CN106977443A - The purposes of hydroxamic acid derivs of one class O benzyls substitution and preparation method thereof and medicine - Google Patents
The purposes of hydroxamic acid derivs of one class O benzyls substitution and preparation method thereof and medicine Download PDFInfo
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Abstract
The hydroxamic acid derivs of one class O benzyls substitution, its formula(Ⅰ)For:
Description
Technical field
The present invention relates to the field of pharmacology related to tumour, and in particular to the hydroxamic acid of class O- benzyls substitution derives
The purposes of thing and preparation method thereof and medicine.
Background technology
Malignant tumour is a kind of complicated disease, has been turned at present after threat human life and health after cardiovascular and cerebrovascular disease
Second largest killer.Due to the diversity of Incidence mechanism and its characteristic for easily shifting and recurring, treat into it
For a great problem.Malignant tumour influences propagation, differentiation and the function of cell, epigenetic by a variety of heredity and the change of molecule
Modification is learned to play a significant role in tumour develops;Histone modification as epigenetics important research content,
The main acetylation including histone end, methylate, phosphorylation, ubiquitination and ADP ribosylation modification etc..Wherein histone
Deacetylase is the focus of epigenetics research, protease histone of the acetylation of histone by the mutual antagonism of a pair of functions
Acetyl transferase (Histone Acetyltransferases, HATs) and histon deacetylase (HDAC) (Histone
Deacetylases, HDACs) regulation and control.In normal cell, this pair of enzymes are in dynamic balance state, and HATs effect makes a group egg
White latter end acetylation, unfolds nucleosomal structure, activated gene transcription, and HDACs function is on the contrary, suppressor is transcribed, at present
Having proven to the occurrence and development of its dysfunction and tumour has direct relation, and the expression of many HDACs family members and activity exist
There is up-regulation to show in kinds of tumors case, such as colorectal cancer, stomach cancer, Hodgkin lymphoma, progranulocyte leukemia show
The generation development of HDACs and tumour is closely related, thus HDACs turns into one of important target enzyme that antineoplastic is studied.
HDACs inhibitor always is that, in one of focus of antineoplastic research field, wherein hydroxamic acid is mesh
The preceding more more deep class of research, such as 2006,2009 and 2015 Food and Drug Administration(FDA)Ratify respectively
The medicine Vorinostat treated for skin T cell lymphoma(SAHA), romidepsin(FK228)With for Huppert's disease
LBH589 (Panobinostat) be hydroxamic acid HDACs inhibitor.
The present invention relates to the hydroxamic acid derivs of the novel O- benzyls substitution of structure, it has obvious suppression to HDACs
Effect, while having obvious activity to leukaemia and lung cancer.
The content of the invention
It is its officinal salt, hydrate, preceding it is an object of the invention to provide the hydroxamic acid derivs of class O- benzyls substitution
Medicine or the metabolite for being metabolized formation in any form;The hydroxamic acid derivs that the present invention also provides the substitution of O- benzyls simultaneously exist
Preparation method, treats the application in the medicine of the disease mediated by histon deacetylase (HDAC).
The object of the present invention is achieved like this, the formula of the hydroxamic acid derivs of class O- benzyls substitution(Ⅰ)For:
(Ⅰ)
R is selected from hydrogen, halogen, alkyl, alkoxy, hydroxyl, cyano group, nitro in formula, wherein the alkyl, alkoxy are optionally further
Replaced by one or more selected from halogen, hydroxyl, cyano group, nitro.
It is preferred that the present invention there is formula(Ⅰ)Compound, the compound is selected from:
1- benzyloxies -3-(2- (5- methoxyl group -1H- indol-3-yls) ethyl carbamide(Ⅰ-1)
1- (3- methylbenzyloxies) -3-(2- (5- methoxyl group -1H- indol-3-yls) ethyl carbamide(Ⅰ-2)
1- (4- methylbenzyloxies) -3-(2- (5- methoxyl group -1H- indol-3-yls) ethyl carbamide(Ⅰ-3)
1- (2- fluorine benzyloxy) -3-(2- (5- methoxyl group -1H- indol-3-yls) ethyl carbamide(Ⅰ-4)
1- (3- fluorine benzyloxy) -3-(2- (5- methoxyl group -1H- indol-3-yls) ethyl carbamide(Ⅰ-5)
1- (4- fluorine benzyloxy) -3-(2- (5- methoxyl group -1H- indol-3-yls) ethyl carbamide(Ⅰ-6)
1- (2- benzyl chlorides epoxide) -3-(2- (5- methoxyl group -1H- indol-3-yls) ethyl carbamide(Ⅰ-7)
1- (3- benzyl chlorides epoxide) -3-(2- (5- methoxyl group -1H- indol-3-yls) ethyl carbamide(Ⅰ-8)
1- (4- benzyl chlorides epoxide) -3-(2- (5- methoxyl group -1H- indol-3-yls) ethyl carbamide(Ⅰ-9)
1- (4- bromo-benzyloxys) -3-(2- (5- methoxyl group -1H- indol-3-yls) ethyl carbamide(Ⅰ-10).
The compound that the present invention is provided is the hydroxamic acid derivs of new O- benzyls substitution, and it has acetylation of histone
Enzyme (HDACs) inhibitory action, thus available for the treatment of the disease relevant with this enzyme.Therefore, the present invention is related particularly to
That states has formula(Ⅰ)Compound, its officinal salt, hydrate, prodrug or the metabolite for being metabolized formation in any form
Application in the disease that treatment is mediated by acetylation of histone enzyme is prepared.
The another technical scheme that the present invention takes is:A kind of medicine for being used to treat the disease mediated by acetylation of histone enzyme
Compositions, its active ingredient at least contains the compound of above-mentioned formula, its officinal salt, hydrate, prodrug or with any
Form is metabolized the metabolite to be formed
According to the present invention, the disease of described acetylation of histone enzyme mediation includes malignant tumour, and malignant tumour includes but do not limited
In leukaemia, liver cancer, colon cancer, stomach cancer, kidney, lung cancer, breast cancer, cancer of pancreas, glioma, lymthoma, fibrosarcoma,
Oophoroma, cervical carcinoma, melanoma and prostate cancer etc..
Present invention simultaneously relates to application of the described compound in tumor is prepared.
Formula of the present invention(Ⅰ)Compound can pass through formula(Ⅱ)Compound and formula(Ⅲ)Compound react and make
It is standby:
Wherein, R such as formulas(Ⅰ)Described in.
The reaction is carried out in a kind of solvent, and the solvent is, for example, ethyl acetate, dichloromethane, chloroform, diformazan
Base formamide, tetrahydrofuran, acetone, dimethyl sulfoxide, reaction temperature are 0 DEG C of reflux temperature to solvent, and reaction uses formula(Ⅱ)
And formula(Ⅲ)Equimolar quality;Carry out in the presence of a base, described alkali includes inorganic base and organic base, described inorganic base can be with
Refer to for example, alkali carbonate class is such as sodium carbonate, potassium carbonate, Tan Suan Cesium;Alkali carbonate class such as saleratus etc.;
Alkali metal hydroxide is such as sodium hydroxide, potassium hydroxide, lithium hydroxide;Described organic base can be mentioned that such as three second
Amine, pyridine, lutidines, n-BuLi, potassium tert-butoxide etc..
The anti-HDACs activity and Anti-tumor angiogenesis of compound can be by using measure as described below in the present invention
Method is determined.
The present invention is explained in following biology testing example description.
The experimental method of actual conditions generally routinely condition or is built according to commodity manufacturer in test case of the present invention
The condition of view.The unreceipted reagent specifically originated, is the common agents of market purchase.
The compounds of this invention of test case 1 can be surveyed to HDACs inhibitory activity by using assay method as described below
It is fixed:
By HeLa cell extracts and Buffer according to 1:2 volume ratio is diluted;With Buffer by diluted chemical compound into 5 ×
Final concentration;Substrate is diluted into 50 times (1mM, 2 × final concentration) with Buffer;Color de LysTM Developer detection reagents
Configured using in preceding 30 min:(e.g., Color de LysTM Developer are diluted 20 times with the Buffer of precooling first
50 μ L add 950 μ L Buffer), TSA is then diluted 100 times with the developer solution of Fresh;In 96 orifice plates, often
Hole is separately added into enzyme and 10 μ L testing compounds after 15 μ L dilutions, and 37 DEG C of 5 min of incubation add 25 μ L substrate (blank well
Not enzyme-added and compound, plus Buffer are replaced;Control wells compound is replaced with Buffer), 96 orifice plates are placed in 37 DEG C of shaking tables
It is incubated 30 min;The Color de LysTM Developer that 50 μ L are now prepared are added per hole, continue to be incubated 30 min;ELIASA
Ultraviolet light absorption angle value under the conditions of 405 nm of upper measure, by determining 405 nm absorbances of control group and target compound group,
The inhibiting rate of compound can be calculated and IC is tried to achieve50Value, the results are shown in Table 1.
Table 1:HDACs inhibitory activity
Compound number | IC50 (µM) | Compound number | IC50 (µM) |
Ⅰ-1 | 0.95 ±0.03 | Ⅰ-7 | 6.84±1.10 |
Ⅰ-2 | 2.01±0.41 | Ⅰ-8 | 1.49±0.14 |
Ⅰ-3 | 1.23±0.17 | Ⅰ-9 | 4.52±0.66 |
Ⅰ-4 | 7.38±0.99 | Ⅰ-10 | 0.21±0.01 |
Ⅰ-5 | 0.37±0.02 | SAHA (control drug) | 1.65±0.22 |
Ⅰ-6 | 8.63±1.02 |
Conclusion:All compounds of the present invention have obvious inhibitory action to HDACs, wherein I -1, I -3, I -5, I -8, I -10 pair
HDACs inhibitory action is better than control drug SAHA.
The antitumor activity of compound can be determined using following assay method in the present invention of test case 2:
Every kind of compound is using being preceding dissolved in DMSO, then with the RPMI-1640 containing 1%DMSO and 5% fresh calf serum
It is diluted to 5~6 concentration gradients.The tumour cell in exponential phase is adjusted to suitable cell density, be inoculated in 96 holes
In culture plate, while adding dilute liquid medicine or the μ l/ holes of negative controls 10, five multiple holes are all provided with.In addition, separately being set on every piece of culture plate
Two zeroing holes.96 orifice plates are moved into 37 DEG C, 5%CO2, saturated humidity incubator in, culture 2d after, add 5mg/ml
The μ l/ holes of MTT test solutions 20, in 37 DEG C, 5%CO2, continue under the conditions of saturated humidity to cultivate after 4h, terminate culture.Then three are added
Join the μ l/ holes of lysate 100, stood overnight in 37 DEG C.Returned to zero, surveyed on ELIASA at 570 nm wavelength with blank control group
Fixed each hole absorbance OD values.IC is calculated according to result50.It the results are shown in Table 2
Table 2:Activity of the preferred compound to tumour cell
Conclusion:The compounds of this invention has obvious activity to leukaemia and colon cancer.
Embodiment
With reference to embodiment, the invention will be further described.It should be noted that following embodiments are only for
It is bright, and it is not intended to limit the present invention.The various change that those skilled in the art are made according to the teachings of the present invention just exists
Within protection domain required by the application claim.
Embodiment 1
N-[2-(5- methoxyl group -3- indoles)Ethyl]-carbamic acid -4- nitro phenyl esters(Ⅱ)
5- methoxytryptamines 19.02g (0.1 mol) is suspended in the dry ml of dichloromethane 200 and the ml (0.2 of pyridine 8.00
Mol in), ice bath stirring.Weigh the g of 4- nitros phenyl chloroformate 20.16 (0.1 mol) and be pre-dissolved in 100 ml drying dichloros
In methane, it is slowly added dropwise to above-mentioned suspension, the h of ice bath stirring reaction 4, reaction solution is washed with water (3 × 150 ml), through nothing
After water magnesium sulfate is dried, decompression suction filtration obtains clear yellow viscous thing, adds the dissolving of 100ml ethanol, and refrigerator crystallization 4h has a large amount of solids to analyse
Go out, filter, and washed with ether, put and dried under infrared lamp, obtain yellow powdery solid, weigh as 28.01 g, yield
167~170 DEG C of 78.90 %, mp..1H NMR (600 MHz, CDCl3 )δ3.85(s, 3H, CH3) ;5.19(s,1H,
NH);7.97(s,1H, NH);3.03(t, J = 6.6 Hz,2H, CH2);3.62(q, J = 6.6 Hz,2H, CH2);
8.22(m, 2H, ArH); 7.21(m, 3H, ArH);7.06(d, J = 2.4 Hz, 2H, ArH);7.02(m, 1H,
ArH)。 IR (KBr) cm-1:(C=O) the ESI-MS of 3400.3 (NH), 3305.8 (NH), 1722.3: 378.20 [M+
Na]+。
Embodiment 2
O- benzyl-hydroxylamine hydrochloride(Ⅲ-1)
Will be equipped with 150 ml refine absolute ethyl alcohol round-bottomed flask be placed in ice bath, after weigh 7.00 g (0.3 mol) metal
Sodium, puts into round-bottomed flask in batches, and is stirred continuously.After after sodium all dissolving, by 21.93 g (0.3 mol) acetoxime
It is pre-dissolved in 100 ml to refine in absolute ethyl alcohol, is added drop-wise in alcohol sodium solution, and 2 h are stirred at room temperature.Measure benzyl chloride 34.60
Ml (37.97 g, 0.3 mol), is slowly dropped in reaction mixture, is stirred at room temperature after 6 h, has a large amount of white solids to give birth to
Into, add 30 ml water quenchings and go out, extracted with ml × 3 of ether 150,3 lurid extracts of merging, through anhydrous slufuric acid
Suction filtration after magnesium is dried, filtrate obtains yellow oily liquid 1a after air-distillation, revolving.The yellow oily liquid 1a of gained is delayed
Slowly it is added drop-wise in 60 ml concentrated hydrochloric acids, is stirred overnight at room temperature.Revolving lets cool rear suction filtration to there is a large amount of white solids to separate out, and filter cake is used
Appropriate absolute ethyl alcohol and ethyl acetate are alternately washed, and disposing mother liquor carries out secondary crystallization with method, merges the solid collected twice, puts
Dried under infrared lamp, obtain the g of white solid 23.46,204~205 DEG C of yield 49.17 %, mp..
Embodiment 3
1- benzyloxies -3-(2- (5- methoxyl group -1H- indol-3-yls) ethyl carbamide(Ⅰ-1)
O- benzyls-g of hydroxylamine hydrochloride 15.96 (0.1 mol) is suspended in the dichloromethane and 27.88 ml of 200 ml dryings
In (0.2 mol) triethylamine.Weigh N- [2-(5- methoxyl group -3- indoles)Ethyl]-the g of carbamic acid -4- nitros phenyl ester 35.50
(0.1 mol) is pre-dissolved in 200 ml dry methylene chlorides, is added in above-mentioned suspension, after 45 DEG C of h of stirring reaction 6, successively
With 1 M HCl (200 ml), H2O (2×200 ml )、1 M NaHCO3 (200 ml)、H2O (2 × 200 ml) is washed,
Organic phase crosses post, obtains white solid (slightly light yellow), puts and is weighed after being dried under infrared lamp as 21.22 g, yield 62.59
89~92 DEG C of %, mp..1H NMR (600 MHz, CDCl3 ) δ3.87(s, 3H, CH3) ;5.75(s,1H, NH);
7.93(s,1H, NH);2.92(t, J = 6.6 Hz,2H, CH2);3.55(q, J = 6.6 Hz,2H, CH2);4.60(s,
2H, CH2);7.30(m, 4H, ArH);7.17(m, 2H, ArH);7.24(d, J = 2.4 Hz, 1H, ArH);7.06
(t, J = 9.8 Hz, 1H, ArH);6.98(s, 1H, ArH);6.90(m, 1H, ArH).13C NMR (151 MHz,
DMSO) δ 160.13;153.46;136.97;131.90;129.13;128.45;128.09;123.73;112.45;
112.03;111.52;100.78;77.72;55.83;40.56;26.24;IR(KBr) cm-1 3419.6(NH) ,3195.8
(NH), 1651.0(C=O)。HRMS-ESI: 340.1661 ([M+H]+, Calcd for C19H22N3O3: 340.1662)。
Embodiment 4
1- (3- methylbenzyloxies) -3-(2- (5- methoxyl group -1H- indol-3-yls) ethyl carbamide(Ⅰ-2)
Synthetic method obtains the g of white solid 23.81,106~108 DEG C of yield 67.45 %, mp. with I -1.1H NMR (600
MHz, CDCl3 ) δ3.87(s, 3H, CH3) ; 2.32(s, 3H, CH3) ;5.76(s,1H, NH);7.88(s,1H,
NH);2.92(t, J = 6.6 Hz,2H, CH2);3.56(q, J = 6.6 Hz,2H, CH2);4.60(s,2H, CH2);
7.26(s, 1H, ArH);7.19(s ,1H, ArH); 7.07(m, 2H, ArH);6.98(s, J = 8.0Hz, 1H,
ArH); 6.88(q, J = 2.4 Hz,2H, ArH).13C NMR (151 MHz, CDCl3) δ 154.13;138.41;
135.15;131.48;129.84;129.53;128.59;127.83;126.12;122.75;112.79;112.52;111.95;
100.57;78.60;55.92;39.85;25.61;21.30;IR(KBr) cm-13435.0 (NH), 3074.3 (NH),
1624.0(C=O)。HRMS-ESI: 354.1803 ( [M+H]+, Calcd for C20H24N3O3: 354.1818)。
Embodiment 5
1- (4- methylbenzyloxies) -3-(2- (5- methoxyl group -1H- indol-3-yls) ethyl carbamide(Ⅰ-3)
Synthetic method obtains the g of white solid 24.99,103~106 DEG C of yield 70.80 %, mp. with I -1.1H NMR (600
MHz, CDCl3 ) δ3.87(s, 3H, CH3) ;5.74(s,1H, NH);7.94(s,1H, NH);2.90(t, J = 6.6
Hz,2H, CH2);3.54(q, J = 6.6 Hz,2H, CH2);4.60(s,2H, CH2);7.29(s, 1H, ArH);7.06
(dt,J=7.2Hz, 5H, ArH); 6.99(s, 1H, ArH);6.89(m,1H, ArH).13C NMR (151 MHz,
DMSO) δ160.12;153.46;137.72;133.88;131.92;129.27;129.22;128.08;123.74;112.45;
112.02;111.52;100.78;77.61;55.83;40.56;26.23;21.27;IR(KBr) cm-1(3415.7 NH),
3319.3 (NH), 3197.8 (NH), 1596.9 (C=O).HRMS-ESI: 354.1796 ( [M+H]+, Calcd for
C20H24N3O3: 354.1818)。
Embodiment 6
1- (2- fluorine benzyloxy) -3-(2- (5- methoxyl group -1H- indol-3-yls) ethyl carbamide(Ⅰ-4)
Synthetic method obtains the g of white solid 22.11,156~159 DEG C of yield 61.92 %, mp. with I -1.1H NMR (600
MHz, CDCl3 ) δ3.87(s, 3H, CH3) ;5.24(s,1H, NH);7.87(s,1H, NH);2.97(t, J = 6.6
Hz,2H, CH2);3.60(q, J = 6.6 Hz,2H, CH2);4.77(s,2H, CH2);7.41(s, 1H, ArH);7.11
(s, 1H, ArH);7.24(d, J = 2.4 Hz, 1H, ArH);7.05(d, J = 2.4 Hz, 2H, ArH); 6.92
(s, 1H, ArH);6.86(q, J = 2.4 Hz,1H, ArH);6.05 (s, 1H,ArH).13C NMR (151 MHz,
DMSO) δ 153.44;131.89;131.09;128.06;124.62;123.68;115.56;115.42;112.42;
112.07;111.51;100.79;55.84;48.00;40.62;40.55;26.39;IR(KBr) cm-13411.8(NH) ,
3062.7(NH), 1215.1(CF), 1539.1(C=O)。HRMS-ESI:358.1552 ( [M+H]+, Calcd for
C19H21N3O3F: 358.1567)。
Embodiment 7
1- (3- fluorine benzyloxy) -3-(2- (5- methoxyl group -1H- indol-3-yls) ethyl carbamide(Ⅰ-5)
Synthetic method obtains the g of white solid 22.58,98~101 DEG C of yield 63.25 %, mp. with I -1.1H NMR (600
MHz, CDCl3 ) δ3.87(s, 3H, CH3) ;5.74(s,1H, NH);7.98(s,1H, NH);2.93(t, J = 6.6
Hz,2H, CH2);3.57(q, J = 6.6 Hz,2H, CH2);4.60(s,2H, CH2);7.29(s, 1H, ArH);7.27
(s, 1H, ArH);7.24(d, J = 2.4 Hz, 1H, ArH);7.05(d, J = 2.4 Hz, 1H, ArH);6.99
(s, 1H, ArH);6.94(d, J = 7.2Hz,1H, ArH);6.88(q, J = 2.4 Hz,2H, ArH);7.28 (d,
J = 7.8 Hz, 2H,ArH); 7.17 (d, J = 7.8 Hz, 2H,ArH)。13C NMR (151 MHz, CDCl3) δ
154.15;131.51;130.28;130.23;127.82;124.54;122.74;115.83;115.74;115.69;115.61;
112.71;112.56;112.01;100.56;77.54;55.91;39.86;25.51;IR(KBr) cm-13411.8(NH) ,
3199.7 (NH), 3064.7 (NH), 1220.9 (CCl), 1651.0 (C=O).HRMS-ESI: 358.1568 ( [M+H]+,
Calcd for C19H21N3O3F: 358.1567)。
Embodiment 8
1- (4- fluorine benzyloxy) -3-(2- (5- methoxyl group -1H- indol-3-yls) ethyl carbamide(Ⅰ-6)
Synthetic method obtains the g of white solid 25.06,138~140 DEG C of yield 70.20 %, mp. with I -1.1H NMR (600
MHz, CDCl3 ) δ3.87(s, 3H, CH3) ;5.73(s,1H, NH);7.96(s,1H, NH);2.93(t, J = 6.6
Hz,2H, CH2);3.57(q, J = 6.6 Hz,2H, CH2);4.60(s,2H, CH2);7.29(s, 1H, ArH);7.27
(s, 1H, ArH);7.24(d, J = 2.4 Hz, 1H, ArH);7.05(d, J = 2.4 Hz, 1H, ArH);7.02
(m, 1H, ArH);6.99(s, 1H, ArH);6.95(d, J = 7.5Hz,1H, ArH);6.88(q, J = 2.4 Hz,
2H, ArH)。13C NMR (151 MHz, DMSO) δ 160.10;153.46;133.24;133.22;131.90;131.45;
131.39;128.09;123.73;115.50;115.35;112.46;112.02;111.53;100.77;76.84;55.83;
40.56;26.23;IR(KBr) cm-1 3413.8 (NH), 3186.2 (NH), 3068.5 (NH), 1211.2 (CF), 1604.7
(C=O)。HRMS-ESI: 358.1549([M+H]+, Calcd for C19H21N3O3F: 358.1567)。
Embodiment 9
1- (2- benzyl chlorides epoxide) -3-(2- (5- methoxyl group -1H- indol-3-yls) ethyl carbamide(Ⅰ-7)
Synthetic method obtains the g of white solid 22.57,108~110 DEG C of yield 60.44 %, mp. with I -1.1H NMR (600
MHz, CDCl3 ) δ3.87(s, 3H, CH3) ;δ3.87(s, 3H, CH3) ;5.74(s,1H, NH);8.00(s,1H,
NH);2.93(t, J = 6.6 Hz,2H, CH2);3.57(q, J = 6.6 Hz,2H, CH2);4.58(s,2H, CH2);
7.29(m, 2H, ArH);7.20(m, 2H, ArH);7.03(m, 2H, ArH); 6.99(s, 1H, ArH); 6.88(q,
J = 2.4 Hz,1H, ArH).13C NMR (151 MHz, CDCl3) δ 159.66;154.11;137.26;131.51;
129.96;128.99;128.88;127.82;127.10;122.76;112.68;122.52;112.03;100.58;77.57;
58.48;55.93;39.83;25.50;IR(KBr) cm-13408.0 (NH), 3195.8 (NH), 3057.0 (NH), 709.7
(CCl), 1633.6(C=O)。HRMS-ESI: 374.1267 ( [M+H]+, Calcd for C19H21N3O3Cl:
374.1271)
Embodiment 10
1- (3- benzyl chlorides epoxide) -3-(2- (5- methoxyl group -1H- indol-3-yls) ethyl carbamide(Ⅰ-8)
Synthetic method obtains the g of white solid 24.94,105~107 DEG C of yield 66.77 %, mp. with I -1.1H NMR (600
MHz, CDCl3 ) δ3.87(s, 3H, CH3) ;5.74(s,1H, NH);7.97(s,1H, NH);2.93(t, J = 6.6
Hz,2H, CH2);3.57(q, J = 6.6 Hz,2H, CH2);4.58(s,2H, CH2);7.30(m, 2H, ArH);7.21
(m, 2H, ArH);7.05(m, 2H, ArH);7.05(d, J = 2.4 Hz, 1H, ArH);6.99(s, 1H, ArH);
6.88(q, J = 2.4 Hz,2H, ArH)。13C NMR (151 MHz, DMSO) δ 160.10;153.51;139.68;
133.41;131.95;130.51;128.76;128.29;128.14;127.58;123.69;112.44;112.11;111.51;
100.92;76.73;55.91;40.52;26.25;IR(KBr) cm-13409.9 (NH), 3305.8 (NH), 3203.5 (NH),
3055.0 (ArH), 707.0 (CCl), 1633.6 (C=O).HRMS-ESI: 374.1263 ( [M+H]+, Calcd for
C19H21N3O3Cl: 374.1271)。
Embodiment 11
1- (4- benzyl chlorides epoxide) -3-(2- (5- methoxyl group -1H- indol-3-yls) ethyl carbamide(Ⅰ-9)
Synthetic method obtains the g of white solid 22.34, yield 59.81%, 135~138 DEG C of mp. with I -1.1H NMR (600
MHz, CDCl3 ) δ3.87(s, 3H, CH3) ;5.30(s,1H, NH);7.94(s,1H, NH);2.93(t, J = 6.6
Hz,2H, CH2);3.55(q, J = 6.6 Hz,2H, CH2);4.57(s,2H, CH2);7.30(s, 1H, ArH);7.26
(s, 2H, ArH); 6.99(s, 1H, ArH);6.90(m,,1H, ArH);7.05(m,3H, ArH);13C NMR (151
MHz, DMSO) δ 160.09;153.46;136.06;133.06;131.90;130.98;128.63;128.09;123.73;
112.45;112.03;111.52;100.77;76.73;55.83;40.56;26.22;IR(KBr) cm-13427.3(NH) ,
3408.8 (NH), 3357.8 (NH), 3078 (ArH), 709.8 (CCl), 1614.3 (C=O).HRMS-ESI: 374.1282
([M+H]+, Calcd for C19H21N3O3Cl: 374.1271)。
Embodiment 12
1- (4- bromo-benzyloxys) -3-(2- (5- methoxyl group -1H- indol-3-yls) ethyl carbamide(Ⅰ-10)
Synthetic method obtains the g of white solid 25.05,114~115 DEG C of yield 59.93 %, mp. with I -1.1H NMR (600
MHz, CDCl3 ) δ3.87(s, 3H, CH3) ;5.68(s,1H, NH);7.94(s,1H, NH);2.93(t, J = 6.6
Hz,2H, CH2);3.55(q, J = 6.6 Hz,2H, CH2);4.55(s,2H, CH2);7.39(m, 2H, ArH);7.26
(s, 1H, ArH); 7.05(d, J = 2.4 Hz, 1H, ArH);6.89(d, J = 2.4Hz ,3H, ArH);6.99
(d, J = 8.5Hz,1H, ArH)。13C NMR (151 MHz, CDCl3) δ 154.18;131.80;130.72;122.76;
112.77;112.59;111.96;100.59;77.66;55.92;39.88;25.48;IR(KBr) cm-13413.8(NH) ,
3319.3 (NH), 3192.0 (NH), 544.7 (CBr), 1654.8 (C=O).HRMS-ESI: 420.0711 ([M+ H]+,
Calcd for C19H21N3O3Br: 420.0702)。
The present invention is described in detail above, its object is to allow the personnel for being familiar with this art to understand this
The content of invention is simultaneously carried out, and it is not intended to limit the scope of the present invention, all Spirit Essence institutes according to the present invention
The equivalent change or modification done, should all cover within the scope of the present invention.
Claims (3)
1. the hydroxamic acid derivs of class O- benzyls substitution, its formula(Ⅰ)For:
(Ⅰ)
Formula(Ⅰ)In:
R is selected from hydrogen, halogen, alkyl, alkoxy, hydroxyl, cyano group, nitro, wherein the alkyl, alkoxy are optionally further by one
Individual or multiple halogen, hydroxyl, cyano group, nitros of being selected from are replaced.
2. the hydroxamic acid derivs that a class O- benzyls replace according to claim 1, its officinal salt, hydrate, prodrug
Or the metabolite of formation is metabolized in any form, the compound is selected from:
Benzyloxy -3-(2- (5- methoxyl group -1H- indol-3-yls) ethyl carbamide(Ⅰ-1)
1- (3- methylbenzyloxies) -3-(2- (5- methoxyl group -1H- indol-3-yls) ethyl carbamide(Ⅰ-2)
1- (4- methylbenzyloxies) -3-(2- (5- methoxyl group -1H- indol-3-yls) ethyl carbamide(Ⅰ-3)
1- (2- fluorine benzyloxy) -3-(2- (5- methoxyl group -1H- indol-3-yls) ethyl carbamide(Ⅰ-4)
1- (3- fluorine benzyloxy) -3-(2- (5- methoxyl group -1H- indol-3-yls) ethyl carbamide(Ⅰ-5)
1- (4- fluorine benzyloxy) -3-(2- (5- methoxyl group -1H- indol-3-yls) ethyl carbamide(Ⅰ-6)
1- (2- benzyl chlorides epoxide) -3-(2- (5- methoxyl group -1H- indol-3-yls) ethyl carbamide(Ⅰ-7)
1- (3- benzyl chlorides epoxide) -3-(2- (5- methoxyl group -1H- indol-3-yls) ethyl carbamide(Ⅰ-8)
1- (4- benzyl chlorides epoxide) -3-(2- (5- methoxyl group -1H- indol-3-yls) ethyl carbamide(Ⅰ-9)
1- (4- bromo-benzyloxys) -3-(2- (5- methoxyl group -1H- indol-3-yls) ethyl carbamide(Ⅰ-10).
3. according to claim 1 a class O- benzyls substitution hydroxamic acid derivs medicine purposes, it is characterized in that water
Compound, prodrug or medicine of the metabolite in the disease for preparing the enzyme mediation for the treatment of acetylation of histone for being metabolized formation in any form
Application in thing.
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CN109369449A (en) * | 2018-12-25 | 2019-02-22 | 浙江工业大学 | A kind of method of synthesizing oxime ether |
WO2019049061A1 (en) * | 2017-09-07 | 2019-03-14 | Glaxosmithkline Intellectual Property Development Limited | 5-(1 h-benzo[d]imidazo-2-yl)-pyridin-2-amine and 5-(3h-imidazo[4,5-b]pyridin-6-yl)-pyridin-2-amine derivatives as c-myc and p300/cbp histone acetyltransferase inhibitors for treating cancer |
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WO2019049061A1 (en) * | 2017-09-07 | 2019-03-14 | Glaxosmithkline Intellectual Property Development Limited | 5-(1 h-benzo[d]imidazo-2-yl)-pyridin-2-amine and 5-(3h-imidazo[4,5-b]pyridin-6-yl)-pyridin-2-amine derivatives as c-myc and p300/cbp histone acetyltransferase inhibitors for treating cancer |
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CN109956884A (en) * | 2019-04-28 | 2019-07-02 | 曹文兵 | A kind of preparation method of Phenylmethoxyamine hydrochloride |
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CN114181107A (en) * | 2021-11-08 | 2022-03-15 | 宁波睿田科技有限公司 | Synthesis method of benzyloxy amine hydrochloride |
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