CN105481736A - Phenylglycine-containing cinnamamide histone deacetylase inhibitor, and preparation method and application thereof - Google Patents
Phenylglycine-containing cinnamamide histone deacetylase inhibitor, and preparation method and application thereof Download PDFInfo
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- ZJPXRUWNGVVHPO-VOTSOKGWSA-N CCOC(/C=C/c1cc(S(N)(=O)=O)ccc1)=O Chemical compound CCOC(/C=C/c1cc(S(N)(=O)=O)ccc1)=O ZJPXRUWNGVVHPO-VOTSOKGWSA-N 0.000 description 1
- YXFVVABEGXRONW-UHFFFAOYSA-N Cc1ccccc1 Chemical compound Cc1ccccc1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 1
- PSJNRWFIRVJIKZ-UHFFFAOYSA-N N=C(C1)C1c1cccc(C=O)c1 Chemical compound N=C(C1)C1c1cccc(C=O)c1 PSJNRWFIRVJIKZ-UHFFFAOYSA-N 0.000 description 1
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- C07C303/36—Preparation of esters or amides of sulfuric acids; Preparation of sulfonic acids or of their esters, halides, anhydrides or amides of amides of sulfonic acids
- C07C303/40—Preparation of esters or amides of sulfuric acids; Preparation of sulfonic acids or of their esters, halides, anhydrides or amides of amides of sulfonic acids by reactions not involving the formation of sulfonamide groups
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- C07C269/00—Preparation of derivatives of carbamic acid, i.e. compounds containing any of the groups, the nitrogen atom not being part of nitro or nitroso groups
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- C07C303/32—Preparation of esters or amides of sulfuric acids; Preparation of sulfonic acids or of their esters, halides, anhydrides or amides of salts of sulfonic acids
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- C07C303/36—Preparation of esters or amides of sulfuric acids; Preparation of sulfonic acids or of their esters, halides, anhydrides or amides of amides of sulfonic acids
- C07C303/38—Preparation of esters or amides of sulfuric acids; Preparation of sulfonic acids or of their esters, halides, anhydrides or amides of amides of sulfonic acids by reaction of ammonia or amines with sulfonic acids, or with esters, anhydrides, or halides thereof
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Abstract
The invention relates to a phenylglycine-containing cinnamamide histone deacetylase inhibitor, and a preparation method and application thereof. The structure of the compound is disclosed as Formula I. The invention also relates to a pharmaceutical composition containing the compound disclosed as Formula I. The compound provided by the invention is used for preparing drugs for preventing and treating mammal diseases related to histone deacetylase activity abnormal expression.
Description
Technical field
The present invention relates to a kind of NSC 630176 containing phenylglycine and its preparation method and application, belong to organic compound synthesis and medical applications technical field.
Background technology
Cancer as a kind of Non Communicable Diseases (NCD), the life and health of the serious threat mankind.Research shows, generation and the development of epigenetic modification and cancer have close ties.Epigenetic modification refers to when nucleotide sequence does not change, and reversible, heritable change of gene function, comprises the modification of DNA and histone.Acetylize/the deacetylation of histone is a dynamic reversing process; by acetylation of histone transferring enzyme (histoneacetyltransferases; and histon deacetylase (HDAC) (histonedeacetylases, HDACs) dual regulation HATs).HDACs is the dependent metalloprotease of a Zn-like ions; it is by the ethanoyl on the epsilon-amino of lysine residue side chain latter end in the zine ion hydrolysis histone of catalytic active center; add the positive charge density of histone; and the electrostatic attraction between electronegative DNA strengthens; thus make whole chromosome structure crimping very close; cause transcription factor and RNA polymerase cannot be combined with DNA, thus the transcribing of suppressor gene.HATs then promotes genetic transcription by opposite effect.Except regulatory gene is transcribed, HDACs can also regulate the activity of some key proteins such as tumor-inhibiting factor p53, heat shock protein 90 and alpha-tubulin and cytokine, plays a key effect to tumour.
At present, in human body, find 18 kinds of HDACs, be divided into four classes according to it from the homology of yeast HDAC albumen and the different of distribution, comprise I class (HDAC1,2,3 and 8), II class (IIa:HDAC4,5,7 and 9; IIb:HDAC6 and 10), III class (SIR1-7) and IV class (HDAC11).Wherein I class, II class and IV class HDACs belong to zine ion dependency metalloprotease, and III class HDACs belongs to NAD+ dependency metalloprotease.
NSC 630176 (histonedeacetylaseinhibitors, HDACi) can the propagation of effective anticancer, and cell death inducing, they all have good inhibit activities to solid tumor, leukemia and lymphoma.Up to now, existing tens of kinds of HDACi enter the clinical study of different steps, and wherein four kinds of HDACi are by the approval listing of U.S. food Drug Administration.Meanwhile, a kind of selectivity HDACi chidamide is also by Chinese food Drug Administration approval listing treatment lymphoma peripheral T cell.Therefore, for HDACs be shot design inhibitor become antitumor drug research focus.
Summary of the invention
The present invention is directed to the deficiencies in the prior art, provide a kind of cinnamide histone deacetylase inhibitor containing phenylglycine, the present invention also provides preparation method and the purposes of this compound.
Technical solution of the present invention is as follows:
One, the cinnamide histone deacetylase inhibitor containing phenylglycine
The present invention contains the cinnamide histone deacetylase inhibitor of phenylglycine, and its optical isomer, diastereomer and racemic mixture, its pharmacy acceptable salt, and solvate or prodrug have the structure shown in following general formula I;
Wherein,
* be steric configuration be S or R, or its raceme;
R is the alkylamino of various isomeries prepared by each seed amino acid, naphthene amino, various amino with substituent virtue;
Preferably, in above-mentioned general formula I, R is that virtue is amino;
Further preferred, above-mentioned formula I is one of following:
(S, E)-N-hydroxyl-3-(3-(N-(2-oxygen-1-phenyl-2-(aniline) ethyl) sulfamic) phenyl) acrylamide (10a),
(S, E)-3-(3-(N-(2-(Cyclohexylamino)-2-oxygen-1-styroyl) sulfamic) phenyl)-N-hydroxyacrylamide (10b),
(S, E)-N-hydroxyl-3-(3-(N-(2-oxygen-1-phenyl-2-(third is amino) ethyl) sulfamic) phenyl) acrylamide (10c),
(S, E)-N-hydroxyl-3-(3-(N-(2-(isopropylamino)-2-oxygen-1-styroyl) sulfamic) phenyl) acrylamide (10d),
(S, E)-3-(3-(N-(2-(fourth is amino)-2-oxygen-1-styroyl) sulfamic) phenyl)-N-hydroxyacrylamide (10e),
(S, E)-N-hydroxyl-3-(3-(N-(2-(isopropylamino)-2-oxygen-1-styroyl) sulfamic) phenyl) acrylamide (10f),
(S, E)-3-(3-(N-(2-(TERTIARY BUTYL AMINE base)-2-oxygen-1-styroyl) sulfamic) phenyl)-N-hydroxyacrylamide (10g),
(S, E)-3-(3-(N-(2-((4-difluorophenyl) is amino)-2-oxygen-1-styroyl) sulfamic) phenyl)-N-hydroxyacrylamide (10h),
(S, E)-3-(3-(N-(2-((4-chlorophenyl) is amino)-2-oxygen-1-styroyl) sulfamic) phenyl)-N-hydroxyacrylamide (10i),
(S, E)-3-(3-(N-(2-((4-bromo phenyl) is amino)-2-oxygen-1-styroyl) sulfamic) phenyl)-N-hydroxyacrylamide (10j),
(S, E)-N-hydroxyl-3-(3-(N-(2-((4-iodine substituted phenyl) is amino)-2-oxygen-1-styroyl) sulfamic) phenyl) acrylamide (10k),
(S, E)-N-hydroxyl-3-(3-(N-(2-((4-p-methoxy-phenyl) is amino)-2-oxygen-1-styroyl) sulfamic) phenyl) acrylamide (10l),
(S, E)-N-hydroxyl-3-(3-(N-(2-oxygen-1-phenyl-2-(o-tolyl amido) ethyl) sulfamic) phenyl) acrylamide (10m),
(S, E)-3-(3-(N-(2-((2-chlorophenyl) is amino)-2-oxygen-1-styroyl) sulfamic) phenyl)-N-hydroxyacrylamide (10n),
(S, E)-3-(3-(N-(2-((3-difluorophenyl) is amino)-2-oxygen-1-styroyl) sulfamic) phenyl)-N-hydroxyacrylamide (10o),
(S, E)-N-hydroxyl-3-(3-(N-(2-((3-p-methoxy-phenyl) is amino)-2-oxygen-1-styroyl) sulfamic) phenyl) acrylamide (10p),
(S, E)-3-(3-(N-(2-((2-chlorophenethyl) is amino)-2-oxygen-1-styroyl) sulfamic) phenyl)-N-hydroxyacrylamide (10q),
(S, E)-N-hydroxyl-3-(3-(N-(2-oxygen-2-(PhenethyIamino)-1-styroyl) sulfamic) phenyl) acrylamide (10r),
(S, E)-N-hydroxyl-3-(3-(N-(2-(naphthalene methyl alcohol-1-base amino)-2-oxygen-1-styroyl) sulfamic) phenyl) acrylamide (10s) or
(S, E)-N-hydroxyl-3-(3-(N-(2-((naphthalene acetamide-1-ylmethyl) is amino)-2-oxygen-1-styroyl) sulfamic) phenyl) acrylamide (10t).
The preparation method of the cinnamide histone deacetylase inhibitor two, containing phenylglycine
The preparation method of described compound, step is as follows:
Be raw material with phenyl aldehyde, through sulfonation, Huo Naer-Wordsworth-Ai Mengsi is obtained by reacting key intermediate 3, and intermediate 3 and thionyl chloride reacts and generate acyl chlorides 4, while with L-phenylglycine for raw material warp (Boc)
2o protects alpha-amino group to generate key intermediate 6, intermediate 6 and different amine carry out condensation should, slough Boc blocking group by EtOAc/HCl and generate key intermediate 8, intermediate 8 and acyl chlorides 4 carry out condensation reaction, and ethyl ester is converted into hydroximic acid obtains target compound;
Synthetic route is as follows:
Wherein R is as described in general formula I;
Reagent in said synthesis route reaction formula: (a) oleum; (b) phosphonoacetate, salt of wormwood, water; (c) thionyl chloride, DMF; (d) (Boc)
2o, triethylamine, methylene dichloride; (e) O-benzotriazole-N, N, N', N'-tetramethyl-urea Tetrafluoroboric acid, triethylamine, methylene dichloride; The saturated HCl solution of (f) EtOAc; (g) toluene, methylene dichloride; (h) NH
2oK, anhydrous methanol.
For compound 10a, concrete preparation process is as follows:
(1) synthesis of compound 3-formylbenzenesulfonic acid sodium (2):
At 0 DEG C, 2.0g phenyl aldehyde is slowly added dropwise in 5mL oleum, 40 DEG C of reactions 16 hours, pour in 150mL frozen water, with 50mL extraction into ethyl acetate 2 times by reaction solution, slowly adding calcium carbonate to PH is 6-7, filter, adding a small amount of sodium carbonate in filtrate to PH is 8, filters, filtrate evaporate to dryness, with dissolve with methanol, filter, filtrate evaporate to dryness obtains compound 2;
(2) synthesis of compound (E)-3-(3-oxyethyl group-3-oxo-1-alkene-1-base) benzene sulfonic acid sodium salt (3):
By 0.5g compound 2,0.7g salt of wormwood, 0.7g phosphonoacetate and 5mL water at room temperature stir 30 minutes, filter the precipitation generated, and by 2ml methanol wash 2 times, filtrate evaporate to dryness obtains the thick product of compound 3;
(3) synthesis of compound (E)-ethyl 3-(3-(chlorosulfonyl) phenyl) acrylate (4):
By 0.53g compound 3,1.7mL thionyl chloride, 2 DMFs are even in stirring at room temperature, reflux 5 hours, react complete at 75 DEG C, and solvent evaporated obtains the thick product of compound 4;
(4) synthesis of compound (S)-2-((uncle-tert-butyl carbonyl) is amino)-2-toluylic acid (6):
15.1gL-phenylglycine is placed in reaction flask, adds 200mL methanol/water, stirring at room temperature dissolve, after add 15.1mLEt
3n, by 32.7g (Boc)
2o is added dropwise in reaction solution, and stirred at ambient temperature 8 hours, revolves steaming and remove solvent, dissolves with 100mL citric acid, with 50mL extraction into ethyl acetate 3 times, with anhydrous sodium sulfate drying, is spin-dried for obtain crude product, uses normal hexane recrystallization, obtain product 6;
(5) synthesis of compound (S) tertiary butyl (2-oxygen-1-phenyl-2-(aniline) ethyl) carbamate (7a):
1.26g compound 6 is dissolved in 50mL methylene dichloride, at 0 DEG C, successively adds 0.61mLEt
3n and 1.93gO-benzotriazole-N, N, N', N'-tetramethyl-urea Tetrafluoroboric acid.Stirring at room temperature 8 hours, revolves steaming and removes solvent, extracts with 100mL acetic acid ethyl dissolution, 50mL citric acid, 50mL saturated sodium carbonate solution, 50mL saturated nacl aqueous solution wash 3 times respectively, with anhydrous sodium sulfate drying, be spin-dried for and obtain crude product, with the compound 7a of re-crystallizing in ethyl acetate;
(6) compound (S)-2-amino-N, the synthesis of 2-diphenylacetamide hydrochloride (8a):
Be dissolved in by 3.4g7a in the saturated HCl solution of 60mLEtOAc, react 5 hours under room temperature, separate out solid, filter, obtaining product 8a, is white solid;
(7) synthesis of compound (S, E)-ethyl 3-(3-(N-(2-oxygen-1-phenyl-2-(anilino) ethyl) sulfamic) phenyl) acrylate (9a):
Compound 0.58g8a is dissolved in 10mL methylene dichloride, successively adds 0.24gEt
3n, be dissolved in the 0.55g compound 4 in 10mL toluene, reaction solution at room temperature stirs and spends the night, with revolving steaming solvent evaporated, with the extraction of 60mL acetic acid ethyl dissolution, 50mL citric acid, 50mL saturated sodium carbonate solution, 50mL saturated nacl aqueous solution wash 3 times respectively, with anhydrous sodium sulfate drying, be spin-dried for and obtain crude product, with the compound 9a of re-crystallizing in ethyl acetate;
(8) synthesis of compound (S, E)-N-hydroxyl-3-(3-(N-(2-oxygen-1-phenyl-2-(aniline) ethyl) sulfamic) phenyl) acrylamide (10a):
0.46g9a is dissolved in 14mLNH
2in the methanol solution of OK, room temperature reaction 3h, TLC monitor reaction; Remove methyl alcohol under reduced pressure, add citric acid and regulate PH to 3-4,20mL extraction into ethyl acetate, 20mL saturated nacl aqueous solution washs 3 times, anhydrous sodium sulfate drying, suction filtration, removed under reduced pressure solvent, and flash column chromatography carries out purifying, obtains target product 10a, faint yellow solid.
The target compound structural formula of synthetic route is as shown in table 1 below:
Table 1 target compound 10a-10t structural formula
Concrete operation step prepared by described compound will be illustrated in instances.
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, ProtectingGroupsinOrganicSynthesis.
Three, the pharmaceutical composition containing the compounds of this invention and application
Present invention also offers the application of above-claimed cpd in the medicine of the mammalian diseases that preparation prevents or treatment is 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, leukemia, malaria or diabetes etc.Therefore, the invention still further relates to the pharmaceutical composition containing formula 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:
" amido prepared by each seed amino acid " refers to various amino acid whose amino, preferred hydrophobic amino acid, as glycine, and L-Ala, α-amino-isovaleric acid, leucine, Isoleucine, phenylalanine, proline(Pro), Serine, Threonine, methionine(Met).
" virtue is amino " refers to that aromatic carbon ring end is connected with amino group, and preferred aromatic ring contains 6-10 carbon atom.
" naphthene amino " refers to replacement or for what replace, saturated or undersaturated annular termination is connected with the group of amido, 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 (I) compound has curative effect and nontoxic salt form.It can have any acidic-group (as carboxyl) to form anion salt, or forms cationic salts by any 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 (magnesium and calcium).Also by using (I) 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-propanedioic acid, ethyl sulfonic acid, benzene methanesulfonic acid, 4-toluene sulfonic acide, cyclohexyl-sulfinic acid, 2 hydroxybenzoic acid, 4-amino-2-hydroxybenzoic acid etc.In addition, the factors such as those of skill in the art can according to solubleness, stability, easy preparation are got certain salt 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.
" solvate " is the title complex that solute (as inhibitors of metalloproteinase) and solvent (as water) are combined to form.See J.Honig etc., TheVanNostrandChemist ' sDictionary, p.650 (1593).The pharmaceutically acceptable solvent that the present invention adopts comprises bioactive those solvents (the such as water not disturbing inhibitors of metalloproteinase, ethanol, acetic acid, N, dinethylformamide, dimethyl sulfoxide (DMSO) and this those skilled in the art's indication or the solvent easily determined).
" optical isomer " used herein, " enantiomorph ", " diastereomer ", " raceme " etc. define the form of the compounds of this invention or all possible steric isomer of physiological derivative.Unless otherwise directed, the chemical name of the compounds of this invention comprises the mixture of all possible stereochemical form, affiliated mixture comprises all diastereomers and the enantiomorph of basic structure molecule, and the single isomeric forms of the compounds of this invention of substantially pure, namely wherein contain lower than 10%, preferably lower than 5%, particularly lower than 2%, most preferably lower than 1% other isomer.The various stereoisomer form of class peptide compounds of the present invention is all obviously included within the scope of the present invention.
The form of formula I other protected forms all right 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 acetylizad lysine side-chain-Boc-Lys (acetyl)-AMC) is 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 II below:
In reaction formula II, Histonedeacetylase 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.
The test of the cytoactive of compound uses Thiazolyl blue detection method (mtt assay), and 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.
Four, the pharmaceutical composition containing the compounds of this invention
Part extension of the present invention can exist in a free form or in the form of salts.Pharmacy acceptable salt of the known chemical compound lot type of those skilled in the art and preparation method thereof.Pharmacy acceptable salt comprises conventional avirulent salt, comprises such compound alkali and quaternary ammonium salt that is inorganic or organic acid form.
Compound of the present invention can form hydrate or solvate.The hydrate that this area number skilled person is known to be formed compound during freeze-drying together with water or form the method for solvate when concentrating with suitable organic solvent in the solution.
The present invention comprises the medicine containing therapeutic dose the compounds of this invention, and the pharmaceutical composition of one or more pharmaceutically acceptable carriers and/or vehicle.Carrier comprises salt solution, buffer saline, glucose, water, glycerine, and ethanol and their binding substances, hereafter discuss in more detail.If needed, said composition can also comprise wetting agent or the emulsifying agent of comparatively a small amount of, or pH buffer reagent.Said composition can be liquid, suspension, emulsion, tablet, pill, capsule, extended release preparation or powder.Said composition can be configured to suppository with traditional tamanori and carrier such as triglyceride.Oral preparations can comprise the mannitol of standard vector as medicine grade, lactose, starch, Magnesium Stearate, soluble saccharin, Mierocrystalline cellulose and magnesiumcarbonate etc.Optionally preparation and determining, is configured to design mixing, granulates and compression or solvent components.In another approach, said composition can be configured to nano particle.
The pharmaceutical carrier used can be solid or liquid.
Typical solid carrier comprises lactose, terra alba, sucrose, talcum, gel, agar, pectin, gum arabic, Magnesium Stearate, stearic acid etc.Solid carrier can comprise one or more may simultaneously as sweetener, lubricant, solubilizing agent, suspension agent, filler, glidant, compression aid, the material of tackiness agent or tablet-disintegrating agents; He can also be encapsulating material.In the powder, carrier is pulverizing solid, and it mixes with pulverizing activeconstituents.Activeconstituents mixes with suitable ratio with the carrier with necessary compression property in tablets, with the shape needed and size compression.Powder and tablet preferably comprise 99% activeconstituents at the most.Suitable solid carrier comprises, such as, and calcium phosphate, Magnesium Stearate, talcum, sugar, lactose, dextrin, starch, gel, Mierocrystalline cellulose, methylcellulose gum, sodium carboxymethyl-cellulose, polyvinylpyrrolidone, low melt wax and ion exchange resin.
Typical liquid vehicle comprises syrup, peanut oil, sweet oil, water etc.Title charge carrier for the preparation of solution, suspension, emulsion, syrup, the composition of tincture and sealing.Activeconstituents can dissolve or be suspended in pharmaceutically acceptable liquid vehicle as water, organic solvent, and this mixture or pharmaceutically acceptable oils or fat.Liquid vehicle can comprise other suitable medicated premixs as solubilizing agent, emulsifying agent, buffer reagent, sanitas, sweetener, sweetener, suspension agent, thickening material, pigment, and viscosity modifier, stablizes shape or osmo-regulators.Suitable example for the liquid vehicle of oral and administered parenterally comprises water and (partly comprises as above-mentioned additive, such as derivatived cellulose, preferably carboxymethyl cellulose sodium salt solution), alcohol (comprises monohydroxy-alcohol and polyvalent alcohol, such as ethylene glycol) and their derivative, and oils (such as fractionated coconut oil and peanut oil).Carrier for administered parenterally can also be that grease is as ethyl oleate and isopropyl myristate.Aseptic liquid vehicle is used for the aseptic fluid composition of administered parenterally.Liquid carrier for pressurized compositions can be halohydrocarbon or other pharmaceutically acceptable propelling agents.Sterile solution or aaerosol solution composition of liquid medicine can be used for, such as, and intravenously, intramuscular, intraperitoneal or subcutaneous injection.Can push or inject gradually by single during injection, entering the interior perfusion of passages through which vital energy circulates of 30 minutes.This compound can also with the form oral administration of liquid or solids composition.
Carrier or vehicle can comprise the time lag material that this area suppresses, and as glyceryl monostearate or distearin, also can comprise wax, ethyl cellulose, Vltra tears, methyl methacrylate etc.When bosom friend is used for oral, generally acknowledge PHOSALPG-50 (phosphoric acid (phospholipid) and 1,2-propylene glycol concentrates, A.Nattermann & Cie.GmbH) in 0.01% tween 80 be used for the preparation of acceptable oral preparations of other compounds, the preparation of the various compound of the present invention can be adapted to.
Medicament forms miscellaneous can be used when giving the compounds of this invention.If use solid carrier, preparation can be tablet, is placed into powder in hard capsule or piller form or lozenge or Lozenge forms.The amount change to a great extent of solid carrier, but preferably from about 25mg to about 1.0g.If use liquid vehicle, preparation can be syrup, emulsion, soft capsule, is pacifying the aseptic injectable solution or suspension that cut open in the liquid suspension of bottle or non-water.
In order to obtain stable water miscible formulation, compound or its to can be learned upper acceptable salt honor organic or inorganic aqueous acid, 0.3M succsinic acid or citric acid solution.Optionally, acid derivative can the suitable basic solution of honor.If can not get soluble form, compound can be dissolved in suitable cosolvent or their combination.The example of suitable cosolvent like this includes but are not limited to, concentration range from the ethanol of 0-60% cumulative volume, propylene glycol, Liquid Macrogol, polysorbate 80, glycerine, polyoxyethylene fatty acid ester, fatty alcohol or glycerol hydroxy groups fatty acid ester etc.
Various release system is known and may be used for the administration of compound or other various preparations, and these preparations comprise tablet, capsule, injectable solution, the capsule in liposome, particulate, microcapsule etc.Introduce non-method and include, but are not limited to skin, intracutaneous, intramuscular, intraperitoneal, intravenous, subcutaneous, nasal cavity, lung, peridural, eyes and (usually preferred) oral route.Compound can pass through easily any or other suitable administrations, such as by injecting or bolus injection, by epithelium or mucous membrane circuit (such as, oral mucosa, rectum and intestinal mucosa etc.) to absorb or by the support of carrying medicament and can administration together with other biological promoting agent.Can whole body or topical.For nose, when the treatment of segmental bronchus or lung disease or prevention, preferred route of administration is oral, nasal administration or segmental bronchus smoke substance or atomizer.
Embodiment
Below in conjunction with embodiment, the present invention is described further, but be not limited thereto.
The synthesis of embodiment 1 the compounds of this invention 10a-10t, for 10a
The synthesis of compound 3-formylbenzenesulfonic acid sodium (2):
Slowly be added dropwise in oleum (5mL) at 0 DEG C by phenyl aldehyde (2.0g, 18.84mmol), 40 DEG C are reacted 16 hours, poured into by reaction solution in frozen water (150mL), with ethyl acetate (2 × 50mL) extraction, slowly adding calcium carbonate to PH is 6-7, filter, adding a small amount of sodium carbonate in filtrate to PH is 8, filters, filtrate evaporate to dryness, with dissolve with methanol, filter, filtrate evaporate to dryness obtains compound 2 (1.9g, productive rate 49%).
1HNMR(400MHz,DMSO)δ10.05(s,1H),8.14(s,1H),7.91(dd,J＝20.2,7.6Hz,2H),7.59(t,J＝7.6Hz,1H).
The synthesis of compound (E)-3-(3-oxyethyl group-3-oxo-1-alkene-1-base) benzene sulfonic acid sodium salt (3):
By compound 2 (0.5g; 2.4mmol); salt of wormwood (0.7g; 4.8mmol); phosphonoacetate (0.7g, 2.9mmol) and water (5mL) at room temperature stir 30 minutes, filter the precipitation generated; with methyl alcohol (2 × 2ml) washing, filtrate evaporate to dryness obtains the thick product of compound 3.
The synthesis of compound (E)-ethyl 3-(3-(chlorosulfonyl) phenyl) acrylate (4):
By compound 3 (0.53g, 2mmol), thionyl chloride (1.7mL, 13.8mmol), DMF (2) is even in stirring at room temperature, reflux 5 hours at 75 DEG C, react complete, solvent evaporated obtains the thick product of compound 4.
The synthesis of compound (S)-2-((uncle-tert-butyl carbonyl) is amino)-2-toluylic acid (6):
L-phenylglycine (15.1g, 100mmol) is placed in reaction flask, adds 200mL methyl alcohol: water (3:1), stirring at room temperature dissolve, after add Et
3n (15.1mL, 150mmol), by (Boc)
2o (32.7g, 150mmol) be added dropwise in reaction solution, stirred at ambient temperature 8 hours, revolves steaming and removes solvent, dissolves with 100mL citric acid, extract by ethyl acetate (3 × 50mL), with anhydrous sodium sulfate drying, be spin-dried for obtain crude product, use normal hexane recrystallization, obtain product 6 (21.8g, productive rate 86%).
The synthesis of compound (S) tertiary butyl (2-oxygen-1-phenyl-2-(aniline) ethyl) carbamate (7a):
Compound 6 (1.26g, 5mmol) is dissolved in methylene dichloride (50mL), at 0 DEG C, successively adds Et
3n (0.61mL, 5mmol) and TBTU (1.93g, 6mmol).Stirring at room temperature 8 hours, revolve steaming and remove solvent, by ethyl acetate (100mL) dissolution extraction, citric acid (3 × 50mL), saturated sodium carbonate solution (3 × 50mL), saturated nacl aqueous solution (3 × 50mL) wash, with anhydrous sodium sulfate drying, be spin-dried for and obtain crude product, with compound 7a (1.44g, the productive rate 88%) Mp:116-118 DEG C of re-crystallizing in ethyl acetate
1hNMR (300MHz, DMSO-d
6) δ 10.25 (s, 1H), 7.61 – 7.44 (m, 5H), 7.33 (ddd, J=19.3,11.4,4.7Hz, 5H), 7.04 (t, J=7.4Hz, 1H), 5.36 (d, J=8.3Hz, 1H), 1.39 (s, 8H), 1.31 (s, 1H) .ESI-MS:m/z:327.2 [M+H]
+.
Compound (S)-2-amino-N, the synthesis of 2-diphenylacetamide hydrochloride (8a):
Be dissolved in by 7a (3.4g, 10mmol) in saturated HCl (60mL) solution of EtOAc, react 5 hours under room temperature, separate out solid, filter, obtaining product 8a, is white solid (2.01g, productive rate 74%) Mp:228-230 DEG C.
1hNMR (400MHz, DMSO-d
6) δ 11.25 (s, 1H), 8.94 (s, 3H), 7.71 (d, J=6.9Hz, 2H), 7.65 (d, J=7.8Hz, 2H), 7.49 – 7.39 (m, 3H), 7.32 (t, J=7.9Hz, 2H), 7.09 (t, J=7.4Hz, 1H), 5.33 (s, 1H) .HRMS (AP-ESI) m/zcalcd [M+H]
+227.1179.
The synthesis of compound (S, E)-ethyl 3-(3-(N-(2-oxygen-1-phenyl-2-(anilino) ethyl) sulfamic) phenyl) acrylate (9a):
Compound 8a (0.58g, 2.2mmol) is dissolved in methylene dichloride (10mL), successively adds Et
3n (0.24g, 2.4mmol), be dissolved in the compound 4 (0.55g in toluene (10mL), 2mmol), reaction solution at room temperature stirs and spends the night, with revolving steaming solvent evaporated, by ethyl acetate (60mL) dissolution extraction, citric acid (3 × 50mL), saturated sodium carbonate solution (3 × 50mL), saturated nacl aqueous solution (3 × 50mL) wash, with anhydrous sodium sulfate drying, be spin-dried for and obtain crude product, with the compound 9a (3.91g, productive rate 80%) of re-crystallizing in ethyl acetate
1hNMR (300MHz, DMSO-d
6) δ 10.28 (s, 1H), 8.84 (d, J=9.8Hz, 1H), 8.00 (s, 1H), 7.76 (t, J=8.0Hz, 2H), 7.56 – 7.42 (m, 2H), 7.41 (d, J=1.7Hz, 1H), 7.38 (d, J=1.3Hz, 1H), 7.36 (d, J=1.1Hz, 1H), 7.33 (s, 1H), 7.30 – 7.15 (m, 5H), 7.00 (t, J=7.3Hz, 1H), 6.55 (d, J=16.1Hz, 1H), 5.25 (d, J=9.8Hz, 1H), 4.21 (q, J=7.1Hz, 2H), 1.28 (t, J=7.1Hz, 3H) .ESI-MS:m/z:465.3 [M+H]
+.
The synthesis of compound (S, E)-N-hydroxyl-3-(3-(N-(2-oxygen-1-phenyl-2-(aniline) ethyl) sulfamic) phenyl) acrylamide (10a):
9a (0.46g, 1.0mmol) is dissolved in NH
2in the methanol solution (14mL) of OK, room temperature reaction 3h, TLC monitor reaction.Remove methyl alcohol under reduced pressure, add citric acid and regulate PH to 3-4, ethyl acetate (3 × 20mL) extracts, and saturated nacl aqueous solution (3 × 20mL) washs, anhydrous sodium sulfate drying, suction filtration, removed under reduced pressure solvent, flash column chromatography carries out purifying, obtains target product 10a, faint yellow solid (0.19mmol, productive rate 42%).Mp:202-204℃.
1HNMR(600MHz，DMSO-d
6)δ10.89(s，1H)，10.38(s，1H)，10.27(s，2H)，8.86(d，J＝9.6Hz，1H)，7.90(s，1H)，7.71(d，J＝7.9Hz，1H)，7.60(d，J＝7.7Hz，1H)，7.43–7.37(m，6H)，7.25–7.19(m，5H)，7.01(t，J＝7.4Hz，1H)，6.51(d，J＝15.8Hz，1H)，5.25(d，J＝9.7Hz，1H).HRMS(AP-ESI)m/zcalcdforC
23H
21N
3O
5S[M-H]
-450.1131，found450.1129.
(S, E)-3-(3-(N-(2-(Cyclohexylamino)-2-oxygen-1-styroyl) sulfamic) phenyl)-N-hydroxyacrylamide (10b): faint yellow solid, productive rate 32%.Mp:177-178℃.
1HNMR(300MHz，DMSO-d
6)δ10.85(s，1H)，9.10(s，1H)，8.59(d，J＝8.6Hz，1H)，8.02(d，J＝7.7Hz，1H)，7.86(s，1H)，7.76–7.64(m，2H)，7.47(dd，J＝17.9，11.7Hz，2H)，7.35–7.27(m，2H)，7.26–7.13(m，3H)，6.51(d，J＝15.8Hz，1H)，5.01(d，J＝8.4Hz，1H)，3.27–3.15(m，1H)，1.59–1.40(m，5H)，1.09–0.91(m，，5H).HRMS(AP-ESI)m/zcalcdforC
23H
27N
3O
5S[M-H]
-456.1602，found456.1599.
(S, E)-N-hydroxyl-3-(3-(N-(2-oxygen-1-phenyl-2-(third is amino) ethyl) sulfamic) phenyl) acrylamide (10c): faint yellow solid, productive rate 32%.Mp:172-174℃.
1HNMR(400MHz，DMSO-d
6)δ10.85(s，1H)，9.13(s，1H)，8.60(s，1H)，8.15(t，J＝5.3Hz，1H)，7.85(s，1H)，7.69(t，J＝7.6Hz，2H)，7.46(dd，J＝20.3，12.2Hz，2H)，7.30(d，J＝6.9Hz，2H)，7.20(dd，J＝15.6，8.0Hz，3H)，6.50(d，J＝15.8Hz，1H)，4.98(d，J＝9.6Hz，1H)，2.85–2.68(m，2H)，1.28–1.12(m，3H)，0.66(t，J＝7.4Hz，3H).HRMS(AP-ESI)m/zcalcdforC
20H
23N
3O
5S[M-H]
-416.1284，found416.1286.
(S, E)-N-hydroxyl-3-(3-(N-(2-(isopropylamino)-2-oxygen-1-styroyl) sulfamic) phenyl) acrylamide (10d): faint yellow solid, productive rate 27%.Mp:174-175℃.
1HNMR(300MHz，DMSO-d
6)δ10.84(s，1H)，9.10(s，1H)，8.58(d，J＝9.7Hz，1H)，8.02(d，J＝7.4Hz，1H)，7.87(s，1H)，7.70(dd，J＝8.1，1.4Hz，2H)，7.53–7.40(m，2H)，7.30(dd，J＝7.9，1.5Hz，2H)，7.26–7.16(m，3H)，6.50(d，J＝15.8Hz，1H)，4.96(d，J＝9.7Hz，1H)，3.50(dq，J＝13.3，6.6Hz，1H)，0.83(dd，J＝6.6，1.6Hz，6H).HRMS(AP-ESI)m/zcalcdforC
20H
23N
3O
5S[M-H]
-416.1291，found416.1286.
(S, E)-3-(3-(N-(2-(fourth is amino)-2-oxygen-1-styroyl) sulfamic) phenyl)-N-hydroxyacrylamide (10e): faint yellow solid, productive rate 29%.Mp:178-179℃.
1HNMR(300MHz，DMSO-d
6)δ10.83(s，1H)，9.10(s，1H)，8.59(d，J＝9.6Hz，1H)，8.11(t，J＝5.4Hz，1H)，7.86(s，1H)，7.74–7.65(m，2H)，7.53–7.40(m，2H)，7.30(dd，J＝7.9，1.6Hz，2H)，7.26–7.16(m，3H)，6.50(d，J＝15.8Hz，1H)，4.97(d，J＝9.6Hz，1H)，2.90–2.70(m，2H)，1.20–0.98(m，4H)，0.75(t，J＝7.1Hz，3H).HRMS(AP-ESI)m/zcalcdforC
21H
25N
3O
5S[M-H]
-430.1445，found430.1442.
(S, E)-N-hydroxyl-3-(3-(N-(2-(isopropylamino)-2-oxygen-1-styroyl) sulfamic) phenyl) acrylamide (10f): faint yellow solid, productive rate 25%.Mp:174-176℃.
1HNMR(300MHz，DMSO-d
6)δ10.83(s，1H)，9.10(d，J＝1.3Hz，1H)，8.59(d，J＝9.6Hz，1H)，8.12(t，J＝5.7Hz，1H)，7.85(s，1H)，7.73–7.65(m，2H)，7.52–7.39(m，2H)，7.31(dd，J＝7.9，1.5Hz，2H)，7.25–7.15(m，3H)，6.49(d，J＝15.8Hz，1H)，5.02(d，J＝9.5Hz，1H)，2.66(t，J＝6.3Hz，2H)，1.45(dp，J＝13.4，6.8Hz，1H)，0.64(d，J＝6.6Hz，6H).HRMS(AP-ESI)m/zcalcdforC
21H
25N
3O
5S[M-H]
-430.1446，found430.1442.
(S, E)-3-(3-(N-(2-(TERTIARY BUTYL AMINE base)-2-oxygen-1-styroyl) sulfamic) phenyl)-N-hydroxyacrylamide (10g): faint yellow solid, productive rate 28%.Mp:182-184℃.
1HNMR(300MHz，DMSO-d
6)δ10.84(s，1H)，8.49(d，J＝9.9Hz，1H)，7.91(s，1H)，7.75(d，J＝4.7Hz，2H)，7.71(d，J＝1.2Hz，1H)，7.57–7.46(m，2H)，7.44(s，1H)，7.32(d，J＝6.7Hz，2H)，7.28–7.18(m，3H)，6.52(d，J＝15.8Hz，1H)，5.03(d，J＝9.8Hz，1H)，0.99(s，9H).HRMS(AP-ESI)m/zcalcdforC
21H
25N
3O
5S[M-H]
-430.1447，found430.1442.
(S; E)-3-(3-(N-(2-((4-difluorophenyl) is amino)-2-oxygen-1-styroyl) sulfamic) phenyl)-N-hydroxyacrylamide (10h): faint yellow solid, productive rate 27%.Mp:130-132℃.
1HNMR(600MHz，DMSO-d
6)δ10.89(s，1H)，10.52(s，1H)，10.08(s，1H)，8.88(d，J＝9.7Hz，1H)，7.90(s，1H)，7.71(d，J＝7.9Hz，1H)，7.61(d，J＝7.7Hz，1H)，7.44–7.36(m，6H)，7.25(t，J＝7.3Hz，2H)，7.23–7.19(m，1H)，7.05(t，J＝8.9Hz，2H)，6.52(d，J＝15.8Hz，1H)，5.24(d，J＝9.6Hz，1H).HRMS(AP-ESI)m/zcalcdforC
23H
20FN
3O
5S[M-H]
-468.1039，found468.1035.
(S; E)-3-(3-(N-(2-((4-chlorophenyl) is amino)-2-oxygen-1-styroyl) sulfamic) phenyl)-N-hydroxyacrylamide (10i): faint yellow solid, productive rate 24%.Mp:204-206℃.
1HNMR(600MHz，DMSO-d
6)δ10.88(s，1H)，10.54(s，1H)，9.14(s，1H)，8.89(s，1H)，7.90(s，1H)，7.70(d，J＝7.8Hz，1H)，7.61(d，J＝7.8Hz，1H)，7.43–7.35(m，6H)，7.29–7.20(m，5H)，6.50(d，J＝15.8Hz，1H)，5.23(s，1H).HRMS(AP-ESI)m/zcalcdforC
23H
20ClN
3O
5S[M-H]
-484.0738，found484.0739.
(S; E)-3-(3-(N-(2-((4-bromo phenyl) is amino)-2-oxygen-1-styroyl) sulfamic) phenyl)-N-hydroxyacrylamide (10j): faint yellow solid, productive rate 31%.Mp:223-225℃.
1HNMR(600MHz，DMSO-d
6)δ10.87(s，1H)，10.48(s，1H)，9.14(s，1H)，8.89(d，J＝9.6Hz，1H)，7.89(s，1H)，7.70(d，J＝7.8Hz，1H)，7.62(d，J＝7.7Hz，1H)，7.39(ddd，J＝22.9，16.2，8.4Hz，8H)，7.23(dt，J＝24.3，7.1Hz，3H)，6.49(d，J＝15.8Hz，1H)，5.21(d，J＝9.4Hz，1H).HRMS(AP-ESI)m/zcalcdforC
23H
20BrN
3O
5S[M-H]
-528.0235，found528.0234.
(S; E)-N-hydroxyl-3-(3-(N-(2-((4-iodine substituted phenyl) is amino)-2-oxygen-1-styroyl) sulfamic) phenyl) acrylamide (10k): faint yellow solid, productive rate 26%.Mp:200-202℃.
1HNMR(600MHz，DMSO-d
6)δ10.85(s，1H)，10.31(d，J＝68.5Hz，1H)，9.14(s，1H)，8.86(s，1H)，7.89(s，1H)，7.69(t，J＝7.8Hz，1H)，7.62(t，J＝7.2Hz，1H)，7.57(d，J＝8.7Hz，1H)，7.44–7.34(m，5H)，7.27–7.19(m，5H)，6.46(dd，J＝15.8，8.0Hz，1H)，5.20(d，J＝16.7Hz，1H).HRMS(AP-ESI)m/zcalcdforC
23H
20IN
3O
5S[M-H]
-576.0101，found576.0096.
(S; E)-N-hydroxyl-3-(3-(N-(2-((4-p-methoxy-phenyl) is amino)-2-oxygen-1-styroyl) sulfamic) phenyl) acrylamide (10l): faint yellow solid, productive rate 23%.Mp:197-199℃.
1HNMR(600MHz，DMSO-d
6)δ10.85(s，1H)，10.12(s，1H)，9.14(s，1H)，8.81(d，J＝9.6Hz，1H)，7.88(s，1H)，7.70(d，J＝7.9Hz，1H)，7.63(d，J＝7.7Hz，1H)，7.45–7.33(m，4H)，7.25(dd，J＝13.3，8.3Hz，4H)，7.20(t，J＝7.2Hz，1H)，6.80(d，J＝9.0Hz，2H)，6.46(d，J＝15.8Hz，1H)，5.17(d，J＝9.6Hz，1H)，3.69(s，3H).HRMS(AP-ESI)m/zcalcdforC
24H
23N
3O
6S[M-H]
-480.1234，found480.1235.
(S, E)-N-hydroxyl-3-(3-(N-(2-oxygen-1-phenyl-2-(o-tolyl amido) ethyl) sulfamic) phenyl) acrylamide (10m): faint yellow solid, productive rate 28%.Mp:161-163℃.
1HNMR(600MHz，DMSO-d
6)δ10.86(s，1H)，9.65(s，1H)，9.14(s，1H)，8.85(d，J＝9.6Hz，1H)，7.93(s，1H)，7.76(d，J＝7.8Hz，1H)，7.71(d，J＝7.5Hz，1H)，7.50(t，J＝7.8Hz，1H)，7.44(t，J＝12.3Hz，3H)，7.27(t，J＝7.4Hz，2H)，7.23(t，J＝7.2Hz，1H)，7.12(d，J＝7.3Hz，1H)，7.09–7.01(m，2H)，6.99(d，J＝7.7Hz，1H)，6.51(d，J＝15.8Hz，1H)，5.33(d，J＝9.5Hz，1H)，1.89(s，3H).HRMS(AP-ESI)m/zcalcdforC
24H
23N
3O
5S[M-H]
-464.1292，found464.1286.
(S; E)-3-(3-(N-(2-((2-chlorophenyl) is amino)-2-oxygen-1-styroyl) sulfamic) phenyl)-N-hydroxyacrylamide (10n): faint yellow solid, productive rate 25%.Mp:158-160℃.
1HNMR(600MHz，DMSO-d
6)δ10.85(s，1H)，9.89(s，1H)，9.13(s，1H)，8.88(s，1H)，7.93(s，1H)，7.76(d，J＝7.8Hz，1H)，7.71(d，J＝7.9Hz，1H)，7.50(t，J＝7.8Hz，1H)，7.46–7.37(m，4H)，7.26(ddd，J＝14.0，13.0，5.3Hz，5H)，7.16(t，J＝6.9Hz，1H)，6.50(d，J＝15.8Hz，1H)，5.45(s，1H).HRMS(AP-ESI)m/zcalcdforC
23H
20ClN
3O
5S[M-H]
-484.0745，found484.0739.
(S; E)-3-(3-(N-(2-((3-difluorophenyl) is amino)-2-oxygen-1-styroyl) sulfamic) phenyl)-N-hydroxyacrylamide (10o): faint yellow solid, productive rate 22%.Mp:204-205℃.
1HNMR(600MHz，DMSO-d
6)δ10.84(s，1H)，10.48(s，1H)，9.13(s，1H)，8.89(s，1H)，7.88(s，1H)，7.70(d，J＝7.8Hz，1H)，7.62(d，J＝7.6Hz，1H)，7.43(t，J＝7.8Hz，1H)，7.40–7.35(m，3H)，7.33(d，J＝11.5Hz，1H)，7.30–7.24(m，3H)，7.24–7.19(m，1H)，7.09(d，J＝8.1Hz，1H)，6.86(dd，J＝8.3，6.4Hz，1H)，6.45(d，J＝15.8Hz，1H)，5.19(d，J＝4.6Hz，1H).HRMS(AP-ESI)m/zcalcdforC
23H
20FN
3O
5S[M-H]
-468.104，found468.1035.
(S; E)-N-hydroxyl-3-(3-(N-(2-((3-p-methoxy-phenyl) is amino)-2-oxygen-1-styroyl) sulfamic) phenyl) acrylamide (10p): faint yellow solid, productive rate 22%.Mp:205-206℃.
1HNMR(600MHz，DMSO-d
6)δ10.84(s，1H)，10.24(s，1H)，9.13(s，1H)，8.85(d，J＝9.5Hz，1H)，7.88(s，1H)，7.70(d，J＝7.8Hz，1H)，7.62(d，J＝7.7Hz，1H)，7.45–7.34(m，4H)，7.25(t，J＝7.3Hz，2H)，7.20(t，J＝7.2Hz，1H)，7.13(t，J＝8.1Hz，1H)，7.05(s，1H)，6.92(d，J＝8.0Hz，1H)，6.60(dd，J＝8.2，1.8Hz，1H)，6.46(d，J＝15.8Hz，1H)，5.19(d，J＝9.5Hz，1H)，3.68(s，3H).HRMS(AP-ESI)m/zcalcdforC
24H
23N
3O
6S[M-H]
-480.1242，found480.1235.
(S; E)-3-(3-(N-(2-((2-chlorophenethyl) is amino)-2-oxygen-1-styroyl) sulfamic) phenyl)-N-hydroxyacrylamide (10q): faint yellow solid, productive rate 30%.Mp:122-124℃.
1HNMR(300MHz，DMSO-d
6)δ10.90(s，1H)，9.11(s，1H)，8.78(d，J＝5.8Hz，1H)，8.71(d，J＝9.3Hz，1H)，7.88(s，1H)，7.70(d，J＝7.8Hz，2H)，7.47(t，J＝7.8Hz，1H)，7.43–7.38(m，1H)，7.37(d，J＝1.1Hz，1H)，7.35(d，J＝2.1Hz，1H)，7.32(d，J＝1.4Hz，1H)，7.24(s，1H)，7.23–7.18(m，3H)，7.14(td，J＝7.5，1.1Hz，1H)，6.92(d，J＝7.5Hz，1H)，6.56(d，J＝15.7Hz，1H)，5.13(d，J＝9.4Hz，1H)，4.13(d，J＝5.2Hz，2H).HRMS(AP-ESI)m/zcalcdforC
25H
24ClN
3O
5S[M-H]
-498.0901，found498.0896.
(S, E)-N-hydroxyl-3-(3-(N-(2-oxygen-2-(PhenethyIamino)-1-styroyl) sulfamic) phenyl) acrylamide (10r): faint yellow solid, productive rate 31%.Mp:156-158℃.
1HNMR(600MHz，DMSO-d
6)δ10.85(s，1H)，9.14(s，1H)，8.62(s，1H)，8.28(t，J＝5.4Hz，1H)，7.87(s，1H)，7.70(dd，J＝13.6，7.8Hz，2H)，7.49(t，J＝7.8Hz，1H)，7.45(d，J＝15.9Hz，1H)，7.26(d，J＝6.5Hz，2H)，7.23–7.18(m，5H)，7.17–7.13(m，1H)，7.00(d，J＝7.0Hz，2H)，6.52(d，J＝15.8Hz，1H)，4.97(s，1H)，3.07(td，J＝13.1，7.1Hz，1H)，3.01(td，J＝13.0，7.2Hz，1H)，2.48(t，J＝7.4Hz，2H).HRMS(AP-ESI)m/zcalcdforC
25H
25N
3O
5S[M-H]
-478.144，found478.1442.
(S, E)-N-hydroxyl-3-(3-(N-(2-(naphthalene methyl alcohol-1-base is amino)-2-oxygen-1-styroyl) sulfamic) phenyl) acrylamide (10s): faint yellow solid, productive rate 26%.Mp:186-188℃.
1HNMR(300MHz，DMSO-d
6)δ10.84(s，1H)，10.24(s，1H)，9.11(s，1H)，8.89(d，J＝9.5Hz，1H)，7.98(s，1H)，7.89(d，J＝7.7Hz，1H)，7.79(d，J＝7.9Hz，1H)，7.72(t，J＝7.7Hz，2H)，7.60(d，J＝8.1Hz，1H)，7.49(t，J＝7.5Hz，4H)，7.45–7.36(m，2H)，7.30(dt，J＝11.7，6.8Hz，4H)，6.52(d，J＝15.8Hz，1H)，5.50(d，J＝9.5Hz，1H).HRMS(AP-ESI)m/zcalcdforC
27H
23N
3O
5S[M-H]
-500.1289，found500.1286.
(S; E)-N-hydroxyl-3-(3-(N-(2-((naphthalene acetamide-1-ylmethyl) is amino)-2-oxygen-1-styroyl) sulfamic) phenyl) acrylamide (10t): faint yellow solid, productive rate 24%.Mp:158-160℃.
1HNMR(300MHz，DMSO-d
6)δ10.84(s，1H)，9.11(s，1H)，8.71(t，J＝5.2Hz，2H)，7.91(d，J＝7.6Hz，1H)，7.87(s，1H)，7.81(d，J＝8.4Hz，2H)，7.68(d，J＝7.8Hz，2H)，7.54–7.38(m，4H)，7.38–7.26(m，3H)，7.24–7.11(m，4H)，6.51(d，J＝15.8Hz，1H)，5.10(d，J＝8.4Hz，1H)，4.53(qd，J＝15.2，5.5Hz，2H).HRMS(AP-ESI)m/zcalcdforC
28H
25N
3O
5S[M-H]
-514.1443，found514.1442.
Embodiment 2. compound 10a-10t inhibition of histone deacetylase activity experiment (external)
HDACs active fluoro analytical procedure is adopted to carry out enzymic activity experiment; mainly in two steps: (1) is containing the Methionin HDACs fluorogenic substrate (Boc-Lys (acetyl)-AMC) of an acylated chains; with the sample incubation containing the HDAC8 expressed; make substrate deacetylate, activate substrate.(2) with the Methionin HDACs fluorogenic substrate (Boc-Lys-AMC) of pancreatin hydrolysis containing an acetylize side face; produce this fluorophor of AMC; fluorescence intensity is measured at excitation wavelength/emission wavelength (390nm/460nm); thus calculate inhibiting rate according to the fluorescence intensity of inhibitor group and control group, and ask calculation IC
50value.Enzymic activity test philosophy sees above states reaction formula IV and associated viscera.Experimental result is in table 2 (the vitro inhibition enzymic activity experimental result of compound 5a-5e, 10a-10e).
The vitro inhibition enzymic activity experimental result of table 2 compound 10a-10t
In a table, numerical value is the mean value of three tests.
SAHA trade(brand)name Zolinza, general Vorinostat by name, for U.S. food Drug Administration (FDA) is in the NSC 630176 of approval listing in 2006.
PXD101 trade(brand)name Beleodaq, general belinostat by name, for U.S. food Drug Administration (FDA) is in the NSC 630176 of approval listing in 2014.
Above-mentioned test result shows;: compound has obvious restraining effect to Hela cell extract; wherein compound 10k; 10r; it is similar that the Inhibiting enzyme activity of 10s will be better than far away positive control drug SAHA and PXD101; there is good DEVELOPMENT PROSPECT, and can be used as the lead compound finding new and effective NSC 630176.
The active experiment in vitro of embodiment 3. target compound antiproliferative effect
The compound chosen in above table 1 carries out the activity experiment of vitro inhibition cancer cell multiplication, the results are shown in Table 3.
Term illustrates:
U937: histocytic lymphoma's cell
K562: human erythroleukemia cell's strain
U266: human myeloma cell cell
HL60: people in loop
KG1: acute myeloblast leukemia cell line
SAHA: trade(brand)name Zolinza, general Vorinostat by name, for U.S. food Drug Administration (FDA) is in the NSC 630176 of approval listing in 2006.
PXD101 trade(brand)name Beleodaq, general belinostat by name, for U.S. food Drug Administration (FDA) is in the NSC 630176 of approval listing in 2014.
DMSO: dimethyl sulfoxide (DMSO)
IC
50: half-inhibition concentration
Experimental procedure:
(1) inoculating cell, is made into individual cells suspension, with 5000, every hole cell with the nutrient solution containing 10% foetal calf serum
Be inoculated into 96 orifice plates, every pore volume 100uL, overnight incubation.
(2) preparation of compound solution, in aseptic, is diluted to the DMSO storing solution of compound with nutrient solution and treats
Surveying 5 concentration, 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 LMTT 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 LDMSO, 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
astandard figures is the mean value ± standard deviation of three tests
Upper table detects data and shows to demonstrate certain activity in the test of compound anti-tumour cell proliferative in vitro.
Claims (8)
1. the cinnamide histone deacetylase inhibitor containing phenylglycine, 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,
* be steric configuration be S or R, or its raceme;
Wherein R is amino prepared by each seed amino acid, aryl amine, aryl C1-3 alkylamino radical, C3-4 alkylamino radical, cycloalkanes amido.
2. compound as claimed in claim 1, is characterized in that, in general formula I, R is that virtue is amino.
3. compound as claimed in claim 1 or 2, it is characterized in that, be one of following compounds:
(S, E)-N-hydroxyl-3-(3-(N-(2-oxygen-1-phenyl-2-(aniline) ethyl) sulfamic) phenyl) acrylamide (10a),
(S, E)-3-(3-(N-(2-(Cyclohexylamino)-2-oxygen-1-styroyl) sulfamic) phenyl)-N-hydroxyacrylamide (10b),
(S, E)-N-hydroxyl-3-(3-(N-(2-oxygen-1-phenyl-2-(third is amino) ethyl) sulfamic) phenyl) acrylamide (10c),
(S, E)-N-hydroxyl-3-(3-(N-(2-(isopropylamino)-2-oxygen-1-styroyl) sulfamic) phenyl) acrylamide (10d),
(S, E)-3-(3-(N-(2-(fourth is amino)-2-oxygen-1-styroyl) sulfamic) phenyl)-N-hydroxyacrylamide (10e),
(S, E)-N-hydroxyl-3-(3-(N-(2-(isopropylamino)-2-oxygen-1-styroyl) sulfamic) phenyl) acrylamide (10f),
(S, E)-3-(3-(N-(2-(TERTIARY BUTYL AMINE base)-2-oxygen-1-styroyl) sulfamic) phenyl)-N-hydroxyacrylamide (10g),
(S, E)-3-(3-(N-(2-((4-difluorophenyl) is amino)-2-oxygen-1-styroyl) sulfamic) phenyl)-N-hydroxyacrylamide (10h),
(S, E)-3-(3-(N-(2-((4-chlorophenyl) is amino)-2-oxygen-1-styroyl) sulfamic) phenyl)-N-hydroxyacrylamide (10i),
(S, E)-3-(3-(N-(2-((4-bromo phenyl) is amino)-2-oxygen-1-styroyl) sulfamic) phenyl)-N-hydroxyacrylamide (10j),
(S, E)-N-hydroxyl-3-(3-(N-(2-((4-iodine substituted phenyl) is amino)-2-oxygen-1-styroyl) sulfamic) phenyl) acrylamide (10k),
(S, E)-N-hydroxyl-3-(3-(N-(2-((4-p-methoxy-phenyl) is amino)-2-oxygen-1-styroyl) sulfamic) phenyl) acrylamide (10l),
(S, E)-N-hydroxyl-3-(3-(N-(2-oxygen-1-phenyl-2-(o-tolyl amido) ethyl) sulfamic) phenyl) acrylamide (10m),
(S, E)-3-(3-(N-(2-((2-chlorophenyl) is amino)-2-oxygen-1-styroyl) sulfamic) phenyl)-N-hydroxyacrylamide (10n),
(S, E)-3-(3-(N-(2-((3-difluorophenyl) is amino)-2-oxygen-1-styroyl) sulfamic) phenyl)-N-hydroxyacrylamide (10o),
(S, E)-N-hydroxyl-3-(3-(N-(2-((3-p-methoxy-phenyl) is amino)-2-oxygen-1-styroyl) sulfamic) phenyl) acrylamide (10p),
(S, E)-3-(3-(N-(2-((2-chlorophenethyl) is amino)-2-oxygen-1-styroyl) sulfamic) phenyl)-N-hydroxyacrylamide (10q),
(S, E)-N-hydroxyl-3-(3-(N-(2-oxygen-2-(PhenethyIamino)-1-styroyl) sulfamic) phenyl) acrylamide (10r),
(S, E)-N-hydroxyl-3-(3-(N-(2-(naphthalene methyl alcohol-1-base amino)-2-oxygen-1-styroyl) sulfamic) phenyl) acrylamide (10s) or
(S, E)-N-hydroxyl-3-(3-(N-(2-((naphthalene acetamide-1-ylmethyl) is amino)-2-oxygen-1-styroyl) sulfamic) phenyl) acrylamide (10t).
4. the preparation method of compound described in claim 1, is characterized in that, step is as follows:
Be raw material with phenyl aldehyde, through sulfonation, Huo Naer-Wordsworth-Ai Mengsi is obtained by reacting key intermediate 3, and intermediate 3 and thionyl chloride reacts and generate acyl chlorides 4, while with L-phenylglycine for raw material warp (Boc)
2o protects alpha-amino group to generate key intermediate 6, intermediate 6 and different amine carry out condensation should, slough Boc blocking group by EtOAc/HCl and generate key intermediate 8, intermediate 8 and acyl chlorides 4 carry out condensation reaction, and ethyl ester is converted into hydroximic acid obtains target compound;
Synthetic route is as follows:
Wherein R is as described in general formula I;
Reagent in said synthesis route reaction formula: (a) oleum; (b) phosphonoacetate, salt of wormwood, water; (c) thionyl chloride, DMF; (d) (Boc)
2o, triethylamine, methylene dichloride; (e) O-benzotriazole-N, N, N', N'-tetramethyl-urea Tetrafluoroboric acid, triethylamine, methylene dichloride; The saturated HCl solution of (f) EtOAc; (g) toluene, methylene dichloride; (h) NH
2oK, anhydrous methanol.
5. the preparation method of (S, E)-N-hydroxyl-3-(3-(N-(2-oxygen-1-phenyl-2-(aniline) ethyl) sulfamic) phenyl) acrylamide (10a), concrete preparation process is as follows:
(1) synthesis of compound 3-formylbenzenesulfonic acid sodium (2):
At 0 DEG C, 2.0g phenyl aldehyde is slowly added dropwise in 5mL oleum, 40 DEG C of reactions 16 hours, pour in 150mL frozen water, with 50mL extraction into ethyl acetate 2 times by reaction solution, slowly adding calcium carbonate to PH is 6-7, filter, adding a small amount of sodium carbonate in filtrate to PH is 8, filters, filtrate evaporate to dryness, with dissolve with methanol, filter, filtrate evaporate to dryness obtains compound 2;
(2) synthesis of compound (E)-3-(3-oxyethyl group-3-oxo-1-alkene-1-base) benzene sulfonic acid sodium salt (3):
By 0.5g compound 2,0.7g salt of wormwood, 0.7g phosphonoacetate and 5mL water at room temperature stir 30 minutes, filter the precipitation generated, and by 2ml methanol wash 2 times, filtrate evaporate to dryness obtains the thick product of compound 3;
(3) synthesis of compound (E)-ethyl 3-(3-(chlorosulfonyl) phenyl) acrylate (4):
By 0.53g compound 3,1.7mL thionyl chloride, 2 DMFs are even in stirring at room temperature, reflux 5 hours, react complete at 75 DEG C, and solvent evaporated obtains the thick product of compound 4;
(4) synthesis of compound (S)-2-((uncle-tert-butyl carbonyl) is amino)-2-toluylic acid (6):
15.1gL-phenylglycine is placed in reaction flask, adds 200mL methanol/water, stirring at room temperature dissolve, after add 15.1mLEt
3n, by 32.7g (Boc)
2o is added dropwise in reaction solution, and stirred at ambient temperature 8 hours, revolves steaming and remove solvent, dissolves with 100mL citric acid, with 50mL extraction into ethyl acetate 3 times, with anhydrous sodium sulfate drying, is spin-dried for obtain crude product, uses normal hexane recrystallization, obtain product 6;
(5) synthesis of compound (S) tertiary butyl (2-oxygen-1-phenyl-2-(aniline) ethyl) carbamate (7a):
1.26g compound 6 is dissolved in 50mL methylene dichloride, at 0 DEG C, successively adds 0.61mLEt
3n and 1.93gO-benzotriazole-N, N, N', N'-tetramethyl-urea Tetrafluoroboric acid; Stirring at room temperature 8 hours, revolves steaming and removes solvent, extracts with 100mL acetic acid ethyl dissolution, 50mL citric acid, 50mL saturated sodium carbonate solution, 50mL saturated nacl aqueous solution wash 3 times respectively, with anhydrous sodium sulfate drying, be spin-dried for and obtain crude product, with the compound 7a of re-crystallizing in ethyl acetate;
(6) compound (S)-2-amino-N, the synthesis of 2-diphenylacetamide hydrochloride (8a):
Be dissolved in by 3.4g7a in the saturated HCl solution of 60mLEtOAc, react 5 hours under room temperature, separate out solid, filter, obtaining product 8a, is white solid;
(7) synthesis of compound (S, E)-ethyl 3-(3-(N-(2-oxygen-1-phenyl-2-(anilino) ethyl) sulfamic) phenyl) acrylate (9a):
Compound 0.58g8a is dissolved in 10mL methylene dichloride, successively adds 0.24gEt
3n, be dissolved in the 0.55g compound 4 in 10mL toluene, reaction solution at room temperature stirs and spends the night, with revolving steaming solvent evaporated, with the extraction of 60mL acetic acid ethyl dissolution, 50mL citric acid, 50mL saturated sodium carbonate solution, 50mL saturated nacl aqueous solution wash 3 times respectively, with anhydrous sodium sulfate drying, be spin-dried for and obtain crude product, with the compound 9a of re-crystallizing in ethyl acetate;
(8) synthesis of compound (S, E)-N-hydroxyl-3-(3-(N-(2-oxygen-1-phenyl-2-(aniline) ethyl) sulfamic) phenyl) acrylamide (10a):
0.46g9a is dissolved in 14mLNH
2in the methanol solution of OK, room temperature reaction 3h, TLC monitor reaction; Remove methyl alcohol under reduced pressure, add citric acid and regulate PH to 3-4,20mL extraction into ethyl acetate, 20mL saturated nacl aqueous solution washs 3 times, anhydrous sodium sulfate drying, suction filtration, removed under reduced pressure solvent, and flash column chromatography carries out purifying, obtains target product 10a, faint yellow solid.
6. the application of the arbitrary described compound of claim 1-3 in the medicine of the mammalian diseases that preparation prevents or treatment is 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, leukemia, malaria or diabetes.
7. be suitable for orally giving a mammiferous pharmaceutical composition, comprise the arbitrary described compound of claim 1-3 and one or more pharmaceutically acceptable carriers or vehicle.
8. be suitable for parenteral and give a mammiferous pharmaceutical composition, comprise the arbitrary described compound of claim 1-3 and one or more pharmaceutically acceptable carriers or vehicle.
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Citations (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101189003A (en) * | 2005-05-13 | 2008-05-28 | 托波塔吉特英国有限公司 | Pharmaceutical formulations of HDAC inhibitors |
| CN101230049A (en) * | 2008-02-27 | 2008-07-30 | 中国药科大学 | Hydroxamic acid histone deacetylase inhibitor as well as preparation method and use thereof |
| WO2008091349A1 (en) * | 2006-02-14 | 2008-07-31 | The President And Fellows Of Harvard College | Bifunctional histone deacetylase inhibitors |
| CN101255124A (en) * | 2008-03-26 | 2008-09-03 | 山东大学 | Cinnamide histone deacetylase inhibitor and preparation method thereof |
| EP2292593A2 (en) * | 2000-09-29 | 2011-03-09 | TopoTarget UK Limited | Carbamic acid compounds comprising a sulfonamide linkage as HDAC inhibitors |
| CN103172540A (en) * | 2013-03-18 | 2013-06-26 | 潍坊博创国际生物医药研究院 | Phenylglycine histone deacetylase inhibitor as well as preparation method and applications thereof |
| CN103664751A (en) * | 2013-08-30 | 2014-03-26 | 中国海洋大学 | Synthesis of benzsulfamide HDAC (Histone Deacetylase) inhibitor and application of benzsulfamide HDAC inhibitor in resisting tumor |
-
2015
- 2015-12-28 CN CN201511003222.XA patent/CN105481736A/en active Pending
Patent Citations (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP2292593A2 (en) * | 2000-09-29 | 2011-03-09 | TopoTarget UK Limited | Carbamic acid compounds comprising a sulfonamide linkage as HDAC inhibitors |
| CN101189003A (en) * | 2005-05-13 | 2008-05-28 | 托波塔吉特英国有限公司 | Pharmaceutical formulations of HDAC inhibitors |
| WO2008091349A1 (en) * | 2006-02-14 | 2008-07-31 | The President And Fellows Of Harvard College | Bifunctional histone deacetylase inhibitors |
| CN101230049A (en) * | 2008-02-27 | 2008-07-30 | 中国药科大学 | Hydroxamic acid histone deacetylase inhibitor as well as preparation method and use thereof |
| CN101255124A (en) * | 2008-03-26 | 2008-09-03 | 山东大学 | Cinnamide histone deacetylase inhibitor and preparation method thereof |
| CN103172540A (en) * | 2013-03-18 | 2013-06-26 | 潍坊博创国际生物医药研究院 | Phenylglycine histone deacetylase inhibitor as well as preparation method and applications thereof |
| CN103664751A (en) * | 2013-08-30 | 2014-03-26 | 中国海洋大学 | Synthesis of benzsulfamide HDAC (Histone Deacetylase) inhibitor and application of benzsulfamide HDAC inhibitor in resisting tumor |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2017148318A1 (en) * | 2016-03-04 | 2017-09-08 | 深圳市塔吉瑞生物医药有限公司 | Substituted acrylamide compound and pharmaceutical composition thereof |
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