CA2136324A1 - 5'-indolinyl oxazolidinones useful against mycobacterium tuberculosis - Google Patents
5'-indolinyl oxazolidinones useful against mycobacterium tuberculosisInfo
- Publication number
- CA2136324A1 CA2136324A1 CA002136324A CA2136324A CA2136324A1 CA 2136324 A1 CA2136324 A1 CA 2136324A1 CA 002136324 A CA002136324 A CA 002136324A CA 2136324 A CA2136324 A CA 2136324A CA 2136324 A1 CA2136324 A1 CA 2136324A1
- Authority
- CA
- Canada
- Prior art keywords
- indolinyl
- oxazolidinone
- acetamidomethyl
- mixture
- oxazolidinones
- 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.)
- Abandoned
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
Landscapes
- 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
5-(S)-N-(1'-Hydroxyacetyl-5'-indolinyl)-5-(acetamidomethyl)-2-oxazolidinone and 5-(S)-N-(1'-(2-thiophenecarbonyl)-5'-indolinyl)-5-(acetamidomethyl)-2-oxazoli_ dinone are useful in treating tuberculosis caused by M. Tuberculosis.
Description
2 13 6 3 2 Li .
WO 94/01110P~/US93/048~0 5'-INDOLn~lYL OXAZOLIDINONES USEFUL AGAINST
~fYCOBAClERlUM TUBE;RCULOSIS
BACKGROUND OF THE_INVENTIC)N
1. Fleld of the Invention 5The invention is the use of hvo ~'-indolinyl ox~zolidionones (I) to treat tuber~ulosis (TB) caused by M. nlberc~fosis.
2 escnption of the Related Art Tuberculosis (TB) is a well known disease which is caused by M. nJberculosis.
At present v~rious agents are used to treat those ir~ected with TB. The most cornmon of these pharmaceutical agents include isor~ia~id, rifampin, etharnbutol, p-aminosalicylic acid, py~inamide, streptomycin, capreomycin, cycloserine, eWonamide and kanarnycin and- ~minoglycosides ~ntibiotics and mixt~res thereof.
Since the introduction of antibiotics and the ~etter health care practices in the 1950's, ~he incidence of TB had declined an ave~age of six percent per year until 1985. Since then there has been a 16 percent per year increase in new TB cases. This increased incidence of TB
has been accompanied by outbreaks of multi-drug resistant strains of M. tubercl~losis. Because TB has never declined in incidence in ~le developing and underdeveloped countries and the additional c~es related to the increase in AIDS, the World Health Organization recently established a Worlcing Group to develop new antibiotics to treat TB which are urgently needed.
Wh,ile there are phamlaceutical agents presently available to treat those infected with TB, it is highly desirable to have a better agent because of the development of M. tu~erculoQs strains resist~nt to current therapeutics.
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-hydroxymethyloxazolidinoneshaving antidepressive utility.
US Reissue Patent 29,607 discloses 3-substituted phenyl-5-hydroxymethylox~olidinones having antidepressive, tranquilizing and sedative utility.
US Patent 4,340,606 discloses 3-(p-alkylsulfonyl~phenyl-5-(hydroxymethyl or acyloxyrnethyl)oxazolidinones having antibacterial activity in mamrnals.
Belgium Pa~ent 892,270 discloses 3-(arylalkyl, arylalkenyl or arylacetylenic substituted)phenyl)-5-(~minomethyl)oxazolidinones which are inhibitors of monoamine oxid~se.
US Paten~ 4,461,773 discloses 3-substituted phenyl-5-hydroxymethyloxa~olidinoneswhich have antibactenal ~ctivity.
European Patent Publications 127,902 and 184,170 disclose 3-substituted phenyl-5-amidomethylox~201idinones which have antibacterial utility.
2 1 3 6 ~ 2 `~
WO 94/01110 PCr/US93/b4850 Antimicrobial Agents and Chemotherapy 1791 (1987) discusses compounds disclosed in Europe3n 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 5 including sulfides, su~xides, sul~ones and sulfonamides which possess antibacteriai activity US Pa~ent 4,801,600 discloses 6'-indolinyloxazolidinones (where the indolinyl nitrogen is meta to the oxazolidinone nitrogen~.
US Patents 5,036,092 and 5,039,690 disclose 6'-indolinyl oxazolidinones whereas the compound of the present invention is a 5'-indolinyl oxazolidinone.
Diagn. Microbiol. Infec~. Dis., 14, 465-471 (1991) discloses that an oxazolidinone, ( )-DUP-721 is active against tuberculosis.
5'-indolinyl oxazolidinones are known, see Intemational Publication No. WO90/02744, published March 22, 1990 based on lntemational Patent Application No. PCI`/US89/03548 filed August 22, 1989. More particularly, 3-(5'-1-hydroxyacetylindolinyl)-SB-(acetamidomethyl)-oxazolidin-2-one more preferably termed 5-(S)-N-(1'-hydroxyacetyl-5'-indolinyl)-5-(acetamidomethyl)-2-oxazolidinone is known, see Intemational Publication No. W090/02744, EXAMPLES 122. The optically active from of the compound is disclosed in EXAMPLE 150.
5-(S)-N-(1'-(2-Thiophenecarbonyl3-5'-indolinyl)-5-(acetamidomethyl)-2-oxazolidinone is also known, see EXAMPLE 146 of Intemational Publication No. W090/02744.
SUMMARY OF INVENTION
Disclosed is a method of treating humans who have tuberculosis caused by Mycobacterium tl bercu~osis which comprises admisitration of an effective amount of a 5'-indolinyl oxazolidinone selected from the group consisting of 5-(S)-N-(l'-hydroxyacetyl-5'-indolinyl)-5-(acetamidomethyl)-2-oxazolidinone and 5-(S)-N-(1 '-(2-thiopheneca~bonyl)-5 '-indolinyl)-5-(acetamidomethyl)-2-oxazolidinone and pharmaceutically acceptable salts therPof.
- DLTAILED DESCRIPTION OF THE INVENTlON
5'-indolinyl oxazolidinones are known, see lntemational 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 (-tl). (~)-3-(5'-1-Hydroxyacetylindolinyl)-SB-(acetamidomethyl)oxazolidin-2-one is known, see In~ernational Publication No. W090/02744, EXAMPLES 122. The antibacterially ~ctive form of the compound is the "S" enantiomer and is disclosed in EXAMPLE 150 ~s obtained by resolution of a racemic mixture. The optically active form was telmed 3-(5'-1-B5 hydroxyacetylindolinyl)-5B-(~ce~midomethyl)oxazolidin-2-one in International Publication No.
W090,~02744 However, a preferred name is 5-(S)-N-(1'-hydroxy~cetyl-5'-indolinvl)-5-~- 213~324 ~ `
:
WO 94/01110 PCr~US93J048~0 (acetamidomethyl)-2-oxazolidinone. 5-(S)-N-( 1 '-(2-Thiophenec~onyl)-5 '-indolinyl)-5-(ace~midomethyl)-2-oxazolidinone is also known, see EXA~LE 146 of International Pu~lication ~o. WO90/02744.
While the racemic forms of the oxazolidinones are useful in treaIing TB, it is highly S prefer~ble to use the active en~ntiomer rather than the racemic form. While the optically active ;
form can be obtained by lesolution of a racemic mixture as set forth in Intemational Publication No. W090/02744, it is preferred to prepare the desired enantiomer by a stereoselective synthesis. One method to produce 5-(S)-N-(1'-hydroxyacetyl-5'-indolinyl)-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 EXA~LES
14-19. Likewise, one method to produce 5-(S)-N-(1'-(2-thiophenecarbonyl)-5'-indolinyl)-5-- (~etamidomethyl)-2-oxazolidinone is by resolution of the racemic form. Another method is by the process of EXAMPLES 10-13. The preferTed method, as discussed below, is by the process of EXAMPLES 14-17 and 20.
The preferred method of malcing the optically active is by starting with the known 1-carbo-t-butyloxy-(N-carboben~yloxy)-5-aminoindoline [US Patent 5,164,510, EXA~LE 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 ~llowing the mixture to walm to 20-25. This method produces in high yield the optically active 5-hydroxymethyl oxazolidinone having the desired stereochemistry (R), i.e., the 5-,B configuralion, see EXAMPLE 14. `
This alcohol is then treated with triphenylphosphine and diethylazodicarboxylate in tetrahydrofuran or ether, to give the optically active 5-phthalimidomethyl oxazolidinone, see EXAMPLE 15.
EXA~LE 16 discloses that the 5-phthalimidomethyl compound is then treated with areagent to remove the phthalimide group such as an aqueous solution of methylamine or hydr 7ine to give the intermediate 5-aminomethyl oxazolidinone. This is not purified, but is immediately ,lcetylated by treatment with acetic anhydride or acetyl chloride in pyridine or methylene chloride to give the (S)-5-acetamidomethyl oxazolidinone with the [carbo-t-butyloxy]- i protecting group on ~ indolinyl nitrogen.
EXAMPLE 1~ discloses the removal of the protecting group by the addition of trifluoroacetic ~cid, either neat, or in methylene chloride, to give the parent indoline ox~zolidinone.
EXAMPLE 18 discloses acylation on the indoline nitrogen is effected by the addition of ~5 benzyloxyl~cetyl chloride in the presence of trieLhy!2~!ir.e or diisopropylethylamine in methylene chk,ride hr ether, to give the benzyloxyacetylindolinyl compound. Trea~nent of this compound 2135~2 i , . ., '' WO 94/01110 PCrlUS93/048~0 with hydrogen in the presence of palladium black or palladium/charcoal in ethyl acetate or methanol (EXAMPLE 19) gives (S)-5-acetamidomethyl 3(5'-1-hydroxyacetylindolinyl)-ox~zolidinone.
When the product of EXAMPLE 17 is acylated with 2-thiophenecarbonyl chloride S (EXA~LE 20) the product is 5-(S)-N-(1'-(2-thiophenecarbonyl)-5'-indolinyl)-5- !-(acetamidomethyl)-2-oxazolidinone .
The 5'-indolinyl oxazolidinones are administered either parenterally or orally. It is known to those skilled in the art how to formulate ~e 5'-indolinyi oxazolidinones into appropriate pharmaceutical dosage forms for oral (tablet, c~psule) or p~renteral (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 ~t doses from about 50 to about 3,000 mg/day. It is preferred that the S'-indolinyl oxazolidinones a~ administered at doses of about 100 to about 2,000 mg/day. The 5'-indolinyl oxa~olidinones are administered orally and the tot~l d~ily dose is divided between one to four doses per day.
The 5'-indolinyi 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, pyra~inamide, streptomycin, kanamycin, capreomycin, cyclosenne, and ethionamide. ',~
It is Icnown to those skilled in the art how to determine if humans are infected with M.
tubercl~losis, ~nd how to dete~nine if these organisms are susceptible to the 5'-indolinyl ox~olidinones.
The exact dosage and frequency of administration depends on the particular 5`-indolinyl ox~zolidinones used, the p~rticular condition being tre~ted, the severity of the condition being tre~ed, the age, weight, general physical condition of the panticular patient, other medication the individual may be taking as is well known to those skilled in the art and can be more accurately de~ermined by measuring the blood level or concentration of the 5'-indolinyl oxazolidinones in the patient's blood ~nd/or the patient's response to the palticular condition being treated.
DE~INITIONS AND CONVENTIONS ,~
The definitions and explanations below are for the terms as used throughout this entire document including both the specification and the cl~ims.
DE~INlTlONS
All temperaNres are in degrees Centigrade.
~LC refers to thin-layer chromatograph - - 213632~ `
WO 94/01110 PCr/US9'3/04850 ~
5 :, THF refers to tetrahydrofuran.
Saline refers to an aqueous saturated sodium chloride solution.
When solvent pairs are used, the ratios of solvents used are volume/volume (v/v).
When the solubility of a solid in a s~lvent is used the ra~io of the solid to the solvent is S weight/volume (wth).
IR refer~ to infrared spectroscopy.
[~]D25 refers to ~he angle of rota~ion 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 10 to the positive ion of a parent plus a hydrogen atom. El refers to electron irnpact. 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 pharmacologicalftoxicological point of view and to the manufacturing pharmaceutical chemist fr~m ~ physical/chemical point of view regarding 15 composition, formulation, stabUity, patient acceptance and bioavailability.
M. tuberculosis refers to Mycobacteri~n tuberculosis.
EX~IP~ES
Without fur~er elaboration, it is believed that one skilled in the art can, using the preceding description, practice the present invention to its fullest extent. The following detailed 20 examples describe how to prepare the various compounds and/or perform the various processes of the invention and are to be constlued as merely iUustr~tive, and not limitations of the preceding disclosure in ~ny way whatsoever. Those skilled in the arl will promptly recognize appropriate variations frorn the procedures both as to reactants and ~s to re~ction conditions and techniques.
25 EXA~LE 1 N-Benzyloxyace~yl-5-nitro-indoline (A) Triethylamine (45 ml) is added to a solution of 5-nitroindoline (42.05 g) in tetrahydrofuran (250 ml) and the mixture cooled to O, then a solution of benzyloxyacetyl chloride (48.6 g) in THF (50 ml) is added over 15 min, and the mixn~re stirred in the ice bath for an ~dditional 1.25 hr, then ~lowed to warm to 20-25 over 3 hr. Aqueous workup yields a 30 solid which is recrystallized fr~m acetone/w~er to give the title compound, mp 137-139.
EXAMPLE 2 N-Benzyloxyacetyl-5-amino-indoline (B) To a mixture of ~-benzyloxy~cetyl-5-nitro-indoline (A, EXAMPLE 1, 12.26 g) in methanol/ethyl acetate (18/82, 1.1 l) under nitrogen is added pa!ladium/charcoal (10%, 1.55 g) and the fl~sk altemately evacuated and filled with hydrogen from a balloon (3 times), then the 35 mixture is allowed to stir at 2~25 for 4 hr. The mixture is degassed ~nd then filtered over di~tom~eous ear~h ~nd the p~d washed with ethyl acet~te. The filtrate is concentra~ed to 21 3~ 3 2 ~
O 94/01110 ; ~ PC~/US93tO4850 volume of about 200 ml and a crystalline solid is precipi~ed, which is collected to give the title compound, mp IOS-106.
EXAMPLE 3 N-Benzyloxyacetyl-5^~(2'-(~)-hydroxy-3'-butyrate)propylamino]indoline (C) S The following procedure is a modification of that described by M. alini, P. Crotti, and F. Macchia, "Metal sal~ as new catalysts for mild and efficient aminolysis of oxiranes,"
Tetrahedron Letters, 31, 4661 (1990). The prior art process uses a full equiv~lent of zinc chloride, but since i~ was found that the reaction stops due to complex formation, and side re~ctions are more prevalent, 5 mole % of zinc chloride is used.
In a flame dned flask, zinc chloride (0.12 g) is dissolved in dry acetonitrile (10 ml), then (R-)glycidyl butyrate (3.0 rnl) is added and the mixture stirred at 20-25, while N-benzyloxyacetyl-S-amino-indoline (B, EXAMPLE 2, 4.94 g) in acetonitrile (65 ml) is slowly added. The mixture is refluxed for a total of 2 days, then poured in~o 200 ml of water and ex~acted with ethyl acetate (5 x 50 ml). The phases are separated and the organic layers dried vith magnesium sulfate and concentrated under reduced pressure to give an oil residue. This is carried on into the following reaction without purification; TLC analysis indicated a spot at Rf=
0.16 on silica gel, acetone/methylene chloride (10/90), for the desired compound. An analytical sample is puzified using this system and gave a sample for MS, calcd for C2~H30O5N2 =
426.2155, found = 426.2153.
EXAlv~LE 4 5-(R)-N-(l'-benzyloxyacety1-5'-indolinyl)-5-(butyryloxymethyl)-2-ox~zolidinone (D) To a mixture of N-benzyloxyacetyl-5-[(2'-(R)-hydroxy-3'-butyra~e)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 ~ slowly warm to 0 over 1 hr. After an additiona~ lS min, dusopropylethylam~ne (5.7 ml) is added in dropwise fashion over 5 min, and the mix~re stirred in the ice bath for 50 min, then allowed to walm to 22, then poured into I N hydrochloric acid (SO 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 bicar~onate, water, and saline, then dried magnesium sulfate, and concentrated under reduced pressure. The residue is purified on silica gel (6 cm x 38 cm column, 40-63 y) with a gradient elution in acetone (2%-9%) in methylene chloride. The appropriate fractions are pooled and concentrated to give the title compound.
EXA~LE 5 S -(R)-N-( l ' -benzyloxyacetyl-S ' -indolinyl)-5 -~butyryloxymethyl)-2-ox~zolidinone (D) A mixture of N-benzyloxyacetyl-5-[(2'-(R)-hydroxy-3'-butyrate)propylarnino]indoline :-- 2136324 WO 94/01110 PCI/US93fO4850 (C, EXAMPLE 3, ~ !j9 g) and carbonyldiimidazole (0.26 g) in THF (3 ml) is refluxed for 7 days, then an ~dditional carbonyldumidazole (0.26 g) and THF (0.5 ml) are added, and the mixture refluxed for S hr. The mixture is poured into 0.5 N aqueous hydrochloric a~id, the layers separated, and the aqueous extracted with ethyl acetate, and purification as above gives ;~
S the title compound, MS Calcd for C~5H2,~06N~ = 452.1947, found = 452.1940; IR (neat) 1742, 1668 cm '.
EXAMPLE 6 5-{R)-N-( I ' -benzyloxyacetyl-S ' -indolinyl)-5 -~ydroxymethyl)-2-oxazolidinone ~E) To a solution of S-(R)-N-(I'-benzyloxyacetyl-S'-indolinyl)-S-(butyryloxymethyl)-2-10 oxazolidinone (D, EXAMPLE 5, 0.050 g) in methanol (I ml) is added sodium methoxide in meth~nol (25%, 2.5 yl), and the mixture is stir~ed at 20 for I hr, then the mixture is `
concentrated to give a residue. Purification on a 250 lu silica gel plate in ethyl acetate (3 elutions) gives the title compound, TLC Rf = 0.28 (ethyl acetate); FAB MS Calcd for C2lHnN2s = 382.1529, found = 382.1529.
EXA~LE 7 S~ N-(I'-benzyloxyacetyl-S'-indolinyl)-S-(azidomethyl)-2-oxazolidinone (1~
Following the general procedure of US Palent 4,801,600 and making non-critical vari~tions, 5 -(R)-N-( 1 '-benzyloxyacetyl-5 '-indolinyl)-S-(hydroxymethyl)-2-oxazolidinone (E, EXAMPLE 6) is converted to the a~ide by treatment with methanesulfonyl chloride and triethyl~nine in me~ylene ch~oride, followed by displacement with sodium azide in refluxing acetone-water. This is immediately carried into the following reaction.
EXAMPLE 8 5-(S)-N-( 1 ' -benzyloxyacetyl-S ' -indolinyl)-S -(acetamidomethyl)-2- oxazolidinone (H) Following the general procedure of EXAMPLE 2 and making non-critical va~i~tions but t~king care to mon~tor the reduction of the azide so that unwanted cleavage of the benzyl group does not take place, S-(R)-N-(1'-benzyloxyacetyl-S'-indolinyl)-S-(azidomethyl)-2-oxazolidinone (F EXA~LF 7? is converted into an amine (G) by treatment witil palladiwn/charcoal in 1 atm of hydrogen in ethyl acetale. Removal of the hydrogen gas and purging with nit~gen is followed by the ~ddition of pyridine and acetic anhydride (2 mole equiv. each), and the reaction stirred at 20-25 for 12 hr, then filtered over dia~omaceous earth, and the filtrate concentrated.
The residue is purified by column chromatography using a gradient of methanol/ethyl acetate to give the title compound.
EXAMPLE 9 5-(S)-N-( I '-Hydroxyacetyl-5 ' -indolinyl)-5-(acetamidomethyl)-2-ox~zolidinone (I) 5-(S)-N-( I '-benzyloxyacetyl-5 ' -indolinyl)-5-(acet~rnidomethyl)-2-oxazolidinone (H, EXAhJfPLE 8) is dissolved in ethyl acetate and the mixture purged with nitrogen gas, then 213632~ ~
WO 94/0111~ ' PC~/lJS93/0485 pal!adium/charcoal is added followed by hydrogen (balloon) and the mLxture is stirred until TLC
analysis shows eomplete conversion of the st~ng material. The mixture is filtered over di~tom~eous earth, concen~ated and the residue is purified by colwnn chromatography on silic~l gel (methanol/ethyl acetate) to give the title compound.
5 EXA~LE 10 N-(t-Butyloxycalbonyl)-5-[(2'-(R)-hydroxy-3'-butyra~e)propylamino]-indoline (J3 Following the general procedure of EXAMPLE~ 3 and making non-critical variations but starting with N-(t-butyloxycarl~onyl3-5-aminoindoline~ the ~tle compound is obtained.
EXA~LE 11 5-(S)-N-(l'-(t-Bucyloxycar~onyl)-5'-indolinyl)-5-(acetamidomethyl)-2-10oxazoUdinone (K) Following ~e general procedure of EXA~LES ~8 and making non-cri~ical variations - but st~ing with N-(t-butyloxycarbonyl)-5-~(2'^(R)-hydroxy-3'-butyrate)pTopylamino]indoline (EXA2~LE 10), the title compound is obtained.
EXA~LE 12 5(S)-N-(5'-in~olinyl)-5-(acetamidomethyl~-2-oxa~olidinone (L) 15A 2~fold excess of trifluoroacetic acid is added slowly over a period of about 5 min to 5-(S)-N-( I '-(t-butyloxycarbonyl)-5 '-indolinyl)-5-(acetamidomethyl)-2-oxazolidinone (K, EXA~LE 11) in methylene chloride at 0. The mixture is stirred for 3 hr at th~t temperature.
Then the mixture is neutralized by the slow ~ddition of s~ed aqueous sodium bicarbonate, the layers separated, and the aqeous phase is extracted with methylene chloride to give the title 20 compound.
EXAMPLE 13 5-(S)-N-(1'-(2-Thiophenecarbonyl~-5'-indolinyl)-5-(acetamidomethyl)-2- ~-oxa~olidinone (P) Following the general procedure of Intemational Publica~on No. W090/~2744, EX~LE 18, and making non-critic:ll variations and s~ing with 5(S)-N-(5'-indolinyl)-5-25 (acetamidomethyl~-2~xazolidinone (L, EXA~LE 12) and using the ~ppropriate corresponding acyl~ting agent the title compound is obtained.
EXA~I,E 14 (R)-3-(5'-1-Carbo-t-butyloxyindolinyl)-5-(hydroxymethyl)-oxazolidin-2-one n-Butyl lithium/hexane (1.6 M, 16.7 ml) is added dropwise over 5 min to a mixture of 30 I-carbo-t-butyloxy-tN-carboberlzyloxy)-S-aminoindoline (IV, US Patent 5,164,510, EXAMPLE
11, 9.371 g) in freshly distilled tet~hydrofu~n (140 ml) at -78 under nitrogen. The mixture is stirred for 10 min, then ~R)-glycidyl butyrate (4.0 ml) is added via syringe, the mixture is stirred for 1 hr at -78, then slowly ~llowed to warm to 20 overnight.
S~ur~ted aqueous ammonium chloride (100 ml) and water (200 ml) is added to the mixture and 35 this mixture is extracted with ethyl acetate (125 ml, then 3 x 100 ml), and the combined orgaruc laye~ are washed wiuh saline, and dried over magnesium sulfate. The mixture is filtere asld the --- 213S~
.. . .
WO 94/01110 PCrlUSg3/04X50 filtr~te is concentraled to give a solid which is recrystallized from hot ethyl acetate/hexanes to give the title compound, mp 15~157; []D=40 (CHClt).
EXAMPLE 15 ~R)-3-(St-l-Carbo-t-butyloxyindolinyl)-5-(phthalimidomethyl)-oxa~olidin-2~ne Diethylazodicarboxyla~e (3.45 mL) is added over 3 min to a mixture of (R)-3-(5'-1-c~rbo-t-butyloxyindolinyl)-5-(hydroxymethyl)-oxæolidin-2-one (EXA~LE 14, 7.103 g), phthalimide (3.228 g) and triphenylphosphine (5.804 g) in freshly distilIed tetrahydrofuran (175 ml) ~t Oo under nitrogen. The mixture is s~irred at 0 for 45 min, then allowed to come to 20 overnight, and the volatile components removed on a rotary e~porator. The residue is purified by cluomatography on silic~ gel 4~63 microns, 4.5 cm (height) x 10.0 cm (diameter) column, eluting with methylene chloride. The appropriate fractions are pooled and concentJated to give - ~e title compound, [alD = -52 (CH3CN); MS (EI, rela~ve abumdance) 463 (M~, 7.5).
EXAMPLE 16 (S)-3-(5'-1-Carbo-t-butyloxyindolinyl)-S-(acetamidomethyl)-oxazolidin-2-one (K) A mixture of (R)-3-(5'-1-carbo-t-butyloxyindolinyl)-5-(phthalimidomethyl)-oxazolidin-2-one (EXA~LE 15, 8.826 g) in absolute ethanol (100 mi) and aqueous methylamine (40%, 50 ml) is heated to reflux under nitrogen for E5 hr. The vola~les are then removed by ~educed pressure with heat at 0.1 Torr to give a concentrate. To this concentrate is ~dded 50 ml of pyndine and 25 ml of acetic anhydride at 20. A slight exotherm occurred, so the flask is cooled in a water bath to maintain the temperature at about 30. After stining for 1.3 hr, the volatiles were removed by vacuum distillation (0.1 Torr), giving a resîdue. This residue is chrom~togr~phed on silica gel 40 63 micron, 9.6 cm dia x 4 cm height, eluting with a gradient of ~cetone in methylene chloride (0-50%, v/v). The appropriat fractions are pooled and concentrated to give a the title compound, mp = 153.5-155~
EXAMPLE 17 (S)-3-~5'-indolinyl)-5-(acetamidomethyl)-oxa~oUdin-2-one (L) Trifluoroacetic acid (5 ml) is added to a mixture of (S)-3-(5'-l~arto-t-butyloxyindoUnyl)-S-(acetamidomethyl)-oxa~olidin-2-one (K, EXAMPLE 16, 4.705 g) in methylene chloride (40 ml) at 0 under nitrogen ~nd the ice bath removed. After 4 hour, the mix~re is concentrated and methylene chloride (8 ml) and trifluo~acetic acid (7 ml) is added at 20-25, After stin~ng for an additional 2 hr, the mixture is concentrated under reduced pressure, and ~he residue is poured into saturated aqueous sodiurn bicarbonate and ice, and the mixture is continuously extracted with methylene chloride (500 ml) for 24 hr. The organic phases are combined, dried over ma~esium sulfate and concentrated to give the title compound, mp 47-50; TLC R~ = 0.11, methanol/ethyl acetate (10/90).
EXAMPLE 18 (S)-3-(5'-l-Benzyloxyacetylindolinyl)-5-(acetamidomethyl)-oxa~olidin-2-one 213632~
WO 94/01110 PCr~US93/04850 Benzyloxyacetyl chloride (2.27 rnl) is added dropw~se over 5 m~n to a mixture of (S)-3-(5'-indolinyl)-5-(acetamidomethyl)-oxazolidin-2-one (L~ EXAMPLE 17, 3.445 g) andtriethylarnine (2.62 ml) in methylene chloride (100 ml) at 0 under r~itrogen. The mixture is slowly allowed to come to 20 overnight. The mixture is cooled to 0, and filtered. the collected 5 sn~terial is washed with water (2 x 50 rnl) and dried in a vacuum oven at 70. The solid is recryst~llized frotn hot methylene chloride and hex~nes to give the title compound, mp 188-189, [a]D = -13 (CHCI3).
EXAMPLE l9 (S)-3-(5'-1-Hydroxyacetylindolinyl)-5-(acetamidomethyl)-oxazolidin-2-one (I) A reaction flask holding a mixture of (S)-3-(5'-1-benzyloxyacetylindolinyl)-5-(acetamidomethyl)-oxazolidin-2-one (~XAMPLE 18, 9.119 g) in methanol/methylene chloride (10/90, 500 ml) is evacuated and filled with nitrogen gas three times, then 0.96 g of palladium bl~ck is added, and the flask again evacuated and filled with nitrogen three times, then ev~cuated and filled with hydrogen from a balloon (three t mes). Af~er stirring of ~e mixture ~
20-25 for a total of 4 hr, the hydrogen is removed and the mixture is filtered over diatomaceous ea~ nd the filtlate was concentrated in vacuo to give a solid. Illis solid is ~iturated with methanol/ethyl acetate (10/90, 200 ml) in a 35 bath, then cooled ~ 20C and the solid collected to give the title compound, mp 198-199, la~D = -210 (DMSO).
EXAMPLE 20 (S)-3-(5'-1-((2-Thiophenecarbonyl)indolinyl)-5-(acetamidomethyl)-oxazolidin-2-one (P) Triethylamine (2.5 ml) followed by 2-thiophenecarbonyl chloride (1.5 ml) is added over
WO 94/01110P~/US93/048~0 5'-INDOLn~lYL OXAZOLIDINONES USEFUL AGAINST
~fYCOBAClERlUM TUBE;RCULOSIS
BACKGROUND OF THE_INVENTIC)N
1. Fleld of the Invention 5The invention is the use of hvo ~'-indolinyl ox~zolidionones (I) to treat tuber~ulosis (TB) caused by M. nlberc~fosis.
2 escnption of the Related Art Tuberculosis (TB) is a well known disease which is caused by M. nJberculosis.
At present v~rious agents are used to treat those ir~ected with TB. The most cornmon of these pharmaceutical agents include isor~ia~id, rifampin, etharnbutol, p-aminosalicylic acid, py~inamide, streptomycin, capreomycin, cycloserine, eWonamide and kanarnycin and- ~minoglycosides ~ntibiotics and mixt~res thereof.
Since the introduction of antibiotics and the ~etter health care practices in the 1950's, ~he incidence of TB had declined an ave~age of six percent per year until 1985. Since then there has been a 16 percent per year increase in new TB cases. This increased incidence of TB
has been accompanied by outbreaks of multi-drug resistant strains of M. tubercl~losis. Because TB has never declined in incidence in ~le developing and underdeveloped countries and the additional c~es related to the increase in AIDS, the World Health Organization recently established a Worlcing Group to develop new antibiotics to treat TB which are urgently needed.
Wh,ile there are phamlaceutical agents presently available to treat those infected with TB, it is highly desirable to have a better agent because of the development of M. tu~erculoQs strains resist~nt to current therapeutics.
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-hydroxymethyloxazolidinoneshaving antidepressive utility.
US Reissue Patent 29,607 discloses 3-substituted phenyl-5-hydroxymethylox~olidinones having antidepressive, tranquilizing and sedative utility.
US Patent 4,340,606 discloses 3-(p-alkylsulfonyl~phenyl-5-(hydroxymethyl or acyloxyrnethyl)oxazolidinones having antibacterial activity in mamrnals.
Belgium Pa~ent 892,270 discloses 3-(arylalkyl, arylalkenyl or arylacetylenic substituted)phenyl)-5-(~minomethyl)oxazolidinones which are inhibitors of monoamine oxid~se.
US Paten~ 4,461,773 discloses 3-substituted phenyl-5-hydroxymethyloxa~olidinoneswhich have antibactenal ~ctivity.
European Patent Publications 127,902 and 184,170 disclose 3-substituted phenyl-5-amidomethylox~201idinones which have antibacterial utility.
2 1 3 6 ~ 2 `~
WO 94/01110 PCr/US93/b4850 Antimicrobial Agents and Chemotherapy 1791 (1987) discusses compounds disclosed in Europe3n 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 5 including sulfides, su~xides, sul~ones and sulfonamides which possess antibacteriai activity US Pa~ent 4,801,600 discloses 6'-indolinyloxazolidinones (where the indolinyl nitrogen is meta to the oxazolidinone nitrogen~.
US Patents 5,036,092 and 5,039,690 disclose 6'-indolinyl oxazolidinones whereas the compound of the present invention is a 5'-indolinyl oxazolidinone.
Diagn. Microbiol. Infec~. Dis., 14, 465-471 (1991) discloses that an oxazolidinone, ( )-DUP-721 is active against tuberculosis.
5'-indolinyl oxazolidinones are known, see Intemational Publication No. WO90/02744, published March 22, 1990 based on lntemational Patent Application No. PCI`/US89/03548 filed August 22, 1989. More particularly, 3-(5'-1-hydroxyacetylindolinyl)-SB-(acetamidomethyl)-oxazolidin-2-one more preferably termed 5-(S)-N-(1'-hydroxyacetyl-5'-indolinyl)-5-(acetamidomethyl)-2-oxazolidinone is known, see Intemational Publication No. W090/02744, EXAMPLES 122. The optically active from of the compound is disclosed in EXAMPLE 150.
5-(S)-N-(1'-(2-Thiophenecarbonyl3-5'-indolinyl)-5-(acetamidomethyl)-2-oxazolidinone is also known, see EXAMPLE 146 of Intemational Publication No. W090/02744.
SUMMARY OF INVENTION
Disclosed is a method of treating humans who have tuberculosis caused by Mycobacterium tl bercu~osis which comprises admisitration of an effective amount of a 5'-indolinyl oxazolidinone selected from the group consisting of 5-(S)-N-(l'-hydroxyacetyl-5'-indolinyl)-5-(acetamidomethyl)-2-oxazolidinone and 5-(S)-N-(1 '-(2-thiopheneca~bonyl)-5 '-indolinyl)-5-(acetamidomethyl)-2-oxazolidinone and pharmaceutically acceptable salts therPof.
- DLTAILED DESCRIPTION OF THE INVENTlON
5'-indolinyl oxazolidinones are known, see lntemational 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 (-tl). (~)-3-(5'-1-Hydroxyacetylindolinyl)-SB-(acetamidomethyl)oxazolidin-2-one is known, see In~ernational Publication No. W090/02744, EXAMPLES 122. The antibacterially ~ctive form of the compound is the "S" enantiomer and is disclosed in EXAMPLE 150 ~s obtained by resolution of a racemic mixture. The optically active form was telmed 3-(5'-1-B5 hydroxyacetylindolinyl)-5B-(~ce~midomethyl)oxazolidin-2-one in International Publication No.
W090,~02744 However, a preferred name is 5-(S)-N-(1'-hydroxy~cetyl-5'-indolinvl)-5-~- 213~324 ~ `
:
WO 94/01110 PCr~US93J048~0 (acetamidomethyl)-2-oxazolidinone. 5-(S)-N-( 1 '-(2-Thiophenec~onyl)-5 '-indolinyl)-5-(ace~midomethyl)-2-oxazolidinone is also known, see EXA~LE 146 of International Pu~lication ~o. WO90/02744.
While the racemic forms of the oxazolidinones are useful in treaIing TB, it is highly S prefer~ble to use the active en~ntiomer rather than the racemic form. While the optically active ;
form can be obtained by lesolution of a racemic mixture as set forth in Intemational Publication No. W090/02744, it is preferred to prepare the desired enantiomer by a stereoselective synthesis. One method to produce 5-(S)-N-(1'-hydroxyacetyl-5'-indolinyl)-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 EXA~LES
14-19. Likewise, one method to produce 5-(S)-N-(1'-(2-thiophenecarbonyl)-5'-indolinyl)-5-- (~etamidomethyl)-2-oxazolidinone is by resolution of the racemic form. Another method is by the process of EXAMPLES 10-13. The preferTed method, as discussed below, is by the process of EXAMPLES 14-17 and 20.
The preferred method of malcing the optically active is by starting with the known 1-carbo-t-butyloxy-(N-carboben~yloxy)-5-aminoindoline [US Patent 5,164,510, EXA~LE 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 ~llowing the mixture to walm to 20-25. This method produces in high yield the optically active 5-hydroxymethyl oxazolidinone having the desired stereochemistry (R), i.e., the 5-,B configuralion, see EXAMPLE 14. `
This alcohol is then treated with triphenylphosphine and diethylazodicarboxylate in tetrahydrofuran or ether, to give the optically active 5-phthalimidomethyl oxazolidinone, see EXAMPLE 15.
EXA~LE 16 discloses that the 5-phthalimidomethyl compound is then treated with areagent to remove the phthalimide group such as an aqueous solution of methylamine or hydr 7ine to give the intermediate 5-aminomethyl oxazolidinone. This is not purified, but is immediately ,lcetylated by treatment with acetic anhydride or acetyl chloride in pyridine or methylene chloride to give the (S)-5-acetamidomethyl oxazolidinone with the [carbo-t-butyloxy]- i protecting group on ~ indolinyl nitrogen.
EXAMPLE 1~ discloses the removal of the protecting group by the addition of trifluoroacetic ~cid, either neat, or in methylene chloride, to give the parent indoline ox~zolidinone.
EXAMPLE 18 discloses acylation on the indoline nitrogen is effected by the addition of ~5 benzyloxyl~cetyl chloride in the presence of trieLhy!2~!ir.e or diisopropylethylamine in methylene chk,ride hr ether, to give the benzyloxyacetylindolinyl compound. Trea~nent of this compound 2135~2 i , . ., '' WO 94/01110 PCrlUS93/048~0 with hydrogen in the presence of palladium black or palladium/charcoal in ethyl acetate or methanol (EXAMPLE 19) gives (S)-5-acetamidomethyl 3(5'-1-hydroxyacetylindolinyl)-ox~zolidinone.
When the product of EXAMPLE 17 is acylated with 2-thiophenecarbonyl chloride S (EXA~LE 20) the product is 5-(S)-N-(1'-(2-thiophenecarbonyl)-5'-indolinyl)-5- !-(acetamidomethyl)-2-oxazolidinone .
The 5'-indolinyl oxazolidinones are administered either parenterally or orally. It is known to those skilled in the art how to formulate ~e 5'-indolinyi oxazolidinones into appropriate pharmaceutical dosage forms for oral (tablet, c~psule) or p~renteral (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 ~t doses from about 50 to about 3,000 mg/day. It is preferred that the S'-indolinyl oxazolidinones a~ administered at doses of about 100 to about 2,000 mg/day. The 5'-indolinyl oxa~olidinones are administered orally and the tot~l d~ily dose is divided between one to four doses per day.
The 5'-indolinyi 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, pyra~inamide, streptomycin, kanamycin, capreomycin, cyclosenne, and ethionamide. ',~
It is Icnown to those skilled in the art how to determine if humans are infected with M.
tubercl~losis, ~nd how to dete~nine if these organisms are susceptible to the 5'-indolinyl ox~olidinones.
The exact dosage and frequency of administration depends on the particular 5`-indolinyl ox~zolidinones used, the p~rticular condition being tre~ted, the severity of the condition being tre~ed, the age, weight, general physical condition of the panticular patient, other medication the individual may be taking as is well known to those skilled in the art and can be more accurately de~ermined by measuring the blood level or concentration of the 5'-indolinyl oxazolidinones in the patient's blood ~nd/or the patient's response to the palticular condition being treated.
DE~INITIONS AND CONVENTIONS ,~
The definitions and explanations below are for the terms as used throughout this entire document including both the specification and the cl~ims.
DE~INlTlONS
All temperaNres are in degrees Centigrade.
~LC refers to thin-layer chromatograph - - 213632~ `
WO 94/01110 PCr/US9'3/04850 ~
5 :, THF refers to tetrahydrofuran.
Saline refers to an aqueous saturated sodium chloride solution.
When solvent pairs are used, the ratios of solvents used are volume/volume (v/v).
When the solubility of a solid in a s~lvent is used the ra~io of the solid to the solvent is S weight/volume (wth).
IR refer~ to infrared spectroscopy.
[~]D25 refers to ~he angle of rota~ion 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 10 to the positive ion of a parent plus a hydrogen atom. El refers to electron irnpact. 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 pharmacologicalftoxicological point of view and to the manufacturing pharmaceutical chemist fr~m ~ physical/chemical point of view regarding 15 composition, formulation, stabUity, patient acceptance and bioavailability.
M. tuberculosis refers to Mycobacteri~n tuberculosis.
EX~IP~ES
Without fur~er elaboration, it is believed that one skilled in the art can, using the preceding description, practice the present invention to its fullest extent. The following detailed 20 examples describe how to prepare the various compounds and/or perform the various processes of the invention and are to be constlued as merely iUustr~tive, and not limitations of the preceding disclosure in ~ny way whatsoever. Those skilled in the arl will promptly recognize appropriate variations frorn the procedures both as to reactants and ~s to re~ction conditions and techniques.
25 EXA~LE 1 N-Benzyloxyace~yl-5-nitro-indoline (A) Triethylamine (45 ml) is added to a solution of 5-nitroindoline (42.05 g) in tetrahydrofuran (250 ml) and the mixture cooled to O, then a solution of benzyloxyacetyl chloride (48.6 g) in THF (50 ml) is added over 15 min, and the mixn~re stirred in the ice bath for an ~dditional 1.25 hr, then ~lowed to warm to 20-25 over 3 hr. Aqueous workup yields a 30 solid which is recrystallized fr~m acetone/w~er to give the title compound, mp 137-139.
EXAMPLE 2 N-Benzyloxyacetyl-5-amino-indoline (B) To a mixture of ~-benzyloxy~cetyl-5-nitro-indoline (A, EXAMPLE 1, 12.26 g) in methanol/ethyl acetate (18/82, 1.1 l) under nitrogen is added pa!ladium/charcoal (10%, 1.55 g) and the fl~sk altemately evacuated and filled with hydrogen from a balloon (3 times), then the 35 mixture is allowed to stir at 2~25 for 4 hr. The mixture is degassed ~nd then filtered over di~tom~eous ear~h ~nd the p~d washed with ethyl acet~te. The filtrate is concentra~ed to 21 3~ 3 2 ~
O 94/01110 ; ~ PC~/US93tO4850 volume of about 200 ml and a crystalline solid is precipi~ed, which is collected to give the title compound, mp IOS-106.
EXAMPLE 3 N-Benzyloxyacetyl-5^~(2'-(~)-hydroxy-3'-butyrate)propylamino]indoline (C) S The following procedure is a modification of that described by M. alini, P. Crotti, and F. Macchia, "Metal sal~ as new catalysts for mild and efficient aminolysis of oxiranes,"
Tetrahedron Letters, 31, 4661 (1990). The prior art process uses a full equiv~lent of zinc chloride, but since i~ was found that the reaction stops due to complex formation, and side re~ctions are more prevalent, 5 mole % of zinc chloride is used.
In a flame dned flask, zinc chloride (0.12 g) is dissolved in dry acetonitrile (10 ml), then (R-)glycidyl butyrate (3.0 rnl) is added and the mixture stirred at 20-25, while N-benzyloxyacetyl-S-amino-indoline (B, EXAMPLE 2, 4.94 g) in acetonitrile (65 ml) is slowly added. The mixture is refluxed for a total of 2 days, then poured in~o 200 ml of water and ex~acted with ethyl acetate (5 x 50 ml). The phases are separated and the organic layers dried vith magnesium sulfate and concentrated under reduced pressure to give an oil residue. This is carried on into the following reaction without purification; TLC analysis indicated a spot at Rf=
0.16 on silica gel, acetone/methylene chloride (10/90), for the desired compound. An analytical sample is puzified using this system and gave a sample for MS, calcd for C2~H30O5N2 =
426.2155, found = 426.2153.
EXAlv~LE 4 5-(R)-N-(l'-benzyloxyacety1-5'-indolinyl)-5-(butyryloxymethyl)-2-ox~zolidinone (D) To a mixture of N-benzyloxyacetyl-5-[(2'-(R)-hydroxy-3'-butyra~e)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 ~ slowly warm to 0 over 1 hr. After an additiona~ lS min, dusopropylethylam~ne (5.7 ml) is added in dropwise fashion over 5 min, and the mix~re stirred in the ice bath for 50 min, then allowed to walm to 22, then poured into I N hydrochloric acid (SO 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 bicar~onate, water, and saline, then dried magnesium sulfate, and concentrated under reduced pressure. The residue is purified on silica gel (6 cm x 38 cm column, 40-63 y) with a gradient elution in acetone (2%-9%) in methylene chloride. The appropriate fractions are pooled and concentrated to give the title compound.
EXA~LE 5 S -(R)-N-( l ' -benzyloxyacetyl-S ' -indolinyl)-5 -~butyryloxymethyl)-2-ox~zolidinone (D) A mixture of N-benzyloxyacetyl-5-[(2'-(R)-hydroxy-3'-butyrate)propylarnino]indoline :-- 2136324 WO 94/01110 PCI/US93fO4850 (C, EXAMPLE 3, ~ !j9 g) and carbonyldiimidazole (0.26 g) in THF (3 ml) is refluxed for 7 days, then an ~dditional carbonyldumidazole (0.26 g) and THF (0.5 ml) are added, and the mixture refluxed for S hr. The mixture is poured into 0.5 N aqueous hydrochloric a~id, the layers separated, and the aqueous extracted with ethyl acetate, and purification as above gives ;~
S the title compound, MS Calcd for C~5H2,~06N~ = 452.1947, found = 452.1940; IR (neat) 1742, 1668 cm '.
EXAMPLE 6 5-{R)-N-( I ' -benzyloxyacetyl-S ' -indolinyl)-5 -~ydroxymethyl)-2-oxazolidinone ~E) To a solution of S-(R)-N-(I'-benzyloxyacetyl-S'-indolinyl)-S-(butyryloxymethyl)-2-10 oxazolidinone (D, EXAMPLE 5, 0.050 g) in methanol (I ml) is added sodium methoxide in meth~nol (25%, 2.5 yl), and the mixture is stir~ed at 20 for I hr, then the mixture is `
concentrated to give a residue. Purification on a 250 lu silica gel plate in ethyl acetate (3 elutions) gives the title compound, TLC Rf = 0.28 (ethyl acetate); FAB MS Calcd for C2lHnN2s = 382.1529, found = 382.1529.
EXA~LE 7 S~ N-(I'-benzyloxyacetyl-S'-indolinyl)-S-(azidomethyl)-2-oxazolidinone (1~
Following the general procedure of US Palent 4,801,600 and making non-critical vari~tions, 5 -(R)-N-( 1 '-benzyloxyacetyl-5 '-indolinyl)-S-(hydroxymethyl)-2-oxazolidinone (E, EXAMPLE 6) is converted to the a~ide by treatment with methanesulfonyl chloride and triethyl~nine in me~ylene ch~oride, followed by displacement with sodium azide in refluxing acetone-water. This is immediately carried into the following reaction.
EXAMPLE 8 5-(S)-N-( 1 ' -benzyloxyacetyl-S ' -indolinyl)-S -(acetamidomethyl)-2- oxazolidinone (H) Following the general procedure of EXAMPLE 2 and making non-critical va~i~tions but t~king care to mon~tor the reduction of the azide so that unwanted cleavage of the benzyl group does not take place, S-(R)-N-(1'-benzyloxyacetyl-S'-indolinyl)-S-(azidomethyl)-2-oxazolidinone (F EXA~LF 7? is converted into an amine (G) by treatment witil palladiwn/charcoal in 1 atm of hydrogen in ethyl acetale. Removal of the hydrogen gas and purging with nit~gen is followed by the ~ddition of pyridine and acetic anhydride (2 mole equiv. each), and the reaction stirred at 20-25 for 12 hr, then filtered over dia~omaceous earth, and the filtrate concentrated.
The residue is purified by column chromatography using a gradient of methanol/ethyl acetate to give the title compound.
EXAMPLE 9 5-(S)-N-( I '-Hydroxyacetyl-5 ' -indolinyl)-5-(acetamidomethyl)-2-ox~zolidinone (I) 5-(S)-N-( I '-benzyloxyacetyl-5 ' -indolinyl)-5-(acet~rnidomethyl)-2-oxazolidinone (H, EXAhJfPLE 8) is dissolved in ethyl acetate and the mixture purged with nitrogen gas, then 213632~ ~
WO 94/0111~ ' PC~/lJS93/0485 pal!adium/charcoal is added followed by hydrogen (balloon) and the mLxture is stirred until TLC
analysis shows eomplete conversion of the st~ng material. The mixture is filtered over di~tom~eous earth, concen~ated and the residue is purified by colwnn chromatography on silic~l gel (methanol/ethyl acetate) to give the title compound.
5 EXA~LE 10 N-(t-Butyloxycalbonyl)-5-[(2'-(R)-hydroxy-3'-butyra~e)propylamino]-indoline (J3 Following the general procedure of EXAMPLE~ 3 and making non-critical variations but starting with N-(t-butyloxycarl~onyl3-5-aminoindoline~ the ~tle compound is obtained.
EXA~LE 11 5-(S)-N-(l'-(t-Bucyloxycar~onyl)-5'-indolinyl)-5-(acetamidomethyl)-2-10oxazoUdinone (K) Following ~e general procedure of EXA~LES ~8 and making non-cri~ical variations - but st~ing with N-(t-butyloxycarbonyl)-5-~(2'^(R)-hydroxy-3'-butyrate)pTopylamino]indoline (EXA2~LE 10), the title compound is obtained.
EXA~LE 12 5(S)-N-(5'-in~olinyl)-5-(acetamidomethyl~-2-oxa~olidinone (L) 15A 2~fold excess of trifluoroacetic acid is added slowly over a period of about 5 min to 5-(S)-N-( I '-(t-butyloxycarbonyl)-5 '-indolinyl)-5-(acetamidomethyl)-2-oxazolidinone (K, EXA~LE 11) in methylene chloride at 0. The mixture is stirred for 3 hr at th~t temperature.
Then the mixture is neutralized by the slow ~ddition of s~ed aqueous sodium bicarbonate, the layers separated, and the aqeous phase is extracted with methylene chloride to give the title 20 compound.
EXAMPLE 13 5-(S)-N-(1'-(2-Thiophenecarbonyl~-5'-indolinyl)-5-(acetamidomethyl)-2- ~-oxa~olidinone (P) Following the general procedure of Intemational Publica~on No. W090/~2744, EX~LE 18, and making non-critic:ll variations and s~ing with 5(S)-N-(5'-indolinyl)-5-25 (acetamidomethyl~-2~xazolidinone (L, EXA~LE 12) and using the ~ppropriate corresponding acyl~ting agent the title compound is obtained.
EXA~I,E 14 (R)-3-(5'-1-Carbo-t-butyloxyindolinyl)-5-(hydroxymethyl)-oxazolidin-2-one n-Butyl lithium/hexane (1.6 M, 16.7 ml) is added dropwise over 5 min to a mixture of 30 I-carbo-t-butyloxy-tN-carboberlzyloxy)-S-aminoindoline (IV, US Patent 5,164,510, EXAMPLE
11, 9.371 g) in freshly distilled tet~hydrofu~n (140 ml) at -78 under nitrogen. The mixture is stirred for 10 min, then ~R)-glycidyl butyrate (4.0 ml) is added via syringe, the mixture is stirred for 1 hr at -78, then slowly ~llowed to warm to 20 overnight.
S~ur~ted aqueous ammonium chloride (100 ml) and water (200 ml) is added to the mixture and 35 this mixture is extracted with ethyl acetate (125 ml, then 3 x 100 ml), and the combined orgaruc laye~ are washed wiuh saline, and dried over magnesium sulfate. The mixture is filtere asld the --- 213S~
.. . .
WO 94/01110 PCrlUSg3/04X50 filtr~te is concentraled to give a solid which is recrystallized from hot ethyl acetate/hexanes to give the title compound, mp 15~157; []D=40 (CHClt).
EXAMPLE 15 ~R)-3-(St-l-Carbo-t-butyloxyindolinyl)-5-(phthalimidomethyl)-oxa~olidin-2~ne Diethylazodicarboxyla~e (3.45 mL) is added over 3 min to a mixture of (R)-3-(5'-1-c~rbo-t-butyloxyindolinyl)-5-(hydroxymethyl)-oxæolidin-2-one (EXA~LE 14, 7.103 g), phthalimide (3.228 g) and triphenylphosphine (5.804 g) in freshly distilIed tetrahydrofuran (175 ml) ~t Oo under nitrogen. The mixture is s~irred at 0 for 45 min, then allowed to come to 20 overnight, and the volatile components removed on a rotary e~porator. The residue is purified by cluomatography on silic~ gel 4~63 microns, 4.5 cm (height) x 10.0 cm (diameter) column, eluting with methylene chloride. The appropriate fractions are pooled and concentJated to give - ~e title compound, [alD = -52 (CH3CN); MS (EI, rela~ve abumdance) 463 (M~, 7.5).
EXAMPLE 16 (S)-3-(5'-1-Carbo-t-butyloxyindolinyl)-S-(acetamidomethyl)-oxazolidin-2-one (K) A mixture of (R)-3-(5'-1-carbo-t-butyloxyindolinyl)-5-(phthalimidomethyl)-oxazolidin-2-one (EXA~LE 15, 8.826 g) in absolute ethanol (100 mi) and aqueous methylamine (40%, 50 ml) is heated to reflux under nitrogen for E5 hr. The vola~les are then removed by ~educed pressure with heat at 0.1 Torr to give a concentrate. To this concentrate is ~dded 50 ml of pyndine and 25 ml of acetic anhydride at 20. A slight exotherm occurred, so the flask is cooled in a water bath to maintain the temperature at about 30. After stining for 1.3 hr, the volatiles were removed by vacuum distillation (0.1 Torr), giving a resîdue. This residue is chrom~togr~phed on silica gel 40 63 micron, 9.6 cm dia x 4 cm height, eluting with a gradient of ~cetone in methylene chloride (0-50%, v/v). The appropriat fractions are pooled and concentrated to give a the title compound, mp = 153.5-155~
EXAMPLE 17 (S)-3-~5'-indolinyl)-5-(acetamidomethyl)-oxa~oUdin-2-one (L) Trifluoroacetic acid (5 ml) is added to a mixture of (S)-3-(5'-l~arto-t-butyloxyindoUnyl)-S-(acetamidomethyl)-oxa~olidin-2-one (K, EXAMPLE 16, 4.705 g) in methylene chloride (40 ml) at 0 under nitrogen ~nd the ice bath removed. After 4 hour, the mix~re is concentrated and methylene chloride (8 ml) and trifluo~acetic acid (7 ml) is added at 20-25, After stin~ng for an additional 2 hr, the mixture is concentrated under reduced pressure, and ~he residue is poured into saturated aqueous sodiurn bicarbonate and ice, and the mixture is continuously extracted with methylene chloride (500 ml) for 24 hr. The organic phases are combined, dried over ma~esium sulfate and concentrated to give the title compound, mp 47-50; TLC R~ = 0.11, methanol/ethyl acetate (10/90).
EXAMPLE 18 (S)-3-(5'-l-Benzyloxyacetylindolinyl)-5-(acetamidomethyl)-oxa~olidin-2-one 213632~
WO 94/01110 PCr~US93/04850 Benzyloxyacetyl chloride (2.27 rnl) is added dropw~se over 5 m~n to a mixture of (S)-3-(5'-indolinyl)-5-(acetamidomethyl)-oxazolidin-2-one (L~ EXAMPLE 17, 3.445 g) andtriethylarnine (2.62 ml) in methylene chloride (100 ml) at 0 under r~itrogen. The mixture is slowly allowed to come to 20 overnight. The mixture is cooled to 0, and filtered. the collected 5 sn~terial is washed with water (2 x 50 rnl) and dried in a vacuum oven at 70. The solid is recryst~llized frotn hot methylene chloride and hex~nes to give the title compound, mp 188-189, [a]D = -13 (CHCI3).
EXAMPLE l9 (S)-3-(5'-1-Hydroxyacetylindolinyl)-5-(acetamidomethyl)-oxazolidin-2-one (I) A reaction flask holding a mixture of (S)-3-(5'-1-benzyloxyacetylindolinyl)-5-(acetamidomethyl)-oxazolidin-2-one (~XAMPLE 18, 9.119 g) in methanol/methylene chloride (10/90, 500 ml) is evacuated and filled with nitrogen gas three times, then 0.96 g of palladium bl~ck is added, and the flask again evacuated and filled with nitrogen three times, then ev~cuated and filled with hydrogen from a balloon (three t mes). Af~er stirring of ~e mixture ~
20-25 for a total of 4 hr, the hydrogen is removed and the mixture is filtered over diatomaceous ea~ nd the filtlate was concentrated in vacuo to give a solid. Illis solid is ~iturated with methanol/ethyl acetate (10/90, 200 ml) in a 35 bath, then cooled ~ 20C and the solid collected to give the title compound, mp 198-199, la~D = -210 (DMSO).
EXAMPLE 20 (S)-3-(5'-1-((2-Thiophenecarbonyl)indolinyl)-5-(acetamidomethyl)-oxazolidin-2-one (P) Triethylamine (2.5 ml) followed by 2-thiophenecarbonyl chloride (1.5 ml) is added over
3 min to a mixture of (S)-3-(5'-indolinyl)-S-(acetamidomethyl)-oxazolidin-2-one (L~ EXAMPLE
17, 3.289 g) in me~ylene chloride (70 ml) under nitrogen at 0. The mixture is allowed to come to 2~25 overnight. The mixture is filtered, and the solid is washed with methylene chloride, followed by water, and then dried in a vacuum oven at S0. The solid is recr,vstallized from acetone-water to give the title compound, mp = 193-198, [a]D = -38 (dimethylformamide).
EXAMPLE A 58 Year Old, 80 kg Male lnfected With M. tuberculosis A 58 yr old, 80 kg white m~le seeks medical attention due to an illness characterized by cough, weakness, night sweats ~nd shortness of breath The patient's chest ra~iograph shows extensivè cavitary disease consistent wi~ a di~gnosis of tuberculosis. Spu~m cultures are positive for M. tuberculosis, and the organism is found to be resistant to isonia~id, rifampin, and streptomycin. The patient is admitted to the hospital and given 5(S)-N~ hydroxyacetyl-5'-indolinyl)-5-(acetamidomethyl)-2-oxazolidinone orally at a total dosage of 2000 mglday for 4 weeks. Signs and symptoms of tuberculosis slowly disappear, viable M. tubercu~osis organisms are no longer isolaled from the patients sputum, and the patients chest radiograph retums to 213~32~ ", WO 94/01 1 10 ~ PCr/US93lO4850 norm~l. The patient is discharged f;rom the hospit~l.
EXAMPLE B 30 Year C)ld, 60 Kg Female Infeeted With M. ~uberc-~Jos~s A 30 yr old, 60 kg black female is diagnosed with pulmonary tubera~losis. Her sput isolate is detennined to be susceptible to ~oth isonia~id and p-aminosalicylic acid. She is 5 ~reated as an outpatient with a regimen of oral isonia2id and p-aminosalicylic acid, however, retums in 3 weeks because her condition does not improve. A new sputum culture grows M.
tuberculosis that is resistant to isoniazid. The pa~ent is given a S(S)-N-(I'-hydroxyacetyl-5'-indolinyl)-5-(acetamidomethyl)-2-ox~olidinone to take orally a~ a dose of lQOO mg/day for two months, in addition to the other antibiotics. Within one month the signs and symptoms of 10 tuberculosis slowly disappear. Sputum cultures taken 3, 6 and 12 months post-therapy are negative for M. ~uberclllosis.
EXAMPL~ C 36 Year Old Male With AIDS Infect~d With M. ~uberculosis A 36 yr old white male with acquired immune deficiency syndrome (AIDS) presents to his physician with fever, weight loss, and cough. The chest ~adiograph reveals a focal nidus of 15 infection in the lung. Expectorated sputum is negative for M. tuberculosis, however, a tissue biopsy taken via bronchoscopy contains culturable M. tuberculosis ln spite of a susceptibility report indicating the isolate is susceptible to the common therapy of isoniazid and rifampin, the patient is placed upon th~e drug therapy (isoniazid, rifampin, and ethambutol) due to his AIDS
condition. The patient initially improves, but then his condition begins to ~lapse. A new 20 spu~rn culhlre indicates the presence of M. ~u~erculosis that has developed ~sistance to rifampin, but is susceptible to 5(S)-N-(1'-hydroxyacety1-5'-indolinyl)-5-(acetamidomethyl)-2^
ox~zolidinone. The rifampin portion of the regimen is replaced by 5-(S)-N-(l'-hydroxyacetyl-5'-indolinyl)-5-(acet~nidomethyl)-2-ox~zolidinone given at an oral dose of lOOO mg/day. Within 3 weeks the signs and symptoms of tuberculosis are resolved; the patient continues to take the 25 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 p~phylactically for life to prevent recurrence of the infectio~
,, /
17, 3.289 g) in me~ylene chloride (70 ml) under nitrogen at 0. The mixture is allowed to come to 2~25 overnight. The mixture is filtered, and the solid is washed with methylene chloride, followed by water, and then dried in a vacuum oven at S0. The solid is recr,vstallized from acetone-water to give the title compound, mp = 193-198, [a]D = -38 (dimethylformamide).
EXAMPLE A 58 Year Old, 80 kg Male lnfected With M. tuberculosis A 58 yr old, 80 kg white m~le seeks medical attention due to an illness characterized by cough, weakness, night sweats ~nd shortness of breath The patient's chest ra~iograph shows extensivè cavitary disease consistent wi~ a di~gnosis of tuberculosis. Spu~m cultures are positive for M. tuberculosis, and the organism is found to be resistant to isonia~id, rifampin, and streptomycin. The patient is admitted to the hospital and given 5(S)-N~ hydroxyacetyl-5'-indolinyl)-5-(acetamidomethyl)-2-oxazolidinone orally at a total dosage of 2000 mglday for 4 weeks. Signs and symptoms of tuberculosis slowly disappear, viable M. tubercu~osis organisms are no longer isolaled from the patients sputum, and the patients chest radiograph retums to 213~32~ ", WO 94/01 1 10 ~ PCr/US93lO4850 norm~l. The patient is discharged f;rom the hospit~l.
EXAMPLE B 30 Year C)ld, 60 Kg Female Infeeted With M. ~uberc-~Jos~s A 30 yr old, 60 kg black female is diagnosed with pulmonary tubera~losis. Her sput isolate is detennined to be susceptible to ~oth isonia~id and p-aminosalicylic acid. She is 5 ~reated as an outpatient with a regimen of oral isonia2id and p-aminosalicylic acid, however, retums in 3 weeks because her condition does not improve. A new sputum culture grows M.
tuberculosis that is resistant to isoniazid. The pa~ent is given a S(S)-N-(I'-hydroxyacetyl-5'-indolinyl)-5-(acetamidomethyl)-2-ox~olidinone to take orally a~ a dose of lQOO mg/day for two months, in addition to the other antibiotics. Within one month the signs and symptoms of 10 tuberculosis slowly disappear. Sputum cultures taken 3, 6 and 12 months post-therapy are negative for M. ~uberclllosis.
EXAMPL~ C 36 Year Old Male With AIDS Infect~d With M. ~uberculosis A 36 yr old white male with acquired immune deficiency syndrome (AIDS) presents to his physician with fever, weight loss, and cough. The chest ~adiograph reveals a focal nidus of 15 infection in the lung. Expectorated sputum is negative for M. tuberculosis, however, a tissue biopsy taken via bronchoscopy contains culturable M. tuberculosis ln spite of a susceptibility report indicating the isolate is susceptible to the common therapy of isoniazid and rifampin, the patient is placed upon th~e drug therapy (isoniazid, rifampin, and ethambutol) due to his AIDS
condition. The patient initially improves, but then his condition begins to ~lapse. A new 20 spu~rn culhlre indicates the presence of M. ~u~erculosis that has developed ~sistance to rifampin, but is susceptible to 5(S)-N-(1'-hydroxyacety1-5'-indolinyl)-5-(acetamidomethyl)-2^
ox~zolidinone. The rifampin portion of the regimen is replaced by 5-(S)-N-(l'-hydroxyacetyl-5'-indolinyl)-5-(acet~nidomethyl)-2-ox~zolidinone given at an oral dose of lOOO mg/day. Within 3 weeks the signs and symptoms of tuberculosis are resolved; the patient continues to take the 25 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 p~phylactically for life to prevent recurrence of the infectio~
,, /
Claims (5)
1. Use of a 5'-indolinyl oxazolidinone selected from the group consisting of 5-(S)-N-(1'-hydroxyacetyl-5'-indolinyl)-5-(acetamidomethyl)-2-oxazolidinone and 5-(S)-N-(1'-(2-thiophenecarbonyl)-5'-indolinyl)-5-(acetamidomethyl)-2-oxazolidinone and pharmaceutically acceptable salts thereof to prepare a medicament to treat humans who have tuberculosis caused by Mycobacterium tuberculosis.
2. Use according to claim 1 where the 5'-indolinyl oxazolidinone (I) is given orally.
3. Use according to claim 1 where the 5'-indolinyl oxazolidinone is 5-(S)-N-(1'-hydroxyacetyl-5'-indolinyl)-5-(acetamidomethyl)-2-oxazolidinone.
4. Use according to claim 1 where the 5'-indolinyl oxazolidinone is
5-(S)-N-(1'-(2-thiophenecarbonyl)-5'-indolinyl)-5-(acetamidomethyl)-2-oxazolidinone.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US90938792A | 1992-07-08 | 1992-07-08 | |
| US909,387 | 1992-07-08 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA2136324A1 true CA2136324A1 (en) | 1994-01-20 |
Family
ID=25427164
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA002136324A Abandoned CA2136324A1 (en) | 1992-07-08 | 1993-05-26 | 5'-indolinyl oxazolidinones useful against mycobacterium tuberculosis |
Country Status (9)
| Country | Link |
|---|---|
| EP (1) | EP0648119A1 (en) |
| JP (1) | JPH07508985A (en) |
| KR (1) | KR950702417A (en) |
| AU (1) | AU666740B2 (en) |
| CA (1) | CA2136324A1 (en) |
| IL (1) | IL106220A0 (en) |
| MX (1) | MX9303764A (en) |
| TW (1) | TW260608B (en) |
| WO (1) | WO1994001110A1 (en) |
Families Citing this family (15)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| 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 |
| GB9717804D0 (en) | 1997-08-22 | 1997-10-29 | Zeneca Ltd | Chemical compounds |
| GB9717807D0 (en) | 1997-08-22 | 1997-10-29 | Zeneca Ltd | Chemical compounds |
| GB9725244D0 (en) | 1997-11-29 | 1998-01-28 | Zeneca Ltd | Chemical compounds |
| CN1311787A (en) | 1998-06-05 | 2001-09-05 | 阿斯特拉曾尼卡有限公司 | Oxazolidinone derivatives, process for their prepn. and pharmaceutical compositions contg. same |
| GB9928568D0 (en) | 1999-12-03 | 2000-02-02 | Zeneca Ltd | Chemical compounds |
| GB0009803D0 (en) | 2000-04-25 | 2000-06-07 | Astrazeneca Ab | Chemical compounds |
| US7141588B2 (en) | 2002-02-25 | 2006-11-28 | Pfizer, Inc. | N-aryl-2-oxazolidinone-5-carboxamides and their derivatives |
| AR038536A1 (en) | 2002-02-25 | 2005-01-19 | Upjohn Co | N-ARIL-2-OXAZOLIDINONA-5- CARBOXAMIDS AND ITS DERIVATIVES |
| US7094900B2 (en) | 2002-08-12 | 2006-08-22 | Pharmacia & Upjohn Company Llc | N-Aryl-2-oxazolidinones and their derivatives |
| EP1565186B1 (en) | 2002-11-21 | 2006-11-02 | Pharmacia & Upjohn Company LLC | N-(4-(piperazin-1-yl)-phenyl-2-oxazolidinone-5-carboxamide derivates and related compounds as antibacterial agents |
| US7304050B2 (en) | 2003-09-16 | 2007-12-04 | Pfizer Inc. | Antibacterial agents |
| MX2022016063A (en) | 2020-06-18 | 2023-04-11 | Akagera Medicines Inc | Oxazolidinone compounds, liposome compositions comprising oxazolidinone compounds and methods of use thereof. |
Family Cites Families (10)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPS5314792A (en) * | 1976-07-24 | 1978-02-09 | Rubuobuna Buratsurabusukay Ara | Copolymers of nnvinylmethylpyrazol and diivinyl crossslinking agent and process for producing same |
| JPS54110186A (en) * | 1978-02-17 | 1979-08-29 | Tokyo Yuuki Kagaku Kougiyou Kk | Method of mamufacturing weak basic anion exchange resin |
| DE3324835A1 (en) * | 1983-07-09 | 1985-01-17 | Cassella Ag, 6000 Frankfurt | CROSSLINKED COPOLYMER, PROCESS FOR PRODUCING IT AND ITS USE AS SORPENT |
| JPS6023854A (en) * | 1983-07-19 | 1985-02-06 | Konishiroku Photo Ind Co Ltd | Photographic element |
| DE3434137A1 (en) * | 1984-09-18 | 1986-03-20 | Basf Ag, 6700 Ludwigshafen | METHOD FOR THE PRODUCTION OF INSOLUBLE, LITTLE SWELLABLE POWDER-SHAPED POLYMERS |
| JPS63130605A (en) * | 1986-11-20 | 1988-06-02 | Tokuyama Soda Co Ltd | Production of anion exchanger |
| US4889632A (en) * | 1987-12-10 | 1989-12-26 | Ceskoslovenska Akademie Ved | Macroporous polymeric membranes for the separation of polymers and a method of their application |
| ATE201870T1 (en) * | 1988-09-15 | 2001-06-15 | Upjohn Co | 3-(NITROGEN SUBSTITUTED)PHENYL-5-BETA-AMIDOMETHYLOXAZOLIDEN-2-ONE |
| GB8829835D0 (en) * | 1988-12-21 | 1989-02-15 | Smith Kline French Lab | Compounds |
| JPH03708A (en) * | 1989-05-29 | 1991-01-07 | Koei Chem Co Ltd | Water-absorptive material |
-
1993
- 1993-05-26 CA CA002136324A patent/CA2136324A1/en not_active Abandoned
- 1993-05-26 KR KR1019950700069A patent/KR950702417A/en not_active Application Discontinuation
- 1993-05-26 AU AU43865/93A patent/AU666740B2/en not_active Expired - Fee Related
- 1993-05-26 WO PCT/US1993/004850 patent/WO1994001110A1/en not_active Application Discontinuation
- 1993-05-26 JP JP6503294A patent/JPH07508985A/en not_active Withdrawn
- 1993-05-26 EP EP93914058A patent/EP0648119A1/en not_active Withdrawn
- 1993-06-08 TW TW082104539A patent/TW260608B/zh active
- 1993-06-23 MX MX9303764A patent/MX9303764A/en unknown
- 1993-07-02 IL IL106220A patent/IL106220A0/en unknown
Also Published As
| Publication number | Publication date |
|---|---|
| KR950702417A (en) | 1995-07-29 |
| IL106220A0 (en) | 1993-11-15 |
| WO1994001110A1 (en) | 1994-01-20 |
| TW260608B (en) | 1995-10-21 |
| AU4386593A (en) | 1994-01-31 |
| JPH07508985A (en) | 1995-10-05 |
| EP0648119A1 (en) | 1995-04-19 |
| AU666740B2 (en) | 1996-02-22 |
| MX9303764A (en) | 1994-01-31 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| JP3188418B2 (en) | 3- (Fused ring-substituted) phenyl-5β-amidomethyloxazolidin-2-ones and 3- (nitrogen atom-substituted) phenyl-5β-amidomethyloxazolidine-2-ones | |
| CA2136324A1 (en) | 5'-indolinyl oxazolidinones useful against mycobacterium tuberculosis | |
| CA3008006C (en) | Biaryl monobactam compounds and methods of use thereof for the treatment of bacterial infections | |
| JP6797464B2 (en) | Nitrogen-containing tricyclic derivative with HIV replication inhibitory effect | |
| CN101282949B (en) | Azole and thiazole derivatives and their use | |
| KR20220154174A (en) | Biaryl derivatives as YAP/TAZ-TEAD protein-protein interaction inhibitors | |
| CN104718213A (en) | 5,5-heteroaromatic anti-infective compounds | |
| RU2215740C2 (en) | Oxazolidinone derivatives and pharmaceutical compositions based on thereof | |
| JP2004525876A (en) | Novel heterocyclic compounds having antibacterial activity, methods for their preparation, and pharmaceutical compositions containing them | |
| JP2009521464A (en) | Nitroimidazole compounds | |
| RU2744784C1 (en) | Benzoxazine-oxazolidinone compound displaced by a nitrogen-containing heterocycle, method of synthesis and application thereof | |
| FI89479C (en) | Process for Preparing a Therapeutically Useful 5-RS Racemic or 5-R Optically Active Oxazolidine-2-Derivative | |
| CN106317072B (en) | Heterocyclic compounds for the treatment of mycobacterial infections and uses thereof | |
| NO325656B1 (en) | Anti-acid fast bacterial agents containing pyridone carboxylic acids as the active ingredient | |
| CN104364240B (en) | Drug for preventing or treating mycobacterial diseases | |
| CN104936964B (en) | Active Luo isoxazoline compounds with enhancing antibiotic activity | |
| JP4310191B2 (en) | Taxane derivative crystal and method for producing the same | |
| TWI570119B (en) | Crystalline (2s)-3-[(3s,4s)-3-[(1r)-1-hydroxyethyl]-4-(4-methoxy-3-[1-(5-methylpyridin-2-yl)azetidin-3-yl]oxy}phenyl)-3-methylpyrrolidin-1-yl]-3-oxopropane-1,2-diol and uses thereof | |
| CA3187516A1 (en) | Polycyclic cap-dependent endonuclease inhibitors for treating or preventing influenza | |
| CN107674014B (en) | 3, 5-dinitrobenzamide compound containing isoindoline fragment and preparation method thereof | |
| FR2737496A1 (en) | 4-ARYL-THIO-PYRIDIN-2 (1H) -ONES, MEDICAMENTS CONTAINING THEM AND USES THEREOF IN TREATING DISEASES RELATED TO HIV 1 AND 2 | |
| CA2086368A1 (en) | Pyrrolylbenzodiazepinones | |
| JPS63215624A (en) | Pyrrolidone derivative and use thereof | |
| CN112898317B (en) | Oxazole compound for sterilization and disinfection in hospital care and preparation method and application thereof | |
| CN112759560B (en) | Benzothiazine-4-ketone compound containing N-aminopiperazine segment and preparation method thereof |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| FZDE | Discontinued |