[go: up one dir, main page]

WO2017181948A1 - Oxazolidone substituée et son application - Google Patents

Oxazolidone substituée et son application Download PDF

Info

Publication number
WO2017181948A1
WO2017181948A1 PCT/CN2017/081010 CN2017081010W WO2017181948A1 WO 2017181948 A1 WO2017181948 A1 WO 2017181948A1 CN 2017081010 W CN2017081010 W CN 2017081010W WO 2017181948 A1 WO2017181948 A1 WO 2017181948A1
Authority
WO
WIPO (PCT)
Prior art keywords
compound
compound according
hydrogen
oxazolidinone compound
pharmaceutically acceptable
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Ceased
Application number
PCT/CN2017/081010
Other languages
English (en)
Chinese (zh)
Inventor
王义汉
邢青峰
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Shenzhen Targetrx Inc
Original Assignee
Shenzhen Targetrx Inc
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Shenzhen Targetrx Inc filed Critical Shenzhen Targetrx Inc
Priority to CN201780004362.XA priority Critical patent/CN108368139B/zh
Publication of WO2017181948A1 publication Critical patent/WO2017181948A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

Links

Classifications

    • 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
    • A61K31/66—Phosphorus compounds
    • A61K31/675—Phosphorus compounds having nitrogen as a ring hetero atom, e.g. pyridoxal phosphate
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
    • C07F9/02—Phosphorus compounds
    • C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
    • C07F9/6558—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom containing at least two different or differently substituted hetero rings neither condensed among themselves nor condensed with a common carbocyclic ring or ring system

Definitions

  • the invention belongs to the field of medicine.
  • the present invention relates to deuterated oxazolidinone derivatives and uses thereof, and more particularly to oxazolidinone compounds which are useful as antibiotics.
  • Antibiotics are one of the most frequently used essential drugs in the clinic.
  • the irregular use of antibiotics due to historical reasons has caused the bacteria to be severely resistant to existing antibiotics.
  • Multidrug-resistant (MDR) bacterial infections have become one of the major threats to public health worldwide.
  • MDR Multidrug-resistant
  • the combination of antibiotics is increasing, and drug-drug interactions also increase the risk of adverse reactions.
  • the "super bacteria" that are resistant to most of the available antibiotics are also spreading around the world at an alarming rate.
  • the development of new and effective antibiotics has not increased with the increase of MDR bacteria.
  • CDER the number of newly approved antibiotics has been decreasing since 1980. Existing antibiotics have been unable to cure the increasing infection and resistance.
  • Sivextro (common name: tedizolid phosphate, formerly known as TR-701) was developed by Cubist Pharmaceuticals Inc. and is an oxazolidinone antibiotic. Sivextro is a prodrug that is rapidly converted to a biologically active tedizolid by phosphatase in the body. The latter binds to the ribosomal 50S subunit of the bacterium, thereby inhibiting protein synthesis. Although at least 10 similar compounds have entered the clinic since Pfizer's similar antibiotic linezolid was approved by the US FDA in 2000, Sivextro is the first second-generation oxazolidinone antibiotic to be approved by the FDA. Compared with the first-generation product linezolid, Sivextro has 2-8 times higher inhibitory activity against some bacteria in vitro, and the safety is also improved to some extent.
  • Deuterated modification is a potentially attractive strategy for improving the metabolic properties of drugs.
  • Helium is a safe, stable, non-radiative isotope of hydrogen. Compared with the C-H bond, the C-D bond formed by ruthenium and carbon is stronger because of the lower vibration frequency.
  • the "heavy hydrogen" version of the drug may be more stable to degradation and longer in the body.
  • Deuterated drugs have a positive impact on safety, efficacy and tolerance, and have excellent research prospects.
  • the present invention discloses an oxazolidinone compound and a composition comprising the same as an effective antibacterial active compound and/or having better pharmacodynamic/pharmacokinetic properties.
  • R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11 , R 12 , R 13 and R 14 are each independently hydrogen, deuterium or halogen. Or trifluoromethyl;
  • R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11 , R 12 , R 13 , R 14 is ⁇ Generation or embarrassment.
  • each of R 1 , R 2 and R 3 is independently hydrazine or hydrogen.
  • R 4 , R 5 and R 6 are each independently hydrazine or hydrogen.
  • R 7 , R 8 and R 9 are each independently hydrazine or hydrogen.
  • R 10 , R 11 and R 12 are each independently hydrazine or hydrogen.
  • R 13 and R 14 are each independently hydrazine or hydrogen.
  • the compound is selected from the group consisting of the compounds or pharmaceutically acceptable salts thereof, but is not limited to the following compounds:
  • the cerium 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%, and even more preferably greater than 75%.
  • the ground is greater than 95%, more preferably greater than 99%.
  • each of R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11 , R 12 , R 13 and R 14 The strontium isotope content in the deuterated position is at least 5%, preferably greater than 10%, more preferably greater than 15%, more preferably greater than 20%, more preferably greater than 25%, still more preferably greater 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 more than 80%, more preferably more than 85%, more preferably more than 90%, more preferably more than 95%, more preferably more than 99%.
  • R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11 , R 12 of the compound of formula (I), R 13 and R 14 at least one of R contains ruthenium, more preferably two R contains ruthenium, more preferably three R contains ruthenium, more preferably four R contains ruthenium, more preferably five R contains ruthenium, more preferably five R-containing ruthenium, more preferably Preferably, the six R-containing yttrium, more preferably the seven R-containing yttrium, more preferably eight R-containing yttrium, more preferably nine R-containing yttrium, more preferably ten R-containing yttrium, more preferably eleven R contains hydrazine, more preferably twelve R ⁇ , more preferably thirteen R ⁇ , more preferably fourteen R ⁇ .
  • the compound does not include a non-deuterated compound.
  • a method of preparing a pharmaceutical composition comprising the steps of: pharmaceutically acceptable carrier and a compound of the first aspect of the invention, or a crystalline form thereof, pharmaceutically acceptable
  • the accepted salt, hydrate or solvate is mixed to form a pharmaceutical composition.
  • a pharmaceutical composition comprising a pharmaceutically acceptable carrier and a compound of the first aspect of the invention, or a crystalline form thereof, a pharmaceutically acceptable salt, hydrated Or a solvate.
  • the oxazolidinone compound of the present invention exhibits inhibitory activity against a broad spectrum of bacteria, methicillin-resistant Staphylococcus aureus, and vancomycin-resistant Enterococcus, and has relatively excellent antibacterial activity at a relatively low concentration or in vivo. .
  • the compound of the present invention can be expressed to include Gram-positive bacteria such as Staphylococcus, Enterococcus and Streptococcus, anaerobic microorganisms such as bacteroids and Clostridium, and acid-tolerant microorganisms such as Mycobacterium tuberculosis and Mycobacterium avium.
  • Gram-positive bacteria such as Staphylococcus, Enterococcus and Streptococcus
  • anaerobic microorganisms such as bacteroids and Clostridium
  • acid-tolerant microorganisms such as Mycobacterium tuberculosis and Mycobacterium avium.
  • composition of the present invention may comprise at least one active ingredient having a function similar to an oxazolidinone derivative.
  • At least one compound of formula (I) can be combined with at least one pharmaceutically acceptable carrier.
  • Pharmaceutically acceptable carriers can include physiological saline, sterile water, Ringer's solution, physiological saline buffer solution, dextrose solution, maltodextrin solution, glycerol, ethanol, and the like.
  • the pharmaceutical composition may contain conventional excipients such as antioxidants, buffers, soil cleaners and the like.
  • the composition is also mixed with a diluent, a diintegrant, a surfactant, a binder, a lubricant, an aqueous solution, a suspension or the like to form an injection, a powder, a capsule, a granule, a tablet or the like.
  • the formulation can be prepared by the method described in Remington's Pharmaceutical Science (latest edition) (Mack Publishing Company, Easton PA, etc.) depending on the disease or component.
  • the compounds of the invention may be administered orally or parenterally, for example, intravenously, subcutaneously, intraperitoneally, topically, and the like.
  • Chemical The dosage of the compound can vary depending on the particular compound employed, the mode of administration, the condition and severity of the condition to be treated, and the various physical factors associated with the subject being treated.
  • a daily dose of about 8 to 30 mg, preferably 12 to 21 mg per kg of body weight, satisfactory results can be obtained according to the use of the present invention. More preferably, the above daily dose is divided into several doses per day.
  • the oxazolidinone derivative of the present invention exhibits inhibitory activity and low toxicity against a broad spectrum of bacteria.
  • a prodrug prepared by reacting a compound having a hydroxyl group with an amino acid or a phosphate has high water solubility.
  • the derivatives of the present invention may be shown to include Gram-positive bacteria such as Staphylococcus, Enterococcus and Streptococcus, anaerobic microorganisms such as bacteroids and Clostridium, and acid-tolerant microorganisms such as Mycobacterium tuberculosis, Mycobacterium avium The potent antibacterial activity of human and animal pathogens.
  • composition containing the oxazolidinone derivative is used in an antibiotic.
  • the invention also includes isotopically labeled compounds, equivalent to the original compounds disclosed herein.
  • isotopes which may be listed as compounds of the present invention include hydrogen, carbon, nitrogen, oxygen, phosphorus, fluorine and chlorine isotopes such as 2 H, 3 H, 13 C, 14 C, 15 N, 17 O, 18 O, 31, respectively.
  • P, 32 P, 18 F and 36 Cl. a compound, or an enantiomer, a diastereomer, an isomer, or a pharmaceutically acceptable salt or solvate of the present invention, wherein an isotope or other isotopic atom containing the above compound is within the scope of the present invention .
  • isotopically-labeled compounds of the present invention such as the radioisotopes of 3 H and 14 C, are also among them, useful in tissue distribution experiments of drugs and substrates. ⁇ , ie 3 H and carbon-14, ie 14 C, are easier to prepare and detect and are preferred in isotopes.
  • Isotopically labeled compounds can be prepared in a conventional manner by substituting a readily available isotopically labeled reagent with a non-isotopic reagent using the protocol of the examples.
  • the beneficial effects of the present invention are: the substituted oxazolidinone compound disclosed by the present invention and the composition comprising the same for the spectrum bacteria (including Gram-positive bacteria such as Staphylococcus, Enterococcus) With Streptococcus, anaerobic microorganisms such as bacteriophages and Clostridium and acid-tolerant microorganisms such as Mycobacterium tuberculosis, Mycobacterium avium, have excellent inhibition and have better pharmacokinetic parameter characteristics.
  • the dosage can be varied and a long acting formulation can be formed to improve suitability.
  • Replacing a hydrogen atom in a compound with hydrazine can increase the drug concentration of the compound in an animal to improve the efficacy of the drug due to its strontium isotope effect. Substitution of a hydrogen atom in a compound with hydrazine may increase the safety of the compound due to inhibition of certain metabolites.
  • the antibacterial activity of the oxazolidinone compound was tested by the method described in Chemotheraphy, 29(1), 76, (1981).
  • the dilute solution of agar was used to include methicillin-resistant Staphylococcus aureus (MRSA) and resistant to vancomycin.
  • MRSA methicillin-resistant Staphylococcus aureus
  • VRE enterococci
  • MIC50 minimum inhibitory concentration
  • the experimental results show that the compound of the present invention exhibits sufficient antibacterial activity against methicillin-resistant Staphylococcus aureus (MRSA) and vancomycin-resistant enterococci (VRE).
  • MRSA methicillin-resistant Staphylococcus aureus
  • VRE vancomycin-resistant enterococci
  • Rats were fed a standard diet and given water. Fasting began 16 hours before the test.
  • the drug was dissolved with PEG400 and dimethyl sulfoxide. Blood was collected from the eyelids at a time point of 0.083 hours, 0.25 hours, 0.5 hours, 1 hour, 2 hours, 4 hours, 6 hours, 8 hours, 12 hours, and 24 hours after administration.
  • Rats were briefly anesthetized after inhalation of ether, and 300 ⁇ L of blood samples were collected from the eyelids in test tubes. There was 30 ⁇ L of 1% heparin salt solution in the test tube. The tubes were dried overnight at 60 ° C before use. After the blood sample collection was completed at a later time point, the rats were anesthetized with ether and sacrificed.
  • Plasma samples were centrifuged at 5000 rpm for 5 minutes at 4 ° C to separate plasma from red blood cells. Pipette 100 ⁇ L of plasma into a clean plastic centrifuge tube, indicating the name and time of the compound. Plasma was stored at -80 °C prior to analysis. The concentration of the compound of the invention in plasma was determined by LC-MS/MS. Pharmacokinetic parameters were calculated based on the plasma concentration of each animal at different time points.
  • the experimental results show that the compound of the present invention has better pharmacokinetics in animals relative to the control compound, and thus has better pharmacodynamics and therapeutic effects.
  • Microsomal experiments human liver microsomes: 0.5 mg/mL, BD Gentest; rat liver microsomes: 0.5 mg/mL, Xenotech; mouse liver microsomes: 0.5 mg/mL, Xenotech; coenzyme (NADPH/NADH): 1 mM, Sigma Life Science; magnesium chloride: 5 mM, 100 mM phosphate buffer (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. Take 25057.5 ⁇ L of phosphate buffer (pH 7.4) into a 50 mL centrifuge tube, add 812.5 ⁇ L of rat liver microsomes, and mix to obtain a liver microsome dilution with a protein concentration of 0.625 mg/mL.
  • 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.
  • the compounds of the present invention exhibited excellent metabolic stability in human liver microsomes, rat liver microsomes, and mouse liver microsome experiments, and were significantly superior to the undeuterated compound Tedizolid. This demonstrates that the deuterated compounds T-1 and T-2 of the present invention significantly improve the metabolic stability of the non-deuterated compounds.

Landscapes

  • Chemical & Material Sciences (AREA)
  • Health & Medical Sciences (AREA)
  • Organic Chemistry (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • General Health & Medical Sciences (AREA)
  • Biochemistry (AREA)
  • Molecular Biology (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Epidemiology (AREA)
  • Animal Behavior & Ethology (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

L'invention concerne un composé d'oxazolidone de formule (I), ou une forme cristalline correspondante, un sel pharmaceutiquement acceptable, un promédicament, un métabolite, un stéréoisomère, un isomère isotopique, un hydrate ou un solvate correspondant, et une composition pharmaceutique comprenant le composé. Le composé a démontré une activité inhibitrice vis-à-vis d'un large spectre de bactéries et une faible toxicité, et il peut être utilisé pour préparer un antibiotique.
PCT/CN2017/081010 2016-04-22 2017-04-19 Oxazolidone substituée et son application Ceased WO2017181948A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
CN201780004362.XA CN108368139B (zh) 2016-04-22 2017-04-19 取代的恶唑烷酮化合物及其应用

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
CN201610255282 2016-04-22
CN201610255282.9 2016-04-22

Publications (1)

Publication Number Publication Date
WO2017181948A1 true WO2017181948A1 (fr) 2017-10-26

Family

ID=60116575

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/CN2017/081010 Ceased WO2017181948A1 (fr) 2016-04-22 2017-04-19 Oxazolidone substituée et son application

Country Status (2)

Country Link
CN (1) CN108368139B (fr)
WO (1) WO2017181948A1 (fr)

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN112940038A (zh) * 2019-12-11 2021-06-11 华创合成制药股份有限公司 新型噁唑烷酮类化合物及其制备方法

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN1894242A (zh) * 2003-12-18 2007-01-10 东亚制药株式会社 新型噁唑烷酮衍生物
CN102164915A (zh) * 2008-10-10 2011-08-24 埃科特莱茵药品有限公司 作为抗菌剂的2-苯并噻吩基-和2-萘基-噁唑烷酮及其氮杂等排体类似物

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN1894242A (zh) * 2003-12-18 2007-01-10 东亚制药株式会社 新型噁唑烷酮衍生物
CN102164915A (zh) * 2008-10-10 2011-08-24 埃科特莱茵药品有限公司 作为抗菌剂的2-苯并噻吩基-和2-萘基-噁唑烷酮及其氮杂等排体类似物

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
SANDERSON, K. ET AL.: "The drug industry is seeking profits by modifying hydrogen in existing medications", NATURE, 16 March 2009 (2009-03-16), pages 1, XP009114123, ISSN: 0028-0836 *

Cited By (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN112940038A (zh) * 2019-12-11 2021-06-11 华创合成制药股份有限公司 新型噁唑烷酮类化合物及其制备方法
WO2021114639A1 (fr) * 2019-12-11 2021-06-17 华创合成制药股份有限公司 Composés d'oxazolidinone de type nouveau et leur procédé de préparation
JP2023505456A (ja) * 2019-12-11 2023-02-09 華創合成制薬股▲ふん▼有限公司 新規オキサゾリジノン系化合物及びその製造方法
EP4074719A4 (fr) * 2019-12-11 2023-06-14 HC Synthetic Pharmaceutical Co., Ltd. Composés d'oxazolidinone de type nouveau et leur procédé de préparation
JP7374533B2 (ja) 2019-12-11 2023-11-07 華創合成制薬股▲ふん▼有限公司 新規オキサゾリジノン系化合物及びその製造方法
US12173020B2 (en) 2019-12-11 2024-12-24 HC Synthetic Pharmaceutical Co., Ltd. New-type oxazolidinone compounds and preparation method therefor

Also Published As

Publication number Publication date
CN108368139A (zh) 2018-08-03
CN108368139B (zh) 2020-12-18

Similar Documents

Publication Publication Date Title
EP1699784B1 (fr) Nouveaux derives d'oxazolidinone
CN109422752A (zh) 一类具有抑制并降解布鲁顿酪氨酸蛋白激酶Btk活性的化合物
CN108358917B (zh) 含有碱性稠环片段的咪唑并[1,2-a]吡啶-3-酰胺类化合物及其制备方法
WO2014015105A1 (fr) Formes solides de (r)-2-(5-(2-(3-éthylureido)-6-fluoro-7-(tétrahydrofuran-2-yl)-1h-benzo[d]imidazol-5-yl)pyrimidin-2-yl)propan-2-yl dihydrogen phosphate et ses sels
EP2766373B1 (fr) Sila-analogues de dérivés d'oxazolidinone et synthèse de ceux-ci
CN106317072B (zh) 用于分枝杆菌感染治疗的杂环化合物及其应用
WO2006003881A1 (fr) Nouveau dérivé d’arylamidine, sel de ce composé et antifongique contenant ces composés
JP5662940B2 (ja) 新規な抗微生物薬
JP6286536B2 (ja) 新規オキサゾリジノン抗菌化合物
US11760751B2 (en) Benzo 2-azaspiro[4.4]nonane compound and use thereof
CN108368139B (zh) 取代的恶唑烷酮化合物及其应用
CN105669664A (zh) 含有碱性氮杂环片段的苯并噻嗪-4-酮类化合物及其制备方法
JP7737734B2 (ja) ピロール誘導体、その調製方法及びその用途
CN107400126A (zh) 新型噁唑烷酮类化合物及其制备方法和在医学上的应用
WO2019234508A1 (fr) Agents de biodéfense
CN106543106B (zh) N-苄基苯甲酰胺类化合物及其制备方法
WO2019042443A1 (fr) Composé ayant une activité de dégradation de la protéine tyrosine kinase jak3
WO2006011499A1 (fr) Nouveau dérivé d’arylamidine, sel de celui-ci et antifongique contenant celui-ci
US9920039B2 (en) 1,2,4-Oxadiazol compounds active against gram-positive pathogens
US20040235900A1 (en) Antimicrobial oxazolifinones with improved pharmacokinetic profile and safety advantages
CN106588916A (zh) N‑(苯氧乙基)咪唑并[1,2‑a]吡啶‑3‑酰胺类化合物及其制备方法
US12180242B2 (en) Pharmaceutical crystal of contezolid acefosamil, preparation method therefor, and uses thereof
EP2072514A1 (fr) 1(2)H-Tétrazol-5-yl-phényl-oxazolidinone en tant qu'agents antibactériens
CN108440446A (zh) 含有肟基片段的苯并噻嗪-4-酮类化合物及其制备方法
CN101096369A (zh) 含噻二唑基的噁唑烷酮化合物及制备方法

Legal Events

Date Code Title Description
NENP Non-entry into the national phase

Ref country code: DE

121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 17785432

Country of ref document: EP

Kind code of ref document: A1

122 Ep: pct application non-entry in european phase

Ref document number: 17785432

Country of ref document: EP

Kind code of ref document: A1