WO2017148318A1 - Composé d'acrylamide substitué et composition pharmaceutique correspondante - Google Patents

Composé d'acrylamide substitué et composition pharmaceutique correspondante Download PDF

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Publication number
WO2017148318A1
WO2017148318A1 PCT/CN2017/074372 CN2017074372W WO2017148318A1 WO 2017148318 A1 WO2017148318 A1 WO 2017148318A1 CN 2017074372 W CN2017074372 W CN 2017074372W WO 2017148318 A1 WO2017148318 A1 WO 2017148318A1
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WIPO (PCT)
Prior art keywords
compound
pharmaceutical composition
histone deacetylase
pharmaceutically acceptable
deacetylase inhibitor
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PCT/CN2017/074372
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English (en)
Chinese (zh)
Inventor
王义汉
金剑
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Shenzhen Targetrx Inc
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Shenzhen Targetrx Inc
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Priority to CN201780003913.0A priority Critical patent/CN108349882B/zh
Publication of WO2017148318A1 publication Critical patent/WO2017148318A1/fr
Anticipated expiration legal-status Critical
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    • 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
    • A61K31/16—Amides, e.g. hydroxamic acids
    • A61K31/18—Sulfonamides
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C311/00—Amides of sulfonic acids, i.e. compounds having singly-bound oxygen atoms of sulfo groups replaced by nitrogen atoms, not being part of nitro or nitroso groups
    • C07C311/15—Sulfonamides having sulfur atoms of sulfonamide groups bound to carbon atoms of six-membered aromatic rings
    • C07C311/21—Sulfonamides having sulfur atoms of sulfonamide groups bound to carbon atoms of six-membered aromatic rings having the nitrogen atom of at least one of the sulfonamide groups bound to a carbon atom of a six-membered aromatic ring

Definitions

  • the invention belongs to the technical field of medicine, and in particular relates to a substituted acrylamide compound and a pharmaceutical composition thereof, which are useful for treating HDAC-mediated related diseases.
  • Histone deacetylase is a class of proteases that play an important role in the structural modification of chromosomes and regulation of gene expression.
  • acetylation of histones facilitates the dissociation of DNA and histone octamers, and the nucleosome structure is relaxed, allowing various transcription factors and co-transcription factors to specifically bind to DNA binding sites, activating genes. Transcription.
  • histone acetylation is in a dynamic equilibrium with histone deacetylation and is regulated by histone acetyltransferase (HAT) and histone deacetylase.
  • HAT histone acetyltransferase
  • HAT transfers the acetyl group of acetyl-CoA to the specific lysine residue at the amino terminus of histones.
  • HDACs deacetylate histones, bind tightly to negatively charged DNA, compact chromatin, and inhibit gene transcription. .
  • HDACi Histone deacetylase inhibitors
  • HDACi 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 not only has a good therapeutic effect on a variety of hematological tumors and solid tumors, but also has the advantages of relatively high selectivity and low toxicity of tumor cells.
  • HDACi In the treatment of malignant tumors, HDACi is effective and well tolerated. Normal cells are highly tolerant to high concentrations of HDACi, so HDACi is considered to be non-toxic, and experiments have shown that low doses of HDACi have neurological and renal protective effects under hypoxia, inflammatory response or load stress. Non-specific HDACi has been reported in stage I and phase II clinical trials for adverse reactions such as nausea, vomiting, abnormal blood system and prolonged QT interval. Non-specific HDACi such as SAHA, LBH589, and ITF-2357 may cause sexual thrombocytopenia or myelosuppression, and whether specific HDACi causes corresponding adverse reactions in tumor research is inconclusive, and there is no report of adverse reactions as low-dose HDACi. Therefore, low doses of HDACi with organ protection and better tolerance are increasingly being used to try to treat chronic diseases.
  • the present invention discloses a substituted acrylamide compound and a composition comprising the same and use thereof, which have better histone deacetylase inhibitory activity and/or have better pharmacodynamics/ Pharmacokinetic properties.
  • a histone deacetylase inhibitor such as a substituted acrylamide compound represented by formula (I), or a crystalline form, a pharmaceutically acceptable salt, a prodrug, a stereoisomer, a hydrate or a solvent compound,
  • R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 and R 11 are each independently hydrogen, deuterium or halogen;
  • An additional condition is that at least one of R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 and R 11 is deuterated or deuterated.
  • R 1 , R 2 , R 3 , R 4 and R 5 are each independently hydrazine or hydrogen.
  • R 6 , R 7 , R 8 and R 9 are each independently hydrazine or hydrogen.
  • R 10 and R 11 are each independently hydrazine or hydrogen.
  • the compound may be selected from the following compounds or a pharmaceutically acceptable salt thereof, but is not limited to the following compounds:
  • the shape and volume of the ruthenium in the drug molecule are substantially the same as those of the hydrogen. If the hydrogen in the drug molecule is selectively replaced with hydrazine, the deuterated drug generally retains the original biological activity and selectivity. At the same time, the inventors have confirmed through experiments that the binding of carbon-germanium bonds is more stable than the combination of carbon-hydrogen bonds, which can directly affect the absorption, distribution, metabolism and excretion of some drugs, thereby improving the efficacy, safety and tolerability of the drugs.
  • the strontium isotope content of the cerium in the deuterated position is at least greater than the natural strontium isotope content (0.015%), preferably greater than 30%, more preferably greater than 50%, more preferably greater than 75%, and even more preferably greater than 95. %, more preferably greater than 99%.
  • the strontium isotope content of each of the deuterated positions of R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 and R 11 is at least 5%, preferably more than 10%, more preferably more than 15%, more preferably more than 20%, more preferably more than 25%, more preferably more than 30%, more preferably more than 35%, more preferably more than 40 More preferably, more than 45%, more preferably more than 50%, more preferably more than 55%, more preferably more than 60%, more preferably more than 65%, more preferably more than 70%, more preferably more than 75% More preferably, it is more than 80%, more preferably more than 85%, more preferably more than 90%, more preferably more than 95%, more preferably more than 99%.
  • R contains ⁇ , more preferably two R contains ⁇ , more preferably three R contains ⁇ , more preferably four R contains ⁇ , more preferably five R contains ⁇ , more preferably six R contains ⁇ , more Preferably, the seven R-containing strontiums, more preferably eight R-containing hydrazines, more preferably nine R-containing hydrazines, more preferably ten R-containing hydrazines, more preferably eleven R-containing hydrazines.
  • the compound does not include a non-deuterated compound.
  • the present invention also discloses a pharmaceutical composition
  • a pharmaceutical composition comprising a pharmaceutically acceptable carrier and the histone deacetylase inhibitor as described above, or a crystalline form thereof, a pharmaceutically acceptable salt, a hydrate thereof Or a pharmaceutical composition of a solvate, stereoisomer, prodrug or isotopic variation.
  • the pharmaceutically acceptable carrier includes a glidant, a sweetener, a diluent, a preservative, a dye/colorant, a flavor enhancer, a surfactant, a wetting agent, a dispersant At least one of a disintegrant, a suspending agent, a stabilizer, an isotonic agent, a solvent or an emulsifier.
  • the pharmaceutical composition is a tablet, a pill, a capsule, a powder, a granule, an ointment, an emulsion, a suspension, a solution, a suppository, an injection, an inhalant, a gel, a microsphere or Aerosol.
  • Typical routes of administration of the pharmaceutical compositions of the invention include, but are not limited to, oral, rectal, transmucosal, enteral, or topical, transdermal, inhalation, parenteral, sublingual, intravaginal, intranasal, intraocular, intraperitoneal , intramuscular, subcutaneous, Intravenous administration. Oral administration or injection administration is preferred.
  • compositions of the present invention can be produced by methods well known in the art, such as conventional mixing methods, dissolution methods,
  • Granulation method sugar-coated pellet method, grinding method, emulsification method, freeze-drying method, and the like.
  • the present invention also provides a method of preparing a pharmaceutical composition comprising the steps of: administering a pharmaceutically acceptable carrier to a histone deacetylase inhibitor as described above, or a crystalline form thereof, a pharmaceutically acceptable salt, The hydrate or solvate is mixed to form a pharmaceutical composition.
  • the active ingredients of the invention may also be used in combination with other active ingredients.
  • the choice of such combination is based on the condition of the treatment, the cross-reactivity of the ingredients, and the combined pharmaceutical properties. It is also possible to administer any of the compounds of the invention in combination with one or more other active ingredients in a single dosage form for simultaneous or sequential administration to a patient.
  • Combination therapies can be administered simultaneously or sequentially. When administered continuously, the combination can be administered in two or more administrations.
  • Combination therapy can provide "synergistic effects" or “synergistic effects”, in other words, when the active ingredients are used together, the effect obtained is greater than the sum of the effects obtained by using the compounds separately.
  • the active ingredient (1) is co-formulated and administered or delivered simultaneously in a combined formulation; (2) administered as a separate formulation or administered in parallel; or (3) obtained by some other dosage regimen Synergy.
  • synergistic effects can be obtained when the compounds are administered or released sequentially, for example, as separate tablets, pills or capsules, or by separate injections of separate syringes.
  • the effective dose of each active ingredient is administered sequentially, i.e., continuously, while in combination therapy, the effective dose of two or more active ingredients is administered together.
  • the invention also discloses the use of a substituted acrylamide histone deacetylase inhibitor as described above, i.e., the compounds of the invention are advantageously useful as therapeutic agents for the treatment of, for example, cell proliferative disorders.
  • treating as used in the treatment of a condition of the present invention generally relates to the treatment of a human or animal (e.g., by a veterinarian) wherein certain desired therapeutic effects are achieved, for example, by inhibiting the progression of the condition (including reducing the rate of progression, Development stops, improves the condition and cures the condition. It also includes treatment as a preventive measure (such as prevention). The use of a patient who has not yet developed a condition but is at risk of developing the condition is also included in the term "treatment.”
  • an effective dose refers to an amount of an HDAC inhibitor that, when administered with a desired therapeutic regimen, produces certain desired therapeutic effects, while having a reasonable benefit/risk ratio.
  • treatment includes combination therapy wherein, for example, two or more treatments are used in combination, either sequentially or simultaneously.
  • the compounds described herein can also be used in combination therapy with other drugs, such as cytotoxic drugs.
  • treatments include, but are not limited to, chemotherapy (administering an active drug including, for example, an HDAC inhibitor, an antibody (eg, in immunotherapy), a prodrug (eg, photodynamic therapy, GDEPT, ADEPT) Etc.), surgery, radiation therapy and gene therapy.
  • the treatment is treatment of a proliferative disorder.
  • proliferative disorder and “proliferative disorder” are used interchangeably herein and refer to excess or abnormally fine. Undesired or uncontrolled cell proliferation of cells (not required), such as neoplastic or proliferative growth.
  • the treatment is treatment of a proliferative disorder characterized by benign, pre-malignant or worsening cell proliferation, including but not limited to tumors, hyperplasia and neoplasms (eg, histiocytoma, glial) Tumor, astrocyoma, osteoma, cancer (see below), psoriasis, bone disease, fibroproliferative diseases (eg, connective tissue), pulmonary fibrosis, atherosclerosis, vascular smooth muscle Cell proliferation (eg, stenosis or restenosis after angioplasty).
  • a proliferative disorder characterized by benign, pre-malignant or worsening cell proliferation, including but not limited to tumors, hyperplasia and neoplasms (eg, histiocytoma, glial) Tumor, astrocyoma, osteoma, cancer (see below), psoriasis, bone disease, fibroproliferative diseases (eg, connective tissue), pulmonary
  • the treatment is treatment of cancer.
  • the treatment is treatment of a cancer such as lung cancer, small cell lung cancer, gastrointestinal cancer, colon cancer, colon cancer, rectal cancer, colorectal cancer, breast cancer, ovarian cancer, prostate cancer, testis Cancer, liver cancer, kidney cancer, bladder cancer, pancreatic cancer, brain cancer, sarcoma, osteosarcoma, Kaposi's sarcoma, melanoma, malignant melanoma, basal cell tumor or leukemia.
  • a cancer such as lung cancer, small cell lung cancer, gastrointestinal cancer, colon cancer, colon cancer, rectal cancer, colorectal cancer, breast cancer, ovarian cancer, prostate cancer, testis Cancer, liver cancer, kidney cancer, bladder cancer, pancreatic cancer, brain cancer, sarcoma, osteosarcoma, Kaposi's sarcoma, melanoma, malignant melanoma, basal cell tumor or leukemia.
  • the treatment is treatment of a condition mediated by HDACs.
  • HDACs mediated disorder refers to a disorder in which the action of HDAC and/or HDAC is important or necessary, for example, for the onset, progression, performance, etc. of the disorder; or refers to the known use of HDAC inhibitors (eg, , a disease treated with trichostatin A).
  • HDAC inhibitors eg, , a disease treated with trichostatin A
  • HDACs inhibitor candidate is capable of treating a HDACs mediated disorder.
  • Experiments that can be conveniently used to evaluate the activity of a particular compound are described, for example, in Watkins et al., International (PCT) Patent Application No. WO 02/30879.
  • halogen means F, Cl, Br, and I unless otherwise specified. More preferably, the halogen atom is selected from the group consisting of F, Cl and Br.
  • deuterated means that one or more hydrogens in the compound or group are replaced by deuterium; deuteration may be monosubstituted, disubstituted, polysubstituted or fully substituted.
  • deuteration may be monosubstituted, disubstituted, polysubstituted or fully substituted.
  • deuterated is used interchangeably with “one or more deuterated”.
  • non-deuterated compound means a compound containing a proportion of germanium atoms not higher than the natural helium isotope content (0.015%).
  • solvate refers to a complex of a compound of the invention that is coordinated to a solvent molecule to form a specific ratio.
  • Hydrophilate means a complex formed by the coordination of a compound of the invention with water.
  • the beneficial effects of the present invention are: the compound of the present invention has excellent inhibition to histone deacetylase; the technique of deuteration changes the metabolism of the compound in the organism, so that the compound has more Good pharmacokinetic parameter characteristics.
  • the dosage can be changed and a long-acting preparation can be formed to improve the applicability; the substitution of a hydrogen atom in the compound with hydrazine increases the drug concentration of the compound in the animal due to its strontium isotope effect, and improves the therapeutic effect of the drug; Substituting a hydrogen atom in a compound inhibits certain metabolites and increases the safety of the compound.
  • each reaction is usually carried out in an inert solvent at room temperature to reflux temperature (e.g., 0 ° C to 100 ° C, preferably 0 ° C to 80 ° C).
  • the reaction time is usually from 0.1 to 60 hours, preferably from 0.5 to 24 hours.
  • Step 5 Compound 8 was synthesized.
  • the aniline (1.023 g) was added to 9 mL of hydrazine and dispersed uniformly.
  • the mixture was sealed with deuterated concentrated hydrochloric acid (1.1 mL), and the microwave reaction was sealed at 180 ° C for 2 hours.
  • the microwave reaction apparatus was closed, and the mixture was cooled to room temperature.
  • the pH was adjusted to about 8 to 9 with sodium bicarbonate solid, and ethyl acetate was extracted.
  • the organic phase was washed with saturated brine and dried over anhydrous sodium sulfate 10 (876 mg).
  • LC-MS 96.15 [M + 1] +; 1 H NMR (500MHz, DMSO-d 6) ⁇ 7.46 (s, 1H).
  • Trimethylphosphonoacetate (compound 6, 1.54g) was dispersed in 6mL of hydrazine water, sealed with 15mg of potassium carbonate, sealed at 80 ° C for 30 minutes, closed the microwave reactor, naturally cooled to room temperature, ethyl acetate The mixture was extracted (10 mL ⁇ 2).
  • 1 H NMR 300 MHz, CDCl 3 ) ⁇ 3.82 (s, 3H), 3.78 (s, 3H), 3.74 (s, 3H).
  • the compound of step 6 is the synthesis of 21.
  • Cell line lymphoma cell JURKAT; CLONE E6-1 was purchased from CAS; cultured in RPMI-1640 medium containing 10% fetal bovine serum, 100 U/ML penicillin, 100 ⁇ G/ML streptomycin.
  • MTS kit Promega, Cat# G1111), 0.25% trypsin (Gibco, Cat #25200), Rpmi-1640 (Gibco, Cat#A10491-01), bovine serum (Gibco, Cat#10099141), DMSO ( Sigma, Cat#D2650), HDAC inhibitor drug screening kit (Biovision, Cat. No. K340-100); MTS assay 96-well plate (CORNING, CAT. NO. 3599); 96-well plate (GREINER, CAT.NO) .655076).
  • Test compounds were dissolved in DMSO to make a 20 mM stock solution. The dilution was diluted in DMSO to 50 times the final concentration of the dilution. Dilute into 2 times the final concentration of the dilution with ultrapure water.
  • Compound IC 50 Assay Compounds of different concentrations prepared in advance dilution were added to 96-well plates with double replicate wells at each concentration. A mixture of HeLa Nuclear Extract and HDAC Substrate was then added. After mixing, incubate for 30 minutes at 37 ° C and add Lysine Developer. After further mixing, the cells were incubated at 37 ° C for 30 minutes, and fluorescence was detected by a microplate reader (BioTek, Synergy 2) at 330 nm excitation light and 440 nm emission light, and data were collected. In addition, negative and positive controls were established with Trichostatin A as a positive reference.
  • Test compounds were dissolved in DMSO to make a 20 mM stock solution. The solution was diluted in DMSO to a final concentration of 200 times. When dosing, use a cell culture medium to dilute to a final concentration of 4 times of the preservation solution (take 4 ⁇ L of 200-fold gradient compound into 196 ⁇ L of complete medium), and take 50 ⁇ L of 4 times the final concentration of the compound into 150 ⁇ L of the culture containing cells. In the board.
  • MTS cell viability assay Cell suspensions in logarithmic growth phase were collected, cells were harvested by centrifugation, 150 ⁇ L of cells were seeded at a defined density in 96-well plates, and 24 ⁇ l of compound diluted in culture medium at 50 ⁇ L/well was added after 24 hours. A well of the same volume of 2% DMSO was added as a control, and the final concentration of DMSO was 0.5%. After the cells were cultured for 72 hours, MTS was assayed for cell viability. The specific method is as follows: 20 ⁇ L LMTS was added to each well, and the OD 490 was detected after being cultured for 1-4 hours in an incubator, with the OD 650 value as a reference.
  • GraphPad Prism software produced dose-response curve and calculate IC 50.
  • A represents an IC 50 ⁇ 100nM
  • B represents 100nM ⁇ IC 50 ⁇ 200nM
  • C represents 200nM ⁇ IC 50 ⁇ 300nM
  • D represents the IC 50> 300nM. (As shown in Table 1 below).
  • Compound 15 of the present invention is comparable to belistatin activity compared to a new drug, belixitastat, developed by Spectrum Biopharmaceutical Company for the treatment of peripheral T-cell lymphoma (PTCL).
  • Compound 21 is superior to belistat, indicating that the compound of the present invention can significantly inhibit histone deacetylase (HDAC), and is thus more suitable for the preparation of diseases associated with histone deacetylase, such as lymphoma.
  • HDAC histone deacetylase
  • Microsomal experiments human liver microsomes: 0.5 mg/mL, Xenotech; rat liver microsomes: 0.5 mg/mL, Xenotech; coenzyme (NADPH/NADH): 1 mM, Sigma Life Science; magnesium chloride: 5 mM, 100 mM phosphate buffer Agent (pH 7.4).
  • Preparation of stock solution A certain amount of the compound powder of the example was accurately weighed and dissolved to 5 mM with DMSO.
  • phosphate buffer 100 mM, pH 7.4.
  • the pH was adjusted to 7.4, diluted 5 times with ultrapure water before use, and magnesium chloride was added to obtain a phosphate buffer (100 mM) containing 100 mM potassium phosphate, 3.3 mM magnesium chloride, and a pH of 7.4.
  • NADPH regeneration system containing 6.5 mM NADP, 16.5 mM G-6-P, 3 U/mL G-6-P D, 3.3 mM magnesium chloride was prepared and placed on wet ice before use.
  • Formulation stop solution acetonitrile solution containing 50 ng/mL propranolol hydrochloride and 200 ng/mL tolbutamide (internal standard). Take 25057.5 ⁇ L of phosphate buffer (pH 7.4) into a 50 mL centrifuge tube, add 812.5 ⁇ L of human liver microsomes, and mix to obtain a liver microsome dilution with a protein concentration of 0.625 mg/mL. 25057.5 ⁇ L of phosphate buffer (pH 7.4) was taken into a 50 mL centrifuge tube, and 812.5 ⁇ L of SD rat liver microsomes were added and mixed to obtain a liver microsome dilution having a protein concentration of 0.625 mg/mL.
  • the corresponding compound had a reaction concentration of 1 ⁇ M and a protein concentration of 0.5 mg/mL.
  • 100 ⁇ L of the reaction solution was taken at 10, 30, and 90 min, respectively, and added to the stopper, and the reaction was terminated by vortexing for 3 min.
  • the plate was centrifuged at 5000 x g for 10 min at 4 °C.
  • 100 ⁇ L of the supernatant was taken into a 96-well plate to which 100 ⁇ L of distilled water was previously added, mixed, and sample analysis was performed by LC-MS/MS.
  • EXPERIMENTAL OBJECTIVE To investigate the pharmacokinetic behavior of the compounds of the present invention after administration of N-hydroxy-3-(3-phenylsulfamoyl-phenyl)acrylamide and the compounds of Examples 1-6 in rats.
  • SD rat grade SPF grade
  • Weight range 180 ⁇ 220g (actual weight range is 187 ⁇ 197g)
  • the blood was taken and placed in an ice box.
  • the blood samples were centrifuged at 4000 rpm, 10 min, 4 ° C for 30 min, and all plasma was collected and stored at -20 ° C immediately. Plasma concentrations in plasma at each time point were determined after sample collection at all time points.
  • the compounds of the present invention have superior activity and excellent pharmacokinetic properties compared to N-hydroxy-3-(3-phenylsulfamoyl-phenyl)acrylamide, and thus are more suitable as A compound that inhibits histone deacetylase is further suitable for the preparation of a medicament for treating cell proliferative diseases and cancer.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
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  • Pharmacology & Pharmacy (AREA)
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  • Life Sciences & Earth Sciences (AREA)
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  • General Health & Medical Sciences (AREA)
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  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
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Abstract

L'invention concerne un composé d'acrylamide substitué et une composition pharmaceutique correspondante, le composé d'acrylamide substitué étant un composé de formule (I), ou une forme cristalline, un sel, promédicament, stéréoisomère, hydrate ou solvate associé pharmaceutiquement acceptable. Le composé selon la présente invention peut inhiber l'activité d'une histone désacétylase (HDAC) et présente également de meilleures propriétés pharmacodynamiques/pharmacocinétiques ; le composé a une grande applicabilité, il est sans danger et peut être utilisé pour la préparation d'une composition pharmaceutique destinée au traitement des maladies conditionnées par l'HDAC, ce qui lui confère de grandes possibilités commerciales.
PCT/CN2017/074372 2016-03-04 2017-02-22 Composé d'acrylamide substitué et composition pharmaceutique correspondante Ceased WO2017148318A1 (fr)

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CN201780003913.0A CN108349882B (zh) 2016-03-04 2017-02-22 一种取代的丙烯酰胺化合物及其药物组合物

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Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN105237444A (zh) * 2015-09-24 2016-01-13 沈阳药科大学 异羟肟酸类化合物及其制备方法和用途
CN105481736A (zh) * 2015-12-28 2016-04-13 山东大学 一种含有苯甘氨酸的肉桂酰胺类组蛋白去乙酰化酶抑制剂及其制备方法和应用

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JP4975941B2 (ja) * 2000-09-29 2012-07-11 トポターゲット ユーケー リミテッド （ｅ）−ｎ−ヒドロキシ−３−（３−スルファモイル−フェニル）アクリルアミド化合物及びその治療用途
US20130040998A1 (en) * 2010-01-08 2013-02-14 Dana-Farber Cancer Institute, Inc. Fluorinated hdac inhibitors and uses thereof

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CN105237444A (zh) * 2015-09-24 2016-01-13 沈阳药科大学 异羟肟酸类化合物及其制备方法和用途
CN105481736A (zh) * 2015-12-28 2016-04-13 山东大学 一种含有苯甘氨酸的肉桂酰胺类组蛋白去乙酰化酶抑制剂及其制备方法和应用

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FINN, P.W. ET AL.: "Novel sulfonamide derivatives as inhibitors of histone deacetylase", HELVETICA CHIMICA ACTA, vol. 88, no. 7, 31 December 2005 (2005-12-31), pages 1630 - 1657, XP002367316 *

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