CN104876887A - Benzofuroxan derivative and preparation method and application thereof - Google Patents
Benzofuroxan derivative and preparation method and application thereof Download PDFInfo
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- C07D271/00—Heterocyclic compounds containing five-membered rings having two nitrogen atoms and one oxygen atom as the only ring hetero atoms
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- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
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Abstract
The invention relates to the field of a medical technology and discloses a Benzofuroxan derivative and a preparation method and an application thereof. According to the invention, 1,4,5,6,7 sites of a Benzofuroxan structure are subjected to derivatization to obtain the Benzofuroxan derivative. The general molecular formula of the Benzofuroxan derivative is as shown in the specification. The compound provided by the invention has an obvious inhibiting effect on tumor cells and can be used in the preparation of antitumor drugs.
Description
Technical field
The present invention relates to medical art, specifically, is benzofuraxan derivative and its production and use.
Background technology
Malignant tumour serious threat human health, tumor therapeuticing method has surgical method, chemotherapy, radiation treatment clinically, and wherein, chemotherapy regimen has become the important means of oncotherapy.At present, clinical conventional antitumor drug mainly contains alkylating agent, antimetabolite, antitumor antibiotics, anti-tumor botanical, hormone etc., but there is the deficiencies such as the large and late result of toxicity is poor.Therefore, research and development new texture types of anti-tumor compound, has important theory significance.
The structure of nitrogen-containing heterocycle compound and the similar of the base such as purine, pyrimidine, have good organism environment consistency, have wide practical use in new drug development.Find through system documentation investigation, different (1-oxidation) benzofuraxan replaced has certain anti-tumor activity, 4-(4-methylpiperazine base)-7-nitro-1-benzofuroxan (XI-006) can suppress the expression of MDMX, activating p53, is potential antineoplastic representation compound that a class keeps tumor suppressor gene activity.
Summary of the invention
The object of the invention is to, a kind of benzofuraxan derivative is provided.
The object of the invention is to, a kind of preparation method of benzofuraxan derivative is also provided, to explore, to enrich the structure activity relationship of such antitumor activity of compound further.
The object of the invention is to, a kind of purposes of benzofuraxan derivative is also provided, can the growth of inhibition tumor cell, there is good anti-tumor activity.
The technical problem that will solve required for the present invention, can be achieved through the following technical solutions:
As a first aspect of the present invention, a kind of benzofuraxan derivative, is characterized in that, to the Isosorbide-5-Nitrae in benzofuraxan structure, and 5,6,7 are carried out modification and obtain benzofuraxan derivative,
The general structure of described benzofuraxan derivative is as follows:
Wherein:
N is selected from 0 or 1;
X: be selected from hydrogen, nitro;
Y: be selected from hydrogen, nitro; And X and Y can be all hydrogen; Can one be hydrogen, one is nitro; But can not nitro be all;
Z: be selected from hydrogen, piperidyl (when Y is nitro, Z is not piperidyl), morpholinyl, R
1substituted amido (
), N-R
1substituted piperazinyl (
, when n be 0, S is nitro, R
1be not methyl), R
1substituted phenylpiperazine base (
), R
1substituted benzyl piperazinyl (
), N-R
1replacement homopiperazine base (
), R
1substituted-phenyl homopiperazine base (
), R
1substituted benzyl homopiperazine base (
);
Wherein R
1: be selected from hydrogen, alkyl, hydroxyalkyl, phenyl;
S: be selected from hydrogen, nitro, piperidyl, morpholinyl, R
1substituted amido (
), N-R
1substituted piperazinyl (
, when n be 0, X is nitro, R
1it is not methyl; When n be 1, X is nitro, R
1be not ethyl, phenyl), R
1substituted phenylpiperazine base (
), R
1substituted benzyl piperazinyl (
), N-R
1replacement homopiperazine base (
), R
1substituted-phenyl homopiperazine base (
), R
1substituted benzyl homopiperazine base (
); Wherein R
1: be selected from hydrogen, alkyl, hydroxyalkyl, phenyl;
And Z and S at least one be hydrogen or nitro; And X, Y, Z and S can not be hydrogen simultaneously.
Further, alkyl is the alkyl of 1-7 carbon atom;
Further, hydroxyalkyl is methylol, hydroxyethyl, hydroxypropyl.
As a second aspect of the present invention, a kind of preparation method of benzofuraxan derivative, is characterized in that, by benzofuraxan and substituting group donor in a solvent heated and stirred react, to the Isosorbide-5-Nitrae in benzofuraxan structure, 5,6,7 are carried out modification and obtain benzofuraxan derivative.
The general structure of described benzofuraxan derivative is as follows:
1) described benzofuraxan derivative is category-A 4-amido-7-nitro benzofuraxan, and available reaction scheme is as follows:
2) described benzofuraxan derivative is category-B 5-amido-6-nitro-1-benzofuroxan, and available reaction scheme is as follows:
3) described benzofuraxan derivative is C class 5-amido-6-nitro benzofuraxan, and available reaction scheme is as follows:
4) described benzofuraxan derivative is D class 4-nitro-5-amido-1-benzofuroxan, and available reaction scheme is as follows:
5) described benzofuraxan derivative is E class 4-nitro-5-amido benzofuraxan, and available reaction scheme is as follows:
The preparation method of category-A benzofuraxan derivative comprises the following steps:
1, prepare 2,6-dichloro nitrosobenzene, be called for short intermediate (2)
2,6-DCA (1) and hydrogen peroxide are heated 48 h in glacial acetic acid and prepares 2,6-dichloro nitrosobenzene (2);
2, prepare 4-chlorine benzofuraxan, be called for short intermediate (3)
Intermediate (2) reacts 0.5 h in dimethyl sulfoxide (DMSO) with at sodiumazide 100 DEG C, after be warming up to 120 DEG C, then react 0.5 h, generate 4-chlorine benzofuraxan (3);
3, prepare 4-chloro-7-nitro benzofuraxan, be called for short intermediate (4)
Intermediate (3) reacts 0.5 h in concentrated sulfuric acid and generates 4-chloro-7-nitro benzofuraxan (4) with SODIUMNITRATE
4,4-amido-7-nitro benzofuraxan (5) is prepared
Intermediate (4) and various replacement amine room temperature reaction 3 h in dehydrated alcohol, generate 4-amido-7-nitro benzofuraxan (5)
The preparation method of category-B benzofuraxan derivative comprises the following steps:
5, prepare chloro-2, the 4-dinitrobenzenes of 1,5-bis-, be called for short intermediate (7)
By 2,4-dichloronitrobenzene (6) in ice bath slowly in instillation nitrosonitric acid, after be warming up to 50 DEG C, continue reaction 12 h, generate chloro-2, the 4-dinitrobenzenes (7) of 1,5-bis-
6, prepare 1-chloro-5-substituted amido-2,4-dinitrobenzene, be called for short intermediate (8)
Reflux intermediate (7) and various replacement amine in dehydrated alcohol 8 h, generates 1-chloro-5-substituted amido-2,4-dinitrobenzene (8);
7, prepare 1-nitrine-5-substituted amido-2,4-dinitrobenzene, be called for short intermediate (9)
By intermediate (8) and sodium azide room temperature reaction 1.5 h in dimethyl sulfoxide (DMSO), generate 1-nitrine-5-substituted amido-2,4-dinitrobenzene (9);
8,5-amido-6-nitro-1-benzofuroxan (10) is prepared
Dissolved by intermediate (9) q. s. toluene, 80 DEG C of reaction 5 h, generate 5-amido-6-nitro-1-benzofuroxan (10).
The preparation method of C class benzofuraxan derivative comprises the following steps:
9,5-amido-6-nitro benzofuraxan (11) is prepared
Dissolved with q. s. toluene by 6-nitro-5-substituted amido-1-benzofuroxan (10), add triphenylphosphine, 80 DEG C of reaction 3 h, generate 5-amido-6-nitro benzofuraxan (11).
The preparation method of D class benzofuraxan derivative comprises the following steps:
10, prepare 4-chloro-2-nitroazide benzene, be called for short intermediate (13)
In 4-chloro-2-nitroaniline (12), adding acetic acid, the vitriol oil, be down to 0 DEG C, add Sodium Nitrite, after reacting completely, add sodium azide, to reacting completely, generating 4-chloro-2-nitroazide benzene (13);
11, prepare the chloro-1-benzofuroxan of 6-, be called for short intermediate (14)
Intermediate (13) q. s. toluene is dissolved, 80 DEG C of reactions, generate the chloro-1-benzofuroxan (14) of 5-;
12, prepare the chloro-1-benzofuroxan of 4-nitro-5-, be called for short intermediate (15)
Intermediate (14) is added in the vitriol oil, in ice bath, slowly drips nitrosonitric acid and vitriol oil mixed solution, continue reaction 4 h, generate the chloro-1-benzofuroxan (15) of 4-nitro-5-;
13,4-nitro-5-amido-1-benzofuroxan (16) is prepared
By intermediate (15) dissolve with ethanol, slowly drip the ethanol solution of various replacement amine, room temperature reaction 4 h, generate 4-nitro-5-amido-1-benzofuroxan.
The preparation method of E class benzofuraxan derivative comprises the following steps:
14, prepare 5-chlorine benzofuraxan, be called for short intermediate (17)
Intermediate (14) and triethyl-phosphite are added in ethanol, back flow reaction, generate intermediate 5-chlorine benzofuraxan (17);
15, prepare 5-chloro-4-nitro benzofuraxan, be called for short intermediate (18)
Intermediate (17) is added in the vitriol oil, is down to 0 DEG C, slowly drip nitrosonitric acid and vitriol oil mixed solution, generate 5-chloro-4-nitro benzofuraxan (18);
16,4-nitro-5-amido benzofuraxan (19) is prepared
By intermediate (18) dissolve with ethanol, slowly drip the ethanol solution of various replacement amine, room temperature reaction 2 h, generate 4-nitro-5-amido benzofuraxan.
As a third aspect of the present invention, in the application of anti-tumor aspect.
Further, the application had in antitumor drug is being prepared in described application.
Beneficial effect of the present invention:
Benzofuraxan derivative prepared by the present invention, by pharmacological evaluation, shows that this compound has certain anti-tumor activity, and especially D compounds is better active, and result of study of the present invention is that good basis is established in the further investigation of this anti-tumor compounds.
Embodiment
Below in conjunction with specific embodiment, the invention will be further described.Should be understood that following examples only for illustration of the present invention but not for limiting scope of the present invention.
The experimental technique of unreceipted actual conditions in the following example, usually conveniently condition, or the condition that manufacturer provides is carried out.
Embodiment 1: prepare category-A benzofuraxan derivative 4-amido-7-nitro benzofuraxan
(1) intermediate 2,6-dichloro nitrosobenzene is prepared
In 100 ml reaction flasks, add the mixing of 2,6-DCA (1.62 g, 10 mmol), Glacial acetic acid 35 ml and 30% hydrogen peroxide (8.0 ml, 70 mmol), 35 DEG C of reaction 48 h.Suction filtration, seasoning, (1.49 g), yield 85.0 %, fusing point 174 ~ 175 DEG C to obtain canescence chip solid 2,6-dichloro nitrosobenzene.
(2) intermediate 4-chlorine benzofuraxan is prepared
In 100 ml reaction flasks, add 2,6-dichloro nitrosobenzene (1.44 g, 8.2 mmol), sodiumazide (0.70 g, 11 mmol) and dimethyl sulfoxide (DMSO) 25 ml, be heated to 100 DEG C, after stopping bubbling, be warming up to 120 DEG C, continue reaction 0.5 h.Add 50 ml water to reaction system, separate out a large amount of solid.Suction filtration, seasoning, (1.17 g), yield 93.1 %, fusing point 83 ~ 84 DEG C to obtain yellow powder 4-chlorine benzofuraxan.
(3) intermediate 4-chloro-7-nitro benzofuraxan is prepared
In 100 ml reaction flasks, add 4-chlorine benzofuraxan (3.86 g, 25 mmol), the vitriol oil 30 ml, be heated to 60 DEG C, drip SODIUMNITRATE (2.50 g, 30 mmol) 50% sulphuric acid soln 10.0 ml, drip finish, be warming up to 85 DEG C, react 0.5 h, solution is poured in trash ice, suction filtration, dry.Solid with ethyl acetate recrystallization, (5.40 g), yield 70.6%, fusing point: 96 ~ 97 DEG C to obtain faint yellow needle-like crystal 4-chloro-7-nitro benzofuraxan.
(4) 4-(4-n-propyl homopiperazine base)-7-nitro-benzofuraxan (A is prepared
1)
In 50 ml reaction flasks, add dehydrated alcohol 15 ml, 4-chloro-7-nitro benzofuraxan (0.1 g, 0.501 mmol) and triethylamine (0.1 ml, 0.69 mmol), be stirred to entirely molten, drip the 10 ml ethanol solutions of N-n-propyl homopiperazine (0.23 g, 0.752 mmol), drip and finish, react 3 h.Suction filtration, obtains brick-red solid A
1(89 mg), yield 38.0%, fusing point: 114 ~ 116 DEG C.(spectroscopic data is in A in table 1
1)
Compd A in table 1
2r group be 4-(4-methoxybenzyl) piperazinyl, method is the same.
Embodiment 2: prepare category-B benzofuraxan derivative 5-amido-6-nitro-1-benzofuroxan
(1) chloro-2, the 4-dinitrobenzenes of intermediate 1,5-bis-are prepared
In 100 ml reaction flasks, add 15 ml nitrosonitric acids, be down to 0 DEG C, slowly drip 2,4-dichloronitrobenzene (4.60 g, 24.3 mmol), drip and finish, be warming up to 50 DEG C, react 12 h.Reaction solution is slowly poured in appropriate trash ice in batches, separates out light yellow solid, suction filtration.Filter cake washes with water, naturally dries, and (5.45 g), yield 94.6%, fusing point: 100 ~ 101 DEG C to obtain chloro-2, the 4-dinitrobenzenes of pale yellow powder 1,5-bis-.
(2) the chloro-5-of intermediate 1-(4-benzamido group)-2,4-dinitrobenzenes are prepared
In 50 ml reaction flasks, add chloro-2, the 4-dinitrobenzenes of 1,5-bis-(0.59 g, 2.5 mmol), 10 ml dehydrated alcohols, benzylamine (0.27 g, 2.5 mmol) and triethylamine (0.4 ml, 2.5 mmol), reflux 8 h.Be down to room temperature, separate out a large amount of crystal, suction filtration, drying at room temperature, (0.63 g), yield 73.5 % to obtain the chloro-5-of yellow powder 1-(4-benzamido group)-2,4-dinitrobenzenes.
(3) intermediate 1-nitrine-5-(4-benzamido group)-2,4-dinitrobenzenes are prepared
In 50 ml reaction flasks, add the chloro-5-of 1-(4-benzamido group)-2,4-dinitrobenzenes (0.63 g, 2.05 mmol), appropriate dmso solution, add sodium azide (128 mg, 2.25 mmol), react 1.5 h.Poured into by reaction solution in trash ice, separate out yellow solid, suction filtration, drying at room temperature, (0.44 g), yield 68.3%, is directly used in next step reaction to obtain 1-nitrine-5-(4-benzamido group)-2,4-dinitrobenzene faint yellow solid.
(4) 5-(4-benzamido group)-6-nitro-1-benzofuroxan (B is prepared
1)
In 50 ml reaction flasks, add 1-nitrine-5-(4-benzamido group)-2,4-dinitrobenzenes (0.44 g, 1.40 mmol), dissolve with q. s. toluene, 80 DEG C of reaction 5 h.Remove solvent under reduced pressure, silica gel column chromatography, obtain atropurpureus powder B
1(210 mg), yield 33.7%, fusing point: 96 ~ 97 DEG C.(spectroscopic data is in B in table 1
1)
Compd B in table 1
2r group be 4-Phenylpiperazinyl, method is the same.
Embodiment 3: preparation C class benzofuraxan derivative 5-amido-6-nitro benzofuraxan
(1) 5-(4-benzamido group)-6-nitro benzofuraxan (C is prepared
1)
Dissolved with q. s. toluene by 5-(4-benzamido group)-6-nitro-1-benzofuroxan, add triphenylphosphine, 80 DEG C of reaction 3h, generate 5-(4-benzamido group)-6-nitro benzofuraxan C
1(48 mg), yield 29.2%, fusing point: 94 ~ 95 DEG C.(spectroscopic data is in C in table 1
1)
Compound C in table 1
2r group be 4-Phenylpiperazinyl, method is the same.
Embodiment 4: preparation D class benzofuraxan derivative 4-nitro-5-amido-1-benzofuroxan
(1) intermediate 4-chloro-2-nitroazide benzene is prepared
In 250 ml reaction flasks, add 4-chloro-2-nitroaniline (2.75 g, 15.94 mmol), acetic acid 30 ml and the vitriol oil 10 ml, be stirred to entirely molten, be down to 0 DEG C, slowly drip the 50 ml aqueous solution of Sodium Nitrite (1.15 g, 16.67 mmol).Drip sodiumazide (1.05 g, 16.15 mmol) the 30 ml aqueous solution, drip and finish, being transferred to room temperature reaction, carrying out to reacting no longer forward, the saturated sodium hydroxide solution of reaction system adjusts pH to 7, be extracted with ethyl acetate, organic phase washed with water twice, saturated nacl aqueous solution washs once, anhydrous sodium sulfate drying.Filter, concentrating under reduced pressure, (2.92 g), yield 92.3% to obtain Tan solid 4-chloro-2-nitroazide benzene.
(2) the chloro-1-benzofuroxan of intermediate 6-is prepared
In 100 ml reaction flasks, add 4-chloro-2-nitroazide benzene (2.92 g, 14.7 mmol), toluene 25 ml, 80 DEG C of reactions.Removal of solvent under reduced pressure, silica gel column chromatography, (2.13 g), yield 85.1% to obtain the chloro-1-benzofuroxan of yellow solid 6-.
(3) the chloro-1-benzofuroxan of intermediate 4-nitro-5-is prepared
In 100 ml reaction flasks, add the chloro-1-benzofuroxan of 5-(1.02 g, 6.0 mmol), the vitriol oil 12 ml, be down to 0 DEG C, slowly drip nitrosonitric acid (0.54 g, 8.57 mmol) and 5.80 g vitriol oil mixed solutions, drip and finish, continue reaction 4 h.Poured into by reaction solution in trash ice, use appropriate extraction into ethyl acetate, organic phase washed with water, saturated nacl aqueous solution respectively wash once, anhydrous sodium sulfate drying.Filter, concentrating under reduced pressure, silica gel column chromatography, (1.06 g), yield 82.0%, fusing point: 138 ~ 140 DEG C to obtain the chloro-1-benzofuroxan of yellow solid 4-nitro-5-.
(4) 5-(4-methylpiperazine)-4-nitro-1-benzofuroxan (D is prepared
1)
In 100 ml reaction flasks, add chloro-1-benzofuroxan (100 mg of 4-nitro-5-, 0.46 mmol), dehydrated alcohol 20 ml and triethylamine (0.1 ml, 0.65 mmol), slow dropping 1-methylpiperazine (93 mg, 0.93 mmol) 5 ml ethanol solutions, room temperature reaction 14 h.Removal of solvent under reduced pressure, dissolves with chloroform, organic phase washed with water twice, and saturated nacl aqueous solution washs once, anhydrous sodium sulfate drying.Filter, removal of solvent under reduced pressure, silica gel column chromatography, obtains red solid D
1(70 mg), yield is 34.8%, fusing point: 136 ~ 139 DEG C.(spectroscopic data is in D in table 1
1)
Compound D in table 1
2r group be 4-isobutyl piperazine base, method is the same.
Embodiment 5: preparation E class benzofuraxan derivative 4-nitro-5-amido benzofuraxan
(1) intermediate 5-chlorine benzofuraxan is prepared
In 100 ml reaction flasks, add the chloro-1-benzofuroxan of 5-(2.03 g, 11.9 mmol), dehydrated alcohol 30 ml and triethyl-phosphite (2.5 ml, 14.3 mmol), back flow reaction.Removal of solvent under reduced pressure, uses acetic acid ethyl dissolution residue, organic phase washed with water twice, and saturated nacl aqueous solution washs once, anhydrous sodium sulfate drying.Filter, concentrating under reduced pressure, (1.84 g), yield 98.9% to obtain brown oil 5-chlorine benzofuraxan.
(2) intermediate 5-chloro-4-nitro benzofuraxan is prepared
In 100 ml reaction flasks, add 5-chlorine benzofuraxan (0.94 g, 6.0 mmol), the vitriol oil 11 ml, be down to 0 DEG C, slowly drip nitrosonitric acid (0.51 g, 8.09 mmol) and 6.1 g vitriol oil mixed solutions.After reacting completely, pour in trash ice, suction filtration.Filter cake washes with water, drying at room temperature, obtains brown solid 5-chloro-4-nitro benzofuraxan (446 mg), yield 36.7%.
(3) 5-(4-methylpiperazine base is prepared)-4-nitro benzofuraxan (E
1)
In 50 ml reaction flasks, add 5-chloro-4-nitro benzofuraxan (130 mg, 0.64 mmol), dehydrated alcohol 20 ml and triethylamine (0.1 ml, 0.72 mmol), slow dropping 1-methylpiperazine (130 mg, 1.28 mmol) 5 ml ethanol solutions, drip finish, room temperature reaction 2 h.Suction filtration, drying at room temperature, obtains faint yellow solid E
1(113 mg), yield 66.5%, fusing point: 203 ~ 205 DEG C.(spectroscopic data is in E in table 1
1)
Compd E in table 1
2r group be diethylin, method is the same.
Enforcement of the present invention is not limited to above embodiment, and time prepared by all the other compounds, adopt compound that corresponding R replaces as raw material, method is the same.
In embodiment, agents useful for same is commercially available analytical pure.
table 1. the structure of part of compounds of the present invention, productive rate and nucleus magnetic hydrogen spectrum data
The compounds of this invention is by pharmacological evaluation, and show that this compound has certain anti-tumor activity, especially the anti-tumor activity of D compounds is better.
The pharmacological evaluation (one) of the compounds of this invention:
Test method:
This research work adopts srb assay to measure target compound to the inhibiting rate of tumour cell.
Medicine and preparation of reagents: accurately take testing sample, be added in 0.5 ml centrifuge tube, adds DMSO 200 μ l, be made into the stoste of 50 mM, 4 DEG C of stored refrigerated.Face the used time, get and be diluted to 5 μMs with 5 % substratum in right amount.
Cell cultures and going down to posterity: the equal adherent culture of cell in RPMI 1640 perfect medium containing 10% foetal calf serum, in 37 DEG C, 5% CO
2, full close humidity under cultivate.Cell covers with substratum sucking-off after at the bottom of ware, wash once with sterilizing PBS, add 1 ml pancreatin cell dissociation buffer peptic cell about 5 min, after slow piping and druming makes cell come off completely, after adding perfect medium 5 ml, dispel cell with transfer pipet, be sub-packed in 3 new Tissue Culture Dishs, after add perfect medium 10 ml, continue cultivate.
Drug treating: collect the tumour cell being cultured to logarithmic phase, with 5% substratum adjustment cell concn, to finite concentration, (Non-small cell lung carcinoma cell NCI H460 concentration is 4 × 10
4individual/ml; Breast cancer cell MCF-7 concentration is 3.5 × 10
4individual/ml; Colon cancer cell HCT-116 concentration is 2 × 10
4individual/ml), in 96 porocyte culture plates, every hole adds 200 μ l cell suspensions.Culture plate is placed in CO
2after cultivating 24 h in incubator, remove former substratum, add the fresh culture of 200 μ l containing 5 μMs of each medicines, each concentration establishes 4 multiple holes, set positive control drug 5 FU 5 fluorouracil (to measure the concentration of the inhibiting rate of Non-small cell lung carcinoma cell NCI H460 as 500 μ g/ml simultaneously, measuring the concentration of the inhibiting rate of breast cancer cell MCF-7, colon cancer cell HCT-116 is 200 μ g/ml) organize and each 6 the multiple holes of negative control group (0.1% DMSO), be placed in CO
2cultivation 48 h is continued in incubator.Take out culture plate, do not remove nutrient solution, every hole adds the 50%(mass/volume of 50 μ l) trichoroacetic acid(TCA) (TCA) fixed cell, be added in lightly on the liquid level of every hole, make the final concentration of TCA be 10%, in 4 DEG C of refrigerators, 1 h is placed after leaving standstill 5 min, thrown away by liquid in culture plate, culture plate each hole deionized water rinsing 5 times, to remove TCA, dry, dry air is to the wet mark of nothing.Every hole adds 4 mg/ml SRB 100 μ l, and room temperature places 15 min, discards in each hole and rinses 5 times with 1% acetic acid after liquid, and after air drying, every hole adds the Tris-Bace solution of 10 mM of 150 μ l, and microplate reader 540 nm wavelength measures absorbance.
Measure each hole OD value by microplate reader, measure wavelength 540 nm, calculate the inhibiting rate of medicine on cell proliferation according to each hole OD value:
Inhibiting rate=[(A540 control wells-A540 dosing holes)/A540 control wells] × 100%
Part of compounds to the inhibiting rate of three strain tumour cells in table 2.
When table 2 part preferred compound concentration is 5 μMs, to the inhibiting rate (%) of tumour cell NCI H460, MCF-7, HCT-116
| Compound | NCI H460 | MCF-7 | HCT-116 |
| 5-Fu | 80.8 | 88.9 | 81.8 |
| A1 | 29.3 | 14.4 | 17.3 |
| A2 | 19.6 | 60.4 | 24.4 |
| B1 | 30.6 | 93.7 | 22.3 |
| B2 | 29.4 | 94.8 | 68.8 |
| C1 | 40.4 | 60.5 | 32.1 |
| C2 | 62.8 | 83.7 | 76.6 |
| D1 | 73.2 | 96.2 | 89.1 |
| D2 | 87.9 | 96.3 | 90.1 |
| E1 | 27.9 | 22.7 | 11.2 |
| E2 | 39.4 | 57.4 | 14.0 |
D compounds is better to the activity of three strain tumour cells, and carried out deep active testing to it, active testing the results are shown in Table 3.
The pharmacological evaluation (two) of the compounds of this invention:
This research work adopts srb assay to measure the IC of compound
50value.
Medicine and preparation of reagents: accurately take testing sample, be added in 0.5 ml centrifuge tube, adds DMSO 200 μ l, be made into the stoste of 50 mM, 4 DEG C of stored refrigerated.Face the used time, get and be diluted to 5 μMs with 5 % substratum in right amount.
Cell cultures and going down to posterity: the equal adherent culture of cell in RPMI 1640 perfect medium containing 10% foetal calf serum, in 37 DEG C, 5% CO
2, full close humidity under cultivate.Cell covers with substratum sucking-off after at the bottom of ware, wash once with sterilizing PBS, add 1 ml pancreatin cell dissociation buffer peptic cell about 5 min, after slow piping and druming makes cell come off completely, after adding perfect medium 5 ml, dispel cell with transfer pipet, be sub-packed in 3 new Tissue Culture Dishs, after add perfect medium 10 ml, continue cultivate.
Drug treating: collect the tumour cell being cultured to logarithmic phase, with 5% substratum adjustment cell concn, to finite concentration, (Non-small cell lung carcinoma cell NCI H460 concentration is 4 × 10
4individual/ml; Breast cancer cell MCF-7 concentration is 3.5 × 10
4individual/ml; Colon cancer cell HCT-116 concentration is 2 × 10
4individual/ml), in 96 porocyte culture plates, every hole adds 200 μ l cell suspensions.Culture plate is placed in CO
2after cultivating 24 h in incubator, remove former substratum, add the fresh culture of 200 μ l containing different concns medicine (5 concentration gradients established by often kind of medicine), each concentration establishes 3 multiple holes, establish the multiple hole of negative control group (0.1% DMSO) 6 simultaneously, be placed in CO
2cultivation 48 h is continued in incubator.Take out culture plate, do not remove nutrient solution, every hole adds the 50%(mass/volume of 50 μ l) trichoroacetic acid(TCA) (TCA) fixed cell, be added in lightly on the liquid level of every hole, make the final concentration of TCA be 10%, in 4 DEG C of refrigerators, 1 h is placed after leaving standstill 5 min, thrown away by liquid in culture plate, culture plate each hole deionized water rinsing 5 times, to remove TCA, dry, dry air is to the wet mark of nothing.Every hole adds 4 mg/ml SRB 100 μ l, and room temperature places 15 min, discards in each hole and rinses 5 times with 1% acetic acid after liquid, and after air drying, every hole adds the Tris-Bace solution of 10 mM of 150 μ l, and microplate reader 540 nm wavelength measures absorbance.
Measure each hole OD value by microplate reader, measure wavelength 540 nm, calculate the inhibiting rate of medicine on cell proliferation according to each hole OD value and calculate its IC
50value:
Table 3 part D compounds is to the IC of MCF-7, HCT-116
50(μM)
| Compound | MCF-7 | HCT-116 |
| XI-006 | 5.8 | 15.3 |
| D1 | 0.19 | 1.0 |
| D6 | 0.13 | 2.0 |
More than show and describe ultimate principle of the present invention, principal character and advantage of the present invention.The technician of the industry should understand; the present invention is not restricted to the described embodiments; what describe in above-described embodiment and specification sheets just illustrates principle of the present invention; the present invention also has various changes and modifications without departing from the spirit and scope of the present invention, and these changes and improvements all fall in the claimed scope of the invention.
Claims (10)
1. a benzofuraxan derivative, is characterized in that, the structural formula of described benzofuraxan derivative is as follows:
Wherein:
N is selected from 0 or 1;
X: be selected from hydrogen, nitro;
Y: be selected from hydrogen, nitro; And X and Y can be all hydrogen; Can one be hydrogen, one is nitro; But can not nitro be all;
Z: be selected from hydrogen, piperidyl (when Y is nitro, Z is not piperidyl), morpholinyl, R
1substituted amido (
), N-R
1substituted piperazinyl (
, when n be 0, S is nitro, R
1be not methyl), R
1substituted phenylpiperazine base (
), R
1substituted benzyl piperazinyl (
), N-R
1replacement homopiperazine base (
), R
1substituted-phenyl homopiperazine base (
), R
1substituted benzyl homopiperazine base (
);
Wherein R
1: be selected from hydrogen, alkyl, hydroxyalkyl, phenyl;
S: be selected from hydrogen, nitro, piperidyl, morpholinyl, R
1substituted amido (
), N-R
1substituted piperazinyl (
, when n be 0, X is nitro, R
1it is not methyl; When n be 1, X is nitro, R
1be not ethyl, phenyl), R
1substituted phenylpiperazine base (
), R
1substituted benzyl piperazinyl (
), N-R
1replacement homopiperazine base (
), R
1substituted-phenyl homopiperazine base (
), R
1substituted benzyl homopiperazine base (
); Wherein R
1: be selected from hydrogen, alkyl, hydroxyalkyl, phenyl;
And Z and S at least one be hydrogen or nitro; And X, Y, Z and S can not be hydrogen simultaneously.
2. benzofuraxan derivative according to claim 1, is characterized in that, described alkyl is the alkyl of 1-7 carbon atom, and described hydroxyalkyl is methylol, hydroxyethyl, or hydroxypropyl.
3. benzofuraxan derivative according to claim 1, is selected from category-A 4-amido-7-nitro benzofuraxan; Category-B 5-amido-6-nitro-1-benzofuroxan; C class 5-amido-6-nitro benzofuraxan; D class 5-amido-4-nitro-1-benzofuroxan; E class 5-amido-4-nitro benzofuraxan.
4. a preparation method for benzofuraxan derivative as claimed in claim 1, is characterized in that, by benzofuraxan and substituting group donor in a solvent heated and stirred react, to the Isosorbide-5-Nitrae in benzofuraxan structure, 5,6,7 are carried out derivatize and obtain.
5. preparation method according to claim 4, is characterized in that,
Described benzofuraxan derivative is 4-amido-7-nitro benzofuraxan, and reaction scheme is as follows:
The preparation of described benzofuraxan derivative comprises the following steps:
(a1) prepare 2,6-dichloro nitrosobenzene, be called for short intermediate (2):
By 2,6-DCA (1) and hydrogen peroxide heated and stirred 48 h in glacial acetic acid, preparation 2,6-dichloro nitrosobenzene (2);
(a2) prepare 4-chlorine benzofuraxan, be called for short intermediate (3):
Intermediate (2) stirs 0.5 h in dimethyl sulfoxide (DMSO) with at sodiumazide 100 DEG C, after be warming up to 120 DEG C and continue reaction 0.5 h, generate 4-chlorine benzofuraxan (3);
(a3) prepare 4-chloro-7-nitro benzofuraxan, be called for short intermediate (4):
Intermediate (3) in concentrated sulfuric acid with SODIUMNITRATE heated and stirred 0.5 h, generate 4-chloro-7-nitro benzofuraxan (4);
(a4) 4-amido-7-nitro benzofuraxan (5) is prepared:
Intermediate (4) and various replacement amine stirred at ambient temperature 3 h in dehydrated alcohol, generate 4-amido-7-nitro benzofuraxan (5).
6. preparation method according to claim 4, is characterized in that,
Described benzofuraxan derivative is 5-amido-6-nitro-1-benzofuroxan, and reaction scheme is as follows:
The preparation of described benzofuraxan derivative comprises the following steps:
(b1) prepare chloro-2, the 4-dinitrobenzenes of 1,5-bis-, be called for short intermediate (7):
By 2,4-dichloronitrobenzene (6) under ice bath slowly in instillation nitrosonitric acid, after be warming up to 50 DEG C and continue reaction 12 h, generate chloro-2, the 4-dinitrobenzenes (7) of 1,5-bis-;
(b2) prepare 1-chloro-5-amido-2,4-dinitrobenzene, be called for short intermediate (8):
By intermediate (7) and various replacement amine reflux 8 h in dehydrated alcohol, generate 1-chloro-5-amido-2,4-dinitrobenzene (8);
(b3) prepare 1-nitrine-5-amido-2,4-dinitrobenzene, be called for short intermediate (9):
By intermediate (8) and sodium azide room temperature reaction 1.5 h in dimethyl sulfoxide (DMSO), generate 1-nitrine-5-amido-2,4-dinitrobenzene (9);
(b4) 5-amido-6-nitro-1-benzofuroxan (10) is prepared:
Dissolved by intermediate (9) q. s. toluene, 80 DEG C of reaction 5 h, generate 5-amido-6-nitro-1-benzofuroxan (10).
7. preparation method according to claim 4, is characterized in that,
Described benzofuraxan derivative is 5-amido-6-nitro benzofuraxan, and reaction scheme is as follows:
(c1) 5-amido-6-nitro benzofuraxan (11) is prepared:
Dissolved with q. s. toluene by 5-amido-6-nitro-1-benzofuroxan (10), add triphenylphosphine, 80 DEG C of reaction 3 h, generate 5-amido-6-nitro benzofuraxan (11).
8. preparation method according to claim 4, is characterized in that,
Described benzofuraxan derivative is 4-nitro-5-amido-1-benzofuroxan, and reaction scheme is as follows:
(d1) prepare 4-chloro-2-nitroazide benzene, be called for short intermediate (13):
In 4-chloro-2-nitroaniline (12), add acetic acid, the vitriol oil, be stirred to entirely molten, add Sodium Nitrite, add sodium azide after reacting completely at 0 DEG C, room temperature continues reaction, generates 4-chloro-2-nitroazide benzene (13);
(d2) prepare the chloro-1-benzofuroxan of 6-, be called for short intermediate (14):
Intermediate (13) q. s. toluene is dissolved, 80 DEG C of reactions, generate the chloro-1-benzofuroxan (14) of 6-;
(d3) prepare the chloro-1-benzofuroxan of 4-nitro-5-, be called for short intermediate (15):
Intermediate (14) is added in the vitriol oil, is placed in ice bath, slowly drip nitrosonitric acid and vitriol oil mixed solution, continue reaction 4 h and generate the chloro-1-benzofuroxan (15) of 4-nitro-5-;
(d4) 4-nitro-5-amido-1-benzofuroxan (16) is prepared:
By intermediate (15) dissolve with ethanol, slowly drip the ethanol solution of various replacement amine, room temperature reaction 4 h, generate 4-nitro-5-amido-1-benzofuroxan.
9. preparation method according to claim 4, is characterized in that,
Described benzofuraxan derivative is 4-nitro-5-amido benzofuraxan, and reaction scheme is as follows:
(e1) prepare 5-chlorine benzofuraxan, be called for short intermediate (17):
Intermediate (14) and triethyl-phosphite are added in ethanol, reflux, generate intermediate 5-chlorine benzofuraxan (17);
(e2) prepare 5-chloro-4-nitro benzofuraxan, be called for short intermediate (18):
Intermediate (17) is added in the vitriol oil, at 0 DEG C, slowly drips nitrosonitric acid and vitriol oil mixed solution, generate 5-chloro-4-nitro benzofuraxan (18);
(e3) 4-nitro-5-amido benzofuraxan (19) is prepared:
By intermediate (18) dissolve with ethanol, slowly drip the ethanol solution of various replacement amine, room temperature reaction 2 h, generate 4-nitro-5-amido benzofuraxan.
10. claim 1 compound is preparing the application in antitumor drug.
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN109748799A (en) * | 2018-12-18 | 2019-05-14 | 内蒙古世杰化工有限公司 | A method of synthesis fluoro- 1,5 2,4-dinitrophenoxy of 2-(5-) acetic acid esters |
| CN116063212A (en) * | 2023-01-28 | 2023-05-05 | 山东国邦药业有限公司 | Preparation method of 4-phenylthio-1, 2-phenylenediamine |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2004001058A2 (en) * | 2001-05-04 | 2003-12-31 | Paratek Pharmaceuticals, Inc. | Transcription factor modulating compounds and methods of use thereof |
| CN103004799A (en) * | 2013-01-06 | 2013-04-03 | 苏州大学 | Application of benzofuroxan derivative to resisting plant pathogenic fungi |
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2015
- 2015-03-23 CN CN201510125389.7A patent/CN104876887A/en active Pending
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2004001058A2 (en) * | 2001-05-04 | 2003-12-31 | Paratek Pharmaceuticals, Inc. | Transcription factor modulating compounds and methods of use thereof |
| CN103004799A (en) * | 2013-01-06 | 2013-04-03 | 苏州大学 | Application of benzofuroxan derivative to resisting plant pathogenic fungi |
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN109748799A (en) * | 2018-12-18 | 2019-05-14 | 内蒙古世杰化工有限公司 | A method of synthesis fluoro- 1,5 2,4-dinitrophenoxy of 2-(5-) acetic acid esters |
| CN116063212A (en) * | 2023-01-28 | 2023-05-05 | 山东国邦药业有限公司 | Preparation method of 4-phenylthio-1, 2-phenylenediamine |
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