US20100063117A1 - Novel oxazolidinone derivative with difluorophenyl moiety, pharmaceutically acceptable salt thereof, preparation method thereof and antibiotic composition containing the same as an active ingredient - Google Patents
Novel oxazolidinone derivative with difluorophenyl moiety, pharmaceutically acceptable salt thereof, preparation method thereof and antibiotic composition containing the same as an active ingredient Download PDFInfo
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- US20100063117A1 US20100063117A1 US12/313,625 US31362508A US2010063117A1 US 20100063117 A1 US20100063117 A1 US 20100063117A1 US 31362508 A US31362508 A US 31362508A US 2010063117 A1 US2010063117 A1 US 2010063117A1
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Classifications
-
- 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
- C07D413/10—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 aromatic rings
-
- 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
- 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
Definitions
- the present invention relates to novel oxazolidinone derivatives with a difluorophenyl moiety, pharmaceutically acceptable salts thereof, a method for preparing the same, and an antibiotic composition containing the same as an active ingredient.
- MRSA methicillin-resistant Staphylococcus aureus
- the antibiotic activity of the oxazolidinone class compounds was first discovered by researchers at E.I. DuPont. This company synthesized the oxazolidinone compounds in 1987 and reported that Dup-721 showed inhibitory activity against Gram-negative anaerobes and Mycobacterium tuberculosis as well as gram-positive strains including MRSA and MRSE.
- the present invention provides a novel oxazolidinone derivative with a difluorophenyl moiety, represented by the following Chemical Formula 1, and a pharmaceutically acceptable salt thereof
- R is hydroxy, amino, halogen, hydrazine, hydroxylamine, an alkyloxyimine of C 1 ⁇ C 4 or allyloxyimine
- the present invention provides a method for preparing the oxazolidinone derivative.
- the present invention provides an antibiotic composition containing the oxazolidinone derivative or a pharmaceutically acceptable salt thereof as an active ingredient.
- the present invention provides a novel oxazolidinone derivative having a difluorophenyl moiety, represented by the following Chemical Formula 1.
- R is hydroxy, amino, halogen, hydrazine, hydroxyimine, an alkyloxyimine of C 1 ⁇ C 4 , or allyloxyimine.
- R is hydroxy, amino, fluoro, chloro, bromo, hydrazine, hydroxyimine, methoxyimine, ethoxyimine, propoxyimine, isopropoxyimine, butoxyimine, isobutoxyimine or allyloxyimine.
- the oxazolidinone derivatives according to the present invention may be used in the form of pharmaceutically acceptable salts.
- these salts are included, for example, acid addition salts formed with pharmaceutically acceptable free acids.
- free acids non-toxic inorganic acids such as hydrochloric acid, bromic acid, sulfonic acid, phosphoric acid, etc.
- non-toxic organic acids such as citric acid, acetic acid, lactic acid, maleic acid, fumaric acid, gluconic acid, methanesulfonic acid, glycolic acid, succinic acid, tartaric acid, 4-toluenesulfonic acid, galucturonic acid, embonic acid, glutamic acid, aspartic acid, etc. are useful, with preference for hydrochloric acid or methanesulfonic acid.
- the acid addition salts of the compounds according to the present invention may be prepared using a typical method, for example, by dissolving the compound of Chemical Formula 1 in a water-miscible organic solvent, e.g., acetone, methanol, ethanol, or acetonitrile, adding excess organic acid or excess inorganic acid in water thereto to form precipitates or crystals. Subsequently, the solvent or excess acid is evaporated, followed by drying or suction filtering the precipitates to prepare acid addition salts thereof.
- a water-miscible organic solvent e.g., acetone, methanol, ethanol, or acetonitrile
- the present invention provides a method for preparing the novel oxazolidinone derivative.
- the method for preparing the novel oxazolidinone derivative of the present invention as illustrated in Reaction Scheme 1, comprises:
- the method according to the present invention may further comprise:
- the method according to the present invention may further comprise:
- Step 9′ Reacting the compound of Chemical Formula 11 with an amine chloride salt to give a compound of Chemical Formula 1c (Step 9′) after Step 8.
- the method may further comprises:
- Step 10′ Reacting a nucleophile with the compound of Chemical Formula 1c in the presence of a base to give a compound of Chemical Formula 1d (Step 10′) after Step 9′.
- R′′ is a C 1 ⁇ C 4 alkyl or allyl, and the compounds of Chemical Formulas 1c and 1d are included within the range of Chemical Formula 1).
- Step 1 the compound of Chemical Formula 2 is reacted with the trifluoronitrobenzene compound of Chemical Formula 3 to produce the compound of Chemical Formula 4.
- the compound of Chemical Formula 2 and 3,4,5-trifluoronitrobenzene are refluxed for 3 hours in acetonitrile to obtain the compound of Chemical Formula 4.
- Step 3 is designed to introduce a carbobenzyloxy (CBZ) group onto the amine group of the compound of Chemical Formula 5, obtained in Step 2, so as to produce the compound of Chemical Formula 6.
- the compound of Chemical Formula 5 is dissolved in acetone and mixed with a sodium hydrogen carbonate solution, after which benzylchloroformate is dropwise added to the reaction mixture in an ice bath to afford the compound of Chemical Formula 6.
- Step 4 uses n-butyl lithium and (R)-glycidyl butyrate in producing an oxazolidinone moiety of Chemical Formula 7 from the compound of Chemical Formula 6, obtained in Step 3.
- n-butyl lithium is dropwise added to a solution of the compound of Chemical Formula 6 in tetrahydrofuran at ⁇ 78° C., followed by the addition of (R)-glycidyl butyrate thereto. While the temperature is elevated to room temperature, the reaction proceeds to form the oxazolidinone moiety of Chemical Formula 7.
- the hydroxy group of the compound of Chemical Formula 7, obtained in Step 4 is mesylated to the compound of Chemical Formula 8 in Step 5.
- the compound of Chemical Formula 7 is reacted with mesyl chloride in the presence of triethyl amine in methylene chloride to give the compound of Chemical Formula 8.
- Step 7 the compound of Chemical Formula 9, obtained in Step 6, is reduced and then acetylated to the compound of Chemical Formula 10.
- the compound of Chemical Formula 9 is reduced in the presence of Pd/C in an H 2 atmosphere, followed by acetylation with pyridine and anhydrous acetic acid to produce the compound of Chemical Formula 10.
- Step 8 is deprotection of the compound of Chemical Formula 10, obtained in Step 7, forming the compound of Chemical Formula 11.
- the compound of Chemical Formula 10 is dissolved in p-toluene sulfonic acid monohydrate and refluxed for 3 hours to give the compound of Chemical Formula 11.
- Step 8 reduction is performed on the compound of Chemical Formula 11 obtained in Step 8 to give the compound of Chemical Formula 1a.
- the oxo group of the compound of Chemical Formula 11 is reduced to the hydroxy group of the compound of Chemical Formula 1a.
- the compound of Chemical Formula 1a obtained in Step 9 is halogenated or aminated to the compound of Chemical Formula 1b.
- DAST may be used to substitute the hydroxy group of the compound of Chemical Formula 1a with a fluoro group.
- the hydroxy group of the compound of Chemical Formula 1a may be mesylated by reaction with amine and mesyl chloride, then azidated with sodium azide, and then reduced to an amine in the presence of palladium.
- Step 9′ the compound of Chemical Formula 11 obtained in Step 8 is reacted with an amine chloride salt to produce the compound of Chemical Formula 1c.
- the compound of Chemical Formula 11 may be dissolved in ethanol, mixed with a 50% aqueous hydroxylamine solution, sodium ethoxide and water, and refluxed for 5 hours to give the hydroxyimine compound.
- the compound of Chemical Formula 11 may be dissolved in methanol and reacted with a 30 ⁇ 35% methoxylamine chloride salt and triethyl amine at room temperature for 10 hours with stirring to give a methoxyimine compound.
- the compound of Chemical Formula 11 is reacted with hydrazine chloride in the presence of triethyl amine in ethanol to afford a hydrazine compound.
- Step 10′ the compound of Chemical Formula 1c obtained in Step 9′ is used as a nucleophile to conduct a nucleophilic substitution in the presence of a base, leading to the compound of Chemical Formula 1d.
- the compound of Chemical Formula 1c is a hydroxyimine compound, it is reacted with ethyl bromide or allyl bromide in the presence of potassium hydroxide to give an ethoxyimine compound or allyloxyimine compound.
- the present invention provides an antibiotic composition containing the oxazolidinone derivative or a pharmaceutically acceptable salt thereof as an active ingredient.
- the present invention provides a method for the treatment of bacterial diseases by administering an oxazolidinone derivative represented by Chemical Formula 1 or a pharmaceutically acceptable salt thereof at a therapeutically effective dose to a subject in need thereof.
- the present invention provides a method for killing a bacterial strain infecting a subject, comprising administering the oxazolidinone derivative represented by Chemical Formula 1 or a pharmaceutically acceptable salt thereof at a therapeutically effective dose to a subject in need thereof.
- the oxazolidinone derivatives or pharmaceutically acceptable salts thereof, useful as active ingredients in the antibiotic composition according to the present invention were found to have anti-bacterial activity as potent as or more potent than that of the commercially available antibiotic Linezolid as they were measured to range in MIC from 0.781 to 3.125 mg/ml in an in vitro assay. Particularly, they showed an MIC of 0.781 mg/ml against Gram-positive bacteria including Haemophilus influenza and non-pathogenic Coagulase negative staphylococci as well as resistant bacteria including vancomycin resistant enterococci (VRE), which has a higher inhibitory activity to Linezolid (MIC, 1.563 ⁇ 3.125 mg/ml) (see Table 2). Accordingly, the oxazolidinone derivatives according to the present invention are useful as novel antibiotics.
- the pharmaceutical composition containing the oxazolidinone derivative or a pharmaceutically acceptable salt thereof in accordance with the present invention may be formulated into the following oral or non-oral dosage forms, but are not limited thereto.
- Oral dosage preparations of the compounds of the present invention may take the form of tablets, pills, hard/soft capsules, solutions, suspensions, emulsions, syrups, granules, elixirs and the like.
- These dosage forms may comprise diluents (e.g., lactose, dextrose, sucrose, manitol, sorbitol, cellulose and/or glycine), lubricants (e.g., silica, talc, stearic acid and magnesium or calcium salts thereof, and/or polyethylene glycol) in addition to the active ingredient.
- diluents e.g., lactose, dextrose, sucrose, manitol, sorbitol, cellulose and/or glycine
- lubricants e.g., silica, talc, stearic acid and magnesium or calcium salts thereof, and/or polyethylene glycol
- tablets may further comprise a binder, such as magnesium aluminum silicate, starch paste, gelatin, methyl cellulose, sodium carboxymethyl cellulose, and/or polyvinylpyrrolidone, and optionally a disintegrant such as starch, agar, alginic acid or sodium salts thereof or an effervescent mixture and/or an adsorbent, a colorant, a flavor, and a sweetener.
- a binder such as magnesium aluminum silicate, starch paste, gelatin, methyl cellulose, sodium carboxymethyl cellulose, and/or polyvinylpyrrolidone
- a disintegrant such as starch, agar, alginic acid or sodium salts thereof or an effervescent mixture and/or an adsorbent, a colorant, a flavor, and a sweetener.
- the pharmaceutical composition containing the derivative of Chemical Formula 1 as an active ingredient may be administered in a non-oral manner.
- Non-oral dosage forms may be injections via subcutaneous, intravenous, intramuscular, or intrathoracic routes.
- non-oral dosage forms they may be prepared by mixing the oxazolidinone derivative of Chemical Formula 1 or pharmaceutically acceptable salt thereof with a stabilizer or buffer in water and loading the solution or suspension onto ampule or vial unit forms.
- the composition intended for oral or non-oral administration is sterilized or sterile and may comprise auxiliary agents such as preservatives, stabilizers, wettable powders or emulsifying agents, osmosis-adjusting salts, and/or buffers, and other therapeutically useful agents. It may be formulated using admixture, granulation or coating methods.
- the effective dosage of the active ingredient in accordance with the present invention depends on various factors, including the patient's age, weight, gender, route of administration, state of health, severity of diseases, etc.
- the compound according to the present invention may be administered at a daily dose ranging from 0.01 to 1,000 mg and preferably from 1 to 500 mg for 70 kg adult patients.
- the compound may be administered in a single dose or may be divided into multiple doses per day according to the instructions of a physician or pharmacist.
- Steps 2 ⁇ 3 Preparation of N-carbobenzyloxy-[3,5-difluoro-4-(7,7-ethylenedioxy-5-azaspiro[2,4]heptan-5-yl)phenyl]aniline
- Step 4 Preparation of (R)- ⁇ N-3-[3,5-difluoro-4-(7,7-ethylenedioxy-5-azaspiro[2,4]heptan-5-yl)phenyl]-2-oxo-5-oxazolidinyl ⁇
- the reaction mixture was mixed with a saturated aqueous ammonium chloride solution (10 mL) and then extracted with ethyl acetate and water.
- Step 5 Preparation of (R)- ⁇ N-3-[3,5-difluoro-4-(7,7-ethylenedioxy-5-azaspiro[2,4]heptan-5-yl)phenyl]-2-oxo-5-oxazolidinyl ⁇ methyl methanesulfonate
- Step 6 Preparation of (R)- ⁇ N-3-[3,5-difluoro-4-(7,7-ethylenedioxy-5-azaspiro[2,4]heptan-5-yl)phenyl]-2-oxo-5-oxazolidinyl ⁇ methyl azide
- Step 7 Preparation of (S)—N- ⁇ 3-[3,5-difluoro-4-(7,7-ethylenedioxy-5-azaspiro[2,4]heptan-5-yl)phenyl]-2-oxo-5-oxazolidinyl ⁇ methyl ⁇ acetamide
- the reaction mixture was added with pyridine (0.2 mL, 1.9 mmol) and anhydrous acetic acid (0.5 mL, 5.3 mmol) and stirred at 0° C. for 30 min and then at room temperature for 2 hours.
- pyridine 0.2 mL, 1.9 mmol
- anhydrous acetic acid 0.5 mL, 5.3 mmol
- Step 8 Preparation of (S)—N- ⁇ 3-[3,5-difluoro-4-(7-oxo-5-azaspiro[2,4]heptan-5-yl)phenyl]-2-oxo-5-oxazolidinyl ⁇ methyl ⁇ acetamide
- Step 9 Preparation of (S)—N- ⁇ 3-[3,5-difluoro-4-(7-hydroxy-5-azaspiro[2,4]heptan-5-yl)phenyl]-2-oxo-5-oxazolidinyl ⁇ methyl ⁇ acetamide
- this purified compound (0.6 g, 1.6 mmol) was dissolved in ethyl acetate (15 mL) and mixed with 10% palladium-charcoal (30 mg) before stirring at room temperature for 14 hours under 1 atm of H 2 .
- the solvent was removed by vacuum distillation.
- the reducing atmosphere was changed to a nitrogen atmosphere, after which to the reaction mixture were added pyridine (0.2 mL, 1.9 mmol) and anhydrous acetic acid (0.5 mL, 5.3 mmol) with stirring at 0° C. for 30 min and then stirring at room temperature for 2 hours.
- oxazolidinone derivatives according to the present invention were assayed for inhibitory activity against various bacteria as described in the following.
- Example 2 the compound of Example 2 and the currently used oxazolidinone class Linezolid were examined for minimal inhibitory concentration (hereinafter, referred to as “MIC”) against Gram-positive strains and resistant bacteria including methicillin-resistant Staphylococcus aureus (MRSA) and vancomycin resistant enterococci by an agar dilution method using Muller-Hinton agar.
- MRSA methicillin-resistant Staphylococcus aureus
- MRSA methicillin-resistant Staphylococcus aureus
- vancomycin resistant enterococci by an agar dilution method using Muller-Hinton agar.
- MIC is intended to refer to the lowest concentration of an antibiotic that will inhibit the growth of a microorganism. MIC values are expressed as ⁇ g/ml.
- Bacterial strains used for this assay included Haemophilus influenza , Coagulase negative staphylococi, Staphylococcus aureus (MRSA), Enterococcus faecalis (VER), Enterococcus faecium (VR 1, VR 2), and Vancomycin resistant enterococci 1 ⁇ 6.
- Example Strains Linezolid
- Example 2 a 3.125 0.781 b 3.125 0.781 c 1.563 1.563 d 1.563 1.563 e 1.563 1.563 f 1.563 1.563 1.563 g 1.563 3.125 h 1.563 1.563 i 1.563 3.125 j 1.563 0.781 k 1.563 0.781 l 1.563 0.781 a: Haemophilus infuenz ) b: Coagulase negative staphylococi ) c: Staphylcoccus aureus (MRSA)) d: Enterococcus faecalis (VRE) e: Enterococcus faecium (VR 1) f: Enterococcus faecium (VR 2) g: Vancomycin resistant enterococci 1 h: Vancomycin resistant enterococci 2 i: Vancomycin resistant enterococci 3 j: Vancomycin resistant enterococci 4
- the oxazolidinone derivative according to the present invention was found to have to have anti-bacterial activity as potent as or more potent than that of the commercially available antibiotic Linezolid because its MIC was within the range of 0.781 ⁇ 3.125 mg/ml.
- the oxazolidinone derivative according to the invention showed an MIC of 0.781 mg/ml against Gram-positive bacteria including Haemophilus influenza and non-pathogenic Coagulase negative staphylococci as well as resistant bacteria including vancomycin resistant enterococci (VRE), which is superior in inhibitory activity to Linezolid (MIC: 1.563 ⁇ 3.125 mg/ml). Accordingly, the oxazolidinone derivatives according to the present invention are useful as novel antibiotics.
- dosages of the oxazolidinone derivatives of Chemical Formula 1 according to the present invention may be formulated in various forms. Formulation examples are given to illustrate dosage preparations containing the compounds of Chemical Formula 1 as active ingredients and not to limit the scope of the present invention.
- the oxazolidinone derivatives or pharmaceutically acceptable salts thereof in accordance with the present invention are usable as an active ingredient for antibiotics.
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US12/277,364 US8168797B2 (en) | 2008-09-16 | 2008-11-25 | Oxazolidinone derivative with difluorophenyl moiety, pharmaceutically acceptable salt thereof, preparation method thereof and antibiotic composition containing the same as an active ingredient |
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KR1020080090659A KR100980681B1 (ko) | 2008-09-16 | 2008-09-16 | 디플루오로페닐 유도체를 갖는 신규한 옥사졸리디논 유도체또는 이의 약학적으로 허용가능한 염, 이의 제조방법 및 이를 유효성분으로 하는 항생제 조성물 |
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US12/277,364 Expired - Fee Related US8168797B2 (en) | 2008-09-16 | 2008-11-25 | Oxazolidinone derivative with difluorophenyl moiety, pharmaceutically acceptable salt thereof, preparation method thereof and antibiotic composition containing the same as an active ingredient |
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CN114957292A (zh) * | 2022-05-11 | 2022-08-30 | 江苏医药职业学院 | (±)-Peharmaline A衍生物及制备方法和应用 |
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CA2990260A1 (en) * | 2015-07-17 | 2017-01-26 | The Global Alliance For Tb Drug Development, Inc. | Substituted phenyloxazolidinones for antimicrobial therapy |
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GB9702213D0 (en) * | 1996-02-24 | 1997-03-26 | Zeneca Ltd | Chemical compounds |
NZ505902A (en) | 1998-01-23 | 2003-08-29 | Upjohn Co | Oxazolidinone compounds useful as antimicrobial agents and combinatorial libraries |
KR100638288B1 (ko) | 1999-12-15 | 2006-10-25 | 동아제약주식회사 | 옥사졸리디논 유도체 및 그 제조방법 |
JP2004518677A (ja) | 2000-12-21 | 2004-06-24 | ファルマシア・アンド・アップジョン・カンパニー | 抗菌性キノロン誘導体および細菌感染を治療するためのその使用 |
KR100490643B1 (ko) * | 2002-10-29 | 2005-05-19 | 한국과학기술연구원 | 새로운 메틸리덴 피페리딘일 옥사졸리딘온 유도체 및이들의 제조방법 |
KR20060033300A (ko) | 2004-10-14 | 2006-04-19 | 일동제약주식회사 | 신규 옥사졸리디논 유도체 및 그 제조방법 |
WO2007093904A1 (en) | 2006-02-14 | 2007-08-23 | Pfizer Products Inc. | Benzoxazinone and benzoxazepinone oxazolidinones as antibacterial agents |
US8288416B2 (en) | 2006-09-25 | 2012-10-16 | Wockhardt Ltd. | Substituted piperidinophenyl oxazolidinones |
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- 2008-11-13 WO PCT/KR2008/006688 patent/WO2010032901A1/en active Application Filing
- 2008-11-20 US US12/313,625 patent/US20100063117A1/en not_active Abandoned
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KR100980681B1 (ko) | 2010-09-07 |
KR20100031837A (ko) | 2010-03-25 |
WO2010032901A1 (en) | 2010-03-25 |
US20100069449A1 (en) | 2010-03-18 |
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