WO2007095784A1 - Dérivés d'oxazolidinone contenant du triazolyle, procédé de préparation et utilisations de ceux-ci - Google Patents

Dérivés d'oxazolidinone contenant du triazolyle, procédé de préparation et utilisations de ceux-ci Download PDF

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Publication number
WO2007095784A1
WO2007095784A1 PCT/CN2006/000662 CN2006000662W WO2007095784A1 WO 2007095784 A1 WO2007095784 A1 WO 2007095784A1 CN 2006000662 W CN2006000662 W CN 2006000662W WO 2007095784 A1 WO2007095784 A1 WO 2007095784A1
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WO
WIPO (PCT)
Prior art keywords
group
phenyl
acid
fluoro
piperazinyl
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Application number
PCT/CN2006/000662
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English (en)
Chinese (zh)
Inventor
Yushe Yang
Houxing Fan
Kaixian Chen
Ruyun Ji
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Shanghai Institute Of Materia Medica, Chinese Academy Of Sciences
Nanjing Changao Pharmaceutical Science & Technology Co., Ltd.
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Application filed by Shanghai Institute Of Materia Medica, Chinese Academy Of Sciences, Nanjing Changao Pharmaceutical Science & Technology Co., Ltd. filed Critical Shanghai Institute Of Materia Medica, Chinese Academy Of Sciences
Publication of WO2007095784A1 publication Critical patent/WO2007095784A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/06—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a carbon chain containing only aliphatic 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
    • 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

Definitions

  • the invention belongs to the field of pharmacy, relates to the field of medicinal chemistry and pharmacology, and more particularly to an oxazolidinone compound containing a triazozolyl group, a preparation method thereof and a preparation for treating an infectious disease, in particular, a multidrug resistance Use in medicines for infectious diseases caused by drug bacteria. Background technique
  • MRSA methicillin-resistant Staphylococcus aureus
  • MRSE Staphylococcus epidermidis
  • VRE vancomycin-resistant enterococci
  • Oxazolidinone is a new class of antibacterial drugs, which are resistant to multi-drug resistant Gram-positive bacteria, such as methicillin-resistant Staphylococcus aureus, vancomycin-resistant Staphylococcus aureus, vancomycin-resistant Enterococcus, penicillin-resistant Streptococcus pneumoniae, and sensitive Gram-positive bacteria all have reluctant antibacterial activity (Angew. Chem. Int. Ed., 2003, 42: 2010; Current Topics in Medicinal Chemistry, 2003) , 3: 1021 ).
  • the initial stage of inhibition of bacterial protein synthesis by oxazolidinone is different from the new structure and unique antibacterial mechanism of existing antibiotics, which has attracted the attention of many pharmaceutical companies (Bioorg. & Med. Chem.
  • Oxazolidinone may develop into the third major class of synthetic resistance after sulfa drugs and quinolones Bacterial drugs, the current research focus is to find new structural compounds with broader antibacterial spectrum, stronger antibacterial activity and less side reactions.
  • An object of the present invention is to provide a novel triazozolyl-containing oxazolidinone compound having an antibacterial activity, particularly an activity against multidrug-resistant bacteria, or a pharmaceutically acceptable salt thereof.
  • Another object of the present invention is to provide a process for producing a novel triazozolyl-containing oxazolidinone compound or a pharmaceutically acceptable salt thereof having antibacterial activity, particularly against multidrug resistance bacteria.
  • Still another object of the present invention is to provide a triazole-containing oxazolidinone compound or a pharmaceutically acceptable salt thereof for the preparation of a medicament for treating an infectious disease, particularly a multidrug-resistant infectious disease caused by an infectious disease Application in .
  • the present invention provides a triazolozolyl-containing oxazolidinone compound having the following structural formula (I): or a pharmaceutically acceptable salt thereof:
  • n is an integer from 1 to 3;
  • n is an integer of 1-2;
  • R 3 is a pit-based or substituted alkyl group, an aryl group or a substituted aryl group, an aromatic heterocyclic group or a substituted aromatic heterocyclic group.
  • the present invention provides a method for preparing a triazole-containing oxazolidinone compound of the formula (II),
  • the method comprises: (R)-3-(3-fluoro-4-piperidylphenyl)-5-(1,2,3-triazole-1-ylindenyl) in a polar aprotic solvent
  • the oxazolidin-2-one hydrochloride is reacted with R 3 CHO to give a triazazolyl-containing oxazolidinone compound of the formula (II); wherein the definition is as described above;
  • triazazolyl-containing oxazolidinone compound of the formula (II) obtained according to the above process of the present invention, wherein the reactive functional group thereon can be further subjected to a reduction reaction of a nitro group, a catalytic hydrogenation of a benzyloxy group, an aldehyde group
  • a reduction reaction of a nitro group, a catalytic hydrogenation of a benzyloxy group, an aldehyde group an aldehyde group
  • triazazolyl-containing oxazolidinone compounds of the present invention are derived by reductive amination of various secondary amines, reduction of aldehyde groups, and aldehyde group formation.
  • the triazinyl-containing oxazolidinone compound of the formula (I) of the present invention or a pharmaceutically acceptable compound thereof has excellent in vitro and in vivo antibacterial activity and drug metabolism characteristics, and can be used for the preparation of a treatment for infectious diseases, In particular, drugs for infectious diseases caused by multidrug-resistant bacteria.
  • the oxazolidinone compound or a pharmaceutically acceptable salt thereof according to the present invention may reduce the inhibitory activity of the acetamidooxazolidinone compound at the C-5 position on MAO-A, thereby reducing the activity Clinical side effects of drugs.
  • the alkyl group represents a saturated or unsaturated, substituted or unsubstituted linear or branched alkyl group, and specifically may, for example, be a methyl group, an ethyl group, a propyl group, an isopropyl group, a butyl group or an isobutyl group.
  • an alkyl group having 1 to 4 carbon atoms such as a methyl group, an ethyl group, a propyl group, an isopropyl group or a butyl group is preferable, and a mercapto group, an ethyl group or a propyl group is more preferable, and most preferably Mercapto or ethyl.
  • Aryl means an aromatic hydrocarbon group, preferably an aryl group of 6 to 14 carbon atoms, specifically a phenyl group, a tolyl group, a xylyl group, a biphenyl group, a naphthyl group, an anthracenyl group, a fluorenyl group or a phenanthryl group, Phenyl or naphthyl is preferred, and phenyl is most preferred.
  • Aromatic heterocyclic group means a five- or six-membered heteroaryl group containing from 1 to 4 hetero atoms selected from an oxygen atom, a nitrogen atom or a sulfur atom, for example, a furyl group, a thiop group, a pyrrolyl group, a mercapyl group. , thiazide, pyrazolyl, isothiazolyl, isoxazolyl, pyridyl, pyrimidinyl, pyridazinyl, pyrazinyl, triazolyl, tetrazolyl, and the like.
  • a thienyl group, a furyl group, a pyridyl group, an oxazolyl group, an isoxazolyl group or a thiazolyl group is preferred, and a thienyl group, a furyl group or a pyridyl group is more preferred.
  • Substituted alkyl group means that the above “alkyl group”, “aryl group” and “aromatic heterocyclic group” are optionally selected from a halogen atom.
  • alkyl, alkoxy, acyloxy, -OH, - Li 2, -N0 2, - HAc, -CH 2 R4R 5, -03 ⁇ 40, substituted -CH NR 7 group.
  • R 5 are each hydrogen or an alkyl group, or a nitrogen atom together with R 5 To form a 4-10 membered saturated or unsaturated ring system; hydrogen or an alkyl group; and R 7 is a hydroxyl group, an amino group, an alkoxy group or an alkyl group substituted amine group.
  • the trinitrogen-containing 11- seat group of the present invention The pharmaceutically acceptable salt of the oxazolidinone compound, specifically, the above compound and hydrochloric acid, hydrobromic acid, hydrofluoric acid, a salt of an inorganic acid such as nitric acid or phosphoric acid, with citric acid, acetic acid, propionic acid, oxalic acid, malonic acid, succinic acid, fumaric acid, maleic acid, lactic acid, malic acid, tartaric acid, citric acid, picric acid, sulphuric acid An acid addition salt of an acid such as acid or ethanesulfonic acid and an acidic amino acid such as aspartic acid or glutamic acid.
  • the present invention provides a method for preparing a triazazolyl-containing oxazolidinone compound of the formula (II),
  • the method comprises: (R)-3-(3-fluoro-4-piperidinyl)-5-(1,2,3-triazoleindolyl)oxazolidine in a polar aprotic solvent Benzene ketone hydrochloride is reacted with R 3 CHO to obtain a triazazolyl-containing oxazolidinone compound of the formula (II); wherein the definition is as described above;
  • the triazolazole-containing oxazolidinone compound of the present invention is obtained by catalytic hydrogenation, reductive amination of an aldehyde group and various secondary amines, reduction of an aldehyde group, and aldehyde group formation.
  • CBZ is benzyloxyl
  • a represents NaN 3 , DMF, 100 ° C
  • b represents vinyl acetate, 80 ° C
  • c represents H 2 /Pd / C
  • R represents an aryl group which may be substituted or an aromatic heterocyclic group which may be substituted;
  • d represents nitrobenzaldehyde, HC0 2 H, DMF, 100 ° C;
  • e represents H 2 /Pd/C;
  • f represents Substituted benzaldehyde or substituted aromatic heterocyclic formaldehyde, HC0 2 H, DMF, 100 ° C;
  • g represents 5-nitro-2-furanfurfural, Ti (Oipr) 4 , NaB ;
  • h represents benzyl Oxy-substituted benzyl chloride, Et 3 N, DMF;
  • i represents H 2 /Pd/C Fundamental
  • Compound 1-3 is catalytically hydrogenated in a polar solvent in the presence of a metal catalyst to obtain a compound 4-6.
  • the compound 1-3 is a solvent of methylene chloride, methanol, ethanol, tetrahydrofuran or two or more components thereof, and is a catalyst of palladium/carbon or other palladium- or nickel-containing metal catalyst.
  • the optimum conditions for the reaction are catalytic hydrogenation at room temperature and pressure, using a mixed solvent of decyl alcohol and dichlorosilane as a solvent, 5% or 10% palladium on carbon as a catalyst.
  • the solvent of choice is a polar aprotic solvent such as hydrazine, hydrazine-dimethyl phthalamide, hydrazine, hydrazine-diethyl hydrazide, acetonitrile or dimethyl sulfoxide, with triethylamine, pyridine, anhydrous potassium carbonate. Or anhydrous sodium carbonate is a base, and the reaction time is 1-24 hours.
  • the optimum conditions are as follows: hydrazine, hydrazine-dimethylformamide as a solvent, and triethylamine as a reaction for 2 hours.
  • Compounds 20, 21 are catalytically hydrogenated in a polar solvent in the presence of a metal catalyst to give compounds 22, 23.
  • a metal catalyst for example, using dichlorosilane, methanol, ethanol, tetrahydrofuran or two or more components thereof as a solvent, palladium/carbon or other palladium- or nickel-containing metal catalyst as a catalyst, catalytic hydrogenation at normal temperature and pressure Compounds 22, 23 were obtained.
  • the optimum conditions for the reaction are a solvent mixture of decyl alcohol and dichloromethane, 5% or 10% palladium on carbon as a catalyst, normal temperature and pressure. Lower catalytic hydrogenation.
  • a Li, C3 ⁇ 4CN, HCOOH, 80 ° C
  • b NaBH 4 , CH 2 C1 2 , MeOH, rm, 2h
  • c represents NH 2 OH HCl, K 2 C0 3 , CH 2 C1 2 , MeOH, 2h
  • d represents NH 2 NH 2 .H 2 0, con.3 ⁇ 4S0 4 , CH 2 C1 2 , MeOH, 12h.
  • Compound 32 is reacted with hydrazine hydrate in a polar solvent at room temperature to give compound 35.
  • compound 32 is reacted with hydrazine hydrate in a solvent of dichloromethane, decyl alcohol, ethanol, tetrahydrofuran or a combination of two or more of them at -10 ° C to give compound 35.
  • the optimum reaction conditions are as follows: sterol or dichloromethane as a solvent, catalyzed by dilute sulfuric acid, and reacted at room temperature for 12 hours.
  • the corresponding pharmaceutically acceptable salt can be obtained by a conventional pharmaceutically acceptable method.
  • the melting point was measured by a MEL-TEMP melting point apparatus, the thermometer was not corrected; ⁇ - MR was recorded with a Varian Mercury 400 nuclear magnetic resonance apparatus, and the chemical shift was expressed by ⁇ (ppm); the silica gel for separation was not described as 200-300. Head.
  • the procedure of Example 4 gave the product 120 mg, yield 53.5%.
  • Example 11 (R)-N-3-[3-Fluoro-4-[4-(2-thienylmethylene)J piperazinyl]phenyl-5- (1,2,3-tri) Zin-1-ylmethyl)oxazolidin-2-one (11 )
  • Test method The minimum inhibitory concentration (MIC) of the series of compounds of the present invention and the positive control drug vancomycin against the tested strain was determined by agar double dilution method. The bacteria were inoculated on agar flat surface containing different drug concentrations using a multi-point inoculation instrument (Denley A400). The inoculation amount was about 10 6 CFU/ml per point, and the results were aseptically grown at 37 ° C for 18-24 hours. The lowest concentration of the drug contained in the pingya medium is the minimum inhibitory concentration (MIC value) of the drug against the bacterium.
  • MIC minimum inhibitory concentration
  • test strains The test strains used were clinical isolates collected from Sichuan province from December 2002 to February 2004, and were re-identified by conventional methods. The test compound was first added with 2ml of DMSO to help it dissolve well enough, then add sterile double distilled water to the desired concentration; vancomycin can be well dissolved to the desired concentration directly with double distilled water, In the liquid culture JHL, 20 ml of force p was added to the liquid MH medium, and the final concentration of the drug in the culture was 8, 4, 2, 0.002, 0.001, 0.0005 ug/mL.
  • the positive control group was LZ and vancomycin.
  • Staphylococcus aureus 10 strains include MSSA 5 forest, MRSA 3 strains.
  • the bacteria used to infect animals are Staphylococcus aureus 05-02, which is a clinical isolate of pathogenic bacteria collected from Chengdu in 2004-2005 and re-identified by API method.
  • mice Healthy Kunming mice were selected as SPF grade, weighing 18-22 g, male and female, provided by the Animal Breeding Laboratory of Sichuan Antibiotic Industry Research Institute. Animal Qualification Certificate No.: No. 005.
  • mice were orally administered orally or intravenously with different concentrations of the test solution, 0.5 ml/20 g per mouse.
  • Mice orally administered with the mice were intragastrically administered 4 hours after the first administration, and observed after administration, and the death of the mice was recorded.
  • the infection control group was set, and the number of mouse deaths within seven days after infection was recorded.
  • test compound has a good therapeutic effect on mice infected with Staphylococcus aureus, and its in vivo efficacy is similar to or better than that of LZ and vancomycin.
  • Bacterial compound administration route ED 50 (mg/kg) 95% confidence limit Staphylococcus aureus 2 po 7.87 05-2 iv 11.21 7.30 ⁇ 168.99
  • test compound was Compound 2. Each compound uses two kinds of inches'

Abstract

L'invention concerne des dérivés d'oxazolidinone contenant du triazolyle représentés par la formule (I), leurs sels acceptables sur le plan pharmaceutique, un procédé de préparation de ceux-ci et leurs utilisations dans la production d'un médicament pour le traitement de maladies infectieuses, en particulier de maladies infectieuses provoquées par des bactéries multirésistantes aux antibiotiques. Lesdits dérivés d'oxazolidinone contenant du triazolyle de l'invention, ou leurs sels acceptables sur le plan pharmaceutique présentent une excellente activité antibiotique et une excellente activité métabolique in vitro ou in vivo, peuvent réduire l'activité inhibitrice des dérivés de C-5 acetamido oxazolidinone à celle de MAO-A, de façon que les réactions négatives cliniques de ces médicaments soient réduites.
PCT/CN2006/000662 2006-02-20 2006-04-13 Dérivés d'oxazolidinone contenant du triazolyle, procédé de préparation et utilisations de ceux-ci WO2007095784A1 (fr)

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CNB2006100239906A CN100406455C (zh) 2006-02-20 2006-02-20 含三氮唑基的噁唑烷酮类化合物及其制备方法和用途
CN200610023990.6 2006-02-20

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Cited By (2)

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US8841306B2 (en) 2008-11-20 2014-09-23 Panacea Biotec Ltd. Antimicrobials
US8906913B2 (en) 2009-06-26 2014-12-09 Panacea Biotec Limited Azabicyclohexanes

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Publication number Priority date Publication date Assignee Title
CN114105857B (zh) * 2020-08-31 2023-09-29 合肥师范学院 3-叠氮二氢吲哚化合物及其制备方法

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WO2006035283A1 (fr) * 2004-09-27 2006-04-06 Ranbaxy Laboratories Limited Derives d'oxazolidinone a activite antimicrobienne

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CA2411859A1 (fr) * 2000-06-05 2001-12-13 Jae-Gul Lee Nouveaux derives oxazolidinone et processus de preparation de ces derives
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WO2001081350A1 (fr) * 2000-04-25 2001-11-01 Astrazeneca Ab Derives d'oxazolidinone ayant une activite antibiotique
WO2006035283A1 (fr) * 2004-09-27 2006-04-06 Ranbaxy Laboratories Limited Derives d'oxazolidinone a activite antimicrobienne

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Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US8841306B2 (en) 2008-11-20 2014-09-23 Panacea Biotec Ltd. Antimicrobials
US8906913B2 (en) 2009-06-26 2014-12-09 Panacea Biotec Limited Azabicyclohexanes

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CN100406455C (zh) 2008-07-30

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