CN103467359A - 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 PDFInfo
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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
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 that contains indoles and its preparation method and application, belong to organic compound and synthesize and the medical applications technical field.
Background technology
Malignant tumour is the No.1 killer who threatens human life's health.The generation of tumour with the development not only relevant with the change of gene order, also with chromosomal after changing substantial connection is arranged.The reversibility covalent modification of histone is the important behaviour form of changing after karyomit(e), comprises phosphorylation/dephosphorylation, acetylize/deacetylation, adenylylation/go adenylylation, uridine acidylate/go the uridine acidylate, methylate/demethylation etc.The reinvent important role of the Acetylation Level of histone to chromosome structure; acetylize/deacetylation is to complete (Shahbazian, M.D. by acetylation of histone enzyme (HATs) and these two kinds interactional metalloprotease co-catalysis of histon deacetylase (HDAC) (HDACs); Grunstein, M.Functions of Site-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; increased the positive charge density of N-terminal; itself and the interaction of DNA with negative charge have been strengthened; make the chromosome structure consolidation more that becomes; and then hindered the combination of transcription factor and DNA; finally make transcribing of gene be suppressed, comprising cancer suppressor gene.Effect and the HDACs of HATs are just the opposite, have finally promoted transcribing of gene.(Legube G, Trouche D.Regulating histone acetyltransferases and deacetylases[J] .Eur mole Biol org (EMBO) reports.2003,4 (10): 944-947) in cancer cells, the running balance between HDACs and HATs has been broken in the abnormal overexpression of HDACs.Except histone, the effect substrate 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 that suppresses HDACs has become a Critical policies of the various diseases treatment that comprises tumour.
At present, have been found that 18 kinds of HDACs in the mankind, by its structure function difference, can be divided into 4 classes, I class HDACs comprises HDAC1,2,3,8; II class HDACs comprises HDAC4,5,6,7,9,10; IV class HDACs comprises HDAC11; III class HDACs comprises sirtuins1-7.Wherein I II IV class HDACs is Zn
2+dependent histon deacetylase (HDAC), III class HDACs is NAD
+the 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 skin T glucagonoma (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, the present invention also provides 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, with and optical isomer, diastereomer and racemic mixture, its pharmacy acceptable salt, solvate or prodrug, have the structure shown in following general formula I.
Wherein:
R
1acyl group, aroyl, 4-hetaroylpyrazol, aryl C1-6 alkyloyl, heteroaryl C1-9 alkyloyl, C1-6 alkyloyl, cycloalkanes acyl group, 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 prepared by hydrogen, each seed amino acid;
R
2hydrogen; The electron-withdrawing groups such as halogen atom, nitro, carboxyl; Alkyl, amino, hydroxyl, methylol, amine methyl, carbamyl etc. are given electric group;
R
3hydrogen, methyl;
X be between the position and contraposition O, the N atom;
Y is
or
* be that steric configuration is 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-brombenzamide base)-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-ethyl butyramide base)-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) amino)-3-(1H-indol-3-yl) propoxy-) phenyl)-N-hydroxyacrylamide (L17),
(S, E)-3-(4-(2-(2-((tertbutyloxycarbonyl) 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-hydroxyl propionyl-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) 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-yl)-3-(1H-indol-3-yl) propoxy-) phenyl)-N-hydroxyacrylamide (L26),
(S, E)-3-(3-(2-((tertbutyloxycarbonyl) 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 amino)-3-(1H-indol-3-yl) propoxy-) phenyl)-N-hydroxyacrylamide (L30),
(S, E)-3-(4-(2-((4-luorobenzyl) amino)-3-(1H-indol-3-yl) propoxy-) phenyl)-N-hydroxyacrylamide (L31),
(S, E)-3-(4-(2-((4-chlorobenzyl) amino)-3-(1H-indol-3-yl) propoxy-) phenyl)-N-hydroxyacrylamide (L32),
(S, E)-3-(4-(2-((4-bromobenzyl) 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) amino)-3-(1-Methyl-1H-indole-3-yl) 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 the Acetyl Chloride 98Min. effect, with (Boc)
2o protection alpha-amino group obtains intermediate 3, then passes through LiAIH
4the reduction 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, perhaps 7 through EtOAc/HCl, slough the Boc blocking group, amino acid or the carboxylic acid condensation of last and various Boc protections are acid amides, and methyl esters is converted into to hydroximic acid obtains target compound;
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, the cycloalkanes acyl group, arylsulfonyl, assorted alkylsulfonyl, aryl C1-6 alkane alkylsulfonyl, heteroaryl C1-9 alkane alkylsulfonyl, C1-8 carbalkoxy or aryl C1-8 carbalkoxy;
Reagent in the 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; (e) the saturated HCl solution of 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 reacts with the cyclosubstituted phenyl aldehyde of benzene, generates schiff bases 11,11 and generates parahelium 12 through sodium borohydride reduction, and Boc protection product 13 is converted into hydroximic acid 14, and last N sloughs protection and generates target compound (L30-L33);
Wherein R is hydrogen; Halogen atom, nitro, the electron-withdrawing groups such as carboxyl; Alkyl, amino, hydroxyl, methylol, the amine methyl, carbamyls etc. are given electric group;
Reagent in the 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: the N methyl protection product 16 on intermediate 4 indole rings reacts with 4 coumaric acid methyl esters, generates intermediate 17,17 through de-Boc, amide condensed, finally generates the hydroximic acid end product;
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, the cycloalkanes acyl group, arylsulfonyl, assorted alkylsulfonyl, aryl C1-6 alkane alkylsulfonyl, heteroaryl C1-9 alkane alkylsulfonyl, C1-8 carbalkoxy or aryl C1-8 carbalkoxy;
Reagent in the said synthesis route reaction formula: (a) CH
3i, KOH, TBABr, H
2o, THF; (b) PPh
3, DEAD, anhydrous THF; (c) the saturated HCl solution of 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 be changed to improve yield to above-mentioned steps; they can determine synthetic route according to the ABC of this area; as the selective reaction thing, solvent and temperature, thus can improve yield with the generation of avoiding side reaction by using various GPF (General Protection False bases.These conventional guard methods can be referring to for example T.Greene, Protecting Groups in Organic Synthesis.
Three, the pharmaceutical composition that contains the compounds of this invention and application
The present invention also provides the application in the medicine of prevention or the treatment mammalian diseases relevant to the active unconventionality expression of histon deacetylase (HDAC) of these compounds.The described related mammalian disease with the active unconventionality expression of histon deacetylase (HDAC) comprises: cancer, neurodegenerative disease, virus infection, inflammation, malaria and diabetes etc.Therefore, the invention still further relates to the pharmaceutical composition that contains (I) structural compounds.
In addition, the present invention also comprises a kind of oral mammiferous pharmaceutical composition that gives that is suitable for, and the arbitrary compound that comprises above-mentioned general formula (I), and pharmaceutically acceptable carrier, optionally comprise one or more pharmaceutically acceptable vehicle.
In addition, the present invention also comprises that a kind of parenteral that is suitable for gives mammiferous pharmaceutical composition, and the arbitrary compound that comprises above-mentioned general formula (I), and pharmaceutically acceptable carrier, optionally comprise 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 that various amino acid whose carboxyls are obtained after acidylate, preferred hydrophobic amino acid, and as glycine, L-Ala; α-amino-isovaleric acid, leucine, Isoleucine, phenylalanine; proline(Pro), Serine, Threonine, methionine(Met).
" aroyl " refers to that the 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 the 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.
" cycloalkanes acyl group " refers to replace 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 monocycle or condensed ring, the ring system of bridged ring or volution.Monocycle has 3-9 atom usually, preferably has 4-7 atom, and many rings contain 7-17 atom, preferably contain 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 can obtain easily anion salt by (II) that uses corresponding acid treatment alkaline form, such acid comprises that mineral acid is 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, easy preparations and give up another kind of salt.The mensuration of these salt and optimization are in those of skill in the art's experience scope.
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 contained in scope of the present invention.
Substituting group as above self also can be replaced by one or more substituting groups, and preferred substituting group comprises, alkyl for example, 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 combination.
Evaluation to the Inhibiting enzyme activity of compound; we (contain HDAC1,2,3 with the hela cell extract; 8 mixed enzyme); tested with the 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) use the sample incubation that contains the HDAC activity (as Hela nucleus extraction liquid; the HDAC8 expressed etc.), make the substrate deacetylate, activate substrate.Second step, use pancreatin hydrolysis Boc-Lys-AMC, produces this fluorophor of AMC (or chromophoric group), in emission wavelength/excitation wavelength (390nm/460nm), measures fluorescence intensity.See following reaction formula III:
In the reaction formula III, Histone deacetylase is histon deacetylase (HDAC), and Trypsin is trypsinase, and 4-amino-7-methylcoumarin is 4-amino-7-methylcoumarin.
We adopt the MTT colorimetry test of the extracorporeal anti-tumor cytoactive of compound, the 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-phenylbenzene tetrazole bromine salt, commodity are called tetrazolium bromide.It is a kind of dyestuff of yellow color.The MTT colorimetry is a kind of method that detects cell survival and growth.Its detection principle is that the succinodehydrogenase in the 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, measure its absorbance value by microplate reader at 570nm wavelength place and can indirectly reflect viable cell quantity.In certain cell count scope, the amount that the MTT crystallization forms 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 the bare mouse different species transplantation model.By nude mice by subcutaneous inoculated tumour cell, administration 20 days, measure gross tumor volume, draws the 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(%),
The accompanying drawing explanation
Fig. 1 is nude mice gross tumor volume graphic representation.
Fig. 2 is U937 nude mice 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 to this.
Embodiment 1:L1-L30's is synthetic, take L7 as example.
1) preparation of tryptophan methyl ester hydrochloride (2)
Tryptophane (20.4g, 100mmol) is dissolved in methyl alcohol (200mL), drips Acetyl Chloride 98Min. (24g, 300mmol) under ice bath, add rear continuation ice bath 0.5h, 75 ℃ of reflux 5h, the TLC detection reaction is 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.
The preparation (3) of 2) (S)-2-((tertbutyloxycarbonyl) amino)-3-(1H-indol-3-yl) methyl propionate
By the thick product 2 of previous step, add in 300mL DCM, then add TEA(30g, 300mmol) make its dissolving.By (BOC)
2o(26.2g, 120mmol) be dissolved in DCM, then the DCM solution of (BOC) 2O is successively added in reaction solution to reaction 4-5h, TLC monitoring reaction.Reaction solution 1M citric acid, saturated NaHCO
3(3 * 100ml), saturated NaCl solution (3 * 100ml) washing.The anhydrous MgSO of organic phase
4dried overnight, suction filtration, remove solvent under reduced pressure, obtains crude product 3, then with a small amount of DCM washing leaching cake of sherwood oil, obtains product 3, is white solid 25.8g (81mmol, 81%) Mp138-139 ℃.The preparation (4) of 3) (S)-2-((tertbutyloxycarbonyl) 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 monitoring reaction.Add the 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) washing, anhydrous MgSO
4drying, suction filtration, remove 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 of 4-hydroxy-methyl cinnamate (6)
4-hydroxycinnamic acid (16.4g, 100mmol) is dissolved in methyl alcohol (200mL), drips Acetyl Chloride 98Min. (24g, 300mmol) under ice bath, 75 ℃ of reflux 5h, the TLC detection reaction is 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, solvent is removed in decompression, 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]
+。
The preparation (7) of 5) (S, E)-3-(4-(2-((tertbutyloxycarbonyl) 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, under ice bath, drips DEAD(5.2g, 30mmol), reaction 1-2h, TLC monitoring reaction.Steam except THF, the flash column chromatography purification, obtain product 7, is 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]
+。
The preparation (8) of 6) (S, E)-3-(4-(2-amino-3-(1H-indol-3-yl) propoxy-) phenyl) methyl acrylate hydrochloride
By the 7 saturated HCl(50mL that are dissolved in EtOAc) in solution, reaction is spent the night, and separates out solid, filters, and obtains 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).0.5h after add compound 8(0.85g, 2.2mmol), room temperature reaction spends the night, and steams except THF, product is dissolved in DCM, the saturated Na of 1M hydrochloric acid (2 * 100mL)
2cO
3(2 * 100mL), saturated NaCl solution (2 * 100mL) washing, anhydrous MgSO
4dried overnight, suction filtration, solvent is removed in decompression, the ethyl acetate petroleum ether recrystallization obtains product 9, is white solid 0.5g(1.1mmol, 51%).
The preparation (L7) of 8) (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 of OK (10mL), room temperature reaction 2h, TLC monitoring reaction.Remove methyl alcohol under reduced pressure, add 1M hydrochloric acid to regulate PH to acid, EtOAc(2 * 30mL) extraction, saturated NaCl solution (3 * 100mL) washing, anhydrous Na
2sO
4drying, suction filtration, solvent is removed in decompression, and the 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: target compound L31-L34's is synthetic, take L31 as example.
The preparation of 1) (E)-3-(4-((S)-2-((Z)-benzylidenei 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), TLC monitoring after room temperature reaction 2h, the rear solvent evaporated that reacts 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 the 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 (tertiary butyl carbonyl) 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, the TLC monitoring reaction, the rear reaction solution that reacts completely is used respectively 1M citric acid solution (2 * 100mL), saturated NaHCO
3solution (2 * 100mL), saturated NaCl solution (2 * 100mL) washing, anhydrous Na
2sO
4dried overnight, obtain white oily matter after evaporate to dryness, be product 13.The vacuum drying oven drying is got step ready and is used.
The preparation of 4) (S, E)-3-(4-(2-(benzyl (tertiary butyl carbonyl) amino)-3-(1H-indol-3-yl) propoxy-) phenyl)-N-hydroxyacrylamide.（14）
Upper step gained is dissolved in NH after the vacuum drying oven dried overnight
2in the methanol solution of OK (10ml), room temperature reaction 2h.Remove methyl alcohol under reduced pressure, add 1M hydrochloric acid to regulate PH to acid, EtOAc(2 * 30mL) extraction, saturated NaCl solution (3 * 100mL) washing, anhydrous Na
2sO
4drying, suction filtration, solvent evaporated, the white solid of vacuum drying oven dried overnight, be product 14.
The preparation of 5) (S, E)-3-(4-(2-(benzyl (tertiary butyl carbonyl) amino)-3-(1H-indol-3-yl) propoxy-) phenyl)-N-hydroxyacrylamide hydrochloride.（L31）
By the 14 saturated HCl(10mL that are dissolved in EtOAc) in solution, reaction is spent the night, and separates out solid, filters, and obtains 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: target compound L36's is synthetic
The preparation (16) of 1) (S)-2-((tertbutyloxycarbonyl) amino)-3-(1-Methyl-1H-indole-3-yl) propyl alcohol
By compound 4(2.9g, 10mmol) be dissolved in 50mLTHF, add successively Tetrabutyl amonium bromide 0.5g, CH
3i(3.5g, 25mmol), add the KOH solution of 15mL50% after stirring, reaction is spent the night, the TLC monitoring, question response fully after reaction solution steam except THF, add EtOAc(50mL * 2) extraction,, 1M citric acid solution (100mL * 2) for organic phase, saturated NaHCO
3solution (2 * 100mL), saturated NaCl solution (2 * 100mL) washing, anhydrous Na
2sO
4drying, suction filtration, solvent is removed in decompression, the ethyl acetate petroleum ether recrystallization, obtain white solid 16,1.6g(5.4mmol, 54%).
The preparation (17) of 2) (S, E)-3-(4-(2-((tertbutyloxycarbonyl) amino)-3-(1-Methyl-1H-indole-3-yl) 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, under ice bath, drips DEAD(1.3g, 7.5mmol), room temperature reaction, TLC monitoring after 2h, after reacting completely, the flash column chromatography purification, obtain product 17, is white solid 1.4g(3mmol, 60%).
The preparation (L35) of 3) (S, E)-3-(4-(2-((tertbutyloxycarbonyl) amino)-3-(1-Methyl-1H-indole-3-yl) propoxy-) phenyl)-N-hydroxyacrylamide
By 17(0.46g, 1mmol) be dissolved in NH
2in the methanol solution of OK (10mL), room temperature reaction 2h, TLC monitoring reaction.Remove methyl alcohol under reduced pressure, add 1M hydrochloric acid to regulate PH to acid, EtOAc(2 * 30mL) extraction, saturated NaCl solution (3 * 100mL) washing, anhydrous Na
2sO
4drying, suction filtration, solvent is removed in decompression, and the 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 compounds
1.HDAC buffer:15mM Tris-HCl(PH8.0), 250 μ M EDTA, 250mM NaCl, 10% glycerine.(the compound method of HDAC buffer: at first prepare the Tris-HCl storing solution 500mL of 1M,
1M*500mL*121.14g/mol=60.57g Tris is dissolved in the distilled water that is slightly less than 500mL, then with concentrated hydrochloric acid, regulates pH to 8, then uses the distilled water polishing to 500mL.Get Tris-HCl storing solution and the 250 μ M*500mL*292.25g/mol=0.03654Gedta of 7.5mL1M, 250mM*500mL*58.44g/mol=7.31g NaCl mixes rear adding distil water to 450mL, then adds 50mL glycerine, obtains 500mLHDAC buffer.)
2.Trypsin solution:10mg/ml pancreatin, 50mM Tris-HCL(PH8.0), 100mM NaCl, at first 2 μ M TSA(prepare the storing solution 500mL that does not contain pancreatin and TSA, 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 before use pancreatin and TSA that appropriate storing solution adds respective amount again).
3. substrate: DMSO dissolves the liquid storage that is made into 30mM, with HDAC buffer, is diluted to 300uM, and making DMSO content is 1% left and right.
4. enzyme liquid: the Hela cell extract, press HDAC buffer dilution for 1:20.
5. step:
A) preparation of 100% solution: 50 μ L HDAC buffer mix with 10 μ L enzyme liquid, after 5min, add 40 μ L substrates to react 30min under 37 ℃, then add 100 μ L Trypsin solution to stop above-mentioned reaction, and react 20min under 37 ℃, 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: after 60 μ L HDAC buffer add 40 μ L substrates, under 37 ℃, react 30min, then add 100 μ L Trypsin solution, and react 20min under 37 ℃, and measure fluorescence intensity in 390nm/460nm, obtain blank absorption.
6. medicine suppresses the determination step that the HDAC enzyme is lived: the HDAC buffer that 50 μ L contain medicine mixes and hatches in advance 5min with 10 μ L enzyme liquid, after adding 40 μ L substrates, react 30min under 37 ℃, then add 100 μ L Trypsin solution to stop above-mentioned reaction, and react 20min under 37 ℃, measure fluorescence intensity in 390nm/460nm.
Finally the inhibiting rate of compound (%) and its respective concentration are carried out to the S fitting of a curve, calculate IC
50value.
Part of compounds shown in general structure of the present invention (I) and positive control drug SAHA the results are shown in following table 1 to the inhibition activity of histon deacetylase (HDAC):
Table 1 part of compounds and positive control drug SAHA are to the active result of the inhibition 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 the Hela cell extract, and wherein compound L 1, L2, and L7, L20, the Inhibiting enzyme activity of L22 will be better than positive control drug SAHA far away.
The test of the extracorporeal anti-tumor cytoactive of embodiment 5 compounds (MTT experiment)
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, be made into the individual cells suspension with the nutrient solution containing 10% foetal calf serum, is inoculated into 96 orifice plates with 5000, every hole cell, every pore volume 100uL, overnight incubation.
(2) preparation of compound solution, in aseptic, be diluted to 5 concentration to be measured by the DMSO storing solution of compound with nutrient solution, between adjacent concentration, is the twice dilution.
(3) compound solution of different concns is added in 95 orifice plates of overnight incubation, add 100 μ L in every hole, each concentration adds three secondary holes.On every side owing to having fringing effect, easily microbiological contamination, therefore do not add cell, do not add compound, and the nutrient solution that adds 100 μ L is as blank.100% hole separately is set, adds cell and, not containing the nutrient solution 100uL of compound, in 37 ℃ of constant incubators, hatch 48h.
(4) dyeing, add 10 μ L MTT solution (5mg/mL prepares with PBS) dyeing 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 the rifle point is not down by the cell sucking-off, add 150 μ L DMSO, at oscillating plate concussion 5-10min clock, the first a ceremonial jade-ladle, used in libation is fully dissolved, measure by microplate reader the OD value that 570nm measures every hole.
Part of compounds MTT experimental result is as shown in table 2 below:
Table 2 compound MTT experimental result
Experimental result shows: compound L 1, and 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, and the 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 bodies
In the right shoulder subcutaneous vaccination of nude mice tumour cell U937, every 100uL (cell counting: 1.8*108/mL), started the administration of dividing into groups after one week, and mice with tumor is divided into to 3 groups, is respectively control group, SAHA group, to be measured group.Dosage 100mg/kg/d, administration volume: each every 200uL/20g, administering mode; Gastric infusion, be administered once every day later, measure every three days gross tumor volume, get each cell mean, draw tumor growth curve (seeing accompanying drawing 1), administration the 16 day, put to death nude mice, dissect tumour and internal organ, experiment finishes, weigh up the weight (seeing accompanying drawing 2 and 3) of knurl piece, and calculate tumour inhibiting rate according to formula.Measure tumour maximum diameter (a) and path (b), calculating 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 compound L 7 and carry out the screening of anti-tumor in vivo cytoactive, adopt the different grafting nude mice of human leukemia cell U937 to be tested, observe the tumor suppression effect of L7 to tumor bearing nude mice.As shown in table 3 below:
The tumor suppression effect of table 3 pair tumor bearing nude mice
| Compound number | Tumor control rate (%) | Relative tumour appreciation rate (%) |
| SAHA | 24.97 | 46.91 |
| L7 | 44.36 | 36.24 |
Experimental result shows: under the 100mg/kg/d dosage, L7 can obviously suppress tumor growth, and tumour inhibiting rate is respectively 46.91%, and positive control drug SAHA is obviously inhibition tumor cell growth also, tumour inhibiting rate 36.24%.From the tumour inhibiting rate result, we can find out, the tumor suppression ability outline of L7 compound, higher than SAHA, is not found obvious toxic side effect yet.Also having in vivo good anti-tumor activity from a series of screening active ingredients result compound L 7, can obviously suppress leukemia cell's growth, can be a leukemic hdac inhibitor of potential treatment.
Claims (9)
1. cinnamide histone deacetylase inhibitor, with and optical isomer, diastereomer and racemic mixture, its pharmacy acceptable salt, solvate or prodrug have the structure shown in following general formula I:
Wherein:
R
1acyl group, aroyl, 4-hetaroylpyrazol, aryl C1-6 alkyloyl, heteroaryl C1-9 alkyloyl, C1-6 alkyloyl, cycloalkanes acyl group, 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 prepared by hydrogen, each seed amino acid;
R
2hydrogen; The electron-withdrawing groups such as halogen atom, nitro, carboxyl; Alkyl, amino, hydroxyl, methylol, amine methyl, carbamyl etc. are given electric group;
R
3hydrogen, methyl;
X be between the position and contraposition O, the N atom;
Y is
or
* be that steric configuration is S or R optical purity or its raceme.
2. compound as claimed in claim 1, is characterized in that: R
1it is aroyl; R
2hydrogen, halogen atom; R
3hydrogen; X is contraposition O atom; Y is
3. compound as claimed in claim 1 is characterized in that for one of following compounds:
(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-brombenzamide base)-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-ethyl butyramide base)-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) amino)-3-(1H-indol-3-yl) propoxy-) phenyl)-N-hydroxyacrylamide (L17),
(S, E)-3-(4-(2-(2-((tertbutyloxycarbonyl) 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-hydroxyl propionyl-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) 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-yl)-3-(1H-indol-3-yl) propoxy-) phenyl)-N-hydroxyacrylamide (L26),
(S, E)-3-(3-(2-((tertbutyloxycarbonyl) 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 amino)-3-(1H-indol-3-yl) propoxy-) phenyl)-N-hydroxyacrylamide (L30),
(S, E)-3-(4-(2-((4-luorobenzyl) amino)-3-(1H-indol-3-yl) propoxy-) phenyl)-N-hydroxyacrylamide (L31),
(S, E)-3-(4-(2-((4-chlorobenzyl) amino)-3-(1H-indol-3-yl) propoxy-) phenyl)-N-hydroxyacrylamide (L32),
(S, E)-3-(4-(2-((4-bromobenzyl) 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) amino)-3-(1-Methyl-1H-indole-3-yl) propoxy-) phenyl)-N-hydroxyacrylamide (L35).
4. the preparation method of compound as claimed in claim 1 is characterized in that synthetic route is as follows:
Synthetic route 1: take L-Trp as starting raw material, generate tryptophan methyl ester hydrochloride 2 under the Acetyl Chloride 98Min. effect, with (Boc)
2o protection alpha-amino group obtains intermediate 3, then passes through LiAIH
4the reduction 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, perhaps 7 through EtOAc/HCl, slough the Boc blocking group, amino acid or the carboxylic acid condensation of last and various Boc protections are acid amides, and methyl esters is converted into to 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, the cycloalkanes acyl group, arylsulfonyl, assorted alkylsulfonyl, aryl C1-6 alkane alkylsulfonyl, heteroaryl C1-9 alkane alkylsulfonyl, C1-8 carbalkoxy or aryl C1-8 carbalkoxy;
Reagent in the 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; (e) the saturated HCl solution of EtOAc; (f) TBTU, triethylamine, anhydrous tetrahydro furan; (g) NH
2oK, anhydrous methanol.
5. the preparation method of compound as claimed in claim 1 is characterized in that synthetic route is as follows:
Synthetic route 2: intermediate 8 reacts with the cyclosubstituted phenyl aldehyde of benzene, generates schiff bases 11,11 and generates parahelium 12 through sodium borohydride reduction, and Boc protection product 13 is converted into hydroximic acid 14, and last N sloughs protection and generates target compound (L30-L33);
Synthetic route 2 reaction formula are as follows:
Wherein R is hydrogen; Halogen atom, nitro, the electron-withdrawing groups such as carboxyl; Alkyl, amino, hydroxyl, methylol, the amine methyl, carbamyls etc. are given electric group;
Reagent in the 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%.
6. the preparation method of compound as claimed in claim 1 is characterized in that synthetic route is as follows:
Synthetic route 3: the N methyl protection product 16 on intermediate 4 indole rings reacts with 4 coumaric acid methyl esters, generates intermediate 17,17 through de-Boc, amide condensed, finally generates the hydroximic acid end product;
Synthetic route 3 reaction formula are 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, the cycloalkanes acyl group, arylsulfonyl, assorted alkylsulfonyl, aryl C1-6 alkane alkylsulfonyl, heteroaryl C1-9 alkane alkylsulfonyl, C1-8 carbalkoxy or aryl C1-8 carbalkoxy;
Reagent in the said synthesis route reaction formula: (a) CH
3i, KOH, TBABr, H
2o, THF; (b) PPh
3, DEAD, anhydrous THF; (c) the saturated HCl solution of EtOAc; (d) TBTU, triethylamine, anhydrous tetrahydro furan; (e) NH
2oK, anhydrous CH
3oH.
7. claim 1, the application of 2 or 3 described compounds in the medicine for preparing the mammalian diseases that prevention or treatment are relevant to the active unconventionality expression of histon deacetylase (HDAC); The described related mammalian disease with the active unconventionality expression of histon deacetylase (HDAC) comprises: cancer, neurodegenerative disease, virus infection, inflammation, malaria and diabetes.
8. one kind is suitable for the oral mammiferous pharmaceutical composition that gives, and comprises claim 1,2 or 3 compound and one or more pharmaceutically acceptable carriers or vehicle.
9. one kind is suitable for parenteral and gives mammiferous drug composition, comprises claim 1,2 or 3 compound and one or more pharmaceutically acceptable carriers or vehicle.
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