CN105481869A - Pyrano [3,2-a] phenazine derivative, preparation method and application thereof - Google Patents

Pyrano [3,2-a] phenazine derivative, preparation method and application thereof Download PDF

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CN105481869A
CN105481869A CN201510894070.0A CN201510894070A CN105481869A CN 105481869 A CN105481869 A CN 105481869A CN 201510894070 A CN201510894070 A CN 201510894070A CN 105481869 A CN105481869 A CN 105481869A
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pyrans
halogen
derivative
compound
preparation
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CN105481869B (en
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江峰
闫玉茹
陆园园
奚涛
刘代春
王志祥
邢莹莹
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China Pharmaceutical University
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China Pharmaceutical University
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
    • C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
    • C07D491/04—Ortho-condensed systems
    • C07D491/044—Ortho-condensed systems with only one oxygen atom as ring hetero atom in the oxygen-containing ring
    • C07D491/052—Ortho-condensed systems with only one oxygen atom as ring hetero atom in the oxygen-containing ring the oxygen-containing ring being six-membered

Abstract

The present invention belongs to the technical fields of pharmaceutical chemistry and medicine, and discloses a pyrano [3,2-a] phenazine derivative, a preparation method and application thereof in preparing antineoplastic drugs. The pyrano [3,2-a] phenazine derivative has a structural formula (I), wherein R1 represents H, halogen, -OCH3, or -NO2; R2 represents H, halogen, -OCH3, or -NO2; R3 represents H, -CH3, -C2H5, -CH(CH3)2, halogen, -OH, -OCH3, -N(CH3)2, -N(C2H5)2 or -NO2; R4 represents H, halogen, or -OCH3; R5 represents H, halogen, or -OCH3; and X represents -CN or -COOC2H5. The invention also discloses a preparation method and application of the pyrano [3,2-a] phenazine derivative in the preparation of antineoplastic drugs, the compound has strong inhibition effect on DNA topoisomerase and significant inhibitory activity on a plurality of multiple tumor cell lines, and shows great potential in the preparation of antineoplastic drugs.

Description

A kind of pyrans also [3,2-α] phenazene derivative and its production and use
Technical field
The present invention relates to pharmaceutical chemistry and medical art, that be specifically related to a class formation novelty, that there is anti-tumor activity pyrans also [3,2-a] phenazene derivative, and the preparation method of these compounds and pharmaceutical use.
Background technology
For a long time, malignant tumour has become one of principal disease of serious harm human life and quality of life.It is reported, malignant tumour has become the primary cause of the death of China resident, and along with ineffective to environment protection of expanding economy and people, the lethality rate of malignant tumour is also in continuous growth.The World Health Organization predicts, to the year two thousand twenty, will have 2,000 ten thousand de novo malignancy cases, wherein death toll reaches 1,200 ten thousand, and the overwhelming majority will occur in developing country.The research and development of antitumor drug are the focuses that global scientific research institution and drugmaker pay close attention to always, and the antitumor drug finding high-efficiency low-toxicity, high specificity is an important topic of medicament research and development.
DNA topoisomerase is that a kind of cell DNA that participates in copies, transcribes, recombinates and the important ribozyme of the basic activity such as reparation, by catalytic dna chain break and the topology status combining control DNA.Due to topoisomerase high expression level in fast proliferating cells is as cancer cells, become the extremely important action target spot of one of antitumor drug research and development.Clinical antitumor agents such as camptothecine, Etoposide and teniposide etc. are all take topoisomerase as the medicine of action target spot.Therefore, the research and development carrying out antitumor drug with DNA topoisomerase for target spot have great importance.
Summary of the invention
The object of this invention is to provide a series of pyrans also [3,2-a] phenazene derivative and preparation method thereof, and provide these compounds preparing the application in antitumor drug.
The general structure of pyrans of the present invention also [3,2-a] phenazene derivative is as shown in structural formula I:
R in formula 1for H, halogen ,-OCH 3or-NO 2; R 2for H, halogen ,-OCH 3or-NO 2; R 3for H ,-CH 3,-C 2h 5,-CH (CH 3) 2, halogen ,-OH ,-OCH 3,-N (CH 3) 2,-N (C 2h 5) 2or-NO 2; R 4for H, halogen or-OCH 3; R 5for H, halogen or-OCH 3.
X is-CN or-COOC 2h 5.
Described halogen is fluorine, chlorine or bromine.
The present invention provide simultaneously a kind of pyrans also [3,2-a] phenazene derivative preparing the application in antitumor drug.
The present invention provides one to prepare the method for pyrans also [3,2-a] phenazene derivative simultaneously, comprises the following steps:
S1. O-Phenylene Diamine id reaction under iron trichloride effect, obtains structural formula such as formula the compound shown in II
S2. the product of step (1) and itrile group derivative and aromatic aldehyde are reacted, reactant is purified, obtains described pyrans also [3,2-a] phenazene derivative.
Described purifying is recrystallization.
The present invention also provides a kind of described pyrans also [3 simultaneously, 2-a] pyrans that obtains of the preparation method of phenazene derivative also [3,2-a] application of phenazene derivative, described pyrans also [3,2-a] phenazene derivative is preparing the application in antitumor drug.
Compared with prior art, the present invention has following beneficial effect:
(1) a kind of pyrans of novel structure also [3,2-a] phenazene derivative is provided, and is applied to antitumor drug.
(2) method provided is simply efficient, can have the diversity derivative of pyrans and the active skeleton of azophenlyene concurrently by rapid build.
(3) experiment proves, the novel pyrans that the present invention relates to also [3,2-a] phenazene derivative has significant restraining effect to multiple JEG-3, has wide application space preparing on cancer therapy drug.
Embodiment
Technical scheme of the present invention is further illustrated below by way of specific embodiment.
Embodiment 1: the synthesis of compound (II)
First O-Phenylene Diamine is dissolved in excessive concentrated hydrochloric acid solution, slowly add the aqueous solution of the iron trichloride of 2 times of equivalents, stirring reaction 1 ~ 5 hours at 60 ~ 70 DEG C, insoluble solid is dissolved in large water gaging after being cooled to room temperature, add strong caustic until produce precipitation, filtrate hcl acidifying after suction filtration, collect solid, vacuum-drying, next step reaction of not purified direct input.
Embodiment 2: the synthesis of compound JP-1
Isosorbide-5-Nitrae-diazabicyclo (2.2.2) octane of the propane dinitrile of compound (II) and 1 times of equivalent, the phenyl aldehyde of 1 times of equivalent, 0.3 times of equivalent under nitrogen protection in ethanol back flow reaction spend the night.Collect solid after being cooled to room temperature, use dehydrated alcohol recrystallization, obtain yellow solid.
Productive rate: 89%; 1hNMR (500MHz, DMSO-d 6) δ 7.99-7.95 (m, 2H), 7.73 (t, J=7.5Hz, 1H), 7.65 (t, J=7.5Hz, 1H), 7.38-7.36 (m, 2H), 7.24 (s, 2H), 7.08-7.04 (m, 4H), 6.51 (s, 2H), 5.54 (s, 1H); ESI-MSm/z:366 [M+H] +.
Embodiment 3: the synthesis of compound JP-2
Method is with embodiment 2, and difference replaces phenyl aldehyde with 4-ethylbenzene formaldehyde, obtains yellow solid.
Productive rate: 85%; 1hNMR (500MHz, DMSO-d 6) δ 8.03 (d, J=8.5Hz, 1H), 7.98-7.95 (m, 1H), 7.76-7.73 (m, 1H), 7.69-7.66 (m, 1H), 7.26 (d, J=8.0Hz, 2H), 7.08-7.02 (m, 5H), 6.50 (s, 2H), (5.51 s, 1H), 2.46 (q, J=7.5Hz, 2H), 1.07 (t, J=7.5Hz, 3H); ESI-MSm/z:394 [M+H] +.
Embodiment 4: the synthesis of compound JP-3
Method is with embodiment 2, and difference replaces phenyl aldehyde with 4-(N, N-dimethyl) amido phenyl aldehyde, obtains yellow solid.
Productive rate: 73%; 1hNMR (500MHz, DMSO-d 6) δ 8.16 (d, J=9.0Hz, 2H), 7.94 (t, J=9.0Hz, 2H), 7.76-7.72 (m, 1H), (7.67-7.61 m, 3H), 7.24 (s, 2H), 7.05 (s, 1H), (6.54 s, 2H), 5.66 (s, 1H), 3.47 (s, 6H); ESI-MSm/z:409 [M+H] +.
Embodiment 5: the synthesis of compound JP-4
Method is with embodiment 2, and difference replaces phenyl aldehyde with 2-fluorobenzaldehyde, obtains yellow solid.
Productive rate: 78%; 1hNMR (500MHz, DMSO-d 6) δ 7.94 (s, 1H), 7.85 (s, 1H), 7.71 (s, 1H), 7.63 (s, 1H), 7.40 (s, 1H), 7.13-7.03 (m, 6H), 6.51 (s, 2H), 5.99 (s, 1H); ESI-MSm/z:384 [M+H] +.
Embodiment 6: the synthesis of compound JP-5
Method is with embodiment 2, and difference replaces phenyl aldehyde with 4-fluorobenzaldehyde, obtains yellow solid.
Productive rate: 90%; 1hNMR (500MHz, DMSO) δ 8.01-7.95 (m, 2H), 7.72 (t, J=7.5Hz, 1H), 7.66 (t, J=7.5Hz, 1H), 7.44-7.40 (m, 2H), 7.11 (s, 2H), (7.08-7.03 m, 3H), 6.52 (s, 2H), 5.55 (s, 1H); ESI-MSm/z:384 [M+H] +.
Embodiment 7: the synthesis of compound JP-6
Method is with embodiment 2, and difference replaces phenyl aldehyde with 2-chlorobenzaldehyde, obtains yellow solid.
Productive rate: 80%; 1hNMR (500MHz, DMSO-d 6) δ 7.95-7.94 (m, 1H), 7.88-7.87 (m, 1H), 7.71 (s, 1H), (7.63 s, 1H), 7.25 (s, 1H), 7.16-7.11 (m, 2H), (7.04 s, 4H), 6.51 (s, 2H), 5.76 (s, 1H); ESI-MSm/z:400 [M+H] +.
Embodiment 8: the synthesis of compound JP-7
Method is with embodiment 2, and difference replaces phenyl aldehyde with 4-chlorobenzaldehyde, obtains yellow solid.
Productive rate: 87%; 1hNMR (500MHz, DMSO-d 6) δ 8.01-7.96 (m, 2H), 7.74 (t, J=7.5Hz, 1H), 7.66 (t, J=7.5Hz, 1H), (7.39-7.37 m, 2H), 7.31-7.29 (m, 2H), 7.11 (s, 2H), (7.04 s, 1H), 6.51 (s, 2H), 5.54 (s, 1H); ESI-MSm/z:400 [M+H] +.
Embodiment 9: the synthesis of compound JP-8
Method is with embodiment 2, and difference replaces phenyl aldehyde with 2-nitrobenzaldehyde, obtains yellow solid.
Productive rate: 80%; 1hNMR (500MHz, DMSO-d 6) δ 7.95-7.94 (m, 1H), 7.91-7.87 (m, 1H), 7.73 (s, 1H), (7.66 s, 1H), 7.22 (s, 1H), 7.17-7.13 (m, 2H), (7.02 s, 4H), 6.53 (s, 2H), 6.19 (s, 1H); ESI-MSm/z:411 [M+H] +.
Embodiment 10: the synthesis of compound JP-9
Method is with embodiment 2, and difference replaces phenyl aldehyde with m-methoxybenzaldehyde, obtains yellow solid.
Productive rate: 84%; 1hNMR (500MHz, DMSO-d 6) δ 8.03 (d, J=7.5Hz, 1H), 7.97 (d, J=7.5Hz, 1H), (7.75 s, 1H), 7.68 (s, 1H), 7.16 (s, 1H), (7.08 s, 2H), 7.03 (s, 1H), 6.99 (s, 1H), 6.88 (d, J=6.0Hz, 1H), 6.69 (d, J=6.5Hz, 1H), (6.49 s, 2H), 5.53 (s, 1H), 3.68 (s, 3H); ESI-MSm/z:396 [M+H] +.
Embodiment 11: the synthesis of compound JP-10
Method is with embodiment 2, and difference replaces phenyl aldehyde with 2,4 dichloro benzene formaldehyde, obtains yellow solid.
Productive rate: 85%; 1hNMR (500MHz, DMSO-d 6) δ 7.94 (d, J=7.5Hz, 1H), 7.83 (d, J=7.5Hz, 1H), 7.71 (t, J=7.5Hz, 1H), 7.63 (t, J=7.5Hz, 1H), 7.55 (s, 1H), 7.21 (s, 1H), 7.17 (s, 1H), 7.08 (s, 2H), 6.96 (s, 1H), 6.51 (s, 2H), 5.94 (s, 1H); ESI-MSm/z:434 [M+H] +.
Embodiment 12: the synthesis of compound JP-11
Method is with embodiment 2, and difference replaces phenyl aldehyde with 3,4-dichlorobenzaldehyde, obtains yellow solid.
Productive rate: 89%; 1hNMR (500MHz, DMSO-d 6) δ 8.01-7.97 (m, 2H), 7.76 (t, J=7.5Hz, 1H), 7.68 (t, J=7.5Hz, 1H), (7.65 s, 1H), 7.50 (d, J=8.0Hz, 1H), 7.33 (d, J=8.0Hz, 1H), 7.17 (s, 2H), 7.05 (s, 1H), 6.52 (s, 2H), 5.57 (s, 1H); ESI-MSm/z:434 [M+H] +.
Embodiment 13: the synthesis of compound JP-12
Method is with embodiment 2, and difference replaces phenyl aldehyde with the fluoro-4-methoxybenzaldehyde of 3-, obtains yellow solid.
Productive rate: 77%; 1hNMR (500MHz, DMSO-d 6) δ 8.04 (d, J=8.5Hz, 1H), 7.97 (d, J=8.5Hz, 1H), 7.75 (t, J=7.5Hz, 1H), 7.68 (t, J=7.5Hz, 1H), 7.19-7.17 (m, 1H), 7.13-7.11 (m, 1H), 7.08 (s, 2H), 7.04-7.01 (m, 2H), 6.49 (s, 2H), 5.51 (s, 1H), 3.72 (s, 3H); ESI-MSm/z:414 [M+H] +.
Embodiment 14: the synthesis of compound JP-13
Method is with embodiment 2, and difference replaces phenyl aldehyde with 3-bromo-4,5-dimethoxy phenyl aldehyde, obtains yellow solid.
Productive rate: 72%; 1hNMR (500MHz, DMSO-d 6) δ 8.09 (d, J=8.0Hz, 1H), 7.99 (d, J=8.0Hz, 1H), 7.78-7.71 (m, 2H), 7.37 (s, 1H), 7.16 (s, 2H), 7.04 (s, 1H), 6.97 (s, 1H), 6.50 (s, 2H), 5.57 (s, 1H), 3.81 (s, 3H), 3.62 (s, 3H); ESI-MSm/z:504 [M+H] +.
Embodiment 15: the synthesis of compound JP-14
Method is with embodiment 2, and difference replaces propane dinitrile with ethyl cyanoacetate, and 4-(N, N-dimethyl) amido phenyl aldehyde replaces phenyl aldehyde, obtains yellow solid.
Productive rate: 73%; 1hNMR (500MHz, DMSO-d 6) δ 8.21 (d, J=8.5Hz, 2H), 7.99 (t, J=8.5Hz, 2H), 7.74-7.70 (m, 1H), 7.66-7.61 (m, 3H), 7.29 (s, 2H), 7.05 (s, 1H), 6.57 (s, 2H), 5.61 (s, 1H), (4.13-4.08 m, 2H), 1.26 (t, J=7.0Hz, 6H), 1.20 (t, J=7.0Hz, 3H); ESI-MSm/z:456 [M+H] +.
Embodiment 16: the synthesis of compound JP-15
Method is with embodiment 2, and difference replaces propane dinitrile with ethyl cyanoacetate, and 2-nitrobenzaldehyde replaces phenyl aldehyde, obtains yellow solid.
Productive rate: 73%; 1hNMR (500MHz, DMSO-d 6) δ 7.98 (d, J=8.5Hz, 1H), 7.92 (d, J=8.5Hz, 1H), 7.84 (d, J=8.5Hz, 1H), 7.74-7.71 (m, 1H), 7.68-7.62 (m, 1H), 7.58 (s, 2H), 7.52-7.49 (m, 1H), 7.41 (dd, J=8.0,1.5Hz, 1H), 7.28-7.24 (m, 1H), 6.99 (s, 1H), (6.79 s, 1H), 6.58 (s, 2H), 4.07-3.97 (m, 2H), 1.08 (t, J=7.0Hz, 3H); ESI-MSm/z:458 [M+H] +.
Embodiment 17: the synthesis of compound JP-16
Method is with embodiment 2, and difference replaces propane dinitrile with ethyl cyanoacetate, and 3-nitrobenzaldehyde replaces phenyl aldehyde, obtains yellow solid.
Productive rate: 74%; 1hNMR (500MHz, DMSO-d 6) δ 8.29 (s, 1H), 8.07 (d, J=7.0Hz, 1H), 7.96 (d, J=7.0Hz, 1H), (7.91 d, J=6.0Hz, 1H), 7.83 (d, J=5.5Hz, 1H), 7.74 (s, 1H), (7.68 s, 1H), 7.56 (s, 2H), 7.48 (s, 1H), (7.03 s, 1H), 6.61 (s, 2H), 5.99 (s, 1H), 4.08 (q, J=7.5Hz, 2H), 1.17 (t, J=7.5Hz, 3H); ESI-MSm/z:458 [M+H] +.
Embodiment 18: the synthesis of compound JP-17
Method is with embodiment 2, and difference replaces propane dinitrile with ethyl cyanoacetate, and 4-nitrobenzaldehyde replaces phenyl aldehyde, obtains yellow solid.
Productive rate: 72%; 1hNMR (500MHz, DMSO-d 6) δ 8.11 (d, J=8.5Hz, 1H), 8.06 (d, J=8.5Hz, 2H), 7.97 (d, J=8.5Hz, 1H), 7.76-7.73 (m, 1H), 7.70-7.66 (m, 3H), 7.55 (s, 1H), 7.02 (s, 2H), 6.60 (s, 2H), (5.97 s, 1H), 4.09 (q, J=7.0Hz, 2H), 1.19 (t, J=7.0Hz, 3H); ESI-MSm/z:458 [M+H] +.
Embodiment 19: the synthesis of compound JP-18
Method is with embodiment 2, and difference replaces propane dinitrile with ethyl cyanoacetate, and 2-fluorobenzaldehyde replaces phenyl aldehyde, obtains yellow solid.
Productive rate: 81%; 1hNMR (500MHz, DMSO-d 6) δ 7.98 (d, J=8.5Hz, 1H), 7.95 (d, J=8.5Hz, 1H), (7.74-7.70 m, 1H), 7.68-7.65 (m, 1H), 7.45 (bs, 2H), (7.43-7.40 t, J=8.5Hz, 1H), (7.06-7.04 m, 2H), 7.01-6.96 (m, 2H), 6.55 (s, 2H), (6.01 s, 1H), 4.06-4.03 (m, 2H), (1.17 t, J=7.0Hz, 3H); ESI-MSm/z:431 [M+H] +.
Embodiment 20: the synthesis of compound JP-19
Method is with embodiment 2, and difference replaces propane dinitrile with ethyl cyanoacetate, and 4-chlorobenzaldehyde replaces phenyl aldehyde, obtains yellow solid.
Productive rate: 79%; 1hNMR (500MHz, DMSO-d 6) δ 8.09 (d, J=8.5Hz, 1H), 7.97 (d, J=8.5Hz, 1H), 7.77-7.73 (m, 1H), 7.70-7.67 (m, 1H), (7.48 s, 2H), 7.41 (s, 1H), 7.39 (s, 1H), 7.22 (dd, J=6.5,2.0Hz, 2H), 7.00 (s, 1H), (6.57 s, 2H), 5.87 (s, 1H), 4.09 (m, 2H), 1.19 (t, J=7.0Hz, 3H); ESI-MSm/z:447 [M+H] +.
Embodiment 21: the synthesis of compound JP-20
Method is with embodiment 2, and difference replaces propane dinitrile with ethyl cyanoacetate, and 2-bromobenzaldehyde replaces phenyl aldehyde, obtains yellow solid.
Productive rate: 81%; 1hNMR (500MHz, DMSO-d 6) δ 8.19 (d, J=8.5Hz, 1H), 7.97 (d, J=8.5Hz, 1H), 7.76-7.73 (m, 1H), 7.70-7.67 (m, 1H), 7.55 (s, 2H), (7.47 dd, J=8.0,1.0Hz, 1H), (7.29 dd, J=7.5,1.0Hz, 1H), 7.19-7.16 (m, 1H), 7.02 (s, 1H), (6.96-6.92 m, 1H), 6.59 (s, 2H), 6.14 (s, 1H), (4.11 q, J=7.0Hz, 2H), (1.20 t, J=7.0Hz, 3H); ESI-MSm/z:491 [M+H] +.
Embodiment 22: the synthesis of compound JP-21
Method is with embodiment 2, and difference replaces propane dinitrile with ethyl cyanoacetate, and 2,3 dichloro benzaldehyde replaces phenyl aldehyde, obtains yellow solid.
Productive rate: 75%; 1hNMR (500MHz, DMSO-d 6) δ 8.03 (d, J=7.5Hz, 1H), 7.94 (d, J=7.5Hz, 1H), (7.74-7.71 m, 1H), 7.69-7.65 (m, 1H), 7.55 (s, 2H), (7.28 d, J=8.0Hz, 2H), (7.15-7.12 m, 1H), 7.00 (s, 1H), 6.57 (s, 2H), (6.20 s, 1H), 4.09-4.02 (m, 2H), (1.14 t, J=7.0Hz, 3H); ESI-MSm/z:481 [M+H] +.
Embodiment 23: the synthesis of compound JP-22
Method is with embodiment 2, and difference replaces propane dinitrile with ethyl cyanoacetate, and 2,4 dichloro benzene formaldehyde replaces phenyl aldehyde, obtains yellow solid.
Productive rate: 72%; 1hNMR (500MHz, DMSO-d 6) δ 8.05 (d, J=8.5Hz, 1H), 7.95 (d, J=8.5Hz, 1H), 7.75-7.71 (m, 1H), 7.69-7.65 (m, 1H), 7.54 (s, 2H), (7.38 d, J=2.5Hz, 1H), 7.35 (d, J=8.0Hz, 1H), 7.21 (dd, J=8.5,2.0Hz, 1H), (7.00 s, 1H), 6.56 (s, 2H), 6.10 (s, 1H), (4.06 q, J=7.0Hz, 2H), (1.17 t, J=7.0Hz, 3H); ESI-MSm/z:481 [M+H] +.
Embodiment 24: the synthesis of compound JP-23
Method is with embodiment 2, and difference replaces propane dinitrile with ethyl cyanoacetate, and the fluoro-4-methoxybenzaldehyde of 3-replaces phenyl aldehyde, obtains yellow solid.
Productive rate: 77%; 1hNMR (500MHz, DMSO-d 6) δ 8.11 (d, J=8.0Hz, 1H), 7.98 (d, J=8.0Hz, 1H), 7.77-7.74 (m, 1H), 7.71-7.68 (m, 1H), 7.46 (s, 2H), (7.18 dd, J=12.5,2.0Hz, 1H), (7.09-7.06 m, 1H), 7.00 (s, 1H), 6.94 (t, J=8.5Hz, 1H), 6.56 (s, 2H), (5.84 s, 1H), 4.13-4.09 (m, 2H), 3.68 (s, 3H), (1.20 t, J=7.0Hz, 3H); ESI-MSm/z:461 [M+H] +.
Embodiment 25: the synthesis of compound JP-24
Method is with embodiment 2, and difference replaces propane dinitrile with ethyl cyanoacetate, and 3-bromo-4,5-dimethoxy phenyl aldehyde replaces 3,4-dichlorobenzaldehyde, obtains yellow solid.
Productive rate: 67%; 1hNMR (500MHz, DMSO-d 6) δ 8.16 (d, J=8.5Hz, 1H), 7.98 (d, J=8.5Hz, 1H), 7.83-7.75 (m, 1H), 7.73-7.70 (m, 1H), 7.50 (s, 2H), (7.33 d, J=2.0Hz, 1H), (7.01 s, 1H), 6.91 (d, J=2.0Hz, 1H), 6.57 (s, 2H), 5.87 (s, 1H), (4.15-4.10 m, 2H), 3.78 (s, 3H), 3.58 (s, 3H), (1.20 t, J=7.0Hz, 3H); ESI-MSm/z:551 [M+H] +.
Embodiment 26: the synthesis of compound JP-25
Method is with embodiment 2, and difference replaces propane dinitrile with ethyl cyanoacetate, and bromo-3, the 5-dimethoxy benzaldehydes of 4-replace 3,4-dichlorobenzaldehyde, obtain yellow solid.
Productive rate: 71%; 1hNMR (500MHz, DMSO-d 6) δ 8.17 (d, J=8.5Hz, 1H), 7.99 (d, J=8.5Hz, 1H), 7.78-7.74 (m, 1H), 7.72-7.69 (m, 1H), 7.52 (s, 2H), 7.01 (s, 1H), 6.81 (s, 2H), 6.55 (s, 2H), 5.93 (s, 1H), 4.13-4.10 (m, 2H), 3.73 (s, 6H), 1.20 (t, J=7.0Hz, 3H); ESI-MSm/z:551 [M+H] +.
Embodiment 55: pyrans described in this patent also [3,2-a] phenazene derivative to the restraining effect of growth of tumour cell
With four kinds of tumor cell line HCT116 (human colorectal cancer cell), MCF7 (human breast cancer cell), HepG2 (human liver cancer cell), A549 (human lung adenocarcinoma cell), with clinical anti-cancer drug hydroxy camptothecine (HCPT) and cis-platinum (Cisplatin) for positive control drug, adopt CCK8 method to carry out cell in vitro poison and measure.First cell is laid in 96 orifice plates, cellar culture 24 hours.Then the pyrans of different concns also [3,2-a] phenazene derivative add in cell, act on after 44 hours, add CCK8 solution in each hole, hatch 4 hours at 37 DEG C, measure its absorbancy.Calculate compound concentration when cell growth inhibiting reaches 50% respectively, with IC 50value represents, result is as shown in table 1.Result shows that compound described in this patent has stronger restraining effect to these four kinds of tumor cell lines in vitro.Therefore pyrans of the present invention also [3,2-a] phenazene derivative can be used for preparing anti-tumor drug.
Restraining effect (the IC of table 1 compound on tumor cell strain growth 50/ μM)

Claims (6)

1. a pyrans also [3,2-a] phenazene derivative, its structural formula is such as formula shown in I:
R in formula 1for H, halogen ,-OCH 3or-NO 2; R 2for H, halogen ,-OCH 3or-NO 2; R 3for H ,-CH 3,-C 2h 5,-CH (CH 3) 2, halogen ,-OH ,-OCH 3,-N (CH 3) 2,-N (C 2h 5) 2or-NO 2; R 4for H, halogen or-OCH 3; R 5for H, halogen or-OCH 3.
X is-CN or-COOC 2h 5.
2. pyrans also [3,2-a] phenazene derivative as claimed in claim 1, it is characterized in that, described halogen is fluorine, chlorine or bromine.
3. the purposes an of pyrans as claimed in claim 1 also [3,2-a] phenazene derivative, it is characterized in that, described pyrans also [3,2-a] phenazene derivative is preparing the application in antitumor drug.
4. prepare the method for pyrans as claimed in claim 1 also [3,2-a] phenazene derivative for one kind, it is characterized in that, comprise the following steps:
S1. O-Phenylene Diamine id reaction under iron trichloride effect, obtains structural formula such as formula the compound shown in II
S2. the product of step (1) and itrile group derivative and aromatic aldehyde are reacted, reactant is purified, obtains described pyrans also [3,2-a] phenazene derivative.
5. the preparation method of pyrans as claimed in claim 4 also [3,2-a] phenazene derivative, it is characterized in that, described purifying is recrystallization.
6. a pyrans as claimed in claim 4 also [3,2-a] application of the pyrans that obtains of the preparation method of phenazene derivative also [3,2-a] phenazene derivative, it is characterized in that, described pyrans also [3,2-a] phenazene derivative is preparing the application in antitumor drug.
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Non-Patent Citations (1)

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Title
ALIREZA HASANINEJAD等: "One-pot, sequential four-component synthesis of benzo[c]pyrano[3,2-a]phenazine, bis-benzo[c]pyrano[3,2-a]phenazine and oxospiro benzo[c]pyrano[3,2-a]phenazine derivatives using 1,4-diazabicyclo[2.2.2]octane (DABCO) as an efficient and reusable solid base c", 《MOL DIVERS》 *

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CN110156703A (en) * 2019-05-21 2019-08-23 中国药科大学 As the phenazene derivative of TrxR1 inhibitor, intermediate product and its preparation method and application
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