CN103467359B - Cinnamon amides histone deacetylase inhibitor with benzpyrole and preparation method and application of same - Google Patents

Cinnamon amides histone deacetylase inhibitor with benzpyrole and preparation method and application of same Download PDF

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CN103467359B
CN103467359B CN201310452667.0A CN201310452667A CN103467359B CN 103467359 B CN103467359 B CN 103467359B CN 201310452667 A CN201310452667 A CN 201310452667A CN 103467359 B CN103467359 B CN 103467359B
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phenyl
propoxy
indol
hydroxyacrylamide
amino
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CN103467359A (en
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徐文方
李晓杨
张颖杰
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Shandong University
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Abstract

The invention relates to cinnamon amides histone deacetylase inhibitor with benzpyrole and a preparation method and application of the innamon amides histone deacetylase inhibitor, and further relates to pharmaceutical compositions of compounds with the general formula (I) structures and pharmaceutical usage of the pharmaceutical compositions of compounds with the general formula (I) structures. The compound has good activity in vivo and in vitro and suitable for diseases with abnormal histone deacetylase activity, such as cancer.

Description

A kind of cinnamide histone deacetylase inhibitor containing indoles and its preparation method and application
Technical field
The present invention relates to a kind of derivative and preparation method thereof and application, be specifically related to a kind of cinnamide histone deacetylase inhibitor containing indoles and its preparation method and application, belong to organic compound synthesis and medical applications technical field.
Background technology
Malignant tumour is the number one killer threatening human life's health.The generation of tumour is not only relevant with the change of gene order with development, also has substantial connection with chromosomal epigenetic changes.The reversibility covalent modification of histone is the important behaviour form of karyomit(e) epigenetic changes, comprise phosphorylation/dephosphorylation, acetylize/deacetylation, adenylylation/go adenylylation, uridine acidylate/go uridine acidylate, methylate/demethylation etc.The Acetylation Level of histone reinvents important role to chromosome structure; acetylize/deacetylation completes (Shahbazian, M.D. by acetylation of histone enzyme (HATs) and histon deacetylase (HDAC) (HDACs) these two kinds interactional metalloprotease co-catalysis; Grunstein, M.Functions ofSite-Specific Histone Acetylation and Deacetylation.Annu.Rev.Biochem., 2007,76 (1), 75-100.).HDACs is by the ethanoyl on the lysine residue terminal amino group in hydrolysis nucleosome histone; add the positive charge density of N-terminal; enhance itself and the interaction with the DNA of negative charge; chromosome structure is made to become consolidation more; and then hinder the combination of transcription factor and DNA; transcribing of gene is finally made to be suppressed, comprising cancer suppressor gene.Effect and the HDACs of HATs are just the opposite, finally facilitate transcribing of gene.(Legube G, TroucheD.Regulating histone acetyltransferases and deacetylases [J] .Eur mole Biolorg (EMBO) reports.2003,4 (10): 944-947) in cancer cells, the abnormal excessive of HDACs expresses the running balance of having broken between HDACs and HATs.Except histone, the substrate specificity of HDACs also comprises transcription factor (p53, E2F, pRb), molecular chaperones (HSP90) and structural protein (tubulin) etc.(Glozak, M.A.; Sengupta, N.; Zhang, X.H.; Seto, E.Gene, 2005,363,15) in recent years, HDACs has become a focus of antitumor research, and the activity of suppression HDACs has become a Critical policies of the various diseases treatment comprising tumour.
At present, have been found that 18 kinds of HDACs in the mankind, can be divided into 4 classes by its structure function difference, I class HDACs comprises HDAC1, and 2,3,8; II class HDACs comprises HDAC4, and 5,6,7,9,10; IV class HDACs comprises HDAC11; III class HDACs comprises sirtuins1-7.Wherein I II IV class HDACs are Zn 2+dependent histon deacetylase (HDAC), III class HDACs is NAD +dependency histon deacetylase (HDAC).
Many hdac inhibitors (HDACi) have entered clinical front or clinical study, result of study shows that HDACi is inhibited to kinds of tumors, comprises cutaneous T-cell knurl (CTCL), glioblastoma multiforme, B cell lymphoma, thyroid carcinoma, nonsmall-cell lung cancer, pernicious renal cell carcinoma, malignant mesothelioma, prostate cancer etc.
Summary of the invention
For the deficiencies in the prior art, the invention provides a kind of cinnamide histone deacetylase inhibitor, present invention also offers preparation method and the purposes of above-claimed cpd.
For solving the problems of the technologies described above, technical scheme of the present invention is:
One, cinnamide histone deacetylase inhibitor
Cinnamide histone deacetylase inhibitor of the present invention, and its optical isomer, diastereomer and racemic mixture, its pharmacy acceptable salt, solvate or prodrug, have the structure shown in following general formula I.
Wherein:
R 1hydrogen, each seed amino acid prepare acyl group, aroyl, 4-hetaroylpyrazol, aryl C1-6 alkyloyl, heteroaryl C1-9 alkyloyl, C1-6 alkyloyl, cycloalkanoyl, arylsulfonyl, assorted alkylsulfonyl, aryl C1-6 alkane alkylsulfonyl, heteroaryl C1-9 alkane alkylsulfonyl, C1-8 carbalkoxy or aryl C1-8 carbalkoxy, aryl C1-6 alkyl;
R 2hydrogen; The electron-withdrawing groups such as halogen atom, nitro, carboxyl; Alkyl, amino, hydroxyl, methylol, amine methyl, carbamyl etc. give electric group;
R 3hydrogen, methyl;
X be between position and contraposition O, atom N;
Y is or
* be steric configuration be S or R optical purity or its raceme.
Preferably, R 1it is aroyl; R 2hydrogen, halogen atom; R 3hydrogen; X is contraposition O atom; Y is
More preferred, above-claimed cpd is one of following:
(S, E)-3-(4-(2-(benzoylamino)-3-(1H-indol-3-yl) propoxy-) phenyl)-N-hydroxyacrylamide (L1),
(S, E)-3-(4-(2-(phenylacetyl amido)-3-(1H-indol-3-yl) propoxy-) phenyl)-N-hydroxyacrylamide (L2),
(S, E)-3-(4-(2-(3-hydrocinnamamide base)-3-(1H-indol-3-yl) propoxy-) phenyl)-N-hydroxyacrylamide (L3),
(S, E)-3-(4-(2-(4-Methyl benzenesulfonyl amido)-3-(1H-indol-3-yl) propoxy-) phenyl)-N-hydroxyacrylamide (L4),
(S, E)-3-(4-(2-([1,1'-xenyl]-4-amide group)-3-(1H-indol-3-yl) propoxy-) phenyl)-N-hydroxyacrylamide (L5),
(S, E)-3-(4-(2-([1,1'-biphenyl]-4-sulfoamido)-3-(1H-indol-3-yl) propoxy-) phenyl)-N-hydroxyacrylamide (L6),
(S, E)-3-(4-(2-(4-chloro-benzoyl amino)-3-(1H-indol-3-yl) propoxy-) phenyl)-N-hydroxyacrylamide (L7),
(S, E)-3-(4-(2-(3-chloro-benzoyl amino)-3-(1H-indol-3-yl) propoxy-) phenyl)-N-hydroxyacrylamide (L8),
(S, E)-3-(4-(2-(2-chloro-benzoyl amino)-3-(1H-indol-3-yl) propoxy-) phenyl)-N-hydroxyacrylamide (L9),
(S, E)-3-(4-(2-(2,4 dichloro benzene formamido-)-3-(1H-indol-3-yl) propoxy-) phenyl)-N-hydroxyacrylamide (L10),
(S, E)-3-(4-(2-(3,5-dichloro-benzoyl amido)-3-(1H-indol-3-yl) propoxy-) phenyl)-N-hydroxyacrylamide (L11),
(S, E)-3-(4-(2-(4-fluorobenzoyl amido)-3-(1H-indol-3-yl) propoxy-) phenyl)-N-hydroxyacrylamide (L12),
(S, E)-3-(4-(2-(4-Bromophenacyl amido)-3-(1H-indol-3-yl) propoxy-) phenyl)-N-hydroxyacrylamide (L13),
(S, E)-3-(4-(2-(4-methoxy benzamide base)-3-(1H-indol-3-yl) propoxy-) phenyl)-N-hydroxyacrylamide (L14),
(S, E)-3-(4-(2-(2-ethylbutanoyl amido)-3-(1H-indol-3-yl) propoxy-) phenyl)-N-hydroxyacrylamide (L15),
(S, E)-3-(4-(2-(dipramide base)-3-(1H-indol-3-yl) propoxy-) phenyl)-N-hydroxyacrylamide (L16),
(S, E)-3-(4-(2-((tertbutyloxycarbonyl) is amino)-3-(1H-indol-3-yl) propoxy-) phenyl)-N-hydroxyacrylamide (L17),
(S, E)-3-(4-(2-(2-((tertbutyloxycarbonyl) is amino) acetamido)-3-(1H-indol-3-yl) propoxy-) phenyl)-N-hydroxyacrylamide (L18),
(E)-3-(4-((S)-2-((S)-2-((tertbutyloxycarbonyl) amino)-4-(methylthio group) butyryl radicals-3-(1H-indol-3-yl) propoxy-) phenyl)-N-hydroxyacrylamide (L19),
(E)-3-(4-((S)-2-((S)-2-((tertbutyloxycarbonyl) amino)-3-hydroxypropanoyl-3-(1H-indol-3-yl) propoxy-) phenyl)-N-hydroxyacrylamide (L20),
(E)-3-(4-((S)-2-((S)-2-((tertbutyloxycarbonyl) amino)-3-maloyl group-3-(1H-indol-3-yl) propoxy-) phenyl)-N-hydroxyacrylamide (L21),
(S, E)-3-(4-(2-(2-Hydroxylbenzamide base)-3-(1H-indol-3-yl) propoxy-) phenyl)-N-hydroxyacrylamide (L22),
(S, E)-3-(4-(2-(2-((2,3-3,5-dimethylphenyl) is amino) phenylformic acid)-3-(1H-indol-3-yl) propoxy-) phenyl)-N-hydroxyacrylamide (L23),
(E)-3-(4-((2S)-2-(2-(4-isobutyl phenenyl) propionamido-)-3-(1H-indol-3-yl) propoxy-) phenyl)-N-hydroxyacrylamide (L24),
(E)-3-(4-((2S)-2-(2-(4-benzoylphenyl) propionamido-)-3-(1H-indol-3-yl) propoxy-) phenyl)-N-hydroxyacrylamide (L25),
(E)-3-(4-((S)-2-((S)-2-(6-methoxyl group naphthyl-2-base)-3-(1H-indol-3-yl) propoxy-) phenyl)-N-hydroxyacrylamide (L26),
(S, E)-3-(3-(2-((tertbutyloxycarbonyl) is amino)-3-(1H-indol-3-yl) propoxy-) phenyl)-N-hydroxyacrylamide (L27),
(S, E)-3-(3-(2-(benzoylamino)-3-(1H-indol-3-yl) propoxy-) phenyl)-N-hydroxyacrylamide (L28),
(S, E)-3-(4-(2-(4-chloro-benzoyl amino)-3-(1H-indol-3-yl) propoxy-) phenyl)-N-hydroxyacrylamide (L29),
(S, E)-3-(4-(2-(benzyl is amino)-3-(1H-indol-3-yl) propoxy-) phenyl)-N-hydroxyacrylamide (L30),
(S, E)-3-(4-(2-((4-luorobenzyl) is amino)-3-(1H-indol-3-yl) propoxy-) phenyl)-N-hydroxyacrylamide (L31),
(S, E)-3-(4-(2-((4-chlorobenzyl) is amino)-3-(1H-indol-3-yl) propoxy-) phenyl)-N-hydroxyacrylamide (L32),
(S, E)-3-(4-(2-((4-bromobenzyl) is amino)-3-(1H-indol-3-yl) propoxy-) phenyl)-N-hydroxyacrylamide (L33),
(S, E)-3-(4-(2-((4-methoxy-benzyl) amino)-3-(1H-indol-3-yl) propoxy-) phenyl)-N-hydroxyacrylamide (L34) or
(S, E)-3-(4-(2-((tertbutyloxycarbonyl) is amino)-3-(1-Methyl-1H-indole-3-base) propoxy-) phenyl)-N-hydroxyacrylamide (L35).
Two, the preparation method of cinnamide histone deacetylase inhibitor
The preparation method of cinnamide histone deacetylase inhibitor of the present invention is one of following:
Synthetic route 1: take L-Trp as starting raw material, generate tryptophan methyl ester hydrochloride 2 under Acetyl Chloride 98Min. effect, with (Boc) 2o protects alpha-amino group to obtain intermediate 3, then through LiAIH 4reduction methyl esters becomes intermediate 4, intermediate 4 is reacted into compound 7 with 4-hydroxycinnamic acid or 3-hydroxycinnamic acid through Mitsunobu, 7 can be converted into hydroxamic acid target compound L17, or 7 slough Boc blocking group through EtOAc/HCl, the last amino acid protected with various Boc or carboxylic acid condensation are acid amides, and methyl esters is converted into hydroximic acid obtains target compound;
Synthetic route 1 reaction formula is as follows:
Wherein R is hydrogen, acyl group prepared by each seed amino acid, aroyl, 4-hetaroylpyrazol, aryl C1-6 alkyloyl, heteroaryl C1-9 alkyloyl, C1-6 alkyloyl, cycloalkanoyl, arylsulfonyl, assorted alkylsulfonyl, aryl C1-6 alkane alkylsulfonyl, heteroaryl C1-9 alkane alkylsulfonyl, C1-8 carbalkoxy or aryl C1-8 carbalkoxy;
Reagent in said synthesis route reaction formula: (a) CH 3oH, Acetyl Chloride 98Min., reflux 5h; (b) (Boc) 2o, triethylamine, methylene dichloride; (c) lithium aluminum hydride, anhydrous tetrahydro furan; (d) DEAD, Ph 3p, anhydrous tetrahydro furan; The saturated HCl solution of (e) EtOAc; (f) TBTU, triethylamine, anhydrous tetrahydro furan; (g) NH 2oK, anhydrous methanol.
The structural formula of the target compound of synthetic route 1 is as follows:
Synthetic route 2: intermediate 8 and the cyclosubstituted phenyl aldehyde of benzene react, generate schiff bases 11,11 and protect product 13 to be converted into hydroximic acid 14 through sodium borohydride reduction generation parahelium 12, Boc, last N sloughs protection and generates target compound (L30-L33);
Synthetic route 2 reaction formula is as follows:
Wherein R is hydrogen; Halogen atom, nitro, the electron-withdrawing groups such as carboxyl; Alkyl, amino, hydroxyl, methylol, amine methyl, carbamyls etc. give electric group;
Reagent in said synthesis route reaction formula: (a) phenyl aldehyde, triethylamine, CH 3oH; (b) NaBH 4, anhydrous CH 3oH, 85%; (c) (Boc) 2o, triethylamine, CH 3oH, 65%; (d) NH 2oK, anhydrous CH 3oH, 30-40%; (e) AcOEt/HCl, 70%.
The structural formula of the target compound of synthetic route 2 is as follows:
Synthetic route 3: N methyl protection the product 16 and 4 coumaric acid methyl esters on intermediate 4 indole ring reacts, and generates intermediate 17,17 through de-Boc, amide condensed, finally generates hydroximic acid end product;
Synthetic route 3 reaction formula is as follows:
Wherein R is hydrogen, acyl group prepared by each seed amino acid, aroyl, 4-hetaroylpyrazol, aryl C1-6 alkyloyl, heteroaryl C1-9 alkyloyl, C1-6 alkyloyl, cycloalkanoyl, arylsulfonyl, assorted alkylsulfonyl, aryl C1-6 alkane alkylsulfonyl, heteroaryl C1-9 alkane alkylsulfonyl, C1-8 carbalkoxy or aryl C1-8 carbalkoxy;
Reagent in said synthesis route reaction formula: (a) CH 3i, KOH, TBABr, H 2o, THF; (b) PPh 3, DEAD, anhydrous THF; The saturated HCl solution of (c) EtOAc; (d) TBTU, triethylamine, anhydrous tetrahydro furan; (e) NH 2oK, anhydrous CH 3oH.
The concrete operation step of described compound will be described in detail in an embodiment.
Those skilled in the art can change to improve yield to above-mentioned steps; they can determine the route of synthesis according to the ABC of this area; as selective reaction thing, solvent and temperature, can by using various GPF (General Protection False base to avoid the generation of side reaction thus to improve yield.The guard method of these routines can see such as T.Greene, Protecting Groups inOrganic Synthesis.
Three, the pharmaceutical composition containing the compounds of this invention and application
Present invention also offers these compounds preventing or treating the application in the medicine of the mammalian diseases relevant to histone deacetylase activity unconventionality expression.Described comprises with the related mammalian disease of histone deacetylase activity unconventionality expression: cancer, neurodegenerative disease, virus infection, inflammation, malaria and diabetes etc.Therefore, the invention still further relates to the pharmaceutical composition containing (I) structural compounds.
In addition, the present invention also comprises one and is suitable for orally giving mammiferous pharmaceutical composition, comprises arbitrary compound of above-mentioned general formula (I), and pharmaceutically acceptable carrier, optionally comprises one or more pharmaceutically acceptable vehicle.
In addition, the present invention also comprises one and is suitable for parenteral and gives mammiferous pharmaceutical composition, comprises arbitrary compound of above-mentioned general formula (I), and pharmaceutically acceptable carrier, optionally comprises one or more pharmaceutically acceptable vehicle.
Detailed Description Of The Invention
Definition used and term
Term and definition implication used herein is as follows:
" acyl group prepared by each seed amino acid " refers to the group obtained after acidylate by various amino acid whose carboxyl, preferred hydrophobic amino acid, as glycine, and L-Ala; α-amino-isovaleric acid, leucine, Isoleucine, phenylalanine; proline(Pro), Serine, Threonine, methionine(Met).
" aroyl " refers to that aromatic carbon ring end is connected with the group of carbonyl, and preferred aromatic ring contains 6-10 carbon atom.
" 4-hetaroylpyrazol " refers to that aromatic heterocycle end is connected with the group of carbonyl, can be monocycle or bicyclic radicals.Preferably heteroaryl comprises thienyl, furyl, pyrryl, pyridyl, pyrazinyl, thiazolyl, pyrimidyl, quinolyl and tetrazole base, benzothiazolyl, benzofuryl, indyl etc.
" cycloalkanoyl " refers to replacement or for what replace, saturated or undersaturated annular termination is connected with the group of carbonyl, and it contains carbon atom and/or one or more heteroatoms.This ring can be the ring system of monocycle or condensed ring, bridged ring or volution.Monocycle has 3-9 atom usually, preferably has 4-7 atom, and many rings contain 7-17 atom, preferably containing 7-13 atom.
" pharmacy acceptable salt " refers to that formula (II) compound has curative effect and nontoxic salt form.It can form anion salt by arbitrary acidic-group (as carboxyl), or forms cationic salts by arbitrary basic group (as amino).Much such salt known in the art.At the upper cationic salts formed of any acidic-group (as carboxyl), or at the upper anion salt formed of any basic group (as amino).It is known in the art that these salt have many, as cationic salts comprises salt and the organic salt (as ammonium salt) of basic metal (as sodium and potassium) and alkaline-earth metal (as magnesium and calcium).Also by using (II) of corresponding acid treatment alkaline form to obtain anion salt easily, such acid comprises mineral acid as sulfuric acid, nitric acid, phosphoric acid etc.; Or organic acid is as acetic acid, propionic acid, oxyacetic acid, 2 hydroxy propanoic acid, Acetylformic acid, oxalic acid, propanedioic acid, succsinic acid, toxilic acid, fumaric acid, oxysuccinic acid, tartrate, 2-hydroxyl-1,2,3-the third three acid, methylsulfonic acid, ethyl sulfonic acid, benzene methanesulfonic acid, 4-toluene sulfonic acide, cyclohexyl-sulfinic acid, 2 hydroxybenzoic acid, 4-amino-2-hydroxybenzoic acid etc.These salt are that those of skill in the art know, and those skilled in the art can prepare any salt that this area knowledge provides.In addition, those of skill in the art can get certain salt according to factors such as solubleness, stability, easily preparation and give up another kind of salt.The mensuration of these salt and optimization are in the experience range of those of skill in the art.
Formula (I) compound can also be that the form of other protected forms or derivative exists, and these forms will be apparent to those skilled in the art, and all should be included within the scope of the present invention.
Substituting group as above self also can be replaced by one or more substituting group, and preferred substituting group comprises, such as alkyl, thiazolinyl, alkoxyl group, hydroxyl, oxygen base, nitro, amino, aminoalkyl group (as aminomethyl etc.), cyano group, halogen, carboxyl, carbonylic alkoxy (as carbonyl oxyethyl group etc.), sulfenyl, aryl, cycloalkyl, heteroaryl, Heterocyclylalkyl (as piperidyl, morpholinyl, pyrryl etc.), imino-, hydroxyalkyl, aryloxy, arylalkyl, and combine.
To the evaluation of the Inhibiting enzyme activity of compound; we with hela cell extract (containing HDAC1,2,3; the mixed enzyme of 8); test with HDACs fluorescence analysis method, be divided into two steps, the first step; HDAC fluorogenic substrate (containing an acetylizad lysine side-chain-Boc-Lys(acetyl)-AMC) with containing the sample incubation of HDAC activity (as Hela nucleus extraction liquid; the HDAC8 etc. expressed), make substrate deacetylate, activate substrate.Second step, uses pancreatin hydrolysis Boc-Lys-AMC, produces this fluorophor of AMC (or chromophoric group), measures fluorescence intensity in emission wavelength/excitation wavelength (390nm/460nm).See reaction formula III below:
In reaction formula III, Histone deacetylase is histon deacetylase (HDAC), and Trypsin is trypsinase, and 4-amino-7-methylcoumarin is 4-amino-7-methylcoumarin.
The test of the extracorporeal anti-tumor cytoactive of compound we adopt MTT colorimetry, MTT full name is 3-(4,5)-dimethylthiahiazo (-z-y1)-3,5-di-phenytetrazoliumromide, Chinese chemistry 3-(4 by name, 5-dimethylthiazole-2)-2,5-diphenyltetrazolium bromide bromine salt, commodity are called tetrazolium bromide.It is a kind of dyestuff of yellow color.MTT colorimetry is a kind of method detecting cell survival and growth.Its Cleaning Principle is that the succinodehydrogenase in viable cell plastosome can make exogenous MTT be reduced to water-insoluble bluish voilet Jie Jing formazan (Formazan) and be deposited in cell, and dead cell is without this function.First a ceremonial jade-ladle, used in libation in dimethyl sulfoxide (DMSO) (DMSO) energy dissolved cell, measuring its absorbance value by microplate reader at 570nm wavelength place can reflect viable cell quantity indirectly.Within the scope of certain cell count, the amount that MTT crystallization is formed is directly proportional to cell count, and then records the inhibiting rate of target compound to tumour cell.
Target compound anti-tumor in vivo cytoactive adopts nude mouse xenograft model.By nude mice by subcutaneous inoculated tumour cell, administration 20 days, measures gross tumor volume, draws tumour curve, weighs up tumor weight and calculate tumour inhibiting rate and Relative tumor proliferation rate
Relative tumour volume (RTV)=V t/V o
The evaluation index of anti-tumor activity is Relative tumor proliferation rate T/C(%),
Accompanying drawing explanation
Fig. 1 is nude mouse tumor volume curve figure.
Fig. 2 is U937 nude mouse tumor weight comparison diagram.
Fig. 3 is U937 tumor tissues photo.
Embodiment
Below in conjunction with embodiment, the present invention is described further, but be not limited thereto.
The synthesis of embodiment 1:L1-L30, for L7.
1) preparation (2) of tryptophan methyl ester hydrochloride
Be dissolved in by tryptophane (20.4g, 100mmol) in methyl alcohol (200mL), drip Acetyl Chloride 98Min. (24g, 300mmol) under ice bath, add rear continuation ice bath 0.5h, 75 DEG C of reflux 5h, TLC detection reaction are complete.Remove most of methyl alcohol under reduced pressure, then add a small amount of methyl alcohol remove under reduced pressure (by HCl steam except), repeat 2-3 time.Add anhydrous diethyl ether, suction filtration obtains the thick product of white solid 2.
2) preparation (3) of (S)-2-((tertbutyloxycarbonyl) is amino)-3-(1H-indol-3-yl) methyl propionate
By thick for previous step product 2, add in 300mL DCM, then add TEA(30g, 300mmol) make it dissolve.By (BOC) 2o(26.2g, 120mmol) be dissolved in DCM, then the DCM solution of (BOC) 2O is successively added in reaction solution, reaction 4-5h, TLC monitoring reaction.Reaction solution 1M citric acid, saturated NaHCO 3(3 × 100ml), saturated NaCl solution (3 × 100ml) is washed.The anhydrous MgSO of organic phase 4dried overnight, suction filtration, removes solvent under reduced pressure, obtains crude product 3, then obtains product 3 with a small amount of DCM washing leaching cake of sherwood oil, is white solid 25.8g (81mmol, 81%) Mp138-139 DEG C.3) preparation (4) of (S)-2-((tertbutyloxycarbonyl) is amino)-3-(1H-indol-3-yl) propyl alcohol
By intermediate 3(9.5g, 30mmol) add in anhydrous THF, successively add LiAIH under ice bath 4(2.25g, 60mmol), room temperature reaction 3-4h, TLC monitor reaction.Add frozen water quencher after reacting completely, remove THF under reduced pressure, with EtOAc(200mL × 2) extract, the saturated NaHCO of organic phase 3(3 × 100mL), saturated NaCl solution (3 × 100mL) is washed, anhydrous MgSO 4drying, suction filtration, removes solvent under reduced pressure, obtains product 4, is faint yellow solid 7.5g (25.8mmol, 86%). 1H-NMR(600MHz,DMSO-d 6):δ1.52(m,9H),δ2.68-2.89(m,2H),δ3.28-3.37(m,2H),δ3.65(m,1H),4.62(t,J=5.4,1H),7.08(s,1H),6.50-7.30(m,4H),7.57(d,J=7.8,1H),δ10.7(s,1H)。
4) preparation (6) of 4-hydroxy-methyl cinnamate
Be dissolved in by 4-hydroxycinnamic acid (16.4g, 100mmol) in methyl alcohol (200mL), drip Acetyl Chloride 98Min. (24g, 300mmol) under ice bath, 75 DEG C of reflux 5h, TLC detection reaction are complete.Remove methyl alcohol under reduced pressure, product is dissolved in EtOAc(300mL), use saturated NaHCO 3solution (2 × 100mL), 1M citric acid solution (2 × 100mL), saturated NaCl solution (2 × 100mL).The anhydrous MgSO of organic phase 4drying, suction filtration, removed under reduced pressure solvent, obtains product 6, is white solid 15.6g (87.5mmol, 87.5%).Mp140-142℃。 1H NMR(300MHz,DMSO-d 6)δ3.69(s,3H),6.43(d,J=16.2Hz,1H),6.81(d,J=8.7Hz,2H),7.54-7.59(m,3H),10.01(s,1H).ESI-MS m/z:179.2[M+H] +。
5) preparation (7) of (S, E)-3-(4-(2-((tertbutyloxycarbonyl) is amino)-3-(1H-indol-3-yl) propoxy-) phenyl) methyl acrylate
By 4(5.8g, 20mmol), 6(4.2g, 24mmol), PPh 3(7.9g, 30mmol) is dissolved in THF, drips DEAD(5.2g, 30mmol under ice bath), reaction 1-2h, TLC monitoring reaction.Steam except THF, flash column chromatography purification, obtain product 7, be white solid 5.4g (12mmol, 60%).Mp109-110℃。 1H NMR(300MHz,DMSO-d 6)δ1.36(s,9H),2.85-3.00(m,2H),3.70(s,3H),3.95-4.07(m,3H),6.51(d,J=15.9Hz,1H),6.93-6.99(m,4H),7.08(t,J=7.4Hz,1H),7.13(d,J=2.1Hz,1H),7.34(d,J=7.8Hz,1H),7.56(d,J=7.8Hz,1H),7.63(d,J=15.9Hz,1H),7.66(d,J=8.4Hz,2H),10.82(d,J=1.5Hz,1H).ESI-MS m/z:451.5[M+H] +。
6) preparation (8) of (S, E)-3-(4-(2-amino-3-(1H-indol-3-yl) propoxy-) phenyl) methyl acrylate hydrochloride
The saturated HCl(50mL of EtOAc is dissolved in by 7) in solution, reaction is spent the night, and separates out solid, and filter, obtaining product 8, is white solid 3.8g(10mmol, 83%).Mp220-222℃。δ3.10-3.24(m,2H),3.71(s,3H),3.71-3.75(m,1H),4.07(dd,J=5.7Hz,J=10.5Hz,1H),4.21(dd,J=5.7Hz,J=10.5Hz,1H),6.53(d,J=15.9Hz,1H),6.97-7.01(m,3H),7.11(t,J=6.9Hz,1H),7.27(d,J=2.4Hz,1H),7.38(d,J=8.1Hz,1H),7.59-7.64(m,2H),7.70(d,J=8.7Hz,2H),8.40(s,2H),11.05(s,1H).ESI-MS m/z:351.5[M+H] +。
7) (S, E)-3-(4-(2-(4-chloro-benzoyl amino))-3-(1H-indol-3-yl) propoxy-) phenyl) preparation (9) of methyl acrylate
4-chloro-benzoic acid (0.31g, 2mmol) is dissolved in THF, under ice bath, adds TBTU(0.71g, 2.2mmol) and TEA(0.3g, 3mmol).Compound 8(0.85g, 2.2mmol is added after 0.5h), room temperature reaction spends the night, and steam except THF, product is dissolved in DCM, 1M hydrochloric acid (2 × 100mL) saturated Na 2cO 3(2 × 100mL), saturated NaCl solution (2 × 100mL) is washed, anhydrous MgSO 4dried overnight, suction filtration, removed under reduced pressure solvent, ethyl acetate petroleum ether recrystallization obtains product 9, is white solid 0.5g(1.1mmol, and 51%).
8) preparation (L7) of (S, E)-3-(4-(2-(4-chloro-benzoyl amino)-3-(1H-indol-3-yl) propoxy-) phenyl)-N-hydroxyacrylamide
By 9(0.5g, 1.1mmol) be dissolved in NH 2in the methanol solution (10mL) of OK, room temperature reaction 2h, TLC monitor reaction.Remove methyl alcohol under reduced pressure, add 1M hydrochloric acid and regulate PH to acid, EtOAc(2 × 30mL) extraction, saturated NaCl solution (3 × 100mL) is washed, anhydrous Na 2sO 4drying, suction filtration, removed under reduced pressure solvent, flash column chromatography carries out purifying, obtains target product L7.White solid 0.12g (0.88mmol, 24%).Mp182-184℃。 1H NMR(300MHz,DMSO-d 6)δ3.11(d,J=6.6Hz,2H),4.06-4.11(m,1H),4.14-4.20(m,1H),4.54-4.61(m,1H),6.32(d,J=15.6Hz,1H),6.93-6.98(m,3H),7.08(t,J=6.9Hz,1H),7.18(d,J=2.1Hz,1H),7.34(d,J=7.8Hz,1H),7.42(d,J=15.9Hz,1H),7.49(d,J=8.4Hz,2H),7.55(d,J=8.7Hz,2H),7.63(d,J=7.8Hz,1H),7.88(d,J=8.7Hz,2H),8.63(d,J=7.8Hz,1H),8.98(s,1H),10.66(s,1H),10.83(d,J=1.5Hz,1H).HRMS(AP-ESI)m/z calcd for C 27H 24ClN 3O 4[M+H] +490.1526,found490.1528。
Embodiment 2: the synthesis of target compound L31-L34, for L31.
1) preparation of (E)-3-(4-((S)-2-((Z)-benzylidenei is amino)--3-(1H-indol-3-yl) propoxy-) phenyl) methyl acrylate.（11）
By 8(0.76g, 2mmol) be dissolved in methyl alcohol, add TEA(0.22g, 2.2mmol), after add phenyl aldehyde (0.21g, 2mmol), after room temperature reaction 2h TLC monitoring, solvent evaporated after reacting completely, the crude product of the product 11 of vacuum drying oven drying.
2) (S, E)-3-(4-(2-(benzyl amino))-3-(1H-indol-3-yl) propoxy-) phenyl) preparation of methyl acrylate.（12）
Upper step gained is dissolved in and heavily steams in methyl alcohol, under ice bath, add NaBH 4(0.15g, 4mmol), TLC monitoring reaction after room temperature reaction 4h.Add frozen water quencher after reacting completely, steam except organic solvent, add EtOAc(3 × 30mL) extraction, anhydrous Na 2sO 4dried overnight.Steaming desolventizes, and obtains yellow oil, is product 12. 1H NMR(300MHz,DMSO-d 6)δ2.95(d,J=6.3Hz,2H),3.14-3.18(m,1H),3.70(s,3H),3.87(s,2H),3.94(d,J=5.1Hz,2H),6.50(d,J=15.9Hz,1H),6.92(t,J=7.5Hz,1H),6.95(d,J=8.7Hz,2H),7.06(t,J=7.4Hz,1H),7.14(d,J=2.4Hz,1H),7.16-7.22(m,1H),7.26-7.33(m,5H),7.43(d,J=7.8Hz,1H),7.63(d,J=15.9Hz,1H),7.65(d,J=8.7Hz,2H),8.99(s,1H),10.83(s,1H).ESI-MS m/z:441.5[M+H] +。
3) (S, E)-3-(4-(2-(benzyl (tert-butyl carbonyl) is amino)-3-(1H-indol-3-yl) propoxy-) phenyl) vinylformic acid first
The preparation of ester.（13）
Upper step gained oily matter is dissolved in DCM, successively adds TEA(0.61g, 6mmol) and (Boc) 2o (0.87g), room temperature reaction spends the night, and TLC monitors reaction, and after reacting completely, reaction solution uses 1M citric acid solution (2 × 100mL) respectively, saturated NaHCO 3solution (2 × 100mL), saturated NaCl solution (2 × 100mL) is washed, anhydrous Na 2sO 4dried overnight, obtains white oil thing after evaporate to dryness, is product 13.Vacuum drying oven drying is got step ready and is used.
4) preparation of (S, E)-3-(4-(2-(benzyl (tert-butyl carbonyl) is amino)-3-(1H-indol-3-yl) propoxy-) phenyl)-N-hydroxyacrylamide.（14）
Upper step gained is dissolved in NH after vacuum drying oven dried overnight 2in the methanol solution (10ml) of OK, room temperature reaction 2h.Remove methyl alcohol under reduced pressure, add 1M hydrochloric acid and regulate PH to acid, EtOAc(2 × 30mL) extraction, saturated NaCl solution (3 × 100mL) is washed, anhydrous Na 2sO 4drying, suction filtration, solvent evaporated, the white solid of vacuum drying oven dried overnight, is product 14.
5) preparation of (S, E)-3-(4-(2-(benzyl (tert-butyl carbonyl) is amino)-3-(1H-indol-3-yl) propoxy-) phenyl)-N-hydroxyacrylamide hydrochloride.（L31）
The saturated HCl(10mL of EtOAc is dissolved in by 14) in solution, reaction is spent the night, and separates out solid, and filter, obtaining product L31, is white solid 0.32g(0.67mmol, 34%).Mp:136-138℃ 1H NMR(300MHz,DMSO-d 6)δ3.17-3.27(m,1H),3.41-3.47(m,1H),3.67(s,1H),4.12-4.17(m,1H),4.25-4.27(m,1H),4.36(s,2H),6.38(d,J=15.6Hz,1H),6.91-6.99(m,3H),7.10(t,J=7.2Hz,1H),7.22(d,J=2.4Hz,1H),7.37(d,J=7.8Hz,2H),7.42-7.50(m,6H),7.64-7.68(m,2H),9.72(s,1H),9.92(s,1H),10.31(s,1H),11.05(d,J=1.8Hz,1H).HRMS(AP-ESI)m/z calcd for C 27H 27N 3O 3[M+H] +442.2125,found442.2125。
Embodiment 3: the synthesis of target compound L36
1) preparation (16) of (S)-2-((tertbutyloxycarbonyl) is amino)-3-(1-Methyl-1H-indole-3-base) propyl alcohol
By compound 4(2.9g, 10mmol) be dissolved in 50mLTHF, add Tetrabutyl amonium bromide 0.5g successively, CH 3i(3.5g, 25mmol), add the KOH solution of 15mL50% after stirring, reaction is spent the night, and TLC monitors, question response completely after reaction solution steam except THF, add EtOAc(50mL × 2) extraction, organic phase with 1M citric acid solution (100mL × 2), saturated NaHCO 3solution (2 × 100mL), saturated NaCl solution (2 × 100mL) is washed, anhydrous Na 2sO 4drying, suction filtration, removed under reduced pressure solvent, ethyl acetate petroleum ether recrystallization, obtains white solid 16,1.6g(5.4mmol, 54%).
2) preparation (17) of (S, E)-3-(4-(2-((tertbutyloxycarbonyl) is amino)-3-(1-Methyl-1H-indole-3-base) propoxy-) phenyl) methyl acrylate
By compound 16(1.5g, 5mmol), 4-coumaric acid methyl esters (1.1g, 6mmol), PPh 3(2.0g, 7.5mmol) is dissolved in and heavily steams in THF, drips DEAD(1.3g, 7.5mmol under ice bath), room temperature reaction, TLC monitoring after 2h, after reacting completely, flash column chromatography purification, obtains product 17, is white solid 1.4g(3mmol, and 60%).
3) preparation (L35) of (S, E)-3-(4-(2-((tertbutyloxycarbonyl) is amino)-3-(1-Methyl-1H-indole-3-base) propoxy-) phenyl)-N-hydroxyacrylamide
By 17(0.46g, 1mmol) be dissolved in NH 2in the methanol solution (10mL) of OK, room temperature reaction 2h, TLC monitor reaction.Remove methyl alcohol under reduced pressure, add 1M hydrochloric acid and regulate PH to acid, EtOAc(2 × 30mL) extraction, saturated NaCl solution (3 × 100mL) is washed, anhydrous Na 2sO 4drying, suction filtration, removed under reduced pressure solvent, flash column chromatography carries out purifying, obtains target product L35.White solid 0.13g (0.28mmol, 28%).Mp:146-148℃ 1H NMR(300MHz,DMSO-d 6)δ1.36(s,9H),2.83-2.99(m,2H),3.72(s,3H),3.93-4.04(m,3H),6.33(dd,J=4.5Hz,J=15.9Hz,1H),6.95(d,J=8.4Hz,2H),6.97-7.02(m,2H),7.10-7.15(m,2H),7.36-7.42(m,2H),7.49(d,J=8.4Hz,2H),7.58(d,J=7.8Hz,1H),8.97(s,1H),10.66(s,1H).HRMS(AP-ESI)m/z calcd for C 26H 31N 3O 5[M+H] +466.2336,found466.2332。
The test of the external Inhibiting enzyme activity of embodiment 4 compound
1.HDAC buffer:15mM Tris-HCl(PH8.0), 250 μMs of EDTA, 250mM NaCl, 10% glycerine.(compound method of HDACbuffer: the Tris-HCl storing solution 500mL first preparing 1M, namely
1M*500mL*121.14g/mol=60.57g Tris is dissolved in and is slightly less than in the distilled water of 500mL, then regulates pH to 8 with concentrated hydrochloric acid, then uses distilled water polishing to 500mL.The Tris-HCl storing solution and 250 μMs of * 500mL*292.25g/mol=0.03654Gedta, the 250mM*500mL*58.44g/mol=7.31g NaCl that get 7.5mL1M mix rear adding distil water to 450mL, then add 50mL glycerine, obtain 500mLHDAC buffer.)
2.Trypsin solution:10mg/ml pancreatin, 50mM Tris-HCL(PH8.0), 100mM NaCl, first 2 μMs of TSA(prepare the storing solution 500mL not containing pancreatin and TSA, namely the Tris-HCl storing solution and the 100mM*500mL*58.44g/mol=2.92gNaCl that get 25mL1M mix rear adding distil water to 500mL, get pancreatin and TSA that appropriate storing solution adds respective amount before use again).
3. substrate: DMSO dissolves the liquid storage being made into 30mM, is diluted to 300uM, makes DMSO content be about 1% with HDAC buffer.
4. enzyme liquid: Hela cell extract, dilutes by 1:20 HDAC buffer.
5. step:
A) preparation of 100% solution: 50 μ L HDAC buffer mix with 10 μ L enzyme liquid, add 40 μ L substrates after 5min and react 30min at 37 DEG C, then add 100 μ L Trypsin solution and stop above-mentioned reaction, and 20min is reacted at 37 DEG C, measure fluorescence intensity in 390nm/460nm, obtain 100% absorption.Do typical curve with AMC as standard substance, calculate enzyme and live.
B) preparation of blank solution: react 30min after 60 μ L HDAC buffer add 40 μ L substrates at 37 DEG C, then 100 μ L Trypsin solution are added, and 20min is reacted at 37 DEG C, measure fluorescence intensity in 390nm/460nm, obtain blank absorption.
6. the determination step that Drug inhibition HDAC enzyme is alive: the HDAC buffer that 50 μ L contain medicine mixes with 10 μ L enzyme liquid hatches 5min in advance, after adding 40 μ L substrates, 30min is reacted at 37 DEG C, then add 100 μ L Trypsin solution and stop above-mentioned reaction, and 20min is reacted at 37 DEG C, measure fluorescence intensity in 390nm/460nm.
Finally the inhibiting rate (%) of compound and its respective concentration are carried out S curve matching, calculate IC 50value.
Part of compounds shown in general structure of the present invention (I) and the inhibit activities of positive control drug SAHA to histon deacetylase (HDAC) the results are shown in table 1 below:
Table 1 part of compounds and positive control drug SAHA are to the inhibit activities result of histon deacetylase (HDAC)
Numbering Hela cell extract IC 50(nM) Numbering Hela cell extract IC 50(nM)
L1 5.22±0.100 L20 10.376±0.533
L2 2.91±0.054 L21 30.177±0.426
L4 42.463±5.363 L22 2.27±0.091
L5 113.565±20.321 L23 67.369±5.465
L6 >300 L24 104.319±10.280
L7 2.5±0.011 L25 43.451±4.476
L15 130.034±1.342 L26 >300
L16 970.789±10.487 L27 35.621±4.890
L17 680.454±5.677 L31 79.94±1.190
L18 70.204±1.336 SAHA 120±11.278
L19 170.018±2.879
Experimental result shows: compound has obvious restraining effect to Hela cell extract, and wherein the Inhibiting enzyme activity of compound L 1, L2, L7, L20, L22 will be better than far away positive control drug SAHA.
The test (MTT experiment) of the extracorporeal anti-tumor cytoactive of embodiment 5 compound
1. experiment material
MTT, RPMI1640 substratum, foetal calf serum, 96 orifice plates, CO 2constant incubator, U.S. BIO-RAD680 type microplate reader human breast cancer cell's strain (MDA-MB-231), Prostatic cancer cell lines (PC-3), human colon cancer cell strain (HCT116), human erythroleukemia cell's strain (K562), human erythroleukemia cell's strain (HEL) and acute myeloblast leukemia cell line (KG1), positive control drug SAHA.
2. experimental procedure
(1) inoculating cell, is made into individual cells suspension with the nutrient solution containing 10% foetal calf serum, is inoculated into 96 orifice plates, every pore volume 100uL, overnight incubation with 5000, every hole cell.
(2) preparation of compound solution, in aseptic, is diluted to 5 concentration to be measured by the DMSO storing solution of compound with nutrient solution, is twice dilution between adjacent concentration.
(3) add in 95 orifice plates of overnight incubation by the compound solution of different concns, add 100 μ L in every hole, each concentration adds three secondary orifices.Around owing to having fringing effect, easy microbiological contamination, does not therefore add cell, does not add compound, and the nutrient solution adding 100 μ L is used as blank.100% hole is separately set, namely adds cell and not containing the nutrient solution 100uL of compound, in 37 DEG C of constant incubators, hatch 48h.
(4) dye, 10 μ L MTT solution (5mg/mL PBS prepares) dyeing are added to 96 orifice plates, after hatching 4h, the centrifugal 10min of 2500rps, then with the volley of rifle fire by nutrient solution sucking-off from hole, notice that rifle point is not down by cell sucking-off, add 150 μ L DMSO, at oscillating plate concussion 5-10min clock, first a ceremonial jade-ladle, used in libation is fully dissolved, measures by microplate reader the OD value that 570nm measures every hole.
Part of compounds MTT experiment result is as shown in table 2 below:
Table 2 compound MTT experiment result
Experimental result shows: compound L 1, L7, L9, L10, L12, L22, L31, L32 all has stronger In Vitro Anti proliferation activity in above five strain cells, and wherein compound L 7, L12 antiproliferative activity is the most obvious, IC 50value is far smaller than SAHA.
The activity of anti-human leukemia cell U937 cell in embodiment 6 target compound body
In nude mice right shoulder subcutaneous vaccination tumour cell U937, every 100uL (cell counting: 1.8*108/mL), starts administration of dividing into groups after one week, mice with tumor is divided into 3 groups, is respectively control group, SAHA group, to be measured group.Dosage 100mg/kg/d, administration volume: every 200uL/20g at every turn, administering mode; Gastric infusion, later every day is administered once, measure gross tumor volume every three days, get each cell mean, draw tumor growth curve (see accompanying drawing 1), administration the 16 day, put to death nude mice, dissect tumour and internal organ, experiment terminates, weigh up the weight (see accompanying drawing 2 and 3) of knurl block, and according to formulae discovery tumour inhibiting rate.Measure tumour maximum diameter (a) and most path (b), calculate gross tumor volume (V): V=ab 2/ 2, and calculate Relative tumor proliferation rate T/C(%).
Relative tumour volume (RTV)=V t/V o
The evaluation index of anti-tumor activity is Relative tumor proliferation rate T/C(%),
Choose the screening that compound L 7 carries out anti-tumor in vivo cytoactive, adopt the different grafting nude mice of human leukemia cell U937 to test, observe L7 to the tumor inhibitory effect of tumor bearing nude mice.As shown in table 3 below:
The tumor inhibitory effect of table 3 pair tumor bearing nude mice
Compound number Tumor control rate (%) Relative tumor appreciation rate (%)
SAHA 24.97 46.91
L7 44.36 36.24
Experimental result shows: under 100mg/kg/d dosage, and L7 can obviously grow by Tumor suppression, and tumour inhibiting rate is respectively 46.91%, and positive control drug SAHA also can obviously grow by inhibition tumor cell, tumour inhibiting rate 36.24%.As can be seen from tumour inhibiting rate result we, the tumor suppression ability outline of L7 compound, higher than SAHA, does not find obvious toxic side effect yet.Also having good anti-tumor activity in vivo from a series of screening active ingredients result compound L 7, obviously can suppress leukemic cell growth, can be a potential leukemic hdac inhibitor for the treatment of.

Claims (4)

1. cinnamide histone deacetylase inhibitor, is characterized in that for one of following compounds:
L1:( s,E)-3-(4-(2-(benzoylamino)-3-(1 h-indol-3-yl) propoxy-) phenyl)- n-hydroxyacrylamide,
L7:( s,E)-3-(4-(2-(4-chloro-benzoyl amino)-3-(1 h-indol-3-yl) propoxy-) phenyl)- n-hydroxyacrylamide:,
L9:( s,E)-3-(4-(2-(2-chloro-benzoyl amino)-3-(1 h-indol-3-yl) propoxy-) phenyl)- n-hydroxyacrylamide,
L12:( s,E)-3-(4-(2-(4-fluorobenzoyl amido)-3-(1 h-indol-3-yl) propoxy-) phenyl)- n-hydroxyacrylamide,
L22:( s,E)-3-(4-(2-(2-Hydroxylbenzamide base)-3-(1 h-indol-3-yl) propoxy-) phenyl)- n-hydroxyacrylamide,
L31:( s,E)-3-(4-(2-((4-luorobenzyl) is amino)-3-(1 h-indol-3-yl) propoxy-) phenyl)- n-hydroxyacrylamide,
L32:( s,E)-3-(4-(2-((4-chlorobenzyl) is amino)-3-(1 h-indol-3-yl) propoxy-) phenyl)- n-hydroxyacrylamide.
2. the application of compound according to claim 1 in the medicine of the mammalian diseases that preparation prevents or treatment is relevant to histone deacetylase activity unconventionality expression; Described with the related mammalian disease of histone deacetylase activity unconventionality expression is: cancer, neurodegenerative disease, virus infection, inflammation, malaria and diabetes.
3. be suitable for orally giving a mammiferous pharmaceutical composition, comprise compound and one or more pharmaceutically acceptable carriers or the vehicle of claim 1.
4. be suitable for parenteral and give a mammiferous pharmaceutical composition, comprise compound and one or more pharmaceutically acceptable carriers or the vehicle of claim 1.
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