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WO2015056799A1 - Dérivé d'acide hydroxamique - Google Patents

Dérivé d'acide hydroxamique Download PDF

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Publication number
WO2015056799A1
WO2015056799A1 PCT/JP2014/077750 JP2014077750W WO2015056799A1 WO 2015056799 A1 WO2015056799 A1 WO 2015056799A1 JP 2014077750 W JP2014077750 W JP 2014077750W WO 2015056799 A1 WO2015056799 A1 WO 2015056799A1
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WO
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Prior art keywords
compound
acid
added
methyl
amino
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Ceased
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PCT/JP2014/077750
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English (en)
Japanese (ja)
Inventor
一 高島
剛 毒島
哲也 薮内
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Taisho Pharmaceutical Co Ltd
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Taisho Pharmaceutical Co Ltd
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Priority to JP2015542911A priority Critical patent/JPWO2015056799A1/ja
Publication of WO2015056799A1 publication Critical patent/WO2015056799A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C259/00—Compounds containing carboxyl groups, an oxygen atom of a carboxyl group being replaced by a nitrogen atom, this nitrogen atom being further bound to an oxygen atom and not being part of nitro or nitroso groups
    • C07C259/04—Compounds containing carboxyl groups, an oxygen atom of a carboxyl group being replaced by a nitrogen atom, this nitrogen atom being further bound to an oxygen atom and not being part of nitro or nitroso groups without replacement of the other oxygen atom of the carboxyl group, e.g. hydroxamic acids
    • C07C259/06—Compounds containing carboxyl groups, an oxygen atom of a carboxyl group being replaced by a nitrogen atom, this nitrogen atom being further bound to an oxygen atom and not being part of nitro or nitroso groups without replacement of the other oxygen atom of the carboxyl group, e.g. hydroxamic acids having carbon atoms of hydroxamic groups bound to hydrogen atoms or to acyclic carbon atoms
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/04—Antibacterial agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2601/00—Systems containing only non-condensed rings
    • C07C2601/02—Systems containing only non-condensed rings with a three-membered ring

Definitions

  • the present invention relates to a novel hydroxamic acid derivative having antibacterial activity against gram-negative bacteria and their drug-resistant bacteria.
  • the present invention also relates to a pharmaceutical composition or antibacterial agent containing a hydroxamic acid derivative.
  • Gram-negative bacteria have an outer membrane consisting of a lipid bilayer that is not present in gram-positive bacteria. Therefore, Gram-negative bacteria tend to have stronger drug resistance compared to Gram-positive bacteria due to drug permeability issues. In addition, gram-negative bacteria are known to have multiple drug efflux proteins. Non-Patent Document 1 discloses that drug efflux proteins are also involved in drug resistance. Furthermore, lipopolysaccharide (LPS), one of the main components of the outer membrane, is greatly involved in toxicity as an endotoxin.
  • LPS lipopolysaccharide
  • Pseudomonas aeruginosa is known to have a strong tendency to exhibit natural resistance to various antibacterial drugs.
  • Pseudomonas aeruginosa is an attenuated bacterium that is ubiquitous in the natural environment and living environment, but usually does not show pathogenicity in healthy individuals.
  • patients who are said to be so-called "complied hosts" that use immunosuppressants by transplantation, etc. patients who are performing medical procedures such as medical catheters, tracheal intubation, and surgery
  • Pseudomonas aeruginosa is a pathogen that causes serious acute infections such as sepsis.
  • Pseudomonas aeruginosa is one of the important causative bacteria of opportunistic and nosocomial infections.
  • Pseudomonas aeruginosa that has acquired resistance to third-generation cephem drugs, carbapenem drugs, aminoglycosides, and the like that are originally expected to have an effect on Pseudomonas aeruginosa has been clinically isolated ( Non-patent document 2).
  • Non-patent Document 3 multidrug-resistant Pseudomonas aeruginosa that has acquired resistance to all the three drugs has been isolated.
  • multidrug-resistant Pseudomonas aeruginosa Since there are few useful drugs when infected with multidrug-resistant Pseudomonas aeruginosa, multidrug-resistant Pseudomonas aeruginosa has become a major problem worldwide as a causative bacterium for intractable infectious diseases. Therefore, development of a drug having a novel mechanism of action is eagerly desired.
  • UDP-3-O-acyl-N-acetylglucosamine deacetylase is an enzyme responsible for the synthesis of lipid A, a hydrophobic anchor of LPS, which is a component of the outer membrane.
  • Lipid A biosynthesis consists of 10 reactions. LpxC catalyzes the second step of its biosynthetic reaction and releases the acetyl group of UDP-3-O-acyl-N-acetylglucosamine (Non-patent Document 4).
  • Lipid A is an essential component for outer membrane formation, and as a result is essential for the survival of Gram-negative bacteria (Non-patent Document 5).
  • LpxC is one of the important enzymes that are rate-limiting in the lipid A biosynthesis process, and is an essential enzyme for lipid A biosynthesis. Therefore, an agent that inhibits the activity of LpxC can be an effective antibacterial agent against Gram-negative bacteria including Pseudomonas aeruginosa, particularly against drug-resistant Pseudomonas aeruginosa, because it has a different mechanism of action from conventional agents. It is highly expected.
  • Patent Documents 1 to 11 As LpxC inhibitors, inhibitors having an amide structure are disclosed in Patent Documents 1 to 11 and Non-Patent Documents 6 to 13.
  • Patent Documents 5 and 9 disclose compounds having a malonic amide skeleton and a diethynyl structure.
  • Patent Document 5 specifically discloses a compound 507 having a cyclopropyl ring at the end of the diethynyl terminal.
  • Patent Document 9 specifically discloses Compound 233 as a compound having a cyclopropyl ring.
  • Patent Document 9 discloses Compound 197, Compound 209, and Compound 221, and Compound 8 discloses a synthesis method and antibacterial activity.
  • Patent Document 5 does not have a methyl group at the carbon atom adjacent to the hydroxamic acid of the skeleton portion. Further, Patent Document 5 does not disclose a compound having an unsubstituted amino group as a substituent at the diethynyl terminal portion. In addition, all the compounds disclosed in Patent Document 9 are compounds having a hydroxymethyl group as a substituent on the cyclopropyl ring, and have a chiral terminal structure. Patent Document 9 does not disclose a compound having an amino group as a substituent at the end of the diethylinyl terminal.
  • An object of the present invention is to provide a novel compound having strong antibacterial activity against Gram-negative bacteria such as Pseudomonas aeruginosa and drug-resistant bacteria and useful as a pharmaceutical product.
  • the present invention is as follows.
  • (1) 2-[ ⁇ 4- [4- (1-Aminocyclopropyl) buta-1,3-diin-1-yl] benzoyl ⁇ (methyl) amino] -N-hydroxy-N ′, 2-dimethyl A compound which is propanediamide or a pharmaceutically acceptable salt thereof.
  • (2) Formula [2] (2S) -2-[ ⁇ 4- [4- (1-Aminocyclopropyl) but-1,3-diin-1-yl] benzoyl ⁇ (methyl) amino] -N-hydroxy-N ′ , 2-dimethylpropanediamide or a pharmaceutically acceptable salt thereof.
  • (3) A pharmaceutical composition comprising the compound according to (1) or (2) or a pharmaceutically acceptable salt thereof.
  • (4) The antibacterial agent containing the compound or its pharmaceutically acceptable salt as described in said (1) or (2).
  • novel hydroxamic acid derivative of the present invention has strong antibacterial activity against gram-negative bacteria such as Pseudomonas aeruginosa and drug-resistant bacteria.
  • “pharmaceutically acceptable salt” means a salt used in chemotherapy and prevention of bacterial infections.
  • examples of the “pharmaceutically acceptable salt” include acetic acid, propionic acid, butyric acid, formic acid, trifluoroacetic acid, maleic acid, tartaric acid, citric acid, stearic acid, succinic acid, ethyl succinic acid, malonic acid, lactobionic acid, Gluconic acid, glucoheptonic acid, benzoic acid, methanesulfonic acid, ethanesulfonic acid, 2-hydroxyethanesulfonic acid, benzenesulfonic acid, paratoluenesulfonic acid (tosylic acid), lauryl sulfuric acid, malic acid, aspartic acid, glutamic acid, adipic acid Acid such as cysteine, N-acetylcysteine, hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid, hydroiodic acid
  • the compound of the present invention includes a compound represented by the formula [1], a compound represented by the formula [2], or a pharmaceutically acceptable salt thereof. Used in the meaning) may form a hydrate or a solvate. Where the compounds of the present invention form hydrates or solvates, they are also included within the scope of the present invention.
  • the “solvent” when the compound of the present invention forms a “solvate” includes, for example, polar solvents (eg, alcohol solvents such as methanol, ethanol, 1-propanol, 2-propanol and butanol, and Ethyl acetate, etc.), inert solvents (for example, halogenated hydrocarbon solvents such as chloroform and methylene chloride, ether solvents such as diethyl ether, isopropyl ether, tetrahydrofuran and dioxane, amide solvents such as dimethylformamide and dimethylacetamide, An aprotic solvent such as dimethyl sulfoxide and acetonitrile, aromatic hydrocarbons such as toluene, and hydrocarbons such as hexane and cyclohexane), 2-butanone and acetone.
  • the “solvent” may be a mixed solvent of the solvents exemplified herein.
  • antibacterial agent means a substance having the ability to act on bacteria such as Gram positive bacteria and Gram negative bacteria to suppress or sterilize their growth. It may be something that suppresses the growth of bacteria or kills some bacteria to reduce their number.
  • Gram-positive bacteria include, for example, Staphylococcus (S. aureus and Staphylococcus epidermidis, etc.), Streptococcus (S. pyogenes, Group B Streptococcus, pneumococci, etc.), Enterococcus (Enterococcus faecalis and Enterococcus Fesium, etc.).
  • Gram-negative bacteria include, for example, Pseudomonas genus (Pseudomonas aeruginosa, etc.), Escherichia genus (E. coli etc.), Klebsiella genus (Klebsiella pneumoniae and Klebsiella oxytoca, etc.), Haemophilus genus (H.
  • the compound of the present invention can be preferably used as an antibacterial agent against gram-negative bacteria.
  • propanediamide may have optical isomers
  • the compound represented by the formula [1] includes optical isomers and a mixture of optical isomers.
  • the pharmaceutical composition or antibacterial agent may contain a specific optical isomer, or may contain a mixture of optical isomers, particularly a racemate.
  • the present invention includes a compound represented by the formula [1] and a pharmaceutically acceptable salt thereof, and also includes a crystal polymorph of the compound represented by the formula [1] and a pharmaceutically acceptable salt thereof. included.
  • the preferred optical isomer of the present invention is represented by the following formula [2]
  • the present invention includes a compound represented by the formula [2] and a pharmaceutically acceptable salt thereof, and also includes a crystal polymorph of the compound represented by the formula [2] and a pharmaceutically acceptable salt thereof. It is included in the present invention.
  • the compounds of the present invention can be combined with one or more pharmaceutically acceptable carriers, excipients or diluents to form a pharmaceutical composition.
  • the carrier, excipient and diluent include water, lactose, dextrose, fructose, sucrose, sorbitol, mannitol, polyethylene glycol, propylene glycol, starch, gum, gelatin, alginate, calcium silicate, calcium phosphate, cellulose, Examples include water syrup, hydroxypropylcellulose, hydroxypropylmethylcellulose, methylcellulose, polyvinylpyrrolidone, alkylparahydroxybenzosorbate, talc, magnesium stearate, stearic acid, glycerin, and various oils (eg, sesame oil, olive oil, and soybean oil).
  • additives such as a bulking agent, a binder, a disintegrant, a pH adjuster, a solubilizer and a flavoring agent that are generally used are mixed as necessary with the carrier, excipient or diluent. May be.
  • the pharmaceutical composition is prepared by a conventional formulation technique using tablets, pills, capsules, granules, powders, solutions, emulsions, suspensions, ointments, injections (including intramuscular injections and intravenous injections), It can be prepared as an oral or parenteral pharmaceutical such as an intravenous drip infusion or a skin patch.
  • the compound of the present invention can be administered to an adult patient in an amount of 30 to 3000 mg, preferably 100 to 1500 mg, parenterally or orally once a day or divided into several times.
  • a preferred dosage form is intravenous infusion or intravenous injection, and a more preferred dosage form is intravenous infusion.
  • the dose can be appropriately increased or decreased depending on the type of disease to be treated, the age, weight and symptoms of the patient.
  • the compounds of the present invention can also be used in combination with other drugs.
  • the present invention will be described in more detail with reference to examples and test examples.
  • the present invention is not limited to these examples.
  • the synthesis method of Compound 1 in the present invention is not limited to the following method, and it may be synthesized using a method well known to those skilled in the art, such as changing the order of each step or undergoing functional group protection / deprotection. it can.
  • the NMR spectrum showed proton NMR, and ⁇ value was expressed in ppm using tetramethylsilane as an internal standard. Elemental analysis was carried out using an apparatus of a vario MICRO cube (elemental). As a carrier in OH type silica gel chromatography and NH type silica gel chromatography, a packed column such as REVERLIS TM manufactured by Grace Japan Co., Ltd. was used. A phase separator manufactured by Biotage Corporation was used.
  • the suspension obtained by adding water (500 mL) to the obtained residue was stirred for 1.5 hours, and then filtered and washed (water, 500 mL).
  • the resulting pale orange solid was dissolved in chloroform (500 mL).
  • the obtained chloroform solution was washed with water (200 mL), dried (anhydrous magnesium sulfate), filtered and concentrated.
  • Compound 1 can also be synthesized by the method shown below.
  • Example 1- (6) To the compound (22.8 g) obtained in Example 1- (6), an aqueous phosphate buffer solution (680 mL) was added, and PLE (Pig Liver Esterase, porcine liver esterase) (342 mg) was added thereto. Stir at room temperature for 26 hours.
  • the phosphate buffer aqueous solution used was a mixture of a 0.2 M aqueous sodium dihydrogen phosphate solution (65 mL) and a 0.2 M aqueous solution of disodium hydrogen phosphate (435 mL) diluted to 1000 mL with water.
  • a 1 mol / L sodium hydroxide aqueous solution (75 mL) was added to the reaction solution to adjust the pH to 8 to 9, followed by extraction with toluene (0.5 L). Since the liquid mixture became foamy at this time, Celite (registered trademark) filtration was performed twice. The aqueous layer obtained after the extraction was adjusted to pH 2-3 by adding phosphoric acid (20 mL), and extracted with AcOEt (1 L). Also at this time, since the mixed liquid became foamy, Celite (registered trademark) filtration was performed. The obtained organic layer was dried by adding anhydrous magnesium sulfate, the desiccant was filtered off, and the solvent was distilled off under reduced pressure.
  • Example 1- (7) Chiral analysis of the compound obtained in Example 1- (7) was performed as follows.
  • the measuring instrument used was Shimadzu high performance liquid chromatography.
  • the model number of each device is as follows. Pump: LC-30AD, autosampler: SIL-30AC, column oven: CTO-20AC, photodiode array detector: SPD-M20A, degasser: DGO-20A5R.
  • As the chiral column AD3 manufactured by Daicel Corporation was used by connecting 4.6 ⁇ 150 mm and 4.6 ⁇ 250 mm in series.
  • the enantiomeric excess (ee) was> 99%.
  • Example 1- (2S) -N, 2-Dimethyl-2- (N-methyl-4-((1- (2,2,2-trifluoroacetamido) cyclopropyl) butane) obtained in Example 1- (13)
  • compound 1 can be obtained by deprotecting the tetrahydropyranyl group by the method of Example 1- (5).
  • Examples of the method for deprotecting the trifluoroacetyl group include P.I. G. M.M. Watts et al., Protective Groups in Organic Synthesis, 4th edition, 2006, John Wiley & Sons, Inc. Is mentioned.
  • the protecting group for the amino group of 1-ethynylcyclopropylamine hydrochloride is not limited to the trifluoroacetyl group described in Example 1- (11), and the above-mentioned “Protective Groups in Organic Synthesis” It is also possible to protect with a well-known protecting group of an amino group as described in the above.
  • Examples of the amino-protecting group include carbamate-based protecting groups such as tert-butoxycarbonyl group and ethoxycarbonyl group, and trityl groups.
  • Examples 1- (12) and 1- (13) After protecting the amino group of 1-ethynylcyclopropylamine hydrochloride with a trityl group to obtain 1-ethynyl-N-tritylcyclopropylamine, Examples 1- (12) and 1- (13) The same method is performed, and the trityl group and the tetrahydropyranyl group are sequentially or simultaneously removed using an appropriate deprotection method as described in “Protective Groups in Organic Synthesis” above. By protecting, compound 1 can be obtained.
  • Test Example 1 Antibacterial Activity Evaluation Test
  • the minimum growth inhibitory concentration (MIC) was measured according to the CLSI (Clinical and Laboratory Standards Institute) standard method using the following micro liquid dilution method. For Legionella pneumophilia ATCC 33152, scrape the test cells cultured for 72 hours on BCYE agar medium, suspend them in McFarland 0.5 equivalent, and dilute the resulting suspension 10 times to obtain the inoculum and did. 0.005 mL of the inoculated bacterial solution was inoculated into BYE ⁇ medium containing the test compound and cultured at 35 ° C. for 72 hours.
  • the test microbial cells cultured for 24 hours on chocolate II agar medium are scraped off and suspended in McFarland 0.5, and the resulting suspension is diluted 10 times to inoculate bacterial solution. It was. 0.005 mL of the inoculum solution was inoculated into an HTM medium containing a test compound and cultured at 35 ° C. for 22 hours. For strains other than the above strains, scrape the test cells cultured overnight on the heart infusion agar medium, suspend them in the equivalent of McFarland 0.5, and dilute the resulting suspension 10 times. The inoculum was used.
  • Test Example 2 Sensitivity Distribution Test Pseudomonas aeruginosa 30 strains and Klebsiella pneumoniae 27 strain (MIC) was determined, the MIC was prevented growth of 90% of the strains was calculated as MIC 90.
  • the MIC measurement of each clinical isolate was performed in the same manner as shown in Test Example 1.
  • the MIC 90 for Compound 1 was 2 ⁇ g / mL for P. aeruginosa and 2 ⁇ g / mL for K. pneumoniae.
  • Test Example 3 Pharmacological effect test in infected animals Pseudomonas aeruginosa TS88 strain (clinical isolate) was used as a bacterium. The cells cultured overnight on the heart infusion agar medium were scraped off and suspended in a physiological saline solution so as to be equivalent to McFarland 3.5. The obtained suspension was diluted to 3 ⁇ 10 5 CFU / mL with 3 w / v% mucin-containing physiological saline to prepare an inoculum solution.
  • mice ICR system, male, 4.5 weeks old were infected by inoculating intraperitoneally with 0.5 mL of the inoculum, and compound 1 (6.25 mg / kg) or vehicle (11 w / v% ⁇ ) 1 hour after inoculation
  • Cyclodextrin sulfobutyl ether sodium salt Captisol: registered trademark, Ligand was administered intravenously.
  • the survival rate 3 days after inoculation in the compound 1 administration group was 100% (8 of 8 cases survived), and the survival rate in the vehicle administration group was 0% (all of 8 cases died).
  • Test Example 4 Solubility Measurement Test 0.5 mL of physiological saline was added to an excess amount of Compound 1, adjusted to pH 4 by adding hydrochloric acid, and then shaken for 24 hours. The amount of dissolution after shaking was measured by HPLC (high performance liquid chromatography), and the solubility was measured. This test was conducted at 25 ° C. The solubility of Compound 1 was 15.6 mg / mL.
  • Test Example 6 Rat Maximum Tolerated Dose (MTD) Test Compound 1 0 (control), 400, 600 and 800 mg / kg were administered as a single intravenous dose (10 mL / kg, 3 mL / kg) to 1 to 3 male / group SD rats. min) and the maximum tolerated dose (MTD) was examined.
  • the control group was similarly administered with 11% Captisol (registered trademark, Ligand) (pH 4). Death was observed in 1/1 cases in the 800 mg / kg group. In the case of death, red tears, kinking and squeaking were observed during administration, and the patient died immediately after the end of administration. The cause of death was not clear.
  • Test Example 7 hERG Channel Binding Test A membrane fraction prepared from cells that stably express human hERG channel was subjected to binding test buffer [final concentration: 10 mM HEPES (pH 7.4), 71.5 mM NaCl, 60 mM KCl, 2 mM MgCl 2]. 1 mM CaCl 2 , 0.1% BSA]. The membrane fraction (final concentration 30 ⁇ g / mL) and [ 35 S] MK-499 (final concentration 0.5 nM) were added to a 96-well plate into which the test compound had been dispensed in advance, and allowed to react at room temperature for 75 minutes. .
  • the reaction solution was suction filtered onto a GF / C filter-plate and washed 5 times with a washing buffer [final concentration: 10 mM HEPES (pH 7.4), 131.5 mM NaCl, 2 mM MgCl 2 , 1 mM CaCl 2 ]. Dry at 45 ° C. MicroScint-O was added to the dried filter plate, and the radioactivity was measured using TopCount NXT. In the above reaction, the difference from the [ 35 S] MK-499 binding amount obtained in the presence of the test compound was defined as the specific binding amount, and the [ 35 S] MK-499 binding amount obtained in the presence of MK-499 was determined as the specific binding amount. Non-specific binding amount.
  • a sigmoid analysis of the concentration response curve was performed to calculate an IC 50 value.
  • the IC 50 value of Compound 1 was 30 ⁇ M or more.
  • Test Example 8 Safety pharmacological test for anesthetized guinea pig cardiovascular system Compound 0 (control) and 70 mg / kg were administered intravenously to anesthetized guinea pigs for 30 minutes (5 mL / kg / 30 min), and the effect on the electrocardiogram was observed. investigated.
  • the control group was similarly administered with 11% Captisol (registered trademark, Ligand) (pH 4). Under artificial respiration and pentobarbital anesthesia, limb standard lead (lead II) electrocardiogram was measured using an electrocardiograph, and analysis was performed at 5-minute intervals from 15 minutes before the start of test substance administration to 30 minutes after the end of administration. .
  • ⁇ QTcB at the end of administration of Compound 1 was ⁇ 0.1%, and maximum was + 0.2% (20 minutes and 45 minutes after the start of administration) (control group: ⁇ 4.6 to ⁇ 1.0%), QTcB There was no apparent effect of test substance administration. It was confirmed that Compound 1 was excellent in safety.
  • novel hydroxamic acid derivative of the present invention has strong antibacterial activity against Gram-negative bacteria such as Pseudomonas aeruginosa and drug-resistant bacteria, and can be used as a pharmaceutical product.

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Abstract

La présente invention concerne un nouveau composé utile comme produit pharmaceutique, qui présente une activité antibactérienne élevée à l'égard des bactéries gram-négatif telles que pseudomonas aeruginosa et à l'égard des bactéries résistantes aux médicaments parmi les bactéries gram-négatif. La présente invention concerne un diamide de 2-[{4-[4-(1-aminocyclopropyl)buta-1,3-diyne-1-yl]benzoyl}(méthyl)amino]-N-hydroxyl-N',2-diméthyl propane représenté par la formule [1], ou un sel pharmaceutiquement acceptable dudit diamide de 2-[{4-[4-(1-aminocyclopropyl)buta-1,3-diyne-1-yl]benzoyl}(méthyl)amino]-N-hydroxyl-N',2-diméthyl propane.
PCT/JP2014/077750 2013-10-18 2014-10-17 Dérivé d'acide hydroxamique Ceased WO2015056799A1 (fr)

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WO2016039433A1 (fr) * 2014-09-12 2016-03-17 富山化学工業株式会社 Composition pharmaceutique comprenant un nouveau dérivé d'acide hydroxamique ou un sel de celui-ci
JP2017014199A (ja) * 2015-06-30 2017-01-19 富山化学工業株式会社 新規なヒドロキサム酸誘導体の製造方法
CN109311828A (zh) * 2016-06-14 2019-02-05 诺华股份有限公司 作为抗菌剂的(r)-4-(5-(环丙基乙炔基)异噁唑-3-基)-n-羟基-2-甲基-2-(甲基磺酰基)丁酰胺的结晶形式
CN116730870A (zh) * 2023-08-08 2023-09-12 中国医学科学院医药生物技术研究所 异羟肟酸类化合物或其可药用盐、及其用途和制备方法

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WO2011132712A1 (fr) * 2010-04-20 2011-10-27 大正製薬株式会社 Nouveau dérivé d'acide hydroxamique
JP2013100277A (ja) * 2011-10-19 2013-05-23 Taisho Pharmaceutical Co Ltd 新規なヒドロキサム酸誘導体を含有する医薬
WO2013170165A1 (fr) * 2012-05-10 2013-11-14 Achaogen, Inc. Agents antibactériens
WO2014165075A1 (fr) * 2013-03-12 2014-10-09 Achaogen, Inc. Agents antibactériens

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Publication number Priority date Publication date Assignee Title
JP2010530372A (ja) * 2007-06-12 2010-09-09 アカオゲン，インコーポレーテッド 抗菌剤
WO2011132712A1 (fr) * 2010-04-20 2011-10-27 大正製薬株式会社 Nouveau dérivé d'acide hydroxamique
JP2013100277A (ja) * 2011-10-19 2013-05-23 Taisho Pharmaceutical Co Ltd 新規なヒドロキサム酸誘導体を含有する医薬
WO2013170165A1 (fr) * 2012-05-10 2013-11-14 Achaogen, Inc. Agents antibactériens
WO2014165075A1 (fr) * 2013-03-12 2014-10-09 Achaogen, Inc. Agents antibactériens

Cited By (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2016039433A1 (fr) * 2014-09-12 2016-03-17 富山化学工業株式会社 Composition pharmaceutique comprenant un nouveau dérivé d'acide hydroxamique ou un sel de celui-ci
US10149911B2 (en) 2014-09-12 2018-12-11 Toyama Chemical Co., Ltd. Pharmaceutical composition containing hydroxamic acid derivative or salt thereof
JP2017014199A (ja) * 2015-06-30 2017-01-19 富山化学工業株式会社 新規なヒドロキサム酸誘導体の製造方法
CN109311828A (zh) * 2016-06-14 2019-02-05 诺华股份有限公司 作为抗菌剂的(r)-4-(5-(环丙基乙炔基)异噁唑-3-基)-n-羟基-2-甲基-2-(甲基磺酰基)丁酰胺的结晶形式
CN116730870A (zh) * 2023-08-08 2023-09-12 中国医学科学院医药生物技术研究所 异羟肟酸类化合物或其可药用盐、及其用途和制备方法
CN116730870B (zh) * 2023-08-08 2023-10-13 中国医学科学院医药生物技术研究所 异羟肟酸类化合物或其可药用盐、及其用途和制备方法

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