WO2008090570A1 - Nouveaux antimicrobiens - Google Patents

Nouveaux antimicrobiens Download PDF

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Publication number
WO2008090570A1
WO2008090570A1 PCT/IN2008/000047 IN2008000047W WO2008090570A1 WO 2008090570 A1 WO2008090570 A1 WO 2008090570A1 IN 2008000047 W IN2008000047 W IN 2008000047W WO 2008090570 A1 WO2008090570 A1 WO 2008090570A1
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oxo
phenyl
oxazolidin
ylmethyl
compound
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PCT/IN2008/000047
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English (en)
Inventor
Rajesh Jain
Sanjay Trehan
Jagattaran Das
Gurmeet Kaur
Sandeep Kanwar
Sitaram Kumar Magadi
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Panacea Biotec Ltd
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Publication of WO2008090570A1 publication Critical patent/WO2008090570A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
    • C07F9/02—Phosphorus compounds
    • C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
    • C07F9/6564—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having phosphorus atoms, with or without nitrogen, oxygen, sulfur, selenium or tellurium atoms, as ring hetero atoms
    • C07F9/6581—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having phosphorus atoms, with or without nitrogen, oxygen, sulfur, selenium or tellurium atoms, as ring hetero atoms having phosphorus and nitrogen atoms with or without oxygen or sulfur atoms, as ring hetero atoms
    • C07F9/6584—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having phosphorus atoms, with or without nitrogen, oxygen, sulfur, selenium or tellurium atoms, as ring hetero atoms having phosphorus and nitrogen atoms with or without oxygen or sulfur atoms, as ring hetero atoms having one phosphorus atom as ring hetero atom

Definitions

  • the present invention relates to novel phenyl oxazolidinone compounds of formula I or their pharmaceutically acceptable analogs, tautomeric forms, stereoisomers, polymorphs, prodrugs, metabolites, salts or solvates thereof.
  • the invention also relates to the processes for the synthesis of novel compounds of formula I or their pharmaceutically acceptable analogs, tautomeric forms, stereoisomers, polymorphs, prodrugs, metabolites, salts or solvates thereof.
  • the present invention also provides pharmaceutical compositions comprising novel compounds of formula I and methods of using them.
  • the compounds of the present invention are useful as antimicrobial agents, effective against a number of aerobic and/or anaerobic Gram positive and/or Gram negative pathogens such as multi drug resistant Staphylococcus spp., Streptococcus spp., Enterococcus spp., Bacterioides spp., Clostridia spp., H. influenza, Moraxella Spp., as well as acid-fast organisms such as Mycobacterium tuberculosis and the like.
  • aerobic and/or anaerobic Gram positive and/or Gram negative pathogens such as multi drug resistant Staphylococcus spp., Streptococcus spp., Enterococcus spp., Bacterioides spp., Clostridia spp., H. influenza, Moraxella Spp., as well as acid-fast organisms such as Mycobacterium tuberculosis and the like.
  • MRSA Methicillin Resistant Staphylococcus aureus
  • VRE Vancomycin Resistant Enterococci
  • GISA Glycopeptide Resistant Staphylococcus aureus
  • Oxazolidinones are a class of antibacterial agents with a unique mechanism of inhibiting bacterial protein synthesis. They inhibit the formation of ribosomal initiation complex involving 30S and 50S ribosoines leading to prevention of initiation complex formation at the stage of protein synthesis. Due to their unique mechanism of action, these compounds are active against pathogens resistant to other clinically useful antibiotics.
  • Several patent publications disclose oxazolidinones as antimicrobial agents.
  • WO 07/114326 US 07/0155798, WO 07/040326, WO 07/095784, WO 07/000432, WO 07/004037 and WO 07/093904 disclose phenyl oxazolidinone derivatives to be useful as antibacterial agents.
  • WO 06/109056, WO 06/035283, WO 03/072553, WO 03/064415 disclose heterobicyclic substituted phenyl oxazolidinones useful as antibacterial agents.
  • WO 96/35691 and WO 00/073301 disclose bicyclic oxazolidinones as antibacterial agents.
  • WO 02/064547 discloses pyridoarylphenyl oxazolidinones as antibacterial agents.
  • WO 04/033451, WO 04/089943, WO 05/005422 and WO 05/005399 disclose bicyclo[3.1.0]hexyl-phenyl-oxazolidinone derivatives useful for treating bacterial infections.
  • Linezolid (sold under the trade name Zyvox ), the first oxazolidinone to receive regulatory approval, has become an important clinical option in the treatment of serious Gram-positive bacterial infections, including those caused by multidrug resistant pathogens such as MRSA and VRE (see WO 95/07272). Inspite of its high potential as an antibiotic and its unique mode of action, no other molecule from oxazolidinone class, except for linezolid, could make it to the clinic. Moreover, development of resistance to an antibiotic is inevitable, and linezolid has been no exception. See, Mutnick, A. H.; Enne, V.; Jones, R. N. Ann. Pharmacother., 2003, 37, 769-774.3.
  • linezolid is not suitable for long duration therapy, although there are cases where patients receiving linezolid for more than two years are without serious side effects. See, Hutchinson, D. K. Expert Opin. Ther. Patents 2004, 14, 1309-1328.
  • Linezolid and its analogs are generally limited in their antimicrobial spectrum to Gram-positive pathogens only.
  • An expanded spectrum and enhanced potency of newer second generation oxazolidinones with activity against Gram-negative pathogens could expand the utility of this class beyond the hospital setting into the treatment of community acquired infections.
  • the compounds of the present invention are novel, none of them having being previously reported in the prior art.
  • the novel compounds of formula I according to the present invention possess improved efficacy particularly enhanced activity against bacterial infections, appreciable bioavailability, reduced associated side effects, good solubility and can be made into formulations with ease.
  • the present invention relates to novel phenyl oxazolidinones of formula I,
  • P represents phosphorus
  • O represents oxygen
  • N represents nitrogen
  • R can be either R 1 X or R 2 ;
  • X represents O, S, -NH, -NR 3 , -CH 2, -CHR 3 , -C(R 3 ) 2 or -(CH 2 ) m -X-
  • R 3 represents hydrogen, Cu io alkyl, C 2-I o alkenyl, C 2-I o alkynyl, acyl, thioacyl, aryl, heteroaryl, heterocyclyl, heteroarylcarbonyl, Ci -6 alkoxycarbonyl, Ci -6 alkoxythiocarbonyl, C 3-6 cyclo- alkoxycarbonyl, C 2-6 alkenyloxycarbonyl, C 2-6 alkenyloxythiocarbonyl, C 2-6 alkenyl- carbonyl, aryloxycarbonyl, aryloxythiocarbonyl, heteroaryloxycarbonyl, heteroarylthiocarbonyl, heteroaryloxythiocarbonyl or carbonyl and its derivatives, each of which may be optionally substituted at
  • R 1 represents hydrogen, C MO alkyl, C 3-2 o cycloalkyl, C 2- ⁇ o alkenyl, C 2- I 0 alkynyl, substituted or unsubstituted aryl, heteroaryl, aralkyl, heteroaralkyl, heterocyclyl, heterocyclylalkyl or heteroarylalkyl, each of which may be optionally substituted at any available position by one or more substituents R a ;
  • R 2 represents C MO alkyl, C 3-2 O cycloalkyl, C 2- ⁇ o alkenyl, C 2- io alkynyl, substituted or unsubstituted aryl, heteroaryl or heterocyclyl, each of which may be optionally substituted at any available position by one or more substituents R a ;
  • Z represents halogen, azido, isothiocyanate, thioalcohol, aryl, nitro, cyano, heteroaryl, OR 3 , NHR 3 or N(R 3 ) 2 where R J is as previously defined, each of which may be optionally substituted at any available position by one or more substituents R a ;
  • T, U, V and W are same or different and independently represent hydrogen or halogen
  • Y represents O, S, -NH or -NR where R 3 is as previously defined;
  • C 6 alkyl, -CH NOH, Ci-C 6 alkyl, C 2 -C 6 alkenyl, C 2- C 6 alkynyl, C,-C 6 alkoxy, C 3 -
  • R 4 and R 5 are independently selected from hydrogen, Ci-C 6 alkyl, C 3 -C 2 ocycloalkyl, C 3 - C 2 ocycloalkylalkyl, C 2 -C 6 alkenyl, C 2- C 6 alkynyl, C)-C 6 alkoxyCi-C 6 alkyl, aryl, heteroaryl, heterocyclyl, heterocyclylalkyl or heteroarylalkyl, optionally substituted with phenyl, -OH,
  • Ci-C 6 alkyl or Ci-C 6 alkoxy are same or different and independently represent 1,2,3 or 4; m is 1,2,3 or 4.
  • Another aspect of the invention provides the processes for the preparation of the novel compounds of formula I or their pharmaceutically acceptable analogs, tautomeric forms, stereoisomers, polymorphs, prodrugs, metabolites, salts or solvates thereof.
  • a further aspect of the present invention provides pharmaceutical compositions, containing compounds of formula I or their pharmaceutically acceptable analogs, tautomeric forms, stereoisomers, polymorphs, prodrugs, metabolites, salts or solvates thereof in combination with one or more pharmaceutically acceptable carrier(s).
  • Another aspect of the invention is to provide methods of using the compounds of formula I of the present invention or compositions comprising the compounds of formula I for the management such as prophylaxis, amelioration and/or treatment of disease(s)/ disorder(s) especially caused by microbial infections which comprises administering to a subject in need thereof the compounds of formula I or compositions comprising a pharmaceutically effective amount of the compounds of formula I.
  • Yet another aspect of the invention is the use of the compounds of formula I as antimicrobial agents, effective against a number of aerobic and/or anaerobic Gram positive and/or Gram negative pathogens such as multi drug resistant Staphylococcus spp., Streptococcus spp., Enterococcus spp., Bactericides spp., Clostridia spp., H. influenza, Moraxella Spp., as well as acid-fast organisms such as Mycobacterium tuberculosis and the like.
  • a number of aerobic and/or anaerobic Gram positive and/or Gram negative pathogens such as multi drug resistant Staphylococcus spp., Streptococcus spp., Enterococcus spp., Bactericides spp., Clostridia spp., H. influenza, Moraxella Spp., as well as acid-fast organisms such as Mycobacterium tuberculosis and the like.
  • the present invention provides a method for treating Gram positive and/or Gram negative pathogens in a mammal by administering a therapeutically effective amount of a compound of formula I or a pharmaceutically acceptable salt.
  • the present invention also encompasses prodrugs and active metabolites of the compounds of the formula I.
  • the present invention relates to novel phenyl oxazolidinones of formula I,
  • P represents phosphorus
  • O represents oxygen
  • N represents nitrogen
  • R can be either R 1 X or R 2 ;
  • X represents O, S, -NH, -NR 3 , -CH 2, -CHR 3 , -C(R 3 ) 2 or -(CH 2 ) m -X-
  • R 3 represents hydrogen, C MO alkyl, C 2-I0 alkenyl, C 2-I0 alkynyl, acyl, thioacyl, aryl, heteroaryl, heterocyclyl, heteroarylcarbonyl, Ci -6 alkoxycarbonyl, Ci -6 alkoxythiocarbonyl, C 3-6 cyclo- alkoxycarbonyl, C 2-6 alkenyloxycarbonyl, C 2-6 alkenyloxythiocarbonyl, C 2-6 alkenyl- carbonyl, aryloxycarbonyl, aryloxythiocarbonyl, heteroaryloxycarbonyl, heteroarylthiocarbonyl, heteroaryloxythiocarbonyl or carbonyl and its derivatives, each of which may be optionally substituted at any available position by
  • R 1 represents hydrogen, Ci -I0 alkyl, C 3-20 cycloalkyl, C 2- io alkenyl, C 2-I0 alkynyl, substituted or unsubstituted aryl, heteroaryl, aralkyl, heteroaralkyl, heterocyclyl, heterocyclylalkyl or heteroarylalkyl, each of which may be optionally substituted at any available position by one or more substituents R a ;
  • R 2 represents C M O alkyl, C 3-20 cycloalkyl, C 2- I 0 alkenyl, C 2- I 0 alkynyl, substituted or unsubstituted aryl, heteroaryl or heterocyclyl, each of which may be optionally substituted at any available position by one or more substituents R a ;
  • Z represents halogen, azido, isothiocyanate, thioalcohol, aryl, nitro, cyano, heteroaryl, OR 3 , NHR 3 or N(R 3 ) 2 where R 3 is as previously defined, each of which may be optionally substituted at any available position by one or more substituents R a ;
  • T, U, V and W are same or different and independently represent hydrogen or halogen
  • Y represents O, S, -NH or -NR 3 where R 3 is as previously defined;
  • Formula Ia wherein R , X, Y, T, U, V, W and Z are defined herein; or their pharmaceutically acceptable analogs, tautomeric forms, stereoisomers, polymorphs, prodrugs, metabolites, salts or solvates thereof.
  • R 1 , X, Y, T, U, V, W and Z are defined herein; or their pharmaceutically acceptable analogs, tautomeric forms, stereoisomers, polymorphs, prodrugs, metabolites, salts or solvates thereof.
  • the present invention provides a compound of formula I wherein Z represents OR 3 , NHR 3 , N(R 3 ) 2 or heteroaryl and R 3 is selected from hydrogen, substituted or unsubstituted alkyl, acyl, thioacyl, Ci -6 alkoxycarbonyl or Ci -6 alkoxythiocarbonyl.
  • the present invention provides a compound of formula I wherein Z represents NHR 3 or heteroaryl and R J is selected from methoxycarbonyl methoxythiocarbonyl, acyl or thioacyl.
  • the present invention provides a compound of formula I wherein heteroaryl represents triazolyl or isoxazolyl.
  • the present invention provides a compound of formula I wherein the substituents on R 3 are selected from halogen, hydroxyl, amino, monoalkylamino, dialkylamino, cyano, nitro, alkoxy, aryl, heteroaryl, hydroxyaryl, pyridyl, hydroxyaalkyl, alkoxyaryl or carboxyl and its derivatives.
  • the present invention provides a compound of formula I wherein U and V represent hydrogen and T and W independently represent hydrogen or fluorine.
  • the present invention provides a compound of formula I wherein both n and n' are 2.
  • the present invention provides a compound of formula I wherein Y represents O. In another embodiment, the present invention provides a compound of formula I wherein wherein X represents O, -NH or S.
  • the present invention provides a compound of formula I wherein R 1 and R 2 are selected from aryl, Ci -6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl or heteroaryl, each of which may be optionally substituted at any available position by one or more substituents R a .
  • alkyl may be straight or branched with 1 to 10 carbon atoms. These groups may further be substituted with one or more substituents selected from but not limited to, for example, halogen, hydroxyl, oxo, carboxyl, carboxyalkyl, azido, alkenyl, alkynyl, alkoxy, cycloalkyl, cycloalkynyl, acyl acyloxy, aryl, heterocyclyl and heteroaryl.
  • cycloalkyl refers to cyclic alkyl groups constituting of 3 to 20 carbon atoms having a single cyclic ring or multiple condensed rings, for example, fused or spiro systems which may optionally contain one or more olefinic bonds, unless otherwise constrained by the definition.
  • Such cycloalkyl groups include, by way of example, single ring structures, for example, cyclopropyl, cyclobutyl, cyclopentenyl, cyclohexyl, cyclooctyl, and the like, or multiple ring structures, for example, adamantyl, and bicyclo[2.2.1] heptane, or cyclic alkyl groups to which is fused an aryl group, for example, indane and the like.
  • Cycloalkyl groups may further be substituted with one or more substituents selected from but not limited to, for example, halogen, hydroxyl, oxo, carboxy, carboxyalkyl, azido, alkenyl, alkynyl, alkoxy, cycloalkyl, cycloalkynyl, acyl acyloxy, aryl, heterocyclyl, heteroaryl.
  • substituents selected from but not limited to, for example, halogen, hydroxyl, oxo, carboxy, carboxyalkyl, azido, alkenyl, alkynyl, alkoxy, cycloalkyl, cycloalkynyl, acyl acyloxy, aryl, heterocyclyl, heteroaryl.
  • alkoxy denotes the group O-alkyl wherein alkyl is the same as defined above.
  • aralkyl refers to alkyl-aryl linked through alkyl (wherein alkyl is the same as defined above) portion and the said alkyl portion contains carbon atoms from 1-6 and the aryl is as defined herein, after.
  • the examples of aralkyl groups include benzyl and the like.
  • aryl refers to a carbocyclic aromatic group, for example phenyl or naphthyl ring and the like optionally substituted with one or more substituents selected from but not limited to, for example, halogen, hydroxyl, alkyl, alkenyl, alkynyl, cycloalkyl, alkoxy, acyl, aryloxy, CF 3 , COOR d (wherein R d can be hydrogen, alkyl, alkenyl, cycloalkyl, aralkyl, heterocyclylalkyl or heteroarylalkyl), cyano, nitro, carboxy, heterocyclyl, heteroaryl, heterocyclylalkyl or heteroarylalkyl.
  • the aryl group may optionally be fused with cycloalkyl group, wherein the said cycloalkyl group may optionally contain heteroatoms selected from O, N, S.
  • aryloxy denotes the group O- aryl wherein aryl is as defined above.
  • heteroaryl refers to an aromatic ring structure containing 5 to 8 carbon atoms, fully or partially unsaturated, or a bicyclic aromatic group having 8 to 10 carbon atoms with one or more heteroatom(s) independently selected from N, O and S and optionally substituted with 1 to 4 substituent(s) selected from but not limited to halogen, hydroxyl, alkyl, alkenyl, alkynyl, cycloalkyl, acyl, carboxy, aryl, alkoxy, aralkyl, cyano, nitro, heterocyclyl, or heteroaryl.
  • heteroaryl groups include oxazolyl, imidazolyl, pyrrolyl, 1,2,3,-triazolyl, 1,2,4-triazolyl, tetrazolyl, thiazolyl, oxadiazolyl, benzoimidazolyl, thiadiazolyl, pyridinyl, pyridazinyl, pyrimidinyl, thienyl, isoxazolyl, triazinyl, furanyl, benzofuranyl, indolyl, benzothiazolyl, benzoxazolyl, and the like.
  • heterocyclyl refers to a non-aromatic monocyclic or bicyclic cycloalkyl group, fully or partially unsaturated having 5 to 10 carbon atoms, with one or more heteroatom(s) independently selected from N, O and S, and are optionally benzofiised or fused heteroaryl of 5-6 ring members and/or are optionally substituted wherein the substituents are selected from but not limited to halogen, hydroxyl, alkyl, alkenyl, alkynyl, cycloalkyl, acyl, carboxy, aryl, alkoxy, aralkyl, cyano, nitro, heterocyclyl, or heteroaryl.
  • heterocyclyl groups include but are not limited to oxazolidinyl, tetrahydrofuranyl, dihydrofuranyl, dihydropyridinyl, dihydroisooxazolyl, dihydrobenzofuryl, azabicyclohexyl, dihydroindonyl, piperidinyl or piperazinyl.
  • Heteroarylalkyl refers to alkyl-heteroaryl group linked through alkyl portion, wherein the alkyl and heteroalkyl are the same as defined previously.
  • Heterocyclylalkyl refers to alkyl-heterocyclyl group linked through alkyl portion, wherein the alkyl and heterocyclyl are the same as defined previously.
  • Halogen refers to Br, Cl, F or I.
  • protecting group when the functional group is termed "protected", this means that the group is in modified form to preclude undesired side reactions at the protected site.
  • protecting group may be used with groups, for example, hydroxyl, amino, carboxyl and examples of such groups are found in T. W. Greene, et al. "Protecting Groups in Organic Synthesis," 3 rd Ed, Wiley, New York, which is incorporated herein by reference.
  • Suitable hydroxyl and amino protecting groups are: trimethylsilyl, triethylsilyl, ⁇ -nitrobenzyloxycarbonyl, /7-nitrobenzyloxycarbonyl, t-butyldiphenylsilyl, t- butyldimethylsilyl, benzyloxycarbonyl, /-butyloxycarbonyl, 2,2,2- trichloroethyloxycarbonyl, allyloxycarbonyl and the like.
  • carboxyl protecting groups are benzhydryl, o-nitrobenzyl, /?-nitrobenzyl, 2-naphthylmethyl, allyl, 2- chloroallyl, benzyl, 2,2,2- trichloroethyl, trimethylsilyl, t-butyldimethylsilyl, t- butyldiphenylsilyl, 2-(trimethylsilyl)ethyl, phenacyl, /?-methoxybenzyl, acetonyl, p- methoxyphenyl, 4-pyridylmethyl, t-butyl and the like.
  • Subject includes humans, non-human mammals (e.g., dogs, cats, rabbits, cattle, horses, sheep and the like) or non-mammals (e.g., birds and the like).
  • non-human mammals e.g., dogs, cats, rabbits, cattle, horses, sheep and the like
  • non-mammals e.g., birds and the like
  • terapéuticaally effective amount means the amount of a compound that, when administered to a subject for treating a disease, is sufficient to effect such treatment for the disease.
  • the “therapeutically effective amount” will vary depending on the compound, the disease and its severity, weight, physical condition and responsiveness of the subject to be treated, among other factors.
  • the compounds provided herein may contain one or more asymmetric carbon atoms and thus can exist as racemates, mixtures of enantiomers, single enantiomers, diastereomeric mixtures and individual diastereomers. All such isomeric forms of these compounds are expressly encompassed herein.
  • Each stereogenic carbon may be independently of the R or 5 configuration.
  • the specific compounds exemplified in this application may be depicted in a particular stereochemical configuration, compounds having the opposite stereochemistry at the chiral centre or mixtures thereof are encompassed herein.
  • Some compounds of the present invention may exhibit cis/trans isomers.
  • the present invention includes each of the geometric isomers and its mixtures.
  • particularly useful compounds of formula Ib include but are not limited to the following:
  • the compounds of the present invention can be prepared in accordance with one or more of the Schemes discussed herein after. All of the starting materials are either commercially available or can be prepared by procedures that would be well known to one of ordinary skill in organic chemistry.
  • L is used to denote an appropriate leaving group and as such may vary in nature depending on the exact reaction conditions employed. Some typical leaving groups may be fluoro, chloro, bromo, iodo, tosyl, mesyl, trifluoromethanesulfonyl and the like, but these should not be construed as limiting as many other leaving groups are also well known to those skilled in the art.
  • the compound of formula IV can also be prepared following literature procedure Gouverneur et al, Tetrahedron 2005, 61, 2395.
  • Compounds of Formula II or IV can be reacted with benzylamine or substituted benzylamine to form compounds of Formula V without any solvent or in a suitable solvent such as methanol, ethanol, isopropanol and the like or mixtures thereof.
  • Compounds of Formula V can be then debenzylated to form compounds of Formula VI.
  • This conversion can be accomplished by hydrogenation over an appropriate catalyst such as palladium, platinum, or ruthenium onactivated carbon in a suitable solvent such as methanol, ethanol, isopropanol and the like or by using 1-chloroethyl chloroformate, CAN, DDQ or by other chemical methods known to those skilled in art.
  • Compounds of Formula VI can be treated with a substituted nitrobenzene derivatives of Formula VII (wherein T 5 U 5 V 5 W are the same as defined earlier and L is an appropriate leaving group such as fluoro, chloro, bromo, iodo) to form compounds of Formula VIII in an appropriate solvent and base.
  • the reaction can be allowed to proceed at an appropriate temperature, which, depending on the solvent may be between 60 to 100 0 C until such time that the reaction is determined to be complete.
  • appropriate solvents include acetonitrile, tetrahydrofuran, methylene dichloride or dichloroethane or other such solvents well known to those skilled in the art.
  • appropriate bases include but are not limited to triethylamine or diisopropylethyl amine.
  • nitro derivatives of Formula VIII can then be reduced to the corresponding amino compounds by a variety of reducing agents such as hydrogenation over an appropriate catalyst such as palladium, platinum, or ruthenium on activated charcoal or chemical methods such as reaction with FeCl 3 or SnCl 2 /HCl or FeZNH 4 Cl or NiCl 2 ZNaBH 4 familiar to those skilled in the art.
  • reducing agents such as hydrogenation over an appropriate catalyst such as palladium, platinum, or ruthenium on activated charcoal or chemical methods such as reaction with FeCl 3 or SnCl 2 /HCl or FeZNH 4 Cl or NiCl 2 ZNaBH 4 familiar to those skilled in the art.
  • the resulting amine can then be treated with benzyl or methyl chloroformate and sodium bicarbonate in presence of water and acetone to form the corresponding benzyl or methyl carbamate derivatives IX which are then deprotonated in the next step with a lithium base such as «-butyllithium and reacted with Glycidyl butyrate in presence of a suitable solvent such as diethylether or tetrahydrofuran to afford the oxazolidinone X.
  • the hydroxyl group can be converted to an amine (that is where Z is amino group) by first conversion of hydroxyl group to a leaving group such as mesylate or tosylate followed by conversion to azide, and finally reduction to amine.
  • the particular method chosen for this reduction can be readily selected by those skilled in the art and is dependent upon the structure of the entirety of the molecule.
  • the hydroxyl group can be converted to Z (wherein Z is as defined earlier).
  • the exact nature of the reagents used for this conversion is dependent on the exact nature of the Z desired. For example, if Z is desired to be acetylamine group, the hydroxyl group is first converted to amino group which is then acylated in the presence of suitable acylating reagents such as acetic anhydride, acetyl chloride or the like. If Z is desired to be carbamate group, the hydroxyl group is first converted to amino group which is then reacted with alkyl chloroformate or the like. If Z is desired to be heterocycle like triazole, hydroxy group is first converted to azide, followed by reaction with 2,5-Norbornadiene or the like.
  • the hydroxyl group is first converted to the mesylate or other appropriate leaving group and then reacted with a suitable hydroxyl containing heterocycle in the presence of suitable base and solvent such as sodium hydride and N, N- dimethylformamide (DMF) or the like.
  • suitable base and solvent such as sodium hydride and N, N- dimethylformamide (DMF) or the like.
  • suitable base and solvent such as sodium hydride and N, N- dimethylformamide (DMF) or the like.
  • suitable base and solvent such as sodium hydride and N, N- dimethylformamide (DMF) or the like.
  • the compounds of Formula XXI can be converted into compounds of Formula XXIII, as shown in Scheme III.
  • the compounds of Formula XXI can be converted into compounds of Formula XXII when R is OR 1 wherein R 1 is preferably ethyl or methyl, by deprotection of phosphate ester group to phosphinic acid in presence of a suitable deprotecting agent such as trimethylsilyl chloride, trimethylsilyl bromide and the like in a suitable solvent such as methylene chloride, dichloroethane, tetrahydrofuran, diethylcther, acetonitrile and the like or mixtures thereof.
  • a suitable deprotecting agent such as trimethylsilyl chloride, trimethylsilyl bromide and the like
  • a suitable solvent such as methylene chloride, dichloroethane, tetrahydrofuran, diethylcther, acetonitrile and the like or mixtures thereof.
  • the compounds of Formula XXII can then be reacted with either alcohol (R 1 OH) or amine (R 1 NH 2 ) or substituted amine (R 1 NR 2 ) or thiol (R 1 SH), wherein R 1 and R 2 are as defined earlier, to form compounds of Formula XXIII in the presence of one of the following suitable reagents such as N,N'-Dicyclohexylcarbodiimide (DCC), 4- dimethylaminopyridine (DMAP); or l-Ethyl-3-[3-dimethyl aminopropyl] carbodiimide hydrochloride (EDC) in presence of Hydroxy benztriazole (HOBt) and N- methylmorphiline; or mixed anhydrides such as benzylchloro formate, ethylchloro formate or tertiary butyl chloro formate; or oxalyl chloride in presence of DMAP; or alkyl/aryl halide in the
  • the suitable solvents required for this conversion include but are not limited to toluene, DMF, methylene chloride, dioxane, acetone, diethylether, tetrahydrofuran and the like.
  • the particular reagents chosen for this conversion can be readily selected by those skilled in the art and is dependent upon the structure of the entirety of the molecule.
  • the compound XVII can also be hydrolysed to hydroxyl compound when R is OR 1 , R 1 preferably ethyl or methyl and different R 1 can be introduced as explained above in conversion of XXI to XXII and finally to XXIII.
  • the compounds of Formula XXIII can then be converted to compounds of Formula XXIV following the reaction with Lawsson's reagent or phosphorous pentasulphide in the presence of a suitable solvent such as toluene, benzene, xylene and the like or mixtures thereof.
  • a suitable solvent such as toluene, benzene, xylene and the like or mixtures thereof.
  • reaction can also be carried out jn the absence of base by reacting two substrates in seal tube (Hii et al, J. Org. Chem. 2006, 71, 2472).
  • the particular method chosen for this conversion can be readily selected by those skilled in the art and is dependent upon the structure of the entirety of the molecule.
  • Compounds of Formula XXV can then be debenzylated to form compounds of Formula XXVI as described in scheme II.
  • the pharmaceutically acceptable salts of compounds of formula I according to the present invention include acid addition salts or base addition salts where appropriate.
  • Pharmaceutically acceptable salts may be obtained using standard procedures well known in the art, for example, by reacting a sufficiently basic compound such as an amine with a suitable acid affording a physiologically acceptable anion.
  • Alkali metal or alkaline earth metal salts of carboxylic acids can also be made.
  • Pharmaceutically acceptable solvates may be hydrates or comprising other solvents of crystallization such as alcohols.
  • prodrugs of the compounds of the present invention which upon in-vivo administration undergo chemical conversion by metabolic processes before becoming active pharmacological substances.
  • prodrugs will be functional derivatives of a compound of the invention which are readily convertible in vivo into the compound of the invention.
  • Conventional procedures for the selection and preparation of suitable prodrug derivatives are described, for example, in “Targeted prodrug design to optimize drug delivery", AAPS PharmaSci (2000), 2(1), E6.
  • the invention also encompasses active "metabolites" of the compound of the present invention.
  • polymorphs For example, using different solvents commonly used or their mixtures for recrystallization; crystallizations at different temperatures; various modes of cooling, ranging from very fast to very slow cooling during crystallizations, heating or melting the compound followed by gradual or fast cooling may also obtain polymorphs.
  • the presence of polymorphs may be determined by solid probe NMR spectroscopy, IR spectroscopy, differential scanning calorimetry, powder X-ray diffraction or such other techniques.
  • the present invention also provides pharmaceutical compositions, comprising compounds of general formula I or their pharmaceutically acceptable analogs, tautomeric forms, stereoisomers, polymorphs, prodrugs, metabolites, salts or solvates thereof together with one or more pharmaceutically acceptable carriers comprising excipients and auxiliaries, which facilitate processing of the active compound into preparations, which can be used pharmaceutically.
  • the pharmaceutical compositions may be in the forms normally employed, such as tablets, capsules, powders, syrups, solutions, suspensions and the like, may contain flavourants, sweeteners etc in suitable solid or liquid carriers or diluents, or in suitable sterile media to form injectable solutions or suspensions.
  • compositions typically contain from 0.1 to 99.9 % by weight of active compound, the remainder of the composition being pharmaceutically acceptable carriers, diluents or solvents.
  • the pharmaceutical compositions of the present invention can be manufactured by the processes well known in the art, for example, by means of conventional mixing, dissolving, dry granulation, wet granulation, dragee-making, levigating, emulsifying, encapsulating, entrapping, lyophilizing processes or spray drying.
  • the compounds or the pharmaceutical compositions comprising such compounds of the present invention may be administered in the form of any pharmaceutical formulation.
  • the pharmaceutical formulation will depend upon the nature of the active compound and its route of administration.
  • any route of administration may be used, for example oral, buccal, pulmonary, topical, parenteral (including subcutaneous, intramuscular and intravenous), transdermal, ocular (ophthalmic), by inhalation, intranasal, transmucosal, implant or rectal administration.
  • parenteral including subcutaneous, intramuscular and intravenous
  • transdermal ocular
  • ocular ophthalmic
  • the compounds of the present invention are administered orally, parenterally or topically.
  • the amount of the novel compounds having the formula I according to the present invention to be incorporated into the pharmaceutical compositions of the present invention can vary over a wide range depending on known factors such as, for example, the disorder to be treated, the severity of the disorder, the patient's body weight, the dosage form, the chosen route of administration and the number of administration per day.
  • the amount of the compound of formula I in the pharmaceutical compositions of the present invention will range from approximately 0.01 mg to about 5000 mg.
  • the daily dose of composition comprising the novel compounds having the formula-I is in the range of about 0.01 mg/kg to about 100 mg/kg based on the body weight of the subject in need thereof which may be administered as a single or multiple doses.
  • novel compounds having the formula I according to the present invention are particularly useful for the treatment of disease(s) or disorder(s) which are particularly acute in nature and which require a short term but mild to moderate treatment, or even some chronic conditions which favorably respond to or are alleviated by the novel compounds having the formula-I or compositions comprising them.
  • the compositions comprising the novel compounds having the formula-I are useful prophylactically or therapeutically depending upon the pathological condition intended to be prevented or treated respectively.
  • the compounds of the present invention are effective against a number of aerobic and/or anaerobic Gram positive and/or Gram negative pathogens such as multi drug resistant Staphylococcus spp., Streptococcus spp., Enterococcus spp., Bacterioides spp., Clostridia spp., H. influenza, Moraxella Spp., as well as acid-fast organisms such as Mycobacterium tuberculosis and the like.
  • a further embodiment of the present invention is the use of a compound of formula I for the manufacture of a medicament for the prophylaxis, amelioration and/or treatment of bacterial infections in a subject in need thereof preferably a mammal including a human.
  • Another embodiment of the present invention provides methods for the management such as prophylaxis, amelioration and/or treatment of bacterial infections in a subject in need thereof preferably a mammal including a human that comprises administering a therapeutically effective amount of compound of formula I.
  • use of the dosage form compositions comprising the novel compounds of formula I for the treatment of diseases/disorders which comprises administrating to a subject in need thereof a pharmaceutically effective amount of the composition.
  • the compounds of the present invention may be used in combination with one or more other active ingredients such as quinolines, ⁇ -lactams e.g., cephalosporins, penicillins, penams, penems and the like in the prophylaxis, amelioration and/or treatment of bacterial infections, where the combination of the active ingredients together are safer or more effective than either active ingredient alone or where incorporation of another active ingredient might reduce the dose of the compound of formula I.
  • active ingredients such as quinolines, ⁇ -lactams e.g., cephalosporins, penicillins, penams, penems and the like in the prophylaxis, amelioration and/or treatment of bacterial infections, where the combination of the active ingredients together are safer or more effective than either active ingredient alone or where incorporation of another active ingredient might reduce the dose of the compound of formula I.
  • MS mass spectra
  • Step 3 Preparation of 4-ethoxy-l-(2-fluoro-4-nitro-phenyl)-[l,4]azaphosphinane-4- oxide
  • 4-ethoxy-[l,4]azaphosphinane 4-oxide (2.3 g, 14.1 mmol) in acetonitrile (10 mL) was added diisopropylethylamine (3.7 mL, 21.15 mmol) and 3,4-difluoronitrobenzene (1.87 mL, 16.92 mmol).
  • the reaction mixture was refluxed at 80 °C for 24 h.
  • Step 4 Preparation of 4-(4-ethoxy-4-oxo-4 ⁇ 5 -[l,4]azaphosphinan-l-y.)-3-fluoro- phenyl-amine
  • Step 6 Preparation of fl?,)-3-[4-(4-ethoxy-4-oxo-4 ⁇ 5 -[l,4]azaphosphinan-l-yl)-3-fluoro- pheny] -S-hydroxylmethyl-oxazolidin-2-one
  • Step 9 Preparation of (S)-iV- ⁇ 3-[4-(4-ethoxy-4-oxo-4 ⁇ 5 -[l,4]azaphophinan-l-yl)-3- fluorophenyl]-2-oxo-oxazolidin-5ylmethyI ⁇ -acetamide
  • To (7?)-5-Azidomethyl-3-[4-(4-ethoxy-4-oxo-4 ⁇ 5 -[ 1 ,4]aza ⁇ hosphinan- 1 -yl)-3-fluoro-phen- yl-oxazolidin-2-one (415 mg, 1.045 mmol) was added thioacetic acid (2.7 mL) and stirring was done at room temperature for 15 h.
  • Reaction mixture was refluxed at 120 0 C for 15 min followed by addition of cyclopentylmethanol (0.04 mL, 0.372 mmol) and refluxing was done for 7 h. Solvent was evaporated and reaction mixture was diluted with dichloromethane (20 mL). Organic layer was washed with 10% HCl then with saturated NaHCO 3 followed by washing with water and brine. The organic layer was dried over anhydrous sodium sulfate and the crude product was then purified by column chromatography using 4% methanol in chloroform to yield the title compound (40 mg, 26.6 %).
  • reaction mixture was refluxed at 120 0 C for 15 min followed by addition of phenol (77 mg, 0.819 mmol) and refluxing was done for 5 h. Solvent was evaporated and reaction mixture was diluted with dichloromethane (20 mL). Organic layer was washed with 10% HCl then with saturated NaHCO 3 . The organic layer was then washed with water and brine, dried over anhydrous sodium sulfate and evaporated to yield the crude product which was then purified by column chromatography using 4% methanol in chloroform to yield the title compound (250 mg, 70 %).
  • Reaction mixture was refluxed at 120 0 C for 15 min followed by addition of benzylamine (0.07 mL, 0.595 mmol) and refluxing was done for 4 h. Solvent was evaporated and reaction mixture was diluted with dichloromethane (20 mL). The organic layer was washed with water and brine, dried over anhydrous sodium sulfate and evaporated to yield the crude product which was then purified by column chromatography using 4% methanol in chloroform to yield the title compound (25mg, 10.2 %).
  • Step 2 Preparation of (S)- ⁇ 3-[4-(4-ethoxy-4-oxo-4 ⁇ 5 -[l,4]azaphosphinan-l-yl)-3,5- difluoro-phenyI]-2-oxo-oxazoIidin-5-ylmethyl ⁇ -carbamic acid methyl ester
  • reaction mixture was diluted with dichloromethane (30 mL). Organic layer was washed with water and brine and then dried over anhydrous sodium sulfate. Solvent was concentrated and crude product was purified by column chromatography using 2 % methanol in chloroform to yield the title compound (150 mg, 56.5 %).
  • Step 1 Preparation of ⁇ 3-[3,5-Difluoro-4-(4-hydroxy-4-oxo-4 ⁇ -[l,4]azaphosphinan-l- yl)-phenyI]-2-oxo-oxazolidi ⁇ -5-ylmethyl ⁇ -carbamic acid methyl ester
  • ⁇ 3-[4-(4-Ethoxy-4-oxo-4 ⁇ 3 -[l,4]azaphosphinan-l-yl)-3,5-difluoro- phenyl]-2-oxo-oxazolidin-5-ylmethyl ⁇ -carbamic acid methyl ester (given in example XV ) (2 g, 4.47 mmol) in dichloromethane bromotrimethylsilane (0.88 mL, 6.71 mmol) was added and dichloromethane was refluxed for overnight.
  • Step 2 Preparation of (S)-(3- ⁇ 3,5-Difluoro-4-[4-(4-methoxy-phenoxy)-4-oxo-4 ⁇ 5 -
  • reaction mixture was refluxed at 120 0 C for 15 min followed by addition of 4-methoxyphenol (65 mg, 0.52 mmol) and refluxing was done for 16 h. Solvent was evaporated and reaction mixture was diluted with dichloromethane (20 mL). Organic layer was washed with 10% HCl then with saturated NaHCO 3 . The organic layer was then washed with water and brine, dried over anhydrous sodium sulfate and evaporated to yield the crude product which was then purified by column chromatography using 3% methanol in chloroform to yield the title compound (130 mg, 51.9 %).
  • reaction mixture was refluxed at 120 0 C for 15 min followed by addition of 4-fluorophenol (26.7 mg, 0.23 mmol) and refluxing was done for 5 h. Solvent was evaporated and reaction mixture was diluted with dichloromethane (20 mL). Organic layer was washed with 10% HCl then with saturated NaHCO 3 . The organic layer was then washed with water and brine, dried over anhydrous sodium sulfate and evaporated to yield the crude product which was then purified by column chromatography using 4% methanol in chloroform to yield the title compound (20 mg, 18.18 %).
  • Analogues of direct phenyl compounds were prepared by taking (Divinyl-phosphinoyl)- benzene instead of divinylphosphinic acid ethyl ester in step 1 in Example I. Rest all the steps were done as in Example 1.
  • Step 1 Preparation of l-Benzyl-4-phenyl-[l,4]azaphosphinane 4-oxide ESIMS (m/z): 287.1 (M+2), 286.2 (M+l), 201.0, 179.1
  • Step 2 Preparation of 4-Phenyl-[l,4]azaphosphinane 4-oxide ESIMS (m/z): 218.0 (M+Na), 196.4 (M+l), 183.2
  • Step 3 Preparation of l-(2,6-Difluoro-4-nitro-phenyI)-4-phenyl-[l,4]azaphosph-inane
  • Step 4 Preparation of 3,5-Difluoro-4-(4-oxo-4-phenyl-4 ⁇ 5 -[l,4]azaphosphinan-l-yl)- phenylamine
  • Step 5 Preparation of [3,5-Difluoro-4-(4-oxo-4-phe ⁇ yl-4 ⁇ 5 -[l,4]azaphosphi ⁇ an-l-y.)- phenylj-carbamic acid benzyl ester
  • Step 7 Preparation of Methanesulfonic acid 3-[3,5-difluoro-4-(4-oxo-4-phenyl-4 ⁇ 5 -
  • Step 8 Preparation of 5-Azidomethyl-3-[3,5-difluoro-4-(4-oxo-4-phenyI-4 ⁇ 5 -
  • Step 9 Preparation of (£)- ⁇ r - ⁇ 3-[3,5-Difluoro-4-(4-oxo-4-phenyl-4 ⁇ 5 -[l,4]azapho- sphinan-l-yl)-phenyl]-2-oxo-oxazolidin-5-ylmethyl ⁇ -acetamide
  • This compound was prepared by taking 5-Azidomethyl-3-[3,5-difluoro-4-(4-oxo-4-phenyl- 4 ⁇ 5 -[l,4]azaphosphinan-l-yl)-phenyl]-oxazolidin-2-one instead of (7?)-5-azidomethyl3-[4-
  • Step 1 Preparation of 5-Aminomethyl-3-[3,5-difluoro-4-(4-oxo-4-phenyI-4 ⁇ 5 -
  • Step 2 Preparation of 4-(4-Fluoro-phenyl)-l-(4-methoxy-benzyl)-[l,4]azaphosphin- ane 4-oxide
  • Step 3 Preparation of 4-(4-fluoro-phenyl)-[l,4]azaphosphinane 4-oxide ESIMS (m/z): 236.2 (M+Na), 214.1 (M+l)
  • Step 4 Preparation of l-(2,6-Difluoro-4-nitro-phenyl)-4(4-Fluoro-phenyl)-[l,4]aza- phosphinane 4-oxide
  • Step 5 Preparation of 3,5-Difluoro-4[4-(4-fluoro-phenyl)-4-oxo-4 ⁇ 5 -[l,4]azaphos- phinan-l-yl]-phenylamine
  • Step 6 Preparation of ⁇ 3,5-Difluoro-4-[4-(4-fluoro-phenyl)-4-oxo-4 ⁇ ' -[l,4]azaphos- phinan-l-yi]-phenyl ⁇ -carbamic acid benzyl ester
  • Step 8 Preparation of Methanesulfonic acid 3- ⁇ 3,5-difluoro-4-[4-(4-fluoro-phenyI)-4- oxo-4 ⁇ 5 -[l,4]azaphosphinan-l-yl]-phenyl ⁇ -2-oxo-oxazolidin-5-ylmethyl ester ESIMS (m/z): 542.2 (M+Na+1), 541.3 (M+Na), 519.1 (M+l)
  • Step 9 Preparation of (S)-iV-(3- ⁇ 3,5-Difluoro-4-[4-(4-fluoro-pheny])-4-oxo-4 ⁇ 5 -
  • Step 1 Preparation of 5-AzidomethyI-3- ⁇ 3,5-difluoro-4-[4-(4-fluoro-phenyl)-4-oxo-
  • Step 2 Preparation of 5-AminomethyI-3- ⁇ 3,5-difluoro-4-[4-(4-fluoro-phenyl)-4-oxo- 4 ⁇ -[l,4]azaphosphinan-l-yl]-phenyl ⁇ -oxazolidin-2-one
  • Step 3 Preparation of (3- ⁇ 3,5-Difluoro-4-[4-(4-fluoro-phenyl)-4-oxo-4 ⁇ s -
  • MIC Minimum Inhibitory Concentration
  • the compounds of the present invention were tested against a panel of standard microorganisms obtained from ATCC (American type culture collection). Linezolid was used as comparator in all the tests.
  • the compound was dissolved in dimethylsulfoxide and two fold serial dilutions were carried out in 96 well microtitre plates.
  • the inoculum was prepared by adjusting the turbidity of actively growing broth culture and added to the wells to obtain a final concentration of approx. 5x10 4 CFU/well.
  • the microtitre plates were incubated at 35 ⁇ 2°C for 16-20 hrs and then read visually.
  • MIC S ( ⁇ g/mL) of some of the compounds of formula 1 are presented in the Table 1.
  • the compounds of the present invention show potential antibacterial activity against Staphylococcus aureus (MRSA) and Enterococci (VRE).

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Abstract

La présente invention porte sur de nouveaux composés de phényl oxazolidinone de formule (I) ou sur leurs analogues, formes tautomères, stéréo-isomères, polymorphes, promédicaments, métabolites, sels ou solvates pharmaceutiquement acceptables de ceux-ci. L'invention porte également sur les procédés pour la synthèse des nouveaux composés de formule (I) ou sur leurs analogues, formes tautomères, stéréo-isomères, polymorphes, promédicaments, métabolites, sels ou solvates pharmaceutiquement acceptables de ceux-ci. La présente invention porte aussi sur des compositions pharmaceutiques comprenant de nouveaux composés de formule (I) et sur des procédés d'utilisation de ceux-ci. Les composés de la présente invention sont utiles comme agents antimicrobiens, efficaces contre un nombre de pathogènes Gram positif et/ou Gram négatif aérobies ou anaérobies, tels que des Staphylococcus spp., Streptococcus spp., Enterococcus spp., Bacterioides spp., Clostridia spp., H. influenza, Moraxella Spp., multirésistants aux médicaments, ainsi que des organismes résistants aux acides tels que Mycobacterium tuberculosis et similaires.
PCT/IN2008/000047 2007-01-25 2008-01-24 Nouveaux antimicrobiens WO2008090570A1 (fr)

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Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2011070592A2 (fr) 2009-12-09 2011-06-16 Panacea Biotec Ltd. Nouveaux dérivés de sucres
CN105820161A (zh) * 2015-01-08 2016-08-03 常州方楠医药技术有限公司 一种利伐沙班中间体5-羟基甲基噁唑烷酮衍生物的合成方法
WO2021014365A1 (fr) 2019-07-22 2021-01-28 Lupin Limited Composés macrocycliques utilisés en tant qu'agonistes sting et procédés et utilisations de ceux-ci

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2002002095A2 (fr) * 2000-06-30 2002-01-10 Pharmacia & Upjohn Company Composition et techniques de traitement d'infections bacteriennes
WO2003093247A2 (fr) * 2002-04-30 2003-11-13 Orchid Chemicals & Pharmaceuticals Ltd Nouveaux agents antibacteriens

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2002002095A2 (fr) * 2000-06-30 2002-01-10 Pharmacia & Upjohn Company Composition et techniques de traitement d'infections bacteriennes
WO2003093247A2 (fr) * 2002-04-30 2003-11-13 Orchid Chemicals & Pharmaceuticals Ltd Nouveaux agents antibacteriens

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2011070592A2 (fr) 2009-12-09 2011-06-16 Panacea Biotec Ltd. Nouveaux dérivés de sucres
CN105820161A (zh) * 2015-01-08 2016-08-03 常州方楠医药技术有限公司 一种利伐沙班中间体5-羟基甲基噁唑烷酮衍生物的合成方法
WO2021014365A1 (fr) 2019-07-22 2021-01-28 Lupin Limited Composés macrocycliques utilisés en tant qu'agonistes sting et procédés et utilisations de ceux-ci

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