CN106008324A - Alpha,beta-unsaturated compounds and application thereof - Google Patents

Alpha,beta-unsaturated compounds and application thereof Download PDF

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CN106008324A
CN106008324A CN201610390429.5A CN201610390429A CN106008324A CN 106008324 A CN106008324 A CN 106008324A CN 201610390429 A CN201610390429 A CN 201610390429A CN 106008324 A CN106008324 A CN 106008324A
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benzylidene
chloro
bromo
trimethoxy
dimethoxy
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秦华利
冷静
王晓燕
郝建宏
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Wuhan University of Technology WUT
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Wuhan University of Technology WUT
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
    • C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D211/80—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members
    • C07D211/84—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen directly attached to ring carbon atoms
    • C07D211/86—Oxygen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C205/00—Compounds containing nitro groups bound to a carbon skeleton
    • C07C205/27—Compounds containing nitro groups bound to a carbon skeleton the carbon skeleton being further substituted by etherified hydroxy groups
    • C07C205/35—Compounds containing nitro groups bound to a carbon skeleton the carbon skeleton being further substituted by etherified hydroxy groups having nitro groups and etherified hydroxy groups bound to carbon atoms of six-membered aromatic rings of the carbon skeleton
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C251/00—Compounds containing nitrogen atoms doubly-bound to a carbon skeleton
    • C07C251/32—Oximes
    • C07C251/34—Oximes with oxygen atoms of oxyimino groups bound to hydrogen atoms or to carbon atoms of unsubstituted hydrocarbon radicals
    • C07C251/44—Oximes with oxygen atoms of oxyimino groups bound to hydrogen atoms or to carbon atoms of unsubstituted hydrocarbon radicals with the carbon atom of at least one of the oxyimino groups being part of a ring other than a six-membered aromatic ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C251/00—Compounds containing nitrogen atoms doubly-bound to a carbon skeleton
    • C07C251/32—Oximes
    • C07C251/50—Oximes having oxygen atoms of oxyimino groups bound to carbon atoms of substituted hydrocarbon radicals
    • C07C251/58—Oximes having oxygen atoms of oxyimino groups bound to carbon atoms of substituted hydrocarbon radicals of hydrocarbon radicals substituted by nitrogen atoms not being part of nitro or nitroso groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C49/00—Ketones; Ketenes; Dimeric ketenes; Ketonic chelates
    • C07C49/587—Unsaturated compounds containing a keto groups being part of a ring
    • C07C49/753—Unsaturated compounds containing a keto groups being part of a ring containing ether groups, groups, groups, or groups
    • C07C49/755—Unsaturated compounds containing a keto groups being part of a ring containing ether groups, groups, groups, or groups a keto group being part of a condensed ring system with two or three rings, at least one ring being a six-membered aromatic ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
    • C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D211/80—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members
    • C07D211/84—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen directly attached to ring carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D309/00—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings
    • C07D309/34—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
    • C07D309/36—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with oxygen atoms directly attached to ring carbon atoms
    • C07D309/38—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with oxygen atoms directly attached to ring carbon atoms one oxygen atom in position 2 or 4, e.g. pyrones

Abstract

The invention discloses alpha,beta-unsaturated compounds and an application thereof, and in particular, relates to the inhibition activity of alpha,beta-unsaturated carbonyl compounds, oxime, oxime ether and derivatives thereof on BRAFV600E, an epidermal growth factor TK kinase and a microporous protein polymerase. The synthesized compounds are proved to be suitable for being used as drugs for preventing and treating tumor diseases, also be suitable for prevention and treatment effects of tumor cells having multidrug resistance and have relatively good application prospects.

Description

α, β-unsaturated compound and application thereof
Technical field
The invention belongs to pharmaceutical technology field, be specifically related to a kind of α, beta-unsaturated carbonyl compound, oxime, oxime ether and spread out Biological application.
Background technology
Multicellular organism regulating cell behavior and guarantee cell as an entirety in cytothesis or growth course Normal increment is a complicated signal transduction path.Defect Mechanism at these signals causes the fault of normal growth, from And cause cancer.Cancer is produced by number of ways and process, due to normal cell and tissue be difficult to produce to all receptors, Approach and signaling mechanism have the cancer therapy drug of effect.Additionally, after periodic anticancer chemotherapy reagent effect, tumor cell passes through Activate anti-apoptotic path and adapt to self, improve it to chemotherapy resistance, escape programmed death.Although by chemotherapeutant Being applied in combination, to prevent drug resistance, cancerous cell adapts to and develops one or more drug resistance approach and ultimately results in treatment of cancer failure.Under Face describes some anticancer main targets suppressed with multidrug resistance in cancerous cell.
A kind of transmembrane glycoprotein, EGF-R ELISA (EGFR), belong to being closely connected of erbB family
Cell-membrane receptor, including EGF-R ELISA (ERBB-1 or HER1), erbB2 (HER2), ERBB- , and ErbB4 (HER4) (HER3).Many human solid tumors, including head and neck, colorectal carcinoma, nonsmall-cell lung cancer (NSCLC), The expression that ovarian cancer and breast carcinoma show, overexpression, or EGF-R ELISA imbalance.EGF-R ELISA Activation may be by increasing Cell motility, multiplication capacity, invasive ability, and cohesive, and the ability of suppression apoptosis supports tumor Growth.The importance of control table skin growth factor receptor signal as strategy of cancer treatment more recently by extensively collecting molecules in inhibiting Agent it turned out, and is carrying out clinical trial.
RAS-RAF-MEK-ERK is by the downstream pathway of tyrosine kinase receptor approach acute activation, and its control is multiple carefully Born of the same parents' response to extracellular signal.This approach activates (particularly melanoma) in tumor cell and causes cell proliferation, survive, And the growth of tumor cell.Human body finds altogether 3 kinds of RAF (ARAF, BRAF, CRAF) and 3 kinds of RAS (NRAS, KRAS, HRAS) gene, it is critical that, BRAF, KRAS and NRAS sport 45%, 2% and 20% in melanoma respectively.Cancer is thin The propagation of born of the same parents and existence are by BRAFV600EMitogen-activated protein kinase (MAPK) pathway activation is stimulated by signaling.Should
The development of the BRAF inhibitor of carcinogenecity, particularly I type BRAF inhibitor, compared with basic chemotherapy, block BRAF Activity conformation kinases, result in significantly entity tumor response and improve body survival rate.
Chemotherapy is one of most basic method for the treatment of cancer, but successfully chemotherapy is hindered by the multidrug resistance of cancerous cell Hinder.The mechanism of the development of cancer therapy drug drug resistance is complicated.Up to the present, best multidrug resistance is by cancer cell membrane The overexpression of adenosine triphosphate.The cancer therapy drug that extensively structure is different can flow out cell by P glycoprotein, therefore, reduces Intracellular treatment level.Can be with reverse multidrug resistance matter by suppression outer row mechanism.Chemotherapy Complications can be by pressing down The development of pharmacy reason regulation and multidrug resistance reagent efflux pump reverse multidrug resistance.
α, β beta-unsaturated carbonyl compounds that is several natural and that synthesize, including chalcone derivative, curcumin, and their conjunction Analog is become to be considered to have anti-tumor activity.The ketone of these compounds is considered the work at cancer chemotherapy by mercaptan Alkylation play a role, it is not necessary to amino and the reaction of hydroxyl, accordingly, because this reactivity, ketenes is likely to be of ratio The character that traditional alkylating agent is more superior, because it has genetoxic less compared with other antitumor and anticancer agents.Additionally, ketenes The material that contains of anti-tumor activity relate to the suppression of approach of a lot of effect, such as NF-kappaB and mitochondrion mediation, trigger The tumor necrosis factor of death receptor, suppresses cell cycle protein dependent kinase or TOP-001 etc..Therefore, Synthesize special α, β beta-unsaturated carbonyl compounds to make a difference very much.Great majority to α, β beta-unsaturated carbonyl compounds (with chalcone derivative And curcumin analogue) based on research, concentrate on the evaluation of active anticancer, seldom report the energy of their reverse multidrug drug resistance Power.More information needs to be used for explaining the ability whether shortage β dicarbapentaborane affects these compounds suppression abc transport, and this Whether compounds has more preferable dual anticancer effect and can be as the reagent of effective reverse multidrug drug resistance.
Summary of the invention
It is an object of the invention to provide a kind of α, β-unsaturated compound, be used as prevention, the medicine for the treatment of tumor disease.
For reaching above-mentioned purpose, use technical scheme as follows:
α, β-unsaturated compound, has a following structural formula:
In structure above, R1Represent following group:
Methylene, secondary amino group, oxygen atom, HC-CH3、N-CH3、Or
R2Represent following group:
Oxygen atom, N-OH or
R’3It is hydrogen atom or methoxyl group；R’4It is hydrogen atom or methoxyl group；R’6Represent chlorine atom or bromine atoms.
α, β-unsaturated compound, has a following structural formula:
In structure above, R1Represent methylene or HC-CH3；
R2、R4、R5、R’3、R’4It is hydrogen atom or methoxyl group respectively；R3Represent hydrogen atom, chlorine atom, methoxyl group, fluorine atom, Bromine atoms, nitro；R’6Represent chlorine atom or bromine atoms；
R6Represent following group:
Oxygen atom, N-OH or
α, β-unsaturated compound, for
2,6-bis-(2-chloro-3-benzylidene) Ketohexamethylene (4a),
2,6-bis-(2-chloro-3,4-dimethoxybenzylidenegroup group) Ketohexamethylene (4b),
2,6-bis-(2-bromo-3,4,5-trimethoxy benzal) Ketohexamethylene (4c),
2,6-bis-(2-chloro-3-benzylidene)-4-methyl cyclohexanone (4d),
2,6-bis-(2-chloro-3,4-dimethoxybenzylidenegroup group)-4-methyl cyclohexanone (4e),
2,6-bis-(2-bromo-3,4,5-trimethoxy benzal)-4-methyl cyclohexanone (4f),
2,6-bis-(2-chloro-3-benzylidene)-4-isopropyl Ketohexamethylene (4g),
2,6-bis-(2-chloro-3,4-dimethoxybenzylidenegroup group)-4-isopropyl Ketohexamethylene (4h),
2,6-bis-(2-bromo-3,4,5-trimethoxy benzal)-4-isopropyl Ketohexamethylene (4i),
3,5-bis-(2-chloro-3-benzylidene) piperidin-4-one (4j),
3,5-bis-(2-chloro-3,4-dimethoxybenzylidenegroup group) piperidin-4-one (4k),
3,5-bis-(2-bromo-3,4,5-trimethoxy benzal) piperidin-4-one (4l),
3,5-bis-(2-chloro-3-benzylidene)-1-methyl piperidine-4-ketone (4m),
3,5-bis-(2-chloro-3,4-dimethoxybenzylidenegroup group)-1-methyl piperidine-4-ketone (4n),
3,5-bis-(2-bromo-3,4,5-trimethoxy benzal)-1-methyl piperidine-4-ketone (4o),
1-benzyl-3,5-two (2-chloro-3-benzylidene) piperidin-4-one (4p),
1-benzyl-3,5-two (2-chloro-3,4-dimethoxybenzylidenegroup group) piperidin-4-one (4q),
1-benzyl-3,5-two (2-bromo-3,4,5-trimethoxy benzal) piperidin-4-one (4r),
3,5-bis-(2-chloro-3-benzylidene) Tetrahydro-pyran-4-one (4s),
3,5-bis-(2-chloro-3,4-dimethoxybenzylidenegroup group) Tetrahydro-pyran-4-one (4t),
3,5-bis-(2-bromo-3,4,5-trimethoxy benzal) Tetrahydro-pyran-4-one (4u),
2-(2-chloro-3-Methoxy-benzylidene)-1,2,3,4-Tetrahydrooxonaphthalene (5a),
2-(2-chloro-3,4-Dimethoxy-benzylidene)-1,2,3,4-Tetrahydrooxonaphthalene (5b),
2-(2-bromo-3,4-Dimethoxy-benzylidene)-1,2,3,4-Tetrahydrooxonaphthalene (5c),
2-(2-chloro-3-Methoxy-benzylidene)-4-methyl-tetrahydro naphthalenone (5d),
2-(2-chloro-3,4-Dimethoxy-benzylidene)-4-methyl-tetrahydro naphthalenone (5e),
2-(2-bromo-3,4,5-Trimethoxy-benzylidene)-4-methyl-tetrahydro naphthalenone (5f),
2-(2-chloro-3-Methoxy-benzylidene)-6-dihydroxy-tetrahydro naphthalenone (5g),
2-(2-chloro-3,4-Dimethoxy-benzylidene)-6-dihydroxy-tetrahydro naphthalenone (5h),
2-(2-bromo-3,4,5-Trimethoxy-benzylidene)-6-dihydroxy-tetrahydro naphthalenone (5i),
2-(2-chloro-3-Methoxy-benzylidene) the chloro-1,2,3,4-Tetrahydrooxonaphthalene of-8-(5j),
2-(2-chloro-3,4-Dimethoxy-benzylidene) the chloro-1,2,3,4-Tetrahydrooxonaphthalene of-8-(5k),
2-(2-bromo-3,4,5-Trimethoxy-benzylidene) the chloro-1,2,3,4-Tetrahydrooxonaphthalene of-8-(5l),
2-(2-chloro-3-Methoxy-benzylidene)-7-methoxy-tetrahydro naphthalenone (5m),
2-(2-chloro-3,4-Dimethoxy-benzylidene)-7-methoxy-tetrahydro naphthalenone (5n),
2-(2-bromo-3,4,5-Trimethoxy-benzylidene)-7-methoxy-tetrahydro naphthalenone (5o),
2-(2-chloro-3-Methoxy-benzylidene)-6-methoxy-tetrahydro naphthalenone (5p),
2-(2-chloro-3,4-Dimethoxy-benzylidene)-6-methoxy-tetrahydro naphthalenone (5q),
2-(2-bromo-3,4,5-Trimethoxy-benzylidene)-6-methoxy-tetrahydro naphthalenone (5r),
2-(2-chloro-3-Methoxy-benzylidene)-7,8-dimethoxy-tetrahydro naphthalenone (5s),
2-(2-chloro-3,4-Dimethoxy-benzylidene)-7,8-dimethoxy-tetrahydro naphthalenone (5t),
2-(2-bromo-3,4,5-Trimethoxy-benzylidene)-7,8-dimethoxy-tetrahydro naphthalenone (5u),
2-(2-chloro-3-Methoxy-benzylidene)-6,9-dimethoxy-tetrahydro naphthalenone (5v),
2-(2-chloro-3,4-Dimethoxy-benzylidene)-6,9-dimethoxy-tetrahydro naphthalenone (5w),
2-(2-bromo-3,4,5-Trimethoxy-benzylidene)-6,9-dimethoxy-tetrahydro naphthalenone (5x),
2-(2-chloro-3-Methoxy-benzylidene) the bromo-1,2,3,4-Tetrahydrooxonaphthalene of-8-(5y),
2-(2-chloro-3,4-Dimethoxy-benzylidene) the bromo-1,2,3,4-Tetrahydrooxonaphthalene of-8-(5z),
2-(2-bromo-3,4,5-Trimethoxy-benzylidene) the bromo-1,2,3,4-Tetrahydrooxonaphthalene of-8-(5aa),
2-(2-chloro-3-Methoxy-benzylidene) the fluoro-1,2,3,4-Tetrahydrooxonaphthalene of-8-(5ab),
2-(2-chloro-3,4-Dimethoxy-benzylidene) the fluoro-1,2,3,4-Tetrahydrooxonaphthalene of-8-(5ac),
2-(2-bromo-3,4,5-Trimethoxy-benzylidene) the fluoro-1,2,3,4-Tetrahydrooxonaphthalene of-8-(5ad),
2-(2-chloro-3-Methoxy-benzylidene)-8-nitro-1,2,3,4-Tetrahydrooxonaphthalene (5ae),
2-(2-chloro-3,4-Dimethoxy-benzylidene)-8-nitro-1,2,3,4-Tetrahydrooxonaphthalene (5af),
2-(2-bromo-3,4,5-Trimethoxy-benzylidene)-8-nitro-1,2,3,4-Tetrahydrooxonaphthalene (5ag),
2,6-pair-(2-bromo-3,4,5-Trimethoxy-benzylidene)-Ketohexamethylene-oxime (7c),
2,6-pair-(2-bromo-3,4,5-Trimethoxy-benzylidene)-4-methyl-cyclohexyl ketone-oxime (7f),
3,5-pair-(2-bromo-3,4,5-Trimethoxy-benzylidene)-1-methyl-pi-4-ketone-oxime (7o),
2-(2-bromo-3,4,5-Trimethoxy-benzylidene)-4-methyl-tetrahydro naphthalenone-oxime (8f),
2-(2-bromo-3,4,5-Trimethoxy-benzylidene)-6-dihydroxy-tetrahydro naphthalenone-oxime (8i),
2-(2-bromo-3,4,5-Trimethoxy-benzylidene)-7-methoxy-tetrahydro naphthalenone-oxime (8o),
2-(2-bromo-3,4,5-Trimethoxy-benzylidene)-7,8-dimethoxy-tetrahydro naphthalenone-oxime (8u),
2-(2-bromo-3,4,5-Trimethoxy-benzylidene)-6,9-dimethoxy-tetrahydro naphthalenone-oxime (8x),
2-(2-chloro-3,4-Dimethoxy-benzylidene)-8-nitro-1,2,3,4-Tetrahydrooxonaphthalene-oxime (8af),
2-(2-bromo-3,4,5-Trimethoxy-benzylidene)-8-nitro-1,2,3,4-Tetrahydrooxonaphthalene-oxime (8ag),
3,5-pair-(2-bromo-3,4,5-Trimethoxy-benzylidene)-1-methyl-cyclohexyl ketone-oxygen-(2-diethylamino-second Base)-oxime (10f),
3,5-pair-(2-bromo-3,4,5-Trimethoxy-benzylidene)-1-methyl-pi-4-ketone-oxygen-(2-diethyl amino Base-ethyl)-oxime (10o),
2-(2-bromo-3,4,5-Trimethoxy-benzylidene)-6,9-dimethoxy-tetrahydro naphthalenone-oxygen-(2-diethyl amino Base-ethyl)-oxime (11x),
2-(2-chloro-3,4-Dimethoxy-benzylidene)-8-nitro-1,2,3,4-Tetrahydrooxonaphthalene-oxygen-(2-Diethylamino-ethyl)- Oxime (11af) or 2-(2-bromo-3,4,5-Trimethoxy-benzylidene)-8-nitro-1,2,3,4-Tetrahydrooxonaphthalene-oxygen-(2-diethylamino-second Base)-oxime (11ag).
Above-mentioned α, β-unsaturated compound is as prevention, the application for the treatment of tumor disease medicine.
Above-mentioned α, β-unsaturated compound is as prevention, the application for the treatment of resistant tumors disease medicament.
Above-mentioned α, β-unsaturated compound includes carbonyl compound, oxime, oxime ether and derivant thereof, by assessing it to seven kinds The ability of the anti-malignant cell proliferation of human cancer cell, and for BRAFV600E, epidermal growth factor TK kinases and micropore egg The inhibitory activity of white polymerase, finds that these compounds are suitable as prevention, the medicine for the treatment of tumor disease.These chemical combination simultaneously The multi-medicine tolerant reversal activity of thing, shows that these compounds are also suitable for the tumor cell with multidrug resistance pre- Anti-, therapeutical effect.
Beneficial effects of the present invention is as follows:
The present invention has synthesized a series of α, beta-unsaturated carbonyl compound, oxime, oxime ether derivatives, lives by measuring its biology Property, it was demonstrated that the compound of present invention synthesis is suitable as prevention, the medicine for the treatment of tumor disease, is also suitable for having simultaneously The prevention of the tumor cell of multidrug resistance, therapeutical effect, have preferable application prospect.
Accompanying drawing explanation
The action effect test of Fig. 1: tubulin polymerization enzyme of the present invention.
Detailed description of the invention
Following example explain technical scheme further, but not as limiting the scope of the invention.
Embodiment 1
The synthesis of compound 2,6-bis-(2-bromo-3,4,5-trimethoxy benzal) Ketohexamethylene (4c):
Ketohexamethylene (10mmol, 1eq) and 2-bromo-3,4,5-front three it is separately added in the round-bottomed flask filling 15mL ethanol Epoxide benzaldehyde (20mmol, 2eq), temperature is maintained at 5 DEG C.Afterwards, 40% sodium hydroxide ethanol solution is added.Mixture exists Stirring reaction 1-24h at 27 DEG C.The outward appearance of precipitation shows the generation of product with color change.With TLC, this reaction is monitored. When the reactions are completed, the ice cancellation reaction of acidifying is added.Carry out recrystallization afterwards or column chromatography procedure obtains the product of purification, produce Rate is 74%.
mp:102-103℃；1H NMR(500MHz,CDCl3)δ:7.82(s,2H),6.89(s,2H),3.75(s,18H), 2.32 (t, J=8.0Hz, 4H), 1.82 (m, 2H)；13C NMR(500MHz,CDCl3)δ:185.4,151.2,146.5,144.2, 144.9,135.9,130.5,108.4,98.6,56.5,56.1,55.5,28.5,27.3；HRMS(ESI)m/z:613.32[M+ H]+,Microanalysis calculated for C26H28Br2O7(612.30), C:51.00%, H:4.61%.Found C:51.22%, H:4.59%.
Embodiment 2
The synthesis of compound 2,6-bis-(2-bromo-3,4,5-trimethoxy benzal)-4-methyl cyclohexanone (4f):
Initiation material be 4-methyl cyclohexanone (10mmol, 1eq) and the bromo-TMB of 2-(20mmol, 2eq), the other the same as in Example 1, productivity is 69%.
Mp:105-106℃；1H NMR(500MHz,CDCl3)δ:7.84(s,2H),6.87(s,2H),3.79(s,18H), 2.02 (d, J=8.5Hz, 4H), 1.72 (m, H)；1.16 (d, J=8.5Hz, 3H)；13C NMR(500MHz,CDCl3)δ: 185.6,150.8,146.9,146.4,145.9,134.8,130.6,107.5,99.8,56.8,56.5,56.0,31.5, 29.3,22.5；HRMS(ESI)m/z:627.65[M+H]+,Microanalysis calculated for C27H30Br2O7 (626.33), C:51.78%, H:4.83%.Found C:51.92%, H:4.99%.
Embodiment 3
The synthesis of compound 3,5-bis-(2-bromo-3,4,5-trimethoxy benzal)-1-methyl piperidine-4-ketone (4o):
Initiation material is 1-methyl piperidine-4-ketone (10mmol, 1eq) and the bromo-TMB of 2- (20mmol, 2eq), the other the same as in Example 1, productivity is 55%.
Mp:140-141℃；1H NMR(500MHz,CDCl3)δ:7.81(s,2H),6.84(s,2H),3.81(s,18H), 2.72(s,4H),2.16(s,3H)；13C NMR(500MHz,CDCl3)δ:184.9,150.6,147.5,145.2,144.9, 135.3,131.8,106.2,99.5,56.7,56.1,55.9,41.5,16.5；HRMS(ESI)m/z:628.32[M+H]+, Microanalysis calculated for C26H29Br2NO7(627.32), C:49.78%, H:4.66%, N:2.23% .Found C:49.91%, H:4.86%, N:2.12%.
Embodiment 4
The synthesis of compound 2-(2-bromo-3,4,5-Trimethoxy-benzylidene)-4-methyl-tetrahydro naphthalenone (5f):
4-methyl-tetrahydro naphthalenone (10mmol, 1eq) and 2-it is separately added into bromo-in the round-bottomed flask filling 15mL ethanol 3,4,5-Trimethoxybenzaldehyde (10mmol, 1eq), temperature is maintained at 5oC.Afterwards, 40% sodium hydroxide ethanol is added molten Liquid.Mixture is 27oStirring reaction 1-24h under C.The outward appearance of precipitation shows the generation of product with color change.Anti-to this with TLC Should be monitored.When the reactions are completed, the ice cancellation reaction of acidifying is added.Carry out recrystallization afterwards or column chromatography procedure obtains pure The product changed, productivity is 69%.
Mp:90-91℃；1H NMR(500MHz,CDCl3) δ: 7.69 (s, H), 7.27 (d, J=7.5Hz, H), 7.19 (d, J =7.5Hz, H), 7.07 (t, J=7.5Hz, H), 6.91 (t, J=7.0Hz, H), 6.47 (s, H), 3.56 (s, 9H), 2.19 (d, J=8.5Hz, 2H), 1.79 (m, H)；1.19 (d, J=8.5Hz, 3H)；13C NMR(500MHz,CDCl3)δ:184.5, 150.7,149.1,147.1,146.8,145.2,137.3,134.5,134.0,130.2,127.3,125.5,124.8, 106.9,98.7,56.9,56.1,55.8,30.4,29.7,21.8；HRMS(ESI)m/z:418.32[M+H]+, Microanalysis calculated for C21H21BrO4(417.29), C:60.44%, H:5.07%.Found C: 60.52%, H:5.15%.
Embodiment 5
The synthesis of compound 2-(2-bromo-3,4,5-Trimethoxy-benzylidene)-6-dihydroxy-tetrahydro naphthalenone (5i):
Initiation material is 6-dihydroxy-tetrahydro naphthalenone (10mmol, 1eq) and the bromo-TMB of 2- (10mmol, 1eq), the other the same as in Example 4, productivity is 72%.
Mp:94-95℃；1H NMR(500MHz,CDCl3) δ: 7.68 (s, H), 7.15 (d, J=7.5Hz, H), 7.02 (t, J =7.0Hz, H), 6.90 (d, J=7.5Hz, H), 6.42 (s, H), 5.81 (s, H), 3.52 (s, 9H), 2.52 (t, J=8.0Hz, 2H), 2.13 (t, J=8.0Hz, 2H)；13C NMR(500MHz,CDCl3)δ:184.9,159.6,149.2,147.2,146.1, 140.2,137.8,134.4,134.0,130.5,126.2,122.4,120.2,105.5,96.1,56.8,56.0,55.8, 31.2,27.8；HRMS(ESI)m/z:420.46[M+H]+,Microanalysis calculated for C20H19BrO5 (419.27), C:57.29%, H:4.57%.Found C:57.52%, H:4.65%.
Embodiment 6
The synthesis of compound 2-(2-bromo-3,4,5-Trimethoxy-benzylidene)-7-methoxy-tetrahydro naphthalenone (5o):
Initiation material is 7-methoxy-tetrahydro naphthalenone (10mmol, 1eq) and the bromo-TMB of 2- (10mmol, 1eq), the other the same as in Example 4, productivity is 76%.
Mp:92-93℃；1H NMR(500MHz,CDCl3) δ: 7.80 (s, H), 7.21 (d, J=8.0Hz, H), 7.02 (s, H), 6.85 (d, J=8.0Hz, H), 6.55 (s, H), 3.59 (s, 3H), 3.50 (s, 9H), 2.50 (t, J=8.0Hz, 2H), 2.18 (t, J=8.0Hz, 2H)；13C NMR(500MHz,CDCl3)δ:185.3,159.9,148.9,147.4,146.3, 141.0,137.2,134.5,134.2,130.5,126.5,123.0,119.1,102.7,99.4,56.8,56.2,56.0, 55.8,30.6,25.9；HRMS(ESI)m/z:456.62[M+Na]+,Microanalysis calculated for C21H21BrO5(433.29), C:58.21%, H:4.89%.Found C:58.51%, H:4.91%.
Embodiment 7
The synthesis of compound 2-(2-bromo-3,4,5-Trimethoxy-benzylidene)-7,8-dimethoxy-tetrahydro naphthalenone (5u):
Initiation material is 7,8-dimethoxy-tetrahydro naphthalenone (10mmol, 1eq) and 2-bromo-3,4,5-trimethoxy-benzene first Aldehyde (10mmol, 1eq), the other the same as in Example 4, productivity is 72%.
Mp:98-99℃；1H NMR(500MHz,CDCl3)δ:7.89(s,H),7.12(s,H),6.75(s,H),6.25(s, H), 3.58 (s, 6H), 3.64 (s, 9H), 2.54 (t, J=8.0Hz, 2H), 2.18 (t, J=8.5Hz, 2H)；13C NMR (500MHz,CDCl3)δ:186.5,152.7,148.3,147.2,146.0,140.6,135.9,134.9,134.4,131.2, 125.2,122.6,119.6,102.2,93.2,56.1,55.9,55.5,55.3,55.0,29.4,21.2；HRMS(ESI)m/z: 464.72[M+H]+,Microanalysis calculated for C22H23BrO6(463.32), C:57.03%, H: 5.00%.Found C:57.25%, H:5.15%.
Embodiment 8
The synthesis of compound 2-(2-bromo-3,4,5-Trimethoxy-benzylidene)-6,9-dimethoxy-tetrahydro naphthalenone (5x):
Initiation material is 6,9-dimethoxy-tetrahydro naphthalenone (10mmol, 1eq) and 2-bromo-3,4,5-trimethoxy-benzene first Aldehyde (10mmol, 1eq), the other the same as in Example 4, productivity is 69%.
Mp:98-99℃；1H NMR (500MHz, CDCl3) δ: 7.85 (s, H), 7.05 (d, J=7.5Hz, H), 6.82 (d, J=7.5Hz, H), 6.24 (s, H), 3.72 (s, 15H), 2.52 (t, J=8.0Hz, 2H), 2.10 (t, J=8.0Hz, 2H)；13C NMR(500MHz,CDCl3)δ:186.2,151.9,148.5,147.4,146.0,140.4,136.2,134.6,134.3, 131.0,125.4,123.1,119.5,102.5,94.0,56.2,55.9,55.4,55.2,55.0,29.8,21.6；HRMS (ESI)m/z:464.36[M+H]+,Microanalysis calculated for C22H23BrO6(463.32),C: 57.03%, H:5.00%.Found C:57.24%, H:5.12%.
Embodiment 9
The synthesis of compound 2-(2-chloro-3,4-Dimethoxy-benzylidene)-8-nitro-1,2,3,4-Tetrahydrooxonaphthalene (5af):
Initiation material is 8-nitro-1,2,3,4-Tetrahydrooxonaphthalene (10mmol, 1eq) and 2-chloro-3,4-dimethoxy benzaldehyde (10mmol, 1eq), the other the same as in Example 4, productivity is 62%.
Mp:94-95℃；1H NMR(500MHz,CDCl3) δ: 7.96 (s, H), 7.64 (d, J=8Hz, H), 7.32 (d, J= 8Hz, H), 7.12 (d, J=7.5Hz, H), 6.92 (d, J=7.5Hz, H), 6.52 (s, H), 3.89 (s, 6H), 2.82 (t, J= 8.0Hz, 2H), 2.24 (t, J=8.0Hz, 2H)；13C NMR(500MHz,CDCl3)δ:190.2,154.5,149.5,147.1, 146.6,138.5,132.1,130.5,129.3,127.5,125.2,124.6,120.8,100.6,94.4,56.8,56.6, 27.3,19.4；HRMS(ESI)m/z:374.80[M+H]+,Microanalysis calculated for C19H16ClNO5 (373.79), C:61.05%, H:4.31%, N:3.75%.Found C:61.46%, H:4.49%, N:3.54%.
Embodiment 10
The synthesis of compound 2-(2-bromo-3,4,5-Trimethoxy-benzylidene)-8-nitro-1,2,3,4-Tetrahydrooxonaphthalene (5ag):
Initiation material is 8-nitro-1,2,3,4-Tetrahydrooxonaphthalene (10mmol, 1eq) and the bromo-TMB of 2- (10mmol, 1eq), the other the same as in Example 4, productivity is 54%.
Mp:98-99℃；1H NMR(500MHz,CDCl3) δ: 7.92 (s, H), 7.66 (d, J=8Hz, H), 7.14 (s, H), 6.89 (d, J=7.5Hz, H), 6.58 (s, H), 3.81 (s, 9H), 2.88 (t, J=8.0Hz, 2H), 2.19 (t, J=8.0Hz, 2H)；13C NMR(500MHz,CDCl3)δ:191.0,154.2,148.6,147.4,146.2,137.2,132.6,130.1, 128.8,127.1,125.3,124.6,121.2,99.4,95.5,56.9,56.6,55.8,25.4,20.2；HRMS(ESI)m/ z:449.50[M+H]+,Microanalysis calculated for C20H18BrNO6(448.26), C:53.59%, H: 4.05%, N:3.12%.Found C:53.64%, H:4.22%, N:3.06%.
Embodiment 11
The synthesis of compound 2,6-pair-(2-bromo-3,4,5-Trimethoxy-benzylidene)-Ketohexamethylene-oxime (7c):
Initiation material is 2,6-bis-(2-bromo-3,4,5-trimethoxy benzal) Ketohexamethylene (4c) (1mmol) and hydrochloric acid hydroxyl Amine (2mmol) reacts 6-8 hour in 10mL ethanol.TLC monitors.After reaction terminates, mixture filters, with dichloromethane and water Extraction, anhydrous magnesium sulfate is dried organic layer, concentrating under reduced pressure after filtration, and by TLC detection compound purity, product passes through ethyl acetate Being recrystallized to give pressed powder, column chromatography ethyl acetate: normal hexane=70:30 purified product, productivity is 54%.
Mp:105-106℃；1H NMR(500MHz,CDCl3)δ:8.39(s,H),7.14(s,2H),6.21(s,2H), 3.75 (s, 18H), 2.10 (d, J=8.5Hz, 4H), 1.81 (m, 2H)；13C NMR(500MHz,CDCl3)δ:164.5,148.6, 146.5,145.4,142.2,134.5,130.1,105.2,98.8,56.9,56.5,56.0,29.2,28.1；HRMS(ESI)m/ z:628.35[M+H]+,Microanalysis calculated for C26H29Br2NO7(627.32), C:49.78%, H: 4.66%, N:2.23%.Found C:49.92%, H:4.72%, N:2.19%.
Embodiment 12
The synthesis of compound 2,6-pair-(2-bromo-3,4,5-Trimethoxy-benzylidene)-4-methyl-cyclohexyl ketone-oxime (7f):
Initiation material is 2,6-couple-(2-bromo-3,4,5-Trimethoxy-benzylidene)-4-methyl-cyclohexyl ketone (4f) (1mmol) with oxammonium hydrochloride. (2mmol), the other the same as in Example 11, productivity is 49%.
Mp:108-109℃；1H NMR(500MHz,CDCl3)δ:8.42(s,H),7.12(s,2H),6.27(s,2H), 3.72 (s, 18H), 2.12 (d, J=8.5Hz, 4H), 1.75 (m, H)；1.24 (d, J=8.5Hz, 3H)；13C NMR(500MHz, CDCl3)δ:162.2,148.8,146.4,145.4,141.6,134.6,130.7,107.4,98.2,56.4,56.2,56.0, 30.2,28.4,22.2；HRMS(ESI)m/z:642.37[M+H]+,Microanalysis calculated for C27H31Br2NO7(641.35), C:50.56%, H:4.87%, N:2.18%.Found C:50.92%, H:4.92%, N: 2.10%.
Embodiment 13
The conjunction of compound 3,5-pair-(2-bromo-3,4,5-Trimethoxy-benzylidene)-1-methyl-pi-4-ketone-oxime (7o) Become:
Initiation material is 3,5-couple-(2-bromo-3,4,5-Trimethoxy-benzylidene)-1-methyl-pi-4-ketone (4o) (1mmol) with oxammonium hydrochloride. (2mmol), the other the same as in Example 11, productivity is 42%.
Mp:132-133℃；1H NMR(500MHz,CDCl3)δ:8.38(s,H),7.14(s,2H),6.29(s,2H), 3.75(s,18H),2.61(s,4H),2.14(s,3H)；13C NMR(500MHz,CDCl3)δ:164.1,150.2,147.3, 145.5,142.2,135.5,131.6,105.9,99.1,56.7,56.3,56.1,42.0,16.2；HRMS(ESI)m/z: 643.14[M+H]+,Microanalysis calculated for C26H30Br2N2O7(642.33), C:48.62%, H: 4.71%, N:4.36%.Found C:48.85%, H:4.79%, N:4.25%.
Embodiment 14
The synthesis of compound 2-(2-bromo-3,4,5-Trimethoxy-benzylidene)-4-methyl-tetrahydro naphthalenone-oxime (8f):
Initiation material be 2-(2-bromo-3,4,5-Trimethoxy-benzylidene)-4-methyl-tetrahydro naphthalenone (5f) (1mmol) and Oxammonium hydrochloride. (2mmol), the other the same as in Example 11, productivity is 50%.
Mp:114-115℃；1H NMR(500MHz,CDCl3) δ: 8.29 (s, H), 7.42 (s, H), 6.85 (t, J=7Hz, H), 6.79 (t, J=7Hz, H), 6.44 (d, J=7.5Hz, H), 6.35 (d, J=7.5Hz, H), 6.28 (s, H), 3.71 (s, 9H), 2.51 (d, J=7Hz, 2H), 2.0 (m, H)；1.25 (d, J=8.5Hz, 3H)；13C NMR(500MHz,CDCl3)δ: 167.2,151.9,148.6,146.5,144.5,139.5,135.7,134.1,132.5,131.2,125.5,122.2, 118.5,99.8,92.5,56.8,56.2,55.5,29.6,24.5,22.5；HRMS(ESI)m/z:433.31[M+H]+, Microanalysis calculated for C21H22BrNO4(432.31), C:58.34%, H:5.13%, N:3.24% .Found C:58.55%, H:5.29%, N:3.12%.
Embodiment 15
The synthesis of compound 2-(2-bromo-3,4,5-Trimethoxy-benzylidene)-6-dihydroxy-tetrahydro naphthalenone-oxime (8i):
Initiation material be 2-(2-bromo-3,4,5-Trimethoxy-benzylidene)-6-dihydroxy-tetrahydro naphthalenone (5i) (1mmol) and Oxammonium hydrochloride. (2mmol), the other the same as in Example 11, productivity is 57%.
Mp:119-120℃；1H NMR(500MHz,CDCl3) δ: 8.32 (s, H), 7.46 (s, H), 6.82 (t, J=7Hz, H), 6.70 (d, J=7.5Hz, H), 6.38 (d, J=7.5Hz, H), 6.22 (s, H), 4.09 (s, H), 3.75 (s, 9H), 2.57 (t, J=7Hz, 2H), 1.98 (t, J=7.5Hz, 2H)；13C NMR(500MHz,CDCl3)δ:167.5,152.2,148.4, 146.1,143.9,139.7,134.9,133.8,132.5,131.1,124.9,121.6,118.7,99.2,92.7,56.9, 56.1,55.8,29.2,24.1；HRMS(ESI)m/z:435.29[M+H]+,Microanalysis calculated for C20H20BrNO5(434.28), C:55.31%, H:4.64%, N:3.23%.Found C:55.52%, H:4.68%, N: 3.20%.
Embodiment 16
The synthesis of compound 2-(2-bromo-3,4,5-Trimethoxy-benzylidene)-7-methoxy-tetrahydro naphthalenone-oxime (8o):
Initiation material is 2-(2-bromo-3,4,5-Trimethoxy-benzylidene)-7-methoxy-tetrahydro naphthalenone (5o) (1mmol) With oxammonium hydrochloride. (2mmol), the other the same as in Example 11, productivity is 55%.
Mp:117-118℃；1H NMR(500MHz,CDCl3) δ: 8.28 (s, H), 7.42 (s, H), 6.81 (d, J=7Hz, H), 6.76 (d, J=7.5Hz, H), 6.42 (s, H), 6.25 (s, H), 3.78 (s, 12H), 2.55 (t, J=7Hz, 2H), 1.99 (t, J=7.5Hz, 2H)；13C NMR(500MHz,CDCl3)δ:168.2,152.8,148.1,146.5,142.1,139.6, 134.2,133.9,132.4,130.2,124.6,120.8,118.2,99.1,92.5,57.5,56.8,56.2,55.7,29.5, 25.1；HRMS(ESI)m/z:449.35[M+H]+,Microanalysis calculated for C21H22BrNO5 (448.31), C:56.26%, H:4.95%, N:3.12%.Found C:56.29%, H:4.99%, N:3.09%.
Embodiment 17
The conjunction of compound 2-(2-bromo-3,4,5-Trimethoxy-benzylidene)-7,8-dimethoxy-tetrahydro naphthalenone-oxime (8u) Become:
Initiation material is 2-(2-bromo-3,4,5-Trimethoxy-benzylidene)-7,8-dimethoxy-tetrahydro naphthalenone (5u) (1mmol) with oxammonium hydrochloride. (2mmol), the other the same as in Example 11, productivity is 59%.
Mp:111-112℃；1H NMR(500MHz,CDCl3)δ:8.29(s,H),7.45(s,H),6.75(s,H),6.42 (s, H), 6.25 (s, H), 3.78 (s, 15H), 2.52 (t, J=7Hz, 2H), 1.97 (t, J=7.5Hz, 2H)；13C NMR (500MHz,CDCl3)δ:168.9,152.4,147.6,146.2,141.9,139.5,134.3,132.4,131.9,130.0, 124.2,120.9,118.7,98.8,92.4,57.5,56.9,56.2,55.7,55.2,29.4,25.8；HRMS(ESI)m/z: 479.35[M+H]+,Microanalysis calculated for C22H24BrNO6(478.33), C:55.24%, H: 5.06%, N:2.93%.Found C:55.29%, H:5.10%, N:2.88%.
Embodiment 18
The conjunction of compound 2-(2-bromo-3,4,5-Trimethoxy-benzylidene)-6,9-dimethoxy-tetrahydro naphthalenone-oxime (8x) Become:
Initiation material is 2-(2-bromo-3,4,5-Trimethoxy-benzylidene)-6,9-dimethoxy-tetrahydro naphthalenone (5x) (1mmol) with oxammonium hydrochloride. (2mmol), the other the same as in Example 11, productivity is 52%.
Mp:112-114℃；1H NMR(500MHz,CDCl3) δ: 8.39 (s, H), 7.15 (s, H), 6.43 (d, J= 7.2Hz, H), 6.38 (d, J=7.4Hz, H), 6.29 (s, H), 3.68 (s, 15H), 2.51 (t, J=6.8Hz, 2H), 1.99 (t, J=7.5Hz, 2H)；13C NMR(500MHz,CDCl3)δ:166.5,151.3,148.1,146.2,145.0,139.2,136.7, 134.2,133.9,131.5,124.8,123.5,117.2,100.1,94.6,56.7,56.4,56.2,55.9,55.5,29.6, 21.5；HRMS(ESI)m/z:479.45[M+H]+,Microanalysis calculated for C22H24BrNO6 (478.33), C:55.24%, H:5.06%, N:2.93%.Found C:55.29%, H:5.18%, N:2.91%.
Embodiment 19
The synthesis of compound 2-(2-chloro-3,4-Dimethoxy-benzylidene)-8-nitro-1,2,3,4-Tetrahydrooxonaphthalene-oxime (8af):
Initiation material be 2-(2-chloro-3,4-Dimethoxy-benzylidene)-8-nitro-1,2,3,4-Tetrahydrooxonaphthalene (5af) (1mmol) and Oxammonium hydrochloride. (2mmol), the other the same as in Example 11, productivity is 57%.
Mp:124-125℃；1H NMR(500MHz,CDCl3) δ: 8.47 (s, H), 7.26 (s, H), 7.14 (d, J= 8.4Hz, H), 7.04 (d, J=7.4Hz, H), 6.87 (d, J=7.2Hz, H), 6.65 (d, J=7.5Hz, H), 6.50 (s, H), 3.74 (s, 6H), 2.75 (t, J=8.2Hz, 2H), 2.14 (t, J=8.2Hz, 2H)；13C NMR(500MHz,CDCl3)δ: 164.5,152.3,149.2,147.8,145.2,138.6,132.9,130.1,128.7,127.1,125.2,124.1, 121.3,99.9,93.7,57.1,56.8,28.8,19.1；HRMS(ESI)m/z:389.80[M+H]+,Microanalysis calculated for C19H17ClN2O5(388.80), C:58.69%, H:4.41%, N:7.21%.Found C: 58.72%, H:4.49%, N:7.25%.
Embodiment 20
The synthesis of compound 2-(2-bromo-3,4,5-Trimethoxy-benzylidene)-8-nitro-1,2,3,4-Tetrahydrooxonaphthalene-oxime (8ag):
Initiation material is 2-(2-bromo-3,4,5-Trimethoxy-benzylidene)-8-nitro-1,2,3,4-Tetrahydrooxonaphthalene (5ag) (1mmol) With oxammonium hydrochloride. (2mmol), the other the same as in Example 11, productivity is 54%.
Mp:98-99℃；1H NMR(500MHz,CDCl3) δ: 8.45 (s, H), 7.32 (s, H), 7.22 (d, J=8.2Hz, H), 7.10 (s, H), 6.75 (d, J=8.2Hz, H), 6.48 (s, H), 3.72 (s, 9H), 2.81 (t, J=8.0Hz, 2H), 2.09 (t, J=8.0Hz, 2H)；13C NMR(500MHz,CDCl3)δ:167.9,154.6,148.4,146.5,145.1,137.6, 131.9,130.0,128.5,126.9,125.1,124.7,120.8,98.8,95.2,56.8,56.5,56.0,25.2,19.7； HRMS(ESI)m/z:449.50[M+H]+,Microanalysis calculated for C20H19BrN2O6(463.28),C: 51.85%, H:4.13%, N:6.05%.Found C:51.59%, H:4.29%, N:6.14%.
Embodiment 21
Compound 3,5-pair-(2-bromo-3,4,5-Trimethoxy-benzylidene)-1-methyl-cyclohexyl ketone-oxygen-(2-diethyl Amino-ethyl) synthesis of-oxime (10f):
Dry acetone 10mL is added in dry round-bottomed flask, the potassium carbonate 5mmol of drying, the hydrochloric acid of cyclic alkyl amine Salt (1.2mmol), 2,6-double-(bromo-3,4, the 5-Trimethoxy-benzylidene of 2-)-4-methyl-cyclohexyl ketone-oximes (7f) (1.0mmol), reflux 8 hours in anhydrous conditions.TLC monitors reaction, after off-test, washing with acetone, filters, with alkalescence oxygen Change aluminum column purification product, productivity 62%.
Mp:106-107℃；1H NMR(500MHz,CDCl3)δ:7.12(s,2H),6.87(s,2H),4.51(m,2H), 3.81 (s, 18H), 2.60 (m, 4H), 2.51 (m, 2H), 2.14 (d, J=8.5Hz, 4H), 1.76 (m, H)；1.70 (t, J= 7.0Hz,6H)；1.25 (d, J=8.5Hz, 3H)；13C NMR(500MHz,CDCl3)δ:164.5,152.5,147.5,145.1, 140.8,135.9,132.4,104.1,98.9,72.1,56.9,56.2,55.8,52.1,48.2,42.5,30.9,17.5, 14.9；HRMS(ESI)m/z:741.52[M+H]+,Microanalysis calculated for C32H44Br2N2O7 (740.52), C:53.52%, H:5.99%, N:3.78%.Found C:53.54%, H:6.12%, N:3.62%.
Embodiment 22
Compound 3,5-pair-(2-bromo-3,4,5-Trimethoxy-benzylidene)-1-methyl-pi-4-ketone-oxygen-(2-diethyl Base amino-ethyl) synthesis of-oxime (10o):
Initiation material is 3,5-pair-(2-bromo-3,4,5-Trimethoxy-benzylidene)-1-methyl-pi-4-ketone-oxime (7o) (1mmol) and the hydrochlorate (1.2mmol) of cyclic alkyl amine, the other the same as in Example 21, productivity is 50%.
Mp:111-113℃；1H NMR(500MHz,CDCl3)δ:7.10(s,2H),6.89(s,2H),4.52(m,2H), 3.78 (s, 18H), 2.62 (s, 4H), 2.55 (m, 2H), 2.42 (m, 4H), 2.19 (s, 3H), 1.75 (t, J=7.0Hz, 6H)；13C NMR(500MHz,CDCl3)δ:164.7,151.3,147.8,145.5,141.4,135.9,132.0,104.7,99.6, 72.2,56.8,56.6,56.2,52.0,48.4,42.1,17.7,14.4；HRMS(ESI)m/z:742.55[M+H]+, Microanalysis calculated for C32H43Br2N3O7(741.51), C:51.83%, H:5.85%, N:5.67% .Found C:51.89%, H:5.92%, N:5.52%.
Embodiment 23
Compound 2-(2-bromo-3,4,5-Trimethoxy-benzylidene)-6,9-dimethoxy-tetrahydro naphthalenone-oxygen-(2-diethyl Base amino-ethyl) synthesis of-oxime (11x):
Initiation material is 2-(2-bromo-3,4,5-Trimethoxy-benzylidene)-6,9-dimethoxy-tetrahydro naphthalenone-oxime (8x) (1mmol) and the hydrochlorate (1.2mmol) of cyclic alkyl amine, the other the same as in Example 21, productivity is 49%.
Mp:121-122℃；1H NMR(500MHz,CDCl3) δ: 7.25 (s, H), 7.02 (d, J=8.0Hz, H), 6.91 (s, H), 6.65 (d, J=8.0Hz, H), 4.50 (m, 2H), 3.68 (s, 15H), 2.87 (t, J=8.0Hz, 2H), 2.55 (m, 2H), 2.40 (m, 4H), 2.08 (t, J=8.0Hz, 2H)；1.70 (t, J=7.0Hz, 6H)；13C NMR(500MHz,CDCl3)δ: 170.2,153.5,148.7,146.1,145.2,135.6,131.0,129.5,127.2,126.2,125.0,124.1, 118.4,98.2,95.1,72.5,56.8,56.2,56.0,55.5,55.2,52.4,48.8,25.1,19.9,14.2；HRMS (ESI)m/z:578.55[M+H]+,Microanalysis calculated for C28H37BrN2O6(577.51),C: 58.23%, H:6.46%, N:4.85%.Found C:58.25%, H:6.72%, N:4.75%.
Embodiment 24
Compound 2-(2-chloro-3,4-Dimethoxy-benzylidene)-8-nitro-1,2,3,4-Tetrahydrooxonaphthalene-oxygen-(2-diethylamino- Ethyl) synthesis of-oxime (11af):
Initiation material is 2-(2-chloro-3,4-Dimethoxy-benzylidene)-8-nitro-1,2,3,4-Tetrahydrooxonaphthalene-oxime (8af) (1mmol) With the hydrochlorate (1.2mmol) of cyclic alkyl amine, the other the same as in Example 21, productivity is 47%.
Mp:117-118℃；1H NMR(500MHz,CDCl3) δ: 7.29 (s, H), 6.99 (d, J=8.0Hz, H), 6.89 (d, J=8.0Hz, H), 6.72 (d, J=8.0Hz, H), 6.58 (d, J=8.0Hz, H), 6.40 (s, H), 4.55 (m, 2H), 3.68 (s, 6H), 3.10 (t, J=8.4Hz, 2H), 2.52 (m, 2H), 2.43 (m, 4H), 2.12 (t, J=8.2,2H), 1.75 (t, J=7.0Hz, 6H)；13C NMR(500MHz,CDCl3)δ:169.5,154.5,148.0,146.9,145.1,136.8, 132.0,129.2,128.5,125.5,124.9,124.1,118.9,98.9,95.2,72.5,56.9,56.1,52.0,48.2, 25.5,20.6,15.1；HRMS(ESI)m/z:488.98[M+H]+,Microanalysis calculated for C25H30ClN3O5(487.98), C:61.53%, H:6.20%, N:8.61%.Found C:61.55%, H:6.25%, N: 8.55%.
Embodiment 25
Compound 2-(2-bromo-3,4,5-Trimethoxy-benzylidene)-8-nitro-1,2,3,4-Tetrahydrooxonaphthalene-oxygen-(2-diethyl amino Base-ethyl) synthesis of-oxime (11ag):
Initiation material is 2-(2-bromo-3,4,5-Trimethoxy-benzylidene)-8-nitro-1,2,3,4-Tetrahydrooxonaphthalene-oxime (8ag) (1mmol) and the hydrochlorate (1.2mmol) of cyclic alkyl amine, the other the same as in Example 21, productivity is 42%.
Mp:119-120℃；1H NMR(500MHz,CDCl3) δ: 7.24 (s, H), 7.05 (d, J=8.0Hz, H), 6.90 (s, H), 6.68 (d, J=8.0Hz, H), 6.42 (s, H), 4.59 (m, 2H), 3.64 (s, 9H), 3.12 (t, J=8.4Hz, 2H), 2.58 (m, 2H), 2.41 (m, 4H), 2.10 (t, J=8.2,2H), 1.72 (t, J=7.0Hz, 6H)；13C NMR(500MHz, CDCl3)δ:169.9,153.5,148.2,146.8,145.9,136.2,131.3,129.9,128.4,126.5,125.2, 124.0,119.1,98.5,94.0,72.4,56.9,56.4,56.0,52.1,48.1,25.7,20.2,14.9；HRMS(ESI) m/z:563.44[M+H]+,Microanalysis calculated for C26H32BrN3O6(562.45), C:55.52%, H: 5.73%, N:7.47%.Found C:55.59%, H:5.92%, N:7.62%.
Activity to the anti-malignant cell proliferation of following human cancer cell: prostate gland cancer cell (PC-3), colon cancer cell (HT-29), breast cancer cell (MCF-7), lung carcinoma cell (H-460), epithelial cancer cells (A-549), pancreatic cancer cell (PaCa- 2) and pancreas cancer cell strain (Panc-1) has carried out the fluoremetry of iodide (PI).The data obtained is shown in Table 1.
Table 1
At large, the compound of test goes out similar anti-malignant cell proliferation activity to different carcinoma cells show, and they are right Various cancer cell suppression activity average variances are less than 8%.Three most active compounds (4c, 4f, 4o) in cyclohexanone derivative Demonstrate the ability of potential anticancer growth.Compound 4f, 4o demonstrate the anticancer work maximum to cancerous cell line used Property, IC50Between 1.1 ± 0.2 and 1.9 ± 0.8 μMs.It addition, compound 4c also shows that strong the pressing down to colon carcinoma cell line System activity, IC50Reach 2.0 ± 1.5 μMs.These compounds have similar inhibition to seven kinds of cancerous cell lines.
The derivant of these 7 kinds of 1,2,3,4-Tetrahydrooxonaphthalene of 5f, 5i, 5o, 5u, 5x, 5af, 5ag also shows that potential anticancer system The effect of growth.5ag demonstrates the anticancer potential optimal to pancreas cancer cell strain, IC50It it is 1.2 ± 0.9 μMs.It is only second to 5ag, 5o Active anticancer IC50It it is 1.4 ± 0.5 μMs.Derivant 5i, 5af, 5f, 5u, 5x also show that noticeable anticancer effect.It After, we are by 34 (c, f, o) derivant of most active Ketohexamethylene and 75 (f, i, o, u, x, af, ag) most activity The derivant of 1,2,3,4-Tetrahydrooxonaphthalene synthesized 10 new oxime analog.10 newly synthesized oxime analog pass through 7 kinds of JEG-3 Carrying out the test of anti-malignant cell proliferation, all of compound demonstrates the IC of the active anticancer to 7 kinds of cancerous cell lines50It is 0.02 Between ± 0.08 μM and 2.9 ± 0.2 μMs.
The most oxime analog of activity is selected as the analog of synthesizing oxime ether, and the analog synthesized has been also carried out anticancer The test of activity.But, the oxime ether analog active anticancer obtained is poor.
10 compounds selecting the most anticancer potential optimal carry out the test of the action effect to tubulin polymerization enzyme, real Test result as shown in Figure 1.Most compounds shows the action effect to tubulin polymerization enzyme, and compound 7f, 8f show Go out the performance that the strongest suppression tubulin polymerization enzyme assembles, according to iodide fluorometric result, only two compounds (7o, 10o) does not demonstrate the performance that suppression tubulin polymerization enzyme assembles, and cytotoxicity and suppression tubulin polymerization are described Enzyme is different process.Compared with chemotherapeutics Docetaxel, the compound of our synthesis does not demonstrate stablizes micro-pipe egg The behavior of white polymerase.
These ten kinds of compounds are carried out EGF-R ELISA inhibitory activity, BRAFV600EInhibitory activity, multidrug resistance are inverse Turn the dependence test of activity.The data obtained is shown in Table 2.
Table 2
As known from Table 2, these ten kinds of compounds have the inhibitory activity of the strongest EGF-R ELISA, and half suppression is dense Degree is between 0.07 ± 0.03 and 8.4 ± 0.2 μM.According to test result, it has been found that compound 7o and 10o is maximally effective, The IC of EGF-R ELISA50Between 0.07 ± 0.03 μM and 0.1 ± 0.05 μM, their EGF-R ELISA presses down Activity processed is similar to positive control Erlotinib (IC50=0.05 ± 0.02 μM).This experiment shows α, β unsaturated carbonyl chemical combination Thing, oxime analog and oxime ether analog are potent epidermal growth factor receptor inhibitors, and are likely used as antitumor drug.
Analyzed in vitro determines these 10 kinds synthesis compounds the most with anticancer activity to BRAFV600EInhibitory activity.According to Test result, the compound of used test demonstrates that half-inhibition concentration is between 0.9 ± 0.4 and 6.3 ± 0.4 μM.Based on α, β The oxime analog of beta-unsaturated carbonyl compounds synthesis demonstrates the strongest BRAFV600EInhibitory activity.It is interesting that 8af, 8ag Demonstrate almost identical BRAFV600EInhibitory activity, simultaneously find there is the value-added potential of anticancer.These find table Bright, this compounds is potential antitumor and anticancer agent and can effectively suppress BRAF enzyme.
By rhodamine accumulation test, cancerous cell multidrug resistance is accumulated by the compound (in non-toxic concentration) of research synthesis Impact.Toxic action by trypan blue these compounds of experimentation.1,2,3,4-Tetrahydrooxonaphthalene structure 8 (f, i, o, u, x, af, Ag) oxime analog activity is optimal, and 7f, 7o, 10o are almost invalid.There is no the mice that people's mdr1 gene is transfected by compound Lymphoma cell is invalid.The combination that traditional chemotherapeutic agents and reversion are modified can be used for treating multidrug resistance cancerous cell.Therefore, both have Can be as potential anti-cancer medicine, again can be as the compound of the double grading of multi-medicine tolerant reversal reagent in following treatment of cancer In have a extensive future.
A series of alpha, beta-unsaturated carbonyl compounds, oxime, oxime ether and the derivant thereof of present invention synthesis use human carcinoma cell line Its antiproliferative activity of evaluating in vitro, and determine that these compounds can be as BRAFV600E, EGF-R ELISA and micropore The inhibitor of albumen polymerase.In these compounds, major part also shows the activity of reverse multidrug drug resistance.In all experiments Compound 8af and 8ag is found to be the most activated.Therefore, α proposed by the invention, beta-unsaturated carbonyl compound, Oxime, oxime ether and derivant thereof have the anticancer and dual function effect of reverse multidrug drug resistance, have broad application prospects.

Claims (5)

1. α, β-unsaturated compound, it is characterised in that there is following structural formula:
In structure above, R1Represent following group:
Methylene, secondary amino group, oxygen atom, HC-CH3、N-CH3、
R2Represent following group:
Oxygen atom, N-OH or
R’3It is hydrogen atom or methoxyl group；R’4It is hydrogen atom or methoxyl group；R’6Represent chlorine atom or bromine atoms.
2. α, β-unsaturated compound, it is characterised in that there is following structural formula:
In structure above, R1Represent methylene or HC-CH3；
R2、R4、R5、R’3、R’4It is hydrogen atom or methoxyl group respectively；R3Represent hydrogen atom, chlorine atom, methoxyl group, fluorine atom, bromine former Son, nitro；R’6Represent chlorine atom or bromine atoms；
R6Represent following group:
Oxygen atom, N-OH or
3. α, β-unsaturated compound, it is characterised in that for
2,6-bis-(2-chloro-3-benzylidene) Ketohexamethylene,
2,6-bis-(2-chloro-3,4-dimethoxybenzylidenegroup group) Ketohexamethylene,
2,6-bis-(2-bromo-3,4,5-trimethoxy benzal) Ketohexamethylene,
2,6-bis-(2-chloro-3-benzylidene)-4-methyl cyclohexanone,
2,6-bis-(2-chloro-3,4-dimethoxybenzylidenegroup group)-4-methyl cyclohexanone,
2,6-bis-(2-bromo-3,4,5-trimethoxy benzal)-4-methyl cyclohexanone,
2,6-bis-(2-chloro-3-benzylidene)-4-isopropyl Ketohexamethylene,
2,6-bis-(2-chloro-3,4-dimethoxybenzylidenegroup group)-4-isopropyl Ketohexamethylene,
2,6-bis-(2-bromo-3,4,5-trimethoxy benzal)-4-isopropyl Ketohexamethylene,
3,5-bis-(2-chloro-3-benzylidene) piperidin-4-one,
3,5-bis-(2-chloro-3,4-dimethoxybenzylidenegroup group) piperidin-4-one,
3,5-bis-(2-bromo-3,4,5-trimethoxy benzal) piperidin-4-one,
3,5-bis-(2-chloro-3-benzylidene)-1-methyl piperidine-4-ketone,
3,5-bis-(2-chloro-3,4-dimethoxybenzylidenegroup group)-1-methyl piperidine-4-ketone,
3,5-bis-(2-bromo-3,4,5-trimethoxy benzal)-1-methyl piperidine-4-ketone,
1-benzyl-3,5-two (2-chloro-3-benzylidene) piperidin-4-one,
1-benzyl-3,5-two (2-chloro-3,4-dimethoxybenzylidenegroup group) piperidin-4-one,
1-benzyl-3,5-two (2-bromo-3,4,5-trimethoxy benzal) piperidin-4-one,
3,5-bis-(2-chloro-3-benzylidene) Tetrahydro-pyran-4-one,
3,5-bis-(2-chloro-3,4-dimethoxybenzylidenegroup group) Tetrahydro-pyran-4-one,
3,5-bis-(2-bromo-3,4,5-trimethoxy benzal) Tetrahydro-pyran-4-one,
2-(2-chloro-3-Methoxy-benzylidene)-1,2,3,4-Tetrahydrooxonaphthalene,
2-(2-chloro-3,4-Dimethoxy-benzylidene)-1,2,3,4-Tetrahydrooxonaphthalene,
2-(2-bromo-3,4-Dimethoxy-benzylidene)-1,2,3,4-Tetrahydrooxonaphthalene,
2-(2-chloro-3-Methoxy-benzylidene)-4-methyl-tetrahydro naphthalenone,
2-(2-chloro-3,4-Dimethoxy-benzylidene)-4-methyl-tetrahydro naphthalenone,
2-(2-bromo-3,4,5-Trimethoxy-benzylidene)-4-methyl-tetrahydro naphthalenone,
2-(2-chloro-3-Methoxy-benzylidene)-6-dihydroxy-tetrahydro naphthalenone,
2-(2-chloro-3,4-Dimethoxy-benzylidene)-6-dihydroxy-tetrahydro naphthalenone,
2-(2-bromo-3,4,5-Trimethoxy-benzylidene)-6-dihydroxy-tetrahydro naphthalenone,
2-(2-chloro-3-Methoxy-benzylidene) the chloro-1,2,3,4-Tetrahydrooxonaphthalene of-8-,
2-(2-chloro-3,4-Dimethoxy-benzylidene) the chloro-1,2,3,4-Tetrahydrooxonaphthalene of-8-,
2-(2-bromo-3,4,5-Trimethoxy-benzylidene) the chloro-1,2,3,4-Tetrahydrooxonaphthalene of-8-,
2-(2-chloro-3-Methoxy-benzylidene)-7-methoxy-tetrahydro naphthalenone,
2-(2-chloro-3,4-Dimethoxy-benzylidene)-7-methoxy-tetrahydro naphthalenone,
2-(2-bromo-3,4,5-Trimethoxy-benzylidene)-7-methoxy-tetrahydro naphthalenone,
2-(2-chloro-3-Methoxy-benzylidene)-6-methoxy-tetrahydro naphthalenone,
2-(2-chloro-3,4-Dimethoxy-benzylidene)-6-methoxy-tetrahydro naphthalenone,
2-(2-bromo-3,4,5-Trimethoxy-benzylidene)-6-methoxy-tetrahydro naphthalenone,
2-(2-chloro-3-Methoxy-benzylidene)-7,8-dimethoxy-tetrahydro naphthalenone,
2-(2-chloro-3,4-Dimethoxy-benzylidene)-7,8-dimethoxy-tetrahydro naphthalenone,
2-(2-bromo-3,4,5-Trimethoxy-benzylidene)-7,8-dimethoxy-tetrahydro naphthalenone,
2-(2-chloro-3-Methoxy-benzylidene)-6,9-dimethoxy-tetrahydro naphthalenone,
2-(2-chloro-3,4-Dimethoxy-benzylidene)-6,9-dimethoxy-tetrahydro naphthalenone,
2-(2-bromo-3,4,5-Trimethoxy-benzylidene)-6,9-dimethoxy-tetrahydro naphthalenone,
2-(2-chloro-3-Methoxy-benzylidene) the bromo-1,2,3,4-Tetrahydrooxonaphthalene of-8-,
2-(2-chloro-3,4-Dimethoxy-benzylidene) the bromo-1,2,3,4-Tetrahydrooxonaphthalene of-8-,
2-(2-bromo-3,4,5-Trimethoxy-benzylidene) the bromo-1,2,3,4-Tetrahydrooxonaphthalene of-8-,
2-(2-chloro-3-Methoxy-benzylidene) the fluoro-1,2,3,4-Tetrahydrooxonaphthalene of-8-,
2-(2-chloro-3,4-Dimethoxy-benzylidene) the fluoro-1,2,3,4-Tetrahydrooxonaphthalene of-8-,
2-(2-bromo-3,4,5-Trimethoxy-benzylidene) the fluoro-1,2,3,4-Tetrahydrooxonaphthalene of-8-,
2-(2-chloro-3-Methoxy-benzylidene)-8-nitro-1,2,3,4-Tetrahydrooxonaphthalene,
2-(2-chloro-3,4-Dimethoxy-benzylidene)-8-nitro-1,2,3,4-Tetrahydrooxonaphthalene,
2-(2-bromo-3,4,5-Trimethoxy-benzylidene)-8-nitro-1,2,3,4-Tetrahydrooxonaphthalene,
2,6-pair-(2-bromo-3,4,5-Trimethoxy-benzylidene)-Ketohexamethylene-oxime,
2,6-pair-(2-bromo-3,4,5-Trimethoxy-benzylidene)-4-methyl-cyclohexyl ketone-oxime,
3,5-pair-(2-bromo-3,4,5-Trimethoxy-benzylidene)-1-methyl-pi-4-ketone-oxime,
2-(2-bromo-3,4,5-Trimethoxy-benzylidene)-4-methyl-tetrahydro naphthalenone-oxime,
2-(2-bromo-3,4,5-Trimethoxy-benzylidene)-6-dihydroxy-tetrahydro naphthalenone-oxime,
2-(2-bromo-3,4,5-Trimethoxy-benzylidene)-7-methoxy-tetrahydro naphthalenone-oxime,
2-(2-bromo-3,4,5-Trimethoxy-benzylidene)-7,8-dimethoxy-tetrahydro naphthalenone-oxime,
2-(2-bromo-3,4,5-Trimethoxy-benzylidene)-6,9-dimethoxy-tetrahydro naphthalenone-oxime,
2-(2-chloro-3,4-Dimethoxy-benzylidene)-8-nitro-1,2,3,4-Tetrahydrooxonaphthalene-oxime,
2-(2-bromo-3,4,5-Trimethoxy-benzylidene)-8-nitro-1,2,3,4-Tetrahydrooxonaphthalene-oxime,
3,5-pair-(2-bromo-3,4,5-Trimethoxy-benzylidene)-1-methyl-cyclohexyl ketone-oxygen-(2-Diethylamino-ethyl)- Oxime,
3,5-pair-(2-bromo-3,4,5-Trimethoxy-benzylidene)-1-methyl-pi-4-ketone-oxygen-(2-diethylamino-second Base)-oxime,
2-(2-bromo-3,4,5-Trimethoxy-benzylidene)-6,9-dimethoxy-tetrahydro naphthalenone-oxygen-(2-diethylamino-second Base)-oxime,
2-(2-chloro-3,4-Dimethoxy-benzylidene)-8-nitro-1,2,3,4-Tetrahydrooxonaphthalene-oxygen-(2-Diethylamino-ethyl)-oxime or 2-(2-bromo-3,4,5-Trimethoxy-benzylidene)-8-nitro-1,2,3,4-Tetrahydrooxonaphthalene-oxygen-(2-Diethylamino-ethyl)-oxime.
4. α described in claim 1 or 2 or 3, β-unsaturated compound is as prevention, the application for the treatment of tumor disease medicine.
5. α described in claim 1 or 2 or 3, β-unsaturated compound is as preventing, treat answering of resistant tumors disease medicament With.
CN201610390429.5A 2016-06-03 2016-06-03 Alpha,beta-unsaturated compounds and application thereof Pending CN106008324A (en)

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GAO-FENG ZHA，等: "Biological evaluation of synthetic α,β-unsaturated carbonyl based cyclohexanone derivatives as neuroprotective novel inhibitors of acetylcholinesterase, butyrylcholinesterase and amyloid-β aggregation", 《BIOORGANIC & MEDICINAL CHEMISTRY》 *
HUA-LI QIN，等: "Synthesis of α,β-Unsaturated Carbonyl-Based Compounds, Oxime and Oxime Ether Analogs as Potential Anticancer Agents for Overcoming Cancer Multidrug Resistance by Modulation of Efflux Pumps in Tumor Cells", 《J. MED. CHEM.》 *

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Publication number Priority date Publication date Assignee Title
JP2020533328A (en) * 2017-09-07 2020-11-19 タイワンジェ ファーマシューティカルズ カンパニー リミテッドＴａｉｗａｎｊ Ｐｈａｒｍａｃｅｕｔｉｃａｌｓ Ｃｏ．， Ｌｔｄ． Benzene condensed heterocyclic derivative and its pharmaceutical composition
JP7296948B2 (en) 2017-09-07 2023-06-23 ニューソアラ バイオファーマ カンパニー リミテッド Benzene-fused heterocyclic derivative and pharmaceutical composition thereof
CN114853630A (en) * 2022-06-07 2022-08-05 温州医科大学 2, 6-diphenylmethylene cyclohexanone oxime compound and preparation method and application thereof
WO2023236809A1 (en) * 2022-06-07 2023-12-14 温州医科大学 2,6-dibenzylidene cyclohexanone oxime compound, method for preparing same, and use thereof

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