CN103896902B - Containing the acylhydrazone and its preparation method and application of 8-oxyethyl group-3-nitro-2H-benzopyran structure - Google Patents

Containing the acylhydrazone and its preparation method and application of 8-oxyethyl group-3-nitro-2H-benzopyran structure Download PDF

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CN103896902B
CN103896902B CN201410041589.XA CN201410041589A CN103896902B CN 103896902 B CN103896902 B CN 103896902B CN 201410041589 A CN201410041589 A CN 201410041589A CN 103896902 B CN103896902 B CN 103896902B
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nitro
acylhydrazone
compound
oxyethyl group
acid
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CN103896902A (en
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张大同
马运通
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Qilu University of Technology
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D311/00—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings
    • C07D311/02—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings ortho- or peri-condensed with carbocyclic rings or ring systems
    • C07D311/04—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring
    • C07D311/58—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring other than with oxygen or sulphur atoms in position 2 or 4
    • C07D311/64—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring other than with oxygen or sulphur atoms in position 2 or 4 with oxygen atoms directly attached in position 8
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links

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Abstract

The invention belongs to technical field of chemistry, relate to a kind of acylhydrazone containing 8-oxyethyl group-3-nitro-2<i>H</iGreatT.G reaT.GT-benzopyran structure and its preparation method and application, its general structure is I: i wherein, R 1be independently aryl or the aryl of replacement, the heteroaryl of a 5-10 atom or the substituted heteroaryl of 6-10 carbon atom; R 2independent is H, methyl or ethyl.The present invention is that raw material is through acylations, Cheng Huan, condensation with vanirone; synthesize the acylhydrazone containing 8-oxyethyl group-3-nitro-2<i>H</iGreatT.G reaT.GT-benzopyran structure, and carry out anti-tumor activity experimental study.Experimental result shows compound of the present invention and has good anti-tumour cell proliferative activity.

Description

Containing the acylhydrazone and its preparation method and application of 8-oxyethyl group-3-nitro-2H-benzopyran structure
Technical field
The present invention relates to containing 8-oxyethyl group-3-nitro-2 hacylhydrazone of-benzopyran structure and its preparation method and application, belongs to technical field of chemistry.
Background technology
Cancer is the general designation of a large class malignant tumour.The feature of cancer cells be unrestrictedly, hyperplasia without end, the nutritive substance in patient body is consumed in a large number, therefore finds the medicine of anticancer propagation to be a kind of Critical policies for the treatment of cancer cells.Although had many cancer therapy drugs (such as: Plicamycin at present, pemetrexed) be applied to clinical, but all there is various defect in these medicines, such as Antitumor test is narrow, toxic side effect is large, and the anticarcinogen tool therefore designing, synthesize new high-efficiency low-toxicity is of great significance.
3-nitro-2 is found through literature survey h-benzo pyran derivative has good anti-tumor activity.The people such as Liu Zhaopeng report 3-nitryl-8-ethyoxyl-2 h-benzopyrans compounds and its preparation method and application, and confirm that this kind of benzopyran compounds has good anti-tumour cell proliferative activity (Liu Zhaopeng etc., see China Patent Publication No. 102584768A).The people such as YanMing report 3-nitro-2 h-chromene is the novel thioredoxin reductase inhibiter of a class, has stronger antiproliferative effect (YanMing etc., 3-Nitro-2 to cancer cells h-chromenesasaNewClassofInhibitorsagainstThioredoxinReduct aseandProliferationofCancerCells, ArchPham.Chem.LifeSci.2012,345,767-770).Acylhydrazone is the common anticancer pharmacophoric group of a class.CenzoCongiu etc. report a class Benzaldehyde,2-hydroxy virtue hydrazone compound and have good anti-tumor activity (CenzoCongiu etc., Bioorganic & MedicinalChemistry, 2013,21,6592-6599).KarsonS.Putt etc. report a class hydrazone compound and are converted into caspase-3 by activation procaspase-3 and play antitumor action (KarsonS.Putt etc., NatureChemicalBiology, 2006,2,543-550).According to medicinal design principle of hybridization, we are by 3-nitro-2 htogether with this two classes pharmacophoric group split of-chromene and acylhydrazone, synthesize a series of containing 8-oxyethyl group-3-nitro-2 hthe acylhydrazone of-benzopyran structure, and anticancer bioactive research is carried out to them.
Summary of the invention
Not enough for prior art, the invention provides containing 8-oxyethyl group-3-nitro-2 hthe acylhydrazone of-benzopyran structure, the present invention also provides preparation method and the purposes of this derivative.
Technical scheme of the present invention is as follows
1, containing 8-oxyethyl group-3-nitro-2 hthe acylhydrazone of-benzopyran structure
There is the structure shown in general formula I, and its pharmacy acceptable salt:
General formula I
Wherein R 1be independently aryl or the aryl of replacement, the heteroaryl of a 5-10 atom or the substituted heteroaryl of 6-10 carbon atom; R 2independent is H, methyl or ethyl.
Preferably, R 1for 2-pyridyl, 3-pyridyl, 3-acetamidophenyl or 4-acetamidophenyl; R 2for H or methyl.
Further preferred, above-mentioned compound of Formula I is one of following:
8-oxyethyl group-3-nitro-2 h-chromene-6-formaldehyde 3-acetamido benzoyl hydrazone (I 1),
8-oxyethyl group-3-nitro-2 h-chromene-6-formaldehyde 2-pyridine carbonylhydrazone (I 2),
8-oxyethyl group-3-nitro-2 h-chromene-6-formaldehyde 3-pyridine carbonylhydrazone (I 3),
8-oxyethyl group-3-nitro-2 h-chromene-6-formaldehyde n-methyl-3-pyridine carbonylhydrazone (I 4),
8-oxyethyl group-3-nitro-2 h-chromene-6-formaldehyde 4-acetamido benzoyl hydrazone (I 5),
2, containing 8-oxyethyl group-3-nitro-2 hthe preparation method of the acylhydrazone of-benzopyran structure
The preparation method of the compound of general formula I of the present invention, step is as follows;
Reagent and condition: step A, vanirone, urotropine, acetic acid/water, backflow; Step B, compound (2), nitroethyl alcohol, positive dibutylamine, Tetra hydro Phthalic anhydride, toluene, backflow; Step C, compound (3), R 1cONR 2nH 2, ethanol, concentrated hydrochloric acid, room temperature.
Wherein, R 1, R 2definition as described in above-mentioned general formula I.
Concrete steps are as follows:
(B) compound (2) is dissolved in toluene, add di-n-butyl amine, Tetra hydro Phthalic anhydride, heating reflux reaction under 120oC, divide in 12 hours and add nitroethyl alcohol 24 times, continue reaction 12 hours, coreaction 24 hours, after TLC detection reaction is complete, with diatomite filtration, filtrate washes twice with saturated sodium bicarbonate solution after being dissolved in methylene dichloride successively, the saturated common salt aqueous solution is washed once, anhydrous sodium sulfate drying, filter, filtrate Rotary Evaporators concentrates, resistates sherwood oil: ethyl acetate=5/1 (v/v) crosses silicagel column, obtain yellow solid (3), yield 20%, fusing point: 108.6 ~ 109.6oC,
(C) compound (3) is joined in dehydrated alcohol, add R 1cONR 2nH 2, add people's two concentrated hydrochloric acids, stirred at ambient temperature reacts 0.5 hour, and product is separated out, and after TLC detection reaction is complete, suction filtration, drying under reduced pressure after filter cake dehydrated alcohol washes three times, obtains solid (I).
The structural formula of target compound I is as following table 1:
Table 1
3, the pharmaceutical composition containing the compounds of this invention and application thereof
The pharmacy acceptable salt of the compound of general formula I of the present invention, be react with acidic substance (as mineral acid), they include, but are not limited to: hydrochloric acid, Hydrogen bromide, sulfuric acid, phosphoric acid etc. form pharmacy acceptable salt, as corresponding hydrochloride, vitriol or phosphoric acid salt etc.Also can adopt and common are machine acid as generation salt such as formic acid, acetic acid, citric acid, tartrate, lactic acid, methylsulfonic acid, toxilic acids.
The compound of general formula I of the present invention or its pharmacy acceptable salt, can make pharmaceutical composition jointly with one or more pharmaceutically acceptable carrier, vehicle or thinner.This pharmaceutical composition can make the formulations such as solid orally ingestible, liquid oral medicine, injection.Described solid and liquid oral medicine comprise: tablet, dispersible tablet, sugar-coat agent, granule, dry powder doses, capsule and solution.Described injection comprises: little pin, infusion solutions, freeze-dried powder etc.
Composition of the present invention, described pharmacy or bromatology can accept auxiliary material and be selected from: weighting agent, disintegrating agent, lubricant, glidant, effervescent, correctives, sanitas, coating material or other vehicle.
Composition of the present invention, described pharmacy or bromatology can accept auxiliary material.Weighting agent is the composition of one or more that weighting agent comprises lactose, sucrose, dextrin, starch, pregelatinized Starch, N.F,USP MANNITOL, sorbyl alcohol, secondary calcium phosphate, calcium sulfate, calcium carbonate, Microcrystalline Cellulose; Described tackiness agent comprises the composition of one or more of sucrose, starch, polyvidone, Xylo-Mucine, hypromellose, hydroxypropylcellulose, methylcellulose gum, polyoxyethylene glycol, medicinal alcohol, water; Described disintegrating agent comprises the composition of one or more of starch, crosslinked polyvidone, croscarmellose sodium, low-substituted hydroxypropyl cellulose, carmethose, gas-producing disintegrant.
The compound or its salt of general formula I of the present invention can be used as effective constituent for the preparation of the medicine for the treatment of human body or veterinary cancer.The activity data of compound of Formula I of the present invention is obtained by CCK8 test kit test experience.
Compound of Formula I of the present invention is effective in quite wide dosage range.The dosage that such as every day takes, within the scope of 10mg-1000mg/ people, is divided into once or administration for several times.The actual dosage taking compound of Formula I of the present invention can be decided according to relevant situation by doctor.These situations comprise: the physical state of patient, route of administration, age, body weight, individual reaction to medicine, the severity etc. of symptom.
The present invention with vanirone be raw material through acylations, Cheng Huan, condensation, synthesized containing 8-oxyethyl group-3-nitro-2 hthe acylhydrazone of-benzopyran structure, and carried out anti-tumor activity experimental study.Experimental result shows compound of the present invention and has good anti-tumour cell proliferative activity.This demonstrate the medicine that compound of the present invention can be used for preparing Therapeutic cancer.Detailed experimental study will be explained in an embodiment.
Embodiment
Embodiment 1,
The synthesis of step (A) intermediate product (2)
By compound (1) (2g, 12mmol), urotropine (3.9g, 28mmol) join in the mixing solutions of acetic acid (30ml) and water (6ml), reflux 3 hours under 120oC, add water (100ml), extraction into ethyl acetate twice (2 × 50ml), merge organic phase, wash twice (2 × 50ml), anhydrous sodium sulfate drying, filter, filtrate Rotary Evaporators concentrates, obtain clear yellow viscous oily liquid 2.9g, sherwood oil: ethyl acetate=5/1 (v/v) crosses silicagel column, obtain greenish yellow solid (2), 467mg, yield 20%, fusing point: 108.6 ~ 109.6oC. 1HNMR(400MHz,DMSO- d 6) δ:11.12(s,1H,PhOH),10.34(s,1H,-CHO),9.85(s,1H,-CHO),7.86(s,1H,ArH),7.57(s,1H,ArH),4.19(q, J=6.8Hz,2H,OCH 2CH 3),1.39(t, J=6.8Hz,3H,OCH 2CH 3).
The synthesis of step (B), intermediate product (3)
Compound 2 (1g, 5.1mmol) is dissolved in (25ml) heavily to steam in toluene, adds di-n-butyl amine (323mg, 2.5mmol), Tetra hydro Phthalic anhydride (1.51g, 10.2mmol), heating reflux reaction under 120oC.Divide in 12 hours and add nitroethyl alcohol (1ml, 13.9mmol) 24 times, continue reaction 12 hours.After TLC detection reaction is complete, with diatomite filtration, filtrate adds methylene dichloride 100ml and dilutes, use successively saturated sodium bicarbonate solution (2 × 50ml) wash twice, the saturated common salt aqueous solution (100ml) washes once, anhydrous sodium sulfate drying, filter, filtrate Rotary Evaporators concentrates, resistates sherwood oil: ethyl acetate=5/1 (v/v) crosses silicagel column, obtain yellow solid (3), 510mg, yield 40%, fusing point: 139.8 ~ 141.8oC. 1HNMR(400MHz,DMSO- d 6) δ:9.83(s,1H,ArCHO),8.15(s,1H,ArCH=C),7.71(s,1H,ArH),7.56(s,1H,ArH),5.38(s,2H,ArOCH 2),4.13(q, J=6.8Hz,2H,OCH 2CH 3),1.3(t, J=6.8Hz,3H,OCH 2CH 3).
Step (C), compound (I 1) synthesis
By compound 3 (60mg, 0.2mmol) join in (3ml) dehydrated alcohol, add 3-acetamido benzoyl hydrazine (46.5mg, 0.24mmol), add people's two concentrated hydrochloric acids (12mol/L), stirred at ambient temperature reacts 0.5 hour, product is separated out, after TLC detection reaction is complete, and suction filtration, drying under reduced pressure after filter cake dehydrated alcohol washes three times, obtains safran solid (I 1), 64mg, yield 61%, fusing point: 224.8 ~ 225.6oC. 1HNMR(400MHz,DMSO- d 6) δ:11.81(s,1H,N-NH),10.13(s,1H,CH 3CONH),8.37(s,1H,N=CH),8.10(d, J=8Hz,1H,ArH),8.06(s,1H,ArCH=C),7.81(d, J=8Hz,1H,ArH),7.56(d, J=8Hz,1H,ArH),7.44(m,3H,ArH),5.3(s,2H,ArOCH 2),4.12(q, J=6.8Hz,2H,OCH 2CH 3),2.06(s,3H,CH 3CONH),1.36(t, J=6.8Hz,3H,OCH 2CH 3).
Embodiment 2-5: the synthetic operation of reference example 1, with different carbohydrazides for raw material can be prepared according to method same above 2, 3, 4, I 5, except different carbohydrazide raw materials, all the other raw materials are identical with the raw material in embodiment 1, and the consumption of each raw material can be drawn by the experiment of calculating and limited number of time, no longer describes in detail herein.Compound structure and fusing point list in table 2.Wherein yield is the mean value of several times experiment.
Table 2
The antiproliferative activity experiment of embodiment 6, compound on tumor cell
The antiproliferative activity experimental technique of compound to human lung adenocarcinoma cell line (A549), human oophoroma cell line (A2780) is as follows: cultivate A549 and A2780 Growth of Cells to logarithmic phase, collecting cell, appropriate substratum suspends, and suspension cell concn is adjusted to 5 × 10 4/ ml.By cell suspension inoculation in 96 porocyte culture plates, every hole 100 μ l, puts into cell culture incubator and cultivates.Treat cell attachment, after 24h, more renew substratum 100 μ l.Add the DMSO solution of medicine to be measured, each concentration all establishes 3 multiple holes, is placed in 37oC, 5%CO 2cultivate 48 hours in incubator, detect by the method for CCK8.
The antiproliferative activity experimental technique of compound to human leukemia cell line (KG-1) is as follows: the KG-1 suspension cell in vegetative period is transferred in centrifuge tube in the lump together with nutrient solution, centrifugal 5 minutes of 800rpm, remove supernatant, add in new nutrient solution to centrifuge tube and form cell suspension.Suspension cell concn is adjusted to 1 × 10 5/ ml, is then inoculated in 96 porocyte culture plates, every hole 100 μ l.Add the DMSO solution of medicine to be measured, each concentration all establishes 3 multiple holes, is placed in 37oC, 5%CO 2cultivate 48 hours in incubator, detect by the method for CCK8.
The antiproliferative activity experimental technique of compound to the former leukemia cell line of the chronic marrow of people (K562) is as follows: Growth of Cells is to logarithmic growth after date, and collecting cell, centrifugal 4 minutes, is resuspended in fresh Growth nutrient solution.By cell suspension inoculation in 96 porocyte culture plates, every hole 200 μ l, adjustment suspension cell concn to 3 × 10 3-1 × 10 4/ hole.Add the DMSO solution of medicine to be measured, each concentration all establishes 4 multiple holes, is placed in 37oC, 5%CO 2cultivate 48 hours in incubator, detect by the method for CCK8.
Table 3 compound is to the growth inhibitory activity (IC of four kinds of tumor cell lines 50, μM)
Lipodox (Dox) is positive control drug; " ND " expression does not detect.
From CCK8 experimental result, compound of the present invention shows stronger growth inhibitory activity to four kinds of cell strains.For A549 cell strain, Compound I 2activity best, its IC 50value is 8.07 μMs.For KG-1 cell strain, I 2and I 3all show good growth inhibitory activity, IC 50value is 0.76 μM and 0.45 μM respectively.For A2780 cell strain, all compounds all show very strong growth inhibitory activity, their IC 50value is all below 0.25 μM.For K562 cell strain, Compound I 1activity best.Its IC 50value is 0.11 μM.
Above experimental result shows that compound of the present invention has good anti-tumour cell proliferative activity, can be used for the medicine preparing Therapeutic cancer.

Claims (9)

1. one kind contains 8-oxyethyl group-3-nitro-2 hthe acylhydrazone of-benzopyran structure, is characterized in that: its general structure is I:
I
Wherein, R 1for 2-pyridyl, 3-pyridyl, 3-acetamidophenyl or 4-acetamidophenyl; R 2for H or methyl.
2. as claimed in claim 1 containing 8-oxyethyl group-3-nitro-2 hthe salt of the acylhydrazone of-benzopyran structure, is characterized in that: generated by the compound of described general formula I and mineral acid or organic acid reaction.
3. as claimed in claim 2 containing 8-oxyethyl group-3-nitro-2 hthe salt of the acylhydrazone of-benzopyran structure, is characterized in that: needed for reaction, mineral acid comprises any one in hydrochloric acid, Hydrogen bromide, sulfuric acid or phosphoric acid, and reaction generates hydrochloride, hydrobromate, vitriol or phosphoric acid salt; Needed for reaction, organic acid comprises any one in formic acid, acetic acid, citric acid, tartrate, lactic acid, methylsulfonic acid, toxilic acid.
4. as claimed in claim 1 containing 8-oxyethyl group-3-nitro-2 hthe acylhydrazone of-benzopyran structure or the salt of this acylhydrazone according to claim 3, it is characterized in that: solid orally ingestible, liquid oral medicine and injection can be made, the auxiliary material needed when being prepared into required formulation comprise in weighting agent, disintegrating agent, tackiness agent, lubricant, glidant, effervescent, correctives, sanitas, coating material one or more.
5. as claimed in claim 4 containing 8-oxyethyl group-3-nitro-2 hthe acylhydrazone of-benzopyran structure or its salt, is characterized in that: weighting agent comprises the composition of one or more of lactose, sucrose, dextrin, starch, N.F,USP MANNITOL, sorbyl alcohol, secondary calcium phosphate, calcium sulfate, calcium carbonate, Microcrystalline Cellulose; Tackiness agent comprises the composition of one or more of sucrose, starch, polyvidone, Xylo-Mucine, hypromellose, hydroxypropylcellulose, methylcellulose gum, polyoxyethylene glycol, medicinal alcohol, water; Disintegrating agent comprises the composition of one or more of starch, crosslinked polyvidone, croscarmellose sodium, low-substituted hydroxypropyl cellulose, carmethose, gas-producing disintegrant.
6. as claimed in claim 1 containing 8-oxyethyl group-3-nitro-2 hthe acylhydrazone of-benzopyran structure or its salt are for the preparation of the medicine for the treatment of human body or veterinary cancer.
7. contain 8-oxyethyl group-3-nitro-2 described in a claim 1 hthe preparation method of the acylhydrazone of-benzopyran structure, is characterized in that: it is obtained by reacting by compound 3, and the general formula of compound 3 is as follows:
, the reaction formula of its preparation method is:
。
8. as claimed in claim 7 containing 8-oxyethyl group-3-nitro-2 hthe preparation method of the acylhydrazone of-benzopyran structure, is characterized in that: compound 3 is obtained by reacting by compound 2, and the general formula of compound 2 is as follows:
, the reaction formula of its preparation method is:
。
9. according to claim 8 containing 8-oxyethyl group-3-nitro-2 hthe preparation method of the acylhydrazone of-benzopyran structure, is characterized in that: be made up successively of following steps:
(1) compound 2 is dissolved in toluene, add di-n-butyl amine, Tetra hydro Phthalic anhydride, heating reflux reaction at 120 DEG C, divide in 12 hours and add nitroethyl alcohol 24 times, continue reaction 12 hours, coreaction 24 hours, after TLC detection reaction is complete, with diatomite filtration, filtrate washes twice with saturated sodium bicarbonate solution after being dissolved in methylene dichloride successively, the saturated common salt aqueous solution is washed once, anhydrous sodium sulfate drying, filter, filtrate Rotary Evaporators concentrates, resistates sherwood oil: ethyl acetate=5/1 (v/v) crosses silicagel column, obtain yellow solid 3, yield 20%, fusing point: 108.6 ~ 109.6 DEG C,
(2) compound 3 is joined in dehydrated alcohol, add R 1cONR 2nH 2, add two concentrated hydrochloric acids, stirred at ambient temperature reacts 0.5 hour, and product is separated out, after TLC detection reaction is complete, and suction filtration, drying under reduced pressure after filter cake dehydrated alcohol washes three times, obtains solid I;
Wherein compound 2,3, R 1cONR 2nH 2general structure as follows successively:
， ， ，
R 1for 2-pyridyl, 3-pyridyl, 3-acetamidophenyl, 4-acetamidophenyl; R 2for H, methyl.
CN201410041589.XA 2014-01-28 2014-01-28 Containing the acylhydrazone and its preparation method and application of 8-oxyethyl group-3-nitro-2H-benzopyran structure Expired - Fee Related CN103896902B (en)

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