CN104592145A - Benzofuroxan histone deacetylase inhibitor as well as preparation method and application thereof - Google Patents

Benzofuroxan histone deacetylase inhibitor as well as preparation method and application thereof Download PDF

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CN104592145A
CN104592145A CN201510019386.5A CN201510019386A CN104592145A CN 104592145 A CN104592145 A CN 104592145A CN 201510019386 A CN201510019386 A CN 201510019386A CN 104592145 A CN104592145 A CN 104592145A
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benzo
oxadiazole
carbonyl
oxide compound
compound
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CN104592145B (en
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徐文方
段文文
张颖杰
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Shandong University
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Shandong University
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D271/00—Heterocyclic compounds containing five-membered rings having two nitrogen atoms and one oxygen atom as the only ring hetero atoms
    • C07D271/12—Heterocyclic compounds containing five-membered rings having two nitrogen atoms and one oxygen atom as the only ring hetero atoms condensed with carbocyclic rings or ring systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/4245—Oxadiazoles
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
    • Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
    • Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change

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  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

The invention relates to a benzofuroxan histone deacetylase inhibitor as well as a preparation method and an application thereof. The compound has a structure as shown in formula I or I' in the specification. The invention further relates to a pharmaceutical composition comprising the compound with the structure as shown in formula I or I'. The compound disclosed by the invention is used for preparing a drug for preventing or treating mammalian diseases associated with benzofuroxan histone deacetylase activity abnormal expression.

Description

A kind of benzo furoxan NSC 630176 and its preparation method and application
Technical field
The present invention relates to a kind of benzo furoxan NSC 630176 and its preparation method and application, belong to technical field of chemistry.
Background technology
Research shows, the generation of tumour and the acetylize of lysine residue of nucleosome core albumen n end and the unbalance of deacetylation have close relationship.Acetylation of histone is a dynamic reversing process, by acetylation of histone transferring enzyme (histoneacetyltransferases, HATs) and histon deacetylase (HDAC) (histone deacetylases, HDACs) dual regulation.HAT by the acetyl grouptransfer of acetyl-CoA on the specific lysine residue of histone N-terminal, this state is conducive to dissociating of DNA and octameric histone, nucleosomal structure relaxes, thus make various transcription factor and collaborative transcription factor can with DNA binding site specific binding, transcribing of activated gene; And the deacetylation that HDAC is held by histone N; make histone positively charged (reaction formula II); thus combine closely with electronegative DNA, chromatin be crimping very close prevent structure, thus suppress the transcriptional expression of some gene (as cancer suppressor gene).In human body, found that HDACs family has 18 members at present, according to its structure, the difference of function and distribution can be divided into four classes.Wherein, I class (HDAC1,2,3 and 8), II class (IIa:HDAC 4,5,7 and 9; IIb:HDAC 6 and 10), IV class (HDAC11) belongs to zine ion dependency lytic enzyme, and III class HDACs (SIR 1-7) is that NAD+ is dependent.
NSC 630176 (histone deacetylase inhibitors; HDACi) then by improving chromatin specific region acetylation of histone; thus the expression of regulating cell apoptosis and differentiation associated protein and stability; cell death inducing and differentiation; HDACi has antitumor spectra extensively simultaneously, the advantage that toxic side effect is low, and they are to solid tumor; leukemia, lymphoma all has good inhibit activities.The metal bonding pad of HDACi can well and the zine ion direct effect of reactive site, and form hydrogen bond with Histidine and tyrosine etc., the capsule that link zone is then lucky with narrow fully contacts, and surperficial cog region is suitable for the edge residue close contact of capsule.Therefore, for HDACs be shot design inhibitor become antitumor drug research focus.
Nitrogen protoxide (NO), as messenger molecule important in organism, participates in the processes such as regulation of blood vessels, neurotransmission, inflammation and immune response, and NO also can developing by number of ways Tumor suppression simultaneously.Although the mechanism of action of NO in tumour progression is still not clear, but the NO continuing lower concentration in body can Promote cell's growth, inhibited apoptosis, the NO of high density then can produce cytotoxicity, inducing apoptosis of tumour cell, stop diffusion and the transfer of tumour cell, and compared with normal cell, tumour cell is more responsive to NO.NO donator type antitumour drug JS-K is listed in quick research and development by NCI and plans.Furoxan-based NO donors (formula II) as NO donor is taken seriously gradually, and increasing investigator attempts utilizing furazan oxynitrides carry out the design and synthesis of tumour medicine as NO donor and obtain certain progress.
Also there is potential using value in HDACi, the effect of this and NO is perfectly in harmony in inflammation, neurotransmission, regulation of blood vessels and cardiovascular disorder, and according to this result of study, both should play synergy in the process of some disease for the treatment of.Key, H.J in 2011 find that both play synergy really when treatment hypertrophic cardiomyopathy; After this, both can play synergy equally when treatment wound healing to have again investigator to find.
Summary of the invention
The present invention is directed to the deficiencies in the prior art, provide a kind of and have the benzofuraxan oxide compound NSC 630176 suppressing deacetylase and release nitrogen protoxide dual function simultaneously, the present invention also provides preparation method and the purposes of this compound.
Technical solution of the present invention is as follows:
One, benzofuraxan oxide compound NSC 630176
Benzofuraxan oxide compound NSC 630176, has general formula I or the structure shown in I ＇, and its optical isomer, diastereomer and racemic mixture, its pharmacy acceptable salt, solvate or prodrug;
Wherein,
X is oxygen or amino;
R 1the saturated aliphatic chain of various C1-8, with the saturated aliphatic chain of side chain, alkene chain, alkynes chain, alkoxy chain, aroyl, heteroaryl, cycloalkyl, C1-8 mixes alkyl, with substituent aromatic base or with substituent heteroaryl;
R 2hydroxamic acid, hydroxyl, carboxyl, methoxycarbonyl, amide group or hydrazide group;
R 3represent hydrogen, ortho position, a position, the fluorine of contraposition, chlorine, bromine, iodine halogen, hydroxyl, amino, methoxyl group, oxyethyl group, or cyano group.
Preferably, in above-mentioned general formula I,
X is oxygen;
R 1the unsaturated fatty chain of the saturated aliphatic chain of C1-8, C1-8, the fragrant chain of C1-9, C1-8's contains heteroatomic aliphatic chain, the heterocycle of C1-9;
R 2hydroxyl, carboxyl, methoxycarbonyl, ethoxycarbonyl, hydroxamic acid;
R 3hydrogen.
Further preferred, above-mentioned formula I is one of following:
5-((4-(hydroxyl amino)-4-oxo butyl) carbonyl) benzo [c] [5] oxadiazole-1-oxide compound (5a);
5-((5-(hydroxyl amino)-5-oxopentyl) carbonyl) benzo [c] [5] oxadiazole-1-oxide compound (5b);
5-((6-(hydroxyl amino)-6-oxo-hexyl) carbonyl) benzo [c] [5] oxadiazole-1-oxide compound (5c);
5-((7-(hydroxyl amino)-7-oxo heptyl) carbonyl) benzo [c] [5] oxadiazole-1-oxide compound (5d);
5-((8-(hydroxyl amino)-8-oxo octyl group) carbonyl) benzo [c] [5] oxadiazole-1-oxide compound (5e);
4-((4-(hydroxyl amino)-4-oxo butyl) carbonyl) benzo [c] [5] oxadiazole-1-oxide compound (10a);
4-((5-(hydroxyl amino)-5-oxopentyl) carbonyl) benzo [c] [5] oxadiazole-1-oxide compound (10b);
4-((6-(hydroxyl amino)-6-oxo-hexyl) carbonyl) benzo [c] [5] oxadiazole-1-oxide compound (10c);
4-((7-(hydroxyl amino)-7-oxo heptyl) carbonyl) benzo [c] [5] oxadiazole-1-oxide compound (10d);
4-((8-(hydroxyl amino)-8-oxo octyl group) carbonyl) benzo [c] [5] oxadiazole-1-oxide compound (10e);
5-((3-carboxyl third oxygen) carbonyl) benzo [c] [5] oxadiazole-1-oxide compound (4a);
5-((4-carboxyl fourth oxygen) carbonyl) benzo [c] [5] oxadiazole-1-oxide compound (4b);
5-((5-carboxyl penta oxygen) carbonyl) benzo [c] [5] oxadiazole-1-oxide compound (4c);
5-((the own oxygen of 6-carboxyl) carbonyl) benzo [c] [5] oxadiazole-1-oxide compound (4d);
5-((7-carboxyl oxygen in heptan) carbonyl) benzo [c] [5] oxadiazole-1-oxide compound (4e);
4-((3-carboxyl third oxygen) carbonyl) benzo [c] [5] oxadiazole-1-oxide compound (9a);
4-((4-carboxyl fourth oxygen) carbonyl) benzo [c] [5] oxadiazole-1-oxide compound (9b);
4-((5-carboxyl penta oxygen) carbonyl) benzo [c] [5] oxadiazole-1-oxide compound (9c);
4-((the own oxygen of 6-carboxyl) carbonyl) benzo [c] [5] oxadiazole-1-oxide compound (9d);
4-((7-carboxyl oxygen in heptan) carbonyl) benzo [c] [5] oxadiazole-1-oxide compound (9e);
5-((4-hydroxybutoxy) carbonyl) benzo [c] [1,2,5] oxadiazole 1-oxide compound (3a);
5-((5-hydroxyl pentyloxy) carbonyl) benzo [c] [1,2,5] oxadiazole 1-oxide compound (3b);
5-((6-hydroxyl hexyloxy) carbonyl) benzo [c] [1,2,5] oxadiazole 1-oxide compound (3c);
5-((7-hydroxyl oxygen in heptan base) carbonyl) benzo [c] [1,2,5] oxadiazole 1-oxide compound (3d);
5-((8-hydroxyl octyloxy) carbonyl) benzo [c] [1,2,5] oxadiazole 1-oxide compound (3e);
4-((4-hydroxybutoxy) carbonyl) benzo [c] [1,2,5] oxadiazole 1-oxide compound (8a);
4-((5-hydroxyl pentyloxy) carbonyl) benzo [c] [1,2,5] oxadiazole 1-oxide compound (8b);
4-((6-hydroxyl hexyloxy) carbonyl) benzo [c] [1,2,5] oxadiazole 1-oxide compound (8c);
4-((7-hydroxyl oxygen in heptan base) carbonyl) benzo [c] [1,2,5] oxadiazole 1-oxide compound (8d);
4-((8-hydroxyl octyloxy) carbonyl) benzo [c] [1,2,5] oxadiazole 1-oxide compound (8e).
Term used herein is as follows with definition implication:
" aromatic base " refers to aromatic carbocyclic group.Preferred aromatic ring contains 6-10 carbon atom.
" heteroaryl " is aromatic heterocycle, can be monocycle or bicyclic radicals.Preferred heteroaryl comprises thienyl, furyl, pyrryl, pyridyl, pyrazinyl, thiazolyl, pyrimidyl, quinolyl, tetrazole base, this sick thiazolyl, benzofuryl or indyl etc.
" assorted alkyl " is saturated or unsaturated, carbon atoms and at least one heteroatomic chain, and wherein any one heteroatoms is non-conterminous.Containing 2-15 atom (carbon atom) in assorted alkyl, preferably containing 2-10 atom.Assorted alkyl can be straight or branched, substituted or unsubstituted.
" cycloalkyl " is substituted or unsubstituted, saturated or undersaturated cyclic group, 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.
" aroyl " refers to that aromatic carbon ring end is connected with the group of carbonyl, and preferred aromatic ring contains 6-10 carbon 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., The Van Nostrand Chemist ' s Dictionary, 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.Such substituting group is included in C.hansch and A.Leo, those substituting groups listed in Substituent Constants for Correlation Analysis in Chemistry and Biology (1979).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.
Two, the preparation method of benzofuraxan NSC 630176 of the present invention
The preparation method of described compound, step is as one of following:
Synthetic route one is as follows:
With the amino 3-nitrobenzoic acid of 4-for raw material, through azide, rearrangement reaction obtains key intermediate 2, and rear priority is through esterification (obtaining 3a-3e), oxidation obtains carboxylic acid cpd 4a-4e, finally makes target product hydroximic acid 5a-5e by oxammonium hydrochloride condensation;
Or synthetic route two is as follows:
With the amino 3-nitrobenzoic acid of 2-for raw material, through azide, rearrangement reaction obtains key intermediate 7, and rear priority is through esterification (obtaining 8a-8e), oxidation obtains carboxylic acid cpd 9a-9e, finally makes target product hydroximic acid 10a-10e by oxammonium hydrochloride condensation;
Reagent in said synthesis route reaction formula: (a) Sodium Nitrite, hydrochloric acid, sodiumazide; (b) toluene; The linear primary glycol of (c) C4-C8, PyBOP, triethylamine; (d) Jones reagent, acetone; (e) isobutyl chlorocarbonate, triethylamine, tetrahydrofuran (THF); Oxammonium hydrochloride, potassium hydroxide, methyl alcohol;
R 1, R 3described in above-mentioned general formula I and I ＇.
The target compound structural formula of synthetic route is as shown in table 1 below:
Table 1 target compound 5a-5e, 10a-10e 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, Protecting Groups in OrganicSynthesis.
Three, the application of benzofuraxan oxide compound NSC 630176
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 parenteral and gives mammiferous pharmaceutical composition, comprises the compound of above-mentioned general formula I, and pharmaceutically acceptable carrier, optionally comprises one or more pharmaceutically acceptable vehicle.Due to the high homology of each hypotype catalytic center of zine ion dependency histon deacetylase (HDAC) (HDACs), select the histone deacetylase 1 of current known X-diffraction crystal structure and 2 mixed enzyme (HDAC1and 2) carry out enzymic activity test.
HDACs active fluoro analytical procedure (two-step approach), can fast, conveniently detect HDACs active, simple to operate, highly sensitive.The first step is containing Methionin HDACs fluorogenic substrate Boc-Lys (the acetyl)-AMC (Boc-Lys (acetyl)-AMC) of an acylated chains; with HDAC1 & 2 sample incubation containing expression; make substrate deacetylate, activate substrate.Second step, Boc-Lys-AMC is hydrolyzed with pancreatin (Trypsin), produce 4-amino-7-methyl-coumarin (AMC) this fluorophor (i.e. chromophoric group), 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 and calculate IC50 value.Enzymic activity test philosophy is shown in following reaction formula IV.
The test of the cytoactive of compound uses Thiazolyl blue detection method (mtt assay), people's red white corpuscle leukemia cell (HEL) and human colon cancer cell (HCT-116) cell suspension are inoculated in 96 orifice plates respectively, every hole adds the substratum of different concns compound, after hatching, dye with MTT, after continuing to hatch, measure the absorbancy (OD value) in every hole at 570nm place in microplate reader, calculate inhibitory rate of cell growth, thus the activity of deterministic compound.
The compound of general formula I external presses down enzyme experiment proves that this compounds is a kind of NSC 630176.
Furazan type NO compound donator is general by degrading with various sulfur alcohol compound as the cysteine residues of protein etc. reacts and discharge NO, strong nucleophilic reagent RS in vivo -ion can make its open loop form nitroso compound intermediate in 3-or the 4-position of l, 2,5-oxadiazole-2-oxide heterocyclic in attack Furoxans type compound, and then elimination reaction occurs generates NO, and the NO of generation can by the O in solution 2rapid oxidation is nitrite ion (NO 2-) and nitrate radical from protecting (NO 3-) (see reaction formula V).According to above-mentioned principle, the external NO release experiment of furazan type NO compound donator is typically employed in 37 DEG C of methods of hatching in L-cys solution and measures.
Griess method is the most classical NO concentration determination method, and its principle is the meta-bolites nitrite ion (NO by measuring NO 2-) content ask to connect and weigh the concentration of NO, nitrite ion (NO 2-) can with Griess reagent (4% sulfanilic amide (Sulphanilamide), 0.2%N-(l-naphthyl) ethylendiamine dihydrochloride, H 3pO 4) carry out diazonium-even nitrogenizing reaction and generate coloured azo-compound (Azo compound) (see reaction formula VI), it has absorption peak within the scope of 540-560nm, measure its absorbancy by visible spectrophotometry and calculate its concentration, this method is easy and simple to handle, is usually used in the release in vitro measuring NO.
Adopt NO detection kit (green skies biotechnology research institute), sample is cell culture supernatant, and cell culture fluid is DMEM+10%FBS, with DMEM+10%FBS dilution standard product, the concentration desirable 0,1 of configuration standard product, 2,5,10,20,40,60,100 μMs, going out to detect absorbance A with 540nm, take absorbance A as ordinate zou, NO 2-concentration C is done X-coordinate and is mapped and obtain typical curve.Human colon cancer cell (HCT-116) is adopted to be inoculated in 24 orifice plates, after the respective concentration adding the testing compound configured is hatched, add the reagent I in test kit and reagent II successively, after under 540nm wavelength, survey absorbancy (OD), after bring typical curve into, corresponding nitric oxide production burst size can be calculated.
The cell intracellular nitric oxide release experiment of the compound of general formula I proves that this compounds can discharge a large amount of nitrogen protoxides in tumour cell.
The derivative of benzofuraxan oxide heterocyclic of the present invention spatially matches with the avtive spot of histon deacetylase (HDAC), can discharge a large amount of nitrogen protoxides again simultaneously, therefore show higher inhibit activities in vitro.
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.
Compound 5d in the present invention; 9d to the inhibit activities of histon deacetylase (HDAC) (HELA cell extract) apparently higher than positive drug; a large amount of nitrogen protoxides can be discharged simultaneously; there is good DEVELOPMENT PROSPECT, and can be used as the lead compound finding new and effective NSC 630176.In addition, in the test of compound 5d, 9d anti-tumour cell proliferative in vitro, demonstrate certain activity, be worth carrying out composition optimizes and exploitation further.
Accompanying drawing explanation
Fig. 1 is that target compound discharges nitric oxide production release spirogram in HCT-116 cell.X-coordinate is compound title, and ordinate zou is the increase multiple (relative to blank group) of the generation nitrate of experiment test.
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 5a-5e
Compound 5-phenylformic acid also [c] [synthesis of 1,2,5] oxadiazole 1-oxide compound (2):
By 4-amino-3-nitrobenzoic acid (3.6g, 20mmol) be placed in reaction flask, add 100mL 35% (V/V) hydrochloric acid stirring at room temperature to dissolve, rear cryosel bath is cooled to 0-5 DEG C, slow dropping 33% (m/V) sodium nitrite in aqueous solution (4.4mL), finish, ice bath stirs 1 hour.The aqueous solution (1.3g/5mL) of slow dropping sodiumazide, keep temperature in bottle lower than 30 DEG C, to finish, continue stirring after 1.5 hours under room temperature, reaction terminates.Filter to obtain faint yellow solid, drying dewaters and obtains compound 1.Compound 1 is placed in reaction flask, adds 100mL toluene, be heated to 80 DEG C of back flow reaction, after about 1 hour, reaction terminates.Filter to obtain faint yellow solid, dry, obtain compound 2 with ethyl alcohol recrystallization. 1H NMR(600MHz,DMSO)δ13.80(s,1H),8.21(d,J＝182.0Hz,1H),7.86(s,2H).
The synthesis of compound 3:
By compound 2 (0.9g, 5mmol), 1.2mL1,4-butyleneglycol, PyBOP (3.1g, 6mmol), triethylamine (1.6mL, 6.5mmol) be placed in reaction flask, dissolve under adding 50mL dry methylene chloride stirring at room temperature, TLC detection reaction is carried out.After 10 hours, reaction terminates.Be spin-dried for solvent, with ethyl acetate (3 × 50mL) dilution extraction, and use distilled water successively, saturated common salt water washing.Be separated organic phase, with anhydrous sodium sulfate drying, be spin-dried for ethyl acetate and obtain crude product, column chromatography purification, eluent V (sherwood oil: ethyl acetate)=2:1, obtains product.
Compound 5-((4-hydroxybutoxy) carbonyl) benzo [c] [1,2,5] oxadiazole 1-oxide compound (3a): faint yellow solid, productive rate: 72%. 1H NMR(600MHz,DMSO)δ8.39–8.05(m,1H),7.95–7.69(m,2H),4.35(t,J＝6.6Hz,2H),3.47(t,J＝6.4Hz,2H),1.82–1.76(m,2H),1.58(dt,J＝13.4,6.5Hz,2H). 13CNMR(125MHz,DMSO)δ166.04,159.91,139.85,132.44,131.39,121.71,66.74,62.37,30.25,27.37.MS:[M+H +]:Found m/z 253.2Calcd m/z 252.2.
Compound 5-((5-hydroxyl pentyloxy) carbonyl) benzo [c] [1,2,5] oxadiazole 1-oxide compound (3b): faint yellow solid, productive rate: 66%. 1H NMR(600MHz,CDCl 3)δ7.77(dd,J＝294.4,137.8Hz,3H),4.36(t,J＝6.6Hz,2H),3.67(t,J＝6.4Hz,2H),1.81(dd,J＝14.8,7.1Hz,2H),1.67–1.59(m,2H),1.56–1.47(m,2H). 13C NMR(151MHz,CDCl 3)δ171.24,164.11,66.28,62.62,32.34,28.55,22.44.MS:[M+H +]:Found m/z 267.3Calcd m/z 266.3.
Compound 5-((6-hydroxyl hexyloxy) carbonyl) benzo [c] [1,2,5] oxadiazole 1-oxide compound (3c): faint yellow solid, productive rate: 68%. 1H NMR(600MHz,DMSO)δ7.88(m,3H),4.32(t,J＝6.3Hz,2H),3.40(dd,J＝11.2,6.2Hz,2H),1.77–1.71(m,2H),1.47–1.38(m,4H),1.39–1.33(m,2H). 13C NMR(131MHz,DMSO)δ166.04,159.91,139.85,132.44,131.39,121.71,66.74,62.37,33.01,29.32,26.58,26.25.MS:[M+H +]:Found m/z 281.3Calcd m/z 280.3.
Compound 5-((7-hydroxyl oxygen in heptan base) carbonyl) benzo [c] [1,2,5] oxadiazole 1-oxide compound (3d): faint yellow solid, productive rate: 71%. 1H NMR(600MHz,CDCl 3)δ8.19(s,1H),7.83(s,1H),7.54(s,1H),4.35(t,J＝6.7Hz,2H),3.63(t,J＝6.6Hz,2H),1.81–1.75(m,2H),1.56(dd,J＝13.5,6.7Hz,2H),1.45(dt,J＝14.4,7.2Hz,2H),1.41–1.36(m,4H). 13C NMR(151MHz,CDCl 3)δ163.96,130.63,120.20,116.65,66.27,62.80,32.62,28.97,28.50,25.90,25.61.MS:[M+H +]:Found m/z 295.3Calcd m/z294.3.
Compound 5-((8-hydroxyl octyloxy) carbonyl) benzo [c] [1,2,5] oxadiazole 1-oxide compound (3e): faint yellow solid, productive rate: 54%. 1H NMR(600MHz,CDCl 3)δ8.01(s,1H),7.67(s,1H),7.38(s,1H),4.43(t,J＝6.5Hz,2H),3.71(t,J＝6.4Hz,2H),1.84–1.70(m,2H),1.61(dd,J＝13.2,6.6Hz,2H),1.42–1.37(m,2H),1.31(dd,J＝17.1,8.1Hz,4H). 13C NMR(151MHz,CDCl 3)δ164.18,145.32,134.94,133.48,128.09,127.92,125.62,66.50,62.85,32.68,29.20,29.10,28.52,25.81,25.62.MS:[M+H +]:Found m/z 30.3Calcd m/z 308.3.
The synthesis of compound 4: (for compound 4a)
Compound 3a (660mg, 2.1mmol) is placed in reaction flask, dissolves under adding 10mL acetone stirring at room temperature, and under condition of ice bath, drip Jones reagent 1.1mL.Finish, continue under room temperature to stir, TLC detection reaction is carried out.After about 5 hours, reaction terminates, and filters out the green precipitate thing of generation, is spin-dried for solvent, with ethyl acetate (3 × 50mL) dilution extraction, and uses distilled water successively, saturated common salt water washing.Be separated organic phase, with anhydrous sodium sulfate drying, be spin-dried for ethyl acetate and obtain crude product, column chromatography purification, eluent V (sherwood oil: ethyl acetate)=1:1, obtains product.
Compound 5-((3-carboxyl third oxygen) carbonyl) benzo [c] [5] oxadiazole-1-oxide compound (4a): faint yellow solid, productive rate: 56%. 1H NMR(600MHz,DMSO)δ12.16(s,1H),8.31(d,J＝183.7Hz,1H),7.98–7.68(m,2H),4.34(t,J＝6.3Hz,2H),2.43(t,J＝7.2Hz,2H),2.01–1.95(m,2H). 13C NMR(151MHz,DMSO)δ177.25,166.04,159.91,139.85,132.44,131.39,121.71,65.66,31.84,24.36.MS:[M+H +]:Found m/z 267.2Calcd m/z 266.2.
Compound 5-((4-carboxyl fourth oxygen) carbonyl) benzo [c] [5] oxadiazole-1-oxide compound (4b): faint yellow solid, productive rate: 67%. 1H NMR(600MHz,DMSO)δ12.06(s,1H),8.58–7.50(m,3H),4.33(t,J＝6.2Hz,2H),2.30(t,J＝7.3Hz,2H),1.79–1.70(m,2H),1.65(dt,J＝14.3,7.3Hz,2H). 13C NMR(151MHz,DMSO)δ174.68,164.22,65.95,33.63,27.99,21.53.
Compound 5-((5-carboxyl penta oxygen) carbonyl) benzo [c] [5] oxadiazole-1-oxide compound (4c): faint yellow solid, productive rate: 72%. 1H NMR(600MHz,DMSO)δ11.98(s,1H),8.51–7.56(m,3H),4.32(t,J＝6.5Hz,2H),2.24(t,J＝7.3Hz,2H),1.74(dd,J＝14.6,6.9Hz,2H),1.57(dd,J＝15.1,7.5Hz,2H),1.44(dd,J＝15.3,8.0Hz,2H). 13C NMR(151MHz,DMSO)δ174.37,159.24,76.02,61.41,29.02,23.87,23.63,20.90,19.73.MS:[M+H +]:Found m/z 295.3Calcd m/z 294.3.
Compound 5-((the own oxygen of 6-carboxyl) carbonyl) benzo [c] [5] oxadiazole-1-oxide compound (4d): faint yellow solid, productive rate: 61%. 1H NMR(600MHz,DMSO)δ10.55(s,1H),8.33–7.50(m,3H),4.36(t,J＝6.6Hz,2H),2.37(t,J＝7.4Hz,2H),1.83–1.75(m,2H),1.71–1.64(m,2H),1.48–1.39(m,4H). 13CNMR(151MHz,DMSO)δ174.37,159.24,76.02,61.41,29.02,23.87,23.63,20.90,19.73.MS:[M+H +]:Found m/z 309.3Calcd m/z 308.3.
Compound 5-((7-carboxyl oxygen in heptan) carbonyl) benzo [c] [5] oxadiazole-1-oxide compound (4e): faint yellow solid, productive rate: 69%. 1H NMR(600MHz,CDCl 3)δ11.58(s,1H),7.78(m,3H),4.35(t,J＝6.5Hz,2H),2.35(t,J＝7.4Hz,2H),1.88–1.74(m,2H),1.70–1.59(m,2H),1.41(dd,J＝32.3,5.2Hz,6H). 13CNMR(151MHz,CDCl 3)δ180.08,164.11,66.37,34.05,28.95,28.92,28.60,25.85,24.61.MS:[M+H +]:Found m/z 323.3Calcd m/z 322.3.
The synthesis of compound 5: (for compound 5a)
4a (550mg, 1.54mmol) is placed in reaction flask, adds the tetrahydrofuran (THF) of mL drying, stirring at room temperature is dissolved, and drips isobutyl chlorocarbonate (0.3mL, 1.85mmol) under rear ice bath, finish, after ice bath stirs 0.5 hour, drip triethylamine (0.55mL, 3.08mmol), finish, under room temperature, continue stirring after 1 hour, the throw out that removed by filtration generates, leave and take filtrate A.By potassium hydroxide (129mg, 2.3mmol), oxammonium hydrochloride (160mg, 2.3mmol) is placed in reaction flask, and the methyl alcohol adding mL drying fully dissolves, and filters undissolved solid, obtains liquor B.Filtrate A is instilled in liquor B, continue stirring at room temperature reaction, TLC detection reaction process.After 4 hours, reaction terminates, and adjusts pH about 3.0, revolve steaming and remove solvent with 2N hydrochloric acid, with ethyl acetate (3 × 50mL) dilution extraction, and uses distilled water successively, saturated common salt water washing.Be separated organic phase, with anhydrous sodium sulfate drying, be spin-dried for ethyl acetate and obtain crude product, column chromatography purification, eluent V (sherwood oil: ethyl acetate)=1:1, obtains product.
Compound 5-((4-(hydroxyl amino)-4-oxo butyl) carbonyl) benzo [c] [5] oxadiazole-1-oxide compound (5a): faint yellow solid, productive rate: 60%. 1H NMR(600MHz,DMSO)δ10.46(s,1H),8.74(s,1H),8.54–8.05(m,1H),8.02–7.50(m,2H),4.31(t,J＝5.6Hz,2H),2.15(t,J＝6.9Hz,2H),2.04–1.92(m,2H). 13C NMR(151MHz,DMSO)δ168.98,164.23,131.55,118.94,117.37,65.73,29.36,24.65.HRMS:[M+Na +]:Found m/z 304.0535Calcd m/z281.0648
Compound 5-((5-(hydroxyl amino)-5-oxopentyl) carbonyl) benzo [c] [5] oxadiazole-1-oxide compound (5b): faint yellow solid, productive rate: 65%. 1H NMR(600MHz,d 6-DMSO)δ10.40(s,1H),8.71(d,J＝5.1Hz,2H),8.18(d,J＝9.4Hz,1H),7.97(d,J＝9.4Hz,1H),4.34(t,J＝6.2Hz,2H),2.03(d,J＝7.4Hz,2H),1.74–1.70(m,2H),1.66(dd,J＝14.7,7.4Hz,2H). 13C NMR(151MHz,d 6-DMSO)δ168.85,164.12,149.36,148.83,133.67,130.98,119.82,117.01,65.48,65.44,31.78,27.57,21.65.HRMS:[M+Na +]:Found m/z 318.0935Calcd m/z 295.0804.
Compound 5-((6-(hydroxyl amino)-6-oxo-hexyl) carbonyl) benzo [c] [5] oxadiazole-1-oxide compound (5c): faint yellow solid, productive rate: 68%. 1H NMR(600MHz,d 6-DMSO)δ10.33(s,1H),8.64(s,1H),7.98(m,3H),4.32(t,J＝6.5Hz,2H),1.99(dd,J＝9.6,5.1Hz,2H),1.78–1.70(m,2H),1.60–1.53(m,2H),1.39(dt,J＝15.0,7.7Hz,2H). 13C NMR(151MHz,CDCl 3)δ170.09,166.04,159.91,139.85,132.44,131.39,121.71,66.74,34.40,29.32,25.95,23.21.HRMS:[M+Na +]:Found m/z332.0848Calcd m/z 309.0961.
Compound 5-((7-(hydroxyl amino)-7-oxo heptyl) carbonyl) benzo [c] [5] oxadiazole-1-oxide compound (5d): faint yellow solid, productive rate: 71%. 1H NMR(600MHz,d 6-DMSO)δ10.34(s,1H),8.66(s,1H),8.51–7.60(m,3H),4.31(t,J＝6.5Hz,2H),1.96(t,J＝7.3Hz,2H),1.75–1.70(m,2H),1.55–1.49(m,2H),1.40(dd,J＝14.8,7.5Hz,2H),1.30(dt,J＝14.8,7.5Hz,2H). 13C NMR(151MHz,d 6-DMSO)δ169.55,164.23,131.44,117.46,66.23,40.42,40.28,40.14,40.00,39.86,39.72,39.58,32.66,28.69,28.35,25.58,25.45.HRMS:[M+Na +]:Found m/z 346.1028Calcd m/z 323.1117.
Compound 5-((8-(hydroxyl amino)-8-oxo octyl group) carbonyl) benzo [c] [5] oxadiazole-1-oxide compound (5e): faint yellow solid, productive rate: 58%. 1H NMR(600MHz,d 6-DMSO)δ10.33(s,1H),8.66(s,1H),8.49–7.56(m,3H),4.30(t,J＝6.4Hz,2H),1.98–1.89(m,2H),1.76–1.67(m,2H),1.52–1.44(m,2H),1.38(dt,J＝14.6,7.2Hz,2H),1.34–1.28(m,2H),1.25(dt,J＝13.7,6.9Hz,2H). 13C NMR(151MHz,d 6-DMSO)δ169.12,163.72,65.79,32.24,28.48,28.38,27.97,25.30,25.06.HRMS:[M+Na +]:Found m/z 360.1194Calcd m/z 337.1274.
The synthesis of compound 7, method is with the synthesis of compound 2. 1H NMR(600MHz,DMSO)δ8.13(ddd,J＝11.6,8.0,1.4Hz,2H),7.53(t,J＝8.0Hz,1H). 13C NMR(151MHz,DMSO)δ165.42,144.68,134.82,132.05,127.84,127.73,126.24.
The synthesis of compound 8, method is with the synthesis of compound 3.
Compound 4-((4-hydroxybutoxy) carbonyl) benzo [c] [1,2,5] oxadiazole 1-oxide compound (8a): faint yellow solid, productive rate: 72%. 1H NMR(600MHz,CDCl 3)δ8.07(d,J＝7.7Hz,1H),7.95(d,J＝8.1Hz,1H),7.38(t,J＝7.9Hz,1H),4.46(t,J＝6.6Hz,2H),3.74(t,J＝6.3Hz,2H),1.92(dt,J＝14.3,7.1Hz,2H),1.73(dd,J＝14.0,7.0Hz,2H). 13C NMR(151MHz,CDCl 3)δ134.92,128.00,125.59,66.21,62.23,29.05,25.18.MS:[M+H +]:Found m/z 253.2Calcd m/z 252.2.
Compound 4-((5-hydroxyl pentyloxy) carbonyl) benzo [c] [1,2,5] oxadiazole 1-oxide compound (8b): faint yellow solid, productive rate: 66%. 1H NMR(600MHz,CDCl 3)δ8.05(dd,J＝7.8,1.1Hz,1H),7.93(dd,J＝8.1,1.0Hz,1H),7.37(t,J＝8.0Hz,1H),4.40(t,J＝6.7Hz,2H),3.64(t,J＝6.5Hz,2H),1.84–1.77(m,2H),1.60–1.57(m,2H),1.47–1.44(m,2H). 13C NMR(151MHz,CDCl 3)δ164.18,145.32,134.95,133.50,128.07,127.94,125.63,66.38,62.67,32.52,28.53,25.72,25.38.MS:[M+H +]:Found m/z267.3Calcd m/z 266.3.
Compound 4-((6-hydroxyl hexyloxy) carbonyl) benzo [c] [1,2,5] oxadiazole 1-oxide compound (8c): faint yellow solid, productive rate: 60%. 1H NMR(600MHz,CDCl 3)δ8.05(dd,J＝7.9,1.6Hz,1H),7.92(dd,J＝8.1,1.6Hz,1H),7.37(t,J＝8.0Hz,1H),4.40(t,J＝6.7Hz,2H),3.66(t,J＝6.4Hz,2H),1.86–1.79(m,2H),1.63(dt,J＝14.6,6.7Hz,2H),1.52(tt,J＝9.6,6.1Hz,2H). 13C NMR(151MHz,CDCl3)δ164.18,145.26,134.98,133.44,127.98,127.96,125.68,117.14,110.89,66.32,62.45,32.09,28.34,22.22.MS:[M+H +]:Found m/z 281.3Calcd m/z 280.3.
Compound 4-((7-hydroxyl oxygen in heptan base) carbonyl) benzo [c] [1,2,5] oxadiazole 1-oxide compound (8d): faint yellow solid, productive rate: 64%. 1H NMR(600MHz,CDCl 3)δ8.04(dd,J＝7.9,1.4Hz,1H),7.91(dd,J＝8.1,1.4Hz,1H),7.36(t,J＝8.0Hz,1H),4.37(t,J＝6.7Hz,2H),3.60(t,J＝6.6Hz,2H),1.77(dd,J＝14.7,6.9Hz,2H),1.54(p,J＝6.8Hz,2H),1.42(dd,J＝14.6,6.9Hz,2H),1.37(dd,J＝11.5,8.0Hz,4H). 13C NMR(151MHz,CDCl 3)δ164.21,145.24,135.04,133.49,128.02,125.68,66.49,62.77,32.59,28.97,28.47,25.87,25.61.MS:[M+H +]:Found m/z 295.3Calcd m/z 294.3.
Compound 4-((8-hydroxyl octyloxy) carbonyl) benzo [c] [1,2,5] oxadiazole 1-oxide compound (8e): faint yellow solid, productive rate: 77%. 1H NMR(600MHz,CDCl 3)δ8.07(dd,J＝7.9,1.6Hz,1H),7.94(dd,J＝8.1,1.5Hz,1H),7.38(t,J＝8.0Hz,1H),4.40(t,J＝6.7Hz,2H),3.63(t,J＝6.6Hz,2H),1.84–1.76(m,2H),1.56(dd,J＝13.8,6.8Hz,2H),1.48–1.42(m,2H),1.39(dd,J＝16.8,8.3Hz,4H). 13C NMR(151MHz,CDCl 3)δ164.18,145.32,134.94,133.48,128.09,127.92,125.62,66.50,62.85,32.68,29.20,29.10,28.52,25.81,25.62.MS:[M+H +]:Found m/z 30.3Calcd m/z 308.3.
The synthesis of compound 9, method is with the synthesis of compound 4.
Compound 4-((3-carboxyl third oxygen) carbonyl) benzo [c] [5] oxadiazole-1-oxide compound (9a): faint yellow solid, productive rate: 70%. 1H NMR(600MHz,DMSO)δ8.07(d,J＝7.7Hz,1H),7.95(d,J＝7.9Hz,1H),7.38(t,J＝7.8Hz,1H),4.46(d,J＝5.9Hz,2H),2.55(t,J＝6.5Hz,2H),2.23–2.08(m,2H). 13C NMR(151MHz,DMSO)δ173.65,159.25,130.30,128.94,123.48,122.81,120.91,60.47,25.72,18.92.MS:[M+H +]:Found m/z 267.2Calcd m/z 266.2.
Compound 4-((4-carboxyl fourth oxygen) carbonyl) benzo [c] [5] oxadiazole-1-oxide compound (9b): faint yellow solid, productive rate: 58%. 1H NMR(600MHz,CDCl 3)δ8.06(d,J＝7.7Hz,1H),7.94(d,J＝8.0Hz,1H),7.38(t,J＝7.9Hz,1H),4.40(t,J＝6.2Hz,2H),2.39(t,J＝7.1Hz,2H),1.82(dd,J＝13.3,6.6Hz,2H),1.75–1.66(m,2H),1.55–1.45(m,2H). 13C NMR(151MHz,CDCl 3)δ179.70,164.28,145.35,135.18,128.20,125.78,66.22,33.86,28.32,25.48,24.28.MS:[M+H +]:Found m/z 281.2Calcdm/z 280.2.
Compound 4-((5-carboxyl penta oxygen) carbonyl) benzo [c] [5] oxadiazole-1-oxide compound (9c): faint yellow solid, productive rate: 62%.H NMR(600MHz,CDCl 3)δ8.04(d,J＝10.0Hz,1H),7.70(d,J＝9.9Hz,1H),7.42(t,J＝9.0Hz,1H),4.33(t,J＝9.5Hz,2H),2.21(t,J＝16.1Hz,2H),1.95–1.71(m,2H),1.68–1.44(m,2H),1.33(m,2H). 13C NMR(151MHz,CDCl 3)δ177.25,167.21,166.47,133.37,130.99,130.33,116.36,66.74,34.54,29.32,25.95,24.89.MS:[M+H +]:Found m/z 295.3Calcd m/z 294.3.
Compound 4-((the own oxygen of 6-carboxyl) carbonyl) benzo [c] [5] oxadiazole-1-oxide compound (9d): faint yellow solid, productive rate: 71%. 1H NMR(600MHz,CDCl 3)δ11.18(s,1H),8.07(d,J＝7.8Hz,1H),7.94(d,J＝7.9Hz,1H),7.38(t,J＝7.9Hz,1H),4.40(t,J＝6.4Hz,2H),2.37(t,J＝7.2Hz,2H),2.08–1.80(m,2H),1.76–1.62(m,2H),1.58–1.32(m,4H). 13C NMR(151MHz,CDCl 3)δ179.36,164.20,145.31,135.02,133.58,128.04,125.64,66.35,33.78,28.60,28.37,25.61,24.47.MS:[M+H +]:Found m/z309.3Calcd m/z 308.3.
Compound 4-((7-carboxyl oxygen in heptan) carbonyl) benzo [c] [5] oxadiazole-1-oxide compound (9e): faint yellow solid, productive rate: 61%. 1H NMR(600MHz,CDCl 3)δ11.01(s,1H),8.08(dd,J＝7.8,1.5Hz,1H),7.95(dd,J＝8.1,1.5Hz,1H),7.39(t,J＝8.0Hz,1H),4.41(t,J＝6.7Hz,2H),2.37(t,J＝7.4Hz,2H),1.85–1.79(m,2H),1.70–1.63(m,2H),1.47(dd,J＝14.1,6.6Hz,2H),1.41(dd,J＝12.0,8.3Hz,4H). 13C NMR(151MHz,CDCl 3)δ179.69,164.18,134.94,133.52,128.08,127.94,125.61,66.42,33.89,28.81,28.75,28.47,25.68,24.49.
The synthesis of compound 10, method is with the synthesis of compound 5.
Compound 4-((4-(hydroxyl amino)-4-oxo butyl) carbonyl) benzo [c] [5] oxadiazole-1-oxide compound (10a): faint yellow solid, productive rate: 62%. 1H NMR(600MHz,DMSO)δ10.46(s,1H),8.77(s,1H),8.19(d,J＝8.0Hz,1H),8.14(d,J＝7.8Hz,1H),7.56(t,J＝7.9Hz,1H),4.33(t,J＝6.1Hz,2H),2.14(t,J＝7.0Hz,2H),2.00–1.94(m,2H). 13C NMR(151MHz,DMSO)δ168.90,164.26,145.09,135.41,132.64,128.72,126.86,65.84,29.22,24.65.HRMS:[M+Na +]:Found m/z 304.0563Calcdm/z281.0648.
Compound 4-((5-(hydroxyl amino)-5-oxopentyl) carbonyl) benzo [c] [5] oxadiazole-1-oxide compound (10b): faint yellow solid, productive rate: 78%. 1H NMR(600MHz,DMSO)δ10.40(s,1H),8.71(s,1H),8.12(d,J＝8.2Hz,1H),8.08(d,J＝8.1Hz,1H),7.48(t,J＝7.4Hz,1H),4.32(t,J＝9.9Hz,2H),2.14(t,J＝16.1Hz,2H),2.00–1.84(m,2H),1.58–1.29(m,2H). 13C NMR(151MHz,DMSO)δ168.79,164.24,145.12,135.44,132.54,128.82,126.86,65.33,34.40,28.81,23.13.HRMS:[M+Na +]:Found m/z 318.0921Calcd m/z 295.0804.
Compound 4-((6-(hydroxyl amino)-6-oxo-hexyl) carbonyl) benzo [c] [5] oxadiazole-1-oxide compound (10c): faint yellow solid, productive rate: 62%. 1H NMR(500MHz,Chloroform)δ10.42(s,1H),8.66(s,1H),8.15(d,J＝8.0Hz,1H),8.01(d,J＝7.7Hz,1H),7.41(t,J＝7.1Hz,1H),4.33(t,J＝9.7Hz,2H),2.14(t,J＝11.2Hz,2H),1.78(tt,J＝14.2,9.7Hz,2H),1.58–1.22(m,4H). 13C NMR(151MHz,DMSO)δ167.79,164.33,145.32,134.24,131.21,128.06,125.76,66.4334.40,29.32,25.95,25.21.HRMS:[M+Na +]:Found m/z 332.0856Calcd m/z 309.0961.
Compound 4-((7-(hydroxyl amino)-7-oxo heptyl) carbonyl) benzo [c] [5] oxadiazole-1-oxide compound (10d): faint yellow solid, productive rate: 66%. 1H NMR(600MHz,d 6-DMSO)δ10.33(s,1H),8.65(s,1H),8.20(d,J＝7.8Hz,1H),8.12(d,J＝7.3Hz,1H),7.57(t,J＝8.0Hz,1H),4.34(t,J＝6.5Hz,2H),1.95(t,J＝7.3Hz,2H),1.78–1.68(m,2H),1.55–1.48(m,2H),1.40(dt,J＝14.8,7.5Hz,2H),1.30(dt,J＝14.6,7.4Hz,2H). 13C NMR(151MHz,d 6-DMSO)δ169.55,164.39,145.11,135.26,132.60,128.70,127.54,126.94,66.35,32.66,28.68,28.37,25.56,25.45.HRMS:[M+Na +]:Found m/z346.1040Calcd m/z 323.1117.
Compound 4-((8-(hydroxyl amino)-8-oxo octyl group) carbonyl) benzo [c] [5] oxadiazole-1-oxide compound (10e): faint yellow solid, productive rate: 68%. 1H NMR(600MHz,d 6-DMSO)δ10.30(s,1H),8.61(s,1H),8.20(dd,J＝8.1,1.4Hz,1H),8.12(dd,J＝7.8,1.4Hz,1H),7.57(t,J＝8.0Hz,1H),4.35(t,J＝6.6Hz,2H),1.94(t,J＝7.3Hz,2H),1.76–1.71(m,2H),1.49(dd,J＝14.7,7.3Hz,2H),1.43–1.37(m,2H),1.34–1.30(m,2H),1.26(dt,J＝13.5,6.8Hz,2H). 13C NMR(151MHz,d 6-DMSO)δ169.59,164.39,145.13,135.23,132.58,128.68,126.97,66.39,32.71,28.92,28.79,28.44,25.72,25.49.HRMS:[M+Na +]:Found m/z 360.3301Calcd m/z 337.1274.
Embodiment 2. compound 5a-5e, 10a-10e inhibition of histone deacetylase activity experiment (In vitro)
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 IC50 value.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 5a-5e, 10a-10e
In a table, numerical value is the mean value ± standard deviation 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.
Above-mentioned test result shows; the compound that benzo furoxan derivative compound antiproliferative effect is stronger all shows the inhibit activities stronger to histon deacetylase (HDAC); there is good DEVELOPMENT PROSPECT, and can be used as the lead compound finding new and effective NSC 630176.
The active experiment in vitro (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:
HEL: people's red white corpuscle leukemia cell
HCT-116: Human colorectal cancer cells
Hela: cervical cancer cell
U937: histocytic lymphoma's cell
ES-2: people's clear cell carcinoma of ovary cell
KG1: leukemia cell line
B16: melanoma cells
PC-3: prostate cancer cell
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.
DMSO: dimethyl sulfoxide (DMSO)
IC50: half-inhibition concentration
1. [material] HEL, HCT-116, Hela, U937, ES-2, KG1, B16, PC-3 cell strain, Methyl thiazoly tetrazolium assay MTT, 10% foetal calf serum, 96 orifice plates.
2. [method]
The above tumor cell line of cell cultures all adopts cellar culture.Logarithmic phase cell is all used during test.
Growth of Cells detects (mtt assay) above cell and is adjusted to 1 × 105/mL, is inoculated in 96 orifice plates (100 μ L/ hole) respectively, 5000 cells/well.Bed board is after 24 hours, the substratum of 100 μ L containing different concns compound is added in every hole, final compound concentration in hole is made to be respectively 100,20,4,0.8,0.16 μM, each concentration establishes three multiple holes, does blank when not adding the hole reading of cell, add the hole that cell do not add compound and do compound blank well, SAHA does compound positive control.In 37 DEG C, hatch 48 hours in 5% carbonic acid gas, every hole adds 20 μ L0.5%MTT staining fluids, after continuing to hatch 4 hours, abandons the substratum in plate, adds dimethyl sulfoxide (DMSO) 20050 μ L/ hole.Microplate reader measures the absorbance in every hole in 490,630nm wavelength place, inhibitory rate of cell growth is calculated as follows:
Table 3 antiproliferative effect experimental result
astandard figures is the mean value ± standard deviation of three tests
Upper table detects data and shows compound 19d, demonstrates certain activity, be worth the experiment of surveying nitric oxide releasing further in the test of 24d anti-tumour cell proliferative in vitro.
Embodiment 4. target compound nitric oxide releasing detection experiment (In vitro)
Illustrate that typical curve is done in requirement with reference to NO detection kit (green skies biotechnology research institute).
HCT-116 cell is selected to be adjusted to 1 × 10 5/ mL, is inoculated in 24 orifice plates (2mL/ hole), 50 × 10 4individual cells/well.Add the substratum of 2 μ L containing 100mM compound in every hole, final compound concentration in hole is respectively, each compound establishes three multiple holes, and blank well adds 2 μ L dimethyl sulfoxide (DMSO) SAHA and does compound positive control.In 37 DEG C, in 5% carbonic acid gas, hatch 3 or 5 hours.Collect the substratum in three multiple holes, centrifugal 1200rm, abandons supernatant and leaves and takes cell, adds 200 μ L cell pyrolysis liquid lysing cell 30 minutes.1200rm is centrifugal, gets 50 μ L/ hole supernatant liquors and is placed in 96 orifice plates, does 3 multiple holes.Add the reagent I50 μ L/ hole in test kit and reagent II50 μ L/ hole successively, in 37 DEG C, 15 minutes are hatched in 5% carbonic acid gas, fluorescence intensity is measured in excitation wavelength (540nm), and calculate its OD value according to control group and blank group, bring typical curve into, calculate nitric oxide production burst size.Experimental result is shown in Fig. 1.
Above-mentioned experiment shows, the compound synthesized in the present invention all can produce relatively large NO, namely shows that the compound related in the present invention can as NO donor.

Claims (7)

1. benzofuraxan oxide compound NSC 630176, has general formula I or the structure shown in I ＇, and its optical isomer, diastereomer and racemic mixture, its pharmacy acceptable salt, solvate or prodrug;
Wherein,
X is oxygen or amino;
R 1the saturated aliphatic chain of various C1-8, with the saturated aliphatic chain of side chain, alkene chain, alkynes chain, alkoxy chain, aroyl, heteroaryl, cycloalkyl, C1-8 mixes alkyl, with substituent aromatic base or with substituent heteroaryl;
R 2hydroxamic acid, hydroxyl, carboxyl, methoxycarbonyl, amide group or hydrazide group;
R 3represent hydrogen, ortho position, a position, the fluorine of contraposition, chlorine, bromine, iodine halogen, hydroxyl, amino, methoxyl group, oxyethyl group, or cyano group.
2. benzofuraxan oxide compound NSC 630176 as claimed in claim 1, is characterized in that,
X is oxygen;
R 1the unsaturated fatty chain of the saturated aliphatic chain of C1-8, C1-8, the fragrant chain of C1-9, C1-8's contains heteroatomic aliphatic chain, the heterocycle of C1-9;
R 2hydroxyl, carboxyl, methoxycarbonyl, ethoxycarbonyl, hydroxamic acid;
R 3hydrogen.
3. compound as claimed in claim 1 or 2, it is characterized in that, be one of following compounds:
5-((4-(hydroxyl amino)-4-oxo butyl) carbonyl) benzo [c] [5] oxadiazole-1-oxide compound (5a);
5-((5-(hydroxyl amino)-5-oxopentyl) carbonyl) benzo [c] [5] oxadiazole-1-oxide compound (5b);
5-((6-(hydroxyl amino)-6-oxo-hexyl) carbonyl) benzo [c] [5] oxadiazole-1-oxide compound (5c);
5-((7-(hydroxyl amino)-7-oxo heptyl) carbonyl) benzo [c] [5] oxadiazole-1-oxide compound (5d);
5-((8-(hydroxyl amino)-8-oxo octyl group) carbonyl) benzo [c] [5] oxadiazole-1-oxide compound (5e);
4-((4-(hydroxyl amino)-4-oxo butyl) carbonyl) benzo [c] [5] oxadiazole-1-oxide compound (10a);
4-((5-(hydroxyl amino)-5-oxopentyl) carbonyl) benzo [c] [5] oxadiazole-1-oxide compound (10b);
4-((6-(hydroxyl amino)-6-oxo-hexyl) carbonyl) benzo [c] [5] oxadiazole-1-oxide compound (10c);
4-((7-(hydroxyl amino)-7-oxo heptyl) carbonyl) benzo [c] [5] oxadiazole-1-oxide compound (10d);
4-((8-(hydroxyl amino)-8-oxo octyl group) carbonyl) benzo [c] [5] oxadiazole-1-oxide compound (10e);
5-((3-carboxyl third oxygen) carbonyl) benzo [c] [5] oxadiazole-1-oxide compound (4a);
5-((4-carboxyl fourth oxygen) carbonyl) benzo [c] [5] oxadiazole-1-oxide compound (4b);
5-((5-carboxyl penta oxygen) carbonyl) benzo [c] [5] oxadiazole-1-oxide compound (4c);
5-((the own oxygen of 6-carboxyl) carbonyl) benzo [c] [5] oxadiazole-1-oxide compound (4d);
5-((7-carboxyl oxygen in heptan) carbonyl) benzo [c] [5] oxadiazole-1-oxide compound (4e);
4-((3-carboxyl third oxygen) carbonyl) benzo [c] [5] oxadiazole-1-oxide compound (9a);
4-((4-carboxyl fourth oxygen) carbonyl) benzo [c] [5] oxadiazole-1-oxide compound (9b);
4-((5-carboxyl penta oxygen) carbonyl) benzo [c] [5] oxadiazole-1-oxide compound (9c);
4-((the own oxygen of 6-carboxyl) carbonyl) benzo [c] [5] oxadiazole-1-oxide compound (9d);
4-((7-carboxyl oxygen in heptan) carbonyl) benzo [c] [5] oxadiazole-1-oxide compound (9e);
5-((4-hydroxybutoxy) carbonyl) benzo [c] [1,2,5] oxadiazole 1-oxide compound (3a);
5-((5-hydroxyl pentyloxy) carbonyl) benzo [c] [1,2,5] oxadiazole 1-oxide compound (3b);
5-((6-hydroxyl hexyloxy) carbonyl) benzo [c] [1,2,5] oxadiazole 1-oxide compound (3c);
5-((7-hydroxyl oxygen in heptan base) carbonyl) benzo [c] [1,2,5] oxadiazole 1-oxide compound (3d);
5-((8-hydroxyl octyloxy) carbonyl) benzo [c] [1,2,5] oxadiazole 1-oxide compound (3e);
4-((4-hydroxybutoxy) carbonyl) benzo [c] [1,2,5] oxadiazole 1-oxide compound (8a);
4-((5-hydroxyl pentyloxy) carbonyl) benzo [c] [1,2,5] oxadiazole 1-oxide compound (8b);
4-((6-hydroxyl hexyloxy) carbonyl) benzo [c] [1,2,5] oxadiazole 1-oxide compound (8c);
4-((7-hydroxyl oxygen in heptan base) carbonyl) benzo [c] [1,2,5] oxadiazole 1-oxide compound (8d);
4-((8-hydroxyl octyloxy) carbonyl) benzo [c] [1,2,5] oxadiazole 1-oxide compound (8e).
4. the preparation method of compound described in claim 1, is characterized in that step is as one of following:
With the amino 3-nitrobenzoic acid of 4-for raw material, through azide, rearrangement reaction obtains key intermediate 2, and rear priority is through esterification, and oxidation obtains carboxylic acid cpd 4a-4e, finally makes target product hydroximic acid 5a-5e by oxammonium hydrochloride condensation;
Synthetic route one is as follows:
Or
With the amino 3-nitrobenzoic acid of 2-for raw material, through azide, rearrangement reaction obtains key intermediate 7, and rear priority is through esterification, and oxidation obtains carboxylic acid cpd 9a-9e, finally makes target product hydroximic acid 10a-10e by oxammonium hydrochloride condensation;
Synthetic route two is as follows:
Reagent in said synthesis route reaction formula: (a) Sodium Nitrite, hydrochloric acid, sodiumazide; (b) toluene; The linear primary glycol of (c) C4-C8, PyBOP, triethylamine; (d) Jones reagent, acetone; (e) isobutyl chlorocarbonate, triethylamine, tetrahydrofuran (THF); Oxammonium hydrochloride, potassium hydroxide, methyl alcohol;
R 1, R 3described in above-mentioned general formula I and I ＇.
5. 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.
6. 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.
7. 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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