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

Info

Publication number
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
Authority
CN
China
Prior art keywords
iii
compound
substituted
ring
group
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Active
Application number
CN201610357637.5A
Other languages
Chinese (zh)
Other versions
CN106045881A (en
Inventor
段迎超
关圆圆
翟晓雨
郑超
郑一超
刘巍
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Henan Tengyu Biotechnology Co ltd
Original Assignee
Xinxiang Medical University
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Xinxiang Medical University filed Critical Xinxiang Medical University
Priority to CN201610357637.5A priority Critical patent/CN106045881B/en
Publication of CN106045881A publication Critical patent/CN106045881A/en
Application granted granted Critical
Publication of CN106045881B publication Critical patent/CN106045881B/en
Active legal-status Critical Current
Anticipated expiration legal-status Critical

Links

Classifications

    • 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

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)

Abstract

本发明公开一类白藜芦醇类衍生物、合成方法及其作为组蛋白赖氨酸特异性去甲基化酶1抑制剂的应用，属于药物化学领域。本发明所述的化合物具有如下通式：通式III中，R优选氢、羟基、甲氧基、硝基或卤素，X代表N原子、C原子。该类化合物对组蛋白赖氨酸特异性去甲基化酶1具有很好的抑制作用，可作为进一步开发的候选或者先导化合物用于开发抗肿瘤、抗艾滋病等疾病治疗药物。

The invention discloses a class of resveratrol derivatives, a synthesis method and an application thereof as an inhibitor of histone lysine specific demethylase 1, belonging to the field of medicinal chemistry. Compounds of the present invention have the general formula: In the general formula III, R is preferably hydrogen, hydroxyl, methoxy, nitro or halogen, and X represents an N atom or a C atom. This type of compound has a good inhibitory effect on histone lysine-specific demethylase 1, and can be used as a candidate or lead compound for further development for the development of anti-tumor, anti-AIDS and other disease treatment drugs.

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)

1.一类白藜芦醇衍生物，其特征在于，具有通式（III）所示结构：1. A class of resveratrol derivatives, characterized in that they have the structure shown in general formula (III): R在A环上为单取代或多取代，取代基选：氢、羟基、硝基或卤素；R is monosubstituted or multisubstituted on the A ring, and the substituents are selected from: hydrogen, hydroxyl, nitro or halogen; 在B环上单取代； X 代表N原子或C原子。 Single substitution on ring B; X represents N atom or C atom. 2.如权利要求1所述的一类白藜芦醇类衍生物，其特征在于，通式（III）中选：R为氢、羟基或F、Cl、Br， R在A环上为单取代或多取代；X代表N原子或C原子。2. A class of resveratrol derivatives as claimed in claim 1, characterized in that, in the general formula (III): R is hydrogen, hydroxyl or F, Cl, Br, and R is monosubstituted on the A ring Or multiple substitutions; X represents N atom or C atom. 3.如权利要求2所述的一类白藜芦醇类衍生物，其特征在于，选以下化合物:3. a class of resveratrol derivatives as claimed in claim 2, is characterized in that, selects following compound: III-1: R基团为3,4-diOH，B环为4位取代，X = C的衍生物；III-1: The R group is 3,4-diOH, the B ring is substituted at the 4-position, and X = C derivative; III-2: R基团为2-F-4,5-diOH，B环为4位取代，X = C的衍生物；III-2: The R group is 2-F-4,5-diOH, the B ring is substituted at the 4-position, and X = C derivative; III-3: R基团为2-Br-4,5-diOH，B环为4位取代，X = C的衍生物；III-3: The R group is 2-Br-4,5-diOH, the B ring is substituted at the 4-position, and X = C derivative; III-4: R基团为3-F-4-OH，B环为4位取代，X = C的衍生物；III-4: The R group is 3-F-4-OH, the B ring is substituted at the 4-position, and X = C derivative; III-5: R基团为4-OH，B环为4位取代，X = C的衍生物；III-5: The R group is 4-OH, the B ring is substituted at the 4-position, and X = C derivative; III-6: R基团为3,4-diOH，B环为3位取代，X = C的衍生物；III-6: The R group is 3,4-diOH, the B ring is substituted at the 3 position, and X = C derivative; III-7: R基团为3,5-diOH，B环为3位取代，X = C的衍生物；III-7: The R group is 3,5-diOH, the B ring is substituted at the 3 position, and X = C derivative; III-8: R基团为2-F-4,5-diOH，B环为3位取代，X = C的衍生物；III-8: The R group is 2-F-4,5-diOH, the B ring is substituted at the 3-position, and X = C derivative; III-9: R基团为2-Br-4,5-diOH，B环为3位取代，X = C的衍生物；III-9: The R group is 2-Br-4,5-diOH, the B ring is substituted at the 3 position, and X = C derivative; III-10: R基团为3-F-4-OH，B环为3位取代，X = C的衍生物；III-10: The R group is 3-F-4-OH, the B ring is substituted at the 3-position, and X = C derivative; III-11: R基团为4-OH，B环为3位取代，X = C的衍生物；III-11: The R group is 4-OH, the B ring is substituted at the 3-position, and X = C derivative; III-12: R基团为3,4-diF，B环为4位取代，X = C的衍生物；III-12: The R group is 3,4-diF, the B ring is substituted at the 4-position, and X = C derivative; III-13: R基团为H，B环为3位取代，X= N的衍生物。III-13: The R group is H, the B ring is substituted at the 3-position, and X=N derivatives. 4.制备如权利要求1或2所述的一类白藜芦醇类衍生物的方法，其特征在于，通过如下步骤实现：4. prepare the method for a class of resveratrol derivatives as claimed in claim 1 or 2, it is characterized in that, realize by following steps: R’在A环上为单取代或多取代，取代基选：氢、甲氧基、硝基或卤素；R' is mono-substituted or multi-substituted on the A ring, and the substituents are selected from: hydrogen, methoxy, nitro or halogen; R在A环上为单取代或多取代，取代基选：氢、羟基、硝基或卤素；R is monosubstituted or multisubstituted on the A ring, and the substituents are selected from: hydrogen, hydroxyl, nitro or halogen; 苯甲醛或取代苯甲醛和氰基取代苄基膦酸二乙酯，在无水DMF中，强碱性化合物存在下，室温搅拌反应，生成化合物I，其中，所述强碱性化合物选自叔丁醇钾、甲醇钠、氢化钠、叔丁醇钠；若化合物I中没有甲氧基取代，则化合物I在甲醇溶液中，三乙胺存在下，与盐酸羟氨回流反应得R不为羟基的化合物III；Benzaldehyde or substituted benzaldehyde and cyano-substituted benzyl phosphonic acid diethyl ester, in anhydrous DMF, in the presence of a strong basic compound, react with stirring at room temperature to generate compound I, wherein the strong basic compound is selected from tertiary Potassium butoxide, sodium methoxide, sodium hydride, sodium tert-butoxide; if there is no methoxy substitution in compound I, then compound I is reacted with hydroxylammonium hydrochloride in the presence of triethylamine in methanol solution to obtain that R is not a hydroxyl group Compound III of 将含甲氧基取代的化合物I溶于二氯甲烷中，-20~-80℃低温条件下，加入三溴化硼，脱甲基得R为羟基的化合物II；化合物II在甲醇溶液中，三乙胺存在下，与盐酸羟氨回流反应得含有羟基的化合物III。Dissolve the methoxy-substituted compound I in dichloromethane, add boron tribromide at a low temperature of -20~-80°C, and demethylate to obtain compound II with R as a hydroxyl group; compound II is in methanol solution, In the presence of triethylamine, react with hydroxylammonium hydrochloride under reflux to obtain compound III containing hydroxyl. 5.如权利要求1-3其中之一所述的一类白藜芦醇类衍生物在药物制备中的应用，其特征在于，将其作为活性成分用于LSD1抑制剂类药物的制备。5. The application of a class of resveratrol derivatives according to any one of claims 1-3 in the preparation of medicines, characterized in that it is used as an active ingredient in the preparation of LSD1 inhibitors medicines.
CN201610357637.5A 2016-05-26 2016-05-26 Resveratrol derivative, its preparation method and the application as LSD1 inhibitor Active CN106045881B (en)

Priority Applications (1)

Application Number Priority Date Filing Date Title
CN201610357637.5A CN106045881B (en) 2016-05-26 2016-05-26 Resveratrol derivative, its preparation method and the application as LSD1 inhibitor

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
CN201610357637.5A CN106045881B (en) 2016-05-26 2016-05-26 Resveratrol derivative, its preparation method and the application as LSD1 inhibitor

Publications (2)

Publication Number Publication Date
CN106045881A CN106045881A (en) 2016-10-26
CN106045881B true CN106045881B (en) 2017-10-31

Family

ID=57175266

Family Applications (1)

Application Number Title Priority Date Filing Date
CN201610357637.5A Active CN106045881B (en) 2016-05-26 2016-05-26 Resveratrol derivative, its preparation method and the application as LSD1 inhibitor

Country Status (1)

Country Link
CN (1) CN106045881B (en)

Families Citing this family (23)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
ES3057783T3 (en) 2016-03-15 2026-03-04 Oryzon Genomics Sa Combinations of lsd1 inhibitors for use in the treatment of neoplastic diseases
CN107474011B (en) * 2017-08-25 2020-03-27 新乡医学院 2-phenyl-4-styrylpyridine LSD1 inhibitor, and preparation method and application thereof
CN107501169B (en) * 2017-08-25 2020-03-27 新乡医学院 Trans-diarylethene LSD1 inhibitor, preparation method and application thereof
CN111484411B (en) * 2020-03-25 2022-08-26 新乡医学院 Extraction method and application of anti-inflammatory effective component of folium artemisiae argyi
CN111592487B (en) * 2020-06-09 2022-07-19 新乡医学院 Hydroximic acid group-containing diarylethene LSD1/HDACs double-target inhibitor, and preparation method and application thereof
US20250073232A1 (en) 2021-04-08 2025-03-06 Oryzon Genomics, S.A. Combinations of lsd1 inhibitors for treating myeloid cancers
EP4522136A1 (en) 2022-05-09 2025-03-19 Oryzon Genomics, S.A. Methods of treating malignant peripheral nerve sheath tumor (mpnst) using lsd1 inhibitors
US20250295660A1 (en) 2022-05-09 2025-09-25 Oryzon Genomics, S.A. Methods of treating nf1-mutant tumors using lsd1 inhibitors
CN120529900A (en) 2022-11-24 2025-08-22 奥莱松基因组股份有限公司 Combination of LSD1 inhibitors and Menin inhibitors for the treatment of cancer
TW202508595A (en) 2023-05-04 2025-03-01 美商銳新醫藥公司 Combination therapy for a ras related disease or disorder
US20250049810A1 (en) 2023-08-07 2025-02-13 Revolution Medicines, Inc. Methods of treating a ras protein-related disease or disorder
AU2024360465A1 (en) 2023-10-12 2026-04-09 Revolution Medicines, Inc. Macrocyclic ras inhibitors
WO2025171296A1 (en) 2024-02-09 2025-08-14 Revolution Medicines, Inc. Ras inhibitors
TW202547461A (en) 2024-05-17 2025-12-16 美商銳新醫藥公司 Ras inhibitors
WO2025255438A1 (en) 2024-06-07 2025-12-11 Revolution Medicines, Inc. Methods of treating a ras protein-related disease or disorder
WO2025265060A1 (en) 2024-06-21 2025-12-26 Revolution Medicines, Inc. Therapeutic compositions and methods for managing treatment-related effects
WO2026006747A1 (en) 2024-06-28 2026-01-02 Revolution Medicines, Inc. Ras inhibitors
WO2026015801A1 (en) 2024-07-12 2026-01-15 Revolution Medicines, Inc. Methods of treating a ras related disease or disorder
WO2026015790A1 (en) 2024-07-12 2026-01-15 Revolution Medicines, Inc. Methods of treating a ras related disease or disorder
WO2026015796A1 (en) 2024-07-12 2026-01-15 Revolution Medicines, Inc. Methods of treating a ras related disease or disorder
WO2026015825A1 (en) 2024-07-12 2026-01-15 Revolution Medicines, Inc. Use of ras inhibitor for treating pancreatic cancer
WO2026050446A1 (en) 2024-08-29 2026-03-05 Revolution Medicines, Inc. Ras inhibitors
WO2026072904A2 (en) 2024-09-26 2026-04-02 Revolution Medicines, Inc. Compositions and methods for treating lung cancer

Family Cites Families (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE1955374A1 (en) * 1969-11-04 1971-05-13 Badische Anilin & Soda Fabrik AG, 6700 Ludwigshafen Optical brightners
EP0006176B1 (en) * 1978-06-09 1982-01-06 Hoechst Aktiengesellschaft Stilbene compounds, process for their preparation and their use as optical brighteners
CN103054869A (en) * 2013-01-18 2013-04-24 郑州大学 Application of amino dithio formic ester compound with triazolyl in preparing medicine taking LSD1 (Lysine Specificity Demethylase 1) as target
CN103319466B (en) * 2013-07-04 2016-03-16 郑州大学 Containing the 1,2,3-triazoles-dithiocarbamates compound of tonka bean camphor parent nucleus, preparation method and application thereof

Also Published As

Publication number Publication date
CN106045881A (en) 2016-10-26

Similar Documents

Publication Publication Date Title
CN106045881B (en) Resveratrol derivative, its preparation method and the application as LSD1 inhibitor
CN103450077B (en) IRE-1 alpha inhibitor
CN107474011B (en) 2-phenyl-4-styrylpyridine LSD1 inhibitor, and preparation method and application thereof
WO2021175079A1 (en) P-phenylenediamine lsd1 inhibitor and preparation method therefor
Mohammadi-Khanaposhtani et al. Design, synthesis, in vitro cytotoxic activity evaluation, and apoptosis-induction study of new 9 (10 H)-acridinone-1, 2, 3-triazoles
UA128183C2 (en) Arrowhead List;Diamond List;Endnote Text;Bullet List;Upper Roman List;Lower Roman List;Numbered List;Square List;Dashed List;Tick List;Heart List;Block Text;Upper Case List;Footnote;Hand List;Footnote Text;Normal;Lower Case List;Plain Text;Implies List;Box List;Star List;Triangle List;Endnote;DERIVATIVES OF MONO- OR DISPLACED INDOLS AS INHIBITORS OF DENGUE VIRUS REPLICATION
UA122973C2 (en) DERIVATIVES OF MONO- OR DYSUBSTITUTED INDOLES AS INHIBITORS OF DENGE VIRUS REPLICATION
JP2015214548A (en) IRE-1α inhibitor
EA024893B1 (en) BENZO[b][1,4]OXAZIN DERIVATIVES AS CALCIUM SENSING RECEPTOR MODULATORS
CN107501169B (en) Trans-diarylethene LSD1 inhibitor, preparation method and application thereof
Zuma et al. Synthesis, in vitro antileishmanial efficacy and hit/lead identification of nitrofurantoin‐triazole hybrids
EA026940B1 (en) Substituted chroman compounds as calcium sensing receptor modulators
JP5946409B2 (en) IRE-1α inhibitor
CN111592487A (en) Hydroximic acid group-containing diarylethene LSD1/HDACs double-target inhibitor, and preparation method and application thereof
AU2014366436B2 (en) Fluorophenyl pyrazol compounds
Cassiano Martinho et al. Synthesis, design, and structure‐activity relationship of a benzenesulfonylpiperazine series against Trypanosoma cruzi
CN107216352A (en) Mitochondrially targeted dihydrogen pyridine derivative and preparation method and application
KR20200112907A (en) Thiophene derivatives and uses thereof
EP4110764A1 (en) Small molecule inhibitors of scl15a4 with anti-inflammatory activity
JP2022511287A (en) Substituted heterocyclic compound as a c-MYC targeting agent
JP2016525561A (en) 2-Benzoylaminobenzamide derivatives as BCL-3 inhibitors
Sharabi-Ronen et al. Anti-neoplastic activity of 1, 3-diaza-2-functionalized-adamantan-6-one compounds against melanoma cells
Man et al. Discovery of pyrazole‐carbohydrazide with indole moiety as tubulin polymerization inhibitors and anti‐tumor candidates
KR20250033306A (en) 1,3,4-Oxadiazole triazole compound as histone deacetylase 6 inhibitor and pharmaceutical composition comprising same
US20210024499A1 (en) Oxidized bis(3-indolyl)methanes and uses thereof

Legal Events

Date Code Title Description
C06 Publication
PB01 Publication
C10 Entry into substantive examination
SE01 Entry into force of request for substantive examination
GR01 Patent grant
GR01 Patent grant
TR01 Transfer of patent right

Effective date of registration: 20230814

Address after: Room 916, block C, V mansion, No.1 Park Road, No.12 Xuesong Road, high tech Industrial Development Zone, Zhengzhou City, Henan Province, 450000

Patentee after: HENAN TENGYU BIOTECHNOLOGY Co.,Ltd.

Address before: 453003 No. 601 Jinsui Avenue, Xinxiang City, Henan Province

Patentee before: XINXIANG MEDICAL University

TR01 Transfer of patent right