CN106045881B - Resveratrol derivative, its preparation method and the application as LSD1 inhibitor - Google Patents

Resveratrol derivative, its preparation method and the application as LSD1 inhibitor Download PDF

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CN106045881B
CN106045881B CN201610357637.5A CN201610357637A CN106045881B CN 106045881 B CN106045881 B CN 106045881B CN 201610357637 A CN201610357637 A CN 201610357637A CN 106045881 B CN106045881 B CN 106045881B
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CN106045881A (en
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段迎超
关圆圆
翟晓雨
郑超
郑一超
刘巍
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Henan Tengyu Biotechnology Co ltd
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Xinxiang Medical University
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C257/00—Compounds containing carboxyl groups, the doubly-bound oxygen atom of a carboxyl group being replaced by a doubly-bound nitrogen atom, this nitrogen atom not being further bound to an oxygen atom, e.g. imino-ethers, amidines
    • C07C257/10—Compounds containing carboxyl groups, the doubly-bound oxygen atom of a carboxyl group being replaced by a doubly-bound nitrogen atom, this nitrogen atom not being further bound to an oxygen atom, e.g. imino-ethers, amidines with replacement of the other oxygen atom of the carboxyl group by nitrogen atoms, e.g. amidines
    • C07C257/18—Compounds containing carboxyl groups, the doubly-bound oxygen atom of a carboxyl group being replaced by a doubly-bound nitrogen atom, this nitrogen atom not being further bound to an oxygen atom, e.g. imino-ethers, amidines with replacement of the other oxygen atom of the carboxyl group by nitrogen atoms, e.g. amidines having carbon atoms of amidino groups bound to carbon atoms of six-membered aromatic rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/24—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with substituted hydrocarbon radicals attached to ring carbon atoms
    • C07D213/54—Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C07D213/58—Amidines

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Abstract

The present invention discloses resveratrol analog derivative, synthetic method and its application as the specific inhibitor of demethylase 1 of istone lysine, belongs to medicinal chemistry art.Compound of the present invention has below formula：In general formula III, the preferred hydrogen of R, hydroxyl, methoxyl group, nitro or halogen, X represent N atoms, C atoms.Such compound has good inhibiting effect to the specific demethylase 1 of istone lysine, can be used to develop the disease therapeuticing medicines such as antitumor, anti-AIDS as the candidate or lead compound further developed.

Description

Resveratrol derivative, its preparation method and the application as LSD1 inhibitor
Technical field
Present invention relates particularly to resveratrol analog derivative, preparation method and its be used as istone lysine specificity The application of the inhibitor of demethylase 1, belongs to field of pharmaceutical chemistry technology.
Background technology
Istone lysine specificity demethylase 1 (Histone Lysine Specific Demethylase 1, LSD1) be first istone lysine being found demethylase (Y.Shi et al, Cell, 2004,29,941- 953).LSD1 is the demethylase of a flavine-adenine-dinucleotide-dependent, by being combined from different molecular chaperoneses Different substrates are acted on, so as to produce different biological functions.LSD1 is combined by CoREST with target gene, can be special The removal H3K4 (Histone 3, Lysine 4) of property single or double methylating, causes genetic transcription to suppress.When LSD1 and hero swash When plain acceptor or ERs are combined, the single or double methyl of the specific removal H3K9 (Histone 3, Lysine 9) of energy Change, the gene transcriptional activation for causing hormone receptor to rely on.LSD1 is by adjusting the interaction of histone and other albumen, influence The activation and suppression of genetic transcription, the important life process such as x chromosome inactivation (Lee MG et al, Nature, 2005,437, 432–435)。
Current research finds that the generation development of the diseases such as LSD1 and tumour, viral infection, metabolic disease, inflammation is equal There is close relationship.LSD1 is overexpression in the Several Kinds of Malignancy such as stomach cancer, prostate cancer, breast cancer and abnormal sharp It is living, cause the abnormal silence of tumor suppressor gene, the growth of tumour can be suppressed, attack and shift by suppressing its activity or downward expression quantity, be The focus target of current antineoplastic research and development.The tranylcypromine class LSD1 inhibitor of Oryzon companies of Spain report, at present Carry out II clinical trial phases, for treat leukaemia (Zheng YC et al, Med Res Rev, 2015,35,1032- 1071)；LSD1/CoREST compounds can activate the transcription of inhibition of HIV by demethylation Tat albumen K51 sites, with small point Sub- inhibitor, which suppresses LSD1 activity, can suppress to infect activation (Sakane N the et al, PLoS of inhibition of HIV in T cell Pathog, 2011,7, e1002184).In the people's cell of varicellazoster virus and herpes simplex infections, reduction LSD1 expression quantity suppresses its activity, can reduce viral mRNA and virus protein expression quantity (Liang Y et al, Nat Med, 2009,15,1312-1317)；LSD1 is suppressed by mutually being acted synergistically with histon deacetylase (HDAC) HDACs IL1 α, IL1 β, the proinflammatory cytokine such as IL6 expression (Janzer A et al, Biochem Biophys Res Commun, 2012,18,665-670).
The LSD1 types reported at present are still deficient in general, and largely remain in laboratory research and face Bed conceptual phase, therefore, obtains new, high activity LSD1 inhibitor, for studying LSD1 biological function, developing new The disease therapeuticing medicine such as antitumor, antiviral, be of great significance.
Resveratrol (Resveratrol) is derived from the natural polyphenol class compound in the plants such as grape, mulberry fruit, due to It has the multiple biological activities such as antitumor, anti-oxidant, causes the extensive concern of people.Research finds resveratrol to LSD1 With certain inhibitory activity.In the active appraisal experiment of enzyme level, resveratrol can suppress LSD1 to methylate p53 with And the demethylation of H3K4me2 substrates, IC50For 15 μ Μ, activity is better than positive control tranylcypromine.
In order to find new LSD1 micromolecular inhibitors, by the further structure optimization to resveratrol, a class is obtained Verakanol derivative, such compound has significant LSD1 inhibitory activity, has not yet to see the synthesis of such compound And the report of LSD1 inhibitory activity.
The content of the invention
It is an object of the present invention to provide resveratrol derivative, possibility is provided for novel drugs screening.
It is another object of the present invention to provide the preparation method of such Verakanol derivative and its it is used as histone The application of lysine specificity demethylase 1 (LSD1) inhibitor.
To achieve the above object, the resveratrol derivant structure formula that provides of the present invention is：
In general formula III, other any positions of R removing link positions on A rings are monosubstituted on A rings or take more Generation, substituent refers to：Hydrogen, hydroxyl, methoxyl group, nitro or halogen, wherein, halogen includes F, Cl, Br, I.
In general formula III, substituentIt is monosubstituted on B rings.
In general formula III, X represents N atoms or C atoms.
Preferably, the atom that the substituent and the position of substitution, X of R representatives are represented is as follows：
(1) R group is that 3,4-diOH, B rings are 3 substitutions, X=C；
(2) R group is that 3,4-diOH, B rings are 4 substitutions, X=C；
(3) R group is 4-OH, and B rings are 3 substitutions, X=C；
(4) R group is 4-OH, and B rings are 4 substitutions, X=C；
(5) R group is that 3,4-diF, B rings are 4 substitutions, X=C；
(6) R group is 2-F-4, and 5-diOH, B rings are 3 substitutions, X=C；
(7) R group is 2-F-4, and 5-diOH, B rings are 4 substitutions, X=C；
(8) R group is 2-Br-4, and 5-diOH, B rings are 3 substitutions, X=C；
(9) R group is 2-Br-4, and 5-diOH, B rings are 4 substitutions, X=C；
(10) R group is that 3,5-diOH, B rings are 3 substitutions, X=C；
(11) R group is 3-F-4-OH, and B rings are 3 substitutions, X=C；
(12) R group is 3-F-4-OH, and B rings are 4 substitutions, X=C；
(13) R group is H, and B rings are 3 substitutions, X=N；
To realize above-mentioned second purpose, the synthetic reaction flow of the compounds of this invention is as shown below：
Concretely comprise the following steps：
Benzaldehyde or substituted benzaldehyde and cyano group substituted benzyl diethyl phosphonate, in dry DMF, strongly alkaline compound is deposited Under, reaction is stirred at room temperature, compound I is generated, wherein, the strongly alkaline compound is selected from potassium tert-butoxide, sodium methoxide, hydrogenation Sodium, sodium tert-butoxide；As not having methoxy substitution in compound I, then compound I is in methanol solution, in the presence of triethylamine, with salt Sour oxyammonia back flow reaction obtains the compound III that R is not hydroxyl.
Compound I containing methoxy substitution is dissolved in dichloromethane, under -20~-80 DEG C of cryogenic conditions, tribromide is added Boron, demethylation obtains the compound II that R is hydroxyl.Compound II is in methanol solution, in the presence of triethylamine, is flowed back with oxammonium hydrochloride React to obtain the compound III containing hydroxyl in structure.
Advantage of the present invention：The compound that the present invention is synthesized is respectively provided with very strong LSD1 inhibitory activity, majority of compounds LSD1 suppresses IC50Respectively less than 1 μM, activity is better than positive control medicine tranylcypromine.The compound of the present invention represents a class The brand-new LSD1 inhibitor of structure, is that the research and development of LSD1 inhibitor class medicines provide the foundation, the biological function for being LSD1 is ground Study carefully there is provided effective tool.It can be used to develop antitumor, anti-AIDS as the candidate or lead compound further developed Deng disease therapeuticing medicine, and synthetic method is simple, and high income, total recovery is conducive to popularization and application up to more than 62%.
Brief description of the drawings
Fig. 1 evaluates * * in block diagram, figure for the compounds of this invention cellular level LSD1 inhibitory activity and represents p<0.05, tool It is statistically significant.
Embodiment
Embodiment is named to elaborate to technical solution of the present invention.
The preparation of embodiment 1 (E) -4- (3,4 dimethoxy styrene base) benzene first cyanogen (I-1)
By compound Veratraldehyde (1.66g, 10mmol) and 4- cyanobenzyls diethyl phosphonate (2.79g, 11mmol) it is dissolved in dry DMF (10mL), is slowly added into potassium tert-butoxide (2.24g, 20mmol) under ice bath stirring, finishes room temperature Reaction 3 hours, (40mL) is slowly added in frozen water by reaction system, there is white solid wash-off, and solid is collected in suction filtration, washing, With acetone recrystallization, suction filtration, vacuum drying obtains white solid 2.21g, yield 83.4%.Mp:102-103℃.1H NMR (400MHz,CDCl3) δ 7.64 (d, 2H, J=8.0Hz), 7.58 (d, 2H, J=8.0Hz), 7.19 (d, 1H, J=16.4Hz), (s, the 3H) of 7.10 (m, 2H), 6.98 (d, 1H, J=16.4Hz), 6.90 (d, 1H, J=8.0Hz), 3.97 (s, 3H), 3.9313C NMR(101MHz,CDCl3)δ149.76,149.22,142.11,132.48,132.22,129.36,126.59,124.74, 120.76,119.17,111.19,110.10,108.88,55.98,55.93.HRMS(ESI)calcd for C17H16NO2[M+ H]+:266.1176,Found:266.1179.
The preparation of embodiment 2 (E) -4- (the fluoro- 4,5- dimethoxy-styryls of 2-) benzene first cyanogen (I-2)
As described in Example 1,3,4- methoxyl groups are replaced with fluoro- 4, the 5- dimethoxy benzaldehydes (1.84g, 10mmol) of 2- Benzaldehyde, obtains white solid 2.12g, yield 74.9%.Mp:130-131℃.1H NMR(400MHz,CDCl3)δ7.66(d,2H,J =8.0Hz), 7.61 (d, 2H, J=8.0Hz), 7.36 (d, 1H, J=16.0Hz), 7.06 (d, 1H, J=8.0Hz), 7.04 (d, 1H, J=16.0Hz), 6.69 (d, 1H, J=12.0Hz), 3.95 (s, 3H), 3.92 (s, 3H)13C NMR(101MHz,CDCl3) δ156.68,154.24,150.50,150.40,145.64,145.62,142.00,132.51,126.37,126.32, 124.47,124.44,119.09,115.29,115.16,110.44,108.35,108.30,100.30,100.02,56.46, 56.24.HRMS(ESI)calcd for C17H15FNO2[M+H]+:284.1081,Found:284.1081.
The preparation of embodiment 3 (E) -4- (the bromo- 4,5- dimethoxy-styryls of 2-) benzene first cyanogen (I-3)
As described in Example 1,3,4- dimethoxies are replaced with 2- bromo-4,5-dimethoxies benzaldehyde (1.23g, 5mmol) Benzaldehyde, obtains white solid 1.31g, yield 76.3%.Mp:149-151℃.1H NMR(400MHz,CDCl3)δ7.67(d, 2H, J=8.0Hz), 7.63 (d, 2H, J=8.0Hz), 7.55 (d, 1H, J=16.0Hz), 7.16 (s, 1H), 7.08 (s, 1H), (s, the 3H) of 6.95 (d, 1H, J=16.0Hz), 3.97 (s, 3H), 3.9213C NMR(101MHz,CDCl3)δ150.10, 148.74,141.70,132.55,130.93,128.19,127.31,126.97,119.04,115.74,115.54,110.69, 108.68,56.25,56.16.HRMS(ESI)calcd for C17H14BrNNaO2[M+Na]+:366.0106,Found: 366.0101.
The preparation of embodiment 4 (E) -4- (the fluoro- 4- methoxyl-styrenes of 3-) benzene first cyanogen (I-4)
As described in Example 1,3,4- dimethoxy benzenes are replaced with the fluoro- 4-methoxybenzaldehydes of 3- (1.54g, 10mmol) Formaldehyde, obtains white solid 2.02g, yield 80.1%.Mp:103-104℃.1H NMR(400MHz,DMSO)δ7.82(d,2H,J =8.0Hz), 7.74 (d, 2H, J=8.0Hz), 7.59 (d, 1H, J=16.4Hz), 7.41 (d, 1H, J=8.0Hz), 7.37 (s, 1H), 7.27 (d, 1H, J=16.4Hz), 7.21 (t, 1H, J=8.8Hz)13C NMR(101MHz,DMSO)δ153.34, 150.91,147.89,147.79,142.36,133.06,131.38,130.26,130.20,127.37,126.37,124.80, 124.77,119.53,114.27,113.93,113.75,109.72,56.48.HRMS(ESI)calcd for C16H11FNO [M-H]-:252.0830,Found:252.0830.
The preparation of embodiment 5 (E) -4- (4- methoxyl-styrenes) benzene first cyanogen (I-5)
As described in Example 1, Veratraldehyde is replaced with 4-methoxybenzaldehyde (1.36g, 10mmol), Obtain white solid 1.70g, yield 72.7%.Mp:113-114℃.1H NMR(400MHz,CDCl3) δ 7.64 (d, 2H, J= 8.0Hz), 7.58 (d, 2H, J=8.0Hz), 7.51 (d, 2H, J=8.8Hz), 7.21 (d, 1H, J=16.4Hz), 6.93-6.99 (m,3H),3.87(s,3H).13C NMR(101MHz,CDCl3)160.09,142.24,132.48,131.97,129.07, 128.30,126.58,124.55,119.21,114.32,110.04,55.39.HRMS(ESI)calcd for C16H13NNaO [M+Na]+:258.0889,Found:258.0893.
The preparation of embodiment 6 (E) -3- (3,4 dimethoxy styrene base) benzene first cyanogen (I-6)
As described in Example 1,4- cyanobenzyls diethyl phosphonates are replaced with 3- cyanobenzyls diethyl phosphonate, obtains white Solid 2.34g, yield 88.3%.Mp:147-148℃.HRMS(ESI)calcd for C17H16NO2[M+H]+:266.1176, Found:266.1177.
The preparation of embodiment 7 (E) -3- (3,5- dimethoxy-styryls) benzene first cyanogen (I-7)
By compound 3,5- dimethoxy benzaldehydes (1.66g, 10mmol) and 3- cyanobenzyls diethyl phosphonate (2.79g, 11mmol) it is dissolved in dry DMF (10mL), is slowly added into potassium tert-butoxide (2.24g, 20mmol) under ice bath stirring, finishes room temperature Reaction 3 hours, (40mL) is slowly added in frozen water by reaction system, there is white solid wash-off, and solid is collected in suction filtration, washing, With acetone recrystallization, suction filtration, vacuum drying obtains white solid 2.10g, yield 79.2%.Mp:114-115℃.1H NMR (400MHz,CDCl3) δ 7.78 (s, 1H), 7.73 (d, 1H, J=8.0Hz), 7.56 (d, 1H, J=8.0Hz), 7.49 (t, 1H, J =8.0Hz), 7.12 (d, 1H, J=16.0Hz), 7.06 (d, 1H, J=16.0Hz), 6.69 (d, 2H, J=2.4Hz), 6.46 (t, 1H, J=2.4Hz), 3.86 (s, 6H)13C NMR(101MHz,CDCl3)δ161.07,138.41,138.34,131.29, 130.81,130.60,129.93,129.50,126.69,118.81,112.93,104.87,100.64,55.43.HRMS (ESI)calcd for C17H16NO2[M+H]+:266.1176,Found:266.1179.
The preparation of embodiment 8 (E) -3- (the fluoro- 4,5- dimethoxy-styryls of 2-) benzene first cyanogen (I-8)
As described in Example 7,3,5- methoxyl groups are replaced with fluoro- 4, the 5- dimethoxy benzaldehydes (1.84g, 10mmol) of 2- Benzaldehyde, obtains white solid 2.14g, yield 75.5%.Mp:130-132℃.1H NMR(400MHz,CDCl3)δ7.78(s, 1H), 7.75 (d, 1H, J=8.0Hz), 7.55 (d, 1H, J=8.0Hz), 7.49 (t, 1H, J=8.0Hz), 7.30 (d, 1H, J= 16.0Hz), 7.05 (d, 1H, J=8.0Hz), 7.01 (d, 1H, J=16.0Hz), 6.96 (d, 1H, J=12.0Hz), 3.95 (s, 3H),3.91(s,3H).13C NMR(101MHz,CDCl3)δ156.53,154.10,150.27,150.17,145.61, 145.58,138.76,130.63,130.31,129.83,129.49,125.92,125.87,123.43,123.40,118.82, 115.32,115.19,112.93,108.36,108.31,100.31,100.02,56.45,56.23.HRMS(ESI)calcd for C17H15FNO2[M+H]+:284.1081,Found:284.1081.
The preparation of embodiment 9 (E) -3- (the bromo- 4,5- dimethoxy-styryls of 2-) benzene first cyanogen (I-9)
As described in Example 7,3,5- dimethoxies are replaced with 2- bromo-4,5-dimethoxies benzaldehyde (1.23g, 5mmol) Benzaldehyde, obtains white solid 2.38g, yield 69.1%.Mp:138-140℃.1H NMR(400MHz,CDCl3)δ7.80(s, 1H), 7.78 (d, 1H, J=8.0Hz), 7.57 (d, 1H, J=8.0Hz), 7.50 (t, 1H, J=8.0Hz), 7.48 (d, 1H, J= 16.4Hz), (s, the 3H) of 7.14 (s, 1H), 7.07 (s, 1H), 6.91 (d, 1H, J=16.4Hz), 3.97 (s, 3H), 3.9213C NMR(101MHz,CDCl3)δ149.94,148.72,138.47,130.84,130.52,130.07,129.88,129.55, 128.26,126.84,118.80,115.52,115.49,112.98,108.64,56.24,56.15.HRMS(ESI)calcd for C17H14BrNNaO2[M+Na]+:366.0106,found:366.0109.
The preparation of embodiment 10 (E) -3- (the fluoro- 4- methoxyl-styrenes of 3-) benzene first cyanogen (I-10)
As described in Example 7,3,5- dimethoxy benzenes are replaced with the fluoro- 4-methoxybenzaldehydes of 3- (1.54g, 10mmol) Formaldehyde, obtain white solid 2.03g, yield 80.3%.Mp:90-92℃.1H NMR(400MHz,DMSO)δ8.04(s,1H), 7.88 (d, 1H, J=2.0Hz), 7.71 (d, 1H, J=2.0Hz), 7.59 (t, 1H, J=8.0Hz), 7.55 (d, 1H, J= 16.4Hz),7.35-7.39(m,2H),7.17-7.22(m,2H),3.87(s,3H).13C NMR(101MHz,DMSO)δ 153.36,150.94,147.70,147.59,138.96,131.39,131.08,130.39,130.17,130.15,129.95, 125.88,124.48,124.45,119.26,114.39,114.37,113.77,113.59,112.35,56.51.HRMS (ESI)calcd for C16H11FNO[M-H]-:252.0830,Found:252.0830.
The preparation of embodiment 11 (E) -3- (4- methoxyl-styrenes) benzene first cyanogen (I-11)
As described in Example 7,3,5- dimethoxy benzaldehydes are replaced with 4-methoxybenzaldehyde (1.36g, 10mmol), Obtain white solid 2.10g, yield 89.2%.Mp:137-139℃.1H NMR(400MHz,CDCl3)δ7.76(s,1H),7.72 (d, 1H, J=8.0Hz), 7.44-7.53 (m, 4H), 7.15 (d, 1H, J=16.0Hz), 6.92-6.96 (m, 3H), 3.86 (s, 3H).13C NMR(101MHz,CDCl3)δ159.92,138.95,130.84,130.29,129.60,129.44,129.14, 128.12,124.03,118.93,114.29,112.85,55.38.HRMS(ESI)calcd for C16H13NNaO[M+Na]+: 258.0889,Found:258.0891.
The preparation of embodiment 12 (E) -3- (2- (pyridin-4-yl) vinyl)-benzene first cyanogen (I-12)
3- cyanobenzyls diethyl phosphonate (2.79g, 11mmol) is dissolved in the tert-butyl alcohol (10mL), under ice bath stirring slowly Potassium tert-butoxide (2.24g, 20mmol) is added, finishes and is stirred 20 minutes under ice bath, then, be slowly added into the uncle of Pyridine-4-Carboxaldehyde Butanol solution (1.07g, 10mmol, 5mL), finishes and is changed to room temperature reaction 1 hour.After reaction terminates, reaction system is slowly added Enter into frozen water (40mL), there is white solid wash-off, solid is collected in suction filtration, washing, and with acetone recrystallization, suction filtration, vacuum is done It is dry, obtain white solid 1.88g, yield 91.2%.Mp:144-145℃.1H NMR(400MHz,CDCl3) δ 8.65 (d, 2H, J= 6.0Hz), 7.83 (s, 1H), 7.78 (d, 1H, J=8.0Hz), 7.63 (d, 1H, J=8.0Hz), 7.54 (t, 1H, J= 8.0Hz), (d, 1H, the J=16.4Hz) of 7.40 (d, 2H, J=6.0Hz), 7.30 (d, 1H, J=16.4Hz), 7.1213C NMR (101MHz,CDCl3)δ150.45,143.57,137.44,131.77,131.01,130.61,130.34,129.72, 128.72,121.00,118.49,113.23.HRMS(ESI)calcd for C14H11N2[M+H]+:207.0917,Found: 207.0918
The preparation of embodiment 13 (E) -4- (the fluoro- styryls of 3,4- bis-) benzene first cyanogen (I-13)
As described in Example 1, Veratraldehyde is replaced with 3,4- difluorobenzaldehydes (1.42g, 10mmol), Obtain white solid 2.0g, yield 83.3%.Mp:103-105℃.1H NMR(400MHz,CDCl3)δ7.74-7.85(m,5H), 7.41-7.53 (m, 3H), 7.37 (d, 1H, J=16.0Hz)13C NMR(101MHz,DMSO)δ151.52,151.37, 151.08,150.92,149.06,148.91,148.58,148.42,141.86,134.89,134.86,134.79,133.12, 130.48,128.63,128.04,127.66,124.83,124.79,124.76,124.73,119.41,118.38,118.21, 115.59,115.42,110.27.HRMS(ESI)calcd for C15H10F2N[M+H]+:242.0776,Found: 242.0773.
The preparation of embodiment 14 (E) -4- (3,4- dihydroxystyryls) benzene first cyanogen (II-1)
By compound I-1 (398mg, 1.5mmol) anhydrous methylene chloride (10mL) dissolvings, nitrogen protection, -35 DEG C of stirrings Under, the dichloromethane solution (2.25g, 9mmol, 5mL) of Boron tribromide is slowly added into, is finished, reaction system is slowly warmed to room temperature, Be stirred overnight at room temperature reaction.Reaction system is slowly added in frozen water (30mL), there is white-yellowish solid precipitation, is filtered, washing, Solid is collected, vacuum drying obtains white-yellowish solid.1H NMR(400MHz,DMSO)δ9.28(br,1H),9.03(br,1H), 7.79 (d, 2H, J=8.0Hz), 7.74 (d, 2H, J=8.0Hz), 7.32 (d, 1H, J=16.4Hz), 7.05 (d, 1H, J= 2.0Hz), 7.03 (d, 1H, J=16.4Hz), 6.95 (dd, 1H, J1=2.0Hz, J2=8.0Hz), 6.77 (d, 1H, J= 8.0Hz).13C NMR(101MHz,DMSO)δ146.96,145.97,142.96,133.23,132.97,128.44,127.11, 123.75,119.87,119.66,116.21,114.26,109.05.HRMS(ESI)calcd for C15H10NO2[M-H]-: 236.0717,Found:236.0716.
The preparation of embodiment 15 (E) -4- (the fluoro- 4,5- dihydroxystyryls of 2-) benzene first cyanogen (II-2)
As described in Example 14, compound I-1 is replaced with compound I-2, obtains white-yellowish solid 286mg, yield 74.7%.Mp:234-235℃.1H NMR (400MHz, DMSO) δ 9.84 (br, 1H), 8.98 (br, 1H), 7.80 (d, 2H, J= 8.0Hz), 7.76 (d, 2H, J=8.0Hz), 7.35 (d, 1H, J=16.0Hz), 7.11 (d, 1H, J=8.0Hz), 7.09 (d, 1H, J=16.0Hz), 6.63 (d, 1H, J=12.0Hz)13C NMR(101MHz,DMSO)δ155.50,153.11,147.96, 147.85,142.68,142.66,142.60,133.02,127.33,126.07,126.02,125.03,119.57,114.51, 114.38,113.14,113.09,109.54,103.72,103.46.HRMS(ESI)calcd for C15H9FNO2[M-H]-: 254.0623,Found:254.0622.
The preparation of embodiment 16 (E) -4- (the bromo- 4,5- dihydroxystyryls of 2-) benzene first cyanogen (II-3)
As described in Example 14, compound I-1 is replaced with compound I-3, obtains white-yellowish solid 395mg, yield 83.3%.Mp:196-197℃.1H NMR (400MHz, DMSO) δ 9.88 (br, 1H), 9.37 (br, 1H), 7.83 (d, 2H, J= 8.0Hz), 7.75 (d, 2H, J=8.0Hz), 7.42 (d, 1H, J=16.0Hz), 7.24 (s, 1H), 7.07 (d, 1H, J= 16.0Hz),7.00(s,1H).13C NMR(101MHz,DMSO)δ148.10,146.06,142.25,133.15,130.60, 127.46,127.10,126.81,119.51,119.46,113.81,113.28,109.85.HRMS(ESI)calcd for C15H9BrNO2[M-H]-:313.9822,Found:313.9822.
The preparation of embodiment 17 (E) -4- (the fluoro- 4-Vinyl phenol bases of 3-) benzene first cyanogen (II-4)
As described in Example 14, compound I-1 is replaced with compound I-4, obtains white-yellowish solid 276mg, yield 76.9%.Mp:162-163℃.1H NMR (400MHz, DMSO) δ 10.18 (br, 1H), 7.81 (d, 2H, J=8.4Hz), 7.73 (d, 2H, J=8.4Hz), 7.52 (dd, 1H, J1=2.0Hz, J2=8.4Hz), 7.38 (d, 1H, J=16.4Hz), 7.28 (dd, 1H,J1=1.6Hz, J2=8.4Hz), 7.20 (d, 1H, J=16.4Hz), 6.99 (t, 1H, J=8.8Hz)13C NMR (101MHz,DMSO)δ152.87,150.47,145.98,145.86,142.55,133.05,131.77,131.75,128.93, 128.86,127.26,125.47,124.65,124.63,119.57,118.33,118.30,114.52,114.34, 109.51.HRMS(ESI)calcd for C15H9FNO[M-H]-:238.0674,Found:238.0669.
The preparation of embodiment 18 (E) -4- (4-Vinyl phenol base) benzene first cyanogen (II-5)
As described in Example 14, compound I-1 is replaced with compound I-5, obtains white-yellowish solid 265mg, yield 79.8%.Mp:180-181℃.1H NMR (400MHz, DMSO) δ 9.76 (br, 1H), 7.80 (d, 2H, J=8.0Hz), 7.73 (d, 2H, J=8.0Hz), 7.49 (d, 2H, J=8.4Hz), 7.39 (d, 1H, J=16.4Hz), 7.12 (d, 1H, J= 16.4Hz), 6.81 (d, 2H, J=8.4Hz)13C NMR(101MHz,DMSO)δ158.57,142.95,133.01,132.81, 129.03,127.89,127.09,123.87,119.64,116.14,109.13.HRMS(ESI)calcd for C15H10NO [M-H]-:220.0768,Found:220.0769.
The preparation of embodiment 19 (E) -3- (3,4- dihydroxystyryls) benzene first cyanogen (II-6)
As described in Example 14, compound I-1 is replaced with compound I-6, obtains khaki solid 294mg, yield 82.6%.Mp:142-143℃.1H NMR (400MHz, DMSO) δ 9.11 (br, 2H), 8.03 (s, 1H), 7.88 (d, 1H, J= 8.0Hz), 7.66 (d, 1H, J=8.0Hz), 7.55 (t, 1H, J=8.0Hz), 7.28 (d, 1H, J=16.0Hz), 7.03 (d, 1H, J=2.0Hz), 6.98 (d, 1H, J=16.0Hz), 6.91 (dd, 1H, J1=2.0Hz, J2=8.0Hz), 6.77 (d, 1H, J =8.0Hz)13C NMR(101MHz,DMSO)δ146.66,145.93,139.48,131.88,131.05,130.50, 130.26,129.76,128.54,123.19,119.53,119.38,116.20,114.07,112.25.HRMS(ESI)calcd for C15H10NO2[M-H]-:236.0717,Found:236.0709.
The preparation of embodiment 20 (E) -3- (3,5- dihydroxystyryls) benzene first cyanogen (II-7)
As described in Example 14, compound I-1 is replaced with compound I-7, obtains khaki solid 271mg, yield 76.1%.Mp:187-189℃.1H NM7R (400MHz, DMSO) δ 9.34 (br, 2H), 8.09 (s, 1H), 7.93 (d, 1H, J= 8.0Hz), 7.71 (d, 1H, J=8.0Hz), 7.58 (t, 1H, J=8.0Hz), 7.28 (d, 1H, J=16.0Hz), 7.11 (d, 1H, J=16.0Hz), 6.47 (s, 2H), 6.20 (s, 1H)13C NMR(101MHz,DMSO)δ159.05,138.93,138.67, 131.97,131.53,131.14,130.30,130.25,126.18,119.31,112.29,105.44,103.33.HRMS (ESI)calcd for C15H10NO2[M-H]-:236.0717,Found:236.0712.
The preparation of embodiment 21 (E) -3- (the fluoro- 4,5- dihydroxystyryls of 2-) benzene first cyanogen (II-8)
As described in Example 14, compound I-1 is replaced with compound I-8, obtains white solid 317mg, yield 82.7%. Mp:186-187℃。1H NMR(400MHz,DMSO)δ9.77(br,1H),9.06(br,1H),8.07(s,1H),7.91(d, 1H, J=8.0Hz), 7.69 (d, 1H, J=8.0Hz), 7.57 (t, 1H, J=8.0Hz), 7.32 (d, 1H, J=16.0Hz), (d, 1H, the J=12.0Hz) of 7.07 (d, 1H, J=8.0Hz), 7.05 (d, 1H, J=16.0Hz), 6.6213C NMR(101MHz, DMSO)δ155.34,152.95,147.62,147.51,142.62,142.60,139.18,131.18,130.97,130.31, 130.10,125.65,125.60,123.89,119.30,114.60,114.47,113.10,113.05,112.32,103.74, 103.48.HRMS(ESI)calcd for C15H9FNO2[M-H]-:254.0623,Found:254.0619.
The preparation of embodiment 22 (E) -3- (the bromo- 4,5- dihydroxystyryls of 2-) benzene first cyanogen (II-9)
As described in Example 14, compound I-1 is replaced with compound I-9, obtains white solid 361mg, yield 76.2%. Mp:168-169℃。1H NMR(400MHz,DMSO)δ9.81(br,1H),9.38(br,1H),8.01(s,1H),7.90(d, 1H, J=8.0Hz), 7.71 (d, 1H, J=8.0Hz), 7.58 (t, 1H, J=8.0Hz), 7.36 (d, 1H, J=16.0Hz), 7.19(s,1H),7.00(m,3H).13C NMR(101MHz,DMSO)δ147.83,146.00,138.82,131.28,131.12, 130.41,130.37,129.49,127.03,126.72,119.45,119.23,113.75,112.96,112.39.HRMS (ESI)calcd for C15H9BrNO2[M-H]-:313.9822,Found:313.9822.
The preparation of embodiment 23 (E) -3- (the fluoro- 4-Vinyl phenol bases of 3-) benzene first cyanogen (II-10)
As described in Example 14, compound I-1 is replaced with compound I-10, obtains white solid 264mg, yield 73.7%.Mp:127-129℃.1H NMR (400MHz, DMSO) δ 10.13 (s, 1H), 8.02 (s, 1H), 7.85 (d, 1H, J= 8.0Hz), 7.69 (d, 1H, J=8.0Hz), 7.58 (t, 1H, J=8.0Hz), 7.44 (dd, 1H, J1=2.0Hz, J1= 12.8Hz), 7.35 (d, 1H, J=16.0Hz), 7.25 (dd, 1H, J1=2.0Hz, J1=8.0Hz), 7.15 (d, 1H, J= 16.0Hz), 6.99 (t, 1H, J=8.0Hz)13C NMR(101MHz,DMSO)δ152.87,150.47,145.72,145.59, 139.11,131.26,130.89,130.50,130.48,130.35,129.84,129.05,128.99,124.94,124.33, 124.30,119.30,118.34,118.31,114.31,114.13,112.32.HRMS(ESI)calcd for C15H9FNO [M-H]-:238.0674,Found:238.0667.
The preparation of embodiment 24 (E) -3- (4-Vinyl phenol base) benzene first cyanogen (II-11)
As described in Example 14, compound I-1 is replaced with compound I-11, obtains white-yellowish solid 259mg, yield 77.8%.Mp:189-191℃.1H NMR (400MHz, DMSO) δ 9.70 (br, 1H), 8.02 (s, 1H), 7.87 (d, 1H, J= 8.0Hz), 7.67 (d, 1H, J=8.0Hz), 7.54 (t, 1H, J=8.0Hz), 7.46 (d, 2H, J=8.0Hz), 7.35 (d, 1H, ), J=16.0Hz 7.07 (d, 1H, J=16.0Hz), 6.81 (d, 2H, J=8.0Hz)13C NMR(101MHz,DMSO)δ 158.30,139.48,131.49,131.07,130.56,130.30,129.72,128.74,128.00,123.32,119.36, 116.10,112.28.HRMS(ESI)calcd for C15H10NO[M-H]-:220.0768,Found:220.0766.
The preparation of embodiment 25 (Z) -4- ((E) -3,4- dihydroxystyryls)-N'- hydroxyls benzenecarboximidamide (III-1)
By compound II-1 (237mg, 1mmol) and hydroxylamine hydrochloride (209mg, 3mmol) methanol (10mL) dissolving, room temperature Stirring is lower to add triethylamine (303mg, 3mmol), finishes, 6 hours of back flow reaction.After reaction terminates, by reaction system vacuum Concentration, concentrate ethyl acetate, water dissolving, divides and takes ethyl acetate layer, successively with water (2 × 20mL), saturated aqueous common salt (1 × 20mL) wash.Anhydrous sodium sulfate drying, after vacuum distillation, crude product silica gel column chromatography separating purification (petroleum ether：Acetone=1: 1) compound as white solid 169mg, yield 62.5%, are obtained.Mp:167-168℃.1H NMR(400MHz,DMSO)δ9.65(br, 1H), 9.09 (br, 2H), 7.66 (d, 2H, J=8.0Hz), 7.54 (d, 2H, J=8.0Hz), 7.14 (d, 1H, J=16.4Hz), 7.01 (s, 1H), 6.95 (d, 1H, J=16.4Hz), 6.89 (d, 1H, J=8.0Hz), 6.75 (d, 1H, J=8.0Hz), 5.81 (s,2H).13C NMR(101MHz,DMSO)δ151.06,146.22,145.91,138.55,132.07,129.76,129.02, 126.17,126.02,124.86,119.20,116.19,113.83.HRMS(ESI)calcd for C15H14N2O2[M-H]-: 269.0932,Found:269.0931.
The system of embodiment 26 (Z) -4- (the fluoro- 4,5- dihydroxystyryls of (E) -2-)-N'- hydroxyls benzenecarboximidamide (III-2) It is standby
By the method for embodiment 25, compound II-1 is replaced with compound II-2, white solid 202mg, yield is obtained 70.4%.Mp:193-194℃.1H NMR (400MHz, DMSO) δ 9.68 (br, 2H), 9.01 (br, 1H), 7.68 (d, 2H, J= 8.0Hz), 7.57 (d, 2H, J=8.0Hz), 7.19 (d, 1H, J=16.0Hz), 7.08 (d, 1H, J=8.0Hz), 7.02 (d, 1H, J=16.0Hz), 6.61 (d, 1H, J=12.0Hz), 5.84 (s, 2H)13C NMR(101MHz,DMSO)δ155.11, 152.73,151.04,147.14,147.03,142.59,138.27,132.48,127.23,127.18,126.36,126.09, 121.57,115.03,114.90,112.81,112.76,103.71,103.45.HRMS(ESI)calcd for C15H12FN2O3 [M-H]-:287.0837,Found:287.0832.
The system of embodiment 27 (Z) -4- (the bromo- 4,5- dihydroxystyryls of (E) -2-)-N'- hydroxyls benzenecarboximidamide (III-3) It is standby
By the method for embodiment 25, compound II-1 is replaced with compound II-3, white solid 288mg, yield is obtained 82.5%.Mp:184-185℃.1H NMR (400MHz, DMSO) δ 9.69 (br, 2H), 9.34 (br, 1H), 7.70 (d, 2H, J= 8.0Hz), 7.56 (d, 2H, J=8.0Hz), 7.29 (d, 1H, J=16.0Hz), 7.21 (s, 1H), 6.98 (s, 1H), 6.94 (d, 1H, J=16.0Hz), 5.83 (s, 2H)13C NMR(101MHz,DMSO)δ150.98,147.45,146.01,137.96, 132.80,128.23,127.39,127.36,126.49,126.19,119.42,113.48,112.71.HRMS(ESI)calcd for C15H15BrN2O3[M+H]+:349.0183,Found:349.0187.
The preparation of embodiment 28 (Z) -4- (the fluoro- 4-Vinyl phenol bases of (E) -3-)-N'- hydroxyls benzenecarboximidamide (III-4),
By the method for embodiment 25, compound II-1 is replaced with compound II-4, white solid 201mg, yield is obtained 73.6%.Mp:184-186℃.1H NMR(400MHz,DMSO)δ9.69(br,2H),7.36-7.67(m,5H),6.95-7.23 (m,4H),5.83(s,2H).13C NMR(101MHz,DMSO)δ168.02,152.90,151.03,150.51,145.32, 145.20,138.20,132.46,129.54,129.47,128.40,126.58,126.34,126.08,123.95,118.31, 114.12,113.94.HRMS(ESI)calcd for C15H14FN2O2[M+H]+:273.1034,Found:273.1031.
The preparation of embodiment 29 (Z) -4- ((E) -4-Vinyl phenol base)-N'- hydroxyls benzenecarboximidamide (III-5)
By the method for embodiment 25, compound II-1 is replaced with compound II-5, white solid 208mg, yield is obtained 81.9%.Mp:192-194℃.1H NMR (400MHz, DMSO) δ 9.66 (br, 1H), 9.62 (br, 1H), 7.67 (d, 2H, J= 8.0Hz), 7.55 (d, 2H, J=8.0Hz), 7.45 (d, 2H, J=8.0Hz), 7.21 (d, 1H, J=16.4Hz), 7.05 (d, 1H, J=16.4Hz), 6.79 (d, 2H, J=8.0Hz), 5.83 (s, 2H)13C NMR(101MHz,DMSO)δ157.90, 151.10,138.58,132.10,129.40,128.44,126.16,126.06,124.99,116.05.HRMS(ESI)calcd for C15H15N2O2[M+H]+:255.1128,Found:255.1127.
The preparation of embodiment 30 (Z) -3- ((E) -3,4- dihydroxystyryls)-N'- hydroxyls benzenecarboximidamide (III-6)
By the method for embodiment 25, compound II-1 is replaced with compound II-6, white solid 192mg, yield is obtained 71.0%.Mp:210-211℃.1H NMR(400MHz,DMSO)δ9.65(br,1H),9.08(br,2H),7.84(s,1H), 7.54 (d, 2H, J=8.0Hz), 7.35 (t, 1H, J=8.0Hz), 7.14 (d, 1H, J=16.0Hz), 7.01 (d, 1H, J= 2.0Hz), 6.95 (d, 1H, J=16.0Hz), 6.90 (dd, 1H, J1=2.0Hz, J2=8.0Hz), 6.75 (d, 1H, J= 8.0Hz),5.87(s,2H).13C NMR(101MHz,DMSO)δ151.24,146.19,145.91,137.85,134.15, 129.67,128.99,128.87,127.16,125.18,124.47,123.25,119.13,116.20,113.80.HRMS (ESI)calcd for C15H14N2O2[M-H]-:269.0932,Found:269.0925.
The preparation of embodiment 31 (Z) -3- ((E) -3,5- hydroxy styrenes base)-N'- hydroxyls benzenecarboximidamide (III-7)
By the method for embodiment 25, compound II-1 is replaced with compound II-7, white solid 217mg, yield is obtained 80.4%.Mp:85-87℃.1H NMR(400MHz,DMSO)δ9.67(br,1H),9.30(br,2H),7.88(s,1H),7.58 (d, 2H, J=8.0Hz), 7.38 (t, 1H, J=8.0Hz), 7.14 (d, 1H, J=16.4Hz), 7.07 (d, 1H, J= 16.4Hz), (s, the 2H) of 6.46 (d, 2H, J=2.4Hz), 6.19 (t, 1H, J=2.4Hz), 5.8913C NMR(101MHz, DMSO)δ159.04,151.16,139.12,137.35,134.18,129.81,128.92,128.09,127.62,125.05, 123.63,105.18,102.90.HRMS(ESI)calcd for C15H15N2O3[M+H]+:271.1077,Found: 271.1079.
The preparation of embodiment 32 (Z) -3- (the fluoro- 4,5- hydroxy styrenes bases of (E) -2-)-N'- hydroxyls benzenecarboximidamide (III-8)
By the method for embodiment 25, compound II-1 is replaced with compound II-8, white solid 223mg, yield is obtained 77.4%.Mp:171-172℃.1H NMR(400MHz,DMSO)δ9.66(br,2H),9.02(br,1H),7.87(s,1H), 7.58 (d, 1H, J=8.0Hz), 7.53 (d, 1H, J=8.0Hz), 7.37 (t, 1H, J=8.0Hz), 7.22 (d, 1H, J= 16.0Hz), 7.08 (d, 1H, J=8.0Hz), 7.02 (d, 1H, J=16.0Hz), 6.62 (d, 1H, J=12.0Hz), 5.89 (s, 2H).13C NMR(101MHz,DMSO)δ155.10,152.72,151.14,147.13,147.01,142.61,137.61, 134.17,128.96,127.49,124.86,123.20,121.52,114.99,114.86,112.73,112.68,103.71, 103.45.HRMS(ESI)calcd for C15H12FN2O3[M-H]-:287.0837,Found:287.0832.
The preparation of embodiment 33 (Z) -3- (the bromo- 4,5- hydroxy styrenes bases of (E) -2-)-N'- hydroxyls benzenecarboximidamide (III-9)
By the method for embodiment 25, compound II-1 is replaced with compound II-9, white solid 303mg, yield is obtained 86.7%.Mp:66-68℃.1H NMR (400MHz, DMSO) δ 9.67 (br, 3H), 7.87 (s, 1H), 7.59 (d, 1H, J= 8.0Hz), 7.54 (d, 1H, J=8.0Hz), 7.40 (t, 1H, J=8.0Hz), 7.30 (d, 1H, J=16.0Hz), 7.21 (s, 1H), (s, the 2H) of 6.98 (s, 1H), 6.94 (d, 1H, J=16.0Hz), 5.8913C NMR(101MHz,DMSO)δ151.19, 147.46,146.02,137.30,134.31,129.08,128.55,127.70,127.39,127.36,125.17,123.34, 119.41,113.52,112.64.HRMS(ESI)calcd for C15H15BrN2O3[M+H]+:349.0183,Found 349.0180.
The preparation of embodiment 34 (Z) -3- (the fluoro- 4-Vinyl phenol bases of (E) -3-)-N'- hydroxyls benzenecarboximidamide (III-10)
By the method for embodiment 25, compound II-1 is replaced with compound II-10, white solid 204mg, yield is obtained 75.1%.Mp:189-190℃.1H NMR(400MHz,DMSO)δ10.05(br,1H),9.67(br,1H),7.87(s,1H), 7.57 (t, 2H, J=8.0Hz), 7.47 (dd, 1H, J1=1.6Hz, J2=12.4Hz), 7.38 (t, 1H, J=8.0Hz), 7.25 (dd,1H,J1=2.0Hz, J2=8.0Hz), 7.20 (d, 1H, J=16.4Hz), 7.13 (d, 1H, J=16.4Hz), 6.98 (t, 1H, J=8.0Hz), 5.88 (s, 2H)13C NMR(101MHz,DMSO)δ152.90,151.24,150.51,145.25, 145.13,137.51,134.24,129.55,129.49,128.94,128.28,127.31,126.95,124.86,123.91, 123.51,118.31,118.28,114.12,113.93.HRMS(ESI)calcd for C15H14FN2O2[M+H]+: 273.1034,Found:273.1030.
The preparation of embodiment 35 (Z) -3- ((E) -4-Vinyl phenol base)-N'- hydroxyls benzenecarboximidamide (III-11)
By the method for embodiment 25, compound II-1 is replaced with compound II-11, white solid 171mg, yield is obtained 67.6%.Mp:184-186℃.1H NMR(400MHz,DMSO)δ9.65(br,1H),9.62(br,1H),7.86(s,1H), 7.54 (d, 2H, J=8.0Hz), 7.45 (d, 2H, J=8.0Hz), 7.36 (t, 1H, J=8.0Hz), 7.21 (d, 1H, J= 16.0Hz), (s, the 2H) of 7.05 (d, 1H, J=16.0Hz), 6.80 (d, 2H, J=8.0Hz), 5.8713C NMR(101MHz, DMSO)δ157.87,151.26,137.86,134.18,129.29,128.89,128.45,128.40,127.14,125.32, 124.52,123.30,116.06.HRMS(ESI)calcd for C15H15N2O2[M+H]+:255.1128,Found: 255.1126.
The preparation of embodiment 36 (Z) -3- ((E) -4-Vinyl phenol base)-N'- hydroxyls benzenecarboximidamide (III-12)
By the method for embodiment 25, compound II-1 is replaced with compound I-12, white solid 207mg, yield is obtained 86.7%.Mp:185-187℃.1H NMR (400MHz, DMSO) δ 9.71 (s, 1H), 8.57 (d, 2H, J=6.0Hz), 7.98 (s, 1H), 7.56-7.67 (m, 5H), 7.42 (t, 1H, J=8.0Hz), 7.32 (d, 1H, J=16.4Hz), 5.92 (s, 2H)13C NMR(101MHz,DMSO)δ151.07,150.53,144.63,136.49,134.38,133.29,129.11,128.15, 126.81,126.13,124.35,121.38.HRMS(ESI)calcd for C14H14N3O[M+H]+240.1131,Found 240.1139
The preparation of embodiment 37 (Z) -4- (the fluoro- styryls of (E) -3,4- two)-N'- hydroxyls benzenecarboximidamide (III-13)
By the method for embodiment 25, compound II-1 is replaced with compound II-13, white solid 193mg, yield is obtained 70.4%.Mp:192-194℃.1H NMR(400MHz,DMSO)δ9.71(br,1H),7.70-7.75(m,3H),7.70(d, 2H, J=8.0Hz), 7.42-7.46 (m, 2H), 7.29 (s, 2H), 5.84 (s, 2H)13C NMR(101MHz,DMSO)δ 151.50,151.38,150.94,149.07,148.94,148.15,148.03,137.58,135.48,133.13,129.77, 127.20,126.76,126.12,124.17,118.28,118.10,115.18,115.01.HRMS(ESI)calcd for C15H13F2N2O[M+H]+:275.0990,Found:275.0997.
The LSD1 inhibitory activity of Verakanol derivative synthesized by the present invention of embodiment 38 is evaluated
(1) enzyme level LSD1 inhibitory activity is evaluated：
1st, experimental method:Sample is the above-claimed cpd synthesized by embodiment, purifying is obtained；Stock sample solution：Weigh 3- 5mg samples are placed in 1.5mL EP pipes, and the solution that concentration is 20mM is then configured to DMSO, and 4 liquid are preserved and placed, during experiment Diluted according to required concentration with DMSO.By testing sample and LSD1 albumen in after incubation at room temperature, LSD1 reaction substrates are added H3K4me2 and incubation reaction, are eventually adding fluorescent dye Amplex and HRPO HRP incubations at room temperature, on ELIASA Exciting light 530nm, transmitting light 590nm detection fluorescence values:
Result of the test calculates IC using SPSS softwares50Value.
2nd, experimental result
LSD1 inhibitory activity measurement results
aData are expressed as:Mean+SD；bn.t.:Undetermined
Most compound, which is can be seen that, from upper table experimental result is respectively provided with very strong LSD1 inhibitory activity, it is most of The LSD1 of compound suppresses IC50Respectively less than 1 μM, activity is better than positive control medicine tranylcypromine.Wherein activity most strong change Compound III-3 and III-9, LSD1 inhibitory activity are 230 times of 2-PCPA.It is brand-new that the compound of the present invention represents a class formation LSD1 inhibitor, be that the research and development of LSD1 inhibitor class medicines provide the foundation, for LSD1 biological function research provide Effective tool.
(2) cellular level LSD1 inhibitory activity is evaluated：
1st, experimental method
2000/hole of gastric carcinoma cell lines MGC-803 cells is inoculated in saturating 96 orifice plate in black wall bottom, various concentrations chemical combination is added Cultivated 5 days after thing III-9；Immunofluorescence dyeing is done using H3K4me2 antibody and green fluorescence secondary antibody, while contaminating cell with DAPI Core counts cell number as internal reference；16 visuals field are chosen per hole using high intension, are taken pictures and green fluorescence with 4 Bei Jingming factories respectively Take pictures statistics, wherein H3K4me2 fluorescence intensities/cell number is the hole individual cells H3K4me2 fluorescence intensity parameters.With Control calculates drug-treated group individual cells H3K4me2 fluorescence intensities and does figure as control.
2nd, experimental result
From accompanying drawing as can be seen that compound III-9 can dose dependent up-regulation MGC-803 cells under various concentrations effect Interior LSD1 substrates H3K4me2 amount, 2.5 μm of ol/L compound III-9 can be such that H3K4me2 amount improves more than 5 times, explanation Compound III-9 also can significantly suppress LSD1 activity in cellular level.

Claims (5)

1. resveratrol derivative, it is characterised in that with formula（III）Shown structure：
R is monosubstituted or polysubstituted, substituent choosing on A rings：Hydrogen, hydroxyl, nitro or halogen；
It is monosubstituted on B rings；X represents N atoms or C atoms.
2. resveratrol analog derivative as claimed in claim 1, it is characterised in that formula（III）Middle choosing：R is hydrogen, hydroxyl Base or F, Cl, Br, R are monosubstituted or polysubstituted on A rings；X represents N atoms or C atoms.
3. resveratrol analog derivative as claimed in claim 2, it is characterised in that select following compound:
III-1:R group is that 3,4-diOH, B rings are 4 substitutions, X=C derivative；
III-2:R group is 2-F-4, and 5-diOH, B rings are 4 substitutions, X=C derivative；
III-3:R group is 2-Br-4, and 5-diOH, B rings are 4 substitutions, X=C derivative；
III-4:R group is 3-F-4-OH, and B rings are 4 substitutions, X=C derivative；
III-5:R group is 4-OH, and B rings are 4 substitutions, X=C derivative；
III-6:R group is that 3,4-diOH, B rings are 3 substitutions, X=C derivative；
III-7:R group is that 3,5-diOH, B rings are 3 substitutions, X=C derivative；
III-8:R group is 2-F-4, and 5-diOH, B rings are 3 substitutions, X=C derivative；
III-9:R group is 2-Br-4, and 5-diOH, B rings are 3 substitutions, X=C derivative；
III-10:R group is 3-F-4-OH, and B rings are 3 substitutions, X=C derivative；
III-11:R group is 4-OH, and B rings are 3 substitutions, X=C derivative；
III-12:R group is that 3,4-diF, B rings are 4 substitutions, X=C derivative；
III-13:R group is H, and B rings are 3 substitutions, X=N derivative.
4. prepare the method for resveratrol analog derivative as claimed in claim 1 or 2, it is characterised in that by as follows Step is realized：
R ' is monosubstituted or polysubstituted, substituent choosing on A rings：Hydrogen, methoxyl group, nitro or halogen；
R is monosubstituted or polysubstituted, substituent choosing on A rings：Hydrogen, hydroxyl, nitro or halogen；
Benzaldehyde or substituted benzaldehyde and cyano group substituted benzyl diethyl phosphonate, in dry DMF, strongly alkaline compound is present Under, be stirred at room temperature reaction, generate compound I, wherein, the strongly alkaline compound be selected from potassium tert-butoxide, sodium methoxide, sodium hydride, Sodium tert-butoxide；If not having methoxy substitution in compound I, compound I is in methanol solution, in the presence of triethylamine, with hydrochloric acid Oxyammonia back flow reaction obtains the compound III that R is not hydroxyl；
Compound I containing methoxy substitution is dissolved in dichloromethane, under -20 ~ -80 DEG C of cryogenic conditions, Boron tribromide is added, takes off Methyl obtains the compound II that R is hydroxyl；Compound II is in methanol solution, in the presence of triethylamine, with oxammonium hydrochloride back flow reaction Compound III that must be containing hydroxyl.
5. application of the resveratrol analog derivative in medicine preparation as described in one of claim 1-3, it is special Levy and be, the preparation of LSD1 inhibitor class medicines is used for as active component.
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