CN103360327B - A kind of phenonaphthazine derivative and its preparation method and application - Google Patents
A kind of phenonaphthazine derivative and its preparation method and application Download PDFInfo
- Publication number
- CN103360327B CN103360327B CN201210538379.2A CN201210538379A CN103360327B CN 103360327 B CN103360327 B CN 103360327B CN 201210538379 A CN201210538379 A CN 201210538379A CN 103360327 B CN103360327 B CN 103360327B
- Authority
- CN
- China
- Prior art keywords
- phenonaphthazine
- derivative
- compound
- msm
- hnmr
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Expired - Fee Related
Links
Landscapes
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The invention belongs to medicine and chemical field, disclose a kind of phenonaphthazine analog derivative and preparation method thereof and the purposes as cancer therapy drug.This phenonaphthazine derivative as shown in structural formula (I), wherein R
1, R
2for H, halogen ,-OCH
3or-NO
2; And R
1, R
2=-O-CH
2-O-; N=1 or 2; R represents various aliphatic amide, comprises chain and ring-shaped fat amine.The present invention discloses the preparation method of this phenonaphthazine derivative and the purposes as cancer therapy drug thereof, this phenonaphthazine derivative has very strong restraining effect to topoisomerase I and topoisomerase II, to multiple JEG-3, there is significant restraining effect, have wide application space preparing on cancer therapy drug.
Description
Technical field
The present invention relates to medicine and chemical field, relate to a kind of phenonaphthazine derivative and its preparation method and application.
Background technology
Cancer is the principal disease threatening human health and life security, and according to statistics, the whole world is about newly-increased cancer patients reaches 4,000,000 people every year.The research and development of cancer therapy drug are the focuses that chemist and medicine scholar pay close attention to always.Finding the cancer therapy drug efficient, highly selective, toxic side effect are little is one of important directions of drug development research.
The duplex character of DNA make its in copying, repair and being faced with in transcription topographic morphologies problem.The topographic morphologies of these nucleic acid substances needs the correct interaction critically regulated and controled to meeting DNA and various different albumen.Topoisomerase (topoisomerases) is exactly the executive of this system precision control, and they are sheared by continuous DNA and maintain the correct topological framework of DNA with being connected again, makes DNA replication dna and transcribes smooth.
Human topoisomerase is high expression level in fast proliferating cells, and at DNA replication dna, transcribe and in Chromosome recombination, play important role.The disappearance of human topoisomerase causes the death of cell the most at last, and thus the nuclease of this high conservative is regarded as a kind of important antitumor action target spot.According to estimates, the medicine of at least one targeted human topoisomerase is contained in the embolic chemotherapy of about half.Therefore, the antitumor drug of R & D design target topoisomerase has great importance.
Summary of the invention
The object of the invention is to, a kind of novel phenonaphthazine derivative is provided, fills up the blank of the antitumor drug of target topoisomerase.
First provide a kind of phenonaphthazine derivative, its structural formula 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; Or R
1and R
2for connecting R simultaneously
1, R
2-the O-CH of position
2-O-,
R is C
2-C
5aliphatic amide,
N=1 or 2.
Described C
2-C
5aliphatic amide is chain or ring-shaped fat, and amine is preferably dimethylin, diethylin, piperidyl, methylpiperazine base, pyrryl or morpholinyl.
Described halogen is fluorine or chlorine,
R1 is preferably-OCH3, R2 and is preferably-OCH3; Or preferably R1 with R2 is the-O-CH2-O-being connected R1 and R2 position simultaneously,
R is preferably dimethylin, diethylin, piperidyl, methylpiperazine base or pyrryl,
The present invention provides a kind of phenonaphthazine derivative preparing the application in cancer therapy drug simultaneously.
The present invention provides a kind of method preparing phenonaphthazine derivative simultaneously, comprises the following steps:
S1.2-hydroxyl-1,4-naphthoquinone and substituted o-phenylenediamine condensation, obtain structural formula as made the compound shown in II
S2. the product of step (1) and two bromoalkanes being reacted, obtaining structural formula as made the compound shown in III
S3. by the product of step S2 and C
2-C
5aliphatic amide reaction, reactant is purified, obtains described phenonaphthazine derivative.
Described purifying is column chromatography or recrystallization.
The application of the phenonaphthazine derivative that the present invention also provides a kind of preparation method of described phenonaphthazine derivative to obtain simultaneously, described phenonaphthazine derivative is preparing the application in cancer therapy drug.
Compared with prior art, the present invention has following beneficial effect:
(1) provide a kind of novel phenonaphthazine derivative, fill up the blank of targeted human topoisomerase medicine.
(2) method provided is simple, and gives number of ways, from the different types of synthesis of multiple angle analysis, enumerates the production method of the derivative of all needs protections.
(3) experiment proves, novel phenonaphthazine derivative disclosed in this invention all has very strong effect to topoisomerase I and II, for topoisomerase double inhibitor, further Mechanism Study shows that the type compound can catch topoisomerase I-DNA break mixture, is the different I toxic agent of topology; Can, in conjunction with the ATP hydrolysis zone (ATPase) suppressing human topoisomerase II α, be topo II catalytic inhibitor, mechanism of action be novel.
(4) further experiment proves, the novel phenonaphthazine derivative that the present invention relates to 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 A-13
2 hydroxy 1,4 naphthoquinone (lawsone) and the O-Phenylene Diamine Glacial acetic acid of 1:1 equivalent are molten, and 60 DEG C are reacted 1 hour.Reaction is finished, cooling, and pour frozen water into, suction filtration obtains red solid, next step reaction of not purified direct input.
Compound A-13
Embodiment 2: the synthesis of compd A 4-1
1,3-dibromopropane of raw material A 3 and 5 times of equivalents, Anhydrous potassium carbonate under nitrogen protection in second eyeball 60 DEG C of reactions spend the night.Pass through purified on silica using petrol ether/ethyl acetate/methylene dichloride (volume ratio 20:1:1) as eluent after revolving desolventizing, obtain yellow solid.
Productive rate: 60%;
1hNMR (400MHz, CDCl
3) δ 9.24 (d, J=7.7Hz, 1H), 8.18 (t; J=7.5Hz, 2H), 8.07 (d, J=8.2Hz; 1H), 7.76 – 7.64 (m, 4H), 7.06 (s; 1H), 4.36 (t, J=5.7Hz; 2H), 3.64 (t, J=6.4Hz; 2H), 2.52 – 2.39 (m, 2H); ESI-MSm/z:367 [M+H]+.
Compd A 4-1
Embodiment 3: the synthesis of compd A 4-2
Raw material A 3, i.e. embodiment 1 product, with the Isosorbide-5-Nitrae-dibromobutane of 5 times of equivalents, Anhydrous potassium carbonate under nitrogen protection in second eyeball 60 DEG C of reactions spend the night.Pass through purified on silica using petrol ether/ethyl acetate/methylene dichloride (volume ratio 20:1:1) as eluent after revolving desolventizing, obtain yellow solid.
Productive rate: 62%;
1hNMR (400MHz, CDCl
3) δ 9.38 – 9.25 (m, 1H), 8.27 (d, J=7.7Hz, 2H), 8.14 (d, J=8.6Hz, 1H), 7.85 – 7.72 (m, 4H), 7.09 (s, 1H), 4.31 (t, J=5.3Hz, 2H), 3.56 (t, J=6.1Hz, 2H), 2.25 – 2.10 (m, 4H) .ESI-MSm/z:381 [M+H]+.
Compd A 4-2
Embodiment 4: the synthesis of compound N KN-a1
The dimethylamine hydrochloride of raw material A 4-1 and 5 times equivalent, Anhydrous potassium carbonate under nitrogen protection in second eyeball 60 DEG C of reactions spend the night.Wash by saturated salt after revolving desolventizing and part amine, dichloromethane extraction, revolves evaporate to dryness dry.Using sherwood oil/methylene chloride/methanol/ammoniacal liquor (volume ratio 25:100:1:2 → 25:100:2:2) as eluent by purified on silica, obtain yellow solid.
Productive rate: 55%;
1hNMR (400MHz, CDCl
3) δ 9.32 (dd, J=4.3,2.8Hz, 1H), 8.34 – 8.25 (m, 2H), 8.17 – 8.11 (m, 1H), 7.83 – 7.72 (m, 4H), 7.13 (s, 1H), 4.36 (t, J=6.2Hz, 2H), 2.63 – 2.57 (m, 2H), 2.32 (s, 6H), 2.21 – 2.13 (m, 2H) .ESI-MSm/z:332 [M+H]+.
Compound N KN-a1
Embodiment 5: the synthesis of compound N KN-a2
Method is with embodiment 4, and difference replaces dimethylamine hydrochloride with diethylamine, obtains yellow solid.
Productive rate: 60%;
1hNMR (400MHz, CDCl
3) δ 9.41 – 9.34 (m, 1H), 8.36 – 8.26 (m, 2H), 8.17 (dd, J=8.3,1.1Hz, 1H), 7.87 – 7.73 (m, 4H), 7.19 (s, 1H), 4.40 (t, J=6.1Hz, 2H), 2.90 – 2.81 (m, 2H), 2.70 (q, J=7.1Hz, 4H), 2.30 – 2.19 (m, 2H), 1.14 (t, J=7.2Hz, 6H) .ESI-MSm/z:360 [M+H]+.
Compound N KN-a2
Embodiment 6: the synthesis of compound N KN-a3
Method is with embodiment 4, and difference replaces dimethylamine hydrochloride with piperidines, obtains yellow solid.
Productive rate: 62%;
1hNMR (400MHz, CDCl
3) δ 9.28 – 9.20 (m, 1H), 8.19 (dd, J=15.0,12.8Hz, 2H), 8.08 (dd, J=8.3,0.9Hz, 1H), 7.79 – 7.64 (m, 4H), 7.01 (s, 1H), 4.26 (dd, J=14.1,7.9Hz, 2H), 2.61 – 2.54 (m, 2H), 2.43 (s, 4H), 2.21 – 2.06 (m, 2H), 1.61 (dt, J=10.9,5.5Hz, 4H), 1.45 (d, J=5.1Hz, 2H) .ESI-MSm/z:372 [M+H]+.
Compound N KN-a3
Embodiment 7: the synthesis of compound N KN-a4
Method is with embodiment 4, and difference replaces dimethylamine hydrochloride with methylpiperazine, obtains yellow solid.
Productive rate: 65%;
1hNMR (400MHz, CDCl
3) δ 9.41 – 9.35 (m, 1H), 8.37 – 8.28 (m, 2H), 8.20 – 8.14 (m, 1H), 7.86 – 7.74 (m, 4H), (7.19 s, 1H), 4.40 (t, J=6.3Hz, 2H), 2.71 – 2.66 (m, 2H), 2.56 (d, J=27.0Hz, 8H), 2.32 (s, 3H), 2.21 (dt, J=13.2,6.5Hz, 2H) .ESI-MSm/z:387 [M+H]+.
Compound N KN-a4
Embodiment 8: the synthesis of compound N KN-a5
Method is with embodiment 4, and difference replaces dimethylamine hydrochloride with pyrroles, obtains yellow solid.
Productive rate: 62%;
1hNMR (400MHz, CDCl
3) δ 9.28 – 9.22 (m, 1H), 8.23 (ddd, J=14.6,7.1,3.2Hz, 2H), 8.12 – 8.04 (m, 1H), 7.79 – 7.67 (m, 4H), 7.04 (s, 1H), 4.29 (t, J=6.2Hz, 2H), 2.77 – 2.69 (m, 2H), 2.59 – 2.49 (m, 4H), 2.24 – 2.08 (m, 2H), 1.84 – 1.74 (m, 4H) .ESI-MSm/z:358 [M+H]+.
Compound N KN-a5
Embodiment 9: the synthesis of compound N KN-a6
Method is with embodiment 4, and difference replaces dimethylamine hydrochloride by morpholine, obtains yellow solid.
Productive rate: 52%;
1hNMR (400MHz, CDCl
3) δ 9.30 (dd, J=7.0,1.3Hz, 1H), 8.26 (d, J=8.4Hz, 2H), 8.14 (t, J=9.3Hz, 1H), 7.85 – 7.70 (m, 4H), (7.10 s, 1H), 4.33 (t, J=6.2Hz, 2H), 3.76 (dd, J=14.1,9.6Hz, 4H), 2.64 (t, J=7.2Hz, 2H), 2.51 (m, 4H), 2.22 – 2.09 (m, 2H) .ESI-MSm/z:374 [M+H]+.
Compound N KN-a6
Embodiment 10: the synthesis of compound N KN-b1
Method is with embodiment 4, and difference replaces compd A 4-1 with compd A 4-2, obtains yellow solid.
Productive rate: 62%;
1hNMR (400MHz, CDCl
3) δ 9.36 – 9.29 (m, 1H), 8.35 – 8.23 (m, 2H), 8.16 – 8.11 (m, 1H), 7.77 (td, J=6.7,2.1Hz, 4H), 7.10 (d, J=2.6Hz, 1H), 4.29 (d, J=5.9Hz, 2H), 2.40 (t, J=7.2Hz, 2H), 2.28 (s, 6H), 2.03 (d, J=5.8Hz, 2H), 1.80 (d, J=6.4Hz, 2H) .ESI-MSm/z:346 [M+H]+.
Compound N KN-b1
Embodiment 11: the synthesis of compound N KN-b2
Method is with embodiment 10, and difference replaces dimethylamine hydrochloride with diethylamine, obtains yellow solid.
Productive rate: 66%;
1hNMR (400MHz, CDCl
3) δ 9.30 – 9.21 (m, 1H), 8.24 (dd, J=10.3,8.1Hz, 2H), 8.10 (d, J=8.3Hz, 1H), 7.80 – 7.66 (m, 4H), 7.03 (s, 1H), 4.30 – 4.17 (m, 2H), 2.61 – 2.48 (m, 6H), 2.02 – 1.91 (m, 2H), 1.80 – 1.69 (m, 2H), 1.04 (t, J=7.1Hz, 6H) .ESI-MSm/z:374 [M+H]+.
Compound N KN-b2
Embodiment 12: the synthesis of compound N KN-b3
Method is with embodiment 10, and difference replaces dimethylamine hydrochloride with piperidines, obtains yellow solid.
Productive rate: 52%;
1hNMR (400MHz, CDCl
3) δ 9.35 – 9.28 (m, 1H), 8.34 – 8.23 (m, 2H), 8.13 (dt, J=10.1,5.3Hz, 1H), 7.84 – 7.69 (m, 4H), (7.10 s, 1H), 4.30 (t, J=6.3Hz, 2H), 2.47 – 2.37 (m, 6H), 2.07 – 1.94 (m, 2H), 1.81 (ddd, J=18.8,8.8,6.2Hz, 2H), 1.61 (dt, J=11.0,5.6Hz, 4H), 1.45 (d, J=4.9Hz, 2H) .ESI-MSm/z:386 [M+H]+.
Compound N KN-b3
Embodiment 13: the synthesis of compound N KN-b4
Method is with embodiment 10, and difference replaces dimethylamine hydrochloride with methylpiperazine, obtains yellow solid.
Productive rate: 67%;
1hNMR (400MHz, CDCl
3) δ 9.33 – 9.24 (m, 1H), 8.26 (t, J=7.6Hz, 2H), 8.12 (d, J=8.3Hz, 1H), 7.82 – 7.68 (m, 4H), 7.07 (s, 1H), 4.28 (t, J=6.0Hz, 2H), 2.71 – 2.43 (m, 10H), 2.29 (s, 3H), 2.05 – 1.94 (m, 2H), 1.81 (dd, J=13.6,6.7Hz, 2H) .ESI-MSm/z:401 [M+H]+.
Compound N KN-b4
Embodiment 14: the synthesis of compound N KN-b5
Method is with embodiment 10, and difference replaces dimethylamine hydrochloride with pyrroles, obtains yellow solid.
Productive rate: 62%;
1hNMR (400MHz, CDCl
3) δ 9.20 – 9.09 (m, 1H), 8.13 (dd, J=9.7,4.2Hz, 2H), 8.02 (d, J=8.3Hz, 1H), 7.72 – 7.57 (m, 4H), 6.87 (s, 1H), 4.14 (dt, J=12.6,6.3Hz, 2H), 2.49 (dd, J=8.9,5.8Hz, 6H), 1.97 – 1.87 (m, 2H), 1.77 (d, J=14.2Hz, 6H) .ESI-MSm/z:372 [M+H]+.
Compound N KN-b5
Embodiment 15: the synthesis of compound N KN-b6
Method is with embodiment 10, and difference replaces dimethylamine hydrochloride by morpholine, obtains yellow solid.
Productive rate: 52%;
1hNMR (400MHz, CDCl
3) δ 9.31 (d, J=7.8Hz, 1H), 8.29 (dd, J=16.9,10.0Hz, 2H), 8.13 (d, J=8.3Hz, 1H), 7.83 – 7.72 (m, 4H), (7.09 s, 1H), 4.36 – 4.24 (m, 2H), 3.76 – 3.69 (m, 4H), 2.56 – 2.41 (m, 6H), 2.05 – 1.97 (m, 2H), 1.80 (dt, J=14.9,7.5Hz, 2H) .ESI-MSm/z:388 [M+H]+.
Compound N KN-b6
Embodiment 16: the synthesis of compound F 17-hydroxy-corticosterone 1-1 and F2-1
The 2 hydroxy 1,4 naphthoquinone (lawsone) (3.48g, 20mmol) of 1:1 equivalent is molten with appropriate Glacial acetic acid with 3,4-diamino-fluorobenzene (2.52g, 20mmol), and 60 DEG C are reacted 1 hour.Pour the water of 5 times amount into, stir, suction filtration dries to obtain red solid.
1,3-dibromopropane of red solid and 5 times of equivalents, Anhydrous potassium carbonate under nitrogen protection in second eyeball 60 DEG C of reactions spend the night.Revolve desolventizing after washing, dichloromethane extraction, revolve evaporate to dryness dry.Using petrol ether/ethyl acetate/methylene dichloride (volume ratio 20:1:1) as eluent by purified on silica, obtain two yellow solid F1-1, F2-1.
F1-1: productive rate: 15%;
1hNMR (400MHz, CDCl
3) δ 9.33 (dd, J=7.7,1.3Hz, 1H), 8.30 (dd, J=9.4,5.9Hz, 2H), 7.83 (ddd, J=9.5,7.3,1.5Hz, 2H), 7.80 – 7.75 (m, 1H), (7.57 ddd, J=9.3,8.1,2.8Hz, 1H), 7.19 (s, 1H), 4.50 (t, J=5.8Hz, 2H), 3.74 (t, J=6.4Hz, 2H), 2.61 – 2.52 (m, 2H) .ESI-MSm/z:385 [M+H]+.
F2-1: productive rate: 35%;
1hNMR (400MHz, CDCl
3) δ 9.37 – 9.31 (m, 1H), 8.33 – 8.28 (m, 1H), 8.17 (dd, J=9.3,5.8Hz, 1H), 7.90 (dd, J=9.4,2.7Hz, 1H), 7.83 (pd, J=7.2,3.5Hz, 2H), 7.65 – 7.56 (m, 1H), (7.18 s, 1H), 4.49 (t, J=5.8Hz, 2H), 3.74 (t, J=6.4Hz, 2H), 2.62 – 2.52 (m, 2H) .ESI-MSm/z:385 [M+H]+.
The synthesis of embodiment 17: Compound C 1-1 and C2-1
4-chloro-2-nitroaniline (3.44g, 20mmol) is molten with Glacial acetic acid, adds zinc powder (13g, 200mmol) under stirring at room temperature in batches, and reaction 1 is little to disappear up to raw material point, rapid suction filtration.Add 2 hydroxy 1,4 naphthoquinone (lawsone) (3.48g, 20mmol) toward filtrate, 60 DEG C are reacted 1 hour.Pour the water of 5 times amount into, stir, suction filtration dries to obtain red solid.1,3-dibromopropane of red solid and 5 times of equivalents, Anhydrous potassium carbonate under nitrogen protection in second eyeball 60 DEG C of reactions spend the night.Revolve desolventizing after washing, dichloromethane extraction, revolve evaporate to dryness dry.Using petrol ether/ethyl acetate/methylene dichloride (volume ratio 20:1:1) as eluent by purified on silica, obtain two yellow solid C1-1, C2-1.
C1-1: productive rate: 15%;
1hNMR (400MHz, CDCl
3) δ 9.23 (d, J=7.0Hz, 1H), 8.23 (d, J=7.8Hz, 1H), 8.13 (d, J=9.0Hz, 1H), 8.07 (s, 1H), 7.77 (p, J=7.3Hz, 2H), 7.64 (dd, J=9.0,1.2Hz, 1H), 7.05 (s, 1H), (4.43 t, J=5.7Hz, 2H), 3.72 (t, J=6.4Hz, 2H), 2.60 – 2.47 (m, 2H) .ESI-MSm/z:401 [M+H]+.
C2-1: productive rate: 30%;
1hNMR (400MHz, CDCl
3) δ 9.34 – 9.27 (m, 1H), 8.31 – 8.27 (m, 1H), 8.27 (d, J=2.0Hz, 1H), 8.08 (d, J=9.1Hz, 1H), 7.85 – 7.77 (m, 2H), 7.72 (dd, J=9.0,2.2Hz, 1H), 7.14 (s, 1H), (4.48 t, J=5.8Hz, 2H), 3.73 (t, J=6.4Hz, 2H), 2.61 – 2.52 (m, 2H) .ESI-MSm/z:401 [M+H]+.
Embodiment 18: the synthesis of compound O1-1 and O2-1
4-methoxyl group-2-N-methyl-p-nitroaniline (3.36g, 20mmol) is molten with Glacial acetic acid, adds zinc powder (13g, 200mmol) under stirring at room temperature in batches, and reaction 1 is little to disappear up to raw material point, rapid suction filtration.Add 2 hydroxy 1,4 naphthoquinone (lawsone) (3.48g, 20mmol) toward filtrate, 60 DEG C are reacted 1 hour.Pour the water of 5 times amount into, stir, suction filtration dries to obtain red solid.
1,3-dibromopropane of red solid and 5 times of equivalents, Anhydrous potassium carbonate under nitrogen protection in second eyeball 60 DEG C of reactions spend the night.Revolve desolventizing after washing, dichloromethane extraction, revolve evaporate to dryness dry.Using petrol ether/ethyl acetate/methylene dichloride (volume ratio 20:1:1) as eluent by purified on silica, obtain two yellow solid O1-1, O2-1.
O1-1: productive rate: 37%;
1hNMR (400MHz, CDCl
3) δ 9.37 – 9.28 (m, 1H), 8.33 – 8.24 (m, 1H), 8.04 (d, J=9.2Hz, 1H), 7.85 – 7.74 (m, 2H), 7.53 (d, J=2.6Hz, 1H), 7.48 (dd, J=9.2,2.7Hz, 1H), 7.18 (s, 1H), 4.46 (t, J=5.7Hz, 2H), (4.04 s, 3H), 3.73 (t, J=6.5Hz, 2H), 2.60 – 2.48 (m, 2H) .ESI-MSm/z:397 [M+H]+.
O2-1: productive rate: 15%;
1hNMR (400MHz, CDCl
3) δ 9.32 (d, J=7.8Hz, 1H), 8.31 (d, J=7.1Hz, 1H), 8.18 (d, J=9.5Hz, 1H), 7.87 – 7.72 (m, 2H), 7.50 – 7.40 (m, 2H), (7.20 s, 1H), 4.49 (t, J=5.7Hz, 2H), 4.03 (s, 3H), 3.74 (t, J=6.5Hz, 2H), 2.63 – 2.50 (m, 2H) .ESI-MSm/z:397 [M+H]+.
Embodiment 19: the synthesis of compounds X 1-1 and X2-1
The 2 hydroxy 1,4 naphthoquinone (lawsone) (3.48g, 20mmol) of 1:1 equivalent is molten with appropriate Glacial acetic acid with 4-nitro-O-Phenylene Diamine (3.06g, 20mmol), and 60 DEG C are reacted 1 hour.Pour the water of 5 times amount into, stir, suction filtration dries to obtain red solid.
1,3-dibromopropane of red solid and 5 times of equivalents, Anhydrous potassium carbonate under nitrogen protection in second eyeball 60 DEG C of reactions spend the night.Revolve desolventizing after washing, dichloromethane extraction, revolve evaporate to dryness dry.Using petrol ether/ethyl acetate/methylene dichloride (volume ratio 20:1:1) as eluent by purified on silica, obtain two yellow solid X1-1, X2-1
X1-1: productive rate: 17%;
1hNMR (400MHz, CDCl
3) δ 9.33 – 9.26 (m, 1H), 8.99 (d, J=2.4Hz, 1H), 8.44 (dd, J=9.3,2.4Hz, 1H), 8.35 – 8.30 (m, 2H), 7.88 – 7.81 (m, 2H), 7.12 (s, 1H), 4.56 (t, J=5.7Hz, 2H), 3.75 (t, J=6.4Hz, 2H), 2.65 – 2.54 (m, 2H) .ESI-MSm/z:412 [M+H]+.
X2-1: productive rate: 33%;
1hNMR (400MHz, CDCl
3) δ 9.31 (dd, J=5.2,4.1Hz, 1H), 9.15 (d, J=2.3Hz, 1H), 8.51 (dd, J=9.3,2.3Hz, 1H), 8.37 – 8.31 (m, 1H), 8.21 (d, J=9.3Hz, 1H), 7.86 (p, J=6.5Hz, 2H), 7.15 (s, 1H), 4.51 (t, J=5.8Hz, 2H), 3.75 (t, J=6.4Hz, 2H), 2.63 – 2.55 (m, 2H) .ESI-MSm/z:412 [M+H]+.
Embodiment 20: the synthesis of compound F 17-hydroxy-corticosterone 1
Intermediate F1-1(384mg, 1mmol) with the Dimethylammonium chloride (405mg, 5mmol) of 5 times of equivalents, Anhydrous potassium carbonate (690mg, 5mmol) under nitrogen protection in second eyeball 60 DEG C of reactions spend the night.Wash with saturated aqueous common salt, saturated sodium bicarbonate solution after revolving desolventizing, dichloromethane extraction, revolves evaporate to dryness dry.Using sherwood oil/methylene chloride/methanol/ammoniacal liquor (volume ratio 75:170:1:2) as eluent by purified on silica, obtain yellow solid F1
Productive rate: 67%;
1hNMR (400MHz, CDCl
3) δ 9.29 – 9.23 (m, 1H), 8.32 – 8.26 (m, 1H), 8.23 (dd, J=9.3,5.9Hz, 1H), 7.83 – 7.74 (m, 2H), 7.71 (dd, J=9.6,2.8Hz, 1H), 7.52 (ddd, J=9.3,8.1,2.8Hz, 1H), 7.08 (s, 1H), 4.35 (t, J=6.3Hz, 2H), 2.63 – 2.55 (m, 2H), 2.32 (s, 6H), 2.21 – 2.13 (m, 2H) .ESI-MSm/z:350 [M+H]+.
Compound F 17-hydroxy-corticosterone 1
Embodiment 21: the synthesis of compound F 17-hydroxy-corticosterone 2
Method, with embodiment 20, replaces F1-1 unlike with F2-1, obtains yellow solid F2.
Productive rate: 57%;
1hNMR (400MHz, CDCl
3) δ 9.29 – 9.20 (m, 1H), 8.31 – 8.23 (m, 1H), 8.08 (dd, J=9.3,5.8Hz, 1H), 7.82 (dd, J=9.5,2.8Hz, 1H), 7.79 – 7.74 (m, 2H), 7.60 – 7.50 (m, 1H), 7.05 (s, 1H), 4.33 (t, J=6.2Hz, 2H), 2.63 – 2.54 (m, 2H), 2.32 (s, 6H), 2.16 (dt, J=13.3,6.5Hz, 2H) and .ESI-MSm/z:350 [M+H]+.
Compound F 17-hydroxy-corticosterone 2
Embodiment 22: the synthesis of Compound C 1
Method, with embodiment 20, replaces F1-1 unlike with C1-1, obtains yellow solid C1.
Productive rate: 66%;
1hNMR (400MHz, CDCl
3) δ 9.10 (dd, J=5.3,3.5Hz, 1H), (8.18 dd, J=6.5,2.5Hz, 1H), (8.01 d, J=9.0Hz, 1H), 7.96 (d, J=1.8Hz, 1H), 7.71 (dd, J=6.4,2.7Hz, 2H), 7.55 (dd, J=9.0,2.0Hz, 1H), (6.88 s, 1H), 4.24 (t, J=6.2Hz, 2H), 2.57 (t, J=7.3Hz, 2H), 2.32 (s, 6H), 2.17 – 2.09 (m, 2H) .ESI-MSm/z:366 [M+H]+.
Compound C 1
Embodiment 23: the synthesis of Compound C 2
Method, with embodiment 20, replaces F1-1 unlike with C2-1, obtains yellow solid C2.
Productive rate: 56%;
1hNMR (400MHz, CDCl
3) δ 9.21 – 9.15 (m, 1H), 8.27 – 8.22 (m, 1H), 8.16 (d, J=2.3Hz, 1H), 7.98 (d, J=9.0Hz, 1H), 7.79 – 7.72 (m, 2H), 7.65 (dd, J=9.0,2.3Hz, 1H), 7.00 (s, 1H), 4.31 (t, J=6.2Hz, 2H), 2.59 (t, J=7.3Hz, 2H), (2.32 s, 6H), 2.16 (dt, J=13.3,6.6Hz, 2H) .ESI-MSm/z:366 [M+H]+.
Compound C 2
Embodiment 24: the synthesis of compound O1
Method, with embodiment 20, replaces F1-1 unlike with O1-1, obtains yellow solid O1.
Productive rate: 52%;
1hNMR (400MHz, CDCl
3) δ 9.32 – 9.25 (m, 1H), 8.34 – 8.27 (m, 1H), 8.00 (d, J=9.2Hz, 1H), 7.80 – 7.73 (m, 2H), 7.48 (d, J=2.6Hz, 1H), 7.46 – 7.42 (m, 1H), 7.10 (s, 1H), 4.33 (t, J=6.2Hz, 2H), 4.01 (s, 3H), 2.62 – 2.55 (m, 2H), 2.31 (s, 6H), 2.20 – 2.11 (m, 2H) .ESI-MSm/z:362 [M+H]+.
Compound O1
Embodiment 25: the synthesis of compound O2
Method, with embodiment 20, replaces F1-1 unlike with O2-1, obtains yellow solid O2.
Productive rate: 66%;
1hNMR (400MHz, CDCl
3) δ 9.26 (m, J=7.8Hz, 1H), 8.30 (m, J=7.7Hz, 1H), 8.12 (d, J=9.2Hz, 1H), 7.75 (dt, J=16.7,7.3Hz, 2H), 7.40 (dd, J=9.2,2.6Hz, 1H), 7.36 (d, J=2.1Hz, 1H), 7.08 (s, 1H), 4.34 (t, J=6.1Hz, 2H), (3.99 s, 3H), 2.59 (t, J=7.3Hz, 2H), 2.31 (s, 6H), 2.21 – 2.12 (m, 2H) .ESI-MSm/z:362 [M+H]+.
Compound O2
Embodiment 26: the synthesis of compounds X 1
Method, with embodiment 20, replaces F1-1 unlike with X1-1, obtains yellow solid X1.
Productive rate: 51%;
1hNMR (400MHz, CDCl
3) δ 9.33 – 9.26 (m, 1H), 8.99 (d, J=2.4Hz, 1H), 8.44 (dd, J=9.3,2.4Hz, 1H), 8.35 – 8.30 (m, 2H), 7.88 – 7.81 (m, 2H), 7.12 (s, 1H), (4.41 t, J=6.3Hz, 2H), 2.62 (t, J=7.2Hz, 2H), 2.34 (s, 6H), 2.21 (dt, J=13.4,6.6Hz, 2H) .ESI-MSm/z:377 [M+H]+.
Compounds X 1
Embodiment 27: the synthesis of compounds X 2
Method, with embodiment 20, replaces F1-1 unlike with X2-1, obtains yellow solid X2.
Productive rate: 52%;
1hNMR (400MHz, CDCl
3) δ 9.31 (dd, J=5.2,4.1Hz, 1H), (9.15 d, J=2.3Hz, 1H), 8.51 (dd, J=9.3,2.3Hz, 1H), 8.37 – 8.31 (m, 1H), 8.21 (d, J=9.3Hz, 1H), 7.86 (p, J=6.5Hz, 2H), 7.15 (s, 1H), 4.43 (t, J=6.2Hz, 2H), 2.63 (t, J=7.2Hz, 2H), (2.34 s, 6H), 2.22 (dt, J=13.3,6.6Hz, 2H) .ESI-MSm/z:377 [M+H]+.
Compounds X 2
Embodiment 28: the synthesis of compd A 7
The sub-dimethyl benzene Glacial acetic acid of the 2 hydroxy 1,4 naphthoquinone (lawsone) of 1:1 equivalent and 1,2-diamino-4,5-is molten, 60 DEG C of reactions 1 hour.Reaction is finished, cooling, and pour frozen water into, suction filtration obtains red solid, next step reaction of not purified direct input.
Compd A 7
Embodiment 29: the synthesis of compound A-28-1
1,3-dibromopropane of compd A 7 and 5 times of equivalents, Anhydrous potassium carbonate under nitrogen protection in second eyeball 60 DEG C of reactions spend the night.Pass through purified on silica using petrol ether/ethyl acetate/methylene dichloride (volume ratio 20/1/1) as eluent after revolving desolventizing, obtain yellow solid.
Productive rate: 60%;
1hNMR (400MHz, CDCl
3) δ 9.34 – 9.26 (m, 1H), 8.35 – 8.27 (m, 1H), 7.86 – 7.68 (m, 2H), 7.52 (t, J=4.9Hz, 1H), 7.40 (d, J=3.2Hz, 1H), (7.19 s, 1H), 6.21 (d, J=3.6Hz, 2H), 4.47 (dd, J=7.5,3.9Hz, 2H), 3.74 (td, J=6.4,3.7Hz, 2H), 2.61 – 2.47 (m, 2H) .ESI-MSm/z:411 [M+H]+.
Compound A-28-1
Embodiment 30: the synthesis of compound N KOON-a1
Method, with embodiment 20, replaces F1-1 unlike with A8-1, obtains yellow solid NKOON-a1.
Productive rate: 52%;
1hNMR (400MHz, CDCl
3) δ 9.25 (d, J=7.8Hz, 1H), 8.31 (d, J=7.5Hz, 1H), 7.83 – 7.67 (m, 2H), 7.45 (d, J=1.8Hz, 1H), 7.33 (d, J=1.8Hz, 1H), 7.09 (d, J=1.4Hz, 1H), 6.16 (d, J=1.5Hz, 2H), 4.34 (t, J=5.5Hz, 2H), 2.59 (t, J=6.6Hz, 2H), 2.31 (d, J=1.5Hz, 6H), 2.22 – 2.12 (m, 2H) .ESI-MSm/z:376 [M+H]+.
Compound N KOON-a1
Embodiment 31: described in this patent, phenonaphthazine derivative is to the restraining effect of topoisomerase
Select the compound of part of representative, adopt the loose method of pBR322 plasmid to carry out cell-free system topoisomerase active mensuration.Wherein recombinant human topoisomerase I is purchased from TaKaRa Reagent Company, and human topoisomerase II α is purchased from TopoGen company.Being mixed with medicine to be measured and superhelix pBR322 plasmid by a certain amount of topoisomerase adds in topoisomerase damping fluid; 30 minutes laggard row agarose gel electrophoresis are hatched in 37 DEG C of water-baths; utilize gel imaging instrument to detect after GelRed dyeing, result is as shown in table 1, table 2.Result shows, the compound described in this patent, when concentration is 25 μm of ol/L and 10 μm of ol/L, has obvious restraining effect to topoisomerase I and II in vitro.Therefore phenonaphthazine derivative of the present invention can be used for the cancer therapy drug that preparation take topoisomerase as target spot.
The restraining effect of table 1 compound when 25 μm of ol/L to topoisomerase I activity
The restraining effect of table 2 compound when 10 μm of ol/L to topoisomerase II activity
Embodiment 32: described in this patent, phenonaphthazine derivative is to the restraining effect of growth of tumour cell
With four kinds of tumor cell line HeLa(cervical cancer cells), A549(human lung carcinoma cell), MCF-7(human breast cancer cell) and, HL-60(human leukemia cell), adopt mtt assay to carry out cell in vitro poison and measure.Logarithmic phase cell adds the novel phenonaphthazine derivative of different concns, acts on after 48 hours, measures its absorbancy.Calculate compound concentration when cell growth inhibiting reaches 50% respectively, with IC
50value represents, result is as shown in table 3.Result shows that compound described in this patent all has stronger restraining effect to these four kinds of tumor cell lines in vitro.Therefore phenonaphthazine derivative of the present invention can be used for preparing anticancer medicine.
Restraining effect (the IC of table 3 compound on tumor cell strain growth
50/ μM)
Claims (5)
1. a phenonaphthazine derivative, is characterized in that, its structural formula as shown in the formula (I):
（I）
R in formula
1for H, halogen ,-OCH
3or-NO
2, R
2for H, halogen ,-OCH
3or-NO
2; Or R
1and R
2for connecting R simultaneously
1, R
2-the O-CH of position
2-O-,
R is dimethylin, diethylin, piperidyl, methylpiperazine base, pyrryl or morpholinyl,
N=1 or 2, and as n=2, be dimethylin when R is different.
2. phenonaphthazine derivative as claimed in claim 1, it is characterized in that, described halogen is fluorine or chlorine.
3. an application for phenonaphthazine derivative as claimed in claim 1, is characterized in that, described phenonaphthazine derivative is preparing the application in cancer therapy drug.
4. prepare a method for phenonaphthazine derivative as claimed in claim 1, it is characterized in that, comprise the following steps:
S1.2-hydroxyl-1,4-naphthoquinone and substituted o-phenylenediamine condensation, obtain the compound of structural formula as shown in (II)
（II）；
S2. the product of step S1 and two bromoalkanes are reacted, obtain the compound of structural formula as shown in (III)
(III);
S3. by the product of step S2 and C
2-C
5aliphatic amide reaction, reactant is purified, obtains described phenonaphthazine derivative;
Substituent R wherein
1, R
2and variable n with define identical, described C in claim 1
2-C
5aliphatic amide be dimethylamine, diethylamine, piperidines, methylpiperazine, pyrroles or morpholine.
5. the preparation method of phenonaphthazine derivative as claimed in claim 4, it is characterized in that, described purifying is column chromatography or recrystallization.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201210538379.2A CN103360327B (en) | 2012-12-13 | 2012-12-13 | A kind of phenonaphthazine derivative and its preparation method and application |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201210538379.2A CN103360327B (en) | 2012-12-13 | 2012-12-13 | A kind of phenonaphthazine derivative and its preparation method and application |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN103360327A CN103360327A (en) | 2013-10-23 |
| CN103360327B true CN103360327B (en) | 2016-04-20 |
Family
ID=49362678
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201210538379.2A Expired - Fee Related CN103360327B (en) | 2012-12-13 | 2012-12-13 | A kind of phenonaphthazine derivative and its preparation method and application |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN103360327B (en) |
Families Citing this family (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN106554321B (en) * | 2015-09-25 | 2019-05-28 | 陆源 | A kind of azophenlyene substance, preparation method and its application |
Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1524859A (en) * | 2003-09-17 | 2004-09-01 | 中山大学 | Phenoxazones, preparing process and pharmaceutical uses thereof |
| WO2006081337A2 (en) * | 2005-01-25 | 2006-08-03 | Whitehead Institute For Biomedical Research | Erastin analogues and their uses for killing cancer cells |
| WO2006081331A2 (en) * | 2005-01-25 | 2006-08-03 | Prolexys Pharmaceuticals, Inc. | Quinoxaline derivatives as antitumor agents |
| CN101218211A (en) * | 2005-01-25 | 2008-07-09 | 普罗历克西医药品公司 | Quinoxaline derivatives as antitumor agents |
Family Cites Families (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPS6120344A (en) * | 1984-07-09 | 1986-01-29 | Toshiba Corp | Bonding method |
| JP4687121B2 (en) * | 2005-01-28 | 2011-05-25 | Ｄｉｃ株式会社 | Benzimidazolone compound and method for producing the same |
-
2012
- 2012-12-13 CN CN201210538379.2A patent/CN103360327B/en not_active Expired - Fee Related
Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1524859A (en) * | 2003-09-17 | 2004-09-01 | 中山大学 | Phenoxazones, preparing process and pharmaceutical uses thereof |
| WO2006081337A2 (en) * | 2005-01-25 | 2006-08-03 | Whitehead Institute For Biomedical Research | Erastin analogues and their uses for killing cancer cells |
| WO2006081331A2 (en) * | 2005-01-25 | 2006-08-03 | Prolexys Pharmaceuticals, Inc. | Quinoxaline derivatives as antitumor agents |
| CN101218211A (en) * | 2005-01-25 | 2008-07-09 | 普罗历克西医药品公司 | Quinoxaline derivatives as antitumor agents |
Non-Patent Citations (3)
| Title |
|---|
| A novel antitumor compound, NC-190, induces topoisomerase II-dependent DNA cleavage and DNA fragmentation;Takehiro Yamagishi,等;《Cancer Chemotherapy and Pharmacology》;19960331;第38卷(第1期);第29-34页 * |
| DNA拓扑异构酶与肿瘤研究;陆东东;《肿瘤防治杂志》;19971230(第04期);第302-303页 * |
| Structure-Based Virtual Screening: An Application to Human Topoisomerase II α;Serge Christmann-Franck,等;《J. Med. Chem.》;20041207;第47卷(第27期);第6840-6853页 * |
Also Published As
| Publication number | Publication date |
|---|---|
| CN103360327A (en) | 2013-10-23 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| EP2857393B1 (en) | N-aryl unsaturated fused ring tertiary amine compound, preparation method thereof and antitumor application thereof | |
| CN101486703A (en) | Flavone compound with antineoplastic activity, preparation thereof and uses thereof | |
| CN104402831B (en) | -5-cyanopyrimidine derivative containing uride construction unit and its production and use | |
| CN108299398B (en) | Carbazole-containing quinazoline derivative with anti-tumor activity and pharmaceutical application thereof | |
| Manikala et al. | Synthesis and biological evaluation of chalcone tethered quinoline derivatives as anticancer agents | |
| CN103360327B (en) | A kind of phenonaphthazine derivative and its preparation method and application | |
| CN102942529B (en) | 4-(4-substituted piperazine)-5,6,7-trialkoxy quinazoline type compound as well as preparation method and application of 4-(4-substituted piperazine)-5,6,7-trialkoxy quinazoline type compound | |
| CN105017245B (en) | Imidazopyridine compound and preparation method and application thereof | |
| CN109232703A (en) | Containing 16- (1 '-aromatic radical -1 ', 2 ', 3 '-triazoles) methylene-androstane -17- ketone derivatives | |
| US9695141B2 (en) | Anticancer miliusane derivatives | |
| CN107827934A (en) | Tetravalence platinum complex with active anticancer, preparation method and application | |
| CN101317845B (en) | Pharmaceutical use of 6-aryl substituted pyridine compounds | |
| CN102382064B (en) | Quinnazolidone derivative, preparation method for same and application thereof | |
| CN104130200B (en) | A kind of 2-substituted-phenyl-4-aryl amine quinazoline derivant and its preparation method and application | |
| CN102276433A (en) | Longistyle C and derivative thereof and application of longistyle C to preparation of anticancer medicines | |
| CN104788498B (en) | A kind of platinum (II) complex using chiral bicyclic diamines as carrier ligand and its preparation method and application | |
| CN108864110A (en) | Naphthoquinones benzopyran derivatives and its synthetic method and application | |
| CN107098914A (en) | A kind of chromene simultaneously [3 ', 4 ':5,6] pyrans simultaneously [2,3 b] quinoline and its preparation method and application | |
| CN103044380A (en) | New simple method for synthesizing 4H-benzopyran ring heterocyclic compound | |
| CN109053732B (en) | Para-fluorine substituted pyridazinone structure-containing spiro [ indolizine-pyrazoline ] derivative and preparation method and application thereof | |
| CN102702116B (en) | 4-(3-chloro-4-methoxylanilino)-6-(3-amidophenyl)quinazoline compound or pharmaceutically-acceptable salt thereof and preparation methods and applications thereof | |
| CN107522700A (en) | A kind of quinazolinone and α, the conjugated derivative of beta unsaturated ketone and its preparation method and application | |
| CN107163047A (en) | Chinese scholartree determines amine derivant and its production and use | |
| CN105418517B (en) | Novel quinazoline derivative LU1509 as well as preparation method and application thereof | |
| CN105693660A (en) | Jaspine B and 3-epi Jaspine B oxo analogs, and preparation method and application thereof |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| C06 | Publication | ||
| PB01 | Publication | ||
| C10 | Entry into substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| C14 | Grant of patent or utility model | ||
| GR01 | Patent grant | ||
| CF01 | Termination of patent right due to non-payment of annual fee | ||
| CF01 | Termination of patent right due to non-payment of annual fee |
Granted publication date: 20160420 Termination date: 20211213 |