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EP0648119A1 - UTILISATION DE 5'-INDOLINYLOXAZOLIDINONES CONTRE LE $i(MYCOBACTERIUM TUBERCULOSIS) - Google Patents

UTILISATION DE 5'-INDOLINYLOXAZOLIDINONES CONTRE LE $i(MYCOBACTERIUM TUBERCULOSIS)

Info

Publication number
EP0648119A1
EP0648119A1 EP93914058A EP93914058A EP0648119A1 EP 0648119 A1 EP0648119 A1 EP 0648119A1 EP 93914058 A EP93914058 A EP 93914058A EP 93914058 A EP93914058 A EP 93914058A EP 0648119 A1 EP0648119 A1 EP 0648119A1
Authority
EP
European Patent Office
Prior art keywords
indolinyl
oxazolidinone
mixture
acetamidomethyl
tuberculosis
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.)
Withdrawn
Application number
EP93914058A
Other languages
German (de)
English (en)
Inventor
Steven Joseph Brickner
Gary Edward Zurenko
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.)
Pharmacia and Upjohn Co
Original Assignee
Upjohn Co
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 Upjohn Co filed Critical Upjohn Co
Publication of EP0648119A1 publication Critical patent/EP0648119A1/fr
Withdrawn legal-status Critical Current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
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/42—Oxazoles
    • 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
    • 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
    • A61P31/06—Antibacterial agents for tuberculosis

Definitions

  • the invention is the use of two 5'-indolinyl oxazolidionones (I) to treat tuberculosis
  • Tuberculosis (TB) is a well known disease which is caused by M. tuberculosis.
  • agents are used to treat those infected with TB.
  • the most common of these pharmaceutical agents include isoniazid, rifampin, ethambutol, p-aminosalicylic acid, pyrazinamide, streptomycin, capreomycin, cycloserine, ethionamide and kanamycin and aminoglycosides antibiotics and mixtures thereof.
  • US Patent 4,128,654 discloses 5-halomethylphenyl-2-oxazolidinones which are useful in controlling fungal and bacterial diseases of plants.
  • US Patent 4,250,318 discloses 3-substituted phenyl-5-hydroxymethyloxazolidinones having anti depressive utility.
  • US Reissue Patent 29,607 discloses 3-substituted phenyl-5-hydroxymethyloxazolidinones having antidepressive, tranquilizing and sedative utility.
  • US Patent 4,340,606 discloses 3-(p-alkylsulfonyl)phenyl-5-(hydroxymethyl or acyloxymethyl)oxazolidinones having antibacterial activity in mammals.
  • Belgium Patent 892,270 discloses 3-(arylalkyl, arylalkenyl or arylacetylenic substituted)phenyl)-5-(aminomethyl)oxazolidinones which are inhibitors of monoamine oxidase.
  • US Patent 4,461,773 discloses 3-substituted phenyl-5-hydroxymethyloxazolidinones which have antibacterial activity.
  • European Patent Publications 127,902 and 184,170 disclose 3-substituted phenyl-5- amidomethyloxazolidinones which have antibacterial utility.
  • Antimicrobial Agents and Chemotherapy 1791 (1987) discusses compounds disclosed in European Patent Publications 127,902 and 184,170, discussed above, and compares these new compounds with known antibiotics.
  • US Patent 4,705,799 discloses aminomethyloxooxazolidinyl benzene derivatives including sulfides, sulfoxides, sulfones and sulfonamides which possess antibacterial activity.
  • US Patent 4,801,600 discloses 6'-indolinyloxazolidinones (where the indolinyl nitrogen is meta to the oxazolidinone nitrogen).
  • DUP-721 is active against tuberculosis.
  • Disclosed is a method of treating humans who have tuberculosis caused by Mycobacterium tuberculosis which comprises admisitration of an effective amount of a 5'- indolinyl oxazolidinone selected from the group consisting of
  • 5 '-indolinyl oxazolidinones are known, see International Publication No. WO90/02744, the compounds of formula (XI).
  • the 5 '-indolinyl oxazolidinones contain an asymmetric center and therefore produce two enantiomers one "S” and the other "R", either of which can be (+/d) and the other (-/l).
  • (+)-3-(5'-l-Hydroxyacetylindolinyl)-5 ⁇ -(acetamidomethyl)oxazolidin-2-one is known, see International Publication No. WO90/02744, EXAMPLES 122.
  • the antibacterially active form of the compound is the "S" enantiomer and is disclosed in EXAMPLE 150 as obtained by resolution of a racemic mixture.
  • the optically active form was termed 3-(5'-l- hydroxyacetylindolinyl)-5B-(acetamidomethyl)oxazolidin-2-one in International Publication No. WO90/02744.
  • a preferred name is 5-(S)-N-( -hydroxyacetyl-5'-indolinyl)-5- (acetamidomethyl)-2-oxazoIidinone.
  • racemic forms of the oxazolidinones are useful in treating TB, it is highly preferable to use the active enantiomer rather than the racemic form.
  • optically active form can be obtained by resolution of a racemic mixture as set forth in International Publication No. WO90/02744, it is preferred to prepare the desired enantiomer by a stereoselective synthesis.
  • One method to produce 5-(S)-N-(r-hydroxyacetyl-5'-indolix ⁇ yl)-5-(acetamidomethyl)- 2-oxazolidinone is by resolution of the racemic form. Another method is by the process of EXAMPLES 1-9. The preferred method, as discussed below, is by the process of EXAMPLES 14-19.
  • the preferred method of making the optically active is by starting with the known 1- carbo-t-butyloxy-(N :a- ⁇ obenzyloxy)-5-aminoindoline [US Patent 5,164,510, EXAMPLE 11, compound (IV)] in a solution of tetrahydrofuran or ether at -78° under an inert atmosphere, preferrably nitrogen, and treating with n-butyl lithium/hexane, followed by the addition of (R)- glycidyl butyrate and allowing the mixture to warm to 20-25°.
  • This method produces in high yield the optically active 5-hydroxymethyl oxazolidinone having the desired stereochemistry (R), i.e., the 5- ⁇ configuration, see EXAMPLE 14.
  • EXAMPLE 16 discloses that the 5-phthalimidomethyl compound is then treated with a reagent to remove the phthalimide group such as an aqueous solution of methylamine or hydrazine to give the intermediate 5-aminomethyl oxazolidinone.
  • EXAMPLE 17 discloses the removal of the protecting group by the addition of trifluoroacetic acid, either neat, or in methylene chloride, to give the parent indoline oxazolidinone.
  • EXAMPLE 18 discloses acylation on the indoline nitrogen is effected by the addition of benzyloxylacetyl chloride in the presence of triethy.ainine or diisopropylethylamine in methylene chloride or ether, to give the benzyloxyacetylindolinyl compound.
  • Treatment of this compound with hydrogen in the presence of palladium black or palladium charcoal in ethyl acetate or methanol gives (S)-5-acetamidomethyI 3(5'-l-hydroxyacetylindolinyl)- oxazolidinone.
  • EXAMPLE 17 When the product of EXAMPLE 17 is acylated with 2-thiophenecarbonyl chloride (EXAMPLE 20) the product is 5-(S)-N-( 1 '-(2-thiophenecarbonyl)-5 ' -indolinyl)-5- (acet ⁇ midomethyl)-2-oxazolidinone.
  • the 5 '-indolinyl oxazolidinones are administered either parenterally or orally. It is known to those skilled in the art how to formulate the 5 '-indolinyl oxazolidinones into appropriate pharmaceutical dosage forms for oral (tablet, capsule) or parenteral (sterile solution) use utilizing an appropriate solvent such as propylene glycol.
  • the 5 '-indolinyl oxazolidinones are useful in treating tuberculosis in humans infected with strains of M. tuberculosis which are susceptible to these antibiotics.
  • the 5 '-indolinyl oxazolidinones are administered at doses from about 50 to about 3,000 mg/day. It is preferred that the 5 '-indolinyl oxazolidinones are administered at doses of about 100 to about 2,000 mg/day.
  • the 5'-indolinyl oxazolidinones are administered orally and the total daily dose is divided between one to four doses per day.
  • the 5 '-indolinyl oxazolidinones can either be used alone, or used in combination with each other or with other antibiotics as is known to those skilled in the art.
  • Preferred drugs to be used in combination with 5 '-indolinyl oxazolidinones include, but are not limited to, isoniazid, rifampin, ethambutol, p-aminosalicylic acid, pyrazinamide, streptomycin, kanamycin, capreomycin, cycloserine, and ethionamide.
  • TLC refers to thin-layer chromatograph.
  • THF refers to tetrahydrofuran.
  • Saline refers to an aqueous saturated sodium chloride solution.
  • the ratios of solvents used are volume/volume (v/v).
  • the solubility of a solid in a solvent is used the ratio of the solid to the solvent is weight volume (wt v).
  • IR refers to infrared spectroscopy.
  • [ ⁇ ] D 25 refers to the angle of rotation of plant polarized light (specific optical rotation) at 25° with the sodium D line (5893A).
  • MS refers to mass spectrometry expressed as m/e or mass/charge unit.
  • [M + H] + refers to the positive ion of a parent plus a hydrogen atom.
  • El refers to electron impact CI refers to chemical ionization.
  • FAB refers to fast atom bombardment.
  • Pharmaceutically acceptable refers to those properties and/or substances which are acceptable to the patient from a pharmacological ⁇ oxicological point of view and to the manufacturing pharmaceutical chemist from a physical/chemical point of view regarding composition, formulation, stability, patient acceptance and bioavailability.
  • M. tuberculosis refers to Mycobacterium tuberculosis.
  • Triethylamine 45 ml is added to a solution of 5-nitroindoline (42.05 g) in tetrahydrofuran (250 ml) and the mixture cooled to 0°, then a solution of benzyloxyacetyl chloride (48.6 g) in THF (50 ml) is added over 15 min, and the mixture stirred in the ice bath for an additional 1.25 hr, then allowed to warm to 20-25° over 3 hr. Aqueous workup yields a solid which is recrystallized from acetone/water to give the title compound, mp 137-139°.
  • EXAMPLE 2 N-Benzyloxyacetyl-5-amino-indoline (B)
  • N-benzyloxyacetyl-5-nitro-indoline (A, EXAMPLE 1, 12.26 g) in methanol/ethyl acetate (18/82, 1.1 1) under nitrogen is added palladium/charcoal (10%, 1.55 g) and the flask alternately evacuated and filled with hydrogen from a balloon (3 times), then the mixture is allowed to stir at 20-25° for 4 hr. The mixture is degassed and then filtered over diatosnaceous earth,, and the pad washed with ethyl acetate. The filtrate is concentrated to a volume of about 200 ml and a crystalline solid is precipitated, which is collected to give the title compound, mp 105-106°. 3 N-Benzyloxyacetyl-5-[(2'-( ⁇ )-hydroxy-3'-butyrate)propylammo]indoline
  • EXAMPLE 4 5-(R)-N-(l'-rjer ⁇ zyloxyacetyl-5'-indol yl)-5-G3utyryloxymethyl)-2- oxazolidinone (D) To a mixture of N-benzyloxyacetyl-5-[(2'-(R)-hydroxy-3'-butyrate)propylamino]indoline (C, EXAMPLE 3, 5.8 g) in methylene chloride (255 ml) under nitrogen at -15° is added a solution of phosgene in toluene (1.93 M, 8.4 ml), and the mixture is allowed to slowly warm to 0° over 1 hr.
  • d ⁇ sopropylethylamine (5.7 ml) is added in dropwise fashion over 5 min, and the mixture stirred in the ice bath for 50 min, then allowed to warm to 22°, then poured into 1 N hydrochloric acid (50 ml). The layers are separated and the aqueous is extracted with methylene chloride (3 x 25 ml). The combined organic layers are washed successively with (75 ml ea) saturated aqueous sodium bicarbonate, water, and saline, then dried magnesium sulfate, and concentrated under reduced pressure.
  • EXAMPLE 6 5-(R)-N-(l '-benzyloxyacetyl-5 '-indolinyl)-5-(hydroxymethyl)-2- oxazolidinone (E) To a solution of 5-( ⁇ )-N-(r-benzyloxyacetyl-5'-indolinyl)-5-(butytyloxymethyl)-2- oxazolidinone (D, EXAMPLE 5, 0.050 g) in methanol (1 ml) is added sodium methoxide in methanol (25%, 2.5 ⁇ l), and the mixture is stirred at 20° for 1 hr, then the mixture is concentrated to give a residue.
  • EXAMPLE 7 5-(R)-N-r ⁇ benzyloxyacetyl-5'-indolinyl)-5-(azidomethyl)-2- oxazolidin ie (F) Following the general procedure of US Patent 4,801,600 and making non-critical variations, 5-(R)-N-(l '-benzyloxya( ⁇ tyl-5'-indol yl)-5-(hydroxymethyl)-2-oxazolidinone (E, EXAMPLE 6) is converted to the azide by treatment with methanesulfonyl chloride and triethylamine in methylene chloride, followed by displacement with sodium azide in refluxing acetone-water. This is immediately carried into the following reaction.
  • EXAMPLE 8 5-(S)-N-(l '-benzyIoxyacetyl-5 '-indolmyl)-5-(acetamidomethyl)-2- oxazolidinone (H) Following the general procedure of EXAMPLE 2 and making non-critical variations but taking care to monitor the reduction of the azide so that unwanted cleavage of the benzyl group does not take place, 5-( )-N-(r-benzyloxyaceryl-5'-ind ⁇ j ⁇ yl)-5-(azidomethyl)-2-oxazolidinone (F, EXAMPLE 7), is converted into an amine (G) by treatment with palladium/charcoal in 1 arm of hydrogen in ethyl acetate.
  • EXAMPLE 8 is dissolved in ethyl acetate and the mixture purged with nitrogen gas, then palladium/charcoal is added followed by hydrogen (balloon) and the mixture is stirred until TLC analysis shows complete conversion of the starting material. The mixture is filtered over diatomaceous earth, concentrated and the residue is purified by column chromatography on silical gel (methanol/ethyl acetate) to give the title compound.
  • EXAMPLE 10 N-(t-Butyloxycartjonyl)-5-[(2'-Gi)-hydroxy-3'-butyrate)propylamino]- indoline (J) Following the general procedure of EXAMPLE 3 and making non-critical variations but stitfting with N-(t-butyloxycartx)nyl)-5-aminoindoline, the title compound is obtained.
  • EXAMPLE 11 5-(S)-N-(l '-(t-Butyloxyca ⁇ tx)nyl)-5'-indolinyl)-5-(acetamidomethyl)-2- oxazolidinone (K)
  • EXAMPLE 13 5-(S)-N-( 1 '-(2-Thiophenecarbonyl)-5 '-indolinyl)-5-(acetamidomethyl)-2- oxazolidinone (P) Following the general procedure of International Publication No. WO90/02744, EXAMPLE 18, and making non-critical variations and starting with 5(S)-N-(5'-indolinyl)-5- (acetamidomethyl)-2-oxazolidinone (L, EXAMPLE 12) and using the appropriate corresponding acylating agent the title compound is obtained.
  • EXAMPLE 16 (S)-3-(5 '- 1 -(_ ⁇ t -t-butyloxymdolmyl)-5-(acetamidomethyl)-oxazolidin-2- one (K) A mixture of ( ⁇ )-3-(5'-l-ca ⁇ t ⁇ o-t-butyloxyindolmyl)-5- ⁇ h alimidomethyl)-oxazolidin-2- one (EXAMPLE 15, 8.826 g) in absolute ethanol (100 ml) and aqueous methylamine (40%, 50 ml) is heated to reflux under nitrogen for 1.5 hr. The volatiles are then removed by reduced pressure with heat at 0.1 Torr to give a concentrate.
  • Trifluoroacetic acid (5 ml) is added to a mixture of (S)-3-(5'-l-carbo-t- butyloxyindolinyl)-5-(acetamidomethyl)-oxazolidin-2-one (K, EXAMPLE 16, 4.705 g) in methylene chloride (40 ml) at 0° under nitrogen and the ice bath removed. After 4 hour, the mixture is concentrated and methylene chloride (8 ml) and trifluoroacetic acid (7 ml) is added at 20-25°.
  • EXAMPLE 18 (S)-3-(5 * -l-Benzyloxyacetylmdoiinyl)-5-(acetamidomethyl)-oxazolidin-2- one Benzyloxyacetyl chloride (2.27 ml) is added dropwise over 5 min to a mixture of (S)-3- (5'-indolinyl)-5-(acetamidomethyl)-oxazolidin-2-one (L, EXAMPLE 17, 3.445 g) and triethylamine (2.62 ml) in methylene chloride (100 ml) at 0° under nitrogen. The mixture is slowly allowed to come to 20° overnight.
  • a 58 yr old, 80 kg white male seeks medical attention due to an illness characterized by cough, weakness, night sweats and shortness of breath.
  • the patient's chest radiograph shows extensive cavitary disease consistent with a diagnosis of tuberculosis. Sputum cultures are positive for M. tuberculosis, and the organism is found to be resistant to isoniazid, rifampin, and streptomycin.
  • the patient is admitted to the hospital and given 5(S)-N-(l'-hydroxyacetyl-5'- indolinyl)-5-(acetamidomethyl)-2-oxazolidinone orally at a total dosage of 2000 mg/day for 4 weeks. Signs and symptoms of tuberculosis slowly disappear, viable M. tuberculosis organisms are no longer isolated from the patients sputum, and the patients chest radiograph returns to normal. The patient is discharged from the hospital.
  • a 30 yr old, 60 kg black female is diagnosed with pulmonary tuberculosis.
  • Her sputum isolate is determined to be susceptible to both isoniazid and p-aminosalicylic acid. She is treated as an outpatient with a regimen of oral isoniazid and p-aminosalicylic acid, however, returns in 3 weeks because her condition does not improve.
  • a new sputum culture grows M. tuberculosis that is resistant to isoniazid.
  • the patient is given a 5(S)-N-(r-hydroxyacetyl-5'- indolinyl)-5-(acetamidomethyl)-2-oxazolidinone to take orally at a dose of 1000 mg/day for two months, in addition to the other antibiotics.
  • a 36 yr old white male with acquired immune deficiency syndrome presents to his physician with fever, weight loss, and cough.
  • the chest radiograph reveals a focal nidus of infection in the lung.
  • Expectorated sputum is negative for M. tuberculosis, however, a tissue biopsy taken via bronchoscopy contains culturable M. tuberculosis.
  • the patient is placed upon three drug therapy (isoniazid, rifampin, and ethambutol) due to his AIDS condition. The patient initially improves, but then his condition begins to relapse.
  • a new sputum culture indicates the presence of M . tuberculosis that has developed resistance to rifampin, but is susceptible to 5(S)-N-(r-hydroxyacetyl-5'-mdolinyl)-5-(acetamidomethyl)-2- oxazolidinone.
  • the rifampin portion of the regimen is replaced by 5-(S)-N-(l'-hydroxyacetyl-5'- indolinyl)-5-(acetamidomethyl)-2-oxazolidinone given at an oral dose of 1000 mg day.
  • Within 3 weeks the signs and symptoms of tuberculosis are resolved; the patient continues to take the three drug regimen for an additional 8 months.
  • a sputum culture taken post-therapy is negative for M. tuberculosis. The patient is then given isoniazid prophylactically for life to prevent recurrence of the infectioa

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  • Health & Medical Sciences (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Veterinary Medicine (AREA)
  • Public Health (AREA)
  • Chemical & Material Sciences (AREA)
  • General Health & Medical Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Animal Behavior & Ethology (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Organic Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • General Chemical & Material Sciences (AREA)
  • Oncology (AREA)
  • Communicable Diseases (AREA)
  • Epidemiology (AREA)
  • Pulmonology (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Heterocyclic Carbon Compounds Containing A Hetero Ring Having Nitrogen And Oxygen As The Only Ring Hetero Atoms (AREA)

Abstract

Le 5-(S)-N-(1'-hydroxyacétyl-5'-indolinyl)-5-(acétamidométhyl)-2-oxazolidinone et le 5-(S)-N-(1'-(2-thiophènecarbonyl)-5'-indolinyl)-5-(acétamidométhyl)-2-oxazolidinone sont utilisés avantageusement dans le traitement de la tuberculose provoquée par le M. tuberculosis.
EP93914058A 1992-07-08 1993-05-26 UTILISATION DE 5'-INDOLINYLOXAZOLIDINONES CONTRE LE $i(MYCOBACTERIUM TUBERCULOSIS) Withdrawn EP0648119A1 (fr)

Applications Claiming Priority (3)

Application Number Priority Date Filing Date Title
US90938792A 1992-07-08 1992-07-08
US909387 1992-07-08
PCT/US1993/004850 WO1994001110A1 (fr) 1992-07-08 1993-05-26 UTILISATION DE 5'-INDOLINYLOXAZOLIDINONES CONTRE LE $i(MYCOBACTERIUM TUBERCULOSIS)

Publications (1)

Publication Number Publication Date
EP0648119A1 true EP0648119A1 (fr) 1995-04-19

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EP93914058A Withdrawn EP0648119A1 (fr) 1992-07-08 1993-05-26 UTILISATION DE 5'-INDOLINYLOXAZOLIDINONES CONTRE LE $i(MYCOBACTERIUM TUBERCULOSIS)

Country Status (9)

Country Link
EP (1) EP0648119A1 (fr)
JP (1) JPH07508985A (fr)
KR (1) KR950702417A (fr)
AU (1) AU666740B2 (fr)
CA (1) CA2136324A1 (fr)
IL (1) IL106220A0 (fr)
MX (1) MX9303764A (fr)
TW (1) TW260608B (fr)
WO (1) WO1994001110A1 (fr)

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GB9601666D0 (en) * 1996-01-27 1996-03-27 Zeneca Ltd Chemical compounds
GB9702213D0 (en) * 1996-02-24 1997-03-26 Zeneca Ltd Chemical compounds
GB9609919D0 (en) 1996-05-11 1996-07-17 Zeneca Ltd Chemical compounds
GB9717807D0 (en) 1997-08-22 1997-10-29 Zeneca Ltd Chemical compounds
GB9717804D0 (en) 1997-08-22 1997-10-29 Zeneca Ltd Chemical compounds
GB9725244D0 (en) 1997-11-29 1998-01-28 Zeneca Ltd Chemical compounds
KR20010052615A (ko) 1998-06-05 2001-06-25 다비드 에 질레스 옥사졸리디논 유도체, 이것의 제조 방법 및 이것을함유하는 약학 조성물
GB9928568D0 (en) 1999-12-03 2000-02-02 Zeneca Ltd Chemical compounds
GB0009803D0 (en) 2000-04-25 2000-06-07 Astrazeneca Ab Chemical compounds
AR038536A1 (es) 2002-02-25 2005-01-19 Upjohn Co N-aril-2-oxazolidinona-5- carboxamidas y sus derivados
US7141588B2 (en) 2002-02-25 2006-11-28 Pfizer, Inc. N-aryl-2-oxazolidinone-5-carboxamides and their derivatives
ES2258234T3 (es) 2002-08-12 2006-08-16 PHARMACIA & UPJOHN COMPANY LLC N-aril-2-oxazolidinonas y sus derivados.
EP1565186B1 (fr) 2002-11-21 2006-11-02 Pharmacia & Upjohn Company LLC Derives de n-(4-(piperazine-1-yl)-phenyl-2-oxazolidinone-5-carboxamides et composes associes servant d'agents antibacteriens
US7304050B2 (en) 2003-09-16 2007-12-04 Pfizer Inc. Antibacterial agents
JP2023531666A (ja) 2020-06-18 2023-07-25 アカゲラ・メディスンズ，インコーポレイテッド オキサゾリジノン化合物、オキサゾリジノン化合物を含むリポソーム組成物、およびそれらの使用方法

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Also Published As

Publication number Publication date
JPH07508985A (ja) 1995-10-05
TW260608B (fr) 1995-10-21
MX9303764A (es) 1994-01-31
AU666740B2 (en) 1996-02-22
IL106220A0 (en) 1993-11-15
KR950702417A (ko) 1995-07-29
WO1994001110A1 (fr) 1994-01-20
AU4386593A (en) 1994-01-31
CA2136324A1 (fr) 1994-01-20

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