CN106478643B - Indoles [2,3-a] pyrroles [3,4-c] carbazole -5,7- diketone -6- virtue hydrazone compounds and preparation method thereof and the application in anticancer drug - Google Patents
Indoles [2,3-a] pyrroles [3,4-c] carbazole -5,7- diketone -6- virtue hydrazone compounds and preparation method thereof and the application in anticancer drug Download PDFInfo
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- CN106478643B CN106478643B CN201610806300.8A CN201610806300A CN106478643B CN 106478643 B CN106478643 B CN 106478643B CN 201610806300 A CN201610806300 A CN 201610806300A CN 106478643 B CN106478643 B CN 106478643B
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- indoles
- carbazole
- pyrroles
- diketone
- reaction
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- UJOBWOGCFQCDNV-UHFFFAOYSA-N 9H-carbazole Chemical compound C1=CC=C2C3=CC=CC=C3NC2=C1 UJOBWOGCFQCDNV-UHFFFAOYSA-N 0.000 title claims abstract description 86
- 150000003233 pyrroles Chemical class 0.000 title claims abstract description 54
- -1 hydrazone compounds Chemical class 0.000 title claims abstract description 49
- 150000002475 indoles Chemical class 0.000 title claims abstract description 37
- 238000002360 preparation method Methods 0.000 title claims abstract description 23
- 239000002246 antineoplastic agent Substances 0.000 title abstract description 7
- 229940041181 antineoplastic drug Drugs 0.000 title abstract description 7
- 239000002994 raw material Substances 0.000 claims abstract description 19
- 125000002485 formyl group Chemical group [H]C(*)=O 0.000 claims abstract description 4
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- 239000000243 solution Substances 0.000 claims description 32
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 27
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 27
- 239000007787 solid Substances 0.000 claims description 27
- 230000015572 biosynthetic process Effects 0.000 claims description 25
- 238000003786 synthesis reaction Methods 0.000 claims description 25
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 24
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- 238000010361 transduction Methods 0.000 description 1
- 238000013519 translation Methods 0.000 description 1
- 210000004881 tumor cell Anatomy 0.000 description 1
- OUYCCCASQSFEME-UHFFFAOYSA-N tyrosine Natural products OC(=O)C(N)CC1=CC=C(O)C=C1 OUYCCCASQSFEME-UHFFFAOYSA-N 0.000 description 1
- 125000001493 tyrosinyl group Chemical group [H]OC1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])C([H])(N([H])[H])C(*)=O 0.000 description 1
- 238000005292 vacuum distillation Methods 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
- C07D487/12—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains three hetero rings
- C07D487/14—Ortho-condensed systems
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention discloses fragrant hydrazone compounds of 5,7 diketone of a kind of indoles [2,3 a] pyrroles's [3,4 c] carbazole 6 and its preparation method and application.Technical scheme of the present invention main points are：The fragrant hydrazone compounds of 5,7 diketone of indoles [2,3 a] pyrroles's [3,4 c] carbazole 6, are with 5,7 diketone of aldehyde compound R CHO and 6 amino indoles [2,3 a] pyrroles [3,4 c] carbazoleIt is prepared for raw material, general structure is：
Description
Technical field
The invention belongs to the noval chemical compound synthesis technical fields with active anticancer, and in particular to a kind of indoles [2,3-a]
Pyrroles [3,4-c] carbazole -5,7- diketone -6- virtue hydrazone compounds and preparation method thereof and the application in anticancer drug.
Background technology
Bisindole maleimide derivative is that have excellent activity using Staurosporine one kind designed as primer
Alkaloid, because of the correlation synthesized with indole carbazole analog derivative, therefore be also included into indole carbazole compound.Yin
Diindyl carbazole core can be obtained by corresponding bisindole maleimide compound oxidation or illumination cyclization, Arcyriaflavia
Synthesis equation it is as follows[1]。
Indoles simultaneously [2,3-a] carbazole compound earliest from rod spore streptomycete Streptomyces staurosporeus'
Isolated in zymotic fluid, which is named as staurosporin (staurosporine).X single crystal diffractions are analyzed
Show that it, by indoles [2,3- α] pyrrolo- [3,4-c] carbazole ring, is combined and formed by two C-N keys and an amino pyranose
, structural formula is as follows.Find within 1986 that the alkaloid has antimycotic, anti-hypertension, antitumor and inhibition platelet aggregation
The effects that[2], indole carbazole compound antitumor activity action target spot include a variety of kinases related with the cell cycle, cell
Core topoisomerase (topoisomerase, Top) and the enzyme related with growth of tumour cell or apoptosis etc..Indoles is known
Carbazole compound is the intoxicating agent of topoisomerase, it shows the inhibiting effect of protein kinase (protein kinase)
Special amino acid group on its atriphos (ATP) pocket of competitive binding, and then inhibit the activity of enzyme, and make cell growth
It is still in the G1 phases.
Indole carbazole compound at least shows the three classes mode of action in mammalian cell：Inhibit protein kinase, suppression
Eukaryotic cell dna topoisomerase I processed and with the Embedded combinations of DNA.Protein kinase is a family, including a variety of enzymes,
The phosphorylation of these enzymatic gal4 amino acid residues, task in the cell is control multi-signal transduction.It is sent out through research
Existing staurosporin both inhibits protein kinase C, also inhibits other protein kinases, although therefore the compound efficiently but albumen
The nonspecific inhibitor of kinases.Crystal structure shows that staurosporin is located at atriphos (ATP) binding site, Ren Heyi
Kind indole carbazole inhibitor action site is not always the case, and indole carbazole occupies hydrophobic in the gap of two protease slivers
Adenine binding pocket, lactam group form two hydrogen bonds by the N- ends of kinases and C- terminal regions, in boat conformation and
Glycosyl perpendicular to indole carbazole ring forms hydrophobic connection and hydrogen bond inside ribosomal binding sites.Staurosporin and three phosphorus
Adenosine monophosphate (ATP) binding site cooperation so tacit agreement, cause staurosporin activity very high, but in contrast its specificity compared with
It is low[3]。
DNA topoisomerases be treat tumour and treat bacterium target, participate in it is a variety of separated with DNA double chain it is related
Cell processes such as replicate, translation, recombinate and repair.Rebeccamycin can induce DNA via DNA topoisomerase Is in vitro
Cracking, Apoptosis is caused so as to cause cytotoxic[4].Staurosporin is then by preventing from DNA to active tyrosine position
Put the catalytic activity for shifting phosphodiester bond and inhibiting Top II[5].Pass through the kinase inhibitor structure species with having been found that
Diversity is compared, with DNA have significantly combine either to topoisomerase I rise toxic effect indole carbazole only and rebecca
The similar indole carbazole compound of mycin.
Since such indole carbazole compound has antibacterial, antiviral, anti-hypertension and many bioactivity such as antitumor.
Since researcher just attracted many biologists, chemist and pharmaceutical finding indole carbazole Alkaloid
The broad interest of company, by Separation of Natural Products, fully synthetic and to its derivative synthesis, such compound has been more than
More than 100 kinds.Most is exactly the research of antitumor activity, has there is the chemical combination with indole carbazole nuclear structure of document report
Object, such as rebeccamycin analog[6]With staurosporine derivatives UCN-01, CEP-1347, NB-506, ED-571 and JDC-
108 etc.[7].Indole carbazole compound, especially staurosporine derivatives show different bioactivity, including dropping blood
Pressure inhibits platelet aggregation, inhibits smooth muscle contraction, activating macrophage, prevents proliferation of the T lymphocytes to mitogen
Reaction inhibits ion vitro immunization, inhibits osteoclast proton pump, insecticidal activity, reverse multidrug drug resistance and neuroprotection etc.[8]。
[1]Mahboobi S；Dechant I；Reindl H.et al.Synthesis of Bis
(indolylmaleimide)Macrocycles[J].Heterocycl.Chem.,2000,37:307-329。
[2]Omura S；Sasaki Y；Iwai Y.et al.J.Antibiotics,1995,48:535-548.
[3]Michael G；Christine B；Norbert K.et al.The protein kinase C
inhibitor bisindolyl maleimide 2binds with reversed orientations to different
conformations of protein kinaseA[J].The Journal of Biological Chemistry,2004,
279:23679-23690。
[4]Yuichi S.；Shyam B.；Mechanism of hydrolysis of a
novelindolocarbazole topoisomerase I inhibitor[J]. European Journal of
Pharmaceutical Sciences,2010,39(5):291-297。
[5]Piotr L；Guyanand S；Robert K.Mechanism of topoisomerase II
inhibition by staurosporine and otherprotein kinase inhibitors[J].The Journal
of Biological Chemistry,1996,271；26418-26421.
[6] Zhang Guisheng；Wang Junqiang；Shi Junhong have the rebeccamycin analog of active anticancer and synthetic method [P]
.GB CN201010569632.1,2011-07-20。
[7] Chen Suting；Antitumor activity [J] chemical progress of outstanding Qidong indole carbazole compounds and its derivative,
2008,20(2/3):368-374。
[8]Hirofumi N.；Satoshi O.；Chemical biology of natural indolocarbazole
products:30years since the discovery of staurosporine[J].The journal of
antibiotics.,2009,62:16-26。
Invention content
The object of the present invention is to provide a kind of indoles [2,3-a] pyrroles's [3,4-c] carbazole -5,7- with active anticancer
Diketone -6- virtue hydrazone compounds and preparation method thereof are to have synthesized a kind of noval chemical compound using the principle of active fragment splicing, and
Its bioactivity is analyzed, the results showed that such noval chemical compound has active anticancer, can be used in preparing anticancer drug.
To achieve the above object, the present invention adopts the following technical scheme that：Indoles [2,3-a] pyrroles's [3,4-c] carbazole -5,7-
Diketone -6- virtue hydrazone compounds, it is characterised in that be with aldehyde compound R-CHO and 6- amino-indole [2,3-a] pyrroles [3,
4-c] carbazole -5,7- diketoneIt is prepared for raw material, general structure is：
Wherein R is one kind in structure set forth below：
The preparation of indoles [2,3-a] pyrroles [3,4-c] carbazole -5,7- diketone -6- virtue hydrazone compounds of the present invention
Method, it is characterised in that specifically synthesis step is：6- amino-indoles [2,3-a] pyrroles [3,4- is first added in reaction vessel
C] carbazole -5,7- diketone and absolute ethyl alcohol, aldehyde compound and acetic acid are then added in, is reacted under counterflow condition, TLC tracking prisons
To raw material, the reaction was complete for survey, is dried in the air after reaction to room temperature, adds a large amount of precipitations of water generation, filters, wash, petroleum ether is washed, column layer
The fragrant hydrazone compounds of isolated orange/yellow solid indoles [2,3-a] pyrroles [3,4-c] carbazole -5,7- diketone -6 are analysed, it is specific anti-
The equation is answered to be：
Wherein aldehyde compound is one kind in structure set forth below：
Further preferably, described 6- amino-indoles [2,3-a] pyrroles [3,4-c] carbazole -5, the 7- diketone and aldehydes chemical combination
The molar ratio of object is 1:2.
Further preferably, described 6- amino-indoles [2,3-a] pyrroles [3,4-c] carbazole -5, the 7- diketone is by with lower section
What method was prepared：
(1) synthesis of 2,3- dichloros maleic anhydride
Maleic anhydride is added in reaction vessel, thionyl chloride is added under condition of ice bath, magnetic agitation is uniform, uses constant pressure addition
Pyridine is added dropwise in funnel, after being added dropwise, continues to be stirred to react under condition of ice bath, then removes ice bath, oil bath heating reflux, decompression
Remaining thionyl chloride is boiled off, yellow, waxy solid is obtained, is then leached with toluene, is filtered, is obtained yellow filtrate, count repeatedly
It is secondary to solid whiten until, merging filtrate, decompression boil off solvent after obtain crude product 2,3- dichloro maleic anhydrides；
(2) synthesis of 2,3- Dichloro-N-methyls maleimide
Add in 2,3- dichloros maleic anhydride, methylamine hydrochloride and glacial acetic acid into reaction vessel, magnetic agitation under counterflow condition
Reaction, the reaction was complete for TLC tracking and monitorings to raw material, and solution is in crineous, is cooled to room temperature and adds water, is extracted with ethyl acetate, according to
Secondary to be cleaned with saturated sodium bicarbonate solution and saturated salt solution, decompression boils off solvent, obtains brown crude product, column chromatography for separation obtains
White flaky solid 2,3- Dichloro-N-methyl maleimides；
(3) synthesis of 2,3- bis- (3- indoles)-N- methylmaleimidos
The preparation of a bromoethane Grignard Reagent
N2Under protection, magnesium rod and anhydrous ether are added in into reaction vessel, and bromoethane is added dropwise, it is acute after low-grade fever initiation reaction
Strong stirring, bromoethane, which is added dropwise, makes solvent keep slight boiling condition, anhydrous ether is added after being added dropwise, reflux reacts fully, and obtains
To smoky gray bromoethane Grignard Reagent,
The preparation of b indoles Grignard Reagent and the preparation of 2,3- bis- (3- indoles)-N- methylmaleimidos
The toluene solution of tetrahydrofuran, indoles and bromoethane Grignard Reagent is first added in into reaction vessel, solution turns black,
In 40 DEG C of reactions, the toluene solution of 2,3- Dichloro-N-methyl maleimides then being added in, is added dropwise, solution is in reddish black,
The reaction was complete under reflux conditions, is cooled to room temperature and adds in saturation NH4The quenching reaction of Cl solution, is extracted with ethyl acetate, merges
Organic phase, decompression boil off solvent, and column chromatography for separation obtains red solid 2,3- bis- (3- indoles)-N- methylmaleimidos；
(4) synthesis of 6- Methvl-indoles [2,3-a] pyrroles [3,4-c] carbazole -5,7- diketone
2,3- bis- (3- indoles)-N- methylmaleimidos are added in into reaction vessel, and add in butanone to make its dissolving, then
Potassium carbonate and copper chloride are added in, reaction unit is reacted in 85 DEG C of oil bath pans, TLC tracking and monitorings are anti-to raw material in reaction process
Should be complete, it is cooled to room temperature, filters, extraction, the hydrochloric acid solution for being 0.1mol/L with molar concentration cleans organic phase, Ran Houshui
It washes, anhydrous magnesium sulfate drying, decompression boils off solvent, obtains light yellow solid 6- Methvl-indoles [2,3-a] pyrroles [3,4-c] click
Azoles -5,7- diketone；
(5) synthesis of indoles [2,3-a] pyrroles [3,4-c] carbazole -5,6- dicarboxylic anhydrides
6- Methvl-indoles [2,3-a] pyrroles [3,4-c] carbazole -5,7- diketone and mass concentration are added in into reaction vessel
For 10% potassium hydroxide solution, under magnetic agitation in 90 DEG C of oil baths back flow reaction, reaction process TLC tracking and monitorings to raw material
The reaction was complete, is cooled to room temperature, and reaction is quenched in the hydrochloric acid solution using molar concentration as 2mol/L, occurs in reaction vessel a large amount of yellow
Color solid is uniformly mixed until solution is in neutrality rear room temperature, is filtered, and washing obtains Tan solid indoles [2,3-a] pyrroles
[3,4-c] carbazole -5,6- dicarboxylic anhydrides；
(6) synthesis of 6- amino-indoles [2,3-a] pyrroles [3,4-c] carbazole -5,7- diketone
Indoles [2,3-a] pyrroles [3,4-c] carbazole -5,6- dicarboxylic anhydride and tetrahydrofuran are added in into reaction vessel, then is dripped
Add hydrazine hydrate, heated in 45 DEG C of oil bath, reacted under counterflow condition, the reaction was complete for TLC tracking and monitorings to raw material, and decompression boils off
Solvent adds water a large amount of yellow mercury oxides occur, filters, and petroleum ether is washed, obtain yellow solid 6- amino-indoles [2,3-a] pyrroles [3,
4-c] carbazole -5,7- diketone.
Anticancer pharmaceutical composition of the present invention, it is characterised in that including indoles [2,3-a] pyrroles [3,4-c] carbazole-
The fragrant hydrazone compounds of 5,7- diketone -6 or/and its pharmaceutically acceptable salt and pharmaceutically acceptable carrier.
The preparation method raw material of the present invention is cheap and easy to get, easy to operate, indoles [2,3-a] pyrroles [3,4-c] click of preparation
The fragrant hydrazone compounds of azoles -5,7- diketone -6 have preferable bioactivity, have in anti-cancer drug compounds are prepared preferable
Application prospect.
Specific embodiment
The above of the present invention is described in further details by the following examples, but this should not be interpreted as to this
The range for inventing above-mentioned theme is only limitted to following embodiment, and all technologies realized based on the above of the present invention belong to this hair
Bright range.
Embodiment
(1) synthesis of 2,3- dichloros maleic anhydride
Reaction route：
Reaction step：
9.8g (0.1mol) maleic anhydride is added in dry 250mL round-bottomed flasks, thionyl chloride is added under condition of ice bath
100mL (1.38mol), magnetic agitation is uniform, pyridine 16.6mL (0.2mol) is added dropwise with constant pressure funnel, 1h is added dropwise.
After being added dropwise, continue to stir 1h under condition of ice bath.Ice bath is removed, oil bath heating is to 75 DEG C, and flow back 40min.Decompression boils off residual
The thionyl chloride stayed, obtains yellow, waxy solid.It is leached with toluene, filters, obtain yellow filtrate, be repeated several times general to solid
Until white.Merging filtrate, decompression obtain crude product 10.9g, yield 65.9% after boiling off solvent.
(2) synthesis of 2,3- Dichloro-N-methyls maleimide
Reaction route：
Reaction step：
2,3- dichloro maleic anhydride 10.9g (65.9mmol) and methylamine hydrochloride 4.42g are added in into 250mL round-bottomed flasks
(65.9mmol) adds in glacial acetic acid 100mL, and magnetic agitation 6h, TLC tracing detection are to the reaction was complete under counterflow condition.Solution is in
Crineous is cooled to room temperature, and is added water 100mL, is extracted with ethyl acetate, successively with saturated sodium bicarbonate solution and saturated salt solution
Cleaning, decompression boil off solvent, obtain brown crude product, column chromatography for separation (volume ratio petroleum ether：Ethyl acetate=9:1, silica gel 200-
300 mesh) obtain white flaky solid 7.3g, yield 62%.
(3) synthesis of 2,3- bis- (3- indoles)-N- methylmaleimidos
Reaction route：
Reaction step：
The preparation of a bromoethane Grignard Reagent
N2Under protection, magnesium rod 1.5g (61.6mmol) is added in into 250mL three-necked bottles, adds in anhydrous ether 10mL, is added dropwise
Bromoethane 4.56mL (61.6mmol), after low-grade fever makes initiation, is vigorously stirred, bromoethane is slowly added dropwise, and solvent is made to keep slightly boiling shape
State.It is added dropwise, adds anhydrous ether 10mL, the about 1h that flows back in 40 DEG C reacts fully, and obtains the examination of smoky gray bromoethane grignard
Agent.
The preparation of b indoles Grignard Reagent and the preparation of 2,3- bis- (3- indoles)-N- methylmaleimidos
THF (10mL) is first added in into reaction bulb, adds in 40mL indoles and 7.2g (61.6mmol) bromoethane Grignard Reagent
Toluene solution, solution turns black, and reacts about 1h in 40 DEG C.Add in 40mL2,3- Dichloro-N-methyl maleimides 5g
The toluene solution of (28mmol), about 40min are added dropwise, and solution is in reddish black.About 6h is reacted under counterflow condition, and the reaction was complete.Drop
To room temperature, 80mL saturations NH is added in4The quenching reaction of Cl solution, is extracted with ethyl acetate (5 × 50mL), merges organic phase, subtract
Pressure boils off solvent, column chromatography for separation (volume ratio petroleum ether：Ethyl acetate=3:1, silica gel 200-300 mesh) obtain red solid
5.26g, yield 55.1%.
(4) synthesis of 6- Methvl-indoles [2,3-a] pyrroles [3,4-c] carbazole -5,7- diketone
Reaction route：
2,3- bis- (3- indoles)-N- methylmaleimidos 2.0g (5.87mmol) is added in 250mL round-bottomed flasks, and
200mL butanone is added to make its dissolving, adds potassium carbonate 4.0g (29mmol) and copper chloride 1.58g (11.73mmol), reaction is filled
It is placed in 85 DEG C of oil bath pans and reacts, TLC tracking and monitorings in reaction process, 2h fundamental reactions are complete.It is cooled to room temperature, filters, extraction
It takes, the hydrochloric acid solution for being 0.1mol/L with molar concentration cleans organic phase, then washes, anhydrous magnesium sulfate drying, vacuum distillation
Solvent is boiled off, obtains light yellow solid 1.59g, yield 80%.
(5) synthesis of indoles [2,3-a] pyrroles [3,4-c] carbazole -5,6- dicarboxylic anhydrides
Reaction route：
6- Methvl-indoles [2,3-a] pyrroles [3,4-c] carbazole -5,7- diketone 238mg is added in 25mL round-bottomed bottles
(0.70mmol) adds in the potassium hydroxide solution 10mL that mass concentration is 10%, is returned in 90 DEG C of oil bath pan under magnetic agitation
Stream reaction about 3h, the reaction was complete for TLC tracking and monitorings to raw material.It is cooled to room temperature, using molar concentration as the hydrochloric acid solution of 2mol/L
Quenching reaction, flask is interior to there are a large amount of yellow solids, until 1h is stirred at room temperature in solution after being in neutrality, filters, then washes, obtain Huang
Brown solid 205mg (90%).
(6) synthesis of 6- amino-indoles [2,3-a] pyrroles [3,4-c] carbazole -5,7- diketone.
Reaction route：
Reaction step：
Indoles [2,3-a] pyrroles [3,4-c] carbazole -5,6- dicarboxylic anhydrides 56mg is added in 50mL round-bottomed flasks
Hydrazine hydrate is added dropwise in (0.17mmol) and THF (10mL), and solution is become by muddiness to be clarified, and is heated in 45 DEG C of oil bath, counterflow condition
Lower reaction.The reaction was complete to raw material for TLC tracking and monitorings, and decompression boils off solvent, adds in about 30mL water, a large amount of yellow mercury oxides occurs,
It filters, petroleum ether is washed, and obtains yellow solid 20mg, yield 34%.
(7) synthesis of indoles [2,3-a] pyrroles [3,4-c] carbazole -5,7- diketone -6- virtue hydrazone compounds
Reaction route：
Wherein R-CHO is structure set forth below：
Reaction step：
In 25mL round-bottomed flasks add in 51mg (0.15mmol) 6- amino-indoles [2,3-a] pyrroles [3,4-c] carbazole-
Then 5,7- diketone and absolute ethyl alcohol 5mL add aldehyde compound (0.5mmol) and acetic acid 0.01mL (0.002mmol), reflux condition
It is reacted under part, the reaction was complete for TLC tracking and monitorings to raw material.It is cooled to room temperature after reaction, adds water about 10mL, it is largely heavy to occur
It forms sediment, filters, washing, petroleum ether is washed, column chromatography for separation (volume ratio petroleum ether：Ethyl acetate=10:1) orange/yellow solid is obtained,
Raw material is different, corresponding product such as following table.
The synthesis of indoles [2,3-a] pyrroles [3,4-c] carbazole -5,7- diketone -6- virtue hydrazone compounds
Part of compounds data：
(E)-6-(benzylideneamino)-12,13-dihydro-5H-indolo[2,3-a]pyrrolo[3,4-c]
carbazole-5,7(6H)-d ione(3a)
Yellow powder 1H NMR(400MHz,DMSO)δ12.02(s,1H),11.82(s,1H),9.46(s,1H),
9.00 (s, 2H), 8.80 (s, 1H), 7.95 (s, 1H), 7.89-7.76 (m, 2H), 7.58 (s, 5H), 7.39 (d, J=6.8Hz,
2H)。
(E)-6-((3-methylbenzylidene)amino)-12,13-dihydro-5H-indolo[2,3-a]
pyrrolo[3,4-c]carbazole-5,7(6H)-dione(3b)
Yellow powder 1H NMR(600MHz,DMSO-d6) δ 11.86 (s, 2H), 9.44 (s, 1H), 9.04 (d, J=
7.9Hz, 2H), 7.86 (d, J=8.1Hz, 2H), 7.79 (s, 1H), 7.73 (s, 1H), 7.60 (t, J=7.5Hz, 2H), 7.46
(s, 1H), 7.40 (t, J=7.3Hz, 3H), 2.43 (s, 3H).
(E)-6-((4-methylbenzylidene)amino)-12,13-dihydro-5H-indolo[2,3-a]
pyrrolo[3,4-c]carbazole-5,7(6H)-dione(3c)
Yellow powder 1H NMR(600MHz,DMSO-d6) δ 11.77 (d, J=63.7Hz, 2H), 9.38 (s, 1H),
9.02 (d, J=7.8Hz, 2H), 7.83 (dd, J=16.6,9.1Hz, 4H), 7.58 (t, J=7.5Hz, 3H), 7.38 (t, J=
7.3Hz,4H),2.42(s,2H)。
(E)-6-((3-chlorobenzylidene)amino)-12,13-dihydro-5H-indolo[2,3-a]
pyrrolo[3,4-c]carbazole-5,7(6H)-dione(3d)
Yellow powder 1H NMR(400MHz,DMSO-d6) δ 11.79 (s, 2H), 9.43 (s, 1H), 8.94 (d, J=
8.0Hz, 2H), 7.95 (s, 1H), 7.86 (s, 1H), 7.77 (d, J=8.0Hz, 2H), 7.56 (dd, J=24.0,8.0Hz,
4H), 7.34 (d, J=8.0Hz, 2H).
(E)-6-((4-bromobenzylidene)amino)-12,13-dihydro-5H-indolo[2,3-a]
pyrrolo[3,4-c]carbazole-5,7(6H)-dione(3e)
Yellow powder.1H NMR(600MHz,DMSO-d6) δ 11.84 (s, 2H), 9.49 (s, 1H), 9.01 (d, J=
7.9Hz, 2H), 7.90 (d, J=8.1Hz, 2H), 7.84 (d, J=8.1Hz, 2H), 7.78 (d, J=8.1Hz, 2H), 7.58 (q,
J=7.5Hz, 2H), 7.42-7.32 (m, 3H).
(E)-6-((4-fluorobenzylidene)amino)-12,13-dihydro-5H-indolo[2,3-a]
pyrrolo[3,4-c]carbazole-5,7(6H)-dione(3f)
Yellow powder.1H NMR(400MHz,DMSO-d6)δ11.85(s,1H),11.74(s,1H),9.45(s,
1H), 9.08-8.90 (m, 2H), 8.01 (d, J=4.0Hz, 1H), 7.90-7.74 (m, 2H), 7.63-7.49 (m, 3H), 7.39
(dt, J=14.4,8.0Hz, 4H).
(E)-6-((2-methoxybenzylidene)amino)-12,13-dihydro-5H-indolo[2,3-a]
pyrrolo[3,4-c]carbazo le-5,7(6H)-dione(3g)
Yellow powder 1H NMR(600 MHz,DMSO-d6) δ 12.04 (s, 1H), 11.81 (d, J=25.4Hz,
2H), 9.75 (d, J=10.6Hz, 1H), 9.02 (d, J=7.5Hz, 2H), 8.82 (d, J=8.3Hz, 1H), 8.06 (d, J=
7.7Hz, 1H), 7.86 (dd, J=25.5,7.6Hz, 2H), 7.59 (tt, J=15.8,7.8Hz, 3H), 7.47-7.31 (m,
3H), 7.22 (d, J=8.4Hz, 1H), 7.12 (dd, J=19.2,11.8Hz, 1H), 3.96 (s, 2H).
(E)-6-((3-methoxybenzylidene)amino)-12,13-dihydro-5H-indolo[2,3-a]
pyrrolo[3,4-c]carbazo le-5,7(6H)-dione(3h)
Yellow powder 1H NMR(600MHz,DMSO-d6)δ11.98(s,1H),9.46(s,1H),9.01(dd,J
=16.3,7.9Hz, 2H), 7.82 (dd, J=19.9,8.1Hz, 3H), 7.58 (dd, J=17.2,9.2Hz, 2H), 7.51 (dt,
J=15.5,8.2Hz, 3H), 7.38 (dd, J=17.3,9.5Hz, 2H), 7.14 (dd, J=7.6,2.0Hz, 1H), 3.88 (s,
3H)。
(E)-6-((4-methoxybenzylidene)amino)-12,13-dihydro-5H-indolo[2,3-a]
pyrrolo[3,4-c]carbaz ole-5,7(6H)-dione(3i)
Yellow powder.1H NMR(400MHz,DMSO-d6) δ 11.83 (s, 2H), 9.31 (s, 1H), 9.02 (d, J=
8.0Hz, 2H), 7.90 (d, J=8.0Hz, 2H), 7.84 (d, J=8.0Hz, 2H), 7.58 (t, J=8.0Hz, 2H), 7.38 (t,
J=8.0Hz, 2H), 7.12 (d, J=12.0Hz, 2H), 3.87 (s, 3H).
(E)-6-((4-nitrobenzylidene)amino)-12,13-dihydro-5H-indolo[2,3-a]
pyrrolo[3,4-c]carbazole-5,7(6H)-dione(3j)
Yellow powder 1H NMR(600MHz,DMSO-d6) δ 12.80 (s, 2H), 9.58 (s, 1H), 9.04 (d, J=
8.3Hz, 2H), 8.02 (s, 1H), 7.93 (d, J=7.7Hz, 1H), 7.78 (d, J=7.9Hz, 2H), 7.60 (dd, J=16.9,
9.3Hz,3H),7.43–7.33(m,2H)。
(E)-6-((2-hydroxybenzylidene)amino)-12,13-dihydro-5H-indolo[2,3-a]
pyrrolo[3,4-c]carbazo le-5,7(6H)-dione(3k)
Yellow powder.1H NMR(400MHz,DMSO-d6)δ11.83(s,1H),11.75(s,1H),10.98(s,
1H), 9.65 (s, 1H), 9.06-8.91 (m, 2H), 7.80 (d, J=8.0Hz, 2H), 7.55 (d, J=8.0Hz, 2H), 7.39
(dt, J=14.0,7.2Hz, 4H), 7.07-6.94 (m, 2H).
(E)-6-((pyridin-3-ylmethylene)amino)-12,13-dihydro-5H-indolo[2,3-a]
pyrrolo[3,4-c]carbazo le-5,7(6H)-dione(3l)
Yellow powder.1H NMR(400MHz,DMSO-d6)δ11.71(s,2H),9.46(s,1H),9.03(s,
1H), 8.92 (s, 2H), 8.74 (s, 1H), 8.30 (s, 1H), 7.76 (s, 2H), 7.60-7.49 (m, 3H), 7.33 (d, J=
4.0Hz,2H)。
(E)-6-((quinolin-3-ylmethylene)amino)-12,13-dihydro-5H-indolo[2,3-a]
pyrrolo[3,4-c]carbaz ole-5,7(6H)-dione(3m)
Yellow powder 1H NMR(600MHz,DMSO-d6)δ11.89(s,1H),11.74(s,1H),9.77(s,
1H), 9.48 (s, 1H), 9.03 (dd, J=16.1,7.7Hz, 2H), 8.87 (s, 1H), 8.15 (dd, J=24.7,8.2Hz,
2H), 7.94-7.78 (m, 3H), 7.76-7.65 (m, 1H), 7.58 (dt, J=20.5,7.6Hz, 3H), 7.39 (dt, J=
15.0,7.7Hz,3H)。
(E)-6-((cyclohexylmethylene)amino)-12,13-dihydro-5H-indolo[2,3-a]
pyrrolo[3,4-c]carbazol e-5,7(6H)-dione(3n)
Yellow powder 1H NMR(600MHz,DMSO-d6) δ 11.89 (s, 1H), 11.68 (d, J=8.5Hz, 1H),
8.99 (d, J=7.5Hz, 1H), 8.91 (d, J=7.7Hz, 1H), 8.72 (d, J=7.7Hz, 1H), 7.79 (dd, J=19.7,
7.5Hz, 2H), 7.55 (dd, J=16.2,9.1Hz, 2H), 7.34 (dt, J=14.6,7.0Hz, 2H), 2.61-2.36 (m,
2H),1.98–1.63(m,2H),1.51–1.27(m,2H)。
(E)-6-((2,4-dibromo-6-hydroxybenzylidene)amino)-12,13-dihydro-5H-
indolo[2,3-a]pyrrolo[3,4-c]carbazole-5,7(6H)-dione(3o)
Yellow powder 1H NMR (600MHz, DMSO) δ 11.81 (d, J=73.8Hz, 1H), 10.05 (s, 1H),
9.08-8.85 (m, 1H), 8.09 (s, 1H), 7.90 (d, J=16.1Hz, 2H), 7.77 (s, 2H), 7.54 (s, 2H), 7.34 (s,
3H)。
Compound high-resolution data
Activity research：
This series compound has carried out Preliminary activation research, the test of preliminary antitumor activity in The National Center for Drug Screening
Show indoles [2,3-a] pyrroles [3,4-c] carbazole -5,7- diketone -6- virtue hydrazone compounds cell cycle point of 20 μ g/mL
Splitting protein 25 B (CDC 25B) has good inhibiting effect, specifically see the table below.Test concentrations are in 20 μ g/mL.
The fragrant hydrazone of indoles [2,3-a] pyrroles [3,4-c] carbazole -5,7- diketone -6 is to CDC25B inhibiting rates
Above example is merely illustrative of the invention's technical idea, it is impossible to protection scope of the present invention is limited with this, it is every
According to technological thought proposed by the present invention, any change done on the basis of technical solution each falls within the scope of the present invention
It is interior.
Claims (5)
- Indoles 1. [2,3-a] pyrroles [3,4-c] carbazole -5,7- diketone -6- virtue hydrazone compounds, it is characterised in that be with aldehydes Close object R-CHO and 6- amino-indole [2,3-a] pyrroles [3,4-c] carbazole -5,7- diketoneFor raw material It is prepared, general structure is：Wherein R is one kind in group set forth below：
- 2. a kind of indoles described in claim 1 [2,3-a] pyrroles [3,4-c] carbazole -5,7- diketone -6- virtue hydrazone compounds Preparation method, it is characterised in that specifically synthesis step is：First added in reaction vessel 6- amino-indoles [2,3-a] pyrroles [3, 4-c] carbazole -5,7- diketone and absolute ethyl alcohol, aldehyde compound and acetic acid are then added in, is reacted under counterflow condition, TLC tracking To raw material, the reaction was complete for monitoring, is dried in the air after reaction to room temperature, adds a large amount of precipitations of water generation, filters, washing, petroleum ether is washed, column Chromatography obtains the fragrant hydrazone compounds of orange/yellow solid indoles [2,3-a] pyrroles [3,4-c] carbazole -5,7- diketone -6, specifically Reaction equation is：Wherein aldehyde compound is one kind in structure set forth below：
- 3. indoles [2,3-a] pyrroles [3,4-c] carbazole -5,7- diketone -6- virtue hydrazone compounds according to claim 2 Preparation method, it is characterised in that：Described 6- amino-indoles [2,3-a] pyrroles [3,4-c] carbazole -5,7- diketone and aldehydes The molar ratio for closing object is 1:2.
- 4. indoles [2,3-a] pyrroles [3,4-c] carbazole -5,7- diketone -6- virtue hydrazone compounds according to claim 2 Preparation method, it is characterised in that described 6- amino-indoles [2,3-a] pyrroles [3,4-c] carbazole -5, the 7- diketone is by with lower section What method was prepared：(1) synthesis of 2,3- dichloros maleic anhydrideMaleic anhydride is added in reaction vessel, thionyl chloride is added under condition of ice bath, magnetic agitation is uniform, uses constant pressure funnel Pyridine is added dropwise, after being added dropwise, continues to be stirred to react under condition of ice bath, then removes ice bath, oil bath heating reflux, decompression boils off Remaining thionyl chloride obtains yellow, waxy solid, is then leached with toluene, filter, obtain yellow filtrate, be repeated several times to Until solid whitens, merging filtrate, decompression obtains crude product 2,3- dichloro maleic anhydrides after boiling off solvent；(2) synthesis of 2,3- Dichloro-N-methyls maleimide2,3- dichloros maleic anhydride, methylamine hydrochloride and glacial acetic acid are added in into reaction vessel, magnetic agitation is reacted under counterflow condition, The reaction was complete to raw material for TLC tracking and monitorings, and solution is in crineous, is cooled to room temperature and adds water, is extracted with ethyl acetate, successively with full It is cleaned with sodium bicarbonate solution and saturated salt solution, decompression boils off solvent, obtains brown crude product, column chromatography for separation obtains white tablets Shape solid 2,3- Dichloro-N-methyl maleimides；(3) synthesis of 2,3- bis- (3- indoles)-N- methylmaleimidosThe preparation of a bromoethane Grignard ReagentN2Under protection, magnesium rod and anhydrous ether are added in into reaction vessel, and bromoethane is added dropwise, acutely stirred after low-grade fever initiation reaction It mixes, bromoethane, which is added dropwise, makes solvent keep slight boiling condition, anhydrous ether is added after being added dropwise, reflux reacts fully, and obtains cigarette Grey bromoethane Grignard Reagent,The preparation of b indoles Grignard Reagent and the preparation of 2,3- bis- (3- indoles)-N- methylmaleimidosThe toluene solution of tetrahydrofuran, indoles and bromoethane Grignard Reagent is first added in into reaction vessel, solution turns black, in 40 DEG C reaction, then add in the toluene solution of 2,3- Dichloro-N-methyl maleimides, be added dropwise, solution be in reddish black, return The reaction was complete under the conditions of stream, is cooled to room temperature and adds in saturation NH4The quenching reaction of Cl solution, is extracted with ethyl acetate, merges organic Phase, decompression boil off solvent, and column chromatography for separation obtains red solid 2,3- bis- (3- indoles)-N- methylmaleimidos；(4) synthesis of 6- Methvl-indoles [2,3-a] pyrroles [3,4-c] carbazole -5,7- diketone2,3- bis- (3- indoles)-N- methylmaleimidos are added in into reaction vessel, adding in butanone makes its dissolving, adds carbon Sour potassium and copper chloride react reaction unit in 85 DEG C of oil bath pans, and TLC tracking and monitorings to raw material has reacted in reaction process Entirely, it is cooled to room temperature, filters, extraction, the hydrochloric acid solution for being 0.1mol/L with molar concentration cleans organic phase, then washes, nothing Water magnesium sulfate is dried, and decompression boils off solvent, obtains light yellow solid 6- Methvl-indoles [2,3-a] pyrroles [3,4-c] carbazole -5, 7- diketone；(5) synthesis of indoles [2,3-a] pyrroles [3,4-c] carbazole -5,6- dicarboxylic anhydrides6- Methvl-indoles [2,3-a] pyrroles [3,4-c] carbazole -5,7- diketone is added in into reaction vessel and mass concentration is 10% potassium hydroxide solution, back flow reaction, reaction process TLC tracking and monitorings are anti-to raw material in 90 DEG C of oil baths under magnetic agitation Should be complete, it is cooled to room temperature, reaction is quenched in the hydrochloric acid solution using molar concentration as 2mol/L, occurs a large amount of yellow in reaction vessel Solid is uniformly mixed until solution is in neutrality rear room temperature, is filtered, and washing obtains Tan solid indoles [2,3-a] pyrroles [3,4-c] carbazole -5,6- dicarboxylic anhydrides；(6) synthesis of 6- amino-indoles [2,3-a] pyrroles [3,4-c] carbazole -5,7- diketoneIndoles [2,3-a] pyrroles [3,4-c] carbazole -5,6- dicarboxylic anhydride and tetrahydrofuran are added in into reaction vessel, then water is added dropwise Hydrazine is closed, heats in 45 DEG C of oil bath, is reacted under counterflow condition, the reaction was complete for TLC tracking and monitorings to raw material, and decompression boils off molten Agent adds water a large amount of yellow mercury oxides occur, filters, and petroleum ether is washed, and obtains yellow solid 6- amino-indoles [2,3-a] pyrroles [3,4- C] carbazole -5,7- diketone.
- 5. a kind of anticancer pharmaceutical composition, it is characterised in that including indoles described in claim 1 [2,3-a] pyrroles [3,4-c] The fragrant hydrazone compounds of carbazole -5,7- diketone -6 or/and its pharmaceutically acceptable salt and pharmaceutically acceptable carrier.
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Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO1993018766A1 (en) * | 1992-03-20 | 1993-09-30 | The Wellcome Foundation Limited | Further indole derivatives with antiviral activity |
| EP0602597A2 (en) * | 1992-12-14 | 1994-06-22 | Banyu Pharmaceutical Co., Ltd. | Process for preparation of indolopyrrolocarbazole derivatives |
-
2016
- 2016-09-07 CN CN201610806300.8A patent/CN106478643B/en not_active Expired - Fee Related
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO1993018766A1 (en) * | 1992-03-20 | 1993-09-30 | The Wellcome Foundation Limited | Further indole derivatives with antiviral activity |
| EP0602597A2 (en) * | 1992-12-14 | 1994-06-22 | Banyu Pharmaceutical Co., Ltd. | Process for preparation of indolopyrrolocarbazole derivatives |
Non-Patent Citations (1)
| Title |
|---|
| Structure-Activity Relationships in a Series of Substituted Indolocarbazoles：Topoisomerase I and Protein Kinase C Inhibition and Antitumoral and Antimicrobial Properties;Elisabete Rodrigues Pereira，等;《J. Med. Chem.》;19961025;第39卷(第22期);第4473页图2、表1 * |
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