WO2016112768A1 - Inhibiteur des histone désacétylases de type benzofuroxan oxide, méthode de préparation et utilisation correspondantes - Google Patents

Inhibiteur des histone désacétylases de type benzofuroxan oxide, méthode de préparation et utilisation correspondantes Download PDF

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WO2016112768A1
WO2016112768A1 PCT/CN2015/097619 CN2015097619W WO2016112768A1 WO 2016112768 A1 WO2016112768 A1 WO 2016112768A1 CN 2015097619 W CN2015097619 W CN 2015097619W WO 2016112768 A1 WO2016112768 A1 WO 2016112768A1
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oxide
benzo
oxadiazole
carbonyl
hydroxyamino
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张颖杰
徐文方
段文文
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山东大学
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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

Definitions

  • the invention relates to a benzofurazan histone deacetylase inhibitor, a preparation method and application thereof, and belongs to the technical field of chemistry.
  • Histone acetylation is a dynamic reversible process that is regulated by histone acetyltransferases (HATs) and histone deacetylases (HDACs). HAT transfers the acetyl group of acetyl-CoA to the specific lysine residue at the amino terminus of histones. This state facilitates the dissociation of DNA from histone octamers, and the nucleosome structure is relaxed, thereby enabling various transcriptions.
  • HATs histone acetyltransferases
  • HDACs histone deacetylases
  • HDAC histone deacetylation of the N-terminus of histones (reaction II), and thus with negatively charged DNA
  • chromatin is a tightly curled repressor structure that inhibits the transcriptional expression of certain genes, such as tumor suppressor genes.
  • HDACs family found in the human body, which can be divided into four categories according to their structure, function and distribution.
  • class I HDAC1, 2, 3 and 8
  • class II IIa: HDAC 4, 5, 7 and 9
  • IIb HDAC 6 and 10
  • class IV HDAC11
  • Class III HDACs SIR 1-7) are NAD+ dependent.
  • Histone deacetylase inhibitors can regulate apoptosis and differentiation-related protein expression and stability by inducing histone acetylation in specific regions of chromatin, and induce apoptosis and differentiation.
  • HDACi has the advantages of wide anti-tumor spectrum and low toxic and side effects. They have good inhibitory activity against solid tumors, leukemias and lymphomas.
  • the metal binding region of HDACi can directly interact with the zinc ion of the active site, form hydrogen bonds with histidine and tyrosine, and the link region is just in full contact with the narrow capsule.
  • the surface recognition region is suitable for the edge of the capsule. The residues are in close contact. Therefore, designing inhibitors for HDACs as targets has become a hot spot in anti-tumor drug research.
  • Nitric oxide is an important messenger molecule in the body, involved in vascular regulation, neurotransmission, inflammation and immune response, and NO can inhibit tumor development through various pathways. Although the mechanism of action of NO in tumor progression is not clear, continuous low concentrations of NO in the body can promote cell growth and inhibit apoptosis, while high concentrations NO can produce cytotoxicity, induce tumor cell apoptosis, prevent the spread and metastasis of tumor cells, and tumor cells are more sensitive to NO than normal cells.
  • the NO donor anti-tumor drug JS-K has been included in the rapid development program by NCI. Furfuryl oxynitride (formula II), which is a NO donor, has been paid more and more attention. More and more researchers have tried to use furfuryl oxynitride as a NO donor for the design and synthesis of tumor drugs and made some progress.
  • HDACi also has potential application value in inflammation, neurotransmission, vascular regulation and cardiovascular disease, which coincides with the role of NO. According to the results of this study, the two should cooperate in the treatment of certain diseases. effect. In 2011, Key, H.J found that in the treatment of cardiac hypertrophy, the two did play a synergistic role; afterwards, some researchers found that the two also play a synergistic role in the treatment of wound healing.
  • the present invention is directed to the deficiencies of the prior art, and provides a benzofuroxime oxide histone deacetylase inhibitor having both a dual action of inhibiting deacetylase and releasing nitric oxide, and the present invention also provides preparation of the compound. Method and use.
  • a benzofuroxime oxide histone deacetylase inhibitor having the structure of Formula I or I', and the tautomer II of Formula I or the tautomer II of Formula I' ', an optical isomer, a mixture of diastereomers and racemates, a pharmaceutically acceptable salt, solvate or prodrug thereof;
  • X is oxygen or an amino group
  • R 1 is a saturated aliphatic chain of various C1-8, a branched saturated aliphatic chain, an olefin chain, an alkyne chain, an alkoxy chain, an aroyl group, a heteroaryl group, a cycloalkyl group, a C1-8 heteroalkyl group.
  • R 2 is hydroxamic acid, hydroxy, carboxy, methoxycarbonyl, amido, hydrazide or N-(2-aminophenyl)amide;
  • R 3 represents a hydrogen, ortho, meta, or parafluoro, chloro, bromo, iodo halogen, hydroxy, amino, methoxy, ethoxy, or cyano group.
  • X is oxygen
  • R 1 is a saturated aliphatic chain of C1-8, an unsaturated aliphatic chain of C1-8, an aromatic chain of C1-9, a fatty chain containing a hetero atom of C1-8, and a heterocyclic ring of C1-9;
  • R 2 is a hydroxyl group, a carboxyl group, a methoxycarbonyl group, an ethoxycarbonyl group, a hydroxamic acid
  • R 3 is hydrogen
  • the above compound of formula I is one of the following:
  • Aromatic group means an aromatic carbocyclic group. Preferred aromatic rings contain from 6 to 10 carbon atoms.
  • Heteroaryl is an aromatic heterocyclic ring which may be a monocyclic or bicyclic group.
  • Preferred heteroaryl groups include thienyl, furyl, pyrrolyl, pyridyl, pyrazinyl, thiazolyl, pyrimidinyl, quinolinyl, tetrazolyl, thiazolyl, benzofuranyl or fluorenyl Wait.
  • Heteroalkyl is a saturated or unsaturated chain containing carbon atoms and at least one heteroatom, wherein any one of the heteroatoms is not adjacent.
  • the heteroalkyl group contains 2 to 15 atoms (carbon atoms), preferably 2 to 10 atoms. Heteroalkyl groups can be straight or branched Chain, substituted or unsubstituted.
  • Cycloalkyl is a substituted or unsubstituted, saturated or unsaturated cyclic group containing a carbon atom and/or one or more heteroatoms.
  • the ring may be a single ring or a fused ring, a bridged ring or a spiro ring.
  • the monocyclic ring usually has 3 to 9 atoms, preferably 4 to 7 atoms, and the polycyclic ring contains 7 to 17 atoms, preferably 7 to 13 atoms.
  • Aroyl means a group having a carbonyl group attached to the end of the aromatic carbocyclic ring, and a preferred aromatic ring contains 6 to 10 carbon atoms.
  • “Pharmaceutically acceptable salt” refers to a salt form of a compound of formula (I) which is therapeutic and non-toxic. It may have any acidic group (such as a carboxyl group) to form an anionic salt, or any basic group (such as an amino group) to form a cationic salt. Many such salts are known in the art. a cationic salt formed on any acidic group such as a carboxyl group, or an anionic salt formed on any basic group such as an amino group, many of which are known in the art, such as a cationic salt including an alkali metal Salts such as sodium and potassium and alkaline earth metals (magnesium and calcium) and organic salts (such as ammonium salts).
  • an anionic salt by treating the basic form of (I) with a corresponding acid, such as an inorganic acid such as sulfuric acid, nitric acid, phosphoric acid, etc.; or an organic acid such as acetic acid, propionic acid, glycolic acid, 2-hydroxyl Propionic acid, 2-oxopropionic acid, oxalic acid, malonic acid, succinic acid, maleic acid, fumaric acid, malic acid, tartaric acid, 2-hydroxy-1,2,3-malonic acid, ethanesulfonic acid, Benzoic acid, 4-methylbenzenesulfonic acid, cyclohexylsulfinic acid, 2-hydroxybenzoic acid, 4-amino-2-hydroxybenzoic acid, and the like.
  • a corresponding acid such as an inorganic acid such as sulfuric acid, nitric acid, phosphoric acid, etc.
  • an organic acid such as acetic acid, propionic acid, glycolic acid, 2-hydroxyl Propionic acid,
  • a “solvate” is a complex formed by the combination of a solute (such as a metalloproteinase inhibitor) and a solvent (such as water). See J. Honig et al, The Van Nostrand Chemist's Dictionary, p. 650 (1593).
  • the pharmaceutically acceptable solvents employed in the present invention include those which do not interfere with the biological activity of metalloproteinase inhibitors (e.g., water, ethanol, acetic acid, N,N-dimethylformamide, dimethyl sulfoxide, and techniques in the art). Solvents referred to by personnel or easily identified).
  • optical isomers As used herein, "optical isomers”, “enantiomers”, “diastereomers”, “racemates” and the like define all possible stereoisomeric forms of the compounds of the invention or physiological derivatives. Unless otherwise indicated, the chemical nomenclature of the compounds of the invention includes mixtures of all possible stereochemical forms, the mixtures comprising all diastereomers and enantiomers of the basic structural molecule, and the substantially pure individual isomers of the compounds of the invention. Form, i.e., other isomers containing less than 10%, preferably less than 5%, especially less than 2%, and most preferably less than 1%. The various stereoisomeric forms of the peptoid compounds of the invention are expressly included within the scope of the invention.
  • substituents may itself be substituted with one or more substituents.
  • substituents include those listed in C. Hanch and A. Leo, Substituent Constants for Correlation Analysis in Chemistry and Biology (1979).
  • Preferred substituents include, for example, alkyl, alkenyl, alkoxy, hydroxy, oxy, nitro, amino, aminoalkyl (such as aminomethyl, etc.), cyano, halogen, carboxy, carbonyl alkoxy ( Such as carbonyl ethoxy, etc., thio, aryl, cycloalkyl, heteroaryl, heterocycloalkyl (such as piperidinyl, morpholinyl, pyrrolyl, etc.), imino, hydroxyalkyl, aryl Oxylate, Arylalkyl, and combinations thereof.
  • the preparation method of the compound is as follows:
  • the synthetic route is as follows:
  • 4-Amino 3-nitrobenzoic acid is used as a raw material, and after azide nitridation, the key intermediate 2 is obtained by rearrangement reaction, followed by esterification (3a-3e), oxidation to obtain carboxylic acid compound 4a-4e, and finally
  • the target product hydroxamic acid 5a-5e is prepared by condensation of hydroxylamine hydrochloride;
  • 2-Amino 3-nitrobenzoic acid is used as a raw material, and after azide nitridation, the key intermediate 7 is obtained by rearrangement reaction, followed by esterification (8a-8e), oxidation to obtain carboxylic acid compound 9a-9e, and finally
  • the target product hydroxamic acid 10a-10e is prepared by condensation of hydroxylamine hydrochloride;
  • the reagents in the above synthetic route are: (a) sodium nitrite, hydrochloric acid, sodium azide; (b) toluene; (c) C4-C8 linear primary diol, PyBOP, triethylamine; (d) Jones reagent, acetone; (e) isobutyl chloroformate, triethylamine, tetrahydrofuran; hydroxylamine hydrochloride, potassium hydroxide, methanol;
  • R 1 and R 3 are as defined in the above formulas I and I'.
  • the present invention also provides the use of the above compounds for the preparation of a medicament for preventing or treating a mammalian disease associated with abnormal expression of histone deacetylase activity.
  • the mammalian diseases associated with abnormal expression of histone deacetylase activity include cancer, neurodegenerative diseases, viral infections, inflammation, leukemia, malaria or diabetes. Accordingly, the present invention also relates to pharmaceutical compositions containing a structural compound of formula I.
  • the present invention also encompasses a pharmaceutical composition suitable for parenteral administration to a mammal, comprising a compound of the above formula I, and a pharmaceutically acceptable carrier, optionally comprising one or more pharmaceutically acceptable excipients Agent.
  • a pharmaceutical composition suitable for parenteral administration to a mammal comprising a compound of the above formula I, and a pharmaceutically acceptable carrier, optionally comprising one or more pharmaceutically acceptable excipients Agent.
  • HDACs zinc ion-dependent histone deacetylases
  • HDAC1and 2 a mixed enzyme of histone deacetylases 1 and 2
  • HDACs active fluorescence analysis method can quickly and easily detect HDACs activity, simple operation, high sensitivity.
  • the first step consists of an acetylated side chain lysine HDACs fluorogenic substrate Boc-Lys(acetyl)-AMC (Boc-Lys(acetyl)-AMC), incubated with the HDAC1&2 sample containing the expression to deacetylate the substrate. Base, activate the substrate.
  • Boc-Lys-AMC is hydrolyzed with Trypsin to produce a fluorescent group (i.e., chromophore) of 4-amino-7-methyl-coumarin (AMC) at excitation wavelength/emission.
  • the fluorescence intensity was measured at a wavelength (390 nm/460 nm), and the inhibition rate was calculated from the fluorescence intensity of the inhibitor group and the control group, and the IC50 value was calculated.
  • the principle of enzyme activity test is shown in the following reaction formula IV.
  • the cell viability of the compound was tested by thiazolyl assay (MTT method), human leukocyte leukemia cells (HEL) and human colon cancer cells (HCT-116) cell suspension were seeded in 96-well plates, and different concentrations of compounds were added to each well. Cultivation After incubation, the cells were stained with MTT, and after incubation, the absorbance (OD value) of each well was measured at 570 nm on a microplate reader, and the cell growth inhibition rate was calculated to determine the activity of the compound.
  • MTT method thiazolyl assay
  • HEL human leukocyte leukemia cells
  • HCT-116 human colon cancer cells
  • the furazan-type NO donor compound generally releases NO by reacting with various thiol compounds such as cysteine residues of proteins, and the strong nucleophile RS - ion can attack the Furoxans-type compound.
  • the 3- or 4-position of the 2,5-oxadiazole-2-oxide heterocyclic ring is opened to form a nitroso compound intermediate, and then the elimination reaction occurs to form NO, and the generated NO can be O 2 in the solution. Rapid oxidation to nitrite ions (NO 2- ) and nitrate removal (NO 3- ) (see Reaction Formula V).
  • the in vitro NO release test of the furazan-type NO donor compound is usually carried out by a method of incubation at 37 ° C in an L-cys solution.
  • the sample is the supernatant of the cell culture medium
  • the cell culture medium is DMEM + 10% FBS
  • the standard is diluted with DMEM + 10% FBS, and the concentration of the standard can be taken as 0. 1,2,5,10, 20,40,60,100 ⁇ M, with 540nm out of the detection absorbance A, absorbance A as the ordinate, NO 2- concentration C as the abscissa plot to obtain the standard curve.
  • Human colon cancer cells (HCT-116) were seeded in 24-well plates, and after incubation with the corresponding concentrations of the tested compounds, the reagents I and II in the kit were sequentially added, and the absorbance was measured at a wavelength of 540 nm ( OD), followed by a standard curve, can calculate the corresponding release of nitric oxide.
  • Intracellular nitric oxide release experiments of compounds of formula I demonstrate that such compounds release large amounts of nitric oxide in tumor cells.
  • the derivative of the benzofurazan oxide heterocycle of the present invention spatially matches the active site of the histone deacetylase, and at the same time releases a large amount of nitric oxide, thus exhibiting high inhibition in vitro. active.
  • Partial extensions of the invention may exist in free form or in the form of a salt.
  • Many compound types of pharmaceutically acceptable salts and methods for their preparation are known to those skilled in the art.
  • Pharmaceutically acceptable salts include the conventional non-toxic salts, including the bases of such compounds with quaternary ammonium salts in the form of inorganic or organic acids.
  • the compounds of the invention may form hydrates or solvates.
  • the invention includes a pharmaceutical composition
  • a pharmaceutical composition comprising a therapeutic amount of a compound of the invention, and one or more pharmaceutically acceptable carriers and/or excipients.
  • Carriers include saline, buffered saline, dextrose, water, glycerol, ethanol, and combinations thereof, as discussed in more detail below.
  • the composition may also contain minor amounts of wetting or emulsifying agents, or pH buffering agents, if desired.
  • the composition may be a liquid, suspension, emulsion, tablet, pill, capsule, sustained release formulation or powder.
  • the composition can be formulated as a suppository with conventional binders and carriers such as triglycerides.
  • Oral formulations may include standard carriers such as pharmaceutical grades of mannitol, lactose, starch, magnesium stearate, sodium saccharin, cellulose and magnesium carbonate, and the like. Depending on the formulation desired, it can be configured to mix, granulate and compress or dissolve the ingredients. In another approach, the composition can be configured as nanoparticles.
  • the pharmaceutical carrier used can be either solid or liquid.
  • Typical solid carriers include lactose, terra alba, sucrose, talc, gel, agar, pectin, acacia, magnesium stearate, stearic acid and the like.
  • the solid carrier may include one or more substances which may act as both a flavoring agent, a lubricant, a solubilizer, a suspending agent, a filler, a glidant, a compression aid, a binder or a tablet-disintegrant; It can be an encapsulating material.
  • the carrier is a finely divided solid which is mixed with the finely divided active ingredient.
  • the active ingredient in the tablet is mixed with the carrier having the necessary compression properties in a suitable ratio, compressed in the desired shape and size.
  • the powders and tablets preferably comprise up to 99% active ingredient.
  • suitable solid carriers include, for example, calcium phosphate, magnesium stearate, talc, sugar, lactose, dextrin, starch, gelatin, cellulose, methylcellulose, sodium carboxymethylcellulose, polyvinylpyrrolidone, Low melting point wax and ion exchange resin.
  • Typical liquid carriers include syrup, peanut oil, olive oil, water, and the like.
  • the yoke carrier is used to prepare solutions, suspensions, emulsions, syrups, elixirs and sealed compositions.
  • the active ingredient can be dissolved or suspended in a pharmaceutically acceptable liquid carrier Such as water, organic solvents, and mixtures of these or pharmaceutically acceptable oils or fats.
  • the liquid carrier may contain other suitable pharmaceutical additives such as solubilizers, emulsifiers, buffers, preservatives, sweeteners, flavoring agents, suspending agents, thickening agents, pigments, viscosity modifiers, stabilizing or osmotic pressure-adjusting Agent.
  • liquid carriers for oral and parenteral administration include water (partially containing additives such as those described above, such as cellulose derivatives, preferably sodium carboxymethylcellulose solution), alcohols (including monohydric and polyhydric alcohols) For example, ethylene glycol) and their derivatives, and oils (such as fractionated coconut oil and peanut oil). Carriers for parenteral administration may also be oils such as ethyl oleate and isopropyl myristate. Sterile liquid carriers are used in sterile liquid compositions for parenteral administration.
  • the liquid carrier used in the pressurized compositions can be a halogenated hydrocarbon or other pharmaceutically acceptable propellant.
  • Sterile or Suspension Liquid pharmaceutical compositions can be used, for example, intravenous, intramuscular, intraperitoneal or subcutaneous injection. At the time of injection, a single push or gradual infusion can be performed for 30 minutes of intravascular perfusion.
  • the compound can also be administered orally in the form of a liquid or solid composition.
  • the carrier or excipient may include time delay materials which are inhibited in the art, such as glyceryl monostearate or glyceryl distearate, and may also include waxes, ethylcellulose, hydroxypropylmethylcellulose, methacrylic acid. Methyl ester, etc.
  • time delay materials such as glyceryl monostearate or glyceryl distearate
  • waxes ethylcellulose, hydroxypropylmethylcellulose, methacrylic acid. Methyl ester, etc.
  • the preparation may be in the form of a tablet, in the form of a powder or pill in a hard capsule or in the form of a lozenge or lozenge.
  • the amount of solid carrier varies to a large extent, but is preferably from about 25 mg to about 1.0 g.
  • the preparation may be a syrup, emulsion, soft capsule, sterile injection solution or suspension in a vial or non-aqueous liquid suspension.
  • the compound or its salt which is acceptable for learning can be an aqueous solution of an organic or inorganic acid, a 0.3 M succinic acid or citric acid solution.
  • acidic derivatives may be honored with a suitable alkaline solution.
  • the compound can be dissolved in a suitable cosolvent or combination thereof.
  • suitable co-solvents include, but are not limited to, ethanol having a concentration ranging from 0 to 60%, propylene glycol, polyethylene glycol 300, polysorbate 80, glycerin, polyoxyethylene fatty acid esters, A fatty alcohol or a glycerol hydroxy fatty acid ester or the like.
  • Non-methods of introduction include, but are not limited to, dermal, intradermal, intramuscular, intraperitoneal, intravenous, subcutaneous, intranasal, pulmonary, epidural, ocular and (usually preferred) oral routes.
  • the compound can be administered by any convenient or other suitable route, such as by infusion or bolus injection, by epithelial or mucosal routes (eg, oral mucosa, rectal and intestinal mucosa, etc.) or by drug-loaded stents and can be used with Other bioactive agents are administered together. It can be administered systemically or locally.
  • the preferred route of administration is oral, nasal or bronchial aerosol or nebulizer.
  • the compounds 5d, 9d of the present invention have a significantly high inhibitory activity against histone deacetylase (HELA cell extract). It is a positive drug and can release a large amount of nitric oxide. It has good development prospects and can be used as a lead compound for the discovery of novel high-efficiency histone deacetylase inhibitors.
  • the compounds 5d, 9d showed some activity in the anti-tumor cell proliferation test in vitro, and it is worth further structural optimization and development.
  • Figure 1 is a graph showing the release amount of nitric oxide released from a target compound in HCT-116 cells.
  • the abscissa is the name of the compound and the ordinate is the multiple of the nitrate produced by the experimental test (relative to the blank group).
  • the enzyme activity experiment was carried out by HDACs active fluorescence analysis method, which was mainly divided into two steps: (1) lysine HDACs fluorescent substrate containing one acetylated side chain (Boc-Lys(acetyl)-AMC), containing HDAC8 containing expression The sample is incubated to deacetylate the substrate and activate the substrate.
  • Vorinostat is a histone deacetylase inhibitor approved by the US Food and Drug Administration (FDA) in 2006.
  • HEL human red leukocyte leukemia cells
  • HCT-116 Human colorectal cancer cells
  • ES-2 Human ovarian clear cell carcinoma
  • KG1 leukemia cell line
  • PC-3 prostate cancer cells
  • SAHA The trade name Zolinza, commonly known as Vorinostat, is a histone deacetylase inhibitor approved by the US Food and Drug Administration (FDA) in 2006.
  • HEL HCT-116, Hela, U937, ES-2, KG1, B16, PC-3 cell line, tetramethylazozolium blue MTT, 10% fetal bovine serum, 96-well plate.
  • MTT method Cell growth assay The above cells were adjusted to 1 ⁇ 105 / mL, and seeded in 96-well plates (100 ⁇ L / well), 5000 cells / well. After plating for 24 hours, 100 ⁇ L of medium containing different concentrations of compound was added to each well to make the final concentration of the compound in the wells 100, 20, 4, 0.8, 0.16 ⁇ M, respectively, with three replicate wells per concentration, without cells. Hole reading Do blank, add cells without compound holes to make compound blank wells, SAHA as a compound positive control.
  • a standard value is the mean ⁇ standard deviation of three trials
  • HCT-116 cells were selected to adjust to 1 ⁇ 10 5 /mL, and seeded in 24-well plates (2 mL/well) at 50 ⁇ 10 4 cells/well. 2 ⁇ L of medium containing 100 mM of compound was added to each well, and the final concentration of the compound in the well was set to three replicate wells per compound, and 2 ⁇ L of dimethyl sulfoxide SAHA was added as a positive control for the blank well. Incubate for 3 or 5 hours at 37 ° C in 5% carbon dioxide. The medium of three replicate wells was collected, centrifuged at 1200 rm, the supernatant was discarded, and cells were lysed by adding 200 ⁇ L of cell lysate for 30 minutes.

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Abstract

La présente invention concerne un inhibiteur des histone désacétylases de type oxyde de benzofuroxane, une méthode de préparation et des utilisations correspondantes. Le composé possède une structure représentée par la formule I ou I', un tautomère II étant représenté par la formule I, et un tautomère II' étant représenté par la formule I'. La présente invention concerne en outre une composition pharmaceutique comprenant un composé de structure représentée par la formule I, I', II ou II'. Le composé de la présente invention est utilisé pour la préparation d'un médicament destiné à la prévention ou au traitement de maladies des mammifères associées à l'expression anormale d'une activité des histone désacétylases.
PCT/CN2015/097619 2015-01-15 2015-12-16 Inhibiteur des histone désacétylases de type benzofuroxan oxide, méthode de préparation et utilisation correspondantes WO2016112768A1 (fr)

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