CN106977425A - Hydroxamic acid derivs with dnmt rna and histon deacetylase (HDAC) inhibitory activity and preparation method and application - Google Patents
Hydroxamic acid derivs with dnmt rna and histon deacetylase (HDAC) inhibitory activity and preparation method and application Download PDFInfo
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- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C259/00—Compounds containing carboxyl groups, an oxygen atom of a carboxyl group being replaced by a nitrogen atom, this nitrogen atom being further bound to an oxygen atom and not being part of nitro or nitroso groups
- C07C259/04—Compounds containing carboxyl groups, an oxygen atom of a carboxyl group being replaced by a nitrogen atom, this nitrogen atom being further bound to an oxygen atom and not being part of nitro or nitroso groups without replacement of the other oxygen atom of the carboxyl group, e.g. hydroxamic acids
- C07C259/06—Compounds containing carboxyl groups, an oxygen atom of a carboxyl group being replaced by a nitrogen atom, this nitrogen atom being further bound to an oxygen atom and not being part of nitro or nitroso groups without replacement of the other oxygen atom of the carboxyl group, e.g. hydroxamic acids having carbon atoms of hydroxamic groups bound to hydrogen atoms or to acyclic carbon atoms
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- 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
- C07D213/60—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 hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D213/78—Carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen, e.g. ester or nitrile radicals
- C07D213/81—Amides; Imides
- C07D213/82—Amides; Imides in position 3
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- C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
- C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
- C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D215/48—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen
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- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D235/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings
- C07D235/02—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings condensed with carbocyclic rings or ring systems
- C07D235/04—Benzimidazoles; Hydrogenated benzimidazoles
- C07D235/06—Benzimidazoles; Hydrogenated benzimidazoles with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached in position 2
- C07D235/08—Radicals containing only hydrogen and carbon atoms
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- C07D317/00—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms
- C07D317/08—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3
- C07D317/44—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3 ortho- or peri-condensed with carbocyclic rings or ring systems
- C07D317/46—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3 ortho- or peri-condensed with carbocyclic rings or ring systems condensed with one six-membered ring
- C07D317/48—Methylenedioxybenzenes or hydrogenated methylenedioxybenzenes, unsubstituted on the hetero ring
- C07D317/62—Methylenedioxybenzenes or hydrogenated methylenedioxybenzenes, unsubstituted on the hetero ring with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to atoms of the carbocyclic ring
- C07D317/68—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen
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- C07D319/10—1,4-Dioxanes; Hydrogenated 1,4-dioxanes
- C07D319/14—1,4-Dioxanes; Hydrogenated 1,4-dioxanes condensed with carbocyclic rings or ring systems
- C07D319/16—1,4-Dioxanes; Hydrogenated 1,4-dioxanes condensed with carbocyclic rings or ring systems condensed with one six-membered ring
- C07D319/18—Ethylenedioxybenzenes, not substituted on the hetero ring
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- C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
- C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
- C07D471/04—Ortho-condensed systems
Abstract
The present invention relates to a kind of hydroxamic acid derivs with dnmt rna and histon deacetylase (HDAC) inhibitory activity and preparation method and application; a kind of hydroxamic acid derivs or its pharmaceutically acceptable salt, hydroxamic acid derivs structural formula is as shown in formula I：Wherein, Ar is aromatic group, the aromatic group be selected from substitution or non-substituted phenyl ring, substitution or non-substituted aromatic heterocycle, substitution or non-substituted benzheterocycle；Replace or non-substituted aromatic heterocycle and heterocycle；N=1,2,3,4,5 or 6；L1Link position be phenyl ring ortho position, meta or para position；L1For saturation or unsaturated carbon chains.
Description
Technical field
The invention belongs to field of medicaments, and in particular to there is one kind dnmt rna and histon deacetylase (HDAC) to press down
Make hydroxamic acid derivs of activity and preparation method and application.
Background technology
Cancer is first cause of disease for causing human death now, and the antineoplastic for researching and developing high-efficiency low-toxicity is extremely urgent.It is swollen
The occurrence and development of knurl were both closely related with gene unconventionality, and also changing with epigenetic has close relation.With gene unconventionality
(amplification, transposition, deletion and the point mutation of such as oncogene or tumor suppressor gene) is different, and the change of epigenetic is not related to DNA sequence dna
Change, the hereditary information of parent can be kept in cell division, but can be taken a turn for the worse under certain condition, make malignant cell group
Body is changed into normal cell.Therefore the enzyme that regulating and controlling effect is played in epigenetic is considered as new the one of antineoplastic research and development
For target spot.
Dnmt rna (DNA methyltransferases, DNMTs) and histon deacetylase (HDAC) (Histone
Deacetylases, HDACs) catalytic dna respectively the deacetylation methylated with histone, be the important regulating and controlling of epigenetic
Mode.High expression can silence tumor suppressor gene, the occurrence and development of promotion tumour in cell by DNMTs and HDACs.It is substantial amounts of
DNMTs inhibitor and HDACs inhibitor are developed to treat tumour, and some DNMTs inhibitor and HDACs inhibitor are facing
Good antitumous effect is shown in bed, two DNMTs inhibitor (azacitidine, Decitabine) and five are had at present
HDACs inhibitor (Vorinostat, Romidepsin, Belinostat, Panobinostat, Chidamide) is listed.
DNA methylation, DNA methylase inhibitor and chromatin remodeling have closely contact in physiological function, together shadow
Ring the expression of tumor suppressor gene.DNMTs and HDACs can also be influenced each other by direct or indirect mode.On the one hand, research is found
When alone DNMTs or HDACs inhibitor, the high expression of another enzyme may still lead to the silence of tumour tumor suppressor gene, such
Compensatory mechanism causes tumour cell to produce drug resistance, reduces therapeutic effect.On the other hand, clinical research shows low dosage
DNMT inhibitor and hdac inhibitor drug combination have obvious cooperative effect.Therefore DNMTs and HDACs suppression is targetted simultaneously
Preparation can may more effectively be such that the tumor suppressor gene of silence expresses again, and make tumour cell be more difficult to produce drug resistance, but mesh
The preceding also report without this respect.
The content of the invention
An object of the present invention is to provide the hydroxamic acid Mutiple Targets that a class has DNMTs and HDACs inhibitory activity
Inhibitor and preparation method thereof.
Hydroxamic acid Mutiple Targets inhibitor provided by the present invention, its structural formula is as shown in formula I.
In above-mentioned Formulas I, Ar is aromatic group, the aromatic group be selected from substitution or non-substituted phenyl ring, substitution or
Non-substituted aromatic heterocycle, substitution or non-substituted benzheterocycle, substitution or non-substituted aromatic heterocycle and heterocycle；
Preferably, the heteroaromatic be selected from 4 yuan, 5 yuan, 6 yuan or 7 yuan heteroaromatics, heterocycle comprising 1,2 or 3 hetero atoms,
Hetero atom is independently selected from N, S, O；
The heteroaromatic is selected from pyridine radicals, pyridinyl-N-oxide, pyrimidine radicals, pyridazinyl, furyl, thienyl, thiazole
Base, imidazole radicals, pyranose, pyrroles；
The benzheterocycle is selected from quinoline, isoquinolyl, purine radicals, indyl, benzimidazole, pyrrolopyridine, dihydro
Ben Bing bioxin, benzodioxole；
Substituent on aromatic group is 1-5, preferably 1,2,3,4 or 5；Alkyl of the substituent selected from C1-C6,
C1-C6 alkenyl, C1-C6 alkynyl, hydroxyl, nitro, methoxyl group, trifluoromethyl, trifluoromethoxy, amino, acrylamido,
Cyano group, fluorine-based, chloro, bromo, iodo；
Preferably, the aromatic group is selected from
N=1,2,3,4,5 or 6；
L1Link position be phenyl ring ortho position, meta or para position；L1For carbon key or alkyl chain, including but not limited to methylene
Base, ethylene group, vinyl, acetenyl.
Compound pharmaceutically acceptable salt falls within protection scope of the present invention shown in above-mentioned Formulas I.
Wherein, the pharmaceutically acceptable salt is inorganic acid salt or acylate.
The inorganic acid salt is selected from the salt of any one following inorganic acid formation：Hydrochloric acid, sulfuric acid or phosphoric acid.
The acylate is selected from the salt of any one following organic acid formation：Acetic acid, trifluoroacetic acid, malonic acid, lemon
Acid and p-methyl benzenesulfonic acid.
Hydroxamic acid derivs shown in above-mentioned Formulas I be preferably it is following any one：
Hydroxamic acid compound shown in above-mentioned Formulas I is prepared by the method comprising the following steps；
1) under condensing agent effect, the compound shown in the compound and formula III shown in Formula II is carried out to react the formula of obtaining
Compound shown in IV；Or the compound shown in Formula II with thionyl chloride, oxalyl chloride or POCl3 is prepared into corresponding acyl
After chlorine derivative the compound obtained shown in formula IV is reacted with the compound progress shown in formula III；
Ar, n or L in Formula II, III or IV1Ar, n or L corresponding with Formulas I1Definition it is identical；
In formula III, R is C1-C4 alkyl.
2) compound shown in formula IV and azanol or hydroxylamine hydrochloride are reacted in alkaline solution, obtains compound shown in Formulas I.
Above method step 1) in, the condensing agent is selected from following at least one：BTA-N, N, N', N'- tetramethyl
Base urea hexafluorophosphoric acid ester N, N'- carbonyl dimidazoles, dicyclohexylcarbodiimide, DIC, 1- (3- dimethylamino
Propyl group) -3- ethyl carbodiimides etc..
The step 1) reaction carry out in organic solvent, the organic solvent be selected from dimethylformamide, dimethyl
One or more in acetamide, chloroform, dichloromethane, acetone, tetrahydrofuran, acetonitrile etc..
Step 1) compound shown in the condensing agent and Formula II, the mol ratio of the compound shown in formula III can be successively
For 1-4:1-2:1-4, concretely 1.5:1:1.1.
The step 1) reaction reaction temperature be 20-80 DEG C, the reaction time be 3-12 hours.
Above method step 2) in, the alkali is selected from ammoniacal liquor, triethylamine, diisopropyl ethyl amine, sodium hydroxide, hydroxide
One or more in potassium, sodium methoxide, caustic alcohol, sodium tert-butoxide, potassium tert-butoxide etc..
The step 2) reaction carried out in the aqueous solution or organic solvent, organic solvent be selected from dimethylformamide, chlorine
One or more in imitative, dichloromethane, methanol, ethanol, acetone, tetrahydrofuran, acetonitrile etc..
Compound shown in formula IV is 1 with azanol or hydroxylamine hydrochloride, the mol ratio of alkali reaction:1-10:1-20, concretely 1:
5:5。
The step 2) reaction reaction temperature be 20-80 DEG C, the reaction time be 0.5-10 hours；
Compound prepared by the present invention passes through high resolution mass spectrum, and nuclear magnetic resonance, fusing point etc. is tested, it was demonstrated that prepared chemical combination
Thing is correct, is compound shown in formula I.
It is also another object of the present invention to provide the application of compound and its pharmaceutically acceptable salt shown in formula I.
Compound shown in formula I or the purposes of its pharmaceutically acceptable salt are its applications at following aspects：
1) application in dnmt rna and/or histon deacetylase (HDAC) inhibitor is prepared；
2) application in eucaryote tumor cell proliferation inhibitor is prepared；
3) application in prevention and/or tumor is prepared.
The dnmt rna (DNMTs) be included in mammalian cell known hypotype (DNMT1, DNMT3A,
DNMT3B)；The histon deacetylase (HDAC) (HDACs) is included in mammalian cell known hypotype, mainly include but
It is not limited to HDAC1, HDAC2, HDAC3, HDAC8, HDAC4, HDAC5, HDAC7, HDAC9, HDAC6, HDAC10, HDAC11.
The eucaryote is mammal；The tumour cell is cancer cell；The cancer cell be leukaemia cancer cell,
Breast cancer cell, liver cancer cells, pancreatic cancer cell, lung carcinoma cell, brain cancer cell, ovarian cancer cell, uterine cancer cells, carcinoma of testis
Cell, skin cancer cell, stomach cancer cell, nasopharyngeal carcinoma cell, colon cancer cell, transitional cell bladder carcinoma cell line or rectum cancer cell；Preferably
The former leukaemia of chronic marrow of behaving and human tissue cell's lymphoma cell.
The leukaemia cancer cell is specially human chronic myelogenous leukemia (CML) cell line k562, and the lymthoma is thin
Born of the same parents are specially human tissue cell lymphoma cell U937, and the lung carcinoma cell is specially human lung carcinoma cell NCI-H520, the people
Brain glioblastoma cell is specially U251, and the black cancer cell is specially A375, and the glioblastoma cells are specially
People's glioblastoma cells A172 and human brain astrocytes blastoma cell U-118MG, the cervical cancer cell is specially
Human cervical cancer cell lines Hela, the nasopharyngeal carcinoma cell is specially human nasopharyngeal epithelioma 1 CNE-2, and the liver cancer cells are specifically people
Hepatoma H22 cells, the breast cancer cell is specially human breast cancer cell line Bcap-37 and MDA-MB-231.
The tumour is cancer；The cancer be leukaemia, lymthoma, lung cancer, black cancer, glioblastoma, cervical carcinoma,
Nasopharyngeal carcinoma, liver cancer, breast cancer, the cancer of the brain, cancer of pancreas, oophoroma, uterine cancer, carcinoma of testis, cutaneum carcinoma, stomach cancer, colon cancer, carcinoma of urinary bladder
Or the carcinoma of the rectum.
Compound shown in formula I or its pharmaceutically acceptable salt can also be used for preparing prevention and/or treatment tumour
Medicine.
The prevention and/or treatment prepared using the compound shown in formula I or its pharmaceutically acceptable salt as active ingredient is swollen
The medicine of knurl, falls within protection scope of the present invention.
The dnmt rna and/or histone prepared with compound shown in formula I or its pharmaceutically acceptable salt goes second
Deacerylase inhibitors, eucaryote tumor cell proliferation inhibitor and prevention and/or treat tumour medicine can by injection,
Injection, collunarium, eye drip, infiltration, absorption, the method that physically or chemically mediates import body such as muscle, intracutaneous, subcutaneous, vein, glued
Membrane tissue；Or imported body after other material mixings or parcel.
When needs, one or more pharmaceutically acceptable carriers can also be added in said medicine.It is described to carry
Body includes the conventional diluent of pharmaceutical field, excipient, filler, adhesive, wetting agent, disintegrant, sorbefacient, surface
Activating agent, absorption carrier, lubricant etc..
The prevention and/or tumor prepared with compound shown in formula I or its pharmaceutically acceptable salt can make
Into diversified forms such as parenteral solution, tablet, pulvis, granule, capsule, oral liquid, paste, cremes.The medicine of above-mentioned various formulations
It can be prepared according to the conventional method of pharmaceutical field.
The compound that the present invention is provided is by kinds of tumor cells system test (including leukaemia, lymphoma cell etc.)
And dnmt rna, histon deacetylase (HDAC) inhibitory activity test, it was demonstrated that compound shown in formula I is a kind of potential
There is the antineoplastic of inhibitory activity to dnmt rna and histon deacetylase (HDAC).The compound that the present invention is provided is former
Material is easy to get, and preparation method is simple, and experiment proves that it has good anticancer effect, has good in antineoplastic design research and development field
Good application prospect.
Embodiment
Below by specific embodiment, the present invention will be described, but the scope of the present invention is not limited to this.
Experimental method described in following embodiments, is the conventional method of organic synthesis unless otherwise specified；The reagent
And biomaterial, unless otherwise specified, obtain from commercial channels.
Embodiment 1
The chloro- N- of 5- (4- (3- (azanol base) -3- propionyl) phenethyl) -2- methoxy benzamides (compound 1)
Embodiment 1a
The tert-butyl group (4- bromophenylethyls) carbamate
4- Bretylium Tosylates (10g, 50mmol) are dissolved in 250 milliliters of dichloromethane, addition di-tert-butyl dicarbonate (12g,
55mmol), stir 3 hours at room temperature, successively with saturated aqueous ammonium chloride, saturated sodium bicarbonate aqueous solution, water, saturated common salt
Water washing reaction solution, organic phase is spin-dried for obtaining crude product after being dried through anhydrous magnesium sulfate.Crystallization obtains title compound (white in ether
Solid, 14.70g, 98% yield).1HNMR (400MHz, Chloroform-d) δ 7.42 (d, J=8.4Hz, 2H), 7.07 (d, J
=8.3Hz, 2H), 4.51 (s, 1H), 3.35 (br, 2H), 2.75 (t, J=7.0Hz, 2H), 1.43 (s, 9H)
Embodiment 1b
(E) -3- (4- (2- ((tertbutyloxycarbonyl) amino) ethyl) phenyl) methyl acrylate
By embodiment 1a (3.0g, 10mmol), Anhydrous potassium carbonate (2.764g, 20mmol), the triphenylphosphine two of catalytic amount two
Palladium bichloride is placed in 50ml round-bottomed flasks, add dimethylformamide (DMF) 30ml, deaeration in condenser and with after nitrogen displacement add
Methyl acrylate (1.8ml, 20mmol).Stayed overnight in 120~130 DEG C of reactions.Reaction is added water and extracted with ethyl acetate after terminating
Take.Organic phase is spin-dried for after being dried through anhydrous magnesium sulfate, and obtain after being washed with deionized water title compound (white solid,
2.53g, 83% yield).1H NMR (400MHz, Chloroform-d) δ 7.68 (d, J=16.0Hz, 1H), 7.47 (d, J=
7.8Hz, 2H), 7.22 (d, J=7.8Hz, 2H), 6.42 (d, J=16.1Hz, 1H), 4.59 (s, 1H), 3.81 (s, 3H),
(s, the 9H) of 3.43-3.31 (m, 2H), 2.82 (t, J=7.0Hz, 2H), 1.34
Embodiment 1c
3- (4- (2- ((tertbutyloxycarbonyl) amino) ethyl) phenyl) methyl propionate
Embodiment 1b (3.05g, 10mmol) is dissolved in 200ml methanol, the palladium carbon of the mass fractions of 300mg 10% is added,
Flow back 3h under the hydrogen of 2 atmospheric pressure in autoclave.Filter afterwards, rotation, which is removed, obtains title compound (in vain after filtrate
Color solid, 3.00g, 98% yield).1H NMR(400MHz,Chloroform-d)δ7.24–6.96(m,4H),4.54(s,
1H), 3.67 (s, 3H), 3.36 (d, J=6.3Hz, 2H), 2.93 (t, J=7.8Hz, 2H), 2.76 (t, J=7.0Hz, 2H),
2.70–2.55(m,2H),1.43(s,9H).
Embodiment 1d
3- (4- (2- aminoethyls) phenyl) methyl propionate
Embodiment 1c (2.54g, 8.28mmol) is dissolved in dichloromethane (40ml), trifluoroacetic acid is added dropwise under ice bath
(12ml, 165mmol), reacts at room temperature 3h afterwards.Liquid is removed with Rotary Evaporators rotation, sodium bicarbonate aqueous solution is added and with acetic acid
Ethyl ester is extracted.Organic phase removes ethyl acetate after anhydrous sodium sulfate drying, and crude product is recrystallized to give title compound in ether
Thing (faint yellow solid, 1.42g, 83% yield).1H NMR(400MHz,Chloroform-d)δ7.16–7.08(m,4H),
(m, the 2H) of 3.67 (s, 3H), 2.99-2.88 (m, 4H), 2.72 (t, J=6.9Hz, 2H), 2.64-2.60
Embodiment 1e
3- (4- (2- (the chloro- 2- methoxy benzamides bases of 5-) ethyl) phenyl) methyl propionate
By embodiment 1d (621mg, 3mmol), the chloro- benzoic acid of 2- methoxyl groups -5- (839mg, 4.5mmol), condensing agent
HBTU (2.56g, 6.75mmol) and DMAP (73mg, 0.6mmol) are dissolved in DMF, and room temperature reaction is stayed overnight.Reaction terminates rear silicon
Glue pillar layer separation obtains title compound (white solid, 844mg, 75% yield).1H NMR(400MHz,Chloroform-d)
δ 8.17 (d, J=2.8Hz, 1H), 7.81 (s, 1H), 7.36 (dd, J=8.8,2.8Hz, 1H), 7.18 (s, 4H), 6.85 (d, J
=8.8Hz, 1H), 3.75 (s, 3H), 3.72 (t, J=6.8Hz, 3H), 3.67 (s, 3H), 2.95 (t, J=7.8Hz, 2H),
2.89 (t, J=6.8Hz, 2H), 2.63 (t, J=7.8Hz, 2H)；13C NMR(101MHz,CDCl3)δ172.71,163.27,
155.35,138.12,136.56,131.60,131.40,128.46,127.91,126.15,122.42,112.19,55.49,
51.06,40.34,35.11,34.54,29.94.
Embodiment 1f
The chloro- N- of 5- (4- (3- (azanol base) -3- propionyl) phenethyl) -2- methoxy benzamides
Embodiment 1e (100mg, 0.26mmol) is added in methanol (2ml), be subsequently added into hydroxylamine hydrochloride (180mg,
2.6mmol) with sodium tert-butoxide (375mg, 3.9mmol), reaction at room temperature is stayed overnight.Reaction removes reaction dissolvent and post color after terminating
Spectrum separates to obtain title compound (faint yellow solid, 31mg, 32% yield).170~172 DEG C of fusing point,1H NMR(400MHz,
DMSO-d6) δ 10.36 (s, 1H), 8.70 (s, 1H), 8.23 (t, J=5.6Hz, 1H), 7.66 (d, J=2.8Hz, 1H), 7.50
(dd, J=8.9,2.8Hz, 1H), 7.20-7.11 (m, 5H), 3.81 (s, 3H), 3.48 (q, J=6.8Hz, 2H), 2.78 (t, J
=7.5Hz, 4H), 2.25 (t, J=7.7Hz, 2H)；13C NMR(101MHz,DMSO)δ168.15,163.33,155.63,
138.77,136.79,131.42,129.48,128.51,128.14,124.61,124.24,114.09,56.18,40.67,
34.40,33.76,30.36.HRMS (ESI) m/z calculated values [M-H] -375.1112, measured value 375.1122.
Embodiment 2
(E) the chloro- N- of -5- (4- (3- (hydroxylamino) -3- oxopropyl -1- alkenyls) phenethyl) -2- methoxy benzamides
(compound 2)
Embodiment 2a
(E) -3- (4- (2- aminoethyls) phenyl) methyl acrylate
Embodiment 1b (2.53g, 8.28mmol) is dissolved in dichloromethane (40ml), trifluoroacetic acid is added dropwise under ice bath
(12ml, 165mmol), reacts at room temperature 3h afterwards.Liquid is removed with Rotary Evaporators rotation, sodium bicarbonate aqueous solution is added and with acetic acid
Ethyl ester is extracted.Organic phase removes ethyl acetate after anhydrous sodium sulfate drying, and crude product is recrystallized to give title compound in ether
Thing (faint yellow solid, 1.15g, 67% yield).1H NMR(400MHz,DMSO-d6)δ7.75(br,2H),7.74–7.60(m,
3H), 7.32 (d, J=8.0Hz, 2H), 6.64 (d, J=16.0Hz, 1H), 3.73 (s, 3H), 3.06 (t, J=7.8Hz, 1H),
2.88 (t, J=7.9Hz, 2H)；13C NMR(101MHz,DMSO)δ166.57,144.11,139.98,132.49,129.19,
128.52,117.37,51.34,33.12,33.05.
Embodiment 2b
(E) -3- (4- (2- (the chloro- 2- methoxy benzamides of 5-) ethyl) phenyl) methyl acrylate
By embodiment 2a (615mg, 3mmol), the chloro- benzoic acid of 2- methoxyl groups -5- (839mg, 4.5mmol), condensing agent
HBTU (2.56g, 6.75mmol) and DMAP (73mg, 0.6mmol) are dissolved in DMF, and room temperature reaction is stayed overnight.Reaction terminates rear silicon
Glue pillar layer separation obtains title compound (white solid, 908mg, 81% yield).1H NMR(400MHz,DMSO-d6)δ8.26
(t, J=5.6Hz, 1H), 7.73-7.57 (m, 4H), 7.50 (dd, J=8.8,2.8Hz, 1H), 7.32 (d, J=8.0Hz, 2H),
7.15 (d, J=8.9Hz, 1H), 6.62 (d, J=16.1Hz, 1H), 3.81 (s, 3H), 3.72 (s, 3H), 3.52 (dt, J=
5.6,7.1Hz, 2H), 2.87 (t, J=7.1Hz, 2H)；13C NMR(101MHz,DMSO)δ166.62,163.44,155.61,
144.31,142.20,131.96,131.37,129.43,129.22,128.32,124.73,124.24,117.01,114.08,
56.17,51.29,40.29,34.65.
Embodiment 2c
(E) the chloro- N- of -5- (4- (3- (hydroxylamino) -3- oxopropyl -1- alkenyls) phenethyl) -2- methoxy benzamides
Embodiment 1e (100mg, 0.27mmol) is added in methanol (2ml), be subsequently added into hydroxylamine hydrochloride (180mg,
2.6mmol) with sodium tert-butoxide (375mg, 3.9mmol), reaction at room temperature is stayed overnight.Reaction removes reaction dissolvent and post color after terminating
Spectrum separates to obtain title compound (faint yellow solid, 37mg, 37% yield).158~160 DEG C of fusing point,1H NMR(400MHz,
DMSO-d6) δ 10.74 (s, 1H), 9.04 (s, 1H), 8.26 (t, J=5.6Hz, 1H), 7.63 (d, J=2.8Hz, 1H), 7.56-
7.48 (m, 3H), 7.44 (d, J=15.7Hz, 1H), 7.30 (d, J=7.8Hz, 2H), 7.15 (d, J=8.9Hz, 1H), 6.43
(d, J=15.8Hz, 1H), 3.82 (s, 3H), 3.51 (q, J=6.7Hz, 2H), 2.85 (t, J=7.1Hz, 2H)；13C NMR
(101MHz,DMSO)δ163.43,155.62,140.93,132.82,131.37,129.44,129.19,127.41,124.77,
124.26,118.37,114.11,56.18,40.36,34.61.HRMS (ESI) m/z calculated values [M+H]+375.1112, are surveyed
Value 375.1122.
Embodiment 3
(E) the chloro- N- of -5- (3- (3- (hydroxylamino) -3- oxopropyl -1- alkenyls) phenethyl) -2- methoxy benzamides
(compound 3)
Embodiment 3a
The tert-butyl group (3- bromophenylethyls) carbamate
Using a Bretylium Tosylate as raw material, preparation method be the same as Example 1a.Yield is 97%.1H NMR(400MHz,
Chloroform-d) δ 7.36 (dd, J=7.5,1.4Hz, 2H), 7.21-7.15 (m, 1H), 7.12 (d, J=7.7Hz, 1H),
(s, the 9H) of 4.55 (s, 1H), 3.36 (q, J=6.8Hz, 2H), 2.77 (t, J=7.1Hz, 2H), 1.44
Embodiment 3b
(E) -3- (3- (2- ((tertbutyloxycarbonyl) amino) ethyl) phenyl) methyl acrylate
Using embodiment 3a as raw material, preparation method be the same as Example 1b.Yield is 86%.1H NMR(400MHz,DMSO-d6)δ
7.64 (d, J=16.1Hz, 1H), 7.58-7.48 (m, 2H), 7.34 (t, J=7.8Hz, 1H), 7.26 (d, J=7.6Hz, 1H),
6.92 (t, J=5.6Hz, 1H), 6.63 (d, J=16.0Hz, 1H), 3.73 (s, 3H), 3.26-3.04 (m, 2H), 2.72 (t, J
=7.3Hz, 2H), 1.36 (s, 9H)；13C NMR(101MHz,DMSO)δ166.54,155.41,144.55,140.14,
133.84,130.83,128.72,128.34,126.10,117.56,77.38,54.78,51.34,40.97,34.99,
28.13.
Embodiment 3c
(E) -3- (3- (2- aminoethyls) phenyl) methyl acrylate
Using embodiment 3b as raw material, preparation method be the same as Example 2a.Yield is 72%.1H NMR(400MHz,DMSO-d6)δ
7.98 (br, 2H), 7.72-7.56 (m, 3H), 7.39 (t, J=7.6Hz, 1H), 7.33 (d, J=7.6Hz, 1H), 6.68 (d, J
=16.1Hz, 1H), 3.73 (s, 1H), 3.07 (t, J=7.9Hz, 1H), 2.91 (br, 1H)；13C NMR(101MHz,DMSO)δ
166.52,144.31,138.12,134.19,130.78,129.07,128.39,126.74,117.94,51.39,32.84.
Embodiment 3d
(E) -3- (3- (2- (the chloro- 2- methoxy benzamides bases of 5-) ethyl) phenyl) methyl acrylate
Using embodiment 3c as raw material, preparation method be the same as Example 2b.Yield is 77%.1H NMR(400MHz,DMSO-d6)δ
8.26 (t, J=5.7Hz, 1H), 7.69-7.56 (m, 4H), 7.50 (dd, J=8.8,2.8Hz, 1H), 7.38 (t, J=7.5Hz,
1H), 7.33 (t, J=7.6Hz, 1H), 7.15 (d, J=8.9Hz, 1H), 6.65 (d, J=16.0Hz, 1H), 3.79 (s, 3H),
3.73 (s, 3H), 3.54 (dt, J=5.7,7.1Hz, 2H), 2.86 (t, J=7.1Hz, 2H)；13C NMR(101MHz,DMSO)δ
166.54,163.49,155.56,144.48,140.10,133.94,131.32,130.88,129.36,128.84,128.45,
126.28,124.88,124.22,117.67,114.05,56.14,51.36,40.23,34.45.
Embodiment 3e
(E) the chloro- N- of -5- (3- (3- (hydroxylamino) -3- oxopropyl -1- alkenyls) phenethyl) -2- methoxy benzamides
Using embodiment 3d as raw material, preparation method be the same as Example 2c.Yield is 35%.124~126 DEG C of fusing point,1H NMR
(400MHz,DMSO-d6) δ 8.27 (t, J=5.6Hz, 1H), 7.63 (d, J=2.8Hz, 1H), 7.50 (dd, J=8.8,
2.8Hz, 1H), 7.48-7.38 (m, 3H), 7.36 (t, J=7.5Hz, 1H), 7.27 (d, J=7.5Hz, 1H), 7.15 (d, J=
8.9Hz, 1H), 6.47 (d, J=15.8Hz, 1H), 3.80 (s, 3H), 3.53 (q, J=6.7Hz, 2H), 2.85 (t, J=
7.1Hz,2H)；13C NMR(101MHz,DMSO)δ163.45,162.59,155.59,139.98,137.80,134.92,
131.36,129.71,129.41,128.85,127.56,125.38,124.76,124.24,119.25,114.07,56.15,
40.44,34.63.HRMS (ESI) m/z calculated values [M-H] -373.0955, measured value 373.0954.
Embodiment 4
(E) the chloro- N- of -2- (4- (3- (hydroxylamino) -3- oxopropyl -1- alkenyls) phenethyl) -5- (trifluoromethyl) benzene first
Acid amides (is changed
Compound 4)
Embodiment 4a
(E) -3- (4- (2- (2- chloro- 5- (trifluoromethyl) benzamido) ethyl) phenyl) methyl acrylate
Using the chloro- 5- of 2- (trifluoromethyl) benzoic acid and embodiment 2a as raw material, preparation method be the same as Example 2b.Yield is
65%.1H NMR(400MHz,DMSO-d6) δ 8.70 (t, J=5.6Hz, 1H), 7.81 (dd, J=8.5,2.2Hz, 1H), 7.74
(d, J=8.4Hz, 1H), 7.70-7.56 (m, 4H), 7.33 (d, J=7.9Hz, 2H), 6.61 (d, J=16.1Hz, 1H), 3.72
(s, 3H), 3.51 (td, J=5.6,7.1Hz, 2H), 2.88 (t, J=7.1Hz, 2H)；19F NMR(376MHz,DMSO)δ-
61.17；13C NMR(101MHz,DMSO)δ166.61,164.75,144.30,142.00,137.68,134.33,131.98,
130.73,129.30,128.25,127.74,127.22,125.49,124.77,116.98,51.30,40.05,34.49.
Embodiment 4b
(E) the chloro- N- of -2- (4- (3- (hydroxylamino) -3- oxopropyl -1- alkenyls) phenethyl) -5- (trifluoromethyl) benzene first
Acid amides
Using embodiment 4a as raw material, preparation method be the same as Example 2c.Yield is 29%.162~163 DEG C of fusing point,1H NMR
(400MHz,DMSO-d6) δ 10.72 (s, 1H), 9.03 (s, 1H), 8.69 (t, J=5.6Hz, 1H), 7.81 (dd, J=8.4,
2.3Hz, 1H), 7.74 (d, J=8.4Hz, 1H), 7.63 (d, J=2.2Hz, 1H), 7.50 (d, J=7.8Hz, 2H), 7.43 (d,
J=15.7Hz, 1H), 7.31 (d, J=7.8Hz, 2H), 6.43 (d, J=15.8Hz, 1H), 3.50 (q, J=6.7Hz, 2H),
2.87 (t, J=7.2Hz, 2H)；13C NMR(101MHz,DMSO)δ164.74,140.73,137.98,137.70,134.32,
132.82,130.72,129.28,127.75,127.42,127.33,125.50,125.46,124.78,122.07,118.31,
(39.15,38.97,34.45.HRMS ESI) m/z calculated values [M-H]-411.0723, measured value 411.0717.
Embodiment 5
(E) -4- hydroxy-ns-(4- (3- (hydroxylamino) -3- oxopropyl -1- alkenyls) phenethyl) -3- methoxybenzoyls
Amine (compound 5)
Embodiment 5a
(E) -3- (4- (2- (4- hydroxy 3-methoxybenzenes formamido) ethyl) phenyl) methyl acrylate
Using vanillic acid and embodiment 2a as raw material, preparation method be the same as Example 2b.Yield is
69%.1H NMR(400MHz,DMSO-d6) δ 9.56 (s, 1H), 8.36 (t, J=5.6Hz, 1H), 7.77-7.55 (m, 3H),
7.47-7.21 (m, 4H), 6.80 (d, J=8.3Hz, 1H), 6.61 (d, J=16.0Hz, 1H), 3.80 (s, 3H), 3.72 (s,
3H), 3.47 (dt, J=5.6,7.3Hz, 2H), 2.87 (t, J=7.3Hz, 2H)；13C NMR(101MHz,DMSO)δ166.63,
165.76,149.28,146.98,144.35,142.48,131.84,129.17,128.31,125.50,120.47,116.90,
114.67,111.18,55.54,51.30,40.40,35.01.
Embodiment 5b
(E) -4- hydroxy-ns-(4- (3- (hydroxylamino) -3- oxopropyl -1- alkenyls) phenethyl) -3- methoxybenzoyls
Amine
Using embodiment 5a as raw material, preparation method be the same as Example 2c.Yield is 34%.150~152 DEG C of fusing point,1H NMR
(400MHz,DMSO-d6) δ 8.33 (s, 1H), 7.46 (d, J=7.8Hz, 2H), 7.42-7.13 (m, 5H), 6.78 (d, J=
8.2Hz, 1H), 6.39 (d, J=15.8Hz, 1H), 3.79 (s, 3H), 3.50-3.41 (m, 2H), 2.83 (t, J=7.4Hz,
2H)；13C NMR(101MHz,DMSO)δ165.82,162.81,149.88,147.10,140.93,137.03,132.94,
129.11,127.27,125.09,120.54,119.00,114.75,111.22,55.54,40.51,35.01.HRMS(ESI)
M/z calculated values [M-H]-355.1294, measured value 355.1303.
Embodiment 6
(E) dioxane between-N- (4- (3- (hydroxylamino) -3- oxopropyl -1- alkenyls) phenethyl) benzo [d] [1,3]
Amylene -5- formamides (compound 6)
Embodiment 6a
(E) -3- (4- (2- (benzo [d] [1,3] dioxole -5- formamides) ethyl) phenyl) methyl acrylate
Using piperic acid and embodiment 2a as raw material, preparation method be the same as Example 2b.Yield is 73%.1H NMR(400MHz,
DMSO-d6) δ 8.39 (t, J=5.6Hz, 1H), 7.75-7.54 (m, 3H), 7.40 (dd, J=8.2,1.7Hz, 1H), 7.34 (d,
J=1.7Hz, 1H), 7.28 (d, J=7.9Hz, 2H), 6.97 (d, J=8.1Hz, 1H), 6.60 (d, J=16.1Hz, 1H),
6.08 (s, 2H), 3.72 (s, 3H), 3.47 (td, J=5.6,7.2Hz, 2H), 2.86 (t, J=7.2Hz, 2H)；13C NMR
(101MHz,DMSO)δ166.64,165.14,149.46,147.15,144.35,142.40,131.85,129.17,128.43,
128.31,121.92,116.91,107.70,107.08,101.50,51.31,40.45,34.84.
Embodiment 6b
(E) dioxane between-N- (4- (3- (hydroxylamino) -3- oxopropyl -1- alkenyls) phenethyl) benzo [d] [1,3]
Diene -5-
Formamide
Using embodiment 6a as raw material, preparation method be the same as Example 2c.Yield is 41%.186~187 DEG C of fusing point,1H NMR
(400MHz,DMSO-d6) δ 10.72 (s, 1H), 9.02 (s, 1H), 8.40 (t, J=5.6Hz, 1H), 7.52-7.37 (m, 4H),
(7.35 d, J=1.7Hz, 1H), 7.27 (d, J=7.8Hz, 2H), 6.97 (d, J=8.1Hz, 1H), 6.41 (d, J=15.8Hz,
1H), 6.09 (s, 2H), 3.46 (q, J=6.7Hz, 2H), 2.84 (t, J=7.3Hz, 2H)；13C NMR(101MHz,DMSO)δ
165.16,162.76,149.45,147.16,141.15,138.08,132.68,129.14,128.50,127.39,121.92,
(118.29,107.69,107.09,101.49,40.53,34.82.HRMS ESI) m/z calculated values [M-H]-353.1137, actual measurement
Value 353.1129.
Embodiment 7
(E)-N- (4- (3- (hydroxylamino) -3- oxopropyl -1- alkenyls) phenethyl) -2,3- dihydrobenzos [b] [1,4] two
Evil English -6- formamides (compound 7)
Embodiment 7a
(E) -3- (4- (2- (2,3- dihydrobenzos [b] [1,4] bioxin -6- formamides) ethyl) phenyl) methyl acrylate
With 2,3- dihydros-Isosorbide-5-Nitrae-benzodioxane -6- carboxylic acids and embodiment 2a for raw material, preparation method be the same as Example 2b.
Rate is 69%.1H NMR(400MHz,DMSO-d6) δ 8.37 (t, J=5.6Hz, 1H), 7.76-7.56 (m, 3H), 7.46-7.18
(m, 4H), 6.90 (d, J=8.1Hz, 1H), 6.59 (d, J=16.1Hz, 1H), 4.40-4.13 (m, 4H), 3.72 (s, 3H),
3.46 (td, J=5.6,7.2Hz, 2H), 2.85 (t, J=7.2Hz, 2H)；13C NMR(101MHz,DMSO)δ166.62,
165.21,145.79,144.33,142.76,142.43,131.85,129.16,128.28,127.52,120.42,116.93,
116.56,116.02,64.21,63.90,51.28,40.36,34.85.
Embodiment 7b
(E)-N- (4- (3- (hydroxylamino) -3- oxopropyl -1- alkenyls) phenethyl) -2,3- dihydrobenzos [b] [1,4] two
Evil English -6-
Formamide
Using embodiment 7a as raw material, preparation method be the same as Example 2c.Yield is 35%.187~189 DEG C of fusing point,1H NMR
(400MHz,DMSO-d6) δ 8.39 (t, J=5.6Hz, 1H), 7.48 (d, J=7.9Hz, 2H), 7.42 (d, J=15.7Hz,
1H), 7.37-7.30 (m, 2H), 7.26 (d, J=7.9Hz, 2H), 6.90 (d, J=8.1Hz, 1H), 6.42 (d, J=15.8Hz,
1H), 4.32-4.23 (m, 4H), 3.45 (q, J=6.7Hz, 2H), 2.84 (t, J=7.3Hz, 2H)；13C NMR(101MHz,
DMSO)δ165.20,162.68,145.78,142.76,141.15,137.96,132.69,129.13,127.53,127.37,
(120.42,118.32,116.56,116.02,64.21,63.90,40.45,34.82.HRMS ESI) m/z calculated values [M-H]-
367.1294, measured value 367.1302.
Embodiment 8
(E) the fluoro- N- of -5- (4- (3- (hydroxylamino) -3- oxopropyl -1- alkenyls) phenethyl) niacinamide (compound 8)
Embodiment 8a
(E) -3- (4- (2- (5- fluoro niacinamide) ethyl) phenyl) methyl acrylate
Using 5- fluorine nicotinic acids and embodiment 2a as raw material, preparation method be the same as Example 2b.Yield is 65%.1H NMR
(400MHz,DMSO-d6) δ 8.87 (t, J=5.6Hz, 1H), 8.84 (t, J=1.8Hz, 1H), 8.74 (d, J=2.8Hz, 1H),
8.03 (ddd, J=9.6,2.9,1.7Hz, 1H), 7.76-7.54 (m, 3H), 7.31 (d, J=8.1Hz, 2H), 6.61 (d, J=
16.0Hz, 1H), 3.72 (s, 3H), 3.53 (dt, J=5.6,7.2Hz, 2H), 2.89 (t, J=7.2Hz, 2H)；19F NMR
(376MHz,DMSO)δ-126.86；13C NMR(101MHz,DMSO)δ167.18,163.86,160.49,157.96,145.00,
144.96,144.87,142.65,140.69,140.47,132.52,132.09,132.06,129.76,128.91,122.23,
122.03,117.56,51.87,41.08,35.19.
Embodiment 8b
(E) the fluoro- N- of -5- (4- (3- (hydroxylamino) -3- oxopropyl -1- alkenyls) phenethyl) niacinamide
Using embodiment 8a as raw material, preparation method be the same as Example 2c.Yield is 33%.189~190 DEG C of fusing point,1H NMR
(400MHz,DMSO-d6) δ 10.74 (s, 1H), 9.07 (s, 1H), 8.88 (t, J=5.6Hz, 1H), 8.85 (s, 1H), 8.74
(d, J=2.8Hz, 1H), 8.04 (d, J=9.4Hz, 1H), 7.50 (d, J=7.8Hz, 2H), 7.43 (d, J=15.8Hz, 1H),
7.29 (d, J=7.8Hz, 2H), 6.42 (d, J=15.8Hz, 1H), 3.52 (q, J=6.8Hz, 2H), 2.88 (t, J=7.2Hz,
2H).19F NMR(376MHz,DMSO)δ-126.86；13C NMR(101MHz,DMSO)δ163.28,162.66,159.93,
157.39,144.44,144.40,140.82,140.12,139.90,137.98,132.78,131.54,131.51,129.18,
(127.42,121.67,121.48,118.34,40.60,34.59.HRMS ESI) m/z calculated values [M+H]+330.1254, actual measurement
Value 330.1261.
Embodiment 9
(E)-N- (4- (3- (hydroxylamino) -3- oxopropyl -1- alkenyls) phenethyl) quinoline -6- formamides (compound 9)
Embodiment 9a
(E) -3- (4- (2- (quinoline -6- formamides) ethyl) phenyl) methyl acrylate
Using QUINOLINE-6-CARBOXYLIC ACID and embodiment 2a as raw material, preparation method be the same as Example 2b.Yield is 71%.1HNMR
(400MHz,DMSO-d6) δ 8.99 (dd, J=4.2,1.7Hz, 1H), 8.85 (t, J=5.5Hz, 1H), 8.47 (td, J=4.2,
1.7Hz, 2H), 8.14 (dd, J=8.8,2.0Hz, 1H), 8.08 (d, J=8.8Hz, 1H), 7.71-7.57 (m, 4H), 7.33
(d, J=8.1Hz, 2H), 6.61 (d, J=16.1Hz, 1H), 3.72 (s, 3H), 3.57 (td, J=5.5,7.2Hz, 2H), 2.93
(t, J=7.2Hz, 2H)；13C NMR(101MHz,DMSO)δ166.63,165.63,151.88,148.52,144.34,
142.32,136.94,132.28,131.91,129.20,128.87,128.35,127.67,127.54,126.98,122.04,
116.95,51.30,40.58,34.82.
Embodiment 9b
(E)-N- (4- (3- (hydroxylamino) -3- oxopropyl -1- alkenyls) phenethyl) quinoline -6- formamides
Using embodiment 9a as raw material, preparation method be the same as Example 2c.Yield is 38%.186~188 DEG C of fusing point,1H NMR
(400MHz,DMSO-d6) δ 8.98 (dd, J=4.2,1.7Hz, 1H), 8.83 (t, J=5.6Hz, 1H), 8.51-8.43 (m,
2H), 8.15 (dd, J=8.8,1.9Hz, 1H), 8.07 (d, J=8.8Hz, 1H), 7.61 (dd, J=8.3,4.2Hz, 1H),
7.50 (d, J=7.8Hz, 2H), 7.43 (d, J=15.8Hz, 1H), 7.32 (d, J=7.8Hz, 2H), 6.42 (d, J=
15.8Hz, 1H), 3.62-3.52 (m, 2H), 2.92 (t, J=7.3Hz, 2H)；13C NMR(101MHz,DMSO)δ165.64,
162.70,151.86,148.53,141.05,137.98,136.92,132.76,132.33,129.18,128.86,127.66,
(127.55,127.42,126.99,122.03,118.35,40.66,34.80.HRMS ESI) m/z calculated values [M-H]-
360.1348, measured value 360.1350.
Embodiment 10
(E)-N- (4- (3- (hydroxylamino) -3- oxopropyl -1- alkenyls) phenethyl) -1H- benzos [d] imidazoles -5- formyls
Amine (compound 10)
Embodiment 10a
(E) -3- (4- (2- (1H- benzos [d] imidazoles -5- formamidos) ethyl) phenyl) methyl acrylate
Using 1H- benzimidazole-5-carboxylic acids and embodiment 2a as raw material, preparation method be the same as Example 2b.Yield is 76%.1H
NMR(400MHz,DMSO-d6) δ 12.71 (s, 1H), 8.54 (t, J=5.6Hz, 1H), 8.33 (s, 1H), 8.20-8.07 (m,
1H), 7.75-7.56 (m, 5H), 7.32 (d, J=7.9Hz, 2H), 6.60 (d, J=16.1Hz, 1H), 3.72 (s, 3H), 3.53
(q, J=6.8Hz, 2H), 2.95-2.87 (m, 2H)；13C NMR(101MHz,DMSO)δ167.75,166.62,166.58,
144.34,143.62,142.52,131.84,129.18,128.29,127.07,124.31,121.18,118.99,116.92,
109.53,51.27,40.50,34.93.
Embodiment 10b
(E)-N- (4- (3- (hydroxylamino) -3- oxopropyl -1- alkenyls) phenethyl) -1H- benzos [d] imidazoles -5- formyls
Amine
Using embodiment 10a as raw material, preparation method be the same as Example 2c.Yield is 32%.179~181 DEG C of fusing point,1H NMR
(400MHz,DMSO-d6) δ 12.68 (s, 1H), 10.74 (s, 1H), 9.03 (s, 1H), 8.54 (t, J=5.5Hz, 1H), 8.32
(s, 1H), 8.14 (s, 1H), 7.72 (br, 1H), 7.62 (br, 1H), 7.49 (d, J=7.8Hz, 2H), 7.42 (d, J=
15.8Hz, 1H), 7.30 (d, J=7.8Hz, 2H), 6.42 (d, J=15.8Hz, 1H), 3.57-3.47 (m, 2H), 2.89 (t, J
=7.3Hz, 2H)；HRMS (ESI) m/z calculated values [M-H]-349.1301, measured value 349.1306.
Embodiment 11
(E)-N- (4- (3- (hydroxylamino) -3- oxopropyl -1- alkenyls) phenethyl) -1H- pyrrolo-es [2,3-b] pyridine -
3- formyls
Amine (compound 11)
Embodiment 11a
(E) -3- (4- (2- (1H- pyrrolo-es [2,3-b] pyridine-3-carboxamide base) ethyl) phenyl) methyl acrylate
Using 7- azaindole -3- carboxylic acids and embodiment 2a as raw material, preparation method be the same as Example 2b.Yield is 61%.1H
NMR(400MHz,DMSO-d6) δ 12.13 (s, 1H), 8.47 (dd, J=8.0,1.6Hz, 1H), 8.29 (d, J=4.7Hz, 1H),
8.18 (t, J=5.7Hz, 1H), 8.14 (d, J=2.5Hz, 1H), 7.68-7.61 (m, 3H), 7.32 (d, J=8.1Hz, 2H),
7.19 (dd, J=7.9,4.7Hz, 1H), 6.60 (d, J=16.1Hz, 1H), 3.72 (s, 3H), 3.54-3.49 (m, 2H), 2.90
(t, J=7.3Hz, 2H)
Embodiment 11b
(E)-N- (4- (3- (hydroxylamino) -3- oxopropyl -1- alkenyls) phenethyl) -1H- pyrrolo-es [2,3-b] pyridine -
3- formyls
Amine
Using embodiment 11a as raw material, preparation method be the same as Example 2c.Yield is 27%.196~198 DEG C of fusing point,1H NMR
(400MHz,DMSO-d6) δ 12.06 (s, 1H), 10.73 (s, 1H), 9.04 (s, 1H), 8.43 (dd, J=7.9,1.7Hz, 1H),
8.26 (dd, J=4.7,1.7Hz, 1H), 8.15-8.08 (m, 2H), 7.49 (d, J=7.7Hz, 2H), 7.42 (d, J=
15.8Hz, 1H), 7.30 (d, J=7.7Hz, 2H), 7.16 (dd, J=7.9,4.7Hz, 1H), 6.42 (d, J=15.8Hz, 1H),
3.49 (q, J=6.8Hz, 2H), 2.87 (t, J=7.3Hz, 2H)；13C NMR(101MHz,DMSO)δ163.79,162.69,
148.27,143.29,141.27,137.99,132.69,129.16,129.07,127.72,127.40,118.31,116.68,
109.48,35.26.HRMS (ESI) m/z calculated values [M-H]-349.1301, measured value 349.1293.
Embodiment 12, mtt assay cell inhibitory effect active testing
Cell in vitro proliferation inhibition test uses mtt assay, using following two cell lines：Human chronic myelogenous leukemia
(CML) cell line k562, human tissue cell lymphoma cell U937.
K562 and U937 is suspension cell, with containing the RPIM-1640 nutrient solutions that volume fraction is 10% hyclone, 37
DEG C, volume fraction be 5% CO2Under the conditions of cellar culture.
Concrete operations are as follows：
First, the compound (i.e. sample) embodiment 1-26 prepared is configured to compound concentration for 5mM/L respectively
DMSO (dimethyl sulfoxide (DMSO)) solution, then by the solution of acquisition through gradient dilution, a series of sample for obtaining concentration gradients is molten
Liquid.
Then, take the logarithm the K562 cells or U937 cells in growth period, with 1.5 × 105Individual/mL cell density connects
Plant in 96 orifice plates, 99 μ L/ holes, the μ L of sample solution 1 then added per hole, it is respectively 0.01,0.05 to make sample effect final concentration,
0.1,0.5,1,5,10,25,50 μM.Every kind of sample, each concentration set three multiple holes, and set positive controls, feminine gender right
According to group and blank control group, wherein, positive controls are separately added into positive control medicine histon deacetylase (HDAC) inhibitor
SAHA and dnmt rna inhibitor SGI-027, negative control group is added with sample solution with the DMSO of concentration, blank pair
Cell is not added with according to group.Act on and MTT solution is added after 72h, 10 μ L/ holes are continued after cultivating 4 hours, in centrifugation at 2000rpm, 4 DEG C
5 minutes, suck and dimethyl sulfoxide (DMSO) (DMSO) is added after supernatant, 100 μ L/ holes are incubated about 10 minutes in 37 DEG C, then shaken with micro
Swing device to vibrate about 5 minutes, make crystallization dissolving complete, OD values are measured at 490nm with ELIASA.
Cell proliferation inhibition rate (Inhibition Rate, IR%) is calculated as follows：
IR%=(negative control OD- sample OD)/(negative control OD- blank control OD) × 100%,
By calculating, the cell in vitro proliferation inhibition activity of the compound prepared by the present invention is obtained, 1 is the results are shown in Table.Its
In, IC50Represented more than 50 μM with "-", IC50Represented more than 10 μM and less than 50 μM with "+", IC50More than 5 μM and less than 10 μM
Represented with " ++ ", IC50Represented more than 1 μM less than 5 μM with " +++ ", IC50Represented less than 1 μM with " ++++".Test result shows,
Majority of compounds shows good anti-K562 and U937 cultivation effects, wherein, 2,3,6 pairs of U937 Proliferation Abilities of compound
IC50Less than 1 μM.
The tumor cell in vitro proliferation inhibition activity of compound prepared by the embodiment 1~11 of table 1
Note：IC50Represent half-inhibition concentration.
Embodiment 13, the experiment of dnmt rna inhibitory activity
Using isotope marks S-adenosylmethionine (3H-SAM) test compound turns in 100mM to DNA methyl
The inhibitory activity of enzyme (DNMT1, DNMT3A, DNMT3B) is moved, and with the dnmt rna inhibitor of reported in literature
NSC319745 is compareed.Compound and corresponding a certain amount of dnmt rna hypotype are mixed in advance, are incubated at room temperature
After 15min, add artificial synthesized biotin labeling oligonucleotides substrate and3H-SAM simultaneously reacts 4h at room temperature.Then will
Reaction system is transferred in the coated high pass orifice of Streptavidin, reacts at room temperature 1h.Radioactive activity passes through liquid scintillation
Counting method is obtained.By comparing the inhibitory activity for obtaining compound to enzyme with negative control group (no inhibitor group).Compound pair
Suppression percentage (%Inhibition) result of different subtype dnmt rna enzyme is as shown in table 2.Showing of test result
Compound has certain inhibitory activity to dnmt rna, and different to different subtype rejection ability.Majority of compounds pair
DNMT1 inhibitory activity is suitable with NSC319745 activity, and DNMT3A/3B inhibitory activity is weaker.Compound 9 is to DNMT3B's
Inhibitory activity is better than the inhibitory activity to DNMT1/3A.The inhibiting rate of three hypotypes of compound 10 pair is all higher than 30%, and right
DNMT3B inhibitory activity is similar to compound N SC319745.Compound 4 shows most strong in listed compound
DNMT1 inhibitory activity (inhibiting rate be more than 60%), and to DNMT3B inhibiting rates nearly 50%, and it is weaker to DNMT3A inhibitory activity
(inhibiting rate 23%).
The dnmt rna inhibitory activity of compound prepared by the embodiment 1~11 of table 2
Embodiment 14, the experiment of histon deacetylase (HDAC) inhibitory activity
Two hypotype HDAC1 and HDAC6 using histon deacetylase (HDAC) family is research objects, and test compound is to group
The inhibitory activity of albumen deacetylase, each compound sets ten concentration gradients, three multiple holes, and is pressed down with the HDAC listed
Preparation SAHA is compareed.Compound is dissolved into reaction buffer first, certain volume is added afterwards goes second containing histone
The cushioning liquid of acylase, incubation at room temperature adds trypsase after 15 minutes and the peptide cushioning liquid of acetylation is used as reaction substrate
To start deacetylation, while making compound concentration and enzyme content reach setting value, it is gently mixed after 60 seconds and is incubated at room temperature,
The kinetic parameter reacted in 1 hour of record under certain exciting light and wavelength of transmitted light.By with negative control group (no inhibitor
Group) compare the inhibitory activity for obtaining compound to enzyme, and calculate the half suppression for obtaining compound to histon deacetylase (HDAC)
Concentration (IC50), as a result as shown in table 3, wherein, IC50Represented more than 10nM and less than 100nM with "+", IC50Less than 10nM with "+
+ " represent.Test result shows half-inhibition concentration (IC of all compounds to HDAC1/650) it is less than 100nM, show to have
Good HDAC1/6 inhibitory activity.IC of the compound 5,6,7,9,10 to HDAC1/650Less than 10nM, the inhibitory activity with SAHA
Quite.
The histon deacetylase (HDAC) inhibitory activity of compound prepared by the embodiment 1~11 of table 3
Claims (10)
1. a kind of hydroxamic acid derivs or its pharmaceutically acceptable salt, hydroxamic acid derivs structural formula is as shown in formula I：
Wherein, Ar is aromatic group, and the aromatic group is selected from replace or non-substituted phenyl ring, replace or non-substituted virtue
Fragrant heterocycle, substitution or non-substituted benzheterocycle, substitution or non-substituted aromatic heterocycle and heterocycle；
N=1,2,3,4,5 or 6；
L1Link position be phenyl ring ortho position, meta or para position；L1For saturation or unsaturated carbon chains, the full of C1-C6 is preferably selected from
Propped up with linear paraffin, the C1-C6 saturated alkane containing side chain or substituent, C1-C6 unsaturated linear paraffin, containing for C1-C6
Unsaturated alkane, methylene, ethylene group, vinyl, the acetenyl of chain or substituent.
2. hydroxamic acid derivs according to claim 1 or its pharmaceutically acceptable salt, wherein, it is described pharmaceutically
The salt of receiving is inorganic acid salt or acylate；
Preferably, the inorganic acid salt is selected from the salt of any one following inorganic acid formation：Hydrochloric acid, sulfuric acid or phosphoric acid；
The acylate is selected from the salt of any one following organic acid formation：Acetic acid, trifluoroacetic acid, malonic acid, citric acid and
P-methyl benzenesulfonic acid.
3. hydroxamic acid derivs according to claim 1 or 2 or its pharmaceutically acceptable salt, wherein, the virtue is miscellaneous
Ring is selected from 4 yuan, 5 yuan, 6 yuan or 7 yuan heteroaromatics, heterocycle comprising 1,2 or 3 hetero atoms, and hetero atom is independently selected from N, S, O；
The heteroaromatic be selected from pyridine radicals, pyridinyl-N-oxide, pyrimidine radicals, pyridazinyl, furyl, thienyl, thiazolyl,
Imidazole radicals, pyranose, pyrroles；
The benzheterocycle is selected from quinoline, isoquinolyl, purine radicals, indyl, benzimidazole, pyrrolopyridine, dihydrobenzo
Bioxin, benzodioxole；
Substituent on the aromatic group is 1-5, preferably 1,2,3,4 or 5；Alkyl of the substituent selected from C1-C6,
C1-C6 alkenyl, C1-C6 alkynyl, hydroxyl, nitro, methoxyl group, trifluoromethyl, trifluoromethoxy, amino, acrylamido,
Cyano group, fluorine-based, chloro, bromo, iodo；
Preferably, the aromatic group is selected from
Most preferably, described hydroxamic acid derivs structural formula is as shown in the table：
4. the preparation side of the hydroxamic acid derivs or its pharmaceutically acceptable salt according to claim any one of 1-3
Method, it comprises the following steps：
1) under condensing agent effect, the compound shown in the compound and formula III shown in Formula II react to obtain formula IV institute
The compound shown；Or the compound shown in Formula II and thionyl chloride, oxalyl chloride or POCl3 are prepared into corresponding acyl chlorides spread out
After biology the compound obtained shown in formula IV is reacted with the compound progress shown in formula III；
Wherein, in, Ar is aromatic group, the aromatic group be selected from substitution or non-substituted phenyl ring, substitution or it is non-substituted
Aromatic heterocycle, substitution or non-substituted benzheterocycle, substitution or non-substituted aromatic heterocycle and heterocycle；
N=1,2,3,4,5 or 6；
L1 link position is the ortho position of phenyl ring, meta or para position；L1 is saturation or unsaturated carbon chains；
R is C1-C4 alkyl；
2) compound shown in formula IV and azanol or hydroxylamine hydrochloride are reacted in alkaline solution, obtains compound shown in Formulas I；
Preferably, step 1) in, the condensing agent is selected from BTA-N, N, N', N'- tetramethylurea hexafluorophosphoric acid ester N,
N'- carbonyl dimidazoles, dicyclohexylcarbodiimide, DIC, 1- (3- dimethylamino-propyls) -3- ethyls carbon two
One or more in imines.
5. preparation method according to claim 4, wherein, step 1) condensing agent and the compound shown in Formula II, formula
The mol ratio of compound shown in III can be followed successively by 1-4:1-2:1-4；
Above method step 2) in, the alkali be selected from ammoniacal liquor, triethylamine, diisopropyl ethyl amine, sodium hydroxide, potassium hydroxide,
One or more in sodium methoxide, caustic alcohol, sodium tert-butoxide, potassium tert-butoxide etc.；
Compound shown in formula IV is 1 with azanol or hydroxylamine hydrochloride, the mol ratio of alkali reaction:1-10:1-20, concretely 1:5:5.
6. the purposes of the compound or its pharmaceutically acceptable salt according to power claim any one of 1-2 is it under
State the application of aspect：
1) application in dnmt rna and/or histon deacetylase (HDAC) inhibitor is prepared；
2) application in eucaryote tumor cell proliferation inhibitor is prepared；Or
3) application in prevention and/or tumor is prepared.
7. purposes according to claim 6, the dnmt rna (DNMTs) is included in mammalian cell
The hypotype (DNMT1, DNMT3A, DNMT3B) known；The histon deacetylase (HDAC) (HDACs) is included in mammalian cell
Known hypotype, mainly including but not limited to HDAC1, HDAC2, HDAC3, HDAC8, HDAC4, HDAC5, HDAC7, HDAC9,
HDAC6, HDAC10, HDAC11；
The eucaryote is mammal；The tumour cell is cancer cell；The cancer cell is leukaemia cancer cell, mammary gland
Cancer cell, liver cancer cells, pancreatic cancer cell, lung carcinoma cell, brain cancer cell, ovarian cancer cell, uterine cancer cells, carcinoma of testis are thin
Born of the same parents, skin cancer cell, stomach cancer cell, nasopharyngeal carcinoma cell, colon cancer cell, transitional cell bladder carcinoma cell line or rectum cancer cell；Preferably it is
The former leukaemia of the chronic marrow of people and human tissue cell's lymphoma cell；
The leukaemia cancer cell is specially human chronic myelogenous leukemia (CML) cell line k562, the lymphoma cell tool
Body behaviour histocytic lymphoma cell U937, the lung carcinoma cell is specially human lung carcinoma cell NCI-H520, the human brain glue
Matter oncocyte is specially U251, and the black cancer cell is specially A375, and the glioblastoma cells are specifically people's glue
Matter blastoma cell A172 and human brain astrocytes blastoma cell U-118MG, the cervical cancer cell is specifically people palace
Neck cancer Cell line Hela, the nasopharyngeal carcinoma cell is specially human nasopharyngeal epithelioma 1 CNE-2, and the liver cancer cells are specially human liver cancer
Cell Line HepG2, the breast cancer cell is specially human breast cancer cell line Bcap-37 and MDA-MB-231.
8. purposes according to claim 6, the tumour is cancer；The cancer is leukaemia, lymthoma, lung cancer, melanin
Cancer, glioblastoma, cervical carcinoma, nasopharyngeal carcinoma, liver cancer, breast cancer, the cancer of the brain, cancer of pancreas, oophoroma, uterine cancer, carcinoma of testis, skin
Skin cancer, stomach cancer, colon cancer, carcinoma of urinary bladder or the carcinoma of the rectum.
9. a kind of pharmaceutical composition, it comprises as compound of the active component as described in claim any one of 1-2 or
Its pharmaceutically acceptable salt and pharmaceutically acceptable auxiliaries.
10. pharmaceutical composition according to claim 9, its dosage form is selected from parenteral solution, tablet, pulvis, granule, glue
Capsule, oral liquid, paste, creme.
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