; N, 8.17; Found:C, 59.89; H, 5.32; N, 8.20%.
The carbazole and the hydrochloride thereof that right side phenyl ring used by embodiment 8 bacteriostatic activity test are connected with two fluorine atoms have 15 kinds, and their structure and code name are such as formula 11.All IIa-IIo are new compound.Embodiment 3-6 sets forth the synthetic method of carbazole IIa, IIb, IId, IIn, IIc, IIe-IIm identical method available with the synthesis of IIo, does not just specifically provide their synthesis step and characterization data here.The preparation of the main raw material (the fluorine-containing pentanoic namely replaced) used in above-mentioned synthetic method can reference X.Kong, H.Zhang, Y.Xiao, C.Cao, Y.Shi, G.Pang, RSCAdv., 2015,5,7035 – 7048.
Embodiment 7: the synthesis of 1,3,4-tri-fluoro-6-methyl-9H-carbazole (IIIa) in formula 4
Chemical equation:
Experimentation: the N-(the bromo-4-aminomethyl phenyl of 2-)-2 taking 0.3161g (1mmol), 4,5-trifluoromethyl aniline, the sodium tert-butoxide of 0.2403g (2.5mmol), the palladium of 1.123mg (0.5mol%), the cuprous iodide of 38.09mg (20mol%) joins in the flat bottle of 4mL containing stirrer, screws the bottle cap with holes with tetrafluoroethylene pad.Add 0.8mL dioxane as solvent with syringe, bottle is placed in the hole of heating plate, be heated to 120 DEG C and keep 10h.After bottle is taken out from the hole of heating plate, be cooled to room temperature, go out reaction with shrend.Use dichloromethane extraction product, anhydrous sodium sulfate drying solution.Be spin-dried for solvent, column chromatography (developping agent is mixed solvent, the sherwood oil of 30-60 DEG C: ether=10:1 (v:v)), obtains corresponding pure products 0.2046mg.Productive rate 87%.
The characterization data of product: MP140.5-141.7 DEG C. 1hNMR (400MHz, CDCl 3): δ=7.98 (br, 1H), 7.94 (s, 1H), 7.31 (d, J=1.2Hz, 2H), 7.00 (td, J=10.4Hz, J=6.0Hz, 1H), 2.53 (s, 3H). 13cNMR (100MHz, CDCl 3): δ=143.1 (ddd, J 1=240.1Hz, J 2=10.7Hz, J 3=2.9Hz), 142.6 (ddd, J 1=236.8Hz, J 2=13.0Hz, J 3=10.2Hz), 141.9 (ddd, J 1=244.2Hz, J 2=14.3Hz, J 3=4.1Hz), 137.9,130.2,128.9,124.8 (dd, J 1=15.2Hz, J 2=9.0Hz), 122.8 (d, J=3.1Hz), 121.2 (m), 114.8 (m), 110.8,101.3 (dd, J 1=24.2Hz, J 2=23.1Hz), 21.4. 19fNMR (376MHz, CDCl 3): δ=-137.5 (dd, J 1=19.2Hz, J 2=1.5Hz) ,-148.8 (dd, J 1=21.1Hz, J 2=1.9Hz) ,-150.8 (t, J=20.7Hz).
Carbazole right side phenyl ring used by embodiment 8 bacteriostatic activity test being connected with three fluorine atoms has 7 kinds, and their structure and code name are such as formula 12.All IIIa-IIIg are new compound.Embodiment 7 gives the synthetic method of carbazole IIIa, the available identical method of synthesis of IIIb-IIIg, does not just specifically provide their synthesis step and characterization data here.The preparation of the main raw material (the fluorine-containing pentanoic namely replaced) used in above-mentioned synthetic method can reference X.Kong, H.Zhang, Y.Xiao, C.Cao, Y.Shi, G.Pang, RSCAdv., 2015,5,7035 – 7048.
Embodiment 8: the experiment of In Vitro Bacteriostatic
One, experimental technique (micro-meat soup doubling dilution)
1) bacterial classification: the experiment bacteria culture information related to is as shown in table 1
Table 1 antibacterial experiment in vitro relates to the relevant information of bacterium
2) activation of bacterial classification: each bacterial classification is taken out from-80 DEG C of refrigerators, streak inoculation (is wherein cultivated in the LB flat board of 18H2,18H4 and 18H5 bacterial strain containing the penbritin that final concentration is 100 μ g/mL) on Luria-Bertani (LB) flat board respectively, and horizontalization plate is incubated overnight in 37 DEG C of incubators.
3) preparation of bacterium liquid: picking list bacterium colony is in the test tube containing LB liquid nutrient medium respectively from above-mentioned each LB flat board, and the nutrient solution wherein inoculating 18H2,18H4 and 18H5 bacterial strain is the penbritin of 100 μ g/mL containing final concentration.Above-mentioned each test tube is placed on shaking table, shaking culture at 37 DEG C, takes out a small amount of bacterium liquid microplate reader at set intervals and measure its optical density(OD) (opticaldensity, OD at wavelength 600nm place 600) value, as bacterium liquid OD 600bacterium liquid is taken out when value is 1, with LB nutrient solution dilution 5,000 times, for subsequent use.
4) preparation of compound solution: each testing compound dimethyl sulfoxide (DMSO) (DMSO) dissolved, be made into the solution of 10mg/mL, then 2 times of dilutions successively respectively, be made into graded series solution, minimum concentration is to 0.01mg/mL.Separately get four kinds of existing microbiotic and be mixed with the series concentration gradient solution identical with above-claimed cpd respectively, these four kinds of microbiotic comprise meropenem (meropenem), Tigecycline (tigecycline), Streptomycin sulphate (straptomycin) and penbritin (ampicillin).In the process of obtain solution, suction pipette head used and plastic syringe use all after sterilization.
5) bacteriostatic experiment: add each testing compound solution of 1 μ L (or antibiotic solution) respectively in each hole of aseptic 96-orifice plate, 1 μ LDMSO is added in contrast wherein in a hole, and then the bacterium liquid added in each hole after 100 μ L dilutions, in 37 DEG C of constant temperature culture 18 ~ 20h after mixing.With the lowest concentration of drug of bacteria growing inhibiting complete in aperture for minimum inhibitory concentration (minimuminhibitoryconcentration, MIC).Above-mentioned experiment repeats 3 times, and experimentally result determines the MIC of each compound.
Two, experimental result:
Part of compounds to the MIC of bacteria tested in table 2.
Table 2 compound is to the minimum inhibitory concentration (μ g/mL) of four kinds of resistant organisms and three kinds of wild-type bacteriums
Note: the 1. bacterial classification that each bacteria culture numbering is corresponding is in table 1.
2. "-" represent survey compound within the scope of test concentrations (0.1 μ g/mL – 100 μ g/mL) without bacteriostatic action.
3. the compound structure that compound number is corresponding is shown in formula 7, formula 8 and formula 9.
As can be seen from Table 2, in the antibacterial experiment in vitro to four kinds of resistant organisms, the compounds exhibit that this experiment is surveyed goes out effect in various degree.1) to the MIC scope of 18H2 bacterial strain at 12.5-100 μ g/mL, its bacteriostatic activity is better than Streptomycin sulphate (without effect within the scope of test concentrations) and penbritin (without effect within the scope of test concentrations), is better than or is equivalent to meropenem (MIC=100 μ g/mL), is weaker than Tigecycline (MIC<3.125 μ g/mL).2) to the MIC scope of 18H4 bacterial strain at 25-100 μ g/mL, be better than or be equivalent to all four kinds of existing microbiotic.3) to the MIC scope of 18H5 bacterial strain at 12.5-100 μ g/mL, its bacteriostatic activity is better than penbritin (without effect within the scope of test concentrations), be better than or be equivalent to Streptomycin sulphate (MIC=100 μ g/mL), be weaker than meropenem (MIC=6.25 μ g/mL) and Tigecycline (MIC<3.125 μ g/mL).4) to the MIC scope of 18H8 bacterial strain at 3.125-50 μ g/mL, its bacteriostatic activity is better than penbritin (within the scope of test concentrations unrestraint effect), the bacteriostatic activity of part of compounds is better than Tigecycline (MIC=12.5 μ g/mL), with Streptomycin sulphate suitable (MIC=3.125 μ g/mL), be weaker than meropenem (MIC=0.78 μ g/mL).
In the antibacterial experiment in vitro to three kinds of wild-type bacteriums, the compound surveyed all has good bacteriostatic action to bacterial strain 1F7 and 1F8, and wherein the bacteriostatic activity of Compound II per g and IIIg is better than meropenem, Tigecycline and Streptomycin sulphate, slightly lower than penbritin.Part of compounds is also inhibited to 1F9 bacterial strain.
As can be seen from Table 2, part of compounds has the bacteriostatic action compared with wide spectrum, as Compound II per b, IId, IIe (molecular structure is shown in the formula 11 after embodiment 6).As can be seen here, part of compounds provided by the invention has and is developed further into the antibiotic potential quality of brand new, has higher Development volue and application prospect.
Embodiment 9: the test of acute toxicity
One, experimental technique: adopt weighting probit method (Bliss method) test compounds LD 50
Laboratory animal: small white mouse, body weight 18 ~ 22g, ♀ ♂ half and half.
Experimental drug: Compound II per d, IIl.
Administering mode: gavage.
1. preliminary experiment: explore dosage range
Gavage concentration is respectively: 200mg/kg, 300mg/kg, 400mg/kg, 500mg/kg, 700mg/kg, 800mg/kg, 1000mg/kg, 1600mg/kg; Find out the minimum dose of 100% death and the maximal dose of 0% death, this i.e. bound dosage (D mand D n).
2. formally test:
1) determine group number, calculate each group of dosage:
Common ratio r is asked by formula: r = D m D n n - 1
Each group of dosage: D is asked by common ratio 1, D 2..., D m, wherein D 1=D n=minimum dose,
D 2=D 1r ..., D n=D n-1r, D m=maximal dose.
2) administration:
1. packet numbering: get small white mouse 36, be divided into 6 groups at random, often organizes 6, ♀ ♂ half and half.
2. administration: gastric infusion.
3. observed and recorded: the reaction after the administration of record small white mouse, death time, statistics death toll.
Two, experimental result:
1. the LD50>1000mg/Kg of Compound II per d
2. the LD50=595mg/Kg of Compound II per l.

Claims (10)

1. a series of fluorine-containing carbazole compound and pharmaceutically acceptable salt, ester, acid amides or prodrug, is characterized in that, its general structure as shown in Equation 1,
R 0for any one in following listed group:
R 1~ R 8for any one in following listed group, R 1~ R 4substituting group has one at least for F atom:
2. a series of fluorine-containing carbazole compound according to claim 1 and pharmaceutically acceptable salt, ester, acid amides or prodrug, is characterized in that, general structure as shown in Equation 2, on the right side of it, phenyl ring only contains a fluorine atom,
M=1-4 in formula 2;
As R ≠ CH 3; R 0during=H, R 1-2be any one of following listed group with R:
R mfor any one of following listed group:
Work as R=CH 3and when the C4 of right side phenyl ring being connected with F substituting group, R 1-2=R 1~ R 8; R 0for any one of following listed group:
R mfor any one of following listed group:
3. a series of fluorine-containing carbazole compound according to claim 1 and pharmaceutically acceptable salt, ester, acid amides or prodrug, is characterized in that, general structure as shown in Equation 3, on the right side of it, phenyl ring only contains two fluorine atoms,
M=1-4 in formula 3;
When the F substituting group of two on the phenyl ring of right side is not connected on C2 and C4 position simultaneously, R 0=H; R 1-2=R 1~ R 8;
R mfor any one of following listed group:
When the F substituting group of two on the phenyl ring of right side is connected on C2 and C4 position, R 1-2=R 1~ R 8; R 0for any one of following listed group:
R mfor any one of following listed group:
4. a series of fluorine-containing carbazole compound according to claim 1 and pharmaceutically acceptable salt, ester, acid amides or prodrug, is characterized in that, general structure as shown in Equation 4, on the right side of it, phenyl ring only contains three fluorine atoms,
Wherein R=R 1~ R 8; R m=R 1~ R 8; M=1-4;
R 0for any one of following listed group:
5. a series of fluorine-containing carbazole compound described in claim 1 and pharmaceutically acceptable salt, ester, acid amides or prodrug, is characterized in that, general structure as shown in Equation 5, on the right side of it, phenyl ring contains four fluorine atoms,
Wherein R 0=H; M=1-4;
R mfor any one of following listed group:
6. the preparation method of the fluorine-containing carbazole compound of formula shown in claim 1 Chinese style 1, it is characterized in that: diarylamine, sodium tert-butoxide, palladium and cuprous iodide are joined in reaction vessel, using dioxane as solvent, be heated to 120 DEG C and keep 10h, be cooled to room temperature, to go out reaction with shrend, use dichloromethane extraction product, anhydrous sodium sulfate drying solution, be spin-dried for solvent, column chromatography for separation, obtains corresponding pure products, and wherein the mol ratio of diarylamine, sodium tert-butoxide, palladium and cuprous iodide is 1:2.5:0.005:0.2.
7. the preparation method of fluorine-containing carbazole compound according to claim 6, is characterized in that, the developping agent of described column chromatography for separation is the sherwood oil of 30-60 DEG C and the mixed solvent of ether, and the volume ratio of sherwood oil and ether is 10:1.
8. the application of fluorine-containing carbazole compound in the bioactive medicine for the preparation of suppression microorganism of formula shown in claim 1 Chinese style 1.
9. application according to claim 8, it is characterized in that, the kind of the described microorganism suppressed by this compounds includes but not limited to carry intestinal bacteria and Klebsiella Pneumoniae, the methicillin-resistant staphylococcus aureus of NDM-1 gene and the bacterial strain such as wild-type e. coli, streptococcus aureus and subtilis.
10. the form of the fluorine-containing carbazole compound of formula shown in the formula 1 of application rights requirement described in 1, comprises lead, raw material and preparation thereof.
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